Pyrimidinamine Compounds, Their Compositions and Uses

Abstract

The present invention provides a pyrimidineamine compound represented by formula (I), or a stereoisomer, tautomer, N-oxide, solvate, or pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising the compound, as well as the use of the compound and its pharmaceutical composition in the preparation of a drug for preventing, treating, and / or alleviating a disease, disorder, and / or condition associated with abnormal PI3-kinase, or inhibiting PI3-kinase activity. The compound provided by the present invention exhibits excellent inhibitory activity and kinase selectivity against PI3-kinase.

Description

Field of the Invention

[0001] The present invention belongs to the field of drugs, and specifically relates to a new class of pyrimidineamine compounds, pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing said compounds, as well as the use of said compounds and pharmaceutical compositions thereof in the preparation of drugs for preventing, treating, and / or alleviating diseases, disorders, and / or conditions associated with abnormal PI3-kinase. Background of the Invention

[0002] The phosphoinositide 3-kinase (PI3K) pathway is an intracellular signaling pathway that plays a regulatory role in cell survival, proliferation, and differentiation. The phosphoinositide 3-kinase (PI3K) enzyme family is a central regulator of growth, proliferation, migration, and metabolism in many cells and tissues. PI3K is a lipid kinase that generates the lipid second messenger phosphatidylinositol-3,4,5-trisphosphate (PIP3), which is used downstream of cell surface receptors to regulate growth, metabolism, survival, and differentiation. PIP3 is produced by four different class I PI3K catalytic isomers, which are divided into two groups: class IA (p110α, p110β, and p110δ) and class IB (p110γ). All class I PI3Ks are constitutively associated with regulatory subunits, and the main difference between class IA and class IB PI3Ks is that they are associated with distinct regulatory subunits. In normal cells, the PI3K / mTOR pathway plays a regulatory role in cell survival, proliferation, and differentiation. However, abnormal activation of this pathway is associated with a variety of human diseases, including cancer, immunodeficiency, inflammation, and developmental disorders. A variety of inhibitors targeting key nodes within the PI3K pathway are in different stages of clinical development for the treatment of a variety of human diseases. (“Small-molecule inhibitors of the PI3K signaling network.” Future MedChem. 2011, 3(5), 549-565).

[0003] Based on differences in gene sequence, structure, adaptor molecules, expression, activation mechanism, and substrate, PI3Ks can be divided into three classes (I, II, and III). Among them, class I PI3K can be further divided into two subclasses, IA and IB, according to the signaling pathway and regulatory proteins. Class IA PI3K (PI3Kα, PI3Kβ, and PI3Kδ) is a heterodimeric complex composed of a catalytic subunit p110 (p110α, p110β, and p110δ, respectively) and a regulatory subunit p85 (e.g., p85α, p85β, p55δ, p55α, and p50α). These signal responses are usually transmitted through receptor tyrosine kinases (RTKs). The signal of class IB PI3Kγ is transmitted through G protein-coupled receptors (GPCRs), and is composed of the catalytic subunit p110γ. The regulatory subunit associated with p110γ is different from that of class IA subtypes.

[0004] The expression patterns of the PI3Kα and PI3Kβ isoforms are ubiquitous, while the PI3Kδ and PI3Kγ isoforms are mainly expressed in leukocytes. The relatively restricted expression patterns of PI3Kδ and PI3Kγ suggest important roles for these two isoforms in the adaptive and innate immune systems (J. Med. Chem. 2012, 55(20), 8559–8581).

[0005] PI3Kδ is required for PI(3,4,5)P3 formation downstream of CD28 and / or T-cell receptor (TCR) signaling. An important role downstream of PI3K signaling of the TCR is the activation of Akt, which phosphorylates anti-apoptotic factors as well as a variety of different transcription factors for cytokine production. Thus, T cells with inactivated PI3Kδ are deficient in proliferation and Th1 and Th2 cytokine secretion. Activation of T cells through CD28 lowers the threshold for TCR activation by antigen and increases the magnitude and duration of the proliferative response. These effects are mediated by a PI3Kδ-dependent increase in the transcription of many genes including IL2, an important T-cell growth factor.

[0006] The role of PI3Kδ in B-cell proliferation, antibody secretion, B-cell antigen and IL-4 receptor signaling, and B-cell antigen presentation function has also been established (J. Immunol. (2007) 178(4) p. 2328-35; Blood (2006) 107(2) p. 642-50), and suggests its role in autoimmune diseases such as rheumatoid arthritis or systemic lupus erythematosus. Thus, PI3K inhibitors would also have good efficacy for the above indications.

[0007] The identification of the activated PI3K pathway in hematological malignancies has led to a great deal of research in this area, and currently, three PI3K inhibitors are approved by the US Food and Drug Administration for the treatment of chronic lymphocytic leukemia; follicular B-cell non-Hodgkin lymphoma; and small lymphocytic lymphoma, etc. Idelalisib (targeting the δ isoform) was the first PI3K inhibitor approved in this field, followed by copanlisib (a pan-PI3K isoform inhibitor that acts mainly on α and δ), and more recently, duvelisib (a PI3Kγ and δ inhibitor). The approval of these PI3K inhibitors is based on their activity in B-cell malignancies that relapse or are refractory after at least two prior treatments. Notably, PI3K inhibitors are targeted / immunomodulatory drugs rather than cytotoxic chemotherapies, and their unique mechanism of action results in differentiated safety. Given the importance of the PI3K pathway in normal white blood cell function, inhibiting PI3K requires a critical balance between effects at the tumor microenvironment level and preserving immune function. (Clinical Lymphoma, Myeloma & Leukemia, 2020, Vol. 21, No. 1, 8-20).

[0008] New PI3K inhibitors are needed that are good candidate drugs. Specifically, the preferred compounds should bind strongly to the PI3K receptor while showing little affinity for other receptors. The compounds should be well absorbed by the gastrointestinal tract, metabolically stable, and have good pharmacokinetic properties. When targeting receptors in the central nervous system, they should cross the blood-brain barrier freely, and when selectively targeting receptors in the peripheral nervous system, they should not cross the blood-brain barrier. They should be non-toxic and show few side effects. In addition, the ideal candidate drugs should be in a physical form that is stable, non-hygroscopic, and easy to formulate. The compounds of the present invention show a specific level of selectivity for PI3Kα, β, γ, and δ of different paralogs. In particular, a specific level of selectivity for PI3Kδ is shown.

[0009] The compounds, compositions, and methods described in the present invention directly address these and other needs. Specifically, the present invention provides a class of compounds that can inhibit, modulate, and / or regulate PI3-kinase activity for the treatment and / or prevention of diseases, disorders, and / or conditions associated with abnormal PI3-kinase. Compared with existing compounds of the same kind, the compounds of the present invention have better pharmacological activities. Specifically, the compounds of the present invention exhibit excellent inhibitory activity and kinase selectivity against PI3-kinase. Therefore, the compounds of the present invention have very good development prospects. Summary of the Invention

[0010] Definition of Terms

[0011] Certain embodiments of the present invention are now described in detail, with examples illustrated by the accompanying structural and chemical formulas. The present invention is intended to cover all alternative, modified, and equivalent technical solutions, which are all included within the scope of the present invention defined by the appended claims. Those skilled in the art should recognize that many methods and materials similar or equivalent to those described in the present invention can be used to practice the present invention. The present invention is in no way limited to the methods and materials described in the present invention. In the case where one or more of the incorporated documents, patents, and similar materials are different from or inconsistent with the present application (including but not limited to the defined terms, term applications, described technologies, etc.), the present application shall prevail.

[0012] "Stereoisomers" refer to compounds that have the same chemical structure but different arrangements of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans isomers), atropisomers, and so on.

[0013] As described in the present invention, the compounds of the present invention can optionally be substituted by one or more substituents, such as the general formula compounds of the present invention, or like the specific examples, subclasses, and a class of compounds included in the present invention.

[0014] It should be understood that the term "optionally substituted" can be used interchangeably with the term "substituted or unsubstituted". Generally, the term "substituted" means that one or more hydrogen atoms in the given structure are replaced by specific substituents, regardless of whether the hydrogen atom is attached to a C, N, or other atom. "Optionally", unless otherwise indicated, an optional substituent group can be substituted at each substitutable position of the said group. When there is more than one position in the given structural formula that can be substituted by one or more substituents selected from a specific group, the substituents can be the same or different at each position.

[0015] The term "optionally substituted with" can be used interchangeably with the term "unsubstituted or substituted with", i.e., the structure is unsubstituted or substituted with one or more substituents described in the present invention. The substituents described in the present invention include, but are not limited to, H, D, oxo (=O), F, Cl, Br, I, -OH, -CN, -NO2, -NR e R f , -C(=O)R 9 , -OC(=O)R 9 , -C(=O)OR 9a , -S(=O) 0-2 R 9 , -OS(=O) 1-2 R 9 , -S(=O) 1-2 OR 9a , -N(R 10a )C(=O)R 10 , -C(=O)NR 10a R 10 , -OC(=O)NR 10a R 10 , -N(R 10a )S(=O) 1-2 R 10 , -S(=O) 1-2 NR 10a R 10 , -N(R 10a )C(=O)NR 10a R 10 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl, C 3-8 cycloalkylC 1-6 alkyl, C<9000039>heterocyclic group, C 2-7 heterocyclic groupC 1-6 alkyl, C 6-12 aryl, C 6-12 arylC 1-6 alkyl, C 1-9 heteroaryl, or C 1-9 heteroarylC 1-6alkyl; wherein each substituent is independently optionally substituted by 0, 1, 2, 3 or 4 groups independently selected from H, D, oxo(=O), F, Cl, Br, -OH, -NH2, -CN, -NO2, C 1-6 alkyl and C 1-6 alkoxy groups, etc. wherein, R e , R f , R 9 , R 9a , R 10 and R 10a are as defined in the present invention.

[0016] In various parts of the present specification, the substituents of the disclosed compounds of the present invention are disclosed according to group types or ranges. It is specifically pointed out that the present invention includes each independent secondary combination of each member of these group types and ranges. For example, the term "C1-C6 alkyl" specifically refers to methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl independently disclosed.

[0017] The term "alkyl" or "alkyl group" used in the present invention refers to a saturated straight-chain or branched-chain monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may optionally be substituted by one or more substituents described in the present invention. Unless otherwise specified in detail, the alkyl group contains 1-20 carbon atoms. In one embodiment, the alkyl group contains 1-12 carbon atoms; in another embodiment, the alkyl group contains 1-6 carbon atoms; in yet another embodiment, the alkyl group contains 1-4 carbon atoms; still in one embodiment, the alkyl group contains 1-3 carbon atoms. The alkyl group may optionally be substituted by one or more substituents described in the present invention.

[0018] Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl (t-Bu, -C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), n-heptyl, n-octyl, and the like.

[0019] The term "alkenyl" refers to a straight-chain or branched-chain monovalent hydrocarbon group having 2 to 12 carbon atoms, with at least one unsaturated site, i.e., having a carbon-carbon sp 2 double bond, which includes "cis" and "trans" configurations, or "E" and "Z" configurations. In one embodiment, the alkenyl group has 2 to 8 carbon atoms; in another embodiment, the alkenyl group has 2 to 6 carbon atoms; in yet another embodiment, the alkenyl group has 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (-CH=CH2), allyl (-CH2CH=CH2), and the like. The alkenyl group may optionally be substituted with one or more substituents described in the present invention.

[0020] The term "alkynyl" means a straight-chain or branched-chain monovalent hydrocarbon group having 2 to 12 carbon atoms, with at least one unsaturated site, i.e., a carbon-carbon sp triple bond. In one embodiment, the alkynyl group contains 2 to 8 carbon atoms; in another embodiment, the alkynyl group contains 2 to 6 carbon atoms; in yet another embodiment, the alkynyl group contains 2 to 4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH2C≡CH), 1-propynyl (-C≡C-CH3), and the like. The alkynyl group may optionally be substituted with one or more substituents described in the present invention.

[0021] The term "alkoxy" means an alkyl group linked to the remainder of the molecule through an oxygen atom, where the alkyl group has the definition as described in the present invention. Unless otherwise specified in detail, the alkoxy group contains 1 to 12 carbon atoms. In one embodiment, the alkoxy group contains 1 to 6 carbon atoms; in another embodiment, the alkoxy group contains 1 to 4 carbon atoms; in yet another embodiment, the alkoxy group contains 1 to 3 carbon atoms. The alkoxy group may optionally be substituted with one or more substituents described in the present invention.

[0022] Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH3), ethoxy (EtO, -OCH2CH3), 1-propoxy (n-PrO, n-propoxy, -OCH2CH2CH3), 2-propoxy (i-PrO, i-propoxy, -OCH(CH3)2), 1-butoxy (n-BuO, n-butoxy, -OCH2CH2CH2CH3), 2-methyl-1-propoxy (i-BuO, i-butoxy, -OCH2CH(CH3)2), 2-butoxy (s-BuO, s-butoxy, -OCH(CH3)CH2CH3), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH3)3), 1-pentyloxy (n-pentyloxy, -OCH2CH2CH2CH2CH3), 2-pentyloxy (-OCH(CH3)CH2CH2CH3), 3-pentyloxy (-OCH(CH2CH3)2), 2-methyl-2-butoxy (-OC(CH3)2CH2CH3), 3-methyl-2-butoxy (-OCH(CH3)CH(CH3)2), 3-methyl-1-butoxy (-OCH2CH2CH(CH3)2), 2-methyl-1-butoxy (-OCH2CH(CH3)CH2CH3), and the like.

[0023] The term "haloalkyl" or "haloalkoxy" means that an alkyl or alkoxy group is substituted by one or more halogen atoms. Examples of such include, but are not limited to, trifluoromethyl (-CF3), trifluoromethoxy (-OCF3), difluoroethyl (-CH2CHF2, -CF2CH3, -CHFCH2F), trifluoroethyl (-CH2CF3, -CF2CH2F, -CFHCHF2), -CF(CH3)2, etc.

[0024] The terms "hydroxyalkyl" or "hydroxy-substituted alkyl" and "hydroxyalkoxy" or "hydroxy-substituted alkoxy" respectively mean an alkyl or alkoxy group which, as the case may be, is substituted by one or more hydroxy groups, where "hydroxyalkyl" and "hydroxyalkyl" can be used interchangeably. Examples of such include, but are not limited to, hydroxymethyl (-CH2OH), 2-hydroxyethyl (-CH2CH2OH), 1-hydroxyethyl (-CH(OH)CH3), 2-hydroxy-2-propyl (-COH(CH3)2), 2-hydroxy-2-methylpropyl (-CH2COH(CH3)2), 3-hydroxypropyl (-CH2CH2CH2OH), 2-hydroxypropyl (-CH2CH(OH)CH3), 2-hydroxy-2-methylpropyl (-CH2CH(OH)(CH3)CH3), hydroxy-methoxy (-OCH2OH), etc.

[0025] The term "cyano-substituted alkyl" or "cyanoalkyl" includes a C 1-10 linear or branched alkyl group substituted by one or more cyano groups. Some examples are that the cyanoalkyl is a C 1-6 "lower cyanoalkyl" substituted by one or more cyano groups, and some other examples are that the cyanoalkyl is a C 1-4 "lower cyanoalkyl" substituted by one or more cyano groups. Examples of such include, but are not limited to, CNCH2-, CNCH2CH2-, CNCH2CH2CH2-, CNCH2CHCNCH2-, etc.

[0026] The term "alkylamino" includes "N-alkylamino" and "N,N-dialkylamino", where the amino group is independently substituted by one or two alkyl groups respectively. Some examples are that the alkylamino is a lower alkylamino group with one or two C 1-6 alkyl groups attached to the nitrogen atom. Some other examples are that the alkylamino is a lower alkylamino group of C 1-3 . Suitable alkylamino groups can be monoalkylamino or dialkylamino. Examples of such include, but are not limited to, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino, etc.

[0027] The term "aminoalkyl" includes a C 1-10 linear or branched alkyl group substituted with one or more amino groups. In some embodiments, the aminoalkyl is a C 1-6 "lower aminoalkyl", and in other embodiments, the aminoalkyl is a C 1-4 "lower aminoalkyl". Such examples include, but are not limited to, aminomethyl, aminoethyl, aminopropyl, aminobutyl, and aminohexyl.

[0028] The term "cycloalkyl" denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic system containing 3-12 carbon atoms. Bicyclic cycloalkyls include spirobicycloalkyls, fused bicycloalkyls and bridged bicycloalkyls. In some embodiments, the cycloalkyl contains 3-12 carbon atoms; in other embodiments, the cycloalkyl contains 3-10 carbon atoms; in other embodiments, the cycloalkyl contains 3-8 carbon atoms; in other embodiments, the cycloalkyl contains 3-7 carbon atoms; in other embodiments, the cycloalkyl contains 3-6 carbon atoms; and in still other embodiments, the cycloalkyl is C7-C 12 cycloalkyl, which contains C7-C 12 monocycloalkyl, C7-C 12 bicycloalkyl (such as C7-C 12 spirobicycloalkyl, C7-C 12 fused bicycloalkyl and C7-C 12 bridged bicycloalkyl) or C7-C 12 tricycloalkyl. The cycloalkyl groups may independently be unsubstituted or substituted with one or more of the substituents described in the present invention. The term "monocyclic cycloalkyl" or "monocycloalkyl" denotes a cycloalkyl of a monocyclic system, where the cycloalkyl has the definition as described above, and the monocyclic cycloalkyl groups may independently be unsubstituted or substituted with one or more of the substituents described in the present invention. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like.

[0029] The term "cycloalkylalkyl" includes a cycloalkyl-substituted alkyl group. In some embodiments, the cycloalkylalkyl group refers to a "lower cycloalkylalkyl" group, i.e., a cycloalkyl group attached to a C 1-6 alkyl group. In other embodiments, the cycloalkylalkyl group refers to a group containing C 1-3"Phenylalkylene" of an alkyl group. Specific examples include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopentylethyl, cyclohexylethyl, etc. The cycloalkyl group on the cycloalkylalkyl can be further substituted by one or more substituents described in the present invention.

[0030] The terms "heterocyclic group" and "heterocycle" are used interchangeably herein and both refer to a monovalent or polyvalent, saturated or partially unsaturated, non-aromatic monocyclic, bicyclic or tricyclic system containing 3 - 12 ring atoms, wherein at least one ring atom is selected from nitrogen, oxygen and sulfur atoms. In some embodiments, the heterocyclic group or heterocycle contains 4 - 12 ring atoms. In some embodiments, the heterocyclic group or heterocycle contains 5 - 12 ring atoms. In some embodiments, the heterocyclic group or heterocycle contains 4 - 8 ring atoms. In some embodiments, the heterocyclic group or heterocycle contains 3 - 10 ring atoms. In some embodiments, the heterocyclic group or heterocycle contains 3 - 8 ring atoms. In some embodiments, the heterocyclic group or heterocycle contains 3 - 6 ring atoms. In some embodiments, the heterocyclic group or heterocycle contains 4 - 7 ring atoms. Unless otherwise specified, the heterocyclic group can be carbon-based or nitrogen-based, and the -CH2- group can optionally be replaced by -C(=O)-, the sulfur atom of the ring can optionally be oxidized to an S-oxide, and the nitrogen atom of the ring can optionally be oxidized to an N-oxide. The heterocyclic group includes saturated heterocyclic groups (heterocycloalkyls) and partially unsaturated heterocyclic groups. The said heterocyclic group has one or more connection points to connect with the rest of the molecule. Examples of the heterocyclic group include, but are not limited to: oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuryl, dihydrofuryl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxolanyl, dithiacyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxolanyl, dithiolanyl, thioxolanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, azepanyl, oxazepinyl (such as, 1,4-oxazepinyl, 1,2-oxazepinyl), diazepinyl (such as, 1,4-diazepinyl, 1,2-diazepinyl), dioxepinyl (such as, 1,4-dioxepinyl, 1,2-dioxepinyl), thiazepinyl (such as 1,4-thiazepinyl, 1,2-thiazepinyl) group (such as, 1,4-oxazepinyl group, 1,2-oxazepinyl group) group (such as, 1,4-diazepinyl group, 1,2-diazepinyl group) group (such as, 1,4-dioxepinyl group, 1,2-dioxepinyl group) group (such as 1,4-thiazepinyl group, 1,2-thiazepinyl (group), indolinyl, 1,2,3,4 - tetrahydroisoquinolinyl, 1,3 - benzodioxolyl, 2 - oxa - 5 - azabicyclo[2.2.1]hept - 5 - yl, 2 - azaspiro[4.4]nonanyl, 1,6 - dioxaspiro[4.4]nonanyl, 2 - azaspiro[4.5]decanyl, 8 - azaspiro[4.5]decanyl, 7 - azaspiro[4.5]decanyl, 3 - azaspiro[5.5]undecanyl, 2 - azaspiro[5.5]undecanyl, octahydro - 1H - isoindolyl, octahydrocyclopenta[c]pyrrolyl, dihydroindolyl, 1,2,3,4 - tetrahydroisoquinolinyl, hexahydrofuro[3,2 - b]furanyl, and dodecahydroisoquinolinyl, etc. Examples of the heterocyclic group in which the - CH2 - group is replaced by - C(=O) - include, but are not limited to, 2 - oxopyrrolidinyl, oxo - 1,3 - thiazolidinyl, 2 - piperidinonyl, and 3,5 - dioxopiperidinyl. Examples of the heterocyclic group in which the sulfur atom is oxidized include, but are not limited to, sulfolanyl, 1,1 - dioxothiomorpholinyl. The said heterocyclic group may optionally be substituted by one or more substituents described in the present invention.

