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EP4605089A1 - Composés utiles dans la modulation de egfr et pi3k - Google Patents

Composés utiles dans la modulation de egfr et pi3k

Info

Publication number
EP4605089A1
EP4605089A1 EP23813109.8A EP23813109A EP4605089A1 EP 4605089 A1 EP4605089 A1 EP 4605089A1 EP 23813109 A EP23813109 A EP 23813109A EP 4605089 A1 EP4605089 A1 EP 4605089A1
Authority
EP
European Patent Office
Prior art keywords
compound
alkyl
ring
mmol
name structure
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.)
Pending
Application number
EP23813109.8A
Other languages
German (de)
English (en)
Inventor
Christopher E. Whitehead
Judith S. LEOPOLD
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.)
Mekanistic Therapeutics LLC
Original Assignee
Mekanistic Therapeutics LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Mekanistic Therapeutics LLC filed Critical Mekanistic Therapeutics LLC
Publication of EP4605089A1 publication Critical patent/EP4605089A1/fr
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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

  • the present disclosure relates to the field of medicinal chemistry.
  • the disclosure relates to a new class of small-molecules having a quinazoline structure or a quinoline structure which function as dual inhibitors of EGFR proteins and PI3K proteins.
  • the disclosure further relates to their use as therapeutics for the treatment of EGFR and/or PI3K mediated diseases or conditions.
  • the disclosure further relates to their use as therapeutics for the treatment of EGFR and/or PI3K mediated diseases or conditions of the central nervous system, which require therapeutics that can penetrate the blood brain barrier.
  • GBM Glioblastoma
  • TCGA Cancer Genome Atlas
  • RTK receptor tyrosine kinase
  • PI3K pathway signaling PI3K pathway signaling.
  • Roughly 66% of GBMs have alterations in both of these classes of signaling defects.
  • Aberrations of EGFR are the most prevalent among RTKs occurring in more than half of GBMs. Alterations in EGFR include amplification, overexpression, and EGFRvIII mutations.
  • EGFR is the most overexpressed RTK in GBM
  • other RTKs can compensate for impaired EGFR signaling.
  • PTEN or PI3K mutations can lead to EGFR pathway activation independent of the EGFR receptor.
  • Mellinghoff et al. showed that the EGFR targeting agents erlotinib and gefitinib only showed benefit in cases where expression of EGFR and wild-type PTEN was high.
  • Haas-Kogan et al. also demonstrated that response to erlotinib in GBM was dependent on high expression of EGFR and low expression of activated AKT.
  • the use of PI3K pathway inhibitors has also not resulted in significant clinical activity against GBM, leading to the combination of PI3K pathway inhibitors with other targeted agents.
  • the ensuing increased ‘leakiness’ provides an opportunity for partitioning of drug molecules into the tumor leading to therapeutic activity. Due to the disseminated nature of GBM, tumor regressions have little effect on overall survival.
  • Drugs like erlotinib and gefitinib are unable to penetrate parts of the brain with functional BBB because they are actively effluxed out of the brain by drug resistance transporters, such as p- glycoprotein (Pgp) and breast cancer resistance protein (BRCP).
  • Pgp p- glycoprotein
  • BRCP breast cancer resistance protein
  • the present disclosure identifies novel small molecule compounds capable of dual targeting of EGFR and PI3K pathways.
  • the compounds of the present disclosure are effective inhibitors of EGFR and PI3K molecules, and are useful for treatment of brain cancers, since the disclosed compounds can penetrate the blood-brain barrier (BBB) in humans and other mammals.
  • BBB blood-brain barrier
  • the present disclosure addresses the need for improved methods for treating cancers associated with aberrant EGFR and PI3K pathway signaling. Indeed, experiments conducted during the course of developing embodiments for the present disclosure designed a new class of potent small-molecules capable of dual targeting of EGFR and PI3K pathways that can penetrate the blood-brain barrier.
  • the present disclosure provides a new class of small-molecules capable of dual targeting of EGFR and PI3K pathways that can penetrate the blood-brain barrier, and their use as therapeutics for the treatment of cancer and other diseases.
  • combination treatment of animals with a therapeutically effective amount of a compound of the present disclosure and a course of an anti cancer agent produces a greater tumor response and clinical benefit in such animals compared to those treated with the compound or anticancer drugs/radiation alone. Since the doses for all approved anticancer drugs and radiation treatments are known, the present disclosure contemplates the various combinations of them with the present compounds.
  • a heterocycloalkyl group can be optionally substituted with one or more substituents such as phospho, aliphatic [e.g., alkyl, alkenyl, or alkynyl], cycloaliphatic, (cycloaliphatic)aliphatic, heterocycloaliphatic, (heterocycloaliphatic)aliphatic, aryl, heteroaryl, alkoxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy, aryloxy, heteroaryl oxy, (araliphatic)oxy, (heteroaraliphatic)oxy, aroyl, heteroaroyl, amino, amido [e.g., (aliphatic)carbonylamino, (cycloaliphatic)carbonylamino, ((cycloaliphatic) aliphatic)carbonylamino, (aryl)carbonylamino, (araliphatic)carbonylamino, (heterocycloaliphatic)carbonyl
  • heterocyclyl group is the same as a “heterocycloalkyl” group, with the exception that a heterocyclyl group can be partially unsaturated, but not aromatic.
  • monocyclic heteroaryls include furyl, thiophene-yl, 2H-pyrrolyl, pyrrolyl, oxazolyl, thazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,3,4-thiadiazolyl, 2H-pyranyl, 4-H-pranyl, pyridyl, pyridazyl, pyrimidyl, pyrazolyl, pyrazyl, or 1,3,5-triazyl.
  • Monocyclic heteroaryls are numbered according to standard chemical nomenclature.
  • heterocycloaliphatic oxy; aryloxy; heteroaryl oxy; (araliphatic)oxy; (heteroaraliphatic)oxy; aroyl; heteroaroyl; amino; oxo (on a non-aromatic carbocyclic or heterocyclic ring of a bicyclic or tricyclic heteroaryl); carboxy; amido; acyl [ e.g., aliphaticcarbonyl; (cycloaliphatic)carbonyl; ((cycloaliphatic)aliphatic)carbonyl; (araliphatic)carbonyl; (heterocycloaliphatic)carbonyl;
  • heterocycloaliphatic aliphatic
  • carbonyl or (heteroaraliphatic)carbonyl]
  • sulfonyl e.g., aliphaticsulfonyl or aminosulfonyl
  • sulfinyl e.g., aliphaticsulfinyl
  • sulfanyl e.g., aliphaticsulfanyl
  • a heteroaryl can be unsubstituted.
  • cyclic moiety and “cyclic group” refer to mono-, bi-, and tri-cyclic ring systems including cycloaliphatic, heterocycloaliphatic, aryl, or heteroaryl, each of which has been previously defined.
  • an "alkoxy” group refers to an alkyl -O- group where "alkyl” has been defined previously.
  • haloalkyl refers to an alkyl group substituted with 1-3 halogen.
  • haloalkyl includes the group -CF3.
  • each of the specific groups for the variables R 1 , X, L, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 and other variables contained therein can be optionally substituted with one or more substituents described herein.
  • Each substituent of a specific group is further optionally substituted with one to three of halo, cyano, oxo, alkoxy, hydroxy, amino, nitro, aryl, cycloaliphatic, heterocycloaliphatic, heteroaryl, haloalkyl, and alkyl.
  • an alkyl group can be substituted with alkylsulfanyl and the alkylsulfanyl can be optionally substituted with one to three of halo, cyano, oxo, alkoxy, hydroxy, amino, nitro, aryl, haloalkyl, and alkyl.
  • the cycloalkyl portion of a (cycloalkyl)carbonylamino can be optionally substituted with one to three of halo, cyano, alkoxy, hydroxy, nitro, haloalkyl, and alkyl.
  • substituted refers generally to the replacement of hydrogen atoms in a given structure with the radical of a specified substituent. Specific substituents are described above in the definitions and below in the description of compounds and examples thereof. Unless otherwise indicated, an optionally substituted group can have a substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted with more than one substituent selected from a specified group, the substituent can be either the same or different at every position.
  • a ring substituent such as a heterocycloalkyl
  • substituents envisioned by this disclosure are those combinations that result in the formation of stable or chemically feasible compounds.
  • stable or chemically feasible refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein.
  • a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40 °C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
  • structures depicted herein also are meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the disclosure. Unless otherwise stated, all tautomeric forms of the compounds of the disclosure are within the scope of the invention.
  • Common prodrugs include acid derivatives such as esters prepared by reaction of parent acids with a suitable alcohol (e.g., a lower alkanol) or esters prepared by reaction of parent alcohol with a suitable carboxylic acid, (e.g., an amino acid), amides prepared by reaction of the parent acid compound with an amine, basic groups reacted to form an acylated base derivative (e.g., a lower alkylamide), or phosphorus-containing derivatives, e.g., phosphate, phosphonate, and phosphoramidate esters, including cyclic phosphate, phosphonate, and phosphoramidate (see, e g., US Patent Application Publication No. US 2007/0249564 Al; herein incorporated by reference in its entirety).
  • a suitable alcohol e.g., a lower alkanol
  • Y is selected from N or CH;
  • R 1 is selected from C1-6 alkyl, halo, CN, OR’, and NR’2, wherein each C1-6 alkyl is optionally and independently substituted with one or more R” substituents;
  • R 2 is selected from hydrogen, halo, CN, C 1-6 alkyl, C 3-7 cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl, wherein each C1-6 alkyl, C3-7 cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl are optionally and independently substituted with one or more R” substituents;
  • Ring A is a phenyl, a 6-membered heterocyclyl, or a 6-membered heteroaryl, optionally substituted with one or more R 3 substituents, or Ring A is a bicyclic moiety selected from Formulas W1 – W4:
  • each R 3 is selected from halo, oxo, NH2, CF3, CH3, OCH3, O(CH 2 ) 3 N(CH 3 ) 2 OCF 3 , OCHF 2 , OH, CN, NHS(O) 2 CH 3 , S(O) 2 CH 3 , C(O)H, C(O)OH, C(CH3)2OH, C(O)CH3, C(O)CF3, C(O)CH2CH3, CH(OH)CH2CH3, CH2OH, C(O)NH2, C(O)NH(CH3), C(O)OH, C(O)NH(CH2CH3), C(O)NH(CH(CH3)2), C(O)NH(C(CH3)3), C(O)N(CH 3 ) 2 , C(O)NH(CN), C(O)NOH(CH 3 ), C(O)OCH 3 , C(O)NHCN, C(O)N(CH 3 )OH, 4- methyl
  • each R 4 is independently selected from halo, OH, CN, oxo, C1-6 alkyl, OC1-6 alkyl, and NH2, wherein each alkyl, is optionally and independently substituted with one or more R’ substituents. [0086] In a further embodiment, each R 4 is independently selected from halo and C1-6 alkyl.
