Substituted Aminobenzyl Heteroaryl Compounds as EGFR and / or PI3K Inhibitors

Abstract

The present disclosure is in the field of medicinal chemistry and relates to a new class of small molecules having formula I, or a pharma- ceutically acceptable salt or solvate thereof, or an enantiomer, mixture of enantiomers, mixture of two or more diastereomers, or isotopic variants thereof, wherein the variable rings A, X, R 1a , R 1b , R 2 , R 3 , R 4 , m, n, and p are described herein and function as dual inhibitors of EGFR and PI3K proteins. The disclosure further relates to the use of the compounds described herein as therapeutic agents for the treatment of diseases and conditions mediated by EGFR and / or PI3K proteins, such as cancer and other diseases. JPEG2024501995000168.jpg24170

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This PCT application claims the benefit of U.S. Provisional Application No. 63 / 129,368, filed December 22, 2020. The entire contents of the aforementioned application are hereby incorporated by reference in their entirety.

[0002] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This disclosure was made with Government support under Grant No. R44 CA213715 awarded by the National Institutes of Health. The Government has certain rights in this disclosure.

[0003] The present disclosure is in the field of medicinal chemistry. In particular, the present disclosure relates to a new class of small molecules having a substituted aminobenzylquinazoline structure or a substituted aminobenzylquinoline structure that function as dual inhibitors of EGFR protein and PI3K protein. The present disclosure further relates to the use of the compounds described herein as therapeutic agents for the treatment of diseases and conditions mediated by EGFR protein and / or PI3K protein, such as cancer and other diseases. [Background technology]

[0004] Each year, over 830,000 patients worldwide are diagnosed with head and neck cancer, and at least 430,000 patients die from the disease (see, e.g., Cramer, JD, et al., Nat Rev Clin Oncol, 2019.16(11):p.669-683). Ninety percent of all head and neck cancers are squamous cell carcinomas (HNSCCs), which are characterized by significant heterogeneity at both clinical and molecular levels (see, e.g., Psyrri, A., TY Seiwert, and A. Jimeno, American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting, 2013:p.246-255). EGFR overexpression is an early and frequent molecular alteration in HNSCC, an alteration that has been shown to be associated with reduced survival (see, e.g., Grandis, JR and DJ Tweardy, Cancer Research, 1993. 53(15): p. 3579-3584). Cetuximab remains the only USFDA-approved EGFR-targeted therapy available for HNSCC. A fundamental problem with EGFR-targeted therapy in HNSCC is patient selection, as no consistent mechanism of resistance has been identified. PI3K mutations, which are particularly common in HPV+ head and neck cancers, increase resistance to EGFR inhibition (see, e.g., Simpson, DR, LK Mell, and EEW Cohen, Oral Oncology, 2015. 51(4): p. 291-298; Young, NR, et al., Molecular Oncology, 2013. 7(3): p. 359-368). Therefore, PIK3CA has emerged as a candidate biomarker for EGFR resistance.The PI3K / AKT / mTOR pathway, which supports tumor cell survival and progression, is abnormally activated in the majority of human tumors (see, for example, Yap, TA, et al., Current Opinion in Pharmacology, 2015.23: p.98-107; Liu, P., et al. Nature Reviews Drug Discovery, 2009.8: p.627-644; Janku, F., TA Yap, and F. Meric-Bernstam, Nature Reviews Clinical Oncology, 2018.15: p.273-291). Squamous cell carcinomas show a particularly high incidence of genomic alterations in this pathway, including PIK3CA mutations and other alterations that result in activation of this pathway, such as PIK3R1, PTEN, and AKT. Despite intensive efforts, the only PI3K inhibitors that have received regulatory approval are idelalisib (PI3Kδ-selective), copanlisib (panPI3K), and alpelisib (PI3Kα-selective). Lack of progress can be largely attributed to unacceptable toxicity, driven in part by the need for high exposure to induce monotherapy activity. The rationale for dual EGFR / PI3K inhibitor programs is driven by the central premise that 1) molecular alterations of downstream players in the PI3K pathway, e.g., PTEN, can eliminate the need for PI3K activity, making a panPI3K / mTOR inhibitor approach superior to an isoform-selective approach (see, e.g., Tao, JJ, et al., Science Signaling, 2014.7(318):p.ra29-ra29), and 2) EGFR and PI3K play reciprocal roles in tumor adaptation when targeting the other kinase. Anti-EGFR therapy has been shown to reverse acquired and intrinsic resistance to PI3Kα inhibition in HNSCC (see, e.g., Elkabets, M., et al., Cancer Cell, 2015.27(4):p.533-546). AXL has been shown to interact with EGFR to activate PLCγ and PKC, leading to activation of mTOR in a PI3K-independent manner.

[0005] Thus, the present disclosure provides compounds of formula I that are small molecule inhibitors of EGFR and / or PI3K enzymes suitable for the treatment of cancer. Summary of the Invention

[0006] The compound of formula I is a substituted benzylamino compound and may have advantages over similar unsubstituted benzylamino compounds or similar phenylamino compounds. For example, the compound of formula I may have properties selected from one or more of the following, compared to similar unsubstituted benzylamino compounds or similar phenylamino compounds: increased solubility in pH 7.4 aqueous buffer, increased solubility in simulated intestinal fluid (SIF), and increased solubility in simulated gastric fluid (SGF). Increased solubility in the above media may be indicative of increased bioavailability in biological systems, such as human subjects. Furthermore, increased bioavailability may allow for a smaller dose of equivalent biological activity compared to the required dose of a less soluble active pharmaceutical ingredient (API).

[0007] In one aspect, the present disclosure provides a compound of formula I [ka] or a pharma- ceutically acceptable salt or solvate thereof, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; During the ceremony, Ring A is selected from phenyl, or 5- or 6-membered heteroaryl; X is N or C-R5; R 1a But H or C 1-6 is selected from the group consisting of alkyl, R 1b But, C 1-6 is selected from the group consisting of alkyl, cycloalkyl, hetercycloalkyl, aryl, heteroaryl, OR', N(R')2, C(O)R', C(O)OR', C(O)N(R')2, halo, CN, and NO2; 1-6The alkyl, cycloalkyl, hetercycloalkyl, aryl, or heteroaryl are optionally and independently substituted with one or more R" substituents; or R 1a and R 1b together with the methylene moiety to which they are attached, C 3-7 forming a spirocyclic ring selected from cycloalkyl or 3-7 membered heterocycloalkyl, each of which is optionally and independently substituted with one or more R″ substituents; Each R2 is independently halo, OH, C 1-6 Alkyl, haloalkyl, OC 1-6 Alkyl, CN, NH2, NHC 1-6 Alkyl, N(C 1-6 alkyl)2, C(O)C 1-6 Alkyl, C(O)OC 1-6 Alkyl, C(O)NH2, C(O)NHC 1-6 Alkyl, and C(O)N(C 1-6 alkyl)2; or one R2 substituent and R 1b The phenyl group to which R2 is bonded and R 1b Together with the carbon atom to which it is attached, they form the general structure [ka] and ring B is a bicyclic group having the formula 3-7 cycloalkyl or 4-7 membered heterocycloalkyl, each of which is optionally selected from halo, OH, C 1-6 Alkyl, haloalkyl, OC 1-6 Alkyl, CN, NH2, NHC 1-6 Alkyl, N(C 1-6 alkyl)2, C(O)C 1-6 Alkyl, C(O)OC 1-6 Alkyl, C(O)NH2, C(O)NHC 1-6 Alkyl, and C(O)N(C 1-6 substituted with one or more substituents independently selected from Each R3 is independently selected from the group consisting of C 1-6is selected from alkyl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, halo, CN, NO2, OR', N(R')2, C(O)R', C(O)OR', C(O)N(R')2, OC(O)OR', OC(O)N(R')2, NR'C(O)N(R')2, SOR', SON(R')2, SO2R', SON(R')2, NR'SOR', NR'SON(R')2, NR'SOR', NR'SON(R')2, NR'SOR', and NR'SON(R')2; 1-6 Alkyl, hetercycloalkyl, and heteroaryl are each optionally and independently substituted with one or more R" substituents; or two R3 substituents, together with the ring A to which they are attached, form a fused bicyclic heterocycloalkyl, a fused bicyclic cycloalkyl, a fused bicyclic aryl, or a fused bicyclic heteroaryl, each of which is optionally and independently substituted with one or more R" substituents; Each R4 is halo, OH, NH2, CN, C 1-6 Alkyl and OC 1-6 alkyl, Each R5 is selected from hydrogen, halo, OH, NH2, CN, and C 1-6 alkyl, Each R' is independently hydrogen, OH, CN, C 1-6 selected from alkyl, cycloalkyl, hetercycloalkyl, aryl, and heteroaryl, each of which is optionally and independently substituted with one or more R″ substituents; Each R” is independently 1-6 Alkyl, cycloalkyl, hetercycloalkyl, aryl, heteroaryl, OC 1-6 Alkyl, oxo, OH, halo, CN, NH2, NHC 1-6 Alkyl, N(C 1-6 alkyl)2, C(O)C 1-6 Alkyl, C(O)OC 1-6 Alkyl, C(O)NH2, C(O)NHC 1-6 Alkyl, and C(O)N(C 1-6 alkyl)2, each C 1-6Alkyl, cycloalkyl, hetercycloalkyl, aryl, and heteroaryl are optionally and independently selected from halo, oxo, alkoxy, CN, NH, C(O)C 1-6 Alkyl, C(O)OC 1-6 Alkyl, and C(O)NHC 1-6 substituted with one or more substituents selected from alkyl, m, n, and p are each an integer selected from 0 to 4.

[0008] In another aspect, the present disclosure includes a pharmaceutical composition comprising a compound or salt according to Formula (I) described herein and a pharma- ceutically acceptable excipient.

[0009] In another aspect, the disclosure includes a method of modulating EGFR and / or PI3K enzyme activity in a biological sample, the method comprising contacting the biological sample with a compound, salt, or composition described herein.

[0010] In another aspect, the disclosure includes a method of preventing or treating an EGFR and / or PI3K mediated disease in a subject, the method comprising administering to the subject a compound, salt, or composition described herein.

[0011] In one embodiment of this aspect, the EGFR and / or PI3K mediated disease is cancer. [Brief description of the drawings]

[0012] [Figure 1] 1 is a line graph showing a therapeutic index study of Compound 2R at 25 mg / Kg, 50 mg / Kg, and 100 mg / Kg versus control for the mean tumor burden of the test groups against the human squamous head and neck cancer model CAL-33. [Diagram 2] 1 is a line graph showing a therapeutic index study of Compound 2R at 10 mg / Kg and 100 mg / Kg versus control for the mean tumor burden of the test groups against the human squamous head and neck cancer model CAL-27. [Diagram 3]1 is a line graph showing an efficacy study of compound 2R at 100 mg / Kg versus control for mean tumor burden of test groups against the human triple-negative breast cancer model HCC-70. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] The present disclosure provides methods for preventing, treating, reducing, inhibiting, or controlling the establishment of a neoplasm, tumor, or cancer, and / or metastasis in a subject comprising administering a compound of formula I or a pharma- ceutically acceptable salt thereof.

[0014] For purposes of this disclosure, the chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 98th Ed. In addition, general principles of organic chemistry are described in "Organic Chemistry", Second Ed., Thomas Sorrell, University Science Books, Sausolito: 2006, and "March's Advanced Organic Chemistry", 7th Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2015, the contents of which are incorporated herein by reference in their entireties.

[0015] definition As used herein, "about" means within an acceptable error range for a particular value as determined by one of ordinary skill in the art, which depends in part on the method of measuring or determining the value, i.e., the limitations of the measurement system. For example, "about" can mean within 1 or more than 1 standard deviation, as is customary in the art. Alternatively, "about" can mean a range of up to 20%. When a particular value is provided in this application and claims, unless otherwise stated, the meaning of "about" should be considered to be within an acceptable error range for that particular value.

[0016] As used herein, "effective amount" is defined as the amount required to give a therapeutic effect to the treated patient, and is typically determined based on the age, surface area, weight, and condition of the patient. The interrelationship of dosages for animals and humans (based on milligrams per square meter of body surface area) is described in Freireich et al., Cancer Chemother.Rep., 50:219 (1966). Body surface area can be approximately determined from the height and weight of the patient. See, for example, Scientific Tables, Geigy Pharmaceuticals, Ardsley, New York, 537 (1970). As used herein, "patient" refers to a mammal, including a human.

[0017] The term "pharmaceutical acceptable salt" as used herein refers to any salt (e.g., obtained by reaction with an acid or base) of the compounds of the present disclosure that is physiologically tolerated in the target patient (e.g., a mammal). The salts of the compounds of the present disclosure may be derived from inorganic or organic acids and bases. Examples of acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, ethanesulfonic acid, formic acid, benzoic acid, malonic acid, sulfonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, and the like. Other acids, such as oxalic acid, while not themselves pharmaceutical acceptable, may be used in the preparation of salts useful as intermediates in obtaining the compounds of the present disclosure and their pharmaceutical acceptable acid addition salts.

[0018] As used herein, a "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial, antifungal), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, gels, binders, excipients, disintegrants, lubricants, sweeteners, flavorings, dyes, such materials, and combinations thereof, as would be known to one of skill in the art (see, e.g., Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329).

[0019] As used herein, "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any material that, when combined with an active ingredient, allows the ingredient to retain biological activity and is non-reactive with the subject's immune system, and may include any and all solvents, diluents, carriers, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc. that are physiologically compatible, non-toxic, and do not interfere with the mechanism of action of the compound of formula I or its pharmaceutically acceptable salt. Preferably, the pharmaceutically acceptable excipient is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal, or epidermal administration (e.g., by injection or infusion). Depending on the route of administration, the compound of formula I or its pharmaceutically acceptable salt may be coated with a material to protect the compound from the action of acids and other natural conditions that may inactivate the compound. Pharmaceutically acceptable excipients include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. The use of such media and agents for pharma- ceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, its use in the pharmaceutical compositions of the present disclosure is contemplated. Supplementary active compounds can also be incorporated into the compositions.

[0020] The phrase "stable or chemically feasible" as used herein refers to a compound that is substantially unchanged when subjected to conditions that allow for production, detection, and preferably recovery, purification, and use for one or more purposes disclosed herein. In some embodiments, a stable compound or chemically feasible compound is a compound that is substantially unchanged when maintained at a temperature of 40° C. or less in the absence of moisture or other chemically reactive conditions for at least one week.

[0021] The therapeutic methods of the present disclosure include administering a safe and effective amount of a compound described herein, or a pharma- ceutically acceptable salt thereof, to a patient in need thereof.

[0022] As used herein, the term "subject" is intended to include humans and non-human animals. Preferred subjects include human patients who need enhanced immune response, which may be beneficial for treating and / or preventing cancer and / or cancer metastasis in the patient. The method is particularly suitable for treating human patients with disorders that can be treated by enhancing T cell-mediated immune response. In certain embodiments, the method is particularly suitable for treating cancer cells in vivo.

[0023] "Such as" has the same meaning as "such as, but not limited to." Similarly, "include" has the same meaning as "including, but not limited to," and "including" has the same meaning as "including, but not limited to."

[0024] The terms "tumor," "cancer," and "neoplasm" are used interchangeably and refer to a cell or population of cells whose growth, proliferation, or survival exceeds that of normal corresponding cells, e.g., a cell proliferative or differentiative disorder. Typically, the growth is uncontrolled. The term "malignant tumor" refers to the invasion of nearby tissues. The term "metastasis" refers to the spread or dissemination of a tumor, cancer, or neoplasm to other sites, locations, or regions within a subject, which sites, locations, or regions are distinct from the primary tumor or cancer.

[0025] As used herein, an "alkyl" group refers to a saturated aliphatic hydrocarbon group containing 1 to 12 (e.g., 1 to 8, 1 to 6, or 1 to 4) carbon atoms. The 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.

[0026] As used herein, an "alkenyl" group refers to an aliphatic carbon group containing 2 to 8 (e.g., 2 to 12, 2 to 6, or 2 to 4) carbon atoms and at least one double bond. Like an alkyl group, an alkenyl group can be linear or branched. Examples of alkenyl groups include, but are not limited to, allyl, isoprenyl, 2-butenyl, and 2-hexenyl.

[0027] As used herein, an "alkynyl" group refers to an aliphatic carbon group containing 2 to 8 (e.g., 2 to 12, 2 to 6, or 2 to 4) carbon atoms and having at least one triple bond. Alkynyl groups can be linear or branched. Examples of alkynyl groups include, but are not limited to, propargyl and butynyl.

[0028] As used herein, an "alkylene" group refers to a divalent alkyl group that simultaneously connects two points of attachment, where the alkylene unit may be divalent on the same carbon or on two different carbons of the alkyl portion. Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, and butylene, as well as branched structures such as -CH2(CH2)-(1,1-ethylene) and -CH2CH2(CH2)-(1,2-propylene).

[0029] As used herein, an "aryl" group refers to a monocyclic, bicyclic, or tricyclic ring system in which all rings in the system are aromatic and do not contain heteroatoms in the rings. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and tetracenyl.

[0030] As used herein, a "carbocycle" or "carbocyclyl" group refers to a monocyclic, bicyclic, or tricyclic (fused or bridged) hydrocarbon ring system that does not contain heteroatoms in the ring structure, and at least one of the rings of the system is non-aromatic and can be fully saturated or partially unsaturated. The term "carbocycle" or "carbocyclyl" encompasses "cycloalkyl" and "cycloalkenyl" groups, each of which are described below.

[0031] As used herein, a "cycloalkyl" group refers to a saturated carbocyclic monocyclic, bicyclic, or tricyclic (fused or bridged) ring system of 3 to 20 (e.g., 5 to 10) carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, norbornyl, 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.

[0032] A "cycloalkenyl" group, as used herein, refers to a non-aromatic carbocyclic monocyclic, bicyclic, or tricyclic (fused or bridged) ring system of 3 to 20 (e.g., 4 to 8) carbon atoms, in which at least one ring of the system has one or more double bonds. Examples of cycloalkenyl groups include cyclopentenyl, 1,4-cyclohexa-di-enyl, cycloheptenyl, cyclooctenyl, hexahydro-indenyl, octahydro-naphthyl, cyclohexenyl, cyclopentenyl, bicyclo[2.2.2]octenyl, or bicyclo[3.3.1]nonenyl.

[0033] As used herein, the terms "heterocycle" and "heterocyclyl" are used interchangeably and refer to a monocyclic, bicyclic, or tricyclic (fused or bridged) non-aromatic hydrocarbon ring system that contains at least one heteroatom in the ring structure and may be fully saturated or partially unsaturated. The terms "heterocycle" and "heterocyclyl" encompass "heterocycloalkyl" and "heterocycloalkenyl" groups, each of which are described below.

[0034] As used herein, a "heterocycloalkyl" group refers to a 3- to 20-membered monocyclic, bicyclic, or tricyclic (fused or bridged) (e.g., 5-10 membered) 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 heterocycloalkyl groups 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[b]thiopheneyl, 2-oxa-bicyclo[2.2.2]octyl, 1-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.

[0035] A "heterocycloalkenyl" group, as used herein, refers to a 3- to 20-membered monocyclic, bicyclic, or tricyclic (fused or bridged) (e.g., 5-10 membered) non-aromatic ring structure in which one or more of the ring atoms is a heteroatom (e.g., N, O, S, or combinations thereof) and at least one of the ring structures has one or more double bonds.

[0036] A "heteroaryl" group, as used herein, refers to a monocyclic, bicyclic, or tricyclic ring system having 4 to 15 ring atoms, where one or more of the ring atoms is a heteroatom (e.g., N, O, S, or a combination thereof) and the monocyclic ring system is aromatic, or at least one of the rings in a bicyclic or tricyclic ring system is aromatic. Heteroaryl groups include benzo-fused ring systems having 2 to 3 rings. For example, benzo-fused groups include benzo (e.g., indolyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furyl, benzo[b]thiophenyl, quinolinyl, or isoquinolinyl) fused with one or two 4-8 membered heterocycloaliphatic moieties. Some examples of heteroaryl are azetidinyl, pyridyl, 1H-indazolyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl, benzofuryl, isoquinolinyl, benzothiazolyl, xanthene, thioxanthene, phenothiazine, dihydroindole, benzo[1,3]dioxole, benzo[b]furyl, benzo[b]thiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, puryl, cinnolyl, quinolyl, quinazolyl, cinnolyl, phthalazyl, quinazolyl, quinoxalyl, isoquinolyl, 4H-quinolidyl, benzo-1,2,5-thiadiazolyl, or 1,8-naphthyridyl.

[0037] Monocyclic heteroaryls include, but are not limited to, furyl, thiophenyl, 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.

[0038] Bicyclic heteroaryls include, but are not limited to, indolyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furyl, benzo[b]thiophenyl, quinolinyl, isoquinolinyl, indolizinyl, isoindolyl, indolyl, benzo[b]furyl, bexo[b]thiophenyl, indazolyl, benzimidazyl, benzthiazolyl, purinyl, 4H-quinolyl, quinolyl, isoquinolyl, cinnolyl, phthalazyl, quinazolyl, quinoxalyl, 1,8-naphthyridyl, or pteridyl.

[0039] As used herein, "cyclic moiety" and "cyclic group" refer to monocyclic, bicyclic, and tricyclic ring systems, including cycloaliphatic, heterocycloaliphatic, aryl, or heteroaryl, each of which is defined above.

[0040] As used herein, "bridged bicyclic ring system" refers to a bicyclic heterocyclic aliphatic ring system or a bicyclic aliphatic ring system in which the rings are bridged. Examples of bridged bicyclic ring systems include, but are not limited to, adamantanyl, norbornanyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.2.3]nonyl, 2-oxabicyclo[2.2.2]octyl, 1-azabicyclo[2.2.2]octyl, 3-azabicyclo[3.2.1]octyl, and 2,6-dioxa-tricyclo[3.3.1.0.3.7]nonyl.

[0041] As used herein, an "alkoxy" group refers to an alkyl-O- group, where "alkyl" is defined above.

[0042] As used herein, "carbonyl" refers to --C(O)--.

[0043] As used herein, "oxo" refers to =O.

[0044] As used herein, "carboxy" refers to --C(O)OH.

[0045] As used herein, an "ester" refers to -C(O)OW, where W is, for example, alkyl, carbocyclyl, or heterocyclyl.

[0046] The compounds of the present disclosure described herein can be optionally substituted with one or more substituents as indicated generally herein or as exemplified by particular classes, subclasses, and species of the present disclosure.

[0047] The phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted." The compounds of the present disclosure described herein can be optionally substituted with one or more substituents as exemplified by the particular classes, subclasses, and species of the present disclosure.

[0048] In general, the term "substituted", whether preceded by the term "optionally" or not, refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents may be the same or different at all positions. A ring substituent, such as a heterocycloalkyl, may be bonded 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 would recognize, the combinations of substituents contemplated by this disclosure are those that result in the formation of a stable or chemically feasible compound.

[0049] As used herein, "treating" when referring to a condition means (1) improving or preventing the condition or one or more of the biological signs of the condition, (2) (a) interfering with one or more points in the biological cascade that leads to or causes the condition, or (b) one or more of the biological signs of the condition, (3) alleviating one or more of the symptoms or effects associated with the condition, or (4) slowing the progression of the condition or one or more of the biological signs of the condition. Those skilled in the art will understand that "prevention" is not an absolute term. In medicine, "prevention" is understood to refer to the prophylactic administration of a drug that substantially reduces the likelihood or severity of a condition or its biological signs, or delays the onset of such a condition or its biological signs.

[0050] Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. Examples of isotopes that may be incorporated into the compounds of the present disclosure and their pharma- ceutically acceptable salts include, but are not limited to, 2 H, 3 H, 11 C. 13 C. 14 C. 15 N, 17 0, 18 0, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 Included are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as I.

[0051] Compounds of the present disclosure and pharma- ceutically acceptable salts of said compounds that contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present disclosure. Isotopically labeled compounds of the present disclosure, e.g., 3 H and 14Incorporating a radioactive isotope, such as C, is useful in drug and / or substrate tissue distribution assays. 3 H) and carbon-14 ( 14 C) Isotopes are particularly preferred for their ease of preparation and detectability. 11 C and 18 The F isotope is particularly useful in PET (positron emission tomography), 125 The 1 isotope is particularly useful in SPECT (single photon emission computed tomography), all of which are useful in brain imaging. 2 Substitution with heavier isotopes, such as H, can provide certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life, or reduced dosage requirements, and may be preferred in some circumstances. Isotopically labeled compounds of the present disclosure can generally be prepared by following the procedures disclosed in the following schemes and / or examples, substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0052] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure. "Isomers" refer to compounds having identical composition and molecular weight but different physical and / or chemical properties, such as (Z) and (E) double bond isomers, and (Z) and (E) stereoisomers. The structural difference may be in the configuration (geometric isomers) or the ability to rotate the plane of polarized light (stereoisomers), such as the R and S configurations of each asymmetric center. Compounds of the present disclosure may contain one or more asymmetric centers, also referred to as chiral centers, and therefore may exist as individual enantiomers, diastereomers, or other stereoisomeric forms, or as mixtures thereof. All such isomeric forms, including mixtures thereof, are included within the present disclosure. Chiral centers may also be present in substituents such as alkyl groups.

[0053] When the stereochemistry of a chiral center present in the compounds of the present disclosure, or in any chemical structure depicted herein, is not specified, the structure is intended to encompass any stereoisomers and all mixtures thereof. Thus, compounds of the present disclosure that contain one or more chiral centers can be used as racemic mixtures, enantiomerically enriched mixtures, or enantiomerically pure individual stereoisomers.

[0054] Individual stereoisomers of the compounds of the present disclosure that contain one or more asymmetric centers can be resolved by methods known to those skilled in the art. For example, such resolution can be carried out by (1) formation of diastereoisomeric salts, complexes, or other derivatives, (2) selective reaction with stereoisomer-specific reagents, for example, by enzymatic oxidation or reduction, or (3) by gas-liquid or liquid chromatography in a chiral environment, for example, on a chiral support such as silica with a chiral ligand attached, or in the presence of a chiral solvent. Those skilled in the art will understand that if the desired stereoisomer is converted to another chemical entity by one of the above separation procedures, further steps are required to liberate the desired form. Alternatively, a particular stereoisomer can be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts, or solvents, or by converting one enantiomer to the other by asymmetric transformation.

[0055] Unless otherwise stated, all tautomeric forms of the compounds of the present disclosure are within the scope of the present disclosure.

[0056] Any numerical range disclosed herein includes the upper and lower limits and each intervening value unless otherwise specified. Except in the examples or where otherwise indicated, numerical values ​​used in the specification and claims (e.g., numerical values ​​expressing amounts of ingredients, reaction conditions) are modified by the term "about". Thus, unless indicated to the contrary, such numerical values ​​are approximations that may vary depending on the desired properties sought to be obtained. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should be construed in light of the number of significant digits and ordinary rounding techniques.

[0057] Notwithstanding that the numerical parameters setting forth the range of the disclosed subject matter are approximations, the numerical values ​​set forth in the examples are reported as precisely as possible, however, any numerical values ​​contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

[0058] Unless otherwise defined, the meanings of technical and scientific terms used herein are those commonly understood by one of ordinary skill in the art to which the disclosed subject matter belongs.

[0059] Embodiment In one aspect, the present disclosure provides a compound of formula I [ka] or a pharma- ceutically acceptable salt or solvate thereof, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof, wherein: Ring A is selected from phenyl, or 5- or 6-membered heteroaryl; X is N or C-R5; R 1a But H or C 1-6 is selected from the group consisting of alkyl, R 1b But, C 1-6is selected from the group consisting of alkyl, cycloalkyl, hetercycloalkyl, aryl, heteroaryl, OR', N(R')2, C(O)R', C(O)OR', C(O)N(R')2, halo, CN, and NO2; 1-6 The alkyl, cycloalkyl, hetercycloalkyl, aryl, or heteroaryl are optionally and independently substituted with one or more R" substituents; or R 1a and R 1b together with the methylene moiety to which they are attached, C 3-7 forming a spirocyclic ring selected from cycloalkyl or 3-7 membered heterocycloalkyl, each of which is optionally and independently substituted with one or more R″ substituents; Each R2 is independently halo, OH, C 1-6 Alkyl, haloalkyl, OC 1-6 Alkyl, CN, NH2, NHC 1-6 Alkyl, N(C 1-6 alkyl)2, C(O)C 1-6 Alkyl, C(O)OC 1-6 Alkyl, C(O)NH2, C(O)NHC 1-6 Alkyl, and C(O)N(C 1-6 alkyl)2; or one R2 substituent and R 1b The phenyl group to which R2 is bonded and R 1b Together with the carbon atom to which it is attached, they form the general structure [ka] and ring B is a bicyclic group having the formula 3-7 cycloalkyl or 4-7 membered heterocycloalkyl, each of which is optionally selected from halo, OH, C 1-6 Alkyl, haloalkyl, OC 1-6 Alkyl, CN, NH2, NHC 1-6 Alkyl, N(C 1-6 alkyl)2, C(O)C 1-6 Alkyl, C(O)OC 1-6 Alkyl, C(O)NH2, C(O)NHC1-6 Alkyl, and C(O)N(C 1-6 substituted with one or more substituents independently selected from Each R3 is independently selected from the group consisting of C 1-6 is selected from alkyl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, halo, CN, NO2, OR', N(R')2, C(O)R', C(O)OR', C(O)N(R')2, OC(O)OR', OC(O)N(R')2, NR'C(O)N(R')2, SOR', SON(R')2, SO2R', SON(R')2, NR'SOR', NR'SON(R')2, NR'SOR', NR'SON(R')2, NR'SOR', and NR'SON(R')2; 1-6 Alkyl, hetercycloalkyl, and heteroaryl are each optionally and independently substituted with one or more R" substituents; or two R3 substituents, together with the ring A to which they are attached, form a fused bicyclic heterocycloalkyl, a fused bicyclic cycloalkyl, a fused bicyclic aryl, or a fused bicyclic heteroaryl, each of which is optionally and independently substituted with one or more R" substituents; Each R4 is halo, OH, NH2, CN, C 1-6 Alkyl and OC 1-6 alkyl, Each R5 is selected from hydrogen, halo, OH, NH2, CN, and C 1-6 alkyl, Each R' is independently hydrogen, OH, CN, C 1-6 selected from alkyl, cycloalkyl, hetercycloalkyl, aryl, and heteroaryl, each of which is optionally and independently substituted with one or more R″ substituents; Each R” is independently 1-6 Alkyl, cycloalkyl, hetercycloalkyl, aryl, heteroaryl, OC 1-6 Alkyl, oxo, OH, halo, CN, NH2, NHC 1-6 Alkyl, N(C 1-6 alkyl)2, C(O)C 1-6 Alkyl, C(O)OC 1-6Alkyl, C(O)NH2, C(O)NHC 1-6 Alkyl, and C(O)N(C 1-6 alkyl)2, each C 1-6 Alkyl, cycloalkyl, hetercycloalkyl, aryl, and heteroaryl are optionally and independently selected from halo, oxo, alkoxy, CN, NH, C(O)C 1-6 Alkyl, C(O)OC 1-6 Alkyl, and C(O)NHC 1-6 substituted with one or more substituents selected from alkyl, m, n, and p are each an integer selected from 0 to 4.

[0060] In one embodiment, R 1a is H.

[0061] In another embodiment, R 1b is C 1-6 Alkyl, cycloalkyl, hetercycloalkyl, aryl, heteroaryl, OC 1-6 Alkyl, OH, NH2, NHC 1-6 Alkyl, N(C 1-6 alkyl)2, C(O)C 1-6 Alkyl, C(O)OC 1-6 Alkyl, C(O)NH2, C(O)NHC 1-6 Alkyl, C(O)N(C 1-6 alkyl), halo, CN, or NO, each C 1-6 Alkyl, cycloalkyl, hetercycloalkyl, aryl, or heteroaryl may optionally and independently be selected from the group consisting of O-C 1-6 Alkyl, oxo, OH, halo, CN, NH2, NHC 1-6 Alkyl, N(C 1-6 alkyl)2, C(O)C 1-6 Alkyl, C(O)OC 1-6 Alkyl, C(O)NH2, C(O)NHC 1-6 Alkyl, C(O)N(C 1-6 Alkyl)2 is substituted.

