Small molecules for the treatment of autoimmune diseases and cancer

Abstract

Disclosed herein are quinazolinyl compounds, compositions, and methods of use thereof. The compounds may be used in the treatment of autoimmune disorders or cancer.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 062,670, filed on 7 August 2020, which is incorporated in its entirety by reference herein.

[0002] This application relates to the fields of chemistry and medicine. More specifically, this application relates to compounds useful in the treatment of autoimmune disorders and cancer. Some embodiments relate to quinazolinyl compounds, methods for producing them, and uses. [Background technology]

[0003] Histone post-translational modifications are epigenetic mechanisms that affect chromatin structure, thereby altering gene expression and ultimately contributing to the pathogenesis of various human diseases, including autoimmune diseases and cancer. Specifically, the N-terminal tails of histones are susceptible to reversible covalent modifications, including acetylation, methylation, phosphorylation, ubiquitination, and ubiquitin-like protein modifications. These modifications alter the histone affinity to the sugar backbone, thereby regulating the ability of transcription factors to access the underlying DNA and consequently affecting replication, transcription, and chromatin stability. [Overview of the project] [Means for solving the problem]

[0004] Some embodiments disclosed herein relate to quinazolinyl compounds, methods for preparing quinazolinyl compounds, compositions comprising quinazolinyl compounds, and treatment methods using quinazolinyl compounds. In some embodiments, quinazolinyl compounds are used to treat autoimmune disorders (for example, in methods for treating subjects with autoimmune disorders). In some embodiments, autoimmune disorders are selected from the group consisting of ulcerative colitis, Crohn's disease, systemic lupus erythematosus, psoriasis, rheumatoid arthritis, type 1 diabetes, multiple sclerosis, celiac disease, graft-versus-host disease (GVHD), Sjögren's syndrome, Graves' disease, Hashimoto's thyroiditis, autoimmune hepatitis, Behçet's disease, atopic dermatitis, Castleman disease, allergic rhinitis, eczema, Dressler syndrome, eosinophilic esophagitis, fibromyalgia, Guillain-Barré syndrome, juvenile arthritis, Kawasaki disease, Mohren's ulcer, mixed connective tissue disease, Parry-Romberg syndrome, primary biliary cirrhosis, primary sclerosing cholangitis, psoriatic arthritis, sarcoidosis, scleroderma, undifferentiated connective tissue disease, uveitis, vasculitis, and vitiligo.

[0005] In some embodiments, quinazolinyl compounds are used to treat cancer. In some embodiments, cancer is selected from the group consisting of colorectal, gastric (stomach), esophageal, liver, pancreatic, breast, prostate, bladder, kidney, ovarian, lung, melanoma, and multiple myeloma.

[0006] In some embodiments, the quinazolinyl compound is a compound of formula (I):

[0007] [ka] or its stereoisomers, tautomers, or pharmaceutically acceptable salts.

[0008] In some embodiments, X 1 It is either a CH2 or a covalent bond.

[0009] In some embodiments, X 2 C1-C are substituted with hydrogen or optionally.10 is alkyl, and X 3 is -CN, optionally substituted C1-C 10 alkyl, optionally substituted 2-10 member heteroalkyl, optionally substituted 3-10 member carbocyclic, optionally substituted (carbocyclic)alkyl, optionally substituted (heterocyclic)alkyl, optionally substituted 6-10 member aryl, optionally substituted 3-10 member heterocyclic, or optionally substituted 5-10 member heteroaryl, selected from the group consisting of, or alternatively, X 2 and X 3 together with the atoms to which they are attached form an optionally substituted 3-10 member heterocyclic ring.

[0010] In some embodiments, X 4 is -CN, -OR 1 -SR 1 halogen, optionally substituted C1-C 10 alkyl, optionally substituted C1-C 10 alkenyl, optionally substituted C1-C 10 alkynyl, optionally substituted 3-10 member carbocyclic, optionally substituted 6-10 member aryl, optionally substituted 3-10 member heterocyclic, optionally substituted 5-10 member heteroaryl, and -NR 2 R 3 selected from the group consisting of.

[0011] In some embodiments, R 1 is hydrogen or optionally substituted C1-C 10 alkyl.

[0012] In some embodiments, each of R 2 and R 3 is independently selected from hydrogen and optionally substituted C 1~10 alkyl, or alternatively, R 2 and R 3These, together with the atoms to which they are bonded, can form optionally substituted 3- to 10-membered heterocyclines or optionally substituted 5- to 10-membered heteroaryls.

[0013] In some embodiments, R 4 is -OR 9 Or it is (heterocyclyl)alkynyl.

[0014] In some embodiments, R 9 The group is selected from methyl, optionally substituted 2- to 10-membered heteroalkyls, and (heterocyclyl)alkyls.

[0015] In some embodiments, R 5 The element is selected from the group consisting of hydrogen, halogens, and -OMe.

[0016] Some embodiments involve compounds of formula (I):

[0017] [ka] [where, X 1 is, -(CH2) o -or covalent, where o is an integer equal to 1, 2, 3, 4, 5, or 6, X 2 is hydrogen, X 3 -CN, C1~C which are replaced by any choice 10 Selected from the group consisting of alkyl, optionally substituted 2-10 member heteroalkyl, optionally substituted 3-10 member carbocyclyl, optionally substituted (carbocyclyl)alkyl, optionally substituted (heterocyclyl)alkyl, optionally substituted 6-10 member aryl, optionally substituted 3-10 member heterocyclyl, or optionally substituted 5-10 member heteroaryl, or instead, X 2 and X 3 These, together with the atoms to which they are bonded, form optionally substituted 3- to 10-membered heterocyclines, X 4 -CN, -OR 1, -SR 1 , halogen, C1~C (optionally substituted) 10 Alkyl, optionally substituted C1-C 10 Alkenyl, C1-C substituted by choice 10 Alkinyl, optionally substituted 3-10 member carbocyclyl, optionally substituted 6-10 member aryl, optionally substituted 3-10 member heterocyclyl, optionally substituted 5-10 member heteroaryl, and -NR 2 R 3 Selected from the group consisting of, R 1 C1-C are substituted with hydrogen or optionally. 10 It is alkyl, R 2 and R 3 Each of them independently consists of hydrogen and optionally substituted C 1~10 Selected from alkyl groups, or alternatively, R bonded to the same nitrogen atom. 2 and R 3 These, together with the atoms to which they are bonded, can form optionally substituted 3-10 member heterocyclines or optionally substituted 5-10 member heteroaryls, R 4 is -OR 9 or (heterocyclyl)alkynyl, R 9 R is selected from the group consisting of methyl, optionally substituted 2-10 member heteroalkyls, and (heterocyclyl)alkyls, 5 This relates to a compound selected from the group consisting of hydrogen, halogens, and -OMe, or its stereoisomers, tautomers, or pharmaceutically acceptable salts.

[0018] In some embodiments, X 3 but,

[0019] [ka] [In the formula, R 6 This is an unsubstituted benzyl, an unsubstituted 3-10 membered carbocyrillic, or a C1-C2 molecule optionally substituted with an amine. 10 If it is alkyl,2 and R 3 If present, these combine to form an optionally substituted 5-membered heteroaryl or an optionally substituted 4-membered heterocycline.

[0020] However, X 3 but,

[0021] [ka] If R 4 teeth,

[0022] [ka] That is the case.

[0023] In some embodiments, the compound of formula (I) is the compound of formula (Ia):

[0024] [ka] [In the formula, the ring "A" is a cycloalkyl ring or a heterocyclyl ring, X a x is selected from the group consisting of CH and N, m is an integer independently selected from 0, 1, 2, and 3, n is an integer independently selected from 0, 1, 2, and 3, l is an integer selected from 0, 1, 2, and 3, and X b CH2, NR b Selected from the group consisting of , O, and SO2, R a It is optionally present and can be provided at any position in the "A" ring by replacing one or more -H atoms of any carbon or nitrogen atom present in the "A" ring, R a R is selected from the group consisting of amino, -OH, and optionally substituted C1-C6 alkyl groups, b[is further represented by a group selected from hydrogen, optionally substituted C1-C6 alkyls, and C-carboxyls]. In some embodiments, n is 1 and m is 3. In some embodiments, X b is O or SO2. In some embodiments, the compound is compound 1, 6, 11, 14, 15, 19, 24, 26, 28, 66, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 105, 106, 107, 108, 116, 117, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 131, 136, 137, 139, 140, 14 Selected from the group consisting of 1, 142, 143, 144, 145, 146, 147, 148, 149, 164, 165, 173, 174, 175, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, or any stereoisomer, tautomer, or pharmaceutically acceptable salt of any of the aforementioned.

[0025] In some embodiments, the compound of formula (I) is the compound of formula (Ib):

[0026] [ka] [where, X 3 It is represented by the ring "B", The "B" ring is further represented by an unsaturated ring selected from the group consisting of optionally substituted cyclopentenyl, optionally substituted phenyl, optionally substituted furyl, optionally substituted thienyl, optionally substituted pyrrolyl, optionally substituted oxazolyl, optionally substituted thiazolyl, optionally substituted imidazolyl, optionally substituted benzimidazolyl, optionally substituted pyrazolyl, optionally substituted isoxazolyl, optionally substituted triazolyl, optionally substituted pyridinyl, optionally substituted pyridadinyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, optionally substituted indolyl, optionally substituted isoindolyl, and optionally substituted benzothienyl. In some embodiments, the "B" ring is,

[0027] [ka] One of the following is selected, and any of these may be optionally substituted by replacing one or more -H atoms of any carbon or nitrogen atom present on the "B" ring.

[0028] In some embodiments, the optional substitution of the "B" ring is selected from one or more amino, -OH, optionally substituted C1-C6 alkyl, and halogen groups.

[0029] In some embodiments, the compound of formula (I) is the compound of formula (Ic):

[0030] [ka] [In the formula, m is an integer independently selected from 0, 1, 2, and 3, n is an integer independently selected from 0, 1, 2, and 3, X b CH2, NR b Selected from the group consisting of , O, and SO2, R aIt is optionally present and can be provided at any position in the "C" ring by replacing one or more -H atoms of any carbon or nitrogen atom present in the "C" ring, R a R is selected from the group consisting of amino, N-amide, -OH, and optionally substituted C1-C6 alkyl groups. b This is further represented by [selected from C1-C6 alkyl and C-carboxy].

[0031] In some embodiments, the compound of formula (I) is the compound of formula (Id):

[0032] [ka] [In the formula, the ring "D" is a cycloalkyl ring or a heterocyclyl ring, X a x is selected from the group consisting of CH and N, m is an integer independently selected from 0, 1, 2, and 3, n is an integer independently selected from 0, 1, 2, and 3, and X b CH2, NR h Selected from the group consisting of , O, and SO2, R a It is optionally present and can be provided at any position in the "D" ring by replacing one or more -H atoms of any carbon or nitrogen atom present in the "D" ring, R a R is selected from the group consisting of halogens, aminos, -OH, and optionally substituted C1-C6 alkyl groups. h [is further represented by a group selected from hydrogen, optionally substituted C1-C6 alkyls, and C-carboxyls. In some embodiments, n is 1 and m is 2. In some embodiments, n is 1 and m is 3. In some embodiments, n is 2 and m is 2.

[0033] In some embodiments, the compound of formula (I) is the compound of formula (Ie):

[0034] [ka] [where, X 4 [is represented by the ring "E", and the "E" ring is an unsaturated ring selected from the group consisting of optionally substituted cyclopentenyl, optionally substituted phenyl, optionally substituted furyl, optionally substituted thienyl, optionally substituted pyrrolyl, optionally substituted oxazolyl, optionally substituted thiazolyl, optionally substituted imidazolyl, optionally substituted benzimidazolyl, optionally substituted pyrazolyl, optionally substituted isoxazolyl, optionally substituted triazolyl, optionally substituted pyridinyl, optionally substituted pyridadinyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, optionally substituted indolyl, optionally substituted isoindolyl, and optionally substituted benzothienyl]. In some embodiments, the "E" ring is,

[0035] [ka] One of the following is selected, and any of them may be optionally substituted by replacing one or more -H atoms of any carbon or nitrogen atom present on the "E" ring.

[0036] In some embodiments, the optional substitution of the "E" ring is selected from one or more of amino, -OH, optionally substituted C1-C6 alkyl, and halogen.

[0037] In some embodiments, the compound of formula (I) is the compound of formula (If):

[0038] [ka] Further represented by, the variable groups are as defined elsewhere in this specification.

[0039] In some embodiments, X 3is a substituted 6-membered heterocyclyl. In some embodiments, X 3 is an unsubstituted 6-membered heterocyclyl. In some embodiments, X 3 is an unsubstituted 6-membered aryl. In some embodiments, X 3 is an unsubstituted 2- to 10-membered heteroalkyl.

[0040] In some embodiments, X 4 is an optionally substituted 4- to 6-membered heterocyclyl. In some embodiments, X 4 is a 5-membered heteroaryl. In some embodiments, X 4 is -CN.

[0041] In some embodiments, X 1 is a covalent bond. In some embodiments, X 1 is CH2.

[0042] In some embodiments, X 2 is hydrogen.

[0043] In some embodiments, R 4 is

[0044]

Chemical formula

[0045] In some embodiments, R 5 is -OMe.

[0046] In some embodiments, the compound of formula (I) is of formula (Ig):

[0047]

Chemical formula

[0048] In some embodiments, the compound of formula (I) is of formula (Ih):

[0049]

Chemical formula

[0050] In some embodiments, the compound of formula (I) is of formula (Ij):

[0051]

Chemical formula

[0052] In some embodiments, the compound of formula (I) is of formula (Ik):

[0053]

Chemical formula

[0054] In some embodiments, the compound is

[0055]

Chemical formula

[0056] One embodiment relates to a pharmaceutical composition comprising a therapeutically effective amount of the above-mentioned compound and a pharmaceutically acceptable excipient.

[0057] One embodiment is a method of treating an autoimmune disorder, the method comprising administering to a subject in need thereof a compound of formula (I):

[0058] [Chemical formula] [wherein, X 1 is CH2 or a covalent bond, X 2 is hydrogen, X 3 is -CN, optionally substituted C1-C 10 alkyl, optionally substituted 2- to 10-membered heteroalkyl, optionally substituted 3- to 10-membered carbocyclyl, optionally substituted (carbocyclyl)alkyl, optionally substituted (heterocyclyl)alkyl, optionally substituted 6- to 10-membered aryl, optionally substituted 3- to 10-membered heterocyclyl, or optionally substituted 5- to 10-membered heteroaryl, or alternatively, X 2 and X 3 together with the atoms to which they are attached form an optionally substituted 3- to 10-membered heterocyclyl, X 4 is -CN, -OR 1 -SR 1 , halogen, optionally substituted C1-C 10 alkyl, optionally substituted C1-C 10 alkenyl, optionally substituted C1-C 10 alkynyl, optionally substituted 3- to 10-membered carbocyclyl, optionally substituted 6- to 10-membered aryl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted 5- to 10-membered heteroaryl, and -NR 2 R 3 selected from the group consisting of, R 1 is hydrogen or optionally substituted C1-C 10 alkyl, R 2 and R 3Each of them independently consists of hydrogen and optionally substituted C 1~10 Selected from alkyl groups, or alternatively, R bonded to the same nitrogen atom. 2 and R 3 These, together with the atoms to which they are bonded, can form optionally substituted 3-10 member heterocyclines or optionally substituted 5-10 member heteroaryls, R 4 is -OR 9 or (heterocyclyl)alkynyl, R 9 R is selected from the group consisting of methyl, optionally substituted 2-10 member heteroalkyls, and (heterocyclyl)alkyls, 5 The present invention relates to a method comprising administering a [selected from the group consisting of hydrogen, halogens, and -OMe], or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0059] Some embodiments are methods for treating autoimmune disorders or cancer, and for subjects requiring such treatment, compounds disclosed elsewhere in this specification, pharmaceutical compositions containing such compounds, and compounds having the following structure:

[0060] [ka] , or compounds according to formula (II):

[0061] [ka] [where, X 7 is CH2 or a covalent bond, R 7 R is a C1-C6 alkyl or 3-6 membered carbocyclyl, 8The present invention relates to a method comprising administering a compound selected from the group consisting of cyclohexyl, a 5-6 member heteroaryl optionally substituted with methyl, or a 5-7 member heterocycline optionally substituted with fluoro, oxo, or C1-C6 alkyl, where A is selected from the group consisting of N, CH, or CH2, and n is an integer independently selected from 0, 1, and 2, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0062] Some embodiments relate to methods for treating autoimmune disorders, comprising administering to a patient having an autoimmune disorder a compound or a pharmaceutical composition disclosed herein. In some embodiments, autoimmune disorders are selected from the group consisting of ulcerative colitis, Crohn's disease, systemic lupus erythematosus, psoriasis, rheumatoid arthritis, type 1 diabetes, multiple sclerosis, celiac disease, graft-versus-host disease (GVHD), Sjögren's syndrome, Graves' disease, Hashimoto's thyroiditis, autoimmune hepatitis, Behçet's disease, atopic dermatitis, Castleman disease, allergic rhinitis, eczema, Dressler syndrome, eosinophilic esophagitis, fibromyalgia, Guillain-Barré syndrome, juvenile arthritis, Kawasaki disease, Mohren's ulcer, mixed connective tissue disease, Parry-Romberg syndrome, primary biliary cirrhosis, primary sclerosing cholangitis, psoriatic arthritis, sarcoidosis, scleroderma, undifferentiated connective tissue disease, uveitis, vasculitis, and vitiligo. In some embodiments, the autoimmune disorder is selected from the group consisting of ulcerative colitis, Crohn's disease, systemic lupus erythematosus, psoriasis, rheumatoid arthritis, type 1 diabetes, multiple sclerosis, and celiac disease. In some embodiments, the autoimmune disorder is Crohn's disease. In some embodiments, the autoimmune disorder is ulcerative colitis.

[0063] Some embodiments relate to methods for treating cancer, comprising administering to a patient having cancer a compound or a pharmaceutical composition disclosed herein. In some embodiments, cancer is selected from the group consisting of colorectal, gastric (stomach), esophageal, liver, pancreatic, breast, prostate, bladder, kidney, ovarian, lung, melanoma, and multiple myeloma. [Brief explanation of the drawing]

[0064] [Figure 1] This figure shows the relative transepithelial resistance of CaCo-2 cells after 24 hours of exposure to the selected conditions. [Figure 2] This figure shows the relative transepithelial resistance of CaCo-2 cells after 24 hours of exposure to the selected conditions. [Figure 3] This figure shows the relative transepithelial resistance of CaCo-2 cells after 48 hours of exposure to the selected conditions. [Figure 4A] This graph shows the percentage change in body weight in mice after treatment with the selected compound. [Figure 4B] This figure shows the colon length of mice after exposure to the selected conditions. [Figure 5A] This graph shows the percentage change in body weight in mice after treatment with the selected compound. [Figure 5B] This figure shows the percentage change in body weight of mice after exposure to the selected conditions. [Figure 5C] This figure shows the colon length of mice after exposure to the selected conditions. [Figure 6] These are four figures showing the inhibitory effects of four compounds on the growth of HT-29 colorectal cancer cells. [Figure 7-1] Figure 7A shows information on colon tissue gene expression after administration of the compounds as disclosed herein. Mice with TNBS-induced colitis treated with compound 2 showed significantly reduced expression of genes related to the inflammatory response (>85 genes, 50 shown for clarity). [Figure 7-2] Figure 7B. Compound 2 (or "cpd2") response 22 gene signatures: Mice with TNBS-induced colitis treated with cpd2 showed significantly reduced expression of genes associated with disruption of inflammatory signaling pathways and extracellular matrix signaling pathways. [Figure 7-3]Figure 7C. Colon tissue gene expression. Mice with TNBS-induced colitis treated with cpd2 showed significantly reduced expression of marker genes compared to untreated or refractory ulcerative colitis patients (marker genes for the mouse / human chimeric monoclonal IgG1 antibody infliximab response to tumor necrosis factor alpha (TNFa) were taken from publicly available studies). [Figure 7-4] Figures 7D-7G. Colon tissue gene expression. Mice with TNBS-induced colitis and the compounds disclosed herein showed significantly reduced expression of marker genes compared to patients with untreated or refractory ulcerative colitis (marker genes for the mouse / human chimeric monoclonal IgG1 antibody infliximab response to tumor necrosis factor alpha (TNFa) were taken from publicly available studies). [Figure 7-5] Figure 7H shows data for mice with TNBS-induced colitis treated with the compounds disclosed herein. The treated mice showed significantly reduced expression of the inflammatory cytokine TNF. [Figure 8] This figure shows the gene expression data of the colon cell line HCT. Cells treated with cpd156 showed significantly reduced expression of genes involved in cell cycle pathways and significantly increased expression of genes related to the p53 signaling pathway. [Figure 9] This figure shows the results of a study on the microbiome of animals with inflammatory bowel disease (IBD). The gut microbiome mainly consists of four phyla: Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria. In patients with inflammatory bowel disease (IBD), the composition of the gut microbiota is altered compared to that of healthy individuals. [Figure 10] This figure shows the effects of compounds 2, 400, and 401 on IL17 expression levels. [Modes for carrying out the invention]

[0065] Detailed explanation Some embodiments disclosed herein relate to quinazolinyl compounds, methods using quinazolinyl compounds, compositions containing quinazolinyl compounds, and treatment methods using quinazolinyl compounds. In some embodiments, the quinazolin compound includes a quinazolin core. In some embodiments, the quinazolin compound includes a cyclic substituent bonded to the quinazolin ring at position 2. In some embodiments, the quinazolin compound includes an amine substituent bonded to the quinazolin ring at position 4. In some embodiments, the quinazolin compound includes an amine at position 4 that contains a cyclic substituent (either pendanted to or directly bonded to the amine), or the amine is part of the cyclic substituent. In some embodiments, the quinazolin compound includes a methoxy group at position 6. In some embodiments, the quinazolin compound includes an alkoxy group at position 7. In some embodiments, the quinazolin compound includes a pendant cyclic group at position 7 that is connected to the biring by either an alkyne or an alkoxy group. The following description provides context and examples, but should not be construed as limiting the scope of the invention as covered by subsequent claims in this specification or any other application claiming priority to this specification. No single component or collection of components is essential or indispensable. Any feature, structure, component, material, step, or method described and / or illustrated in any embodiment of this specification may be used together with or instead of any feature, structure, component, material, step, or method described and / or illustrated in any other embodiment of this specification.

[0066] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this disclosure pertains. All patents, applications, published applications, and other publications are incorporated in their entirety by reference. If multiple definitions exist for any term herein, the definitions in this section shall prevail unless otherwise noted.

[0067] A “prodrug” is a drug that is converted to a parent drug in vivo. Prodrugs are often useful because, under certain circumstances, they may be easier to administer than the parent drug. For example, they may be available to an organism by oral administration while the parent is not. Prodrugs may also have improved solubility in pharmaceutical compositions than the parent drug. An example of a prodrug, though not limited to this, would be a compound that is administered as an ester ("prodrug") to facilitate its passage across cell membranes where water solubility is detrimental to mobility, but is then metabolized and hydrolyzed into an active entity, a carboxylic acid, once inside the cell where water solubility is beneficial. Further examples of prodrugs may be short peptides (polyamino acids) bound to an acid group, where the peptide is metabolized to expose the active site. Conventional procedures for selecting and preparing appropriate prodrug derivatives are described, for example, in Design of Prodrugs, (H. Bundgaard, ed., Elsevier, 1985), which is incorporated herein by reference in its entirety.

[0068] The term “prodrug ester” refers to a derivative of a compound disclosed herein formed by adding any of several esterifying groups that are hydrolyzable under physiological conditions. Examples of prodrug ester groups include pivoyloxymethyl, acetoxymethyl, phthalidyl, indanyl, and methoxymethyl, as well as other such groups known in the art, including the (5-R-2-oxo-1,3-dioxolene-4-yl)methyl group. Other examples of prodrug ester groups can be found, for example, in T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14, ACSSymposium Series, American Chemical Society (1975), and in “Bioreversible Carriers in Drug Design: Theory and Application,” edited by E.B. Roche, Pergamon Press: New York, pp. 14–21 (1987) (which provides examples of esters useful as prodrugs for compounds containing carboxyl groups). Each of the above references is incorporated herein by reference in its entirety.

[0069] The “metabolites” of the compounds disclosed herein include active species that are produced when the compounds are introduced into a biological environment.

[0070] A "solvate" refers to a compound formed by the interaction of a solvent, a compound, a metabolite, or a salt thereof with a solvent as described herein. A suitable solvate is a pharmaceutically acceptable solvate, including a hydrate.

[0071] The term "pharmaceutically acceptable salt" means a salt that retains the biological efficacy and properties of a compound, and is not undesirable for use in pharmaceuticals in a biological or otherwise manner. In many cases, the compounds herein can form acid and / or base salts thanks to the presence of amino and / or carboxyl groups or similar groups. Pharmaceutically acceptable acid addition salts can be formed using inorganic and organic acids. Examples of inorganic acids from which salts can be derived include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Examples of organic acids from which salts can be derived include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Pharmaceutically acceptable base addition salts can be formed using inorganic and organic bases. Examples of inorganic bases from which salts can be derived include sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum, with ammonium, potassium, sodium, calcium, and magnesium salts being particularly preferred. Examples of organic bases from which salts can be derived include primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, specifically isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. Many such salts are known in the art, as described in WO87 / 05297, Johnston et al., published September 11, 1987 (the entire publication is incorporated herein by reference).

[0072] When referring to numerical values, the terms “or the range including and / or spanning the aforementioned values” (and variations thereof) mean including any range including or spanning the aforementioned values. For example, if the reaction temperature is expressed as “20°C, 30°C, 40°C, 50°C, or the range including and / or spanning the aforementioned values,” this includes the specific temperature provided, or the temperature range spanning 20°C to 50°C, 20°C to 40°C, 20°C to 30°C, 30°C to 50°C, 30°C to 40°C, or 40°C or 50°C.

[0073] The term "C" used in this specification a ~C b " or "C a~b "(or similar wording)" [where "a" and "b" are integers] refers to the number of carbon atoms in the specified group. That is, a group can contain "a" to "b" carbon atoms (including both ends). Therefore, for example, "C1-C4 alkyl" or "C 1~4 The "alkyl" group refers to all alkyl groups having 1 to 4 carbon atoms, namely CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, and (CH3)3C-.

[0074] As used herein, the term "halogen" or "halo" means one of the radiation-stable atoms in the seventh column of the periodic table, such as fluorine, chlorine, bromine, or iodine, with fluorine and chlorine being preferred.

[0075] As used herein, “alkyl” means a linear or branched hydrocarbon chain that is completely saturated (i.e., does not contain double or triple bonds). Alkyl compounds may have 1 to 20 carbon atoms (wherever they appear herein, numerical ranges such as “1 to 20” refer to each integer within a given range; for example, “1 to 20 carbon atoms” means that an alkyl group may consist of 1, 2, 3, etc., up to 20 carbon atoms, but this definition also covers instances where the term “alkyl” does not specify a numerical range). Alkyl compounds may also be medium-sized alkyl groups having 1 to 9 carbon atoms. Alkyl compounds may also be lower alkyl groups having 1 to 4 carbon atoms. The alkyl group of a compound is “C 1~4 It may be named as "alkyl" or a similar name. For example, "C 1~4 The term "alkyl" indicates the presence of 1 to 4 carbon atoms in the alkyl chain; that is, alkyl chains are selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, and t-butyl. Typical alkyl groups, but not limited to any one form, include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, and hexyl.

[0076] As used herein, “haloalkyl” means a linear or branched alkyl group having 1 to 12 carbon atoms in the chain, in which one or more hydrogen atoms are substituted with halogens. Examples of haloalkyl groups include, but are not limited to, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH2CH2Cl, -CH2CF2CF3, and other groups that may be considered equivalent to any one of the above examples in light of the common art and the teachings provided herein.

[0077] As used herein, “alkoxy” refers to the formula -OR [wherein R is alkyl as defined above], for example, “C 1~9The term "alkoxy" refers to a compound that is not limited to this, but examples include methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy.

[0078] As used herein, "polyethylene glycol" refers to the formula

[0079] [ka] [wherein n is an integer greater than 1, and R is hydrogen or alkyl]. The number of repeating units "n" can be indicated by referring to the number of members. Thus, for example, "2-5 member polyethylene glycol" means that n is an integer selected from 2 to 5. In some embodiments, R is selected from methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy.

[0080] As used herein, “heteroalkyl” means a linear or branched hydrocarbon chain containing one or more heteroatoms. Heteroatoms are given their obvious and common meaning in organic chemistry, and include, but are not limited to, elements other than carbon, such as nitrogen (e.g., aminos), oxygen (e.g., alkoxys, ethers, hydroxyls), sulfur, and halogens. Heteroalkyl groups may have 1 to 20 carbon atoms, but this definition also covers instances where the term “heteroalkyl” does not specify a numerical range. Heteroalkyl groups may be medium-sized heteroalkyl groups having 1 to 9 carbon atoms. Heteroalkyl groups may also be lower heteroalkyl groups having 1 to 4 carbon atoms. In various embodiments, heteroalkyl groups may have 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 or 2 heteroatoms, or 1 heteroatom. The heteroalkyl group of a compound is “C 1~4It may be named as "heteroalkyl" or a similar name. A heteroalkyl group may contain one or more heteroatoms. For example, "C 1~4 The term "heteroalkyl" indicates that a heteroalkyl chain contains 1 to 4 carbon atoms, and furthermore, one or more heteroatoms are present in the main chain.

[0081] The term "aromatic" refers to a ring or ring system having a conjugated pi-electron system, including both carbocyclic aromatic groups (e.g., phenyl) and heterocyclic aromatic groups (e.g., pyridine). This term includes monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of atoms) groups, provided that the entire ring system is aromatic.

[0082] As used herein, “aryl” refers to an aromatic ring or ring system (i.e., two or more fused rings sharing two adjacent carbon atoms) containing only carbon atoms in its ring backbone. If the aryl is a ring system, all rings in the system are aromatic. While an aryl group may have 6 to 18 carbon atoms, this definition also covers instances of the term “aryl” where no numerical range is specified. In some embodiments, an aryl group has 6 to 10 carbon atoms. 6~10 "Aryl," "C6 or C 10 They may be named as "aryl" or similarly. Examples of aryl groups, but are not limited to them, include phenyl, naphthyl, azlenyl, and anthracenyl.

[0083] As used herein, “aryloxy” and “arylthio” refer to RO- and RS-[wherein R is an aryl as defined above], for example, “C 6~10 "Aryloxy" and "C 6~10 This refers to "arylthio" and other similar terms, but is not limited to them; phenyloxy is another example.

[0084] "Aralkyl" or "arylalkyl" means "C 7~14Examples of substituents include aryl groups linked via an alkylene group, such as "aralkyl," but are not limited to these, including benzyl, 2-phenylethyl, 3-phenylpropyl, and naphthylalkyl groups. In some cases, the alkylene group is a lower alkylene group (i.e., C 1~4 (Alkylene group)

[0085] As used herein, “heteroaryl” means an aromatic ring or ring system (i.e., two or more fused rings sharing two adjacent atoms) that contains one or more heteroatoms, i.e., elements other than carbon, including but not limited to nitrogen, oxygen, and sulfur, in its ring backbone. If the heteroaryl is a ring system, all rings in the system are aromatic. A heteroaryl group may have 5 to 18 ring members (i.e., the number of atoms constituting the ring backbone, including carbon atoms and heteroatoms), but this definition also covers occurrences of the term “heteroaryl” where a numerical range is not specified. In some embodiments, a heteroaryl group has 5 to 10 ring members or 5 to 7 ring members. A heteroaryl group may be named “5-7 membered heteroaryl,” “5-10 membered heteroaryl,” or similar names. In various embodiments, a heteroaryl contains 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom. For example, in various embodiments, the heteroaryl ring contains 1 to 4 nitrogen atoms, 1 to 3 nitrogen atoms, 1 to 2 nitrogen atoms, 2 nitrogen atoms and 1 sulfur or oxygen atom, 1 nitrogen atom and 1 sulfur or oxygen atom, or 1 sulfur or oxygen atom. Examples of heteroaryl rings, but not limited to, include furyl, thienyl, phthalazinyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolinyl, isoquinlinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indolyl, isoindolyl, and benzothienyl.

[0086] A "heteroaralkyl" or "heteroarylalkyl" is a heteroaryl group linked as a substituent via an alkylene group. Examples, though not limited to these, include 2-thienylmethyl, 3-thienylmethyl, furylmethyl, thienylethyl, pyrrolylalkyl, pyridylalkyl, isoxazollylalkyl, and imidazolylalkyl. In some cases, the alkylene group is a lower alkylene group (i.e., C 1~4 (Alkylene group)

[0087] As used herein, "carbocyclyl" means a non-aromatic cyclic ring or cyclic system containing only carbon atoms in the cyclic backbone. If a carbocyclyl is a cyclic system, two or more rings may be joined together in a condensed, bridging, or spiroconjoined manner. Carbocyclyls may have any degree of saturation, provided that at least one ring in the cyclic system is non-aromatic. Therefore, examples of carbocyclyls include cycloalkyls, cycloalkenyls, and cycloalkynyls. A carbocyclyl group may have 3 to 20 carbon atoms, but this definition also covers instances where the term "carbocyclyl" does not specify a numerical range. A carbocyclyl group may be a medium-sized carbocyclyl having 3 to 10 carbon atoms. A carbocyclyl group may also be a carbocyclyl having 3 to 6 carbon atoms. A carbocyclyl group is "C 3~6 They may be named as "carbocykrill" or similarly. Examples of carbocyclyl rings, but are not limited to them, include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,3-dihydroindene, bicyclic[2.2.2]octanyl, adamantyl, and spiro[4.4]nonanyl.

[0088] "(Carbocyclyl)alkyl" means "C 4~10The substituent is a carbocyclyl group connected via an alkylene group, such as "(carbocykyl)alkyl," but is not limited to this. Examples include cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylethyl, cyclopropylisopropyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, and cycloheptylmethyl. In some cases, the alkylene group is a lower alkylene group.

[0089] As used herein, "cycloalkyl" means a fully saturated carbocyclyl ring or ring system. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0090] As used herein, "cycloalkenyl" means a carbocykyl ring or ring system having at least one double bond, in which none of the rings are aromatic. One example is cyclohexenyl.

[0091] As used herein, “heterocyclyl” means a non-aromatic cyclic ring or ring system containing at least one heteroatom in the ring backbone. Heterocyclyls may be linked together in a condensed, bridging, or spiroconjoined manner. Heterocyclyls may have any degree of saturation, provided that at least one ring in the ring system is not aromatic. Heteroatoms may be present in either non-aromatic or aromatic rings in the ring system. Heterocyclyl groups may have 3 to 20 ring members (i.e., the number of atoms constituting the ring backbone, including carbon atoms and heteroatoms), but this definition also covers occurrences of the term “heterocyclyl” where a numerical range is not specified. Heterocyclyl groups may be medium-sized heterocyclyls having 3 to 10 ring members. Heterocyclyl groups may also be heterocyclyls having 3 to 6 ring members. Heterocyclyl groups may be named “3-6 membered heterocyclyl” or similarly.

[0092] In various embodiments, the heterocyclil contains 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom. For example, in various embodiments, the heterocyclil contains 1 to 4 nitrogen atoms, 1 to 3 nitrogen atoms, 1 to 2 nitrogen atoms, 2 nitrogen atoms and 1 sulfur or oxygen atom, 1 nitrogen atom and 1 sulfur or oxygen atom, or 1 sulfur or oxygen atom. In a preferred 6-membered monocyclic heterocyclil, the heteroatoms are selected from 1 to 3 of O, N, or S, and in a preferred 5-membered monocyclic heterocyclil, the heteroatoms are selected from 1 or 2 heteroatoms selected from O, N, or S. Examples of heterocyclyl rings, though not limited to these, include azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanil, imidazolinyl, imidazolidinyl, morpholinyl, oxylanil, oxepanil, thiepanil, piperidinyl, piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidonyl, pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 1,3-dioxynyl, 1,3-dioxanyl, 1,4-dioxynyl, 1,4-dioxanyl, 1,3-oxathianyl, 1,4-oxathianyl, 2H-1,2-oxadi Examples include yl, trioxanil, hexahydro-1,3,5-triazinyl, 1,3-dioxolyl, 1,3-dioxolanil, 1,3-dithiolyl, 1,3-dithiolanil, isoxazolinil, isoxazolidinyl, oxazolinil, oxazolidinyl, oxazolidinyl, oxazolidinyl, thiazolinil, thiazolidinyl, 1,3-oxathiolanil, indolinil, isoindolinil, tetrahydrofuranil, tetrahydropyranil, tetrahydrothiophenyl, tetrahydrothiopyranil, tetrahydro-1,4-thiadinyl, thiamorpholinil, dihydrobenzofuranil, benzimidazolidinyl, and tetrahydroquinoline. The sulfur of the heterocyclyl ring may be provided as a dioxide (e.g., -S(O)2-).

