CN116284043A

CN116284043A - Tricyclic compound and medical application thereof

Info

Publication number: CN116284043A
Application number: CN202111564949.0A
Authority: CN
Inventors: 段文虎; 耿美玉; 詹正生; 艾菁; 彭霞; 季寅淳; 丁健
Original assignee: Shanghai Institute of Materia Medica of CAS
Current assignee: Shanghai Institute of Materia Medica of CAS
Priority date: 2021-12-20
Filing date: 2021-12-20
Publication date: 2023-06-23

Abstract

The invention relates to a tricyclic compound and medical application thereof. Specifically, the compound has a tricyclic compound with a structure shown in a formula (I), and also relates to a medicinal salt, a prodrug, a hydrate or a solvate of the compound, a preparation method of the compound and a pharmaceutical composition containing the compound, wherein the compound can be used as a tyrosine kinase inhibitor, especially an AXL kinase inhibitor, and is used for preparing a medicament for preventing and/or treating diseases related to tyrosine kinase dysfunction.

Description

Tricyclic compound and medical application thereof

Technical Field

The invention belongs to the fields of pharmaceutical chemistry and pharmacotherapeutics, and in particular relates to application of tricyclic compounds as tyrosine kinase inhibitors, especially AXL kinase inhibitors in preparing medicines for preventing and/or treating diseases related to tyrosine kinase dysfunction.

Background

Tyrosine kinases maintain normal physiological functions of cells by catalyzing the tyrosine phosphorylation of proteins. More than half of the tyrosine kinases are receptor tyrosine kinases, others are protein tyrosine kinases. Receptor tyrosine kinases function as receptors for growth factors, differentiation factors, cytokines or hormones and are expressed in specific cell types. The over-expression of various tyrosine kinases is closely related to the occurrence and development of tumors, and the inhibition of the activity of the tyrosine kinases by small molecule inhibitors can show remarkable anti-tumor curative effect. The first tyrosine kinase inhibitor antitumor drug was the ABL1 inhibitor imatinib, which demonstrates that inhibition of aberrant kinase can inhibit cancer progression. The fusion gene BCR-ABL1 is a protein that binds together a portion of the ABL1 gene and BCR gene. About 95% of Chronic Myelogenous Leukemia (CML) patients have this abnormality BCR-ABL1, 25% of Acute Lymphoblastic Leukemia (ALL) patients and rare Acute Myelogenous Leukemia (AML) patients also have this abnormality, and imatinib is one of the best therapeutic drugs to treat these leukemias. Since ABL1 inhibitors were anti-tumor drugs, a variety of tyrosine kinases such as SRC, FAK, JAKs, EGFR, ERBB2, FGFRs, VEGFRs, IGF1R, FLT3, RET, PDGFR, and the like have been developed as inhibitors for tumor targeted therapies.

The activation of the receptor tyrosine kinase AXL kinase superfamily plays an important regulatory role in regulating the inflammatory immune response of the body. In tumors, AXL synergistically acts on the functional integrity of tumor cells and tumor microenvironments, and is a leading key target for development of anti-tumor drugs. AXL promotes tumor cell survival, is an important Epithelial Mesenchymal Transition (EMT) inducing molecule, and is closely related to tumor metastasis and recurrence. Besides regulating tumor cells, AXL is an important regulatory enzyme target of microenvironment, and is directly and indirectly involved in interactions between and with tumor cells in multiple tumor microenvironment matrix cells, such as macrophages and fibroblasts with high abundance in a tumor promotion microenvironment, key inhibitory cells and marrow-derived inhibitory cells, and the like, strengthen the immunosuppressive microenvironment, synergistically promote tumors, mediate drug resistance of immunotherapy, targeted therapy, chemotherapy and the like. Therefore, the AXL inhibitor is expected to become an important basic drug based on a tumor microenvironment remodeling combined drug strategy. Currently, there are no AXL inhibitors on the market, and a few AXL inhibitors are in the early clinical stage. In view of the prospect of developing the AXL kinase inhibitor compound into an anti-tumor drug, the development of the AXL kinase inhibitor has important medical value.

Disclosure of Invention

The invention aims to provide a novel compound with tyrosine kinase inhibitory activity, a medicinal salt thereof, a prodrug thereof, a hydrate or a solvate thereof, and a preparation method and application of the compound.

An object of the present invention is to provide tricyclic compounds having the structure represented by the formula (I), pharmaceutically acceptable salts thereof, prodrugs thereof, and hydrates or solvates thereof

Another object of the present invention is to provide a method for preparing the above tricyclic compound.

It is a further object of the present invention to provide a pharmaceutical composition comprising a therapeutically effective amount of one or more selected from the tricyclic compounds described above, pharmaceutically acceptable salts thereof, prodrugs thereof, and hydrates or solvates thereof.

It is still another object of the present invention to provide a pharmaceutical use of one or more selected from the above tricyclic compounds, pharmaceutically acceptable salts thereof, prodrugs thereof, and hydrates or solvates thereof as tyrosine kinase inhibitors in the preparation of a medicament for preventing and/or treating diseases associated with tyrosine kinase dysfunction.

In a first aspect of the present invention, there is provided a compound of formula (I), a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate or solvate thereof:

wherein ring a is selected from the group consisting of substituted and unsubstituted: a 5-6 membered aryl or heteroaryl, a C5-C6 alicyclic, or a 5-6 membered heterocyclic group; wherein the substitution refers to substitution with one or more R;

X, Y, P and Q are each independently selected from: o, S, N-R ^a1 Or CR (CR) ^a R ^b ；

Z, U, M, V and W are each independently selected from: C-R ^a2 Or N;

b is selected from

Wherein (1)>

Represents a ligation site;

F. l, E are each independently selected from: bond, N-R ^a3 C=g or CR ^a’ R ^b’ The method comprises the steps of carrying out a first treatment on the surface of the Wherein G is selected from: o, S, N-R ^a4 Or CR (CR) ^a” R ^b” ；

Ring C is selected from the group consisting of substituted or unsubstituted: a 5-12 membered heterocyclyl, a C6-C12 aryl, a 5-12 membered heteroaryl; wherein the substitution refers to substitution with one or more R;

R ³ each independently selected from the group consisting of substituted and unsubstituted: C1-C3 alkyl, C6-C12 aryl, 5-12 membered heteroaryl, C3-C12 cycloalkyl, 3-12 membered heterocyclyl; wherein the substitution refers to substitution with one or more R;

R ^a 、R ^b 、R ^a1 、R ^a2 、R ^a3 、R ^a4 、R ^a’ 、R ^b’ 、R ^a” 、R ^b” 、R ¹ and R is ² Each independently selected from: hydrogen atom, halogen, amino, hydroxyl, cyano, carboxyl, formyl, trifluoromethyl, C1-C3 alkyl, C1-C3 alkoxy and C3-C6 cycloalkyl; or R is ^a And R is ^b The C atoms to which they are attached may form a substituted or unsubstituted 3-5 membered ring; or R is ^a’ And R is ^b’ The C atoms to which they are attached may form a substituted or unsubstituted 3-5 membered ring; or R is ^a” And R is ^b” The C atoms to which they are attached may form a substituted or unsubstituted 3-5 membered ring; wherein the substitution refers to substitution with one or more R;

R is selected from: oxygen atom, halogen, amino, hydroxyl, cyano, carboxyl, formyl, trifluoromethyl, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocyclic group, C6 aryl and 5-6 membered heteroaryl; wherein the C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocyclyl may be further substituted with one or more groups selected from the group consisting of: halogen, amino, hydroxyl, cyano, carboxyl, formyl, trifluoromethyl, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C6 aryl and 5-6 membered heteroaryl.

In another preferred embodiment, R is selected from: oxygen atom, halogen, amino, hydroxyl, cyano, carboxyl, formyl, trifluoromethyl, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocyclic group, halogenated C1-C3 alkyl, halogenated C1-C3 alkoxy, C1-C3 alkyl-C3-C6 cycloalkyl, C1-C3 alkyl-3-6 membered heterocyclic group.

In another preferred embodiment, the 3-5 membered ring is selected from: C3-C5 cycloalkyl, 3-5 membered heterocyclyl.

In another preferred embodiment, F, L, E are each independently selected from: bond, N-H, C = O, C = S, CH ₂ 、

In another preferred embodiment, rings C and R ³ Each independently selected from the group consisting of substituted and unsubstituted: 5-6 membered aromatic or heteroaromatic ring, [6+6 ] ]Aromatic or condensed rings, [6+6 ]]Heteroaryl or fused rings, [6+5 ]]Heteroaryl or fused rings, [5+5 ]]Heteroaromatic rings or fused rings.

In another preferred embodiment, R ³ Selected from the following groups, each independently substituted or unsubstituted: C1-C3 alkyl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl (preferably 5-6 membered heteroaryl), C3-C6 cycloalkyl, 3-6 membered heterocyclyl; preferably substituted or unsubstituted benzyl, phenyl, naphthyl, pyridyl, pyrazinyl, thienyl, furyl, thiazolyl, imidazolyl, oxazolyl, quinolinyl, isoquinolinyl, benzofuryl, benzothienyl, benzimidazolyl, benzopyrazinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, piperidinyl, piperazinyl, oxetanyl, oxolanyl, dioxanyl; more preferably, R ³ Selected from:

wherein the substitution means substitution with one or more R, and R is defined as above.

In a further preferred embodiment of the present invention,

selected from: />

Therein, F, E, G, R ³ Preferably G is O or S as defined above.

In a further preferred embodiment of the present invention,

selected from: / >

R ^c 、R ^d 、R ^e Each independently selected from: hydrogen atom, halogen, amino, hydroxyl, cyano, carboxyl, formyl, trifluoromethyl, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl and 3-6 membered heterocyclic group; wherein the C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocyclyl may be further substituted with one or more groups selected from the group consisting of: halogen, amino, hydroxyl, cyano, carboxyl, formyl, trifluoromethyl, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl and 3-6 membered heterocyclic group; alternatively, R ^c And R is R ^d The atoms to which they are attached may constitute a substituted or unsubstituted group of: a C6 aryl, a 5-6 membered heteroaryl, a C5-C7 alicyclic, or a 5-7 membered heterocyclyl; wherein the substitution refers to substitution with one or more R;

alternatively, R ^d And R is R ^e The atoms to which they are attached may constitute a substituted or unsubstituted group of: a C6 aryl, a 5-6 membered heteroaryl, a C5-C7 alicyclic, or a 5-7 membered heterocyclyl; wherein the substitution refers to substitution with one or more R;

R ³ is defined as above.

In another preferred embodiment, the compound has a structure represented by formula (II), (III), (IV), (V), (VI):

wherein ring A is selected from a substituted or unsubstituted C6 aryl or 5-6 membered heteroaryl;

R ^c 、R ^d 、R ^e Each independently selected from: hydrogen atom, halogen, amino, hydroxyl, cyano, carboxyl, formyl, trifluoromethyl, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl and 3-6 membered heterocyclic group; wherein the C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocyclyl may be further substituted with one or more groups selected from the group consisting of: halogen, amino, hydroxy, cyanoCarboxyl, formyl, trifluoromethyl, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl and 3-6 membered heterocyclic group;

alternatively, R ^c And R is R ^d The atoms to which they are attached may constitute a substituted or unsubstituted group of: a C6 aryl, a 5-6 membered heteroaryl, a C5-C7 alicyclic, or a 5-7 membered heterocyclyl; wherein the substitution refers to substitution with one or more R;

R、R ¹ 、R ² 、R ³ x, Y, P, Q, G, Z, U, M, V, W, F, E are defined as in claim 1.

In another preferred embodiment, Z is CH.

In another preferred embodiment, X is O.

In another preferred embodiment, Y is NH.

In another preferred embodiment, Z is CH, X is O, and Y is NH.

In another preferred embodiment, ring a is a substituted or unsubstituted 5-6 membered aryl or heteroaryl, preferably a substituted or unsubstituted phenyl, pyridyl, pyrazinyl, thienyl, furyl, thiazolyl, imidazolyl, oxazolyl; wherein said substitution is substituted with one or more R's, R's being as defined in claim 1.

In a further preferred embodiment of the present invention,

is->

Preferably +.>

In a further preferred embodiment of the present invention,

is->

Wherein n is 0, 1, 2, 3 or 4; r is R ^a2 Is defined as above.

In another preferred embodiment, B is selected from:

in another preferred embodiment, the compound is selected from the following compounds:

in a second aspect of the invention there is provided a pharmaceutical composition comprising a therapeutically effective amount of one or more selected from the compounds of the first aspect and pharmaceutically acceptable salts thereof, and optionally a pharmaceutically acceptable carrier.

In a third aspect the present invention provides the use of a compound according to the first aspect, a pharmaceutically acceptable salt thereof, a prodrug, a hydrate or solvate thereof or a pharmaceutical composition according to the second aspect, for the manufacture of a medicament for the prophylaxis and/or treatment of a disease selected from the group consisting of:

a) Tumor-related diseases;

b) Tyrosine kinase dysfunction-related diseases.

In another preferred embodiment, the tyrosine kinase dysfunction includes, but is not limited to, AXL kinase dysfunction.

In another preferred embodiment, the tumor-associated disease is selected from the group consisting of: papilloma, bud glioma, melanoma, lung cancer (e.g., non-small cell lung cancer), ovarian cancer, prostate cancer, squamous cell carcinoma, astrocytoma, head cancer, neck cancer, bladder cancer, breast cancer, colorectal cancer, thyroid cancer, pancreatic cancer, gastric cancer, hepatocellular carcinoma, leukemia, lymphoma, hemangioma, keloids, respiratory cancer, brain cancer, genital cancer, digestive tract cancer, urinary tract cancer, eye cancer, liver cancer, skin cancer, head and neck cancer, thyroid cancer, parathyroid cancer, and distant metastases thereof, lymphoma, sarcoma, colon cancer, bone cancer, kidney cancer, testicular cancer, skin cancer, renal cell carcinoma.

In a fourth aspect of the present invention there is provided a method of the first aspect of a compound, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate or solvate thereof, wherein the method comprises: reacting the formula (Ia) with the formula (Ib) in an inert solvent in the presence of a catalyst to form a compound of formula (I);

Therein, A, B, X, Y, P, Q, Z, U, M, V, W, R ¹ 、R ² 、R ³ Is defined as in claim 1.

In a fifth aspect of the invention there is provided a method of treating a tumour associated disease, the method comprising administering to a subject a therapeutically effective amount of a compound of the first aspect, a pharmaceutical composition thereof, a pharmaceutically acceptable salt or solvate thereof.

In another preferred embodiment, the compounds of the present invention may be formulated into powders, tablets, granules, capsules, solutions, emulsions, suspensions, and the like.

It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein.

Drawings

FIG. 1 shows the growth inhibition of BaF3/TEL-AXL nude mice by compounds.

Detailed Description

Through long-term and intensive researches, the inventor unexpectedly develops a tricyclic compound with a novel structure, which can be used as a tyrosine kinase inhibitor, especially an ALX inhibitor, for resisting tumors, and has important significance in developing novel antitumor drugs. On this basis, the inventors completed the present invention.

Terminology

In the present invention, unless otherwise indicated, terms used have the ordinary meanings known to those skilled in the art.

When substituents are described by conventional formulas written from left to right, the substituents also include chemically equivalent substituents obtained when writing formulas from right to left. For example, -CH ₂ O-is equivalent to-OCH ₂ -。

In the present invention, the term "halogen" refers to F, cl, br or I.

