2-amino-4-methylquinazoline compounds, processes for their preparation, uses and pharmaceutical compositions

Abstract

This invention relates to 2-amino-4-methylquinazoline compounds, their preparation methods, uses, and pharmaceutical compositions. Specifically, it provides a compound represented by Formula I, which is a phosphatidylinositol 3-kinase δ (PI3Kδ) inhibitor that can be used to prevent and / or treat diseases related to PI3Kδ activity, such as tumors, autoimmune diseases, immunodeficiency diseases, inflammation, kidney diseases, cardiovascular diseases, metabolic / endocrine disorders, or neurological diseases.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology and relates to a 2-amino-4-methylquinazoline compound, its preparation method, uses, and pharmaceutical composition. Background Technology

[0002] Phosphatidylinositol 3-kinase (PI3K) is a class of lipid kinases, which can be divided into three major categories: I, II, and III based on their structural and functional characteristics. Among them, class I PI3K has been studied most extensively and plays a core role in regulating key life processes such as cell proliferation, survival, growth, and metabolism, thus becoming an important target in the development of anti-tumor drugs. Class I PI3K includes four subtypes: PI3Kα, PI3Kβ, PI3Kδ, and PI3Kγ. PI3Kα and PI3Kβ are widely expressed in various tissues, while PI3Kδ and PI3Kγ are mainly enriched in immune cells, suggesting their potential application value in immune-related diseases.

[0003] Numerous studies have confirmed that abnormal activation of PI3Kδ is closely related to the development and progression of B-cell malignancies (such as follicular lymphoma), with Idelalisib, the first approved PI3Kδ inhibitor, being a prime example. Recent research has further revealed that PI3Kδ inhibitors not only directly inhibit tumor cell proliferation but also activate anti-tumor immune responses by relieving the immunosuppressive function of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), and exhibit synergistic effects with immune checkpoint drugs such as PD-1 / PD-L1 inhibitors. Furthermore, by optimizing dosing strategies (such as intermittent administration), it is possible to maintain anti-tumor efficacy while reducing immune-related adverse reactions and extending the therapeutic window.

[0004] In the field of inflammation and autoimmune diseases, PI3Kδ inhibitors have also shown broad therapeutic potential. Their mechanism involves the regulation of key immune cell functions: inhibition of PI3Kδ can regulate the differentiation and cytokine secretion of T cells (especially Th1 and Th17), and inhibit antibody production and antigen presentation functions of B cells, thus providing a therapeutic strategy for autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus. Simultaneously, this target also plays a central role in the chemotaxis, activation, and release of inflammatory mediators of neutrophils and macrophages, supporting its application in inflammatory diseases such as chronic obstructive pulmonary disease, asthma, idiopathic pulmonary fibrosis, and acute lung injury. Furthermore, for PI3Kδ activation syndrome caused by PIK3CD gene activation mutations, the selective p110δ inhibitor CDZ173 has been approved for clinical use, further validating the therapeutic value of this target.

[0005] In addition, although PI3Kδ is a promising therapeutic target, inhibitors targeting this target face another key challenge in clinical development: subtype selectivity. PI3Kδ shares high homology with the class I PI3Kα subtype in terms of its catalytic domain. This structural similarity makes it difficult to develop highly selective PI3Kδ inhibitors. PI3Kα plays a crucial role in various tissues throughout the body, particularly in the insulin signaling pathway and cellular basal metabolism and growth. Inhibition of PI3Kα has been shown to be a major cause of dose-limiting toxicities such as hyperglycemia and diarrhea. Therefore, obtaining PI3Kδ inhibitors with high selectivity relative to PI3Kα has become another key direction in research and development in this field. Excellent δ / α subtype selectivity means that immune cell function under pathological conditions can be more precisely regulated, while minimizing interference with PI3Kα-mediated basic physiological functions. This not only has the potential to significantly reduce metabolic toxicity, improve the therapeutic index and patient tolerability, but also provides the possibility of achieving stronger immunomodulatory and anti-tumor efficacy at higher doses or longer treatment courses. It is the fundamental guarantee for promoting safer and more effective clinical application of PI3Kδ targeted therapy in the fields of tumor immunology and autoimmune diseases.

[0006] In summary, PI3Kδ has become an important target in the fields of B-cell malignancies, tumor immunotherapy, inflammation, and autoimmune diseases, and its excellent δ / α subtype selectivity is also crucial. Therefore, despite the progress made in drug development, there is still an urgent need to develop novel PI3Kδ inhibitors with novel structures, higher selectivity, better in vivo efficacy, and good safety profiles to address unmet clinical needs. Summary of the Invention

[0007] To address the problems existing in the prior art, this invention provides a novel selective PI3Kδ inhibitor, its preparation method, pharmaceutical composition, and uses. This type of selective PI3Kδ inhibitor not only has excellent inhibitory effects on PI3Kδ subtypes but also exhibits excellent δ / α subtype selectivity, thereby providing preventive and / or therapeutic effects on PI3Kδ-mediated diseases such as tumors, autoimmune diseases, immunodeficiency diseases, kidney diseases, cardiovascular diseases, inflammation, metabolic / endocrine dysfunction, or neurological diseases.

[0008] Specifically, in a first aspect, the present invention provides a compound of Formula I, or a stereoisomer, geometric isomer, tautomer, prodrug, pharmaceutically acceptable salt, crystal form, or solvate thereof.

[0009] in: R 1Selected from 5-6 saturated heterocyclic groups, wherein the 5-6 saturated heterocyclic group is optionally surrounded by 1-3 groups selected from R a The groups are replaced; R a Selected from hydroxyl, mercapto, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C3-C6 cycloalkyl, 6-10 aryl, 5-6 heteroaryl, hydroxy-C1-C6 alkylene, -C(O)-R b -S(O)-R c -S(O)2-R d ; R b R c R d Each is independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, and C3-C6 cycloalkyl; R 2 Selected from hydrogen, cyano, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C3-C6 cycloalkyl, and C1-C6 haloalkyl; R 3 Selected from C1-C6 alkyl groups; X is N or CR 4 ; R 4 It is selected from hydrogen, cyano, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, and C1-C6 haloalkyl.

[0010] In some implementation schemes, R 1 Selected from 6-membered saturated heterocyclic groups, wherein the 6-membered saturated heterocyclic group is optionally surrounded by 1-2 elements selected from R a The group is replaced by the group.

[0011] In some implementation schemes, R 1 The group is selected from piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl, and each of the piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl groups is independently and optionally composed of 1-2 groups selected from R. a The group is replaced by the group.

[0012] In some implementation schemes, R 1 The group is selected from piperidinyl, piperazinyl, and morpholinyl, and each of the piperidinyl, piperazinyl, and morpholinyl groups is independently and optionally surrounded by 1-2 groups selected from R. a The group is replaced by the group.

[0013] In some implementation schemes, R a Selected from hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, phenyl, 6-membered heteroaryl, hydroxy-C1-C6 alkylene, -C(O)-R b .

[0014] In some implementation schemes, R a Selected from hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, hydroxy-C1-C6 alkylene, -C(O)-R b .

[0015] In some implementation schemes, R a Selected from hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, phenyl, pyridyl, pyrimidinyl, hydroxy-C1-C6 alkylene, -C(O)-R b .

[0016] In some implementation schemes, R a Selected from hydroxyl, methyl, ethyl, isopropyl, methoxy, cyclopropyl, cyclopentyl, phenyl, , , , .

[0017] In some implementation schemes, R b R c R d Each is independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, and C3-C6 cycloalkyl.

[0018] In some implementation schemes, R b R c R d Each is independently selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, and cyclopentyl.

[0019] In some implementation schemes, R b Selected from C1-C6 alkyl groups.

[0020] In some implementation schemes, R b Selected from methyl, ethyl, n-propyl, and isopropyl.

[0021] In some implementation schemes, R b It is a methyl group.

[0022] In some implementation schemes, R 1 Selected from , , .

[0023] In some implementation schemes, R e R f R gEach is independently selected from hydrogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, phenyl, 6-membered heteroaryl, hydroxy-C1-C6 alkylene, -C(O)-R h .

[0024] In some implementation schemes, R e R f R g Each is independently selected from hydrogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, hydroxy-C1-C6 alkylene, -C(O)-R h .

[0025] In some implementation schemes, R e R f R g Each is independently selected from hydrogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, phenyl, pyridyl, pyrimidinyl, hydroxy-C1-C6 alkylene, -C(O)-R h .

[0026] In some implementation schemes, R e R f R g Each is independently selected from hydrogen, hydroxyl, methyl, ethyl, isopropyl, methoxy, cyclopropyl, cyclopentyl, phenyl, , , , .

[0027] In some implementation schemes, R e Selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, -C(O)-R h .

[0028] In some implementation schemes, R e Selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, pyridyl, pyrimidinyl, -C(O)-R h .

[0029] In some implementation schemes, R e Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, , , .

[0030] In some implementation schemes, R e Selected from hydrogen, ethyl, isopropyl, cyclopropyl, cyclopentyl, phenyl, , , .

[0031] In some implementation schemes, R f Selected from hydrogen, hydroxyl, C1-C6 alkoxy, and hydroxy-C1-C6 alkylene.

[0032] In some implementation schemes, R f Selected from hydrogen, hydroxyl, methoxy, ethoxy, .

[0033] In some implementation schemes, R f Selected from hydrogen, hydroxyl, methoxy, .

[0034] In some implementation schemes, R g Selected from hydrogen and C1-C6 alkyl groups.

[0035] In some implementation schemes, R g Selected from hydrogen and methyl.

[0036] In some implementation schemes, R h Selected from C1-C6 alkyl groups.

[0037] In some implementation schemes, R h Selected from methyl, ethyl, n-propyl, and isopropyl.

[0038] In some implementation schemes, R h It is a methyl group.

[0039] In some implementation schemes, R 1 Selected from , , , , , , , , , , , , , , .

[0040] In some implementation schemes, R 2 It is selected from hydrogen, cyano, halogen, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl.

[0041] In some implementation schemes, R 2 Selected from hydrogen, methyl, methoxy, fluorine, chlorine, cyano, and -CF3.

[0042] In some implementation schemes, R 3 It is a methyl group.

[0043] In some implementation schemes, R 4 It is selected from hydrogen, cyano, halogen, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl.

[0044] In some implementation schemes, R 4 It is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl.

[0045] In some implementation schemes, R 4 Selected from hydrogen, methyl, methoxy, fluorine, chlorine, and -CF3.

[0046] In some embodiments, the compound has the structure shown in Formula I-1.

[0047] in: R 1 R 2 R 4 Each is independent as described above.

[0048] In some implementation schemes, R 1 Selected from , .

[0049] In some implementation schemes, R e -C(O)-R h R h Selected from C1-C6 alkyl groups, preferably methyl.

[0050] In some implementation schemes, R e for .

[0051] In some implementation schemes, R f It is a hydroxyl group.

[0052] In some implementation schemes, R g Selected from hydrogen and C1-C6 alkyl groups.

[0053] In some implementation schemes, R g Selected from hydrogen and methyl.

[0054] In some implementation schemes, R 1 Selected from , , .

[0055] In some implementation schemes, R 2Selected from cyano, halogen, and C1-C6 alkoxy groups.

[0056] In some implementation schemes, R 2 Selected from methoxy, fluorine, chlorine, and cyano groups.

[0057] In some implementation schemes, R 2 Selected from cyano and halogen.

[0058] In some implementation schemes, R 2 Selected from chlorine and cyano groups.

[0059] In some implementation schemes, R 4 Selected from halogens, C1-C6 alkyl groups, and C1-C6 haloalkyl groups.

[0060] In some implementation schemes, R 4 Selected from methyl, chlorine, and -CF3.

[0061] In some implementation schemes, R 4 Selected from C1-C6 haloalkyl groups.

[0062] In some implementation schemes, R 4 It is -CF3.

[0063] In some embodiments, the compound is selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

[0064] In a second aspect, the present invention provides pharmaceutical compositions comprising the aforementioned compound or its stereoisomers, geometric isomers, tautomers, prodrugs, pharmaceutically acceptable salts, crystal forms, or solvates.

[0065] In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, diluent, and / or excipient.

[0066] In some embodiments, the pharmaceutical composition further comprises additional active ingredients for the prevention and / or treatment of tumors.

[0067] In a third aspect, the present invention provides the use of the aforementioned compound or its stereoisomers, geometric isomers, tautomers, prodrugs, pharmaceutically acceptable salts, crystal forms or solvates, or the aforementioned pharmaceutical compositions in the preparation of medicaments for the treatment and / or prevention of PI3Kδ-mediated diseases.

[0068] In addition, the present invention also provides a method for treating and / or preventing PI3Kδ-mediated diseases, comprising administering to a subject in need an effective amount of the aforementioned compound or its stereoisomers, geometric isomers, tautomers, prodrugs, pharmaceutically acceptable salts, crystal forms or solvates or the aforementioned pharmaceutical compositions.

[0069] Furthermore, the present invention also provides the aforementioned compound or its stereoisomers, geometric isomers, tautomers, prodrugs, pharmaceutically acceptable salts, crystal forms or solvates, or the aforementioned pharmaceutical compositions for the treatment and / or prevention of PI3Kδ-mediated diseases.

[0070] In some implementations, the PI3Kδ-mediated diseases include tumors (such as B-cell malignancies, specifically follicular lymphoma), autoimmune diseases (such as rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus), immunodeficiency diseases, kidney diseases, cardiovascular diseases, inflammation, inflammatory diseases (such as chronic obstructive pulmonary disease, asthma, idiopathic pulmonary fibrosis, acute lung injury), PI3Kδ activation syndrome, metabolic / endocrine dysfunction, or neurological diseases.

[0071] Terminology Definition

[0072] The following are definitions of some of the terms used in this invention; other undefined terms have meanings known to those skilled in the art.

[0073] In this invention, unless otherwise explicitly stated, the descriptive phrases “...each independently selected from” or “each…independently selected from” used throughout this document are interchangeable. They can mean either that the specific options expressed by the same or different symbols in different groups do not affect each other, or that the specific options expressed by the same or different symbols in the same group do not affect each other.

[0074] The substituents of the compounds of this invention are disclosed according to the type or scope of the functional groups. In particular, this invention includes every independent secondary combination of each member of these types and scopes of functional groups.

[0075] The term "C1-C6 alkyl" refers to any straight-chain or branched group containing 1-6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, tert-pentyl, n-hexyl, etc., preferably "C1-C4 alkyl".

[0076] The term "C1-C6 alkylene" refers to any of the above "C1-C6 alkyl" groups that have lost a hydrogen atom to obtain a divalent group, such as methylene.

[0077] The term "C1-C4 alkyl" refers to any straight-chain or branched group containing 1-4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, etc.