  • Ring B and Ring B’ together make a fused bicyclic heteroaryl ring system, optionally substituted with one or more instances of R 4 , wherein Ring B is a 5 membered heterocyclyl or a 5 membered heteroaryl, and Ring B’ is a fused phenyl ring or a fused pyridyl ring.
  • Ring B and Ring B’ together make a fused bicyclic heteroaryl ring system, optionally substituted with one or more instances of R 4 , wherein Ring B is a 5 membered heterocyclyl or a 5 membered heteroaryl, and Ring B’ is a fused phenyl ring.
  • Ring B and Ring B’ together make a fused bicyclic heteroaryl ring system, optionally substituted with one or more instances of R 4 , wherein Ring B is a 5 membered heterocyclyl, and Ring B’ is a fused phenyl ring.
  • Ring B and Ring B’ together form a bicyclic moiety selected , halo, CN, or C 1-6 alkyl.
  • X 1 is selected from N or C-CN.
  • Y is CH.
  • the compound is a compound of Formula Ia: ormu a a wherein, each X 3 is independently N or CH, wherein the CH can be independently substituted by R 3 ; and m and p are each independently 0, 1, 2, or 3.
  • at least two X 3 substituents are CH.
  • at least one X 3 substituent is N.
  • X 1 is N.
  • the compound is a compound of Formula Ib: wherein, each X 3 is independently N or CH, wherein the CH can be independently substituted by R 3 ; and m and p are each independently 0, 1, 2, or 3.
  • At least one X 3 substituent is N.
  • both X 3 substituents are N.
  • each R 3 is independently selected from halo, oxo, NH2, CF3, CH3, OCH3, OH, CN, and CH2OH.
  • m is 0 or 1.
  • each R 4 is independently selected from halo and C 1-6 alkyl.
  • m is 0, 1, or 2.
  • Ring A is selected from , , , compound of Formula Ic: wherein, X 1 is N or C-CN; R 4’ is selected from hydrogen or halogen; R 4” is halogen; R 5 is selected from hydrogen, NH2, halo, C1-4 alkyl, and C1-4 alkoxy; and X 3 is N or CR 6 , wherein R 6 is selected from hydroxy, C(O)OR’, C(O)N(R’)2, (C1-6 alkyl)SO 2 , and (C 1-6 alkyl)SO 2 N(R’). [00106] In one embodiment of this aspect, R 4’ is selected from hydrogen or fluoro. [00107] In another embodiment, R 4” is chloro.
  • R 5 is selected from hydrogen, NH 2 , chloro, and methoxy.
  • R 6 is selected from hydroxy, C(O)N(CH3)2, and CH3SO2N(R’).
  • the compound is a compound of Formula IIa: wherein, Ring A is a bicyclic moiety selected from Formula W1, W2, W3, and W4; 4 wherein each of Formula W1 –W4 are each optionally and independently substituted with one or more R 3 substituents; , , Cmpd Name Structure Cmpd Name Structure Cmpd Name Structure Cmpd Name Structure Cmpd Name Structure Cmpd Name Structure Cmpd Name Structure Cmpd Name Structure Cmpd Name Structure Cmpd Name Structure Cmpd Name Structure Cmpd Name Structure Cmpd Name Structure Cmpd Name Structure Cmpd Name Structure Cmpd Name Structure Cmpd Name Structure Cmpd Name Structure Cmpd Name Structure Cmpd Name Structure Cmpd Name Structure Cmpd Name Structure Cmpd Name Structure Cmpd Name Structure Cmpd Name Structure Cmpd Name Structure Cmp
  • the disclosure includes a method of treating, ameliorating, or preventing a EGFR and/or PI3K mediated disease or condition in a patient, comprising administering to said patient a therapeutically effective amount of a compound, or salt or pharmaceutical composition thereof.
  • EGFR and/or PI3K mediated disease or condition is a hyperproliferative disease or condition.
  • said disease or condition is cancer.
  • said cancer is glioblastoma or glioblastoma multiform.
  • said patient is a human patient.
  • said compound crosses the blood brain barrier (BBB) in vivo.
  • BBB blood brain barrier
  • the method further comprises administering to said patient one or more anticancer agents.
  • said anticancer agent is a chemotherapeutic agent.
  • said anticancer agent is radiation therapy.
  • the disclosure includes a kit comprising a compound described herein, or salt or pharmaceutical composition thereof, and instructions for administering said compound to a patient having a EGFR and/or PI3K mediated disease or condition.
  • said condition is cancer.
  • said cancer is glioblastoma or glioblastoma multiform.
  • the compound has an in vivo half-life of at least about 30 minutes.
  • a compound of the invention is relatively stable in the presence of mouse liver microsomes (MLM).
  • MLM mouse liver microsomes
  • a compound of the invention has a long half-life in the presence of MLM.
  • the compound has a half- life of at least about 5 minutes in the presence of MLM.
  • the compound has a half-life of at least about 10 minutes in the presence of MLM.
  • the compound has a half-life of at least about 15 minutes in the presence of MLM.
  • the compound has a half-life of at least about 25 minutes in the presence of MLM.
  • the compound has a half-life of at least about 30 minutes in the presence of MLM.
  • a compound of the invention is relatively stable in the presence of human liver microsomes (HLM).
  • HLM human liver microsomes
  • a compound of the invention has a long half-life in the presence of HLM.
  • the compound has a half- life of at least about 5 minutes in the presence of HLM.
  • the compound has a half-life of at least about 10 minutes in the presence of HLM.
  • the compound has a half-life of at least about 15 minutes in the presence of HLM.
  • the compound has a half-life of at least about 25 minutes in the presence of HLM.
  • compositions of this disclosure comprise a therapeutically effective amount of a compound of Formula I, wherein a "therapeutically effective amount" is an amount that is (a) effective to measurably modulate EGFR and/or PI3K in a biological sample or in a patient, or (b) effective in treating and/or ameliorating a disease or disorder that is mediated by EGFR and/or PI3K.
  • the term "pharmaceutically acceptable salt” refers to those salts that are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference.
  • Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate,
  • Some examples of materials that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as twin 80, phosphates, glycine, sorbic acid, or potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, or zinc salts), colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, methylcellulose, hydroxypropyl methylcellulose, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzy
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i
  • the dosage form also may comprise buffering agents.
  • Solid compositions of a similar type also may be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art.
  • Solid dosage forms optionally may contain opacifying agents.
  • These solid dosage forms also can be of a composition such that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • embedding compositions examples include polymeric substances and waxes.
  • Solid compositions of a similar type also may be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
  • the active compounds also can be in micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • inert diluent such as sucrose, lactose or starch.
  • Such dosage forms also may comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms also may comprise buffering agents. They may optionally contain opacifying agents and also can be of a composition such that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • Absorption enhancers also can be used to increase the flux of the compound across the skin.
  • the rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • the compounds of the disclosure preferably are formulated in dosage unit form for ease of administration and uniformity of dosage.
  • dosage unit form refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present disclosure will be decided by the attending physician within the scope of sound medical judgment.
  • the specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts.
  • the amount of the compounds of the present disclosure that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration, and other factors.
  • anticancer agents such as: agents that induce apoptosis; polynucleotides (e.g., anti-sense, ribozymes, siRNA); polypeptides (e.g., enzymes and antibodies); biological mimetics; alkaloids; alkylating agents; antitumor antibiotics; antimetabolites; hormones; platinum compounds; monoclonal or polyclonal antibodies (e.g., antibodies conjugated with anticancer drugs, toxins, defensins), toxins; radionuclides; biological response modifiers (e.g., interferons (e.g., IFN- ⁇ ) and interleukins (e.g., IL-2)); adoptive immunotherapy agents; hematopoietic growth factors; agents that induce tumor cell differentiation (e.g., all-trans-retinoic acid); gene therapy reagents (e.g., antisense therapy reagents and nucleo
  • anticancer agents comprise agents that induce or stimulate apoptosis.
  • Agents that induce apoptosis include, but are not limited to, radiation (e.g., X-rays, gamma rays, UV); tumor necrosis factor (TNF)-related factors (e.g., TNF family receptor proteins, TNF family ligands, TRAIL, antibodies to TRAIL-R1 or TRAIL-R2); kinase inhibitors (e.g., epidermal growth factor receptor (EGFR) kinase inhibitor, vascular growth factor receptor (VGFR) kinase inhibitor, fibroblast growth factor receptor (FGFR) kinase inhibitor, platelet-derived growth factor receptor (PDGFR) kinase inhibitor, and Bcr-Abl kinase inhibitors (such as GLEEV
  • compositions and methods of the present disclosure provide a compound of the disclosure and at least one anti-hyperproliferative or antineoplastic agent selected from alkylating agents, antimetabolites, and natural products (e.g., herbs and other plant and/or animal derived compounds).
  • at least one anti-hyperproliferative or antineoplastic agent selected from alkylating agents, antimetabolites, and natural products (e.g., herbs and other plant and/or animal derived compounds).
  • chemotherapeutic agents suitable for use in the compositions and methods of the present disclosure include, but are not limited to: 1) vinca alkaloids (e.g., vinblastine (VLB), vincristine); 2) epipodophyllotoxins (e.g., etoposide and teniposide); 3) antibiotics (e.g., dactinomycin (actinomycin D), daunorubicin (daunomycin; rubidomycin), doxorubicin, bleomycin, plicamycin (mithramycin), and mitomycin (mitomycin C)); 4) enzymes (e.g., L-asparaginase); 5) biological response modifiers (e.g., interferon-alfa); 6) platinum coordinating complexes (e.g., cisplatin (cis-DDP) and carboplatin); 7) anthracenediones (e.g., mitoxantrone
  • vinca alkaloids e
  • chemotherapeutic agents include, but are not limited to, PI3K inhibitors (e.g., idelalisib and copanlisib), BCL-2 inhibitors (e.g., venetoclax), BTK inhibitors (e.g., ibrutinib and acalabrutinib), etoposide, CD20 antibodies (e.g., rituximab, ocrelizumab, obinutuzumab, ofatumumab, ibritumomab tiuxetan, tositumomab, and ublituximab), aletuzumab, bendamustine, cladribine, doxorubicin, chlorambucil, prednisone, midostaurin, lenalidomide, pomalidomide, checkpoint inhibitors (e.g., ipilimumab, nivolumab, pemboliz
  • Anticancer agents further include compounds which have been identified to have anticancer activity.
