Small molecules for the treatment of kinase-related diseases

Abstract

Disclosed herein are quinazolinyl compounds, compositions, and methods of use thereof. The compounds can be used in the treatment of kinase-associated disorders, including cancer, autoimmune diseases, and Duchenne muscular dystrophy.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 165,604, filed March 24, 2021, which is incorporated by reference in its entirety.

[0002] This application relates to the fields of chemistry and medicine. More specifically, this application relates to compounds useful in the treatment of kinase-associated disorders (cancer, autoimmune diseases and Duchenne muscular dystrophy). [Background technology]

[0003] 2. Description of Related Art Protein kinases selectively modify other proteins by adding covalent phosphates to them (phosphorylation). Phosphorylation results in a change in the function of the target protein (substrate), usually by altering the enzyme activity, cellular location, or association with other proteins. Protein kinase inhibitors are a class of enzyme inhibitors that block the action of one or more protein kinases. Phosphorylation regulates many biological processes, and protein kinase inhibitors can be used to treat diseases caused by overactive protein kinases (including mutated or overexpressed kinases in cancer, autoimmune diseases, and Duchenne muscular dystrophy) or to modulate cell functions to overcome other disease factors. Summary of the Invention

[0004] Some embodiments disclosed herein relate to quinazolinyl compounds, methods of using quinazolinyl compounds, compositions comprising quinazolinyl compounds, and methods of treatment using quinazolinyl compounds. Quinazolinyl compounds have the following structure: [ka] and numbering conventions. In some embodiments, the quinazolinyl compound is substituted at the 2-position, 4-position, 6-position, 7-position, or any one combination of the foregoing. In some embodiments, the quinazoline compound comprises an amine substituent attached to the quinazoline ring at the 4-position. In some embodiments, the amine at the 4-position is attached to a heteroaryl or heterocyclic substituent. In some embodiments, the quinazoline compound comprises a methoxy group at the 6-position. In some embodiments, the quinazoline compound comprises an alkoxy or alkynyl group at the 7-position. In some embodiments, the alkoxy or alkynyl group at the 7-position comprises a pendant heterocyclic group.

[0005] As disclosed elsewhere herein, in some embodiments, the quinazolinyl compound is substituted at position 2. In some embodiments, the substituent at position 2 can include an optionally substituted 6-10 membered aryl, an optionally substituted 3-10 membered heterocyclyl, an optionally substituted 5-10 membered heteroaryl, an optionally substituted carbamido, -CN, amino, monosubstituted amino, disubstituted amino, or a combination of the foregoing.

[0006] In some embodiments, the substituent at the 2-position may be optionally substituted as disclosed herein. In some embodiments, when the substituent at the 2-position includes one or more optional substituents, 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, when the substituent at the 2-position includes one or more additional optional substituents, the one or more optional substitutions may be independently selected from the group consisting of amino, -OH, optionally substituted C1-C6 alkyl, and halogen.

[0007] As disclosed elsewhere herein, in some embodiments, the quinazolinyl compound is substituted at the 4-position with an amine. In some embodiments, the quinazoline compound includes an amine at the 4-position that includes a cyclic substituent (either pendant or directly attached to the amine), or the amine is part of the cyclic substituent. In some embodiments, the substituent at the 4-position can be an optionally substituted heterocyclyl.

[0008] In some embodiments, the substituent at the 4-position may be optionally substituted as disclosed herein. In some embodiments, when the substituent at the 4-position includes one or more optional substituents, the one or more optional substitutions may be independently selected from the group consisting of C1-C3 alkyl, C1-C3 alkenyl, halo, cyano, hydroxy, and C1-C3 alkoxy. In some embodiments, when the substituent at the 4-position includes one or more additional optional substituents, the one or more optional substitutions may be independently selected from the group consisting of -OH, optionally substituted C1-C6 alkyl, and halogen.

[0009] As disclosed elsewhere herein, in some embodiments, the quinazolinyl compound is substituted at position 7 with alkoxy or (heterocyclyl)alkynyl. In some embodiments, the alkoxy includes an optionally substituted 2-10 membered heteroalkyl.

[0010] In some embodiments, the 7-position may be optionally substituted as described herein. In some embodiments, when the 7-position substituent includes one or more optional substituents, 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, when the 7-position substituent includes one or more optional substituents, the one or more optional substitutions may be independently selected from the group consisting of amino, -OH, optionally substituted C1-C6 alkyl, and halogen.

[0011] Some embodiments disclosed herein include a quinazolinyl compound of formula (I): [ka] or a stereoisomer, tautomer, or pharma- ceutically acceptable salt thereof, methods of using these quinazolinyl compounds, compositions comprising these quinazolinyl compounds, and methods of treatment using these quinazolinyl compounds. In some embodiments, R 1 is an optionally substituted 6- to 10-membered aryl, an optionally substituted 3- to 10-membered heterocyclyl, an optionally substituted 5- to 10-membered heteroaryl, an optionally substituted carbamide, -CN and -NR 4 R 5 R 4 and R 5 each is independently selected from hydrogen, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 carbocyclyl, or alternatively, R 4 and R 5 taken together form an optionally substituted 3- to 10-membered heterocyclyl, R 2 -OR 6 or optionally substituted (heterocyclyl)alkynyl, where R 6 is selected from the group consisting of methyl, optionally substituted 2-10 membered heteroalkyl, (carbocyclyl)alkyl, and (heterocyclyl)alkyl; R 3 is hydrogen, halogens, and C 1~6 alkoxy; R a is hydrogen or optionally substituted C1-C 10 and the A ring is an optionally substituted heteroaryl, or an optionally substituted heterocyclyl.

[0012] In some embodiments, the compound of formula (I) has the following structure: [ka] [ka] [ka] [ka] [ka] [ka] The term "convolutional eigenvalue" may be represented by one or more of:

[0013] In some embodiments, the disclosed quinazolinyl compounds directly target and / or inhibit one or protein kinases. In some embodiments, the disclosed quinazolinyl compounds may be particularly advantageous in the context of treating kinase-associated diseases. In some embodiments, the disclosed quinazolinyl compounds may be particularly advantageous in the context of treating kinase-associated cancers, autoimmune diseases, and Duchenne muscular dystrophy. In some embodiments, the compounds disclosed herein are characterized by their ability to bind to one or more of protein kinases and treat and / or prevent cancers, autoimmune diseases, and Duchenne muscular dystrophy (DMD). In some embodiments, the protein kinase is selected from the group consisting of CLK1, CLK2, CLK3, CLK4, FMS, JNK1, JNK2, JNK3, PLK4, FLT3, FLT3(D835V), FLT3(ITD), FLT3(F691L), FLT3(N841I), FLT3(D835H), FLT3(D835Y), FLT3(K663Q), FLT3(N841l), MYLK4, NUAK2, CSF1R, DAPK3, RIOK2, HIPK1, ALK, MYLK, EGFR, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, VEGFR, JAK1, ABL1, DAPK2, and LTK. In some embodiments, the protein kinase is selected from the group consisting of abl, Akt, Aurora-A, Auroa-B, Aurora-C, ATK, bcr-abl, Blk, Brk, Btk, c-Kit, c-Met, s-Src, c-fms, CDK1, CDK2 CDK4, CDK6, CDK7, CDK8, CDK9, CDK10, rRaf1, CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, ERK, Fak, fes, Fgr, fit-1, FLK-4, Fps, Fyn, Hck, HER, Hck, IGF-1R, INS-R, Jak, KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, Ros, Tie1, Tie2, Trk, Yes, and Zap70.In some embodiments, the protein kinase is selected from the group consisting of CLK1, CLK4, PLK4, FLT3, JNK1. In some embodiments, the disclosed quinazolinyl compounds directly target and / or inhibit protein kinases involved in the mitogen-activated protein kinase (MAPK) signaling pathway. In some embodiments, the disclosed quinazolinyl compounds directly target and / or inhibit lipid kinases (e.g., for treating cancer, autoimmune disease, and / or DMD). In some embodiments, the disclosed quinazolinyl compounds directly target and / or inhibit lipid kinases (e.g., PI3K), which constitute another group of kinases structurally similar to protein kinases. [Brief description of the drawings]

[0014] [Figures 1A-1E] Figures showing various embodiments disclosed herein. Figure 1A shows the general structure of a quinazolinyl structure, which may be substituted with any one of the following: substituent A at the 2-position, substituent B at the 4-position, substituent C at the 6-position, and substituent D at the 7-position.

[0015] [Figure 1B] A list of substituent A structures. This list is non-limiting and the substituent A may include other structures (as disclosed elsewhere herein). Any of these substituents may be further optionally substituted by replacing the -H atom with a substituent.

[0016] [Figure 1C] A list of substituent B structures. This list is non-limiting and the substituent B may include other structures (as disclosed elsewhere herein). Any of these substituents may be further optionally substituted by replacing the -H atom with a substituent.

[0017] [Figure 1D] List of substituent C structures. This list is non-limiting and the substituent C may include other structures (as disclosed elsewhere herein). Any of these substituents may be further optionally substituted by replacing the -H atom with a substituent.

[0018] [Figure 1E] A list of substituent D structures. This list is non-limiting and the substituent D may include other structures (as disclosed elsewhere herein). Any of these substituents may be further optionally substituted by replacing the -H atom with a substituent.

[0019] [Figure 2] An exemplary reaction scheme for a method of preparing a structure of formula (I).

[0020]

[0023] FIG. 3A depicts the results of a tumor growth rate study in test subjects treated with embodiments of the quinazolinyl compounds disclosed herein.

[0021]

[0023] FIG. 3B depicts the results of a tumor burden study in test subjects treated with embodiments of the quinazolinyl compounds disclosed herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] Some embodiments disclosed herein relate to quinazolinyl compounds, methods of using quinazolinyl compounds (e.g., for kinase inhibition and / or for treating kinase-associated disorders), compositions comprising quinazolinyl compounds, and methods of making quinazolinyl compounds. In some embodiments, the quinazolinyl compounds comprise a quinazolinyl nucleus. In some embodiments, the quinazoline compounds comprise an amine heteroaryl substituent attached to the quinazoline ring at the 4-position. In some embodiments, the quinazoline compounds comprise a methoxy group at the 6-position. In some embodiments, the quinazoline compounds comprise an alkoxy group at the 7-position. In some embodiments, the quinazoline compounds comprise a pendant cyclic group (e.g., a 5-membered heterocyclic group such as pyrrolidine) at the 7-position connected to the bicycle with either an alkyne or alkoxy group. In some embodiments, the quinazolinyl structures disclosed herein may be used to inhibit kinases and / or for treating kinase-associated disorders. The following description provides context and examples, but should not be construed to limit the scope of the invention covered by subsequent claims in this specification or any other application claiming priority hereof. No single component or collection of components is essential or essential. Any feature, structure, component, material, step, or method described and / or illustrated in any embodiment herein can be used with or in place of any feature, structure, component, material, step, or method described and / or illustrated in any other embodiment herein.

[0023] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs.All patents, applications, published applications, and other publications are incorporated by reference in their entirety.In the event that there are multiple definitions for terms herein, those in this section prevail unless otherwise stated.

[0024] Whenever a group is described as being "optionally substituted," the group can be unsubstituted or substituted with one or more of the indicated substituents. Similarly, when a group is described as being "unsubstituted or substituted" (or "substituted or unsubstituted"), if substituted, the substituents may be selected from one or more of the indicated substituents. If no substituents are indicated, it means that the indicated "optionally substituted" or "substituted" group may be individually and independently substituted with one or more groups selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), cycloalkyl(alkyl), heteroaryl(alkyl), heterocyclyl(alkyl), hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, nitro, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, amino, monosubstituted amine groups, disubstituted amine groups, monosubstituted amine(alkyl), disubstituted amine(alkyl), diamino groups, polyamino, diether groups, and polyether.

[0025] In some embodiments, substituted groups are substituted with one or more substituents individually and independently selected from C1-C4 alkyl, amino, hydroxy, and halogen.

[0026] As used herein, "C a ~C b" [where "a" and "b" are integers] refers to the number of carbon atoms in the group. The designated group can contain from "a" to "b" carbon atoms (inclusive). Thus, for example, a "C1-C4 alkyl" group refers to all alkyl groups having from 1 to 4 carbons, i.e., CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, and (CH3)3C-. When "a" and "b" are not indicated, the broadest ranges described by these definitions are intended to be construed.

[0027] When two "R" groups are described as being "together," the R groups and the atoms to which they are attached can form a cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclic ring. For example, and without limitation, NR x R y R in the group x and R y are shown to be "together", this means that they are covalently bonded to each other to form a ring: [ka] Similarly, when two R groups are said to form a ring "together with the atom to which they are attached" (e.g., a carbocyclyl, heterocyclyl, aryl, or heteroaryl ring), this means that the collective unit of the atoms and the two R groups is the recited ring. The ring is not otherwise limited by the definition of each R group in each individual instance. For example, the substructure: [ka] exists and R x and R y is defined as being selected from the group consisting of hydrogen and alkyl, or R x and R y together with the nitrogen to which they are attached form a heterocyclyl (or R x and R yare "taken together" to form a heterocyclyl, this is R x and R y can be selected from hydrogen or alkyl, or alternatively, the substructure can be selected from the structure: [ka] wherein ring H is the indicated nitrogen-containing heterocyclyl ring.

[0028] Similarly, when two "adjacent" R groups are said to form a ring "together with the atoms to which they are attached," this means that the collective unit of the atoms, intervening bonds, and two R groups is the recited ring. For example, the substructure: [ka] exists and R x and R y is defined as being selected from the group consisting of hydrogen and alkyl, or R x and R y together with the atom to which they are attached form an aryl or carbocyclyl (or R x and R y "come together" to form a carbocyclyl, this is R x and R y can be selected from hydrogen or alkyl, or alternatively, the substructure can be selected from the structure: [ka] wherein A is an aryl ring or carbocyclyl having the double bond shown.

[0029] As used herein, the term "alkyl" refers to a fully saturated aliphatic hydrocarbon group. The alkyl moiety may be branched or straight chain. Examples of branched alkyl groups include, but are not limited to, iso-propyl, sec-butyl, t-butyl, and the like. Examples of straight chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and the like. The alkyl group may have 1-20 carbon atoms (wherever it appears herein, a numerical range such as "1-20" refers to each integer in the given range, e.g., "1-20 carbon atoms" means that the alkyl group may consist of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms, but this definition also covers occurrences of the term "alkyl" where no numerical range is specified). An "alkyl" group may be a medium sized alkyl having 1-12 carbon atoms. An "alkyl" group may also be a lower alkyl having 1-6 carbon atoms. The alkyl group may be substituted or unsubstituted. By way of example only, "C1-C5 alkyl" indicates that there are 1-5 carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight chain), and the like. Exemplary alkyl groups include, but are not limited in any manner to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, and hexyl.

[0030] As used herein, the term "alkylene" refers to a divalent, fully saturated, straight-chain aliphatic hydrocarbon group. Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, and octylene. An alkylene group is: [ka] , followed by the number of carbon atoms, followed by " *For example, [ka] represents ethylene. The alkylene group may have 1 to 20 carbon atoms (wherever it appears herein, a numerical range such as "1 to 20" refers to each integer in the given range, e.g., "1 to 20 carbon atoms" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, but this definition also covers occurrences of the term "alkylene" where no numerical range is specified). The alkylene group may be a medium-sized alkyl having 1 to 12 carbon atoms. The alkylene group can also be a lower alkyl having 1 to 6 carbon atoms. The alkylene group may be substituted or unsubstituted. For example, a lower alkylene group may be a C alkyl group by replacing one or more hydrogens of the lower alkylene group and / or by replacing both hydrogens on the same carbon with C alkyl groups. 3~6 Monocyclic cycloalkyl groups (e.g. [ka] ) to replace

[0031] As used herein, the term "alkenyl" refers to a monovalent straight or branched chain radical of 2 to 20 carbon atoms containing a carbon double bond, including, but not limited to, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like. Alkenyl groups can be unsubstituted or substituted. Alkenyl groups can have 2 to 20 carbon atoms (wherever it occurs herein, a numerical range such as "2 to 20" refers to each integer in the given range, e.g., "2 to 20 carbon atoms" means that the alkenyl group can consist of 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms). Alkenyl groups can be medium size alkenyls having 2 to 12 carbon atoms. Alkenyl groups can also be lower alkenyls having 2 to 6 carbon atoms. Alkenyl groups can be represented in the same manner as used for alkyl. For example, "C2-C5 alkenyl" includes 1-propenyl (e.g., "C3 alkenyl"), 1-butenyl (e.g., "C4 alkenyl"), 2-butenyl (e.g., "C4 alkenyl"), 1-pentenyl (e.g., "C5 alkenyl"), and so forth.

[0032] As used herein, the term "alkynyl" refers to a monovalent straight or branched chain radical of 2 to 20 carbon atoms containing a carbon triple bond, including, but not limited to, 1-propynyl, 1-butynyl, 2-butynyl, and the like. Alkynyl groups can be unsubstituted or substituted. Alkynyl groups can have 2 to 20 carbon atoms (wherever it appears herein, a numerical range such as "2 to 20" refers to each integer in the given range, e.g., "2 to 20 carbon atoms" means that the alkynyl group can consist of 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms). Alkynyl groups can be medium size alkynyls having 2 to 12 carbon atoms. Alkynyl groups can also be lower alkynyls having 2 to 6 carbon atoms. Alkynyl groups can be represented in the same manner as used for alkyl. For example, "C2-C5 alkynyl" includes 1-propynyl (e.g., "C3 alkynyl"), 1-butynyl (e.g., "C4 alkynyl"), 2-butynyl (e.g., "C4 alkynyl"), 1-pentynyl (e.g., "C5 alkynyl"), and so forth.

[0033] As used herein, "cycloalkyl" refers to a fully saturated (no double or triple bonds) mono- or polycyclic (e.g., bicyclic) hydrocarbon ring system. When composed of more than one ring, the rings may be joined together in a fused, bridged, or spiro fashion. As used herein, the term "fused" refers to two rings that have two atoms and one bond in common. As used herein, the term "bridged cycloalkyl" refers to a compound in which a cycloalkyl contains one or more bond atoms connecting non-adjacent atoms. As used herein, the term "spiro" refers to two rings that have one atom in common, where the two rings are not joined by a bridge. Cycloalkyl groups can contain 3-30 atoms in the ring, 3-20 atoms in the ring, 3-10 atoms in the ring, 3-8 atoms in the ring, or 3-6 atoms in the ring. Cycloalkyl groups can be unsubstituted or substituted. Examples of monocycloalkyls include, but are not limited in any manner to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of fused cycloalkyls are decahydronaphthalenyl, dodecahydro-1H-phenalenyl, and tetradecahydroanthracenyl, examples of bridged cycloalkyls are bicyclo[1.1.1]pentyl, adamantanyl, and norbornanyl, and examples of spirocycloalkyls include spiro[3.3]heptane, and spiro[4.5]decane.

[0034] As used herein, "cycloalkenyl" refers to a mono- or polycyclic (e.g., bicyclic) hydrocarbon ring system containing one or more double bonds in at least one ring, provided that if more than one is present, the double bonds cannot form a fully delocalized pi-electron system across all rings (otherwise the group is "aryl" as defined herein). Cycloalkenyl groups can contain 3-10 atoms in a ring, 3-8 atoms in a ring, or 3-6 atoms in a ring. When composed of more than one ring, the rings may be connected together in a fused, bridged, or spiro fashion. Cycloalkenyl groups can be unsubstituted or substituted.

[0035] As used herein, "aryl" refers to a carbocyclic (all carbon) monocyclic or polycyclic (e.g., bicyclic) aromatic ring system (including fused ring systems in which two carbocyclic rings share a chemical bond) having a fully depolarized pi-electron system throughout all rings. The number of carbon atoms in an aryl group can vary. For example, an aryl group can be any of C6 to C8. 14 Aryl groups, C6-C 10The heteroaryl group may be an aryl group, or a C6 aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene, and azulene. The aryl group may be substituted or unsubstituted. As used herein, "heteroaryl" refers to a monocyclic or polycyclic (e.g., bicyclic) aromatic ring system (a ring system that includes a fully delocalized pi-electron system) that contains one or more heteroatoms (e.g., 1, 2, or 3 heteroatoms), i.e., elements other than carbon, including, but not limited to, nitrogen, oxygen, and sulfur. The number of atoms in the ring of a heteroaryl group may vary. For example, a heteroaryl group can contain 4 to 14 atoms in the ring, 5 to 10 atoms in the ring, or 5 to 6 atoms in the ring, e.g., 9 carbon atoms and 1 heteroatom, 8 carbon atoms and 2 heteroatoms, 7 carbon atoms and 3 heteroatoms, 8 carbon atoms and 1 heteroatom, 7 carbon atoms and 2 heteroatoms, 6 carbon atoms and 3 heteroatoms, 5 carbon atoms and 4 heteroatoms, 5 carbon atoms and 1 heteroatom, 4 carbon atoms and 2 heteroatoms, 3 carbon atoms and 3 heteroatoms, 4 carbon atoms and 1 heteroatom, 3 carbon atoms and 2 heteroatoms, or 2 carbon atoms and 3 heteroatoms. Additionally, the term "heteroaryl" includes fused ring systems in which two rings, e.g., at least one aryl ring and at least one heteroaryl ring, or at least two heteroaryl rings, share at least one chemical bond.Examples of heteroaryl rings include, but are not limited to, furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, and triazine. Heteroaryl groups can be substituted or unsubstituted.

[0036] As used herein, "heteroalkyl" refers to a straight or branched hydrocarbon chain (e.g., alkyl) containing one or more heteroatoms. Heteroatoms are given their plain and ordinary meaning in organic chemistry, including elements other than carbon, including, but not limited to, nitrogen (e.g., amino, monosubstituted amines, disubstituted amines, etc.), oxygen (e.g., alkoxy, ether, hydroxyl, etc.), sulfur, and halogens. Heteroalkyl groups can have 1-20 carbon atoms, although this definition also covers occurrences of the term "heteroalkyl" where no numerical range is specified. Heteroalkyl groups may be medium size heteroalkyls having 1-12 carbon atoms. Heteroalkyl groups can also be lower heteroalkyls having 1-6 carbon atoms. In various embodiments, heteroalkyls can have 1-4 heteroatoms, 1-3 heteroatoms, 1 or 2 heteroatoms, or 1 heteroatom. The heteroalkyl groups of a compound are defined as "C 1~4 A heteroalkyl group may be designated as "heteroalkyl" or similar designation. A heteroalkyl group may contain one or more heteroatoms. By way of example only, "C 1~4"Heteroalkyl" indicates that the heteroalkyl chain has 1 to 4 carbon atoms and that one or more heteroatoms are present in the backbone of the chain. Heteroalkyl groups can be substituted or unsubstituted.