[0078] The term “C1-C6 alkoxy” refers to any of the above “C1-C6 alkyl” connected to the rest of the molecule by an oxygen atom (-O-), preferably “C1-C4 alkoxy”.

[0079] The term “C1-C6 alkylthio” refers to any of the above “C1-C6 alkyl” linked to the rest of the molecule by a sulfur atom (-S-), preferably “C1-C4 alkylthio”.

[0080] The term “C1-C6 haloalkyl” refers to a group obtained by replacing one or more (e.g., 2 or 3) hydrogen atoms in any of the above “C1-C6 alkyl” with a halogen (preferably fluorine), such as trifluoromethyl.

[0081] The term "hydroxy-C1-C6 alkylene" refers to a group obtained by covalently linking a hydroxyl group to any of the aforementioned "C1-C6 alkylene groups," such as... For other similar descriptions, please refer to the foregoing explanation for clarification.

[0082] The term "C3-C6 cycloalkyl" refers to a saturated monocyclic, fused, spirocyclic, or polycyclic structure having 3 to 6 carbon ring atoms. Examples of such groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0083] The term "C6-C10 aryl" refers to an aromatic hydrocarbon group with 6 to 10 carbon atoms. It is the part remaining after removing one hydrogen atom from an aromatic hydrocarbon molecule, such as phenyl or naphthyl.

[0084] The term "heteroaryl" refers to an aromatic monocyclic, bicyclic, tricyclic, or more cyclic group comprising 5-, 6-, 7-, 8-, 9-, or 10-membered (preferably 5-10- or 5-6-membered) rings having at least one heteroatom (N, O, or S), wherein the heteroatom-containing ring optionally also has one, two, or three heteroatoms selected from N, O, or S. For a heteroaryl group to be bicyclic, tricyclic, or polycyclic, each ring must constitute an aromatic system. The carbon or sulfur atoms on the rings may optionally be oxidized (i.e., forming C(=O), sulfoxide, or sulfone), thereby forming part of the heteroaryl group. Non-limiting examples of the heteroaryl group include, for example, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, imidazolyl, thiazolyl, isothiazolyl, thiazolyl, pyrroleyl, phenyl-pyrroleyl, furanyl, phenyl-furanyl, oxazolyl, isoxazolyl, pyrazolyl, thiophenyl, benzofuranyl, benzothiophenyl, benzimidazolyl, inzolyl, quinolinyl, isoquinolinyl, etc.

[0085] The term "heterocyclic group" refers to a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered (preferably 3-7-, 3-6-, 5-10-, 5-8-, or 5-6-membered) carbon ring in which one or more carbon atoms are replaced by heteroatoms such as nitrogen, oxygen, and sulfur, and the ring as a whole does not constitute an aromatic system. The carbon or sulfur atoms on the ring may optionally be oxidized (i.e., forming C(=O), sulfoxide, or sulfone), thereby forming part of the heterocyclic group. Furthermore, the heterocyclic group includes monoheterocyclic groups, spiroheterocyclic groups, bridged heterocyclic groups, or fused heterocyclic groups. Non-limiting examples of heterocyclic groups include, for example, pyran, pyrrolidine, pyrrololine, imidazoline, imidazoline, pyrazole, pyrazolidine, pyrazolidine, thiazoline, thiazoline, dihydrofuran, tetrahydrofuran, 1,3-dioxolane, piperidine, piperazine, morpholine, morpholino, tetrahydropyrrolo, thiomorpholino, etc. The "heterocyclic group" is preferably a 4-6 member monoheterocyclic group or a 7-8 member spiroheterocyclic group. For example, a "6-membered heterocyclic group" refers to a 6-membered saturated or partially unsaturated carbon ring, wherein one or more carbon atoms are replaced by heteroatoms such as nitrogen, oxygen, and sulfur. Non-limiting examples of 6-membered heterocyclic groups include, for example, pyran, piperidine, piperazine, morpholine, thiomorpholino, etc., or such as... For example, a "5-membered heterocyclic group" refers to a 5-membered saturated or partially unsaturated carbon ring in which one or more carbon atoms are replaced by heteroatoms such as nitrogen, oxygen, and sulfur. Non-limiting examples of 5-membered heterocyclic groups include, for example, pyrrolidine, pyrrololine, imidazoline, imidazoline, pyrazolidine, pyrazolidine, pyrazolidine, thiazoline, thiazoline, 1,3-dioxolane, etc. For example, a "4-membered heterocyclic group" refers to a 4-membered saturated or partially unsaturated carbon ring in which one or more carbon atoms are replaced by heteroatoms such as nitrogen, oxygen, and sulfur. Non-limiting examples of 4-membered heterocyclic groups include... .

[0086] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0087] The term "hydroxyl group" refers to -OH.

[0088] The term "thiol" refers to -SH.

[0089] The term "cyano" refers to -CN.

[0090] The term "inhibitor" refers to a compound or agent that can inhibit the biological function of a target protein or polypeptide, such as inhibiting the activity or expression of the target protein or polypeptide.

[0091] The term "effective amount" refers to the amount of a compound or pharmaceutical composition described herein sufficient to achieve the intended application as described below, including but not limited to the treatment of a disease. Effective amounts may vary depending on: the intended application (in vivo or in vitro); or the individual being treated and the disease condition, such as the individual's weight and age, the severity of the disease; the route of administration, etc. Effective amounts can be readily determined by those skilled in the art.

[0092] "Optionally" means that the event or environment described below may, but does not have to, occur; this description includes the possibility that the event or environment may or may not occur. For example, "optionally halogenated alkyl group" means that a halogen may, but does not have to, be present; this description includes both cases where the alkyl group is halogenated and cases where the alkyl group is not halogenated. Other similar descriptions are understood in accordance with the foregoing description.

[0093] In this invention, similar to "R" 1 The group is selected from piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl, and each of the piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl groups is independently and optionally composed of 1-2 groups selected from R. aThe description "substituted by substituents" indicates that piperidinyl, piperazine, morpholinyl, and thiomorpholinyl groups may or may not be substituted by substituents. When piperidinyl, piperazine, morpholinyl, or thiomorpholinyl groups are substituted by substituents, the substituents of each group may be the same or different. When piperidinyl, piperazine, morpholinyl, or thiomorpholinyl groups are substituted by multiple (e.g., two) substituents, each substituent may be the same or different. For example, if R... a The substituents are selected from methyl, ethyl, hydroxy, and mercapto. Therefore, the two substituents of piperidinyl can be methyl and ethyl, the two substituents of piperazineyl can be hydroxy and mercapto, the two substituents of morpholinoyl can both be methyl, and the two substituents of thiomorpholinoyl can both be hydroxy. For other similar descriptions, please refer to the foregoing explanation.

[0094] The compounds described in this invention may contain one or more chiral centers, which exist in different stereoisomeric forms. All stereoisomers of the compounds of this invention, including but not limited to diastereomers, enantiomers, and transisomers, as well as mixtures thereof (such as racemic mixtures), are within the scope of this invention.

[0095] The compounds described in this invention include their geometric isomers. For example, if the compounds of this invention contain double bonds or fused rings, these compounds may exist as geometric isomers, and their cis, trans, and mixtures of cis and trans forms are all included within the scope of this invention.

[0096] The compounds described in this invention include their tautomers. Tautomers are structural isomers that interconvert at different energies via low-energy barriers, such as keto-enol and imine-enamine tautomerization.

[0097] The compounds described in this invention also include their isotope-labeled compounds. The term "isotope-labeled compound" refers to a compound in which one or more atoms are replaced by atoms having the same atomic number but a different atomic mass number than those normally found in nature. Examples of isotopes suitable for this invention include, but are not limited to, isotopes of hydrogen. 2 H and 3 H; carbon isotopes 11 C 13 C and 14 C; isotopes of chlorine 36 Cl; isotopes of fluorine 18 F; Isotopes of iodine 123 I and 125 I; Nitrogen isotopes 13 N and 15 N; isotopes of oxygen 15 O、 17 O and 18O; isotopes of phosphorus 32 Isotopes of P and sulfur 35 S.

[0098] Various solvates and hydrates of the compounds or their salts described in this invention, as well as their polymorphs, are also included within the scope of this invention.

[0099] The term "solvent" (or "solvent compound") refers to a compound that also includes stoichiometric or non-stoichiometric solvents bound by non-covalent intermolecular forces. A solvate can be the disclosed compound or a pharmaceutically acceptable salt thereof. When the solvent is water, the solvate is a "hydrate". Pharmaceutically acceptable solvates and hydrates are, for example, complexes comprising, to some extent, 1 to some extent, 10 to some extent, 1 to some extent, 3 to some extent, or 4 solvent or water molecules.

[0100] The term "crystal form" refers to the crystal structure of a substance. During crystallization, various factors alter the intramolecular or intermolecular bonding patterns, resulting in different arrangements of molecules or atoms in the crystal lattice, thus forming different crystal structures. The compounds of this invention can exist in one crystal structure or multiple crystal structures, i.e., they possess "polymorphism." The compounds of this invention can exist in different crystal forms. The term "polymorphic compound" refers to a compound that exhibits two or more different crystal forms.

[0101] Prodrugs of the compounds described in this invention are also included within the scope of this invention. Some derivatives of the compounds described in this invention possess weak or no pharmacological activity, but when these derivatives are administered into the body, they can be converted into pharmacologically active compounds of this invention through processes such as hydrolysis and cleavage. These derivatives are referred to as "prodrugs." Further information on the use of prodrugs can be found in *Pro-drugs as Novel Delivery Systems*, Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and *Bioreversible Carriers in Drug Design*, Pergamon Press, 1987 (ed. EB Roche, American Pharmaceutical Association).

[0102] The compounds described in this invention include pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to a salt that is pharmaceutically acceptable and possesses the pharmacological activity required by the parent compound. Pharmaceutically acceptable salts are described in detail by Berge et al. in J. Pharma. Sci., 1977, 66, 1-19, which is incorporated herein by reference. The compounds described in this invention may contain sufficient acidic groups, sufficient basic groups, or both types of functional groups, and accordingly react with some inorganic or organic base, or inorganic and organic acid, to form pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, phosphates, monohydrophosphates, dihydrophosphates, metaphosphates, pyrophosphates, hydrochlorides, hydrobromates, hydroiodates, acetates, propionates, decanoates, caprylates, octanoates, acrylates, formates, isobutyrates, hexanoates, heptanoates, propynylates, oxalates, malonates, succinates, caprylates, sebacic acid salts, fumarates, maleates, butyn-1,4-dicitates, hexyn-1,6-dicitates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, and lactoses. Salts, γ-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, and mandelate; or including alkali metal salts such as sodium, potassium, and lithium salts; alkaline earth metal salts such as calcium and magnesium salts; other metal salts such as aluminum, iron, zinc, copper, nickel, and cobalt salts; inorganic alkali salts such as ammonium salts; organic alkali salts such as tert-octylamine, dibenzylamine, morpholine, glucosamine, phenylglycine alkyl ester, ethylenediamine, N-methylglucosamine, guanidine, diethylamine, triethylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, chloroprocaine, procaine, diethanolamine, N-benzyl-phenylethylamine, piperazine, tetramethylamine, and tris(hydroxymethyl)aminomethane.

[0103] When used as a pharmaceutical, the compounds described herein are typically administered in the form of a pharmaceutical composition. Therefore, pharmaceutical compositions comprising the compounds described herein and pharmaceutically acceptable carriers, diluents, or excipients are also included within the scope of this invention. Carriers, excipients, and additives as used herein include any and all solvents, diluents or other liquid excipients, dispersants or suspending agents, surfactants, isotonic agents, thickeners or emulsifiers, preservatives, solid binders, lubricants, etc., suitable for the desired particular dosage form. Various carriers for formulating pharmaceutically acceptable compositions and known techniques for their preparation are disclosed in Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JC Boylan, 1988–1999, Marcel Dekker, New York, the contents of which are incorporated herein by reference.

[0104] The pharmaceutical compositions of this invention can be administered via any route suitable for the condition to be treated. In particular, administration is possible via: parenteral administration, for example, in the form of an injectable solution or suspension; enteral administration, for example, orally, in the form of tablets or capsules; and topical administration, for example, in the form of lotions, gels, ointments, or emulsions, or in the form of nasal or suppositories. Topical application is, for example, to the skin. Another form of topical administration is administration to the eye. In other words, the compositions of this invention can be formulated into the following dosage forms: parenteral formulations, for example, injectable solutions or suspensions; enteral formulations, for example, oral formulations, such as tablets or capsules; and topical formulations, such as lotions, gels, ointments, emulsions, nasal formulations, suppositories, transdermal formulations, or ophthalmic formulations.

[0105] Pharmaceutical compositions can be administered in solid, semi-solid, liquid, or gaseous form, or may be in the form of dry powders, such as lyophilized forms. Pharmaceutical compositions can be packaged in easily deliverable forms, including, for example, solid dosage forms such as capsules, pouches, sachets, gelatin, paper, tablets, suppositories, granules, pills, lozenges, and tablets. The type of packaging will generally depend on the route of administration. Implantable, sustained-release formulations and transdermal formulations are also covered.

[0106] Examples of materials that can serve as pharmaceutically acceptable carriers include, but are not limited to: ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffers (e.g., phosphates), glycine, sorbic acid or potassium sorbate, mixtures of metaglycerides of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene block copolymers, lanolin, sugars (e.g., lactose, glucose, and sucrose), and starches (e.g., corn starch). The composition may contain: potato starch, cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; tragacanth gum powder; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols, such as propylene glycol or polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffers, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; and phosphate buffer, as well as other non-toxic and compatible lubricants, such as sodium lauryl sulfate and magnesium stearate. Colorants, releasing agents, coating agents, sweeteners, flavorings and aromas, preservatives and antioxidants may also be present in the composition, at the discretion of the formulation personnel.

