CN116806220A - Wnt pathway inhibitor compound - Google Patents

Abstract

The invention relates to a Wnt channel inhibitor compound shown in a formula (I), a pharmaceutical composition containing the compound and application of the compound in preventing and/or treating cancers, tumors, inflammatory diseases, autoimmune diseases or immune-mediated diseases.

Description

Wnt pathway inhibitor compound

The present application claims priority to chinese patent application 202110847130.9 entitled "a Wnt pathway inhibitor compound" filed on 7.26 of 2021, the contents of which are incorporated herein by reference in their entirety.

Technical Field

The application relates to a heterocyclic compound, in particular to a high-activity Wnt channel inhibitor and application thereof.

Background

The Wnt/beta-catenin signal transduction pathway is a pathway conserved in biological evolution. In normal somatic cells, β -catenin acts only as a cytoskeletal protein complex with E-cadherein at the cell membrane to maintain cell adhesion of the isotype and prevent cell migration. When the Wnt signal channel is not activated, the beta-catenin in cytoplasm is phosphorylated and forms a beta-catenin degradation complex with APC, axin, GSK3 beta and the like, so that the ubiquitin system is started to degrade the beta-catenin through a proteasome way, and the beta-catenin in cytoplasm is maintained at a lower level. When the cell is stimulated by Wnt signals, the Wnt protein is combined with a specific receptor Frizzled protein on a cell membrane, the activated Frizzled receptor recruits an intracellular disheveled protein, the degradation activity of a beta-catenin degradation complex formed by GSK3 beta and other proteins is inhibited, and the beta-catenin protein in a free state in cytoplasm is stabilized. The stably accumulated beta-catenin in cytoplasm enters the nucleus and then binds with LEF/TCF transcription factor family to start the transcription of downstream target genes (such as c-myc, c-jun, cyclin D1, etc.). Overactivation of the Wnt/β -catenin signaling pathway is closely associated with the occurrence of a variety of cancers (including colon, stomach, breast, etc.). For example, abnormal activation of Wnt canonical signaling pathway and nuclear accumulation of β -catenin protein are widely present in colorectal cancer, and proliferation of cancers such as colon cancer can be inhibited by inhibiting Wnt signaling pathway activity. Mutations of APC exist in more than 85% of colorectal cancers, and the mutated APC blocks the phosphorylation degradation of beta-catenin to induce the occurrence of colorectal cancers. In addition, the mutation of Axin and the mutation of beta-catenin can cause the intracellular aggregation of beta-catenin and activate Wnt/beta-catenin channels.

While inhibition of the Wnt signaling pathway is known to be effective in preventing and/or treating cancer, tumors, inflammatory diseases, autoimmune diseases, and immune-mediated diseases, there is currently no satisfactory effective Wnt pathway inhibitor compound in the art. Thus, there is a need in the art to investigate effective Wnt pathway inhibitor compounds.

Disclosure of Invention

The invention provides a compound which has a structure shown in a formula (I) and inhibits Wnt pathway activity or pharmaceutically acceptable salt, isotope derivative and stereoisomer thereof:

wherein:

-represents the presence or absence of a single bond;

r1 represents C ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl, 3-6 membered heterocycloalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, and said R1 may optionally be selected from 0, 1, 2, 3: hydrogen, halogen, OR ^a Nitro, (C) ₁ -C ₆ ) Alkyl, (C) ₁ -C ₆ ) Alkoxy, (C) ₁ -C ₆ ) Haloalkyl, (C) ₃ -C ₆ ) Cycloalkyl, halo (C) ₃ -C ₆ ) Cycloalkyl, 3-6 membered heterocycloalkyl, halo 3-6 membered heterocycloalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, cyano, SR ^a Halo (C) ₁ -C ₆ ) Alkoxy, halo (C) ₃ -C ₆ ) Cycloalkoxy, halo (C) ₁ -C ₆ ) Alkylthio, (C) ₃ -C ₆ ) Cycloalkyloxy, (C) ₃ -C ₆ ) Cycloalkylthio, halo (C) ₃ -C ₆ ) A substituent of a cycloalkylthio group;

X represents a covalent bond or- (CR) ^a R ^a’ ) _m -、-(CR ^a Ra’) _m -O-(CR ^a R ^a’ ) _n -、-(CR ^a R ^a’ ) _m -N(R ^b )-(CR ^a R ^a’ ) _n -、-(CR ^a R ^a’ ) _m -S-(CR ^a R ^a’ ) _n -、-(CR ^a R ^a’ ) _m C(O)(CR ^a R ^a’ ) _n -、-(CR ^a R ^a’ ) _m S(O) ₂ (CR ^a R ^a’ ) _n -、-(CR ^a R ^a’ ) _m C(O)N(R ^b )(CR ^a R ^a’ ) _n -、-(CR ^a R ^a’ ) _m S(O) ₂ N(R ^b )(CR ^a R ^a’ ) _n -、-(CR ^a R ^a’ ) _m N(R ^b )C(O)(CR ^a R ^a’ ) _n -、-(CR ^a R ^a’ ) _m N(R ^b )S(O) ₂ (CR ^a R ^a’ ) _n -、-(CR ^a R ^a’ ) _m OC(O)N(R ^b )(CR ^a R ^a’ ) _n -、-(CR ^a R ^a’ ) _m N(R ^b )C(O)O(CR ^a R ^a’ ) _n -、-(CR ^a R ^a ’) _m N(R ^b )C(O)N(R ^b’ )(CR ^a R ^a’ ) _n -、-(CR ^a R ^a’ ) _m N(R ^b )S(O) ₂ N(R ^b’ )(CR ^a R ^a’ ) _n -；

Cy represents C ₃ -C ₅ Cycloalkyl OR 4-5 membered cycloheteroalkyl, and which may optionally be substituted with 0, 1 OR 2 groups selected from hydrogen, halogen, -OR ^a 、(C ₁ -C ₆ ) Alkyl, (C) ₁ -C ₆ ) Haloalkyl, (C) ₃ -C ₆ ) Cycloalkyl, cyano and hydroxy (C) ₁ -C ₆ ) Substituted by alkyl;

R ² represents hydrogen, (C) ₁ -C ₆ ) Alkyl, (C) ₁ -C ₆ ) Haloalkyl, (C) ₃ -C ₆ ) Cycloalkyl or hydroxy (C) ₁ -C ₆ ) An alkyl group;

R ³ and R is ^3’ Each independently represents hydrogen, halogen, OR ^a 、(C ₁ -C ₆ ) Alkyl, (C) ₃ -C ₆ ) Cycloalkyl, hydroxy C ₁ -C ₆ Alkyl or (C) ₁ -C ₆ ) Alkoxy (C) ₁ -C ₆ ) An alkyl group;

or R is ³ And R is ^3’ Together with the carbon atoms to which they are attached form a 3-to 6-membered saturated or unsaturated ring which may optionally contain 1 or 2 heteroatoms selected from O, S and N and which may optionally be substituted with 0, 1 or 2 heteroatoms selected from halogen, hydroxy and C ₁ -C ₆ Substituted by alkyl;

or R is ² 、R ³ Or R is ² 、R ^3’ Together with the atoms to which they are attached form a 4-6 membered saturated or unsaturated ring which optionally contains 1 or 2 heteroatoms selected from O, S and N and which optionally is additionally substituted with 0, 1, 2 halogen, hydroxy, C ₁ -C ₆ Alkyl substituted;

R ⁴ and R is ^4’ Each independently represents hydrogen, C ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl, hydroxy C ₁ -C ₆ Alkyl, halogenated C ₁ -C ₆ Alkyl, (C) ₁ -C ₆ ) Alkoxy (C) ₁ -C ₆ ) An alkyl group;

or R is ⁴ And R is R ^4’ Together form = O;

R ^T and R is ^T’ Each independently represents hydrogen, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, hydroxy C ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl, halogen, OR ^a ；

Or R is ^T And R is ^T’ Together with the atoms to which they are attached form a 3-6 membered ring;

wherein when- - -represents that a single bond is not present, A represents (CR ^L R ^L’ ) _p Wherein R is ^L And R is ^L’ Each independently represents hydrogen, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, hydroxy C ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl, halogen, OR ^a Or R is ^L And R is ^L’ Together with the carbon atoms to which they are attached, form a 3-6 membered ring which may optionally contain 0, 1 or 2 heteroatoms selected from O, S and N, and which may optionally be substituted with 0, 1 or 2 substituents selected from halogen and hydroxy;

wherein when- - -represents a single bond, A represents CR ^H Wherein R is ^H Represents hydrogen, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, hydroxy C ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl, halogen, OR ^a ；

Wherein R is ^a 、R ^a’ 、R ^b 、R ^b’ Each independently represents hydrogen or C ₁ -C ₆ An alkyl group;

wherein m, n, p each independently represent 0, 1 or 2.

Among the above-mentioned compounds of the structure of formula (I) or pharmaceutically acceptable salts, isotopic derivatives, stereoisomers thereof, it is preferable that the compound has the structure of the following formula (II) or pharmaceutically acceptable salts, isotopic derivatives, stereoisomers thereof,

Wherein R is ¹ 、R ² 、R ³ 、R ^3’ 、R ⁴ 、R ^4’ X, cy have the above definition.