[0037] As used herein, "heterocyclyl" or "heteroalicyclyl" refers to monocyclic, bicyclic and tricyclic ring systems of 3, 4, 5, 6, 7, 8, 9, 10, up to 18 members, in which carbon atoms together with 1-5 heteroatoms constitute said ring system. However, heterocycles may optionally contain one or more unsaturated bonds positioned such that a completely delocalized pi-electron system does not occur throughout all rings. Heteroatoms are elements other than carbon, including but not limited to oxygen, sulfur and nitrogen. Heterocycles may further contain one or more carbonyl or thiocarbonyl functional groups, so that the definition includes oxo and thio systems, such as lactams, lactones, cyclic imides, cyclic thioimides, and cyclic carbamates. When composed of more than one ring, the rings may be joined together in a fused, bridged, or spiro fashion. As used herein, the term "fused" refers to two rings that have two atoms and one bond in common. As used herein, the term "bridged heterocyclyl" or "bridged heteroalicyclyl" refers to a compound in which a heterocyclyl or heteroalicyclyl contains one or more bond atoms connecting non-adjacent atoms. As used herein, the term "spiro" refers to two rings that have one atom in common, and the two rings are not joined by a bridge. Heterocyclyl and heteroalicyclyl groups can contain 3-30 atoms in the ring, 3-20 atoms in the ring, 3-10 atoms in the ring, 3-8 atoms in the ring, or 3-6 atoms in the ring. For example, 5 carbon atoms and 1 heteroatom, 4 carbon atoms and 2 heteroatoms, 3 carbon atoms and 3 heteroatoms, 4 carbon atoms and 1 heteroatom, 3 carbon atoms and 2 heteroatoms, 2 carbon atoms and 3 heteroatoms, 1 carbon atom and 4 heteroatoms, 3 carbon atoms and 1 heteroatom, or 2 carbon atoms and 1 heteroatom. In addition, any nitrogen in the heteroalicyclic may be quaternized. The heterocyclyl or heteroalicyclic group may be unsubstituted or substituted.Examples of such "heterocyclyl" or "heteroalicyclyl" groups include, but are not limited to, 1,3-dioxine, 1,3-dioxane, 1,4-dioxane, 1,2-dioxolane, 1,3-dioxolane, 1,4-dioxolane, 1,3-oxathiane, 1,4-oxathiine, 1,3-oxathiolane, 1,3-dithiole, 1,3-dithiolane, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, trioxane, hexahydro-1,3,5-triazine, imidazoline, cyclohexane, cyclohexane-1,3,5-triazine ... phosphorus, imidazolidine, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, morpholine, oxirane, piperidine N-oxide, piperidine, piperazine, pyrrolidine, azepane, pyrrolidone, pyrrolidione, 4-piperidone, pyrazoline, pyrazolidine, 2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran, thiamorpholine, thiamorpholine sulfoxide, thiamorpholine sulfone, and their benzo-fused analogs (e.g., benzimidazolidinone, tetrahydroquinoline, and / or 3,4-methylenedioxyphenyl). Examples of spiroheterocyclyl groups include 2-azaspiro[3.3]heptane, 2-oxaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, 2-oxaspiro[3.4]octane, and 2-azaspiro[3.4]octane.

[0038] As used herein, "aralkyl" and "aryl(alkyl)" refer to an aryl group connected, as a substituent, through a lower alkylene group. The lower alkylene and aryl groups of an aralkyl can be substituted or unsubstituted. Examples include, but are not limited to, benzyl, 2-phenylalkyl, 3-phenylalkyl, and naphthylalkyl.

[0039] As used herein, "cycloalkyl(alkyl)" refers to a cycloalkyl group connected, as a substituent, through a lower alkylene group. The lower alkylene and cycloalkyl groups of the cycloalkyl(alkyl) can be substituted or unsubstituted.

[0040] As used herein, "heteroaralkyl" and "heteroaryl(alkyl)" refer to a heteroaryl group connected, as a substituent, through a lower alkylene group. The lower alkylene and heteroaryl groups of a heteroaralkyl can be substituted or unsubstituted. Examples include, but are not limited to, 2-thienylalkyl, 3-thienylalkyl, furylalkyl, thienylalkyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl, and imidazolylalkyl, and their benzo-fused analogs.

[0041] "Heteroalicyclyl(alkyl)" and "heterocyclyl(alkyl)" refer to a heterocyclic or heteroalicyclic group connected, as a substituent, through a lower alkylene group. The lower alkylene and heterocyclyl of (heteroalicyclyl)alkyl can be substituted or unsubstituted. Examples include, but are not limited to, tetrahydro-2H-pyran-4-yl(methyl), piperidin-4-yl(ethyl), piperidin-4-yl(propyl), tetrahydro-2H-thiopyran-4-yl(methyl), and 1,3-thiazinane-4-yl(methyl).

[0042] As used herein, the term "hydroxy" refers to an --OH group.

[0043] As used herein, "alkoxy" refers to a group of formula -OR, where R is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl) as defined herein. A non-limiting list of alkoxy is methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, phenoxy, and benzoxy. Alkoxy can be substituted or unsubstituted.

[0044] As used herein, "acyl" refers to hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), and heterocyclyl(alkyl) as substituents connected through a carbonyl group. Examples include formyl, acetyl, propanoyl, benzoyl, and acryl. Acyl can be substituted or unsubstituted.

[0045] An "O-carboxy" group refers to an "RC(=O)O-" group, where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl), as defined herein. O-carboxy can be substituted or unsubstituted.

[0046] The terms "ester" and "C-carboxy" refer to the group "-C(=O)OR" where R can be the same as defined for O-carboxy. Esters and C-carboxy can be substituted or unsubstituted.

[0047] A "thiocarbonyl" group refers to a "-C(=S)R" group where R can be the same as defined for O-carboxy. The thiocarbonyl can be substituted or unsubstituted. An "O-carbamyl" group refers to a -C(=S)R group where R A and R B may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl); or R A and R B taken together form a heteroaryl or heterocyclic ring, "-OC(=O)N(R A R B )" group. O-Carbamyl can be substituted or unsubstituted.

[0048] An "N-carbamyl" group is a group consisting of R and R A ROC(═O)N(R ) may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). A N-carbamyl refers to a "—" group. N-carbamyl can be substituted or unsubstituted.

[0049] An "O-carbamyl" group is a group consisting of R and R A may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). A N-carbamyl refers to the "—R" group. N-carbamyl can be substituted or unsubstituted.

[0050] A "carbamide" group is a group consisting of R and R Awherein R is an integer from 1 to 5, R is an integer from 1 to 5, and R is an integer from 1 to 5, R is an integer from 1 to 5, and R is an integer from 1 to 5, R is an integer from 1 to 5, and R is an integer from 1 to 5, A )-R" group. The carbamide can be substituted or unsubstituted.

[0051] A "carbonate" group refers to a "-OC(=O)OR" group, where R can be alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). Carbonates can be substituted or unsubstituted.

[0052] An "O-thiocarbamyl" group is R A and R B may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl); or R A and R B taken together form a heteroaryl or heterocyclic ring, "-OC(=S)-N(R A R B )" group. O-Carbamyl can be substituted or unsubstituted. O-Thiocarbamyl can be substituted or unsubstituted.

[0053] An "N-thiocarbamyl" group is a group consisting of R and R A ROC(=S)N(R) may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). AN-thiocarbamyl can be substituted or unsubstituted.

[0054] A "C-amide" group is a group consisting of R A and R B may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl); or R A and R B taken together form a heteroaryl or heterocyclic ring, "-C(=O)-N(R A R B ) group. The C-amide can be substituted or unsubstituted.

[0055] An "N-amide" group is one in which R and R A may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). A N-amides can be substituted or unsubstituted.

[0056] An "S-sulfonamide" group is R A and R B may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl); or R A and R B taken together form a heteroaryl or heterocyclic ring, "-SO2N(R A R B )" group. The S-sulfonamide can be substituted or unsubstituted.

[0057] An "N-sulfonamide" group is one selected from R and R A may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). A N-sulfonamides can be substituted or unsubstituted.

[0058] As used herein, a "cyano" group refers to a "-CN" group.

[0059] As used herein, the term "halogen atom" or "halogen" means any one of the radiostable atoms in column 7 of the periodic table of the elements, e.g., fluorine, chlorine, bromine, and iodine.

[0060] As used herein, a "nitro" group refers to a "-NO2" group.

[0061] As used herein, a "sulfenyl" group refers to a "-SR" group, where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). The sulfenyl can be substituted or unsubstituted.

[0062] As used herein, a "sulfinyl" group refers to a "-S(=O)-R" group, where R can be the same as defined for sulfenyl. Sulfinyl can be substituted or unsubstituted.

[0063] As used herein, a "sulfonyl" group refers to a "SO2R" group, where R can be the same as defined for sulfenyl. The sulfonyl can be substituted or unsubstituted.

[0064] As used herein, "haloalkyl" refers to an alkyl group in which one or more of the hydrogen atoms have been replaced by halogen (e.g., mono-haloalkyl, di-haloalkyl, tri-haloalkyl, and polyhaloalkyl). Such groups include, but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1-chloro-2-fluoromethyl, 2-fluoroisobutyl, and pentafluoroethyl. Haloalkyl can be substituted or unsubstituted.

[0065] As used herein, "haloalkoxy" refers to an alkoxy group in which one or more hydrogen atoms are replaced by halogen (e.g., mono-haloalkoxy, di-haloalkoxy, and tri-haloalkoxy). Such groups include, but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-chloro-2-fluoromethoxy, and 2-fluoroisobutoxy. Haloalkoxy can be substituted or unsubstituted.

[0066] As used herein, the terms "amino" and "unsubstituted amino" refer to the group --NH.

[0067] As used herein, a "monosubstituted amine" group is R A may be alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl), as defined herein. A " group. R A can be substituted or unsubstituted. Mono-substituted amine groups include, for example, mono-alkylamine groups, mono-C1-C6 alkylamine groups, mono-arylamine groups, mono-C6-C 10 arylamine groups, etc. Examples of mono-substituted amine groups include, but are not limited to, -NH(methyl), -NH(phenyl), etc.

[0068] As used herein, a "disubstituted amine" group is R A and R B may be independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl); or R A and R B taken together to form a heteroaryl or heterocyclic ring, "-NR A R B " group. R A and R B can be independently substituted or unsubstituted. Disubstituted amine groups include, for example, di-alkylamine groups, di-C1-C6 alkylamine groups, di-arylamine groups, di-C6-C 10 arylamine groups, etc. Examples of disubstituted amine groups include, but are not limited to, -N(methyl)2, -N(phenyl)(methyl), -N(ethyl)(methyl), and the like.

[0069] As used herein, a "monosubstituted amine(alkyl)" group refers to a monosubstituted amine as provided herein connected as a substituent via a lower alkylene group. The monosubstituted amine(alkyl) can be substituted or unsubstituted. Monosubstituted amine(alkyl) groups include, for example, mono-alkylamine(alkyl) groups, mono-C1-C6 alkylamine(C1-C6 alkyl) groups, mono-arylamine(alkyl) groups, mono-C6-C8 ... 10 arylamine (C1-C6 alkyl) groups, etc. Examples of monosubstituted amine (alkyl) groups include, but are not limited to, -CH2NH(methyl), -CH2NH(phenyl), -CH2CH2NH(methyl), -CH2CH2NH(phenyl), etc.

[0070] As used herein, a "disubstituted amine(alkyl)" group refers to a disubstituted amine as provided herein connected as a substituent through a lower alkylene group. The disubstituted amine(alkyl) can be substituted or unsubstituted. Disubstituted amine(alkyl) groups include, for example, di-alkylamine(alkyl) groups, di-C1-C6 alkylamine(C1-C6 alkyl) groups, di-arylamine(alkyl) groups, di-C6-C8 ... 10 arylamine (C1-C6 alkyl) groups, etc. Examples of disubstituted amine (alkyl) groups include, but are not limited to, -CH2N(methyl)2, -CH2N(phenyl)(methyl), -CH2N(ethyl)(methyl), -CH2CH2N(methyl)2, -CH2CH2N(phenyl)(methyl), -NCH2CH2(ethyl)(methyl), etc.

[0071] As used herein, the term "diamino-" refers to R A , R C , and R D may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl), as defined herein; R B connects two "N" groups, (R A , R C and R D and "-N(R A )R B -N(R C )(R D ) group. A , R B , R C , and R D may be independently further substituted or unsubstituted.

[0072] As used herein, the term "polyamino" refers to "-(N(R A )R B -) n -N(RC )(R D For purposes of illustration, the term polyamino refers to -N(R A ) alkyl-N(R A ) alkyl-N(R A ) alkyl-N(R A ) alkyl-H. In some embodiments, the alkyl of the polyamino is as disclosed elsewhere herein. Although this example has only four repeating units, the term "polyamino" can consist of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 repeating units. R A , R C , and R D may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl), as defined herein; R B connects two "N" groups, (R A , R C and R D and independently may be a substituted or unsubstituted alkylene group. A , R C , and R D may be further independently substituted or unsubstituted. As described herein, polyamino comprises amine groups having intervening alkyl groups, where alkyl is as defined elsewhere herein.

[0073] As used herein, the term "ether" refers to a repeating -alkyl-O-alkyl group. For illustration, the term ether can include -(C1-C6 alkyl)-O-(C1-C6 alkyl). In some embodiments, the alkyl of the polyether is as disclosed elsewhere herein. As used herein, the term "diether-" refers to a repeating -alkyl-O-alkyl group, as defined herein. Acan be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl); R B connects two "O" groups and may be a substituted or unsubstituted alkylene group, "-OR B OR A " group. R A may be independently further substituted or unsubstituted.

[0074] As used herein, the term "polyether" refers to a repeating -(OR B -) n OR A For illustration purposes, the term polyether refers to the -Oalkyl-Oalkyl-Oalkyl-Oalkyl-OR A In some embodiments, the alkyl of the polyether is as disclosed elsewhere herein. Although this example has only four repeating units, the term "polyether" may consist of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 repeating units. R A R may be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl), as defined herein. B R can be a substituted or unsubstituted alkylene group. A may be further independently substituted or unsubstituted. As described herein, polyethers include ether groups having intervening alkyl groups, where alkyl is as defined elsewhere herein and may be optionally substituted.

[0075] Where the number of substituents is not specified (e.g., haloalkyl), one or more substituents may be present. For example, "haloalkyl" may include one or more of the same or different halogens. As another example, "C1-C3 alkoxyphenyl" may include one or more of the same or different alkoxy groups containing 1, 2, or 3 atoms. As another example, C2-C6 alkynyl may include 1, 2, or 3 triple bonds.

[0076] As used herein, radical refers to a species that has a single unpaired electron such that the species containing the radical may be covalently bonded to another species. Thus, in this context, a radical is not necessarily a free radical. Rather, a radical refers to a specific portion of a larger molecule. The term "radical" can be used interchangeably with the term "group."

[0077] As used herein, "natural amino acid side chain" refers to the side chain substituent of a naturally occurring amino acid. Naturally occurring amino acids have a substituent attached to the α-carbon. 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.

[0078] As used herein, "unnatural amino acid side chain" refers to a side chain substituent of an amino acid that does not occur in nature. Unnatural amino acids include β-amino acids (β 3 and β 2), homoamino acids, proline and pyruvate derivatives, 3-substituted alanine derivatives, glycine derivatives, ring-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 by reference in its entirety.

[0079] Two substituents, together with the atom or atoms to which they are attached, may form a ring that is spiro or fused with the remainder of the compound.

[0080] It will be understood that a particular radical nomenclature can include either a monoradical or a diradical, depending on the context. For example, if a substituent requires two points of attachment to the remainder of the molecule, the substituent will be understood to be a diradical. For example, a substituent identified as an alkyl, which requires two points of attachment, includes diradicals such as -CH2-, -CH2CH2-, -CH2CH(CH3)CH2-, etc. Other radical nomenclature explicitly indicates that the radical is a diradical, such as "alkylene" or "alkenylene."

[0081] Whenever a substituent is shown as a diradical (i.e., having two points of attachment to the remainder of the molecule), it is understood that the substituent may be attached in any orientation unless otherwise specified. Thus, for example, -AE- or [ka] Substituents depicted as include those where the substituent is oriented such that A is attached to the left-most attachment point of the molecule, and those where A is attached to the right-most attachment point of the molecule.

[0082] The term "agent" or "test agent" includes any substance, molecule, element, compound, entity, or combination thereof, including, but not limited to, for example, proteins, polypeptides, peptides or mimetics, small organic molecules, polysaccharides, polynucleotides, etc. It can be a natural product, a synthetic compound, or a chemical, or a combination of two or more substances. Unless otherwise specified, the terms "agent," "substance," and "compound" are used interchangeably herein.

[0083] The term "analog" is used herein to refer to a molecule that is structurally similar to a reference molecule, but is modified in a targeted and controlled manner by replacing certain substituents of the reference molecule with alternative substituents.Compared to the reference molecule, an analog would be expected by those skilled in the art to show the same, similar or improved utility.The synthesis and screening of analogs to identify mutants of known compounds with improved characteristics (such as higher binding affinity to target molecules) is a well-known technique in pharmaceutical chemistry.

[0084] In any compound described herein having one or more chiral centers, unless the absolute stereochemistry is expressly indicated, it is understood that each center may be independently of the R-configuration or S-configuration, or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic, diastereomerically pure, diastereomerically enriched, or a stereoisomeric mixture. Furthermore, in any compound described herein having one or more double bonds resulting in a geometric isomer that can be defined as E or Z, it is understood that each double bond may be independently E or Z, or a mixture thereof. In any compound described herein having one or more chiral centers, it is understood that all possible diastereomers are also envisioned. In any compound described herein, it is understood that all tautomers are envisioned. It is also understood that in any compound described herein, all isotopes of the atoms involved are envisioned. For example, any instance of hydrogen may include hydrogen-1 (protium), hydrogen-2 (deuterium), hydrogen-3 (tritium) or other isotopes; any instance of carbon may include carbon-12, carbon-13, carbon-14 or other isotopes; any instance of oxygen may include oxygen-16, oxygen-17, oxygen-18 or other isotopes; any instance of fluorine may include one or more of fluorine-18, fluorine-19 or other isotopes; any instance of sulfur may include sulfur-32, sulfur-34, sulfur-35, sulfur-36 or other isotopes.

[0085] As used herein, the term "inhibitor" refers to any compound, molecule, or composition that inhibits or reduces the activity of a target biomolecule. Inhibition can be achieved, for example, by blocking phosphorylation of the target (e.g., competing with the phosphorylating entity adenosine triphosphate (ATP)), by binding to a position outside the active site and affecting its activity by conformational changes, or by depriving kinases of access to the molecular chaperone system on which they depend for cellular stability, leading to their ubiquitination and degradation.

[0086] A "prodrug" refers to an agent that is converted to the parent drug in vivo. Prodrugs are often useful because, under some circumstances, they may be easier to administer than the parent drug. They may, for example, be bioavailable by oral administration, whereas the parent may not. A prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. A non-limiting example of a prodrug would be a compound that is administered as an ester ("prodrug") to facilitate penetration across cell membranes where water solubility is detrimental to mobility, but is then metabolically hydrolyzed to the active entity, a carboxylic acid, once inside the cell where water solubility is beneficial. A further example of a prodrug may be a short peptide (polyamino acid) bonded with an acid group, where the peptide is metabolized to reveal the active moiety. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, (ed. H. Bundgaard, Elsevier, 1985), which is incorporated herein by reference in its entirety. The quinazolinyl compounds disclosed herein can be modified as prodrugs that release the quinazolinyl compound once inside the subject's body.

[0087] The term "prodrug ester" refers to derivatives of compounds disclosed herein (e.g., quinazolinyl compounds) formed by adding any of several ester-forming groups that are hydrolyzed 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 (5-R-2-oxo-1,3-dioxolen-4-yl)methyl groups. 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, ACS Symposium Series, American Chemical Society (1975), and in "Bioreversible Carriers in Drug Design: Theory and Application," ed. by EB Roche, Pergamon Press: New York, pp. 14-21 (1987) (providing examples of esters useful as prodrugs of compounds containing carboxyl groups). Each of the above references is incorporated herein by reference in its entirety.

[0088] "Metabolites" of the compounds disclosed herein include active species produced upon introduction of the compounds into the biological milieu.

[0089] "Solvate" refers to a compound formed by the interaction of a solvent with a compound, metabolite, or salt thereof described herein. Suitable solvates are pharma- ceutically acceptable solvates, including hydrates.

[0090] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of a compound that are not biologically or otherwise undesirable for use in a pharmaceutical product. In many cases, the compounds herein can form acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, 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, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like, with ammonium, potassium, sodium, calcium, and magnesium salts being particularly preferred. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. Many such salts are known in the art, as described in US4783443A, Johnston et al., published September 11, 1987 (incorporated herein by reference in its entirety).

[0091] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except where any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic composition is contemplated. In addition, various adjuvants such as those commonly used in the art may be included. Considerations regarding the inclusion of various components in pharmaceutical compositions are described, for example, in Gilman et al. (eds.) (1990), Goodman and Gilman's The Pharmacological Basis of Therapeutics, 8th Edition, Pergamon Press, which is incorporated herein by reference in its entirety.

[0092] As used herein, an "effective amount" or "therapeutically effective amount" refers to an amount of a therapeutic agent effective to alleviate or reduce to some extent the likelihood of development of one or more of the symptoms of a disease or condition (including curing the disease or condition). By "curing" is meant that the symptoms of the disease or condition are eliminated, although certain long-term or permanent effects may exist even after a cure has been achieved (such as extensive tissue damage).

[0093] The "patient" or "subject" to be treated as disclosed herein is, in some embodiments, a human patient, although it should be understood that the principles of the subject matter of the present disclosure are effective with respect to all vertebrate species, including mammals, which are intended to be included in the terms "subject" and "patient". Suitable subjects are generally mammalian subjects. The subject matter described herein finds use in research, as well as veterinary and medical applications. As used herein, the term "mammal" includes, but is not limited to, humans, non-human primates, cows, sheep, goats, pigs, horses, cats, dogs, rabbits, rodents (e.g., rats or mice), monkeys, and the like. Human subjects include neonatal, infant, juvenile, adult, and geriatric subjects.

[0094] The terms "treatment," "treating," "treating," and the like shall be given their ordinary meaning and shall generally be used herein to include obtaining a desired pharmacological and / or physiological effect. The effect may be prophylactic in that a disease or its symptoms are completely or partially prevented, and / or may be therapeutic in that a disease and / or adverse effects resulting from the disease are partially or completely stabilized or cured. As used herein, "treatment" shall be given its ordinary meaning and shall cover any treatment of disease in a mammal, particularly a human, including (a) preventing the disease or condition from occurring in a subject who may be affected by the disease or condition but has not yet been diagnosed as having it, (b) inhibiting a disease symptom, e.g., halting its progression, and / or (c) relieving a disease symptom, e.g., causing regression of the disease or condition.

[0095] The section headings used herein are for organizational purposes only and are not to be construed as limiting the described subject matter in any manner. All literature and similar materials cited in this application, including but not limited to patents, patent applications, papers, books, treatises, and Internet web pages, are expressly incorporated herein by reference in their entirety for all purposes. In the event that the definition of a term in an incorporated reference appears to differ from the definition provided in the present teachings, the definition provided in the present teachings shall prevail. It will be understood that there is an implied "about" before the temperatures, concentrations, times, etc. discussed in the present teachings such that slight, non-substantial variations are within the scope of the present teachings herein. In this application, the use of the singular includes the plural unless specifically stated otherwise.

[0096] Terms and phrases used in this application, and variations thereof, unless expressly stated otherwise, particularly in the appended claims, should be construed as open ended as opposed to limiting. As examples of the foregoing, the term "including" should be read to mean "including without limitation," "including but not limited to," and the like; as used herein, the term "comprising" is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; the term "having" should be interpreted as "having at least," and the term "include" should be interpreted as "including but not limited to," the term "examples" is used to provide illustrative examples of the items under discussion rather than an exclusive or limiting list thereof, and the use of terms such as "preferably," "preferred," "desired," or "desirable," and words of similar import, should not be understood as implying that a particular feature is critical, essential, or even essential to the structure or function of the invention, but instead is merely intended to highlight alternative or additional features that may or may not be utilized in a particular embodiment of the invention. Additionally, the term "comprising" is intended to be construed synonymously with the phrases "having at least" or "including at least." When used in the context of a method, the term "comprising" means that the method includes at least the recited steps and may include additional steps. When used in the context of a compound, composition, or device, the term "comprising" means that the compound, composition, or device includes at least the recited features or components, but may also include additional features or components. Similarly, a group of items joined by the conjunction "or" should not be read as necessarily mutually exclusive within the group, but rather as "and / or" unless expressly stated otherwise.