[0107] The compounds described in this invention can be used alone or in combination with other therapeutic agents for treating the diseases or conditions described in this invention (e.g., cancer). In some embodiments, the compounds described in this invention are combined in a pharmaceutical combination formulation with a second compound having anti-proliferative properties or for treating highly proliferative diseases (e.g., cancer), or in a dosing regimen as a combination therapy. The second compound in the pharmaceutical combination formulation or dosing regimen preferably has an activity complementary to that of the compounds described in this invention so that they do not adversely affect each other. Such compounds are suitably present in the combination in an amount effective for the intended purpose. In one embodiment, the compounds of this invention are combined with other antitumor drugs.The antitumor drugs include: alkylating agents, including but not limited to cyclophosphamide, nitrogen mustard, melphalan, cyclophosphamide, and carmustine; platinum-based drugs, including but not limited to carboplatin, cisplatin, and oxaliplatin; topoisomerase inhibitors, including but not limited to topotecan, camptothecin, topotecan, and irinotecan; antibiotics, including but not limited to cyclophosphamide, actinomycin D, daunorubicin, doxorubicin, mitoxantrone, bleomycin, and procainoxantrone; antimicrotubule or antimitotic agents, including but not limited to paclitaxel, vinorelbine, docetaxel, and doxorubicin; and antimetabolites, including but not limited to fluorouracil, methotrexate, cytarabine, and mecaptopurine. Thioguanine and gemcitabine; antibodies, including but not limited to Herceptin and bevacizumab; hormones, including but not limited to Letrazole, Vorazole, tamoxifen, toremifene, fulvestrant, flutamide, nilumethoxazole, and triptorelin; kinase inhibitors, including but not limited to EGFR kinase inhibitors such as gefitinib, erlotinib, lapatinib, and afatinib; and VEGFR inhibitors such as sorafenib and regoraf. Enib, sunitinib, cabozantinib, pazopanib, vandetanib, axitinib; ALK inhibitors, including but not limited to crizotinib, ceritinib, alectinib; Bcr-Abl inhibitors, including but not limited to imatinib, ponatinib, nilotinib, dasatinib; BTK inhibitors Drugs, including but not limited to ibrutinib; B-RAF inhibitors, including but not limited to vemurafenib; cyclin-dependent kinase CDK4 / 6 inhibitors, such as palbociclib; mTOR inhibitors, including but not limited to rapamycin and everolimus; deacetylase inhibitors, including but not limited to vorinostat; PD1 / PDL1 antibodies, such as Keytruda (pembrolizumab) and Opdivo (nivolumab).

[0108] In some embodiments, the compounds of the present invention may be formulated as a combination drug with a second therapeutic agent for treating autoimmune or inflammatory diseases (e.g., acute lung injury, multiple sclerosis, rheumatoid arthritis, COPD, asthma, etc.) or used as a combination therapy in a dosing regimen.

[0109] In one specific embodiment, the PI3Kδ inhibitor of the present invention can be used in combination with drugs that target different inflammatory signaling pathways, such as JAK inhibitors (e.g., ruxolitinib) and TYK2 inhibitors (e.g., deuterocelexitinib), to produce a synergistic anti-inflammatory effect and improve treatment efficacy.

[0110] In one specific embodiment, the PI3Kδ inhibitor of the present invention is used in combination with the following drugs to treat COPD: PDE4 inhibitors (e.g., roflumilast), bronchodilators such as muscarinic antagonists (e.g., ipratropium bromide and tiotropium) and β2 receptor agonists (e.g., salmeterol and formoterol), and inhaled corticosteroids (e.g., fluticasone and budesonide).

[0111] In one specific implementation, for activated PI3Kδ syndrome (APDS) and its associated autoimmune complications (such as IgA vasculitis nephritis) caused by PIK3CD gene activating mutations, the PI3Kδ inhibitor of the present invention can be used in combination with immunomodulatory regimens (such as glucocorticoids, rituximab).

[0112] In one specific implementation, the PI3Kδ inhibitor of the present invention can be used in combination with one or more drugs for treating multiple sclerosis to form a synergistic treatment regimen. Specifically, it can be combined with drugs that promote myelin repair to simultaneously achieve the dual goals of immune regulation and nerve repair; it can also be used in combination with BTK inhibitors to enhance the immune regulation effect by jointly regulating the function of immune cells such as B cells; or it can be combined with symptomatic treatment drugs such as those that improve walking ability to improve the patient's quality of life while controlling the disease progression.

[0113] In one specific embodiment, the compounds of the present invention can be used in combination with other drugs for treating acute lung injury, including but not limited to: glucocorticoids, such as prednisolone, methylprednisolone, dexamethasone, hydrocortisone, beclomethasone, budesonide, fluticasone, triamcinolone, fluticasone propionate, mometasone furoate; bronchodilators, such as salbutamol, ipratropium bromide, terbutaline; antibiotics, such as amoxicillin-clavulanate potassium, piperacillin-tazobactam, meropenem-sulbactam, cefuroxime, cefotetan, cefoperazone-sulbactam, ceftazidime, ceftriaxone, cefepime, imipenem-cilastatin, meropenem, ertapenem, erythromycin, azithromycin, clarithromycin. Levofloxacin, moxifloxacin, ciprofloxacin, vancomycin, teicoplanin; nitric oxide donors, such as milrinone, nitroglycerin, sodium nitroprusside, sildenafil, tadalafil, vardenafil, isosorbide dinitrate; anticoagulants, such as heparin sodium, warfarin, rivaroxaban, dabigatran etexilate, apixaban, fondaparinux sodium; diuretics, such as furosemide, spironolactone; expectorants and mucolytics, such as ambroxol hydrochloride, acetylcysteine, carbocysteine, erdosteine; lung protectants and adjuvant anti-inflammatory drugs, such as ulinastatin, Xuebijing injection, thymosin α1, glutathione, vitamin C, vitamin E, pentoxifylline, infliximab, adalimumab.

[0114] In one specific embodiment, the compounds of the present invention can be used in combination with immune checkpoint drugs such as PD-1 / PD-L1 inhibitors to produce a synergistic effect, including but not limited to pembrolizumab, nivolumab, sintilimab, toripalimab, camrelizumab, atezolizumab, durvalumab, and envorimab.

[0115] In this invention, "treatment" generally refers to achieving the desired pharmacological and / or physiological effect. This effect may be preventative based on the complete or partial prevention of the disease or its symptoms; and / or therapeutic based on the partial or complete stabilization or cure of the disease and / or side effects resulting from the disease. As used herein, "treatment" encompasses any treatment of a patient's disease, including: (a) prevention of disease or symptoms occurring in a patient who is susceptible to the disease or its symptoms but has not yet been diagnosed with the disease; (b) suppression of the symptoms of the disease, i.e., prevention of its progression; or (c) relief of the symptoms of the disease, i.e., causing the disease or its symptoms to regress.

[0116] In this invention, "subject" refers to a vertebrate. In some embodiments, vertebrate refers to a mammal. Mammals include, but are not limited to, livestock (such as cattle), pets (such as cats, dogs, and horses), primates, mice, and rats. In some embodiments, mammal refers to a human.

[0117] Beneficial effects

[0118] The compounds of this invention not only exhibit significant inhibitory activity against PI3Kδ, but also significant selectivity against PI3Kα. Surprisingly, some compounds show even stronger activity and selectivity: for example, the title compounds prepared in Examples 5, 6, 11, 12, 15, 16, 17, 18, 22, and 33, with IC50 values ​​for PI3Kδ... 50 Values ​​less than 10 nM show a selectivity for PI3Kα greater than 200 times; in particular, the title compounds prepared in Examples 17, 18, 22, and 33 show a selectivity for PI3Kα greater than 1000 times. Detailed Implementation

[0119] The embodiments of the present invention will now be described in detail with reference to examples. However, those skilled in the art will understand that the following examples are for illustrative purposes only and are not intended to limit the scope of the invention. Various objects and advantages of the present invention will become apparent to those skilled in the art from the following detailed description of preferred embodiments.

[0120] I. Preparation of Compounds

[0121] 1. General preparation method

[0122] The compounds described in this invention can be synthesized according to the synthetic schemes described herein and / or techniques well known in the art. For example, the compounds provided by this invention can be prepared according to the following general synthetic methods.

[0123] In a general synthetic method, the compound shown in formula (II) is prepared according to scheme-1.

[0124] Option-1

[0125] Specifically, in Scheme-1, the 4-methylquinazoline derivatives of the present invention can be prepared by a 6-step reaction. For example, starting with compound A, compound B is prepared by a coupling reaction; compound B is prepared by a halogenation reaction; compound C is prepared by a cyclization reaction; compound E is prepared by an alkylation reaction and an acylation reaction; compound F is prepared by a Miyaura borosilicate reaction; and compound D and compound G are prepared by a coupling reaction to obtain the 4-methylquinazoline derivatives shown in formula (II).

[0126] In a general synthetic method, the compound shown in formula (III) is prepared according to scheme-2.

[0127] Option 2

[0128] Specifically, in Scheme-2, the 4-methylquinazoline derivatives of the present invention can be prepared by a three-step reaction. For example, starting with compound H, compound I' is prepared by a substitution reaction; compound I' is prepared by a Miyaura borate esterification reaction; and compound J and compound D are coupled to prepare the 4-methylquinazoline derivatives shown in formula (III).

[0129] Those skilled in the art will recognize that the synthetic methods of some embodiments described in detail herein can be readily applied to the synthesis of other embodiments. In some embodiments, the compounds described herein can be prepared by appropriate combinations of synthetic methods well known in the art. Many starting materials and other reagents are available from commercial suppliers, such as Alfaisa (China) Chemical Co., Ltd., or can be readily prepared using synthetic methods commonly used in the art.

[0130] 1 H NMR spectra are recorded on instruments operating at 400 MHz or 500 MHz. 1 ¹H NMR spectra were obtained in solution form (reported in ppm), using CDCl₃ (7.26 ppm), DMSO-d₆ (2.50 ppm), or the internal standard tetramethylsilane (0.00 ppm) as reference standards. When reporting peak multiplicity, the following abbreviations were used: s (singleton), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad peak), dd (doublet), dt (doubletuplet). Coupling constants were given in Hertz (Hz).

[0131] In the following preparation methods and examples, "Me" refers to methyl, "PE" refers to petroleum ether, "EA" refers to ethyl acetate, "DCM" refers to dichloromethane, "MeOH" refers to methanol, "DMSO-d6" refers to deuterated dimethyl sulfoxide, "equiv" refers to equivalent, "PdCl2(dppf)" refers to 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride, "HCl" refers to hydrochloric acid, "TFA" refers to trifluoroacetic acid, "rt" refers to room temperature, "M" refers to moles per liter, "mL" refers to milliliters, "μL" refers to microliters, "mmol" refers to millimoles, "nM" refers to nanomoles, and "℃" refers to degrees Celsius.

[0132] 2. Intermediate Synthesis

[0133] Synthesis of intermediate B: Intermediate B1: 1-(2-amino-5-(6-methoxypyridin-3-yl)phenyl)ethyl-1-one

[0134] A mixture of 1-(2-amino-5-bromophenyl)ethyl-1-one (428 mg, 2 mmol), 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridine (564 mg, 2.4 mmol), and 2M potassium carbonate aqueous solution (3 mL, 6 mmol, 3.0 equiv) in dioxane (10 mL) was degassed, and then [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (146 mg, 0.2 mmol, 0.1 equiv) was added. The resulting reaction mixture was degassed and purged with argon (three cycles), and then stirred at 100°C under an argon atmosphere for 5 hours. The reaction mixture was cooled to room temperature, and volatiles were removed under reduced pressure. The residue was diluted with water (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with water (30 mL × 2) and brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by rapid column chromatography (silica gel, MeOH / DCM = 1 / 20) to give a yellow solid (368 mg, yield 76%).

[0135] 1 H NMR (400 MHz, DMSO- d 6) δ 8.44 (d, J = 2.6 Hz, 1H), 7.98 (dd, J =8.6, 2.6 Hz, 1H), 7.95 (d, J = 2.2 Hz, 1H), 7.57 (dd, J = 8.7, 2.2 Hz, 1H), 7.29 (s, 2H), 6.90 – 6.82 (m, 2H), 3.87 (s, 3H), 2.60 (s, 3H).

[0136] Intermediate B2: 1-(2-amino-5-(6-methoxy-5-methylpyridin-3-yl)phenyl)ethyl-1-one

[0137] The title compound was prepared from 1-(2-amino-5-bromophenyl)ethyl-1-one following the synthetic steps of intermediate B1.

[0138] 1 H NMR (400 MHz, DMSO- d 6) δ 8.26 (d, J = 2.4 Hz, 1H), 7.94 (d, J= 2.2Hz, 1H), 7.83 (d, J = 2.5 Hz, 1H), 7.56 (dd, J = 8.6, 2.2 Hz, 1H), 7.27 (s,2H), 6.85 (d, J = 8.7 Hz, 1H), 3.90 (s, 3H), 2.60 (s, 3H), 2.20 (s, 3H).

[0139] Intermediate B3: 1-(2-amino-5-(5,6-dimethoxypyridin-3-yl)phenyl)ethyl-1-one

[0140] The title compound was prepared from 1-(2-amino-5-bromophenyl)ethyl-1-one following the synthetic steps of intermediate B1.

[0141] 1 H NMR (400 MHz, DMSO- d 6) δ 7.95 (d, J = 1.9 Hz, 2H), 7.60 (dd, J =8.7, 2.0 Hz, 1H), 7.48 (d, J = 1.8 Hz, 1H), 7.30 (s, 2H), 6.86 (d, J = 8.7Hz, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 2.61 (s, 3H).

[0142] Intermediate B4: 1-(2-amino-5-(5-fluoro-6-methoxypyridin-3-yl)phenyl)ethyl-1-one

[0143] The title compound was prepared from 1-(2-amino-5-bromophenyl)ethyl-1-one following the synthetic steps of intermediate B1.

[0144] 1 H NMR (400 MHz, ) δ 8.34 (d, J = 1.8 Hz, 1H), 8.08 (dd, J = 12.3, 2.2 Hz, 1H), 8.04 (d, J = 2.4 Hz, 1H), 7.67 (dd, J= 8.7, 1.9 Hz, 1H), 7.35(s, 2H), 6.91 (d, J = 8.7 Hz, 1H), 4.02 (s, 3H), 2.67 (s, 3H).

[0145] Intermediate B5: 1-(2-amino-5-(5-chloro-6-methoxypyridin-3-yl)phenyl)ethyl-1-one

[0146] The title compound was prepared from 1-(2-amino-5-bromophenyl)ethyl-1-one following the synthetic steps of intermediate B1.

[0147] 1 H NMR (400 MHz, DMSO- d 6) δ 8.42 (d, J = 2.2 Hz, 1H), 8.21 (d, J = 2.2Hz, 1H), 7.99 (d, J = 2.2 Hz, 1H), 7.62 (dd, J = 8.7, 2.2 Hz, 1H), 7.34 (s,2H), 6.85 (d, J = 8.7 Hz, 1H), 3.96 (s, 3H), 2.62 (s, 3H).

[0148] Intermediate B6: 1-(2-amino-5-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)phenyl)ethyl-1-one

[0149] The title compound was prepared from 1-(2-amino-5-bromophenyl)ethyl-1-one following the synthetic steps of intermediate B1.

[0150] 1 H NMR (400 MHz, DMSO- d 6) δ 8.72 (d, J = 2.5 Hz, 1H), 8.27 (d, J = 2.5Hz, 1H), 8.03 (d, J = 2.2 Hz, 1H), 7.65 (dd, J = 8.7, 2.2 Hz, 1H), 7.36 (s,2H), 6.88 (d, J= 8.7 Hz, 1H), 4.01 (s, 3H), 2.62 (s, 3H).

