WO2022067462A1 - Procédé de préparation d'inhibiteurs de kras g12c - Google Patents

Procédé de préparation d'inhibiteurs de kras g12c Download PDF

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WO2022067462A1
WO2022067462A1 PCT/CN2020/118666 CN2020118666W WO2022067462A1 WO 2022067462 A1 WO2022067462 A1 WO 2022067462A1 CN 2020118666 W CN2020118666 W CN 2020118666W WO 2022067462 A1 WO2022067462 A1 WO 2022067462A1
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alkyl
mmol
pyrrolo
dihydro
pyrimidin
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PCT/CN2020/118666
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English (en)
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Qi JI
Chao YU
Ce Wang
Hanzi SUN
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Beigene (Beijing) Co., Ltd.
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Priority to PCT/CN2020/118666 priority Critical patent/WO2022067462A1/fr
Publication of WO2022067462A1 publication Critical patent/WO2022067462A1/fr

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    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • Disclosed herein is a process for preparing compounds (including stereoisomers, pharmaceutical acceptable salts) that are useful for inhibiting Kras G12C mutant protein.
  • RAS is one of the most well-known oncogene. In human, three RAS genes (HRAS, KRAS and NRAS) encode four highly homologous RAS proteins (HRAS, KRAS-4A, KRAS-4B and NRAS) . RAS proteins are small GTPases, they function as binary molecular switches that involved in transduction of extracellular growth and differentiation signaling.
  • RAS generally cycles between a GDP-bound “off” state and a GTP-bound “on” state. This cycle is regulated by several factors. Guanine nucleotide exchange factors (GEFs) , including SOS1 and SOS2 facilitate the exchange and formation of GTP-bound RAS. While, GTPase-activating proteins (GAPs) , for example NF-1 promote the hydrolysis of GTP and therefore turn RAS back to GDP-bound inactivate state (Kessler et al, PNAS, 2019, 116 (32) : 15823–15829) .
  • GEFs Guanine nucleotide exchange factors
  • GAPs GTPase-activating proteins
  • RAS initiate conformational changes in two specific regions Switch 1 and Switch 2, which allows engagement and activation of downstream effector proteins to initiate a cascade of intracellular signaling pathways.
  • These effectors include RAF–MEK–ERK and PI3K-AKT–mTOR pathways, both of which have crucial roles in regulating cell proliferation, differentiation and survival (Cox et al., Nature Reviews Drug Discovery, 2014, 13: 828-851) .
  • RAS mutations have been identified in around 30%of human tumors. These mutations occur frequently as single-base missense mutations in codons 12, 13 or 61, resulting in stabilization of the activated GTP-bound RAS form and constitutive activation of RAS downstream signaling pathways.
  • KRAS is the most frequently mutated RAS in cancer, account for 85%of all RAS-driven cancers, followed by NRAS (12%) and HRAS (3%) .
  • KRAS mutation has been detected in around 95%of pancreatic ductal adenocarcinoma, 50%of colorectal adenocarcinoma and 30%of lung adenocarcinoma. The majority of KRAS mutations occur at residue 12, and the mutation type varied in different cancers.
  • G12D glycine to lysine
  • NSCLC non-small cell lung cancer
  • RAS has long been considered as a therapeutic target for many cancers.
  • no anti-RAS small molecular has been clinically approved.
  • the main reason is that druggable pockets on the surface of RAS is lacking (Papke et al., Science, 2017, 355: 1158–1163) .
  • Several inhibitors that directly target KRAS G12C are under the investigation (Patricelli et al, Cancer Discovery, 2016, 6 (3) ; 316–29) (Fell et al, ACS Med. Chem. Lett. 2018, 9, 12, 1230-1234) .
  • WO2015/054572A1 provides compounds having activity as inhibitors of G12C mutant RAS protein.
  • WO2016/164675A1 and WO2017/015562A1 disclose substituted quinazoline compounds as KRAS G12C inhibitors.
  • WO2014/152588 A1 discloses tetracyclic compounds as inhibitors of G12C mutant Ras protein as anti-cancer agents.
  • One objective of the present invention is to provide a process for preparing of compounds exhibiting potent KRAS G12C inhibitory activity.
  • a process for preparing the compound of Formula (A) is a process for preparing the compound of Formula (A) :
  • L 1 and L 2 are each selected from a single bond, -CO-NH-, -NH-CO-, -O-, -NR a -, -NR a (CH 2 ) m -, -S-, - (CH 2 ) m -, -O- (CH 2 ) m -, -O-CH (R a ) -, -CH (R a ) -, -CH (R a ) (CH 2 ) m -, - (CH 2 ) m -O-, -CO-, -SO 2 -, cycloalkylene, oxetandiyl, tetrahydrofurandiyl, tetrahydropyrandiyl, azetidindiyl, pyrrilidindiyl, piperidindiyl, or piperizindiyl;
  • R 1 is selected from -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -NR b R c , cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of said -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with at least one R 6 (in case there are more than one R 6 , each R 6 are identical or different to each other) ;
  • R 2 is selected from -NR b R c , cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of said cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with at least one R 6 (such as – (R 6 ) q , wherein each R 6 are the same or different in case q is more than 1) ;
  • each R 6 is selected from -C 1-8 alkyl, halogen, hydroxy, oxo, -C 1-8 alkoxy, -NR b R c , cycloalkyl, heterocyclyl, aryl, or heteroaryl; said -C 1-8 alkyl, -C 1-8 alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with at least one hydroxy, amino, CN or cycloalkyl, heterocyclyl, aryl or heteroaryl;
  • R 3 is selected from hydrogen, oxo, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of said -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with halogen, hydroxy, -C 1-8 alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
  • R 5 is selected from -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, oxo, -NR b R c , -CO-NR d R e , cycloalkyl, heterocyclyl, aryl, or heteroaryl, - (CH 2 ) m -CN, or hydrogen;
  • R 4 is selected from
  • each R a , R b and R c are independently hydrogen, deuterium (D) , cyano (CN) , halogen, hydroxy, -C 1- 8 alkoxy, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CO-NR d R e , each of said -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with R f ; or (R a and R b ) , or (R a and R c ) together with the atom (s) to which they are attached, form a 4-to 6 membered ring, said ring is optionally substituted with at least one R g ;
  • each R f is selected from halogen, hydroxy, oxo, -C 1-8 alkoxy, -NR d R e , -CO-NR d R e , -NR d -CO-R e , cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each said -C 1-8 alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with halogen, hydroxy or –C 1-4 alkyl;
  • R d , R e and R g are each independently hydrogen, deuterium (D) , halogen, oxo, -C 1-8 alkyl;
  • each said -C 1-8 alkyl is optionally substituted with at least one halogen, oxo, CF 3 or -COCH 3 ;
  • p, q and t are independently selected from 0, 1, 2, 3 or 4;
  • each m and n are independently 0, 1, 2, 3, 4, 5 or 6;
  • Step 1 R 1 -L 1 is linked to the nitrogen of compound I, by reduction amination with corresponding aldehyde, Buchwald coupling with corresponding aryl or heteroaryl halogen, S N 1/S N 2/S N Ar substitution with corresponding starting materials, Mitsunobu reaction with corresponding alcohol, amide coupling with corresponding acyl chloride/carboxylic acid or urea formation with corresponding starting materials, to give compound II;
  • Step 2 LG 1 is substituted by PG 1 protected piperazine analogs to give compound III;
  • Step 3 R 1 -L 2 group is installed to the resulting compound III, by substitution of LG 2 via S N Ar or Buchwald coupling to get compound IV;
  • Step 4 PG 1 protecting group of compound IV is removed
  • Step 5 R 4 is installed onto the top nitrogen of piperazine by amide and/or sulfonamide coupling to give target Formula (A) ;
  • LG 1 , LG 2 , LG 3 , LG 4 and PG 1 are leaving groups.
