Cross Reference To Related Applications

[001] The present application claims priority under 35 U.S.C. § 119(e) to U.S. provisional application USSN 63/417,869, filed October 20, 2022, which is incorporated herein by reference in its entirety.

Statement Regarding Federally Sponsored Research or Development

[002] This invention was made with government support under Grant No. R44CA213715 awarded by the National Institutes of Health. The government has certain rights in the invention.

Technical Field

[003] The present disclosure relates to the field of medicinal chemistry. In particular, 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.

Background

[004] Glioblastoma (GBM), the most common malignant primary brain tumor in adults, frequently exhibits aberrant EGFR and PI3K pathway signaling. According to The Cancer Genome Atlas (TCGA), up to 90% of GBMs have alterations in either receptor tyrosine kinase (RTK) or 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. Greater than 60% of GBMs display altered PI3K pathway signaling, manifested as either loss or mutation of PTEN (41%) or mutation of PI3K (25%). Consequently, there has been considerable effort to develop agents to treat GBM, targeting either EGFR or PI3K signaling independently. [005] While GBMs show a high incidence of both EGFR and PI3K pathway aberrations, use of targeted inhibitors of either pathway alone in the clinical setting has been led to disappointing response rates and minimal effects on progression-free and long-term survival. A myriad of factors account for the failure of pre-clinical efficacy to translate into clinical benefit, including compensatory signaling and/or lack of brain penetration. While EGFR is the most overexpressed RTK in GBM, other RTKs can compensate for impaired EGFR signaling. Alternatively, 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. In particular, direct targeting of both the EGFR and PI3K pathways has shown significant promise pre-clinically. Unfortunately, there have been a limited number of trials assessing the efficacy of the combination of EGFR and PI3K pathway approach in GBM. The combination of sirolimus and an EGFR inhibitor (gefitinib or erlotinib) initially showed hints of efficacy as evidenced by an objective response rate of 19% and roughly half of patients exhibiting stable disease. However, subsequent Phase II trials of rapamycin analogs combined with EGFR inhibitors failed to show meaningful clinical activity. Buck et al. reported that the mTOR inhibitor rapamycin synergizes with the EGFR inhibitor erlotinib in several cell lines exhibiting resistance to erlotinib treatment alone. The full potential of this synergistic combination could never be achieved because rapamycin induces phosphorylation of AKT resulting in pathway reactivation. Conventional wisdom suggests that a pan-PI3K inhibitor in combination with an EGFR inhibitor would have superior efficacy compared to mTOR/EGFR inhibitor combinations. Unfortunately, this strategy has not been widely pursued clinically for GBM patients, in part because both of the combination partners need to possess requisite brain penetration properties.

[006] Brain tumors compromise the integrity of the BBB allowing for the increased accumulation of fluid and plasma proteins. 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).

[007] Taken together, evidence supports a significant medical need for dual targeting of EGFR and PI3K pathways with small molecules that can penetrate the BBB.

Summary of the Invention

[008] The present disclosure identifies novel small molecule compounds capable of dual targeting of EGFR and PI3K pathways.

[009] In some aspects, 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.

[0010] 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.

[0011] As such, 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.

[0012] Accordingly, the present disclosure contemplates that exposure of animals (e.g., humans) suffering from cancer (e.g., cancer associated with aberrant EGFR and PI3K pathway signaling) (e.g., and/or cancer related disorders) to therapeutically effective amounts of drug(s) that are capable of inhibiting the activity of both EGFR and PI3K.

[0013] In some related embodiments, the cancers that may be treatable are brain cancers that are treatable with the compounds of the present disclosure, which are capable of crossing the BBB will inhibit the growth of such cancer cells or supporting cells outright and/or render such cells as a population more susceptible to the cell death-inducing activity of cancer therapeutic drugs or radiation therapies.

[0014] Moreover, the present disclosure contemplates that such a therapeutic effect is enhanced (e.g., synergized) through combination treatment (e.g., simultaneous, non-simultaneous) with radiotherapy or temozolimide. Indeed, the present disclosure contemplates that dual inhibitors of EGFR and PI3K activity satisfy an unmet need for the treatment of multiple cancer types, either when administered as monotherapy to induce cell growth inhibition, apoptosis and/or cell cycle arrest in cancer cells, or when administered in a temporal relationship with additional agent(s), such as other cell death-inducing or cell cycle disrupting cancer therapeutic drugs (e.g., MAPK pathway inhibitors) or radiation therapies (combination therapies), so as to render a greater proportion of the cancer cells or supportive cells susceptible to executing the apoptosis program compared to the corresponding proportion of cells in an animal treated only with the cancer therapeutic drug or radiation therapy alone.

[0015] In certain embodiments of the disclosure, 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.

[0016] The Applicants have found that certain small-molecules are capable of dual targeting of EGFR and PI3K, are can penetrate the blood-brain barrier, and serve as therapeutics for the treatment of cancer and other diseases. Thus, the present disclosure relates to such smallmolecules, and increasing the sensitivity of cells to inducers of apoptosis and/or cell cycle arrest. Certain compounds of the present disclosure may exist as stereoisomers including optical isomers. The present disclosure includes all stereoisomers, as pure individual stereoisomer preparations and enriched preparations of each. Both the racemic mixtures of such stereoisomers, as well as the individual diastereomers and enantiomers that may be separated according to known methods are well known to those of skill in the art.

Detailed Description

[0017] Definitions

[0018] For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," 5th Ed., Ed.: Smith, M B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0019] As used herein, an "alkyl" group refers to a saturated aliphatic hydrocarbon group containing 1-12 (e.g., 1-8, 1-6, or 1-4) carbon atoms. An alkyl group can be straight or branched. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-heptyl, or 2-ethylhexyl. An alkyl group can be substituted (i.e., optionally substituted) with one or more substituents such as halo, phospho, cycloaliphatic [e g., cycloalkyl or cycloalkenyl], heterocycloaliphatic [e.g., heterocycloalkyl or heterocycloalkenyl], aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, acyl [e.g., (aliphatic)carbonyl, (cycloaliphatic)carbonyl, or (heterocycloaliphatic)carbonyl], nitro, cyano, amido [e.g., (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkyl alkyl)carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino alkylaminocarbonyl, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, arylaminocarbonyl, or heteroarylaminocarbonyl], amino [e.g., aliphaticamino, cycloaliphaticamino, or heterocycloaliphaticamino], sulfonyl [e.g., aliphatic-SCh-], sulfinyl, sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, carboxy, carbamoyl, cycloaliphaticoxy, heterocycloaliphaticoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroarylalkoxy, alkoxycarbonyl, alkylcarbonyloxy, or hydroxy. Without limitation, some examples of substituted alkyls include carboxyalkyl (such as HOOC-alkyl, alkoxycarbonylalkyl, and alkyl carbonyloxyalkyl), cyanoalkyl, hydroxyalkyl, alkoxyalkyl, acylalkyl, aralkyl, (alkoxy aryl)alkyl, (sulfonylamino)alkyl (such as (alkyl-SO2-amino)alkyl), aminoalkyl, amidoalkyl, (cycloaliphatic)alkyl, or haloalkyl.

[0020] As used herein, an "aryl" group used alone or as part of a larger moiety as in "aralkyl," "aralkoxy," or "aryl oxy alkyl" refers to monocyclic (e.g., phenyl); bicyclic (e.g., indenyl, naphthalenyl, tetrahydronaphthyl, tetrahydroindenyl); and tricyclic (e.g., fluorenyl tetrahydrofluorenyl, or tetrahydroanthracenyl, anthracenyl) ring systems in which the monocyclic ring system is aromatic or at least one of the rings in a bicyclic or tricyclic ring system is aromatic. The bicyclic and tricyclic groups include benzofused 2-3 membered carbocyclic rings. For example, a benzofused group includes phenyl fused with two or more C4-8 carbocyclic moieties. An aryl is optionally substituted with one or more substituents including aliphatic [e.g., alkyl, alkenyl, or alkynyl]; cycloaliphatic; (cycloaliphatic)aliphatic; heterocycloaliphatic; (heterocycloaliphatic)aliphatic; aryl; heteroaryl; alkoxy;

(cycloaliphatic)oxy; (heterocycloaliphatic)oxy; aryloxy; heteroaryloxy; (araliphatic)oxy; (heteroaraliphatic)oxy; aroyl; heteroaroyl; amino; oxo (on a non-aromatic carbocyclic ring of a benzofused bicyclic or tricyclic aryl); nitro; carboxy; amido; acyl [e.g., (aliphatic)carbonyl;

(cycloaliphatic)carbonyl; ((cycloaliphatic)aliphatic)carbonyl; (araliphatic)carbonyl; (heterocycloaliphatic)carbonyl; ((heterocycloaliphatic)aliphatic)carbonyl; or (heteroaraliphatic)carbonyl]; sulfonyl [e.g., aliphatic-SCh- or amino-SCh-]; sulfinyl [e g., aliphatic-S(O)- or cycloaliphatic-S(O)-]; sulfanyl [e.g., aliphatic-S-]; cyano; halo; hydroxy; mercapto; sulfoxy; urea; thiourea; sulfamoyl; sulfamide; or carbamoyl. Alternatively, an aryl can be unsubstituted.

[0021] Non-limiting examples of substituted aryls include haloaryl [e.g., mono-, di (such as p,m- dihaloaryl), and (trihalo)aryl]; (carboxy)aryl [e.g., (alkoxycarbonyl)aryl, ((aralkyl)carbonyloxy)aryl, and (alkoxycarbonyl)aryl]; (amido)aryl [e.g., (aminocarbonyl)aryl, (((alkylamino)alkyl)aminocarbonyl)aryl, (alkylcarbonyl)aminoaryl, (arylaminocarbonyl)aryl, and (((heteroaryl)amino)carbonyl)aryl]; aminoaryl [e.g., ((alkylsulfonyl)amino)aryl or ((dialkyl)amino)aryl]; (cyanoalkyl)aryl; (alkoxy )aryl; (sulfamoyl)aryl [e.g., (aminosulfonyl)aryl]; (alkyl sulfonyl)aryl; (cyano)aryl; (hydroxyalkyl)aryl; ((alkoxy)alkyl)aryl; (hydroxy)aryl, ((carboxy)alkyl)aryl; (((dialkyl)amino)alkyl)aryl; (nitroalkyl)aryl;

(((alkylsulfonyl)amino)alkyl)aryl; ((heterocycloaliphatic)carbonyl)aryl;

((alkylsulfonyl)alkyl)aryl; (cyanoalkyl)aryl; (hydroxyalkyl)aryl; (alkylcarbonyl)aryl; alkylaryl; (trihaloalkyl)aryl; /?-amino-m-alkoxycarbonylaryl; /i-amino-/M-cyanoaryl; p-halo-/??-aminoaryl; or (m-(heterocycloaliphatic)-<?-(alkyl))aryl.

[0022] As used herein, a "cycloalkyl" group refers to a saturated carbocyclic mono- or bicyclic (fused or bridged) ring of 3-10 (e.g., 5-10) carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, norbomyl, cubyl, octahydro-indenyl, decahydro-naphthyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2.]decyl, bicyclo[2.2.2]octyl, adamantyl, or ((aminocarbonyl)cycloalkyl)cycloalkyl.

[0023] A cycloalkyl 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)carbonylamino, ((heterocycloaliphatic)aliphatic)carbonylamino, (heteroaryl)carbonylamino, or (heteroaraliphatic)carbonylamino], nitro, carboxy [e.g., HOOC-, alkoxycarbonyl, or alkylcarbonyloxy], acyl [e.g., (cycloaliphatic)carbonyl, ((cycloaliphatic) aliphatic)carbonyl, (araliphatic)carbonyl, (heterocycloaliphatic)carbonyl, ((heterocycloaliphatic)aliphatic)carbonyl, or (heteroaraliphatic)carbonyl], cyano, halo, hydroxy, mercapto, sulfonyl [e.g., alkyl-SCh- and aryl-SCh-], sulfinyl [e.g., alkyl-S(O)-], sulfanyl [e.g., alkyl-S-], sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.

[0024] As used herein, a “cyclyl” group is the same as a “cycloalkyl” group, with the exception that a cyclyl group can be partially unsaturated, but not aromatic.

[0025] As used herein, a "heterocycloalkyl" group refers to a 3-10 membered mono- or bicylic (fused or bridged) (e.g., 5- to 10-membered mono- or bicyclic) saturated ring structure, in which one or more of the ring atoms is a heteroatom (e.g., N, O, S, or combinations thereof). Examples of a heterocycloalkyl group include piperidyl, piperazyl, tetrahydropyranyl, tetrahydrofuryl, 1,4- dioxolanyl, 1,4-dithianyl, 1,3-dioxolanyl, oxazolidyl, isoxazolidyl, morpholinyl, thiomorpholyl, octahydrobenzofuryl, octahydrochromenyl, octahydrothiochromenyl, octahydroindolyl, octahydropyrindinyl, decahydroquinolinyl, octahydrobenzo[6]thiopheneyl, 2-oxa- bicyclo[2.2.2]octyl, l-aza-bicyclo[2.2.2]octyl, 3-aza-bicyclo[3.2.1]octyl, and 2,6-dioxa- tricyclo[3.3.1.0 ^3,7 ]nonyl. A monocyclic heterocycloalkyl group can be fused with a phenyl moiety to form structures, such as tetrahydroisoquinoline, that would be categorized as heteroaryls.

[0026] 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 amino, ((heterocycloaliphatic) aliphatic)carbonylamino, (heteroaryl)carbonylamino, or (heteroaraliphatic)carbonylamino], nitro, carboxy [e.g., HOOC-, alkoxycarbonyl, or alkylcarbonyloxy], acyl [e.g., (cycloaliphatic)carbonyl, ((cycloaliphatic) aliphatic)carbonyl, (araliphatic)carbonyl, (heterocycloaliphatic)carbonyl, ((heterocycloaliphatic)aliphatic)carbonyl, or (heteroaraliphatic)carbonyl], nitro, cyano, halo, hydroxy, mercapto, sulfonyl [e.g., alkylsulfonyl or arylsulfonyl], sulfinyl [e.g., alkylsulfinyl], sulfanyl [e.g., alkylsulfanyl], sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.

[0027] As used herein, a “heterocyclyl” group is the same as a “heterocycloalkyl” group, with the exception that a heterocyclyl group can be partially unsaturated, but not aromatic.

[0028] A "heteroaryl" group, as used herein, refers to a monocyclic, bicyclic, or tricyclic ring system having 4 to 15 ring atoms wherein one or more of the ring atoms is a heteroatom (e.g., N, O, S, or combinations thereof) and in which the monocyclic ring system is aromatic or at least one of the rings in the bicyclic or tricyclic ring systems is aromatic. A heteroaryl group includes a benzofused ring system having 2 to 3 rings. For example, a benzofused group includes benzo fused with one or two 4 to 8 membered heterocycloaliphatic moieties (e.g., indolizyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[Z>]furyl, benzo[/>]thiophene-yl, quinolinyl, or isoquinolinyl). Some examples of heteroaryl are azetidinyl, pyridyl, IH-indazolyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl, benzofuryl, isoquinolinyl, benzthiazolyl, xanthene, thioxanthene, phenothiazine, dihydroindole, benzo[l,3]di oxole, benzo[b]furyl, benzo[b]thiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, puryl, cinnolyl, quinolyl, quinazolyl,cinnolyl, phthalazyl, quinazolyl, quinoxalyl, isoquinolyl, 4H-quinolizyl, benzo-l,2,5-thiadiazolyl, or 1,8-naphthyridyl.

[0029] Without limitation, 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.

[0030] Without limitation, bicyclic heteroaryls include indolizyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[£>] furyl, benzo[Z»]thiophenyl, quinolinyl, isoquinolinyl, indolizyl, isoindolyl, indolyl, benzo[Z>]furyl, bexo[Z>]thiophenyl, indazolyl, benzimidazyl, benzthiazolyl, purinyl, 4H-quinolizyl, quinolyl, isoquinolyl, cinnolyl, phthalazyl, quinazolyl, quinoxalyl, 1,8- naphthyridyl, or pteridyl. Bicyclic heteroaryls are numbered according to standard chemical nomenclature.

[0031] A heteroaryl is optionally substituted with one or more substituents such as 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; 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]; nitro; cyano; halo; hydroxy; mercapto; sulfoxy; urea; thiourea; sulfamoyl; sulfamide; or carbamoyl. Alternatively, a heteroaryl can be unsubstituted.

[0032] Non-limiting examples of substituted heteroaryls include (halo)heteroaryl [e.g., mono- and di-(halo)heteroaryl]; (carboxy)heteroaryl [e.g., (alkoxycarbon yl)heteroaryl]; cyanoheteroaryl; aminoheteroaryl [e.g., ((alkylsulfonyl)amino)heteroaryl and ((dialkyl)amino)heteroaryl]; (amido)heteroaryl [e.g., aminocarbonylheteroaryl, ((alkylcarbonyl)amino)heteroaryl, ((((alkyl)amino)alkyl)aminocarbonyl)heteroaryl, (((heteroaryl)amino)carbonyl)heteroaryl, ((heterocycloaliphatic)carbonyl)heteroaryl, and ((alkyl carb onyl )ami no)heteroaryl ] ; (cyanoal kyl )h eteroaryl ; ( al koxy)heteroaryl ;

(sulfamoyl)heteroaryl [e.g., (aminosulfonyl)heteroaryl]; (sulfonyl)heteroaryl [e.g., (alkyl sulfonyl)heteroaryl ] ; (hydroxyalkyl)heteroaryl ; (alkoxyalkyl)heteroaryl ;

(hydroxy)h eteroaryl; ((carboxy)alkyl)heteroaryl; (((dialkyl)amino)alkyl]heteroaryl; (heterocycloaliphatic)heteroaryl; (cycloaliphatic)heteroaryl; (nitroalkyl )heteroaryl; (((alkylsulfonyl)amino)alkyl)heteroaryl; ((alkylsulfonyl)alkyl)heteroaryl; (cyanoalkyl)heteroaryl; (acyl)heteroaryl [e.g., (alkylcarbonyl )heteroaryl]; (alkyl)heteroaryl; or (haloalkyl)heteroaryl [e g., trihaloalkylheteroaryl],

[0033] As used herein, "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. [0034] As used herein, an "alkoxy" group refers to an alkyl -O- group where "alkyl" has been defined previously.

[0035] As used herein, a "haloalkyl" group refers to an alkyl group substituted with 1-3 halogen. For instance, the term haloalkyl includes the group -CF3.

[0036] As used herein, a "carbonyl" refers to -C(O)-. [0037] As used herein, an "oxo" refers to =0.

[0038] The phrase "optionally substituted" is used herein interchangeably with the phrase "substituted or unsubstituted." As described herein, compounds of the disclosure can optionally be substituted with one or more substituents, such as are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the disclosure. As described herein, the variables R ¹ , X, L, X ¹ , X ² , X ³ , X ⁴ , X ³ , X ⁶ and other variables contained in Formula (I), (II), and (TI-A) described herein encompass specific groups, such as alkyl and aryl. Unless otherwise noted, 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. For instance, 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. As an additional example, the cycloalkyl portion of a (cycloalkyl)carbonylamino can be optionally substituted with one to three of halo, cyano, alkoxy, hydroxy, nitro, haloalkyl, and alkyl. When two alkoxy groups are bound to the same atom or adjacent atoms, the two alkxoy groups can form a ring together with the atom(s) to which they are bound.

[0039] As used herein, the term "substituted," whether preceded by the term "optionally" or not, 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, can be bound to another ring, such as a cycloalkyl, to form a spiro-bicyclic ring system, e.g., both rings share one common atom. As one of ordinary skill in the art will recognize, combinations of substituents envisioned by this disclosure are those combinations that result in the formation of stable or chemically feasible compounds.

[0040] As used herein, the phrase "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. In some embodiments, 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.

[0041] Unless otherwise stated, 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. Additionally, unless otherwise stated, structures depicted herein also are meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a ¹³ C- or ¹⁴ C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools or probes in biological assays, or as therapeutic agents.

[0042] It is noted that the use of the descriptors "first," "second," "third," or the like is used to differentiate separate elements (e.g., solvents, reaction steps, processes, reagents, or the like) and may or may not refer to the relative order or relative chronology of the elements described. [0043] The term “anticancer agent” as used herein, refer to any therapeutic agents (e.g., chemotherapeutic compounds and/or molecular therapeutic compounds), antisense therapies, radiation therapies, or surgical interventions, used in the treatment of hyperproliferative diseases such as cancer (e.g., in mammals, e.g.., in humans). [0044] The term “prodrug” as used herein, refers to a pharmacologically inactive derivative of a parent “drug” molecule that requires biotransformation (e.g., either spontaneous or enzymatic) within the target physiological system to release, or to convert (e.g., enzymatically, physiologically, mechanically, electromagnetically) the prodrug into the active drug. Prodrugs are designed to overcome problems associated with stability, water solubility, toxicity, lack of specificity, or limited bioavailability. Exemplary prodrugs comprise an active drug molecule itself and a chemical masking group (e.g., a group that reversibly suppresses the activity of the drug). Some prodrugs are variations or derivatives of compounds that have groups cleavable under metabolic conditions. Prodrugs can be readily prepared from the parent compounds using methods known in the art, such as those described in A Textbook of Drug Design and Development, Krogsgaard-Larsen and H. Bundgaard (eds.), Gordon & Breach, 1991, particularly Chapter 5: "Design and Applications of Prodrugs"; Design of Prodrugs, H. Bundgaard (ed.), Elsevier, 1985; Prodrugs: Topical and Ocular Drug Delivery, K. B. Sloan (ed.), Marcel Dekker, 1998; Methods in Enzymology, K. Widder et al. (eds.), Vol. 42, Academic Press, 1985, particularly pp. 309-396; Burger's Medicinal Chemistry and Drug Discovery, 5th Ed., M. Wolff (ed.), John Wiley & Sons, 1995, particularly Vol. 1 and pp. 172-178 and pp. 949-982; Pro-Drugs as Novel Delivery Systems, T. Higuchi and V. Stella (eds.), Am. Chem. Soc., 1975; and Bioreversible Carriers in Drug Design, E. B. Roche (ed.), Elsevier, 1987.

[0045] Exemplary prodrugs become pharmaceutically active in vivo or in vitro when they undergo solvolysis under physiological conditions or undergo enzymatic degradation or other biochemical transformation (e.g., phosphorylation, hydrogenation, dehydrogenation, glycosylation). Prodrugs often offer advantages of water solubility, tissue compatibility, or delayed release in the mammalian organism. (See e.g., Bundgard, Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam (1985); and Silverman, The Organic Chemistry of Drug Design and Drug Action,/?/?. 352-401, Academic Press, San Diego, CA (1992)). 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).

[0046] The term “pharmaceutically acceptable salt” as used herein, refers to any salt (e.g., obtained by reaction with an acid or a base) of a compound of the present disclosure that is physiologically tolerated in the target patient (e.g., a mammal). Salts of the compounds of the present invention may be derived from inorganic or organic acids and bases. Examples of acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, sulfonic, naphthalene-2-sulfonic, benzenesulfonic acid, and the like. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the disclosure and their pharmaceutically acceptable acid addition salts.

[0047] Examples of bases include, but are not limited to, alkali metal (e.g., sodium) hydroxides, alkaline earth metal (e.g., magnesium) hydroxides, ammonia, and compounds of formula NW/, wherein W is Ci-4 alkyl, and the like.

[0048] Examples of salts include, but are not limited to: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, chloride, bromide, iodide, 2-hydroxyethanesulfonate, lactate, maleate, mesylate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, phenyl propionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, undecanoate, and the like. Other examples of salts include anions of the compounds of the present disclosure compounded with a suitable cation such as Na ⁺ , NELi ⁺ , and NW? (wherein W is a Ci-4 alkyl group), and the like. For therapeutic use, salts of the compounds of the present disclosure are contemplated as being pharmaceutically acceptable. However, salts of acids and bases that are non- pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.

[0049] The term "solvate" as used herein, refers to the physical association of a compound of the disclosure with one or more solvent molecules, whether organic or inorganic. This physical association often includes hydrogen bonding. In certain instances, the solvate is capable of isolation, for example, when one or more solvate molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate" encompasses both solution-phase and isolable solvates. Exemplary solvates include hydrates, ethanolates, and methanolates.

[0050] The phrase "stable or chemically feasible," as used herein, 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. In some embodiments, 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.

[0051] The methods of treatment of the disclosure comprise administering a safe and effective amount of a compound described herein or a pharmaceutically-acceptable salt thereof to a patient in need thereof.

[0052] As used herein, the term "subject" is intended to include human and non-human animals. Preferred subjects include human patients in need of enhancement of an immune response that may be beneficial in the patient’s treatment and/or prevention of cancer and/or cancer metastasis. The methods are particularly suitable for treating human patients having a disorder that can be treated by augmenting the T-cell mediated immune response. In a particular embodiment, the methods are particularly suitable for treatment of cancer cells in vivo.

[0053] “ Such as” has the same meaning as "such as but not limited to." Similarly, "include" has the same meaning as “include but not limited to,” while “including” has the same meaning as “including but not limited to.”

[0054] The terms "tumor," "cancer" and "neoplasia" are used interchangeably and refer to a cell or population of cells whose growth, proliferation or survival is greater than growth, proliferation or survival of a normal counterpart cell, e.g. a cell proliferative or differentiative disorder. Typically, the growth is uncontrolled. The term "malignancy" refers to invasion of nearby tissue. The term "metastasis" refers to spread or dissemination of a tumor, cancer or neoplasia to other sites, locations or regions within the subject, in which the sites, locations or regions are distinct from the primary tumor or cancer.

[0055] The term “therapeutically effective amount,” as used herein, refers to that amount of the therapeutic agent sufficient to result in amelioration of one or more symptoms of a disorder, or prevent advancement of a disorder, or cause regression of the disorder. For example, with respect to the treatment of cancer, in one embodiment, a therapeutically effective amount will refer to the amount of a therapeutic agent that decreases the rate of tumor growth, decreases tumor mass, decreases the number of metastases, increases time to tumor progression, or increases survival time by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%.

[0056] As used herein, "treat" in reference to a condition means: (1) to ameliorate the condition or one or more of the biological manifestations of the condition, (2) to interfere with (a) one or more points in the biological cascade that leads to or is responsible for the condition or (b) one or more of the biological manifestations of the condition, (3) to alleviate one or more of the symptoms or effects associated with the condition, or (4) to slow the progression of the condition or one or more of the biological manifestations of the condition.

[0057] The terms “increasing the sensitivity of,” “sensitize,” and “sensitizing,” as used herein, refer to making, through the administration of a first agent (e.g., a quinazoline compound of the disclosure), an animal or a cell within an animal more susceptible, or more responsive, to the biological effects (e.g., promotion or retardation of an aspect of cellular function including, but not limited to, cell division, cell growth, proliferation, invasion, angiogenesis, necrosis, or apoptosis) of a second agent. The sensitizing effect of a first agent on a target cell can be measured as the difference in the intended biological effect (e.g., promotion or retardation of an aspect of cellular function including, but not limited to, cell growth, proliferation, invasion, angiogenesis, or apoptosis) observed upon the administration of a second agent with and without administration of the first agent. The response of the sensitized cell can be increased by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, at least about 150%, at least about 200%, at least about 250%, at least 300%, at least about 350%, at least about 400%, at least about 450%, or at least about 500% over the response in the absence of the first agent.

[0058] The term "dysregulation of apoptosis," as used herein, refers to any aberration in the ability of (e.g., predisposition) a cell to undergo cell death via apoptosis. Dysregulation of apoptosis is associated with or induced by a variety of conditions, non-limiting examples of which include, autoimmune disorders (e.g., systemic lupus erythematosus, rheumatoid arthritis, graft-versus-host disease, myasthenia gravis, or Sjogren's syndrome), chronic inflammatory conditions (e.g., psoriasis, asthma or Crohn's disease), hyperproliferative disorders (e.g, tumors, B cell lymphomas, or T cell lymphomas), viral infections (e.g, herpes, papilloma, or HIV), and other conditions such as osteoarthritis and atherosclerosis.

[0059] The term “hyperproliferative disease,” as used herein, refers to any condition in which a localized population of proliferating cells in a patient is not governed by the usual limitations of normal growth. Examples of hyperproliferative disorders include tumors, neoplasms, lymphomas and the like. A neoplasm is said to be benign if it does not undergo invasion or metastasis and malignant if it does either of these. A “metastatic” cell means that the cell can invade and destroy neighboring body structures. Hyperplasia is a form of cell proliferation involving an increase in cell number in a tissue or organ without significant alteration in structure or function. Metaplasia is a form of controlled cell growth in which one type of fully differentiated cell substitutes for another type of differentiated cell.

[0060] The pathological growth of activated lymphoid cells often results in an autoimmune disorder or a chronic inflammatory condition. As used herein, the term “autoimmune disorder” refers to any condition in which an organism produces antibodies or immune cells which recognize the organism's own molecules, cells or tissues. Non-limiting examples of autoimmune disorders include autoimmune hemolytic anemia, autoimmune hepatitis, Berger’s disease or IgA nephropathy, celiac sprue, chronic fatigue syndrome, Crohn’s disease, dermatomyositis, fibromyalgia, graft versus host disease, Grave’s disease, Hashimoto’s thyroiditis, idiopathic thrombocytopenia purpura, lichen planus, multiple sclerosis, myasthenia gravis, psoriasis, rheumatic fever, rheumatic arthritis, scleroderma, Sjogren's syndrome, systemic lupus erythematosus, type 1 diabetes, ulcerative colitis, vitiligo, and the like.

[0061] The term “neoplastic disease,” as used herein, refers to any abnormal growth of cells being either benign (non-cancerous) or malignant (cancerous).

[0062] The term "normal cell," as used herein, refers to a cell that is not undergoing abnormal growth or division. Normal cells are non-cancerous and are not part of any hyperproliferative disease or disorder. [0063] The term “anti -neoplastic agent,” as used herein, refers to any compound that retards the proliferation, growth, or spread of a targeted (e.g., malignant) neoplasm.

[0064] The terms “prevent,” “preventing,” and “prevention,” as used herein, refer to a decrease in the occurrence of pathological cells (e.g., hyperproliferative or neoplastic cells) in a patient. The prevention may be complete, e.g., the total absence of pathological cells in a subject. The prevention may also be partial, such that the occurrence of pathological cells in a subject is less than that which would have occurred without the present disclosure. The skilled artisan will appreciate that "prevention" is not an absolute term. In medicine, "prevention" is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or severity of a condition or biological manifestation thereof, or to delay the onset of such condition or biological manifestation thereof.

[0065] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable vehicle" encompasses any of the standard pharmaceutical carriers, solvents, surfactants, or vehicles. Suitable pharmaceutically acceptable vehicles include aqueous vehicles and nonaqueous vehicles. Standard pharmaceutical carriers and their formulations are described in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 19th ed. 1995.

[0066] Unless defined otherwise, the meanings of technical and scientific terms as used herein are those commonly understood by one of ordinary skill in the art to which the disclosed subject matter belongs.

[0067] Embodiments

[0068] In one aspect, the disclosure includes a compound of Formula I

Formula I or a pharmaceutically acceptable salt thereof, wherein X ¹ is selected from N or C-R ² ;