Further, the present invention also provides a compound having the following formula (III) and pharmaceutically acceptable salts, isotopic derivatives, stereoisomers thereof:

wherein R is ¹ 、R ² 、R ³ 、R ^3’ 、R ⁴ 、R ^4’ 、R ^T 、R ^T’ 、R ^L 、R ^L’ X, cy are as defined above.

In some embodiments of the invention, wherein R ² Represents hydrogen, C ₁ -C ₆ Alkyl, hydroxy (C) ₁ -C ₆ Alkyl) or C ₃ -C ₆ Cycloalkyl groups.

In some embodiments of the invention, wherein R ³ ，R ^3’ Each independently represents hydrogen, C ₁ -C ₆ Alkyl, hydroxy (C) ₁ -C ₆ Alkyl) or C ₃ -C ₆ Cycloalkyl groups.

At the bookIn some embodiments of the invention, wherein R ⁴ ，R ^4’ Each independently represents hydrogen, C ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl, or R ⁴ And R is R ^4’ Together form =o.

In some embodiments of the invention, wherein Cy represents C ₃ -C ₅ Cycloalkyl or 4-5 membered cycloheteroalkyl; preferably, cy represents

In some embodiments of the invention, X represents a covalent bond or- (CR) ^a R ^a’ ) _m -、-(CR ^a R ^a’ ) _m -O-(CR ^a R ^a’ ) _n -、-(CR ^a R ^a’ ) _m -N(R ^b )-(CR ^a R ^a’ ) _n -、-(CR ^a R ^a’ ) _m -S-(CR ^a R ^a’ ) _n -、-(CR ^a R ^a’ ) _m C(O)N(R ^b )(CR ^a R ^a’ ) _n -、-(CR ^a R ^a’ ) _m S(O) ₂ N(R ^b )(CR ^a R ^a’ ) _n -、-(CR ^a R ^a’ ) _m N(R ^b )C(O)(CR ^a R ^a’ ) _n -、-(CR ^a R ^a’ ) _m N(R ^b )S(O) ₂ (CR ^a R ^a’ ) _n -、-(CR ^a R ^a’ ) _m OC(O)N(R ^b )(CR ^a R ^a’ ) _n -、-(CR ^a R ^a’ ) _m N(R ^b )C(O)O(CR ^a R ^a’ ) _n -、-(CR ^a R ^a ’) _m N(R ^b )C(O)N(R ^b’ )(CR ^a R ^a’ ) _n -、-(CR ^a R ^a’ ) _m N(R ^b )S(O) ₂ N(R ^b’ )(CR ^a R ^a’ ) _n -。

In some embodiments of the invention, X represents-O-, -NR ^b -、-CR ^a R ^a’ -、-OCR ^a R ^a’ -、-CR ^a R ^a’ O-、-C(O)-、-C(O)NR ^b -、-NR ^b C(O)-、-NR ^b -C(O)-NR ^b -、-CR ^a R ^a’ -C(O)NR ^b -、-CR ^a R ^a’ -NR ^b C(O)-、-S-、-NR ^b S(O) ₂ -、-SO ₂ NR ^b 、-OC(O)NR ^b -、-S(O) ₂ 、-C(O)NR ^b -、-C(O)CR ^a R ^a’ -、-CR ^a R ^a’ C(O)NR ^b -、-NR ^b C(O)CR ^a R ^a’ -、-NR ^b C (O) O-; wherein R is ^a 、R ^a’ 、R ^b Each independently represents hydrogen or C ₁ -C ₆ An alkyl group.

In some embodiments of the invention, X represents- (CR) ^a R ^a’ ) _m -O-(CR ^a R ^a’ ) _n -, preferably-O-, -OCR ^a R ^a’ -、-CR ^a R ^a’ O-, more preferably-O-or-O-CH ₂ -。

In some embodiments of the invention, R ^T And R is ^T’ Represents hydrogen.

In some embodiments of the invention, R ^L And R is ^L’ Represents hydrogen.

In some embodiments of the invention, R ^H Represents hydrogen.

In some embodiments of the invention, R ¹ Represents C substituted by 0, 1, 2 or 3 substituents ₃ -C ₆ Cycloalkyl, 3-6 membered heterocycloalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, wherein the substituents are selected from halogen, (C) ₁ -C ₆ ) Alkyl, (C) ₁ -C ₆ ) Haloalkyl, (C) ₃ -C ₆ ) Cycloalkyl, halo (C) ₃ -C ₆ ) Cycloalkyl, 3-6 membered heterocycloalkyl, halo 3-6 membered heterocycloalkyl, C ₆ -C ₁₀ Aryl and 5-10 membered heteroaryl.

In some embodiments of the invention, R ¹ Represent C ₃ -C ₆ Cycloalkyl, 3-6 membered heterocycloalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, and R as described ¹ Can be optionally selected from 0, 1, 2 and 3: hydrogen, halogen, (C) ₁ -C ₆ ) Alkyl, (C) ₁ -C ₆ ) Haloalkyl, (C) ₃ -C ₆ ) Cycloalkyl, halo (C) ₃ -C ₆ ) The substituents of cycloalkyl groups are substituted.

In some embodiments of the invention, R ¹ Selected from:

in some embodiments of the invention, R ¹ Selected from:

in some preferred aspects, the invention provides a compound having the structure:

further, the invention also provides a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt, an isotope derivative or a stereoisomer thereof.

Further, the invention also provides application of the compound or pharmaceutically acceptable salt, the homoleptin derivative, the stereoisomer or the pharmaceutical composition of the invention in preparing medicines for preventing and/or treating cancers, tumors, inflammatory diseases, autoimmune diseases or immune mediated diseases. It is particularly noted that, in this context, when referring to "compounds" of the structures of formulae (I) to (III), stereoisomers, diastereomers, enantiomers, racemic mixtures, and isotopic derivatives thereof are also generally contemplated.

Accordingly, the present invention provides a method for preventing and/or treating cancer, tumor, inflammatory disease, autoimmune disease or immune-mediated disease, comprising administering to a subject a compound of the present invention or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer or a pharmaceutical composition of the present invention.

It is well known to those skilled in the art that salts, solvates, hydrates of a compound are alternative forms of the compound, which can all be converted into the compound under certain conditions, and therefore, particular attention is paid herein to the compounds of the formulae (I) to (III), generally also including pharmaceutically acceptable salts thereof, and further including solvates and hydrates thereof.

Similarly, when a compound is referred to herein, prodrugs, metabolites, and nitrogen oxides thereof are also generally included.

Pharmaceutically acceptable salts according to the invention may be formed using, for example, the following mineral or organic acids: by "pharmaceutically acceptable salt" is meant a salt which is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like commensurate with a reasonable benefit/risk ratio. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by reacting the free base or free acid with a suitable reagent alone, as outlined below. For example, the free base function may be reacted with a suitable acid. Examples of pharmaceutically acceptable inorganic acid addition salts are salts of amino groups with inorganic acids (e.g., hydrochloric, hydrobromic, phosphoric, sulfuric and perchloric) or organic acids (e.g., acetic, oxalic, maleic, tartaric, citric, succinic or malonic) or by using other methods in the art such as ion exchange. Other pharmaceutically acceptable salts include adipic acid salts, sodium alginate, ascorbate, aspartic acid salts, benzenesulfonate salts, benzoate salts, bisulfate salts, borate salts, butyric acid salts, camphoric acid salts, citric acid salts, cyclopentanepropionate salts, digluconate salts, dodecylsulfate salts, ethanesulfonate salts, formate salts, fumaric acid salts, glucoheptonate salts, glycerophosphate salts, gluconate salts, southern sulfate salts, heptanoate salts, caproate salts, hydroiodic acid salts, 2-hydroxy-ethanesulfonate salts, lactobionate salts, lactate salts, laurate salts, lauryl sulfate salts, malate salts, maleate salts, malonate salts, methanesulfonate salts, 2-naphthalenesulfonate salts, nicotinate salts, nitrate salts, oleate salts, oxalate salts, palmitate salts, pamoate salts, pectate salts, persulfates, 3-phenylpropionate salts, phosphate salts, bitter salts, pivalate salts, propionate salts, stearate salts, succinate salts, sulfate salts, tartrate salts, thiocyanate salts, p-toluenesulfonate salts, undecanoate salts, valerate salts, and the like. Representative alkali or alkaline earth metal salts include salts of sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include non-toxic ammonium salts, quaternary ammonium salts, and amine cations formed with counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates, as appropriate.

The pharmaceutically acceptable salts of the invention may be prepared by conventional methods, for example by dissolving the compounds of the invention in a water miscible organic solvent (e.g. acetone, methanol, ethanol and acetonitrile), adding thereto an excess of an organic or inorganic acid aqueous solution to precipitate the salt from the resulting mixture, removing the solvent and the remaining free acid therefrom, and then isolating the precipitated salt.

The precursors or metabolites of the invention may be precursors or metabolites well known in the art, as long as the precursors or metabolites are converted into compounds by in vivo metabolism. For example, "prodrugs" refer to those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like commensurate with a reasonable benefit/risk ratio, and are effective for their intended use. The term "prodrug" refers to a compound that is rapidly transformed in vivo to produce the parent compound of the formula described above, for example by metabolism in vivo, or N-demethylation of a compound of the invention.