  • Aspect 2 The process according to Aspect 1, wherein R 1 is selected from -C 2-4 alkenyl, 5-to 6-membered carbocyclic aromatic ring (such as phenyl) , 7-to 12-membered bi-carbocyclic ring (such as naphthalene, indene, or indane) , 10-to 15-membered tri-carbocyclic ring (such as fluorene, anthracene, phenalene, phenanthrene) , 7-to 12-membered bicyclic heteroaryl comprising at least one heteroatom selected from N, O and S with the remaining ring atoms being carbon; each of said -C 2-4 alkenyl, 5-to 6-membered carbocyclic aromatic ring, 7-to 12-membered bi-carbocyclic ring, 10-15 membered tri-carbocyclic ring, and 7-to 12-membered bicyclic heteroaryl is optionally substituted with at least one R 6 (such as
  • Aspect 3 The process according to any one of Aspects 1 or 2, wherein R 1 is selected from phenyl, naphthalene, indane, fluorene, indazole, or dihydroacenaphthylene, quinoline, isoquinoline, or indole, wherein said phenyl, naphthalene, indane, fluorene, indazole, dihydroacenaphthylene, quinoline, isoquinoline, or indole is optionally substituted with at least one R 6 , R 6 is selected from -C 1-8 alkyl, -C 1- 8 alkoxy, -haloC 1-8 alkyl, oxo, halogen, hydroxy, -NH 2 , or C 3-6 cycloalkyl.
  • R 1 is selected from phenyl, naphthalene, indane, fluorene, indazole, or dihydroacenaphthylene,
  • Aspect 7 The process according to any one of Aspects 1-6, wherein L 1 is selected from single bond, -CO-NH-, -CH 2 -, -CO-, or -CH (CH 3 ) -.
  • Aspect 9 The process according to any one of Aspects 1-8, wherein L 2 is selected from a single bond, -O-CH 2 -, -O-CH 2 CH 2 -, -O-CH 2 CH 2 CH 2 -, -O-, -O-CH (CH 3 ) -, -NH-CH 2 -, -NH-CH 2 CH 2 -, -O-CH (CH 3 ) CH 2 -, wherein the asterisks *refers to linking positions.
  • Aspect 10 The process according to any one of Aspects 1-9, wherein R 2 is selected from -NR b R c , each R 6 is selected from halogen, hydroxy, -C 1-8 alkyl, , -C 1-8 alkoxy; -C 1-8 alkyl is optionally substituted with hydroxy, or halogen; each q is 0, 1, 2 or 3; R b and R c are independently hydrogen, deuterium (D) , halogen, or -C 1-8 alkyl.
  • Aspect 11 The process according to Aspect 10, wherein R 6 is selected from CH 3 , OH, CH 2 OH, F, -CHF 2 , -OCH 3 , Cl, or Br, or
  • Aspect 12 The process according to any one of Aspects 1-11, wherein R 2 is selected from (such as ) , (such as ) ,
  • Aspect 13 The process according to any one of Aspects 1-12, wherein R 2 is selected from
  • Aspect 14 The process according to any one of Aspects 1-13, wherein R 3 is selected from hydrogen, oxo, or -C 1-8 alkyl.
  • Aspect 15 The process according to any one of Aspects 1-14, wherein is selected from
  • Aspect 16 The process according to any one of Aspects 1-15, wherein R 4 is selected from
  • R a is selected from hydrogen, deuterium (D) , halogen (F, Cl, Br or I) , -C 1-8 alkyl or -C 1-8 alkoxy, said -C 1- 8 alkyl or -C 1-8 alkoxy is optionally substituted with at least one halogen (such as F, Cl) , hydroxy, -C 1- 8 alkoxy, or -NR d COR e ;
  • R b is selected from hydrogen and -C 1-8 alkyl
  • R c is selected from hydrogen, halogen (such as Cl) , -C 1-8 alkyl, -CN, -NR d R e , -CO-NR d R e , or heteroaryl (such as pyridinyl, pyrazole or imidazole) said -C 1-8 alkyl is optionally substituted with at least one R f ;
  • each R f is selected from halogen (e.g., F, Br, Cl) , hydroxy, -NR d R e , -C 1-8 alkoxy, -C 4-7 heterocyclyl (such as azetidine, pyrrolidine, piperidine, morpholine) , wherein each said -C 1-8 alkoxy or -C 4-7 heterocyclyl is optionally substituted with halogen, hydroxy or –C 1-4 alkyl;
  • halogen e.g., F, Br, Cl
  • hydroxy -NR d R e
  • -C 1-8 alkoxy such as azetidine, pyrrolidine, piperidine, morpholine
  • R d and R e are each independently hydrogen, deuterium (D) , halogen or -C 1-8 alkyl, wherein each said -C 1-8 alkyl is optionally substituted with at least one halogen or -COCH 3 ; or
  • R a and R b together with the atoms to which they are attached, form a 4-to 6-membered ring selected from R c is selected from hydrogen, hydroxy, -C 1-8 alkoxy, or -C 1-8 alkyl; said ring is optionally substituted with oxo.
  • Aspect 17 The process according to any one of Aspects 1-16, wherein R 4 is selected wherein R a is selected from hydrogen, hydroxy, or -C 1-8 alkyl (such as -CH 3 ) ; each R b and R c are independently selected from hydrogen or -C 1-8 alkyl (such as -CH 3 ) .
  • Aspect 18 The process according to any one of Aspects 1-17 wherein R 4 is selected from
  • Aspect 19 The process according to any one of Aspects 1-18 wherein R 4 is selected from
  • Aspect 21 The process according to Aspect 1, Formula (A) is selected from
  • Aspect 22 The process according to any one of Aspects 1-21, LG 1 , LG 2 , LG 3 and LG 4 each are independently selected from halogen, OH, phenol, OMs or OTs; and/or PG1 is selected from Boc, Cbz, Bn or PMB.
