WO2018192536A1 - Pyrimido-heterocyclic compound serving as bruton tyrosine kinase inhibitor and applications thereof - Google Patents

Abstract

The present invention relates to a heterocyclic compound serving as a Bruton tyrosine kinase inhibitor and applications thereof. Specifically, the present invention relates to a compound that is represented by formula I and that has Bruton tyrosine kinase inhibition activity, a pharmaceutical composition containing the compound represented by formula I, and the applications of the compound in the preparation of drugs for the treatment or prevention of Bruton tyrosine kinase-related diseases or for inhibiting Bruton tyrosine kinase.

Description

Pyrimido-heterocyclic compound as Bruton's tyrosine kinase inhibitor and application thereof Technical field

The present invention relates to the field of medicinal chemistry; in particular, the present invention relates to compounds having Bruton's tyrosine kinase inhibitory activity and uses thereof.

Background technique

Immune cells can usually be divided into two types: T cells and B cells. The main function of B cells is to secrete various antibodies to help the body resist the invasion of various foreign enemies. Bruton tyrosine kinase (Bruton tyrosine kinase) is mainly expressed in B cells and is distributed in the lymphatic system, hematopoiesis and blood system. In recent years, studies on B cells, especially B-cell non-Hodgkin's lymphoma and rheumatoid arthritis, have found that Bruton's tyrosine kinase is often abnormally expressed. Bruton's tyrosine kinase is a key kinase in the B cell antigen receptor (BCR) signaling pathway, which regulates the maturation and differentiation of normal B cells and is also closely related to a variety of B cell lymphoid tissue disorders.

Bruton's tyrosine kinase is a member of the Tec family of non-receptor protein tyrosine kinases. The Tec family is the second largest family of human non-receptor kinases, second only to the Src family, and its major members include Bruton's tyrosine kinase, BMX (etk), ITK, TEC, and TXK (RLK). Bruton's tyrosine kinase was identified in 1993 as a defective protein in human X-linked agammaglobulinemia (XLA). This protein is expressed at all stages of development of B cells (except for the final differentiated plasma cells), and Bruton's tyrosine kinase is a gene essential for cell differentiation and proliferation during the transition of pre-B lymphocytes to late B cells. And expressed in B cell lymphoma, acute lymphoblastic leukemia (ALL) and plasmacytoma. In addition, a small amount is expressed in bone marrow cells and erythroid progenitor cells.

The Bruton tyrosine kinase structure contains five major domains, namely the PH domain (Pleckstrin homology), the TH domain (Tec homology), the SH3 domain (Src homology 3), and the SH2 domain (Src homology 2). And the SH1 domain (Src homology1). The PH domain contains the transcription factor BAP-135/TFII-I and the binding site of the activity down-regulation factors PIN1, I Bruton's tyrosine kinase, and is also responsible for mediating Bruton's tyrosine kinase and second messenger phospholipids. The role of phosphatidylinositol triphosphate (PIP3). The TH domain is adjacent to the PH domain and consists of 80 amino acid residues, including the Bruton tyrosine kinase motif (Zn cofactor binding site), the PKC-beta binding site, and the proline-rich motif. Conservative area. The SH1 domain comprises an activation loop, an ATP binding site, a catalytic converter, and an allosteric inhibitory fragment. Activation (phosphorylation) of Bruton's tyrosine kinase occurs initially in the activation loop of the SH1 domain, and further activation occurs in the SH2 and SH3 domains comprising the major autophosphorylation sites. These SH domains also contain the nuclear localization signal (NLS) and nuclear export sequence (NES) required for Bruton's tyrosine kinase for nuclear shuttle. There are multiple receptors downstream of Bruton's tyrosine kinase, including growth factors. , B cell antigens, chemokines and non-specific immune receptors. Thus, activation of Bruton's tyrosine kinase can trigger a variety of cellular processes such as cell proliferation, survival, differentiation, angiogenesis, cytokine synthesis, and antigen presentation.

Bruton's tyrosine kinase activation process is complex, and an important step in this process is the migration of Bruton's tyrosine kinase to the cell membrane. Some receptors on the cell membrane are activated by the stimulation of the corresponding ligand, which activates and phosphorylates the intracellular signal transduction kinase PI3K, which in turn converts the PIP2 on the membrane into the second messenger PIP3. . PIP3 binds to the PH domain of Bruton's tyrosine kinase, Bruton's tyrosine kinase is subsequently recruited to the cell membrane, Tyr-551 residues are phosphorylated by Syk and Lyn kinase, followed by Tyr-223 residues The autophosphorylation reaction and the physiologically active Bruton tyrosine kinase can bind to the adaptor protein BLNK/SLP65 through its SH2 domain, and the resulting complex subsequently activates phospholipase C-γ2 (PLC-γ2), which in turn triggers The cascade reaction ultimately leads to continuous intracellular calcium influx and indirectly activates downstream signaling pathways such as the MEK/ERK, p38MAPK, and NK/SAPK pathways. Bruton's tyrosine kinase function-acquired mutations have also been confirmed in colorectal cancer, acute lymphoblastic leukemia (ALL), and chronic myeloid leukemia (CML). Therefore, abnormal activation of Bruton's tyrosine kinase-dependent pathway has been shown to be closely related to the development of various tumors.

Bruton's tyrosine kinase small molecule inhibitors have good prospects for the treatment of hematological malignancies and autoimmune disorders. Ibrutinib (ibrutinib) is currently the most attractive Bruton tyrosine kinase targeting inhibitor, and has significant therapeutic effects on various B cell tumors and autoimmune diseases in preclinical and clinical studies. It has been approved by the US FDA for the treatment of mantle cell lymphoma (MCL) and CLL. Several other compounds, such as CC-292 and ONO-4059, have also entered the clinical research phase or the late clinical phase.

There remains a need in the art to develop potent and specific Bruton tyrosine kinase inhibitors.

Summary of the invention

It is an object of the present invention to provide a Bruton tyrosine kinase inhibitor having high activity and specificity and its use in the preparation of a medicament for treating Bruton's tyrosine kinase-mediated diseases.

In a first aspect, the invention provides the use of a compound of Formula I or a salt thereof for the preparation of a Bruton's tyrosine kinase inhibitor or for the manufacture of a medicament for the treatment or prevention of Bruton's tyrosine kinase mediated disease:

In the formula,

R is hydrogen, C ₁ -C ₃ lower alkyl, C ₁ -C ₃ lower alkoxy, halogen (eg, F, Cl, Br), amino, substituted amino;

X is N or CR ⁵ R ⁶ ;

Y is C or O;

When X is N,

Is a double bond, and Y is C;

When X is CR ⁵ R ⁶ ,

Is a single bond, and Y is O; or when X is CR ⁵ R ⁶

Is a double bond, and Y is C;

B is selected from the group consisting of an optionally substituted (C3-C8)cycloalkyl, (C3-C8)heterocyclyl, (C6-C10)aryl or (C5-C10)arylheterocyclyl;

R ^{1 is} selected from the group consisting of: H, an optionally substituted C ₁ -C ₆ alkyl group, NR ⁷ R ⁸ , an optionally substituted C ₆ -C ₁₀ aryl group;

R ^{3 is} selected from the group consisting of hydrogen, optionally substituted C ₁ -C ₁₀ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, optionally substituted C ₃ -C ₈ cycloalkyl, any A substituted C ₁ -C ₁₀ alkoxy group, an optionally substituted aryl group, an optionally substituted benzyl group, an optionally substituted heterocyclic group, an optionally substituted aromatic heterocyclic group, -O-(CH) _z -OC ₁ -C ₃ alkyl; z is an integer from 1 to 3, preferably 1;

R ^{4 is} selected from the group consisting of hydrogen, optionally substituted C ₁ -C ₆ alkyl, nitro, amino, halogen, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted acyloxy, optionally substituted Amido, optionally substituted acyl;

m is independently an integer from 0 to 7, preferably from 1 to 7, more preferably from 1 to 3;

R ⁵ and R ⁶ are each independently H, or C ₁ -C ₆ alkyl (preferably C ₁ -C ₃ alkyl);

R ⁷ and R ⁸ are each independently H or a C ₁ -C ₆ alkyl group.

In a preferred embodiment, B is selected from various substituted benzene ring, nitrogen-containing five-membered ring, a nitrogen-containing six-membered ring or a C ₃ -C ₈ cycloalkyl.

In a specific embodiment, B is selected from the group consisting of:

R ^{4 is} selected from:

In a specific embodiment, the compound is as shown in Formula I-1 below:

In the formula,

A is a benzene ring, a five- or six-membered heterocyclic ring, a C ₃ -C ₈ cycloalkyl group or R';

When A is R', n is 0, and R' is selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl or C ₆ -C ₁₀ arylformyl;

R ^{2 is} selected from the group consisting of hydrogen, halogen, optionally substituted C ₁ -C ₆ alkoxy, hydroxy, optionally substituted acyloxy, amino, optionally substituted acylamino, optionally substituted C ₁ -C ₆ Alkyl, CN, sulfonate, aminosulfonyl, carbamoyl, carboxy, optionally substituted alkoxycarbonyl, optionally substituted phenyl, optionally substituted N-alkylpiperazinyl, optionally substituted Morpholinyl, optionally substituted piperidinyl, optionally substituted pyrrolyl, optionally substituted pyrrolidinyl, -NR _a R _b , optionally substituted pyridyl; R _a and R _b are each independently selected from Alkyl and alkenyl;

n is independently an integer from 0 to 7, preferably from 1 to 7, more preferably from 1 to 3;

X, Y, B, R ¹ , R ³ , R ⁴ and m are as defined above.

In a specific embodiment, the compound is as shown in Formula II-1 below:

In the formula,

B, R ² , R ³ , R ⁴ , m and n are as defined above;

Alternatively, the compound is represented by the following formula II-2:

In the formula,

B, R ² , R ⁴ , R ⁵ , R ⁶ , m and n are as defined above;

Alternatively, the compound is as shown in the following formula II-3:

In the formula,

B, R ¹ , R ² , R ³ , R ⁴ , m and n are as defined above.

In a specific embodiment,

In formula II-1,

R ^{2 is} selected from the group consisting of hydrogen, halogen, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted pyrrolidinyl, -NR _a R _b , carbamoyl, optionally substituted acylamino, -(CH ₂ ) _o - an optionally substituted N-alkylpiperazinyl group, an optionally substituted morpholino group, an optionally substituted piperidinyl group, o is an integer of 0-2, and R _a and R _b are each independently selected from C _{a 1-} C ₃ alkyl group; wherein R ^{2 is} not at the 2-position of the benzene ring where it is located;

R ^{3 is} selected from the group consisting of: hydrogen, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₆ -C ₁₀ aryl, optionally substituted C ₃ -C ₈ cycloalkyl;

B is selected from a benzene ring or a nitrogen-containing five-membered ring;

R ^{4 is} selected from the group consisting of: an optionally substituted acylamino group, an optionally substituted acyl group;

m and n are as defined above;

In formula II-2,

R ⁵ and R ^{6 are} independently selected from H, substituted or unsubstituted C ₁ -C ₆ (preferably C ₁ -C ₃ )alkyl;

B is a benzene ring;

R ^{2 is} selected from the group consisting of: an optionally substituted C ₁ -C ₆ alkyl group (preferably a C ₁ -C ₃ alkyl group), an optionally substituted N-alkyl piperazinyl group, an optionally substituted C ₁ -C ₆ alkoxy group Base (preferably C ₁ -C ₃ alkoxy);

R ^{4 is} selected from the group consisting of: an optionally substituted acylamino group;

m and n are as defined above.

In a second aspect, the present invention provides a compound selected from the group consisting of a compound or a pharmaceutically acceptable salt thereof for the preparation of a Bruton's tyrosine kinase inhibitor or for the preparation or treatment of a Bruton's tyrosine kinase mediated disease Use in medicine:

In a specific embodiment, the Bruton tyrosine kinase mediated disease is cancer or an autoimmune disorder.

In a specific embodiment, the cancer is selected from the group consisting of acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), mantle cell lymphoma (MCL), colorectal cancer; said autoimmune disorders include classes Rheumatoid arthritis, anti-organ transplant rejection, anti-psoriasis, lupus erythematosus.

In a third aspect, the present invention provides a method of treating or preventing Bruton's tyrosine kinase-mediated disease comprising administering a compound of the first or second aspect of the invention or a pharmaceutical composition comprising the same The object you need.

In a fourth aspect, the present invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof:

In the formula,

X, Y, B, R ¹ , R ³ , R ⁴ and m are as defined above;

among them,

R is hydrogen, C ₁ -C ₃ lower alkyl, C ₁ -C ₃ lower alkoxy, halogen (eg, F, Cl, Br), amino or NR ^c R ^d , and R ^c , R ^{d are} independently selected from H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl or (C ₆ -C ₁₀ ) arylcarbonyl;

and / or

R ^{3 is} selected from the group consisting of hydrogen, (C ₃ -C ₆ )cycloalkyl, (C ₁ -C ₈ )heterocyclyl, (C ₁ -C ₈ )alkoxy, -O-(CH) _n - OC ₁ -C ₃ alkyl, benzyl, (C ₆ -C ₁₀ )aryl or (C ₅ -C ₁₀ )arylheterocyclyl, wherein the aryl and aromatic heterocyclic groups may optionally be one Substituted to five or less groups: halogen, nitro, cyano, hydroxy, amino, (C ₁ -C ₈ )alkyl, (C ₁ -C ₈ )alkoxy, (C ₃ -C ₆ )cycloalkane , (C ₆ -C ₁₀ ) aryloxy, (C ₅ -C ₁₀ )heterocyclyl, -O-(CH) _z -OC ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyloxy , C ₃ -C ₆ heterocycloalkyloxy, amide, optionally substituted carbamoyl; z is an integer from 1 to 3, preferably 1;

and / or

R ^{4 is} selected from the group consisting of:

In a preferred embodiment,

R is hydrogen, C ₁ -C ₃ lower alkyl, C ₁ -C ₃ lower alkoxy, halogen (eg, F, Cl, Br), amino;

R ^{3 is} selected from the group consisting of hydrogen, (C ₃ -C ₆ )cycloalkyl, (C ₁ -C ₈ )heterocyclyl, (C ₁ -C ₈ )alkoxy, -O-(CH) _n - OC ₁ -C ₃ alkyl, benzyl, (C ₆ -C ₁₀ )aryl or (C ₅ -C ₁₀ )arylheterocyclyl, wherein the aryl and aromatic heterocyclic groups may optionally be one Substituted to five or less groups: halogen, nitro, cyano, hydroxy, amino, (C ₁ -C ₈ )alkyl, (C ₁ -C ₈ )alkoxy, (C ₃ -C ₆ )cycloalkane , (C ₆ -C ₁₀ ) aryloxy, (C ₅ -C ₁₀ )heterocyclyl, -O-(CH) _z -OC ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyloxy , C ₃ -C ₆ heterocycloalkyloxy, amide, optionally substituted carbamoyl; z is an integer from 1 to 3, preferably 1;

or

R is hydrogen, C ₁ -C ₃ lower alkyl, C ₁ -C ₃ lower alkoxy, halogen (eg, F, Cl, Br), amino;

R ^{4 is} selected from the group consisting of:

or

R ^{3 is} selected from the group consisting of hydrogen, (C ₃ -C ₆ )cycloalkyl, (C ₁ -C ₈ )heterocyclyl, (C ₁ -C ₈ )alkoxy, -O-(CH) _n - OC ₁ -C ₃ alkyl, benzyl, (C ₆ -C ₁₀ )aryl or (C ₅ -C ₁₀ )arylheterocyclyl, wherein the aryl and aromatic heterocyclic groups may optionally be one Substituted to five or less groups: halogen, nitro, cyano, hydroxy, amino, (C ₁ -C ₈ )alkyl, (C ₁ -C ₈ )alkoxy, (C ₃ -C ₆ )cycloalkane , (C ₆ -C ₁₀ ) aryloxy, (C ₅ -C ₁₀ )heterocyclyl, -O-(CH) _z -OC ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyloxy , C ₃ -C ₆ heterocycloalkyloxy, amide, optionally substituted carbamoyl; z is an integer from 1 to 3, preferably 1;

R ^{4 is} selected from the group consisting of:

In a specific embodiment, the compound is as shown in Formula I-1 below:

In the formula,

A is R', n is 0, and R' is selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl or (C ₆ -C ₁₀ ) arylcarbonyl;

X, Y, B, R ¹ , R ³ , R ⁴ and m are as defined above.

In a specific embodiment, R 'is C ₁ -C ₆ alkyl (preferably C ₁ -C ₃ alkyl), C ₁ -C ₆ haloalkyl (preferably C ₁ -C ₃ haloalkyl).

In a specific embodiment, R ^{3 is} selected from the group consisting of

In a specific embodiment, R ³ is:

It is to be understood that within the scope of the present invention, the various technical features of the present invention and the various technical features specifically described hereinafter (as in the embodiments) may be combined with each other to constitute a new or preferred technical solution. Due to space limitations, we will not repeat them here.

detailed description

After extensive and intensive research, the inventors unexpectedly discovered a number of structurally novel compounds that inhibit Bruton's tyrosine kinase with high activity and selectivity, some of which are Bruton's tyrosine. IC ₅₀ values of inhibition of kinase activity levels reached nM. The present invention has been completed on this basis.

The present inventors synthesized a series of candidate compounds having Bruton's tyrosine kinase inhibitory activity. Through the structural optimization design of the obtained candidate compounds, a number of novel pyrimidopyrimidine heterocyclic compounds with potential Bruton's tyrosine kinase inhibitory activity were discovered. The obtained compound was evaluated for molecular level activity, and the IC ₅₀ value of the Bruton tyrosine kinase inhibitory activity of the plurality of compounds reached the nM level.

Definition of Terms

The groups to which the invention relates have the meaning as commonly understood in the art. For the sake of clarity, some of the groups covered in this article are defined as follows:

As used herein, "alkyl" refers to a saturated branched or straight-chain alkyl group having a carbon chain length of from 1 to 10 carbon atoms, and preferred alkyl groups include 2-8, 1-6, 1-4, 3-8 alkyl groups of 1-3 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, heptyl, and the like. The alkyl group may be substituted by one or more substituents, for example by halogen or haloalkyl. For example, the alkyl group may be an alkyl group substituted with 1 to 4 fluorine atoms, or the alkyl group may be an alkyl group substituted with a fluoroalkyl group. The alkyl groups described herein may also be substituted with an aryl group to form, for example, a benzyl group.

Similarly, "cycloalkyl" as used herein refers to a substituted or unsubstituted saturated cyclic alkyl group having a carbon chain length of from 3 to 10, preferably from 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, Cyclopentyl, cyclohexyl, cycloheptyl and the like.

As used herein, "alkoxy" refers to an oxy group substituted with an alkyl group. The preferred alkoxy group is an alkoxy group having 1 to 6 carbon atoms, more preferably an alkoxy group having 1 to 4 carbon atoms, and more preferably an alkoxy group having 1 to 3 carbon atoms. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, and the like. The alkoxy group may be substituted by one or more substituents, for example by halogen or haloalkyl. For example, the alkoxy group may be an alkyl group substituted with 1 to 4 fluorine atoms, or the alkyl group may be an alkyl group substituted with a fluoroalkyl group.

As used herein, "alkenyl" generally denotes a monovalent hydrocarbon radical having at least one double bond, usually containing from 2 to 8 carbon atoms, preferably from 2 to 6 carbon atoms, and may be straight or branched. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, hexenyl, and the like.

As used herein, "alkynyl" generally denotes a monovalent hydrocarbon radical having at least one triple bond, usually containing from 2 to 8 carbon atoms, preferably from 2 to 6 carbon atoms, more usually from 2 to 4 carbon atoms, and may be straight-chain Or branching. Examples of alkenyl groups include ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, hexynyl and the like.

As used herein, "halogen" means fluoro, chloro, bromo or iodo.

As used herein, "aryl" refers to a monocyclic, bicyclic or tricyclic aromatic group containing from 6 to 14 carbon atoms, including phenyl, naphthyl, phenanthryl, anthryl, fluorenyl, fluorenyl, tetrahydronaphthalene. Base, indanyl group, and the like. The aryl group may be optionally substituted with from 1 to 5 (eg, 1, 2, 3, 4 or 5) substituents selected from the group consisting of halogen, C1-4 aldehyde group, C1-6 alkyl group, cyano group, Nitro, amino, hydroxy, hydroxymethyl, halogen substituted alkyl (eg trifluoromethyl), halogen substituted alkoxy (eg trifluoromethoxy), carboxyl, C1-4 alkoxy, ethoxy A formyl group, a N(CH3) group, a C1-4 acyl group or the like, a heterocyclic group or a heteroaryl group.

As used herein, "heterocyclyl" includes, but is not limited to, a 5- or 6-membered heterocyclic group containing from 1 to 3 heteroatoms selected from O, S or N, including but not limited to furyl, thienyl, pyrrolyl, Pyrrolidinyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, pyranyl, pyridyl, pyrimidinyl, pyrazinyl, piperidinyl, morpholinyl and the like.

As used herein, "aromatic heterocyclic" means having from 5 to 14 ring atoms and having 6, 10 or 14 electrons are shared on the ring system. Further, the ring atom contained is a carbon atom and optionally 1-3 hetero atoms from oxygen, nitrogen, and sulfur. Useful aromatic heterocyclic groups include piperazinyl, morpholinyl, piperidinyl, pyrrolidinyl, thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, including but not limited to 2-pyridyl, 3-pyridyl and 4-pyridyl, pyrazinyl, pyrimidinyl and the like.

The aromatic heterocyclic group may be optionally substituted with from 1 to 5 (for example, 1, 2, 3, 4 or 5) substituents selected from the group consisting of halogen, C1-4 aldehyde group, C1-6 straight chain or branch Alkenyl, cyano, nitro, amino, hydroxy, hydroxymethyl, halogen substituted alkyl (eg trifluoromethyl), halogen substituted alkoxy (eg trifluoromethoxy), carboxyl, C1- 4 alkoxy, ethoxycarbonyl, N(CH3) and C1-4 acyl.

As used herein, "acyloxy" refers to a group of the formula "-OC(O)-R", wherein R may be selected from alkyl, alkenyl (eg, C1-6 or C1-3 alkenyl) And alkynyl groups. The R can be optionally substituted.

As used herein, "amido" refers to a group of the formula "-R'-NH-C(O)-R" wherein R' may be selected from hydrogen or alkyl and R may be selected from alkyl, alkenyl. (e.g., C1-6, or C1-3 alkenyl), alkynyl, NR _c R _d is substituted alkyl, NR _c R _d is substituted alkenyl and NR _c R _d group substituted alkynyl, halogen a substituted alkyl group, an alkenyl group substituted by a cyano group, wherein R _c and R _d may be selected from an alkyl group and an alkenyl group.

As used herein, acyl refers to an atomic group remaining after removal of one or more hydroxyl groups by an organic or inorganic oxyacid, the general formula of which is represented by RC(O)-, wherein R may be selected from alkyl or alkenyl groups (eg, , C1-6, or C1-3 alkenyl), alkynyl, NR _c R _d is substituted alkyl, NR _c R _d is substituted alkenyl and NR _c R _d group substituted alkynyl, substituted by halogen An alkyl group, an alkenyl group substituted by a cyano group, wherein R _c and R _d may be selected from the group consisting of an alkyl group and an alkenyl group.

As used herein, "arylcarbonyl" refers to an aryl group, such as a (C6-C10) aryl group, formed with a formyl group, and attached to the host structure of the compound via a formyl group.

As used herein, "optionally substituted" means that the substituent to which it is modified may be optionally substituted with from 1 to 5 (eg, 1, 2, 3, 4 or 5) substituents selected from halogen: C1 a 4-aldehyde group, a C1-6 straight or branched alkyl group, a cyano group, a nitro group, an amino group, a hydroxyl group, a hydroxymethyl group, a halogen-substituted alkyl group (for example, a trifluoromethyl group), a halogen-substituted alkoxy group ( For example, trifluoromethoxy), carboxyl, C1-4 alkoxy, ethoxycarbonyl, N(CH3), and C1-4 acyl.

Compounds of the invention and uses thereof

For the purposes of the present invention, the present invention provides the use of a compound of the formula I below or a salt thereof for the preparation of a Bruton's tyrosine kinase inhibitor or for the preparation of a medicament for the treatment or prevention of a Bruton's tyrosine kinase mediated disease :

In the formula,

R is hydrogen, C ₁ -C ₃ lower alkyl, C ₁ -C ₃ lower alkoxy, halogen (eg, F, Cl, Br), amino, substituted amino;

X is N or CR ⁵ R ⁶ ;

Y is C or O;

When X is N,

Is a double bond, and Y is C;

When X is CR ⁵ R ⁶ ,

Is a single bond, and Y is O; or when X is CR ⁵ R ⁶

Is a double bond, and Y is C;

B is selected from the group consisting of: an optionally substituted (C3-C8) cycloalkyl, (C3-C8) heterocyclyl, (C6-C10) aryl or (C5-C10) aromatic heterocyclic group; R ¹ is selected from :H, optionally substituted C ₁ -C ₆ alkyl, NR ⁷ R ⁸ , optionally substituted C ₆ -C ₁₀ aryl; R ^{3 is} selected from: hydrogen, optionally substituted C ₁ -C ₁₀ alkyl , C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, optionally substituted C ₃ -C ₈ cycloalkyl, optionally substituted C ₁ -C ₁₀ alkoxy, optionally substituted aryl , optionally substituted benzyl, optionally substituted heterocyclic, optionally substituted aromatic heterocyclic, -O-(CH) _z -OC ₁ -C ₃ alkyl; z is an integer from 1 to 3, preferably 1; R ^{4 is} selected from the group consisting of hydrogen, optionally substituted C ₁ -C ₆ alkyl, nitro, amino, halogen, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted acyloxy, any Substituted substituted amido, optionally substituted acyl; m is independently 0-7, preferably 1-7, more preferably 1-3 integer; R ⁵ and R ⁶ are each independently H, or C ₁ -C ₆ alkyl (preferably C ₁ -C ₃ alkyl); R ⁷ and R ⁸ are each independently H, or C ₁ -C ₆ alkyl.

In a preferred embodiment, B is selected from various substituted benzene ring, nitrogen-containing five-membered ring, a nitrogen-containing six-membered ring or a C ₃ -C ₈ cycloalkyl.