In the present invention, the term "amino" includes NH ₂ C1-C6 alkylamino (i.e. -NH-C1-C6 alkyl or-N- (C1-C6 alkyl) ₂ ) Wherein alkyl has the definition as described above, representative examples of C1-C6 alkylamino include, but are not limited to, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino, tert-butylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, di-sec-butylamino, di-tert-butylamino, and the like.

In the present invention, the term "alkyl" by itself or as part of another substituent means a straight or branched chain hydrocarbon group having the indicated number of carbon atoms, and "C1-C6 alkyl" means a straight or branched chain alkyl group comprising 1 to 6 (e.g., including 1, 2, 3, 4, 5 or 6) carbon atoms, preferably, a C1-C3 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, neopentyl, tert-pentyl, or the like. In the present invention, alkyl is intended to include substituted alkyl.

In the present invention, the term "C1-C3 alkoxy" by itself or as part of another substituent means a straight or branched chain alkoxy group having 1 to 3 carbon atoms, having the formula C1-C3 alkyl-O-structure, including without limitation methoxy, ethoxy, propoxy, isopropoxy, and the like.

In the present invention, the term "C3-C12 cycloalkyl" by itself or as part of another substituent means a cyclic alkyl group having 3 to 12 (e.g., including 3, 4, 5, 6, 7 or 8) carbon atoms in the ring, preferably C3-C6 cycloalkyl, including, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. In the present invention, cycloalkyl is intended to include substituted cycloalkyl.

In the present invention, the term "3-12 membered heterocyclyl" refers to a 3-12 membered saturated or unsaturated heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O, S, wherein the ring system of each heterocyclyl may be monocyclic or polycyclic, including (but not limited to) the following groups: tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl, tetrahydrothienyl, piperidinyl, azetidinyl, azepanyl, morpholinyl, and the like. The heterocyclic group may be fused to an aryl, heteroaryl, heterocyclic or cycloalkyl ring (e.g., to form a [6+5], [6+6] fused ring system, etc.), wherein the ring attached to the parent structure is a heterocyclic group.

In the present invention, the term "fused ring" refers to a bicyclic ring sharing two ring atoms, e.g

Etc.

In the present invention, the term "alicyclic" refers to a saturated or unsaturated cyclic hydrocarbon group containing only carbon atoms, wherein each cyclic system may be monocyclic or polycyclic, and alicyclic includes cycloalkyl and cycloalkenyl, preferably 5-7 membered alicyclic, more preferably 6 membered alicyclic. Examples of alicyclic rings include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclohexenyl, cyclopentenyl, cyclohexadienyl, cyclopentadienyl, and the like.

In the present invention, the term "aryl" refers to an aromatic ring group containing no heteroatoms in the ring, which may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring. Such as phenyl (i.e., six-membered aromatic ring), naphthyl (i.e., [6+6] aromatic ring), and the like, wherein the six-membered aromatic ring is also intended to include six-membered aromatic ring and 5-6 membered cycloalkyl and six-membered aromatic ring and 5-6 membered heterocycloalkyl. Aryl is preferably C6-C12 aryl, more preferably C6-C10 aryl. Examples of aryl groups include phenyl, naphthyl. Aryl groups may be optionally substituted or unsubstituted.

In the present invention, the term "heteroaryl (ring)" refers to a heteroaromatic group containing 1, 2 or 3 heteroatoms selected from N, O, S, the ring system of the heteroaryl group may be monocyclic or polycyclic (including fused ring forms). In the present invention, heteroaryl and heteroaryl rings are used interchangeably, preferably 5-12 membered heteroaryl, more preferably 5-10, more preferably 5-6 membered heteroaryl non-limiting examples include: pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazolyl, purine, carbazole, indolyl, indazolyl, benzothienyl, benzofuranyl, benzimidazolyl, benzotriazole, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, isomerized quinolinyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl, naphthyridinyl, tetrazolyl, and the like. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring. The term "[6+5+6] aromatic heterocycle" refers to a fused 6, 5, 6 tricyclic ring system such as dibenzo [ b, d ] thiophene, and the term "[6+5] aromatic heterocycle" refers to a fused 6, 5 bicyclic ring system such as benzothienyl, benzofuranyl, benzimidazolyl, benzotriazole, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, "[6+6] aromatic heterocycle", "[5+5] aromatic heterocycle, or fused ring" has similar meaning. Heteroaryl groups may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxy, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylthio, oxo, amido, sulfonamide, formyl, carboxamide, carboxyl, carboxylate and the like. In the present invention, the "heteroaryl ring", "aromatic heterocycle", "heteroaryl" have the same meaning as the substituents.

In the present invention, the term "C1-C3 alkyl-C6-C12 aryl" refers to a C1-C3 alkyl group substituted with a C6-C12 aryl group, such as benzyl. C1-C3 alkyl 5-12 membered heteroaryl, C1-C3 alkyl C3-C12 cycloalkyl, C1-C3 alkyl 3-12 membered heterocyclyl have similar meanings.

In the present invention, the term "formyl" refers to a group comprising-CHO.

In the present invention, the term "hydroxy" refers to-OH.

In the present invention, the term "carboxyl group" means-COOH.

In the present invention, the term "cyano" -CN.

In the present invention, the term "substituted" means that one or more hydrogen atoms on a particular group are replaced with a particular substituent. The specific substituents are those described in the foregoing for each of the examples or are those found in each of the examples. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substitutable site of the group, which may be the same or different at each position. Those skilled in the art will appreciate that combinations of substituents contemplated by the present invention are those that are stable or chemically achievable.

In the present invention, the term "plurality" independently means 2, 3, 4, 5.

Active ingredient

As used herein, the term "compound of the invention" or "active ingredient of the invention" is used interchangeably to refer to a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound (e.g., deuterated compound) or prodrug thereof. The term also includes racemates and optical isomers.

Preferably, the tricyclic compounds of formula (I), (II), (III), (VI), (V), (VI) of the present invention are selected from the compounds in table 1 below:

TABLE 1

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Pharmaceutically acceptable salts

The term "pharmaceutically acceptable salt" refers to salts (including zwitterionic and like internal salts) that have efficacy similar to the parent compound and are biologically or otherwise acceptable (e.g., are neither toxic nor harmful to the subject). Accordingly, embodiments of the present invention provide pharmaceutically acceptable salts of the compounds of the present invention. The term "salt" as used herein means any of the following acid salts formed from inorganic and/or organic acids, as well as basic salts formed from inorganic and/or organic bases. Salts of the compounds of the invention may be formed by methods known to those of ordinary skill in the art, for example, by reacting a compound of the invention with an amount of an acid or base (e.g., an equivalent amount of an acid or base) in a medium (e.g., such medium may allow precipitation of the salt therein; or with water as a medium followed by lyophilization).

Exemplary acid salts include acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, fumarate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, methylsulfonate ("mesylate"), naphthalenesulfonate, nitrate, oxalate, phosphate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, tosylate, and the like. Suitable acid salts may be prepared by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid (e.g., hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, or benzoic acid). Furthermore, acids suitable for forming pharmaceutically acceptable salts are also selected from the following references: (1) stahl et al, camill G (eds.) Handbook of Pharmaceutical salts properties, selection and use (2002); (2) zurich, wiley-VCH.S. bergel al, journal of Pharmaceutical Sciences (1977) 66 (1), 1-19; (3) gould, international J.of pharmaceuticals (1986) 33,201-217; (4) anderson el al, the Practice of Medicinal Chemistry (1996), academic Press, new York; (5) the Orange Book (Food & Drug Administration, washing, D.C. on The same web site).

Exemplary basic salts include ammonium salts, alkali metal salts (e.g., sodium, lithium, and potassium salts), alkaline earth metal salts (e.g., calcium and magnesium salts), salts containing organic bases (e.g., organic amines) (e.g., dicyclohexylamine), t-butylamine, choline, and salts with amino acids (e.g., arginine, lysine), and the like. Basic nitrogen-containing groups can form quaternary ammonium salts with, for example, lower alkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g., decyl, lauryl, and stearyl chlorides, bromides, and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others. The compounds bearing acidic groups can be mixed with suitable pharmaceutically acceptable salts to prepare alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), and salts formed from suitable organic ligands (e.g., quaternary ammonium salts). In addition, pharmaceutically acceptable esters can be used to improve the solubility or hydrolytic properties of the compounds in the presence of carboxyl or hydroxyl groups.

All such acid and base salts are pharmaceutically acceptable salts within the scope of the invention and, for the purposes of this invention, are considered equivalent to the corresponding parent compounds of the invention.

In addition, when the compounds of the present invention contain both basic groups (such as, but not limited to, primary, secondary, tertiary aliphatic or cyclic amines, aromatic or heteroaryl amines, pyridines or imidazoles) and acidic groups (such as, but not limited to, tetrazoles or carboxylic acids), the zwitterionic species that can be formed ("inner salts") are also encompassed within the term "salts" of the present patent. Certain compounds of the invention may exist in zwitterionic form, having both anionic and cationic centers in the same compound, and having a net neutral charge, such zwitterionic also being encompassed by the invention.

Tyrosine kinase

Process for the preparation of compounds

Several methods for preparing the compounds of formula (I), (II), (III), (IV), (V), (VI) and pharmaceutically acceptable salts thereof are described in the schemes and examples below. The starting materials and intermediates are purchased from commercial sources, manufactured by known procedures, or otherwise described. In some cases, the order of the steps of the reaction scheme may be altered to promote the reaction or to avoid unwanted side reaction products.

Subjecting a compound of formula (Ia) and formula (Ib) to a condensation reaction in the presence of a condensing agent, thereby forming a compound of formula (I);

the condensing agent includes, but is not limited to EDCI (CAS number: 25952-53-8), HATU (CAS number: 148893-10-1), HBTU (CAS number: 94790-37-1), BOP (CAS number: 56602-33-6);

therein, A, B, X, Y, P, Q, Z, U, M, V, W, R ¹ 、R ² R3 is as defined above.

Application method

The therapeutically useful compounds of the present invention include, for example, compounds of formula (I), (II), (III), (IV), (V), (VI). The compounds of examples 1 to 33 and pharmaceutically acceptable salts of the above compounds are administered to patients for the purpose of inhibiting tyrosine kinase activity and/or anti-tumor. The term "administering" refers to providing a compound to a person in need of treatment. When a compound of this patent is administered in combination with one or more other drugs (e.g., other antineoplastic drugs), the term "administering" refers to providing the patient with a combination of a compound of this patent, a pharmaceutically acceptable salt thereof, and the other drug.

The compounds disclosed in this patent may be tyrosine kinase inhibitors. These compounds are useful in the treatment of diseases or disorders including, but not limited to, cell proliferation disorders. Cell proliferation disorders include, but are not limited to, cancer, benign papillomatosis, gestational trophoblastic disease, and benign neoplastic diseases, such as papillomas (warts) and genital papillomas.

In particular embodiments, the disease or disorder to be treated is a cell proliferation disorder. In certain embodiments, the cell proliferative disorder is cancer. In specific embodiments, the cancer is selected from brain and spinal cancers, head and neck cancers, leukemia and blood cancers, skin cancers, cancers of the reproductive system, cancers of the gastrointestinal system, cancers of the liver and bile ducts, renal and bladder cancers, bone cancers, lung cancers, malignant mesothelioma, sarcomas, lymphomas, adenocarcinomas, thyroid cancers, cardiac tumors, germ cell tumors, malignant neuroendocrine (carcinoid) tumors, midline tract cancers, and unidentified primary cancers (i.e., metastatic cancers are found but the primary foci of cancer are not yet known). In certain embodiments, the cancer is present in an adult patient; in other embodiments, the cancer is present in a pediatric patient. In certain embodiments, the cancer is associated with aids.

In particular embodiments, the cancer is selected from brain cancer and spinal cancer. In particular embodiments, the cancer is selected from anaplastic astrocytoma, glioblastoma, astrocytoma, and estuary neuroblastoma (also known as olfactory blastoma). In particular embodiments, the brain cancer is selected from astrocytomas (e.g., capillary astrocytomas, subependymal giant astrocytomas, diffuse astrocytomas, polymorphic yellow astrocytomas, anaplastic astrocytomas, giant glioblastomas, secondary glioblastomas, primary adult glioblastomas), primary childhood glioblastomas, oligodendrogliomas (e.g., oligodendrogliomas, anaplastic oligodendrogliomas), oligodendroastrocytomas (e.g., oligodendroastrocytomas, anaplastic oligodendroastrocytomas), ependymomas (e.g., mucinous papillary medulloblastomas and anaplastic ependymomas), medulloblastomas, primitive extraneuroblastomas, schwannomas, meningiomas; atypical meningiomas, anaplastic meningiomas, pituitary adenomas, brain stem gliomas, cerebellar astrocytomas, brain astrocytomas/glioblastomas, optic nerve pathways and hypothalamic gliomas and primary central nervous system lymphomas. In specific examples of these embodiments, the brain cancer is selected from glioma, glioblastoma multiforme, paraganglioma, and supratentorial primary neuroectodermal tumor (SPNET).

In particular embodiments, the cancer is selected from head and neck cancers, including nasopharyngeal cancers, nasal and paranasal sinus cancers, hypopharyngeal cancers, oral cancers (e.g., squamous cell cancers, lymphomas and sarcomas), lip cancers, oropharyngeal cancers, salivary gland tumors, laryngeal cancers (e.g., laryngeal squamous cell cancers, rhabdomyosarcoma), and eye cancers. In particular embodiments, the eye cancer is selected from intraocular melanoma and retinoblastoma.

In particular embodiments, the cancer is selected from leukemia and hematological cancer. In particular embodiments, the cancer is selected from myeloproliferative neoplasms, myelodysplastic syndrome, myelodysplastic/myeloproliferative neoplasms, acute Myelogenous Leukemia (AML), myelodysplastic syndrome (MDS), chronic Myelogenous Leukemia (CML). Myeloproliferative neoplasms (MPNs), post-MIPN acute myelogenous leukemia, post-MDS acute myelogenous leukemia, del (5 q) -associated high-risk MDS or AML, advanced chronic myelogenous leukemia, angioimmunoblastic lymphoma, acute lymphoblastic leukemia, langrans cell histiocytosis, hairy cell leukemia, plasmacytoma including plasmacytoma and multiple myeloma. The leukemias referred to herein may be acute or chronic.

In particular embodiments, the cancer is selected from skin cancer. In particular embodiments, the skin cancer is selected from melanoma, squamous cell carcinoma, and basal cell carcinoma.

In a specific embodiment, the cancer is selected from cancers of the reproductive system. In particular embodiments, the cancer is selected from breast cancer, cervical cancer, vaginal cancer, ovarian cancer, prostate cancer, penile cancer, and testicular cancer. In particular examples of these embodiments, the cancer is a breast cancer selected from the group consisting of ductal cancer and phyllostatic tumor. In particular examples of these embodiments, the breast cancer may be a male breast cancer or a female breast cancer. In particular examples of these embodiments, the cancer is cervical cancer selected from squamous cell carcinoma and adenocarcinoma. In particular examples of these embodiments, the cancer is ovarian cancer selected from epithelial cancers.