[0097] In addition, the phrase "consisting essentially of" will be understood to include the elements specifically recited and those additional elements that do not materially affect the basic and novel characteristics of the claimed technology. The phrase "consisting of" excludes any element not specified.

[0098] With respect to the use of virtually any plural and / or singular term herein, those skilled in the art can translate from the plural to the singular and / or from the singular to the plural, as appropriate to the context and / or application. Various singular / plural permutations may be expressly indicated herein for clarity. The indefinite article "a" or "an" does not exclude a plurality. The mere fact that certain measurements are recited in mutually different dependent claims does not indicate that combinations of these measurements cannot be used to advantage. Any reference signs in the claims should not be construed as limiting the scope.

[0099] introduction Many diseases result from the improper regulation of normal processes, including those that control cell division, differentiation, and cell death by apoptosis. Protein kinases play a crucial role in these regulatory processes. Kinase inhibitors have been used to treat diseases, such as cancer (e.g., by inhibiting the mitotic process). However, despite the fact that inhibitors of various kinases are known, there remains a need for selective inhibitors to be used for the treatment of diseases, such as hyperproliferative diseases, that offer one or more advantages over current compounds. These advantages include improved activity and / or efficacy, beneficial kinase selectivity profiles according to the respective therapeutic needs, improved side effect profiles, such as fewer undesirable side effects, less intense side effects, or reduced (cyto)toxicity, improved targeting of mutant receptors in diseased cells, improved physicochemical properties, such as solubility / stability in water, body fluids, and / or pharmaceutical formulations, improved pharmacokinetic properties, such as allowing for dose reduction or easier administration schemes, easier drug substance manufacturing, such as by shorter synthetic routes or easier purification. Some embodiments disclosed herein relate to compounds that achieve one or more of these advantages (or others).Some embodiments disclosed herein relate to compounds that address one or more shortcomings of known drug substances.

[0100] Kinase inhibitors are disclosed herein that disrupt kinase activity and / or inhibit protein kinase.In some embodiments, quinazolinyl compounds, methods of using quinazolinyl compounds, compositions that include quinazolinyl compounds, and methods of treatment using quinazolinyl compounds are disclosed herein.In some embodiments, the disclosed quinazolinyl compounds are kinase inhibitors.In some embodiments, the disclosed quinazolinyl compounds are useful in methods of treating cancer, autoimmune disease, and / or DMD.

[0101] In some embodiments, the disclosed quinazolinyl compounds directly target and / or inhibit one or more protein kinases selected from the group consisting of CLK1, CLK2, CLK3, CLK4, FMS, JNK1, JNK2, JNK3, PLK4, FLT3, FLT3(D835V), FLT3(ITD), FLT3(F691L), FLT3(N841I), FLT3(D835H), FLT3(D835Y), FLT3(K663Q), FLT3(N841l), MYLK4, NUAK2, CSF1R, DAPK3, RIOK2, HIPK1, ALK, MYLK, EGFR, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, VEGFR, JAK1, ABL1, DAPK2, and LTK. In some embodiments, the disclosed quinazolinyl compounds are selected from the group consisting of abl, Akt, Aurora-A, Auroa-B, Aurora-C, ATK, bcr-abl, Blk, Brk, Btk, c-Kit, c-Met, s-Src, c-fms, CDK1, CDK2 Directly targets and / or inhibits one or more protein kinases selected from the group consisting of CDK4, CDK6, CDK7, CDK8, CDK9, CDK10, rRaf1, CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, ERK, Fak, fes, Fgr, fit-1, FLK-4, Fps, Fyn, Hck, HER, Hck, IGF-1R, INS-R, Jak, KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, Ros, Tie1, Tie2, Trk, Yes, and Zap70. In some embodiments, the disclosed quinazolinyl compounds directly targets and / or inhibits protein kinases involved in mitogen-activated protein kinase (MAPK) signaling pathways. In some embodiments, the disclosed quinazolinyl compounds directly targets and / or inhibits lipid kinases. In some embodiments, the disclosed quinazolinyl compounds directly target and / or inhibit lipid kinases (eg, PI3K), which constitute another group of kinases that are structurally similar to protein kinases.

[0102] compound As disclosed elsewhere herein, some embodiments relate to a quinazolinyl compound. In some embodiments, the quinazolinyl compound is represented by one or more of formulas (I), (IA), (IB), or (IC). In some embodiments, the quinazolinyl compound is represented by any one or more of the structures in Figures 1A-1E.

[0103] Compounds of formula (I) Some embodiments include a quinazolinyl compound having the structure of Formula (I): [ka] (or a stereoisomer, tautomer, or pharma- ceutically acceptable salt thereof).

[0104] In some embodiments, R 1 is an optionally substituted 6- to 10-membered aryl, an optionally substituted 3- to 10-membered heterocyclyl, an optionally substituted 5- to 10-membered heteroaryl, an optionally substituted carbamide, -CN, and -NR 4 R 5 In some embodiments, R 4 and R 5 each is independently selected from hydrogen, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 carbocyclyl, or alternatively, R 4 and R 5 taken together form an optionally substituted 3- to 10-membered heterocyclyl. In some embodiments, R 2 -OR 6 or an optionally substituted (heterocyclyl)alkynyl. In some embodiments, R 6 is selected from the group consisting of methyl, optionally substituted 2-10 membered heteroalkyl, and (heterocyclyl)alkyl. 3 is hydrogen, halogens, and C 1~6In some embodiments, R a is hydrogen or optionally substituted C1-C 10 In some embodiments, the A ring is an optionally substituted heteroaryl.

[0105] As disclosed elsewhere herein, in some embodiments, the A ring is an optionally substituted heteroaryl. In some embodiments, the A ring is an optionally substituted heteroaryl having 5 ring members. In some embodiments, the A ring contains 1, 2, 3, or 4 heteroatoms. In some embodiments, when the A ring contains one or more optional substituents, the optional substituents are as disclosed elsewhere herein. In some embodiments, when the A ring contains one or more optional substituents, the one or more optional substituents are independently an optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 may be selected from the group consisting of alkenyl, optionally substituted C3-C6 carbocyclyl, optionally substituted ether (e.g., optionally substituted -(C1-C6 alkyl)-O-(C1-C6 alkyl)), halo, cyano, hydroxy, and C1-C3 alkoxy. In some embodiments, when the A ring comprises one or more optional substituents, the one or more optional substituents may be independently selected from the group consisting of optionally substituted C1-C 10 In some embodiments, when the A ring includes one or more optional substituents, the one or more optional substituents may be independently selected from the group consisting of C1-C3 alkyl, C1-C4 carbocyclyl, halo, cyano, hydroxy, and C1-C3 alkoxy. In some embodiments, when the A ring includes one or more optional substituents, the one or more optional substituents may be independently selected from the group consisting of C1-C3 alkyl, and C1-C4 carbocyclyl.

[0106] In some embodiments, the A ring has the ring structure (AIa): [ka] In some embodiments, X a , X b , X c , and X d Each of X is independently selected from the group consisting of C, N, O, and S. In some embodiments, X a , X b , X c , and X d Any one or more of may be one or more R b or H groups (e.g., in the formula X a , X b , X c , and / or X d is a C or N atom. In some embodiments, R b Each instance, if present, is independently optionally substituted C1 through C 10 In some embodiments, R is selected from the group consisting of alkyl, C3-C6 carbocyclyl, and optionally substituted C3-C6 carbocyclyl. b Each instance, if present, is independently selected from optionally substituted C1-C3 alkyl, optionally substituted C2-C 10 alkenyl, and optionally substituted C3-C4 carbocyclyl. In some embodiments, n is an integer selected from 0, 1, 2, 3, or 4. In some embodiments, n is 2. In some embodiments, n is 1. In some embodiments, n is 0. In some embodiments, each R b When present, replaces a -H bonded to a C or N atom in the ring structure (AIa). In some embodiments, R b Each instance of, if any, [ka] In some embodiments, m is an integer selected from 1, 2, 3, or 4. In some embodiments, m is an integer selected from 1 or 2. In some embodiments, R b Each instance of, if any, [ka] is selected from the group consisting of:

[0107] In some embodiments, the ring structure (AIa) is [ka] and each variable is as defined elsewhere herein. In some embodiments, each R b When present, replaces a -H bonded to a C or N atom in the ring structure (AIa).

[0108] In some embodiments, the ring structure (AIa) is [ka] and each variable is as defined elsewhere herein. In some embodiments, each R b When present, replaces a -H bonded to a C or N atom in the ring structure (AIa).

[0109] In some embodiments, the A ring has the following structure: [ka] any of which may be substituted with a substituent (e.g., optionally substituted C1-C 10It may be further optionally substituted by substitution with alkyl and optionally substituted C3-C6 carbocyclyl).

[0110] In some embodiments, the A ring is [ka] The structure is selected from the group consisting of:

[0111] In some embodiments, the A ring is: [ka] In some embodiments, the A ring is not a structure represented by one or more of the following: [ka] is not a structure represented by one or more of

[0112] As disclosed elsewhere herein, in some embodiments, R 1 is an optionally substituted 6- to 10-membered aryl, an optionally substituted 3- to 10-membered heterocyclyl, an optionally substituted 5- to 10-membered heteroaryl, an optionally substituted carbamide, -CN, and -NR 4 R 5 (In the formula, R 4 and R 5 is as defined elsewhere herein. In some embodiments, R 1 When R is a heteroaryl or heterocyclyl group, the ring can contain 1, 2, 3, 4 or more heteroatoms. 1 has the following structure: [ka] any of which may be further optionally substituted by replacing one or more -H atoms of any carbon or nitrogen atom present with a substituent. The one or more optional substitutions may be independently selected from the group consisting of C1-C3 alkyl, halo, cyano, hydroxy, ether (e.g., -(C1-C6 alkyl)-O-(C1-C6 alkyl)) and C1-C3 alkoxy. In some embodiments, R 1 When a substituent includes one or more optional substituents, the one or more optional substituents may be independently selected from the group consisting of amino, -OH, C1-C6 alkyl, and halogen.

[0113] As disclosed elsewhere herein, in some embodiments, R 2 -OR 6 or optionally substituted (heterocyclyl)alkynyl, 6 is as disclosed elsewhere herein. In some embodiments, R 2 is (heterocyclyl)alkynyl, wherein the alkynyl is C2-C6 alkynyl.

[0114] In some embodiments, R 2 has the following structure: [ka] [In the formula, R c is a 3-8 membered heterocyclyl having 1-2 heteroatoms, or a 2-6 membered heteroalkyl having 1-2 heteroatoms. 2 has the following structure: [ka] [In the formula, R c is a 3-8 membered heterocyclyl having 1-2 heteroatoms. cis heterocyclyl having one heteroatom in the heterocyclic group. In some embodiments, R c is below: [ka] In some embodiments, R c is a heteroalkyl having one heteroatom in the heteroalkyl group. In some embodiments, R c is below: [ka] It is represented by the structure as shown in:

[0115] In some embodiments, o is an integer selected from 1, 2, 3, 4, or 5. In some embodiments, o is an integer selected from 1, 2, 3, or 4. In some embodiments, o is 3. In some embodiments, o is 1.

[0116] In some embodiments, R 2 teeth, [ka] is selected from the group consisting of:

[0117] As disclosed elsewhere herein, in some embodiments, R 3 is hydrogen, halogens, and C 1~6 In some embodiments, R 3 is -OMe.

[0118] As disclosed elsewhere herein, in some embodiments, R a is hydrogen or optionally substituted C1-C 10 In some embodiments, R a is hydrogen. In some embodiments, R a is methyl.

[0119] In some embodiments of the structure of formula (I), R a is -H and R 3 is -OMe, and R 1 but, [ka] and R 2 But the following structure: [ka] When the A ring is one of: [ka] isn't it.

[0120] In some embodiments, Formula (I) has the following structure: [ka] does not include any of the following:

[0121] In some embodiments, Formula (I) has the following structure: [ka] does not include any of the following:

[0122] In some embodiments, Formula (I) has the following structure: [ka] does not include any of the following:

[0123] In some embodiments of the structure of formula (I), R 2 but, [ka] If R 1 teeth, [ka] isn't it.

[0124] In some embodiments of the structure of formula (I), R 2 but, [ka] If R 1 teeth, [ka] It is.

[0125] In some embodiments, the compound of formula (I) is [ka] [ka] [ka] [ka] [ka] [ka] The compound is represented by a compound selected from the group consisting of:

[0126] In some embodiments, the compound of formula (I) is selected from the group consisting of 2-(4,4-difluoropiperidin-1-yl)-6-methoxy-N-(1H-pyrazol-3-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine, 2-(4,4-difluoropiperidin-1-yl)-6-methoxy-N-(5-methyl-1H-pyrazol-3-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine, N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(4,4-difluoropiperidin-1-yl)-6- Methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine, N-(5-cyclobutyl-1H-pyrazol-3-yl)-2-(4,4-difluoropiperidin-1-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine, 2-(4,4-difluoropiperidin-1-yl)-6-methoxy-N-(1H-pyrrol-2-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine, 2-(4,4-difluoropiperidin-1-yl)-N-(1H-imidazo N-(2-(4,4-difluoropiperidin-1-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-yl)oxazol-4-amine, N-(2-(4,4-difluoropiperidin-1-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-yl)-5-methyloxazol-2-amine, N-(2-(4,4-difluoropiperidin-1-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-yl)-5-methyloxazol-2-amine, N-(2-(4,4-difluoropiperidin-1-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-yl) N-(2-(4,4-difluoropiperidin-1-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-yl)-5-methyl-1,3,4-oxadiazol-2-amine, N-(2-(4,4-difluoropiperidin-1-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-yl)-5-methyl-1,3,4-thiadiazol-2-amine, 2-(4,4-difluoropiperidin-1-yl)-6-methoxy-N-(5-methyl-4H-1,2,4-triazol-3-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine, 2-(4,4-difluoropiperidin-1-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)-N-(1H-tetrazol-5-yl)quinazolin-4-amine, N-(2-(4,4-difluoropiperidinyl) N-(2-(4,4-difluoropiperidin-1-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-yl)thiazol-4-amine, N-(2-(4,4-difluoropiperidin-1-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-yl)-1,2,4-oxadiazol-3-amine, N-(2-(4,4-difluoropiperidin-1-yl)-6-methoxy-7-(3-(pyrrolidine- 1-yl)propoxy)quinazolin-4-yl)-1,2,4-thiadiazol-3-amine, N-(2-(4,4-difluoropiperidin-1-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-yl)-1,2,4-thiadiazol-3-amine, 2-(4,4-difluoropiperidin-1-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)-N-(2H-1,2 ,3-triazol-4-yl)quinazolin-4-amine, 6-methoxy-2-(4-methoxypiperidin-1-yl)-N-(5-methyl-1H-pyrazol-3-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine, 6-methoxy-N2,N2-dimethyl-N4-(5-methyl-1H-pyrazol-3-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-2,4-diamine, N, 2-Butyl-6-methoxy-N4-(5-methyl-1H-pyrazol-3-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-2,4-diamine, 6-methoxy-N-(5-methyl-1H-pyrazol-3-yl)-2-(piperazin-1-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine, 6-methoxy-N-(5-methyl-1H-pyrazol-3-yl)-2-(4-methylpiperazin-1-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine, 6-methoxy-N-(5-methyl-1H-pyrazol-3-yl)-2-morpholino-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine, N 2 -Cyclopropyl-6-methoxy-N4-(5-methyl-1H-pyrazol-3-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline-2,4-diamine, 2-(azetidin-1-yl)-6-methoxy-N-(5-methyl-1H-pyrazol-3-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline-4-amine, 6-methoxy-N-(5-methyl-1H-pyrazol-3-yl)-2-(pyrrolidine-1-yl)propoxy)quinazoline-2,4-diamine, 6-Methoxy-4-((5-methyl-1H-pyrazol-3-yl)amino)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine, 6-Methoxy-4-((5-methyl-1H-pyrazol-3-yl)amino)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-2-carbonitrile, 6-Methoxy-N-(5-methyl-1H-pyrazol-3-yl)-2-(piperidin-1-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine, 6-Methoxy-N 4 -(5-methyl-1H-pyrazol-3-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline-2,4-diamine, 2-(3,5-difluorophenyl)-6-methoxy-N-(5-methyl-1H-pyrazol-3-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline-4-amine, 6-methoxy-N 2 -(2-Methoxyethyl)-N 4-(5-methyl-1H-pyrazol-3-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-2,4-diamine, 1-(6-methoxy-4-((5-methyl-1H-pyrazol-3-yl)amino)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-2-yl)-3-methylurea, 2-(4,4-difluoropiperidin-1-yl)-6-methoxy-N-(5-methyl-1H-pyrazol-3-yl)-7-(3-( pyrrolidin-1-yl)prop-1-yn-1-yl)quinazolin-4-amine, N-(2-(4,4-difluoropiperidin-1-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)prop-1-yn-1-yl)quinazolin-4-yl)-5-methylisoxazol-3-amine, N-(2-(4,4-difluoropiperidin-1-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)prop-1-yn-1-yl)quinazolin -4-yl)-5-methylthiazol-2-amine, N-(2-(4,4-difluoropiperidin-1-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)prop-1-yn-1-yl)quinazolin-4-yl)-5-methyloxazol-2-amine, N-(2-(4,4-difluoropiperidin-1-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)prop-1-yn-1-yl)quinazolin-4-yl)-5-methyl-1, 3,4-Oxadiazol-2-amine, 2-(4,4-difluoropiperidin-1-yl)-6-methoxy-N-(5-methyl-1H-imidazol-2-yl)-7-(3-(pyrrolidin-1-yl)prop-1-yn-1-yl)quinazolin-4-amine, 1-(6-methoxy-4-((5-methyl-1H-pyrazol-3-yl)amino)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-2-yl)piperidin-4-ol, N 4 -(5-ethyl-1H-pyrazol-3-yl)-6-methoxy-N 2 ,N 2 -Dimethyl-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline-2,4-diamine, N 2 -Butyl-N 4-(5-ethyl-1H-pyrazol-3-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-2,4-diamine, N-(5-ethyl-1H-pyrazol-3-yl)-6-methoxy-2-(piperazin-1-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine, N-(5-ethyl-1H-pyrazol-3-yl)-6-methoxy-2-(4-methylpiperazin-1-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine, N-(5-ethyl-1H-pyrazol-3-yl)-6-methoxy-2-morpholino-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine, N 2 -Cyclopropyl-N 4 -(5-ethyl-1H-pyrazol-3-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline-2,4-diamine, 2-(azetidin-1-yl)-N-(5-ethyl-1H-pyrazol-3-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline-4-amine, N-(5-ethyl-1H-pyrazol-3-yl)-6-methoxy-2-(pyrrolidin-1-yl)propoxy )-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine, 4-((5-ethyl-1H-pyrazol-3-yl)amino)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-2-carbonitrile, N-(5-ethyl-1H-pyrazol-3-yl)-6-methoxy-2-(piperidin-1-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine, N 4 -(5-ethyl-1H-pyrazol-3-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-2,4-diamine, 2-(3,5-difluorophenyl)-N-(5-ethyl-1H-pyrazol-3-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine, N 4 -(5-ethyl-1H-pyrazol-3-yl)-6-methoxy-N 2-(2-methoxyethyl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-2,4-diamine, 1-(4-((5-ethyl-1H-pyrazol-3-yl)amino)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-2-yl)-3-methylurea, N-(5-ethyl-1H-pyrazol-3-yl)-6-methoxy-2-(4-methoxypiperidin-1-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine, N 4 -(5-Cyclopropyl-1H-pyrazol-3-yl)-6-methoxy-N 2 ,N 2 -Dimethyl-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline-2,4-diamine, N 2 -Butyl-N 4 -(5-cyclopropyl-1H-pyrazol-3-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline-2,4-diamine, N-(5-cyclopropyl-1H-pyrazol-3-yl)-6-methoxy-2-(piperazin-1-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline-4-amine, N-(5-cyclopropyl-1H-pyrazol-3-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline-4-amine, N-(5-cyclopropyl-1H-pyrazol-3-yl)-6-methoxy-2-morpholino-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine, N-(5-cyclopropyl-1H-pyrazol-3-yl)-6-methoxy-2-morpholino-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine, 2 -Cyclopropyl-N 4-(5-cyclopropyl-1H-pyrazol-3-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline-2,4-diamine, 2-(azetidin-1-yl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline-4-amine, N-(5-cyclopropyl-1H-pyrazol-3-yl)-6-methoxy-2-(pyrrolidine-1-yl)propoxy N-(5-cyclopropyl-1H-pyrazol-3-yl)-6-methoxy-2-(piperidin-1-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine, 4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-2-carbonitrile, N-(5-cyclopropyl-1H-pyrazol-3-yl)-6-methoxy-2-(piperidin-1-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine, N 4 -(5-cyclopropyl-1H-pyrazol-3-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-2,4-diamine, N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3,5-difluorophenyl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine, N 4 -(5-Cyclopropyl-1H-pyrazol-3-yl)-6-methoxy-N 2 -(2-Methoxyethyl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-2,4-diamine, 1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-2-yl)-3-methylurea, N-(5-cyclopropyl-1H-pyrazol-3-yl)-6-methoxy-2-(4-methoxypiperidin-1-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine, 6-methoxy-N 4 -(5-(methoxymethyl)-1H-pyrazol-3-yl)-N2,N2-dimethyl-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline-2,4-diamine, N 2 -Butyl-6-methoxy-N4 -(5-(methoxymethyl)-1H-pyrazol-3-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-2,4-diamine, 6-methoxy-N-(5-(methoxymethyl)-1H-pyrazol-3-yl)-2-(piperazin-1-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine, 6-methoxy-N-(5-(methoxymethyl)-1H-pyrazol-3-yl)-2-(4-methylpiperazin-1-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine, Lysin-1-yl)propoxy)quinazolin-4-amine, 6-methoxy-N-(5-(methoxymethyl)-1H-pyrazol-3-yl)-2-morpholino-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine, 2-(3,5-difluorophenyl)-6-methoxy-N-(5-(methoxymethyl)-1H-pyrazol-3-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine, 6-methoxy-N2-(2-methoxyethyl)-N 4-(5-(methoxymethyl)-1H-pyrazol-3-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-2,4-diamine, 1-(6-methoxy-4-((5-(methoxymethyl)-1H-pyrazol-3-yl)amino)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-2-yl)-3-methylurea, 6-methoxy-N-(5-(methoxymethyl)-1H-pyrazol-3-yl)-2-(4-methoxypiperidin-1-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine, 2 -(4,4-difluoropiperidin-1-yl)-6-methoxy-N-(5-(methoxymethyl)-1H-pyrazol-3-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine, (E)-2-(4,4-difluoropiperidin-1-yl)-6-methoxy-N-(5-(prop-1-en-1-yl)-1H-pyrazol-3-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine, 2-(4,4-difluoropiperidin-1-yl)-N-(4,5-dimethyl-1H-pyrazol-3-yl )-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine, 2-(4,4-difluoropiperidin-1-yl)-6-methoxy-N-(4-methyl-1H-pyrazol-3-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine, 2-(4,4-difluoropiperidin-1-yl)-N-(4-ethyl-1H-pyrazol-3-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine, 2-(4,4-difluoropiperidin-1-yl)-7 -(3-(dimethylamino)propoxy)-6-methoxy-N-(5-(methoxymethyl)-1H-pyrazol-3-yl)quinazolin-4-amine, 2-(4,4-difluoropiperidin-1-yl)-7-(3-(dimethylamino)propoxy)-N-(5-isopropyl-1H-pyrazol-3-yl)-6-methoxyquinazolin-4-amine, 2-(4,4-difluoropiperidin-1-yl)-7-(3-(dimethylamino)propoxy)-N-(5-ethyl-1H-pyrazol-3-yl)-6-methoxyquinazolin-4-amine, 2-(4,4-Difluoropiperidin-1-yl)-7-(3-(dimethylamino)propoxy)-6-methoxy-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine, N-(5-(tert-butyl)-1H-pyrazol-3-yl)-2-(4,4-difluoropiperidin-1-yl)-7-(3-(dimethylamino)propoxy)-6-methoxyquinazolin-4-amine, (E)-2-(4,4-difluoropiperidin-1-yl)-7-(3-(dimethylamino)propoxy)-6-methoxy-N-(5-(prop-1-en-1 -yl)-1H-pyrazol-3-yl)quinazolin-4-amine, N-(5-(tert-butyl)-1H-pyrazol-3-yl)-2-(4,4-difluoropiperidin-1-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine, 2-(4,4-difluoropiperidin-1-yl)-N-(5-ethyl-1H-pyrazol-3-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine, 2-(4,4-difluoropiperidin-1-yl)-N-(5-isopropyl)-1H-pyrazol-3-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine, Propyl-1H-pyrazol-3-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine, 2-(4,4-difluoropiperidin-1-yl)-6-methoxy-N-methyl-N-(5-methyl-1H-pyrazol-3-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine, 6-methoxy-N-(5-(methoxymethyl)-1H-pyrazol-3-yl)-2-(pyrrolidin-1-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine, N-( 2-(4,4-difluoropiperidin-1-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-yl)isoxazol-3-amine, 2-(4,4-difluoropiperidin-1-yl)-6-methoxy-N-(1H-pyrrol-3-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine, 2-(4,4-difluoropiperidin-1-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)-N-(thiophen-2-yl)quinazolin-4-amine, 2-(4,The compound is represented by a compound selected from the group consisting of 4-difluoropiperidin-1-yl)-N-(furan-2-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine, and 4-(6-methoxy-4-(methyl(5-methyl-1H-pyrazol-3-yl)amino)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-2-yl)thiomorpholine 1,1-dioxide.

