WO2019099524A1 - Kras g12c inhibitors - Google Patents

Kras g12c inhibitors Download PDF

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Publication number
WO2019099524A1
WO2019099524A1 PCT/US2018/061060 US2018061060W WO2019099524A1 WO 2019099524 A1 WO2019099524 A1 WO 2019099524A1 US 2018061060 W US2018061060 W US 2018061060W WO 2019099524 A1 WO2019099524 A1 WO 2019099524A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
alkyl
mmol
optionally substituted
formula
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.)
Ceased
Application number
PCT/US2018/061060
Other languages
English (en)
French (fr)
Inventor
James F. Blake
Laurence E. Burgess
Mark Joseph Chicarelli
James Gail CHRISTENSEN
Adam Cook
Jay Bradford Fell
John P. Fischer
Matthew Arnold Marx
Macedonio J. MEJIA
Pavel SAVECHENKOV
Guy P.A. VIGERS
Christopher Ronald Smith
Martha E. Rodriguez
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.)
Array Biopharma Inc
Mirati Therapeutics Inc
Original Assignee
Array Biopharma Inc
Mirati 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 to HRP20230377TT priority Critical patent/HRP20230377T1/hr
Priority to BR112020009818-3A priority patent/BR112020009818A2/pt
Priority to MX2020005063A priority patent/MX2020005063A/es
Priority to LTEPPCT/US2018/061060T priority patent/LT3710439T/lt
Priority to EP18879484.6A priority patent/EP3710439B1/en
Priority to SG11202004427TA priority patent/SG11202004427TA/en
Priority to JP2020526612A priority patent/JP7322019B2/ja
Priority to CA3082579A priority patent/CA3082579A1/en
Priority to SI201830912T priority patent/SI3710439T1/sl
Priority to CN201880086849.1A priority patent/CN111989321B/zh
Priority to KR1020207016494A priority patent/KR102861303B1/ko
Priority to AU2018369759A priority patent/AU2018369759B2/en
Priority to FIEP18879484.6T priority patent/FI3710439T3/fi
Priority to EA202091186A priority patent/EA202091186A1/ru
Priority to CN202410549759.9A priority patent/CN118459460A/zh
Priority to UAA202003509A priority patent/UA125802C2/uk
Priority to PL18879484.6T priority patent/PL3710439T3/pl
Priority to IL274601A priority patent/IL274601B2/en
Application filed by Array Biopharma Inc, Mirati Therapeutics Inc filed Critical Array Biopharma Inc
Priority to RS20230345A priority patent/RS64182B1/sr
Priority to ES18879484T priority patent/ES2944547T3/es
Priority to DK18879484.6T priority patent/DK3710439T3/da
Priority to MYPI2020001151A priority patent/MY200356A/en
Publication of WO2019099524A1 publication Critical patent/WO2019099524A1/en
Priority to ZA2020/02105A priority patent/ZA202002105B/en
Priority to PH12020550622A priority patent/PH12020550622A1/en
Anticipated expiration legal-status Critical
Priority to CONC2020/0007244A priority patent/CO2020007244A2/es
Priority to NL301279C priority patent/NL301279I2/nl
Priority to FIC20240021C priority patent/FIC20240021I1/fi
Priority to LTPA2024517C priority patent/LTC3710439I2/lt
Priority to FR24C1026C priority patent/FR24C1026I2/fr
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • 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
    • 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
    • A61K31/5355—Non-condensed oxazines and containing further heterocyclic 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
    • A61K31/535—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
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • C07D491/08—Bridged systems
    • 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