"solvate" as used herein means a physical association of a compound of the invention with one or more solvent molecules (whether organic or inorganic). The physical association includes hydrogen bonding. In some cases, for example when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate will be able to be isolated. The solvent molecules in the solvate may be present in a regular arrangement and/or in a disordered arrangement. The solvate may comprise a stoichiometric or non-stoichiometric solvent molecule. "solvate" encompasses both solution phases and separable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolamides. Solvation methods are well known in the art.

The term "stereoisomers" as used herein is divided into conformational isomerism and configurational isomerism, which may be also divided into cis-trans isomerism and optical isomerism (i.e. optical isomerism), and conformational isomerism refers to a stereoisomerism phenomenon that an organic molecule with a certain configuration makes each atom or group of molecules generate different arrangement modes in space due to rotation or twisting of carbon and carbon single bonds, and commonly includes structures of alkane and cycloalkane compounds, such as chair-type conformations and boat-type conformations, which occur in cyclohexane structures. "stereoisomers" means that when a compound of the invention contains one or more asymmetric centers, it is useful as racemate and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The compounds of the invention have asymmetric centers, each of which produces two optical isomers, and the scope of the invention includes all possible optical isomers and diastereomeric mixtures and pure or partially pure compounds. The compounds described herein may exist in tautomeric forms having different points of attachment of hydrogen through displacement of one or more double bonds. For example, the ketone and its enol form are keto-enol tautomers. Each tautomer and mixtures thereof are included in the compounds of the present invention. All enantiomers, diastereomers, racemates, meso, cis-trans isomers, tautomers, geometric isomers, epimers, mixtures thereof and the like of the compounds of formula (I) to (III) are included within the scope of the present invention.

The term "isotopically-labeled" as used herein refers to molecules wherein the compound is isotopically labeled. Isotopes commonly used as isotopic labels are: the hydrogen isotope is selected from the group consisting of, ² h and ³ h is formed; carbon isotopes: ¹¹ C, ¹³ c and C ¹⁴ C, performing operation; chlorine isotopes: ³⁵ cl and Cl ³⁷ Cl; fluorine isotopes: ¹⁸ f, performing the process; iodine isotopes: ¹²³ i and ¹²⁵ i, a step of I; nitrogen isotopes: ¹³ n and ¹⁵ n; oxygen isotopes: ¹⁵ O, ¹⁷ o and ¹⁸ isotopes of O and sulfur ³⁵ S, S. These isotopically-labeled compounds can be used to study the distribution of a pharmaceutical molecule in a tissue. In particular deuterium ³ H and carbon ¹³ C, because they are easily labeled and conveniently detected, the application is wider. Certain heavy isotopes, such as heavy hydrogen @, for example ² H) The substitution can enhance the metabolic stability and prolong the half-life period, thereby achieving the aim of reducing the dosage and providing curative effect advantages. Isotopically-labeled compounds generally begin with a starting material that has been labeled, and are synthesized using known synthetic techniques like synthesizing non-isotopically-labeled compounds.

The invention also provides the use of the compounds of the invention in the manufacture of a medicament for the prophylaxis and/or treatment of cancer, tumour, inflammatory disease, autoimmune disease or immune mediated disease.

Furthermore, the present invention provides a pharmaceutical composition for preventing and/or treating cancer, tumor, inflammatory disease, autoimmune disease, neurodegenerative disease, attention-related disease or immune-mediated disease, comprising the compound of the present invention as an active ingredient. The pharmaceutical composition may optionally comprise a pharmaceutically acceptable carrier.

Furthermore, the present invention provides a method for preventing and/or treating cancer, tumor, inflammatory disease, autoimmune disease, neurodegenerative disease, attention-related disease or immune-mediated disease comprising administering to a mammal in need thereof a compound of the present invention.

Representative examples of inflammatory, autoimmune and immune-mediated diseases may include but are not limited to, arthritis, rheumatoid arthritis, spinal arthritis, gouty arthritis, osteoarthritis, juvenile arthritis, other arthritic conditions, lupus, systemic Lupus Erythematosus (SLE), skin-related diseases, psoriasis, eczema, dermatitis, allergic dermatitis, pain, lung disease, pulmonary inflammation, adult Respiratory Distress Syndrome (ARDS), pulmonary sarcoidosis, chronic pulmonary inflammatory diseases, chronic Obstructive Pulmonary Disease (COPD), cardiovascular diseases, atherosclerosis, myocardial infarction, congestive heart failure, myocardial ischemia reperfusion injury, inflammatory bowel disease, crohn's disease, ulcerative colitis, irritable bowel syndrome, asthma, sjogren's syndrome, autoimmune thyroid disease urticaria (rubella), multiple sclerosis, scleroderma, organ transplant rejection, xenograft, idiopathic Thrombocytopenic Purpura (ITP), parkinson's disease, alzheimer's disease, diabetes-related diseases, inflammation, pelvic inflammatory disease, allergic rhinitis, allergic bronchitis, allergic sinusitis, leukemia, lymphoma, B-cell lymphoma, T-cell lymphoma, myeloma, acute Lymphoblastic Leukemia (ALL), chronic Lymphoblastic Leukemia (CLL), acute Myelogenous Leukemia (AML), chronic Myelogenous Leukemia (CML), hairy cell leukemia, hodgkin's disease, non-hodgkin's lymphoma, multiple myeloma, myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), diffuse large B-cell lymphoma and follicular lymphoma.

Representative examples of cancers or tumors may include but are not limited to, skin cancer, bladder cancer, ovarian cancer, breast cancer, stomach cancer, pancreatic cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, neuroblastoma, rectal cancer, colon cancer, familial adenomatous polyposis, hereditary non-polyposis colorectal cancer, esophageal cancer, lip cancer, laryngeal cancer, hypopharynx cancer, tongue cancer, salivary gland cancer, stomach cancer, adenocarcinoma, medullary thyroid cancer, papillary thyroid cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, urinary carcinoma, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma, and peripheral nerve ectodermal tumors hodgkin's lymphoma, non-hodgkin's lymphoma, burkitt's lymphoma, acute Lymphoblastic Leukemia (ALL), chronic Lymphocytic Leukemia (CLL), acute Myelogenous Leukemia (AML), chronic Myelogenous Leukemia (CML), adult T-cell leukemia lymphoma, diffuse large B-cell lymphoma (DLBCL), hepatocellular carcinoma, gall bladder carcinoma, bronchogenic carcinoma, small cell lung carcinoma, non-small cell lung carcinoma, multiple myeloma, basal cell carcinoma, teratoma, retinoblastoma, choriocarcinoma, seminoma, rhabdomyosarcoma, craniopharyngeal pipe carcinoma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, ewing's sarcoma, or plasmacytoma.

The compounds of the present invention or pharmaceutically acceptable salts thereof may provide enhanced anticancer effects when administered in combination with additional anticancer agents or immune checkpoint inhibitors for the treatment of cancer or tumors.

Representative examples of anticancer agents for the treatment of cancer or tumors may include, but are not limited to, cell signaling inhibitors, chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan, carmustine, lomustine, streptozotocin, cisplatin, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbazine, methotrexate, fluorouracil, cytarabine, gemcitabine, mercaptopurine, fludarabine, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, topotecan, irinotecan, etoposide, trabectedin, dactinomycin, doxorubicin, epirubicin, daunomycin, mitoxantrone, bleomycin, mitomycin C, ixabepilone, tamoxifen, gonadorelin analog, megestrol, prednisone, dexamethasone, prednisone, thalidomide, interferon alpha calcium folinate, sirolimus lipidates, everolimus, afatinib, alisertib, amuvatinib, apatinib, axitinib, bortezomib, bosutinib, britinib, cabotinib, ceridinib, crenolanib, crizotinib, dabrafenib, dacatinib, danarotinib, dasatinib, multi-vitamin tinib, erlotinib, foretinib, ganetespib, gefitinib, ibrutinib, enotinib, imatinib, triamcinolone acetonide, dacatinib, dacalotinib, and pharmaceutical compositions thereof iniparib, lapatinib, lenvatinib, linifanib, linsitinib, masitinib, momellotinib, mo Tisha, lenatinib, nilotinib, niraparib, oprozomib, olaparib, pazopanib, picilinib, ponatinib, quinartinib, regorafenib, rigosertib, rucaparib, ruxolitinib, secatinib, saridegib, sorafenib, sunitinib, tiratinib, tivantinib, tivozanib, tofacitinib, trimitinib, vandetanib, velipine, vemurafenib, sevelipinib, sorafenib, and the like, velmoroxydine, volasentib, alemtuzumab, bevacizumab, belantuotuzumab Shan Kangwei, katuzumab, cetuximab, denouzumab, gemtuzumab, ipilimumab, nituzumab, ofatuzumab, panitumumab, rituximab, tositumomab, trastuzumab, PI3K inhibitors, CSF1R inhibitors, A2A and/or A2B receptor antagonists, IDO inhibitors, anti-PD-1 antibodies, anti-PD-L1 antibodies, LAG3 antibodies, TIM-3 antibodies, anti-CTLA-4 antibodies, or any combination thereof.

The compounds of the present invention or pharmaceutically acceptable salts thereof may provide enhanced therapeutic effects when administered in combination with additional therapeutic agents for the treatment of inflammatory, autoimmune and immune-mediated diseases.