[0062] In another embodiment, R1b is C 1-6 Alkyl, OC 1-6 Alkyl, OH, NH2, NHC 1-6 Alkyl, N(C 1-6 alkyl)2, C(O)C 1-6 Alkyl, C(O)NH2, C(O)NHC 1-6 Alkyl, C(O)N(C 1-6 alkyl), halo, or CN, each C 1-6 Alkyl is optionally and independently selected from O-C 1-6 Substituted with alkyl, OH, halo, or CN.

[0063] In a further embodiment, R 1b is C 1-6 Alkyl, OC 1-6 alkyl, OH, halo, or CN, each C 1-6 The alkyl is optionally and independently substituted with OH, CN, or halo.

[0064] In still further embodiments, R 1b is C 1-6 Alkyl, C 1-6 Alkyl-OH or CN.

[0065] In still further embodiments, R 1b is methyl, CN, or CH2OH.

[0066] In another embodiment, R 1a and R 1b together with the methylene moieties to which they are attached, 3-7 cycloalkyl or 3- to 7-membered heterocycloalkyl, each of which optionally and independently represents a spirocyclic ring selected from C 1-6 Alkyl, OC 1-6 Alkyl, oxo, OH, halo, CN, C(O)C 1-6 Alkyl, C(O)OC 1-6 Alkyl, C(O)NH2, C(O)NHC 1-6 Alkyl, or C(O)N(C 1-6 alkyl)2, each C 1-6The alkyl is optionally and independently substituted with one or more substituents selected from halo, alkoxy, CN, or NH2.

[0067] In another embodiment, R 1a and R 1b together with the methylene moieties to which they are attached, 3-7 Forms a spirocyclic ring selected from cycloalkyl or 3-7 membered heterocycloalkyl, each of which is optionally and independently substituted with oxo, OH, halo, or CN.

[0068] In a further embodiment, R 1a and R 1b together with the methylene moieties to which they are attached, 3-7 It forms an unsubstituted spirocyclic ring selected from cycloalkyl or 3- to 7-membered heterocycloalkyl.

[0069] In still further embodiments, R 1a and R 1b together with the methylene moieties to which they are attached, [ka] Form.

[0070] In another embodiment, each R2 substituent is independently selected from halo, OH, C 1-6 Alkyl, haloalkyl, OC 1-6 Alkyl, CN, NH2, C(O)C 1-6 alkyl, and C(O)NH2.

[0071] In a further embodiment, each R2 substituent is independently selected from halo and OH.

[0072] In one embodiment, n is 0 or 1.

[0073] In a further embodiment, n is 0.

[0074] In one embodiment, one R2 substituent and R 1b represents the phenyl group to which R2 is bonded and R 1b Together with the carbon atom to which it is attached, they form the general structure [ka] and ring B is a bicyclic group having the formula 3-7 cycloalkyl or 4-7 membered heterocycloalkyl, each of which is optionally selected from halo, OH, C 1-6 Alkyl, haloalkyl, OC 1-6 Alkyl, CN, NH2, C(O)C 1-6 Alkyl, C(O)OC 1-6 substituted with one or more substituents independently selected from alkyl, C(O)NH2, or C(O)NH2.

[0075] In one embodiment, ring B is C 4-6 cycloalkyl or 4-6 membered heterocycloalkyl, each of which is optionally selected from halo, OH, OC 1-6 Alkyl, CN, or NH2, C(O)C 1-6 Substituted with one or more substituents independently selected from alkyl.

[0076] In a further embodiment, ring B is C 4-5 cycloalkyl or 5-membered heterocycloalkyl, each of which is optionally substituted with OH.

[0077] In another embodiment, the general structure [ka] teeth, [ka] is selected from.

[0078] In one embodiment, each R is independently C 1-6 Alkyl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, halo, CN, NO2, OH, OC1-6 Alkyl, N(C 1-6 alkyl)2, NH(C 1-6 alkyl), NH2, C(O)H, C(O)C 1-6 Alkyl, COOH, C(O)OC 1-6 Alkyl, C(O)NH2, C(O)NH(C 1-6 alkyl), C(O)NH(C 3-6 Cycloalkyl), C(O)NH(CN), C(O)NH(OH), C(O)N(C 1-6 alkyl)(OH), C(O)N(C 1-6 Alkyl)2, OC(O)OC 1-6 Alkyl, OC(O)NH2, OC(O)NH(C 1-6 alkyl), OC(O)N(C 1-6 alkyl)2, NHC(O)NH2, NHC(O)NH(C 1-6 alkyl), NHC(O)N(C 1-6 Alkyl)2, N(C 1-6 alkyl)C(O)NH2, N(C 1-6 Alkyl)C(O)NH(C 1-6 alkyl), N(C 1-6 Alkyl)C(O)N(C 1-6 Alkyl)2, SO(C 1-6 alkyl), SONH2, SONH(C 1-6 alkyl), SON(C 1-6 Alkyl)2, SO2(C 1-6 alkyl), SO2NH2, SO2NH(C 1-6 alkyl), SO2N(C 1-6 Alkyl)2, N(C 1-6 Alkyl)SO(C 1-6 alkyl), NHSO(C 1-6 alkyl), N(C 1-6 Alkyl)SO2(C 1-6 alkyl), NHSO2(C 1-6 alkyl), NHSO2NH2, NHSO2NH(C 1-6 alkyl), NHSO2N(C 1-6 Alkyl)2, N(C 1-6 Alkyl)SO2NH2, N(C 1-6 Alkyl)SO2NH(C 1-6 alkyl), and N(C1-6 Alkyl)SO2N(C 1-6 alkyl)2, each C 1-6 Alkyl, heteroaryl, and heterocycloalkyl are each optionally and independently substituted with one or more R″ substituents.

[0079] In another embodiment, each R is independently C 1-6 Alkyl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, halo, CN, NO2, OH, OC 1-6 Alkyl, N(C 1-6 alkyl)2, NH(C 1-6 alkyl), NH2, C(O)H, C(O)C 1-6 Alkyl, COOH, C(O)OC 1-6 Alkyl, C(O)NH2, C(O)NH(C 1-6 alkyl), C(O)NH(C 3-6 Cycloalkyl), C(O)NH(CN), C(O)NH(OH), C(O)N(C 1-6 alkyl)(OH), C(O)N(C 1-6 Alkyl)2, OC(O)OC 1-6 Alkyl, OC(O)NH2, OC(O)NH(C 1-6 alkyl), OC(O)N(C 1-6 alkyl)2, NHC(O)NH2, NHC(O)NH(C 1-6 alkyl), NHC(O)N(C 1-6 Alkyl)2, N(C 1-6 alkyl)C(O)NH2, N(C 1-6 Alkyl)C(O)NH(C 1-6 alkyl), N(C 1-6 Alkyl)C(O)N(C 1-6 Alkyl)2, SO2(C 1-6 alkyl), SO2NH2, SO2NH(C 1-6 alkyl), SO2N(C 1-6 alkyl)2, NHSO2(C 1-6 alkyl), N(C 1-6 Alkyl)SO2(C 1-6 alkyl), NHSO2NH2, NHSO2NH(C 1-6 alkyl), NHSO2N(C1-6 Alkyl)2, N(C 1-6 Alkyl)SO2NH2, N(C 1-6 Alkyl)SO2NH(C 1-6 alkyl), and N(C 1-6 Alkyl)SO2N(C 1-6 alkyl)2, each C 1-6 Alkyl, heteroaryl, and heterocycloalkyl are each optionally and independently substituted with one or more R″ substituents.

[0080] In one embodiment, each R is independently C 1-6 Alkyl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, halo, CN, OH, OC 1-6 Alkyl, NH2, C(O)H, C(O)NH2, C(O)NH(C 1-6 alkyl), C(O)NH(C 3-6 Cycloalkyl), C(O)NH(CN), C(O)NH(OH), C(O)N(C 1-6 alkyl)(OH), C(O)N(C 1-6 alkyl)2, NHC(O)NH2, NHC(O)NH(C 1-6 alkyl), NHC(O)N(C 1-6 Alkyl)2, N(C 1-6 alkyl)C(O)NH2, N(C 1-6 Alkyl)C(O)NH(C 1-6 alkyl), N(C 1-6 Alkyl)C(O)N(C 1-6 Alkyl)2, SO2(C 1-6 alkyl), SO2NH2, SO2NH(C 1-6 alkyl), SO2N(C 1-6 Alkyl)2, N(C 1-6 Alkyl)SO2(C 1-6 alkyl), NHSO2(C 1-6 alkyl), NHSO2NH2, NHSO2NH(C 1-6 alkyl), NHSO2N(C 1-6 alkyl)2, each C 1-6Alkyl, heteroaryl, and heterocycloalkyl are each optionally and independently substituted with one or more R″ substituents.

[0081] In another embodiment, each R is independently C 1-6 Alkyl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, halo, CN, OH, OC 1-6 Alkyl, NH2, C(O)H, C(O)NH2, C(O)NH(C 1-6 alkyl), C(O)NH(C 3-6 Cycloalkyl), C(O)NH(CN), C(O)NH(OH), C(O)N(C 1-6 alkyl)(OH), C(O)N(C 1-6 alkyl)2, NHC(O)NH(C 1-6 alkyl), SO2(C 1-6 alkyl), NHSO2(C 1-6 alkyl), each C 1-6 Alkyl, heteroaryl, and heterocycloalkyl are each optionally and independently substituted with one or more R″ substituents.

[0082] In further embodiments, each R is independently C 1-6 Alkyl, triazolyl, oxadiazolyl, halo, CN, OH, OC 1-6 Alkyl, NH2, C(O)H, C(O)NH2, C(O)NH(C 1-6 alkyl), C(O)NH(C 3-6 Cycloalkyl), C(O)NH(CN), C(O)NH(OH), C(O)N(C 1-6 alkyl)(OH), C(O)N(C 1-6 alkyl)2, NHC(O)NH(C 1-6 alkyl), SO2(C 1-6 alkyl), NHSO2(C 1-6 alkyl), each C 1-6 Alkyl, triazolyl, and oxadiazolyl are each optionally and independently selected from oxo, OH, halo, C 1-6 Alkyl, NH2, NHC 1-6 Alkyl, and N(C 1-6and substituted with one or more substituents independently selected from:

[0083] In still further embodiments, each R3 substituent is independently selected from halo, CN, NH2, OH, C(O)H, C(O)N(CH3)2, C(O)NH(CH3), C(O)NH(Et), C(O)NH(isopropyl), C(O)NH(tert-butyl), C(O)NH(cyclopropyl), C(O)NCH3(CN), C(O)NH(OH), C(O)NCH3(OH), C(O)NH2, NHC(O)NHCH3, NHS(O)2CH3, S(O)2CH3, methyl, methoxy, NHS(O)2CH2CH2N(CH3)2, CF3, CH2OH, C(CH3)2OH, [ka] is selected from.

[0084] In one embodiment, the compound of formula I is a compound of formula Ia [ka] or a pharma- ceutically acceptable salt or solvate thereof, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; wherein each X' is independently CH, C-R3, or N.

[0085] In one embodiment, the ring [ka] is phenyl, pyridyl, pyrimidyl, pyrazyl, or triazyl, optionally substituted by R3.

[0086] In a further embodiment, the ring [ka] teeth, [ka] It is.

[0087] In one embodiment, p is 0, 1, or 2.

[0088] In a further embodiment, p is 1 or 2.

[0089] In another further embodiment, the ring [ka] teeth, [ka] [ka] is selected from.

[0090] In one embodiment, two R3 substituents, together with the ring A to which they are attached, form a fused bicyclic heteroaryl, optionally and independently substituted with one or more R" substituents.

[0091] In a further embodiment, two R3 substituents, together with the ring A to which they are attached, form a fused bicyclic heteroaryl, optionally and independently, C 1-6 Alkyl, halo, OH, OC 1-6 Alkyl, oxo, CN, NH2, NH(C 1-6 alkyl), and N(C 1-6 and substituted with one or more substituents independently selected from:

[0092] In still further embodiments, two R3 substituents, together with the ring A to which they are attached, form a fused bicyclic heteroaryl, optionally and independently, C 1-6 Substituted with one or more substituents independently selected from alkyl, oxo, and NH2.

[0093] In one embodiment, the compound of formula I is a compound of formula Ib [ka] or a pharma- ceutically acceptable salt or solvate thereof, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; During the ceremony, Ring C is phenyl, a 5- to 6-membered heteroaryl, or a 5- to 6-membered heterocyclic ring; X' is CH, CR'', or N.

[0094] In one embodiment, ring C of formula Ib is a phenyl ring.

[0095] In one embodiment, ring C of formula Ib is a 5-membered heteroaryl or a 5-membered heterocyclic ring.

[0096] In further embodiments, ring C of formula Ib is pyrrole, pyrazole, imidazole, triazole, oxazole, hydrofuran, dihydrofuran, hydropyrrole, dihydropyrrole, hydroimidazole, dihydroimidazole, hydrooxazole, dihydrooxazole, or [ka] It is.

[0097] In one embodiment, the compound of formula I is a compound of formula Ic-1, formula Ic-2, or formula Ic-3: [ka] or a pharma- ceutically acceptable salt or solvate thereof, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; wherein each X' is independently CH or N.

[0098] In another embodiment, the ring of formula Ic-1 [ka] teeth, [ka] It is.

[0099] In another embodiment, the ring of formula Ic-2 [ka] teeth, [ka] It is.

[0100] In another embodiment, the ring of formula Ic-3 [ka] teeth, [ka] It is.

[0101] In a further embodiment, ring A is [ka] is a bicyclic group selected from

[0102] In one embodiment, m is 0.

[0103] In another embodiment, X is N.

[0104] In another embodiment, X is CH or C-CN.

[0105] In a further embodiment, X is C-CN.

[0106] In another aspect, the disclosure includes a pharmaceutical composition comprising a compound of Formula I, Ia, Ib, Ic-1, Ic-2, or Ic-3 as described herein, or a pharma- ceutically acceptable salt or solvate thereof, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof, and a pharma- ceutically acceptable excipient.

[0107] In another aspect, the disclosure includes a method of modulating EGFR and / or PI3K enzyme activity in a biological sample, the method comprising contacting the biological sample with a compound, salt, or composition described herein.

[0108] In another aspect, the disclosure includes a method of preventing or treating an EGFR and / or PI3K mediated disease in a subject, the method comprising administering to the subject a compound, salt, or composition described herein.

[0109] In one embodiment, the EGFR and / or PI3K mediated disease is cancer.

[0110] In further embodiments, the cancer is selected from the group consisting of neoplasms, giant cell and spindle cell carcinomas; small cell carcinomas; papillary carcinomas; squamous cell carcinomas; lymphoepithelial carcinomas; basal cell carcinomas; pilomatrix carcinomas; transitional cell carcinomas; papillary transitional cell carcinomas; adenocarcinomas, gastrinomas, cholangiocarcinomas, hepatocellular carcinomas; hepatocellular carcinomas and cholangiocarcinomas in combination, trabecular adenocarcinomas, adenoid cystic carcinomas; adenocarcinomas in adenomatous polyps; adenocarcinomas, familial adenomatous polyposis, solid carcinomas; carcinoid tumors, bronchioloalveolar adenocarcinomas, papillary adenocarcinomas, chromophobe carcinomas; acidophilic carcinomas; acidophilic adenocarcinomas, basophilic carcinomas; clear cell adenocarcinomas, granular cell carcinomas; follicular adenocarcinomas. , papillary and follicular adenocarcinoma, nonencapsulated sclerosing carcinoma;adrenal cortical carcinoma;endometrioid carcinoma;adnexal carcinoma;apocrine gland carcinoma, sebaceous gland adenocarcinoma, cerumen adenocarcinoma, mucoepidermoid carcinoma;cystadenocarcinoma, papillary cystadenocarcinoma, papillary serous cystadenocarcinoma, mucinous cystadenocarcinoma, mucinous adenocarcinoma, signet ring cell carcinoma;invasive ductal carcinoma;medullary carcinoma;lobular carcinoma;inflammatory carcinoma;Paget's disease, breast;acinic cell carcinoma;adenosquamous carcinoma;adenocarcinoma with squamous metaplasia,thymoma,malignant;ovarian stromal tumor,thecal cell tumor,granulosa cell tumor,androblastoma,Sertoli cell carcinoma;Leydig cell tumor,lipid cell tumor,Pa Laganglioma, extramammary paraganglioma, pheochromocytoma, hemangiosarcoma, amelanotic melanoma; superficial spreading melanoma; melanoma in giant pigmented nevi; epithelioid cell melanoma; blue nevi, sarcoma; fibrosarcoma, fibrous histiocytoma, myxosarcoma, liposarcoma, leiomyosarcoma, rhabdomyosarcoma, embryonal rhabdomyosarcoma, alveolar rhabdomyosarcoma, stromal sarcoma; mixed tumors; mixed Müllerian tumor; nephroblastoma, hepatoblastoma, carcinosarcoma, mesenchymoma, Brenner tumor, phyllodes tumor, synovial sarcoma; mesothelioma, dysgerminoma, embryonal carcinoma; teratoma, ovarian goiter, choriocarcinoma, mesonephroma ), angiosarcoma, hemangioendothelioma, Kaposi's sarcoma; hemangiopericytoma, lymphangiosarcoma, osteosarcoma, parosteal osteosarcoma, chondrosarcoma, chondroblastoma, mesenchymal chondrosarcoma, giant cell tumor of bone; Ewing's sarcoma; odontogenic tumor, ameloblastic sarcoma, ameloblastic fibrosarcoma, pinealoma, chordoma, glioma, ependymoma, astrocytoma, protoplasmic astrocytoma, fibrous astrocytoma, astroblastoma, glioblastoma, oligodendroglioma, oligodendroglioma, primitive neuroectodermal, cerebellar sarcoma; ganglioblastoma, neuroblastoma, retinoblastoma, olfactory tumor; meningioma, neurofibrosarcoma, neurilemmoma, granular cell tumor, lymphoma; Hodgkin's disease; Hodgkin's;The tumor is selected from paragranulomatous, lymphoma-small lymphocytic, lymphoma-large cell, diffuse; lymphoma, follicular; mycosis fungoides, other specified non-Hodgkin's lymphoma; histiocytosis, multiple myeloma, mast cell sarcoma; immunoproliferative small intestinal disease; leukemia; lymphocytic leukemia; plasma cell leukemia; erythroleukemia, lymphosarcoma cell leukemia; myeloid leukemia; basophilic leukemia; eosinophilic leukemia; monocytic leukemia; mast cell leukemia; megakaryoblastic leukemia; myeloid sarcoma; and hairy cell leukemia.

[0111] In still further embodiments, the cancer is selected from prostate cancer, liver cancer, renal cancer, lung cancer, breast cancer, colorectal cancer, pancreatic cancer, brain cancer, hepatocellular carcinoma, lymphoma, leukemia, gastric cancer, cervical cancer, ovarian cancer, thyroid cancer, melanoma, head and neck carcinoma, head and neck cancer, breast cancer, skin cancer, and soft tissue sarcoma, and / or other forms of cancer.

[0112] In still further embodiments, the cancer is selected from breast cancer, head and neck carcinoma, head and neck cancer, and skin cancer.

[0113] In one embodiment, the head and neck cancer is squamous cell head and neck cancer. In another embodiment, the breast cancer is triple negative breast cancer.

[0114] In another embodiment, the cancer is a metastatic or malignant cancer.

[0115] In some embodiments, the compound of formula I is a compound selected from the compounds listed in Table 1, or a pharma- ceutically acceptable salt or solvate thereof, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof.

[0116] In one embodiment, the compounds or salts described herein have a solubility, measured at a simulated intestinal fluid pH of 6.8, that is at least 0.5 times more soluble than the compound of formula X or X'; [ka] wherein R2, R3, R4, X, m, n, p, and ring A are as defined for formula I.

[0117] In a further embodiment, the compound or salt is at least twice as soluble as the compound of formula X or X'.

[0118] In another further embodiment, the compound or salt is at least 5 times more soluble than the compound of formula X or X'.

[0119] In still further embodiments, the compound or salt is at least 10 times more soluble than the compound of formula X or X'.

[0120] In one embodiment, the compound of formula X is comparative compound 2 and the compound of formula X′ is comparative compound 1 or comparative compound 2. [ka] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9]

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

[0121] In another aspect, the disclosure provides a compound of formula Ia-1 [ka] or a pharma- ceutically acceptable salt or solvate thereof, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; During the ceremony, each X' is N, C-R3, or CH; R 1a But H or C 1-6 is selected from the group consisting of alkyl, R 1b But, C 1-6 is selected from the group consisting of alkyl, cycloalkyl, hetercycloalkyl, aryl, heteroaryl, OR', N(R')2, C(O)R', C(O)OR', C(O)N(R')2, halo, CN, and NO2; 1-6 The alkyl, cycloalkyl, hetercycloalkyl, aryl, or heteroaryl are optionally and independently substituted with one or more R" substituents; Each R2 is independently halo, OH, C 1-6 Alkyl, haloalkyl, OC 1-6 Alkyl, CN, NH2, NHC 1-6 Alkyl, N(C 1-6 alkyl)2, C(O)C 1-6 Alkyl, C(O)OC 1-6 Alkyl, C(O)NH2, C(O)NHC 1-6 Alkyl, and C(O)N(C 1-6 alkyl)2; Each R3 is independently selected from the group consisting of C 1-6is selected from alkyl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, halo, CN, NO2, OR', N(R')2, C(O)R', C(O)OR', C(O)N(R')2, OC(O)OR', OC(O)N(R')2, NR'C(O)N(R')2, SOR', SON(R')2, SO2R', SON(R')2, NR'SOR', NR'SON(R')2, NR'SOR', NR'SON(R')2, NR'SOR', and NR'SON(R')2; 1-6 Alkyl, hetercycloalkyl, and heteroaryl are each optionally and independently substituted with one or more R" substituents; Each R4 is halo, OH, NH2, CN, C 1-6 Alkyl and OC 1-6 alkyl, Each R' is independently hydrogen, OH, CN, C 1-6 selected from alkyl, cycloalkyl, hetercycloalkyl, aryl, and heteroaryl, each of which is optionally and independently substituted with one or more R″ substituents; Each R” is independently 1-6 Alkyl, cycloalkyl, hetercycloalkyl, aryl, heteroaryl, OC 1-6 Alkyl, oxo, OH, halo, CN, NH2, NHC 1-6 Alkyl, N(C 1-6 alkyl)2, C(O)C 1-6 Alkyl, C(O)OC 1-6 Alkyl, C(O)NH2, C(O)NHC 1-6 Alkyl, and C(O)N(C 1-6 alkyl)2, each C 1-6 Alkyl, cycloalkyl, hetercycloalkyl, aryl, and heteroaryl are optionally and independently selected from halo, oxo, alkoxy, CN, NH, C(O)C 1-6 Alkyl, C(O)OC 1-6 Alkyl, and C(O)NHC 1-6 substituted with one or more substituents selected from alkyl, m, n, and p are each an integer selected from 0 to 4.

[0122] In one embodiment, R 1a is H.

[0123] In another embodiment, R 1b is C 1-6 Alkyl, C 1-6 Alkyl-OH or CN.

[0124] In a further embodiment, R 1b is methyl, CN, or CH2OH.

[0125] In one embodiment, each R2 substituent is independently selected from halo and OH.

[0126] In another embodiment, n is 0.

[0127] In one embodiment, each R3 substituent is independently selected from halo, CN, NH2, OH, C(O)H, C(O)N(CH3)2, C(O)NH(CH3), C(O)NH(Et), C(O)NH(isopropyl), C(O)NH(tert-butyl), C(O)NH(cyclopropyl), C(O)NCH3(CN), C(O)NH(OH), C(O)NCH3(OH), C(O)NH2, NHC(O)NHCH3, NHS(O)2CH3, S(O)2CH3, methyl, methoxy, NHS(O)2CH2CH2N(CH3)2, CF3, CH2OH, C(CH3)2OH, [ka] is selected from.

[0128] In one embodiment, the ring [ka] is phenyl, pyridyl, pyrimidyl, pyrazyl, or triazyl, optionally substituted by R3.

[0129] In a further embodiment, the ring [ka] teeth, [ka] It is.

[0130] In one embodiment, p is 1 or 2.

[0131] In one embodiment, the compound of formula Ia-1 is a compound of formula Ia-2 [ka]

[0132] In another embodiment, the ring of formula Ia-2 [ka] teeth, [ka] is selected from.

[0133] In one embodiment, m is 0.

[0134] In another embodiment, the compound of formula Ia-1 is a compound selected from compounds 1, 2, 2R, 2S, 3-6, 11, 14-16, 21, 22, 29-33, 36, 37, 45, 107-111, 111R, 111S, 112, 113, 118, 132-135, 138, 141, 142, and 148.

[0135] In one aspect, the disclosure includes a pharmaceutical composition comprising a compound or salt described herein and a pharma- ceutically acceptable excipient.

[0136] In another aspect, the disclosure includes a method of modulating EGFR and / or PI3K enzymes in a biological sample, the method comprising contacting the biological sample with a compound or salt described herein.

[0137] In yet another aspect, the disclosure includes a method of preventing or treating an EGFR and / or PI3K mediated disease in a subject, the method comprising administering to the subject a compound or salt described herein.

[0138] In one embodiment of this aspect, the EGFR and / or PI3K mediated disease is cancer.

[0139] In another embodiment, the cancer is selected from prostate cancer, liver cancer, renal cancer, lung cancer, breast cancer, colorectal cancer, pancreatic cancer, brain cancer, hepatocellular carcinoma, lymphoma, leukemia, gastric cancer, cervical cancer, ovarian cancer, thyroid cancer, melanoma, head and neck carcinoma, head and neck cancer, skin cancer, and soft tissue sarcoma, and / or other forms of cancer.

[0140] In a further embodiment, the cancer is a metastatic or malignant cancer.

[0141] In another embodiment, the cancer is selected from breast cancer, head and neck carcinoma, head and neck cancer, and skin cancer.

[0142] In a further embodiment, the head and neck cancer is squamous cell head and neck cancer.

[0143] In another further embodiment, the breast cancer is triple negative breast cancer.

[0144] In another aspect, the disclosure provides a compound of formula I: [ka] the compound of formula I has increased solubility compared to the compound of formula X or the compound of formula X'; [ka] In the formula, R 1a , R 1b , R2, R3, R4, X, m, n, p, and ring A are all defined herein.

[0145] In one embodiment of this aspect, R1a is hydrogen and R 1b is C 1-6 In a further embodiment, R 1a is hydrogen and R 1b is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, or hexyl. 1a is hydrogen and R 1b is methyl.

[0146] In one embodiment of this aspect, the compound of formula I is selected from the compounds listed in Table 1. In a further embodiment of this aspect, the compound of formula I is selected from compounds 2, 2R, 2S, 8, 10, 22, 48, 48R, 48S, 111, 111R, and 111S. In a further embodiment of this aspect, the compound of formula I is selected from compounds 2R, 48R, and 111R.

[0147] In one embodiment of this aspect, the compound of formula X′ is Comparative Compound 1 or Comparative Compound 3, having the following structure: [ka]

[0148] In another embodiment of this aspect, the compound of formula X is comparative compound 2, which has the structure [ka]

[0149] In one embodiment, the compound of formula I is at least 0.5 times more soluble than the compound of formula X or the compound of formula X'. In another embodiment, the compound of formula I is at least 2 times more soluble than the compound of formula X or the compound of formula X'. In another embodiment, the compound of formula I is at least 5.0 times more soluble than the compound of formula X or the compound of formula X'. In another embodiment, the compound of formula I is at least 10 times more soluble than the compound of formula X or the compound of formula X'. In another embodiment, the compound of formula I is at least 50 times more soluble than the compound of formula X or the compound of formula X'. In another embodiment, the compound of formula I is at least 100 times more soluble than the compound of formula X or the compound of formula X'.

[0150] In one embodiment, the compound of formula I has increased solubility in phosphate buffered saline (PBS) at about pH 7.4 over the compound of formula X or the compound of formula X'.

[0151] In another embodiment, the compound of formula I has increased solubility in simulated intestinal fluid (SIF) over the compound of formula X or the compound of formula X'.

[0152] In another embodiment, the compound of formula I has increased solubility in simulated gastric fluid (SGF) over the compound of formula X or the compound of formula X'.

[0153] Pharmaceutically Acceptable Salts, Compositions, and Formulations It will also be understood that certain compounds of the present disclosure may be present for treatment in free form or, where appropriate, as a pharma- ceutically acceptable derivative thereof (e.g., salt). According to the present disclosure, a pharma- ceutically acceptable derivative includes, but is not limited to, a pharma- ceutically acceptable prodrug, salt, ester, salt of such an ester, or any other adduct or derivative that is capable of providing, directly or indirectly, a compound not described herein, or a metabolite or residue thereof, when administered to a patient in need thereof.

[0154] As used herein, the term "pharmaceutically acceptable salt" refers to salts that are suitable, within the scope of sound medical judgment, for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like.

[0155] Pharmaceutically acceptable salts are well known in the art.For example, S. M. Berge et al. provide a detailed description of pharma-ceutical acceptable salts in J.Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference.Pharmaceutically acceptable salts of the compounds of the present disclosure include those derived from suitable inorganic and organic acids and bases.Examples of pharma-ceutically acceptable non-toxic acid addition salts include the salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or 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 pharma- ceutically acceptable salts include adipate, alginate, ascorbate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, and lactobionate. Salts derived from appropriate bases include salts of alkali metal, alkaline earth metal, ammonium, and N-type salts, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 109, 109, 109, 109, 109, 109, 109, 110, 11 + (C 1-4Examples of suitable pharmaceutically acceptable salts include quaternary salts of any basic nitrogen-containing groups of the compounds disclosed herein. Water- or oil-soluble or dispersible 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, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations (formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates).

[0156] The compound of formula I or a pharma- ceutically acceptable salt thereof can be formulated as a pharmaceutical composition comprising a therapeutically or prophylactically effective amount of the compound or salt and one or more pharma- ceutically compatible (acceptable) ingredients. In some embodiments, a pharmaceutical composition of a compound of formula I or a pharma- ceutically acceptable salt thereof and a pharmaceutical excipient is provided, in which an effective amount of the compound or salt is admixed with an excipient suitable for administration to a mammal. In a preferred embodiment, the compound of formula I or a pharma- ceutically acceptable salt thereof is formulated for administration to a human. The present disclosure provides a pharmaceutical composition comprising a compound of formula I or a pharma- ceutically acceptable salt thereof, formulated for administration to a human subject in need thereof. A formulated composition comprising a compound of formula I or a pharma- ceutically acceptable salt thereof will generally comprise one or more pharma- ceutically compatible (acceptable) ingredients.

[0157] Exemplary pharmaceutical or non-pharmaceutical compositions typically include one or more carriers (sterile liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like). Water is a more typical carrier when the pharmaceutical composition is administered intravenously. Saline and aqueous dextrose and glycerol solutions can also be used as liquid carriers, particularly for injectable solutions. Suitable excipients include, for example, amino acids, starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, skimmed milk powder, glycerol, propylene, glycol, water, ethanol, and the like. If necessary, the compositions can contain small amounts of wetting or emulsifying agents, or pH buffering agents. These compositions can take the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained-release formulations, and the like. Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by EW Martin. Such compositions will typically contain a therapeutically effective amount of a compound of formula I in purified form or a pharma- ceutically acceptable salt thereof, together with a suitable amount of carrier to provide the form for proper administration to a subject. The formulation corresponds to the mode of administration.