[0031] Also in one embodiment, the heterocyclic group is a heterocyclic group composed of 4 - 7 atoms, which refers to a monovalent or polyvalent, saturated or partially unsaturated non - aromatic monocyclic or bicyclic ring containing 4 - 7 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur, and oxygen atoms. Unless otherwise specified, the heterocyclic group composed of 4 - 7 atoms can be carbon - based or nitrogen - based, and the - CH2 - group can optionally be replaced by - C(=O) -. The sulfur atom in the ring can optionally be oxidized to S - oxide. The nitrogen atom in the ring can optionally be oxidized to N - oxide. The heterocyclic group composed of 4 - 7 atoms has one or more connection points to connect with the rest of the molecule. Among them, examples of the monocyclic heterocyclic group composed of 4 - 7 atoms include, but are not limited to: azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrrolinyl, pyrazolinyl, pyrazolyl, imidazolinyl, imidazolyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, tetrahydropyranyl, dihydropyranyl, 2H - pyranyl, 4H - pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxolanyl, dithiolanyl, thioxolanyl, 1,2 - oxazinyl, 1,2 - thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl(1,4 - oxazepinyl, 1,2 - oxazepinyl), diazepinyl(1,4 - diazepinyl, 1,2 - diazepinyl), and thiazepinyl(1,4 - thiazepinyl, 1,2 - thiazepinyl) group (1,4 - oxazepinyl group, 1,2 - oxazepinyl group) group (1,4 - diazepinyl group, 1,2 - diazepinyl group) group (1,4 - thiazepinyl group, 1,2 - thiazepinyl (radicals), etc.; examples of bicyclic heterocyclic groups composed of 4 to 7 atoms include, but are not limited to: 3-azabicyclo[3,2,0]heptane, 3-oxabicyclo[3,2,0]heptane, etc.; examples of heterocyclic groups composed of 4 to 7 atoms in which the -CH2- group is replaced by -C(=O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidinonyl, and 3,5-dioxopiperidinyl; examples of heterocyclic groups composed of 4 to 7 atoms in which the sulfur atom is oxidized include, but are not limited to, sulfolanyl, 1,1-dioxotetrahydrothiophene, 1,1-dioxotetrahydropyran, 1,1-dioxothiomorpholinyl. The heterocyclic groups composed of 4 to 7 atoms may optionally be substituted by one or more substituents described in the present invention.

[0032] The term "heterocyclylalkyl" includes alkyl groups substituted by a heterocyclyl group, where both the heterocyclyl group and the alkyl group have the meanings as described in the present invention. Such examples include, but are not limited to, tetrahydrofuranylmethyl, pyrrol-2-ylmethyl, morpholin-4-ylethyl, piperazin-4-ylethyl, piperidin-4-ylethyl, etc.

[0033] The term "aryl" refers to monocyclic, bicyclic, and tricyclic carbocyclic systems containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, where at least one ring system is aromatic, each ring system contains a ring composed of 3 to 7 atoms, and has one or more connection points to the rest of the molecule. The term "aryl" can be used interchangeably with the term "aromatic ring". Examples of aryl groups can include phenyl, naphthyl, and anthracenyl. The aryl groups may independently and optionally be substituted by one or more substituents described in the present invention.

[0034] The term "arylalkyl" or "aralkyl" includes aryl-substituted alkyl groups. In some embodiments, the arylalkyl group refers to a "lower arylalkyl" group, i.e., an aryl group attached to an alkyl group of C 1-6 In other embodiments, the arylalkyl group refers to a "phenylalkylene" containing an alkyl of C 1-3 Specific examples include, but are not limited to, benzyl, diphenylmethyl, phenethyl, etc. The aryl on the arylalkyl may be further substituted by one or more substituents described in the present invention.

[0035] The term "heteroaryl" refers to a monocyclic, bicyclic, and tricyclic system containing 5 - 12 ring atoms, or 5 - 10 ring atoms, or 5 - 6 ring atoms, wherein at least one ring is aromatic and at least one aromatic ring contains one or more heteroatoms, and each ring system contains a ring composed of 5 - 7 atoms and has one or more connection points connected to the rest of the molecule. The term "heteroaryl" can be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound". In one embodiment, the heteroaryl is a heteroaryl composed of 5 - 12 atoms containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In another embodiment, the heteroaryl is a heteroaryl composed of 5 - 10 atoms containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In another embodiment, the heteroaryl is a heteroaryl composed of 5 - 6 atoms containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. The heteroaryl group is optionally substituted by one or more substituents described in the present invention.

[0036] Examples of heteroaryl groups include, but are not limited to, 2 - furyl, 3 - furyl, N - imidazolyl, 2 - imidazolyl, 4 - imidazolyl, 5 - imidazolyl, 3 - isoxazolyl, 4 - isoxazolyl, 5 - isoxazolyl, 2 - oxazolyl, 4 - oxazolyl, 5 - oxazolyl, N - pyrrolyl, 2 - pyrrolyl, 3 - pyrrolyl, 2 - pyridyl, 3 - pyridyl, 4 - pyridyl, 2 - pyrimidinyl, 4 - pyrimidinyl, 5 - pyrimidinyl, pyridazinyl (such as 3 - pyridazinyl), 2 - thiazolyl, 4 - thiazolyl, 5 - thiazolyl, tetrazolyl (such as 5 - tetrazolyl), triazolyl (such as 2 - triazolyl and 5 - triazolyl), 2 - thienyl, 3 - thienyl, pyrazolyl (such as 2 - pyrazolyl), isothiazolyl, 1,2,3 - oxadiazolyl, 1,2,5 - oxadiazolyl, 1,2,4 - oxadiazolyl, 1,2,3 - triazolyl, 1,2,3 - thiadiazolyl, 1,3,4 - thiadiazolyl, 1,2,5 - thiadiazolyl, pyrazinyl, 1,3,5 - triazinyl; also include the following bicyclics, but are by no means limited to these bicyclics: benzimidazolyl, benzofuryl, benzothienyl, indolyl (such as 2 - indolyl), purinyl, quinolinyl (such as 2 - quinolinyl, 3 - quinolinyl, 4 - quinolinyl), isoquinolinyl (such as 1 - isoquinolinyl, 3 - isoquinolinyl or 4 - isoquinolinyl), imidazo[1,2 - a]pyridyl, pyrazolo[1,5 - a]pyridyl, pyrazolo[1,5 - a]pyrimidinyl, imidazo[1,2 - b]pyridazinyl, [1,2,4]triazolo[4,3 - b]pyridazinyl, [1,2,4]triazolo[1,5 - a]pyrimidinyl, [1,2,4]triazolo[1,5 - a]pyridyl, and so on.

[0037] The term "heteroarylalkyl" means an alkyl group substituted by one or more heteroaryl groups, where both the heteroaryl and alkyl groups have the meanings as described in the present invention. Examples of such include, but are not limited to, pyridin-2-ylmethyl, imidazol-2-ylmethyl, furan-2-ylethyl, indol-3-ylmethyl, and the like.

[0038] The term "halogen" refers to F, Cl, Br or I.

[0039] "Pharmaceutically acceptable salts" used in the present invention refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in the literature: S.M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. The salts formed from pharmaceutically acceptable non-toxic acids include, but are not limited to, inorganic acid salts formed by reacting with amino groups such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, and organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or other methods described in the literature such as ion exchange to obtain these salts. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. The salts obtained by appropriate bases include salts of alkali metals, alkaline earth metals, ammonium and N + (C 1-4 alkyl)4. The present invention also contemplates quaternary ammonium salts formed from compounds of any group containing N. Water-soluble or oil-soluble or dispersible products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations formed with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1-8 sulfonates and aromatic sulfonates.

[0040] The "solvate" of the present invention refers to an association formed by one or more solvent molecules and the compound of the present invention. Solvents forming solvates include, but are not limited to, water, isopropyl alcohol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association in which the solvent molecule is water.

[0041] Description of the Compounds of the Present Invention

[0042] The present invention discloses a novel class of pyrimidineamine compounds, which can be used as inhibitors of PI3-kinase activity, especially PI3K-δ activity, for preventing, treating, and / or alleviating diseases, disorders, and / or conditions associated with abnormal PI3-kinase, such as respiratory diseases, viral infections, non-viral respiratory infections, allergic diseases, autoimmune diseases, inflammatory diseases, cardiovascular diseases, malignant blood diseases, neurodegenerative diseases, pancreatitis, multiple organ failure, kidney diseases, platelet aggregation, cancer, sperm motility, transplant rejection, graft rejection, lung injury, or pain, etc. Compared with existing compounds of the same kind, the compounds of the present invention have better pharmacological activities. Specifically, the compounds of the present invention show excellent inhibitory activity and kinase selectivity against PI3-kinase. Therefore, the compounds of the present invention have very good development prospects.

[0043] The disclosed compounds of the present invention can show strong inhibitory activity against PI3-kinase, especially PI3K-δ. On the one hand, the present invention relates to a pyrimidineamine compound having the structure shown in formula (I):

[0044]

[0045] or its stereoisomers, tautomers, N-oxides, solvates, or pharmaceutically acceptable salts;

[0046] Wherein,

[0047] W is C 3-8 cycloalkyl, C 2-9 heterocyclic group, C 6-12 aryl, or C 1-9 heteroaryl; wherein W is optionally substituted by 0, 1, 2, 3, or 4 R 7 substituents;

[0048] R a , R b and R 1 are each independently H, D, F, -CN, -NO2, -NH2, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6Aminoalkyl, or C 1-6 Cyanoalkyl;

[0049] R 2 、R 4 、R 5 and R 6 are each independently H, D, F, Cl, Br, I, -OH, -CN, -NO2, -NR e R f 、C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, C 2-9 heterocyclic group, C 3-8 cycloalkyl, C 6-10 aryl, or C 1-9 heteroaryl; wherein each of said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, C 2-9 heterocyclic group, C 3-8 cycloalkyl, C 6-10 aryl and C 1-9 heteroaryl is independently optionally substituted with 0, 1, 2, 3 or 4 groups independently selected from H, D, oxo(=O), F, Cl, Br, I, -OH, -NH2, -CN, -NO2, C 1-6 alkyl and C 1-6 alkoxy;

[0050] R 3 is H, D, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, -NR 10a R 10 、-C(=O)R9 、 -OC(=O)R 9 、 -C(=O)OR 9a 、 -S(=O) 0-2 R 9 、 -OS(=O) 1-2 R 9 、 -S(=O) 1-2 OR 9a 、 -N(R 10a )C(=O)R 10 、 -C(=O)NR 10a R 10 、 -OC(=O)NR 10a R 10 、 -N(R 10a )S(=O) 1-2 R 10 、 -S(=O) 1-2 NR 10a R 10 、 -N(R 10a )C(=O)NR 10a R 10 、 C 3-8 cycloalkyl, C 3-8 cycloalkyl C 1-6 alkyl, C 2-9 heterocyclic group, C 2-9 heterocyclic group C 1-6 alkyl, C 6-12 aryl, C 6-12 aryl C 1-6 alkyl, C 1-9 heteroaryl, or C 1-9 heteroaryl C 1-6 alkyl; wherein R 3 is optionally substituted by 0, 1, 2, 3 or 4 R 8 ;

[0051] R 7 and R 8 , each time it appears, is independently H, D, oxo (=O), F, Cl, Br, I, -OH, -CN, -NO2, -NH2, -C(=O)R 9 、 -OC(=O)R 9 、 -C(=O)OR 9a 、 -S(=O) 0-2 R 9 、 -OS(=O) 1-2 R 9 、 -S(=O) 1-2 OR 9a 、 -N(R 10a )C(=O)R 10 、 -C(=O)NR10a R 10 ,-OC(=O)NR 10a R 10 ,-N(R 10a )S(=O) 1-2 R 10 ,-S(=O) 1- 2NR 10a R 10 ,-N(R 10a )C(=O)NR 10a R 10 ,C 1-6 alkyl,C 2-6 alkenyl,C 2-6 alkynyl,C 1-6 haloalkyl,C 1-6 hydroxyalkyl,C 1-6 aminoalkyl,C 1-6 cyanoalkyl,C 1-6 alkoxy,C 1-6 alkylamino,C 3-8 cycloalkyl,C 3-8 cycloalkylC 1-6 alkyl,C 2-9 heterocyclic group,C 2-9 heterocyclic groupC 1-6 alkyl,C 6-12 aryl,C 6-12 arylC 1-6 alkyl,C 1-9 heteroaryl,orC 1-9 heteroarylC 1-6 alkyl;wherein each -C(=O)R 9 ,-OC(=O)R 9 ,-C(=O)OR 9a ,-S(=O) 0-2 R 9 ,-OS(=O) 1-2 R 9 ,-S(=O) 1- 2OR 9a ,-N(R 10a )C(=O)R 10 ,-C(=O)NR 10a R 10 ,C 1-6 alkyl,C 2-6 alkenyl,C 2-6 alkynyl,C 1-6 haloalkyl,C 1-6 hydroxyalkyl,C 1-6 aminoalkyl,C 1-6 cyanoalkyl,C 1-6 alkoxy,C 1-6alkylamino, C 3-8 cycloalkyl, C 3-8 cycloalkyl C 1-6 alkyl, C 2-9 heterocyclic group, C 2-9 heterocyclic group C 1-6 alkyl, C 6-12 aryl, C 6-12 aryl C 1-6 alkyl, C 1-9 heteroaryl and C 1-9 heteroaryl C 1-6 The alkyl is independently optionally substituted by 0, 1, 2, 3 or 4 groups independently selected from H, D, oxo(=O), F, Cl, Br, -OH, -NH2, -CN, -NO2, C 1-6 alkyl and C 1-6 alkoxy; and

[0052] R e 、R f 、R 9 、R 9a 、R 10 and R 10a , upon each occurrence, are each independently H, D, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl C 1-6 alkyl, C 2-9 heterocyclic group, C 2-9 heterocyclic group C 1-6 alkyl, C 6-12 aryl, C 6-12 aryl C 1-6 alkyl, C 1-9 heteroaryl, or C 1-9 heteroaryl C 1-6 alkyl; wherein each of said C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl C 1-6 alkyl, C 2-9 heterocyclic group, C 2-9 heterocyclic group C 1-6 alkyl, C 6-12 aryl, C 6-12 aryl C 1-6 alkyl, C 1-9 heteroaryl and C 1-9 heteroaryl C 1-6The alkyl group is independently optionally substituted with 0, 1, 2, 3, or 4 groups independently selected from H, D, oxo (═O), F, Cl, Br, I, -OH, -NH2, -CN, -NO2, C 1-6 alkyl group and C 1-6 alkoxy group.

[0053] In some embodiments, W is C 3-6 heterocyclic group, phenyl group, or heteroaryl group composed of 5 to 6 atoms; wherein W is optionally substituted with 0, 1, 2, 3, or 4 R 7 substituents.

[0054] In some embodiments, W is phenyl group, pyridyl group, pyridazinyl group, pyrazinyl group, pyrimidinyl group, triazinyl group, pyrazolyl group, thiazolyl group, imidazolyl group, oxazolyl group, thiadiazolyl group,

[0055] wherein Y 1 is O, S, or -NH-; and

[0056] wherein W is optionally substituted with 0, 1, 2, 3, or 4 R 7 substituents.

[0057] In some embodiments, R a , R b and R 1 are each independently H, D, F, Cl, Br, I, -OH, -CN, -NO2, -NH2, methyl group, ethyl group, methoxy group, ethoxy group, halomethyl group, or haloethyl group.

[0058] In some embodiments, R 2 is -NR e R f , C 1-4 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl group, C 1-4 alkoxy group, C 1-4 haloalkyl group, cyclopropyl group, phenyl group, or heteroaryl group composed of 5 to 6 atoms; wherein each of the -NR e R f , C 1-4 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl group, C 1-4 alkoxy group, C 1-4 haloalkyl group, cyclopropyl group, phenyl group, and heteroaryl group composed of 5 to 6 atoms are independently optionally substituted with 0, 1, 2, 3, or 4 groups independently selected from H, D, oxo (═O), F, Cl, Br, I, -OH, -NH2, -CN, -NO2, C 1-4 alkyl group and C 1-4 alkoxy group.

[0059] In some embodiments, R 2 is H, D, F, Cl, Br, I, -OH, -CN, -NO2, -NH2, methyl, ethyl, isopropyl, methoxy, ethoxy, vinyl, allyl, ethynyl, propynyl, halomethyl, haloethyl, phenyl, or cyclopropyl.

[0060] In some embodiments, R 3 is C 2-4 alkenyl, C 2-4 alkynyl, -NR 10a R 10 -, -C(=O)NR 10a R 10 -, C 3-6 cycloalkyl, C 3-6 heterocyclic group, phenyl, or heteroaryl composed of 5 - 6 atoms; wherein R 3 is optionally substituted by 0, 1, 2, 3, or 4 R 8 groups.

[0061] In some embodiments, R 3 is

[0062] vinyl, ethynyl, -C(=O)NH-C 1-3 alkyl, wherein,

[0063] represents a single bond or a double bond;

[0064] X 1 is O, S, -NH-, -(CH2) t1 -, -X 2 -(CH2) t1 -, or -(CH2) t1 -X 2 -(CH2) t2 -;

[0065] X 2 is, independently at each occurrence, O, S, -NH-, or -CH2-;

[0066] X 3 is O, S, or -NH-;

[0067] each of t1 and t2 is independently 0, 1, 2, or 3; and

[0068] n is 1, 2, or 3;

[0069] wherein R 3 is optionally substituted by 0, 1, 2, 3, or 4 R 8 groups.

[0070] In some embodiments, R 3 is vinyl, ethynyl, -C(=O)NH-C 1-3 alkyl, wherein R 3 is optionally substituted with 0, 1, 2, 3, or 4 R 8 groups.

[0071] In some embodiments, R 4 , R 5 , and R 6 are each independently H, D, F, Cl, Br, I, -OH, -CN, -NO2, -NH2, methyl, ethyl, isopropyl, methoxy, ethoxy, vinyl, propenyl, ethynyl, propynyl, halomethyl, haloethyl, phenyl, or cyclopropyl.

[0072] In some embodiments, R 7 and R 8 , each time they appear, are independently H, D, oxo(=O), F, Cl, Br, I, -OH, -CN, -NO2, -NH2, -C(=O)R 9 , -OC(=O)R 9 , -C(=O)OR 9a , -S(=O) 0-2 R 9 , -OS(=O) 1-2 R 9 , -S(=O) 1-2 OR 9a , -N(R 10a )C(=O)R 10 , -C(=O)NR 10a R 10 , -OC(=O)NR 10a R 10 , -N(R 10a )S(=O) 1-2 R 10 , -S(=O) 1-2 NR 10a R 10 , -N(R 10a )C(=O)NR 10a R 10 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 aminoalkyl, C 1-4 cyanoalkyl, C 1-4 alkoxy, C 1-4 alkylamino, cyclopropyl, C3-6 a heterocyclic group, a phenyl group, or a pyridyl group; wherein each -C(=O)R 9 , -OC(=O)R 9 , -C(=O)OR 9a , -S(=O) 0-2 R 9 , -OS(=O) 1-2 R 9 , -S(=O) 1-2 OR 9a , -N(R 10a )C(=O)R 10 , -C(=O)NR 10a R 10 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 aminoalkyl, C 1-4 cyanoalkyl, C 1-4 alkoxy, C 1-4 alkylamino, cyclopropyl, C 3-6 the heterocyclic group, the phenyl group, and the pyridyl group are each independently optionally substituted with 0, 1, 2, 3, or 4 groups independently selected from H, D, oxo(=O), F, Cl, Br, -OH, -NH2, -CN, -NO2, C 1-4 alkyl and C 1-4 alkoxy.

[0073] In some embodiments, R e , R f , R 9 , R 9a , R 10 and R 10a , upon each occurrence, are each independently H, D, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 3-6 cycloalkyl, C 3-6 cycloalkylC 1-6 alkyl, C 3-6 heterocyclic group, C 3-6 heterocyclic groupC 1-4 alkyl, C 6-10 aryl, C 6-10 arylC 1-4 alkyl, C 1-9 heteroaryl, or C 1-9 heteroarylC 1-4 alkyl; wherein each C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C3-6 Cycloalkyl, C 3-6 Cycloalkyl C 1-6 Alkyl, C 3-6 Heterocyclic group, C 3-6 Heterocyclic group C 1-4 Alkyl, C 6-10 Aryl, C 6-10 Aryl C 1-4 Alkyl, C 1-9 Heteroaryl and C 1-9 Heteroaryl C 1-4 The alkyl is independently optionally substituted with 0, 1, 2, 3, or 4 groups independently selected from H, D, oxo(=O), F, Cl, Br, I, -OH, -NH2, -CN, -NO2, C 1-4 Alkyl and C 1-4 and alkoxy groups.