  • Examples include, but are not limited to, 3-AP, 12-O-tetradecanoylphorbol- 13-acetate, 17AAG, 852A, ABI-007, ABR-217620, ABT-751, ADI-PEG 20, AE-941, AG- 013736, AGRO100, alanosine, AMG 706, antibody G250, antineoplastons, AP23573, apaziquone, APC8015, atiprimod, ATN-161, atrasenten, azacitidine, BB-10901, BCX-1777, bevacizumab, BG00001, bicalutamide, BMS 247550, bortezomib, bryostatin-1, buserelin, calcitriol, CCI-779, CDB-2914, cefixime, cetuximab, CG0070, cilengitide, clofarabine, combretastatin A4 phosphate, CP-675,206, CP-7
  • the present disclosure relates to a new class of small-molecules having a quinazoline structure or quinoline structure which function as dual inhibitors of EGFR protein and PI3K protein, and their use as therapeutics for the treatment of conditions characterized by aberrant EGFR and PI3K expression (e.g., cancer and other diseases (e.g., autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, allergy, asthma, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, sperm motility, transplantation rejection, graft rejection, lung injuries, etc)).
  • cancer and other diseases e.g., autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, allergy, asthma, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, sperm motility, transplantation rejection, graft rejection, lung injuries, etc.
  • quinazoline compounds and quinoline compounds function as inhibitors of both EGFR and PI3K, and serve as therapeutics for the treatment of cancer and other diseases.
  • the present disclosure relates to quinazoline compounds and quinoline compounds useful for inhibiting EGFR and PI3K activity (e.g., thereby facilitating cell apoptosis), and increasing the sensitivity of cells to inducers of apoptosis and/or cell cycle arrest.
  • Certain quinazoline compounds and quinoline compounds of the present disclosure may exist as stereoisomers including optical isomers.
  • the disclosure also relates to the use of compounds for sensitizing cells to additional agent(s), such as inducers of apoptosis and/or cell cycle arrest, and chemoprotection of normal cells through the induction of cell cycle arrest prior to treatment with chemotherapeutic agents.
  • additional agent(s) such as inducers of apoptosis and/or cell cycle arrest, and chemoprotection of normal cells through the induction of cell cycle arrest prior to treatment with chemotherapeutic agents.
  • the compounds of the disclosure are useful for the treatment, amelioration, or prevention of disorders, such as those responsive to induction of apoptotic cell death, e.g., disorders characterized by dysregulation of apoptosis, including hyperproliferative diseases such as cancer characterized with cells aberrant EGFR protein activity (e.g., ERBB1) and PI3K protein activity (e.g., PI3K ⁇ ) (e.g., colorectal cancer).
  • EGFR protein activity e.
  • Buck et al demonstrated that the mTOR inhibitor rapamycin synergizes with the EGFR inhibitor erlotinib in several cell lines that were resistant to erlotinib treatment alone (e.g., Ratushny V, et al., Cell Signal.2009;21: 1255-1268).
  • Ratushny V et al.
  • Cell Signal.2009;21: 1255-1268 the full potential of this synergistic combination was not achieved because rapamycin induces phosphorylation of AKT resulting in pathway reactivation (e.g., Ratushny V, et al., Cell Signal.2009;21: 1255-1268).
  • An important aspect of the present disclosure is that compounds of the disclosure induce cell cycle arrest and/or apoptosis and also potentiate the induction of cell cycle arrest and/or apoptosis either alone or in response to additional apoptosis induction signals. Therefore, it is contemplated that these compounds sensitize cells to induction of cell cycle arrest and/or apoptosis, including cells that are resistant to such inducing stimuli.
  • the EGFR and PI3K inhibitors of the present disclosure e.g., quinazoline compounds
  • quinoline compounds can be used to induce apoptosis in any disorder that can be treated, ameliorated, or prevented by the induction of apoptosis.
  • a non-limiting exemplary list of these diseases and conditions includes, but is not limited to, colorectal cancer, non-small cell lung carcinoma, head or neck carcinoma, glioblastoma multiform cancer, pancreatic cancer, breast cancer, prostate cancer, lymphoma, skin cancer, colon cancer, melanoma, malignant melanoma, ovarian cancer, brain cancer, primary brain carcinoma, head–neck cancer, glioma, glioblastoma, liver cancer, bladder cancer, non-small cell lung cancer, , breast carcinoma, ovarian carcinoma, lung carcinoma, small-cell lung carcinoma, Wilms' tumor, cervical carcinoma, testicular carcinoma, bladder carcinoma, pancreatic carcinoma, stomach carcinoma, colon carcinoma, prostatic carcinoma, genitourinary carcinoma, thyroid carcinoma, esophageal carcinoma, myeloma, multiple myeloma, adrenal carcinoma, renal cell carcinoma, endometrial carcinoma, adrenal cortex carcinoma, malignant pancreatic insulinoma, malignant carcinoid carcinoma, choriocar
  • Radiosensitizers enhance the killing of tumor cells. Radioprotectors protect healthy tissue from the harmful effects of radiation.
  • Any type of radiation can be administered to a patient, so long as the dose of radiation is tolerated by the patient without unacceptable negative side-effects.
  • Suitable types of radiotherapy include, for example, ionizing (electromagnetic) radiotherapy (e.g., X-rays or gamma rays) or particle beam radiation therapy (e.g., high linear energy radiation).
  • Ionizing radiation is defined as radiation comprising particles or photons that have sufficient energy to produce ionization, i.e., gain or loss of electrons (as described in, for example, U.S.5,770,581 incorporated herein by reference in its entirety).
  • compositions within the scope of this disclosure include all compositions wherein the compounds of the present disclosure are contained in an amount which is effective to achieve its intended purpose. While individual needs vary, determination of optimal ranges of effective amounts of each component is within the skill of the art.
  • the compounds may be administered to mammals, e.g. humans, orally at a dose of 0.0025 to 50 mg/kg, or an equivalent amount of the pharmaceutically acceptable salt thereof, per day of the body weight of the mammal being treated for disorders responsive to induction of apoptosis. In one embodiment, about 0.01 to about 25 mg/kg is orally administered to treat, ameliorate, or prevent such disorders. For intramuscular injection, the dose is generally about one-half of the oral dose.
  • Example 9 Synthesis of (4-(6-chloroindolin-1-yl)-6-(1H-pyrazolo[3,4- b]pyridin-5-yl)quinoline-3-carbonitrile), Compound 9 [00243] Step 1: Synthesis of 6-bromo-4-(6-chloroindolin-1-yl)quinoline-3-carbonitrile (2c) [002 ] o a st rre so ut on o ( mg, . mmo ) n , - oxane ( .
  • Example 15 Synthesis of 4-(6-chloroindolin-1-yl)-6-(5-methoxypyridin-3- yl)quinazoline, Compound 15 [00266] To a stirred solution of 1c (200 mg, 0.55 mmol) in 1,4 dioxane (5.00 mL) placed in a microwave vial, were added 3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridine (155 mg, 0.66 mmol), and a solution of Cs2CO3 (543 mg, 1.67 mmol) in H2O (1.00 mL) at rt, the mixture was de-gassed with Ar(g) for 10 min.
  • Example 25 Synthesis of 5-(4-(6-chloroindolin-1-yl)quinazolin-6- yl)nicotinaldehyde, Compound 25 [00286] To a stirred solution of 1m (200 mg, 0.49 mmol) in 1,4 dioxane (5.00 mL) placed in microwave vial, was added 5-bromonicotinaldehyde (91.3 mg, 0.49 mmol), a solution of Cs2CO3 (478.9 mg, 1.47 mmol) in H2O (1.00 mL) at rt, and the mixture was de-gassed with Ar(g) for 10 min.
  • Example 26 Synthesis of 5-(4-(6-chloroindolin-1-yl)quinazolin-6- yl)pyrimidin-2-ol, Compound 26 [00288] To a stirred solution of 1m (230 mg, 0.56 mmol) in 1,4 dioxane (5.00 mL) placed in microwave vial, was added 5-bromopyrimidin-2-ol(98.9 mg, 0.56 mmol), a solution of Cs 2 CO 3 (551 mg, 1.69 mmol) in H 2 O (1.00 mL) at rt, and the mixture was de-gassed with Ar(g) for 10 min.
  • Example 28 Synthesis of 4-(6-chloroindolin-1-yl)-6-(1H-pyrazolo[4,3- b]pyridin-6-yl)quinazoline, Compound 28 [0029 L) placed in microwave vial, was added 6-bromo-1H-pyrazolo[4,3-b]pyridine (99.6 mg, 0.56 mmol), a solution of Cs 2 CO 3 (493 mg, 1.51 mmol) in H 2 O (1.00 mL) at rt, and the mixture was de-gassed with Ar(g) for 10 min.
  • Pd(dppf)Cl2 ⁇ CH2Cl2 (0.43 g, 0.35 mmol) was added in one lot, the vial was sealed. and the mixture was stirred at 100 °C for 2 h.
  • the reaction mixture was diluted with EtOAc (100 mL), washed with water (100 mL), brine (100 mL), dried over anhydrous Na 2 SO 4, filtered and concentrated under vacuum to obtain crude product.
  • the crude product was purified by silica gel chromatography using 40% EtOAc in hexane.
  • Example 35 Synthesis of 6-(4-(6-chloro-5-fluoroindolin-1-yl)quinazolin-6- yl)oxazolo[4,5-b]pyridin-2(3H)-one, Compound 35 [0 ed in a sealed tube, under N2 atmosphere at rt, was added 6-bromooxazolo[4,5-b]pyridin-2(3H)-one ( 0.074 g, 0.34 mmol), a solution of Cs2CO3 (0.22 g, 0.69 mmol) in H2O (1.00 mL) at rt, and the mixture was de-gassed with Ar (g) for 10 min.
  • Example 36 Synthesis of 6-(1H-benzo[d][1,2,3]triazol-5-yl)-4-(6-chloro-5- fluoroindolin-1-yl)quinazoline, Compound 36 [00311] To a stirred solution of 1n (0.20 g, 0.47 mmol) in 1,4 dioxane (10.0 mL), placed in a sealed tube, under N2 atmosphere at rt, was added 5-bromo-1H-benzo[d][1,2,3]triazole (0.14 g, 0.70 mmol), a solution of Cs 2 CO 3 (0.45 g, 1.41 mmol) in H 2 O (2.00 mL) at rt, and the mixture was de-gassed with Ar (g) for 10 min.
  • Pd(dppf)Cl2 ⁇ CH2Cl2 (0.026 g, 0.03 mmol) was added in one lot, and the reaction mixture was heated to 120 °C for 16 h. The reaction mixture was cooled to rt and then concentrated under vaccum to obtain the crude product.
  • Example 38 Synthesis of 6-(4-(6-chloro-5-fluoroindolin-1-yl)quinazolin-6-yl)- 1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one, Compound 38 [0 o a s e so u o o . g, . o , o a e .
  • the reaction mixture was diluted with water (100 mL) and extracted with CH2Cl2 (2 ⁇ 20 mL), washed with sat. NaHCO3 (50 mL) and brine (50 mL). The organic layer was dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to afford the crude product.
  • the crude product was purified by silica gel chromatography using 10% methanol in CH 2 Cl 2 . The fractions containing the product were combined and concentrated under vacuum to obtain (5-bromopyridin-3-yl)(4-methylpiperazin-1-yl)methanone, 1q, (0.25 g, 35% yield) as a pale yellow liquid.