[0127] In some embodiments, an optionally substituted group (such as, for example, those of formula (I)) may be substituted with one or more substituents independently selected from C1-C4 alkyl, C1-C4 alkoxy, amino, hydroxy, and halogen. In some embodiments, when substituted, R 1 The optional substituents of are selected from one or more of amino, -OH, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, and halogen. In some embodiments, when substituted, R 2 The optional substituents of are selected from one or more of amino, -OH, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, and halogen. In some embodiments, when substituted, R a The optional substituents of are selected from one or more of amino, -OH, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, and halogen.

[0128] Compounds of formula (IA) In some embodiments, the compound of formula (I) has the structure of formula (IA): [ka] wherein the A ring is further represented by ring structure (AIa) and the remaining variables are as defined elsewhere herein. In some embodiments, ring structure (AIa) is the following structure: [ka] is further represented by one of:

[0129] Compound of formula (IB) In some embodiments, the compound of formula (I) has the structure of formula (IB): [ka] [wherein ring B is represented by heteroaryl; R 7 is selected from the group consisting of C1-C6 alkyl, and C1-C6 alkynyl; R 8 is O or absent (e.g., a quinazolinyl ring and R 7 (a direct bond), with the remaining variables being as defined elsewhere herein. In some embodiments, the B ring is further represented by: [ka] In some embodiments, R 7 If present, R 8 Together with [ka] The structure is selected from the group consisting of:

[0130] Compound of formula (IC) In some embodiments, the compound of formula (I) has the structure of formula (IC): [ka] [wherein p and q are integers selected from 1, 2, or 3; X e is C(R d )2, N(R d ), O, S, and S(O)2; R d Each instance, if present, is further represented by: -H, halogen, and C1-C6 alkyl. dEach instance of, when present, is independently selected from the group consisting of: -H, -F, and -Me.

[0131] In some embodiments, when variables in a formula (e.g., any of formulas (IA), (IB), (IC), (II), (IIp), etc.) are undefined, those variables may be defined as provided elsewhere herein (e.g., such as for formula (I)).

[0132] Treatment Some embodiments relate to the treatment of a disorder comprising administering to a subject in need thereof a quinazolinyl compound or a pharmaceutical composition comprising a quinazolinyl compound described herein. In some embodiments, the disorder relates to a kinase enzyme.

[0133] Cancer arises from the modulation of the normal processes that control cell division, differentiation, and apoptotic cell death, and protein kinases play a critical role in this regulatory process. Thus, a partial, non-limiting list of such kinases that directly target the disclosed quinazolinyl compound targets include CLK1, CLK2, CLK3, CLK4, FMS, JNK1, JNK2, JNK3, PLK4, FLT3, FLT3(D835V), FLT3(ITD), FLT3(F691L), FLT3(N841I), FLT3(D835H), FLT3(D835Y), FLT3(K663Q), FLT3(N841l), MYLK4, NUAK2, CSF1R, DAPK3, RIOK2, HIPK1, ALK, MYLK, EGFR, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, VEGFR, JAK1, ABL1, DAPK2, LTK. Other cancer-associated kinases targeted by the disclosed quinazolinyls include (without limitation) abl, Akt, Aurora-A, Auroa-B, Aurora-C, ATK, bcr-abl, Blk, Brk, Btk, c-Kit, c-Met, s-Src, c-fms, CDK1, CDK2 These include CDK4, CDK6, CDK7, CDK8, CDK9, CDK10, rRaf1, CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, ERK, Fak, fes, Fgr, fit-1, FLK-4, Fps, Fyn, Hck, HER, Hck, IGF-1R, INS-R, Jak, KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, Ros, Tie1, Tie2, Trk, Yes, and Zap70.

[0134] In mammalian biology, such protein kinases include the mitogen-activated protein kinase (MAPK) signaling pathway. In some embodiments, the disclosed quinazolinyl compounds are used in methods of disrupting the MAPK signaling pathway (e.g., to treat cancer, autoimmune disease, and / or DMD).

[0135] Lipid kinases (e.g., PI3K) constitute another group of kinases that are structurally similar to protein kinases. In some embodiments, the disclosed quinazolinyl compounds may be used in methods of treating lipid kinase-mediated disorders (e.g., cancer, autoimmune disease, and / or DMD).

[0136] Some embodiments relate to a method of treating a kinase (e.g., protein or lipid) associated disease or disorder (e.g., cancer, autoimmune disease, and / or DMD), comprising administering to a subject in need thereof a quinazolinyl compound described herein or a pharmaceutical composition described herein. In some embodiments, the kinase associated disease is cancer, autoimmune disease, and / or DMD. In some embodiments, the cancer is selected from the group consisting of colorectal, gastric, stomach, esophageal, liver, pancreatic, breast, prostate, bladder, kidney, ovarian, lung, melanoma, and multiple myeloma. In some embodiments, the autoimmune disease is 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), Sjogren's syndrome, Graves' disease, Hashimoto's thyroiditis, autoimmune hepatitis, Behcet's disease, atopic dermatitis, Castleman's disease, allergic rhinitis, eczema, Dressler's syndrome, eosinophilic esophagitis, fibromyalgia, Guillain-Barre syndrome, juvenile arthritis, Kawasaki disease, Mooren'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, methods of treating cancer include administering to a patient suspected of having or at risk of having cancer one or more compounds of formula (I). In some embodiments, methods of treating cancer, autoimmune disease, and / or DMD include administering to a patient having cancer, autoimmune disease, and / or DMD one or more compounds of formula (I).

[0137] In some embodiments, the kinase inhibited by the quinazolinyl compounds is selected from the group consisting of CLK1, CLK4, PLK4, FLT3, and JNK1. All these kinases have been found to be associated with cancer diseases, JNK1 with autoimmune diseases, and CLK1 / 4 with Duchenne muscular dystrophy (DMD).

[0138] In some embodiments, the compounds disclosed herein are characterized by their ability to bind to one or more of the kinases disclosed herein.In some embodiments, the compounds of formula (I) are characterized by a dissociation constant (Kd) for the kinases disclosed herein of about 1200nM, 1000nM, 780nM, 500nM, 250nM, 150nM, 100nM, 50nM, 25nM, 10nM, 5nM, 1nM, 0.1nM, 0.01nM or less, or inclusive and / or between the aforementioned values.In some embodiments, the Kd value can be measured in 0.9% DMSO aqueous solution.In some embodiments, the Kd is measured using the ligand-binding affinity beads disclosed elsewhere herein. In some embodiments, Kd is measured by incubating the mixed kinase, ligand-bound affinity beads, and compound in 1× binding buffer (e.g., 20% SeaBlock, 0.17×PBS, 0.05% Tween 20, 6 mM DTT).

[0139] In some embodiments, the compounds disclosed herein are characterized by their ability to bind to one or more of CLK1, CLK4, PLK4, FLT3, and / or JNK1 disclosed herein. In some embodiments, the compounds of formula (I) are characterized by a dissociation constant (Kd) for CLK1, CLK4, PLK4, FLT3, and / or JNK1 of about 1200nM, 1000nM, 780nM, 500nM, 250nM, 150nM, 100nM, 50nM, 25nM, 10nM, 5nM, 1nM, 0.1nM, 0.01nM or less, or inclusive and / or ranges therebetween. In some embodiments, a compound disclosed herein is characterized by its ability to bind to one or more of CLK1, CLK2, CLK3, CLK4, FMS, JNK1, JNK2, JNK3, PLK4, FLT3, FLT3(D835V), FLT3(ITD), FLT3(F691L), FLT3(N841I), FLT3(D835H), FLT3(D835Y), FLT3(K663Q), FLT3(N841l), MYLK4, NUAK2, CSF1R, DAPK3, RIOK2, HIPK1, ALK, MYLK, EGFR, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, VEGFR, JAK1, ABL1, DAPK2, and / or LTK disclosed herein.In some embodiments, the compound of formula (I) is selected from the group consisting of CLK1, CLK2, CLK3, CLK4, FMS, JNK1, JNK2, JNK3, PLK4, FLT3, FLT3(D835V), FLT3(ITD), FLT3(F691L), FLT3(N841I), FLT3(D835H), FLT3(D835Y), FLT3(K663Q), FLT3(N841l), MYLK4, NUAK2, CSF1R, DAPK3, RIOK2, HIPK1, ALK, MYLK, EGFR, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, VEGFR, JAK1, ABL1, DAPK2, and / or LTK, characterized by a dissociation constant (Kd) of about 1200nM, 1000nM, 780nM, 500nM, 250nM, 150nM, 100nM, 50nM, 25nM, 10nM, 5nM, 1nM, 0.1nM, 0.01nM or less, or a range including and / or between the aforementioned values. In some embodiments, the compounds disclosed herein are ... The present invention is characterized by its ability to bind to one or more of CDK4, CDK6, CDK7, CDK8, CDK9, CDK10, rRaf1, CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, ERK, Fak, fes, Fgr, fit-1, FLK-4, Fps, Fyn, Hck, HER, Hck, IGF-1R, INS-R, Jak, KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, Ros, Tie1, Tie2, Trk, Yes, and / or Zap70.In some embodiments, the compound of formula (I) is selected from the group consisting of abl, Akt, Aurora-A, Auroa-B, Aurora-C, ATK, bcr-abl, Blk, Brk, Btk, c-Kit, c-Met, s-Src, c-fms, CDK1, CDK2 CDK4, CDK6, CDK7, CDK8, CDK9, CDK10, rRaf1, CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, ERK, Fak, fes, Fgr, fit-1, FLK-4, Fps, Fyn, Hck, HER, Hck, IGF-1R, INS-R, Jak, KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, P For YK2, Ros, Tie1, Tie2, Trk, Yes, and / or Zap70, the Kd is characterized by a dissociation constant (Kd) of about 1200nM, 1000nM, 780nM, 500nM, 250nM, 150nM, 100nM, 50nM, 25nM, 10nM, 5nM, 1nM, 0.1nM, 0.01nM or less, or a range including and / or between the aforementioned values. In some embodiments, the Kd value can be measured in 0.9% DMSO aqueous solution. In some embodiments, the Kd is measured using ligand-bound affinity beads as disclosed elsewhere herein. In some embodiments, the Kd is measured by incubating the mixed kinase, ligand-bound affinity beads, and compound in 1× binding buffer (e.g., 20% SeaBlock, 0.17×PBS, 0.05% Tween 20, 6mM DTT).

[0140] In some embodiments, the kinase enzyme target (e.g., of inhibition) is a mutant enzyme and not a wild-type enzyme. In some embodiments, the inhibitor can be a compound of formula (I). In some embodiments, the compound of formula (I) is at least 1.1, 2, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 times more potent for the mutant than for the wild-type. In some embodiments, the IC of the compound of formula (I) is 50 is 0.5, 0.1, 0.05, or 0.01% of the wild type for the mutant (i.e., IC 50(wherein the IC value is smaller for the mutant). In some embodiments, the IC of the compound of formula (I) for the mutant or mutation is 50 is about 100 nM or less (e.g., it is at least as potent as 100 nM). In some embodiments, the IC 50 is about 10 nM or less (e.g., it is at least as potent as 10 nM). In some embodiments, the IC 50 is less than or equal to single digit nM (e.g., it is at least as potent as single digit nM). In some embodiments, the IC 50 is at least as effective for the mutant or variant as it is for the wild-type kinase.

[0141] In some embodiments, the kinase enzyme target (e.g., of inhibition) is a mutant CLK1, CLK4, PLK4, FLT3, and / or JNK1 enzyme, and not a wild-type enzyme. In some embodiments, the inhibitor can be a compound of formula (I). In some embodiments, the compound of formula (I) is at least 1.1, 2, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 times more potent for the mutant than for the wild-type. In some embodiments, the IC of a compound of formula (I) is 50 is 0.5, 0.1, 0.05, or 0.01% of the magnitude of the wild type for mutant CLK1, CLK4, PLK4, FLT3, and / or JNK1 (i.e., IC 50 In some embodiments, the IC of a compound of formula (I) for a mutant or variant of CLK1, CLK4, PLK4, FLT3, and / or JNK1 is 50 is about 100 nM or less (e.g., it is at least as potent as 100 nM). In some embodiments, the IC 50is about 10 nM or less (e.g., it is at least as potent as 10 nM). In some embodiments, the IC of a compound of formula (I) for a mutant or mutated version of CLK1, CLK4, PLK4, FLT3, and / or JNK1 is 50 is in the single digit nM or less (e.g., it is at least as potent as the single digit nM). In some embodiments, the IC of a compound of formula (I) for a mutant or mutated CLK1, CLK4, PLK4, FLT3, and / or JNK1 is 50 is at least as effective for the mutant or variant as it is for the wild-type kinase.

[0142] In some embodiments, the kinase enzyme target (e.g., of inhibition) is CLK1, CLK2, CLK3, CLK4, FMS, JNK1, JNK2, JNK3, PLK4, FLT3, FLT3(D835V), FLT3(ITD), FLT3(F691L), FLT3(N841I), FLT3(D835H), FLT3(D835Y), FLT3(K663Q), FLT3(N841l), MYLK4, NUAK2, CSF1R, DAPK3, RIOK2, HIPK1, ALK, MYLK, EGFR, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, VEGFR, JAK1, ABL1, DAPK2, and / or LTK enzymes, and not a wild-type enzyme. In some embodiments, the inhibitor can be a compound of formula (I). In some embodiments, the compound of formula (I) is at least 1.1, 2, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 times more potent for the mutant than for the wild type. In some embodiments, the IC 50is 0.5, 0.1, 0.05, or 0.01% of the magnitude of the wild type for mutant CLK1, CLK2, CLK3, CLK4, FMS, JNK1, JNK2, JNK3, PLK4, FLT3, FLT3(D835V), FLT3(ITD), FLT3(F691L), FLT3(N841I), FLT3(D835H), FLT3(D835Y), FLT3(K663Q), FLT3(N841l), MYLK4, NUAK2, CSF1R, DAPK3, RIOK2, HIPK1, ALK, MYLK, EGFR, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, VEGFR, JAK1, ABL1, DAPK2, and / or LTK (i.e., IC 50 In some embodiments, the IC of a compound of formula (I) for a mutant or mutation of CLK1, CLK2, CLK3, CLK4, FMS, JNK1, JNK2, JNK3, PLK4, FLT3, FLT3(D835V), FLT3(ITD), FLT3(F691L), FLT3(N841I), FLT3(D835H), FLT3(D835Y), FLT3(K663Q), FLT3(N841l), MYLK4, NUAK2, CSF1R, DAPK3, RIOK2, HIPK1, ALK, MYLK, EGFR, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, VEGFR, JAK1, ABL1, DAPK2, and / or LTK is 0.01 to 0.001. 50 is about 100 nM or less (e.g., it is at least as potent as 100 nM). In some embodiments, the IC of a compound of formula (I) on mutants or mutations of CLK1, CLK2, CLK3, CLK4, FMS, JNK1, JNK2, JNK3, PLK4, FLT3, FLT3(D835V), FLT3(ITD), FLT3(F691L), FLT3(N841I), FLT3(D835H), FLT3(D835Y), FLT3(K663Q), FLT3(N841l), MYLK4, NUAK2, CSF1R, DAPK3, RIOK2, HIPK1, ALK, MYLK, EGFR, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, VEGFR, JAK1, ABL1, DAPK2, and / or LTK. 50is about 10 nM or less (e.g., it is at least as potent as 10 nM). In some embodiments, the IC of a compound of formula (I) on mutants or mutations of CLK1, CLK2, CLK3, CLK4, FMS, JNK1, JNK2, JNK3, PLK4, FLT3, FLT3(D835V), FLT3(ITD), FLT3(F691L), FLT3(N841I), FLT3(D835H), FLT3(D835Y), FLT3(K663Q), FLT3(N841l), MYLK4, NUAK2, CSF1R, DAPK3, RIOK2, HIPK1, ALK, MYLK, EGFR, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, VEGFR, JAK1, ABL1, DAPK2, and / or LTK. 50 is in the single digit nM or less (e.g., it is at least as potent as the single digit nM). In some embodiments, the IC of a compound of formula (I) on mutants or mutations of CLK1, CLK2, CLK3, CLK4, FMS, JNK1, JNK2, JNK3, PLK4, FLT3, FLT3(D835V), FLT3(ITD), FLT3(F691L), FLT3(N841I), FLT3(D835H), FLT3(D835Y), FLT3(K663Q), FLT3(N841l), MYLK4, NUAK2, CSF1R, DAPK3, RIOK2, HIPK1, ALK, MYLK, EGFR, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, VEGFR, JAK1, ABL1, DAPK2, and / or LTK is 0.01 to 0.01. 50 is at least as effective for the mutant or variant as it is for the wild-type kinase.

[0143] In some embodiments, the kinase enzyme target (e.g., of inhibition) is mutant abl, Akt, Aurora-A, Auroa-B, Aurora-C, ATK, bcr-abl, Blk, Brk, Btk, c-Kit, c-Met, s-Src, c-fms, CDK1, CDK2 CDK4, CDK6, CDK7, CDK8, CDK9, CDK10, rRaf1, CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, ERK, Fak, fes, Fgr, fit-1, FLK-4, Fps, Fyn, Hck, HER, Hck, IGF-1R, INS-R, Jak, KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, Ros, Tie1, Tie2, Trk, Yes, and / or Zap70 enzymes, but not wild-type enzymes. In some embodiments, the inhibitor can be a compound of formula (I). In some embodiments, the compound of formula (I) is at least 1.1, 2, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 times more potent for the mutant than for the wild-type. In some embodiments, the IC of the compound of formula (I) 50mutant abl, Akt, Aurora-A, Auroa-B, Aurora-C, ATK, bcr-abl, Blk, Brk, Btk, c-Kit, c-Met, s-Src, c-fms, CDK1, CDK2 For CDK4, CDK6, CDK7, CDK8, CDK9, CDK10, rRaf1, CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, ERK, Fak, fes, Fgr, fit-1, FLK-4, Fps, Fyn, Hck, HER, Hck, IGF-1R, INS-R, Jak, KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, Ros, Tie1, Tie2, Trk, Yes, and / or Zap70, the IC50 value is 0.5, 0.1, 0.05, or 0.01% of that for the wild type (i.e., the IC50 value is smaller for the mutant). In some embodiments, the IC of a compound of formula (I) on a mutant or mutated abl, Akt, Aurora-A, Auroa-B, Aurora-C, ATK, bcr-abl, Blk, Brk, Btk, c-Kit, c-Met, s-Src, c-fms, CDK1, CDK2 CDK4, CDK6, CDK7, CDK8, CDK9, CDK10, rRaf1, CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, ERK, Fak, fes, Fgr, fit-1, FLK-4, Fps, Fyn, Hck, HER, Hck, IGF-1R, INS-R, Jak, KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, Ros, Tie1, Tie2, Trk, Yes, and / or Zap70. 50is about 100 nM or less (eg, it is at least as potent as 100 nM). In some embodiments, the IC of a compound of formula (I) on a mutant or mutated abl, Akt, Aurora-A, Auroa-B, Aurora-C, ATK, bcr-abl, Blk, Brk, Btk, c-Kit, c-Met, s-Src, c-fms, CDK1, CDK2 CDK4, CDK6, CDK7, CDK8, CDK9, CDK10, rRaf1, CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, ERK, Fak, fes, Fgr, fit-1, FLK-4, Fps, Fyn, Hck, HER, Hck, IGF-1R, INS-R, Jak, KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, Ros, Tie1, Tie2, Trk, Yes, and / or Zap70. 50 is about 10 nM or less (eg, it is at least as potent as 10 nM). In some embodiments, the IC of a compound of formula (I) on a mutant or mutated abl, Akt, Aurora-A, Auroa-B, Aurora-C, ATK, bcr-abl, Blk, Brk, Btk, c-Kit, c-Met, s-Src, c-fms, CDK1, CDK2 CDK4, CDK6, CDK7, CDK8, CDK9, CDK10, rRaf1, CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, ERK, Fak, fes, Fgr, fit-1, FLK-4, Fps, Fyn, Hck, HER, Hck, IGF-1R, INS-R, Jak, KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, Ros, Tie1, Tie2, Trk, Yes, and / or Zap70. 50is less than or equal to single digit nM (eg, it is at least as potent as single digit nM). In some embodiments, the IC of a compound of formula (I) on a mutant or mutated abl, Akt, Aurora-A, Auroa-B, Aurora-C, ATK, bcr-abl, Blk, Brk, Btk, c-Kit, c-Met, s-Src, c-fms, CDK1, CDK2 CDK4, CDK6, CDK7, CDK8, CDK9, CDK10, rRaf1, CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, ERK, Fak, fes, Fgr, fit-1, FLK-4, Fps, Fyn, Hck, HER, Hck, IGF-1R, INS-R, Jak, KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, Ros, Tie1, Tie2, Trk, Yes, and / or Zap70. 50 is at least as effective for the mutant or variant as it is for the wild-type kinase.

[0144] In some embodiments of the method, the subject has taken (or is still taking) a multi-targeted kinase inhibitor ("MKI") or targeted kinase inhibitor. Upon taking the MKI or targeted inhibitor, the subject develops a tumor that becomes resistant to the previous MKI or targeted inhibitor. At this point, a compound of formula (I) can simply be administered. In the alternative, it can be determined whether the subject currently has a tumor that has a kinase mutation therein (e.g., an amino acid change resulting in resistance to the previous treatment). If the subject has a tumor with the noted mutation, the subject can be administered a compound of formula (I).