In particular embodiments, the cancer is selected from cancers of the gastrointestinal system. In particular embodiments, the cancer is selected from the group consisting of esophageal cancer, gastric cancer, gastrointestinal carcinoid, pancreatic cancer, gall bladder cancer, colorectal cancer, and anal cancer. In examples of these embodiments, the cancer is selected from the group consisting of esophageal squamous cell carcinoma, esophageal adenocarcinoma, gastric adenocarcinoma, gastrointestinal carcinoid, gastrointestinal stromal tumor, gastric lymph Kong Liu, gastrointestinal lymphoma, pancreatic solid pseudopapilloma, pancreatic blastoma, islet cell tumor, pancreatic cancer including acinar cell carcinoma and ductal adenocarcinoma, cholecystokinase adenocarcinoma, large intestine adenocarcinoma, and anal squamous cell carcinoma.

In particular embodiments, the cancer is selected from liver and bile duct cancers. In a particular embodiment, the cancer is liver cancer (also known as hepatocellular carcinoma). In particular embodiments, the cancer is cholangiocarcinoma; in examples of these embodiments, the cholangiocarcinoma is selected from intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma.

In particular embodiments, the cancer is selected from kidney cancer and bladder cancer. In particular embodiments, the renal cancer is selected from renal cell carcinoma, wilms' cell carcinoma, and transitional cell carcinoma. In particular embodiments, the bladder cancer is selected from urothelial cancer (transitional cell carcinoma), squamous cell carcinoma, and adenocarcinoma.

In particular embodiments, the cancer is selected from bone cancer. In particular embodiments, the bone cancer is selected from osteosarcoma, osteomalignant fibrous histiocytoma, ewing's sarcoma, chordoma (bone cancer along the spine).

In particular embodiments, the cancer is selected from lung cancer. In particular embodiments, the lung cancer is selected from the group consisting of non-small cell lung cancer, bronchogenic tumors, and pleural pneumoblastoma.

In particular embodiments, the cancer is selected from malignant mesothelioma. In particular embodiments, the cancer is selected from the group consisting of epithelial mesothelioma and sarcoma.

In particular embodiments, the cancer is selected from sarcomas. In particular embodiments, the sarcoma is selected from the group consisting of central chondrosarcoma, central and periosteal osteosarcoma, fibrosarcoma, tenosynovial clear cell sarcoma, and kaposi's sarcoma.

In particular embodiments, the cancer is selected from lymphomas. In particular embodiments, the cancer is selected from hodgkin's lymphoma (e.g., reed Sternberg cells), non-hodgkin's lymphoma (e.g., diffuse large B-cell lymphoma, follicular lymphoma, mycosis fungoides, SZAREY syndrome, primary central nervous system lymphoma), cutaneous T-cell lymphoma, primary central nervous system lymphoma.

In particular embodiments, the cancer is selected from adenocarcinomas. In particular embodiments, the cancer is selected from the group consisting of adrenocortical carcinoma, pheochromocytoma, paraganglioma, pituitary tumor, thymoma, and thymoma.

In particular embodiments, the cancer is selected from thyroid cancer. In particular embodiments, the thyroid cancer is selected from medullary thyroid cancer, papillary thyroid cancer, and follicular thyroid cancer.

In particular embodiments, the cancer is selected from germ cell tumors. In particular embodiments, the cancer is selected from malignant extracranial germ cell tumors and malignant extragonadal germ cell tumors. In particular examples of these embodiments, the malignant extragonadal germ cell tumor is selected from the group consisting of non-seminomas and seminomas.

In certain embodiments, the cancer is selected from cardiac tumors. In particular embodiments, the cardiac tumor is selected from the group consisting of malignant teratoma, lymphoma, rhabdomyosarcoma, hemangiosarcoma, chondrosarcoma, infantile fibrosarcoma, and synovial sarcoma.

In particular embodiments, the cell proliferation disorder is selected from benign papillomatosis, benign tumor disease, and gestational trophoblastic disease. In particular embodiments, the benign neoplastic disease is selected from the group consisting of cutaneous papillomas (warts) and genital papillomas. In particular embodiments, the gestational trophoblastic disease is selected from the group consisting of a phonophora and a gestational trophoblastic tumor (e.g., invasive mole, choriocarcinoma, placental trophoblastic tumor, and epithelioid trophoblastic tumor).

The term "treatment" as used herein refers to all processes in which there may be a slowing, interrupting, arresting, controlling, or stopping of the progression of the diseases or disorders described herein. These terms do not necessarily indicate complete elimination of all disease or disorder symptoms.

The term "administering" is understood to include providing a subject with a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above.

The amount of compound administered to the subject is an amount sufficient to inhibit tyrosine kinase activity and thereby exert anti-tumor activity. In one embodiment, the amount of the compound may be an "effective amount" or a "therapeutically effective amount" that will elicit the biological or medical (i.e., treatment-related) response of a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician. In one embodiment, the amount of the compound may be an "effective amount" or a "therapeutically effective amount" such that the amount of the test compound administered will cause, respectively, a tissue, system, animal, or person sought by a researcher, veterinarian, medical doctor or other clinician. The effective amount is not necessarily based on toxicity and safety considerations associated with the administration of the compound.

The effective amount of the compound will vary with the particular compound selected (e.g., considering the activity, efficacy, and/or half-life of the compound); a mode of administration; the severity of the condition being treated and the condition being treated; age, size, weight and physical condition of the subject to be treated; a medical history of the subject; duration of treatment; nature of the co-therapy; a desired therapeutic effect; and similar factors that may be determined by one of skill in the art.

The compounds disclosed herein may be administered by any suitable route, including oral and non-oral administration. Parenteral administration is typically by injection or infusion, including intravenous, intramuscular, and subcutaneous injection or infusion.

The compounds of the present disclosure may be administered at one time or according to a dosing regimen, wherein multiple doses are administered at different time intervals over a given period of time. For example, the administration may be once, twice, three times or four times daily. The dosage is administered until the desired therapeutic effect is achieved or maintained indefinitely. The reasonable dosing regimen of the compounds disclosed herein depends on the pharmacokinetic properties of the compound, such as absorption, distribution, and half-life, which properties can be determined by one of skill in the art. Furthermore, for the compounds disclosed herein, a reasonable dosage regimen, including the duration of administration of the regimen, depends on the disease or condition being treated, the severity of the disease or condition, the age and physical condition of the subject being treated, the medical history of the subject being treated, the nature of the co-therapy, the desired therapeutic effect, and like factors within the knowledge and expertise of those skilled in the art. Those skilled in the art will adapt a given dosing regimen based on the individual subject's response to the dosing regimen, or in accordance with the individual subject's needs. Typical daily dosages may vary with the particular route of administration selected.

An embodiment of the invention provides a method of treating a cell proliferative disorder comprising administering to a subject a therapeutically effective amount of a compound of formula (I), (II), (III), (IV), (V), (VI), or a pharmaceutically acceptable salt of the above. In particular embodiments, the disease or disorder to be treated is a cell proliferation disorder. In a specific implementation of these examples, the cell proliferation disorder is cancer. Wherein the cancer is selected from brain and spine cancer, head and neck cancer, leukemia and blood cancer, skin cancer, cancer of the reproductive system, cancer of the gastrointestinal system, cancer of the liver and bile duct, renal and bladder cancer, bone cancer, lung cancer, malignant mesothelioma, sarcoma, lymphoma, adenocarcinoma, thyroid cancer, heart tumor, germ cell tumor, malignant neuroendocrine (carcinoid) tumor, midline bundle cancer and primary tumor of unknown origin.

In one embodiment, disclosed herein is a pharmaceutical use of a compound of formula (I), (II), (III), (IV), (V), (VI), or a pharmaceutically acceptable salt. The primary therapeutic effect of the compound is to inhibit tyrosine kinase activity in a subject (e.g., a mammal) by administering to the subject an effective amount of the compound.

One embodiment disclosed herein is a pharmaceutical composition comprising at least one compound of formula (I), (II), (III), (IV), (V), (VI), or at least one pharmaceutically acceptable salt of the above compound for inhibiting tyrosine kinase activity.

One embodiment disclosed herein is the use of a compound of formula (I), (II), (III), (IV), (V), (VI), or a pharmaceutically acceptable salt thereof, for the preparation of a medicament having tyrosine kinase inhibitory activity. In embodiments, the disease or disorder to be treated is a cell proliferation disorder. In a specific embodiment of these examples, the cell proliferation disorder is cancer. Wherein the cancer is selected from brain and spinal cancer, head and neck cancer, leukemia and blood cancer, skin cancer, cancer of the reproductive system, cancer of the gastrointestinal system, liver cancer and bile duct cancer, kidney cancer, bladder cancer, bone cancer, lung cancer, malignant mesothelioma, sarcoma, lymphoma, adenocarcinoma, thyroid cancer, heart tumor, germ cell tumor, malignant neuroendocrine (carcinoid) tumor, midline tract cancer, and primary cancer of unknown origin.

Pharmaceutical composition

The term "pharmaceutical composition" refers to a dosage form comprising a specified amount of a specified compound, as well as any dosage form that is prepared directly or indirectly from a specified amount of a specified compound. The term includes dosage forms comprising a compound of formula (I), (II), (III), (IV), (V), (VI) or a pharmaceutically acceptable salt of the above compound, and one or more pharmaceutically acceptable carriers or excipients. Thus, the disclosed pharmaceutical compositions comprise any pharmaceutical dosage form of a compound of the invention admixed with one or more pharmaceutically acceptable carriers or excipients. The term "pharmaceutically acceptable" means that the carrier or adjuvant is compatible with the compounds and other ingredients of the pharmaceutical compositions disclosed herein.

In order to inhibit the activity of tyrosine kinase, the compounds of formula (I), (II), (III), (IV), (V), (VI) or pharmaceutically acceptable salts of the compounds are formulated with corresponding carriers or adjuvants. These compounds may be administered in conventional manner with other drugs, either as stand alone therapeutic agents or in combination with other drugs. These compounds may be administered alone, but are generally administered by selecting the drug carrier according to the chosen route of administration and standard pharmaceutical practice.

In one embodiment, the pharmaceutical compositions disclosed herein comprise a compound of formula (I), (II), (III), (IV), (V), (VI), or a pharmaceutically acceptable salt of the above compound, and one or more pharmaceutically acceptable carriers or excipients. The pharmaceutical compositions may be prepared in large packages in which a therapeutically effective dose of the compounds of the invention may be provided and then administered to a subject, such as a powder or syrup. Alternatively, the pharmaceutical compositions may be prepared in unit package form, wherein each individual package comprises a therapeutically effective amount of a compound of formula (I), (II), (III), (IV), (V), (VI), or a pharmaceutically acceptable salt of the above.

The compounds of the present disclosure and pharmaceutically acceptable carriers or excipients are formulated into a suitable dosage form for administration to a subject in a rational manner of administration. Dosage forms include (1) oral dosage forms such as tablets, capsules, tablets, pills, tablets, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets and ointments; (2) Parenteral administration, such as sterile solutions, suspensions, and reconstituted powders. Suitable pharmaceutically acceptable carriers or excipients are determined by the particular dosage form selected. Furthermore, the choice of pharmaceutically acceptable carrier or adjuvant will also depend on the particular function in the pharmaceutical composition. For example, certain pharmaceutically acceptable carriers or excipients can be selected to facilitate the production of a unified dosage form; certain pharmaceutically acceptable carriers or excipients are selected to aid in the production of stable dosage forms; certain pharmaceutically acceptable carriers or excipients facilitate transport or concordance of the compounds disclosed herein from one organ or body part of a subject to another organ or body part of the subject; certain pharmaceutically acceptable carriers or excipients may be selected to enhance patient compliance.

Suitable pharmaceutically acceptable excipients include the following types: diluents, lubricants, binders, disintegrants, fillers, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, flavor masking agents, colorants, anti-caking agents, hemostatic agents, chelating agents, plasticizers, tackifiers, antioxidants, preservatives, stabilizers, surfactants, and buffers.

Those skilled in the art will have knowledge and skills in the art to select suitable pharmaceutically acceptable carriers and excipients to prepare pharmaceutical compositions of the compounds of the present invention. The following documents describe pharmaceutically acceptable carriers and excipients for reference to those skilled in the art: (1) REMINGTON' S PHARMACEUTICAL SCIENCES (Mack Publishing Company); (2) THE HANDBOOK OF PHARMACEUTICAL ADDITIVES (Gower Publishing Limited); (3) THE HANDBOOK OF PHARMACEUTICAL EXCIPIENTS (the American Pharmaceutical Association and the Pharmaceutical Press).

The pharmaceutical compositions of the present invention are prepared using techniques and methods known to those skilled in the art. Methods commonly used in the art are generally described in Remington's Pharmaceutical Sciences (Mack Publishing Company).

In one embodiment, the present invention relates to a solid oral dosage form, such as a tablet or capsule, comprising a therapeutically effective amount of a compound of formula (I), (II), (III), (IV), (V), (VI), or a pharmaceutically acceptable salt of the above, and a diluent or filler. Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starches (e.g., corn starch, potato starch and pregelatinized starch), cellulose and its derivatives (e.g., microcrystalline cellulose), calcium sulfate and monocalcium phosphate. The solid oral dosage form may also include a binder. Suitable binders include starches (e.g., corn starch, potato starch, and pregelatinized starch), gelatin, gum arabic, sodium alginate, alginic acid, astragalus root, guar gum, povidone, cellulose and derivatives thereof (e.g., microcrystalline cellulose). The solid oral dosage form may further include disintegrants including cilobrone, sodium starch glycolate, croscarmellose, alginic acid and sodium carboxymethylcellulose. The solid oral dosage form may also include a lubricant. Suitable lubricants include stearic acid, magnesium stearate, calcium stearate and talc.

Formulations for oral administration may be microencapsulated where appropriate. The composition may also be prepared to prolong or sustain release, for example, by coating or embedding particulate materials in polymers, waxes, and the like.

The compounds disclosed herein may also be coupled to soluble polymers as targeted drug carriers. Such polymers include polyvinylpyrrolidone, pyrrole polymers, polyhydroxypropyl methacrylamidophenol, polyhydroxyethyl aspartophenol or polyvinylalkoxypolylysine substituted by palmitoyl residues. In addition, the compounds of the present invention may be coupled to a class of biodegradable polymers useful for controlled release of drugs, such as polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and hydrogel cross-linked or amphiphilic block copolymers.

In one embodiment, the present invention relates to a liquid oral dosage form. Oral solutions, such as solutions, syrups and pellets, may be prepared in unit dosage form to provide a subject with a predetermined amount of the compound or pharmaceutically acceptable salt thereof. Syrups can be prepared by dissolving the compounds of this patent in a suitably flavored aqueous solution, and preparing the medicament by using a non-toxic alcohol carrier. Suspensions can be formulated in a nontoxic transporter by dispersing a compound disclosed in this patent. Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavor additives such as peppermint oil, or other natural sweeteners or saccharin or other artificial sweeteners and the like may also be added.

In one embodiment, the invention also relates to a pharmaceutical composition for parenteral administration. Ingredients suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous sand nonaqueous sterile suspensions, which may include suspending agents and thickening agents. The ingredients may be presented in unit-dose or multi-dose containers, such as sealed ampoules and vials, and may be stored in a freeze-dried condition requiring only the addition of the sterile liquid carrier, such as water for injection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.

Combination drug

The compounds of formula (I), (II), (III), (IV), (V), (VI) and/or pharmaceutically acceptable salts thereof may be used in combination with one or more other active agents. In particular embodiments, one or more compounds of formula (I), (II), (III), (IV), (V), (VI), or pharmaceutically acceptable salts of one or more of the above compounds and one or more other active agents may be co-administered. The additional active agent may be administered in a single dosage form with the compound of formula (I), (II), (III), (IV), (V), (VI) or a pharmaceutically acceptable salt of the above compound, or the formulation of the additional active agent may be administered separately from the dosage form containing the compound of formula (I), (II), (III), (IV), (V), (VI) or a pharmaceutically acceptable salt of the above.

Other active agents may be administered as pharmaceutically acceptable salts where appropriate.

The other active agent may be one or more selected from tyrosine kinase inhibitors, anticancer agents, chemotherapeutic agents, immunomodulators, immune checkpoint inhibitors, vascular growth factor (VEGF) receptor inhibitors, topoisomerase II inhibitors, alkylating agents, antitumor antibiotics, retinoic acid and immunomodulators (including but not limited to anti-cancer vaccines). It will be appreciated that such other active agents may be provided as pharmaceutically acceptable salts; it will be appreciated that the description of the other active agents described above may be repeated; it will also be appreciated that these combination regimens are to be optimized, i.e., the combination of the compounds of formulae (I), (II), (III), (IV), (V), (VI) or the pharmaceutically acceptable salts of the foregoing and one or more other active agents will be determined according to the needs of the individual patient.

The compounds of the present disclosure may be used in combination with one or more other active agents, including, but not limited to, other anti-cancer agents for preventing, treating, controlling, ameliorating or reducing the risk of a particular disease or disorder (e.g., a cell proliferation disorder). In one embodiment, the compounds of the present disclosure are used in combination with one or more other anti-cancer agents for preventing, treating, ameliorating or reducing the risk of a particular disease or disorder, wherein the compounds of the present disclosure are effective such that the other active agents can be administered simultaneously or sequentially with the compounds of the present disclosure by a particular mode of administration and dosage.

When the compounds of the present disclosure are used concurrently with one or more other active agents, such pharmaceutical compositions comprising other active agents in addition to the compounds disclosed herein are also within the scope of protection. Thus, the pharmaceutical compositions of the present patent disclosure contain one or more additional active agents in addition to the active compound of the present patent. Further disclosed are compounds disclosed herein. The compounds of the present disclosure may be administered simultaneously with or before or after one or more other active agents. The compounds disclosed herein may be administered alone in the same or different modes of administration as the other active agents, or may be administered simultaneously with the pharmaceutical compositions of the other active agents.

The pharmaceutical composition disclosed in the present patent may be a pharmaceutical composition comprising a compound of formula (I), (II), (III), (IV), (V), (VI) or a pharmaceutically acceptable salt of the foregoing compound, and one or more other active agents; it may also be a pharmaceutical composition comprising a compound of formula (I), (II), (III), (IV), (V), (VI), or a pharmaceutically acceptable salt thereof, in combination with one or more other active agents, alone or in kit form, or in any form for simultaneous or separate administration as intended.

The weight ratio of the compounds of formula (I), (II), (III), (IV), (V), (VI) or pharmaceutically acceptable salts of the foregoing compounds to the other active agents is variable and will depend on the therapeutically effective dose of the individual agents. Typically, a therapeutically effective dose of each drug will be used. The combination of the compounds disclosed in this patent with other active agents should generally be within the weight ranges described above, but in each case a therapeutically effective dose of each active agent should be used. In such combinations, the compounds disclosed herein and the other active agents may be administered separately or simultaneously. Furthermore, the administration of a single drug may be performed before, simultaneously with, or after the administration of other drugs.

In one embodiment, the present invention provides a composition comprising a compound of formula (I), (II), (III), (IV), (V), (VI) or a pharmaceutically acceptable salt of the foregoing compound, and at least one other active agent as a combined preparation for simultaneous, separate or sequential use. In one embodiment, the therapy is used to treat a cell proliferation disorder, such as cancer.

In one embodiment, the invention provides a kit comprising two or more separate pharmaceutical compositions, at least one of which comprises a compound of formula (I), (II), (III), (IV), (V), (VI) or a pharmaceutically acceptable salt of the foregoing. In particular embodiments, the kit comprises means for separately retaining the compositions, such as containers, split-bottles or split-oil packs. An example of such a kit is a blister pack, typically used for the packaging of tablets, capsules and the like.

The kits of the invention may be used for administration of different dosage forms, e.g. oral and parenteral, for administration of separate pharmaceutical compositions at different dosage intervals, or for titration of separate pharmaceutical compositions against each other. For ease of compliance, such kits typically contain instructions for administration.

The invention discloses the use of compounds of formula (I), (II), (III), (IV), (V), (VI) or pharmaceutically acceptable salts of the above compounds for the treatment of cell proliferation disorders by combination with another active agent. The invention also provides other active agents useful in the treatment of cell proliferative disorders by administering a compound of formula (I), (II), (III), (IV), (V), (VI) or a pharmaceutically acceptable salt of the compound.

The invention also provides the use of a compound of formula (I), (II), (III), (IV), (V), (VI) or a pharmaceutically acceptable salt of the above compound for the treatment of a cell proliferation disorder, wherein the patient has previously been treated (e.g. within 24 hours) with another active agent. The invention also provides other active agents for treating cell proliferative disorders, wherein the patient has been previously treated (e.g., within 24 hours) with a compound of formula (I), (II), (III), (IV), (V), (VI) or a pharmaceutically acceptable salt of the foregoing compound. The second agent may be administered one week, several weeks, one month or several months after administration.

Tyrosine kinase inhibitors the tyrosine kinase inhibitors referred to herein include, but are not limited to, EGFR inhibitors (e.g., afatinib, dacatinib, vandetanib, lenatinib, octeninib, etc.), ALK inhibitors, and the like, for use in combination with compounds of formula (I), (II), (III), (IV), (V), (VI) or pharmaceutically acceptable salts of the foregoing compounds.

CLTA4 and PD-1 pathways are important negative regulators of immune responses. Activated T cells up-regulate CTLA-4, which binds antigen-presenting cells and inhibits T cell activation, IL-2 gene expression and T cell proliferation, which are observed in colon cancer, metastatic prostate cancer and metastatic melanoma mouse models. PD-1 binds to active T cells and inhibits T cell activation, and PD-1 antagonists have also demonstrated antitumor effects. CTLA-4 and PD-1 antagonists, including ipilimumab, tremelimumab, nivolumab, pembrolizumab, CT-011, AMP-224 and MDX-1106, may be administered in combination with a compound of formula (I), (II), (III), (IV), (V), (VI) or a pharmaceutically acceptable salt thereof.

By "PD-1 antagonist" or "PD-1 pathway antagonist" is meant any compound or biological macromolecule that prevents the binding of PD-L1 expressed on a cancer cell to PD-1 expressed on an immune cell (T cell, B cell or NKT cell) while also favoring the prevention of the binding of PD-L2 expressed on a cancer cell to PD-1 expressed on an immune cell. Names that are synonymous with PD-1 also include: PDCD1, PD1, CD279 and SLEB2; names that are synonymous with PD-L1 also include: PDCD1L1, PDL1, B7H1, B7-4, CD274 and B7-H; names that are synonymous with PD-L2 also include: PDCD1L2, PDL 2B 7-DC, btdc, and CD273. In any of the methods of treatment, medicaments and uses of the invention for treating humans, the PD-1 antagonist blocks the binding of human PD-L to human PD-1, in particular blocks the binding of human PD-L1 and PD-L2 to human PD-1. Human PD-1 amino acid sequences can be found in NCBI library No.: NP-005009; human PD-L1 and PD-L2 amino acid sequences can be found in NCBI library No. NP-054862 and NP-079515, respectively.

PD-1 antagonists, including monoclonal antibodies or antigen-binding fragments thereof, specifically bind to PD-1 or PD-L1, and preferably specifically bind to human PD-1 or human PD-L1, can be used in combination with any of the therapeutic methods, medicaments and uses disclosed in this patent. The monoclonal antibody may be a human antibody, a humanized antibody or a chimeric antibody, and may include a human constant region. In some embodiments, the human constant region is selected from the group consisting of IgG1, igG2, igG3, and IgG4, and in preferred embodiments, the human constant region is IgG1 or IgG4. In some embodiments, the antigen binding fragment is selected from the group consisting of Fab, fab '-SH, F (ab') ₂ scFv and Fv fragments.

Examples of monoclonal antibodies that bind to human PD-1 and are used in combination with the methods of treatment, medicaments and uses disclosed herein are described in the following patents: US7488802, US7521051, US8008449, US8354509, US8168757, WO2004/004771, WO2004/072286 and WO2004/056875.

Examples of monoclonal antibodies that bind to human PD-L1 and are useful in combination with the methods of treatment, medicaments and uses of the invention are described in patents W02013/019906, W02010/077634A1 and U.S. Pat. No. 8383796, and include MPDL3280A, BMS-936559, MEDI4736 and MSB0010718C; patent WO2013/019906 also discloses an antibody against PD-L1 comprising a heavy chain region (SEQ ID NO: 24) and a light chain variable region (SEQ ID NO: 21).

Other PD-1 antagonists that may be used in combination with any of the therapeutic methods, medicaments and uses disclosed in this patent include immunoadhesions that specifically bind to PD-1 or PD-L1, and preferably specifically bind to human PD-1 or human PD-L1, e.g., fusion proteins containing an extracellular segment, or PD-1 binding portions of PD-L1 or PD-L2 are fused to a constant region of an immunoglobulin molecule, such as an Fc region. Examples of immunoadhesion molecules that specifically bind to PD-1 are described in patents WO2010/027827 and WO 2011/066342. Specific fusion proteins of PD-1 antagonists that can be used in combination with the methods of treatment, medicaments and uses of the invention include AMP-224 (also known as B7-DCIg), which is a PD-L2-FC fusion protein that binds to human PD-1.

Cytotoxic agents that may be used in combination with a compound of formula (I), (II), (III), (IV), (V), (VI) or a pharmaceutically acceptable salt of the foregoing compounds include, but are not limited to, arsenic trioxide (trade name:

) Asparaginase (also known as L-asparaginase, and Erwinia L-asparaginase, trade name +.>

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)。

The compounds of formula (I), (II), (III), (IV), (V), (VI) or pharmaceutically acceptable salts of the foregoing compounds may be used in combination with chemotherapeutic agents including abiraterone acetate, acitretin, dehydrovinblastine, olo Sha Liting, bexarotene, bicalutamide, BMS 184536, 2,3,4,5, 6-pentafluoro-N- (3-fluoro-4-methoxyphenyl) benzenesulfonamide, bleomycin, N, N-dimethyl-L-valine-N-methyl-L-valine-L-prolyl-1-proline-tert-butylamine, tumor necrosis factor, gibberellin, chloro Ding Babi, cyclophosphamide, docetaxel, carboplatin, carmustine, cisplatin, nostalgin, cytarabine, dacarbazine, dactinomycin, daunorubicin, decitabine, dolastatin, doxorubicin, etoposide, 5-fluorouracil, finasteride, flutamide, hydroxyurea, ifosfamide, lioxazolamide, lomethamine, rhodamine, MDV3100, sinapine (nitrogen mustard), melphalan, milbezoamide, rhizopus, streptavidine, mitomycin, methotrexate, taxanes, nilutamide, nivalizumab, olanpride, pralidoxime, methyl (yl) benzyl, RPR10981, estramustine phosphate, tazidine, tazizanol, vindesine, vinblastine, and vincristine. Where appropriate, these chemotherapeutic agents may be administered in the form of pharmaceutically acceptable salts.

Examples of Vascular Endothelial Growth Factor (VEGF) receptor inhibitors include, but are not limited to bevacizumab (trade name:

) Axitinib (patent No.: WO 01/002369), brivanib, motesanib (patent No.: WO 02/068470), pasireolide (also known as SO 230, patent No.: WO 02/010192), sorafenib (trade name:

). Where appropriate, these inhibitors may be administered in the form of pharmaceutically acceptable salts.

Examples of topoisomerase II inhibitors include, but are not limited to, etoposide (also known as VP-16 and etoposide phosphate, trade name

And->

) Teniposide (also known as VM-26, trade name

Examples of alkylating agents include, but are not limited to, 5-azacytidine (trade name:

) Decitabine (trade name: />

) Temozolomide (trade name: />

And->

) Dactinomycin (also known as actinomycin-D, trade name: />

) Melphalan (trade name: />

) Altretamine (also known as hexamethylmelamine, trade name: />

) Carmustine (trade name: />

) Bendamustine (trade name:

) Busulfan (trade name: />

And->

) Carboplatin (trade name:

) Lomustine (also known as CCNU, trade name: / >

) Cisplatin (also known as CDDP, trade name:

and->

) Chloramphenicol (trade name: />

) Cyclophosphamide (trade name:

and->

) Dacarbazine (also known as DTIC, DIC, trade name: />

) Ifosfamide (trade name: />

) Methyl (yl) benzyl hydrazine (trade name: />

) Nitrogen mustard (trade name: />

) ChainMycin (trade name:>

) Thiotepa (also known as thiophosphamide, trade name: />

). Where appropriate, these alkylating agents may be administered in the form of pharmaceutically acceptable salts.

Examples of antitumor antibiotics include, but are not limited to, doxorubicin (trade name:

and->

) Bleomycin (trade name: />

) Daunorubicin (trade name: />

) Daunorubicin liposome (trade name: />

) Mitoxantrone (also known as DHAD, trade name: />

) Epirubicin (trade name: ELLENCE ^TM ) Idamycin (also known as desmethoxydaunorubicin, trade name: />

And

) Mitomycin C (trade name: />

). Where appropriate, these antitumor antibiotics may be administered in the form of pharmaceutically acceptable salts.

Examples of retinoic acid include, but are not limited to, alisretinoic acid (trade name:

) Retinoic acid (also known as all-trans retinoic acid, trade name: />

) Isotretinoin (also known as 13-c/s-retinoic acid, trade name:

And->

) Bexarotene (trade name: />

). Where appropriate, these compounds may be administered in the form of pharmaceutically acceptable salts.

The invention has the main advantages that:

1. the compound has a novel structure, and can be used as a tyrosine kinase inhibitor, in particular an ALX inhibitor;

2. the compound has good metabolic characteristics;

3. the compound has high in-vivo anti-tumor activity.

The invention will be further specifically illustrated by the following detailed experimental procedures in examples. These exemplary compounds are depicted in neutral form in the examples below. In some cases, the compounds are isolated as salts according to the method and/or intrinsic molecular properties used for final purification. These examples are merely illustrative of the invention and are not intended to limit the scope of the patent in any way. Unless defined or otherwise indicated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

Example 1

N- (4- ((10H-benzo [ b ] pyrido [2,3-e ] [1,4] oxazin-4-yl) oxy) -3-fluorophenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide (I-1)

Step (1): 2, 4-dichloro-3- (2-nitrophenoxy) pyridine (1-1)

A mixture of 5 g of 2-chloro-3- (2-nitrophenoxy) pyridine-1-oxide and 10 ml of phosphorus oxychloride was heated and stirred at 95℃for 3 hours under argon. Concentrating the reaction solution to dryness, adding water into the residue, treating the residue with saturated sodium bicarbonate aqueous solution, extracting the residue with ethyl acetate, and concentrating an organic phase to dryness; the residue was taken up in methylene chloride: petroleum ether=1:1 column chromatography gives 1.4 g of 2, 4-dichloro-3- (2-nitrophenoxy) pyridine (1-1) as an off-white solid in 26% yield. ¹ H NMR(300MHz,CDCl ₃ )δ8.29(d,J＝5.1Hz,1H),8.07(dd,J＝1.8,8.4Hz,1H),7.44-7.51(m,2H),7.21-7.26(m,1H),6.62(dd,J＝1.2,8.7Hz,1H).

Step (2): 4- ((2-chloro-3- (2-nitrophenoxy) pyridin-4-yl) oxy) -3-fluoroaniline (1-2)

A mixture of 500 mg of compound 1-1, 200 mg of 2-fluoro-4-aminophenol, 235 mg of potassium tert-butoxide and 5 ml of N, N-dimethylacetamide was heated for 4 hours under argon atmosphere at 85 ℃. The reaction mixture was treated with water, extracted with ethyl acetate, the organic phase concentrated to dryness,the residue was taken up in methylene chloride: ethyl acetate=1:1 column chromatography gave 592 mg of 4- ((2-chloro-3- (2-nitrophenoxy) pyridin-4-yl) oxy) -3-fluoroaniline (1-2) as a light brown solid in 95% yield. ¹ H NMR(400MHz,CDCl ₃ )δ8.14(d,J＝5.6Hz,1H),8.02(dd,J＝1.6,8.4Hz,1H),7.47-7.52(m,1H),7.13-7.20(m,1H),6.91(t,J＝8.8Hz,1H),6.85(dd,J＝1.2,8.8Hz,1H),6.67(dd,J＝1.2,5.6Hz,1H),6.40-6.47(m,2H),3.81(br s,2H).

Step (3): n- (4- ((2-chloro-3- (2-nitrophenoxy) pyridin-4-yl) oxy) -3-fluorophenyl) acetamide (1-3)

292 microliters of acetyl chloride in ice bath was slowly added dropwise to a solution containing 592 milligrams of compound 1-2, 690 microliters of triethylamine and 8 milliliters of acetone, and after the dropwise addition was completed, the mixture was stirred overnight at room temperature. Adding water to the reaction mixture, extracting with ethyl acetate, and concentrating the organic phase to dryness; the residue was taken up in methylene chloride: ethyl acetate=1:1 column chromatography gave N- (4- ((2-chloro-3- (2-nitrophenoxy) pyridin-4-yl) oxy) -3-fluorophenyl) acetamide (1-3) as a light brown solid 649 mg in 98% yield. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.26(s,1H),8.27(d,J＝5.6Hz,1H),8.08(dd,J＝1.6,8.0Hz,1H),7.80(dd,J＝2.0,12.0Hz,1H),7.64-7.69(m,1H),7.27-7.35(m,3H),7.05(d,J＝8.8Hz,1H),6.96(d,J＝5.6Hz,1H),2.06(s,3H).

Step (4): n- (4- ((3- (2-aminophenoxy) -2-chloropyridin-4-yl) oxy) -3-fluorophenyl) acetamide (1-4)

A mixture of 649 mg of Compound 1-3, 453 mg of iron powder, 868 mg of ammonium chloride, 30 ml of methanol and 6 ml of water was stirred with heating at 70℃for 1 hour. The reaction solution is cooled to room temperature, treated by saturated sodium bicarbonate aqueous solution and extracted by ethyl acetate, and the organic phase is concentrated to dryness to obtain N- (4- ((3- (2-aminophenoxy) -2-chloropyridin-4-yl) oxy) -3-fluorophenyl) acetamide (1-4) 571 mg of light brown solid was obtained in 95% yield. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.26(s,1H),8.18(d,J＝5.6Hz,1H),7.81(dd,J＝2.4,13.2Hz,1H),7.22-7.34(m,2H),6.86(d,J＝5.6Hz,1H),6.74-6.81(m,2H),6.37-6.46(m,2H),5.06(s,2H),2.06(s,3H).

Step (5): 4- ((10H-benzo [ b ] pyrido [2,3-e ] [1,4] oxazin-4-yl) oxy) -3-fluoroaniline (1-5)

565 mg of Compound 1-4, 71 mg Pd ₂ (dba) ₃ A mixture of 89 mg Xantphos, 1.99 g cesium carbonate and 17 ml 1, 4-dioxane was reacted under argon at 120℃for 3 hours. Cooling the reaction solution to room temperature, filtering, and concentrating the filtrate to dryness; the residue was dissolved in 20 ml of methanol, 2.4 ml of 6N hydrochloric acid was added thereto, and stirred at 90℃for 2 hours under argon atmosphere. The reaction solution was cooled to room temperature, treated with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was separated, concentrated to dryness, and the residue was taken up in dichloromethane: ethyl acetate=1:1 column chromatography to give 4- ((10H-benzo [ b) as a light brown solid ]Pyrido [2,3-e][1,4]Oxazin-4-yl) oxy) -3-fluoroaniline (1-5) 177 mg, 40% yield of the 2-step reaction. ¹ H NMR(400MHz,DMSO-d ₆ )δ8.99(s,1H),7.40(d,J＝6.0Hz,1H),6.99(t,J＝9.2Hz,1H),6.80(t,J＝7.6Hz,1H),6.58-6.71(m,3H),6.51(dd,J＝2.8,13.6Hz,1H),6.40(dd,J＝2.4,8.8Hz,1H),5.92(d,J＝6.0Hz,1H),5.43(br s,2H).

Step (6): n- (4- ((10H-benzo [ b ] pyrido [2,3-e ] [1,4] oxazin-4-yl) oxy) -3-fluorophenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide (I-1)

A mixture of 45 mg 1- ((4-fluorophenyl) carbamoyl) cyclopropane-1-carboxylic acid, 62 mg of compound 1-5, 114 mg of HATU, 105. Mu.l of diisopropylethylamine and 2 ml of N, N-dimethylformamide was stirred at room temperatureAnd (5) at night. The reaction was concentrated to dryness and the residue was taken up in dichloromethane: thin layers were prepared with methanol=96:4 to give N- (4- ((10H-benzo [ b) as a white solid]Pyrido [2,3-e][1,4]Oxazin-4-yl) oxy) -3-fluorophenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide (I-1) 67 mg in 65% yield. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.33(s,1H),10.01(s,1H),9.10(s,1H),7.85(dd,J＝2.0,13.6Hz,1H),7.61-7.66(m,2H),7.41-7.44(m,2H),7.31(t,J＝9.0Hz,1H),7.17(t,J＝8.8Hz,2H),6.77-6.81(m,1H),6.59-6.69(m,3H),6.02(d,J＝5.6Hz,1H),1.46(m,4H).

Example 2

N- (4- ((10H-benzo [ b ] pyrido [2,3-e ] [1,4] oxazin-4-yl) oxy) phenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide (I-2)

Step (1): 4- ((2-chloro-3- (2-nitrophenoxy) pyridin-4-yl) oxy) aniline (2-1)

Preparation of 4- ((2-chloro-3- (2-nitrophenoxy) pyridin-4-yl) oxy) aniline (2-1) the same compound 1-2 was obtained as a light brown solid in 78% yield. ¹ H NMR(400MHz,DMSO-d ₆ )δ8.21(d,J＝5.6Hz,1H),8.08(dd,J＝1.6,8.0Hz,1H),7.63-7.68(m,1H),7.30-7.34(m,1H),7.10(dd,J＝1.2,8.4Hz,1H),6.78-6.81(m,3H),6.56-6.61(m,2H),5.20(s,2H).

Step (2): n- (4- ((2-chloro-3- (2-nitrophenoxy) pyridin-4-yl) oxy) phenyl) acetamide (2-2)

Preparation of N- (4- ((2-chloro-3- (2-nitrophenoxy) pyridin-4-yl) oxy) phenyl) acetamide (2-2) the same compound 1-3 gave a light brown solid in 90% yield. ¹ H NMR(300MHz,CDCl ₃ )δ8.15(d,J＝5.7Hz,1H),8.02(dd,J＝1.5,8.1Hz,1H),7.48-7.53(m,3H),7.22(t,J＝7.8Hz,1H),6.94(d,J＝9.0Hz,2H),6.84(d,J＝9.0Hz,1H),6.72(d,J＝5.7Hz,1H),2.19(s,3H).

Step (3): n- (4- ((3- (2-aminophenyl) -2-chloropyridin-4-yl) oxy) phenyl) acetamide (2-3)

Preparation of N- (4- ((3- (2-aminophenyl) -2-chloropyridin-4-yl) oxy) phenyl) acetamide (2-3) the same compound 1-4 was obtained as a light brown solid in 94% yield. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.08(s,1H),8.16(d,J＝5.6Hz,1H),7.65(d,J＝8.8Hz,2H),7.06(d,J＝8.8Hz,2H),6.83(d,J＝5.6Hz,1H),6.73-6.81(m,2H),6.42-6.47(m,2H),5.02(s,2H),2.04(s,3H).

Step (4): 4- ((10H-benzo [ b ] pyrido [2,3-e ] [1,4] oxazin-4-yl) oxy) aniline (2-4)

4- ((10H-benzo [ b ]]Pyrido [2,3-e][1,4]Oxazin-4-yl) oxy) aniline (2-4) was prepared as compound 1-5 to give a pale brown solid in 48% yield in 2 steps. ¹ H NMR(300MHz,DMSO-d ₆ )δ8.95(s,1H),7.39(d,J＝6.0Hz,1H),6.75-6.83(m,3H),6.58-6.70(m,5H),5.94(d,J＝6.0Hz,1H),5.08(br s,2H).

Step (5): n- (4- ((10H-benzo [ b ] pyrido [2,3-e ] [1,4] oxazin-4-yl) oxy) phenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide (I-2)

N- (4- ((10H-benzo [ b ])]Pyrido [2,3-e][1,4]Oxazin-4-yl) oxy) phenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide (I-2) was prepared in the same manner as compound I-1 to give an off-white solid in 61% yield. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.12(s,1H),10.07(s,1H),9.08(s,1H),7.62-7.68(m,4H),7.45(d,J＝6.0Hz,1H),7.07-7.18(m,4H),6.76-6.80(m,1H),6.59-6.65(m,3H),6.06(d,J＝6.0Hz,1H),1.45(m,4H).

Example 3

N- (4- ((10H-benzo [ b ] pyrido [2,3-e ] [1,4] oxazin-4-yl) oxy) phenyl) -N' -phenylcyclopropane-1, 1-dicarboxamide (I-3)

N- (4- ((10H-benzo [ b ])]Pyrido [2,3-e][1,4]Oxazin-4-yl) oxy) phenyl) -N' -phenylcyclopropane-1, 1-dicarboxamide (I-3) was prepared in the same manner as compound I-1 to give a white solid in 58% yield. ¹ H NMR(300MHz,DMSO-d ₆ )δ10.07(s,1H),10.06(s,1H),9.06(s,1H),7.60-7.68(m,4H),7.45(d,J＝5.7Hz,1H),7.33(t,J＝8.1Hz,2H),7.04-7.11(m,3H),6.75-6.81(m,1H),6.59-6.63(m,3H),6.07(d,J＝5.7Hz,1H),1.47(m,4H).

Example 4

N- (4- ((10H-benzo [ b ] pyrido [2,3-e ] [1,4] oxazin-4-yl) oxy) phenyl) -N' -benzylcyclopropane-1, 1-dicarboxamide (I-4)

N- (4- ((10H-benzo [ b ])]Pyrido [2,3-e][1,4]Oxazin-4-yl) oxy) phenyl) -N' -benzyl cyclopropane-1, 1-dicarboxamide (I-4) was prepared in the same manner as compound I-1 to give a pale brown solid in 46% yield. ¹ H NMR(400MHz,CDCl ₃ )δ10.66(s,1H),7.60(d,J＝9.2Hz,2H),7.42(d,J＝5.6Hz,1H),7.26-7.39(m,5H),7.08(d,J＝9.2Hz,2H),6.91(br s,1H),6.69-6.81(m,3H),6.47(dd,J＝1.2,7.6Hz,1H),6.20(t,J＝5.2Hz,1H),6.10(d,J＝5.6Hz,1H),4.48(d,J＝5.2Hz,2H),1.74-1.79(m,2H),1.33-1.36(m,2H).

Example 5

N- (4- ((10H-benzo [ b ] pyrido [2,3-e ] [1,4] oxazin-4-yl) oxy) phenyl) -N' - (pyridin-3-yl) cyclopropane-1, 1-dicarboxamide (I-5)

Step (1): 1- ((4- ((10H-benzo [ b ] pyrido [2,3-e ] [1,4] oxazin-4-yl) oxy) phenyl) carbamoyl) cyclopropane-1-carboxylic acid methyl ester (5-1)

1- ((4- ((10H-benzo [ b)]Pyrido [2,3-e][1,4]Oxazin-4-yl) oxy) phenyl) carbamoyl) cyclopropane-1-carboxylic acid methyl ester (5-1) the same compound I-1 was prepared to give a light brown solid in 93% yield. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.36(s,1H),9.05(s,1H),7.66(d,J＝8.8Hz,2H),7.44(d,J＝5.6Hz,1H),7.11(d,J＝8.8Hz,2H),6.76-6.80(m,1H),6.59-6.64(m,3H),6.07(d,J＝5.6Hz,1H),3.68(s,3H),1.41-1.44(m,2H),1.37-1.40(m,2H).

Step (2): 1- ((4- ((10H-benzo [ b ] pyrido [2,3-e ] [1,4] oxazin-4-yl) oxy) phenyl) carbamoyl) cyclopropane-1-carboxylic acid (5-2)

A mixture of 105 mg of compound 5-1, 32 mg of lithium hydroxide monohydrate, 3 ml of tetrahydrofuran and 3 ml of water was stirred overnight at room temperature. The reaction solution is treated by 1N hydrochloric acid and filtered to obtain 1- ((4- ((10H-benzo [ b)]Pyrido [2,3-e ][1,4]Oxazin-4-yl) oxy) phenyl) carbamoyl) cyclopropane-1-carboxylic acid (5-2) as a white solid in 93% yield. ¹ H NMR(400MHz,DMSO-d ₆ )δ13.06(br s,1H),10.59(s,1H),9.05(s,1H),7.66(d,J＝8.8Hz,2H),7.44(d,J＝5.6Hz,1H),7.10(d,J＝8.8Hz,2H),6.76-6.80(m,1H),6.59-6.64(m,3H),6.07(d,J＝5.6Hz,1H),1.42(s,4H).

Step (3): n- (4- ((10H-benzo [ b ] pyrido [2,3-e ] [1,4] oxazin-4-yl) oxy) phenyl) -N' - (pyridin-3-yl) cyclopropane-1, 1-dicarboxamide (I-5)

N- (4- ((10H-benzo [ b ])]Pyrido [2,3-e][1,4]Oxazin-4-yl) oxy) phenyl) -N' - (pyridin-3-yl) cyclopropane-1, 1-dicarboxamide (I-5) was prepared in the same manner as compound I-1 to give a light brown solid in 93% yield. ¹ H NMR(300MHz,DMSO-d ₆ )δ10.24(s,1H),10.11(s,1H),9.07(s,1H),8.79(d,J＝2.4Hz,1H),8.28(dd,J＝1.2,4.4Hz,1H),8.02-8.05(m,1H),7.68(d,J＝9.2Hz,2H),7.45(d,J＝6.0Hz,1H),7.37(q,J＝4.8,8.0Hz,1H),7.11(d,J＝9.2Hz,2H),6.76-6.79(m,1H),6.59-6.64(m,3H),6.06(d,J＝6.0Hz,1H),1.47(m,4H).

Example 6

N- (4- ((10H-benzo [ b ] pyrido [2,3-e ] [1,4] oxazin-4-yl) oxy) phenyl) -1, 5-dimethyl-3-oxo-2-phenyl-2, 3-dihydro-1H-pyrazole-4-carboxamide (I-6)

N- (4- ((10H-benzo [ b ])]Pyrido [2,3-e][1,4]Oxazin-4-yl) oxy) phenyl) -1, 5-dimethyl-3-oxo-2-phenyl-2, 3-dihydro-1H-pyrazole-4-carboxamide (I-6) was prepared as compound I-1 to give a brown solid in 80% yield. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.77(s,1H),9.08(s,1H),7.57-7.85(m,4H),7.53(t,J＝7.2Hz,1H),7.43-7.45(m,3H),7.12(d,J＝9.2Hz,2H),6.76-6.80(m,1H),6.59-6.65(m,3H),6.09(d,J＝6.0Hz,1H),3.36(s,3H),2.70(s,3H).

Example 7

N- (4- ((10H-benzo [ b ] pyrido [2,3-e ] [1,4] oxazin-4-yl) oxy) -3-fluorophenyl) -1, 5-dimethyl-3-oxo-2-phenyl-2, 3-dihydro-1H-pyrazole-4-carboxamide (I-7)

N- (4- ((10H-benzo [ b ])]Pyrido [2,3-e][1,4]Oxazin-4-yl) oxy) -3-fluoroPreparation of phenyl) -1, 5-dimethyl-3-oxo-2-phenyl-2, 3-dihydro-1H-pyrazole-4-carboxamide (I-7) the same compound I-1 was obtained as a light brown solid in 89% yield. ¹ H NMR(500MHz,DMSO-d ₆ )δ10.90(s,1H),9.07(s,1H),7.92(dd,J＝2.5,13.0Hz,1H),7.58-7.61(m,2H),7.53(t,J＝7.5Hz,1H),7.43-7.44(m,3H),7.24-7.29(m,2H),6.77-6.80(m,1H),6.60-6.68(m,3H),6.06(d,J＝6.0Hz,1H),3.37(s,3H),2.70(s,3H).

Example 8

N- (4- ((10H-benzo [ b ] pyrido [2,3-e ] [1,4] oxazin-4-yl) oxy) -3-fluorophenyl) -1- (4-fluorophenyl) -2-oxo-1, 2-dihydropyridine-3-carboxamide (I-8)

N- (4- ((10H-benzo [ b ])]Pyrido [2,3-e][1,4]Oxazin-4-yl) oxy) -3-fluorophenyl) -1- (4-fluorophenyl) -2-oxo-1, 2-dihydropyridine-3-carboxamide (I-8) was prepared as compound I-1 to give a yellow solid in 85% yield. ¹ H NMR(500MHz,DMSO-d ₆ )δ12.06(s,1H),9.08(s,1H),8.59(dd,J＝2.5,7.5Hz,1H),8.13(dd,J＝2.5,7.0Hz,1H),8.00(dd,J＝2.5,13.0Hz,1H),7.59-7.63(m,2H),7.40-7.45(m,4H),7.32(t,J＝9.0Hz,1H),6.77-6.80(m,1H),6.74(t,J＝7.0Hz,1H),6.60-6.66(m,3H),6.08(d,J＝6.0Hz,1H).

Example 9

N- (4- ((10H-benzo [ b ] pyrido [2,3-e ] [1,4] oxazin-4-yl) oxy) phenyl) -1- (4-fluorophenyl) -2-oxo-1, 2-dihydropyridine-3-carboxamide (I-9)

N- (4- ((10H-benzo [ b ])]Pyrido [2,3-e][1,4]Oxazin-4-yl) oxy) phenyl) -1- (4-fluorophenyl) -2-oxo-1, 2-dihydropyridine-3-carboxamide (I-9) was prepared as compound I-1 to give a yellow solid in 99% yield. ¹ H NMR(500MHz,DMSO-d ₆ )δ11.93(s,1H),9.06(s,1H),8.59(dd,J＝2.5,7.5Hz,1H),8.11(dd,J＝2.5,7.0Hz,1H),7.73-7.76(m,2H),7.58-7.63(m,2H),7.40-7.46(m,3H),7.11-7.14(m,2H),6.76-6.79(m,1H),6.73(t,J＝7.0Hz,1H),6.59-6.64(m,3H),6.12(d,J＝5.5Hz,1H).

Example 10

N- (4- ((10H-benzo [ b ] pyrido [2,3-e ] [1,4] oxazin-4-yl) oxy) -3-fluorophenyl) -5- (4-fluorophenyl) -4-oxo-1, 4-dihydropyridine-3-carboxamide (I-10)

N- (4- ((10H-benzo [ b ])]Pyrido [2,3-e][1,4]Oxazin-4-yl) oxy) -3-fluorophenyl) -5- (4-fluorophenyl) -4-oxo-1, 4-dihydropyridine-3-carboxamide (I-10) the same compound I-1 was prepared in the form of a light brown solid with a yield of 91%. ¹ H NMR(500MHz,DMSO-d ₆ )δ13.14(s,1H),12.68(br s,1H),9.08(s,1H),8.62(s,1H),8.09(s,1H),8.02(dd,J＝2.5,13.0Hz,1H),7.69-7.73(m,2H),7.45(d,J＝5.5Hz,1H),7.40-7.42(m,1H),7.24-7.32(m,3H),6.77-6.81(m,1H),6.60-6.68(m,3H),6.09(d,J＝5.5Hz,1H).

Example 11

N- (4- ((10H-benzo [ b ] pyrido [2,3-e ] [1,4] oxazin-4-yl) oxy) phenyl) -5- (4-fluorophenyl) -4-oxo-1, 4-dihydropyridine-3-carboxamide (I-11)

N- (4- ((10H-benzo [ b ])]Pyrido [2,3-e][1,4]Oxazin-4-yl) oxy) phenyl) -5- (4-fluorophenyl) -4-oxo-1, 4-dihydropyridine-3-carboxamide (I-11) was prepared as compound I-1 to give a pale yellow solid in 66% yield. ¹ H NMR(600MHz,DMSO-d ₆ )δ13.00(s,1H),12.64(br s,1H),9.06(s,1H),8.61(d,J＝1.2Hz,1H),8.08(d,J＝1.8Hz,1H),7.74-7.77(m,2H),7.69-7.73(m,2H),7.46(d,J＝6.0Hz,1H),7.24-7.28(m,2H),7.12-7.14(m,2H),6.77-6.79(m,1H),6.60-6.64(m,3H),6.12(d,J＝6.0Hz,1H).

Example 12

N- (4- ((10H-benzo [ b ] pyrido [2,3-e ] [1,4] oxazin-4-yl) oxy) -3-fluorophenyl) -5- (4-fluorophenyl) -1-methyl-4-oxo-1, 4-dihydropyridine-3-carboxamide (I-12)

N- (4- ((10H-benzo [ b ])]Pyrido [2,3-e][1,4]Oxazin-4-yl) oxy) -3-fluorophenyl) -5- (4-fluorophenyl) -1-methyl-4-oxo-1, 4-dihydropyridine-3-carboxamide (I-12) was prepared as compound I-1 to give a white solid in 90% yield. ¹ H NMR(500MHz,DMSO-d ₆ )δ13.17(s,1H),9.08(s,1H),8.69(d,J＝2.5Hz,1H),8.16(d,J＝2.0Hz,1H),8.01(dd,J＝2.0,13.0Hz,1H),7.70-7.74(m,2H),7.45(d,J＝6.0Hz,1H),7.40-7.43(m,1H),7.26-7.32(m,3H),6.77-6.81(m,1H),6.60-6.68(m,3H),6.08(d,J＝6.0Hz,1H),3.92(s,3H).

Example 13

N- (4- ((10H-benzo [ b ] pyrido [2,3-e ] [1,4] oxazin-4-yl) oxy) phenyl) -5- (4-fluorophenyl) -1-methyl-4-oxo-1, 4-dihydropyridine-3-carboxamide (I-13)

N- (4- ((10H-benzo [ b ])]Pyrido [2,3-e][1,4]Oxazin-4-yl) oxy) phenyl) -5- (4-fluorophenyl) -1-methyl-4-oxo-1, 4-dihydropyridine-3-carboxamide (I-13) was prepared as compound I-1 to give an off-white solid in 95% yield. ¹ H NMR(600MHz,DMSO-d ₆ )δ13.00(s,1H),9.07(s,1H),8.68(d,J＝2.4Hz,1H),8.15(d,J＝2.4Hz,1H),7.71-7.77(m,4H),7.46(d,J＝6.0Hz,1H),7.26-7.30(m,2H),7.12-7.15(m,2H),6.77-6.79(m,1H),6.60-6.65(m,3H),6.12(d,J＝6.0Hz,1H),3.92(s,3H).

Example 14

N- (4- ((10H-benzo [ b ] pyrido [2,3-e ] [1,4] oxazin-4-yl) oxy) -3-fluorophenyl) -1-ethyl-5- (4-fluorophenyl) -4-oxo-1, 4-dihydropyridine-3-carboxamide (I-14)

N-(4- ((10H-benzo [ b ])]Pyrido [2,3-e ][1,4]Oxazin-4-yl) oxy) -3-fluorophenyl) -1-ethyl-5- (4-fluorophenyl) -4-oxo-1, 4-dihydropyridine-3-carboxamide (I-14) was prepared as compound I-1 to give a light brown solid in 85% yield. ¹ H NMR(600MHz,DMSO-d ₆ )δ13.17(s,1H),9.09(s,1H),8.77(d,J＝2.4Hz,1H),8.25(d,J＝2.4Hz,1H),8.01(dd,J＝2.4,13.2Hz,1H),7.73-7.75(m,2H),7.45(d,J＝6.0Hz,1H),7.43(dd,J＝2.4,9.0Hz,1H),7.27-7.32(m,3H),6.80(t,J＝7.8Hz,1H),6.60-6.68(m,3H),6.08(d,J＝6.0Hz,1H),4.24(q,J＝7.2Hz,2H),1.45(t,J＝7.2Hz,3H).

Example 15

N- (4- ((10H-benzo [ b ] pyrido [2,3-e ] [1,4] oxazin-4-yl) oxy) phenyl) -1-ethyl-5- (4-fluorophenyl) -4-oxo-1, 4-dihydropyridine-3-carboxamide (I-15)

N- (4- ((10H-benzo [ b ])]Pyrido [2,3-e][1,4]Oxazin-4-yl) oxy) phenyl) -1-ethyl-5- (4-fluorophenyl) -4-oxo-1, 4-dihydropyridine-3-carboxamide (I-15) was prepared as compound I-1 to give a light brown solid in 95% yield. ¹ H NMR(600MHz,DMSO-d ₆ )δ12.99(s,1H),9.06(s,1H),8.75(d,J＝2.4Hz,1H),8.23(d,J＝2.4Hz,1H),7.73-7.77(m,4H),7.46(d,J＝6.0Hz,1H),7.27-7.30(m,2H),7.12-7.15(m,2H),6.77-6.79(m,1H),6.60-6.64(m,3H),6.12(d,J＝6.0Hz,1H),4.23(q,J＝7.2Hz,2H),1.44(t,J＝7.2Hz,3H).

Example 16

N- (4- ((10H-benzo [ b ] pyrido [2,3-e ] [1,4] oxazin-4-yl) oxy) -3-fluorophenyl) -5- (4-fluorophenyl) -4-oxo-1- (2, 2-trifluoroethyl) -1, 4-dihydropyridine-3-carboxamide (I-16)

N- (4- ((10H-benzo [ b ])]Pyrido [2,3-e][1,4]Preparation assimilation of oxazin-4-yl) oxy) -3-fluorophenyl) -5- (4-fluorophenyl) -4-oxo-1- (2, 2-trifluoroethyl) -1, 4-dihydropyridine-3-carboxamide (I-16)Compound I-1 was obtained as a pale brown solid in 98% yield. ¹ H NMR(600MHz,DMSO-d ₆ )δ12.79(s,1H),9.10(s,1H),8.87(d,J＝2.4Hz,1H),8.29(d,J＝2.4Hz,1H),8.01(dd,J＝2.4,13.2Hz,1H),7.66-7.69(m,2H),7.45(d,J＝6.0Hz,1H),7.43-7.45(m,1H),7.30-7.34(m,3H),6.78-6.80(m,1H),6.60-6.67(m,3H),6.09(d,J＝6.0Hz,1H),5.30(q,J＝8.4Hz,2H).

Example 17

N- (4- ((10H-benzo [ b ] pyrido [2,3-e ] [1,4] oxazin-4-yl) oxy) -3-fluorophenyl) -1-cyclopropyl-5- (4-fluorophenyl) -4-oxo-1, 4-dihydropyridine-3-carboxamide (I-17)

N- (4- ((10H-benzo [ b ]) ]Pyrido [2,3-e][1,4]Oxazin-4-yl) oxy) -3-fluorophenyl) -1-cyclopropyl-5- (4-fluorophenyl) -4-oxo-1, 4-dihydropyridine-3-carboxamide (I-17) was prepared as compound I-1 to give a white solid in 92% yield. ¹ H NMR(500MHz,DMSO-d ₆ )δ13.02(s,1H),9.08(s,1H),8.62(d,J＝2.0Hz,1H),8.13(d,J＝2.5Hz,1H),8.00(dd,J＝2.5,12.5Hz,1H),7.70-7.75(m,2H),7.45(d,J＝8.5Hz,1H),7.41-7.43(m,1H),7.25-7.32(m,3H),6.77-6.80(m,1H),6.60-6.67(m,3H),6.08(d,J＝6.0Hz,1H),3.85-3.90(m,1H),1.23-1.26(m,2H),1.05-1.10(m,2H).

Example 18

N- (4- ((10H-benzo [ b ] pyrido [2,3-e ] [1,4] oxazin-4-yl) oxy) phenyl) -1-cyclopropyl-5- (4-fluorophenyl) -4-oxo-1, 4-dihydropyridine-3-carboxamide (I-18)

N- (4- ((10H-benzo [ b ])]Pyrido [2,3-e][1,4]Oxazin-4-yl) oxy) phenyl) -1-cyclopropyl-5- (4-fluorophenyl) -4-oxo-1, 4-dihydropyridine-3-carboxamide (I-18) the same compound I-1 was prepared in the form of a light brown solid with a yield of 99%. ¹ H NMR(500MHz,DMSO-d ₆ )δ12.85(s,1H),9.05(s,1H),8.62(d,J＝2.0Hz,1H),8.12(d,J＝2.0Hz,1H),7.70-7.77(m,4H),7.46(d,J＝6.0Hz,1H),7.25-7.29(m,2H),7.12-7.15(m,2H),6.75-6.79(m,1H),6.60-6.64(m,3H),6.12(d,J＝6.0Hz,1H),3.85-3.89(m,1H),1.22-1.26(m,2H),1.05-1.09(m,2H).

Example 19

N- (4- ((10H-benzo [ b ] pyrido [2,3-e ] [1,4] oxazin-4-yl) oxy) -3-fluorophenyl) -5- (4-fluorophenyl) -1-isopropyl-4-oxo-1, 4-dihydropyridine-3-carboxamide (I-19)

N- (4- ((10H-benzo [ b ])]Pyrido [2,3-e][1,4]Oxazin-4-yl) oxy) -3-fluorophenyl) -5- (4-fluorophenyl) -1-isopropyl-4-oxo-1, 4-dihydropyridine-3-carboxamide (I-19) was prepared as compound I-1 to give a pale yellow solid in 94% yield. ¹ H NMR(600MHz,DMSO-d ₆ )δ13.17(s,1H),9.10(s,1H),8.76(d,J＝2.4Hz,1H),8.27(d,J＝2.4Hz,1H),8.02(dd,J＝2.4,13.2Hz,1H),7.71-7.75(m,2H),7.45(d,J＝5.4Hz,1H),7.41-7.43(m,1H),7.27-7.33(m,3H),6.78-6.80(m,1H),6.60-6.68(m,3H),6.08(d,J＝6.0Hz,1H),4.62-4.66(m,1H),1.52(d,J＝6.6Hz,6H).

Example 20

N- (4- ((10H-benzo [ b ] pyrido [2,3-e ] [1,4] oxazin-4-yl) oxy) phenyl) -5- (4-fluorophenyl) -1-isopropyl-4-oxo-1, 4-dihydropyridine-3-carboxamide (I-20)

N- (4- ((10H-benzo [ b ]) ]Pyrido [2,3-e][1,4]Oxazin-4-yl) oxy) -3-fluorophenyl) -5- (4-fluorophenyl) -1-isopropyl-4-oxo-1, 4-dihydropyridine-3-carboxamide (I-19) was prepared as compound I-1 to give a pale yellow solid in 96% yield. ¹ H NMR(500MHz,DMSO-d ₆ )δ12.98(s,1H),9.06(s,1H),8.75(d,J＝2.5Hz,1H),8.26(d,J＝2.5Hz,1H),7.72-7.77(m,4H),7.46(d,J＝6.0Hz,1H),7.26-7.32(m,2H),7.12-7.14(m,2H),6.76-6.80(m,1H),6.60-6.64(m,3H),6.13(d,J＝6.0Hz,1H),4.60-4.67(m,1H),1.52(d,J＝6.5Hz,6H).

Example 21

N- (4- ((10H-benzo [ b ] pyrido [2,3-e ] [1,4] oxazin-4-yl) oxy) -3-fluorophenyl) -5- (4-fluorophenyl) -4-oxo-1- ((tetrahydrofuran-3-yl) methyl) -1, 4-dihydropyridine-3-carboxamide (I-21)

N- (4- ((10H-benzo [ b ])]Pyrido [2,3-e][1,4]Oxazin-4-yl) oxy) -3-fluorophenyl) -5- (4-fluorophenyl) -4-oxo-1- ((tetrahydrofuran-3-yl) methyl) -1, 4-dihydropyridine-3-carboxamide (I-21) was prepared as compound I-1 to give a pale yellow solid in 87% yield. ¹ H NMR(500MHz,DMSO-d ₆ )δ13.11(s,1H),9.08(s,1H),8.79(d,J＝2.0Hz,1H),8.28(d,J＝2.5Hz,1H),8.01(dd,J＝2.5,13.0Hz,1H),7.71-7.75(m,2H),7.45(d,J＝6.0Hz,1H),7.41-7.43(m,1H),7.26-7.33(m,3H),6.77-6.81(m,1H),6.60-6.67(m,3H),6.09(d,J＝6.0Hz,1H),4.17-4.26(m,2H),3.80-3.84(m,1H),3.72-3.75(m,1H),3.68(q,J＝7.5Hz,1H),3.48(dd,J＝6.0,9.0Hz,1H),2.77-2.83(m,1H),1.91-1.98(m,1H),1.61-1.68(m,1H).

Example 22

N- (4- ((10H-benzo [ b ] pyrido [2,3-e ] [1,4] oxazin-4-yl) oxy) phenyl) -5- (4-fluorophenyl) -4-oxo-1- ((tetrahydrofuran-3-yl) methyl) -1, 4-dihydropyridine-3-carboxamide (I-22)

N- (4- ((10H-benzo [ b ])]Pyrido [2,3-e][1,4]Oxazin-4-yl) oxy) phenyl) -5- (4-fluorophenyl) -4-oxo-1- ((tetrahydrofuran-3-yl) methyl) -1, 4-dihydropyridine-3-carboxamide (I-22) was prepared as compound I-1 to give a light brown solid in 74% yield. ¹ H NMR(500MHz,DMSO-d ₆ )δ12.94(s,1H),9.06(s,1H),8.77(d,J＝2.5Hz,1H),8.27(d,J＝2.0Hz,1H),7.71-7.77(m,4H),7.46(d,J＝6.0Hz,1H),7.26-7.31(m,2H),7.12-7.15(m,2H),6.75-6.80(m,1H),6.60-6.64(m,3H),6.13(d,J＝6.0Hz,1H),4.17-4.25(m,2H),3.80-3.84(m,1H),3.72-3.75(m,1H),3.68(q,J＝7.5Hz,1H),3.48(dd,J＝5.5,9.0Hz,1H),2.77-2.83(m,1H),1.91-1.99(m,1H),1.61-1.68(m,1H).

Example 23

N- (4- ((10H-benzo [ b ] pyrido [2,3-e ] [1,4] oxazin-4-yl) oxy) -3-fluorophenyl) -5- (4-fluorophenyl) -4-oxo-1- ((tetrahydro-2H-pyran-4-yl) methyl) -1, 4-dihydropyridine-3-carboxamide (I-23)

N- (4- ((10H-benzo [ b ])]Pyrido [2,3-e][1,4]Oxazin-4-yl) oxy) -3-fluorophenyl) -5- (4-fluorophenyl) -4-oxo-1- ((tetrahydro-2H-pyran-4-yl) methyl) -1, 4-dihydropyridine-3-carboxamide (I-23) was prepared as compound I-1 to give a light brown solid in 90% yield. ¹ H NMR(500MHz,DMSO-d ₆ )δ13.13(s,1H),9.08(s,1H),8.72(d,J＝2.0Hz,1H),8.23(d,J＝2.0Hz,1H),8.01(dd,J＝2.5,13.0Hz,1H),7.71-7.75(m,2H),7.45(d,J＝6.0Hz,1H),7.40-7.43(m,1H),7.26-7.32(m,3H),6.77-6.81(m,1H),6.60-6.67(m,3H),6.09(d,J＝6.0Hz,1H),4.11(d,J＝7.0Hz,2H),3.88(dd,J＝3.5,10.0Hz,2H),3.24-3.29(m,2H),2.08-2.13(m,1H),1.44-1.48(m,2H),1.27-1.35(m,2H).

Example 24

N- (4- ((10H-benzo [ b ] pyrido [2,3-e ] [1,4] oxazin-4-yl) oxy) phenyl) -5- (4-fluorophenyl) -4-oxo-1- ((tetrahydro-2H-pyran-4-yl) methyl) -1, 4-dihydropyridine-3-carboxamide (I-24)

N- (4- ((10H-benzo [ b ])]Pyrido [2,3-e][1,4]Oxazin-4-yl) oxy) phenyl) -5- (4-fluorophenyl) -4-oxo-1- ((tetrahydro-2H-pyran-4-yl) methyl) -1, 4-dihydropyridine-3-carboxamide (I-24) was prepared as compound I-1 to give a light brown solid in 55% yield. ¹ H NMR(400MHz,CDCl ₃ )δ12.68(s,1H),8.58(d,J＝2.4Hz,1H),7.78(d,J＝8.8Hz,2H),7.54-7.57(m,2H),7.47(d,J＝2.4Hz,1H),7.44(d,J＝6.0Hz,1H),7.19(t,J＝8.8Hz,2H),7.10(d,J＝9.2Hz,2H),6.91(br s,1H),6.67-6.80(m,3H),6.46(d,J＝7.6Hz,1H),6.14(d,J＝5.6Hz,1H),4.05(dd,J＝3.2,9.6Hz,2H),3.89(d,J＝7.2Hz,2H),3.42(t,J＝11.2Hz,2H),2.09-2.13(m,1H),1.58-1.62(m,2H),1.39-1.50(m,2H).

Example 25

N- (4- ((10H-benzo [ b ] pyrido [2,3-e ] [1,4] oxazin-4-yl) oxy) phenyl) -N' - (5-methylisoxazol-3-yl) cyclopropane-1, 1-dicarboxamide (I-25)

A mixture of 120 mg of compound 2-4, 166 mg of 1- ((5-methylisoxazol-3-yl) carbamoyl) cyclopropane-1-carboxylic acid, 219 mg EDCI and 5 ml of N, N-dimethylformamide was stirred overnight at room temperature. The reaction was concentrated to dryness and the residue was taken up in dichloromethane: methanol=98:2 column chromatography to give N- (4- ((10H-benzo [ b ")]Pyrido [2,3-e ][1,4]Oxazin-4-yl) oxy) phenyl) -N' - (5-methylisoxazol-3-yl) cyclopropane-1, 1-dicarboxamide (I-25) as a light brown solid, 30 mg, 11% yield. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.10(s,1H),9.96(s,1H),9.08(s,1H),7.66(d,J＝9.2Hz,2H),7.45(d,J＝5.6Hz,1H),7.11(t,J＝9.2Hz,2H),6.76-6.80(m,1H),6.59-6.85(m,4H),6.06(d,J＝5.6Hz,1H),2.38(s,3H),1.48-1.49(m,4H).

Example 26

N- (4- ((10H-benzo [ b ] pyrido [2,3-e ] [1,4] oxazin-4-yl) oxy) phenyl) -N' - (1-methylpiperidin-4-yl) cyclopropane-1, 1-dicarboxamide (I-26)

A mixture of 40 mg of compound 5-2, 23 mg of methylpiperidin-4-amine, 89 mg of BOP, 28. Mu.l of triethylamine and 1 ml of N, N-dimethylformamide was stirred overnight at room temperature. The reaction was concentrated to dryness and the residue was taken up in dichloromethane: methanol: ammonia = 200:10:1 column chromatography to give N- (4- ((10H-benzo [ b ")]Pyrido [2,3-e][1,4]Oxazin-4-yl) oxy) phenyl) -N' - (1-methylpiperidin-4-yl) cyclopropane-1, 1-dicarboxamide (I)26 48 mg of light brown solid, 96% yield. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.50(s,1H),9.08(s,1H),7.96(d,J＝7.6Hz,1H),7.62-7.66(m,2H),7.45(d,J＝6.0Hz,1H),7.07-7.11(m,2H),6.76-6.80(m,1H),6.60-6.65(m,3H),6.06(d,J＝6.0Hz,1H),3.71-3.76(m,1H),2.97-3.00(m,2H),2.38-2.44(m,5H),1.76-1.80(m,2H),1.57-1.67(m,2H),1.34-1.40(m,4H).

Example 27

N- (4- ((10H-benzo [ b ] pyrido [2,3-e ] [1,4] oxazin-4-yl) oxy) phenyl) -N' -cyclopropylcyclopropane-1, 1-dicarboxamide (I-27)

N- (4- ((10H-benzo [ b ])]Pyrido [2,3-e][1,4]Oxazin-4-yl) oxy) phenyl) -N' -cyclopropylcyclopropane-1, 1-dicarboxamide (I-27) was prepared as compound I-26 to give an off-white solid in 89% yield. ¹ H NMR(600MHz,DMSO-d ₆ )δ10.68(s,1H),9.06(s,1H),7.90(d,J＝4.2Hz,1H),7.62-7.65(m,2H),7.45(d,J＝6.0Hz,1H),7.07-7.10(m,2H),6.76-6.79(m,1H),6.59-6.64(m,3H),6.06(d,J＝6.0Hz,1H),2.65-2.69(m,1H),1.35-1.37(m,2H),1.32-1.34(m,2H),0.59-0.63(m,2H),0.48-0.50(m,2H).

Example 28

N- ((4- ((10H-benzo [ b ] pyrido [2,3-e ] [1,4] oxazin-4-yl) oxy) phenyl) thiocarbamoyl) -2-phenylacetamide (I-28)

A mixture of 117 mg of phenylacetic acid and 1 ml of thionyl chloride was stirred for 1 hour at 50℃under argon atmosphere. The reaction mixture was concentrated to dryness, and the residue was dissolved in 20 ml of acetonitrile, then 166 mg of potassium thiocyanate and 50 mg of compound 2-4 were added, and the reaction mixture was stirred at room temperature for 3 hours. After saturated sodium bicarbonate treatment, the reaction mixture was extracted with ethyl acetate, the organic phase was concentrated to dryness and the residue was taken up in dichloromethane: methanol=98:2 column chromatography to give N- ((4- ((10H-benzo [ b)]Pyrido [2,3-e][1,4]Oxazin-4-yl) oxy) phenyl) thiocarbamoyl) -2-phenylacetamide (I-28) as a white solid 24 mg in 30% yield. ¹ H NMR(300MHz,DMSO-d ₆ )δ12.34(s,1H),11.72(s,1H),9.11(s,1H),7.65(d,J＝8.7Hz,2H),7.49(d,J＝6.0Hz,1H),7.26-7.35(m,5H),7.15(d,J＝8.7Hz,2H),6.75-6.81(m,1H),6.59-6.64(m,3H),6.18(d,J＝6.0Hz,1H),3.81(s,2H).

Example 29

N- (4- ((10H-benzo [ b ] pyrido [2,3-e ] [1,4] oxazin-4-yl) oxy) phenyl) -2, 2-difluoro-2- (quinolin-6-yl) acetamide (I-29)

N- (4- ((10H-benzo [ b ])]Pyrido [2,3-e][1,4]Oxazin-4-yl) oxy) phenyl) -2, 2-difluoro-2- (quinolin-6-yl) acetamide (I-29) was prepared as compound I-25 in the form of a pale yellow solid in 65% yield. ¹ H NMR(400MHz,DMSO-d ₆ )δ11.00(s,1H),9.10(s,1H),9.04(dd,J＝1.6,4.0Hz,1H),8.61(d,J＝8.4Hz,1H),8.40(s,1H),8.22(d,J＝8.8Hz,1H),8.03(dd,J＝1.6,8.8Hz,1H),7.77(d,J＝8.8Hz,2H),7.68(q,J＝4.0,8.4Hz,1H),7.46(d,J＝5.6Hz,1H),7.16(d,J＝8.8Hz,2H),6.76-6.80(m,1H),6.59-6.62(m,3H),6.11(d,J＝5.6Hz,1H).

Example 30

N- (4- ((10H-benzo [ b ] pyrido [2,3-e ] [1,4] oxazin-4-yl) oxy) phenyl) -1- (4-fluorophenyl) -2, 5-dioxo-1, 2,5,6,7, 8-hexahydroquinoline-3-carboxamide (I-30)

N- (4- ((10H-benzo [ b ])]Pyrido [2,3-e][1,4]Oxazin-4-yl) oxy) phenyl) -1- (4-fluorophenyl) -2, 5-dioxo-1, 2,5,6,7, 8-hexahydroquinoline-3-carboxamide (I-30) was prepared as compound I-1 in the form of a pale yellow solid in 71% yield. LRMS (ESI) M/z [ M+H ] ⁺ :575.3.

Example 31

N- (4- ((10H-benzo [ b ] pyrido [2,3-e ] [1,4] oxazin-4-yl) oxy) -3-fluorophenyl) -1- (4-fluorophenyl) -2, 5-dioxo-1, 2,5,6,7, 8-hexahydroquinoline-3-carboxamide (I-31)

N- (4- ((10H-benzo [ b ])]Pyrido [2,3-e][1,4]Oxazin-4-yl) oxy) -3-fluorophenyl) -1- (4-fluorophenyl) -2, 5-dioxo-1, 2,5,6,7, 8-hexahydroquinoline-3-carboxamide (I-31) was prepared as compound I-1 to give a yellow solid in 86% yield. LRMS (ESI) M/z [ M+H] ⁺ :593.3.

Example 32

N- (4- ((10H-benzo [ b ] pyrido [2,3-e ] [1,4] oxazin-4-yl) oxy) phenyl) -5- (3, 5-difluorophenyl) -4-oxo-1- ((tetrahydro-2H-pyran-4-yl) methyl) -1, 4-dihydropyridine-3-carboxamide (I-32)

N- (4- ((10H-benzo [ b ])]Pyrido [2,3-e][1,4]Oxazin-4-yl) oxy) phenyl) -5- (3, 5-difluorophenyl) -4-oxo-1- ((tetrahydro-2H-pyran-4-yl) methyl) -1, 4-dihydropyridine-3-carboxamide (I-32) was prepared as compound I-1 to give a white solid in 80% yield. LRMS (ESI) M/z [ M+H] ⁺ :623.3.

Example 33

N- (4- ((10H-benzo [ b ] pyrido [2,3-e ] [1,4] oxazin-4-yl) oxy) -3-fluorophenyl) -5- (3, 5-difluorophenyl) -4-oxo-1- ((tetrahydro-2H-pyran-4-yl) methyl) -1, 4-dihydropyridine-3-carboxamide (I-33)

N- (4- ((10H-benzo [ b ])]Pyrido [2,3-e][1,4]Oxazin-4-yl) oxy) -3-fluorophenyl) -5- (3, 5-difluorophenyl) -4-oxo-1- ((tetrahydro-2H-pyran-4-yl) methyl) -1, 4-dihydropyridine-3-carboxamide (I-33) was prepared as compound I-1 to give an off-white solid in 85% yield. LRMS (ESI) M/z [ M+H ] ⁺ :641.3.

Example 34

N- (4- ((10H-benzo [ b ] pyrido [2,3-e ] [1,4] oxazin-4-yl) oxy) -3-fluorophenyl) -5- (3, 5-difluorophenyl) -1-isopropyl-4-oxo-1, 4-dihydropyridine-3-carboxamide (I-34)

Example 35

N- (4- ((10H-benzo [ b ] pyrido [2,3-e ] [1,4] oxazin-4-yl) oxy) -3-fluorophenyl) -1-isopropyl-4-oxo-5- (3, 4, 5-trifluorophenyl) -1, 4-dihydropyridine-3-carboxamide (I-35)

Example 36

N- (4- ((10H-benzo [ b ] pyrido [2,3-e ] [1,4] oxazin-4-yl) oxy) -3-fluorophenyl) -5- (4-bromophenyl) -1-isopropyl-4-oxo-1, 4-dihydropyridine-3-carboxamide (I-36)

Example 37 inhibition Activity of Compounds on tyrosine kinase AXL

1. The experimental method comprises the following steps:

(1) the enzyme substrate Poly (Glu, tyr) 4:1 was diluted to 20. Mu.g/mL with potassium ion-free PBS (10 mM sodium phosphate buffer, 150mM NaCl, pH 7.2-7.4), and the coated ELISA plate was placed at 125. Mu.L/well and reacted at 37℃for 12-16 hours. The liquid in the wells was discarded. Plates were washed three times with T-PBS (potassium ion free PBS containing 0.1% Tween-20, 200. Mu.L/well) for 5 minutes each. The ELISA plate was dried in an oven at 37℃for 1-2 hours.

(2) Each well is filled with reaction buffer (50mM HEPES pH 7.4,50mM MgCl) ₂ ,0.5mM MnCl ₂ ,0.2mM Na ₃ VO ₄ 49. Mu.L of 1mM DTT diluted ATP solution was added to each well with 1. Mu.L of the compound to be tested (compound well) or DMSO at the corresponding concentration (negative control well) ) A further 50. Mu.L of the kinase domain recombinant protein of AXL kinase diluted with reaction buffer was added to initiate the reaction, and two wells without ATP control were used for each experiment. Put on a shaking table (100 rpm) at 37℃for 1 hour. The wells were discarded and the plates were washed three times with T-PBS.

(3) Antibody PY99 dilutions (antibody diluted with 5mg/mL of T-PBS 1:500 containing BSA) were added, 100. Mu.L/well, and the mixture was subjected to shaking reaction at 37℃for 0.5 hours. The wells were discarded and the plates were washed three times with T-PBS. Horseradish peroxidase-labeled goat anti-mouse secondary antibody dilutions (antibody diluted with 5mg/mL of T-PBS 1:2000 containing BSA) were added, 100. Mu.L/well, and the mixture was subjected to shaking reaction at 37℃for 0.5 hours. The wells were discarded and the plates were washed three times with T-PBS.

(4) 100. Mu.L/well of OPD color development solution (containing 0.03% H) was added at 2mg/mL ₂ O ₂ Is diluted with 0.1M citric acid-sodium citrate buffer (pH=5.4) and is reacted at 25℃for 1 to 10 minutes in the absence of light. Add 2M H ₂ SO ₄ The reaction was stopped at 50. Mu.L/well and read with a wavelength-tunable microplate reader VERSAmax at 490nm.

(5) Analysis of results

IC ₅₀ The values were obtained by four-parameter regression using a random software attached to the microplate reader.

2. Experimental results

The molecular level activity test shows that the tricyclic compound provided by the patent has obvious inhibition activity on AXL kinase, wherein the compounds I-11, I-12, I-14, I-15, I-17, I-18, I-19, I-20, I-22, I-24 and I-30 inhibit the activity of the AXL enzyme ₅₀ A value of less than 10nM; compounds I-11, I-14, I-17, I-18, I-20, I-22, I-24 inhibit IC on AXL enzyme activity ₅₀ Values less than 5nM, significantly better than positive compound R428 (Cancer res.2010,70, 1544-1554.) compound IC for AXL kinase inhibitory activity ₅₀ As shown in table 2.

Compounds of table 2 IC for AXL kinase inhibitory activity ₅₀

EXAMPLE 38 inhibition of BaF3/TEL-AXL tumor cell proliferation by Compounds

1. Experimental method

Proliferation inhibition of BaF3/TEL-AXL cells by the compounds was tested using the CCK-8 cell counting kit (Dojindo). The method comprises the following specific steps: baF3/TEL-AXL cells in the logarithmic growth phase were inoculated at an appropriate density into 96-well plates, 90. Mu.L per well, incubated overnight, incubated with different concentrations of compound for 72 hours, and solvent control groups (negative controls) were set. After the compound acts on cells for 72 hours, the effect of the compound on cell proliferation is detected by using a CCK-8 cell counting kit (Dojindo), 10 mu L of CCK-8 reagent is added to each hole, and the mixture is placed in a 37 ℃ incubator for 2-4 hours, and then is read by a full-wave microplate reader SpectraMax 190, and the measurement wavelength is 450nm.

The inhibition (%) of the compound against tumor cell growth was calculated using the following formula:

Inhibition (%) = (OD control well-OD dosing well)/OD control well x 100%

2. Experimental results

Compounds with BaF3/TEL-AXL cell inhibition Activity IC ₅₀ The experimental results of (2) are shown in Table 3.

Table 3 Compounds IC for BaF3/TEL-AXL cell inhibitory Activity ₅₀

The activity test of BaF3/TEL-AXL cell level shows that the compounds I-11, I-12, I-14, I-15, I-17, I-18, I-19, I-20, I-22, I-24 and I-19 have the following structuresIC below 10nM ₅₀ Is obviously superior to a positive drug R428 (Cancer Res.2010,70, 1544-1554.) wherein the compounds I-15, I-18, I-19 and I-20 inhibit the proliferation of BaF3/TEL-AXL cells ₅₀ Less than 1nM.

EXAMPLE 39 growth inhibition of Compound I-19 on BaF3/TEL-AXL nude mice subcutaneously transplanted tumors

1. Experimental method

BaF3/TEL-AXL cells were cultured in 5X 10 cells ⁶ And (3) respectively subcutaneously inoculating the strain to the armpit on the right side of the nude mouse, and transferring the strain to the nude mouse for three generations after forming a transplanted tumor. Cutting tumor tissue in vigorous growth period into 1.5mm ³ Left and right, under aseptic conditions, the mice were inoculated subcutaneously in the right armpit. The diameter of the transplanted tumor is measured by a vernier caliper for subcutaneous transplantation of the nude mice, and the tumor grows to 100-200mm ³ Animals were then randomly grouped. Compounds I-19 were orally administered 1 time per day at 1mg/kg, 3mg/kg and 10mg/kg doses for 11 consecutive days. The negative control group was given an equal volume of blank control. The positive control group was orally administered R428 2 times daily at a dose of 50mg/kg. Throughout the experiment, the diameter of the transplanted tumor was measured 2 times per week while weighing the mice. Tumor Volume (TV) is calculated as: tv=1/2×a×b ² Wherein a and b respectively represent length and width. Based on the measured results, the relative tumor volume (relative tumor volume, RTV) is calculated as: rtv=v _t /V ₀ . Wherein V is ₀ For measuring the volume of the tumor obtained at the time of divided administration (i.e. d 0), V _t Tumor volume at each measurement. The evaluation indexes of the antitumor activity are as follows: 1) Relative tumor proliferation rate T/C (%), the calculation formula is as follows: T/C (%) = (T _RTV /C _RTV )×100％，T _RTV : treatment group RTV; c (C) _RTV : negative control RTV; 2) Tumor volume growth inhibition rate TGI) is calculated as follows: TGI% = [1- (T) _Vt -T _V0 )/(C _Vt -C _V0 )]×100％，T _Vt Tumor volume measured for each treatment group; t (T) _V0 Tumor volume obtained upon administration of the therapeutic component cage; c (C) _Vt Tumor volume measured for each time for the control group; c (C) _V0 Tumor volumes obtained when the control component was administered in cages.

2. Experimental results

At the end of the administration (d 11), each of the compound I-19 administration groups had a significant inhibitory effect on the growth of BaF3/TEL-AXL nude mice transplanted tumors, with tumor inhibition rates (TGI) of 99.6%, 99.6% and 100.7% in the 1mg/kg, 3mg/kg and 10mg/kg dose groups (1 time per day), respectively. Wherein the 10mg/kg dose group was comparable to the 50mg/kg dose (2 times per day) of the positive drug R428, TGI (103.1%), indicating that Compound I-19 has high anti-tumor activity in vivo (FIG. 1A); the body weight of each dose group had no significant effect at the same period (fig. 1B).

EXAMPLE 40 preparation of pharmaceutical compositions

Tablet

The above materials are mixed uniformly, and 1000 tablets are prepared by conventional process. Suitable aqueous or non-aqueous coatings may be used to enhance palatability, improve appearance and stability, or delay absorption.

Capsule

Compound I-19 g

140 g of starch

Microcrystalline cellulose 80 g

Mixing the above materials according to conventional method, and making into 1000 capsules.

All documents mentioned in this application are incorporated by reference as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the claims appended hereto.

Claims

1. A compound of formula (I), a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate or solvate thereof:

Z, U, M, V and W are each independently selected from: C-R ^a2 Or N;

b is selected from

Wherein (1)>

Represents a ligation site;

R ^a 、R ^b 、R ^a1 、R ^a2 、R ^a3 、R ^a4 、R ^a’ 、R ^b’ 、R ^a” 、R ^b” 、R ¹ and R is ² Each independently selected from: hydrogen atom, halogen, amino, hydroxy, cyano, carboxyl, methylAcyl, trifluoromethyl, C1-C3 alkyl, C1-C3 alkoxy and C3-C6 cycloalkyl; or R is ^a And R is ^b The C atoms to which they are attached may form a substituted or unsubstituted 3-5 membered ring; or R is ^a’ And R is ^b’ The C atoms to which they are attached may form a substituted or unsubstituted 3-5 membered ring; or R is ^a” And R is ^b” The C atoms to which they are attached may form a substituted or unsubstituted 3-5 membered ring; wherein the substitution refers to substitution with one or more R;

2. The compound of claim 1, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate or solvate thereof, wherein the compound has a structure represented by formula (II), (III), (IV), (V), (VI):

R ^c 、R ^d 、R ^e each independently selected from: hydrogen atom, halogen, amino, hydroxyl, cyano, carboxyl, formyl, trifluoromethyl, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl and 3-6 membered heterocyclic group; wherein the C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocyclyl may be further substituted with one or more groups selected from the group consisting of: halogen, amino, hydroxy, cyano, carboxyl, formyl A group, trifluoromethyl, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocyclyl;

3. A compound, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof according to claim 1, characterized in that ring a is a substituted or unsubstituted 5-6 membered aryl or heteroaryl, preferably a substituted or unsubstituted phenyl, pyridinyl, pyrazinyl, thienyl, furanyl, thiazolyl, imidazolyl, oxazolyl; wherein said substitution is substituted with one or more R's, R's being as defined in claim 1.

4. A compound, pharmaceutically acceptable salt thereof, prodrug thereof, hydrate or solvate thereof according to any one of claim 1 to 3,

Is->

Preferably +.>

5. According to claim 1-4 a compound according to any of claims, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate or solvate thereof, wherein B is selected from:

6. a compound according to any one of claims 1 to 5, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate or solvate thereof, wherein the compound is selected from the group consisting of:

7. a pharmaceutical composition comprising a therapeutically effective amount of one or more selected from the compounds according to any one of claims 1-6 and pharmaceutically acceptable salts thereof, and optionally a pharmaceutically acceptable carrier.

8. Use of a compound according to any one of claims 1 to 6, a pharmaceutically acceptable salt thereof, a prodrug, a hydrate or a solvate thereof or a pharmaceutical composition according to claim 7 for the preparation of a medicament for the prophylaxis and/or treatment of a disease selected from the group consisting of:

a) Tumor-related diseases;

b) Tyrosine kinase dysfunction-related diseases.

9. The use according to claim 8, wherein the tumor-related disease is selected from the group consisting of: papilloma, bud glioma, melanoma, lung cancer (e.g., non-small cell lung cancer), ovarian cancer, prostate cancer, squamous cell carcinoma, astrocytoma, head cancer, neck cancer, bladder cancer, breast cancer, colorectal cancer, thyroid cancer, pancreatic cancer, gastric cancer, hepatocellular carcinoma, leukemia, lymphoma, hemangioma, keloids, respiratory cancer, brain cancer, genital cancer, digestive tract cancer, urinary tract cancer, eye cancer, liver cancer, skin cancer, head and neck cancer, thyroid cancer, parathyroid cancer, and distant metastases thereof, lymphoma, sarcoma, colon cancer, bone cancer, kidney cancer, testicular cancer, skin cancer, renal cell carcinoma.

10. A process for preparing a compound according to claim 1, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate or solvate thereof, comprising: reacting the formula (Ia) with the formula (Ib) in an inert solvent in the presence of a catalyst to form a compound of formula (I);