[0158] The pharma- ceutically acceptable carrier or vehicle can be particulate, so that the composition is, for example, in tablet or powder form.The carrier can be liquid, so that the composition is, for example, an oral syrup, flavored water, or injectable liquid.

[0159] When intended for oral administration, the compositions are preferably in solid or liquid form, with semi-solid, semi-liquid, suspension, and gel forms being included in the forms considered herein as either solid or liquid.

[0160] As a solid composition for oral administration, the composition can be formulated in the form of powder, granules, compressed tablets, pills, capsules, chewable tablets, wafers, etc. Such solid compositions typically contain one or more inert diluents. In addition, one or more of the following may be present: binders such as carboxymethylcellulose, ethylcellulose, microcrystalline cellulose, or gelatin; excipients such as starch, lactose, or dextrin; disintegrants such as alginic acid, sodium alginate, Primogel, corn starch, etc.; lubricants such as magnesium stearate or Sterotex; lubricants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; flavors such as peppermint, methyl salicylate, or orange flavor, and colorants.

[0161] When the composition is in the form of a capsule, e.g., a gelatin capsule, it can contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol, cyclodextrin, or fatty oils.

[0162] The composition may be in the form of a liquid, such as an elixir, syrup, solution, emulsion, or suspension. The liquid may be useful for oral administration or delivery by injection. For oral administration, the composition may include one or more of a sweetener, a preservative, a dye / colorant, and a flavor enhancer. In some embodiments, the composition is formulated into a powder, and the end user mixes the powder in an aqueous solution for oral administration. The composition for administration by injection (above) may also include one or more of a surfactant, a preservative, a wetting agent, a dispersing agent, a suspending agent, a buffer, a stabilizer, and an isotonic agent.

[0163] The composition and preparation of capsules are well known in the art. For example, capsules may be made of gelatin (e.g., type A, type B), carrageenan (e.g., kappa, iota, lambda), and / or modified cellulose (e.g., hydroxypropyl methylcellulose, methylcellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate), and optionally one or more excipients, such as oils (e.g., fish oil, olive oil, corn oil, soybean oil, coconut oil, triglycerides, diglycerides, and monoglycerides). ), plasticizers (e.g., glycerol, glycerin, sorbitol, polyethylene glycol, citric acid, citric acid esters such as triethyl citrate, polyalcohols), cosolvents (e.g., triacetin, propylene carbonate, ethyl lactate, propylene glycol, oleic acid, dimethyl isosorbide, stearyl alcohol, cetyl alcohol, cetostearyl alcohol, glyceryl behenate, glyceryl palmitostearate), surfactants, buffers, lubricants, humectants, preservatives, colorants, and flavors. Capsules can be hard or soft. Examples of hard capsules include ConiSnap®, DRcaps®, OceanCaps®, Pearlcaps®, Plantcaps®, DUOCAP®, Vcaps®, and Vcaps®. Additionally, capsules are available from Capsugel®. Hard capsules can be prepared, for example, by forming two elastic capsule halves, filling one of the halves with a fill containing the compound of formula I or a pharma- ceutically acceptable salt thereof, and sealing the capsule halves together. The fill can be in any suitable form, such as dry powder, granules, suspension, or liquid. Examples of soft capsules include soft gelatin (also called softgel or soft elastic) capsules, such as SGcaps®. Soft capsules can be prepared, for example, by rotary die, plate, reciprocating die, or Accogel® machine methods. In an embodiment, the capsule can be a liquid-filled hard capsule or a soft gelatin capsule.

[0164] Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine a free-flowing form of the compound of formula I or its pharma- ceutically acceptable salt, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active agent, or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets can optionally be coated or scored to provide sustained, extended, delayed, or controlled release. Methods of formulating such sustained, extended, delayed, or controlled release compositions are known in the art and are disclosed in issued U.S. patents, including, but not limited to, U.S. Patents 4,369,174, 4,842,866, and references cited therein. Coatings, such as enteric coatings, can be used to deliver the compound to the intestine (see, e.g., U.S. Patent Nos. 6,638,534, 5,217,720, 6,569,457, and references cited therein).In addition to tablets, other dosage forms, such as capsules, granules, and gel-caps, can be formulated to provide sustained, extended, delayed, or controlled release.

[0165] In one embodiment, the pharmaceutical composition is formulated for parenteral administration. Examples of pharmaceutical compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions, each containing, for example, antioxidants, buffers, bacteriostats, and / or solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions, each containing, for example, suspending agents and / or thickening agents. The formulations can be provided in unit-dose or multi-dose containers, for example, sealed ampoules or vials, and can be stored in a freeze-dried (lyophilized) state, requiring only the addition of a sterile liquid carrier, such as water, immediately prior to use. In one embodiment, the pharmaceutical composition is formulated for intravenous administration.

[0166] In some embodiments, the pharmaceutical composition further comprises a pharma- ceutically acceptable excipient. A pharma- ceutically acceptable excipient can be any substance that is not itself a therapeutic agent, but is used as a carrier, diluent, adjuvant, binder, and / or vehicle for the delivery of a therapeutic agent to a patient, or that is added to a pharmaceutical composition to improve its handling or storage characteristics, or to allow or facilitate the formation of a compound or pharmaceutical composition into a unit dosage form for administration. Pharmaceutically acceptable excipients are known in the pharmaceutical arts and are disclosed, for example, in Remington: The Science and Practice of Pharmacy, 21.sup.st Ed. (Lippincott Williams & Wilkins, Baltimore, Md., 2005). As known to those skilled in the art, pharma-ceutically acceptable excipients can serve a variety of functions and can be described as wetting agents, buffers, suspending agents, lubricants, emulsifiers, disintegrants, absorbents, preservatives, surfactants, colorants, flavorings, and sweeteners.Examples of pharma- ceutically acceptable excipients include, but are not limited to, (1) sugars such as lactose, glucose, and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and its derivatives such as carboxymethylcellulose, ethylcellulose, cellulose acetate, hydroxypropylmethylcellulose, and hydroxypropylcellulose; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository wax; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) pH buffer solutions; (21) polyesters, polycarbonates, and / or polyanhydrides; and (22) other non-toxic compatible substances used in pharmaceutical formulations.

[0167] The materials used in preparing pharmaceutical compositions can be non-toxic in the amounts used.It will be clear to those skilled in the art that the optimal dosage of active ingredients in pharmaceutical compositions depends on various factors.Relevant factors include, but are not limited to, the type of animal (e.g., human), the specific form of the compound of formula I or its pharmaceutically acceptable salt, the mode of administration, the composition used, and the severity of the disease or condition being treated.

[0168] In addition to administering the compounds as raw chemicals, the compounds of the present disclosure may be administered as part of a pharmaceutical preparation containing a suitable pharma- ceutically acceptable carrier, including excipients and adjuvants that facilitate processing of the compounds into pharma- ceutically usable preparations. Preparations, particularly those that can be administered orally or topically and are used as one of the administrations, such as tablets, dragees, slow release lozenges and capsules, mouth rinses and mouth washes, gels, liquid suspensions, hair rinses, hair gels, shampoos, and rectally administrable preparations, such as suppositories, and suitable solutions for administration by intravenous infusion, injection, topical or oral administration, contain about 0.01 to 99 percent, in one embodiment about 0.25 to 75 percent, of the active compound together with the excipients.

[0169] The pharmaceutical compositions of the present disclosure can be administered to any patient who can experience the beneficial effects of the compounds of the present disclosure.The most important of such patients are mammals, such as humans, although the present disclosure is not intended to be so limited.Other patients include veterinary animals (cattle, sheep, pigs, horses, dogs, cats, etc.).

[0170] 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 oral route. The dosage administered will depend on the age, health, and weight of the recipient, type of concurrent treatment, if any, frequency of treatment, and the nature of the desired effect.

[0171] The pharmaceutical preparations of the present disclosure are manufactured in a manner known per se, for example by conventional mixing, granulation, dragee-making, dissolving or lyophilization processes. Thus, pharmaceutical preparations for oral use can be obtained by combining the active compound with a solid excipient, adding suitable auxiliaries as required, and then optionally grinding the mixture obtained and processing the mixture of granules to obtain tablets or dragee cores.

[0172] Suitable excipients are in particular starch pastes using fillers such as sugars, for example lactose or sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, and binders such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone. If desired, disintegrants can be added, for example the above-mentioned starches, as well as carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof, for example sodium alginate. Auxiliaries are in particular flow regulators and lubricants, for example silica, talc, stearin or a salt thereof, for example magnesium stearate or calcium stearate, and / or polyethylene glycol. Dragee cores are, if necessary, provided with a suitable coating that is resistant to gastric juices. For this purpose, concentrated sugar solutions can be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.To produce coatings that are resistant to gastric juice, solutions of suitable cellulose preparations such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate are used.Dyes or pigments can be added to tablets or dragee coatings, for example, for identification or to characterize dose combinations of active compounds.

[0173] Other pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, as well as soft sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Push-fit capsules can contain the active compound in the form of granules, which can be mixed with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally a stabilizer. In soft capsules, the active compound is dissolved or suspended in a suitable liquid, such as fatty oils or liquid paraffin in one embodiment. In addition, stabilizers can be added.

[0174] Possible pharmaceutical preparations that can be used rectally include, for example, suppositories, which are made up of a combination of one or more active compounds and a suppository base.Suitable suppository bases are, for example, natural or synthetic triglycerides or paraffin hydrocarbons.In addition, it is also possible to use gelatin rectal capsules, which are made up of a combination of active compounds and a base.Possible base materials include, for example, liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons.

[0175] Suitable formulations for parenteral administration include aqueous solutions of the active compound in water-soluble form, for example, water-soluble salts, and alkaline solutions. In addition, suspensions of the active compound may be administered as suitable oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils, for example, sesame oil, or synthetic fatty acid esters, for example, ethyl oleate or triglycerides, or polyethylene glycol-400. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, including, for example, sodium carboxymethylcellulose, sorbitol, and / or dextran. Optionally, the suspension may also contain stabilizers.

[0176] The topical compositions of the present disclosure, in one embodiment, are formulated as oils, creams, lotions, ointments, etc., by selecting a suitable carrier. Suitable carriers include vegetable or mineral oils, white petrolatum (white soft paraffin), branched chain fats or oils, animal fats, and high molecular weight alcohols (greater than C12). The carrier can be any carrier in which the active ingredient is soluble. Optionally, emulsifiers, stabilizers, humectants, and antioxidants, as well as agents that impart color or fragrance, can also be included. In addition, transdermal penetration enhancers can be used in these topical formulations. Examples of such enhancers can be found in U.S. Pat. Nos. 3,989,816 and 4,444,762, each of which is incorporated herein by reference in its entirety.

[0177] Ointment can be prepared by mixing the solution of active ingredient in vegetable oil such as almond oil with warm soft paraffin and allowing the mixture to cool.The typical example of such an ointment is that which contains about 30% by weight of almond oil and about 70% by weight of white soft paraffin.Lotion can be conveniently prepared by dissolving active ingredient in suitable high molecular weight alcohol such as propylene glycol or polyethylene glycol.

[0178] Those skilled in the art will readily appreciate that the above is merely a detailed description of certain preferred embodiments of the present disclosure. Various modifications and variations of the above compositions and methods can be readily accomplished using expertise available in the art and are within the scope of the present disclosure.

[0179] Treatment method In some embodiments of the present disclosure, the compounds of formula I or pharma- ceutically acceptable salts thereof can be used under a variety of conditions and therapeutic applications to treat a variety of diseases or conditions associated with aberrant expression of PI3K and / or EGFR activity, including cancer.

[0180] The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. The compounds of the present disclosure are preferably formulated into unit dosage forms for ease of administration and uniformity of dosage. The expression "unit dosage form" as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. However, it will be understood that the total daily usage of the compounds and compositions of the present disclosure will be determined by the attending physician within the scope of sound medical judgment. The specific effective dosage level for any particular patient or organism will depend on a variety of factors, including factors well known in the medical arts, such as the disorder and severity of the disorder being treated; the activity of the particular compound employed; the particular composition employed; the age, weight, general health, sex, and diet of the patient; the time of administration, route of administration, and excretion rate of the particular compound employed; the duration of treatment; and drugs used in conjunction or concomitantly with the particular compound employed. The term "patient" as used herein means an animal, preferably a mammal, and most preferably a human.

[0181] The pharma- ceutically acceptable compositions of the present disclosure may be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (by powder, ointment, drops, or patch), buccally, as an oral or nasal spray, etc., depending on the severity of the infection being treated. In certain embodiments, the compounds of the present disclosure may be administered orally or parenterally at dosage levels of about 0.01 mg / kg to about 50 mg / kg, preferably about 0.5 mg / kg to about 25 mg / kg of subject body weight per day, one or more times per day, to obtain the desired therapeutic effect.

[0182] Liquid dosage forms for oral administration include, but are not limited to, pharma- ceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs.In addition to the active compounds, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof.Besides inert diluents, oral compositions may also contain adjuvants, such as wetting agents, emulsifiers, and suspending agents, sweeteners, flavorings, and flavorings.

[0183] Injectable preparations, for example, injectable sterile aqueous or oleaginous suspensions, can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Injectable sterile preparations can also be injectable sterile solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents, for example, as solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, USP, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any non-irritating fixed oils can be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0184] 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 which can be dissolved or dispersed in sterile water or other injectable sterile medium prior to use.

[0185] In order to prolong the effect of the disclosed compounds, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This can be accomplished by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends on its rate of dissolution, which in turn may depend on 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 on the ratio of compound to polymer and the nature of the particular polymer used, the release rate of the compound can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable depot formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0186] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing a compound of the present disclosure with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol or a suppository wax, which is solid at ambient temperature but liquid at body temperature and thus will melt in the rectal or vaginal cavity and release the active compound.

[0187] 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 pharma- ceutically 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, for example, 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) humectants 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 forms may also comprise buffering agents.

[0188] Similar types of solid compositions can also be used as fillers in soft and hard filled gelatin capsules using such excipients as lactose or milk sugar, and high molecular weight polyethylene glycols. 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 formulation art. They can optionally contain opacifying agents, and can also be of a composition that releases the active ingredient 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. Similar types of solid compositions can also be used as fillers in soft and hard filled gelatin capsules using such excipients as lactose or milk sugar, and high molecular weight polyethylene glycols.

[0189] The active compound may also be in microencapsulated form with one or more of the excipients mentioned above. The solid dosage forms of tablets, dragees, capsules, pills, and granules may be prepared with coatings and shells, such as enteric coatings, release-controlling coatings, and other coatings well known in the pharmaceutical formulation 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 may also contain, as is customary, additional substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage forms may also contain buffering agents. They may optionally contain opacifying agents, and may also be of a composition that releases the active ingredient only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that may be used include polymeric substances and waxes.

[0190] Dosage forms for topical or transdermal administration of the compounds of the present disclosure include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is mixed under sterile conditions with a pharma- ceutically acceptable carrier and any necessary preservatives or buffers that may be required. Ophthalmic formulations, ear drops, and eye drops are also contemplated as being within the scope of the present disclosure. In addition, the present disclosure contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of the compound to the body. Such dosage forms are prepared by dissolving or dispensing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0191] The present disclosure may be used to treat neoplastic diseases, such as solid or non-solid cancers. As used herein, "treatment" encompasses the prevention, alleviation, control, and / or inhibition of neoplastic diseases. Such diseases include sarcoma, cancer, adenocarcinoma, melanoma, myeloma, blastoma, glioma, lymphoma, or leukemia. Exemplary cancers include, for example, cancer, sarcoma, adenocarcinoma, melanoma, neuro(blastoma, glioma), mesothelioma, and neoplastic disorders of the reticuloendothelial, lymphatic, or hematopoietic systems (e.g., myeloma, lymphoma, or leukemia). In certain aspects, neoplasms, tumors, or cancers include lung adenocarcinoma, lung cancer, diffuse or interstitial gastric cancer, colon adenocarcinoma, prostate adenocarcinoma, esophageal cancer, breast cancer, pancreatic adenocarcinoma, ovarian adenocarcinoma, adenocarcinoma of the adrenal gland, endometrial adenocarcinoma, or uterine adenocarcinoma, and carcinoma of the head and neck.

[0192] Neoplasms, tumors, and cancers include benign, malignant, metastatic, and non-metastatic varieties, including neoplasms, tumors, or cancers of any stage (I, II, III, IV, or V) or grade (G1, G2, G3, etc.), or neoplasms, tumors, cancers, or metastases that are progressing, worsening, stable, or in remission. Cancers that may be treated according to the present disclosure include, but are not limited to, cells or neoplasms of the bladder, blood, bone, bone marrow, brain, breast, colon, esophagus, gastrointestinal system, gums, head, kidney, liver, lung, nasopharynx, neck, ovaries, prostate, skin, stomach, testes, tongue, or uterus. In addition, the cancer may be of the following histological types, specifically, but not limited to: neoplasm, malignant; carcinoma; carcinoma, undifferentiated; giant cell and spindle cell carcinoma; small cell carcinoma; papillary carcinoma; squamous cell carcinoma; lymphoepithelial carcinoma; basal cell carcinoma; pilomatrix carcinoma; transitional cell carcinoma; papillary transitional cell carcinoma; adenocarcinoma, gastrinoma, malignant; cholangiocarcinoma, hepatocellular carcinoma; combined hepatocellular carcinoma and cholangiocarcinoma, trabecular adenocarcinoma, adenoid cystic carcinoma; Adenocarcinoma in adenomatous polyps; Adenocarcinoma, familial adenomatous polyposis, solid tumors; Carcinoid tumors, malignant; Bronchioloalveolar adenocarcinoma, papillary adenocarcinoma, chromophobe carcinoma; Eosinophilic carcinoma; Eosinophilic adenocarcinoma, basophilic carcinoma; Clear cell adenocarcinoma, granular cell carcinoma; Follicular adenocarcinoma, papillary and follicular adenocarcinoma, nonencapsulated sclerosing carcinoma; Adrenal cortical carcinoma; Endometrioid carcinoma; Adnexal carcinoma of the skin; Apocrine gland carcinoma, Sebaceous gland adenocarcinoma, Cerumen adenocarcinoma, Mucoepidermoid carcinoma; Cystic gland , papillary cystadenocarcinoma, papillary serous cystadenocarcinoma, mucinous cystadenocarcinoma, mucinous adenocarcinoma, signet ring cell carcinoma; invasive ductal carcinoma; medullary carcinoma; lobular carcinoma; inflammatory carcinoma; Paget's disease, breast; acinic cell carcinoma; adenosquamous carcinoma; adenocarcinoma with squamous metaplasia; thymoma, malignant; ovarian stromal tumor, malignant; theca cell tumor, malignant; granulosa cell tumor, malignant; androblastoma, malignant; Sertoli cell carcinoma; Leydig cell tumor, malignant; lipid cell alveolar tumor, malignant;paraganglioma, malignant;extramammary paraganglioma, malignant;pheochromocytoma, hemangiosarcoma, malignant melanoma;amelanotic melanoma;superficial spreading melanoma;malignant melanoma in giant pigmented nevi;epithelioid cell melanoma;blue nevi, malignant;sarcoma;fibrosarcoma, fibrous histiocytoma, malignant;myxosarcoma, liposarcoma, leiomyosarcoma, rhabdomyosarcoma, embryonal rhabdomyosarcoma, alveolar rhabdomyosarcoma, stromal sarcoma;mixed tumors;Mixed Mullerian tumor;Nephroblastoma, hepatoblastoma, carcinosarcoma, mesenchymoma, malignant;Brenner tumor, malignant;Phyllodes tumor, malignant;Synovial sarcoma;Mesothelioma, malignant;Dysgerminoma, embryonal carcinoma;Teratoma, malignant;Ovarian goiter, malignant;Choriocarcinoma, mesonephroma, malignant;Angiosarcoma, hemangioendothelioma, malignant;Kaposi's sarcoma;Hemangiopericytoma, malignant;Lymphangiosarcoma, osteosarcoma, Parosteal osteosarcoma, chondrosarcoma, chondroblastoma, malignant;mesenchymal chondrosarcoma, giant cell tumor of bone;Ewing's sarcoma;odontogenic tumor, malignant;ameloblastic sarcoma, ameloblastoma, malignant;ameloblastic fibrosarcoma, pinealoma, malignant;chordoma, glioma, malignant;ependymoma, astrocytoma, protoplasmic astrocytoma, fibrous astrocytoma, astroblastoma, glioblastoma, oligodendroglioma, oligodendroma Dendroblastoma, primitive neuroectodermal, cerebellar sarcoma; ganglioneuroblastoma, neuroblastoma, retinoblastoma, olfactory nerve tumor; meningioma, malignant; neurofibrosarcoma, schwannoma, malignant; granular cell tumor, malignant; malignant lymphoma; Hodgkin's disease; Hodgkin's; paragranuloma, malignant lymphoma, small lymphocytic, malignant lymphoma-large cell, diffuse; malignant lymphoma, follicular; mycosis fungoides, others certain non-Hodgkin's lymphomas; malignant histiocytosis, multiple myeloma, mast cell sarcoma; immunoproliferative small intestinal disease; leukemia; lymphocytic leukemia; plasma cell leukemia; erythroleukemia, lymphosarcoma cell leukemia; myeloid leukemia; basophilic leukemia; eosinophilic leukemia; monocytic leukemia; mast cell leukemia; megakaryoblastic leukemia; myeloid sarcoma; and hairy cell leukemia. Preferably, the neoplastic disease may be a tumor associated with a cancer selected from prostate cancer, liver cancer, kidney cancer, lung cancer, breast cancer, colorectal cancer, pancreatic cancer, brain cancer, hepatocellular carcinoma, lymphoma, leukemia, gastric cancer, cervical cancer, ovarian cancer, thyroid cancer, melanoma, head and neck carcinoma, head and neck cancer, skin cancer, and soft tissue sarcoma, and / or other forms of cancer. The tumor may be a metastatic or malignant tumor.

[0193] In some embodiments, the neoplastic disease to be treated is pancreatic cancer, breast cancer, lung cancer, prostate cancer, and skin cancer. Most preferably, the neoplastic disease to be treated is pancreatic cancer, colorectal cancer, and / or head and neck carcinoma.

[0194] Combination therapy Some embodiments of the present disclosure provide methods for administering an effective amount of a compound of the present disclosure and at least one additional therapeutic agent (including, but not limited to, chemotherapeutic antineoplastic agents, apoptosis modulating agents, antibacterial agents, antiviral agents, antifungal agents, and anti-inflammatory agents), and / or therapeutic techniques (e.g., surgical intervention, and / or radiation therapy). In certain embodiments, the additional therapeutic agent is an anti-cancer agent.

[0195] Many suitable anti-cancer agents are contemplated for use in the methods of the present disclosure. Indeed, the present disclosure contemplates the administration of many anti-cancer agents, including, but not limited to, agents that induce apoptosis, polynucleotides (e.g., antisense agents, ribozymes, siRNAs), polypeptides (e.g., enzymes and antibodies), biomimetics, alkaloids, alkylating agents, antitumor antibiotics, antimetabolites, hormones, platinum compounds, monoclonal or polyclonal antibodies (e.g., antibodies conjugated to anticancer agents, 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, tumor differentiation inducers (e.g., all-trans-retinoic acid), gene therapy agents (e.g., antisense therapy agents and nucleotides), tumor vaccines, angiogenesis inhibitors, proteosome inhibitors, NF-KB modulators, anti-CDK compounds, HDAC inhibitors, and the like. Many other examples of chemotherapeutic compounds and anti-cancer therapies suitable for co-administration with the disclosed compounds will be known to those of skill in the art.

[0196] In certain embodiments, the anti-cancer agent comprises an agent that induces or stimulates apoptosis. Agents that induce apoptosis include, but are not limited to, radiation (e.g., X-rays, gamma rays, ultraviolet light), tumor necrosis factor (TNF)-related factors (e.g., antibodies against TNF family receptor proteins, TNF family ligands, TRAIL, TRAIL-R1, or TRAIL-R2), kinase inhibitors (e.g., epidermal growth factor receptor (EGFR) kinase inhibitors, vascular growth factor receptor (VGFR) kinase inhibitors, fibroblast growth factor receptor (FGFR) kinase inhibitors, platelet-derived growth factor receptor (PDGFR) kinase inhibitors, and Bcr-Abl kinase inhibitors (e.g., GLEEVEC), antisense molecules, antibodies (e.g., HERCEPTIN, RITUXAN, ZEVALIN, and Avastin), antiestrogens (e.g., raloxene and taloxifene), antiandrogens (e.g., flutamide, bicalutamide, finasteride, aminoglutethamide, ketoconazole, and corticosteroids), cyclooxygenase-2 (COX-2) inhibitors (e.g., celecoxib, anti-inflammatory drugs (e.g., butazolidine, decadron, deltasone, dexamethasone intensol, dexone, hexadrol, hydroxychloroquine, methicorten, oradexon, orazone, oxyphenbutazone, pediaprex, phenylbutazone ... , PLAQUENIL, PREDNISOLONE, PREDNISONE, PRELONE, and TANDEARIL), and cancer chemotherapy 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, cell signaling molecules, ceramides and cytokines, staurosporine, etc.

[0197] In still other embodiments, the compositions and methods of the present disclosure provide a compound of the present disclosure and at least one anti-hyperproliferative or anti-neoplastic agent selected from alkylating agents, antimetabolites, and natural products (e.g., herbs and other plant and / or animal derived compounds).

[0198] 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) alkylsulfonates (e.g., busulfan); 4) nitrosoureas (e.g., carmustine (BCNU), lomustine (CCNU); semustine (methyl-CCNU), and streptozocin (streptozotocin)); and 5) triazenes (e.g., dacarbazine (DTIC, dimethyltriazenoimide-azolecarboxamide)).

[0199] In some embodiments, antimetabolites suitable for use in the compositions and methods of the present invention 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 (fluorodeoxyuridine, FudR), and cytarabine (cytosine arabinoside)), and 3) purine analogs (e.g., mercaptopurine (6-mercaptopurine, 6-MP), thioguanine (6-thioguanine, TG), and pentostatin (2'-deoxycoformycin)).

[0200] 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 alpha), 6) platinum coordination 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) adrenal cortical suppressants (e.g., mitotane ((o,p'-DDD) and aminoglutethimide), 11) adrenal cortical steroids (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).

[0201] Any oncolytic agent commonly used in the context of cancer therapy finds use in the compositions and methods of the present disclosure. For example, the United States Food and Drug Administration maintains a formulary of oncolytic agents approved for use in the United States. The USFDA's international counterparts maintain similar formularies. Table 2 provides a list of exemplary antineoplastic agents approved for use in the United States. Those skilled in the art will understand that the "product labeling" required for all chemotherapeutic agents approved in the United States describes the approved indications, administration information, toxicity data, etc. for the exemplary agents.

Table 2-1

Table 2-2

Table 2-3

Table 2-4

Table 2-5

Table 2-6

Table 2-7

Table 2-8

[0202] Anti-cancer agents further include compounds that have been identified to have anti-cancer activity, including, but not limited to, 3-AP, 12-O-tetradecanoylphorbol-13-acetate, 17AAG, 852A, ABI-007, ABR-217620, ABT-751, ADI-PEG20, AE-941, AG-013736, AGRO100, alanosine, AMG706, antibody G250, antineoplaston, AP2357. 3, Apaziquone, APC8015, Atiprimod, ATN-161, Atrasenten, Azacitidine, BB-10901, BCX-1777, Bevacizumab, BG00001, Bicalutamide, BMS247550, Bortezomib, Bryostatin-1, Buserelin, Calcitriol, CCI-779, CDB-2914, Cefixime, Setuki Cimab, CG0070, cilengitide, clofarabine, combretastatin A4 phosphate, CP-675,206, CP-724,714, CpG7909, 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, Ilofulven, Ixabepilone, Lapatinib, Lenalidomide, Lestaurtinib, Leuprolide, LMB-9 immunotoxin, Lonafarnib, Luniliximab, Mahosfamide, 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, PSC8 33, PXD101, pyrazoloacridine, R115777, RAD001, ranpirnase, rebeccamycin analog, rhu angiostatin protein, rhuMab2C4, rosiglitazone, rubitecan, S-1, S-8184, satraplatin, SB-, 15992, SGN-0010, SGN-40, sorafenib, SR31747A, ST1571, SU011248, suberoylanilide hydroxamic acid, suramin, talavos These include tat, 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.

[0203] For a more detailed description of anti-cancer and other therapeutic agents, one of skill in the art can refer to any number of instruction manuals, including, but not limited to, the Physician's Desk Reference and Goodman and Gilman's "Pharmaceutical Basis of Therapeutics," 10th Edition, Eds. Hardman et al., 2002.

[0204] The amount of each of the active agents described herein can include the amount of each agent that has been found to be a clinically relevant amount that aggregates to provide therapeutic benefit when administered in combination.For example, the additional active agent can be administered or provided in a composition that is administered with the compound of the present disclosure in an amount that can cause adverse effects and can be titrated when studied in clinical trials of the combination.In each case, the combination can be administered separately or provided in a composition that can be formulated in a single composition, and can be administered in either an individual therapeutically effective amount when the combination as a whole is therapeutically effective, or when one or both of the active agents of the combination are administered at suboptimal or subtherapeutic levels.

[0205] The present disclosure provides a method for administering the disclosed compounds together with radiation therapy.The present disclosure is not limited by the type, amount, or delivery and administration system used to deliver therapeutic doses of radiation to animals.For example, animals can receive photon radiation therapy, particle beam radiation therapy, other types of radiation therapy, and combinations thereof.In some embodiments, radiation is delivered to animals using a linear accelerator.In yet other embodiments, radiation is delivered using a gamma knife.

[0206] The radiation source can be external or internal to the animal. External radiation therapy is the most common and involves directing a beam of high-energy radiation through the skin to the tumor site, for example, using a linear accelerator. Although the radiation beam is localized to the tumor site, it is nearly impossible to avoid exposure to normal, healthy tissue. However, external radiation is usually well tolerated by animals. Internal radiation therapy involves placing radiation-emitting sources, such as beads, wires, pellets, capsules, particles, etc., inside the body at or near the tumor site, including the use of a delivery system that specifically targets cancer cells (e.g., using particles bound to cancer cell-binding ligands). Such placements can be removed after treatment or left inactive in the body. Types of internal radiation therapy include, but are not limited to, brachytherapy, interstitial radiation, intracavitary radiation, radioimmunotherapy, etc.

[0207] The animals are optionally treated with radiosensitizers (e.g., metronidazole, misonidazole, intra-arterial Budr, intravenous iodooxyuridine (IudR), nitroimidazoles, 5-substituted-4-nitroimidazoles, 2H-isoindoledione, [[(2-bromoethyl)-amino]methyl]-nitro-1H-imidazole-1-ethanol, nitroaniline derivatives, DNA-affinity hypoxia-selective cytotoxins, halogenated DNA ligands, 1,2,4 benzotriazine oxide, 2-nitroimidazole derivatives, fluorine-containing nitroazole derivatives, benzamides, nicotinamides, acridine-intercalators, , 5-thiotrazol derivatives, 3-nitro-1,2,4-triazole, 4,5-nitroimidazole derivatives, hydroxylated texelpline, cisplatin, mitomycin, tiripazamine, nitrosoureas, mercaptopurine, methotrexate, fluorouracil, bleomycin, vincristine, carboplatin, epirubicin, doxorubicin, cyclophosphamide, vindesine, etoposide, paclitaxel, fever (hypersemia), etc.), radioprotectors (e.g., cysteamine, aminoalkyl dihydrogen phosphorothioates, amifostine (WR2721), IL-1, IL-6, etc.). Radiosensitizers enhance the killing of tumor cells. Radioprotectors protect healthy tissue from the harmful effects of radiation.