[0145] Administration and Pharmaceutical Compositions In some embodiments, the quinazolinyl compound is administered in a therapeutically effective dosage. In some embodiments, the daily dosage may generally be from about 0.25 mg / kg to about 120 mg / kg or more of body weight, from about 0.5 mg / kg or less to about 70 mg / kg, from about 1.0 mg / kg to about 50 mg / kg of body weight, or from about 1.5 mg / kg to about 10 mg / kg of body weight. Thus, for administration to a 70 kg person, the dosage range would be from about 17 mg / day to about 8000 mg / day, from about 35 mg / day to about 7000 mg / day or more, from about 70 mg / day to about 6000 mg / day, from about 100 mg / day to about 5000 mg / day, or from about 200 mg to about 3000 mg / day. The amount of active compound administered will, of course, depend 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.

[0146] Administration of the quinazolinyl compounds or pharma- ceutically acceptable salts disclosed herein can be via any of the accepted modes of administration for drugs that serve similar utility, including, but not limited to, oral, subcutaneous, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal, or intraocular. Oral and parenteral administration are customary in the treatment of the indications that are the subject of preferred embodiments.

[0147] The quinazolinyl compound that is useful as described above can be formulated into pharmaceutical compositions for use in treating 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), the entirety of which is incorporated by reference.Thus, some embodiments include pharmaceutical compositions that include (a) a safe and therapeutically effective amount of the compound described herein (including its enantiomer, diastereoisomer, tautomer, polymorph and solvate), or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable carrier, diluent, excipient, or combination thereof.

[0148] In addition to the selected compound that is useful as described above, some embodiments include compositions that contain pharma- ceutically acceptable carriers. The term "pharma- ceutically acceptable carriers" or "pharma- ceutically acceptable excipients" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharma- ceutically active substances is well known in the art. Except where any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic composition is contemplated. In addition, various adjuvants, such as those commonly used in the art, may be included. Considerations regarding the inclusion of various components in pharmaceutical compositions are described, for example, in Gilman et al. (eds.) (1990), Goodman and Gilman's The Pharmacological Basis of Therapeutics, 8th Edition, Pergamon Press, which is incorporated herein by reference in its entirety.

[0149] Some examples of substances which can serve as pharma- ceutically acceptable carriers or components thereof are 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; powdered tragacanth, malt, gelatin, talc, solid lubricants such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and cocoa oil; polyols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers such as TWEENS; wetting agents such as sodium lauryl sulfate; colorants, flavorings, tableting agents, stabilizers, antioxidants, preservatives, pyrogen-free water, isotonic saline, and phosphate buffer solutions.

[0150] The choice of pharma- ceutically acceptable carrier to be used in conjunction with a subject quinazolinyl compound is basically determined by the way the compound is to be administered.

[0151] The quinazolinyl compositions described herein are preferably provided in unit dosage form. As used herein, a "unit dosage form" is a composition containing an amount of compound suitable for administration in a single dose to an animal, preferably a mammalian subject, in accordance with good medical practice. However, the preparation of a single or unit dosage form does not imply that the dosage form is administered once per day or once during the course of treatment. Such dosage forms are intended to be administered once, twice, three times, or more per day, may be administered as an infusion over a period of time (e.g., from about 30 minutes to about 2-6 hours) or may be administered as a continuous infusion, and may be given multiple times during the course of treatment, although single administration is not specifically excluded. Those skilled in the art will understand that the formulations are not specifically intended for the entire course of treatment, and such decisions are left to the skilled artisan in the art of treatment rather than formulation.

[0152] The quinazolinyl compositions useful as described above can be in any of a variety of suitable forms for various routes of administration, for example, oral, nasal, rectal, topical (including transdermal), ocular, intracerebral, intracranial, intrathecal, intraarterial, intravenous, intramuscular, or other parental routes of administration. Those skilled in the art will appreciate that oral and nasal compositions include compositions administered by inhalation and are prepared using available methods. Depending on the particular route of administration desired, a variety of pharmaceutically acceptable carriers well known in the art can be used. Pharmaceutically acceptable carriers include, for example, solid or liquid fillers, diluents, hydrotropes, surfactants, and encapsulating materials. Optional pharmaceutically active materials that do not substantially interfere with the inhibitory activity of the compound can be included. 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. Techniques and compositions for making dosage forms useful in the methods described herein are described in the following references: 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), all of which are incorporated herein by reference.

[0153] A variety of oral dosage forms can be used, including solid forms such as tablets, capsules, granules, and bulk powders. Tablets can be compressed, powdered tablets, enteric coated, sugar coated, film coated, or multiple 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 reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifiers, suspending agents, diluents, sweeteners, melting agents, colorants, and flavorings.

[0154] In some embodiments, the oral formulation comprises dimethylacetamide (DMA). In some embodiments, the oral formulation comprises 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 ranges including and / or ranging between the aforementioned values. In some embodiments, the oral formulation comprises propylene glycol (PG). In some embodiments, the oral formulation comprises 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 ranges including and / or ranging between the aforementioned values. In some embodiments, the oral formulation comprises polyethylene glycol (PEG). In some embodiments, the oral formulation comprises 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 ranges including and / or ranging between the aforementioned values. In some embodiments, the oral formulation comprises 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 ranges including and / or spanning the aforementioned values.

[0155] Pharmaceutically acceptable carriers suitable for preparing unit dosage forms for oral administration are well known in the art. Tablets typically contain conventional pharma- ceutically compatible 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; lubricants such as magnesium stearate, stearic acid, and talc. Glidants 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 solid diluents as disclosed above. The selection of the carrier component will depend on secondary considerations such as taste, cost, and shelf life, which are not critical, and can be readily made by one of ordinary skill in the art.

[0156] Oral compositions also include solutions, emulsions, suspensions, etc. Pharmaceutically acceptable carriers suitable for preparing such compositions are well known in the art. Typical components of carriers for syrups, elixirs, emulsions, and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol, and water. For suspensions, typical suspending agents include methylcellulose, sodium carboxymethylcellulose, AVICEL RC-591, tragacanth, and sodium alginate, typical wetting agents include lecithin and polysorbate 80, and typical preservatives include methylparaben and sodium benzoate. Oral liquid compositions can also contain one or more components such as sweeteners, flavorings, and colorings disclosed above.

[0157] Such compositions may also be coated by conventional methods, typically with a pH or time-dependent coating, so that the target compound is released in the gastrointestinal tract near the desired local application or at various times to prolong the desired effect.Such dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate, ethylcellulose, Eudragit coating, wax, and shellac.

[0158] The compositions described herein may optionally include other medicament actives (e.g., active pharmaceuticals). In some embodiments, the compositions may include one or more quinazolinyl compounds disclosed elsewhere herein.

[0159] Other compositions useful for achieving systemic delivery of the subject compound include sublingual, buccal and nasal dosage forms.Such compositions typically comprise one or more of soluble filler substances such as sucrose, sorbitol and mannitol, and binders such as acacia, microcrystalline cellulose, carboxymethylcellulose and hydroxypropylmethylcellulose.They may also comprise the glidants, lubricants, sweeteners, colorants, antioxidants and flavorants disclosed above.

[0160] Liquid compositions formulated for topical ophthalmic use are formulated so that they can be administered locally to the eye. Comfort should be maximized as much as possible, but formulation considerations (e.g., drug stability) may require less than optimal comfort. If comfort cannot be maximized, the solution should be formulated so that the topical ophthalmic solution is tolerable to patients. In addition, ophthalmically acceptable solutions should either be packaged for single use or contain a preservative to prevent contamination over multiple uses.

[0161] In ophthalmic applications, solutions or medicines are often prepared using saline as the main vehicle. Ophthalmic solutions should preferably be maintained at a comfortable pH using an appropriate buffer system. The formulations may also contain conventional pharma- ceutically acceptable preservatives, stabilizers, and surfactants.

[0162] The preservatives that can be used in the pharmaceutical compositions disclosed herein include, but are not limited to, benzalkonium chloride, PHMB, chlorobutanol, thimerosal, phenylmercuric acetate, and phenylmercuric nitrate.Useful surfactants are, for example, Tween 80.Similarly, various useful vehicles can be used in the ophthalmic preparations disclosed herein.These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropylmethylcellulose, poloxamer, carboxymethylcellulose, hydroxyethylcellulose, and purified water.

[0163] Isotonicity adjusting agents may be added as necessary or convenient, including, but not limited to, salts, particularly sodium chloride, potassium chloride, mannitol, and glycerin, or any other suitable ophthalmically acceptable isotonicity adjusting agent.

[0164] Various buffers and means for adjusting pH may be used as long as the resulting preparation is ophthalmologically acceptable. In many compositions, the pH will be 4 to 9. Thus, buffers include acetate buffers, citrate buffers, phosphate buffers, and borate buffers. Acids or bases may be used to adjust the pH of these formulations as needed.

[0165] In a similar vein, ophthalmically acceptable antioxidants include, but are not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, and butylated hydroxytoluene.

[0166] Another vehicle component that may be included in the ophthalmic formulation is a chelating agent. A useful chelating agent is edetate disodium, although other chelating agents may be used instead or in conjunction therewith.

[0167] For topical use, creams, ointments, gels, solutions, or suspensions containing the compounds disclosed herein are used. Topical formulations may generally be comprised of a pharmaceutical carrier, cosolvent, emulsifier, penetration enhancer, preservative system, and emollient.

[0168] For intravenous administration, the compounds and compositions described herein may be dissolved or dispersed in a pharma- ceutically acceptable diluent, such as saline or dextrose solution. Suitable excipients may be included to achieve the desired pH, including, but not limited to, NaOH, sodium carbonate, sodium acetate, HCl, and citric acid. In various embodiments, the pH of the final composition ranges from 2 to 8, or preferably 4 to 7. Antioxidant excipients may include sodium bisulfite, acetone sodium 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. Additional acceptable excipients are described in Powell et al., Compendium of Excipients for Parenteral Formulations, PDA J Pharm Sci and Tech, 1998, 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, 65 287-332, both of which are incorporated by reference in their entirety. Antimicrobial agents may also be included to achieve a bacteriostatic or fungistatic solution, including, but not limited to, phenylmercuric nitrate, thimerosal, benzethonium chloride, benzalkonium chloride, phenol, cresol, and chlorobutanol.

[0169] Compositions for intravenous administration may be provided to the caregiver in one more solid form that is reconstituted with a suitable diluent, such as sterile water, saline, or dextrose in water, immediately prior to administration. In other embodiments, the compositions are provided in a solution ready for parenteral administration. In yet other embodiments, the compositions are provided in a solution that is further diluted prior to administration. In embodiments involving administration of a combination of a compound described herein with another agent, the combination may be provided to the caregiver as a mixture, or the caregiver may mix the two agents prior to administration, or the two agents may be administered separately.

[0170] The actual dose of the active compounds described herein will depend on the particular compound and the condition being treated, and the selection of an appropriate dose is well within the knowledge of one of ordinary skill in the art.

[0171] The quinazolinyl compounds and compositions described herein, if desired, can be presented in a pack or dispenser device that contains one or more unit dosage forms containing active ingredient.Such a pack or device can include, for example, metal or plastic foil, such as blister pack, or glass, and rubber stopper, such as in vial.The pack or dispenser device can be accompanied by instructions for administration.The compounds and compositions described herein can be formulated in a compatible pharmaceutical carrier, and can also be prepared, placed in a suitable container, and labeled for the treatment of indicated conditions.

[0172] The amount of the compound in the formulation can vary within the entire range used by those skilled in the art. Typically, the formulation contains about 0.01-99.99 wt% of the compound of the present technology based on the total formulation, with the balance being one or more suitable pharmaceutical excipients, based on weight percent (wt%). Preferably, the compound is present at a level of about 1-80 wt%. Representative pharmaceutical formulations are described below.

[0173] In some embodiments, oral formulations of the compounds described herein can be easily formulated by combining active compounds with pharma- ceutically acceptable carriers and excipients. Such carriers allow the compounds of the present disclosure to be formulated for oral ingestion by subjects as tablets, pills, capsules, liquids, gels, syrups, slurries, suspensions, emulsions, and the like. Pharmacological preparations for oral use may be made using solid excipients, and after adding suitable auxiliary agents if desired, the resulting mixture is optionally milled, and the mixture of granules is processed to obtain tablets. Suitable excipients are sugars, including lactose, sucrose, mannitol, or sorbitol, cellulose preparations, such as corn starch, wheat starch, rice starch, potato starch, gelatin, methylcellulose, hydroxypropylmethylcellulose, and sodium carboxymethylcellulose, among others.

[0174] In some embodiments, pharmaceutical compositions of the compounds described herein that can be used orally include push-fit capsules made of gelatin and soft sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. The 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.

[0175] Some embodiments include the compounds described herein encapsulated in soft capsules, where the active compound may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. Additionally, stabilizers can be added.

[0176] In some embodiments, the dosage of the composition administered will depend on a number of factors, including the subject being treated, the stage of the autoimmune disease, the route of administration, and the judgment of the prescribing clinician.

[0177] Method of preparation The compounds disclosed herein may be synthesized by the methods described below or by modifications of these methods. In some embodiments, the method of synthesizing a quinazolinyl compound includes obtaining a quinazolinyl precursor (e.g., Formula (IIp)) and reacting it with an amine-containing group. [ka] In some embodiments, X is a halogen atom (e.g., F, Cl, I, or Br), and the remaining variables are as defined elsewhere herein. In some embodiments, X is Cl. In some embodiments, R 2 -OR 6 or an optionally substituted (heterocyclyl)alkynyl. In some embodiments, R 6 is selected from the group consisting of methyl, optionally substituted 2-10 membered heteroalkyl, and (heterocyclyl)alkyl. 3 is selected from the group consisting of hydrogen, halogen, and -OMe. a is hydrogen or optionally substituted C1-C 10 In some embodiments, the A ring is an optionally substituted heteroaryl.

[0178] In some embodiments, a method of synthesizing a quinazolinyl compound includes obtaining a quinazolinyl precursor (e.g., of formula (II)) and converting it to a compound of formula HR 1 with a nucleophilic group having the formula: [ka]

[0179] In some embodiments, X is a halogen atom (e.g., F, Cl, I, or Br), and the remaining variables are as defined elsewhere herein. 1is an optionally substituted 6- to 10-membered aryl, an optionally substituted 3- to 10-membered heterocyclyl, an optionally substituted 5- to 10-membered heteroaryl, an optionally substituted carbamide, -CN, and -NR 4 R 5 In some embodiments, R 4 and R 5 each independently represents hydrogen, optionally substituted C 1~6 Alkyl or optionally substituted C 3~6 or alternatively, R 4 and R 5 taken together form an optionally substituted 3-10 membered heterocyclyl. In some embodiments, X is Cl. In some embodiments, R 2 -OR 6 or an optionally substituted (heterocyclyl)alkynyl. In some embodiments, R 6 is selected from the group consisting of methyl, optionally substituted 2-10 membered heteroalkyl, and (heterocyclyl)alkyl. 3 is selected from the group consisting of hydrogen, halogen, and -OMe. a is hydrogen or optionally substituted C1-C 10 In some embodiments, the A ring is an optionally substituted heteroaryl.

[0180] Figure 2 shows an exemplary synthesis of a compound of formula (I). As shown in Figure 2, in some embodiments, a compound of formula (I) is prepared by one or more of the following steps: first halogen (e.g., chloro) substitution, second halogen (e.g., chloro) substitution, coupling (e.g., palladium), and / or third halogen (e.g., chloro) substitution. In some embodiments, the synthesis results in 2-amino and 4-amino functionalized regions of the 6,7-dialkoxyquinazoline scaffold as shown in general scheme 1 of Figure 2. An exemplary set of conditions for scheme 1 were as follows: (i) HNR a (Ring A) (1.5 equivalents), DIPEA (1~10 equivalents), DMF, NaI, 70°C, (ii) HNR a (Ring A) (1.05 equiv), K2CO3 (3 equiv), Xantphos (0.2 equiv), Pd(OAc)2 (0.15 equiv), DMF / THF, 70°C, (iii) HR 1 (5-20 equiv.), DIPEA (6-10 equiv.), DMF, iPrOH, 2-BuOH, or combinations, 90° C. convention heating.

[0181] Methods for modifying the process include, inter alia, temperature, solvents, reagents, etc., known to those skilled in the art. In general, 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 may be accomplished by conventional protecting groups, such as those described in Protective Groups in Organic Chemistry (JFW MacOmie, ed., Plenum Press, 1973) and PGM Green, TW Hutts, Protecting Groups in Organic Synthesis (3rd ed.) Wiley, New York (1999), both of which are hereby incorporated by reference in their entirety. Protecting groups may be removed at a convenient subsequent step using methods known in the art. Synthetic chemical transformations useful in the synthesis of applicable compounds are known in the art, such as 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 hereby incorporated by reference in their entirety. The routes shown and described herein are exemplary only and are not intended or should be construed to limit the scope of the claims in any manner. Those skilled in the art will be able to understand modifications of the disclosed syntheses and devise alternative routes based on the disclosure herein. All such modifications and alternative routes are within the scope of the claims.

[0182] When the compounds of the present technology contain one or more chiral centers, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers, or as d(l) stereoisomers, or as stereoisomer-enriched mixtures. Unless otherwise specified, all such stereoisomers (and enriched mixtures) are included within the scope of the present technology. Pure stereoisomers (or enriched 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 resolved, for example, using chiral column chromatography, chiral resolving agents, and the like.

[0183] 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, Calif., USA), Emka-Chemce, or Sigma (St. Louis, Mo., USA). Others may 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 supplements (Elsevier Science Publishers, 1989), Organic Reactions, volumes 1-40 (John Wiley, and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley, and Sons, 5th ed., 2001), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), or obvious modifications thereof.

[0184] It will be clear to those skilled in the art that the methods for preparing precursors and functional groups related to the compounds claimed in the present invention are generally described in the literature.In these reactions, it is also possible to use variants that are themselves known to those skilled in the art, but are not mentioned in more detail.In the light of the literature and this disclosure, those skilled in the art are fully equipped with the necessary knowledge to prepare any of the compounds.

[0185] It will be understood that those skilled in the art of organic chemistry can easily carry out the operations without further instruction, i.e., it is well within the domain and skill of the person skilled in the art to carry out these operations. These include reduction of carbonyl compounds to their corresponding alcohols, oxidation, acylation, aromatic substitution (both electrophilic and nucleophilic), etherification, esterification, and saponification. These operations are described in standard texts such as March Advanced Organic Chemistry (Wiley), Carey and Sundberg, Advanced Organic Chemistry (incorporated herein in its entirety by reference). Unless otherwise specified, all intermediate compounds in this disclosure were used without further purification.

[0186] Those skilled in the art will easily understand that certain reactions are best carried out by masking or protecting other functional groups in the molecule, thus avoiding any undesired side reactions and / or increasing the yield of the reaction. To achieve such an increase in yield or to avoid undesired 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 manipulations 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 herein by reference in its entirety.

[0187] The trademarks used herein are only examples 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 expected. Therefore, the examples and the trademarks used therein are non-limiting, and they are not intended to be limiting, but merely illustrative of how those skilled in the art may choose to perform one or more of the embodiments of the present disclosure.

[0188] Working Example The following examples are presented for the purpose of illustrating various embodiments of the present disclosure, and are not intended to limit the present disclosure in any manner. Those skilled in the art will easily understand that the present disclosure is fully adapted to carry out the objects and achieve the objects and advantages mentioned, as well as those objects, objects and advantages inherent herein. Modifications thereof and other uses encompassed within the spirit of the present disclosure, as defined by the scope of the claims, will occur to those skilled in the art.

[0189] General Procedure All reactions were carried out under an atmosphere of argon. Reagents and solvents were used from commercial sources without additional purification. Hydrogenation reactions were carried out under a balloon. Microwave reactions were carried out using a CEM Discover SP microwave synthesizer. Sample purification was carried out on a Buchi Pureflash with ELSD purification system using pre-packed commercial silica gel columns. Thin-layer chromatography (TLC) was carried out on aluminum plates using Merck Kiesegel 60 F254 (230-400 mesh) fluorescent treated silica visualized under UV light (254 nm) or by staining with potassium permanganate or ninhydrin solutions as appropriate. All nuclear magnetic resonance (NMR) spectra were acquired on a Bruker Avance III HD 400 MHz NMR spectrometer and chemical shifts are reported in ppm (δ). HPLC / MS was performed on a Sciex 5500 Qtrap mass spectrometry coupled to a Shidmazu Nexera X2 UHPLC using a Phenomenex Luna C18 column (50 × 2.0 mm, 3 μm particle size) with the following method: gradient mobile phase A contained 0.1% formic acid in water, mobile phase B contained 0.1% formic acid in acetonitrile, 0–0.9 min A / B (95:5); 0.9–2.2 min A / B (5:95); 2.2–4.14 min A / B (5:95); 4.14–4.20 min A / B (95:5); 4.2–6 min 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. The ion spray voltage, drying gas temperature, ion source gas 1, and ion source gas 2 settings were 4500 V, 500 °C, 35 V, and 45 V, and the ESI was set in positive mode using full scan. The purity of all compounds was analyzed on an Agilent 1260 Infinity II Lab LC Series HPLC (1260 Quat pump, 1260 vial autosampler, ICC column oven, 1260 DAD WR detector). Samples were injected onto a Phenomenex Synergi Polar RP column (150 × 4.6 mm, 4 μm, 80 Å).The gradient mobile phase (A: water with 0.1% trifluoroacetic acid, B: acetonitrile with 0.1% trifluoroacetic acid; A / B (99:1) from 0 min; A / B (1:99) from 0–15 min; A / B (1:99) from 15–18 min; A / B (99:1) from 18–18.1 min; A / B (99:1) from 18.1–20 min) was pumped at a flow rate of 1 mL / min. The UV detector was set at 254 nm and the column oven was set at 35 °C. The injection volume was 10 µL unless otherwise specified. All compounds evaluated in biological assays had ≥90% purity and in animal studies had ≥95% purity. EXAMPLES

[0190] Synthesis of 6-methoxy-N-(5-methyl-1H-pyrazol-3-yl)-2-(pyrrolidin-1-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine (Compound 1) [ka] Preparation: To a solution of 2-chloro-6-methoxy-N-(5-methyl-1H-pyrazol-3-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine (0.09 g, 0.21 mmol), DIPEA (0.11 mL, 0.62 mmol), and pyrrolidone (0.07 g, 1.03 mmol) in anhydrous THF (3 mL) / 2-butanol (1 mL) mixture under argon. The tube was then sealed and heated to 90° C. for 3 days. The cooled reaction was quenched with saturated NaHCO3 (2 mL) and then extracted with 8:2 dichloromethane / isopropanol mixture (3×50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by Buchi Pureflash chromatography on a silica gel cartridge (24 g) using 95:5 CH2Cl2:MeOH w / 2% 7N ammonia to give 6-methoxy-N-(5-methyl-1H-pyrazol-3-yl)-2-(pyrrolidin-1-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine (0.04 g, 47%) as a light brown solid. 1H NMR (400 MHz, DMSO-d6): δ 12.01 (bs, 1H), 9.83 (s, 1H), 7.78 (s, 1H), 6.75 (s, 1H), 6.70 (bs, 1H), 4.11 (t, 2H, J = 8.0 Hz), 3.84 (s, 3H), 3.54 (m, 4H), 3.31 (m, 2H, partially masked under water), 2.55 (t, 2H, J = 8.0 Hz), 2.46 (m, 4H), 2.25 (s, 3H), 1.93 (m, 7H), 1.70 (m, 4H).MS(ESI): C 24 H 33 Calculated for F2N7O2: 451, Found: 452 (M+H) + . EXAMPLES