  • a pharmaceutical composition comprising the compound disclosed herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.
  • a method of inhibiting KRAS G12C activity which comprises administering to an individual the compound disclosed herein, or a pharmaceutically acceptable salt thereof, including the compound of formula (I) or the specific compounds exemplified herein.
  • a method of treating a disease or disorder in a patient comprising administering to the patient a therapeutically effective amount of the compound disclosed herein, or a pharmaceutically acceptable salt thereof as a KRAS G12C inhibitor, wherein the compound disclosed herein includes the compound of formula (I) or the specific compounds exemplified herein.
  • the disease or disorder is associated with inhibition of KRAS G12C interaction.
  • the disease or disorder is cancer.
  • a or “an” entity refers to one or more of that entity.
  • a compound refers to one or more compounds or at least one compound.
  • ...substituted with a substituent means that one or more substituents are substituted as long as valence and stability permit.
  • the terms “a” (or “an” ) , “one or more” , and “at least one” can be used interchangeably herein.
  • alkyl herein refers to a hydrocarbon group selected from linear and branched saturated hydrocarbon groups comprising from 1 to 18, such as from 1 to 12, further such as from 1 to 10, more further such as from 1 to 8, or from 1 to 6, or from 1 to 4, carbon atoms.
  • alkyl groups comprising from 1 to 6 carbon atoms include, but not limited to methyl, ethyl, 1-propyl or n-propyl ( “n-Pr” ) , 2-propyl or isopropyl ( “i-Pr” ) , 1-butyl or n-butyl ( “n-Bu” ) , 2-methyl-1-propyl or isobutyl ( “i-Bu” ) , 1-methylpropyl or s-butyl ( “s-Bu” ) , 1, 1-dimethylethyl or t-butyl ( “t-Bu” ) , 1-pentyl, 2- pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl
  • alkyloxy herein refers to an alkyl group as defined above bonded to oxygen, represented by -Oalkyl.
  • alkyloxy e.g., C 1-6 alkyloxy or C 1-4 alkyloxy includes, but not limited to, methoxy, ethoxyl, isopropoxy, propoxy, n-butoxy, tert-butoxy, pentoxy and hexoxy and the like.
  • haloalkyl refers to an alkyl group in which one or more hydrogen is/are replaced by one or more halogen atoms such as fluoro, chloro, bromo, and iodo.
  • haloalkyl include C 1-6 haloalkyl or C 1-4 haloalkyl, but not limited to F 3 C-, ClCH 2 -, CF 3 CH 2 -, CF 3 CCl 2 -, and the like.
  • alkenyl group e.g., C 2-6 alkenyl
  • examples of the alkenyl group, e.g., C 2-6 alkenyl include, but not limited to ethenyl or vinyl, prop-1-enyl, prop-2-enyl, 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1, 3-dienyl, 2-methylbuta-1, 3-dienyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, and hexa-1, 3-dienyl groups.
  • alkynyl herein refers to a hydrocarbon group selected from linear and branched hydrocarbon group, comprising at least one C ⁇ C triple bond and from 2 to 18, such as 2 to 8, further such as from 2 to 6, carbon atoms.
  • alkynyl group e.g., C 2-6 alkynyl
  • examples of the alkynyl group, e.g., C 2-6 alkynyl include, but not limited to ethynyl, 1-propynyl, 2-propynyl (propargyl) , 1-butynyl, 2-butynyl, and 3-butynyl groups.
  • cycloalkyl refers to a hydrocarbon group selected from saturated and partially unsaturated cyclic hydrocarbon groups, comprising monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups.
  • the cycloalkyl group may comprise from 3 to 12, such as from 3 to 10, further such as 3 to 8, further such as 3 to 6, 3 to 5, or 3 to 4 carbon atoms.
  • the cycloalkyl group may be selected from monocyclic group comprising from 3 to 12, such as from 3 to 10, further such as 3 to 8, 3 to 6 carbon atoms.
  • Examples of the monocyclic cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl groups.
  • saturated monocyclic cycloalkyl group e.g., C 3-8 cycloalkyl
  • saturated monocyclic cycloalkyl group include, but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups.
  • bicyclic cycloalkyl groups include those having from 7 to 12 ring atoms arranged as a bicyclic ring selected from [4, 4] , [4, 5] , [5, 5] , [5, 6] and [6, 6] ring systems, or as a bridged bicyclic ring selected from bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane, and bicyclo [3.2.2] nonane.
  • the bicyclic cycloalkyl groups include those arranged as a bicyclic ring selected from [5, 6] and [6, 6] ring systems, such as wherein the wavy lines indicate the points of attachment.
  • the ring may be saturated or have at least one double bond (i.e. partially unsaturated) , but is not fully conjugated, and is not aromatic, as aromatic is defined herein.
  • cycloalkylene refers to a divalent cyclopropyl as defined herein.
  • a cyclopropylene may be represented by and so on, wherein asterisks refers to linking positions.
  • oxetandiyl is a divalent group derived from oxetane, which may be represented by
  • aryl used alone or in combination with other terms refers to a group selected from: 5-and 6-membered carbocyclic aromatic rings, for example, phenyl; bicyclic ring systems such as 7 to 12 membered bicyclic ring systems wherein at least one ring is carbocyclic and aromatic, selected, for example, from naphthalene, and indane; and tricyclic ring systems such as 10 to 15 membered tricyclic ring systems wherein at least one ring is carbocyclic and aromatic, for example, fluorene.
  • a monocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10 ring-forming carbon atoms (i.e., C 5-10 aryl) .
  • Examples of a monocyclic or bicyclic aromatic hydrocarbon ring includes, for example, but not limited to, phenyl, naphth-1-yl, naphth-2-yl, anthracenyl, phenanthrenyl rings, and the like.
  • the aromatic hydrocarbon ring is a naphthalene ring (naphth-1-yl or naphth-2-yl) or phenyl ring.
  • the aromatic hydrocarbon ring is a phenyl ring.
  • halogen or halo refers to F, Cl, Br or I.
  • heteroaryl herein refers to a group selected from:
  • 5-to 7-membered aromatic, monocyclic rings comprising at least one heteroatom, for example, from 1 to 4, or, in some embodiments, from 1 to 3, heteroatoms, selected from N, O, and S, with the remaining ring atoms being carbon;
  • 8-to 12-membered bicyclic rings comprising at least one heteroatom, for example, from 1 to 4, or, in some embodiments, from 1 to 3, or, in other embodiments, 1 or 2, heteroatoms, selected from N, O, and S, with the remaining ring atoms being carbon and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring; and
  • 11-to 14-membered tricyclic rings comprising at least one heteroatom, for example, from 1 to 4, or in some embodiments, from 1 to 3, or, in other embodiments, 1 or 2, heteroatoms, selected from N, O, and S, with the remaining ring atoms being carbon and wherein at least one ring is aromatic and at least one heteroatom is present in an aromatic ring.