[0151] Intermediate B7: 1-(2-amino-5-(2-methoxypyrimidin-5-yl)phenyl)ethyl-1-one

[0152] The title compound was prepared from 1-(2-amino-5-bromophenyl)ethyl-1-one following the synthetic steps of intermediate B1.

[0153] 1 H NMR (400 MHz, DMSO- d 6) δ 8.90 (s, 2H), 8.03 (d, J = 1.8 Hz, 1H), 7.63 (dd, J = 8.7, 1.9 Hz, 1H), 7.37 (s, 2H), 6.88 (d, J = 8.7 Hz, 1H), 3.94(s, 3H), 2.61 (s, 3H).

[0154] Synthesis of intermediate C: Intermediate C1: 1-(2-amino-3-bromo-5-(6-methoxypyridin-3-yl)phenyl)ethane-1-one

[0155] 1-(2-amino-5-(6-methoxypyridin-3-yl)phenyl)ethyl-1-one (484 mg, 2 mmol) and NBS (374 mg, 2.1 mmol) were added to dichloromethane (10 mL) and stirred overnight at room temperature. The mixture was diluted with 50 mL of water and extracted with dichloromethane (50 mL × 3). The combined organic layers were washed with water (50 mL × 2) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by rapid column chromatography (silica gel, EA / PE = 1 / 9, v / v) to give a yellow solid (366 mg, 57% yield).

[0156] 1 H NMR (400 MHz, DMSO- d 6) δ 8.49 (d, J = 2.6 Hz, 1H), 8.08 – 8.01 (m,2H), 8.00 (d, J = 2.1 Hz, 1H), 6.88 (d, J= 8.7 Hz, 1H), 3.88 (s, 3H), 2.68(s, 3H).

[0157] Intermediate C2: 1-(2-amino-3-bromo-5-(6-methoxy-5-methylpyridin-3-yl)phenyl)ethyl-1-one

[0158] The title compound was prepared from intermediate B2 following the synthetic steps of intermediate C1.

[0159] 1 H NMR (400 MHz, DMSO- d 6) δ 8.31 (d, J = 2.5 Hz, 1H), 8.06 (d, J = 2.1Hz, 1H), 7.99 (d, J = 2.1 Hz, 1H), 7.89 (d, J = 2.4 Hz, 1H), 7.28 (s, 2H), 3.91 (s, 3H), 2.68 (s, 3H), 2.21 (s, 3H).

[0160] Intermediate C3: 1-(2-amino-3-bromo-5-(5,6-dimethoxypyridin-3-yl)phenyl)ethyl-1-one

[0161] The title compound was prepared from intermediate B3 following the synthetic steps of intermediate C1.

[0162] 1 H NMR (400 MHz, DMSO- d 6) δ 8.10 – 8.03 (m, 2H), 8.01 (d, J = 1.9 Hz, 1H), 7.54 (d, J = 1.8 Hz, 1H), 7.31 (s, 2H), 3.89 (s, 6H), 2.69 (s, 3H).

[0163] Intermediate C4: 1-(2-amino-3-bromo-5-(5-fluoro-6-methoxypyridin-3-yl)phenyl)ethyl-1-one

[0164] The title compound was prepared from intermediate B4 following the synthetic steps of intermediate C1.

[0165] 1 H NMR (400 MHz, DMSO- d 6) δ 8.34 (d, J = 2.2 Hz, 1H), 8.16 – 8.07 (m,2H), 8.05 (d, J = 2.2 Hz, 1H), 7.35 (s, 2H), 3.97 (s, 3H), 2.68 (s, 3H).

[0166] Intermediate C5: 1-(2-amino-3-bromo-5-(5-chloro-6-methoxypyridin-3-yl)phenyl)ethyl-1-one

[0167] The title compound was prepared from intermediate B5 following the synthetic steps of intermediate C1.

[0168] 1 H NMR (400 MHz, DMSO- d 6) δ 8.48 (d, J = 2.3 Hz, 1H), 8.30 (d, J = 2.2Hz, 1H), 8.10 (d, J = 2.1 Hz, 1H), 8.07 (d, J = 2.1 Hz, 1H), 7.36 (s, 2H), 3.97 (s, 3H), 2.69 (s, 3H).

[0169] Intermediate C6: 1-(2-amino-3-bromo-5-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)phenyl)ethyl-1-one

[0170] The title compound was prepared from intermediate B6 following the synthetic steps of intermediate C1.

[0171] 1 H NMR (400 MHz, DMSO- d 6) δ 8.77 (d, J = 2.5 Hz, 1H), 8.36 (d, J = 2.5Hz, 1H), 8.22 – 8.06 (m, 2H), 7.37 (s, 2H), 4.02 (s, 3H), 2.69 (s, 3H).

[0172] Intermediate C7: 1-(2-amino-3-bromo-5-(2-methoxypyrimidin-5-yl)phenyl)ethyl-1-one

[0173] The title compound was prepared from intermediate B7 following the synthetic steps of intermediate C1.

[0174] 1 H NMR (400 MHz, DMSO- d 6) δ 8.95 (s, 2H), 8.14 (d, J = 1.6 Hz, 1H), 8.09 (d, J = 2.1 Hz, 1H), 7.39 (s, 2H), 3.95 (s, 3H), 2.68 (s, 3H).

[0175] Synthesis of intermediate D: Intermediate D1: 8-bromo-6-(6-methoxypyridin-3-yl)-4-methylquinazoline-2-amine

[0176] 1-(2-amino-3-bromo-5-(6-methoxypyridin-3-yl)phenyl)ethane-1-one (450 mg, 1.4 mmol) was added to a 50% aqueous cyanamide solution (14 mL), followed by concentrated hydrochloric acid (3.5 mL). The mixture was stirred at 120°C for 20 minutes, and the reaction mixture was cooled to room temperature. The pH was adjusted to 8 with sodium hydroxide solution, and the mixture was filtered and the filter cake was washed. The filtrate was collected and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with water (50 mL × 2) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by rapid column chromatography (silica gel, MeOH / DCM = 1 / 20, v / v) to give the product as a yellow solid (170 mg, yield 35%).

[0177] 1 H NMR (400 MHz, DMSO- d 6) δ 8.62 (d, J = 2.5 Hz, 1H), 8.32 (d, J = 1.9Hz, 1H), 8.18 (d, J = 1.8 Hz, 1H), 8.18 – 8.14 (m, 1H), 7.11 (s, 2H), 6.93(d, J= 8.6 Hz, 1H), 3.91 (s, 3H), 2.81 (s, 3H).

[0178] Intermediate D2: 8-bromo-6-(6-methoxy-5-methylpyridin-3-yl)-4-methylquinazoline-2-amine

[0179] The title compound was prepared from intermediate C2 following the synthetic steps of intermediate D1.

[0180] 1 H NMR (400 MHz, DMSO- d 6) δ 8.48 – 8.43 (m, 2H), 8.33 (d, J = 1.7 Hz,1H), 8.22 – 8.17 (m, 1H), 8.07 – 8.02 (m, 2H), 7.10 (s, 2H), 3.95 (s, 3H), 2.83 (s, 3H), 2.25 (s, 3H).

[0181] Intermediate D3: 8-bromo-6-(5,6-dimethoxypyridin-3-yl)-4-methyl-quinazolin-2-amine

[0182] The title compound was prepared from intermediate C3 following the synthetic steps of intermediate D1.

[0183] 1 H NMR (400 MHz, ) δ 8.42 (d, J = 2.0 Hz, 1H), 8.24 (d, J = 2.0 Hz, 1H), 8.18 (d, J = 2.1 Hz, 1H), 7.71 (d, J = 2.1 Hz, 1H), 7.14 (s, 2H), 3.97 (s, 3H), 3.96 (s, 3H), 2.87 (s, 3H).

[0184] Intermediate D4: 8-bromo-6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazoline-2-amine

[0185] The title compound was prepared from intermediate C4 following the synthetic steps of intermediate D1.

[0186] 1 H NMR (400 MHz, DMSO- d 6) δ 8.48 (d, J = 2.1 Hz, 1H), 8.38 (d, J = 2.0Hz, 1H), 8.31 – 8.21 (m, 2H), 7.14 (s, 2H), 4.00 (s, 3H), 2.81 (s, 3H).

[0187] Intermediate D5: 8-bromo-6-(5-chloro-6-methoxypyridin-3-yl)-4-methylquinazoline-2-amine

[0188] The title compound was prepared from intermediate C5 following the synthetic steps of intermediate D1.

[0189] 1 H NMR (400 MHz, DMSO- d 6) δ 8.60 (d, J = 2.3 Hz, 1H), 8.44 (d, J = 2.3Hz, 1H), 8.39 (d, J = 2.0 Hz, 1H), 8.25 (d, J = 2.0 Hz, 1H), 7.12 (s, 2H), 4.00 (s, 3H), 2.82 (s, 3H).

[0190] Intermediate D6: 8-bromo-6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-4-methylquinazoline-2-amine

[0191] The title compound was prepared from intermediate C6 following the synthetic steps of intermediate D1.

[0192] 1 H NMR (400 MHz, DMSO- d 6) δ 8.88 (d, J = 2.5 Hz, 1H), 8.49 (d, J = 2.5Hz, 1H), 8.43 (d, J = 2.0 Hz, 1H), 8.28 (d, J= 2.0 Hz, 1H), 7.14 (s, 2H), 4.05 (s, 3H), 2.82 (s, 3H).

[0193] Intermediate D7: 8-bromo-6-(2-methoxypyrimidin-5-yl)-4-methylquinazoline-2-amine

[0194] The title compound was prepared from intermediate C7 following the synthetic steps of intermediate D1.

[0195] Synthesis of intermediate F: Intermediate F1: 1-(4-(5-bromo-2-methylphenyl)piperazin-1-yl)ethane-1-one

[0196] 5-Bromo-2-methylaniline (3.721 g, 20 mmol) and di(2-chloroethyl)amine hydrochloride (3.57 g, 20 mmol) were added to 10 mL of diethylene glycol monomethyl ether and stirred at 150°C for 12 hours. The reaction mixture was cooled to room temperature, and the residue was diluted with dichloromethane (100 mL). Acetic anhydride (3.757 mL, 40 mmol) and triethylamine (13.861 mL, 100 mmol) were added, and the mixture was stirred overnight at room temperature. Extraction was performed with dichloromethane (100 mL × 3). The combined organic layers were washed with water (100 mL × 2) and brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by rapid column chromatography (silica gel, EA / PE = 2 / 1, v / v) to give a product as a yellowish-white solid (2.511 g, 42% yield).

[0197] 1 H NMR (400 MHz, DMSO- d 6) δ 7.19 – 7.13 (m, 2H), 7.11 (d, J = 1.8 Hz,1H), 3.67 – 3.49 (m, 4H), 2.84 (t, J = 4.9 Hz, 2H), 2.77 (t, J = 5.1 Hz, 2H), 2.22 (s, 3H), 2.04 (s, 3H).

[0198] Intermediate F2: 1-(4-(5-bromo-2-methoxyphenyl)piperazin-1-yl)ethyl-1-one

[0199] The title compound was prepared from 5-bromo-2-methoxyaniline following the synthetic steps of intermediate F1.

[0200] 1 H NMR (400 MHz, DMSO- d 6) δ 7.13 (dd, J = 8.6, 2.4 Hz, 1H), 6.95 (d, J = 2.5 Hz, 1H), 6.91 (d, J = 8.7 Hz, 1H), 3.78 (s, 3H), 3.58 – 3.49 (m, 4H), 2.96 (t, J = 5.0 Hz, 2H), 2.89 (t, J = 5.1 Hz, 2H), 2.02 (s, 3H).

[0201] Intermediate F3: 1-(4-(5-bromo-2-fluorophenyl)piperazin-1-yl)ethane-1-one

[0202] The title compound was prepared from 5-bromo-2-fluoroaniline following the synthetic steps of intermediate F1.

[0203] 1 H NMR (400 MHz, DMSO- d 6) δ 7.20 – 7.10 (m, 3H), 3.63 – 3.51 (m, 4H), 3.03 (t, J = 5.1 Hz, 2H), 2.97 (t, J = 5.2 Hz, 2H), 2.03 (s, 3H).

[0204] Intermediate F4: 1-(4-(5-bromo-2-chlorophenyl)piperazin-1-yl)ethane-1-one

[0205] The title compound was prepared from 5-bromo-2-chloroaniline following the synthetic steps of intermediate F1.

[0206] 1 H NMR (400 MHz, DMSO- d 6) δ 7.39 (d, J= 8.3 Hz, 1H), 7.32 – 7.19 (m,2H), 3.70 – 3.50 (m, 4H), 2.99 (t, J = 4.9 Hz, 2H), 2.93 (t, J = 5.1 Hz (2H), 2.04 (s, 3H).

[0207] Intermediate F5: 1-(4-(5-bromo-2-(trifluoromethyl)phenyl)piperazin-1-yl)ethane-1-one

[0208] The title compound was prepared from 5-bromo-2-trifluoromethylaniline following the synthetic steps of intermediate F1.

[0209] 1 H NMR (400 MHz, DMSO- d 6) δ 7.76 (d, J = 1.9 Hz, 1H), 7.63 (d, J = 8.5Hz, 1H), 7.60 – 7.53 (m, 1H), 3.64 – 3.43 (m, 4H), 2.89 (t, J = 4.9 Hz, 2H), 2.83 (t, J = 5.1 Hz, 2H), 2.04 (s, 3H).

[0210] Synthesis of intermediates I1-I16: Intermediate I1: 1-(4-(3-bromophenyl)piperazin-1-yl)ethyl-1-one

[0211] 1-(3-bromophenyl)piperazine hydrochloride (277 mg, 1 mmol), DCM (5 mL), acetic anhydride (113 μL, 1.2 mmol), and triethylamine (334 μL) were added sequentially to a round-bottom flask. The mixture was stirred at room temperature and monitored by TLC until the reaction was complete. The reaction solution was diluted with water (30 mL) and extracted with dichloromethane (30 mL × 3). The combined organic layers were washed with water (30 mL × 2) and brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by rapid column chromatography (silica gel, EA / PE = 1 / 3, v / v) to give a product as a yellowish-white solid (282 mg, 98% yield).

[0212] 1H NMR (400 MHz, ) δ 7.19 – 7.12 (m, 1H), 7.09 (t, J = 2.2 Hz, 1H), 6.98 – 6.91 (m, 2H), 3.57 – 3.52 (m, 4H), 3.23 – 3.17 (m, 2H), 3.16 – 3.08(m, 2H), 2.03 (s, 3H).

[0213] Intermediate I2: 2-(4-acetylpiperazin-1-yl)-4-bromobenzonitrile

[0214] 4-Bromo-2-fluorobenzonitrile (2 g, 10 mmol) and 4-acetylpiperazine (2.563 g, 20 mmol) were added to 5 mL of acetonitrile and stirred overnight at 110°C. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with water (100 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with water (50 mL × 2) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by rapid column chromatography (silica gel, EA / PE = 7 / 3, v / v) to give a product as a pale yellow solid (2.711 g, 88% yield).