[0093] "(heterocyclyl)alkyl" refers to a heterocyclyl group linked via an alkylene group as a substituent. Examples, though not limited to these, include imidazolinylmethyl and indolinylethyl.

[0094] "(heterocyclyl)alkynyl" refers to a heterocyclyl group that is substituted via an alkynylene group.

[0095] As used herein, "acyl" means, as defined herein, where R is hydrogen, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~7 -C(=O)R refers to carbocyclyl, aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl compounds. Non-exclusive examples include formyl, acetyl, propanoyl, benzoyl, and acrylic.

[0096] The "O-carboxyl" group is defined herein as having R being hydrogen, C being hydrogen. 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~7 This refers to a "-OC(=O)R" group selected from carbocyclyl, aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl.

[0097] A "C-carboxyl" group is defined herein as a group where R is hydrogen, -NH2, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~7 This refers to a "-C(=O)OR" group selected from carbocyclyl, aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl groups. A non-restrictive example is carboxyl (i.e., -C(=O)OH).

[0098] The "cyano" group refers to the "-CN" group.

[0099] The "cyanato" group refers to the "-OCN" group.

[0100] The "isocyanato" group refers to the "-NCO" group.

[0101] The "thiocyanate" group refers to the "-SCN" group.

[0102] The "isothiocyanate" group refers to the "-NCS" group.

[0103] A "sulfinyl" group is defined herein as having R being hydrogen, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~7 Carbocyclyl, C 6~10 This refers to a "-S(=O)R" group selected from aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl groups.

[0104] A "sulfonyl" group is defined herein as having R being hydrogen, C being hydrogen. 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~7 Carbocyclyl, C 6~10 This refers to a "-SO2R" or "-SO2-" group selected from aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl groups. Sulfonyls can be provided within a heterocyclyl ring.

[0105] The "S-sulfonamide" group is defined as R as defined herein. A and R B Each of them independently produces hydrogen and C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~7 Carbocyclyl, C 6~10 Selected from aryls, 5-10 membered heteroaryls, and 5-10 membered heterocyclines, "-SO2NR A R B It refers to the base.

[0106] The "N-sulfonamide" group is defined as R as defined herein. A and R B Each of them independently produces hydrogen and C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~7 Carbocyclyl, C 6~10 Selected from aryls, 5-10 membered heteroaryls, and 5-10 membered heterocyclines, "-N(R A )SO2R B It refers to the base.

[0107] The "O-carbamyl" group is defined herein as R A and R B Each of them independently produces hydrogen and C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~7 Carbocyclyl, C 6~10 "-OC(=O)NR" is selected from aryls, 5-10 membered heteroaryls, and 5-10 membered heterocyclines. A R B It refers to the base.

[0108] The "N-carbamyl" group is defined as R A and R B Each of them independently produces hydrogen and C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~7 Carbocyclyl, C 6~10 Selected from aryls, 5-10 membered heteroaryls, and 5-10 membered heterocyclines, "-N(R A )OC(=O)R B It refers to the base.

[0109] The "O-thiocarbamyl" group is defined as R as defined herein. A and R B Each of them independently produces hydrogen and C 1~6 Alkyl, C2~6 Alkenil, C 2~6 Alkinyl, C 3~7 Carbocyclyl, C 6~10 Selected from aryls, 5-10 member heteroaryls, and 5-10 member heterocyclines, "-OC(=S)NR A R B It refers to the base.

[0110] The "N-thiocarbamyl" group is defined as R A and R B Each of them independently produces hydrogen and C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~7 Carbocyclyl, C 6~10 Selected from aryls, 5-10 membered heteroaryls, and 5-10 membered heterocyclines, "-N(R A )OC(=S)R B It refers to the base.

[0111] The "C-amide" group is defined as R A and R B Each of them independently produces hydrogen and C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~7 Carbocyclyl, C 6~10 Selected from aryls, 5-10 membered heteroaryls, and 5-10 membered heterocyclines, "-C(=O)NR A R B It refers to the base.

[0112] The "N-amide" group is defined as R A and R B Each of them independently produces hydrogen and C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~7 Carbocyclyl, C 6~10 Selected from aryls, 5-10 membered heteroaryls, and 5-10 membered heterocyclines, "-N(R A)C(=O)R B It refers to the base.

[0113] The "amino" group is defined as R as defined herein. A and R B Each of them independently produces hydrogen and C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~7 Carbocyclyl, C 6~10 Selected from aryls, 5-10 membered heteroaryls, and 5-10 membered heterocyclines, "-NR A R B It refers to the base.

[0114] An "aminoalkyl" group refers to an amino group connected via an alkylene group.

[0115] The "alkoxyalkyl" group is a "C 2~8 This refers to alkoxy groups that are linked via alkylene groups, such as "alkoxyalkyl groups."

[0116] As used herein, "natural amino acid side chain" refers to the side chain substituents of naturally occurring amino acids. Naturally occurring amino acids have substituents bonded to the α-carbon. Examples of naturally occurring amino acids include arginine, lysine, aspartic acid, glutamic acid, glutamine, asparagine, histidine, serine, threonine, tyrosine, cysteine, methionine, tryptophan, alanine, isoleucine, leucine, phenylalanine, valine, proline, and glycine.

[0117] As used herein, "unnatural amino acid side chain" refers to a side chain substituent of an amino acid that does not exist in nature. Examples of unnatural amino acids include β-amino acids (β 3 and β 2Examples include homoamino acids, proline and pyruvate derivatives, trisubstituted alanine derivatives, glycine derivatives, cyclic substituted phenylalanine and tyrosine derivatives, linear core amino acids, and N-methyl amino acids. Exemplary unnatural amino acids are available from Sigma-Aldridge and are listed under “unnatural amino acids & derivatives”. See also Travis S. Young and Peter G. Schultz, “Beyond the Canonical 20 Amino Acids: Expanding the Genetic Lexicon,” J. Biol. Chem., 2010, 285: 11039–11044, which is incorporated in its entirety as a reference.

[0118] As used herein, substituted groups are derived from unsubstituted parent groups and involve the exchange of one or more hydrogen atoms for another atom or group. Unless otherwise specified, when a group is considered "substituted," this means that the group is either a C1-C6 alkyl (optionally substituted with -OH or C-carboxy), a C1-C6 alkenyl, a C1-C6 alkynyl, a C1-C6 heteroalkyl, a C3-C7 carbocyrill (optionally substituted with halo, -OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, or C1-C6 haloalkoxy), or a C3-C7-carbocyrill-C1-C6-alkyl (halo, C1-C6 alkyl (Optionally substituted with C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5-10 member heterocyclyl (N-amide, -OH, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5-10 member heterocyclyl-C1-C6-alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), A Reels (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), aryl(C1-C6)alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5-10 member heteroaryl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5-1 0-membered heteroaryl(C1~C6)alkyl (optionally substituted with halo, C1~C6 alkyl, C1~C6 alkoxy, C1~C6 haloalkyl, and C1~C6 haloalkoxy), halo, cyano, hydroxy, C1~C6 alkoxy, C1~C6 alkoxy(C1~C6)alkyl (i.e., ether), aryloxy, sulfhydryl (mercapto), halo(C1~C6)alkyl (e.g., -CF3), halo(C1~C6)alkoxy (e.g., -OCF3), C1~C6 alkylthio, arylthio,This means that the group is substituted with one or more substituents independently selected from amino, amino(C1-C6)alkyl, nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amide, N-amide, S-sulfonamide, N-sulfonamide, C-carboxy, O-carboxy, acyl, cyanato, isocyanato, thiocyanato, isothiocyanato, sulfinyl, sulfonyl, -O-NH2, and oxo (=O). Whenever a group is described as "optionally substituted" or containing one or more "optionally substituted" substituents, that group may be substituted with any of the substituents listed above.

[0119] The two substituents, together with the atom or group of atoms to which they are bonded, may form a spiro or a fused ring with the rest of the compound.

[0120] In some embodiments, one or more substituted groups are substituted with one or more substituents individually and independently selected from C1-C4 alkyl, amino, hydroxy, and halogen groups.

[0121] It will be understood that certain radical nomenclature can include either monoradicals or diradicals, depending on the context. For example, if a substituent requires two bonding points with the rest of the molecule, it will be understood that the substituent is a diradical. Diradicals such as -CH2-, -CH2CH2-, and -CH2CH(CH3)CH2- are examples of substituents identified as alkyls that require two bonding points. Other radical nomenclature explicitly indicates that the radical is a diradical, such as an "alkylene" or "alkenylene".

[0122] As used herein, the term "alkylene" refers to a divalent, fully saturated, linear aliphatic hydrocarbon group. Examples of alkylene groups, but not limited to, include methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, and octylene. Alkylene groups are,

[0123] [ka] Next, the number of carbon atoms, followed by " * It can be expressed as ". For example,

[0124] [ka] Represents ethylene. An alkylene group may have 1 to 30 carbon atoms (wherever it appears herein, numerical ranges such as "1 to 30" refer to each integer within a given range; for example, "1 to 30 carbon atoms" means that an alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to 30 carbon atoms, but this definition also covers appearances of the term "alkylene" where no numerical range is specified). An alkylene group may also be a medium-sized alkyl having 1 to 12 carbon atoms. An alkylene group may also be a lower alkyl having 1 to 6 carbon atoms. An alkylene group may be substituted or unsubstituted. For example, a lower alkylene group may be substituted by replacing one or more hydrogens of a lower alkylene group and / or both hydrogens on the same carbon. 3~6 Monocyclic cycloalkyl groups (for example)

[0125] [ka] It can be replaced by substituting it with ).

[0126] When two R groups are said to "together with the atom to which they are bonded" to form a ring (e.g., a carbocyclyl, heterocyclyl, aryl, or heteroaryl ring), this means that the collective unit of the atom and the two R groups is an enumerated ring. The ring is otherwise not limited by the definition of each R group in each individual case. For example, the following substructure:

[0127] [ka] There exists, R 1 and R 2 It is defined as being selected from the group consisting of hydrogen and alkyl, or R 1 and R 2 When they combine with the nitrogen they are bound to to form a heterocycline, this is R 1 and R 2 This means that the base structure can be selected from hydrogen or alkyl, or alternatively, the base structure is structure:

[0128] [ka] [In the formula, ring A is a heterocyclyl ring containing the indicated nitrogen.]

[0129] Ring structure

[0130] [ka] When expressed as shown, this means that an R group can be attached to any position in the ring by replacing the -H with -R. For example, the following ring:

[0131] [ka] Regarding this, the following ring structure:

[0132] [ka] any of the following [in the formula,

[0133] [ka] One example is "[This indicates a connection with the rest of the structure]."

[0134] Similarly, when two "adjacent" R groups are said to form a ring "together with the atom to which they are bonded," this means that the collective unit of the atom, the intervening bond, and the two R groups is an enumerated ring. For example, the following substructure:

[0135] [ka] There exists, R 1 and R 2 It is defined as being selected from the group consisting of hydrogen and alkyl, or R 1 and R 2 When they combine with the atoms they are bonded to to form an aryl or carbocykrine, this is R 1 and R 2 This means that the base structure can be selected from hydrogen or alkyl, or alternatively, the base structure is structure:

[0136] [ka] [In the formula, A is an aryl ring or carbocyrill having the double bond shown.]

[0137] Whenever a substituent is shown as a diradical (i.e., having two bonding points to the rest of the molecule), it should be understood that the substituent can be bonded in any orientation unless otherwise specified. Therefore, for example, -AE- or

[0138] [ka] Examples of substituents shown include cases where the substituent is oriented such that A is bonded to the leftmost bond point of the molecule, and cases where A is bonded to the rightmost bond point of the molecule.

[0139] The terms “drug” or “test drug” include any substance, molecule, element, compound, entity, or combination thereof. These include, but are not limited to, proteins, polypeptides, peptides or mimetic compounds, small organic molecules, polysaccharides, polynucleotides, etc. These may be natural products, synthetic compounds, chemical substances, or combinations of two or more substances. Unless otherwise specified, the terms “drug,” “substance,” and “compound” are used interchangeably herein.

[0140] The term "analog" is used herein to refer to a molecule that is structurally similar to a reference molecule but has been modified in a targeted and controlled manner by replacing specific substituents of the reference molecule with alternative substituents. Compared to the reference molecule, the analogue would be expected by those skilled in the art to exhibit the same, similar, or improved utility. The synthesis and screening of analogues to identify variants of known compounds with improved characteristics (such as higher binding affinity to a target molecule) is a well-known technique in pharmaceutical chemistry.

[0141] The term "mammal" is used in its ordinary biological sense. Therefore, it specifically includes, but is not limited to, primates including monkeys (chimpanzees, apes, and monkeys) and humans, cattle, horses, sheep, goats, pigs, rabbits, dogs, cats, rats, and mice, as well as many other species.

[0142] The term “microbial infection” means the infiltration of a host organism by pathogenic microorganisms, whether the organism is a vertebrate, invertebrate, fish, plant, bird, or mammal. This includes the overgrowth of microorganisms normally present in or on the bodies of mammals or other organisms. More generally, a microbial infection can be any situation in which the presence of a microbial population causes harm to the host mammal. Thus, a mammal is “suffering” a microbial infection if an excess number of microbial populations are present in or on the body of the mammal, or if the effect of the presence of the microbial population causes harm to the cells or other tissues of the mammal. Specifically, this description applies to bacterial infections. The compounds of the preferred embodiments are also useful for treating microbial growth or contamination of cell cultures or other media, or inanimate surfaces or objects, and it should be noted that nothing other than the treatment of higher organisms should limit the preferred embodiments unless expressly specified so in the claims.

[0143] The terms “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” include any and all solvents, dispersions, coatings, antibacterial and antifungal agents, isotonic agents and absorption retarders. The use of such media and agents for pharmaceutically active substances is well known in the art. Unless any conventional media or agent is incompatible with the active ingredient, its use in therapeutic compositions is intended. Furthermore, various adjuvants, such as those commonly used in the art, may be included. Considerations regarding the inclusion of various components in pharmaceutical compositions are, for example, in Gilman et al. (eds.) (1990), Goodman and Gilman, The Pharmacological Basis of Therapeutics, 8th edition, Pergamon Press, which is incorporated entirely by reference herein.

[0144] As used herein, “Subject” (or “Patient”) means human or non-human mammals, such as dogs, cats, mice, rats, cattle, sheep, pigs, goats, non-human primates, or birds, such as chickens, and any other vertebrates or invertebrates.

[0145] As used herein, “effective dose” or “therapeutic dose” means an amount of therapeutic agent effective to reduce or decrease to some extent the likelihood of one or more of the symptoms of a disease or condition occurring (including curing the disease or condition). “Cure” means the elimination of the symptoms of the disease or condition, although certain long-term or permanent effects may remain even after a cure has been achieved (such as extensive tissue damage).

[0146] As used herein, “to treat,” “treatment,” or “to treat” means administering a pharmaceutical composition for prophylactic and / or therapeutic purposes. The term “prophylactic treatment” means treating a patient who is not yet showing symptoms of a disease or condition but is susceptible to or otherwise at risk of developing a particular disease or condition, thereby reducing the patient’s likelihood of developing the disease or condition. The term “therapeutic treatment” means administering a treatment to a subject.

[0147] As used herein when referring to components, the term "weight percentage" is calculated by dividing the weight of the component by the weight of the composition containing that component and multiplying by 100%. For example, if 5 grams of component A are added to 95 grams of component B, the weight percentage of component A is 5% (e.g., 5g of A / (5g of A + 95g of B) × 100%).

[0148] introduction As disclosed elsewhere in this specification, post-translational modifications of histones are epigenetic mechanisms that affect chromatin structure, thereby altering gene expression and ultimately contributing to the pathogenesis of various human diseases, including autoimmune diseases and cancer. Specifically, the N-terminal tails of histones are susceptible to reversible covalent modifications, including acetylation, methylation, phosphorylation, ubiquitination, and ubiquitin-like protein modifications. These modifications alter the histone affinity to the sugar backbone, thereby regulating the ability of transcription factors to access the underlying DNA and thus affecting replication, transcription, and chromatin stability. Therefore, identifying drugs that target these histone modifying enzymes could lead to novel therapeutic agents for various human diseases.

[0149] Histones can be methylated by various histone methyltransferases (HMTs), and methylation can be removed by proteins called histone demethylases (HDMs). Histone tail methylation can occur at either lysine or arginine residues on histone H3 and H4. Lysine can be monomethylated, dimethylated, and trimethylated, while arginine can only be monomethylated or dimethylated. G9A (also known as EHMT2) is a nuclear histone lysine methyltransferase belonging to the Su(var)3-9 family that catalyzes histone H3 lysine 9 dimethylation (H3K9me2), a reversible modification commonly associated with transcriptional gene silencing. Structurally, it is composed of an ankyrin repeat capable of recognizing H3K9me1 / 2, as well as a catalytic SET domain that governs enzymatic activity. In addition to histone methylation, G9A also has non-histone targets, including the tumor suppressor gene p53.

[0150] G9A is a key regulator of the immune system, particularly influencing T cell populations. Specifically, G9A-mediated H3K9me2-dependent regulation of T cell responses is associated with T cell function, including T regulatory cells, and the development of various autoimmune diseases, including inflammatory bowel disease, lupus, and type 1 diabetes. Furthermore, G9A has been shown to affect congenital lymphocytes, a major regulator of disease-associated immune mechanisms, and interestingly, mice lacking the G9A gene were resistant to developing allergic pneumonia. Taken together, G9A plays a pro-inflammatory role in the pathogenesis of multiple autoimmune disorders, and therefore inhibiting it may have therapeutic effects.

[0151] G9A has been identified as having oncogenic functions involved in the pathogenesis of various cancer types. Specifically, G9A expression levels are increased in esophageal, hepatic, non-small cell lung cancer, melanoma, multiple myeloma, breast, prostate, gastric, pancreatic, colorectal, uterine, and bladder cancers. Furthermore, high G9A levels have been associated with poor prognosis. In addition, there is strong evidence regarding the correlation between the effects of G9A on cell adhesion molecules and increased G9A activity during hypoxia, supporting the role of G9A as a major factor in metastasis. Taken together, these findings highlight the importance of G9A in carcinogenesis and suggest that targeting G9A activity may constitute a novel strategy for treating several cancer types.

[0152] Some embodiments disclosed herein relate to substituted quinazoline compounds. In some embodiments, the compounds disclosed herein are useful for treating one or more medical conditions. In some embodiments, the compounds may be useful in treating autoimmune disorders. In some embodiments, the compounds are useful in treating cancer. In some embodiments, the compounds target G9A. In some embodiments, the compounds treat G9A-mediated inflammation.

[0153] compound Several embodiments disclosed herein relate to quinazolinyl compounds, methods using quinazolinyl compounds, compositions containing quinazolinyl compounds, and treatment methods using quinazolinyl compounds. The quinazolinyl compounds have the following structure:

[0154] [ka] and may be represented by numbering conventions. In some embodiments, the quinazolinyl compound is substituted at one or more of the 2, 4, 6, and 7 positions, or in any combination of the aforementioned positions.

[0155] In some embodiments, the quinazoline compound includes a cyclic substituent bonded to the quinazoline ring at position 2. In some embodiments, the quinazoline compound includes an amine substituent bonded to the quinazoline ring at position 4. In some embodiments, the quinazoline compound includes an amine at position 4 that contains a cyclic substituent (either pendanted to or directly bonded to the amine), or the amine is part of the cyclic substituent. In some embodiments, the quinazoline compound includes a methoxy group at position 6. In some embodiments, the quinazoline compound includes an alkoxy group at position 7. In some embodiments, the quinazoline compound includes a pendant cyclic group at position 7 that is connected to the two rings by either an alkyne or an alkoxy group.

[0156] As disclosed elsewhere in this specification, in some embodiments, the quinazolinyl compound is substituted at position 2. In some embodiments, the substituent at position 2 may be cyano, alkoxy, thioalkyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted amino. In some embodiments, the substituent at position 2 may be -CN, -OR 1 , -SR 1 , C1~C replaced by arbitrary selection 10Alkyl, optionally substituted C1-C 10 Alkenyl, C1-C substituted by choice 10 The group is selected from alkynyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 6-10 membered aryl, optionally substituted 3-10 membered heterocyclyl, optionally substituted 5-10 membered heteroaryl, and amino.

[0157] In some embodiments, the 2-position substituent may be optionally substituted as disclosed herein. In some embodiments, if the 2-position substituent includes one or more additional optional substituents, the one or more optional substitutions may independently be C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C3-C7 carbocykryl, C3-C7-carbocykryl-C1-C6-alkyl, 5-10 member heterocyclyl, 5-10 member heterocyclyl-C1-C6-alkyl, aryl, aryl(C1-C6)alkyl, 5-10 member heteroaryl, 5-10 member heteroaryl(C1-C6)alkyl, halo, cyano, hydroxy, C1-C6 alcoholic The following can be selected: C1-C6 alkoxy(C1-C6)alkyl, aryloxy, sulfhydryl, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, C1-C6 alkylthio, arylthio, amino, amino(C1-C6)alkyl, nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amide, N-amide, S-sulfonamide, N-sulfonamide, C-carboxy, O-carboxy, acyl, cyanato, isocyanato, thiocyanato, isothiocyanato, sulfinyl, sulfonyl, -O-NH2, and oxo(=O). In some embodiments, if the 2-position substituent includes one or more additional optional substituents, the one or more optional substitutions may be independently selected from C1-C6 alkyl, C1-C6 heteroalkyl, C3-C7 carbocykryl, C3-C7-carbocykryl-C1-C6-alkyl, 5-10 member heterocyclyl, 5-10 member heteroaryl, halo, cyano, hydroxy, C1-C6 alkoxy, amino, C-amide, N-amide, C-carboxy, O-carboxy, acyl, and oxo (=O). In some embodiments, if the 2-position substituent includes one or more additional optional substituents, the one or more optional substitutions may be independently selected from C1-C6 alkyl, C1-C6 heteroalkyl, and fluoro.

[0158] As disclosed elsewhere in this specification, in some embodiments, the quinazolinyl compound is substituted at position 4 with an amine. In some embodiments, the quinazolinyl compound contains an amine at position 4 that includes a cyclic substituent (either pendanted to or directly bonded to the amine), or the amine is part of the cyclic substituent. In some embodiments, the substituent at position 4 may be an amine substituted with an optionally substituted heterocyclyl, or an amine substituted with -CN, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted carbocyl, optionally substituted (carbocyl)alkyl, optionally substituted (heterocyclyl)alkyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl. In some embodiments, the substituent at position 4 may be an optionally substituted 3- to 10-membered heterocyclyl, and -CN, optionally substituted C1- to C1 10 The molecules are selected from alkyls, optionally substituted 2-10 member heteroalkyls, optionally substituted 3-10 member carbocyryls, optionally substituted (carbocyryl)alkyls, optionally substituted (heterocyclyl)alkyls, optionally substituted 6-10 member aryls, optionally substituted 3-10 member heterocyclyls, optionally substituted 5-10 member heteroaryls, optionally substituted acyls, optionally substituted O-carboxys, optionally substituted C-carboxys, optionally substituted C-amides, optionally substituted N-amides, optionally substituted O-carbamyls, or optionally substituted N-carbamyls, and are amines substituted with one or more substituents selected from these.

[0159] In some embodiments, the 4-position substituent may be optionally substituted as disclosed herein. In some embodiments, if the 4-position substituent includes one or more additional optional substituents, the one or more optional substitutions may independently be C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C3-C7 carbocyclyl, C3-C7-carbocyclyl-C1-C6-alkyl, 5-10 member heterocyclyl, 5-10 member heterocyclyl-C1-C6-alkyl, aryl, aryl(C1-C6)alkyl, 5-10 member heteroaryl, 5-10 member heteroaryl(C1-C6)alkyl, halo, cyano, hydroxy, C1-C6 alkyl The following can be selected: coxy, C1-C6 alkoxy(C1-C6)alkyl, aryloxy, sulfhydryl, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, C1-C6 alkylthio, arylthio, amino, amino(C1-C6)alkyl, nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amide, N-amide, S-sulfonamide, N-sulfonamide, C-carboxy, O-carboxy, acyl, cyanato, isocyanato, thiocyanato, isothiocyanato, sulfinyl, sulfonyl, -O-NH2, and oxo. In some embodiments, if the 4-position substituent includes one or more additional optional substituents, the one or more optional substitutions may be independently selected from C1-C6 alkyl, C1-C6 heteroalkyl, C3-C7 carbocykryl, C3-C7-carbocykryl-C1-C6-alkyl, 5-10 member heterocyclyl, 5-10 member heteroaryl, halo, cyano, hydroxy, C1-C6 alkoxy, amino, C-amide, N-amide, C-carboxy, O-carboxy, acyl, and oxo.In some embodiments, if the 4-position substituent includes one or more additional optional substituents, the one or more optional substitutions may be independently selected from C1-C6 alkyl, C1-C6 heteroalkyl, C3-C7 carbocyryl optionally substituted with halo, -OH, halo, cyano, hydroxy, C1-C6 alkoxy, amino, N-amide, acyl, -O-NH2, and oxo-substituted 5-10 membered heterocyclyl.

[0160] As disclosed elsewhere in this specification, in some embodiments, the quinazolinyl compound is substituted at the 6-position with hydrogen, a halogen, or an alkoxy. In some embodiments, the substituent is fluoro or methoxy.

[0161] As disclosed elsewhere in this specification, in some embodiments, the quinazolinyl compound is substituted at the 7-position with an alkoxy or (heterocyclyl)alkynyl. In some embodiments, the alkoxy includes alkyl, optionally substituted 2- to 10-membered heteroalkyl, or (heterocyclyl)alkyl.

[0162] In some embodiments, the 7-position may be optionally substituted as described herein. In some embodiments, if the substituent at the 7-position includes one or more additional optional substituents, the one or more optional substitutions are independently C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C3-C7 carbocykryl, C3-C7-carbocykryl-C1-C6-alkyl, 5-10 member heterocyclyl, 5-10 member heterocyclyl-C1-C6-alkyl, aryl, aryl(C1-C6)alkyl, 5-10 member heteroaryl, 5-10 member heteroaryl(C1-C6)alkyl, halo, cyano, hydroxy, C1-C6 alkyl The following can be selected: coxy, C1-C6 alkoxy(C1-C6)alkyl, aryloxy, sulfhydryl, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, C1-C6 alkylthio, arylthio, amino, amino(C1-C6)alkyl, nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amide, N-amide, S-sulfonamide, N-sulfonamide, C-carboxy, O-carboxy, acyl, cyanato, isocyanato, thiocyanato, isothiocyanato, sulfinyl, sulfonyl, -O-NH2, and oxo. In some embodiments, if the 7-position substituent includes one or more additional optional substituents, the one or more optional substitutions may be independently selected from C1-C6 alkyl, C1-C6 heteroalkyl, C3-C7 carbocykryl, C3-C7-carbocykryl-C1-C6-alkyl, 5-10 member heterocyclyl, 5-10 member heteroaryl, halo, cyano, hydroxy, C1-C6 alkoxy, amino, C-amide, N-amide, C-carboxy, O-carboxy, acyl, and oxo. In some embodiments, if the 7-position substituent includes one or more additional optional substituents, the one or more optional substitutions may be independently selected from C1-C6 alkyl and amino.

[0163] Some embodiments relate to pharmaceutical compositions comprising therapeutically effective amounts of the compounds described herein and pharmaceutically acceptable excipients.

[0164] In any compound described herein having one or more chiral centers, where absolute stereochemistry is not explicitly indicated, it will be understood that each center may independently be in an R-configuration, an S-configuration, or a mixture thereof. Therefore, the compounds provided herein may be enantiomerically pure, enantiomerically rich, racemic, diastereomerically pure, diastereomerically rich, or stereoisomerically mixed. Furthermore, in any compound described herein having one or more double bonds that produce geometric isomers that can be defined as E or Z, it will be understood that each double bond may independently be E or Z or a mixture thereof.

[0165] Compound of formula (I) Some embodiments include quinazolinyl compounds having the structure of formula (I):

[0166] [ka] (or relating to stereoisomers, tautomers, or pharmaceutically acceptable salts thereof.)

[0167] In some embodiments, the variable groups of formula (I) are as disclosed elsewhere in this specification. For brevity, a variable group defined for one formula may be used to define the same variable group in another formula. For example, in some embodiments, the variable groups of formula (I) are as disclosed elsewhere in this specification for formula (I), and / or as disclosed elsewhere in this specification for any other formula having a variable group shared with those provided in formula (I). 4 As one example of its use, R 4 If is defined in one form for expression (Ia), then R 4 Even if the specific definition of is not provided in relation to formula (I), R 4 The same definition of can be used for equation (I). Similarly, R 4If is defined in one form for equation (I), then R 4 Even if the definition of is not specifically provided with respect to equation (Ia), R 4 The same definition of can be used for expression (Ia) (or other expressions).

[0168] In some embodiments, X 1 is, -(CH2) o -or covalent. In some embodiments, o is an integer equal to 1, 2, 3, 4, 5, or 6. In some embodiments, X 1 C1~C are replaced by optional selection. 10 It is an alkylene. 2 C1-C are substituted with hydrogen or optionally. 10 It is alkyl. In some embodiments, X 2 C1-C are substituted with hydrogen or optionally. 10 It is alkyl. In some embodiments, X 3 C1~C is a combination of -CN, -OH, and C1~C of any choice. 10 Selected from the group consisting of alkyl, optionally substituted 2-10 member heteroalkyl, optionally substituted 3-10 member carbocyryl, optionally substituted (carbocyryl)alkyl, optionally substituted (heterocyclyl)alkyl, optionally substituted 6-10 member aryl, optionally substituted 3-10 member heterocyclyl, optionally substituted 5-10 member heteroaryl, optionally substituted amino, optionally substituted sulfonyl, optionally substituted acyl, optionally substituted O-carboxy, optionally substituted C-carboxy, optionally substituted C-amide, optionally substituted N-amide, optionally substituted O-carbamyl, or optionally substituted N-carbamyl. In some embodiments, X 2 and X 3 These, together with the atoms to which they are bonded, form optionally substituted 3- to 10-membered heterocyclines. The optionally substituted substituents may be selected from those substituents disclosed elsewhere in this specification.

[0169] In some embodiments, X 3 Equation (IX3):

[0170] [ka] It can be expressed by [wherein X a X is selected from the group consisting of CH and N, m is an integer independently selected from 0, 1, 2, 3, or 4, n is an integer independently selected from 0, 1, 2, 3, or 4, and X b It is selected from the group consisting of CH2, NH, O, S, and SO2, R a Each of the cases, if present, is independently selected from the group consisting of amino, -OH, halogen, cyano, hydroxy, optionally substituted C1-C6 alkyl, C-carboxy, and optionally substituted C1-C6 alkoxy(C1-C6)alkyl, where l is an integer selected from 0, 1, 2, 3, or 4. In some embodiments, ring "A" is a cycloalkyl ring or a heterocyclyl ring. As disclosed elsewhere in this specification and as readily apparent to those skilled in the art, each R a This refers to one or more -H atoms of any carbon or nitrogen atom present within the "A" ring (X, where appropriate). b and X a The substituents on the "A" ring can be provided at any position by replacing any -H atom that may be present on it. The optional substituents on the "A" ring can be selected from substituents disclosed elsewhere in this specification. In some embodiments, if the substituents on the "A" ring are optionally substituted with one or more optional substitutions, the one or more optional substitutions can be independently selected from the group consisting of C1-C3 alkyl, halo, C1-C3 alkoxy and.

[0171] In some embodiments, n is 0 and m is 1. In some embodiments, n is 1 and m is 1. In some embodiments, n is 1 and m is 3. In some embodiments, n is 2 and m is 2. In some embodiments, n is 3 and m is 2.

[0172] In some embodiments, X b O, SO2, -N(R a ), -C(R a )H, and -C(R a Selected from the group consisting of )2.

[0173] In some embodiments, the substituent at position 4 of formula (I) (for example, -N(X) 2 )-X 1 -X 3 ) has the following structure:

[0174] [ka] [ka] [ka] It is represented by one of the following, and any of them is -N(X 2 )-X 1 -X 3 It may be further optionally substituted by replacing one or more -H atoms of any carbon or nitrogen atoms present within it. In some embodiments, -N(X 2 )-X 1 -X 3 If the substituent includes one or more optional substitutions, the optional substitutions are as disclosed elsewhere in this specification. In some embodiments, -N(X 2 )-X 1 -X 3If includes one or more optional substitutions, the one or more optional substitutions may be independently selected from the group consisting of C1-C3 alkyl, halo, cyano, hydroxy, amino, C1-C3 alkoxy, 3-6 membered carbocykryl, and 3-6 membered heterocyclyl. In some embodiments, R a and l are as defined elsewhere in this specification.

[0175] X 1 , X 2 , or X 3 In some embodiments where it is stated that one or more of the substituents are optionally substituted, the optional substituents may be selected from substituents disclosed elsewhere in this Spec. 1 , X 2 , or X 3 In some embodiments where it is stated that one or more of the elements are optionally substituted, the optional substitutions may be independently selected from the group consisting of C1-C3 alkyl groups, halogens, -OH groups, -CN groups, and C1-C3 alkoxy groups.

[0176] In some embodiments, X 4 This is as disclosed elsewhere in this specification. In some embodiments, X 4 -CN, -OR 1 , -SR 1 , halogen, C1~C (optionally substituted) 10 Alkyl, optionally substituted C1-C 10 Alkenyl, C1-C substituted by choice 10 Alkinyl, optionally substituted 3-10 member carbocyclyl, optionally substituted 6-10 member aryl, optionally substituted 3-10 member heterocyclyl, optionally substituted 5-10 member heteroaryl, and -NR 2 R 3 Selected from the group consisting of . Optional substituents may be selected from substituents disclosed elsewhere in this specification. In some embodiments, X 4If the formula includes one or more optional substitutions, the one or more optional substitutions may be independently selected from the group consisting of C1-C3 alkyl, halo, cyano, hydroxy, and C1-C3 alkoxy.

[0177] In some embodiments, R 1 C1-C are substituted with hydrogen or optionally. 10 It is alkyl. Optional substituents may be selected from substituents disclosed elsewhere in this specification. In some embodiments, R 1 If the formula includes one or more optional substitutions, the one or more optional substitutions may be independently selected from the group consisting of C1-C3 alkyl, halo, cyano, hydroxy, and C1-C3 alkoxy.

[0178] In some embodiments, R 2 and R 3 Each of them independently consists of hydrogen and optionally substituted C 1~10 Selected from alkyl groups, or alternatively, R bonded to the same nitrogen atom. 2 and R 3 These, together with the atoms to which they are bonded, may form optionally substituted 3- to 10-membered heterocyclines or optionally substituted 5- to 10-membered heteroaryls. The optional substituents may be selected from those disclosed elsewhere in this specification. In some embodiments, R 2 and / or R 3 If the formula includes one or more optional substitutions, the one or more optional substitutions may be independently selected from the group consisting of C1-C3 alkyl, halo, cyano, hydroxy, and C1-C3 alkoxy.

[0179] In some embodiments, X 4 Equation (IX4):

[0180] [ka] Represented by [wherein X fb is selected from the group consisting of CH and N, b is an integer independently selected from 0, 1, 2, 3, or 4, c is an integer independently selected from 0, 1, 2, 3, or 4, and X g It is selected from the group consisting of CH2, NH, O, S, and SO2, R f Each of the cases, if present, is independently selected from the group consisting of amino, -OH, halogen, cyano, hydroxy, optionally substituted C1-C6 alkyl, C-carboxy, and optionally substituted C1-C6 alkoxy(C1-C6)alkyl, where d is an integer selected from 0, 1, 2, 3, or 4. In some embodiments, the ring "D" is a cycloalkyl ring or a heterocyclyl ring. As disclosed elsewhere in this specification and as readily apparent to those skilled in the art, each R f This refers to one or more -H atoms of any carbon or nitrogen atom present within the "D" ring (X, where appropriate). f and X g The substituents on the "D" ring can be provided at any position by replacing any -H atom that may be present on it. The optional substituents on the "D" ring can be selected from substituents disclosed elsewhere in this specification. In some embodiments, if the substituents on the "D" ring are optionally substituted with one or more optional substitutions, the one or more optional substitutions can be independently selected from the group consisting of C1-C3 alkyl, halo, C1-C3 alkoxy and.