  • the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to one another. In some embodiments, the total number of S and O atoms in the heteroaryl group is not more than 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle is not more than 1.
  • the heteroaryl group contains more than one heteroatom ring member, the heteroatoms may be the same or different. The nitrogen atoms in the ring (s) of the heteroaryl group can be oxidized to form N-oxides.
  • a monocyclic or bicyclic aromatic heterocyclic ring has 5-to 10-ring forming members with 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen and the remaining ring members being carbon.
  • the monocyclic or bicyclic aromatic heterocyclic ring is a monocyclic or bicyclic ring comprising 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.
  • the monocyclic or bicyclic aromatic heterocyclic ring is a 5-to 6-membered heteroaryl ring, which is monocyclic and which has 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the monocyclic or bicyclic aromatic heterocyclic ring is a 8-to 10-membered heteroaryl ring, which is bicyclic and which has 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.
  • heteroaryl group or the monocyclic or bicyclic aromatic heterocyclic ring examples include, but are not limited to, (as numbered from the linkage position assigned priority 1) pyridyl (such as 2-pyridyl, 3-pyridyl, or 4-pyridyl) , cinnolinyl, pyrazinyl, 2, 4-pyrimidinyl, 3, 5-pyrimidinyl, 2, 4-imidazolyl, imidazopyridinyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl (such as 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, or 1, 3, 4-thiadiazolyl) , tetrazolyl, thienyl (such as thien-2-yl, thien-3-yl) , triazinyl, benzothienyl, furyl or furanyl, benzofuryl, benzoimidazo
  • heterocyclic or “heterocycle” or “heterocyclyl” herein refers to a ring selected from 4-to 12-membered monocyclic, bicyclic and tricyclic, saturated and partially unsaturated rings comprising at least one carbon atoms in addition to at least one heteroatom, such as from 1-4 heteroatoms, further such as from 1-3, or further such as 1 or 2 heteroatoms, selected from oxygen, sulfur, and nitrogen.
  • a heterocyclyl group is 4-to 7-membered monocyclic ring with one heteroatom selected from N, O and S.
  • Heterocycle herein also refers to a 5-to 7-membered heterocyclic ring comprising at least one heteroatom selected from N, O, and S fused with 5-, 6-, and /or 7-membered cycloalkyl, carbocyclic aromatic or heteroaromatic ring, provided that the point of attachment is at the heterocyclic ring when the heterocyclic ring is fused with a carbocyclic aromatic or a heteroaromatic ring, and that the point of attachment can be at the cycloalkyl or heterocyclic ring when the heterocyclic ring is fused with cycloalkyl.
  • Heterocycle herein also refers to an aliphatic spirocyclic ring comprising at least one heteroatom selected from N, O, and S, provided that the point of attachment is at the heterocyclic ring.
  • the rings may be saturated or have at least one double bond (i.e. partially unsaturated) .
  • the heterocycle may be substituted with oxo.
  • the point of the attachment may be carbon or heteroatom in the heterocyclic ring.
  • a heterocycle is not a heteroaryl as defined herein.
  • heterocycle examples include, but not limited to, (as numbered from the linkage position assigned priority 1) 1-pyrrolidinyl, 2-pyrrolidinyl, 2, 4-imidazolidinyl, 2, 3-pyrazolidinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2, 5-piperazinyl, pyranyl, 2-morpholinyl, 3-morpholinyl, oxiranyl, aziridinyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, 1, 2-dithietanyl, 1, 3-dithietanyl, dihydropyridinyl, tetrahydropyridinyl, thiomorpholinyl, thioxanyl, piperazinyl, homopiperazinyl, homopiperidinyl, azepanyl, oxepanyl, thiepanyl, 1,
  • a substituted heterocycle also includes a ring system substituted with one or more oxo moieties, such as piperidinyl N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl and 1, 1-dioxo-1-thiomorpholinyl.
  • oxo moieties such as piperidinyl N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl and 1, 1-dioxo-1-thiomorpholinyl.
  • fused ring refers to a polycyclic ring system, e.g., a bicyclic or tricyclic ring system, in which two rings share only two ring atoms and one bond in common.
  • fused rings may comprise a fused bicyclic cycloalkyl ring such as those having from 7 to 12 ring atoms arranged as a bicyclic ring selected from [4, 4] , [4, 5] , [5, 5] , [5, 6] and [6, 6] ring systems as mentioned above; a fused bicyclic aryl ring such as 7 to 12 membered bicyclic aryl ring systems as mentioned above, a fused tricyclic aryl ring such as 10 to 15 membered tricyclic aryl ring systems mentioned above; a fused bicyclic heteroaryl ring such as 8-to 12-membered bicyclic heteroaryl rings as mentioned above, a fused tricyclic heteroaryl ring such as 11-to 14
  • Compounds disclosed herein may contain an asymmetric center and may thus exist as enantiomers. Where the compounds disclosed herein possess two or more asymmetric centers, they may additionally exist as diastereomers. Enantiomers and diastereomers fall within the broader class of stereoisomers. All such possible stereoisomers as substantially pure resolved enantiomers, racemic mixtures thereof, as well as mixtures of diastereomers are intended to be included. All stereoisomers of the compounds disclosed herein and /or pharmaceutically acceptable salts thereof are intended to be included. Unless specifically mentioned otherwise, reference to one isomer applies to any of the possible isomers. Whenever the isomeric composition is unspecified, all possible isomers are included.
  • the term “substantially pure” as used herein means that the target stereoisomer contains no more than 35%, such as no more than 30%, further such as no more than 25%, even further such as no more than 20%, by weight of any other stereoisomer (s) . In some embodiments, the term “substantially pure” means that the target stereoisomer contains no more than 10%, for example, no more than 5%, such as no more than 1%, by weight of any other stereoisomer (s) .
  • keto and enol forms are also intended to be included where applicable.
  • reaction products from one another and /or from starting materials.
  • the desired products of each step or series of steps is separated and /or purified (hereinafter separated) to the desired degree of homogeneity by the techniques common in the art.
  • separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography.
  • Chromatography can involve any number of methods including, for example: reverse-phase and normal phase; size exclusion; ion exchange; high, medium and low pressure liquid chromatography methods and apparatus; small scale analytical; simulated moving bed ( "SMB” ) and preparative thin or thick layer chromatography, as well as techniques of small scale thin layer and flash chromatography.
  • SMB simulated moving bed
  • Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as by chromatography and /or fractional crystallization.
  • Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or MosheR a s acid chloride) , separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereoisomers to the corresponding pure enantiomers.
  • an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or MosheR a s acid chloride
  • Enantiomers can also be separated by use of a chiral HPLC column.
  • a single stereoisomer e.g., a substantially pure enantiomer
  • Racemic mixtures of chiral compounds of the invention can be separated and isolated by any suitable method, including: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions. See: Wainer, Irving W., Ed. Drug Stereochemistry: Analytical Methods and Pharmacology. New York: Marcel Dekker, Inc., 1993.