Further, B can be selected from:

R ^{4 is} selected from:

Further, the compound of the present invention can be represented by the following formula I-1:

In the formula,

A is a benzene ring, a five- or six-membered heterocyclic ring, a C ₃ -C ₈ cycloalkyl group or R';

When A is R', n is 0, and R' is selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl or C ₆ -C ₁₀ arylformyl;

R ^{2 is} selected from the group consisting of hydrogen, halogen, optionally substituted C ₁ -C ₆ alkoxy, hydroxy, optionally substituted acyloxy, amino, optionally substituted acylamino, optionally substituted C ₁ -C ₆ Alkyl, CN, sulfonate, aminosulfonyl, carbamoyl, carboxy, optionally substituted alkoxycarbonyl, optionally substituted phenyl, optionally substituted N-alkylpiperazinyl, optionally substituted Morpholinyl, optionally substituted piperidinyl, optionally substituted pyrrolyl, optionally substituted pyrrolidinyl, -NR _a R _b , optionally substituted pyridyl; R _a and R _b are each independently selected from Alkyl and alkenyl;

n is independently an integer from 0 to 7, preferably from 1 to 7, more preferably from 1 to 3;

X, Y, B, R ¹ , R ³ , R ⁴ and m are as defined above.

Still further, the compounds of the invention are as shown in the following formula II-1:

In the formula,

B, R ² , R ³ , R ⁴ , m and n are as defined above;

Alternatively, the compound is represented by the following formula II-2:

In the formula,

B, R ² , R ⁴ , R ⁵ , R ⁶ , m and n are as defined above;

Alternatively, the compound is as shown in the following formula II-3:

In the formula,

B, R ¹ , R ² , R ³ , R ⁴ , m and n are as defined above.

Further,

In formula II-1,

R ^{2 is} selected from the group consisting of hydrogen, halogen, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted pyrrolidinyl, -NR _a R _b , carbamoyl, optionally substituted acylamino, -(CH ₂ ) _o - an optionally substituted N-alkylpiperazinyl group, an optionally substituted morpholino group, an optionally substituted piperidinyl group, o is an integer of 0-2, and R _a and R _b are each independently selected from C _{a 1-} C ₃ alkyl group; wherein R ^{2 is} not at the 2-position of the benzene ring where it is located;

R ^{3 is} selected from the group consisting of: hydrogen, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₆ -C ₁₀ aryl, optionally substituted C ₃ -C ₈ cycloalkyl;

B is selected from a benzene ring or a nitrogen-containing five-membered ring;

R ^{4 is} selected from the group consisting of: an optionally substituted acylamino group, an optionally substituted acyl group;

m and n are as defined above;

In formula II-2,

R ⁵ and R ^{6 are} independently selected from H, substituted or unsubstituted C ₁ -C ₆ (preferably C ₁ -C ₃ )alkyl;

B is a benzene ring;

R ^{2 is} selected from the group consisting of: an optionally substituted C ₁ -C ₆ alkyl group (preferably a C ₁ -C ₃ alkyl group), an optionally substituted N-alkyl piperazinyl group, an optionally substituted C ₁ -C ₆ alkoxy group Base (preferably C ₁ -C ₃ alkoxy);

R ^{4 is} selected from the group consisting of: an optionally substituted acylamino group;

m and n are as defined above.

In a specific embodiment, the invention provides a compound selected from the group consisting of or a pharmaceutically acceptable salt thereof for the preparation of a Bruton's tyrosine kinase inhibitor or for the preparation or treatment of Bruton's tyrosine kinase-mediated Use of drugs for disease:

The above table shows the structure of the compound of the present invention and its Bruton's tyrosine kinase inhibitory activity, wherein:

The compound having the activity designated "A" has an IC ₅₀ ≤ 10 nM;

The compound having the activity designated "B" has an IC ₅₀ of 10 < IC ₅₀ ≤ ₁₀₀ nM;

The compound having the activity designated as "C" has an IC ₅₀ of 100 < IC ₅₀ ≤ 1000 nM;

The compound having the activity designated "D" has an IC ₅₀ of 1000 nM < IC ₅₀ .

The present invention provides a pharmaceutical composition for inhibiting Bruton's tyrosine kinase comprising a therapeutically effective amount of the present invention, based on the ability of the compound of the present invention to have Bruton's tyrosine kinase inhibitory activity. A compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

Examples of pharmaceutically acceptable salts of the compounds of the invention include, but are not limited to, inorganic and organic acid salts such as the hydrochloride, hydrobromide, sulfate, citrate, lactate, tartrate, maleate salts. , fumarate, mandelate and oxalate; and inorganic and formed with bases such as sodium hydroxy, tris(hydroxymethyl)aminomethane (TRIS, tromethamine) and N-methyl glucosamine Organic base salt.

While the needs of each individual vary, one skilled in the art can determine the optimal dosage of each active ingredient in the pharmaceutical compositions of the present invention. In general, the compound of the present invention or a pharmaceutically acceptable salt thereof is orally administered to a mammal per day in an amount of from about 0.0025 to 50 mg/kg body weight. Preferably, however, it is about 0.01 to 10 mg per kilogram of oral administration. For example, a unit oral dose can include from about 0.01 to 50 mg, preferably from about 0.1 to 10 mg, of a compound of the invention. The unit dose may be administered one or more times per day in one or more tablets, each tablet containing from about 0.1 to 50 mg, conveniently from about 0.25 to 10 mg of the compound of the invention or a solvate thereof.

The pharmaceutical composition of the present invention can be formulated into a form suitable for various administration routes, including but not limited to being formulated for parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, oral, intrathecal, intracranial A form of administration, intranasal or topical, for the treatment of tumors and other diseases. The amount administered is an amount effective to ameliorate or eliminate one or more conditions. For the treatment of a particular disease, an effective amount is an amount sufficient to ameliorate or in some way alleviate the symptoms associated with the disease. Such doses can be administered as a single dose or can be administered according to an effective therapeutic regimen. The amount administered may cure the disease, but administration is usually to improve the symptoms of the disease. Repeated administration is generally required to achieve the desired improvement in symptoms. The dosage of the drug will be determined by the age of the patient, the health and weight, the type of concurrent treatment, the frequency of treatment, and the desired therapeutic benefit.

The pharmaceutical preparation of the present invention can be administered to any mammal as long as they can obtain the therapeutic effect of the compound of the present invention. The most important of these mammals is humans.

The compounds of the invention or pharmaceutical compositions thereof are useful in the treatment of a variety of diseases mediated by Bruton's tyrosine kinase. Herein, the Bruton's tyrosine kinase-mediated disease is a cancer or an autoimmune disease; wherein the cancer includes a hematological malignancy or a solid tumor, such as acute lymphoblastic leukemia (ALL), chronic granulocytes Leukemia (CML), mantle cell lymphoma (MCL), colorectal cancer; the autoimmune diseases include rheumatoid arthritis, anti-organ transplant rejection, anti-psoriasis or lupus erythematosus.

The pharmaceutical preparations of the invention can be made in a known manner. For example, it is manufactured by a conventional mixing, granulating, tableting, dissolving, or freeze drying process. In the manufacture of oral formulations, the mixture can be selectively milled by combining the solid adjuvant with the active compound. If necessary or necessary, after adding an appropriate amount of auxiliary agent, the mixture of particles is processed to obtain a tablet or tablet core.

Suitable excipients are, in particular, fillers, such as sugars such as lactose or sucrose, mannitol or sorbitol; cellulose preparations or calcium phosphates, such as tricalcium phosphate or calcium hydrogen phosphate; and binders, such as starch pastes, including corn starch. , wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, or polyvinylpyrrolidone. If necessary, a disintegrating agent such as the above-mentioned starch, and carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate may be added. Adjuvants are especially flow regulators and lubricants, for example, silica, talc, stearates such as calcium magnesium stearate, stearic acid or polyethylene glycol. If desired, the tablet core can be provided with a suitable coating that is resistant to gastric juice. For this purpose, a concentrated sugar solution can be applied. This solution may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, a lacquer solution and a suitable organic solvent or solvent mixture. For the preparation of a gastric juice resistant coating, a suitable cellulose solution such as cellulose acetate phthalic acid or hydroxypropyl methylcellulose phthalic acid can be used. A dye or pigment can be added to the coating of the tablet or tablet core. For example, a combination for identifying or for characterizing the dosage of an active ingredient.

Based on the above compounds and pharmaceutical compositions, the invention further provides a method of treating or preventing Bruton's tyrosine kinase mediated diseases, comprising administering to a subject in need thereof a compound or pharmaceutical composition of the invention. Methods of administration include, but are not limited to, various methods of administration well known in the art, which can be determined based on the actual circumstances of the patient. These methods include, but are not limited to, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, intrathecal, intracranial, nasal or topical routes of administration.

In a specific embodiment, the invention provides a novel structure of a compound of formula I or a salt thereof:

In the formula,

X, Y, B, R ¹ , R ³ , R ⁴ and m are as defined above;

among them,

R is hydrogen, C ₁ -C ₃ lower alkyl, C ₁ -C ₃ lower alkoxy, halogen (eg, F, Cl, Br), amino or NR ^c R ^d , and R ^c , R ^{d are} independently selected from H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl or (C ₆ -C ₁₀ ) arylcarbonyl;

and / or

R ^{3 is} selected from the group consisting of hydrogen, (C ₃ -C ₆ )cycloalkyl, (C ₁ -C ₈ )heterocyclyl, (C ₁ -C ₈ )alkoxy, -O-(CH) _n - OC ₁ -C ₃ alkyl, benzyl, (C ₆ -C ₁₀ )aryl or (C ₅ -C ₁₀ )arylheterocyclyl, wherein the aryl and aromatic heterocyclic groups may optionally be one Substituted to five or less groups: halogen, nitro, cyano, hydroxy, amino, (C ₁ -C ₈ )alkyl, (C ₁ -C ₈ )alkoxy, (C ₃ -C ₆ )cycloalkane , (C ₆ -C ₁₀ ) aryloxy, (C ₅ -C ₁₀ )heterocyclyl, -O-(CH) _z -OC ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyloxy , C ₃ -C ₆ heterocycloalkyloxy, amide, optionally substituted carbamoyl; z is an integer from 1 to 3, preferably 1;

and / or

R ^{4 is} selected from the group consisting of:

In a preferred embodiment, the above R, R ³ and R ⁴ may be arbitrarily combined. For example, it can be the following combination:

R is hydrogen, C ₁ -C ₃ lower alkyl, C ₁ -C ₃ lower alkoxy, halogen (eg, F, Cl, Br), amino;

R ^{3 is} selected from the group consisting of hydrogen, (C ₃ -C ₆ )cycloalkyl, (C ₁ -C ₈ )heterocyclyl, (C ₁ -C ₈ )alkoxy, -O-(CH) _n - OC ₁ -C ₃ alkyl, benzyl, (C ₆ -C ₁₀ )aryl or (C ₅ -C ₁₀ )arylheterocyclyl, wherein the aryl and aromatic heterocyclic groups may optionally be one Substituted to five or less groups: halogen, nitro, cyano, hydroxy, amino, (C ₁ -C ₈ )alkyl, (C ₁ -C ₈ )alkoxy, (C ₃ -C ₆ )cycloalkane , (C ₆ -C ₁₀ ) aryloxy, (C ₅ -C ₁₀ )heterocyclyl, -O-(CH) _z -OC ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyloxy , C ₃ -C ₆ heterocycloalkyloxy, amide, optionally substituted carbamoyl; z is an integer from 1 to 3, preferably 1;

or

R is hydrogen, C ₁ -C ₃ lower alkyl, C ₁ -C ₃ lower alkoxy, halogen (eg, F, Cl, Br), amino;

R ^{4 is} selected from the group consisting of:

or

R ^{3 is} selected from the group consisting of hydrogen, (C ₃ -C ₆ )cycloalkyl, (C ₁ -C ₈ )heterocyclyl, (C ₁ -C ₈ )alkoxy, -O-(CH) _n - OC ₁ -C ₃ alkyl, benzyl, (C ₆ -C ₁₀ )aryl or (C ₅ -C ₁₀ )arylheterocyclyl, wherein the aryl and aromatic heterocyclic groups may optionally be one Substituted to five or less groups: halogen, nitro, cyano, hydroxy, amino, (C ₁ -C ₈ )alkyl, (C ₁ -C ₈ )alkoxy, (C ₃ -C ₆ )cycloalkane , (C ₆ -C ₁₀ ) aryloxy, (C ₅ -C ₁₀ )heterocyclyl, -O-(CH) _z -OC ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyloxy , C ₃ -C ₆ heterocycloalkyloxy, amide, optionally substituted carbamoyl; z is an integer from 1 to 3, preferably 1;

R ^{4 is} selected from the group consisting of:

In a specific embodiment, the novel compounds of the invention are represented by the following formula I-1:

In the formula,

A is R', n is 0, and R' is selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl or (C ₆ -C ₁₀ ) arylcarbonyl;

X, Y, B, R ¹ , R ³ , R ⁴ and m are as defined above.

Further, R' may be a C ₁ -C ₆ alkyl group (preferably a C ₁ -C ₃ alkyl group), a C ₁ -C ₆ haloalkyl group (preferably a C ₁ -C ₃ haloalkyl group).

In a preferred embodiment, R ³ may be selected from the group consisting of:

More preferred

In a specific embodiment, the substituents in the formula of the present invention are each a corresponding group in any of the specific compounds disclosed herein.

Advantages of the invention:

1. The compound of the present invention has excellent inhibitory activity against Bruton's tyrosine kinase;

2. The compounds of the invention are highly selective for Bruton's tyrosine kinase;

3. The compound of the present invention lays a foundation for the development of a drug capable of inhibiting Bruton's tyrosine kinase with high activity and high selectivity, and has great industrialization and commercialization prospects as well as market value, and has significant economic benefits.

The technical solutions of the present invention are further described below in conjunction with the specific embodiments, but the following embodiments are not intended to limit the present invention, and all the application methods according to the principles and technical means of the present invention are within the scope of the present invention. The experimental methods in the following examples which do not specify the specific conditions are usually in accordance with conventional conditions or according to the conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.

Materials and Methods

1. Bruton's tyrosine kinase inhibitory activity detection method

1.1 Bruton's tyrosine kinase recombinant protein expression

1) Construction of PfastBac1-Bluton tyrosine kinase vector

The Bruton tyrosine kinase target fragment (M1-S695) was amplified by PCR, and the PCR product and the vector PfastBac 1 were digested with BamHI and XhoI, and the digested products were ligated and transformed into DH5α competent cells. Cloning and sequencing confirmed that the correct recombinant plasmid pFastBac1-brutton tyrosine kinase was finally obtained.

2) Acquisition of baculovirus

The constructed plasmid was transposed to DH10Bac competent cells for blue and white spot screening, and the transposon was successfully picked. The rods were extracted after shaking, and the rods were identified by bacterial PCR. The correct bacmids were transfected into Sf9 cells to obtain P1 virus strains of P1, P2 and higher titers, respectively.

3) Bruton's tyrosine kinase protein expression and identification

Sf9 cells were cultured to the log phase (about 2×10 ⁶ cells/mL), and the P3 virus strain with high titer was added to the Sf9 cell culture medium containing the log phase growth, and cultured at 27 ° C for 3 days, 500 × g Centrifuge for 5 min, discard the supernatant, collect the bacteria, and store at -80 °C. Protein expression was then detected by Western Blot.

1.2 Purification of Bruton's tyrosine kinase recombinant protein

The cell pellet expressed by the P3 virus strain was collected by centrifugation at 1790 rpm at room temperature. The lysate used for lysing the cells was 250 mM NaCl, 0.25% NP-40, 50 mM CHES (pH 9.0). The cells were disrupted by a high-pressure cell disrupter, and then centrifuged at 12000 rpm for 45 min at 4 ° C, and the supernatant was collected. The supernatant was added to a Ni-NTA column, and the protein of interest was eluted using an imidazole concentration gradient method, and the eluted protein solution was collected. Concentrate the eluate containing the protein of interest and switch to the lowest concentration of imidazole. At 4 ° C, the TEV enzyme was added for dialysis and digestion for 16 h, and the Ni-NTA column was again passed, and the His-Tag-free flow-through solution was collected. The buffer used for the digestion was 200 mM NaCl, 20 mM CHES (pH 9.0). 1 mM TCEP. Finally, the purified protein was separated by HiTrap Superdex 75 molecular sieve, and the equilibrium buffer used for the molecular sieve was 100 mM NaCl, 10 mM Tris-HCl pH 8.5, 1 mM TCEP.

1.3 Molecular level screening of Bruton's tyrosine kinase inhibitors

Bruton's tyrosine kinase inhibitor molecular level screening experiment using ThermoFisher

Assay Kit (PV3190). The experimental method is: the concentration of the compound to be tested is diluted by concentration, and 2.5 μL of Test Compounds is added to the 384-well plate, three parallel controls of each group, plus 5 μL of Bruton tyrosine kinase Kinase/Peptide Substrate Mixture, 2.5 μL ATP. Solution, shake for 30s, mix for 1h at room temperature; add 5μL Development Solution, mix for 30s, incubate for 1h at room temperature; then add 5μL Stop Reagent, shake for 30s, mix and use the microplate reader to detect the fluorescence signal, the excitation wavelength is 400nm, The emission wavelengths were 445 nm and 520 nm, respectively. Determination of inhibition for a compound at 7 concentrations gradient, calculated by Origin 8.0 curve fit IC ₅₀ values for each compound.

The synthesis of the 7(8H)-pteridin compounds of the present invention is as follows:

Reagents and conditions: (a) amine, DIPEA, 1,4-dioxane, rt; (b) ArNH2, DIPEA, 1,4-dioxane, rt; (c) Pd/C, H2, EtOH (d) R2COCOOEt, HOAc, EtOH, reflux.

In the above preparation scheme, R ¹ , R ² , R ³ , R ⁴ and R ⁵ refer to the definition of the corresponding group above. One skilled in the art can prepare the compounds of the present invention by using various starting compounds conventionally obtained in the art as starting materials according to actual preparation needs.

Example 1

The specific synthesis method of the above steps a-d is as follows:

Synthesis of (4-(2-chloro-5-nitropyrimidin-4-amino)phenyl)carbamic acid tert-butyl ester

Weigh 2,4-dichloro-5-nitropyrimidine (190 mg, 0.98 mmol) in a 25 mL round bottom flask, add 6 mL of 1,4-dioxane, stir at room temperature, and take (4-aminobenzene) Tert-butyl carbamate (200 mg, 0.96 mmol), N,N-diisopropylethylamine (137 mg, 1.06 mmol) was dissolved in 4 mL of 1,4-dioxane and added dropwise to the above reaction mixture. After completion of the dropwise addition, stirring was continued at room temperature for 1 hour, and TLC was traced until complete conversion of the starting material. The solvent was removed by rotary evaporation. ) tert-butyl carbamate orange solid 301 mg, yield 82%.

^{1 H NMR (400MHz, DMSO-} d 6): δ10.38 (s, 1H), 9.47 (s, 1H), 9.12 (s, 1H), 7.49 (d, J = 8.4Hz, 2H), 7.39 (d , J = 8.4 Hz, 2H), 1.49 (s, 9H).

Synthesis of (4-(2-(4-methoxyphenylamino)-5-nitropyrimidine-4-amino)phenyl)carbamic acid tert-butyl ester

(4-(2-Chloro-5-nitropyrimidin-4-amino)phenyl)carbamic acid tert-butyl ester (50 mg, 0.14 mmol), p-methoxyaniline (17 mg, 0.14 mmol), N, N Diisopropylethylamine (18 mg, 0.18 mmol) was placed in a 10 mL round bottom flask, and 5 mL of 1,4-dioxane was added and stirred at room temperature for 4 hrs. The solvent was removed by rotary evaporation, and the crude was purifiedjjjjjjjjjjjjjj Tert-butyl pyridyl-4-amino)phenyl)carbamate Yellow solid 51 mg, yield 82%.

^{1 H NMR (400MHz, DMSO-} d6): δ10.30 (s, 1H), 10.26 (s, 1H), 9.45 (s, 1H), 9.04 (s, 1H), 7.49 (d, J = 8.8Hz, 2H), 7.45 (d, J = 8.8 Hz, 2H), 7.40 (d, J = 8.6 Hz, 2H), 6.75 (d, J = 8.6 Hz, 2H), 3.73 (s, 3H), 1.50 (s, 9H).

Synthesis of (4-(5-Amino-2-(4-methoxyphenylamino)pyrimidine-4-amino)phenyl)carbamic acid tert-butyl ester

(4-(2-(4-Methoxyphenylamino)-5-nitropyrimidin-4-amino)phenyl)carbamic acid tert-butyl ester (45 mg, 0.10 mmol) was placed in a 50 mL round bottom flask 20 mL of ethanol, 5 mg of palladium on carbon (10% Pd) were added, hydrogen gas was introduced, and the mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was filtered with suction, and the filtrate was evaporated to dryness. mjjjjjjjjjjjj tert-Butyl oxyphenylamino)pyrimidine-4-amino)phenyl)carbamate, pale pink solid 30 mg, yield 83%.

^{1 H NMR (400MHz, DMSO-} d6): δ9.23 (s, 1H), 8.42 (s, 1H), 8.10 (s, 1H), 7.62 (d, J = 9.2Hz, 2H), 7.56 (s, 1H), 7.53 (d, J = 9.2 Hz, 2H), 7.40 (d, J = 8.8 Hz, 2H), 6.77 (d, J = 8.8 Hz, 2H), 3.70 (s, 3H), 1.48 (s, 9H).

Synthesis of (4-(2-(4-methoxyphenylamino)-7-oxo-8(7H)-pteridinyl)phenyl)carbamic acid tert-butyl ester

(4-(5-Amino-2-(4-methoxyphenylamino)pyrimidin-4-amino)phenyl)carbamic acid tert-butyl ester (30 mg, 0.07 mmol) was weighed in a 10 mL round bottom flask. 0.29 mL of glacial acetic acid and 5 mL of absolute ethanol were added, followed by the addition of ethyl glyoxylate (50% in toluene) (16 mg, 0.08 mmol). After completion of the reaction, a solid precipitated and suction filtered, and the cake was washed with ethanol, aqueous ammonia, and deionized water, and dried. (4-(2-(4-Methoxyphenylamino)-7-oxo-8(7H)-pteridinyl)phenyl)carbamic acid tert-butyl ester yellow solid (yield: 76%).

^{1 H NMR (400MHz, DMSO-} d 6): δ10.08 (s, 1H), 9.64 (s, 1H), 8.84 (s, 1H), 8.03 (s, 1H), 7.65 (d, J = 8.4Hz , 2H), 7.30-7.28 (m, 4H), 6.61 (br, 2H), 3.67 (s, 3H), 1.52 (s, 9H).

Synthesis of 8-(4-aminophenyl)-2-(4-methoxyphenyl)-7(8H)-pteridinone (No. 1)

(4-(2-(4-Methoxyphenylamino)-7-oxo-8(7H)-pteridinyl)phenyl)carbamic acid tert-butyl ester (18 mg, 0.04 mmol) was weighed in 5 mL In a round bottom flask, 2 mL of dichloromethane was added, and the mixture was stirred at 0 ° C, and 0.5 mL of trifluoroacetic acid was added. It was then stirred at 0 ° C for 1 hour and at room temperature for 1 hour. After the reaction is completed, the solution is neutralized by adding a saturated sodium hydrogencarbonate solution until the solution is alkaline, and extracted with dichloromethane (3×50 mL). The organic phase is washed with deionized water and saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was spun dry. There was obtained 14 mg of 8-(4-aminophenyl)-2-(4-methoxyphenyl)-7(8H)-pteridinone as a yellow solid. Mp>300°C.

^{1 H NMR (400MHz, DMSO-} d 6): δ10.04 (br, 1H), 8.81 (s, 1H), 8.00 (s, 1H), 7.40 (d, J = 7.6Hz, 2H), 6.98 (d , J = 8.4 Hz, 2H), 6.73 (d, J = 8.4 Hz, 2H), 6.67 (br, 2H), 5.44 (s, 2H), 3.70 (s, 3H). ¹³ C NMR (100 MHz, DMSO-d ₆ ): δ 159.19, 158.53, 157.17, 154.95, 151.76, 149.66, 146.68, 133.17, 129.22, 122.66, 121.04, 120.70, 114.37, 113.87, 55.55. HPLC purity: 97.6%, Retention time = 12.59 min. HRMS (ESI): exact mass calcd for C ₁₉ H ₁₇ N ₆ O ₂ [M+H] ⁺ , 361.1413, found 361.1414.

The following compounds were synthesized according to the methods described above:

8-(3-Aminophenyl)-2-(4-methoxyphenyl)-7(8H)-pteridinone (No. 2)

Yellow solid, yield 86%, mp 270.5-270.9 ° C.

^{1 H NMR (400MHz, DMSO-} d6): δ10.06 (br, 1H), 8.83 (s, 1H), 8.01 (s, 1H), 7.41 (d, J = 8.0Hz, 2H), 7.22 (t, J = 8.0 Hz, 1H), 6.75 (d, J = 7.6 Hz, 1H), 6.67 (br, 2H), 6.53 (s, 1H), 6.48 (d, J = 7.6 Hz, 1H), 5.35 (s, 2H), 3.69 (s, 3H). HPLC purity: 94.4%, Retention time = 12.90 min. HRMS (ESI): exact mass calcd for C19H17N6O2 [M+H]+, 361.1413, found 361.1413.

2-(3-Aminophenyl)-8-(4-methoxyphenyl)-7(8H)-pteridinone (No. 3)

Yellow solid, yield 85%, mp 244.5-245.4 ° C.

^{1 H NMR (400MHz, DMSO-} d6): δ9.91 (s, 1H), 8.85 (s, 1H), 8.04 (s, 1H), 7.35 (d, J = 8.8Hz, 2H), 7.16 (d, J = 8.8 Hz, 2H), 6.68-6.65 (m, 3H), 6.16 (d, J = 7.2 Hz, 1H), 4.63 (s, 2H), 3.86 (s, 3H). HPLC purity: 98.9%, Retention Time=12.57min.HRMS(ESI): exact mass calcd for C19H17N6O2[M+H]+, 361.1413, found 361.1411.

2-(4-Aminophenyl)-8-(4-methoxyphenyl)-7(8H)-pteridinone (No. 4)

Yellow solid, yield 88%, mp 281.5-282.3 ° C.

^{1 H NMR (400MHz, DMSO-} d6): δ9.87 (s, 1H), 8.77 (s, 1H), 7.97 (s, 1H), 7.32 (d, J = 8.8Hz, 2H), 7.13 (d, J = 8.8 Hz, 2H), 7.08 (br, 2H), 6.24 (br, 2H), 4.84 (s, 2H), 3.88 (s, 3H). HPLC purity: 95.2%, Retention time = 11.91 min. HRMS ( ESI): exact mass calcd for C19H17N6O2[M+H]+, 361.1413, found 361.1417.