  • Step 2 Synthesis of (5-(4-(6-chloro-5-fluoroindolin-1-yl)quinazolin-6- yl)pyridin-3-yl)(4-methylpiperazin-1-yl)methanone (Compound 39): [00320] To a stirred solution of 1q (0.25 g, 0.88 mmol) in 1,4 dioxane (10.0 mL), placed in sealed tube, under N2 atmosphere at rt, was added 1n (0.25 g, 0.58 mmol), a solution of Cs 2 CO 3 (0.56 g, 1.74 mmol) in H 2 O (2.00 mL) at rt, and the mixture was de-gassed with Ar (g) for 10 min.
  • Pd(dppf)Cl2 ⁇ CH2Cl2 (0.033 g, 0.04 mmol) was added in one lot, and the reaction mixture was heated to 120 °C for 16 h. The reaction mixture was cooled to rt and then concentrated under vaccum to obtain the crude product.
  • Example 40 Synthesis of (2-amino-5-(4-(6-chloro-5-fluoroindolin-1- yl)quinazolin-6-yl)pyridin-3-yl)(4-methylpiperazin-1-yl)methanone, Compound 40 [00322] Step 1: Preparation of (2-amino-5-bromopyridin-3-yl)(4-methylpiperazin-1- yl)methanone (1s): [00323] To a stirred solution of 1r (0.50g, 2.31 mmol) in DMF (10.0 mL), at rt, was added 1p (0.25 mL, 2.54 mmol), HOBt (0.46 g, 3.46 mmol), EDC•HCl (0.66 g, 3.46 mmol) followed by i-Pr 2 EtN (0.98mL, 7.41 mmol).
  • the reaction mixture was stirred at rt for 16h.
  • the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 ⁇ 20 mL), washed with sat. NaHCO3 (50 mL) and brine (50 mL).
  • the organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the crude product.
  • the crude product was purified by silica gel chromatography using 10% methanol in DCM. The fractions containing the product were combined and concentrated under vacuum to obtain (2- amino-5-bromopyridin-3-yl)(4-methylpiperazin-1-yl)methanone, 1s, (0.24 g, 34% yield) as a pale yellow liquid.
  • Example 41 Synthesis of (5-(4-(6-chloro-5-fluoroindolin-1-yl)quinazolin-6- yl)pyridin-3-yl)(3-(dimethylamino)azetidin-1-yl)methanone, Compound 41 [00327]
  • Step 1 Synthesis of tert-butyl 3-(dimethylamino)azetidine-1-carboxylate (1u): [00328] To a stirr anol (200.0 mL) at rt, was added Dimethyl amine (40 mL), Acetic acid (3.00 mL), followed by 10% Pd/C (3.00 g).
  • the reaction mixture was stirred at rt for 16 h under hydrogen atmosphere.
  • the reaction mixture was filtered through celite pad and the obtained filtrate was concentrated under vacuum to afford crude compound.
  • the crude compound was basified to pH ⁇ 10 with 6.0 N NaOH then the reaction mixture was extracted with EtOAc (2 ⁇ 200 mL), and brine (200 mL).
  • the organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the pure product tert-butyl 3-(dimethylamino)azetidine-1-carboxylate, 1u, (3.20 g, 55% yield) as a brown liquid.
  • Step 2 Synthesis of N,N-dimethylazetidin-3-amine (1v): [00330] To a s . , . (15.0 mL) at rt, was added 4.0 M Dioxane in HCl (4.0 mL) and the reaction mixture was stirred for 4 h.
  • Step 3 Preparation of (5-bromopyridin-3-yl)(3-(dimethylamino)azetidin-1- yl)methanone (1w): [00332] at rt, was added 1v (0.20 mg, 1.48 mmol), HOBt (0.20 g, 1.48 mmol), EDC•HCl (0.28 g, 1.48 mmol) followed by Et 3 N (0.65 mL, 4.95 mmol). The reaction mixture was stirred at rt. for 16 h. The reaction mixture was diluted with water (50.0 mL) and extracted with CH 2 Cl 2 (2 ⁇ 20.0 mL), washed with sat.
  • Step 4 Synthesis of (5-(4-(6-chloro-5-fluoroindolin-1-yl)quinazolin-6- yl)pyridin-3-yl)(3-(dimethylamino)azetidin-1-yl)methanone (Compound 41): [00334] To a stirred solution of 1w (0.07 g, 0.24mmol) in 1,4 dioxane (5.00 mL), placed in a sealed tube, under N 2 atmosphere at rt, was added 1n (0.07 g, 0.16 mmol), a solution of Cs2CO3 (0.15 g, 0.48 mmol) in H2O (1.00 mL) at rt, and the mixture was de-gassed with Ar(g) for 10 min.
  • Pd(dppf)Cl 2 ⁇ CH 2 Cl 2 (0.009 g, 0.011 mmol) was added in one lot, and the reaction mixture was heated to 120 °C for 16 h. The reaction mixture was cooled to rt and then concentrated under vaccum to obtain the crude product.
  • Example 42 Synthesis of (2-amino-5-(4-(6-chloro-5-fluoroindolin-1- yl)quinazolin-6-yl)pyridin-3-yl)(3-(dimethylamino)azetidin-1-yl)methanone, Compound 42 [00336] Step 1: Preparation of (2-amino-5-bromopyridin-3-yl)(3- (dimethylamino)azetidin-1-yl)methanone (1x): [00337] . , . .
  • Step 2 Synthesis of (2-amino-5-(4-(6-chloro-5-fluoroindolin-1-yl)quinazolin- 6-yl)pyridin-3-yl)(3-(dimethylamino)azetidin-1-yl)methanone (Compound 42): in a sealed tube under N 2 atmosphere at rt, was added 1n (0.08 g, 0.18 mmol), a solution of Cs2
  • Pd(dppf)Cl2 ⁇ CH2Cl2 (0.01 g, 0.012 mmol) was added in one lot, and the reaction mixture was heated to 120 °C for 16 h. The reaction mixture was cooled to rt and then concentrated under vaccum to obtain the crude product.
  • Step 2 Synthesis of 5-(4-indolin-1-ylquinazolin-6-yl)pyrimidin-2-amine (Compound 43) [00344 . , .
  • Example 45 Synthesis of 5-[4-(6-fluoroindolin-1-yl)quinazolin-6- yl]pyrimidin-2-amine, Compound 45 [00351]
  • Step 1 Synthesis of 6-bromo-4-(6-fluoroindolin-1-yl)quinazoline (1aa)
  • 6-fluoroindoline (112.66 mg, 821.40 ⁇ mol, 1 eq). The mixture was stirred at 80 o C for 2 h. LCMS showed the starting material was consumed completely, and desired MS was detected.
  • Example 46 Synthesis of 5-[4-(5,6-difluoroindolin-1-yl)quinazolin-6- yl]pyrimidin-2-amine, Compound 46 [00356]
  • Step 1 Synthesis of 6-bromo-4-(5,6-difluoroindolin-1-yl)quinazoline (1ab)
  • i- PrOH 2 mL
  • the mixture was stirred at 80 o C for 2 h.
  • LCMS showed the starting material was consumed completely, and desired MS was detected.
  • Example 47 Synthesis of 5-[4-(7-fluoroindolin-1-yl)quinazolin-6- yl]pyrimidin-2-amine, Compound 47 [00361] Step 1: Synthesis of 6-bromo-4-(7-fluoroindolin-1-yl)quinazoline (1ac) [00362] To a s o u on o - romo- -c oro-qu joso ne ( mg, 821.40 ⁇ mol, 1 eq) in i- PrOH (2 mL) was added 7-fluoroindoline (112.66 mg, 821.40 ⁇ mol, 1 eq).
  • Step 2 Synthesis of 5-[4-(7-fluoroindolin-1-yl)quinazolin-6-yl]pyrimidin-2- amine (Compound 47) [00365] To a stirred solution of 1ac (200 mg, 581.09 ⁇ mol, 1 eq) in DMF (3 mL) and H 2 O (0.5 mL) was added (2-aminopyrimidin-5-yl)boronic acid (80.73 mg, 581.09 ⁇ mol, 1 eq), Cs 2 CO 3 (567.99 mg, 1.74 mmol, 3 eq) and Pd(dppf)Cl 2 (42.52 mg, 58.11 ⁇ mol, 0.1 eq) the mixture was bubbled with N 2 for 1 minute, and stirred at 100 °C for 2 h.
  • Example 48 Synthesis of 4-(6-chloro-5-fluoro-indolin-1-yl)-6-(1H- pyrazolo[3,4-b]pyridin-5-yl)quinoline-3-carbonitrile, Compound 48 [00367]
  • Step 1 Synthesis of 6-bromo-4-(6-chloro-5-fluoro-indolin-1-yl)quinoline-3- carbonitrile (2d)
  • i-PrOH 5 mL
  • Step 2 Synthesis of 4-(6-chloro-5-fluoro-indolin-1-yl)-6-(1H-pyrazolo[3,4- b]pyridin-5-yl)quinoline-3-carbonitrile (Compound 48) [00370] To a stirred solution of 1g (182.61 mg, 745.07 ⁇ mol, 1 eq) in DMF (5 mL) and H 2 O (1 mL) was added 6-2d (300 mg, 745.07 ⁇ mol, 1 eq), Pd(dppf)Cl 2 (54.52 mg, 74.51 ⁇ mol, 0.1 eq) and Cs 2 CO 3 (728.27 mg, 2.24 mmol, 3 eq) the mixture was bubbled with N 2 for 1 minute, and stirred at 100 o C for 3 h.
  • Example 49 Synthesis of 6-(2-aminopyrimidin-5-yl)-4-(6-chloro-5-fluoro- indolin-1-yl)quinoline-3-carbonitrile, Compound 49 [ 00372] To a stirred solution of 1d (103.51 mg, 745.07 ⁇ mol, 1 eq) in DMF (5 mL) and H 2 O (1 mL) was added 2d (300 mg, 745.07 ⁇ mol, 1 eq) Pd(dppf)Cl 2 (54.52 mg, 74.51 ⁇ mol, 0.1 eq) and Cs2CO3 (728.28 mg, 2.24 mmol, 3 eq) the mixture was bubbled with N2 for 1 minute, and stirred at 100 o C for 3 h.
  • Example 50 Synthesis of 4-(6-chloro-5-fluoro-indolin-1-yl)-6-(5, 6- dimethoxy-3-pyridyl) quinoline-3-carbonitrile, Compound 50 [00374]
  • Step 1 Synthesis of 4-(6-chloro-5-fluoro-indolin-1-yl)-6-(4, 4, 5, 5- tetramethyl-1, 3, 2-dioxaborolan-2-yl) quinoline-3-carbonitrile (2e)
  • OK (2.56 g, 26.08 mmol, 3 eq)
  • Pd(dppf)Cl2.CH2Cl2 709.86 mg, 869.25 ⁇ mol, 0.1 eq) and 1l (2.65 g, 10.43 mmol, 1.2 eq)
  • the mixture was purged with Ar, the reaction was stirred at 115 °C for 4 h.