  • “Pharmaceutically acceptable salts” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • a pharmaceutically acceptable salt may be prepared in situ during the final isolation and purification of the compounds disclosed herein, or separately by reacting the free base function with a suitable organic acid or by reacting the acidic group with a suitable base.
  • the free base can be obtained by basifying a solution of the acid salt.
  • an addition salt such as a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds.
  • a pharmaceutically acceptable salt thereof include salts of at least one compound of Formula (I) , and salts of the stereoisomers of at least one compound of Formula (I) , such as salts of enantiomers, and /or salts of diastereomers.
  • Treating refers to administering at least one compound and /or at least one stereoisomer thereof, and /or at least one pharmaceutically acceptable salt thereof disclosed herein to a subject in recognized need thereof that has, for example, cancer.
  • an effective amount refers to an amount of at least one compound and /or at least one stereoisomer thereof, and /or at least one pharmaceutically acceptable salt thereof disclosed herein effective to "treat” as defined above, a disease or disorder in a subject.
  • At least one substituent includes, for example, from 1 to 4, such as from 1 to 3, further as 1 or 2, substituents, provided that valence and stability permit.
  • at least one substituent R 7 disclosed herein includes from 1 to 4, such as from 1 to 3, further as 1 or 2, substituents selected from the list of R 7 as disclosed herein;
  • at least one substituent R 10 disclosed herein includes from 1 to 4, such as from 1 to 3, further as 1 or 2, substituents selected from the list of R 10 as disclosed herein.
  • the target compounds are synthesized according to general schemes A and B.
  • R 1 -L1 can be linked to the nitrogen of intermediate I, by reduction amination with corresponding aldehyde, Buchwald coupling with corresponding aryl/heteroaryl halogen, S N 1/S N 2/S N Ar substitution with corresponding starting materials, Mitsunobu reaction with corresponding alcohol, amide coupling with corresponding acyl chloride/carboxylic acid or urea formation with corresponding starting materials, to give intermediate II.
  • LG 1 is substituted by PG 1 protected piperazine analogs to give intermediate III.
  • R 1 -L 2 group is installed to the resulting intermediate III, by substitution of LG 2 via S N Ar or Buchwald coupling.
  • R 4 is installed onto the top nitrogen of piperazine by Amide/sulfonamide coupling to give target compound VI.
  • Scheme B is an alternative route for the target compounds, with similar reactions and better efficiency for library production.
  • reaction flasks were fitted with rubber septa for the introduction of substrates and reagents via syringe; and glassware was oven dried and /or heat dried.
  • column chromatography purification was conducted on a Biotage system (Manufacturer: Dyax Corporation) having a silica gel column or on a silica SepPak cartridge (Waters) , or was conducted on a Teledyne Isco Combiflash purification system using prepacked silica gel cartridges.
  • 1 H NMR spectra were recorded on a Varian instrument operating at 400 MHz. 1 H-NMR spectra were obtained using CDCl 3 , CD 2 Cl 2 , CD 3 OD, D 2 O, d 6 -DMSO, d 6 -acetone or (CD 3 ) 2 CO as solvent and tetramethylsilane (0.00 ppm) or residual solvent (CDCl 3 : 7.25 ppm; CD 3 OD: 3.31 ppm; D 2 O: 4.79 ppm; d 6 -DMSO: 2.50 ppm; d 6 -acetone: 2.05; (CD 3 ) 2 CO: 2.05) as the reference standard.
  • Steps 1 and 2 tert-butyl 4- (2-chloro-6- (naphthalen-1-ylmethyl) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazine-1-carboxylate
  • Step 3 tert-butyl (S) -4- (2- ( (1-methylpyrrolidin-2-yl) methoxy) -6- (naphthalen-1-ylmethyl) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazine-1-carboxylate
  • Step 4 (S) -2- ( (1-methylpyrrolidin-2-yl) methoxy) -6- (naphthalen-1-ylmethyl) -4- (piperazin-1-yl) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidine hydrochloride
  • Step 5 (S) -1- (4- (2- ( (1-methylpyrrolidin-2-yl) methoxy) -6- (naphthalen-1-ylmethyl) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazin-1-yl) prop-2-en-1-one
  • Example 1 15 mg, 24%) .
  • 1 H NMR (400 MHz, CD 3 OD) ⁇ 8.30-8.27 (m, 1H) , 7.88-7.81 (m, 2H) , 7.54-7.42 (m, 4H) , 6.78 -6.71 (m, 1H) , 6.25 -6.21 (m, 1H) , 5.78 -5.75 (m, 1H) , 4.46 -4.36 (m, 2H) , 4.32 (s, 2H) , 4.11 (s, 2H) , 3.74 (s, 2H) , 3.70 (s, 8H) , 3.65-3.55 (m, 1H) , 3.38-3.32 (m, 1H) , 3.24-3.22 (m, 1H) , 2.72 (s, 3H) , 2.22-2.14 (m, 1H) , 1.97-1.90 (m,
  • Example 2 (20 mg, 19%) .
  • Step 1 2, 4-dichloro-6- (2, 3-dimethylbenzyl) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidine
  • Step 2 benzyl (S) -4- (2-chloro-6- (2, 3-dimethylbenzyl) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate
  • Step 3 benzyl (S) -2- (cyanomethyl) -4- (6- (2, 3-dimethylbenzyl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazine-1-carboxylate
  • Step 4 2- ( (S) -4- (6- (2, 3-dimethylbenzyl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
  • Step 5 2- ( (S) -1-acryloyl-4- (6- (2, 3-dimethylbenzyl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
  • Step 1 tert-butyl 2, 4-dichloro-5, 7-dihydro-6H-pyrrolo [3, 4-d] pyrimidine-6-carboxylate
  • Step 2 tert-butyl (S) -4- (4- ( (benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2-chloro-5, 7-dihydro-6H-pyrrolo [3, 4-d] pyrimidine-6-carboxylate
  • Step 3 tert-butyl 4- ( (S) -4- ( (benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -5, 7-dihydro-6H-pyrrolo [3, 4-d] pyrimidine-6-carboxylate
  • (S) -4- (4- ( (benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2-chloro-5, 7-dihydro-6H-pyrrolo [3, 4-d] pyrimidine-6-carboxylate 13.40 g, 26.12 mmol
  • (S) - (1-methylpyrrolidin-2-yl) methanol (7.30 g, 63.37 mmol) tris (dibenzylideneacetone) dipalladium (1.83
  • Step 4 benzyl (S) -2- (cyanomethyl) -4- (2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazine-1-carboxylate
  • Step 1 benzyl (S) -2- (cyanomethyl) -4- (2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6- (naphthalen-1-ylmethyl) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazine-1-carboxylate
  • Step 2 2- ( (S) -4- (2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6- (naphthalen-1-ylmethyl) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
  • Step 3 2- ( (S) -1-acryloyl-4- (2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6- (naphthalen-1-ylmethyl) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
  • Example 6 (10 mg, 11.3%) .