N-(3-(2-((4-methoxyphenyl)amino)-7-oxo-8(7H)pteridinyl)phenyl)acrylamide (No. 6)

Yellow solid, yield 74%, mp 260.9-261.5 ° C.

^{1 H NMR (400MHz, DMSO-} d6): δ10.42 (s, 1H), 10.10 (br, 1H), 8.85 (s, 1H), 8.05 (s, 1H), 7.84 (d, J = 8.0Hz, 1H), 7.78 (s, 1H), 7.56 (t, J = 8.0 Hz, 1H), 7.31 (br, 2H), 7.13 (d, J = 8.0 Hz, 1H), 6.58 (br, 2H), 6.45 ( Dd, J = 16.8, 10.4 Hz, 1H), 6.26 (dd, J = 16.8, 1.6 Hz, 1H), 5.77 (dd, J = 10.4, 1.6 Hz, 1H), 3.65 (s, 3H). HPLC purity: 97.0%, Retention time=13.11min.HRMS(ESI):exact mass calcd for C22H19N6O3[M+H]+,415.1519,found 415.1516.

N-(4-(2-((4-methoxyphenyl)amino)-7-oxo-8(7H)pteridinyl)phenyl)propanamide (No. 7)

Yellow solid, yield 78%, mp 258.5-259.1 ° C.

^{1 H NMR (400MHz, DMSO-} d6): δ10.15 (s, 1H), 10.08 (br, 1H), 8.85 (s, 1H), 8.04 (s, 1H), 7.80 (d, J = 8.4Hz, 2H), 7.35-7.33 (m, 4H), 6.61 (br, 2H), 3.67 (s, 3H), 2.41 (q, J = 7.6 Hz, 2H), 1.14 (t, J = 7.6 Hz, 3H). HPLC purity: 99.3%, Retention time=13.05 min. HRMS (ESI): exact mass calcd for C22H21N6O3[M+H]+, 417.1675, found 417.1674.

N-(3-(2-((4-methoxyphenyl)amino)-7-oxo-8(7H)pteridinyl)phenyl)propanamide (No. 8)

Yellow solid, yield 80%, mp 298.9-299.4 ° C.

1H NMR (400MHz, DMSO-d6): δ 10.13 (s, 1H), 10.09 (s, 1H), 8.85 (s, 1H), 8.04 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H) ), 7.71 (s, 1H), 7.53 (t, J = 8.0 Hz, 1H), 7.31 (br, 2H), 7.07 (d, J = 8.0 Hz, 1H), 6.59 (br, 2H), 3.67 (s) , 3H), 2.33 (q, J = 7.6 Hz, 2H), 1.07 (t, J = 7.6 Hz, 3H). HPLC purity: 98.1%, Retention time = 13.13 min. HRMS (ESI): exact mass calcd for C22H21N6O3 [M+H]+, 417.1675, found 417.1678.

N-(3-((8-(4-methoxyphenyl)-7-oxo-8(7H)pteridin-2-yl)phenyl)acrylamide (No. 9)

Yellow solid, yield 73%, mp 243.3-244.0 ° C.

^{1 H NMR (400MHz, DMSO-} d 6): δ10.17 (s, 1H), 10.01 (s, 1H), 8.89 (s, 1H), 8.07 (s, 1H), 7.63 (br, 1H), 7.33 (d, J = 8.8 Hz, 2H), 7.27 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.11 (d, J = 8.8 Hz, 2H), 6.89 (br , 1H), 6.46 (dd, J = 17.0, 10.2 Hz, 1H), 6.25 (dd, J = 17.0, 1.8 Hz, 1H), 5.74 (dd, J = 10.2, 1.8 Hz, 1H), 3.85 (s, 3H). HPLC purity: 99.0%, Retention time = 12.91 min. HRMS (ESI): exact mass calcd for C ₂₂ H ₁₉ N ₆ O ₃ [M+H] ⁺ , 415.1519, found 415.1519.

N-(4-((8-(4-methoxyphenyl)-7-oxo-8(7H) pteridin-2-yl)phenyl)acrylamide (No. 10)

Yellow solid, yield 77%, mp 275.3-276.4 ° C.

^{1 H NMR (400MHz, DMSO-} d6): δ10.19 (br, 1H), 10.03 (s, 1H), 8.87 (s, 1H), 8.05 (s, 1H), 7.36-7.34 (m, 6H), 7.16 (d, J = 8.4 Hz, 2H), 6.41 (dd, J = 17.0, 10.2 Hz, 1H), 6.23 (dd, J = 17.0, 1.6 Hz, 1H), 5.72 (dd, J = 10.2, 1.6 Hz) , 1H), 3.92 (s, 1H). HPLC purity: 96.9%, Retention time = 12.75 min. HRMS (ESI): exact mass calcd for C22H19N6O3 [M+H]+, 415.115, found 415.1524.

4-(2-((4-Methoxyphenyl)amino)-7-oxo-8(7H)pteridinyl) phenyl acrylate (No. 11)

Yellow solid, yield 69%, mp 257.2-258.0 ° C.

^{1 H NMR (400MHz, DMSO-} d6): δ10.15 (s, 1H), 8.87 (s, 1H), 8.06 (s, 1H), 7.51 (d, J = 8.8Hz, 2H), 7.45 (d, J = 8.8 Hz, 2H), 7.31 (br, 2H), 6.69 (br, 2H), 6.60 (dd, J = 17.2, 1.6 Hz, 1H), 6.51 (dd, J = 17.2, 9.9 Hz, 1H), 6.22 (dd, J = 9.9, 1.6 Hz, 1H), 3.67 (s, 3H). HPLC purity: 97.8%, Retention time = 15.64 min. HRMS (ESI): exact mass calcd for C22H18N5O4 [M+H]+, 416.1359, found 416.1359.

(E)-4-(Dimethylamino)-N-(4-(2-((4-methoxyphenyl)amino)-7-oxo-8(7H)pteridinyl)phenyl)- 2-butenamide (No. 12)

Yellow solid, yield 55%, mp 273.5-274.3 °C.

^{1 H NMR (400MHz, DMSO-} d6): δ10.45 (s, 1H), 10.10 (br, 1H), 8.85 (s, 1H), 8.05 (s, 1H), 7.87 (d, J = 8.8Hz, 2H), 7.37 (d, J = 8.8 Hz, 2H), 7.30 (br, 2H), 6.82 (td, J = 15.4, 6.0 Hz, 1H), 6.60 (br, 2H), 6.40 (d, J = 15.4) Hz, 1H), 3.63 (s, 3H), 3.27 (d, J = 5.2 Hz, 2H), 2.33 (s, 6H). HPLC purity: 97.7%, Retention time = 10.47 min. HRMS (ESI): exact mass Calcd for C25H26N7O3[M+H]+, 472.2097, found 472.2095.

(E)-4-(Dimethylamino)-N-(3-(2-((4-methoxyphenyl)amino)-7-oxo-8(7H)pteridinyl)phenyl)- 2-butenamide (No. 13)

Yellow solid, yield 47%, mp 185.1-185.9 ° C.

^{1 H NMR (400MHz, DMSO-} d6): δ10.33 (s, 1H), 10.08 (br, 1H), 8.86 (s, 1H), 8.05 (s, 1H), 7.83 (d, J = 8.0Hz, 1H), 7.78 (s, 1H), 7.55 (t, J = 8.0 Hz, 1H), 7.32 (br, 2H), 7.11 (d, J = 8.0 Hz, 1H), 6.74 (td, J = 15.2, 5.6 Hz, 1H), 6.59 (br, 2H) 6.30 (d, J = 15.2 Hz, 1H), 3.66 (s, 3H), 3.06 (d, J = 5.6 Hz, 2H), 2.17 (s, 6H). HPLC Purity: 98.3%, Retention time=10.74min.HRMS(ESI):exact mass calcd for C25H24N7O3[M+H]+,472.2097,found 472.2094.

(E)-4-(Dimethylamino)-N-(4-(7-oxo-2-(phenylamino)-8(7H)pteridinyl)phenyl)-2-butenamide (No. 14 )

Yellow solid, yield 53%, mp 225.3-226.1 ° C.

^{1 H NMR (400MHz, DMSO-} d6): δ10.37 (s, 1H), 10.19 (br, 1H), 8.90 (s, 1H), 8.08 (s, 1H), 7.87 (d, J = 8.4Hz, 2H), 7.42 (d, J = 7.6 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 7.03 (br, 1H), 6.88 (t, J = 7.6 Hz, 1H), 6.82 (td, J = 15.4, 5.6 Hz, 1H), 6.37 (d, J = 15.4 Hz, 1H), 3.14 (d, J = 5.6 Hz, 2H), 2.24 (s, 6H). HPLC purity: 98.2%, Retention time = 10.55 min. HRMS (ESI): exact mass calcd for C24H24N7O2 [M+H]+, 442.1991, found 442.1989.

(E)-4-(Dimethylamino)-N-(3-(7-oxo-2-(phenylamino)-8(7H)pteridinyl)phenyl)-2-butenamide (No. 15 )

Yellow solid, yield 46%, mp 183.8-184.3 ° C.

^{1 H NMR (400MHz, DMSO-} d6): δ10.32 (s, 1H), 10.17 (s, 1H), 8.90 (s, 1H), 8.08 (s, 1H), 7.81-7.79 (m, 2H), 7.55 (t, J = 8.0 Hz, 1H), 7.41 (d, J = 7.2 Hz, 2H), 7.12 (d, J = 8.0 Hz, 1H), 7.01 (br, 2H), 6.87 (t, J = 7.2) Hz, 1H), 6.73 (td, J = 15.2, 5.6 Hz, 1H), 6.28 (d, J = 15.2 Hz, 1H), 3.05 (d, J = 5.6 Hz, 2H), 2.16 (s, 6H). HPLC purity: 98.2%, Retention time = 10.85 min. HRMS (ESI): exact mass calcd for C24H24N7O2 [M+H]+, 442.1991, found 442.1996.

N-(4-(7-oxo-2-phenylamino)-8(7H)pteridinyl)phenyl)acrylamide (No. 16)

Yellow solid, yield 79%, mp>300 °C.

^{1 H NMR (400MHz, DMSO-} d6): δ10.44 (s, 1H), 10.19 (br, 1H), 8.90 (s, 1H), 8.09 (s, 1H), 7.88 (d, J = 8.4Hz, 2H), 7.41-7.38 (m, 4H), 7.03 (br, 2H), 6.88 (t, J = 7.2 Hz, 1H), 6.53 (dd, J = 16.8, 10.4 Hz, 1H), 6.35 (dd, J = 16.8, 1.6 Hz, 1H), 5.84 (dd, J = 10.4, 1.6 Hz, 1H). HPLC purity: 96.1%, Retention time = 12.68 min. HRMS (ESI): exact mass calcd for C21H17N6O2 [M+H] +,385.1413,found 385.1405.

N-(3-(7-oxo-2-phenylamino)-8(7H)pteridinyl)phenyl)acrylamide (No. 17)

Yellow solid, yield 74%, mp 270.1-270.9 ° C.

^{1 H NMR (400MHz, DMSO-} d6): δ10.42 (s, 1H), 10.19 (s, 1H), 8.91 (s, 1H), 8.09 (s, 1H), 7.84-7.81 (m, 2H), 7.57 (t, J = 8.0 Hz, 1H), 7.41 (br, 2H), 7.15 (d, J = 7.6 Hz, 1H), 7.02 (br, 2H), 6.87 (t, J = 7.6 Hz, 1H), 6.45 (dd, J = 16.8, 10.4 Hz, 1H), 6.26 (dd, J = 16.8, 1.6 Hz, 1H), 5.77 (dd, J = 10.4, 1.6 Hz, 1H). HPLC purity: 96.8%, Retention time =13.27min.HRMS(ESI):exact mass calcd for C21H17N6O2[M+H]+,385.1413,found 385.1413.

N-(4-(2-((4-Chlorophenyl)amino)-7-oxo-8(7H)pteridinyl)phenyl)acrylamide (No. 18)

Yellow solid, yield 81%, mp > 300 ° C.

^{1 H NMR (400MHz, DMSO-} d6): δ10.46 (s, 1H), 10.34 (s, 1H), 8.92 (s, 1H), 8.11 (s, 1H), 7.88 (d, J = 8.8Hz, 2H), 7.41-7.36 (m, 4H), 7.06 (br, 2H), 6.53 (dd, J = 16.8, 10.4 Hz, 1H), 6.36 (dd, J = 16.8, 1.6 Hz, 1H), 5.84 (dd , J = 10.4, 1.6 Hz, 1H). HPLC purity: 94.3%, Retention time = 14.43 min. HRMS (ESI): exact mass calcd for C21H16N6O2Cl [M+H]+, 419.1023, found 419.1031.

N-(3-(2-((4-Chlorophenyl)amino)-7-oxo-8(7H)pteridinyl)phenyl)acrylamide (No. 19)

Yellow solid, yield 78%, mp 259.1-259.8 ° C.

^{1 H NMR (400MHz, DMSO-} d6): δ10.44 (s, 1H), 10.34 (br, 1H), 8.93 (s, 1H), 8.11 (s, 1H), 7.84 (s, 1H), 7.81 ( d, J = 8.4 Hz, 1H), 7.59 (t, J = 8.0 Hz, 1H), 7.43 (d, J = 7.2 Hz, 2H), 7.15 (d, J = 7.6 Hz, 1H), 6.46 (dd, J = 16.8, 10.4 Hz, 1H), 6.26 (dd, J = 16.8, 1.8 Hz, 1H), 5.77 (dd, J = 10.12, 1.8 Hz, 1H). HPLC purity: 97.4%, Retention time = 13.83 min. HRMS (ESI): exact mass calcd for C21H16N6O2Cl[M+H]+, 419.1023, found 419.1027.

N-(4-(2-((4-morpholinyl)amino)-7-oxo-8(7H)pteridinyl)phenyl)acrylamide (No. 20)

Red solid, yield 63%, mp>300 °C.

^{1 H NMR (400MHz, DMSO-} d6): δ10.44 (s, 1H), 10.00 (s, 1H), 8.82 (s, 1H), 8.02 (s, 1H), 7.88 (d, J = 8.0Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.22 (br, 2H), 6.59 (br, 2H), 6.52 (dd, J = 17.2, 10.2 Hz, 1H), 6.33 (d, J = 17.2) Hz, 1H), 5.85 (d, J = 10.2 Hz, 1H), 3.67 (br, 4H), 2.92 (br, 4H). HPLC purity: 97.3%, Retention time = 12.21 min. HRMS (ESI): exact mass Calcd for C25H24N7O3[M+H]+,470.1941,found 470.1932.

N-(3-(2-((4-morpholinyl)amino)-7-oxo-8(7H)pteridinyl)phenyl)acrylamide (No. 21)

Red solid, yield 87%, mp>300 °C.

^{1 H NMR (400MHz, DMSO-} d 6): δ10.43 (s, 1H), 10.06 (s, 1H), 8.84 (s, 1H), 8.03 (s, 1H), 7.92 (br, 1H), 7.72 (s, 1H), 7.56 (t, J = 7.6 Hz, 1H), 7.27 (br, 2H), 7.12 (d, J = 7.2 Hz, 1H), 6.58 (br, 2H), 6.45 (dd, J = 16.8, 10.4 Hz, 1H), 6.26 (d, J = 16.8 Hz, 1H), 5.78 (d, J = 10.4 Hz, 1H), 3.71 (br, 4H), 2.94 (br, 4H). HPLC purity: 98.7 %, Retention time = 11.71 min. HRMS (ESI): exact mass calcd for C ₂₅ H ₂₄ N ₇ O ₃ [M+H] ⁺ , 470.1941, found 470.1939.

N-(4-(2-(4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxo-8(7H)pteridinyl)phenyl)acrylamide twenty two)

Red solid, yield 72%, mp 299.1-299.8 ° C.

^{1 H NMR (400MHz, DMSO-} d 6): δ10.51 (s, 1H), 10.06 (s, 1H), 8.83 (s, 1H), 8.03 (s, 1H), 7.89 (d, J = 8.4Hz , 2H), 7.37 (d, J = 8.4 Hz, 2H), 7.17 (d, J = 6.4 Hz, 1H), 6.56-6.49 (m, 3H), 6.34 (d, J = 16.8 Hz, 1H), 5.85 (d, J = 10.8 Hz, 1H), 2.94 (br, 4H), 2.37 (br, 4H), 2.20 (s, 3H). HPLC purity: 97.0%, Retention time = 10.02 min. HRMS (ESI): exact Mass calcd for C ₂₆ H ₂₇ N ₈ O ₂ [M+H] ⁺ ,483.2257,found 483.2259.

N-(3-(2-(4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxo-8(7H)pteridinyl)phenyl)acrylamide twenty three)

Red solid, yield 81%, mp 268.3-269.1 ° C.

^{1 H NMR (400MHz, DMSO-} d 6): δ10.45 (s, 1H), 10.06 (s, 1H), 8.84 (s, 1H), 8.04 (s, 1H), 7.93 (br, 1H), 7.73 (s, 1H), 7.56 (t, J = 8.0 Hz, 1H), 7.25 (br, 2H), 7.12 (d, J = 8.0 Hz, 1H), 6.57 (br, 2H), 6.46 (dd, J = 16.8, 10.4 Hz, 1H), 6.27 (dd, J = 16.8, 1.8 Hz, 1H), 5.78 (dd, J = 10.4, 1.8 Hz, 1H), 2.98 (br, 4H), 2.42 (br, 4H), 2.22 (s, 3H). HPLC purity: 96.5%, Retention time = 9.99 min. HRMS (ESI): exact mass calcd for C ₂₆ H ₂₇ N ₈ O ₂ [M+H] ⁺ , 483.2257, found 483.2259.

N-(3-(7-oxo-2-((4-(piperidin-1-yl)phenyl)amino)-7-oxo-8(7H)pteridinyl)phenyl)acrylamide ( No. 24)

Red solid, yield 75%, mp 279.3-280.2 ° C.

^{1 H NMR (400MHz, DMSO-} d 6): δ10.44 (s, 1H), 10.03 (s, 1H), 8.83 (s, 1H), 8.02 (s, 1H), 7.94 (br, 1H), 7.73 (s, 1H), 7.55 (t, J = 8.0 Hz, 1H), 7.24 (br, 2H), 7.11 (d, J = 8.0 Hz, 1H), 6.57 (br, 2H), 6.46 (dd, J = 17.0, 10.2 Hz, 1H), 6.26 (dd, J = 17.0, 1.8 Hz, 1H), 5.77 (dd, J = 10.2, 1.8 Hz, 1H), 2.95 (br, 4H), 1.57 (br, 4H), 1.49 (br, 2H). HPLC purity: 95.3%, Retention time = 15.12 min. HRMS (ESI): exact mass calcd for C ₂₆ H ₂₆ N ₇ O ₂ [M+H] ⁺ , 468.2148, found 468.2146.

N-(3-(7-oxo-2-((4-(pyrrolidin-1-yl)phenyl)amino)-7-oxo-8(7H)pteridinyl)phenyl)acrylamide ( No. 25)

Red solid, yield 77%, mp 279.5-280.1 ° C.

^{1 H NMR (400MHz, DMSO-} d 6): δ10.40 (s, 1H), 9.92 (s, 1H), 8.79 (s, 1H), 7.99 (s, 1H), 7.90 (br, 1H), 7.74 (br, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.20 (br, 2H), 7.10 (d, J = 8.0 Hz, 1H), 6.46 (dd, J = 17.0, 10.2 Hz, 1H) , 6.26 (dd, J = 17.0, 1.8 Hz, 1H), 6.20 (br, 2H), 5.77 (dd, J = 10.2, 1.8 Hz, 1H), 3.10 (br, 4H), 1.91 (br, 4H). HPLC purity: 99.3%, Retention time = 15.12 min. HRMS (ESI): exact mass calcd for C ₂₅ H ₂₄ N ₇ O ₂ [M+H] ⁺ , 454.1991, found 454.1995.

N-(3-(2-(4-(Diethylamino)phenyl)amino)-7-oxo-8(7H)pteridinyl)phenyl)acrylamide (No. 26)

Red solid, yield 72%, mp 273.5-274.5 °C.

^{1 H NMR (400MHz, DMSO-} d 6): δ10.42 (s, 1H), 9.92 (s, 1H), 8.80 (s, 1H), 8.00 (s, 1H), 7.92 (br, 1H), 7.73 (s, 1H), 7.53 (t, J = 8.0 Hz, 1H), 7.19 (br, 2H), 7.09 (d, J = 8.0 Hz, 1H), 6.46 (dd, J = 17.0, 10.2 Hz, 1H) , 6.32 (br, 2H), 6.27 (dd, J = 17.0, 1.8 Hz, 1H), 5.76 (dd, J = 10.2, 1.8 Hz, 1H), 3.20 (br, 4H), 1.00 (t, J = 6.8) Hz, 6H). HPLC purity: 96.2%, Retention time = 14.69 min. HRMS (ESI): exact mass calcd for C ₂₅ H ₂₆ N ₇ O ₂ [M+H] ⁺ , 456.2148, found 456.2143.

N-(3-(2-((4-Acetylaminophenyl)amino)-7-oxo-8(7H)pteridinyl)phenyl)acrylamide (No. 27)

Yellow solid, yield 78%, mp 295.3-295.8 °C.

^{1 H NMR (400MHz, DMSO-} d 6): δ10.43 (s, 1H), 10.16 (br, 1H), 9.78 (s, 1H), 8.87 (s, 1H), 8.06 (s, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.79 (s, 1H), 7.56 (t, J = 8.0 Hz, 1H), 7.32 (br, 2H), 7.23 (br, 2H), 7.15 (d, J = 8.0 Hz, 1H), 6.46 (dd, J = 17.0, 10.2 Hz, 1H), 6.25 (dd, J = 17.0, 1.8 Hz, 1H), 5.76 (dd, J = 10.2, 1.8 Hz, 1H), 1.98 ( s, 3H). HPLC purity: 95.4%, Retention time = 10.68 min. HRMS (ESI): exact mass calcd for C ₂₃ H ₂₀ N ₇ O ₃ [M+H] ⁺ , 442.1628, found 442.1624.

4-((8-(3-Acrylaminophenyl)-7-oxo-7,8-dihydropteridin-2-yl)amino)benzamide (No. 28)

Yellow solid, yield 76%, mp 299.3-299.8 ° C.

^{1 H NMR (400MHz, DMSO-} d 6): δ10.43 (s, 1H), 10.40 (s, 1H), 8.95 (s, 1H), 8.13 (s, 1H), 7.86 (s, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.71 (br, 1H), 7.61 (t, J = 8.0 Hz, 1H), 7.55 (d, J = 7.6 Hz, 2H), 7.47 (br, 2H), 7.18 (d, J = 7.6 Hz, 2H), 6.44 (dd, J = 17.0, 10.2 Hz, 1H), 6.25 (dd, J = 17.0, 1.8 Hz, 1H), 5.76 (dd, J = 10.2, 1.8 Hz, 1H). HPLC purity: 95.6%, Retention time = 10.00 min. HRMS (ESI): exact mass calcd for C ₂₂ H ₁₈ N ₇ O ₃ [M+H] ⁺ , 428.1471, found 428.1476.

N-(4-(2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxo-8(7H)-pteridinyl) Phenyl) acrylamide (No. 29)

Red solid, yield 71%, mp 265.4-266.2 ° C.

^{1 H NMR (400MHz, DMSO-} d 6): δ10.43 (s, 1H), 8.80 (s, 1H), 8.42 (s, 1H), 8.03 (s, 1H), 7.85 (d, J = 8.6Hz , 2H), 7.34 (d, J = 8.6 Hz, 2H), 7.25 (d, J = 8.8 Hz, 1H), 6.54 - 6.48 (m, 2H), 6.33 (dd, J = 17.0, 1.6 Hz, 1H) , 6.02 (br, 1H), 5.84 (dd, J = 10.2, 1.6 Hz, 1H), 3.76 (s, 3H), 3.02 (br, 4H), 2.43 (br, 4H), 2.23 (s, 3H). HPLC purity: 97.1%, Retention time = 11.44 min. HRMS (ESI): exact mass calcd for C ₂₇ H ₂₉ N ₈ O ₃ [M+H] ⁺ , 513.2363, found 513.2362.

N-(3-(2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxo-8(7H)-pteridinyl) Phenyl) acrylamide (No. 30)

Red solid, yield 77%, mp 184.7-185.1 ° C.

^{1 H NMR (400MHz, DMSO-} d 6): δ10.41 (s, 1H), 8.80 (s, 1H), 8.44 (br, 1H), 8.02 (s, 1H), 7.86 (br, 1H), 7.71 (s, 1H), 7.52 (t, J = 8.0 Hz, 1H), 7.30 (d, J = 7.6 Hz, 1H), 7.09 (d, J = 8.0 Hz, 1H), 6.53 (s, 1H), 6.46 (dd, J = 17.0, 10.2 Hz, 1H), 6.26 (dd, J = 17.0, 1.8 Hz, 1H), 6.02 (br, 1H), 5.78 (dd, J = 10.2, 1.8 Hz, 1H), 3.76 ( s, 3H), 3.04 (br, 4H), 2.44 (br, 4H), 2.23 (s, 3H). HPLC purity: 96.2%, Retention time = 10.68 min. HRMS (ESI): exact mass calcd for C ₂₇ H ₂₉ N ₈ O ₃ [M+H] ⁺ , 513.2363, found 513.2361.

N-(4-(2-(4-methoxyphenyl)amino)-6-methyl-7-oxo-8(7H)-pteridinyl)phenyl)acrylamide (No. 31)

Yellow solid, yield 78%, mp>300 °C.

^{1 H NMR (400MHz, DMSO-} d 6): δ10.44 (s, 1H), 9.90 (br, 1H), 8.77 (s, 1H), 7.87 (d, J = 8.8Hz, 2H), 7.50 (d , J = 8.8 Hz, 2H), 7.29 (br, 2H), 6.59 (br, 2H), 6.52 (dd, J = 17.0, 10.0 Hz, 1H), 6.33 (dd, J = 17.0, 1.9 Hz, 1H) , 5.82 (dd, J = 10.0, 1.9 Hz, 1H), 3.61 (s, 3H), 2.42 (s, 3H). HPLC purity: 95.9%, Retention time = 13.60 min. HRMS (ESI): exact mass calcd for C ₂₃ H ₂₁ N ₆ O ₃ [M+H] ⁺ , 429.1675, found 429.1671.

N-(3-(2-(4-methoxyphenyl)amino)-6-methyl-7-oxo-8(7H)-pteridinyl)phenyl)acrylamide (No. 32)

Yellow solid, yield 66%, mp 285.3-286.0 ° C.