[0215] 1 H NMR (400 MHz, DMSO- d 6) δ 7.69 (d, J = 8.2 Hz, 1H), 7.42 – 7.26 (m,2H), 3.74 – 3.49 (m, 4H), 3.23 (t, J = 5.0 Hz, 2H), 3.16 (t, J = 5.1 Hz (2H), 2.06 (s, 3H).

[0216] Intermediate I3: 4-bromo-2-(piperidin-1-yl)benzonitrile

[0217] The title compound was prepared from 4-bromo-2-fluorobenzonitrile following the synthetic steps of intermediate I2.

[0218] 1 H NMR (400 MHz, DMSO- d 6) δ 7.62 (d, J = 8.2 Hz, 1H), 7.28 (d,J = 1.8Hz, 1H), 7.23 (dd, J = 8.3, 1.8 Hz, 1H), 3.13 (t, J = 5.3 Hz, 4H), 1.71 –1.61 (m, 4H), 1.60 – 1.49 (m, 2H).

[0219] Intermediate I4: 4-bromo-2-(4-methoxypiperidin-1-yl)benzonitrile

[0220] The title compound was prepared from 4-bromo-2-fluorobenzonitrile following the synthetic steps of intermediate I2.

[0221] 1 H NMR (400 MHz, DMSO- d 6) δ 7.62 (d, J = 8.2 Hz, 1H), 7.31 (d, J = 1.8Hz, 1H), 7.24 (dd, J = 8.3, 1.5 Hz, 1H), 3.41 – 3.33 (m, 3H), 3.27 (s, 3H), 3.05 – 2.93 (m, 2H), 2.02 – 1.90 (m, 2H), 1.66 – 1.53 (m, 2H).

[0222] Intermediate I5: 4-bromo-2-(4-hydroxypiperidin-1-yl)benzonitrile

[0223] The title compound was prepared from 4-bromo-2-fluorobenzonitrile following the synthetic steps of intermediate I2.

[0224] 1 H NMR (400 MHz, DMSO- d 6) δ 7.62 (d, J = 8.2 Hz, 1H), 7.30 (d, J = 1.9Hz, 1H), 7.22 (dd, J = 8.2, 1.8 Hz, 1H), 4.75 (d, J= 4.3 Hz, 1H), 3.70 –3.60 (m, 1H), 3.46 – 3.35 (m, 2H), 3.01 – 2.90 (m, 2H), 1.92 – 1.79 (m, 2H),1.61 – 1.46 (m, 2H).

[0225] Intermediate I6: 4-bromo-2-(4-hydroxy-4-methylpiperidin-1-yl)benzonitrile

[0226] The title compound was prepared from 4-bromo-2-fluorobenzonitrile following the synthetic steps of intermediate I2.

[0227] 1 H NMR (400 MHz, DMSO- d 6) δ 7.60 (d, J = 8.2 Hz, 1H), 7.31 (d, J = 1.8Hz, 1H), 7.21 (dd, J = 8.3, 1.8 Hz, 1H), 4.37 (s, 1H), 3.28 – 3.11 (m, 4H), 1.67 – 1.57 (m, 4H), 1.18 (s, 3H).

[0228] Intermediate I7: 4-bromo-2-(4-(2-hydroxypropane-2-yl)piperidin-1-yl)benzonitrile

[0229] The title compound was prepared from 4-bromo-2-fluorobenzonitrile following the synthetic steps of intermediate I2.

[0230] 1 H NMR (400 MHz, DMSO- d 6) δ 7.61 (d, J = 8.2 Hz, 1H), 7.28 (d, J = 1.8Hz, 1H), 7.22 (dd, J = 8.3, 1.8 Hz, 1H), 4.17 (s, 1H), 3.67 – 3.53 (m, 2H), 2.74 (t, J = 11.6 Hz, 2H), 1.86 – 1.73 (m, 2H), 1.47 – 1.25 (m, 3H), 1.07 (s, 6H).

[0231] Intermediate I8: 4-(5-bromo-2-cyanophenyl)piperazine-1-carboxylic acid tert-butyl ester

[0232] The title compound was prepared from 4-bromo-2-fluorobenzonitrile following the synthetic steps of intermediate I2.

[0233] 1 H NMR (400 MHz, DMSO- d 6) δ 7.67 (d, J = 8.2 Hz, 1H), 7.34 (d, J = 1.8Hz, 1H), 7.31 (dd, J = 8.2, 1.8 Hz, 1H), 3.54 – 3.41 (m, 4H), 3.21 – 3.08 (m, 4H), 1.42 (s, 9H).

[0234] Intermediate I9: 4-bromo-2-(4-ethylpiperazin-1-yl)benzonitrile

[0235] The title compound was prepared from 4-bromo-2-fluorobenzonitrile following the synthetic steps of intermediate I2.

[0236] 1 H NMR (400 MHz, DMSO- d 6) δ 7.63 (d, J = 8.3 Hz, 1H), 7.30 (d, J = 3.2Hz, 1H), 7.26 (dd, J = 8.2, 3.2 Hz, 1H), 3.18 (t, J = 4.9 Hz, 4H), 2.55 –2.51 (m, 4H), 2.38 (q, J = 7.1 Hz, 2H), 1.02 (t, J = 7.2 Hz, 3H).

[0237] Intermediate I10: 4-bromo-2-(4-isopropylpiperazin-1-yl)benzonitrile

[0238] The title compound was prepared from 4-bromo-2-fluorobenzonitrile following the synthetic steps of intermediate I2.

[0239] 1 H NMR (400 MHz, DMSO- d 6) δ 7.63 (d, J = 8.2 Hz, 1H), 7.29 (d, J = 1.8Hz, 1H), 7.25 (dd, J = 8.2, 1.8 Hz, 2H), 3.17 (t, J = 4.7 Hz, 4H), 2.76 –2.64 (m, 1H), 2.59 (t, J = 4.8 Hz, 4H), 1.00 (d, J = 6.5 Hz, 6H).

[0240] Intermediate I11: 4-bromo-2-(4-cyclopropylpiperazin-1-yl)benzonitrile

[0241] The title compound was prepared from 4-bromo-2-fluorobenzonitrile following the synthetic steps of intermediate I2.

[0242] 1 H NMR (400 MHz, DMSO- d 6) δ 7.64 (d, J = 8.1 Hz, 1H), 7.28 (d, J = 1.8Hz, 1H), 7.26 (dd, J = 8.2, 1.8 Hz, 1H), 3.14 (t, J = 4.8 Hz, 4H), 2.69 (t, J = 4.8 Hz, 4H), 1.74 – 1.65 (m, 1H), 0.44 (dt, J = 6.2, 3.0 Hz, 2H), 0.37 –0.29 (m, 2H).

[0243] Intermediate I12: 4-bromo-2-(4-cyclopentylpiperazin-1-yl)benzonitrile

[0244] The title compound was prepared from 4-bromo-2-fluorobenzonitrile following the synthetic steps of intermediate I2.

[0245] 1 H NMR (400 MHz, DMSO- d6) δ 7.63 (d, J = 8.2 Hz, 1H), 7.28 (d, J = 1.8Hz, 1H), 7.26 (dd, J = 8.2, 1.9 Hz, 1H), 3.18 (t, J = 4.8 Hz, 4H), 2.56 (t, J = 4.8 Hz, 4H), 2.52 (s, 1H), 1.86 – 1.74 (m, 2H), 1.68 – 1.44 (m, 4H), 1.43 –1.24 (m, 2H).

[0246] Intermediate I13: 4-bromo-2-(4-phenylpiperazin-1-yl)benzonitrile

[0247] The title compound was prepared from 4-bromo-2-fluorobenzonitrile following the synthetic steps of intermediate I2.

[0248] 1 H NMR (400 MHz, DMSO- d 6) δ 7.68 (d, J = 8.2 Hz, 1H), 7.39 (d, J = 1.9Hz, 1H), 7.31 (dd, J = 8.3, 1.8 Hz, 1H), 7.28 – 7.20 (m, 2H), 7.03 – 6.97 (m,2H), 6.82 (t, J = 7.2 Hz, 1H), 3.37 – 3.33 (m, 4H), 3.32 – 3.28 (m, 4H).

[0249] Intermediate I14: 4-bromo-2-(4-(pyridin-2-yl)piperazin-1-yl)benzonitrile

[0250] The title compound was prepared from 4-bromo-2-fluorobenzonitrile following the synthetic steps of intermediate I2.

[0251] 1 H NMR (400 MHz, DMSO- d 6) δ 8.14 (dd, J = 4.8, 2.1 Hz, 1H), 7.68 (d,J = 8.2 Hz, 1H), 7.57 (ddd, J = 8.9, 7.1, 2.0 Hz, 1H), 7.38 (d, J = 2.0 Hz, 1H), 7.30 (dd, J = 8.3, 1.9 Hz, 1H), 6.90 (d, J = 8.6 Hz, 1H), 6.68 (dd, J =7.2, 4.9 Hz, 1H), 3.66 (t, J = 4.9 Hz, 4H), 3.34 – 3.29 (m, 4H).

[0252] Intermediate I15: 4-bromo-2-(4-(pyrimidin-2-yl)piperazin-1-yl)benzonitrile

[0253] The title compound was prepared from 4-bromo-2-fluorobenzonitrile following the synthetic steps of intermediate I2.

[0254] 1 H NMR (400 MHz, DMSO- d 6) δ 8.40 (d, J = 4.7 Hz, 2H), 7.68 (d, J = 8.3Hz, 1H), 7.37 (d, J = 1.9 Hz, 1H), 7.31 (dd, J = 8.2, 1.9 Hz, 1H), 6.68 (t, J = 4.7 Hz, 1H), 3.90 (t, J = 5.0 Hz, 4H), 3.26 (t, J = 5.0 Hz, 4H).

[0255] Intermediate I16: 4-bromo-2-morpholinobenzonitrile

[0256] The title compound was prepared from 4-bromo-2-fluorobenzonitrile following the synthetic steps of intermediate I2.

[0257] 1 H NMR (400 MHz, DMSO- d 6) δ 7.67 (d, J= 8.2 Hz, 1H), 7.34 (d, J = 1.8Hz, 1H), 7.31 (dd, J = 8.2, 1.8 Hz, 1H), 3.79 – 3.71 (m, 4H), 3.22 – 3.13 (m, 4H).

[0258] General synthesis methods for intermediates G and J: Method 2: A mixture of substituted aryl bromide (F or I') (1.0 equivalent), bis(pinacol)diboron (1.2 equivalent), potassium acetate (2.0 equivalent), and PdCl2(dppf) (0.05–0.10 equivalent) in 1,4-dioxane was degassed and backfilled with argon (three cycles). The reaction mixture was stirred at 100°C for 5 hours under an argon atmosphere, then cooled to room temperature and filtered. The filtrate was concentrated, and the resulting residue was used directly for the next step without purification.

[0259] Intermediate G1: 1-(4-(2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborphanecyclopentan-2-yl)phenyl)piperazin-1-yl)ethane-1-one)

[0260] The title compound was prepared from intermediate F1 according to method 2.

[0261] Intermediate G2: 1-(4-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)piperazin-1-yl)ethyl-1-one

[0262] The title compound was prepared from intermediate F2 according to method 2.

[0263] Intermediate G3: 1-(4-(2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)piperazin-1-yl)ethane-1-one)

[0264] The title compound was prepared from intermediate F3 according to method 2.

[0265] Intermediate G4: 1-(4-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)piperazin-1-yl)ethane-1-one)

[0266] The title compound was prepared from intermediate F4 according to method 2.

[0267] Intermediate G5: 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborphanecyclopentan-2-yl)-2-(trifluoromethyl)phenyl)piperazin-1-yl)ethane-1-one

[0268] The title compound was prepared from intermediate F5 according to method 2.

[0269] Intermediate J1: 1-(4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)piperazin-1-yl)ethyl-1-one)

[0270] The title compound was prepared from intermediate I1 according to method 2.

[0271] Intermediate J2: 2-(4-acetylpiperazin-1-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzonitrile

[0272] The title compound was prepared from intermediate I2 according to method 2.

[0273] Intermediate J3: 2-(piperidin-1-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzonitrile

[0274] The title compound was prepared from intermediate I3 according to method 2.

[0275] Intermediate J4: 2-(4-methoxypiperidin-1-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)benzonitrile

[0276] The title compound was prepared from intermediate I4 according to method 2.

[0277] Intermediate J5: 2-(4-hydroxypiperidin-1-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzonitrile

[0278] The title compound was prepared from intermediate I5 according to method 2.

[0279] Intermediate J6: 2-(4-hydroxy-4-methylpiperidin-1-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)benzonitrile

[0280] The title compound was prepared from intermediate I6 according to method 2.

[0281] Intermediate J7: 2-(4-(2-hydroxypropane-2-yl)piperidin-1-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)benzonitrile

[0282] The title compound was prepared from intermediate I7 ​​according to method 2.

[0283] Intermediate J8: 4-(2-cyano-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)piperazine-1-carboxylic acid tert-butyl ester

[0284] The title compound was prepared from intermediate I8 according to method 2.

[0285] Intermediate J9: 2-(4-ethylpiperazin-1-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)benzonitrile

[0286] The title compound was prepared from intermediate I9 according to method 2.

[0287] Intermediate J10: 2-(4-isopropylpiperazin-1-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)benzonitrile

[0288] The title compound was prepared from intermediate I10 according to method 2.

[0289] Intermediate J11: 2-(4-cyclopropylpiperazin-1-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)benzonitrile

[0290] The title compound was prepared from intermediate I11 according to method 2.

[0291] Intermediate J12: 2-(4-cyclopentylpiperazin-1-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)benzonitrile

[0292] The title compound was prepared from intermediate I12 according to method 2.

[0293] Intermediate J13: 2-(4-phenylpiperazin-1-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)benzonitrile

[0294] The title compound was prepared from intermediate I13 according to method 2.

[0295] Intermediate J14: 2-(4-(pyridin-2-yl)piperazin-1-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzonitrile

[0296] The title compound was prepared from intermediate I14 according to method 2.

[0297] Intermediate J15: 2-(4-(pyrimidin-2-yl)piperazin-1-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzonitrile

[0298] The title compound was prepared from intermediate I15 according to method 2.

[0299] Intermediate J16: 2-morpholino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzonitrile

[0300] The title compound was prepared from intermediate I16 according to method 2.