  • 1 H NMR (400 MHz, DMSO-d 6 ) ⁇ ppm: 8.31-8.24 (m, 1H) , 7.97-7.92 (m, 1H) , 7.90-7.88 (d, 1H, J 8.0Hz) , 7.59-7.46 (m, 4H) , 6.89-6.73 (m, 1H) , 6.24-6.13 (m, 1H) , 5.81-5.71 (m, 1H) , 4.91-4.71 (m, 1H) , 4.61-4.48 (m, 1H) , 4.48-4.39 (m, 1H) , 4.38-4.24 (m, 3H) , 4.19-4.08 (m, 2H) , 4.04-3.89 (m, 1H) , 3.
  • Step 1 benzyl (S) -2- (cyanomethyl) -4- (2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6- (naphthalen-1-ylmethyl) -6H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazine-1-carboxylate
  • Step 2 2- ( (S) -4- (2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6- (naphthalen-1-ylmethyl) -6H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
  • Step 3 2- ( (S) -1-acryloyl-4- (2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6- (naphthalen-1-ylmethyl) -6H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
  • Example 7 (10 mg, 11.4%) .
  • Example 8 2- ( (S) -1-acryloyl-4- (6- ( (8-methylnaphthalen-1-yl) methyl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
  • Step 1 benzyl (S) -2- (cyanomethyl) -4- (6- ( (8-methylnaphthalen-1-yl) methyl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazine-1-carboxylate
  • Step 2 2- ( (S) -4- (6- ( (8-methylnaphthalen-1-yl) methyl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
  • Step 3 2- ( (S) -1-acryloyl-4- (6- ( (8-methylnaphthalen-1-yl) methyl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
  • Example 8 (8 mg, 12.0%) .
  • Example 12 2- ( (2S) -1-acryloyl-4- (6- (1, 2-dihydroacenaphthylen-1-yl) -2- ( (1- (tetrahydro-2H-pyran-4-yl) piperidin-4-yl) oxy) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
  • Step 2 tert-butyl (S) -4- (4- ( (benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- ( (1- (tetrahydro-2H-pyran-4-yl) piperidin-4-yl) oxy) -5, 7-dihydro-6H-pyrrolo [3, 4-d] pyrimidine-6-carboxylate
  • Step 3 benzyl (S) -2- (cyanomethyl) -4- (2- ( (1- (tetrahydro-2H-pyran-4-yl) piperidin-4-yl) oxy) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazine-1-carboxylate
  • Step 4 benzyl (2S) -2- (cyanomethyl) -4- (6- (1, 2-dihydroacenaphthylen-1-yl) -2- ( (1- (tetrahydro-2H-pyran-4-yl) piperidin-4-yl) oxy) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazine-1-carboxylate
  • Step 5 2- ( (2S) -4- (6- (1, 2-dihydroacenaphthylen-1-yl) -2- ( (1- (tetrahydro-2H-pyran-4-yl) piperidin-4-yl) oxy) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
  • Step 6 2- ( (2S) -1-acryloyl-4- (6- (1, 2-dihydroacenaphthylen-1-yl) -2- ( (1- (tetrahydro-2H-pyran-4-yl) piperidin-4-yl) oxy) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
  • Example 12 (4 mg, 3.6%) .
  • Step 1 tert-butyl 4- ( (S) -4- ( (benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- ( (S) -2- (hydroxymethyl) pyrrolidin-1-yl) -5, 7-dihydro-6H-pyrrolo [3, 4-d] pyrimidine-6-carboxylate
  • Step 2 benzyl (S) -2- (cyanomethyl) -4- (2- ( (S) -2- (hydroxymethyl) pyrrolidine-1-yl) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazine-1-carboxylate
  • Step 3 benzyl (2S) -2- (cyanomethyl) -4- (6- (1, 2-dihydroacenaphthylen-1-yl) -2- ( (S) -2- (hydroxymethyl) pyrrolidin-1-yl) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazine-1-carboxylate
  • Step 4 2- ( (2S) -4- (6- (1, 2-dihydroacenaphthylen-1-yl) -2- ( (S) -2- (hydroxymethyl) pyrrolidin-1-yl) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
  • Step 5 2- ( (2S) -1-acryloyl-4- (6- (1, 2-dihydroacenaphthylen-1-yl) -2- ( (S) -2- (hydroxymethyl) pyrrolidin-1-yl) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
  • Example 13 (8 mg, 6.9%) .
  • Step 1 tert-butyl 4- ( (S) -4- ( (benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- ( (R) -1- (pyridin-4-yl) ethoxy) -5, 7-dihydro-6H-pyrrolo [3, 4-d] pyrimidine-6-carboxylate
  • Step 2 benzyl (S) -2- (cyanomethyl) -4- (2- ( (R) -1- (pyridin-4-yl) ethoxy) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazine-1-carboxylate
  • Step 3 benzyl (2S) -2- (cyanomethyl) -4- (6- (1, 2-dihydroacenaphthylen-1-yl) -2- ( (R) -1- (pyridin-4-yl) ethoxy) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazine-1-carboxylate
  • Step 4 2- ( (2S) -4- (6- (1, 2-dihydroacenaphthylen-1-yl) -2- ( (R) -1- (pyridin-4-yl) ethoxy) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
  • Step 5 2- ( (2S) -1-acryloyl-4- (6- (1, 2-dihydroacenaphthylen-1-yl) -2- ( (R) -1- (pyridin-4-yl) ethoxy) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
  • Example 15 2- ( (S) -1-acryloyl-4- (6- ( (S) -1, 2-dihydroacenaphthylen-1-yl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazin-2-yl) acetonitrile and 2- ( (S) -1-acryloyl-4- (6- ( (R) -1, 2-dihydroacenaphthylen-1-yl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
  • Step 1 Benzyl (2S) -2- (cyanomethyl) -4- (6- (1, 2-dihydroacenaphthylen-1-yl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazine-1-carboxylate
  • Step 2 2- ( (2S) -4- (6- (1, 2-dihydroacenaphthylen-1-yl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
  • Step 3 2- ( (S) -1-acryloyl-4- (6- ( (S) -1, 2-dihydroacenaphthylen-1-yl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazin-2-yl) acetonitrile and 2- ( (S) -1- acryloyl-4- (6- ( (R) -1, 2-dihydroacenaphthylen-1-yl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
  • Example 16 2- ( (S) -1-acryloyl-4- (6- ( (S) -1, 2-dihydroacenaphthylen-1-yl) -2- (3- (dimethylamino) azetidin-1-yl) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazin-2-yl) acetonitrile and 2- ( (S) -1-acryloyl-4- (6- ( (R) -1, 2-dihydroacenaphthylen-1-yl) -2- (3- (dimethylamino) azetidin-1-yl) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
  • Example 17 2- ( (S) -1-acryloyl-4- (6- ( (S) -1, 2-dihydroacenaphthylen-1-yl) -2- ( (1-methylpiperidin-4-yl) oxy) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazin-2-yl) acetonitrile and 2- ( (S) -1-acryloyl-4- (6- ( (R) -1, 2-dihydroacenaphthylen-1-yl) -2- ( (1-methylpiperidin-4-yl) oxy) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
  • Step 1 benzyl (S) -2- (cyanomethyl) -4- (2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6- (naphthalen-2-ylmethyl) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazine-1-carboxylate
  • Step 2 2- ( (S) -4- (2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6- (naphthalen-2-ylmethyl) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
  • Step 3 2- ( (S) -1-acryloyl-4- (2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6- (naphthalen-2-ylmethyl) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
  • Example 20 (8 mg, 14.4%) .