^{1 H NMR (400MHz, DMSO-} d 6): δ10.42 (s, 1H), 9.93 (br, 1H), 8.78 (s, 1H), 7.83 (d, J = 8.0Hz, 1H), 7.77 (s , 1H), 7.56 (t, J = 8.0 Hz, 1H), 7.31 (br, 2H), 7.11 (d, J = 8.0 Hz, 1H), 6.58 (br, 2H), 6.45 (dd, J = 17.0, 10.2 Hz, 1H), 6.26 (d, J = 17.0 Hz, 1H), 5.77 (d, J = 10.2 Hz, 1H), 3.65 (s, 3H), 2.42 (s, 3H). HPLC purity: 98.6%, Retention time = 13.51 min. HRMS (ESI): exact mass calcd for C ₂₃ H ₂₁ N ₆ O ₃ [M+H] ⁺ , 429.1675, found 429.1675.

(S)-8-(1-acryloyl-3-pyrrolidinyl)-2-((2-methoxy)-4-(4-methyl-1-piperazinyl)phenyl)amino)- 7(8H) pteridinone (No. 33)

Orange-red solid with a yield of 40%.

^{1 H NMR (400MHz, DMSO-} d 6): δ8.96 (s, 1H), 8.73 (s, 0.5H), 8.72 (s, 0.5H), 7.86 (s, 0.5H), 7.84 (s, 0.5 H), 7.32 (m, 1H), 6.57 (s, 1H), 6.43-6.42 (m, 1H), 6.16 (ddd, J = 16.8, 10.0, 2.4 Hz, 1H), 5.72 (dd, J = 10.0, 2.4 Hz, 1H), 5.65 (dd, J = 10.0, 2.4 Hz, 1H), 4.08 (t, J = 10.2 Hz, 0.5H), 3.88-3.82 (m, 0.5H), 3.76 (s, 3H), 3.67-3.62 (m, 1H), 3.58-3.55 (m, 1H), 3.21-3.17 (m, 4H), 2.81-2.71 (m, 1H), 2.68-2.61 (m, 4H), 2.38 (s, 1.4) H), 2.34 (s, 1.6H), 2.04-1.96 (m, 2H). HRMS (ESI) (m/z): [M+H] ⁺ calcd for C ₂₅ H ₃₁ N ₈ O ₃ , 491.2519; 491.2520. HPLC purity: 95.7%, retention time = 9.43min.

(R)-8-(1-acryloyl-3-pyrrolidinyl)-2-((2-methoxy)-4-(4-methyl-1-piperazinyl)phenyl)amino)- 7(8H) pteridinone (No. 34)

Orange-red solid with a yield of 40%.

^{1 H NMR (400MHz, DMSO-} d 6): δ8.94 (s, 1H), 8.72-8.71 (m, 1H), 7.86-7.84 (m, 1H), 7.33 (t, J = 8.4Hz, 1H) , 6.56 (s, 1H), 6.42-6.40 (m, 1H), 6.16 (ddd, J = 16.8, 10.4, 2.4 Hz, 1H), 5.70 (dd, J = 10.4, 2.4 Hz, 1H), 5.65 (dd , J = 10.4, 2.4 Hz, 1H), 4.10 (t, J = 10.2 Hz, 0.5H), 3.88 - 3.83 (m, 0.6H), 3.76 (s, 3H), 3.67 - 3.62 (m, 1H), 3.58-3.55 (m, 1H), 3.15-3.10 (m, 4H), 2.82-2.64 (m, 1H), 2.45 (br, 4H), 2.23 (s, 3H), 2.06-1.96 (m, 1H). HRMS (ESI) (m/z): [M+H] ⁺ calcd for C ₂₅ H ₃₁ N ₈ O ₃ , 491.2519; found, 491.2473.

(S)-8-(1-acryloyl-3-piperidinyl)-2-((2-methoxy)-4-(4-methyl-1-piperazinyl)phenyl)amino)- 7(8H)pteridone (No. 35)

Orange-red solid with a yield of 38%.

^{1 H NMR (400MHz, DMSO-} d 6): δ9.14 (br, 1H), 8.71 (s, 1H), 7.83 (s, 1H), 7.22-7.21 (m, 1H), 6.80-6.62 (m, 2H), 6.48-6.47 (m, 1H), 6.15-6.08 (m, 1H), 5.71-5.60 (m, 1H), 4.82-4.76 (m, 0.6H), 4.34-4.24 (m, 1H), 3.95 -3.92 (m, 1H), 3.74 (s, 3H), 3.14 (br, 4H), 2.46 (br, 4H), 1.64 (br, 2H), 1.34-1.30 (m, 1H). HRMS (ESI) ( m/z): [M+H] ⁺ calcd for C ₂₆ H ₃₃ N ₈ O ₃ , 505.2676; found, 505.2676.

N-(3-(2-((3-methoxy-4-(methyl-1-piperazinyl)phenyl)amino)-7-oxo-8(7H)-pteridinyl)phenyl ) acrylamide (No. 36)

Red solid, 55% yield.

^{1 H NMR (400MHz, DMSO-} d 6): δ10.41 (s, 1H), 10.00 (br, 1H), 8.86 (s, 1H), 8.04 (s, 1H), 7.87 (d, J = 8.0Hz , 1H), 7.73 (s, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.11 (d, J = 8.0 Hz, 1H), 7.04-6.95 (m, 2H), 6.48-6.42 (m, 2H), 6.27 (dd, J = 17.2, 2.0 Hz, 1H), 5.77 (dd, J = 10.0, 2.0 Hz, 1H), 3.55 (s, 3H), 2.83 (br, 4H), 2.43 (br, 4H) ), 2.22 (s, 3H). HRMS (ESI) (m/z): [M+H] ⁺ calcd for C ₂₇ H ₂₉ N ₈ O ₃ , 513.2363; found, 513.2362.

N-(3-(2-(3-methoxy-4-(4-methyl-1-piperazinyl)phenyl)amino)-7-oxo)-8(7H)pteridinyl) Phenyl)acrylamide (No. 37)

Yellow solid with a yield of 63%.

^{1 H NMR (400MHz, DMSO-} d 6): δ10.41 (s, 1H), 10.04 (s, 1H), 8.86 (s, 1H), 8.04 (s, 1H), 7.87 (d, J = 8.0Hz , 1H), 7.76 (s, 1H), 7.55 (t, J = 8.0 Hz, 1H), 7.22 (s, 1H), 7.13-7.10 (m, 2H), 6.70-6.69 (m, 1H), 6.45 ( Dd, J = 17.0, 10.2 Hz, 1H), 6.26 (dd, J = 17.0, 2.0 Hz, 1H), 5.76 (dd, J = 10.2, 2.0 Hz, 1H), 2.70 (br, 4H), 2.44 (br) , 4H), 2.23 (s, 3H), 1.97 (s, 3H). HRMS (ESI) (m/z): [M+H] ⁺ calcd for C ₂₇ H ₂₉ N ₈ O ₂ , 497.2413; found, 497.2428 .

N-(3-(2-(2-methoxy-5-methyl-4-(4-methyl-1-piperazinyl)phenyl)amino)-7-oxo-8 (7H) -pteridinyl)phenyl)acrylamide (No. 38)

Red solid, yield 50%.

^{1 H NMR (400MHz, DMSO-} d 6): δ10.38 (s, 1H), 8.82 (s, 1H), 8.37 (s, 1H), 8.04 (s, 1H), 7.82 (d, J = 8.0Hz , 1H), 7.74 (s, 1H), 7.53 (t, J = 8.0 Hz, 1H), 7.29 (s, 1H), 7.10 (d, J = 8.8 Hz, 1H), 6.62 (s, 1H), 6.45 (dd, J = 16.8, 2.0 Hz, 1H), 6.25 (dd, J = 16.8, 2.0 Hz, 1H), 5.77-5.76 (m, 1H), 3.78 (s, 1H), 2.76 (br, 4H), 2.46 (br, 4H), 2.24 (s, 3H), 1.85 (s, 3H). HRMS (ESI) (m/z): [M+H] ⁺ calcd for C ₂₈ H ₃₁ N ₈ O ₃ , 527.2519; Found, 527.2518.

N-(3-(2-((4-(4-acetyl-1-piperazinyl)-2-methoxyphenyl)amino)-7-oxo-8(7H)-pteridinyl) Phenyl) acrylamide (No. 39)

Red solid, yield 50%.

^{1 H NMR (400MHz, DMSO-} d 6): δ10.36 (s, 1H), 8.80 (s, 1H), 8.44 (s, 1H), 8.03 (s, 1H), 7.86 (d, J = 8.0Hz , 1H), 7.69 (t, J = 2.0 Hz, 1H), 7.52 (t, J = 8.0 Hz, 1H), 7.32 (d, J = 8.8 Hz, 1H), 7.09 (d, J = 8.0 Hz, 1H) ), 6.57 (d, J = 2.4 Hz, 1H), 6.45 (dd, J = 17.0, 2.0 Hz, 1H), 6.27 (dd, J = 17.0, 10.0 Hz, 1H), 6.09 (br, 1H), 5.77 (dd, J = 10.0, 2.0 Hz, 1H), 3.77 (s, 1H), 3.58-3.54 (m, 4H), 3.06-3.00 (m, 4H), 2.05 (s, 3H). HRMS (ESI) ( m/z): [M+H] ⁺ calcd for C ₂₈ H ₂₉ N ₈ O ₄ , 541.2312; found, 541.2312.

N-(3-(2-((4-(2-(4-methyl-1-piperazinyl)ethyl)phenyl)amino)-7-oxo-8(7H)-pteridinyl) Phenyl) acrylamide (No. 40)

Yellow solid, yield 50%.

^{1 H NMR (400MHz, DMSO-} d 6): δ10.41 (s, 1H), 10.13 (s, 1H), 8.88 (s, 1H), 8.07 (s, 1H), 7.88 (d, J = 8.0Hz , 1H), 7.77 (s, 1H), 7.57 (t, J = 8.0 Hz, 1H), 7.31-7.30 (m, 2H), 7.14 (d, J = 8.0 Hz, 1H), 6.86 (br, 2H) , 6.45 (dd, J = 16.8, 10.0 Hz, 1H), 6.26 (dd, J = 16.8, 2.0 Hz, 1H), 5.77 (dd, J = 10.0, 2.0 Hz, 1H), 2.56 (t, J = 7.6) Hz, 2H), 2.39-2.31 (m, 9H), 2.15 (s, 3H). HRMS (ESI) (m/z): [M+H] ⁺ calcd for C ₂₈ H ₃₁ N ₈ O ₂ , 511.2570; Found, 511.2571.

N-(3-(2-(2-(ethoxyethoxy))-4-(4-methyl-1-piperazinyl)phenyl)amino)-7-oxo-8(7H)- Pteridinyl)phenyl)acrylamide (No. 41)

Orange-red solid with a yield of 61%.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ8.78 (s, 1H), 8.65-8.62 (m, 1H), 8.24 (s, 1H), 8.07 (s, 1H), 7.85 (s, 1H), 7.41 (br, 3H), 6.93 (d, J = 5.6 Hz, 1H), 6.44 (s, 1H), 6.33 (d, J = 17.0 Hz, 1H), 6.10 (dd, J = 17.0, 10.4 Hz, 1H) , 5.78 (d, J = 10.4 Hz, 1H), 4.10 (br, 2H), 3.69 (br, 2H), 3.43 (s, 3H), 3.08 (br, 4H), 2.54 (br, 4H), 2.34 ( s,3H).HRMS(ESI)(m/z):[M+H] ⁺ calcd for C ₂₉ H ₃₃ N ₈ O ₄ ,557.2625;found,557.2621.

N-(3-(2-(4-(4-(2-hydroxyethyl)-1-piperazinyl)-2-methoxyphenyl)amino)-7-oxo-8 (7H) -pteridinyl)phenyl)acrylamide (No. 43)

Orange solid, yield 53%.

^{1 H NMR (400MHz, DMSO-} d 6): δ10.39 (s, 1H), 8.79 (s, 1H), 8.43 (s, 1H), 8.02 (s, 1H), 7.85 (d, J = 7.6Hz , 1H), 7.71 (s, 1H), 7.52 (t, J = 8.0 Hz, 1H), 7.30 (d, J = 7.6 Hz, 1H), 7.09 (d, J = 8.0 Hz, 1H), 6.52 (s) , 1H), 6.45 (dd, J = 16.8, 10.0 Hz, 1H), 6.27 (dd, J = 16.8, 2.0 Hz, 1H), 6.02 (br, 1H), 5.78 (dd, J = 10.0, 2.0 Hz, 1H), 4.43 (t, J = 5.2 Hz, 1H), 3.76 (s, 3H), 3.56-3.52 (m, 2H), 3.04 (br, 4H), 2.53 (t, J = 4.8 Hz, 4H), 2.44 (t, J = 6.0 Hz, 1H). HRMS (ESI) (m/z): [M+H] ⁺ calcdfor C ₂₉ H ₃₃ N ₈ O ₃ , 543.2468; found, 543.2466.

N-(3-(2-((4-(2-(4-methyl-1-piperazinyl)ethyl)phenyl)amino)-7-oxo-8(7H)-pteridinyl) Phenyl) acrylamide (No. 44)

Red solid, yield 50%.

^{1 H NMR (400MHz, DMSO-} d 6): δ10.41 (s, 1H), 8.80 (s, 1H), 8.43 (s, 1H), 8.03 (s, 1H), 7.88-7.87 (m, 1H) , 7.70 (s, 1H), 7.52 (t, J = 8.0 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.09 (d, J = 8.0 Hz, 1H), 6.52 (s, 1H) , 6.46 (dd, J = 17.2, 10.0 Hz, 1H), 6.27 (dd, J = 17.2, 2.0 Hz, 1H), 6.04 (br, 1H), 5.78 (dd, J = 10.0, 2.0 Hz, 1H), 3.76 (s, 3H), 3.60-3.58 (m, 2H), 2.58 (t, J = 10.8 Hz, 2H), 2.20-2.18 (m, 7H), 1.82-1.79 (d, J = 12 Hz, 2H), 1.48-1.40 (m, 2H). HRMS (ESI) (m/z): [M+H] ⁺ calcd for C ₂₉ H ₃₃ N ₈ O ₃ , 541.2676; found, 541.2674.

N-(3-(6-isopropyl-2-((4-(4-methyl-1-piperazinyl)phenyl)amino)-7-oxo-8(7H)-pteridinyl) Phenyl) acrylamide (No. 45)

Red solid 163 mg, yield 75%.

^{1 H NMR (400MHz, DMSO-} d 6): δ10.42 (s, 1H), 9.85 (br, 1H), 8.79 (s, 1H), 7.91 (d, J = 6.4Hz, 1H), 7.71 (s , 1H), 7.55 (t, J = 8.0 Hz, 1H), 7.25 (s, 2H), 7.11 (d, J = 8.0 Hz, 1H), 6.59-6.58 (m, 2H), 6.45 (dd, J = 17.0, 10.2 Hz, 1H), 6.26 (dd, J = 17.0, 2.0 Hz, 1H), 5.78 (dd, J = 10.2, 2.0 Hz, 1H), 3.45-3.38 (m, 1H), 2.97 (br, 4H) ), 2.42 (br, 4H), 2.21 (s, 3H), 1.25 (d, J = 6.8 Hz, 6H). HRMS (ESI) (m/z): [M+H] ⁺ calcd for C ₂₉ H ₃₃ N ₈ O ₂ , 525.2726; found, 525.2728.

N-(3-(2-(2-methoxy-4-(4-methyl-1-piperazinyl)phenyl)amino)-7-oxo-6-phenyl-8(7H) -pteridinyl)phenyl)acrylamide (No. 46)

Red solid, yield 75%.

^{1 H NMR (400MHz, DMSO-} d 6): δ10.41 (s, 1H), 8.87 (s, 1H), 8.41 (s, 1H), 8.21-8.19 (m, 2H), 7.89-7.88 (m, 1H), 7.75 (t, J = 2.0 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.50-7.48 (m, 3H), 7.35 (d, J = 8.8 Hz, 1H), 7.17- 7.14 (m, 1H), 6.54 (d, J = 2.0 Hz, 1H), 6.46 (dd, J = 17.0, 10.2 Hz, 1H), 6.27 (dd, J = 17.0, 2.0 Hz, 1H), 6.05 (br , 1H), 5.78 (dd, J = 10.2, 2.0 Hz, 1H), 3.78 (s, 3H), 3.05 (br, 4H), 2.45 (br, 4H), 2.23 (s, 3H). HRMS (ESI) (m/z): [M+H] ⁺ calcd for C ₃₃ H ₃₃ N ₈ O ₃ , 589.2676; found, 589.2676.

8-(1-Aroyl-4-piperidinyl)-2-((2-methoxy-4-(4-methyl-1-piperazinyl)phenyl)amino)-7(8H)- Dendidone (No. 47)

Orange solid, yield 53%.

^{1 H NMR (400MHz, DMSO-} d 6): δ8.83 (s, 1H), 8.71 (s, 1H), 7.83 (s, 1H), 7.53 (br, 1H), 6.85 (dd, J = 17.2, 10.4 Hz, 1H), 6.61 (d, J = 2.4 Hz, 1H), 6.47 (d, J = 8.0 Hz, 1H), 6.13 (dd, J = 17.2, 2.4 Hz, 1H), 5.70 (dd, J = 10.4, 2.4 Hz, 1H), 5.29 (br, 1H), 4.60 (d, J = 10.4 Hz, 1H), 4.20 (d, J = 12.8 Hz, 1H), 3.80 (s, 3H), 3.13 (t, J=4.8 Hz, 4H), 2.59-2.53 (m, 3H), 2.45 (t, J = 4.8 Hz, 4H), 2.22 (s, 3H), 1.67 (d, J = 10.0 Hz, 2H), 1.23 ( s, 1H).

(R)-8-((1-acryloyl-3-piperidyl)methyl)-2-((2-methoxy-4-(4-methyl-1-piperazinyl)phenyl) Amino)-7(8H)-pteridinone (No. 48)

Orange solid, yield 61%.

^{1 H NMR (400MHz, DMSO-} d 6): δ8.92 (s, 1H), 8.74 (s, 1H), 7.91-7.89 (m, 1H), 7.50-7.44 (m, 1H), 6.75 (dd, J=16.8, 10.4 Hz, 1H), 6.64 (s, 1H), 6.56-6.51 (m, 1H), 6.02 (d, J = 16.8 Hz, 1H), 5.64-5.54 (m, 1H), 4.13-4.10 (m, 1H), 3.94-3.83 (m, 3H), 3.76 (s, 3H), 3.16 (br, 4H), 3.03-2.98 (m, 1H), 2.84-2.74 (m, 1H), 2.47 (t , J = 4.8 Hz, 4H), 1.92-1.91 (m, 1H), 1.64-1.57 (m, 2H), 1.30-1.23 (m, 3H).

(S)-8-((1-acryloyl-3-piperidyl)methyl)-2-((2-methoxy-4-(4-methyl-1-piperazinyl)phenyl) Amino)-7(8H)-pteridinone (No. 49)

Orange solid, yield 54%.

^{1 H NMR (400MHz, DMSO-} d 6): δ8.92 (s, 1H), 8.74 (s, 1H), 7.91-7.89 (m, 1H), 7.49-7.43 (m, 1H), 6.75 (dd, J=16.4, 10.4 Hz, 1H), 6.64 (s, 1H), 6.56-6.51 (m, 1H), 6.02 (d, J = 16.4 Hz, 1H), 5.64-5.54 (m, 1H), 4.13-4.08 (m, 1H), 3.94-3.86 (m, 3H), 3.76 (s, 3H), 3.16 (br, 4H), 3.03-2.97 (m, 1H), 2.84-2.74 (m, 1H), 2.47 (t , J = 4.8 Hz, 4H), 1.92 (br, 1H), 1.64-1.57 (m, 2H), 1.30-1.20 (m, 3H).

N-(3-(2-(4-(2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-7-oxo-8 ( 7H)-pteridinylphenyl)acrylamide (No. 50)

Red solid, yield 61%.

^{1 H NMR (400MHz, DMSO-} d 6): δ10.37 (s, 1H), 8.76 (s, 1H), 8.41 (br, 1H), 7.99 (s, 1H), 7.84-7.83 (m, 1H) , 7.69 (t, J = 2.0 Hz, 1H), 7.51 (t, J = 8.0 Hz, 1H), 7.26-7.19 (m, 1H), 7.09 (d, J = 8.0 Hz, 1H), 6.45 (dd, J=16.8, 10.4 Hz, 1H), 6.29-6.24 (m, 2H), 5.77 (dd, J = 10.4, 2.0 Hz, 1H), 3.74 (s, 3H), 2.84 (s, 3H), 2.35-2.33 (m, 2H), 2.19 (s, 6H).

N-(3-(2-((4-((2-(2-methylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-6-isopropyl-7 -oxo-8(7H)-pteridinyl)phenyl)acrylamide (No. 51)

Orange solid, yield 62%.

^{1 H NMR (400MHz, DMSO-} d 6): δ10.37 (s, 1H), 8.72 (s, 1H), 8.21 (s, 1H), 7.84 (d, J = 8.0Hz, 1H), 7.69 (s , 1H), 7.51 (t, J = 8.0 Hz, 1H), 7.26 (d, J = 7.6 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 6.45 (dd, J = 16.8, 10.4 Hz) , 1H), 6.29-6.24 (m, 2H), 5.87 (br, 1H), 5.76 (dd, J = 10.4, 2.0 Hz, 1H), 3.75 (s, 3H), 3.43-3.38 (m, 1H), 2.84 (s, 3H), 2.34 (t, J = 6.8 Hz, 2H), 2.19 (s, 6H), 1.24 (d, J = 6.8 Hz, 6H).

N-(3-(2-((4-((2-methylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-7-oxo-6- Phenyl-8(7H)-pteridinyl)phenyl)acrylamide (No. 52)

Red solid, yield 64%.

^{1 H NMR (400MHz, DMSO-} d 6): δ10.39 (s, 1H), 8.83 (s, 1H), 8.38 (br, 1H), 8.21-8.18 (m, 2H), 7.87 (d, J = 7.2 Hz, 1H), 7.75 (s, 1H), 7.53 (t, J = 8.0 Hz, 1H), 7.49-7.47 (m, 3H), 7.28 (br, 1H), 7.15 (d, J = 8.4 Hz, 1H), 6.46 (dd, J = 16.8, 10.0 Hz, 1H), 6.29-6.25 (m, 2H), 5.83 (br, 1H), 5.76 (dd, J = 10.0, 2.0 Hz, 1H), 3.76 (s) , 3H), 3.35 (br, 2H), 2.85 (s, 3H), 2.35 (t, J = 5.6 Hz, 2H), 2.20 (s, 6H).

(R)-8-((1-acryloyl-3-piperidinyl)methyl)-6-isopropyl-2-((2-methoxy-4-(4-methyl-1-) Zinyl)phenyl)amino)-7(8H)-pteridinone (No. 53)

Yellow solid, yield 55%.

^{1 H NMR (400MHz, DMSO-} d 6): δ8.70 (br, 2H), 7.57-7.52 (m, 1H), 6.76 (dd, J = 16.4,10.4Hz, 1H), 6.64 (s, 1H) , 6.57-6.51 (m, 1H), 6.05-5.98 (m, 1H), 5.64-5.53 (m, 1H), 4.15-3.96 (m, 3H), 3.90-3.87 (m, 1H), 3.78 (s, 3H), 3.16 (br, 4H), 3.04-2.75 (m, 2H), 2.47 (t, J = 3.6 Hz, 4H), 2.24 (s, 3H), 1.94 (br, 1H), 1.66-1.61 (m , 2H), 1.20 (d, J = 6.8 Hz, 6H).

(R)-8-(1-acryloyl-3-piperidinyl)-2-((2-methoxy)-4-(4-methyl-1-piperazinyl)phenyl)amino)- 7(8H) pteridinone (No. 54)

Orange solid, 46% yield.

^{1 H NMR (400MHz, DMSO-} d 6): δ9.17 (s, 1H), 8.71 (s, 1H), 7.83 (s, 1H), 7.20 (br, 1H), 6.81 (br, 1H), 6.68 -6.62(m,2H), 6.47(br,1H),6.14-6.08(m,1H),5.72-5.61(m,1H),4.78-4.72(m,1H),4.35-4.24(m,1H) , 3.95-3.82 (m, 1H), 3.73 (s, 3H), 3.14 (br, 4H), 2.46 (br, 4H), 2.23 (s, 3H), 1.62 (br, 2H), 1.34-1.26 (m , 1H).

N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-5-((6-isopropyl-8-methyl)-7-oxo-7,8- Dihydro-2-pteridinyl)amino)-4-methoxyphenyl)acrylamide (No. 55)

Yellow solid with a yield of 43%.

^{1 H NMR (400MHz, DMSO-} d 6): δ10.08 (s, 1H), 8.96 (s, 1H), 8.73 (s, 1H), 8.64 (s, 1H), 7.02 (s, 1H), 6.42 (dd, J = 16.4, 10.0 Hz, 1H), 6.24 (d, J = 16.4 Hz, 1H), 5.75 (d, J = 10.4 Hz, 1H), 3.85 (s, 3H), 3.59 (s, 3H) , 3.43-3.36 (m, 1H), 2.89 (br, 2H), 2.71 (s, 3H), 2.35 (br, 2H), 2.23 (s, 6H), 1.20 (d, J = 6.8 Hz, 6H).

(S)-8-(1-acryloyl-3-pyrrolidinyl)-6-isopropyl-2-((3-methyl-4-(4-methyl-1-piperazinyl)phenyl )amino)-7(8H)-pteridinone (No. 56)

Yellow solid with a yield of 81%.

^{1 H NMR (400MHz, DMSO-} d 6): δ9.90 (s, 1H), 8.77 (s, 0.6H), 8.76 (s, 0.4H), 7.49-7.41 (m, 2H), 6.93 (t, J=7.2 Hz, 1H), 6.73-6.47 (m, 1H), 6.23-6.15 (m, 1H), 6.03-5.94 (m, 1H), 5.76-5.65 (m, 1H), 4.22 (t, J = 8.8 Hz, 0.6H), 4.02-3.86 (m, 1.7H), 3.83-3.65 (m, 1.7H), 3.47-3.40 (m, 1H), 2.92-2.85 (m, 1H), 2.78 (br, 4H) ), 2.46 (br, 4H), 2.23 (s, 3H), 2.20 (s, 3H), 2.14 - 2.07 (m, 1H), 1.20 (d, J = 6.4 Hz, 6H). HRMS (ESI) (m) /z): [M+H] ⁺ calcd for C ₂₈ H ₃₇ N ₈ O ₂ [M+H] ⁺ 517.3039; found, 517.3038.