Representative examples of therapeutic agents for the treatment of inflammatory, autoimmune, and immune-mediated diseases may include, but are not limited to, steroidal drugs (e.g., prednisone, hydropannisone, methyl hydropanitudine, cortisone, hydroxy cortisone, betamethasone, dexamethasone, etc.), methotrexate, leflunomide, anti-tnfα agents (e.g., etanercept, infliximab, ada Li Shan resistance, etc.), calcineurin inhibitors (e.g., tacrolimus, pimecrolimus, etc.), and antihistamines (e.g., diphenhydramine, hydroxyzine, loratadine, ebastine, ketotifen, cetirizine, levocetirizine, fexofenadine, etc.), and at least one or more therapeutic agents selected therefrom may be included in the pharmaceutical compositions of the present invention.

The compound of the present invention or a pharmaceutically acceptable salt thereof may be administered orally or parenterally as an active ingredient in an effective amount ranging from 0.1 to 2,000mg/kg body weight/day, preferably 1 to 1,000mg/kg body weight/day in the case of mammals including humans (body weight of about 70 kg), and administered in divided doses, single or 4 times daily, or with/without following a predetermined time. The dosage of the active ingredient may be adjusted according to a number of relevant factors, such as the condition of the subject to be treated, the type and severity of the disease, the rate of administration and the opinion of the physician. In some cases, amounts less than the above dosages may be suitable. An amount greater than the above dosage may be used if it does not cause deleterious side effects and may be administered in divided doses per day.

In addition, the present invention provides a method for preventing and/or treating a tumor, cancer, viral infection, organ transplant rejection, neurodegenerative disease, attention-related disease or autoimmune disease, comprising administering to a mammal in need thereof a compound of the present invention or a pharmaceutical composition of the present invention.

The pharmaceutical compositions of the present invention may be formulated according to any of the conventional methods into dosage forms for oral administration or parenteral administration (including intramuscular, intravenous and subcutaneous routes, intratumoral injection), such as tablets, granules, powders, capsules, syrups, emulsions, microemulsions, solutions or suspensions.

The pharmaceutical compositions of the invention for oral administration can be prepared by mixing the active ingredient with, for example, the following carriers: cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, surfactants, suspending agents, emulsifying agents and diluents.

Examples of carriers employed in the pharmaceutical compositions for injectable administration of the present invention may be water, salt solutions, dextrose-like solutions (glucose), alcohols, glycols, ethers (e.g., polyethylene glycol 400), oils, fatty acids, fatty acid esters, glycerides, surfactants, suspending agents and emulsifiers.

Other features of the present application will become apparent in the course of describing exemplary embodiments of the application, which are presented to illustrate the application and are not intended to be limiting thereof, the following examples being prepared, isolated and characterized using the methods disclosed herein.

The compounds of the present application may be prepared in a variety of ways known to those skilled in the art of organic synthesis, and may be synthesized using the methods described below as well as synthetic methods known in the art of organic synthetic chemistry or by variations thereof as will be appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reaction is carried out in a solvent or solvent mixture suitable for the kit materials used and for the transformation to be effected. Those skilled in the art of organic synthesis will understand that the functionality present on the molecule is a function of the proposed transformations. This sometimes requires judgment to change the order or starting materials of the synthesis steps to obtain the desired compounds of the application.

Detailed Description

Terminology

The terms used in the present application, including the specification and claims, are defined as follows, unless otherwise indicated. Conventional methods of mass spectrometry, nuclear magnetism, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are used, if not otherwise indicated. In the present application, the use of "or" and "means" and/or "unless otherwise indicated.

In the description and claims, a given formula or name shall encompass all stereoisomers and optical isomers thereof, as well as racemates in which the above isomers exist. Unless otherwise indicated, all chiral (enantiomers and diastereomers) and racemic forms are within the scope of the present invention. Various geometric isomers of c=c double bonds, c=n double bonds, ring systems, etc. may also be present in the compounds, and all such stable isomers are contemplated within the present invention. The present invention describes cis-and trans- (or E-and Z-) geometric isomers of the compounds of the present invention, and which may be separated into mixtures of isomers or separate isomeric forms. The compounds of the invention may be isolated in optically active or racemic forms. All processes for preparing the compounds of the invention and intermediates prepared therein are considered part of the present invention. When preparing the enantiomeric or diastereomeric products, they can be separated by conventional methods, for example by chromatography or fractional crystallization. Depending on the process conditions, the end products of the invention are obtained in free (neutral) or salt form. Both the free form and the salt of these end products are within the scope of the invention. If desired, one form of the compound may be converted to another form. The free base or acid may be converted to a salt; the salt may be converted to the free compound or another salt; mixtures of the isomeric compounds of the invention may be separated into the individual isomers. The compounds of the invention, free forms and salts thereof, may exist in various tautomeric forms in which hydrogen atoms are transposed to other parts of the molecule and thereby the chemical bonds between the atoms of the molecule are rearranged. It is to be understood that all tautomeric forms that may exist are included within the invention.

Unless otherwise defined, the definition of substituents of the invention are each independent of, and not interrelated with, each other, e.g., by way of example, and not by way of exhaustive, in one aspect, R for a substituent ^a (or R) ^a ') which are independent of each other in the definition of the different substituents. Specifically, for R ^a (or R) ^a ') in one substituentAlternatively, R is not meant to be ^a (or R) ^a ') have the same definition in all other substituents. More specifically, for example (by way of non-exhaustive list) for NR ^a R ^a In' when R ^a (or R) ^a Where the definition of') is selected from hydrogen, it is not meant to be in-C (O) -NR ^a R ^a In' R ^a (or R) ^a ') is necessarily hydrogen. In another aspect, when more than one R is present in a substituent ^a (or R) ^a ') at the same time, these R ^a (or R) ^a ') are also independent of each other. For example, in the substituent- (CR) ^a R ^a’ ) _m -O-(CR ^a R ^a’ ) _n In the case where m+n is 2 or more, m+n R's therein ^a (or R) ^a ') are independent of each other and may have the same or different meanings.

Unless otherwise defined, when a substituent is noted as "optionally substituted", the substituent is selected from, for example, substituents such as alkyl, cycloalkyl, aryl, heterocyclyl, halogen, hydroxy, alkoxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amino (wherein 2 amino substituents are selected from alkyl, aryl or arylalkyl), alkanoylamino, aroylamino, aralkylamino, substituted alkanoylamino, substituted arylamino, substituted aralkylamino, thio, alkylthio, arylthio, arylalkylthio, arylthiocarbonyl, arylalkylthiocarbonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, for example, -SO ₂ NH ₂ Substituted sulphonylamino, nitro, cyano, carboxyl, carbamoyl, e.g. -CONH ₂ Substituted carbamoyl radicals such as the-CONH alkyl, -CONH aryl, -CONH arylalkyl or in the case of having two substituents on the nitrogen selected from alkyl, aryl or arylalkyl radical, alkoxycarbonyl radicalsAryl, substituted aryl, guanidino, heterocyclyl, such as indolyl, imidazolyl, furanyl, thienyl, thiazolyl, pyrrolidinyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, homopiperazinyl, and the like, and substituted heterocyclyl.

The term "alkyl" or "alkylene" as used herein is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms. For example, "C ₁ -C ₆ Alkyl "means an alkyl group having 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl). In this context, alkyl is preferably alkyl having 1 to 6, more preferably having 1 to 4 carbon atoms.

The term "alkenyl" denotes a straight or branched hydrocarbon radical containing one or more double bonds and typically having a length of 2 to 20 carbon atoms. For example, "C2-C6 alkenyl" contains two to six carbon atoms. Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like. In this context, alkenyl groups are preferably C ₂ -C ₆ Alkenyl groups.

The term "alkynyl" denotes a straight or branched hydrocarbon radical containing one or more triple bonds and typically ranging in length from 2 to 20 carbon atoms. For example, "C ₂ -C ₆ Alkynyl "contains two to six carbon atoms. Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, and the like. In this context, alkynyl is preferably C ₂ -C ₆ Alkynyl groups.

The term "alkoxy" or "alkyloxy" refers to an-O-alkyl group. "C ₁ -C ₆ Alkoxy "(or alkyloxy) is intended to include C ₁ 、C ₂ 、C ₃ 、C ₄ 、C ₅ 、C ₆ An alkoxy group. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and t-butoxy. Herein, a text isThe alkoxy group is preferably an alkoxy group having 1 to 6, more preferably 1 to 4 carbon atoms. Similarly, "alkylthio" or "thio" means an alkyl group as defined above having the indicated number of carbon atoms attached via a sulfur bridge; such as methyl-S-and ethyl-S-.

The term "carbonyl" refers to an organofunctional group (c=o) formed by the double bond connection of two atoms of carbon and oxygen.

The term "aryl", alone or as part of a larger moiety such as "aralkyl", "arylalkoxy" or "aryloxyalkyl", refers to a monocyclic, bicyclic or tricyclic ring system having a total of 5 to 12 ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. In certain embodiments of the present invention, "aryl" refers to an aromatic ring system including, but not limited to, phenyl, biphenyl, indanyl, 1-naphthyl, 2-naphthyl, and tetrahydronaphthyl. The term "aralkyl" or "arylalkyl" refers to an alkyl residue attached to an aryl ring, non-limiting examples of which include benzyl, phenethyl, and the like. The fused aryl group may be attached to another group at a suitable position on the cycloalkyl ring or aromatic ring. The dashed lines drawn from the ring system indicate that the bond may be attached to any suitable ring atom.