  • Step 2 Synthesis of 4-(6-chloro-5-fluoro-indolin-1-yl)-6-(5, 6-dimethoxy-3- pyridyl) quinoline-3-carbonitrile (Compound 50) [ g, . ⁇ , q .
  • Example 51 Synthesis 4-(6-chloro-5-fluoro-indolin-1-yl)-6-[5-(1-hydroxy-1- methyl-ethyl)-3-pyridyl]quinoline-3-carbonitrile, Compound 51 0.1 mL) was added Cs 2 CO 3 (326.03 mg, 1.00 mmol, 3 eq), Pd(dppf)Cl 2 (24.41 mg, 33.35 ⁇ mol, 0.1 eq) and 2-(5-bromo-3-pyridyl)propan-2-ol (72.07 mg, 333.55 ⁇ mol, 1 eq), the mixture was bubbled N2, the reaction was stirred at 100 °C for 3 h.
  • Example 54 Synthesis 6-(2-amino-1, 3-benzoxazol-5-yl)-4-(6-chloro-5-fluoro- indolin-1-yl) quinoline-3-carbonitrile, Compound 54 [00385] To a solution of 2e (150 mg, 333.55 ⁇ mol, 1 eq) in DMF (0.5 mL) and H 2 O (0.1 mL) was added Cs2CO3 (326.03 mg, 1.00 mmol, 3 eq), Pd(dppf)Cl2 (24.41 mg, 33.35 ⁇ mol, 0.1 eq) and 5-bromo-1,3-benzoxazol-2-amine (71.06 mg, 333.55 ⁇ mol, 1 eq) , the mixture was bubbled with N 2 , the reaction was stirred at 100 °C for 3 h.
  • Example 55 Synthesis 4-(6-chloro-5-fluoro-indolin-1-yl)-6-(1- methylpyrazolo [4, 3-b] pyridin-6-yl) quinoline-3-carbonitrile, Compound 55 [ .1 mL) was added Cs 2 CO 3 (326.03 mg, 1.00 mmol, 3 eq), Pd(dppf)Cl 2 (24.41 mg, 33.35 ⁇ mol, 0.1 eq) and 6-bromo-1-methyl-pyrazolo[4,3-b]pyridine (70.73 mg, 333.55 ⁇ mol, 1 eq), the mixture was bubbled N2, the reaction was stirred at 100 °C for 3 h.
  • Step 2 Synthesis of N-[3-(5-bromo-2-pyridyl) oxetan-3-yl]-2-methyl- propane-2-sulfinamide (1ae) [00392] 2, 5-dibromopyridine (830.02 mg, 3.50 mmol, 1 eq) was dissolved in toluene (5 mL) and the reaction mixture was cooled to -60 °C before N-BUTYLLITHIUM (2.5 M, 2.05 mL, 1.46 eq) was added dropwise and the mixture stirred for 10 minutes.1ad (700 mg, 3.99 mmol, 1.14 eq) in 0.5 mL of toluene (3 m
  • Step 3 Synthesis of 3-(5-bromo-2-pyridyl) oxetan-3-amine (1af) [00394] To a solution of 1ae (330 mg, 990.27 ⁇ mol, 1 eq) in MeOH (3 mL) was added dropwise HCl/EtOAc (4 M, 505.04 ⁇ L, 2.04 eq) at 0 °C ,the mixture was stirred at 0 °C for 1 h. LCMS showed starting material was consumed completely and the MS of desired product was detected.
  • Step 4 Synthesis of 6-[6-(3-aminooxetan-3-yl)-3-pyridyl]-4-(6-chloro-5- fluoro-indolin-1-yl) quinoline-3-carbonitrile (Compound 56) [00396] To a solution of 2e (78.53 mg, 174.62 ⁇ mol, 1 eq) in DMF (0.5 mL) and H 2 O (0.1 mL) was added Cs2CO3 (170.68 mg, 523.86 ⁇ mol, 3 eq), Pd(dppf)Cl2 (12.78 mg, 17.46 ⁇ mol, 0.1 eq) and 1af (40 mg, 174.62 ⁇ mol, 1 eq), the mixture was bubbled with N2, the reaction was stirred at 100 °C for 2 h.
  • Example 58 Synthesis of 4-(6-chloro-5-fluoro-indolin-1-yl)-6-(2- methoxypyrimidin-5-yl)quinazoline, Compound 58 [00405] To a stirred solution of 5-bromo-2-methoxy-pyrimidine (99.90 mg, 528.55 ⁇ mol, 1.5 eq) in dioxane (0.5 mL) , H2O (0.1 mL) was added 1n (150 mg, 352.37 ⁇ mol, 1 eq), Pd(dppf)Cl 2 (25.78 mg, 35.24 ⁇ mol, 0.1 eq), Cs 2 CO 3 (344.43 mg, 1.06 mmol, 3 eq) the mixture was bubbled with N2 for 1 minute, and the mixture was stirred at 100 °C for 3 h.
  • Example 59 Synthesis of 6-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6- yl]-1H-1,8-naphthyridin-4-one, Compound 59 ⁇ mol, 1.3 eq) in dioxane (3 mL) , H2O (0.5 mL) was added 1n (70 mg, 164.44 ⁇ mol, 1 eq), Cs2CO3 (160.73 mg, 493.32 ⁇ mol, 3 eq), Pd(dppf)Cl2 (12.03 mg, 16.44 ⁇ mol, 0.1 eq) the mixture was bubble with N 2 for 1 minute, and the mixture was stirred at 100 o C for 4 h.
  • Example 60 Synthesis of 5-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6- yl]-3-methylsulfonyl-pyridin-2-amine, Compound 60 [00409] Step 1: Synthesis of 3-methylsulfonylpyridin-2-amine (1ag) [00410] 3-bro methansulfinate (1.53 g, 15.03 mmol, 1.3 eq), CuI (220.16 mg, 1.16 mmol, 0.1 eq), NaOH (92.47 mg, 2.31 mmol, 0.2 eq) and L-PROLINE (266.18 mg, 2.31 mmol, 0.2 eq) were taken up into a microwave tube in DMSO (15 mL).
  • Step 2 Synthesis of 5-bromo-3-methylsulfonyl-pyridin-2-amine (1ah)
  • a solution of 1ag (200 mg, 1.16 mmol, 1 eq),NBS (227.38 mg, 1.28 mmol, 1.1 eq) in ACN (2 mL) was stirred at 20 o C for 0.5 h.
  • LCMS showed the starting material was consumed completely and desired MS was detected.
  • the reaction mixture was concentrate in vacuum.5-bromo-3-methylsulfonyl-pyridin-2-amine, 1ah, (200 mg, 796.49 ⁇ mol, 68.58% yield) was obtained as a yellow solid.
  • Step 3 Synthesis of 5-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6-yl]-3- methylsulfonyl-pyridin-2-amine (Compound 60) [00414] To a stirred solution of 1ah (44.24 mg, 176.18 ⁇ mol, 1.5 eq) in H 2 O (0.4 mL), DMF (3 mL) was added 1n (50 mg, 117.46 ⁇ mol, 1 eq), Pd(dppf)Cl2 (8.59 mg, 11.75 ⁇ mol, 0.1 eq), Cs2CO3 (114.81 mg 352.37 ⁇ mol, 3 eq) the mixture was bubbled with N2 for 1 minute, and the mixture was stirred at 100 o C for 3 h.
  • Step 2 Synthesis of 1-(2-amino-5-(4-(6-chloro-5-fluoroindolin-1- yl)quinazolin-6-yl)pyridin-3-yl)ethan-1-one (Compound 61) [00419] To a stirred solution of 1ai (60 mg, 279.01 ⁇ mol, 1.3 eq) in dioxane (3 mL) , H2O (0.5 mL) was added 1n (91.36 mg, 214.62 ⁇ mol, 1 eq), Cs2CO3 (209.78 mg, 643.87 ⁇ mol, 3 eq) Pd(dppf)Cl 2 (15.70 mg, 21.46 ⁇ mol, 0.1 eq) the mixture was bubbled with N 2 for 1 minute, and the mixture was stirred at 100 °C for 3 h.
  • Example 62 Synthesis of 2-[5-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin- 6-yl]-3-pyridyl]propan-2-ol, Compound 62 [00421] To a stirred solution of 1n (100 mg, 234.91 ⁇ mol, 1 eq) in dioxane (4 mL) and H2O (1 mL) was added 2-(5-bromo-3-pyridyl)propan-2-ol (76.14 mg, 352.37 ⁇ mol, 1.5 eq), Pd(dppf)Cl2 (17.19 mg, 23.49 ⁇ mol, 0.1 eq), Cs2CO3 (229.62 mg, 704.74 ⁇ mol, 3 eq), the mixture was bubbled with N 2 for 1 minute, and the mixture was stirred at 100 °C for 2 h.
  • Example 64 Synthesis of 6-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6- yl]-1H-benzimidazol-2-amine, Compound 64 [00425] To a stirred solution of 1n (100 mg, 234.91 ⁇ mol, 1 eq) in dioxane (4 mL) and H 2 O (1 mL) was added 6-bromo-1H-benzimidazol-2-amine (64.76 mg, 305.39 ⁇ mol, 1.3 eq), Pd(dppf)Cl 2 (17.19 mg, 23.49 ⁇ mol, 0.1 eq), Cs 2 CO 3 (229.62 mg, 704.74 ⁇ mol, 3 eq), the mixture was bubbled with N2 for 1 minute, and the reaction mixture was stirred at 100 o C for 2 h.
  • Step 2 Synthesis of 4-bromo-5,6-dihydrocyclopenta[c]pyridin-7-one (1ak)
  • 1aj 1.15 mmol, 1 eq
  • n-BuLi 2.5 M, 3.32 mL, 2 eq
  • the mixture was stirred at -60 o C for 4 h.
  • the mixture was added water (10 mL) at -60 o C.
  • Step 2 Synthesis of 4-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6-yl]-7- methyl-5,6-dihydrocyclopenta[c]pyridin-7-ol (Compound 67)
  • Step 3 Synthesis of 1-(5-bromo-2-methyl-3-pyridyl)vinyloxy-tert-butyl- dimethyl-silane (1au) [00462] To a stirred solution of 1at (300 mg, 1.40 mmol, 1 eq), DIEA (271.69 mg, 2.10 mmol, 366.16 ⁇ L, 1.5 eq) in CH2Cl2 (10 mL) was added [tert-butyl(dimethyl)silyl] trifluoromethanesulfonate (740.93 mg, 2.80 mmol, 644.29 ⁇ L, 2 eq) at 0 °C.