[0181] In some embodiments, n is 0 and m is 1. In some embodiments, n is 1 and m is 1. In some embodiments, n is 1 and m is 3. In some embodiments, n is 2 and m is 2. In some embodiments, n is 3 and m is 2.

[0182] In some embodiments, X g O, SO2, -N(R f ), -C(R f )H, and -C(R f Selected from the group consisting of )2.

[0183] In some embodiments, the substituent at position 2 of formula (I) (for example, X 4 ) has the following structure:

[0184] [ka] Represented by one of the following [wherein p is an integer equal to 1, 2, 3, 4, or 5, q is an integer equal to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, the variable group is as provided elsewhere herein, and / or any of these structures is X 4 [These may be optionally substituted by replacing one or more -H atoms of any carbon or nitrogen atom present above.] In some embodiments, X 4 If includes one or more optional substitutions, the one or more optional substitutions may be independently selected from the group consisting of C1-C3 alkyl, halo, cyano, hydroxy, and C1-C3 alkoxy. In some embodiments, R f And d are as defined elsewhere in this specification.

[0185] In some embodiments, R 4 is -OR 9 or (heterocyclyl)alkynyl. In some embodiments, R 9 The group is selected from hydrogen, C1-C3 alkyl (e.g., methyl), optionally substituted 2-10 member heteroalkyl, optionally substituted (carbocyrill)alkyl, optionally substituted (heterocyclyl)alkyl, optionally substituted (aryl)alkyl, and optionally substituted (heteroaryl)alkyl. In some embodiments, the heterocyclyl or carbocyrill contains 3-10 ring members (e.g., 3-6 members, 3-7 members, etc.). In some embodiments, the heteroaryl or aryl contains 6-10 ring members. In some embodiments, R 9The (amino)C1-C6 alkyl group is a (amino)C1-C6 alkyl group. In some embodiments, the heterocyclyl ring is a pyrrolidinyl ring.

[0186] In some embodiments, R 4 The formula is as follows:

[0187] [ka] It is represented by one of the following [wherein X h x is selected from the group consisting of CH and N, f is an integer independently selected from 0, 1, 2, 3, or 4, g is an integer independently selected from 0, 1, 2, 3, or 4, and X i It is selected from the group consisting of CH2, NH, O, S, and SO2, R g Each of the cases, if present, is independently selected from the group consisting of amino, -OH, halogen, cyano, hydroxy, optionally substituted C1-C6 alkyl, C-carboxy, and optionally substituted C1-C6 alkoxy(C1-C6)alkyl, where h is an integer selected from 0, 1, 2, 3, or 4, and i is an integer selected from 1, 2, 3, 4, 5, 6, or 7 (including the range spanning the aforementioned values). In some embodiments, the ring "F" is a cycloalkyl ring or a heterocyclyl ring. As disclosed elsewhere in this specification and as readily apparent to those skilled in the art, each R g This refers to one or more -H atoms of any carbon or nitrogen atom present within the "F" ring (X, where appropriate). h and X i The substituents on the "F" ring can be provided at any position by replacing any -H atom that may be present on it. The optional substituents on the "F" ring can be selected from substituents disclosed elsewhere in this specification. In some embodiments, if the substituents on the "F" ring are optionally substituted with one or more optional substitutions, the one or more optional substitutions can be independently selected from the group consisting of C1-C3 alkyl, halo, C1-C3 alkoxy and. In some embodiments, i is 1 or 3.

[0188] In some embodiments, R 4 The structure is as follows:

[0189] [ka] As shown in the respective sections, it is 3-(pyrrolidine-1-yl)propoxyl or 3-(pyrrolidine-1-yl)propa-1-in-1-yl.

[0190] In some embodiments, R 5 These are hydrogen, halogens, and -C 1~6 Selected from the group consisting of alkoxys. In some embodiments, R 5 The element is selected from the group consisting of hydrogen, halogens, and -OMe.

[0191] In some embodiments, X 3 but

[0192] [ka] [In the formula, R 6 This is an unsubstituted benzyl, an unsubstituted 3-10 membered carbocyrillic, or a C1-C2 molecule optionally substituted with an amine. 10 If it is alkyl, 2 and R 3 If present, they combine to form an optionally substituted five-membered heteroaryl or an optionally substituted four-membered heterocycline.

[0193] In some embodiments, X 3 but

[0194] [ka] If R 4 teeth

[0195] [ka] That is the case.

[0196] In some embodiments, X 3 is a substituted 6-membered heterocyclyl. In some embodiments, X 3 X is an unsubstituted 6-membered heterocyclyl. In some embodiments, X 3 is an unsubstituted 6-membered aryl. In some embodiments, X 3 These are unsubstituted 2- to 10-membered heteroalkyl groups.

[0197] In some embodiments, X 4 X is a 4- to 6-membered heterocycline that has been optionally substituted. In some embodiments, X 4 is a 5-membered heteroaryl. In some embodiments, X 4 is -CN.

[0198] In some embodiments, X 1 It is a covalent bond. In some embodiments, X 1 It is CH2.

[0199] In some embodiments, X 2 It is hydrogen.

[0200] In some embodiments, R 4 teeth

[0201] [ka] That is the case.

[0202] In some embodiments, R 5 It is -OMe.

[0203] Equation (I) is given when n is 2, m is 2, and R a In some embodiments, including formula (IX3) where isopropyl, X b is not N. Equation (I) is such that n is 2, m is 2, and X b R aIn some embodiments, including the substituent formula (IX3), its R a The substituent is not isopropyl. n is 2, m is 2, R a In some embodiments, where isopropyl, X b It is not N. n is 2, m is 2, and R a In some embodiments, where isopropyl, X b is not N. Equation (I) is such that n is 2, m is 2, and X b R a In some embodiments, including the substituent formula (IX3), its R a The substituent is not a C3 alkyl group. Formula (I) is where n is 2, m is 2, and X b N is R a In some embodiments, including the substituent formula (IX3), X b The R above a The substituent is not a C3 alkyl group. Formula (I) is where n is 2, m is 2, and X b N is R a In some embodiments, including the substituent formula (IX3), X b The R above a The substituent is not methyl. Formula (I) is where n is 2, m is 2, and X b N is R a In some embodiments, including the substituent formula (IX3), X b The R above a The substituent is not a C3 alkyl or C3 carbocyric. Formula (I) is where n is 2, m is 2, and X b N is R a In some embodiments, including the substituent formula (IX3), X b The R above a The substituent is not a C7 (carbocykyl) alkyl group. Formula (I) is where n is 2, m is 2, and X b N is R a In some embodiments, including the substituent formula (IX3), X b The R above aThe substituents are not C6 alkyl or C6 carbocyrill. In some embodiments, formula (I) lacks compounds having a 7-membered heterocyclyl group and / or a 7-membered carbocyrill group. In some embodiments where formula (I) contains a 6-membered heterocyclyl group and / or a 6-membered carbocyrill group, formula (I) lacks a 7-membered heterocyclyl group and / or a 7-membered carbocyrill group. In some embodiments where formula (I) contains a 6-membered heterocyclyl group, a 6-membered carbocyrill group, a 7-membered heterocyclyl group, and / or a 7-membered carbocyrill group, these cyclyl groups may be substituted or unsubstituted.

[0204] Partial Embodiments of the Compound of Formula (I) In some embodiments, the compound of formula (I) is

[0205] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] One of the following can be selected.

[0206] In some embodiments, formula (I) does not include one or more of the structures (for example, 158, 159, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, or 415).

[0207] In some embodiments, the quinazolinyl compound having the structure of formula (I) is selected from one or more of the following: 4-((2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide; 2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)-N-(tetrahydro-2H-pyran-4-yl)quinazoline-4-amine; 2-(4,4-difluoropiperidine-1-yl)-6-methoxy-N-(1-(2-methoxyethyl)piperidine-4-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; 2-(4,4-difluoropiperidine-1-yl)-6-methoxy-N-(2-methoxyethyl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; 2-(4,4-difluoropiperidine-1-yl)-6-methoxy-N-((1-methylpiperidine-4-yl)methyl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; 2-(4-((2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)amino)piperidine-1-yl)acetic acid; 2-(4,4-difluoropiperidine-1-yl)-6-methoxy-N-(pyridine-4-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; 2-(4,4-difluoropiperidine-1-yl)-6-methoxy-N-(piperidine-4-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; 2-((2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)amino)acetamide; 4-((2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide; 2-(4,4-difluoropiperidine-1-yl)-6-methoxy-N-(oxetan-3-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; (R)-2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)-N-(tetrahydro-2H-pyran-3-yl)quinazoline-4-amine; (S)-2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)-N-(tetrahydro-2H-pyran-3-yl)quinazoline-4-amine; 2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)-N-(tetrahydro-2H-pyran-3-yl)quinazoline-4-amine; 3-((2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide; (2S)-N2-(2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazolin-4-yl)-N1-((tetrahydrofuran-2-yl)methyl)propane-1,2-diamine; 2-(4,4-difluoropiperidine-1-yl)-6-methoxy-N-(morpholinomethyl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; 2-(4,4-difluoropiperidine-1-yl)-6-methoxy-N-(morpholinomethyl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; 1-(4-((2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)amino)piperidine-1-yl)ethane-1-one; 2-(4,4-difluoropiperidine-1-yl)-N-isopropyl-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; 2-(4,4-difluoropiperidine-1-yl)-N-(3-isopropoxypropyl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; N-(2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazolin-4-yl)methanesulfonamide; N-((aminooxy)carbonyl)-2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; N-cyclopentyl-2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; (2R,4r,6S)-N-(2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazolin-4-yl)-N',N',2,6-tetramethyltetrahydro-4H-pyran-4,4-diamine; 2-(4,4-difluoropiperidine-1-yl)-6-methoxy-N-(piperazine-1-ylmethyl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; (R)-2-((2-((2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazolin-4-yl)amino)propyl)amino)ethane-1-ol; ((2R,5R)-4-(((2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)amino)methyl)-5-methylmorpholine-2-yl)methanol; 4-(2-((2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)amino)propyl)cyclohexane-1-ol; N-benzyl-2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; 2-(4,4-difluoropiperidine-1-yl)-6-methoxy-N-phenyl-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; 2-(4,4-difluoropiperidine-1-yl)-6-methoxy-N-(pyridine-4-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; 2-(4,4-difluoropiperidine-1-yl)-6-methoxy-N-(pyridine-3-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; 2-(4,4-difluoropiperidine-1-yl)-6-methoxy-N-(pyridine-2-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; 2-(4,4-difluoropiperidine-1-yl)-N-(6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; (S)-1-((2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazolin-4-yl)amino)-2,2,2-trifluoroethane-1-ol; 1-((2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)amino)ethane-1-ol; (1S,2S)-2-((2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazolin-4-yl)amino)-1-(dimethylamino)butan-1-ol; (R)-N-(cyclopenta-2-en-1-yl)-2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; 2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)-N-(trifluoromethyl)quinazoline-4-amine; 2-(4,4-difluoropiperidine-1-yl)-6-methoxy-N-(pyridine-4-ylmethyl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; 2-(4,4-difluoropiperidine-1-yl)-6-methoxy-N-(pyridine-3-ylmethyl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; 2-(4,4-difluoropiperidine-1-yl)-6-methoxy-N-(pyridine-2-ylmethyl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; (1S,2R)-1-((2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)amino)-1-(dimethylamino)propan-2-ol; N-(3,5-difluorophenyl)-2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; N-(2,4-difluorophenyl)-2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; (S)-2-(4,4-difluoropiperidine-1-yl)-6-methoxy-N-(piperidine-2-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; (S)-N-(2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)-2-isopropoxy-N'-methylethane-1,1-diamine; 2-((2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)amino)acetonitrile; 2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)-N-(thiophen-2-yl)quinazoline-4-amine; 2-(4,4-difluoropiperidine-1-yl)-N-(furan-2-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; 2-(4,4-difluoropiperidine-1-yl)-6-methoxy-N-(1H-pyrrole-2-yl)-7-(3-(pyrroridine-1-yl)propoxy)quinazoline-4-amine; 2-(4,4-difluoropiperidine-1-yl)-6-methoxy-N-(1H-pyrrole-3-yl)-7-(3-(pyrroridine-1-yl)propoxy)quinazoline-4-amine; 2-(4,4-difluoropiperidine-1-yl)-6-methoxy-N-(1H-pyrazole-3-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; N-(2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)isoxazole-3-amine; N-Cyclopropyl-2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; N-(2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)cyanamide; N-(2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)methanediamine; (2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)carbamate; Methyl(2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)carbamate; ((2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)amino)methanol; ((2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)amino)methyl acetate, 2-(4,4-difluoropiperidine-1-yl)-6-methoxy-N-(((3-methylazetidine-3-yl)oxy)methyl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; (R)-2-(cyclopropylamino)-2-((2(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3(pyrrolidine-1-yl)propoxy)quinazolin-4-yl)amino)propan-1-ol; (R)-2-((2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)amino)-3-methylbutan-2-ol; 2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)-N-((S)-1-(((R)-1,1,1-trifluoropropan-2-yl)oxy)ethyl)quinazoline-4-amine; 2-(4,4-difluoropiperidine-1-yl)-N-isobutyl-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; (R)-2-(4,4-difluoropiperidine-1-yl)-6-methoxy-N-(2-(4-methoxypiperidine-1-yl)propyl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; (S)-1-Cyclobutyl-N-(2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)-N',N'-dimethylmethanediamine; (R)-1-Cyclopropyl-N-(2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)methanediamine; 2-(4,4-difluoropiperidine-1-yl)-N-((isopropylthio)methyl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; (R)-N-((2,2-difluoro-1-methylcyclopropyl)methyl)-2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; 2-(4,4-difluoropiperidine-1-yl)-N-(1H-indole-3-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; (3S,4R)-4-(((R)-1-((2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazolin-4-yl)amino)ethyl)amino)tetrahydrofuran-3-ol; (R)-2-(4,4-difluoropiperidine-1-yl)-N-(3-isopentyltetrahydro-2H-pyran-3-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; 1-(2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)piperidine-3-amine; 4-((6-Methoxy-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide; 4-((2-(azetidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide; 4-((6-Methoxy-2-(1H-Pyrazole-1-yl)-7-(3-(Pyrrolidine-1-yl)propoxy)Quinazolin-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide; 4-((2-(1H-imidazole-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide; 4-((6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)-2-(1H-1,2,4-triazole-1-yl)quinazolin-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide; 4-((2-(1H-indole-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide; 4-((2-(1H-benzo[d]imidazole-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide; 4-((6-Methoxy-2-(5-methylfuran-2-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide; 4-((6-Methoxy-2-(5-methyl-1H-pyrrole-2-yl)-7-(3-(pyrroridine-1-yl)propoxy)quinazoline-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide; 4-((6-Methoxy-2-(5-methyloxazol-2-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide; 4-((6-Methoxy-2-(2-methyloxazol-5-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide; 4-((6-Methoxy-2-(5-methylthiazole-2-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide; 4-((6-Methoxy-2-(2-methylthiazole-5-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide; 4-((2-cyclopentyl-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide; 4-((2-ethyl-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide; 4-((2-amino-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide; 4-((6-Methoxy-2-(methylamino)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide; 4-((2-(dimethylamino)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide; 4-((6-Methoxy-2-(piperazine-1-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide; 4-((2-cyclopropyl-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide; 4-((2-(isopropylamino)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide; 4-((6-Methoxy-2-((Methoxymethyl)amino)-7-(3-(Pyrrolidine-1-yl)propoxy)Quinazolin-4-yl)amino)Tetrahydro-2H-thiopyran-1,1-dioxide; 4-((6-methoxy-2-morpholino-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide; 4-(4-((1,1-dioxidetetrahydro-2H-thiopyran-4-yl)amino)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-2-yl)thiomorpholine 1,1-dioxide; 4-((2-ethoxy-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide; 4-((2-(isopropylthio)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide; 4-((6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)-2-(tetrahydropyrimidine-1(2H)-yl)quinazoline-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide; 4-((6-Methoxy-2-(piperidine-3-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide; 4-((6-Methoxy-2-(4-methylpiperazine-1-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide; 4-((6-Methoxy-2-(4-methyl-1,4-diazepan-1-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide; 4-((2-chloro-6-methoxy-7-(3-(pyrroridine-1-yl)propoxy)quinazoline-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide; 4-((7-(benzyloxy)-2-chloro-6-methoxyquinazolin-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide; 2-Chloro-N-(1-isopropylpiperidine-4-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; 2-Chloro-6-methoxy-N-(oxetan-3-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; 2-Chloro-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)-N-(tetrahydro-2H-pyran-4-yl)quinazoline-4-amine; 6-Methoxy-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)propoxy)-N-(tetrahydro-2H-pyran-3-yl)quinazoline-4-amine; 7-(3-(dimethylamino)propoxy)-6-methoxy-2-(pyrrolidine-1-yl)-N-(tetrahydro-2H-pyran-3-yl)quinazoline-4-amine; 6-Methoxy-7-(3-(piperidine-1-yl)propoxy)-2-(pyrrolidine-1-yl)-N-(tetrahydro-2H-pyran-3-yl)quinazoline-4-amine; 7-(3-(piperidine-1-yl)propoxy)-2-(pyrrolidine-1-yl)-N-(tetrahydro-2H-pyran-3-yl)quinazoline-4-amine; 6-Fluoro-7-(3-(piperidine-1-yl)propoxy)-2-(pyrrolidine-1-yl)-N-(tetrahydro-2H-pyran-3-yl)quinazoline-4-amine; 6-Methoxy-2-(4-methyl-1,4-diazepan-1-yl)-7-(3-(pyrrolidine-1-yl)propoxy)-N-(tetrahydro-2H-pyran-3-yl)quinazoline-4-amine; 6-Fluoro-7-(3-(piperidine-1-yl)propoxy)-2-(1H-pyrazole-1-yl)-N-(tetrahydro-2H-pyran-3-yl)quinazoline-4-amine; 6-Methoxy-7-(3-(pyrrolidine-1-yl)propoxy)-N-(tetrahydro-2H-pyran-3-yl)-2-(1H-1,2,4-triazole-1-yl)quinazoline-4-amine; 2-(1H-indole-3-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)-N-(tetrahydro-2H-pyran-3-yl)quinazoline-4-amine; 6-Methoxy-2-(5-methylfuran-2-yl)-7-(3-(pyrrolidine-1-yl)propoxy)-N-(tetrahydro-2H-pyran-3-yl)quinazoline-4-amine; 6-Methoxy-2-(5-methyloxazol-2-yl)-7-(3-(pyrrolidine-1-yl)propoxy)-N-(tetrahydro-2H-pyran-3-yl)quinazoline-4-amine; 6-Methoxy-2-(5-methylthiazole-2-yl)-7-(3-(pyrrolidine-1-yl)propoxy)-N-(tetrahydro-2H-pyran-3-yl)quinazoline-4-amine; 2-Ethinyl-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)-N-(tetrahydro-2H-pyran-3-yl)quinazoline-4-amine; 2-(1H-imidazole-1-yl)-6-methoxy-N-(pyridine-4-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; 2-(1H-imidazole-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)-N-(tetrahydro-2H-pyran-4-yl)quinazoline-4-amine; (S)-6-methoxy-N2,N2-dimethyl-7-(3-(pyrrolidine-1-yl)propoxy)-N4-(tetrahydro-2H-pyran-3-yl)quinazoline-2,4-diamine; 4-((7-(benzyloxy)-2-(4,4-difluoropiperidine-1-yl)-6-methoxyquinazoline-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide; 3-((6-Methoxy-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide; 3-((2-(azetidine-1-yl)-7-(3-(dimethylamino)propoxy)-6-methoxyquinazoline-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide; 3-((6-methoxy-7-(3-(piperidine-1-yl)propoxy)-2-(pyrrolidine-1-yl)quinazoline-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide; 3-((7-(3-(piperidine-1-yl)propoxy)-2-(pyrrolidine-1-yl)quinazolin-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide; 3-((6-fluoro-7-(3-(piperidine-1-yl)propoxy)-2-(pyrrolidine-1-yl)quinazolin-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide; 3-((6-Methoxy-2-(4-methyl-1,4-diazepan-1-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide; 3-((6-fluoro-2-(1H-imidazole-1-yl)-7-(3-(piperidine-1-yl)propoxy)quinazoline-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide; 3-((2-(1H-indole-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide; 3-((2-cyclopentyl-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide; 3-((6-Methoxy-2-(5-methyl-1H-pyrrole-2-yl)-7-(3-(pyrroridine-1-yl)propoxy)quinazoline-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide; 3-((6-Methoxy-2-(2-methyloxazol-5-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide; 3-((6-Methoxy-2-(2-methylthiazole-5-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide; 4-((1,1-dioxidetetrahydro-2H-thiopyran-3-yl)amino)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-2-carbonitrile; 6,7-Dimethoxy-2-(pyrroridine-1-yl)-N-(tetrahydro-2H-pyran-3-yl)quinazoline-4-amine; 3-((6,7-dimethoxy-2-(pyrrolidine-1-yl)quinazolin-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide; 1-(6,7-dimethoxy-2-(pyrrolidine-1-yl)quinazoline-4-yl)piperidine-3-amine; 1-(6,7-dimethoxy-2-(pyrrolidine-1-yl)quinazolin-4-yl)piperidine-3-ol; 3-((2-(4,4-difluoropiperidine-1-yl)-7-hydroxy-6-methoxyquinazoline-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide; 2-(1H-imidazole-1-yl)-N-(1-isopropylpiperidine-4-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; N-(1-isopropylpiperidine-4-yl)-6-methoxy-2-(1H-pyrazole-1-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; (S)-6-Methoxy-N-(piperidine-3-yl)-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; (R)-6-Methoxy-N-(piperidine-3-yl)-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; 1-(6-methoxy-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)piperidine-3-amine; N-(1-(6-methoxy-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)piperidine-3-yl)acetamide; 1-(2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)piperidine-3-amine; 1-(6-fluoro-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)piperidine-3-amine; 6-Methoxy-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)propoxy)-N-(tetrahydro-2H-pyran-4-yl)quinazoline-4-amine; 6-Methoxy-N-(piperazine-1-ylmethyl)-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; 1-(6-fluoro-2-(1H-imidazole-1-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)piperidine-3-amine; 1-(6-Methoxy-2-(4-methyl-1,4-diazepan-1-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)piperidine-3-amine; 1-(6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)-2-(1H-1,2,4-triazole-1-yl)quinazoline-4-yl)piperidine-3-amine; 1-(6-fluoro-2-(1H-pyrazole-1-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)piperidine-3-amine; 2-(1H-indole-1-yl)-6-methoxy-4-(piperidine-1-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline; 2-(1H-indole-3-yl)-6-methoxy-4-(piperidine-1-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline; 1-(2-cyclopentyl-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)piperidine-3-amine; 6-Methoxy-2-(piperidine-1-yl)-7-(3-(pyrrolidine-1-yl)propoxy)-N-(tetrahydro-2H-pyran-4-yl)quinazoline-4-amine; 2-(azetidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)-N-(tetrahydro-2H-pyran-4-yl)quinazoline-4-amine; 6-Methoxy-2-(1H-pyrazole-1-yl)-7-(3-(pyrrolidine-1-yl)propoxy)-N-(tetrahydro-2H-pyran-4-yl)quinazoline-4-amine; 2-(1H-imidazole-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)-N-(tetrahydro-2H-pyran-4-yl)quinazoline-4-amine; 6-Methoxy-7-(3-(pyrrolidine-1-yl)propoxy)-N-(tetrahydro-2H-pyran-4-yl)-2-(1H-1,2,4-triazole-1-yl)quinazoline-4-amine; 2-(1H-indole-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)-N-(tetrahydro-2H-pyran-4-yl)quinazoline-4-amine; 2-(1H-benzo[d]imidazole-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)-N-(tetrahydro-2H-pyran-4-yl)quinazoline-4-amine; 6-Methoxy-2-(5-methylfuran-2-yl)-7-(3-(pyrrolidine-1-yl)propoxy)-N-(tetrahydro-2H-pyran-4-yl)quinazoline-4-amine; 6-Methoxy-2-(5-methyl-1H-pyrrole-2-yl)-7-(3-(pyrroridine-1-yl)propoxy)-N-(tetrahydro-2H-pyran-4-yl)quinazoline-4-amine; 6-Methoxy-2-(5-methyloxazol-2-yl)-7-(3-(pyrrolidine-1-yl)propoxy)-N-(tetrahydro-2H-pyran-4-yl)quinazoline-4-amine; 6-Methoxy-2-(2-methyloxazol-5-yl)-7-(3-(pyrrolidine-1-yl)propoxy)-N-(tetrahydro-2H-pyran-4-yl)quinazoline-4-amine; 6-Methoxy-2-(5-methylthiazole-2-yl)-7-(3-(pyrrolidine-1-yl)propoxy)-N-(tetrahydro-2H-pyran-4-yl)quinazoline-4-amine; 6-Methoxy-2-(2-methylthiazole-5-yl)-7-(3-(pyrrolidine-1-yl)propoxy)-N-(tetrahydro-2H-pyran-4-yl)quinazoline-4-amine; 2-Cyclopentyl-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)-N-(tetrahydro-2H-pyran-4-yl)quinazoline-4-amine; 2-Ethyl-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)-N-(tetrahydro-2H-pyran-4-yl)quinazoline-4-amine; 6-Methoxy-7-(3-(pyrrolidine-1-yl)propoxy)-N4-(tetrahydro-2H-pyran-4-yl)quinazoline-2,4-diamine; 6-Methoxy-N2-methyl-7-(3-(pyrrolidine-1-yl)propoxy)-N4-(tetrahydro-2H-pyran-4-yl)quinazoline-2,4-diamine; 6-Methoxy-N2,N2-dimethyl-7-(3-(pyrrolidine-1-yl)propoxy)-N4-(tetrahydro-2H-pyran-4-yl)quinazoline-2,4-diamine; 6-Methoxy-2-(piperazine-1-yl)-7-(3-(pyrrolidine-1-yl)propoxy)-N-(tetrahydro-2H-pyran-4-yl)quinazoline-4-amine; 2-Cyclopropyl-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)-N-(tetrahydro-2H-pyran-4-yl)quinazoline-4-amine; N2-Isopropyl-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)-N4-(tetrahydro-2H-pyran-4-yl)quinazoline-2,4-diamine; 6-Methoxy-N2-(2-methoxyethyl)-7-(3-(pyrrolidine-1-yl)propoxy)-N4-(tetrahydro-2H-pyran-4-yl)quinazoline-2,4-diamine; 6-Methoxy-2-morpholino-7-(3-(pyrrolidine-1-yl)propoxy)-N-(tetrahydro-2H-pyran-4-yl)quinazoline-4-amine; 4-(6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)-4-((tetrahydro-2H-pyran-4-yl)amino)quinazoline-2-yl)thiomorpholine 1,1-dioxide; 2-Ethoxy-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)-N-(tetrahydro-2H-pyran-4-yl)quinazoline-4-amine; 2-(isopropylthio)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)-N-(tetrahydro-2H-pyran-4-yl)quinazoline-4-amine; N-(6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)-4-((tetrahydro-2H-pyran-4-yl)amino)quinazolin-2-yl)cyclopropanecarboxamide; 6-Methoxy-7-(3-(pyrrolidine-1-yl)propoxy)-N-(tetrahydro-2H-pyran-4-yl)-2-(tetrahydropyrimidine-1(2H)-yl)quinazoline-4-amine; 6-Methoxy-2-(piperidine-3-yl)-7-(3-(pyrrolidine-1-yl)propoxy)-N-(tetrahydro-2H-pyran-4-yl)quinazoline-4-amine; 6-Methoxy-N-(piperazine-1-ylmethyl)-2-(piperidine-1-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; 2-(azetidine-1-yl)-6-methoxy-N-(piperazine-1-ylmethyl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; 6-Methoxy-N-(piperazine-1-ylmethyl)-2-(1H-pyrazole-1-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; 2-(1H-imidazole-1-yl)-6-methoxy-N-(piperazine-1-ylmethyl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; 2-(1H-indole-1-yl)-6-methoxy-N-(piperazine-1-ylmethyl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; 6-Methoxy-N-(piperazine-1-ylmethyl)-7-(3-(pyrrolidine-1-yl)propoxy)-2-(1H-1,2,4-triazole-1-yl)quinazoline-4-amine; 2-(1H-benzo[d]imidazole-1-yl)-6-methoxy-N-(piperazine-1-ylmethyl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; 6-Methoxy-2-(5-methylfuran-2-yl)-N-(piperazine-1-ylmethyl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; 6-Methoxy-2-(5-methyl-1H-pyrrole-2-yl)-N-(piperazine-1-ylmethyl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; 6-Methoxy-2-(5-methyloxazol-2-yl)-N-(piperazine-1-ylmethyl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; 6-Methoxy-2-(2-methyloxazol-5-yl)-N-(piperazine-1-ylmethyl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; 6-Methoxy-2-(5-methylthiazole-2-yl)-N-(piperazine-1-ylmethyl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; 6-Methoxy-2-(2-methylthiazole-5-yl)-N-(piperazine-1-ylmethyl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; 2-Cyclopentyl-6-methoxy-N-(piperazine-1-ylmethyl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; 2-Ethyl-6-methoxy-N-(piperazine-1-ylmethyl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; 6-Methoxy-N4-(piperazine-1-ylmethyl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-2,4-diamine; 6-Methoxy-N2-methyl-N4-(piperazine-1-ylmethyl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-2,4-diamine; 6-Methoxy-N2,N2-dimethyl-N4-(piperazine-1-ylmethyl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-2,4-diamine; 6-Methoxy-2-morpholino-N-(piperazine-1-ylmethyl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; 2-Cyclopropyl-6-methoxy-N-(piperazine-1-ylmethyl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; N2-Isopropyl-6-methoxy-N4-(piperazine-1-ylmethyl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-2,4-diamine; 6-Methoxy-N2-(2-methoxyethyl)-N4-(piperazine-1-ylmethyl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-2,4-diamine; 6-Methoxy-2-morpholino-N-(piperazine-1-ylmethyl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; 4-(6-Methoxy-4-((piperazine-1-ylmethyl)amino)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-2-yl)thiomorpholine 1,1-dioxide; 1-(6-methoxy-7-(3-(piperidine-1-yl)propoxy)-2-(pyrrolidine-1-yl)quinazoline-4-yl)piperidine-3-ol; 1-(6-methoxy-7-(3-(piperidine-1-yl)propoxy)-2-(pyrrolidine-1-yl)quinazoline-4-yl)piperidine-3-amine; 1-(7-(3-(dimethylamino)propoxy)-6-methoxy-2-(pyrrolidine-1-yl)quinazoline-4-yl)piperidine-3-amine; 1-(2-(azetidine-1-yl)-7-(3-(dimethylamino)propoxy)-6-methoxyquinazoline-4-yl)piperidine-3-amine; 2-(azetidine-1-yl)-N-(1-isopropylpiperidine-4-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; 4-((4-(dimethylamino)cyclohexyl)amino)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-2-carbonitrile; 6-Methoxy-2-(4-methylpiperazine-1-yl)-7-(3-(pyrrolidine-1-yl)propoxy)-N-(tetrahydro-2H-pyran-4-yl)quinazoline-4-amine; 6-Methoxy-2-(4-methyl-1,4-diazepan-1-yl)-7-(3-(pyrrolidine-1-yl)propoxy)-N-(tetrahydro-2H-pyran-4-yl)quinazoline-4-amine; 4-((2-(4,4-difluoropiperidine-1-yl)-7-hydroxy-6-methoxyquinazoline-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide; 4-((2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)quinazolin-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide; 6-Methoxy-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)-N-(tetrahydro-2H-pyran-3-yl)quinazoline-4-amine; 6-Methoxy-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)-N-(tetrahydro-2H-pyran-4-yl)quinazoline-4-amine; 3-((6-Methoxy-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)quinazolin-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide; 1-(6-methoxy-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)quinazoline-4-yl)piperidine-3-amine; 1-(6-methoxy-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)quinazoline-4-yl)piperidine-3-ol; 4-((6-Methoxy-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)quinazolin-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide; 6-Methoxy-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)-N-(tetrahydro-2H-pyran-4-yl)quinazoline-4-amine; 6-Methoxy-N-(piperazine-1-ylmethyl)-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)propa-1-in-1-yl)quinazoline-4-amine; 6-Methoxy-N-(pyridine-3-yl)-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)propa-1-in-1-yl)quinazoline-4-amine; N-(2-isopropoxyethyl)-6-methoxy-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)quinazoline-4-amine; 4-((6-Methoxy-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)quinazolin-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide; 6-Methoxy-N-(piperazine-1-ylmethyl)-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)propa-1-in-1-yl)quinazoline-4-amine; 6-Methoxy-N-(morpholinomethyl)-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)quinazoline-4-amine; N-(3-isopropoxypropyl)-6-methoxy-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)quinazoline-4-amine; (2S)-N2-(6-Methoxy-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)propa-1-in-1-yl)quinazolin-4-yl)-N1-((tetrahydrofuran-2-yl)methyl)propane-1,2-diamine; N-isopropyl-6-methoxy-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)quinazoline-4-amine; N-(2-(azetidine-3-yloxy)ethyl)-6-methoxy-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)quinazoline-4-amine; 2-(4-((6-Methoxy-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)quinazoline-4-yl)amino)piperidine-1-yl)acetic acid; 6-Methoxy-N-(2-methoxyethyl)-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)propa-1-in-1-yl)quinazoline-4-amine; 6-Methoxy-N-(pyridine-2-yl)-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)propa-1-in-1-yl)quinazoline-4-amine; 6-Methoxy-N-(pyridine-3-yl)-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)propa-1-in-1-yl)quinazoline-4-amine; 6-Methoxy-N-(pyridine-4-yl)-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)propa-1-in-1-yl)quinazoline-4-amine; N-((aminooxy)carbonyl)-6-methoxy-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)quinazoline-4-amine; N-(6-Methoxy-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)propa-1-in-1-yl)quinazolin-4-yl)cyclopropanecarboxamide; 4-(2-((6-Methoxy-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)quinazolin-4-yl)amino)propyl)cyclohexane-1-ol; (R)-2-((2-((6-Methoxy-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)quinazolin-4-yl)amino)propyl)amino)ethane-1-ol; ((2R,5R)-4-(((6-Methoxy-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)quinazolin-4-yl)amino)methyl)-5-methylmorpholine-2-yl)methanol; N-cyclopentyl-6-methoxy-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)quinazoline-4-amine; 1-(4-((6-Methoxy-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)quinazoline-4-yl)amino)piperidine-1-yl)ethane-1-one; 6-Methoxy-N-methyl-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)quinazoline-4-amine; 2-((6-Methoxy-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)quinazolin-4-yl)amino)acetonitrile; N-(3,5-difluorophenyl)-6-methoxy-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)quinazoline-4-amine; (1S,2S)-1-(dimethylamino)-2-((6-methoxy-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)propa-1-in-1-yl)quinazolin-4-yl)amino)propan-1-ol; (S)-2,2,2-trifluoro-1-((6-methoxy-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)quinazolin-4-yl)amino)ethane-1-ol; 6-Methoxy-N-(pyridine-2-ylmethyl)-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)propa-1-in-1-yl)quinazoline-4-amine; 6-Methoxy-N-(pyridine-3-ylmethyl)-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)propa-1-in-1-yl)quinazoline-4-amine; 6-Methoxy-N-(pyridine-4-ylmethyl)-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)propa-1-in-1-yl)quinazoline-4-amine; (S)-6-Methoxy-N-(piperidine-2-yl)-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)propa-1-in-1-yl)quinazoline-4-amine; (S)-2-isopropoxy-N-(6-methoxy-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)quinazolin-4-yl)-N'-methylethane-1,1-diamine; 6-Methoxy-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)-N-(thiophen-2-yl)quinazoline-4-amine; N-(furan-2-yl)-6-methoxy-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)propa-1-in-1-yl)quinazoline-4-amine; 6-Methoxy-N-(1H-pyrrole-2-yl)-2-(pyrroridine-1-yl)-7-(3-(pyrroridine-1-yl)propa-1-in-1-yl)quinazoline-4-amine; 6-Methoxy-N-(1H-pyrrole-3-yl)-2-(pyrroridine-1-yl)-7-(3-(pyrroridine-1-yl)propa-1-in-1-yl)quinazoline-4-amine; 6-Methoxy-N-(1H-pyrazole-3-yl)-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)propa-1-in-1-yl)quinazoline-4-amine; N-(6-methoxy-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)quinazolin-4-yl)isoxazole-3-amine; N-(6-methoxy-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)quinazoline-4-yl)isoxazole-3-amine; N-(6-methoxy-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)quinazolin-4-yl)oxazole-5-amine; N-(6-methoxy-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)quinazolin-4-yl)thiazole-5-amine; 6-Methoxy-N-(1H-pyrrole-3-yl)-2-(pyrroridine-1-yl)-7-(3-(pyrroridine-1-yl)propa-1-in-1-yl)quinazoline-4-amine; N-Cyclopropyl-6-methoxy-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)quinazoline-4-amine; 6-Methoxy-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)-N-(trifluoromethyl)quinazoline-4-amine; N-(6-methoxy-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)quinazolin-4-yl)cyanamide; 6-Methoxy-N-(oxetan-3-yl)-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)propa-1-in-1-yl)quinazoline-4-amine; N-benzyl-6-methoxy-2-(pyrroridine-1-yl)-7-(3-(pyrroridine-1-yl)propa-1-in-1-yl)quinazoline-4-amine; 4-((2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)quinazolin-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide; 4-((6-methoxy-2-morpholino-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)quinazolin-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide; 4-((2-(azetidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)quinazoline-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide; 4-((6-Methoxy-2-(4-methyl-1,4-diazepan-1-yl)-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)quinazolin-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide; 4-((2-cyclopentyl-6-methoxy-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)quinazolin-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide; 4-((2-cyclopropyl-6-methoxy-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)quinazolin-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide; 4-((2-(dimethylamino)-6-methoxy-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)quinazolin-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide; 4-((6-Methoxy-2-(4-methylpiperazine-1-yl)-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)quinazoline-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide; 4-((2-(1,4-diazepan-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)quinazolin-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide; 2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)-N-(tetrahydro-2H-pyran-4-yl)quinazoline-4-amine; 6-Methoxy-2-morpholino-7-(3-(pyrrolidine-1-yl)propa-1-in-1-yl)-N-(tetrahydro-2H-pyran-4-yl)quinazoline-4-amine; 2-(azetidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)-N-(tetrahydro-2H-pyran-4-yl)quinazoline-4-amine; 6-Methoxy-2-(4-methyl-1,4-diazepan-1-yl)-7-(3-(pyrrolidine-1-yl)propa-1-in-1-yl)-N-(tetrahydro-2H-pyran-4-yl)quinazoline-4-amine; 2-Cyclopentyl-6-methoxy-7-(3-(pyrroridine-1-yl)prop-1-in-1-yl)-N-(tetrahydro-2H-pyran-4-yl)quinazoline-4-amine; 2-Cyclopropyl-6-methoxy-7-(3-(pyrroridine-1-yl)propa-1-in-1-yl)-N-(tetrahydro-2H-pyran-4-yl)quinazoline-4-amine; 6-Methoxy-N2,N2-dimethyl-7-(3-(pyrroridine-1-yl)prop-1-in-1-yl)-N4-(tetrahydro-2H-pyran-4-yl)quinazoline-2,4-diamine; 6-Methoxy-2-(4-methylpiperazine-1-yl)-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)-N-(tetrahydro-2H-pyran-4-yl)quinazoline-4-amine; 2-(1,4-diazepan-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propa-1-in-1-yl)-N-(tetrahydro-2H-pyran-4-yl)quinazoline-4-amine; 2-(4,4-difluoropiperidine-1-yl)-6-methoxy-N-(piperidine-4-yl)-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)quinazoline-4-amine; 2-(4,4-difluoropiperidine-1-yl)-6-methoxy-N-(methoxymethyl)-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)quinazoline-4-amine; 2-(4,4-difluoropiperidine-1-yl)-6-methoxy-N-(oxetane-3-yl)-7-(3-(pyrrolidine-1-yl)propa-1-in-1-yl)quinazoline-4-amine; 2-(4,4-difluoropiperidine-1-yl)-6-methoxy-N-(piperidine-4-ylmethyl)-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)quinazoline-4-amine; 2-(4,4-difluoropiperidine-1-yl)-6-methoxy-N-((1-methylpiperidine-4-yl)methyl)-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)quinazoline-4-amine; 2-(4,4-difluoropiperidine-1-yl)-6-methoxy-N-(piperazine-1-ylmethyl)-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)quinazoline-4-amine; 2-(4,4-difluoropiperidine-1-yl)-6-methoxy-N-(morpholinomethyl)-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)quinazoline-4-amine; 2-(4,4-difluoropiperidine-1-yl)-6-methoxy-N-(pyridine-4-yl)-7-(3-(pyrrolidine-1-yl)propa-1-in-1-yl)quinazoline-4-amine; 2-(4,4-difluoropiperidine-1-yl)-6-methoxy-N-(pyridine-3-yl)-7-(3-(pyrrolidine-1-yl)propa-1-in-1-yl)quinazoline-4-amine; 2-(4,4-difluoropiperidine-1-yl)-6-methoxy-N-(pyridine-2-yl)-7-(3-(pyrrolidine-1-yl)propa-1-in-1-yl)quinazoline-4-amine; N-cyclopentyl-2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)quinazoline-4-amine; 2-(4,4-difluoropiperidine-1-yl)-6-methoxy-N-(5-methylfuran-2-yl)-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)quinazoline-4-amine; N-(2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)quinazolin-4-yl)-2-methyloxazole-5-amine; N-(2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)quinazolin-4-yl)-2-methylthiazole-5-amine; 2-(4,4-difluoropiperidine-1-yl)-6-methoxy-N-(5-methyl-1H-pyrazole-3-yl)-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)quinazoline-4-amine; 2-((2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)quinazoline-4-yl)amino)acetamide; 2-(4,4-difluoropiperidine-1-yl)-6-methoxy-N-(2-methoxyethyl)-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)quinazoline-4-amine; N-Cyclopropyl-2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)quinazoline-4-amine; N-Cyclobutyl-2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)quinazoline-4-amine; 2-(4,4-difluoropiperidine-1-yl)-6-methoxy-N-(oxetane-3-yl)-7-(3-(pyrrolidine-1-yl)propa-1-in-1-yl)quinazoline-4-amine; 2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)-N-(trifluoromethyl)quinazoline-4-amine; N-(2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propa-1-in-1-yl)quinazolin-4-yl)cyclopropanecarboxamide; N-(3,5-difluorophenyl)-2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)quinazoline-4-amine; 2-(4,4-difluoropiperidine-1-yl)-6-methoxy-N-(piperidine-4-yl)-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)quinazoline-4-amine; 2-(4,4-difluoropiperidine-1-yl)-6-methoxy-N-(piperidine-3-yl)-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)quinazoline-4-amine; 2-(4,4-difluoropiperidine-1-yl)-6-methoxy-N-(piperidine-2-yl)-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)quinazoline-4-amine; 2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)-N-(pyrrolidine-3-yl)quinazoline-4-amine; 2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)-N-(pyrrolidine-2-yl)quinazoline-4-amine; 2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)-N-(tetrahydrofuran-3-yl)quinazoline-4-amine; 3-((2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)quinazolin-4-yl)amino)tetrahydrothiophene 1,1-dioxide; 2-((2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)quinazolin-4-yl)amino)tetrahydrothiophene 1,1-dioxide; N-(2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)quinazolin-4-yl)methanesulfonamide; 1-(2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)quinazoline-4-yl)-3-methylurea; 1-(2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)quinazoline-4-yl)piperidine-2-amine; 1-(2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)quinazoline-4-yl)piperidine-3-amine; 2-(4,4-difluoropiperidine-1-yl)-N-(1-isopropylpiperidine-4-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; 2-Cyclohexyl-N-(1-isopropylpiperidine-4-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; N-(1-cyclohexylpiperidine-4-yl)-2-(4-isopropyl-1,4-diazepan-1-yl)-6-methoxy-7-(3-(piperidine-1-yl)propoxy)quinazoline-4-amine; N-(1-isopropylpiperidine-4-yl)-6-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-7-(3-(piperidine-1-yl)propoxy)quinazoline-4-amine; N-(1-isopropylpiperidine-4-yl)-6-methoxy-2-morpholino-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; 4-(4-((1-cyclopropylpiperidine-4-yl)amino)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-2-yl)thiomorpholine 1,1-dioxide; N-(1-benzylpiperidine-4-yl)-2-(4-isopropyl-1,4-diazepan-1-yl)-6,7-dimethoxyquinazoline-4-amine; 6-Methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidine-4-yl)-7-(3-(pyrrolidine-1-yl)propa-1-in-1-yl)quinazoline-4-amine; 7-((5-aminopentyl)oxy)-N4-(1-(5-aminopentyl)piperidine-4-yl)-N2-(3-(dimethylamino)propyl)-6-methoxyquinazoline-2,4-diamine; N2-Hexyl-6,7-dimethoxy-N4-(1-methylpiperidine-4-yl)quinazoline-2,4-diamine; 2-(4-(cyclohexylmethyl)-1,4-diazepan-1-yl)-N-(1-isopropylpiperidine-4-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; N-(1-isopropylpiperidine-4-yl)-6-methoxy-2-(4-phenyl-1,4-diazepan-1-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; 2-(4-benzyl-1,4-diazepan-1-yl)-N-(1-isopropylpiperidine-4-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; N-(1-isopropylpiperidine-4-yl)-6-methoxy-2-(piperidine-1-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; 2-(azepan-1-yl)-N-(1-isopropylpiperidine-4-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; N-(1-isopropylpiperidine-4-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)-2-(tetrahydro-2H-pyran-4-yl)quinazoline-4-amine; N-(1-isopropylpiperidine-4-yl)-6-methoxy-2-morpholino-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; 4-(4-((1-cyclopropylpiperidine-4-yl)amino)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-2-yl)thiomorpholine 1,1-dioxide; N-(1-isopropylpiperidine-4-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)-2-(3,3,4,4-tetrafluoropyrrolidine-1-yl)quinazoline-4-amine; 2-Cyclohexyl-N-(1-isopropylpiperidine-4-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; 7-(3-(4,4-difluoropiperidine-1-yl)propoxy)-N-(1-isopropylpiperidine-4-yl)-6-methoxy-2-(tetrahydro-2H-pyran-4-yl)quinazoline-4-amine; 2-(azepan-1-yl)-N-(1-isopropylpiperidine-4-yl)-6-methoxy-7-(3-(piperidine-1-yl)propoxy)quinazoline-4-amine; N-(1-isopropylpiperidine-4-yl)-6-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-7-(3-(piperidine-1-yl)propoxy)quinazoline-4-amine; 2-(4-isopropyl-1,4-diazepan-1-yl)-N-(1-isopropylpiperidine-4-yl)-6-methoxy-7-(3-(piperidine-1-yl)propoxy)quinazoline-4-amine; N-(1-cyclopropylpiperidine-4-yl)-2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; 4-(4-((1-isopropylpiperidine-4-yl)amino)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-2-yl)thiomorpholine 1,1-dioxide; N-(1-(cyclohexylmethyl)piperidine-4-yl)-2-(4-isopropyl-1,4-diazepan-1-yl)-6-methoxy-7-(3-(piperidine-1-yl)propoxy)quinazoline-4-amine; N-(1-cyclohexylpiperidine-4-yl)-2-(4-isopropyl-1,4-diazepan-1-yl)-6-methoxy-7-(3-(piperidine-1-yl)propoxy)quinazoline-4-amine; N-(1-cyclohexylpiperidine-4-yl)-6-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-7-(3-(piperidine-1-yl)propoxy)quinazoline-4-amine; 6-Methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidine-4-yl)-7-(3-(piperidine-1-yl)propoxy)quinazoline-4-amine; 6-Methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidine-4-yl)-7-(3-morpholinopropoxy)quinazoline-4-amine; 6-Methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidine-4-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; 7-(2-(dimethylamino)ethoxy)-6-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidine-4-yl)quinazoline-4-amine; 7-(3-(dimethylamino)propoxy)-6-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidine-4-yl)quinazoline-4-amine; 6-Methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidine-4-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; 7-(4-(dimethylamino)butoxy)-6-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidine-4-yl)quinazoline-4-amine; 7-((5-(dimethylamino)pentyl)oxy)-6-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidine-4-yl)quinazoline-4-amine; 7-((6-(dimethylamino)hexyl)oxy)-6-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidine-4-yl)quinazoline-4-amine; 1-(6,7-dimethoxy-2-(pyrrolidine-1-yl)quinazoline-4-yl)piperidine-2-amine; 1-(6-Methoxy-2-(4-methyl-1,4-diazepan-1-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)piperidine-2-amine; 1-(6-methoxy-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)piperidine-2-amine; 1-(6-methoxy-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)propa-1-in-1-yl)quinazoline-4-yl)piperidine-2-amine; 1-(2-(1H-imidazole-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)piperidine-2-amine; 1-(2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)piperidine-2-amine; 1-(6-methoxy-7-(3-(piperidine-1-yl)propoxy)-2-(pyrrolidine-1-yl)quinazoline-4-yl)piperidine-2-amine; 1-(2-(azetidine-1-yl)-7-(3-(dimethylamino)propoxy)-6-methoxyquinazoline-4-yl)piperidine-2-amine; 1-(6-methoxy-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)piperidine-2-ol; 1-(6-methoxy-7-(3-(piperidine-1-yl)propoxy)-2-(pyrrolidine-1-yl)quinazoline-4-yl)piperidine-2-ol; 1-(6,7-dimethoxy-2-(pyrrolidine-1-yl)quinazolin-4-yl)piperidine-2-ol; 1-(6-Methoxy-2-(4-methyl-1,4-diazepan-1-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)piperidine-2-ol; 1-(6-methoxy-2-(1H-pyrazole-1-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)piperidine-2-ol; 1-(6-methoxy-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)quinazoline-4-yl)piperidine-2-ol; 1-(2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)piperidine-2-ol; 1-(2-(azetidine-1-yl)-7-(3-(dimethylamino)propoxy)-6-methoxyquinazoline-4-yl)piperidine-2-ol; 2-((2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)amino)acetamide; 2-(4,4-difluoropiperidine-1-yl)-N-(1-isopropylpiperidine-4-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; 2-Cyclohexyl-N-(1-isopropylpiperidine-4-yl)-6-methoxy-7-(3-(piperidine-1-yl)propoxy)quinazoline-4-amine; 2-Cyclohexyl-7-(2-(2-(dimethylamino)ethoxy)ethoxy)-N-(1-isopropylpiperidine-4-yl)-6-methoxyquinazoline-4-amine; 2-Cyclohexyl-7-(3-(4,4-difluoropiperidine-1-yl)propoxy)-N-(1-isopropylpiperidine-4-yl)-6-methoxyquinazoline-4-amine; N-(1-isopropylpiperidine-4-yl)-6-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; 2-(4-ethyl-1,4-diazepan-1-yl)-N-(1-isopropylpiperidine-4-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; 2-(4-isopropyl-1,4-diazepan-1-yl)-N-(1-isopropylpiperidine-4-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; 2-(4-cyclohexyl-1,4-diazepan-1-yl)-N-(1-isopropylpiperidine-4-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; 6-Methoxy-2-(4-methyl-1,4-diazepan-1-yl)-7-(3-(methylamino)propoxy)-N-(1-methylpiperidine-4-yl)quinazoline-4-amine; 7-(3-(diethylamino)propoxy)-6-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidine-4-yl)quinazoline-4-amine; 6-Methoxy-7-(3-(methyl(propyl)amino)propoxy)-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidine-4-yl)quinazoline-4-amine; 6-Methoxy-2-(4-methyl-1,4-diazepan-1-yl)-7-((5-methylhexyl)oxy)-N-(1-methylpiperidine-4-yl)quinazoline-4-amine; 6-Methoxy-7-(4-Methoxybutoxy)-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidine-4-yl)quinazoline-4-amine; tert-butyl(4-((6-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-4-((1-methylpiperidine-4-yl)amino)quinazoline-7-yl)oxy)butyl)carbamate; 7-(4-aminobutoxy)-6-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidine-4-yl)quinazoline-4-amine; 5-((6-Methoxy-2-(4-methyl-1,4-diazepan-1-yl)-4-((1-methylpiperidine-4-yl)amino)quinazoline-7-yl)oxy)pentanamide; 7-(2-(2-(dimethylamino)ethoxy)ethoxy)-6-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidine-4-yl)quinazoline-4-amine; 6-Methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidine-4-yl)-7-(2-(2-(pyrrolidine-1-yl)ethoxy)ethoxy)quinazoline-4-amine; N1-(2-((6-Methoxy-2-(4-methyl-1,4-diazepan-1-yl)-4-((1-methylpiperidine-4-yl)amino)quinazoline-7-yl)oxy)ethyl)-N1,N2,N2-trimethylethane-1,2-diamine; 6-Methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidine-4-yl)-7-(piperidine-3-ylmethoxy)quinazoline-4-amine; 2-(4-ethyl-1,4-diazepan-1-yl)-N-(1-isopropylpiperidine-4-yl)-6-methoxy-7-(3-(piperidine-1-yl)propoxy)quinazoline-4-amine, and 4-(4-((1-cyclopropylpiperidine-4-yl)amino)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-2-yl)thiomorpholine 1,1-dioxide.