(S)-8-(1-acryloyl-3-pyrrolidinyl)-2-((3-methyl-4-(4-methyl-1-piperazinyl)phenyl)amino)-6- Phenyl-7(8H)-pteridinone (No. 57)

Orange solid, yield 77%.

^{1 H NMR (400MHz, DMSO-} d 6): δ10.09 (s, 1H), 8.88 (s, 1H), 8.13 (br, 2H), 7.52-7.49 (m, 5H), 6.98-6.96 (m, 1H), 6.74-6.48 (m, 1H), 6.23-6.15 (m, 1H), 6.13-6.02 (m, 1H), 5.73-5.65 (m, 1H), 4.28-4.24 (m, 0.5H), 4.12 -3.90 (m, 1.7H), 3.85-3.67 (m, 1.8H), 3.52-3.44 (m, 1H), 2.94-2.89 (m, 1H), 2.82 (br, 4H), 2.28 (s, 3H) , 2.22 (s, 3H). HRMS (ESI) (m/z): [M+H] ⁺ calcd for C ₃₁ H ₃₅ N ₈ O ₂ [M+H] ⁺ 551.2883; found, 551.2880.

(S)-8-(1-acryloyl-3-pyrrolidinyl)-6-isopropyl-2-((2-methoxy-4-(4-methyl-1-piperazinyl)benzene Amino)-7(8H)-pteridinone (No. 58)

Orange solid, yield 54%.

^{1 H NMR (400MHz, DMSO-} d 6): δ8.71 (s, 1H), 8.69 (s, 0.5H), 8.68 (s, 0.5H), 7.39 (t, J = 7.6Hz, 1H), 6.57 (s, 1H), 6.41 (d, J = 8.8 Hz, 1H), 6.17 (dd, J = 16.4 Hz, 10.8 Hz, 1H), 5.86-5.80 (m, 1H), 5.72-5.63 (m, 1H) , 4.12 (t, J = 8.8 Hz, 0.6H), 3.91-3.86 (m, 0.6H), 3.77 (s, 3H), 3.69-3.64 (m, 1H), 3.59 (br, 1H), 3.40-3.38 (m, 0.8H), 3.12 (br, 4H), 2.81-2.70 (m, 1H), 2.45 (br, 4H), 2.23 (s, 3H), 2.09-1.98 (m, 1H), 1.18 (d, J = 6.4 Hz, 6H). HRMS (ESI) (m / z): [M + H] ⁺ calcd for 533.2989; found, 533.2994.

(S)-8-(1-acryloyl-3-pyrrolidinyl)-2-((2-methoxy-4-(4-methyl-1-piperazinyl)phenyl)amino)-6 -Phenyl-7(8H)-pteridinone (No. 59)

Red solid, yield 63%.

^{1 H NMR (400MHz, DMSO-} d 6): δ8.90 (s, 1H), 8.79 (s, 1H), 8.10 (br, 2H), 7.46 (br, 3H), 7.41-3.39 (m, 1H) , 6.58-6.42 (m, 3H), 6.17 (dd, J = 16.4 Hz, 10.4 Hz, 1H), 5.98-5.82 (m, 1H), 5.72-5.64 (m, 1H), 4.16 (t, J = 8.8 Hz, 0.6H), 3.95-3.90 (m, 0.6H), 3.78 (s, 3H), 3.71 (t, J = 9.6 Hz, 0.8H), 3.60 (br, 1H), 3.40-3.34 (m, 1H) ), 3.13(br,4H), 2.83-2.71(m,1H), 2.45(br,4H), 2.23(s,3H),2.12-2.02(m,1H).HRMS(ESI)(m/z) :[M+H] ⁺ calcd for C ₃₁ H ₃₅ N ₈ O ₃ [M+H] ⁺ 567.2832;found,567.2831.

(S,E)-8-(1-(4-(Dimethylamino)-2-butenoyl)-3-pyrrolidinyl)-2-((3-methyl-4-(4-methyl) 1-pyrazinyl)phenyl)amino)-6-phenyl-7(8H)-pteridinone (No. 61)

Orange solid, yield 82%.

^{1 H NMR (400MHz, DMSO-} d 6): δ10.10 (s, 1H), 8.88 (s, 1H), 8.12 (s, 2H), 7.49 (br, 5H), 6.97 (d, J = 8.4Hz , 1H), 6.72-6.61 (m, 1H), 6.54-6.31 (m, 1H), 6.10-6.00 (m, 1H), 4.28-4.24 (m, 0.6H), 4.05-4.00 (m, 0.7H) , 3.93-3.86 (m, 1.5H), 3.81-3.76 (m, 1.5H), 3.73-3.67 (m, 1H), 3.55 (br, 4H), 3.18 (d, J = 6.8 Hz, 2H), 3.08 (d, J = 5.2 Hz, 1H), 2.83 (br, 4H), 2.57 (s, 3H), 2.32 (s, 1.5H), 2.30 (s, 1.5H), 2.57 (s, 3H), 2.22 ( s, 3H), 2.17 (s, 3H). HRMS (ESI) (m/z): [M+H] ⁺ calcd for C ₃₄ H ₄₂ N ₉ O ₂ [M+H] ⁺ 608.3461; found, 608.3466.

(E)-8-(1-(4-(Dimethylamino)-2-butenoyl)-4-piperidinyl)-2-((2-methoxy-4-(4-methyl) 1-piperazinyl)phenyl)amino)-7(8H)-pteridinone (No. 62)

Red solid, yield 71%, mp 157.3-157.6 ° C.

^{1 H NMR (400MHz, DMSO-} d 6): δ8.86 (s, 1H), 8.72 (s, 1H), 7.83 (s, 1H), 7.54 (br, 1H), 6.64-6.62 (m, 3H) , 6.47 (d, J = 7.6 Hz, 1H), 5.27 (br, 1H), 4.61-4.58 (m, 1H), 4.21-4.18 (m, 1H), 3.79 (s, 3H), 3.14 (br, 4H) ), 3.05-3.04 (br, 2H), 2.57 (br, 4H), 2.46 (t, J = 4.0 Hz, 4H), 2.23 (s, 3H), 2.16 (s, 6H), 1.67 (br, 2H) .HRMS (ESI) (m/z): [M+H] ⁺ calcd for C ₂₉ H ₄₀ N ₉ O ₃ , 562.3254; found, 562.3259.

N-(3-(6-isopropyl-2-((3-methoxy-4-(4-methyl-1-piperazinyl)phenyl)amino)-7-oxo-8 (7H) ) pteridinyl)phenyl)acrylamide (No. 64)

Yellow solid, yield 69%. mp 249.0-249.5 ° C.

^{1 H NMR (400MHz, DMSO-} d 6): δ10.42 (s, 1H), 9.83 (br, 1H), 8.82 (s, 1H), 7.87 (d, J = 8.0Hz, 1H), 7.73 (s , 1H), 7.53 (t, J = 8.0 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 7.04 (br, 1H), 6.96 (br, 1H), 6.49-6.42 (m, 2H) , 6.26 (dd, J = 16.8 Hz, 2.0 Hz, 1H), 5.77 (dd, J = 10.0 Hz, 2.0 Hz, 1H), 3.55 (s, 3H), 3.44 - 3.39 (m, 1H), 2.82 (br , 4H), 2.42 (br, 4H), 2.21 (s, 3H), 1.25 (d, J = 6.8 Hz, 6H). HRMS (ESI) (m/z): [M+H] ⁺ calcd for C ₃₀ H ₃₅ N ₈ O ₃ , 555.2832; found, 555.2838.

N-(3-(2-(3-methoxy-4-(4-methyl-1-piperazinyl)phenyl)amino)-7-oxo-6-(trifluoromethyl)- 8(7H)-pteridinyl)phenyl)acrylamide (No. 65)

Brown solid, yield 59%, mp > 300 ° C.

^{1 H NMR (400MHz, DMSO-} d 6): δ10.44 (s, 1H), 10.40 (s, 1H), 9.00 (s, 1H), 7.88 (d, J = 7.2Hz, 1H), 7.81 (s , 1H), 7.56 (t, J = 8.0 Hz, 1H), 7.14 (d, J = 8.0 Hz, 1H), 7.01 (d, J = 7.2 Hz, 1H), 6.95 (s, 1H), 6.49-6.42 (m, 2H), 6.27 (d, J = 16.4 Hz, 1H), 5.77 (d, J = 10.4 Hz, 1H), 3.53 (s, 3H), 2.83 (br, 4H), 2.41 (br, 4H) , 2.21 (s, 3H). HRMS (ESI) (m/z): [M+H] ⁺ calcd for C ₂₈ H ₂₈ N ₈ O ₃ F ₃ , 581.2236; found, 581.2241.

(S)-8-(1-acryloyl-3-pyrrolidinyl)-2-((3-methyl-4-(4-methyl-1-piperazinyl)phenyl)amino)-7(8H ) pteridone (No. 66)

Yellow solid, yield 45%, mp 215.5-215.7 ° C.

^{1 H NMR (400MHz, DMSO-} d 6): δ10.08 (s, 1H), 8.81 (d, J = 3.2Hz, 1H), 7.89 (d, J = 6.8Hz, 1H), 7.47-7,42 (m, 2H), 6.93 (t, J = 6.8 Hz, 1H), 6.72-6.46 (m, 1H), 6.22-6.6.14 (m, 1H), 5.98-5.88 (m, 1H), 5.75-5.64 (m, 1H), 4.20 (t, J = 8.8, 1H), 4.00-3.64 (m, 4H), 3.47-3.40 (m, 1H), 2.78 (br, 4H), 2.45 (s, 3H), 2.23 (s, 3H), 2.20 (br, 4H). HRMS (ESI) (m/z): [M+H] ⁺ calcd for C ₂₅ H ₃₁ N ₈ O ₂ , 475.2570; found, 475.2550.

(S)-8-(1-acryloyl-3pyrrolidinyl)-2-((3-methoxy-4(4-methyl-1-piperazinyl)phenyl)amino)-6-benzene Base-7(8H) pteridinone (No. 67)

Orange solid, yield 40%, mp 208.3-208.8 ° C.

^{1 H NMR (400MHz, DMSO-} d 6): δ10.10 (s, 1H), 8.88 (d, J = 3.2,1H), 8.13-8.12 (m, 2H), 7.48 (d, J = 2.4Hz, 1H), 7.47 (s, 1H), 7.34 - 7.27 (m, 2H), 6.81 (t, J = 8.4 Hz, 1H), 6.74 - 6.48 (m, 1H), 6.23 - 6.15 (m, 1H), 6.12 -6.04 (m, 1H), 5.76-5.65 (m, 1H), 4.25 (t, J = 9.2, 1H), 4.13 - 3.76 (m, 3H), 3.76 (s, 3H), 3.74 - 3.67 (m, 1H), 3.51-3.44 (m, 1H), 2.91 (br, 4H), 2.44 (br, 4H), 2.21 (s, 3H). HRMS (ESI) (m/z): [M+H] ⁺ calcd For C ₃₁ H ₃₅ N ₈ O ₃ , 567.2832; found, 567.2835.

(S,E)-8-(1-(4-(Dimethylamino)-2-butenoyl)3-pyrrolidinyl)-2-((3-methyl-4-(4-methyl) 1-piperazinyl)phenyl)amino)-6-isopropyl-7(8H)pteridone (No. 68)

Red solid, yield 62%, mp 159.9-160.7 ° C.

^{1 H NMR (400MHz, DMSO-} d 6): δ9.94 (s, 1H), 8.77 (d, J = 3.6Hz, 1H), 7.49-7.40 (m, 2H), 6.94 (d, J = 8.4, 1H), 6.72-6.61 (m, 1H), 6.53 (d, J = 15.2 Hz, 0.5H), 6.34 (d, J = 15.2 Hz, 0.5H), 6.04-5.91 (m, 1H), 4.22 (t , J=8.4 Hz, 1H), 4.00-3.64 (m, 4H), 3.40-3.35 (m, 2H), 3.22 (t, J = 6.4 Hz, 1H), 3.10 (d, J = 6.0 Hz, 1H) , 2.82 (br, 4H), 2.61 (br, 4H), 2.34 (d, 11.2 Hz, 3H), 2.28 (s, 3H), 2.20 (br, 4H), 2.19 (s, 3H), 1.20 (d, J = 6.8 Hz, 6H). HRMS (ESI) (m/z): [M+H] ⁺ calcd for C ₃₁ H ₄₄ N ₉ O ₂ , 574.3618; found, 574.3584.

N-(3-(6-isopropyl-2-((2-methoxy-4-(4-methyl-1-piperazinyl)phenyl)amino)-7-oxo-8 (7H) ) pteridinyl)phenyl)acrylamide (No. 69)

Orange solid, yield 65%, mp 242.9-243.9 °C.

^{1 H NMR (400MHz, DMSO-} d 6): δ10.42 (s, 1H), 8.75 (s, 1H), 8.26 (s, 1H), 7.87 (d, J = 7.2Hz, 1H), 7.71 (s , 1H), 7.53 (t, J = 8.0 Hz, 1H), 7.34 (d, J = 8.8 Hz, 1H), 7.10 (d, J = 8.8 Hz, 1H), 6.53 (d, J = 2.0 Hz, 1H) ), 6.46 (dd, J = 16.8 Hz, 10.0 Hz, 1H), 6.27 (dd, J = 16.8 Hz, 2.0 Hz, 1H), 6.12-6.00 (m, 1H), 5.78 (dd, J = 10.0 Hz, 2.0 Hz), 3.76 (s, 3H), 3.44 - 3.41 (m, 1H), 3.04 (br, 4H), 2.43 (t, J = 4.8 Hz, 4H), 2.22 (s, 3H), 1.25 (d, J = 6.8 Hz, 6H). HRMS (ESI) (m/z): [M+H] ⁺ calcd for C ₃₀ H ₃₅ N ₈ O ₃ , 555.2832; found, 555.2821.

N-(3-(2-(2-methoxy-5-methyl-4-(4-methyl-1-piperazinyl)phenyl)amino)-7-oxo-6-phenyl -8(7H)pteridinyl)phenyl)acrylamide (No. 70)

Yellow solid, yield 62%, mp 292.9-293.4 ° C.

^{1 H NMR (400MHz, DMSO-} d 6): δ10.41 (s, 1H), 8.90 (s, 1H), 8.36 (br, 1H), 8.21-8.18 (m, 2H), 7.84 (d, J = 8.0 Hz, 1H), 7.80 (s, 1H), 7.55 (t, J = 8.0 Hz, 1H), 7.50-7.48 (m, 3H), 7.33 (s, 1H), 7.16 (d, J = 7.6 Hz, 1H), 6.63 (s, 1H), 6.45 (dd, J = 16.8 Hz, 10.0 Hz, 1H), 6.26 (dd, J = 16.8 Hz, 1.6 Hz), 5.77 (dd, J = 10.0 Hz, 1.6 Hz, 1H), 3.79 (s, 3H), 2.77 (br, 4H), 2.48 (br, 4H), 2.25 (s, 3H), 1.85 (br, 3H). HRMS (ESI) (m/z): [M +H] ⁺ calcd for C ₃₄ H ₃₅ N ₈ O ₃ ,603.2832;found,603.2834.

N-(3-(6-isopropyl-2-((2-methoxy-5-methyl-4-(4-methyl-1-piperazinyl)phenyl)amino)-7-oxyl -8(7H)pteridinyl)phenyl)acrylamide (No. 71)

Orange solid, yield 60%, mp 227.5-228.5 ° C.

^{1 H NMR (400MHz, DMSO-} d 6): δ10.40 (s, 1H), 8.79 (s, 1H), 8.22 (s, 1H), 7.82 (d, J = 8.0Hz, 1H), 7.73 (s , 1H), 7.53 (t, J = 8.0 Hz, 1H), 7.31 (s, 1H), 7.11 (d, J = 7.6 Hz, 1H), 6.62 (s, 1H), 6.44 (dd, J = 16.8 Hz) , 10.0 Hz, 1H). 6.25 (dd, J = 16.8 Hz, 0.8 Hz, 1H), 5.75 (d, J = 10.0 Hz, 1H), 3.78 (s, 3H), 3.43 - 3.39 (m, 1H), 2.77(br,4H), 2.26(s,3H), 1.85(br,3H), 1.24(d,J=6.8Hz,6H).HRMS(ESI)(m/z):[M+H] ⁺ calcd For C ₃₁ H ₃₇ N ₈ O ₃ ,569.2989;found,569.2989.

(S)-8-(1-acryloyl-3-pyrrolidinyl)-2-((4-((2-(dimethylamino)ethyl))(methyl)amino)-3-methylbenzene Amino)-6-phenyl-7(8H)pteridone (No. 72)

Red solid, yield 40%, mp 256.1-256.4 ° C.

^{1 H NMR (400MHz, DMSO-} d 6): δ10.08 (s, 1H), 8.88 (d, J = 3.2Hz, 1H), 8.13-8.12 (m, 2H), 7.52-7.45 (m, 5H) , 7.02 (dd, J=8.4 Hz, 5.6 Hz, 1H), 6.74-6.49 (m, 1H), 6.23-6.15 (m, 1H), 6.12-6.02 (m, 1H), 5.75-5.65 (m, 1H) ), 4.28-4.23 (m, 1H), 4.15-4.12 (m, 1H), 3.94-3.68 (m, 3H), 3.52-3.44 (m, 1H), 2.90 (t, J = 6.8 Hz, 2H), 2.61(s,3H), 2.35 (t, J=6.8Hz, 2H), 2.22(s,3H), 2.13(br,6H).HRMS(ESI)(m/z):[M+H] ⁺ calcd For C ₃₁ H ₃₇ N ₈ O ₂ , 553.3039; found, 553.3031.

(S)-8-(1-acryloyl-3-pyrrolidinyl)-2-((4-(2-(dimethylamino)ethyl)(methyl)amino)-3-methoxy Phenyl)amino)-6-phenyl-7(8H)pteridone (No. 73)

Dark red solid, yield 49%, mp 260.0-260.2 ° C.

^{1 H NMR (400MHz, DMSO-} d 6): δ10.09 (s, 1H), 8.88 (d, J = 2.8Hz, 1H), 8.131 (br, 2H), 7.49-7.48 (m, 3H), 7.34 -7.25 (m, 2H), 6.81 (t, J = 7.2 Hz, 1H), 6.76-6.49 (m, 1H), 6.23-6.05 (m, 2H), 5.75-5.65 (m, 1H), 4.25 (t , J = 8.4 Hz, 1H). 4.06 - 3.82 (m, 3H), 3.77 (s, 3H), 3.74 - 3.67 (m, 1H), 3.05 (t, J = 7.2 Hz, 2H), 2.94 - 2.79 ( m,1H), 2.68(s,3H), 2.36(t,J=7.2Hz, 2H), 2.13(s,6H).HRMS(ESI)(m/z):[M+H] ⁺ calcd for C ₃₁ H ₃₇ N ₈ O ₃ , 569.2989; found, 569.2988.

N-(3-(2-(3-methoxy-4-(4-methyl-1-piperazinyl)phenyl)amino)-7-oxo-6-phenyl-8(7H) Pteridinyl)phenyl)acrylamide (No. 74)

Red solid, yield 81%, mp 264.7-265.5 ° C.

^{1 H NMR (400MHz, DMSO-} d 6): δ10.43 (s, 1H), 10.01 (s, 1H), 8.93 (s, 1H), 8.22-8.19 (m, 2H), 7.90 (d, J = 7.6 Hz, 1H), 7.79 (s, 1H), 7.56 (t, J = 8.0 Hz, 1H), 7.49 (t, J = 3.2 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 7.07 (br, 1H), 6.97 (br, 1H), 6.46 (dd, J = 16.8 Hz, 10.0 Hz, 1H), 6.27 (dd, J = 16.8 Hz, 1.6 Hz, 1H), 5.77 (dd, J = 10.0) Hz, J=1.6 Hz, 1H), 3.56 (s, 3H), 2.83 (br, 4H), 2.41 (br, 4H), 2.21 (s, 3H). HRMS (ESI) (m/z): [M +H] ⁺ calcd for C ₃₃ H ₃₃ N ₈ O ₃ ,589.2676;found,589.2642.

N-(3-(6-Cyclohexyl-2-((2-methoxy-4-(4-methyl-1-piperazinyl)phenyl)amino)-7-oxo-8 (7H) Pteridinyl)phenyl)acrylamide (No. 75)

Yellow solid, yield 82%, mp 268.9-269.4 ° C.

^{1 H NMR (400MHz, DMSO-} d 6): δ10.40 (s, 1H), 8.73 (s, 1H), 8.24 (s, 1H), 7.85 (d, J = 8.0Hz, 1H), 7.69 (t , J = 1.6 Hz, 1H), 7.52 (t, J = 8.0 Hz, 1H), 7.33 (d, J = 9.2 Hz, 1H), 7.10-7.08 (m, 1H), 6.53 (d, J = 2.4 Hz) , 1H), 6.45 (dd, J = 16.8 Hz, 10.0 Hz, 1H), 6.26 (dd, J = 16.8 Hz, 2.0 Hz, 1H), 6.06 (br, 1H), 5.77 (dd, J = 10.0 Hz, 2.0 Hz, 1H), 3.76 (s, 3H), 3.03 (br, 4H), 2.43 (t, J = 4.8 Hz, 4H), 2.22 (s, 3H), 3.41 (d, J = 12.0 Hz, 2H) , 1.82 (d, J = 12.0 Hz, 2H), 1.72 (d, J = 12.0 Hz, 2H), 1.53-1.23 (m, 6H). HRMS (ESI) (m/z): [M+H] ⁺ calcd for C ₃₃ H ₃₉ N ₈ O ₃ , 595.3145; found, 595.3141.

(S)-8-((1-acryloyl-3-piperidyl)methyl)-2-((2-methoxy-4-(4-methyl-1-piperazinyl)phenyl) Amino)-6-phenyl-7(8H)pteridone (No. 76)

Red solid, yield 49%, mp 208.3-209.3 ° C.

^{1 H NMR (400MHz, DMSO-} d 6): δ8.88 (s, 1H), 8.81 (s, 1H), 8.18-8.16 (m, 2H), 7.59-7.52 (m, 1H), 7.47 (t, J = 3.2 Hz, 3H), 6.75 (dd, J = 16.4 Hz, 10.0, 1H), 6.64 (s, 1H), 6.55 (dd, J = 17.2 Hz, 8.8 Hz, 1H), 6.03 (d, J = 16.4 Hz, 1H), 5.58 (dd, J = 32.8 Hz, 10.0 Hz, 1H), 4.19-4.06 (m, 3H), 3.89-3.83 (m, 1H), 3.79 (s, 3H), 3.17 (br, 4H), 3.05-2.55 (m, 2H), 2.48 (t, J = 4.8 Hz, 4H), 2.24 (s, 3H), 2.00 (br, 1H), 1.66 (br, 2H), 1.26-1.23 (m , 2H). HRMS (ESI) (m/z): [M+H] ⁺ calcd for C ₃₃ H ₃₉ N ₈ O ₃ , 595.3145; found, 595.3157.

(R)-8-(1-acryloyl-3-piperidinyl)-2-((2-methoxy-4-(4-methyl-1-piperazinyl)phenyl)amino)-6 -Phenyl-7(8H)pteridone (No. 77)

Red solid, yield 38%, mp 134.9-135.1 ° C.

^{1 H NMR (400MHz, DMSO-} d 6): δ9.17 (s, 1H), 8.79 (s, 1H), 8.11-8.09 (m, 2H), 7.77-7.46 (m, 3H), 7.24 (br, 1H), 6.84-6.63 (m, 2H), 6.49 (s, 1H), 6.06-6.19 (m, 1H), 5.67 (dd, J = 37, 2 Hz, 9.6 Hz, 1H), 5.00-4.27 (m, 3H), 3.75 (s, 3H), 3.14 (s, 4H), 2.49 (s, 4H), 2.24 (s, 3H), 1.69 (br, 2H), 1.35 (br, 1H), 1.23 (s, 1H) ). HRMS (ESI) (m/z): [M+H] ⁺ calcd for C ₃₂ H ₃₇ N ₈ O ₃ , 581.2989; found, 581.2972.

(R)-8-(1-acryloyl-3-piperidinyl)-6-cyclohexyl-2-((2-methoxy-4-(4-methyl-1-piperazinyl)phenyl )amino)-7(8H)pteridone (No. 78)

Yellow solid, yield 53%, mp 94.2-94.7 ° C.

^{1 H NMR (400MHz, DMSO-} d 6): δ8.96 (s, 1H), 8.65 (s, 1H), 7.23 (br, 1H), 6.83-6.61 (m, 2H), 6.47 (s, 1H) , 6.15-6.08 (m, 1H), 5.66 (dd, J = 36 Hz, 9.6 Hz, 1H), 4.84 (br, 1H), 4.29 (br, 1H), 3.95 (br, 1H), 3.72 (s, 3H) ), 3.13 (br, 4H), 2.46 (br, 4H), 2.23 (s, 3H), 1.81-1.63 (m, 7H), 1.44-1.23 (m, 9H). HRMS (ESI) (m/z) :[M+H] ⁺ calcd for C ₃₂ H ₄₃ N ₈ O ₃ ,587.3458;found 587.3458.

N-(3-(2-((3-methyl-4-(4-methyl-1-piperazinyl)phenyl)amino)-7-oxy-6-phenyl-8(7H) butterfly Pyridyl)phenyl)acrylamide (No. 79)

Yellow solid, yield 68%, mp 265.0-265.2 °C.

^{1 H NMR (400MHz, DMSO-} d 6): δ10.43 (s, 1H), 10.04 (s, 1H), 8.92 (s, 1H), 8.22-8.19 (m, 2H), 7.89 (d, J = 8.0 Hz, 1H), 7.81 (s, 1H), 7.57 (t, J = 8.0 Hz, 1H), 7.50-7.49 (m, 3H), 7.25 (s, 1H), 7.19 (s, 1H), 7.17 ( s, 1H), 6.71 (br, 1H), 6.46 (dd, J = 16.8 Hz, 10.4 Hz, 1H), 6.26 (dd, J = 16.8 Hz, 1.6 Hz, 1H), 5.77 (dd, J = 10.4 Hz) , 1.6 Hz, 1H), 2.7 (br, 4H), 2.44 (br, 4H), 2.23 (s, 3H), 1.98 (s, 3H). HRMS (ESI) (m/z): [M+H] ⁺ calcd for C ₃₃ H ₃₃ N ₈ O ₂ , 573.2726; found, 573.2729.