[0208] Any type of radiation can be administered to the animal, so long as the dose of radiation is tolerated by the animal without unacceptable negative side effects. Suitable types of radiation therapy include, for example, ionizing (electromagnetic) radiation therapy (e.g., X-rays or gamma rays) or particle beam radiation therapy (e.g., high linear energy radiation). Ionizing radiation is defined as radiation that contains particles or photons with sufficient energy to produce ionization, i.e., gain or loss of electrons (e.g., as described in US 5,770,581, which is incorporated herein by reference in its entirety). The effect of radiation can be at least partially controlled by the clinician. In one embodiment, the dose of radiation is fractionated for maximum target cell exposure and reduced toxicity.

[0209] In one embodiment, the total dose of radiation administered to the animal is from about .01 Gray (Gy) to about 100 Gy. In another embodiment, from 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) is administered over the course of treatment. In some embodiments, the complete dose of radiation can be administered over the course of one day, although the total dose is ideally divided and administered over several days. Desirably, radiation therapy 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 to 8 weeks). Thus, a daily dose of radiation would include 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 radiation dose should be sufficient to induce destruction of the targeted cells. If extended over a period of time, in one embodiment, radiation is not administered every day, thereby allowing the animal to rest and realize the effects of the therapy. For example, radiation is desirably administered for 5 consecutive days and not administered for 2 days in 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 animal's response and any potential side effects. Radiation therapy can be initiated at any time during the treatment period. In one embodiment, radiation is initiated during week 1 or 2 and administered for the remainder of the treatment period. For example, radiation is administered during weeks 1-6 or weeks 2-6 of a treatment period that includes 6 weeks, for example, to treat solid tumors. Alternatively, radiation is administered during weeks 1-5 or weeks 2-5 of a treatment period that includes 5 weeks. However, these exemplary radiation therapy administration schedules are not intended to limit the present disclosure.

[0210] Antibacterial therapeutic agents may also be used as therapeutic agents in the present disclosure. Any agent capable of killing, inhibiting, or otherwise attenuating the function of microorganisms, and any agent intended to have such activity, may be used. Antibacterial agents include, but are not limited to, natural and synthetic antibiotics, antibodies, inhibitory proteins (e.g., defensins), antisense nucleic acids, membrane disrupting agents, and the like, used alone or in combination. In fact, any type of antibiotic may be used, including, but not limited to, antibacterial agents, antiviral agents, antifungal agents, and the like.

[0211] In some embodiments of the present disclosure, the compound of the present disclosure and one or more therapeutic or anti-cancer agents are administered to the animal under one or more of the following conditions: different periodicity, different duration, different concentrations, different routes of administration, etc. In some embodiments, the compound is administered before the therapeutic or anti-cancer agent, for example, 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 before administration of the therapeutic or anti-cancer agent. In some embodiments, the compound is administered after the therapeutic or anti-cancer agent, for example, 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 administration of the anti-cancer agent. In some embodiments, the compound and the therapeutic or anti-cancer agent are administered simultaneously but on different schedules, for example, the compound is administered daily while the therapeutic or anti-cancer 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 and the therapeutic or anti-cancer agent is administered once a day, once a week, once every two weeks, once every three weeks, or once every four weeks. EXAMPLES

[0212] General synthesis scheme Compounds of formula I can be synthesized using the general method provided in Scheme 1. According to Scheme 1, a bromide 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. The compound of formula G2 can then be coupled to a compound of formula G5 using coupling chemistry known to those skilled in the art, such as palladium catalyzed coupling conditions, to provide a compound of formula I. 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. It will also be understood that the order of reactions specified in Scheme 1 can be reversed, such that a compound of formula G2 is reacted with a compound of formula G3 to form an intermediate product, which is then reacted with a compound of formula G4 to provide a compound of formula I. Additionally, the compound represented by formula G4 can have a stereocenter, R 1a and R 1b It will be understood that the enantiomers of the compound of formula G4 will differ. Furthermore, the compound of formula G4 may be a single enantiomer or a racemic mixture of enantiomers that will provide the enantiomeric compound or racemic compound of formula I, respectively. It will be generally understood by those skilled in the art that reaction conditions that are successful when using one enantiomer of the compound of formula G4 as the starting material will most likely be equally successful for the other enantiomer of the compound of formula G4. [ka]

[0213] Compounds of formula I can also be synthesized according to scheme 2. Following the scheme, compounds of formula G6 first undergo nucleophilic substitution with amines of formula G7. The resulting compounds of formula G8 (wherein Xa is a suitable group for functional group interconversion to tetramethyl-1,3,2-dioxaborolane) are converted to compounds of formula G9. Exposure of compounds of formula G9 to compounds of formula G10 under coupling conditions, for example palladium-catalyzed coupling conditions, provides compounds of formula I. [ka]

[0214] Synthesis Example Example 1: N-[5-[4-(1-phenylethylamino)quinazolin-6-yl]-3-pyridyl]methanesulfonamide (Compound 1) [ka] Step 1: Synthesis of (5-amino-3-pyridyl)boronic acid (2a) To a stirred solution of BPD (1.76 g, 6.94 mmol, 1.2 equiv) in dioxane (5 mL) was added 5-bromopyridin-3-amine, 1a, (1 g, 5.78 mmol, 1 equiv), AcOK (1.70 g, 17.34 mmol, 3 equiv), and Pd(dppf)Cl2.CH2Cl2 (472.02 mg, 578.00 μmol, 0.1 equiv), the reaction was purged with Ar three times and stirred at 100 °C under Ar for 16 h. LCMS showed complete consumption of starting material and MS of desired product was detected. The crude product was triturated with EtOAc (6 mL) at 25 °C for 60 min. It was then filtered and the filtrate was concentrated in vacuo. Compound 2a (5-amino-3-pyridyl)boronic acid (2 g, crude) was obtained as a black solid.

[0215] Step 2: Synthesis of 6-(5-amino-3-pyridyl)-N-(1-phenylethyl)quinazolin-4-amine (3a) To a stirred solution of (5-amino-3-pyridyl)boronic acid, 2a, (402.32 mg, 1.83 mmol, 2 equiv) in DMF (4 mL) and HO (1.5 mL) was added 6-bromo-N-(1-phenylethyl)quinazolin-4-amine (300 mg, 914.06 μmol, 1 equiv), KPO (582.07 mg, 2.74 mmol, 3 equiv), and Pd(PPh) (105.63 mg, 91.41 μmol, 0.1 equiv) and the reaction was stirred under N at 100° C. for 4 h. LCMS showed complete consumption of starting material and MS of desired product was detected. The reaction was filtered and the filtrate was purified by preparative HPLC (column: C18-1 150*30mm*5um; mobile phase: [water (TFA)-ACN]; B%: 1%-45%, 8 min). Compound 3a, 6-(5-amino-3-pyridyl)-N-(1-phenylethyl)quinazolin-4-amine (80 mg, 175.66 μmol, 19.22% yield, TFA) was obtained as a white solid.

[0216] Step 3: Synthesis of N-methylsulfonyl-N-[5-[4-(1-phenylethylamino)quinazolin-6-yl]-3-pyridyl]methanesulfonamide (4a) To a stirred solution of 6-(5-amino-3-pyridyl)-N-(1-phenylethyl)quinazolin-4-amine, 3a (40 mg, 117.16 μmol, 1 equiv.) in dry DCM (2 mL) was added TEA (59.28 mg, 585.81 μmol, 81.54 μL, 5 equiv.) and the reaction was degassed with N2 and cooled to 0° C. Then, MsCl (50 mg, 436.49 μmol, 33.78 μL, 3.73 equiv.) was added dropwise to the reaction at 0° C. The reaction was stirred under N2 at 0° C. for 1 h. TLC (PE:EtOAc=1:1, R f=0.53) indicated starting material remained and a new spot formed. Then MsCl (50 mg, 436.49 μmol, 33.78 μL, 3.73 equiv) was added and the mixture was stirred at 0° C. for 1 h. LCMS indicated starting material was completely consumed and MS of desired product was detected. The reaction was quenched by addition of 5 mL water and extracted with DCM (3*5 mL). The organic layer was washed with brine (5 mL), dried over anhydrous Na2SO4, then filtered and concentrated in vacuum. Compound 4a, N-methylsulfonyl-N-[5-[4-(1-phenylethylamino)quinazolin-6-yl]-3-pyridyl]methanesulfonamide (40 mg, 80.39 μmol, 68.61% yield) was obtained as a yellow oil.

[0217] Step 4: Synthesis of N-[5-[4-(1-phenylethylamino)quinazolin-6-yl]-3-pyridyl]methanesulfonamide (Compound 1) To a stirred solution of N-methylsulfonyl-N-[5-[4-(1-phenylethylamino)quinazolin-6-yl]-3-pyridyl]methanesulfonamide, 4a, (40 mg, 80.39 μmol, 1 equiv.) in MeOH (2 mL), K2CO3 (22.22 mg, 160.78 μmol, 2 equiv.) was added and the reaction was stirred at 60 °C for 2 h. LCMS showed that the starting material was completely consumed and MS of the desired product was detected. The reaction was filtered and the filtrate was purified by preparative HPLC (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 20%-50%, 10 min). Compound 1, N-[5-[4-(1-phenylethylamino)quinazolin-6-yl]-3-pyridyl]methanesulfonamide (5.64 mg, 13.33 μmol, 16.58% yield, 99.13% purity) was obtained as a white solid. 1H NMR(400MHz,DMSO-d6)δ ppm 8.82(s,2H),8.66(br d,J=7.88Hz,1H),8.47(d,J=2.25Hz,1H),8.44(s,1H),8.07(dd,J=8.63,1.63Hz,1H),7.93(t,J=2.06Hz,1H),7.80(d,J=8.63Hz,1H),7 .45(d,J=7.50Hz,2H),7.32(t,J=7.57Hz,2H),7.19-7.25(m,1H),5.65(t,J=7.25Hz,1H),3.12(s,3H),1.62(d,J=7.13Hz,3H).MS(M+H) + =420.1

[0218] Example 2: Synthesis of N-[2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]-N-methylsulfonyl-methanesulfonamide (3b) [ka] Step 1: Synthesis of 2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine (2c) To a stirred solution of 5-bromo-2-chloro-pyridin-3-amine, 1c (20 g, 96.41 mmol, 1 equiv.) in dioxane (250 mL), 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 equiv.), KOAc (23.65 g, 241.01 mmol, 2.5 equiv.), and Pd(dppf)Cl2 (3.53 g, 4.82 mmol, 0.05 equiv.) were added, the mixture was purged with N2 three times, and then stirred at 100° C. for 16 h. TLC (petroleum ether / ethyl acetate=5:1, R f=0.25) indicated that a small amount of starting material remained and a new spot 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 over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column (ISCO 120 g silica, 10-15% ethyl acetate in petroleum ether, gradient over 15 min). Compound 2c, 2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine (6.75 g, 26.52 mmol, 30% yield) was obtained as a yellow solid.

[0219] Step 2: Synthesis of N-[2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]-N-methylsulfonyl-methanesulfonamide (3b) To a stirred solution of 2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine, 2c, (27 g, 106.08 mmol, 1 equiv) in DCM (200 mL) was added TEA (42.94 g, 424.33 mmol, 59.06 mL, 4 equiv), MsCl (31.170 g, 272.11 mmol, 21.06 mL, 2.57 equiv) at 0° C. The mixture was stirred at 0° C. for 1 h. TLC (petroleum ether / ethyl acetate=3:1, R f =0.84) indicated complete consumption of the starting material and the formation of a new spot. The reaction mixture was concentrated in vacuo. 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 vacuo to give the crude product. Compound 3b, N-[2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]-N-methylsulfonyl-methanesulfonamide (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)

[0220] Example 3: Synthesis of N-[2-chloro-5-[4-(1-phenylethylamino)quinazolin-6-yl]-3-pyridyl]methanesulfonamide (Compound 2) [ka] Step 1: Synthesis of 6-bromo-N-(1-phenylethyl)quinazolin-4-amine (2b) To a stirred solution of 6-bromo-4-chloro-quinazoline, 1b, (3 g, 12.32 mmol, 1 equiv) in i-PrOH (30 mL) was added 1-phenylethanamine (1.49 g, 12.32 mmol, 1.57 mL, 1 equiv) and TEA (1.99 g, 19.71 mmol, 2.74 mL, 1.6 equiv) and the reaction was stirred at 80° C. under N2 for 16 h. LCMS showed complete consumption of starting material and MS of desired product was detected. The reaction mixture was cooled to ambient temperature, 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. Compound 2b, 6-bromo-N-(1-phenylethyl)quinazolin-4-amine (3 g, 9.14 mmol, 74.19% yield) was obtained as a white solid.

[0221] Step 2: Synthesis of N-[2-chloro-5-[4-(1-phenylethylamino)quinazolin-6-yl]-3-pyridyl]methanesulfonamide (compound 2) To a stirred solution of 6-bromo-N-(1-phenylethyl)quinazolin-4-amine, 2b, (50 mg, 152.34 μmol, 1 equiv.) in DMF (2 mL) and HO (0.5 mL), N-[2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]-N-methylsulfonyl-methanesulfonamide (62.57 mg, 152.34 μmol, 1 equiv.), KPO (97.01 mg, 457.03 μmol, 3 equiv.), and Pd(PPh) (17.60 mg, 15.23 μmol, 0.1 equiv.) were added and the reaction was stirred at 80° C. under N for 3 h. LCMS showed complete consumption of starting material and MS of desired product was detected. The reaction was filtered and the filtrate was evaporated to give the product. The crude product was purified by preparative HPLC (column: Phenomenex C18 75*30mm*3um; mobile phase: [water (NH4HCO3)-ACN]; B%: 10%~40%, 8 min). Compound 2 N-[2-chloro-5-[4-(1-phenylethylamino)quinazolin-6-yl]-3-pyridyl]methanesulfonamide (8.53mg, 18.79μmol, 12.33% yield, 100% purity) was obtained as a white solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 9.98(br s,1H),8.85(d,J=1.63Hz,1H),8.79(d,J=2.25Hz,1H),8.67(br d,J=7.88Hz,1H),8.44(s,1H),8.24(d,J=2.38Hz,1H),8.14(dd,J=8.76,1.75Hz,1H),7.80(d,J=8.63Hz,1H),7.45(d,J=7. 38Hz,2H),7.33(t,J=7.57Hz,2H),7.16-7.27(m,1H),5.65(t,J=7.25Hz,1H),3.17(s,3H),1.63(d,J=7.00Hz,3H).MS(M+H) + =454.0

[0222] Compounds 2R and 2S were synthesized analogously to compound 2 in Example 3 using the appropriate chiral version of intermediate 2b.

[0223] Compound 2R:1 H NMR(400MHz,DMSO-d6)δ=10.97(br d,J=7.6Hz,1H),9.97(br s,1H),9.45(s,1H),8.94-8.86(m,2H),8.43(dd,J=1.6,8.8Hz,1H),8.36(d,J=2.4Hz,1H),8.01(d,J=8.8Hz,1H),7.57(d ,J=7.4Hz,2H),7.40-7.33(m,2H),7.31-7.24(m,1H),5.85(t,J=7.2Hz,1H),3.25(s,3H),1.75(d,J=7.0Hz,3H).MS(M+H) + =454.0

[0224] Compound 2S: 1 H NMR(400MHz,DMSO-d6)δ=9.98(br s,1H),8.85(s,1H),8.79(d,J=2.2Hz,1H),8.67(br d,J=7.7Hz,1H),8.44(s,1H),8.24(d,J=2.2Hz,1H),8.14(dd,J=1.6,8.7Hz,1H),7.80(d,J=8.7Hz,1H),7.45(d,J=7.5H z,2H),7.33(t,J=7.6Hz,2H),7.26-7.19(m,1H),5.65(quin,J=7.1Hz,1H),3.17(s,3H),1.63(d,J=7.0Hz,3H).MS(M+H) + =454.1

[0225] Example 4: N-[2-メトキシ-5-[4-(1-フェニルエチルアミノ)キナSynthesis of ゾリン-6-イル]-3-ピリジル]メタンスルホンアミド (Compound 3)

change

[0226] Example 5: [ka] Step 1: Synthesis of (5-amino-6-methyl-3-pyridyl)boronic acid (2) To a stirred solution of 5-bromo-2-methyl-pyridin-3-amine, 1d, (1g, 5.35mmol, 1eq) in dioxane (5mL) was added BPD (1.63g, 6.42mmol, 1.2eq), AcOK (1.57g, 16.04mmol, 3eq), and Pd(dppf)Cl2.CH2Cl2 (436.62mg, 534.65μmol, 0.1eq), the reaction was purged with Ar 3 times and stirred at 100°C under Ar for 16h. LCMS showed the starting material was completely consumed and MS of the desired product was detected. The reaction mixture was poured into water (50mL). The aqueous phase was extracted with ethyl acetate (50mL*2). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Compound 2d, (5-amino-6-methyl-3-pyridyl)boronic acid (2.8 g, crude) was obtained as a black oil.

[0227] Step 2: Synthesis of 6-(5-amino-6-methyl-3-pyridyl)-N-(1-phenylethyl)quinazolin-4-amine (3d) To a stirred solution of 6-bromo-N-(1-phenylethyl)quinazolin-4-amine, 2d, (420.59 mg, 1.28 mmol, 1 equiv) in DMF (4 mL) and HO (1.5 mL) was added (5-amino-6-methyl-3-pyridyl)boronic acid (194.51 mg, 1.28 mmol, 1 equiv), KPO (815.12 mg, 3.84 mmol, 3 equiv), and Pd(PPh) (147.91 mg, 128.00 μmol, 0.1 equiv) and the reaction was stirred under N at 100° C. for 4 h. LCMS showed complete consumption of starting material and MS of desired product was detected. The reaction was filtered and the filtrate was purified by preparative HPLC (column: C18-1 150*30mm*5um; mobile phase: [water (TFA)-ACN]; B%: 1%~45%, 8 min.) to give compound 3d, 6-(5-amino-6-methyl-3-pyridyl)-N-(1-phenylethyl)quinazolin-4-amine (70 mg, 144.70 μmol, 10.78% yield, TFA) as a yellow solid.

[0228] Step 3: Synthesis of N-[2-methyl-5-[4-(1-phenylethylamino)quinazolin-6-yl]-3-pyridyl]-N-methylsulfonyl-methanesulfonamide (4d) To a stirred solution of 6-(5-amino-6-methyl-3-pyridyl)-N-(1-phenylethyl)quinazolin-4-amine (40 mg, 112.54 μmol, 1 eq) in DCM (2 mL) was added TEA (56.94 mg, 562.69 μmol, 78.32 μL, 5 eq) and the reaction was degassed with N2 and cooled to 0 °C. Then MsCl (55 mg, 1.57 mmol, 37.16 μL, 4 eq) was added dropwise to the reaction at 0 °C. The reaction was stirred at 0 °C under N2 for 1 h. LCMS showed that the starting material was completely consumed and MS of the desired product was detected. The reaction was quenched by the addition of 5 mL of water and extracted with DCM (3*5 mL). The organic layer was washed with brine (5 mL), dried over anhydrous Na2SO4, then filtered and concentrated in vacuo. Compound 4d, N-[2-methyl-5-[4-(1-phenylethylamino)quinazolin-6-yl]-3-pyridyl]-N-methylsulfonyl-methanesulfonamide (40 mg, 78.18 μmol, 69.47% yield) was obtained as a yellow oil.

[0229] Step 4: Synthesis of N-[2-methyl-5-[4-(1-phenylethylamino)quinazolin-6-yl]-3-pyridyl]methanesulfonamide (compound 4) To a stirred solution of N-[2-methyl-5-[4-(1-phenylethylamino)quinazolin-6-yl]-3-pyridyl]-N-methylsulfonyl-methanesulfonamide, 4d, (40 mg, 78.18 μmol, 1 equiv.) in MeOH (2 mL), K2CO3 (21.61 mg, 156.37 μmol, 2 equiv.) was added and the reaction was stirred at 60 °C for 2 h. LCMS showed the starting material was completely consumed and MS of the desired product was detected. The reaction was filtered and the filtrate was purified by preparative HPLC (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 25%-50%, 10 min). Compound 4, N-[2-methyl-5-[4-(1-phenylethylamino)quinazolin-6-yl]-3-pyridyl]methanesulfonamide (3.5 mg, 8.91 μmol, 11.40% yield, 96.59% purity) was obtained as a white solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 8.79(s,1H),8.76(s,1H),8.64(br d,J=7.88Hz,1H),8.42(s,1H),8.08(dd,J=8.63,1.63Hz,1H),7.99(d,J=1.88Hz,1H),7.78( d,J=8.63Hz,1H),7.45(d,J=7.50Hz,2H),7.32(t,J=7.57Hz,2H),7.18-7.25(m,1H),5.65(br t,J=7.25Hz,1H),3.05(s,3H),2.56(s,3H),1.62(d,J=7.13Hz,3H).MS(M+H) + =434.2

[0230] Example 6: Synthesis of 6-(2-aminopyrimidin-5-yl)-N-(1-phenylethyl)quinazolin-4-amine (Compound 7) [ka] To a solution of 6-bromo-N-(1-phenylethyl)quinazolin-4-amine (100 mg, 304.69 μmol, 1 equiv.) in DMF (0.5 mL) and HO (0.1 mL), CsCO (297.82 mg, 914.06 μmol, 3 equiv.), Pd(dppf)Cl (22.29 mg, 30.47 μmol, 0.1 equiv.), and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (67.36 mg, 304.69 μmol, 1 equiv.) were added, the mixture was purged with N for 1 min, and stirred at 100° C. for 2 h. LCMS showed complete consumption of starting material and MS of desired product was detected. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The crude product was purified by preparative HPLC (column: Phenomenex luna C18 80*40mm*3um; mobile phase: [water (0.04% HCl)-ACN]; B%: 10%~40%, 7 min) to give compound 7, 6-(2-aminopyrimidin-5-yl)-N-(1-phenylethyl)quinazolin-4-amine (13.84 mg, 36.53 μmol, 11.99% yield, 100% purity, HCl) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 10.67(br d,J=5.63Hz,1H),9.20(s,1H)8.98(s,2H),8.90(s,1H),8.40(dd,J=8.76,1.75Hz,1H),7.91(d,J=8.75Hz,1H),7.55 (d,J=7.38Hz,2H),7.35-7.40(m,2H),7.26-7.31(m,1H),5.85(quin,J=7.29Hz,1H),1.74(d,J=7.00Hz,3H).MS(M+H) + =343.1

[0231] Example 7: Synthesis of N-(1-phenylethyl)-6-(1H-pyrazolo[3,4-b]pyridin-5-yl)quinazolin-4-amine (Compound 8) [ka] To a stirred solution of N-(1-phenylethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-amine (100 mg, 266.47 μmol, 1 equiv.) in DMF (2 mL) and HO (0.4 mL) was added CsCO (260.47 mg, 799.41 μmol, 3 equiv.), Pd(dppf)Cl (19.50 mg, 26.65 μmol, 0.1 equiv.), and 5-bromo-2H-pyrazolo[3,4-b]pyridine (52.77 mg, 266.47 μmol, 1 equiv.), the mixture was purged with N, and the reaction was stirred at 100° C. for 3 h. LCMS showed complete consumption of starting material and MS of desired product was detected. The reaction mixture was concentrated in vacuo. The crude product was purified by preparative HPLC (column: Phenomenex luna C18 80*40mm*3um; mobile phase: [water (0.04% HCl)-ACN]; B%: 19%-39%, 7 min). Compound N-(1-phenylethyl)-6-(1H-pyrazolo[3,4-b]pyridin-5-yl)quinazolin-4-amine (5.33mg, 12.39μmol, 4.65% yield, 93.63% purity, HCl) was obtained as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 10.50(br s,1H),9.17(s,1H),9.09(d,J=2.13Hz,1H),8.95(s,1H),8.73(d,J=2.13Hz,1H),8.52(dd,J=8.75,1.75Hz,1H),8.31(s,1H),7.96(d, MS(M+H) + =367.1

[0232] Example 8: Synthesis of 6-(2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-N-(1-phenylethyl)quinazolin-4-amine (Compound 10) [ka] To a solution of N-(1-phenylethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-amine (100 mg, 266.47 μmol, 1 equiv.) in DMF (2 mL) and HO (0.4 mL) was added CsCO (260.47 mg, 799.42 μmol, 3 equiv.), Pd(dppf)Cl (19.50 mg, 26.65 μmol, 0.1 equiv.), and 6-bromo-2-methyl-1H-imidazo[4,5-b]pyridine (56.50 mg, 266.47 μmol, 1 equiv.), the mixture was purged with N and stirred at 100° C. for 3 h. LCMS showed complete consumption of starting material and MS of desired product was detected. The reaction mixture was concentrated in vacuum and the crude product was purified by preparative HPLC (column: Phenomenex Luna C18 100*30mm*5um; mobile phase: [water (0.04% HCl)-ACN]; B%: 1%-35%, 10 min). Compound 10, 6-(2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-N-(1-phenylethyl)quinazolin-4-amine (7.09 mg, 17.01 μmol, 6.38% yield, 100% purity, HCl) was obtained as a white solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 10.98(br s,1H),9.47(br s,1H),9.09(s,1H),8.94(s,1H),8.76(br s,1H),8.56(dd,J=8.76,1.63Hz,1H),8.02(d,J=8.63Hz,1H),7.59(d,J=7.50Hz,2H),7.34-7.42( m,2H),7.25-7.32(m,1H),5.87(quin,J=7.10Hz,1H),2.79(s,3H),1.77(d,J=7.00Hz,3H).MS(M+H) + =381.1

[0233] Example 9: Synthesis of 2-[5-[4-(1-phenylethylamino)quinazolin-6-yl]-3-pyridyl]propan-2-ol (Compound 21) [ka] To a stirred solution of N-(1-phenylethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-amine (100 mg, 266.47 μmol, 1 equiv.) in DMF (1 mL) and HO (0.2 mL) was added CsCO (260.47 mg, 799.42 μmol, 3 equiv.), Pd(dppf)Cl (19.50 mg, 26.65 μmol, 0.1 equiv.), and 2-(5-bromo-3-pyridyl)propan-2-ol (57.58 mg, 266.47 μmol, 1 equiv.), the mixture was purged with N and the mixture was stirred at 100° C. for 3 h. LCMS showed complete consumption of starting material and MS of desired product was detected. The reaction mixture was concentrated in vacuo. The crude product was purified by preparative HPLC (column: Welch Xtimate C18 100*25mm*3um; mobile phase: [water (0.04% HCl)-ACN]; B%: 5%-35%, 8 min). Compound 2-[5-[4-(1-phenylethylamino)quinazolin-6-yl]-3-pyridyl]propan-2-ol (61.61 mg, 141.46 μmol, 53.09% yield, 96.65% purity, HCl) was obtained as a brown solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 11.55(br d,J=7.75Hz,1H)9.95(d,J=1.25Hz,1H)9.48(d,J=1.75Hz,1H)9.26(s,1H)8.90-8.95(m,2H)8.62(dd,J=8.82,1.69Hz,1H)8.05(d,J=8.7 5Hz,1H)7.63(d,J=7.38Hz,2H)7.32-7.39(m,2H)7.23-7.29(m,1H)5.86(quin,J=7.13Hz,1H)1.80(d,J=7.00Hz,3H)1.65(s,6H).MS(M+H) + =385.1

[0234] Example 10: Synthesis of 6-(5,6-dimethoxy-3-pyridyl)-N-(1-phenylethyl)quinazolin-4-amine (Compound 22) [ka] To a solution of N-(1-phenylethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-amine (200 mg, 532.95 μmol, 1 equiv.) in DMF (2.5 mL) and H2O (0.5 mL) was added Cs2CO3 (520.93 mg, 1.60 mmol, 3 equiv.), 5-bromo-2,3-dimethoxy-pyridine (116.21 mg, 532.95 μmol, 1 equiv.), Pd(dppf)Cl2 (39.00 mg, 53.29 μmol, 0.1 equiv.) and the mixture was purged with N2 for 1 min and then stirred at 100 °C for 3 h. LCMS showed complete consumption of starting material and MS of desired product was detected. The reaction mixture was concentrated in vacuo. The crude product was purified by preparative HPLC (column: Welch Xtimate C18 100*25mm*3um; mobile phase: [water (0.04% HCl)-ACN]; B%: 25%~45%, 8 min). Compound 22, 6-(5,6-dimethoxy-3-pyridyl)-N-(1-phenylethyl)quinazolin-4-amine (18.27 mg, 41.49 μmol, 7.79% yield, 96.04% purity, HCl) was obtained as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 10.77(br d,J=6.97Hz,1H),9.25(s,1H),8.90(s,1H),8.40-8.46(m,1H),8.26(d,J=1.96Hz,1H),7.84-7.93(m,2H),7.56(d,J=7.58Hz,2H ),7.34-7.39(m,2H),7.29(d,J=7.34Hz,1H),5.85(quin,J=7.18Hz,1H),3.95(d,J=9.05Hz,6H),1.75(d,J=6.97Hz,3H).MS(M+H) + =387.1

[0235] Example 11: Synthesis of N-(1-phenylethyl)-6-(3H-triazolo[4,5-b]pyridin-6-yl)quinazolin-4-amine (Compound 24) [ka] Step 1: Synthesis of N-(1-phenylethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-amine (2e) To a stirred solution of 6-bromo-N-(1-phenylethyl)quinazolin-4-amine, 1e, (4 g, 12.19 mmol, 1 equiv) in dioxane (8 mL) was added AcOK (3.60 g, 36.68 mmol, 3.01 equiv), Pd(dppf)Cl2.CH2Cl2 (995.27 mg, 1.22 mmol, 0.1 equiv), BPD (3.71 g, 14.62 mmol, 1.2 equiv), the mixture was purged with Ar, and the mixture was stirred at 110 °C under Ar for 4 h. LCMS showed the starting material was completely consumed and MS of the desired product was detected. TLC (PE:EtOAc = 1:1, R f =0.35) indicated complete consumption of the starting material and formation of a new spot. The residue was partitioned between ethyl acetate (100 mL) and H2O (50 mL). The separated organic layer was washed with water, dried over Na2SO4, and evaporated to dryness. The residue was purified by flash column (ISCO 10 g silica, 50-60% ethyl acetate in petroleum ether, gradient over 20 min). Compound 2e, N-(1-phenylethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-amine (1.5 g, 4.00 mmol, 32.80% yield) was obtained as a brown oil. 1 H NMR(400MHz,DMSO-d6)δ ppm 8.85(d,J=7.75Hz,1H),8.80(s,1H),8.42(s,1H),7.98(dd,J=8.32,1.06Hz,1H),7.63(d,J=8.25Hz,1H),7.45(d,J=7.38 Hz,2H),7.31(t,J=7.63Hz,2H),7.13-7.25(m,1H),5.64(quin,J=7.19Hz,1H),1.56-1.66(m,3H),1.08(s,12H).MS(M+H) + =376.3

[0236] Step 2: Synthesis of N-(1-phenylethyl)-6-(3H-triazolo[4,5-b]pyridin-6-yl)quinazolin-4-amine (compound 24) To a stirred solution of N-(1-phenylethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-amine, 2e, (150 mg, 399.71 μmol, 1 equiv) in DMF (2.5 mL) and HO (0.5 mL) was added KPO (254.54 mg, 1.20 mmol, 3 equiv), palladium, triphenylphosphane (46.19 mg, 39.97 μmol, 0.1 equiv), and 6-bromo-3H-trazolo[4,5-b]pyridine (63.64 mg, 319.77 μmol, 0.8 equiv), the mixture was purged with N and then stirred at 100° C. for 3 h. LCMS showed complete consumption of starting material and MS of desired product was detected. The reaction mixture was concentrated in vacuo. The crude product was purified by preparative HPLC (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 15%~40%, 8min). Compound 24, N-(1-phenylethyl)-6-(3H-triazolo[4,5-b]pyridin-6-yl)quinazolin-4-amine (3.47mg, 9.36μmol, 2.34% yield, 99.14% purity) was obtained as a white solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 9.25(d,J=2.00Hz,1H),8.95(d,J=1.75Hz,1H),8.83(s,1H),8.66(br d,J=7.63Hz,1H),8.45(s,1H),8.31(dd,J=8.63,1.88Hz,1H),7.82(d,J=8.63Hz,1H),7.48(d,J=7.63Hz ,2H),7.34(t,J=7.57Hz,2H),7.19-7.27(m,1H),5.67(t,J=7.25Hz,1H),1.64(d,J=7.13Hz,3H).MS(M+H) + =368.1