Definitions

  • Y is a bond, O, S or NR 5 ;
  • heteroarylalkyl wherein each of the Z, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl may be optionally substituted with one or more R 9 ;
  • m is zero or an integer between 1 and 2;
  • each R 10 is independently hydrogen, acyl, Cl - C3 alkyl, heteroalkyl or hydroxyalkyl;
  • R 11 is haloalkyl
  • methods for inhibiting KRas G12C activity in a in a cell comprising contacting the cell with a compound of Formula I, Formula I-A, Formula 1- B, Formula II, Formula II-A or Formula II-B.
  • the contacting is in vitro. In one embodiment, the contacting is in vivo.
  • the present invention relates to inhibitors of KRas G12C.
  • the present invention relates to compounds that irreversibly inhibit the activity of KRas G12C,
  • regulatory agency is a country’s agency for the approval of the medical use of pharmaceutical agents with the country.
  • a regulatory agency is the U.S. Food and Drug Administration (FDA).
  • a "therapeutically effective amount" of a compound is an amount that is sufficient to ameliorate, or in some manner reduce a symptom or stop or reverse progression of a condition, or negatively modulate or inhibit the activity of KRas G12C. Such amount may be administered as a single dosage or may be administered according to a regimen, whereby it is effective.
  • the aryl is phenyl substituted with one or more R 7 groups independently selected from halogen, hydroxyl, Cl - C3 alkyl, haloalkyl, Q-haloalkyl, and alkoxy. In one embodiment, the aryl is phenyl substituted with one or more R 7 groups independently selected from halogen, haloalkyl, methyl, isopropyl, methoxy, Q-haloalkyl and hydroxyl. In one embodiment, the aryl is phenyl substituted with one or more R 7 groups independently selected from methyl, trifluoromethyl, 2,2,2-trifluoroethyl, hydroxyl,
  • Formula I includes compounds having the Formula I-A:
  • R 1 is -C(0)C(R A ) . C(R B ) P , wherein— . is a double bond and p is two, one R B is hydrogen and R A and one R B and the carbon atoms to which they are attached form a 5-8 membered partially saturated cycloalkyl substituted with oxo.
  • hydroxypyrrolindinyl fluoropyrrolidinyl, difluoropyrrolidinyl, (N-methyl)fluoropyrrolidinyl, (N-methyl)difluoropyrrolidinyl, methoxyethylpyrrolidinyl, alkoxy-substituted N- methylpyrrolidinyl (e.g., (N-methyl)methoxypyrrolidinyl), piperazinyl,
  • liver nephroblastoma
  • lymphoma lymphoma
  • leukemia bladder and urethra
  • squamous cell carcinoma transitional cell carcinoma, adenocarcinoma
  • prostate adenocarcinoma, sarcoma
  • testis seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma
  • Liver Liver:
  • compositions comprising such compounds and salts also may be co-reacted
  • R 1 is introduced to provide a compound of Formula I, for example by treating with an acid chloride having the formula C1-C(0)C(R A ) C(R B ) P or Cl-S0 2 C(R A ) — .
  • C(R B ) P or an anhydride having the formula C(R B ) p ⁇ C(R A )C(0)0C(0)C(R A ) C(R B ) P , where R A , R B and p are as defined for Formula I.
  • Step A ethyl 2-methyl-3-oxo-4-phenyl-butanoate.
  • ethyl 3-oxo-4-phenyl-butanoate 4.00 g, 19.4 mmol.
  • THF 50.0 mL
  • sodium hydride 931 mg, 23.3 mmol
  • a solution of methyl iodide (3.03 g, 21.3) was next added drop-wise. After addition was completed, the reaction mixture was warmed to 20 °C and stirred for two hours at 20°C.
  • Step B 2-methylnaphthalene-l ,3-diol.
  • a solution of ethyl 2-methyl-3-oxo-4-phenyl- butanoate (3.60 g, 16.3 mmol) in concentrated sulfuric acid (19.9 g, 203 mmol) was stirred at 15 °C for 12 hours.
  • the reaction mixture was poured into ice-water (30.0 mL) and the resulting solid collected by filtration and dried under vacuum to afford 2-methylnaphthalene-l,3-diol (1.80 g, 10.3 mmol, 63.2% yield) as a red solid.
  • Step B /eH-butyl (2y)-2-(cvanomethyl)-4-[7-(2,3-dimethylphenyl)-2-methylsulfinyl-6,8- dihvdro-5//-pyrido[3,4- ⁇ /lpyrimidin-4-ynpiperazine-l-carboxylate.
  • Step C fe/7-butyl (2S , )-2-(cvanomethyl)-4-[7-(2,3-dimethylphenyl)-2-[[(2S r )-l- methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-57/-pyrido[3,4- ⁇ i]pyrimidin-4-yllpiperazine-l- carboxylate.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Oncology (AREA)
  • Hematology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Plural Heterocyclic Compounds (AREA)
PCT/US2018/061060 2017-11-15 2018-11-14 Kras g12c inhibitors Ceased WO2019099524A1 (en)

Priority Applications (29)