[0208] In some embodiments, formula (I) does not contain one or more of the following compounds: 2-(4,4-difluoropiperidine-1-yl)-N-(1-isopropylpiperidine-4-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; 2-cyclohexyl-N-(1-isopropylpiperidine-4-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; N-(1-cyclohexylpiperidine-4-yl)-2-(4-isopropyl N-(1-isopropylpiperidine-4-yl)-6-methoxy-7-(3-(piperidine-1-yl)propoxy)quinazoline-4-amine; N-(1-isopropylpiperidine-4-yl)-6-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-7-(3-(piperidine-1-yl)propoxy)quinazoline-4-amine; N-(1-isopropylpiperidine-4-yl)-6-methoxy-2-morpholino-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; 4-(4-((1-cycloprop Lupiperidine-4-yl)amino)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-2-yl)thiomorpholine 1,1-dioxide;2-cyclohexyl-N-(1-isopropylpiperidine-4-yl)-7-methoxy-8-(3-(pyrrolidine-1-yl)propoxy)-3H-benzo[e][1,4]diazepine-5-amine;6-methoxy-2-(5-methylfuran-2-yl)-N-((1-methylpiperidine-4-yl)methyl)-7-(3-(pyrrolidine-1-yl)propoxy) Quinoline-4-amine; 5'-Methoxy-6'-(3-(pyrrolidine-1-yl)propoxy)spiro[cyclobutan-1,3'-indole]-2'-amine; N-(1-benzylpiperidine-4-yl)-2-(4-isopropyl-1,4-diazepan-1-yl)-6,7-dimethoxyquinazoline-4-amine; 6-Methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidine-4-yl)-7-(3-(pyrrolidine-1-yl)propa-1-in-1-yl)quinazoline-4-amine;7-((5-aminopentyl)oxy)-N4-(1-(5-aminopentyl)piperidine-4-yl)-N2-(3-(dimethylamino)propyl)-6-methoxyquinazoline-2,4-diamine; 6-methoxy-2-(5-methylfuran-2-yl)-N-(1-methylpiperidine-4-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinoline-4-amine; 6-methoxy-2-(5-methyl-1H-pyrrole-2-yl)-N-(1-methylpiperidine-4-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinoline-4- Amine; N2-Hexyl-6,7-dimethoxy-N4-(1-methylpiperidine-4-yl)quinazoline-2,4-diamine; 2-(4-(cyclohexylmethyl)-1,4-diazepan-1-yl)-N-(1-isopropylpiperidine-4-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; N-(1-isopropylpiperidine-4-yl)-6-methoxy-2-(4-phenyl-1,4-diazepan-1-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; 2- (4-benzyl-1,4-diazepan-1-yl)-N-(1-isopropylpiperidine-4-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine;N-(1-isopropylpiperidine-4-yl)-6-methoxy-2-(piperidine-1-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine;2-(azepan-1-yl)-N-(1-isopropylpiperidine-4-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine;N -(1-isopropylpiperidine-4-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)-2-(tetrahydro-2H-pyran-4-yl)quinazoline-4-amine; N-(1-isopropylpiperidine-4-yl)-6-methoxy-2-morpholino-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; 4-(4-((1-cyclopropylpiperidine-4-yl)amino)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-2-yl)thiomorpholine 1,1-dioxide;N-(1-isopropylpiperidine-4-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)-2-(3,3,4,4-tetrafluoropyrrolidine-1-yl)quinazoline-4-amine;2-cyclohexyl-N-(1-isopropylpiperidine-4-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine;7-(3-(4,4-difluoropiperidine-1-yl)propoxy)-N-(1-isopropylpiperidine-4-yl)-6-methoxy-2-(tetrahydro-2H-pyra N-4-yl)quinazolin-4-amine; 2-(azepan-1-yl)-N-(1-isopropylpiperidine-4-yl)-6-methoxy-7-(3-(piperidine-1-yl)propoxy)quinazolin-4-amine; N-(1-isopropylpiperidine-4-yl)-6-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-7-(3-(piperidine-1-yl)propoxy)quinazolin-4-amine; 2-(4-isopropyl-1,4-diazepan-1-yl)-N-(1-isopropylpiperidine-4-yl)-6-methoxy-7- (3-(piperidine-1-yl)propoxy)quinazoline-4-amine; N-(1-cyclopropylpiperidine-4-yl)-2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine; 4-(4-((1-isopropylpiperidine-4-yl)amino)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-2-yl)thiomorpholine 1,1-dioxide; N-(1-(cyclohexylmethyl)piperidine-4-yl)-2-(4-iso Propyl-1,4-diazepan-1-yl)-6-methoxy-7-(3-(piperidine-1-yl)propoxy)quinazoline-4-amine; N-(1-cyclohexylpiperidine-4-yl)-2-(4-isopropyl-1,4-diazepan-1-yl)-6-methoxy-7-(3-(piperidine-1-yl)propoxy)quinazoline-4-amine; N-(1-cyclohexylpiperidine-4-yl)-6-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-7-(3-(piperidine-1-yl)propoxy)quinazoline-4-amine;6-Methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidine-4-yl)-7-(3-(piperidine-1-yl)propoxy)quinazoline-4-amine; 6-Methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidine-4-yl)-7-(3-morpholinopropoxy)quinazoline-4-amine; 6-Methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidine-4-yl)-7-(3-(pyrrolidine-1 -yl)propoxy)quinazoline-4-amine;7-(2-(dimethylamino)ethoxy)-6-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidine-4-yl)quinazoline-4-amine;7-(3-(dimethylamino)propoxy)-6-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidine-4-yl)quinazoline-4-amine;6-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidine N-4-yl)-7-(3-(pyrroridine-1-yl)propoxy)quinazoline-4-amine;7-(4-(dimethylamino)butoxy)-6-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidine-4-yl)quinazoline-4-amine;7-((5-(dimethylamino)pentyl)oxy)-6-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidine-4-yl)quinazoline-4-amine;7-((6-(dimethylamino)hexyl )oxy)-6-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidine-4-yl)quinazoline-4-amine;2-(4,4-difluoropiperidine-1-yl)-N-(1-isopropylpiperidine-4-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine;2-cyclohexyl-N-(1-isopropylpiperidine-4-yl)-6-methoxy-7-(3-(piperidine-1-yl)propoxy)quinazoline-4-amine;2-Cyclohexyl-7-(2-(2-(dimethylamino)ethoxy)ethoxy)-N-(1-isopropylpiperidine-4-yl)-6-methoxyquinazoline-4-amine; 2-Cyclohexyl-7-(3-(4,4-difluoropiperidine-1-yl)propoxy)-N-(1-isopropylpiperidine-4-yl)-6-methoxyquinazoline-4-amine; N-(1-isopropylpiperidine-4-yl)-6-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-7-(3-(pyrrolidine-1-yl) (Propoxy)quinazolin-4-amine; 2-(4-ethyl-1,4-diazepan-1-yl)-N-(1-isopropylpiperidine-4-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazolin-4-amine; 2-(4-isopropyl-1,4-diazepan-1-yl)-N-(1-isopropylpiperidine-4-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazolin-4-amine; 2-(4-cyclohexyl-1,4-diazepan-1-yl)-N-(1-isopropyl (Pyrrolicpiperidine-4-yl)-6-methoxy-7-(3-(pyrroridine-1-yl)propoxy)quinazoline-4-amine; 6-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-7-(3-(methylamino)propoxy)-N-(1-methylpiperidine-4-yl)quinazoline-4-amine; 7-(3-(diethylamino)propoxy)-6-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidine-4-yl)quinazoline-4-amine; 6-methoxy-7-(3- (methyl(propyl)amino)propoxy)-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidine-4-yl)quinazoline-4-amine; 6-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-7-((5-methylhexyl)oxy)-N-(1-methylpiperidine-4-yl)quinazoline-4-amine; 6-methoxy-7-(4-methoxybutoxy)-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidine-4-yl)quinazoline-4-amine;tert-butyl(4-((6-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-4-((1-methylpiperidine-4-yl)amino)quinazolin-7-yl)oxy)butyl)carbamate; 7-(4-aminobutoxy)-6-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidine-4-yl)quinazolin-4-amine; 5-((6-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-4-((1-methylpiperidine-4-yl)amino)quinazolin-7-yl)oxy)pentanamide; 7-(2-(2-(dimethylamino)ethoxy)ethoxy)-6-methoxy-2-(4-methyl-1,4-di; Azepan-1-yl)-N-(1-methylpiperidine-4-yl)quinazolin-4-amine; 6-Methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidine-4-yl)-7-(2-(2-(pyrroridine-1-yl)ethoxy)ethoxy)quinazolin-4-amine; N1-(2-((6-Methoxy-2-(4-methyl-1,4-diazepan-1-yl)-4-((1-methylpiperidine-4-yl)amino)quinazolin-7-yl)oxy)ethyl)-N1,N2,N2-trimethylethane-1,2-diamine; 6-Methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidine (n-4-yl)-7-(piperidine-3-ylmethoxy)quinazolin-4-amine; 2-(4-ethyl-1,4-diazepan-1-yl)-N-(1-isopropylpiperidine-4-yl)-6-methoxy-7-(3-(piperidine-1-yl)propoxy)quinazolin-4-amine; 4-(4-((1-cyclopropylpiperidine-4-yl)amino)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazolin-2-yl)thiomorpholine 1,1-dioxide, and / or compounds of formula (I) lack any particular combination of 2-, 4-, 6-, and 7-quinazolinyl substituents among the aforementioned compounds in this paragraph. To demonstrate instances where formula (I) lacks specific combinations of 2-, 4-, 6-, and 7-quinazolinyl substituents in the structure provided in this paragraph, 2-(4-ethyl-1,4-diazepan-1-yl)-N-(1-isopropylpiperidine-4-yl)-6-methoxy-7-(3-(piperidine-1-yl)propoxy)quinazolin-4-amine is used for illustrative purposes. For example, in some embodiments, if the substituent at position 4 is N-(1-isopropylpiperidine-4-yl)amine, the structure of formula (I) may lack one or more of (4-ethyl-1,4-diazepan-1-yl) at position 2, methoxy at position 6, and / or (3-(piperidine-1-yl)propoxy) at position 7.As a further example, in some embodiments, when the substituent at position 2 is (4-ethyl-1,4-diazepan-1-yl), the structure of formula (I) may lack one or more of the following: N-(1-isopropylpiperidine-4-yl)-amine at position 4, methoxy at position 6, and / or (3-(piperidine-1-yl)propoxy) at position 7. Finally, in some embodiments, when the substituent at position 7 is (3-(piperidine-1-yl)propoxy), the structure of formula (I) may lack one or more of the following: N-(1-isopropylpiperidine-4-yl)amine at position 4, (4-ethyl-1,4-diazepan-1-yl) at position 2, and / or methoxy at position 6.

[0209] Compound of formula (Ia) Some embodiments include quinazolinyl compounds having the structure of formula (Ia):

[0210] [ka] This relates to (or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof). In some embodiments, the variable group of formula (Ia) is as disclosed elsewhere in this specification. For example, in some embodiments, the variable group of formula (Ia) is as disclosed elsewhere in this specification for formula (Ia), or as disclosed elsewhere in this specification for any other formula (e.g., formula (I)) having a variable group shared with that in formula (Ia). In some embodiments, the variable group of the "A" ring is as disclosed elsewhere in this specification. In some embodiments, the ring "A" is a cycloalkyl ring or a heterocyclyl ring. In some embodiments, X am is selected from the group consisting of CH and N. In some embodiments, m is an integer independently selected from 0, 1, 2, and 3. In some embodiments, n is an integer independently selected from 0, 1, 2, and 3. In some embodiments, X b CH2, NR b Selected from the group consisting of , O, and SO2. In some embodiments, R a These elements are optionally present and can be provided at any position in the "A" ring by replacing one or more -H atoms of any carbon or nitrogen atom present in the "A" ring.

[0211] In some embodiments, R a The substituent is selected from the group consisting of amino, -OH, and optionally substituted C1-C6 alkyl groups. The optional substituent may be selected from substituents disclosed elsewhere in this specification.

[0212] In some embodiments, R b The substituent is selected from the group consisting of hydrogen, optionally substituted C1-C6 alkyl groups, and C-carboxyls. The optional substituent may be selected from substituents disclosed elsewhere in this specification.

[0213] In some embodiments, n is 1 and m is 3.

[0214] In some embodiments, X b It is either O or SO2.

[0215] In some embodiments, the structure of equation (I) is represented by the structure of equation Ia. For example, in some embodiments, X of equation (I) 3 teeth

[0216] [ka] It can be represented by:

[0217] Compound of formula (Ib) Some embodiments include quinazolinyl compounds having the structure of formula (Ib):

[0218] [ka] This relates to (or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof). In some embodiments, the variable group of formula (Ib) is as disclosed elsewhere in this specification. For example, in some embodiments, the variable group of formula (Ib) is as disclosed elsewhere in this specification for formula (Ib), or as disclosed elsewhere in this specification for any other formula (e.g., formula (I)) having a variable group shared with that in formula (Ib).

[0219] In some embodiments, X 3 This is represented by the ring "B".

[0220] In some embodiments, the "B" ring is an unsaturated ring selected from the group consisting of optionally substituted cyclopentenyl, optionally substituted phenyl, optionally substituted furyl, optionally substituted thienyl, optionally substituted pyrrolyl, optionally substituted oxazolyl, optionally substituted thiazolyl, optionally substituted imidazolyl, optionally substituted benzimidazolyl, optionally substituted pyrazolyl, optionally substituted isoxazolyl, optionally substituted triazolyl, optionally substituted pyridinyl, optionally substituted pyridadinyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, optionally substituted indolyl, optionally substituted isoindolyl, and optionally substituted benzothienyl.

[0221] In some embodiments, the "B" ring is

[0222] [ka] One of the following is selected, and any of these may be optionally substituted by replacing one or more -H atoms of any carbon or nitrogen atom present on the "B" ring.

[0223] In some embodiments, the optional substitution of the "B" ring is selected from one or more amino, -OH, optionally substituted C1-C6 alkyl, and halogen groups. In some embodiments, the optional substituent may be selected from substituents disclosed elsewhere in this specification.

[0224] In some embodiments, the structure of equation (I) is represented by the structure of equation (Ib). For example, in some embodiments, X of equation (I) 3 teeth,

[0225] [ka] It can be represented by:

[0226] Compound of formula (Ic) Some embodiments include quinazolinyl compounds having the structure of formula (Ic):

[0227] [ka] This relates to (or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof). In some embodiments, the variable group of formula (Ic) is as disclosed elsewhere in this specification. For example, in some embodiments, the variable group of formula (Ic) is as disclosed elsewhere in this specification for formula (Ic), or as disclosed elsewhere in this specification for any other formula (e.g., formula (I)) having a variable group shared with that in formula (Ic).

[0228] In some embodiments, m is an integer independently selected from 0, 1, 2, and 3.

[0229] In some embodiments, n is an integer independently selected from 0, 1, 2, and 3.

[0230] In some embodiments, X b CH2, NR b The group is selected from the group consisting of , O, and SO2.

[0231] In some embodiments, R a It is optionally present and can be provided at any position in the "C" ring by replacing one or more -H atoms of any carbon or nitrogen atom present in the "C" ring.

[0232] In some embodiments, R a The substituent is selected from the group consisting of amino, N-amide, -OH, and optionally substituted C1-C6 alkyl groups. In some embodiments, the optional substituent may be selected from substituents disclosed elsewhere in this specification.

[0233] In some embodiments, R b The C1-C6 alkyl and C-carboxyl groups are selected from these.

[0234] In some embodiments, the structure of equation (I) is represented by the structure of equation (Ic). For example, in some embodiments, X of equation (I) 2 -NX 1 -X 3 teeth,

[0235] [ka] It can be represented by:

[0236] Compound of formula (Id) Some embodiments include quinazolinyl compounds having the structure of formula (Id):

[0237] [ka] This relates to (or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof). In some embodiments, the variable group of formula (Id) is as disclosed elsewhere in this specification. For example, in some embodiments, the variable group of formula (Id) is as disclosed elsewhere in this specification for formula (Id), or as disclosed elsewhere in this specification for any other formula (e.g., formula (I)) having a variable group shared with that in formula (Id).

[0238] In some embodiments, the ring "D" is a cycloalkyl ring or a heterocyclyl ring. In some embodiments, X f b is selected from the group consisting of CH and N. In some embodiments, b is an integer independently selected from 0, 1, 2, 3, or 4. In some embodiments, c is an integer independently selected from 0, 1, 2, 3, or 4. In some embodiments, X g CH2, NR h Selected from the group consisting of , O, and SO2. In some embodiments, R f These are optionally present, and each instance can be provided at any position in the "D" ring by replacing one or more -H atoms of any carbon or nitrogen atom present in the "D" ring. In some embodiments, d is an integer selected from 0, 1, 2, 3, or 4.

[0239] In some embodiments, R f The substituent is selected from the group consisting of halogens, aminos, -OH groups, and optionally substituted C1-C6 alkyl groups. In some embodiments, the optional substituent may be selected from substituents disclosed elsewhere in this specification.

[0240] In some embodiments, R h The substituent is selected from the group consisting of hydrogen, optionally substituted C1-C6 alkyl groups, and C-carboxyls. In some embodiments, the optional substituent may be selected from substituents disclosed elsewhere in this specification.

[0241] In some embodiments, n is 1 and m is 2. In some embodiments, n is 1 and m is 3. In some embodiments, n is 2 and m is 2. In some embodiments, n is 0.

[0242] In some embodiments, the structure of equation (I) is represented by the structure of equation (Id). For example, in some embodiments, X of equation (I) 4 teeth,

[0243] [ka] It can be represented by:

[0244] Compounds of formula (Ie) Some embodiments include quinazolinyl compounds having the structure of formula (Ie):

[0245] [ka] This relates to (or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof). In some embodiments, the variable group of formula (Ie) is as disclosed elsewhere in this specification. For example, in some embodiments, the variable group of formula (Ie) is as disclosed elsewhere in this specification for formula (Ie), or as disclosed elsewhere in this specification for any other formula (e.g., formula (I)) having a variable group shared with that in formula (Ie).

[0246] In some embodiments, X 4The ring is represented by the ring "E". In some embodiments, the "E" ring is an unsaturated ring selected from the group consisting of optionally substituted cyclopentenyl, optionally substituted phenyl, optionally substituted furyl, optionally substituted thienyl, optionally substituted pyrrolyl, optionally substituted oxazolyl, optionally substituted thiazolyl, optionally substituted imidazolyl, optionally substituted benzimidazolyl, optionally substituted pyrazolyl, optionally substituted isoxazolyl, optionally substituted triazolyl, optionally substituted pyridinyl, optionally substituted pyridadinyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, optionally substituted indolyl, optionally substituted isoindolyl, and optionally substituted benzothienyl.