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: 4 wherein each of Formula W1 –W4 are each optionally and independently substituted with one or more R ³ substituents; each X is CH, C-R ³ , or N; each X’ is N or O; Ring E is phenyl, a six membered heteroaryl, or a 5 or 6 membered cyclyl or heterocyclyl; each R ³ is R’ or a substituent selected from oxo, OH, halo, CN, C _1-6 alkyl, cyclyl, hetercyclyl, aryl, heteroaryl, OR’, NH2, NHR’, N(R’)2, NHS(O2)R’, N(S(O2)R’)2, C(O)H, C(O)OH, C(O)R’, C(O)OR’, C(O)NH ₂ , C(O)NHR’, C(O)NR’ ₂ , and S(O ₂ )R’, wherein each alkyl, cyclyl, hetercyclyl, aryl, and heteroaryl are optionally and independently substituted with one or more R’ substituents; or two R ³ substituents on a single carbon atom may combine to form a 3-6 membered spirocyclic cycloalkyl or heterocycloalkyl; Ring B and Ring B’ together make a fused bicyclic heterocyclyl or 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 phenyl, a 6 membered heterocyclyl, or a 6 membered heteroaryl; each R ⁴ is independently selected from halo, OH, CN, oxo, C1-6 alkyl, OR’, NH2, NHR’, N(R’)2, C(O)R’, C(O)OR’, C(O)NH2, C(O)NHR’, and C(O)N(R’)2, wherein each alkyl, is optionally and independently substituted with one or more R’ substituents; each R’ is independently selected from R”, OH, CN, C1-6 alkyl, cyclyl, hetercyclyl, aryl, and heteroaryl, each of which is optionally and independently substituted with one or more R” substituents; each R” is independently selected from oxo, OH, halo, CN, C _1-6 alkyl, cyclyl, hetercyclyl, aryl, heteroaryl, OC1-6 alkyl, NH2, NHC1-6 alkyl, N(C1-6 alkyl)2, C(O)C1-6 alkyl, C(O)OC1-6 alkyl, C(O)NH2, C(O)NHC1-6 alkyl, and C(O)N(C1-6 alkyl)2, wherein each alkyl, cyclyl, hetercyclyl, aryl, and heteroaryl is optionally and independently substituted with one or more substituents selected from halo, oxo, alkoxy, CN, NH2, C(O)C1-6 alkyl, C(O)OC1-6 alkyl, and C(O)NHC1-6 alkyl; and n is an integer selected from 0, 1, 2, 3, or 4. [0069] In one embodiment of this aspect, X ¹ is N. [0070] In another embodiment, X ¹ is C-R ² . [0071] In one embodiment, R ² is selected from hydrogen, halo, CN, and C _1-6 alkyl, wherein each C _1-6 alkyl, is optionally and independently substituted with one or more R” substituents. [0072] In a further embodiment, R ² is CN. [0073] In one embodiment, R ¹ is selected from C1-6 alkyl, halo, CN, OR’, and NR’2, wherein each C _1-6 alkyl is optionally and independently substituted with one or more R” substituents. [0074] In a further embodiment, R ¹ is selected from methyl, CN, or halo. [0075] In one embodiment, n is 0 or 1. [0076] In a further embodiment, n is 0. [0077] In one embodiment, each R ³ is R’ or a substituent selected from oxo, OH, halo, CN, C1-6 alkyl, cyclyl, hetercyclyl, aryl, heteroaryl, OR’, NH2, NHR’, N(R’)2, NHS(O2)R’, N(S(O2)R’)2, C(O)H, C(O)OH, C(O)R’, C(O)OR’, C(O)NH ₂ , C(O)NHR’, C(O)NR’ ₂ , and S(O ₂ )R’, wherein each alkyl, cyclyl, hetercyclyl, aryl, and heteroaryl are optionally and independently substituted with one or R’ substituents. [0078] In another embodiment, each R ³ is selected from oxo, OH, halo, CN, OR’, NH2, NHR’, N(R’) ₂ , NHS(O ₂ )R’, C(O)OH, C(O)H, C(O)R’, C(O)OR’, C(O)NH ₂ , C(O)NHR’, C(O)NR’ ₂ , S(O2)R’, C1-6 alkyl, C3-6 cycloalkyl, a 3-6 membered hetercyclyl, and a 5-6 membered heteroaryl, wherein each alkyl, cycloalkyl, hetercyclyl, phenyl, and heteroaryl are optionally and independently substituted with one or R’ substituents. [0079] In another embodiment, each R ³ is selected from halo, oxo, amino, OH, CN, C _1-6 alkyl, C(O)H, OC1-6 alkyl, alkoxycarbonyl, C1-6 haloalkyl, carboxyl, C1-6 haloalkoxy, alkylsulfonyl, aminosulfonyl, alkylsulfonylamino, hydroxyalkyl, hydroxyalkylcarbonyl, alkylcarbonyl, aminocarbonyl, alkylaminocarbonyl, cycloalkylcarbonyl, cyanoaminocarbonyl, hydroxyaminocarbonyl, cycloalkylaminocarbonyl, heterocyclocarbonyl, cyanoaminocarbonyl, hydroxyaminocarbonyl, alkylheterocyclyl, heterocyclyl, alkylheterocyclylcarbonyl, aminoazetidinyl, aminooxetanyl, hydroxycyclopropanyl, hydroxyheterocyclyl, aminoheterocyclyl, aminoheterocyclylcarbonyl, pyrrolidinyl, cyclopropylamino, N- methyltriazolyl, imidazolyl, pyrazolyl, aminoalkoxy, and triazolyl. [0080] In a further embodiment, 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- methylpiperazin-1-yl, 4-methylpiperazin-1-yl-carbonyl, 3-dimethylamino-azetidin-1-yl, 3- dimethylamino-azetidin-1-yl-carbonyl, 3-aminooxetan-3-yl, 3-hydroxyoxetan-3-yl, 1- hydroxycyclopropanyl, pyrrolidin-1-yl, pyrrolidin-1-yl-carbonyl, cyclopropylamino, cyclopropylaminocarbonyl, 4-methyl-1,2,4-triazol-3-yl, 1,2,4-triazol-1-yl, imidazole-1-yl, 1- methyl-1,2,3-triazol-4-yl, and 1,2,4-triazol-3-yl. [0081] In one embodiment, Ring A is a phenyl, a 6-membered heterocyclyl, or a 6-membered heteroaryl, optionally substituted with one or more R ³ substituents [0082] In another embodiment, Ring A is a bicyclic moiety selected from Formula W1, W2, W3, and W4: W4 wherein each of Formula W1 –W4 are each optionally and independently substituted with one or more R ³ substituents; [0083] In a further embodiment, Ring A is selected from , , , O O , , alkyl, OC1-6 alkyl, NH2, NHC1-6 alkyl, N(C1-6 alkyl)2, C(O)C1-6 alkyl, C(O)OC1-6 alkyl, C(O)NH2, C(O)NHC1-6 alkyl, and C(O)N(C1-6 alkyl)2, wherein each alkyl, is optionally and independently substituted with one or more R’ substituents. [0085] In one embodiment, 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. [0087] In one embodiment, 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. [0088] In one embodiment, 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. [0089] In another embodiment, 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. [0090] In a further embodiment, Ring B and Ring B’ together form a bicyclic moiety selected , halo, CN, or C _1-6 alkyl. [0092] In a further embodiment, X ¹ is selected from N or C-CN. [0093] In another embodiment, Y is CH. [0094] In one embodiment, 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. [0095] In one embodiment, at least two X ³ substituents are CH. [0096] In another embodiment, at least one X ³ substituent is N. [0097] In one embodiment, X ¹ is N. [0098] In one embodiment, 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. [0099] In one embodiment, at least one X ³ substituent is N. [00100] In another embodiment, both X ³ substituents are N. [00101] In one embodiment, each R ³ is independently selected from halo, oxo, NH2, CF3, CH3, OCH3, OH, CN, and CH2OH. [00102] In one embodiment, m is 0 or 1. [00103] In another embodiment, each R ⁴ is independently selected from halo and C _1-6 alkyl. [00104] In one embodiment, m is 0, 1, or 2. In another embodiment, 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. [00108] In another embodiment, R ⁵ is selected from hydrogen, NH ₂ , chloro, and methoxy. [00109] In another embodiment, R ⁶ is selected from hydroxy, C(O)N(CH3)2, and CH3SO2N(R’). [00110] In one embodiment, 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 F Cmpd Name Structure Cmpd Name Structure Cmpd Name Structure Cmpd Name Structure Cmpd Name Structure Cmpd Name Structure 1 Cmpd Name Structure Cmpd Name Structure Cmpd Name Structure Cmpd Name Structure Cmpd Name Structure Cmpd Name Structure Cmpd Name Structure Cmpd Name Structure [00112] In one aspect, the disclosure includes a compound selected from: Cmpd Name Structure [00113] In another aspect, the disclosure includes a pharmaceutical composition comprising a compound described herein, or salt thereof, and a pharmaceutically acceptable excipient. [00114] In another aspect, 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. [00115] In one embodiment, EGFR and/or PI3K mediated disease or condition is a hyperproliferative disease or condition. [00116] In a further embodiment, said disease or condition is cancer. [00117] In another embodiment, said cancer is glioblastoma or glioblastoma multiform. [00118] In one embodiment, said patient is a human patient. [00119] In another embodiment, said compound crosses the blood brain barrier (BBB) in vivo. [00120] In one embodiment, the method further comprises administering to said patient one or more anticancer agents. [00121] In a further embodiment, said anticancer agent is a chemotherapeutic agent. [00122] In another further embodiment, said anticancer agent is radiation therapy. [00123] In another aspect, 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. [00124] In a further embodiment, said condition is cancer. [00125] In still a further embodiment, said cancer is glioblastoma or glioblastoma multiform. [00126] In one embodiment, the kit further comprises one or more anticancer agents. [00127] In another embodiment, said compound, salt thereof, or composition, is to be administered together with one or more anticancer agents. [00128] In one embodiment, a compound of the invention is relatively stable to metabolism in vivo. In one embodiment, a compound of the invention has a long half-life in vivo. In another embodiment, the compound has an in vivo half-life of at least about 5 minutes. In another embodiment, the compound has an in vivo half-life of at least about 10 minutes. In another embodiment, the compound has an in vivo half-life of at least about 15 minutes. In another embodiment, the compound has an in vivo half-life of at least about 25 minutes. In another embodiment, the compound has an in vivo half-life of at least about 30 minutes. [00129] In one embodiment, a compound of the invention is relatively stable in the presence of mouse liver microsomes (MLM). In one embodiment, a compound of the invention has a long half-life in the presence of MLM. In another embodiment, the compound has a half- life of at least about 5 minutes in the presence of MLM. In another embodiment, the compound has a half-life of at least about 10 minutes in the presence of MLM. In another embodiment, the compound has a half-life of at least about 15 minutes in the presence of MLM. In another embodiment, the compound has a half-life of at least about 25 minutes in the presence of MLM. In another embodiment, the compound has a half-life of at least about 30 minutes in the presence of MLM. [00130] In one embodiment, a compound of the invention is relatively stable in the presence of human liver microsomes (HLM). In one embodiment, a compound of the invention has a long half-life in the presence of HLM. In another embodiment, the compound has a half- life of at least about 5 minutes in the presence of HLM. In another embodiment, the compound has a half-life of at least about 10 minutes in the presence of HLM. In another embodiment, the compound has a half-life of at least about 15 minutes in the presence of HLM. In another embodiment, the compound has a half-life of at least about 25 minutes in the presence of HLM. In another embodiment, the compound has a half-life of at least about 30 minutes in the presence of HLM. [00131] Pharmaceutical Compositions [00132] The compounds described herein can be formulated into pharmaceutical compositions that further comprise a pharmaceutically acceptable carrier, diluent, adjuvant or vehicle. In one embodiment, the present disclosure provides a pharmaceutical composition comprising a compound of the disclosure described above, and a pharmaceutically acceptable carrier, diluent, adjuvant or vehicle. In one embodiment, the present disclosure is a pharmaceutical composition comprising an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent, adjuvant or vehicle. Pharmaceutically acceptable carriers include, for example, pharmaceutical diluents, excipients or carriers suitably selected with respect to the intended form of administration, and consistent with conventional pharmaceutical practices. [00133] According to another embodiment, the disclosure provides a composition comprising a compound of this disclosure or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. Pharmaceutical 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. [00134] The term "patient," as used herein, means an animal, preferably a mammal, and most preferably a human. [00135] It also will be appreciated that certain of the compounds of the present disclosure can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable derivative (e.g., a salt) thereof. According to the present disclosure, a pharmaceutically acceptable derivative includes, but is not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any other adduct or derivative that upon administration to a patient in need is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof. [00136] As used herein, 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. [00137] 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. Examples of pharmaceutically acceptable, nontoxic acid addition salts include salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable 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, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N ⁺ (C1-4 alkyl)4 salts. This disclosure also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersable products may be obtained by such quaternization. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate. [00138] A pharmaceutically acceptable carrier may contain inert ingredients that do not unduly inhibit the biological activity of the compounds. The pharmaceutically acceptable carriers should be biocompatible, e.g., non-toxic, non-inflammatory, non-immunogenic or devoid of other undesired reactions or side-effects upon the administration to a subject. Standard pharmaceutical formulation techniques can be employed. [00139] The pharmaceutically acceptable carrier, adjuvant, or vehicle, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the compounds described herein, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, the use of such conventional carrier medium is contemplated to be within the scope of this invention. As used herein, the phrase "side effects" encompasses unwanted and adverse effects of a therapy (e.g., a prophylactic or therapeutic agent). Side effects are always unwanted, but unwanted effects are not necessarily adverse. An adverse effect from a therapy (e.g., prophylactic or therapeutic agent) might be harmful, uncomfortable, or risky. Side effects include, but are not limited to, fever, chills, lethargy, gastrointestinal toxicities (including gastric and intestinal ulcerations and erosions), nausea, vomiting, neurotoxicities, nephrotoxicities, renal toxicities (including such conditions as papillary necrosis and chronic interstitial nephritis), hepatic toxicities (including elevated serum liver enzyme levels), myelotoxicities (including leukopenia, myelosuppression, thrombocytopenia and anemia), dry mouth, metallic taste, prolongation of gestation, weakness, somnolence, pain (including muscle pain, bone pain and headache), hair loss, asthenia, dizziness, extra-pyramidal symptoms, akathisia, cardiovascular disturbances and sexual dysfunction. [00140] 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 acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents. Preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator. [00141] The compositions of the present disclosure may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intraocular, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions of this disclosure may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation also may be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. [00142] For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives, are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions also may contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers that are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation. [00143] The pharmaceutically acceptable compositions of this disclosure may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents also may be added. [00144] Alternatively, the pharmaceutically acceptable compositions of this disclosure may be administered in the form of suppositories for rectal or vaginal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum or vaginal cavity to release the drug. Such materials include cocoa butter, polyethylene glycol or a suppository wax that is solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound. [00145] The pharmaceutically acceptable compositions of this disclosure also may be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, skin, or lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs. [00146] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches also may be used. [00147] For topical applications, the pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. [00148] For ophthalmic use, the pharmaceutically acceptable compositions may be formulated, e.g., as micronized suspensions in isotonic, pH adjusted sterile saline or other aqueous solution, or, preferably, as solutions in isotonic, pH adjusted sterile saline or other aqueous solution, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum. The pharmaceutically acceptable compositions of this disclosure also may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents. [00149] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, 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. Besides inert diluents, the oral compositions also can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. [00150] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation also may be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may be used in the preparation of injectables. [00151] The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. [00152] In order to prolong the effect of a compound of the present disclosure, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide- polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations also are prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues. [00153] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, 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) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form also may comprise buffering agents. [00154] 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. Examples of embedding compositions that can be used 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. [00155] 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. In such solid dosage forms the active compound may be admixed with at least one 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. In the case of capsules, tablets and pills, 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. Examples of embedding compositions that can be used include polymeric substances and waxes. [00156] Dosage forms for topical or transdermal administration of a compound of this disclosure include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, and eye drops also are contemplated as being within the scope of this disclosure. Additionally, the present disclosure contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. 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. [00157] The compounds of the disclosure preferably are formulated in dosage unit form for ease of administration and uniformity of dosage. As used herein, the phrase "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. [00158] 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. Preferably, the compositions should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of the inhibitor can be administered to a patient receiving these compositions. [00159] Depending upon the particular condition, or disease, to be treated or prevented, additional therapeutic agents, which are normally administered to treat or prevent that condition, also may be present in the compositions of this disclosure. As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease, or condition, are known as "appropriate for the disease, or condition, being treated." [00160] Some embodiments of the present disclosure provide methods for administering an effective amount of a compound of the disclosure and at least one additional therapeutic agent (including, but not limited to, chemotherapeutic antineoplastics, apoptosis-modulating agents, antimicrobials, antivirals, antifungals, and anti-inflammatory agents) and/or therapeutic technique (e.g., surgical intervention, and/or radiotherapies). In a particular embodiment, the additional therapeutic agent(s) is an anticancer agent. [00161] A number of suitable anticancer agents are contemplated for use in the methods of the present disclosure. Indeed, the present disclosure contemplates, but is not limited to, administration of numerous 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-α) 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 nucleotides); tumor vaccines; angiogenesis inhibitors; proteosome inhibitors: NF- КB modulators; anti-CDK compounds; HDAC inhibitors; and the like. Numerous other examples of chemotherapeutic compounds and anticancer therapies suitable for co- administration with the disclosed compounds are known to those skilled in the art. [00162] In certain embodiments, 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 GLEEVEC)); antisense molecules; antibodies (e.g., HERCEPTIN, RITUXAN, ZEVALIN, and AVASTIN); anti-estrogens (e.g., raloxifene and tamoxifen); anti- androgens (e.g., flutamide, bicalutamide, finasteride, aminoglutethamide, ketoconazole, and corticosteroids); cyclooxygenase 2 (COX-2) inhibitors (e.g., celecoxib, meloxicam, NS-398, and non-steroidal anti-inflammatory drugs (NSAIDs)); anti-inflammatory drugs (e.g., butazolidin, DECADRON, DELTASONE, dexamethasone, dexamethasone intensol, DEXONE, HEXADROL, hydroxychloroquine, METICORTEN, ORADEXON, ORASONE, oxyphenbutazone, PEDIAPRED, phenylbutazone, PLAQUENIL, prednisolone, prednisone, PRELONE, and TANDEARIL); and cancer chemotherapeutic drugs (e.g., irinotecan (CAMPTOSAR), CPT-11, fludarabine (FLUDARA), dacarbazine (DTIC), dexamethasone, mitoxantrone, MYLOTARG, VP-16, cisplatin, carboplatin, oxaliplatin, 5-FU, doxorubicin, gemcitabine, bortezomib, gefitinib, bevacizumab, TAXOTERE or TAXOL); cellular signaling molecules; ceramides and cytokines; staurosporine, and the like. [00163] In still other embodiments, the 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). [00164] Alkylating agents suitable for use in the present compositions and methods include, but are not limited to: 1) nitrogen mustards (e.g., mechlorethamine, cyclophosphamide, ifosfamide, melphalan (L-sarcolysin); and chlorambucil); 2) ethylenimines and methylmelamines (e.g., hexamethylmelamine and thiotepa); 3) alkyl sulfonates (e.g., busulfan); 4) nitrosoureas (e.g., carmustine (BCNU); lomustine (CCNU); semustine (methyl-CCNU); and streptozocin (streptozotocin)); and 5) triazenes (e.g., dacarbazine (DTIC; dimethyltriazenoimid- azolecarboxamide). [00165] In some embodiments, antimetabolites suitable for use in the present compositions and methods include, but are not limited to: 1) folic acid analogs (e.g., methotrexate (amethopterin)); 2) pyrimidine analogs (e.g., fluorouracil (5-fluorouracil; 5-FU), floxuridine (fluorode-oxyuridine; FudR), and cytarabine (cytosine arabinoside)); and 3) purine analogs (e.g., mercaptopurine (6-mercaptopurine; 6-MP), thioguanine (6-thioguanine; TG), and pentostatin (2’-deoxycoformycin)). [00166] In still further embodiments, 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); 8) substituted ureas (e.g., hydroxyurea); 9) methylhydrazine derivatives (e.g., procarbazine (N-methylhydrazine; MIH)); 10) adrenocortical suppressants (e.g., mitotane (o,p’–DDD) and aminoglutethimide); 11) adrenocorticosteroids (e.g., prednisone); 12) progestins (e.g., hydroxyprogesterone caproate, medroxyprogesterone acetate, and megestrol acetate); 13) estrogens (e.g., diethylstilbestrol and ethinyl estradiol); 14) antiestrogens (e.g., tamoxifen); 15) androgens (e.g., testosterone propionate and fluoxymesterone); 16) antiandrogens (e.g., flutamide): and 17) gonadotropin-releasing hormone analogs (e.g., leuprolide). [00167] Any oncolytic agent that is routinely used in a cancer therapy context finds use in the compositions and methods of the present disclosure. For example, the U.S. Food and Drug Administration maintains a formulary of oncolytic agents approved for use in the United States. International counterpart agencies to the U.S.F.D.A. maintain similar formularies. Those skilled in the art will appreciate that the “product labels” required on all U.S. approved chemotherapeutics describe approved indications, dosing information, toxicity data, and the like, for the exemplary agents. [00168] For example, chemotherapeutic agents or other anti-proliferative agents may be combined with the compounds of this disclosure to treat proliferative diseases and cancer. Examples of known 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, pembolizumab, atezolizumab, avelumab, durvalumab), engineered cell therapy (e.g., CAR-T therapy - Kymriah®, Yescarta®), Gleevec™, adriamycin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, taxol, interferons, and platinum derivatives. [00169] And, in some instances, radiation therapy is administered during the treatment course wherein a compound of the present disclosure (or a pharmaceutically acceptable salt thereof) is administered to a patient in need thereof. [00170] 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-724,714, CpG 7909, curcumin, decitabine, DENSPM, doxercalciferol, E7070, E7389, ecteinascidin 743, efaproxiral, eflornithine, EKB-569, enzastaurin, erlotinib, exisulind, fenretinide, flavopiridol, fludarabine, flutamide, fotemustine, FR901228, G17DT, galiximab, gefitinib, genistein, glufosfamide, GTI-2040, histrelin, HKI-272, homoharringtonine, HSPPC-96, hu14.18-interleukin-2 fusion protein, HuMax-CD4, iloprost, imiquimod, infliximab, interleukin-12, IPI-504, irofulven, ixabepilone, lapatinib, lenalidomide, lestaurtinib, leuprolide, LMB-9 immunotoxin, lonafarnib, luniliximab, mafosfamide, MB07133, MDX-010, MLN2704, monoclonal antibody 3F8, monoclonal antibody J591, motexafin, MS- 275, MVA-MUC1-IL2, nilutamide, nitrocamptothecin, nolatrexed dihydrochloride, nolvadex, NS-9, O6-benzylguanine, oblimersen sodium, ONYX-015, oregovomab, OSI-774, panitumumab, paraplatin, PD-0325901, pemetrexed, PHY906, pioglitazone, pirfenidone, pixantrone, PS-341, PSC 833, PXD101, pyrazoloacridine, R115777, RAD001, ranpirnase, rebeccamycin analogue, rhuAngiostatin protein, rhuMab 2C4, rosiglitazone, rubitecan, S-1, S- 8184, satraplatin, SB-, 15992, SGN-0010, SGN-40, sorafenib, SR31747A, ST1571, SU011248, suberoylanilide hydroxamic acid, suramin, talabostat, talampanel, tariquidar, temsirolimus, TGFa-PE38 immunotoxin, thalidomide, thymalfasin, tipifarnib, tirapazamine, TLK286, trabectedin, trimetrexate glucuronate, TroVax, UCN-1, valproic acid, vinflunine, VNP40101M, volociximab, vorinostat, VX-680, ZD1839, ZD6474, zileuton, and zosuquidar trihydrochloride. [00171] For a more detailed description of anticancer agents and other therapeutic agents, those skilled in the art are referred to any number of instructive manuals including, but not limited to, the Physician's Desk Reference and to Goodman and Gilman's "Pharmaceutical Basis of Therapeutics" tenth edition, Eds. Hardman et al., 2002. [00172] The amount of additional therapeutic agent present in the compositions of this disclosure will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent. [00173] Methods of Treatment [00174] The compounds of the disclosure are modulators (e.g., inhibitors) of the activity or function of proteins of the phosphoinositide 3 ' OH kinase family (PIK3) (e.g., PIK3Cα, PIK3δ, PIK3β, PIK3Cγ, PI3Kα) and modulation (e.g., inhibition) of the activity or function of proteins of the epidermal growth factor EGFR family (e.g., ERBB receptor tyrosine kinase family (e.g., ERBB1, ERBB2, ERBB4, ERBB1)). [00175] PI3K is negatively regulated by phosphatase and tensin homolog (PTEN) (see, e.g., Hamada K, et al., 2005 Genes Dev 19 (17): 2054–65). Numerous studies have shown a link between PIK3CA mutation/PTEN loss and EGFR targeted resistance leading to poor overall survival (see, e.g., Atreya CE, Sangale Z, Xu N, et al. Cancer Med.2013;2: 496-506; Sawai H, et al., BMC Gastroenterol.2008;8: 56; Bethune G, et al., J Thorac Dis.2010;2: 48-51; Spano JP, et al., Ann Oncol.2005;16: 189-194; Heimberger AB, et al., J Transl Med.2005;3: 38). The quinazoline compounds and quinoline compounds synthesized during the course of developing embodiments for the present disclosure were designed based on a central hypothesis that dual targeting of EGFR and PIK3CA would be efficacious in patients with colorectal cancer that are EGFR positive and are either PIK3CA mutated or null PTEN expressers (see, e.g., Psyrri A, et al., Am Soc Clin Oncol Educ Book.2013: 246-255; Lui VW, et al., Cancer Discov.2013;3: 761- 769; Jin G, et al., Lung Cancer.2010;69: 279-283; Buck E, et al., Mol Cancer Ther.2006;5: 2676-2684; Fan QW, et al., Cancer Res.2007;67: 7960-7965; Gadgeel SM, et al., Clin Lung Cancer.2013;14: 322-332. [00176] As such, 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)). Indeed, through targeting both EGFR and PI3K, the compounds of the present disclosure are useful in treating subjects with EGFR positive colorectal cancer that harbor an activating mutation in PI3K ^ or are PTEN null. [00177] Accordingly, the present disclosure contemplates that exposure of patients (e.g., humans) suffering from a condition characterized by aberrant EGFR protein activity (e.g., ERBB1) and PI3K protein activity (e.g., PI3K ^) (e.g., cancer (e.g., and/or cancer related disorders)) to therapeutically effective amounts of drug(s) having a quinazoline structure (e.g., small molecules having a quinazoline structure) or a quinoline structures (e.g., small molecules having a quinoline structure) that inhibit the activity of both EGFR and PI3K will inhibit the growth of cells characterized by aberrant EGFR and PI3K protein expression (e.g., colorectal cancer cells having aberrant EGFR and PI3K protein expression) and/or render such cells as a population more susceptible to the cell death-inducing activity of additional therapeutic drugs (e.g., cancer therapeutic drugs or radiation therapies). The present disclosure contemplates that inhibitors of both EGFR and PI3K satisfy an unmet need for the treatment of multiple conditions characterized with aberrant EGFR and PI3K activity (e.g., cancer), either when administered as monotherapy to induce cell growth inhibition, apoptosis and/or cell cycle arrest in such cells (e.g., cancer cells), or when administered in a temporal relationship with additional agent(s), such as other cell death-inducing or cell cycle disrupting therapeutic drugs (e.g., cancer therapeutic drugs or radiation therapies) (combination therapies), so as to render a greater proportion of the cells (e.g., cancer cells) or supportive cells susceptible to executing the apoptosis program compared to the corresponding proportion of cells in a patient treated only with the therapeutic drug or radiation therapy alone. [00178] In certain embodiments of the disclosure wherein the condition being treated is cancer characterized with aberrant EGFR protein activity (e.g., ERBB1) and PI3K protein activity (e.g., PI3K ^) (e.g., colorectal cancer), combination treatment of patients with a therapeutically effective amount of a compound of the present disclosure and a course of an anticancer agent produces a greater tumor response and clinical benefit in such patients 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. [00179] As noted, the Applicants have found that certain 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. Thus, 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 includes all stereoisomers, both as pure individual stereoisomer preparations and enriched preparations of each, and both the racemic mixtures of such stereoisomers as well as the individual diastereomers and enantiomers that may be separated according to methods that are well known to those of skill in the art. [00180] The disclosure also provides the use of compounds to induce cell cycle arrest and/or apoptosis in cells characterized with aberrant EGFR protein activity (e.g., ERBB1) and PI3K protein activity (e.g., PI3K ^). 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. [00181] 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). In certain embodiments, the compounds can be used to treat, ameliorate, or prevent such types of cancer (e.g., colorectal cancer) that is characterized by resistance to cancer therapies (e.g., those cancer cells which are chemoresistant, radiation resistant, hormone resistant, and the like). In certain embodiments, the cancer is colorectal cancer, head & neck cancer, glioblastoma multiform, and/or non-small cell lung cancer (NSCLC). In other embodiments, the compounds can be used to treat other characterized by aberrant expression of EGFR and PI3K proteins (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). [00182] The disclosure also provides pharmaceutical compositions comprising the compounds of the disclosure in a pharmaceutically acceptable carrier. [00183] The disclosure also provides kits comprising a compound of the disclosure and instructions for administering the compound to a patient. The kits may optionally contain other therapeutic agents, e.g., anticancer agents or apoptosis-modulating agents. [00184] Moreover, the present disclosure provides methods for simultaneously inhibiting both EGFR protein activity and PI3K protein activity in cells through exposing such cells to one or more of the quinazoline or quinoline compounds of the present disclosure. [00185] In spite of compelling evidence for PI3K/AKT pathway activation leading to resistance to EGFR targeting agents, only recently have researchers sought to combine EGFR targeting agents with PI3K/AKT/MTOR pathway inhibitors both pre-clinically and clinically. For example, 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). However, 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). Others have explored dual inhibition of EGFR and PI3K/AKT pathways in several cell lines and cancer histotypes, providing further support for this combination treatment strategy (see, e.g., Eichhorn PJ, et al., Cancer Res.2008;68: 9221-9230). The compounds of the present disclosure overcame such limitations and represent dual potency inhibitors of both EGFR protein activity (e.g., ERBB1) and PI3K protein activity (e.g., PI3K ^). Specifically, utilizing x-ray crystal structure and structure-activity relationships gleaned from known PI3K and EGFR inhibiting agents, such experiments resulted in the identification of “active cores” for PI3K inhibiting agents facilitating high inhibitory activity against PI3K, and the identification of “active cores” for EGFR inhibiting agents facilitating high inhibitory activity against EGFR, respectively (see, Example I). The quinazoline and quinoline compounds of the present disclosure were accordingly synthesized to target the “active cores” for PI3K and the “active cores” for EGFR, thereby rendering such compounds as having “dual potency” against EGFR protein activity (e.g., ERBB1) and PI3K protein activity (e.g., PI3K ^). [00186] Accordingly, the present disclosure relates to compounds which function as inhibitors of EGFR protein activity (e.g., ERBB1) and PI3K protein activity (e.g., PI3K ^). By inhibiting the activity of EGFR protein activity (e.g., ERBB1) and PI3K protein activity (e.g., PI3K ^), these compounds sensitize cells to inducers of apoptosis and/or cell cycle arrest and, in some instances, themselves induce apoptosis and/or cell cycle arrest. Therefore, the disclosure relates to methods of sensitizing cells to inducers of apoptosis and/or cell cycle arrest and to methods of inducing apoptosis and/or cell cycle arrest in cells, comprising contacting the cells with a compound of the disclosure alone or in combination with additional agent(s), e.g., an inducer of apoptosis or a cell cycle disrupter. [00187] The disclosure further relates to methods of treating, ameliorating, or preventing conditions in a patient characterized with cells having aberrant EGFR protein activity (e.g., ERBB1) and PI3K protein activity (e.g., PI3K ^), such as those conditions that are responsive to induction of apoptosis, comprising administering to the patient a compound of the disclosure and additional agent(s), e.g., an inducer of apoptosis. Such disorders include those characterized by a dysregulation of apoptosis and those characterized by the proliferation of cells having aberrant EGFR protein activity (e.g., ERBB1) and PI3K protein activity (e.g., PI3K ^) (e.g., colorectal cancer). Indeed, through targeting both EGFR and PI3K, the compounds of the present disclosure are useful in treating subjects with EGFR positive colorectal cancer that harbor an activating mutation in PI3K ^ or are PTEN null. [00188] 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) (e.g., quinoline compounds) can be used to induce apoptosis in any disorder that can be treated, ameliorated, or prevented by the induction of apoptosis. [00189] In some embodiments, the compositions and methods of the present disclosure are used to treat diseased cells, tissues, organs, or pathological conditions and/or disease states in a patient (e.g., a mammalia patient including, but not limited to, humans and veterinary animals). In this regard, various diseases and pathologies are amenable to treatment or prophylaxis using the present methods and compositions. 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, choriocarcinoma, mycosis fungoides, malignant hypercalcemia, cervical hyperplasia, leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic granulocytic leukemia, acute granulocytic leukemia, hairy cell leukemia, neuroblastoma, rhabdomyosarcoma, Kaposi's sarcoma, polycythemia vera, essential thrombocytosis, Hodgkin's disease, non-Hodgkin's lymphoma, soft-tissue sarcoma, osteogenic sarcoma, primary macroglobulinemia, and retinoblastoma, and the like, T and B cell mediated autoimmune diseases; inflammatory diseases; infections; hyperproliferative diseases; AIDS; degenerative conditions, vascular diseases, and the like. In some embodiments, the cancer cells being treated are metastatic. In other embodiments, the cancer cells being treated are resistant to anticancer agents. [00190] In other embodiments, the disorder is any disorder having cells having aberrant EGFR protein activity (e.g., ERBB1) and PI3K protein activity (e.g., PI3K ^) (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)). [00191] The present disclosure provides methods for administering a compound of the disclosure with radiation therapy. The disclosure is not limited by the types, amounts, or delivery and administration systems used to deliver the therapeutic dose of radiation to a patient. For example, the patient may receive photon radiotherapy, particle beam radiation therapy, other types of radiotherapies, and combinations thereof. In some embodiments, the radiation is delivered to the patient using a linear accelerator. In still other embodiments, the radiation is delivered using a gamma knife. [00192] The source of radiation can be external or internal to the patient. External radiation therapy is most common and involves directing a beam of high-energy radiation to a tumor site through the skin using, for instance, a linear accelerator. While the beam of radiation is localized to the tumor site, it is nearly impossible to avoid exposure of normal, healthy tissue. However, external radiation is usually well tolerated by patients. Internal radiation therapy involves implanting a radiation-emitting source, such as beads, wires, pellets, capsules, particles, and the like, inside the body at or near the tumor site including the use of delivery systems that specifically target cancer cells (e.g., using particles attached to cancer cell binding ligands). Such implants can be removed following treatment, or left in the body inactive. Types of internal radiation therapy include, but are not limited to, brachytherapy, interstitial irradiation, intracavity irradiation, radioimmunotherapy, and the like. [00193] The patient may optionally receive radiosensitizers (e.g., metronidazole, misonidazole, intra-arterial Budr, intravenous iododeoxyuridine (IudR), nitroimidazole, 5- substituted-4-nitroimidazoles, 2H-isoindolediones, [[(2-bromoethyl)-amino]methyl]-nitro-1H- imidazole-1-ethanol, nitroaniline derivatives, DNA-affinic hypoxia selective cytotoxins, halogenated DNA ligand, 1,2,4 benzotriazine oxides, 2-nitroimidazole derivatives, fluorine- containing nitroazole derivatives, benzamide, nicotinamide, acridine-intercalator, 5-thiotretrazole derivative, 3-nitro-1,2,4-triazole, 4,5-dinitroimidazole derivative, hydroxylated texaphrins, cisplatin, mitomycin, tiripazamine, nitrosourea, mercaptopurine, methotrexate, fluorouracil, bleomycin, vincristine, carboplatin, epirubicin, doxorubicin, cyclophosphamide, vindesine, etoposide, paclitaxel, heat (hyperthermia), and the like), radioprotectors (e.g., cysteamine, aminoalkyl dihydrogen phosphorothioates, amifostine (WR 2721), IL-1, IL-6, and the like). Radiosensitizers enhance the killing of tumor cells. Radioprotectors protect healthy tissue from the harmful effects of radiation. [00194] 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). The effects of radiation can be at least partially controlled by the clinician. In one embodiment, the dose of radiation is fractionated for maximal target cell exposure and reduced toxicity. [00195] In one embodiment, the total dose of radiation administered to a patient is about .01 Gray (Gy) to about 100 Gy. In another embodiment, about 10 Gy to about 65 Gy (e.g., about 15 Gy, 20 Gy, 25 Gy, 30 Gy, 35 Gy, 40 Gy, 45 Gy, 50 Gy, 55 Gy, or 60 Gy) are administered over the course of treatment. While in some embodiments a complete dose of radiation can be administered over the course of one day, the total dose is ideally fractionated and administered over several days. Desirably, radiotherapy is administered over the course of at least about 3 days, e.g., at least 5, 7, 10, 14, 17, 21, 25, 28, 32, 35, 38, 42, 46, 52, or 56 days (about 1-8 weeks). Accordingly, a daily dose of radiation will comprise approximately 1-5 Gy (e.g., about 1 Gy, 1.5 Gy, 1.8 Gy, 2 Gy, 2.5 Gy, 2.8 Gy, 3 Gy, 3.2 Gy, 3.5 Gy, 3.8 Gy, 4 Gy, 4.2 Gy, or 4.5 Gy), or 1-2 Gy (e.g., 1.5-2 Gy). The daily dose of radiation should be sufficient to induce destruction of the targeted cells. If stretched over a period, in one embodiment, radiation is not administered every day, thereby allowing the patient to rest and the effects of the therapy to be realized. For example, radiation desirably is administered on 5 consecutive days, and not administered on 2 days, for each week of treatment, thereby allowing 2 days of rest per week. However, radiation can be administered 1 day/week, 2 days/week, 3 days/week, 4 days/week, 5 days/week, 6 days/week, or all 7 days/week, depending on the patient’s responsiveness and any potential side effects. Radiation therapy can be initiated at any time in the therapeutic period. In one embodiment, radiation is initiated in week 1 or week 2, and is administered for the remaining duration of the therapeutic period. For example, radiation is administered in weeks 1-6 or in weeks 2-6 of a therapeutic period comprising 6 weeks for treating, for instance, a solid tumor. Alternatively, radiation is administered in weeks 1-5 or weeks 2-5 of a therapeutic period comprising 5 weeks. These exemplary radiotherapy administration schedules are not intended, however, to limit the present disclosure. [00196] Antimicrobial therapeutic agents may also be used as therapeutic agents in the present disclosure. Any agent that can kill, inhibit, or otherwise attenuate the function of microbial organisms may be used, as well as any agent contemplated to have such activities. Antimicrobial agents include, but are not limited to, natural and synthetic antibiotics, antibodies, inhibitory proteins (e.g., defensins), antisense nucleic acids, membrane disruptive agents and the like, used alone or in combination. Indeed, any type of antibiotic may be used including, but not limited to, antibacterial agents, antiviral agents, antifungal agents, and the like. [00197] In some embodiments of the present disclosure, a compound of the disclosure and one or more therapeutic agents or anticancer agents are administered to a patient under one or more of the following conditions: at different periodicities, at different durations, at different concentrations, by different administration routes, etc. In some embodiments, the compound is administered prior to the therapeutic or anticancer agent, e.g., 0.5, 1, 2, 3, 4, 5, 10, 12, or 18 hours, 1, 2, 3, 4, 5, or 6 days, or 1, 2, 3, or 4 weeks prior to the administration of the therapeutic or anticancer agent. In some embodiments, the compound is administered after the therapeutic or anticancer agent, e.g., 0.5, 1, 2, 3, 4, 5, 10, 12, or 18 hours, 1, 2, 3, 4, 5, or 6 days, or 1, 2, 3, or 4 weeks after the administration of the anticancer agent. In some embodiments, the compound and the therapeutic or anticancer agent are administered concurrently but on different schedules, e.g., the compound is administered daily while the therapeutic or anticancer agent is administered once a week, once every two weeks, once every three weeks, or once every four weeks. In other embodiments, the compound is administered once a week while the therapeutic or anticancer agent is administered daily, once a week, once every two weeks, once every three weeks, or once every four weeks. [00198] 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. Typically, 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. For example, a suitable intramuscular dose would be about 0.0025 to about 25 mg/kg, or from about 0.01 to about 5 mg/kg. [00199] The unit oral dose may comprise from about 0.01 to about 1000 mg, for example, about 0.1 to about 100 mg of the compound. The unit dose may be administered one or more times daily as one or more tablets or capsules each containing from about 0.1 to about 10 mg, conveniently about 0.25 to 50 mg of the compound or its solvates. [00200] In a topical formulation, the compound may be present at a concentration of about 0.01 to 100 mg per gram of carrier. In a one embodiment, the compound is present at a concentration of about 0.07-1.0 mg/mL, for example, about 0.1-0.5 mg/mL, and in one embodiment, about 0.4 mg/mL. [00201] In addition to administering the compound as a raw chemical, the compounds of the disclosure may be administered as part of a pharmaceutical preparation containing suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the compounds into preparations which can be used pharmaceutically. The preparations, particularly those preparations which can be administered orally or topically and which can be used for one type of administration, such as tablets, dragees, slow release lozenges and capsules, mouth rinses and mouth washes, gels, liquid suspensions, hair rinses, hair gels, shampoos and also preparations which can be administered rectally, such as suppositories, as well as suitable solutions for administration by intravenous infusion, injection, topically or orally, contain from about 0.01 to 99 percent, in one embodiment from about 0.25 to 75 percent of active compound(s), together with the excipient. [00202] The pharmaceutical compositions of the disclosure may be administered to any patient which may experience the beneficial effects of the compounds of the disclosure. Foremost among such patients are mammals, e.g., humans, although the disclosure is not intended to be so limited. Other patients include veterinary patients (cows, sheep, pigs, horses, dogs, cats and the like). [00203] The compounds and pharmaceutical compositions thereof may be administered by any means that achieve their intended purpose. For example, administration may be by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, intrathecal, intracranial, intranasal or topical routes. Alternatively, or concurrently, administration may be by the oral route. The dosage administered will be dependent upon the age, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired. [00204] General Synthetic Procedures [00205] Additional embodiments are disclosed in further detail in the following general synthetic procedures and specific synthetic examples, which are not in any way intended to limit the scope of the claims. [00206] Examples [00207] Compounds of Formula I can be synthesized using the general methods provided in Scheme 1. In accordance with Scheme 1, a bromide or iodide compound of formula G1 can be converted to a borane compound of formula G2 by reacting with an agent such as 4,4,5,5- tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1,3,2-dioxaborolane, or the like. A compound of formula G2 can then be coupled to a compound of formula G5, wherein XA is a functional group appropriate for coupling to a compound of formula G2, to provide a compound of Formula I. The coupling can be accomplished using chemistry known to those having skill in the art, such as palladium catalyzed coupling conditions. The compound of formula G5 can be synthesized by reacting a compound of formula G3 with a compound of formula G4 under nucleophilic aromatic substitution conditions, wherein X ¹ is defined herein and G6 and G7 can be substituted as described herein. It will be also understood that the order of reactions as specified in Scheme 1 can also be reversed, so that a compound of formula G2 reacts with a compound of formula G3 to form an intermediate product, followed by reacting the intermediate product with a compound of formula G4 to provide a compound of Formula I. [00208] Scheme 1: Synthesis of compounds of Formula I [00209] me 2. Following the scheme, a compound of Formula G6 first undergoes nucleophilic substitution with an amine of Formula G7, wherein X ¹ is defined herein and G6 and G7 can be substituted as described herein. The resulting compound of Formula G8, wherein Xa is a group appropriate for functional group interconversion to the tetramethyl-1,3,2-dioxaborolane compound of Formula G9. Exposure of the compound of Formula of G9 to a compound of Formula G10 under coupling conditions, for example palladium catalyzed coupling conditions provides a compound of Formula I. [00210] Scheme 2: Alternative route to compounds of Formula I

[00211] [00212] The following examples are provided so that the invention may be more fully understood, and are not intended to limit the invention in any way. [00213] Example 1: Synthesis of 5-(4-(6-chloroindolin-1-yl)quinazolin-6- yl)pyrimidin-2-amine, Comparitive Compound 1 [00214] Step 1: 6-chloroindoline (1b) [00215] To a stirred solution of 1a (5.00 g, 33.1 mmol) in AcOH (93.0 mL), under N ₂ atmosphere at rt, was added NaCNBH3 (6.24 g, 99.3 mmol) portion-wise over a period of 5 minutes, and the reaction mixture was stirred for 4 h. The reaction mixture was quenched with ice cold water and basified to pH =14 by slow addition of solid NaOH (note: exothermic reaction was observed). The aqueous mixture was extracted with MTBE (2 × 200 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography using EtOAc ^Hexanes (20 ^30%) as eluent. The fractions containing the product were combined and concentrated under vacuum to obtain 6- chloroindoline, 1b, (3.40 g, 68% yield) as a brown liquid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 6.97 (d, J = 7.6 Hz, 1H), 6.63 (dd, J = 8.0 Hz, J = 2.0 Hz , H), 6.57 (d, J = 2.0 Hz, 1H), 3.57 (t, J = 8.4 Hz, 2H), 2.97 (t, J = 8.0 Hz, 2H), MS (ESI + APCI; multimode): 154.0 [M + H] ⁺ . [00216] Step 2: Synthesis of 6-bromo-4-(6-chloroindolin-1-yl)quinazoline (1c) [002 ropanol (50 mL) was added 6-chloroindoline, 1b (0.63 g, 4.10 mmol). The reaction mixture was heated to reflux (85 ^o C) for six hours. The reaction was complete by TLC and an orange precipitate had formed in the reaction mixture. The reaction mixture was filtered while hot over a medium fritted funnel. The filtered solid was rinsed with excess isopropanol (50 mL) and then dried overnight to provide 0.629g. A second solid was isolated from the filtrate after sitting overnight. This solid was dried to provide a second crop of 6-bromo-4-(6-chloroindolin-1-yl)quinazoline, 1c, (0.531 g) (total yield 1.16g, 78%). Rf = 0.43 (1:1 Ethyl Acetate:Heptane), LC/MS (ESI + m/z 361,363). [00218] Step 3: Synthesis of 5-(4-(6-chloroindolin-1-yl)quinazolin-6-yl)pyrimidin-2- amine (Comparative Compound 1) [00219] To a solution consisting of 1c (0.205 g, 0.568 mmol) in Ethanol (4.5 mL) was added 2-aminopyrimidine-5-boronic acid, 1d (0.083 g, 0.597 mmol). Next SiliaCatDpp-Pd (0.220 g, 0.25 mmol/g, 0.06 mmol) was added, followed by the addition of potassium carbonate (2.0 M aqueous solution, 0.57 mL, 1.13 mmol). A stir bar was added to the 5mL microwave vial and the vial was capped under N2 atmosphere. The reaction mixture was heated in Biotage Emerys Optimizer microwave at 125 ^o C for 30 minutes. The crude reaction mixture was filtered over a medium fritted funnel and rinsed with excess ethanol. To the crude filtrate was added Silica G60 (25g) and concentrated under reduced pressure to afford the dry loaded material onto Silica. The dry load column was placed on top of a pre-equilibrated Silicycle 25g column. Purification of the crude material on a Biotage Isolera column eluting with a gradient of 0-10% methanol in dichloromethane afforded 5-(4-(6-chloroindolin-1-yl)quinazolin-6-yl)pyrimidin-2- amine, Comparative Compound 1, (40 mg, 18.8% yield, 95% purity) as a yellow solid. ¹ H NMR (400MHz, DMSO-d6) ^ 8.72 (br s, 1H), 8.66 (br s, 2H), 8.23 (br s, 1H), 8.17 (br d, J=7.32 Hz, 1H), 7.91 (br d, J=8.33 Hz, 1H), 7.60 (br s, 1H), 7.32 (br d, J=6.68 Hz, 1H), 7.02 (br d, J=7.23 Hz, 1H), 6.88 (br s, 2H), 4.60 (br s, 2H) 3.28-3.10 (m, 2H); MS: (ESI ⁺ m/z 375.1, ESI ^– m/z 373.05); TLC: (90:10:0.5, DCM:MeOH:NH ₄ OH) R _f = 0.63 [00220] Example 2: 4-(6-chloroindolin-1-yl)-6-(1H-pyrrolo[2,3-b]pyridin-5- yl)quinazoline, Comparative Compound 2 added pyrrolo[2,3-b]pyridine-5-boronic acid pinacol ester, 1e, (0.145 g, 0.596 mmol). Next SiliaCatDpp-Pd (0.220 g, 0.25 mmol/g, 0.06 mmol) was added, followed by the addition of potassium carbonate (2.0 M aqueous solution, 0.57 mL, 1.13 mmol). A stir bar was added to the 5 mL microwave vial and the vial was capped under N ₂ atmosphere. The reaction mixture was heated in Biotage Emerys Optimizer microwave at 125 ^o C for 30 minutes. The crude reaction mixture was filtered over a medium fritted funnel and rinsed with excess ethanol. To the crude filtrate was added Silica G60 (25 g) and concentrated under reduced pressure to afford the dry loaded material onto Silica. The dry load column was placed on top of a pre-equilibrated Silicycle 25 g column. Purification of the crude material on a Biotage Isolera column eluting with a gradient of 0-10% methanol in dichloromethane. The column provided mixed fractions which were triturated in ethanol solution overnight at 40 ^o C. Filtering this solution over a fritted funnel afforded 4-(6-chloroindolin-1-yl)-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)qu inazoline, Comparative Compound 2, (25 mg, 11% yield, 95% purity) as a yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ ) ^ 11.79 (br s, 1H), 8.77 (s, 1H), 8.62 (s, 1H), 8.39-8.19 (m, 4H), 7.99 (br d, J=8.51 Hz, 1H), 7.63 (s, 1H), 7.55 ( br s, 1H), 7.35 (br d, J=8.05 Hz, 1H), 7.06 (br d, J=8.23 Hz, 1H), 6.53 (br s, 1H), 4.64 (br t, J=7.87 Hz, 2H) 3.30-3.10 (m, 2H); MS: (ESI ⁺ m/z 398.1, ESI ^– m/z 396.1); TLC: (90:10:0.5, DCM:MeOH:NH4OH) Rf = 0.65 [00222] Example 3: Preparation of 4-(6-chloroindolin-1-yl)-6-(1H-pyrazolo[3,4- b]pyridin-5-yl)quinazoline, Compound 3 [ 00 3] o t e st rred so ut on o c n , d oxane ( .50 m ) was c arged w t g (0.184 g, 0.75 mmol), K2CO3 (0.14 g, 1.04 mmol) in water (0.9 mL) de gas 10 min to it added Pd(dppf)Cl2 DCM complex (23.0 mg, 0.029 mmol) and degas 10 min in seal tube heated to 110 °C for 24 h. The reaction mass was cooled to rt added (0.9 mL) of acetic acid and then concentrated under reduced pressure to get crude was used to column chromatography (12.0 g) silica eluted using 5 to 6% methanol in dichloromethane, combined column fractions and concentrated under reduced pressure to afford 4-(6-chloroindolin-1-yl)-6-(1H-pyrazolo[3,4- b]pyridin-5-yl)quinazoline, Compound 3, (100 mg, 59 %,) as a light yellow color solid. ¹ H NMR (400 MHz, DMSO-d6): δ 8.95 (d, J = 2 Hz, 1 H), 8.78 (s, 1 H), 8.63 (d, J = 1.6 Hz, 1 H), 8.44 (d, J = 1.6 Hz, 1 H), 8.32 (dd, J = 8.4, 1.6 Hz, 1 H), 8.23 (d, J = 1.2 Hz, 1 H), 8.01 (d, J = 8.8 Hz, 1 H), 7.72 (d, J = 2.0 Hz, 1 H), 7.35 (d, J = 8.0 Hz, 1H), 7.07 (dd, J = 7.6, 1.6 Hz, 1 H), 4.68 (t, J = 8 Hz, 2 H), 3.21 (t, J = 8.4 Hz, 2 H). [00224] Example 4: Synthesis of 5-(4-(6-chloroindolin-1-yl)quinazolin-6-yl)-3- (trifluoromethyl)pyridin-2-amine, Compound 4 [00225] To the stirred solution of 1c (0.16 g, 0.44 mmol) in 1, 4 dioxane (5.00 mL) was charged with 1h (0.230 g, 0.80 mmol), K2CO3 (0.15 g, 1.11 mmol) in water (1.0 mL) degas 10 min to it added Pd(dppf)Cl2 DCM complex (25.0 mg, 0.031 mmol) and degas 10 min in seal tube heated to 110 °C for 24 h. The reaction mass was cooled to rt added (0.9 mL) of acetic acid and then concentrated under reduced pressure to get crude was used to column chromatography (12.0 g) silica eluted using 5 to 6% methanol in dichloromethane, combined column fractions and concentrated under reduced pressure to afford 5-(4-(6-chloroindolin-1-yl)quinazolin-6-yl)-3- (trifluoromethyl)pyridin-2-amine, Compound 4, (130 mg, 66 %) as a light yellow color solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.76 (s, 1 H), 8.63 (s, 1 H), 8.26 (s, 1 H), 8.24-8.22 (m, 1 H), 8.07 (s, 1 H), 7.94 (d, J = 8.8 Hz, 1 H), 7.56 (s, 1 H), 7.35 (d, J = 8 Hz, 1 H), 7.05 (d, J = 8.8 Hz, 1 H), 6.73 (brs, 2 H), 4.60 (t, J = 8 Hz, 2 H), 3.19 (t, J = 8.0 Hz, 2 H). [00226] Example 5: Synthesis of 4-(6-chloroindolin-1-yl)-6-(1-methylpyrazolo[4,3- b]pyridin-6-yl)quinazoline, Compound 5 [00227] Step 1: Synthesis of 4-(6-chloroindolin-1-yl)-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)quinazoline (1m) . , . , . , ced in resealable tube at rt, was added bis pinacolate diborane (1.69 g, 6.68 mmol) and KOAc (1.64 g, 16.7 mmol). The reaction mixture was de-gassed with Ar (g) for 10 min. Pd(dppf)Cl ₂ ∙CH ₂ Cl ₂ (227 mg, 0.2 mmol) was added in one lot, the tube was sealed, and the mixture was stirred at 120 °C for 2 h. The reaction mixture was cooled to rt, and concentrated under vacuum to obtain the crude product. The crude product was triturated with MTBE (50 mL), filtered under vacuum, washed with MTBE (30 mL), and vacuum dried to obtain 4-(6-chloroindolin-1-yl)-6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)quinazoline, 1m, (1.50 g, 66% yield) as a brown solid. MS (ESI + APCI; multimode): 408.1 [M + H] ⁺ . [00229] Step 2: Synthesis of 4-(6-chloroindolin-1-yl)-6-(1-methylpyrazolo[4,3- b]pyridin-6-yl)quinazoline (Compound 5) ^N _N Cl Cl O N ^N _N N [00230] To a stirred solution of 6-bromo-1-methyl-pyrazolo[4,3-b]pyridine (26.01 mg, 122.64 μmol, 1 eq) in DMF (2 mL) and H2O (0.5 mL) was added 1m (50 mg, 122.64 μmol, 1 eq), K ₃ PO ₄ (78.10 mg, 367.92 μmol, 3 eq) and Pd(dppf)Cl ₂ (8.97 mg, 12.26 μmol, 0.1 eq), the reaction was stirred at 80 °C for 3 h under N ₂ . LCMS showed starting material was consumed completely and the MS of desired product was detected. The reaction was filtered, and filtrate was purified by prep-HPLC (column: Phenomenex Luna C18150*30mm*5um; mobile phase: [water (TFA)-ACN]; B%: 10%-40%, 8min).4-(6-chloroindolin-1-yl)-6-(1-methylpyrazolo[4,3- b]pyridin-6-yl)quinazoline, Compound 5, (29.9 mg, 55.43 μmol, 45.20% yield, 97.68% purity, TFA) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 8.96 - 9.01 (m, 2 H), 8.67 (s, 1 H), 8.59 (s, 1 H), 8.51 (dd, J=8.69, 1.44 Hz, 1 H), 8.35 (s, 1 H), 8.05 (d, J=8.50 Hz, 2 H), 7.45 (d, J=8.13 Hz, 1 H), 7.23 (dd, J=7.94, 1.69 Hz, 1 H), 4.87 (br t, J=7.75 Hz, 2 H), 4.17 (s, 3 H), 3.26 (br t, J=7.75 Hz, 2 H). MS (M + H) ⁺ =413.0 [00231] Example 6: Synthesis of 4-(6-chloro-5-fluoroindolin-1-yl)-6-(1H-pyrazolo[3,4- b]pyridin-5-yl)quinazoline, Compound 6 [00232] Step 1: Synthesis of 6-chloro-5-fluoro-indoline (1j) [00233] To a so , . mmol, 1 eq) in AcOH (40 mL) was added NaCNBH ₃ (4.45 g, 70.76 mmol, 3 eq) the mixture was stirred at 20 °C for12 h. LCMS showed starting material was consumed completely and the MS of desired product was detected. TLC (PE : EtOAc = 3 : 1, R _f = 0.38) showed the starting material was consumed completely and new spot was formed. Cooled to 25 ^o C, the mixture was added H ₂ O (30 mL), the mixture was adjusted pH = 9 by adding saturated NaHCO3 aqueous solution slowly, extracted with ethyl acetate (20 mL * 2). The combined organics were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 40 g silica, 15-30% ethyl acetate in petroleum ether, gradient over 20 min).6-chloro-5-fluoro-indoline, 1j, (2.1 g, 12.24 mmol, 51.88% yield) was obtained as yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 7.06 (d, J=9.17 Hz, 1 H), 6.52 (d, J=6.23 Hz, 1 H), 5.60 (br s, 1 H), 3.43 (t, J=8.44 Hz, 2 H), 2.90 (t, J=8.56 Hz, 2 H). MS (M + H) ⁺ =172.2 [00234] Step 2: Synthesis of 6-bromo-4-(6-chloro-5-fluoro-indolin-1-yl) quinazoline (1k) [0023 ed 6- bromo-4-chloroquinazoline (368.92 mg, 1.52 mmol, 1 eq), the mixture was stirred at 80 °C for 1 h. LCMS showed starting material was consumed completely and the MS of desired product was detected. The reaction mixture was concentrated in vacuum.6-bromo-4-(6-chloro-5-fluoro- indolin-1-yl) quinazoline, 1k, (500 mg, 1.32 mmol, 87.16% yield) was obtained as a yellow solid. MS (M + H) ⁺ =380.1 [00236] Step 3: Synthesis of 4-(6-chloro-5-fluoroindolin-1-yl)-6-(1H-pyrazolo[3,4- b]pyridin-5-yl)quinazoline (Compound 6) [00237] To the stirred solution of 1k (0.16 g, 0.42 mmol) in 1, 4 dioxane (5.00 mL) was charged with 1g (0.186 g, 0.75 mmol), K2CO3 (0.14 g, 1.05 mmol) in water (1.0 mL) degas 10 min to it added Pd(dppf)Cl2 DCM complex (24.0 mg, 0.029 mmol) and degas 10 min in seal tube heated to 110 °C for 24 h. The reaction mass was cooled to rt added (1.0 mL) of acetic acid and then concentrated under reduced pressure to get crude was used to column chromatography (12.0 g) silica eluted using 5 to 6% methanol in dichloromethane, combined column fractions and concentrated under reduced pressure to afford 4-(6-chloro-5-fluoroindolin-1-yl)-6-(1H- pyrazolo[3,4-b]pyridin-5-yl)quinazoline, Compound 6, (80 mg, 48 %) as an light yellow color solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 13.80 (brs, 1 H), 8.96 (d, J = 2.0 Hz, 1 H), 8.75 (s, 1 H), 8.64 (d, J = 2 Hz, 1 H), 8.46 (d, J = 2.0 Hz, 1 H), 8.31 (dd, J = 8.8, 1.6 Hz, 1 H), 8.24 (d, J = 1.2 Hz, 1 H), 7.99 (d, J = 8.8 Hz, 1 H), 7.95 (d, J = 6.8 Hz, 1 H), 7.44 (d, J = 8.8 Hz, 1 H) 4.74 (t, J = 8.0 Hz, 2 H), 3.23 (t, J = 8.0 Hz, 2 H). [00238] Example 7: Synthesis of 5-(4-(6-chloro-5-fluoroindolin-1-yl)quinazolin-6- yl)pyrimidin-2-amine, Compound 7 [00239] To the stirred solution of 1k (0.16 g, 0.42 mmol) in 1, 4 dioxane (5.00 mL) was charged with 1d (0.16 g, 0.73 mmol), K2CO3 (0.14 g, 1.05 mmol) in water (1.0 mL) degas 10 min to it added Pd(dppf)Cl2 DCM complex (24.0 mg, 0.029 mmol) and degas 10 min in seal tube heated to 110 °C for 24 h. The reaction mass was cooled to rt added (0.9 mL) of acetic acid and then water (2.0 mL) concentrated under reduced pressure to get crude was used to column chromatography (12.0 g) silica eluted using 5 to 6% methanol in dichloromethane, combined column fractions and concentrated under reduced pressure to afford 5-(4-(6-chloro-5- fluoroindolin-1-yl)quinazolin-6-yl)pyrimidin-2-amine, Compound 7, (130 mg, 78 %) as an light yellow color solid. ¹ H NMR (400 MHz, DMSO-d6): δ 8.71 (s, 1 H), 8.70 (s, 2 H), 8.28 (d, J = 1.6 Hz, 1 H), 8.19 (dd, J = 8.8, 2 Hz, 1 H), 7.92 (d, J = 8.8 Hz, 1 H), 7.87 (d, J = 6.8 Hz, 1 H), 7.43 (d, J = 8.8 Hz, 1 H), 6.91 (brs, 2 H), 4.68 (t, J = 8.0 Hz, 2 H), 3.21 (t, J = 8.0 Hz, 2 H). [00240] Example 8: Synthesis of 5-(4-(6-chloro-5-fluoroindolin-1-yl)quinazolin-6-yl)- 3-(trifluoromethyl)pyridin-2-amine, Compound 8 _F ^F CF Cl ₃ CF ₃ Cl . g, . , . as charged with 1h (0.20 g, 0.75 mmol), K2CO3 (0.14 g, 1.05 mmol) in water (1.0 mL) degas 10 min to it added Pd(dppf)Cl2 DCM complex (24.0 mg, 0.029 mmol) and degas 10 min in seal tube heated to 110 °C for 24 h. The reaction mass was cooled to rt added (0.9 mL) of acetic acid and then concentrated under reduced pressure to get crude was used to column chromatography (12.0 g) silica eluted using 5 to 6% methanol in dichloromethane, combined column fractions and concentrated under reduced pressure to afford 5-(4-(6-chloro-5-fluoroindolin-1-yl)quinazolin-6- yl)-3-(trifluoromethyl)pyridin-2-amine, Compound 8, (100 mg, 52 %) as an light yellow color solid. ¹ H NMR (400 MHz, DMSO-d6): δ 8.72 (s, 1 H), 8.65 (brs, 1 H), 8.29 (brs, 1 H), 8.22 (dd, J = 8.8, 1.6 Hz, 1 H), 8.09 (d, J = 2.0 Hz, 1 H), 7.92 (d, J = 8.4 Hz, 1 H), 7.81 (d, J = 6.8 Hz, 1 H), 7.44 (d, J = 8.8 Hz, 1 H), 6.72 (brs, 2 H), 4.65 (t, J = 8.0 Hz, 2 H), 3.21 (t, J = 8.0 Hz, 2 H). [00242] 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 ( . m ), under N ₂ atmosphere at rt, was added 6-bromo-4-chloroquinoline-3-carbonitrile (250 mg, 0.94 mmol), and the reaction mixture was stirred at 90 °C for 16 h. The reaction mixture was cooled to rt, whereupon the product precipitated. The precipitated product was collected by filtration under vacuum, washed with MTBE: Hexanes (5:1, 20.0 mL) and dried under vacuum to obtain 6- bromo-4-(6-chloroindolin-1-yl)quinoline-3-carbonitrile, 2c, (200 mg, 55% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6): δ 9.08 (s, 1H), 8.19 (s, 1H), 8.07 (s, 2H), 7.30 (d, J = 8.0 Hz, 1H), 6.90 (d, J = 8.0 Hz, 1H), 6.57 (s, 1H), 4.40 – 4.29 (m, 2H), 3.38 – 3.21 (m, 2H), MS (ESI + APCI; multimode): 386.0 [(M +2) + H] ⁺ . [00245] Step 2: Synthesis of 4-(6-chloroindolin-1-yl)-6-(1H-pyrazolo[3,4-b]pyridin-5- yl)quinoline-3-carbonitrile (Compound 9) [ 00246] To a stirred solution of 2c (200 mg, 0.52 mmol) in 1,4 dioxane (5.00 mL) placed in round bottom flask, was added 1g (320.0 mg, 1.30 mmol), a solution of Cs2CO3 (509 mg, 1.56 mmol) in H2O (1.00 mL) at rt, and the reaction mixture was de-gassed with Ar(g) for 10 min. Pd(dppf)Cl ₂ ∙CH ₂ Cl ₂ (29.8 mg, 0.02 mmol), was added in one lot, and the mixture was stirred at 100 °C for 2 h. The reaction mixture was cooled to rt, and concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel chromatography using 100% EtOAc as eluent. The fractions containing the product were combined and concentrated under vacuum to obtain 4-(6-chloroindolin-1-yl)-6-(1H-pyrazolo[3,4-b]pyridin-5-yl)q uinoline-3- carbonitrile, Compound 9, (65 mg, 30% yield) as a light yellow solid. ¹ H NMR (400 MHz, DMSO-d6): δ 13.5 (br s, 1H), 9.02 (s, 1H), 8.77 (d, J = 2.0 Hz, 1H), 8.46 (d, J = 2.0 Hz, 1H), 8.30 (dd, J = 8.4 Hz, J = 1.6 Hz, 1H), 8.25 – 8.21 (m, 2H), 8.15 (br s, 1H), 7.28 (d, J = 8.0 Hz, 1H), 6.88 (dd, J = 8.0 Hz, J = 1.6 Hz, 1H), 6.50 (s, 1H), 4.40 (t, J = 8.8 Hz, 2H), 3.33 (t, J = 10.4 Hz, 2H), MS (ESI + APCI; multimode): 423.2 [M + H] ⁺ . HPLC: 99.3 (% of AUC). [00247] Example 10: Synthesis of 6-(2-aminopyrimidin-5-yl)-4-(6-chloroindolin-1- yl)quinoline-3-carbonitrile, Compound 10 g, . , . p ced in RB flask, was added 2b (139 mg, 0.62 mmol), a solution of Cs2CO3 (339 mg, 1.04 mmol) in H2O (2.00 mL) at rt, and the reaction mixture was de-gassed with Ar(g) for 10 min. Pd(dppf)Cl ₂ ∙CH ₂ Cl ₂ (21.3 mg, 0.02 mmol) was added in one lot, and the mixture was stirred at 100 °C for 2 h. The reaction mixture was cooled to rt, and concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel chromatography using CH ₃ OH ^CH ₂ Cl ₂ (3 ^5%) as eluent. The fractions containing the product were combined and concentrated under vacuum to obtain 6-(2-aminopyrimidin-5-yl)-4-(6-chloroindolin-1- yl)quinoline-3-carbonitrile, Compound 10, (72 mg, 34% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6): δ 8.97 (s, 1H), 8.52 (s, 2H), 8.17 (d, J = 1.6 Hz, 2H), 8.03 (t, J = 0.8 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 6.87 (dd, J = 7.6 Hz, J = 2.0 Hz, 1H), 6.56 (br s, 2H), 6.44 (s, 1H), 4.38 (t, J = 8.0 Hz, 2H), 3.36 – 3.29 (m, 2 H), MS (ESI + APCI; multimode): 399.1 [M + H] ⁺ . HPLC: 97.8 (% of AUC). [00249] Example 11: Synthesis of Synthesis of 4-(6-chloroindolin-1-yl)-6-imidazo[1,5- a]pyrimidin-3-yl-quinazoline, Compound 11 N Cl Cl , py . g, . μmol, 1 eq) in DMF (1.5 mL) and H2O (0.3 mL) was added 1m (60 mg, 147.17 μmol, 1 eq), K3PO4 (93.72 mg, 441.50 μmol, 3 eq) and Pd(dppf)Cl2 (10.77 mg, 14.72 μmol, 0.1 eq), the reaction was stirred at 80 °C for 3 h under N ₂ . LCMS showed starting material was consumed completely and the MS of desired product was detected. The reaction was filtered, and filtrate was used for purified directly. The filtrate was purified by prep-HPLC (column: Phenomenex Luna 80*30mm*3 μm;mobile phase: [water(0.04%HCl)-ACN];B%: 10%-25%,8min).4-(6- chloroindolin-1-yl)-6-imidazo[1,5-a]pyrimidin-3-yl-quinazoli ne, Compound 11, (7.96 mg, 17.38 μmol, 11.81% yield, 95.03% purity, HCl) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 9.46 (br s, 1 H), 9.07 (s, 1 H), 8.89 - 9.01 (m, 2 H), 8.74 (s, 1 H), 8.50 (dd, J=8.82, 1.31 Hz, 1 H), 8.30 (s, 1 H), 8.21 (d, J=8.63 Hz, 1 H), 7.98 (br s, 1 H), 7.50 (d, J=8.13 Hz, 1 H), 7.33 (dd, J=8.00, 1.88 Hz, 1 H), 5.00 (br t, J=7.63 Hz, 2 H), 3.29 (br t, J=7.57 Hz, 2 H). MS (M + H) ⁺ =399.0 [00251] Example 12: Synthesis of N-[2-chloro-5-[4-(6-chloro-5-fluoro-indolin-1-yl) quinazolin-6-yl]-3-pyridyl] methanesulfonamide, Compound 12 [00252] Step 1: Synthesis of 2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridin-3-amine (4b) [00253] To a 4a, (20 g, 96.41 mmol, 1 eq) in dioxane (250 mL) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1,3,2-dioxaborolane (29.38 g, 115.69 mmol, 1.2 eq), KOAc (23.65 g, 241.01 mmol, 2.5 eq), and Pd(dppf)Cl2 (3.53 g, 4.82 mmol, 0.05 eq). The mixture was purged with N23 times, and then stirred at 100 °C for 16 h. TLC (Petroleum ether/Ethyl acetate=5:1, Rf=0.25) showed a little starting material was remaining and a new spot was formed. The reaction mixture was poured into water (150 mL). The aqueous phase was extracted with ethyl acetate (300 mL*3). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash column (ISCO 120 g silica, 10-15% Ethyl acetate in Petroleum ether, gradient over 15 min).2-chloro-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl) pyridin-3-amine, 4b, (6.75 g, 26.52 mmol, 30% yield) was obtained as a yellow solid. [00254] Step 2: Synthesis of N-[2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-3-pyridyl]-N-methylsulfonyl-methanesulfonamide (4c) [00255] T (200 mL) was added TEA (42.94 g, 424.33 mmol, 59.06 mL, 4 eq), MsCl (31.170 g, 272.11 mmol, 21.06 mL, 2.57 eq) at 0 ^o C. The mixture was stirred at 0 ^o C for 1 h. TLC (Petroleum ether/Ethyl acetate=3:1, Rf=0.84) showed starting material was consumed completely and new spot was formed. The reaction mixture was concentrated in vacuum. The residue was poured into MeOH (10 mL). The mixture was stirred at 20 °C for 1 h, filtered, and the filter cake was concentrated in vacuum to give the crude product. N-[2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 3-pyridyl]- N-methylsulfonyl-methanesulfonamide, 4c, (20 g, 48.70 mmol, 46% yield) was obtained as a white solid. ¹ H NMR (400 MHz, CHLOROFORM-d) δ = 8.77 (d, J = 1.8 Hz, 1H), 8.04 (d, J = 1.6 Hz, 1H), 3.53 (s, 6H), 1.45 - 1.32 (m, 12H) [00256] Step 3: Synthesis of 4-(6-chloro-5-fluoro-indolin-1-yl)-6-iodo-quinazoline (3a) [00257] To a stirred solution of 1j (2 g, 11.66 mmol, 1 eq) in i-PrOH (30 mL) was added 4-chloro-6-iodoquinazoline (3.39 g, 11.66 mmol, 1 eq), the mixture was stirred at 80 °C for 2 h. LCMS showed the starting material was consumed completely and desired MS was detected. The reaction mixture was concentrated in vacuum.4-(6-chloro-5-fluoro-indolin-1-yl)-6-iodo- quinazoline, 3a, (4.8 g, 11.28 mmol, 96.76% yield) was obtained as a yellow solid. MS (M + H) ⁺ = 426.0. [00258] Step 4: Synthesis of N-[2-chloro-5-[4-(6-chloro-5-fluoro-indolin-1-yl) quinazolin-6-yl]-3-pyridyl] methanesulfonamide (Compound 12)