[0191] Synthesis of 2-chloro-6-methoxy-N-(5-methyl-1H-pyrazol-3-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine (Compound 2) [ka] To a solution of commercially available 2,4-dichloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (1.00 g, 2.81 mmol), K2CO3 (0.30, 3.09 mmol), and 3-amino-5-methyl-1H-pyrazole (0.76 g, 5.61 mmol) in anhydrous DMF (3 mL) under argon. The tube was then sealed and heated to 90 °C. Upon completion after 2 days, the cooled reaction was quenched with saturated NaHCO3 (2 mL) and then extracted with an 8:2 dichloromethane / isopropanol mixture (3 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by Buchi Pureflash chromatography on a silica gel cartridge (80 g) using 95:5 CH2Cl2:MeOH w / 2% 7N ammonia to give 2-chloro-6-methoxy-N-(5-methyl-1H-pyrazol-3-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine (0.19 g, 23%) as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ 12.24 (bs, 1H), 10.55 (s, 1H), 8.02 (s, 1H), 7.12 (s, 1H), 6.57 (bs, 1H), 4.17 (t, 2H, J = 8.0 Hz), 3.92 (s, 3H), 2.57 (m, 2H), 2.49 (m, 4H, masked under DMSO-d), 2.27 (s, 3H), 1.96 (p, 2H, J = 8.0 Hz), 1.70 (m, 4H). MS (ESI): C 20 H 25 Calculated for ClN6O2: 416, Found: 417 (M+H) + . EXAMPLES

[0192] Synthesis of 2-(4,4-difluoropiperidin-1-yl)-6-methoxy-N-(5-methyl-1H-pyrazol-3-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine (compound 3) [ka] To a solution of commercially available 2,4-dichloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (0.20 g, 0.56 mmol), DIPEA (0.98 mL, 5.61 mmol), sodium iodide (0.09 g, 0.59 mmol), and 3-amino-5-methyl-1H-pyrazole (0.06 g, 0.59 mmol) in anhydrous DMF (3 mL) under argon. The tube was then sealed and heated to 50° C. The reaction was monitored by TLC and HPLC / MS of 417. Upon completion after 2 days, the cooled reaction was quenched with saturated NaHCO3 (2 mL) and then extracted with an 8:2 dichloromethane / isopropanol mixture (3×50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude was dissolved in 2-butanol (3 ml) followed by the addition of DIPEA (0.44 mL, 2.53 mmol) and 4,4-difluoropiperidine hydrochloride (0.33 g, 2.11 mmol). The sealed tube was then heated to 90° C. for 4 days. The cooled mixture was quenched with saturated NaHCO3 and extracted with an 8:2 dichloromethane / isopropanol mixture (3×50 mL) and then washed once with brine. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by Buchi Pureflash chromatography on a silica gel cartridge (24 g) using 95:5 CH2Cl2:MeOH w / 2% 7N ammonia to give 2-(4,4-difluoropiperidin-1-yl)-6-methoxy-N-(5-methyl-1H-pyrazol-3-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine (0.06 g, 23%) as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 7.86 (s, 1H), 6.93 (s, 1H), 6.92 (s, 1H), 6.51 (bs, 1H), 4.18 (t, 2H, J = 8.0 Hz), 4.01 (m, 4H), 3.86 (s, 3H), 2.34 (s, 3H), 2.15-1.95 (m, 7H), 1.77 (m, 4H). MS (ESI): C 25 H 33 Calculated value for F2N7O2: 501, Found value: 502 (M+H) + . 1 H NMR (400 MHz, DMSO-d6): δ 12.08 (bs, 1H), 9.89 (s, 1H), 7.81 (s, 1H), 6.80 (s, 1H), 6.43 (s, 1H), 4.10 (t, 2H, J = 8.0 Hz), 3.90 (m, 4H), 3.84 (s, 3H), 2.53 (t, 2H, J = 8.0 Hz, partially masked under DMSO-d6), 2.44 (m, 4H), 2.26 (s, 3H), 2.02-1.91 (m, 6H), 1.69 (m, 4H). MS (ESI): 25 H 33 Calculated value for F2N7O2: 501, Found value: 502 (M+H) + . EXAMPLES

[0193] Synthesis of 2-(azetidin-1-yl)-6-methoxy-N-(5-methyl-1H-pyrazol-3-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine (compound 4) [ka] Preparation: To a solution of 2-chloro-6-methoxy-N-(5-methyl-1H-pyrazol-3-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine (0.11 g, 0.26 mmol), DIPEA (0.13 mL, 0.77 mmol), and azetidine (0.07 g, 1.29 mmol) in anhydrous THF (3 mL) / 2-butanol (1 mL) mixture under argon. The tube was then sealed and heated to 90° C. for 3 days. The cooled reaction was quenched with saturated NaHCO3 (2 mL) and then extracted with an 8:2 dichloromethane / isopropanol mixture (3×50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by Buchi Pureflash chromatography on a silica gel cartridge (24 g) using 95:5 CH2Cl2:MeOH w / 2% 7N ammonia to give 2-(azetidin-1-yl)-6-methoxy-N-(5-methyl-1H-pyrazol-3-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine (0.04 g, 47%) as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ 12.01 (bs, 1H), 9.93 (s, 1H), 7.81 (s, 1H), 6.79 (s, 1H), 6.69 (bs, 1H), 4.08 (t, 2H, J = 8.0 Hz), 4.02 (t, 4H, J = 8.0 Hz), 3.84 (s, 3H), 3.31 (m, 2H, partially masked under water), 2.54 (t, 2H, J = 8.0 Hz), 2.45 (m, 4H), 2.24 (s, 3H), 1.92 (p, 2H, J = 4.0 Hz), 1.69 (m, 4H). MS (ESI): C 23 H 31 Calculated for F2N7O2: 437, Found: 438 (M+H) + . EXAMPLES

[0194] Synthesis of N-(2-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-yl)-5-methylthiazol-2-amine (compound 5) [ka] Preparation: A solution of commercially available 2,4-dichloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (0.20 g, 0.56 mmol), K2CO3 (0.23 g, 1.68 mmol), 2-amino-5-methylthiazole (0.67 g, 0.59 mmol), and Xantphos (0.03 g, 0.11 mmol) in anhydrous 1:1 DMF / THF (4 mL) was bubbled with argon for 40 min. Palladium(II) acetate (0.01 g, 0.08 mmol) was then added and bubbling with argon continued for an additional 15 min. The tube was then sealed and heated to 70° C. After completion overnight (20 h), the cooled reaction was filtered through a pad of Celite and concentrated in vacuo. The residue was purified by Buchi Pureflash chromatography on a pre-neutralized silica gel cartridge (40 g) using 9:1 CH2Cl2:MeOH w / 2% 7N ammonia to give N-(2-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-yl)-5-methylthiazol-2-amine (0.10 g, 42%) as an orange solid. 1 H NMR (400 MHz, DMSO-d6): δ 12.05 (bs, 1H), 7.98 (s, 1H), 7.22 (d, 1H, J = 0.5 Hz), 7.18 (s, 1H), 4.18 (t, 2H, J = 8.0 Hz), 3.92 (s, 3H), 2.59 (t, 2H, J = 8.0 Hz), 2.53 (m, 4H, partially masked under DMSO-d), 2.38 (s, 3H), 1.96 (p, 2H, J = 8.0 Hz), 1.70 (m, 4H). MS (ESI): C 20 H 24 Calculated for ClN5O2S: 433, Found: 434 (M+H) + . EXAMPLES

[0195] Synthesis of N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(4,4-difluoropiperidin-1-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine (Compound 6) [ka] Preparation: To a solution of commercially available 2,4-dichloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (0.30 g, 0.84 mmol), DIPEA (0.44 mL, 2.53 mmol), sodium iodide (0.14 g, 0.93 mmol), and 3-cyclopropyl-1H-pyrazol-5-amine (0.15 g, 0.93 mmol) in anhydrous DMF (6 mL) under argon. The tube was then sealed and heated to 70° C. The reaction was monitored by TLC and HPLC / MS on 443. Upon completion after 2 days, DIPEA (1.00 mL, 5.89 mmol) and 4,4-difluoropiperidine hydrochloride (0.66 g, 4.21 mmol) were then added. The sealed tube was heated to 90° C. for 4 days. The cooled mixture was quenched with saturated NaHCO3 and extracted with an 8:2 dichloromethane / isopropanol mixture (3 x 50 mL), then washed once with brine. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by Buchi Pureflash chromatography on a pre-neutralized silica gel cartridge (40 g) with 8:2 CHCl2:MeOH w / 2% 7N ammonia to give N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(4,4-difluoropiperidin-1-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine (0.14 g, 31%) as a beige solid. 1H NMR (400 MHz, DMSO-d6): δ 12.13 (s, 1H), 9.89 (s, 1H), 7.80 (s, 1H), 6.80 (s, 1H), 6.32 (s, 1H), 4.10 (t, 2H, J = 8.0 Hz), 3.89 (m, MS (ESI): C 27 H 35 Calculated for F2N7O2: 527, Found: 528 (M+H) + . EXAMPLES

[0196] Synthesis of N-(5-(tert-butyl)-1H-pyrazol-3-yl)-2-(4,4-difluoropiperidin-1-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine (Compound 7) [ka] Preparation: To a solution of commercially available 2,4-dichloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (0.30 g, 0.84 mmol), DIPEA (0.44 mL, 2.53 mmol), sodium iodide (0.14 g, 0.93 mmol), and 3-(tert-butyl)-1H-pyrazol-5-amine (0.13 g, 0.93 mmol) in anhydrous DMF (6 mL) under argon. The tube was then sealed and heated to 70° C. The reaction was monitored by TLC and HPLC / MS at 459. Upon completion after 2 days, DIPEA (1.00 mL, 5.89 mmol) and 4,4-difluoropiperidine hydrochloride (0.66 g, 4.21 mmol) were then added. The sealed tube was heated to 90° C. for 4 days. The cooled mixture was quenched with saturated NaHCO3 and extracted with an 8:2 dichloromethane / isopropanol mixture (3 x 50 mL), then washed once with brine. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by Buchi Pureflash chromatography on a pre-neutralized silica gel cartridge (40 g) with 8:2 CHCl2:MeOH w / 2% 7N ammonia to give N-(5-(tert-butyl)-1H-pyrazol-3-yl)-2-(4,4-difluoropiperidin-1-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine (0.15 g, 32%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 12.10 (s, 1H), 9.93 (s, 1H), 7.81 (s, 1H), 6.81 (s, 1H), 6.50 (s, 1H), 4.10 (t, 2H, J = 8.0 Hz), 3.92 (m, MS (ESI): C 28 H 39 Calculated for F2N7O2: 543, Found: 544 (M+H)+ . EXAMPLES

[0197] Synthesis of 2-(4,4-difluoropiperidin-1-yl)-N-(5-ethyl-1H-pyrazol-3-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine (compound 8) [ka] Preparation: To a solution of commercially available 2,4-dichloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (0.30 g, 0.84 mmol), DIPEA (0.44 mL, 2.53 mmol), sodium iodide (0.14 g, 0.93 mmol), and 3-amino-5-ethyl-1H-pyrazole (0.1 g, 0.93 mmol) in anhydrous DMF (6 mL) under argon. The tube was then sealed and heated to 70° C. The reaction was monitored by TLC and HPLC / MS at 459. Upon completion after 2 days, DIPEA (1.00 mL, 5.89 mmol) and 4,4-difluoropiperidine hydrochloride (0.66 g, 4.21 mmol) were then added. The sealed tube was heated to 90° C. for 4 days. The cooled mixture was quenched with saturated NaHCO3 and extracted with an 8:2 dichloromethane / isopropanol mixture (3 x 50 mL), then washed once with brine. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by Buchi Pureflash chromatography on a pre-neutralized silica gel cartridge (40 g) with 8:2 CHCl2:MeOH w / 2% 7N ammonia to give 2-(4,4-difluoropiperidin-1-yl)-N-(5-ethyl-1H-pyrazol-3-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine (0.13 g, 31%) as a beige solid. 1H NMR (400 MHz, DMSO-d6): δ 12.09 (s, 1H), 9.90 (s, 1H), 7.81 (s, 1H), 6.81 (s, 1H), 6.47 (s, 1H), 4.10 (t, 2H, J = 8.0 Hz), 3.91 (m, 4H), 3.84 (s, 3H), 2.63 (q, 2H, J = 8.0 Hz), 2.53 (t, 2H, J = 8.0 Hz), 2.44 (m, 4H), 1.98 (m, 4H), 1.93 (p, 2H, J = 8.0 Hz), 1.68 (m, 4H), 1.22 (t, 3H, J = 8.0 Hz).MS (ESI): C 26 H 35 Calculated for F2N7O2: 515, Found: 516 (M+H) + . EXAMPLES

[0198] Synthesis of N-(2-(4,4-difluoropiperidin-1-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-yl)-5-methylthiazol-2-amine (Compound 9) [ka] Preparation: To a solution of N-(2-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-yl)-5-methylthiazol-2-amine (0.09 g, 0.21 mmol), DIPEA (0.36 mL, 2.07 mmol), and 4,4-difluoropiperidine hydrochloride (0.13 g, 0.83 mmol) in anhydrous DMF (3 mL) mixture under argon. The tube was then sealed and heated to 90° C. for 4 days. The cooled reaction was quenched with saturated NaHCO3 (2 mL) and then extracted with 8:2 dichloromethane / isopropanol mixture (3×50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by Buchi Pureflash chromatography on a pre-neutralized silica gel cartridge (24 g) using 8:2 CH2Cl2:MeOH w / 2% 7N ammonia to give N-(2-(4,4-difluoropiperidin-1-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-yl)-5-methylthiazol-2-amine (0.07 g, 62%) as a golden light brown solid. 1 H NMR (400 MHz, DMSO-d6): δ 11.62 (bs, 1H), 7.92 (s, 1H), 7.20 (d, 1H, J = 0.5 Hz), 6.87 (s, 1H), 4.12 (t, 2H, J = 8.0 Hz), 4.03 (m, 4H), 3.86 (s, 3H), 2.53 (t, 2H, J = 8.0 Hz), 2.44 (m, 4H), 2.39 (d, 3H, J = 4.0 Hz), 2.03 (m, 4H), 1.93 (p, 2H, J = 8.0 Hz), 1.68 (m, 4H). MS (ESI): C 25 H 32 Calculated value for F2N6O2S: 518, Found value: 519 (M+H) + . EXAMPLES

[0199] Synthesis of N-(5-cyclobutyl-1H-pyrazol-3-yl)-2-(4,4-difluoropiperidin-1-yl)-6-methoxy-7-(3-(pyrrolidine-1-)propoxy)quinazolin-4-amine (Compound 10) [ka] Preparation: To a solution of commercially available 2,4-dichloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (0.30 g, 0.84 mmol), DIPEA (0.44 mL, 2.53 mmol), sodium iodide (0.14 g, 0.93 mmol), and 3-amino-5-cyclobutyl-1H-pyrazole (0.13 g, 0.93 mmol) in anhydrous DMF (6 mL) under argon. The tube was then sealed and heated to 70° C. The reaction was monitored by TLC and HPLC / MS at 457. Upon completion after 3 days, DIPEA (1.00 mL, 5.89 mmol) and 4,4-difluoropiperidine hydrochloride (0.66 g, 4.21 mmol) were then added. The sealed tube was heated to 90° C. for 4 days. The cooled mixture was quenched with saturated NaHCO3 and extracted with an 8:2 dichloromethane / isopropanol mixture (3 x 50 mL), then washed once with brine. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by Buchi Pureflash chromatography on a pre-neutralized silica gel cartridge (40 g) with 9:1 CHCl2:MeOH w / 2% 7N ammonia to give N-(5-cyclobutyl-1H-pyrazol-3-yl)-2-(4,4-difluoropiperidin-1-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine (0.13 g, 29%) as a beige solid. 1H NMR (400 MHz, DMSO-d6): δ 12.13 (s, 1H), 9.92 (s, 1H), 7.81 (s, 1H), 6.81 (s, 1H), 6.54 (s, 1H), 4.10 (t, 2H, J = 8.0 Hz), 3.92 (m, 4H), 3.84 (s. 3H), 3.51 (p, 1H, J = 8.0 Hz), 2.53 (t, 2H, J = 8.0 Hz), 2.44 (m, 4H), 2.32 (m, 2H), 2.11 (m, 2H), 2.03-1.86 (m, 8H), 1.68 (m, 4H). MS (ESI): C 28 H 37 Calculated for F2N7O2: 541, Found: 542 (M+H) + . EXAMPLES

[0200] Synthesis of N-(2-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-yl)-5-methyl-1,3,4-thiadiazol-2-amine (Compound 11) [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), K2CO3 (0.29 g, 2.11 mmol), 2-amino-5-1,3,4-thiadiazole (0.08 g, 0.74 mmol), and Xantphos (0.08 g, 0.14 mmol) in anhydrous 1:1 DMF / THF (4 mL) was bubbled with argon for 40 min. Palladium(II) acetate (0.02 g, 0.11 mmol) was then added and bubbling with argon continued for an additional 15 min. The tube was then sealed and heated to 70° C. After completion overnight (20 h), the cooled reaction was filtered through a pad of Celite and concentrated in vacuo. The residue was purified by Buchi Pureflash chromatography on a pre-neutralized silica gel cartridge (40 g) using 9:1 CH2Cl2:MeOH w / 2% 7N ammonia to give N-(2-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-yl)-5-methyl-1,3,4-thiadiazol-2-amine (0.16 g, 52%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6): δ NH (not observed), 7.86 (s, 1H), 7.10 (s, 1H), 4.18 (t, 2H, J = 6.2 Hz), 3.91 (s, 3H), 2.87 (t, 2H, J = 7.6 Hz), 2.82 (m, 4H), 2.59 (s, 3H), 2.05 (p, 2H, J = 4.0 Hz), 1.80 (m, 4H). MS (ESI): C 19 H 23 Calculated for ClN6O2S: 434, Found: 435 (M+H) + . EXAMPLES

[0201] Synthesis of N-(2-(4,4-difluoropiperidin-1-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-yl)-5-methyl-1,3,4-thiadiazol-2-amine (Compound 12) [ka] Preparation: To a solution of N-(2-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-yl)-5-methyl-1,3,4-thiadiazol-2-amine (0.15 g, 0.34 mmol), DIPEA (0.60 mL, 3.45 mmol), and 4,4-difluoropiperidine hydrochloride (0.22 g, 1.38 mmol) in anhydrous DMF (6 mL) mixture under argon. The tube was then sealed and heated to 90° C. for 4 days. The cooled reaction was quenched with saturated NaHCO3 (2 mL) and then extracted with 8:2 dichloromethane / isopropanol mixture (3×50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by Buchi Pureflash chromatography on a pre-neutralized silica gel cartridge (24 g) using 8:2 CH2Cl2:MeOH w / 2% 7N ammonia to give N-(2-(4,4-difluoropiperidin-1-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-yl)-5-methyl-1,3,4-thiadiazol-2-amine (0.14 g, 80%) as a light yellow solid. 1 H NMR (400 MHz, DMSO-d6): δ NH (not observed), 7.91 (s, 1H), 6.88 (s, 1H), 4.13 (t, 2H, J = 6.4 Hz), 4.00 (m, 4H), 3.87 (s, 3H), 2.55 (t, 2H, J = MS (ESI): C 24 H 31 Calculated value for F2N7O2S: 519, Found value: 520 (M+H) + . EXAMPLES

[0202] Synthesis of 2-(4,4-difluoropiperidin-1-yl)-N-(5-isopropyl-1H-pyrazol-3-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine (Compound 13) [ka] Preparation: To a solution of commercially available 2,4-dichloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (0.30 g, 0.84 mmol), DIPEA (0.44 mL, 2.53 mmol), sodium iodide (0.14 g, 0.93 mmol), and 5-isopropyl-1H-pyrazol-3-amine (0.12 g, 0.93 mmol) in anhydrous DMF (6 mL) under argon. The tube was then sealed and heated to 70° C. The reaction was monitored by TLC and HPLC / MS at 445. Upon completion after 3 days, DIPEA (1.00 mL, 5.89 mmol) and 4,4-difluoropiperidine hydrochloride (0.66 g, 4.21 mmol) were then added. The sealed tube was heated to 90° C. for 4 days. The cooled mixture was quenched with saturated NaHCO3 and extracted with an 8:2 dichloromethane / isopropanol mixture (3 x 50 mL), then washed once with brine. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by Buchi Pureflash chromatography on a pre-neutralized silica gel cartridge (40 g) with 9:1 CHCl2:MeOH w / 2% 7N ammonia to give 2-(4,4-difluoropiperidin-1-yl)-N-(5-isopropyl-1H-pyrazol-3-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine (0.12 g, 28%) as a beige solid. 1H NMR (400 MHz, DMSO-d6): δ 12.09 (s, 1H), 9.92 (s, 1H), 7.81 (s, 1H), 6.81 (s, 1H), 6.48 (s, 1H), 4.10 (t, 2H, J = 6.4 Hz), 3.91 (m, 4H), 3.84 (s, 3H), 2.95 (septet, 2H, J = 6.8 Hz), 2.53 (t, 2H, J = 7.2 Hz), 2.44 (m, 4H), 1.98 (m, 4H), 1.92 (m, 2H), 1.67 (m, 4H), 1.25 (d, 6H, J = 6.8 Hz). MS (ESI): C 27 H 37 Calculated for F2N7O2: 529, Found: 530 (M+H) + . EXAMPLES

[0203] Synthesis of 2-(4,4-difluoropiperidin-1-yl)-6-methoxy-N-methyl-N-(5-methyl-1H-pyrazol-3-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine (Compound 14) [ka] Preparation: To a solution of commercially available 2,4-dichloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (0.30 g, 0.84 mmol), DIPEA (0.44 mL, 2.53 mmol), sodium iodide (0.14 g, 0.93 mmol), and N,5-dimethyl-1H-pyrazol-3-amine (0.10 g, 0.93 mmol) in anhydrous DMF (6 mL) under argon. The tube was then sealed and heated to 70° C. The reaction was monitored by TLC and HPLC / MS of 431. Upon completion after 3 days, DIPEA (1.00 mL, 5.89 mmol) and 4,4-difluoropiperidine hydrochloride (0.66 g, 4.21 mmol) were then added. The sealed tube was then heated to 90° C. for 4 days. The cooled mixture was quenched with saturated NaHCO3 and extracted with an 8:2 dichloromethane / isopropanol mixture (3 x 50 mL), then washed once with brine. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by Buchi Pureflash chromatography on a pre-neutralized silica gel cartridge (80 g) with 9:1 CHCl2:MeOH w / 2% 7N ammonia to give 2-(4,4-difluoropiperidin-1-yl)-6-methoxy-N-methyl-N-(5-methyl-1H-pyrazol-3-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine (0.15 g, 35%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 12.39 (s, 1H), 6.78 (s, 1H), 6.28 (s, 1H), 5.90 (s, 1H), 4.06 (t, 2H, J = 6.4 Hz), 3.38 (s, 3H), 3.35 (s, MS (ESI): C 26 H 35 Calculated value for F2N7O2: 515, Measured value: 516 (M) + . EXAMPLES