  • Step 4 Synthesis of [1-(5-bromo-2-methyl-3-pyridyl)cyclopropoxy]-tert- butyl-dimethyl-silane (5)
  • TFA 694.59 mg, 6.09 mmol, 451.03 ⁇ L, 5 eq
  • CH2I2 (1.63 g, 6.09 mmol, 491.42 ⁇ L, 5 eq) 1au (400 mg, 1.22 mmol, 1 eq) at 0 °C.
  • the mixture was stirred at 25 °C for 16 h.
  • Step 5 Synthesis of 1-(5-bromo-2-methyl-3-pyridyl)cyclopropanol (1aw) [00466] A solut OH (4 M, 3.84 mL, 13.13 eq) was stirred at 25 °C for 1 h. LCMS showed the starting material was consumed completely and desired MS was detected. The reaction mixture was concentrated in vacuum.
  • the mixture was stirred at 25 °C for 16 h. LCMS showed the starting material was consumed completely and desired MS was detected.
  • the reaction mixture was poured into sat.NH4Cl (10 mL) .
  • the aqueous phase was extracted with ethyl acetate (20 mL*2).
  • the combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum.
  • the crude product was purified by flash column (ISCO 20 g silica, 20- 24 % ethyl acetate in petroleum ether, gradient over 20 min).
  • Example 71 Synthesis of 7-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6- yl]-2-methyl-1H-pyrrolo[3,4-c]pyridin-3-one, Compound 71 [00475]
  • Step 1 Synthesis of methyl 5-bromo-4-(bromomethyl)pyridine-3-carboxylate (1ay)
  • [00476] A solution of methyl 5-bromo-4-methyl-pyridine-3-carboxylate (250 mg, 1.09 mmol, 1 eq), NBS (212.75 mg, 1.20 mmol, 1.1 eq), AIBN (53.53 mg, 326.00 ⁇ mol, 0.3 eq) in 262340-537651 CCl4 (5 mL) was stirred at 90 o C for 16 h.
  • Step 2 Synthesis of 7-bromo-2-methyl-1H-pyrrolo[3,4-c]pyridin-3-one (1az)
  • a solution of methyl 1ay (240 mg, 776.81 ⁇ mol, 1 eq), methanamine; hydrochloride (150 mg, 2.22 mmol, 2.86 eq), TEA (314.42 mg, 3.11 mmol, 432.49 ⁇ L, 4 eq) in DMF (3 mL) was stirred at 100 o C for 2 h. LCMS showed the starting material was consumed completely and desired MS was detected. The reaction mixture was poured into water (10 mL).
  • Step 3 Synthesis of 7-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6-yl]-2- methyl-1H-pyrrolo[3,4-c]pyridin-3-one (Compound 71)
  • 1n 216.32 mg, 508.17 ⁇ mol, 1 eq
  • H2O 0.5 mL
  • DMF 5 mL
  • Pd(dppf)Cl 2 37.18 mg, 50.82 ⁇ mol, 262340-537651 0.1 eq
  • Cs2CO3 496.72 mg, 1.52 mmol, 3 eq
  • the crude product was purified by flash column (ISCO 10 g silica, 0-20% ethyl acetate in petroleum ether, gradient over 10 min).4,6-dichloropyrido[3,2-d]pyrimidine, 4a, (130 mg, crude) was obtained as a white solid.
  • Step 2 Synthesis of 6-chloro-4-(6-chloroindolin-1-yl)pyrido[3,2-d]pyrimidine (4b) [00491] L) was added 1b (95.99 mg, 624.92 ⁇ mol, 1 eq), the mixture was stirred at 90 °C for 2 h. LCMS showed starting material was consumed completely and one main peak with desired ms was detected.
  • Step 2 Synthesis of 4-(6-chloro-5-fluoro-indolin-1-yl)-6-(1H-pyrazolo[3,4- b]pyridin-5-yl)pyrido[3,2-d]pyrimidine (Compound 76) 262340-537651 [ 596.72 ⁇ mol, 1 eq), Pd(dppf)Cl2.CH2Cl2 (48.73 mg, 59.67 ⁇ mol, 0.1 eq), K3PO4 (2 M, 895.09 ⁇ L, 3.0 eq) and DMF (4 mL). Then the sealed tube was bubbled with nitrogen for 30s and heated to 100 °C.
  • Step 2 Synthesis of 4-(6-fluoroindolin-1-yl)-6-(1H-pyrazolo[3,4-b]pyridin-5- yl)pyrido[3,2-d]pyrimidine (Compound 77) [ , , , , 864.60 ⁇ mol, 1.3 eq), Pd(dppf)Cl 2 .CH 2 Cl 2 (54.31 mg, 66.51 ⁇ mol, 0.1 eq),K 3 PO 4 (3 M, 665.08 ⁇ L, 3 eq) and DMF (5 mL). Then the sealed tube was bubbled with nitrogen for 30s and heated to 100 °C.
  • Step 2 Synthesis of 6-(1H-pyrazolo[3,4-b]pyridin-5-yl)pyrido[3,2- d]pyrimidin-4-ol (4d) 262340-537651
  • 6-chloropyrido[3,2-d]pyrimidin-4-ol 1.5 g, 8.26 mmol, 1 eq
  • DMF 21 mL
  • Pd(dppf)Cl2.CH2Cl2 674.61 mg, 826.09 ⁇ mol, 0.1 eq
  • K 3 PO 4 (4 M, 6.20 mL, 3 eq)
  • 1g 3.04 g, 12.39 mmol, 1.5 eq.
  • Example 79 Synthesis of 4-(6-methylindolin-1-yl)-6-(1H-pyrazolo[3,4- b]pyridin-5-yl)pyrido[3,2-d]pyrimidine, Compound 79 [00514] Step 1: Synthesis of 6-chloro-4-(6-methylindolin-1-yl)pyrido[3,2- d]pyrimidine (4f) [00515] g, . ⁇ , L) was added 6- methylindoline (133.17 mg, 999.88 ⁇ mol, 1 eq), the mixture was stirred at 90 °C for 2 h.
  • Example 81 Synthesis of 4-(6-chloro-5-fluoro-indolin-1-yl)-6-(3H- triazolo[4,5-b]pyridin-6-yl)quinazoline, Compound 81 F F Cl [ 00521] To a solution of 1n (60 mg, 140.95 ⁇ mol, 1 eq) in DMF (0.5 mL) and H 2 O (0.1 mL) was added Cs2CO3 (137.77 mg, 422.84 ⁇ mol, 3 eq), Pd(dppf)Cl2 (10.31 mg, 14.09 ⁇ mol, 0.1 eq) and 6-bromo-3H-triazolo[4,5-b]pyridine (42.07 mg, 211.42 ⁇ mol, 1.5 eq), the reaction was stirred at 100 °C for 3 h under N 2 .
  • Example 82 Synthesis of 5-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6- yl]-4-methyl- pyrimidin-2-amine, Compound 82 F F Cl , , , O (1 mL) was added 5-bromo-4-methyl-pyrimidin-2-amine (72.88 mg, 387.61 ⁇ mol, 1.1 eq), Cs2CO3 (344.43 mg, 1.06 mmol, 3 eq), Pd(dppf)Cl2 (25.78 mg, 35.24 ⁇ mol, 0.1 eq) the mixture was bubbled with N 2 for 1 minute, and the mixture was stirred at 100 o C for 3 h.
  • the crude product was purified by prep-HPLC (Waters Xbridge Prep OBD C18150*40mm*10um column; 40-75 % acetonitrile in a 10 mM ammonium bicarbonate solution in water, 8min gradient.5-[4-(6-chloro-5-fluoro- indolin-1-yl)quinazolin-6-yl]-4-methoxy-pyrimidin -2-amine, Compound 84, (26.20 mg, 61.86 ⁇ mol, 17.55% yield, 99.83% purity) was obtained as a pale yellow solid.
  • Example 86 Synthesis of 6-(4-(6-chloro-5-fluoroindolin-1-yl)quinazolin-6- yl)-1,2,4-triazin-3-amine, Compound 86 [ O (1 mL) was added 6-bromo-1,2,4-triazin-3-amine (92.49 mg, 528.55 ⁇ mol, 1.5 eq), Pd(dppf)Cl2 (25.78 mg, 35.24 ⁇ mol, 0.1 eq), Cs 2 CO 3 (344.43 mg, 1.06 mmol, 3 eq) the mixture was bubbled with N2 for 1 minute, and the mixture was stirred at 100 o C for 3 h.
  • Example 89 Synthesis of 2-amino-5-[4-(6-chloro-5-fluoro-indolin-1- yl)quinazolin-6-yl]-N,N -dimethyl-pyridine-3-carboxamide, Compound 89 F F O N Cl Cl [00 L), H2O (0.1 mL) was added 2-amino-N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridine-3-carboxamide (104.86 mg, 360.15 ⁇ mol, 1 eq), Cs 2 CO 3 (352.04 mg, 1.08 mmol, 3 eq), Pd(dppf)Cl2 (26.35 mg, 36.02 ⁇ mol, 0.1 eq) the mixture was bubbled with N2 for 1 minute, and the mixture was stirred at 100 o C for 2 h.
  • Example 90 Synthesis of 3-amino-6-[4-(6-chloro-5-fluoro-indolin-1- yl)quinazolin-6-yl]-1H-pyrazin-2-one, Compound 90
  • Example 91 Synthesis of 5-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6- yl]pyridine-2-carboxamide, Compound 91 [0 g, . ⁇ , q .
  • Example 92 Synthesis of 4-(6-chloro-5-fluoroindolin-1-yl)-6-(1-methyl-1H- pyrazolo[4,3-b]pyridin-6-yl)quinazoline, Compound 92 F F N N Cl [ g, .
  • Example 93 Synthesis of 4-(6-chloro-5-fluoro-indolin-1-yl)-6-imidazo[1,5- a]pyrimidin- 3-yl-quinazoline, Compound 93 F F N Cl Cl [ ⁇ mol, 1 eq) in DMF (10 mL) was added 1n (200 mg, 469.82 ⁇ mol, 1 eq), K3PO4 (199.46 mg, 939.65 ⁇ mol, 2 eq), ditert-butyl(cyclopentyl)phosphane;dichloropalladium;iron (30.62 mg, 46.98 ⁇ mol, 0.1 eq), the mixture was bubbled with Ar, and the mixture was stirred at 80 °C for 16 h.
  • Example 94 Synthesis of [5-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6- yl]-3-pyridyl]-pyrrolidin-1-yl-methanone, Compound 94
  • Step 1 Synthesis of (5-bromo-3-pyridyl)-pyrrolidin-1-yl-methanone (1ba) 262340-537651 O Cl O N HN r
  • a stirred solution of 5-bromopyridine-3-carbonyl chloride (200 mg, 907.23 ⁇ mol, 1 eq) in DCM (3 mL) was added pyrrolidine (64.52 mg, 907.23 ⁇ mol, 75.73 ⁇ L, 1 eq) ,TEA (275.41 mg, 2.72 mmol, 378.82 ⁇ L, 3 eq), the reaction was stirred at 25 °C for 30 min.