[0074] In some embodiments, R 7 and R 8 , each time it appears, are independently H, D, oxo(=O), F, Cl, Br, I, -OH, -CN, -NO2, -NH2, -CH3, -CH2CH3, -CH(CH3)CH3, -CH2CH(OH)CH3, -CH2CH2OH, -CF3, -CH2CF3, cyclopropyl,

[0075] In some embodiments, wherein the compound is a compound having one of the following structures:

[0076]

[0077]

[0078]

[0079]

[0080] or its stereoisomers, tautomers, N-oxides, solvates, or pharmaceutically acceptable salts.

[0081] Unless otherwise specified, the stereoisomers, tautomers, solvates, metabolites, or pharmaceutically acceptable salts of the compounds represented by formula (I) are all included within the scope of the present invention.

[0082] The compounds disclosed in the present invention may contain asymmetric or chiral centers and thus may exist in different stereoisomeric forms. The present invention aims to include all stereoisomeric forms of the compounds represented by formula (I), including but not limited to diastereoisomers, enantiomers, atropisomers, and geometric (or conformational) isomers, as well as mixtures thereof such as racemic mixtures, as part of the present invention.

[0083] In the structures disclosed in the present invention, when the stereochemistry of any particular chiral atom is not specified, then all stereoisomers of that structure are contemplated within the scope of the present invention and are included in the compounds disclosed in the present invention. When the stereochemistry is specified by a solid wedge or a dashed line representing a particular configuration, then the stereoisomers of that structure are thereby defined and specified.

[0084] The compounds represented by formula (I) may exist in the form of salts. In one embodiment, the salts refer to pharmaceutically acceptable salts. The term "pharmaceutically acceptable" means that the substance or composition must be chemically and / or toxicologically compatible with the other ingredients of the formulation and / or the mammal to be treated therewith. In another embodiment, the salts need not be pharmaceutically acceptable salts and may be intermediates for the preparation and / or purification of the compounds represented by formula (I) and / or for the separation of the enantiomers of the compounds represented by formula (I).

[0085] On the other hand, the present invention relates to intermediates for the preparation of the compounds represented by formula (I).

[0086] On the other hand, the present invention relates to methods for the preparation, separation, and purification of the compounds represented by formula (I).

[0087] On the other hand, the present invention provides a pharmaceutical composition comprising the compounds of the present invention. In one embodiment, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable excipient, diluent, or carrier, or a combination thereof. In another embodiment, the pharmaceutical composition may be in the form of a liquid, solid, semi-solid, gel, or spray.

[0088] In some embodiments, the pharmaceutical composition of the present invention further comprises an additional therapeutic agent.

[0089] On the other hand, the present invention relates to the use of the compounds of the present invention or the pharmaceutical compositions of the present invention in the preparation of a medicament for preventing, treating, and / or alleviating diseases, disorders, and / or conditions associated with abnormal PI3-kinase, or for inhibiting PI3-kinase activity.

[0090] In some embodiments, the PI3-kinase abnormality-related diseases, disorders, and / or conditions are selected from respiratory diseases, viral infections, non-viral respiratory infections, allergic diseases, autoimmune diseases, inflammatory diseases, cardiovascular diseases, hematological malignancies, neurodegenerative diseases, pancreatitis, multiple organ failure, kidney diseases, platelet aggregation, cancer, sperm motility, transplant rejection, graft rejection, lung injury, or pain.

[0091] In some embodiments, the PI3-kinase abnormality-related diseases, disorders, and / or conditions are selected from asthma, chronic obstructive pulmonary disease (COPD), viral respiratory infections, exacerbation of viral respiratory diseases, aspergillosis, leishmaniasis, allergic rhinitis, atopic dermatitis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, thrombosis, atherosclerosis, hematological malignancies, neurodegenerative diseases, pancreatitis, multiple organ failure, kidney diseases, platelet aggregation, cancer, sperm motility, transplant rejection, graft rejection, lung injury, pain associated with rheumatoid arthritis or osteoarthritis, back pain, systemic inflammatory pain, post-hepatic neuralgia, diabetic neuropathy, inflammatory neuropathic pain (trauma), trigeminal neuralgia, or central pain.

[0092] In some embodiments, the cancer is selected from acute myeloid leukemia, myelodysplastic syndrome, myeloproliferative disease, chronic myeloid leukemia, T-cell acute lymphoblastic leukemia, B-cell acute lymphoblastic leukemia, non-Hodgkin lymphoma, B-cell lymphoma, solid tumors, or breast cancer.

[0093] In some embodiments, the PI3-kinase is PI3K-δ.

[0094] Pharmaceutical Compositions, Formulations, and Administration of the Compounds of the Invention

[0095] The present invention provides a pharmaceutical composition comprising a compound disclosed in the present invention, or a compound listed in the Examples, or a stereoisomer, tautomer, N-oxide, solvate, metabolite, or pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient, diluent, carrier, solvent, or combination thereof. The amount of the compound in the pharmaceutical composition disclosed in the present invention refers to the amount capable of effectively detecting the inhibition of a protein kinase in a biological sample or in a patient.

[0096] It should also be recognized that certain compounds of the present invention may exist in free form for treatment, or, if appropriate, in the form of their pharmaceutically acceptable derivatives. Some non-limiting embodiments of pharmaceutically acceptable derivatives include pharmaceutically acceptable salts, esters, salts of these esters, or any additional adducts or derivatives that can directly or indirectly provide the compounds, metabolites, or residues described in the present invention when administered to a patient in need.

[0097] A variety of carriers for formulating pharmaceutically acceptable compositions, and well-known techniques for their preparation, are disclosed in the literature such as Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D. B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988 - 1999, Marcel Dekker, New York, the respective contents of which are incorporated herein by reference. Except for any conventional carrier that is incompatible with the compounds disclosed herein, such as by producing any undesired biological effect, or interacting in a detrimental manner with any other component in a pharmaceutically acceptable composition, its use is within the scope of the present invention.

[0098] The pharmaceutical compositions provided by the present invention can be co-formulated with other active ingredients that do not impair the intended therapeutic effect, or with substances that supplement the intended effect.

[0099] Use of the compounds and compositions of the present invention

[0100] The compounds of the present invention are inhibitors of kinase activity, particularly inhibitors of PI3-kinase activity. Compounds as PI3-kinase inhibitors can be used to treat disorders in which the underlying pathology (at least in part) is attributed to inappropriate PI3-kinase activity, such as asthma, chronic obstructive pulmonary disease (COPD), viral infections, non-viral respiratory infections, allergic diseases, autoimmune diseases, inflammatory diseases, cardiovascular diseases, hematological malignancies, neurodegenerative diseases, pancreatitis, multiple organ failure, kidney diseases, platelet aggregation, cancer, sperm motility, transplant rejection, graft rejection, lung injury or pain, etc. "Inappropriate PI3-kinase activity" refers to any PI3-kinase activity that deviates from the normal PI3-kinase activity desired in a particular patient. Inappropriate PI3-kinase can take, for example, the form of an abnormal increase in activity, or a distortion or dysregulation of PI3-kinase. These inappropriate activities can result from, for example, overexpression or mutation of protein kinases that lead to inappropriate or uncontrolled activation. Thus, in another aspect, the present invention relates to methods for treating said diseases or disorders.

[0101] Such diseases or disorders include, but are not limited to, respiratory diseases, including asthma, chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis (IPF); viral infections, including viral respiratory infections and exacerbations of viral respiratory diseases, such as asthma and COPD; non-viral respiratory infections, including aspergillosis and leishmaniasis; allergic diseases, including allergic rhinitis and atopic dermatitis; autoimmune diseases, including rheumatoid arthritis and multiple sclerosis; inflammatory diseases, including inflammatory bowel disease; cardiovascular diseases, including thrombosis and atherosclerosis; hematological malignancies; neurodegenerative diseases; pancreatitis; multiple organ failure; kidney diseases; platelet aggregation; cancer; sperm motility; transplant rejection; graft rejection; lung injury; and pain, including pain associated with rheumatoid arthritis or osteoarthritis, back pain, systemic inflammatory pain, post-hepatic neuralgia, diabetic neuropathy, inflammatory neuropathic pain (trauma), trigeminal neuralgia and central pain. In one embodiment, such disorders include respiratory diseases, including asthma and chronic obstructive pulmonary disease (COPD); allergic diseases, including allergic rhinitis and atopic dermatitis; autoimmune diseases, including rheumatoid arthritis and multiple sclerosis; inflammatory diseases, including inflammatory bowel disease; cardiovascular diseases, including thrombosis and atherosclerosis; hematological malignancies; neurodegenerative diseases; pancreatitis; multiple organ failure; kidney diseases; platelet aggregation; cancer; sperm motility; transplant rejection; graft rejection; lung injury; and pain, including pain associated with rheumatoid arthritis or osteoarthritis, back pain, systemic inflammatory pain, post-hepatic neuralgia, diabetic neuropathy, inflammatory neuropathic pain (trauma), trigeminal neuralgia and central pain.

[0102] In such diseases or disorders, the cancer is selected from acute myeloid leukemia, myelodysplastic syndromes, myeloproliferative diseases, chronic myeloid leukemia, T-cell acute lymphoblastic leukemia, B-cell acute lymphoblastic leukemia, non-Hodgkin lymphoma, B-cell lymphoma, solid tumors, or breast cancer.

[0103] The treatment method of the present invention comprises administering to a patient in need thereof a safe and effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Each embodiment of the present invention includes a method of treating any disorder or disease mentioned in the present invention by administering to a patient in need thereof a safe and effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0104] Combined therapy

[0105] The compounds of the present invention can be administered as a single active agent, or can be administered in combination with other therapeutic agents, including other compounds having the same or similar therapeutic activity and determined to be safe and effective for such combination administration.

[0106] On the one hand, the present invention provides a method for treating, preventing or ameliorating a disease or disorder, comprising administering a safe and effective amount of a combined medicament comprising a compound disclosed herein of the present invention and one or more therapeutic active agents. In some embodiments, the combined medicament comprises one or two other therapeutic agents.

[0107] Examples of other therapeutic agents include, but are not limited to: anti-cancer agents, including chemotherapeutic agents and anti-proliferative agents; anti-inflammatory agents; and immunomodulators or immunosuppressants.

[0108] On the other hand, the present invention provides a product comprising a compound of the present invention and at least one other therapeutic agent, which can be formulated into a combination for simultaneous, separate or sequential administration in therapy. In some embodiments, the therapy is for treating a disease or condition mediated by one or more protein kinases, such as PI3k-kinase activity. The product provided by the combined preparation includes a composition present in the same pharmaceutical composition and comprising a compound disclosed herein of the present invention and other therapeutic agents, or the compound disclosed herein of the present invention and other therapeutic agents in different forms, for example, a kit.

[0109] On the other hand, the present invention provides a pharmaceutical composition comprising a compound disclosed herein of the present invention and one or more other therapeutic agents. In some embodiments, the pharmaceutical composition may comprise a pharmaceutically acceptable excipient as described above.

[0110] On the other hand, the present invention provides a kit comprising two or more separate pharmaceutical compositions, wherein at least one pharmaceutical composition comprises a compound disclosed herein of the present invention. In some embodiments, the kit includes means for separately holding the compositions, such as containers, separate bottles or separate foil blisters. An example of such a kit is a blister pack, which is commonly used for packaging tablets, capsules, etc.

[0111] The compound disclosed herein of the present invention can be administered as a single active component or, for example, as an adjuvant, in combination with other therapeutic agents.

[0112] In some embodiments, the other therapeutic agents include, for example, immunosuppressants, immunomodulators or other anti-inflammatory agents, drugs for treating or preventing acute or chronic rejection of allogeneic or xenogeneic transplantation, or inflammation, or autoimmune diseases, or chemotherapeutic agents, such as anti-proliferative agents for malignant tumor cells.

[0113] The compound of formula (I) of the present invention is co-administered with other immunosuppressants / immunomodulators, anti-inflammatory agents, chemotherapeutic agents or anti-infective agents, wherein the dosage of the co-administered immunosuppressants / immunomodulators, anti-inflammatory agents, chemotherapeutic agents or anti-infective agents depends on the type of combination, whether it is a steroid compound or a calcineurin inhibitor, and the specific drug and treatment situation being used for treatment, etc.

[0114] Examples of anti-inflammatory agents include non-steroidal anti-inflammatory drugs (NSAIDs). Examples of NSAIDs include sodium cromoglycate, nedocromil sodium, phosphodiesterase (PDE) inhibitors (such as theophylline, PDE4 inhibitors, or mixed PDE3 / PDE4 inhibitors), leukotriene antagonists, leukotriene synthesis inhibitors (such as montelukast), iNOS inhibitors, trypsin and elastase inhibitors, β-2 integrin antagonists and adenosine receptor agonists or antagonists (such as, adenosine 2α receptor agonists), cytokine antagonists (such as chemokine receptor antagonists, including CCR3 antagonists), cytokine synthesis inhibitors, or 5-lipoxygenase inhibitors.

[0115] The compounds of formula (I) can also be advantageously used in combinations with other compounds, or in combinations with other therapeutic agents, especially anti-proliferative agents. Such anti-proliferative agents include, but are not limited to, aromatase inhibitors; anti-estrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule active agents; alkylating agents; histone deacetylase inhibitors; compounds that induce the process of cell differentiation; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; anti-tumor antimetabolites; platinum compounds; compounds that target / reduce protein or lipid kinase activity and other anti-angiogenic compounds; compounds that target, reduce or inhibit protein or lipid phosphatase activity; gonadorelin agonists; anti-androgens; methionine aminopeptidase inhibitors; bisphosphonates; biological response modifiers; anti-proliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic subtypes; telomerase inhibitors; proteasome inhibitors; agents for treating hematological malignancies; compounds that target, reduce or inhibit Flt-3 activity; Hsp90 inhibitors; temozolomide and calcium folinate.

[0116] "Combination" means a fixed combination in a single dosage unit form or a kit of parts for combined administration, wherein the compounds disclosed in the present invention and the combination partner can be independently administered at the same time or can be administered separately at certain time intervals, especially such that the combination partner exhibits cooperation, such as synergism. As used in the present invention, terms such as "co-administration" or "combined administration" are intended to encompass the administration of the selected combination partner to a single individual (such as a patient) in need thereof, and are intended to include treatment regimens in which the substances need not be administered by the same route of administration or simultaneously.

[0117] Method of treatment

[0118] In some embodiments, the treatment methods disclosed in the present invention include administering a safe and effective amount of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention to a patient in need thereof. Each embodiment disclosed in the present invention includes a method for treating a disease or disorder described in the present invention by administering a safe and effective amount of a compound disclosed in the present invention or a pharmaceutical composition comprising a compound disclosed in the present invention to a patient in need thereof.

[0119] In some embodiments, the compounds disclosed in the present invention or the pharmaceutical compositions comprising the compounds disclosed in the present invention can be administered as a single dose, or according to a dosing regimen, at different time intervals over a specified period of time. For example, once, twice, three times, or four times a day. In one embodiment, it is administered once a day. In another embodiment, it is administered twice a day. Administration can be continued until a desired therapeutic effect is achieved or to maintain the desired therapeutic effect indefinitely. The appropriate dosing regimen for the compounds disclosed in the present invention or the pharmaceutical compositions comprising the compounds disclosed in the present invention depends on the pharmacokinetic properties of the compound, such as dilution, distribution, and half-life, which can be determined by a person skilled in the art. In addition, the appropriate dosing regimen for the compounds disclosed in the present invention or the pharmaceutical compositions comprising the compounds disclosed in the present invention, including the duration of implementing the regimen, depends on factors within the knowledge and experience of a person skilled in the art such as the disease being treated, the severity of the disease being treated, the age and physical condition of the patient being treated, the medical history of the patient being treated, the nature of concurrent therapies, the desired therapeutic effect, etc. A person skilled in the art should also understand that adjustments to the appropriate dosing regimen may be required for the response of an individual patient to the dosing regimen or when an individual patient's needs change over time.

[0120] The pharmaceutical composition or combination / union of the present invention may be about 1 - 1000 mg of the active ingredient, or about 1 - 500 mg, or about 1 - 250 mg, or about 1 - 150 mg, or about 0.5 - 100 mg, or about 1 - 50 mg of the active ingredient per unit dose for an individual weighing about 50 - 70 kg. The therapeutically effective dose of the compound, pharmaceutical composition, or their combination depends on the species, body weight, age of the individual, and the severity of the individual disease, disorder, or condition to be treated. A physician, clinician, or veterinarian of ordinary skill in the art can easily determine the effective amount of each active ingredient for preventing, treating, or inhibiting the progression of a disease or disorder. The dose characteristics cited above have been confirmed in in vitro and in vivo tests using favorable mammals such as mice, rats, dogs, monkeys, or isolated organs, tissues, and their specimens. The compounds of the present invention can be used in vitro in the form of a solution, such as an aqueous solution, and can also be used in vivo via the intestine, parenterally, and preferably intravenously in the form of a suspension or an aqueous solution. The range of the therapeutically effective amount in vivo depends on the route of administration and is between about 0.01 - 500 mg / kg, or between about 1 - 100 mg / kg.

[0121] The compounds disclosed in the present invention can be administered simultaneously with, before, or after one or more other therapeutic agents. The compounds of the present invention and other therapeutic agents can be administered separately via the same or different administration routes, or administered in the form of the same pharmaceutical composition.

[0122] General synthetic scheme

[0123] To describe the present invention, the following examples are listed. However, it should be understood that the present invention is not limited to these examples, which are only provided to illustrate the methods for practicing the present invention.

[0124] Generally, the compounds of the present invention can be prepared by the methods described in the present invention, unless otherwise specified, where the definitions of the substituents are as shown in formula (I). The following reaction schemes and examples are used to further illustrate the content of the present invention.

[0125] Unless otherwise indicated, all temperatures in the following examples are in degrees Celsius. Reagents are purchased from commercial suppliers, such as Aldrich Chemical Company, Alfa Chemical Company, Shanghai Shaoyuan Reagent Co., Ltd., SAIN Chemical Technology (Shanghai) Co., Ltd., Shanghai Baide Pharmaceutical Technology Co., Ltd., Shanghai Haohong Biomedical Technology Co., Ltd. The reagents used in the present invention can be used without further purification unless otherwise specified. Common solvents are purchased from commercial suppliers such as Beijing Haiyuan Weiye Technology Co., Ltd.

[0126] Anhydrous THF, dioxane, DCM, toluene, and DMF are all purchased from commercial suppliers, such as Energychemical company and Aldrich Chemical Company. EtOAc, PE, CH3CN, NMP, and DMSO are treated with anhydrous Na2SO4 before use.

[0127] The following reactions are generally carried out under a positive pressure of nitrogen or argon or with a drying tube over an anhydrous solvent (unless otherwise indicated). The reaction flasks are all stoppered with appropriate rubber stoppers, and the substrates are injected via a syringe. The glassware is dried.

[0128] The chromatographic column used is a silica gel column. Silica gel (300 - 400 mesh) is purchased from Qingdao Ocean Chemical Factory.

[0129] 1 1H NMR spectra and 13 13C / 2D data are collected on a Bruker Avance III 400 MHz. 11H NMR spectra were recorded in CDC13, DMSO-d6, CD3OD or acetone-d6 as solvents (in ppm), using TMS (0 ppm) or chloroform (7.26 ppm) as reference standards. When multiplets occurred, the following abbreviations were used: s (singlet), d (doublet), t (triplet), m (multiplet), br (broadened), brs (broadened singlet), dd (doublet of doublets), dt (doublet of triplets). Coupling constants were expressed in Hertz (Hz).

[0130] LC / MS was performed on an Agilent 1260 (binary pump / DAD detector) coupled to an Agilent 6120 / 6125 mass spectrometer.

[0131] Method 1:

[0132] Column: HALO C18 2.7μm, 4.6mm × 30mm, Mobile phase: MeCN (0.05% HCOOH) - Water (0.05% HCOOH); Gradient: 5% to 95% MeCN, elution for 0.8 min, hold for 0.8 min, total run time is 2.0 min; Flow rate: 1.8 mL / min; Column temperature: 45 °C;

[0133] Method 2:

[0134] Column: HALO C18 2.7μm, 4.6mm × 50mm, Mobile phase: MeCN (0.025% trifluoroacetic acid) - water (0.025% trifluoroacetic acid); Gradient: 5% to 95% MeCN, elution for 1.0 min, hold for 1.0 min, total run time is 2.5 min; Flow rate: 1.8 mL / min; Column temperature: 45 °C.