[0025 (0.4 mL) was added 4c (96.49 mg, 234.95 μmol, 1 eq), Cs2CO3 (229.65 mg, 704.85 μmol, 3 eq) and Pd(dppf)Cl2 (17.19 mg, 23.50 μmol, 0.1 eq). The mixture was stirred at 100 °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. The crude product was purified by prep-HPLC (column: Phenomenex Luna 80*30mm*3 μm; mobile phase: [water (0.04%HCl)-ACN]; B%: 20%-45%, 8min). N-[2-chloro-5-[4-(6-chloro-5-fluoro-indolin-1-yl) quinazolin-6-yl]-3-pyridyl]methanesulfonamide, Compound 12, (12.44 mg, 23.58 μmol, 10.04% yield, 95.60% purity) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 9.95 (br s, 1 H), 8.95 (s, 1 H), 8.75 (d, J=2.25 Hz, 1 H), 8.58 (s, 1 H), 8.38 (dd, J=8.82,1.44 Hz, 1 H), 8.28 (br d, J=6.75 Hz, 1 H), 8.23 (d, J=2.25 Hz, 1 H), 8.05 (d, J=8.63 Hz, 1 H), 7.53 (d, J=8.76 Hz, 1 H), 4.87 (br t, J=7.63 Hz, 2 H), 3.24 - 3.27 (m, 2 H), 3.19 (s, 3 H). MS (M + H) ⁺ = 504.1 [00260] Example 13: Synthesis of 6-(6-chloro-5-methoxypyridin-3-yl)-4-(6- chloroindolin-1-yl)quinazoline, Compound 13 [00261] [00262] 5-bromo-2-chloro-3-methoxypyridine (200 mg, 0.90 mmol) and Cs2CO3 (882 mg, 2.71 mmol) in H2O (4.00 mL) was added to a stirred solution of 1m (552 mg, 1.35 mmol) in 1,4 dioxane (20.0 mL) at rt. The mixture was de-gassed with Ar(g) for 10 min. Pd(dppf)Cl ₂ ∙CH ₂ Cl ₂ (51.7 mg, 0.06 mmol) was added in one lot, and the reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was then cooled to rt and concentrated under vaccum to obtain the crude product. The crude product was purified by silica gel chromatography using 100% EtOAc as eluent. The fractions containing the product were combined and concentrated under vacuum to obtain 6-(6-chloro-5-methoxypyridin-3-yl)-4-(6-chloroindolin-1-yl)q uinazoline, Compound 13, (180 mg, 47% yield) as a yellow-green solid. ¹ H NMR (400 MHz, DMSO-d6): δ 8.78 (s, 1H), 8.46 (d, J = 1.6 Hz, 1H), 8.40 (d, J = 2.0 Hz 1H), 8.32 (dd, J = 8.8 Hz, J = 2.0 Hz, 1H), 8.00 (d, J = 8.8 Hz, 1H), 7.89 (d, J = 2.0 Hz, 1H), 7.73 (d, J = 2.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.07 (dd, J = 8.0 Hz, J = 2.0 Hz, 1H), 4.66 (t, J = 8.0 Hz, 2H), 4.02 (s, 3H), 3.19 (t, J = 8.0 Hz, 2H), MS (ESI + APCI; multimode): 423.1 [M + H] ⁺ . HPLC: 96.8 (% of AUC). [00263] Example 14: Synthesis of 4-(6-chloroindolin-1-yl)-6-(2-methyl-3H- imidazo[4,5-b]pyridin-6-yl)quinazoline, Compound 14 [00264] Step 2: Synthesis of 4-(6-chloroindolin-1-yl)-6-(2-methyl-3H-imidazo[4,5- b]pyridin-6-yl)quinazoline (Compound 14): 6-bromo-2-methyl-3H-imidazo[4,5-b]pyridine (100 mg, 0.47 mmol) and a solution of Cs ₂ CO ₃ (459 mg, 1.41 mmol) in H ₂ O (2.00 mL) were added to a stirred solution of 1m (288 mg, 0.70 mmol) in 1,4 dioxane (10.0 mL). The mixture was placed in a resealable tube and de-gassed with Ar(g) for 10 min. Pd(dppf)Cl ₂ ∙CH ₂ Cl ₂ (24.1 mg, 0.03 mmol) was then added in one lot and the tube was sealed. The reaction mixture was stirred at 120 °C for 12 h. Then the reaction mixture was cooled to rt, and concentrated under vaccum to obtain the crude product. The crude product was purified by silica gel chromatography using 100% EtOAc as eluent. The fractions containing the product were combined and concentrated under vacuum to obtain 4-(6- chloroindolin-1-yl)-6-(2-methyl-3H-imidazo[4,5-b]pyridin-6-y l)quinazoline, Compound 14, (80 mg, 41% yield) as a light brown solid. ¹ H NMR (400 MHz, DMSO-d6-Vt (90°C)): 8.78 (s, 1H), 8.59 (s, 1H), 8.33 (d, J = 1.6 Hz, 1H), 8.26–8.23 (m, 1H), 8.14 (s, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.54 (J = 1.6 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.01 (d, J = 2.0 Hz, 1H), 4.59 (t, J = 8.0 Hz, 2H), 3.21 (t, J = 7.6 Hz, 2H), 2.54 (s, 3H), MS (ESI + APCI; multimode): 413.2. [M + H] ⁺ . HPLC: 95.9 (% of AUC). [00265] 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. Pd(dppf)Cl ₂ ∙CH ₂ Cl ₂ (31.8 mg, 0.03 mmol) was added in one lot, the vial was sealed, and the reaction mixture was heated in a microwave reactor at 120 °C for 1.5 h. The reaction mixture cooled to rt and concentrated under vaccum to obtain the crude product. The crude product was purified by silica gel chromatography to using 100% EtOAc as eluent. The fractions containing the product were combined and concentrated under vacuum to obtain 4-(6-chloroindolin-1-yl)-6-(5- methoxypyridin-3-yl)quinazoline, Compound 15 (84 mg, 37% yield) as a yellow-green solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.78 (s, 1H), 8.60 (s, 1H), 8.59 (s, 1H), 8.42 (s, 1H), 8.35–8.28 (m, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.73 – 7.69 (m, 2H), 7.35 (d, J = 8.0 Hz, 1H), 7.06 (dd, J = 8.0 Hz, J = 1.6 Hz, 1H), 4.65 (t, J = 8.0 Hz, 2H), 3.92 (s, 3H), 3.19 (t, J = 8.0 Hz, 2H), MS (ESI + APCI; multimode): 389.1 [M + H] ⁺ . HPLC: 99.8 (% of AUC). [00267] Example 16: Synthesis of 4-(6-chloroindolin-1-yl)-6-(5,6-dimethoxypyridin- 3-yl)quinazoline, Compound 16 , were added 5-bromo-2,3-dimethoxypyridine (107 mg, 0.49 mmol), a solution of Cs2CO3 (479 mg, 1.47 mmol) in H2O (2.00 mL), and the mixture was de-gassed with Ar(g) for 10 min. Pd(dppf)Cl ₂ ∙CH ₂ Cl ₂ (28.0 mg, 0.03 mmol) was added in one lot, and the mixture was stirred at 100 °C for 2 h. The reaction mixture was cooled to rt, and concentrated under vaccum to obtain the crude product. The crude product was purified by silica gel chromatography using 100% EtOAc as eluent. The fractions containing the product were combined and concentrated under vacuum to obtain 4-(6-chloroindolin-1-yl)-6-(5,6-dimethoxypyridin-3-yl)quinaz oline, Compound 16, (60 mg, 28% yield) as a yellow green solid. ¹ H NMR (400 MHz, DMSO-d6): δ 8.77 (s, 1H), 8.33 (s, 1H), 8.27 (d, J = 8.8 Hz, 1H), 8.12 (d, J = 1.2 Hz, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 5.2 Hz, 2H), 7.35 (d, J = 8.0 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), 4.63 (t, J = 8.4 Hz, 2H), 3.92 (s, 3H), 3.89 (s, 3H), 3.19 (t, J = 7.6 Hz, 2H), MS (ESI + APCI; multimode): 419.1 [M + H] ⁺ . HPLC: 98.0 (% of AUC). [00269] Example 17: Synthesis of 4-(6-chloroindolin-1-yl)-6-(6-methoxypyrazin-2- yl)quinazoline, Compound 17 [00270] To a stirred solution of 1m (300 mg, 0.73 mmol) in 1,4 dioxane (20.0 mL) at rt, was added 2-bromo-6-methoxypyrazine (107 mg, 0.73 mmol), a solution of Cs ₂ CO ₃ (718 mg, 2.21 mmol) in H ₂ O (4.00 mL), and the mixture was de-gassed with Ar(g) for 10 min. Pd(dppf)Cl2∙CH2Cl2 (42.1 mg, 0.05 mmol) was added in one lot, and the mixture was stirred at 120 °C for 2 h. The reaction mixture was cooled to rt, and concentrated under vaccum to obtain the crude product. The crude product was purified by silica gel chromatography using 100% EtOAc as eluent. The fractions containing the product were combined and concentrated under vacuum to obtain 4-(6-chloroindolin-1-yl)-6-(6-methoxypyrazin-2-yl)quinazolin e, Compound 17, (110 mg, 39% yield) as a yellow green solid. ¹ H NMR (400 MHz, DMSO-d6): δ 8.95 (t, J = 6.8 Hz, 2H), 8.78 (s, 1H), 8.63 (dd, J = 8.8 Hz, J = 1.6 Hz, 1H), 8.32 (s, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 2.0 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.06 (dd, J = 8.0 Hz, J = 2.0 Hz, 1H), 4.66 (t, J = 8.0 Hz, 2H), 3.99 (s, 3H), 3.21 (t, J = 8.0 Hz, 2H), MS (ESI + APCI; multimode): 390.1 [M + H] ⁺ . HPLC: 99.7 (% of AUC). [00271] Example 18: Synthesis of 4-(6-chloroindolin-1-yl)-6-(3-methyl-1H- pyrazolo[3,4-b]pyridin-5-yl)quinazoline, Compound 18 Cl N Cl g, . , . t rt, was added 5-bromo-3-methyl-1H-pyrazolo[3,4-b]pyridine (100 mg, 0.47 mmol), a solution of Cs2CO3 (460 mg, 1.41 mmol) in H2O (2.00 mL), and the mixture was de-gassed with Ar(g) for 10 min. Pd(dppf)Cl ₂ (24.1 mg, 0.03 mmol) was added in one lot, the tube was sealed, and the mixture was stirred at 120 °C for 12 h. The reaction mixture was cooled to rt and concentrated under vaccum to obtain the crude product. The crude product was purified by silica gel chromatography using CH ₃ OH - CH ₂ Cl ₂ (5 ^10%) as eluent. The fractions containing the product were combined and concentrated under vacuum to obtain 4-(6-chloroindolin-1-yl)-6-(3- methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)quinazoline, Compound 18, (30 mg, 16%, AMRI Lot # IN-ASR-K-90-3, ALB-215209) as a brown solid. ¹ H NMR (400 MHz, DMSO-d6): δ 13.34 (s, 1H), 8.90 (d J = 2.0 Hz, 1H), 8.79 (s, 1H), 8.57 (s, 1H), 8.41 (s, 1H), 8.34 (d, J = 8.8 Hz, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.06 (dd, J = 8.0 Hz, J = 1.6 Hz, 1H), 4.65 (t, J = 8.4 Hz, 2H), 3.20 (t, J = 8.0 Hz, 2H), 2.56 (s, 3H), MS (ESI + APCI; multimode): 413.2 [M + H] ⁺ . HPLC: 95.2 (% of AUC). [00273] Example 19: Synthesis of 4-(6-chloroindolin-1-yl)-6-(3-methoxy-1H- pyrazolo[3,4-b]pyridin-5-yl)quinazoline, Compound 19 , , laced in resealable tube at rt, was added 5-bromo-3-methoxy-1H-pyrazolo[3,4-b]pyridine (100 mg, 0.44 mmol), a solution of Cs ₂ CO ₃ (430 mg, 1.32 mmol) in H ₂ O (2.00 mL), and the mixture was de- gassed with Ar(g) for 10 min. Pd(dppf)Cl2 (22.5 mg, 0.03 mmol) was added in one lot, tube was sealed, and the reaction mixture was stirred at 120 °C for 12 h. The reaction mixture was cooled to rt, and concentrated under vaccum to obtain the crude product. The crude product was purified by silica gel chromatography using CH3OH ^CH2Cl2 (5 ^10%) as eluent. The fractions containing the product were combined and concentrated under vacuum to obtain 4-(6- chloroindolin-1-yl)-6-(3-methoxy-1H-pyrazolo[3,4-b]pyridin-5 -yl)quinazoline, Compound 19, (72.2 mg, 39% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.71 (s, 1H), 8.89 (d, J = 2.0 Hz, 1H), 8.76 (s, 1H), 8.46 (d, J = 2.0 Hz, 1H), 8.40 (d, J = 1.6 Hz, 1H), 8.31 (dd, J = 8.8 Hz, J = 1.6 Hz, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.69 (d, J = 1.6 Hz, 1H), 7.35 (d, J = 7.6 Hz, 1H), 7.05 (dd, J = 8.0 Hz, J = 2.0 Hz, 1H), 4.64 (t, J = 8.0 Hz, 2H), 4.04 (s, 3H), 3.20 (t, J = 8.0 Hz, 2H), MS (ESI + APCI; multimode): 429.1 [M + H] ⁺ . HPLC: 98.7 (% of AUC). [00275] Example 20: Synthesis of 4-(6-chloroindolin-1-yl)-6-(5-methoxypyrazin-2- yl)quinazoline, Compound 20 [00276] To a stirred solution of 1m (200 mg, 0.49 mmol) in 1,4 dioxane (10.0 mL) at rt, was added 2-bromo-5-methoxypyrazine (71.0 mg, 0.49 mmol), a solution of Cs2CO3 (479 mg, 1.47 mmol) in H ₂ O (2.00 mL), and the mixture was de-gassed with Ar(g) for 10 min. Pd(dppf)Cl2∙CH2Cl2 (28.0 mg, 0.03 mmol) was added in one lot, and the reaction mixture was stirred at 120 °C for 2 h. The reaction mixture was cooled to rt, and concentrated under vaccum to obtain the crude product. The crude product was purified by silica gel chromatography using 100% EtOAc as eluent. The fractions containing the product were combined and concentrated under vacuum to obtain 4-(6-chloroindolin-1-yl)-6-(5-methoxypyrazin-2-yl)quinazolin e, Compound 20 (66 mg, 34% yield) as a yellow green solid. ¹ H NMR (400 MHz, DMSO-d6): δ 8.95 (s, 1H), 8.76 (d, J = 4.0 Hz, 2H), 8.54 (d, J = 8.0 Hz, 1H), 8.43 (s, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.72 (s, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.06 (dd, J = 8.0 Hz, J = 1.2 Hz, 1H), 4.64 (t, J = 8.0 Hz, 2H), 3.98 (s, 3H), 3.20 ⁺ (t, J = 7.6 Hz, 2H), MS (ESI + APCI; multimode): 390.1 [M + H] . HPLC: 97.6 (% of AUC). [00277] Example 21: Synthesis of 6-(3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)-4-(6- chloroindolin-1-yl)quinazoline, Compound 21 [00278] To a stirred solution of 1m (200 mg, 0.49 mmol) in 1,4 dioxane (10.0 mL) placed in sealed tube at rt, was added 6-bromo-3H-[1,2,3]triazolo[4,5-b]pyridine (97.0 mg, 0.49 mmol), a solution of Cs ₂ CO ₃ (479 mg, 1.47 mmol) in H ₂ O (2.00 mL), and the mixture was de-gassed with Ar(g) for 10 min. Pd(dppf)Cl2 (25.1 mg, 0.03 mmol) was added in one lot, the tube was sealed, and the mixture was stirred at 110 °C for 12 h. The reaction mixture was cooled to rt, and concentrated under vaccum to obtain the crude product. The crude product was purified by silica gel chromatography using CH3OH ^CH2Cl2 (5 ^10%) as eluent. The fractions containing the product were combined and concentrated under vacuum to obtain 6-(3H-[1,2,3]triazolo[4,5- b]pyridin-6-yl)-4-(6-chloroindolin-1-yl)quinazoline, Compound 21, (100 mg, 51% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.14 (d, J = 1.6 Hz, 1H), 8.78 (s, 2H), 8.53 (s, 1H), 8.38 (dd, J = 8.8 Hz, J = 1.6 Hz, 1H), 8.02 (d, J = 8.8 Hz, 1H), 7.78 (J = 1.6 Hz, 1H), 7.36 (d, J = 7.6 Hz, 1H), 7.07 (dd, J = 8.0 Hz, J = 1.6 Hz, 1H), 4.71 (t, J = 8.0 Hz, 2H), 3.20 (t, J = 7.6 Hz, 2H), MS (ESI + APCI; multimode): 400.1 [M + H] ⁺ . HPLC: 97.2 (% of AUC). [00279] Example 22: Synthesis of 5-(4-(6-chloroindolin-1-yl)quinazolin-6-yl)pyridin- 2-ol, Compound 22 [00280] To a stirred solution of 1m (233 mg, 0.57 mmol) in 1,4 dioxane (5.0 mL) placed in microwave vial, was added 5-bromopyridin-2-ol (99.5 mg, 0.57 mmol), a solution of Cs2CO3 (558.0 mg, 1.71 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 (32.7 mg, 0.04 mmol) was added in one lot, and the vial was sealed. The reaction mixture was heated in a microwave reactor at 120 °C for 1 h. The reaction mixture was cooled to rt and concentrated under vaccum to obtain the crude product. The crude product was purified by silica gel chromatography using CH ₃ OH ^CH ₂ Cl ₂ (5 ^10%) as eluent. The fractions containing the product were combined and concentrated under vacuum to obtain 5-(4- (6-chloroindolin-1-yl)quinazolin-6-yl)pyridin-2-ol, Compound 22, (27 mg, 13% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6): δ 11.94 (s, 1H), 8.72 (s, 1H), 8.20 (s, 1H), 8.14 (d, J = 8.8 Hz, 1H), 7.95 – 7.88 (m, 3H), 7.64 (d, J = 1.6 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.05 (d, J = 6.4 Hz, 1H), 6.47 (d, J = 9.2 Hz, 1H), 4.62 (t, J = 8.0 Hz, 2H), 3.20 (t, J = 7.6 Hz, 2H), MS (ESI + APCI; multimode): 375.1 [M + H] ⁺ . HPLC: 96.0 (% of AUC). [00281] Example 23: Synthesis of 5-(4-(6-chloroindolin-1-yl)quinazolin-6-yl)pyridin- 3-ol, Compound 23 OH Cl 3 [00282] To a stirred solution of 1m (230 mg, 0.56 mmol) in 1,4 dioxane (10.0 mL) at rt, was added 5-bromopyridin-3-ol (97.6 mg, 0.56 mmol), a solution of Cs2CO3 (550 mg, 1.69 mmol) in H ₂ O (2.00 mL), and the mixture was de-gassed with Ar(g) for 10 min. Pd(dppf)Cl2∙CH2Cl2 (32.2 mg, 0.03 mmol) was added in one lot, and the mixture was stirred at 100 °C for 2 h. The reaction mixture was cooled to rt and concentrated under vaccum to obtain the crude product. The crude product was purified by silica gel chromatography using 100% EtOAc as eluent. The fractions containing the product were combined and concentrated under vacuum to obtain 5-(4-(6-chloroindolin-1-yl)quinazolin-6-yl)pyridin-3-ol, Compound 23, (70 mg, 33% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6): δ 10.14 (s, 1H), 8.77 (s, 1H), 8.45 (s, 1H), 8.35 (s, 2H), 8.20 (d, J = 8.8 Hz, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.67 (s, 1H), 7.49 (s, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), 4.64 (t, J = 8.0 Hz, 2H), 3.20 (t, J = 8.0 Hz, 2H), MS (ESI + APCI; multimode): 375.1 [M + H] ⁺ . HPLC: 96.3 (% of AUC). [00283] Example 24: Synthesis of 4-(6-chloroindolin-1-yl)-6-(5- (methylsulfonyl)pyridin-3-yl)quinazoline, Compound 24 [00284 L) placed in microwave vial, was added 3-bromo-5-(methylsulfonyl)pyridine (116 mg, 0.49 mmol), a solution of Cs2CO3 (479 mg, 1.47 mmol) in H2O (1.00 mL) at rt, and the mixture was de-gassed with Ar(g) for 10 min. Pd(dppf)Cl2∙CH2Cl2 (28.0 mg, 0.03 mmol) was added in one lot, the vial was sealed, and the reaction mixture was heated in a microwave reactor at 120 °C for 1 h. The reaction mixture was cooled to rt and concentrated under vaccum to obtain the crude product. The crude product was purified by silica gel chromatography using 100% EtOAc as eluent. The fractions containing the product were combined and concentrated under vacuum to obtain 4-(6- chloroindolin-1-yl)-6-(5-(methylsulfonyl)pyridin-3-yl)quinaz oline, Compound 24, (60 mg, 18%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6): δ 9.34 (d, J = 2.0 Hz, 1H), 9.10 (d, J = 2.0 Hz, 1H), 8.78 (s, ), . 7 (s, 1H), 8.55 (s, 1H), 8.37 (d, J = 8.8 Hz, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.79 (d, J = 1.2 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.07 (d, J = 8.0 Hz, J = 1.6 Hz, 1H), 4.69 (t, J = 8.0 Hz, 2H), 3.43 (s, 3H), 3.20 (t, J = 8.0 Hz, 2H), MS (ESI + APCI; multimode): 437.1 [M + H] ⁺ . HPLC: 96.1 (% of AUC). [00285] 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. Pd(dppf)Cl ₂ ∙CH ₂ Cl ₂ (28.0 mg, 0.03 mmol) was added in one lot, the vial was sealed, and the mixture was heated in a microwave reactor at 120 °C for 1 h. The reaction mixture was cooled to rt and concentrated under vaccum to obtain the crude product. The crude product was purified by silica gel chromatography using 100% EtOAc as eluent. The fractions containing the product were combined and concentrated under vacuum to obtain 5-(4-(6- chloroindolin-1-yl)quinazolin-6-yl)nicotinaldehyde, Compound 25, (70 mg, 37% yield) as a pale yellow solid. ¹ H NMR (400 MHz, DMSO-d6): δ 10.21 (s, 1H), 9.28 (d, J = 2.0 Hz, 1H), 9.10 (d, J = 1.2 Hz, 1H), 8.78 (s, 2H), 8.62 (s, 1H), 8.50 (d, J = 1.2 Hz, 1H), 8.34 (t, J = 1.6 Hz, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 1.6 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.07 (dd, J = 8.0 Hz, J = 1.6 Hz, 1H), 4.67 (t, J = 8.0 Hz, 2H), 3.19 (t, J = 8.0 Hz, 2H), (ESI + APCI; multimode): 387.1 [M + H] ⁺ . HPLC - 97.4 (% of AUC). [00287] 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. Pd(dppf)Cl2∙CH2Cl2 (32.2 mg, 0.03 mmol) was added in one lot, the vial was sealed, and the mixture was heated in a microwave reactor at 120 °C for 1h. The reaction mixture was cooled to rt, and concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel chromatography using CH ₃ OH ^CH ₂ Cl ₂ (5 ^10%) the fractions containing the product were combined and concentrated under vacuum to obtain 5-(4-(6-chloroindolin-1- yl)quinazolin-6-yl)pyrimidin-2-ol, Compound 26, (39 mg, 18% yield) as a yellow- green solid. ¹ H NMR (400 MHz, DMSO-d6): δ 12.35 (br s, 1H), 8.73 (s, 2H), 8.31 (s, 2H), 8.18 (d, J = 8.4 Hz, 1H), 7.92 (d, J = 8.8 Hz, 1H), 7.72 (s, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), 4.65 (t, J = 8.0 Hz, 2H), 3.19 (t, J = 8.0 Hz, 2H), MS (ESI + APCI; MULTIMODE): 376.1 (M+H) ⁺ , HPLC: 98.9 (% of AUC). [00289] Example 27: Synthesis of 6-([1,2,4]triazolo[4,3-a]pyridin-7-yl)-4-(6- chloroindolin-1-yl)quinazoline, Compound 27 [002 g, . , . ) placed in microwave vial, was added 7-bromo-[1,2,4]triazolo[4,3-a]pyridine (99.6 mg, 0.56 mmol), a solution of Cs ₂ CO ₃ (493.3 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 (28.9 mg, 0.03 mmol) was added in one lot, the vial was sealed, and the reaction mixture was heated in a microwave reactor at 120 °C for 1 h. The reaction mixture was cooled to rt, and concentrated under vaccum to obtain the crude product. The crude product was purified by silica gel chromatography using CH ₃ OH ^CH ₂ Cl ₂ (5 ^10%) as eluent. The fractions containing the product were combined and concentrated under vacuum to obtain 6-([1,2,4]triazolo[4,3-a]pyridin-7-yl)-4-(6-chloroindolin- 1-yl)quinazoline, Compound 27, (120 mg, 60% yield) as a yellow green solid. ¹ H NMR (400 MHz, DMSO-d6): δ 9.28 (s, 1H), 8.78 (s, 1H), 8.69 (d, J = 7.2 Hz, 1H), 8.55 (s, 1H), 8.39 (d, J = 8.8 Hz, 1H), 8.25 (s, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.77 (s, 1H), 7.48 (d, J = 6.8 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.07 (dd, J = 8.0 Hz, J = 1.6 Hz, 1H), 4.71 (t, J = 8.0 Hz, 2H), 3.21(t, J = 8.0 Hz, 2H), MS (ESI + APCI; multimode): 399.1 [M + H] ⁺ . HPLC: 96.9 (% of AUC). [00291] 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)Cl ₂ ∙CH ₂ Cl ₂ (28.9 mg, 0.03 mmol) was added in one lot, the vial was sealed, and the mixture was heated in a microwave reactor at 120 °C for 1 h. The reaction mixture was cooled to rt, and concentrated under vaccum to obtain the crude product. The crude product was purified by silica gel chromatography using CH ₃ OH ^CH ₂ Cl ₂ (gradient 5 ^10%) as eluent. The fractions containing the product were combined and concentrated under vacuum to obtain 4-(6-chloroindolin-1-yl)-6-(1H-pyrazolo[4,3-b]pyridin-6-yl)q uinazoline, Compound 28, (60 mg, 29%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6): δ 13.52 (s, 1H), 8.93 (d, J = 2.0Hz, 1H), 8.79 (s, 1H), 8.49 (d, J = 2.0 Hz, 1H), 8.37 – 8.33 (m, 3H), 8.02 (d, J = 8.8 Hz, 1H), 7.74 (d, J = 2.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.07 (dd, J = 8.0 Hz, J = 2.0 Hz, 1H), 4.70 (t, J = 8.0 Hz, 2H), 3.20 (t, J = 8.0 Hz, 2H), MS (ESI + APCI; multimode): 399.2 [M + H] ⁺ . HPLC: 98.5 (% of AUC). [00293] Example 29: Synthesis of 6-([1,2,4]triazolo[4,3-a]pyrimidin-6-yl)-4-(6- chloroindolin-1-yl)quinazoline, Compound 29 [00294] To a stirred solution of 1m (200 mg, 0.49 mmol) in 1,4-dioxane (5.00 mL) placed in microwave vial, was added 6-bromo-[1,2,4]triazolo[4,3-a]pyrimidine (98.0 mg, 0.56 mmol), a solution of Cs ₂ CO ₃ (479 mg, 1.47 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 (28.0 mg, 0.03 mmol) was added in one lot, and the vial was closed. The reaction mixture was irradiated with microwaves at 120 °C for 1 h. The reaction mixture was cooled to rt, and concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel chromatography using 100% EtOAc as eluent. The fractions containing the product were combined and concentrated under vacuum to obtain 6- ([1,2,4]triazolo[4,3-a]pyrimidin-6-yl)-4-(6-chloroindolin-1- yl)quinazoline, Compound 29, (125 mg, 43% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.93 (s, 1H), 9.38 (d, J = 2.4 Hz, 1H), 8.77 (d, J = 3.6 Hz, 1H), 8.60 (d, J = 1.6 Hz, 1H), 8.80 (dd, J = 8.8 Hz, J = 2.0 Hz, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.87(d, J = 2.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.08 (dd, J = 8.0 Hz, J = 2.0 Hz, 1H), 4.74 (t, J = 8.0 Hz, 2H), 3.21 (t, J = 8.0 Hz, 2H), MS (ESI + APCI; multimode): 400.2 [M + H] ⁺ . HPLC: 97.0 (% of AUC). [00295] Example 30: Synthesis of 5-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6- yl]-N,N-dimethyl-pyridine-3-carboxamide, Compound 30 [00296] Step 1: Synthesis of 4-(6-chloro-5-fluoroindolin-1-yl)-6-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)quinazoline (1n): [00297] To a stirred solution of 1k (1.35 g, 3.57 mmol) in Toluene (50.0 mL), placed in a 3 neck round bottom flask, under N2 atmosphere at rt,were added bis pinacolate diborane (2.71 g, 4.64 mmol), KOAc (2.24 g, 10.7 mmol), 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. The fractions containing the product were combined and concentrated under vacuum to obtain 4-(6-chloro-5-fluoroindolin-1-yl)-6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)quinazoline, 1n, (800 mg, 52% yield) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d6): δ 8.76 (s, 1H), 8.47 (s, 1H), 8.07(d, J = 8.4 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 6.4 Hz, 1H), 7.43 (d, J = 8.8 Hz, 1H), 4.55 (t, J = 8.0 Hz, 2H), 3.25 (t, J = 8.0 Hz, 2H), 1.32 (s, 12H) ; MS (ESI + APCI; multimode): 425.0 [(M + H] ⁺ . [00298] Step 2: Synthesis of 5-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6-yl]-N,N- dimethyl-pyridine-3-carboxamide (Compound 30) [00299] To a stirred solution of 1n (60 mg, 140.95 μmol, 1 eq) in DMF (1.5 mL) and H ₂ O (0.3 mL) was added 5-bromo-N,N-dimethyl-pyridine-3-carboxamide (32.29 mg, 140.95 μmol, 1 eq), Cs2CO3 (137.77 mg, 422.84 μmol, 3 eq) and Pd(dppf)Cl2 (10.31 mg, 14.09 μmol, 0.1 eq), the reaction was stirred at 100 °C for 3 h under N ₂ . 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. The crude product was purified by prep-HPLC (column: Phenomenex Luna 80*30 mm * 3 μm; mobile phase: [water (0.04%HCl)-ACN]; B%: 10%-40%, 8min). 5-[4-(6-chloro-5-fluoro-indolin-1-yl) quinazolin-6-yl]-N,N-dimethyl-pyridine- 3-carboxamide, Compound 30, (8.4 mg, 16.82 u mol, 11.94% yield, 97% purity, HCl) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 9.20 - 9.26 (m, 1 H), 9.03 - 9.10 (m, 1 H), 8.77 - 8.83 (m, 1 H), 8.70 - 8.76 (m, 1 H), 8.53 - 8.59 (m, 1 H), 8.38 - 8.52 (m, 2 H), 8.23 (d, J=8.68 Hz, 1 H), 7.60 (d, J=8.56 Hz, 1 H), 5.02 (s, 2 H), 3.30 (br t, J=7.40 Hz, 2 H), 2.95 - 3.06 (m, 6 H). MS (M + H) ⁺ = 448.0. [00300] Example 31: Synthesis of 5-[4-(6-chloro-5-fluoro-indolin-1-yl) quinazolin-6- yl] pyridin-3-ol, Compound 31 [00 0.4 mL) was added Cs2CO3 (229.65 mg, 704.84 μmol, 3 eq), Pd(dppf)Cl2 (17.19 mg, 23.49 μmol, 0.1 eq) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-ol (51.94 mg, 234.95 μmol, 1 eq), the reaction was stirred at 100 °C for 3 h under N ₂ . 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. The crude product was purified by prep-HPLC (column: Phenomenex Luna 80*30mm*3 μm; mobile phase: [water (0.04%HCl)-ACN]; B%: 5%-30%, 8min). 5-[4-(6-chloro-5-fluoro-indolin-1-yl) quinazolin-6-yl] pyridin-3-ol, Compound 31, (52.13 mg, 121.44 μmol, 51.69% yield, 100% purity, HCl) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 11.38 (br s, 1 H), 9.03 (s, 1 H), 8.75 (d, J=1.63 Hz, 1 H), 8.66 (s, 1 H), 8.29 - 8.58 (m, 3 H), 7.98 - 8.27 (m, 2 H), 7.58 (d, J=8.76 Hz, 1 H), 4.97 (br t, J=7.57 Hz, 2 H), 3.30 (br t, J=7.50 Hz, 2 H). MS (M + H) ⁺ = 393.0 [00302] Example 32: Synthesis of 4-(6-chloro-5-fluoro-indolin-1-yl)-6-(5- methylsulfonyl-3-pyridyl) quinazoline, Compound 32