  • Step 2 Synthesis of [5-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6-yl]-3- pyridyl]-pyrrolidin-1-yl-methanone (Compound 94) [00551] To a stirred solution of 1n (60 mg, 140.95 ⁇ mol, 1 eq) in DMF (3 mL) and H2O (0.6 mL) was added 1ba (43.15 mg, 169.14 ⁇ mol, 1.2 eq), Cs 2 CO 3 (137.77 mg, 422.84 ⁇ mol, 3 eq) and Pd(dppf)Cl 2 (10.31 mg, 14.09 ⁇ mol, 0.1 eq), the reaction was stirred at 100 °C for 3 h under N2.
  • Step 2 Synthesis of [2-amino-5-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin- 6-yl]-3-pyridyl]-pyrrolidin-1-yl-methanone (Compound 95) [00556] To a stirred solution of 1n (70 mg, 164.44 ⁇ mol, 1 eq) in DMF (1 mL) and H 2 O (0.2 mL) was added 1bb (44.42 mg, 164.44 ⁇ mol, 1 eq), Cs 2 CO 3 (160.73 mg, 493.32 ⁇ mol, 3 eq) and Pd(dppf)Cl2 (12.03 mg, 16.44 ⁇ mol, 0.1 eq), the reaction was stirred at 100 °C for 3h under 262340-537651 N2.
  • Example 96 Synthesis of 5-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6- yl]-N-methyl-pyridine-3-carboxamide, Compound 96 F F O NH Cl [ O (0.2 mL) was added 5-bromo-N-methyl-pyridine-3-carboxamide (30.31 mg, 140.95 ⁇ mol, 1 eq),Cs2CO3 (137.77 mg, 422.84 ⁇ mol, 3 eq) and Pd(dppf)Cl 2 (10.31 mg, 14.09 ⁇ mol, 0.1 eq), the reaction was stirred at 100 °C for 3 h under N 2 .
  • Example 100 Synthesis of 4-(6-chloro-5-fluoro-indolin-1-yl)-6-(5-hydroxy-3- pyridyl) quinoline-3-carbonitrile, Compound 100 L) was added Cs2CO3 (173.88 mg, 533.68 ⁇ mol, 3 eq), Pd(dppf)Cl2 (13.02 mg, 17.79 ⁇ mol, 0.1 eq) and 5-bromopyridin-3-ol (30.95 mg, 177.89 ⁇ mol, 1 eq) the mixture was bubbled with N2,the reaction was stirred at 100°C for 3 h.
  • Example 103 Synthesis of 4-(6-chloro-5-fluoro-indolin-1-yl)-6-(1H- pyrazolo[3,4-c]pyridin-4-yl)quinoline-3-carbonitrile, Compound 103 , , L) was added Cs2CO3 (173.88 mg, 533.68 ⁇ mol, 3 eq), Pd(dppf)Cl2 (13.02 mg, 17.79 ⁇ mol, 0.1 eq) and 4-bromo-2H-pyrazolo[3,4-c]pyridine (35.23 mg, 177.89 ⁇ mol, 1 eq), the mixture was bubbled with N2, the reaction was stirred at 100 °C for 3 h.
  • Example 110 Synthesis of 6-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6- yl]-N-cyclopropyl-pyrazine-2-carboxamide, Compound 110 262340-537651 [00595] To a stirred solution of methyl 6-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6- yl]pyrazine-2-carboxylate (60 mg, 137.67 ⁇ mol, 1 eq) in THF (2 mL) was added cyclopropanamine (11.79 mg, 206.50 ⁇ mol, 14.31 ⁇ L, 1.5 eq), Al(CH 3 ) 3 (2 M, 275.33 ⁇ L, 4 eq), the reaction was stirred at 80 °C for 2 h under N2.
  • Step 2 Synthesis of 5-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6-yl]-N- hydroxy-N-methyl-pyridine-3-carboxamide (Compound 113) F F O N OH Cl [ , . , .
  • Example 116 Synthesis of 4-(6-chloro-5-fluoro-indolin-1-yl)-6-[5-(4H-1,2,4- triazol-3-yl)-3-pyridyl]quinazoline, Compound 116 [00610] To a stirred solution of 1n (60 mg, 140.95 ⁇ mol, 1 eq) in H2O (0.3 mL) and DMF (1.5 mL) was added 3-bromo-5-(4H-1,2,4-triazol-3-yl)pyridine (31.72 mg, 140.95 ⁇ mol, 1 eq), K 3 PO 4 (89.76 mg, 422.84 ⁇ mol, 3 eq) and Pd(dppf)Cl 2 (10.31 mg, 14.09 ⁇ mol, 0.1 eq), the reaction was stirred at 80 °C for 3 h under N2.
  • Example 119 Synthesis of [5-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6- yl]-3-pyridyl]methanol, Compound 119 Cl .76 262340-537651 mg, 422.85 ⁇ mol, 3 eq) and Pd(dppf)Cl2 (10.31 mg, 14.10 ⁇ mol, 0.1 eq), then the mixture was bubbled with N2 for 1 minutes and stirred at 80 °C for 3 h. LCMS showed starting material was consumed completely and the MS of desired product was detected. The reaction was filtered, then the filtrate was concentrated in vacuum.
  • Example 120 Synthesis of 5-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6- yl]-2-methoxy-pyridine-3-carbonitrile, Compound 120 F N F N Cl [ g, . ⁇ , .
  • Example 123 Synthesis of 6-[4-(6-chloroindolin-1-yl)quinazolin-6-yl]-3H- oxazolo[4,5-b]pyridin-2-one, Compound 123 [00 d H2O (0.3 mL) was added 6-bromo-3H-oxazolo[4,5-b]pyridin-2-one (31.64 mg, 147.17 ⁇ mol, 1 eq) K 3 PO 4 (93.72 mg, 441.51 ⁇ mol, 3 eq) and Pd(dppf)Cl 2 (10.77 mg, 14.72 ⁇ mol, 0.1 eq), the reaction was stirred at 80 °C for 3 h under N 2 .
  • Example 126 Synthesis of 5-[4-(6-chloro-5-fluoro-indolin-1-yl)pyrido[3,2- d]pyrimidin-6-yl]pyrimidin-2-amine, Compound 126 [00 g, . ⁇ , q 2 O (0.5 mL) was added 1d (12.43 mg, 89.51 ⁇ mol, 1 eq), K 3 PO 4 (57.00 mg, 268.53 ⁇ mol, 3 eq) and Pd(PPh3)4 (10.34 mg, 8.95 ⁇ mol, 0.1 eq), the reaction was stirred at 80 °C for 3 h under N2.
  • Example 127 Synthesis of 5-(4-(6-chloro-5-fluoroindolin-1-yl)pyrido[3,2- d]pyrimidin-6-yl)pyridin-2-amine, Compound 127 210 262340-537651 [0 O (0.5 mL) was added (6-aminopyridin-3-yl)boronic acid (12.43 mg, 89.51 ⁇ mol, 1 eq), K3PO4 (57.00 mg, 268.53 ⁇ mol, 3 eq) and Pd(PPh 3 ) 4 (10.34 mg, 8.95 ⁇ mol, 0.1 eq), the reaction was stirred at 80 °C for 3 h under N 2 .
  • reaction mixture was degassed with N21 min three times.
  • the resulting mixture was stirred at 80 °C for 3 h.
  • LC-MS showed starting material was consumed completely and major peak with desired mass was detected.
  • the reaction mixture was filtered.
  • the filtrate was purified by prep-HPLC (column: Phenomenex Luna 80 * 30 mm * 3 um; mobile phase: [water (HCl)- ACN]; B%: 10%-50%, 8 min).
  • Example 129 Synthesis of 5-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6-yl]spiro[1H- pyrrolo[2,3-b]pyridine-3,1'-cyclopropane]-2-one, Compound 156 To a so , .
  • Example 131 Synthesis of 5-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6-yl]-2-methyl- pyridin-3-ol, Compound 158 213 262340-537651
  • reaction mixture was degassed with N 2 1 min three times. The resulting mixture was stirred at 100 °C for 3 h. LC-MS showed starting material was consumed completely and major peak with desired mass was detected. Upon cooling to 25 °C, the reaction mixture was added thiourea (resin) to remove excess Pd(dppf)Cl 2 and then filtered. The filtrate was purified by prep-HPLC (column: Phenomenex Luna 80 * 30 mm * 3 um; mobile phase: [water (HCl)-ACN]; B%: 10%-40%, 8min).
  • Example 132 Synthesis of 2-chloro-5-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6- yl]pyridin-3-ol, Compound 159 mg, .75 262340-537651 umol, 0.1 eq) and K3PO4 (74.80 mg, 352.38 umol, 3 eq). Then the reaction mixture was degassed with N 2 1 min three times. The resulting mixture was stirred at 100 °C for 3 h. LC-MS showed starting material was consumed completely and major peak with desired mass was detected.
  • Step 3 Synthesis of 1-(5-bromo-3-pyridyl)-2,2,2-trifluoro-ethane-1,1-diol(Compound 179)
  • 1m 30 mg, 73.58 umol, 1 eq
  • 1-(5-bromo-3-pyridyl)-2,2,2-trifluoro-ethane- 1,1-diol 20.02 mg, 73.58 umol, 1 eq
  • Pd(dppf)Cl 2 5.38 mg, 7.36 umol, 0.1 eq
  • K3PO4 46.86 mg, 220.75 umol, 3 eq).
  • reaction mixture was degassed with N21 min three times.
  • the resulting mixture was stirred at 80 °C for 3 h.
  • LC-MS showed starting material was consumed completely and major peak with desired mass was detected.
  • the reaction mixture was filtered.
  • Example 142 N-[5-[4-(6-chloro-5-fluoro-indolin-1-yl)-3-cyano-6-quinolyl]-2-methoxy-3- pyridyl]methanesulfonamide, Compound 188 223 262340-537651 )-3-pyridyl]-N- methylsulfonyl-methanesulfonamide (57.30 mg, 141.05 ⁇ mol, 1 eq) and 1k (80 mg, 141.05 ⁇ mol, 1 eq) in H 2 O (0.2 mL) and DMF (1 mL) was added Pd(dppf)Cl 2 (10.32 mg, 14.10 ⁇ mol, 0.1 eq) and K3PO4 (89.82 mg, 423.14 ⁇ mol, 3 eq).
  • reaction mixture was degassed with N2 for 1 min.
  • the resulting mixture was stirred at 100 °C for 3 h.
  • LC-MS showed starting material was consumed completely and major peak with desired mass was detected.
  • the reaction mixture was filtered.
  • the filtrate was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18150 * 40 mm * 10 um; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 45%-75% B over 8.0 min).