[0135] Purity tests were performed by RP-HPLC:

[0136] Compound purity tests were performed on RP-HPLC (Shimadzu 2010 / 2030)

[0137] Method 1:

[0138] Column: Gemini 4.6 × 150mm 5um; Mobile phase: H2O (0.05% trifluoroacetic acid) - MeCN (0.05% trifluoroacetic acid). Gradient:

[0139] 10% to 100% MeCN, elute for 8 minutes, hold for 2 minutes. Flow rate: 1.2 mL / min, column temperature: 35°C / 40°C. Method 2:

[0140] Column: XBRIDGE 2.1×50 mm, 3.5 μm; Mobile phase: H2O (0.05% trifluoroacetic acid) - MeCN (0.05% trifluoroacetic acid). Gradient:

[0141] From 10% to 100% MeCN, elute for 7 minutes, hold for 1 minute. Flow rate: 0.8 mL / min, column temperature: 35°C / 40°C.

[0142] Compound purification by SFC:

[0143] SFC purification was carried out on a Thar P80 equipped with a UV detector.

[0144] Method: Column CHIRALPAK AD-H 250 mm, 20 mm, 5 μm, modifier: 30% EtOH (0.2% NH4OH).

[0145] Compound purification by RP-HPLC:

[0146] RP-HPLC purification was carried out on a Gilson purification system (322 or 306 pump and GX-281 fraction collector), Shimadzu LC20Ap and Waters MS trigger purification system;

[0147] Method 1:

[0148] Columns Gemini C18 21x150 mm, 5 μm Xbrige C18 19x150 mm, 5 μm, Spolar C18 20x150 mm and Ultimate AQ-C18 30x250 mm, 10 μm

[0149] Mobile phase:

[0150] 1. Aqueous solution of MeCN (0.1% HCOOH), flow rate: 20 ml / min, 50 ml / min, column 30x250 mm, 10 μm; Wavelength: 210 - 400 nm. Inject the sample into DMSO (+ optional formic acid and water), linear gradient from 10% to 95% MeCN, elute for 10 minutes.

[0151] 2. Aqueous solution of MeCN (0.1% trifluoroacetic acid), flow rate: 20 ml / min, 50 ml / min, column 30 x 250 mm, 10 μm; wavelength: 210 - 400 nm. Inject the sample into DMSO (+ optional formic acid and water), with a linear gradient from 10% to 95% MeCN, eluting for 10 minutes.

[0152] 3. Aqueous solution of MeCN (0.1% NH3-H2O / 10 mM NH4AC), flow rate: 20 ml / min, 50 ml / min, column 30 x 250 mm, 10 μm; wavelength: 210 - 400 nm. Inject the sample into DMSO (+ optional formic acid and water), with a linear gradient from 10% to 95% MeCN, eluting for 10 minutes.

[0153] Typical synthetic procedures for preparing the compounds disclosed in the present invention are shown in the following Synthetic Scheme 1. Unless otherwise stated, R 1 、R 2 、R 3 、R 4 、R 5 、R a 、R b and W all have the definitions as described in the present invention.

[0154] Synthetic Scheme 1:

[0155]

[0156] The compounds of formula I of the present invention can be synthesized as shown in Scheme 1. Compound (i) can be acylated with an acylating reagent (such as R a R b -COCl) to form an ester, which can be rearranged under Lewis acid conditions to obtain a ketone (ii). Using NX 1 S (NX 1 S = N-chlorosuccinimide, N-bromosuccinimide or N-iodosuccinimide) to halogenate the ketone can obtain compound (iii), where X 1 = Cl, Br or I. The phenol can be converted into a trifluoromethanesulfonate (iv) using standard conditions (such as Tf2O). The trifluoromethanesulfonate group of (iv) can be coupled with R 2 -M under standard Suzuki conditions or standard Stille conditions or standard Negishi conditions to obtain a derivative of (v), where M is boric acid, borate or a suitably substituted metal (such as R 2 -Sn(Bu)4 or Zn-R 2 ). Alternatively, R 2-M can be an alkyl ether (where M is H and is attached to a hydroxyl group), and its nucleophilic substitution with compound (iii) is carried out by heating under basic conditions to obtain a derivative of formula (v). Compound (v) can be heated with ethylene glycol under acidic conditions to obtain compound (vi). The X 1 group of (vi) can be coupled with R 3 -M under standard Suzuki conditions or standard Stille conditions or standard Negishi conditions, where M is boric acid, a borate ester or a suitably substituted metal (such as R 3 -B(OH)2, R 3 -Sn(Bu)4 or Zn-R 3 ), to obtain a derivative of (vii). Compound (vii) is deprotected under acidic conditions to obtain (viii), which is then heated with hydroxylamine hydrochloride in pyridine to obtain compound (ix). Compound (ix) is reacted with a suitable reducing agent (such as Raney nickel, etc.) and ammonia water to obtain a derivative of (x). (xi) is heated with compound (x) under basic conditions to obtain the compound (xii) of formula I of the present invention. Examples

[0157] Example 1 4-(3-(1-((6-Amino-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-yl)amino)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one

[0158]

[0159] Step 1) 1-(5-Chloro-4-fluoro-2-hydroxyphenyl)ethan-1-one

[0160] Acetyl chloride (1.93 g, 0.024 mol) was added to a mixture of 4-chloro-3-fluorophenol (3 g, 0.02 mol) and AlCl3 (5.47 g, 0.04 mol) in DCM (10 mL), and the mixture was stirred at 25 °C for 2 h. Then DCM was distilled off, and the residue was heated at 140 °C for 2 h. After cooling to room temperature, the mixture was quenched with 10% HCl (20 mL), and the solid was filtered. The filter cake was washed with water (20 mL) and dried in vacuo to obtain 1-(5-chloro-4-fluoro-2-hydroxyphenyl)ethan-1-one (4 g, yield 93%) as a brown solid. MS (ESI): 187.0 [M-H] - . 1 1H NMR (400 MHz, DMSO) δ 12.17 (s, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.07 (d, J = 10.8 Hz, 1H), 2.63 (s, 3H).

[0161] Step 2) 1-(5-chloro-4-fluoro-2-hydroxy-3-iodophenyl)ethan-1-one

[0162] To a solution of 1-(5-chloro-4-fluoro-2-hydroxyphenyl)ethan-1-one (3 g, 15.9 mmol) in HOAc (30 mL) was added NIS (4.3 g, 19 mmol), and the mixture was heated to 80 °C and reacted for 16 h. The mixture was quenched with an aqueous Na2SO3 solution (20 mL), and then the mixture was concentrated in vacuo. The residue was diluted with EtOAc (60 mL) and then washed with brine (30 mL × 3). The separated organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (EA / PE = 1 / 5) to give 1-(5-chloro-4-fluoro-2-hydroxy-3-iodophenyl)ethan-1-one (4 g, 76% yield) as a yellow solid. MS (ESI): 314.9 [M+H] + 。 1 1H NMR (400 MHz, CDCl3) δ 13.44 (d, J = 2.0 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 2.66 (s, 3H).

[0163] Step 3) 1-(5-chloro-2-ethoxy-4-fluoro-3-iodophenyl)ethan-1-one

[0164] To a solution of 1-(5-chloro-4-fluoro-2-hydroxy-3-iodophenyl)ethan-1-one (1.1 g, 3.5 mmol) and K2CO3 (0.97 g, 7 mmol) in DMF (5 mL) was added iodoethane (0.82 g, 5.2 mmol), and the mixture was heated at 60 °C for 2 h. After cooling to room temperature, the mixture was diluted with EtOAc (40 mL) and then washed with brine (30 mL × 3). The separated organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (EA / PE = 1 / 5) to give 1-(5-chloro-2-ethoxy-4-fluoro-3-iodophenyl)ethan-1-one (1.2 g, 91% yield) as a yellow oil. MS (ESI): 342.7 [M+H] + 。 1 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 8.4 Hz, 1H), 3.97 (q, J = 6.8 Hz, 2H), 2.63 (s, 3H), 1.50 (t, J = 6.8 Hz, 4H).

[0165] Step 4) 2-(5-chloro-2-ethoxy-4-fluoro-3-iodophenyl)-2-methyl-1,3-dioxolane

[0166] To a solution of 1-(5-chloro-2-ethoxy-4-fluoro-3-iodophenyl)ethanone (1.2 g, 3.5 mmol) and ethylene glycol (0.43 g, 7 mmol) in toluene (30 mL) was added PTSA (60 mg, 0.3 mmol), and the mixture was refluxed with a Dean-Stark water separator for 16 h. After cooling to room temperature, the mixture was diluted with EtOAc (30 mL) and then washed with an aqueous solution of NaHCO3 (30 mL). The separated organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (EA / PE = 1 / 5) to give 2-(5-chloro-2-ethoxy-4-fluoro-3-iodophenyl)-2-methyl-1,3-dioxolane (1 g, 71% yield) as a colorless oil. MS (ESI): 386.8 [M+H] + 。 1 H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 8.8 Hz, 1H), 4.13 - 4.05 (m, 3H), 3.85 - 3.82 (m, 2H), 1.74 (s, 3H), 1.50 (t, J = 6.8 Hz, 3H).

[0167] Step 5) Ethyl (E)-3-(3-chloro-6-ethoxy-2-fluoro-5-(2-methyl-1,3-dioxolan-2-yl)phenyl)acrylate

[0168] A solution of 2-(5-chloro-2-ethoxy-4-fluoro-3-iodophenyl)-2-methyl-1,3-dioxolane (800 mg, 2.07 mmol), ethyl prop-2-enoate (414 mg, 4.14 mmol), palladium(II) diacetate (46.5 mg, 0.2 mmol), tri-o-tolylphosphine (63 mg, 0.2 mmol) and Et3N (419 mg, 4.14 mmol) in DMA (20 mL) was heated at 90 °C for 16 h. After cooling to room temperature, the mixture was diluted with EtOAc (70 mL) and then washed with brine (30 mL × 3). The separated organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (EA / PE = 1 / 5) to give ethyl (E)-3-(3-chloro-6-ethoxy-2-fluoro-5-(2-methyl-1,3-dioxolan-2-yl)phenyl)acrylate (650 mg, 83.2% yield) as a colorless oil. MS (ESI): 359.1 [M+H] + 。

[0169] Step 6) Ethyl 3-(3-chloro-6-ethoxy-2-fluoro-5-(2-methyl-1,3-dioxolan-2-yl)phenyl)-4-nitrobutanoate

[0170] Ethyl (E)-3-(3-chloro-6-ethoxy-2-fluoro-5-(2-methyl-1,3-dioxolan-2-yl)phenyl)acrylate (1 g, 2.8 mmol) was added to a solution of nitromethane (0.85 g, 14 mmol), and DBU (0.47 g, 3 mmol) was added. The mixture was stirred at 60 °C for 16 h. The mixture was diluted with EtOAc (60 mL) and then washed with brine (40 mL × 2). The separated organic layer was dried over Na2SO4, concentrated in vacuo, and the residue was purified by silica gel chromatography (EA / PE = 1 / 5) to give ethyl 3-(3-chloro-6-ethoxy-2-fluoro-5-(2-methyl-1,3-dioxolan-2-yl)phenyl)-4-nitrobutyrate (500 mg, 39.3% yield) as a colorless oil. MS (ESI): 420.1 [M+H] + 。 1 H NMR (400 MHz, CDCl3) δ 7.54 (d, J = 8.8 Hz, 1H), 4.86 - 4.80 (m, 1H), 4.72 - 4.66 (m, 1H), 4.53 - 4.43 (m, 1H), 4.12 (q, J = 7.1 Hz, 2H), 4.08 - 4.00 (m, 3H), 3.87 - 3.80 (m, 2H), 2.90 - 2.83 (m, 1H), 2.78 - 2.72 (m, 1H), 1.72 (s, 3H), 1.49 (t, J = 6.8 Hz, 3H), 1.23 (t, J = 7.2 Hz, 3H).

[0171] Step 7) 4-(3-Chloro-6-ethoxy-2-fluoro-5-(2-methyl-1,3-dioxolan-2-yl)phenyl)pyrrolidin-2-one

[0172] Ethyl 3-(3-chloro-6-ethoxy-2-fluoro-5-(2-methyl-1,3-dioxolan-2-yl)phenyl)-4-nitrobutyrate (500 mg, 0.43 mmol) and Raney nickel (70 mg, 1.19 mmol) in EtOH (20 mL) were hydrogenated with an H2 balloon, and the mixture was stirred at 25 °C for 2 h. Then the mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in toluene (30 mL), and the mixture was heated at 110 °C for 16 h. After cooling to room temperature, the mixture was concentrated in vacuo to give 4-(3-chloro-6-ethoxy-2-fluoro-5-(2-methyl-1,3-dioxolan-2-yl)phenyl)pyrrolidin-2-one (400 mg, 78% yield) as a white solid. MS (ESI): 344.1 [M+H] + 。

[0173] Step 8) 4-(3-Acetyl-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one

[0174] To a solution of 4-(3-chloro-6-ethoxy-2-fluoro-5-(2-methyl-1,3-dioxolan-2-yl)phenyl)pyrrolidin-2-one (400 mg, 1.16 mmol) in MeOH (20 mL) was added 6N HCl (4 mL), and the mixture was stirred at 25 °C for 16 h. The mixture was concentrated in vacuo, and the residue was diluted with aqueous NaHCO3 (20 mL). The mixture was extracted with EtOAc (30 mL x 2), and the combined organic layers were washed with brine (30 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel chromatography (PE / EA = 1 / 2) to give 4-(3-acetyl-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one (200 mg, 48.5% yield) as a white solid. MS (ESI): 300.1 [M+H] + 。 1 H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 8.4 Hz, 1H), 4.26 - 4.17 (m, 1H), 3.86 (q, J = 7.2 Hz, 2H), 3.73 - 3.68 (m, 2H), 3.63 - 3.58 (m, 1H), 2.75 - 2.65 (m, 2H), 2.61 (s, 3H), 1.43 (t, J = 7.2 Hz, 3H).

[0175] Step 9) (E)-4-(3-chloro-6-ethoxy-2-fluoro-5-(1-(hydroxyimino)ethyl)phenyl)pyrrolidin-2-one

[0176] To a solution of 4-(3-acetyl-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one (50 mg, 0.17 mmol) and pyridine (26 mg, 0.33 mmol) in EtOH (20 mL) was added NH2OH·HCl (13 mg, 0.18 mmol), and the mixture was heated at 70 °C for 16 h. After cooling to room temperature, the mixture was concentrated in vacuo, and the residue was diluted with EtOAc (30 mL), then washed with brine (20 mL×2). The separated organic layer was dried over Na2SO4 and concentrated in vacuo to give (E)-4-(3-chloro-6-ethoxy-2-fluoro-5-(1-(hydroxyimino)ethyl)phenyl)pyrrolidin-2-one (50 mg, 85% yield) as a yellow solid. MS (ESI): 315.0 [M+H] + 。

[0177] Step 10) 4-(3-(1-aminoethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one

[0178] (E)-4-(3-Chloro-6-ethoxy-2-fluoro-5-(1-(hydroxyimino)ethyl)phenyl)pyrrolidin-2-one (35 mg, 0.11 mmol), Raney nickel (7 mg, 0.11 mmol) and thiophene (9.4 mg, 0.11 mmol) in a mixture of MeOH (10 mL) and NH₃·H₂O (1 mL) were hydrogenated at 25 °C for 16 h. The mixture was then filtered and the filtrate was concentrated in vacuo to give 4-(3-(1-aminoethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one (30 mg, 71.8% yield) as a white solid. MS (ESI): 283.9 [M - NH₃ + H] + 。

[0179] Step 11) 4-(3-(1-((6-Amino-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-yl)amino)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one

[0180] A solution of 4-(3-(1-aminoethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one (30 mg, 0.1 mmol), 6-chloro-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-amine (21 mg, 0.1 mmol) and DIEA (26 mg, 0.2 mmol) in 2-pentanol (10 mL) was heated at 90 °C for 16 h. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was diluted with EtOAc (60 mL) and then washed with brine (40 mL × 2). The separated organic layer was dried over Na₂SO₄ and concentrated in vacuo. The residue was purified by preparative HPLC (ACN - H₂O 0.1% FA, gradient 40% to 60%) to give 4-(3-(1-((6-amino-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-yl)amino)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one (20 mg, 40% yield) as a white solid. MS (ESI): 476.1 [M + H] + 。 11H NMR (400 MHz, DMSO) δ 8.53 (d, J = 7.2 Hz, 1H), 8.00 (d, J = 2.4 Hz, 1H), 7.83 (s, 1H), 7.71 - 7.55 (m, 2H), 7.49 (d, J = 8.4, 1H), 5.62 - 5.56 (m, 1H), 4.15 - 4.09 (m, 1H), 4.06 - 4.00 (m, 1H), 3.91 - 3.83 (m, 1H), 3.64 - 3.55 (m, 1H), 3.30 - 3.22 (m, 1H), 2.61 - 2.55 (m, 1H), 2.45 (s, 3H), 2.40 - 2.34 (m, 1H), 1.47 (d, J = 6.8 Hz, 3H), 1.41 (t, J = 6.8, 3H).

[0181] Example 2 4-(3-(1-((6-Amino-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-yl)amino)ethyl)-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one

[0182]

[0183] Step 1) 1-(5-Chloro-4-fluoro-2-hydroxyphenyl)ethan-1-one

[0184] To a mixture of 4-chloro-3-fluorophenol (3 g, 0.02 mol) and AlCl3 (5.47 g, 0.04 mol) in DCM (10 mL) was added acetyl chloride (1.93 g, 0.024 mol), and the resulting mixture was stirred at 25 °C for 2 h. Then DCM was distilled off, and the residue was heated at 140 °C for 2 h. After cooling to room temperature, the mixture was quenched with 10% HCl (20 mL), and the solid was filtered. The filter cake was washed with water (20 mL) and dried in vacuo to give 1-(5-chloro-4-fluoro-2-hydroxyphenyl)ethan-1-one (4 g, yield 93%) as a brown solid. MS (ESI): 187.0 [M-H] - . 1 1H NMR (400 MHz, DMSO) δ 12.17 (s, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.07 (d, J = 10.8 Hz, 1H), 2.63 (s, 3H).

[0185] Step 2) 1-(5-Chloro-4-fluoro-2-hydroxy-3-iodophenyl)ethan-1-one

[0186] To a solution of 1-(5-chloro-4-fluoro-2-hydroxyphenyl)ethanone (3 g, 15.9 mmol) in HOAc (30 mL) was added NIS (4.3 g, 19 mmol), and the mixture was heated to 80 °C and reacted for 16 h. The mixture was quenched with an aqueous Na2SO3 solution (20 mL), and then the mixture was concentrated in vacuo. The residue was diluted with EtOAc (60 mL) and then washed with brine (30 mL × 3). The separated organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (EA / PE = 1 / 5) to give 1-(5-chloro-4-fluoro-2-hydroxy-3-iodophenyl)ethan-1-one (4 g, 76% yield) as a yellow solid. MS (ESI): 314.9 [M+H] + 。 1 H NMR (400 MHz, CDCl3) δ 13.44 (d, J = 2.0 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 2.66 (s, 3H).

[0187] Step 3) 1-(5-chloro-2-ethoxy-4-fluoro-3-iodophenyl)ethan-1-one

[0188] To a solution of 1-(5-chloro-4-fluoro-2-hydroxy-3-iodophenyl)ethanone (1.1 g, 3.5 mmol) and K2CO3 (0.97 g, 7 mmol) in DMF (5 mL) was added iodoethane (0.82 g, 5.2 mmol), and the mixture was heated at 60 °C for 2 h. After cooling to room temperature, the mixture was diluted with EtOAc (40 mL) and then washed with brine (30 mL × 3). The separated organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (EA / PE = 1 / 5) to give 1-(5-chloro-2-ethoxy-4-fluoro-3-iodophenyl)ethan-1-one (1.2 g, 91% yield) as a yellow oil. MS (ESI): 342.7

[0189] [M+H] + 。 1 H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 8.4 Hz, 1H), 3.97 (q, J = 6.8 Hz, 2H), 2.63 (s, 3H), 1.50 (t, J = 6.8 Hz, 4H).

[0190] Step 4) 2-(5-chloro-2-ethoxy-4-fluoro-3-iodophenyl)-2-methyl-1,3-dioxolane

[0191] To a solution of 1-(5-chloro-2-ethoxy-4-fluoro-3-iodophenyl)ethanone (1.2 g, 3.5 mmol) and ethylene glycol (0.43 g, 7 mmol) in toluene (30 mL) was added PTSA (60 mg, 0.3 mmol), and the mixture was refluxed with a Dean-Stark water separator for 16 h. After cooling to room temperature, the mixture was diluted with EtOAc (30 mL) and washed with an aqueous solution of NaHCO3 (30 mL). The separated organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (EA / PE = 1 / 5) to give 2-(5-chloro-2-ethoxy-4-fluoro-3-iodophenyl)-2-methyl-1,3-dioxolane (1 g, 71% yield) as a colorless oil. MS (ESI): 386.8 [M+H] + 。 1 H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 8.8 Hz, 1H), 4.13 - 4.05 (m, 3H), 3.85 - 3.82 (m, 2H), 1.74 (s, 3H), 1.50 (t, J = 6.8 Hz, 3H).