N-(3-(2-((2-methyl-1-piperazinyl)piperidinyl)phenyl)amino)-7-oxo-6- Phenyl-8(7H)pteridinyl)phenyl)acrylamide (No. 80)

Red solid, yield 40%, mp>300 °C.

^{1 H NMR (400MHz, DMSO-} d 6): δ10.44 (s, 1H), 8.86 (s, 1H), 8.41 (s, 1H), 8.20-8.19 (m, 2H), 7.90 (br, 1H) , 7.75 (s, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.50-7.48 (m, 3H), 7.33 (d, J = 6.4 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H),6,52(br,1H), 6.47(dd,J=16.8Hz,10.0Hz,1H), 6.27(dd,J=16.8Hz,1.6Hz,1H),6.04(br,1H),5.78 (dd, J = 10.0 Hz, 1.6 Hz), 3.77 (s, 3H), 3.61 (d, J = 8.4 Hz, 2H), 2.60-2.54 (m, 5H), 2.39-2.30 (m, 5H), 1 , 81 (d, J = 11.6 Hz, 2H), 1.51-1.43 (m, 2H). HRMS (ESI) (m/z): [M+H] ⁺ calcd for C ₃₈ H ₄₂ N ₉ O ₃ , 672.3411 ;found,672.3407.

8-(1-acryloyl-3-pyrrolidinyl)-2-((3-methyl-4-(4-methyl-1-piperazinyl)phenyl)amino)-6-phenyl-7 (8H) pteridinone (No. 81)

Orange solid, yield 65%.

^{1 H NMR (400MHz, DMSO-} d 6): δ10.08 (s, 1H), 8.87 (d, J = 2.8Hz, 1H), 8.13-8.11 (m, 2H), 7.51-7.46 (m, 5H) , 6.97-6.93 (m, 1H), 6.70 (dd, J = 16.8 Hz, 10.4, 1H), 6.51 (dd, J = 16.8 Hz, 10.4 Hz, 1H), 6.23 - 6.15 (m, 1H), 6.11 6.01 (m, 1H), 5.75-5.65 (m, 1H), 4.25 (t, J = 8.8 Hz, 1H), 4.06-3.68 (m, 3H), 3.52-3.45 (m, 1H), 2.95-2.86 ( m, 1H), 2.79 (br, 4H), 2.46 (br, 4H), 2.23 (s, 3H), 2.21 (s, 3H), 2.17-2.12 (m, 1H). HRMS (ESI) (m/z ): [M+H] ⁺ calcd for C ₃₁ H ₃₅ N ₈ O ₂ , 551.2883; found, 551.2883.

(S)-8-(1-acryloyl-3-pyrrolidinyl)-6-cyclohexyl-2-((2-methoxy-4-(4-methyl-1-piperazinyl)phenyl) )amino)-7(8H)pteridone (No. 82)

Orange solid, yield 49%, mp 117.9-118.2 ° C.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.71 (s, 1H), 8.66 (d, J = 3.6 Hz, 1H), 7.39 (t, J = 8.0 Hz, 1H), 6.63-6.59 (m) , 0.5H), 6.57 (s, 1H), 6.49-6.45 (m, 0.5H), 6.41 (d, J = 9.2 Hz, 1H), 6.20-6.13 (m, 1H), 5.82 (br, 1H), 5.73-5.63(m,1H), 4.11(t,J=9.2Hz,0.5H), 3.87(dd,J=12.0Hz,8.8Hz,0.5H),3.69-3.58(m,2H),3.18-3.04 (m, 5H), 2.80-2.65 (m, 1H), 2.45 (br, 4H), 2.23 (s, 3H), 2.09 (br, 0.5H), 1.99 (br, 0.5H), 1.81 (t, J) =11.2 Hz, 4H), 1.70 (d, J = 11.2 Hz, 1H), 1.45-1.16 (m, 6H). HRMS (ESI) (m/z): [M+H] ⁺ calcd for C ₃₁ H ₄₁ N ₈ O ₃ , 573.3302; found, 573.3304.

8-(3-Aminophenyl)-2-((2-methoxy-4-(4-methyl-1-piperazinyl)phenyl)amino)-6-phenyl-7(8H) butterfly Pyridone (No. 83)

Orange solid, yield 84%, mp 235.5-235.7 ° C.

^{1 H NMR (400MHz, DMSO-} d 6): δ8.84 (s, 1H), 8.39 (br, 1H), 8.19-8.17 (m, 2H), 7.49-7.47 (m, 4H), 7.21 (t, J = 8.0 Hz, 1H), 6.72 (d, J = 7.2 Hz, 1H), 6.571-6.56 (m, 2H), 6.52 (d, J = 8.0 Hz, 1H), 6.19 (br, 1H), 5.34 ( s, 2H), 3.79 (s, 3H), 3.08 (br, 4H), 2.45 (t, J = 4.4 Hz, 4H), 2.23 (s, 3H). HRMS (ESI) (m/z): [M +H] ⁺ calcd for C ₃₀ H ₃₁ N ₈ O ₂ , 535.2570; found, 535.2569.

N-(3-(6-(4-fluorophenyl)-2-((2-methoxy-4-(4-methyl-1-piperazinyl)phenyl)amino)-7-oxo -8(7H)pteridinyl)phenyl)acrylamide (No. 84)

Orange solid, yield 73%, mp 262.3-262.7 ° C.

^{1 H NMR (400MHz, DMSO-} d 6): δ10.43 (s, 1H), 8.87 (s, 1H), 8.44 (s, 1H), 8.29 (dd, J = 8.4Hz, 6.0Hz, 1H), 7.89 (br, 1H), 7.77 (s, 1H), 7.55 (t, J = 8.0 Hz, 1H), 7.36-7.31 (m, 3H), 7.15 (d, J = 8.4 Hz, 1H), 6.54 (s) , 1H), 6.47 (dd, J = 16.8 Hz, 10.0 Hz, 1H), 6.28 (dd, J = 16.8 Hz, 1.6 Hz, 1H), 6.04 (br, 1H), 5.78 (dd, J = 10.0 Hz, 1.6 Hz, 1H), 3.78 (s, 3H), 3.05 (br, 4H), 2.44 (t, J = 4.4 Hz, 4H), 2.23 (s, 3H). HRMS (ESI) (m/z): [ M+H] ⁺ calcd for C ₃₃ H ₃₂ N ₈ O ₃ F, 607.2581; found, 607.2589.

N-(3-(6-(2-fluorophenyl)-2-((2-methoxy-4-(4-methyl-1-piperazinyl)phenyl)amino)-7-oxo -8(7H)pteridinylphenyl)acrylamide (No. 85)

Orange solid, yield 67%.

^{1 H NMR (400MHz, DMSO-} d 6): δ10.42 (s, 1H), 8.85 (s, 1H), 8.50 (s, 1H), 7.86 (s, 1H), 7.76 (s, 1H), 7.64 -7.68 (t, J = 8.0 Hz, 1H), 7.52 - 7.56 (t, J = 8.0 Hz, 2H), 7.31 - 7.35 (t, J = 8.0 Hz, 3H), 7.14 (d, J = 8.0 Hz, 1H), 6.54 (s, 1H), 6.46 (dd, J = 16.0 Hz, 8.0 Hz, 1H), 6.27 (d, J = 16.0 Hz, 1H), 6.03 (br, 1H), 5.78 (d, J = 8.0 Hz, 1H), 3.77 (s, 3H), 3.05 (br, 4H), 2.43 (s, 4H), 2.22 (s, 3H). HRMS (ESI) (m/z): [M+H] ⁺ Calcd for C ₃₃ H ₃₂ N ₈ O ₃ F, 607.2503; found, 607.2534.

N-(3-(2-(2-methoxy-4-(4-methyl-1-piperazinyl)phenyl)amino)-6-(4-methoxyphenyl)-7- Oxo-8 (7H) pteridinyl) phenyl) acrylamide (No. 88)

Orange solid, yield 65%, mp 296.5-297.3 ° C.

^{1 H NMR (400MHz, DMSO-} d 6): δ10.43 (s, 1H), 8.84 (s, 1H), 8.34 (s, 1H), 8.26 (d, J = 8.8Hz, 1H), 7.89 (d , J = 7.2 Hz, 1H), 7.74 (s, 1H), 7.55 (t, J = 8.0 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 7.05 (d, J = 9.2 Hz, 1H), 6.54 (s, 1H), 6.47 (dd, J = 16.8 Hz, 10.0 Hz, 1H), 6.27 (dd, J = 16.8 Hz, 1.6 Hz, 1H) ), 6.06 (br, 1H), 5.78 (d, J = 10.0 Hz, 1.6 Hz, 1H), 3.84 (s, 3H), 3.78 (s, 3H), 3.05 (br, 4H), 2.44 (br, 4H) ), 2.23(s,3H).HRMS(ESI)(m/z):[M+H] ⁺ calcd for C ₃₄ H ₃₅ N ₈ O ₄ ,619.2781;found,619.2780.

N-(3-(6-(3,5-Difluorophenyl)-2-((2-methoxy-4-(4-methyl-1-piperazinyl)phenyl)amino)-7 -oxo-8(7H)pteridinyl)phenyl)acrylamide (No. 89)

Red solid, yield 64%, mp 291.2-291.4 ° C.

^{1 H NMR (400MHz, DMSO-} d 6): δ10.43 (s, 1H), 8.92 (s, 1H), 8.57 (s, 1H), 7.96 (d, J = 7.2Hz, 1H), 7.87 (br , 1H), 7.77 (s, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.43 - 7.39 (m, 1H), 7.33 (s, 1H), 7.14 (d, J = 7.2 Hz, 1H) , 6.54 (s, 1H), 6.47 (dd, J = 16.8 Hz, 10.0, 1H), 6.27 (dd, J = 16.8 Hz, 1.6 Hz, 1H), 6.00 (br, 1H), 5.78 (dd, J = 10.0 Hz, 1.6 Hz, 1H), 3.77 (s, 3H), 3.05 (br, 4H), 2.43 (br, 4H), 2.22 (s, 3H). HRMS (ESI) (m/z): [M+ H] ⁺ calcd for C ₃₃ H ₃₁ N ₈ O ₃ F ₂ , 625.2487; found, 625.2482.

N-(3-(6-(3,4-difluorophenyl)-2-((2-methoxy-4-(4-methyl-1-piperazinyl)phenyl)amino)-7 -oxo-8(7H)pteridinyl)phenyl)acrylamide (No. 90)

Orange solid, yield 67%, Mp > 300 ° C.

^{1 H NMR (400MHz, DMSO-} d 6): δ10.43 (s, 1H), 8.89 (s, 1H), 8.50 (br, 1H), 8.28-8.23 (m, 1H), 8.15 (br, 1H) , 7.87 (s, 1H), 7.77 (s, 1H), 7.61 - 7.52 (m, 2H), 7.34 (s, 1H), 7.14 (d, J = 8.4 Hz, 1H), 6.54 (s, 1H), 6.47 (dd, J = 16.8 Hz, 10.0 Hz, 1H), 6.27 (dd, J = 16.8 Hz, 1.6 Hz, 1H), 6.02 (br, 1H), 5.78 (dd, J = 10.0 Hz, 1.6 Hz, 1H) ), 3.77 (s, 3H), 3.05 (br, 4H), 2.43 (t, J = 4.4 Hz, 4H), 2.22 (s, 3H). HRMS (ESI) (m/z): [M+H] ⁺ calcd for C ₃₃ H ₃₁ N ₈ O ₃ F ₂ , 625.2487; found, 625.2478.

N-(3-(2-(2-methoxy-4-(4-methyl-1-piperazinyl)phenyl)amino)-6-(3-methoxyphenyl)-7- Oxo-8 (7H) pteridinyl) phenyl) acrylamide (No. 91)

Brown solid, yield 52%, Mp > 300 ° C.

^{1 H NMR (400MHz, DMSO-} d 6): δ10.42 (s, 1H), 8.88 (s, 1H), 8.45 (s, 1H), 7.89 (s, 1H), 7.82-7.81 (m, 2H) , 7.76 (s, 1H), 7.55 (t, J = 8.0 Hz, 1H), 7.41 (t, J = 8.0 Hz, 1H), 7.36-7.34 (br, 1H), 7.16 (d, J = 7.6 Hz, 1H), 7.08 (d, J = 8.4 Hz, 1H), 6.54 (s, 1H), 6.47 (dd, J = 16.8 Hz, 10.4 Hz, 1H), 6.28 (d, J = 17.2 Hz, 1H), 6.04 (br, 1H), 5.80 (m, 1H), 3.82 (s, 3H), 3.78 (s, 3H), 3.05 (br, 4H), 2.44 (br, 4H), 2.23 (s, 3H). HRMS ( ESI) (m/z): [M+H] ⁺ calcd for C ₃₄ H ₃₅ N ₈ O ₄ , 619.2278; found, 619.2780.

N-(3-(2-(2-methoxy-4-(4-methyl-1-piperazinyl)phenyl)amino)-4-methyl-6-phenyl-7-oxo -8(7H)pteridinylphenyl)acrylamide (No. 92)

Brown solid, yield 85%.

^{1 H NMR (400MHz, DMSO-} d 6): δ10.40 (s, 1H), 8.25-8.28 (m, 2H), 8.20 (s, 1H), 7.90 (d, J = 8.0Hz, 1H), 7.72 (s, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.48-7.50 (m, 3H), 7.38 (d, J = 8.0 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H) , 6.53 (d, J = 4.0 Hz, 1H), 6.46 (dd, J = 16.0 Hz, 8.0 Hz, 1H), 6.27 (dd, J = 16.0 Hz, 4.0 Hz, 1H), 6.03 (br, 1H), 5.77 (m, 1H), 3.82 (s, 3H), 3.03 (s, 4H), 2.72 (s, 3H), 2.44 (br, 4H), 2.23 (s, 3H). HRMS (ESI) (m/z ): [M+H] ⁺ calcd for C ₃₄ H ₃₅ N ₈ O ₄ , 603.2754; found, 603.2750.

N-(3-(6-(4-fluorophenyl)-2-((2-methoxy-4-(4-methyl-1-piperazinyl)phenyl)amino)-4-methyl) -7-oxo-8(7H)pteridinyl)phenyl)acrylamide (No. 93)

Brown solid, yield 73%.

^{1 H NMR (400MHz, DMSO-} d 6): δ10.48 (s, 1H), 8.33-8.37 (m, 2H), 8.22 (s, 1H), 7.91 (d, J = 8.0Hz, 1H), 7.74 (s, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.30-7.38 (m, 3H), 7.12 (d, J = 8.0 Hz, 1H), 6.53 (s, 1H), 6.48 (dd, J = 16.0 Hz, 8.0 Hz, 1H), 6.27 (d, J = 16.0 Hz, 1H), 6.01 (br, 1H), 5.78 (d, J = 8.0 Hz, 1H), 3.77 (s, 3H), 3.06 (s, 4H), 2.70 (s, 3H), 2.53 (s, 4H), 2.29 (s, 3H). HRMS (ESI) (m/z): [M+H] ⁺ calcd for C ₃₄ H ₃₅ N ₈ O ₄ , 621.2738; found, 603.2726.

The synthesis of the 1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one compounds of the present invention is as follows:

Reagents and conditions: (a) tert-butyl (3-aminophenyl)carbamate, DIPEA, CH ₃ CN, reflux, 6 h; (b) LiAlH ₄ , THF, 0 ° C, 4 h; (c) MnO ₂ , CH ₂ Cl ₂ , room temperature, overnight; (d) Grignard reagent, THF, 0 ° C, 5 h; (e) CDI, K ₂ CO ₃ , THF, reflux, overnight; (f) arylamine, trifluoroacetic acid, fluoro ethanol, reflux, 24h; (g) trifluoroacetic acid, CH ₂ Cl _2, rt, 5h; (h) acryloyl _{chloride, Et 3 N, CH 2 Cl} 2, 0 ℃ to room temperature overnight.

Example 2

The specific synthesis method of the above steps a-h is as follows:

Synthesis of ethyl 4-((3-((tert-butoxycarbonyl)amino)phenyl)amino)-2-chloropyrimidine-5-carboxylate

Ethyl 2,4-dichloro-5-pyrimidinecarboxylate (22.100 g, 100 mmol), DIPEA (12.900 g, 100 mmol) was weighed in a 500 mL single-necked flask and dissolved in 100 mL of acetonitrile. Further, tert-butyl (3-aminophenyl)carbamate (20.800 g, 100 mmol) was dissolved in 100 mL of acetonitrile, and the mixture was added dropwise to the mixture. The TLC was traced to the conversion of the starting material, cooled to room temperature, suction filtered, washed with acetonitrile and dried to give 4-((3-((tert-butoxycarbonyl)amino)phenyl)amino)-2-chloropyrimidine-5. - 33.710 g of ethyl formate.

^{1 H NMR (400MHz, DMSO-} d 6) δ10.23 (s, 1H), 9.50 (s, 1H), 8.80 (s, 1H), 7.70 (s, 1H), 7.35 (d, J = 8.0Hz, 1H), 7.29 (t, J = 8.0 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 4.38 (q, J = 7.2 Hz, 2H), 1.49 (s, 9H), 1.36 (t, J = 7.2 Hz, 3H). LC-MS: m/z: 393.1 (M+H) ⁺ .

(3-((2-Chloro-5-(hydroxymethyl)pyrimidin-4-yl)amino)phenyl)carbamic acid tert-butyl ester

An ethyl 4-((3-((tert-butoxycarbonyl)amino)phenyl)amino)-2-chloropyrimidine-5-carboxylate (31.360 g, 80 mmol) was weighed in a 5000 mL two-necked flask, and 100 mL of anhydrous tetrahydrofuran was added. Dissolve and stir for 10 minutes in an ice bath. Further, lithium aluminum hydride (12.160 g, 320 mmol) was dissolved in 150 mL of anhydrous tetrahydrofuran, and slowly added dropwise to the above reaction mixture, and the mixture was stirred for 4 hours. The TLC was used to trace the conversion of the starting material. The reaction mixture was poured into 250 mL of saturated aqueous NH ₄ Cl solution, and extracted with ethyl acetate. The organic layer was collected, dried over anhydrous Na ₂ SO ₄ and evaporated. The crude product was purified by silica gel column chromatography ( petroleum ether / ethyl acetate = 2:1, v/v). 3.38 g of (3-((2-chloro-5-(hydroxymethyl)pyrimidin-4-yl)amino)phenyl)carbamic acid tert-butyl ester.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.38 (s, 1H), 7.78 (s, 1H), 7.70 (s, 1H), 7.34 (d, J = 8.4 Hz, 1H), 7.25 (t, J = 8.0 Hz, 1H), 7.05 (d, J = 8.0 Hz, 1H), 6.66 (s, 1H), 4.65 (s, 2H), 1.52 (s, 9H). LC-MS: m/z: 351.1 (M +H) ⁺ .

(3-((2-Chloro-5-formylpyrimidin-4-yl)amino)phenyl)carbamic acid tert-butyl ester

(3-((2-Chloro-5-(hydroxymethyl)pyrimidin-4-yl)amino)phenyl)carbamic acid tert-butyl ester (3.500 g, 10 mmol) was weighed in a 100 mL single-neck flask, and 40 mL of dichloromethane was added. Dissolved. Manganese dioxide (58%, 15.000 g, 100 mmol) was added portionwise and stirred at room temperature overnight. TLC was used to track the conversion of the starting material, and the diatomaceous earth was suction filtered, and the filtrate was dried. The crude product was purified by silica gel column chromatography ( petroleum ether / ethyl acetate = 4:1, v/v). (2.850 g of tert-butyl 3-((2-chloro-5-formylpyrimidin-4-yl)amino)phenyl)carbamate).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ10.60 (s, 1H), 9.89 (s, 1H), 8.56 (s, 1H), 7.82 (t, J = 2.0Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H), 7.31 (t, J = 8.0 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 6.58 (s, 1H), 1.53 (s, 9H). LC-MS: m/ z: 349.1 (M+H) ⁺ .

(3-((2-Chloro-5-(1-hydroxyethyl)pyrimidin-4-yl)amino)phenyl)carbamic acid tert-butyl ester

(3-((2-Chloro-5-formylpyrimidin-4-yl)amino)phenyl)carbamic acid tert-butyl ester (1.044 g, 3 mmol) was weighed in a 50 mL two-necked flask, dissolved in 20 mL of anhydrous tetrahydrofuran, argon Gas protection, stirring in an ice bath for 10 minutes. Further, methylmagnesium bromide (1 M in THF, 9 mL) was added, and the mixture was slowly added to the mixture, and the mixture was stirred for 5 hours. TLC was used to carry out the conversion of the starting material. The reaction mixture was poured into 30 mL of saturated aqueous NH ₄ Cl, and ethyl acetate was evaporated. The organic layer was collected, dried over anhydrous Na ₂ SO ₄ and evaporated. The crude product was purified by silica gel column chromatography ( petroleum ether / ethyl acetate = 2:1, v/v). There was obtained 0.831 g of (3-((2-chloro-5-(1-hydroxyethyl)pyrimidin-4-yl)amino)phenyl)carbamic acid tert-butyl ester.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.83 (s, 1H), 7.77 (s, 1H), 7.70 (s, 1H), 7.29 (d, J = 8.4 Hz, 1H), 7.23 (t, J = 8.0 Hz, 1H), 7.05 (d, J = 8.0 Hz, 1H), 6.67 (s, 1H), 4.87 (q, J = 6.4 Hz, 1H), 1.55 (d, J = 6.4 Hz, 3H), 1.52 (s, 9H). LC-MS: m/z: 365.1 (M+H) ⁺ .

(3-(7-Chloro-4-methyl-2-oxo-2H-pyrimido[4,5-d][1,3]oxazine-1(4H)-yl)phenyl)carbamic acid Butyl ester

(3-((2-Chloro-5-(1-hydroxyethyl)pyrimidin-4-yl)amino)phenyl)carbamic acid tert-butyl ester (0.815 g, 2.2 mmol), potassium carbonate (0.455 g, 3.3 mmol), 1,1'-carbonyldiimidazole (1.069 g, 6.6 mmol) in a 25 mL single-necked flask was charged with 10 mL of anhydrous tetrahydrofuran and refluxed overnight. TLC followed the conversion of the starting material, added ice water, extracted with dichloromethane, and the organic layer was collected, dried over anhydrous Na ₂ SO ₄ and evaporated. The crude product was purified by silica gel column chromatography ( petroleum ether / ethyl acetate = 2:1, v/v). (3-(7-Chloro-4-methyl-2-oxo-2H-pyrimido[4,5-d][1,3]oxazin-1(4H)-yl)phenyl)carbamic acid Tert-butyl ester 0.754g.

^{1 H NMR (400MHz, DMSO-} d 6) δ9.59 (s, 1H), 8.54 (s, 1H), 7.61 (s, 1H), 7.41-7.36 (m, 2H), 6.98 (d, J = 6.8 Hz, 1H), 5.86 (q, J = 6.4 Hz, 1H), 1.74 (d, J = 6.4 Hz, 3H), 1.47 (s, 9H). LC-MS: m/z: 391.1 (M+H) ⁺ .

(3-(7-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-4-methyl-2-oxo-2H-pyrimidine[4 ,5-d][1,3]oxazine-1(4H)-yl)phenyl)carbamic acid tert-butyl ester

Weighing (3-(7-chloro-4-methyl-2-oxo-2H-pyrimido[4,5-d][1,3]oxazin-1(4H)-yl)phenyl)amino Tert-butyl formate (0.737 g, 1.89 mmol), 2-methoxy-4-(4-methylpiperazin-1-yl)aniline (0.502 g, 2.27 mmol) in a 50 mL two-necked flask, 15 mL of trifluoroethanol Dissolved, trifluoroacetic acid (210 μL, 2.84 mmol) was added dropwise, argon-protected, and refluxed for 24 hours. TLC feedstock conversion tracking, cooled to room temperature, saturated aqueous NaHCO ₃ until basic. The organic layer was collected, dried over anhydrous Na ₂ SO ₄ and evaporated. The crude product was purified by silica gel column chromatography (dichloromethane/methanol = 30:1, v/v). (3-(7-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-4-methyl-2-oxo-2H-pyrimidine[ 4,5-d][1,3] tert-butyl ester of oxazine-1(4H)-yl)phenyl)carbamate 0.294 g%.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.46 (s, 1H), 8.18 (d, J = 8.8Hz, 1H), 7.79 (s, 1H), 7.74 (s, 1H), 7.24-7.20 (m, 3H), 6.69 (s, 1H), 6.54 (d, J = 2.4 Hz, 1H), 6.50 (dd, J = 8.8 Hz, J = 2.4 Hz, 1H), 4.52 (q, J = 6.8 Hz, 1H) , 3.85 (s, 3H), 3.17 (t, J = 4.4 Hz, 4H), 2.60 (t, J = 4.8 Hz, 4H), 2.36 (s, 3H), 1.51 (s, 9H), 1.49 (d, J=6.0 Hz, 3H). LC-MS: m/z: 576.3 (M+H) ⁺ .

N-(3-(7-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-4-methyl-2-oxo-2H-pyrimidine [4,5-d][1,3]oxazin-1(4H)-yl)phenyl)acrylamide (No. 94)

Weigh (3-(7-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-4-methyl-2-oxo-2H-pyrimidine and [4,5-d][1,3]trozine-1(4H)-yl)phenyl)carbamic acid tert-butyl ester (0.277 g, 0.48 mmol) in 25 mL single-necked flask, dissolved in 6 mL of dichloromethane Add 1 mL of trifluoroacetic acid and stir at room temperature for 5 hours. The TLC tracks the conversion of the starting material and is neutralized to a basic state by adding a saturated aqueous solution of NaHCO ₃ . The organic layer was separated, dried over anhydrous Na ₂ SO ₄ and evaporated.

The previous Boc removal product (0.187 g, 0.39 mmol) was dissolved in dichloromethane (5 mL) and triethylamine (0.060 g, 0.6 mmol) Further, acryloyl chloride (42 μL, 0.51 mmol) was dissolved in 1 mL of dichloromethane, and the mixture was stirred and stirred at room temperature overnight. The TLC tracks the conversion of the starting material and is neutralized to a basic state by adding a saturated aqueous solution of NaHCO ₃ . Extracted with dichloromethane, the organic layer was collected, dried over anhydrous Na ₂ SO _4, solvent was removed by rotary evaporation, the crude product is separated and purified by silica gel column chromatography (dichloromethane / methanol = 20: 1, v / v ). N-(3-(7-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-4-methyl-2-oxo-2H-pyrimidine) And [4,5-d][1,3]oxazine-1(4H)-yl)phenyl)acrylamide 0.091 g.