[0237] Example 12: Synthesis of 6-(1-methylpyrazolo[4,3-b]pyridin-6-yl)-N-(1-phenylethyl)quinazolin-4-amine (Compound 27) [ka] To a stirred solution of N-(1-phenylethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-amine (100 mg, 266.47 μmol, 1 equiv.) in DMF (2 mL) and H2O (0.4 mL), Cs2CO3 (260.47 mg, 799.42 μmol, 3 equiv.), Pd(dppf)Cl2 (19.50 mg, 26.65 μmol, 0.1 equiv.), and 6-bromo-1-methyl-pyrazolo[4,3-b]pyridine (56.50 mg, 266.47 μmol, 1 equiv.) were added, the mixture was purged with N2, and then stirred at 100 °C for 3 h. LCMS showed complete consumption of starting material and MS of desired product was detected. The reaction mixture was concentrated in vacuo. The crude product was purified by preparative HPLC (column: Phenomenex luna C18 80*40mm*3um; mobile phase: [water (0.04% HCl)-ACN]; B%: 15%~35%, 7min) to give compound 27, 6-(1-methylpyrazolo[4,3-b]pyridin-6-yl)-N-(1-phenylethyl)quinazolin-4-amine (42.87mg, 99.21μmol, 37.23% yield, 96.48% purity, HCl) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 10.91(br d,J=7.46Hz,1H),9.50(br s,1H),9.15(d,J=1.83Hz,1H),8.86-8.97(m,2H),8.60(dd,J=8.68,1.71Hz,1H),8.38(d,J=0.61Hz,1H),8.01(d,J=8.80Hz,1H),7 .59(d,J=8.07Hz,2H),7.38(t,J=7.52Hz,2H),7.24-7.33(m,1H),5.80-5.97(m,1H),4.21(s,3H),1.77(d,J=6.97Hz,3H).MS(M+H) + =381.1

[0238] Example 13: Synthesis of 2-amino-N,N-dimethyl-5-[4-(1-phenylethylamino)quinazolin-6-yl]pyridine-3-carboxamide (Compound 36) [ka] To a stirred solution of 6-bromo-N-(1-phenylethyl)quinazolin-4-amine (150 mg, 457.03 μmol, 1 equiv) in DMF (3 mL) and HO (0.5 mL) was added 2-amino-N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-carboxamide (133.07 mg, 457.03 μmol, 1 equiv), CsCO (446.73 mg, 1.37 mmol, 3 equiv), and Pd(dppf)Cl (33.44 mg, 45.70 μmol, 0.1 equiv), sparged with N for 1 min, and stirred at 100° C. for 3 h. LCMS showed complete consumption of starting material and MS of desired product was detected. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC (column: Welch Xtimate C18 100*25mm*3um; mobile phase: [water (0.04% HCl)-ACN]; B%: 10%~40%, 8 min). Compound 36 2-amino-N,N-dimethyl-5-[4-(1-phenylethylamino)quinazolin-6-yl]pyridine-3-carboxamide (80.96 mg, 174.17 μmol, 38.11% yield, 96.58% purity, HCl) was obtained as a white solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 10.87(br d,J=7.13Hz,1H),9.29(s,1H),8.89(s,1H),8.78(d,J=2.25Hz,1H),8.40-8.47(m,2H),7.91(d,J=8.88H) z,1H),7.56(d,J=7.38Hz,2H),7.33-7.40(m,2H),7.24-7.31(m,1H),5.85(quin,J=7.13Hz,1H),3.00(br d,J=11.01Hz,6H),1.75(d,J=7.00Hz,3H).MS(M+H) + =413.1

[0239] Example 14: Synthesis of 5-[4-(1-phenylethylamino)quinazolin-6-yl]-1,3-benzoxazol-2-amine (Compound 41) [ka] To a solution of N-(1-phenylethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-amine (100 mg, 266.47 μmol, 1 equiv.) in DMF (0.5 mL) and HO (0.1 mL), CsCO (260.47 mg, 799.42 μmol, 3 equiv.), Pd(dppf)Cl (19.50 mg, 26.65 μmol, 0.1 equiv.), and 5-bromo-1,3-benzoxazol-2-amine (56.77 mg, 266.47 μmol, 1 equiv.) were added, the mixture was purged with N and then stirred at 100° C. for 3 h. LCMS showed complete consumption of starting material and MS of desired product was detected. The reaction mixture was concentrated in vacuo. The crude product was purified by preparative HPLC (column: Phenomenex Luna C18 100*30mm*5um; mobile phase: [water (0.04% HCl)-ACN]; B%: 10%~40%, 10 min) to give compound 41 5-[4-(1-phenylethylamino)quinazolin-6-yl]-1,3-benzoxazol-2-amine (23.95mg, 62.28μmol, 23.37% yield, 99.18% purity) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 10.55(br d,J=7.38Hz,1H),9.07(s,1H),8.92(s,1H),8.42(dd,J=8.76,1.75Hz,1H),7.93(br d,J=8.63Hz,2H),7.78(s,1H),7.49-7.59(m,4H),7.35-7.42(m,2H),7.25-7.33(m,1H),5.87(quin,J=7.13Hz,1H),1.74(d,J=7.13Hz,3H).MS(M+H) + =382.1

[0240] Example 15: [ka] Step 1: Synthesis of (Z)-3-(4-bromoanilino)-2-cyano-prop-2-enoic acid ethyl ester (2f) To a solution of 4-bromoaniline (184.88 g, 1.07 mol, 1 equiv.) in toluene (1.5 L) was added ethyl (E)-2-cyano-3-ethoxy-prop-2-enoate (200 g, 1.18 mol, 1.1 equiv.) and the mixture was stirred at 110° C. for 6 h. TLC (petroleum ether / ethyl acetate=3:1, R f =0.88) indicated complete consumption of the starting material and the formation of a new spot. The reaction mixture was filtered and the filter cake was concentrated in vacuo to give the crude product. Compound 2f, (Z)-3-(4-bromoanilino)-2-cyano-prop-2-enoate ethyl (143 g, 484.53 mmol, 45.08% yield) was obtained as a white solid. 1 H NMR(400MHz,chloroform-d)δ=10.74(br d,J=13.0Hz,1H),8.68-7.78(m,1H),7.54-7.46(m,2H),7.10-6.96(m,2H),4.35-4.21(m,2H),1.35(td,J=7.1,9.5Hz,3H)

[0241] Step 2: Synthesis of 6-bromo-4-hydroxy-quinoline-3-carbonitrile (3f) A solution of (Z)-ethyl 3-(4-bromoanilino)-2-cyano-prop-2-enoate (23 g, 77.93 mmol, 1 equiv.) in Ph2O (200 mL) was stirred at 270° C. for 8 h. TLC (petroleum ether / ethyl acetate=3:1, R f =0.43) indicated that a small amount of starting material remained and a new spot formed. The reaction mixture was poured into MTBE (200 mL). The reaction mixture was filtered and the filter cake was concentrated in vacuo to give the crude product. Compound 3f, 6-bromo-4-hydroxy-quinoline-3-carbonitrile (38.16 g, crude) was obtained as a brown solid. 1H NMR(400MHz,DMSO-d6)δ=12.96(br s,1H),8.76(s,1H),8.16(br s,1H),7.99-7.85(m,1H),7.58(br d,J=8.8Hz,1H).

[0242] Step 3: Synthesis of N-[2-chloro-5-(3-cyano-4-hydroxy-6-quinolyl)-3-pyridyl]methanesulfonamide (4f) To a stirred solution of N-[2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]-N-methylsulfonylmethanesulfonamide, 3b, (4 g, 9.74 mmol, 1 equiv.) in dioxane (30 mL) and HO (6 mL) was added 6-bromo-4-hydroxy-quinoline-3-carbonitrile, 3f, (3.15 g, 12.66 mmol, 1.3 equiv.), CsCO (9.52 g, 29.22 mmol, 3 equiv.), Pd(dppf)Cl (712.64 mg, 973.94 μmol, 0.1 equiv.) and the mixture was flushed with N three times and stirred at 100° C. for 2 h. LCMS showed complete consumption of starting material and the desired MS was detected. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC (column: Agela DuraShell C18 250*70mm*10um; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 1%-20%, 20min). Compound 4f N-[2-chloro-5-(3-cyano-4-hydroxy-6-quinolyl)-3-pyridyl]methanesulfonamide (2.52g, 6.72mmol, 69.03% yield) was obtained as a yellow solid. MS(M+H) + =375.0

[0243] Step 4: Synthesis of N-[2-chloro-5-(4-chloro-3-cyano-6-quinolyl)-3-pyridyl]methanesulfonamide (5f) To a solution of POCl3 (18 mL), N-[2-chloro-5-(3-cyano-4-hydroxy-6-quinolyl)-3-pyridyl]methanesulfonamide (2.5 g, 6.67 mmol, 1 equiv.) was added, the mixture was purged with N2 three times and stirred at 130°C for 16 h. LCMS showed that the starting material was completely consumed and the desired MS was detected. The reaction mixture was concentrated in vacuum. The residue was dissolved with ethyl acetate (10 mL). The mixture was poured into water (20 mL) and the aqueous phase was extracted with ethyl acetate (20 mL*2). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The crude product was purified by flash column (ISCO 20 g silica, 70% ethyl acetate in petroleum ether, gradient over 20 min). TLC (petroleum ether / ethyl acetate=0:1, R f =0.78) Compound 5f, N-[2-chloro-5-(4-chloro-3-cyano-6-quinolyl)-3-pyridyl]methanesulfonamide (1.2 g, 3.05 mmol, 45.75% yield) was obtained as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ=9.95(s,1H),9.26(s,1H),8.82(d,J=2.3Hz,1H),8.57(d,J=1.9H) z,1H),8.45-8.42(m,1H),8.36-8.32(m,1H),8.31(d,J=2.3Hz,1H),3.21(s,3H).MS(M+H) + =393.0

[0244] Step 5: Synthesis of N-[2-chloro-5-[3-cyano-4-(1-phenylethylamino)-6-quinolyl]-3-pyridyl]methanesulfonamide (compound 48) To a stirred solution of N-[2-chloro-5-(4-chloro-3-cyano-6-quinolyl)-3-pyridyl]methanesulfonamide (80 mg, 203.43 μmol, 1 equiv.) in MeCN (3 mL), 1-phenylethanamine (24.65 mg, 203.43 μmol, 25.95 μL, 1 equiv.) and TEA (32.94 mg, 325.50 μmol, 45.30 μL, 1.6 equiv.) were added and the mixture was stirred at 90 °C for 2 h. LCMS showed that the starting material was completely consumed and the desired MS was detected. The reaction mixture was concentrated in vacuum and the crude product was purified by preparative HPLC (column: Phenomenex luna C18 80*40 mm*3 um; mobile phase: [water (0.04% HCl)-ACN]; B%: 23%-50%, 7 min). Compound 48, N-[2-chloro-5-[3-cyano-4-(1-phenylethylamino)-6-quinolyl]-3-pyridyl]methanesulfonamide (41.7 mg, 81.06 μmol, 39.85% yield, 100% purity, HCl) was obtained as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ=10.00(s,1H),9.38(br s,1H),9.13(s,1H),8.96(br s,1H),8.87(d,J=2.3Hz,1H),8.37-8.27(m,2H),8.07(d,J=8.6Hz,1H),7.51-7.45(m,2H),7.39(t ,J=7.6Hz,2H),7.33-7.27(m,1H),6.10-5.95(m,1H),3.20(s,3H),1.81(d,J=6.6Hz,3H).MS(M+H) + =478.0.

[0245] Compounds 48R and 48S were synthesized using a procedure similar to compound 48 in Example 15, substituting (1R)-1-phenylethanamine or (1S)-1-phenylethanamine for racemic 1-phenylethanamine.

[0246] Compound 48R: 1H NMR(400MHz,DMSO-d6)δ=10.00(s,1H),9.03(s,1H),8.98(br d,J=6.9Hz,1H),8.87-8.80(m,2H),8.31-8.25(m,2H),8.02(d,J=8.8Hz, 1H),7.49-7.44(m,2H),7.38(t,J=7.6Hz,2H),7.32-7.26(m,1H),5.98(br t,J=7.2Hz,1H),3.20(s,3H),1.78(d,J=6.8Hz,3H).MS(M+H) + =478.0.

[0247] Compound 48S: 1 H NMR(400MHz,DMSO-d6)δ=10.00(br s,1H),9.04(s,1H),9.00(br s,1H),8.88-8.80(m,2H),8.32-8.25(m,2H),8.02(d,J=8.8Hz,1H),7.50-7.43(m,2H),7.38(t,J=7.5Hz,2H),7.35-7.26(m,1H),5.98(br t,J=7.2Hz,1H),3.20(s,3H),1.78(d,J=6.7Hz,3H).MS(M+H) + =478.0.

[0248] Example 16: Synthesis of 6-(2-aminopyrimidin-5-yl)-4-(1-phenylethylamino)quinoline-3-carbonitrile (Compound 53) [ka] Step 1: Synthesis of 6-bromo-4-(1-phenylethylamino)quinoline-3-carbonitrile (2g) To a stirred solution of 6-bromo-4-chloro-quinoline-3-carbonitrile (1 g, 3.74 mmol, 1 equiv.) in i-PrOH (15 mL), TEA (605.22 mg, 5.98 mmol, 832.49 μL, 1.6 equiv.) 1-phenylethanamine (543.59 mg, 4.49 mmol, 572.20 μL, 1.2 equiv.) was added and the mixture was stirred at 80° C. for 12 h. LCMS showed that the starting material was completely consumed and the desired MS was detected. The reaction mixture was concentrated in vacuo. Compound 2g, 6-bromo-4-(1-phenylethylamino)quinoline-3-carbonitrile (1.1 g, 3.12 mmol, 83.54% yield) was obtained as a brown solid. MS (M+H) + =354.1.

[0249] Step 2: Synthesis of 6-(2-aminopyrimidin-5-yl)-4-(1-phenylethylamino)quinoline-3-carbonitrile (compound 53) To a stirred solution of 6-bromo-4-(1-phenylethylamino)quinoline-3-carbonitrile (500 mg, 1.42 mmol, 1 equiv) in DMF (5 mL) and HO (1 mL) was added (2-aminopyrimidin-5-yl)boronic acid (197.20 mg, 1.42 mmol, 1 equiv), Pd(PPh3)4 (1.64 g, 1.42 mmol, 1 equiv), and K3PO4 (903.96 mg, 4.26 mmol, 3 equiv), the mixture was purged with N2 for 1 min and stirred at 100 °C for 3 h. LCMS showed complete consumption of starting material and the desired MS was detected. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC (column: Phenomenex luna C18 250*50mm*10um; mobile phase: [water (0.04% HCl)-ACN]; B%: 10%~40%, 10 min). Compound 53 6-(2-aminopyrimidin-5-yl)-4-(1-phenylethylamino)quinoline-3-carbonitrile (157.87mg, 379.75μmol, 26.75% yield, 96.91% purity, HCl) was obtained as a yellow solid. 1H NMR(400MHz,DMSO-d6)δ=10.09(br d,J=8.3Hz,1H),9.36(s,1H),9.18(s,2H),9.08(s,1H),8.41(dd,J=1.6,8.8Hz,1H),8.14(d,J=8.9Hz,1H),7 .55(d,J=7.4Hz,2H),7.43-7.35(m,2H),7.33-7.28(m,1H),6.14-6.03(m,1H),1.87(d,J=6.8Hz,3H).MS(M+H) + =367.1.

[0250] Compound 53R was synthesized using an analogous procedure to compound 53 in Example 16, using chiral starting materials.

[0251] Compound 53R: 1 H NMR(400MHz,DMSO-d6)δ=10.00(br s,1H),9.30(br s,1H),9.12(br s,1H),9.07(s,1H),8.40(br d,J=8.8Hz,1H),8.13(br d,J=8.7Hz,1H),7.54(br d,J=7.6Hz,2H),7.42-7.37(m,2H),7.34-7.27(m,1H),6.19-5.86(m,1H),1.86(br d,J=6.6Hz,3H).MS(M+H) + =367.1

[0252] Example 17: [ka] Step 1: Synthesis of 6-bromo-4-(1-phenylethylamino)quinoline-3-carbonitrile (2h) To a stirred solution of 6-bromo-4-chloro-quinoline-3-carbonitrile (1 g, 3.74 mmol, 1 equiv.) in i-PrOH (15 mL), TEA (605.22 mg, 5.98 mmol, 832.49 μL, 1.6 equiv.), 1-phenylethanamine (543.59 mg, 4.49 mmol, 572.20 μL, 1.2 equiv.) were added and the mixture was stirred at 80° C. for 12 h. LCMS showed that the starting material was completely consumed and the desired MS was detected. The reaction mixture was concentrated in vacuo. Compound 2h, 6-bromo-4-(1-phenylethylamino)quinoline-3-carbonitrile (1.1 g, 3.12 mmol, 83.54% yield) was obtained as a brown solid. MS (M+H) + =354.1.

[0253] Step 2: Synthesis of 6-(2-aminopyrimidin-5-yl)-4-(1-phenylethylamino)quinoline-3-carbonitrile (compound 54) To a stirred solution of 6-bromo-4-(1-phenylethylamino)quinoline-3-carbonitrile (500 mg, 1.42 mmol, 1 equiv) in DMF (5 mL) and HO (1 mL) was added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridine (348.02 mg, 1.42 mmol, 1 equiv), Pd(PPh3)4 (164.04 mg, 142.00 μmol, 0.1 equiv), and K3PO4 (903.96 mg, 4.26 mmol, 3 equiv), the mixture was purged with N2 for 1 min and stirred at 100 °C for 3 h. LCMS showed that the starting material was concentrated in vacuo. The reaction mixture was filtered and the filtrate was concentrated to give 20 mg of crude product. The crude product was purified by preparative HPLC (column: Phenomenex luna C18 80*40mm*3um; mobile phase: [water (0.1% TFA)-ACN]; B%: 17%-30%, 7 min). Compound 54, 4-(1-phenylethylamino)-6-(1H-pyrazolo[3,4-b]pyridin-5-yl)quinoline-3-carbonitrile (10.40mg, 20.62μmol, 1.45% yield, 100% purity, TFA) was obtained as a pale yellow solid. 1H NMR(400MHz,DMSO-d6)δ=9.18-9.00(m,2H),8.97-8.86(m,1H),8.78(s,1H),8.71(d,J=1.8Hz,1H),8.35(br d,J=8.8Hz,1H),8.30(s,1H),8.00(d,J=8.7Hz,1H),7.47(br d,J=7.6Hz,2H),7.38(t,J=7.5Hz,2H),7.32-7.23(m,1H),6.08-5.88(m,1H),1.79(d,J=6.7Hz,3H).MS(M+H) + =391.1.

[0254] Example 18: Synthesis of 4-[[(1R)-1-phenylethyl]amino]-6-(1H-pyrazolo[3,4-b]pyridin-5-yl)quinoline-3-carbonitrile (Compound 54R) [ka] Step 1: Synthesis of 6-bromo-4-chloro-quinoline-3-carbonitrile (2i) To a solution of 6-bromo-4-hydroxy-quinoline-3-carbonitrile (10 g, 40.15 mmol, 1 equiv.) in SOCl2 (50 mL) was added DMF (293.47 mg, 4.02 mmol, 308.92 μL, 0.1 equiv.), the mixture was purged with N2, and the reaction was stirred at 20 °C for 12 h. LCMS showed that the starting material was completely consumed and MS of the desired product was detected. The reaction mixture was concentrated in vacuo. Compound 2i 6-bromo-4-chloro-quinoline-3-carbonitrile (10.3 g, 38.50 mmol, 95.90% yield) was obtained as a black solid. MS (M+H) + =269.1

[0255] Step 2: Synthesis of 6-bromo-4-[[(1R)-1-phenylethyl]amino]quinoline-3-carbonitrile (3i) To a solution of 6-bromo-4-chloro-quinoline-3-carbonitrile, 2i, (2 g, 7.48 mmol, 1 equiv.) in i-PrOH (15 mL), (1R)-1-phenylethanamine (996.58 mg, 8.22 mmol, 1.06 mL, 1.1 equiv.) and TEA (1.21 g, 11.96 mmol, 1.66 mL, 1.6 equiv.) were added, the mixture was purged with N2, and the reaction was stirred at 80 °C for 12 h. LCMS showed that the starting material was completely consumed and MS of the desired product was detected. The reaction mixture was filtered and the filtrate was concentrated in vacuo. Compound 3i, 6-bromo-4-[[(1R)-1-phenylethyl]amino]quinoline-3-carbonitrile (2.4 g, 6.81 mmol, 91.14% yield) was obtained as a black oil. MS (M+H) + =352.1

[0256] Step 3: Synthesis of 4-[[(1R)-1-phenylethyl]amino]-6-(1H-pyrazolo[3,4-b]pyridin-5-yl)quinoline-3-carbonitrile (compound 54R) To a solution of 6-bromo-4-[[(1R)-1-phenylethyl]amino]quinoline-3-carbonitrile (1.57 g, 4.46 mmol, 1 equiv.) in DMF (15 mL) and HO (3 mL) was added CsCO (4.36 g, 13.37 mmol, 3 equiv.), Pd(dppf)Cl (326.15 mg, 445.73 μmol, 0.1 equiv.), and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridine (1.09 g, 4.46 mmol, 1 equiv.), the mixture was purged with N, and the reaction was stirred at 100° C. for 3 h. LC-MS showed complete consumption of starting material and MS of desired product was detected. The reaction was filtered and the filter cake was concentrated in vacuum. The filter cake was purified by preparative HPLC (column: Phenomenex luna C18 250*50mm*10um; mobile phase: [water (0.04% HCl)-ACN]; B%: 15%-45%, 10 min). Compound 54R, 4-[[(1R)-1-phenylethyl]amino]-6-(1H-pyrazolo[3,4-b]pyridin-5-yl)quinoline-3-carbonitrile (70.43mg, 159.40μmol, 3.58% yield, 96.62% purity, HCl) was obtained as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 9.79(br s,1H),9.25(br s,1H),9.13(br d,J=9.17Hz,2H),8.78(br d,J=1.59Hz,1H),8.50(br d,J=8.80Hz,1H),8.32(s,1H),8.10-8.21(m,1H),7.52(br d,J=7.46Hz,2H),7.41(t,J=7.64Hz,2H),7.28-7.35(m,1H),6.10(br t,J=6.97Hz,1H),1.85(br d,J=6.60Hz,3H).MS(M+H) + =391.1

[0257] Example 19: Synthesis of 4-(1-phenylethylamino)-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)quinoline-3-carbonitrile (Compound 55) [ka] To a solution of 4-(1-phenylethylamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-3-carbonitrile (80 mg, 200.35 μmol, 1 equiv.) in DMF (0.5 mL) and HO (0.1 mL) was added CsCO (195.84 mg, 601.06 μmol, 3 equiv.), Pd(dppf)Cl (14.66 mg, 20.04 μmol, 0.1 equiv.), and 5-bromo-1H-pyrrolo[2,3-b]pyridine (39.48 mg, 200.35 μmol, 1 equiv.), the mixture was purged with N, and the reaction was stirred at 100° C. for 3 h. LCMS showed complete consumption of starting material and MS of desired product was detected. The reaction was purified by preparative HPLC (column: Phenomenex luna C18 80*40mm*3um; mobile phase: [water (0.04% HCl)-ACN]; B%: 20%~40%, 7 min). Compound 55, 4-(1-phenylethylamino)-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)quinoline-3-carbonitrile (12.19 mg, 28.28 μmol, 14.11% yield, 98.80% purity, HCl) was obtained as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 12.00(br s,1H)9.81(br d,J=7.82Hz,1H)9.20(s,1H)9.13(s,1H)8.84(d,J=1.96Hz,1H)8.54(s, 1H)8.49(dd,J=8.80,1.34Hz,1H)8.14(d,J=8.80Hz,1H)7.59-7.64(m,1H )7.52(d,J=7.46Hz,2H)7.41(t,J=7.64Hz,2H)7.28-7.35(m,1H)6.62(dd,J=3.30,1.71Hz,1H)6.00-6.18(m,1H)1.85(d,J=6.60Hz,3H).MS(M+H) + =390.0

[0258] Example 20: Synthesis of 6-(2-methyl-3H-imidazo[4,5-b]pyridin-6-yl)-4-(1-phenylethylamino)quinoline-3-carbonitrile (Compound 56) [ka] To a stirred solution of 4-(1-phenylethylamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-3-carbonitrile (120 mg, 300.53 μmol, 1 equiv.) in DMF (0.5 mL) and HO (0.1 mL) was added CsCO (293.76 mg, 901.60 μmol, 3 equiv.), Pd(dppf)Cl (21.99 mg, 30.05 μmol, 0.1 equiv.), and 6-bromo-2-methyl-1H-imidazo[4,5-b]pyridine (82.84 mg, 390.69 μmol, 1.3 equiv.), the mixture was purged with N and stirred at 100° C. for 3 h. LCMS showed complete consumption of starting material and MS of desired product was detected. The reaction mixture was filtered, and the filtrate was concentrated in vacuum to give the crude product (20 mg), which was purified by preparative HPLC (column: Phenomenex luna C18 80*40 mm*3 um; mobile phase: [water (0.04% HCl)-ACN]; B%: 12%-28%, 7 min). Compound 56 6-(2-methyl-3H-imidazo[4,5-b]pyridin-6-yl)-4-(1-phenylethylamino)quinoline-3-carbonitrile (9 mg, 18.76 μmol, 6.24% yield, 91.93% purity, HCl) was obtained as a brown solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 10.26(br d,J=8.07Hz,1H)9.51(s,1H)9.17(s,1H)9.09(s,1H)8.92(s,1H)8.52(br d,J=8.80Hz,1H)8.20(d,J=8.68Hz,1H)7.57(br d,J=7.70Hz,2H)7.35-7.43(m,2H)7.26-7.33(m,1H)6.01-6.15(m,1H)2.85(s,3H)1.89(br d,J=6.60Hz,3H).MS(M+H) + =405.1

[0259] Example 21: Synthesis of 6-(5-hydroxy-3-pyridyl)-4-(1-phenylethylamino)quinoline-3-carbonitrile (Compound 61) [ka] To a stirred solution of 4-(1-phenylethylamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-3-carbonitrile (100 mg, 250.44 μmol, 1 equiv.) in DMF (0.5 mL) and HO (0.1 mL) was added CsCO (244.80 mg, 751.33 μmol, 3 equiv.), Pd(dppf)Cl (18.33 mg, 25.04 μmol, 0.1 equiv.), and 5-bromopyridin-3-ol (43.58 mg, 250.44 μmol, 1 equiv.), the mixture was purged with N and stirred at 100° C. for 3 h. LCMS showed complete consumption of starting material and MS of desired product was detected. The reaction was filtered, the filter cake was washed with DMSO, and then the filtrate was concentrated in vacuum. The crude product was purified by preparative HPLC (column: Phenomenex Luna C18 150*30mm*5um; mobile phase: [water (0.1% TFA)-ACN]; B%: 1%-35%, 8 min). Compound 61, 6-(5-hydroxy-3-pyridyl)-4-(1-phenylethylamino)quinoline-3-carbonitrile (30.91 mg, 62.70 μmol, 25.03% yield, 97.45% purity, TFA) was obtained as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 9.24(br d,J=8.19Hz,1H),9.06(d,J=1.22Hz,1H),8.92(s,1H),8.68(d,J=1.59Hz,1H),8.26-8.35(m,2H),8.01(d,J=8.68Hz,1H),7. 86(s,1H),7.43-7.49(m,2H),7.38(t,J=7.64Hz,2H),7.25-7.33(m,1H),5.94-6.06(m,1H),1.79(d,J=6.72Hz,3H).MS(M+H) + =367.1

[0260] Example 22: Synthesis of 6-(5-cyano-3-pyridyl)-4-(1-phenylethylamino)quinoline-3-carbonitrile (Compound 64) [ka] To a solution of 4-(1-phenylethylamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-3-carbonitrile (100 mg, 250.44 μmol, 1 equiv.) in DMF (2 mL) and HO (0.4 mL) was added CsCO (244.80 mg, 751.33 μmol, 3 equiv.), Pd(dppf)Cl (18.33 mg, 25.04 μmol, 0.1 equiv.), and 5-bromopyridine-3-carbonitrile (45.83 mg, 250.44 μmol, 1 equiv.), the mixture was purged with N, and the reaction was stirred at 100° C. for 3 h. LCMS showed complete consumption of starting material and MS of desired product was detected. The reaction was filtered and the filtrate was purified by preparative HPLC (column: Phenomenex Luna 80*30mm*3um; mobile phase: [water (HCl)-ACN]; B%: 15%~45%, 8 min). Compound 64, 6-(5-cyano-3-pyridyl)-4-(1-phenylethylamino)quinoline-3-carbonitrile (12.41 mg, 28.52 μmol, 11.39% yield, 94.65% purity, HCl) was obtained as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 10.04(br d,J=7.82Hz,1H),9.51(d,J=2.20Hz,1H),9.41(s,1H),9.14(s,2H),9.01(t,J=1.96Hz,1H),8.52(dd,J=8.74,1.41Hz,1H),8.20(d,J=8. 68Hz,1H),7.54(d,J=7.46Hz,2H),7.40(t,J=7.52Hz,2H),7.27-7.35(m,1H),6.10(quin,J=7.06Hz,1H),1.87(d,J=6.60Hz,3H).MS(M+H) + =376.2

[0261] Example 23: Synthesis of 6-(6-amino-5-cyano-3-pyridyl)-4-(1-phenylethylamino)quinoline-3-carbonitrile (Compound 65) [ka] To a solution of 4-(1-phenylethylamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-3-carbonitrile (100 mg, 250.44 μmol, 1 equiv.) in DMF (2.5 mL) and HO (0.4 mL) was added CsCO (244.80 mg, 751.33 μmol, 3 equiv.), Pd(dppf)Cl (18.33 mg, 25.04 μmol, 0.1 equiv.), and 2-amino-5-bromo-pyridine-3-carbonitrile (49.59 mg, 250.44 μmol, 1 equiv.), the mixture was purged with N, and the reaction was stirred at 100° C. for 3 h. LCMS showed complete consumption of starting material and MS of desired product was detected. The reaction was filtered and the filtrate was purified by preparative HPLC (column: Phenomenex luna C18 80*40mm*3um; mobile phase: [water (HCl)-ACN]; B%: 17%~43%, 7 min). Compound 65, 6-(6-amino-5-cyano-3-pyridyl)-4-(1-phenylethylamino)quinoline-3-carbonitrile (26.28mg, 59.16μmol, 23.62% yield, 96.10% purity, HCl) was obtained as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 9.86(br d,J=7.46Hz,1H)9.05-9.19(m,2H)8.83-8.96(m,1H)8.60(d,J=2.20Hz,1H)8.35-8.43(m,1H)8.01-8.15(m,1H) )7.52(d,J=7.46Hz,2H)7.38-7.42(m,2H)7.30-7.34(m,1H)5.85-6.27(m,1H)1.86(d,J=6.72Hz,3H).MS(M+H) + =391.1