[0247] In some embodiments, the "E" ring is

[0248] [ka] A substituent is selected from any of the following, any of which may be optionally substituted by replacing one or more -H atoms of any carbon or nitrogen atom present on the "E" ring. In some embodiments, if the E ring contains one or more optional substituents, the one or more optional substituents may be independently selected from the group consisting of C1-C3 alkyl, halo, cyano, hydroxy, and C1-C3 alkoxy. In some embodiments, the optional substituent of the "E" ring is selected from one or more of amino, -OH, optionally substituted C1-C6 alkyl, and halogen. In some embodiments, the optional substituent may be selected from substituents disclosed elsewhere in this specification.

[0249] In some embodiments, the structure of equation (I) is represented by the structure of equation (Ie). For example, in some embodiments, X in equation (I) 4 teeth,

[0250] [ka] It can be represented by:

[0251] Compound of formula (If) Some embodiments include quinazolinyl compounds having the structure of formula (If):

[0252] [ka] This relates to (or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof). In some embodiments, the variable group of formula (If) is as disclosed elsewhere in this specification. For example, in some embodiments, the variable group of formula (If) is as disclosed elsewhere in this specification for formula (If), or as disclosed elsewhere in this specification for any other formula (e.g., formula (I)) having a variable group shared with that in formula (If). In some embodiments, the pyrrolidinyl ring is optionally substituted. In some embodiments, if the pyrrolidinyl ring includes one or more optionally substituted groups, one or more optionally substituted groups may be independently selected from the group consisting of C1-C3 alkyl, halo, cyano, hydroxy, and C1-C3 alkoxy. In some embodiments, the structure of formula (I) is represented by the structure of formula (If). For example, in some embodiments, the R of formula (I) 4 teeth,

[0253] [ka] It can be represented by:

[0254] Compound of formula (Ig) Some embodiments include quinazolinyl compounds having the structure of formula (Ig):

[0255] [ka] This relates to (or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof). In some embodiments, the variable group of formula (Ig) is as disclosed elsewhere in this specification. For example, in some embodiments, the variable group of formula (Ig) is as disclosed elsewhere in this specification for formula (Ig), or as disclosed elsewhere in this specification for any other formula (e.g., formula (I)) having a variable group shared with that in formula (Ig). In some embodiments, the pyrrolidinyl ring is optionally substituted. In some embodiments, if the pyrrolidinyl ring includes one or more optionally substituted, one or more optionally substituted may be independently selected from the group consisting of C1-C3 alkyl, halo, cyano, hydroxy, and C1-C3 alkoxy.

[0256] In some embodiments, X 3 This is as disclosed elsewhere in this specification. In some embodiments, X 3 X is selected from the group consisting of optionally substituted 2- to 10-membered heteroalkyls, optionally substituted 3- to 10-membered heterocyclines, or optionally substituted 5- to 10-membered heteroaryls. In some embodiments, X 4 -CN or -NR 2 R 3 That is the case.

[0257] In some embodiments, the structure of formula (I) is represented by the structure of formula (Ig). For example, in some embodiments, the R of formula (I) 4 teeth,

[0258] [ka] It can be represented by:

[0259] Compound of formula (Ih) Some embodiments include quinazolinyl compounds having the structure of formula (Ih):

[0260] [ka] This relates to (or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof). In some embodiments, the variable group of formula (Ih) is as disclosed elsewhere herein. For example, in some embodiments, the variable group of formula (Ih) is as disclosed elsewhere herein for formula (Ih), or as disclosed elsewhere herein for any other formula (e.g., formula (I)) having a variable group shared with that in formula (Ih). In some embodiments, X 5 It is oxygen or sulfonyl.

[0261] In some embodiments, the structure of expression (I) is represented by the structure of expression (If). For example, in some embodiments, X of expression (I) 3 teeth,

[0262] [ka] It can be represented by:

[0263] Compound of formula (Ij) Some embodiments include quinazolinyl compounds having the structure of formula (Ij):

[0264] [ka] This relates to (or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof). In some embodiments, the variable group of formula (Ih) is as disclosed elsewhere in this specification. For example, in some embodiments, the variable group of formula (Ih) is as disclosed elsewhere in this specification for formula (Ih), or as disclosed elsewhere in this specification for any other formula (e.g., formula (I)) having a variable group shared with that in formula (Ih).

[0265] In some embodiments, X 6The element is selected from the group consisting of hydrogen, -NH2, -OH, and N-amides.

[0266] In some embodiments, the structure of equation (I) is represented by the structure of equation (Ij). For example, in some embodiments, X of equation (I) 2 -NX 1 -X 3 teeth,

[0267] [ka] It can be represented by:

[0268] Compound of formula (Ik) Some embodiments include quinazolinyl compounds having the structure of formula (Ik):

[0269] [ka] This relates to (or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof). In some embodiments, the variable group of formula (Ik) is as disclosed elsewhere herein. For example, in some embodiments, the variable group of formula (Ik) is as disclosed elsewhere herein for formula (Ik), or as disclosed elsewhere herein for any other formula having a variable group shared with that in formula (Ik). In some embodiments, X 8 The element is selected from the group consisting of hydrogen, -NH2, -OH, and N-amides.

[0270] In some embodiments, the structure of equation (I) is represented by the structure of equation (Ik). For example, in some embodiments, X of equation (I) 2 -NX 1 -X 3 teeth,

[0271] [ka] It can be represented by:

[0272] Compound of formula (II) Some embodiments include quinazolinyl compounds having the structure of formula (II):

[0273] [ka] (or relating to stereoisomers, tautomers, or pharmaceutically acceptable salts thereof.)

[0274] In some embodiments, the variable group of formula (II) is as disclosed elsewhere in this specification. For example, in some embodiments, the variable group of formula (II) is as disclosed elsewhere in this specification for formula (II), or as disclosed elsewhere in this specification for any other formula (e.g., formula (I)) having a variable group shared with that in formula (II). In some embodiments, r is an integer equal to 0 or 1. In some embodiments, A is selected from the group consisting of N, CH, or CH2. In some embodiments, X 3 X is optionally replaced. In some embodiments, X 3 If the compound includes one or more optional substitutions, the one or more optional substitutions may be independently selected from the group consisting of C1-C3 alkyl, halo, cyano, hydroxy, C1-C3 alkoxy, and 3-6 membered carbocyclyl compounds.

[0275] The compound of formula (II) is

[0276] [ka] It can be selected from the following.

[0277] Compound of formula (IIa) Some embodiments include quinazolinyl compounds having the structure of formula (II):

[0278] [ka] (or relating to stereoisomers, tautomers, or pharmaceutically acceptable salts thereof.)

[0279] In some embodiments, the variable group of formula (IIa) is as disclosed elsewhere in this specification. For example, in some embodiments, the variable group of formula (IIa) is as disclosed elsewhere in this specification for formula (IIa), or as disclosed elsewhere in this specification for any other formula having a variable group shared with that in formula (IIa). In some embodiments, X 7 is CH2 or a covalent bond. In some embodiments, R 7 is a C1-C6 alkyl or a 3-6 membered carbocyric. In some embodiments, R 8 A is selected from the group consisting of cyclohexyl, 5-6 member heteroaryls optionally substituted with methyl, or 5-7 member heterocyclines optionally substituted with fluoro, oxo, or C1-C6 alkyl groups. In some embodiments, A is selected from the group consisting of N, CH, or CH2. In some embodiments, n is an integer independently selected from 0, 1, and 2.

[0280] Further compounds In some embodiments, the compound

[0281] [ka] It is possible.

[0282] Some embodiments relate to pharmaceutical compositions comprising therapeutically effective amounts of the compounds described herein and pharmaceutically acceptable excipients.

[0283] Treatment method Some embodiments relate to treating a subject using the compounds or pharmaceutical compositions described herein. In some embodiments, the compounds are those of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ij), (Ik), (II), and (IIa).

[0284] In some embodiments, a method is provided for treating subjects having gastrointestinal and / or autoimmune disorders. In some embodiments, the method includes acquiring knowledge of the gastrointestinal and / or autoimmune disorder in the subject. In some embodiments, the method includes administering an effective amount of the compound disclosed herein to the subject (e.g., one having a gastrointestinal and / or autoimmune disorder).

[0285] Some embodiments relate to treatments for gastrointestinal and / or autoimmune disorders, which include administering the compounds or pharmaceutical compositions described herein to subjects in need thereof.

[0286] In some embodiments, autoimmune disorders are selected from the group consisting of inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, systemic lupus erythematosus, psoriasis, rheumatoid arthritis, type 1 diabetes, multiple sclerosis, celiac disease, graft-versus-host disease (GVHD), Sjögren's syndrome, Graves' disease, Hashimoto's thyroiditis, autoimmune hepatitis, Behçet's disease, atopic dermatitis, Castleman disease, allergic rhinitis, eczema, Dressler syndrome, eosinophilic esophagitis, fibromyalgia, Guillain-Barré syndrome, juvenile arthritis, Kawasaki disease, Mohren's ulcer, mixed connective tissue disease, Parry-Romberg syndrome, primary biliary cirrhosis, primary sclerosing cholangitis, psoriatic arthritis, sarcoidosis, scleroderma, undifferentiated connective tissue disease, uveitis, vasculitis, and vitiligo. In some embodiments, for a compound to have therapeutic potential in ulcerative colitis and Crohn's disease, it is important that it is effective in both inducing healing and suppressing inflammation. Surprisingly, in some embodiments, the compounds and compositions disclosed herein induce healing and / or suppress inflammation in the gastrointestinal tract (e.g., the small or large intestine). In some embodiments, the compound or composition reduces markers of inflammation, inflammatory bowel disease (IBD), ulcerative colitis, and / or Crohn's disease, comprising one or more of Ccl2, Ccl3, Ccl7, Ccl9, Csf3, Csf3r, Cxcl1, Cxcl2, Cxcl3, Cxcl5, Il1a, Il1b, Il1r2, Il11, Il13ra2, Il6, Mmp3, Osm, Osmr, Ptgs2, Stc1, and / or Tnfrsf11b.

[0287] Some embodiments relate to methods for treating G9a-mediated inflammation, comprising administering a compound or pharmaceutical composition disclosed herein to a patient in need of treatment. Some embodiments relate to methods for inhibiting the G9a protein, comprising administering a compound or pharmaceutical composition disclosed herein to a patient in need of treatment.

[0288] Some embodiments describe methods for reducing inflammation by lowering levels of pro-inflammatory cytokines (e.g., CXCL2, CXCL3, S100A8.9, IL6) and / or metalloproteinases (MMP3, MMP13), comprising administering the compounds or pharmaceutical compositions disclosed herein to a patient in need of treatment.

[0289] Some embodiments relate to treating gastrointestinal and / or autoimmune diseases (e.g., IBD, ulcerative colitis, Crohn's disease, etc.) and / or inflammation, as disclosed elsewhere in this specification. In some embodiments, the method involves administering to a patient a compound (e.g., an effective amount) or composition disclosed herein. In some embodiments, the compound induces the production and / or activity of T regulatory cells. In some embodiments, the compound has virtually no effect on IL17 protein levels.

[0290] In some embodiments, a method is provided for relieving and / or treating the destructive effects of combined exposure of intestinal epithelial cells to TNFα and / or IFNγ, comprising administering a compound or pharmaceutical composition disclosed herein to a patient in need of treatment. In some embodiments, a method is provided for reducing the level of electrical resistance in intestinal epithelial cells, comprising administering a compound or pharmaceutical composition disclosed herein to a patient in need of treatment. In some embodiments, a method is provided for reversing cytokine-induced barrier damage in the intestines (e.g., intestinal epithelial cells), comprising administering a compound or pharmaceutical composition disclosed herein to a patient in need of treatment.

[0291] Some embodiments relate to methods for improving intestinal health, comprising administering a compound or pharmaceutical composition disclosed herein to a patient in need of treatment. In some embodiments, the intestinal microbiome is improved (e.g., the intestinal tract, including the small or large intestine). In some embodiments, the levels of beneficial bacteria are increased and the levels of harmful bacteria are decreased. In some embodiments, administration of the compounds or pharmaceutical compositions disclosed herein results in a decrease in the Firmicutes phylum (e.g., Megasphaera massiliensis), an increase in the Bacteroidetes phylum (e.g., one or more of Bacteroides (B) caecimuris, B. sartorii, B. thetaiotaomicron, Duncanella muris, Bacteroides mediterraneensis, Prevotella copri), an increase in Proteobacteria (e.g., etc.), and an increase in the Verrucomicrobia phylum (e.g., Akkermansia muciniphila). In some embodiments, administration of the compounds or pharmaceutical compositions disclosed herein results in an increase in one or more of the phylum Firmicutes (e.g., Megasfera masiliensis). In some embodiments, compounds resulting in an increase in proteobacteria (e.g., Sutterella wadsworthensis) are predicted to be potential candidates. In some embodiments, administration of the compounds disclosed herein induces a greater abundance of bacteria associated with the anti-inflammatory effect.

[0292] In some embodiments, a method is provided to diagnose the potential of drug candidates that may be effective in treating inflammatory bowel disease (IBD), ulcerative colitis, and / or Crohn's disease. In some embodiments, the method includes testing a bacterial panel to predict the effectiveness of the drug candidate. In some embodiments, a drug that results in increased levels of beneficial bacteria and / or decreased levels of harmful bacteria is predicted to be a potential candidate for the treatment of IBD, ulcerative colitis, and / or Crohn's disease. In some embodiments, compounds that result in one or more of the following are predicted to be potential drug candidates: a decrease in Firmicutes (e.g., Megasfera masiliensis), an increase (e.g., enrichment) in Bacteroidetes (e.g., one or more of Bacteroides (B) cesimulis, Bee sultrii, Bee tethaiotaomicron, Duncaniera muris, Bacteroides mediteraneensis, Prevotella copri), an increase in Proteobacteria (e.g., Stellera waswotensis), and / or an increase in Vercomicrobium (e.g., Ackermansia muciniphila). In some embodiments, compounds that result in an increase in Firmicutes (e.g., Megasfera masiliensis) are predicted to be potential candidates. In some embodiments, a diagnostic test is provided in the kit. In some embodiments, the kit includes instructions for use. In some embodiments, the kit includes culture medium.

[0293] Some embodiments are CD4 +The present invention relates to a method for reducing infiltration of the lamina propria by T cells, neutrophils, and / or macrophages (and / or other pro-inflammatory cells), comprising administering a compound or pharmaceutical composition disclosed herein to a patient in need of treatment. Some embodiments relate to a method for reducing infiltration of the lamina propria by CD4+ T cells, neutrophils, and / or macrophages in a patient suffering from an inflammatory disease, comprising administering a compound or pharmaceutical composition disclosed herein to a patient in need of treatment. Some embodiments relate to an inflammatory disease such as IBD, Crohn's disease, or colitis. Some embodiments relate to a method for reducing and / or eliminating the severity of diarrhea, weight loss, and rectal prolapse associated with gastrointestinal disorders (e.g., Crohn's disease, IBD, etc.), comprising administering a compound or pharmaceutical composition disclosed herein to a patient in need of treatment.

[0294] In some embodiments, a method is provided for treating a subject having cancer. In some embodiments, the method includes obtaining knowledge of the presence of cancer in the subject. In some embodiments, the method includes administering an effective amount of the compound disclosed herein to the subject.

[0295] Some embodiments relate to methods for treating cancer, comprising administering a compound or a pharmaceutical composition described herein to a subject in need thereof.

[0296] In some embodiments, the cancer is selected from the group consisting of colorectal cancer (e.g., colon or rectum), gastric cancer (stomach), cancer of the esophagus, liver cancer, pancreatic cancer, breast cancer, prostate cancer, bladder cancer, kidney cancer, ovarian cancer, lung cancer, melanoma, and multiple myeloma. In some embodiments, the compound causes activation and / or upregulation of genes that have activity to induce a tumor-reducing response, including p53 signaling pathway genes (e.g., KEGG), HDAC histone deacetylate genes (e.g., REAC), and TF factor genes (e.g., p53 and / or p63). In some embodiments, the compound causes inhibition and / or downregulation of genes associated with increased cancer growth, including cell cycle genes (KEGG), DNA replication-related genes (KEGG), E2F-1 genes, and / or E2F-4 genes. In some embodiments, genes related to and / or downregulated by the compounds disclosed herein may include one or more of CCNE2, E2F2, CCNA2, BUB1, CDC25C, CDKN2C, CCNB2, ORC1, PLK1, CDC20, TTK, ESPL1, CDK1, BUB1B, CDC45, MAD2L1, E2F1, CCNB1, MCM5, CDC6, PKMYT1, ORC6, MCM6, MCM7, MCM2, MCM4, RBL1, CDC25A, SKP2, MCM3, CDC7, WEE1, PTTG1, CHEK2, DBF4, CHEK1, and / or SMC1A. In some embodiments, genes related to and / or downregulated by the compounds disclosed herein may include one or more of TP53I3, ZMAT3, SERPINE1, CDKN1A, MDM2, PMAIP1, RRM2B, FAS, SERPINB5, SESN2, GADD45A, SESN1, CD82, THBS1, and / or CCND1.

[0297] In some embodiments, the compounds disclosed herein showed a remarkable and / or beneficial improvement in efficacy and / or pharmaceutical properties. In some embodiments, the compounds disclosed herein showed an unexpected improvement in permeability as measured using the PAMPA test. In some embodiments, the compounds disclosed herein showed an improvement of approximately 1 × 10⁻⁶ -8 The above is approximately 2.5 x 10 -8 The above is approximately 5 x 10 -8 The above is approximately 7.5 x 10 -8 In summary, approximately 1 x 10 -7 The above is approximately 5 x 10 -7 In summary, approximately 1 x 10 -6 The above is approximately 5 x 10 -6 In summary, approximately 1 x 10 -5 Transparency (P) of the above or the range including and / or spanning the aforementioned values. e ) has.

[0298] In some embodiments, the half-life of the compounds disclosed herein in a subject is at least about 45 minutes or equal to, at least about 55 minutes or equal to, at least about 60 minutes or equal to, at least about 2 hours or equal to, at least about 3 hours or equal to, at least about 5 hours or equal to, or a range including and / or spanning the aforementioned values.

[0299] In some embodiments, cytochrome P450 inhibition is low for patients requiring treatment with respect to the compounds or pharmaceutical compositions disclosed herein.

[0300] Administration and pharmaceutical composition In some embodiments, the compound is administered in therapeutically effective doses. In some embodiments, the daily dose can generally be approximately 0.25 mg / kg to approximately 120 mg / kg or more in body weight, approximately 0.5 mg / kg or less to approximately 70 mg / kg, approximately 1.0 mg / kg to approximately 50 mg / kg, or approximately 1.5 mg / kg to approximately 10 mg / kg. Therefore, for administration to a 70 kg person, the dose range would be approximately 17 mg / day to approximately 8000 mg / day, approximately 35 mg / day or less to approximately 7000 mg / day or more, approximately 70 mg / day to approximately 6000 mg / day, approximately 100 mg / day to approximately 5000 mg / day, or approximately 200 mg to approximately 3000 mg / day. The amount of the active compound administered depends, of course, on the subject and condition being treated, the severity of the disease, the mode and schedule of administration, and the judgment of the prescribing physician.

[0301] The compounds disclosed herein or pharmaceutically acceptable salts thereof may be administered via any of the accepted modes of administration for agents serving a similar utility, but are not limited to, oral, subcutaneous, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, intrapulmonary, transvaginal, rectal, or intraocular methods. Oral and parenteral administration are customary in the treatment of indications that are the subject of preferred embodiments.

[0302] As described above, useful compounds can be formulated into pharmaceutical compositions for use in the treatment of these conditions. Standard formulation techniques are used, such as those disclosed in Remington's The Science and Practice of Pharmacy, 21st edition, Lippincott Williams & Wilkins (2005), which is incorporated in its entirety by reference. Accordingly, some embodiments include pharmaceutical compositions comprising (a) a safe and therapeutically effective amount of a compound described herein (including its enantiomers, diastereoisomers, tautomers, polymorphs, and solvates), or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable carrier, diluent, excipient, or combination thereof.

[0303] In addition to the useful selected compounds described above, some embodiments include compositions containing pharmaceutically acceptable carriers. The terms “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” include any and all solvents, dispersions, coatings, antibacterial and antifungal agents, isotonic agents and absorption retarders, etc. The use of such media and agents for pharmaceutically active substances is well known in the art. Unless any conventional media or agent is incompatible with the active ingredient, its use in therapeutic compositions is intended. Furthermore, various adjuvants, such as those commonly used in the art, may be included. Considerations regarding the inclusion of various components in pharmaceutical compositions are, for example, described in Gilman et al. (eds.) (1990), Goodman and Gilman, The Pharmacological Basis of Therapeutics, 8th edition, Pergamon Press, which is incorporated entirely herein by reference.

[0304] Some examples of substances that can serve as pharmaceutically acceptable carriers or components include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and methylcellulose; solid lubricants such as tragacanth powder, malt, gelatin, talc, stearic acid, and magnesium stearate; vegetable oils such as calcium sulfate, peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and cocoa oil; polyols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; emulsifiers such as alginic acid and TWEEN®; humectants such as sodium lauryl sulfate; colorants, flavorings, tableting agents, stabilizers, antioxidants, preservatives, water free of pyrogens, isotonic saline, and phosphate buffer solutions.

[0305] The choice of pharmaceutically acceptable carrier to be used in conjunction with the target compound is basically determined by the method of administering the compound.

[0306] The compositions described herein are preferably provided in unit dosage forms. As used herein, “unit dosage form” refers to a composition containing an amount of the compound suitable for administration in a single dose to an animal, preferably a mammal, subject to good medical practice. However, the preparation of a single or unit dosage form does not imply that the dosage form is to be administered once daily or once during the course of treatment. Such dosage forms may be intended to be administered once, twice, three times, or more times daily, and may be administered as an infusion over a period of time (e.g., about 30 minutes to about 2-6 hours) or as a continuous infusion, and may be given multiple times during the course of treatment, but single doses are not specifically excluded. Those skilled in the art will understand that the formulation is not specifically intended for the entire course of treatment, and such determination is left to the technician of the treatment field rather than to the formulation.

[0307] As described above, useful compositions can be any of a variety of suitable forms for various routes of administration, for example, oral, nasal, rectal, topical (including percutaneous), ocular, intracerebral, intracranial, subarachnoid, intra-arterial, intravenous, intramuscular, or other parental routes of administration. Those skilled in the art will understand that oral and nasal compositions include compositions administered by inhalation and are prepared using available methods. Depending on the desired specific route of administration, a variety of pharmaceutically acceptable carriers known in the art may be used. Examples of pharmaceutically acceptable carriers include solid or liquid fillers, diluents, hydrotropes, surfactants, and encapsulating materials. They may include any selected pharmaceutically active material that does not substantially interfere with the inhibitory activity of the compound. The amount of carrier used in conjunction with the compound is sufficient to provide a practical amount of material for administration per unit dose of the compound. The techniques and compositions for producing useful dosage forms in the methods described herein are described in the following references, all of which are incorporated herein by reference: Modern Pharmaceutics, 4th edition, Chapters 9 and 10 (Banker & Rhodes, eds., 2002); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1989); and Ansel, Introduction to Pharmaceutical Dosage Forms, 8th edition (2004).

[0308] Various oral dosage forms are available, including solid forms such as tablets, capsules, granules, and bulk powders. Tablets may be compressed, powder tablets, enteric coated, sugar coated, film coated, or multi-compressed, containing suitable binders, lubricants, diluents, disintegrants, colorants, flavorings, flow inducers, and melting agents. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions, and / or suspensions restored from non-foaming granules, as well as effervescent formulations restored from effervescent granules, containing suitable solvents, preservatives, emulsifiers, suspending agents, diluents, sweeteners, melting agents, colorants, and flavorings.

[0309] In some embodiments, the oral formulation contains dimethylacetamide (DMA). In some embodiments, the oral formulation contains DMA in an amount (wt%) of about 1% or less, about 5% or less, about 7.5% or less, about 10% or less, about 15% or less, or including and / or spanning the aforementioned values. In some embodiments, the oral formulation contains propylene glycol (PG). In some embodiments, the oral formulation contains PG in an amount (wt%) of about 10% or less, about 20% or less, about 25% or less, about 30% or less, about 35% or less, or including and / or spanning the aforementioned values. In some embodiments, the oral formulation contains polyethylene glycol (PEG). In some embodiments, the oral formulation contains PEG in an amount (wt%) of about 15% or less, about 25% or less, about 30% or less, about 35% or less, about 40% or less, or including and / or spanning the aforementioned values. In some embodiments, the oral formulation contains water. In some embodiments, the oral formulation contains water in an amount (wt%) of about 15% or less, about 25% or less, about 30% or less, about 35% or less, about 40% or less, or including and / or spanning the aforementioned values.

[0310] Pharmaceutically acceptable carriers suitable for the preparation of unit dosage forms for oral administration are well known in the art. Tablets typically contain conventional pharmaceutically acceptable adjuvants such as inert diluents such as calcium carbonate, sodium carbonate, mannitol, lactose, and cellulose; binders such as starch, gelatin, and sucrose; disintegrants such as starch, alginic acid, and croscarmelose; and lubricants such as magnesium stearate, stearic acid, and talc. Flow enhancers such as silicon dioxide can be used to improve the flow characteristics of powder mixtures. Colorants such as FD&C dyes can be added for appearance. Sweeteners and flavorings such as aspartame, saccharin, menthol, peppermint, and fruit flavors are useful adjuvants for chewable tablets. Capsules typically contain one or more of the solid diluents disclosed above. The selection of carrier components depends on secondary considerations such as taste, cost, and storability, which are not critical and can be easily performed by those skilled in the art.

[0311] Oral compositions include solutions, emulsifiers, and suspensions. Pharmaceutically acceptable carriers suitable for the preparation of such compositions are well known in the art. Typical components of carriers for syrups, elixirs, emulsifiers, and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol, and water. Typical suspensions include methylcellulose, sodium carboxymethylcellulose, AVICEL RC-591, tragacanth, and sodium alginate; typical humectants include lecithin and polysorbate 80; and typical preservatives include methylparaben and sodium benzoate. Oral liquid compositions may also contain one or more components such as the sweeteners, flavorings, and colorants disclosed above.

[0312] Furthermore, such compositions may be coated by conventional methods, typically using pH or time-dependent coatings, so that the target compound is released in the gastrointestinal tract near the desired topical application, or at various time points to extend the desired effect. Typical, but not limited to, such dosage forms include one or more of cellulose phthalate acetate, polyvinyl phthalate acetate, hydroxypropyl methylcellulose phthalate, ethylcellulose, Eudragit coatings, waxes, and shellac.

[0313] The compositions described herein may optionally contain other pharmacoactive substances (e.g., active pharmaceuticals). In some embodiments, the compositions may contain one or more quinazolinyl compounds disclosed elsewhere in this specification.

[0314] Other compositions useful for achieving systemic delivery of the target compound include sublingual, buccal, and nasal dosage forms. Such compositions typically contain soluble filler substances such as sucrose, sorbitol, and mannitol, as well as one or more binders such as acacia, microcrystalline cellulose, carboxymethylcellulose, and hydroxypropylmethylcellulose. They may also contain the flow enhancers, lubricants, sweeteners, colorants, antioxidants, and flavorings disclosed above.

[0315] Liquid compositions formulated for topical ophthalmic use are formulated for topical administration to the eye. Comfort should be maximized, but sometimes a level of comfort may be required that does not meet optimal formulation considerations (e.g., drug stability). If maximum comfort cannot be achieved, the liquid formulation should be formulated to be tolerable to the patient. Furthermore, ophthalmally acceptable liquid formulations should either be packaged for single use or contain preservatives to prevent contamination over multiple uses.

[0316] In ophthalmic applications, solutions or pharmaceuticals are often prepared using physiological saline as the primary vehicle. Ophthalmic solutions should preferably be maintained at a comfortable pH using an appropriate buffering system. These formulations may also contain conventionally pharmaceutically acceptable preservatives, stabilizers, and surfactants.

[0317] Preservatives that may be used in the pharmaceutical compositions disclosed herein include, but are not limited to, benzalkonium chloride, PHMB, chlorobutanol, thimerosal, phenylmercury acetate, and phenylmercury nitrate. A useful surfactant is, for example, Tween 80. Similarly, various useful vehicles may be used in the ophthalmic preparations disclosed herein. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methylcellulose, poloxamer, carboxymethylcellulose, hydroxyethylcellulose, and purified water.

[0318] Isotonic modifiers may be added as needed or for convenience. These include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol, and glycerin, or any other suitable ophthalmologically acceptable isotonic modifier.

[0319] Various buffers and means can be used to adjust the pH, provided that the resulting preparation is ophthalmologically acceptable. In many compositions, the pH is between 4 and 9. Therefore, buffers include acetic acid buffers, citrate buffers, phosphate buffers, and borate buffers. Acids or bases may be used to adjust the pH of these formulations as needed.

[0320] In a similar context, ophthalmologically acceptable antioxidants include, but are not limited to, sodium bisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, and butylated hydroxytoluene.

[0321] Other excipient components that may be included in ophthalmic formulations are chelating agents. A useful chelating agent is disodium edetate, but other chelating agents may be used instead or in combination with it.

[0322] For topical use, creams, ointments, gels, solutions, or suspensions containing the compounds disclosed herein are used. Topical formulations generally consist of a pharmaceutical carrier, a co-solvent, an emulsifier, a penetration enhancer, a preservative system, and a softening agent.

[0323] For intravenous administration, the compounds and compositions described herein may be dissolved or dispersed in a pharmaceutically acceptable diluent such as physiological saline or dextrose solution. Appropriate excipients may be included to achieve the desired pH, but are not limited to, NaOH, sodium carbonate, sodium acetate, HCl, and citric acid. In various embodiments, the pH of the final composition is in the range of 2 to 8, or preferably 4 to 7. Antioxidant excipients may include sodium bisulfite, acetone bisulfite, sodium formaldehyde sulfoxylate, thiourea, and EDTA. Other non-limiting examples of suitable excipients found in the final intravenous composition may include sodium or potassium phosphate, citric acid, tartaric acid, gelatin, and carbohydrates such as dextrose, mannitol, and dextran. Further acceptable excipients are described in Powell et al., *Compendium of Excipients for Parenteral Formulations*, PDA J Pharm Sci and Tech, 1998, pp. 52 238–311, and Nema et al., *Excipients and Their Role in Approved Injectable Products: Current Usage and Future Directions*, PDA J Pharm Sci and Tech, 2011, pp. 65 287–332, both of which are incorporated herein by reference in their entirety. Bacteriostatic or fungal solutions may also be achieved by including, but are not limited to, antimicrobial agents including phenylmercury nitrate, thimerosal, benzethonium chloride, benzalkonium chloride, phenol, cresol, and chlorobutanol.

[0324] Compositions for intravenous administration may be provided to the caregiver in one more solid form, which is restored immediately before administration with sterile water, saline solution, or a suitable diluent such as dextrose in water. In other embodiments, the composition is provided as a solution ready for parenteral administration. In yet another embodiment, the composition is provided as a solution to be further diluted before administration. In embodiments involving the administration of a combination of a compound described herein with another drug, the combination may be provided to the caregiver as a mixture, or the caregiver may mix the two drugs before administration, or the two drugs may be administered separately.

[0325] The actual doses of the active compounds described herein depend on the specific compound and the condition being treated, and the selection of an appropriate dose is well within the knowledge of those skilled in the art.

[0326] The compounds and compositions described herein may be presented in packs or dispenser devices containing, if desired, one or more unit dosage forms containing the active ingredients. Such packs or devices may include, for example, metal or plastic foil such as blister packs, or glass and rubber stoppers such as those in vials. Dosage instructions may be attached to the packs or dispenser devices. The compounds and compositions described herein may be compounded in suitable pharmaceutically acceptable carriers, and may also be prepared, placed in appropriate containers, and labeled for use in the indicated conditions.

[0327] The amount of compound in a formulation can vary within the range used by those skilled in the art. Typically, a formulation contains about 0.01 to 99.99 wt% of the compound of this art based on weight percent (wt%) of the total formulation, with the balance being one or more suitable pharmaceutically acceptable excipients. Preferably, the compound is present at a level of about 1 to 80 wt%. Representative pharmaceutically acceptable formulations are listed below.

[0328] The compounds and compositions described herein may be administered orally, intraperitoneally (ip), intravenously (iv), and by enema.

[0329] The pharmaceutical compositions described herein may take the form of solutions, suspensions, emulsifiers, tablets, pills, capsules, powders, patches, gels, creams, ointments, and sustained-release formulations. The pharmaceutical compositions described herein may further include, but are not limited to, pharmaceutically acceptable excipients, including humectants, emulsifiers, and pH adjusters.

[0330] In some embodiments, intravenous formulations of the compounds described herein include water, physiological saline, dextrose aqueous solution, and glycerol solution as carriers.

[0331] In some embodiments, the parenteral formulations of the compounds described herein may be suspensions prepared as oily or aqueous injection suspensions. The oily suspension injection may use a suitable lipophilic solvent or vehicle, such as fatty oils like sesame oil, or esters like synthetic fatty acids, ethyl oleate, triglycerides, or liposomes.

[0332] In some embodiments, transmucosal or transdermal formulations may use a permeable barrier suitable for penetration (such as PEG).

[0333] In some embodiments, oral formulations of the compounds described herein can be readily formulated by combining the active compound with pharmaceutically acceptable carriers and excipients. Such carriers enable the formulation of the compounds of this disclosure for oral administration by subjects, such as tablets, pills, capsules, liquids, gels, syrups, slurries, suspensions, etc. Pharmacological preparations for oral use may be prepared using solid excipients, with the addition of appropriate adjuvants if desired, and the resulting mixture optionally ground to process the granular mixture to obtain tablets. Suitable excipients include, in particular, sugars containing lactose, sucrose, mannitol, or sorbitol, cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, methylcellulose, hydroxypropyl methylcellulose, and sodium carboxymethylcellulose, and other fillers.

[0334] In some embodiments, enteric coatings can be used to prevent exposure of the compounds of this disclosure to the gastric environment.

[0335] In some embodiments, pharmaceutical compositions of the compounds described herein that can be used orally include push-fit capsules made from gelatin and soft, sealed capsules made from gelatin and a plasticizer such as glycerol or sorbitol. Push-fit capsules may contain the active ingredient mixed with a filler such as lactose, a binder such as starch, a lubricant such as talc or magnesium stearate, and optionally a stabilizer.

[0336] Some embodiments include compounds described herein encapsulated in soft capsules, which may dissolve or suspend the active compound in a suitable liquid such as fatty oil, liquid paraffin, or liquid polyethylene glycol. Further stabilizers may be added.

[0337] In some embodiments, the dosage of the composition to be administered will depend on several factors, including the subject being treated, the stage of the autoimmune disease, the route of administration, and the judgment of the prescribing clinician.

[0338] Intermediates and preparation methods for synthesizing quinazolinyl compounds Some embodiments relate to methods for producing quinazolinyl compounds and intermediates for producing quinazolinyl compounds.

[0339] In some embodiments, quinazolinyl compounds can generally be prepared by two consecutive substitutional synthesis reactions (e.g., halogen substitution reactions). The first substitution is provided in the following reaction scheme (where the intermediate has the structure shown in formula (IIIa) or (IIIb):

[0340] [ka] [In the formula, G a is a substituteable group such as a halogen (e.g., Cl), G b [The variable group may be a substituteable group such as a halogen (e.g., Cl), and the rest of the variable group may be as provided elsewhere in this specification.] In some embodiments, the condition is an amine (e.g., HN(X) 2 )X 1 X 3 The invention includes providing ). In some embodiments, reaction (i) is carried out under basic conditions (for example, in the presence of an organic base such as diisopropylethylamine (DIPEA) or triethylamine (TEA)). In some embodiments, reaction (i) is carried out in the presence of NaH. In some embodiments, reaction (i) is carried out at room temperature. In some embodiments, reaction (i) is carried out at high temperatures. In some embodiments, reaction (i) is carried out at temperatures of about 20°C or higher, about 30°C or higher, about 40°C or higher, about 50°C or higher, about 60°C or higher, about 70°C or higher, about 80°C or higher, or in a range including or spanning the aforementioned values. In some embodiments, HN(X 2 )X 1 X 3 The base is present in stoichiometric equivalence or excess (1–5 equivalents). In some embodiments, the base is present in stoichiometric equivalence or excess (1–10 equivalents). In some embodiments, a polar solvent (e.g., DMF, THF, MeOH, EtOH, iPrOH, 2-BuOH, or a combination thereof) is used.