  • reaction mixture was degassed with N 2 1 min three times.
  • the resulting mixture was stirred at 100 °C for 3 h.
  • LC-MS showed starting material was consumed completely and major peak with desired mass was detected.
  • the reaction mixture was filtered.
  • the filtrate was purified by prep-HPLC (column: Phenomenex luna C18100 * 40 mm * 5 um; mobile phase: [H 2 O (0.04% HCl)-ACN]; gradient: 30%-60% B over 8.0 min).
  • Example 144 Synthesis of N-[5-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6-yl]-2- methoxy-3-pyridyl]methanesulfonamide(MTX-229F) Synthetic Scheme: )-3- pyridyl]methanesulfonamide(4e) To a solution of 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine, 4d, (300 mg, 1.20 mmol, 1 eq) in DCM (8 mL) was added TEA (364.14 mg, 3.60 mmol, 500.88 uL, 3 eq).
  • Step 2 Synthesis of N-[5-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6-yl]-2-methoxy-3- pyridyl]methanesulfonamide (Compound 131)
  • 1k 0.05 g, 132.06 umol, 1 eq
  • 4e 90.43 mg, 132.06 umol, 59.332% purity, 1 eq
  • DMF 2 mL
  • H2O 0.4 mL
  • K3PO4 84.09 mg, 396.17 umol, 3 eq
  • Pd(dppf)Cl2 9.66 mg, 13.21 umol, 0.1 eq).
  • EGFR ErbB1
  • PIK3CA/PIK3R1 Recombinant human full length protein, Histidine-tagged, expressed in insect cells. Co-expressed with PIK3R1, Phosphoinositide-3-Kinase, regulatory subunit 1 (p85 alpha), untagged.
  • Equation of first order kinetics was used to calculate T1/2 and CLint(mic) ( ⁇ L/min/mg). Equation of first order kinetics: C ⁇ ⁇ k e ⁇ t t C 0 ⁇ e w hen C ⁇ 1 C ⁇ 1 1/ 2 mg /mL microsomal protein in reaction system m g mic g liver ⁇ rosomes c ) ⁇ g liver kgbody weight [00671] ility of the compounds of the disclosure can be measured by determining its 1 ⁇ 2 life in the presence microsomes.
  • Example 147 Solubility Assessment
  • Preparation of stock solutions The stock solutions of test compounds and control compound diclofenac were prepared in DMSO at the concentrations of 10 mM.
  • Simulated Intestinal Fluid (SIF) Prepared by dissolving 6.8 g of KH2PO4 into about 500 mL ultrapure water and adjust the solution to a pH 6.8 with 0.1 M NaOH.10 g trypsin is then dissolved into ultrapure water.
  • MDCK-MDR1 or MDCKII-BCRP Cells 50 ⁇ L and 25 mL of cell culture medium were added to each well of the Transwell insert and reservoir, respectively. The HTS transwell plates were then incubated at 37 °C, 5% CO2 for 1 hour before cell seeding. MDCK-MDR1 cells were diluted to 1.56 ⁇ 10 6 cells/mL with culture medium and 50 ⁇ L of cell suspension were dispensed into the filter well of the 96-well HTS Transwell plate. This final cell concentration is 5.45 ⁇ 10 5 cells/cm 2 . Cells were cultivated for 4-8 days in a cell culture incubator at 37 °C, 5% CO2, 95% relative humidity.
  • the stock solutions of the test compounds and control compounds were diluted in DMSO to get 400 ⁇ M 248 262340-537651 solutions and then diluted with HBSS (10 mM HEPES, pH 7.4) to get 1 ⁇ M working solutions.
  • HBSS 10 mM HEPES, pH 7.4
  • PSC833 a known inhibitor of Pgp
  • HBSS HBSS
  • Ko 143 a known inhibitor of BCRP
  • the final concentration of DMSO in the incubation system is 0.5 %.
  • Plasma samples were collected in CD1 mice each time point by heart puncture. A volume of 0.3 ml was collected and transferred into plastic micro centrifuge tubes containing the anticoagulant K2-EDTA. Collection tubes with blood samples and anticoagulant were inverted several times for proper mixing of the tube contents and then placed on wet ice. The samples were then centrifuged at 4000 g for 5 minutes at 4°C to obtain plasma. The samples were stored in a freezer at -75 ⁇ 15°C prior to analysis. [00707] Brain Samples Processing and Storage: The mouse was fully exsanguinated prior to tissue collection.
  • Procedure open chest cavity, cut ventricle and perform a gentle iv saline flush (saline flush volume ⁇ 10 ml) with the animal placed head down at a 45 degree angle to facilitate blood removal.
  • Brain tissue samples were collected at adopted time points, quick frozen in ice box and kept at -75 ⁇ 15°C. All tissue samples were weighed and homogenized with water by tissue weight (g) to water volume (mL) at ratio 1:3 before analysis. The actual concentration is the detected value multiplied by the dilution factor of 4.
  • the desired serial concentrations of working solutions were achieved by diluting stock solution of analyte with 50% acetonitrile in water solution.5 ⁇ L of working solutions (1, 2, 4, 20, 100, 200, 1000, 2000, 4000ng/mL) were added to 10 ⁇ L of the blank CD1 mouse plasma to achieve calibration standards of 0.5 ⁇ 2000 ng/mL (0.5, 1, 2, 10, 50, 100, 500, 1000, 2000 ng/mL) in a total volume of 15 ⁇ L.
  • Four quality control samples at 1 ng/mL, 2 ng/mL, 50 ng/mL and 1600 ng/mL for plasma were prepared independently of those used for the calibration curves. These QC samples were prepared on the day of analysis in the same way as calibration standards.
  • Bioanalysis Brain Samples All of the brain samples were added with Water by brain weight (g) to Water volume (mL) ratio 1:3 for homogenization. The actual concentration 252 262340-537651 (ng/g) is the detected value (ng/mL) multiplied by 4.
  • the desired serial concentrations of working solutions were achieved by diluting stock solution of analyte with 50% acetonitrile in water solution.15 ⁇ L of working solutions (1, 2, 4, 20, 100, 200, 1000, 2000, 4000ng/mL) were added to 30 ⁇ L of the blank CD1 mouse brain homogenate to achieve calibration standards of 0.5 ⁇ 2000 ng/mL (0.5, 1, 2, 10, 50, 100, 500, 1000, 2000 ng/mL) in a total volume of 45 ⁇ L.
  • Four quality control samples at 1 ng/mL, 2 ng/mL, 50 ng/mL and 1600 ng/mL for brain homogenate were prepared independently of those used for the calibration curves. These QC samples were prepared on the day of analysis in the same way as calibration standards.
  • PK Sample Analysis Concentrations of compounds in the plasma and tissue samples were analyzed using a LC-MS/MS method. WinNonlin (PhoenixTM, version 6.1) was used for pharmacokinetic calculations. The following pharmacokinetic parameters ware calculated, whenever possible from the plasma and brain concentration versus time data: C 0 , C max , T max , T 1/2 , AUC inf , AUC last , Brain to Plasma ratio. [00710] The pharmacokinetic data was described using descriptive statistics such as mean, standard deviation.
  • Table 7a PK Parameters for Compound 7: PK P arameter Unit IV IP PO IV IP PO 7 9
  • Table 7b PK Parameters for Comparative Compound XX: X 262340-537651 PK P arameter Unit IV PO IV PO 9
  • PGP and BCRP multi-drug resistance transporters
  • the likelihood for brain penetration can be improved by ensuring that the drug candidate is not a substrate of efflux proteins such as P-gp or BCRP.
  • the brain-to-plasma ratio (Kp) is a pharmacokinetic parameter used in pharmacology and drug development to measure the distribution of a drug between the brain and plasma (the liquid portion of blood). It is an important indicator of how well a drug can penetrate the blood-brain barrier. Kp can be calculated from pharmacokinetic parameters such as Cmax, AUC last values calculated from plasma and brain concentrations. A Kp value greater than 1 indicates that a drug has a higher concentration in the brain than in the plasma, which suggests good penetration of the blood-brain barrier. Kp values much less than 1 indicates poor brain penetration.
  • Comparative Compound XX was assessed as a “weak substrate” for the P-gp efflux protein and “not a substrate” for the BCRP efflux protein. Accordingly, Table 8a provides the in vivo brain to plasma ratio for Comparative Compound XX, as determined by the protocol above. Even though Comparative Compound XX is only a weak substrate for P-gp, the brain to plasma ratio of the compound is less than 1 for Cmax and AUClast.
  • Table 8a Brain to Plasma Ratio for Comparative Compound XX IV – 5 mg/Kg IP – 50 mg/Kg PO – 100 mg/Kg 254 262340-537651 Plasma Brain K p Plasma Brain K p Plasma Brain K p P- gp efflux protein and “not a substrate” for the BCRP efflux protein. Accordingly, Table 8b provides the in vivo brain to plasma ratio for Compound 7, as determined by the protocol above. Compound 7 is not a substrate for P-gp or BCRP, and the brain to plasma ratio of the compound is between 3-4 for Cmax and between 3-9 for AUClast, depending on the route of administration.
  • Table 8 Brain to Plasma Ratio for Compound 7 IV – 5 mg/Kg IP – 50 mg/Kg PO – 100 mg/Kg f the blood brain barrier as experimentally having Kp values greater than or equal to 1.
  • the present disclosure provides therapeutically effective compounds that are effective in crossing the blood brain barrier, and have been shown experimentally to have Kp values greater than or equal to 1, using the methods and assays provided in the examples herein.
  • Other embodiments [00721] It is to be understood that while the disclosure has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims. 255

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Abstract

La présente divulgation relève du domaine de la chimie médicinale. La divulgation concerne en particulier une nouvelle classe de petites molécules ayant une structure quinazoline ou une structure quinoléine de Formule (I), dans laquelle le cycle A, les cycles B et B', Y, X1, R1 et n sont tels que décrits, qui fonctionnent en tant qu'inhibiteurs doubles des protéines EGFR et de protéines PI3K. La divulgation concerne également leur utilisation en tant qu'agents thérapeutiques dans le traitement des maladies ou affections induites par EGFR et/ou PI3K. La divulgation concerne en outre leur utilisation en tant qu'agents thérapeutiques pour le traitement de maladies ou d'affections induites par EGFR et/ou PI3K du système nerveux central, qui nécessitent des agents thérapeutiques qui peuvent pénétrer dans la barrière hémato-encéphalique.
EP23813109.8A 2022-10-20 2023-10-19 Composés utiles dans la modulation de egfr et pi3k Pending EP4605089A1 (fr)

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US5736534A (en) * 1994-02-23 1998-04-07 Pfizer Inc. 4-heterocyclyl-substituted quinazoline derivatives, processes for their preparation and their use as anti-cancer agents
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US7205404B1 (en) 1999-03-05 2007-04-17 Metabasis Therapeutics, Inc. Phosphorus-containing prodrugs
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