[0262] Example 24: Synthesis of 6-[5-(1-hydroxy-1-methyl-ethyl)-3-pyridyl]-4-(1-phenylethylamino)quinoline-3-carbonitrile (Compound 67) [ka] To a stirred solution of 4-(1-phenylethylamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-3-carbonitrile (120 mg, 300.53 μmol, 1 equiv) in DMF (0.5 mL) and HO (0.1 mL) was added CsCO (293.76 mg, 901.60 μmol, 3 equiv), Pd(dppf)Cl (21.99 mg, 30.05 μmol, 0.1 equiv), and 2-(5-bromo-3-pyridyl)propan-2-ol (84.42 mg, 390.69 μmol, 1.3 equiv), the mixture was purged with N and stirred at 100° C. for 3 h. LCMS showed complete consumption of starting material and MS of desired product was detected. The reaction mixture was filtered, the filter cake was washed with MeOH, and the filtrate was concentrated in vacuum. The crude product was purified by preparative HPLC (column: Phenomenex Luna 80*30mm*3um; mobile phase: [water (0.04% HCl)-ACN]; B%: 5%-25%, 8 min). Compound 67, 6-[5-(1-hydroxy-1-methyl-ethyl)-3-pyridyl]-4-(1-phenylethylamino)quinoline-3-carbonitrile (36.18mg, 77.82μmol, 25.89% yield, 95.70% purity, HCl) was obtained as a brown solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 10.72(br d,J=8.07Hz,1H)9.91(s,1H)9.62(s,1H)9.39(s,1H)9.11(s,1H)8.94(s,1H)8.60(br d,J=8.68Hz,1H)8.25(d,J=8.80Hz,1H)7.62(d,J=7.58Hz,2H)7.37(t,J=7.52Hz,2 H)7.24-7.33(m,1H)6.02-6.15(m,1H)1.93(d,J=6.60Hz,3H)1.64(s,6H).MS(M+H) + =409.1

[0263] Example 25: Synthesis of 6-(5,6-dimethoxy-3-pyridyl)-4-(1-phenylethylamino)quinoline-3-carbonitrile (Compound 68) [ka] Step 1: Synthesis of 6-bromo-4-(1-phenylethylamino)quinoline-3-carbonitrile (2j) To a solution of 6-bromo-4-chloro-quinoline-3-carbonitrile (8 g, 29.91 mmol, 1 equiv.) i-PrOH (30 mL), 1-phenylethanamine (3.99 g, 32.90 mmol, 4.20 mL, 1.1 equiv.) and TEA (4.84 g, 47.85 mmol, 6.66 mL, 1.6 equiv.) were added and the reaction was stirred at 80° C. for 12 h. LCMS showed that the starting material was completely consumed and MS of the desired product was detected. The reaction mixture was concentrated in vacuo. Compound 2j, 6-bromo-4-(1-phenylethylamino)quinoline-3-carbonitrile (9 g, 25.55 mmol, 85.44% yield) was obtained as a grey solid. MS (M+H) + =352.1

[0264] Step 2: Synthesis of 4-(1-phenylethylamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-3-carbonitrile (3j) To a solution of 6-bromo-4-(1-phenylethylamino)quinoline-3-carbonitrile, 2j, (7 g, 19.87 mmol, 1 equiv.) in dioxane (80 mL) was added AcOK (5.85 g, 59.61 mmol, 3 equiv.), Pd(dppf)Cl2.CH2Cl2 (1.62 g, 1.99 mmol, 0.1 equiv.), BPD (6.06 g, 23.84 mmol, 1.2 equiv.), the mixture was purged with Ar, and the reaction was stirred at 110 °C for 8 h. LCMS showed the starting material was completely consumed and MS of the desired product was detected. TLC (PE:EtOAc = 3:1, R f=0.24) indicated complete consumption of starting material and formation of a new spot. The reaction mixture was cooled to room temperature, quenched with water (50 mL) and extracted with ethyl acetate (40 mL*2). The combined organics were washed with brine (30 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, 50-70% ethyl acetate in petroleum ether, gradient over 40 min). Compound 2j, 4-(1-phenylethylamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-3-carbonitrile (5.5 g, 13.77 mmol, 69.32% yield) was obtained as a brown oil. MS(M+H) + =400.3

[0265] Step 3: Synthesis of 6-(5,6-dimethoxy-3-pyridyl)-4-(1-phenylethylamino)quinoline-3-carbonitrile (compound 68) To a solution of 4-(1-phenylethylamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-3-carbonitrile, 3j, (230 mg, 576.02 μmol, 1 equiv.) in DMF (0.5 mL) and HO (0.1 mL), CsCO (563.04 mg, 1.73 mmol, 3 equiv.), Pd(dppf)Cl (42.15 mg, 57.60 μmol, 0.1 equiv.), and 5-bromo-2,3-dimethoxy-pyridine (163.28 mg, 748.83 μmol, 1.3 equiv.) were added, the mixture was purged with N, and the reaction was stirred at 100° C. for 3 h. LCMS showed complete consumption of starting material and MS of desired product was detected. The reaction mixture was concentrated in vacuo. The crude product was purified by preparative HPLC (column: Phenomenex Luna 80*30mm*3um; mobile phase: [water (0.04% HCl)-ACN]; B%: 10%-30%, 8 min). Compound 68, 6-(5,6-dimethoxy-3-pyridyl)-4-(1-phenylethylamino)quinoline-3-carbonitrile (39.53 mg, 88.45 μmol, 15.36% yield, 100% purity, HCl) was obtained as a yellow solid. 1H NMR(400MHz,DMSO-d6)δ ppm 9.05(br s,1H)8.89(br s,1H)8.25-8.39(m,2H)8.00(br d,J=8.68Hz,1H)7.70-7.82(m,1H)7.45-7.52(m,2H)7.39(t,J=7.58Hz,2H)7.23-7.34(m,1H)6.00(br d,J=5.99Hz,1H)3.83-4.05(m,6H)1.80(br d,J=6.60Hz,3H).MS(M+H) + =411.1

[0266] Example 26: Synthesis of 4-(1-phenylethylamino)-6-(3H-triazolo[4,5-b]pyridin-6-yl)quinoline-3-carbonitrile (Compound 70) [ka] To a solution of 4-(1-phenylethylamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-3-carbonitrile (150 mg, 375.66 μmol, 1 equiv.) in DMF (2 mL) and H2O (0.4 mL), Cs2CO3 (367.20 mg, 1.13 mmol, 3 equiv.), Pd(dppf)Cl2 (27.49 mg, 37.57 μmol, 0.1 equiv.), and 6-bromo-3H-triazolo[4,5-b]pyridine (97.19 mg, 488.36 μmol, 1.3 equiv.) were added, the mixture was purged with N2 and stirred at 100 °C for 3 h. LCMS showed complete consumption of starting material and MS of desired product was detected. The reaction mixture was concentrated in vacuo. The crude product was purified by preparative HPLC (column: Phenomenex Luna C18 75*30mm*3um; mobile phase: [water (0.04% HCl)-ACN]; B%: 5%-35%, 8 min). Compound 70, 4-(1-phenylethylamino)-6-(3H-triazolo[4,5-b]pyridin-6-yl)quinoline-3-carbonitrile (21.49 mg, 49.03 μmol, 13.05% yield, 97.63% purity, HCl) was obtained as an off-white solid. 1H NMR(400MHz,DMSO-d6)δ=9.36-9.29(m,1H),9.23-9.15(m,1H),9.07-8.82(m,2H),8.56-8.41(m,1H),8.14-7.97(m,1H),7.49(br d,J=6.9Hz,2H),7.43-7.35(m,2H),7.33-7.25(m,1H),6.10-5.90(m,1H),1.80(br d,J=6.4Hz,3H).MS(M+H) + =392.1

[0267] Example 27: Synthesis of 6-(1-methylpyrazolo[4,3-b]pyridin-6-yl)-4-(1-phenylethylamino)quinoline-3-carbonitrile (Compound 73) [ka] To a stirred solution of 4-(1-phenylethylamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-3-carbonitrile (200 mg, 500.89 μmol, 1 equiv.) in DMF (2 mL) and HO (0.4 mL), CsCO (489.59 mg, 1.50 mmol, 3 equiv.), Pd(dppf)Cl (36.65 mg, 50.09 μmol, 0.1 equiv.), and 6-bromo-1-methyl-pyrazolo[4,3-b]pyridine (138.07 mg, 651.15 μmol, 1.3 equiv.) were added, the mixture was purged with N and stirred at 100° C. for 3 h. LCMS showed complete consumption of starting material and MS of desired product was detected. The reaction mixture was concentrated in vacuo. The crude product was purified by preparative HPLC (column: Phenomenex Luna 80*30mm*3um; mobile phase: [water (0.04% HCl)-ACN]; B%: 10%-30%, 8 min). Compound 73, 6-(1-methylpyrazolo[4,3-b]pyridin-6-yl)-4-(1-phenylethylamino)quinoline-3-carbonitrile (70.96 mg, 175.44 μmol, 35.03% yield, 100% purity) was obtained as a yellow solid. 1H NMR(400MHz,DMSO-d6)δ ppm 9.94(br s,1H),9.42(br s,1H),9.17(s,1H),9.10(s,1H),8.88(br s,1H),8.55(br d,J=8.75Hz,1H),8.38(s,1H),8.15(br d,J=8.75Hz,1H),7.54(br d,J=7.75Hz,2H),7.40(t,J=7.63Hz,2H),7.27-7.34(m,1H),6.10(br t,J=7.07Hz,1H),4.20(s,3H),1.86(br d,J=6.38Hz,3H).MS(M+H) + =405.1

[0268] Example 28: Synthesis of 6-(2-amino-1,3-benzoxazol-5-yl)-4-(1-phenylethylamino)quinoline-3-carbonitrile (Compound 87) [ka] To a solution of 4-(1-phenylethylamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-3-carbonitrile (120 mg, 300.53 μmol, 1 equiv.) in DMF (2.5 mL) and H2O (0.5 mL), Cs2CO3 (293.76 mg, 901.60 μmol, 3 equiv.), Pd(dppf)Cl2 (21.99 mg, 30.05 μmol, 0.1 equiv.), and 5-bromo-1,3-benzoxazol-2-amine (83.23 mg, 390.69 μmol, 1.3 equiv.) were added, the mixture was purged with N2 and stirred at 100 °C for 3 h. LCMS showed complete consumption of starting material and MS of desired product was detected. The reaction mixture was concentrated in vacuo. The crude product was purified by preparative HPLC (column: Phenomenex Luna 80*30mm*3um; mobile phase: [water (0.04% HCl)-ACN]; B%: 5%~25%, 8 min). Compound 87, 6-(2-amino-1,3-benzoxazol-5-yl)-4-(1-phenylethylamino)quinoline-3-carbonitrile (15.31 mg, 34.64 μmol, 11.53% yield, 100% purity, HCl) was obtained as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 9.83(br s,1H),9.11(s,2H),8.40(dd,J=8.82,1.31Hz,1H),8.11(br d,J=8.75Hz,1H),8.02(br s,1H),7.82(s,1H),7.57(s,2H),7.51(d,J=7.50Hz,2H),7.41(t,J=7.57Hz ,2H),7.27-7.35(m,1H),5.95-6.20(m,1H),1.84(d,J=6.63Hz,3H).MS(M+H) + =406.1

[0269] Example 29: Synthesis of N-[2-chloro-5-[3-cyano-4-[[(1R)-1-(4-fluorophenyl)ethyl]amino]-6-quinolyl]-3-pyridyl]methanesulfonamide (Compound 97R) [ka] Step 1: Synthesis of (Z)-3-(4-bromoanilino)-2-cyano-prop-2-enoic acid ethyl ester (2k) To a solution of 4-bromoaniline (184.88 g, 1.07 mol, 1 equiv.) in toluene (1.5 L) was added ethyl (E)-2-cyano-3-ethoxy-prop-2-enoate (200 g, 1.18 mol, 1.1 equiv.) and the mixture was stirred at 110° C. for 6 h. TLC (petroleum ether / ethyl acetate=3:1, R f =0.88), indicating complete consumption of the starting material and the formation of a new spot. The reaction mixture was filtered and the filter cake was concentrated in vacuo. Compound 2k, (Z)-ethyl 3-(4-bromoanilino)-2-cyano-prop-2-enoate (150 g, 508.25 mmol, 47.29% yield) was obtained as a white solid. 1 H NMR (400 MHz, chloroform-d) δ = 10.75 (br d, J = 13.0 Hz, 1H), 8.42-7.78 (m, 1H), 7.52 (br d, J = 8.6 Hz, 2H), 7.07-6.94 (m, 2H), 4.36-4.24 (m, 2H), 1.43-1.30 (m, 3H).

[0270] Step 2: Synthesis of 6-bromo-4-hydroxy-quinoline-3-carbonitrile (3k) A solution of (Z)-3-(4-bromoanilino)-2-cyano-prop-2-enoic acid ethyl ester, 2k, (40 g, 135.53 mmol, 1 equiv.) in Ph2O (400 mL) was stirred at 270° C. for 8 h. TLC (petroleum ether / ethyl acetate=3:1, R f =0.43) indicated that a small amount of starting material remained and a new spot formed. The reaction mixture was poured into MTBE (200 mL). The reaction mixture was filtered and the filter cake was concentrated in vacuo to give compound 3k, 6-bromo-4-hydroxy-quinoline-3-carbonitrile (2 g, 8.03 mmol, 5.92% yield) as a yellow solid.

[0271] Step 3: Synthesis of N-[2-chloro-5-(3-cyano-4-hydroxy-6-quinolyl)-3-pyridyl]methanesulfonamide (4k) To a stirred solution of N-[2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]-N-methylsulfonylmethanesulfonamide, 3b, (1.7 g, 4.14 mmol, 1 equiv) in dioxane (30 mL), HO (5 mL) was added 6-bromo-4-hydroxy-quinoline-3-carbonitrile, 3k, (1.55 g, 6.21 mmol, 1.5 equiv), Pd(dppf)Cl2 (302.87 mg, 413.93 μmol, 0.1 equiv), Cs2CO3 (4.05 g, 12.42 mmol, 3 equiv), the mixture was purged with N2 for 1 min, and the mixture was stirred at 100° C. for 16 h. LCMS showed complete consumption of starting material and the desired MS was detected. The reaction mixture was concentrated in vacuo. The crude residue was purified by preparative HPLC (Agela DuraShell C18 250*80mm*10um column; 1-30% acetonitrile in 10mM ammonium bicarbonate solution in water, 20min gradient). Compound 4k, N-[2-chloro-5-(3-cyano-4-hydroxy-6-quinolyl)-3-pyridyl]methanesulfonamide (1g, 2.67mmol, 64.46% yield) was obtained as a white solid. MS(M+H) + =375.0.

[0272] Step 4: Synthesis of N-[2-chloro-5-(4-chloro-3-cyano-6-quinolyl)-3-pyridyl]methanesulfonamide (5k) A solution of N-[2-chloro-5-(3-cyano-4-hydroxy-6-quinolyl)-3-pyridyl]methanesulfonamide, 4k, (1g, 2.67mmol, 1eq) in POCl3 (16.50g, 107.61mmol, 10mL, 40.33eq) was stirred at 120°C for 16 hours. LCMS showed that the starting material was completely consumed and the desired MS was detected. The reaction mixture was concentrated in vacuum. The reaction mixture was dissolved with DCM (10mL) and poured into water (30mL). The aqueous phase was extracted with ethyl acetate (30mL*2). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated in vacuum. Compound 5k, N-[2-chloro-5-(4-chloro-3-cyano-6-quinolyl)-3-pyridyl]methanesulfonamide (600 mg, 1.53 mmol, 57.19% yield) was obtained as a yellow solid. MS (M+H) + =393.0.

[0273] Step 5: Synthesis of N-[2-chloro-5-[3-cyano-4-[[(1R)-1-(4-fluorophenyl)ethyl]amino]-6-quinolyl]-3-pyridyl]methanesulfonamide (compound 97R) To a stirred solution of N-[2-chloro-5-(4-chloro-3-cyano-6-quinolyl)-3-pyridyl]methanesulfonamide, 5k, (100 mg, 254.29 μmol, 1 equiv.) in i-PrOH (3 mL), (1R)-1-(4-fluorophenyl)ethanamine (35.39 mg, 254.29 μmol, 1 equiv.), TEA (41.17 mg, 406.87 μmol, 56.63 μL, 1.6 equiv.) were added and the mixture was stirred at 80 °C for 16 h. LCMS showed that the starting material was completely consumed and the desired MS was detected. The reaction mixture was concentrated and the crude residue was purified by preparative HPLC (Phenomenex Gemini-NX 150*30 mm*5 um column; 20-50% acetonitrile in 0.1% trifluoroacetic acid solution in water, 9 min gradient). Compound 97R, N-[2-chloro-5-[3-cyano-4-[[(1R)-1-(4-fluorophenyl)ethyl]amino]-6-quinolyl]-3-pyridyl]methanesulfonamide (14.70 mg, 23.93 μmol, 9.41% yield, 99.31% purity, TFA) was obtained as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ=9.98(br s,1H),9.01(s,1H),8.90-8.81(m,2H),8.78(br s,1H),8.32-8.22(m,2H),8.01(d,J=8.8Hz,1H),7.50(dd,J=5.4,8.4Hz,2H),7.20(t,J=8.8Hz,2H),5.94(br t,J=7.1Hz,1H),3.20(s,3H),1.76(d,J=6.6Hz,3H).MS(M+H) + =496.0.

[0274] Compound 97S was synthesized using the same procedure as compound 97R in Example 29, but substituting (1R)-1-(4-fluorophenyl)ethanamine for (1S)-1-(4-fluorophenyl)ethanamine.

[0275] Compound 97S: 1H NMR(400MHz,DMSO-d6)δ=9.98(br s,1H),9.00(s,1H),8.90-8.75(m,3H),8.31-8.23(m,2H),8.01(d,J=8.6Hz,1H),7.50(dd,J=5.4,8.4Hz,2H),7.20(t,J=8.8Hz,2H),5.94(br t,J=6.9Hz,1H),3.20(s,3H),1.76(d,J=6.6Hz,3H).MS(M+H) + =496.0.

[0276] Example 30: Synthesis of N-[2-chloro-5-[3-cyano-4-(indan-1-ylamino)-6-quinolyl]-3-pyridyl]methanesulfonamide (Compound 101) [ka]

[0277] To a solution of N-[2-chloro-5-(4-chloro-3-cyano-6-quinolyl)-3-pyridyl]methanesulfonamide (70 mg, 178.01 μmol, 1 equiv.) in i-PrOH (1 mL), TEA (54.04 mg, 534.02 μmol, 74.33 μL, 3 equiv.) and indan-1-amine (23.71 mg, 178.01 μmol, 22.80 μL, 1 equiv.) were added. The mixture was stirred at 80 °C for 2 h. LCMS showed that the starting material was completely consumed and the desired MS was detected. The reaction mixture was concentrated in vacuum. The crude product was purified by preparative HPLC (column: Phenomenex luna C18 80*40 mm*3 um; mobile phase: [water (0.04% HCl)-ACN]; B%: 25%-45%, 7 min). Compound 101, N-[2-chloro-5-[3-cyano-4-(indan-1-ylamino)-6-quinolyl]-3-pyridyl]methanesulfonamide (20.04 mg, 38.07 μmol, 21.39% yield, 100% purity, HCl) was obtained as a pale yellow solid. 1H NMR(400MHz,DMSO-d6)δ=9.99(s,1H),9.86(br d,J=8.4Hz,1H),9.19(s,1H),9.03(d,J=1.3Hz,1H),8.79(d,J=2.4Hz,1H),8.39(dd,J =1.6,8.8Hz,1H),8.27(d,J=2.4Hz,1H),8.20(d,J=8.8Hz,1H),7.43(d,J=7.4Hz,1H),7 .41-7.32(m,2H),7.31-7.25(m,1H),6.30(q,J=8.0Hz,1H),3.17(s,3H),3.16-3.09(m, 1H),3.06-2.95(m,1H),2.76(dtd,J=2.8,7.9,12.8Hz,1H),2.46-2.38(m,1H).MS(M+H) + =490.0.

[0278] Example 31: Synthesis of N-[2-chloro-5-[3-cyano-4-[(2-hydroxyindan-1-yl)amino]-6-quinolyl]-3-pyridyl]methanesulfonamide (Compound 103) [ka] To a solution of N-[2-chloro-5-(4-chloro-3-cyano-6-quinolyl)-3-pyridyl]methanesulfonamide (60 mg, 152.58 μmol, 1 equiv.) in MeCN (1 mL), 1-aminoindan-2-ol (22.76 mg, 152.58 μmol, 1 equiv.) and TEA (46.32 mg, 457.73 μmol, 63.71 μL, 3 equiv.) were added. The mixture was stirred at 80°C for 2 h. LCMS showed that the starting material was completely consumed and the desired MS was detected. The reaction mixture was concentrated in vacuum and the crude product was purified by preparative HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 um; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 18%-48%, 8 min). Compound 103, N-[2-chloro-5-[3-cyano-4-[(2-hydroxyindan-1-yl)amino]-6-quinolyl]-3-pyridyl]methanesulfonamide (10.94 mg, 21.62 μmol, 14.17% yield, 100% purity) was obtained as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δ=9.90(br s,1H),8.86(d,J=1.6Hz,1H),8.79(d,J=2.3Hz,1H),8.62(s,1H),8.26(d,J=2.3Hz,1H),8.20(br d,J=9.1Hz,1H),8.14(dd,J=1.7,8.7Hz,1H),7.99(d,J=8.6Hz,1H),7.38(d,J=7.0Hz,1H),7.35-7.24(m,3H), 5.92(dd,J=4.9,9.0Hz,1H),5.48(d,J=4.6Hz,1H),4.79-4.73(m,1H),3.23-3.16(m,1H),3.15(s,3H),2.98(br d,J=15.4Hz,1H).MS(M+H) + =506.2.

[0279] Example 32: Synthesis of N-[2-chloro-5-[3-cyano-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-6-quinolyl]-3-pyridyl]methanesulfonamide (Compound 104S) [ka] To a stirred solution of N-[2-chloro-5-(4-chloro-3-cyano-6-quinolyl)-3-pyridyl]methanesulfonamide (80 mg, 203.43 μmol, 1 equiv.) in MeCN (3 mL), (2S)-2-amino-2-phenyl-ethanol (33.49 mg, 244.12 μmol, 1.2 equiv.), TEA (32.94 mg, 325.50 μmol, 45.30 μL, 1.6 equiv.) were added and the mixture was stirred at 90 °C for 2 h. LCMS showed that the starting material was completely consumed and the desired MS was detected. The reaction mixture was concentrated in vacuo. The crude product was purified by preparative HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 um; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 5%-30%, 8 min). Compound 104S, N-[2-chloro-5-[3-cyano-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-6-quinolyl]-3-pyridyl]methanesulfonamide (28 mg, 56.68 μmol, 27.86% yield, 100% purity) was obtained as a white solid. 1 H NMR(400MHz,DMSO-d6)δ=9.96(br s,1H),8.98(s,1H),8.85(d,J=2.0Hz,1H),8.46(s,1H),8.27(d,J=2.1H z,1H),8.21-8.12(m,2H),7.97(d,J=8.6Hz,1H),7.46(d,J=7.5Hz,2H), 7.36(t,J=7.6Hz,2H),7.30-7.24(m,1H),5.79-5.71(m,1H),5.33(t,J= 5.9Hz,1H),3.97-3.88(m,1H),3.86-3.78(m,1H),3.19(s,3H).MS(M+H) + =494.2.

[0280] Compound 104R was synthesized using the same procedure as compound 104S in Example 32, but substituting (2S)-2-amino-2-phenyl-ethanol for (2R)-2-amino-2-phenyl-ethanol.

[0281] Compound 104R: 1H NMR(400MHz,DMSO-d6)δ=9.97(br s,1H),8.99(s,1H),8.86(d,J=2.0Hz,1H),8.47(s,1H),8.28(d,J=2.3Hz, 1H),8.22-8.12(m,2H),7.98(d,J=8.6Hz,1H),7.47(d,J=7.4Hz,2H),7.37 (t,J=7.5Hz,2H),7.32-7.25(m,1H),5.80-5.72(m,1H),5.34(t,J=5.9Hz, 1H),3.98-3.89(m,1H),3.83(td,J=5.2,10.9Hz,1H),3.20(s,3H).MS(M+H) + =494.2

[0282] Example 33: Synthesis of N-[2-chloro-5-[3-cyano-4-[(1-phenylcyclopropyl)amino]-6-quinolyl]-3-pyridyl]methanesulfonamide (Compound 106) [ka] To a stirred solution of N-[2-chloro-5-(4-chloro-3-cyano-6-quinolyl)-3-pyridyl]methanesulfonamide (100 mg, 254.29 μmol, 1 equiv.) in MeCN (2 mL), 1-phenylcyclopropanamine hydrochloride (43.14 mg, 254.29 μmol, 1 equiv.), pyridine hydrochloride (47.02 mg, 406.87 μmol, 1.6 equiv.) were added and the mixture was stirred at 90 °C for 2 h. LCMS showed that the starting material was completely consumed and the desired MS was detected. The reaction mixture was filtered to obtain the filtrate, which was purified by preparative HPLC (column: Phenomenex Gemini-NX 80*40 mm*3 um; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 10%-40%, 8 min). Compound 106, N-[2-chloro-5-[3-cyano-4-[(1-phenylcyclopropyl)amino]-6-quinolyl]-3-pyridyl]methanesulfonamide (19.4 mg, 39.21 μmol, 15.42% yield, 99.04% purity) was obtained as an off-white solid. 1H NMR(400MHz,DMSO-d6)δ=9.93(br s,1H),9.15(s,1H),8.92(d,J=1.6Hz,1H),8.83(d,J=2.3Hz,1H),8.48(s,1H),8.30(d,J=2.4Hz,1H),8.18(dd,J=1. 8,8.7Hz,1H),7.99(d,J=8.6Hz,1H),7.34-7.28(m,2H),7.21-7.15(m,3H),3.17(s,3H),1.78-1.69(m,2H),1.59(br s,2H).MS(M+H) + =490.2.

[0283] Example 34: Synthesis of N-[2-chloro-5-[4-[[(1S)-1-(4-fluorophenyl)ethyl]amino]quinazolin-6-yl]-3-pyridyl]methanesulfonamide (Compound 111S) [ka] Step 1: Synthesis of N-[(1S)-1-(4-fluorophenyl)ethyl]-6-iodo-quinazolin-4-amine (2l) To a solution of 4-chloro-6-iodo-quinazoline (2 g, 6.88 mmol, 1 equiv.) in i-PrOH (20 mL), (1S)-1-(4-fluorophenyl)ethanamine (1.05 g, 7.57 mmol, 1.1 equiv.), TEA (1.11 g, 11.02 mmol, 1.53 mL, 1.6 equiv.) were added and the mixture was stirred at 80° C. for 16 h. LCMS showed that the starting material was completely consumed and the desired MS was detected. The reaction mixture was concentrated in vacuo. Compound 2l, N-[(1S)-1-(4-fluorophenyl)ethyl]-6-iodo-quinazolin-4-amine (2.5 g, 6.36 mmol, 92.35% yield) was obtained as a yellow oil. MS (M+H) + =394.1.

[0284] Step 2: Synthesis of N-[2-chloro-5-[4-[[(1S)-1-(4-fluorophenyl)ethyl]amino]quinazolin-6-yl]-3-pyridyl]methanesulfonamide (compound 111S) To a stirred solution of N-[2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]-N-methylsulfonylmethanesulfonamide, 3b, (2.09 g, 5.09 mmol, 1 equiv.) in DMF (15 mL) / HO (3 mL) was added a mixture of N-[(1S)-1-(4-fluorophenyl)ethyl]-6-iodo-quinazolin-4-amine, 2l, (2 g, 5.09 mmol, 1 equiv.), Pd(PPh3)4 (587.78 mg, 508.65 μmol, 0.1 equiv.), K3PO4 (3.24 g, 15.26 mmol, 3 equiv.), purged three times with N2 and the mixture was stirred at 100° C. for 5 h. LCMS indicated complete consumption of starting material and the desired MS was detected. The reaction mixture was filtered and the filtrate was purified by preparative HPLC (Agela DuraShell C18 250*80mm*10um column; 15-45% acetonitrile in 10mM ammonium bicarbonate solution in water, 20min gradient) to give compound 111S, N-[2-chloro-5-[4-[[(1S)-1-(4-fluorophenyl)ethyl]amino]quinazolin-6-yl]-3-pyridyl]methanesulfonamide (993.30mg, 2.10mmol, 41.38% yield, 100% purity) as a yellow solid. 1 H NMR(400MHz,DMSO-d6+D2O)δ=8.78(d,J=2.0Hz,1H),8.74(d,J=2.2Hz,1H),8.51(s,1H),8.21(d,J=2.2Hz,1H),8.13(dd,J=2.0,8.6Hz,1H) ,7.83(d,J=8.8Hz,1H),7.50(dd,J=5.5,8.6Hz,2H),7.15-7.08(m,2H),5.68(d,J=6.8Hz,1H),3.18(s,3H),1.64(d,J=7.1Hz,3H).MS(M+H) + =472.1.

[0285] Compound 111R was synthesized using the same procedure as compound 111S in Example 34, but substituting (1S)-1-(4-fluorophenyl)ethanamine for (1R)-1-(4-fluorophenyl)ethanamine.

[0286] Compound 111R: 1 H NMR(400MHz,DMSO-d6,T=273+80K)δ=8.73(d,J=2.0Hz,1H),8.71(d,J=2.2Hz,1H),8.43(s,1H),8.19(d,J=2.2Hz,1H),8.08(dd,J=2.0,8.6Hz,1H ),7.81(d,J=8.6Hz,1H),7.48(dd,J=5.7,8.4Hz,2H),7.10(t,J=8.8Hz,2H),5.63(q,J=7.0Hz,1H),3.16(s,3H),1.62(d,J=6.8Hz,3H)).MS(M+H) + =472.1.

[0287] Example 35: Synthesis of 6-(2-aminopyrimidin-5-yl)-N-[(1R)-1-(4-fluorophenyl)ethyl]quinazolin-4-amine (Compound 121R) [ka] Step 1: Synthesis of N-(3-ethynylphenyl)-6-iodo-quinazolin-4-amine (2m) To a stirred solution of 4-chloro-6-iodo-quinazoline, 1m, (300 mg, 1.03 mmol, 1 equiv.) in i-PrOH (5 mL), (1R)-1-(4-fluorophenyl)ethanamine (143.73 mg, 1.03 mmol, 1 equiv.), TEA (167.20 mg, 1.65 mmol, 229.99 μL, 1.6 equiv.) were added and the mixture was stirred at 80° C. for 15 h. LCMS showed that the starting material was completely consumed and the desired MS was detected. The reaction mixture was concentrated in vacuo. Compound 2m, N-[(1R)-1-(4-fluorophenyl)ethyl]-6-iodo-quinazolin-4-amine (300 mg, 762.98 μmol, 73.88% yield) was obtained as a yellow solid. MS (M+H) + =394.1.

[0288] Step 2: Synthesis of 6-(2-aminopyrimidin-5-yl)-N-[(1R)-1-(4-fluorophenyl)ethyl]quinazolin-4-amine (compound 121R) To a stirred solution of N-[(1R)-1-(4-fluorophenyl)ethyl]-6-iodo-quinazolin-4-amine, 2m, (300 mg, 762.98 μmol, 1 equiv.) in DMF (5 mL), HO (1 mL), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (168.67 mg, 762.98 μmol, 1 equiv.), KPO (485.86 mg, 2.29 mmol, 3 equiv.), Pd(PPh) (88.17 mg, 76.30 μmol, 0.1 equiv.) was added, the mixture was purged with N for 1 min, and the mixture was stirred at 120° C. for 16 h. LCMS showed the starting material was completely consumed and the desired MS was detected. The reaction mixture was filtered and the filtrate was directly purified. The crude residue was purified by preparative HPLC (Phenomenex luna C18 250*50mm*10um; 10-40% acetonitrile in 0.05% hydrochloric acid solution in water, 10 min gradient). Compound 121R, 6-(2-aminopyrimidin-5-yl)-N-[(1R)-1-(4-fluorophenyl)ethyl]quinazolin-4-amine (283.62 mg, 707.18 μmol, 92.69% yield, 98.95% purity, HCl) was obtained as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6,T=273+80K)δ=10.78(br s,1H),9.30(br s,1H),9.00(s,2H),8.83(s,1H),8.37(dd,J=1.8,8.8Hz,1H),7.99(d,J=8.8Hz,1H),7.64(dd, J=5.5,8.6Hz,2H),7.17(t,J=8.8Hz,2H),5.88(t,J=7.2Hz,1H),1.78(d,J=7.0Hz,3H).MS(M+H) + =361.2.