  • Step 1 Benzyl (S) -2- (cyanomethyl) -4- (6- ( (2, 3-dihydrobenzofuran-4-yl) methyl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazine-1-carboxylate
  • Step 2 2- ( (S) -4- (6- ( (2, 3-dihydrobenzofuran-4-yl) methyl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
  • Step 3 2- ( (S) -1-acryloyl-4- (6- ( (2, 3-dihydrobenzofuran-4-yl) methyl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
  • Step 1 benzyl (S) -2- (cyanomethyl) -4- (6- (2-fluoro-5-hydroxybenzyl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazine-1-carboxylate
  • Step 2 2- ( (S) -4- (6- (2-fluoro-5-hydroxybenzyl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
  • Step 3 2- ( (S) -1-acryloyl-4- (6- (2-fluoro-5-hydroxybenzyl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
  • Example 22 (4 mg, 6.1%) .
  • Step 1 benzyl (S) -2- (cyanomethyl) -4- (6- (2-fluoro-6-hydroxybenzyl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazine-1-carboxylate
  • Step 2 2- ( (S) -4- (6- (2-fluoro-6-hydroxybenzyl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
  • Step 3 2- ( (S) -1-acryloyl-4- (6- (2-fluoro-6-hydroxybenzyl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
  • Example 23 (10 mg, 4.1%) .
  • Step 1 Benzyl (S) -2- (cyanomethyl) -4- (6- ( (8-hydroxynaphthalen-1-yl) methyl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazine-1-carboxylate
  • Step 2 2- ( (S) -4- (6- ( (8-hydroxynaphthalen-1-yl) methyl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
  • Step 3 2- ( (S) -1-acryloyl-4- (6- ( (8-hydroxynaphthalen-1-yl) methyl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
  • Example 25 2- ( (S) -1-acryloyl-4- (6- ( (3-hydroxynaphthalen-1-yl) methyl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
  • Step 1 benzyl (S) -2- (cyanomethyl) -4- (2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6- (naphthalen-2-yl) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazine-1-carboxylate
  • Step 2 2- ( (S) -4- (2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6- (naphthalen-2-yl) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
  • Step 3 2- ( (S) -1-acryloyl-4- (2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6- (naphthalen-2-yl) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
  • Example 26 (3 mg, 2.7%) .
  • Step 1 benzyl (S) -2- (cyanomethyl) -4- (6- (2, 3-dihydro-1H-inden-4-yl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazine-1-carboxylate
  • 4-bromo-2, 3-dihydro-1H-indene 110 mg, 0.56 mmol
  • tris dibenzylideneacetone
  • Step 2 2- ( (S) -4- (6- (2, 3-dihydro-1H-inden-4-yl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
  • Step 3 2- ( (S) -1-acryloyl-4- (6- (2, 3-dihydro-1H-inden-4-yl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
  • Example 27 (11 mg, 15.2%) .
  • Example 28 2- ( (S) -1-acryloyl-4- (6- (8-methylnaphthalen-1-yl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
  • Step A benzyl (S) -2- (cyanomethyl) -4- (6- (3- (methoxymethoxy) -1-naphthoyl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazine-1-carboxylate
  • Step B 2- ( (S) -4- (6- (3- (methoxymethoxy) -1-naphthoyl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
  • Step C 2- ( (S) -1-acryloyl-4- (6- (3- (methoxymethoxy) -1-naphthoyl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
  • Step D 2- ( (S) -1-acryloyl-4- (6- (3-hydroxy-1-naphthoyl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
  • Step 1 benzyl (S) -4- (6- (8-chloro-1-naphthoyl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate
  • Step 2 2- ( (S) -4- (6- (8-chloro-1-naphthoyl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
  • Step 3 2- ( (S) -1-acryloyl-4- (6- (8-chloro-1-naphthoyl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
  • Example 30 (6.98 mg, 4.56 %) .
  • 1 H NMR 400 MHz, DMSO-d 6 ) ⁇ 8.23 –8.21 (m, 1H) , 8.15 –8.13 (m, 1H) , 7.82 –7.66 (m, 4H) , 6.95 –6.75 (m, 1H) , 6.29 –6.15 (m, 1H) , 5.88 –5.75 (m, 1H) , 5.11 –4.99 (m, 2H) , 4.71 –4.57 (m, 5H) , 4.23 –4.10 (m, 3H) , 3.84 –3.57 (m, 2H) , 3.03 –2.82 (m, 9H) , 2.24 –1.80 (m, 4H) .
  • MS (ESI) m/z [M+H] + 600.6.
  • Example 32 was prepared in the same manner from 1-naphthoic acid.
  • 1 H NMR 400 MHz, DMSO-d 6 ) ⁇ 8.06 –8.02 (m, 2H) , 7.86 –7.82 (m, 1H) , 7.62 –7.58 (m, 4H) , 6.86 –6.73 (m, 1H) , 6.23 –6.03 (m, 1H) , 5.81 –5.69 (m, 1H) , 5.16 –4.65 (m, 4H) , 4.44 –4.40 (m, 1H) , 4.18 –3.98 (m, 5H) , 3.85 –3.65 (m, 2H) , 3.06 –2.67 (m, 6H) , 2.30 –2.27 (m, 3H) , 1.67 –1.47 (m, 4H) .
  • MS (ESI) m/z [M+H] + 566.6.
  • Example 33 was prepared in the same manner from 8-methyl-1-naphthoic acid.
  • 1 H NMR 400 MHz, DMSO-d 6 ) ⁇ 8.11 –8.09 (m, 1H) , 7.96 –7.94 (m, 1H) , 7.54 –7.48 (m, 4H) , 6.92–6.72 (m, 1H) , 6.19 –6.15 (m, 1H) , 5.88 –5.75 (m, 1H) , 5.14 –4.87 (m, 3H) , 4.75 –4.56 (m, 4H) , 4.35 –4.08 (m, 3H) , 3.77 –3.61 (m, 2H) , 3.01 –2.85 (m, 9H) , 2.62 (s, 3H) , 2.24 –1.79 (m, 4H) .