The term "cycloalkyl" refers to a monocyclic or bicyclic cyclic alkyl group. Monocyclic cyclic alkyl means C ₃ -C ₈ Including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornyl. Branched cycloalkyl groups such as 1-methylcyclopropyl and 2-methylcyclopropyl are included in the definition of "cycloalkyl". The cyclic alkyl group of the bicyclic ring includes bridged, spiro or fused ring cycloalkyl groups. In this context, cycloalkyl is preferably C ₃ -C ₆ Cycloalkyl groups.

The term "cycloalkenyl" refers to a monocyclic or bicyclic cyclic alkenyl. Monocyclic cyclic alkenyl means C ₃ -C ₈ Cyclic alkenyl groups of (c) including, but not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and norbornenyl. Branched cycloalkenyl groups such as 1-methylcyclopropenyl and 2-methylcycloproplyAlkenyl groups are included in the definition of "cycloalkenyl". Bicyclic cyclic alkenyl includes bridged, spiro, or fused cyclic alkenyl.

"halo" or "halogen" includes fluoro, chloro, bromo and iodo. "haloalkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms and substituted with 1 or more halogens. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Examples of haloalkyl groups also include "fluoroalkyl groups" intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms and substituted with 1 or more fluorine atoms.

"haloalkoxy" or "haloalkyloxy" means an oxygen-bridged haloalkyl as defined above having the indicated number of carbon atoms. For example, "halo C ₁ -C ₆ Alkoxy "is intended to include C ₁ 、C ₂ 、C ₃ 、C ₄ 、C ₅ 、C ₆ Haloalkoxy groups. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, 2-trifluoroethoxy, and pentafluoroethoxy. Similarly, "haloalkylthio" or "thiohaloalkoxy" means a thio-bridged haloalkyl as defined above having the indicated number of carbon atoms; such as trifluoromethyl-S-and pentafluoroethyl-S-.

In the present disclosure, C is used when referring to some substituents _x1 -C _x2 This means that the number of carbon atoms in the substituent group may be x1 to x 2. For example, C ₀ -C ₈ Represents that the radical contains 0, 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, C ₁ -C ₈ Representing that the radicals contain 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, C ₂ -C ₈ Representing that the radicals contain 2, 3, 4, 5, 6, 7 or 8 carbon atoms, C ₃ -C ₈ Representing that the radicals contain 3, 4, 5, 6, 7 or 8 carbon atoms, C ₄ -C ₈ Representing that the radicals contain 4, 5, 6, 7 or 8 carbon atoms, C ₀ -C ₆ Represents that the radical contains 0, 1, 2, 3, 4, 5 or 6 carbon atoms, C ₁ -C ₆ Representing that the radicals contain 1, 2, 3, 4, 5 or 6 carbon atoms, C ₂ -C ₆ Representing that the radicals contain 2, 3, 4, 5 or 6 carbon atoms, C ₃ -C ₆ Meaning that the group contains 3, 4, 5 or 6 carbon atoms.

In the present disclosure, the expression "x1-x2 membered ring" is used when referring to a cyclic group (e.g., aryl, heteroaryl, cycloalkyl, and heterocycloalkyl), which means that the number of ring atoms of the group can be x1 to x 2. For example, the 3-12 membered cyclic group may be a 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 membered ring, the number of ring atoms of which may be 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; the 3-6 membered ring represents that the cyclic group may be a 3, 4, 5 or 6 membered ring, and the number of ring atoms may be 3, 4, 5 or 6; the 3-8 membered ring represents that the cyclic group may be a 3, 4, 5, 6, 7 or 8 membered ring, and the number of ring atoms may be 3, 4, 5, 6, 7 or 8; the 3-9 membered ring represents that the cyclic group may be a 3, 4, 5, 6, 7, 8 or 9 membered ring, and the number of ring atoms may be 3, 4, 5, 6, 7, 8 or 9; the 4-7 membered ring represents that the cyclic group may be a 4, 5, 6 or 7 membered ring, and the number of ring atoms may be 4, 5, 6 or 7; the 5-8 membered ring represents that the cyclic group may be a 5, 6, 7 or 8 membered ring, and the number of ring atoms may be 5, 6, 7 or 8; the 5-12 membered ring represents that the cyclic group may be a 5, 6, 7, 8, 9, 10, 11 or 12 membered ring, and the number of ring atoms may be 5, 6, 7, 8, 9, 10, 11 or 12; the 6-12 membered ring means that the cyclic group may be a 6, 7, 8, 9, 10, 11 or 12 membered ring, and the number of ring atoms may be 6, 7, 8, 9, 10, 11 or 12. The ring atom may be a carbon atom or a heteroatom, for example a heteroatom selected from N, O and S. When the ring is a heterocyclic ring, the heterocyclic ring may contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more ring heteroatoms, for example heteroatoms selected from N, O and S.

In the present disclosure, the one or more halogens may each be independently selected from fluorine, chlorine, bromine, and iodine.

The term "heteroaryl" means a stable 3-, 4-, 5-, 6-, or 7-membered aromatic monocyclic or aromatic bicyclic or 7-, 8-, 9-, 10-, 11-, 12-membered aromatic polycyclic heterocycle which is fully unsaturated or partially unsaturated and which contains carbon atoms and 1,2,3 or 4 heteroatoms independently selected from N, O and S; and includes any of the following polycyclic groups wherein any of the heterocycles defined above is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The nitrogen atom is substituted or unsubstituted (i.e., N or NR, where R is H or another substituent if defined). The heterocycle may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. If the resulting compound is stable, the heterocyclyl groups described herein may be substituted on a carbon or nitrogen atom. The nitrogen in the heterocycle may optionally be quaternized. Preferably, when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to each other. Preferably, the total number of S and O atoms in the heterocycle is no greater than 1. When the term "heterocycle" is used, it is intended to include heteroaryl. Examples of aryl radicals include, but are not limited to, acridinyl, azetidinyl, azepinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothienyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzotriazole, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4 aH-carbazolyl, carbolinyl, chromanyl, chromen, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro [2,3-b ] tetrahydrofuranyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, imidazopyridinyl, indolyl (indolenyl), indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinyl (atinoyl), isobenzofuranyl, isochromanyl isoindazolyl, isoindolinyl, isoindolyl, isoquinolyl, isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolyl, oxadiazolyl, 1,2, 3-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,3, 4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolopyridinyl, oxazolidinyl, naphthyridinyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidinonyl, 2H-pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrazolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2, 5-thiadiazinyl, 1,2, 3-thiadiazinyl, 1,2, 4-thiadiazinyl, 1,2, 5-thiadiazinyl, 1,3, 4-thiadiazinyl, thianthrenyl, thiazolyl, thienyl, thiazolopyridinyl thienothiazolyl, thienooxazolyl, thienoimidazolyl, thienyl, triazinyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, 1,2, 5-triazolyl, 1,3, 4-triazolyl and xanthenyl, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, indolyl, isoindolyl, indolinyl, 1H-indazolyl, benzimidazolyl, 1,2,3, 4-tetrahydroquinolinyl, 1,2,3, 4-tetrahydroisoquinolinyl, 5,6,7, 8-tetrahydro-quinolinyl, 2, 3-dihydro-benzofuranyl, chromanyl, 1,2,3, 4-tetrahydro-quinoxalinyl and 1,2,3, 4-tetrahydro-quinazolinyl. The term "heteroaryl" may also include biaryl structures formed from "aryl" and monocyclic "heteroaryl" as defined above, such as, but not limited to "-phenyl bipyridyl-", "-phenyl bipyrimidinyl", "-pyridinyl biphenyl", "-pyridinyl bipyrimidinyl-", "-pyrimidinyl biphenyl-"; wherein the invention also includes fused and spiro compounds containing, for example, the above-described heterocycles.

The term "heterocycloalkyl" as used herein refers to a monocyclic heterocycloalkyl system, or a bicyclic heterocycloalkyl system, and also includes spiroheterocycles or bridged heterocycloalkyl groups. A monocyclic heterocycloalkyl group refers to a 3-8 membered, saturated or unsaturated, but not aromatic, cyclic alkyl system containing at least one heteroatom selected from O, N, S and P. Bicyclic heterocycloalkyl system refers to a bicyclic system formed by a heterocycloalkyl fused to a phenyl, or a cycloalkyl, or a cycloalkenyl, or a heterocycloalkyl, or a heteroaryl.

The term "bridged cycloalkyl" as used herein refers to polycyclic compounds sharing two or more carbon atoms. Can be classified into bicyclic bridged ring hydrocarbons and polycyclic bridged ring hydrocarbons. The former is composed of two alicyclic rings sharing more than two carbon atoms; the latter is a bridged cyclic hydrocarbon consisting of three or more rings.

The term "spirocycloalkyl" as used herein refers to a polycyclic hydrocarbon having a single ring of carbon atoms in common with each other (referred to as spiro atoms).

The term "bridged ring hetero group" as used herein refers to a polycyclic compound having a common two or more carbon atoms, the ring having at least one heteroatom selected from O, N and S atoms. Can be divided into two-ring bridged heterocyclic rings and multiple-ring bridged heterocyclic rings.

The term "heterospirocyclic" as used herein refers to a polycyclic hydrocarbon having a single ring with a single carbon atom (referred to as the spiro atom) in common, the ring containing at least one heteroatom selected from O, N and S atoms.