[003 (0.4 mL) was added Cs2CO3 (229.65 mg, 704.84 μmol, 3 eq), Pd(dppf)Cl2 (17.19 mg, 23.49 μmol, 0.1 eq) and 3-methylsulfonyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -yl)pyridine (66.53 mg, 234.95 μmol, 1 eq), the reaction was stirred at 100 °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. The crude product was purified by prep- HPLC (column: Phenomenex Luna 80*30mm*3 μm; mobile phase: [water (0.04%HCl)-ACN]; B%: 10%-30%, 8min).4-(6-chloro-5-fluoro-indolin-1-yl)-6-(5-methylsulfonyl -3-pyridyl) quinazoline, Compound 32, (5.9 mg, 12.52 μmol, 5.33% yield, 96.54% purity) was obtained as a brown gum. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 9.40 (br s, 1 H), 8.97 - 9.21 (m, 2 H), 8.67 - 8.84 (m, 2 H), 8.41 - 8.65 (m, 2 H)m, 8.08 (br d, J=8.00 Hz, 1 H), 7.59 (br d, J=7.75 Hz, 1 H), 5.01 (br s, 2 H), 3.38 - 3.40 (m, 3 H), 3.33 -3.35 (m, 2 H). MS (M + H) ⁺ = 455.0 [00304] Example 33: Synthesis of 5-[4-(6-chloro-5-fluoro-indolin-1-yl) quinazolin-6- yl] pyridine-3-carbaldehyde, Compound 33 [00305] To a solution of 3a (100 mg, 234.95 μmol, 1 eq) in DMF (2 mL) and H ₂ O (0.4 mL) was added Cs2CO3 (229.65 mg, 704.84 μmol, 3 eq), Pd(dppf)Cl2 (17.19 mg, 23.49 μmol, 0.1 eq) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-ca rbaldehyde (54.76 mg, 234.95 μmol, 1 eq), the reaction was stirred at 100 °C for 3 h under N2. 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. The crude product was purified by prep-HPLC (column: NP-1; mobile phase: [Heptane-EtOH]; B%: 5%-95%, 16 min) 5-[4-(6- chloro-5-fluoro-indolin-1-yl) quinazolin-6-yl] pyridine-3-carbaldehyde, Compound 33, (28.54 mg, 70.50 μmol, 30.01% yield, 100% purity) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ = 10.27 - 10.16 (m, 1H), 9.36 - 9.26 (m, 1H), 9.16 - 9.04 (m, 1H), 8.80 - 8.72 (m, 1H), 8.68 - 8.59 (m, 1H), 8.56 - 8.46 (m, 1H), 8.40 - 8.26 (m, 1H), 8.04 - 7.93 (m, 2H), 7.44 (d, J = 8.9 Hz, 1H), 4.73 (br t, J = 8.0 Hz, 2H), 3.26 - 3.19 (m, 2H). MS (M + H) ⁺ = 405.1 [00306] Example 34: Synthesis of 5-(4-(6-chloro-5-fluoroindolin-1-yl)quinazolin-6- yl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one, Compound 34 [00307] To a stirred solution of 1n (0.15 g, 0.35 mmol) in 1,4 dioxane (10.0 mL), placed in a sealed tube, under N2 atmosphere at rt, was added 5-bromo-1,3-dihydro-2H-pyrrolo[2,3- b]pyridin-2-one (0.11 g, 0.52 mmol), a solution of Cs2CO3 (0.34 g, 1.05 mmol) in H2O (2.00 mL) at rt, and the mixture was de-gassed with Ar (g) for 10 min. Pd(dppf)Cl ₂ ∙CH ₂ Cl ₂ (0.019 g, 0.024 mmol) was added in one lot, and the reaction mixture was heated to 120 °C for 4 h. The reaction mixture was cooled to rt and then concentrated under vaccum to obtain the crude product. The crude product was purified by silica gel chromatography using CH ₃ OH ^CH ₂ Cl ₂ (1 ^10%) as eluent to afford the product, which was triturated with methanol, filtered under vacuum and dried to obtain 5-(4-(6-chloro-5-fluoroindolin-1-yl)quinazolin-6-yl)-1,3-dih ydro-2H- pyrrolo[2,3-b]pyridin-2-one, Compound 34, (45.0 mg, 17% yield) as a brown solid. ¹ H NMR (400 MHz, DMSO-d6): δ 11.16 (s, 1H), 8.73 (s, 1H), 8.49 (d, J = 2.0 Hz, 1H), 8.32 (d, J = 1.6 Hz, 1H), 8.23-8.15 (m, 1H), 8.02 (s, 1H),7.96- 7.90 (m, 2H), 7.44(d, J = 8.8 Hz, 1H), 4.70 (t, J = 8.0 Hz, 2H), 3.64 (s, 2H), 3.23(t, J = 8.0 Hz, 2H); MS (ESI + APCI; multimode): 432.0 [M + H] ⁺ ; HPLC: 95.3 (% of AUC). [00308] 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. Pd(dppf)Cl ₂ (0.013 g, 0.016 mmol) was added in one lot, and the reaction mixture was heated to 120 °C for 4 h. The reaction mixture was cooled to rt and then concentrated under vaccum to obtain the crude product. The crude product was purified by silica gel chromatography using CH ₃ OH ^CH ₂ Cl ₂ (1 ^10%) as eluent to afford the product, which was triturated with methanol, filtered under vacuum and dried to obtain 6-(4-(6- chloro-5-fluoroindolin-1-yl)quinazolin-6-yl)oxazolo[4,5-b]py ridin-2(3H)-one, Compound 35, (25.0 mg) as a light yellow solid. ¹ H NMR (400 MHz, DMSO-d6): δ 12.5 (s, 1H), 8.73 (s, 1H), 8.49 (d, J = 2.0 Hz, 1H), 8.38 (s, 1H), 8.24 (d, J = 8.8 Hz, 1H), 8.14 (d, J = 1.6 Hz, 1H), 7.97 - 7.94 (m, 2H), 7.44 (d, J = 8.8 Hz, 1H), 4.71 (t, J =8.0 Hz, 2H), 3.22 (t, J = 8.0 Hz, 2H); MS (ESI + APCI; multimode): 434 [M + H] ⁺ . HPLC: 98.1 (% of AUC). [00310] 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 (0.022 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. The crude product was purified by silica gel chromatography using CH ₃ OH ^CH ₂ Cl ₂ (1 ^10%) as eluent to afford the product, which was triturated with methanol, filtered under vacuum and dried to obtain 6-(1H- benzo[d][1,2,3]triazol-5-yl)-4-(6-chloro-5-fluoroindolin-1-y l)quinazoline, Compound 36, (35.0 mg, 19% yield) as a light brown solid. ¹ H NMR (400 MHz, DMSO-d6): δ 15.87 (s, 1H), 8.75 (s, 1H), 8.46 (s, 1H), 8.33 (dd, J = 8.8 Hz, J = 8.8 Hz, 1H), 8.00 - 7.94 (m, 4H), 7.44 (d, J = 8.8 Hz, 1H), 4.71 (t, J = 8.0 Hz, 2H), 3.22 (t, J = 8.0 Hz, 2H); MS (ESI + APCI; multimode): 417 [M + H] ⁺ ; HPLC: 95.4 (% of AUC). [00312] Example 37: Synthesis of 2-amino-5-(4-(6-chloro-5-fluoroindolin-1- yl)quinazolin-6-yl)nicotinaldehyde, Compound 37 [0 ced in a sealed tube, under N2 atmosphere at rt, was added 2-amino-5-bromonicotinaldehyde (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. The crude product was purified by silica gel chromatography using CH ₃ OH ^CH ₂ Cl ₂ (1 ^10%) as eluent to afford the product, which was triturated with methanol, filtered under vacuum and dried to obtain 2- amino-5-(4-(6-chloro-5-fluoroindolin-1-yl)quinazolin-6-yl)ni cotinaldehyde, Compound 37, ( 96.0 mg, 48% yield) as a light yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.99 (s, 1H), 8.73 (t, J = 7.6 Hz, 2H), 8.50 (d, J = 2.4 Hz, 1H), 8.35 (s, 1H), 8.25 - 8.23 (m, 1H), 7.95 (d, J = 8.8 Hz, 1H), 7.88 (d, J = 6.8 Hz, 1H), 7.74 (s, 2H), 7.43 (d, J = 8.8 Hz, 1H), 4.69 (t, J = 8.0 Hz, 2 H), 3.22 (t, J = 8.0 Hz, 2 H); MS (ESI + APCI; multimode): 420 [M + H] ⁺ ; HPLC: 98.7 (% of AUC). [00314] 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 . , p aced in a sealed tube, under N2 atmosphere at rt, was added 6-bromo-1,3-dihydro-2H-imidazo[4,5- b]pyridin-2-one (0.15 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)Cl ₂ ∙CH ₂ Cl ₂ (0.024 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. The crude product was purified by preparative HPLC (Method: performed using a WATERS MASS BASED AUTOPURIFICATION HPLC system with a binary solvent system A and B using a gradient elution: HPLC Method: GEMINI C18@10 µm (30 × 150 mm, 10 µ); mobile phase, A= 0.05% TFA in H ₂ O and B= ACN; Flow rate: 30 mL/min, Injection volume: 300 µL, Runtime: 15min, gradient: 90-55%A, 10-45% B (0.0-10 min); (UV detection at 220 nm). The fractions containing only the pure product were combined for concentration to obtain 6-(4-(6-chloro-5-fluoroindolin-1-yl)quinazolin-6-yl)-1,3-dih ydro-2H-imidazo[4,5-b]pyridin-2- one, Compound 38, (18.0 mg, 9% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ VT (90 ^C) NMR):δ 11.1 (brs, 1H), 10.6 (brs, 1H), 8.73 (s, 1H), 8.28 (d, J = 2.0 Hz, 1H), 8.23 (d, J = 2.0 Hz, 1H), 8.15 (dd, J = 8.8 Hz, J = 8.4 Hz, 1H), 7.96 - 7.91 (m , 1H), 7.76 (d, J = 6.8 Hz, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.35 - 7.32 (m , 1H), 4.62 (t, J = 8.0 Hz, 2H), 3.23 (t, J = 8.4 Hz, 2H), MS (ESI + APCI; multimode): 433 [M + H] ⁺ . HPLC: 96.7% (% of AUC). [00316] Example 39: Synthesis of (5-(4-(6-chloro-5-fluoroindolin-1-yl)quinazolin-6- yl)pyridin-3-yl)(4-methylpiperazin-1-yl)methanone, Compound 39 [00317] Step 1: Preparation of (5-bromopyridin-3-yl)(4-methylpiperazin-1- yl)methanone (1q) [00318] To a stirred solution of 1o (0.50g, 2.47 mmol) in CH2Cl2 (20.0 mL), at rt, was added 1p (0.3 mL, 2.97 mmol), HOBt (0.50 g, 3.70 mmol), EDC•HCl (0.70 g, 3.70 mmol) followed by Et ₃ N (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 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. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.79 (d, J = 2.4 Hz, 1H), 8.58 (d, J = 1.6 Hz, 1H), 8.12 (t, J = 4.0 Hz, 1H), 3.61 (brs, 2H), 3.31 (brs, 2H), 2.36 (brs, 2H), 2.27 (brs, 2H), 2.19 (s, 3H); MS (ESI + APCI; multimode): 285 [M + H] ⁺ . [00319] 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. The crude product was purified by silica gel chromatography using CH ₃ OH ^CH ₂ Cl ₂ (1 ^10%) as eluent to afford the product, which was triturated with methanol, filtered under vacuum and dried to obtain (5-(4-(6-chloro-5- fluoroindolin-1-yl)quinazolin-6-yl)pyridin-3-yl)(4-methylpip erazin-1-yl)methanone, Compound 39, (165 mg, 55% yield) as a light yellow solid. ¹ H NMR (400 MHz, DMSO-d6): δ 9.10 (s, 1H), 8.76(s, 1H), 8.63 (s, 1H), 8.48 (s, 1H), 8.31 (d, J = 8.8 Hz, 1H), 8.22 (s, 1H), 8.00 – 7.95 (m, 2H), 7.45 (d, J = 8.8 Hz, 1H), 4.72 (t, J = 15.6 Hz, 2H), 3.67 (s, 2H), 3.38 (s, 2H), 3.22 (t, J = 8.0 Hz, 2 H), 2.40 (s, 2H), 2.31(d, J = 14.4 Hz, 2 H), 2.20 (s, 3H); MS (ESI + APCI; multimode): 503 [M + H] ⁺ ; HPLC: >99 (% of AUC). [00321] Example 40: Synthesis of (2-amino-5-(4-(6-chloro-5-fluoroindolin-1- yl)quinazolin-6-yl)pyridin-3-yl)(4-methylpiperazin-1-yl)meth anone, 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. ¹ H NMR (400 MHz, DMSO-d6): δ 8.06 (s, 1H), 7.52 (s, 1H), 6.17 (s, 2H), 3.41 (brs, 4H), 2.30 (s, 4H), 2.18 (s, 3H); MS (ESI + APCI; multimode): 299 [M + H] ⁺ . [00324] 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): a sealed tube, under N2 atmosphere at rt, was added 4 (0.22 g, 0.51 mmol), a solution of Cs2CO3 (0.49 g, 1.53 mmol) in H ₂ O (2.00 mL) at rt, and the mixture was de-gassed with Ar (g) for 10 min. Pd(dppf)Cl ₂ ∙CH ₂ Cl ₂ (0.029 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. The crude product was purified by silica gel chromatography using CH ₃ OH ^CH ₂ Cl ₂ (1 ^10%) as eluent to afford the product, which was triturated with methanol, filtered under vacuum and dried to obtain (2-amino-5-(4-(6-chloro-5- fluoroindolin-1-yl)quinazolin-6-yl)pyridin-3-yl)(4-methylpip erazin-1-yl)methanone, Compound 40, (105 mg, 37% yield) as a light yellow solid. ¹ H NMR (400 MHz, DMSO-d6): δ 8.72(s, 1H), 8.47 (d, J = 2.4 Hz, 1H), 8.23- 8.17 (m, 2H), 7.91 (d, J = 8.8 Hz, 1H), 7.76 (t, J = 6.8 Hz, 2H), 7.43 (d, J = 8.8 Hz, 1H), 6.23 (s, 2H), 4.63 (t, J = 8.0 Hz, 2H), 3.48 (brs, 4H), 3.26-3.19 (m, 2H), 2.32 (d, J = 1.6 Hz, 4 H), 2.19 (s, 3H); MS (ESI + APCI; multimode): 518 [M + H] ⁺ ; HPLC: 98.8% (% of AUC). [00326] 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. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 3.80 (brs, 2H), 3.60 (brs, 2H), 2.96 - 2.91 (m, 1H), 2.03 (s, 6H), 1.37 (s, 9H); MS (ESI + APCI; multimode): 201.0 [M + H] ⁺ . [00329] 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. The reaction mixture was concentrated under vaccum to obtain the crude product. The crude product was triturated with MTBE (15 mL), filtered under vacuum, to obtain N,N-dimethylazetidin-3-amine, 1v, (380 mg, crude) as a pale yellow solid. The crude compound was directly used in the next step. MS (ESI + APCI; multimode): 101 [M + H] ⁺ . [00331] 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. NaHCO3 (50.0 mL) and brine (50.0 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 CH ₂ Cl ₂ . The fractions containing the product were combined and concentrated under vacuum to obtain (5-bromopyridin-3-yl)(3-(dimethylamino)azetidin-1-yl)methano ne, 1w, (0.07 g, 25% yield) as a pale yellow liquid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.84 (d, J = 2.4 Hz, 1H), 8.78(d, J = 1.6 Hz, 1H),8.23 (t, J = 4.0 Hz, 1H), 4.32 - 4.30 (m, 1H), 4.19 - 4.15 (m, 1H), 4.09 - 4.05 (m, 1H), 3.86 - 3.82 (m, 1H), 3.10 - 3.06 (m, 1H), 2.08 (s, 6H); MS (ESI + APCI; multimode): 284 [M + H] ⁺ . [00333] 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. The crude product was purified by silica gel chromatography using CH ₃ OH ^CH ₂ Cl ₂ (1 ^10%) as eluent to afford the product, which was triturated with methanol, filtered under vacuum and dried to obtain (5-(4-(6-chloro-5- fluoroindolin-1-yl)quinazolin-6-yl)pyridin-3-yl)(3-(dimethyl amino)azetidin-1-yl)methanone, Compound 41, (50.0 mg, 60% yield) as a light green solid. ¹ H NMR (400 MHz, DMSO-d6): δ 9.13 (d, J = 2.4 Hz, 1H), 8.84 (d, J = 2.0 Hz, 1H), 8.75 (s, 1H), 8.49 (d, J = 1.6 Hz, 1H), 8.35- 8.29(m, 2H), 8.02- 7.96(m, 2H), 7.43 (d, J = 8.8 Hz, 1H), 4.72 (t, J = 8.0 Hz, 2 H), 4.39 (t, J = 8.0 Hz, 2 H), 4.21- 4.18(m, 1H), 4.13- 4.11(m, 1H), 3.90- 3.86 (m, 1H), 3.22 (t, J = 8.0 Hz, 2 H), 3.12-3.07(m, 1H), 2.09 (s, 6H); MS (ESI + APCI; multimode): 503 [M + H] ⁺ ; HPLC: 97.9 (% of AUC). [00335] 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] . , . . , t, was added 1v (0.18 g, 1.38 mmol), HOBt (0.18 g, 1.38 mmol), EDC•HCl (0.26 g, 1.38 mmol) followed by i-Pr2EtN (0.80 mL, 4.60 mmol). The reaction mixture was stirred at rt for 16 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 × 50 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 CH ₂ Cl ₂ . The fractions containing the product were combined and concentrated under vacuum to obtain (2-amino-5-bromopyridin-3-yl)(3-(dimethylamino)azetidin-1-yl )methanone, 1x, (0.09 g, 32% yield) as a pale yellow liquid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.12 (d, J = 2.4 Hz, 1H), 7.72 (d, J = 2.4 Hz, 1H), 6.84 (s, 2H), 4.25 (brs, 1H), 4.10- 4.02 (m, 2H), 3.81 (brs, 1H), 3.06 - 3.02 (m, 1H), 2.07 (s, 6H); MS (ESI + APCI; multimode): 299 [M + H] ⁺ [00338] 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 Cs2CO3 (0.17 g, 0.54 mmol) in H2O (1.00 mL) at rt, and the mixture was de-gassed with Ar (g) for 10 min. 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. The crude product was purified by silica gel chromatography using CH3OH ^CH2Cl2 (1 ^10%) as eluent to afford the product, which was triturated with methanol, filtered under vacuum and dried to obtain (2-amino-5-(4-(6-chloro-5- fluoroindolin-1-yl)quinazolin-6-yl)pyridin-3-yl)(3-(dimethyl amino)azetidin-1-yl)methanone, Compound 42 (75.0 mg, 72% yield) as a light green solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.72 (s, 1H), 8.52 (d, J = 2.4 Hz, 1H), 8.26 (d, J = 1.6 Hz, 1H), 8.21 (dd, J = 10.4 Hz, J = 7.2 Hz, 1H), 7.96-7.91 (m, 2H), 7.83 (d, J = 6.8 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 6.93 (s, 2H), 4.69- 4.66 (m, 2H), 4.31-4.21 (m, 1H), 4.14 - 4.04(m, 2H), 3.98-3.84 (m, 1H), 3.25-3.19 (m, 2H), 3.17- 3.03 (m, 1H), 2.07 (s, 6H); MS (ESI + APCI; multimode): 518 [M + H] ⁺ ; HPLC: 98.3 (% of AUC). [00340] Example 43: Synthesis of 5-(4-indolin-1-ylquinazolin-6-yl)pyrimidin-2-amine, Compound 43 [00341] Step 1: Synthesis of 6-bromo-4-indolin-1-yl-quinazoline (1y) [00342] To a so 21.40 μmol, 1 eq) in i- PrOH (2 mL) was added indoline (97.88 mg, 821.40 μmol, 92.34 μL, 1 eq). The mixture was stirred at 80 °C for 2 h. LCMS showed the starting material was consumed completely, and desired MS was detected. The reaction mixture was concentrated in vacuum to give a crude product.6-bromo-4-indolin-1-yl-quinazoline, 1y, (300 mg, crude) was obtained as a yellow solid. MS (M + H) ⁺ = 328.0. [00343] Step 2: Synthesis of 5-(4-indolin-1-ylquinazolin-6-yl)pyrimidin-2-amine (Compound 43) [00344 . , . μmol, 1 eq) in DMF (2 mL) and H ₂ O (0.4 mL) was added (2-aminopyrimidin-5-yl)boronic acid (60 mg, 431.90 μmol, 1 eq), Pd(dppf)Cl2 (31.60 mg, 43.19 μmol, 0.1 eq) and Cs2CO3 (422.17 mg, 1.30 mmol, 3 eq). The mixture was purged with N2 for 1 minute, and then the mixture was stirred at 100 °C for 2 h under N ₂ atmosphere. LCMS showed the starting material was consumed completely, and desired MS was detected. The reaction mixture filtered to give a filtrate, and the filtrate was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875*30mm*3 μm;mobile phase:[water(0.04% HCl)-ACN];B%: 3%-30%,8min).5-(4-indolin-1-ylquinazolin-6- yl)pyrimidin-2-amine, Compound 43, (17.34 mg, 46.01 μmol, 10.65% yield, 100% purity, HCl) was obtained as a yellow solid. ¹ H NMR (400MHz, DMSO-d6) δ = 8.96 (s, 1H), 8.89 (s, 2H), 8.57 (d, J=1.4 Hz, 1H), 8.42 (dd, J=1.7, 8.8 Hz, 1H), 8.24 (br d, J=7.4 Hz, 1H), 8.09 (d, J=8.8 Hz, 1H), 7.49 (d, J=7.4 Hz, 1H), 7.40 - 7.35 (m, 1H), 7.31 - 7.25 (m, 1H), 4.93 (br t, J=7.4 Hz, 2H), 3.29 (br t, J=7.3 Hz, 2H). MS (M + H) ⁺ = 341.1. [00345] Example 44: Synthesis of 5-[4-(6-methylindolin-1-yl)quinazolin-6- yl]pyrimidin-2-amine, Compound 44 [00346] Step 1: Synthesis of 6-bromo-4-(6-methylindolin-1-yl)quinazoline (1z) [00347] To a mg, 821.40 μmol, 1 eq) in i-PrOH (2 mL) was added 6-methylindoline (109.40 mg, 821.40 μmol, 1 eq). The mixture was stirred at 80 °C for 2 h. LCMS showed the starting material was consumed completely, and desired MS was detected. The reaction mixture was concentrated in vacuum to give a crude product. 6-bromo-4-(6-methylindolin-1-yl)quinazoline, 1z, (350 mg, crude) was obtained as a yellow solid. MS (M + H) ⁺ = 340.2. [00348] Step 2: Synthesis of 5-[4-(6-methylindolin-1-yl)quinazolin-6-yl]pyrimidin-2- amine (Compound 44) [00349] To a solution of 1z (146.94 mg, 431.90 μmol, 1 eq) in DMF (1.5 mL) and H ₂ O (0.3 mL) was added (2-aminopyrimidin-5-yl)boronic acid (60 mg, 431.90 μmol, 1 eq), Cs2CO3 (422.17 mg, 1.30 mmol, 3 eq) and Pd(dppf)Cl2 (31.60 mg, 43.19 μmol, 0.1 eq). The mixture was purged with N ₂ for 1 minute and stirred at 100 °C for 2 hr under N ₂ atmosphere. LCMS showed the starting material was consumed completely, and desired MS was detected. The reaction mixture was filtered to give a filtrate. The filtrate was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875*30mm*3 μm; mobile phase: [water (10 mM NH4HCO3)- ACN];B%: 20%-50%,10min).5-[4-(6-methylindolin-1-yl)quinazolin-6-yl]py rimidin-2-amine, Compound 44, (1.69 mg, 4.56 μmol, 1.06% yield, 95.62% purity) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ = 8.71 (s, 1H), 8.63 (s, 2H), 8.22 (d, J = 1.8 Hz, 1H), 8.17 (dd, J = 1.9, 8.7 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.31 (s, 1H), 7.22 (d, J = 7.5 Hz, 1H), 6.90 (s, 2H), 6.85 - 6.81 (m, 1H), 4.52 (t, J = 7.9 Hz, 2H), 3.14 (br t, J = 7.8 Hz, 2H), 2.25 (s, 3H). MS (M + H) ⁺ = 355.1. [00350] 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) [00352] To a g, 821.40 μmol, 1 eq) in i-PrOH (2 mL) was added 6-fluoroindoline (112.66 mg, 821.40 μmol, 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. The reaction mixture was concentrated in vacuum to give a crude product.6-bromo-4-(6-fluoroindolin-1-yl)quinazoline, Compound 1aa, (345 mg, crude) was obtained as a yellow solid. MS (M + H) ⁺ = 344.2. [00353] Step 2: Synthesis of 5-[4-(6-fluoroindolin-1-yl)quinazolin-6-yl]pyrimidin-2- amine (Compound 45) [00354] To a stirred solution of 1aa (200 mg, 581.09 μmol, 1 eq) in DMF (3 mL) and H2O (0.5 mL) was added (2-aminopyrimidin-5-yl)boronic acid (80.73 mg, 581.09 μmol, 1 eq), Cs ₂ CO ₃ (567.99 mg, 1.74 mmol, 3 eq) and Pd(dppf)Cl ₂ (42.52 mg, 58.11 μmol, 0.1 eq) the mixture was bubbled with N2 for 1 minute, and 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 filtered, and filtrate was purified directly. The filtrate was purified by prep-HPLC (column: Phenomenex luna C18100*40mm*5 μm;mobile phase: [water(0.1%TFA)-ACN];B%: 5%- 35%,8min).5-[4-(6-fluoroindolin-1-yl)quinazolin-6-yl]pyrimid in-2-amine, Compound 45, (5.86 mg, 12.40 μmol, 2.13% yield, 100% purity, TFA) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ = 8.89 (s, 1H), 8.75 (s, 2H), 8.46 - 8.40 (m, 1H), 8.32 (dd, J = 1.8, 8.8 Hz, 1H), 7.94 (d, J = 8.8 Hz, 1H), 7.85 - 7.75 (m, 1H), 7.42 (dd, J = 6.0, 8.0 Hz, 1H), 7.13 - 6.89 (m, 3H), 4.84 (br t, J = 7.8 Hz, 2H), 3.22 (br t, J = 7.6 Hz, 2H). MS (M + H) ⁺ = 359.1. [00355] 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) [00357] To a 1.40 μmol, 1 eq) in i- PrOH (2 mL) was added 5,6-difluoroindoline(127.44 mg, 821.40 μmol, 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. The reaction mixture was concentrated in vacuum to give a crude product.6-bromo-4-(5,6-difluoroindolin-1-yl)quinazoline, 1ab, (368 mg, crude) was obtained as a yellow solid. MS (M + H) ⁺ = 362.2. [00358] Step 2: Synthesis of 5-[4-(5,6-difluoroindolin-1-yl)quinazolin-6-yl]pyrimidin- 2-amine (Compound 46)

[00 d H ₂ O (0.5 mL) was added (2-aminopyrimidin-5-yl)boronic acid (76.72 mg, 552.23 μmol, 1 eq), Cs ₂ CO ₃ (539.78 mg, 1.66 mmol, 3 eq) and Pd(dppf)Cl ₂ (40.41 mg, 55.22 μmol, 0.1 eq) the mixture was bubbled with N ₂ for 1 minute, and 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 H2O+MEOH (1:1, 30 mL), stirred at 20 ^o C for 3 h. Filtered, and filter cake was concentrated in vacuum.5-[4-(5,6-difluoroindolin-1-yl)quinazolin-6-yl]pyrimi din-2-amine, Compound 46, (162.60 mg, 426.11 μmol, 77.16% yield, 98.63% purity) was obtained as a gray solid. ¹ H NMR (400 MHz, DMSO-d6) δ = 8.71 (br s, 3H), 8.30 (br s, 1H), 8.21 - 8.14 (m, 1H), 7.97 - 7.88 (m, 1H), 7.84 - 7.72 (m, 1H), 7.50 - 7.36 (m, 1H), 6.90 (br s, 2H), 4.69 (br s, 2H), 3.19 (br s, 2H). MS (M + H) ⁺ = 377.1. [00360] 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 nazo ne ( mg, 821.40 μmol, 1 eq) in i- PrOH (2 mL) was added 7-fluoroindoline (112.66 mg, 821.40 μmol, 1 eq). The mixture was stirred at 80 °C for 2 h. LCMS showed the starting material was consumed completely, and desired MS was detected. The reaction mixture was concentrated in vacuum to give a crude product.6-bromo-4-(7-fluoroindolin-1-yl)quinazoline, 1ac, (353 mg, crude) was obtained as a yellow solid. [00363] MS (M + H) ⁺ = 344.2. [00364] 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 μmol, 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 μmol, 1 eq), Cs ₂ CO ₃ (567.99 mg, 1.74 mmol, 3 eq) and Pd(dppf)Cl ₂ (42.52 mg, 58.11 μmol, 0.1 eq) the mixture was bubbled with N ₂ for 1 minute, and stirred at 100 °C for 2 h. LCMS showed the starting material was consumed completely and desired MS was detected. The reaction mixture was filtered, and filtrate was purified by prep-HPLC (column: Phenomenex luna C18 80*40mm*3 μm; mobile phase: [water (0.04%HCl)-ACN];B%: 15%-45%,7min).5-[4-(7- fluoroindolin-1-yl)quinazolin-6-yl]pyrimidin-2-amine, Compound 47, (5.81 mg, 14.72 μmol, 2.53% yield, 100% purity, HCl) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ = 8.99 (s, 1H), 8.88 (s, 2H), 8.47 (d, J = 1.5 Hz, 1H), 8.43 (d J = 1.8, 8.8 Hz, 1H), 8.08 (d, J = 8.8 Hz, 1H), 7.35 - 7.28 (m, 2H), 7.21 (s, 1H), 4.85 (br t, J = 7.3 Hz, 2H), 3.29 (br t, J = 7.4 Hz, 2H). MS (M + H) ⁺ = 359.1. [00366] 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) [003 e-3- carbonitrile (592.39 mg, 2.21 mmol, 1 eq) in i-PrOH (5 mL) was stirred at 80 ^o C for 12 h. LCMS showed the starting material was consumed completely and desired MS was detected. The reaction mixture was concentrate in vacuum. Compound 6-bromo-4-(6-chloro-5-fluoro-indolin- 1-yl)quinoline-3-carbonitrile (800 mg, 1.99 mmol, 89.72% yield) was obtained as a yellow solid. MS (M + H) ⁺ = 404.1. [00369] 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 μmol, 1 eq) in DMF (5 mL) and H ₂ O (1 mL) was added 6-2d (300 mg, 745.07 μmol, 1 eq), Pd(dppf)Cl ₂ (54.52 mg, 74.51 μmol, 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. LCMS showed the starting material was consumed completely and desired MS was detected. The reaction mixture was filtered, and filtrate was purified by directly. The residue was purified by prep-HPLC (column: Phenomenex luna C18250*50mm*10 μm;mobile phase: [water(0.04%HCl)-ACN];B%: 30%-60%,10min). 4-(6-chloro-5-fluoro- indolin-1-yl)-6-(1H-pyrazolo[3,4-b]pyridin-5-yl)quinoline-3- carbonitrile, Compound 48, (21.29 mg, 43.72 μmol, 5.87% yield, 98.03% purity, HCl) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ = 9.07 (s, 1H), 8.85 (d, J = 1.9 Hz, 1H), 8.61 (d, J = 2.0 Hz, 1H), 8.37 (br d, J = 8.8 Hz, 1H), 8.34 (s, 1H), 8.25 (d, J = 8.8 Hz, 1H), 8.22 (s, 1H), 7.43 (d, J = 8.8 Hz, 1H), 6.90 (d, J = 6.1 Hz, 1H), 4.63 - 4.56 (m, 1H), 4.34 (br d, J = 8.4 Hz, 1H), 3.43 - 3.22 (m, 2H). MS (M + H) ⁺ = 441.1. [00371] 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 μmol, 1 eq) in DMF (5 mL) and H ₂ O (1 mL) was added 2d (300 mg, 745.07 μmol, 1 eq) Pd(dppf)Cl ₂ (54.52 mg, 74.51 μmol, 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. LCMS showed the starting material was consumed completely and desired MS was detected. The reaction mixture was filtered, and filtrate was purified by prep- HPLC (column: Phenomenex luna C18250*50mm*10 μm;mobile phase: [water(0.04%HCl)- ACN];B%: 30%-60%,10min).6-(2-aminopyrimidin-5-yl)-4-(6-chloro-5-fluor o-indolin-1- yl)quinoline-3-carbonitrile, Compound 49, (31.24 mg, 65.95 μmol, 8.85% yield, 95.69% purity, HCl) was obtained as an orange solid. ¹ H NMR (400 MHz, DMSO-d6) δ = 9.11 (s, 1H), 8.92 (s, 2H), 8.38 - 8.29 (m, 2H), 8.28 - 8.22 (m, 1H), 7.45 (br d, J = 8.9 Hz, 1H), 6.98 (br d, J = 5.8 Hz, 1H), 4.69 (br d, J = 6.6 Hz, 1H), 4.30 (br d, J = 8.4 Hz, 1H), 3.32 (br t, J = 8.0 Hz, 2H). MS (M + H) ⁺ = 417.1. [00373] 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 μmol, 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. LCMS showed starting material was consumed completely and the MS of desired product was detected. TLC (PE : EtOAc = 3 : 1, Rf = 0.35) showed the starting material was consumed completely and new spot was formed. The reaction mixture was cooled to room temperature and quenched by water (20 mL), extracted with ethyl acetate (20 mL *2). The combined organics were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 80 g silica, 40-60 % ethyl acetate in petroleum ether, gradient over 30 min).4-(6-chloro-5-fluoro-indolin-1-yl)-6-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) quinoline-3-carbonitrile, 2e, (2.2 g, 4.89 mmol, 56.28% yield) was obtained as a yellow solid. MS (M + H) ⁺ =450.2 [00376] Step 2: Synthesis of 4-(6-chloro-5-fluoro-indolin-1-yl)-6-(5, 6-dimethoxy-3- pyridyl) quinoline-3-carbonitrile (Compound 50) [ g, . μ , q . 0.1 mL) was added Cs2CO3 (326.03 mg, 1.00 mmol, 3 eq), Pd(dppf)Cl2 (24.41 mg, 33.35 μmol, 0.1 eq) and 5-bromo-2,3-dimethoxy-pyridine (72.73 mg, 333.55 μmol, 1 eq), the mixture was bubbled N ₂ , the reaction was stirred at 100 °C for 3 h. LC-MS showed starting material was consumed completely and the MS of desired product was detected. The reaction mixture was concentrated in vacuum. The crude product was purified by prep-HPLC (column: Phenomenex luna C1880*40mm*3 μm;mobile phase: [water(0.04%HCl)-ACN];B%: 55%-77%,7min).4-(6- chloro-5-fluoro-indolin-1-yl)-6-(5, 6-dimethoxy-3-pyridyl) quinoline-3-carbonitrile, Compound 50, (54.69 mg, 105.22 μmol, 31.55% yield, 95.69% purity, HCl) was obtained as a brown solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 9.04 (s, 1 H), 8.31 (br d, J=8.92 Hz, 1 H), 8.20 (d, J=8.68 Hz, 1 H), 8.14 (s, 1 H), 8.04 (d, J=1.71 Hz, 1 H), 7.36 - 7.50 (m, 2 H), 6.85 (d, J=6.11 Hz, 1 H), 4.31 - 4.59 (m, 2 H), 3.90 (s, 3 H), 3.83 (s, 3 H), 3.18 - 3.47 (m, 2 H). MS (M + H) ⁺ =461.0 [00378] 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 μmol, 0.1 eq) and 2-(5-bromo-3-pyridyl)propan-2-ol (72.07 mg, 333.55 μmol, 1 eq), the mixture was bubbled N2, the reaction was stirred at 100 °C for 3 h. LCMS showed starting material was consumed completely and the MS of desired product was detected. The reaction was concentrated in vacuum. The crude product was purified by prep-HPLC (column: Phenomenex luna C1880*40mm*3 μm;mobile phase: [water (0.04%HCl)-ACN]; B%: 32%-50%,7min).4-(6- chloro-5-fluoro-indolin-1-yl)-6-[5-(1-hydroxy-1-methyl-ethyl )-3-pyridyl]quinoline-3- carbonitrile, Compound 51, (70 mg, 131.49 μmol, 39.42% yield, 93.05% purity, HCl) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 9.26 (s, 1 H), 9.13 (s, 1 H), 8.92 (s, 1 H), 8.76 (s, 1 H), 8.53 (d, J=1.34 Hz, 1 H), 8.46 (dd, J=8.80, 1.59 Hz, 1 H), 8.32 (d, J=8.80 Hz, 1 H), 7.48 - 7.78 (m, 1 H), 7.44 (d, J=8.80 Hz, 1 H), 7.02 (d, J=6.11 Hz, 1 H), 4.62 - 4.72 (m, 1 H), 4.26 - 4.35 (m, 1 H), 3.32 (br t, J=7.95 Hz, 2 H), 1.56 (s, 6 H) MS (M + H) ⁺ =459.1 [00380] Example 52: Synthesis 4-(6-chloro-5-fluoro-indolin-1-yl)-6-(2-methyl-3H- imidazo [4, 5-b] pyridin-6-yl) quinoline-3-carbonitrile, Compound 52 5 mL) was added Cs2CO3 (326.03 mg, 1.00 mmol, 3 eq), Pd(dppf)Cl2 (24.41 mg, 33.35 μmol, 0.1 eq) and 6-bromo-2-methyl-1H-imidazo[4,5-b]pyridine (70.73 mg, 333.55 μmol, 1 eq), the mixture was bubbled with N ₂ , the reaction was stirred at 100 °C for 3 h. LCMS showed starting material was consumed completely and the MS of desired product was detected. The reaction was concentrated in vacuum. The crude product was twice purified by prep-HPLC (column: Phenomenex Luna C1875*30mm*3 μm;mobile phase: [water(0.04%HCl)-ACN];B%: 10%- 40%,8min) and by prep- HPLC(column: Phenomenex Luna C18150*30mm*5um;mobile phase: [water(0.1%TFA)-ACN]; B%: 25%-65%, 8min). 4-(6-chloro-5-fluoro-indolin-1-yl)-6-(2- methyl-3H-imidazo [4, 5-b] pyridin-6-yl) quinoline-3-carbonitrile, Compound 52, (3.95 mg, 8.68 μmol, 2.60% yield, 100% purity) was obtained as a yellow solid. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.05 (s, 1 H), 8.73 (s, 1 H), 8.34 - 8.40 (m, 2 H), 8.30 (s, 1 H), 8.25 (d, J=8.66 Hz, 1 H), 7.42 (d, J=8.91 Hz, 1 H), 6.84 (d, J=6.15 Hz, 1 H), 4.47 - 4.58 (m, 1 H), 4.31 - 4.41 (m, 1 H), 3.30 - 3.38 (m, 2 H), 2.68 (s, 3 H). MS (M + H) ⁺ =459.1 [00382] Example 53: Synthesis 4-(6-chloro-5-fluoro-indolin-1-yl)-6-(3H-triazolo [4, 5- b]pyridin-6-yl) quinoline-3-carbonitrile, Compound 53 [00383] To a solution of 2e (150 mg, 333.55 μmol, 1 eq) in DMF (2.5 mL) and H2O (0.5 mL) was added Cs2CO3 (326.03 mg, 1.00 mmol, 3 eq), Pd(dppf)Cl224.41 mg, 33.35 μmol, 0.1 eq) and 6-bromo-3H-triazolo[4,5-b]pyridine (66.38 mg, 333.55 μmol, 1 eq), the mixture was stirred at 100 °C for 3 h under N2. LCMS showed starting material was consumed completely and the MS of desired product was detected. The reaction was concentrated in vacuum. The crude product was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [water (0.05%NH ₃ H ₂ O+10 mM NH ₄ HCO ₃ )-ACN];B%: 15%- 45%,8min). 4-(6-chloro-5-fluoro-indolin-1-yl)-6-(3H-triazolo [4, 5-b]pyridin-6-yl) quinoline-3- carbonitrile, Compound 53, (16.56 mg, 37.39 μmol, 11.21% yield, 99.76% purity) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 8.98 - 9.09 (m, 2 H), 8.78 (br s, 1 H), 8.36 - 8.47 (m, 2 H), 8.27 (d, J=9.26 Hz, 1 H), 7.42 (d, J=8.88 Hz, 1 H), 6.88 (d, J=6.25 Hz, 1 H), 4.59 (td, J=9.22, 6.82 Hz, 1 H), 4.31 (d, J=8.00 Hz, 1 H), 2.54 (s, 2 H). MS (M + H) ⁺ =442.1 [00384] 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 μmol, 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 μmol, 0.1 eq) and 5-bromo-1,3-benzoxazol-2-amine (71.06 mg, 333.55 μmol, 1 eq) , the mixture was bubbled with N ₂ , the reaction was stirred at 100 °C for 3 h. LCMS showed starting material was consumed completely and the MS of desired product was detected. The reaction was filtered, the liquor was concentrated in vacuum. The crude product was purified by prep-HPLC (column: Phenomenex luna C1880*40mm*3 μm;mobile phase: [water (0.04%HCl)-ACN];B%: 35%- 55%,7min).6-(2-amino-1, 3-benzoxazol-5-yl)-4-(6-chloro-5-fluoro-indolin-1-yl) quinoline-3- carbonitrile, Compound 54, (20.05 mg, 39.56 μmol, 11.86% yield, 97.15% purity, HCl) was obtained as brown solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 9.11 (s, 1 H), 8.62 (br s, 1 H), 8.27 - 8.32 (m, 1 H), 8.21 - 8.26 (m, 1 H), 8.18 - 8.21 (m, 1 H), 7.51 - 7.59 (m, 2 H), 7.43 (dd, J=16.81, 8.50 Hz, 2 H), 6.94 (d, J=6.11 Hz, 1 H), 4.51 - 4.57 (m, 1 H), 4.41 - 4.49 (m, 1 H), 3.18 - 3.43 (m, 2 H). MS (M + H) ⁺ =456.0 [00386] 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 μmol, 0.1 eq) and 6-bromo-1-methyl-pyrazolo[4,3-b]pyridine (70.73 mg, 333.55 μmol, 1 eq), the mixture was bubbled N2, the reaction was stirred at 100 °C for 3 h. LCMS showed starting material was consumed completely and the MS of desired product was detected. The reaction was filtered, the liquor was concentrated in vacuum. The crude product was purified by prep-HPLC (column: Phenomenex Luna C1875*30mm*3 μm; mobile phase: [water (0.04%HCl)-ACN];B%: 20%- 50%,8min), afford crude product (30mg),the crude product was purified by prep-HPLC (column: Phenomenex Luna C1875*30mm*3 μm;mobile phase: [water(0.04%HCl)-ACN];B%: 35%- 65%,8min).4-(6-chloro-5-fluoro-indolin-1-yl)-6-(1-methylpyra zolo [4, 3-b] pyridin-6-yl) quinoline-3-carbonitrile, Compound 55, (14.95 mg, 29.99 μmol, 8.99% yield, 98.55% purity, HCl) was obtained as an orange solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 9.16 (s, 1 H), 8.91 (d, J=1.83 Hz, 1 H), 8.56 (s, 1 H), 8.44 - 8.51 (m, 2 H), 8.29 - 8.37 (m, 2 H), 7.47 (d, J=8.92 Hz, 1 H) 7.07 (d, J=6.11 Hz, 1 H) 4.68 (br d, J=7.95 Hz, 1 H) 4.33 - 4.50 (m, 1 H) 4.16 (s, 3 H) 3.33 (br d, J=3.67 Hz, 2 H). MS (M + H) ⁺ =455.0 [00388] Example 56: Synthesis of 6-[6-(3-aminooxetan-3-yl)-3-pyridyl]-4-(6-chloro-5- fluoro-indolin-1-yl) quinoline-3-carbonitrile, Compound 56 [00389] Step 1: Synthesis of 2-methyl-N-(oxetan-3-ylidene)propane-2-sulfinamide (1ad) [00390] To a solution of oxetan-3-one (2 g, 27.75 mmol, 1 eq) and 2-methylpropane-2- sulfinamide (3.36 g, 27.75 mmol, 1 eq) in EtOH (30 mL) was added tetraethoxytitanium (6.33 g, 27.75 mmol, 5.76 mL, 1 eq). The mixture was stirred at 80 °C for 16 hr. LCMS showed starting material was consumed completely and the MS of desired product was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 40 g silica, 10-60 % ethyl acetate in petroleum ether, gradient over 20 min). Based on TLC (Petroleum ether: Ethyl acetate = 1/1, Rf = 0.70). 2-methyl-N-(oxetan-3- ylidene)propane-2-sulfinamide, 1ad, (1.4 g, 7.99 mmol, 28.78% yield) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ), δ ppm 5.54 - 5.67 (m, 2 H), 5.44 - 5.53 (m, 2 H), 1.18 - 1.20 (m, 9 H). MS (M + H) ⁺ =176.1 [00391] 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 mL) was added and the reaction mixture stirred at -60 °C for 30 minutes. LCMS showed starting material was consumed completely and the MS of desired product was detected. The reaction mixture was quenched with MeOH (aq, 5 mL), and then the reaction mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12 g Sepa Flash® Silica Flash Column, Eluent of 0~100% Ethyl acetate/Petroleum ether gradient @ 50 mL/min). Based on TLC (PE: EA=1: 1, Rf =0.20). N-[3-(5-bromo-2-pyridyl) oxetan-3-yl]-2-methyl-propane-2-sulfinamide, 1ae, (1 g, 3.00 mmol, 85.64% yield) was obtained as a yellow oil. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (d, J=2.32 Hz, 1 H), 8.12 (dd, J=8.44, 2.45 Hz, 1 H), 7.55 (d, J=8.44 Hz, 1 H), 5.08 (d, J=6.11 Hz, 1 H), 4.86 - 4.94 (m, 2 H), 4.82 (d, J=6.23 Hz, 1 H), 4.44 - 4.51 (m, 1 H), 1.15 (s, 9 H). (M + H) ⁺ = 333.1 [00393] Step 3: Synthesis of 3-(5-bromo-2-pyridyl) oxetan-3-amine (1af) [00394] To a solution of 1ae (330 mg, 990.27 μmol, 1 eq) in MeOH (3 mL) was added dropwise HCl/EtOAc (4 M, 505.04 μL, 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. The reaction mixture was partitioned between EtOAc (50 mL) solvent and water (50 mL).3-(5-bromo-2-pyridyl) oxetan-3-amine, 1af, (100 mg, 436.54 μmol, 44.08% yield) was obtained as a yellow oil. (M + H) ⁺ = 228.1 [00395] 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 μmol, 1 eq) in DMF (0.5 mL) and H ₂ O (0.1 mL) was added Cs2CO3 (170.68 mg, 523.86 μmol, 3 eq), Pd(dppf)Cl2 (12.78 mg, 17.46 μmol, 0.1 eq) and 1af (40 mg, 174.62 μmol, 1 eq), the mixture was bubbled with N2, the reaction was stirred at 100 °C for 2 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. The crude product was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [water (0.04% NH4HCO3)-ACN]; B%: 30%-55%, 10min) 6- [6-(3-aminooxetan-3-yl)-3-pyridyl]-4-(6-chloro-5-fluoro-indo lin-1-yl) quinoline-3-carbonitrile, Compound 56, (8.87 mg, 18.80 μmol, 10.76% yield, 100% purity) was obtained as a brown oil. [00397] ¹ H NMR (400 MHz, DMSO-d6) δ ppm 9.03 - 9.06 (m, 1 H), 8.93 (d, J=1.88 Hz, 1 H), 8.28 - 8.37 (m, 2 H), 8.24 (d, J=8.63 Hz, 1 H), 8.17 (dd, J=8.32, 2.44 Hz, 1 H), 7.78 (d, J=8.38 Hz, 1 H), 7.42 (br d, J=8.76 Hz, 1 H), 6.81 - 6.89 (m, 1 H), 4.87 - 4.97 (m, 2 H), 4.59 (d, J=5.50 Hz, 2 H), 4.52 (br d, J=6.63 Hz, 1 H), 4.30 - 4.39 (m, 1 H), 3.27 - 3.29 (m, 2 H), 2.76 (br s, 2 H) [00398] ¹ H NMR (400 MHz, DMSO+D ₂ O-d ₆ ) δ ppm 8.98 - 9.03 (m, 1 H), 8.89 (d, J=1.88 Hz, 1 H), 8.28 - 8.33 (m, 1 H), 8.26 (s, 1 H), 8.20 - 8.25 (m, 1 H), 8.14 (dd, J=8.32, 2.31 Hz, 1 H), 7.75 (d, J=8.25 Hz, 1 H), 7.40 (br d, J=8.88 Hz, 1 H), 6.75 - 6.82 (m, 1 H), 4.89 (d, J=5.63 Hz, 2 H), 4.59 (d, J=5.63 Hz, 2 H), 4.44 - 4.54 (m, 1 H), 4.29 - 4.39 (m, 1 H), 3.17 - 3.42 (m, 2 H) [00399] (M + H) ⁺ = 472.2 [00400] Example 57: Synthesis of 3-[5-[4-(6-chloro-5-fluoro-indolin-1-yl) quinazolin- 6-yl]-2-pyridyl] oxetan-3-amine, Compound 57 [00401] To a solution of 1af (13.34 mg, 58.22 μmol, 1 eq) in DMF (0.5 mL) and H2O (0.1 mL) was added Cs2CO3 (56.90 mg, 174.66 μmol, 3 eq), 1n (24.78 mg, 58.22 μmol, 1 eq) and Pd(dppf)Cl ₂ (4.26 mg, 5.82 μmol, 0.1 eq), the mixture was bubbled with N ₂ , the reaction was stirred at 100 °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. The crude product was purified by prep-HPLC (column: Phenomenex C1875*30mm*3 μm; mobile phase: [water (0.04% NH4HCO3)-ACN]; B%: 25%-55%, 8min) 3-[5-[4-(6-chloro- 5-fluoro-indolin-1-yl) quinazolin-6-yl]-2-pyridyl] oxetan-3-amine, Compound 57, (1.85 mg, 4.13 μmol, 7.09% yield, 100% purity) was obtained as a brown oil. [00402] ¹ H NMR (400 MHz, DMSO-d6) δ ppm 9.11 (d, J=2.25 Hz, 1 H), 8.82 (s, 1 H), 8.53 (s, 1 H), 8.26 - 8.40 (m, 2 H), 7.99 - 8.10 (m, 2 H), 7.87 (d, J=8.13 Hz, 1 H), 7.51 (d, J=9.13 Hz, 1 H), 5.00 (d, J=5.63 Hz, 2 H), 4.79 (br t, J=8.13 Hz, 2 H), 4.67 (d, J=5.75 Hz, 2 H), 3.30 (br t, J=7.94 Hz, 2 H), 2.82 (br s, 2 H) [00403] ¹ H NMR (400 MHz, DMSO+ D2O-d6) δ ppm 8.89 - 8.93 (m, 1 H), 8.63 (s, 1 H), 8.33 (d, J=1.75 Hz, 1 H), 8.16 - 8.21 (m, 1 H), 8.14 (dd, J=8.32, 2.44 Hz, 1 H), 7.90 (d, J=8.75 Hz, 1 H), 7.81 (d, J=6.75 Hz, 1 H), 7.69 (d, J=8.38 Hz, 1 H), 7.32 (d, J=8.76 Hz, 1 H), 4.82 (d, J=5.88 Hz, 2 H), 4.57 - 4.62 (m, 2 H), 4.52 (d, J=5.88 Hz, 2 H), 3.12 (br t, J=7.94 Hz, 2 H). [00404] 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 μmol, 1.5 eq) in dioxane (0.5 mL) , H2O (0.1 mL) was added 1n (150 mg, 352.37 μmol, 1 eq), Pd(dppf)Cl ₂ (25.78 mg, 35.24 μmol, 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. LCMS showed the starting material was consumed completely and desired MS was detected. The reaction mixture was concentrate in vacuum. The crude residue was purified by prep-HPLC (Waters Xbridge Prep OBD C18150*40mm*10um column; 45-65 % acetonitrile in a 10 mM ammonium bicarbonate solution in water, 8 min gradient).4-(6-chloro-5-fluoro-indolin-1-yl)-6-(2- methoxypyrimidin-5-yl)quinazoline, Compound 58, (13.90 mg, 33.40 μmol, 9.48% yield, 98.01% purity) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6, T=273+80K) δ = 9.04 (s, 2H), 8.76 (s, 1H), 8.43 (s, 1H), 8.25 (d, J = 8.2 Hz, 1H), 7.99 (d, J = 9.5 Hz, 1H), 7.92 (d, J = 6.8 Hz, 1H), 7.39 (d, J = 9.0 Hz, 1H), 4.70 (t, J = 8.3 Hz, 2H), 4.02 (s, 3H), 3.29 - 3.21 (m, 2H). MS (M + H) ⁺ = 408.0. [00406] Example 59: Synthesis of 6-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6- yl]-1H-1,8-naphthyridin-4-one, Compound 59 μmol, 1.3 eq) in dioxane (3 mL) , H2O (0.5 mL) was added 1n (70 mg, 164.44 μmol, 1 eq), Cs2CO3 (160.73 mg, 493.32 μmol, 3 eq), Pd(dppf)Cl2 (12.03 mg, 16.44 μmol, 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. LCMS showed the starting material was consumed completely and desired MS was detected. The reaction mixture was concentrate in vacuum. The crude residue was purified by prep-HPLC (Phenomenex luna C18100*40mm*5 μm column; 10-40 % acetonitrile in a 0.1% trifluoroacetic acid solution in water, 8 min gradient).6-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6- yl]- 1H-1,8-naphthyridin-4-one, Compound 59, (17.90 mg, 31.65 μmol, 19.25% yield, 98.65% purity, TFA) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ = 12.42 (br s, 1H), 9.24 (d, J = 2.5 Hz, 1H), 9.01 (s, 1H), 8.80 (d, J = 2.6 Hz, 1H), 8.71 - 8.65 (m, 1H), 8.52 (dd, J = 1.6, 8.8 Hz, 1H), 8.35 (d, J = 6.8 Hz, 1H), 8.01 (dd, J = 5.2, 8.1 Hz, 2H), 7.56 (d, J = 8.8 Hz, 1H), 6.22 - 6.15 (m, 1H), 4.96 (br t, J = 7.6 Hz, 2H), 3.29 (br t, J = 7.5 Hz, 2H). MS (M + H) ⁺ = 444.0. [00408] 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). The sealed tube was bubbled with N ₂ for 1 minute and heated at 160 ^o C for 1 h under microwave. TLC (Petroleum ether/Ethyl acetate=1:1, Rf=0.39) showed starting material was consumed completely and new spot was formed. The reaction mixture was poured into water (100 mL). The aqueous phase was extracted with ethyl acetate (200 mL*2). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash column (ISCO 20 g silica, 50-70% Ethyl acetate in Petroleum ether, gradient over 15 min).3-methylsulfonylpyridin-2-amine, 1ag, (500 mg, 2.90 mmol, 25.12% yield) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ = 8.26 (dd, J = 1.9, 4.8 Hz, 1H), 7.89 (dd, J = 1.8, 7.8 Hz, 1H), 6.76 (dd, J = 4.8, 7.9 Hz, 1H), 6.74 - 6.67 (m, 2H), 3.17 (s, 3H). [00411] Step 2: Synthesis of 5-bromo-3-methylsulfonyl-pyridin-2-amine (1ah) [00412] 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 μmol, 68.58% yield) was obtained as a yellow solid. MS (M + H) ⁺ =253.0 [00413] 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 μmol, 1.5 eq) in H ₂ O (0.4 mL), DMF (3 mL) was added 1n (50 mg, 117.46 μmol, 1 eq), Pd(dppf)Cl2 (8.59 mg, 11.75 μmol, 0.1 eq), Cs2CO3 (114.81 mg 352.37 μmol, 3 eq) the mixture was bubbled with N2 for 1 minute, and the mixture was stirred at 100 ^o C for 3 h. LCMS showed the starting material was consumed completely and desired MS was detected. The reaction mixture was filtered, and filtrate was purified directly. The filtrate was purified by prep-HPLC (Waters Xbridge BEH C18 100*30mm*10uM column; 30-55 % acetonitrile in a 10 mM ammonium bicarbonate solution in water, 8 min gradient) to afford 20 mg crude product. The crude residue was purified by prep- HPLC (Phenomenex Gemini-NX 150*30mm*5um column; 15-45 % acetonitrile in a 0.1% trifluoroacetic acid solution in water, 9 min gradient).5-[4-(6-chloro-5-fluoro-indolin-1- yl)quinazolin-6-yl]-3-methylsulfonyl-pyridin-2-amine, Compound 60, (13.10 mg, 22.43 μmol, 19.10% yield, 100% purity, TFA) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO- d6) δ = 8.92 (s, 1H), 8.77 (d, J = 2.5 Hz, 1H), 8.46 (s, 1H), 8.33 (d, J = 8.7 Hz, 1H), 8.24 (d, J = 2.5 Hz, 1H), 8.19 (br d, J = 6.7 Hz, 1H), 7.96 (d, J = 8.7 Hz, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.05 (br s, 2H), 4.85 (br t, J = 7.7 Hz, 2H), 3.28 (s, 3H), 3.27 - 3.23 (m, 2H). MS (M + H) ⁺ = 470.0. [00415] Example 61: Synthesis of 1-(2-amino-5-(4-(6-chloro-5-fluoroindolin-1- yl)quinazolin-6-yl)pyridin-3-yl)ethan-1-one, Compound 61 [00416] Step 1: Synthesis of 1-(2-amino-5-bromo-3-pyridyl)ethanone (1ai) [00417] To a stirred solution of 1-(2-amino-3-pyridyl)ethanone (100 mg, 734.48 μmol, 1 eq) in ACN (1.5 mL) was added NBS (137.26 mg, 771.20 μmol, 1.05 eq), the mixture was stirred at 20 °C for 0.5 h. LCMS showed the starting material was consumed completely and desired MS was detected. The residue was purified by flash column (ISCO 10 g silica, 50-60% Ethyl acetate in Petroleum ether, gradient over 15 min). Based on TLC (Petroleum ether : Ethyl acetate = 1/1, R _f = 0.33).1-(2-amino-5-bromo-3-pyridyl)ethanone, 1ai, (110 mg, 511.52 μmol, 69.64% yield) was obtained as a yellow solid. ¹ H NMR (400 MHz, CHLOROFORM-d) δ = 8.26 (d, J = 2.3 Hz, 1H), 8.08 (d, J = 2.3 Hz, 1H), 2.57 (s, 3H). MS (M + H) ⁺ = 217.0. [00418] 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 μmol, 1.3 eq) in dioxane (3 mL) , H2O (0.5 mL) was added 1n (91.36 mg, 214.62 μmol, 1 eq), Cs2CO3 (209.78 mg, 643.87 μmol, 3 eq) Pd(dppf)Cl ₂ (15.70 mg, 21.46 μmol, 0.1 eq) the mixture was bubbled with N ₂ for 1 minute, and the mixture was stirred at 100 °C for 3 h. LCMS showed the starting material was consumed completely and desired MS was detected. The crude residue was purified by prep-HPLC (Phenomenex Synergi C18150*25*10um column; 15-35 % acetonitrile in a 0.1% trifluoroacetic acid solution in water, 8 min gradient).1-(2-amino-5-(4-(6-chloro-5-fluoroindolin-1- yl)quinazolin-6-yl)pyridin-3-yl)ethan-1-one, Compound 61, (35.70 mg, 63.67 μmol, 29.66% yield, 97.71% purity, TFA) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ = 8.96 (s, 1H), 8.73 (d, J = 2.3 Hz, 1H), 8.57 (d, J = 2.4 Hz, 1H), 8.54 - 8.51 (m, 1H), 8.45 (br d, J = 8.8 Hz, 1H), 8.30 - 8.23 (m, 1H), 7.98 (br d, J = 8.8 Hz, 1H), 7.55 (d, J = 8.8 Hz, 1H), 4.91 (br t, J = 7.6 Hz, 2H), 3.28 (br t, J = 7.5 Hz, 2H), 2.68 (s, 3H). MS (M + H) ⁺ = 434.0. [00420] 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 μmol, 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 μmol, 1.5 eq), Pd(dppf)Cl2 (17.19 mg, 23.49 μmol, 0.1 eq), Cs2CO3 (229.62 mg, 704.74 μmol, 3 eq), the mixture was bubbled with N ₂ for 1 minute, and the mixture was stirred at 100 °C for 2 h. LCMS showed the starting material was consumed completely and desired MS was detected. The reaction mixture was concentrate in vacuum. The crude residue was purified by prep-HPLC (Waters Xbridge Prep OBD C18150*40mm*10um column; 30-60 % acetonitrile in a 10 mM ammonium bicarbonate solution in water, 8 min gradient).2-[5-[4-(6-chloro-5-fluoro-indolin-1- yl)quinazolin-6-yl]-3-pyridyl]propan-2-ol, Compound 62, (64.90 mg, 143.86 μmol, 61.24% yield, 96.40% purity) was obtained as a brown solid. ¹ H NMR (400 MHz, DMSO-d6) δ = 8.85 (br s, 1H), 8.75 (br s, 2H), 8.41 (br s, 1H), 8.26 (br d, J = 8.3 Hz, 1H), 8.17 (br s, 1H), 8.00 (br d, J = 8.1 Hz, 1H), 7.90 (br d, J = 5.4 Hz, 1H), 7.43 (br d, J = 8.1 Hz, 1H), 5.30 (br s, 1H), 4.69 (br s, 2H), 3.23 (br d, J =7.3 Hz, 2H), 1.53 (br s, 6H). MS (M + H) ⁺ = 435.1. [00422] Example 63: Synthesis of 5-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6- yl]-1,3-benzoxazol-2-amine, Compound 63 [00423] To a stirred solution of 1n (100 mg, 234.91 μmol, 1 eq) in dioxane (4 mL) and H ₂ O (1 mL) was added 5-bromo-1,3-benzoxazol-2-amine (75.07 mg, 352.37 μmol, 1.5 eq), Pd(dppf)Cl ₂ (17.19 mg, 23.49 μmol, 0.1 eq), Cs ₂ CO ₃ (229.62 mg, 704.74 μmol, 3 eq) the mixture was bubbled with N2 for 1 minute, and 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 concentrated in vacuum. The crude residue was purified by prep-HPLC (Phenomenex luna C18 250*50mm*10 μm column; 20-50 % acetonitrile in a 0.1% trifluoroacetic acid solution in water, 10 min gradient).5-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6- yl]-1,3-benzoxazol-2-amine, Compound 63, (62.00 mg, 109.85 μmol, 46.76% yield, 96.72% purity, TFA) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ = 8.97 (s, 1H), 8.49 (s, 1H), 8.38 (br d, J = 8.6 Hz, 1H), 8.27 (br d, J = 6.6 Hz, 1H), 7.96 (d, J = 8.8 Hz, 1H), 7.68 - 7.64 (m, 1H), 7.62 (s, 1H), 7.55 (d, J = 8.8 Hz, 1H), 7.52 - 7.46 (m, 1H), 7.46 - 7.39 (m, 1H), 4.91 (br t, J = 7.5 Hz, 2H), 3.29 (br t, J = 7.6 Hz, 2H). MS (M + H) ⁺ = 432.0. [00424] 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 μmol, 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 μmol, 1.3 eq), Pd(dppf)Cl ₂ (17.19 mg, 23.49 μmol, 0.1 eq), Cs ₂ CO ₃ (229.62 mg, 704.74 μmol, 3 eq), the mixture was bubbled with N2 for 1 minute, and the reaction mixture 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 concentrate in vacuum. The crude residue was purified by prep-HPLC (Phenomenex Gemini-NX 150*30mm*5um column; 10-40 % acetonitrile in a 0.1% trifluoroacetic acid solution in water, 9 min gradient) to afford 20 mg crude product. The crude product was purified by prep-HPLC (Phenomenex luna C18100*40mm*5 μm column; 10-43 % acetonitrile in a 0.1% trifluoroacetic acid solution in water, 8 min gradient).6-[4-(6-chloro-5- fluoro-indolin-1-yl)quinazolin-6-yl]-1H-benzimidazol-2-amine , Compound 64, (10.40 mg, 19.09 μmol, 8.12% yield, 100% purity, TFA) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ = 12.73 (br s, 2H), 8.85 (d, J = 2.7 Hz, 1H), 8.57 (br d, J = 7.6 Hz, 2H), 8.40 (br s, 1H), 8.27 (br d, J = 8.4 Hz, 1H), 8.05 (br s, 1H), 7.99 (d, J = 8.7 Hz, 1H), 7.72 (s, 1H), 7.70 - 7.64 (m, 1H), 7.49 (d, J = 8.4 Hz, 2H), 4.77 (br t, J = 6.7 Hz, 2H), 3.28 - 3.23 (m, 2H). MS (M + H) ⁺ = 431.0. [00426] Example 65: Synthesis of 4-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6- yl]-5,6-dihydrocyclopenta[c]pyridin-7-one, Compound 65 [00427] Step 1: Synthesis of ethyl 3-(3,5-dibromo-4-pyridyl)propanoate (1aj) [00428] To a s g, 7.97 mmol, 1 eq) in THF (20 mL) was added LDA (2 M, 4.38 mL, 1.1 eq) at -60 ^o C, and the mixture was stirred at - 60 ^o C for 0.5 h. ethyl 2-bromoacetate (3.33 g, 19.92 mmol, 2.21 mL, 2.5 eq) was added, the mixture was stirred at -60 ^o C for 3 h. TLC (Petroleum ether/Ethyl acetate=10:1, R _f =0.44) showed starting material was consumed completely and new spot was formed. The reaction mixture was slowly added sat.NH4Cl (10 mL) at -60 ^o C. The aqueous phase was extracted with ethyl acetate (10 mL*2). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash column (ISCO 40 g silica, 8-10% Ethyl acetate in Petroleum ether, gradient over 15 min). Ethyl 3-(3,5-dibromo-4- pyridyl)propanoate, 1aj, (1.5 g, 4.45 mmol, 55.85% yield) was obtained as a yellow solid. ¹ H NMR (400 MHz, CHLOROFORM-d) δ = 8.59 (s, 2H), 4.19 (q, J = 7.1 Hz, 2H), 3.33 - 3.25 (m, 2H), 2.61 - 2.54 (m, 2H),1.29 (t, J = 7.1 Hz, 3H). [00429] Step 2: Synthesis of 4-bromo-5,6-dihydrocyclopenta[c]pyridin-7-one (1ak) [00430] To a stirred solution of 1aj (1.4 g, 4.15 mmol, 1 eq) in THF (20 mL) was slowly added n-BuLi (2.5 M, 3.32 mL, 2 eq) at -60 ^o C. The mixture was stirred at -60 ^o C for 4 h. TLC (Petroleum ether/Ethyl acetate=3:1, R _f =0.31) showed starting material was consumed completely and new spot was formed. The mixture was added water (10 mL) at -60 ^o C. The aqueous phase was extracted with ethyl acetate (30 mL*3). The combined organic phase was dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum. The residue was purified by flash column (ISCO 40 g silica, 15-20% Ethyl acetate in Petroleum ether, gradient over 15 min). 4- bromo-5,6-dihydrocyclopenta[c]pyridin-7-one, 1ak, (150 mg, 707.40 μmol, 17.03% yield) was obtained as a white solid. ¹ H NMR (400 MHz, CHLOROFORM-d) δ = 8.91 (s, 1H), 8.82 (s, 1H), 3.17 - 3.09 (m, 2H), 2.81 - 2.73 (m, 2H). [00431] Step 3: Synthesis of 4-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6-yl]-5,6- dihydrocyclopenta[c]pyridin-7-one (Compound 65) [00432] To a stirred solution of 1n (100 mg, 234.91 μmol, 1 eq) in dioxane (4 mL) and H2O (0.8 mL) was added 4-bromo-5,6-dihydrocyclopenta[c]pyridin-7-one (64.76 mg, 305.39 μmol, 1.3 eq), Pd(dppf)Cl2 (17.19 mg, 23.49 μmol, 0.1 eq), Cs2CO3 (229.62 mg, 704.74 μmol, 3 eq) the mixture was bubbled with N ₂ for 1 minute, and the mixture was stirred at 100 ^o C for 2 h. LCMS showed the stating material was consumed completely and desired MS was detected. The reaction mixture was concentrated in vacuum. The crude residue was purified by prep-HPLC (Phenomenex Gemini-NX 150*30mm*5um column; 20-50 % acetonitrile in a 0.1% trifluoroacetic acid solution in water, 9 min gradient).4-[4-(6-chloro-5-fluoro-indolin-1- yl)quinazolin-6-yl]-5,6-dihydrocyclopenta[c]pyridin-7-one, Compound 65, (49.20 mg, 86.85 μmol, 36.97% yield, 96.19% purity, TFA) was obtained as a brown solid. ¹ H NMR (400 MHz, DMSO-d6) δ = 9.02 - 8.97 (m, 1H), 8.95 (s, 2H), 8.54 - 8.49 (m, 1H), 8.37 - 8.28 (m, 2H), 8.10 - 8.02 (m, 1H), 7.58 - 7.49 (m, 1H), 4.91 - 4.81 (m, 2H), 3.34 - 3.21 (m, 4H), 2.77 - 2.70 (m, 2H). MS (M + H) ⁺ =431.0 [00433] Example 66: Synthesis of 4-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6- yl]-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol, Compound 66 [00434] Step 1: Synthesis of 4-bromo-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol (1al) [00435] To H (5 mL) was added NaBH4 (107.05 mg, 2.83 mmol, 1.5 eq) at 0 ^o C. The mixture was stirred at 20 ^o C for 16 h. LCMS showed the starting material was consumed completely and desired MS was detected. The reaction mixture was concentrated in vacuum. The crude residue was purified by prep- HPLC (Phenomenex Gemini-NX 150*30mm*5um column; 1-30 % acetonitrile in a 0.1% trifluoroacetic acid solution in water, 9 min gradient).4-bromo-6,7-dihydro-5H- cyclopenta[c]pyridin-7-ol, 1al, (200 mg, 609.60 μmol, 32.32% yield, TFA) was obtained as a white solid. [00436] Step 2: Synthesis of 4-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6-yl]-6,7- dihydro-5H-cyclopenta[c]pyridin-7-ol (Compound 66) [00437] A stirred solution of 1n (100 mg, 234.91 μmol, 1 eq) in dioxane (4 mL) and H2O (0.5 mL), then 1al (92.48 mg, 281.89 μmol, 1.2 eq, TFA), Pd(dppf)Cl2 (17.19 mg, 23.49 μmol, 0.1 eq), Cs ₂ CO ₃ (229.62 mg, 704.74 μmol, 3 eq) was added, the mixture was purged with N ₂ for 1 minute, and the mixture was stirred at 100 ^o C for 3 h. LCMS showed the starting material was consumed completely and desired MS was detected. The reaction mixture was concentrated in vacuum. The crude residue was purified by prep-HPLC (Phenomenex Gemini-NX C18 75*30mm*3 μm column; 30-60 % acetonitrile in a 10 mM ammonium bicarbonate solution in water, 12 min gradient).4-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6- yl]-6,7-dihydro-5H- cyclopenta[c]pyridin-7-ol, Compound 66, (22.10 mg, 49.89 μmol, 21.24% yield, 97.72% purity) was obtained as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ = 8.76 (s, 1H), 8.57 (d, J = 8.5 Hz, 2H), 8.22 (s, 1H), 8.08 (dd, J = 1.7, 8.7 Hz, 1H), 7.97 (d, J = 8.6 Hz, 1H), 7.90 (d, J = 6.7 Hz, 1H), 7.43 (d, J = 8.8 Hz, 1H), 5.53 (d, J = 5.7 Hz, 1H), 5.25 (q, J = 6.2 Hz, 1H), 4.64 (br t, J = 8.0 Hz, 2H), 3.20 (br t, J = 7.9 Hz, 2H), 3.08 - 2.90 (m, 2H), 2.41 - 2.31 (m, 1H), 1.89 - 1.77 (m, 1H). MS (M + H) ⁺ =433.0 [00438] Example 67: 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 [00439] Step 1: Synthesis of 4-bromo-7-methyl-5,6-dihydrocyclopenta[c]pyridin-7-ol (1am) [00440] To a stirred solution of 1ak (500 mg, 2.36 mmol, 1 eq) in THF (5 mL) was added MeMgBr (3 M, 1.18 mL, 1.5 eq) at -60 ^o C, and the mixture was stirred at 20 ^o C for 3 h. LCMS showed the starting material was remained and desired MS was detected. The reaction mixture was poured into water (10 mL). The aqueous phase was extracted with dichloromethane (20 mL*2). The combined organic phase was dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum. The crude product was purified by flash column (ISCO 10 g silica, 60 - 70% ethyl acetate in petroleum ether, gradient over 20 min). Based on TLC (Petroleum ether: Ethyl acetate = 0/1, R _f = 0.40).4-bromo-7-methyl-5,6-dihydrocyclopenta[c]pyridin-7-ol, 1am, (300 mg, 1.32 mmol, 55.78% yield) was obtained as a green oil. [00441] 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)