  • MS (ESI) m/z [M+H] + 580.7.
  • Example 36 2- ( (S) -1-acryloyl-4- (6- (2-fluoro-6-hydroxybenzoyl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
  • Example 38 4- ( (S) -4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -N- (naphthalen-1-yl) -5, 7-dihydro-6H-pyrrolo [3, 4-d] pyrimidine-6-carboxamide
  • Step 1 phenyl naphthalen-1-ylcarbamate
  • Step 2 benzyl (S) -2- (cyanomethyl) -4- (2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6- (naphthalen-1-ylcarbamoyl) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazine-1-carboxylate
  • Step 3 4- ( (S) -3- (cyanomethyl) piperazin-1-yl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -N- (naphthalen-1-yl) -5, 7-dihydro-6H-pyrrolo [3, 4-d] pyrimidine-6-carboxamide
  • Step 4 4- ( (S) -4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -N- (naphthalen-1-yl) -5, 7-dihydro-6H-pyrrolo [3, 4-d] pyrimidine-6-carboxamide
  • Example 39 4- ( (S) -4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -N- (8-methylnaphthalen-1-yl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -5, 7-dihydro-6H-pyrrolo [3, 4-d] pyrimidine-6-carboxamide
  • Step 3 benzyl (S) -4- (6- (9H-fluoren-9-yl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate
  • Step 4 2- ( (S) -4- (6- (9H-fluoren-9-yl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
  • Step 5 2- ( (S) -4- (6- (9H-fluoren-9-yl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) -1-acryloylpiperazin-2-yl) acetonitrile
  • Example 40 (18 mg, 26.1%) .
  • Step 1 methyl 5-methyl-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-indazole-4-carboxylate
  • Step 2 (5-methyl-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-indazol-4-yl) methanol
  • Step 3 5-methyl-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-indazole-4-carbaldehyde
  • Step 4 benzyl (S) -2- (cyanomethyl) -4- (6- ( (5-methyl-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-indazol-4-yl) methyl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazine-1-carboxylate
  • Step 5 2- ( (S) -4- (6- ( (5-methyl-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-indazol-4-yl) methyl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
  • Step 6 2- ( (S) -4- (6- ( (5-methyl-1H-indazol-4-yl) methyl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
  • Step 7 2- ( (S) -1-acryloyl-4- (6- ( (5-methyl-1H-indazol-4-yl) methyl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
  • Example 41 (1.36 mg, 2.3%) .
  • Step 1 benzyl (S) -2- (cyanomethyl) -4- (6- ( (2-methoxynaphthalen-1-yl) methyl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazine-1-carboxylate
  • Step 2 2- ( (S) -4- (6- ( (2-hydroxynaphthalen-1-yl) methyl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
  • Step 3 1- ( (4- ( (S) -4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -5, 7-dihydro-6H-pyrrolo [3, 4-d] pyrimidin-6-yl) methyl) naphthalen-2-yl acrylate
  • Step 4 2- ( (S) -1-acryloyl-4- (6- ( (2-hydroxynaphthalen-1-yl) methyl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
  • Step 1 2- ( (S) -4- (2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
  • Step 2 2- ( (S) -1-acryloyl-4- (6-acryloyl-2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3, 4-d] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
  • Example 43 (4.71 mg, 9 %yield) .
  • 1 H NMR 400 MHz, CD 3 OD
  • Example F Biological assays
  • the KRAS (aa 1-169) G12C, C51S, C80L, C118S with a His-tag was expressed, purified and loaded with GDP in house. All protein and substrate solutions were prepared in assay buffer containing 25 mM HEPES pH7.5, 10 mM MgCl 2 , and 0.01%Triton X-100. Purified GDP-loaded KRAS (aa 1-169) G12C, C51S, C80L, C118S protein was pre-incubated with a serially diluted compound at 24°C for 3 hrs.
  • Purified SOS1 (aa 564-1049) protein, GTP ⁇ S (Sigma) and GST-cRaf RBD (aa 1-149) were then added to each well and incubated at 24 °C for additional 3 hrs. This addition initiates the nucleotide exchange reaction and transition of inactive GDP loaded KRAS G12C to active GTP ⁇ S KRAS G12C which binds to GST-cRaf RBD. Following the incubation, Mab Anti-6HIS-Tb cryptate (Cisbio) and Mab Anti GST-XL665 (Cisbio) were added and further incubated at 24 °C for 3 hrs.
  • the inhibition percentage of nucleotide exchange reaction in presence of increasing concentrations of compounds was calculated based on the ratio of fluorescence at 665 nm to that at 620 nm detected on a BMG PHERAstar FSX instrument.
  • the IC 50 value of each compound was calculated from fitting the data to the four-parameter logistic model by Dotmatics.
  • Example No. IC 50 (nM) Example No. IC 50 (nM) 1 3280 29 2.42 2 46000 30 15 3 23700 31 301 5 56.1 32 39.5 6 27.7 33 22.4 7 174 34 505 8 495 35 256 9 265 36 238 10 415 37 27.9 11 170 38 1570 12 379 40 1510 15 492 (P1) ; 5.27 (P2) 41 77.2 16 5650 (P1) ; 256 (P2) 42 9980 17 2200 (P1) ; 949 (P2) 44 9010 18 1560 45 12.6 19 976 46 172 20 2880 47 102 21 92.5 50 6.16 22 9.63 51 16.1 23 28.1 52 8.51 24 101 53 14.9 25 3.27 54 639 26 1080 55 ⁇ 5.1 27 3720 56 941 28 178

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Abstract

L'invention concerne un procédé de préparation de composés qui inhibent KRas G12C.
PCT/CN2020/118666 2020-09-29 2020-09-29 Procédé de préparation d'inhibiteurs de kras g12c WO2022067462A1 (fr)

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CN115583937A (zh) * 2022-11-21 2023-01-10 北京志道生物科技有限公司 以吲哚或氮杂吲哚为母核的kras抑制剂及其制备方法
US11845761B2 (en) 2020-12-18 2023-12-19 Erasca, Inc. Tricyclic pyridones and pyrimidones

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WO2007146122A2 (fr) * 2006-06-09 2007-12-21 Neurogen Corporation Tétrahydropyrido[3,4-d]pyrimidines et analogues associés
WO2008136756A1 (fr) * 2007-05-08 2008-11-13 Astrazeneca Ab Dérivés de pyrrolopyrimidin-7-one et leur utilisation comme produits pharmaceutiques
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11845761B2 (en) 2020-12-18 2023-12-19 Erasca, Inc. Tricyclic pyridones and pyrimidones
CN115583937A (zh) * 2022-11-21 2023-01-10 北京志道生物科技有限公司 以吲哚或氮杂吲哚为母核的kras抑制剂及其制备方法

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