The term "substituted" as used herein means that at least one hydrogen atom is replaced with a non-hydrogen group, provided that the normal valence is maintained and that the substitution results in a stable compound. As used herein, a ring double bond is a double bond formed between two adjacent ring atoms (e.g., c= C, C =n or n=n).

In the case where nitrogen atoms (e.g., amines) are present on the compounds of the present invention, these nitrogen atoms may be converted to N-oxides by treatment with an oxidizing agent (e.g., mCPBA and/or hydrogen peroxide) to obtain other compounds of the present invention. Thus, the nitrogen atoms shown and claimed are considered to both encompass the nitrogen shown and its N-oxides to obtain the derivatives of the invention.

When any variable occurs more than one time in any composition or formula of a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-3R, then the group may optionally be substituted with up to three R groups, and R is independently selected at each occurrence from the definition of R. Furthermore, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

The term "patient" as used herein refers to an organism treated by the methods of the present invention. Such organisms preferably include, but are not limited to, mammals (e.g., murine, simian, monkey, horse, bovine, porcine, canine, feline, etc.) and most preferably refer to humans.

The term "effective amount" as used herein means the amount of a drug or pharmaceutical agent (i.e., a compound of the present invention) that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician. Furthermore, the term "therapeutically effective amount" means an amount of: such amounts result in improved treatment, cure, prevention, or alleviation of a disease, disorder, or side effect, or a reduction in the rate of progression of a disease or disorder, as compared to a corresponding subject not receiving such amounts. An effective amount may be administered in one or more administrations, or dosages and is not intended to be limited to a particular formulation or route of administration. The term also includes within its scope an effective amount to enhance normal physiological function.

The term "treatment" as used herein includes any effect that results in an improvement in a condition, disease, disorder, etc., such as a reduction, decrease, modulation, improvement or elimination, or improvement of symptoms thereof.

The term "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions, and/or dosage forms which are: it is suitable for use in contact with human and animal tissue without undue toxicity, irritation, allergic response, and/or other problems or complications commensurate with a reasonable benefit/risk ratio, within the scope of sound medical judgment.

The phrase "pharmaceutically acceptable carrier" as used herein means a pharmaceutical substance, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc, magnesium stearate, calcium or zinc stearate, or stearic acid), or solvent encapsulating material, which involves carrying or transporting the subject compound from one organ or body part to another organ or body part. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the patient.

The term "pharmaceutical composition" means a composition comprising a compound of the invention and at least one other pharmaceutically acceptable carrier. "pharmaceutically acceptable carrier" refers to a medium commonly accepted in the art for delivery of biologically active agents to animals, particularly mammals, and includes (i.e., adjuvants, excipients or vehicles such as diluents, preservatives, fillers, flow control agents, disintegrants, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, antibacterial agents, antifungal agents, lubricants, and dispersing agents, depending upon the mode of administration and the nature of the dosage form.

Specific pharmaceutical and medical terminology

The term "acceptable" as used herein, means that a prescription component or active ingredient does not unduly adversely affect the health of the general therapeutic objective.

The term "cancer", as used herein, refers to an abnormal growth of cells that is not controllable and is capable of metastasis (transmission) under certain conditions. Cancers of this type include, but are not limited to, solid tumors (e.g., bladder, intestine, brain, chest, uterus, heart, kidney, lung, lymphoid tissue (lymphoma), ovary, pancreas, or other endocrine organ (e.g., thyroid), prostate, skin (melanoma), or hematological tumors (e.g., non-leukemia).

The term "co-administration" or similar terms, as used herein, refers to administration of several selected therapeutic agents to a patient, administered at the same or different times, in the same or different modes of administration.

The term "enhance" or "potentiating," as used herein, means that the intended result can be increased or prolonged in either efficacy or duration. Thus, in enhancing the therapeutic effect of a drug, the term "capable of enhancing" refers to the ability of the drug to increase or prolong the efficacy or duration of the drug in the system. As used herein, "potentiating value" means that the ability of another therapeutic agent to be maximally enhanced in an ideal system.

The term "immunological disorder" refers to a disease or condition that produces an adverse or detrimental response to an endogenous or exogenous antigen. As a result, the cells are often dysfunctional, or thus destroyed and dysfunctional, or destroy organs or tissues that may develop immune symptoms.

The term "kit" is synonymous with "product package".

The term "subject" or "patient" includes mammals and non-mammals. Mammals include, but are not limited to, mammals: humans, non-human primates such as gorillas, apes, and monkeys; agricultural animals such as cattle, horses, goats, sheep, pigs; domestic animals such as rabbits and dogs; laboratory animals include rodents such as rats, mice, guinea pigs, and the like. Non-mammalian animals include, but are not limited to, birds, fish, and the like. In a preferred aspect, the mammal selected is a human.

The terms "treat," "course of treatment," or "therapy" as used herein include alleviation, inhibition, or amelioration of symptoms or conditions of a disease; inhibit the occurrence of complications; improving or preventing underlying metabolic syndrome; inhibiting the occurrence of a disease or condition, such as controlling the progression of a disease or condition; alleviating a disease or symptom; causing the disease or symptom to subside; alleviating complications caused by diseases or symptoms, or preventing and/or treating signs caused by diseases or symptoms.

As used herein, a compound or pharmaceutical composition, upon administration, may result in an improvement in a disease, symptom, or condition, particularly an improvement in severity, delay of onset, slow progression, or decrease in duration. Whether stationary or temporary, continuous or intermittent, may be due to or associated with administration.

Route of administration

Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transdermal, vaginal, auditory canal, nasal, and topical. Further, by way of example only, parenteral administration includes intramuscular, subcutaneous, intravenous, intramedullary, ventricular, intraperitoneal, intralymphatic, and intranasal.

In one aspect, the administration of the compounds described herein is topical rather than systemic. In particular embodiments, the depot is administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Furthermore, in another specific embodiment, the drug is administered by a targeted drug delivery system. For example, liposomes encapsulated by organ-specific antibodies. In this particular embodiment, the liposomes are selectively targeted to a specific organ and absorbed.

Pharmaceutical composition and dosage

The invention also provides pharmaceutical compositions comprising a therapeutically effective amount of one or more compounds of the invention, and optionally one or more other therapeutic agents described above, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents. The compounds of the invention may be administered by any suitable means for any of the above uses, for example, orally, such as tablets, pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions), syrups and emulsions; sublingual delivery; is taken orally; parenteral, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion techniques (e.g., in the form of sterile injectable aqueous or nonaqueous solutions or suspensions); transnasally, including administration to the nasal membrane, such as by inhalation spray; topical, such as in the form of a cream or ointment; or rectally, such as in the form of suppositories; or intratumoral injection. They may be administered alone, but are typically administered using a drug carrier selected based on the chosen route of administration and standard pharmaceutical practice.

Pharmaceutical carriers are formulated according to a number of factors within the purview of one skilled in the art. These factors include, but are not limited to: the type and nature of the active agent formulated; a subject to whom the active agent-containing composition is to be administered; the intended route of administration of the composition; and targeted therapeutic indications. Pharmaceutically acceptable carriers include aqueous and nonaqueous liquid media and various solid and semi-solid pharmaceutically acceptable carriers.

The carrier may include a number of different ingredients and additives in addition to the active agent, such other ingredients being included in the formulation for a variety of reasons known to those skilled in the art, such as stabilizers, binders, and the like. For a description of suitable pharmaceutical carriers and the factors involved in carrier selection, see a number of readily available sources, for example, allen l.v. jr.et al remington: the Science and Practice of Pharmacy (2 Volumes), 22nd Edition (2012), pharmaceutical Press.

Of course, the dosage regimen of the compounds of the invention will vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health condition, medical condition and weight of the recipient; the nature and extent of the symptoms; the type of concurrent treatment; treatment frequency; the route of administration, the renal and hepatic function of the patient, and the desired effect. According to general guidelines, when used for the indicated effects, the daily oral dosage of each active ingredient should be from about 0.001 mg/day to about 10-5000 mg/day, preferably from about 0.01 mg/day to about 1000 mg/day, and most preferably from about 0.1 mg/day to about 250 mg/day. During constant infusion, the most preferred dosage for intravenous administration should be about 0.01 mg/kg/min to about 10 mg/kg/min. The compounds of the present invention may be administered in a single daily dose, or the total daily dose may be administered in divided doses of two, three or four times daily.

The compounds are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as pharmaceutical carriers) suitably selected with respect to the intended form of administration (e.g., oral tablets, capsules, elixirs and syrups) and consistent with conventional pharmaceutical practices.

Dosage forms suitable for administration (pharmaceutical compositions) may contain from about 1 mg to about 2000 mg of active ingredient per dosage unit. In these pharmaceutical compositions, the active ingredient will typically be present in an amount of about 0.1 to 95% by weight, based on the total weight of the composition.

Typical capsules for oral administration contain at least one compound of the invention (250 mg), lactose (75 mg) and magnesium stearate (15 mg). The mixture was passed through a 60 mesh screen and packaged into size 1 gelatin capsules.

Typical injectable formulations can be prepared as follows: at least one compound of the invention (250 mg) is placed in a bottle in a sterile manner, lyophilized in a sterile manner and sealed. For use, the vial contents were mixed with 2mL of physiological saline to produce an injectable formulation.