^{1 H NMR (400MHz, DMSO-} d 6) δ10.46 (s, 1H), 8.23 (s, 1H), 7.85 (d, J = 8.0Hz, 1H), 7.81 (s, 1H), 7.67 (s, 1H), 7.47 (t, J = 8.0 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 8.0 Hz, 1H), 6.56 (d, J = 1.2 Hz, 1H) , 6.48 (dd, J = 16.8 Hz, J = 9.6 Hz, 1H), 6.27 (dd, J = 17.2 Hz, J = 1.6 Hz, 1H), 6.11-6.09 (m, 1H), 5.77 (dd, J = 16.8 Hz, J=1.6 Hz, 1H), 5.73 (q, J=6.4 Hz, 1H), 3.76 (s, 3H), 3.22-3.20 (m, 4H), 3.02-2.99 (m, 4H), 2.61 ( s, 3H), 1.70 (d, J = 6.4 Hz, 3H). HRMS (ESI) (m/z): (M+H) ⁺ calcd for C ₂₈ H ₃₂ N ₇ O ₄ 530.2516, found, 530.2512.

The following compounds were synthesized according to the above procedures a-g:

N-(3-(7-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-4-ethyl-2-oxo-2H-pyrimidine [4,5-d][1,3]oxazin-1(4H)-yl)phenyl)acrylamide (No. 95)

^{1 H NMR (400MHz, DMSO-} d 6) δ10.46 (s, 1H), 8.22 (s, 1H), 7.85 (d, J = 8.4Hz, 1H), 7.81 (s, 1H), 7.66 (s, 1H), 7.47 (t, J = 8.0 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H), 7.09 (d, J = 8.0 Hz, 1H), 6.55 (d, J = 2.0 Hz, 1H) , 6.48 (dd, J = 16.8 Hz, J = 6.8 Hz, 1H), 6.27 (dd, J = 16.8 Hz, J = 1.6 Hz, 1H), 6.10-6.09 (m, 1H), 5.77 (dd, J = 10.0 Hz, J=1.6 Hz, 1H), 5.55 (t, J = 6.8 Hz, 1H), 3.76 (s, 3H), 3.19 (t, J = 4.4 Hz, 4H), 2.92 (t, J = 4.4 Hz) , 4H), 2.56 (s, 3H), 2.09-1.95 (m, 2H), 1.03 (t, J = 7.2 Hz, 3H). HRMS (ESI) (m/z): (M+H) ⁺ calcd for C ₂₉ H ₃₄ N ₇ O ₄ 544.2672, found, 544.2654.

N-(3-(7-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-4-propyl-2-oxo-2H-pyrimidine) [4,5-d][1,3]oxazin-1(4H)-yl)phenyl)acrylamide (No. 96)

^{1 H NMR (400MHz, DMSO-} d 6) δ10.45 (s, 1H), 8.22 (s, 1H), 7.85 (d, J = 8.0Hz, 1H), 7.80 (s, 1H), 7.66 (s, 1H), 7.47 (t, J = 8.0 Hz, 1H), 7.25 (d, J = 8.4 Hz, 1H), 7.08 (d, J = 8.0 Hz, 1H), 6.54 (d, J = 2.0 Hz, 1H) , 6.48 (dd, J = 16.8 Hz, J = 10.0 Hz, 1H), 6.26 (dd, J = 16.8 Hz, J = 1.6 Hz, 1H), 6.10-6.09 (m, 1H), 5.77 (dd, J = 9.6 Hz, J = 1.6 Hz, 1H), 5.60 (t, J = 7.2 Hz, 1H), 3.76 (s, 3H), 3.14 (t, J = 4.4 Hz, 4H), 2.79 (t, J = 4.4 Hz) , 4H), 2.47 (s, 3H), 2.00-1.92 (m, 2H), 1.56-1.44 (m, 2H), 0.99 (t, J = 7.2 Hz, 3H). HRMS (ESI) (m/z) :(M+H) ⁺ calcd for C ₃₀ H ₃₆ N ₇ O ₄ 558.2829,found,558.2836.

N-(3-(7-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-4-isopropyl-2-oxo-2H-pyrimidine) And [4,5-d][1,3]oxazin-1(4H)-yl)phenyl)acrylamide (No. 97)

^{1 H NMR (400MHz, DMSO-} d 6) δ10.52 (s, 1H), 8.22 (s, 1H), 7.87 (d, J = 8.0Hz, 1H), 7.85 (s, 1H), 7.64 (s, 1H), 7.47 (t, J = 8.0 Hz, 1H), 7.26 (d, J = 7.6 Hz, 1H), 7.05 (d, J = 7.6 Hz, 1H), 6.57 (d, J = 1.6 Hz, 1H) , 6.50 (dd, J = 16.8 Hz, J = 10.0 Hz, 1H), 6.26 (dd, J = 16.8 Hz, J = 1.6 Hz, 1H), 6.14-6.10 (m, 1H), 5.77 (dd, J = 10.0 Hz, J = 1.6 Hz, 1H), 5.40 (d, J = 4.8 Hz, 1H), 3.77 (s, 3H), 3.18 (t, J = 4.4 Hz, 4H), 2.74 (s, 3H), 2.27 -2.22 (m, 1H), 1.04 (d, J = 6.8 Hz, 3H), 0.99 (d, J = 6.8 Hz, 3H). HRMS (ESI) (m/z): (M+H) ⁺ calcd for C ₃₀ H ₃₆ N ₇ O ₄ 558.2829, found, 558.2831.

N-(3-(7-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-2-oxo-2H-pyrimido[4,5- d][1,3]oxazin-1(4H)-yl)phenyl)acrylamide (No. 98)

¹ H NMR (400 MHz, CDCl ₃ + CD ₃ OD) δ 8.09 (s, 1H), 7.89 (s, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.47 (t, J = 8.0 Hz, 1H), 7.42-7.39 (m, 1H), 7.07 (d, J = 7.6 Hz, 1H), 6.42-6.38 (m, 2H), 6.15 (d, J = 7.2 Hz, 1H), 5.71 (dd, J = 9.2 Hz, J = 2.8 Hz, 1H), 5.36 (s, 2H), 3.80 (s, 3H), 3.37 (t, J = 4.8 Hz, 4H), 3.24 (t, J = 4.8 Hz, 4H), 2.82 (s, 3H). HRMS (ESI) (m / z): (M + H) ⁺ calcd for C ₂₇ H ₃₀ N ₇ O ₄ 516.2359, found, 516.2364.

The specific synthesis method of compound 006-008 is as follows:

Reagents and conditions: (a) Grignard reagent, THF, 0 ° C, 6 h; (b) CDI, K ₂ CO ₃ , THF, reflux, overnight; (c) arylamine, trifluoroacetic acid, trifluoroethanol, reflux , 24h; (d) trifluoroacetic acid, CH ₂ Cl ₂ , rt, 5h; (e) acryloyl chloride, Et ₃ N, CH ₂ Cl ₂ , 0 ° C to room temperature overnight.

(3-((2-Chloro-5-(2-hydroxypropan-2-yl)pyrimidin-4-yl)amino)phenyl)carbamic acid tert-butyl ester

Ethyl 4-((3-((tert-butoxycarbonyl)amino)phenyl)amino)-2-chloropyrimidine-5-carboxylate (2.352 g, 6 mmol) was weighed in a 50 mL two-neck flask, and 20 mL of anhydrous tetrahydrofuran was added. Dissolved, argon protected, stirred in an ice bath for 10 minutes. Further, methylmagnesium bromide (1 M in THF, 24 mL) was added, and the mixture was slowly added to the reaction mixture, and the mixture was stirred for 6 hours. Conversion of starting material followed by TLC, the reaction mixture was poured into 50mL saturated aqueous solution of NH ₄ Cl, extracted with ethyl acetate, the organic layer was collected, dried over anhydrous Na ₂ SO _4, solvent was removed by rotary evaporation. The crude product was purified by silica gel column chromatography ( petroleum ether / ethyl acetate = 2.5:1, v/v). There was obtained 1.86 g of tert-butyl 3-((2-chloro-5-(2-hydroxypropan-2-yl)pyrimidin-4-yl)amino)phenyl)carbamate.

^{1 H NMR (400MHz, DMSO-} d 6) δ10.01 (s, 1H), 9.41 (s, 1H), 8.12 (s, 1H), 7.62 (t, J = 2.0Hz, 1H), 7.40 (dd, J=8.0 Hz, J=1.2 Hz, 1H), 7.25 (t, J=8.4 Hz, 1H), 7.13 (d, J=8.8 Hz, 1H), 6.43 (s, 1H), 1.56 (s, 6H) , 1.48 (s, 9H). LC-MS: m/z: 379.1 (M+H) ⁺ .

(3-(7-Chloro-4,4-dimethyl-2-oxo-2H-pyrimido[4,5-d][1,3]oxazin-1(4H)-yl)phenyl) Tert-butyl carbamate

(3-((2-Chloro-5-(2-hydroxypropan-2-yl)pyrimidin-4-yl)amino)phenyl)carbamic acid tert-butyl ester (1.512 g, 4 mmol), potassium carbonate (0.828) g, 6 mmol), 1,1'-carbonyldiimidazole (1.296 g, 8 mmol) in a 25 mL single-necked flask was charged with 10 mL of anhydrous tetrahydrofuran and refluxed overnight. TLC followed the conversion of the starting material, added ice water, extracted with dichloromethane, and the organic layer was collected, dried over anhydrous Na ₂ SO ₄ and evaporated. The crude product was purified by silica gel column chromatography ( petroleum ether / ethyl acetate = 2.5:1, v/v). (3-(7-chloro-4,4-dimethyl-2-oxo-2H-pyrimido[4,5-d][1,3]oxazin-1(4H)-yl)phenyl ) tert-butyl carbamate 1.049 g.

^{1 H NMR (400MHz, DMSO-} d 6) δ9.57 (s, 1H), 8.64 (s, 1H), 7.57 (s, 1H), 7.41-7.36 (m, 2H), 7.01-6.99 (m, 1H ), 1.79 (s, 6H), 1.47 (s, 9H). LC-MS: m/z: 405.1 (M+H) ⁺ .

(3-(7-((2-Methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-4,4-dimethyl-2-oxo-2H-pyrimidine And [4,5-d][1,3]oxazine-1(4H)-yl)phenyl)carbamic acid tert-butyl ester

Weighing (3-(7-chloro-4,4-dimethyl-2-oxo-2H-pyrimido[4,5-d][1,3]oxazin-1(4H)-yl)benzene Tert-butyl carbamate (1.010 g, 2.5 mmol), 2-methoxy-4-(4-methylpiperazin-1-yl)phenylamine (0.663 g, 3 mmol) in a 50 mL two-necked flask, 15 mL three The fluoroethanol was dissolved, and trifluoroacetic acid (280 μL, 3.77 mmol) was added dropwise thereto, and the mixture was subjected to argon gas and refluxed for 24 hours. TLC feedstock conversion tracking, cooled to room temperature, saturated aqueous NaHCO ₃ until basic. The organic layer was collected, dried over anhydrous Na ₂ SO ₄ and evaporated. The crude product was purified by silica gel column chromatography (dichloromethane/methanol = 25:1, v/v). (3-(7-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-4,4-dimethyl-2-oxo-2H- Pyrimido[4,5-d][1,3]oxazine-1(4H)-yl)phenyl)carbamic acid tert-butyl ester 0.516 g.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.07 (s, 1H), 7.51 (d, J = 8.4Hz, 2H), 7.47-7.43 (m, 2H), 7.01 (d, J = 7.2Hz, 1H) , 6.45 (s, 1H), 6.44 (d, J = 2.4 Hz, 1H), 6.18-6.16 (m, 1H), 3.82 (s, 3H), 3.16 (t, J = 4.4 Hz, 4H), 2.67 ( t, J = 4.4 Hz, 4H), 2.42 (s, 3H), 1.80 (s, 6H), 1.49 (s, 9H). LC-MS: m/z: 590.4 (M+H) ⁺ .

N-(3-(7-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-4,4-dimethyl-2-oxo-2H -pyrimido[4,5-d][1,3]oxazin-1(4H)-yl)phenyl)acrylamide (No. 99)

Weighing (3-(7-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-4,4-dimethyl-2-oxo-2H -pyrimido[4,5-d][1,3]oxazine-1(4H)-yl)phenyl)carbamic acid tert-butyl ester (0.500 g, 0.85 mmol) in a 25 mL single-neck flask, 6 mL dichloromethane After dissolving, 1 mL of trifluoroacetic acid was added dropwise, and the mixture was stirred at room temperature for 5 hours. The TLC tracks the conversion of the starting material and is neutralized to a basic state by adding a saturated aqueous solution of NaHCO ₃ . The organic layer was separated, dried over anhydrous Na ₂ SO ₄ and evaporated.

The previous Boc product (0.335 g, 0.68 mmol) was dissolved in dichloromethane (5 mL) and triethylamine (0.102 g, 1.02 mmol). Further, acryloyl chloride (72 μL, 0.88 mmol) was dissolved in 1 mL of dichloromethane, and the mixture was stirred and stirred at room temperature overnight. The TLC tracks the conversion of the starting material and is neutralized to a basic state by adding a saturated aqueous solution of NaHCO ₃ . Extracted with dichloromethane, the organic layer was collected, dried over anhydrous Na ₂ SO _4, solvent was removed by rotary evaporation, the crude product is separated and purified by silica gel column chromatography (dichloromethane / methanol = 20: 1, v / v ). N-(3-(7-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-4,4-dimethyl-2-oxo- 2H-pyrimido[4,5-d][1,3]oxazine-1(4H)-yl)phenyl)acrylamide 0.165 g.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.08 (s, 1H), 7.79 (d, J = 8.0Hz, 1H), 7.74 (s, 1H), 7.47 (t, J = 8.0Hz, 1H), 7.38 -7.36 (m, 1H), 7.05 (d, J = 7.6 Hz, 1H), 6.41 (d, J = 2.0 Hz, 1H), 6.36-6.33 (m, 2H), 6.13 (s, 1H), 5.70 ( Dd, J = 9.2 Hz, J = 2.4 Hz, 1H), 3.80 (s, 3H), 3.17 (t, J = 4.4 Hz, 4H), 2.80 (t, J = 4.4 Hz, 4H), 2.50 (s, 3H), 1.80 (s, 6H). HRMS (ESI) (m/z): (M+H) ⁺ calcd for C ₂₉ H ₃₄ N ₇ O ₄ 544.2672, found, 544.2698.

The following 007 and 008 compounds were synthesized according to the method of the above steps a-e:

N-(3-(7-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-4,4-diethyl-2-oxo-2H -pyrimido[4,5-d][1,3]oxazin-1(4H)-yl)phenyl)acrylamide (No. 100)

_{^{1 H NMR (400MHz, CDCl 3}} ) δ9.42 (s, 1H), 7.96 (s, 1H), 7.89 (s, 1H), 7.81 (d, J = 5.6Hz, 1H), 7.53 (s, 1H) , 7.42 (t, J = 8.0 Hz, 1H), 7.33 - 7.31 (m, 1H), 6.99 (d, J = 7.6 Hz, 1H), 6.55-6.49 (m, 1H), 6.36-6.32 (m, 2H) ), 6.12 (d, J = 7.6 Hz, 1H), 5.65 (d, J = 10.4 Hz, 1H), 3.78 (s, 3H), 3.41 (t, J = 4.4 Hz, 4H), 3.21 (t, J = 4.4 Hz, 4H), 2.80 (s, 3H), 2.11-1.96 (m, 4H), 1.00 (t, J = 7.2 Hz, 6H). HRMS (ESI) (m/z): (M+H) ⁺ calcd forC ₃₁ H ₃₈ N ₇ O ₄ 572.2985,found,572.2981.

N-(3-(7-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-4,4-diisopropyl-2-oxo) -2H-pyrimido[4,5-d][1,3]oxazin-1(4H)-yl)phenyl)acrylamide (No. 101)

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.06 (s, 1H), 7.96 (s, 1H), 7.77 (d, J = 4.8Hz, 1H), 7.49 (s, 1H), 7.41 (t, J = 8.0 Hz, 1H), 6.97 (d, J = 8.0 Hz, 1H), 6.40 (d, J = 2.0 Hz, 1H), 6.36 (dd, J = 16.8 Hz, J = 1.2 Hz, 1H), 6.18-6.12 (m, 2H), 5.68 (dd, J = 10.4 Hz, J = 1.2 Hz, 1H), 3.79 (s, 3H), 3.09 (t, J = 4.4 Hz, 4H), 2.58 (t, J = 4.8 Hz) , 4H), 2.36 (s, 3H), 2.07-2.00 (m, 2H), 1.96-1.89 (m, 2H), 1.54-1.38 (m, 4H), 0.97 (t, J = 7.2 Hz, 6H). HRMS (ESI) (m/z): (M+H) ⁺ calcd for C ₃₃ H ₄₂ N ₇ O ₄ 600.3298, found, 600.3297.

The specific synthesis of compounds 132-133 is as follows:

Reagents and conditions: (a) R ¹ NH ₂ , DIPEA, 1,4-dioxane, rt; (b) R ² H ₂ , DIPEA, 1,4-dioxane, rt; (c) Pd /C, H2, EtOH; (d) YCOCOOEt, HOAc, EtOH, reflux.

In the above preparation scheme, R, R1, R2, Y refer to the definition of the corresponding group above. One skilled in the art can prepare the compounds of the present invention by using various starting compounds conventionally obtained in the art as starting materials according to actual preparation needs.

Example 3

The specific synthesis method of the above steps a-d is as follows:

Synthesis of (4-(2-chloro-6-methyl-5-nitropyrimidin-4-amino)phenyl)carbamic acid tert-butyl ester

2,4-Dichloro-6-methyl-5-nitropyrimidine 2.07 g (10 mmol) and potassium carbonate 2.07 g (15 mmol) were weighed into a 250 mL round bottom flask, and 100 mL of dichloromethane was added thereto, and mechanical stirring was carried out at room temperature. Weigh 2.08 g (10 mmol) of (3-aminophenyl)carbamic acid tert-butyl ester in 50 ml of dichloromethane, and slowly add dropwise to the reaction. After the completion of the dropwise addition, continue stirring under ice bath for about 1 hour. TLC traces to complete conversion of the raw materials, directly removes the solvent by rotary evaporation under reduced pressure, recrystallizes with ethanol, and the filter cake is dried and then beaten with 1000 ml of water, and then washed with 500 ml of water to obtain a relatively pure compound (4-(2). -Chloro-6-methyl-5-nitropyrimidine-4-amino)phenyl)carbamic acid tert-butyl ester 3.41 g of an orange solid, yield about 90%.

^{1 H NMR (400MHz, DMSO-} d 6): δ9.91 (s, 1H), 9.43 (s, 1H), 7.64 (s, 1H), 7.27-7.31 (m, 1H), 7.23-7.24 (m, 2H), 2.55 (s, 3H), 1.48 (s, 9H).

(3-((2-(2-methoxy-4-(4-methylpiperazinyl)phenyl)amino)-6-methyl-5-nitropyrimidin-4-yl)amino)benzene Synthesis of tert-butyl carbamate

2.21 g (10 mmol) of 2-methoxy-4-(4-methyl-1-piperazine)phenylamine, 2.58 g (20 mmol) of N,N-diisopropylethylamine, (3-(2- Chloro-5-nitropyrimidine-4-amino)phenyl)carbamic acid tert-butyl ester 3.79g (10mmol) was placed in a 250ml round bottom flask, dissolved in 100ml of tetrahydrofuran, protected with argon, heated to reflux overnight, TLC traced to the starting material Complete conversion. Approximately 70 ml of the solvent was removed by rotary evaporation, the solid was filtered with suction, and the filter cake was washed with 50 ml of tetrahydrofuran. The solvent was evaporated to remove most of the solvent, then poured into water, and a reddish brown solid was precipitated, suction filtered, washed with deionized water and dried. Purification by dichloromethane/methanol to give (3-((2-(2-methoxy-4-(4-methylpiperazinyl))phenyl)amino)-6-methyl-5-nitro Pyrimidine-4-yl)amino)phenyl)carbamic acid tert-butyl ester reddish brown solid 91g, yield about 71%.

^{1 H NMR (400MHz, DMSO-} d 6): δ10.27 (s, 1H), 9.42 (s, 1H), 8.86 (s, 1H), 7.52 (s, 1H), 7.39 (d, J = 8.0Hz , 1H), 7.19 (s, 2H), 7.09 (s, 1H), 6.60 (s, 1H), 6.32 (s, 1H), 3.76 (s, 3H), 3.42 (s, 3H), 3.15 (s, 4H), 2.61 (s, 4H), 2.27 (s, 3H), 1.47 (s, 9H).

(3-((5-Amino-2-((2-methoxy-4-(4-methylpiperazinyl)phenyl)amino)-6-methylpyrimidin-4-yl)amino)phenyl) Synthesis of tert-butyl carbamate

Weighing (3-((2-(2-methoxy-4-(4-methylpiperazinyl)phenyl)amino)-6-methyl-5-nitropyrimidin-4-yl)amino) Phenyl)carbamic acid tert-butyl ester (5.64 g, 10 mmol), palladium carbon catalyst (0.56 g, 0.5 mmol, 10% Pd) in a 500 mL round bottom flask, dissolved in 100 mL of methanol and 200 ml of dichloromethane, Hydrogen was reacted at room temperature for 12 hours. The TLC was used to track the conversion of the starting material, suction filtration, the filtrate was spun dry, and the crude product was recrystallized from ethanol to give (3-((5-amino-4-((2-methoxy-4-(4-methylpiperazinyl))benzene) Tert-butyl)amino)-6-methylpyrimidin-4-yl)amino)phenyl)carbamic acid tert-butyl ester white solid 4.86 g, yield 91%.

^{1 H NMR (400MHz, DMSO-} d 6) δ10.27 (s, 1H), 9.42 (s, 1H), 8.87 (d, J = 8.0Hz, 1H), 7.53 (s, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.16 (t, J = 8.0 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), 6.60 (d, J = 2.4 Hz, 1H), 6.38 (dd, J = 8.8 Hz, J = 2.4 Hz, 1H), 4.39 (s, 2H), 3.76 (s, 3H), 3.42 (s, 3H), 3.07 (t, J = 4.4 Hz, 4H), 2.48 (t, J = 4.4 Hz, 4H), 2.25 (s, 3H), 1.48 (s, 9H).

(3-(2-((2-methoxy-4-(4-methyl-1-piperazinyl)phenyl)amino)-4-methyl-7-oxo-6-phenyl-8) Synthesis of (7H)-pteridinylphenyl)carbamic acid tert-butyl ester

Weighing (3-((5-amino-2-((2-methoxy-4-(4-methylpiperazinyl)phenyl)amino)-6-methylpyrimidin-4-yl)amino)benzene 2.67 g (5 mmol) of tert-butyl carbamate was placed in a 250 mL round bottom flask, 10 mL glacial acetic acid, 150 mL absolute ethanol was added, then 890 mg (5 mmol) of ethyl benzoylformate was added, and heated to reflux for about 8 h. TLC tracks to complete conversion of the feedstock. After completion of the reaction, the solvent was removed by rotary evaporation, and a small amount of ethanol was added thereto, and the mixture was filtered with suction. The filter cake was washed with ethanol, aqueous ammonia, and deionized water, and dried. If there is an impurity, it is washed once with ethanol to obtain (3-(2-((2-methoxy-4-(4-methyl-1-piperazinyl)phenyl)amino)-4-methyl-) tert-Butyl 7-oxo-6-phenyl-8(7H)-pteridinyl)phenyl)carbamate Red orange solid 2.2 g, yield 70%.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.64 (s, 1H), 8.24 - 8.26 (m, 2H), 8.21. (s, 1H), 7.59 (s, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.47-7.50 (m, 3H), 7.44 (d, J = 8.0 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.00 (d, J = 8.0 Hz, 1H) , 6.54 (s, 1H), 6.07 (br, 1H), 3.79 (s, 3H), 3.07 (br, 4H), 2.71 (s, 3H), 2.46 (br, 4H), 2.24 (s, 3H), 1.45 (s, 9H).

8-(3-Aminophenyl)-2-((2-methoxy-4-(4-methyl-1-piperazinyl)phenyl)amino)-4-methyl-6-phenyl- Synthesis of 7(8h)-acridone

Weighing (3-(2-((2-methoxy-4-(4-methyl-1-piperazinyl)phenyl)amino)-4-methyl-7-oxo-6-phenyl) -8(7H)-pteridinylphenyl)carbamic acid tert-butyl ester 6.48 g (10 mmol) was placed in a 250 mL round bottom flask, and 100 mL of dichloromethane was added thereto, and stirred at 0 ° C, and 25 mL of trifluoroacetic acid was added dropwise. Then, the mixture was stirred under an ice bath for 0.5 h, stirred at room temperature for 2 h, and TLC was followed until complete conversion of the starting material. After the reaction is completed, the solvent is directly removed by rotary evaporation, dissolved in water, neutralized with a saturated sodium hydrogencarbonate solution until the solution is alkaline, a large amount of solid is precipitated, suction filtration, and the filter cake is washed with deionized water and dried to obtain 8-(3) -aminophenyl)-2-((2-methoxy-4-(4-methyl-1-piperazinyl)phenyl)amino)-4-methyl-6-phenyl-7 (8h) - Acridone red solid 4.99 g, yield 91%.

1H NMR (400MHz, DMSO-d 6): δ9.64 (s, 1H), 8.24-8.26 (m, 2H), 8.21 (s, 1H), 7.59 (s, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.47-7.50 (m, 3H), 7.44 (d, J = 8.0 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.00 (d, J = 8.0 Hz, 1H), 6.54 (s, 1H), 5.32 (s, 2H), 3.79 (s, 3H), 3.07 (br, 4H), 2.71 (s, 3H), 2.46 (br, 4H), 2.24 (s, 3H), 1.45 (s, 9H).

N-(3-(2-((2-methoxy-4-(4-methyl-1-piperazinyl)phenyl)amino)-4-methyl-7-oxo-6-phenyl) Synthesis of -8(7H)-pteridinylphenyl)acrylamide (No. 102)

Weigh 8-(3-aminophenyl)-2-((2-methoxy-4-(4-methyl-1-piperazinyl)phenyl)amino)-4-methyl-6-benzene Base-7(8h)-acridone 1.4g (2.55mmol) was placed in a 100mL round bottom flask, 3mL N-methylpyrrolidone was added, stirred under ice bath, and 275mg (3.06mmol) of acryloyl chloride was dissolved in 20mL acetonitrile. The mixture was added dropwise to the above reaction solution. After the completion of the dropwise addition, the mixture was stirred for 0.5 hour under ice-cooling, and stirred at room temperature for 3 hr. The reaction solution was rotary evaporated to remove the solvent, and then added dropwise to aqueous sodium hydrogencarbonate, and a red solid was precipitated, filtered, filtered, washed with deionized water, dried and purified by dichloromethane/methanol to afford N-(3-( 2-((2-Methoxy-4-(4-methyl-1-piperazinyl)phenyl)amino)-4-methyl-7-oxo-6-phenyl-8(7H)- Pteridine)phenyl)acrylamide orange red solid 1.0 g, yield 67%.