[0204] Synthesis of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine (Compound 15) [ka] Preparation: To a solution of commercially available 2,4-dichloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (4.00 g, 11.23 mmol), DIPEA (4.89 mL, 18.07 mmol), sodium iodide (3.63 g, 13.47 mmol), and 3-cyclopropyl-1H-pyrazol-5-amine (1.66 g, 13.47 mmol) in anhydrous DMF (40 mL) under argon. The tube was then sealed and heated to 70° C. Upon completion after 24 h, the cooled reaction was slowly poured into cold water (400 mL) and the crude precipitate was collected by filtration. The crude residue was purified by Buchi Pureflash chromatography on a silica gel cartridge (330 g) using 95:5 CH2Cl2:MeOH w / 2% 7N ammonia to give 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine (2.13 g, 43%) as a light brown solid. 1 H NMR (400 MHz, DMSO-d6): δ 12.26 (s, 1H), 10.53 (s, 1H), 8.00 (s, 1H), 7.11 (s, 1H), 6.50 (s, 1H), 4.16 (t, 2H, J = 6.4 Hz), 3.92 (s, MS (ESI): C 22 H 27 Calculated for ClN6O2: 442, Found: 443 (M+H) + . EXAMPLES

[0205] Synthesis of 2-chloro-N-(5-ethyl-1H-pyrazol-3-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine (compound 16) [ka] Preparation: To a solution of commercially available 2,4-dichloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (4.00 g, 11.23 mmol), DIPEA (4.89 mL, 18.07 mmol), sodium iodide (3.63 g, 13.47 mmol), and 3-amino-5-ethyl-1H-pyrazole (1.50 g, 13.47 mmol) in anhydrous DMF (40 mL) under argon. The tube was then sealed and heated to 70° C. Upon completion after 24 h, the cooled reaction was slowly poured into cold water (400 mL) and the crude precipitate was collected by filtration. The crude residue was purified by Buchi Pureflash chromatography on a silica gel cartridge (330 g) using 95:5 CH2Cl2:MeOH w / 2% 7N ammonia to give 2-chloro-N-(5-ethyl-1H-pyrazol-3-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine (1.91 g, 40%) as a light brown solid. 1 H NMR (400 MHz, DMSO-d6): δ 12.27 (s, 1H), 10.55 (s, 1H), 8.02 (s, 1H), 7.11 (s, 1H), 6.60 (s, 1H), 4.158 (t, 2H, J = 6.4 Hz), 3.92 (s, 3H), 2.64 (quartet, 2H, J = 7.6 Hz), 2.54 (t, 2H, J = 7.2 Hz), 2.44 (m, 4H), 1.94 (quintet, 2H, J = 6.8 Hz), 1.68 (m, 4H), 1.23 (t, 3H, J = 7.6 Hz). MS (ESI): C 21 H 27Calculated for ClN6O2: 430, Found: 431 (M+H) + . EXAMPLES

[0206] Synthesis of 2-chloro-6-methoxy-N-(5-(methoxymethyl)-1H-pyrazol-3-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine (Compound 17) [ka] Preparation: To a solution of commercially available 2,4-dichloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (3.00 g, 8.42 mmol), DIPEA (3.67 mL, 21.05 mmol), sodium iodide (1.51 g, 10.11 mmol), and 5-(methoxymethyl)-1H-pyrazol-3-amine (1.28 g, 10.11 mmol) in anhydrous DMF (30 mL) under argon. The tube was then sealed and heated to 70° C. Upon completion after 24 h, the cooled reaction was slowly poured poor into cold water (350 mL) and the crude precipitate was collected by filtration. The crude residue was purified by Buchi Pureflash chromatography on a silica gel cartridge (330 g) using 95:5 CH2Cl2:MeOH w / 2% 7N ammonia to give 2-chloro-6-methoxy-N-(5-(methoxymethyl)-1H-pyrazol-3-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine (1.29 g, 34%) as a beige solid. 1 H NMR (400 MHz, DMSO-d6): δ 12.63 (bs, 1H), 10.63 (bs, 1H), 7.98 (s, 1H), 7.09 (s, 1H), 6.77 (s, 1H), 4.45 (s, 2H), 4.13 (t, 2H, J = MS (ESI): C 21 H27 Calculated value for ClN6O3: 446, Found value: 446 (M) + . EXAMPLES

[0207] N 4 -(5-ethyl-1H-pyrazol-3-yl)-6-methoxy-N 2 ,N 2 Synthesis of -dimethyl-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline-2,4-diamine (Compound 18) [ka] Preparation: To a solution of 2-chloro-N-(5-ethyl-1H-pyrazol-3-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine (0.20 g, 0.46 mmol), DIPEA (0.81 mL, 4.64 mmol), and dimethylamine hydrochloride (0.15 g, 1.86 mmol) in anhydrous DMF (5 mL) under argon. The tube was then sealed and heated to 90° C. for 4 days. The cooled reaction was quenched with saturated NaHCO3 (2 mL) and then extracted with an 8:2 dichloromethane / isopropanol mixture (3×50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by Buchi Pureflash chromatography on a silica gel cartridge (40 g) using 95:5 CH2Cl2:MeOH w / 2% 7N ammonia to give N 4 -(5-ethyl-1H-pyrazol-3-yl)-6-methoxy-N 2 ,N 2 To this was obtained -dimethyl-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline-2.4-diamine (0.12 g, 58%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 12.05 (bs, 1H), 9.83 (s, 1H), 7.78 (s, 1H), 6.76 (s, 1H), 6.62 (bs, 1H), 4.09 (t, 2H, J = 6.8 Hz), 3.84 (s, 3H), 3.14 (s, 6H), 2.61 (q, 2H, J = 7.2 Hz), 2.54 (t, 2H, J = 6.8 Hz), 2.47 (m, 4H), 1.93 (p, 1H, J = 6.8 Hz), 1.69 (m, 4H), 1.22 (t, 3H, J = 7.6 Hz). MS (ESI): C 23 H 33 Calculated N7O2: 439.6, Measured 439.6 (M) + . EXAMPLES

[0208] Synthesis of N-(5-ethyl-1H-pyrazol-3-yl)-6-methoxy-2-(pyrrolidin-1-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine (Compound 19) [ka] Preparation: To a solution of 2-chloro-N-(5-ethyl-1H-pyrazol-3-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine (0.20 g, 0.46 mmol), DIPEA (0.81 mL, 4.64 mmol), and pyrrolidine (0.17 g, 1.91 mmol) in anhydrous THF (6 mL) / 2-butanol (2 mL) mixture under argon. The tube was then sealed and heated to 90° C. for 4 days. The cooled reaction was quenched with saturated NaHCO3 (2 mL) and then extracted with an 8:2 dichloromethane / isopropanol mixture (3×50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by Buchi Pureflash chromatography on a silica gel cartridge (40 g) using 95:5 CH2Cl2:MeOH w / 2% 7N ammonia to give N-(5-ethyl-1H-pyrazol-3-yl)-6-methoxy-2-(pyrrolidin-1-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine (0.12 g, 54%) as a beige solid. 1 H NMR (400 MHz, DMSO-d6): δ 12.02 (bs, 1H), 9.84 (s, 1H), 7.79 (s, 1H), 6.76 (bs, 1H), 6.75 (s, 1H), 4.09 (t, 2H, J = 6.8 Hz), 3.54 (m, MS (ESI): C 25 H 35 Calculated N7O2: 465.6, Measured 465.8 (M) + . EXAMPLES

[0209] Synthesis of N-(5-ethyl-1H-pyrazol-3-yl)-6-methoxy-2-morpholino-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine (Compound 20) [ka] Preparation: To a solution of 2-chloro-N-(5-ethyl-1H-pyrazol-3-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine (0.20 g, 0.46 mmol), DIPEA (0.81 mL, 4.64 mmol), and morpholine (0.20 g, 2.32 mmol) in anhydrous THF (6 mL) / 2-butanol (2 mL) mixture under argon. The tube was then sealed and heated to 90° C. for 4 days. The cooled reaction was quenched with saturated NaHCO3 (2 mL) and then extracted with an 8:2 dichloromethane / isopropanol mixture (3×50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by Buchi Pureflash chromatography on a silica gel cartridge (40 g) using 95:5 CH2Cl2:MeOH w / 2% 7N ammonia to give N-(5-ethyl-1H-pyrazol-3-yl)-6-methoxy-2-morpholino-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine (0.06 g, 25%) as a beige solid. 1 H NMR (400 MHz, DMSO-d6): δ 12.08 (bs, 1H), 9.88 (s, 1H), 7.80 (s, 1H), 6.49 (bs, 1H), 4.09 (t, 2H, J = 6.8 Hz), 3.84 (s, 3H), 3.68 (m, MS (ESI): C 25 H 35 Calculated N7O3: 481.6, Measured 481.6 (M) + . EXAMPLES

[0210] Synthesis of N-(5-ethyl-1H-pyrazol-3-yl)-6-methoxy-2-(4-methoxypiperidin-1-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine (Compound 21) [ka] Preparation: To a solution of 2-chloro-N-(5-ethyl-1H-pyrazol-3-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine (0.20 g, 0.46 mmol), DIPEA (0.81 mL, 4.64 mmol), and 4-methoxypiperidine (0.21 g, 1.86 mmol) in anhydrous THF (6 mL) / 2-butanol (2 mL) mixture under argon. The tube was then sealed and heated to 90° C. for 4 days. The cooled reaction was quenched with saturated NaHCO3 (2 mL) and then extracted with an 8:2 dichloromethane / isopropanol mixture (3×50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by Buchi Pureflash chromatography on a silica gel cartridge (40 g) using 95:5 CH2Cl2:MeOH w / 2% 7N ammonia to give N-(5-ethyl-1H-pyrazol-3-yl)-6-methoxy-2-(4-methoxypiperidin-1-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine (0.09 g, 39%) as a beige solid. 1H NMR (400 MHz, DMSO-d6): δ 12.06 (bs, 1H), 9.83 (s, 1H), 7.78 (s, 1H), 6.76 (s, 1H), 6.49 (bs, 1H), 4.28 (m, 2H), 4.09 (t, 2H, J = 6.8 Hz), 3.82 (s, 3H), 3.44-3.25 (m, 6H, partially masked under water), 3.24 (s, 3H), 2.62 (q, 2H, J = 7.6 Hz), 2.56 (t, 2H, J = 6.8 H), 2.48 (m, 4H), 1.93 (p, 2H, J = 6.8 Hz), 1.88 (m, 2H), 1.70 (m,4H), 1.38 (m, 2H), 1.22 (t, 3H, J = 7.6 Hz). MS (ESI): C 27 H 39 Calculated N7O3: 509.6, Measured 509.6 (M) + . EXAMPLES

[0211] N 4 -(5-Cyclopropyl-1H-pyrazol-3-yl)-6-methoxy-N 2 ,N 2 Synthesis of -dimethyl-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline-2,4-diamine (Compound 22) [ka] Preparation: To a solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine (0.20 g, 0.45 mmol), DIPEA (0.77 mL, 4.52 mmol), and dimethylamine hydrochloride (0.15 g, 1.81 mmol) in anhydrous DMF (5 mL) under argon. The tube was then sealed and heated to 90° C. for 4 days. The cooled reaction was quenched with saturated NaHCO3 (2 mL) and then extracted with an 8:2 dichloromethane / isopropanol mixture (3×50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by Buchi Pureflash chromatography on a silica gel cartridge (40 g) using 95:5 CH2Cl2:MeOH w / 2% 7N ammonia to give N 4 -(5-Cyclopropyl-1H-pyrazol-3-yl)-6-methoxy-N 2 ,N 2 To this was obtained -dimethyl-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-2.4-amine (0.12 g, 58%) as a light yellow solid. 1 H NMR (400 MHz, DMSO-d6): δ 12.09 (bs, 1H), 9.81 (s, 1H), 7.77 (s, 1H), 6.76 (s, 1H), 6.50 (bs, 1H), 4.09 (t, 2H, J = 6.8 Hz), 3.83 (s, MS (ESI): C 24 H 33 Calculated N7O2: 451.6, Measured 451.8 (M) + . EXAMPLES

[0212] Synthesis of N-(5-cyclopropyl-1H-pyrazol-3-yl)-6-methoxy-2-(pyrrolidin-1-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine (Compound 23) [ka] Preparation: To a solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine (0.20 g, 0.45 mmol), DIPEA (0.77 mL, 4.52 mmol), and pyrrolidine (0.16 g, 2.26 mmol) in a mixture of THF (6 mL) / 2-butanol (2 mL) under argon. The tube was then sealed and heated to 90° C. for 4 days. The cooled reaction was quenched with saturated NaHCO3 (2 mL) and then extracted with an 8:2 dichloromethane / isopropanol mixture (3×50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by Buchi Pureflash chromatography on a silica gel cartridge (40 g) using 95:5 CH2Cl2:MeOH w / 2% 7N ammonia to give N-(5-cyclopropyl-1H-pyrazol-3-yl)-6-methoxy-2-(pyrrolidin-1-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine (0.07 g, 34%) as a beige solid. 1 H NMR (400 MHz, DMSO-d6): δ 12.05 (bs, 1H), 9.84 (s, 1H), 7.77 (s, 1H), 6.75 (s, 1H), 6.63 (bs, 1H), 4.09 (t, 2H, J = 6.8 Hz), 3.83 (s, MS (ESI): C 26 H 35 Calculated N7O2: 477.6, Measured 477.8 (M)+ . EXAMPLES

[0213] Synthesis of N-(5-cyclopropyl-1H-pyrazol-3-yl)-6-methoxy-2-morpholino-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine (Compound 24) [ka] Preparation: To a solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine (0.20 g, 0.45 mmol), DIPEA (0.77 mL, 4.52 mmol), and morpholine (0.16 g, 2.26 mmol) in anhydrous THF (6 mL) / 2-butanol (2 mL) mixture under argon. The tube was then sealed and heated to 90° C. for 4 days. The cooled reaction was quenched with saturated NaHCO3 (2 mL) and then extracted with an 8:2 dichloromethane / isopropanol mixture (3×50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by Buchi Pureflash chromatography on a silica gel cartridge (40 g) using 95:5 CH2Cl2:MeOH w / 2% 7N ammonia to give N-(5-cyclopropyl-1H-pyrazol-3-yl)-6-methoxy-2-morpholino-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine (0.08 g, 37%) as a beige solid. 1H NMR (400 MHz, DMSO-d6): δ 12.11 (bs, 1H), 9.86 (s, 1H), 7.79 (s, 1H), 6.78 (s, 1H), 6.36 (bs, 1H), 4.09 (t, 2H, J = 6.8 Hz), 3.84 (s, MS (ESI): C 26 H 35 Calculated N7O2: 493.6 Measured 493.8 (M) + . EXAMPLES

[0214] Synthesis of N-(5-cyclopropyl-1H-pyrazol-3-yl)-6-methoxy-2-(4-methoxypiperidin-1-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine (Compound 25) [ka] Preparation: To a solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine (0.20 g, 0.45 mmol), DIPEA (0.77 mL, 4.52 mmol), and 4-methoxypiperidine (0.21 g, 1.81 mmol) in anhydrous THF (6 mL) / 2-butanol (2 mL) mixture under argon. The tube was then sealed and heated to 90° C. for 4 days. The cooled reaction was quenched with saturated NaHCO3 (2 mL) and then extracted with 8:2 dichloromethane / isopropanol mixture (3×50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by Buchi Pureflash chromatography on a silica gel cartridge (40 g) using 95:5 CH2Cl2:MeOH w / 2% 7N ammonia to give N-(5-cyclopropyl-1H-pyrazol-3-yl)-6-methoxy-2-(4-methoxypiperidin-1-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine (0.08 g, 34%) as a beige solid. 1 H NMR (400 MHz, DMSO-d6): δ 12.12 (bs, 1H), 9.81 (s, 1H), 7.77 (s, 1H), 6.76 (s, 1H), 6.35 (bs, 1H), 4.27 (m, 2H), 4.09 (t, 2H, J = 6.8 Hz), 3.83 (s, 3H), 3.41 (m, 1H), 3.31-3.22 (m, 4H), 3.28 (s, 3H), 2.53 (t, 2H, J = 6.8 Hz), 2.44 (m, 4H), 1.90 (m, 5H), 1.68 (m, 4H), 1.36 (m, 2H), 0.95 (m, 2H), 0.66 (m, 2H). MS (ESI): C 28 H 39 Calculated value of N7O3: 521.7 Found value: 521.8 (M) + . EXAMPLES

[0215] 6-Methoxy-N 4 -(5-(methoxymethyl)-1H-pyrazol-3-yl)-N 2 ,N 2 Synthesis of -dimethyl-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline-2,4-diamine (Compound 26) [ka] Preparation: To a solution of 2-chloro-6-methoxy-N-(5-(methoxymethyl)-1H-pyrazol-3-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine (0.20 g, 0.45 mmol), DIPEA (0.78 mL, 4.47 mmol), and dimethylamine hydrochloride (0.15 g, 1.79 mmol) in anhydrous DMF (5 mL) under argon. The tube was then sealed and heated to 90° C. for 4 days. The cooled reaction was quenched with saturated NaHCO3 (2 mL) and then extracted with an 8:2 dichloromethane / isopropanol mixture (3×50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by Buchi Pureflash chromatography on a silica gel cartridge (40 g) using 95:5 CH2Cl2:MeOH w / 2% 7N ammonia to give 6-methoxy-N 4 -(5-(methoxymethyl)-1H-pyrazol-3-yl)-N 2 ,N 2 To this was obtained -dimethyl-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline-2.4-diamine (0.01 g, 7%) as a light yellow solid. 1 H NMR (400 MHz, DMSO-d6): δ12.43 (bs, 1H), 9.90 (bs, 1H), 7.78 (s, 1H), 7.02 (s, 1H), 6.78 (s, 1H), 4.42 (s, 2H), 4.13 (t, 2H, J = 6.8 MS (ESI): C 23 H33 Calculated N7O3: 455.6, Measured 455.9 (M) + . EXAMPLES

[0216] Synthesis of 6-methoxy-N-(5-(methoxymethyl)-1H-pyrazol-3-yl)-2-(pyrrolidin-1-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine (Compound 27) [ka] Preparation: To a solution of 2-chloro-6-methoxy-N-(5-(methoxymethyl)-1H-pyrazol-3-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine (0.20 g, 0.45 mmol), DIPEA (0.78 mL, 4.47 mmol), and pyrrolidine (0.16 g, 2.24 mmol) in anhydrous THF (6 mL) / 2-butanol (2 mL) mixture under argon. The tube was then sealed and heated to 90° C. for 4 days. The cooled reaction was quenched with saturated NaHCO3 (2 mL) and then extracted with 8:2 dichloromethane / isopropanol mixture (3×50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by Buchi Pureflash chromatography on a silica gel cartridge (40 g) using 95:5 CH2Cl2:MeOH w / 2% 7N ammonia to give 6-methoxy-N-(5-(methoxymethyl)-1H-pyrazol-3-yl)-2-(pyrrolidin-1-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine (0.02 g, 10%) as a beige solid. 1H NMR (400 MHz, DMSO-d6): δ 12.40 (bs, 1H), 9.91 (bs, 1H), 7.78 (s, 1H), 7.01 (s, 1H), 6.77 (s, 1H), 4.41 (s, 2H), 4.09 (t, 2H, J = 6.8 MS (ESI): C 25 H 35 Calculated N7O3: 481.6, Measured 481.8 (M) + . EXAMPLES

[0217] Synthesis of 6-methoxy-N-(5-(methoxymethyl)-1H-pyrazol-3-yl)-2-morpholino-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine (Compound 28) [ka] Preparation: To a solution of 2-chloro-6-methoxy-N-(5-(methoxymethyl)-1H-pyrazol-3-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine (0.20 g, 0.45 mmol), DIPEA (0.78 mL, 4.47 mmol), and morpholine (0.19 g, 2.24 mmol) in anhydrous THF (6 mL) / 2-butanol (2 mL) mixture under argon. The tube was then sealed and heated to 90° C. for 4 days. The cooled reaction was quenched with saturated NaHCO3 (2 mL) and then extracted with 8:2 dichloromethane / isopropanol mixture (3×50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by Buchi Pureflash chromatography on a silica gel cartridge (40 g) using 95:5 CH2Cl2:MeOH w / 2% 7N ammonia to give 6-methoxy-N-(5-(methoxymethyl)-1H-pyrazol-3-yl)-2-morpholino-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine (0.03 g, 12%) as a light yellow solid. 1 H NMR (400 MHz, DMSO-d6): δ 12.45 (bs, 1H), 9.94 (bs, 1H), 7.79 (s, 1H), 7.04 (s, 1H), 6.78 (s, 1H), 4.42 (s, 2H), 4.09 (t, 2H, J = 6.8 MS (ESI): C 25 H 35 Calculated value for N7O4: 497.6, Found value: 497.9 (M) + . EXAMPLES

[0218] Synthesis of 6-methoxy-N-(5-(methoxymethyl)-1H-pyrazol-3-yl)-2-(4-methoxypiperidin-1-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine (Compound 29) [ka] Preparation: To a solution of 2-chloro-6-methoxy-N-(5-(methoxymethyl)-1H-pyrazol-3-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine (0.20 g, 0.45 mmol), DIPEA (0.78 mL, 4.47 mmol), and 4-methoxypiperidine (0.21 g, 1.79 mmol) in anhydrous THF (6 mL) / 2-butanol (2 mL) mixture under argon. The tube was then sealed and heated to 90° C. for 4 days. The cooled reaction was quenched with saturated NaHCO3 (2 mL) and then extracted with 8:2 dichloromethane / isopropanol mixture (3×50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by Buchi Pureflash chromatography on a silica gel cartridge (40 g) using 95:5 CH2Cl2:MeOH w / 2% 7N ammonia to give 6-methoxy-N-(5-(methoxymethyl)-1H-pyrazol-3-yl)-2-(4-methoxypiperidin-1-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine (0.05 g, 23%) as a beige solid. 1 H NMR (400 MHz, DMSO-d6): δ 12.44 (bs, 1H), 9.88 (bs, 1H), 7.78 (s, 1H), 6.79 (s, 1H), 6.66 (s, 1H), 4.42 (s, 2H), 4.10 (t, 2H, J = 6.8 Hz), 3.80 (s, 3H), 3.79 (s, 3H), 3.76 (m, 4H), 3.33-3.14 (m, 4H), 2.60 (m, 4H), 1.97 (p, 2H, J = 6.8 Hz), 1.82 (m, 4H), 1.74 (m, 4H). MS (ESI): C 27 H39 Calculated value for N7O4: 525.7, Measured value: 525.8 (M) + . EXAMPLES

[0219] Synthesis of 2-(4,4-difluoropiperidin-1-yl)-6-methoxy-N-(5-(methoxymethyl)-1H-pyrazol-3-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine (Compound 30) [ka] Preparation: To a solution of 2-chloro-6-methoxy-N-(5-(methoxymethyl)-1H-pyrazol-3-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine (0.20 g, 0.45 mmol), DIPEA (0.78 mL, 4.47 mmol), and 4-methoxypiperidine (0.21 g, 1.79 mmol) in anhydrous THF (6 mL) / 2-butanol (2 mL) mixture under argon. The tube was then sealed and heated to 90° C. for 4 days. The cooled reaction was quenched with saturated NaHCO3 (2 mL) and then extracted with 8:2 dichloromethane / isopropanol mixture (3×50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by Buchi Pureflash chromatography on a silica gel cartridge (40 g) using 95:5 CH2Cl2:MeOH w / 2% 7N ammonia to give 2-(4,4-difluoropiperidin-1-yl)-6-methoxy-N-(5-(methoxymethyl)-1H-pyrazol-3-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine (0.02 g, 7%) as a beige solid. 1H NMR (400 MHz, DMSO-d6): δ 12.49 (bs, 1H), 9.98 (bs, 1H), 7.84 (s, 1H), 7.06 (s, 1H), 6.63 (s, 1H), 4.44 (s, 2H), 4.15 (t, 2H, J = 6.8 MS (ESI): C 26 H 35 Calculated value for F2N7O3: 525.7, Measured value: 525.8 (M) + .