The scope of the present invention includes pharmaceutical compositions (alone or in combination with a pharmaceutical carrier) comprising a therapeutically effective amount of at least one compound of the present invention as an active ingredient. Optionally, the compounds of the present invention may be used alone, in combination with other compounds of the present invention, or in combination with one or more other therapeutic agents (e.g., anticancer agents or other pharmaceutically active substances).

Regardless of the route of administration selected, the compounds of the invention (which may be used in a suitable hydrated form) and/or the pharmaceutical compositions of the invention are formulated into pharmaceutical dosage forms by conventional methods known to those skilled in the art.

The actual dosage level of the active ingredient in the pharmaceutical compositions of the present invention may be varied to achieve amounts of the active ingredient that are effective to achieve the desired therapeutic response, composition and mode of administration for a particular patient, but which are non-toxic to the patient.

The selected dosage level will depend on a variety of factors including the activity of the particular compound of the invention or an ester, salt or amide thereof employed; a route of administration; administration time; the rate of excretion of the particular compound being used; the rate and extent of absorption; duration of treatment; other drugs, compounds and/or substances used in combination with the particular compound used; the age, sex, weight, condition, general health and previous medical history of the patient being treated.

A physician or veterinarian of ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, to achieve a desired therapeutic effect, a physician or veterinarian may begin the relative amounts of the compound of the invention used in the pharmaceutical composition at a level less than that required and step up the dosage until the desired effect is achieved. In general, a suitable daily dose of a compound of the invention will be the amount of the compound at the lowest dose effective to produce a therapeutic effect. Such effective dosages will generally depend on the factors described above. Generally, oral, intravenous, intraventricular and subcutaneous dosages of the compounds of the invention for patients range from about 0.01 to about 50mg/kg body weight/day. If desired, an effective daily dose of the active compound may be administered separately at appropriate intervals throughout the day in two, three, four, five, six or more sub-doses, optionally in unit dosage form. In certain aspects of the invention, the administration is once daily.

Although the compounds of the present invention may be administered alone, it is preferable to administer the compounds in the form of a pharmaceutical formulation (composition). Kit/product package

For use in the treatment of the above indications, the kit/product package is also described herein. These kits may consist of a conveyor, a pack or a container box which may be divided into multiple compartments to hold one or more containers, such as vials, tubes and the like, each of which contains a separate one of the components of the method. Suitable containers include bottles, vials, syringes, test tubes, and the like. The container is made of acceptable glass or plastic materials.

For example, the container may contain one or more of the compounds described herein, possibly in the form of pharmaceutical compounds, and possibly in the form of a mixture with other ingredients described herein. The container may have a sterile outlet (e.g., the container may be an iv bag or vial, and the vial stopper may be pierced by a hypodermic needle). Such kits may contain a compound, as well as instructions, tags, or instructions for use as described herein.

A typical kit may include one or more containers, each containing one or more materials (e.g., reagents, or concentrated mother liquor, and/or equipment) to accommodate commercial popularization and use of the compound by the user. Such materials include, but are not limited to, buffers, diluents, filters, needles, syringes, conveyors, bags, containers, bottles and/or tubes with a content list and/or instructions for use, and with instructions for packaging. The complete set of instructions is included.

The label may be displayed on or closely associated with the container. The appearance of a label on a container means that the label letters, numbers or other features are affixed, molded, engraved on the container; the label may also be present in a container box or shipping box containing a variety of containers, such as in a product insert. A label may be used to indicate a particular therapeutic use of the contents. The label may also indicate instructions for use of the content, such as described in the methods above.

All of the features described in this specification (including any accompanying claims, abstract and drawings), and/or all of the steps in any method or process so described, may be present in any combination, unless certain features or steps are mutually exclusive in the same combination.

The above-mentioned features of the invention, or of the embodiments, may be combined in any desired manner. All of the features disclosed in this specification may be combined with any combination of the features disclosed in this specification, and the various features disclosed in this specification may be substituted for any alternative feature serving the same, equivalent or similar purpose. The disclosed features are thus merely representative of general examples of equivalent or similar features, unless specified otherwise.

The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental procedures, which do not address the specific conditions in the examples below, are generally carried out under conventional conditions or under conditions recommended by the manufacturer. All percentages, ratios, proportions, or parts are by weight unless otherwise indicated.

The units in weight volume percent are well known to those skilled in the art and refer, for example, to the weight of solute (g) in 100 milliliters of solution. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred methods and materials described herein are presented for illustrative purposes only.

Examples

Universal procedure

When the preparation route is not included, the raw materials and reagents used in the present invention are known products, and can be synthesized according to the methods known in the art, or can be obtained by purchasing commercial products. The commercial reagents used were all used without further purification.

Room temperature refers to 20-30 ℃.

The reaction examples are not particularly described, and the reactions are all carried out under nitrogen atmosphere. The nitrogen atmosphere is defined as the reaction flask being attached to a balloon of about 1L of nitrogen.

The hydrogenation reaction is usually vacuumized, filled with hydrogen and repeatedly operated for 3 times. The hydrogen atmosphere is defined as the reaction flask being connected to a balloon of hydrogen gas of about 1L.

Microwave reaction is usedInitiator + microwave reactor.

The structure of the compounds of the present invention is determined by Nuclear Magnetic Resonance (NMR) and Mass Spectrometry (MS). NMR shift (. Delta.) of 10 ^-6 Units of (ppm) are given. NMR was determined using (Bruker Assetnd ^TM 500. Nuclear magnetic instrument, wherein the measuring solvent is deuterated dimethyl sulfoxide (DMSO-d 6), deuterated chloroform (CDCl) ₃ ) Deuterated methanol (CD) ₃ OD), internal standard is Tetramethylsilane (TMS). The following abbreviations are used for multiplicity of NMR signals: s=singlet, brs=broad, d=doublet, t=triplet, m=multiplet. Coupling constants are listed as J values, measured in Hz.

LC-MS was determined using a Thermo liquid chromatography apparatus (UltiMate 3000+MSQ PLUS). HPLC was determined using a Thermo high pressure liquid chromatograph (UltiMate 3000). Reverse phase preparative chromatography a Thermo (UltiMate 3000) reverse phase preparative chromatograph was used. Quick column chromatography using Ai Jieer (FS-9200T) automatic column passing machine, silica gel pre-packed column using Santai And (5) preassembling the column. Cigarette for thin layer chromatography silica gel plateThe specification of the thin layer chromatography separation and purification product adopted by the Taihuanghai HSGF254 or Qingdao GF254 silica gel plate is 0.4 mm-0.5 mm.

Example 1

(S) -4, 5-dimethyl-2- ((trans-3- (3, 4, 5-trifluorophenoxy) cyclobutyl) amino) -4,5,9, 10-tetrahydro-6H, 8H-pyrido [3,2, 1-des ] pteridin-6-one

Compound 1 was prepared by the following steps:

the first step: cis-3-BOC-aminocyclobutanol 1a (250 mg,1.34 mmol), methylsulfonic anhydride (463mg, 2.67 mmol) and N, N-diisopropylethylamine (517 mg,4.01 mmol) were dissolved in dichloromethane (2 mL) and stirred overnight at room temperature. TLC monitored the end of the reaction, the reaction was diluted with dichloromethane, washed successively with water and saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give yellow solid 1b (300 mg, yield 84%). ¹ H NMR(500MHz,DMSO-d6)δ7.23(d,J＝8.3Hz,1H),4.69-4.64(m,1H),3.63-3.60(m,1H),3.13(s,3H),2.70-2.62(m,2H),2.16-2.09(m,2H),1.37(s,9H)。

And a second step of: compound 1b (300 mg,1.13 mmol), compound 1c (251 mg,1.70 mmol) and cesium carbonate (737 mg,2.26 mmol) were dissolved in N, N-dimethylformamide (2 mL) and stirred overnight at 80 ℃. LCMS monitored the end of the reaction, the reaction was diluted with ethyl acetate, washed sequentially with water and saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=20/1) to give 1d (280 mg, 78% yield) as a white solid. ESI-MS (m/z): 318.6[ M+H ] ] ⁺ 。

And a third step of: compound 1d (280 mg, 882. Mu. Mol) was dissolved in methylene chloride (2 mL) and added dropwise1, 4-Dioxahexacyclic hydrochloride solution (4M, 1.10 mL) was stirred overnight at room temperature. LCMS monitored the end of the reaction and the reaction concentrated to give 1e as a white solid (170 mg, 75% yield). ESI-MS (m/z): 218.4[ M+H ]] ⁺ 。

Fourth step: 2, 4-dichloropyrido [3,2-d ]]Pyrimidine 1f (1.7 g,8.50 mmol) and methyl (S) -2- (methylamino) propionate hydrochloride 1g (1.70 g,11.05 mmol) were dissolved in tetrahydrofuran (40 mL), triethylamine (2.58 g,25.50mmol,3.53 mL) was added, and stirred overnight at room temperature. LCMS monitored the end of the reaction, the reaction was concentrated and the residue was purified by column chromatography on silica gel to give a yellow oil for 1h (1.1 g, 46% yield). ESI-MS (m/z): 281.2[ M+H ]] ⁺ 。