[0301] 3. Synthesis of the compounds in the examples: General synthetic methods for 4-methylquinazoline derivatives: Method 3: A stirred mixture of the key intermediate (D, 1.0 equivalent), arylboronic ester (G or J, 1.2 equivalent), 2 M K₂CO₃ aqueous solution (3.0 equivalent), and PdCl₂(dppf) (0.05–0.10 equivalent) in dioxane was degassed and backfilled with argon (three cycles). The reaction mixture was then stirred at 100 °C for 5 hours under an argon atmosphere. The reaction mixture was cooled to room temperature, and volatiles were removed under reduced pressure. The residue was diluted with water (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with water (30 mL × 2) and brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by rapid column chromatography (silica gel, MeOH / DCM = 1 / 20). The crude product was slurried with methanol overnight, filtered, and the filter cake was collected to obtain the desired compound.

[0302] Method 4: The compound obtained in Method 3 (90 mg, 0.15 mmol), TFA (2.5 mL), and DCM (2.5 mL) were stirred at room temperature for 0.5 hours, then concentrated under reduced pressure, diluted with water (20 mL), and the pH was adjusted to 8 with saturated sodium bicarbonate solution. Extraction was performed with ethyl acetate (30 mL × 3). The combined organic layers were washed with water (30 mL × 2) and brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The mixture was concentrated, and the solid was slurried with methanol overnight. The residue was filtered, and the filter cake was collected to obtain a yellow solid.

[0303] Example 1: 1-(4-(3-(2-amino-6-(6-methoxypyridin-3-yl)-4-methyl-quinazolin-8-yl)phenyl)piperazin-1-yl)ethyl-1-one

[0304] The title compound was prepared from intermediates D1 and J1 according to method 3.

[0305] 1 H NMR (400 MHz, DMSO- d 6) δ 8.65 (d, J = 2.3 Hz, 1H), 8.20 (dd, J =8.5, 2.5 Hz, 1H), 8.16 (s, 1H), 7.90 (s, 1H), 7.30 (t, J = 7.9 Hz, 1H), 7.27(s, 1H), 7.14 (d, J = 7.6 Hz, 1H), 6.97 (d, J= 7.5 Hz, 1H), 6.93 (d, J = 8.5Hz, 1H), 6.68 (s, 2H), 3.91 (s, 3H), 3.67 – 3.49 (m, 4H), 3.25 – 3.18 (m,2H), 3.18 – 3.05 (m, 2H), 2.83 (s, 3H), 2.04 (s, 3H).

[0306] Example 2: 1-(4-(5-(2-amino-6-(6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)-2-fluorophenyl)piperazin-1-yl)ethyl-1-one

[0307] The title compound was prepared from intermediate D1 and intermediate G3 according to method 3.

[0308] 1 H NMR (400 MHz, DMSO- d 6) δ 8.65 (d, J = 2.6 Hz, 1H), 8.20 (dd, J =8.7, 2.6 Hz, 1H), 8.16 (d, J = 2.1 Hz, 1H), 7.94 (d, J = 2.1 Hz, 1H), 7.41(dd, J = 8.8, 2.1 Hz, 1H), 7.37 – 7.28 (m, 1H), 7.22 (dd, J = 12.5, 8.3 Hz, 1H), 6.93 (d, J = 8.6 Hz, 1H), 6.73 (s, 2H), 3.91 (s, 3H), 3.61 (p, J = 3.7Hz, 4H), 3.16 – 3.07 (m, 2H), 3.04 (t, J = 5.1 Hz, 2H), 2.82 (s, 3H), 2.04(s, 3H).

[0309] Example 3: 2-(4-acetylpiperazin-1-yl)-4-(2-amino-6-(6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl)benzonitrile

[0310] The title compound was prepared from intermediates D1 and J2 according to method 3.

[0311] 1 H NMR (500 MHz, DMSO- d 6) δ 8.66 (d, J = 2.6 Hz, 1H), 8.26 – 8.09 (m,2H), 8.02 (d, J = 2.1 Hz, 1H), 7.78 (d, J = 7.9 Hz, 1H), 7.54 (d, J = 1.6 Hz, 1H), 7.47 (dd, J = 7.9, 1.4 Hz, 1H), 6.93 (d, J = 8.6 Hz, 1H), 6.80 (s, 2H), 3.91 (s, 3H), 3.69 – 3.59 (m, 4H), 3.26 (t, J = 5.0 Hz, 2H), 3.20 (t, J = 5.0Hz, 2H), 2.83 (s, 3H), 2.05 (s, 3H).

[0312] Example 4: 1-(4-(3-(2-amino-6-(6-methoxy-5-methylpyridin-3-yl)-4-methyl-quinazolin-8-yl)phenyl)piperazin-1-yl)ethyl-1-one

[0313] The title compound was prepared from intermediate D2 and intermediate J1 according to method 3.

[0314] 1 H NMR (400 MHz, ) δ 8.50 – 8.44 (m, 1H), 8.15 (d, J = 2.1 Hz, 1H), 8.05 (dd, J = 2.5, 0.9 Hz, 1H), 7.90 (d, J = 2.1 Hz, 1H), 7.33 – 7.27 (m,1H), 7.27 – 7.23 (m, 1H), 7.16 – 7.10 (m, 1H), 6.97 (dd, J= 8.3, 1.8 Hz,1H), 6.66 (s, 2H), 3.93 (s, 3H), 3.66 – 3.49 (m, 4H), 3.25 – 3.18 (m, 2H),3.18 – 3.12 (m, 2H), 2.83 (s, 3H), 2.24 (s, 3H), 2.04 (s, 3H).

[0315] Example 5: 1-(4-(5-(2-amino-6-(6-methoxy-5-methylpyridin-3-yl)-4-methylquinazoline-8-yl)-2-fluorophenyl)piperazin-1-yl)acetoone

[0316] The title compound was prepared from intermediates D2 and G3 according to method 3.

[0317] 1 H NMR (400 MHz, DMSO- d 6) δ 8.48 (d, J = 2.6 Hz, 1H), 8.15 (d, J = 2.2Hz, 1H), 8.06 (s, 1H), 7.94 (d, J = 2.3 Hz, 1H), 7.44 – 7.37 (m, 1H), 7.35 –7.27 (m, 1H), 7.22 (dd, J = 12.5, 8.4 Hz, 1H), 6.72 (s, 2H), 3.93 (s, 3H), 3.69 – 3.53 (m, 4H), 3.17 – 3.07 (m, 2H), 3.08 – 2.96 (m, 2H), 2.83 (s, 3H), 2.24 (s, 3H), 2.04 (s, 3H).

[0318] Example 6: 2-(4-acetylpiperazin-1-yl)-4-(2-amino-6-(6-methoxy-5-methylpyridin-3-yl)-4-methylquinazoline-8-yl)benzonitrile

[0319] The title compound was prepared from intermediates D2 and J2 according to method 3.

[0320] 1 H NMR (400 MHz, DMSO- d 6) δ 8.49 (d,J = 2.4 Hz, 1H), 8.21 (d, J = 2.1Hz, 1H), 8.07 (d, J = 2.4 Hz, 1H), 8.02 (d, J = 2.1 Hz, 1H), 7.79 (d, J = 8.0Hz, 1H), 7.52 (d, J = 1.5 Hz, 1H), 7.46 (dd, J = 8.0, 1.5 Hz, 1H), 6.80 (s,2H), 3.93 (s, 3H), 3.71 – 3.56 (m, 4H), 3.26 (t, J = 4.8 Hz, 2H), 3.19 (t, J = 5.1 Hz, 2H), 2.83 (s, 3H), 2.24 (s, 3H), 2.05 (s, 3H).

[0321] Example 7: 1-(4-(3-(2-amino-6-(5,6-dimethoxypyridin-3-yl)-4-methyl-quinazolin-8-yl)phenyl)piperazin-1-yl)ethyl-1-one

[0322] The title compound was prepared from intermediate D3 and intermediate J1 according to method 3.

[0323] 1 H NMR (500 MHz, DMSO- d 6) δ 8.16 – 8.09 (m, 2H), 7.90 (s, 1H), 7.64(s, 1H), 7.28 (t, J = 7.7 Hz, 1H), 7.23 (s, 1H), 7.10 (d, J = 7.1 Hz, 1H), 6.95 (d, J = 7.4 Hz, 1H), 6.64 (s, 2H), 3.89 (s, 6H), 3.62 – 3.49 (m, 4H), 3.18 (t, J = 5.1 Hz, 2H), 3.12 (t, J = 5.3 Hz, 2H), 2.81 (s, 3H), 2.01 (s, 3H).

[0324] Example 8: 1-(4-(3-(2-amino-6-(5-fluoro-6-methoxypyridin-3-yl)-4-methyl-quinazolin-8-yl)phenyl)piperazin-1-yl)ethyl-1-one

[0325] The title compound was prepared from intermediate D4 and intermediate J1 according to method 3.

[0326] 1 H NMR (400 MHz, ) δ 8.50 (d, J = 2.0 Hz, 1H), 8.27 (dd, J = 12.0, 2.1 Hz, 1H), 8.21 (d, J = 2.1 Hz, 1H), 7.94 (d, J = 2.1 Hz, 1H), 7.30 (t, J =7.9 Hz, 1H), 7.29 – 7.24 (m, 1H), 7.18 – 7.12 (m, 1H), 6.98 (dd, J = 8.1, 2.0Hz, 1H), 6.71 (s, 2H), 4.00 (s, 3H), 3.66 – 3.54 (m, J = 2.9, 2.4 Hz, 4H), 3.25 – 3.18 (m, 2H), 3.18 – 3.11 (m, 2H), 2.83 (s, 3H), 2.04 (s, 3H).

[0327] Example 9: 1-(4-(5-(2-amino-6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)-2-fluorophenyl)piperazin-1-yl)acetoone

[0328] The title compound was prepared from intermediate D4 and intermediate G3 according to method 3.

[0329] 1 H NMR (400 MHz, DMSO- d 6) δ 8.51 (s, 1H), 8.28 (d, J = 11.9 Hz, 1H), 8.21 (s, 1H), 7.98 (s, 1H), 7.41 (d, J= 8.6 Hz, 1H), 7.34 (d, J = 8.5 Hz, 1H), 7.22 (dd, J = 12.5, 8.4 Hz, 1H), 6.77 (s, 2H), 4.00 (s, 3H), 3.72 – 3.53(m, 4H), 3.11 (d, J = 5.9 Hz, 2H), 3.04 (d, J = 4.9 Hz, 2H), 2.83 (s, 3H), 2.04 (s, 3H).

[0330] Example 10: 2-(4-acetylpiperazin-1-yl)-4-(2-amino-6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl)benzonitrile

[0331] The title compound was prepared from intermediate D4 and intermediate J2 according to method 3.

[0332] 1 H NMR (400 MHz, DMSO- d 6) δ 8.52 (d, J = 2.1 Hz, 1H), 8.34 – 8.23 ​​(m,2H), 8.06 (d, J = 2.2 Hz, 1H), 7.79 (d, J = 7.9 Hz, 1H), 7.53 (s, 1H), 7.48(d, J = 8.0 Hz, 1H), 6.85 (s, 2H), 4.00 (s, 3H), 3.71 – 3.58 (m, 4H), 3.26(t, J = 4.9 Hz, 2H), 3.19 (t, J = 5.2 Hz, 2H), 2.84 (s, 3H), 2.05 (s, 3H).

[0333] Example 11: 1-(4-(5-(2-amino-6-(5-chloro-6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl)-2-fluorophenyl)piperazin-1-yl)acetoone

[0334] The title compound was prepared from intermediate D5 and intermediate G3 according to method 3.

[0335] 1 H NMR (400 MHz, DMSO- d 6) δ 8.64 (d, J = 2.2 Hz, 1H), 8.47 (d, J = 2.2Hz, 1H), 8.22 (d, J = 2.1 Hz, 1H), 7.99 (d, J = 2.1 Hz, 1H), 7.47 – 7.37 (m,1H), 7.37 – 7.27 (m, 1H), 7.22 (dd, J = 12.6, 8.3 Hz, 1H), 6.77 (s, 2H), 4.00(s, 3H), 3.68 – 3.53 (m, 4H), 3.11 (t, J = 5.0 Hz, 2H), 3.04 (t, J = 4.9 Hz, 2H), 2.83 (s, 3H), 2.04 (s, 3H).

[0336] Example 12: 2-(4-acetylpiperazin-1-yl)-4-(2-amino-6-(5-chloro-6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl)benzonitrile

[0337] The title compound was prepared from intermediate D5 and intermediate J2 according to method 3.

[0338] 1 H NMR (400 MHz, DMSO- d 6) δ 8.65 (d, J = 2.2 Hz, 1H), 8.48 (d, J = 2.3Hz, 1H), 8.28 (d, J = 2.2 Hz, 1H), 8.06 (d, J = 2.1 Hz, 1H), 7.79 (d, J = 8.0Hz, 1H), 7.53 (d, J = 1.3 Hz, 1H), 7.48 (dd, J= 8.0, 1.4 Hz, 1H), 6.85 (s,2H), 4.00 (s, 3H), 3.74 – 3.54 (m, 4H), 3.26 (t, J = 5.1 Hz, 2H), 3.19 (t, J = 4.9 Hz, 2H), 2.84 (s, 3H), 2.05 (s, 3H).

[0339] Example 13: 1-(4-(3-(2-amino-6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-4-methylquinazoline-8-yl)phenyl)piperazin-1-yl)acet-1-one

[0340] The title compound was prepared from intermediate D6 and intermediate J1 according to method 3.

[0341] 1 H NMR (400 MHz, DMSO- d 6) δ 8.93 (d, J = 2.5 Hz, 1H), 8.51 (d, J = 2.5Hz, 1H), 8.26 (d, J = 2.2 Hz, 1H), 7.98 (d, J = 2.2 Hz, 1H), 7.34 – 7.25 (m,2H), 7.15 (d, J = 7.6 Hz, 1H), 6.98 (d, J = 8.5 Hz, 1H), 6.74 (s, 2H), 4.05(s, 3H), 3.70 – 3.54 (m, 4H), 3.21 (t, J = 5.1 Hz, 2H), 3.15 (t, J = 5.2 Hz, 2H), 2.84 (s, 3H), 2.04 (s, 3H).

[0342] Example 14: 1-(4-(5-(2-amino-6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-4-methylquinazolin-8-yl)-2-methylphenyl)piperazin-1-yl)ethane-1-one

[0343] The title compound was prepared from intermediate D6 and intermediate G1 according to method 3.

[0344] 1 H NMR (400 MHz, DMSO- d 6) δ 8.91 (d, J = 2.5 Hz, 1H), 8.50 (d, J = 2.5Hz, 1H), 8.23 ​​(d, J = 2.3 Hz, 1H), 7.97 (d, J = 2.2 Hz, 1H), 7.38 – 7.34 (m,1H), 7.31 (d, J = 7.9 Hz, 1H), 7.24 (d, J = 7.8 Hz, 1H), 6.72 (s, 2H), 4.04(s, 3H), 3.70 – 3.47 (m, 4H), 2.95 (t, J = 4.9 Hz, 2H), 2.91 – 2.85 (m, 2H), 2.84 (s, 3H), 2.34 (s, 3H), 2.03 (s, 3H).