[0289] Example 36: Synthesis of 4-(1-phenylethylamino)-6-(3-quinolyl)quinoline-3-carbonitrile (Compound 122) [ka] To a stirred solution of 4-(1-phenylethylamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-3-carbonitrile (100 mg, 250.44 μmol, 1 equiv.) in DMF (2.5 mL) and HO (0.5 mL), CsCO (244.80 mg, 751.33 μmol, 3 equiv.), Pd(dppf)Cl (18.33 mg, 25.04 μmol, 0.1 equiv.), and 3-bromoquinoline (52.11 mg, 250.44 μmol, 33.62 μL, 1 equiv.) were added, the mixture was purged with N and stirred at 100° C. for 3 h. LCMS showed complete consumption of starting material and MS of desired product was detected. The reaction mixture was concentrated in vacuo. The crude product was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 35%~65%, 8min). Compound 122, 4-(1-phenylethylamino)-6-(3-quinolyl)quinoline-3-carbonitrile (19.89mg, 49.67μmol, 19.83% yield, 100% purity) was obtained as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 9.53(s,1H),9.12(s,1H),8.83(s,1H),8.47(s,1H),8.31(br dd,J=14.43,8.56Hz,2H),8.08-8.16(m,2H),8.01(d,J=8.44Hz,1H),7.82(br t,J=7.58Hz,1H),7.64-7.74(m,1H),7.46(br d,J=7.58Hz,2H),7.35(br t,J=7.46Hz,2H),7.20-7.29(m,1H),5.89(br t,J=7.15Hz,1H),1.75(br d, J=6.60Hz, 3H). MS(M+H) + =401.1

[0290] Example 37: Synthesis of 4-(1-phenylethylamino)-6-(3-pyridyl)quinoline-3-carbonitrile (Compound 123) [ka] To a stirred solution of 4-(1-phenylethylamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-3-carbonitrile (100 mg, 250.44 μmol, 1 equiv.) in DMF (0.5 mL) and HO (0.1 mL) was added CsCO (244.80 mg, 751.33 μmol, 3 equiv.), Pd(dppf)Cl (18.33 mg, 25.04 μmol, 0.1 equiv.), and 3-bromopyridine (39.57 mg, 250.44 μmol, 24.13 μL, 1 equiv.), the mixture was purged with N and stirred at 100° C. for 3 h. LCMS showed complete consumption of starting material and MS of desired product was detected. The reaction mixture was concentrated in vacuo. The crude product was purified by preparative HPLC (column: Phenomenex luna C18 100*40mm*5um; mobile phase: [water (0.1% TFA)-ACN]; B%: 1%-35%, 8 min). Compound 123, 4-(1-phenylethylamino)-6-(3-pyridyl)quinoline-3-carbonitrile (28.25mg, 60.83μmol, 24.29% yield, 100% purity, TFA) was obtained as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ=9.30(br s,1H),9.22(d,J=1.3Hz,1H),9.11(s,1H),8.95(s,1H),8.76(d,J=4.6Hz,1H),8.47(br d,J=7.7Hz,1H),8.39(dd,J=1.4,8.7Hz,1H),8.04(d,J=8.7Hz,1H),7.75(dd,J=5.2,7.8Hz,1H),7.51-7.45 (m,2H),7.39(t,J=7.6Hz,2H),7.33-7.25(m,1H),6.03(quin,J=6.9Hz,1H),1.80(d,J=6.7Hz,3H).MS(M+H) + =351.1.

[0291] Example 38: Synthesis of 4-(1-phenylethylamino)-6-(1H-pyrazolo[4,3-c]pyridin-3-yl)quinoline-3-carbonitrile (Compound 124) [ka] To a stirred solution of 4-(1-phenylethylamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-3-carbonitrile (100 mg, 250.44 μmol, 1 equiv.) in DMF (2.5 mL) and HO (0.5 mL) was added CsCO (244.80 mg, 751.33 μmol, 3 equiv.), Pd(dppf)Cl (18.33 mg, 25.04 μmol, 0.1 equiv.), and 3-bromo-1H-pyrazolo[4,3-c]pyridine (49.59 mg, 250.44 μmol, 49.59 μL, 1 equiv.), the mixture was purged with N and stirred at 100° C. for 3 h. LCMS showed complete consumption of starting material and MS of desired product was detected. The reaction mixture was concentrated in vacuum. The crude product was purified by preparative HPLC (column: Phenomenex luna C18 100*40mm*5um; mobile phase: [water (0.1% TFA)-ACN]; B%: 1%-35%, 8 min) to give compound 124, 4-(1-phenylethylamino)-6-(1H-pyrazolo[4,3-c]pyridin-3-yl)quinoline-3-carbonitrile (7.96 mg, 15.17 μmol, 6.06% yield, 96.13% purity, TFA) as a grey solid. 1 H NMR(400MHz,DMSO-d6)δ=15.06-14.65(m,1H),9.92(s,1H),9.30(d,J=1.3Hz,1H),8.84(br d,J=6.8Hz,1H),8.71(s,1H),8.62(d,J=6.7Hz,1H),8.53(dd,J=1.6,8.7Hz,1H),8.15(d,J=6.7Hz,1H),8.06(d,J=8.6Hz ,1H),7.46(d,J=7.5Hz,2H),7.35(t,J=7.6Hz,2H),7.30-7.20(m,1H),5.98-5.83(m,1H),1.76(d,J=6.6Hz,3H).MS(M+H) + =391.1

[0292] Example 39: Synthesis of 4-(1-phenylethylamino)-6-(1H-pyrazolo[3,4-c]pyridin-3-yl)quinoline-3-carbonitrile (Compound 125) [ka] To a stirred solution of 4-(1-phenylethylamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-3-carbonitrile (100 mg, 250.44 μmol, 1 equiv) in DMF (2.5 mL) and HO (0.5 mL) was added CsCO (244.80 mg, 751.33 μmol, 3 equiv), Pd(dppf)Cl (18.33 mg, 25.04 μmol, 0.1 equiv), and 3-bromo-1H-pyrazolo[3,4-c]pyridine (59.51 mg, 300.53 μmol, 59.51 μL, 1.2 equiv), the mixture was purged with N for 1 min and stirred at 100° C. for 3 h. LCMS showed complete consumption of starting material and MS of desired product was detected. The reaction was filtered, the filter cake was washed with DMSO, and then the filtrate was concentrated in vacuum. The crude product was purified by preparative HPLC (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 35%-60%, 8 min). Compound 125, 4-(1-phenylethylamino)-6-(1H-pyrazolo[3,4-c]pyridin-3-yl)quinoline-3-carbonitrile (7.28mg, 18.65μmol, 7.45% yield, 100% purity) was obtained as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 14.02(br s,1H),9.15(br d,J=9.41Hz,2H),8.46(s,1H),8.40(br d,J=7.21Hz,2H),8.13(br d,J=5.13Hz,1H),7.99(br MS(M+H) + =391.0

[0293] Example 40: Synthesis of 6-(5-cyano-6-methoxy-3-pyridyl)-4-(1-phenylethylamino)quinoline-3-carbonitrile (Compound 126) [ka] To a solution of 4-(1-phenylethylamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-3-carbonitrile (100 mg, 250.44 μmol, 1 equiv.) in DMF (2.5 mL) and HO (0.4 mL) was added CsCO (244.80 mg, 751.33 μmol, 3 equiv.), Pd(dppf)Cl (18.33 mg, 25.04 μmol, 0.1 equiv.), and 5-bromo-2-methoxy-pyridine-3-carbonitrile (53.35 mg, 250.44 μmol, 1 equiv.), the mixture was purged with N, and the reaction was stirred at 100° C. for 3 h. LCMS showed complete consumption of starting material and MS of desired product was detected. The crude product was purified by preparative HPLC (column: Phenomenex Luna 80*30mm*3um; mobile phase: [water (0.04% HCl)-ACN]; B%: 20%~40%, 8 min). Compound 126, 6-(5-cyano-6-methoxy-3-pyridyl)-4-(1-phenylethylamino)quinoline-3-carbonitrile (22.91 mg, 50.74 μmol, 20.26% yield, 97.87% purity, HCl) was obtained as a white solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 9.50(br s,1H),9.15(br s,1H),9.10(d,J=2.20Hz,1H),9.00(s,1H),8.90(d,J=2.32Hz,1H),8.40(d,J=8.56Hz,1H),8 .02-8.10(m,1H),7.50(d,J=7.46Hz,2H),7.39(t,J=7.58Hz,2H),7.27-7.34(m,1H),6.05(br t,J=7.34Hz,1H)4.09(s,3H)1.83(d,J=6.72Hz,3H).MS(M+H) + =406.1

[0294] Example 41: Synthesis of 6-[3-(2-oxo-3H-1,3,4-oxadiazol-5-yl)phenyl]-4-(1-phenylethylamino)quinoline-3-carbonitrile (Compound 127) [ka] To a solution of 5-(3-bromophenyl)-3H-1,3,4-oxadiazol-2-one (50 mg, 207.43 μmol, 1 equiv) in DMF (1 mL) and HO (0.2 mL) was added CsCO (202.76 mg, 622.30 μmol, 3 equiv), Pd(dppf)Cl (15.18 mg, 20.74 μmol, 0.1 equiv), and 4-(1-phenylethylamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-3-carbonitrile (82.83 mg, 207.43 μmol, 1 equiv), the mixture was purged with N, and the reaction was stirred at 100° C. for 3 h. LCMS showed complete consumption of starting material and MS of desired product was detected. The crude product was purified by preparative HPLC (column: Phenomenex Luna 80*30mm*3um; mobile phase: [water (0.04% HCl)-ACN]; B%: 15%-40%, 8 min). Compound 127, 6-[3-(2-oxo-3H-1,3,4-oxadiazol-5-yl)phenyl]-4-(1-phenylethylamino)quinoline-3-carbonitrile (10.32 mg, 21.96 μmol, 10.59% yield, 100% purity, HCl) was obtained as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 12.73(s,1H),9.45(br s,1H),9.06(s,1H),8.96(s,1H),8.34(d,J=8.80Hz,1H),8.17(s,1H),7.99-8.09(m,2H),7.88(d,J=7 .82Hz,1H),7.69-7.77(m,1H),7.41-7.48(m,2H),7.35(t,J=7.64Hz,2H),7.22-7.30(m,1H),6.00(br t,J=7.34Hz,1H),1.78(d,J=6.72Hz,3H).MS(M+H) + =434.0

[0295] Example 42: Synthesis of 4-(1-phenylethylamino)-6-[3-(4H-1,2,4-triazol-3-yl)phenyl]quinoline-3-carbonitrile (Compound 128) [ka] To a solution of 4-(1-phenylethylamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-3-carbonitrile (100 mg, 250.44 μmol, 1 equiv.) in DMF (2.5 mL) and HO (0.4 mL) was added CsCO (244.80 mg, 751.33 μmol, 3 equiv.), Pd(dppf)Cl (18.33 mg, 25.04 μmol, 0.1 equiv.), and 3-(3-bromophenyl)-1H-1,2,4-triazole (56.11 mg, 250.44 μmol, 1 equiv.), the mixture was purged with N, and the reaction was stirred at 100° C. for 3 h. LCMS showed complete consumption of starting material and MS of desired product was detected. The reaction was filtered and the filtrate was purified by preparative HPLC (column: Phenomenex Luna 80*30mm*3um; mobile phase: [water (HCl)-ACN]; B%: 10%~35%, 8 min). Compound 128, 4-(1-phenylethylamino)-6-[3-(4H-1,2,4-triazol-3-yl)phenyl]quinoline-3-carbonitrile (12.89mg, 28.46μmol, 11.36% yield, 100% purity, HCl) was obtained as a white solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 9.82(br s,1H),9.15-9.23(m,1H),9.12(s,1H),8.53(br s,2H),8.43(d,J=8.31Hz,1H),8.05-8.19(m,2H),7.97(br d,J=7.82Hz,1H),7.71(t,J=7.76Hz,1H),7.50(d,J=7.58Hz,2H),7.40(t,J=7.58Hz,2H),7.27-7.34(m,1H),6.09(br t,J=7.40Hz,1H),1.84(d,J=6.60Hz,3H).MS(M+H) +=417.1

[0296] Example 43: Synthesis of 6-[5-(2-oxo-3H-1,3,4-oxadiazol-5-yl)-3-pyridyl]-4-(1-phenylethylamino)quinoline-3-carbonitrile (Compound 129) [ka] To a solution of 5-(5-bromo-3-pyridyl)-3H-1,3,4-oxadiazol-2-one (181.84 mg, 751.33 μmol, 1 equiv) in DMF (1 mL) and HO (0.2 mL) was added CsCO (734.39 mg, 2.25 mmol, 3 equiv), Pd(dppf)Cl (54.98 mg, 75.13 μmol, 0.1 equiv), and 4-(1-phenylethylamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-3-carbonitrile (300 mg, 751.33 μmol, 1 equiv), the mixture was purged with N, and the reaction was stirred at 100° C. for 3 h. LCMS showed complete consumption of starting material and MS of desired product was detected. The reaction was filtered, and then the filtrate was concentrated in vacuo. The crude product was purified by preparative HPLC (column: Phenomenex luna C18 80*40mm*3um; mobile phase: [water (HCl)-ACN]; B%: 22%~45%, 7 min). Compound 129, 6-[5-(2-oxo-3H-1,3,4-oxadiazol-5-yl)-3-pyridyl]-4-(1-phenylethylamino)quinoline-3-carbonitrile (46.87 mg, 99.53 μmol, 13.25% yield, 100% purity, HCl) was obtained as a yellow solid. 1H NMR(400MHz,DMSO-d6)δ ppm 12.97(s,1H),9.82(br d,J=7.63Hz,1H),9.35(d,J=2.13Hz,1H),9.27(s,1H),9.13(s,1H),9.08(d,J=2.00Hz,1H),8.62(t,J=2.06Hz,1H),8.53(dd,J=8.76,1.50Hz,1H )8.16(d,J=8.75Hz,1H)7.51(d,J=7.38Hz,2H)7.41(t,J=7.57Hz,2H)7.29-7.35(m,1H)6.09(quin,J=7.07Hz,1H)1.85(d,J=6.63Hz,3H).MS(M+H) + =435.0

[0297] Example 44: Synthesis of 6-(3,5-difluoro-4-hydroxy-phenyl)-4-(1-phenylethylamino)quinoline-3-carbonitrile (Compound 130) [ka] To a solution of 4-(1-phenylethylamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-3-carbonitrile (80 mg, 200.35 μmol, 1 equiv.) in DMF (2 mL) and HO (0.4 mL) was added CsCO (195.84 mg, 601.06 μmol, 3 equiv.), Pd(dppf)Cl (14.66 mg, 20.04 μmol, 0.1 equiv.), and 4-bromo-2,6-difluoro-phenol (41.87 mg, 200.35 μmol, 1 equiv.), the mixture was purged with N, and the reaction was stirred at 100° C. for 3 h. LCMS showed complete consumption of starting material and MS of desired product was detected. The reaction was filtered, and then the filtrate was purified by preparative HPLC (column: Phenomenex Luna C18 150*30mm*5um; mobile phase: [water (0.04% TFA)-ACN]; B%: 1%-40%, 8 min). Compound 130, 6-(3,5-difluoro-4-hydroxy-phenyl)-4-(1-phenylethylamino)quinoline-3-carbonitrile (11.49mg, 22.29μmol, 11.13% yield, 100% purity, TFA) was obtained as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 10.60(br s,1H),8.86(s,2H)8.75(br s,1H),8.25(br d,J=8.88Hz,1H),7.88-7.95(m,1H)7.66-7.74(m,2H),7.43-7.48(m,2H),7.38(t,J=7.63Hz,2H),7.25-7.32(m,1H),5.97(br t,J=6.82Hz,1H),1.79(d,J=6.63Hz,3H).MS(M+H) + =402.1

[0298] Example 45: Synthesis of 6-(3,5-dichloro-4-hydroxy-phenyl)-4-(1-phenylethylamino)quinoline-3-carbonitrile (Compound 131) [ka] To a solution of 4-(1-phenylethylamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-3-carbonitrile (80 mg, 200.35 μmol, 1 equiv.) in DMF (2 mL) and H2O (0.4 mL) was added Cs2CO3 (195.84 mg, 601.06 μmol, 3 equiv.), Pd(dppf)Cl2 (14.66 mg, 20.04 μmol, 0.1 equiv.), and 4-bromo-2,6-dichloro-phenol (48.47 mg, 200.35 μmol, 1 equiv.), the mixture was purged with N2, and the reaction was stirred at 100 °C for 3 h. LCMS showed complete consumption of starting material and MS of desired product was detected. The reaction was filtered and then the filtrate was concentrated in vacuo. The crude product was purified by preparative HPLC (column: Phenomenex Luna 80*30mm*3um; mobile phase: [water (0.04% HCl)-ACN]; B%: 20%~40%, 8 min). Compound 131, 6-(3,5-dichloro-4-hydroxy-phenyl)-4-(1-phenylethylamino)quinoline-3-carbonitrile (15.23mg, 32.35μmol, 16.15% yield, 100% purity, HCl) was obtained as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 10.59(br s,1H),9.53(br s,1H),8.99(br s,2H),8.34(d,J=8.68Hz,1H),8.02(br d,J=8.80Hz,1H),7.98(s,2H),7.48(d,J=7.58Hz,2H),7.39(t,J=7.58Hz,2H),7.26-7.33(m,1H),6.04(br t,J=7.15Hz,1H),1.83(d,J=6.60Hz,3H).MS(M+H) + =434.0

[0299] Example 46: Synthesis of 2-methoxy-5-[4-[[(1R)-1-phenylethyl]amino]quinazolin-6-yl]pyridine-3-carbonitrile (Compound 132) [ka] To a stirred solution of 5-bromo-2-methoxy-pyridine-3-carbonitrile (45.41 mg, 213.18 μmol, 1 equiv.) in HO (0.2 mL) and DMF (1 mL) was added N-[(1R)-1-phenylethyl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-amine (80 mg, 213.18 μmol, 1 equiv.), CsCO (208.37 mg, 639.54 μmol, 3 equiv.), and Pd(dppf)Cl (15.60 mg, 21.32 μmol, 0.1 equiv.) and the reaction was stirred at 100° C. under N for 3 h. LCMS showed complete consumption of starting material and MS of desired product was detected. The reaction was filtered and then the filtrate was concentrated in vacuo. The crude product was purified by preparative HPLC (column: Phenomenex Luna 80*30mm*3um; mobile phase: [water (0.04% HCl)-ACN]; B%: 10%~35%, 8 min). Compound 132, 2-methoxy-5-[4-[[(1R)-1-phenylethyl]amino]quinazolin-6-yl]pyridine-3-carbonitrile (3.4 mg, 8.91 μmol, 4.18% yield, 100% purity) was obtained as a pale solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 9.75-9.94(m,1H),8.99(d,J=2.57Hz,1H),8.93(d,J=0.98Hz,1H),8.75-8.83(m,2H),8.34-8.43(m,1H),7.85(d,J=8.80Hz,1H),7 .49(d,J=7.58Hz,2H),7.37(t,J=7.52Hz,2H),7.23-7.33(m,1H),5.72-5.87(m,1H),4.08(s,3H),1.69(d,J=6.97Hz,3H).MS(M+H) + =382.0

[0300] Example 47: Synthesis of methyl 5-[4-[[(1R)-1-phenylethyl]amino]quinazolin-6-yl]pyridine-3-carboxylate (Compound 135) [ka] Step 1: Synthesis of 6-bromo-N-[(1R)-1-phenylethyl]quinazolin-4-amine (2n) To a stirred solution of 6-bromo-4-chloro-quinazoline, 1n, (4 g, 16.43 mmol, 1 equiv) in i-PrOH (40 mL) was added (1R)-1-phenylethanamine (1.99 g, 16.43 mmol, 2.12 mL, 1 equiv) and TEA (2.66 g, 26.28 mmol, 3.66 mL, 1.6 equiv) and the reaction was stirred at 80° C. under N2 for 3 h. LCMS showed complete consumption of starting material and MS of desired product was detected. The reaction was cooled to ambient temperature, 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. Compound 2n, 6-bromo-N-[(1R)-1-phenylethyl]quinazolin-4-amine (5.6 g, crude) was obtained as a yellow solid.

[0301] Step 2: Synthesis of N-[(1R)-1-phenylethyl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-amine (3n) To a stirred solution of 6-bromo-N-[(1R)-1-phenylethyl]quinazolin-4-amine, 2n, (5.6 g, 17.06 mmol, 1 equiv) in dioxane (60 mL) was added BPD (5.20 g, 20.47 mmol, 1.2 equiv), Pd(dppf)Cl2.CH2Cl2 (1.39 g, 1.71 mmol, 0.1 equiv), and AcOK (5.02 g, 51.19 mmol, 3 equiv) and the reaction was stirred at 110 °C under N2 for 12 h. LCMS showed complete consumption of starting material and MS of desired product was detected. The reaction was cooled to ambient temperature, 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 40 g silica, 40-60% ethyl acetate in petroleum ether, gradient over 20 min). TLC (PE:EtOAc=2:1, R f=0.30) Compound 3n, N-[(1R)-1-phenylethyl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-amine (1.8 g, 4.80 mmol, 28.11% yield) was obtained as a yellow oil.

[0302] Step 3: Synthesis of methyl 5-[4-[[(1R)-1-phenylethyl]amino]quinazolin-6-yl]pyridine-3-carboxylate (compound 135) To a stirred solution of methyl 5-bromopyridine-3-carboxylate, 3n, (41.45 mg, 191.86 μmol, 1.2 equiv) in DMF (1.5 mL) and HO (0.3 mL) was added N-[(1R)-1-phenylethyl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-amine (60 mg, 159.88 μmol, 1 equiv), KPO (101.81 mg, 479.65 μmol, 3 equiv), and Pd(dppf)Cl (11.70 mg, 15.99 μmol, 0.1 equiv) and the reaction was stirred at 80 °C under N for 3 h. LCMS showed complete consumption of starting material and MS of desired product was detected. The reaction was filtered and the filtrate was used directly for purification. The crude product was purified by preparative HPLC (column: Phenomenex Luna 80*30mm*3um; mobile phase: [water (TFA)-ACN]; B%: 20%~45%, 8 min). Compound 135, methyl 5-[4-[[(1R)-1-phenylethyl]amino]quinazolin-6-yl]pyridine-3-carboxylate (9.16 mg, 23.19 μmol, 14.50% yield, 97.326% purity) was obtained as a brown solid. 1H NMR(400MHz,DMSO-d6)δ ppm 10.22-10.35(m,1H),9.34(d,J=2.20Hz,1H),9.19(d,J=1.71Hz,1H),9.0 8(s,1H),8.92(s,1H),8.67-8.72(m,1H),8.51(d,J=9.05Hz,1H),7.91(d, J=8.80Hz,1H),7.50(d,J=7.34Hz,2H),7.38(t,J=7.52Hz,2H),7.25-7.3 4(m,1H),5.75-5.96(m,1H),3.96(s,3H),1.72(d,J=6.97Hz,3H).MS(M+H) + =385.0

[0303] Example 48: Synthesis of 6-[4-[[(1R)-1-phenylethyl]amino]quinazolin-6-yl]-3H-isobenzofuran-1-one (Compound 136) [ka] To a stirred solution of 6-bromo-3H-isobenzofuran-1-one (40.87 mg, 191.86 μmol, 1.2 equiv) in DMF (1.5 mL) and HO (0.3 mL) was added N-[(1R)-1-phenylethyl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-amine (60 mg, 159.88 μmol, 1 equiv), KPO (101.81 mg, 479.65 μmol, 3 equiv), and Pd(dppf)Cl (11.70 mg, 15.99 μmol, 0.1 equiv) and the reaction was stirred under N at 80° C. for 3 h. LCMS showed complete consumption of starting material and MS of desired product was detected. The reaction was filtered, the filtrate was concentrated, and the crude product was purified by preparative HPLC (column: Phenomenex Luna 80*30mm*3um; mobile phase: [water (TFA)-ACN]; B%: 20%~50%, 8 min). Compound 136, 6-[4-[[(1R)-1-phenylethyl]amino]quinazolin-6-yl]-3H-isobenzofuran-1-one (23.53 mg, 60.08 μmol, 37.57% yield, 97.385% purity) was obtained as a pale yellow solid. 1H NMR(400MHz,DMSO-d6)δ ppm 10.33(br d,J=7.70Hz,1H),9.07(d,J=1.47Hz,1H),8.91(s,1H),8.49(dd,J=8.80,1.59Hz,1H),8.37(s,1H),8.28(dd,J=8.01,1.53Hz,1H),7.83-7.9 6(m,2H),7.50(d,J=7.46Hz,2H),7.39(t,J=7.52Hz,2H),7.25-7.33(m,1H),5.77-5.94(m,1H),5.53(s,2H),1.72(d,J=6.97Hz,3H).MS(M+H) + =382.0

[0304] Example 49: Synthesis of N-[(1R)-1-phenylethyl]-6-[3-(4H-1,2,4-triazol-3-yl)phenyl]quinazolin-4-amine (Compound 137) [ka] Step 1: Synthesis of 6-iodo-N-[(1R)-1-phenylethyl]quinazolin-4-amine (2p) To a stirred solution of 4-chloro-6-iodo-quinazoline, 1p, (3 g, 10.33 mmol, 1 equiv) in i-PrOH (30 mL) was added (1R)-1-phenylethanamine (1.25 g, 10.33 mmol, 1.33 mL, 1 equiv) and TEA (1.67 g, 16.52 mmol, 2.30 mL, 1.6 equiv) and the reaction was stirred at 80° C. under N2 for 3 h. LCMS showed complete consumption of starting material and MS of desired product was detected. The reaction was cooled to ambient temperature, 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. Compound 2p, 6-iodo-N-[(1R)-1-phenylethyl]quinazolin-4-amine (3.2 g, 8.53 mmol, 82.58% yield) was obtained as a yellow oil.

[0305] Step 2: Synthesis of N-[(1R)-1-phenylethyl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-amine (3p) To a stirred solution of 6-iodo-N-[(1R)-1-phenylethyl]quinazolin-4-amine, 2p, (3.20 g, 8.53 mmol, 1 equiv) in dioxane (30 mL) was added BPD (2.17 g, 8.53 mmol, 1 equiv) Pd(dppf)Cl2 (624.05 mg, 853.00 μmol, 0.1 equiv), and AcOK (2.51 g, 25.59 mmol, 3 equiv) and the reaction was stirred at 110 °C under Ar for 12 h. LCMS showed complete consumption of starting material and MS of desired product was detected. The reaction was cooled to ambient temperature, 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 80 g silica, 40-60% ethyl acetate in petroleum ether, gradient over 20 min). TLC (PE:EtOAc=1:1, R f =0.30) Compound 3p, N-[(1R)-1-phenylethyl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-amine (2.4 g, 6.40 mmol, 74.98% yield) was obtained as a yellow oil.

[0306] Step 3: Synthesis of N-[(1R)-1-phenylethyl]-6-[3-(4H-1,2,4-triazol-3-yl)phenyl]quinazolin-4-amine (Compound 137) To a stirred solution of 3-(3-bromophenyl)-1H-1,2,4-triazole (35.82 mg, 159.88 μmol, 1 equiv) in DMF (1 mL) and HO (0.2 mL) was added N-[(1R)-1-phenylethyl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-amine, 3p, (60 mg, 159.88 μmol, 1 equiv), CsCO (156.28 mg, 479.65 μmol, 3 equiv), and Pd(dppf)Cl (11.70 mg, 15.99 μmol, 0.1 equiv) and the reaction was stirred at 100 °C under N for 12 h. LCMS showed complete consumption of starting material and MS of desired product was detected. The reaction was filtered, then the filtrate was concentrated in vacuum. The crude product was purified by preparative HPLC (column: Phenomenex Luna 80*30mm*3um; mobile phase: [water (0.1% TFA)-ACN]; B%: 10%-30%, 8 min). Compound 137, N-[(1R)-1-phenylethyl]-6-[3-(4H-1,2,4-triazol-3-yl)phenyl]quinazolin-4-amine (7.9 mg, 20.13 μmol, 12.59% yield, 100% purity) was obtained as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 10.09-10.48(m,1H),9.02(s,1H),8.89(s,1H),8.45(s,1H),8.41(d,J=8.92Hz,1H),8.13(br d,J=8.19Hz,1H),7.90(d,J=8.68Hz,2H),7.65-7.78(m,1H),7.50(d,J=7.34Hz,2H),7.38 (t,J=7.46Hz,2H),7.26-7.32(m,1H),5.71-5.98(m,1H),1.72(d,J=7.09Hz,3H).MS(M+H) + =393.1

[0307] Example 50: Synthesis of 6-imidazo[1,2-a]pyrazin-3-yl-N-(1-phenylethyl)quinazolin-4-amine (Compound 139) [ka] Step 1: Synthesis of 6-iodo-N-(1-phenylethyl)quinazolin-4-amine (2q) To a solution of 4-chloro-6-iodo-quinazoline, 1q, (500 mg, 1.72 mmol, 1 equiv) in i-PrOH (5 mL) was added 1-phenylethanamine (208.58 mg, 1.72 mmol, 219.56 μL, 1 equiv) and TEA (522.51 mg, 5.16 mmol, 718.72 μL, 3 equiv) and the mixture was stirred at 80° C. for 2 h. LCMS showed that the starting material was completely consumed and the desired MS was detected. The reaction mixture was concentrated in vacuo to give the crude product. Compound 2q, 6-iodo-N-(1-phenylethyl)quinazolin-4-amine (800 mg, crude) was obtained as a brown solid. MS (M+H) + =376.1.

[0308] Synthesis of 6-imidazo[1,2-a]pyrazin-3-yl-N-(1-phenylethyl)quinazolin-4-amine (Compound 139) To a stirred solution of 6-iodo-N-(1-phenylethyl)quinazolin-4-amine, 2q, (200 mg, 533.04 μmol, 1 equiv) in dioxane (2 mL) was added imidazo[1,2-a]pyrazine (127.00 mg, 1.07 mmol, 2 equiv), Pd(OAc)2 (5.98 mg, 26.65 μmol, 0.05 equiv), PPh3 (13.98 mg, 53.30 μmol, 0.1 equiv), Cs2CO3 (347.35 mg, 1.07 mmol, 2 equiv), the mixture was purged with N2 for 1 min, and the mixture was stirred at 100° C. for 16 h. LCMS showed complete consumption of starting material and the desired MS was detected. The reaction mixture was filtered to obtain the filtrate, and the filtrate was purified by preparative HPLC (column: Phenomenex luna C18 80*40mm*3um; mobile phase: [water (0.04% HCl)-ACN]; B%: 18%~42%, 7 min). Compound 139, 6-imidazo[1,2-a]pyrazin-3-yl-N-(1-phenylethyl)quinazolin-4-amine (60.6 mg, 150.42 μmol, 28.22% yield, 100% purity, HCl) was obtained as a yellow solid. 1H NMR(400MHz,DMSO-d6)δ=10.77(br d,J=7.6Hz,1H),9.28(dd,J=1.4,8.5Hz,2H),8.96(s,1H),8.83(dd,J=1.4,4.8Hz,1H),8.44(dd,J=1.7,8.7Hz,1H),8.37(s,1H),8.13- 8.04(m,2H),7.54(d,J=7.4Hz,2H),7.37(t,J=7.4Hz,2H),7.32-7.25(m,1H),5.86(quin,J=7.1Hz,1H),1.73(d,J=7.0Hz,3H).MS(M+H) + =367.1.