Application Number Priority Date Filing Date Title
PL18879484.6T PL3710439T3 (pl) 2017-11-15 2018-11-14 Inhibitory kras g12c
MX2020005063A MX2020005063A (es) 2017-11-15 2018-11-14 Inhibidores de kras g12c.
LTEPPCT/US2018/061060T LT3710439T (lt) 2017-11-15 2018-11-14 Kras g12c inhibitoriai
EP18879484.6A EP3710439B1 (en) 2017-11-15 2018-11-14 Kras g12c inhibitors
SG11202004427TA SG11202004427TA (en) 2017-11-15 2018-11-14 Kras g12c inhibitors
JP2020526612A JP7322019B2 (ja) 2017-11-15 2018-11-14 Ｋｒａｓ ｇ１２ｃ阻害剤
CA3082579A CA3082579A1 (en) 2017-11-15 2018-11-14 Kras g12c inhibitors
SI201830912T SI3710439T1 (sl) 2017-11-15 2018-11-14 Zaviralci mutacije kras g12c
CN201880086849.1A CN111989321B (zh) 2017-11-15 2018-11-14 Kras g12c抑制剂
KR1020207016494A KR102861303B1 (ko) 2017-11-15 2018-11-14 Ｋｒａｓ ｇ12ｃ 억제제
AU2018369759A AU2018369759B2 (en) 2017-11-15 2018-11-14 KRas G12C inhibitors
FIEP18879484.6T FI3710439T3 (fi) 2017-11-15 2018-11-14 Kras g12c:n estäjiä
EA202091186A EA202091186A1 (ru) 2017-11-15 2018-11-14 ИНГИБИТОРЫ KRas G12C
CN202410549759.9A CN118459460A (zh) 2017-11-15 2018-11-14 Kras g12c抑制剂
UAA202003509A UA125802C2 (uk) 2017-11-15 2018-11-14 Інгібітори kras g12c
HRP20230377TT HRP20230377T1 (hr) 2017-11-15 2018-11-14 Inhibitori mutacije kras g12c
BR112020009818-3A BR112020009818A2 (pt) 2017-11-15 2018-11-14 inibidores kras g12c
IL274601A IL274601B2 (en) 2017-11-15 2018-11-14 Kras g12c inhibitors
RS20230345A RS64182B1 (sr) 2017-11-15 2018-11-14 Inhibitori kras g12c
ES18879484T ES2944547T3 (es) 2017-11-15 2018-11-14 Inhibidores de KRas G12C
DK18879484.6T DK3710439T3 (da) 2017-11-15 2018-11-14 Kras g12c-hæmmere
MYPI2020001151A MY200356A (en) 2017-11-15 2018-11-14 Kras g12c inhibitors
ZA2020/02105A ZA202002105B (en) 2017-11-15 2020-05-04 Kras g12c inhibitors
PH12020550622A PH12020550622A1 (en) 2017-11-15 2020-05-13 Kras g12c inhibitors
CONC2020/0007244A CO2020007244A2 (es) 2017-11-15 2020-06-12 Inhibidores de kras g12c
NL301279C NL301279I2 (nl) 2017-11-15 2024-06-10 Adagrasib, desgewenst in de vorm van een farmaceutisch aanvaardbaar zout
FIC20240021C FIC20240021I1 (fi) 2017-11-15 2024-06-10 Adagrasibi tai sen farmaseuttisesti hyväksyttävä suola
LTPA2024517C LTC3710439I2 (enExample) 2017-11-15 2024-06-11
FR24C1026C FR24C1026I2 (fr) 2017-11-15 2024-06-13 Inhibiteurs de kras g12c

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201762586775P 2017-11-15 2017-11-15
US62/586,775 2017-11-15

Publications (1)

Publication Number Publication Date
WO2019099524A1 true WO2019099524A1 (en) 2019-05-23

Family

ID=66431793

Family Applications (2)

Application Number Title Priority Date Filing Date
PCT/US2018/061060 Ceased WO2019099524A1 (en) 2017-11-15 2018-11-14 Kras g12c inhibitors
PCT/US2019/032249 Ceased WO2020101736A1 (en) 2017-11-15 2019-05-14 Kras g12c inhibitors

Family Applications After (1)

Application Number Title Priority Date Filing Date
PCT/US2019/032249 Ceased WO2020101736A1 (en) 2017-11-15 2019-05-14 Kras g12c inhibitors

Country Status (34)

Country Link
US (4) US10689377B2 (enExample)
EP (3) EP3710439B1 (enExample)
JP (2) JP7322019B2 (enExample)
KR (1) KR102861303B1 (enExample)
CN (2) CN111989321B (enExample)
AU (1) AU2018369759B2 (enExample)
BR (1) BR112020009818A2 (enExample)
CA (1) CA3082579A1 (enExample)
CL (1) CL2020001271A1 (enExample)
CO (1) CO2020007244A2 (enExample)
CY (2) CY1125974T1 (enExample)
DK (1) DK3710439T3 (enExample)
EA (1) EA202091186A1 (enExample)
ES (2) ES2944547T3 (enExample)
FI (2) FI3710439T3 (enExample)
FR (1) FR24C1026I2 (enExample)
HR (1) HRP20230377T1 (enExample)
HU (2) HUE061599T2 (enExample)
IL (1) IL274601B2 (enExample)
LT (2) LT3710439T (enExample)
MX (1) MX2020005063A (enExample)
MY (1) MY200356A (enExample)
NL (1) NL301279I2 (enExample)
PH (1) PH12020550622A1 (enExample)
PL (1) PL3710439T3 (enExample)
PT (1) PT3710439T (enExample)
RS (1) RS64182B1 (enExample)
SA (1) SA520411982B1 (enExample)
SG (1) SG11202004427TA (enExample)
SI (1) SI3710439T1 (enExample)
TW (1) TWI809005B (enExample)
UA (1) UA125802C2 (enExample)
WO (2) WO2019099524A1 (enExample)
ZA (1) ZA202002105B (enExample)