[0341] In some embodiments, a second substitution is provided in the following reaction scheme. The intermediate has the structure shown in formula (IIIa) below:

[0342] [ka] It may have [wherein the formula the variable group is as provided elsewhere in this specification]. In some embodiments, the condition is HX 4This includes providing the following. In some embodiments, reaction (ii) is carried out under basic conditions (e.g., in the presence of an organic base such as DIPEA or TEA). In some embodiments, reaction (ii) is carried out in the presence of NaH. In some embodiments, reaction (ii) is carried out at room temperature. In some embodiments, reaction (ii) is carried out at high temperatures. In some embodiments, reaction (i) is carried out at temperatures of about 20°C or higher, about 30°C or higher, about 40°C or higher, about 50°C or higher, about 60°C or higher, about 70°C or higher, about 80°C or higher, about 100°C or higher, about 120°C or higher, about 140°C or higher, or a range including or spanning the aforementioned values. In some embodiments, HX 4 The base is present in stoichiometric equivalents or in excess (1 to 20 equivalents). In some embodiments, the base is present in stoichiometric equivalents or in excess (1 to 10 equivalents). In some embodiments, a polar solvent (e.g., DMF, THF, MeOH, EtOH, iPrOH, 2-BuOH, or a combination thereof) is used. Alternatively, reaction (ii) may be carried out at high temperatures (e.g., 20°C, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 100°C, 120°C, 140°C, or a range including or spanning the aforementioned values) in the presence of K2CO3 or Cs2CO3 (2 to 3 equivalents), BINAP or xanthophos (0.1 to 0.4 equivalents), and Pd(OAc)2 or Pd(PPh3)4 (0.1 to 0.25 equivalents).

[0343] [ka] [In the formula, G c [ is an alcohol protecting group (such as an OBz group), and the remaining variable groups are as provided elsewhere in this specification.] In some embodiments, the structure of formula (IIId) is the following structure:

[0344] [ka] That is the case.

[0345] In some embodiments, the compound of formula (IIIe) is deprotected using deprotection conditions (such as hydrogenation conditions) (as shown in formula (IIIf)) to expose the hydroxyl group at position 7 of the quinazolinyl ring. In some embodiments, deprotection is carried out using a metal catalyst (e.g., Pd / c) in the presence of hydrogen and a solvent (e.g., MeOH, EtOH, THF, or dioxane). In some embodiments, the reaction is carried out at room temperature. In some embodiments, the structure of formula (IIIe) is as follows:

[0346] [ka] That is the case.

[0347] In some embodiments, the hydroxyl group is converted to a leaving group, as shown in the following scheme. In some embodiments, the leaving group (OLg) is converted to a triflate (OTf - ), Toshilate (OTs - ), Mesylate (OMs - ) and so on.

[0348] [ka] [In the formula, the variable group is as provided elsewhere herein (and OLg is OTf, OTs, OMs, etc.)]. In some embodiments, reaction (iv) is carried out at room temperature in the presence of N-phenylbissulfonamide (e.g., PhN(Tf)2), a base (e.g., K2CO3), and a solvent (e.g., THF). In some embodiments, the leaving group is removed in reaction (v) in the presence of H-R4 (1-3 equivalents), a metal catalyst (e.g., Pd(PPh3)Cl2 (0.1-0.25 equivalents), CuI (1-2 equivalents), Cs2CO3), and a solvent (e.g., MeCN). Alternatively, the leaving group is removed in reaction (v) in the presence of a solvent (e.g., THF) in the presence of a boronic acid, H-R4 (1-3 equivalents), a metal catalyst (e.g., Pd(PPh3)4 (0.1-0.25 equivalents)), and CsF2, LiCl, and CuI. In some embodiments, reaction (v) is carried out at a temperature of about 50°C or higher, about 60°C or higher, about 70°C or higher, about 80°C or higher, about 100°C or higher, or a range including or spanning the aforementioned values.

[0349] [ka]

[0350] X 4 To prepare compounds in which the nitrile is used, 1,4-diazabicyclo[2.2.2]octane (DABCO) may be used in the presence of NaCN and a solvent (e.g., DMSO). In some embodiments, reaction (ii) is carried out at a temperature of about 50°C or higher, about 60°C or higher, about 70°C or higher, about 80°C or higher, about 100°C or higher, or a range including or spanning the aforementioned values.

[0351] As will be readily apparent to those skilled in the art, in some embodiments, intermediate compounds are provided, such as those of formulas (IIIa), (IIIb), (IIIc), (IIId), (IIIf), and (IIIg). In some embodiments, the intermediate compound is of the following formula (IIIg):

[0352] [ka] [wherein -OLg is -OTf]. In some embodiments, the structure of formula (IIIg) is

[0353] [ka] It is represented by [this].

[0354] The compounds disclosed herein may be synthesized by the methods described below or by modifications thereof. Modifications to these methods include, among others, temperatures, solvents, reagents, etc., as are known to those skilled in the art. Generally, during any of the processes for preparing the compounds disclosed herein, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules involved. This can be achieved by conventional protecting groups, such as those described in Protective Groups in Organic Chemistry (JFWMcOmie, Plenum Press, 1973), both of which are incorporated herein in their entirety by reference, and in Protecting Groups in Organic Synthesis (3rd edition), Wiley, New York (1999), PGMGreen, TWWutts. Protecting groups may be removed at a convenient subsequent step using methods known in the art. Useful synthetic chemical transformations in the synthesis of applicable compounds are known in the art, for example, those described in R. Larock, *Comprehensive Organic Transformations*, VCH Publishers, 1989, or L. Paquette (ed.), *Encyclopedia of Reagents for Organic Synthesis*, John Wiley and Sons, 1995, both of which are incorporated herein in their entirety by reference. The routes shown and described herein are illustrative only and are not intended to, or should be construed to, limit the claims in any way. Those skilled in the art will be able to understand modifications of the disclosed synthesis and devise alternative routes based on the disclosure herein. All such modifications and alternative routes are within the scope of the claims.

[0355] If a compound in this art contains one or more chiral centers, such a compound can be prepared or isolated as a pure stereoisomer, i.e., as individual enantiomers, or as a d(l) stereoisomer, or as a stereoisomer-rich mixture. Unless otherwise specified, all such stereoisomers (and stereoisomer-rich mixtures) are included within the scope of this art. Pure stereoisomers (or stereoisomer-rich mixtures) can be prepared, for example, using optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be separated, for example, using chiral column chromatography, chiral resolving agents, etc.

[0356] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce, or Sigma (St. Louis, Missouri, USA). Others can be prepared by procedures described in standard reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplement (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March's Advanced Organic Chemistry (John Wiley, and Sons, 5th edition, 2001), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), or by obvious modifications thereof.

[0357] It will be apparent to those skilled in the art that methods for preparing precursors and functional groups related to the claimed compounds in this invention are generally described in the literature. These reactions may also utilize variants that are known to those skilled in the art but not described in more detail. Those skilled in the art will have sufficient knowledge, in view of the literature and this disclosure, to prepare any of the compounds.

[0358] It will be understood that the operations can be easily performed by technicians in the field of organic chemistry without further instructions; that is, these operations are well within the realm and skill of those skilled in the art. These operations include the reduction, oxidation, acylation, aromatic substitution (both electrophilic and nucleophilic), etherification, esterification, and saponification of carbonyl compounds to their corresponding alcohols. These operations are described in standard texts such as March Advanced Organic Chemistry (Wiley), Carey and Sundberg, and Advanced Organic Chemistry (which is incorporated herein by reference in its entirety). Unless otherwise specified, all intermediate compounds in this disclosure were used without further purification.

[0359] Those skilled in the art will readily understand that it is best to carry out certain reactions by shielding or protecting other functional groups within the molecule, thereby avoiding any undesirable side reactions and / or increasing the reaction yield. To achieve such yield increases or to avoid undesirable reactions, those skilled in the art often utilize protecting groups. These reactions can be found in the literature and are well within the scope of those skilled in the art. Many examples of these operations can be found, for example, in T. Greene and P. Wuts, Protecting Groups in Organic Synthesis, 4th edition, John Wiley & Sons (2007), which is incorporated in its entirety herein by reference.

[0360] The trademarks used herein are illustrative only and reflect the exemplary materials used at the time of this disclosure. Those skilled in the art will understand that variations in lot, manufacturing process, etc., are to be expected. Accordingly, the examples and the trademarks used therein are not limiting and are not intended to be restrictive, but merely examples of how those skilled in the art may choose to carry out one or more of the embodiments of this disclosure. [Examples]

[0361] The following embodiments are provided for illustrative purposes to illustrate various embodiments of the Disclosure and are not intended to limit the Disclosure in any way. Those skilled in the art will readily understand that the Disclosure is well-suited to perform its purpose and to achieve the mentioned subject matter and benefits, as well as those purposes, subject matter and benefits specific to this Spec. Modifications and other uses of the Disclosure that are included within the scope of the claims will be readily apparent to those skilled in the art.

[0362] General procedure The following abbreviations have the meanings indicated.

[0363] [Table 1]

[0364] Some compounds of the formulas disclosed herein (e.g., formula (I)) were prepared as described below. All reactions were carried out under an argon atmosphere. Reagents and solvents were used from commercially available sources without further purification. Hydrogenation reactions were performed under balloon conditions. Microwave reactions were performed using a CEM Discover SP microwave synthesizer. Sample purification was performed using a Buchi Pureflash with an ELSD purification system, using pre-packed commercial silica gel columns. Thin-layer chromatography (TLC) was performed on aluminum plates using Merck Kiesegel 60 F254 (230-400 mesh) fluorescently treated sil, visualized under ultraviolet light (254 nm), or stained with potassium permanganate or ninhydrin solution as appropriate. All nuclear magnetic resonance (NMR) spectra were acquired using a Bruker Avance III HD 400 MHz NMR spectrometer, and chemical shifts are reported in ppm(δ). HPLC / MS was performed using a Sciex 5500 Qtrap mass spectrometry system connected to a Shidmazu Nexera X2 UHPLC system with a Phenomenex Luna C18 column (50 × 2.0 mm, 3 μm particle size), following the procedure below. Mobile phase A contained 0.1% formic acid in water, and mobile phase B contained 0.1% formic acid in acetonitrile. The flow rate was 0.4 mL / min, the column temperature was 35°C, and the autosampler temperature was maintained at 4°C. The ion spray voltage, dry gas temperature, ion source gas 1, and ion source gas 2 settings were 4500V, 500°C, 35V, and 45V, and ESI was set to positive mode using full scan. The purity of all compounds was analyzed using an Agilent 1260 Infinity II Lab LC Series HPLC (1260 Quat pump, 1260 vial autosampler, ICC column oven, 1260 DAD WR detector).The sample was injected into a Phenomenex Synergi Polar RP column (150 × 4.6 mm, 4 μm, 80 Å). The gradient mobile phase (A: water containing 0.1% trifluoroacetic acid, B: acetonitrile containing 0.1% trifluoroacetic acid; A / B (99:1) from 0 min; A / B (1:99) from 0 to 15 min; A / B (1:99) from 15 to 18 min; A / B (99:1) from 18 to 18.1 min; A / B (99:1) from 18.1 to 20 min)) was pumped at a flow rate of 1 mL / min. The UV detector was set to 254 nm and the column oven was set to 35°C. Unless otherwise specified, the injection volume was 10 μL. All compounds evaluated in biological assays had a purity of ≥90%, and in animal studies, a purity of ≥95%.

[0365] pH solubility Saturated solutions of the selected compounds were prepared at pH 1, 4, 6.5, and 7.4. The selected pH conditions are within the extreme values ​​of the normal physiological pH of the human gastrointestinal tract. Solubility tests of the drugs under different pH conditions were performed by adding an excess amount of the drug to each pH condition, starting with 1 mg / mL, and then saturating the solution by visual observation of the undissolved material. The saturated solutions were continuously shaken at 6,000 rpm for 24 hours at room temperature. The saturated solutions were filtered through a Millipore 0.22 μm PVDF hydrophilic filter and subjected to HPLC to evaluate the solubility of the test compounds. The filtered saturated solutions were diluted with acetonitrile:water (50:50) in a calibration standard curve. The calibration curve for the test compounds contained seven (7) standards with concentrations of 0.25, 0.5, 1.0, 5.0, 10, 25, 50, and 100 μg / mL prepared in acetonitrile:water (50:50).

[0366] The compounds were measured in filtered saturated solutions using an Agilent 1260 Infinity II Lab LC Series HPLC (1260 quat pump, 1260 vial autosampler, ICC column oven, 1260 DAD WR detector). Chromatographic separation was achieved using a Phenomenex Synergi Polar RP column (150 × 4.6 mm, 4 μm, 80 Å). The mobile phase was pumped at a flow rate of 1 mL / min with a gradient (A: water containing 0.1% trifluoroacetic acid, B: acetonitrile containing 0.1% trifluoroacetic acid; A / B (99:1) from 0 min; A / B (1:99) from 0 to 10 min; A / B (1:99) from 10 to 12 min; A / B (99:1) from 12 to 12.1 min; A / B (99:1) from 12.1 to 13 min). Elution detection was monitored at 254 nm. The column oven was set to 35°C. Unless otherwise specified, the injection volume was 10 μL. Data acquisition and peak integration were performed using OpenLAB CDS version 2.4 (Agilent) running on Windows (Microsoft).

[0367] Formulation stability A 5 mg / mL test compound was formulated with 10% dimethylacetamide (DMA), 30% propylene glycol, 35% PEG-300, and 25% water (H2O). The formulation solution was stored at 4°C and 25°C. Samples were collected at the following time points: days 1, 3, 5, 7, 10, and 14. Before preparing samples for physical stability analysis, the samples collected at each time point were examined by visual observation of their physical condition (texture and color). For chemical stability, the samples were diluted 1:250 with acetonitrile (ACN) for potency analysis and then diluted to a 100 ug / mL final solution for impurity profiling. Samples were prepared in triplicates for potency analysis. The samples were then injected into an HPLC to determine the concentration of the test compound and its impurity profile. An Agilent 1260 Infinity II Lab LC Series HPLC system, including a 1260 Quat pump, 1260 vial autosampler, ICC column oven, and 1260 DAD WR detector, was used. Chromatographic separation was achieved using a Phenomenex Synergi Polar RP column (150 × 4.6 mm, 4 μm, 80 Å). The flow rate was 1 mL / min, and detection was set to 254 nm. Unless otherwise specified, the injection volume was 10 μL. The mobile phase consisted of A, water containing 0.1% trifluoroacetic acid, and B, acetonitrile containing 0.1% trifluoroacetic acid. For the potency analysis, the gradient was A / B(99:1) from 0 min; A / B(1:99) from 0 to 10 min; A / B(1:99) from 10 to 12 min; A / B(99:1) from 12 to 12.1 min; and A / B(99:1) from 12.1 to 13 min. For the impurity profile, the gradient was A / B(99:1) from 0 min; A / B(1:99) from 0 to 15 min; A / B(1:99) from 15 to 18 min; A / B(99:1) from 18 to 18.1 min; and A / B(99:1) from 18.1 to 20 min. Data acquisition and peak integration were performed using OpenLAB CDS version 2.4 (Agilent) running on Windows (Microsoft).

[0368] Microsomal stability For each species tested (human, rat, mouse), a working concentration of 2 μg / mL was prepared from a 0.5 mg / mL DMSO stock solution of each test substance by adding 3 μL of 0.5 mg / mL test substance stock solution to 747 μL of 1 mg / mL liver matrix in the liver matrix. Incubation was performed at 37 ± 2°C in a 2.0 mL well-capacity 96-deep-well plate (96-DWP) by gentle, continuous mixing in a shaking water bath. Samples were collected in double batches at the following time points: 0, 5, 10, 15, 30, and 60 minutes. The final mixture contained 1 μg / mL of the drug and 0.5 mg / mL of the liver matrix. First, the test substance in 50 μL of liver matrix was added to the 96-DWP, and the mixture was preheated in the 96-DWP in a 37°C water bath for 2 minutes. The enzymatic reaction was initiated by adding 50 μL of the corresponding 2×NADPH regeneration system (NRS) cofactor solution to all sample wells and stopped by adding 300 μL of stop solution (acetonitrile containing 10 ng / mL tolbutamide as an internal standard (I.Std.)). The samples were stirred for 10 minutes and then centrifuged at 4500 rpm for 20 minutes. 25 μL of the supernatant was diluted to fresh 96-DWP for LC-MS / MS analysis with 475 μL of acetonitrile containing I.Std.

[0369] All samples were analyzed using an electrospray ionization (ESI) liquid chromatography / mass spectrometry (LC / MS) system with Shidmazu Nexera X2 UHPLC and Sciex 5500 quadrupole ion trap (Qtrap) mass spectrometry. The LC-MS / MS instrument monitored each of the test compounds under study based on their respective mass-to-charge ratio (m / z) transitions and MS parameters. Chromatographic separation was achieved using gradient elution on a Phenomenex Luna C18 column (50 × 2.0 mm, 3 μm particle size). Mobile phase A contained 0.1% formic acid in water, and mobile phase B contained 0.1% formic acid in acetonitrile; A / B (99:1) for 0-1 min; A / B (1:99) for 1-4 min; A / B (1:99) for 4-8 min; A / B (99:1) for 8-8.20 min; and A / B (99:1) for 8.2-9 min. The flow rate was 0.4 mL / min, the column temperature was 35°C, and the autosampler temperature was maintained at 4°C. For detection, electrospray ionization was operated in positive mode using multiple reaction monitoring (MRM).

[0370] Data acquisition, peak integration, or m / z (mass-to-charge ratio of non-blank peaks) were obtained using Analyst® version 1.7.1 (Sciex) running on Windows® (Microsoft). Half-life calculations were generated and calculated using Graphpad Prism® software. The half-life of the test compound was calculated based on the first-order reaction rate. To calculate the half-life, the data was converted to linear regression (y = log(y), where the "y" axis represents the percentage of compound remaining at any given time relative to time 0 minutes, and the "x" axis represents time in minutes).

[0371] Compound / API stability Shelf life testing is part of drug development and maintenance. Active pharmaceutical ingredients (APIs) can be sensitive to the effects of heat, light, and oxygen. API stability testing provides evidence of how the quality of the API / drug changes over time under the influence of various environmental factors such as temperature, humidity, and light. API stability was tested using the following procedure.

[0372] The API in powder form was accurately weighed into 25 individual containers, each containing 15 mg + 2 mg of API, and the samples were randomly divided into four groups. Each group was stored at one of the following temperatures at 60% relative humidity: -20°C, 4°C, 25°C, or 40°C at 75% relative humidity. The samples were collected at the following time points: 1 month, 2 months, 3 months, 6 months, 9 months, and 12 months. At each time point, the physical state of the sample (texture and color) was observed and recorded visually before preparation for analysis of physical stability. For each sample, the API was restored in its original container by adding an appropriate volume of DMSO to obtain a 4.0 mg / mL stock solution. 25 μL of the 4.0 mg / mL sample stock solution was diluted with 975 μL of acetonitrile to a final concentration of 100 μg / mL of API. The sample solutions were injected into an HPLC for determination of potency and impurity profiles. The calibration curves for the test compound included seven (five) standards prepared in acetonitrile at concentrations of 1.0, 5.0, 10, 25, 50, and 100 μg / mL.

[0373] An Agilent 1260 Infinity II Lab LC Series HPLC system, including a 1260 Quat pump, 1260 vial autosampler, ICC column oven, and 1260 DAD WR detector, was used. Chromatographic separation was achieved using a Phenomenex Synergi Polar RP column (150 × 4.6 mm, 4 μm, 80 Å). The flow rate was 1 mL / min, and detection was set to 254 nm. Unless otherwise specified, the injection volume was 10 μL. The mobile phase consisted of A, water containing 0.1% trifluoroacetic acid, and B, acetonitrile containing 0.1% trifluoroacetic acid. For the potency analysis, the gradient was A / B(99:1) from 0 min; A / B(1:99) from 0 to 10 min; A / B(1:99) from 10 to 12 min; A / B(99:1) from 12 to 12.1 min; and A / B(99:1) from 12.1 to 13 min. For the impurity profile, the gradient was A / B(99:1) from 0 min; A / B(1:99) from 0 to 15 min; A / B(1:99) from 15 to 18 min; A / B(99:1) from 18 to 18.1 min; and A / B(99:1) from 18.1 to 20 min. Data acquisition and peak integration were performed using OpenLAB CDS version 2.4 (Agilent) running on Windows (Microsoft). The impurity profile was determined by the relative percentage peak area of ​​each detected peak.

[0374] PAMPA assay The parallel membrane permeability (PAMPA) assay is a non-cell-based assay designed to predict the in vivo permeability of drugs to biological membranes in the early stages of drug discovery. The assay was performed using the 96-well Corning Gentest Pre-coated PAMPA Plate System (catalog no. 353015). The Corning Gentest Pre-coated PAMPA plate system is designed as a 96-well insert system with a 0.45 μm PVDF (polyvinylidene fluoride) filter plate pre-coated with a structured three-layer phospholipid (lipid / oil / lipid) and a compatible receiver microplate.

[0375] A donor solution of the test compound (300 μL, 20 μM in PBS / MeOH 90:10) was added to each well of the donor plate. 200 μL of PBS / MeOH 90:10 was added to each well of the acceptor plate. The acceptor plate was connected to the donor plate and incubated at room temperature (RT) for 5 hours without agitation. The compound was tested in triplicate on each plate. At the end of incubation, the drug concentrations in the initial donor solution, acceptor, and donor wells were determined using LC / MS / MS. A 5-point standard curve ranging from 0.1 to 1000 nM was prepared for each test compound. Before analysis, the analyte samples were diluted to the standard curve concentrations with ACN / H2O 50:50.

[0376] All samples were analyzed using an electrospray ionization (ESI) liquid chromatography / mass spectrometry (LC / MS) system with Shidmazu Nexera X2 UHPLC and Sciex 5500 quadrupole ion trap (Qtrap) mass spectrometry. The LC-MS / MS instrument monitored each of the test compounds under study based on their respective mass-to-charge ratio (m / z) transitions and MS parameters. Chromatographic separation was achieved using gradient elution on a Phenomenex Luna C18 column (50 × 2.0 mm, 3 μm particle size). Mobile phase A contained 0.1% formic acid in water, and mobile phase B contained 0.1% formic acid in acetonitrile; A / B (99:1) for 0-1 min; A / B (1:99) for 1-4 min; A / B (1:99) for 4-8 min; A / B (99:1) for 8-8.20 min; and A / B (99:1) for 8.2-9 min. The flow rate was 0.4 mL / min, the column temperature was 35°C, and the autosampler temperature was maintained at 4°C. For detection, electrospray ionization was operated in positive mode using multiple reaction monitoring (MRM).

[0377] Data acquisition and peak integration were performed using Analyst® version 1.7.1 (Sciex) running on Windows® (Microsoft). Standard curve regression and sample concentrations were generated and calculated using Analyst®. Concentrations in the sample solution were determined based on the measured peak area ratio from the analyte's response to the internal standard, referencing the standard calibration curve. All sample calculations were calculated using 1 / x 2 The calculation was performed using linear regression with weighting (x is the concentration at a given calibration standard level).

[0378] The permeability of the test compound was calculated using the following formula. Transparency (cm / s):P e ={-ln[1-C A (t) / C 平衡 ]} / [A*(1 / V D +1 / V A )*t] During the ceremony, A = Filter area = 0.3 cm² 3 V A = Acceptor well volume (0.2 mL) V D = Donnerwell volume (0.2 mL) t = incubation time = 5 hours = 18000 seconds, C A (t) = concentration of the compound in the acceptor well at time t (nM), C D (t) = concentration of the compound in the Donner well at time t (nM), and C 平衡 =[C D (t)*V D +C A (t)*V A ] / (V D +V A )

[0379] Modeling of compounds All claimed structures were generated by computer-aided molecular docking using the available software SeeSAR v.10. The publicly available crystal structure data for compound UNC-0638 (3RJW-UNC0638) bound to the G9a protein was downloaded from the Protein Databank (https: / / www.rcsb.org / ) to estimate affinity binding. The built-in "inspirator" function was used to generate novel compounds with good affinity within the scope of the claims.

[0380] Direct inhibition of CYP by test compounds in human cytochrome P450 assays Many drugs inhibit cytochrome P450 enzymes, leading to clinically significant alterations in the pharmacokinetics of other drugs. In vitro cytochrome P450 inhibition can provide crucial information in evaluating potential clinical drug-drug interactions and is useful for focusing in vivo studies on areas of interest. The cytochrome P450 inhibition assay was developed by preparing a working cocktail solution consisting of six probe substrates: 10 μM ethoxyresorphin (CYP1A2), 100 μM rosiglitazone (CYP2C8), 50 μM diclofenac (CYP2C9), 300 μM S-mephenytoin (CYP2C19), 50 μM dextromethorphan (CYP2D6), and 20 μM midazolam (CYP3A4). The mixture solution consisted of 140 μL of 0.286 mg / mL pooled human liver microsome working solution and 20 μL of the test working solution, a standard control inhibitor, or a positive control placebo. A 20 μL substrate cocktail mixture working solution was prepared. The mixture solution was preheated for 5 minutes in a gentle shaking bath at 37 ± 2°C. The enzymatic reaction was initiated by adding 20 μL of NRS working solution to the mixture solution and incubated at 37 ± 2°C for 10 minutes. To halt the reaction, 400 μL of cold stop solution (acetonitrile containing 50 ng / mL tolbutamide as an internal standard (I.Std.)) was added to the mixture solution. The final concentrations of the test compound, inhibitor, substrate, and cofactor are shown in Table 0.1 below. Two individual samples were prepared for each test compound. The extracted samples were vortexed and then centrifuged at 4500 rpm for 7 minutes using an Eppendorf Centrifuge 5910R. 200 μL of the supernatant was diluted in 200 μL of 50% methanol and placed in a 96-DW plate for LC / MS / MS analysis.

[0381] [Table 2]

[0382] All samples were analyzed using an electrospray ionization (ESI) liquid chromatography / mass spectrometry (LC / MS) system with Shidmazu Nexera X2 UHPLC and Sciex 5500 quadrupole ion trap (Qtrap) mass spectrometry. The LC-MS / MS instrument monitored each of the substrate metabolites based on their respective mass-to-charge ratio (m / z) transitions and MS parameters. Chromatographic separation was achieved using gradient elution on a Phenomenex Luna C18 column (50 × 2.0 mm, 3 μm particle size). Mobile phase A contained 0.1% formic acid in water, and mobile phase B contained 0.1% formic acid in acetonitrile; 0-1 min was A / B (95:5); 1-2.4 min was A / B (15:85); 2.4-4 min was A / B (10:90); 4-4.1 min was A / B (95:5); and 4.1-6 min was A / B (95:5). The flow rate was 0.4 mL / min, the column temperature was 35°C, and the autosampler temperature was maintained at 4°C. For detection, electrospray ionization was operated in positive mode using multiple reaction monitoring (MRM).

[0383] Data acquisition and peak integration were performed using Analyst® version 1.7.1 (Sciex) running on Windows® (Microsoft). Concentration-response plots were used to determine the effect of inhibitors on the enzyme reaction. A typical concentration-response plot provides the activity fraction (Y-axis) plotted as a function of log inhibitor concentration (X-axis). Data are fitted using an S-shaped dose-response equation, also known as a three-parameter logistic equation. The IC50 concentration of the compound that yields 50% inhibition of maximum activity is used. 50 This is referred to as the (inhibitor concentration that produces 50% inhibition). 50 The values ​​are calculated using Prism GraphPad software, version 9. An IC50 value is obtained only if the data fits the curve, and the IC50 is >100 if the % inhibition is less than 50% at 100 μM. [Example 1]

[0384] Synthesis of 4-((2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)amino)tetrahydro-2H-thiopyran 1,1-dioxide (compound 1)

[0385] [ka] Preparation: A solution of commercially available 2,4-dichloro-6-methoxy-7-(3-(pyrrolin-1-yl)propoxy)quinazoline (0.15 g, 0.42 mmol) and 4-aminotetrahydro-2H-thiopyran (0.94 g, 0.63 mmol) in anhydrous DMF (2 mL) was mixed with DIPEA (0.44 mL, 2.53 mmol). The sealed tube was heated to 50 °C under an argon atmosphere. The reaction was monitored by TLC with dichloromethane and LC-MS of 469.1. At completion after 3 days, the cooled reaction mixture was quenched with saturated NaHCO3 and extracted with an 8:2 dichloromethane / isopropanol mixture (5 × 50 mL). The combined organic layers were dehydrated with anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude product was dissolved in 2 ml of 2-butanol to which DIPEA (0.44 mL, 2.53 mmol) and 4,4-difluoropiperidine hydrochloride (0.33 g, 2.11 mmol) were added, and the sealed tube was heated at 90°C for 3 days. The cooled mixture was extracted with a dichloromethane / isopropanol (8:2) mixture and washed with saturated NaHCO3 and brine. The combined organic layers were dehydrated with anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by Buchi Pureflash chromatography on a silica gel cartridge (24 g) using 8:2 CH2Cl2:MeOH w / 2% 7N ammonia to obtain 4-((2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazolin-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide (0.14 g, 60%) as a beige solid. 1H NMR (400 MHz, CDCl3): δ 6.91 (s, 1H), 6.69 (s, 1H), 5.11 (d, 1H, J = 8.0 Hz), 4.42 (m, 1H), 4.17 (t, 2H, J = 8.0 Hz), 3.95 (m, 4H), 3.92 (s, 3H), 3.17 (m, 4H), 2.61 (t, 2H, J = 8.0 Hz), 2.55-2.47 (m, 6H), 2.32 (m, 2H), 2.09 (m, 2H), 1.99 (m, 4H), 1.76 (m, 4H). MS (ESI): C 26 H 37 Calculated value for F2N5O4S: 553, Measured value: 554 (M+H) + . [Example 2]

[0386] Synthesis of 2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)-N-(tetrahydro-2H-pyran-4-yl)quinazoline-4-amine (compound 2)

[0387] [ka] Preparation: A solution of commercially available 2,4-dichloro-6-methoxy-7-(3-(pyrroridine-1-yl)propoxy)quinazoline (0.15 g, 0.42 mmol) and 4-aminotetrahydro-2H-thiopyran (0.64 g, 0.63 mmol) in anhydrous DMF (2 mL) was mixed with DIPEA (0.44 mL, 2.53 mmol). The sealed tube was heated to 50 °C under an argon atmosphere. The reaction was monitored by TLC with dichloromethane and HPLC / MS on 421.1. After 3 days, the reaction was completed, and the cooled mixture was quenched with saturated NaHCO3 and extracted with an 8:2 dichloromethane / isopropanol mixture (3 × 50 mL). The combined organic layer was dehydrated with anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude product was dissolved in 2 ml of 2-butanol to which DIPEA (0.44 mL, 2.53 mmol) and 4,4-difluoropiperidine hydrochloride (0.33 g, 2.11 mmol) had been added, and the sealed tube was then heated at 90°C for 3 days. The cooled mixture was quenched with saturated NaHCO3, extracted with an 8:2 dichloromethane / isopropanol mixture (3 × 50 mL), and then washed once with brine. The combined organic layers were dehydrated with anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by Buchi Pureflash chromatography on a silica gel cartridge (24 g) using 8:2 CH2Cl2:MeOH w / 2% 7N ammonia (8:2) to obtain 2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)-N-(tetrahydro-2H-pyran-4-yl)quinazoline-4-amine (0.12 g, 57%) as a beige solid. 1H NMR (400 MHz, CDCl3): δ 6.90 (s, 1H), 6.69 (s, 1H), 4.96 (d, 1H, J = 8.0 Hz), 4.31 (m, 1H), 4.17 (m, 2H), 4.04 (m, 2H), 3.96 (m, 4H), 3.91 (s, 3H), 3.56 (ddd, 2H, J = 12.0, 12.0, 4.0 Hz), 2.61 (m, 2H), 2.50 (m, 4H), 2.09 (m, 3H), 2.04-1.94 (m, 4H), 1.76 (m, 4H), 1.62 (m, 3H). MS (ESI): C 26 H 37 Calculated value for F2N5O3: 505, measured value: 506 (M+H) + . [Example 3]

[0388] Synthesis of 2-(4,4-difluoropiperidine-1-yl)-6-methoxy-N-(1-(2-methoxyethyl)piperidine-4-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine (compound 3)

[0389] [ka] Preparation: A solution of commercially available 2,4-dichloro-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline (0.15 g, 0.42 mmol) and 1-(2-methoxyethyl)piperidine-4-amine (0.10 g, 0.63 mmol) in anhydrous DMF (2 mL) was mixed with DIPEA (0.44 mL, 2.53 mmol). The sealed tube was heated to 50 °C under an argon atmosphere. The reaction was monitored by TLC with dichloromethane and HPLC / MS on 478.2. Upon completion after 3 days, the cooled reaction was quenched with saturated NaHCO3, extracted with an 8:2 dichloromethane / isopropanol mixture (3 × 50 mL), and then washed once with brine. The combined organic layer was dehydrated with anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude product was dissolved in 2 ml of 2-butanol to which DIPEA (0.44 mL, 2.53 mmol) and 4,4-difluoropiperidine hydrochloride (0.33 g, 2.11 mmol) had been added, and the sealed tube was then heated at 90°C for 3 days. The cooled mixture was quenched with saturated NaHCO3, extracted with an 8:2 dichloromethane / isopropanol mixture (3 × 50 mL), and then washed once with brine. The combined organic layers were dehydrated with anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by Buchi Pureflash chromatography on a silica gel cartridge (24 g) using 8:2 CH2Cl2:MeOH w / 2% 7N ammonia (8:2) to obtain 2-(4,4-difluoropiperidine-1-yl)-6-methoxy-N-(1-(2-methoxyethyl)piperidine-4-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine (0.11 g, 48%) as a beige solid. 1H NMR (400 MHz, CDCl3): δ 6.88 (s, 1H), 6.68 (s, 1H), 4.96 (d, 1H, J = 8.0 Hz), 4.16 (t, 2H, J = 8.0 Hz), 4.10 (m, 1H), 3.96 (m, 4H), 3.84 (s, 3H), 3.53 (m, 2H), 3.36 (s, 3H), 2.97 (m, 2H), 2.70 (m, 2H), 2.61 (m, 4H), 2.22 (m, 2H), 2.13 (m, 4H), 1.98 (m, 5H), 1.81 (m, 4H), 1.65 (m, 2H). MS (ESI): C 29 H 44 Calculated value for F2N6O3: 562, Measured value: 563 (M+H) + . [Example 4]

[0390] Synthesis of 2-(4,4-difluoropiperidine-1-yl)-6-methoxy-N-(2-methoxyethyl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine (compound 4)

[0391] [ka] Preparation: A solution of commercially available 2,4-dichloro-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline (0.15 g, 0.42 mmol) and 2-methoxyethylamine (0.05 g, 0.63 mmol) in anhydrous DMF (2 mL) was mixed with DIPEA (0.44 mL, 2.53 mmol). The sealed tube was heated to 50 °C under an argon atmosphere. The reaction was monitored by TLC with dichloromethane and HPLC / MS on 394.3. Upon completion after 3 days, the cooled reaction was quenched with saturated NaHCO3, extracted with an 8:2 dichloromethane / isopropanol mixture (3 × 50 mL), and then washed once with brine. The combined organic layer was dehydrated with anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude product was dissolved in 2 ml of 2-butanol to which DIPEA (0.44 mL, 2.53 mmol) and 4,4-difluoropiperidine hydrochloride (0.33 g, 2.11 mmol) had been added, and the sealed tube was then heated at 90°C for 3 days. The cooled mixture was quenched with saturated NaHCO3, extracted with an 8:2 dichloromethane / isopropanol mixture (3 × 50 mL), and then washed once with brine. The combined organic layers were dehydrated with anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by Buchi Pureflash chromatography on a silica gel cartridge (24 g) using 8:2 CH2Cl2:MeOH w / 2% 7N ammonia to obtain 2-(4,4-difluoropiperidine-1-yl)-6-methoxy-N-(2-methoxyethyl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine (0.113 g, 56%) as a beige solid. 1H NMR (400 MHz, CDCl3): δ 6.89 (s, 1H), 6.74 (s, 1H), 5.55 (t, 1H, J = 8.0 Hz), 4.16 (m, 2H), 3.97 (m, 4H), 3.89 (s, 3H), 3.77 (dd, 2H, J = 12.0, 4.0 Hz), 3.64 (t, 2H, J = 4.0 Hz), 3.40 (s, 3H), 2.62 (t, 2H, J = 8.0 Hz), 2.51 (m, 4H), 2.10 (p, 2H, J =8.0 Hz), 1.97 (m, 4H), 1.77 (m, 4H). MS (ESI): C 24 H 35 Calculated value for F2N5O3: 479, Measured value: 480 (M+H) + . [Example 5]

[0392] Synthesis of 2-(4,4-difluoropiperidine-1-yl)-6-methoxy-N-((1-methylpiperidine-4-yl)methyl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine (compound 5)

[0393] [ka] Preparation: A solution of commercially available 2,4-dichloro-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline (0.15 g, 0.42 mmol) and (1-methyl-4-piperidinyl)methanamine (0.08 g, 0.63 mmol) in anhydrous DMF (2 mL) was mixed with DIPEA (0.44 mL, 2.53 mmol). The sealed tube was heated to 50 °C under an argon atmosphere. The reaction was monitored by TLC with dichloromethane and HPLC / MS on 448.2. Upon completion after 3 days, the cooled reaction was quenched with saturated NaHCO3, extracted with an 8:2 dichloromethane / isopropanol mixture (3 × 50 mL), and then washed once with brine. The combined organic layer was dehydrated with anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude product was dissolved in 2 ml of 2-butanol to which DIPEA (0.44 mL, 2.53 mmol) and 4,4-difluoropiperidine hydrochloride (0.33 g, 2.11 mmol) had been added, and the sealed tube was then heated at 90°C for 3 days. The cooled mixture was quenched with saturated NaHCO3, extracted with an 8:2 dichloromethane / isopropanol mixture (3 × 50 mL), and then washed once with brine. The combined organic layers were dehydrated with anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by Buchi Pureflash chromatography on a silica gel cartridge (24 g) using 8:2 CH2Cl2:MeOH w / 2% 7N ammonia to obtain 2-(4,4-difluoropiperidine-1-yl)-6-methoxy-N-((1-methylpiperidine-4-yl)methyl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine (0.09 g, 41%) as a beige solid. 1H NMR (400 MHz, CDCl3): δ 6.89 (s, 1H), 6.69 (s, 1H), 5.26 (dd, 1H, J = 8.0, 4.0 Hz), 4.16 (dd, 2H, J = 8.0, 4.0 Hz), 3.97 (m, 4H), 3.90 (s, 3H), 3.50 (dd, 2H, J = 8.0. 4.0 Hz), 2.86 (m, 2H), 2.61 (dd, 2H, J = 8.0, 4.0 Hz), 2.50 (m, 4H), 2.26 (s, 3H), 2.09 (p, 2H, J = 8.0 Hz), 1.98 (m, 4H), 1.89 (m, 3H), 1.75 (m, 6H), 1.39 (ddd, 2H, J = 12.0, 12.0, 4.0 Hz). MS (ESI): C 28 H 42 Calculated value for F2N6O2: 532, measured value: 533 (M+H) + . [Example 6]

[0394] Synthesis of (R)-6-methoxy-N-(piperidine-3-yl)-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine (compound 159)

[0395] [ka] Preparation: A solution of commercially available 2,4-dichloro-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline (0.10 g, 0.28 mmol) and (R)-1-boc-3-aminopiperidine (0.08 g, 0.42 mmol) in anhydrous 1:1 DMF / 2-butanol (2 mL) was mixed with DIPEA (0.88 mL, 3.36 mmol). The sealed tube was heated to 50 °C under an argon atmosphere. The reaction was monitored by TLC using dichloromethane. Upon completion after 2 days (HPLC / MS = 520), excess pyrrolidine (3.43 g, 48.25 mmol) was added, and the mixture was heated to 90 °C for 3 days. The cooled mixture was quenched with saturated NaHCO3, extracted with an 8:2 dichloromethane / isopropanol mixture (3 × 25 mL), and then washed once with brine. The combined organic layers were dehydrated with anhydrous Na2SO4, filtered, and concentrated under vacuum.