[0309] Example 51: Synthesis of 2-[(6-imidazo[1,2-a]pyrazin-3-ylquinazolin-4-yl)amino]-2-phenyl-ethanol (Compound 140) [ka] Step 1: Synthesis of 2-[(6-iodoquinazolin-4-yl)amino]-2-phenyl-ethanol (2r) To a solution of 4-chloro-6-iodo-quinazoline, 1r, (200 mg, 688.50 μmol, 1 equiv.) in i-PrOH (2 mL), TEA (209.00 mg, 2.07 mmol, 287.49 μL, 3 equiv.) and 2-amino-2-phenyl-ethanol (94.45 mg, 688.50 μmol, 1 equiv.) were added and the mixture was stirred at 80° C. for 2 h. LCMS showed that the starting material was completely consumed and the desired MS was detected. The reaction mixture was concentrated in vacuo to give the crude product. Compound 2r, 2-[(6-iodoquinazolin-4-yl)amino]-2-phenyl-ethanol (300 mg, crude) was obtained as a yellow solid. MS (M+H) + =392.0.

[0310] Step 2: Synthesis of 2-[(6-imidazo[1,2-a]pyrazin-3-ylquinazolin-4-yl)amino]-2-phenyl-ethanol (compound 140) To a solution of 2-[(6-iodoquinazolin-4-yl)amino]-2-phenyl-ethanol, 2r, (200 mg, 511.24 μmol, 1 equiv.) in dioxane (2 mL) was added imidazo[1,2-a]pyrazine (121.80 mg, 1.02 mmol, 2 equiv.), PPh3 (13.41 mg, 51.12 μmol, 0.1 equiv.), Cs2CO3 (333.14 mg, 1.02 mmol, 2 equiv.), and Pd(OAc)2 (5.74 mg, 25.56 μmol, 0.05 equiv.). The mixture was purged with N2 for 1 min, and then the mixture was stirred under N2 atmosphere at 100 °C for 16 h. LCMS showed that the starting material was completely consumed and the desired MS was detected. The reaction mixture was filtered to obtain the filtrate, and the filtrate was purified by preparative HPLC (column: Phenomenex luna C18 250*50mm*10um; mobile phase: [water (0.04% HCl)-ACN]; B%: 10%~40%, 10 min). Compound 140, 2-[(6-imidazo[1,2-a]pyrazin-3-ylquinazolin-4-yl)amino]-2-phenyl-ethanol (36.29 mg, 82.84 μmol, 16.20% yield, 95.62% purity, HCl) was obtained as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ=10.96(br d,J=7.5Hz,1H),9.58-9.47(m,1H),9.36(d,J=1.3Hz,1H),9.00-8.91(m ,2H),8.51(s,1H),8.46(dd,J=1.7,8.7Hz,1H),8.19-8.07(m,2H),7.55 (d,J=7.3Hz,2H),7.40-7.32(m,2H),7.31-7.25(m,1H),5.78-5.67(m,1H),4.08(dd,J=8.8,11.4Hz,1H),3.86(dd,J=4.6,11.4Hz,1H).MS(M+H) + =383.1.

[0311] Example 52: Synthesis of N-[5-[4-(benzylamino)quinazolin-6-yl]-2-chloro-3-pyridyl]methanesulfonamide (Comparative Compound 1) [ka] To a stirred solution of N-benzyl-6-iodo-quinazolin-4-amine (1.8 g, 4.98 mmol, 1 equiv) in DMF (25 mL) and HO (5 mL) was added N-[2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]-N-methylsulfonyl-methanesulfonamide (2.05 g, 4.98 mmol, 1 equiv), KPO (3.17 g, 14.95 mmol, 3 equiv), Pd(PPh) (575.89 mg, 498.37 μmol, 0.1 equiv), the mixture was purged with N for 1 min, and the mixture was stirred at 100° C. for 4 h. LCMS showed complete consumption of starting material and the desired MS was detected. The reaction mixture was filtered, and the filtrate was concentrated and purified by preparative HPLC (Phenomenex luna c18 250mm*100mm*15um column; 15-45% acetonitrile in 0.1% trifluoroacetic acid solution in water, 42 min gradient). Comparison compound 1, N-[5-[4-(benzylamino)quinazolin-6-yl]-2-chloro-3-pyridyl]methanesulfonamide (738.80mg, 1.30mmol, 26.09% yield, 97.46% purity, TFA) was obtained as a white solid. 1 H NMR(400MHz,DMSO-d6)δ=10.63-10.61(m,1H),10.05(s,1H),8.92(s,2H),8.77(s,1H),8.43-8.40(m,1H),8.26(s,1H), 7.98-7.94(m,1H),7.45-7.43(m,2H),7.39-7.35(m,2H),7.32-7.30(m,1H),5.01(d,J=5.2Hz,2H),3.19(s,3H).MS(M+H) + =440.1.

[0312] Assay Examples In the following example assay, the activity of the compounds of the present disclosure can be compared to the following three compounds: [ka]

[0313] Comparative Compound 2 is a dual enzyme inhibitor against EGFR and PI3K. Descriptions and syntheses of Comparative Compound 2 and Comparative Compound 3 can be found in International Application No. PCT / US2015 / 065827, filed December 15, 2015, and are referenced as Mol211 and Mol167, respectively, the entire disclosures of which are incorporated herein by reference.

[0314] Example 53: Affinity of selected compounds of the present disclosure for PI3Ka, EGFR, and DNA-PK enzymes. The Z'-LYTE® biochemical assay uses a fluorescence-based coupled enzyme format and is based on the differential sensitivity of phosphorylated and non-phosphorylated peptides to proteolytic cleavage (Figure 6). A peptide substrate is labeled with two fluorophores (one at each end) that constitute a FRET pair. In the primary reaction, a kinase transfers the gamma carboxylate 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 the non-phosphorylated FRET peptide. Phosphorylation of the FRET peptide inhibits cleavage by the developing reagent. Cleavage destroys FRET between the donor (i.e., coumarin) and acceptor (i.e., fluorescein) fluorophores on the FRET peptide, while uncleaved phosphorylated FRET peptides maintain FRET. Reaction progress is quantified using a ratiometric method that calculates the ratio of donor emission to acceptor emission following excitation of the donor fluorophore at 400 nm (emission ratio).

[0315] A notable advantage of this ratiometric method for quantifying reaction progress is the elimination of well-to-well variations in FRET peptide concentration and signal intensity. As a result, the assay produces very high Z'-factor values ​​(>0.7) at low percent phosphorylation.

[0316] Both cleaved and uncleaved FRET peptides contribute to the fluorescent signal and thus the emission ratio. The degree of phosphorylation of the FRET peptide can be calculated from the emission ratio. If the FRET peptide is phosphorylated (i.e., no kinase inhibition), the emission ratio will remain low, and if the FRET peptide is unphosphorylated (i.e., kinase inhibition), the emission ratio will be high.

[0317] Enzyme: The ADAPTA Universal Kinase Assay is a homogeneous, fluorescence-based immunoassay for the detection of ADP. In contrast to ATP depletion assays, the ADAPTA assay is highly sensitive to ADP formation, such that the 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.

[0318] 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 wells and the reaction is incubated for 60 minutes. After the reaction, a detection solution consisting of europium-labeled anti-ADP antibody, Alexa Fluor® 647-labeled ADP tracer, and EDTA (to stop the kinase reaction) is added to the assay wells. ADP formed by the kinase reaction (in the absence of inhibitors) displaces the Alexa Fluor® 647-labeled ADP tracer from the antibody, resulting in a decrease in the TR-FRET signal. In the presence of inhibitors, 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.

[0319] Z′-LYTE® Assay Conditions: Test Compounds: Test compounds are screened in 1% DMSO (final) in the wells. 10-point titrations are performed with 3-fold serial dilutions from the starting concentration.

[0320] Peptide / kinase mixtures: All peptide / kinase mixtures are diluted to 2x working concentration in the appropriate kinase buffer.

[0321] ATP Solutions: All ATP solutions are diluted to 4x working concentration in kinase buffer (50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCl2, 1 mM EGTA). Apparent ATP Km is pre-determined using the Z'-LYTE® assay.

[0322] Developing Reagent Solution: Dilute the developing reagent with the developing buffer.

[0323] 10x Novel PKC Lipid Mix: 2 mg / mL phosphatidylserine, 0.2 mg / mL DAG in 20 mM HEPES, pH 7.4, 0.3% CHAPS. For 5 mL of 10x Novel PKC Lipid Mix: 1. Add 10 mg phosphatidylserine (Avanti Polar Lipids Part#8400032C or 840039C) and 1 mg DAG (Avanti Polar Lipids Part#800811C) to a glass tube. 2. Remove chloroform from lipid mixture by evaporating under nitrogen stream to a clear thin film. The thinnest film will result by continuously rotating the tube at an angle to ensure maximum surface area of ​​lipid solution. 3. Add 5 mL of resuspension buffer, 20 mM HEPES, 0.3% CHAPS, pH 7.4 to the dry lipid mix. 4. Heat slowly to 50-60°C for 1-2 minutes, vortexing briefly until the lipids are dissolved into a clear or slightly hazy solution. The lipids typically go into solution after 2-3 heating / vortexing cycles. 5. Cool to room temperature, aliquot into single-use volumes, and store at -20°C.

[0324] Assay protocol: Barcoded Corning, low volume NBS, black 384 well plates (Corning catalog #4514) 1. 2.5μL-4x test compound or 100x 100nL + 2.4μL kinase buffer. 2.5μL-2x peptide / kinase mixture. 3. 2.5μL-4x ATP solution. 4. Shake plate for 30 seconds. 5. Kinase reaction incubation for 60 minutes at room temperature. 6. 5μL-developing reagent solution. 7. Shake plate for 30 seconds. 8. Developing reaction incubation for 60 minutes at room temperature. 9. Read on fluorescent plate reader and analyze data.

[0325] In a typical experiment, each data point uses 100 nL to 100x the test compound in 100% DMSO. Typically, 100 nL of a 10 μM solution of the test compound is used for each experiment, which corresponds to 1 pmole of test compound. Thus, a 10 μM single point assay would use 100 pmoles of test compound, a 10 point titration would use approximately 200 pmoles of test compound, with 100 pmoles for the initial test and another 100 pmoles for the serial dilutions.

[0326] ADP formation is determined by calculating the emission ratio from the assay wells, which 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 following equation:

[0327] Because ADAPTA technology measures ADP formation (i.e., the conversion of ATP to ADP), it can be used to measure any type of ATP hydrolysis, including the intrinsic ATP enzymatic activity of kinases. In this case, the substrate is water, not a lipid or peptide. The SelectScreen® service screens CHUKs in this manner, so that no substrate is included in the kinase reaction. A reference for using intrinsic ATP enzymatic activity to screen kinase inhibitors is provided below.

[0328] Adapta® Assay Conditions Test Compounds: Test compounds are screened in 1% DMSO (final) in the wells. 10-point titrations are performed with 3-fold serial dilutions from the starting concentration.

[0329] Substrate / kinase mixes: All substrate / kinase mixes are diluted to 2x working concentration in the appropriate kinase buffer (see Kinase-specific Assay Conditions section for full instructions).

[0330] ATP Solutions: All ATP solutions are diluted to 4x working concentration in water. The apparent ATP Km is previously determined using a radiometric assay unless substrate is not available when the Adapta® assay is performed.

[0331] 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 an EC60 concentration of tracer for ATP between 5 and 150 μM.

[0332] Assay protocol: Barcoded Corning, low volume, white 384 well plate (Corning catalog #4512) 1. 2.5μL-4x test compound in 30mM HEPES or 100x in 100% DMSO 100nL + 2.4μL 30mM HEPES. 2. 2.5μL-4x ATP solution. 3. 5μL-2x substrate / kinase mix. 4. Shake plate for 30 seconds. 5. Centrifuge for 1 minute at 1000xg. 6. Kinase reaction incubation for 60 minutes at room temperature. 7. 5μL-detection mix. 8. Shake plate for 30 seconds. 9. Centrifuge for 1 minute at 1000xg. 10. Equilibrate detection mix for 60 minutes at room temperature. 11. Read on a fluorescent plate reader and analyze data.

[0333] In a typical experiment, each data point uses 100 nL to 100x the test compound in 100% DMSO. Typically, 100 nL of a 10 μM solution of the test compound is used for each experiment, which corresponds to 1 pmole of test compound. Thus, a 10 μM single point assay would use 100 pmoles of test compound, a 10 point titration would use approximately 200 pmoles of test compound, with 100 pmoles for the initial test and another 100 pmoles for the serial dilutions.

[0334] The affinity of selected compounds of the present disclosure versus Comparative Compound 1 and Comparative Compound 2 for PI3Ka, EGFR, and DNA-PK enzymes is shown in Table 3 below, as a median inhibitory concentration (IC 50 ) in Table 3. 50 Data are presented as "++++" (values ​​are ≦2 nM), "+++" (values ​​are greater than 2 nM and less than or equal to 20 nM), "++" (values ​​are greater than 20 nM and less than or equal to 200 nM), and "+" (values ​​are greater than 200 nM). NT is "not tested." [Table 3]

[0335] The affinity of selected compounds of the present disclosure versus Comparative Compound 1 and Comparative Compound 2 for PI3Ka, EGFR, and DNA-PK enzymes is presented below in Table 4 as percent inhibition at 100 nM. The % inhibition at 100 nM data in Table 4 is presented as "*" (values ​​are 10% or less), "**" (values ​​are greater than 10% and less than or equal to 80%), "***" (values ​​are greater than 80% and less than or equal to 90%), and "****" (values ​​are greater than 90%). [Table 4-1] [Table 4-2]

[0336] Example 54: Effect of Compound 2 on tumor volume in xenografted mice. Xenograft studies. Six to seven week old female NCR nude mice (CrTac:NCr-Foxn1nu from Taconic) were implanted in the right axillary region with 5 × 10 6 Cells were implanted subcutaneously. Mice were randomized into treatment groups and treatment was initiated when tumors reached 100-200 mg. Compound 2R was administered daily by oral gavage as a fine suspension in propylene glycol 1:2 in 1% Tween80 / Na3PO4 based on individual animal body weight (0.2 mL / 20 g). Subcutaneous tumor volume and body weight were measured 2-3 times per week. Tumor volume was calculated by measuring two perpendicular diameters with a caliper and using the formula: tumor volume = (length x width2) / 2. Individual mice were dosed daily until tumor burden reached 500 mg for CAL-27 and HCC-70 models, or 1000 mg for CAL-33 model, and progression-free survival was calculated. Percent increase in survival was calculated by comparing the median time to reach either 500 mg or 1000 mg in treatment groups with the vehicle control group. Complete response (CR) is defined as tumor below the threshold of palpation (<40 mg).

[0337] Figures 1-3 show the performance of compound 2R in controlling tumor size. Single agent activity of compound 2R was demonstrated in models of squamous cell head and neck cancer (PIK3CA mutant human CAL-33, PI3K gamma mutant human CAL-27) and triple negative breast cancer (human HCC-70). Tumor growth curves, as well as survival and objective response data are summarized in the attached Figures 1-3 and the following table. In all of these studies, compound 2R was well tolerated at the highest dose tested (100 mg / kg), with no signs of weight loss or other clinical signs despite daily administration for more than 50 days. [Table 5]

[0338] Example 55: Assessment of metabolic stability in liver microsomes. Working solutions: 5 μL of compound and control stock solutions (10 mM in dimethylsulfoxide (DMSO)) were diluted with 495 μL of acetonitrile (ACN) (intermediate solution concentration: 100 μM, 99% ACN)

[0339] NADPH cofactor preparation: NADPH powder: β-nicotinamide adenine dinucleotide phosphate reduced form, tetrasodium salt; NADPH·4Na. Weigh out an appropriate amount of NADPH powder and dilute it with 10 mM MgCl2 solution (working solution concentration: 10 units / mL; final concentration in reaction system: 1 unit / mL).

[0340] Liver microsome preparation: Microsome working solutions of appropriate concentrations were prepared in 100 mM potassium phosphate buffer. Cold (4°C) acetonitrile (ACN) containing 200 ng / mL tolbutamide and 200 ng / mL labetalol as the stop solution was used as the starting standard (IS).

[0341] Assay procedure: Empty "incubation" plates T60 and NCF60 are pre-warmed for 10 min. Liver microsomes are diluted to 0.56 mg / mL in 100 mM phosphate buffer. 445 μL of microsome working solution (0.56 mg / mL) is transferred to pre-warmed "incubation" plates T60 and NCF60, and "incubation" plates T60 and NCF60 are then pre-incubated for 10 min at 37° C. with constant shaking. 54 μL of liver microsomes are transferred to blank plates, then 6 μL of NAPDH cofactor is added to blank plates, then 180 μL of quenching solution is added to blank plates. 5 μL of compound working solution (100 μM) is added to "incubation" plates (T60 and NCF60) containing microsomes and mixed vigorously three times.

[0342] For the NCF60 plate, add 50 μL of buffer and mix vigorously 3 times. Start timing: Incubate the plate at 37° C. for 60 minutes with shaking. For the “quenching” plate T0, add 180 μL of quenching solution and 6 μL of NAPDH cofactor. Make sure the plate is cooled to prevent evaporation. For the T60 plate, mix vigorously 3 times and immediately remove 54 μL of the 0 minute time point mixture to the “quenching” plate. Then add 44 μL of NAPDH cofactor to the incubation plate (T60). Start timing: Incubate the plate at 37° C. for 60 minutes with shaking. At 5, 10, 20, 30, and 60 minutes, add 180 μL of quenching solution to the “quenching” plate, mix once, and sequentially transfer 60 μL samples from the T60 plate to the “quenching” plate for each time point. For NCF60: Mix once and transfer 60 μL sample from NCF60 incubation at 60 min to "Quenching" plate containing Quenching Solution. Shake all sampled plates for 10 min and then centrifuge at 4000 rpm for 20 min at 4° C. Transfer 80 μL of supernatant to 240 μL HPLC water and mix on a plate shaker for 10 min. Each bioanalytical plate was sealed and shaken for 10 min prior to LC-MS / MS analysis.

[0343] The first order kinetic equation was used to calculate T1 / 2 and CLint(mic) (μL / min / mg).

number

[0344] The biological stability of the compounds of the present disclosure can be measured by determining their half-life in the presence of microsomes. Presented in Table 5 are the half-lives of selected compounds of the present disclosure in the presence of human liver microsomes (HLM) or mouse liver microsomes (MLM) as described above. In Table 5, the half-lives are presented as "++++" (values ​​are greater than 60 minutes), "+++" (values ​​are greater than 30 minutes and less than or equal to 60 minutes), "++" (values ​​are greater than 15 minutes and less than or equal to 30 minutes), and "+" (values ​​are less than or equal to 15 minutes). [Table 6]

[0345] The results in Table 5 suggest that compounds of the present disclosure will have robust biological stability in vivo, as the majority of the compounds tested have half-lives greater than 60 minutes in the presence of both human and mouse liver microsomes.

[0346] Example 56: Evaluation of the solubility of compounds of the present disclosure. Preparation of stock solutions: Stock solutions of test compounds and the control compound diclofenac were prepared in DMSO at a concentration of 10 mM.

[0347] Simulated Gastric Fluid (SGF): An aqueous mixture (pH=1.2) containing hydrochloric acid, sodium chloride, and pepsin.

[0348] Simulated intestinal fluid (SIF): Prepared by dissolving 6.8 g of KH2PO4 in approximately 500 mL of ultrapure water and adjusting the solution to pH 6.8 with 0.1 M NaOH. Then, dissolve 10 g of trypsin in ultrapure water. Mix the two solutions well and dilute with ultrapure water to a final volume of 1000 mL.

[0349] Procedure for solubility determination: 15 μL of stock solution (10 mM) of each sample was placed in their appropriate 96-well rack in order. 485 μL of (SIF, SGF, PBS7.4, FESSIF, or FESSGF) was added to each vial of the uncapped soluble sample plate. Assays were performed in duplicate. One stir bar was added to each vial and sealed using a molded PTFE / silicone plug. The soluble sample plate was then transferred to an Eppendorf Thermomixer Comfort plate shaker and shaken at 1100 rpm at 25° C. for 2 hours. Upon completion of the 2 hours, the plugs were removed, the stir bars were removed using a large magnet, and the samples from the soluble sample plate were transferred to a filter plate. All samples were filtered using a vacuum manifold. A 5 μL aliquot and 5 μL of DMSO were taken from the filtrate, followed by the addition of 490 μL of a mixture of internal standards containing H2O and acetonitrile (1:1). A certain percentage of ultrapure water was used to dilute the dilutions depending on the peak shape, and the dilution factor was changed according to the solubility value and LC-MS signal response.

[0350] Preparation of 300 μM standard substance (STD): 6 μL from 10 mM DMSO STD plate was transferred to the remaining blank plate, then 194 μL DMSO was added to the plate to have a STD concentration of 300 μM. 5 μL DMSO STD and 5 μL SIF from 300 μM DMSO STD plate were transferred to the remaining blank plate, then 490 μL of a mixture of internal standards containing H2O and acetonitrile (1:1) was added to the plate to have a final STD concentration of 3 μM. A certain percentage of ultrapure water was used to dilute the dilution according to the peak shape. The concentration of the standard sample was changed according to the LC-MS signal response.

[0351] Sample analysis procedure: The plate was placed in a well plate autosampler. Samples were evaluated by LC-MS / MS analysis.

[0352] Data Analysis: All calculations were performed using Microsoft Excel. Filtrates were analyzed and quantified against standards of known concentration using LC coupled with mass spectrometry peak identification and quantification. Solubility values ​​for test and control compounds were calculated as follows:

number

[0353] Any values ​​for the compound that were not within the specified limits were rejected and the experiment was repeated.

[0354] Solubility data for selected compounds of the present disclosure are provided in Table 6. The solubility data in Table 6 are presented as "****" (value is greater than 200 μM), "***" (value is greater than 100 μM and less than or equal to 200 μM), "**" (value is greater than 20 μM and less than or equal to 100 μM), and "*" (value is less than or equal to 20 μM). NT is "not tested." [Table 7]

[0355] The results in Table 6 show that the solubility of the compounds of the present disclosure is significantly improved compared to comparative compounds 1-3. Seven of the ten compounds tested show improved solubility in simulated intestinal fluid, with compounds 2R and 2S being at least five times more soluble. Compound 2R also shows the same improvement in solubility in PBS buffer. As known to those skilled in the art, increased solubility of an active pharmaceutical ingredient (API) can indicate increased bioavailability, for example, in an orally administered composition.

[0356] Example 57: Pharmacokinetic evaluation of compound 2R The pharmacokinetics of compound 2R (HCl salt) and comparative compound 2 were studied after single intravenous and / or oral administration to mice, dogs, and monkeys (n=3 for all species). The IV and PO solution formulations of comparative compound 2 contained propylene glycol 20% (w / v), 50 mM trisodium phosphate (pH 12) 75% (w / v), and Kolliphor EL 5% (w / v). The compound 2R formulation contained 1:2 propylene glycol: 1% Tween 80 / Na3PO4 (50 mM). Subsequent pharmacokinetic data analysis was performed using the noncompartmental analysis module of Phoenix / WINNONLIN 6.3 (Pharsight, St. Louis, Missouri, USA), and the linear trapezoidal rule was used for AUC calculation. The terminal elimination half-life (t1 / 2) was calculated based on the terminal phase data points (≧3); Tmax=time of maximum observed concentration; AUClast / D=area under the concentration-time curve from time 0 to last observed concentration / divided by dose; Cl_obs=systemic clearance; Cmax=maximum observed concentration; F=bioavailability of oral dose form. Blood samples were assayed for compound using protein precipitation with acetonitrile followed by HPLC / MS / MS analysis. Blood concentration-time data were analyzed by non-compartmental methods.

[0357] IV PK parameters of comparative compound 2 and compound 2R [Table 8]

[0358] Oral PK parameters of comparative compound 2 and compound 2R [Table 9]

[0359] The enhanced solubility of Compound 2R resulted in improved exposure as represented by the PK parameter AUClast / D compared to the comparator Compound 2. IV pharmacokinetic analysis demonstrated an approximately 3-fold increase in exposure in mice (AUClast / D=14,240 vs. 5094 hr*mg / ml) and monkeys (AUClast / D=3783 vs. 1067) administered Compound 2R. Dogs showed an approximately 15-fold increase in exposure when administered Compound 2R intravenously compared to the comparator Compound 2 (AUClast / D=28655 vs. 1975). Oral PK analysis in mice revealed a similar trend as reflected by a 3-fold enhanced exposure with Compound 2R compared to the comparator Compound 2. However, the improvement in exposure in response to oral treatment with compound 2R was particularly strong in both dogs (>28-fold) and monkeys (>74-fold), as indicated by AUClast / D values ​​of 13,808 vs. 487 h*mg / ml (dogs) and 2222 vs. 30 h*mg / ml (monkeys).

[0360] Other embodiments All publications and patents referenced in this disclosure are incorporated herein by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. If the meaning of a term in any of the patents or publications incorporated by reference conflicts with the meaning of the term used in this disclosure, the meaning of the term in this disclosure is intended to control. Furthermore, the above discussion discloses and describes merely exemplary embodiments of the present disclosure. Those skilled in the art will readily recognize that from such discussion and the accompanying drawings and claims, various changes, modifications, and variations therein can be made without departing from the spirit and scope of the present disclosure as defined in the following claims.

Claims

1. Compound of formula Ia-1 【Chemistry 1】 or a pharma- ceutically acceptable salt or solvate thereof, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof, During the ceremony, Each X' is N, C-R ３ or CH, R １ａ But H or C １－６ is selected from the group consisting of alkyl, R １ｂ But, C １－６ Alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, OR′, N(R′) ２ , C(O)R', C(O)OR', C(O)N(R') ２ , Halo, CN, and NO ２ Each C is selected from the group consisting of １－６ The alkyl, cycloalkyl, hetercycloalkyl, aryl, or heteroaryl are optionally and independently substituted with one or more R″ substituents; Each R ２ But independently, halo, OH, C １－６ Alkyl, haloalkyl, OC １－６ Alkyl, CN, NH ２ , N.H.C. １－６ Alkyl, N(C １－６ Alkyl) ２ , C(O)C １－６ Alkyl, C(O)OC １－６ Alkyl, C(O)NH ２ , C(O)NHC １－６ Alkyl, and C(O)N(C １－６ Alkyl) ２ Selected from or Each R ３ But independently, C １－６ Alkyl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, halo, CN, NO ２ , OR', N(R') ２ , C(O)R', C(O)OR', C(O)N(R') ２ , OC(O)OR', OC(O)N(R') ２ ,NR'C(O)N(R') ２ , SOR', SON(R') ２ , S.O. ２ R', SO ２ N(R') ２ , NR'SOR', NR'SON(R') ２ , NR'SO ２ R' and NR'SO ２ N(R') ２ is selected from C １－６ Alkyl, hetercycloalkyl, and heteroaryl are each optionally and independently substituted with one or more R″ substituents; Each R ４ But, halo, OH, NH ２ , C.N., C. １－６ Alkyl and O.C. １－６ alkyl, Each R' is independently hydrogen, OH, CN, C １－６ selected from alkyl, cycloalkyl, hetercycloalkyl, aryl, and heteroaryl, each of which is optionally and independently substituted with one or more R″ substituents; Each R" is independently C １－６ Alkyl, cycloalkyl, hetercycloalkyl, aryl, heteroaryl, OC １－６ Alkyl, oxo, OH, halo, CN, NH ２ , N.H.C. １－６ Alkyl, N(C １－６ Alkyl) ２ , C(O)C １－６ Alkyl, C(O)OC １－６ Alkyl, C(O)NH ２ , C(O)NHC １－６ Alkyl, and C(O)N(C １－６ Alkyl) ２ Each C is selected from the group consisting of １－６ Alkyl, cycloalkyl, hetercycloalkyl, aryl, and heteroaryl are optionally and independently selected from halo, oxo, alkoxy, CN, NH ２ , C(O)C １－６ Alkyl, C(O)OC １－６ Alkyl, and C(O)NHC １－６ substituted with one or more substituents selected from alkyl, A compound or salt wherein m, n, and p are each an integer selected from 0 to 4.

2. R １ａ The compound or salt of claim 1 , wherein

3. R １ｂ is C １－６ Alkyl, C １－６ The compound or salt of claim 1, which is alkyl-OH, or CN.

4. R １ｂ is methyl, CN, or CH ２ 4. The compound or salt of claim 3, wherein:

5. Each R ２ 5. The compound or salt of any one of claims 1 to 4, wherein the substituents are independently selected from halo and OH.

6. 6. The compound or salt of claim 5, wherein n is 0.

7. Each R ３ The substituents are independently halo, CN, NH ２ , OH, C(O)H, C(O)N(CH ３ ) ２ ,C(O)NH(CH ３ ), C(O)NH(Et), C(O)NH(isopropyl), C(O)NH(tert-butyl), C(O)NH(cyclopropyl), C(O)NCH ３ (CN), C(O)NH(OH), C(O)NCH ３ (OH), C(O)NH ２ ,NHC(O)NHCH ３ , N.H.S. (O) ２ CH ３ , S(O) ２ CH ３ , methyl, methoxy, NHS(O) ２ CH ２ CH ２ N (CH ３ ) ２ , C.F. ３ , C.H. ２ OH, C(CH ３ ) ２ O.H. 【Chemistry 2】 7. The compound or salt according to claim 1 , selected from:

8. ring 【Chemistry 3】 is phenyl, pyridyl, pyrimidyl, pyrazyl, or triazyl, and optionally R ３ 8. The compound or salt of claim 1 , substituted by:

9. ring 【Chemistry 4】 teeth, 【Chemistry 5】 9. The compound or salt of claim 8,

10. 10. The compound or salt according to claim 8 or 9, wherein p is 1 or 2.

11. The compound of formula Ia-1 is a compound of formula Ia-2, or a salt thereof, according to claim 1: 【Chemistry 6】

12. ring 【Chemistry 7】 teeth, 【Chemistry 8】 12. The compound or salt of claim 11, selected from:

13. 2. The compound or salt of claim 1, wherein m is 0.

14. The compound of formula Ia-1 is: 【Table 1】 【Table 2】 【Table 3】 【Table 4】 【Table 5】 【Table 6】 【Table 7】 【Table 8】 2. The compound or salt of claim 1, which is a compound selected from:

15. 15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14, or a pharma- ceutically acceptable salt or solvate thereof, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof, and a pharma- ceutically acceptable excipient.

16. 15. A method of modulating EGFR and / or PI3K enzymes in an in vitro biological sample, comprising contacting the biological sample with a compound or salt according to any one of claims 1 to 14.

17. A composition comprising a therapeutically effective amount of a compound of formula Ia-1 for use in treating cancer in a human.

18. The composition of claim 17, wherein the human cancer is a cancer mediated by EGFR and / or PI3K enzymes.

19. 18. The composition of claim 17, wherein the human cancer is selected from prostate cancer, liver cancer, renal cancer, lung cancer, breast cancer, colorectal cancer, pancreatic cancer, brain cancer, hepatocellular carcinoma, lymphoma, leukemia, gastric cancer, cervical cancer, ovarian cancer, thyroid cancer, melanoma, head and neck carcinoma, head and neck cancer, skin cancer, and soft tissue sarcoma, and / or other forms of cancer.

20. 20. The composition of claim 19, wherein the head and neck cancer is squamous cell head and neck cancer and the breast cancer is triple negative breast cancer.

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