[0192] Step 5) Ethyl (E)-3-(3-chloro-6-ethoxy-2-fluoro-5-(2-methyl-1,3-dioxolan-2-yl)phenyl)acrylate

[0193] A solution of 2-(5-chloro-2-ethoxy-4-fluoro-3-iodophenyl)-2-methyl-1,3-dioxolane (800 mg, 2.07 mmol), ethyl prop-2-enoate (414 mg, 4.14 mmol), palladium(II) diacetate (46.5 mg, 0.2 mmol), tri-o-tolylphosphine (63 mg, 0.2 mmol) and Et3N (419 mg, 4.14 mmol) in DMA (20 mL) was heated at 90 °C for 16 h. After cooling to room temperature, the mixture was diluted with EtOAc (70 mL) and then washed with brine (30 mL × 3). The separated organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (EA / PE = 1 / 5) to give ethyl (E)-3-(3-chloro-6-ethoxy-2-fluoro-5-(2-methyl-1,3-dioxolan-2-yl)phenyl)acrylate (650 mg, 83.2% yield) as a colorless oil. MS (ESI): 359.1 [M+H] + 。

[0194] Step 6) Ethyl 3-(3-chloro-6-ethoxy-2-fluoro-5-(2-methyl-1,3-dioxolan-2-yl)phenyl)-4-nitrobutanoate

[0195] To a solution of ethyl (E)-3-(3-chloro-6-ethoxy-2-fluoro-5-(2-methyl-1,3-dioxolan-2-yl)phenyl)acrylate (1 g, 2.8 mmol) in nitromethane (0.85 g, 14 mmol) was added DBU (0.47 g, 3 mmol), and the mixture was stirred at 60 °C for 16 h. The mixture was diluted with EtOAc (60 mL), and then washed with brine (40 mL × 2). The separated organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (EA / PE = 1 / 5) to give ethyl 3-(3-chloro-6-ethoxy-2-fluoro-5-(2-methyl-1,3-dioxolan-2-yl)phenyl)-4-nitrobutyrate (500 mg, 39.3% yield) as a colorless oil. MS (ESI): 420.1 [M+H] + 。 1 H NMR (400 MHz, CDCl3) δ 7.54 (d, J = 8.8 Hz, 1H), 4.86 - 4.80 (m, 1H), 4.72 - 4.66 (m, 1H), 4.53 - 4.43 (m, 1H), 4.12 (q, J = 7.1 Hz, 2H), 4.08 - 4.00 (m, 3H), 3.87 - 3.80 (m, 2H), 2.90 - 2.83 (m, 1H), 2.78 - 2.72 (m, 1H), 1.72 (s, 3H), 1.49 (t, J = 6.8 Hz, 3H), 1.23 (t, J = 7.2 Hz, 3H).

[0196] Step 7) 4-(3-Chloro-6-ethoxy-2-fluoro-5-(2-methyl-1,3-dioxolan-2-yl)phenyl)pyrrolidin-2-one

[0197] A solution of ethyl 3-(3-chloro-6-ethoxy-2-fluoro-5-(2-methyl-1,3-dioxolan-2-yl)phenyl)-4-nitrobutyrate (500 mg, 0.43 mmol) and Raney nickel (70 mg, 1.19 mmol) in EtOH (20 mL) was hydrogenated with an H2 balloon, and the mixture was stirred at 25 °C for 2 h. Then the mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in toluene (30 mL), and the mixture was heated at 110 °C for 16 h. After cooling to room temperature, the mixture was concentrated in vacuo to give ethyl 3-(3-chloro-6-ethoxy-2-fluoro-5-(2-methyl-1,3-dioxolan-2-yl)phenyl)-4-nitrobutyrate (400 mg, 78% yield) as a white solid. MS (ESI): 344.1 [M+H] + 。

[0198] Step 8) 4-(3-Acetyl-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one

[0199] To a solution of ethyl 3-(3-chloro-6-ethoxy-2-fluoro-5-(2-methyl-1,3-dioxolan-2-yl)phenyl)-4-nitrobutyrate (400 mg, 1.16 mmol) in MeOH (20 mL) was added 6N HCl (4 mL), and the mixture was stirred at 25 °C for 16 h. The mixture was concentrated in vacuo, and the residue was diluted with an aqueous solution of NaHCO3 (20 mL). The mixture was extracted with EtOAc (30 mL x 2), and the combined organic layers were washed with brine (30 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel chromatography (PE / EA = 1 / 2) to give 4-(3-acetyl-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one (200 mg, 48.5% yield) as a white solid. MS (ESI): 300.1 [M+H] + 。 1 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 8.4 Hz, 1H), 4.26 - 4.17 (m, 1H), 3.86 (q, J = 7.2 Hz, 2H), 3.73 - 3.68 (m, 2H), 3.63 - 3.58 (m, 1H), 2.75 - 2.65 (m, 2H), 2.61 (s, 3H), 1.43 (t, J = 7.2 Hz, 3H).

[0200] Step 9) (E)-4-(3-chloro-6-ethoxy-2-fluoro-5-(1-(hydroxyimino)ethyl)phenyl)pyrrolidin-2-one

[0201] To a solution of 4-(3-acetyl-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one (50 mg, 0.17 mmol) and pyridine (26 mg, 0.33 mmol) in EtOH (20 mL) was added NH2OH·HCl (13 mg, 0.18 mmol), and the mixture was heated at 70 °C for 16 h. After cooling to room temperature, the mixture was concentrated in vacuo, and the residue was diluted with EtOAc (30 mL) and then washed with brine (20 mL × 2). The separated organic layer was dried over Na2SO4 and concentrated in vacuo to give (E)-4-(3-chloro-6-ethoxy-2-fluoro-5-(1-(hydroxyimino)ethyl)phenyl)pyrrolidin-2-one (50 mg, 85% yield) as a yellow solid. MS (ESI): 315.0 [M+H] + 。

[0202] Step 10) 4-(3-(1-aminoethyl)-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one

[0203] A mixture of (E)-4-(3-chloro-6-ethoxy-2-fluoro-5-(1-(hydroxyimino)ethyl)phenyl)pyrrolidin-2-one (50 mg, 0.16 mmol) and Ni (9 mg, 0.16 mmol) in MeOH (20 mL) and NH₃·H₂O (2 mL) was hydrogenated with an H₂ balloon. The mixture was stirred at 25 °C for 16 h. It was filtered and the filtrate was concentrated in vacuo to give 4-(3-(1-aminoethyl)-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one (40 mg, 67% yield) as a light white solid. MS (ESI): 250.1 [M - NH₃ + H] + .

[0204] Step 11) 4-(3-(1-((6-amino-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-yl)amino)ethyl)-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one

[0205] A solution of 4-(3-(1-aminoethyl)-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one (40 mg, 0.13 mmol), 6-chloro-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-amine (28 mg, 0.13 mmol) and DIEA (34 mg, 0.27 mmol) in 2-pentanol (5 mL) was heated at 80 °C for 16 h. After cooling to room temperature, the mixture was concentrated in vacuo and the residue was diluted with EtOAc (50 mL). The mixture was washed with brine (30 mL × 2), the organic layer was dried over Na₂SO₄ and concentrated. The residue was purified by preparative HPLC (ACN - H₂O 0.1% FA, gradient 30% to 60%) to give 4-(3-(1-((6-amino-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-yl)amino)ethyl)-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one (25 mg, 39% yield) as a white solid. MS (ESI): 442.2 [M + H] + . 11H NMR (400 MHz, DMSO) δ 8.66 (d, J = 7.2 Hz, 1H), 8.01 (d, J = 1.6 Hz, 1H), 7.80 (s, 1H), 7.64 - 7.42 (m, 2H), 7.34 - 7.28 (m, 1H), 7.04 - 6.98 (m, 1H), 5.68 - 5.61 (m, 1H), 4.10 - 3.98 (m, 2H), 3.88 - 3.82 (m, 1H), 3.62 - 3.51 (m, 1H), 3.31 - 3.24 (m, 1H), 2.58 - 2.54 (m, 1H), 2.44 (s, 3H), 2.38 - 2.31 (m, 1H), 1.46 (d, J = 6.8 Hz, 3H), 1.41 (t, J = 7.2, 3H).

[0206] Example 3 4-{3-[(1S)-1-{[6-Amino-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-yl]amino}ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide

[0207]

[0208] Step 1) 4-Bromo-N,N-dimethylpyridine-2-carboxamide

[0209] To a mixture of 4-bromopyridine-2-carboxylic acid (1.1 g, 5.40 mmol), dimethylamine (0.66 g, 8.10 mmol) in DCM (15 mL) was added HATU (3.08 g, 8.10 mmol) and DIEA (1.4 g, 10.8 mmol), and then the mixture was stirred at room temperature for 5 h. LCMS showed the reaction was complete. The mixture was diluted with water (60 mL), and then the mixture was extracted with DCM (30 mL × 3). The combined organic layers were washed with brine (20 mL × 4), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography (PE:EA = 2 / 1) to give 4-bromo-N,N-dimethylpyridine-2-carboxamide (1.10 g, 70.7% yield) as a white solid. MS (ESI): 229.9 [M+H] + .

[0210] Step 2) N,N-Dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxamide

[0211] At room temperature, 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.34 g, 5.2 mmol), Pd(dppf)Cl2 (0.32 g, 0.4 mmol) and KOAc (1.30 g, 13.2 mmol) were added to a solution of 4-bromo-N,N-dimethylpyridine-2-carboxamide (1.0 g, 4.4 mmol) in dioxane (15 mL). The mixture was stirred at 80 °C for 6 h. LCMS showed the formation of the product. The solution was concentrated in vacuo to give N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxamide (1.10 g, 63.6% yield) as a black oil, which was used directly in the next step. MS (ESI): 299.1 [M+Na] + 。

[0212] Step 3) 1-(5-chloro-2-hydroxy-3-iodo-4-methylphenyl)ethanone

[0213] At room temperature, NIS (1.64 g, 7.3 mmol) was added to a solution of 1-(5-chloro-2-hydroxy-4-methylphenyl)ethanone (0.9 g, 4.9 mmol) in HOAc (15 mL). The mixture was stirred at 80 °C for 16 h. LCMS showed that the main peak was the product. The reaction was quenched with saturated aqueous Na2SO3 solution (10 mL). The solution was concentrated in vacuo and extracted with DCM (50 mL×3). The organic layer was washed with brine (50 mL×3), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column (200 - 300 mesh, PE:EA = 1:1) to give 1-(5-chloro-2-hydroxy-3-iodo-4-methylphenyl)ethanone (1.1 g, 73.3% yield) as a yellow oil. MS (ESI): 311.8 [M+H] + 。

[0214] Step 4) 1-(5-chloro-3-iodo-2-methoxy-4-methylphenyl)ethanone

[0215] At room temperature, MeI (1.51 g, 10.5 mmol) and K2CO3 (0.98 g, 7.0 mmol) were added to a solution of 1-(5-chloro-2-hydroxy-3-iodo-4-methylphenyl)ethanone (1.1 g, 3.5 mmol) in DMF (15 mL). The mixture was stirred at room temperature for 4 h. LCMS showed the reaction was complete. The mixture was diluted with water (80 mL) and then extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL x 4), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column (200 - 300 mesh, PE:EA = 2:1) to give 1-(5-chloro-3-iodo-2-methoxy-4-methylphenyl)ethanone (0.90 g, 78.2% yield) as a yellow oil. MS(ESI): 324.9 [M+H] + 。

[0216] Step 5) 4-(3-acetyl-5-chloro-2-methoxy-6-methylphenyl)-N,N-dimethylpyridine-2-carboxamide

[0217] To a solution of 1-(5-chloro-3-iodo-2-methoxy-4-methylphenyl)ethanone (0.9 g, 2.8 mmol) in dioxane (40 mL) and H2O (10 mL) were added N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxamide (1.16 g, 4.2 mmol), Pd(dppf)Cl2 (0.23 g, 0.2 mmol), and Cs2CO3 (1.82 g, 5.6 mmol). The mixture was stirred at N2 and 100 °C for 16 h. LCMS showed the main peak was the product. The mixture was concentrated in vacuo and then diluted with water (60 mL). The mixture was extracted with DCM (50 mL x 3), the combined organic layers were washed with brine (100 mL x 2), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column (200 - 300 mesh, PE:EA = 2:1) to give 4-(3-acetyl-5-chloro-2-methoxy-6-methylphenyl)-N,N-dimethylpyridine-2-carboxamide (0.82 g, 67.8% yield) as a white solid. MS(ESI): 347.0 [M+H] + 。

[0218] Step 6) 4-{3-chloro-5-[(1E)-1-(hydroxyimino)ethyl]-6-methoxy-2-methylphenyl}-N,N-dimethylpyridine-2-carboxamide

[0219] At room temperature, NH2OH·HCl (30.0 mg, 0.43 mmol) and pyridine (45.60 mg, 0.58 mmol) were added to a solution of 4-(3-acetyl-5-chloro-2-methoxy-6-methylphenyl)-N,N-dimethylpyridine-2-carboxamide (100 mg, 0.29 mmol) in EtOH (5 mL). The mixture was heated at 70 °C for 8 h. LCMS showed the reaction was complete. The mixture was concentrated in vacuo and diluted with water (30 mL). The solution was extracted with DCM (30 mL × 3), and the combined organic layers were washed with brine (30 mL × 3), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography (200 - 300 mesh, PE:EA = 2:1) to give 4-{3-chloro-5-[(1E)-1-(hydroxyimino)ethyl]-6-methoxy-2-methylphenyl}-N,N-dimethylpyridine-2-carboxamide (80 mg, 61.4% yield) as a transparent oil. MS (ESI): 362.0 [M+H] + 。

[0220] Step 7) 4-[3-(1-Aminoethyl)-5-chloro-2-methoxy-6-methylphenyl]-N,N-dimethylpyridine-2-carboxamide

[0221] At room temperature, Raney nickel (50 mg) and thiophene (0.5 mL) were added to a solution of 4-{3-chloro-5-[(1E)-1-(hydroxyimino)ethyl]-6-methoxy-2-methylphenyl}-N,N-dimethylpyridine-2-carboxamide (80 mg, 0.22 mmol) in NH3·H2O (5 mL). The mixture was stirred under H2 at room temperature for 4 h. LCMS showed the reaction was complete. The reaction was filtered, and the filtrate was concentrated in vacuo to give 4-[3-(1-aminoethyl)-5-chloro-2-methoxy-6-methylphenyl]-N,N-dimethylpyridine-2-carboxamide (70 mg, 94.1% yield) as a transparent oil. MS (ESI): 348.1 [M+H] + 。

[0222] Step 8) 4-{3-[(1S)-1-{[6-Amino-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-yl]amino}ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide

[0223] At room temperature, 6-chloro-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-amine (50.20 mg, 0.24 mmol) and DIEA (41.70 mg, 0.32 mmol) were added to a solution of 4-[3-(1-aminoethyl)-5-chloro-2-methoxy-6-methylphenyl]-N,N-dimethylpyridine-2-carboxamide (75 mg, 0.25 mmol) in 2-pentanol (5 mL). The mixture was heated at 90 °C for 4 h. LCMS showed the reaction was complete. After cooling to room temperature, the solution was diluted with water (50 mL) and then extracted with DCM (30 mL × 3). The combined organic layers were washed with brine (30 mL x 3), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by preparative HPLC (ACN--H2O (0.1% FA) gradient: 40-60%) to give 4-{3-[(1S)-1-{[6-amino-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-yl]amino}ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide (28.6 mg, 25.4% yield) as a white solid. MS (ESI): 522.8 [M+H] + 。 1 H NMR (400 MHz, DMSO) δ 8.71 (dd, J = 16.2, 6.1 Hz, 2H), 8.02 (s, 1H), 7.55 - 7.37 (m, 4H), 5.6 - 5.57 (m, 1H), 3.38 (s, 3H), 3.03 (s, 3H), 2.96 (s, 3H), 2.46 (s, 3H), 2.04 (s, 3H), 1.52 (d, J = 6.9 Hz, 3H).

[0224] Example 4 4-(1-((6-Amino-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-yl)amino)ethyl)-6-chloro-3-ethoxy-2-(5-oxopyrrolidin-3-yl)benzonitrile

[0225]

[0226] Step 1) 4-Acetyl-6-chloro-3-ethoxy-2-(5-oxopyrrolidin-3-yl)benzonitrile

[0227] To a solution of 4-(3-acetyl-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one (200 mg, 0.567 mmol) in DMSO (10 mL) was added NaCN (49 mg, 1 mmol), and the mixture was heated at 80 °C for 3 h. After cooling to room temperature, the mixture was diluted with water (20 mL) and then extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (30 mL × 2), dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel chromatography (EA / PE = 2 / 1) to give 4-acetyl-6-chloro-3-ethoxy-2-(5-oxopyrrolidin-3-yl)benzonitrile (110 mg, 46.4% yield) as a yellow solid. MS (ESI): 307.0 [M+H] + 。 1 H NMR (400 MHz, CDCl3) δ 7.49 (s, 1H), 5.87 (s, 1H), 4.44 - 4.34 (m, 1H), 3.87 (q, J = 7.2 Hz, 2H), 3.88 - 3.68 (m, 2H), 2.85 - 2.61 (m, 2H), 2.61 (s, 3H), 1.43 (t, J = 7.2 Hz, 3H).

[0228] Step 2) (E)-6-chloro-3-ethoxy-4-(1-(hydroxyimino)ethyl)-2-(5-oxopyrrolidin-3-yl)benzonitrile

[0229] To a solution of 4-acetyl-6-chloro-3-ethoxy-2-(5-oxopyrrolidin-3-yl)benzonitrile (110 mg, 0.36 mmol) and pyridine (57 mg, 0.71 mmol) in EtOH (20 mL) was added NH2OH·HCl (27 mg, 0.39 mmol), and the mixture was heated at 60 °C for 16 h. After cooling to room temperature, the mixture was concentrated in vacuo, and the residue was diluted with EtOAc (50 mL). The mixture was washed with brine (30 mL × 2), and the separated organic layer was dried over Na2SO4, concentrated to give (E)-6-chloro-3-ethoxy-4-(1-(hydroxyimino)ethyl)-2-(5-oxopyrrolidin-3-yl)benzonitrile (90 mg, 70% yield) as a yellow solid. MS (ESI): 322.1 [M+H] + 。 1 H NMR (400 MHz, CDCl3) δ 13.44 (d, J = 2.0 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 2.66 (s, 3H).

[0230] Step 3) 4-(1-aminoethyl)-6-chloro-3-ethoxy-2-(5-oxopyrrolidin-3-yl)benzonitrile

[0231] A mixture of (E)-6-chloro-3-ethoxy-4-(1-(hydroxyimino)ethyl)-2-(5-oxopyrrolidin-3-yl)benzonitrile (40 mg, 0.12 mmol), Ni (5 mg), and thiophene (21 mg, 0.25 mmol) in a solution of MeOH (30 mL) and NH₃·H₂O (1 mL) was hydrogenated at 25 °C for 16 h. The mixture was then filtered and the filtrate was concentrated in vacuo to give 4-(1-aminoethyl)-6-chloro-3-ethoxy-2-(5-oxopyrrolidin-3-yl)benzonitrile (30 mg, 70.6% yield) as a yellow solid. MS (ESI): 307.8 [M+H] + 。

[0232] Step 4) 4-(1-((6-Amino-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-yl)amino)ethyl)-6-chloro-3-ethoxy-2-(5-oxopyrrolidin-3-yl)benzonitrile

[0233] A solution of 4-(1-aminoethyl)-6-chloro-3-ethoxy-2-(5-oxopyrrolidin-3-yl)benzonitrile (30 mg, 0.1 mmol), 6-chloro-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-amine (21 mg, 0.1 mmol), and DIEA (25 mg, 0.19 mmol) in 2-pentanol (5 mL) was heated at 90 °C for 16 h. After cooling to room temperature, the mixture was concentrated in vacuo and the residue was diluted with EtOAc (40 mL). The mixture was washed with brine (30 mL × 2), the separated organic layer was dried over Na₂SO₄, and concentrated in vacuo. The residue was purified by preparative HPLC (ACN-H₂O 0.1% FA, gradient 20% to 50%) to give 4-(1-((6-amino-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-yl)amino)ethyl)-6-chloro-3-ethoxy-2-(5-oxopyrrolidin-3-yl)benzonitrile (10.1 mg, 20% yield) as a white solid. MS (ESI): 483.1 [M+H] + 。 11H NMR (400 MHz, DMSO) δ 8.50 (d, J = 6.4 Hz, 1H), 7.99 - 7.93 (m, 2H), 7.79 - 7.65 (m, 2H), 7.60 (d, J = 3.6 Hz, 1H), 5.57 - 5.53 (m, 1H), 4.32 - 4.22 (m, 2H), 3.92 - 3.88 (m, 1H), 3.69 - 3.61 (m, 1H), 3.51 - 3.44 (m, 1H), 2.61 - 2.57 (m, 2H), 2.46 (s, 3H), 1.49 (d, J = 4.8 Hz, 3H), 1.44 (t, J = 6.8 Hz, 3H).