[0396] The crude product (LCMS=555.2) was hydrolyzed with 40% trifluoromethylacetic acid in dichloromethane (5 mL) for 20 hours. The mixture was then neutralized with 1 N aqueous NaOH and extracted with an 8:2 dichloromethane / isopropanol mixture (3 × 25 mL). The combined organic layers were dehydrated with anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by Buchi Pureflash chromatography on a silica gel cartridge (12 g) using 8:2 CH2Cl2:MeOH w / 2% 7N ammonia to obtain (R)-6-methoxy-N-(piperidine-3-yl)-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine (0.33 g, 48%) as a beige solid. 1H NMR (400 MHz, CDCl3): δ 6.9 (s, 1H), 6.75 (s, 1H), 5.44 (d, 1H, J = 4.0 Hz), 4.31 (m, 1H), 4.15 (dd, 2H, J = 8.0 Hz, 4.0 Hz), 3.90 (s, 3H), 3.61 (m, 4H), 3.27 (dd, 1H, J = 8.0, 2.0 Hz), 2.86 (m, 1H), 2.75 (m, 1H), 2.70 (dd, 1H, J = 12.0, 4.0 Hz), 2.60 (t, 2H, J = 8.0 Hz), 2.49 (m, 4H), 2.08 (p, 2H, J = 8.0 Hz), 1.92 (m, 5H), 1.76 (m, 7H), 1.56 (m, 1H). MS (ESI): C 25 H 38 Calculated value of N6O2: 454, measured value: 455 (M+H) + . [Example 7]

[0397] Synthesis of 2-(4-((2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)amino)piperidine-1-yl)acetic acid (compound 6)

[0398] [ka] Preparation: Commercially available 2,4-dichloro-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline (0.10 g, 0.28 mmol) and (4-aminopiperidine-1-yl) acetate hydrochloride (0.08 g, 0.42 mmol) were added to anhydrous DMF (2 mL) with DIPEA (0.29 mL, 0.21 mmol). The sealed tube was heated to 50 °C under an argon atmosphere. The reaction was monitored by TLC using dichloromethane and HPLC / MS on 478.2. At completion after 3 days, the precipitate intermediate was collected by filtration washing with isopropanol and dried under vacuum. The crude product was suspended in isopropanol (2 ml) containing DIPEA (0.44 mL, 2.53 mmol) and 4,4-difluoropiperidine hydrochloride (0.33 g, 2.11 mmol), and the sealed tube was microwaved at 150°C for 90 minutes. The precipitate was collected by filtration washing with cold acetonitrile and dried under vacuum to obtain 2-(4-((2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazolin-4-yl)amino)piperidine-1-yl)acetic acid (0.05 g, 48%) as a beige solid. 1 ¹H NMR (400 MHz, DMSO-d): δ (Low solubility was a problem, and a clear spectrum could not be obtained). MS (ESI): C 28 H 440 Calculated value for F2N6O4: 562, measured value: 563 (M+H) + . [Example 8]

[0399] Synthesis of 2-chloro-N-(1-isopropylpiperidine-4-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine (compound 113)

[0400] [ka] Preparation: A solution of commercially available 2,4-dichloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (0.50 g, 1.40 mmol) and 4-amino-1-isopropylpiperidine (0.30 g, 2.11 mmol) in anhydrous 1:1 DMF / 2-butanol (7 mL) was mixed with DIPEA (0.73 mL, 4.21 mmol). The sealed tube was heated to 50 °C under an argon atmosphere for 3 days. The cooled reaction was quenched with saturated NaHCO3, extracted with an 8:2 dichloromethane / isopropanol mixture (3 × 50 mL), and then washed once with brine. The combined organic layer was dehydrated with anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by Buchi Pureflash chromatography on a silica gel cartridge (24 g) using 8:2 CH2Cl2:MeOH w / 2% 7N ammonia to obtain 2-chloro-N-(1-isopropylpiperidine-4-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine (0.43 g, 67%) as a yellow solid. 1 H NMR (400 MHz, CDCl3): δ 7.10 (s, 1H), 6.75 (s, 1H), 5.30 (d, 1H, J = 8.0 Hz), 4.21 (m, 1H), 4.15 (t, 2H, J = 4.0 Hz), 3.94 (s, 3H), 2.87 (m, 2H), 2.76 (Septet, 1H, J = 8.0 Hz), 2.60 (t, 2H, J = 8.0 Hz), 2.49 (m, 4H), 2.37 (dt, 2H, J = 12.0, 4.0 Hz), 2.15 (m 2H), 2.08 (p, 2H, J = 8.0 Hz), 1.76 (m, 4H), 1.56 (dq, 2H, J = 8.0, 4.0 Hz), 1.05 (s, 3H), 1.03 (s, 3H). MS (ESI): C 24 H 36 Calculated value for ClN5O2: 462, measured value: 463 (M+H) + . [Example 9]

[0401] Synthesis of 2-(azetidine-1-yl)-N-(1-isopropylpiperidine-4-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine (compound 234)

[0402] [ka] Preparation: 2-chloro-N-(1-isopropylpiperidine-4-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine (0.08 g, 0.16 mmol) and azetidine hydrochloride (0.08 g, 0.81 mmol) were dissolved in anhydrous 1:1 DMF / 2-butanol (7 mL) and DIPEA (0.22 mL, 1.30 mmol) was added. The sealed tube was heated to 90°C under an argon atmosphere for 2 days. The cooled reaction was quenched with saturated NaHCO3, extracted with an 8:2 dichloromethane / isopropanol mixture (3 × 25 mL), and then washed once with brine. The combined organic layer was dehydrated with anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by Buchi Pureflash chromatography on a silica gel cartridge (24 g) using 8:2 CH2Cl2:MeOH w / 2% 7N ammonia to obtain 2-(azetidine-1-yl)-N-(1-isopropylpiperidine-4-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine (0.03 g, 44%) as a grayish-white solid. 1 H NMR (400 MHz, CDCl3): δ 6.93 (s, 1H), 6.68 (s, 1H), 4.94 (d, 1H, J = 8.0 Hz), 4.15-4.10 (m, 7H), 3.89 (s, 3H), 2.89 (m, 2H), 2.77 (septet, 1H, J = 8.0 Hz), 2.6 (m, 2H), 2.51 (m, 4H), 2.35-2.24 (m, 4H), 2.16 (m 2H), 2.10 (m, 2H), 1.76 (m, 4H), 1.55 (m, 2H), 1.06 (s, 3H), 1.05 (s, 3H). MS (ESI): C 27 H 42Calculated value of N6O2: 482, measured value: 483 (M+H) + . [Example 10]

[0403] Synthesis of (S)-6-methoxy-N-(piperidine-3-yl)-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine (compound 158)

[0404] [ka] Preparation: A solution of commercially available 2,4-dichloro-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline (0.25 g, 0.70 mmol) and (S)-1-boc-3-aminopiperidine (0.21 g, 1.05 mmol) in anhydrous DMF (5 mL) was mixed with DIPEA (0.36 mL, 2.10 mmol). The sealed tube was heated to 50 °C under an argon atmosphere. The reaction was monitored by TLC using dichloromethane. At completion after 2 days (HPLC / MS=520), excess pyrrolidine (3.43 g, 48.25 mmol) was added, and the mixture was heated to 90 °C for 3 days. The cooled mixture was quenched with saturated NaHCO3, extracted with an 8:2 dichloromethane / isopropanol mixture (3 × 50 mL), and then washed once with brine. The combined organic layers were dehydrated with anhydrous Na2SO4, filtered, and concentrated under vacuum.

[0405] The crude product (LCMS=555.2) was hydrolyzed with 40% trifluoromethylacetic acid in dichloromethane (5 mL) for 20 hours. The mixture was then neutralized with 1 N aqueous NaOH and extracted with an 8:2 dichloromethane / isopropanol mixture (3 × 50 mL). The combined organic layers were dehydrated with anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by Buchi Pureflash chromatography on a silica gel cartridge (12 g) using 8:2 CH2Cl2:MeOH w / 2% 7N ammonia to obtain (S)-6-methoxy-N-(piperidine-3-yl)-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine (0.16 g, 50%) as a beige solid. 1 H NMR (400 MHz, CDCl3): δ 6.9 (s, 1H), 6.76 (s, 1H), 5.45 (d, 1H, J = 4.0 Hz), 4.30 (m, 1H), 4.15 (dd, 2H, J = 8.0 Hz, 4.0 Hz), 3.89 (s, 3H), 3.60 (m, 4H), 3.26 (dd, 1H, J = 8.0, 2.0 Hz), 2.86 (m, 1H), 2.78 (m, 1H), 2.70 (dd, 1H, J = 12.0, 4.0 Hz), 2.60 (t, 2H, J = 8.0 Hz), 2.49 (m, 4H), 2.08 (p, 2H, J = 8.0 Hz), 1.92 (m, 5H), 1.75 (m, 7H), 1.56 (m, 1H). MS (ESI): C 25 H 38 Calculated value of N6O2: 454, measured value: 455 (M+H) + . [Example 11]

[0406] Synthesis of N-(1-isopropylpiperidine-4-yl)-6-methoxy-2-(1H-pyrazole-1-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine (compound 157)

[0407] [ka] Preparation: 2-chloro-N-(1-isopropylpiperidine-4-yl)-6-methoxy-7-(3-(pyrroridine-1-yl)propoxy)quinazoline-4-amine (0.08 g, 0.16 mmol), potassium carbonate (0.11 g, 0.81 mmol), and pyrazole (0.22 g, 3.25 mmol) were dissolved in anhydrous acetonitrile (3 mL). The sealed tubes were microwaved at 160 °C for 3 hours under an argon atmosphere. The cooled reaction was quenched with saturated NaHCO3, extracted with an 8:2 dichloromethane / isopropanol mixture (3 × 25 mL), and then washed once with brine. The combined organic layers were dehydrated with anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by Buchi Pureflash chromatography on a silica gel cartridge (24 g) using 9:1 CH2Cl2:MeOH w / 2% 7N ammonia to obtain N-(1-isopropylpiperidine-4-yl)-6-methoxy-2-(1H-pyrazole-1-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine (0.07 g, 85%) as a yellow solid. 1 H NMR (400 MHz, CDCl3): δ 8.56 (dd, 1H, J = 4.0, 2.0 Hz), 7.77 (dd, 1H, J = 2.0, 2.0 Hz), 7.34 (s, 1H), 6.83 (s, 1H), 6.42 (dd, 1H, J = 4.0, 2.0 Hz), 5.40 (d. Hz), 2.50 (m, 4H), 2.37 (dt, 2H, J = 12.0, 4.0 Hz), 2.22 (m, 2H), 2.08 (p, 2H, J = 8.0 Hz), 1.76 (m, 4H), 1.61 (dq, 2H, J = 8.0, 4.0 Hz), 1.07 (s, 3H), 1.06 (s, 3H). MS (ESI): C 27 H 39 Calculated value of N7O2: 493, measured value: 494 (M+H) + . [Example 12]

[0408] Synthesis of 2-(1H-imidazole-1-yl)-N-(1-isopropylpiperidine-4-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine (compound 156)

[0409] [ka] Preparation: 2-chloro-N-(1-isopropylpiperidine-4-yl)-6-methoxy-7-(3-(pyrroridine-1-yl)propoxy)quinazoline-4-amine (0.08 g, 0.16 mmol), potassium carbonate (0.11 g, 0.81 mmol), and imidazole (0.22 g, 3.25 mmol) were dissolved in anhydrous acetonitrile (3 mL). The sealed tubes were microwaved at 160 °C for 3 hours under an argon atmosphere. The cooled reaction was quenched with saturated NaHCO3, extracted with an 8:2 dichloromethane / isopropanol mixture (3 × 25 mL), and then washed once with brine. The combined organic layers were dehydrated with anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by Buchi Pureflash chromatography on a silica gel cartridge (24 g) using 9:1 CH2Cl2:MeOH w / 2% 7N ammonia (8:2) to obtain 2-(1H-imidazole-1-yl)-N-(1-isopropylpiperidine-4-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine (0.07 g, 86%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.61 (dd, 1H, J = 4.0, 2.0 Hz), 7.90 (dd, 1H, J = 4.0, 2.0 Hz), 7.16 (s, 1H), 7.12 (dd, 1H, J = 4.0, 2.0 Hz), 6.81 (s, 1H), 5.39 (d, 1H, J = 8.0 Hz), 4.23 (t, 2H, J = 8.0 Hz), 4.19 (m, 1H), 3.96 (s, 3H), 2.94 (m, 2H), 2.79 (septet, 1H, J = 8.0 Hz), 2.64 (dd, 2H, J = 8.0, 4.0 Hz), 2.52 (m, 4H), 2.37 (dt, 2H, J = 8.0, 2.0 Hz), 2.21 (m, 2H), 2.12 (p, 2H, J = 8.0 Hz), 1.78 (m, 4H), 1.62 (dq, 2H, J = 12.0, 4.0 Hz), 1.08 (s, 3H), 1.07 (s, 3H). MS (ESI): C 27 H 39 Calculated value of N7O2: 493, measured value: 494 (M+H) + . [Example 13]

[0410] Synthesis of 2-(4,4-difluoropiperidine-1-yl)-6-methoxy-N-(pyridine-4-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine (compound 7)

[0411] [ka] Preparation: A solution of commercially available 2,4-dichloro-6-methoxy-7-(3-(pyrroridine-1-yl)propoxy)quinazoline (0.15 g, 0.42 mmol) and 4-aminopyridine (0.04 g, 0.46 mmol) in anhydrous THF (3 mL) was mixed with an excess of 60% sodium hydride (0.11 g, 2.73 mmol). The mixture was stirred under an argon balloon for 30 minutes. The tube was then sealed and heated to 50°C under an argon atmosphere. The reaction was monitored by TLC with dichloromethane and HPLC / MS with 414. At completion after 20 hours, the cooled reaction was quenched with saturated NH4Cl (2 mL), followed by saturated NaHCO3 (50 mL). The mixture was then extracted with an 8:2 dichloromethane / isopropanol mixture (3 × 50 mL) and washed once with brine. The combined organic layers were dehydrated with anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude product was dissolved in 1:1 THF / 2-butanol (4 ml) to which DIPEA (0.44 mL, 2.53 mmol) and 4,4-difluoropiperidine hydrochloride (0.33 g, 2.11 mmol) had been added, and the sealed tube was then heated at 110°C for 3 days. The cooled mixture was quenched with saturated NaHCO3, extracted with an 8:2 dichloromethane / isopropanol mixture (3 × 50 mL), and then washed once with brine. The combined organic layers were dehydrated with anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by Buchi Pureflash chromatography on a silica gel cartridge (24 g) using 9:1 CH2Cl2:MeOH w / 2% 7N ammonia to obtain 2-(4,4-difluoropiperidine-1-yl)-6-methoxy-N-(pyridine-4-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine (0.10 g, 50%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.51 (dd, 1H, J = 4.0, 1.0 Hz), 7.60 (dd, 1H, J = 8.0, 1.0 Hz), 7.20 (s, 1H), 6.97 (s, 1H), 6.88 (s, 1H), 4.20 (t, 2H, J = 8.0 Hz), 4.01 (m, 4H), 3.94 (s, 3H), 2.67 (m, 2H), 2.56 (m, 4H), 2.13 (septet, 1H, J = 8.0 Hz), 2.03 (m, 5H), 1.79 (m, 4H). MS (ESI): C 26 H 32 Calculated value for F2N6O2: 498, measured value: 499 (M+H) + . [Example 14]

[0412] Synthesis of 4-((1-isopropylpiperidine-4-yl)amino)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-2-carbonitrile (compound 235)

[0413] [ka] Preparation: 2-chloro-N-(1-isopropylpiperidine-4-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine (0.10 g, 0.22 mmol) and 1,4-diazobicyclo[2.2.2]octane (0.03 g, 0.22 mmol) were dissolved in anhydrous dimethyl sulfoxide (1.5 mL). The mixture was stirred at room temperature for 2 hours, then sodium cyanide (0.01 g, 0.23 mmol) was added. The sealed tube was heated to 120 °C under an argon atmosphere for 4 days. The cooled reaction was quenched with brine (50 mL) and extracted with an 8:2 dichloromethane / isopropanol mixture (3 × 50 mL). The combined organic layer was dehydrated with anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by Buchi Pureflash chromatography on a silica gel cartridge (12 g) using 8:2 CH2Cl2:MeOH w / 2% 7N ammonia (8:2) to obtain 4-((1-isopropylpiperidine-4-yl)amino)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-2-carbonitrile (0.07 g, 71%) as a beige solid. 1 H NMR (400 MHz, CDCl3): δ 7.18 (s, 1H), 7.08 (s, 1H), 6.25 (d, 1H, J = 8.0 Hz), 4.41 (m, 1H), 4.20 (t, 2H, J = 8.0 Hz), 4.01 (s, 3H), 3.21 (d, 2H, J = 12.0 Hz), 3.14 (septet, 1H, J = 8.0 Hz), 2.74 (m, 2H), 2.70-2.62 (m, 6H), 2.28-2.10 (m, 6H), 1.83 (m, 4H), 1.27 (s, 3H), 1.25 (s, 3H). MS (ESI): C 25 H 36 Calculated value for N6O2: 452, measured value: 453 (M+H) + . [Example 15]

[0414] Synthesis of 2-(4,4-difluoropiperidine-1-yl)-6-methoxy-N-(piperidine-4-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine (compound 8)

[0415] [ka] Preparation: A solution of commercially available 2,4-dichloro-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline (0.15 g, 0.42 mmol) and 1-boc-4-aminopiperidine (0.13 g, 0.63 mmol) in anhydrous DMF (2 mL) was mixed with DIPEA (0.44 mL, 2.53 mmol). The sealed tube was heated to 50 °C under an argon atmosphere. The reaction was monitored by TLC using dichloromethane. At completion after 3 days (HPLC / MS = 520.2), excess pyrrolidine (3.43 g, 48.25 mmol) was added, and the mixture was heated to 90 °C for 3 days. The cooled mixture was quenched with saturated NaHCO3, extracted with an 8:2 dichloromethane / isopropanol mixture (3 × 50 mL), and then washed once with brine. The combined organic layers were dehydrated with anhydrous Na2SO4, filtered, and concentrated under vacuum.

[0416] The crude product (HPLC / MS=605.2) was hydrolyzed with 40% trifluoromethylacetic acid in dichloromethane (2.5 mL) for 20 hours. The mixture was then neutralized in an ice bath with 10 N aqueous NaOH and saturated sodium bicarbonate, and extracted with an 8:2 dichloromethane / isopropanol mixture (3 × 50 mL). The combined organic layer was dehydrated with anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by Buchi Pureflash chromatography on a silica gel cartridge (12 g) using 8:2 CH2Cl2:MeOH w / 2% 7N ammonia to obtain 2-(4,4-difluoropiperidine-1-yl)-6-methoxy-N-(piperidine-4-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine (0.10 g, 48%) as a beige solid. 1H NMR (400 MHz, CDCl3): δ 6.89 (s, 1H), 6.69 (s, 1H), 4.99 (d, 1H, J = 8.0 Hz), 4.16 (t, 2H, J = 8.0 Hz), 3.96 (m, 4H), 3.91 (s, 3H), 3.15 (dt, 2H, J = 12.0, 4.0 Hz), 2.77 (dd, 2H, J = 12.0, 4.0 Hz), 2.63 (t, 2H, J = 8.0 Hz), 2.53 (m, 4H), 2.12 (m, 4H), 1.98 (m, 5H), 1.77 (m, 5H), 1.47 (ddd, 2H, J = 12.0, 12.0, 4.0 Hz). MS (ESI): C 26 H 38 Calculated value for F2N6O2: 504, measured value: 505 (M+H) + . [Example 16]

[0417] Synthesis of 2-chloro-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)-N-(tetrahydro-2H-pyran-4-yl)quinazoline-4-amine (compound 115)

[0418] [ka] Preparation: A solution of commercially available 2,4-dichloro-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline (1.50 g, 4.21 mmol) and tetrahydro-2H-pyran-4-amine (0.639 g, 6.32 mmol) in anhydrous DMF (12 mL) was mixed with DIPEA (2.20 mL, 12.63 mmol). The sealed tube was heated at 50 °C under an argon atmosphere for 10 days. The cooled reaction was quenched with saturated NaHCO3, extracted with an 8:2 dichloromethane / isopropanol mixture (3 × 50 mL), and then washed once with brine. The combined organic layers were dehydrated with anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by Buchi Pureflash chromatography on a silica gel cartridge (80 g) using 8:2 CH2Cl2:MeOH w / 2% 7N ammonia to obtain 2-chloro-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)-N-(tetrahydro-2H-pyran-4-yl)quinazoline-4-amine (1.08 g, 61%) as a yellow solid. 1 H NMR (400 MHz, CDCl3): δ 7.10 (s, 1H), 6.81 (s, 1H), 5.42 (d, 1H, J = 8.0 Hz), 4.46 (m, 1H), 4.14 (m, 2H), 4.02 (dd, 2H, J = 12.0, 4.0 Hz), 3.95 (s, 3H), 3.58 (dt, 2H, J = 12.0, 2.0 Hz), 2.63 (t, 2H, J = 8.0 Hz), 2.51 (m, 4H), 2.10 (m, 4H), 1.76 (m, 4H), 1.62 (ddd, 2H, J = 12.0, 12.0, 4.0 Hz). MS (ESI): C 21 H 29 Calculated value for ClN4O3: 420, measured value: 421 (M+H) + . [Example 17]

[0419] Synthesis of 2-((2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)amino)acetamide (compound 9)

[0420] [ka] Preparation: DIPEA (0.59 mL, 3.36 mmol) was added to a solution of commercially available 2,4-dichloro-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline (0.20 g, 0.56 mmol) and glycinamide hydrochloride (0.93 g, 0.84 mmol) in anhydrous DMF (2 mL). The sealed tube was heated to 50 °C under an argon atmosphere. The reaction was monitored by TLC using dichloromethane and by HP / LCMS (measured value 394.1). After 3 days, the cooled reaction was extracted with an 8:2 dichloromethane / isopropanol mixture (4 × 50 mL) and washed with saturated sodium bicarbonate. The combined organic layer was dehydrated with anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The crude product was dissolved in 2-butanol (1 ml) containing DIPEA (1.18 mL, 6.72 mmol) and supplemented with 4,4-difluoropiperidine hydrochloride (1.03 mL, 12.35 mmol), and the sealed tube was heated at 90°C for 4 days. The cooled mixture was extracted with a dichloromethane / isopropanol (8:2) mixture and washed with saturated NaHCO3 and brine. The combined organic layers were dehydrated with anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by Buchi Pureflash chromatography on a silica gel cartridge (24 g) using 9:1 CH2Cl2:MeOH w / 2% 7N ammonia to obtain 2-((2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazolin-4-yl)amino)acetamide (0.13 g, 49%) as a pale orange solid. 1 H NMR (400 MHz, DMSO-d): δ 6.89 (s, 1H), 6.84 (s, 1H), 6.16 (s, 1H), 6.06 (bs, 1H), 5.54 (s, 1H), 4.21 (d, 2H, J = 8.0 Hz), 4.17 (m, 2H), 3.96 (m, 4H), 3.89 (s, 3H), 2.70 (m, 2H), 2.60 (m, 4H), 2.13 (m, 2H), 1.96 (m, 4H), 1.81 (m, 4H). MS (ESI): C 23 H32 Calculated value for F2N6O3: 478, Measured value: 479 (M+H) + . [Example 18]

[0421] Synthesis of 2-(azetidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)-N-(tetrahydro-2H-pyran-4-yl)quinazoline-4-amine (compound 174)

[0422] [ka] Preparation: A solution of 7-(3-(pyrroridine-1-yl)propoxy)-N-(tetrahydro-2H-pyran-4-yl)quinazoline-4-amine (0.15 g, 0.36 mmol) and azetidine hydrochloride (0.33 g, 3.56 mmol) in anhydrous THF (2 mL) was mixed with DIPEA (1.55 mL, 8.91 mmol). The sealed tube was heated at 90°C under an argon atmosphere for 7 days. The cooled reaction was quenched with saturated NaHCO3, extracted with an 8:2 dichloromethane / isopropanol mixture (3 × 25 mL), and then washed once with brine. The combined organic layers were dehydrated with anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by Buchi Pureflash chromatography on a silica gel cartridge (24 g) using 8:2 CH2Cl2:MeOH w / 2% 7N ammonia to obtain 2-(azetidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)-N-(tetrahydro-2H-pyran-4-yl)quinazoline-4-amine (0.04 g, 27%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 6.94 (s, 1H), 6.70 (s, 1H), 4.98 (d, 1H, J = 8.0 Hz), 4.34 (m, 1H), 4.18-4.10 (m, 6H), 4.01 (m, 2H), 3.90 (s, 3H), 3.54 (dt, 2H, J = 12.0, 0.2 Hz), 2.62 (t, 2H, J = 8.0 Hz), 2.52 (m, 4H), 2.29 (m, 2H), 2.16-2.02 (m, 4H), 1.76 (m, 4H), 1.59 (ddd, 2H, J = 8.0, 8.0, 4.0 Hz). MS (ESI): C 24 H 35 Calculated value of N5O3: 441, measured value: 442 (M+H) + . [Example 19]

[0423] Synthesis of 6-methoxy-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)propoxy)-N-(tetrahydro-2H-pyran-4-yl)quinazoline-4-amine (compound 164)

[0424] [ka] Preparation: A solution of 7-(3-(pyrrolidine-1-yl)propoxy)-N-(tetrahydro-2H-pyran-4-yl)quinazoline-4-amine (0.15 g, 0.36 mmol) and pyrrolidine (0.20 g, 3.56 mmol) in anhydrous THF (2 mL) was mixed with DIPEA (0.09 mL, 0.53 mmol). The sealed tube was heated to 90 °C under an argon atmosphere for 3 days. The cooled reaction was quenched with saturated NaHCO3, extracted with an 8:2 dichloromethane / isopropanol mixture (3 × 25 mL), and then washed once with brine. The combined organic layers were dehydrated with anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by Buchi Pureflash chromatography on a silica gel cartridge (24 g) using 8:2 CH2Cl2:MeOH w / 2% 7N ammonia to obtain 6-methoxy-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)propoxy)-N-(tetrahydro-2H-pyran-4-yl)quinazoline-4-amine (0.15 g, 89%) as a beige solid. 1 H NMR (400 MHz, CDCl3): δ 7.21 (s, 1H), 6.88 (s, 1H), 5.56 (d, 1H, J 8.0 Hz), 4.34 (m, 1H), 4.15 (m, 2H), 4.01 (m, 2H), 3.90 (s, 3H), 3.65 (m, 4H), 3.54 (dt, 2H, J = 12.0, 0.2 Hz), 2.72 (m, 2H), 2.65 (m, 4H), 2.12 (m, 4H), 1.96 (m, 4H), 1.82 (m, 4H), 1.68 (ddd, 2H, J = 8.0, 8.0, 4.0 Hz). MS (ESI): C 25 H 37 Calculated value of N5O3: 455, measured value: 456 (M+H) + . [Example 20]

[0425] Synthesis of 6-methoxy-2-morpholino-7-(3-(pyrrolidine-1-yl)propoxy)-N-(tetrahydro-2H-pyran-4-yl)quinazoline-4-amine (compound 195)

[0426] [ka] Preparation: A solution of 7-(3-(pyrroridine-1-yl)propoxy)-N-(tetrahydro-2H-pyran-4-yl)quinazoline-4-amine (0.15 g, 0.36 mmol) and morpholine (0.10 g, 1.78 mmol) in anhydrous THF (2 mL) was mixed with DIPEA (0.09 mL, 0.53 mmol). The sealed tube was heated to 90°C under an argon atmosphere for 3 days. The cooled reaction was quenched with saturated NaHCO3, extracted with an 8:2 dichloromethane / isopropanol mixture (3 × 25 mL), and then washed once with brine. The combined organic layers were dehydrated with anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by Buchi Pureflash chromatography on a silica gel cartridge (24 g) using 8:2 CH2Cl2:MeOH w / 2% 7N ammonia to obtain 6-methoxy-2-morpholino-7-(3-(pyrrolidine-1-yl)propoxy)-N-(tetrahydro-2H-pyran-4-yl)quinazoline-4-amine (0.16 g, 96%) as a beige solid. 1 H NMR (400 MHz, CDCl3): δ 6.90 (s, 1H), 6.70 (s, 1H), 4.99 (d, 1H, J = 8.0 Hz), 4.32 (m, 1H), 4.15 (m, 2H), 4.02 (m, 2H), 3.91 (s, 3H), 3.77 (s, 4H), 3.55 (dt, 2H, J = 8.0, 2.0 Hz), 2.66 (m, 2H), 2.56 (m, 4H), 2.11 (m, 4H), 1.79 (m, 4H), 1.62 (ddd, 2H, J = 8.0, 8.0, 4.0 Hz). MS (ESI): C 25 H 37 Calculated value for N5O4: 471, Measured value: 472 (M+H) + . [Example 21]

[0427] Synthesis of 6-Methoxy-2-(4-methylpiperazine-1-yl)-7-(3-(pyrrolidine-1-yl)propoxy)-N-(tetrahydro-2H-pyran-4-yl)quinazoline-4-amine (compound 236)

[0428] [ka] Preparation: A solution of 7-(3-(pyrrolidine-1-yl)propoxy)-N-(tetrahydro-2H-pyran-4-yl)quinazoline-4-amine (0.10 g, 0.24 mmol) and 1-methylpiperazine (0.07 g, 1.19 mmol) in anhydrous THF (1.5 mL) was mixed with DIPEA (0.09 mL, 0.53 mmol). The sealed tube was heated to 90 °C under an argon atmosphere for 3 days. The cooled reaction was quenched with saturated NaHCO3, extracted with an 8:2 dichloromethane / isopropanol mixture (3 × 25 mL), and then washed once with brine. The combined organic layers were dehydrated with anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by Buchi Pureflash chromatography on a silica gel cartridge (24 g) using 8:2 CH2Cl2:MeOH w / 2% 7N ammonia to obtain 6-methoxy-2-(4-methylpiperazin-1-yl)-7-(3-(pyrrolidine-1-yl)propoxy)-N-(tetrahydro-2H-pyran-4-yl)quinazoline-4-amine (0.11 g, 97%) as a grayish-white solid. 1 H NMR (400 MHz, CDCl3): δ 6.89 (s, 1H), 6.68 (s, 1H), 4.94 (d, 1H, J = 4.0 Hz), 4.32 (m, 1H), 4.15 (t, 2H, J = 8.0 Hz), 4.03 (m, 2H), 3.90 (s, 3H), 3.83 (m, 4H), 3.56 (dt, 2H, J = 12.0, 2.0 Hz), 2.63 (t, 2H, J = 8.0 Hz), 2.53 (m, 4H), 2.47 (m, 4H), 2.33 (s, 3H), 2.15-2.05 (m, 4H), 1.77 (m, 4H), 1.61 (ddd, 2H, J = 8.0, 8.0, 4.0 Hz). MS (ESI): C 26 H 40 Calculated value for N6O3: 484, measured value: 485 (M+H) + . [Example 22]

[0429] Synthesis of 6-Methoxy-2-(4-methyl-1,4-diazepan-1-yl)-7-(3-(pyrrolidine-1-yl)propoxy)-N-(tetrahydro-2H-pyran-4-yl)quinazoline-4-amine (compound 237)

[0430] [ka] Preparation: A solution of 7-(3-(pyrrolidine-1-yl)propoxy)-N-(tetrahydro-2H-pyran-4-yl)quinazoline-4-amine (0.10 g, 0.24 mmol) and 1-methylhomopiperazine (0.07 g, 1.19 mmol) in anhydrous THF (1.5 mL) was mixed with DIPEA (0.09 mL, 0.53 mmol). The sealed tube was heated to 90 °C under an argon atmosphere for 3 days. The cooled reaction was quenched with saturated NaHCO3, extracted with an 8:2 dichloromethane / isopropanol mixture (3 × 25 mL), and then washed once with brine. The combined organic layer was dehydrated with anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by Buchi Pureflash chromatography on a silica gel cartridge (24 g) using 9:1 CH2Cl2:MeOH w / 2% 7N ammonia to obtain 6-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-7-(3-(pyrrolidine-1-yl)propoxy)-N-(tetrahydro-2H-pyran-4-yl)quinazoline-4-amine (0.12 g, 99%) as a grayish-white solid. 1H NMR (400 MHz, CDCl3): δ 6.88 (s, 1H), 6.68 (s, 1H), 4.91 (d, 1H, J = 8.0 Hz), 4.29 (m, 1H), 4.15 (m, 2H), 4.03 (m, 2H), 3.95 (m, 2H), 3.90 (s, 3H), 3.85 (t, 2H, J = 8.0 Hz), 3.55 (dt, J = 12.0, 4.0 Hz), 2.68 (t, 2H, J = 4.0 Hz), 2.62 (t, 2H, J = 8.0 Hz), 2.51 (m, 4H), 2.35 (s, 3H), 2.15-2.05 (m, 4H), 1.99 (m, 2), 1.77 (m, 4H), 1.61 (ddd, 2H, J = 8.0, 8.0, 4.0 Hz). MS (ESI): C 27 H 42 Calculated value for N6O3: 498, measured value: 499 (M+H) + . [Example 24]