[0345] Example 15: 1-(4-(5-(2-amino-6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-4-methylquinazolin-8-yl)-2-methoxyphenyl)piperazin-1-yl)acetoone

[0346] The title compound was prepared from intermediate D6 and intermediate G2 according to method 3.

[0347] 1 H NMR (400 MHz, DMSO- d 6) δ 8.92 (d, J = 2.4 Hz, 1H), 8.50 (d, J = 2.4Hz, 1H), 8.21 (d, J = 2.1 Hz, 1H), 7.97 (d, J = 2.1 Hz, 1H), 7.33 (dd, J =8.3, 2.1 Hz, 1H), 7.30 (d, J = 2.1 Hz, 1H), 7.03 (d, J= 8.4 Hz, 1H), 6.72(s, 2H), 4.05 (s, 3H), 3.86 (s, 3H), 3.62 – 3.55 (m, 4H), 3.05 (s, 2H), 2.98(s, 2H), 2.83 (s, 3H), 2.02 (s, 3H).

[0348] Example 16: 1-(4-(5-(2-amino-6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-4-methylquinazolin-8-yl)-2-fluorophenyl)piperazin-1-yl)ethane-1-one

[0349] The title compound was prepared from intermediate D6 and intermediate G3 according to method 3.

[0350] 1 H NMR (400 MHz, DMSO- d 6) δ 8.93 (d, J = 2.5 Hz, 1H), 8.51 (d, J = 2.5Hz, 1H), 8.25 (d, J = 2.2 Hz, 1H), 8.02 (d, J = 2.1 Hz, 1H), 7.42 (dd, J =8.7, 2.2 Hz, 1H), 7.39 – 7.31 (m, 1H), 7.22 (dd, J = 12.5, 8.3 Hz, 1H), 6.78(s, 2H), 4.05 (s, 3H), 3.69 – 3.54 (m, 4H), 3.10 (t, J = 5.0 Hz, 2H), 3.04(t, J = 5.1 Hz, 2H), 2.84 (s, 3H), 2.04 (s, 3H).

[0351] Example 17: 1-(4-(5-(2-amino-6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-4-methylquinazolin-8-yl)-2-chlorophenyl)piperazin-1-yl)ethane-1-one

[0352] The title compound was prepared from intermediates D6 and G4 according to method 3.

[0353] 1 H NMR (400 MHz, DMSO- d 6) δ 8.93 (d, J = 2.4 Hz, 1H), 8.52 (d, J = 2.5Hz, 1H), 8.28 (d, J = 2.2 Hz, 1H), 8.04 (d, J = 2.2 Hz, 1H), 7.56 – 7.45 (m,2H), 7.40 (dd, J = 8.2, 2.0 Hz, 1H), 6.80 (s, 2H), 4.05 (s, 3H), 3.68 – 3.51(m, 4H), 3.08 (t, J = 4.9 Hz, 2H), 3.01 (t, J = 5.1 Hz, 2H), 2.84 (s, 3H), 2.04 (s, 3H).

[0354] Example 18: 2-(4-acetylpiperazin-1-yl)-4-(2-amino-6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-4-methylquinazoline-8-yl)benzonitrile

[0355] The title compound was prepared from intermediate D6 and intermediate J2 according to method 3.

[0356] 1 H NMR (400 MHz, DMSO- d 6) δ 8.94 (d, J = 2.5 Hz, 1H), 8.54 (d, J = 2.5Hz, 1H), 8.32 (d, J = 2.1 Hz, 1H), 8.10 (d, J = 2.1 Hz, 1H), 7.80 (d, J = 8.0Hz, 1H), 7.57 – 7.51 (m, 1H), 7.51 – 7.44 (m, 1H), 6.87 (s, 2H), 4.05 (s,3H), 3.68 – 3.61 (m, 4H), 3.25 (t, J = 4.8 Hz, 2H), 3.19 (t, J= 5.0 Hz, 2H), 2.05 (s, 3H).

[0357] Example 19: 1-(4-(5-(2-amino-6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-4-methylquinazoline-8-yl)-2-(trifluoromethyl)phenyl)piperazin-1-yl)acetoone

[0358] The title compound was prepared from intermediates D6 and G5 according to method 3.

[0359] 1 H NMR (400 MHz, DMSO- d 6) δ 8.95 (d, J = 2.5 Hz, 1H), 8.54 (d, J = 2.5Hz, 1H), 8.32 (d, J = 2.2 Hz, 1H), 8.08 (d, J = 2.3 Hz, 1H), 7.96 – 7.83 (m,1H), 7.83 – 7.64 (m, 2H), 6.81 (s, 2H), 4.05 (s, 3H), 3.73 – 3.45 (m, 4H), 2.97 (t, J = 4.8 Hz, 2H), 2.91 (t, J = 4.9 Hz, 2H), 2.85 (s, 3H), 2.03 (s, 3H).

[0360] Example 20: 4-(2-amino-6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-4-methylquinazoline-8-yl)-2-(piperidin-1-yl)benzonitrile

[0361] The title compound was prepared from intermediates D6 and J3 according to method 3.

[0362] 1 H NMR (400 MHz, DMSO- d 6) δ 8.93 (d, J = 5.5 Hz, 1H), 8.53 (d, J = 5.7Hz, 1H), 8.31 (d, J = 5.1 Hz, 1H), 8.07 (d,J = 4.9 Hz, 1H), 7.73 (dd, J =7.9, 2.7 Hz, 1H), 7.48 – 7.42 (m, 1H), 7.38 (d, J = 8.1 Hz, 1H), 6.84 (s,2H), 4.04 (s, 3H), 3.18 (t, J = 4.7 Hz, 4H), 2.84 (s, 3H), 1.77 – 1.64 (m, 4H), 1.63 – 1.48 (m, 2H).

[0363] Example 21: 4-(2-amino-6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-4-methylquinazoline-8-yl)-2-(4-methoxypiperidin-1-yl)benzonitrile

[0364] The title compound was prepared from intermediates D6 and J4 according to method 3.

[0365] 1 H NMR (400 MHz, DMSO- d 6) δ 8.93 (d, J = 2.4 Hz, 1H), 8.53 (d, J = 2.5Hz, 1H), 8.31 (d, J = 2.1 Hz, 1H), 8.07 (d, J = 2.1 Hz, 1H), 7.74 (d, J = 8.0Hz, 1H), 7.47 (d, J = 1.5 Hz, 1H), 7.44 – 7.34 (m, 1H), 6.83 (s, 2H), 4.05(s, 3H), 3.50 – 3.41 (m, 2H), 3.40 – 3.36 (m, 1H), 3.28 (s, 3H), 3.08 – 2.94(m, 2H), 2.84 (s, 3H), 2.08 – 1.94 (m, 2H), 1.71 – 1.57 (m, 2H).

[0366] Example 22: 4-(2-amino-6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-4-methylquinazoline-8-yl)-2-(4-hydroxypiperidin-1-yl)benzonitrile

[0367] The title compound was prepared from intermediates D6 and J5 according to method 3.

[0368] 1 H NMR (400 MHz, DMSO- d 6) δ 8.96 (d, J = 2.4 Hz, 1H), 8.56 (d, J = 2.4Hz, 1H), 8.34 (s, 1H), 8.10 (s, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.40 (d, J =8.0 Hz, 1H), 6.87 (s, 1H), 4.07 (s, 3H), 3.74 – 3.62 (m, 1H), 3.56 – 3.47 (m,3H), 3.06 – 2.94 (m, 2H), 2.87 (s, 3H), 1.99 – 1.86 (m, 2H), 1.72 – 1.54 (m, 2H).

[0369] Example 23: 4-(2-amino-6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-4-methylquinazoline-8-yl)-2-(4-hydroxy-4-methylpiperidin-1-yl)benzonitrile

[0370] The title compound was prepared from intermediates D6 and J6 according to method 3.

[0371] 1 H NMR (400 MHz, DMSO- d 6) δ 8.94 (d, J = 2.4 Hz, 1H), 8.53 (d, J = 2.4Hz, 1H), 8.31 (d, J = 2.1 Hz, 1H), 8.08 (d, J = 2.2 Hz, 1H), 7.72 (d, J = 8.0Hz, 1H), 7.45 (d, J = 1.5 Hz, 1H), 7.37 (dd, J= 8.0, 1.4 Hz, 1H), 6.83 (s, 2H), 4.33 (s, 1H), 4.05 (s, 3H), 3.32 – 3.24 (m, 3H), 3.26 – 3.15 (m, 2H), 2.84 (s, 3H), 1.74 – 1.58 (m, 4H), 1.19 (s, 3H).

[0372] Example 24: 4-(2-amino-6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-4-methylquinazoline-8-yl)-2-(4-(2-hydroxypropane-2-yl)piperidin-1-yl)benzonitrile

[0373] The title compound was prepared from intermediates D6 and J7 according to method 3.

[0374] 1 H NMR (400 MHz, DMSO- d 6) δ 8.93 (d, J = 2.4 Hz, 1H), 8.52 (d, J = 2.5Hz, 1H), 8.31 (d, J = 2.1 Hz, 1H), 8.07 (d, J = 2.1 Hz, 1H), 7.72 (d, J = 7.9Hz, 1H), 7.47 (s, 1H), 7.38 (d, J = 8.0 Hz, 1H), 6.82 (s, 2H), 4.18 (s, 1H), 3.75 – 3.63 (m, 2H), 2.84 (s, 3H), 2.76 (t, J = 11.7 Hz, 2H), 1.90 – 1.77 (m,2H), 1.56 – 1.39 (m, 2H), 1.39 – 1.28 (m, 1H), 1.09 (s, 6H).

[0375] Example 25: 4-(2-amino-6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-4-methylquinazoline-8-yl)-2-(piperazin-1-yl)benzonitrile

[0376] The title compound was prepared from intermediates D6 and J8 according to methods 3 and 4.

[0377] 1 H NMR (400 MHz, DMSO- d 6) δ 8.94 (d, J = 2.7 Hz, 1H), 8.53 (d, J = 2.5Hz, 1H), 8.32 (d, J = 2.2 Hz, 1H), 8.08 (d, J = 2.1 Hz, 1H), 7.75 (d, J = 8.0Hz, 1H), 7.44 (d, J = 1.5 Hz, 1H), 7.40 (dd, J = 8.0, 1.5 Hz, 1H), 6.84 (s, 2H), 4.05 (s, 3H), 3.15 (t, J = 4.8 Hz, 4H), 2.89 (t, J = 4.7 Hz, 4H), 2.85 (s, 3H).

[0378] Example 26: 4-(2-amino-6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-4-methylquinazoline-8-yl)-2-(4-ethylpiperazin-1-yl)benzonitrile

[0379] The title compound was prepared from intermediates D6 and J9 according to method 3.

[0380] 1 H NMR (400 MHz, DMSO- d 6) δ 8.94 (s, 1H), 8.53 (s, 1H), 8.32 (s, 1H), 8.08 (s, 1H), 7.75 (d, J = 7.9 Hz, 1H), 7.48 (s, 1H), 7.42 (d, J = 8.0 Hz,1H), 6.84 (s, 2H), 4.05 (s, 3H), 3.29 – 3.20 (m, 4H), 2.84 (s, 3H), 2.70 –2.56 (m, 4H), 2.45 – 2.30 (m, 2H), 1.04 (t, J = 7.1 Hz, 3H).

[0381] Example 27: 4-(2-amino-6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-4-methylquinazoline-8-yl)-2-(4-isopropylpiperazin-1-yl)benzonitrile

[0382] The title compound was prepared from intermediates D6 and J10 according to method 3.

[0383] 1 H NMR (400 MHz, DMSO- d 6) δ 8.94 (s, 1H), 8.53 (s, 1H), 8.32 (s, 1H), 8.08 (s, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.47 (s, 1H), 7.42 (d, J = 7.9 Hz,1H), 6.83 (s, 2H), 4.05 (s, 3H), 3.27 – 3.15 (m, 4H), 2.85 (s, 3H), 2.69 –2.60 (m, 4H), 1.21 – 1.13 (m, 1H), 1.02 (d, J = 6.5 Hz, 6H).

[0384] Example 28: 4-(2-amino-6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-4-methylquinazoline-8-yl)-2-(4-cyclopropylpiperazin-1-yl)benzonitrile

[0385] The title compound was prepared from intermediates D6 and J11 according to method 3.

[0386] 1 H NMR (400 MHz, DMSO- d 6) δ 8.93 (d, J = 2.6 Hz, 1H), 8.53 (d, J = 2.4Hz, 1H), 8.31 (d, J = 2.1 Hz, 1H), 8.08 (d, J = 2.1 Hz, 1H), 7.75 (d, J = 7.9Hz, 1H), 7.47 (s, 1H), 7.42 (d, J= 8.0 Hz, 1H), 6.84 (s, 2H), 4.04 (s, 3H), 3.19 (t, J = 4.8 Hz, 4H), 2.84 (s, 3H), 2.74 (t, J = 4.9 Hz, 4H), 1.78 – 1.66(m, 1H), 0.44 (dd, J = 6.7, 4.5 Hz, 2H), 0.37 – 0.27 (m, 2H).

[0387] Example 29: 4-(2-amino-6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-4-methylquinazoline-8-yl)-2-(4-cyclopentylpiperazin-1-yl)benzonitrile

[0388] The title compound was prepared from intermediates D6 and J12 according to method 3.

[0389] 1 H NMR (400 MHz, DMSO- d 6) δ 8.94 (d, J = 2.5 Hz, 1H), 8.53 (d, J = 2.6Hz, 1H), 8.32 (d, J = 2.2 Hz, 1H), 8.09 (d, J = 2.2 Hz, 1H), 7.76 (d, J = 8.0Hz, 1H), 7.49 (s, 1H), 7.42 (d, J = 8.0 Hz, 1H), 6.85 (s, 2H), 4.05 (s, 3H),3.29 – 3.19 (m, 4H), 2.84 (s, 3H), 2.70 – 2.52 (m, 5H), 1.90 – 1.76 (m, 2H),1.72 – 1.42 (m, 4H), 1.42 – 1.27 (m, 2H).

[0390] Example 30: 4-(2-amino-6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-4-methylquinazoline-8-yl)-2-(4-phenylpiperazin-1-yl)benzonitrile

[0391] The title compound was prepared from intermediates D6 and J13 according to method 3.