[0234] Example 5 4-(3-(1-((6-Amino-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-yl)amino)ethyl)-5-chloro-2-ethoxy-6-methylphenyl)pyrrolidin-2-one

[0235]

[0236] Step 1) 1-(5-Chloro-2-hydroxy-3-iodo-4-methylphenyl)ethan-1-one

[0237] To a solution of 1-(5-chloro-2-hydroxy-4-methylphenyl)ethan-1-one in acetic acid (15 mL) was added NIS (3.48 g, 15.5 mmol), and the mixture was heated to 80 °C and reacted for 16 h. Cooled to room temperature, quenched with Na2SO3 (10 mL). The mixture was concentrated and extracted three times with DCM (50 mL × 3). The combined organic phases were washed three times with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel chromatography (PE:EA = 3:1) to obtain 1-(5-chloro-2-hydroxy-3-iodo-4-methylphenyl)ethan-1-one (2.5 g, 76.0% yield) as a yellow liquid. MS (ESI): 310.9 [M+H] + Step 2) 1-(5-Chloro-2-ethoxy-3-iodo-4-methylphenyl)ethan-1-one

[0238] To a solution of 1-(5-chloro-2-hydroxy-3-iodo-4-methylphenyl)ethan-1-one (1.5 g, 4.80 mmol) in DMF (10 mL) were added iodoethane (1.12 g, 7.20 mmol) and K2CO3 (1.33 g, 9.60 mmol). The mixture was heated to 60 °C and stirred for 16 h. The mixture was diluted with water (80 mL) and extracted three times with DCM (50 mL × 3). The combined organic phases were washed four times with saturated brine (30 mL × 4), dried over anhydrous Na2SO4, concentrated, and the residue was purified by silica gel chromatography (PE:EA = 3:1) to give 1-(5-chloro-2-ethoxy-3-iodo-4-methylphenyl)ethan-1-one (1.55 g, 95.0% yield) as a yellow liquid. MS (ESI): 338.6 [M+H] + 。

[0239] Step 3) 2-(5-chloro-2-ethoxy-3-iodo-4-methylphenyl)-2-methyl-1,3-dioxolane

[0240] To a toluene solution (50 mL) of 1-(5-chloro-2-ethoxy-3-iodo-4-methylphenyl)ethan-1-one were added ethylene glycol (0.57 g, 9.2 mmol) and PTSA (0.08 g, 0.4 mmol). The mixture was protected with nitrogen and heated to 130 °C and stirred for 24 h. After cooling to room temperature, it was concentrated, and the residue was purified by column chromatography (PE:EA = 5:1) to give 2-(5-chloro-2-ethoxy-3-iodo-4-methylphenyl)-2-methyl-1,3-dioxolane (1.6 g, 91.4% yield) as a transparent oil. MS (ESI): 382.7 [M+H] + 。

[0241] Step 4) Ethyl (E)-3-[3-chloro-6-ethoxy-2-methyl-5-(2-methyl-1,3-dioxolan-2-yl)phenyl]acrylate

[0242] 2-(5-chloro-2-ethoxy-3-iodo-4-methylphenyl)-2-methyl-1,3-dioxolane (1.6 g, 4.2 mmol), ethyl acrylate (0.84 g, 8.4 mmol), palladium acetate (0.09 g, 0.4 mmol), tri-o-tolylphosphine (0.13 g, 0.4 mmol) and triethylamine (1.27 g, 12.6 mmol) were added to DMA (5 mL). The mixture was protected with nitrogen and heated to 90 °C and stirred for 16 h. The mixture was diluted with water (80 mL) and extracted three times with DCM (50 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 4), dried over anhydrous Na2SO4, concentrated, and the residue was purified by column chromatography (PE:EA = 4:1) to give ethyl (E)-3-(3-chloro-6-ethoxy-2-methyl-5-(2-methyl-1,3-dioxolan-2-yl)phenyl)acrylate (1.40 g, 94.5% yield) as a yellow oil. MS (ESI): 354.9 [M+H] + 。

[0243] Step 5) Ethyl 3-(3-chloro-6-ethoxy-2-methyl-5-(2-methyl-1,3-dioxolan-2-yl)phenyl)-4-nitrobutyrate

[0244] DBU (0.60 g, 3.95 mmol) was added to a solution of ethyl (E)-3-(3-chloro-6-ethoxy-2-methyl-5-(2-methyl-1,3-dioxolan-2-yl)phenyl)acrylate (1.40 g, 3.95 mmol) in CH3NO2 (10 mL). The mixture was heated to 60 °C and stirred for 24 h. The mixture was washed with water (80 mL), then extracted three times with DCM (30 mL × 3). The combined organic phases were washed three times with saturated brine (60 mL × 3), dried over anhydrous Na2SO4, concentrated, and the residue was purified by column chromatography (PE:EA = 3:1) to give ethyl 3-(3-chloro-6-ethoxy-2-methyl-5-(2-methyl-1,3-dioxolan-2-yl)phenyl)-4-nitrobutyrate (0.58 g, 35.3% yield) as a yellow oil. MS (ESI): 416.1 [M+H] + 。

[0245] Step 6) 4-(3-chloro-6-ethoxy-2-methyl-5-(2-methyl-1,3-dioxolan-2-yl)phenyl)pyrrolidin-2-one

[0246] Ethyl 3-(3-chloro-6-ethoxy-2-methyl-5-(2-methyl-1,3-dioxolan-2-yl)phenyl)-4-nitrobutanoate (0.6 g, 1.44 mmol) and Raney nickel (200 mg) in methanol solution (10 mL) were hydrogenated with a hydrogen balloon, and the mixture was stirred at room temperature for 7 h. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was separated and purified by column chromatography (PE:EA = 1:1) to give 4-(3-chloro-6-ethoxy-2-methyl-5-(2-methyl-1,3-dioxolan-2-yl)phenyl)pyrrolidin-2-one (0.35 g, 71.4% yield) as a transparent oil. MS (ESI): 339.9 [M+H] + 。

[0247] Step 7) 4-(3-acetyl-5-chloro-2-ethoxy-6-methylphenyl)pyrrolidin-2-one

[0248] To a solution of 4-[3-chloro-6-ethoxy-2-methyl-5-(2-methyl-1,3-dioxolan-2-yl)phenyl]pyrrolidin-2-one (0.35 g, 1.04 mmol) in MeOH (5 mL) was added 6N HCl (3 mL), and the mixture was stirred at 25 °C for 0.5 h. The mixture was concentrated in vacuo to give 4-(3-acetyl-5-chloro-2-ethoxy-6-methylphenyl)pyrrolidin-2-one (290 mg, 95.4% yield) as a white solid. MS (ESI): 296.1 [M+H] + 。

[0249] Step 8) 4-(3-chloro-6-ethoxy-5-((1E)-1-(hydroxyimino)ethyl)-2-methylphenyl)pyrrolidin-2-one

[0250] To a solution of 4-(3-acetyl-5-chloro-2-ethoxy-6-methylphenyl)pyrrolidin-2-one (100 mg, 0.34 mmol) and pyridine (53.49 mg, 0.68 mmol) in EtOH (10 mL) was added NH2OH.HCl (35.24 mg, 0.51 mmol), and the mixture was heated to 70 °C and stirred for 16 h. After cooling to room temperature, the mixture was concentrated in vacuo, the residue was diluted with water (30 mL), then washed 3 times with DCM (30 mL x 3), the organic phases were combined, washed three times with saturated brine (30 mL x 3), dried over anhydrous Na2SO4, and then concentrated in vacuo. The residue was separated and purified by silica gel chromatography (PE:EA = 2:1) to give 4-(3-chloro-6-ethoxy-5-((1E)-1-(hydroxyimino)ethyl)-2-methylphenyl)pyrrolidin-2-one (102 mg, 97.1% yield) as a transparent liquid. MS (ESI): 311.1 [M+H]+ .

[0251] Step 9) 4-(3-(1-Aminoethyl)-5-chloro-2-ethoxy-6-methylphenyl)pyrrolidin-2-one

[0252] A mixture of 4-(3-chloro-6-ethoxy-5-((1E)-1-(hydroxyimino)ethyl)-2-methylphenyl)pyrrolidin-2-one (102 mg, 0.33 mmol), Raney-Ni (50 mg), thiophene (0.5 mL) and NH3.H2O (5 mL) was hydrogenated at 25 °C for 4 h. The mixture was filtered and the filtrate was concentrated in vacuo to give 4-(3-(1-aminoethyl)-5-chloro-2-ethoxy-6-methylphenyl)pyrrolidin-2-one (90 mg, 92.4% yield) as a yellow oil. MS (ESI): 280.7 [M+H] + .

[0253] Step 10) 4-(3-(1-((6-Amino-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-yl)amino)ethyl)-5-chloro-2-ethoxy-6-methylphenyl)pyrrolidin-2-one

[0254] 4-(3-(1-Aminoethyl)-5-chloro-2-ethoxy-6-methylphenyl)pyrrolidin-2-one (90 mg, 0.30 mmol), 2-pentanol (5 mL), 6-chloro-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-amine (54.20 mg, 0.26 mmol) and DIEA were heated to 90 °C and stirred for 4 h. It was cooled to room temperature, diluted with water (50 mL), then extracted with DCM (30 mL x 3). The combined organic phases were washed with saturated brine (30 mL x 3), dried over anhydrous Na2SO4, and the mixture was concentrated in vacuo. The residue was purified by preparative HPLC (ACN--H2O (0.1% FA) gradient: 30%-50%) to give 4-(3-(1-((6-amino-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-yl)amino)ethyl)-5-chloro-2-ethoxy-6-methylphenyl)pyrrolidin-2-one (46.5 mg, 32.50% yield) as a white solid. MS (ESI): 471.9 [M+H] + . 11H NMR (400 MHz, DMSO) δ 8.68 (d, J = 5.4 Hz, 1H), 8.04 (s, 1H), 7.91 (d, J = 3.3 Hz, 1H), 7.35 (d, J = 3.5 Hz, 1H), 5.66 - 5.51 (m, 1H), 4.37 - 4.25 (m, 1H), 4.15 - 3.99 (m, 1H), 3.85 - 3.68 (m, 1H), 3.67 - 3.61 (m, 1H), 3.34 - 3.14 (m, 2H), 2.62 - 2.53 (m, 1H), 2.45 (s, 3H), 2.40 - 2.30 (m, 1H), 2.25 (d, J = 0.8 Hz, 3H), 1.46 (dd, J = 6.8, 2.2 Hz, 3H), 1.40 (t, J = 6.8 Hz, 3H).

[0255] Example 6: 4-(3-(1-(6-Amino-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyrimidin-4-yl)amino)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one

[0256]

[0257] Step 1) 4,6-Dichloropyrimidine-5-carbonyl chloride

[0258] To a solution of 4,6-dichloropyrimidine-5-carboxylic acid (950 mg, 4.67 mmol) and DMF (34 mg, 0.47 mmol) in dichloromethane (30 mL) was slowly added thionyl chloride (1.67 g, 14 mmol). The mixture was stirred at 60 °C for 16 h. The solution was concentrated under reduced pressure to give 4,6-dichloropyrimidine-5-carbonyl chloride (1 g, 91.28%) as a yellow oil. MS (ESI): 210.9 [M + H] + .

[0259] Step 2) N'-Acetyl-4,6-dichloropyrimidine-5-carbohydrazide

[0260] At room temperature, a solution of 4,6-dichloropyrimidine-5-carbonyl chloride (4.2 g, 20 mmol) in DCM (50 mL) was slowly added to a solution of acetylhydrazine (1.5 g, 20 mmol) and DIEA (18 g, 0.14 mol) in DCM (80 mL), and the mixture was stirred at room temperature for 2 hours. After the mixture was quenched with water (200 mL), it was extracted with dichloromethane (300 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (methanol:dichloromethane = 1:20) to obtain N'-acetyl-4,6-dichloropyrimidine-5-carbohydrazide (350 mg, 10.37% yield) as a yellow solid. MS (ESI): 248.8 [M+H] + 。

[0261] Step 3) N'-acetyl-4-amino-6-chloropyrimidine-5-carbohydrazide

[0262] Ammonia water (10 mL) was added to a solution of N'-acetyl-4,6-dichloropyrimidine-5-carbohydrazide (350 mg, 1.4 mmol) in 1,4-dioxane (50 mL), and the mixture was stirred at room temperature for 2 hours. The solution was concentrated under reduced pressure, and the concentrate was purified by silica gel chromatography (methanol / dichloromethane = 1 / 10) to obtain N'-acetyl-4-amino-6-chloropyrimidine-5-carbohydrazide (350 mg, 97.62% yield) as a yellow solid. MS (ESI): 230.0 [M+H] + 。

[0263] Step 4) 6-chloro-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyrimidin-4-amine

[0264] At room temperature, Burgess reagent (726 mg, 3.04 mmol) was added to a solution of N'-acetyl-4-amino-6-chloropyrimidine-5-carbohydrazide (325 mg, 1.52 mmol) in toluene (30 mL), and the mixture was stirred at 110 °C for 1 hour. After cooling to room temperature, the mixture was diluted with EtOAc (100 mL), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 4:1) to obtain 6-chloro-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyrimidin-4-amine (115 mg, 33.87% yield) as a white solid. MS (ESI): 211.9 [M+H] + 。

[0265] Step 5) 4-(3-(1-(6-amino-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyrimidin-4-yl)amino)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one

[0266] Dissolve 4-(3-(1-aminoethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one (30 mg, 0.1 mmol), 6-chloro-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyrimidin-4-amine (21 mg, 0.1 mmol) and N,N-diisopropylethylamine (26 mg, 0.2 mmol) in 2-pentanol (10 mL). Stir the mixture at 90 °C for 9 hours. Concentrate the solution under reduced pressure, dilute with ethyl acetate (30 mL), wash with saturated sodium chloride solution, dry the organic phase over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The crude product is obtained by high-performance preparative liquid chromatography (ACN-H2O (0.1% FA) gradient 40%-60%) to give (4-(3-(1-(6-amino-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyrimidin-4-yl)amino)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one (11.3 mg, 24% yield) as a white solid. MS (ESI): 476.1 [M+H] + 。 1 1H NMR (400 MHz, DMSO) δ 8.42 - 8.37 (m, 1H), 8.01 (d, J = 2.6 Hz, 1H), 7.84 (s, 1H), 7.45 - 7.20 (m, 3H), 5.64 - 5.57 (m, 1H), 4.15 - 4.09 (m, 1H), 4.06 - 4.00 (m, 1H), 3.90 - 3.83 (m, 1H), 3.65 - 3.58 (m, 1H), 3.29 - 3.24 (m, 1H), 2.59 (s, 3H), 2.54 (dd, J = 3.9, 2.0 Hz, 1H), 2.38 - 2.30 (m, 1H), 1.48 - 1.38 (m, 6H).

[0267] Example 7 (S)-4-(3-(1-((6-amino-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-yl)amino)ethyl)-5-chloro-6-fluoro-2-methoxyphenyl)-N,N-dimethylpicolinamide

[0268]

[0269] Step 1) 4-bromo-N,N-dimethylpicolinamide

[0270] To a solution of 4-bromopicolinic acid (796 mg, 3.94 mmol) in dichloromethane (20 mL) were added dimethylamine hydrochloride (482 mg, 5.91 mmol), N,N-diisopropylethylamine (1.5 g, 11.82 mmol) and HATU (3 g, 7.88 mmol), and the mixture was stirred at room temperature for 16 h. The mixture was quenched with water (20 mL) and then extracted with dichloromethane (60 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to give 4-bromo-N,N-dimethylpicolinamide (630 mg, 62.81% yield) as a yellow oil. MS (ESI): 230.9 [M+H] + 。

[0271] Step 2) N,N-Dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide

[0272] To a solution of 4-bromo-N,N-dimethylpicolinamide (315 mg, 1.38 mmol) and bis(pinacolato)diboron (419 mg, 1.65 mmol) in dioxane (10 mL) were added anhydrous potassium acetate (405 mg, 4.13 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (112 mg, 0.14 mmol), and the mixture was stirred at 80 °C for 16 h. The mixture was concentrated in vacuo to give N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide (265 mg, 70% yield) as a yellow oil, which was used directly in the next step without further purification. MS (ESI): 195.0 [M+H] + 。

[0273] Step 3) 4-(3-Acetyl-5-chloro-6-fluoro-2-methoxyphenyl)-N,N-dimethylpicolinamide

[0274] To a solution of N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide (265 mg, 1.37 mmol) and 1-(5-chloro-4-fluoro-3-iodo-2-methoxyphenyl)ethan-1-one (448.7 mg, 1.37 mmol) in dioxane (25 mL) and water (5 mL) were added potassium carbonate (565.5 mg, 4.10 mmol) and 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium (111.5 mg, 0.14 mmol). The mixture was stirred at 80 °C for 16 h. The solution was concentrated under reduced pressure, diluted with ethyl acetate (200 mL), washed with saturated sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol = 97:3) to give 4-(3-acetyl-5-chloro-6-fluoro-2-methoxyphenyl)-N,N-dimethylpicolinamide as a yellow oil (263 mg, 49.4% yield). MS (ESI): 350.5 [M+H] + 。

[0275] Step 4) (E)-4-(3-chloro-2-fluoro-5-(1-(hydroxyimino)ethyl)-6-methoxyphenyl)-N,N-dimethylpicolinamide

[0276] To a solution of 4-(3-acetyl-5-chloro-6-fluoro-2-methoxyphenyl)-N,N-dimethylpicolinamide (62 mg, 0.18 mmol) and hydroxylamine hydrochloride (18.4 mg, 0.27 mmol) in ethanol (10 mL) under nitrogen protection was added pyridine (42 mg, 0.53 mmol). The mixture was stirred at 60 °C for 16 h. The solution was concentrated under reduced pressure, diluted with ethyl acetate (30 mL), washed with saturated sodium chloride solution, and the organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give (E)-4-(3-chloro-2-fluoro-5-(1-(hydroxyimino)ethyl)-6-methoxyphenyl)-N,N-dimethylpicolinamide (60 mg, 74.21% yield) as a yellow oil. MS (ESI): 366.0 [M+H] + 。

[0277] Step 5) 4-(3-(1-aminoethyl)-5-chloro-6-fluoro-2-methoxyphenyl)-N,N-dimethylpicolinamide

[0278] To a mixture of (E)-4-(3-chloro-2-fluoro-5-(1-(hydroxyimino)ethyl)-6-methoxyphenyl)-N,N-dimethylnicotinamide (58 mg, 0.16 mmol) and Raney nickel (20 mg) in methanol (30 mL) was added ammonia water (2 mL, 20%) and thiophene (2 mL), and the mixture was stirred under hydrogen for 15 h. The mixture was filtered and the filter cake was washed with methanol (30 mL). The filtrate was concentrated under reduced pressure to give 4-(3-(1-aminoethyl)-5-chloro-6-fluoro-2-methoxyphenyl)-N,N-dimethylnicotinamide (55 mg, 83.80% yield) as a yellow oil. MS (ESI): 351.9 [M+H] + 。

[0279] Step 6) (S)-4-(3-(1-((6-Amino-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-yl)amino)ethyl)-5-chloro-6-fluoro-2-methoxyphenyl)-N,N-dimethylnicotinamide

[0280] To a solution of 4-(3-(1-aminoethyl)-5-chloro-6-fluoro-2-methoxyphenyl)-N,N-dimethylnicotinamide (46 mg, 0.13 mmol) and 6-chloro-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-amine (28 mg, 0.13 mmol) in sec-amyl alcohol (10 mL) was added N,N-diisopropylethylamine (68 mg, 0.52 mmol), and the mixture was stirred at 90 °C for 9 h. The solution was concentrated under reduced pressure, diluted with dichloromethane (30 mL), washed with saturated sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by high performance preparative liquid chromatography (ACN-H2O (0.1% FA) gradient 30-70) to give (S)-4-(3-(1-((6-amino-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-yl)amino)ethyl)-5-chloro-6-fluoro-2-methoxyphenyl)-N,N-dimethylnicotinamide (8.7 mg, 12.61% yield) as a white solid. MS (ESI): 527.8 [M+H] + 。 1 H NMR (400 MHz, DMSO) δ 8.73 (dd, J = 5.1, 0.7 Hz, 1H), 8.66 (d, J = 7.2 Hz, 1H), 8.00 (s, 1H), 7.75 - 7.42 (m, 5H), 5.62 (dd, J = 14.0, 7.0 Hz, 1H), 3.45 (s, 3H), 3.03 (s, 3H), 2.97 (s, 3H), 2.46 (s, 3H), 1.54 (d, J = 6.9 Hz, 3H).

[0281] Example 8 (S)-4-(3-((R)-(1-((6-amino-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-yl)amino)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one

[0282]

[0283] Step 1) (R)-4-(3-acetyl-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one

[0284] The 4-(3-acetyl-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one (1100.0 mg) synthesized in Step 8 of Example 1 was separated and purified by chiral column chromatography (Method: SFC Thar prep 80, Column: CHIRALPAK IC 250 mm×20 mm, 5 μm, Eluent: 35% EtOH (NH4OH 0.2%), Flow rate: 40 g / min) to obtain (R)-4-(3-acetyl-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one (260.2 mg). MS(ESI): 300.1 [M+H] + .

[0285] Step 2) (R,E)-4-(3-chloro-6-ethoxy-2-fluoro-5-(1-(hydroxyimino)ethyl)phenyl)pyrrolidin-2-one

[0286] To a solution of (R)-4-(3-acetyl-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one (50.1 mg, 0.17 mmol) and pyridine (26.2 mg, 0.33 mmol) in EtOH (25 mL) was added NH2OH·HCl (13.8 mg, 0.19 mmol), and the mixture was heated at 70 °C for 18 h. After cooling to room temperature, the mixture was concentrated in vacuo, and the residue was diluted with EtOAc (30 mL) and then washed with brine (20 mL×2). The separated organic layer was dried over Na2SO4 and concentrated in vacuo to obtain (R,E)-4-(3-chloro-6-ethoxy-2-fluoro-5-(1-(hydroxyimino)ethyl)phenyl)pyrrolidin-2-one (50.9 mg, 86.5% yield) as a yellow solid. MS(ESI): 315.0 [M+H] + .

[0287] Step 3) (4R)-4-(3-(1-aminoethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one

[0288] (R,E)-4-(3-chloro-6-ethoxy-2-fluoro-5-(1-(hydroxyimino)ethyl)phenyl)pyrrolidin-2-one (38 mg, 0.12 mmol), Raney nickel (10.1 mg, 0.16 mmol) and thiophene (13.6 mg, 0.11 mmol) in a mixture of MeOH (10 mL) and NH3.H2O (1.5 mL) were hydrogenated at 25 °C for 16 h. The mixture was then filtered and the filtrate was concentrated in vacuo to give (4R)-4-(3-(1-aminoethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one (26.5 mg, 63.4% yield) as a white solid. MS (ESI): 283.9 [M-NH3+H] + 。

[0289] Step 4) (R)-4-(3-((R)-1-aminoethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one

[0290] (4R)-4-(3-(1-aminoethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one (25.0 mg) was separated and purified by chiral column chromatography (Method: SFC Thar prep 80, Column: CHIRALPAK IC 250 mm×20 mm, 5 μm, Eluent: 40% EtOH (NH4OH 0.2%), Flow rate: 40 g / min) to give (R)-4-(3-((R)-1-aminoethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one (10.1 mg).

[0291] Step 5) (S)-4-(3-((R)-(1-((6-amino-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-yl)amino)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one

[0292] (R)-4-(3-((R)-1-Aminoethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one (10.2 mg, 0.03 mmol), 6-chloro-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-amine (7 mg, 0.03 mmol) and DIEA (13.1 mg, 0.1 mmol) in 2-pentanol (5 mL) were heated at 90 °C for 20 h. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was diluted with EtOAc (30 mL) and then washed with brine (20 mL × 2). The separated organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC (ACN-H2O 0.1 FA, gradient 40% to 60%) to give (S)-4-(3-((R)-(1-((6-amino-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-yl)amino)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one (5.9 mg, 34.8% yield) as a white solid. MS (ESI): 476.1 [M+H] + 。

[0293] Example 9 (R)-4-(3-((R)-(1-((6-Amino-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-yl)amino)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one

[0294]

[0295] Step 1) (S)-4-(3-Acetyl-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one

[0296] 4-(3-Acetyl-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one (1100.0 mg) synthesized in Step 8 of Example 1 was separated and purified by chiral column chromatography (Method: SFC Thar prep 80, Column: CHIRALPAK IC 250 mm × 20 mm, 5 μm, Eluent: 35% EtOH (NH4OH 0.2%), Flow rate: 40 g / min) to give (S)-4-(3-acetyl-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one (278.9 mg). MS (ESI): 300.1 [M+H] + 。

[0297] Step 2) (S,E)-4-(3-Chloro-6-ethoxy-2-fluoro-5-(1-(hydroxyimino)ethyl)phenyl)pyrrolidin-2-one

[0298] To a solution of (S)-4-(3-acetyl-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one (50.5 mg, 0.18 mmol) and pyridine (26.3 mg, 0.33 mmol) in EtOH (25 mL) was added NH2OH·HCl (13.7 mg, 0.19 mmol), and the mixture was heated at 70 °C for 16 h. After cooling to room temperature, the mixture was concentrated in vacuo, and the residue was diluted with EtOAc (30 mL) and then washed with brine (20 mL × 2). The separated organic layer was dried over Na2SO4 and concentrated in vacuo to give (S,E)-4-(3-chloro-6-ethoxy-2-fluoro-5-(1-(hydroxyimino)ethyl)phenyl)pyrrolidin-2-one (56.1 mg, 95.3% yield) as a yellow solid. MS(ESI): 315.0 [M+H] + 。

[0299] Step 3) (4S)-4-(3-(1-aminoethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one

[0300] A mixture of (S,E)-4-(3-chloro-6-ethoxy-2-fluoro-5-(1-(hydroxyimino)ethyl)phenyl)pyrrolidin-2-one (38.2 mg, 0.12 mmol), Raney nickel (10.1 mg, 0.16 mmol) and thiophene (13.5 mg, 0.11 mmol) in MeOH (10 mL) and NH3·H2O (1.5 mL) was hydrogenated at 25 °C for 16 h. Then the mixture was filtered and the filtrate was concentrated in vacuo to give (4S)-4-(3-(1-aminoethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one (27.7 mg, 66.3% yield) as a white solid. MS(ESI): 283.9 [M-NH3+H] + 。

[0301] Step 4) (S)-4-(3-((R)-1-aminoethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one

[0302] (4S)-4-(3-(1-aminoethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one (27.7 mg) was separated and purified by chiral column chromatography (Method: SFC Thar prep 80, Column: CHIRALPAK IC 250 mm × 20 mm, 5 μm, Eluent: 40% EtOH (NH4OH 0.2%), Flow rate: 40 g / min) to give (S)-4-(3-((R)-1-aminoethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one (16.1 mg).

[0303] Step 5) (R)-4-(3-((R)-(1-((6-amino-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-yl)amino)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one

[0304] A solution of (S)-4-(3-((R)-1-aminoethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one (10.1 mg, 0.03 mmol), 6-chloro-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-amine (7.0 mg, 0.03 mmol) and DIEA (13.2 mg, 0.1 mmol) in 2-pentanol (6.0 mL) was heated at 90 °C for 12 h. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was diluted with EtOAc (30 mL) and then washed with brine (20 mL × 2). The separated organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC (ACN-H2O 0.1 FA, gradient 40% to 60%) to give (R)-4-(3-((R)-(1-((6-amino-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-yl)amino)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one (5.5 mg, 32.4% yield) as a white solid. MS (ESI): 476.1 [M+H] + 。

[0305] Example 10 (S)-4-(3-((S)-(1-((6-amino-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-yl)amino)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one

[0306]

[0307] Step 1) (R)-4-(3-((S)-1-aminoethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one

[0308] (4R)-4-(3-(1-aminoethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one (25.0 mg) was separated and purified by chiral column chromatography (Method: SFC Thar prep 80, Column: CHIRALPAK IC 250 mm × 20 mm, 5 μm, Eluent: 40% EtOH (NH4OH 0.2%), Flow rate: 40 g / min) to give (R)-4-(3-((S)-1-aminoethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one (12.7 mg).

[0309] Step 2) (S)-4-(3-((S)-(1-((6-Amino-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-yl)amino)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one

[0310] A solution of (R)-4-(3-((S)-1-aminoethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one (12.0 mg, 0.03 mmol), 6-chloro-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-amine (10 mg, 0.04 mmol) and DIEA (13.2 mg, 0.1 mmol) in 2-pentanol (6.0 mL) was heated at 90 °C for 12 h. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was diluted with EtOAc (30 mL) and then washed with brine (20 mL × 2). The separated organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC (ACN-H2O 0.1 FA, gradient 40% to 60%) to give (S)-4-(3-((S)-(1-((6-amino-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-yl)amino)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one (7.3 mg, 36.1% yield) as a white solid. MS (ESI): 476.1 [M+H] + 。

[0311] Example 11 (R)-4-(3-((S)-(1-((6-Amino-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-yl)amino)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one

[0312]

[0313] Step 1) (S)-4-(3-((S)-1-aminoethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one

[0314] (4S)-4-(3-(1-aminoethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one (27.7 mg) was separated and purified by chiral column chromatography (Method: SFC Thar prep 80, Column: CHIRALPAK IC 250 mm × 20 mm, 5 μm, Eluent: 40% EtOH (NH4OH 0.2%), Flow rate: 40 g / min) to give (S)-4-(3-((S)-1-aminoethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one (18.2 mg).

[0315] Step 2) (R)-4-(3-((S)-(1-((6-Amino-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-yl)amino)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one

[0316] A solution of (S)-4-(3-((S)-1-aminoethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one (15.0 mg, 0.04 mmol), 6-chloro-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-amine (10.2 mg, 0.04 mmol) and DIEA (13.1 mg, 0.1 mmol) in 2-pentanol (6.0 mL) was heated at 90 °C for 19 h. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was diluted with EtOAc (30 mL) and then washed with brine (20 mL × 2). The separated organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC (ACN-H2O 0.1 FA, gradient 40% to 60%) to give (R)-4-(3-((S)-(1-((6-amino-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-yl)amino)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one (7.1 mg, 28.4% yield) as a white solid. MS (ESI): 476.1 [M+H] + 。

[0317] Example 12 4-(3-((R)1-((6-Amino-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-yl)amino)ethyl)-5-chloro-2-ethoxy-6-methylphenyl)pyrrolidin-2-one

[0318]

[0319] Step 1) 4-(3((R)-(1-aminoethyl)-5-chloro-2-ethoxy-6-methylphenyl)pyrrolidin-2-one

[0320] 4-(3-(1-Aminoethyl)-5-chloro-2-ethoxy-6-methylphenyl)pyrrolidin-2-one (150.0 mg) was separated and purified by chiral column chromatography (Method: SFC Thar prep 80, Column: CHIRALPAK IC 250 mm × 20 mm, 5 μm, Eluent: 40% EtOH (NH4OH 0.2%), Flow rate: 40 g / min) to give 4-(3((R)-(1-aminoethyl)-5-chloro-2-ethoxy-6-methylphenyl)pyrrolidin-2-one (38.9 mg).

[0321] Step 2) 4-(3-((R)-1-((6-amino-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-yl)amino)ethyl)-5-chloro-2-ethoxy-6-methylphenyl)pyrrolidin-2-one

[0322] A solution of 4-(3((R)-(1-aminoethyl)-5-chloro-2-ethoxy-6-methylphenyl)pyrrolidin-2-one (35.0 mg, 0.12 mmol), 6-chloro-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-amine (28.1 mg, 0.12 mmol) and DIEA (26.5 mg, 0.2 mmol) in 2-pentanol (5.0 mL) was heated at 90 °C for 19 h. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was diluted with EtOAc (30 mL) and then washed with brine (20 mL×2). The separated organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC (ACN-H2O 0.1 FA, gradient 40% to 60%) to give (S)-4-(3-((R)-(1-((6-amino-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-yl)amino)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one (22.2 mg, 40.1% yield) as a white solid. MS (ESI): 471.9 [M+H] + 。

[0323] Example 13 4-(3-((S)-1-((6-amino-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-yl)amino)ethyl)-5-chloro-2-ethoxy-6-methylphenyl)pyrrolidin-2-one

[0324]

[0325] Step 1) 4-(3((S)-(1-aminoethyl)-5-chloro-2-ethoxy-6-methylphenyl)pyrrolidin-2-one

[0326] 4-(3-(1-aminoethyl)-5-chloro-2-ethoxy-6-methylphenyl)pyrrolidin-2-one (150.0 mg) was separated and purified by chiral column chromatography (Method: SFC Thar prep 80, Column: CHIRALPAK IC 250 mm×20 mm, 5 μm, Eluent: 40% EtOH (NH4OH 0.2%), Flow rate: 40 g / min) to give 4-(3((S)-(1-aminoethyl)-5-chloro-2-ethoxy-6-methylphenyl)pyrrolidin-2-one (39.6 mg).

[0327] Step 2) 4-(3-((S)-1-((6-amino-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-yl)amino)ethyl)-5-chloro-2-ethoxy-6-methylphenyl)pyrrolidin-2-one

[0328] A solution of 4-(3((S)-(1-aminoethyl)-5-chloro-2-ethoxy-6-methylphenyl)pyrrolidin-2-one (35.1 mg, 0.12 mmol), 6-chloro-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-amine (28.5 mg, 0.12 mmol) and DIEA (26.1 mg, 0.2 mmol) in 2-pentanol (5.0 mL) was heated at 90 °C for 19 h. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was diluted with EtOAc (30 mL) and then washed with brine (20 mL × 2). The separated organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC (ACN-H2O 0.1 FA, gradient 40% to 60%) to give (S)-4-(3-((S)-(1-((6-amino-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-yl)amino)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one (20.1 mg, 36.3% yield) as a white solid. MS (ESI): 471.9 [M+H] + 。

[0329] Example 14 (S)-4-(3-((R)-1-(6-amino-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyrimidin-4-yl)amino)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one

[0330]

[0331] A solution of (R)-4-(3-((R)-1-aminoethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one (10.1 mg, 0.03 mmol), 6-chloro-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-amine (7.1 mg, 0.03 mmol) and DIEA (15.6 mg, 0.12 mmol) in 2-pentanol (5.0 mL) was heated at 80 °C for 24 h. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was diluted with EtOAc (30 mL) and then washed with brine (20 mL × 2). The separated organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC (ACN-H2O 0.1 FA, gradient 40% to 60%) to give (S)-4-(3-((R)-1-(6-amino-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyrimidin-4-yl)amino)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one (4.7 mg, 30.1% yield) as a white solid. MS (ESI): 476.1 [M+H] + 。

[0332] Example 15 (S)-4-(3-((S)-1-(6-amino-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyrimidin-4-yl)amino)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one

[0333]

[0334] A solution of (R)-4-(3-((S)-1-aminoethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one (15.1 mg, 0.04 mmol), 6-chloro-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-amine (10.5 mg, 0.04 mmol) and DIEA (16.8 mg, 0.13 mmol) in 2-pentanol (5.0 mL) was heated at 90 °C for 16 h. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was diluted with EtOAc (30 mL) and then washed with brine (20 mL × 2). The separated organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC (ACN-H2O 0.1 FA, gradient 40% to 60%) to give (S)-4-(3-((S)-1-(6-amino-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyrimidin-4-yl)amino)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one (4.7 mg, 32.8% yield) as a yellow solid. MS (ESI): 476.1 [M+H] + 。

[0335] Example 16 (R)-4-(3-((R)-1-(6-amino-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyrimidin-4-yl)amino)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one

[0336]

[0337] A solution of (S)-4-(3-((R)-1-aminoethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one (12.6 mg, 0.04 mmol), 6-chloro-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-amine (8.8 mg, 0.04 mmol) and DIEA (15.3 mg, 0.12 mmol) in 2-pentanol (6.0 mL) was heated at 90 °C for 12 h. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was diluted with EtOAc (10 mL) and then washed with brine (10 mL × 2). The separated organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC (ACN-H2O 0.1% FA, gradient 40% to 60%) to give (R)-4-(3-((R)-1-(6-amino-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyrimidin-4-yl)amino)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one (6.3 mg, 31.8% yield) as a white solid. MS (ESI): 476.1 [M+H] + 。

[0338] Example 17 (R)-4-(3-((S)-1-(6-amino-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyrimidin-4-yl)amino)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one

[0339]

[0340] A solution of (S)-4-(3-((R)-1-aminoethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one (10.6 mg, 0.03 mmol), 6-chloro-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-amine (7.2 mg, 0.03 mmol) and DIEA (13.5 mg, 0.1 mmol) in 2-pentanol (6.0 mL) was heated at 90 °C for 12 h. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was diluted with EtOAc (10 mL) and then washed with brine (10 mL × 2). The separated organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC (ACN-H2O 0.1 FA, gradient 40% to 60%) to give (R)-4-(3-((S)-1-(6-amino-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyrimidin-4-yl)amino)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one (7.1 mg, 42.7% yield) as a white solid. MS (ESI): 476.1 [M+H] + 。

[0341] Example 18 (R)-4-(3-((S)1-((6-amino-5-(2-methyl-2H-tetrazol-5-yl)pyrimidin-4-yl)amino)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one

[0342]

[0343] Step 1) 5-Iodo-2-methyl-2H-tetrazole

[0344] To a solution of 2-methyl-1,2,3,4-tetrazol-5-amine (5 g, 50.5 mmol), copper(I) iodide (9.62 g, 50.5 mmol) and CH2I2 (68 g, 0.25 mol) in THF (50 mL) was added isoamyl nitrite (21.3 g, 0.18 mol). The mixture was heated to 60 °C and stirred for 2 h. After cooling to room temperature, the mixture was diluted with EtOAc (100 mL) and then washed with saturated brine (60 mL x2). The organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (EA / PE = 1 / 10) to give 5-iodo-2-methyl-2H-tetrazole (3.6 g, 32.3% yield) as a white solid. MS (ESI): 210.8 [M+H] + 。

[0345] Step 2) 2-Methyl-5-(tert-butylstannyl)-2H-tetrazole

[0346] At -78 °C, n-butyllithium (5.9 mL, 14 mmol) was slowly added dropwise to a solution of 5-iodo-2-methyl-2H-tetrazole (2.0 g, 9.5 mmol) in THF (30 mL), and stirring was continued for 1 h. Then (n-Bu)3SnCl (4.64 g, 14.25 mmol) was added, and the mixture was warmed to 25 °C and stirred for an additional 4 h. The reaction was then quenched with an aqueous NH4Cl solution (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic phases were washed with saturated brine (40 mL × 2), dried over anhydrous Na2SO4, concentrated in vacuo, and the residue was purified by column chromatography (PE / EA = 20 / 1) to give 2-methyl-5-(tributylstannyl)-2H-tetrazole (2.58 g, 65.2% yield) as a yellow oil. MS (ESI): 374.9 [M+H] + 。

[0347] Step 3) 4,6-Dimethoxy-5-(2-methyl-2H-tetrazol-5-yl)pyrimidine

[0348] To a solution of 5-bromo-4,6-dimethoxypyrimidine (500 mg, 2.28 mmol) in DMF (20 mL) was added 2-methyl-5-(tributylstannyl)-2H-tetrazole (1.7 g, 4.57 mmol) and Pd(dppf)Cl2 (370 mg, 0.46 mmol). The mixture was warmed to 120 °C and stirred for 24 h. After cooling to room temperature, the mixture was concentrated in vacuo, and the residue was diluted with water (50 mL) and then extracted with EtOAc (50 mL × 3). The combined organic phases were washed with saturated brine (40 mL × 2), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography (PE / EA = 2 / 1) to give 4,6-dimethoxy-5-(2-methyl-2H-tetrazol-5-yl)pyrimidine (310 mg, 58% yield) as a yellow oil. MS (ESI): 223.0 [M+H] + 。

[0349] Step 4) 4,6-Dihydroxy-5-(2-methyl-2H-tetrazol-5-yl)pyrimidine

[0350] To a solution of 4,6-dimethoxy-5-(2-methyl-2H-tetrazol-5-yl)pyrimidine (310 mg, 1.40 mmol) in AcOH (10 mL) was added concentrated hydrochloric acid (2.0 mL). The mixture was warmed to 100 °C and stirred for 5 h. After cooling to room temperature, the mixture was concentrated in vacuo to give 4,6-dihydroxy-5-(2-methyl-2H-tetrazol-5-yl)pyrimidine (280 mg, 93% yield) as a yellow solid. MS (ESI): 195.1 [M+H] + 。

[0351] Step 5) 4,6-Dichloro-5-(2-methyl-2H-tetrazol-5-yl)pyrimidine

[0352] Dissolve 4,6-dihydroxy-5-(2-methyl-2H-tetrazol-5-yl)pyrimidine (40 mg, 0.21 mmol) in POCl3 (5 mL), then add DIEA (80 mg, 0.62 mmol), and heat the mixture to 100 °C and stir for 5 h. Cool to room temperature, concentrate in vacuo, dilute the residue with H2O (20 mL), and then extract with EtOAc (30 mL x 3). Combine the organic phases, wash with saturated brine (50 mL x 2), dry over anhydrous Na2SO4, and concentrate in vacuo to obtain 4,6-dichloro-5-(2-methyl-2H-tetrazol-5-yl)pyrimidine (50 mg, 94.56% yield) as a yellow solid. MS (ESI): 230.9 [M+H] + 。

[0353] Step 6) 6-Chloro-5-(2-methyl-2H-tetrazol-5-yl)pyrimidin-4-amine

[0354] At 0 °C, add NH3.H2O (73 mg, 0.52 mmol) to a solution of 4,6-dichloro-5-(2-methyl-2H-tetrazol-5-yl)pyrimidine (40 mg, 0.17 mmol) in dioxane (10 mL), warm to 25 °C and stir for 16 h. Then concentrate in vacuo, dilute the residue with EtOAc (100 mL), and wash with brine (40 mL x 2). Separate the organic phase, dry over anhydrous Na2SO4, and concentrate in vacuo to obtain 6-chloro-5-(2-methyl-2H-tetrazol-5-yl)pyrimidin-4-amine (37 mg, 90.93% yield) as a yellow solid. MS (ESI): 212.0 [M+H] + 。

[0355] Step 7) 4-(3-(1-((6-Amino-5-(2-methyl-2H-tetrazol-5-yl)pyrimidin-4-yl)amino)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one

[0356] To a solution of 6-chloro-5-(2-methyl-2H-tetrazol-5-yl)pyrimidin-4-amine (36 mg, 0.17 mmol) in 2-pentanol (20 mL) was added 4-(3-(1-aminoethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one (51.16 mg, 0.17 mmol) and DIEA (66 mg, 0.51 mmol), and the mixture was heated to 100 °C and stirred for 18 h. After cooling to room temperature, it was concentrated in vacuo. The residue was diluted with water (20 mL), and then extracted with EtOAc (30 mL x 3). The combined organic phases were washed with saturated brine (50 mL x 2), then dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was separated by high-performance preparative liquid chromatography (-Gemini-C18 150 x 21.2 mm, 5 μm: ACN--H2O (0.1% FA), 15%-50%) and chiral high-performance preparative chromatography (chiralpak-AD, CO2-MeOH (DEA)) to give (R)-4-(3-((S)1-((6-amino-5-(2-methyl-2H-tetrazol-5-yl)pyrimidin-4-yl)amino)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one (3.6 mg) and (R)-4-(3-((R)1-((6-amino-5-(2-methyl-2H-tetrazol-5-yl)pyrimidin-4-yl)amino)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one (3.0 mg) as white solids.