1H NMR (400MHz, DMSO-d 6): δ10.40 (s, 1H), 8.25-8.27 (m, 2H), 8.20 (s, 1H), 7.90 (d, J = 8.0Hz, H), 7.72 ( s, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.48-7.50 (m, 3H), 7.38 (d, J = 8.0 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 6.53 (d, J = 4.0 Hz, 1H), 6.46 (q, J = 8.0, 1H), 6.27 (dd, J = 8.0, 4.0 Hz, 1H), 6.03 (br, 1H), 5.78 (dd, J = 8.0, 4.0 Hz, 1H), 3.78 (s, 3H), 3.03 (br, 4H), 2.72 (s, 3H), 2.44 (t, J = 4.0 Hz, 4H), 2.23 (s, 3H).

N-(3-(6-(4-fluoro-phenyl)-2-((2-methoxy-4-(4-methyl-1-piperazinyl)phenyl)amino)-4-) Synthesis of yl-7-oxo-8(7H)-pteridinyl)phenyl)acrylamide (No. 103)

Reddish brown solid with a yield of 61%.

1H NMR (400MHz, DMSO-d ₆ ): δ 10.48 (s, 1H), 8.33 - 8.37 (m, 2H), 8.22 (s, 1H), 7.91 (d, J = 8.0 Hz, H), 7.74 ( s, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.30-7.38 (m, 3H), 7.12 (d, J = 8.0 Hz, 1H), 6.53 (s, 1H), 6.48 (q, J) = 8.0, 1H), 6.27 (dd, J = 8.0, 2.0 Hz, 1H), 6.01 (br, 1H), 5.78 (d, J = 8.0 Hz, 1H), 3.77 (s, 3H), 3.06 (br, 4H), 2.70 (s, 3H), 2.53 (br, 4H), 2.29 (s, 3H).

The specific synthesis of compounds 134-137 is as follows:

Reagents and conditions: (a) R ¹ NH ₂ , DIPEA, acetonitrile, reflux, 6h.; (b) lithium aluminum hydride, THF, 0 ° C, 4h.; (c) manganese dioxide, dichloromethane, 6h; d) Grignard reagent, THF, 0 ° C, 4 h; (e) manganese dioxide manganese dioxide, dichloromethane, 6 h; (f) YCH ₂ COOEt, K ₂ CO ₃ , DMF, 8 h; (g) m- CPBA, dichloromethane, 12 h; (h) R ² NH ₂ , TFA, 2-Butanol, 110 °C.

In the above preparation scheme, R ¹ , R ² , R ⁵ and Y refer to the definition of the corresponding group above. One skilled in the art can prepare the compounds of the present invention by using various starting compounds conventionally obtained in the art as starting materials according to actual preparation needs.

Example 4

The specific synthesis method of the above steps a-d is as follows:

Synthesis of 4-(3-tert-butoxycarbonylaminoaniline)-2-methylthiopyrimidine-5-ethyl carbonate

2.33 g (10 mmol) of 4-chloro-2-methylthiopyrimidine-5-ethyl carbonate, 2.08 g (10 mmol) of (3-aminophenyl)carbamic acid tert-butyl ester, and 2.88 g (20 mmol) of DIPEA were weighed. In a 250 ml flask, 80 ml of acetonitrile was added to dissolve, and then heated to reflux. After about 4 hours of reaction, TLC was traced to complete conversion of the starting material, the reaction was stopped, cooled to room temperature, directly filtered, cold acetonitrile washing cake was filtered three times, and the filter cake was baked in an infrared oven. Dry, to give pure 4-(3-tert-butoxycarbonylaminoaniline)-2-methylthiopyrimidine-5-ethyl carbonate as a white solid, 3.84 g,yield 95%.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ10.37 (s, 1H), 8.76 (s, 1H), 7.90 (s, 1H), 7.34 (d, J = 8.0Hz, 1H), 7.24 (t, J = 8.0 Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H), 6.53 (s, 1H), 4.38 (q, J = 8.0 Hz, J = 16.0 Hz, 2H), 2.55 (s, 3H), 1.52 (s, 9H), 1.40 (t, J = 8.0 Hz, 3H).

Synthesis of (tert-Butyl-3-(5-(hydroxymethyl)-2-(methylthio)pyrimidine-4-substituted amino)benzamide carbonate

Weighed 2.02 g (5 mmol) of 4-(3-tert-butoxycarbonylaminoaniline)-2-methylthiopyrimidine-5-ethyl carbonate in a 250 ml flask, and dissolved in 50 ml of anhydrous tetrahydrofuran under ice bath conditions. 20 ml of LiAlH ₄ (1M in THF) was slowly added dropwise, and the reaction was continued for 0.5 hour under ice bath. TLC was followed until complete conversion of the starting material, then saturated ammonium chloride was added to the reaction to stop the reaction, and the tetrahydrofuran was removed by rotary evaporation. The mixture was extracted with EtOAc. EtOAc (EtOAc m.j. Butyl-3-(5-(hydroxymethyl)-2-(methylthio)pyrimidine-4-substituted amino)benzamide carbonate white solid 760 mg, yield 42%.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.02 (s, 1H), 7.86 (s, 1H), 7.80 (s, 1H), 7.36 (dd, J = 4.0,8.0Hz, 1H), 7.22 (t, J = 8.0 Hz, 1H), 6.95 (dd, J = 4.0, 8.0 Hz, 1H), 6.52 (s, 1H), 4.61 (s, 2H), 2.52 (s, 3H), 1.52 (s, 9H).

Synthesis of tert-butyl 3-((5-formyl-2-(methylthio)pyrimidine-4-substituted)amino)phenyl)carbamate

Weigh 362 mg (1 mmol) of (tert-butyl-3-(5-(hydroxymethyl))-2-(methylthio)pyrimidine-4-substituted amino)benzamide carbonate in a 100 ml flask, add 50 ml of dichloro The methane was dissolved, and then 870 mg (10 mmol) of activated manganese dioxide was added and stirred at room temperature for about 4 hours. TLC was traced until the starting material was completely converted, the diatomaceous earth was filtered off with suction, and the solvent was evaporated to remove the solvent. The crude product was purified by silica gel column chromatography. Ethyl ester = 10:1, v/v) afforded 3-((5-formyl-2-(methylthio)pyrimidine-4-substituted)amino)phenyl)carbamic acid tert-butyl ester as pale yellow solid 306mg The yield is 85%.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ10.61 (s, 1H), 9.77 (s, 1H), 8.43 (s, 1H), 7.98 (s, 1H), 7.36 (dd, J = 4.0,8.0Hz, 1H), 7.25-7.29 (m, 1H), 7.03 (dd, J = 4.0, 8.0 Hz, 1H), 6.51 (s, 1H), 2.59 (s, 3H), 1.53 (s, 9H).

Synthesis of tert-butyl 3-(2-(methylthio)-7-oxopyrido[2,3-d]pyrimidine-8(7H)-substituted)phenyl)carbamate

3-((5-Formyl-2-(methylthio)pyrimidine-4-substituted)amino)phenyl)carbamic acid tert-butyl ester 360 mg (1 mmol) and (EtO) ₂ P(O)CH ₂ CO ₂ Et was dissolved in 50 ml of anhydrous THF in a 100 ml flask, then 48 mg of NaH (2 mmol) was added in an ice bath. After the addition, the mixture was stirred at room temperature for about 4 hours. TLC was traced to complete conversion of the starting material, and the mixture was slowly diluted with water, and the filtrate was evaporated. The solvent was removed, and the crude was purified mjjjjjjjjjjjjjjjjjj d] Pyrimidine-8(7H)-substituted)phenyl)carbamic acid tert-butyl ester 270 mg,yield 71%.

_{^{1 H NMR (500MHz, CDCl 3}} ) δ9.10 (s, 1H), 8.09 (dt, J = 7.5,2.0Hz, 1H), 7.72 (t, J = 2.0Hz, 1H), 7.56 (d, J = 11.0 Hz, 1H), 7.41 (t, J = 7.4 Hz, 1H), 7.34 (dt, J = 7.5, 2.0 Hz, 1H), 6.65 (s, 1H), 6.44 (d, J = 10.8 Hz, 1H) , 2.54 (s, 3H), 1.50 (s, 9H).

Synthesis of tert-butyl 3-(2-(methylsulfonyl)-7-oxopyrido[2,3-d]pyrimidine-8(7H)-substituted)phenyl)carbamate

3-(2-(methylsulfonyl)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-substituted)phenyl)carbamic acid tert-butyl ester 922 mg (2.4 mmol) in 100 ml The flask was dissolved in 60 ml of dichloromethane, and 1.24 g (7.2 mmol) of m-CPBA was added in portions under ice-cooling for 30 min. After the addition, the mixture was slowly warmed to room temperature and stirred for about 8 hours. TLC was traced until the starting material was completely converted, and 30 ml was added. saturated Na ₂ S ₂ O ₃ and stirring was continued for half an hour, extracted with methylene chloride, dried over anhydrous sodium sulfate, and the solvent removed by rotary, the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 evaporated: 1, v / v Separation to give 3-(2-(methylsulfonyl)-7-oxopyrido[2,3-d]pyrimidine-8(7-hydro)-substituted)phenyl)carbamic acid tert-butyl ester 808 mg, The yield was 81%.

^{1 H NMR (500MHz, CDCl3)} δ9.17 (s, 1H), 8.30 (t, J = 2.0Hz, 1H), 7.61-7.55 (m, 2H), 7.39 (t, J = 7.5Hz, 1H), 7.16 (dt, J = 7.5, 2.0 Hz, 1H), 6.63 (s, 1H), 6.44 (d, J = 10.8 Hz, 1H), 3.25 (s, 3H), 1.50 (s, 9H).

(3-(2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2,3-d]pyrimidine-8 Synthesis of (7-hydrogen)-substituted)phenyl)carbamic acid tert-butyl ester

3-(2-(methylthio)-7-oxopyrido[2,3-d]pyrimidine-8(7H)-substituted)phenyl)carbamic acid tert-butyl ester 808 mg (1.94 mmol), 2 -Methoxy-4-(4-methylpiperazine-1-substituted) aniline 430 mg (1.94 mmol) in a 100 ml flask, dissolved in 50 ml of sec-butanol, then TFA 145 μl (1.94 mmol), 110 The mixture was heated and stirred for about 12 hours at °C, and the residue was completely purified by TLC. The solvent was removed by rotary evaporation. The crude product was purified by silica gel column chromatography (dichloromethane/methanol = 30:1, v/v) to give (3-(2- ((2-Methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2,3-d]pyrimidine-8(7-hydrogen)-substitution Phenyl)carbamic acid tert-butyl ester yellow solid 756mg, yield 70%.

¹ H NMR (500MHz, CDCl ₃ ) δ 8.71 (s, 1H), 8.53 (t, J = 1.9 Hz, 1H), 7.56 (d, J = 10.8 Hz, 1H), 7.46-7.35 (m, 2H) , 7.24 (dt, J = 7.3, 2.1 Hz, 1H), 6.91 (d, J = 7.5 Hz, 1H), 6.60 (s, 1H), 6.44 (d, J = 10.8 Hz, 1H), 6.40 - 6.31 ( m, 2H), 5.10 (s, 1H), 3.94 (s, 3H), 3.20 (t, J = 5.2 Hz, 4H), 2.98 (t, J = 5.1 Hz, 4H), 2.60 (s, 3H), 1.50 (s, 9H).

8-(3-Aminophenyl)-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[2,3-d]pyrimidine- Synthesis of 7(8H)-one

(3-(2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2,3-d]pyrimidine- 8(7H)-substituted)phenyl)carbamic acid tert-butyl ester 756mg (1.36mmol) in a 50ml flask, dissolved in 16ml of dichloromethane, then added 4ml of TFA, stirred at room temperature for 4h, TLC tracking to complete conversion of the starting material, rotation The solvent was evaporated, and the crude was purified mjjjjjjjjjjjjjjjj (4-Methylpiperazin-1-yl)phenyl)amino)pyrido[2,3-d]pyrimidin-7(8-hydro)-one yellow solid 571 mg, yield 92%.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.71 (s, 1H), 8.08 (s, 1H), 7.78 (d, J = 9.6, 1H), 7.45 (d, J = 8.8, 1H), 7.18 (t, J = 8.0 Hz, 1H), 6.71 (d, J = 8.4 Hz, 1H), 6.55 (d, J = 2.4 Hz, 2H), 6.36 - 6.41 (m, 3H), 6.15 (br, 1H) , 5.25 (br, 2H), 3.79 (s, 3H), 3.06 (t, J = 4.8 Hz, 4H), 2.45 (t, J = 4.8 Hz, 4H), 2.23 (s, 3H).

N-(3-(2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2,3-d]pyrimidine Synthesis of -8(7-hydrogen)-substituted)phenyl)acrylamide (No. 104)

8-(3-Aminophenyl)-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[2,3-d]pyrimidine -7 (8-hydro)-ketone 571 mg (1.25 mmol) was dissolved in 20 ml of anhydrous dichloromethane in a 50 ml flask, and 225 mg (2.5 mmol) of acryloyl chloride was slowly added dropwise to the system at 0 ° C. 4h, TLC was traced to complete conversion of the starting material, and the solvent was removed by rotary evaporation. The crude product was separated by silica gel column chromatography (dichloromethane/methanol=30:1, v/v) to give N-(3-(2-((2-) Methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2,3-d]pyrimidine-8(7H)-substituted)phenyl) Acrylamide yellow solid 316mg, yield 62%.

^{1 H NMR (400MHz, DMSO-} d 6) δ10.34 (s, 1H), 8.74 (s, 1H), 8.15 (s, 1H), 7.86-7.92 (m, 2H), 7.60 (s, 1H), 7.51 (t, J = 8.0 Hz, 1H), 7.29 (d, J = 8.8 Hz, 1H), 7.01 (d, J = 8.0 Hz, 1H), 6.52 (d, J = 1.6 Hz, 1H), 6.40- 6.47 (m, 2H), 6.28 (dd, J = 1.6, 17.2 Hz, 1H), 6.02 (br, 1H), 5.78 (m, 1H), 3.77 (s, 3H), 3.03 (m, 4H), 2.44 (m, 4H), 2.03 (s, 3H).

N-(3-(2-(2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-methyl-7-oxopyridine[2, Synthesis of 3-d]pyrimidine-8(7H)-substituted)phenyl)acrylamide (No. 105)

^{1 H NMR (400MHz, DMSO-} d 6) δ10.33 (s, 1H), 8.80 (s, 1H), 8.09 (s, 1H), 7.89 (d, J = 6.8Hz, 1H), 7.56 (s, 1H), 7.50 (t, J = 8.0 Hz, 1H), 7.28 (d, J = 8.8 Hz, 1H), 6.98 (d, J = 7.6 Hz, 1H), 6.51 (s, 1H), 6.47 (dd, J=1.6, 17.2 Hz, 1H), 6.32 (s, 1H), 6.27 (d, J = 6.8 Hz, 1H), 6.01 (br, 1H), 5.78 (m, 1H), 3.78 (s, 3H), 3.03 (m, 4H), 2.43 - 2.46 (m, 7H), 2.03 (s, 3H).

N-(3-(2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxo-5-phenylpyrido[2, Synthesis of 3-d]pyrimidine-8(7H)-substituted)phenyl)acrylamide (No. 106)

^{1 H NMR (400MHz, DMSO-} d 6) δ10.45 (s, 1H), 8.42 (s, 1H), 8.27 (s, 1H), 7.90 (s, 1H), 7.52-7.67 (m, 8H), 7.29 (d, J = 8.8 Hz, 1H), 7.07 (d, J = 7.6 Hz, 1H), 6.57 (s, 1H), 6.51 (dd, J = 10.0, 16.8 Hz, 1H), 6.39 (s, 1H) ), 6.29 (dd, J = 2.0, 10.0 Hz, 1H), 6.10 (br, 1H), 5.79 (dd, J = 2.0, 16.8 Hz 1H), 3.78 (s, 3H), 2.96 (m, 4H), 2.43 (s, 3H).

N-(3-(2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-methyl-7-oxo-6-phenyl) Synthesis of pyrido[2,3-d]pyrimidine-8(7H)-substituted)phenyl)acrylamide (No. 107)

^{1 H NMR (400MHz, DMSO-} d 6) δ10.34 (s, 1H), 8.89 (s, 1H), 8.11 (s, 1H), 7.87 (d, J = 8.0Hz, 1H), 7.64 (s, 1H), 7.51 (t, J = 8.0 Hz, 1H), 7.44 (t, J = 7.2 Hz, 1H), 7.34 - 7.38 (m, 1H), 7.29 - 7.31 (m, 3H), 7.04 (d, J) = 8.0 Hz, 1H), 6.53 (d, J = 1.6 Hz, 1H), 6.47 (dd, dd, J = 17.2, 10.0 Hz, 1H), 6.27 (dd, J = 1.6, 16.8 Hz, 1H), 6.03 (br,1H), 5.78 (dd, J=1.6, 10.0 Hz 1H), 3.79 (s, 3H), 3.03 (m, 4H), 2.44-2.45 (m, 4H), 2.30 (s, 3H), 2.23 (s, 3H).

All documents mentioned in the present application are hereby incorporated by reference in their entirety in their entireties in the the the the the the the the In addition, it should be understood that various modifications and changes may be made by those skilled in the art in the form of the appended claims.

Claims (14)

1. Use of a compound of formula I or a salt thereof for the preparation of a Bruton's tyrosine kinase inhibitor or for the preparation of a medicament for the treatment or prevention of Bruton's tyrosine kinase mediated disease:

   

   In the formula,

   R is hydrogen, C ₁ -C ₃ lower alkyl, C ₁ -C ₃ lower alkoxy, halogen (eg, F, Cl, Br), amino, substituted amino;

   X is N or CR ⁵ R ⁶ ;

   Y is C or O;

   When X is N,

   

   Is a double bond, and Y is C;

   When X is CR ⁵ R ⁶ ,

   

   Is a single bond, and Y is O; or when X is CR ⁵ R ⁶

   

   Is a double bond, and Y is C;

   B is selected from the group consisting of an optionally substituted (C3-C8)cycloalkyl, (C3-C8)heterocyclyl, (C6-C10)aryl or (C5-C10)arylheterocyclyl;

   R ^{1 is} selected from the group consisting of: H, an optionally substituted C ₁ -C ₆ alkyl group, NR ⁷ R ⁸ , an optionally substituted C ₆ -C ₁₀ aryl group;

   R ^{3 is} selected from the group consisting of hydrogen, optionally substituted C ₁ -C ₁₀ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, optionally substituted C ₃ -C ₈ cycloalkyl, any A substituted C ₁ -C ₁₀ alkoxy group, an optionally substituted aryl group, an optionally substituted benzyl group, an optionally substituted heterocyclic group, an optionally substituted aromatic heterocyclic group, -O-(CH) _z -OC ₁ -C ₃ alkyl; z is an integer from 1 to 3, preferably 1;

   R ^{4 is} selected from the group consisting of hydrogen, optionally substituted C ₁ -C ₆ alkyl, nitro, amino, halogen, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted acyloxy, optionally substituted Amido, optionally substituted acyl;

   m is independently an integer from 0 to 7, preferably from 1 to 7, more preferably from 1 to 3;

   R ⁵ and R ⁶ are each independently H, or C ₁ -C ₆ alkyl (preferably C ₁ -C ₃ alkyl);

   R ⁷ and R ⁸ are each independently H or a C ₁ -C ₆ alkyl group.
2. The compound of claim 1 wherein B is selected from the group consisting of

   

   

   R ^{4 is} selected from:

   

   
3. The use according to claim 1 or 2, wherein the compound is represented by the following formula I-1:

   

   In the formula,

   A is a benzene ring, a five- or six-membered heterocyclic ring, a C ₃ -C ₈ cycloalkyl group or R';

   When A is R', n is 0, and R' is selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl or C ₆ -C ₁₀ arylformyl;

   R ^{2 is} selected from the group consisting of hydrogen, halogen, optionally substituted C ₁ -C ₆ alkoxy, hydroxy, optionally substituted acyloxy, amino, optionally substituted acylamino, optionally substituted C ₁ -C ₆ Alkyl, CN, sulfonate, aminosulfonyl, carbamoyl, carboxy, optionally substituted alkoxycarbonyl, optionally substituted phenyl, optionally substituted N-alkylpiperazinyl, optionally substituted Morpholinyl, optionally substituted piperidinyl, optionally substituted pyrrolyl, optionally substituted pyrrolidinyl, -NR _a R _b , optionally substituted pyridyl; R _a and R _b are each independently selected from Alkyl and alkenyl;

   n is independently an integer from 0 to 7, preferably from 1 to 7, more preferably from 1 to 3;

   X, Y, B, R ¹ , R ³ , R ⁴ and m are as defined in claim 1.
4. The use according to claim 3, wherein the compound is represented by the following formula II-1:

   

   In the formula,

   B, R ² , R ³ , R ⁴ , m and n are as defined in claim 3;

   Alternatively, the compound is represented by the following formula II-2:

   

   In the formula,

   B, R ² , R ⁴ , R ⁵ , R ⁶ , m and n are as defined in claim 3;

   Alternatively, the compound is as shown in the following formula II-3:

   

   In the formula,

   B, R ¹ , R ² , R ³ , R ⁴ , m and n are as defined in claim 3.
5. The use according to claim 4, characterized in that

   In formula II-1,

   R ^{2 is} selected from the group consisting of hydrogen, halogen, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted pyrrolidinyl, -NR _a R _b , carbamoyl, optionally substituted acylamino, -(CH ₂ ) _o - an optionally substituted N-alkylpiperazinyl group, an optionally substituted morpholino group, an optionally substituted piperidinyl group, o is an integer of 0-2, and R _a and R _b are each independently selected from C _{a 1-} C ₃ alkyl group; wherein R ^{2 is} not at the 2-position of the benzene ring where it is located;

   R ^{3 is} selected from the group consisting of: hydrogen, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₆ -C ₁₀ aryl, optionally substituted C ₃ -C ₈ cycloalkyl;

   B is selected from a benzene ring or a nitrogen-containing five-membered ring;

   R ^{4 is} selected from the group consisting of: an optionally substituted acylamino group, an optionally substituted acyl group;

   m and n are as defined in claim 4;

   In formula II-2,

   R ⁵ and R ^{6 are} independently selected from H, substituted or unsubstituted C ₁ -C ₆ (preferably C ₁ -C ₃ )alkyl;

   B is a benzene ring;

   R ^{2 is} selected from the group consisting of: an optionally substituted C ₁ -C ₆ alkyl group (preferably a C ₁ -C ₃ alkyl group), an optionally substituted N-alkyl piperazinyl group, an optionally substituted C ₁ -C ₆ alkoxy group Base (preferably C ₁ -C ₃ alkoxy);

   R ^{4 is} selected from the group consisting of: an optionally substituted acylamino group;

   m and n are as defined in claim 4.
6. Use of a compound selected from the group consisting of a compound or a pharmaceutically acceptable salt thereof for the preparation of a Bruton tyrosine kinase inhibitor or a medicament for the treatment or prevention of a Bruton's tyrosine kinase mediated disease:

   

   

   

   

   

   

   

   

   

   

   
7. The use according to any one of claims 1 to 6, wherein the Bruton's tyrosine kinase-mediated disease is cancer or an autoimmune disorder.
8. The use according to claim 7, wherein the cancer is selected from the group consisting of acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), mantle cell lymphoma (MCL), and colorectal cancer; Autoimmune disorders include rheumatoid arthritis, anti-organ transplant rejection, anti-psoriasis, and lupus erythematosus.
9. A method of treating or preventing a Bruton's tyrosine kinase-mediated disease, comprising administering a compound according to any one of claims 1 to 6 or a pharmaceutical composition comprising the compound to a subject in need thereof.
10. a compound of formula I or a pharmaceutically acceptable salt thereof:

    

    In the formula,

    X, Y, B, R ¹ , R ³ , R ⁴ and m are as defined in claim 1 or 2;

    among them,

    R is hydrogen, C ₁ -C ₃ lower alkyl, C ₁ -C ₃ lower alkoxy, halogen (for example, F, Cl, Br), amino or NR ^c R ^d , and R ^c , R ^{d are} independently selected from H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl or (C ₆ -C ₁₀ ) arylcarbonyl;

    and / or

    R ^{3 is} selected from the group consisting of hydrogen, (C ₃ -C ₆ )cycloalkyl, (C ₁ -C ₈ )heterocyclyl, (C ₁ -C ₈ )alkoxy, -O-(CH) _n - OC ₁ -C ₃ alkyl, benzyl, (C ₆ -C ₁₀ )aryl or (C ₅ -C ₁₀ )arylheterocyclyl, wherein the aryl and aromatic heterocyclic groups may optionally be one Substituted to five or less groups: halogen, nitro, cyano, hydroxy, amino, (C ₁ -C ₈ )alkyl, (C ₁ -C ₈ )alkoxy, (C ₃ -C ₆ )cycloalkane , (C ₆ -C ₁₀ ) aryloxy, (C ₅ -C ₁₀ )heterocyclyl, -O-(CH) _z -OC ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyloxy , C ₃ -C ₆ heterocycloalkyloxy, amide, optionally substituted carbamoyl; z is an integer from 1 to 3, preferably 1;

    and / or

    R ^{4 is} selected from the group consisting of:

    

    
11. The compound according to claim 10 or a salt thereof, wherein the compound is represented by the following formula I-1:

    

    In the formula,

    A is R', n is 0, and R' is selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl or (C ₆ -C ₁₀ ) arylcarbonyl;

    X, Y, B, R ¹ , R ³ , R ⁴ and m are as defined in claim 10.
12. The compound according to claim 11, wherein R' is a C ₁ -C ₆ alkyl group (preferably a C ₁ -C ₃ alkyl group), a C ₁ -C ₆ haloalkyl group (preferably a C ₁ -C ₃ haloalkyl group). ).
13. The compound according to any one of claims 10 to 12, wherein R ^{3 is} selected from the group consisting of

    
14. The compound of claim 13 wherein R ³ is: