WO2014023083A1 - PI3Kδ INHIBITOR - Google Patents

Abstract

Disclosed are a PI3Kδ inhibitor compound of formula (I), pharmaceutically acceptable salts, stereoisomers or deuterated compounds thereof, preparation methods of these compounds, a pharmaceutical preparation containing these compounds, and the use thereof for preparing a medicine for treating inflammatory disorders or tumours.

Description

 PI3K6 inhibitor ι, technical field

 The invention belongs to the technical field of medicine, and particularly relates to an ΡΒΚδ inhibitor, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a progeny thereof, a preparation method of the compound, a pharmaceutical preparation containing the same, and a preparation of the compound in the preparation Use in inflammatory diseases or drugs for tumors.

2. Background technology

 A tumor is a new organism formed by the body under the action of various tumorigenic factors, causing changes in cellular genetic material, resulting in abnormal gene expression and abnormal cell proliferation. Tumor cells lose normal growth regulation and have the ability to grow autonomously or relatively independently. When the tumorigenic factors stop, they can continue to grow and consume a lot of nutrients. If found and treated in time, cancer cells can be transferred to all parts of the body to grow and reproduce, and release a variety of toxins, leading to weight loss, anemia, and impaired organ function to death.

 The method of tumor treatment mainly includes three aspects: drug treatment, surgical treatment and radiation therapy. Because surgical treatment and radiation therapy are difficult to completely eradicate tumors, and the effect on patients with advanced tumors is not obvious, the role of drug treatment in cancer treatment is becoming more and more obvious. Traditional anti-tumor drugs cannot distinguish between tumor cells and normal tissue cells, often leading to serious side effects. Targeted drugs use cancer cells as specific targets to accurately target tumors, greatly improving treatment levels and reducing defects. The response rate, for example, increased the median survival time of advanced colorectal cancer by 66.7%, and the treatment efficiency of advanced breast cancer increased by 71.3%.

 As pharmaceutical companies accelerate the development of targeted antineoplastic agents, coupled with strong demand for this class of antineoplastic agents, molecularly targeted drugs have become the fastest growing unit in the global antitumor drug market. The phosphoinositide 3-kinase (PBK) signaling pathway is one of the most highly mutated systems in human cancer. PI3K signaling is also a key factor in many other human diseases. PBK signaling is involved in many Symptoms, including allergic contact dermatitis, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, chronic obstructive pulmonary disease, psoriasis, multiple sclerosis, asthma, disorders involving diabetes complications, and inflammation of the cardiovascular system Sexual complications such as acute coronary syndrome.

PI3K is a member of a unique and conserved family of intracellular lipid kinases that phosphorylate phosphatidylinositol or 3'-OH on phosphoinositides. The PI3K family contains 15 kinases with different substrate specificities, expression patterns, and modes of regulation. Class I ΡΙ3Κ (ρ110α, ρ110β, ρ110δ, pi 10γ) is normally activated by tyrosine kinase or G protein-coupled receptors to produce PIP3, while PIP3 binds to downstream effectors such as the Akt/PDK1 pathway, mTOR, Tec family kinase, and Rho Those effectors in the family GTPase. Class II and steroid PI3K play a key role in intracellular transport through the synthesis of PI(3)P and PI(3,4)P2 Function. PIKK is a protein kinase (mTORCl) that controls cell growth or protein kinases (ATM, ATR, DNA-PK, and hSmg-l) that monitor genomic integrity.

 The δ isoform of class I PI3K is involved in a variety of diseases and biological processes. ΡΙ3Κδ is mainly expressed in hematopoietic cells including leukocytes such as sputum cells, dendritic cells, neutrophils, mast cells, sputum cells, and macrophages. In mammalian immune system functions such as sputum cell function, sputum cell activation, mast cell activation, dendritic cell function, and neutrophil activity are essential for ΡΙ3Κδ. Due to the indispensable role of ΡΙ3Κδ in immune system function, ΡΙ3Κδ is also involved in a variety of diseases associated with abnormal immunity, such as allergies, inflammatory diseases, inflammation-mediated angiogenesis, rheumatoid arthritis, autoimmune system. Diseases such as lupus, asthma, emphysema and other respiratory diseases.

 The downstream mediators of the ΡΙ3Κ signal transduction pathway include the mammalian target (mTOR) of Akt and rapamycin. Akt has a platelet leukocyte C kinase substrate homologous (PH) domain that binds to PIP3, where binding to PIP3 results in activation of Akt kinase. Akt sulfates a variety of substrates and is the corresponding core downstream effector of PI3K for a variety of cells. An important function of Akt is to enhance mTOR activity by phosphorylating TSC2 and other mechanisms. mTOR is a serine-threonine kinase associated with the PI3K family of lipid kinases. mTOR is involved in a variety of biological processes including cell growth, cell proliferation, cell motility and survival. Disorders of the mTOR pathway have been reported in various types of cancer. mTOR is a multifunctional kinase that integrates growth factors and nutrient signaling to regulate protein translation, nutrient uptake, self-adhesion, and mitochondrial function. Therefore, kinases, especially PI3K, are the main targets for drug development.

 CAL-101 is a ΡΙ3Κδ-specific inhibitor. The original research company is Calistoga Pharmaceutical Co., Ltd., which was purchased by Gilead in 2011. It is the most advanced drug for ΡΙ3Κδ target research. It is currently in clinical phase III study. The main clinical indication is chronic lymphocytes. Leukemia, non-Hodgkin's lymphoma, acute myeloid leukemia, allergic rhinitis, etc. The structure is as follows:

 The effectiveness of ΡΙ3Κδ inhibitors in the treatment of tumors and inflammation has been reported in both Intellikine patent WO2009088990 and Icos patent US6667300. At present, there are no ΡΙ3Κδ inhibitors listed on the market. Therefore, it is necessary to develop more ΡΙ3Κδ inhibitor structure types, and select compounds with good efficacy and safety for cancer and inflammation treatment to meet clinical needs.

3, the content of the invention The invention provides the following technical solutions:

 Technical solution 1 :

 a salt of the formula (I), a stereoisomer thereof or a progeny thereof:

(I)

 among them-

X ¹ , X ² , X ³ , X ⁴ , Y are each independently N or CR ³ , and R ³ is hydrogen, halogen, hydroxy, carboxy, trifluoromethyl, Cw alkyl, CL ₆ decyloxy, -N ^{(R a) (R a '} ), cyano, C _{2. 6} alkenyl, C _{2. 6} alkynyl group, a carbamoyl group, carbamoyl group, sulfamoyl group, alkyl with 3-14 membered ring, 6 a 14-membered aryl group, a 3-14 membered heterocyclic group, a 7-12 membered spirocyclic group or a 7-12 membered bridged ring group;

L is a covalent bond or -N(R ^a )- _;

L is a covalent bond, R ¹ is benzo ring monoalkenyl, benzo-diene-C ₄ _ ₈ cycloalkyl group, C _{3. 8} monocyclic alkenyl and phenyl, and phenyl group and cycloalkadienyl Ομ _8, the a bicyclic heteroaryl obtained by condensing (phenyl or 5-6 membered monocyclic heteroaryl) with (C _{3 .8} cyclomonoalkenyl, C _{4 —8} cyclodienyl or 3-8 membered heterocycloalkenyl) a 7-12 membered spiro group or a 7-12 membered bridged ring group, and R ^{1 is} optionally substituted with 1-3 R ^b groups,

When L is -N(R ^a )-, R ¹ is Q. ₆ alkyl, Q. ₆ alkyl formyl, Cw alkylsulfonyl, 3-14 membered cycloalkyl, 6-14 membered aryl, 6 a 14-membered aryl hydrazino group, a 3-14 membered heterocyclic group, a 7-12 membered spirocyclic group or a 7-12 membered bridged ring group, and R ^{1 is} optionally substituted with 1-3 R ^b groups,

R ^a, R ^a 'independently represent hydrogen, ₆ embankment group, alkenyl group, C _{2. 6} alkynyl, alkyl with 3-14 membered ring, 6-14 membered aryl, 3-14 membered heterocyclyl, 7 -12 yuan spiro ring base or 7-12 yuan bridge ring base;

Z is -0-, -C(R ⁴ 'R ⁴ )- or -N(R ⁴ )-;

W is -0-, -C(R ⁵ 'R ⁵ )- or -N(R ⁵ )-;

R ⁴ , R ⁴ ', R ⁵ , R ⁵ ' are each independently hydrogen, unsubstituted or substituted with at least one hydroxyl group or at least one halogen. ₆ alkyl or 3-14 membered cyclodecyl;

R ² is a 6-10 membered bicyclic heterocycloalkyl group which is unsubstituted or substituted by at least one R ^b , from (phenyl or 5-6 membered monocyclic heteroaryl) to (5-6 membered monocyclic heteroaryl) a fused bicyclic heteroaryl group, a 7-12 membered spiro ring group or a 7-12 membered bridged ring group;

R ^b is hydrogen, oxo, halogen, cyano, hydroxy, amino, C _1-6 alkylamino, bis(C _1-6 alkyl)amine, carboxy, Aminosulfonyl, carbamoyl, C hydrazino, decyloxy, halo fluorenyl, halo. 6 decyloxy, hydroxy C hydrazino, amino C _1-6 alkoxy, carboxy fluorenyl, amino Formyl.6 alkyl, d- ₆ mercaptocarbonyloxy, C _1-6 alkoxycarbonyl, C _1-6 fluorenylcarbonyl, C _2-6 alkenyl, C ₂ alkynyl, 3-14 membered ring Mercapto, 3-14 membered cyclodecyloxy, 6-14 membered aryl, 6-14 membered aryloxy, 3-14 membered heterocyclic, 3-14 membered heterocyclyloxy, 7-12 Elemental ring or 7-12 yuan bridged ring base.

 Technical solution la:

 a salt of the formula (I), a stereoisomer thereof or a progeny thereof:

(I)

 among them:

X ¹ , X ² , X ³ , X ⁴ , Y are each independently N or CR ³ , and R ³ is hydrogen, halogen, trifluoromethyl, C^ decyl, d. ₆ alkoxy, -N(R ^a) (R ^a '), cyano, C _{2. 6} alkenyl, C _{2. 6} alkynyl group, a 3-14 membered cycloalkyl, 6-14 membered aryl, 3-14 membered heterocyclyl, 7- 12-membered spiro ring base or 7-12 yuan bridged ring base;

L is a covalent bond or -N(R ^a )- _;

When L is a covalent bond, R ¹ is a benzocyclomonoalkenyl group, a benzo C _{4 -8} cyclodienyl group, a C _{3 -8} cyclomonoalkylene group, and a. ₄ . ₈ -cyclodienylphenyl, by (phenyl or 5-6 membered monocyclic heteroaryl) with (C _{3 .8} cyclomonoalkenyl, C _{4 8} cyclodienyl or 3-8 membered Cycloalkenyl) fused bicyclic heteroaryl, 7-12 membered spiro or 7-12 membered bridged ring, and R ^{1 is} optionally substituted with 1-3 R ^b ,

When L is -N(R ^a )-, ! ^为为. ^ mercapto, .6 fluorenyl, .6 fluorenyl, 3-14 membered cyclodecyl, 6-14 membered aryl, 6-14 membered aryl C^ fluorenyl, 3-14 membered heterocyclic ring a 7-12 membered spiro group or a 7-12 membered bridged ring group, and R ^{1 is} optionally substituted with 1-3 R ^b groups,

R ^a , R ^a ' independently represent hydrogen, d. ₆ fluorenyl, C ₂ _e alkenyl, C _{2 -6} alkynyl, 3-14 membered cycloalkyl, 6-14 membered aryl, 3-14 membered a ring group, a 7-12 membered spiro ring group or a 7-12 membered bridged ring group;

Z is -0-, -C(R ⁴ 'R ⁴ )- or -N(R ⁴ )-;

W is -0-, -C(R ⁵ 'R ⁵ )- or -N(R ⁵ )-;

R ⁴ , R ⁴ ', R ⁵ , R ⁵ ' are each independently hydrogen, Cw decyl or 3-14 membered fluorenyl unsubstituted or substituted with at least one hydroxy or at least one halogen;

R ² is a 6-10 membered bicyclic heterocycloalkyl group which is unsubstituted or substituted by at least one R ^b , which is derived from (phenyl or 5-6 member a bicyclic heteroaryl group, a 7-12 membered spiro ring group or a 7-12 membered bridged ring group fused to a (5-6 membered monocyclic heteroaryl group);

R ^b is hydrogen, oxo, halogen, cyano, hydroxy, amino, . ₆ alkylamino, bis(Cw decyl)amine, carboxy, aminosulfonyl, carbamoyl, Cw fluorenyl, C^垸Oxy, halo Cw fluorenyl, halo C ₆ alkoxy, hydroxy. ^alkyl, aminoalkoxy, carboxy d. ₆ fluorenyl, carbamoyl C ₆ alkyl, Q- ₆ carbonyloxy, Ci- ₆ alkoxycarbonyl, alkylcarbonyl, C _{2 -6} alkenyl, C alkynyl, 3-14 membered cycloalkyl, 3-14 membered cycloalkyloxy, 6-14 membered aryl, 6-14 membered aryloxy, 3-14 membered heterocyclic, 3-14 membered Heterocyclyloxy, 7-12 membered spiro or 7-12 membered bridged ring.

 Technical Solution 2:

A compound according to the invention, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a deuterated product thereof:

 among them-

X ¹ , X ² , X ³ , X ⁴ are each independently CR ³ , and R ³ is hydrogen, halogen, hydroxy, trifluoromethyl, C oxime, Cw alkoxy, -N(R ^a )(R ^a '), cyano, C _{2. 6} alkenyl, C ₂ _ ₆ alkynyl group, a 3-8 membered monocyclic ring embankment, phenyl, or 3-8 membered monocyclic heterocycloalkyl, 3-8 membered heteroaryl a cycloalkenyl group, a 5-6 membered monocyclic heteroaryl group;

 Y is N;

When L is a covalent bond, R ¹ is benzox- _{8 8} cyclomonoalkenyl, benzo C ₈ cyclobutadienyl, C _{3 -8} cyclomonophenylene, and C _{4 8} cyclodiene benzene. a group obtained by condensing (phenyl or 5-6 membered monocyclic heteroaryl) with (C _{3 .8} cyclomonoalkenyl, C _{4 8} cyclodienyl or 3-8 membered heterocycloalkenyl) Bicyclic heteroaryl, 7-12 membered spiro or 7-12 membered bridged ring, and R ^{1 is} optionally substituted with 1-3 R ^b ,

When L is -N(R ^a )-, ! ^为为. ^ mercapto, _-6 alkylformyl, Cw alkylsulfonyl, 3-14 membered cyclodecyl, 6-14 membered aryl, 6-14 membered arylalkyl group, 3-14 membered heterocyclic group, a 7-12 membered spiro group or a 7-12 membered bridged ring group, and R ^{1 is} optionally substituted with 1-3 R ^b groups,

R ^a , R ^a ' independently represent hydrogen, C^ fluorenyl, C ₂ -6 alkenyl, C^ ₆ alkynyl, 3-14 membered cyclodecyl, 6-14 membered aryl, 3-14 membered heterocyclic group , 7-12 yuan spiro ring base or 7-12 yuan bridge ring base;

Z is -C(R ⁴ 'R ⁴ )-;

W is -N(R ⁵ )-;

R ⁴ , R ⁴ ', R ⁵ are each independently hydrogen, C! _-6 alkyl or 3-14 membered cycloalkyl which is unsubstituted or substituted with at least one hydroxyl group or at least one halogen;

R ² is a 6-10 membered bicyclic heterocyclic fluorenyl group which is unsubstituted or substituted by at least one R ^b , by (phenyl or 5-6 member a bicyclic heteroaryl group, a 7-12 membered spiro ring group or a 7-12 membered bridged ring group fused to a (5-6 membered monocyclic heteroaryl group);

R ^b is hydrogen, oxo, halogen, cyano, hydroxy, amino, Q.6 alkylamino, bis(Cw decyl)amine, carboxy, aminosulfonyl, carbamoyl, C _1-6 fluorenyl , C _1-6 methoxy, halogenated d. ₆ fluorenyl, halogenated CM methoxy, hydroxy. ₆ fluorenyl, amino C methoxy, carboxy. 6 fluorenyl, carbamoyl fluorenyl, d_ ₆ mercaptocarbonyloxy, -6 methoxycarbonyl, C ₆ alkylcarbonyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, 3-8 membered cyclodecyl, 3-8 membered cyclodecyloxy Phenyl, phenyloxy, 3-8 membered monocyclic heterocyclic fluorenyl, 3-8 membered heterocycloalkenyl, 5-6 membered monocyclic heteroaryl, 3-8 membered monocyclic heterocycloalkyl Oxyl, 3-8 membered heterocycloalkenyloxy, 5-6 membered monocyclic heteroaryloxy.

 Technical Solution 3:

The compound according to any one of the above aspects, wherein the compound, the pharmaceutically acceptable salt thereof, the stereoisomer thereof or the progeny thereof,

 Has the following structure:

Wherein X ¹ , X ² , X ³ , X ⁴ , Y, L, R ¹ , R ² , R ⁴ and R ⁵ have the meanings as described in the first aspect, la or 2.

 Technical Solution 4:

The compound according to any one of claims 1 to 3, the pharmaceutically acceptable salt thereof, the stereoisomer thereof or the progeny thereof,

 Medium:

X ¹ , X ² , X ³ , X ⁴ are each independently CR ³ , and R ³ is hydrogen, halogen, hydroxy, trifluoromethyl, C _1-6 alkyl, _-6 alkoxy or amino;

 Y is N;

L is a covalent bond, R ¹ by (phenyl or 5-6 membered monocyclic heteroaryl) and (C ₃ _ ₈ alkenyl group or a monocyclic C _{4. 8} cycloalkadienyl group or a 3-8 membered heterocyclic ring Alkenyl) fused bicyclic heteroaryl or 7-12 membered spiroheterocyclyl, and R ^{1 is} optionally substituted by 1-3 R ^b ,

Z is -CH(R ⁴ )-; W is -N(R ⁵ )-;

R ⁴ , R ⁵ are each independently hydrogen, a C group or a 3-5 membered cycloalkyl group which is unsubstituted or substituted with at least one hydroxyl group or at least one halogen;

R ^b is hydrogen, oxo, halogen, cyano, Cw alkyl, d ₃ alkoxy, trifluoromethyl, amino or 3-8 membered monocyclic heterocycloalkyl, 3-8 membered heterocycloalkenyl, 5-6 membered monocyclic heteroaryl.

Technical solution 5 _:

A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a progeny thereof:

 among them-

X ¹ , X ² , X ³ , X ⁴ are each independently CR ³ , and R ³ is hydrogen, fluorine, chlorine, trifluoromethyl or methyl;

 Y is N;

L is a covalent bond, R ¹ by (phenyl or 5-6 membered monocyclic heteroaryl) and (C ^ alkylene group or a monocyclic C _{5. 6} cycloalkadienyl group or a 5-6 membered heterocycloalkenyl a fused bicyclic heteroaryl or 7-12 membered spiroheterocyclyl, and R ^{1 is} optionally substituted by 1-3 R ^b ,

Z is -CH(R ⁴ )-, R ⁴ is hydrogen, unsubstituted or substituted with at least one hydroxy or fluorine d. ₃ fluorenyl or cyclopropyl; W is -NR ⁵ )-, R ⁵ independently Is hydrogen or methyl;

R ^b is halogen.

 Technical Solution 6:

A compound according to any one of claims 1 to 5, which is a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a progeny thereof:

 among them-

X ¹ , X ² , X ³ , X ⁴ are each independently CR ³ , and R ³ is hydrogen, halogen, hydroxy, trifluoromethyl, d. ₆ alkyl, decyloxy, -N(R ^a )(R ^a ') or cyano;

Y is N; L is -N(R ^a )-, and R ¹ is C _1-6 fluorenyl, C hydrazinoyl, C ₆ fluorenylsulfonyl, 3-6 membered cycloalkyl, 6-14 membered aryl, 6 a 14-membered aryl C _1-3 fluorenyl group, a 3-14 membered heterocyclic group, a 7-12 membered spiro group or a 7-12 membered bridged ring group, and R ^{1 is} optionally substituted with 1-3 R ^b ,

R ^a , R ^a ' independently represent hydrogen, C 垸 ,, alkenyl, alkynyl, 3-14 membered cyclodecyl, 6-14 membered aryl, 3-14 membered heterocyclic group, 7-12 membered snail a ring group or a 7-12 member bridged ring group;

Z is -CH(R ⁴ )-;

W is -N(R ⁵ )-;

R ⁴ , R ⁵ are each independently hydrogen, unsubstituted or substituted with at least one hydroxyl group or at least one halogen. ₃ fluorenyl or 3-5 membered fluorenyl;

R ^b is hydrogen, oxo, cyano, cyano, hydroxy, amino, d. ₆ alkylamino, bis(d- ₆ alkyl)amine, carboxy, aminosulfonyl, carbamoyl, Cw decyloxy, C^alkyl, halo. ₆ fluorenyl, 3-6 membered cyclodecyl, 3-6 membered cycloalkyloxy, 3-8 membered monocyclic heterocyclic fluorenyl, 3-8 membered heterocycloalkenyl, 5-6 membered monocyclic heteroaryl, 3-8 membered monocyclic heterocycloalkyloxy, 3-8 membered heterocycloalkenyloxy, 5-6 membered monocyclic heteroaryloxy.

 Technical Solution 7:

A compound, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a progeny thereof according to any one of claims 1 to 3, wherein:

X ¹ , X ² , X ³ , X ⁴ are each independently CR ³ , and R ³ is hydrogen, halogen, hydroxy, trifluoromethyl, C^ fluorenyl or C _1-6 fluorenyloxy;

 Y is N;

L is -N(R ^a ) -, ^ is . ₃ fluorenyl, d. ₃ fluorenyl, d ₃ alkylsulfonyl, 3-6 membered cyclodecyl, 6-14 membered aryl, 6-14 _ embankment _3-membered aryl group, a 5-6 membered monocyclic heterocyclyl group embankment, 5-6 membered heterocycloalkenyl, 5-6 membered monocyclic heteroaryl, alkyl with 6-10 membered bicyclic heterocyclyl, 7- a 12-membered spiro group or a 7-12 membered bridged ring group, and R ^{1 is} optionally substituted with 1-3 R ^b groups,

R ^a represents hydrogen, C _1-6 alkyl, 3-14 membered cyclodecyl or 6-14 membered aryl;

Z is -CH(R ⁴ )-, R ⁴ is hydrogen, Cw alkyl or cyclopropyl which is unsubstituted or substituted with at least one hydroxyl group or at least one halogen; W is -N(R ⁵ )-, and R ^{5 is} independently hydrogen or methyl;

R ² is

;

R ^b is hydrogen, oxo, cyano, cyano, hydroxy, amino, d. ₆ decylamino, bis(d. ₆ fluorenyl)amine, d. ₆ decyloxy, C _1-6 alkyl, Halogen C _1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered cyclodecyloxy, 5-6 membered monocyclic heterocycloalkyl, 5-6 membered heterocycloalkenyl, 5-6 Monomonocyclic heteroaryl, 5-6 membered monocyclic heterocyclononyloxy, 5-6 membered heterocycloalkenyloxy, 5-6 membered monocyclic heteroaryloxy.

 Technical Solution 8:

A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a progeny thereof:

 among them-

X ¹ , X ² , X ^s , X ⁴ are each independently CR ³ , R ³ is hydrogen, fluorine, chlorine, hydroxyl, trifluoromethyl or methyl; Y is N;

L is -N(R ^a ) -, ! ^为为. ^ mercapto, acetyl, methylsulfonyl, phenyl, pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, thiazolyl, imidazolyl, pyrazolyl, imidazolyl, pyrazinyl, anthracene Indenyl, isodecyl, carbazolyl, benzimidazolyl, pyridopyrazolyl, fluorenyl, piperazinyl, quinolyl, tetrahydropyranyl, piperidinyl, morpholinyl, pyrazine a pyridin-2-one, cyclohexyl, cyclopentyl or benzyl group, and R ^{1 is} optionally substituted by from 1 to 3 R ^b ,

R ^a represents hydrogen, C _w fluorenyl, 3-8 membered cycloalkyl or 6-14 membered aryl;

Z is -CH(R ⁴ )-, R ⁴ is hydrogen, d_ ₃ fluorenyl or cyclopropyl which is unsubstituted or substituted with at least one hydroxyl group or at least one fluorine;

W is -N(R ⁵ )-, and R ^{5 is} independently hydrogen or methyl;

R ² is

;

R ^b is hydrogen, oxo, cyano, cyano, hydroxy, amino, _-6 fluorenylamino, bis(Cw fluorenyl)amine, Q. ₆ alkoxy, C^alkyl, halo fluorenyl, 3-6 membered ring fluorenyl group, 3-6 membered cycloalkyloxy group, 5-6 membered monocyclic heterocyclic fluorenyl group, 5-6 membered heterocycloalkenyl group, 5-6 membered monocyclic heteroaryl group, 5- 6-membered monocyclic heterocycloalkyloxy group, 5-6 membered heterocycloalkenyloxy group, 5-6 membered monocyclic heteroaryloxy group. Technical solution 9:

A compound according to any one of the preceding claims, wherein the pharmaceutically acceptable salt, the stereoisomer thereof or the progeny thereof:

 among them:

X ¹ , X ² , X ³ , X ⁴ are each independently CR ³ , R ³ is hydrogen, fluorine, chlorine, hydroxyl, trifluoromethyl or methyl; Y is N;

L is -N(R ^a ) -, 1^ is. _1-3 fluorenyl, acetyl, methylsulfonyl, phenyl, pyridyl, pyridin-2-one, cyclohexyl, cyclopentyl or benzyl, and R ^{1 is} optionally 1-3 R ^b Replace,

R ^a represents hydrogen, methyl, ethyl, cyclopropyl or phenyl;

Z is -CH(R ⁴ )-, R ⁴ is hydrogen, fluorenyl or cyclopropyl which is unsubstituted or substituted with at least one hydroxyl group or at least one fluorine;

W is -NR ⁵ )-, R ^{5 is} independent

R ²

R ^b is hydrogen, oxo, cycline, cyano, ₃ fluorenyl, ₃ decyloxy or trifluoromethyl.

 Technical Solution 10:

A compound according to any one of the preceding claims, wherein the compound, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a progeny thereof, is selected from the group consisting of:

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 Technical Solution 11:

The compound according to any one of claims 1 to 10, the pharmaceutically acceptable salt thereof, the stereoisomer thereof or the progeny thereof, the compound is selected from the group consisting of -

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An acceptable salt, a stereoisomer thereof or a progeny thereof, and one or more pharmaceutically acceptable carriers.

 Technical Solution 13:

A compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a progeny thereof, or a composition according to claim 12, which is prepared for use in therapy and/or Or use in drugs that prevent inflammatory diseases and/or tumors.

 Technical Solution 14:

A method of treating and/or preventing an inflammatory disease and/or a tumor, the method comprising administering to a subject in need thereof a therapeutically effective amount of the compound according to any one of the technical solutions 1 to 1 or 1 to A pharmaceutically acceptable salt, a stereoisomer thereof or a progeny thereof, or a therapeutically effective amount of the composition of claim 12.

 Technical Solution 15:

A compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a progeny thereof, or a composition according to claim 12, which is used for treatment and/or Or prevent inflammatory diseases and/or tumors.

 Technical solution 16:

In the technical schemes 13, 14, and 15, the inflammatory disease is selected from the group consisting of allergy, asthma, rheumatoid arthritis, osteoarthritis, allergic conjunctivitis, allergic keratitis, dry eye, chronic obstructive pulmonary disease (COPD), lupus erythematosus, psoriasis, multiple sclerosis, and end stage renal disease, and the tumor is selected from the group consisting of leukemia, lymphoma, myelosynthesis, non-Hodgkin's lymphoma, and chronic spontaneous myelofibrosis.

4, the specific implementation

 Definition

 In the present invention, the term "halogen" means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

In the present invention, the term "hospital group" means a straight or branched hydrocarbon group having no double bond or triple bond. Examples of the alkyl group include a _6- mercapto group, a d- ₅ fluorenyl group, an alkyl group, and a d- ₃ fluorenyl group each having 1 to 6 carbon atoms, 1 to 5 carbon atoms, 1 to 4 carbon atoms, and 1 3 carbon atoms. Specific examples of sulfhydryl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-methylpropyl, 1-methylpropyl, 1,1-dimethylethyl , n-pentyl, 3-methylbutyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, and 1,2-dimethylpropyl.

In the present invention, the term "cycloalkyl" refers to a cyclic hydrocarbyl group which does not have a double bond or a triple bond. From the viewpoint of the number of atoms of the ring-forming carbon atom of the fluorenyl group, the cycloalkyl group includes a 3-14 membered ring fluorenyl group, a 3-12 membered ring fluorenyl group, and a 3-10 membered ring fluorenyl group. a 3-8 membered ring fluorenyl group, a 3-6 membered ring fluorenyl group, a 5-10 membered ring fluorenyl group, a 5-8 membered ring fluorenyl group, and a 4-6 membered ring fluorenyl group each having 3 to 14 ring-forming groups Carbon atom, 3-12 ring-forming carbon atoms, 3-10 ring-forming carbon atoms, 3-8 ring-forming carbon atoms, 3-6 ring-forming carbon atoms, 5-10 ring-forming carbon atoms, 5- 8 ring-forming carbon atoms, and 4-6 ring-forming carbon atoms. From the ring number of the cycloalkyl group, the cycloalkyl group includes a monocyclic cyclodecyl group and a fused ring cycloalkyl group. A monocyclic cycloalkyl group has only one ring. A fused ring cyclodecyl group refers to a group formed by two or more monocyclic ring fluorenyl groups sharing two adjacent carbon atoms with each other. The monocyclic cyclodecyl group includes a 3-8 membered monocyclic cyclodecyl group, a 3-6 membered monocyclic cyclodecyl group, a 5-8 membered monocyclic cycloalkyl group, and a 5-6 membered monocyclic cyclodecyl group. Specific examples of the monocyclic cyclodecyl group include a cyclopropenyl group, a cyclobutane group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group. The monocyclic fluorenyl group may be further substituted, for example, a _6-8 -membered monocyclic fluorenyl group substituted by a ₆ alkyl group includes, but is not limited to, methylcyclopropenyl, dimethylcyclopropenyl, methyl Cyclobutanyl, dimethylcyclobutyl fluorenyl, methylcyclopentyl, dimethylcyclopentanyl, methylcyclohexane, and dimethylcyclohexyl. The fused ring cyclodecyl group includes a 6-14 membered fused ring cyclodecyl group, a 6-12 membered fused ring cyclodecyl group, an 8-12 membered fused ring cyclodecyl group, and a 7-10 membered fused ring ring fluorenyl group, such as 6-14. A bicyclocycloalkyl group, a 6-12 membered bicyclic cyclodecyl group, an 8-12 membered bicyclic cyclodecyl group, and a 7-10 membered bicyclic cycloalkyl group. Examples of fused ring cyclodecyl groups include, but are not limited to: bicyclo[3.1.0]hexyldecyl, bicyclo[4丄0]heptinyl, bicyclo[2.2.0]hexyl, bicyclo[3.2. 0] heptyl, bicyclo[4.2.0]octyl, octahydro-1H-indenyl, decahydronaphthyl, and tetradecafluorophenanyl.

In the present invention, the term "alkenyl" means a straight or branched hydrocarbon group containing at least one double bond. Alkenyl groups comprising ₆ alkenyl, C _{2. 5} alkenyl, C _M alkenyl, and C _{2. 3} alkenyl group, each having 2-6 carbon atoms, 2-5 carbon atoms, 2-4 carbon Atom, and 2-3 carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-methylvinyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl -1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3- Pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-methyl-2- Butenyl, 2-methyl-2-butenyl, ₃ -methyl- ₂ -butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3- Methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1- Ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1- Methyl-1-pentenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 1-methyl-2-pentyl Alkenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl, 2-methyl 3-pentenyl, 3-methyl-3-pentenyl, 4-methyl 3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl ,

1.1-Dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-1-butenyl, 1,2-dimethyl-2- Butyl,

1.2-dimethyl-3-butenyl, 1,3-dimethylbutenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butene Base, 2,2-dimethyl-3-butenyl, 2,3-dimethylbutenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl- 3-butenyl, 3,3-dimethylbutenyl, 3,3-dimethyl-2-butenyl, 1-ethyl-1-butenyl, 1-ethyl-2- Butenyl, 1-ethyl-3-butenyl, 2-ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1, 1,2-trimethyl-2-propene , 1-ethyl small methyl-2-propenyl, 1-ethyl-2-methylpropenyl, 1-ethyl-2-methyl-2-propenyl, 1,3-butadiene , 1, 3-pentadiene, 1, 4-pentadiene, and 1, 4-hexadiene.

In the present invention, the term "cycloalkenyl" means a cyclic hydrocarbon group containing at least one double bond. Cycloalkenyl groups include C _{3. 8} monocyclic alkenyl group, C ₃ _ ₇ cycloalkyl mono alkenyl, and C _{3. 6} cycloalkyl mono alkenyl group, each having 3-8 carbon atoms, 3-7 carbon atoms, and 3-6 carbon atoms. The cycloalkenyl group further includes a C _{4 .8} cyclodienyl group, a C _{4 -7} cyclodienyl group, and a C _{4 6} cyclodienyl group each having 4 to 8 carbon atoms and 4 to 7 carbon atoms. And 4-6 carbon atoms. The cycloalkenyl group also includes a cyclotrienyl group, a cyclotetraenyl group and the like. Specific examples of the cycloalkenyl group include, but are not limited to, a cyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group, a 1, 3-cyclopentadienyl group, a cyclohexenyl group, a 1, 4-cyclohexadienyl group, and Cyclooctylalkenyl.

In the present invention, the term "alkynyl" means a straight or branched hydrocarbon group containing at least one triple bond. Alkynyl groups include C _{2. 6} alkynyl, C _{2 _. 5} alkynyl group, C ₂ alkynyl group, and C ₂ .3 alkynyl group, each having 2-6 carbon atoms, 2-5 carbon atoms, 2-4 One carbon atom, and two to three carbon atoms. Specific examples of alkynyl groups include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 3-pentyl Alkynyl, 4-pentynyl, 1-methyl-2-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1 ,1-dimethyl- 2-propynyl, 1-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-2-pentyne , 1-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl 4-pentynyl, 4-methyl-2-pentynyl, 1,1 -dimethyl-2-butynyl, 1,1 -dimethyl-3-butynyl, 1,2- Dimethyl-3-butynyl, 2,2-dimethyl-3-butynyl, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl, 2-ethyl 3-butynyl, and 1-ethyl-1-methyl-2-propynyl.

In the present invention, the term "alkoxy" means "alkyloxy" or "hospital-0-", wherein alkyl is as defined above. The alkoxy groups include .6 methoxy, C _M methoxy, CM alkoxy, and. ^垸oxy, each having 1 to 6 carbon atoms, 1 to 5 carbon atoms, 1 to 4 carbon atoms, and 1 to 3 carbon atoms. Specific examples of the decyloxy group include, but are not limited to, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a t-butoxy group, a sec-butoxy group, a pentyloxy group, Neopentyloxy, and hexyloxy.

In the present invention, the term "aryl" means an aromatic hydrocarbon group. The aryl group includes a 6-14 membered aryl group, a 8-14 membered aryl group, a 6-10 membered aryl group, and a 6-8 membered aryl group, each of which has 6 from the viewpoint of the number of atoms of the ring-forming carbon atom of the aryl group. - 14 ring-forming carbon atoms, 8-14 ring-forming carbon atoms, 6-10 ring-forming carbon atoms, 6-8 ring-forming carbon atoms. From the ring number of the aryl group, the aryl group includes a monocyclic aryl group and a fused ring aryl group. A monocyclic aryl group has only one ring. An example of a monocyclic aryl group is phenyl. A fused ring aryl group refers to a group formed by two or more single ring structures sharing two adjacent carbon atoms with each other, wherein at least one single ring structure is aromatic. The fused ring aryl group includes "completely aromatic fused ring aryl group" and "partial aromatic fused ring aryl group". A fully aromatic fused ring aryl group means that all of the rings forming the fused ring aryl group are aromatic. Examples of fully aromatic fused ring aryl groups include, but are not limited to, naphthalene and phenanthrene. Partially aromatic fused ring aryl means that the ring forming part of the fused ring aryl group is not aromatic, that is, the partially aromatic fused ring aryl group is through an aromatic carbocyclic ring and a non-aromatic carbocyclic ring such as a cyclic monoene. The base or cyclodienyl group is formed by condensing. Partial aromatic fused ring aryl includes benzo C _3-8 cycloalkenyl, benzene And C ^ cycloalkadienyl group, phenyl group and monocyclic alkenyl, and C _{4. 8} and cycloalkadienyl group. Specific examples of the partially aromatic fused ring aryl group include, but are not limited to, 2,3-dihydro-1H-indenyl, 1H-indenyl, 1,2,3,4-tetrahydronaphthyl, 1,4-dihydrogen Naphthyl and the like.

 In the present invention, "heterocyclic group" means a cyclic group containing at least one hetero atom selected from nitrogen, oxygen and sulfur as a ring-constituting atom. The heterocyclic group may have 3 to 14 ring-forming atoms (abbreviated as a 3-14 membered heterocyclic group, the same applies hereinafter), 3 to 10 ring-forming atoms, 3 to 8 ring-forming atoms, 4 to 12 ring-forming atoms, 5-10 ring-forming atoms, 5-8 ring-forming atoms, or 5-6 ring-forming atoms. The heterocyclic group includes a monocyclic heterocyclic fluorenyl group, a bicyclic heterocyclic fluorenyl group, a heterocycloalkenyl group, a monocyclic heteroaryl group, and a bicyclic heteroaryl group.

Monocyclic heterocycloalkyl refers to a monocyclic cycloalkyl group in which at least one carbon atom is replaced by a hetero atom selected from N, 0 and S. The monocyclic heterocyclic fluorenyl group may have 3-8 ring-forming atoms (abbreviated as 3-8 membered monocyclic heterocycloalkyl group, the same applies hereinafter), 3-6 ring-forming atoms, 5-6 ring-forming atoms, or 5 -8 ring-forming atoms, and the monocyclic heterocyclic fluorenyl group has 1-2, 1-3 or 1-4 hetero atoms selected from N, 0 and S as ring-forming atoms. Examples of the 3-8 membered monocyclic heterocyclic fluorenyl group include: aziridine, azetidinyl, thietane, tetrahydrofuranyl, tetrahydropyrrolyl, imidazolium, pyrazolyl, 1,4-dioxanone, 1,3-dioxanthyl, 1,3-dithiohexanyl, piperidinyl, morpholinyl, piperazinyl and the like. Further, CH ₂ as a ring atom may be oxidized, and the monocyclic heterocyclic fluorenyl group may be substituted with oxo, for example, piperidin-2-one or the like.

 Bicyclic heterocycloalkyl refers to a fused ring cyclic fluorenyl group having two rings wherein at least one carbon atom is replaced by a hetero atom selected from N, 0 and S. The bicyclic heterocyclic fluorenyl group includes a 6-10 membered bicyclic heterocyclic fluorenyl group including 6-10 ring-forming atoms, and 1-2, 1-3 or 1-4 as a ring-forming atom, selected g, 0, and The hetero atom of S. Examples of the 6-10 membered bicyclic heterocyclic fluorenyl group include: a cyclobutane tetrahydropyrrolyl group (e.g., 3-azabicyclo[3.2.0]heptanyl), a cyclopentamethylenetetrahydropyrrolyl group (e.g., an octahydrocyclo ring). Pentadiene [c]pyrrole), and azetidinium imidazolidinyl (such as 2,4,6-triazabicyclo[3.2.0]heptane).

 Heterocyclenyl means a cycloalkenyl group in which at least one carbon atom is replaced by a hetero atom selected from N, 0 and S. The heterocyclenyl group may have 3-8 ring-forming atoms (abbreviated as 3-8 membered heterocycloalkenyl, the same applies hereinafter), 5-8 ring-forming atoms, or 5-6 ring-forming atoms, and has 1-2 , 1-3 or 1-4 as a ring-forming atom selected from hetero atoms of 0 and S. Examples of the 3-8 membered heterocycloalkenyl group include: 2,5-dihydrothiophenyl, 4,5-dihydropyrazolyl, 1,2-dihydropyridyl, 3,4-dihydro-2H-pyridyl Benzyl, 5,6-dihydro-4H-oxazinyl, oxepanethylene, thiaheptatrienyl, azepanene, 1,3-diazepine Trienyl, azacyclotetradecenyl and the like. Further, the heterocycloalkenyl group may be substituted with oxo, such as pyridin-2-one, and pyran-4-one.

Monocyclic heteroaryl refers to a 5-6 membered monocyclic heteroaryl group which is aromatic and includes 5-6 ring-forming atoms and 1-4 heteroatoms selected as β-rings, 0 and S as ring-forming atoms. . Examples of monocyclic heteroaryl groups include: furyl, thienyl, pyrrolyl, thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, 1, 4-dioxacyclobutadienyl, 2H-1,2-oxazinyl, 4H-1,2-oxazinyl, 6H-1,2-oxazinyl, 4H-1,3-oxazinyl , 6H-1,3-oxazinyl, 4H-1,4-oxazinyl, pyridazinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1, 3,5-triazinyl, and 1,2,4,5-tetrazinyl.

In the present invention, the bicyclic heteroaryl group includes a bicyclic heteroaryl group obtained by condensing (phenyl or 5-6 membered monocyclic heteroaryl) with (5-6 membered monocyclic heteroaryl), and a bicyclic heteroaryl group obtained by condensing a 5- or 6-membered monocyclic heteroaryl group with (C _{3 .8} cyclomonoalkenyl, C _{4 .8} cyclodienyl or 3-8 membered heterocycloalkenyl), For example, a bicyclic heteroaryl group obtained by condensing (phenyl or 5-6 membered monocyclic heteroaryl) with (C^cyclomonoalkenyl, C ₅ —6 cyclodienyl or 5-6 membered heterocycloalkenyl) .

 Examples of the bicyclic heteroaryl group obtained by condensing (phenyl or 5-6 membered monocyclic heteroaryl) with (5-6 membered monocyclic heteroaryl) include: benzofuranyl, benzisofuranyl, Benzothiophenyl, fluorenyl, benzoxazolyl, benzimidazolyl, oxazolyl, benzotriazolyl, quinolyl, isoquinolyl, pyridopyrazolyl, pyridopyrrolyl, Pyrimidopyrazolyl, pyrimidopyrrolyl, pyridazinopyrazolyl, pyridazinopyrrolidinyl, acridinyl, phenanthryl, benzoxazinyl, pyridazinyl, quinazolinyl, quinoxaline Base, acridinyl, fluorenyl, and naphthyridinyl.

A (phenyl or 5-6 membered monocyclic heteroaryl) and (C ₃ _ ₈ monocyclic alkenyl group, C _{4. 8} cycloalkadienyl group or a 3-8 membered heterocycloalkenyl) to give a fused bicyclic heteroaryl Examples of the aryl group include: 1,3-dihydrobenzofuranyl, benzo[[1.3]dioxolyl, isoindolinyl, porphyrinyl, chromanyl, 1,2, 3,4-tetrahydropyrrolo[3,4-(]pyrrolyl, dihydropyrrolopyridyl, dihydropyrrolopyrimidinyl, dihydropyrrolopyridazinyl, tetrahydropyrrolopyridinyl, tetrahydropyrrole And pyrimidinyl, tetrahydropyrrolopyridazinyl and the like.

 In the present invention, the term "bridged ring group" means a cyclic group in which two rings share two ring-forming atoms which are not directly connected. The ring-forming atoms may all be carbon atoms or the ring-forming atoms may contain heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. The bridged ring group may contain an unsaturated bond. Examples of bridged ring groups include "7-12 membered bridged ring group" or "7-12 membered bridged heterocyclic group" (referred to as 7-12 membered bridge (hetero) ring group), wherein 7-12 yuan bridge (hetero) ring The group contains 7 to 12 ring-forming atoms, the ring-forming atoms may all be carbon atoms or the ring-forming atoms may contain hetero atoms selected from nitrogen, oxygen and sulfur. The "7-12 yuan bridge (hetero) ring group" includes "7-12 yuan saturated bridge (hetero) ring group" and "7-12 yuan unsaturated bridge (hetero) ring group". The "7-12 membered saturated bridge (hetero) ring group" means a cyclic group in which all rings in the bridge (hetero) ring group are saturated, including, for example, "7-10 member saturated bridge (hetero)" Ring group ", and "7-8 member saturated bridge (hetero) ring group" and the like. The "7-12 member unsaturated bridge (hetero) ring group" means a cyclic group having at least one ring which is unsaturated in the bridge (hetero) ring group, including, for example, "7-10 member unsaturated" Bridge (hetero) ring base", and "7-8 yuan unsaturated bridge (hetero) ring base" and the like.

Specific examples of the bridge (hetero) ring constituting the 7-12-membered saturated bridge heterocyclic group include, but are not limited to:

Specific examples of the 7-12-membered unsaturated bridge (hetero) ring include, but are not limited to:

 In the present invention, the term "spirocyclic group" means a cyclic group in which at least two rings share one ring-forming atom. The ring-forming atoms may all be carbon atoms or the ring-forming atoms may contain heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. The spiro group can contain an unsaturated bond. Examples of the spiro group include "7-12-membered spiro group" and "7-12-membered spiroheterocyclyl" (abbreviated as 7-12-membered spiro (hetero) ring group), which contain 7 to 12 ring-forming atoms, The ring-forming atoms may all be carbon atoms or the ring-forming atoms may contain heteroatoms selected from nitrogen, oxygen and sulfur; "7-11 element snail (hetero) ring group", "8-11 element snail" Hetero) ring group ", and "9-10 element snail (hetero) ring group". The "7-12 membered spiro (hetero) ring group" includes "7-12 member saturated snail (hetero) ring group" and "7-12 member unsaturated snail (hetero) ring group". The "7-12-membered saturated spiro (hetero) ring group" means a cyclic group in which all of the rings in the spiro(hetero) ring group are saturated, including, for example, "7-11-membered saturated snail (hetero)" Ring group ", "8-11 yuan saturated snail (hetero) ring group", "9-10 yuan saturated snail (hetero) ring group" and the like. The "7-12 member unsaturated spiro(hetero) ring group" means a cyclic group in which at least one ring of the spiro (hetero) ring group is unsaturated, including, for example, "7-11 member unsaturated snail" (hetero) ring group", "8-11 yuan unsaturated snail (hetero) ring group", "9-10 yuan unsaturated snail (hetero) ring group" and the like.

 Specific examples of the spiro (hetero) ring constituting the 7-12-membered saturated spiro (hetero) ring group include, but are not limited to:

Specific examples of the spiro (hetero) ring constituting the 7-12-membered unsaturated spiro(hetero) ring group include, but are not limited to:

In the present invention, "pharmaceutically acceptable salts" include alkali metal salts such as sodium salts, potassium salts, lithium salts and the like; alkaline earth metal salts such as calcium salts, magnesium salts, etc.; other metal salts such as aluminum salts, iron Salt, zinc salt, copper salt, nickel salt, cobalt salt, etc.; inorganic alkali salt, such as ammonium salt; organic base salt, such as t-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, benzene Glycosyl decyl ester, ethylenediamine salt, N-methylglucamine salt, sulfonium salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N,N,-dibenzylethylene Amine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzyl-phenethylamine salt, piperazine salt, tetramethylamine salt, tris(hydroxymethyl)amino group a hydrohalide salt, such as a hydrofluoride salt, a hydrochloride salt, a hydrobromide salt, a hydroiodide salt, or the like; a mineral acid salt such as a nitrate salt, a perchlorate salt, a sulfate salt, a phosphate salt, etc.; Alkane sulfonates such as methanesulfonate, triflate, ethanesulfonate, etc.; aryl sulfonates such as besylate, p-benzenesulfonate, etc.; organic acid salts such as acetic acid salt Malate, fumarate, succinate, citrate, tartrate, oxalate, maleate, etc.; amino acid salts such as glycinate, trimethylglycine, arginine, ammonia Acid salts, glutamate, aspartate, and the like.

 In the present invention, the compound also includes "stereoisomers" thereof. When one or more asymmetric carbon atoms are present in the structure of the compound, an enantiomer is produced; when the compound contains an alkenyl group or a cyclic structure, a cis/trans isomer is produced; when the compound is present with a ketone or an anthracene When it occurs, it will produce tautomers and so on. All such isomers and mixtures are within the scope of the invention.

 In the present invention, the compound also includes "deuterated matter" thereof. When a hydrogen atom in a compound is partially or completely replaced by its isotope 氘 (symbol D), the substance produced is also within the scope of the present invention.

Preferred compounds of the invention -

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More preferred compounds of the invention:

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 Structural structure number

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The invention also provides pharmaceutical compositions. The pharmaceutical composition comprises a compound of the formula (I) of the present invention, and a progeny thereof And pharmaceutically acceptable salts or stereoisomers thereof, and one or more pharmaceutically acceptable carriers (e.g., excipients, binders, moisturizers, disintegrants, thickeners, and the like).

 The compound of the formula (I), the deuterated compound, the pharmaceutically acceptable salt thereof or the stereoisomer thereof of the present invention can be formulated into a pharmaceutical preparation together with one or more pharmaceutically acceptable carriers. The pharmaceutical preparation refers to a conventional preparation for clinical use, and can be administered to a patient in need of such treatment by oral or parenteral administration. Such as tablets, granules, capsules, powders, injections, inhalants, sublingual preparations, syrups, gels, ointments, suppositories, lotions, nasal drops, eye drops, sprays, transdermal formulations and the like. These preparations can be prepared by a conventional method, by adding a pharmaceutically acceptable carrier such as an excipient, a binder, a moisturizer, a disintegrating agent, a thickener or the like.

 The present invention also provides the use of a compound of the formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a compound thereof for the preparation of a medicament for the treatment and/or prevention of an inflammatory disease or tumor. The inflammatory disease is selected from the group consisting of allergy, asthma, rheumatoid arthritis, osteoarthritis, allergic conjunctivitis, allergic keratitis, dry eye, chronic obstructive pulmonary disease (COPD), lupus erythematosus, psoriasis, multiple Sexual sclerosis and end stage renal disease. The tumor diseases are selected from leukemia, lymphoma, myelosynthesis, non-Hodgkin's lymphoma, and chronic spontaneous bone marrow fibrosis. The invention also provides a preparation method of the above compound:

 In the following preparation aspects and subsequent examples, the following abbreviations are used:

 DIEA: N,N-diisopropylethylamine

 HATU: 2-(7-azobenzotriazole)-Ν,Ν,Ν',Ν'-tetramethylurea hexafluorophosphate

 DMF: Ν, Ν-dimethylformamide

 Et: ethyl

 EtOH: Ethanol

 Bu: butyl

 BuOH: Butanol

 Boc: tert-butoxycarbonyl

 DCM: Dichloromethane

 DMAP: 4-dimethylaminopyridine

 TLC: Thin layer chromatography

 TFA: trifluoroacetic acid

 THF: tetrahydrofuran

Me: methyl Py= pyridine

 EA: ethyl acetate

 PE: petroleum ether

 Ac: acetyl

 HOAc: Acetic acid

 LS-MS: Liquid Chromatography - Mass Spectrometry

 Ts: p-toluenesulfonyl

 TsCl: p-toluenesulfonyl chloride

 THP: tetrahydropyran scheme 1

 Intermediate 3 Intermediate 4 Formula ( I )

Reaction step

 (1) Raw material 1 (1 equivalent) is dissolved in dichloromethane, a small amount of DMF is added dropwise, and oxalyl chloride (for example, 1.1-1.5 equivalent) is added dropwise in an ice bath. The reaction is stirred at room temperature for several hours, and dissolved by dioxane. The mixed solution of the raw material 2 and sodium hydrogencarbonate dioxane and water was slowly added dropwise under ice-cooling, and the mixture was stirred at room temperature. After the reaction was completed, the mixture was extracted, concentrated, and subjected to column chromatography to give Intermediate 1.

 (2) Dissolving Intermediate 1 in a suitable solvent (such as methanol or ethanol), adding Pd/C thereto, passing hydrogen gas, reacting at room temperature, ending the reaction, filtering out Pd/C, and concentrating the organic phase to obtain an intermediate. 2.

(3) In a dry reaction flask, intermediate 2 (1 equivalent), starting material 3 (for example, 1.2-2 equivalents), tertiary amine (such as DIEA or triethylamine, etc.) (for example, 1.2-2 equivalents) Mixture (such as HATU or EDCI, etc.) (for example, 1-1.2 equivalents) is added to dichloromethane (or a mixed solvent of dichloromethane and DMF or DMA), stirred at room temperature, and the reaction is over. After extraction, concentration under reduced pressure and column chromatography gave Intermediate 3.

 (4) The intermediate 3 is dissolved in a suitable solvent (e.g., ethanol), concentrated hydrochloric acid or a hydrochloric acid gas is added dropwise thereto in an ice bath, and the reaction is heated for several hours, cooled and concentrated to give Intermediate 4.

 (5) Dissolve intermediate 4 (1 equivalent) in a suitable solvent (such as t-butanol), add starting material 4 (for example, 1-1.5 equivalents), base (such as triethylamine or diisopropyl (ethyl)amine (for example, 2-5 equivalents), heating (generally solvent reflux) to the disappearance of intermediate 4, concentration, silica gel column chromatography or preparative liquid phase purification to give compound of formula (I).

X ¹ , X ² , X ³ , X ⁴ , Z, W, L, R ¹ , R ² in the upper reaction equation are as defined above. In the starting material 4, X represents a halogen such as chlorine, bromine, iodine or the like. If necessary, the functional group to be protected may be protected by a conventional protective agent, after which the protecting group is removed by a conventional method; if necessary, some compounds may also be prepared, for example, the preparation of the starting material 1. Scenario 2

 It can also be prepared by referring to the following preparation methods:

Reaction step

 (1) Mixing raw material 1 (1 equivalent), raw material 2' (for example, 1-1.5 equivalents), triphenyl phosphite (for example, 1-1.5 equivalents), adding a solvent amount of pyridine, heating (45 ° C to 85 Γ) After several hours of reaction, the intermediate 1 is obtained, and the next reaction is directly carried out.

 (2) The raw material 3 (for example, 1-1.5 equivalents) is directly added to the reaction system of the previous step, heated (100 ° C) for several hours, cooled, concentrated, and subjected to column chromatography to obtain an intermediate 2'.

(3) Dissolve intermediate 2, (1 equivalent) in a suitable solvent (such as dichloromethane, ether or methanol), cool at room temperature or ice water, add trifluoroacetic acid, or pass hydrochloric acid to react to intermediate 2 'disappear, concentrate, get intermediate 3,.

 (4) Dissolving the intermediate 3' (1 equivalent) in a suitable solvent (such as t-butanol), adding the starting material 4' (for example, 1-1.5 equivalents), a base such as triethylamine or diisopropyl (ethyl) Amine) (for example, 2-5 equivalents), heated (generally solvent reflux), reacted to the intermediate 3' disappeared, concentrated, purified by silica gel column chromatography or purified to give a compound of formula (I).

X ¹ , X ² , X ³ , X ⁴ , Y, Z, W, L, R ¹ , R ² in the upper reaction equation are as defined above. In the starting material 4, X represents a halogen such as chlorine, bromine, iodine or the like. If necessary, the functional group to be protected may be protected with a conventional protective agent, after which the protecting group is removed by a conventional method; if necessary, some compounds may also be prepared. Option 3

Intermediate 3 Intermediate ₄ ^ '

Reaction steps:

 (1) In a dry reaction flask, raw material 1 (generally methyl or ethyl ester) (1 equivalent), raw material 2 (for example, 1.2-2 equivalents), tertiary amine (such as DIEA or triethylamine) (for example, 1.5-3 equivalents) and a condensing agent (such as HATU or EDCI) (for example, 1-1.2 equivalents) are added to methylene chloride (or a mixed solvent of dichloromethane and DMF or DMA), stirred at room temperature, and extracted after the reaction is completed. Concentration under reduced pressure and column chromatography gave Intermediate 1.

 (2) Hydrolyzing the ester group of the intermediate 1 under basic conditions, usually adding an aqueous solution of lithium hydroxide, sodium hydroxide or potassium hydroxide, or a mixed solvent of tetrahydrofuran, methanol and water. The acid is adjusted to be weakly acidic, the product is precipitated, and the aqueous phase is extracted once, and the intermediate 2 is combined.

(3) In a dry reaction flask, intermediate 2 (1 equivalent), starting material 3 (for example, 1-1.5 equivalents), tertiary amine (such as DIEA or triethylamine) (for example, 1.5-3 equivalents) and a condensing agent (eg, HATU or EDCI) (eg, 1-1.2 equivalents) is added to dichloromethane (or a mixed solvent of methylene chloride and DMF or DMA), stirred at room temperature, extracted after completion of the reaction, concentrated under reduced pressure, and column chromatography Intermediate 3 was obtained. Steps 4 and 5 are the same as steps 4 and 5 of Preparation Method 1.

X ¹ , X ² , X ³ , X ⁴ , Y, Z, W, L, RR ² in the upper reaction equation are as defined above. In the starting material 4, X represents a halogen such as chlorine, bromine, iodine or the like. If necessary, the functional group to be protected may be protected with a conventional protective agent, after which the protecting group is removed by a conventional method; if necessary, some compounds may also be prepared. Example

 The above content of the present invention will be further described in detail below by way of specific embodiments in the form of embodiments. However, the scope of the above-mentioned subject matter of the present invention should not be construed as being limited to the following examples. Any technique implemented based on the above description of the present invention is within the scope of the present invention. Biological Activity Experiments The beneficial effects of the compounds of the present invention are further illustrated by the biological activity experiments of the compounds of the present invention. Other compounds of the present invention have the same beneficial effects as the compounds of the present invention enumerated in the test, but should not be construed as a compound of the present invention. It has only the following beneficial effects. Experimental Example 1 In vitro enzymatic inhibitory activity of the compound of the present invention

Test article: The compound of the present invention is prepared according to the method of the preparation example;

experimental method:

 1. The compound was stored in DMSO as a mother liquor of 1 mM. During the experiment, the mother liquor was diluted 100-fold to 10 μM with 100% DMSO. ΙΟμΜ is the highest concentration of this experiment, and then diluted 4 times in a row, a total of 10 concentrations, respectively, 2·5μΜ, 0.625μΜ, 0.156μΜ, 0.039μΜ, 0.009μΜ, 0.00244μΜ, 0.61ηΜ, 0.15 ηΜ, 0.04 ηΜ;

 2. Take 4 diluted compound solution in a 96-well plate;

3. Add 1 μl of lx kinase buffer to the 96-well plate. Lx kinase buffer: 50 mM HEPES, pH 7.5; 3 mM MgCl ₂ , 1 mM EGTA, 100 mM NaCl, 0.03% CHAPS, 2 mM DTT;

 4. Mix the two solutions of step 2 and step 3 and incubate for lOmin;

 5. Take 2.5 μί of the above mixture in a 384-well plate, duplicate wells, and set aside;

 6. Take 2.5 L of kinase solution in a 384-well plate and shake, the final concentration of ΡΙ3Κδ enzyme is 5.7 nM;

7. Take 5 μί of the substrate solution (ΡΙΡ ₂ ) in a 384-well plate and hydrazine reaction buffer in a 384-well plate and shake;

8. Incubate for 2 h at room temperature;

9. The reaction solution was stopped in a 384-well plate, shaken for 15 min, and Caliper was read. 10. IC _5Q calculation

Calculate the suppression rate (%) = (maximum conversion rate - conversion rate) I (maximum conversion rate - minimum conversion rate) χ ιοο, curve fitting using XL fit software, and IC _{5 is obtained} . value.

Experimental results:

 Table 1 In vitro enzymatic inhibitory activity of the compounds of the invention

The test product ΡΒΚδ enzymatic inhibition activity IC ₅ . (nM)

 Compound 1 100

 Compound 2 52

 Compound 4 13

 Compound 5 86.52

 Compound 6 33.5

 Compound 7 26.2

 Compound 8 28.8

 Compound 9 14.3

 Compound 12 47.5

 Compound 13 86

 Compound 19 45

 Compound 22 16.8

 Compound 23 29

 Compound 24 11.58

 Compound 25 34.5

 Compound 28 36.7

 Compound 29 27.4

 Compound 30 5.4

 Compound 31 28

 Compound 32 13.6

 Compound 33 6.5

 Compound 34 7.2

 Compound 35 14.3

 Compound 36 10

 Compound 37 33

 Compound 38 27

Compound 41 39 Test product ΡΒΚδ enzymatic inhibition activity IC _5Q (nM)

 Compound 42 11

 Compound 43 4.5

 Compound 44 85.92

 Compound 53 27

 Compound 57 9.3

 Compound 59 3.3

 Compound 60 3.7

 Compound 61 4.5

 Compound 62 43

 Compound 63 8.3

 Compound 64 11

 Compound 65 44.6

 Compound 71 3.6 Experimental conclusion: As can be seen from Table 1, the compound of the present invention has a good inhibitory activity against the ΡΙ3Κδ enzyme.

Experimental Example 2 Inhibitory activity of the compound of the present invention on sputum cells in vitro

Test sample: The compound of the present invention, self-made, the chemical name and structural formula are shown in the preparation examples of each compound; Experimental method:

 1. Isolation of Balb/c mice Β cells

 (1) The spleens of Balb/c mice were smashed, mashed in MACS (Miltenyl Biotec) buffer, and filtered through a 40 μm nylon cell sieve to obtain a single cell suspension.

 (2) Centrifuge the obtained cell suspension at 400 g, 4 °C for five minutes, remove the supernatant, add 1 ml of red blood cell lysate at room temperature, and gently resuspend the cell pellet. Two minutes later, pre-chilled MACS buffer was added. Filter the cell suspension into a new centrifuge tube with a 40 μηη cell strainer, 4 . C, 400 g was centrifuged for 5 minutes to collect the cells.

(3) Adjust the cell density to 10 ⁷ cells/40 μl with MACS buffer before adding the beads. 10 μΐ of the biotinylated antibody mixture was added per 10 ⁷ cells. After mixing, incubate on ice for 20 minutes, add 30 μM of MACS buffer and 20 μM of biotinylated antibody mixture beads per 10 ⁷ cells and incubate on ice for 20 minutes. After centrifugation, the cells were resuspended in 500 μM of MACS buffer. The pre-cooled MACS sorting column was placed in a MACS sorter and the cell suspension was applied to a MACS sorting column. The cells under the flow of unbound antibody are collected.

(4) The cells before and after sorting were detected by flow cytometry using PE anti-biotin antibody and CD45R (B220) antibody. 2. Cytotoxicity experiment and IC _5Q determination

 (1) Freshly isolated mouse B cells were counted using a hemocytometer (steps 1-4), and cell viability was determined to be above 98% by trypan blue staining.

(2) The cell density was adjusted to 3.89× ^{10 5} cells per ml using a medium, and a 90 μΐ cell suspension was taken with a multichannel pipette into a 96-well plate to obtain a final cell density of 3.5×10 ⁴ cells per well.

(3) Dilute the test compound and the positive compound in DMSO to form a stock solution, and add 10 μΐ of the prepared compound solution to a 96-well plate (three-point repetition for each concentration of each compound). Incubate for 30 minutes in a 37 V, 5% C0 ₂ incubator, then add 50 μΐ Β cell stimulation mix: 3 μ§ ηύ LPS + 5 ng/ml recombinant mouse IL-4 (final concentration).

(4) The cell plates were incubated for 72 hours in a 37 V, 5% C0 ₂ incubator and tested by CTG.

 (5) Melt the CTG reagent and equilibrate to room temperature. Transfer to a 96-well plate with a multi-channel pipettor, 5 (^1 CTG reagent/well, shake in a microplate fast shaker for 2 minutes and then place in the dark. 10 minutes, use Envision to detect luminescence readings

 3. Data analysis

The data obtained will be analyzed using Excel 2007 and GraphPad Prism 5.0 software. To calculate IC _5Q , a non-linear S-curve regression will be used to fit the data to obtain a dose-response curve. GraphPad Prism 5.0 software will automatically give IC ₅ o. value. Cell viability was calculated using the following formula: V sample V2 solvent control X 100%, V sample is the reading of compound treated wells, and V2 solvent control is the average of solvent control well (V2) readings.

 Inhibitory activity of the compounds of the invention on B cells in vitro

Inhibitory activity of in vitro B cells in the test article IC ₅ . ( μ Μ)

 Compound 8 0.75

 Compound 9 0.65

 Compound 30 0.016

 Compound 33 0.034

 Compound 34 0.12

 Compound 53 0.111

 Compound 57 0.01

 Compound 60 0.032

 Compound 61 0.05

 Compound 63 0.04

 Compound 72 0.32 Experimental conclusion: As can be seen from Table 2, the compound of the present invention has a good inhibitory activity against sputum cells.

Experimental Example 3 In vivo pharmacological activity of the compound of the present invention

Test sample: the compound of the present invention, self-made, the chemical name and structural formula are shown in the preparation examples of each compound; The efficacy of the inventive compound in the test of lipopolysaccharide-induced tumor necrosis factor alpha release.

experimental method:

 BALB/C mice, male, 22-25 g. They were randomly divided into model group, compound group 30, compound group 33, compound group 53 and CAL-101 group, with 5 rats in each group, and the dose was 30 mg/kg. The model group was intragastrically administered with the corresponding drug. The drug was administered by intraperitoneal injection of lipopolysaccharide (LPS) 15 mg/kg 30 min later. After LPS induction for 1 h, 500 μl of blood was taken from the sinus of the mouse eye. The heparin anticoagulant was mixed in a 1.5 ml-primary centrifuge tube, centrifuged at 3500 rpm in an eppendorf 5424R centrifuge, centrifuged at 4 °C for 10 min, and stored in -80 plasma. C, Mouse TNF-alpha Elisa Ready-set-go kit for the detection of TNF-α in plasma.

 TNF-α inhibition rate in plasma = (model group mean - mean group of administration groups) / model group mean X 100%

 Experimental results and conclusions:

 Table 3 Inhibition of TNFa by the compounds of the invention

 Test sample TNFa inhibition rate (%)

 Compound 30 52.4

 Compound 33 52.0

 Compound 53 51.7

 CAL-101 41.2 It can be seen from Table 3 that compared with the model group, the test samples CAL-101, Compound 30, Compound 33, and Compound 53 all significantly reduced the TNFa content in mouse plasma, and the inhibition rate was 41.2% (p, respectively). <0.01), 52.0% (p<0.001), 52.4% (p<0.001), 51.7% (p<0.001), the compound of the present invention has more significant inhibition of TNFa in mouse plasma compared with the CAL-101 group. effect. Preparation example

The raw materials used in the preparation examples are commercially available, for example, from Jinan Qiguang Science and Trade (Chemical Reagent) Co., Ltd., Shanghai Darui Fine Chemicals Co., Ltd., Shanghai Jingyan Chemical Technology Co., Ltd., Beijing Bailingwei Technology Co., Ltd. Company, Shanghai Demer Chemical Co., Ltd., Alfa Aesar (Tianjin) Chemical Co., Ltd., Nanjing Yaoshi Drug Research and Development Co., Ltd., etc. Example 1 Preparation of f5)-2-"l-f9H-indol-6-ylamino)propyl -3- phenylamino) quinazolin-4f3H>-one (Compound 1)

 (1) Preparation of (5)-2-[2-(tert-Butoxycarbonylamino)butyrylamino]benzoic acid ethyl ester

 In a dry single-mouth bottle, add (5)-2-(tert-butoxycarbonylamino)butyric acid (18.33 g, 90.2 mmol), DIEA (31.3 mL, 180 mmol), HATU (23 g, 60.5 mmol), 150 mL Dichloromethane and 2 mL of DMF were dissolved. Stir at room temperature for 30 π ώ, add 2-aminobenzoic acid ethyl ester (10 g, 60.5 mmol), stir at room temperature for 16 h, remove the chloroformin by rotary evaporation, add water, acetic acid The ester was extracted, and the mixture was concentrated. mjjjjjjjjj

 (2) Preparation of (5)-2-[2-(tert-butoxycarbonylamino)butyrylamino]benzoic acid

 In a dry reaction flask, add (5) ethyl 2-[2-(tert-butoxycarbonylamino)butyrylamino]benzoate (2.94 g, 8.4 mmol), 10 mL methanol, 10 mL THF and 20 mL water Add lithium hydroxide monohydrate (0.806 g, 19.2 mmol), stir at room temperature overnight, complete the reaction by TLC, remove methanol and tetrahydrofuran by rotary evaporation, adjust pH to 3-4 with 2 N aqueous hydrochloric acid, and elute with white solid. The ethyl ester was extracted and dried to give a white solid (2.52 g).

 (3) Preparation of (5)-1-oxo-1-[2-(2-benzofluorenyl)phenylamino]butan-2-ylcarbamic acid tert-butyl ester

 In a dry reaction flask, add (5)-2-[2-(tert-butoxycarbonylamino)butyrylamino]benzoic acid (2 g, 6.2 mmol), DIEA (3.24 mL, 18.6 mmol), HATU (2.61 g) , 6.86 mmol), 40 mL of dichloromethane and 2 mL of DMF as solvent. Stir at room temperature for 30 min, force B into phenylhydrazine (0.675 g, 6.24 mmol), stir at room temperature for 48 h, stop the reaction, remove the dichloro by rotary evaporation. Methane, water was added, and ethyl acetate was evaporated, and the mixture was evaporated. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj

 (4) Preparation of (5)-2-(1-aminopropyl)-3-(phenylamino)quinazoline-4(3H)-one hydrochloride

In a dry reaction flask, weigh out (5)-1-oxo-1-[2-(2-benzofluorenyl)phenylamino]butan-2-ylcarbamic acid tert-butyl ester (1.0 g, 2.42 Methanol), dissolved in 40 mL of ethanol, added 4 mL of concentrated hydrochloric acid with stirring in an ice water bath, stirred for 30 min, heated to 85 ° C and stirred for 16 h. LC-MS showed the reaction was completed, and then concentrated to give a white solid. Used for the next step.

 (5) Preparation of (5)-2-[l-(9H-嘌呤-6-ylamino)propyl]-3-(phenylamino)quinazoline-4(3H)-one

 The previous product (5)-2-(1-aminopropyl)-3-(phenylamino)quinazolin-4(3H)-one hydrochloride was dissolved in 20 mL of tert-butanol and added to DIEA (2.1 mL) , 12.1 mmol), stirred for half an hour in an ice bath, then added 6-chloro-9H-indole (376 mg, 2.43 mmol), protected with nitrogen at 85 ° C, protected from light for 6 h, cooled, concentrated, reversed The phase was obtained as a white solid (116 mg).

Mass spectrometry (Μ+Η): 413.2

1H-NMR ( ₆ -DMSO, 400 ΜΗζ): δ 12.9 (1Η, br s), 9.10 (1H, s), 8.23-8.12 (1H, m), 8.11-8.02 (2H, m), 7.85-7.76 ( 1H, m), 7.76-7.68 (1H, m), 7.61 (1H, d), 7.50 (1H, t), 7.26-7.15 (2H, m), 6.94 (2H, d), 6.84 (1H, t) , 5.53 (1H, m), 2.22-2.11 (1H, m), 2.05-1.92 (1H, m), 0.995 (3H, t). Example 2 2-KS)-: 9H-嘌呤-6-ylamino Preparation of propyl]-5-fluoroanilinoquinazoline~(3H)-one (Compound 2)

 (1) Preparation of 2-fluoro-6-nitro-N'-phenylbenzohydrazide

2-Fluoro-6-nitrobenzoic acid (7.4 g, 40.0 mmol) was dissolved in 50 mL of CH ₂ Cl ₂ and 0.4 mL of DMF, and oxalyl chloride (7.61 g, 60.0 mmol) was slowly added dropwise thereto, and stirred at room temperature for two hours. After that, the solvent was removed by concentration, then dissolved in 8 mL of dioxane, and dropped to phenylhydrazine (4.32 g, 40.0 mmol), NaHC0 ₃ (6.72 g, 80.0 mmol) of dioxane (20 mL) under cooling. And water (20 mL) solution, the mixture was added to the room temperature and stirred for half an hour. After concentration under reduced pressure to a volume of one third, ethyl acetate was extracted, dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (petroleum ether: ethyl acetate = 2:1) gave 4.7 g of white solid.

 (2) Preparation of 2-amino-6-fluoro-N'-phenylbenzohydrazide

2-Fluoro-6-nitro-N'-phenylbenzohydrazide (1.5 g, 5.45 mmol) was dissolved in 20 mL of methanol and added thereto. S3

0.5 g of 10% Pd/C, hydrogen gas, reacted at room temperature for 36 h, the reaction was completed, Pd/C was filtered off, and the organic phase was concentrated to obtain 1.3 g, yield 97.2%.

 (3) Preparation of (5)-1-[3-fluoro-2-(2-benzofluorenyl)phenylamino]-1-oxobutan-2-ylcarbamic acid tert-butyl ester

 In a dry reaction flask, (5)-2-(tert-butoxycarbonylamino)butyric acid (166 mg, 0.817 mmol), 2-amino-6-fluoro-T '-phenylbenzoic acid hydrazide (100 mg , 0.408 mmol), DIEA (0.093 mL, 0.533 mmol) and HATU (170 mg, 0.448 mmol) were added to 12 mL of dichloromethane, stirred at room temperature for 48 h, added with water and dichloromethane, dichloromethane The organic layer was combined, washed with EtOAc EtOAc (EtOAc m. %.

 (4) Preparation of (5 -2-(1-aminopropyl)-5-fluoro-3-(phenylamino)quinazoline-4(3H)-one hydrochloride

 (5)-1-[3-Fluoro-2-(2-benzohydrazino)phenylamino]-1-oxobutan-2-ylcarbamic acid tert-butyl ester (421 mg, 0.978 mmol) was dissolved in 20 In mL ethanol, 2 mL of concentrated hydrochloric acid was added dropwise to the reaction flask under ice bath. After stirring for half an hour, the reaction was transferred to an oil bath at 85 ° C for 16 h, cooled and concentrated to give a white solid. .

 (5) Preparation of 2-[(5)-l-(9H-indol-6-ylamino)propyl]-5-fluoro-3-(phenylamino)quinazoline-4(3H)-one

 (S)-2-(l-Aminopropyl)-5-fluoro-3-(phenylamino)quinazolin-4(3H)-one hydrochloride obtained from the above step was added to 20 mL of tert-butanol ( Approximately 0.978 mmol) and DIEA (0.68 mL, 3.91 mmol) were stirred in an ice bath for half an hour, then 6-chloro-9H-indole (152 mg, 0.98 mmol) was added thereto, and the mixture was heated to 85 ° C for 24 h, cooled. Concentration, silica gel column chromatography (EtOAc) elute

Mass Spectrometry (M+H): 431

1H-NMR (DMSO-i/ ₆ , 400 MHz, 80 °C): δ 12.74 (1Η, s), 8.86 (1Η, s), 8.19-8.00 (2H, m), 7.83-7.74 (1H, m) , 7.48 (1H, d), 7.29-7.13 (4H, m), 6.93-6.78 (3H, m), 5.78 (1H, s), 2.24-1.88 (2H, m), 1.03-0.91 (3H, m) .

Example 3 (S>-2-[l-i9H-indol-6-ylamino)propyl1-5-chloro-3-(phenylamino)quinazoline~4(3ff)-ketone ί compound 4) Preparation

 (1) Preparation of methyl 2-amino-6-chlorobenzoate

 2-amino-6-chlorobenzoic acid (10 g, 58.3 mmol), 120 mL of DMF was added to a dry reaction flask, and potassium carbonate (12 g, 86.8 mmol), iodothymidine (9.88 g, 69.6 mmol) was added to the ice bath. ), the reaction was stirred overnight at room temperature in the dark. The solvent was evaporated to dryness and purified by chromatography to yield 10.3 g.

 Preparation of (2) 03⁄4-2-[2-(tert-Butoxycarbonylamino)butyrylamino]-6-chlorobenzoic acid methyl ester

 Add 100 mL DMF, 100 mL DCM, 2-amino-6-chlorobenzoic acid methyl ester (10.3 g, 55.5 mmol), (5)-2-(tert-butoxycarbonylamino)butyric acid (18.0) to the reaction flask. g, 88.6 mmol), DIEA (12.6 mL, 72.4 mmol), HATU (23.3 g, 61.3 mmol). A part of the solvent was evaporated, water was added, ethyl acetate was evaporated, washed with water, and dried, and column chromatography to give pale yellow liquid 15.8 g, yield 76.8%.

 (3) Preparation of (S)-2-[2-(tert-butoxycarbonylamino)butyrylamino]-6-chlorobenzoic acid

 Methyl (5)-2-[2-(tert-butoxycarbonylamino)butyrylamino]-6-chlorobenzoate (15.7 g, 42.3 mmol) was dissolved in 200 mL of tetrahydrofuran and 60 mL of methanol. The aqueous lithium oxyhydroxide solution was stirred overnight at room temperature. A part of the solvent was removed, water was added, and diluted with hydrochloric acid to adjust to pH 4, ethyl acetate was extracted several times, dried, and dried to give a pale yellow oil, 15.0 g, yield 99.3%.

 (4) Preparation of 0S)-l-[3-chloro-2-(2-benzofluorenyl)phenylamino]-1-oxobutan-2-ylcarbamic acid tert-butyl ester

(5)-2-[2-(tert-Butoxycarbonylamino)butyrylamino]-6-chlorobenzoic acid (7.48 g, 21.0 mmol), 50 mL DCM and 50 mL DMF, DIEA were added to the dried reaction flask. (9.1 mL, 52.3 mmol), phenylhydrazine hydrochloride (4.48 g, 31.0 mmol), HATU (10.37 g, 27.3 mmol). Remove some solvent by rotary evaporation, add water, Ethyl acetate extraction, water washing, and column chromatography gave white solid (yield: 7.86 g).

 (5) Preparation of (5)-2-(1-aminopropyl)-5-chloro-3-(phenylamino)quinazoline-4(3H)-one hydrochloride

 ( )-1-[3-Chloro-2-(2-benzofluorenyl)phenylamino]-1-oxobutan-2-ylcarbamic acid tert-butyl ester (500 mg, 1.12 mmol) was added to the reaction flask. ), 10 mL of ethanol, 3 mL of concentrated hydrochloric acid, and refluxed under heating overnight. After cooling to room temperature, a white solid precipitated, which was filtered, washed with iced ice and diethyl ether. A white solid 200 mg was obtained in a yield of 48.8%.

(6) Preparation of (S)-2-[l-(9H-indol-6-ylamino)propyl]-5-chloro-3-(phenylamino)quinazoline-4(3H)-one

 (5)-2-(1-Aminopropyl)-5-chloro-3-(phenylamino)quinazolin-4(3H)-one hydrochloride (200 mg, 0.547 mmol) was added to the dried reaction flask. , 15 mL of tert-butanol, 2 mL of DIEA, 6-chloro-9Η-嘌呤 (113 mg, 0.73 mrnol), and refluxed for 3 days. The solvent was evaporated to dryness, and then purified to give white crystals of llO.

Mass spectrometry (Μ+Η): 447.2

1H-NMR ( _6- DMS0, 400 ΜΗζ): δ 12.97 (H, br s), 8.99 (IH, s), 8.22-8.12 (IH, m), 8.09 (IH, m), 7.80-7.61 (2H, (m), 7.52 (2H, m) -1.92 (IH, m), 0.999 (3H, t).

Example 4 (5V2-[1-(7-pyrrolo-[2,3-dl-pyrimidin-4-ylamino)propyl1-5-chloro-3-(phenylamino)quinazoline-4f3H)-one ( Preparation of compound 5)

 (5)-2-(1-Aminopropyl)-5-chloro-3-(phenylamino)quinazolin-4(3H)-one hydrochloride (600 mg, 1.64 mmol) was dissolved in tert-butanol 10 mL, add 4-chloro-7H-pyrrolo[2,3-purine (300 mg, 1.95 mmol), then add DIEA (0.8 mL, 4.59 mmol), reflux for 7 days, spin dry solvent, pass the preparation The phase obtained 200 mg of product in a yield of 27.3%. Mass spectrometry (Μ+Η): 446.2

 1H-NMR ( <i-DMS0, 400 ΜΗζ): δ 11.51 (IH, s), 8.93 (IH, s), 7.98 (1H, s), 7.82 (IH, d), 7.66 (1H, t), 7.47 (2H, t), 7.27 (2H, t), 7.16-7.08 (2H, m), 6.87 (IH, t), 6.80-6.75 (IH, m), 6.74-6.65 (1H, m), 5.45-5.35 (IH, m), 2.20-2.08 (IH, m), 1.95-1.80 (1H, m), 1.06 (3H, t).

Example 5 Preparation of tf)-2-[1-(9H-indol-6-ylamino)propyl1-3-phenylamino-5-trifluoromethylquinazoline-4f3H)-one (Compound 6)

(1) Preparation of 2-hydroxyimino-N-(3-trifluoromethylphenyl)acetamide

 In a 2 L reaction flask, hydrated trichloroacetaldehyde (100 g, 0.605 mol) and anhydrous sodium sulfate (700 g, 4.93 mol) were dissolved in 1.4 L of water and heated to 35 ° C. The aniline (87 g, 0.54 mol) was dissolved in 400 mL of water and added to the above reaction solution. Then, 56 mL of concentrated hydrochloric acid was added dropwise and kept at the same temperature, and 200 of hydrochloric acid light amine (135 g, 1.94 mol) was dissolved. The mL solution was added to the system. After completion, the reaction solution was heated to 90 ° C for 2 h, then cooled down. When the temperature was lowered to 50 Ό, the filter was lightly washed three times with water and dried in a vacuum oven overnight. 112 g was obtained with a yield of 89.3%.

 (2) Preparation of 4-(trifluoromethyl)porphyrin-2,3-dione

 In a dry reaction flask, 86% concentrated sulfuric acid (430 mL) was heated to 60 ° C and dried 2-hydroxyimino-N-(3-trifluoromethylphenyl)acetamide (100 g, 431 mmol) Add the batch to the reaction flask in batches for 1 h, keep the temperature of the system not more than 65 Γ, and then heat up to 85 °C for 20 minutes, then cool to room temperature. Pour into 2 L of ice water and stir for half an hour. The yellow solid precipitated, filtered and dried to give 20 g of product.

(3) Preparation of 2-amino-6-(trifluoromethyl)benzoic acid

 Add 220 mL of 5% sodium hydroxide solution (275 mmol) and 220 mL of 30% aqueous hydrogen peroxide solution to the dried reaction flask, and add 4-(trifluoromethyl)porphyrin-2,3-dione in batches. (17 g, 79 mmol), the mixture was heated to 50 ° C for 1 h, then cooled, filtered, and the filtrate was adjusted to pH 4, and solids were precipitated, filtered and dried to give a pale-yellow solid, 11 g, yield 6.78 %.

 (4) Preparation of (5)-2-[2-(tert-butoxycarbonylamino)butyrylamino]-6-(trifluoromethyl)benzoic acid

In a dry reaction flask, 2-amino-6-(trifluoromethyl)benzoic acid (5.2 _& 25.3 11∞01), (5)-2-(tert-butoxycarbonyl) Amino)butyric acid (5.2 g, 25.6 mmol), DIEA (3.44 g, 26.6 mmol) and HATU (10.16 g, 26.7 mmol) were added to 50 mL of DMF, stirred at room temperature for 7 days, and water and dichloromethane were added. The methyl chloride was extracted, and the organic layer was combined, washed with water, and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate.

 (5) Preparation of (5)-1-(4-oxo-5-trifluoromethyl-4H-benzo[[1,3]oxazin-2-yl)propylcarbamic acid tert-butyl ester In the reaction flask, (5)-2-[2-(tert-butoxy-ylamino)butyrylamino]-6-(trifluoromethyl)benzoic acid (2.6 g, 6.66 mmol), 50 mL of tert-butyl The alcohol, acetic anhydride (3.15 g, 30.9 mmol) was heated to reflux overnight. The solution was distilled under reduced pressure and the obtained product was used directly in the next step.

 (6) Preparation of (5)-1-(4-oxo-3-phenylamino-5-trifluoromethyl-3,4-dihydroquinazolin-2-yl)propylcarbamic acid tert-butyl ester

 The above product was dissolved in 15 mL of pyridine, phenylhydrazine (756 tng, 6.99 mmol) was added, and the mixture was heated to 100 ° C for 8 hours. The solvent was evaporated to dryness and purified by column chromatography to yield 1.5 g of pale yellow solid.

 (7) Preparation of (5)-2-(1-aminopropyl)-3-phenylamino-5-(trifluoromethyl)quinazoline-4(3H)-one hydrochloride

 (5) Small (4-oxo-3-phenylamino-5-trifluoromethyl-3,4-dihydroquinazolin-2-yl)propylcarbamic acid tert-butyl ester in a dry reaction flask (1.5 g, 3.24 mmol) was dissolved in absolute ethanol (30 mL), and hydrogen chloride gas was passed through the system until the reaction was completed. After evaporation, 1.2 g of a solid (hydrochloride salt) was obtained.

 (8) Preparation of (52-[9H-indol-6-ylamino)propyl1-3-anilino-5-(trifluoromethyl)quinazoline-4(3/)-one In a reaction flask, (5)-2-(1-aminopropyl)-3-phenylamino-5-(trifluoromethyl)quinazoline-4(3H)-one salt was added to 30 mL of tert-butanol. Acid salt (800 mg, 2.01 mmol) and DIEA (1.4 mL, 8.04 mmol), then added 6-chloro-9 hydrazine (619 1^, 4.00:1^101), and reacted at 85 Ό for 24 h. , chilled, concentrated, preparative chromatographic separation afforded 194 mg of white solid.

Mass spectrometry (M+H): 481.2

1H-NMR (^-DMS0, 400 MHz): δ 12.92 (1Η, br s), 9.13 (1H, s), 8.22-8.11 (1H, m), 8.10 (1H, s), 8.02-7.84 (3H, m), 7.84-7.63 (1H, m), 7.29-7.15 (2H, t), 6.99 (1H, d), 6.86 (1H, t), 6.69 (1H, d), 5.48 (1H, m), 2.25 -2.10 (1H, m), 2.02-1.89 (1H, m), 1.01, 0.87 (3H, two triplets). Example 6 i5)-2-U-(9ff-嘌呤-6-ylamino)propyl Preparation of -3-μ-fluorophenylamino)-5-(trifluoromethyl)quinazolin-40g)-one (Compound 7)

(1) (5)-l-[4-Oxo- ^5- (trifluoromethyl)-4H-benzo[][l,3]oxazin-2-yl]propylcarbamic acid tert-butyl ester In a dry reaction flask, 2-amino-6-(trifluoromethyl)benzoic acid (1.5 g, 7.31 mmol) was dissolved in 50 mL of pyridine, followed by (5)-2-(tert-butoxycarbonylamino) Butyric acid (1.5 g, 7.38 mmol), triphenyl phosphite (2.3 g, 7.41 mmol) was reacted at 60 ° C for 24 h until the starting material disappeared.

(2) (5)-1-[3-( ⁴ -Fluorophenylamino)-4-oxo-5-(trifluoromethyl)-3,4-dihydroquinazolin-2-yl]propyl Preparation of tert-butyl carbamate

 To the above reaction solution, p-fluorobenzoic acid hydrochloride (1.5 g, 9.23 mmol) was added, and the mixture was heated to 100 ° C for 8 h until the starting material disappeared. After cooling, the organic solvent was spun off and subjected to column chromatography (PE: EA = 6:1) to afford 1.5 g of pale yellow solid.

 (3) Preparation of (5)-2-(1-aminopropyl)-3-(4-fluorophenylamino)-5-(trifluoromethyl)quinazolin-4(3H)-one hydrochloride In a dry reaction flask, (5)-1-[3-(4-fluorophenylamino)-4-oxo-5-(trifluoromethyl)-3,4-dihydroquinazolin-2- Tert-butyl propyl carbamate (1.5 g, 3.12 mmol) was dissolved in 30 mL of absolute ethanol, and hydrogen chloride gas was passed through the system until the reaction was complete. After rotary distillation, 1.2 g of solid (hydrochloride) was obtained. 92.3%.

 (4) (5 -2-[l-(9H-嘌呤-6-ylamino)propyl]-3-(4-fluoroanilino)-5-(trifluoromethyl)quinazoline-4 (3H Preparation of ketone

 In a dry reaction flask, add (5 2-(1-aminopropyl)-3-(4-fluorophenylamino)-5-(trifluoromethyl)quinazolin-4 to 30 mL of tert-butanol ( 3H)-ketone hydrochloride (1.0 g, 2.40 mmol) and DIEA (2.0 mL, 11.5 mmol), 6-chloro-9H-indole (700 mg, 4.53 mmol), reaction at 85 ° C for 24 h, cooling , concentration, preparative chromatography to give a white solid 600 mg, yield 50%.

Mass spectrometry (Μ+Η): 499.2 S9

'H-NMR^-DMSO, 400 MHz): δ 12.98 (1H, s), 9.12 (1H, s), 8.22-8.10 (2H, m), 8.00-7.81 (4H, m), 7.16-7.00 (4H , m), 5.44 (1H, m), 2.21-1.80 (2H, m), 1.02 (3H, t).

Example 7 (S)-2-[W9 嘌呤-6-ylamino)propyl1-5-fluoro-3-(4-fluorophenylamino)-quinazoline-4(3^)-one-f compound 8 Preparation

 (1) Preparation of 2-fluoro-NH4-fluorophenyl)-6-nitrobenzoyl hydrazide

2-Fluoro-6-nitrobenzoic acid (5.5 g, 29.7 mmol) was dissolved in 50 mL of CH ₂ C1 ₂ and 0.4 mL of DMF, and oxalyl chloride (5.66 g, 44.6 mmol) was slowly added dropwise thereto, and stirred at room temperature for two hours. Thereafter, the solvent was removed by concentration, and then dissolved in 8 mL of dioxane, and it was added dropwise to p-fluorophenylhydrazine hydrochloride (4.829 g, 29.7 mmol), NaHC0 ₃ (6.72 g, 80 mmol). After adding 6 mL of a solution of 20 mL and 20 mL of water, the mixture was stirred at room temperature and stirred for half an hour. After concentration under reduced pressure to one-third volume, ethyl acetate was extracted, dried over anhydrous sodium sulfate, filtered, and concentrated. Recrystallization from diethyl ether gave 4.4 g of a pale yellow product, yield 50.5.

 (2) Preparation of 2-amino-6-fluoro-N'-(4-fluorophenyl)benzoyl hydrazide

 2-Fluoro-N-(4-fluorophenyl)-6-nitrobenzoic acid hydrazide (4.4 g, 15.0 mmol) was dissolved in 60 mL of methanol, and 0.5 g of 10% Pd/C was added thereto. Hydrogen was reacted at room temperature for 36 h, the reaction was completed, Pd/C was filtered off, and the organic phase was concentrated to give 3.8 g, yield 96.3%.

(3) Preparation of (5)-1-[3-fluoro-2-[2-(4-fluorophenyl)decanoyl]phenylamino]-1-oxobutan-2-ylcarbamic acid tert-butyl ester In a dry reaction flask, (5)-2-(tert-butoxycarbonylamino)butyric acid (5.8 g, 28.6 mmol), 2-amino-6-fluoro-N'-(4-fluorophenyl)benzene The hydrazide (3.8 g, 14.4 mmol), DIEA (3.7 mL, 21.2 mmol) and HATU (6.0 g, 15.8 mmol) were added to 200 mL of dichloromethane, stirred at room temperature for 48 h, and water and dichloromethane were added. Dichloromethane is extracted, the organic phase is combined, washed with water, washed with saturated brine, and the organic layer is dried over anhydrous sodium sulfate. The white solid was obtained in 3.4 g, yield 52.6%.

 (4) Preparation of (5)-2-(1-aminopropyl)-5-fluoro-3-(4-fluorophenylamino)quinazoline-4(3H)-one hydrochloride

 (5)-1-[3-Fluoro-2-[2-(4-fluorophenyl)decanoyl]phenylamino]-1-oxobutan-2-ylcarbamic acid tert-butyl ester (3.4 g, 7.58 mmol) was dissolved in 60 mL of ethanol. 10 mL of concentrated hydrochloric acid was added dropwise to the reaction flask under ice bath. After stirring for half an hour, the reaction was transferred to an oil bath for 85 h under reflux for 16 h. 1.6 g of white solid, yield 57.5%.

 (5) CS)-2-[l-(9H-嘌呤-6-ylamino)propyl]-5-fluoro-3-(4-fluorophenylamino)-quinazoline-4(3H)-one Preparation

 Add (5)-2-(1-aminopropyl)-5-fluoro-3-(4-fluorophenylamino)quinazolin-4(3H)-one hydrochloride (600) to 20 mL of tert-butanol Mg, 1.64 mmol) and DIEA (0.71 mL, 4.08 mmol) were stirred in an ice bath for half an hour, then 6-chloro-9H-indole (378 mg, 2.45 mrnol) was added thereto, and the reaction was allowed to react at 85 ° C for 24 h. , cooling, concentration, preparative chromatography to give a white solid, 140 mg, yield 19.0%.

Mass spectrometry (Μ+Η): 449.2

1H-NMR ( _6- DMS0, 400 ΜΗζ): δ 12.96 (1Η, br s), 8.99 (1H, s), 8.22-8.08 (2H, m), 7.66-7.47 (1H, m), 7.38 (1H, d), 7.24 (1H, t), 7.13-6.99 (4H, m), 6.78-6.69 (1H, m), 5.47 (1H, m), 2.20-2.07 (1H, m), 2.06-1.85 (1H, m), 1.01 (3H, t).

Example 8 i5)-2-ll-i9H-indole-6-ylamino)propyl]-5-chloro-3-(4-fluorophenylamino)quinazoline-4(3^)-one (combination

(1) Preparation of (5)-1-[3-chloro-2-[2-(4-fluorophenyl)decanoyl]phenylamino]-1-oxobutan-2-ylcarbamic acid tert-butyl ester 1.50 g (4.20 mmol) of (S)-2-[2-(tert-butoxycarbonylamino)butyrylamino]-6-chlorobenzoic acid, 20 mL of DCM and 10 mL of DMF, 1.8 mL were added to the dried reaction flask. (10.33 mmol) DIEA, 1.03 g (6.33 mmol) p-fluorophenylhydrazine hydrochloride, 2.08 g (5.47 mmol) HATU, stirring overnight at room temperature. Rotate some solvent, add water, B Ethyl acetate extraction, water washing, column chromatography ( petroleum ether: ethyl acetate = 3:1) afforded 1.95 g of pale yellow solid.

 (2) Preparation of (>S)-2-(l-aminopropyl)-5-chloro-3-(4-fluorophenylamino)quinazoline-4(3H)-one hydrochloride

 (5)-1-(3-Chloro-2-[2-(4-fluorophenyl)decanoyl]phenylamino]-1-oxobutan-2-ylcarbamic acid tert-butyl ester was added to the reaction flask. (640 mg, 1.38 mmol), 10 mL of ethanol, 3 mL of concentrated hydrochloric acid. After cooling to room temperature, a white solid precipitated, which was filtered, washed with ethyl ether and diethyl ether. A white solid of 200 mg was obtained in a yield of 37.8%.

 (3) (5)-2-[l-(9H-Indol-6-ylamino)propyl]-5-chloro-3-(4-fluorophenylamino)quinazolin-4(3H)-one Preparation

 (5)-2-(1-Aminopropyl)-5-chloro-3-(4-fluorophenylamino)quinazolin-4(3H)-one hydrochloride (200 mg) was added to the dried reaction flask. , 0.522 mmol), 15 mL of tert-butanol, 2 mL of DIEA, 155 mg (1.0 mmol) of 6-chloro-9H-indole, and refluxed for 3 days. The solvent was evaporated to dryness (mjqqqqqqqq

Mass spectrometry (Μ+Η): 465.2

1H-NMR ( _6- DMS0, 400 ΜΗζ): δ 12.97 (IH, br s), 8.98 (IH, s), 8.30-8.08 (2H, m), 7.90-7.59 (2H, m), 7.57-7.46 ( 2H, m), 7.16-6.98 (4H, m), 5.44 (IH, m), 2.20-2.05 (IH, m), 2.05-1.92 (IH, m), 1.01 (3H, t).

Example 9 (S)-2-fl-f3H~imidazo[4,5-Wpyridin-7-ylamino)propyl1-5-chloro-3-ί4-fluorophenylamino)quinazoline-4 ( Preparation of 3-ketone (Compound 10)

 (1) Preparation of 7-chloro-3H-imidazo[4,5-b]pyridine-3-carboxylic acid tert-butyl ester

 In a dry reaction flask, add 10 mL of dichloromethane, 1.34 g (8.73 mmol) of 7-chloro-3H-imidazo[4,5-b]pyridine, 2.85 g (13.1 mmol) of di-tert-butyl dicarbonate. , 10 mg DMAP, stirred at room temperature for 1 hour, the solution became clear from turbidity, and the reaction was terminated by TLC. The solvent was evaporated to dryness (mjqqqqqqq

(2) (5)-2-[l-(3H-Imidazo[4,5-b]pyridin-7-ylamino)propyl]-5-chloro-3-(4-fluorophenylamino) quinazole Porphyrin-4(3H)_ W

 Preparation of 62 ketone

 In a dry microwave reaction tube, 1.80 g (7.10 mmol) of 7-chloro-3H-imidazo[4,5-b]pyridine-3-carboxylic acid tert-butyl ester, (5)-2-(1-aminopropane) were added. -5-Chloro-3-(4-fluoroanilino)quinazolin-4(3H)-one 1.40 g (4.04 mmol), 10 mL of n-butanol, 1.4 mL (8.04 mmol) DIEA, microwave heated to The reaction was carried out at 180 ° C for 20 min. The solvent was dried and purified by column chromatography (EtOAc:EtOAc:EtOAc:EtOAc:

Mass Spectrometry (M+H): 464.0

1H-NMR (i/ ₆ -DMSO, 400 MHz): 6 12.60 (IH, br s), 9.32-8.93 (1H, m), 8.14-7.59 (5H, m), 7.18-6.91 (2H, m), 6.90-6.60 (4H, m), 5.46 (1H, m), 2.23-2.05 (1H, m), 2.05-1.80 (IH, m), 1.16 (3H, m).

Example 10 (S)-4-f2-iW9ff-嘌呤-6-ylamino)propyl1-5-fluoro-4-oxoquinazolin-3 (4 n-ylamino 1benzonitrile f compound 12 Preparation

 (1) Preparation of 4-cyanobenzoquinone hydrochloride

The p-aminobenzonitrile (25 g, 211 mmol) was dissolved in 200 mL of concentrated hydrochloric acid, and 100 mL of an aqueous solution of sodium nitrite (15.8 g, 229 mmol) was added dropwise at -15 °C, and the reaction solution was The mixture was added dropwise to a reaction system of stannous chloride dihydrate (238 g, 1.05 mol) and 185 mL of concentrated hydrochloric acid at -10 ° C, and the mixture was stirred at -0 ° C for 15 min, and the solid was suction filtered. The solid was washed with diethyl ether and dried to give &lt

 (2) Preparation of N'-(4-cyanophenyl)-2-fluoro-6-nitrobenzoyl hydrazide

2-fluoro-6-nitrobenzoic acid (5.55 g, 30.0 mmol) was dissolved in 50 mL C¾Cl ₂ and 0.3 mL DMF, to which was slowly added dropwise oxalyl chloride (5.71 g, 45.0 mmol), stirring at room temperature 2 h, The solvent was removed by concentration, then dissolved in 6 mL of dioxane, and then added dropwise to 4-cyanobenzoquinone hydrochloride (5.09 g, 30.0 mmol), NaHC0 ₃ (7.56 g, 90.0 mmol). In a solution of 15 mL of 15 mL and 15 mL of water, the mixture was added to room temperature and stirred for half an hour. After concentration under reduced pressure to a volume of one-third, ethyl acetate was extracted, dried over anhydrous sodium sulfate, filtered, and concentrated. Silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) afforded 6.

 (3) Preparation of 2-amino-N'-(4-cyanophenyl)-6-fluorobenzoic acid hydrazide

 N'-(4-cyanophenyl)-2-fluoro-6-nitrobenzoic acid hydrazide (4.2 g, 14.0 mmol) was dissolved in 30 mL of methanol, and 0.6 g of 10% Pd/C was added thereto. With hydrogen gas, the reaction was carried out at room temperature for 18 h, the reaction was completed, Pd/C was filtered off, and the solid obtained by concentration of the organic phase was directly used for the next reaction.

 (4) Preparation of (5)-1-[2-[2-(4-cyanophenyl)decanoyl]-3-fluorophenylamino]-1-oxobutan-2-ylcarbamic acid tert-butyl ester In a dry reaction flask, the crude 2-amino-N'-(4-cyanophenyl)-6-fluorobenzoic acid hydrazide obtained in the previous step (about 14.0 mmol) > (5)-2- (t-butyl) Oxycarbonylamino)butyric acid (4.26 g, 21.0 mmol), DIEA (3.17 mL, 18.2 mmol) and HATU (6.38 g, 16.8 !1^101) were added to 40^^ dichloromethane, and stirred at room temperature for 64 h. The mixture was extracted with water and dichloromethane, and then evaporated, evaporated, evaporated, evaporated. 1) A white solid of 2.65 g was obtained in a two-step total yield of 41.6%.

 (5) Preparation of 0S)-4-[2-(l-aminopropyl)-5-fluoro-4-oxoquinazoline-3(4H)-ylamino]benzonitrile hydrochloride

 (5)-1-[2-[2-(4-Cyanophenyl)decanoyl]-3-fluorophenylamino]-1-oxobutan-2-ylcarbamic acid tert-butyl ester (1.37 g, 3.0 mmol) was dissolved in 30 mL of ethanol, and 3 mL of concentrated hydrochloric acid was added dropwise to the reaction flask under ice bath. After stirring for half an hour, the reaction was transferred to an oil bath at 85 ° C for 24 h, cooled and concentrated to give white. The solid was used directly in the next step.

(6) (5)-4-[2-[l-(9H-嘌呤-6-ylamino)propyl]-5-fluoro-4-oxoquinazolin-3(4H)-ylamino]benzene Preparation of carbonitrile To 20 mL of tert-butanol was added (5)-4-[2-(1-aminopropyl)-5-fluoro-4-oxoquinazoline-3(4H)- Base amino)benzonitrile hydrochloride (about 3.0 mmol) and DIEA (1.56 mL, 9.0 mmol) were stirred in an ice bath for half an hour, then 6-chloro-9H-indole (556 mg, 3.6 mmol) was added. The reaction was carried out at 85 ° C for 36 h, cooled, concentrated, EtOAcjjjjjjj

Mass spectrometry (Μ+Η): 456.2

'H-NMR^-DMSO, 400 MHz): δ 12.94 (1H, s), 9.67 (1Η, s), 8.28-8.03 (2H, m), 7.95-7.24 (6H, m), 7.08-6.28 (2H , m), 5.38 (1H, m), 2.20-1.79 (2H, m), 1.01 (3H, m). Example 11 tf)-2-[1-(9-fluoren-6-ylamino)propyl]-5-fluoro-3-f3-fluorophenylamino)-quinazoline-4ag)-one (Compound 13) Preparation

 (1) Preparation of 2-fluoro-NH3-fluorophenyl)-6-nitrobenzoyl hydrazide

Add 3-fluorophenylhydrazine hydrochloride (4.8 g, 29.73 mmol) to 15 mL of dioxane and 15 mL of water, then add NaHC0 ₃ (5 g, 59.5 mmol), then add dropwise to the system. 2-Fluoro-6-nitrobenzoyl chloride (6.05 & 29.73 mmol) in 10 mL of dioxane solution, added dropwise to room temperature, stirred for 3 h, concentrated to a one-third volume under reduced pressure, solid precipitated. The crude product was obtained by suction~~~~~~~~~~~~~~~~~~~~~~~~~

 (2) Preparation of 2-amino-6-fluoro-N'-(3-fluorophenyl)benzoyl hydrazide

 2-Fluoro-N-(3-fluorophenyl)-6-nitrobenzoic acid hydrazide (5.67 g, 19.3 mmol) was dissolved in 100 mL of methanol, and 600 mg of 10% Pd/C was added thereto. Hydrogen was reacted at room temperature for 24 h, the reaction was completed, Pd/C was filtered off, and the organic phase was concentrated to give 4.8 g, yield 94.3%.

 (3) Preparation of (5)-1-[3-fluoro-2-[2-(3-fluorophenyl)decanoyl]phenylamino]-1-oxobutan-2-ylcarbamic acid tert-butyl ester In a dry reaction flask, (5)-2-(tert-butoxycarbonylamino)butyric acid (5.8 g, 28.5 mmd), 2-amino-6-fluoro-'-(3-fluorophenyl)benzoyl肼 (3.8 g, 14.4 mmol), DIEA (3.7 mL, 21.2 mmol) and HATU (6.0 g, 15.8 mmol) were added to 80 mL of DMF, stirred at room temperature for 48 h, spin dry DMF, add water and dichloromethane. The mixture was extracted with chloroform, and the organic layer was combined, washed with brine, and evaporated.

 (4) Preparation of (5)-2-(1-aminopropyl)-5-fluoro-3-(3-fluorophenylamino)quinazoline-4(3H)-one hydrochloride

(5)-1-[3-Fluoro-2-[2-(3-fluorophenyl)decanoyl]phenylamino]-1-oxobutan-2-ylcarbamic acid tert-butyl ester (3.6 g, 8 mmol) was dissolved in 40 mL of ethanol, and 5 mL of concentrated hydrochloric acid was added dropwise to the reaction flask under ice bath. After stirring for half an hour, the reaction was transferred to an oil bath at 85 ° C for 4 days, cooled, concentrated, and prepared. The liquid phase gives a white solid 650 mg, The rate is 22.1%.

 (5) (5)-2-[l-(9H-Indol-6-ylamino)propyl]-5-fluoro-3-(3-fluorophenylamino)-quinazoline-4(3H)-one Preparation

 Adding (5)-2-(1-aminopropyl)-5-fluoro-3-(3-fluorophenylamino)quinazolin-4(3H)-one salt obtained in the above step to 40 mL of tert-butanol The acid salt (650 mg, 1.77 mmol) and DIEA (0.92 mL, 5.28 mmol) were stirred in an ice bath for half an hour, then 6-chloro-9H-indole (819 mg, 5.30 Inmol) was added thereto at 85 °C. The reaction was carried out for 24 h, cooled and evaporated, mjjjjjjj

Mass spectrometry (Μ+Η): 449.2

¹ H-NMR (^-DMSO, 400 MHz): δ 12.99 (1Η, br s), 9.23 (1H, s), 8.22-8.11 (1H, m), 8.05 (1H, s), 7.95-7.70 (2H , m), 7.39 (1H, d), 7.31-7.19 (2H, m), 6.92-6.74 (2H, m), 6.70-6.61 (1H, m), 5.40 (1H, m), 2.17-2.05 (1H , m), 2.04-1.85 (1H, m), 1.02 (3H, t).

Example 12 iS)-2-[M9-Indol-6-ylamino)propyl1-5-fluoro-3-(3-methoxyphenylaminoquinazolin-4) (3H-ketone (Compound 14) Preparation

 (1) Preparation of 2-fluoro-N'-(3-methoxyphenyl)-6-nitrobenzoyl hydrazide

2-Fluoro-6-nitrobenzoic acid (5.55 g, 30.0 mmol) was dissolved in 50 mL CH ₂ Cl ₂ and 0.3 mL DMF, and oxalyl chloride (5.71 g, 45.0 mmol) was slowly added dropwise thereto, and stirred at room temperature for 2 h. The solvent was removed by concentration, then dissolved in 6 mL of dioxane, and then added dropwise to 3-methoxyphenylhydrazine hydrochloride (5.23 g, 30.0 mmol), NaHC0 ₃ (7.56 g, 90.0 mmol). After 15 mL of dioxane and 15 mL of water, the mixture was added dropwise to room temperature and stirred for half an hour. After concentration under reduced pressure to a volume of one-third, ethyl acetate was extracted, dried over anhydrous sodium sulfate, filtered and concentrated. The title was obtained by silica gel column chromatography (EtOAc (EtOAc)

 (2) Preparation of 2-amino-6-fluoro-N'-(3-methoxyphenyl)benzoyl hydrazide

2-Fluoro-N'-(3-methoxyphenyl)-6-nitrobenzoic acid hydrazide (3.05 g, 10.0 mmol) was dissolved in 30 mL of methanol, and 0.5 g of 10% Pd/ was added thereto. C, pass hydrogen, react at room temperature for 18 h, the reaction is over, filter out Pd/C, there is After concentration of the organic phase, 2.7 g was obtained with a yield of 98.1%.

 (3) (5)-1-[3-Fluoro-2-[2-(3-methoxyphenyl)decanoyl]phenylamino]-1-oxobutan-2-ylcarbamic acid tert-butyl ester In a dry reaction flask, (5)-2-(tert-butoxycarbonylamino)butyric acid (3.0 g, 14.76 mmol), 2-amino-6-fluoro-N'-(3-methoxyphenyl) Benzoyl hydrazide (2.7 g, 9.81 mmol), DIEA (2.3 mL, 13.3 mmol) and HATU (4.0 g, 10.5 mmol) were added to 20 mL of dichloromethane, stirred at room temperature for 64 h, water and dichloro Methane, methylene chloride extraction, combined organic phase, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated. The solid was 1.4 g, and the yield was 31.0%.

 (4) Preparation of (5)-2-(1-aminopropyl)-5-fluoro-3-(3-methoxyphenylamino)quinazoline-4(3H)-one hydrochloride

 tert-Butyl ()-1-[3-fluoro-2-[2-(3-methoxyphenyl)decanoyl]phenylamino]-1-oxobutan-2-ylcarbamate (600 mg, 1.31 mmol) was dissolved in 20 mL of ethanol. 2 mL of concentrated hydrochloric acid was added dropwise to the reaction flask under ice bath. After stirring for half an hour, the reaction was transferred to an oil bath at 85 ° C for 24 h, cooled and concentrated to give white. The solid was used directly in the next step.

(5) (5)-2-[l-(9H-Indol-6-ylamino)propyl]-5-fluoro-3-(3-methoxyphenylamino)quinazoline-4 (3H) - Preparation of ketone

 The (5)-2-(1-aminopropyl)-5-fluoro-3-(3-methoxyphenylamino)quinazoline-4(3H)- obtained in the above step was added to 20 mL of tert-butanol. Ketone hydrochloride (about 1.31 mmol) and DIEA (0.68 mL, 3.91 mmol) were stirred in an ice bath for half an hour, then 6-chloro-9H-indole (242 mg, 1.57 mmol) was added thereto at 85 °C. The reaction was carried out for 36 h, cooled, EtOAcjjjjjjjj

Mass Spectrum (M+H): 461.2

 'H-NMR^-DMSO, 400 MHz, 80 °C): δ 12.97 (IH, s), 9.00 (IH, s), 8.22-8.05 (2H, m), 7.85-7.69 (2H, m), 7.40 (IH, d), 7.32-7.21 (1H, m), 7.17-7.05 (IH, m), 6.60-6.41 (3H, m), 5.47 (IH, s), 3.68 (3H, s), 2.20-2.08 (IH, m), 2.02-1.92 (1H, m), 0.998 (3H, t).

Example 13 i5)-2-fl-(9H-嘌呤-6-ylamino)propyl 1-5-fluoro-3-ί3-(trifluoromethyl)phenylaminoquinazoline

Preparation of -4(3Η)-Μ (Compound 15)

(1) Preparation of 2-fluoro-6-nitro-N-[3-(trifluoromethyl)phenyl]benzoic acid hydrazide

Add 3-(trifluoromethyl)phenylhydrazine hydrochloride (6.32 g, 29.73 mmol) to 15 mL of dioxane and 15 mL of 7 and then add NaHC0 ₃ (5 g, 59.5 mmol) and then to system The 2-fluoro-6 nitrobenzoyl chloride dioxane solution (10 mL, 29.73 mmol) was added dropwise, and the mixture was added to room temperature, stirred for 3 h, and concentrated to a one-third volume after reduced pressure. The solid was precipitated, and the crude product was obtained by suction, washed with diethyl ether and ethyl acetate, filtered, and dried to give 5.3 g of white solid.

 (2) Preparation of 2-amino-6-fluoro-N'-[3-(trifluoromethyl)phenyl]benzoic acid hydrazide

 2-Fluoro-6-nitro-N43-(trifluoromethyl)phenyl]benzoic acid hydrazide (5.3 g, 15.4 mmol) was dissolved in 100 mL of methanol, and 600 mg of 10% Pd/C was added thereto. The reaction was carried out for 24 h at room temperature, the reaction was completed, Pd/C was filtered off, and the organic phase was concentrated to give 4.76 g, yield 98.7%.

 (3) (5)-1-[3-Fluoro-2-[2-[3-(trifluoromethyl)phenyl]indoloyl]phenylamino]-1-oxobutan-2-ylcarbamic acid Preparation of tert-butyl ester

 In a dry reaction flask, (5)-2-(tert-butoxycarbonylamino)butyric acid (5.8 g, 28.5 mmol), 2-amino-6-fluoro-N'-[3-(trifluoromethyl) Phenyl]benzoyl hydrazide (4.51 g, 14.4 mmol), DIEA (3.7 mL, 21.2 mmol) and 11 into 711 (6.0 §, 15.8 11^101) were added to 8011^0]^^, stirred at room temperature for 48 h. The mixture was evaporated to dryness. , yield 18.0%.

 (4) Preparation of (-2-(1-aminopropyl)-5-fluoro-3-[3-(trifluoromethyl)phenylamino]quinazoline-4(3H)-one hydrochloride

 (5) tert-butyl [3-fluoro-2-[2-[3-(trifluoromethyl)phenyl]decanoyl]phenylamino]oxyxobutan-2-ylcarbamate (1.29 g) , 2.59 mmol) was dissolved in 40 mL of ethanol. 5 mL of concentrated hydrochloric acid was added dropwise to the reaction flask under ice bath. After stirring for half an hour, the reaction was transferred to an oil bath at 85 ° C for 4 days, cooled and concentrated. The liquid phase was prepared to give a white solid, 220 mg, yield 20.4%.

 (5) CS)-2-[l-(9H-Indol-6-ylamino)propyl]-5-fluoro-3-[3-(trifluoromethyl)phenylamino]-quinazoline-4 ( Preparation of 3 /)-ketone

 (<S)-2-(l-Aminopropyl)-5-fluoro-3-[3-(trifluoromethyl)phenylamino]quinazoline-4 was added to 40 mL of tert-butanol. (3/)-ketohydrochloride (220 mg, 0.528 mmol) and DIEA (0.28 mL, 1.61 mmol), stirred for half an hour in ice bath, then 6-chloro-9H-indole (243 mg, 1.57 mmol) The reaction was allowed to react at 85 ° C for 24 h, cooled, concentrated, and purified tolulululu

Mass spectrometry (M+H): 499.2

1H-NMR ( _{tf -} DMS0, 400 MHz): δ 12.96 (1H, s s), 9.38 (1H, s), 8.19-7.96 (2H, m), 7.92-7.64 (2H, m), 7.56-7.35 (2H, m), 7.31-7.13 (4H, m), 5.43 (1H, m), 2.21-2.06 (IH, m), 2.04-1.98 (IH, m), 1.02 (3H, t).

Example 14 (S)-3-[2-[l-(9ff-嘌呤-6~ylamino)propyl]-5-fluoro-4-oxoquinazoline-3i4ff)-ylamino 1 benzoate ( Preparation of compound 16)

 (1) Preparation of N'-(3-cyanophenyl)-2-fluoro-6-nitrobenzoyl hydrazide

2-Fluoro-6-nitrobenzoic acid (5.55 g, 30.0 mmol) was dissolved in 50 mL CH ₂ Cl ₂ and 0.3 mL DMF, and oxalyl chloride (5.71 g, 45.0 mmol) was slowly added dropwise thereto, and stirred at room temperature for two hours. After that, the solvent was removed by concentration, then dissolved in 6 mL of dioxane, and then added dropwise to 3-cyanobenzoquinone hydrochloride (5.09 g, 30.0 mmol) NaHC0 ₃ (7.56 g, 90.0 mmol). In a solution of hexacyclohexane (15 mL) and water (15 mL), the mixture was added dropwise to room temperature, stirred for half an hour, concentrated under reduced pressure to one-third volume, extracted with ethyl acetate, dried over anhydrous sodium sulfate and filtered. The organic phase was concentrated and purified by silica gel chromatography eluting eluting

 (2) Preparation of 2-amino-N'-(3-cyanophenyl)-6-fluorobenzoic acid hydrazide

 N'-(3-cyanophenyl)-2-fluoro-6-nitrobenzoic acid hydrazide (4.2 g, 14.0 mmol) was dissolved in 30 mL of methanol, and 0.6 g of 10% Pd/C was added thereto. With hydrogen gas, the reaction was carried out at room temperature for 18 h, the reaction was completed, Pd/C was filtered off, and the solid obtained by concentration of the organic phase was directly used for the next reaction.

 (3) (5)-1-[2-[2-(3-Cyanophenyl)fluorenylcarbonyl]-3-fluoro-phenylamino]-1-oxobutan-2-ylcarbamic acid tert-butyl ester In the preparation of the dried reaction flask, the crude 2-amino-N'-(3-cyanophenyl)-6-fluorobenzoic acid hydrazide obtained in the above step (about 14.0 mmol), (5)-2- (uncle Butoxycarbonylamino)butyric acid (4.26 g, 21.0 mmol), DIEA (3.3 mL, 19 mmol) and HATU (6.38 g, 16.8 mmol) were added to 40 mL of dichloromethane, stirred at room temperature for three days, water and two The mixture is extracted with chloroformamide, chloroform, and the organic phase is washed with water and brine. 2.9 g of a white solid were obtained in a two-step total yield of 45.5%.

(4) Preparation of CS)-3-[2-(l-aminopropyl)-5-fluoro-4-oxoquinazolin-3(4H)-ylamino]benzonitrile hydrochloride (5)-l-[2-[2-(3-Cyanophenyl)indolecarbonyl]-3-fluoro-phenylamino]-oxobutan-2-ylcarbamic acid tert-butyl ester (1.37 g, 3.0 Methyl) was dissolved in 30 mL of ethanol, and 3 mL of concentrated hydrochloric acid was added dropwise to the reaction flask under ice bath. After stirring for half an hour, the reaction was transferred to an oil bath at 85 ° C for 24 h, cooled and concentrated to give a white solid. Used in the next step.

 (5) (5)-3-[2-[l-(9H-嘌昤-6-ylamino)propyl]-5-fluoro-4-oxoquinazolin-3(4H-amino)benzophenone Preparation of nitrile

 Adding (S)-3-[2-(l-aminopropyl)-5-fluoro-4-oxoquinazolin-3(4H)-ylamino]benzene obtained in the above step to 20 mL of tert-butanol The carbonitrile hydrochloride (about 3.0 mmol) and DIEA (1.56 mL, 9.0 mmol) were stirred in an ice bath for half an hour, then 6-chloro-9H-indole (556 mg, 3.6 mmol) was added thereto, and the reaction was at 85 °. The reaction was carried out for 36 h at C, cooled, concentrated and purified by column chromatography (ethyl acetate (100%)) to yield 168 mg of white solid.

Mass spectrometry (Μ+Η): 456.2

 ^-NMRC^-DMSO, 400 ΜΗζ): δ 12.95 (1Η, s), 9.37 (1H, s), 8.20-8.07 (2H, m), 7.96-7.72 (2H, m), 7.47-7.20 (6H, m), 5.38 (1H, m), 2.18-1.85 (2H, m), 1.02 (3H, t).

Example 15 (S)-2-[1-(9H-Indol-6-ylamino)propyl1-3-ί3,5-difluorophenylamino)quinazolin-4i3H)-one (Compound 17) Preparation

 (l) Preparation of N"-(3,5-difluorophenyl)-2-nitrobenzoyl hydrazide

In a dry reaction flask, o-nitrobenzoic acid (5 g, 30 mmol) was dissolved in 50 mL CH ₂ Cl ₂ and 1 mL DMF, and oxalyl chloride (5.71 g, 45 mmol) was slowly added dropwise thereto under ice-water bath. After the completion of the dropwise addition, the mixture was stirred at room temperature for 2 h, the solvent was removed, dissolved in 5 mL of dioxane, and dropped into an ice bath containing 3,5-difluorophenylhydrazine hydrochloride (5.42 g, 30 mmol) NaHC0 ₃ (10.08 g, 120 mmol) in 20 mL of dioxane and 20 mL of water, add dropwise to room temperature and stir for 30 min, distill off part of the solvent, add water, precipitate with white solid, filter, dry, White solid 7.3 g, yield 83%.

(2) Preparation of 2-amino-N-(3,5-difluorophenyl)benzoyl hydrazide In a dry reactor, add N-(3,5-difluorophenyl)-2-nitrobenzoic acid hydrazide (7.3 g, 24.9 mmol), 60 mL methanol as solvent, 10% Pd/C 0.8 g The dry hydrogen was passed through, and the reaction was allowed to stand overnight. TLC showed that the reaction was completed, and filtered, and then evaporated to yield 6.4 g of white solid.

 (3) (<5)-1-[2-[2-(3,5-Difluorophenyl)decylcarbonyl]phenylamino]-1-oxobutan-2-ylcarbamic acid tert-butyl ester To prepare a dry single-mouth bottle, add (5)-2-(tert-butoxycarbonylamino)butyric acid (3.09 g, 15.2 mmol), DIEA (7.86 mL, 45.1 mmol), HATU (6.34 g, 16.7 mmol), 80 Dissolve mL of methylene chloride and 2 mL of DMF, stir at room temperature for 30 min, add 2-amino-N-(3,5-difluorophenyl)benzoyl hydrazide (4 g, 15.2 mmol), stir at room temperature for 72 h The methylene chloride was spun off, water was added, and the mixture was extracted with ethyl acetate. The mixture was concentrated and purified by column chromatography to yield white solid (1.2 g).

(4) Preparation of (5)-2-(1-aminopropyl)-3-(3,5-difluorophenylamino)quinazoline-4(3H)-one hydrochloride

 In a dry reaction flask, weigh out (5)-1-[2-[2-(3,5-difluorophenyl)decylcarbonyl]phenylamino]-1-oxobutan-2-ylcarbamic acid Tert-butyl ester (1.2 g, 2.68 mmol), dissolved in 50 mL of ethanol, added 5 mL of concentrated hydrochloric acid with stirring in an ice water bath, stirred for 30 min, heated to 85 ° C for 16 h, LC-MS showed the reaction was completed, after cooling Concentration gave a white solid which was taken directly to next.

 (5) Preparation of (5)-2-[l-(9H-indol-6-ylamino)propyl]-3-(3,5-difluorophenylamino)quinazolin-4(3H)-one

 The product of the previous step (5 -2-(1-aminopropyl)-3-(3,5-difluoroanilino)quinazolin-4(3H)-one hydrochloride was dissolved in 20 mL of t-butanol. Add DIEA (0.8 mL, 4.6 mmol), stir for half an hour in an ice bath, then add 6-chloro-9H-indole (185 mg, 1.2 mmol), under 85 Torr, nitrogen-protected, protected from light for 5 h, cooled , concentrated, reversed to give a white solid, 98 mg, mp.

Mass spectrometry (Μ+Η): 449.2

1H-NMR ( ₆ -DMSO, 400 ΜΗζ): δ 12.95 (1Η, br s), 9.50 (1H, s), 8.21-8.11 (1H, m), 8.07 (1H, d), 8.01 (1H, s) , 7.98-7.85 (1H, m), 7.80 (1H, t), 7.59 (1H, d), 7.51 (1H, t), 6.75-6.55 (3H, m), 5.40 (1H, m), 2.17-2.07 (1H, m), 2.02-1.90 (1H, m), 1.03 (3H, t).

Example 16 (S)-2-[l-i9H-indol-6-ylamino)propyl]-3-(3,5-difluorophenylamino)-5-fluoroquinazoline-4 (3^) - Preparation of ketone (Compound 18)

 (l) Preparation of N-(3,5-difluorophenyl)-2-fluoro-6-nitrobenzoyl hydrazide

2-Fluoro-6-nitrobenzoic acid (16.51 g, 89.2 mmol) was dissolved in 100 mL of CH ₂ Cl ₂ , and oxalyl chloride (17 _& 13411^01) was slowly added dropwise thereto, stirred at room temperature for 2 h, and concentrated. Solvent, then add dioxane to a 30 mL solution for use. Add 3,5-difluorophenylhydrazine hydrochloride (5.37 g, 29.73 mmol) to 30 mL of dioxane and water (1:1), then add NaHC0 ₃ (5 g, 59.5 mmol), then A 10 mL (about 29.73 mmol) 2-fluoro-6-nitrobenzoyl chloride dioxane solution was added dropwise to the system, and the mixture was added dropwise to room temperature, stirred for 3 h, and concentrated to one-third volume under reduced pressure. After that, a solid was precipitated, and the crude product was obtained by suction, washed with diethyl ether and ethyl acetate, filtered, and dried to give 5.8 g of white solid.

 (2) Preparation of 2-amino-N'-(3,5-difluorophenyl)-6-fluorobenzoic acid hydrazide

 N-(3,5-Difluorophenyl)-2-fluoro-6-nitrobenzoylhydrazide (5.8 g, 18.6 mmol) was dissolved in 100 mL of methanol, and 600 mg of 10% Pd/ was added thereto. C, hydrogen gas, reaction at room temperature for 24 h, the reaction is completed, Pd / C is filtered off, the organic phase is concentrated to obtain 5.1 g, the yield is 97.3%.

 (3) (S)-l-[2-[2-(3,5-Difluorophenyl)decanoyl]-3-fluorophenylamino]-1-oxobutan-2-ylcarbamic acid tert-butyl Preparation of ester

 In a dry reaction flask, (5)-2-(tert-butoxycarbonylamino)butyric acid (5.8 g, 28.5 mmol), 2-amino-N'-(3,5-difluorophenyl)-6- Fluorobenzoic acid hydrazide (4.06 g, 14.4 mmol), DIEA (3.7 mL, 21.2 mmol) and HATU (6.0 g, 15.8 mmol) were added to 80 mL DMF, stirred at room temperature for 48 h, and most of the DMF was removed and water was added. The organic layer was combined with water, washed with brine, and brine, and evaporated.

 (4) Preparation of (5)-2-(1-aminopropyl)-3-(3,5-difluorophenylamino)-5-fluoroquinazoline-4(3H)-one hydrochloride

(5)-1-[2-[2-(3,5-Difluorophenyl)decanoyl]-3-fluorophenylamino]-1-oxobutan-2-ylcarbamic acid tert-butyl ester (1.5 g, 3.22 mmol) was dissolved in 40 mL of ethanol, and 5 mL of concentrated hydrochloric acid was added dropwise thereto in an ice bath. After stirring for half an hour, the reaction was transferred to an oil bath at 85 ° C for 4 days, cooled and concentrated. The liquid phase was prepared to give a white solid 440 mg, yield 35.4%.

 (5) (5)-2-[l-(9H-Indol-6-ylamino)propyl]-3-(3,5-difluorophenylamino)-5-fluoroquinazoline-4 (3H) Preparation of ketone

 To 40 mL of tert-butanol, CS)-2-(l-aminopropyl)-3-(3,5-difluorophenylamino)-5-fluoroquinazoline-4(3H)- The ketone hydrochloride (440 mg, 1.14 mmol) and DIEA (0.6 mL, 3.4 mmol) were stirred in ice bath for half an hour, then 6-chloro-9H-indole (529 mg, 3.42 mmol) was added and warmed to 85 The mixture was reacted for 24 h, EtOAc (EtOAc)EtOAc.

Mass spectrometry (Μ+Η): 467.2

 ^-NMR^-DMSO, 400 ΜΗζ): δ 12.97 (IH, br s), 9.41 (IH, s), 8.30-7.90 (3H, m), 7.84-7.71 (IH, m), 7.39 (IH, d ), 7.32-7.22 (IH, m), 6.80-6.67 (2H, m), 6.65-6.55 (IH, m), 5.36 (IH, m), 2.16-2.00 (IH, m), 1.96-1.82 (IH , m), 1.02 (3H, t).

Example 17 (S)-2-"1-(9#-嘌呤-6-ylamino)propyl1-5-chloro-3-f3,5-difluorophenylamino)quinazoline-4 (3H) - Preparation of ketone (Compound 19)

 (1) (5)-1-[3-Chloro-2-[2-(3,5-difluorophenyl)indolecarbonyl]phenylamino]-1-oxobutan-2-ylcarbamic acid tert-butyl ester Preparation

7.48 g (21.0 mmol) of (5)-2-[2-(tert-butoxycarbonylamino)butyrylamino]-6-chlorobenzoic acid, 50 mL of DCM and 50 mL of DMF, 9.1 mL were added to the dried reaction flask. (52.3 mmol) DIEA, 5.60 g (31.0 mmol) of 3,5-difluorophenylhydrazine hydrochloride, 10.37 g (27.3 mmol) of HATU. A portion of the solvent was removed by EtOAc (EtOAc)EtOAc. (2) Preparation of (S)-2-(l-aminopropyl)-5-chloro-3-(3,5-difluorophenylamino)quinazolin-4 (3H>ketone hydrochloride in a reaction flask 900 mg (1.86 mmol) of (5)-1-[3-chloro-2-[2-(3,5-difluorophenyl)fluorenylcarbonyl]phenylamino]-1-oxobutan-2-yl Tert-butyl carbamate, 10 mL of ethanol, 3 mL of concentrated hydrochloric acid, and the mixture was evaporated to reflux overnight. The mixture was cooled to room temperature, and a white solid was precipitated, filtered, filtered, iced and ethyl ether.

 (3) (5)-2-[l-(9H-Indol-6-ylamino)propyl]-5-chloro-3-(3,5-difluorophenylamino)quinazoline-4 (3H) - Preparation of ketones 300 mg (0.748 mmol) of (5>2-(1-aminopropyl)-5-chloro-3-(3,5-difluorophenylamino)quinazoline- 4(3H)-ketohydrochloride, 15 mL tert-butanol, 2 mL DIEA, 155 mg (1.00 mmol) 6-chloro-9H-indole, heated under reflux for 3 days. Solvent removal by rotary evaporation, column chromatography (oil Ether: ethyl acetate 1:1:1:3) gave 272 mg as a white solid.

Mass Spectrometry (M+H): 483.1

1H-NMR (i ₆ -DMS0, 400 MHz): δ 12.96 (1Η, br s), 9.39 (1H, s), 8.20-8.09 (1H, m), 8.02 (1H, s), 7.77-7.60 (2H , m), 7.57-7.48 (2H, m), 6.81-6.69 (2H, m), 6.67-6.56 (1H, m), 5.35 (1H, m), 2.15-1.92 (2H, m), 1.02 (3H , t).

Example 18 iS)-2-〖9-嘌呤-6-ylamino)propyl l-3-(2,6-difluorophenylamino)-5-fluoroquinazoline-4i3ff-ketone

 (1) Preparation of W-(2,6-difluorophenyl)-2-fluoro-6-nitrobenzoyl hydrazide

2-Fluoro-6-nitrobenzoic acid (5.5 g, 29.7 mmol) was dissolved in 50 mL of CH ₂ Cl ₂ and 0.4 mL of DMF, and oxalyl chloride (5.66 g, 44.6 mmol) was slowly added dropwise thereto, and stirred at room temperature for two hours. After that, the solvent was removed by concentration, then dissolved in 8 mL of dioxane, cooled, and then dropped to 2,6-difluorophenylhydrazine hydrochloride (5.0 g, 27.7 mmol), NaHC0 ₃ (6.72 g, 80.0 mmol) In a solution of dioxane (20 mL) and water (20 mL), the mixture was added dropwise to room temperature, stirred for half an hour, concentrated under reduced pressure to one-third volume, extracted with ethyl acetate and dried over anhydrous sodium sulfate. , suction filtration, concentration of organic phase, Recrystallization from diethyl ether gave 4.8 g of pale yellow product, yield 5.57.

 (2) Preparation of 2-amino-NH2,6-difluorophenyl)-6-fluorobenzoic acid hydrazide

 N-(2,6-difluorophenyl)-2-fluoro-6-nitrobenzoylhydrazide (4.8 g, 15.4 mmol) was dissolved in 60 mL of methanol, and 0.5 g of 10% Pd/ was added thereto. C, hydrogen gas, reaction at room temperature for 36 h, the reaction is completed, Pd / C is filtered off, the organic phase is concentrated to obtain 4.2 g, the yield is 97.0%.

 (3) (5)-1-[2-[2-(2,6-Difluorophenyl)indolecarbonyl]-3-fluorophenylamino]-1-oxobutan-2-ylcarbamic acid tert-butyl ester Preparation

 In a dry reaction flask, (5)-2-(tert-butoxycarbonylamino)butyric acid (6.06 g, 29.8 mmol), 2-amino-iV-(2,6-difluorophenyl)-6-fluoro Benzoyl hydrazide (4.2 g, 14.93 mmol), DIEA (2.9 mL, 16.7 mmol) and HATU (6.25 g,

16.4 mmol), added to 200 mL of dichloromethane, stirred at room temperature for 48 h, added with water and dichloromethane, and extracted with dichloromethane. The organic phase was washed, washed with brine, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by preparative chromatography to afford white crystals (yield: 303.

 (4) Preparation of (5)-2-(1-aminopropyl)-3-(2,6-difluorophenylamino)-5-fluoroquinazoline-4(3H)-one hydrochloride

 (5)-1-[2-[2-(2,6-Difluorophenyl)indolecarbonyl]-3-fluorophenylamino]-1-oxobutan-2-ylcarbamic acid tert-butyl ester (3.0 g, 6.43 mmol) was dissolved in 60 mL of ethanol, and 10 mL of concentrated hydrochloric acid was added dropwise to the reaction flask under ice bath. After stirring for half an hour, the reaction was transferred to an oil bath at 85 ° C for 16 h, cooled and concentrated to prepare a chromatogram. Isolated 1.3 g of white solid, yield

52.5 %.

 (5) (<S)-2-[l-(9H-嘌呤-6-ylamino)propyl]-3-(2,6-difluorophenylamino)-5-fluoroquinazoline-4 (3H Preparation of ketones To (20)-2-(1-aminopropyl)-3-(2,6-difluorophenylamino)-5-fluoroquinazoline-4 (3H) was added to 20 mL of tert-butanol. - ketohydrochloride (1.3 g, 3.38 mmol) and DIEA (1.75 mL, 10 mmol), stirred for half an hour under ice bath, then 6-chloro-9H-indole (1.6 g, 10.4 mmol). The reaction was allowed to react at 85 ° C for 24 h, cooled, concentrated, and chromatographed to give a white solid (1.01 g, yield: 64.1%).

Mass spectrometry (Μ+Η): 447.2

 1H-NMR (^-DMS0, 400 ΜΗζ): δ 13.00 (1Η, br s), 9.09 (1H, s), 8.25-8.05 (2H, m), 7.89-7.80 (1H, m), 7.57 (1H, d), 7.39-7.27 (2H, m), 7.06-6.85 (3H, m), 6.05 (1H, m), 2.26-2.12 (1H, m), 2.01-1.88 (lH, m), 0.92 (3H, t).

Example 19 (S)-5-fluorofluorophenylamino)-2-[1-[methyl(9ff-嘌吟-6-yl)amino]propyl quinazolin-4 (3ffl-ketone (Compound 21) Preparation O.

 -OH

BocHN-

 (1) Preparation of 2-fluoro-N-(4-fluorophenyl)-6-nitrobenzoyl hydrazide

2-Fluoro-6-nitrobenzoic acid (5.5 g, 29.7 mmol) was dissolved in 50 mL of CH ₂ C1 ₂ and 0.4 mL of DMF, and oxalyl chloride (5.66 g, 44.6 mrnol) was slowly added dropwise thereto, and stirred at room temperature for two hours. After that, the solvent was removed by concentration, and then dissolved in 8 mL of dioxane, and it was dropped into p-fluorophenylhydrazine hydrochloride (4.829 g, 29.7 mmol), NaHC0 ₃ (6.72 g, 80 mmol) of dioxane under cooling. In a solution of six rings (20 mL) and water (20 mL), the mixture was stirred at room temperature, stirred for half an hour, concentrated to a one-third volume under reduced pressure, extracted with ethyl acetate, dried over anhydrous sodium sulfate and filtered. The organic phase was concentrated, and then crystallised from diethyl ether.

 (2) Preparation of 2-amino-6-fluoro-N'-(4-fluorophenyl)benzoyl hydrazide

 2-Fluoro-N-(4-fluorophenyl)-6-nitrobenzoic acid hydrazide (4.4 g, 15.0 mmol) was dissolved in 60 mL of methanol, and 0.5 g of 10% Pd/C was added thereto. Hydrogen was reacted at room temperature for 36 h, the reaction was completed, Pd/C was filtered off, and the organic phase was concentrated to give 3.8 g, yield 96.2%.

 (3) Preparation of (5)-2-(tert-butoxycarbonyl (methyl)amino)butyric acid

(5)-2-(tert-Butoxycarbonylamino)butanoic acid (15.0 g, 73.8 mmol) was dissolved in anhydrous THF (600 mL), and 60% NaH kerosene dispersion (29.6 g, 740 mmol) Stir at room temperature for 30 minutes, add CH ₃ I (104.92 g, 739 mmol) dropwise, and react overnight. Dissolve the organic solvent, dissolve in 200 mL of water, adjust pH with 7 N HCl, extract with EA, and then steam to obtain ll. .O g product, yield 68.6 %.

(4) (-1-[3-Fluoro-2-[2-(4-fluorophenyl)indolecarbonyl]phenylamino]-1-oxobutan-2-yl(methyl)carbamic acid tert-butyl ester Preparation In a dry reaction flask, (5)-2-(tert-butoxycarbonyl(methyl)amino)butyric acid (5.2 _& 23.9 11∞101), 2-amino-6-fluoro-(4-fluorophenyl) Benzoyl hydrazide (3.2 g, 12.2 mmol), DIEA (2.3 mL, 13.2 mmol) and HATU (5.02 g, 13.2 mmol) were added to 200 mL DMF, stirred at room temperature for 7 days, water and dichloromethane were added, The mixture was extracted with chloroformamide, and the organic layer was combined, washed with brine, and evaporated.

 (5) Preparation of (5)-5-fluoro-3-(4-fluorophenylamino)-2-[1-(methylamino)propyl]quinazoline-4(3H)-one hydrochloride

 (5) tert-butyl [3-fluoro-2-[2-(4-fluorophenyl)phosphonium]phenylamino]-1-oxobutan-2-yl(methyl)carbamate (2.6 g , 5.62 mmol) was dissolved in 60 mL of ethanol. 10 mL of concentrated hydrochloric acid was added dropwise to the reaction flask under ice bath. After stirring for half an hour, the reaction was transferred to an oil bath at 85 ° C for 64 h, cooled and concentrated to prepare a chromatogram. 0.40 g of a white solid was isolated in a yield of 18.7%.

 (6) (5)-5-Fluoro-3-(4-fluorophenylamino)-2-[1-[methyl(9H-indol-6-yl)amino]propyl]quinazoline-4 (3H Preparation of -ketone To 10 mL of tert-butanol was added (5)-5-fluoro-3-(4-fluorophenylamino)-2-[1-(methylamino)propyl]quinazoline-4 (3H) --ketohydrochloride (300 mg, 0.788 mmol) and DIEA (0.45 mL, 2.58 mmol), stirred for half an hour in an ice bath, then added 6-chloro-9H-indole (241 mg, 1.56 mmol). The reaction was carried out at 85 ° C for 72 h, cooled, concentrated, and chromatographed to give a yellow solid (yield: 140 mg).

Mass Spectrometry (M+H): 463.1

1H-NMR (i/ ₆ -DMS0, 400 MHz): 5 12.82 (1H, s), 8.85-8.47 (2H, m), 8.15-7.46 (4H, m), 7.39-7.26 (1H, m), 7.10 -6.86 (1H, m), 6.77-6.66 (1H, m), 6.62-6.51 (1H, m), 6.46-5.94 (1H, m), 3.66-2.94 (3H, d), 2.27-1.98 (2H, m), 0.93 (3H, t).

Example 20 (S)-2-[l-i9H-indol-6-ylamino)propyl]-5-chloro-3-[methyllutylphenyl)amino-1quinazoline-4f3H)-one (compound) Preparation of 22)

1

W 201

 77

(1) Preparation of (5)-l-[3-chloro-2-(2-methyl-2-phenylhydrazolyl)phenylamino]-1-oxobutan-2-ylcarbamic acid tert-butyl ester (5)-2-[2-(tert-Butoxycarbonylamino)butyrylamino]-6-chlorobenzoic acid (1.50 g, 4.20 mmol), 20 mL DCM and 10 mL DMF, 1.47 were added to the dried reaction flask. mL (8.44 mmol) DIEA, 770 mg (6.3 mmol) 1-methyl-1-phenylhydrazine, 2.08 g (5.47 mmol) EtOAc. A part of the solvent was removed by rotary evaporation, water was evaporated, ethyl acetate was evaporated.

 (2) Preparation of (5)-2-(1-aminopropyl)-5-chloro-3-[methyl(phenyl)amino]quinazoline-4(3H)-one hydrochloride

 (5)-1-(3-Chloro-2-(2-methyl-2-phenylhydrazinoyl)phenylamino]-1-oxobutan-2-ylcarbamic acid tert-butyl ester was added to the reaction flask. (750 mg, 1.63 mmol), 10 mL of ethanol, 3 mL of concentrated hydrochloric acid. After cooling to room temperature, a white solid precipitated, which was filtered, washed with iced water and diethyl ether. A white solid of 450 mg was obtained in a yield of 73.0%.

 (3) (·3⁄4-2-[1-(9 嘌呤-6-ylamino)propyl]-5-chloro-3-[methyl(phenyl)amino]quinazolin-4(3H)-one Preparation

 (5)-2-(1-Aminopropyl)-5-chloro-3-[methyl(phenyl)amino]quinazolin-4(3H)-one hydrochloride was added to the dried reaction flask. 450 mg, 1.19 mmol), 15 mL of tert-butanol, 2 mL of DIEA, 6-chloro-9H-indole (308 mg, 1.99 mmol), and refluxed for 2 days. The solvent was evaporated to dryness, and 260 mg of white solid was obtained by column chromatography. The reversed product was obtained by further reversed to obtain 100 mg of the isomer with a smaller retention time on the HPLC. The isomer was retained on the HPLC for 120 mg, the total yield was 40.1%. . The two isomers are placed in a mixed solvent of acetonitrile water to be converted into each other.

Mass Spectrum (M+H): 461.2

The isomers with less retention time on HPLC:

1H-NMR ( _6- DMS0, 400 MHz): δ 12.90 (1Η, br s), 8.20-7.99 (2H, m), 7.77-7.65 (2H, m), 7.62-7.48 (2H, m), 7.25- 7.10 (2H, m), 6.92-6.70 (3H, m), 5.44 (1H, m), 3.45 (3H, s), 2.20-2.07 (1H, m), 2.07-1.90 (1H, m), 1.01 ( 3H, t).

Retention of isomers on HPLC:

1H-NMR (i/ ₆ -DMS0, 400 MHz): δ 12.97 (1H, br s), 8.22-8.09 (2H, m), 7.94 (1H, m), 7.74 (1H, t), 7.61 (1H, d), 7.54 (1H, d), 7.24 (2H, t), 6.87 (1H, t), 6.66 (2H, d), 5.50 (1H, m), 3.39 (3H, s), 2.02-1.87 (2H , m), 0.886 (3H, t).

Example 21 ffl-2-il-(9iy-indol-6-ylamino)propyl]-5-fluoro-3-[methyl(phenyl)amino quinazolin-4(3^)-one ( Preparation of compound 23)

(1) Preparation of 2-fluoro-N ¹ -methyl-6-nitro-N ¹ -phenylbenzoyl hydrazide

2-Fluoro-6-nitrobenzoic acid (3.7 g, 20.0 mmol) was dissolved in 20 mL CH ₂ C1 ₂ and 0.2 mL DMF, and oxalyl chloride (3.87 g, 30.5 mmol) was slowly added dropwise thereto, and stirred at room temperature for 2 h. After that, the solvent was removed by concentration, then dissolved in 4 mL of dioxane, and then dropped to 1-methyl-1-phenylindole (2.4 g, 19.6 mmol) NaHC0 ₃ (3.36 g, 40.0 mmol). After adding dropwise to 10 mL of dioxane and 10 mL of water, the mixture was stirred at room temperature and stirred for half an hour. After concentration under reduced pressure to one-third volume, ethyl acetate was extracted, dried over anhydrous sodium sulfate, filtered, and concentrated. The title was obtained by silica gel column chromatography (ethyl ether: ethyl acetate = 2:1).

 (2) Preparation of 2-amino-6-fluoromethyl-N-phenylbenzohydrazide

 2-Fluoromethyl-6-nitrophenylbenzoic acid hydrazide (4.9 g, 16.94 mmol) was dissolved in 30 mL of methanol, 0.5 g of 10% Pd/C was added thereto, hydrogen was passed, and the reaction was carried out at room temperature. h, the reaction was completed, Pd/C was filtered off, and the organic phase was concentrated to give 4.31 g, yield 98.1%.

 (3) Preparation of (5)-1-[3-fluoro-2-(2-methyl-2-phenylhydrazylcarbonyl)phenylamino]-1-oxobutan-2-ylcarbamic acid tert-butyl ester In a dry reaction flask, (5)-2-(tert-butoxycarbonylamino)butyric acid (6.08 g, 29.92 mmol), 2-amino-6-fluoromethyl-N-phenylbenzohydrazide (4.31 g) , 16.62 mmol), DIEA (4.5 mL, 25.8 mmol) and HATU (8.36 g, 21.99 mmol) were added to N,N-dimethylformamide (30 mL), stirred at room temperature for 48 h, water and dichloromethane The organic layer was combined with EtOAc (EtOAc) (EtOAc m. g, yield 43.3%.

 (4) (5)-1-[5-fluoro-4-oxo-3-(methyl(phenyl)amino)-3,4-dihydroquinazolin-2-yl]propylcarbamic acid Preparation of butyl ester

In a dry reaction flask, (5)-1-[3-fluoro-2-(2-methyl-2-phenylnonylcarbonyl)phenylamino]- 1 -oxobutan-2-ylcarbamic acid Butyl ester (1.31 g, 2.95 mmol) and DMAP (0.38 g, 3.11 mmol) were added to tert-butanol (30 mL), stirred at room temperature for 64 h, cooled, and concentrated under reduced vacuum. =1 : 1), giving a white solid 0.58 g, The yield was 46.1%.

 (5) Preparation of (S)-2-(l-aminopropyl)-5-fluoro-3-(methyl(phenyl)amino)quinazoline-4(3H)-one hydrochloride

 In a dry reaction flask, (5)-1-[5-fluoro-4-oxo-3-(methyl(phenyl)amino)-3,4-dihydroquinazolin-2-yl]-propyl The tert-butyl carbamate (0.58 g, 1.36 mmol) was dissolved in a mixed solution of 10 mL of dichloromethane and 10 mL of ethanol, and 4 mL of concentrated hydrochloric acid was added dropwise thereto, stirred at room temperature for 2 h, and concentrated under reduced pressure. The solid was used directly in the next step.

(6) (S)-2-[l-(9H-Indol-6-ylamino)propyl]-5-fluoro-3-[methyl(phenyl)amino]quinazoline-4(3H)- Preparation of Ketones To (20)-2-(1-aminopropyl)-5-fluoro-3-(methyl(phenyl)amino)quinazolin-4(3H)-one was added to 20 mL of tert-butanol. Hydrochloride (about 1.36 mmol^D DIEA (0.3 mL, 1.72 mmol), stirred for half an hour in an ice bath, then added 6-chloro-9H-indole (210 mg, 1.36 mmol) and warmed to 85 °C The reaction was carried out for 36 h, cooled, concentrated and purified with silicagel eluting The isomer, the total yield was 20.7%. The two isomers were placed in a mixed solvent of acetonitrile water to convert each other.

Mass Spectrometry (M+H): 445.2

Isomers with less retention time on HPLC -

'H-NMRC^-DMSO, 400 MHz): δ 12.90 (1Η, br s), 8.20-7.90 (2H, m), 7.86-7.65 (2H, m), 7.47 (1H, m), 7.35-7.05 ( 3H, m), 6.95-6.60 (3H, m), 5.43 (1H, m), 3.45 (3H, s), 2.20-1.80 (2H, m), 1.02 (3H, t).

Retention of isomers on HPLC:

 'H-NMR^-DMSO, 400 MHz): δ 12.98 (1H, br s), 8.22-8.10 (2H, m), 7.94 (1H, m), 7.86-7.77 (1H, m), 7.49 (1H, d), 7.32-7.20 (3H, m), 6.87 (1H, t), 6.75-6.62 (2H, m), 5.51 (1H, m), 3.40 (3H, s), 2.05-1.83 (2H, m) , 0.882 (3H, t).

Example 22 iS)-2-[1-(9ff-嘌呤-6-ylamino)propyl 1-5-chloro-3-K4-fluorophenyl) 甲基methyl)amino 1 quinazoline

Preparation of ketone (compound 24)

(1) 0S)-l-[5-Chloro-3-(4-fluorophenylamino)-4-oxo-3,4-dihydroquinazolin-2-yl]propylcarbamic acid tert-butyl ester In a dry reaction flask, (5)-2-(1-aminopropyl)-5-chloro-3-(4-fluorophenylamino)quinazolin-4 (3H keto hydrochloride (840 mg, 2.19 mmol) was dissolved in 20 mL of dichloromethane, and then added (0.92 mL, 6.60 mmol) of triethylamine, Boc ₂ 0 (720 mg, 3.30 mmol), DMAP (20 mg, 0.16 mmol), and allowed to react overnight at room temperature. The solvent was dried and purified by column chromatography to yield white crystals (yield:

 (2) (5)-1-[5-Chloro-3-[(4-fluorophenyl)(methyl)amino]-4-oxo-3,4-dihydroquinazolin-2-yl] Preparation of tert-butyl propyl carbamate

 CS)-l-[5-Chloro-3-(4-fluorophenylamino)-4-oxo-3,4-dihydroquinazolin-2-yl]propylcarbamic acid tert-butyl ester (800 mg , 1.79 mmol) was dissolved in 10 mL of DMF, then potassium carbonate (371 mg, 2.68 mmol), iodothymidine (381 mg, 2.68 mmol), and stirred at room temperature overnight. The solvent was evaporated to dryness to give 580 mg of white solid.

(3) (5)-2-(1-Aminopropyl)-5-chloro-3-[(4-fluorophenyl)(methyl)amino]quinazolin-4(3H)-one hydrochloride Preparation

 (5)-1-[5-Chloro-3-[(4-fluorophenyl)(methyl)amino]-4-oxo-3,4-dihydroquinazolin-2-yl]propyl The tert-butyl carbamate (580 mg, 1.26 mmol) was dissolved in 15 mL of dichloromethane, and the dried HC1 gas was passed in an ice bath for 1 h, and the reaction was terminated by TLC. The solvent was dried directly to give a crude 530 mg white solid.

 (4) (5)-2-[l-(9H-Indol-6-ylamino)propyl]-5-chloro-3-[(4-fluorophenyl)(methyl)amino]quinazoline Preparation of -4(3 /)-ketone

In the dried reaction flask, (<S)-2-(l-aminopropyl)-5-chloro-3-[(4-fluorophenyl)(methyl)amino]quinazoline-4 (3H) was added separately. - ketone hydrochloride crude 530 mg, 15 mL tert-butanol, 3 mL DIEA, 6-chloro-9H-indole (300 mg, 1.94 mmol), and refluxed for 2 days. The solvent was evaporated to dryness and purified by column chromatography to yield 370 mg of white solid. Mass spectrometry (Μ+Η): 479.2 O-NMRC^-DMSO, 400 MHz): δ 12.94 (1H, d), 8.18-7.93 (2H, m), 7.85-7.66 (2H, m), 7.64-7.50 (2H, m), 7.11-6.95 ( 2H, m), 6.94-6.65 (2H, m), 5.55-5.35 (1H, m), 3.43-3.38 (3H, d) _; 2.20-1.85 (2H, m), 1.01-0.897 (3H, m).

Example 23 f5 2-il-fflg-嘌吟-6-ylamino)propyl 1-5-fluoro-3-K4-fluorophenyl) (methyl)amino 1 quinazoline

Preparation of -4(3H)-one (Compound 25)

 (1) Preparation of 2-fluoro-N-(4-fluorophenyl)-6-nitrobenzoyl hydrazide

2-Fluoro-6-nitrobenzoic acid (5.5 g, 29.7 mmol) was dissolved in 50 mL of CH ₂ C1 ₂ and 0.4 mL of DMF, and oxalyl chloride (5.66 g, 44.6 mmol) was slowly added dropwise thereto, and stirred at room temperature for two hours. After that, the solvent was removed by concentration, then dissolved in 8 mL of dioxane, and it was dropped into p-fluorophenylhydrazine hydrochloride (4.829 g, 29.7 mmol), NaHC0 ₃ (6.72 g, 80 mmol) of dioxane under cooling. In a solution of six rings (20 mL) and water (20 mL), the mixture was added dropwise to room temperature, stirred for half an hour, concentrated to a one-third volume under reduced pressure, extracted with ethyl acetate, dried over anhydrous sodium sulfate and filtered. The organic phase was concentrated, and then crystallised from diethyl ether to afford pale white product 4.4 g.

 (2) Preparation of 2-amino-6-fluoro-N'-(4-fluorophenyl)benzoic acid hydrazide

 2-Fluoro-indolyl (4-fluorophenyl)-6-nitrobenzoic acid hydrazide (4.4 g, 15.0 mmol) was dissolved in 60 mL of methanol, and 0.5 g of 10% Pd/C was added thereto. After reacting at room temperature for 36 h, the reaction was completed, Pd/C was filtered off, and the organic phase was concentrated to obtain 3.8 g, yield 96.2%.

(3) Preparation of (5)-1-[3-fluoro-2-[2-(4-fluorophenyl)fluorenyl]phenylamino]-1-oxobutan-2-ylcarbamic acid tert-butyl ester In a dry reaction flask, (S)-2-(tert-butoxycarbonylamino)butyric acid (5.8 g, 28.6 mmol), 2-amino-6-fluoro_'-(4-fluorophenyl)benzoyl肼 (3.8 g, 14.4 mmol), DIEA (3.7 mL, 21.2 mmol) and HATU (6.0 g, 15.8 mmol) were added to 200 mL of dichloromethane, stirred at room temperature for 48 h, water and dichloromethane, dichloro The formazan was extracted, and the organic layer was combined, washed with brine, brine, evaporated, evaporated

 (4) (5)-1-[5-Fluoro-3-(4-fluorophenylamino)-4-oxo-3,4-dihydroquinazolin-2-yl]propylcarbamic acid tert-butyl ester Preparation of (5)-1-[3-fluoro-2-[2-(4-fluorophenyl)indolecarbonyl]phenylamino]-1-oxobutan-2-ylcarbamic acid tert-butyl ester (1.8 g ,

4.01 mmol) was dissolved in 60 mL of tert-butanol. DMAP (0.54 g, 4.42 mmol) was added to the reaction mixture and refluxed overnight.

 (5) (5)-1-[5-fluoro-3-[(4-fluorophenyl)(methyl)amino]-4-oxo-3,4-dihydroquinazolin-2-yl] Preparation of tert-butyl propyl carbamate

In a dry reaction flask, (5> 1-[5-fluoro-3-(4-fluorophenylamino)-4-oxo-3,4-dihydroquinazolin-2-yl]propylcarbamic acid butyl ester (1.1 g, 2.56 mmol) was dissolved in 20 mL of dry of DMF, _{CH 3 I (U6 g, 8.17} mmol), K 2 CO 3 (0.70 g, 5.06 mmol), stirred at room temperature 72 h. the reaction was poured The mixture was poured into 100 mL of ice water, and the mixture was extracted three times with ethyl acetate. The organic phase was combined, washed three times with saturated brine and dried, and then evaporated.

 (6) Preparation of (-G-aminopropyl)-5-fluoro-3-[(4-fluorophenyl)(methyl)amino]quinazolin-4(3H)-one hydrochloride In the flask, (5)-1-[5-fluoro-3-[(4-fluorophenyl)(methyl)amino]-4-oxo-3,4-dihydroquinazolin-2-yl ] tert-butyl propyl carbamate (980 mg, 2.20 mmol) dissolved in absolute ethanol (30 mL), hydrogen chloride gas was passed through the system until the reaction was complete, and 800 mg of solid (hydrochloride) was obtained after rotary evaporation. The rate is 95.5 %.

 (7) (S)-2-[l-(9H-Indol-6-ylamino)propyl]-5-fluoro-3-[(4-fluorophenyl)(methyl)amino]quinazoline- Preparation of 4(3 /)-ketone

 In a dry reaction flask, add (5)-2-(1-aminopropyl)-5-fluoro-3-[(4-fluorophenyl)(methyl)amino]quinazole to 30 mL of tert-butanol. Porphyrin-4(3H)-one hydrochloride (623 mg, 1.64 mmol) and DIEA (0.71 mL, 4.07 mmol) were stirred for half an hour in an ice bath, then 6-chloro-9H-indole (378 mg, 2.45 mmol), the reaction was carried out at 85 ° C. 24, cooled, concentrated, and chromatographed to afford 209 mg of white solid.

Mass spectrometry (Μ+Η): 463.2

1H-NMR (i/(j-DMS0, 400 ΜΗζ): δ 12.88 (1Η, br s), 8.19-8.03 (2H, m), 7.85-7.73 (2H, m), 7.51-7.40 (1H, m) , 7.32-7.23 (1H, m), 7.11-6.94 (2H, m), 6.92-6.67 (2H, m), 5.45 (1H, m), 3.43 (3H, s), 2.18-1.84 (2H, m) , 1.04 (3H, t). Example 24 (S -2-[1-(9-嘌吟-6-ylamino)propyl]-3-[cyclopropyl(4-fluorophenyl)amino]-S-fluoroquinazoline

 (1) Preparation of N-(l-ethoxycyclopropyl)-4-fluoroaniline

 In a dry reaction flask, p-fluoroaniline (11.1 g, 100 mmol) was dissolved in 250 mL of methanol and added to dry 4A molecular sieves, then 50 mL of glacial acetic acid and 1-ethoxy-1-trimethylsiloxy ring were added. Propane (22.6 g, 130 mmol) was stirred at room temperature until the starting material disappeared.

 (2) Preparation of N-cyclopropyl-4-fluoroaniline

Sodium borohydride (28 g, 740 mmol) was added in batches to the reaction mixture. After completion, it was refluxed under N ₂ overnight, cooled, filtered, and then distilled under reduced pressure, then 200 mL of ice water was added to adjust pH to neutral. The EA was extracted three times, and the organic phases were combined, washed with 2N NaOH solution, dried, and concentrated under reduced pressure to give 6.8 g of product.

(3) Preparation of N-cyclopropyl-4-fluoronitrosoaniline

 In a dry reaction flask, N-cyclopropyl-4-fluoroaniline (6.4 g, 42.3 mmol) was dissolved in 35 mL of glacial acetic acid under ice bath, and then sodium nitrite (3.8 g, dissolved in the solution was added dropwise to the solution. 55.1 mmol) of 40 mL of aqueous solution, and keep the temperature not exceeding 20 V for 2 h. After the pH was adjusted to neutral in an ice bath, EA was extracted three times. The organic phase was combined and concentrated under reduced pressure. Column chromatography (PE: EA = 5:1) gave a white solid, 4.2 g, yield 55.1 %.

 (4) Preparation of 1-cyclopropyl-1-(4-fluorophenyl)fluorene

In a dry reaction flask, N-cyclopropyl-4-fluoro was dissolved in lithium tetrahydroaluminum (1 M, 22.5 mL) under ice bath. A solution of nitrosoaniline (4.0 g, 22.2 mmol) in 20 mL of THF was stirred vigorously. After completion of the reaction, 30 mL of ethyl acetate was added dropwise to quench. After half an hour, add 40% NaOH solution and stir for half an hour. The organic phase was washed twice with ethyl acetate. EtOAc was evaporated.

 (5) Preparation of N-cyclopropyl-2-fluoro-N-(4-fluorophenyl)-6-nitrobenzoyl hydrazide

2-Fluoro-6-nitrobenzoic acid (2.8 g, 15.1 mmol) was dissolved in 30 mL of CH ₂ Cl ₂ and 0.4 mL of DMF, and oxalyl chloride (2.8 g, 22.1 mmol) was slowly added dropwise thereto, and stirred at room temperature for two hours. After that, the solvent was removed by concentration, then dissolved in 8 mL of dioxane, and then dropped to 15 mL of 1-cyclopropyl-1-(4-fluorophenyl)indole (2.5 g, 15.0 mmol) under cooling. After the dropwise addition, the mixture was stirred at room temperature for half an hour, concentrated under reduced pressure to a volume of one-third, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to give a pale yellow product. , yield 48.0%.

 (6) Preparation of 2-aminocyclopropyl-6-fluoro-indole 4-fluorophenyl)benzoyl hydrazide

 N-cyclopropyl-2-fluoro-N-(4-fluorophenyl)-6-nitrobenzoic acid hydrazide (2.4 g, 7.2 mmol) was dissolved in 50 mL of methanol, and 0.3 g 10% was added thereto. Pd/C, hydrogen gas, reacted at room temperature for 12 h, the reaction was completed, Pd C was filtered off, and the organic phase was concentrated to obtain 2.0 g, yield 9.16%.

 (7) (5)-1-[2-[2-Cyclopropyl-2-(4-fluorophenyl)indolecarbonyl]-3-fluorophenylamino]-1-oxobutan-2-ylcarbamic acid Preparation of tert-butyl ester

In a dry reaction flask, (5)-2-(tert-butoxycarbonylamino)butyric acid (1.48 _& 7.3 11^ ₀ 1), 2-aminocyclopropyl-6-fluoro-iV-(4-fluorobenzene Benzoyl hydrazide (2.0 g, 6.6 mmol), DIEA (1.3 mL, 7.5 mmol) and HATU (2.77 _& 7.3 11^101) were added to 50 11^ 01^^, stirred at room temperature for 48 h, added water and The mixture was extracted with chloroform, and the organic layer was combined, washed with brine, and brine.

 (8) (5)-1 -[3-[Cyclopropyl(4-fluorophenyl)amino]-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl]-propyl Preparation of tert-butyl carbamate

 (5) Small [2-[2-cyclopropyl-2-(4-fluorophenyl)indolecarbonyl]-3-fluorophenylamino]-1-oxobutan-2-ylcarbamic acid tert-butyl ester ( 1.8 g, 3.68 mmol) was dissolved in 60 mL of tert-butanol. DMAP (0.54 g, 4.42 mmol) was added to the reaction mixture and refluxed overnight. After cooling, the mixture was evaporated to give a white solid.

 (9) (5)-2-(1-Aminopropyl)-3-[cyclopropyl(4-fluorophenyl)amino]-5-fluoroquinazolin-4(3H)-one hydrochloride In a dry reaction flask, (5)-1 -[3-[cyclopropyl(4-fluorophenyl)amino]-5-fluoro-4-oxo-3,4-dihydroquinazoline-2 -yl] tert-butyl propyl carbamate (1.1 g, 2.34 mmol) dissolved in 30 mL of absolute ethanol, hydrogen chloride gas was passed through the system until the reaction was complete, and after steaming, 700 mg of solid (hydrochloride) was obtained. The rate is 73.5 %.

(10) (5)-2-[l-(9H-Indol-6-ylamino)propyl]-3-[cyclopropyl(4-fluorophenyl)amino]-5-fluoroquinazoline-4 (3H)-ketone Preparation

 In a dry reaction flask, add (5)-2-(1-aminopropyl)-3-[cyclopropyl(4-fluorophenyl)amino]-5-fluoroquinazoline to 30 mL of tert-butanol. -4(3H)-one hydrochloride (665 mg, 1.63 mmol) and DIEA (0.71 mL, 4.08 mmol), and stirred for half an hour in an ice bath, then added 6-chloro-9H-indole (378 mg, 2.45) (mmol), the reaction was reacted at 85 ° C for 24 h, cooled, concentrated, and chromatographed to give a white solid 135 mg, yield 17.0 %.

Mass Spectrum (M+H): 489.2

1H-NMR ( _6- DMS0, 400 MHz): δ 12.66 (1Η, s), 8.07-7.83 (3H, m), 7.63 (2H, t), 7.34 (1H, dd), 6.70-6.45 (4H, m ), 5.67-5.56 (1H, m), 3.29-3.22 (1H, m), 2.26-2.12 (1H, m), 2.01-1.83 (1H, m), 1.46-1.35 (1H, s), 1.13-1.01 (1H, s), 0.97 (3H, t), 0.80-0.57 (2H, m).

Example 25 (S)-2-[1-f9#-嘌呤-6-ylamino)propyl1-3-(diphenylamino)-5-fluoroquinazoline-4 (3^-ketone (compound) Preparation of 27)

 (1) Preparation of (S)-l-(5-fluoro-4-oxo-4H-benzo[rf][l,3]oxazine-2-yl)propylcarbamic acid tert-butyl ester

 Add 2-amino-6-fluorobenzoic acid (1.00 g, 6.45 mmol), (5)-2-(tert-butoxycarbonylamino)butyric acid (1.571 g, 7.73 mmol) to a dry 100 mL reaction vial. 8.0 mL of pyridine was added, and finally triphenyl phosphite (2.00 g, 6.45 mmol) was added and stirred in an oil bath at 55 ° C for 10 hours. The system was used directly for the next reaction.

(2) Preparation of tert-butyl CS-l-[3-(diphenylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl]propylcarbamate Preparation of (S)-l-(5-fluoro-4-oxo-4H-benzo[d][l,3]oxazine-2-yl)propylcarbamic acid tert-butyl ester in the reaction solution directly added two Phenylhydrazine (1.305 g, 7.08 mmol) was stirred under reflux in an oil bath of 100 °C for 8 hours, then cooled, concentrated under reduced pressure and purified by column chromatography (PE: EA=6:1) g, the yield in two steps is 63.5 %. (3) Preparation of (S)-2-(l-aminopropyl)-3-(diphenylamino)-5-fluoroquinazolin-4(3H)-one trifluoroacetate in dry lOO (5)-1-[3-(Diphenylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl]propylcarbamic acid tert-butylate was added to the mL reaction flask. Ester (1.00 g, 2.05 mmol), dissolved in 20 mL of dichloromethane, 10 mL of trifluoroacetic acid was added dropwise in an ice bath, and the addition was completed, then the mixture was stirred at room temperature, and the reaction was carried out under TLC. After completion, the reaction was stopped, and then concentrated under reduced pressure, and the obtained product was directly used for the next reaction.

 (4) (5)-2-[l-(9H-Indol-6-ylamino)propyl]-3-(diphenylamino)-5-fluoroquinazolin-4(3/)-one Preparation

 The product obtained in the previous step was dissolved in 40 mL of t-butanol in a 100 mL dry reaction flask. The pH was adjusted to basic with DIEA, then 6-chloro-9H-indole (0.380 g, 2.46 mmol) was added. The reaction was refluxed in an oil bath at 90 ° C for 48 hours. Then, it was cooled and concentrated under reduced pressure, and purified by liquid chromatography to yield white solid (0.3 g).

Mass Spectrum (M+H): 507.2

 'H-NMRC^-DMSO, 400 MHz): δ 12.95 (1Η, s), 8.17-8.04 (2H, m), 7.92-7.77 (2H, m), 7.53-7.42 (1H, m), 7.41-7.10 (11H, m), 5.65 (1H, m), 2.02-1.40 (2H, m), 0.74 (3H, t).

Example 26 Cy)-2-[1-(9 y-嘌呤-6-ylamino)propyl]-3-(cyclohexylamino)-5-fluoroquinazoline-4(3H)-one

 (1) Preparation of methyl 2-fluoro-6-nitrobenzoate

2-Fluoro-6-nitrobenzoic acid (12.03 g, 65.0 mmol) was dissolved in 50 mL of CH ₂ C1 ₂ and 0.3 mL of DMF, and oxalyl chloride (12.35 g, 97.3 mmol) was slowly added dropwise thereto, and stirred at room temperature for two hours. After that, the solvent was removed by concentration, and then dissolved in 8 mL of dioxane, and slowly added dropwise to 100 mL of anhydrous methanol in an ice bath. After the dropwise addition was completed, the reaction was transferred to room temperature for two hours, and concentrated under reduced pressure. , 12.70 g of a white solid was obtained, yield 98.1%. (2) Preparation of methyl 2-amino-6-fluorobenzoate

 Methyl 2-fluoro-6-nitrobenzoate (12.70 g, 63.8 mmol) was dissolved in 30 mL of methanol, 10% Pd/C (65 mg) was added, and the reaction was carried out under a hydrogen atmosphere for 8 hours, and Pd was filtered off. /C, concentrated to give 10.60 g of white solid, yield 98.2

%.

 (3) Preparation of (5)-2-[2-(tert-Butoxycarbonylamino)butyrylamide]-6-fluorobenzoic acid methyl ester

In a dry reaction flask, methyl 2-amino-6-fluorobenzoate (8.46 & 50 dish 11 ₀ 1), (5)-2-(tert-butoxycarbonylamino)butyric acid (12.19 g, 60 mmol) DIEA (10.2 mL, 58.6 mmol) and HATU (24.72 g, 65 mmol) were added to 100 mL of NN-dimethylformamide, stirred at room temperature for 64 h, added with water and dichloromethane, dichloromethane extract, combined The organic layer was washed with EtOAc (EtOAc m.).

 (4) Preparation of (5)-2-t2-(tert-butoxycarbonylamino)butyrylamino]-6-fluorobenzoic acid

 Methyl (5)-2-[2-(tert-butoxycarbonylamino)butyrylamide]-6-fluorobenzoate (12.14 g, 34.3 mmol) was dissolved in 100 mL of tetrahydrofuran. A 50 mL aqueous solution of lithium hydroxide (4.31 g, 103 mmol). The reaction was carried out at room temperature for 4 h, and the reaction was completed by TLC. Water was added to the system, pH-3-4 was adjusted with dilute hydrochloric acid, solid was precipitated, filtered, and dried to give a white solid 10.22 g.

 (5) Preparation of (5)-1-(5-fluoro-4-oxo-4H-benzo[[1,3]oxazin-2-yl)propylcarbamic acid tert-butyl ester

 (5)-2-[2-(tert-Butoxycarbonylamino)butyrylamino]-6-fluorobenzoic acid (3.4 g, 10 mmol) and acetic anhydride (4.1 g, 40.2 mmol) dissolved in 100 mL tert The alcohol was reacted at 100 ° C for 8 hours, cooled, and concentrated under reduced pressure to give a white solid, 2.94 g.

 (6) Preparation of CS)-l-[3-(cyclohexylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl]propylcarbamic acid tert-butyl ester (5)-1-(5-fluoro-4-oxo-4H-benzo[][l,3]oxazin-2-yl)propylcarbamic acid tert-butyl ester (806 mg, 2.50 mmol) and ring Hexylguanidine hydrochloride (452 mg, 3.0 mmol) was dissolved in 30 mL of pyridine, stirred at 100 ° C for 8 hours, cooled, concentrated under reduced pressure, and the residue obtained was obtained by column chromatography (PE: EA = 1:1). Light yellow solid 609 mg, yield 58.2%.

 (7) Preparation of (5)-2-(1-aminopropyl)-3-(cyclohexylamino)-5-fluoroquinazoline-4(3H)-one trifluoroacetate

 (5)-1-[3-(Cyclohexylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl]propylcarbamic acid tert-butyl ester (609 mg, 1.46 mmol), trifluoroacetic acid (6 mL) was added dropwise in an ice bath of dichloromethane (20 mL). After the dropwise addition, the reaction was stirred at room temperature for 2 hours, and the reaction was completed by TLC. The crude solid was used directly in the next step.

(8) CS)-2-[l-(9H-嘌吟-6-ylamino)propyl]-3-(cyclohexylamino)-5-fluoroquinazoline-4 (3H> ketone prepared on The obtained solid (5)-2-(1-aminopropyl)-3-(cyclohexylamino)-5-fluoroquinazoline-4(3H)-one trifluoroacetate (about 1.46 mmol) was dissolved in 20 mL of tert-butanol, DIEA (0.76 mL, 4.36 mmol) was added, and stirred for half an hour in an ice bath, then 6-chloro-9H-indole (271 mg, 1.75 mmol) was added. The reaction was allowed to react at 85 ° C for 36 h, cooled, concentrated and purified eluting with EtOAc EtOAc Mass Spectrum (M+H): 437.2

lH-NMR (flf ₆ -DMSO, 400 MHz): δ 12.85 (IH, br s), 8.22-8.13 (2H, m), 7.82-7.69 (IH, m), 7.52-7.35 (2H, m), 7.26 (IH, t), 6.26 (IH, s), 5.98 (IH, m), 2.15-1.98 (1H, m), 1.92-1.48 (6H, m), 1.35-1.05 (6H, m), 0.945 (3H , m).

Example 27 (S)-2-[l-i9ff-嘌呤-6-ylamino)ethyl 1-3-(phenylamino)quinazoline-4 (3-ketone (Compound 29)

 (1) Preparation of 2-aminobenzoic acid

 Ethyl 2-aminobenzoate (1.652 g, 10 mmol), lithium hydroxide monohydrate (1.68 g, 40 mmol), and 30 mL of methanol were added to the dried reaction flask. The reaction was stirred at room temperature for 3 h. Upon completion, the reaction was quenched, EtOAc (EtOAc m.).

 (2) Preparation of (5) small (4-oxo-4H-benzo[1,3]oxazin-2-yl)ethylcarbamic acid tert-butyl ester

 In a dry single-mouth reaction flask, add 2-aminobenzoic acid (1.00 g, 7.29 mmol), (<S)-2-tert-butoxycarbonylaminopropionic acid (1.52 g, 8.03 mmol) and triphenyl phosphite (2.492). g, 8.03 mmol), 10 mL of pyridine was added as a solvent, and the reaction was carried out at 55 ° C for 12 h. Without further treatment, the next reaction was carried out directly.

 (3) Preparation of CS)-l-[4-oxo-3-(phenylamino)-3,4-dihydroquinazolin-2-yl]ethylcarbamic acid tert-butyl ester

In the reaction system of the previous step, phenylhydrazine (0.868 g, 8.03 mmol) was directly added, and the temperature was raised to 100 ° C for 10 h. After cooling, the mixture was directly added to the silica gel and column chromatography (petroleum ether: ethyl acetate = 6:1) The white solid was 1.256 g, and the yield in two steps was 45.3 %. (4) Preparation of (S)-2-(l-aminoethyl)-3-(phenylamino)quinazolin-4(3H)-one trifluoroacetate

 In a dry reaction flask, add (5) small [4-oxo-3-(phenylamino)-3,4-dihydroquinazolin-2-yl]ethylcarbamic acid tert-butyl ester (0.761 g, 2.0 Methyl) 5 mL of dichloromethane, 5 mL of trifluoroacetic acid, and stirred at room temperature for 3 h. The reaction was quenched and the solvent was evaporated to give a white solid, 0.758 g, yield 96.1 %.

 (5) Preparation of (5)-2-[l-(9H-嘌呤-6-ylamino)ethyl]-3-(phenylamino)quinazoline-4(3H)-one

 (5)-2-(1-Aminoethyl)-3-(phenylamino)quinazolin-4(3H)-one trifluoroacetate (0.758 g, 1.92 mmol), 6 -Chloro-9H-indole (0.326 g, 2.11 mmol), add 10 mL of tert-butanol, DIEA (1.82 mL, 10.5 mmol), react at 90 °C for 12 h, directly spin dry and mix, prepare liquid phase to purify white The solid was 0.258 g and the yield was 33.7%.

Mass spectrometry (M+H): 399.2

1H-NMR ( _6- DMS0, 400 MHz): δ 12.99 (IH, s), 9.12 (IH, s), 8.22-8.03 (3H, m), 7.91-7.74 (2H, m), 7.61 (1H, d ), 7.50 (1H, t), 7.30-7.15 (2H, m), 6.98 (2H, d), 6.85 (1H, t), 5.52 (1H, m), 1.66 (3H,d).

Example 28 iS)-2-[1-(9-Indol-6-ylamino)ethyl1-5-chloro-3-(phenylamino)quinazolin-4(3H)-one oxime compound 30) Preparation

 (1) Preparation of (5)-1-(5-chloro-4-oxo-4H-benzo[[1,3]oxazin-2-yl)ethylcarbamic acid tert-butyl ester

 In a dry reaction flask, add 2-amino-6-chlorobenzoic acid (857 mg, 4.99 mmol), (5)-2-(tert-butoxycarbonylamino)propionic acid (1.13 g, 5.97 mmol), 5 mL Pyridine, triphenyl phosphite (1.86 g, 5.99 mmol), 55 was reacted overnight. The reaction was monitored by LC-MS and used directly in the next step.

 (2) Preparation of CS)-l-[5-chloro-4-oxo-3-(phenylamino)-3,4-dihydroquinazolin-2-yl]ethylcarbamic acid tert-butyl ester

Add phenylhydrazine hydrochloride (867 mg, 6.0 mmol) to the reaction system, and raise the temperature to 100 °C for 8 hours. Time. The solvent was spin-dried, and column chromatography (petroleum ether: ethyl acetate = 5:1) gave a white solid (2.0 g).

 (3) Preparation of (5)-2-(1-aminoethyl)-5-chloro-3-(phenylamino)quinazoline-4(3H)-one trifluoroacetate

 In a dry reaction flask, tert-butyl 03⁄4-1-[5-chloro-4-oxo-3-(phenylamino)-3,4-dihydroquinazolin-2-yl]ethylcarbamate ( 880 mg, 2.12 mmol) was dissolved in a mixture of 6 mL of dichloromethane and 3 mL of trifluoroacetic acid. The solvent was spun and the resulting product was used directly in the next step.

 (4) Preparation of (>S)-2-[l-(9H-indol-6-ylamino)ethyl]-5-chloro-3-(phenylamino)quinazoline-4(3H)-one

 (S)-2-(l-Aminoethyl)-5-chloro-3-(phenylamino)quinazolin-4(3)-one trifluoroacetate (about 2.12 mmol) was dissolved in the previous step. To 15 mL of tert-butanol, DIEA (2 mL, 11.5 mmol), 6-chloro-9H-indole (395 mg, 2.55 mmol) was added and the mixture was refluxed for two days. The solvent was evaporated to dryness (methanol) (EtOAc:EtOAc:EtOAc:

Mass spectrometry (M+H): 433.2

1H-NMR ( _6- DMS0, 400 MHz): δ 12.98 (1H, s), 9.01 (1Η, s), 8.25-8.07 (2Η, m), 7.90-7.60 (2H, m), 7.57-7.48 (2H , m), 7.25 (2H, t), 7.03 (2H, d), 6.86 (1H, t), 5.48 (1H, m), 1.65 (3H, d). Example 29 (S)-2-『l -i9 嘌呤-6-ylamino)ethyl 1-5-fluoro-3-(phenylamino)quinazolin-4(3H)-one (compound)

 (1) Preparation of 2-amino-6-fluoro-N-phenylbenzohydrazide

 2-Fluoro-6-nitrophenylbenzoic acid hydrazide ( 1.38 g, 5.01 mmol) was dissolved in 20 mL of methanol, 0.3 g of 100% Pd/C was added thereto, and hydrogen was passed through at room temperature for 24 h. After completion of the reaction, Pd/C was filtered off, and the organic phase was concentrated to give 1.20 g, yield 97.7%.

(2) Preparation of (5)-1-[3-fluoro-2-(2-phenylhydrazinecarbonyl)phenylamino]-1-oxopropan-2-ylcarbamic acid tert-butyl ester In a dry reaction flask, (5)-2-(tert-butoxycarbonylamino)propionic acid (1.11 g, 5.87 mmol), 2-amino-6-fluoro-N-phenylbenzoic acid hydrazide (1.20 g, 4.89 mmol), DIEA (1.3 mL, 7.47 mmol) and HATU (2.23 g, 5.86 mmol) were added to 40 mL of dichloromethane, stirred at room temperature for 48 h, added water and dichloromethane, dichloromethane extract, combined The organic layer was washed with EtOAc (EtOAc m.).

 (3) Preparation of (5)-2-(1-aminoethyl)-5-fluoro-3-(phenylamino)quinazoline-4(3H)-one hydrochloride

 Dissolve tert-butyl (5)-1-[3-fluoro-2-(2-phenylhydrazinecarbonyl)phenylamino]-1-oxopropan-2-ylcarbamate (1.55 g, 3.72 mmol) in 30 mL In ethanol, 3 mL of concentrated hydrochloric acid was added dropwise to the reaction flask under ice bath, and after stirring for half an hour, the reaction was transferred to an oil bath at 85 ° C for 16 h, cooled and concentrated to give a white solid which was used directly to the next.

 (4) Preparation of (5>2-[l-(9H-indol-6-ylamino)ethyl]-5-fluoro-3-(phenylamino)quinazoline-4(3H)-one

 (20)-2-(1-Aminoethyl)-5-fluoro-3-(phenylamino)quinazolin-4(3H)-one hydrochloride obtained from the above step was added to 20 mL of tert-butanol ( About 3.72 01) and 01 £8 (1.95 ^^, 11.2 !1111101), stir for half an hour in an ice bath, then add 6-chloro-9H-indole (575 mg, 3.72 mmol) to the reaction at 85 °C. Lower reaction for 24 h, cooling, concentration, column chromatography

(Ethyl acetate) gave 612 mg as a white solid.

Mass spectrometry (Μ+Η): 417.2

1H-NMR ( ₆ -DMSO, 400 ΜΗζ): δ 12.98 (1H, s), 9.03 (1Η, s), 8.25-8.06 (2Η, m), 7.91-7.69 (2H, m), 7.54-7.15 (4H , m), 7.07-6.68 (3H, m), 5.51 (1H, m), 1.65 (3H, d).

Example 30 (S)-2-"l-(9H~嘌呤-6-ylamino)ethyl 1-3-(phenylamino)-5-(trifluoromethyl)quinazolinone

(1) Preparation of (5)-1-[4-oxo-5-(trifluoromethyl)-4H-benzo[[1,3]oxazin-2-yl]ethylcarbamic acid tert-butyl ester In a dry reaction flask, 2-amino-6-(trifluoromethyl)benzoic acid (1.5 g, 7.31 mmol) was dissolved in 50 mL of pyridine, followed by (5)-2-(tert-butoxycarbonylamino). Propionic acid (1.6 g, 8.46 mmol), triphenyl phosphite (2.3 g, ⁷ . After mmol), it was reacted at 60 ° C for 24 h until the starting material disappeared.

 (2) (5)-1-[4-Oxo-3-(phenylamino)-5-(trifluoromethyl)-3,4-dihydroquinazolin-2-yl]ethylcarbamic acid Preparation of butyl ester

 To the above reaction solution, phenylhydrazine (0.95 g, 8.78 mmol) was added, and the mixture was heated to 100 ° C for 8 h until the starting material disappeared. After cooling, the organic solvent was rotated and subjected to column chromatography (PE: EA = 6:1) to yield 1.5 g of pale yellow solid.

(3) Preparation of (5)-2-(1-aminoethyl)-3-(phenylamino)-5-(trifluoromethyl)quinazoline-4(3H)-one hydrochloride

 In a dry reaction flask, (5)-1-[4-oxo-3-(phenylamino)-5-(trifluoromethyl)-3,4-dihydroquinazolin-2-yl] The tert-butyl carbamate (1.5 g, 3.34 mmol) was dissolved in 30 mL of absolute ethanol, and hydrogen chloride gas was passed through the system until the reaction was completed. After rotary evaporation, 1.2 g of a solid (hydrochloride salt) was obtained, yield 93.4%.

 (4) (5)-2-n-(9H-Indol-6-ylamino)ethyl]-3-(phenylamino)-5-(trifluoromethyl)quinazolin-4(3H)-one In a dry reaction flask, add (5)-2-(1-aminoethyl)-3-(phenylamino)-5-(trifluoromethyl)quinazoline 4 to 30 mL of tert-butanol. 3H)-ketohydrochloride (1.0 g, 2.60 mmol) and DffiA (2.0 mL, 11.5 mmol), 6-chloro-9H-indole (700 mg, 4.53 mmol), reaction at 85 ° C for 24 h, cooling Concentration, preparative chromatography gave 610 mg of white solid.

Mass spectrometry (M+H): 467.2

1H-NMR ( _6- DMS0, 400 MHz): δ 12.99 (IH, s), 9.16 (IH, s), 8.16 (IH, d), 8.13 (1H, s), 8.01-7.84 (4H, m), 7.26 (2H, t), 7.03 (2H, d), 6.87 (IH, t), 5.49 (IH, m), 1.67 (3H, d).

Example 31 (S)-2-[W9#-嘌呤-6-ylamino)ethyl 1-5-chloro-3-(4-fluorophenylamino)quinazoline -4ί3/Π-ketone

(1) Preparation of (5)-1-(5-chloro-4-oxo-4H-benzo[[1,3]oxazin-2-yl)ethylcarbamic acid tert-butyl ester In a dry reaction flask, add 2-amino-6-chlorobenzoic acid (857 mg, 4.99 mmol), («S)-2-(tert-butoxycarbonylamino)propionic acid (1.13 g, 5.97 mmol), 5 mL of hydrazine, triphenyl phosphite (1.86 g, 5.99 mmol), reacted at 55 °C overnight. The reaction was monitored by LC-MS and used directly in the next step.

 (2) Preparation of (5) small [5-chloro-3-(4-fluorophenylamino)-4-oxo-3,4-dihydroquinazolin-2-yl]ethylcarbamic acid tert-butyl ester In the previous reaction system, p-fluorobenzoic acid hydrochloride (975 mg, 6.0 mmol) was added, and the temperature was raised to 100 ° C for 8 h. The solvent was evaporated to dryness (methanol) (EtOAc:EtOAc:

 (3) Preparation of (5)-2-(1-aminoethyl)-5-chloro-3-(4-fluorophenylamino)quinazoline-4(3H)-one trifluoroacetate

 In a dry reaction flask, (5)-1-[5-chloro-3-(4-fluorophenylamino)-4-oxo-3,4-dihydroquinazolin-2-yl]ethylamino The tert-butyl formate (800 mg, 1.85 mmol) was dissolved in a mixture of 6 mL of dichloromethane and 3 mL of trifluoroacetic acid. The solvent was spun and the resulting product was used directly in the next step.

(4) (5)-2-[l-(9H-Indol-6-ylamino)ethyl]-5-chloro-3-(4-fluorophenylamino)quinazolin-4(3H)-one Preparation

 The above product (5)-2-(1-aminoethyl)-5-chloro-3-(4-fluorophenylamino)quinazolin-4(3H)-one trifluoroacetate (about 1.85 mmol) Dissolved in 15 mL of tert-butanol, added DIEA (2 mL, 11.5 mmol), 6-chloro-9H-indole (344 mg, 2.23 mmol), and refluxed for two days. The solvent was evaporated to dryness and purified by column chromatography to yield 390 mg of white solid.

 Normal phase HPLC, Daisy chiral analytical column (OD-H, 5.0 μιη, 150X4.6 mm), mobile phase: n-hexane: ethanol = 90:10, flow rate 1.0 mL/min, column temperature 35 V, detection wavelength 270 Ran, injection concentration 0.5 mg/mL (ethanol dissolution), injection volume: ΙΟ μί, determination of chiral purity is 73.9:26.1 (S:R).

Mass Spectrometry (M+H): 451.2

1H-NMR ( ₆ -DMSO, 400 MHz): δ 12.97 (1H, s), 8.99 (1 Η, s), 8.30-8.09 (2H, m), 8.00-7.89 (1H, m), 7.77-7.60 (2H , m), 7.57-7.46 (2H, m), 7.16-7.00 (3H, m), 5.48 (1H, m), 1.65 (3H, d). Example 32 (S)-2-〖l-i9 - Preparation of 嘌呤-6-ylamino)ethyl]-5-fluoro-3-(4-fluorophenylamino)quinazolin-4f3ff)-one (Compound 34)

 (1) Preparation of 2-fluoro-N'-(4-fluorophenyl)-6-nitrobenzoyl hydrazide

2-Fluoro-6-nitrobenzoic acid (19.9 g, 107 mmol) was dissolved in 150 mL of CH ₂ Cl ₂ and 2 mL of DF, and oxalyl chloride (14.1 mL, 161 mrnol) was slowly added dropwise thereto, and stirred at room temperature for 2 h. After that, the solvent was removed by concentration, then dissolved in 15 mL of dioxane, and then dropped to p-fluorophenylhydrazine hydrochloride (17.5 g, 107 mmol) NaHC0 ₃ (6.72 g, 80.0 mmol) of dioxane under cooling. Ring 20 mL and water 20 mL solution, add dropwise to room temperature, stir for 0.5 h, concentrate under reduced pressure to one-third volume, extract with ethyl acetate, dry over anhydrous sodium sulfate, suction filtration, concentrate organic phase, ether Recrystallization gave 16.6 g of a pale yellow product, yield 52.

 (2) Preparation of 2-amino-6-fluoro-N'-(4-fluorophenyl)benzoyl hydrazide

 2-Fluoro-N'-(4-fluorophenyl)-6-nitrobenzoic acid hydrazide (4.4 g, 15.0 mmol) was dissolved in 60 mL of methanol, and 0.5 g of 10% Pd/C was added thereto. The reaction was carried out for 36 h at room temperature, the reaction was completed, Pd/C was filtered off, and the solid obtained by concentration of the organic phase was directly used for the next reaction.

 (3) Preparation of CS)-l-[3-fluoro-2-[2-(4-fluorophenyl)decanoyl]phenylamino]-1-oxopropan-2-ylcarbamic acid tert-butyl ester

 In the dried reaction flask, the crude 2-amino-6-fluoro-N,-(4-fluorophenyl)benzoic acid hydrazide obtained in the previous step (about 15.0 mmol). (5)-2-(tert-butoxy Carbonylamino)propionic acid (4.25 g, 22.5 imnol), DIEA (3.39 mL, 19.5 mmol) and HATU (6.84 g, 18.0 mmol) were added to 200 mL of dichloromethane, stirred at room temperature for 48 h, water and dichloro The hydrazine is extracted with chloroform, and the organic phase is combined with water and washed with saturated brine. The organic layer is dried over anhydrous sodium sulfate. Petroleum ether: ethyl acetate = 2:1) gave 3.9 g of a white solid.

 (4) Preparation of (5)-2-(1-aminoethyl)-5-fluoro-3-(4-fluorophenylamino)quinazoline-4(3H)-one hydrochloride

tert-Butyl 03⁄4-1-[3-fluoro-2-[2-(4-fluorophenyl)decanoyl]phenylamino]-1-oxobutan-2-ylcarbamate (3.4 g, 7.8 mmol) Dissolve in 50 mL of ethanol, add 5 mL of concentrated hydrochloric acid to the reaction flask under ice bath, stir for half an hour, then transfer the reaction to an oil bath at 85 ° C for 24 h, cool and concentrate to give a white solid 2.56 g. , the yield was 93.6%. ( ⁵ ) (5)-2-[l-(9H-Indol-6-ylamino)ethyl]-5-fluoro-3-(4-fluorophenylamino)quinazolin-4(3H)-one Preparation of (5)-2-(1-aminopropyl)-5-fluoro-3-(4-fluorophenylamino)quinazolin-4(3H)-one hydrochloride (40 mL) 1.05 g, 3.0 mmol) and DIEA (1.56 mL, 9.0 mmol) were stirred in an ice bath for half an hour, then 6-chloro-9H-indole (556 mg, 3.6 mmol) was added thereto and the temperature was raised to 85 ° C. h, EtOAc (EtOAc) m.

 Mass spectrometry (Μ+Η): 435.2

'H-NMR (i/ ₆ -DMSO, 400 MHz): δ 12.99 (1H, s), 9.01 (1Η, s), 8.16 (2H, m), 7.95 (1H, m 7.84-7.69 (1H, m) , 7.37 (1H, d), 7.24 (1H, t), 7.15-7.00 (4H, m), 5.51 (1H, m), 1.65 (3H, d). Example 33 tfV2-fl-(9H-嘌呤- 6-ylamino)ethylfluorophenylamino)quinazolin-4i3H)-one (compound)

 (1) Preparation of 2-aminobenzoic acid

 Add 2-nitrobenzoic acid (10 g, 59.8 mmol) to a dry reaction flask, dissolve in 200 mL of methanol, slowly add 10 g of 10% palladium on carbon, pass hydrogen, replace the air three times, react at room temperature for 6 hours, filter The filter cake was washed three times with methanol and concentrated to give 7.1 g of pale yellow solid.

 (2) Preparation of (5)-1-(4-oxo-4H-benzo[ ][l,3]oxazol-2-yl)ethylcarbamic acid tert-butyl ester

 In a dry, single-mouth reaction flask, add 2-aminobenzoic acid (2 g, 14.6 mmol), (5)-2-(tert-butoxycarbonylamino)propionic acid (3 g, 15.9 mmol) and triphenyl phosphite ( 5 g, 16.1 mmol), 15 mL of pyridine was added as a solvent, and the reaction was carried out at 55 ° C for 12 h. Without further treatment, the next reaction was carried out directly.

 (3) Preparation of (5)-1-(3-(4-fluorophenylamino)-4-oxo-3,4-dihydroquinazolin-2-yl]ethylcarbamic acid tert-butyl ester

In the reaction system of the previous step, p-fluorobenzoquinone hydrochloride (2.6 g, 16.0 mmol) was directly added and the temperature was raised to 100. After reacting for 8 h, the mixture was directly added to silica gel for cooling, and 5 g of a white solid was obtained by the column, and the yield in two steps was 85.9 %. (4) Preparation of (S)-2-(l-aminoethyl)-3-(4-fluorophenylamino)quinazolin-4(3H)-one trifluoroacetate in a dry reaction flask, (5) 2-(1-tert-Butoxycarbonylaminoethyl)-3-(4-fluorophenylamino)quinazolin-4(3H)-one (2 g, 5 mmol), methylene chloride mL mL, 13 mL of trifluoroacetic acid, stirred at room temperature for 3 h, then quenched and then evaporated to give a white solid 1.9 g.

 (5) Preparation of (5)-2-(l-(9H-嘌呤-6-ylamino)ethyl)-3-(4-fluorophenylamino)quinazoline-4(3H)-one

 (5)-2-(1-Aminoethyl)-3-(4-fluorophenylamino)quinazolin-4(3H)-one trifluoroacetate (1.5 g, 3.64 mmol) was added to a dry reaction flask. , 6-chloro-9H-indole (0.93 g, 6 mmol), 10 mL of tert-butanol, DIEA (4.7 mL, 27 mmol), 12 h at 90 °C, directly spin dry, prepare liquid phase The white solid was purified to a white solid (yield: 33%). Mass Spectrometry (Μ+Η)·· 417.2

¹ H-NMR ( ₆ -DMSO, 400 MHz): δ 12.98 (1 Η, s), 9.08 (1H, s), 8.23-8.02 (2H, m), 8.05 (1H, d), 7.98-7.66 (3H, m), 7.58 (1H, d), 7.49 (1H, t), 7.15-7.00 (3H, m), 5.53 (1H, m), 1.66 (3H, d). Example 34 (S)-2-" l-i9H-嘌呤-6-ylamino)ethyl -3- -3- fluorophenylamino) -5-(trifluoromethyl) quinazoline

- - Ketone (Compound 36) Preparation

 (1) (5)-1-[4-Oxo-5-(trifluoromethyl)-4H-benzo[][l,3]oxazin-2-yl]ethylcarbamic acid tert-butyl ester In a dry reaction flask, 2-amino-6-(trifluoromethyl)benzoic acid (1.5 g, 7.31 mmol) was dissolved in 50 mL of pyridine, followed by (5)-2-(tert-butoxycarbonylamino) Propionic acid (1.6 g, 8.46 mmol), triphenyl phosphite (2.3 g, 7.41 mmol) was reacted at 60 ° C for 24 h until the starting material disappeared.

 (2) (5) Small [3-(4-fluorophenylamino)-4-oxo-5-(trifluoromethyl)-3,4-dihydroquinazolin-2-yl]ethylcarbamic acid Preparation of tert-butyl ester

To the above reaction solution, p-fluorobenzoic acid hydrochloride (1.5 g, 9.23 mmol) was added, and the mixture was heated to 100 ° C for 8 h until the starting material disappeared. After cooling, the organic solvent was spun off and column chromatography (PE: EA = 6:1) gave a pale yellow solid 1.6 g. The rate is 46.9 %.

 (3) Preparation of (5)-2-(l-aminoethyl)-3-(4-fluorophenylamino)-5-(trifluoromethyl)quinazoline-4(3H)-one hydrochloride

 In a dry reaction flask, (-1-[3-(4-fluorophenylamino)-4-oxo-5-(trifluoromethyl)-3,4-dihydroquinazolin-2-yl] tert-Butyl ethylcarbamate (1.6 g, 3.43 mmol) was dissolved in 30 mL of absolute ethanol, and hydrogen chloride gas was passed through the system until the reaction was completed. After rotary distillation, 1.3 g of solid (hydrochloride) was obtained, yield 94.1%. .

 (4) (5)-2-[l-(9H-Indol-6-ylamino)ethyl]-3-(4-fluoroanilino)-5-(trifluoromethyl)quinazoline-4 ( Preparation of 3H)-ketone

 In a dry reaction flask, add (-2-(1-aminoethyl)-3-(4-fluorophenylamino)-5-(trifluoromethyl)quinazolin-4 to 30 mL of tert-butanol. 3H)-ketohydrochloride (1.0 g, 2.48 mmol) and DIEA (2.0 mL, 11.5 mmol), 6-chloro-9H-indole (700 mg, 4.53 mmol), reaction at 85 ° C for 24 h, cooling , concentration, preparative chromatography to give a white solid 500 mg, yield 41.

Mass Spectrometry (M+H): 485.20

 1H-NMR (rDMS0, 400 MHz): δ 12.99 (1Η, s), 9.13 (1H, s), 8.24-8.12 (2H, m), 8.07-7.78 (4H, m), 7.20-7.01 (4H, m ), 5.49 (1H, m), 1.66 (3H, d).

Example 35 iS 2-il-f^-indol-6-ylamino)ethyl1-5-chloro-3-0-chloro-4-fluoroanilino)quinazoline-40H)-one oxime 37) Preparation

 (1) Preparation of 2-chloro-4-fluorophenylhydrazine hydrochloride

Add 1.46 g (10 mmol) of 2-chloro-4-fluoroaniline to a mixture of 20 mL of concentrated hydrochloric acid and 10 mL of trifluoroacetic acid Add 828 mg (12 mmol) sodium nitrite (dissolved in 6 mL water) to the solvent, and react for 1 hour in an ice bath. Slowly add 3.38 g (15 mmol) of stannous chloride dihydrochloride solution (15 mL thick). Hydrochloric acid), after completion, was allowed to react to room temperature for 12 hours. The filter cake was filtered with suction and dried with diethyl ether, and dried to give a white solid, 1.10 g, yield 55.8%.

 (2) (-1-[5-Chloro-3-(2-chloro-4-fluoroanilino)-4-oxo-3,4-dihydroquinazolin-2-yl]ethylcarbamic acid Preparation of butyl ester

 In a dry reaction flask, add 858 mg (5.00 mmol) of 2-amino-6-chlorobenzoic acid, 1.04 g (5.50 mmol) of (S)-2-(tert-butoxycarbonylamino)propionic acid, 10 mL of pyridine, 1.71 g (5.52 mmol) of triphenyl phosphite, reacted at 55 V for 10 hours. 2-Chloro-4-fluorophenylhydrazine hydrochloride 1.10 g (5.58 mmol) was added, and the temperature was raised to 100 ° C for 8 hours. The solvent was dried and purified by column chromatography (ethyl ether: ethyl acetate = 5:1) to yield white solid 1.30 g, yield 55.6

%.

 (3) Preparation of (5)-2-(1-aminoethyl)-5-chloro-3-(2-chloro-4-fluoroanilino)quinazoline-4(3H)-one

 In a dry reaction flask, 1.30 g (2.78 mmol) of (5)-1-[5-chloro-3-(2-chloro-4-fluoroanilino)-4-oxo-3,4-dihydroquine The tert-butyl oxazolin-2-yl]ethylcarbamate was dissolved in a mixed solvent of 10 mL of dichloromethane and 5 mL of trifluoroacetic acid, and the mixture was stirred for 2 hr. The solvent was spun and the resulting product was used directly in the next step.

 (4) (5)-2-[l-(9H-Indol-6-ylamino)ethyl]-5-chloro-3-(2-chloro-4-fluoroanilino)quinazoline-4 (3H Preparation of ketones The above product (5)-2-(1-aminoethyl)-5-chloro-3-(2-chloro-4-fluoroanilino)quinazolin-4(3H)-one (about 2.78 mmol) was dissolved in 15 mL of tert-butanol, and DIEA (2 mL, 11.5 mmol), 474 mg (3.07 mmol) of 6-chloro-9H-indole was added and the mixture was refluxed for two days. The solvent was evaporated to dryness (mjqqqqqqqq

Mass Spectrometry (M+H): 485.1

1H-NMR (i/ ₆ -DMS0, 400 MHz): δ 12.95 (1Η, s), 8.60 (1H, s), 8.14 (2H, s), 8.05-7.94 (1H, m), 7.70 (1H, t ), 7.59-7.47 (2H, m), 7.43-7.35 (1H, m), 7.30-7.10 (2H, m), 5.44 (1H, s), 1.67 (3H, d).

Example 36 (S 2-[1-I9H-indol-6-ylamino)ethyl1-5-chloro-3-f4-fluoro-2-methylanilino)quinazoline-40m-ketone Preparation of 38)

 (1) Preparation of 4-fluoro-2-methylphenylhydrazine hydrochloride

 Add 1.00 g (8 mmol) of 4-fluoro-2-methylaniline to 20 mL of concentrated hydrochloric acid, add 1.10 g (1. 9 mmol) of sodium nitrite (dissolved in 6 mL of water), and react for 1 hour in an ice bath. 4.50 g (20 mmol) of a solution of stannous chloride in hydrochloric acid (15 mL of concentrated hydrochloric acid) was added dropwise, and the mixture was transferred to room temperature for 12 hours. The filter cake was filtered with suction and dried with diethyl ether.

 (2) (5) Small [5-chloro-3-(4-fluoro-2-methylanilino)-4-oxo-3,4-dihydroquinazolin-2-yl]ethylcarbamic acid Preparation of tert-butyl ester

 In a dry reaction flask, add 858 mg (5.00 mmol) of 2-amino-6-chlorobenzoic acid, 1.04 g (5.50 mmol) of (5)-2-(tert-butoxycarbonylamino)propionic acid, 10 mL of pyridine, 1.71 g (5.52 mmol) of triphenyl benzoate, 55 V for 10 hours. 4-fluoro-2-methylphenylhydrazine hydrochloride 800 mg (4.53 mmol) was added and the temperature was raised to 100 V for 8 hours. After cooling, the solvent was evaporated to dryness mjjjjjjjjjjjjjjj

 (3) Preparation of (5)-2-(1-aminoethyl)-5-chloro-3-(4-fluoro-2-methylanilino)quinazoline-4(3H)-one

In a dry reaction flask, 1.40 g (3.13 mmol) of (5)-1-[5-chloro-3-(4-fluoro-2-methylanilino)-4-oxo-3,4-dihydrogen The tert-butyl quinazolin-2-yl]ethylcarbamate was dissolved in a mixed solvent of 10 mL of dichloromethane and 5 mL of trifluoroacetic acid, and the mixture was stirred for 2 hr. The solvent was spun and the resulting product was used directly in the next step. One (4) (5)-2-[l-(9H-Indol-6-ylamino)ethyl]-5-chloro-3-(4-fluoro-2-methylanilino)quinazoline-4 Preparation of (3H)-ketone

 The above product (5)-2-(1-aminoethyl)-5-chloro-3-(4-fluoro-2-methylanilino)quinazolin-4(3H)-one (about 3.13 mmol) Dissolved in 20 mL of tert-butanol, added DIEA (2 mL, 11.5 mmol), 534 mg (3.45 mmol) of 6-chloro-9H-indole, and refluxed for two days. After cooling, the solvent was evaporated to dryness elution elution elution elution

Mass spectrometry (Μ+Η): 465.2

 1H-NMR (-DMS0, 400 ΜΗζ): δ 12.95 (1Η, s), 8.28 (1H, s), 8.13 (2H, s), 7.95-7.84 (1H, s), 7.70 (1H, t), 7.59 -7.47 (2H, m), 7.07-6.85 (2H, m), 5.48 (1H, m), 2.36 (3H, s), 1.73-1.63 (3H, m).

Example 37 (S)-2-[l-(9H-嘌呤-6-ylamino 1ethyl1-5-chloro-3-f2,6-dichloro-4-fluoroanilino)quinazoline-40ίΠ - Preparation of ketone (Compound 39)

 (1) Preparation of 2,6-dichloro-4-fluorophenylhydrazine hydrochloride

1.80 g (10 mmol) of 2,6-dichloro-4-fluoroaniline was added to a mixed solvent of 20 mL of concentrated hydrochloric acid and 10 mL of trifluoroacetic acid, and 828 mg (12 mmol) of sodium nitrite (dissolved in 6 mL) was added. In water), react for 1 hour in an ice bath, slowly add 3.38 g (15 mmol) of a solution of stannous chloride dihydrochloride (15 mL of concentrated hydrochloric acid), add, and move to The reaction was carried out for 12 hours at room temperature. The filter cake was filtered with suction and dried with diethyl ether, and evaporated.

(2) (5)-1-[5-Chloro-3-(2,6-dichloro-4-fluoroanilino)-4-oxo-3,4-dihydroquinazolin-2-yl] Preparation of tert-butyl ethylcarbamate

 In a dry reaction flask, add 858 mg (5.00 mmol) 2-amino-6-chlorobenzoic acid, 1.04 g (5.50 mmol) (5)-2-(tert-butoxycarbonylamino)propionic acid, lO mL B ratio Pyridine, 1.71 g (5.52 mmol) of triphenyl phosphite, 55. C reaction for 10 hours. 2,6-Dichloro-4-fluorophenylhydrazine hydrochloride 1.27 g (5.49 mmol) was added, and the temperature was raised to 100 ° C for 8 hours. After cooling, the solvent was evaporated to dryness (mjjjjjjjd

 (3) Preparation of (5)-2-(1-aminoethyl)-5-chloro-3-(2,6-dichloro-4-fluoroanilino)quinazoline-4(3H)-one

 In a dry reaction flask, 2.10 g (4.19 mmol) of (5)-1-[5-chloro-3-(2,6-dichloro-4-fluoroanilino)-4-oxo-3,4- The tert-butyl dihydroquinazolin-2-yl]ethylcarbamate was dissolved in a mixed solvent of 10 mL of dichloromethane and 5 mL of trifluoroacetic acid, and the mixture was stirred for 2 hr. The solvent was spun and the resulting product was used directly in the next step.

 (4) (5)-2-[l-(9H-Indol-6-ylamino)ethyl]-5-chloro-3-(2,6-dichloro-4-fluoroanilino)quinazoline- Preparation of 4(3H)-one

 The above product (5)-2-(1-aminoethyl)-5-chloro-3-(2,6-dichloro-4-fluoroanilino)quinazolin-4(3H)-one (about 4.19 mmol) was dissolved in 20 mL of tert-butanol, and DIEA (2 tnL, 11.5 mmol), 714 mg (4.62 mmol) of 6-chloro-9H-indole was added and the mixture was refluxed for two days. After cooling, the solvent was evaporated to dryness eluted eluted elution elution elution elution elution

Mass spectrometry (Μ+Η): 519.1

 'H-NMR^-DMSO, 400 MHz): δ 13.04 (IH, s), 8.63 (IH, s), 8.17 (2H, d), 7.80 (IH, t), 7.77-7.71 (IH, m), 7.59 (1H, d), 7.57-7.49 (IH, m), 7.42-7.27 (2H, m), 6.18 (1H, m), 1.65 (3H, m).

Example 38 tfV241-(9H-Indol-6-ylamino)ethyl 1-5-chloro-3-(4-fluoro-2,6-dimethylanilino)quinazolin-4(3H)-one Preparation of (Compound 40)

(1) Preparation of 4-fluoro-2,6-dimethylphenylhydrazine hydrochloride

 Add 1.39 g (10 mmol) of 2,6-dimethyl-4-fluoroaniline to a mixed solvent of 20 mL of concentrated hydrochloric acid and 10 mL of trifluoroacetic acid, and add 828 mg (12 mmol) of sodium nitrite (dissolved in 6 In mL water, the reaction was carried out for 1 hour in an ice bath, and 3.38 g (15 mmol) of a solution of stannous chloride in hydrochloric acid (15 mL of concentrated hydrochloric acid) was slowly added dropwise, and the mixture was transferred to room temperature for 15 hours. The filter cake was filtered with suction and dried with diethyl ether, and evaporated.

 (2)-[5-Chloro-3-(4-fluoro-2,6-dimethylanilino)-4-oxo-3,4-dihydroquinazolin-2-yl]ethylcarbamic acid Preparation of tert-butyl ester

 In a dry reaction flask, add 858 mg (5.00 mmol) of 2-amino-6-chlorobenzoic acid, 1.04 g (5.50 mmol) of 0S)-2-(tert-butoxycarbonylamino)propionic acid, 10 mL of pyridine, 1.71. g (5.52 mmol) triphenyl phosphite, 55 V reaction for 10 hours. 2,6-Dimethyl-4-fluorophenylhydrazine hydrochloride 1.14 g (5.98 mmol) was added and the temperature was raised to 100 for 8 hours. The solvent was dried and purified by column chromatography (ethyl ether: ethyl acetate = 5:1).

(3) (5)-2-(1-Aminoethyl)-5-chloro-3-(4-fluoro-2,6-dimethylanilino)quinazolin-4(3H)-one hydrochloride Preparation of the salt in a dry reaction flask, 580 mg (1.26 mmol) of (5)-1-[5-chloro-3-(2,6-dimethyl-4-fluoroanilino)-4-oxo- tert-Butyl 3,4-dihydroquinazolin-2-yl]ethylcarbamate was dissolved in 10 mL of dichloromethane, and HCl was introduced in an ice bath. After 15 minutes, the reaction was terminated by TLC. The solvent was spun and the resulting product was used directly in the next step.

(4) (<S)-2-[l-(9H-嘌呤-6-ylamino)ethyl]-5-chloro-3-(4-fluoro-2,6-dimethylanilino)quinazole Preparation of porphyrin-4(3H)-one The above product (5)-2-(1-aminoethyl)-5-chloro-3-(2,6-dimethyl-4-fluoroanilino)quinazolin-4(3H)-one salt The acid salt (about 1.26 mmol) was dissolved in 20 mL of tert-butanol, and DIEA (2 mL, 11.5 mmol), 232 mg (1.50 mmol) of 6-chloro-indole was added and the mixture was refluxed for two days. The solvent was dried and the liquid phase was separated to give a white solid (yield: 300 mg).

Mass spectrometry (M+H): 479.2

1H-NMR (i ₆ -DMSO, 400 MHz): δ 13.05 (1 Η, s), 8.19-8.15 (2H, m), 7.86 (1H, s), 7.77 (1H, t), 7.68 (1H, d) , 7.56 (1H, dd), 7.45-7.35 (1H, m), 6.94-6.85 (1H, m), 6.74-6.63 (1H, m), 6.31 (1H, m), 2.38 (3H, s), 1.84 (3H, s), 1.67 (3H, d).

Example 39 ί5)-2-Κ9-Indol-6-ylamino)(cyclopropyl)methyl]-5-fluoro-3-(4-fluorophenylamino)quinazoline-4i3H)- ketone compound Preparation of 41)

 (1) Preparation of 2-amino-6-fluorobenzoic acid

 Add 2-fluoro-6-nitrobenzoic acid (8.325 g, 45.0 mmol) to a dry 250 mL reaction vial, dissolve in methanol, then add 0.900 g of 10% Pd/C, stir at room temperature overnight, then Pd/ It was filtered off and concentrated under reduced pressure to give a pale yellow solid (yield: 6.

 (2) Preparation of (5)-cyclopropyl (tert-butyl 5-fluoro-4-oxo-4H-benzo[1,3]oxazin-2-yl)methylcarbamate

 Add 2-amino-6-fluorobenzoic acid (1.085 g, 7.0 mmol), (5)-2-(tert-butoxycarbonylamino)-2-cyclopropylacetic acid (1.505 g, in a dry 50 mL reaction flask. 7.0 mmol), then 6.0 mL of pyridine, triphenyl phosphite (2.170 g, 7.0 mmol) was added and stirred in an oil bath at 55 °C for 10 hours. The system was used directly for the next reaction.

(3) OS)-cyclopropyl[5-fluoro-3-(4-fluorophenylamino)-4-oxo-3,4-dihydroquinazolin-2-yl]methylcarbamic acid tert-butyl ester Preparation In the reaction liquid for preparing (5)-cyclopropyl (5-fluoro-4-oxo-4H-benzo[[1,3]oxazin-2-yl)methylcarbamic acid tert-butyl ester, directly added to the reaction solution Fluorine hydrochloride (1.138 g, 7.0 mmol) was stirred under reflux in an oil bath at 100 ° C for 8 h, then cooled, concentrated under reduced pressure and purified by column chromatography (PE: EA=6:1) The pale yellow solid was 2.130 g, and the two-step yield was 68.7%.

 (4) Preparation of (5)-2-[Amino(cyclopropyl)methyl]-5-fluoro-3-(4-fluorophenylamino)quinazolin-4(3H)-one trifluoroacetate

 Add (-cyclopropyl[5-fluoro-3-(4-fluorophenylamino)-4-oxo-3,4-dihydroquinazolin-2-yl]methyl to a dry 100 mL reaction vial Tert-butyl carbamate (0.630 g, 1.42 rnmol), dissolved in 12.0 mL of dichloromethane, added 6.0 mL of trifluoroacetic acid in an ice bath, added dropwise, then taken to room temperature and stirred, TLC detection After the reaction of the lower starting material was completed, the reaction was stopped, and then concentrated under reduced pressure, and the obtained product was directly used for the next reaction.

 (5) CS)-2-[(9H-Indol-6-ylamino)(cyclopropyl)methyl]-5-fluoro-3-(4-fluorophenylamino)quinazolin-4(3H) - Preparation of ketone (5)-2-[Amino(cyclopropyl)methyl]-5-fluoro-3-(4-fluorophenylamino)quinazoline obtained in the previous step in a 100 mL dry reaction flask -4(3H)-one was dissolved in 20.0 mL of tert-butanol, the system was adjusted to basic with DIEA, then 6-chloro-9Η-嘌呤 (0.264 g, 1.71 mmol) was added in an oil bath at 90 °C The reaction was refluxed for 48 hours. Then, it was cooled and concentrated under reduced pressure, and purified by chromatography.

Mass spectrometry (Μ+Η): 461.2

1H-NMR (i/ ₆ -DMSO, 400 ΜΗζ): δ 12.97 (1H, br s), 9.11 (1H, s), 8.22-8.00 (2H, m), 7.88-7.75 (1H, m), 7.60- 7.45 (2H, m), 7.28 (1H, t), 7.06-6.84 (3H, m), 6.74-6.63 (1H, m), 5.49-5.27 (1H, m), 1.59-1.40 (1H, m), 0.75-0.30 (4H, m).

Example 40 (S)-2-"(9-Indol-6-ylamino)(cyclopropyl)methyl]-5-chloro-3-(4-fluorophenylamino)quinazoline-4 (3 -

(1) Preparation of (5)-(5-chloro-4-oxo-4H-benzo[rf][l,3]oxazin-2-yl)(cyclopropyl)methylcarbamic acid tert-butyl ester In a dry reaction flask, add 515 mg (3.0 mmol) of 2-amino-6-chlorobenzoic acid, 710 mg (3.3 mmol)

(5)-2-(tert-Butoxycarbonylamino)-2-cyclopropylacetic acid, 5 mL of pyridine, 1.02 g (3.3 mmol) of triphenyl phosphite, 55 V overnight. The reaction was monitored by LC-MS.

 (2) (5)-[5-Chloro-3-(4-fluorophenylamino)-4-oxo-3,4-dihydroquinazolin-2-yl](cyclopropyl)methylcarbamic acid Preparation of tert-butyl ester

 In the above reaction system, 536 mg (3.3 mmol) of p-fluoroquinone hydrochloride was added, and the temperature was raised to 100 ° C for 8 hours. The solvent was evaporated to dryness (methanol) (EtOAc:EtOAc:EtOAc:

(3) Preparation of (S)-2-[Amino(cyclopropyl)methyl]-5-chloro-3-(4-fluorophenylamino)quinazolin-4(3H)-one trifluoroacetate In a dry reaction flask, 1.2 g (2.61 mm ₀ l) (5 -[5-chloro-3-(4-fluorophenylamino)-4-oxo-3,4-dihydroquinazolin-2- Tert-butyl (cyclopropyl)methylcarbamate was dissolved in a mixture of 10 mL of dichloromethane and 5 mL of trifluoroacetic acid. The mixture was stirred for 1 hour in an ice bath, and the reaction was terminated by TLC. The resulting product was used directly in the next step.

 (4) (5)-2-[(9H-Indol-6-ylamino)(cyclopropyl)methyl]-5-chloro-3-(4-fluorophenylamino)quinazolin-4(3H) - Preparation of ketone (5)-2-(Amino(cyclopropyl)methyl)-5-chloro-3-(4-fluorophenylamino)quinazolin-4(3H)-one The fluoroacetate was dissolved in 15 mL of tert-butanol, and 2 mL of DIEA, 445 mg (2.88 mmol) of 6-chloro-9H-indole was added, and the mixture was heated under reflux for two days. The solvent was evaporated to dryness (mjqqqqqqqqq

Mass Spectrometry (M+H): 477.2

 ^-NMRC^-DMSO, 400 MHz): δ 12.98 (1H, s), 9.10 (1Η, s), 8.29-8.02 (2H, m), 7.82-7.47 (4H, m), 7.06-6.84 (4H, m), 5.40 (1H, m), 1.59-1.41 (1H, m), 0.76-0.32 (4H, m).

Example 41 ffl-2-[W9H-indol-6-ylamino)propyl]-5-chloro-3-(pyridin-3-ylamino)quinazolin-4 (3-one-f compound 43)

 (l) Preparation of (5)-l-(5-chloro-4-oxo-4H-benzo[[1,3]oxazin-2-yl)propylcarbamic acid tert-butyl ester

 In a dry reaction flask, add 2.2 g (6.17 mmol) of 0S)-2-[2-(tert-butoxycarbonylamino)butyrylamino]-6-chlorobenzoic acid, 25 mL of tert-butanol, 3.15 g (30.8). Ethyl acetate was heated and refluxed overnight. The solvent was spun dry and used directly in the next step.

 (2) CS)-l-[5-Chloro-4-oxo-3-(pyridin-3-ylamino)-3,4-dihydroquinazolin-2-yl]propylcarbamic acid tert-butyl ester Preparation

 Half of the above product (about 3.09 mmol) was dissolved in 5 mL of pyridine, 3-mercaptopyridine hydrochloride (524 mg, 3.60 mmol) was added, and heated to 100 °C for 8 h. The solvent was evaporated to dryness (methanol) (EtOAc:EtOAc:EtOAc:

 (3) Preparation of (S)-2-(l-aminopropyl)-5-chloro-3-(pyridin-3-ylamino)quinazoline-4(3H)-one trifluoroacetate

 (5)-1-(5-Chloro-4-oxo-3-(pyridin-3-ylamino)-3,4-dihydroquinazolin-2-yl]propylcarbamic acid tert-butyl ester ( 630 mg, 1.47 mmol) was dissolved in 10 mL of a mixture of dichloromethane and 5 mL of trifluoroacetic acid. The reaction was carried out in an ice bath for 1 h, and the reaction was terminated by TLC. The solvent was spun dry to give a yellow solid which was used directly in the next step.

 (4) (<S)-2-[l-(9H-嘌呤-6-ylamino)propyl]-5-chloro-3-(pyridin-3-ylamino)quinazolin-4(3H)- Preparation of ketone

 (5)-2-(1-Aminopropyl)-5-chloro-3-(pyridin-3-ylamino)quinazolin-4 (3H ketone trifluoroacetate (about 1.47 mmol) dissolved in 20 Add DIE A (2 mL, 11.5 mmol), 340 mg (2.20 mmol) of 6-chloro-9H-indole in mL-tert-butanol, and heat to reflux for 1 day. The solvent was evaporated to dryness. A white solid of 150 mg was obtained in a two-step yield of 22.8%.

Mass spectrometry (M+H): 448.2

'H-NMR (c? ₆ -DMSO, 400 MHz): δ 12.96 (1H, s), 9.27 (1Η, s), 8.35 (1H, s), 8.21-8.01 (3H, m), 7.97-7.86 ( 1H, m), 7.79-7.60 (1H, m), 7.59-7.48 (2H, m), 7.45-7.34 (1H, m), 7.31-7.05 (1H, m), 5.45 (1H, m), 2.20- 1.78 (2H, m), 1.02 (3H, t). Example 42 (S)-2-"M9 嘌呤-6-ylamino)propyl1-5-fluoro-3-(pyridin-3-ylamino)-quinazoline-4ί3^-one ketone compound 44) Preparation

 (1) Preparation of 2-fluoro-6-nitro-N-(pyridin-3-yl)benzoylhydrazide

2-Fluoro-6-nitrobenzoic acid (12.03 g, 65.0 mmol) was dissolved in 50 mL CH ₂ Cl ₂ and 0.3 mL DMF, and oxalyl chloride (12.347 g, 97.3 mrnol) was slowly added dropwise thereto, and stirred at room temperature for 2 h. The solvent was removed by concentration, then dissolved in 12 mL of dioxane, and then dropped to 3-mercaptopyridine (7.09 g, 65.0 mmol), NaHC0 ₃ (10.92 g, 130.0 mmol) of dioxane 30 under cooling. In a solution of 30 mL of water and 30 mL of water, the mixture was stirred at room temperature, stirred for half an hour, concentrated to a one-third volume under reduced pressure, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and evaporated. 14.65 g, yield 81.5%.

 (2) Preparation of 2-amino-6-fluoro(pyridin-3-yl)benzoyl hydrazide

 2-Fluoro-6-nitro-N-(P-pyridin-3-yl)benzoyl hydrazide (14.65 g, 53.0 mmol) was dissolved in 130 mL of methanol, and 1.5 g of 10% Pd/C was added thereto. With hydrogen gas, the reaction was carried out for 42 h at room temperature, the reaction was completed, Pd/C was filtered off, and the solid obtained by concentration of the organic phase was directly used for the next reaction.

 (3) (5)-1-[3-Fluoro-2-[2-(pyridin-3-yl)nonylcarbonyl]phenylamino]-1-oxobutan-2-ylcarbamic acid tert-butyl ester Preparation

In the dried reaction flask, the crude 2-amino-6-fluoro(pyridin-3-yl)benzoyl hydrazide obtained in the previous step (about 53.0 mmol), (5)-2-(tert-butoxycarbonylamino) butyl Acid (12.93 g, 63.6 mmol), DIEA (10.2 mL, 58.5 mmol) and HATU (24.2 g, 63.7 mmol) were added to 100 mL of dimethylformamide, stirred at room temperature for 64 h, water and dichloromethane were added.垸, chloroformin extraction, combined organic phase, washed with water, washed with brine, dried over anhydrous sodium sulfate, and evaporated. The solid was 6.52 g, and the total yield of the two steps was 28.5%. (4) Preparation of (5)-2-(1-aminopropyl)-5-fluoro-3-(pyridin-3-ylamino)quinazolin-4(3H)-one hydrochloride (5) 1-[3-Fluoro-2-[2-(pyridin-3-yl)nonylcarbonyl]phenylamino]tert-butyl-2-oxobutan-2-ylcarbamate (6.52 & 15.11 11^01) In 50 11 ^ ethanol, 5 mL of concentrated hydrochloric acid was added dropwise to the reaction flask under ice bath. After stirring for half an hour, the reaction was transferred to an oil bath at 85 ° C for 24 h. After cooling, the pH was adjusted to 8, and concentrated. The phase was prepared to give a white solid (yield: EtOAc).

 (5) (5)-2-[l-(9H-Indol-6-ylamino)propyl]-5-fluoro-3-(pyridin-3-ylamino)quinazolin-4(3H)-one Preparation

 Add (5)-2-(1-aminopropyl)-5-fluoro-3-(pyridin-3-ylamino)quinazolin-4(3H)-one hydrochloride (20 mL) to tert-butanol ( 0.95 g, 2.72 mmol) and DIEA (0.6 mL, 3.44 mmol) were stirred for half an hour in an ice bath, then 6-chloro-9H-indole (562 mg, 3.64 mmol) was added and the reaction was carried out at 85 °C. h, EtOAc (EtOAc) m.

Mass spectrometry (M+H): 432.2

1H-NMR ( _d -DMSO, 400 MHz): δ 12.96 (IH, s), 9.28 (1H, s), 8.37-8.30 (1H, m), 8.20-8.11 (IH, m), 8.11-8.02 (2H , m), 7.95-7.72 (2H, m), 7.45-7.34 (2H, m), 7.31-7.18 (2H, m), 5.46 (1R m), 2.20-1.82 (2H, m), 1.02 (3H, t).

Example 43 Preparation of tfV2-il-(9 嘌呤-6-ylamino)propyl1-5-fluoro-34methyl(pyridin-3-yl)amino-1 quinazolin-4-3-one (Compound 45)

 (1) Preparation of 4-methyl(pyridin-3-yl)benzenesulfonamide

3-aminopyridine (14.1 g, 0.15 mol) and p-toluenesulfonic acid chloride (30 g, 0.157 mol) dissolved in 20 mL of pyridine The reaction was carried out at 100 ° C for 2 hours, cooled, and the reaction mixture was poured into ice water to give a solid, which was filtered, and then recrystallized from anhydrous ethanol to give 36 g of white solid.

 (2) Preparation of NA-dimethyl(pyridin-3-yl)benzenesulfonamide

 4-Methyl(pyridin-3-yl)benzenesulfonamide (4.96 g, 20 mmol) and potassium carbonate (5.52 g, 40 mmol) in 40 mL of EtOAc. The mixture was added dropwise to the reaction mixture over a half hour, and the mixture was refluxed for 2 hours, cooled, suction filtered, and the solid was washed with acetone, and the filtrate was concentrated to give 4.7 g of a brown oil.

(3) Preparation of N-methylpyridine-3-amine

 N,4-dimethyl(pyridin-3-yl)benzenesulfonamide (4.96 g, 18.9 mmol) was dissolved in 80% concentrated sulfuric acid (20 mL), reacted at 100 ° C for 4 hours, cooled, The reaction mixture was adjusted to pH with EtOAc (EtOAc)EtOAc.EtOAc.

 (4) Preparation of N-methyl-N-nitrosopyridine-3-amine

 N-methylpyridin-3-amine (1.86 g, 17.2 mmol) was dissolved in 25 mL of concentrated hydrochloric acid, and sodium nitrite (1.43 g, 20.7 mmol) in 25 mL aqueous solution was added dropwise under -15 Torr, and the mixture was dropped. The reaction was transferred to a room temperature for one hour, and the mixture was adjusted to pH 9 with aqueous ammonia, and ethyl acetate was evaporated.

 (5) Preparation of 3-(1-methylindenyl)pyridine

 A solution of N-methyl-N-nitrosopyridine-3-amine (2.15 g, 15.7 mmol) in anhydrous tetrahydrofuran (20 mL) was slowly added dropwise to a solution of lithium tetrahydrogen aluminum tetrahydrofuran in an ice water bath. (17 mL), stirring for one hour in an ice bath, adding 10 mL of 40% sodium hydroxide solution, extracting with ethyl acetate, dried over anhydrous potassium carbonate, and concentrated under reduced pressure to give 1.73 g of brown oil. The rate is 89.2%.

 (6) Preparation of (5)-1-(5-fluoro-4-oxo-4H-benzo[d][l,3]oxazine-2-yl)propylcarbamic acid tert-butyl ester

 2-Amino-6-fluorobenzoic acid (776 mg, 5.0 mmol), (5)-2-(tert-butoxycarbonylamino)butyric acid (1.22 g, 6.0 mmol) and triphenyl phosphite (1.55 g, 5.0 mmol) was dissolved in 8 mL of pyridine at 55 ° C for 10 hours, cooled, and the reaction solution was used directly for the next reaction.

 (7) (5)-1-[5-fluoro-3-[methyl(pyridin-3-yl)amino]-4-oxo-3,4-dihydroquinazolin-2-yl]propyl Preparation of tert-butyl carbamate

(5)-1-(5-Fluoro-4-oxo-4H-benzo[d][l,3]oxazin-2-yl)propylcarbamic acid tert-butyl ester obtained from the above step (about 5.0 mmol) 3-(1-methylindenyl)pyridine (739 mg, 6.0 mmol) was added directly to the reaction mixture. The reaction was heated to 100 ° C for 8 hours, cooled, and concentrated under reduced pressure. (PE: EA = 1:1) gave a brown solid 603 mg. (8) (5)-2-(1-Aminopropyl)-5-fluoro-3-[methyl(pyridin-3-yl)amino]quinazolin-4(3H)-one trifluoroacetate Preparation of (5) small [5-fluoro-3-[methyl(pyridin-3-yl)amino]-4-oxo-3,4-dihydroquinazolin-2-yl]propylcarbamic acid tert-Butyl ester (603 mg, 1.41 mmol) dissolved in dichloromethane (20 mL). Trifluoroacetic acid (5 mL) was slowly added dropwise in an ice bath. After the dropwise addition, the reaction was transferred to room temperature and stirred for two hours. After completion, the crude solid obtained by concentration under reduced pressure was used directly in the next step.

 (9) (5 -2-[l-(9H-Indol-6-ylamino)propyl]-5-fluoro-3-[methyl(pyridin-3-yl)amino]quinazoline-4 (3H )- Preparation of ketone

 Add (5)-2-(1-aminopropyl)-5-fluoro-3-[methyl(P-pyridin-3-yl)amino]quinazoline-4 (3H) to 20 mL of tert-butanol - Ketone trifluoroacetate (about 1.41 mmol) and DIEA (0.74 mL, 4.24 mmol), stirred for half an hour in an ice bath, then added 6-chloro-9H-indole (240 mg, 1.55 mmol). The reaction was carried out at 85 ° C for 36 h, cooled, EtOAc EtOAcjjjjjj

Mass spectrometry (M+H): 446.2

 1H-NMR (^-DMSO, 400 MHz): δ 12.97 (1Η, s), 8.28-7.77 (6H, m), 7.49 (1H, d), 7.34-7.07 (3H, m), 5.49 (1H, m ), 3.50-3.41 (3H, m), 2.18-1.80 (2H, m), 1.30-0.82 (3H, m).

Example 44 Fluorine -2414 methyl (9ff-fluoren-6-yl)amino 1 propyl l-3- pyridine -3-ylamino) quinazoline

- -m (Compound 46) preparation

 (1) Preparation of CS)-2-[tert-butoxycarbonyl (methyl)amino]butyric acid

CS)-2-(tert-butoxycarbonylamino)butyric acid (20.32 g, 100 mmol) was dissolved in 600 mL of anhydrous tetrahydrofuran under ice bath, and 60% sodium hydride (40 g, 1 mol) was added and stirred at room temperature for 30 min. After adding CH ₃ I (141.9 g, 1 mol) dropwise, the reaction was completed overnight, and most of the organic solvent was removed under reduced pressure, then poured into 200 mL of water, adjusted to pH 7, and extracted with ethyl acetate. The aqueous solution was dried over sodium sulfate, filtered, filtered, evaporated, evaporated,]]]]]

 (2) Preparation of 3-mercaptopyridine hydrochloride

 Dissolve 3-aminopyridine (19.95 g, 212 mmol) in concentrated hydrochloric acid (200 mL) at -15! : An aqueous solution (100 mL) of sodium nitrite (15.80 g, 229 mmol) was added dropwise, and the reaction solution was added dropwise at -10 °C to stannous chloride dihydrate (58.7 g, 260 mmol). Concentrated hydrochloric acid (185 mL) in the reaction system, after completion, at 0 °. The solid was filtered under suction for 15 min, and the solid was washed with diethyl ether and dried to give 17.96 g of white solid.

(3) Preparation of (5)-1-(5-fluoro-4-oxo-4H-benzo[[1,3]oxazin-2-yl)propyl(methyl)carbamic acid tert-butyl ester 2-Amino-6-fluorobenzoic acid (776 mg, 5.0 mmol), (5)-2-[tert-butoxycarbonyl(methyl)amino]butyric acid (1.31 g, 6.0 mmol) and triphenyl phosphite ( 1.55 g, 5.0 mmol) was dissolved in pyridine (12 mL). The mixture was stirred at 55 ° C for 10 hours, cooled, and the reaction solution was directly used for the next reaction.

 (4) (5)-1-[5-fluoro-4-oxo-3-(pyridin-3-ylamino)-3,4-dihydroquinazolin-2-yl]propyl(methyl)amino Preparation of tert-butyl formate

 (5)-1-(5-fluoro-4-oxo-4H-benzo[][l,3]oxazin-2-yl)propyl(methyl)carbamic acid tert-butyl ester obtained in the upward step ( Approximately 5.0 mmol) of 3-mercaptopyridine hydrochloride (874 mg, 6.0 mmol) was added directly to the reaction mixture. The mixture was warmed to 100 ° C and stirred for 8 hours, cooled and concentrated under reduced pressure. (ethyl acetate 100% by volume) 624 mg of a brown solid was obtained.

 (5) (5)-5-fluoro-2-[1-(methylamino)propyl]-3-(pyridin-3-ylamino)quinazolin-4(3H)-one trifluoroacetate Preparation of (5 -1-[5-fluoro-4-oxo-3-(pyridin-3-ylamino)-3,4-dihydroquinazolin-2-yl]propyl(methyl)carbamate tert-Butyl ester (624 mg, 1.46 mmol) was dissolved in dichloromethane (20 mL) in an ice bath, and 6 mL of trifluoroacetic acid was slowly added dropwise. The reaction was stirred at room temperature for 2 hours, and the reaction was completed by TLC. The resulting crude solid was concentrated and used directly in the next step.

 (6) CS)-5-fluoro-2-[1-[methyl(9H-indol-6-yl)amino]propyl]-3-(pyridin-3-ylamino)quinazoline-4 (3H )- Preparation of ketone

 The solid obtained in the above step (5)-5-fluoro-2-[1-(methylamino)propyl]-3-(pyridin-3-ylamino)quinazolin-4(3H)-one trifluoroacetic acid The salt (about 1.46 mmol) was dissolved in 20 mL of tert-butanol, DIEA (0.76 mL, 4.36 mmol) was added, and stirred for half an hour in an ice bath, then 6-chloro-9H-indole (271 mg, 1.75 mmol) was added thereto. The reaction was carried out at 85 ° C for 36 h, cooled, concentrated and purified eluted elute

Mass spectrometry (Μ+Η): 446.2

^-NMRC^-DMSO, 400 ΜΗζ): δ 12.82 (1Η, s), 9.07, 8.81 (1H, two singlets), 8.11-7.78 (4H, m), 7.76-7.48 (2H, m), 7.40-7.05 (2H, m), 6.92-6.60 (1H, m), 5.31 (1H, m), 3.65, 2.94 (3H, two singlets), 2.25-1.92 (2H, m), 1.22 (3H, m).

Example 45 (S)-2-[M9 T-嘌吟-6-ylamino)propyl 1-5-fluoro-3-(pyridin-4-ylamino)quinazoline-40m-ketone

 (1) Preparation of 4-mercaptopyridine

 P-chloropyridine hydrochloride (25.3 g, 168.7 mmol) and 85% hydrazine hydrate (47 mL, 824 mmol) were mixed and stirred under reflux for one hour, cooled, solidified, suction filtered, washed with isopropyl alcohol Solid, 16.1 g of 4-mercaptopyridine was obtained in a yield of 87.5%.

 (2) Preparation of 2-fluoro-N-(2-fluoro-6-nitrobenzoyl)-6-nitro-N-(pyridin-4-yl)benzoylhydrazide

2-Fluoro-6-nitrobenzoic acid (12. 03 g, 65.0 mmol) was dissolved in 50 mL CH ₂ C1 ₂ and 0.3 mL DMF, and oxalyl chloride (12.347 g, 97.3 mmol) was slowly added dropwise thereto, and stirred at room temperature for two hours. After that, the solvent was removed by concentration, then dissolved in 12 mL of dioxane, and then dropped to 4-pyridylpyridine (7.09 g, 65.0 mmol), NaHC0 ₃ (10.92 g, 130 mmol) of dioxane under cooling. (30 mL) and water (30 mL) were added dropwise to room temperature, stirred for half an hour, concentrated to a one-third volume under reduced pressure, extracted with ethyl acetate, dried over anhydrous sodium sulfate and filtered. The phase gave a brown solid of 14.66 g, yield 50.9%.

 (3) Preparation of 2-fluoro-6-nitro-N'-(pyridin-4-yl)benzoylhydrazide

 Dissolve 2-fluoro-N-(2-fluoro-6-nitrobenzoyl)-6-nitro-N-(pyridin-4-yl)benzoylhydrazide (14.66 g, 33.1 mmol) in 20 mL To the solution, 85% hydrazine hydrate (15 mL) was added to the solution, and the mixture was stirred at room temperature for 2 hr. The yield was 92.4%.

 (4) Preparation of 2-amino-6-fluoro-N'-(pyridin-4-yl)benzoylhydrazide

2-Fluoro-6-nitro-N'-(pyridin-4-yl)benzoylhydrazide (8.45 g, 30.6 mmol) was dissolved in 130 mL of methanol. 1.5 g of 10% Pd/C was added thereto, hydrogen gas was passed, and the reaction was carried out at room temperature for 42 hours. The reaction was completed, Pd/C was filtered off, and the solid obtained by concentration of the organic phase was directly used for the next reaction.

 (5) Preparation of (S)-l-[3-fluoro-2-[2-(pyridin-4-yl)indolylcarbonyl]aniline]-1-oxobutan-2-ylcarbamic acid tert-butyl ester

 In the dried reaction flask, the crude 2-amino-6-fluoro-N'-(pyridin-4-yl)benzoyl hydrazide obtained in the previous step (about 30.6 mmol), (5)-2-(tert-butoxy) Carbonylamino)butyric acid (9.33 g, 45.9 mmol), DIEA (6.4 mL, 36.75 mmol) and HATU (13.96 g, 36.71 mmol) were added to NN-dimethylformamide (80 mL). The mixture was extracted with water and dichloromethane, and then evaporated, evaporated, evaporated, evaporated. 1), 3.76 g of a white solid was obtained, and the total yield of the two steps was 28.5%.

 (6) Preparation of (5)-2-(1-aminopropyl)-5-fluoro-3-(pyridin-4-ylamino)quinazoline-4(3H)-one hydrochloride

 (5)-1-[3-Fluoro-2-[2-(pyridin-4-yl)anthracenecarbonyl]aniline] tert-butyl (0. In 50 mL of ethanol, 5 mL of concentrated hydrochloric acid was added dropwise to the reaction flask in an ice bath. After stirring for half an hour, the reaction was transferred to an oil bath at 85 ° C for 24 h, cooled to pH-8, concentrated, and prepared. Purification in the liquid phase gave 0.95 g of a white solid.

 (7) (5)-2-[l-(9H-Indol-6-ylamino)propyl]-5-fluoro-3-(pyridin-4-ylamino)quinazolin-4(3H)-one Preparation of (5)-2-(1-aminopropyl)-5-fluoro-3-(pyridin-4-ylamino)quinazoline obtained in the above step from 20 mL of tert-butanol

-4(3H)-one hydrochloride (0.65 g, 1.86 mmol) and DIEA (0.6 mL, 3.44 mmol), and stirred for half an hour in an ice bath, then 6-chloro-9H-indole (480 mg, 3.1) The reaction was quenched at 85 ° C for 36 h, cooled, concentrated and purified eluting elut elut

Mass spectrometry (M+H): 432.2

1H-NMR ( ₆ -DMSO, 400 MHz): δ 9.78 (1H, d), 9.81-9.74 (1Η, m), 9.72 (1Η, d), 8.62 (1Η, s), 8.31 (1H, s), 7.76 (1H, dd), 7.42 (1H, d), 7.36 (1H, d), 7.29 (1H, t), 7.15 (1H, d), 5.48 (1H, m), 2.27-2.14 (1H, m) , 2.03-1.87 (1H, m), 1.06 (3H, t).

Example 46 iS)-2-"1-(9H-indol-6-ylamino)ethyl1-5-chloro-3-f5-fluoropyridin-2-ylamino)quinazoline-4i3m-ketone (compound) Preparation of 53)

 CF.COOH

(1) 5-fluoro-2-mercaptopyridine

 2,5-Difluoropyridine (1.50 g, 13.0 mmol), 80% hydrazine hydrate (0.90 mL, 13.7 mmol) was added to a microwave tube, and heated to 120 V in a microwave for 1 hour. After cooling to room temperature, it was filtered, and the filter cake was washed with petroleum ether and dried to give a white solid, 525 mg, yield 31.8%.

 (2) Preparation of (5)-1-(5-chloro-4-oxo-4H-benzo[[1,3]oxazin-2-yl)ethylcarbamic acid tert-butyl ester

 Add 2-amino-6-chlorobenzoic acid (515 mg, 3.0 mmol), (5)-2-(tert-butoxycarbonylamino)propionic acid (624 mg, 3.3 mmol) to a dry 100 mL reaction vial. Pyridine 5.0 mL was added, and finally triphenyl phosphite (1.110 g, 3.55 mmol) was added and stirred in an oil bath at 55 ° C for 10 hours. The system was used directly for the next reaction.

 (3) (>S)-l-[5-Chloro-3-(5-fluoropyridin-2-ylamino)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl Preparation of tert-butyl carbamate

 In the reaction liquid for preparing (5)-1-(5-chloro-4-oxo-4H-benzo[[1,3]oxazin-2-yl)ethylcarbamic acid tert-butyl ester, directly added 5- Fluor-2-mercaptopyridine (420 mg, 3.3 mmol) was stirred under reflux in an oil bath at 100 ° C for 8 hours, then cooled, concentrated under reduced pressure and purified by column chromatography (PE: EA = 10:1). The pale yellow liquid was 700 mg, and the two-step yield was 53.7%.

(4) (5)-2-(1-Aminoethyl)-5-chloro-3-(5-fluoropyridin-2-ylamino)quinazolin-4(3H)-one trifluoroacetate Preparation of (5)-1-[5-chloro-3-(5-fluoropyridin-2-ylamino)-4-oxo-3,4-dihydroquinazoline - in a dry 100 mL reaction flask tert-Butyl 2-ethyl]ethylcarbamate (700 mg, 1.61 mmol) was dissolved in 20.0 mL of dichloromethane, and 10.0 mL of trifluoroacetic acid was added dropwise under ice-cooling, and the addition was completed, then stirring was continued at room temperature. After the reaction of the starting material was completed under the TLC test, the reaction was stopped, and then concentrated under reduced pressure, and the obtained product was directly used for the next reaction. (5) (S)-2-[l-(9H-Indol-6-ylamino)ethyl]-5-chloro-3-(5-fluoropyridin-2-ylamino)quinazoline-4 (3H Preparation of the ketone. The product obtained in the previous step was dissolved in 40.0 mL of t-butanol in a 100 mL dry reaction flask. The system was adjusted to pH with DIEA, then 6-chloro-9H-indole (308 mg, 1.99 mmol) was added. The reaction was refluxed in an oil bath at 90 ° C for 48 hours. Then, it was concentrated by cooling under reduced pressure, and chromatographed to give a white solid (0.190 g). Mass spectrometry (Μ+Η): 451.7

 'H-NMR^-DMSO, 400 MHz): δ 12.97 (IH, br s), 9.79, 9.64 (IH, two singlets), 8.19-8.07 (2H, m), 8.02-7.93 (IH, m), 7.81 -7.58 (4H, m), 7.57-7.51 (IH, m), 7.06-6.95 (1H, m), 5.78, 5.56 (IH, two multiplets), 1.61, 1.44 (3H, two doublets).

Example 47 2-[M9#-嘌吟-6-ylamino)-2,2,2-trifluoroethyl]-5-chloro-3-ί4-fluoroanilino)quinazoline -40m-

 (1) Preparation of (5)-3,3,3-trifluoro-2-(1-phenethylimine)propionic acid ethyl ester

 The glacial acetic acid (4.2 g, 70 mmol) was dissolved in 20 mL of chloroform. (S)-l-phenylethylamine (8.47 g, 70 mmol) was added at room temperature, stirred for 5 min, added 3,3,3 a solution of ethyl trifluoro-2-oxopropionate (10.88 g, 64 mmol) in 20 mL of chloroform, EtOAc (EtOAc:EtOAc) The yield was 46.7%.

(2) Preparation of ethyl 3,3,3-trifluoro-2-(1-phenylethylamino)propanoate

 Ethyl (<S)-3,3,3-trifluoro-2-(1-phenethylimine)propanoate (8.2 g, 30 mmol) was dissolved in 20 mL of triethylamine and stirred at room temperature 16 h. The system was spun dry to give 8 g of crude material which was used directly in the next step.

 (3) Preparation of 2-amino-3,3,3-trifluoropropionic acid ethyl ester hydrochloride

8 g of the crude product in the previous step was dissolved in 20 mL of diethyl ether, and then 8 mL of 1 N HCl was added and stirred at room temperature for 16 h. The system was spun dry to give 4 g of crude product.

 (4) Preparation of 2-amino-3,3,3-trifluoropropionate

 4 g of the crude product in the previous step was dissolved in 10 mL of concentrated HC1 and reacted at 90 ° C for 8 h. Direct spinning of the system gave 2.9 g of crude product.

 (5) Preparation of 2-(tert-butoxycarbonylamino)-3,3,3-trifluoropropionic acid

 In a 100 mL reaction flask, 2.9 g of the crude product in the previous step was dissolved in a mixed solvent of 25 mL of THF and 25 mL of water, then sodium carbonate (2.8 g, 26.4 mmol) was added, followed by di-tert-butyl dicarbonate (2.88 g). , 13.2 mmol), react at room temperature for 16 h. The THF in the spin-drying system was neutralized to pH = 2-3, extracted with ethyl acetate, dried and dried to give the product 1.95 g.

 (6) Preparation of tert-butyl 1-(5-chloro-4-oxo-4H-benzo[[1,3]oxazin-2-yl)-2,2,2-trifluoroethylcarbamate In a dry 100 mL reaction flask was added 2-amino-6-chlorobenzoic acid (987 mg, 5.75 mmol), 2-(tert-butoxycarbonylamino)-3,3,3-trifluoropropionic acid (1.95 g, 8.0 mmol), then 6 mL of pyridine was added, and finally triphenyl phosphite (L84 g, 5.9 mmol) was added and stirred in an oil bath at 55 ° C for 15 h. The system was used directly for the next reaction.

 (7) 1-[5-Chloro-3-(4-fluoroanilino)-4-oxo-3,4-dihydroquinazolin-2-yl]-2,2,2-trifluoroethyl Preparation of tert-butyl carbamate

 To the reaction liquid of the above step, p-fluorobenzoic acid hydrochloride (1.07 g, 6.58 mmol) was directly added, and the reaction was stirred under reflux in an oil bath at 100 ° C for 8 hours, then cooled, concentrated under reduced pressure, and purified by column chromatography. PE: EA = 10: 1-4: 1) Purification afforded 330 mg of solid. The yield in two steps was 11.8%.

 Preparation of (8) 2-(1-Amino-2,2,2-trifluoroethyl)-5-chloro-3-(4-fluoroanilino)quinazolin-4(3H)-one hydrochloride

 Add 1-[5-chloro-3-(4-fluoroanilino)-4-oxo-3,4-dihydroquinazolin-2-yl]-2,2 to a dry 100 mL reaction vial. tert-Butyl 2-trifluoroethylcarbamate (330 mg, 0.68 mmol), dissolved in 20.0 mL of dichloromethane, HCl in an ice bath, reacted for 2 h, TLC detected the reaction of the starting material completely, stopped The reaction was concentrated under reduced pressure to give a crude product (300 mg).

 (9) 2-[l-(9H-Indol-6-ylamino)-2,2,2-trifluoroethyl]-5-chloro-3-(4-fluoroanilino)quinazoline-4 ( Preparation of 3H)-ketone

 300 mg of the product obtained in the previous step was dissolved in 20.0 mL of tert-amyl alcohol in a 100 mL dry reaction flask, then 6-chloro-9H-indole (195 mg, 1.26 mmol) was added, followed by 5 drops of glacial acetic acid, then 90 ° The reaction was carried out in an oil bath of C for 24 h. Then cooled, neutralized to neutral with saturated aqueous sodium bicarbonate, concentrated under reduced pressure, column chromatography

(PE: EA = 10: 1-1: 3) gave a white solid (yield: 110 mg).

Mass Spectrum (M+H): 505.2 ¹ H-NMR ( -DMS0, 400 MHz): δ 12.96 (1H, s), 8.92 (1H, s), 8.50-8.20 (1H, m), 8.18-8.05 (2H, m), 7.85 (1H, t ), 7.78 (1H, d), 7.66 (1H, t), 7.25-6.95 (1H, m), 6.80-6.45 (4H, m).

Example 48 Preparation of SV2-[l-i9-indol-6-ylamino)ethyl 1-5-chloro-3-ylideneamino)quinazoline-4ί3-one (Compound 57)

 (1) Preparation of N-methyl-N-nitrosomethylamine

 Add dimethylamine hydrochloride (4.89 g, 60.0 mmol) to a dry 250 mL reaction flask, then slowly add 50 mL of glacial acetic acid and add sodium nitrite (5.38 g, 78.0 mmol) in an ice bath. The 40 mL aqueous solution was stirred at room temperature overnight. After no raw material was detected by LC-MS, the reaction was stopped, and the resulting reaction liquid was used directly for the next reaction.

 (2) Preparation of 1,1-dimethylhydrazine

 The zinc powder (15.60 g, 239 mmol) was slowly added to the reaction solution for preparing N-methyl-N-nitrosomethylamine in an ice bath, and stirred at room temperature until no material was detected by TLC, and the reaction was stopped. , the zinc powder is filtered, and the obtained filtrate is directly used for the reaction in the step (4).

 (3) Preparation of (5)-1-(5-chloro-4-oxo-4H-benzo[d][l,3]oxazine-2-yl)ethylcarbamic acid tert-butyl ester

 Add 2-amino-6-chlorobenzoic acid (1.72 g, 10.0 mmol), (<S)-2-(tert-butoxycarbonylamino)propionic acid (2.08 g, 11.0 mmol) in a dry 100 mL reaction flask. Then, 10.0 mL of pyridine was added, and finally triphenyl phosphite (3.10 g, 10.0 mmol) was added, and the mixture was stirred for 10 hours in an oil bath at 55 °C. The system was used directly for the next reaction.

(4) (5) Preparation of small [5-chloro-3-(dimethylamino)-4-oxo-3,4-dihydroquinazolin-2-yl]ethylcarbamic acid tert-butyl ester in preparation (5) 1-(5-chloro-4-oxo-4H-benzo[d][l,3]oxazine-2-yl)ethylcarbamic acid tert-butyl ester is directly added to the reaction solution, 1-dimethylhydrazine, the reaction was stirred under reflux in an oil bath at 100 ° C for 8 hours, then cooled and concentrated under reduced pressure. Purification by column chromatography (PE: EA = 10:1) gave a pale yellow liquid, 1.42 g,.

(5) Preparation of (5)-2-(1-aminoethyl)-5-chloro-3-(dimethylamino)quinazoline-4(3H)-one trifluoroacetate

 Add (5)-1-[5-chloro-3-(dimethylamino)-4-oxo-3 4-dihydroquinazolin-2-yl]ethylcarbamic acid to a dry 100 mL reaction vial tert-Butyl ester (0.710 g 1.94 mmol) was dissolved in 20.0 mL of dichloromethane, and 10.0 mL of trifluoroacetic acid was added dropwise in an ice bath. After the addition was completed, stirring was continued at room temperature, and the reaction was completed after TLC. The reaction was stopped, and then concentrated under reduced pressure, and the obtained product was directly used for the next reaction.

 (6) Preparation of (S)-2-[l-(9H-嘌呤-6-ylamino)ethyl]-5-chloro-3-(dimethylamino)quinazoline-4(3H)-one

 The product of the previous step was dissolved in 40.0 mL of tert-butanol in a 100 mL dry reaction flask, the system was adjusted to basic with DIEA, then 6-chloro-9H-indole (0.330 g 2.13 mmol) was added at 90 The reaction was refluxed in an oil bath at ° C for 48 hours. Then, it was cooled and concentrated under reduced pressure, and purified by preparative chromatography to give a white solid, 0.270 g, a two-step yield, 36.2% mass spectrum (Μ+Η): 384.80

 'H-NMR^-DMSO, 400 MHz): δ 12.96 (1Η, s), 8.15 (2H, s), 7.86-7.77 (1H m), 7.66 (1H t),

7.52-7.45 (2H, m), 5.83 (1H, m), 3.09, 3.07 (6H, two singlets), 1.57 (3H, d).

Example 49 (S-2-[1-H-(9H-嘌呤-6-ylamino)ethyl]-5-chloro-3-"methylf-ethyl)amino 1 quinazolinone

Preparation of (Compound 59)

 (1) Preparation of N-methyl-N-nitrosoethylamine

 N-Methylethylamine (5.9 g OO mmol) was dissolved in glacial acetic acid (50 mL) and stirred for 10 min. Sodium nitrite (9.0 g, nOmmol) was dissolved in water (40 mL) and slowly added dropwise to the system. After the addition was completed, the mixture was allowed to react at room temperature for 2 hours. The reaction was monitored by LC-MS and the system was used directly in the next step.

 (2) Preparation of N-methylethyl hydrazine

The reaction solution for preparing N-methylnitrosylamine was transferred to an ice bath and stirred, and zinc powder (26 g, 400 mmol) was slowly added. After the addition was completed, the mixture was stirred in an ice bath for half an hour and then transferred to room temperature. 12 hours. TLC monitoring reaction junction Bunch. After suction filtration, the filter cake was washed with ethyl acetate, and the filtrate was evaporated to give 5.8 g of colorless oil.

(3) Preparation of (5)-1-(5-chloro-4-oxo-4H-benzo[[1,3]oxazin-2-yl)ethylcarbamic acid tert-butyl ester

 Add 2-amino-6-chlorobenzoic acid (1.72 g, 10.0 mmol), (S)-2-(tert-butoxycarbonylamino)propionic acid (2.37 g, 12.5 mmol) to a dry 100 mL reaction flask. 25 mL of pyridine was added, and finally triphenyl phosphite (3.40 g, 11.0 mmol) was added, and the mixture was stirred for 10 hours in an oil bath at 55 °C. The system was used directly for the next reaction.

 (4) (5)-1-[5-Chloro-3-[methyl(ethyl)amino]-4-oxo-3,4-dihydroquinazolin-2-yl]ethylcarbamic acid Preparation of butyl ester

 Adding N- directly to the reaction solution for preparing (5)-1-(5-chloro-4-oxo-4H-benzo[[1,3]oxazin-2-yl)ethylcarbamic acid tert-butyl ester Methyl ethyl hydrazine (1.11 g, 15.0 mmol) was stirred under reflux in an oil bath of 100 ° for 12 hours, then cooled, concentrated under reduced pressure and purified by column chromatography (PE: EA = 1:1) to give a white solid. 1.48 g, the yield in two steps was 38.9%.

 (5) Preparation of (5)-2-(1-aminoethyl)-5-chloro-3-[methyl(ethyl)amino]quinazoline-4(3H)-one

 Add (5) small [5-chloro-3-[methyl(ethyl)amino]-4-oxo-3,4-dihydroquinazolin-2-yl]B to a dry 100 mL reaction vial Tert-butyl carbamate (0.148 g, 0.389 mmol) was dissolved in 10.0 mL of dichloromethane, and 5.0 mL of trifluoroacetic acid was added dropwise in an ice bath. After the addition was completed, stirring was continued at room temperature, and the reaction was complete under TLC. Thereafter, the reaction was stopped, and then concentrated under reduced pressure, and the obtained product was directly used for the next reaction.

 (6) (5)-2-[l-(9H-Indol-6-ylamino)ethyl]-5-chloro-3-[methyl(ethyl)amino]quinazoline-4(3H)- Ketone Preparation (5)-2-(1-Aminoethyl)-5-chloro-3-[methyl(ethyl)amino]quinazoline-4 (3H) obtained in the previous step in a 100 mL dry reaction flask. The ketone was dissolved in 20.0 mL of tert-butanol, the pH of the system was adjusted to basic with DIEA, then 6-chloro-9H-indole (60 mg, 0.39 mmol) was added and refluxed in an oil bath at 90 ° C for 48 hours. . Then, it was concentrated by cooling under reduced pressure, and purified by preparative chromatography to afford white crystals (yield: 73 mg).

Mass spectrometry (Μ+Η): 399.2

1H-NMR ( ₆ -DMSO, 400 ΜΗζ): δ 12.95 (1Η, br s), 8.19-8.10 (2H, m), 7.89-7.80 (0.5H, m), 7.73-7.62 (1.5H, m), 7.55-7.45 (2H, m), 6.10-5.81 (1H, m), 3.60-3.37 (1.5H, m), 3.26-3.14 (0.5H, m), 3.04, 3.01 (3H, two singlets), 1.60- 1.53 (3H, m), 1.06 (3H, q).

Example 50 Preparation of iS 2-[l-f9-indol-6-ylamino)ethyl-1-trimethylamino)-5-fluoroquinazoline-4(3^)-one (Compound 60)

 (1) Preparation of N-methyl-N-nitrosomethylamine

 Add dimethylamine hydrochloride (4.89 g, 60.0 mrnol) to a dry 250 mL reaction flask, then slowly add 50 mL of glacial acetic acid and add sodium nitrite (5.38 g, 78.0 mmol) in an ice bath. The 40 mL aqueous solution was stirred at room temperature overnight. After no raw material was detected by LC-MS, the reaction was stopped, and the resulting reaction liquid was used directly for the next reaction.

 (2) Preparation of 1,1-dimethylhydrazine

 The zinc powder (15.60 g, 239 mmol) was slowly added to the reaction solution for preparing N-methyl-N-nitrosomethylamine in an ice bath, and stirred at room temperature until no material was detected by TLC, and the reaction was stopped. The zinc powder is filtered, and the filtrate is concentrated and used directly in the fourth step reaction.

 (3) Preparation of (5)-1-(5-fluoro-4-oxo-4H-benzo[[1,3]oxazin-2-yl)ethylcarbamic acid tert-butyl ester

 Add 2-amino-6-fluorobenzoic acid (1.55 g, 10.0 mmol), (5)-2-(tert-butoxycarbonylamino)propionic acid (2.08 g, 11.0 mmol) to a dry 100 mL reaction vial. 10.0 mL of pyridine was added, and finally triphenyl phosphite (3.10 g, 10.0 mmol) was added and stirred in an oil bath at 55 ° C for 10 hours. The system was used directly for the next reaction.

 (4) Preparation of (5)-1-(3-(dimethylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl]ethylcarbamic acid tert-butyl ester

 Adding 1,1- directly to the reaction solution of (-1-(5-fluoro-4-oxo-4H-benzo[[1,3]oxazin-2-yl)ethylcarbamic acid tert-butyl ester) The pyridine solution of dimethyl hydrazine was stirred and refluxed in an oil bath at 100 ° C for 8 hours, then cooled, concentrated under reduced pressure, and purified by column chromatography (PE: EA = 10:1) to give a pale yellow liquid, 2.42 g. The two-step yield was 69.1%.

 (5) Preparation of (5)-2-(1-aminoethyl)-3-(dimethylamino)-5-fluoroquinazoline-4(3H)-one

Add (S)-l-[3-(dimethylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl]ethylamino to a dry 100 mL reaction flask Tert-butyl formate (2.42 g, 6.91 mmol) was dissolved in 20.0 mL of dichloromethane, and 10.0 mL of trifluoroacetic acid was added dropwise in an ice bath. After the addition was completed, stirring was continued at room temperature. After completion, the reaction was stopped, and then concentrated under reduced pressure, and the obtained product was directly used for the next reaction. (6) (5)-2-[l-(9H-Indol-6-ylamino)ethyl]-3-(dimethylamino)-5-fluoroquinazolin-4(3H)-one was prepared at 100 In a mL-dried reaction flask, the product obtained in the previous step was dissolved in 40.0 mL of tert-butanol, the pH of the system was adjusted to basic with DIEA, and then 6-chloro-9H-indole (0.80 g, 5.18 mmol) was added at 90 The reaction was refluxed in the bath for 48 hours. Then, it was concentrated by cooling under reduced pressure, and purified by preparative chromatography to give a white solid (0.260 g). Mass Spectrum (M+H): 369.2

1H-NMR (J ₍₅ -DMSO, 400 MHz): δ 12.96 (1H, s), 8.15 (2 Η, s), 7.84-7.77 (1H, m), 7.72 (1H, dd), 7.36 (1H, d ), 7.22 (1H, dd), 5.84 (1H, m), 3.09, 3.07 (6H, two singlets), 1.58 (3H, d). Example 51 (S)-2-〖l-i9#-嘌呤- Preparation of 6-ylamino)ethyl1-3-(methylfethyl)amino)-5-fluoroquinazolin-4(3^-one (Compound 61)

 (1) Preparation of N-methyl nitrosoamine

 N-Methylethylamine (5.9 g, 100 mmol) was dissolved in glacial acetic acid (50 mL) and stirred for 10 min. Sodium nitrite (9.0 g, 130 mmol) was dissolved in water (40 mL) and slowly added dropwise to the system. After the addition was completed, the mixture was allowed to react at room temperature for 2 hours. The reaction was monitored by LC-MS and the system was used directly in the next step.

 (2) Preparation of N-methylethyl hydrazine

 The reaction solution for preparing N-methyl-N-nitrosoethylamine was transferred to an ice bath and stirred, and zinc powder (26 g, 400 mmol) was slowly added. After the addition, the mixture was stirred in an ice bath for half an hour. The reaction was allowed to proceed to room temperature for 12 hours. The TLC monitors the end of the reaction. After suction filtration, the cake was washed with ethyl acetate, and the filtrate was evaporated to give 5.8 g of colorless oil. The yield of the above two steps was 78.3%.

(3) Preparation of (5)-1-(5-fluoro-4-oxo-4H-benzo[[1,3]oxazin-2-yl)ethylcarbamic acid tert-butyl ester

Add 2-amino-6-fluorobenzoic acid (4.2 g, 27.1 mmol), (5)-2-(tert-butoxycarbonylamino)propionic acid (6.4 g, 33.8 mmol) to a dry 100 mL reaction vial. 42 mL of pyridine was added, and finally triphenyl phosphite (9.2 g, 29.7 mmol) was added and stirred in an oil bath at 55 ° C for 10 hours. The system was used directly for the next reaction. ( ⁴ ) (5) tert-butyl [ ³ - (methyl(ethyl)amino)-5-fluoro- ⁴ -oxo-3,4-dihydroquinazolin-2-yl]ethylcarbamate Preparation

 Adding N- directly to the reaction solution for preparing (5)-1-(5-fluoro-4-oxo-4H-benzo[[1,3]oxazin-2-yl)ethylcarbamic acid tert-butyl ester Methyl ethyl hydrazine (2.2 g, 29.7 mmol) was stirred under reflux in an oil bath at 100 ° C for 8 hours, then cooled, concentrated under reduced pressure and purified by column chromatography (PE: EA = 1 : 1 ) The liquid was 3.5 g and the yield in two steps was 35.4%.

(5) Preparation of (5)-2-(1-aminoethyl)-3-(methyl(ethyl)amino)-5-fluoroquinazoline-4(3H)-one

 Add (5) small [3-(methyl(ethyl)amino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl]B to a dry 100 mL reaction vial Tert-butyl carbamate (1.0 g, 2.74 mmol) was dissolved in 15.0 mL of dichloromethane, and 5.0 mL of trifluoroacetic acid was added dropwise in an ice bath. After the addition was completed, stirring was continued at room temperature. After completion, the reaction was stopped, and then concentrated under reduced pressure, and the obtained product was directly used for the next reaction.

 (6) (5)-2-[l-(9H-Indol-6-ylamino)ethyl]-3-(methyl(ethyl)amino)-5-fluoroquinazoline-4(3H)- Ketone preparation

 (5)-2-(1-Aminoethyl)-3-(methyl(ethyl)amino)-5-fluoroquinazoline-4(3H)- obtained in the previous step in a 100 mL dry reaction flask. The ketone was dissolved in 15.0 mL of tert-butanol, and the system was adjusted to basic with DIEA. 6-chloro-9-indole (424 mg, 2.74 minol) was added, and the mixture was refluxed in an oil bath at 90 ° C for 48 hours. Then, it was concentrated by cooling under reduced pressure, and was subjected to preparative chromatography to give a white solid (yield: 80 mg).

Mass spectrometry (Μ+Η): 383.2

 'H-NMR (^-DMSO, 400 MHz): δ 12.96 (1H, s), 8.25-8.06 (2Η, m), 7.90-7.58 (2Η, m), 7.43-7.34 (1H, m), 7.27- 7.17 (1H, m), 6.09-5.82 (1H, m), 3.61-3.37 (1.5H, m), 3.27-3.15 (0.5 H, m), 3.05, 3.01 (3H, two singlets), 1.61-1.52 ( 3H, m), 1.06 (3H, q).

Example 52 Preparation of fS)-2-[W9 嘌呤-6-ylamino)propyl1-3-(diethylamino)-5-fluoroquinazolinone (Compound 62)

 (1) Preparation of N-ethyl-N-nitrosoethylamine

 Diethylamine (10.95 g, 150.0 mmol) was added to a dry 500 mL reaction flask, then 120 mL of glacial acetic acid was slowly added, and 120 mL of sodium nitrite (13.46 g, 195.0 mmol) was added dropwise in an ice bath. The aqueous solution was stirred at room temperature overnight. Then, the pH is adjusted to neutral with dilute alkali, and the aqueous phase is extracted with dichloromethane. The organic phase is combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by column chromatography (PE: EA=6:1) The liquid was 13.31 g and the yield was 87%.

 (2) Preparation of 1,1-diethylanthracene

 Add N-ethyl-N-nitrosoethylamine (1.02 g, 10.0 mmol) to a dry 50 mL reaction flask, then add 3.0 mL of glacial acetic acid and slowly add zinc powder (2.60 g) in an ice bath. , 40.0 mmol), stirring at room temperature, until no raw materials were detected by TLC, the reaction was stopped, the zinc powder was filtered, and the obtained filtrate was directly used for the fourth step reaction.

 (3) Preparation of (5 -1-(5-fluoro-4-oxo-4H-benzo[ ][l,3]oxazol-2-yl)propylcarbamic acid tert-butyl ester

 Add 2-amino-6-fluorobenzoic acid (0.50 g, 3.22 mmol), (5 -2-(tert-butoxycarbonylamino)butyric acid (0.787 g, 3.87 mmol) to a dry 100 mL reaction flask, then Pyridine (8.0 mL) was added, and finally triphenyl phosphite (1.110 g, 3.55 mmol) was added, and the mixture was stirred for 10 hours in an oil bath at 55 ° C. The system was directly used for the next reaction.

(4) (5)-1-[3-(Diethylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl]propylcarbamic acid tert-butyl ester The preparation is directly added to the reaction liquid for preparing (5)-1-(5-fluoro-4-oxo-4H-benzo[][l,3]oxazin-2-yl)propylcarbamic acid tert-butyl ester. 1,1-diethyl hydrazine, at 100! The reaction was stirred under reflux for 8 hours, then cooled, concentrated under reduced pressure, and purified by column chromatography (PE: EA = 10:1) to give a pale yellow liquid of 0.710 g.

 (5) Preparation of (5)-2-(1-aminopropyl)-3-(diethylamino)-5-fluoroquinazoline-4(3H)-one

Add (-1-[3-(diethylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-) to a dry 100 mL reaction vial Tert-butyl carbamic acid tert-butyl ester (0.710 g, 1.81 mmol) was dissolved in 20.0 mL of dichloromethane, and 10.0 mL of trifluoroacetic acid was added dropwise under ice bath, and the addition was completed, then stirring was continued at room temperature. After the reaction of the starting material was completed under the TLC test, the reaction was stopped, and then concentrated under reduced pressure, and the obtained product was directly used for the next reaction.

 (6) Preparation of (5)-2-[l-(9H-indol-6-ylamino)propyl]-3-(diethylamino)-5-fluoroquinazoline-4(3H)-one

 The product of the previous step was dissolved in 40.0 mL of tert-butanol in a 100 mL dry reaction flask, the pH of the system was made alkaline with DIEA, then 6-chloro-9H-indole (0.308 g, 1.99 mmol) was added. The reaction was refluxed in an oil bath at 90 ° C for 48 hours. Then, it was concentrated by cooling under reduced pressure, and was chromatographed to give a white solid (yield: 0.260 g). Mass Spectrometry (M+H): 411.20

1H-NMR ( ₆ -DMSO, 400 MHz): δ 12.99 (IH, s), 8.25-8.13 (2H, m), 7.81-7.73 (IH, m), 7.50-7.38 (2H, m), 7.32-7.15 (IH, m), 6.12 (IH, m), 3.71-3.20 (4H, m), 2.16-1.80 (2H, m), 1.22 (3H, m), 1.05-0.92 (6H, m).

Example 53 Preparation of iS)-2-[W9 嘌呤-6-ylamino)propyl]-5-chloro-3-(dimethylamino)quinazoline-4 (3-one (complex 63)

 (1) Preparation of (5 -1-(5-chloro-4-oxo-4H-benzo[[1,3]oxazin-2-yl)propylcarbamic acid tert-butyl ester

 2-Amino-6-chlorobenzoic acid (1.71 g, 10.0 mmol), (S)-2-(tert-butoxycarbonylamino)butyric acid (2.23 g, 11.0 mmol) and phosphorous acid trioxide were added to a dry reaction flask. Phenyl ester (3.10 g, 10.0 mmol), dissolved in 10 mL of pyridine,

The reaction was stirred at 55 'C for 8 hours and used directly for the next reaction without treatment.

 (2) Preparation of (5)-1-[5-chloro-3-(dimethylamino)-4-oxo-3,4-dihydroquinazolin-2-yl]propylcarbamic acid tert-butyl ester

 Directly add 1,1-dimethylhydrazine (0.66 g, 11.0 mmol) to the reaction system of the previous step, heat up to 100 °C for 8 h, cool and add directly to the silica gel. Column chromatography (petroleum ether-petroleum ether) : ethyl acetate = 5:1) gave a pale yellow oil of 2.5 g.

 (3) Preparation of (5)-2-(1-aminopropyl)-5-chloro-3-(dimethylamino)quinazoline-4(3H)-one

(5) Small [5-chloro-3-(dimethylamino)-4-oxo-3,4-dihydroquinazolin-2-yl]propylcarbamic acid tert-butyl ester was added to the dried reaction flask. (2.5 g, 6.56 mmol), dissolved in 20 mL of dichloromethane, added with trifluoromethane in an ice bath 10 mL of acetic acid was added, and the mixture was transferred to room temperature for 2 hours after the dropwise addition. After the reaction was stopped, the solvent and trifluoroacetic acid were spun off, and the obtained product was directly used for the next reaction.

 (4) Preparation of (5)-2-[l-(9H-indol-6-ylamino)propyl]-5-chloro-3-(dimethylamino)quinazoline-4(3H)-one

 The product of the previous step was dissolved in 30 mL of tert-butanol, 6-chloro-9H-indole (1.11 g, 7.18 mmol), DIEA (3.25 mL, 18.7 mmol), and refluxed in an oil bath at 90 °C. hour. The mixture was cooled, concentrated under reduced pressure, and purified to give white crystals (yield: 0.230 g).

Mass spectrometry (M+H): 399.2

'H-NMR (i/ ₆ -DMSO, 400 MHz): δ 12.88 (1Η, s), 8.15 (2H, s), 7.71-7.64 (1H, m), 7.64 (1H, t), 7.50-7.44 ( 2H, m), 5.78 (1H, m), 3.09, 3.06 (6H, two singlets), 2.05-1.86 (2H, m), 1.03 (3H, t).

Example 54 (S)-2-[1-(9H~嘌呤-6-ylamino)propyl]dimethylamino)-5-fluoroquinazolinone (combination)

 (1) Preparation of N-methylnitrosomethylamine

 Add dimethylamine hydrochloride (4.89 g, 60.0 mmol) to a dry 250 mL reaction flask, then slowly add 50 mL of glacial acetic acid and add sodium nitrite (5.38 g, 78.0 mmol) in an ice bath. The 40 mL aqueous solution was stirred at room temperature overnight. After no raw material was detected by LC-MS, the reaction was stopped, and the resulting reaction liquid was used directly for the next reaction.

 (2) Preparation of 1,1-dimethylhydrazine

 Zinc powder (15.60 g, 239 mmol) was slowly added to the reaction solution for preparing N-methylnitrosylamine in an ice bath, and stirred at room temperature until no material was detected by TLC, the reaction was stopped, and zinc was filtered. Powder, concentrate the filtrate and use it directly in the step (4).

(3) Preparation of (5)-1-(5-fluoro-4-oxo-4H-benzo[[1,3]oxazin-2-yl)propylcarbamic acid tert-butyl ester Add 2-amino-6-fluorobenzoic acid (1.55 g, 10.0 mmol), (5)-2-(tert-butoxycarbonylamino)butyric acid (2.23 g, l lO mmol) to a dry 100 mL reaction flask. Then, 10.0 mL of pyridine was added, and finally triphenyl phosphite (3.10 g, 10.0 mmol) was added, and the mixture was stirred for 10 hours in an oil bath at 55 °C. The system was used directly for the next reaction.

 (4) Preparation of (5) small [3-(dimethylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl]propylcarbamic acid tert-butyl ester

 Adding 1,1- directly to the reaction solution of (-1-(5-fluoro-4-oxo-4H-benzo[[1,3]oxazin-2-yl)propylcarbamic acid tert-butyl ester) The pyridine solution of dimethyl hydrazine was stirred and refluxed in an oil bath of 100 ° 0 for 8 hours, then cooled, concentrated under reduced pressure, and purified by column chromatography (PE: EA = 10:1) to yield 2.12 g of pale yellow liquid. The two-step yield was 58.2%.

(5) Preparation of (5)-2-(1-aminopropyl)-3-(dimethylamino)-5-fluoroquinazoline-4(3H)-one

 Add (5)-1-[3-(dimethylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl]propylamino to a dry 100 mL reaction vial Tert-butyl formate (2.12 g, 5.82 mmol) was dissolved in 20.0 mL of dichloromethane, and 10.0 mL of trifluoroacetic acid was added dropwise in an ice bath. After the addition was completed, the mixture was stirred at room temperature under TLC. After the reaction of the starting material was completed, the reaction was stopped, and then concentrated under reduced pressure, and the obtained product was directly used for the next reaction.

 (6) Preparation of 0S)-2-[l-(9H-indol-6-ylamino)propyl]-3-(dimethylamino)-5-fluoroquinazoline-4(3H)-one

 The product of the previous step was dissolved in 40.0 mL of tert-butanol in a 100 mL dry reaction vial. The system was adjusted to pH with DIEA, then 6-chloro-9H-indole (0.80 g, 5.18 mmol) was added. The reaction was refluxed for 48 hours in an oil bath of 90. Then, it was concentrated by cooling under reduced pressure, and purified by preparative chromatography to yield white crystals (0.230 g). Mass Spectrometry (M+H): 383.2

1H-NMR ( ₆ -DMSO, 400 MHz): δ 12.95 (1H, s), 8.15 (2 Η, s), 7.76-7.63 (2H, m), 7.35 (1H, d), 7.21 (1H, t), 5.80 (1H, m), 3.09, 3.07 (6H, two singlets), 2.06-1.88 (2H, m), 1.03 (3H, t).

Example 55 Preparation of iS V42-[1-(9 嘌呤-6-ylamino)ethyl 1-5-fluoro-4-oxoquinazoline-3f4g)-yl acetamide hydrochloride (Compound 65)

 (1) Preparation of (5)-1-(5-fluoro-4-oxo-4H-benzo[[1,3]oxazin-2-yl)ethylcarbamic acid tert-butyl ester

 Add 2-amino-6-fluorobenzoic acid (1.550 g, 10.0 mmol), (5)-2-(tert-butoxycarbonylamino)propionic acid (2.079 g, 11.0 mmol) to a dry lOO mL reaction vial. 10.0 mL of pyridine was added, and finally triphenyl phosphite (3.100 g, 10 mmol) was added, and the mixture was stirred for 10 hours in an oil bath at 55 °C. The system was used directly for the next reaction.

(2) Preparation of (5)-1-(3-acetamido-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamic acid tert-butyl ester

 Directly added to the reaction solution for preparing (5)-1-(5-fluoro-4-oxo-4H-benzo[^][1,3]oxazin-2-yl)ethylcarbamic acid tert-butyl ester Acetylhydrazine (0.814 g, 11.0 mmol) was stirred under reflux in an oil bath of 100 ° C for 8 hours, then cooled, concentrated under reduced pressure and purified by column chromatography (PE: EA = 2: 1-100% EA) The pale yellow solid was 0.53 g, and the two-step yield was 14.5%.

 (3) Preparation of CS)-N-[2-(l-aminoethyl)-5-fluoro-4-oxoquinazoline-3(4H)-yl]acetamide

 Add CS)-l-(3-acetamido-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamic acid tert-butyl ester to a dry 100 mL reaction vial (0.45 g, 1.23 mmol), dissolved in 20.0 mL of dichloromethane, and added 5.0 mL of trifluoroacetic acid under ice bath. After the addition was completed, the mixture was stirred at room temperature and the reaction was complete under TLC. Thereafter, the reaction was stopped, and then concentrated under reduced pressure, and the obtained product was directly used for the next reaction.

Preparation of ( ₄ ) ₆ _Chloro _ ₉ _ (tetrahydro _ ₂ /_pyran _ ₂ _ yl)_9H-嘌呤

Add 6-chloro-9H-indole (25.36 g, 164 mmol), p-toluenesulfonic acid monohydrate (0.565 g, 2.97 mmol) and dihydropyran (44.9 mL, 492) to a dry 100 mL reaction flask. Methyl ether was refluxed for 2 hours in an oil bath at 90 ° C, cooled to room temperature and washed with 2 N NaHC0 ₃ (2×100 mL) and saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate and dried and evaporated.

(5) N-[5-fluoro-4-oxo-2-[(15)-1-[9-(tetrahydro-2H-pyran-2-yl)-9H-indol-6-ylamino] Ethyl]quinazoline Preparation of -3(4H)-yl]acetamide

 CS)-N-[2-(l-aminoethyl)-5-fluoro-4-oxoquinazolin-3(4H)-yl group obtained in step (3) in a 50 mL dry reaction flask The acetamide was dissolved in 5.0 mL of n-butanol, the pH of the system was adjusted to basic with DIEA, and then 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-indole (0.351 g, 1.47 mmol), refluxing in an oil bath at 110 °C for 4 hours. After cooling and concentration under reduced pressure, a plate was separated (dichloromethane:methanol = 13:1) to give a pale yellow solid (yield: 0.135 g).

 (6) (5)-N-[2-[l-(9H-嘌呤-6-ylamino)ethyl]-5-fluoro-4-oxoquinazolin-3(4H)-yl]acetamide Preparation of hydrochloride

 N-[5-fluoro-4-oxo-2-[(15)-1-[9-(tetrahydro-2H-pyran-2-yl)-9H-indol-6-ylamino]ethyl ] quinazoline-3(4H)-yl]acetamide (0.13 g, 0.279 mmol) was dissolved in 5 mL of methanol. To the system was added 2 portions of concentrated hydrochloric acid. The mixture was stirred for 2 hr and then evaporated to dryness to give a white solid. The yellow solid was dissolved in 3 mL of methanol, and then 10 mL of diethyl ether was slowly added dropwise to precipitate a solid, which was filtered to give a yellow solid, 57 mg, yield 48.7%.

Mass spectrometry (Μ+Η): 483.1

1H-NMR ( _6- DMS0, 400 ΜΗζ): δ 11.00 (1Η, br s), 9.56-9.08 (1H, m), 8.65-8.51 (2H, m), 7.92-7.81 (1H, m), 7.62- 7.51 (1H, m), 7.42-7.31 (1H, m), 5.77-5.55 (1H, m), 2.06, 2.02 (3H, two singlets), 1.62, 1.55 (3H, two doublets).

Example 56 iS V- [2-[1-(9-嘌呤-6-ylamino)ethyl 1-5-fluoro-4-oxoquinazoline-3(4g)-yl]methanesulfonamide

 (l) Preparation of CS-l-(5-fluoro-4-oxo-4H-benzo[[1,3]oxazin-2-yl)ethylcarbamic acid tert-butyl ester

Add 2-amino-6-fluorobenzoic acid (1.550 g, 10.0 mmol), (5)-2-(tert-butoxycarbonylamino)propionic acid (2.079 g, 11.0 mmol) to a dry 100 mL reaction vial. 10.0 mL of pyridine was added, and finally triphenyl phosphite (3.10 g, 10.0 mmol) was added, and the mixture was stirred for 10 hours in an oil bath at 55 °C. The system was used directly for the next reaction. (2) (5)-1-[5-Fluoro-3-(methylsulfonylamino)-4-oxo-3,4-dihydroquinazolin-2-yl]ethylcarbamic acid tert-butyl ester Preparation of the direct addition of a (5)-1-(5-fluoro-4-oxo-4H-benzo[[1,3]oxazin-2-yl)ethylcarbamic acid tert-butyl ester in the reaction solution Sulfonyl hydrazide ( 1.22 g, 11.1 mmol) at 100 °. The reaction was stirred under reflux for 8 hours, then cooled and concentrated under reduced pressure and purified by column chromatography (PE: EA=4: 1-2:1) to yield 1.10 g of pale yellow solid. The yield in two steps was 27.50%.

 (3) Preparation of (5)-N-[2-(l-aminoethyl)-5-fluoro-4-oxoquinazoline-3(4H)-yl]methanesulfonamide

 Add (5)-1-[5-fluoro-3-(methylsulfonamido)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl to a dry lOO mL reaction vial Tert-butyl carbamate (0.52 g, 1.30 mmol), dissolved in 20.0 mL of dichloromethane, 10.0 mL of trifluoroacetic acid was added dropwise in an ice bath, and the addition was completed. Stirring was continued at room temperature under TLC. After the reaction of the starting material was completed, the reaction was stopped, concentrated under reduced pressure, and the obtained product was directly used for the next reaction.

 (4) CS)-N-[2-[l-(9H-嘌呤-6-ylamino)ethyl]-5-fluoro-4-oxoquinazolin-3(4H)-yl]methanesulfonamide Preparation The product obtained in the previous step was dissolved in 10.0 mL of t-butanol in a 50 mL dry reaction flask. The system was adjusted to basic with DIEA, then 6-chloro-9H-indole (0.239 g, 1.55 mmol) was added. The reaction was refluxed in an oil bath at 90 ° C for 48 hours. Then, it was concentrated by cooling under reduced pressure, and was purified by chromatography to yield white solid (0.152 g). Mass spectrometry (Μ+Η): 419.1

 丽-醒SO, 400 ΜΗζ): δ 13.01 (1H, s), 11.12 (1Η, br s), 8.24-8.10 (2H, m), 7.89-7.78 (2H, m), 7.48 (1H, d), 7.33 (1H, t), 5.83 (1H, m), 3.35 (3H, s), 1.59 (3H, m).

Example 57 ffl-2-[l-i9 嘌呤-6-ylamino)propyl 1-5-fluoro-3-(isoindoline-2-yl)quinazoline-4am-one

(1) Preparation of tert-butyl isoindoline-2-ylcarbamate Add 1,2-bis(bromomethyl)benzene (5.28 g, 20 mmol) and tert-butoxycarbonyl hydrazine (2.64 g, 20 mmol) to a dry reaction flask, dissolve in 10 mL of dry DMF, and warm to 50 °C. Triethylamine (5.6 mL, 40.2 mmol) was added slowly, the reaction was continued at this temperature for half an hour, then cooled to room temperature and the reaction was continued for 3 hours. Water was added, and ethyl acetate was extracted three times. The organic phase was washed with water, dried and concentrated to give , the crude yield was 85.4%.

 (2) Preparation of isoindoline-2-amine hydrochloride

 In a dry reaction flask, tert-butyl isoindoline-2-ylcarbamate (4.0 g, 17.1 mmol) and 10 mL of anhydrous methanol were added, and dried hydrogen chloride gas was applied thereto for 1 hour and filtered to give a white solid 2.7. g, yield 92.5%.

(3) Preparation of (5) small (5-fluoro-4-oxo-4H-benzo[[1,3]oxazin-2-yl)propylcarbamic acid tert-butyl ester

 In a dry single-mouth reaction flask, add 6-fluoro-2-aminobenzoic acid (1.0 g, 6.45 mmol), (5)-2-tert-butoxycarbonylaminobutyric acid (1.44 g, 7.09 mmol) and triphenyl phosphite. The ester (2.36 g, 7.61 mmol) was added to 10 mL of pyridine as a solvent, and reacted at 55 ° C for 12 h. Without further treatment, the next reaction was carried out directly.

 (4) (5) Small [5-fluoro-3-(isoindolino-2-yl)-4-oxo-3,4-dihydroquinazolin-2-yl]propylcarbamic acid tert-butyl Preparation of ester

 In the reaction system of the previous step, iso-porphyrin-2-aminohydrochloride (1.21 g, 7.09 mmol) was directly added, and the temperature was raised to 100 ° C for 10 h. After cooling, the mixture was directly added to the silica gel and column chromatography (oil) Ether: ethyl acetate = 3:1) gave a white solid, 1.4 g, and a two-step yield of 49.5 %.

 (5) Preparation of (5)-2-(1-aminopropyl)-5-fluoro-3-(isoindol-2-yl)quinazolin-4(3)-one trifluoroacetate

 In a dry reaction flask, add (5) small [5-fluoro-3-(iso-oxoindol-2-yl)-4-oxo-3,4-dihydroquinazolin-2-yl]-propane Tert-butyl carbamate (0.65 g, 1.48 mmol), adding 5 mL of dichloromethane, 5 mL of trifluoroacetic acid, stirring at room temperature for 3 h, quenching the reaction, then solvent was evaporated to give an oil of 0.64 g. 95.6 %.

(6) (5)-2-[l-(9H-Indol-6-ylamino)propyl]-5-fluoro-3-(isoindol-2-yl)quinazoline-4 (3H) - Preparation of ketones The dried reaction flask was charged with (5)-2-(1-aminopropyl)-3-(isoindolino-2-yl)-5-fluoro-quinazoline-4(3H)- Ketone trifluoroacetate (0.64 g, 1.41 mmol), 6-chloro-9H-indole (0.26 g, 1.68 mmol), 10 mL of tert-butanol, DIEA (1.45 mL, 8.33 mmol), 9 (TC) After 12 h, it was directly spin-dried, and the liquid phase was purified to obtain a white solid (0.29 _g , yield: 45.1 %).

Mass spectrometry (Μ+Η): 457.2

1H-NMR (i/ ₆ -DMSO, 400 ΜΗζ): δ 12.95 (IH, s), 8.15 (2H, s), 7.86-7.70 (2H, m), 7.42 (1H, d), 7.37-7.19 (5H , m), 5.95 (1H, m), 4.91 (IH, d), 4.82-4.69 (2H, m), 4.51 (IH, d), 2.13-1.92 (2H, m), 1.02 (3H, t).

Example 58 (S -2-[l-i9^T-嘌呤-6-ylamino)ethyl]-5-chloro-3-f5-fluoroindol-1-yl)quinazoline-4 (3 -ketone

 (1) Preparation of 5-fluoroporphyrin

 In a 250 mL round bottom flask, 150 mL of glacial acetic acid and 5-fluoro-1H-indole (12 g, 88.8 mmol) were added, and sodium cyanoborohydride (11. 2 g, 178 mmol) was added to the system in portions. In the middle, LC-MS monitored the progress of the reaction, and the reaction was completed at room temperature for 2.5 hours. The system was poured into ice water, the pH was adjusted to neutral with 40% sodium hydroxide, extracted three times with dichloromethane, and the organic phases were combined and dried to yield 11.4 g, yield 93.6%.

 (2) Preparation of 5-fluoro-1-nitrosoporphyrin

 In a 250 mL round bottom flask, 5-fluoroporphyrin (10 g, 72.9 mmol) was dissolved in 75 mL of glacial acetic acid in an ice bath, and then sodium nitrite (5.5 g) was added dropwise to the solution. 79.7 mmol) of 80 mL aqueous solution, the temperature of the control system does not exceed 20. C, LC-MS was used to monitor the progress of the reaction for 3 hours. The pH was adjusted to neutral with 40% sodium hydroxide in an ice-bath, and extracted three times with ethyl acetate. The organic phase was combined, concentrated and purified by column chromatography (PE: EA=10:1) 86.7%.

 (3) Preparation of 5-fluoroporphyrin-1-amine

 In a 500 mL dry three-necked flask, 5-fluoro-1-nitrosoporphyrin (10 g, 60.2 mmol) and 150 mL of dry tetrahydrofuran were added, and the system was replaced with nitrogen. The system was placed in an ice water bath, and 90 mL of 1 M lithium aluminum hydride was added to the system, and the mixture was reacted for 4 hours in an ice water bath. After the reaction was completed, it was quenched by dropwise addition of 120 mL of ethyl acetate. After 1 hour, 100 mL of a 40% sodium hydroxide solution was added dropwise and stirred for 30 minutes, extracted with ethyl acetate, and the organic layer was concentrated. : C3⁄4OH = 20:1) gave a brown solid 6.3 g, yield 68.8%.

 (4) Preparation of (5)-1-(5-chloro-4-oxo-4H-benzo[[1,3]oxazin-2-yl)ethylcarbamic acid tert-butyl ester

In a dry reaction flask, add 2-amino-6-chlorobenzoic acid (2 g, 11.7 mmol), (5)-2-(tert-butoxycarbonyl ammonia) Base) propionic acid (2.4 g, 12.7 mmol), 20 mL of B-pyridyl, triphenyl phosphite (3.63 g, 11.7 mmol), at 55. The reaction was carried out in an oil bath for 10 hours and used directly for the next reaction.

 (5) (5)-1-[5-Chloro-3-(5-fluoroporphyrinyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethylcarbamic acid Preparation of tert-butyl ester

 In the upward reaction system, 5-fluoroporphyrin-1-amine (1.78 g, 11.7 mmol) was added, and the mixture was heated to 100 ° C to carry out a reaction, and the progress of the reaction was monitored by LC-MS. The solvent was dried and purified by preparative chromatography to yield 2 g of a beige solid.

 (6) Preparation of (5)-2-(1-aminoethyl)-5-chloro-3-(5-fluoroindol-1-yl)quinazolin-4(3H)-one hydrochloride

 In a dry reaction flask, (5) small [5-chloro-3-(5-fluoroporphyrinyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl Tert-butyl carbamate (1 g, 2.2 mmol) was dissolved in 20 mL of 1,4-dioxane, hydrogen chloride gas was passed through the system, and the progress of the reaction was monitored by LC-MS. The reaction was completed in 4 hours, and the solvent was removed by rotary evaporation. The product (hydrochloride) was 0.86 g, yield 99%.

 (7) (5)-2-[l-(9H-Indol-6-ylamino)ethyl]-5-chloro-3-(5-fluoroindol-1-yl)quinazolin-4 ( Preparation of 3H)-ketone In a dry reaction flask, add 0S)-2-(l-aminoethyl)-5-chloro-3-(5-fluoroindoline-1-yl) to 30 mL of tert-butanol. Quinazoline-4(3H)-one hydrochloride (0.2 g, 0.51 mmol) and DIEA (0.261 g, 2.02 mmol), then 6-chloro-9H-indole (86 mg, 0.56 mmol) The reaction was allowed to react at 90 ° C for 18 hours, cooled, concentrated, and chromatographed to give a pale yellow solid, 35 mg, yield 14.4%.

Mass spectrometry (M+H): 476.8

 'H-NMRC^-DMSO, 400 MHz): δ 12.90 (1Η, br s), 8.25-7.97 (3H, m), 7.76-7.64 (1H, m), 7.61-7.45 (2H, m), 7.07 ( 1H, d), 6.81 (1H, t), 6.63-6.52 (1H, m), 5.84 (1H, m), 4.17-4.03 (1H, m), 4.03-3.88 (1H, m), 3.24-3.13 ( 1H, m), 3.05-2.86 (1H, m), 1.55 (3H, d).

Example 59 Preparation of (5 -2-[l-(9H-indol-6-ylamino)ethyl1-5-chloro-7-fluoro-3-(anilino)quinazolinone (Compound 72)

 (1) Preparation of N-(3-chloro-5-fluorophenyl)-2-(hydroxyimine)acetamide

 In a 2 L reaction flask, chlorinated trichloroacetaldehyde (6.19 g, 37.4 mmol) and anhydrous sodium sulfate (53 g, 373 mmol) were dissolved in 100 mL of water, and 2.6 mL of concentrated hydrochloric acid was added. 3-Chloro-5-fluoroaniline (5.0 g, 34.3 mmol) was added to the above reaction solution, and 30 mL of a solution containing hydroxylamine hydrochloride (7.3 g, 105 mmol) was added to the system. The reaction was refluxed for 2 h, then cooled and cooled. When the temperature was lowered to 50 ° C, the mixture was filtered. The pale yellow filter cake was washed three times with water and then dried to give 5.5 g, yield 74.1%.

 (2) Preparation of 4-chloro-6-fluoroporphyrin-2,3-dione

 In a dry reaction flask, 20 mL of concentrated sulfuric acid was heated to 55 ° C. Dry N-(3-chloro-5-fluorophenyl)-2-(hydroxyimine)acetamide (5 g, 23.1 mmol) The batch was added to the reaction flask to keep the temperature of the system not exceeding 65 ° C. After the completion, the temperature was raised to 100 ° C for 1 hour, and then the temperature was lowered to room temperature. Pour into 200 mL of ice water and stir for half an hour, brown solid precipitated, filtered and dried to give 3.2 g of product, yield 6.93 %.

 (3) Preparation of 2-amino-6-chloro-4-fluorobenzoic acid

 Add 42 mL of 5% sodium hydroxide solution and 42 mL of 30% aqueous hydrogen peroxide solution to the dry reaction flask, and add 4-chloro-6-fluoroporphyrin-2,3-dione (3 g, 15 in batches). After heating, the temperature was raised to 50 °C for 1 h, then the temperature was lowered, filtered, and the filtrate was adjusted to pH 4, and a solid precipitated, which was filtered, and the filtrate was extracted with ethyl acetate, and the mixture was evaporated to dryness to give a pale yellow solid 1.7 g. , yield 59.8%.

 (4) Preparation of (5)-1-(5-chloro-7-fluoro-4-oxo-4H-benzo[][l,3]oxazin-2-yl)ethylcarbamic acid tert-butyl ester

In a dry reaction flask, add 2-amino-6-chloro-4-fluorobenzoic acid (1.5 g, 7.91 mmol), (5>2-(tert-butoxycarbonylamino)propionic acid (1.7 g, 8.99 mmol). , 10 mL of pyridine, triphenyl phosphite (2.4 g, 7.73 mmol), The reaction was carried out in a 55 ° C oil bath for 10 hours and used directly for the next reaction.

 (5) Preparation of (5)-H5-chloro-7-fluoro-4-oxo-3-(anilino)-3,4-dihydroquinazolin-2-yl]ethylcarbamic acid tert-butyl ester

 In the upward reaction system, phenylhydrazine hydrochloride (1.27 g, 8.78 mmol) was added, and the mixture was heated to 100 ° C for 8 hours. The solvent was evaporated to dryness (mjqqqqqqq

(6) Preparation of (5)-2-(1-aminoethyl)-5-chloro-7-fluoro-3-(anilino)-quinazoline-4(3H)-one hydrochloride

 In a dry reaction flask, CS)-l-[5-chloro-7-fluoro-4-oxo-3-(anilino)-3,4-dihydroquinazolin-2-yl]ethylamino Tert-butyl formate (0.86 g, 2.0 mmol) was dissolved in ethyl acetate (40 mL), and hydrogen chloride gas was passed through the system until the reaction was completed, and the solvent was evaporated to give a product of 0.7 g, yield 95%.

 (7) Preparation of (5 2-[l-(9H-嘌呤-6-ylamino)ethyl]-5-chloro-7-fluoro-3-(anilino)quinazoline-4(3H)-one In a dry reaction flask, add (-2-(1-aminoethyl)-5-chloro-7-fluoro-3-(anilino)-quinazoline-4(3H)- to 30 mL of tert-butanol. Ketone hydrochloride (0.7 g, 1.9 mmol) and DIEA (0.98 g, 7.6 mmol), then 6-chloro-9H-indole (0.29 g, 1.9 mmol) was added, and the reaction was allowed to react at 90 ° C for two days. Cooling, concentration, preparative chromatography gave a white solid, 120 mg, yield 14.0%.

Mass Spectrometry (M+H): 451.1

¹ H-NMR (^-DMSO, 400 MHz): δ 12.98 (1H, br s), 9.22, 9.02 (IH, two singlets), 8.25-8.08 (2H, m), 7.94-7.71 (1H, m), 7.61-7.51 (IH, m), 7.48-7.15 (3H, m), 7.10-6.71 (3H, m), 5.85, 5.49 (IH, two br s), 1.65, 1.46 (3H, two doublets).

Example 60 iS>-2-il-i9 嘌呤-6-ylamino)ethyl 1-5-fluoro-34(4-fluorobenzyl)(methyl)amino-1 quinazoline-4(3H)-m Preparation of (Compound 73)

(1) Preparation of N-(4-fluorobenzyl)-N-nitrosomethylamine

 1-(4-Fluorophenyl)methylmethylamine (4.2 g, 30 mmol) was dissolved in glacial acetic acid (60 mL) and stirred for 10 min. Sodium nitrite (9.0 g, 130 mmol) was dissolved in water (40 mL) and slowly added dropwise to the system. After the dropwise addition, the mixture was allowed to react to room temperature for 2 hours. The reaction was monitored by LC-MS and the system was used directly in the next step.

 (2) Preparation of 1-(4-fluorobenzyl)-1-methylindole

 The reaction solution of the previous step was transferred to an ice bath and stirred, and zinc powder (7.8 g, 119 mmol) was slowly added. After the addition, the mixture was stirred in an ice bath for half an hour and then transferred to room temperature for 12 hours. The TLC monitors the end of the reaction. After suction filtration, the filter cake was washed with ethyl acetate, and the filtrate was evaporated to dryness. The yield was 49.7%.

 (3) Preparation of (5)-1-(5-fluoro-4-oxo-4H-benzo[[1,3]oxazin-2-yl)ethylcarbamic acid tert-butyl ester

 Add 2-amino-6-fluorobenzoic acid (1.55 g, 10.0 mmol), (5)-2-(tert-butoxycarbonylamino)propionic acid (2.37 g, 12.5 mmol) in a dry 100 mL reaction flask. Then, 25 mL of pyridine was added, and finally triphenyl phosphite (3.40 g, 11.0 mmol) was added, and the mixture was stirred for 10 hours in an oil bath at 55 °C. The system was used directly for the next reaction.

(4) (5)-1-[5-fluoro-3-[(4-fluorobenzyl)(methyl)amino]-4-oxo-3,4-dihydroquinazolin-2-yl] Preparation of tert-butyl ethylcarbamate

 In the reaction solution for preparing CS)-l-(5-fluoro-4-oxo-4H-benzo[[1,3]oxazin-2-yl)ethylcarbamic acid tert-butyl ester, 1-( directly) 4-fluorobenzyl)-1-methylindole (1.85 g, 12.0 mmol), stirred under reflux in an oil bath of 100 ° C for 12 hours, then cooled, concentrated under reduced pressure, column chromatography (PE: EA=10) :1) Purified white solid 1.92 g, the yield in two steps was 43.2%.

 (5) Preparation of (5)-2-(1-aminoethyl)-5-fluoro-3-[(4-fluorobenzyl)(methyl)amino]quinazoline-4(3H)-one

Add (5 -1-[5-fluoro-3-[(4-fluorobenzyl)(methyl)amino]-4-oxo-3,4-dihydroquinazoline to a dry lOO mL reaction vial _ ₂ -yl]ethyl carbamic acid tert-butyl ester (890 mg, 2.0 mmol) was dissolved in 7.0 mL of dichloromethane, and 3.0 mL of trifluoroacetic acid was added dropwise in an ice bath. After the addition was completed, stirring was continued at room temperature. After the reaction of the starting material was completed by TLC, the reaction was stopped, then concentrated under reduced pressure, and the obtained product was directly used for the next reaction.

 (6) (5)-2-[l-(9H-Indol-6-ylamino)ethyl]-5-fluoro-3-[(4-fluorobenzyl)(methyl)amino]quinazoline- Preparation of 4(3H)-one

 (5)-2-(1-Aminoethyl)-5-fluoro-3-[(4-fluorobenzyl)(methyl)amino]quinazoline was obtained in the previous step in a 100 mL dry reaction flask. 4(3H)-one was dissolved in 20.0 mL of tert-butanol, the system was adjusted to pH with DIEA, then 6-chloro-9H-indole (308 mg, 2.0 mmol) was added in an oil bath at 90 °C. The reaction was refluxed for 24 hours. Then, it was cooled and concentrated under reduced pressure, and purified by preparative chromatography to yield white crystals of 0.260 g.

Mass Spectrum (M+H): 463.3 1H-NMR ((i-DMSO, 400 MHz): 5 12.94 (1H, s), 8.25-8.08 (2H, m), 7.97-7.60 (2H, m), 7.58-7.43 (2H, m), 7.39 ( 1H, t), 7.25 (1H, dd), 7.19 (1H, t), 7.06 (IH, t), 6.19-5.95 (1H, m), 4.72-4.41 (2H, m), 3.02-2.90 (3H, m), 1.54, 1.46 (3H, two doublets).

Claims

Rights request

A compound of the formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a progeny thereof:

 among them:

X ¹ , X ² , X ³ , X ⁴ , Y are each independently N or CR ³ , and R ³ is hydrogen, halogen, hydroxy, carboxy, trifluoromethyl, .6 alkyl, C _1-6 alkoxy -N(R ^A )(R ^A ';), cyano, alkenyl, alkynyl, carbamoyl, C^alkyl formyl, aminosulfonyl, 3-14 membered cyclodecyl, 6-14 An aryl group, a 3-14 membered heterocyclic group, a 7-12 membered spirocyclic group or a 7-12 membered bridged ring group;

L is a covalent bond or -N(R ^A )- _;

L is a covalent bond, R ¹ is benzo-C ₃ ^ monoalkenyl cycloalkyl, benzo-C ₄ _ ₈ cycloalkadienyl group, phenyl group and monocyclic alkenyl, and C _{4. 8} cycloalkadienyl and phenyl, a (phenyl or 5-6 membered monocyclic heteroaryl) and (C _{3. 8} monocyclic alkenyl group, cycloalkadienyl group or a 3-8 membered heterocycloalkenyl) to give a fused bicyclic heteroaryl group, 7 a -12 membered spiro or a 7-12 membered bridged ring group, and R ^{1 is} optionally substituted with 1-3 R ^B groups,

When L is -N(R ^A )-, R ¹ is ₆ fluorenyl, Cw fluorenyl, CL ₆ alkylsulfonyl, 3-14 membered cyclodecyl, 6-14 membered aryl, 6-14 An aryl C _M fluorenyl group, a 3-14 membered heterocyclic group, a 7-12 membered spirocyclic group or a 7-12 membered bridged ring group, and R ^{1 is} optionally substituted by 1 to 3 R ^B groups,

R ^A , R ^A ' independently represent hydrogen, fluorenyl, CM alkenyl, C _{2 -6} alkynyl, 3-14 membered cyclodecyl, 6-14 membered aryl, 3-14 membered heterocyclic, 7- 12-membered spiro ring base or 7-12 yuan bridged ring base;

Z is -0-, -C(R ⁴ 'R ⁴ )- or -N(R ⁴ )-;

W is -0-, -C(R ⁵ 'R ⁵ )- or -N(R ⁵ )-;

R ⁴ , R ⁴ ', R ⁵ , R ⁵ ' are each independently hydrogen, C oxime or 3-14 membered fluorenyl unsubstituted or substituted with at least one hydroxy or at least one halogen;

R ² is a 6-10 membered bicyclic heterocycloalkyl group which is unsubstituted or substituted by at least one R ^B , from (phenyl or 5-6 membered monocyclic heteroaryl) to (5-6 membered monocyclic heteroaryl) a fused bicyclic heteroaryl group, a 7-12 membered spiro ring group or a 7-12 membered bridged ring group; R ^b is hydrogen, oxo, halogen, cyano, hydroxy, amino, C _1-6 fluorenylamino, bis(Cw fluorenyl)amine, carboxy, aminosulfonyl, carbamoyl, fluorenyl, C _{1 -6} methoxy, halo C _1-6 alkyl, halo C _1-6 decyloxy, hydroxy C _1-6 alkyl, amino C _1-6 decyloxy, carboxy C _1-6 fluorenyl, Carbamate C _1-6 alkyl, .6 fluorenylcarbonyloxy, C _{1 -6} fluorenyloxycarbonyl, C _1-6 alkylcarbonyl, C _2-6 alkenyl, C ₂ alkynyl, 3-14 Indenosyl, 3-14 membered cycloalkyloxy, 6-14 membered aryl, 6-14 membered aryloxy, 3-14 membered heterocyclic, 3-14 membered heterocyclyloxy, 7 -12 yuan spiro ring base or 7-12 yuan bridge ring base.

2. A compound, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a progeny thereof according to claim 1 wherein:

X ¹ , X ² , X ³ , X ⁴ are each independently CR ³ , and R ³ is hydrogen, halogen, hydroxy, trifluoromethyl, C _1-6 alkyl, CL ₆ alkoxy, -N (R ^A (R ^A '), cyano, alkenyl, C ₂ alkynyl, 3-8 membered monocyclic cycloalkyl, phenyl or 3-8 membered monocyclic heterocycloalkyl, 3-8 membered heterocycloalkenyl , 5-6 membered monocyclic heteroaryl;

 Y is N;

L is a covalent bond, R ¹ is benzo-C _3-8 cycloalkyl monoalkenyl, benzo cycloalkadienyl group, phenyl group and monocyclic alkenyl, and phenyl group and cycloalkadienyl ^ ₈ by (phenyl or a bicyclic heteroaryl group, a 7-12 membered spiro ring obtained by condensing a 5-6 membered monocyclic heteroaryl group with (C^cyclomonoalkenyl, C«cyclodienyl or 3-8 membered heterocycloalkenyl) a 7-12 membered bridged ring group, and R ^{1 is} optionally substituted with 1-3 R ^B groups,

When L is -N(R ^A )-, R ¹ is C _1-6 alkyl, C _1-6 alkyl formyl, C 垸 sulfonyl, 3-14 membered cyclodecyl, 6-14 aryl a 6-14 membered aryl CM alkyl group, a 3-14 membered heterocyclic group, a 7-12 membered spirocyclic group or a 7-12 membered bridged ring group, and R ^{1 is} optionally substituted with 1-3 R ^B groups. ,

R ^A , R ^A ' independently represent hydrogen, alkyl, alkenyl, C ₂ . ₆ alkynyl, 3-14 membered cycloalkyl, 6-14 membered aryl, 3-14 membered heterocyclic, 7-12 Elemental ring or 7-12 yuan bridged ring base;

Z is -C(R ⁴ 'R ⁴ )-;

W is -N(R ⁵ )-;

R ⁴ , R ⁴ ', R ⁵ are each independently hydrogen, unsubstituted or substituted with at least one hydroxyl group or at least one halogen. ₆ fluorenyl or 3-14 membered cyclodecyl;

R ² is a 6-10 membered bicyclic heterocycloalkyl group which is unsubstituted or substituted by at least one R ^B , from (phenyl or 5-6 membered monocyclic heteroaryl) to (5-6 membered monocyclic heteroaryl) a fused bicyclic heteroaryl group, a 7-12 membered spiro ring group or a 7-12 membered bridged ring group;

R ^B is hydrogen, oxo, halogen, cyano, hydroxy, amino, decylamino, bis(-6-yl)amine, carboxy, Aminosulfonyl, carbamoyl, Cw alkyl, C _1-6 decyloxy, halo Cw fluorenyl, halo C _1-6 decyloxy, hydroxy. ^Alkyl, amino C _1-6 decyloxy, carboxy C _1-6 fluorenyl, carbamoyl C fluorenyl, C _1-6 fluorenylcarbonyloxy, C _1-6 fluorenyloxycarbonyl, C ₆ Alkylcarbonyl, C _2-6 alkenyl, alkynyl, 3-8 membered cycloalkyl, 3-8 membered cyclodecyloxy, phenyl, phenyloxy, 3-8 membered monocyclic heterocycloalkyl 3-8 membered heterocycloalkenyl, 5-6 membered monocyclic heteroaryl, 3-8 membered monocyclic heterocycloalkyloxy, 3-8 membered heterocycloalkenyloxy, 5-6 membered monocyclic ring Heteroaryloxy.

3. A compound according to claim 1, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a progeny thereof, having the following structure:

Wherein X ¹ , X ² , X ³ , X ⁴ , Y, L, R ¹ , R ² , R ⁴ and R ⁵ have the meanings as defined in claim 1.

4. A compound, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a progeny thereof according to claim 1, wherein:

X ¹ , X ² , X ³ , X ⁴ are each independently CR ³ , and R ³ is hydrogen, halogen, hydroxy, trifluoromethyl, Q- ₆ fluorenyl, C ₆ alkoxy or amino;

 Y is N;

L is a covalent bond, and R ^{1 is} fused to (C^cyclomonoalkenyl, C cyclodienyl or 3-8 membered heterocycloalkenyl) by (phenyl or 5-6 membered monocyclic heteroaryl) The resulting bicyclic heteroaryl or 7-12 membered spiroheterocyclyl, and R ^{1 is} optionally substituted with 1-3 R ^b ,

Z is -CH(R ⁴ )-;

W is -N(R ⁵ )-;

R ⁴ , R ⁵ are each independently hydrogen, d_ ₃ fluorenyl or 3-5 membered cycloalkyl which is unsubstituted or substituted with at least one hydroxyl group or at least one halogen;

R ^b is hydrogen, oxo, halogen, cyano, C _1-3 alkyl, C _1-3 decyloxy, trifluoromethyl, amino or 3-8 membered monocyclic heterocyclic fluorenyl, 3-8 Heterocycloalkenyl, 5-6 membered monocyclic heteroaryl.

5. A compound, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a progeny thereof according to claim 1 wherein:

X ¹ , X ² , X ³ , X ⁴ are each independently CR ³ , and R ³ is hydrogen, fluorine, chlorine, trifluoromethyl or methyl;

 Y is N;

L is a covalent bond, and R ^{1 is} thickened by (phenyl or 5-6 membered monocyclic heteroaryl) with (C^cyclomonoalkenyl, C^cyclodienyl or 5-6 membered heterocycloalkenyl) a resulting bicyclic heteroaryl or 7-12 membered spiroheterocyclyl, and R ^{1 is} optionally substituted by 1-3 R ^B ,

Z is -CH(R ⁴ )-, R ⁴ is hydrogen, unsubstituted or substituted with at least one hydroxy or fluorine d. ₃ fluorenyl or cyclopropyl; W is -NR ⁵ )-, R ⁵ independently Is hydrogen or methyl;

R ^B is a halogen.

6. A compound, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a progeny thereof according to claim 1 wherein:

X ¹ , X ² , X ³ , X ⁴ are each independently CR ³ , and R ³ is hydrogen, halogen, hydroxy, trifluoromethyl, C decyl, CL ₆ decyloxy, -N(R ^A )(R ^A ') or cyano;

 Y is N;

L is -N(R ^A ) -, R ¹ is alkyl, C hydrazinoyl, C alkylsulfonyl, 3-6 membered cyclodecyl, 6-14 membered aryl, 6-14 membered aryl a C _1-3 fluorenyl group, a 3-14 membered heterocyclic group, a 7-12 membered spirocyclic group or a 7-12 membered bridged ring group, and R ^{1 is} optionally substituted by 1 to 3 R ^B groups,

R ^a, R ^a 'independently represent hydrogen, d. ₆ embankment group, C alkenyl, C _{2. 6} alkynyl group, a 3-14 membered cycloalkyl, 6-14 membered aryl, 3-14 membered heterocyclyl , 7-12 yuan spiro ring base or 7-12 yuan bridge ring base;

Z is -CH(R ⁴ )-;

W is -N(R ⁵ )-;

R ⁴ , R ⁵ are each independently hydrogen, C _W thiol or 3-5 membered fluorenyl unsubstituted or substituted with at least one hydroxy or at least one halogen;

R ^b is hydrogen, oxo, halogen, cyano, hydroxy, amino, C _1-6 fluorenylamino, bis(C ₆ fluorenyl)amine, carboxy, sulfamoyl, carbamoyl, C _1-6 Alkoxy, C _1-6 fluorenyl, halogenated C _1-6 fluorenyl, 3-6 membered cycloalkyl, 3-6 membered cycloalkyloxy, 3-8 membered monocyclic heterocyclic fluorenyl, 3 -8 membered heterocycloalkenyl, 5-6 membered monocyclic heteroaryl, 3-8 membered monocyclic heterocycloalkyloxy, 3-8 membered heterocycloalkenyloxy, 5-6 membered monocyclic heteroaryl Baseoxy.

7. A compound according to claim 1, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a progeny thereof - wherein

X ¹ , X ² , X ³ , X ⁴ are each independently CR ³ , and R ³ is hydrogen, halogen, hydroxy, trifluoromethyl, C^alkyl or d. ₆ alkoxy;

 Y is N;

L is -N(R ^a ) -, R ¹ is _.3 alkyl, d- ₃ mercapto formyl, Cw alkylsulfonyl, 3-6 membered cyclodecyl, 6-14 membered aryl, 6-14 a monoaryl C _1-3 alkyl group, a 5-6 membered monocyclic heterocyclic fluorenyl group, a 5-6 membered heterocycloalkenyl group, a 5-6 membered monocyclic heteroaryl group, a 6-10 membered bicyclic heterocycloalkyl group, a 7-12 membered spiro group or a 7-12 membered bridged ring group, and R ^{1 is} optionally substituted with 1-3 R ^b groups,

R ^a represents hydrogen, Cw fluorenyl, 3-14 membered cyclodecyl or 6-14 membered aryl;

Z is -CH(R ⁴ )-, R ⁴ is hydrogen, unsubstituted or substituted with at least one hydroxyl group or at least one halogen. _3- mercapto or cyclopropyl;

W is -N(R ⁵ )-, and R ^{5 is} independently hydrogen or methyl;

R ^B is hydrogen, oxo, halogen, cyano, hydroxy, amino, C alkylamino, bis(d. ₆ fluorenyl)amine, Q- ₆ alkoxy, _-6 alkyl, halogen C _{1- 6} alkyl, 3-6 membered cyclodecyl, 3-6 membered cyclodecyloxy, 5-6 membered monocyclic heterocycloalkyl, 5-6 membered heterocycloalkenyl, 5-6 membered monocyclic heteroaryl A 5-6 membered monocyclic heterocycloalkyloxy group, a 5-6 membered heterocycloalkenyloxy group, a 5-6 membered monocyclic heteroaryloxy group.

8. A compound, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a progeny thereof, according to claim 1: among them-

X ¹ , X ² , X ³ , X ⁴ are each independently CR ³ , R ³ is hydrogen, fluorine, chlorine, hydroxyl, trifluoromethyl or methyl; Y is N;

L is -N(R ^a ) -, R ¹ is C _1-3 alkyl, acetyl, methylsulfonyl, phenyl, pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, thiazolyl, imidazole , pyrazolyl, imidazolyl, pyrazolyl, fluorenyl, isodecyl, carbazolyl, benzimidazolyl, pyridopyrazolyl, fluorenyl, piperazinyl, quinolyl, Tetrahydropyranyl, piperidinyl, morpholinyl, pyrazinyl, pyridin-2-one, cyclohexyl, cyclopentyl or benzyl, and R ^{1 is} optionally substituted by 1-3 R ^b ,

R ^a represents hydrogen, fluorenyl, 3-8 membered cyclodecyl or 6-14 membered aryl;

Z is -CH(R ⁴ )-, R ⁴ is hydrogen, Cw decyl or cyclopropyl which is unsubstituted or substituted with at least one hydroxyl group or at least one fluorine;

W is -N(R ⁵ )-, and R ^{5 is} independently hydrogen or methyl;

R ^b is hydrogen, oxo, cyano, cyano, hydroxy, amino, alkylamino, bis(d. ₆ fluorenyl)amine, C _1-6 decyloxy, C _1-6 alkyl, halogenated C fluorenyl, 3-6 membered cyclodecyl, 3-6 membered cycloalkyloxy, 5-6 membered monocyclic heterocyclic fluorenyl, 5-6 membered heterocycloalkenyl, 5-6 membered monocyclic heteroaryl A 5-6 membered monocyclic heterocycloalkyloxy group, a 5-6 membered heterocycloalkenyloxy group, a 5-6 membered monocyclic heteroaryloxy group.

9. A compound, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a progeny thereof according to claim 1 wherein:

X ¹ , X ² , X ³ , X ⁴ are each independently CR ³ , R ³ is hydrogen, fluorine, chlorine, hydroxyl, trifluoromethyl or methyl; Y is N;

L is -N(R ^a )-, and R ¹ is C ₃ fluorenyl, acetyl, methylsulfonyl, phenyl, pyridyl, pyridin-2-one, cyclohexyl, cyclopentyl or benzyl, and R ^{1 is} optionally substituted by 1-3 R ^b ,

R ^a represents hydrogen, methyl, ethyl, cyclopropyl or phenyl;

Z is -CH(R ⁴ )-, R ⁴ is hydrogen, Cw alkyl or cyclopropyl which is unsubstituted or substituted with at least one hydroxyl group or at least one fluorine;

W is -N(R ⁵ )-, and R ^{5 is} independently hydrogen or methyl; > 3⁄4

R ² is _NH ,

R ^b is hydrogen, oxo, m, cyano, C _1-3 fluorenyl, C _1-3 decyloxy or trifluoromethyl. a compound selected from the group consisting of a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a progeny thereof:

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fC6000/ClOZM3/X3d £SO£ZOItlOZ ΟΛλ

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a compound selected from the group consisting of a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a progeny thereof:

6tl

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OSl

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1ST

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12. A pharmaceutical composition comprising a compound of any one of claims 1-11, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a progeny thereof, and one or more pharmaceutically acceptable carriers .

13. A compound according to any one of claims 1 to 11, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a progeny thereof or a composition according to claim 12 for use in the treatment and/or prevention Use in inflammatory diseases and/or tumor drugs.

14. The use according to claim 13, wherein the inflammatory disease is selected from the group consisting of allergy, asthma, rheumatoid arthritis, osteoarthritis, allergic conjunctivitis, allergic keratitis, dry eye, chronic obstructive pulmonary disease (COPD), lupus erythematosus, psoriasis, multiple sclerosis, and end stage renal disease, and the tumor is selected from the group consisting of leukemia, lymphoma, myelosynthesis, non-Hodgkin's lymphoma, and chronic spontaneous myelofibrosis.