H2O (1 mL) was added 1am (64.30 mg, 281.89 μmol, 1.2 eq), Pd(dppf)Cl2 (17.19 mg, 23.49 μmol, 0.1 eq), Cs ₂ CO ₃ (229.62 mg, 704.74 μmol, 3 eq), the mixture was bubbled with N ₂ for 1 minute, and stirred at 100 ^o C for 2 h. LCMS showed the starting material was consumed completely and desired MS was detected. The reaction was concentrate in vacuum. The crude residue was purified by prep-HPLC (Phenomenex Gemini-NX C1875*30mm*3 μm column; 30- 60 % acetonitrile in a 10 mM ammonium bicarbonate solution in water, 12 min gradient).4-[4- (6-chloro-5-fluoro-indolin-1-yl)quinazolin-6-yl]-7-methyl-5, 6-dihydrocyclopenta[c]pyridin-7-ol, Compound 67, (28.60 mg, 62.96 μmol, 26.80% yield, 98.38% purity) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ = 8.76 (s, 1H), 8.58 (s, 1H), 8.54 (s, 1H), 8.23 (s, 1H), 8.08 (br d, J = 1.1 Hz, 1H), 7.99 (s, 1H), 7.90 (d, J = 7.0 Hz, 1H), 7.43 (d, J = 8.8 Hz, 1H), 5.30 (s, 1H), 4.64 (br t, J = 8.2 Hz, 2H), 3.25 - 3.17 (m, 2H), 3.08 - 2.90 (m, 2H), 2.08 (t, J = 6.8 Hz, 2H), 1.54 (s, 3H). MS (M + H) ⁺ =447.0 [00443] Example 68: Synthesis of 1-[5-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin- 6-yl]-3-pyridyl]propan-1-one, Compound 68 [00444] Step 1: Synthesis of 5-bromo-N-methoxy-N-methyl-pyridine-3-carboxamide (1an) [00445] A solution of 5-bromopyridine-3-carboxylic acid (5 g, 24.75 mmol, 1 eq), N- methoxymethanamine;hydrochloride (2.66 g, 27.23 mmol, 1.1 eq), EDCI (5.22 g, 27.23 mmol, 1.1 eq), TEA (2.76 g, 27.23 mmol, 3.79 mL, 1.1 eq), HOBt (1.00 g, 7.43 mmol, 0.3 eq) in DMF (50 mL) 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 water (100 mL). The aqueous phase was extracted with ethyl acetate (100 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 40 g silica, 0-10 % ethyl acetate in petroleum ether, gradient over 20 min). Based on TLC (Petroleum ether: Ethyl acetate = 2/1, R _f = 0.45). 5-bromo-N- methoxy-N-methyl-pyridine-3-carboxamide, 1an, (3.1 g, 12.65 mmol, 51.10% yield) was obtained as colorless oil. MS (M + H) ⁺ = 245.0. [00446] Step 2: Synthesis of 1-(5-bromo-3-pyridyl)ethanone (1ao) [00447] To a stirred solution of 1an (3.1 g, 12.65 mmol, 1 eq) in THF (30 mL) was added MeMgBr (3 M, 6.32 mL, 1.5 eq) at -78 °C, and the mixture was stirred at 25 °C for 4 h. LCMS showed the starting material was consumed completely and desired MS was detected. The reaction mixture was poured into water (100 mL). The aqueous phase was extracted with ethyl acetate (100 mL*2). The combined organic phase was dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum.1-(5-bromo-3-pyridyl)ethenone, 1ao, (2.5 g, 12.50 mmol, 98.80% yield) was obtained as a yellow oil. MS (M + H) ⁺ = 200.0. [00448] Step 3: Synthesis of 3-bromo-5-(1-((tert- butyldimethylsilyl)oxy)vinyl)pyridine (1ap) [00449] To a stirred solution of 1ao (1 g, 5.00 mmol, 1 eq), DIEA (969.16 mg, 7.50 mmol, 1.31 mL, 1.5 eq) in CH2Cl2 (15 mL) was added [tert- butyl(dimethyl)silyl]trifluoromethanesulfonate (2.64 g, 10.00 mmol, 2.30 mL, 2 eq) at 0 °C. The mixture was stirred at 0 °C for 2 h. LCMS showed the starting material was consumed completely and desired MS was detected. The reaction mixture was poured into water (20 mL). The aqueous phase was extracted with ethyl acetate (100 mL*2). The combined organic phase was dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum.3-bromo-5-(1-((tert- butyldimethylsilyl)oxy)vinyl)pyridine, 1ap, (2.4 g, crude) was obtained as a yellow solid. MS (M + H) ⁺ = 316.1. [00450] Step 4: Synthesis of [1-(5-bromo-3-pyridyl)cyclopropoxy]-tert-butyl- dimethyl-silane (1aq) [00451] To a stirred at solution of 1ap (0.5 g, 1.59 mmol, 1 eq) in DCM (10 mL) was added ZnEt2 (1 M, 7.95 mL, 5 eq), CH2I2 (2.13 g, 7.95 mmol, 641.70 μL, 5 eq) at 0 °C. 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 water (100 mL). The aqueous phase was extracted with ethyl acetate (200 mL*2). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum. [1-(5-bromo-3- pyridyl)cyclopropoxy]-tert-butyl-dimethyl-silane, 1aq, (300 mg, 913.74 μmol, 57.44% yield) was obtained as a yellow oil. MS (M + H) ⁺ = 328.1 [00452] Step 5: Synthesis of 1-(5-bromo-3-pyridyl)propan-1-one (1ar) [00453] A solution of 1aq (250 mg, 761.45 μmol, 1 eq) in HCl/MeOH (4 M, 5.00 mL, 26.27 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 concentrate in vacuum. The crude residue was purified by prep-HPLC (Welch Xtimate C18100*25mm*3 μm; 1-20 % acetonitrile in a 0.05% hydrochloric acid solution in water, 8 min gradient).1-(5-bromo-3- pyridyl)propan-1-one, 1ar, (200 mg, crude) was obtained as a yellow oil. MS (M + H) ⁺ =216.0 [00454] Step 6: Synthesis of 1-[5-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6-yl]-3- pyridyl]propan-1-one (Compound 68) [0 0455] To a stirred solution of 1n (117.64 mg, 276.35 μmol, 1 eq) in H2O (0.2 mL) and DMF (1 mL) was added 1ar (76.90 mg, 359.25 μmol, 1.3 eq, HCl), Cs ₂ CO ₃ (270.12 mg, 829.04 μmol, 3 eq), Pd(dppf)Cl ₂ (20.22 mg, 27.63 μmol, 0.1 eq), and the mixture was purged with N ₂ for 1 minute, and stirred at 100 °C for 2 h. LCMS showed the starting material was consumed completely and desired MS was detected. The reaction mixture was filtered, and filtrate was purified by prep-HPLC (Phenomenex Gemini-NX C1875*30mm*3 μm column; 30-60 % acetonitrile in a 10 mM ammonium bicarbonate solution in water, 12 min gradient) to afford 20 mg crude product. The crude product was purified by prep-HPLC (Daicel ChiralPak IG (250*30mm, 10um); 28-58 % acetonitrile in a 0.04% hydrochloric acid solution in water, 8 min gradient).1-[5-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin -6-yl]-3-pyridyl]propan-1-one, Compound 68, (5.7 mg, 12.14 μmol, 4.39% yield, 100% purity, HCl) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ = 9.30 (d, J = 2.1 Hz, 1H), 9.21 (d, J = 1.9 Hz, 1H), 9.07 (s, 1H), 8.74 (d, J = 1.4 Hz, 1H), 8.69 (t, J = 2.0 Hz, 1H), 8.57 (dd, J = 1.6, 8.7 Hz, 1H), 8.45 (d, J = 6.6 Hz, 1H), 8.17 (d, J = 8.8 Hz, 1H), 7.60 (d, J = 8.8 Hz, 1H), 5.01 (br t, J = 7.6 Hz, 2H), 3.30 (br t, J = 7.4 Hz, 2H), 3.23 (q, J = 7.1 Hz, 2H), 1.14 (t, J = 7.1 Hz, 3H). MS (M + H) ⁺ =433.0 [00456] Example 69: Synthesis of 1-[5-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin- 6-yl]-2-methyl-3-pyridyl]cyclopropanol, Compound 69 [00457] Step 1: Synthesis 5-bromo-N-methoxy-N,2-dimethyl-pyridine-3-carboxamide (1as) [00458] A so (1 g, 4.63 mmol, 1 eq) , N-methoxymethanamine hydrochloride (903.05 mg, 9.26 mmol, 2 eq), HATU (2.11 g, 5.55 mmol, 1.2 eq), DIEA (2.39 g, 18.52 mmol, 3.23 mL, 4 eq) in DMF (20 mL) 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 water (100 mL). The aqueous phase was extracted with ethyl acetate (100mL*2). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The crude product was purified by flash column (ISCO 40 g silica, 0-10 % ethyl acetate in petroleum ether, gradient over 20 min). Based on TLC (Petroleum ether : Ethyl acetate = 2/1, R _f = 0.45).5-bromo-N-methoxy-N,2-dimethyl-pyridine-3- carboxamide, 1as, (1.1 g, 4.25 mmol, 91.72% yield) was obtained as a yellow oil. MS (M + H) ⁺ =259.0 [00459] Step 2: Synthesis of 1-(5-bromo-2-methyl-3-pyridyl)ethanone (1at) [00460] To a st rred so ut on o as ( . g, . 5 mmo , eq) n HF (20 mL) was added MeMgBr (3 M, 2.12 mL, 1.5 eq) at -78 °C, and the mixture was stirred at 25 °C for 4 h. LCMS showed the starting material was consumed completely and desired MS was detected. The reaction mixture was poured into water (100 mL) at 0 °C. The aqueous phase was extracted with ethyl acetate (100 mL*2). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum.1-(5-bromo-2-methyl-3-pyridyl)ethenone, 1at, (0.8 g, 3.74 mmol, 88.03% yield) was obtained as a yellow oil. MS (M + H) ⁺ =215.9 [00461] 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 μL, 1.5 eq) in CH2Cl2 (10 mL) was added [tert-butyl(dimethyl)silyl] trifluoromethanesulfonate (740.93 mg, 2.80 mmol, 644.29 μL, 2 eq) at 0 °C. The mixture was stirred at 0 °C for 2 h. TLC (Petroleum ether/Ethyl acetate=3:1, R _f = 0.76) showed starting material was consumed completely and new spot was formed. The reaction mixture was poured into water (20 mL). The aqueous phase was extracted with ethyl acetate (100 mL*2). The combined organic phase was dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum. 1-(5-bromo-2-methyl-3-pyridyl)vinyloxy-tert-butyl-dimethyl-s ilane, 1au, (0.48 g, crude) was obtained as a yellow oil. [00463] Step 4: Synthesis of [1-(5-bromo-2-methyl-3-pyridyl)cyclopropoxy]-tert- butyl-dimethyl-silane (5) [00464] To a s rre so u on o n ₂ ( , . m , eq) n (10 mL) was added TFA (694.59 mg, 6.09 mmol, 451.03 μL, 5 eq), CH2I2 (1.63 g, 6.09 mmol, 491.42 μL, 5 eq) 1au (400 mg, 1.22 mmol, 1 eq) at 0 °C. 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 water (100 mL). The aqueous phase was extracted with ethyl acetate (200 mL*2). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum. [1-(5-bromo-2-methyl-3-pyridyl)cyclopropoxy]-tert-butyl-dime thyl- silane, 1av, (500 mg, crude) was obtained as a yellow oil. MS (M + H) ⁺ = 344.1 [00465] 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 crude residue was purified by prep-HPLC (Welch Xtimate C18100*25mm*3 μm; 1-20 % acetonitrile in a 0.05% hydrochloric acid solution in water, 8 min gradient).1-(5-bromo-2-methyl-3- pyridyl)cyclopropanol, 1aw, (60 mg, 226.80 μmol, 19.41% yield, HCl) was obtained as a yellow oil. ¹ H NMR (400 MHz, DMSO-d6) δ = 8.79 (d, J = 2.3 Hz, 1H), 8.27 (d, J = 2.1 Hz, 1H), 2.76 (s, 3H), 1.06 - 1.00 (m, 2H), 1.00 - 0.94 (m, 2H). MS (M + H) ⁺ = 228.0 [00467] Step 6: Synthesis of 1-[5-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6-yl]-2- methyl-3-pyridyl]cyclopropanol (Compound 69) [ , . , , and H2O (0.2 mL) was added 1n (96.55 mg, 226.80 μmol, 1 eq), Pd(dppf)Cl2 (16.60 mg, 22.68 μmol, 0.1 eq), Cs ₂ CO ₃ (221.69 mg, 680.41 μmol, 3 eq) the mixture was purged with N ₂ for 1 mintue, and stirred at 100 °C for 2 h. LCMS showed the starting material was consumed completely, and the MS of desired product was detected. The reaction mixture filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18100*30mm*10um;mobile phase: [water(10Mm NH4HCO3)-ACN];B%: 28%- 262340-537651 48%,10min).1-[5-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazoli n-6-yl]-2-methyl-3- pyridyl]cyclopropanol, Compound 69, (10.3 mg, 22.30 μmol, 9.83% yield, 96.75% purity) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 8.74 - 8.79 (m, 2 H), 8.36 (s, 1 H), 8.25 (br d, J=8.63 Hz, 1 H), 7.98 (d, J=8.63 Hz, 1 H), 7.93 (d, J=2.00 Hz, 1 H), 7.84 (d, J=6.63 Hz, 1 H), 7.45 (d, J=8.88 Hz, 1 H), 5.82 (s, 1 H), 4.66 (br t, J=8.07 Hz, 2 H), 3.22 (br t, J=7.94 Hz, 2 H), 2.71 (s, 3 H), 0.99 - 1.06 (m, 2 H), 0.89 - 0.98 (m, 2 H). MS (M + H) ⁺ =447.0 [00469] Example 70: Synthesis of 1-[5-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin- 6-yl]-2-methyl-3-pyridyl]propan-1-ol, Compound 70 [00470] Step 1: Synthesis of 1-(5-bromo-2-methyl-3-pyridyl)propan-1-ol (1ax) [00471] To a stirred solution of ethyl 5-bromo-2-methyl-pyridine-3-carboxylate (1 g, 4.10 mmol, 1 eq) in THF (10 mL), then EtMgBr(3 M, 4.10 mL, 3 eq), Ti(OEt)4 (1.40 g, 6.15 mmol, 1.27 mL, 1.5 eq) was added at 0 °C. 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). Based on TLC(Petroleum ether : Ethyl acetate = 5/1, R _f = 0.48).1-(5-bromo-2-methyl-3-pyridyl)propan-1-ol, 1ax, (300 mg, 1.30 mmol, 31.82% yield) was obtained as a yellow solid. MS (M + H) ⁺ = 230.0. [00472] Step 2: Synthesis of 1-[5-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6-yl]-2- methyl-3-pyridyl]propan-1-ol (Compound 70) 262340-537651 F F H _O ^HO Cl Cl [ nd H ₂ O (0.5mL) was added 1n (77.08 mg, 181.08 μmol, 1 eq), Cs ₂ CO ₃ (177.00 mg, 543.24 μmol, 3 eq), Pd(dppf)Cl2 (13.25 mg, 18.11 μmol, 0.1 eq) the mixture was purged with N2 for 1 minute, and the mixture was stirred at 100 °C for 2 h. LCMS showed the starting material was consumed completely and desired MS was detected. The reaction mixture was concentrate in vacuum. The crude residue was purified by prep-HPLC (Phenomenex luna C18100*40mm*5 μm column; 5- 30 % acetonitrile in a 0.1% trifluoroacetic acid solution in water, 8 min gradient).1-[5-[4-(6- chloro-5-fluoro-indolin-1-yl)quinazolin-6-yl]-2-methyl-3-pyr idyl]propan-1-ol, Compound 70, (70.50 mg, 124.48 μmol, 68.75% yield, 99.40% purity, TFA) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ = 9.08 - 8.88 (m, 2H), 8.65 - 8.45 (m, 2H), 8.40 (br d, J = 8.5 Hz, 1H), 8.25 - 8.14 (m, 1H), 8.09 - 8.00 (m, 1H), 7.52 (br d, J = 8.8 Hz, 1H), 4.84 (br d, J = 6.8 Hz, 3H), 3.27 (br t, J = 7.5 Hz, 2H), 2.73 - 2.63 (m, 3H), 1.80 - 1.62 (m, 2H), 0.94 (br t, J = 7.3 Hz, 3H). MS (M + H) ⁺ = 449.1. [00474] 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 μmol, 0.3 eq) in 262340-537651 CCl4 (5 mL) was stirred at 90 ^o C for 16 h. LCMS showed the starting material was consumed completely and desired MS was detected. The reaction mixture was poured into water (10mL). The aqueous phase was extracted with dichloromethane (10mL*2). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum. Methyl 5-bromo-4- (bromomethyl)pyridine-3-carboxylate, 1ay, (250 mg, crude) was obtained as a yellow solid. MS (M + H) ⁺ = 309.9. [00477] Step 2: Synthesis of 7-bromo-2-methyl-1H-pyrrolo[3,4-c]pyridin-3-one (1az) [00478] A solution of methyl 1ay (240 mg, 776.81 μmol, 1 eq), methanamine; hydrochloride (150 mg, 2.22 mmol, 2.86 eq), TEA (314.42 mg, 3.11 mmol, 432.49 μL, 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). The aqueous phase was extracted with ethyl acetate (20 mL*2). The combined organic phase was dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum.7-bromo-2-methyl-1H- pyrrolo[3,4-c]pyridin-3-one, 1az, (150 mg, 660.63 μmol, 85.04% yield) was obtained as a yellow oil. MS (M + H) ⁺ = 229.0. [00479] 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) [00480] To a stirred solution of 1n (216.32 mg, 508.17 μmol, 1 eq) in H2O (0.5 mL) and DMF (5 mL) was added 1az (150 mg, 660.63 μmol, 1.3 eq), Pd(dppf)Cl ₂ (37.18 mg, 50.82 μmol, 262340-537651 0.1 eq), Cs2CO3 (496.72 mg, 1.52 mmol, 3 eq) the mixture was bubbled with N2 for 1 minute, and 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 filtered, and filtrate was purified by prep- HPLC (Phenomenex Gemini-NX C1875*30mm*3 μm column; 20-50 % acetonitrile in a 10 mM ammonium bicarbonate and 0.05% ammonium solution in water, 8 min gradient) to afford 30 mg crude product. The crude residue was purified by prep-HPLC (Waters Xbridge BEH C18 100*30mm*10um column; 25-55 % acetonitrile in a 10 mM ammonium bicarbonate solution in water, 8 min gradient).7-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6- yl]-2-methyl-1H- pyrrolo[3,4-c]pyridin-3-one, Compound 71, (6.7 mg, 15.03 μmol, 2.96% yield, 100% purity) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ = 8.96 (s, 1H), 8.94 - 8.90 (m, 1H), 8.78 (s, 1H), 8.36 (d, J = 1.6 Hz, 1H), 8.21 (dd, J = 1.8, 8.8 Hz, 1H), 8.02 (d, J = 8.6 Hz, 1H), 7.95 (d, J = 6.6 Hz, 1H), 7.44 (d, J = 8.9 Hz, 1H), 4.75 (s, 2H), 4.67 (t, J = 8.0 Hz, 2H), 3.21 (br t, J = 7.9 Hz, 2H), 3.09 (s, 3H). MS (M + H) ⁺ =446.0 [00481] Example 72: Synthesis of 4-(6-chloro-5-fluoro-indolin-1-yl)-6-(1H-pyrrolo [2,3-b]pyridin-5-yl) quinazoline, Compound 72 F F Cl [ g, . μ , q . mL) was added Cs2CO3 (137.77 mg, 422.84 μmol, 3 eq), Pd(dppf)Cl2 (10.31 mg, 14.09 μmol, 0.1 eq) and 5-bromo-1H-pyrrolo[2,3-b]pyridine (27.77 mg, 140.95 μmol, 1 eq), the reaction was stirred at 100 °C for 3 h under N2. 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. The crude product was purified by prep-HPLC (column: Phenomenex Luna 80*30mm*3 μm;mobile phase: [water(0.04%HCl)-ACN];B%: 10%-30%,8min). 4-(6-chloro-5- fluoro-indolin-1-yl)-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)quinaz oline, Compound 72, (1.81 mg, 4.00 μmol, 2.84% yield, 100% purity, HCl) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 11.91 (br s, 1 H), 9.05 (s, 1 H), 8.70 (d, J=2.25 Hz, 1 H) 8.63 (d, J=1.50 Hz, 1 262340-537651 H), 8.52 (dd, J=8.75, 1.63 Hz, 1 H), 8.41 - 8.47 (m, 2 H) 8.06 (d, J=8.75 Hz, 1 H), 7.53 - 7.64 (m, 2 H) 6.58 (dd, J=3.31, 1.81 Hz, 1 H) 5.02 (br t, J=7.50 Hz, 2 H) 3.33 - 3.34 (m, 2 H). MS (M + H) ⁺ = 416.0 [00483] Example 73: Synthesis of 2-amino-5-[4-(6-chloro-5-fluoro-indolin-1- yl)quinazolin-6-yl] pyridine-3-carbonitrile, Compound 73 F N F Cl N Cl [ O (1 mL) was added 2-amino-5-bromo-pyridine-3-carbonitrile (76.75 mg, 387.61 μmol, 1.1 eq), Cs ₂ CO ₃ (344.43 mg, 1.06 mmol, 3 eq), Pd(dppf)Cl ₂ (25.78 mg, 35.24 μmol, 0.1 eq) the mixture was bubbled with N2 for 1 minute, and the mixture was stirred at 100 ^o C for 3 h. LCMS showed the starting material was consumed completely and desired MS was detected. The reaction mixture was filtered and filtrate was purified by prep-HPLC (Phenomenex luna C1880*40mm*3 μm; 15-50 % acetonitrile in a 0.04% hydrochloric acid solution in water, 7 min gradient).2- amino-5-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6-yl] pyridine-3-carbonitrile, Compound 73, (15.50 mg, 31.47 μmol, 8.93% yield, 92.02% purity, HCl) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.03 (s, 1H), 8.74 (d, J = 2.4 Hz, 1H), 8.57 - 8.50 (m, 1H), 8.50 - 8.38 (m, 3H), 8.05 (d, J = 8.8 Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.32 (br s, 1H), 4.99 (br t, J = 7.5 Hz, 2H), 3.30 (br t, J = 7.4 Hz, 2H). MS (M + H) ⁺ = 417.1. [00485] Example 74: Synthesis of 5-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6- yl]pyridin-2-amine, Compound 74 F F Cl 262340-537651 [00486] To a stirred solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2- amine (72.66 mg, 330.14 μmol, 1 eq) in dioxane (3 mL), H2O (0.3 mL) was added 1k (150 mg, 396.17 μmol, 1.2 eq), Cs ₂ CO ₃ (322.70 mg, 990.42 μmol, 3 eq), Pd(dppf)Cl ₂ (24.16 mg, 33.01 μmol, 0.1 eq), the mixture was bubbled with N2 for 1 minute, and the mixture was stirred at 120 ^o C for 2 h. LCMS showed the starting material was consumed completely and desired MS was detected. The reaction mixture was concentrated in vacuum. The crude residue was purified by prep-HPLC (Phenomenex luna C18100*40mm*3 μm; 1-25 % acetonitrile in a 0.04% hydrochloric acid solution in water, 8 min gradient).5-[4-(6-chloro-5-fluoro-indolin-1- yl)quinazolin-6-yl]pyridin-2-amine, Compound 74, (82.20 mg, 191.47 μmol, 58.00% yield, 99.76% purity, HCl) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ = 9.02 (s, 1H), 8.63 - 8.52 (m, 2H), 8.49 - 8.36 (m, 4H), 8.14 (d, J = 8.8 Hz, 1H), 7.58 (d, J = 8.8 Hz, 1H), 7.20 (d, J = 9.3 Hz, 1H), 4.98 (br t, J = 7.5 Hz, 2H), 3.30 (br t, J = 7.4 Hz, 2H). MS (M + H) ⁺ = 392.1. [00487] Example 75: Synthesis of 4-(6-chloroindolin-1-yl)-6-(1H-pyrazolo[3,4- b]pyridin-5-yl)pyrido[3,2-d]pyrimidine, Compound 75 [00488] Step 1: Synthesis of 4,6-dichloropyrido[3,2-d]pyrimidine (4a) [00489] A solu , g, 1.10 mmol, 1 eq) in POCl ₃ (2 mL) was stirred at 90 °C for 12 h. LCMS showed reactant was consumed complete and one main peak with desired compound was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The crude residue was poured to ethyl acetate (10 mL) and the mixture was added to ice-water (10 mL), the mixture was basified by saturated sodium bicarbonate to pH = 8~9 at 0 °C, then the mixture extracted with ethyl acetate (15 mL*4), the organic was concentrated under reduced pressure to give a crude product. 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. ¹ H NMR (400MHz, CHLOROFORM-d) δ = 9.14 (s, 1H), 8.35 (d, J=8.8 Hz, 1H), 7.87 (d, J=8.8 Hz, 1H). 262340-537651 [00490] 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 μmol, 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. The reaction mixture was filtered and the filter cake was washed with i-PrOH (1 mL*3) and dried under reduced pressure to give a crude product.6-chloro-4-(6-chloroindolin-1-yl)pyrido[3,2- d]pyrimidine, 4b, (130 mg, 409.87 μmol, 65.59% yield) was obtained as a yellow solid. ¹ H NMR (400MHz, CHLOROFORM-d) δ 8.81 (s, 2H), 8.74 (s, 1H), 7.81 (br d, J=8.4 Hz, 1H), 7.34 - 7.29 (m, 1H), 7.27 - 7.23 (m, 1H), 5.15 (br t, J=7.7 Hz, 2H), 3.37 (br t, J=7.5 Hz, 2H). MS (M + H) ⁺ = 317.0. [00492] Step 3: Synthesis of 4-(6-chloroindolin-1-yl)-6-(1H-pyrazolo[3,4-b]pyridin-5- yl)pyrido[3,2-d]pyrimidine (Compound 75) O Cl [00493] To a sealed tube was added: 4b (130 mg, 409.87 μmol, 1 eq), 1g (130.59 mg, 532.83 μmol, 1.3 eq), Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (33.47 mg, 40.99 μmol, 0.1 eq), K ₃ PO ₄ (3 M, 409.87 μL, 3.0 eq) and DMF (0.4 mL). Then the sealed tube was bubbled with nitrogen for 30s and heated to 100°C. Then the sealed tube was stirred at 100°C for 20h. LCMS showed starting material was remained and desired product was formed. The mixture was poured into water (10 262340-537651 mL), filtered. The filter cake was triturated with MeOH (10 mL) at 25 ^o C for 15 min, the filter cake dissolved in DMSO (10 mL). The solution was purified by prep-HPLC:column: Waters Xbridge BEH C18100*25mm*5um;mobile phase: [water(10 mM NH4HCO3)-ACN];B%: 40%- 60%,8min.4-(6-chloroindolin-1-yl)-6-(1H-pyrazolo[3,4-b]pyrid in-5-yl)pyrido[3,2-d]pyrimidine, Compound 75, (13 mg, 32.18 μmol, 7.85% yield, 98.96% purity) was obtained as yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 13.89 (s, 1H), 9.38 (s, 1H), 9.02 (s, 1H), 8.78 (s, 1H), 8.62- 8.57 (m, 1H), 8.55 (s, 1H), 8.33-8.29 (m, 2H), 7.38-7.36 (m, 1H), 7.14-7.10 (m, 1H), 5.15 (t, J = 8 Hz, 2H), 3.28 (s, 2H). MS (M + H) ⁺ = 400.0 [00494] Example 76: 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 [00495] Step 1: Synthesis of 6-chloro-4-(6-chloro-5-fluoro-indolin-1-yl)pyrido[3,2- d]pyrimidine (4c) [00496] To a stirred solution of 4,6-dichloropyrido[3,2-d]pyrimidine (140 mg, 699.91 μmol, 1 eq) in i-PrOH (0.5 mL) was added 1j (120.10 mg, 699.91 μmol, 1 eq). Then the mixture was stirred at 80°C for 12h. LCMS showed starting material was completely consumed and desired product was formed. The mixture was filtered to afford the filter cake.6-chloro-4-(6- chloro-5-fluoro-indolin-1-yl)pyrido[3,2-d]pyrimidine, 4c, (200 mg, 596.72 μmol, 85.26% yield) was obtained as a yellow solid. [00497] 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 μmol, 1 eq), Pd(dppf)Cl2.CH2Cl2 (48.73 mg, 59.67 μmol, 0.1 eq), K3PO4 (2 M, 895.09 μL, 3.0 eq) and DMF (4 mL). Then the sealed tube was bubbled with nitrogen for 30s and heated to 100 °C. Then the mixture was stirred at 100°C for 12h. LCMS showed starting material was completely consumed and desired product was formed. The mixture was poured into water (10 mL), filtered. The filter cake was triturated with ethyl acetate (10 mL) at 25 ^o C for 15 min, the filter cake dissolved in DMSO (10 mL). The crude product was purified by prep-HPLC: column: Phenomenex luna C18250*50mm*10 μm; mobile phase: [water(0.05%HCl)-ACN]; B%: 20%- 60%,10min.4-(6-chloro-5-fluoro-indolin-1-yl)-6-(1H-pyrazolo[ 3,4-b]pyridin-5-yl)pyrido[3,2- d]pyrimidine, Compound 76, (75.11 mg, 158.72 μmol, 26.60% yield, 96.0% purity, HCl) was obtained as yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ , T=273+80K) δ = 9.36-9.35 (m, 1H), 9.01-9.00 (m, 1H), 8.98 1H), 8.81 (d, J = 6.8 Hz, 1H), 8.71 (d, J = 8.8 Hz, 1H), 8.50 (d, J = 4.8 Hz, 1H), 8.29 (s, 1H), 7.55-7.47 (m, 1H), 5.30 (t, J = 8 Hz, 2H), 3.41 (br t, J = 8 Hz, 2H). MS (M + H) ⁺ = 418.1. [00499] Example 77: Synthesis of 4-(6-fluoroindolin-1-yl)-6-(1H-pyrazolo[3,4- b]pyridin-5-yl)pyrido[3,2-d]pyrimidine, Compound 77 [00500] Step 1: Synthesis of 6-chloro-4-(6-fluoroindolin-1-yl)pyrido[3,2-d]pyrimidine (4d) 262340-537651 [00501] To a solution of 4a (200 mg, 999.88 μmol, 1 eq) in i-PrOH (3 mL) was added 6- fluoroindoline (137.14 mg, 999.88 μmol, 1 eq), the mixture was stirred at 90 °C for 2 h. LC-MS showed Reactant 1 was consumed completely and desired ms was detected. The reaction mixture was filtered. The filter cake was washed with i-PrOH (1 mL*3) and then dried under reduced pressure to give a crude product.6-chloro-4-(6-fluoroindolin-1-yl)pyrido[3,2-d]pyrimi dine, 4d, (278 mg, 924.46 μmol, 92.46% yield) was obtained as a pale yellow solid. ¹ H NMR (400 MHz, CHLOROFORM-d) δ = 9.02 (d, J = 8.8 Hz, 1H), 8.80 (s, 1H), 8.52 (d, J = 10.8 Hz, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.38 – 7.34(m, 1H), 7.08 - 7.00 (m, 1H), 5.21 (t, J = 8 Hz, 2H), 3.39 (t, J = 7.6 Hz, 2H). MS (M + H) ⁺ = 301.1. [00502] 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 μmol, 1.3 eq), Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (54.31 mg, 66.51 μmol, 0.1 eq),K ₃ PO ₄ (3 M, 665.08 μL, 3 eq) and DMF (5 mL). Then the sealed tube was bubbled with nitrogen for 30s and heated to 100 °C. Then the sealed tube was stirred at 100 °C for 10 h. LCMS showed starting material was completely consumed and desired product was formed. The reaction mixture was poured to water (10 mL), filtered, the filter cake was washed with water (1 mL*3) to give a crude product. The crude product was poured to ethyl acetate (5 mL) and stirred at 25 °C for 20 min. Then the mixture was filtered, the filter cake was washed with ethyl acetate (1 mL*3) to give a crude product. The crude residue was purified by prep-HPLC (Waters Xbridge Prep OBD C18 150*40mm*10um column; 25-70% acetonitrile in a 10 mM ammonium bicarbonate solution in water, 8 min gradient). 4-(6-fluoroindolin-1-yl)-6-(1H-pyrazolo[3,4-b]pyridin-5-yl)p yrido[3,2- d]pyrimidine, Compound 77, (95.63 mg, 236.99 μmol, 35.63% yield, 95.01% purity) was obtained as pale yellow solid. ¹ H NMR (400 MHz, CHLOROFORM-d, T=273+80K) δ = 262340-537651 13.67s(s,1 H), 9.38 (s, 1H), 8.99 (s, 1H), 8.78 (s, 1H), 8.58-8.55 (m, 1H), 8.36-8.28 (m, 3H), 7.38-7.34 (m, 1H), 6.90-68.85 (m, 1H), 5.20 (t, J = 8 Hz, 2H), 3.32 (t, J = 7.6 Hz, 2H). MS (M + H) ⁺ = 384.2. [00504] Example 78: Synthesis of 4-(6-bromoindolin-1-yl)-6-(1H-pyrazolo[3,4- b]pyridin-5-yl)pyrido[3,2-d]pyrimidine, Compound 78 [00505] Step 1: Synthesis of 6-chloropyrido[3,2-d]pyrimidin-4-ol [00506] A solutio -chloro-pyridine-2-carboxamide (12 g, 69.94 mmol, 1 eq) in triethylorthoformate (106.92 g, 721.46 mmol, 120.00 mL, 10.32 eq) was stirred at 150 °C for 20 h. TLC (Petroleum ether : Ethyl acetate = 1:1, R _f = 0.02 and Dichloromethane : Methanol = 10:1, Rf =0.52) indicated Reactant 1 was consumed completely and one new spot formed. The reaction mixture was filtered and the filter cake was washed with methyl tertiary butyl ether (5 mL*3), the filter cake was dried under reduced pressure to give a crude product (13 g). The crude product was poured to ethyl acetate (50 mL) and stirred at 20 °C for 30 min, filtered and the filter cake was washed with ethyl acetate (5 mL*3) and dried in vacuum to give a crude product (12 g). Then the crude product was added to methanol (30 mL), the mixture was heated to 80 °C and stirred at 80 °C for 30 min. Then the mixture was filtered at 80 °C, the filter cake was washed with methanol (5 mL*3) and dried in vacuum to give a crude product.6- chloropyrido[3,2-d]pyrimidin-4-ol (10 g, 55.07 mmol, 78.75% yield) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.76 (s, 1H), 8.20 (s, 1H), 8.15 (d, J = 8.4 Hz, 1H), 7.88(d, J = 8.8 Hz, 1H). [00507] Step 2: Synthesis of 6-(1H-pyrazolo[3,4-b]pyridin-5-yl)pyrido[3,2- d]pyrimidin-4-ol (4d) 262340-537651 [00508] To a stirred solution of 6-chloropyrido[3,2-d]pyrimidin-4-ol (1.5 g, 8.26 mmol, 1 eq) in DMF (21 mL) and was added Pd(dppf)Cl2.CH2Cl2 (674.61 mg, 826.09 μmol, 0.1 eq), K ₃ PO ₄ (4 M, 6.20 mL, 3 eq), 1g (3.04 g, 12.39 mmol, 1.5 eq). Then the mixture was stirred at 100 °C for 10 h. LC-MS showed Reactant 1 was consumed completely and desired ms was detected. The stirred reaction mixture was poured to water (50 mL), filtered. The filter cake was poured to MeOH (20 mL), the mixture was stirred at 20 °C for 20 min, filtered and the filter cake was dried under reduced pressure to give a crude product.6-(1H-pyrazolo[3,4-b]pyridin-5- yl)pyrido[3,2-d]pyrimidin-4-ol, 4d, (1.5 g, 5.68 mmol, 68.72% yield) was obtained as a purple solid. MS (M + H) ⁺ = 265.2. [00509] Step 3: Synthesis of 4-chloro-6-(1H-pyrazolo[3,4-b]pyridin-5-yl)pyrido[3,2- d]pyrimidine (4e) [00510] ido[3,2- d]pyrimidin-4-ol (100 mg, 378.44 μmol, 1 eq) in POCl3 (2 mL) was added TEA (153.18 mg, 1.51 mmol, 210.70 μL, 4.0 eq). Then the mixture was stirred at 100 °C for 1.5 h. The mixture was monitored by LCMS. The desired product was changed to R1 easily under QC. POCl ₃ was removed in vacuum.4-chloro-6-(1H-pyrazolo[3,4-b]pyridin-5-yl)pyrido[3,2 -d]pyrimidine, 4e, (100 mg, crude) was obtained as brown gum. [00511] Step 4: Synthesis of 4-(6-bromoindolin-1-yl)-6-(1H-pyrazolo[3,4-b]pyridin-5- yl)pyrido[3,2-d]pyrimidine (Compound 78) 262340-537651 [00512] To a stirred solution of 4e (100 mg, 353.75 μmol, 1 eq) in i-PrOH (3 mL) was added 6-bromoindoline (70.06 mg, 353.75 μmol, 1.0 eq). Then the mixture was stirred at 80 °C for 12 h. LCMS showed starting material was completely consumed and desired product was formed. The mixture was concentrated to afford the crude product. The crude product was purified by prep-HPLC: column: Phenomenex Luna C18150*30mm*5um; mobile phase: [water(0.04%HCl)-ACN]; B%: 30%-55%, 10min.4-(6-bromoindolin-1-yl)-6-(1H-pyrazolo[3,4- b]pyridin-5-yl)pyrido[3,2-d]pyrimidine, Compound 78, (7.97 mg, 15.26 μmol, 4.31% yield, 99.03% purity, HCl) was obtained as pale yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ = 9.39 (s, 1H), 9.06 (s, 1H), 9.01 (s, 1H), 8.79 (s, 1H), 8.74 (d, J = 8.8 Hz, 1H), 8.42 (d, J = 9.2 Hz, 1H), 8.33 (s, 1H), 7.41 (s, 2H), 5.25 (t, J = 8 Hz, 2H), 3.34 (t, J = 8 Hz, 2H). MS (M + H) ⁺ = 443.9, 446.0. [00513] 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, . μ , L) was added 6- methylindoline (133.17 mg, 999.88 μmol, 1 eq), the mixture was stirred at 90 °C for 2 h. LC-MS showed ~2% of reactant 1 was remained and 58% of desired compound was detected. The reaction mixture was filtered. The filter cake was washed with isopropanol (1 mL*3) and dried under reduced pressure to give a crude product.6-chloro-4-(6-methylindolin-1-yl)pyrido[3,2- d]pyrimidine, 4f, (230 mg, 775.05 μmol, 77.52% yield) as a yellow solid. ¹ H NMR (400 MHz, CHLOROFORM-d) δ = 9.01 (d, J = 8.8 Hz, 1H), 8.76 (s, 1H), 8.52 (s, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.32-7.29 (m, 1H), 7.17 (d, J = 7.6 Hz, 1H), 5.14 (t, J = 7.6 Hz, 2H), 3.37 (t, J = 7.6 Hz, 2H), 2.49 (s, 3 H). MS (M + H) ⁺ = 297.1. 262340-537651 [00516] Step 2: Synthesis of 4-(6-methylindolin-1-yl)-6-(1H-pyrazolo[3,4-b]pyridin-5- yl)pyrido[3,2-d]pyrimidine (Compound 79) [0 , , , , 876.15 μmol, 1.3 eq), Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (55.04 mg, 67.40 μmol, 0.1 eq), K ₃ PO ₄ (3 M, 673.96 μL, 3 eq) and DMF (5 mL). Then the sealed tube was bubbled with nitrogen for 30s and heated to 100 °C. Then the sealed tube was stirred at 100 °C for 10 h. LCMS showed starting material was completely consumed and desired product was formed. The reaction mixture was poured to water (10 mL) and filtered. The filter cake was washed with water (1 mL*3) to give a crude product. The crude product was poured to ethyl acetate (5 mL) and stirred at 25 °C for 20 min. The crude residue was purified by prep-HPLC (Phenomenex luna C18250*50mm*10 μm column; 15-55% acetonitrile in a 0.04% hydrochloric acid solution in water, 10 min gradient).4- (6-methylindolin-1-yl)-6-(1H-pyrazolo[3,4-b]pyridin-5-yl)pyr ido[3,2-d] pyrimidine, Compound 79, (111.12 mg, 236.89 μmol, 35.15% yield, 96.43% purity, HCl) was obtained as yellow solid. ¹ H NMR (400 MHz, CHLOROFORM-d) δ = 9.40 (s, 1 H), 9.07 (s, 1H), 9.01 (s, 1H), 8.77 (d, J = 8.8 Hz , 1H), 8.48 (s, 1H), 8.43 (d, J = 8.8 Hz, 1H), 8.34 (s, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.12 (d, J = 7.6 Hz, 1H), 5.26 (t, J = 7.6 Hz, 2H), 3.35 (t, J = 7.6 Hz, 2H), 2.40 (s, 3 H). MS (M + H) ⁺ = 380.0. [00518] Example 80: Synthesis of 4-(6-chloro-5-fluoro-indolin-1-yl)-6-(3-methyl-1H- pyrazolo [3,4-b]pyridin-5-yl) quinazoline, Compound 80