Cited By (116)

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WO2020055758A1 (en) 2018-09-10 2020-03-19 Mirati Therapeutics, Inc. Combination therapies
WO2020055755A1 (en) 2018-09-10 2020-03-19 Mirati Therapeutics, Inc. Combination therapies
WO2020055761A1 (en) 2018-09-10 2020-03-19 Mirati Therapeutics, Inc. Combination therapies
WO2020055760A1 (en) 2018-09-10 2020-03-19 Mirati Therapeutics, Inc. Combination therapies
WO2020118066A1 (en) 2018-12-05 2020-06-11 Mirati Therapeutics, Inc. Combination therapies
WO2020165732A1 (en) 2019-02-12 2020-08-20 Novartis Ag Pharmaceutical combination comprising tno155 and a krasg12c inhibitor
CN112300153A (zh) * 2019-07-26 2021-02-02 博瑞生物医药（苏州）股份有限公司 一种杂环化合物、药物组合物和用途
CN112300195A (zh) * 2019-08-02 2021-02-02 上海济煜医药科技有限公司 四并环类化合物及其制备方法和应用
CN112390788A (zh) * 2019-08-13 2021-02-23 苏州闻天医药科技有限公司 一种用于抑制krasg12c突变蛋白的化合物及其制备方法和用途
WO2021055728A1 (en) 2019-09-18 2021-03-25 Merck Sharp & Dohme Corp. Small molecule inhibitors of kras g12c mutant
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CN112694475A (zh) * 2019-10-23 2021-04-23 苏州泽璟生物制药股份有限公司 环烷基类和杂环烷基类抑制剂及其制备方法和应用
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CN112824410A (zh) * 2019-11-21 2021-05-21 苏州泽璟生物制药股份有限公司 氮杂七元环类抑制剂及其制备方法和应用
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WO2021106231A1 (en) * 2019-11-29 2021-06-03 Taiho Pharmaceutical Co., Ltd. A compound having inhibitory activity against kras g12d mutation
WO2021124222A1 (en) * 2019-12-20 2021-06-24 Novartis Ag Pyrazolyl derivatives useful as anti-cancer agents
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WO2021169990A1 (zh) * 2020-02-24 2021-09-02 泰励生物科技（上海）有限公司 用于癌症治疗的kras抑制剂
CN113423703A (zh) * 2019-05-29 2021-09-21 上海翰森生物医药科技有限公司 含氮杂环类衍生物调节剂、其制备方法和应用
WO2021219072A1 (zh) * 2020-04-30 2021-11-04 上海科州药物研发有限公司 作为kras抑制剂的杂环化合物的制备及其应用方法
WO2021218939A1 (zh) * 2020-04-28 2021-11-04 贝达药业股份有限公司 稠环化合物及其在医药上的应用
CN113651814A (zh) * 2019-12-19 2021-11-16 北京加科思新药研发有限公司 Kras突变蛋白抑制剂
WO2021245055A1 (en) 2020-06-02 2021-12-09 Boehringer Ingelheim International Gmbh Annulated 2-amino-3-cyano thiophenes and derivatives for the treatment of cancer
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WO2021259972A1 (en) 2020-06-24 2021-12-30 Boehringer Ingelheim International Gmbh Anticancer combination therapy comprising a sos1 inhibitor and a kras g12c inhibitor
CN113912608A (zh) * 2020-07-10 2022-01-11 江苏恒瑞医药股份有限公司 嘧啶并嘧啶酮类衍生物、其制备方法及其在医药上的应用
WO2022056307A1 (en) * 2020-09-11 2022-03-17 Mirati Therapeutics, Inc. Crystalline forms of a kras g12c inhibitor
WO2022052895A1 (zh) 2020-09-11 2022-03-17 南京明德新药研发有限公司 氮杂环丁烷取代化合物的晶型
WO2022060836A1 (en) 2020-09-15 2022-03-24 Revolution Medicines, Inc. Indole derivatives as ras inhibitors in the treatment of cancer
WO2022060583A1 (en) 2020-09-03 2022-03-24 Revolution Medicines, Inc. Use of sos1 inhibitors to treat malignancies with shp2 mutations
US11312724B2 (en) 2020-01-08 2022-04-26 Ascentage Pharma (Suzhou) Co., Ltd. Spirocyclic tetrahydroquinazolines
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