[0431] Synthesis of 4-(6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)-4-((tetrahydro-2H-pyran-4-yl)amino)quinazoline-2-yl)thiomorpholine 1,1-dioxide (compound 196)

[0432] [ka] Preparation: DIPEA (0.12 mL, 0.71 mmol) was added to a solution of 7-(3-(pyrrolidine-1-yl)propoxy)-N-(tetrahydro-2H-pyran-4-yl)quinazoline-4-amine (0.15 g, 0.36 mmol) and thiomorpholine 1,1-dioxide (0.24 g, 1.78 mmol) in anhydrous THF (3 mL). The sealed tube was heated at 90°C under an argon atmosphere for 10 days. The precipitate was collected by filtration to obtain 4-(6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)-4-((tetrahydro-2H-pyran-4-yl)amino)quinazoline-2-yl)thiomorpholine 1,1-dioxide (0.11 g, 61%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 6.92 (s, 1H), 6.87 (s, 1H), 5.48 (bs, 1H), 4.36 (m, 4H), 4.27 (m, 1H), 4.17 (m, 2H), 4.04 (m, 4H), 3.92 (s, 3H), 3.54 (m, 3H), 3.26 (m, 3H), 3.05 (m, 5H), 2.45 (m, 2H), 2.13 (m, 4H), 2.06 (m, 3H), 1.70 (ddd, 2H, J = 8.0, 8.0, 4.0 Hz). MS (ESI): C 25 H 37 Calculated value for N5O5S: 519, Measured value: 520 (M+H) + . [Example 25]

[0433] Synthesis of 4-((2-chloro-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazolin-4-yl)amino)tetrahydro-2H-thiopyran 1,1-dioxide (compound 111)

[0434] [ka] Preparation: A solution of commercially available 2,4-dichloro-6-methoxy-7-(3-(pyrroridine-1-yl)propoxy)quinazoline (2.03 g, 5.69 mmol) and 4-aminotetrahydro-2H-thiopyran (1.27 g, 8.54 mmol) in anhydrous 3:1 DMF / isopropanol (20 mL) was mixed with DIPEA (1.98 mL, 11.39 mmol). The sealed tube was heated at 50°C under an argon atmosphere for 6 days. The cooled reaction was concentrated under vacuum. The residue was dried and packed onto silica (15 g), and purified by Buchi Pureflash chromatography on a silica gel cartridge (80 g) using 9:1 CH2Cl2:MeOH w / 2% 7N ammonia to obtain 4-((2-chloro-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazolin-4-yl)amino)tetrahydro-2H-thiopyran 1,1-dioxide (1.93 g, 72%) as a beige solid. 1H NMR (400 MHz, CDCl3): δ 7.07 (s, 1H), 6.99 (s, 1H), 6.27 (d, 1H, J = 8.0 Hz), 4.65 (m, 1H), 4.15 (t, 2H, J = 8.0 Hz), 3.95 (s, 3H), 3.29 (m,3H), 3.16 (m, 2H), 2.90 (m, 1H), 2.70 (t, 2H, J = 8.0 Hz), 2.62 (m, 4H), 2.48 (m, 2H), 2.37 (m, 4H), 2.19 (m, 1H), 2.14 (p, 2H, J = 8.0 Hz), 1.99 (m, 1H), 1.81 (m, 4H). MS (ESI): C 21 H 29 Calculated value of ClN4O4S: 469, Measured value: 469 (M) + , 471 (M+2H) + . [Example 26]

[0435] Synthesis of 4-((6-methoxy-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)amino)tetrahydro-2H-thiopyran 1,1-dioxide (compound 80)

[0436] [ka] Preparation: A solution of 4-((2-chloro-6-methoxy-7-(3-(pyrroridine-1-yl)propoxy)quinazolin-4-yl)amino)tetrahydro-2H-thiopyran 1,1-dioxide (0.15 g, 0.32 mmol) and pyrrolidine (0.11 g, 1.60 mmol) in anhydrous THF (2 mL) was mixed with DIPEA (0.08 mL, 0.48 mmol). The sealed tube was heated at 90°C under an argon atmosphere for 5 days. The cooled reaction was quenched with saturated NaHCO3, extracted with an 8:2 dichloromethane / isopropanol mixture (3 × 25 mL), and then washed once with brine. The combined organic layer was dehydrated with anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by Buchi Pureflash chromatography on a silica gel cartridge (24 g) using 8:2 CH2Cl2:MeOH w / 2% 7N ammonia to obtain 4-((6-methoxy-2-(pyrrolidine-1-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazolin-4-yl)amino)tetrahydro-2H-thiopyran 1,1-dioxide (0.15 g, 89%) as a grayish-white solid. 1 H NMR (400 MHz, CDCl3): δ 6.92 (s, 1H), 6.71 (s, 1H), 5.08 (d, 1H, J = 8.0 Hz), 4.44 (m, 1H), 4.14 (t, 2H, J = 8.0 Hz), 3.90 (s, 3H), 3.59 (m, 4H), 3.15 (m, 4H), 2.61 (t, 2H, J = 8.0 Hz), 2.53 (m, 2H), 2.51 (m, 4H), 2.28 (m, 2H), 2.08 (p, 2H, J = 8.0 Hz), 1.95 (m, 4H), 1.76 (m, 4H). MS (ESI): C 25 H 37 Calculated value of N5O4S: 503, Measured value: 504 (M+H) + . [Example 27]

[0437] Synthesis of 4-((6-methoxy-2-morpholino-7-(3-(pyrrolidine-1-yl)propoxy)quinazolin-4-yl)amino)tetrahydro-2H-thiopyran 1,1-dioxide (compound 102)

[0438] [ka] Preparation: A solution of 4-((2-chloro-6-methoxy-7-(3-(pyrrolin-1-yl)propoxy)quinazolin-4-yl)amino)tetrahydro-2H-thiopyran 1,1-dioxide (0.15 g, 0.32 mmol) and morpholine (0.14 g, 1.60 mmol) in anhydrous THF (2 mL) was mixed with DIPEA (0.08 mL, 0.48 mmol). The sealed tube was heated at 90°C under an argon atmosphere for 5 days. The cooled reaction was quenched with saturated NaHCO3, extracted with an 8:2 dichloromethane / isopropanol mixture (3 × 25 mL), and then washed once with brine. The combined organic layers were dehydrated with anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by Buchi Pureflash chromatography on a silica gel cartridge (24 g) using 8:2 CH2Cl2:MeOH w / 2% 7N ammonia to obtain 4-((6-methoxy-2-morpholino-7-(3-(pyrrolidine-1-yl)propoxy)quinazolin-4-yl)amino)tetrahydro-2H-thiopyran 1,1-dioxide (0.13 g, 80%) as a grayish-white solid. 1 H NMR (400 MHz, CDCl3): δ 6.90 (s, 1H), 6.71 (s, 1H), 5.15 (d, 1H, J = 8.0 Hz), 4.43 (m, 1H), 4.16 (t, 2H, J = 8.0 Hz), 3.91 (s. 3H), 3.77 (bs, 8H), 3.16 (dd, 4H, J = 8.0, 4.0 Hz), 2.66 (t, 2H, J = 8.0 Hz), 2.56 (m, 4H), 2.52 (m, 2H), 2.31 (m, 2H), 2.12 (p, 2H, J = 8.0 Hz), 1.79 (m, 4H). MS (ESI): C 25 H 37 Calculated value for N5O5S: 519, Measured value: 520 (M+H) + . [Example 28]

[0439] Synthesis of 4-((6-methoxy-2-(4-methylpiperazine-1-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide (compound 109)

[0440] [ka] Preparation: A solution of 4-((2-chloro-6-methoxy-7-(3-(pyrrolin-1-yl)propoxy)quinazolin-4-yl)amino)tetrahydro-2H-thiopyran 1,1-dioxide (0.10 g, 0.21 mmol) and 1-methylpiperazine (0.11 g, 1.07 mmol) in anhydrous THF (2 mL) was mixed with DIPEA (0.06 mL, 0.32 mmol). The sealed tube was heated at 90 °C under an argon atmosphere for 5 days. The cooled reaction was quenched with saturated NaHCO3, extracted with an 8:2 dichloromethane / isopropanol mixture (3 × 25 mL), and then washed once with brine. The combined organic layer was dehydrated with anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by Buchi Pureflash chromatography on a silica gel cartridge (24 g) using 8:2 CH2Cl2:MeOH w / 2% 7N ammonia to obtain 4-((6-methoxy-2-(4-methylpiperazin-1-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazolin-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide (0.09 g, 81%) as a grayish-white solid. 1 H NMR (400 MHz, CDCl3): δ 6.90 (s, 1H), 6.69 (s, 1H), 5.07 (d, 1H, J = 8.0 Hz), 4.43 (m, 1H), 4.15 (t, 2H, J = 8.0 Hz), 3.91 (s, 3H), 3.82 (m, 4H), 3.16 (m, 4H), 2.63 (t, 2H, J = 8.0 Hz), 2.33 (s, 3H), 2.27 (m, 3H), 2.10 (p, 2H, J = 8.0 Hz), 1.94 (bs, 1H), 1.77 (m, 4H). MS (ESI): C 26 H 40Calculated value of N6O4S: 532, Measured value: 533 (M+H) + . [Example 29]

[0441] Synthesis of 4-(4-((1,1-dioxidetetrahydro-2H-thiopyran-4-yl)amino)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-2-yl)thiomorpholine 1,1-dioxide (compound 103)

[0442] [ka] Preparation: DIPEA (0.11 mL, 0.64 mmol) was added to a solution of 4-((2-chloro-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazolin-4-yl)amino)tetrahydro-2H-thiopyran 1,1-dioxide (0.15 g, 0.32 mmol) and thiomorpholine 1,1-dioxide (0.22 g, 1.60 mmol) in anhydrous THF (2 mL). The sealed tubes were heated at 90°C under an argon atmosphere for 12 days. The reaction was carried out under cooling conditions, and the precipitate was collected by filtration and washing with cold THF to obtain 4-(4-((1,1-dioxidetetrahydro-2H-thiopyran-4-yl)amino)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-2-yl)thiomorpholine 1,1-dioxide (0.09 g, 81%) as a beige solid. 1H NMR (400 MHz, CDCl3 / DMSO-d mixture): δ 6.88 (s, 1H), 6.71 (s, 1H), 5.12 (d, 1H, J = 8.0 Hz), 4.38 (m 1H), 4.15 (t, 2H, J = 8.0 Hz), 3.93 (m, 2H), 3.90 (s, 1H), 3.84 (t, 2H, J = 8.0 Hz), 3.16 (m, 3H), 2.67 (m 2H), 2.60 (t, 2H, J = 8.0 Hz), 2.55 (m, 2H) 2.48 (m 4H), 2.35 (s, 3H), 2.28 (m, 1H), 2.08 (p, 2H, J = 8.0 Hz), 1.98 (m, 4H), 1.76 (m, 4H). MS (ESI): C 25 H 37 Calculated value of N5O6S2: 567, measured value: 568 (M+H) + . [Example 30]

[0443] Synthesis of 4-((6-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazolin-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide (compound 110)

[0444] [ka] Preparation: A solution of 4-((2-chloro-6-methoxy-7-(3-(pyrrolin-1-yl)propoxy)quinazolin-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide (0.10 g, 0.21 mmol) and 1-methylhomopiperazine (0.12 g, 1.07 mmol) in anhydrous THF (2 mL) was mixed with DIPEA (0.05 mL, 0.32 mmol). The sealed tube was heated at 90 °C under an argon atmosphere for 5 days. The cooled reaction was quenched with saturated NaHCO3, extracted with an 8:2 dichloromethane / isopropanol mixture (3 × 25 mL), and then washed once with brine. The combined organic layer was dehydrated with anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by Buchi Pureflash chromatography on a silica gel cartridge (24 g) using 9:1 CH2Cl2:MeOH w / 2% 7N ammonia to obtain 4-((6-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazolin-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide (0.12 g, 99%) as a grayish-white solid. 1 H NMR (400 MHz, CDCl3): δ 6.89 (s, 1H), 6.68 (s, 1H), 5.02 (d, 1H, J = 8.0 Hz), 4.38 (m, 1H), 4.16 (t, 2H, J = 8.0 Hz), 3.94 (m, 2H), 3.90 (s, 3H), 3.84 (t, 2H, J = 8.0 Hz), 3.16 (m, 4H) 2.69 (m, 2H), 2.63 (t, 2H, J = 8.0 Hz), 2.59-2.45 (m, 8H), 2.36 (s, 3H), 2.28 (m, 2H), 2.10 (p, 2H, J = 8.0 Hz), 1.99 (m, 3H), 1.77 (m, 4H). MS (ESI): C 27 H 42 Calculated value of N6O4S: 546, Measured value: 547 (M+H) + . [Example 31]

[0445] 4-((7-(benzyloxy)-2-chloro-6-methoxyquinazolin-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide (compound-133)

[0446] [ka] Preparation: A solution of commercially available 7-(benzyloxy)-2,4-dichloro-6-methoxyquinazoline (2.00 g, 5.97 mmol) and 4-aminotetrahydro-2H-thiopyran (1.34 g, 8.95 mmol) in anhydrous DMF (15 mL) was mixed with DIPEA (2.60 mL, 14.92 mmol). The sealed tube was heated to 50 °C under an argon atmosphere for 6 days. The cooled reaction was concentrated under vacuum. The crude solid was suspended in a minimum amount of methanol and sonicated, and the precipitate was collected by filtration to obtain 4-((7-(benzyloxy)-2-chloro-6-methoxyquinazoline-4-yl)amino)tetrahydro-2H-thiopyran 1,1-dioxide (2.67 g, 100%) as a white solid. 1 H NMR (400 MHz, DMSO-d): δ 8.07 (d, 1H, J = 8.0 Hz), 7.65 (s, 1H), 7.48 (d, 2H, J = 4.0 Hz), 7.41 (dd, 2H, J = 4.0, 4.0 Hz), 7.36 (d, 1H, J = 4.0 Hz), 7.18 (s, 1H), 4.53 (m, 1H), 3.90 (s, 3H), 3.45 (td, 2H, J = 12.0, 4.0 Hz), 3.12 (d, 2H, J = 8.0 Hz), 2.25-2.10 (m, 4H). MS (ESI): C 21 H 22 Calculated value of ClN3O4S: 447, measured value: 448 (M+H) + . [Example 32]

[0447] 4-((7-(benzyloxy)-2-(4,4-difluoropiperidine-1-yl)-6-methoxyquinazoline-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide (compound-134)

[0448] [ka] Preparation: 4,4-difluoropiperidine hydrochloride (2.29 g, 14.51 mmol) was added to a suspension of 4-((7-(benzyloxy)-2-chloro-6-methoxyquinazolin-4-yl)amino)tetrahydro-2H-thiopyran 1,1-dioxide (1.30 g, 2.90 mmol) and DIPEA (0.44 mL, 2.53 mmol) in anhydrous 2-butanol (20 mL). The sealed tube was stirred and heated to 90°C under an argon atmosphere. At completion after 5 days, the cooled reaction mixture was quenched with saturated NaHCO3 and extracted with an 8:2 dichloromethane / isopropanol mixture (3 × 50 mL). The combined organic layers were dehydrated with anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude solid was suspended in a minimum amount of dichloromethane and sonicated, and the precipitate was collected by filtration to obtain 4-((7-(benzyloxy)-2-(4,4-difluoropiperidine-1-yl)-6-methoxyquinazolin-4-yl)amino)tetrahydro-2H-thiopyran 1,1-dioxide (1.35 g, 87%) as a white solid. 1 H NMR (400 MHz, DMSO-d): δ 7.52 (d, 1H, J = 8.0 Hz), 7.51 (s, 1H), 7.52 (d, 2H, J = 8.0 Hz), 7.40 (m, 2H), 7.34 (m 1H), 6.87 (s, 1H), 5.18 (s, 2H), 4.48 (m, 1H), 3.91 (m, 4H), 3.83 (s, 3H), 3.43 (td, 2H, J = 12.0, 4.0 Hz), 3.14 (d, 2H, J = 12.0 Hz), 2.25 (m, 2H), 2.13 (m, 2H), 1.95 (m, 4H). MS (ESI): C 26 H 30 Calculated value for F2N4O4S: 532, Measured value: 533 (M+H) + . [Example 33]

[0449] 4-((2-(4,4-difluoropiperidine-1-yl)-7-hydroxy-6-methoxyquinazoline-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide (compound-238)

[0450] [ka] Preparation: A suspension of 4-((7-(benzyloxy)-2-(4,4-difluoropiperidine-1-yl)-6-methoxyquinazoline-4-yl)amino)tetrahydro-2H-thiopyran 1,1-dioxide (1.10 g, 2.90 mmol) was added to 10% palladium carbon (0.22 g, 0.21 mmol) in anhydrous ethanol (120 mL) that had been foamed for 20 minutes under an argon atmosphere. The mixture was then foamed with hydrogen gas for 15 minutes using a needle to introduce the solution. The reaction was stirred and maintained under a hydrogen balloon over the weekend. After completion, the mixture was diluted with THF (300 mL) and filtered through a Celite pad. The solvent was concentrated to a solid. The crude solid was then suspended in a minimum amount of methanol and sonicated, and the precipitate was collected by filtration to obtain 4-((2-(4,4-difluoropiperidine-1-yl)-7-hydroxy-6-methoxyquinazolin-4-yl)amino)tetrahydro-2H-thiopyran 1,1-dioxide (1.35 g, 87%) as a white solid. 1 H NMR (400 MHz, DMSO-d): δ 9.77 (s, 1H), 7.42 (m, 2H), 6.65 (s, 1H), 4.47 (m, 1H), 3.87 (m, 4H), 3.82 (s, 3H), 3.41 (td, 2H, J = 12.0, 4.0 Hz), 3.14 (m, 2H), 2.25 (m, 2H), 2.12 (m, 2H), 1.94 (m, 4H). MS (ESI): C 19 H 24 Calculated value for F2N4O4S: 442, Measured value: 443 (M+H) + . [Example 34]

[0451] 2-(4,4-difluoropiperidine-1-yl)-4-((1,1-dioxidetetrahydro-2H-thiopyran-4-yl)amino)-6-methoxyquinazoline-7-yltrifluoromethanesulfonate (compound-i-1)

[0452] [ka] Preparation: A suspension of 4-((2-(4,4-difluoropiperidine-1-yl)-7-hydroxy-6-methoxyquinazolin-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide (0.45 g, 1.02 mmol) in anhydrous THF (20 mL) under an argon atmosphere was mixed with potassium carbonate (0.28 g, 2.05 mmol) and N-phenyl-bis(trifluoromethanesulfonimide (0.48 g, 1.33 mmol)). The reaction was stirred for 24 hours. After completion, the reaction was quenched with saturated NaHCO3, extracted with an 8:2 dichloromethane / isopropanol mixture (5 × 50 mL), and then washed once with brine. The combined organic layer was dehydrated with anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was packed solid onto silica (5 g) and 95:5 CH2Cl2:MeOH w / 2% The solution was purified by Buchi Pureflash chromatography using 7N ammonia on a silica gel cartridge (80g) to obtain 2-(4,4-difluoropiperidine-1-yl)-4-((1,1-dioxidetetrahydro-2H-thiopyran-4-yl)amino)-6-methoxyquinazoline-7-yltrifluoromethanesulfonate (0.56g, 95%) as a white solid. 1 H NMR (400 MHz, DMSO-d): δ 7.88 (d, 1H, J = 12.0 Hz), 7.83 (s, 1H), 7.32 (s, 1H), 4.53 (m, 1H), 3.96 (s, 3H), 3.92 (m, 4H), 3.45 (td, 2H, J = 12.0, 4.0 Hz), 3.16 (d, 2H, J = 12.0 Hz), 2.27 (m, 2H), 2.14 (m, 4H), 1.97 (m, 4H). MS (ESI): C 20 H 23Calculated value for F2N4O6S2: 574, Measured value: 574 (M) + . [Example 35]

[0453] 4-((2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)quinazolin-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide (compound 248)

[0454] [ka] Preparation: A pressure vessel was filled with 1-(propa-2-in-1-yl)pyrrolidine hydrochloride (355 mg, 2.44 mmol), cesium carbonate (1.36 g, 4.18 mmol), and anhydrous acetonitrile (5 mL) under argon and stirred for 5 minutes. Then, 2-(4,4-difluoropiperidine-1-yl)-4-((1,1-dioxidetetrahydro-2H-thiopyran-4-yl)amino)-6-methoxyquinazoline-7-yltrifluoromethanesulfonate (200 mg, 0.35 mmol) and copper(I) iodide (7.96 mg, 0.042 mmol) were added. The mixture was foamed under argon for 15 minutes before the addition of bis(triphenylphosphine)palladium(II) chloride (24.43 mg, 0.035 mmol), and the sealed vessel was heated at 80°C for 4 hours. After completion, the cooled reaction mixture was filtered through a Celite pad and thoroughly washed with acetonitrile. The solvent was concentrated under vacuum and dried and packed onto silica (3.5 g). It was then purified by Buchi Pureflash chromatography on a silica gel cartridge (40 g) using 95:5 CH2Cl2:MeOH w / 2% 7N ammonia to obtain 4-((2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)quinazolin-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide (1.35 g, 87%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d): δ 7.76 (d, 1H, J = 8.0 Hz), 7.51 (s, 1H), 7.31 (s, 1H), 4.51 (m, 1H), 3.90 (m, 4H), 3.86 (s, 3H), 3.44 (td, 2H, J = 12.0, 4.0 Hz), 3.15 (d, 2H, J = 12.0 Hz), 2.60 (m, 4H), 2.26 (m, 2H), 2.14 (m, 2H), 1.96 (m, 4H), 1.73 (m, 4H). MS (ESI): C 26 H 33 Calculated value for F2N5O3S: 533, Measured value: 534 (M+H) + . [Example 36]

[0455] 2-Chloro-6-methoxy-N-(oxetan-3-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine (compound-114)

[0456] [ka] Preparation: A solution of commercially available 2,4-dichloro-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline (2.00 g, 5.61 mmol) and 3-oxetanamine (0.62 g, 8.42 mmol) in anhydrous DMF (15 mL) was mixed with DIPEA (2.93 mL, 16.84 mmol). The sealed tube was heated to 50 °C under an argon atmosphere for 3 days. The cooled reaction was quenched with saturated NaHCO3, extracted with an 8:2 dichloromethane / isopropanol mixture (3 × 50 mL), and then washed once with brine. The combined organic layers were dehydrated with anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by Buchi Pureflash chromatography on a silica gel cartridge (80g) using 95:5 CH2Cl2:MeOH w / 2% 7N ammonia to obtain 2-chloro-6-methoxy-N-(oxetan-3-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine (1.37g, 62%) as a beige solid. 1H NMR (400 MHz, CDCl3-d): δ 7.10 (s, 1H), 6.92 (s, 1H), 6.25 (d, 1H, J = 8.0 Hz), 5.38 (m, 1H), 5.10 (t, 2H, J = 8.0 Hz), 4.65 (t, 2H, J = 4.0 Hz), 4.14 (t, 2H, J = 4.0 Hz), 3.95 (s, 3H), 2.61 (dd, 2H, J = 8.0 Hz), 2.50 (m, 4H), 2.08 (m, 2H), 1.76 (m, 4H). MS (ESI): C 19 H 25 Calculated value for ClN4O3: 392, measured value: 393 (M+H) + . [Example 37]

[0457] 2-(4,4-difluoropiperidine-1-yl)-6-methoxy-N-(oxetan-3-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine (compound 11)

[0458] [ka] Preparation: A solution of 2-chloro-6-methoxy-N-(oxetan-3-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine (0.20 g, 0.51 mmol) and 4,4-difluoropiperidine (0.31 g, 2.55 mmol) in anhydrous THF (8 mL) was mixed with DIPEA (0.33 g, 2.55 mmol). The sealed tube was heated to 90 °C for 8 days under an argon atmosphere. The cooled mixture was quenched with saturated NaHCO3, extracted with an 8:2 dichloromethane / isopropanol mixture (3 × 50 mL), and then washed once with brine. The combined organic layers were dehydrated with anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by Buchi Pureflash chromatography on a silica gel cartridge (40 g) using 9:1 CH2Cl2:MeOH w / 2% 7N ammonia to obtain 2-(4,4-difluoropiperidine-1-yl)-6-methoxy-N-(oxetan-3-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine (0.30 g, 42%) as a grayish-white solid. 1 H NMR (400 MHz, CDCl3): δ 6.91 (s, 1H), 6.89 (s, 1H), 5.96 (bs, 1H), 5.24 (m, 1H), 5.02 (t, 2H, J = 8.0 Hz), 4.72 (t, 2H, J = 4.0 Hz), 4.15 (t, 2H, J = 8.0 Hz), 3.94 (m, 4H), 3.92 (s, 3H), 2.86 (m, 2H), 2.81 (m, 4H), 2.23 (m, 2H), 1.97 (m, 4H), 1.90 (m, 4H). MS (ESI): C 24 H 33 Calculated value for F2N5O: 477, measured value: 478 (M+H) + . [Example 38]

[0459] 2-(1H-imidazole-1-yl)-6-methoxy-N-(pyridine-4-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine (compound-130)

[0460] [ka] Preparation: A solution of commercially available 2,4-dichloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (0.25 g, 0.70 mmol) and 4-aminopyridine (0.07 g, 0.77 mmol) in anhydrous THF (5 mL) was mixed with an excess of 60% sodium hydride (0.04, 0.91 mmol). The mixture was stirred under an argon balloon for 30 minutes. The tube was then sealed and heated to 50°C under an argon atmosphere. The reaction was monitored by TLC with dichloromethane and HPLC / MS with 414. At completion after 20 hours, the cooled reaction was quenched with saturated NH4Cl (2 mL), followed by saturated NaHCO3 (50 mL). The mixture was then extracted with an 8:2 dichloromethane / isopropanol mixture (3 × 50 mL) and washed once with brine. The combined organic layers were dehydrated with anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude product was dissolved in anhydrous acetonitrile (5 ml), followed by the addition of K2CO3 (0.48 g, 1.76 mmol) and imidazole (0.96 g, 14.04 mmol). The sealed tube was then microwaved at 160°C for 5 hours. The cooled mixture was quenched with saturated NaHCO3, extracted with an 8:2 dichloromethane / isopropanol mixture (3 × 50 mL), and then washed once with brine. The combined organic layers were dehydrated with anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by Buchi Pureflash chromatography on a silica gel cartridge (40g) using 9:1 CH2Cl2:MeOH w / 2% 7N ammonia to obtain 2-(1H-imidazole-1-yl)-6-methoxy-N-(pyridine-4-yl)-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-amine (0.05g, 16%) as a yellow solid. 1H NMR (400 MHz, DMSO-d): δ 10.04 (s, 1H), 8.60 (dd, 2H, J = 4.0, 1.0 Hz), 8.54 (s, 1H), 7.92 (m, 4H), 7.24 (s, 1H), 7.15 (s, 1H), 4.23 (t, 2H, J = 8.0 Hz), 3.99 (s. 3H), 2.59 (t, 2H, J = 8.0 Hz), 2.47 (m, 4H), 1.99 (p, 2H, J = 8.0 Hz), 1.71 (m, 4H). MS (ESI): C 24 H 27 Calculated value for F2N7O2: 445, measured value: 446 (M+H) + . [Example 39]

[0461] 2-(1H-imidazole-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)-N-(tetrahydro-2H-pyran-4-yl)quinazoline-4-amine (compound 131)

[0462] [ka] Preparation: Potassium carbonate (0.23 g, 1.68 mmol) was added to a solution of commercially available 2,4-dichloro-6-methoxy-7-(3-(pyrroridine-1-yl)propoxy)quinazoline (0.30 g, 0.84 mmol) and 4-aminotetrahydro-2H-thiopyran (0.09 g, 0.93 mmol) in anhydrous DMF (2 mL). The sealed tube was heated to 50 °C under an argon atmosphere. The reaction was monitored by TLC with dichloromethane and HPLC / MS on 421.1. After completion, the cooled reaction was quenched with brine and extracted with an 8:2 dichloromethane / isopropanol mixture (3 × 50 mL). The combined organic layer was dehydrated with anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The crude product was dissolved in acetonitrile (3.5 ml) supplemented with potassium carbonate (0.23 g, 1.68 mmol) and imidazole (0.46 g, 6.74 mmol), and the sealed tube was microwaved at 160°C for 5 hours. The cooled mixture was quenched with saturated NaHCO3, extracted with an 8:2 dichloromethane / isopropanol mixture (3 × 50 mL), and then washed once with brine. The combined organic layers were dehydrated with anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by Buchi Pureflash chromatography on a silica gel cartridge (40 g) using 8:2 CH2Cl2:MeOH w / 2% 7N ammonia (8:2) to obtain 2-(1H-imidazole-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)-N-(tetrahydro-2H-pyran-4-yl)quinazoline-4-amine (0.20 g, 53%) as a beige solid. 1H NMR (400 MHz, CDCl3): δ 8.56 (t, 1H, J = 1.2 Hz), 8.02 (d, 1H, J = 7.2 Hz), 7.92 (t, 1H, J = 1.2 Hz), 7.68 (s, 1H), 7.09 (s, 1H), 7.07 (t, 1H, J = 1.2 Hz), 4.48 (m, 1H), 4.16 (t, 2H, J = 6.8 Hz), 3.95 (dd, 2H, J = 10.8, 3.2 Hz), 3.91 (s, 3H), 3.54 (tt, 2H, J = 12.0, 2.0 Hz), 2.53 (t, 2H, J = 7.2 Hz), 2.44 (m, 4H), 1.96 (m, 4H), 1.68 (m, 6H). MS (ESI): C 24 H 32 Calculated value for N6O3: 452, measured value: 453 (M+H) + . [Example 40]

[0463] (R)-2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)-N-(tetrahydro-2H-pyran-3-yl)quinazoline-4-amine (compound 12)

[0464] [ka] Preparation: A solution of commercially available 2,4-dichloro-6-methoxy-7-(3-(pyrroridine-1-yl)propoxy)quinazoline (0.25 g, 0.70 mmol) and (R)-tetrahydro-2H-pyran-3-amine hydrochloride (0.145 g, 0.11 mmol) in anhydrous DMF (6 mL) was mixed with DIPEA (0.37 mL, 2.11 mmol). The sealed tube was heated to 50 °C under an argon atmosphere. The reaction was monitored by TLC with dichloromethane and HPLC / MS on 421.2. Upon completion after 3 days, the cooled reaction was quenched with saturated NaHCO3 and extracted with an 8:2 dichloromethane / isopropanol mixture (3 × 50 mL). The combined organic layer was dehydrated with anhydrous Na2SO4, filtered, and concentrated under vacuum. The c...

Claims

1. Compounds of formula (II), or their stereoisomers, tautomers, or pharmaceutically acceptable compounds A compound that is a salt of [something]. 【Chemistry 1】 [In the formula, X １ It is a covalent bond, X2 is hydrogen, and X ３ This is expressed by equation (IX3), 【Chemistry 2】 [In the formula, X a CH is, m is 2, n is 2, X ｂ O and SO ２ Selected from the group consisting of, l is 0, X 4 is -NR ２ R ３ And, R bonded to the same nitrogen atom ２ and R ３ together with the atoms to which they are attached form an optionally halogen-substituted 6-membered heterocyclyl, R ４ is, -OR ９ And, R ９ teeth, 【Transformation 3】 And, R ５ is -OMe, A is N, r is 0.

2. X ｂ However, SO ２ The compound according to claim 1.

3. The compound according to claim 1, wherein Xb is O.

4. X 4 However, the compound according to claim 1, represented by formula (IX4). 【Chemistry 4】 [In the formula, X ｆ N is, b is an integer independently selected from 1, 2, or 3. c is an integer independently selected from 0, 1, 2, or 3. d is an integer independently selected from 0, 1, 2, or 3. X ｇ CH ２ NH, O and SO ２ Selected from the group consisting of, R ｆ It is optionally present and can be provided at any position in the "D" ring by replacing one or more -H atoms of any carbon or nitrogen atom present in the "D" ring. R ｆ It is a halogen.

5. A compound according to claim 1, selected from the group consisting of the following compounds: 4-((2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide; 2-(4,4-difluoropiperidine-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-yl)propoxy)-N-(tetrahydro-2H-pyran-4-yl)quinazoline-4-amine; 6-Methoxy-2-morpholino-7-(3-(pyrrolidine-1-yl)propoxy)-N-(tetrahydro-2H-pyran-4-yl)quinazoline-4-amine; 4-((6-methoxy-2-morpholino-7-(3-(pyrrolidine-1-yl)propoxy)quinazoline-4-yl)amino)tetrahydro-2H-thiopyran-1,1-dioxide; Alternatively, a compound that is a stereoisomer, tautomer, or pharmaceutically acceptable salt of any of the aforementioned compounds.

6. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 5 and a pharmaceutically acceptable excipient.

7. A pharmaceutical composition according to claim 6, for use in a method for treating inflammation.

8. The pharmaceutical composition according to claim 7, which downregulates the expression of inflammatory genes and disrupts extracellular matrix signaling pathways.

9. The pharmaceutical composition according to claim 7, wherein the inflammatory gene is Ccl2, Ccl3, Ccl7, Ccl9, Csf3, Csf3r, Cxcl1, Cxcl2, Cxcl3, Cxcl5, Il1a, Il1b, Il1r2, Il11, Il13ra2, Il6, Mmp3, Osm, Osmr, Ptgs2, Stc1, or Tnfrsf11b.

10. The pharmaceutical composition according to claim 6 for use in a method for treating a gastrointestinal tract or autoimmune disorder.

11. The aforementioned disorder is an autoimmune disorder. The pharmaceutical composition according to claim 10, wherein the autoimmune disorder is selected from the group consisting of ulcerative colitis, Crohn's disease, systemic lupus erythematosus, psoriasis, rheumatoid arthritis, type 1 diabetes mellitus, multiple sclerosis, celiac disease, graft-versus-host disease (GVHD), Sjögren's syndrome, Graves' disease, Hashimoto's thyroiditis, autoimmune hepatitis, Behçet's disease, atopic dermatitis, Castleman disease, allergic rhinitis, eczema, Dressler syndrome, eosinophilic esophagitis, fibromyalgia, Guillain-Barré syndrome, juvenile arthritis, Kawasaki disease, Mohren's ulcer, mixed connective tissue disease, Parry-Romberg syndrome, primary biliary cirrhosis, primary sclerosing cholangitis, psoriatic arthritis, sarcoidosis, scleroderma, undifferentiated connective tissue disease, uveitis, vasculitis, and vitiligo.

12. The pharmaceutical composition according to claim 10, wherein the disorder is Crohn's disease.

13. The pharmaceutical composition according to claim 10, wherein the disorder is ulcerative colitis.

14. The aforementioned disorder is one or more of IBD, Crohn's disease, and ulcerative colitis. The aforementioned compounds result in a decrease in the expression of marker genes for IBD, Crohn's disease, and / or ulcerative colitis. The pharmaceutical composition according to claim 10, wherein the marker gene comprises one or more of Ccl2, Ccl3, Ccl7, Ccl9, Csf3, Csf3r, Cxcl1, Cxcl2, Cxcl3, Cxcl5, Il1a, Il1b, Il1r2, Il11, Il13ra2, Il6, Mmp3, Osm, Osmr, Ptgs2, Stc1, and Tnfrsf11b.

15. The pharmaceutical composition according to claim 6 for use in a method of treating cancer.

16. The pharmaceutical composition according to claim 6 for use in a method for improving the intestinal microbiome in a patient.

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