262340-537651 F F N Cl Cl [ 3 mL) was added K3PO4 (97.23 mg, 458.08 μmol, 3 eq), Pd(PPh3)4 (17.64 mg, 15.27 μmol, 0.1 eq) and 5-bromo-3-methyl-1H-pyrazolo[3,4-b]pyridine (48.57 mg, 229.04 μmol, 1.5 eq), the reaction was stirred at 100 °C for 12h. 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. The crude product was purified by prep-HPLC (column: Phenomenex C18 75*30mm*3 μm; mobile phase: [water (10 mmol NH4HCO3)-ACN];B%: 25%-55%,8min). 4-(6- chloro-5-fluoro-indolin-1-yl)-6-(3-methyl-1H-pyrazolo[3,4-b] pyridin-5-yl)quinazoline, Compound 80, (3.57 mg, 8.29 μmol 5.43% yield, 100% purity) was obtained as a off-white solid. ¹ H NMR (400 MHz, DMSO-d6) δ = 13.57 - 12.91 (m, 1H), 8.93 (d, J = 2.1 Hz, 1H), 8.76 (s, 1H), 8.60 (d, J = 2.1 Hz, 1H), 8.44 (d, J = 1.6 Hz, 1H), 8.33 (dd, J = 1.8, 8.8 Hz, 1H), 8.00 (d, J = 8.6 Hz, 1H), 7.89 (d, J = 6.6 Hz, 1H), 7.45 (d, J = 8.9 Hz, 1H), 4.71 (t, J = 8.1 Hz, 2H), 3.23 (br t, J = 7.9 Hz, 2H), 2.57 (s, 3H). MS (M + H) ⁺ = 431.1 [00520] 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 μmol, 1 eq) in DMF (0.5 mL) and H ₂ O (0.1 mL) was added Cs2CO3 (137.77 mg, 422.84 μmol, 3 eq), Pd(dppf)Cl2 (10.31 mg, 14.09 μmol, 0.1 eq) and 6-bromo-3H-triazolo[4,5-b]pyridine (42.07 mg, 211.42 μmol, 1.5 eq), the reaction was stirred at 100 °C for 3 h under N ₂ . LCMS showed starting material was consumed 262340-537651 completely and the MS of desired product was detected. The reaction was filtered, then the filtrate was concentrated in vacuum. The crude product was purified by prep-HPLC (column: Phenomenex C1875*30mm*3 μm;mobile phase: [water( 10 mmol NH ₄ HCO ₃ )-ACN];B%: 30%- 60%,8min).4-(6-chloro-5-fluoro-indolin-1-yl)-6-(3H-triazolo[ 4,5-b]pyridin-6-yl)quinazoline, Compound 81, (3.84 mg, 9.19 μmol, 6.52% yield, 100% purity) was obtained as pale yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.11 (d, J = 1.9 Hz, 1H), 8.80 - 8.71 (m, 2H), 8.51 (s, 1H), 8.35 (dd, J = 1.6, 8.6 Hz, 1H), 8.04 - 7.92 (m, 2H), 7.43 (d, J = 8.9 Hz, 1H), 4.74 (br t, J = 8.0 Hz, 2H), 3.22 (br t, J = 7.9 Hz, 2H). MS (M + H) ⁺ = 418.1 [00522] 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 μmol, 1.1 eq), Cs2CO3 (344.43 mg, 1.06 mmol, 3 eq), Pd(dppf)Cl2 (25.78 mg, 35.24 μmol, 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. LCMS showed the starting material was consumed completely and desired MS was detected. The reaction mixture was concentrated in vacuum. The crude residue was purified by prep-HPLC (Phenomenex luna C18250*50mm*10 μm; 10-40 % acetonitrile ina 0.04% hydrochloric acid solution in water, 10 min gradient) to afford 80 mg crude product. The crude product was purified by prep-HPLC (Waters Xbridge BEH C18100*30mm*10um column; 30-60 % acetonitrile in a 10 mM ammonium bicarbonate solution in water, 8 min gradient). 5-[4-(6- chloro-5-fluoro-indolin-1-yl)quinazolin-6-yl]-4-methyl- pyrimidin-2-amine, Compound 82, (54.70 mg, 134.45 μmol, 38.16% yield, 100% purity) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ = 8.74 (s, 1H), 8.16 (s, 1H), 8.04 (s, 1H), 7.92 (s, 2H), 7.83 (d, J = 6.6 Hz, 1H), 7.42 (d, J = 8.9 Hz, 1H), 6.73 (s, 2H), 4.60 (br t, J = 8.0 Hz, 2H), 3.19 (br t, J = 7.9 Hz, 2H), 2.31 (s, 3H). MS (M + H) ⁺ = 407.1. 262340-537651 [00524] Example 83: Synthesis of 5-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6- yl]-4-(trifluoromethyl)pyrimidin-2-amine, Compound 83 F F Cl Cl [ 3 mg, 422.84 μmol, 1.2 eq) in dioxane (0.5 mL), H ₂ O (0.1 mL) was added 1n (150 mg, 352.37 μmol, 1 eq), Cs ₂ CO ₃ (344.43 mg, 1.06 mmol, 3 eq), Pd(dppf)Cl ₂ (25.78 mg, 35.24 μmol, 0.1 eq) the mixture was bubbled with N2 for 1 minute, and the mixture was stirred at 100 °C for 3 h. LCMS showed the starting material was consumed completely and desired MS was detected. The reaction mixture was filtered, and filtrate was purified directly. The crude residue was purified by prep-HPLC (Welch Xtimate C18150*25mm*5um; 25-45 % acetonitrile ina 0.04% hydrochloric acid solution in water, 8 min gradient). 5-[4-(6-chloro-5-fluoro-indolin-1- yl)quinazolin-6-yl]-4-(trifluoromethyl)pyrimidin-2-amine, Compound 83, (38.30 mg, 77.02 μmol, 21.86% yield, 100% purity, HCl) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6+D2O) δ = 9.01 (s, 1H), 8.50 (s, 1H), 8.43 - 8.31 (m, 2H), 8.06 (br d, J = 8.9 Hz, 1H), 8.01 - 7.96 (m, 1H), 7.54 (d, J = 8.8 Hz, 1H), 4.81 (br t, J = 7.4 Hz, 2H), 3.26 (br t, J = 7.3 Hz, 2H). MS (M + H) ⁺ = 461.1. [00526] Example 84: Synthesis of 5-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6- yl]-4-methoxy-pyrimidin -2-amine, Compound 84 [00527] To a stirred solution of 5-bromo-4-methoxy-pyrimidin-2-amine (79.08 mg, 387.61 μmol, 1.1 eq) in dioxane (0.5 mL), H ₂ O (0.1 mL) was added 1n (150 mg, 352.37 μmol, 1 262340-537651 eq), Cs2CO3 (344.43 mg, 1.06 mmol, 3 eq), Pd(dppf)Cl2 (25.78 mg, 35.24 μmol, 0.1 eq), the mixture was bubbled with N2 for 1 minute, and the mixture was stirred at 120 °C for 2 h. LCMS showed the starting material was consumed completely and desired MS was detected. The reaction mixture was concentrated in vacuum. The residue was purified by prep-HPLC (Phenomenex Luna C18100*30mm*5um; 1-30 % acetonitrile in a 0.04% hydrochloric acid solution in water, 8 min gradient) to afford 50 mg crude product. 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 μmol, 17.55% yield, 99.83% purity) was obtained as a pale yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ = 8.71 (s, 1H), 8.24 (s, 2H), 8.04 (s, 1H), 7.87 (d, J = 8.8 Hz, 1H), 7.82 (d, J = 6.6 Hz, 1H), 7.43 (d, J = 8.9 Hz, 1H), 6.85 (s, 2H), 4.60 (br t, J = 7.9 Hz, 2H), 3.88 (s, 3H), 3.21 (br t, J = 7.8 Hz, 2H). MS (M + H) ⁺ = 423.1. [00528] Example 85: Synthesis of 2-amino-5-[4-(6-chloro-5-fluoro-indolin-1- yl)quinazolin-6-yl]pyrimidin-4-ol, Compound 85 [00529] To a stirred solution of Compound 84 (30 mg, 70.95μmol, 1 eq) in AcOH (3 mL) was added HBr (775.75 mg, 3.55 mmol, 520.64 μL, 37% purity, 50 eq), the mixture was stirred at 65 ^o C for 3 h. LCMS showed the starting material was consumed completely and desired MS was detected. The reaction mixture was concentrated in vacuum. The residue was adjusted pH~9 by adding sat. NaOH. The crude residue was purified by prep-HPLC (Phenomenex luna C18 80*40mm*3 μm; 5-45 % acetonitrile in a 0.04% hydrochloric acid solution in water, 7 min gradient). 2-amino-5-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6-yl ]pyrimidin-4-ol, Compound 85, (19.19 mg, 41.63 μmol, 58.68% yield, 96.60% purity, HCl) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.01 (s, 1H), 8.75 (s, 1H), 8.44 - 8.37 (m, 1H), 262340-537651 8.35 - 8.27 (m, 2H), 8.22 (s, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.57 (d, J = 8.8 Hz, 1H), 4.87 (br t, J = 7.6 Hz, 2H), 3.30 (br t, J = 7.4 Hz, 2H). MS (M + H) ⁺ = 409.0. [00530] 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 μmol, 1.5 eq), Pd(dppf)Cl2 (25.78 mg, 35.24 μmol, 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. LCMS showed the starting material was consumed completely and desired MS was detected. The reaction mixture was concentrated in vacuum. The crude residue was purified by prep-HPLC (Phenomenex Gemini- NX C1875*30mm*3 μm column; 30-50 % acetonitrile in a10 mM ammonium bicarbonate solution in water, 8 min gradient).6-(4-(6-chloro-5-fluoroindolin-1-yl)quinazolin-6-y l)-1,2,4- triazin-3-amine, Compound 86, (12.3 mg, 31.23 μmol, 8.86% yield, 99.27% purity) was obtained as a yellow solid.). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.97 (s, 1H), 8.73 (d, J = 7.8 Hz, 2H), 8.54 (br d, J = 8.8 Hz, 1H), 8.01 - 7.92 (m, 2H), 7.51 - 7.40 (m, 3H), 4.70 (br t, J = 7.9 Hz, 2H), 3.24 (br t, J = 7.9 Hz, 2H). MS (M + H) ⁺ = 394.1. [00532] Example 87: Synthesis of [2-amino-5-[4-(6-chloro-5-fluoro-indolin-1- yl)quinazolin-6-yl]-3-pyridyl]methanol, Compound 87 F F HO Cl 262340-537651 [00533] To a stirred solution of (2-amino-5-bromo-3-pyridyl)methanol (85.85 mg, 422.84 μmol, 1.2 eq) in dioxane (5 mL), H2O (1 mL) was added 1n (150 mg, 352.37 μmol, 1 eq), Cs ₂ CO ₃ (344.43 mg, 1.06 mmol, 3 eq), Pd(dppf)Cl ₂ (25.78 mg, 35.24 μmol, 0.1 eq), the mixture was bubbled with N2 for 1 minute, and the mixture was stirred at 100 °C for 3 h. LCMS showed the starting material was consumed completely and desired MS was detected. The reaction mixture was concentrate in vacuum. The crude residue was purified by prep-HPLC (Kromasil C18 (250*50mm*10 μm) column; 25-55 % acetonitrile in a 10 mM ammonium bicarbonate solution in water, 10 min gradient). [2-amino-5-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6- yl]-3-pyridyl]methanol, Compound 87, (29.10 mg, 68.27 μmol, 19.37% yield, 98.97% purity) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ = 8.71 (s, 1H), 8.31 (d, J = 2.3 Hz, 1H), 8.23 - 8.19 (m, 1H), 8.18 - 8.12 (m, 1H), 7.92 (d, J = 8.8 Hz, 1H), 7.84 - 7.79 (m, 1H), 7.76 (d, J = 6.6 Hz, 1H), 7.43 (d, J = 8.8 Hz, 1H), 5.98 (s, 2H), 5.24 (t, J = 5.4 Hz, 1H), 4.63 (br t, J = 8.0 Hz, 2H), 4.44 (d, J = 5.4 Hz, 2H), 3.22 (br t, J = 8.0 Hz, 2H). MS (M + H) ⁺ = 422.1. [00534] Example 88: Synthesis of 2-amino-5-[4-(6-chloro-5-fluoro-indolin-1- yl)quinazolin-6-yl]pyridine-3-carboxamide, Compound 88 F F O NH ₂ Cl [ 422.84 μmol, 1.2 eq) in dioxane (0.5 mL), H2O (0.1 mL) was added 1n (150 mg, 352.37 μmol, 1 eq), Cs ₂ CO ₃ (344.43 mg, 1.06 mmol, 3 eq), Pd(dppf)Cl ₂ (25.78 mg, 35.24 μmol, 0.1 eq) the mixture was bubbled with N2 for 1 minute, and the mixture was stirred at 100 °C for 3 h. LCMS showed the starting material was consumed completely and desired MS was detected. The reaction mixture was filtered, the filtrate was purified by prep-HPLC (Kromasil C18 (250*50mm*10 μm) column; 25-55 % acetonitrile in a 10 mM ammonium bicarbonate solution in water, 10 min gradient).2-amino-5-[4-(6-chloro-5-fluoro-indolin-1-yl)quina zolin-6- yl]pyridine-3-carboxamide, Compound 88, (33.80 mg, 74.80 μmol, 21.23% yield, 96.23% purity) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ = 8.71 (s, 1H), 8.57 (d, 262340-537651 J = 2.0 Hz, 1H), 8.39 - 8.31 (m, 2H), 8.31 - 8.22 (m, 1H), 8.22 - 8.06 (m, 1H), 7.94 (d, J = 8.8 Hz, 1H), 7.91 - 7.83 (m, 1H), 7.43 (br d, J = 8.9 Hz, 4H), 4.68 (br t, J = 8.1 Hz, 2H), 3.22 (br t, J = 7.8 Hz, 2H). MS (M + H) ⁺ = 435.1. [00536] 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-dioxaborol an-2- yl)pyridine-3-carboxamide (104.86 mg, 360.15 μmol, 1 eq), Cs ₂ CO ₃ (352.04 mg, 1.08 mmol, 3 eq), Pd(dppf)Cl2 (26.35 mg, 36.02 μmol, 0.1 eq) the mixture was bubbled with N2 for 1 minute, and the mixture 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 filtered, and filtrate was purified by prep-HPLC (Phenomenex luna C1880*40mm*3 μm; 10-40 % acetonitrile in a 0.04% hydrochloric acid solution in water, 7 min gradient). 2-amino-5-[4-(6-chloro-5-fluoro- indolin-1-yl)quinazolin-6-yl]-N,N -dimethyl-pyridine-3-carboxamide, Compound 89, (13.90 mg, 26.00 μmol, 7.22% yield, 93.42% purity, HCl) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ = 8.98 (s, 1H), 8.63 (d, J = 2.1 Hz, 1H), 8.52 (s, 1H), 8.4 (m, 1H), 8.36 - 8.23 (m, 2H), 8.06 (d, J = 8.9 Hz, 1H), 7.56 (d, J = 8.8 Hz, 1H), 4.92 (br t, J = 7.6 Hz, 2H), 3.29 (br t, J = 7.6 Hz, 2H), 2.99 (br d, J = 16.5 Hz, 6H). MS (M + H) ⁺ = 463.1. [00538] Example 90: Synthesis of 3-amino-6-[4-(6-chloro-5-fluoro-indolin-1- yl)quinazolin-6-yl]-1H-pyrazin-2-one, Compound 90