[0220] Other quinazolinyl compounds disclosed herein can be synthesized in a similar manner as for compounds 1-30. EXAMPLES

[0221] Kinase inhibition assay The activity of compounds 1, 3, 4, 6, 7, 8, 9, 10 and 13 in inhibiting CLK1, CLK4, PLK4 and FLT3 kinases was determined. Stock solutions of the compounds to be evaluated were prepared. IC 50 Values ​​were determined by Eurofins DiscoverX service using either KinaseProfiler or KdElect kinase activity detection assays. Results are shown in Table 1. Compound 1 is a selective CLK1 / 4 inhibitor. +++:IC 50 :<1uM ++ :IC 50 :1~5uM + :IC 50 :5~10uM - :I C 50 :>10uM TIFF2024511012000089.tif65164 EXAMPLES

[0222] Cancer Cytotoxicity Assay The cytotoxicity of compounds 1, 3, 4, 6, 7, 8, 9, 10, 12 and 13 against cancer cell lines was determined. For each cell line, cells were counted and diluted to a final density of 2.5, 5, 10 and 20 thousand per well in 96-well plates per 100 μL of their respective growth medium to determine the optimal plating density for the cell viability assay. The Promega Real-Time-Glo cell viability kit was used to determine the optimal concentration for cell plating such that each cell line was in the linear portion of its growth curve after 72 hours of culture. Test compound IC 50 For the determination of AAT Bioquest IC, different cancer cell lines were plated in 96-well plates at the pre-determined optimal density for each cell line. Test compounds were then added at different concentrations for the generation of 6-point curves, and cell density was determined using the Promega Real-Time-Glo Cell Viability Kit after 24, 48, and 72 hours of culture. 50 Use the calculator to calculate the IC at 72 hours for the test compound. 50 was calculated. +++: IC 50 : <1uM ++ : IC 50 : 1-5uM + : IC 50 : 5-10uM - : I C 50 : >10uM.

[0223] Colorectal Cancer Cytotoxicity The results of cell proliferation assay of compounds 1, 3, 4, 6, 7, 8, 9, 10, 12 and 13 against colorectal cancer cell lines HCT-116 and HT-29 demonstrate that the compounds show remarkable ability of inhibiting colorectal cancer cell growth after 72 hours of treatment.The results are shown in Table 2. TIFF2024511012000090.tif70164

[0224] Kidney Cancer Cytotoxicity The results of cell proliferation assay of compounds 1, 3, 4, 6, 7, 8, 9, 10, 12 and 13 against colorectal cancer cell lines A-498 and 786-O demonstrate that the compounds show remarkable ability of inhibiting renal cancer cell growth after 72 hours of treatment.The results are shown in Table 3. TIFF2024511012000091.tif70163

[0225] Ovarian cancer cytotoxicity The results of cell proliferation assay of compounds 1, 3, 4, 6, 7, 8, 9, 10, 12 and 13 against ovarian cancer cell lines SKOV-3 and OV-90 demonstrate that the compounds show remarkable ability of inhibiting colorectal cancer cell growth after 72 hours of treatment. The results are shown in Table 4. TIFF2024511012000092.tif71163

[0226] leukemia cell cytotoxicity The results of cell proliferation assay of compounds 1, 3, 4, 6, 7, 8, 9, 10, 12 and 13 against colorectal cancer cell lines HCT-116 and HT-29 demonstrate that the compounds show remarkable ability of inhibiting leukemia cell growth after 72 hours of treatment.The results are shown in Table 5. TIFF2024511012000093.tif70164 EXAMPLES

[0227] Reduction in colorectal tumor burden Male nude mice (NU / J, Jackson Laboratories) aged 6–8 weeks were administered a subcutaneous injection of 5 × 10 HT-29 cells diluted 1:1 in Matrigel cell culture medium into the rear hind flank. Tumor nodules were then grown to 100–200 mm 3 Mice were monitored daily until tumor size reached 100 μL, at which point they were randomized into treatment groups based on their body weight and tumor size and treatment. Mice (10 mice per group) were IP injected with 100 μL of either vehicle control or Compound 8 (5 mg / kg) every 48 hours. Tumor nodules were then determined using the formula V=(L *Tumor volumes were calculated using the formula: 1000 mm x 1000 mm (W x 2) / 2, where L is the length and W is the width of the tumor. Differences in xenograft volume between different groups were analyzed by single factor analysis of variance of the log-transformed tumor volume data. 3 Mice bearing tumors greater than 1 were euthanized to avoid excessive suffering.

[0228] Figure 3A shows that over the course of the 16-day study, test subjects treated with compound 8 experienced significantly slower tumor growth compared to test subjects treated with a vehicle control. Figure 3B shows that test subjects treated with vehicle and compound 8 experienced a 600% and 370% increase, respectively. At day 16, test subjects treated with compound 8 had significantly smaller tumors compared to test subjects treated with vehicle. EXAMPLES

[0229] Prophetic examples of compounds with anticancer activity The following compounds are evaluated for their ability to block cancer cell growth in colon (HT-29), liver (HepG2), pancreatic (MiaPaca-2) and bladder (5637) cancer cell lines. Specifically, the Promega Real-Time-Glo cell viability kit was used to determine optimal concentrations for cell plating such that each cell line was in the linear portion of its growth curve after 72 hours of culture. Test compound IC 50 For the determination of AAT Bioquest IC, different cancer cell lines are plated in 96-well plates at a pre-determined optimal density for each cell line. Test compounds are then added at different concentrations to generate a 6-point curve, and cell density is determined using the Promega Real-Time-Glo cell viability kit after 24, 48, and 72 hours of culture. 50 Use the calculator to calculate the IC at 72 hours for the test compound. 50 Additionally, the results in Table 3 are presented using the following scoring system: +++:IC 50 :<1uM ++ :IC 50 :1~5uM + :IC 50 :5~10uM - :I C 50 :>10uM TIFF2024511012000094.tif201164 EXAMPLES

[0230] Colon Cancer Treatment Based on our clinical experience, the following results are expected using controlled studies.

[0231] The colon is the final part of the digestive tract. Colon cancer typically strikes older adults, but can occur at any age. It usually begins as small non-cancerous (benign) clumps of cells called polyps that form on the inside of the colon. Over time, some of these polyps can become colon cancer. A cohort of 90 patients with colon tumors, ages 50-75 years, are identified by an oncologist. A detailed investigation report is prepared for each patient, complete with signs of symptoms and their severity. Tumor size is measured using MRI imaging. Common symptoms in patients include diarrhea and / or constipation, abdominal pain and cramps, rectal pain, rectal bleeding, weight loss, and fatigue. A colonoscopy is also performed to look at the patient's tumor. This report establishes the patient baseline. Experimental patients (n=30; "EXPT1") receive Compound 1 orally once daily. Experimental patients (n=30; "EXPT2") receive compound 27 orally once daily. Control patients (n=30; "CONT") receive placebo orally once daily. The study is conducted over a 3-month period, after which patient outcomes are measured by an oncologist. Patients treated with EXPT1 report improvement in each symptom of colon cancer. They also experience an average 80% reduction in tumor size. Instead, patients in the EXPT2 or CONT groups show no reduction in symptoms and / or increase in symptoms over the course of the study. Tumor size increases over the course of the study. The difference between the EXPT2 and CONT groups is not significantly greater. The difference between the improved outcomes of the EXPT1 group versus the EXPT2 or CONT groups is statistically significant. EXAMPLES

[0232] Pancreatic Cancer Treatment Based on the inventor's clinical experience, the following results are expected using controlled studies.

[0233] Pancreatic cancer is a type of cancer that begins in the pancreas, an organ that releases enzymes that aid digestion and produces hormones to manage blood sugar levels. Pancreatic cancer typically strikes older adults, but can occur at any age. Pancreatic ductal adenocarcinoma is the most common type and begins in the cells that line the ducts that carry digestive enzymes out of the pancreas. Pancreatic cancer is largely treatable in the early stages, but rarely detectable until it spreads to other organs and causes recognizable symptoms. A cohort of 90 patients with pancreatic tumors aged 50-75 years are identified by an oncologist. A detailed investigation report is prepared for each patient, complete with signs of symptoms and their severity. MRI imaging is used to measure tumor size. Common symptoms for patients include jaundice, dark urine, abdominal pain that radiates to the back, skin itching, blood clots, and fatigue. This report establishes the patient baseline. Experimental patients (n=30; "EXPT1") receive Compound 1 orally once daily. Experimental patients (n=30; "EXPT2") receive compound 27 orally once daily. Control patients (n=30; "CONT") receive placebo orally once daily. The study is conducted over a 3-month period, after which patient outcomes are measured by oncologists. Patients treated with EXPT1 report improvement in each symptom of pancreatic cancer. They also experience an average 80% reduction in tumor size. Instead, patients in the EXPT2 or CONT groups show no reduction in symptoms and / or increase in symptoms over the course of the study. Tumor size increases over the course of the study. The difference between the EXPT2 and CONT groups is not significantly greater. The difference between the improved outcomes in the EXPT1 group versus the EXPT2 or CONT groups is statistically significant. EXAMPLES

[0234] Bladder Cancer Treatment Based on the inventor's clinical experience, the following results are expected using controlled studies.

[0235] Bladder cancer is a type of cancer that begins in the cells of the bladder, which is located in the lower abdomen and functions to store urine. Pancreatic cancer typically strikes older adults, but can occur at any age. It most often begins in the ureteral epithelial cells that line the inside of the bladder. Most bladder cancer is diagnosed at an early stage, when it is largely treatable, but even early stage bladder cancer can recur after successful treatment. A cohort of 90 patients with bladder cancer, ages 50-75 years, is identified by an oncologist. A detailed investigation report is prepared for each patient, complete with signs of symptoms and their severity. Common symptoms for patients include blood in the urine (hematuria), frequent and / or painful urination, and back pain. This report establishes the patient baseline. Experimental patients (n=30; "EXPT1") receive Compound 1 orally once daily. Experimental patients (n=30; "EXPT2") receive compound 27 orally once daily. Control patients (n=30; "CONT") receive placebo orally once daily. The study is conducted over a 3-month period, after which patient outcomes are measured by an oncologist. Patients treated with EXPT1 report improvement in each symptom of pancreatic cancer. Instead, patients in the EXPT2 or CONT groups show a decrease in symptoms and / or no increase in symptoms over the course of the study. The differences between the EXPT2 and CONT groups are not significantly greater. The differences between the improved outcomes in the EXPT1 group versus the EXPT2 or CONT groups are statistically significant.

[0236] Although some embodiments have been illustrated and described, one of ordinary skill in the art, after reading the foregoing specification, may make modifications, equivalent substitutions, and other types of alterations to the compounds of the present technology or their salts, pharmaceutical compositions, derivatives, prodrugs, metabolites, tautomers, or racemic mixtures as described herein. Each of the above aspects and embodiments may also include or incorporate variations or aspects as disclosed herein with respect to any or all of the other aspects and embodiments.

[0237] The present technology is also not intended to be limited with respect to the specific embodiments described herein, which are intended as single illustrations of individual embodiments of the technology. As will be apparent to those skilled in the art, many modifications and variations of the present technology can be made without departing from its spirit and scope. In addition to those listed herein, functionally equivalent methods within the scope of the present technology will be apparent to those skilled in the art from the foregoing description. Such modifications and variations are intended to fall within the scope of the appended claims. It should be understood that the present technology is not limited to specific methods, reagents, compounds, compositions, labeled compounds or biological systems, which can of course vary. It should also be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting. Thus, it is intended that the specification be considered merely exemplary, with the breadth, scope and spirit of the present technology being indicated only by the appended claims, the definitions therein and any equivalents thereof.

[0238] In addition, when features or aspects of the present disclosure are described in terms of a Markush group, one of skill in the art will recognize that the present disclosure is also described in terms of any individual member or subgroup of members of the Markush group. Each of the narrower species and subgeneric groupings that fall within the generic disclosure also form part of the present technology. This includes the generic description of the present technology with a condition or negative limitation that removes any subject matter from the genus, regardless of whether the deleted item is specifically recited herein.

[0239] All publications, patent applications, issued patents, and other documents (e.g., journals, articles, and / or textbooks) referenced in this specification are incorporated herein by reference as if each individual publication, patent application, issued patent, or other document was specifically and individually indicated to be incorporated by reference in its entirety. Definitions contained in the text incorporated by reference are excluded to the extent that they conflict with definitions within this disclosure.

[0240] Other embodiments are set forth in the following claims, along with the full scope of equivalents to which such claims are entitled.

[0241] While the subject matter has been particularly shown and described with reference to preferred and various alternative embodiments, it will be understood by those skilled in the relevant art that various changes in form and details can be made therein without departing from the spirit and scope of the present disclosure.

Claims

1. Compounds of formula (I): 【Chemistry 1】 [In the formula, R １ is an optionally substituted 6- to 10-membered aryl, an optionally substituted 3- to 10-membered heterocyclyl, an optionally substituted 5- to 10-membered heteroaryl, an optionally substituted carbamido, -CN, and -NR ４ R ５ is selected from the group consisting of R ４ and R ５ Each of is independently selected from hydrogen, optionally substituted C １ ~C ６ Alkyl or optionally substituted C ３ ~C ６ or alternatively, R ４ and R ５ taken together form an optionally substituted 3- to 10-membered heterocyclyl; R ２ is -OR ６ or an optionally substituted (heterocyclyl)alkynyl, R ６ is selected from the group consisting of optionally substituted 2-10 membered heteroalkyl, (carbocyclyl)alkyl, and (heterocyclyl)alkyl; R 3 is a halogen or C １～６ is alkoxy; R ａ is hydrogen or optionally substituted C １ ~C １０ is alkyl, The A ring is an optionally substituted heteroaryl having 5 ring members. Compounds of formula (I) which do not contain any of the following structures: 【Chemistry 2】 【Chemistry 3】 【Chemistry 4】 or a stereoisomer, tautomer, or pharma- ceutically acceptable salt thereof.

2. The A ring is as follows: 【Chemistry 5】 is selected from one of The compound of claim 1, any of which may be optionally substituted by replacing one or more -H atoms of any carbon or nitrogen atom present on the A ring.

3. The A ring has the ring structure (AIa): 【Chemistry 6】 [In the formula, X ａ , X ｂ , X ｃ , and X ｄ is independently selected from the group consisting of C, N, O, and S; X ａ , X ｂ , X ｃ and any one or more of Xd is one or more R ｂ or H groups, R ｂ Each instance, if present, independently represents an optionally substituted C １ ~C １０ Alkyl, optionally substituted C ２ ~C １０ alkenyl, and optionally substituted C ３ ~C ６ carbocyclyl; n is an integer selected from 0, 1, 2, 3, or 4.

2. The compound of claim 1 , represented by:

4. The ring structure (AIa) is 【Chemistry 7】 [In the formula, Each R ｂ When present, replaces a -H bonded to a C or N atom in the ring structure (AIa).

4. The compound of claim 3, represented by a structure selected from the group consisting of:

5. The ring structure (AIa) is 【Chemistry 8】 5. The compound of claim 4, represented by a structure selected from the group consisting of:

6. R ｂ Each instance of, if present, 【Chemistry 9】 wherein m is an integer selected from 1, 2, 3, or 4.

4. The compound of claim 3 selected from the group consisting of:

7. R ｂ Each instance of, if present, 【Chemistry 10】 7. The compound of claim 6, selected from the group consisting of:

8. The compound of claim 3 , wherein n is 1.

9. The A ring is 【Chemistry 11】 2. The compound of claim 1, wherein the compound has a structure selected from the group consisting of:

10. The compound of claim 3 , wherein n is 0.

11. The A ring is selected from the following groups: 【Chemistry 12】 The compound of claim 1, which is not one of:

12. R １ but, 【Chemistry 13】 2. The compound of claim 1, wherein the compound has a structure selected from the group consisting of:

13. R ２ (heterocyclyl)C ２ ~C ６ The compound of claim 1 which is alkynyl.

14. R ２ has the following structure: 【Chemistry 14】 [In the formula, R ｃ is a 3-8 membered heterocyclyl having 1-2 heteroatoms; o is an integer selected from 1, 2, 3, or 4.

2. The compound of claim 1 , represented by:

15. 15. The compound of claim 14, wherein o is 1.

16. R ２ has the following structure: 【Chemistry 15】 [In the formula, R ｃ is a 3- to 8-membered heterocyclyl having 1 to 2 heteroatoms, or a 2- to 6-membered heteroalkyl having 1 to 2 heteroatoms; o is an integer selected from 1, 2, 3, 4, or 5.

2. The compound of claim 1 , represented by:

17. 17. The compound of claim 16, wherein o is 3.

18. The compound of claim 16, wherein o is 2.

19. R ｃ The compound of claim 1 , wherein has one heteroatom.

20. R ｃ has the following structure: 【Chemistry 16】 14. The compound of claim 13,

21. R ｃ has the following structure: 【Chemistry 17】 17. The compound of claim 16,

22. R ２ but, 【Chemistry 18】 2. The compound of claim 1 selected from the group consisting of:

23. R ３ The compound of claim 1, wherein is -OMe.

24. R ａ The compound of claim 1 , wherein is —H.

25. R ａ The compound of claim 1 , wherein is methyl.

26. R ａ is -H, and R ３ is -OMe, and R １ but, 【Chemistry 19】 and R ２ has the following structure: 【Chemistry 20】 When the A ring is one of: 【Chemistry 21】 The compound of claim 1 which is not:

27. R ２ but, 【Chemical 22】 If R １ teeth, 【Chemistry 23】 The compound of claim 1 which is not:

28. R ２ but, 【Chemistry 24】 If R １ teeth, 【Chemistry 25】 2. The compound of claim 1 ,

29. The compound of formula (I) 【Chemistry 26】 【change】 【change】 【change】 【change】 【change】 2. The compound of claim 1, represented by a compound selected from the group consisting of:

30. If substituted, R １ The optional substituents are amino, —OH, optionally substituted C １ ~C ６ Alkyl, optionally substituted C １ ~C ６ 2. The compound of claim 1, wherein the aryl group is selected from one or more of: alkoxy, and halogen.

31. If substituted, R ２ The optional substituents are amino, —OH, optionally substituted C １ ~C ６ Alkyl, optionally substituted C １ ~C ６ 2. The compound of claim 1, wherein the aryl group is selected from one or more of: alkoxy, and halogen.

32. If substituted, R ａ The optional substituents are amino, —OH, optionally substituted C １ ~C ６ Alkyl, optionally substituted C １ ~C ６ 2. The compound of claim 1, wherein the aryl group is selected from one or more of: alkoxy, and halogen.

33. 33. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 32 and a pharma- ceutically acceptable excipient.

34. 33. A compound according to any one of claims 1 to 32 for use in a method for inhibiting a kinase enzyme.

35. Kinases include CLK1, CLK2, CLK3, CLK4, FMS, JNK1, JNK2, JNK3, PLK4, FLT3, FLT3(D835V), FLT3(ITD), FLT3(F691L), FLT3(N841I), FLT3(D835H), FLT3(D835Y), FLT3(K663Q), FLT3(N841l), MYLK4, NUAK2, CSF1R, DAPK3, RIOK2, HIPK1, ALK, MYLK, EGFR, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, VEGFR, JAK1, ABL1, DAPK2, LTK, abl, Akt, Aurora-A, Aurora-B, Aurora-C, ATK, bcr-abl, Blk, Brk, Btk, c-Kit, c-Met, s-Src, c-fms, CDK1, CDK2 35. The compound of claim 34, selected from the group consisting of CDK4, CDK6, CDK7, CDK8, CDK9, CDK10, rRaf1, CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, ERK, Fak, fes, Fgr, fit-1, FLK-4, Fps, Fyn, Hck, HER, Hck, IGF-1R, INS-R, Jak, KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, Ros, Tie1, Tie2, Trk, Yes, Zap70, or a combination thereof.

36. 35. The compound of claim 34, wherein the kinase is selected from the group consisting of CLK1, CLK2, CLK3, CLK4, FMS, JNK1, JNK2, JNK3, PLK4, FLT3, FLT3(D835V), FLT3(ITD), FLT3(F691L), FLT3(N841I), FLT3(D835H), FLT3(D835Y), FLT3(K663Q), FLT3(N841l), MYLK4, NUAK2, CSF1R, DAPK3, RIOK2, HIPK1, ALK, MYLK, EGFR, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, VEGFR, JAK1, ABL1, DAPK2, and LTK.

37. Kinases include Akt, Aurora-A, Aurora-B, Aurora-C, ATK, bcr-abl, Blk, Brk, Btk, c-Kit, c-Met, s-Src, c-fms, CDK1, and CDK2.

35. The compound of claim 34, selected from the group consisting of CDK4, CDK6, CDK7, CDK8, CDK9, CDK10, rRaf1, CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, ERK, Fak, fes, Fgr, fit-1, FLK-4, Fps, Fyn, Hck, HER, Hck, IGF-1R, INS-R, Jak, KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, Ros, Tie1, Tie2, Trk, Yes, and Zap70.

38. 35. The compound of claim 34, wherein the kinase is selected from the group consisting of CLK1, CLK4, PLK4, FLT3, and JNK1.

39. 33. A compound according to any one of claims 1 to 32 for use in a method for treating a kinase-associated disease.

40. 40. The compound of claim 39, wherein the kinase-associated disease is selected from cancer, autoimmune diseases, and Duchenne muscular dystrophy.

41. A compound of formula (II): 【Chemical 27】 A method for preparing a compound of formula (IIp): 【Chemistry 28】 with a compound having the following structure: 【Chemical 29】 [In the formula, X is a halogen atom; R ２ is -OR ６ or an optionally substituted (heterocyclyl)alkynyl, R ６ is selected from the group consisting of optionally substituted 2-10 membered heteroalkyl, and (heterocyclyl)alkyl; R 3 is selected from the group consisting of hydrogen, halogen, and -OMe; R ａ is hydrogen or optionally substituted C １ ~C １０ is alkyl, The A ring is an optionally substituted heteroaryl. The method of claim 1, further comprising mixing the 42. A compound of formula (I): 【Chemistry 30】 A method for preparing H-R １ With a compound represented by formula (II) 【Chemistry 31】 [In the formula, X is a halogen atom; R １ is an optionally substituted 6- to 10-membered aryl, an optionally substituted 3- to 10-membered heterocyclyl, an optionally substituted 5- to 10-membered heteroaryl, an optionally substituted carbamido, -CN, and -NR ４ R ５ is selected from the group consisting of R ４ and R ５ Each of is independently selected from hydrogen, optionally substituted C １～６ Alkyl or optionally substituted C ３～６ or alternatively, R ４ and R ５ taken together form an optionally substituted 3- to 10-membered heterocyclyl; R ２ is -OR ６ or an optionally substituted (heterocyclyl)alkynyl, R ６ is selected from the group consisting of optionally substituted 2-10 membered heteroalkyl, and (heterocyclyl)alkyl; R 3 is selected from the group consisting of hydrogen, halogen, and -OMe; R ａ is hydrogen or optionally substituted C １ ~C １０ is alkyl, The A ring is an optionally substituted heteroaryl. The method of claim 1, further comprising mixing the

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