[0392] 1 H NMR (400 MHz, DMSO- d 6) δ 8.95 (d, J = 2.4 Hz, 1H), 8.54 (d, J = 2.4Hz, 1H), 8.33 (d, J = 2.2 Hz, 1H), 8.12 (d, J = 2.1 Hz, 1H), 7.80 (d, J = 7.9Hz, 1H), 7.57 (d, J = 1.5 Hz, 1H), 7.47 (dd, J = 8.0, 1.5 Hz, 1H), 7.28 –7.20 (m, 2H), 7.05 – 6.98 (m, 2H), 6.88 (s, 2H), 6.81 (t, J = 7.2 Hz, 1H), 4.05 (s, 3H), 3.45 – 3.36 (m, 8H), 2.85 (s, 3H).

[0393] Example 31: 4-(2-amino-6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-4-methylquinazoline-8-yl)-2-(4-(pyridin-2-yl)piperazin-1-yl)benzonitrile

[0394] The title compound was prepared from intermediates D6 and J14 according to method 3.

[0395] 1 H NMR (400 MHz, DMSO- d 6) δ 8.94 (d, J = 2.4 Hz, 1H), 8.53 (d, J = 2.6Hz, 1H), 8.32 (d, J = 2.3 Hz, 1H), 8.21 – 8.12 (m, 1H), 8.11 (d, J = 2.3 Hz, 1H), 7.80 (d, J = 7.9 Hz, 1H), 7.62 – 7.52 (m, 2H), 7.47 (d,J = 8.0 Hz, 1H), 6.91 (d, J = 8.6 Hz, 1H), 6.86 (s, 2H), 6.75 – 6.56 (m, 1H), 4.05 (s, 3H), 3.70 (t, J = 4.6 Hz, 4H), 3.35 (t, J = 5.1 Hz, 4H), 2.85 (s, 3H).

[0396] Example 32: 4-(2-amino-6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-4-methylquinazoline-8-yl)-2-(4-(pyrimidin-2-yl)piperazin-1-yl)benzonitrile

[0397] The title compound was prepared from intermediates D6 and J15 according to method 3.

[0398] 1 H NMR (400 MHz, DMSO- d 6) δ 8.94 (s, 1H), 8.53 (s, 1H), 8.39 (d, J =4.7 Hz, 2H), 8.32 (s, 1H), 8.10 (s, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.56 (s,1H), 7.48 (d, J = 8.1 Hz, 1H), 6.85 (s, 2H), 6.66 (t, J = 4.7 Hz, 1H), 4.05(s, 3H), 3.95 (t, J = 5.4 Hz, 4H), 3.32 – 3.27 (m, 4H), 2.85 (s, 3H).

[0399] Example 33: 4-(2-amino-6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-4-methylquinazoline-8-yl)-2-morpholinobenzonitrile

[0400] The title compound was prepared from intermediates D6 and J16 according to method 3. 1 H NMR (400 MHz, DMSO- d 6) δ 8.94 (d,J = 2.4 Hz, 1H), 8.53 (d, J = 2.4 Hz, 1H), 8.32 (d, J = 2.1Hz, 1H), 8.09 (d, J = 2.1 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 1.6Hz, 1H), 7.46 (dd, J = 8.0, 1.5 Hz, 1H), 6.86 (s, 2H), 4.05 (s, 3H), 3.80 (t, J = 4.5 Hz, 4H), 3.24 (t, J = 4.6 Hz (4H), 2.85 (s, 3H).

[0401] Example 34: 1-(4-(3-(2-amino-6-(2-methoxypyrimidin-5-yl)-4-methyl-quinazolin-8-yl)phenyl)piperazin-1-yl)ethyl-1-one

[0402] The title compound was prepared from intermediate D7 and intermediate J1 according to method 3.

[0403] 1 H NMR (400 MHz, ) δ 9.14 – 9.08 (m, 2H), 8.25 (s, 1H), 7.96 (s, 1H),7.34 – 7.25 (m, 2H), 7.15 (d, J = 6.8 Hz, 1H), 6.98 (d, J = 7.1 Hz, 1H), 6.73(s, 2H), 3.98 (d, J = 2.7 Hz, 3H), 3.64 – 3.53 (m, 4H), 3.26 – 3.18 (m, 2H), 3.18 – 3.10 (m, 2H), 2.83 (s, 3H), 2.04 (s, 3H).

[0404] II. Evaluation of the Pharmacological Activity of the Compound

[0405] Experimental Example 1: Biochemical Detection of PI3Kα and PI3Kδ Activities

[0406] The efficacy of the compounds of the present invention for PI3Kα and PI3Kδ was evaluated using an in vitro kinase assay. The kinase activities of PI3Kα and PI3Kδ were determined by detecting the level of ADP produced during the kinase reaction using a luciferase-based cryo-optical assay. The ADP-Glo ​​kinase assay kit was purchased from Promega. All assays were performed at room temperature using 384-well plates. PI3Kα and PI3Kδ kinases were obtained from Invitrogen. The substrate was PIP2 (Invitrogen). The kinase buffer solution consisted of 50 mM Hepes (pH 7.5), 3 mM MgCl2, 100 mM NaCl, 1 mM EGTA, 0.03% CHAPS, and 2 nM DTT. PI3Kα and PI3Kδ kinase solutions were prepared by diluting the kinase buffer solution to 6.6 nM. The substrate solution consisted of 100 μM PIP2 and 50 μM ATP. The test compound in 100% DMSO was diluted 25-fold in 1× kinase buffer. 2.5 μL of the diluted compound solution and 2.5 μL of PI3Kα and PI3Kδ kinase solutions were added to each well of a 384-well plate. The reaction was initiated by adding 5 μL of substrate solution to each well, with a final reaction volume of 10 μL, ATP concentration of 25 μM, PIP2 concentration of 50 μM, and PI3Kα and PI3Kδ kinase concentrations of 1.65 nM. The plate was capped and the reaction was incubated at room temperature for 1 hour, followed by termination of the reaction by adding 10 μL of ADP-Glo ​​reagent to each well. The plate was incubated for 15 minutes, and then read using a cold light reader on an EnVision 2104 multilabel microplate reader.

[0407] The inhibition percentage is calculated based on the following formula: Inhibition % = 100 - (max-sample RLU) / (max-min) 100. Where sample RLU is the cold light reading at a given compound concentration, min refers to the reading of the DMSO control, and max refers to the reading of the control without enzyme activity. The IC50 of the compound is calculated using the XLfit program in Excel. 50 The results are shown in Table 1.

[0408] Table 1: Inhibitory activity of the compounds in the examples against PI3Kα and PI3Kδ kinases

[0409] As can be seen from the results in Table 1, the compounds of the present invention not only exhibit significant inhibitory activity against PI3Kδ, but also significant selectivity against PI3Kα. In particular, some compounds show very strong activity and selectivity: for example, the title compounds prepared in Examples 5, 6, 11, 12, 15, 16, 17, 18, 22, and 33, with IC50 values ​​for PI3Kδ... 50 Values ​​less than 10 nM show a selectivity for PI3Kα greater than 200 times; in particular, the title compounds prepared in Examples 17, 18, 22, and 33 show a selectivity for PI3Kα greater than 1000 times.

[0410] It should be understood that the invention described herein is not limited to specific methodologies, experimental protocols, or reagents, as these can vary. The discussions and examples provided herein are for illustrative purposes only and are not intended to limit the scope of the invention, which is defined solely by the claims.

Claims

1. A compound represented by Formula I, or a stereoisomer, geometric isomer, tautomer, prodrug, pharmaceutically acceptable salt, crystal form, or solvate thereof. in: R 1 Selected from 5-6 saturated heterocyclic groups, wherein the 5-6 saturated heterocyclic group is optionally surrounded by 1-3 groups selected from R a The groups are replaced; R a Selected from hydroxyl, mercapto, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C3-C6 cycloalkyl, 6-10 aryl, 5-6 heteroaryl, hydroxy-C1-C6 alkylene, -C(O)-R b -S(O)-R c -S(O)2-R d ; R b R c R d Each is independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, and C3-C6 cycloalkyl; R 2 Selected from hydrogen, cyano, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C3-C6 cycloalkyl, and C1-C6 haloalkyl; R 3 Selected from C1-C6 alkyl groups; X is N or CR 4 ; R 4 It is selected from hydrogen, cyano, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, and C1-C6 haloalkyl.

2. The compound of claim 1, or its stereoisomers, geometric isomers, tautomers, prodrugs, pharmaceutically acceptable salts, crystal forms, or solvates, wherein, R 1 Selected from 6-membered saturated heterocyclic groups, wherein the 6-membered saturated heterocyclic group is optionally surrounded by 1-2 elements selected from R a The groups are replaced; Preferably, R 1 The group is selected from piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl, and each of the piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl groups is independently and optionally composed of 1-2 groups selected from R. a The groups are replaced; Preferably, R 1 The group is selected from piperidinyl, piperazinyl, and morpholinyl, and each of the piperidinyl, piperazinyl, and morpholinyl groups is independently and optionally surrounded by 1-2 groups selected from R. a The groups are replaced; Or, R a Selected from hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, phenyl, 6-membered heteroaryl, hydroxy-C1-C6 alkylene, -C(O)-R b ; Preferably, R a Selected from hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, hydroxy-C1-C6 alkylene, -C(O)-R b ; Preferably, R a Selected from hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, phenyl, pyridyl, pyrimidinyl, hydroxy-C1-C6 alkylene, -C(O)-R b ; Preferably, R a Selected from hydroxyl, methyl, ethyl, isopropyl, methoxy, cyclopropyl, cyclopentyl, phenyl, , , , ; Or, R b R c R d Each is independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, and C3-C6 cycloalkyl; Preferably, R b R c R d Each is independently selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, and cyclopentyl; Preferably, R b Selected from C1-C6 alkyl groups; Preferably, R b Selected from methyl, ethyl, n-propyl, and isopropyl; Preferably, R b It is a methyl group.

3. The compound of claim 1 or 2, or its stereoisomers, geometric isomers, tautomers, prodrugs, pharmaceutically acceptable salts, crystal forms, or solvates, wherein, R 1 Selected from , , ; R e R f R g Each is independently selected from hydrogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, phenyl, 6-membered heteroaryl, hydroxy-C1-C6 alkylene, -C(O)-R h ; Preferably, R e R f R g Each is independently selected from hydrogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, hydroxy-C1-C6 alkylene, -C(O)-R h ; Preferably, R e R f R g Each is independently selected from hydrogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, phenyl, pyridyl, pyrimidinyl, hydroxy-C1-C6 alkylene, -C(O)-R h ; Preferably, R e R f R g Each is independently selected from hydrogen, hydroxyl, methyl, ethyl, isopropyl, methoxy, cyclopropyl, cyclopentyl, phenyl, , , , ; Preferably, R e Selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, -C(O)-R h ; Preferably, R e Selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, pyridyl, pyrimidinyl, -C(O)-R h ; Preferably, R e Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, , , ; Preferably, R e Selected from hydrogen, ethyl, isopropyl, cyclopropyl, cyclopentyl, phenyl, , , ; Preferably, R f Selected from hydrogen, hydroxyl, C1-C6 alkoxy, and hydroxy-C1-C6 alkylene; Preferably, R f Selected from hydrogen, hydroxyl, methoxy, ethoxy, ; Preferably, R f Selected from hydrogen, hydroxyl, methoxy, ; Preferably, R g Selected from hydrogen and C1-C6 alkyl groups; Preferably, R g Selected from hydrogen and methyl; R h Selected from C1-C6 alkyl groups; Preferably, R h Selected from methyl, ethyl, n-propyl, and isopropyl; Preferably, R h It is a methyl group.

4. The compound according to any one of claims 1-3, or its stereoisomers, geometric isomers, tautomers, prodrugs, pharmaceutically acceptable salts, crystal forms, or solvates, wherein, R 1 Selected from , , , , , , , , , , , , , , .

5. The compound according to any one of claims 1-4, or a stereoisomer, geometric isomer, tautomer, prodrug, pharmaceutically acceptable salt, crystal form, or solvate thereof, wherein, R 2 Selected from hydrogen, cyano, halogen, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl; Preferably, R 2 Selected from hydrogen, methyl, methoxy, fluorine, chlorine, cyano, and -CF3; Or, R 3 It is methyl; Or, R 4 Selected from hydrogen, cyano, halogen, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl; Preferably, R 4 Selected from hydrogen, halogens, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl; Preferably, R 4 Selected from hydrogen, methyl, methoxy, fluorine, chlorine, and -CF3.

6. The compound according to any one of claims 1-5, or a stereoisomer, geometric isomer, tautomer, prodrug, pharmaceutically acceptable salt, crystal form, or solvate thereof, wherein, The compound has the structure shown in Formula I-1. in: R 1 R 2 R 4 Each is independently defined as described in any one of claims 1-5.

7. The compound of claim 6, or a stereoisomer, geometric isomer, tautomer, prodrug, pharmaceutically acceptable salt, crystal form, or solvate thereof, wherein, R 1 Selected from , ; R e -C(O)-R h R h Selected from C1-C6 alkyl groups, preferably methyl; Preferably, R e for ; R f It is a hydroxyl group; R g Selected from hydrogen and C1-C6 alkyl groups; Preferably, R g Selected from hydrogen and methyl; Preferably, R 1 Selected from , , ; R 2 Selected from cyano, halogen, and C1-C6 alkoxy groups; Preferably, R 2 Selected from methoxy, fluorine, chlorine, and cyano groups; Preferably, R 2 Selected from cyano and halogen; Preferably, R 2 Selected from chloro and cyano groups; R 4 Selected from halogens, C1-C6 alkyl groups, and C1-C6 haloalkyl groups; Preferably, R 4 Selected from methyl, chlorine, and -CF3; Preferably, R 4 Selected from C1-C6 haloalkyl groups; Preferably, R 4 It is -CF3.

8. The compound according to any one of claims 1-7, or a stereoisomer, geometric isomer, tautomer, prodrug, pharmaceutically acceptable salt, crystal form, or solvate thereof, wherein, The compound is selected from: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 9. A pharmaceutical composition comprising the compound of any one of claims 1-8 or a stereoisomer, geometric isomer, tautomer, prodrug, pharmaceutically acceptable salt, crystal form or solvate thereof; Optionally, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, diluent, and / or excipient; Optionally, the pharmaceutical composition may further comprise additional active ingredients for the prevention and / or treatment of tumors.

10. Use of the compound of any one of claims 1-8 or its stereoisomers, geometric isomers, tautomers, prodrugs, pharmaceutically acceptable salts, crystal forms or solvates, or the pharmaceutical composition of claim 9 in the preparation of a medicament for treating and / or preventing PI3Kδ-mediated diseases; Preferably, the PI3Kδ-mediated diseases include tumors (such as B-cell malignancies, specifically follicular lymphoma), autoimmune diseases (such as rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus), immunodeficiency diseases, kidney diseases, cardiovascular diseases, inflammation, inflammatory diseases (such as chronic obstructive pulmonary disease, asthma, idiopathic pulmonary fibrosis, acute lung injury), PI3Kδ activation syndrome, metabolic / endocrine dysfunction, or neurological diseases.

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