262340-537651 F F O Cl Cl [ ₂ O (0.1 mL) was added 3-amino-6-bromo-1H-pyrazin-2-one (80.34 mg, 422.84 μmol, 1.2 eq), CS2CO3 (344.43 mg, 1.06 mmol, 3 eq), Pd(dppf)Cl2 (25.78 mg, 35.24 μmol, 0.1 eq) the mixture was bubbled with N ₂ for 1 minute, and the mixture was stirred at 100 ^o C for 1 h. LCMS showed the starting material was consumed completely and desired MS was detected. The reaction mixture was filtered, the filtrate was purified by prep-HPLC (Welch Xtimate C18 150*25mm*5um; 10-30 % acetonitrile in a 0.04% hydrochloric acid solution in water, 8 min gradient).3-amino-6-[4-(6-chloro-5-fluoro-indolin-1-yl)quina zolin-6-yl]-1H-pyrazin-2-one, Compound 90, (14.10 mg, 31.46 μmol, 8.93% yield, 99.36% purity, HCl) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6, T=273+80K) δ = 8.90 (s, 1H), 8.47 (s, 1H), 8.29 - 8.22 (m, 2H), 8.05 (d, J = 8.8 Hz, 1H), 7.49 (d, J = 8.6 Hz, 1H), 7.25 (s, 1H), 4.87 (t, J = 7.8 Hz, 2H), 3.32 (t, J = 7.8 Hz, 2H). MS (M + H) ⁺ = 409.0. [00540] Example 91: Synthesis of 5-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6- yl]pyridine-2-carboxamide, Compound 91 [0 g, . μ , q . , H2O (0.1 mL) was added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-ca rboxamide (58.29 mg, 234.95 μmol, 1 eq), Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (19.19 mg, 23.49 μmol, 0.1 eq), K ₃ PO ₄ (149.61 mg, 704.84 μmol, 3 eq), the mixture was bubbled with N ₂ for 1 minute, and the mixture was stirred at 90 °C for 1 h. LCMS showed the starting material was consumed completely and 262340-537651 desired MS was detected. The reaction was filtered, and the filtrate was purified by prep-HPLC (Phenomenex Gemini-NX 150*30mm*5um column; 25-55 % acetonitrile in a10 mM ammonium bicarbonate solution in water, 8 min gradient). 5-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin- 6-yl]pyridine-2-carboxamide, Compound 91, (13.39 mg, 31.89 μmol, 13.57% yield, 100% purity) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ = 9.06 (s, 1H), 8.77 (s, 1H), 8.53 (s, 1H), 8.41 (d, J = 8.4 Hz, 1H), 8.33 (d, J = 8.3 Hz, 1H), 8.19 - 8.12 (m, 2H), 8.03 - 7.98 (m, 2H), 7.71 (br s, 1H), 7.45 (d, J = 9.2 Hz, 1H), 4.75 (s, 2H), 3.27 - 3.20 (m, 2H). MS (M + H) ⁺ = 420.1. [00542] ¹ H NMR (400 MHz, DMSO-d6) δ = 9.19 (s, 1H), 8.78 (s, 1H), 8.70 (dd, J = 1.4, 4.8 Hz, 1H), 8.48 (s, 1H), 8.24 (d, J = 8.8 Hz, 1H), 8.20 (s, 1H), 8.04 (d, J = 8.3 Hz, 2H), 7.97 (d, J = 4.8 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 4.69 (t, J = 8.0 Hz, 2H), 3.21 (br t, J = 7.9 Hz, 2H). MS (M + H) ⁺ = 417.1. [00543] 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, . μ , q , y py , py (99.62 mg, 469.82 μmol, 1 eq), Pd(dppf)Cl2.CH2Cl2 (57.55 mg, 70.47 μmol, 0.15 eq) and Na2CO3 (2 M, 704.74 μL, 3 eq) were taken up into a microwave tube in H2O (0.5 mL), ACN (5 mL) .The mixture was bubbled with N ₂ for 1 min. And the sealed tube was heated at 100 °C for 30 min under microwave. LCMS showed the starting material was consumed completely and desired MS was detected. The reaction mixture was filtered, and filter caked was purified directly. The crude residue was purified by prep-HPLC (Phenomenex Gemini-NX C18 75*30mm*3 μm column; 30-60 % acetonitrile in a 10 mM ammonium bicarbonate solution in water, 8 min gradient). 4-(6-chloro-5-fluoroindolin-1-yl)-6-(1-methyl-1H-pyrazolo[4, 3- b]pyridin-6-yl)quinazoline, Compound 92, (36.80 mg, 82.19 μmol, 17.49% yield, 96.23% purity) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6, T=273+80K) δ = 8.95 (s, 262340-537651 1H), 8.79 (s, 1H), 8.53 (s, 1H), 8.47 (s, 1H), 8.37 (d, J = 8.8 Hz, 1H), 8.28 (s, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.89 (d, J = 6.6 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H), 4.71 (t, J = 8.2 Hz, 2H), 4.16 (s, 3H), 3.26 (t, J = 8.0 Hz, 2H). MS (M + H) ⁺ = 431.1. [00545] 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 [ μmol, 1 eq) in DMF (10 mL) was added 1n (200 mg, 469.82 μmol, 1 eq), K3PO4 (199.46 mg, 939.65 μmol, 2 eq), ditert-butyl(cyclopentyl)phosphane;dichloropalladium;iron (30.62 mg, 46.98 μmol, 0.1 eq), the mixture was bubbled with Ar, and the mixture was stirred at 80 °C for 16 h. LCMS showed the starting material was consumed completely and desired MS was detected. The reaction mixture was filtered, and filtrate was purified directly. The crude residue was purified by prep-HPLC (Phenomenex Gemini-NX C1875*30mm*3 μm column ; 33-53 % acetonitrile in a 10 mM ammonium bicarbonate solution in water, 6 min gradient) to afford 80 mg crude product. The crude product was purified by prep-HPLC (Phenomenex Luna C18 200*40mm*10um column; 22-52 % acetonitrile in a 0.1% trifluoroacetic acid solution in water, 10 min gradient).4-(6-chloro-5-fluoro-indolin-1-yl)-6-imidazo[1,5-a ]pyrimidin- 3-yl- quinazoline, Compound 93, (38.50 mg, 92.36 μmol, 19.66% yield, 100% purity, TFA) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ = 9.33 - 9.23 (m, 1H), 8.96 (s, 1H), 8.79 (d, J = 2.1 Hz, 1H), 8.68 - 8.58 (m, 2H), 8.40 (dd, J = 1.6, 8.8 Hz, 1H), 8.31 (br d, J = 6.6 Hz, 1H), 8.03 (d, J = 8.8 Hz, 1H), 7.74 (br s, 1H), 7.53 (d, J = 8.8 Hz, 1H), 4.92 (br t, J = 7.8 Hz, 2H), 3.29 (br t, J = 7.7 Hz, 2H)). MS (M + H) ⁺ = 417.1. [00547] Example 94: Synthesis of [5-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6- yl]-3-pyridyl]-pyrrolidin-1-yl-methanone, Compound 94 [00548] Step 1: Synthesis of (5-bromo-3-pyridyl)-pyrrolidin-1-yl-methanone (1ba) 262340-537651 O Cl O N HN r [00549] A stirred solution of 5-bromopyridine-3-carbonyl chloride (200 mg, 907.23 μmol, 1 eq) in DCM (3 mL) was added pyrrolidine (64.52 mg, 907.23 μmol, 75.73 μL, 1 eq) ,TEA (275.41 mg, 2.72 mmol, 378.82 μL, 3 eq), the reaction was stirred at 25 °C for 30 min. LCMS showed starting material was consumed completely and the MS of desired product was detected. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. No purification, used for next step. (5-bromo-3-pyridyl)-pyrrolidin-1-yl- methanone, 1ba, (90 mg, 352.79 μmol, 38.89% yield) was obtained as a yellow solid. [00550] 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 μmol, 1 eq) in DMF (3 mL) and H2O (0.6 mL) was added 1ba (43.15 mg, 169.14 μmol, 1.2 eq), Cs ₂ CO ₃ (137.77 mg, 422.84 μmol, 3 eq) and Pd(dppf)Cl ₂ (10.31 mg, 14.09 μmol, 0.1 eq), the reaction was stirred at 100 °C for 3 h under N2. 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. The crude product was purified by prep-HPLC (column: Phenomenex luna C1880*40 mm*3 μm;mobile phase: [water(0.04%HCl)-ACN];B%: 30%-50%,7min). [5-[4-(6-chloro-5-fluoro- indolin-1-yl)quinazolin-6-yl]-3-pyridyl]-pyrrolidin-1-yl-met hanone, Compound 94, (96.114% purity, HCl) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.19 (d, 262340-537651 J=1.50 Hz, 1 H), 9.04 - 9.10 (m, 1 H), 8.83 (s, 1 H), 8.71 (s, 1 H), 8.51 - 8.58 (m, 1 H), 8.46 (br d, J=1.63 Hz, 2 H), 8.17 (d, J=8.75 Hz, 1 H), 7.59 (d, J=8.63 Hz, 1 H), 5.01 (br t, J=7.44 Hz, 2 H), 3.48 - 3.53 (m, 4 H), 3.30 (br t, J=7.32 Hz, 2 H), 1.82 - 1.95 (m, 4 H). MS (M + H) ⁺ =474.0 [00552] Example 95: Synthesis of [2-amino-5-[4-(6-chloro-5-fluoro-indolin-1- yl)quinazolin-6-yl]-3-pyridyl]-pyrrolidin-1-yl-methanone, Compound 95 [00553] Step 1: Synthesis of (2-amino-5-bromo-3-pyridyl)-pyrrolidin-1-yl-methanone (1bb) [00554] To a s DMF (3 mL) was added pyrrolidine (78.65 mg, 1.11 mmol, 92.31 μL, 1.2 eq), HATU (525.62 mg, 1.38 mmol, 1.5 eq) and DIEA (357.31 mg, 2.76 mmol, 481.55 μL, 3 eq), the reaction was stirred at 25 °C for 30 min. LCMS showed starting material was consumed completely and the MS of desired product was detected. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (50mL). The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. (2-amino-5-bromo-3-pyridyl)-pyrrolidin-1-yl-methanone, 1bb, (210 mg, 777.42 μmol, 84.36% yield) was obtained as a yellow solid. [00555] 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 μmol, 1 eq) in DMF (1 mL) and H ₂ O (0.2 mL) was added 1bb (44.42 mg, 164.44 μmol, 1 eq), Cs ₂ CO ₃ (160.73 mg, 493.32 μmol, 3 eq) and Pd(dppf)Cl2 (12.03 mg, 16.44 μmol, 0.1 eq), the reaction was stirred at 100 °C for 3h under 262340-537651 N2. 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. The crude product was purified by prep-HPLC(column: Phenomenex Luna 80*30mm*3 μm;mobile phase: [water(0.04%HCl)-ACN];B%: 10%-30%,8min. [2-amino-5-[4-(6-chloro-5-fluoro-indolin-1- yl)quinazolin-6-yl]-3-pyridyl]-pyrrolidin-1-yl-methanone, Compound 95, (10.14 mg, 19.30 μmol, 11.74% yield, 100% purity, HCl) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ +D2O) δ ppm 8.82 (s, 1 H), 8.42 (br d, J=5.75 Hz, 2 H), 8.21 - 8.35 (m, 2 H), 8.19 (s, 1 H), 7.92 (d, J=8.92 Hz, 1 H), 7.43 - 7.51 (m, 1 H), 4.76 - 4.89 (m, 2 H), 3.44 - 3.56 (m, 2 H), 3.31 - 3.42 (m, 2 H), 3.20 - 3.30 (m, 2 H), 1.78 - 1.89 (m, 4 H). MS (M + H) ⁺ =489.0 [00557] 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 μmol, 1 eq),Cs2CO3 (137.77 mg, 422.84 μmol, 3 eq) and Pd(dppf)Cl ₂ (10.31 mg, 14.09 μmol, 0.1 eq), the reaction was stirred at 100 °C for 3 h under N ₂ . 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. The crude product was purified by prep-HPLC (column: Phenomenex Luna 80*30 mm*3 μm; mobile phase: [water (0.04%HCl)-ACN]; B%: 10%-40%,8min).5-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazoli n-6-yl]-N-methyl-pyridine-3- carboxamide, Compound 96, (9.05 mg, 19.24 μmol, 13.65% yield, 100% purity, HCl) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.25 (d, J=2.00 Hz, 1 H), 9.11 - 9.17 (m, 1 H), 9.09 (d, J=1.75 Hz, 1 H), 9.06 (s, 1 H), 8.84 (s, 1 H), 8.78 (d, J=1.25 Hz, 1 H), 8.59 (dd, J=8.69, 1.44 Hz, 1 H), 8.45 (d, J=6.75 Hz, 1 H), 8.18 (d, J=8.75 Hz, 1 H), 7.59 (d, J=8.75 Hz, 1 H), 5.07 (br t, J=7.57 Hz, 2 H), 3.30 (br t, J=7.38 Hz, 2 H), 2.84 (d, J=4.38 Hz, 3 H). MS (M + H) ⁺ = 434.0. 262340-537651 [00559] Example 97: Synthesis of 2-amino-5-[4-(6-chloro-5-fluoro-indolin-1- yl)quinazolin-6-yl]-N-methyl-pyridine-3-carboxamide, Compound 97 [00560] Step 1: Synthesis of 2-amino-5-bromo-N-methyl-pyridine-3-carboxamide (2) [00561] To a s DMF (3 mL) was added methanamine hydrochloride (74.67 mg, 1.11 mmol, 1.2 eq), HATU (525.62 mg, 1.38 mmol, 1.5 eq) and DIEA (357.32 mg, 2.76 mmol, 481.56 μL, 3 eq), the reaction was stirred at 25 °C for 30 min. LCMS showed starting material was consumed completely and the MS of desired product was detected. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. 2-amino-5-bromo-N-methyl-pyridine-3- carboxamide, 1bc, (100 mg, 434.67 μmol, 47.17% yield) was obtained as a yellow solid. [00562] Step 2: Synthesis of 2-amino-5-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin- 6-yl]-N-methyl-pyridine-3-carboxamide (Compound 97) F F O NH Cl [ o a s e so u o o g, . μ o , eq a 2O (0.6 mL) was added 1bc (38.91 mg, 169.14 μmol, 1.2 eq), K ₃ PO ₄ (89.76 mg, 422.84 μmol, 3 eq) and Pd(PPh3)4 (16.29 mg, 14.09 μmol, 0.1 eq), the reaction was stirred at 100 °C for 12 h under N2. 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. The crude product was purified by prep-HPLC (column: Phenomenex Luna 80*30mm*3 μm;mobile phase: [water(0.04%HCl)-ACN];B%: 30%-55%,8min).2-amino-5-[4-(6-chloro-5-fluoro-indolin-1- 262340-537651 yl)quinazolin-6-yl]-N-methyl-pyridine-3-carboxamide, Compound 97, (4.98 mg, 10.13 μmol, 7.19% yield, 98.747% purity, HCl) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO- d ₆ +D2O) δ ppm 8.94 (s, 1 H), 8.51 - 8.64 (m, 3 H), 8.41 (d, J=9.13 Hz, 1 H), 8.35 (d, J=6.75 Hz, 1 H), 7.93 - 8.03 (m, 1 H), 7.54 (d, J=8.76 Hz, 1 H), 4.86 - 4.97 (m, 2 H), 3.22 - 3.35 (m, 2 H), 2.80 (s, 3 H). MS (M + H) ⁺ = 449.0 [00564] Example 98: Synthesis of 2-amino-5-[4-(6-chloro-5-fluoro-indolin-1- yl)quinazolin-6-yl]-N,N-dimethyl-pyridine-3-carboxamide, Compound 98 [00565] To a stirred solution of 1n (55 mg, 129.20 μmol, 1 eq) in DMF (1.5 mL) and H2O (0.3 mL) was added 5-bromo-N-cyclopropyl-pyridine-3-carboxamide (31.15 mg, 129.20 μmol, 1 eq), Cs ₂ CO ₃ (126.29 mg, 387.61 μmol, 3 eq) and Pd(dppf)Cl ₂ (9.45 mg, 12.92 μmol, 0.1 eq), the reaction was stirred at 100 °C for 3 h under N ₂ . 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. The crude product was purified by prep-HPLC (column: Phenomenex Luna 80*30 mm*3 μm; mobile phase [column: Waters Xbridge BEH C18100*30 mm*10 μm;mobile phase: [water( 10 mM NH4HCO3)-ACN];B%:35%-65%,10 min).5-[4-(6- chloro-5-fluoro-indolin-1-yl)quinazolin-6-yl]-N-cyclopropyl- pyridine-3-carboxamide, Compound 98, (5.06 mg, 11.00 μmol, 8.52% yield, 100% purity) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 9.09 - 9.18 (m, 1 H), 8.95 - 9.00 (m, 1 H), 8.69 - 8.79 (m, 2 H), 8.46 - 8.53 (m, 2 H), 8.29 - 8.35 (m, 1 H), 7.98 - 8.06 (m, 1 H), 7.90 - 7.97 (m, 1 H), 7.39 - 7.48 (m, 1 H), 4.72 (t, J=8.19 Hz, 2 H), 3.23 (br t, J=8.00 Hz, 2 H), 2.83 - 2.94 (m, 1 H), 0.71 - 0.78 (m, 2 H), 0.58 - 0.64 (m, 2 H). MS (M + H) ⁺ = 460.2. [00566] Example 99: Synthesis of 2-amino-5-[4-(6-chloro-5-fluoro-indolin-1- yl)quinazolin-6-yl]-N-cyclopropyl-pyridine-3-carboxamide, Compound 99 [00567] Step 1: Synthesis of 2-amino-5-bromo-N-cyclopropyl-pyridine-3- carboxamide (1bd) 262340-537651 [00568] To a stirred solution of 1r (200 mg, 921.57 μmol, 1 eq) in DMF (2 mL) was added cyclopropanamine (63.14 mg, 1.11 mmol, 76.63 μL, 1.2 eq), HATU (525.62 mg, 1.38 mmol, 1.5 eq) and DIEA (357.32 mg, 2.76 mmol, 481.56 μL, 3 eq), the reaction was stirred at 25 °C for 30 min. LCMS showed starting material was consumed completely and the MS of desired product was detected. The reaction was cooled to ambient temperature, quenched with water (30 mL) and extracted with ethyl acetate (30 mL). The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by flash column (ISCO 20 g silica,30-50% ethyl acetate in petroleum ether, gradient over 20 min) based on TLC (PE：EtOAc = 2：1, R _f = 0.40). 2-amino-5-bromo-N-cyclopropyl- pyridine-3-carboxamide, 1bd, (200 mg, 780.95 μmol, 84.74% yield) was obtained as a white solid. [00569] Step 2: Synthesis of 2-amino-5-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin- 6-yl]-N-cyclopropyl-pyridine-3-carboxamide (Compound 99) [00570] To a stirred solution of 1bd (43.32 mg, 169.14 μmol, 1.2 eq) in DMF (1 mL) and H ₂ O (0.2 mL) was added 1n (60 mg, 140.95 μmol, 1 eq), Pd(PPh ₃ ) ₄ (16.29 mg, 14.09 μmol, 0.1 eq) and K3PO4 (89.76 mg, 422.84 μmol, 3 eq), the reaction was stirred at 100 °C for 4 h under N2. 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. The crude 262340-537651 product was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*30mm*10um;mobile phase: [water( NH4HCO3)-ACN];B%: 35%-65%,10min).2-amino-5- [4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6-yl]-N-cyclop ropyl-pyridine-3-carboxamide, Compound 99, (6.24 mg, 13.14 μmol, 9.32% yield, 100% purity) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 8.68 - 8.75 (m, 1 H), 8.50 - 8.61 (m, 2 H), 8.29 - 8.35 (m, 1 H), 8.19 - 8.27 (m, 2 H), 7.95 (d, J=8.76 Hz, 1 H), 7.80 (d, J=6.63 Hz, 1 H), 7.44 (d, J=8.88 Hz, 1 H), 7.21 - 7.34 (m, 2 H), 4.65 (t, J=7.94 Hz, 2 H), 3.15 - 3.26 (m, 2 H), 2.76 - 2.89 (m, 1 H), 0.69 - 0.75 (m, 2 H), 0.45 - 0.62 (m, 2 H). MS (M + H) ⁺ =475.1 [00571] 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 μmol, 3 eq), Pd(dppf)Cl2 (13.02 mg, 17.79 μmol, 0.1 eq) and 5-bromopyridin-3-ol (30.95 mg, 177.89 μmol, 1 eq) the mixture was bubbled with N2,the reaction was stirred at 100°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. The crude product was purified by prep-HPLC (column: Phenomenex luna C1880*40mm*3 μm;mobile phase: [water(0.04%HCl)-ACN];B%: 20%-42%,7min).4-(6- chloro-5-fluoro-indolin-1-yl)-6-(5-hydroxy-3-pyridyl) quinoline-3-carbonitrile, Compound 100, (10.95 mg, 22.29 μmol, 12.53% yield, 92.28% purity, HCl) was obtained as an orange solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 11.75 (br s, 1 H) 9.09 (s, 1 H) 8.76 (s, 1 H) 8.46 (s, 1 H) 8.42 (s, 1 H) 8.33 - 8.36 (m, 1 H) 8.26 - 8.29 (m, 1 H) 8.19 (br s, 1 H) 7.43 (d, J=8.92 Hz, 1 H) 6.95 (d, J=6.11 Hz, 1 H) 4.65 (br d, J=8.44 Hz, 1 H) 4.23 - 4.29 (m, 1 H) 3.31 (br s, 2 H). MS (M + H) ⁺ = 417.0 [00573] Example 101: Synthesis of 4-(6-chloro-5-fluoro-indolin-1-yl)-6-(3- quinolyl)quinoline-3-carbonitrile, Compound 101 262340-537651 (0.4 mL) was added Cs2CO3 (173.88 mg, 533.68 μmol, 3 eq), Pd(dppf)Cl2 (13.02 mg, 17.79 μmol, 0.1 eq) and 3-bromoquinoline (37.01 mg, 177.89 μmol, 23.88 μL, 1 eq) the mixture was bubbled with N ₂ , the reaction was stirred at 100 ^o 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. The crude product was purified by prep-HPLC (column: Phenomenex luna C18100*40mm*3 μm;mobile phase: [water(0.04%TFA)-ACN];B%: 30%-60%,8min) to afford crude product (15 mg). The crude product was purified by prep- HPLC(column: Phenomenex luna C1880*40mm*3 μm;mobile phase: [water(0.04%HCl)- ACN];B%: 52%-82%,7min). 4-(6-chloro-5-fluoro-indolin-1-yl)-6-(3-quinolyl)quinoline-3 - carbonitrile, Compound 101, (9.72 mg, 19.50 μmol, 10.96% yield, 97.78% purity, HCl) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 9.36 (d, J=2.08 Hz, 1 H), 9.08 (s, 1 H), 8.92 (s, 1 H), 8.45 - 8.55 (m, 2 H), 8.30 (d, J=9.17 Hz, 1 H), 8.07 - 8.19 (m, 2 H), 7.90 (t, J=7.34 Hz, 1 H), 7.70 - 7.80 (m, 1 H), 7.45 (d, J=8.92 Hz, 1 H), 6.96 (d, J=6.23 Hz, 1 H), 4.63 (q, J=8.56 Hz, 1 H), 4.34 (q, J=8.84 Hz, 1 H), 3.29 - 3.41 (m, 2 H). MS (M + H) ⁺ = 451.1 [00575] Example 102: Synthesis of 4-(6-chloro-5-fluoro-indolin-1-yl)-6-(3-pyridyl) quinoline-3-carbonitrile, Compound 102 L) q) 262340-537651 and 3-bromopyridine (28.11 mg, 177.89 μmol, 17.14 μL, 1 eq), the mixture was bubbled with N2, the reaction was stirred at 100 °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. The crude product was purified by prep-HPLC (column: Phenomenex luna C1880*40mm*3 μm;mobile phase: [water (0.04%HCl)-ACN];B%: 28%- 52%,7min). 4-(6-chloro-5-fluoro-indolin-1-yl)-6-(3-pyridyl)quinoline-3- carbonitrile, Compound 102, (18.8 mg, 39.78 μmol, 22.36% yield, 92.53% purity, HCl) was obtained as an orange solid. ¹ H NMR (400 MHz, DMSO-d6) δ = 9.29 (d, J = 1.5 Hz, 1H), 9.11 (s, 1H), 8.88 (d, J = 4.5 Hz, 1H), 8.79 (br d, J = 8.1 Hz, 1H), 8.54 (d, J = 1.8 Hz, 1H), 8.42 (dd, J = 2.0, 8.7 Hz, 1H), 8.30 (d, J = 8.8 Hz, 1H), 8.03 (dd, J = 5.5, 7.9 Hz, 1H), 7.43 (d, J = 8.9 Hz, 1H), 6.97 (d, J = 6.1 Hz, 1H), 4.69 (br d, J = 8.7 Hz, 1H), 4.26 (q, J = 8.4 Hz, 1H), 3.32 (br t, J = 8.3 Hz, 2H). MS (M + H) ⁺ = 401.0 [00577] 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 μmol, 3 eq), Pd(dppf)Cl2 (13.02 mg, 17.79 μmol, 0.1 eq) and 4-bromo-2H-pyrazolo[3,4-c]pyridine (35.23 mg, 177.89 μmol, 1 eq), the mixture was bubbled with N2, the reaction was stirred at 100 °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. The crude product was purified by prep-HPLC (column: Phenomenex Luna 80*30mm*3 μm;mobile phase: [water(0.04%HCl)-ACN];B%: 10%-40%,8min). 4-(6-chloro-5-fluoro-indolin-1-yl)-6-(1H-pyrazolo[3,4-c]pyri din-4- yl)quinoline-3-carbonitrile, Compound 103, (2.52 mg, 5.05 μmol, 2.84% yield, 95.60% purity, HCl) was obtained as a orange solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.51 (br s, 1H), 9.14 (s, 262340-537651 1H), 8.59 (s, 1H), 8.47 - 8.39 (m, 3H), 8.37 - 8.31 (m, 1H), 7.42 (d, J = 8.9 Hz, 1H), 6.93 (d, J = 6.2 Hz, 1H), 4.52 - 4.40 (m, 2H), 3.30 (br t, J = 8.1 Hz, 2H). MS (M + H) ⁺ = 441.0 [00579] Example 104: Synthesis of methyl 6-[4-(6-chloro-5-fluoro-indolin-1- yl)quinazolin-6-yl]pyrazine-2-carboxylate, Compound 104 F F O O Cl Cl [ ded methyl 6-chloropyrazine-2-carboxylate (20.27 mg, 117.46 μmol, 1 eq), K3PO4 (74.80 mg, 352.37 μmol, 3 eq) and Pd(PPh3)4 (13.57 mg, 11.75 μmol, 0.1 eq) , the reaction was stirred at 80 °C for 3 h under N ₂ . LCMS showed starting material was consumed completely and the MS of desired product was detected. The reaction was filtered, and filtrate was used for purified directly. The filtrate was purified by prep-HPLC (column: Phenomenex Luna C18150*30mm*5um; mobile phase: [water (TFA)-ACN]; B%: 15%-50%, 8min). Methyl 6-[4-(6-chloro-5-fluoro-indolin-1-yl) quinazolin-6-yl] pyrazine-2-carboxylate, Compound 104, (3.28 mg, 5.88 μmol, 5.01% yield, 98.58% purity, TFA) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 9.69 (s, 1 H), 9.24 (s, 1 H), 9.04 (s, 1 H), 8.89 (s, 1 H), 8.70 - 8.78 (m, 1 H), 8.16 (br d, J=6.38 Hz, 1 H), 8.07 (d, J=8.76 Hz, 1 H), 7.52 (d, J=8.88 Hz, 1 H), 4.84 (br t, J=8.00 Hz, 2 H), 3.99 (s, 3 H), 3.27 - 3.31 (m, 2 H). MS (M + H) ⁺ = 436.1 [00581] Example 105: Synthesis of 6-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6- yl]pyrazine-2-carboxylic acid, Compound 105 F F O OH Cl 262340-537651 [00582] To a stirred solution of 1n (50 mg, 117.46 μmol, 1 eq) in DMF (2 mL) and H2O (0.5 mL) was added 6-chloropyrazine-2-carboxylic acid (18.62 mg, 117.46 μmol, 1 eq), K3PO4 (74.80 mg, 352.37 μmol, 3 eq) and Pd(dppf)Cl ₂ (8.59 mg, 11.75 μmol, 0.1 eq), the reaction was stirred at 80 °C for 3 h under N2. LCMS showed starting material was consumed completely and the MS of desired product was detected. The reaction was filtered, and filtrate was used for purified directly. The filtrate was purified by prep-HPLC (column: Phenomenex Luna C18 150*30mm*5um; mobile phase: [water (TFA)-ACN]; B%: 10%-45%, 8min).6-[4-(6-chloro-5- fluoro-indolin-1-yl)quinazolin-6-yl]pyrazine-2-carboxylic acid, Compound 105, (18.39 mg, 34.32 μmol, 29.22% yield, 100% purity, TFA) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.65 (s, 1 H), 9.20 (s, 1 H), 9.03 (d, J=1.38 Hz, 1 H), 8.88 (s, 1 H), 8.75 (dd, J=8.88, 1.50 Hz, 1 H), 8.18 (d, J=6.75 Hz, 1 H), 8.04 (d, J=8.76 Hz, 1 H), 7.50 (d, J=8.75 Hz, 1 H), 4.79 - 4.90 (m, 2 H), 3.27 (br t, J=7.69 Hz, 2 H). MS (M + H) ⁺ =422.0 [00583] Example 106: Synthesis of 6-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6- yl]-N-methyl-pyrazine-2-carboxamide, Compound 106 [00584] To a stirred solution of Compound 104 (60 mg, 137.67 μmol, 1 eq) in THF (2 mL) was added methanamine;hydrochloride (13.94 mg, 206.50 μmol, 1.5 eq), K2CO3 (38.05 mg, 275.33 μmol, 2 eq), the reaction was stirred at 20 °C for 12 h. LCMS showed starting material was consumed completely and the MS of desired product was detected. The reaction was filtered, and filtrate was purified by prep-HPLC (column: Phenomenex Luna C18 150*30mm*5um; mobile phase: [water (TFA)-ACN]; B%: 20%-50%, 8 min). 6-[4-(6-chloro-5- fluoro-indolin-1-yl)quinazolin-6-yl]-N-methyl-pyrazine-2-car boxamide, Compound 106, (10.84 mg, 19.23 μmol, 13.97% yield, 97.35% purity, TFA) was obtained as a brown solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 9.65 (s, 1 H), 9.17 (s, 1 H), 9.12 (s, 1 H), 9.03 - 9.09 (m, 1 H), 9.00 (dd, J=8.88, 1.38 Hz, 1 H), 8.89 (s, 1 H), 8.22 (d, J=6.63 Hz, 1 H), 8.02 (d, J=8.76 Hz, 1 H), 7.51 262340-537651 (d, J=8.88 Hz, 1 H), 4.90 (br t, J=7.75 Hz, 2 H), 3.27 (br t, J=7.69 Hz, 2 H), 2.91 (d, J=4.88 Hz, 3 H). MS (M + H) ⁺ =435.0 [00585] Example 107: Synthesis of 6-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6- yl]-N-ethyl-pyrazine-2-carboxamide, Compound 107 [00586] Step 1: Synthesis of 6-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6- yl]pyrazine-2-carbonyl chloride (1be) [00587] To a stirred solution of Compound 105 (60 mg, 142.24 μmol, 1 eq) in DCM (2 mL) was added SOCl ₂ (25.38 mg, 213.37 μmol, 15.48 μL, 1.5 eq), the reaction was stirred at 25 °C for 1h. LCMS showed starting material was consumed completely and the MS of desired product was detected. The reaction was concentrated in vacuum. 6-[4-(6-chloro-5-fluoro- indolin-1-yl) quinazolin-6-yl] pyrazine-2-carbonyl chloride, 1be, (60 mg, 136.28 μmol, 95.81% yield) was obtained as a black oil. [00588] Step 2: Synthesis of 6-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6-yl]-N- ethyl-pyrazine-2-carboxamide (Compound 107) [00589] g, . μ , q ) was added ethanamine (18.43 mg, 408.85 μmol, 26.75 μL, 3 eq) and TEA (68.95 mg, 681.42 μmol, 94.85 μL, 5 eq), the reaction was stirred at 25 °C for 1 h. LCMS showed starting material was consumed completely and the MS of desired product was detected. The reaction was filtered, and 262340-537651 filtrate was used for purified directly. The crude product was purified by prep-HPLC (column: Waters Xbridge BEH C18100*30mm*10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 35%-70%, 8min). 6-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6-yl]-N-ethy l-pyrazine-2- carboxamide, Compound 107, (2.54 mg, 5.41 μmol, 3.97% yield, 95.65% purity) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) 1H NMR (400 MHz, DMSO-d6) δ ppm 9.64 (s, 1 H), 9.12 - 9.19 (m, 2 H), 8.76 - 8.83 (m, 2 H), 8.18 (s, 1 H), 8.10 (d, J=6.88 Hz, 1 H), 8.03 (d, J=8.76 Hz, 1 H), 7.47 (d, J=8.76 Hz, 1 H), 4.85 (t, J=8.13 Hz, 2 H), 3.24 (br t, J=7.94 Hz, 2 H), 1.47 (s, 9 H). MS (M + H) ⁺ =477.1 [00590] Example 108: Synthesis of 6-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6- yl]-N-isopropyl-pyrazine-2-carboxamide, Compound 108 ) in THF (2 mL) was added propan-2-amine (12.21 mg, 206.50 μmol, 17.74 μL, 1.5 eq), Al(CH3)3 (2 M, 275.33 μL, 4 eq), the reaction was stirred at 80 °C for 2 h under N ₂ . LCMS showed starting material was consumed completely and the MS of desired product was detected. The reaction mixture was quenched with MeOH (2 mL) and filtered, concentrated. The reaction was filtered, and filtrate was used for purified directly. The filtrate was purified by prep-HPLC (column: Phenomenex Luna C18150*30mm*5um; mobile phase: [water (TFA)-ACN]; B%: 30%-60%, 8min).6-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6-yl]- N-isopropyl-pyrazine-2- carboxamide, Compound 108, (8.95 mg, 14.96 μmol, 10.87% yield, 96.43% purity, TFA) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.65 (s, 1 H), 9.20 (s, 1 H), 9.17 (s, 1 H), 8.99 (br d, J=8.75 Hz, 1 H), 8.91 (br s, 1 H), 8.71 (br d, J=8.25 Hz, 1 H), 8.22 - 8.30 (m, 1 H), 8.04 (d, J=8.76 Hz, 1 H), 7.53 (d, J=8.76 Hz, 1 H), 4.86 - 5.06 (m, 2 H), 4.21 (br dd, J=14.57, 6.94 Hz, 1 H), 3.27 (br t, J=7.63 Hz, 2 H), 1.26 (d, J=6.63 Hz, 6 H). MS (M + H) ⁺ =463.0 262340-537651 [00592] Example 109: Synthesis of N-tert-butyl-6-[4-(6-chloro-5-fluoro-indolin-1-yl) quinazolin-6-yl] pyrazine-2-carboxamide, Compound 109 [00 added 2-methylpropan-2-amine (29.90 mg, 408.85 μmol, 42.96 μL, 3 eq) and TEA (41.37 mg, 408.85 μmol, 56.91 μL, 3 eq), the reaction was stirred at 25 °C for 1 h. LCMS showed starting material was consumed completely and the MS of desired product was detected. The reaction was filtered, and filtrate was used for purified directly. The crude product was purified by prep- HPLC (column: Waters Xbridge BEH C18100*30mm*10um; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; B%: 45%-75%, 8min). N-tert-butyl-6-[4-(6-chloro-5-fluoro-indolin-1-yl) quinazolin-6-yl] pyrazine-2-carboxamide, Compound 109, (5.72 mg, 11.86 μmol, 8.70% yield, 98.90% purity) was obtained as a pale-yellow solid. ¹ H NMR (400 MHz, DMSO-d6) 1H NMR (400 MHz, DMSO-d6) δ ppm 9.64 (s, 1 H), 9.12 - 9.19 (m, 2 H), 8.76 - 8.83 (m, 2 H), 8.18 (s, 1 H), 8.10 (d, J=6.88 Hz, 1 H), 8.03 (d, J=8.76 Hz, 1 H), 7.47 (d, J=8.76 Hz, 1 H), 4.85 (t, J=8.13 Hz, 2 H), 3.24 (br t, J=7.94 Hz, 2 H), 1.47 (s, 9 H). MS (M + H) ⁺ =477.1 [00594] 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 μmol, 1 eq) in THF (2 mL) was added cyclopropanamine (11.79 mg, 206.50 μmol, 14.31 μL, 1.5 eq), Al(CH ₃ ) ₃ (2 M, 275.33 μL, 4 eq), the reaction was stirred at 80 °C for 2 h under N2. LCMS showed starting material was consumed completely and the MS of desired product was detected. The reaction mixture was quenched with MeOH (2mL) and filtered, concentrated. The reaction was filtered, and filtrate was used for purified directly. The filtrate was purified by prep-HPLC (column: Phenomenex C1875*30mm*3 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 45%-65%, 8 min).6-[4-(6- chloro-5-fluoro-indolin-1-yl)quinazolin-6-yl]-N-cyclopropyl- pyrazine-2-carboxamide, Compound 110, (4.33 mg, 9.39 μmol, 6.82% yield, 100% purity) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 9.62 (s, 1 H), 9.14 (s, 1 H) 9.10 (s, 1 H), 8.86 - 9.04 (m, 2 H), 8.77 (s, 1 H), 7.93 - 8.12 (m, 2 H), 7.47 (d, J=8.76 Hz, 1 H), 4.80 (br t, J=8.00 Hz, 2 H), 3.21 - 3.27 (m, 2 H), 2.89 - 2.98 (m, 1 H), 0.65 - 0.81 (m, 4 H). MS (M + H) ⁺ =461.1 [00596] Example 111: Synthesis of methyl 5-[4-(6-chloro-5-fluoro-indolin-1- yl)quinazolin-6-yl]pyridine-3-carboxylate, Compound 111 F F O O Cl [ g, . μ , q . MF (1.5 mL) was added methyl 5-bromopyridine-3-carboxylate (33.49 mg, 155.04 μmol, 1.1 eq), K ₃ PO ₄ (89.76 mg, 422.84 μmol, 3 eq) and Pd(dppf)Cl ₂ (10.31 mg, 14.09 μmol, 0.1 eq), the reaction was stirred at 80°C for 3h under N2. LCMS showed starting material was consumed completely and the MS of desired product was detected. The reaction was filtered, and filtrate was used for purified directly. The filtrate was purified by prep-HPLC (column: Phenomenex Luna C18150*30mm*5um; mobile phase: [water (TFA)-ACN]; B%: 10%-45%, 8min). Methyl 5-[4-(6-chloro-5-fluoro-indolin-1-yl) quinazolin-6-yl] pyridine-3-carboxylate, Compound 111, (4.78 mg, 8.62 μmol, 6.11% yield, 98.959% purity, TFA) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.29 (d, J=2.20 Hz, 1 H), 9.15 (d, J=1.71 Hz, 1 H), 8.91 (s, 1 262340-537651 H), 8.54 - 8.71 (m, 2 H), 8.42 (d, J=8.68 Hz, 1 H), 8.15 (br d, J=6.60 Hz, 1 H), 8.01 (d, J=8.68 Hz, 1 H), 7.52 (d, J=8.92 Hz, 1 H), 4.75 - 4.91 (m, 2 H), 3.94 (s, 3 H), 3.26 (br t, J=7.95 Hz, 2 H). MS (M + H) ⁺ =435.0 [00598] Example 112: Synthesis of 5-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6- yl]-N-cyano-pyridine-3-carboxamide, Compound 112 [00599] To a solution of 1n (50 mg, 117.46 μmol, 1 eq) in DMF (2 mL) and H2O (0.6 mL) was added 5-bromo-N-cyano-pyridine-3-carboxamide (26.55 mg, 117.46 μmol, 1 eq), K ₃ PO ₄ (74.80 mg, 352.37 μmol, 3 eq) and Pd(dppf)Cl2 (8.59 mg, 11.75 μmol, 0.1 eq). The reaction mixture was stirred at 80 °C for 3 h under N2. LCMS showed starting material was consumed completely and the MS of desired product was detected. The reaction was filtered, and filtrate was purified by prep-HPLC (column: Phenomenex Luna C18150*30mm*5um;mobile phase: [water(TFA)-ACN];B%: 20%-50%,8min).5-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazoli n-6-yl]- N-cyano-pyridine-3-carboxamide, Compound 112, (12.65 mg, 28.44 μmol, 24.21% yield, 100% purity) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ +D2O) δ ppm 9.04 (d, J=1.60 Hz, 1 H) , 8.99 (d, J=2.40 Hz, 1 H), 8.73 (s, 1 H), 8.53 (s, 1 H), 8.42 (s, 1 H), 8.28 – 8.25 (m, 1 H), 7.99 (d, J=8.80 Hz, 1 H), 7.92 (d, J=8.75 Hz, 1 H), 7.40 (d, J=8.80 Hz, 1 H), 4.70 (br t, J=8.0 Hz, 2 H,) 3.32 (br t, J=8.0 Hz, 2 H). MS (M + H) ⁺ =445.1. [00600] Example 113: 5-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6-yl]-N- hydroxy-N-methyl-pyridine-3-carboxamide, Compound 113 [00601] Step 1: Synthesis of 5-bromo-N-hydroxy-N-methyl-pyridine-3-carboxamide (1bf) 262340-537651 [00602] To a stirred solution of 5-bromopyridine-3-carboxylic acid (500 mg, 2.48 mmol, 1 eq) in DMF (8 mL) was added N-methylhydroxylamine (206.72 mg, 2.48 mmol, 1 eq, HCl), HATU (1.41 g, 3.71 mmol, 1.5 eq) and DIEA (959.70 mg, 7.43 mmol, 1.29 mL, 3 eq), the reaction was stirred at 25 °C for 30 min. LCMS showed starting material was consumed completely and the MS of desired product was detected. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column (ISCO 12 g silica, 40-60 % ethyl acetate in petroleum ether, gradient over 20 min). Based on TLC (PE : EtOAc = 1 : 1,Rf = 0.30), 5-bromo-N-hydroxy-N-methyl- pyridine-3-carboxamide, 1bf, (200 mg, 865.63 μmol, 34.97% yield) was obtained as a yellow solid. [00603] 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 [ , . , . MF (1.5 mL) was added 5-bromo-N-hydroxy-N-methyl-pyridine-3-carboxamide (39.08 mg, 169.14 μmol, 1.2 eq), Pd(dppf)Cl ₂ (10.31 mg, 14.09 μmol, 0.1 eq) and K ₃ PO ₄ (89.76 mg, 422.84 μmol, 3 eq), the reaction was stirred at 100 °C for 3 h under N ₂ . LCMS showed starting material was consumed completely and the MS of desired product was detected. The reaction was filtered, and filtrate was used for purified directly. The crude product was purified by prep-HPLC (column: Phenomenex Luna C18150*30mm*5um; mobile phase: [water (TFA)-ACN]; B%: 5%-40%, 201 262340-537651 8min). 5-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6-yl]-N-hydr oxy-N-methyl-pyridine-3- carboxamide, Compound 113, (31.67 mg, 69.82 μmol, 49.54% yield, 99.176% purity) was obtained as a yellow gum. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.12 (br s, 1 H), 8.98 (s, 1 H), 8.85 (s, 1 H), 8.62 (d, J=1.13 Hz, 1 H), 8.39 - 8.47 (m, 2 H), 8.32 (d, J=6.75 Hz, 1 H), 8.02 (d, J=8.76 Hz, 1 H), 7.54 (d, J=8.76 Hz, 1 H), 4.92 (br t, J=7.69 Hz, 2 H), 3.33 (s, 3 H), 3.24 - 3.30 (m, 2 H). MS (M + H) ⁺ =450.0 [00605] Example 114: Synthesis of 6-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6- yl]-3H-isobenzofuran-1-one, Compound 114 F F O O Cl MF (1.5 mL) was added 6-bromo-3H-isobenzofuran-1-one (33.03 mg, 155.04 μmol, 1.1 eq), K3PO4 (89.76 mg, 422.84 μmol, 3 eq) and Pd(dppf)Cl ₂ (10.31 mg, 14.09 μmol, 0.1 eq), the reaction was stirred at 80°C for 3 h under N2. LCMS showed starting material was consumed completely and the MS of desired product was detected. The reaction was filtered, and filtrate was used for purified directly. The crude product was purified by prep-HPLC (column: Phenomenex Luna C18150*30mm*5um; mobile phase: [water (TFA)-ACN]; B%: 15%-50%, 8min). Compound 6- [4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6-yl]-3H-isobe nzofuran-1-one, Compound 114, (11.2 mg, 24.82 μmol, 17.61% yield, 95.714% purity) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.91 (s, 1 H), 8.56 (s, 1 H), 8.41 (dd, J=8.62, 1.53 Hz, 1 H), 8.21 - 8.29 (m, 2 H), 8.19 (br d, J=6.60 Hz, 1 H), 7.99 (d, J=8.80 Hz, 1 H), 7.85 (d, J=8.07 Hz, 1 H), 7.52 (d, J=8.68 Hz, 1 H), 5.50 (s, 2 H), 4.86 (br t, J=7.64 Hz, 2 H), 3.25 - 3.29 (m, 2 H). MS (M + H) ⁺ = 432.0 [00607] Example 115: Synthesis of 4-(6-chloro-5-fluoro-indolin-1-yl)-6-[3-(4H-1,2,4- triazol-3-yl)phenyl]quinazoline, Compound 115 202 262340-537651 [00608] To a stirred solution of 1n (60 mg,140.95 μmol, 1 eq) in DMF (2 mL) and H2O (0.4 mL) was added 3-(3-bromophenyl)-4H-1,2,4-triazole (34.74 mg, 155.05 μmol, 1.1 eq) K3PO4 (89.76 mg, 422.85 μmol, 3 eq) and Pd(dppf)Cl2 (10.31 mg, 14.10 μmol, 0.1 eq), then the mixture was bubbled with N2 for 1 minute, 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. The crude product was purified by prep-HPLC(column: Phenomenex Luna 80*30mm*3 μm;mobile phase: [water(0.04%HCl)- ACN];B%: 15%-45%,8min).4-(6-chloro-5-fluoro-indolin-1-yl)-6-[3-(4H-1, 2,4-triazol-3- yl)phenyl]quinazoline, Compound 115, (20.52 mg, 42.81 μmol, 30.37%yield, 100% purity, HCl) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ = 9.04 (s, 1H), 8.63 (d, J = 1.4 Hz, 1H), 8.48 (dd, J = 1.6, 8.8 Hz, 2H), 8.43 (s, 1H), 8.39 (br d, J = 6.8 Hz, 1H), 8.12 (d, J = 7.8 Hz, 1H), 8.07 (d, J = 8.6 Hz, 1H), 7.92 (br d, J = 8.0 Hz, 1H), 7.69 (t, J = 7.8 Hz, 1H), 7.58 (d, J = 8.8 Hz, 1H), 4.97 (br t, J = 7.6 Hz, 2H), 3.30 - 3.28 (m, 2H). MS (M + H) ⁺ =443.0 [00609] 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 μmol, 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 μmol, 1 eq), K ₃ PO ₄ (89.76 mg, 422.84 μmol, 3 eq) and Pd(dppf)Cl ₂ (10.31 mg, 14.09 μmol, 0.1 eq), the reaction was stirred at 80 °C for 3 h under N2. LCMS showed starting material was consumed 203 262340-537651 completely and the MS of desired product was detected. The reaction was filtered, and filtrate was used for purified directly. The filtrate was purified by prep-HPLC (column: Phenomenex Luna C18150*30mm*5um; mobile phase: [water (TFA)-ACN]; B%: 10%-45%, 8min).4-(6- chloro-5-fluoro-indolin-1-yl)-6-[5-(4H-1, 2, 4-triazol-3-yl)-3-pyridyl] quinazoline, Compound 116, (9.05 mg, 15.93 μmol, 11.30% yield, 98.21% purity, TFA) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.27 (d, J=1.75 Hz, 1 H), 9.11 (d, J=2.13 Hz, 1 H), 8.99 (s, 1 H), 8.70 (t, J=2.06 Hz, 1 H), 8.66 (br d, J=1.50 Hz, 2 H), 8.48 (dd, J=8.76, 1.63 Hz, 1 H), 8.31 (d, J=6.75 Hz, 1 H), 8.03 (d, J=8.76 Hz, 1 H), 7.54 (d, J=8.75 Hz, 1 H), 4.93 (br t, J=7.75 Hz, 2 H), 3.28 (br t, J=7.57 Hz, 2 H). MS (M + H) ⁺ =444.0 [00611] Example 117: Synthesis of [5-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6- yl]-2-pyridyl]methanol, Compound 117 F F OH Cl [00612] To a stirred solution of 1n (60 mg,140.95 μmol, 1 eq) in DMF (2 mL) and H2O (0.4 mL) was added (5-bromo-2-pyridyl)methanol (29.15 mg, 155.05 μmol, 1.1eq) K3PO4 (89.76 mg, 422.85 μmol, 3 eq) and Pd(dppf)Cl ₂ (10.31 mg, 14.10 μmol, 0.1 eq), then the mixture was bubbled with N ₂ for 1 minute, 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. The crude product was purified by prep- HPLC(column: Phenomenex Luna C1875*30mm*3 μm;mobile phase:[water(0.04%HCl)- ACN];B%: 5%-35%,8min) [5-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6-yl]-2- pyridyl]methanol, Compound 117, (6.7 mg, 15.11 μmol, 10.72% yield, 100%purity, HCl) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ = 9.08 (d, J = 2.0 Hz, 1H), 9.04 (s, 1H), 8.68 (d, J = 1.6 Hz, 1H), 8.55 (dd, J = 1.9, 8.3 Hz, 1H), 8.50 (dd, J = 1.8, 8.8 Hz, 1H), 8.42 (d, J = 6.6 Hz, 1H), 8.13 (d, J = 8.8 Hz, 1H), 7.83 (d, J = 8.1 Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H), 4.98 (br t, J = 7.7 Hz, 2H), 4.77 (s, 2H), 3.30 (br s, 2H). MS (M + H) + =407.0 204 262340-537651 [00613] Example 118: Synthesis of 2-[5-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin- 6-yl]-2-pyridyl]propan-2-ol, Compound 118 F F OH Cl Cl [00614] To a stirred solution of 1n, (60 mg,140.95 μmol, 1 eq) in DMF (2 mL) and H2O (0.4 mL) was added 2-(5-bromo-2-pyridyl)propan-2-ol (33.50 mg, 155.05 μmol,1.1 eq) K ₃ PO ₄ (89.76 mg, 422.85 μmol, 3 eq) and Pd(dppf)Cl ₂ (10.31 mg, 14.10 μmol, 0.1 eq), then the mixture was bubbled with N2 for 1 minute, 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. The crude product was purified by prep- HPLC(column: Phenomenex Luna 80*30mm*3 μm;mobile phase: [water(0.04%HCl)- ACN];B%: 10%-40%,8min). 2-[5-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6-yl]-2- pyridyl]propan-2-ol, Compound 118, (24.69 mg, 52.38 μmol, 37.16%yield, 100% purity, HCl) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ = 9.00 - 8.94 (m, 2H), 8.59 (s, 1H), 8.41 (dd, J = 1.6, 8.7 Hz, 1H), 8.30 (br d, J = 7.5 Hz, 2H), 8.00 (d, J = 8.8 Hz, 1H), 7.86 (d, J = 8.3 Hz, 1H), 7.54 (d, J = 8.8 Hz, 1H), 4.91 (br t, J = 7.8 Hz, 2H), 3.27 (br t, J = 7.6 Hz, 2H), 1.50 (s, 6H). MS (M + H) ⁺ =435.0 [00615] 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 μmol, 3 eq) and Pd(dppf)Cl2 (10.31 mg, 14.10 μmol, 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. The crude product was purified by prep- HPLC(column: Phenomenex luna C1880*40mm*3 μm;mobile phase:[water(0.04%HCl)- ACN];B%: 5%-40%,7min) [5-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6-yl]-3- pyridyl]methanol, Compound 119, (23.24 mg, 52.42 μmol, 37.19% yield,100% purity, HCl) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ = 9.15 (d, J = 1.8 Hz, 1H), 9.03 (s, 1H), 8.75 (s, 1H), 8.71 (d, J = 1.3 Hz, 1H), 8.56 (br s, 1H), 8.50 (dd, J = 1.5, 8.8 Hz, 1H), 8.41 (d, J = 6.8 Hz, 1H), 8.13 (d, J = 8.8 Hz, 1H), 7.58 (d, J = 8.8 Hz, 1H), 4.98 (br t, J = 7.6 Hz, 2H), 4.74 (s, 2H), 3.30 (br s, 2H). MS (M + H) ⁺ =407.0 [00617] 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, . μ , . H ₂ O (0.3 mL) was added Pd(dppf)Cl ₂ (10.31 mg, 14.09 μmol, 0.1 eq), K ₃ PO ₄ (2 M, 211.42 μL, 3 eq) and 5-bromo-2-methoxy-pyridine-3-carbonitrile (33.03 mg, 155.04 μmol, 1.1 eq), the mixture was purged with N2 for 3 times, 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, and filtrate was used for purified directly. The crude product was purified by prep-HPLC (column: Phenomenex Luna C18150*30mm*5um; mobile phase: [water (TFA)-ACN]; B%: 10%- 50%,8min).5-[4-(6-chloro-5-fluoro-indolin-1-yl) quinazolin-6-yl]-2-methoxy-pyridine-3- carbonitrile, Compound 120, (89.694% purity) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 8.96 (d, J=2.40 Hz, 1 H), 8.76 - 8.87 (m, 2 H), 8.46 - 8.54 (m, 1 H), 8.33 (br d, J=8.58 Hz, 1 H), 8.09 - 8.20 (m, 1 H), 7.94 - 8.01 (m, 1 H), 7.49 (br d, J=9.49 Hz, 1 H), 4.75 - 4.86 (m, 2 H), 4.08 (s, 3 H), 3.27 (br d, J=7.79 Hz, 2 H). MS (M + H) ⁺ =432.0 206 262340-537651 [00619] Example 121: Synthesis of 2-[5-[4-(6-chloroindolin-1-yl)quinazolin-6-yl]-3- pyridyl]propan-2-ol, Compound 121 ) and H ₂ O (0.3 mL) was added 2-(5-bromo-3-pyridyl)propan-2-ol (31.80 mg, 147.17 μmol, 1 eq) K ₃ PO ₄ (93.72 mg, 441.50 μmol, 3 eq) and Pd(dppf)Cl2 (10.77 mg, 14.72 μmol, 0.1 eq), the reaction was stirred at 80 °C for 3 h under N2. LCMS showed starting material was consumed completely and the MS of desired product was detected. The reaction was filtered, and the filtrate was purified by prep-HPLC (column: Phenomenex Luna 80*30mm*3 μm; mobile phase: [water (0.04%HCl)- ACN]; B%: 1%-30%, 8min). 2-[5-[4-(6-chloroindolin-1-yl)quinazolin-6-yl]-3-pyridyl]pro pan-2- ol, Compound 121, (36.76 mg, 79.49 μmol, 54.02% yield, 98.041% purity, HCl) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.19 (d, J=1.22 Hz, 1 H), 9.05 (s, 1 H), 8.89 (d, J=1.71 Hz, 1 H), 8.68 - 8.77 (m, 2 H), 8.53 (dd, J=8.74, 1.41 Hz, 1 H), 8.24 (s, 1 H), 8.15 (d, J=8.68 Hz, 1 H), 7.48 (d, J=8.07 Hz, 1 H), 7.31 (dd, J=8.07, 1.83 Hz, 1 H), 4.90 - 5.01 (m, 2 H), 3.26 (br t, J=7.40 Hz, 2 H), 1.58 (s, 6 H). MS (M + H) ⁺ = 417.0 [00621] Example 122: Synthesis of 6-[4-(6-chloroindolin-1-yl)quinazolin-6-yl]-1,3- dihydroimidazo[4,5-b]pyridin-2-one, Compound 122 [006 22] To a stirred solution of 1m (60 mg, 147.17 μmol, 1 eq) in DMF (1.5 mL) and H2O (0.3 mL) was added 6-bromo-1,3-dihydroimidazo[4,5-b]pyridin-2-one (31.50 mg, 147.17 μmol, 1 eq) K ₃ PO ₄ (93.72 mg, 441.51 μmol, 3 eq) and Pd(dppf)Cl ₂ (10.77 mg, 14.72 μmol, 0.1 eq), the reaction was stirred at 80 °C for 3 h under N2. LCMS showed starting material was consumed 207 262340-537651 completely and the MS of desired product was detected. The reaction was filtered, and filtrate was used for purified directly. The filtrate was purified by prep-HPLC (column: Phenomenex luna C1880*40mm*3 μm;mobile phase: [water(0.04%HCl)-ACN];B%: 5%-45%,7min).6-[4- (6-chloroindolin-1-yl)quinazolin-6-yl]-1,3-dihydroimidazo[4, 5-b]pyridin-2-one, Compound 121, (19.95 mg, 44.20 μmol, 30.04% yield, 100% purity, HCl) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.52 - 11.60 (m, 1 H), 11.14 (s, 1 H), 9.04 (s, 1 H), 8.52 - 8.58 (m, 1 H), 8.42 (d, J=8.92 Hz, 1 H), 8.34 (d, J=1.71 Hz, 1 H), 8.22 (br s, 1 H), 8.03 (d, J=8.68 Hz, 1 H), 7.64 (s, 1 H), 7.48 (d, J=8.07 Hz, 1 H), 7.28 - 7.34 (m, 1 H), 4.95 (br t, J=7.70 Hz, 2 H), 3.26 (br t, J=7.46 Hz, 2 H). MS (M + H) ⁺ =415.0 [00623] 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 μmol, 1 eq) K ₃ PO ₄ (93.72 mg, 441.51 μmol, 3 eq) and Pd(dppf)Cl ₂ (10.77 mg, 14.72 μmol, 0.1 eq), the reaction was stirred at 80 °C for 3 h under N ₂ . LCMS showed starting material was consumed completely and the MS of desired product was detected. The reaction was filtered, and the filtrate was purified by prep-HPLC (column: C18-1150*30mm*5um; mobile phase: [water (TFA)-ACN]; B%: 5%-50%, 8min).6-[4-(6-chloroindolin-1-yl)quinazolin-6-yl]-3H- oxazolo[4,5-b]pyridin-2-one, Compound 123, (22.18 mg, 41.86 μmol, 28.44% yield, 100% purity, TFA) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 8.92 (s, 1 H), 8.53 (d, J=1.83 Hz, 1 H), 8.49 (d, J=1.34 Hz, 1 H), 8.36 (dd, J=8.74, 1.53 Hz, 1 H), 8.18 (d, J=1.83 Hz, 1 H), 7.94 - 8.04 (m, 2 H), 7.43 (d, J=7.95 Hz, 1 H), 7.21 (dd, J=8.01, 1.90 Hz, 1 H), 4.83 (br t, J=7.76 Hz, 2 H), 3.24 (br t, J=7.70 Hz, 2 H). MS (M + H) ⁺ =416.0 [00625] Example 124: Synthesis of 5-[4-(6-chloroindolin-1-yl)quinazolin-6-yl]-1,3- dihydropyrrolo[2,3-b]pyridin-2-one, Compound 124 208 262340-537651 [00 nd H ₂ O (0.3 mL) was added 5-bromo-1,3-dihydropyrrolo[2,3-b]pyridin-2-one (31.35 mg, 147.17 μmol, 1 eq) K3PO4 (93.72 mg, 441.51 μmol, 3 eq) and Pd(dppf)Cl2 (10.77 mg, 14.72 μmol, 0.1 eq), the reaction was stirred at 80 °C for 3 h under N ₂ . LCMS showed starting material was consumed completely and the MS of desired product was detected. The reaction was filtered, and filtrate was purified by prep-HPLC (column: C18-1150*30mm*5um; mobile phase: [water (TFA)- ACN]; B%: 5%-50%, 8min).5-[4-(6-chloroindolin-1-yl)quinazolin-6-yl]-1,3- dihydropyrrolo[2,3-b]pyridin-2-one, Compound124, (1.2 mg, 2.27 μmol, 1.54% yield, 100% purity, TFA) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 11.18 (s, 1 H), 8.88 (s, 1 H), 8.51 (d, J=2.13 Hz, 1 H), 8.41 (s, 1 H), 8.29 (dd, J=8.76, 1.63 Hz, 1 H), 8.03 (s, 1 H), 7.96 (d, J=8.76 Hz, 1 H), 7.92 (br s, 1 H), 7.41 (d, J=8.00 Hz, 1 H), 7.17 (dd, J=7.82, 1.69 Hz, 1 H), 4.77 (br t, J=7.75 Hz, 2 H), 3.65 (s, 2 H), 3.23 (br s, 2 H). MS (M + H) ⁺ =414.0 [00627] Example 125: Synthesis of 4-(6-chloro-5-fluoro-indolin-1-yl)-6-(1H-pyrazolo [4,3-b]pyridin-6-yl) quinazoline, Compound 125 [00628] To a solution of 1n (65 mg, 152.6 μmol, 1 eq) in DMF (1.5 mL) and H2O (0.3 mL) was added K ₃ PO ₄ (97.23 mg, 458.08 μmol, 3 eq), Pd(PPh ₃ ) ₄ (17.64 mg, 15.27 μmol, 0.1 eq) and 6-bromo-1H-pyrazolo[4,3-b]pyridine (45.35 mg, 229.04 μmol, 1.5 eq), the reaction was stirred at 100 °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 209 262340-537651 vacuum. The crude product was purified by prep-HPLC (column: Phenomenex C1875*30mm*3 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 25%-55%, 8min). 4-(6-chloro-5-fluoro- indolin-1-yl)-6-(1H-pyrazolo [4,3-b]pyridin-6-yl) quinazoline, Compound 125, (4.02 mg, 9.64 μmol, 6.32% yield, 100% purity) was obtained as a off-white solid. ¹ H NMR (400 MHz, DMSO- d6) δ = 13.51 (br s, 1H), 8.95 (d, J = 1.9 Hz, 1H), 8.77 (s, 1H), 8.51 (d, J = 1.8 Hz, 1H), 8.40 - 8.30 (m, 3H), 8.01 (d, J = 8.8 Hz, 1H), 7.96 (d, J = 6.8 Hz, 1H), 7.44 (d, J = 8.9 Hz, 1H), 4.75 (t, J = 8.1 Hz, 2H), 3.24 (br t, J = 7.9 Hz, 2H). MS (M + H) ⁺ = 417.1 [00629] 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, . μ , q ₂ O (0.5 mL) was added 1d (12.43 mg, 89.51 μmol, 1 eq), K ₃ PO ₄ (57.00 mg, 268.53 μmol, 3 eq) and Pd(PPh3)4 (10.34 mg, 8.95 μmol, 0.1 eq), the reaction was stirred at 80 °C for 3 h under N2. LCMS showed starting material was consumed completely and the MS of desired product was detected. The reaction was filtered, and the filtrate was purified by prep-HPLC (column: Phenomenex Luna C18150*30mm*5um; mobile phase: [water (TFA)-ACN]; B%: 15%-50%, 8min).5-[4-(6-chloro-5-fluoro-indolin-1-yl)pyrido[3,2-d]pyri midin-6-yl]pyrimidin-2-amine, Compound 126, (1.13 mg, 2.14 μmol, 2.39% yield, 96.25% purity, TFA) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 9.07 (s, 2 H), 8.79 (s, 1 H), 8.68 (d, J=7.00 Hz, 1 H), 8.44 (d, J=8.88 Hz, 1 H), 8.23 (d, J=8.88 Hz, 1 H), 7.48 (d, J=8.88 Hz, 1 H), 7.15 - 7.27 (m, 2 H), 5.12 (t, J=8.19 Hz, 2 H), 3.32 (br s, 2 H). MS (M + H) ⁺ =394.0 [00631] 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 μmol, 1 eq), K3PO4 (57.00 mg, 268.53 μmol, 3 eq) and Pd(PPh ₃ ) ₄ (10.34 mg, 8.95 μmol, 0.1 eq), the reaction was stirred at 80 °C for 3 h under N ₂ . LCMS showed starting material was consumed completely and the MS of desired product was detected. The reaction was filtered, and the filtrate was purified by prep-HPLC (column: Phenomenex Luna C18150*30mm*5um; mobile phase: [water (TFA)- ACN]; B%: 15%-50%, 8min).5-(4-(6-chloro-5-fluoroindolin-1-yl)pyrido[3,2-d]pyrim idin-6- yl)pyridin-2-amine, Compound 127, (8.08 mg, 12.14 μmol, 10.39% yield, 96.14% purity, HCl) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 8.93 (s, 1 H), 8.85 (d, J=1.13 Hz, 1 H), 8.75 (d, J=7. H), 8.70 (br d, J=9.38 Hz, 1 H), 8.55 (d, J=9.00 Hz, 1 H), 8.39 (d, J=8.88 Hz, 1 H), 7.54 (d, J=8.75 Hz, 1 H), 7.21 (d, J=9.38 Hz, 1 H), 5.15 (br t, J=8.00 Hz, 2 H), 3.35 (br t, J=7.94 Hz, 2 H). MS (M + H) ⁺ =393.0 [00633] Example 128: Synthesis of 5-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6- yl]-3,3-dihydroxy-1H-pyrrolo[2,3-b]pyridin-2-one, Compound 155 262340-537651 To a stirred solution of 1n (49.88 mg, 117.18 umol, 1 eq) and 5-bromo-1H-pyrrolo[2,3- b]pyridine-2,3-dione (26.60 mg, 117.18 umol, 1 eq) in DMF (2 mL) and H2O (0.4 mL) was added Pd(dppf)Cl ₂ (8.57 mg, 11.72 umol, 0.1 eq) and K ₃ PO ₄ (74.62 mg, 351.54 umol, 3 eq). Then the 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). Compound 155, 5-[4-(6-chloro-5-fluoro-indolin-1- yl)quinazolin-6-yl]-3,3-dihydroxy-1H-pyrrolo[2,3-b]pyridin-2 -one (3.2 mg, 6.72 umol, 5.73% yield, 97.36% purity) was obtained as yellow solid. MS (M+H) ⁺ = 464.1. ¹ H NMR (400 MHz, DMSO-d6) δ = 9.00 (s, 1H), 8.85 (d, J = 2.4 Hz, 1H), 8.52 (s, 1H), 8.39 - 8.30 (m, 2H), 8.28 (d, J = 2.4 Hz, 1H), 8.07 (br d, J = 8.8 Hz, 2H), 7.57 (d, J = 8.8 Hz, 1H), 4.93 (br t, J = 7.4 Hz, 2H), 3.29 (br t, J = 7.4 Hz, 2H). Example 129: Synthesis of 5-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6-yl]spiro[1 H- pyrrolo[2,3-b]pyridine-3,1'-cyclopropane]-2-one, Compound 156 To a so , . , , , - cyclopropane]-2-one (28.08 mg, 117.46 umol, 1 eq) in DMF (2 mL) and H2O (0.4 mL) was added Pd(dppf)Cl2 (8.59 mg, 11.75 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. Upon cooling to 25 °C, the reaction mixture was filtered. The filtrate was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18150 * 40 mm * 10 um; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; B%: 35%-65%, 8 min). Compound 156, 5-[4-(6- chloro-5-fluoro-indolin-1-yl)quinazolin-6-yl]spiro[1H-pyrrol o[2,3-b]pyridine-3,1'- 212 262340-537651 cyclopropane]-2-one (5.63 mg, 11.86 umol, 10.10% yield, 96.48% purity) was obtained as a pale yellow solid. MS (M+H) ⁺ = 458.1. ¹ H NMR (400 MHz, DMSO-d6) δ = 11.32 (br s, 1H), 8.73 (s, 1H), 8.49 (d, J = 2.4 Hz, 1H), 8.33 (d, J = 1.8 Hz, 1H), 8.22 (dd, J = 1.8, 8.8 Hz, 1H), 7.95 (d, J = 8.8 Hz, 1H), 7.87 (d, J = 6.8 Hz, 1H), 7.81 (d, J = 2.0 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 4.67 (t, J = 8.2 Hz, 2H), 3.22 (br t, J = 8.0 Hz, 2H), 1.78 (t, J = 3.8 Hz, 2H), 1.59 (t, J = 3.8 Hz, 2H). Example 130: Synthesis of 5-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6-yl]-2-meth oxy- pyridin-3-ol , Compound 157 ethoxy-pyridin-3-ol (23.96 mg, 117.46 umol, 1 eq) in DMF (2 mL) and H ₂ O (0.4 mL) was added Pd(dppf)Cl ₂ (8.59 mg, 11.75 umol, 0.1 eq) and K3PO4 (74.80 mg, 352.38 umol, 3 eq). Then the reaction mixture was degassed with N21 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 to remove excess Pd(dppf)Cl2, and then filtered. The filtrate was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18150 * 40 mm * 10 um; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; B%: 20%-60%, 8 min).5-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6-yl]-2 -methoxy-pyridin-3-ol, Compound 157, (15.85 mg, 37.48 umol, 31.91% yield, 100% purity) was obtained as yellow solid. MS (M + H) ⁺ = 423.1. ¹ H NMR (400 MHz, DMSO-d6) δ = 9.73 (s, 1H), 8.73 (s, 1H), 8.28 (s, 1H), 8.15 (dd, J = 1.6, 8.8 Hz, 1H), 8.05 (d, J = 2.0 Hz, 1H), 7.94 (d, J = 8.8 Hz, 1H), 7.87 (d, J = 6.6 Hz, 1H), 7.48 - 7.37 (m, 2H), 4.67 (t, J = 8.0 Hz, 2H), 3.93 (s, 3H), 3.22 (br t, J = 8.0 Hz, 2H). Example 131: Synthesis of 5-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6-yl]-2-meth yl- pyridin-3-ol, Compound 158 213 262340-537651 To a stirred solution of 1n (50 mg, 117.46 umol, 1 eq) and 5-bromo-2-methyl-pyridin-3-ol (22.09 mg, 117.46 umol, 1 eq) in DMF (2 mL) and H2O (0.4 mL) was added Pd(dppf)Cl2 (8.59 mg, 11.75 umol, 0.1 eq) and K ₃ PO ₄ (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. 