[0357] (R)-4-(3-((S)1-((6-Amino-5-(2-methyl-2H-tetrazol-5-yl)pyrimidin-4-yl)amino)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one: MS (ESI): 475.9 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.45 (d, J = 7.1 Hz, 1H), 7.97 (s, 1H), 7.84 (s, 1H), 7.45 (s, 2H), 7.39 (d, J = 8.4 Hz, 1H), 5.62 (q, J = 7.0 Hz, 1H), 4.50 (s, 3H), 4.18 (dq, J = 13.8, 6.9 Hz, 1H), 4.04 (dt, J = 18.0, 9.0 Hz, 1H), 3.87 (dq, J = 14.1, 7.0 Hz, 1H), 3.64 (t, J = 9.4 Hz, 1H), 3.29 (s, 1H), 2.59 - 2.52 (m, 1H), 2.30 (dd, J = 17.3, 8.1 Hz, 1H), 1.48 (d, J = 6.8 Hz, 3H), 1.42 (t, J = 7.0 Hz, 3H).

[0358] (R)-4-(3-((R)1-((6-Amino-5-(2-methyl-2H-tetrazol-5-yl)pyrimidin-4-yl)amino)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one

[0359]

[0360] (R)-4-(3-((R)1-((6-Amino-5-(2-methyl-2H-tetrazol-5-yl)pyrimidin-4-yl)amino)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one was obtained by the same method as in Example 18: MS(ESI): 475.8 [M+H] + . 1 H NMR(400 MHz, DMSO) δ 8.45 (d, J = 7.2 Hz, 1H), 7.98 (s, 1H), 7.84 (s, 1H), 7.45 (s, 2H), 7.39 (d, J = 8.4 Hz, 1H), 5.67 - 5.56 (m, 1H), 4.50 (s, 3H), 4.16 (dt, J = 14.2, 7.0 Hz, 1H), 4.03 (dd, J = 17.7, 8.8 Hz, 1H), 3.95 - 3.85 (m, 1H), 3.58 (t, J = 9.8 Hz, 1H), 3.29 - 3.23 (m, 1H), 2.59 (dd, J = 17.7, 9.4 Hz, 1H), 2.37 (dd, J = 17.5, 8.8 Hz, 1H), 1.48 (d, J = 6.9 Hz, 3H), 1.42 (t, J = 6.9 Hz, 3H).

[0361] Biological assay

[0362] Kinase Activity Assay The activity of the compounds of the present invention as PI3K and mTOR kinase inhibitors can be evaluated by the following assays. General Description of Kinase Assay The kinase assay is performed by detecting myelin basic protein (MBP) incorporated with γ-33P-ATP. Prepare a 20 μg / mL MBP (Sigma #M-1891) tris(hydroxymethyl)aminomethane buffered saline solution (TBS; 50 mM Tris pH 8.0, 138 mM NaCl, 2.7 mM KCl), and coat a high-binding white 384-well plate (Greiner), 60 μL per well. Incubate at 4 °C for 24 hours. Then wash the plate 3 times with 100 μL of TBS. The kinase reaction is carried out in a kinase buffer (5 mM Hepes pH 7.6, 15 mM NaCl, 0.01% bovine serum albumin (Sigma #I-5506), 10 mM MgCl2, 1 mM DTT, 0.02% Triton X-100) with a total volume of 34 μL. Dissolve the compound in DMSO and add it to each well, with the final concentration of DMSO being 1%. Each data point is measured twice, and at least two assays are performed for each compound. For example, the final concentration of the enzyme is 10 nM or 20 nM. Add unlabeled ATP (10 μM) and γ-33P-labeled ATP (2 × 106 cpm per well, 3000 Ci / mmole) to start the reaction. The reaction is carried out with shaking at room temperature for 1 hour. Wash the 384-well plate with 7x PBS, and then add 50 μL of scintillation fluid to each well. A Wallac Trilux counter can also be used.

[0363] The above assay method can obtain the inhibitory IC50 and / or inhibition constant Ki. IC50 is defined as the concentration of the compound that inhibits 50% of the enzyme activity under the assay conditions. Make a curve with 10 concentration points using a 1 / 2 log dilution factor to estimate the IC 50 value (for example, make a typical curve with the following compound concentrations: 10 μM, 3 μM, 1 μM, 0.3 μM, 0.1 μM, 0.03 μM, 0.01 μM, 0.003 μM, 0.001 μM, and 0 μM).

[0364] General Assay Protocol for PI3 Kinase

[0365] PI3K (p110α / p85α) (h) [Non-radioactive test]

[0366] PI3K (p110α / p85α) (h) was incubated in a buffer solution containing 10 μM phosphatidylinositol-4,5-bisphosphate and MgATP (concentration determined according to requirements). After adding the ATP solution, the reaction was initiated. After incubating at room temperature for 30 minutes, a termination solution containing EDTA and biotinylated phosphatidylinositol-3,4,5-trisphosphate was added to terminate the reaction. Finally, a detection buffer was added, including europium-labeled anti-GST monoclonal antibody, GST-labeled GRP1PH domain, and streptavidin-allophycocyanin. The microplate was read in the time-resolved fluorescence mode, and the homogeneous time-resolved fluorescence (HTRF) signal was determined by the equation HTRF = 10000 × (Em665nm / Em620 nm).

[0367] PI3K (p110β / p85α) (h) [Non-radioactive test]

[0368] PI3K (p110β / p85α) (h) was incubated in a buffer solution containing 10 μM phosphatidylinositol-4,5-bisphosphate and MgATP (concentration determined according to requirements). After adding the ATP solution, the reaction was initiated. After incubating at room temperature for 30 minutes, a termination solution containing EDTA and biotinylated phosphatidylinositol-3,4,5-trisphosphate was added to terminate the reaction. Finally, a detection buffer was added, including europium-labeled anti-GST monoclonal antibody, GST-labeled GRP1PH domain, and streptavidin-allophycocyanin. The microplate was read in the time-resolved fluorescence mode, and the homogeneous time-resolved fluorescence (HTRF) signal was determined by the equation HTRF = 10000 × (Em665nm / Em620 nm).

[0369] PI3K (p110δ / p85α) (h) [Non-radioactive test]

[0370] PI3K (p110δ / p85α) (h) was incubated in a buffer solution containing 10 μM phosphatidylinositol-4,5-bisphosphate and MgATP (concentration determined according to requirements). After adding the ATP solution, the reaction was initiated. After incubating at room temperature for 30 minutes, a termination solution containing EDTA and biotinylated phosphatidylinositol-3,4,5-trisphosphate was added to terminate the reaction. Finally, a detection buffer was added, including europium-labeled anti-GST monoclonal antibody, GST-labeled GRP1PH domain, and streptavidin-allophycocyanin. The microplate was read in the time-resolved fluorescence mode, and the homogeneous time-resolved fluorescence (HTRF) signal was determined by the equation HTRF = 10000 × (Em665nm / Em620 nm).

[0371] PI3K (p120γ) (h) [Non-radioactive test]

[0372] PI3K (p120γ) (h) was incubated in a buffer solution containing 10 μM phosphatidylinositol-4,5-bisphosphate and MgATP (the concentration was determined according to requirements). After adding the ATP solution, the reaction was started. After incubating at room temperature for 30 minutes, a termination solution containing EDTA and biotinylated phosphatidylinositol-3,4,5-trisphosphate was added to terminate the reaction. Finally, a detection buffer was added, including europium-labeled anti-GST monoclonal antibody, GST-labeled GRP1PH domain, and streptavidin-allophycocyanin. The microplate was read in the time-resolved fluorescence mode, and the homogeneous time-resolved fluorescence (HTRF) signal was determined by the equation HTRF = 10000 × (Em665 nm / Em620 nm).

[0373] The kinase assay in the present invention was completed by Eurofins in France (Eurofins Cerep SA, Le Bois L'Evêque, 86600 Celle L'Evescault, France), and the test results are shown in Table 1, where +: >100 nM; ++: 50 - 100 nM; +++: 10 - 50 nM; ++++: <10 nM.

[0374] Table 1. Kinase inhibition data of the compounds of the present invention

[0375]

[0376] NT: Not tested.

[0377] The test results show that the compounds of the present invention have good inhibitory activity against the PI3K kinase family, especially good inhibitory activity and selectivity against the δ subtype.

[0378] Cell activity assay

[0379] The cell activity of the compounds of the present invention as PI3K kinase inhibitors can be evaluated by the following assay.

[0380] General description of the cell assay:

[0381] PI3K-α, γ subtypes: First, the compound is diluted from the stock concentration to 5 mM with 100% DMSO. In the second step, the 5 mM compound is used as the first point and serially diluted 10-fold with 100% DMSO for 10 points. In the third step, it is diluted 250-fold with serum-free medium, and at this time the DMSO concentration is 0.4%. Then, 50 μL of the compound diluted with the medium is transferred to a 50 μL cell plate, and at this time the DMSO concentration is 0.2%, and the final concentrations of the compound are 10000 nM, 2500 nM, 625 nM, 156.25 nM, 39.06 nM, 9.77 nM, 2.44 nM, 0.61 nM, 0.15 nM, 0.04 nM.

[0382] PI3K-β, δ subtypes: First, the compound is diluted from the stock concentration to 1.25 mM with 100% DMSO. In the second step, the 1.25 mM compound is used as the first point and serially diluted 10-fold with 100% DMSO for 10 points. In the third step, it is diluted 35.714-fold with serum-free medium, and then 2.5 μL of the compound diluted with the medium is transferred to a 30 μL cell plate, incubated in an incubator for 1 hour, and then 2.5 μL of anti-IgM is added. At this time the DMSO concentration is 0.2%, and the final concentrations of the compound are 2500 nM, 625 nM, 156.25 nM, 39.06 nM, 9.77 nM, 2.44 nM, 0.61 nM, 0.15 nM, 0.04 nM, 0.01 nM.

[0383] PI3K-α Inhibitory Activity Detection Method

[0384] SKOV-3 cells are seeded into a 96-well cell culture plate at a density of 60000 cells / 50 μL / well, and the cell medium is serum-free RPMI-1640. Cultured overnight in a 37 °C, 5% CO2 incubator. Add 50 μL / well of the test compound to the cells and culture in a 37 °C, 5% CO2 incubator for 60 minutes. The final DMSO concentration is 0.2%. Aspirate the medium, and add 50 μL of 1x lysis buffer to each well. Shake at room temperature for 45 minutes. Transfer 16 μL of the lysate to a 384-well plate, and add 4 μL of the premixed antibody of the Phospho-AKT (Ser473) kit from Cisbio. Centrifuge at 1000 rpm / min for one minute, and incubate at 22 °C for 4 hours, then read with Spark (665 nm / 615 nm).

[0385] PI3K-β Inhibitory Activity Detection Method

[0386] 786 - O cells were seeded into a cell culture - grade 96 - well plate at a density of 30,000 cells / 50 μL / well. The cell culture medium was serum - free RPMI - 1640. They were cultured overnight in an incubator at 37 °C and 5% CO₂. 50 μL / well of the test compound was added to the cells and cultured in an incubator at 37 °C and 5% CO₂ for 60 minutes. The final DMSO concentration was 0.2%. The culture medium was aspirated, and 50 μL of 1x lysis buffer was added to each well. It was shaken at room temperature for 45 minutes. 16 μL of the lysate was transferred to a 384 - well plate, and 4 μL of the premixed antibody of the Phospho - AKT(Ser473) kit from Cisbio was added. It was centrifuged at 1000 rpm / min for one minute and incubated at 22 °C for 4 hours, then read with Envision (665 nm / 615 nm).

[0387] PI3K - δ Inhibitory Activity Detection Method

[0388] Raji cells were seeded at 50,000 cells per well in 30 μL in a 96 - well plate and cultured. The cell culture medium was serum - free RPMI - 1640. The cells were incubated overnight in an incubator at 5% CO₂ and 37 °C. After serum - free starvation for 18 hours, 2.5 μL of the compound (14X) was added to the cells and incubated in the incubator for 60 minutes. Then 2.5 μL (14X, diluted with serum - containing medium) of anti - human IgM (Jackson Immuno Research) was added and stimulated in the incubator for 30 minutes (final concentration was 10 μg / mL). 11.5 μL of 4x lysis buffer was added to each well. It was shaken at room temperature for 45 minutes. 16 μL of the lysate was added and transferred to a 384 - well plate, and 4 μL of the premixed antibody of the Phospho - AKT(Ser473) kit from Cisbio was added. It was centrifuged at 1000 rpm / min for one minute and incubated at 22 °C for 4 hours, then read with Spark (665 nm / 615 nm).

[0389] PI3K - γ Inhibitory Activity Detection Method

[0390] Resuspend RAW264.7 cells with serum-free DMEM medium, and add 60,000 cells / 45 μL of cell suspension to each well of a 96-well plate. Place the cells in an incubator at 5% CO2 and 37 °C overnight. After serum-free starvation for 18 hours, add 50 μL of the compound and culture in the incubator for 60 min. Then add 5 μL of 25 nM C5a (R&D Systems, diluted with serum medium) and stimulate for 5 min. Aspirate the medium and add 50 μL of 1x lysis buffer to each well. Shake at room temperature for 45 minutes. Transfer 16 μL of the lysate to a 384-well plate, and add 4 μL of the premixed antibody of the Phospho-AKT (Ser473) kit from Cisbio. Centrifuge at 1000 rpm / min for one minute at 22 °C. After incubation for 4 hours, read with Spark (665 nm / 615 nm).

[0391] The kinase assay in the present invention was completed by BioDuro (Jiangsu) Co., Ltd., and the test results are shown in Table 2, where +: >100 nM; ++: 50 - 100 nM; +++: 10 - 50 nM; ++++: <10 nM.

[0392] Table 2 Cell activity data of the compounds of the present invention

[0393]

[0394] The test results show that the compounds of the present invention have significant inhibitory activity against PI3Kδ and very obvious selectivity for it.

[0395] Finally, it should be noted that there are other ways to implement the present invention. Accordingly, the embodiments of the present invention are illustrative, but not limited to the content described in the present invention, and may also be modifications within the scope of the present invention or equivalent content added in the claims. All publications or patents cited in the present invention will be used as references for the present invention.

Claims

1. A compound having the structure shown in formula (I): or its stereoisomers, or a pharmaceutically acceptable salt; wherein, W is phenyl or a heteroaryl group consisting of 5 atoms, wherein said heteroaryl group contains 1, 2, 3 or 4 heteroatoms independently selected from N or O; wherein W is optionally substituted by 0, 1, 2, 3 or 4 R 7 substituted; R a is C 1-6 alkyl or C 1-6 haloalkyl; R b and R 1 each independently is H, D or F; R 2 is C 1-6 alkoxy, and the C 1-6 alkoxy is independently optionally substituted with 0, 1, 2, 3 or 4 groups independently selected from H, D, F, Cl, Br, I or -OH; R 4 and R 5 each independently is H, D, F, Cl, Br, I, -OH, -CN, C 1-6 alkyl, C 1-6 haloalkyl or C 1-6 hydroxyalkyl; R 6 is H, D, F, Cl, Br or I; R 3 Yes represents a single bond or a double bond; X 1 is -NH-; X 2 is -CH2-; and n is 1; wherein R 3 is optionally substituted with 0, 1, 2, 3 or 4 R 8 groups; R 7 is H, D, F, Cl, Br, I, C 1-4 alkyl, C 1-4 haloalkyl or C 1-4 hydroxyalkyl; R 8 is H, D, F, Cl, Br, I, -OH, -C(=O)R 9 , -OC(=O)R 9 , -C(=O)OR 9a , -N(R 10a )C(=O)R 10 , -C(=O)NR 10a R 10 , -OC(=O)NR 10a R 10 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 cyanoalkyl or cyclopropyl; and R 9 、R 9a 、R 10 and R 10a ,at each occurrence, are independently H, D, C 1-4 alkyl, C 1-4 haloalkyl or C 1-4 hydroxyalkyl.

2. The compound according to claim 1, wherein W is phenyl, where Y 1 is O or -NH-; and wherein W is optionally substituted with 0, 1, 2, 3 or 4 Rs 7 substituted.

3. The compound according to claim 1, wherein R a is methyl, ethyl, halogenated methyl or halogenated ethyl.

4. The compound according to claim 1, wherein, R b and R 1 are each independently H or D.

5. The compound according to claim 1, wherein, R 2 is C 1-4 alkoxy; wherein said C 1-4 alkoxy is independently optionally substituted with 0, 1, 2, 3 or 4 groups independently selected from H, D, F, Cl, Br, I or -OH.

6. The compound according to claim 1, wherein, R 2 is methoxy or ethoxy.

7. The compound according to claim 1, wherein R 4 and R 5 each independently is H, D, F, Cl, Br, I, -OH, -CN, methyl, ethyl, halogenated methyl or halogenated ethyl.

8. The compound according to claim 1, wherein R 6 is H or D.

9. The compound according to claim 1, wherein R 7 is H, D, F, Cl, Br, I, -CH3, -CH2CH3, -CH(CH3)CH3, -CH2CH(OH)CH3, -CH2CH2OH, -CF3, -CH2CF3 or 10. The compound according to claim 1, wherein R 8 is H, D, F, Cl, Br, I, -OH, -CH3, -CH2CH3, -CH(CH3)CH3, -CH2CH(OH)CH3, -CH2CH2OH, -CF3, -CH2CF3, cyclopropyl, 11. The compound according to claim 1, which is a compound having one of the following structures: or its stereoisomers, or a pharmaceutically acceptable salt.

12. A pharmaceutical composition, which comprises the compound according to any one of claims 1-11 or its stereoisomers, or a pharmaceutically acceptable salt, and a pharmaceutically acceptable excipient.

13. A pharmaceutical composition, which comprises the compound according to any one of claims 1-11 or its stereoisomers, or a pharmaceutically acceptable salt, and a pharmaceutically acceptable diluent or carrier, or a combination thereof.

14. The pharmaceutical composition according to claim 12, which further comprises an additional therapeutic agent.

15. Use of a compound according to any one of claims 1-11 or a pharmaceutical composition according to any one of claims 13-14 for the manufacture of a medicament for inhibiting PI3-kinase activity; said PI3-kinase being PI3K-δ, wherein, The drug for inhibiting PI3-kinase activity is used for treating selected from acute myeloid leukemia, chronic myeloid leukemia, T-cell acute lymphoblastic leukemia, B-cell acute lymphoblastic leukemia, non-Hodgkin lymphoma, or B-cell lymphoma.

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