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). 5-[4-(6-chloro-5-fluoro- indolin-1-yl)quinazolin-6-yl]-2-methyl-pyridin-3-ol, Compound 158, (12.03 mg, 27.14 umol, 23.10% yield, 100% purity, HCl) was obtained as a yellow solid. MS (M+H) ⁺ = 407.1. ¹ H NMR (400 MHz, DMSO-d6) δ = 11.79 (br s, 1H), 8.98 (s, 1H), 8.69 (d, J = 1.2 Hz, 1H), 8.61 (d, J = 1.2 Hz, 1H), 8.39 (dd, J = 1.4, 8.8 Hz, 1H), 8.33 (d, J = 6.6 Hz, 1H), 8.22 (br s, 1H), 8.11 (d, J = 8.6 Hz, 1H), 7.55 (d, J = 8.8 Hz, 1H), 4.92 (br t, J = 7.6 Hz, 2H), 3.29 (br t, J = 7.6 Hz, 2H), 2.60 (s, 3H). 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. Upon cooling to 25 °C, the reaction mixture was added thiourea (resin) to remove excess Pd(dppf)Cl2, and then filtered. The filtrate was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18150 * 40 mm * 10 um; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; B%: 15%-55%, 8 min).2- chloro-5-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6-yl] pyridin-3-ol, Compound 159, (13.03 mg, 30.50 umol, 25.96% yield, 100% purity) was obtained as a yellow solid. MS (M + H) ⁺ = 427.1. ¹ H NMR (400 MHz, DMSO-d6) δ = 8.75 (s, 1H), 8.37 (d, J = 1.2 Hz, 2H), 8.17 (dd, J = 1.4, 8.6 Hz, 1H), 8.03 - 7.90 (m, 2H), 7.65 (d, J = 1.8 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 4.70 (br t, J = 8.0 Hz, 2H), 3.23 (br t, J = 7.8 Hz, 2H). Example 133: Synthesis of [5-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6-yl]-2-met hyl- 3-pyridyl]methanol, Compound 163 F HO F HO Cl To a sti ridyl)methanol (23.73 mg, 117.46 umol, 1 eq) in DMF (2 mL) and H2O (0.4 mL) was added Pd(dppf)Cl2 (8.59 mg, 11.75 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. Upon cooling to 25 °C, the reaction mixture was added thiourea (resin) to remove excess Pd(dppf)Cl2 and then filtered. The filtrate was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18150 * 40 mm * 10 um; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; B%: 20%-60%, 8 min). [5-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6-yl]-2-met hyl-3-pyridyl]methanol, Compound 163, (10.41 mg, 24.73 umol, 21.06% yield, 100% purity) was obtained as a yellow solid. MS (M + H) ⁺ = 421.2. ¹ H NMR (400 MHz, DMSO-d6) δ = 8.79 - 8.71 (m, 2H), 8.37 (d, J = 1.4 Hz, 1H), 8.23 (dd, J = 1.6, 8.7 Hz, 1H), 8.07 (d, J = 1.8 Hz, 1H), 7.99 (d, J = 8.6 Hz, 1H), 215 262340-537651 7.87 (d, J = 6.6 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 5.34 (t, J = 5.4 Hz, 1H), 4.67 (br t, J = 8.0 Hz, 2H), 4.61 (d, J = 5.2 Hz, 2H), 3.22 (br t, J = 8.0 Hz, 2H), 2.49 (br s, 3H). Example 134: Synthesis of [2-chloro-5-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6- yl]-3- pyridyl]methanol, Compound 164 To a so , , .1 3 mg, 117.46 umol, 1 eq) in DMF (2 mL) and H ₂ O (0.4 mL) was added Pd(dppf)Cl ₂ (8.59 mg, 11 .75 umol, 0.1 eq) and K ₃ PO ₄ (74.80 mg, 352.38 umol, 3 eq). Then the reaction mixture was degas sed with N21 min three times. The resulting mixture was stirred at 100 °C for 3 h. LC-MS showe d starting material was consumed completely and major peak with desired mass was detected. Up on cooling to 25 °C, the reaction mixture was added thiourea (resin) to remove excess Pd(dppf)C l2 and then filtered. The filtrate was purified by prep-HPLC (column: Phenomenex Luna 80 * 30 mm * 3 um;mobile phase: [water (HCl)-ACN]; B%: 15%-45%, 8 min). [2-chloro-5-[4-(6-chloro -5-fluoro-indolin-1-yl)quinazolin-6-yl]-3-pyridyl]methanol, Compound 164, (7.24 mg, 15.15 um ol, 12.90% yield, 100% purity, HCl) was obtained as a yellow solid.MS (M + H) ⁺ = 441.1. ¹ H N MR (400 MHz, DMSO-d6) δ = 9.00 (s, 1H), 8.79 (d, J = 2.4 Hz, 1H), 8.61 (d, J = 1.4 Hz, 1H), 8. 41 (dd, J = 1.6, 8.8 Hz, 1H), 8.37 - 8.29 (m, 2H), 8.08 (d, J = 8.8 Hz, 1H), 7.56 (d, J = 8.8 Hz, 1H ), 4.92 (br t, J = 7.6 Hz, 2H), 4.64 (s, 2H), 3.28 (br t, J = 7.6 Hz, 2H) Example 135: Synthesis of [5-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6-yl]-2-met hoxy- 3-pyridyl]methanol, Compound 165 216 262340-537651 To a solution of 1n (50 mg, 117.46 umol, 1 eq) and (5-bromo-2-methoxy-3-pyridyl)methanol (25.61 mg, 117.46 umol, 1 eq) in DMF (2 mL) and H2O (0.4 mL) was added Pd(dppf)Cl2 (8.59 mg, 11.75 umol, 0.1 eq) and K ₃ PO ₄ (74.80 mg, 352.38 umol, 3 eq). Then the reaction mixture was degassed with N21 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: Waters Xbridge Prep OBD C18150 * 40 mm * 10 um; mobile phase: [water (NH4HCO3)-ACN]; B%: 40%-70%, 8 min). [5-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6-yl]-2-met hoxy-3-pyridyl]methanol, Compound 165, (5.41 mg, 12.19 umol, 10.38% yield, 98.42% purity) was obtained as a pale yellow solid. MS (M+H) ⁺ = 437.1. ¹ H NMR (400 MHz, DMSO-d6) δ = 8.74 (s, 1H), 8.49 (d, J = 2.4 Hz, 1H), 8.33 (d, J = 1.4 Hz, 1H), 8.19 (dd, J = 1.6, 8.6 Hz, 1H), 8.10 (d, J = 2.0 Hz, 1H), 7.97 (d, J = 8.6 Hz, 1H), 7.87 (d, J = 6.6 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 5.28 (t, J = 5.6 Hz, 1H), 4.68 (br t, J = 8.0 Hz, 2H), 4.54 (d, J = 5.6 Hz, 2H), 3.94 (s, 3H), 3.23 (br t, J = 7.8 Hz, 2H). Example 137: Synthesis of 4-(6-chloroindolin-1-yl)-6-[6-(4H-1,2,4-triazol-3-yl)-3- pyridyl]quinazoline, Compound 171 217 262340-537651 Step 1: Synth esis of (NE)-5-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6-yl]-N - (dimethylaminomethylene)pyridine-2-carboxamide A solution of Compound 91 (30 mg, 71.46 μmol, 1 eq) and DMF-DMA (12.77 mg, 107.18 μmol, 14.24 μL, 1.5 eq) in toluene (2 mL) was degassed with N ₂ 1 min three times and then stirred at 120 °C for 3 h. LC-MS showed starting material was consumed completely and one new peak was detected. Upon cooling to 15 °C, the reaction mixture was concentrated under reduced pressure to give a residue. (NE)-5-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6-yl]- N-(dimethylaminomethylene)pyridine-2-carboxamide (30 mg, 63.17 μmol, 88.40% yield) was obtained as a black solid, which directly used for next step. Step 2: Synthesis of 4-(6-chloroindolin-1-yl)-6-[6-(4H-1,2,4-triazol-3-yl)-3- pyridyl]quinazoline(Compound 171) To a solution of (NE)-5-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6-yl]-N - (dimethylaminomethylene)pyridine-2-carboxamide (30 mg, 63.17 μmol, 1 eq) in AcOH (1 mL) was added hydrazine;hydrate (8 mg, 159.81 μmol, 2.53 eq) dropwise. The resulting mixture was stirred at 15 °C for 12 h. LC-MS showed starting material was consumed completely and major peak with desired mass was detected. The reaction mixture was filtered and then concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18100 * 30 mm * 3 um; mobile phase: [H ₂ O (0.04% HCl)-ACN]; gradient: 15%-45% B over 8.0 min). 4-(6-chloro-5-fluoro-indolin-1-yl)-6-[6-(4H-1,2,4-triazol-3- yl)-3- pyridyl]quinazoline, Compound 171, (3 mg, 5.90 μmol, 9.34% yield, 94.45% purity, HCl) was obtained as a yellow solid.MS (M+H) ⁺ = 444.0. ¹ H NMR (400 MHz, DMSO-d6) δ = 9.18 (br s, 218 262340-537651 1H), 9.07 (s, 1H), 8.74 (s, 1H), 8.57 (br d, J = 8.4 Hz, 1H), 8.52 - 8.38 (m, 3H), 8.26 (br d, J = 8.0 Hz, 1H), 8.17 (br d, J = 8.6 Hz, 1H), 7.60 (d, J = 8.8 Hz, 1H), 5.03 (br t, J = 7.4 Hz, 2H), 3.31 (br t, J = 7.4 Hz, 2H). Example 138: 4-(6-chloro-5-fluoro-indolin-1-yl)-6-[6-(4H-1,2,4-triazol-3- yl)-3- pyridyl]quinoline-3-carbonitrile, Compound 172 carboxamide: To a solution of 5-bromopyridine-2-carboxamide (134.10 mg, 667.09 μmol, 1.5 eq) and 2e (200 mg, 444.73 μmol, 1 eq) in H ₂ O (0.2 mL) and DMF (1 mL) was added Pd(dppf)Cl ₂ (32.54 mg, 44.47 μmol, 0.1 eq) and K ₃ PO ₄ (283.21 mg, 1.33 mmol, 3 eq). Then the reaction mixture was degassed with N21 min three times. The resulting mixture was stirred at 100 °C for 12 h. LC-MS showed reactant 2 was consumed completely and major peak with desired mass was detected. Upon cooling to 15 °C, the reaction mixture was diluted with water (3 mL) and then filtered and the filter cake was washed with MeOH (3 * 3 mL) and then concentrated under reduced pressure to give a residue. 5-[4-(6-chloro-5-fluoro-indolin-1-yl)-3-cyano-6-quinolyl]pyr idine-2- carboxamide (110 mg, 202.67 μmol, 45.57% yield, 81.78% purity) was obtained as a brown solid, which directly used for next step. Step 2: Synthesis of (NE)-5-[4-(6-chloro-5-fluoro-indolin-1-yl)-3-cyano-6-quinoly l]-N-(dimet hylaminomethylene)pyridine-2-carboxamide A solution of 5-[4-(6-chloro-5-fluoro-indolin-1-yl)-3-cyano-6-quinolyl]pyr idine-2-carboxamide (60 mg, 135.18 μmol, 1 eq) and DMF-DMA (24.16 mg, 202.77 μmol, 26.94 μL, 1.5 eq) in toluene (2 mL) was degassed with N ₂ 1 min three times and then stirred at 120 ^o C for 12 h. LC-MS showed 219 262340-537651 starting material was consumed completely and one new peak was detected. Upon cooling to 15 °C, the reaction mixture was concentrated under reduced pressure to give a residue. No further purification and directly used for next step. (NE)-5-[4-(6-chloro-5-fluoro-indolin-1-yl)-3-cyano- 6-quinolyl]-N-(dimethylaminomethylene)pyridine-2-carboxamide (60 mg, crude) was obtained as a black solid. Step 3: Synthesis of 4-(6-chloro-5-fluoro-indolin-1-yl)-6-[6-(4H-1,2,4-triazol-3- yl)-3- pyridyl]quinoline-3-carbonitrile(Compound 172) To a solution of (NE)-5-[4-(6-chloro-5-fluoro-indolin-1-yl)-3-cyano-6-quinoly l]-N- (dimethylaminomethylene)pyridine-2-carboxamide (60 mg, 120.26 μmol, 1 eq) in AcOH (1 mL) was added hydrazine;hydrate (20 mg, 399.52 μmol, 3.32 eq) dropwise. The resulting mixture was stirred at 15 °C for 12 h. LC-MS showed starting material was consumed completely and major peak with desired mass was detected. The reaction mixture was added sat. NaHCO3 aqueous solution (2 ml) to adjust pH (7-8) at 0 °C under an ice bath and then extracted with ethyl acetate (3 * 2 mL). The organic layer was washed with brine (2 mL), dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18100 * 30 mm * 3 um; mobile phase: [H ₂ O (0.04% HCl)-ACN]; gradient: 25%-50% B over 8.0 min). 4-(6-chloro-5-fluoro-indolin-1-yl)-6-[6-(4H- 1,2,4-triazol-3-yl)-3-pyridyl]quinoline-3-carbonitrile, Compound 172, (2.9 mg, 5.46 μmol, 4.54% yield, 94.87% purity, HCl) was obtained as a pale yellow solid. MS (M+H) ⁺ = 468.0. ¹ H NMR (400 MHz, DMSO-d6) δ = 9.10 (s, 1H), 9.00 (s, 1H), 8.58 - 8.36 (m, 4H), 8.32 - 8.26 (m, 1H), 8.23 (br d, J = 8.4 Hz, 1H), 7.45 (br d, J = 8.8 Hz, 1H), 6.94 (d, J = 6.4 Hz, 1H), 4.61 (br d, J = 7.6 Hz, 1H), 4.38 (br d, J = 8.4 Hz, 1H), 3.41 - 3.25 (m, 2H). Example 139: Synthesis of 1-(5-bromo-3-pyridyl)-2,2,2-trifluoro-ethane-1,1-diol, Compound 179 Step 1: Synthesis of 1-(5-bromo-3-pyridyl)-2,2,2-trifluoro-ethanol 220 262340-537651 To a solution of 5-bromopyridine-3-carbaldehyde (500 mg, 2.69 mmol, 1 eq) and TMSCF3 (420.45 mg, 2.96 mmol, 1.1 eq) in THF (7 mL) was added TBAF (1 M, 2.69 mL, 1 eq) at 0 °C under an ice bath. Then the reaction mixture was stirred at 25°C for 2 h. LC-MS showed starting material was consumed completely and major peak with desired mass was detected. The reaction mixture was diluted with water (10 mL) and then extracted with ethyl acetate (3 * 6 mL). The organic layer was washed with brine (6 mL), dried over anhydrous Na ₂ SO ₄ , then filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 12 g silica, 5- 20 % ethyl acetate in petroleum ether, gradient over 20 min). 1-(5-bromo-3-pyridyl)-2,2,2- trifluoro-ethanol (600 mg, 2.34 mmol, 87.18% yield, 100% purity) was obtained as a pale yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ = 8.76 (d, J = 2.0 Hz, 1H), 8.68 (s, 1H), 8.13 (s, 1H), 7.22 (d, J = 6.0 Hz, 1H), 5.45 - 5.29 (m, 1H) Step 2: Synthesis of 1-(5-bromo-3-pyridyl)-2,2,2-trifluoro-ethane-1,1-diol A solution of 1-(5-bromo-3-pyridyl)-2,2,2-trifluoro-ethanol (500 mg, 1.95 mmol, 1 eq) in EtOAc (5 mL) was added 2-IODOXYBENZOIC ACID (1.09 g, 3.91 mmol, 2 eq). The reaction mixture was stirred at 78 °C for 4 h. LC-MS showed starting material was consumed completely and major peak with desired mass was detected. TLC(petroleum ether: ethyl acetate=1:1，Rf=0.6) showed the starting material was consumed completely and one new spot was formed. The reaction was filtered after the reaction mixture was cold to 25 °C and then washed with EtOAc (3 mL * 3). The mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 * 10 mL). The organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 12 g silica, 10-30% ethyl acetate in petroleum ether, gradient over 20 min). 1-(5-bromo-3-pyridyl)- 2,2,2-trifluoro-ethane-1,1-diol (300 mg, 1.10 mmol, 56.47% yield) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ = 8.79 (d, J = 2.0 Hz, 1H), 8.73 (d, J = 1.6 Hz, 1H), 8.08 (t, J = 2.0 Hz, 1H), 8.05 (s, 2H). Step 3: Synthesis of 1-(5-bromo-3-pyridyl)-2,2,2-trifluoro-ethane-1,1-diol(Compou nd 179) To a solution of 1m (30 mg, 73.58 umol, 1 eq) and 1-(5-bromo-3-pyridyl)-2,2,2-trifluoro-ethane- 1,1-diol (20.02 mg, 73.58 umol, 1 eq) in H ₂ O (0.2 mL) and dioxane (1 mL) was added Pd(dppf)Cl ₂ (5.38 mg, 7.36 umol, 0.1 eq) and K3PO4 (46.86 mg, 220.75 umol, 3 eq). Then the 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 221 262340-537651 detected. The reaction mixture was filtered upon cooling to 25 °C. The filtrate was purified by prep-HPLC (column: Phenomenex Luna 80 * 30 mm * 3 um; mobile phase: [water (HCl)-ACN]; B%: 20%-50%, 8 min).1-[5-[4-(6-chloroindolin-1-yl)quinazolin-6-yl]-3-pyridy l]-2,2,2-trifluoro- ethane-1,1-diol, Compound 179, (12.56 mg, 24.66 umol, 33.51% yield, 100% purity, HCl) was obtained as a yellow solid. MS (M+H) ⁺ = 473.1. ¹ H NMR (400 MHz, DMSO-d6) δ = 9.15 (d, J = 1.6 Hz, 1H), 9.07 (s, 1H), 8.86 (s, 1H), 8.69 (s, 1H), 8.45 (d, J = 8.6 Hz, 1H), 8.35 (s, 1H), 8.27 (s, 1H), 8.15 (d, J = 8.8 Hz, 1H), 8.12 - 7.89 (m, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.32 (dd, J = 1.6, 8.0 Hz, 1H), 4.97 (br t, J = 7.4 Hz, 2H), 3.27 (br t, J = 7.4 Hz, 2H) Example 140: Synthesis of 1-[5-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6-yl]-3- pyridyl]-2,2,2-trifluoro-ethane-1,1-diol, Compound 180 To a solution of 1n (50 mg, 117.46 umol, 1 eq) and 1-(5-bromo-3-pyridyl)-2,2,2-trifluoro- ethane-1,1-diol (31.95 mg, 117.46 umol, 1 eq) in H ₂ O (0.2 mL) and dioxane (1 mL) was added Pd(dppf)Cl ₂ (8.59 mg, 11.75 umol, 0.1 eq) and K ₃ PO ₄ (74.80 mg, 352.37 umol, 3 eq). Then the 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. Upon cooling to 25 °C, the reaction mixture was filtered. The filtrate was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18150 * 40 mm * 10 um; mobile phase: [water (NH4HCO3)-ACN]; B%: 35%-75%, 8 min).1-[5-[4-(6-chloro-5-fluoro- indolin-1-yl)quinazolin-6-yl]-3-pyridyl]-2,2,2-trifluoro-eth ane-1,1-diol, Compound 180, (7.75 mg, 15.79 μmol, 13.44% yield, 100% purity) was obtained as a pale yellow solid. MS (M+H) ⁺ = 491.1. ¹ H NMR (400 MHz, DMSO-d6) δ = 9.07 (d, J = 2.2 Hz, 1H), 8.84 - 8.72 (m, 2H), 8.44 (d, J = 1.4 Hz, 1H), 8.28 - 8.18 (m, 2H), 8.02 (d, J = 8.8 Hz, 1H), 7.99 (s, 2H), 7.93 (d, J = 6.8 Hz, 1H), 7.44 (d, J = 9.2 Hz, 1H), 4.70 (t, J = 8.0 Hz, 2H), 3.23 (br t, J = 7.8 Hz, 2H). 222 262340-537651 Example 141: Synthesis of 4-(6-chloro-5-fluoro-indolin-1-yl)-6-[5-(2,2,2-trifluoro-1,1 - dihydroxy-ethyl)-3-pyridyl]quinoline-3-carbonitrile, Compound 181 To a so oro-ethane- 1,1-diol (30.24 mg, 111.18 umol, 1 eq) in H ₂ O (0.2 mL) and dioxane (1 mL) was added Pd(dppf)Cl ₂ (8.14 mg, 11.12 umol, 0.1 eq) and K ₃ PO ₄ (70.80 mg, 333.55 umol, 3 eq). Then the 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. Upon cooling to 25 °C, 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%: 25%-55%, 8 min).4-(6-chloro-5-fluoro-indolin-1-yl)-6-[5-(2,2,2-trifluor o-1,1- dihydroxy-ethyl)-3-pyridyl]quinoline-3-carbonitrile, Compound 181, (12.03 mg, 21.00 umol, 18.88% yield, 96.22% purity, HCl) was obtained as a yellow solid. MS (M+H) ⁺ = 515.1. ¹ H NMR (400 MHz, DMSO-d6) δ = 9.09 (s, 1H), 8.99 (d, J = 2.0 Hz, 1H), 8.82 (d, J = 1.4 Hz, 1H), 8.32 - 8.24 (m, 3H), 8.21 (s, 1H), 8.07 - 7.90 (m, 1H), 7.42 (d, J = 8.8 Hz, 1H), 6.89 (d, J = 6.0 Hz, 1H), 4.56 - 4.47 (m, 1H), 4.40 (q, J = 8.8 Hz, 1H), 3.37 - 3.25 (m, 2H). 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 μmol, 1 eq) and 1k (80 mg, 141.05 μmol, 1 eq) in H ₂ O (0.2 mL) and DMF (1 mL) was added Pd(dppf)Cl ₂ (10.32 mg, 14.10 μmol, 0.1 eq) and K3PO4 (89.82 mg, 423.14 μmol, 3 eq). Then the 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. Upon cooling to 15 °C, 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). N-[5-[4-(6-chloro-5-fluoro-indolin-1-yl)-3-cyano-6-quinolyl] -2- methoxy-3-pyridyl]methanesulfonamide, Compound 188, (17.50 mg, 33.24 μmol, 23.57% yield, 99.52% purity) was obtained as a yellow solid. MS (M + H) ⁺ = 524.0. ¹ H NMR (400 MHz, DMSO- d6) δ = 9.38 (br s, 1H), 9.03 (s, 1H), 8.31 (d, J = 2.0 Hz, 1H), 8.27 - 8.19 (m, 2H), 8.17 (s, 1H), 7.91 (d, J = 2.4 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 6.80 (d, J = 6.4 Hz, 1H), 4.53 - 4.42 (m, 1H), 4.41 - 4.30 (m, 1H), 3.97 (s, 3H), 3.33 (br s, 2H), 3.05 (s, 3H). Example 143: Synthesis of N-[2-chloro-5-[4-(6-chloro-5-fluoro-indolin-1-yl)-3-cyano-6- quinolyl]-3-pyridyl]methanesulfonamide, Compound 189 262340-537651 To a stirred solution of 4c (57.94 mg, 141.07 μmol, 1 eq) and 2d (80 mg, 141.07 μmol, 1 eq) in H2O (0.2 mL) and DMF (1 mL) was added Pd(dppf)Cl2 (10.32 mg, 14.11 μmol, 0.1 eq) and K ₃ PO ₄ (89.83 mg, 423.20 μmol, 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. Upon cooling to 15 °C, 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). N-[2-chloro-5-[4-(6-chloro-5-fluoro-indolin-1-yl)-3-cyano-6- quinolyl]-3-pyridyl]methanesulfonamide, Compound 189, (33.53 mg, 58.58 μmol, 41.53% yield, 98.69% purity, HCl) was obtained as a orange solid. MS (M+H) ⁺ = 528.1. ¹ H NMR (400 MHz, DMSO-d6) δ = 9.89 (s, 1H), 9.07 (s, 1H), 8.60 (d, J = 2.0 Hz, 1H), 8.39 - 8.20 (m, 3H), 8.13 (d, J = 2.4 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 6.88 (d, J = 6.0 Hz, 1H), 4.53 (br d, J = 7.6 Hz, 1H), 4.34 (br d, J = 8.4 Hz, 1H), 3.39 - 3.25 (m, 2H), 3.15 (s, 3H). 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)pyr idin-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). Then MsCl (412.22 mg, 3.60 mmol, 278.53 uL, 3 eq) dissolved in DCM (2 mL) was dropwised added to the mixture at 0 °C after degassing with N ₂ 1 min three times. The resulting mixture was stirred at 0 °C for 2 h. LC-MS showed starting material was consumed completely and one major peak with desired mass was detected. The reaction mixture was quenched by water (5 ml) and then extracted with ethyl acetate (3 * 5 mL). The organic layer was washed with brine (5 mL), dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure to 225 262340-537651 give a residue. No purification and directly used for next step directly. N-[2-methoxy-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]-N-methylsulf onyl-methanesulfonamide, 4e, (0.5 g, 730.18 umol, 60.87% yield, 59.332% purity) was obtained as a yellow solid. Step 2: Synthesis of N-[5-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6-yl]-2-m ethoxy-3- pyridyl]methanesulfonamide (Compound 131) To a solution of 1k (0.05 g, 132.06 umol, 1 eq) and 4e (90.43 mg, 132.06 umol, 59.332% purity, 1 eq) in DMF (2 mL) and H2O (0.4 mL)was added K3PO4 (84.09 mg, 396.17 umol, 3 eq) and Pd(dppf)Cl2 (9.66 mg, 13.21 umol, 0.1 eq). The resulting mixture was degassed with N21 min three times and then 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 15 °C, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Waters Xbridge Prep OBD C18150 * 40 mm * 10 um; mobile phase: [water (NH4HCO3)- ACN]; B%: 40%-70%,8min). After prep-HPLC purification, the eluent was concentrated to remove organic solvents. The residual aqueous solution was lyophilized to give a residue. N-[5-[4-(6-chloro-5-fluoro-indolin-1-yl)quinazolin-6-yl]-2-m ethoxy-3- pyridyl]methanesulfonamide, Compound 131, (8.66 mg, 17.32 umol, 13.12% yield, 100% purity) was obtained as a pale yellow solid. MS (M+H) ⁺ = 500.1. ¹ H NMR (400 MHz, DMSO- d6) δ = 9.19 (s, 1H), 8.74 (s, 1H), 8.40 (d, J = 2.4 Hz, 1H), 8.34 (d, J = 1.6 Hz, 1H), 8.18 (dd, J = 1.8, 1.6 Hz, 1H), 8.00 - 7.95 (m, 2H), 7.91 (d, J = 6.8 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 4.69 (t, J = 8.0 Hz, 2H), 3.98 (s, 3H), 3.22 (br t, J = 8.0 Hz, 2H), 3.07 (s, 3H) [00634] In the following examples, the biological activity of the compounds of the invention are sometimes compared herein to Comparative Compound 1 and Comparative Compound 2, which are identified as: 226 262340-537651 Compound Name Structure 5-(4-(6- [ ] xamp e : n y o se ec e compoun s o e sc osure or uman PI3Ka, EGFR, and DNA-PK enzymes. [00636] Enzyme materials description [00637] EGFR (ErbB1): Recombinant human protein, catalytic domain (amino acids 668- 1210), GST-tagged, expressed in insect cells. Activated in vitro via autophosphorylation. [00638] DNA-PK: Native human, purified from MOLT4 cells. [00639] 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. [00640] Protocol [00641] The Z´-LYTE® biochemical assay employs a fluorescence-based, coupled- enzyme format and is based on the differential sensitivity of phosphorylated and non- phosphorylated peptides to proteolytic cleavage. The peptide substrate is labeled with two fluorophores—one at each end—that make up a FRET pair. In the primary reaction, the kinase transfers the gamma-phosphate of ATP to a single tyrosine, serine or threonine residue in a synthetic FRET-peptide. In the secondary reaction, a site-specific protease recognizes and cleaves non-phosphorylated FRET-peptides. Phosphorylation of FRET-peptides suppresses cleavage by the Development Reagent. Cleavage disrupts FRET between the donor (i.e., coumarin) and acceptor (i.e., fluorescein) fluorophores on the FRET-peptide, whereas uncleaved, phosphorylated FRET-peptides maintain FRET. A ratiometric method, which calculates the ratio 227 262340-537651 (the Emission Ratio) of donor emission to acceptor emission after excitation of the donor fluorophore at 400 nm, is used to quantitate reaction progress. [00642] A significant benefit of this ratiometric method for quantitating reaction progress is the elimination of well-to-well variations in FRET-peptide concentration and signal intensities. As a result, the assay yields very high Z´-factor values (>0.7) at a low percent phosphorylation. [00643] Both cleaved and uncleaved FRET-peptides contribute to the fluorescence signals and therefore to the Emission Ratio. The extent of phosphorylation of the FRET-peptide can be calculated from the Emission Ratio. The Emission Ratio will remain low if the FRET-peptide is phosphorylated (i.e., no kinase inhibition) and will be high if the FRET-peptide is non- phosphorylated (i.e., kinase inhibition). [00644] Enzyme: The ADAPTA universal kinase assay is a homogenous, fluorescent based immunoassay for the detection of ADP. In contrast to ATP depletion assays, the ADAPTA assay is extremely sensitive to ADP formation such that a majority of the signal change occurs in the first 10-20% conversion of ATP to ADP. This makes the ADAPTA universal kinase assay ideally suited for use with low activity kinases. [00645] The principle of the ADAPTA universal kinase assay is outlined below. The assay itself can be divided into two phases: a kinase reaction phase, and an ADP detection phase. In the kinase reaction phase, all components required for the kinase reaction are added to the well, and the reaction is allowed to incubate for 60 minutes. After the reaction, a detection solution consisting of a europium labeled anti-ADP antibody, an Alexa Fluor® 647 labeled ADP tracer, and EDTA (to stop the kinase reaction) is added to the assay well. ADP formed by the kinase reaction (in the absence of an inhibitor) will displace the Alexa Fluor® 647 labeled ADP tracer from the antibody, resulting in a decrease in the TR-FRET signal. In the presence of an inhibitor, the amount of ADP formed by the kinase reaction is reduced, and the resulting intact antibody- tracer interaction results in a high TR-FRET signal. [00646] Z′-LYTE® Assay Conditions: [00647] Test Compounds: The Test Compounds are screened in 1% DMSO (final) in the well. For 10 point titrations, 3-fold serial dilutions are conducted from the starting concentration of the customer’s choosing. [00648] Peptide/Kinase Mixtures: All Peptide/Kinase Mixtures are diluted to a 2X working concentration in the appropriate Kinase Buffer. 228 262340-537651 [00649] ATP Solution: All ATP Solutions are diluted to a 4X working concentration in Kinase Buffer (50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCl2, 1 mM EGTA). ATP Km apparent is previously determined using a Z´-LYTE® assay. [00650] Development Reagent Solution: The Development Reagent is diluted in Development Buffer. [00651] 10X Novel PKC Lipid Mix: 2 mg/mL Phosphatidyl Serine, 0.2 mg/mL DAG in 20 mM HEPES, pH 7.4, 0.3% CHAPS. For 5 mL 10X Novel PKC Lipid Mix: 1. Add 10 mgs Phosphatidyl Serine (Avanti Polar Lipids Part# 8400032C or 840039C) and 1 mg DAG (Avanti Polar Lipids Part# 800811C) to a glass tube.2. Remove the chloroform from lipid mixture by evaporating to a clear, thin film under a stream of nitrogen. Continuous rotation of the tube, at an angle to ensure maximum surface area of the lipid solution, will promote the thinnest film.3. Add 5 mL resuspension buffer, 20 mM HEPES, 0.3% CHAPS, pH 7.4, to the dried lipid mix 4. Heat gently to 50-60 ^C for 1-2 minutes and vortex in short intervals until the lipids are dissolved to a clear or slightly hazy solution. The lipids are typically in solution after 2-3 heat/vortex cycles.5. Cool to room temperature, aliquot into single use volumes and store at –20 ^C. [00652] Assay Protocol: Bar-coded Corning, low volume NBS, black 384-well plate (Corning Cat. #4514) 1.2.5 μL – 4X Test Compound or 100 nL 100X plus 2.4 μL kinase buffer. 2.5 μL – 2X Peptide/Kinase Mixture.3.2.5 μL – 4X ATP Solution.4.30-second plate shake.5. 60-minute Kinase Reaction incubation at room temperature.6.5 μL – Development Reagent Solution.7.30-second plate shake.8.60-minute Development Reaction incubation at room temperature.9. Read on fluorescence plate reader and analyze the data. [00653] ADP formation is determined by calculating the emission ratio from the assay well. The emission ratio is calculated by dividing the intensity of the tracer (acceptor) emission by the intensity of the Eu (donor) emission at 615 nm as shown in the equation below. [00654] Since the ADAPTA technology measures ADP formation (i.e. conversion of ATP to ADP) it can be used to measure any type of ATP hydrolysis, including intrinsic ATPase activity of kinases. In this case, the substrate is water, not a lipid or peptide. The SelectScreen® service screens CHUK in this way, so a substrate is not included in the kinase reaction. A reference for using intrinsic ATPase activity to screen for kinase inhibitors is provided below. [00655] Adapta® Assay Conditions 229 262340-537651 [00656] Test Compounds: The Test Compounds are screened in 1% DMSO (final) in the well. For 10 point titrations, 3-fold serial dilutions are conducted from the starting concentration of the customer’s choosing. [00657] Substrate/Kinase Mixtures: All Substrate/Kinase Mixtures are diluted to a 2X working concentration in the appropriate Kinase Buffer (see section Kinase Specific Assay Conditions for a complete description). [00658] ATP Solution: All ATP Solutions are diluted to a 4X working concentration in water. ATP Km apparent is previously determined using a radiometric assay except when no substrate is available in which case an Adapta® assay is conducted. [00659] Detection Mix: The Detection Mix is prepared in TR-FRET Dilution Buffer. The Detection mix consists of EDTA (30 mM), Eu-anti-ADP antibody (6 nM) and ADP tracer. The detection mix contains the EC60 concentration of tracer for 5-150 ^M ATP. [00660] Assay Protocol: Bar-coded Corning, low volume, white 384-well plate (Corning Cat. #4512)1.2.5 μL – 4X Test Compound in 30 mM HEPES or 100 nL 100X in 100% DMSO plus 2.4 μL 30 mM HEPES.2.2.5 μL – 4X ATP Solution.3.5 μL – 2X Substrate/Kinase Mixture.4.30-second plate shake.5.1-minute centrifuge at 1000 x g.6.60-minute Kinase Reaction incubation at room temperature.7.5 μL – Detection Mix.8.30-second plate shake.9. 1-minute centrifuge at 1000 x g.10.60-minute Detection Mix equilibration at room temperature. 11. Read on fluorescence plate reader and analyze the data. [00661] The affinity for PI3Ka, EGFR, and DNA-PK enzymes of selected compounds of the disclosure vs. Comparative Compound 1 and Comparative Compound 2 is presented as the percent inhibition at 100 nM, in Table 2 below. The % inhibition at 100 nM data in Table 2 is presented as “*” (value is 10% or less), “**” (value is greater than 10% and less than or equal to 80%), “***” (value is greater than 80% and less than or equal to 90%) and “****” (value is greater than 90%). The affinity for PI3Ka, EGFR, and DNA-PK enzymes of selected compounds of the disclosure vs. Comparative Compound 1 and Comparative Compound 2 is presented as the 50% inhibitory concentration (IC ₅₀ ) in Table 3 below. The IC ₅₀ data in Table 3 is presented as “++++” (value is 20 nM or less), “+++” (value is greater than 20 nM and less than or equal to 200 nM), “++” (value is greater than 200 nM and less than or equal to 2000 nM) and “+” (value is greater than 2000 nM). NT is “not tested.” 230 262340-537651 [00662] Table 2: Affinity for PI3Ka, EGFR, and DNA-PK enzymes of selected compounds of the disclosure vs. Comparative Compound 1 and Comparative Compound 2 presented as the percent inhibition at 100 nM. PI3Ka % Inh. EGFR % Inh. DNA-PK % Inh. Compound @ 100nM @ 100nM @ 100nM 231 262340-537651 PI3Ka % Inh. EGFR % Inh. DNA-PK % Inh. Compound @ 100nM @ 100nM @ 100nM 232 262340-537651 PI3Ka % Inh. EGFR % Inh. DNA-PK % Inh. Compound @ 100nM @ 100nM @ 100nM 233 262340-537651 PI3Ka % Inh. EGFR % Inh. DNA-PK % Inh. Compound @ 100nM @ 100nM @ 100nM 234 262340-537651 PI3Ka % Inh. EGFR % Inh. DNA-PK % Inh. Compound @ 100nM @ 100nM @ 100nM 235 262340-537651 PI3Ka % Inh. EGFR % Inh. DNA-PK % Inh. Compound @ 100nM @ 100nM @ 100nM 236 262340-537651 PI3Ka % Inh. EGFR % Inh. DNA-PK % Inh. Compound @ 100nM @ 100nM @ 100nM 237 262340-537651 [00663] Table 3: Affinity for PI3Ka, EGFR, and DNA-PK enzymes of selected compounds of the disclosure vs. Comparative Compound 1 and Comparative Compound 2 presented as the 50% inhibitory concentration (IC ₅₀ ) in nM. PI3Ka IC50 EGFR IC50 DNA-PK Compound (nM) (nM) IC50 (nM) 238 262340-537651 Compound 40 +++ ++++ ++++ Compound 42 +++ ++++ ++++ [00664] Example 146: Assessment of metabolic stability in liver microsomes. 239 262340-537651 [00665] Working solution: 5 μL of compound and control stock solution (10 mM in dimethyl sulfoxide (DMSO)) were diluted with 495 μL of acetonitrile (ACN) (intermediate solution concentration: 100 μM, 99% ACN) [00666] NADPH Cofactor Preparation: NADPH powder: β-Nicotinamide adenine dinucleotide phosphate reduced form, tetrasodium salt; NADPH·4Na. The appropriate amount of NADPH powder was weighed and diluted into a 10 mM MgCl2 solution (working solution concentration: 10 unit/mL; final concentration in reaction system: 1 unit/mL) [00667] Liver Microsomes Preparation: The appropriate concentrations of microsome working solutions were prepared in 100 mM potassium phosphate buffer. Cold (4°C) acetonitrile (ACN) containing 200 ng/mL tolbutamide and 200 ng/mL labetalol as internal standards (IS) was used as the stop solution [00668] Assay Procedure: Pre-warm empty 'Incubation' plates T60 and NCF60 for 10 minutes. Dilute liver microsomes to 0.56 mg/mL in 100 mM phosphate buffer. Transfer 445 μL microsome working solutions (0.56 mg/mL) into pre-warmed 'Incubation' plates T60 and NCF60, Then pre-incubate 'Incubation' plates T60 and NCF60 for 10 min at 37°C with constant shaking. Transfer 54 µL liver microsomes to blank plate, then add 6 µL NAPDH cofactor to blank plate, and then add 180 µL quenching solution to blank plate. Add 5 µL compound working solution (100 μM) into 'incubation' plates (T60 and NCF60) containing microsomes and mix 3 times thoroughly. [00669] For the NCF60 plate, add 50 μL of buffer and mix 3 times thoroughly. Start timing; plate will be incubated at 37°C for 60 min while shaking. In 'Quenching' plate T0, add 180 µL quenching solution and 6 µL NAPDH cofactor. Ensure the plate is chilled to prevent evaporation. For the T60 plate, mix 3 times thoroughly, and immediately remove 54 µL mixture for the 0-min time point to 'Quenching' plate. Then add 44 µL NAPDH cofactor to incubation plate (T60). Start timing; plate will be incubated at 37°C for 60 min while shaking. At 5, 10, 20, 30, and 60 min, add 180 µL quenching solution to 'Quenching' plates, mix once, and serially transfer 60 µL sample from T60 plate per time point to 'Quenching' plates. For NCF60: mix once, and transfer 60 µL sample from the NCF60 incubation to 'Quenching' plate containing quenching solution at the 60-min time point. All sampling plates are shaken for 10 min, then centrifuged at 4000 rpm for 20 minutes at 4°C. Transfer 80 µL supernatant into 240 µL HPLC 240 262340-537651 water, and mix by plate shaker for 10 min. Each bioanalysis plate was sealed and shaken for 10 minutes prior to LC-MS/MS analysis. [00670] The equation of first order kinetics was used to calculate T1/2 and CLint(mic) (μL/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 ½ life in the presence microsomes. Presented in Table 4, is the ½ life of selected compounds of the disclosure in the presence of human liver microsomes (HLM) or mouse liver microsomes (MLM) as described above. In Table 4, ½ life is presented as “++++” (value is greater than or equal to 30 minutes), “+++” (value is greater than or equal 15 minutes and less than 30 minutes), “++” (value is greater than 10 minutes and less than 15 minutes) and “+” (value is 10 minutes or less). [00672] Table 4: ½ life of selected compounds of the disclosure in the presence of human liver microsomes (HLM) or mouse liver microsomes (MLM). Compound ½ life minutes (HLM) ½ life minutes (MLM) 241 262340-537651 Compound ½ life minutes (HLM) ½ life minutes (MLM) Compound 30 + + 242 262340-537651 Compound ½ life minutes (HLM) ½ life minutes (MLM) Compound 68 + + 243 262340-537651 Compound ½ life minutes (HLM) ½ life minutes (MLM) Compound 122 + + 244 262340-537651 Compound ½ life minutes (HLM) ½ life minutes (MLM) Compound 180 ++++ +++ [ ld possess robust biological stability in vivo, as most of the compounds tested have a half-life greater than 30 minutes in the presence of both human liver microsomes and mouse liver microsomes. [00674] Example 147: Solubility Assessment [00675] Preparation of stock solutions: The stock solutions of test compounds and control compound diclofenac were prepared in DMSO at the concentrations of 10 mM. [00676] Simulated Gastric Fluid (SGF): An aqueous mixture including hydrochloric acid, sodium chloride, and pepsin (pH = 1.2). [00677] 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. The two solutions are mixed well and diluted with ultrapure water to a final volume of 1000 mL. [00678] Procedure for solubility determination: 15 µL of stock solution (10 mM) of each sample was placed in order into their proper 96-well rack.485 µL of (SIF, SGF, PBS 7.4, FESSIF, or FESSGF) was added into each vial of the cap-less Solubility Sample plate. The assay was performed in duplicate. Add one stir stick to each vial and seal using a molded PTFE/Silicone plug. Then the solubility sample plate was transferred to the Eppendorf Thermomixer Comfort plate shaker and shaken at 25°C at 1100 rpm for 2 hours. After completion of the 2 hours, plugs were removed and the stir sticks were removed using a big magnet, the samples from the Solubility Sample plate were transferred into the filter plate. Using the Vacuum Manifold, all the samples were filtered. Aliquot of 5 µL and 5 µL DMSO were taken from the filtrate followed by addition of 490 µL of a mixture of H ₂ O and acetonitrile containing internal standard (1:1). A certain proportion of ultrapure water was used to dilute the diluent according to the peak shape. The dilution factor was changed according to the solubility values and the LC-MS signal response. 245 262340-537651 [00679] Preparation of 300 µM standards (STD): From the 10 mM DMSO STD plate, 6 µL was transferred into the remaining empty plate, and then 194 µL of DMSO was added to that plate to have a STD concentration of 300 µM. From the 300 µM DMSO STD plate, 5 µL DMSO STD and 5 µL SIF was transferred into the remaining empty plate, and then 490 µL of a mixture of H2O and acetonitrile containing internal standard (1:1) was added to that plate to have a final STD concentration of 3 µM. A certain proportion of ultrapure water was used to dilute the diluent according to the peak shape. The concentrations of the standard samples were changed according to the LC-MS signal response. [00680] Procedure for sample analysis: The plate was placed into the well plate autosampler. The samples were evaluated by LC-MS/MS analysis. [00681] Data analysis: All calculations were carried out using Microsoft Excel. The filtrate was analyzed and quantified against a standard of known concentration using LC coupled with mass spectral peak identification and quantitation. Solubility values of the test compound and control compound were calculated as follows: [Sample]= ^{^^^^ ^^^^^ ^^^^^^×^^^ ^^^ ^^^×^^ ^^^^^^×[^^^] ^^^^ ^^^^^ ^^^×^^^ ^^^} _^^^^^^ [00682] Any value of the compounds that was not within the specified limits was rejected and the experiment was repeated. [00683] The solubility data for selected compounds of the disclosure is provided in Table 5. The solubility data in Table 5 is presented as “****” (value is greater than or equal to 200 μM), “***” (value is greater than or equal to 50 μM and less than 200 μM), “**” (value is greater than or equal to 10 μM and less than 50 μM) and “*” (value is less than 10 μM). Blank cells are “not tested.” [00684] Table 5: Solubility data for selected compounds of the disclosure. Solubility pH 7.4 Solubility Solubility C d 246 262340-537651 Solubility pH 7.4 Solubility Solubility Compound PBS buffer SIF SGF 247 262340-537651 Solubility pH 7.4 Solubility Solubility Compound PBS buffer SIF SGF [00 a p e : ssess e o e u s a es o -gp o . [00686] Madin-Darby canine kidney (MDCK) cells expressing either human P-gp or human BCRP were used to determine whether Example molecules were substrates of these transporters. MDCKII-BCRP and MDCK-MDR1 cells obtained from the Netherlands Cancer Institute (Amsterdam). [00687] Preparation of MDCK-MDR1 or MDCKII-BCRP Cells [00688] 50 μL 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 1.56х10 ⁶ cells/mL with culture medium and 50 μL 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. Cell culture medium was replaced every other day, beginning no later than 24 hours after initial plating. [00689] Preparation of Solutions [00690] To prepare the HBSS (10 mM HEPES, pH 7.4), accurately weigh 2.38 g of HEPES and 0.35 g sodium hydrogen carbonate and add into 900 mL of pure water, then sonicate to dissolve the content. Transfer 100 mL of 10× HBSS into the solution, and place the solution on a stirrer, slowly adjust pH with sodium hydrate to 7.4, following with filtering. [00691] Digoxin is used as the reference substrate of Pgp (MDR1). Pitavastatin is used as the reference substrate of BCRP. Metoprolol is used as a negative control substrate. The stock solutions of the test compounds and control compounds were diluted in DMSO to get 400 μM 248 262340-537651 solutions and then diluted with HBSS (10 mM HEPES, pH 7.4) to get 1 μM working solutions. To determine the rate of drug transport in the presence of the Pgp inhibitor, PSC833 a known inhibitor of Pgp, is added to both apical and basolateral compartments at a final concentration of 10 μM. To determine the rate of drug transport in the presence of the BCRP inhibitor, Ko 143 a known inhibitor of BCRP, is added to both apical and basolateral compartments at a final concentration of 30 μM. The final concentration of DMSO in the incubation system is 0.5 %. [00692] Performing the Drug Transport Assay [00693] Remove the MDCK-MDR1 or MDCKII-BCRP Cells plate from the incubator. Wash the monolayer twice with pre-warmed HBSS (10 mM HEPES, pH 7.4). Then incubate the plate at 37 °C for 30 minutes. [00694] To determine the rate of drug transport in the apical to basolateral direction. Add 125 μL of the working solution to the Transwell insert (apical compartment), and transfer 50 μL sample immediately from the apical compartment to 200 μL of acetonitrile containing IS (100 nM alprazolam, 200 nM Caffeine and 100 nM tolbutamide) in a new 96-well plate as the initial donor sample (A-B). Vortex at 1000 rpm for 10 minutes. Fill the wells in the receiver plate (basolateral compartment) with 235 μL of transport buffer. [00695] To determine the rate of drug transport in the basolateral to apical direction. Add 285 μL of the working solution to the receiver plate wells (basolateral compartment), and transfer 50 μL sample immediately from the basolateral compartment to 200 μL of acetonitrile containing IS (100 nM alprazolam, 200 nM Caffeine, 100 nM tolbutamide and 200 nM Labetalol) in a new 96-well plate as the initial donor sample (B-A). Vortex at 1000 rpm for 10 minutes. Fill the Transwell insert (apical compartment) with 75 μL of transport buffer. The apical to basolateral direction and the basolateral to apical direction need to be done at the same time. Incubate the Transwell plate at 37 °C, 5% CO2 with shaking at 150 rpm on a rotary shaker for 2 hours. [00696] At the end of the incubation, 50 μL samples from donor sides (apical compartment for Ap→Bl flux, and basolateral compartment for Bl→Ap) and receiver sides (basolateral compartment for Ap→Bl flux, and apical compartment for Bl→Ap) were transferred to wells of a new 96-well plate, followed by the addition of 4 volume of acetonitrile containing IS (100 nM alprazolam, 200 nM Caffeine, 100 nM tolbutamide and 200 nM Labetalol). Samples were Vortexed for 10 minutes and then centrifuged at 3,220 g for 40 minutes. An aliquot of 100 249 262340-537651 µL of the supernatant was mixed with an appropriate volume of ultra-pure water before LC- MS/MS analysis. [00697] Data analysis [00698] All calculations are carried out using Microsoft Excel. Peak areas are determined from extracted ion chromatograms. [00699] Apparent permeability (Papp) can be calculated for drug transport assays using the following equation: where, “P _app ” is apparent permeability (cm/s x 10 ^-6 ); “dQ/dt” is the rate of drug transport (pmol/second); “A” is the surface area of the membrane (cm ² ); and “D ₀ ” is the initial donor concentration (nM; pmol/cm ³ ). [00700] Efflux ratio can be determined using the following equation: where, “Papp (B-A)” indicates the apparent permeability coefficient in basolateral to apical direction; and “P _app (A-B)” indicates the apparent permeability coefficient in apical to basolateral direction. [00701] Efflux ratios greater than two indicates a potential substrate for either P-gp or BCRP efflux transporter protein. Efflux ratio data for selected compounds of the disclosure is provided in Table 6. Efflux ratios between 2 and 3 are weak substrates. Efflux ratios greater than 3 are strong subtrates of either PGP or BCRP or both. The efflux ratio data in Table 6 is presented as “Not a substrate” (if the value is less than or equal 2), “Weak Substrate” (if the value is greater 2 but less than 3), and “Strong Substrate” (if the value is greater than or equal 3). Blank cells are “not tested.” [00702] Table 6: Efflux ratios of select compounds of these disclosure 250 262340-537651 Compound PGP BCRP Compound 1 Not a Substrate Not a Substrate 251 262340-537651 Compound 159 Not a Substrate Not a Substrate [0 compounds of the invention. [00704] Pharmacokinetic samples [00705] Pharmacokinetic study to assess plasma and brain concentrations of compounds were conducted using up to three routes of administration, IV, IP and PO. Brain and Plasma samples were taken at 8 time points 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24h. A total of 3 animals were used at each time point and each route to yield a total of up to 72 animals used in the study. [00706] Blood Samples Processing and Storage: 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 µL of working solutions (1, 2, 4, 20, 100, 200, 1000, 2000, 4000ng/mL) were added to 10 μL 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 μL. 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. [00708] 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 µL of working solutions (1, 2, 4, 20, 100, 200, 1000, 2000, 4000ng/mL) were added to 30 μL 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 μL. 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. [00709] 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. [00711] Table 7a: PK Parameters for Compound 7: PK P _arameter ^{Unit IV IP PO IV IP PO} 7 9 [00712] Table 7b: PK Parameters for Comparative Compound XX: X 262340-537651 PK P _arameter ^{Unit IV PO IV PO} 9 [00 ular transport. To achieve significant drug exposure in the brain, an agent must cross a cellular membrane separating blood and brain. Agents must cross via passive diffusion or active transport. Most drug molecules permeate the barrier via passive diffusion. The barrier between the brain and blood is equipped with multi-drug resistance transporters (PGP and BCRP) that actively efflux molecules from the brain back into the bloodstream. 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. [00714] 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. For cancers of the brain it is desirable to have Kp values greater than or equal to 1. [00715] 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. [00716] 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. [00718] 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. [00720] 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