Fifth step: compound 1h (1.1 g,3.92 mmol) was dissolved in tetrahydrofuran (20 mL), aqueous hydrochloric acid (6N, 0.65 mL) and platinum dioxide (88 mg,0.39 mmol) were added, the reaction system was replaced with hydrogen gas with a hydrogen balloon, and stirred at room temperature under hydrogen balloon pressure for 48 hours, and LCMS monitored the reaction to completion. The reaction solution was diluted with methanol, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to give 1i (900 mg, yield 90%) as a white solid. ESI-MS (m/z): 253.2[ M+H ] ] ⁺ 。

Sixth step: compound 1i (50 mg, 197umol), compound 1e (65 mg,257 umol) and p-toluenesulfonic acid monohydrate (3.7 mg,19 umol) were dissolved in n-butanol (2 mL) and reacted at microwave 160℃for 2 hours. LCMS monitored the end of the reaction. The reaction solution was purified by reverse phase preparative HPLC to give 1 as a white solid (13 mg, yield 15%). ESI-MS (m/z): 434.3[ M+H ]] ⁺ ； ¹ H NMR(500MHz,DMSO-d6)δ6.90-6.82(m,3H),4.86-4.81(m,1H),4.42-4.36(m,1H),4.12(q,J＝6.8Hz,1H),4.05-4.00(m,1H),3.30-3.24(m,1H),2.94(s,3H),2.55-2.52(m,2H),2.48-2.38(m,2H),2.36-2.28(m,2H),1.97-1.88(m,1H),1.85-1.76(m,1H),1.23(d,J＝6.8Hz,3H)。

Example 2

(S) -4, 5-dimethyl-2- ((trans-3- ((6- (trifluoromethyl) pyridin-3-yl) oxo) cyclobutyl) amino) -4,5,9, 10-tetrahydro-6H, 8H-pyrido [3,2, 1-des ] pteridin-6-one

Compound 2 was prepared by the following steps:

the first step: compound 1b (500 mg,1.88 mmol), compound 2a (463mg, 2.83 mmol) and cesium carbonate (1.23 g,3.77 mmol) were dissolved in N, N-dimethylformamide (2 mL) and stirred overnight at 80 ℃. LCMS monitored the end of the reaction, the reaction was diluted with ethyl acetate, washed sequentially with water and saturated brine, the organic phase was dried over anhydrous sodium sulfate, the reaction concentrated, and the residue purified by silica gel column chromatography (dichloromethane/methanol=20/1) to give 2b (500 mg, 79% yield) as a white solid. ESI-MS (m/z): 333.3[ M+H ]] ⁺ 。

And a second step of: compound 2b (500 mg,1.50 mmol) was dissolved in dichloromethane (2 mL), and 1, 4-dioxane solution of hydrochloric acid (4M, 1.88 mL) was added dropwise and stirred at room temperature overnight. LCMS monitored the end of the reaction and the reaction concentrated to give 2c as a white solid (300 mg, 74% yield). ESI-MS (m/z): 233.5[ M+H ] ] ⁺ 。

And a third step of: compound 1i (50 mg, 197umol), compound 2c (68 mg,256 umol) and p-toluenesulfonic acid monohydrate (3.7 mg,19 umol) were dissolved in n-butanol (2 mL) and reacted at microwave 160℃for 2 hours. LCMS monitored the end of the reaction. The reaction solution was purified by reverse phase preparative HPLC to give white solid 2 (10.1 mg, yield 11%). ESI-MS (m/z): 449.2[ M+H ]] ⁺ ； ¹ H NMR(500MHz,DMSO-d6)δ8.38(d,J＝2.8Hz,1H),7.83(d,J＝8.7Hz,1H),7.46(dd,J＝8.7,2.9Hz,1H),6.91(d,J＝6.9Hz,1H),5.05-5.00(m,1H),4.46-4.42(m,1H),4.12(q,J＝6.9Hz,1H),4.03-3.99(m,2H),3.28-3.25(m,1H),2.95(s,3H),2.50-2.38(m,4H),1.97-1.87(m,1H),1.84-1.77(m,1H),1.23(d,J＝6.7Hz,3H)。

Example 3

(R) -4, 6-dimethyl-N- (trans-3- (3, 4, 5-trifluorophenoxy) cyclobutyl) -5, 6-dihydro-4H-pyrrolo [3,2, 1-des ] pteridin-2-amine

Compound 3 was prepared by the following steps:

the first step: compound 3a (500 mg,2.66 mmol), compound 3b (946 mg,3.99 mmol), potassium carbonate (1.47 g,10.64 mmol) and 18-crown-6 (351 mg,1.33 mmol) were dissolved in 1, 4-dioxane (10 mL) and stirred overnight at 80 ℃. LCMS monitored the end of the reaction, the reaction was diluted with ethyl acetate, washed sequentially with water and saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to give 3c (600 mg, 65% yield) as a yellow solid. ESI-MS (m/z): 345.3[ M+H ]] ⁺ 。

And a second step of: compound 3c (600 mg,1.74 mmol) was dissolved in dichloromethane (2 mL), 1, 4-dioxane solution of hydrochloric acid (4M, 2.17 mL) was added dropwise, and the mixture was stirred at room temperature overnight. LCMS monitored the end of the reaction and the reaction concentrated to give a white solid 3d (400 mg, 81% yield). ESI-MS (m/z): 245.3[ M+H ] ] ⁺ 。

And a third step of: compound 3d (400 mg,1.63 mmol) and N, N-diisopropylethylamine (630 mg,4.90 mmol) were dissolved in 1, 4-dioxane (5 mL) and stirred overnight at 100deg.C. LCMS monitored the end of the reaction, the reaction concentrated and the residue purified by silica gel column chromatography (dichloromethane/methanol=10/1) to give 3e as a yellow solid (150 mg, 44% yield). ESI-MS (m/z): 209.4[ M+H ]] ⁺ 。

Fourth step: compound 3e (150 mg, 428 mol), methyl iodide (153 mg,1.08 mmol) and cesium carbonate (460 mg,1.44 mmol) were dissolved in N, N-dimethylformamide (2 mL) and stirred at 80 ℃Mix overnight. LCMS monitored the end of the reaction, the reaction was diluted with ethyl acetate, washed with water and then saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=20/1) to give 3f (100 mg, yield 62%) as a yellow solid. ESI-MS (m/z): 223.4[ M+H ]] ⁺ 。

Fifth step: compound 3f (30 mg, 134. Mu. Mol), compound 1e (68 mg, 256. Mu. Mol) and trifluoroacetic acid (1.5 mg, 13. Mu. Mol) were dissolved in n-butanol (2 mL) and reacted at microwave 160℃for 2 hours. LCMS monitored the end of the reaction. The reaction solution was purified by reverse phase preparative HPLC to give 3 as a white solid (6.8 mg, 12% yield). ESI-MS (m/z): 404.2[ M+H ] ] ⁺ ； ¹ H NMR(500MHz,DMSO-d6)δ8.19(s,1H),7.30(d,J＝2.8Hz,1H),6.92-6.82(m,2H),6.04(d,J＝2.8Hz,1H),4.93-4.81(m,1H),4.46-4.41(m,1H),4.37-4.24(m,1H),3.64(dd,J＝12.4,3.9Hz,1H),3.35-3.30(m,1H),3.05(s,3H),2.48-2.42(m,2H),2.38-2.33(m,2H),1.42(d,J＝6.4Hz,3H)。

Example 4

(R) -4, 6-dimethyl-N- (trans-3- ((6- (trifluoromethyl) pyridin-3-yl) oxo) cyclobutyl) -5, 6-dihydro-4H-pyrrolo [3,2, 1-des ] pteridin-2-amine

Compound 4 was prepared by the following steps:

the first step: compound 3f (30 mg, 134. Mu. Mol), compound 2b (40 mg, 175. Mu. Mol) and trifluoroacetic acid (1.5 mg, 13. Mu. Mol) were dissolved in n-butanol (2 mL) and reacted at microwave 160℃for 2 hours. LCMS monitored the end of the reaction. The reaction solution was purified by reverse phase preparative HPLC to give 4 as a white solid (9.3 mg, 16% yield). ESI-MS (m/z): 419.5[ M+H ]] ⁺ ； ¹ H NMR(400MHz,DMSO-d6)δ8.39(d,J＝2.8Hz,1H),8.20(s,1H),7.84(d,J＝8.7Hz,1H),7.47(dd,J＝8.7,2.9Hz,1H),7.30(d,J＝2.8Hz,1H),6.69(br s,1H),6.04(d,J＝2.8Hz,1H),5.08-5.02(m,1H),4.53-4.45(m,1H),4.35-4.25(m,1H),3.64(dd,J＝12.3,3.9Hz,2H),3.05(s,3H),2.50-2.40(m,4H),1.42(d,J＝6.4Hz,3H)。

Example 5

(S) -4, 6-dimethyl-N- (trans-3- ((6- (trifluoromethyl) pyridin-3-yl) oxo) cyclobutyl) -5, 6-dihydro-4H-pyrrolo [3,2, 1-des ] pteridin-2-amine

Compound 5 was prepared by the following steps:

the first step: compound 3a (792 mg,4.21 mmol), compound 5a (1 g,4.21 mmol), potassium carbonate (2.33 g,16.86 mmol) and 18-crown-6 (557 mg,2.11 mmol) were dissolved in 1, 4-dioxane (10 mL) and stirred overnight at 80 ℃. LCMS monitored the end of the reaction, the reaction was diluted with ethyl acetate, washed sequentially with water and saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to give 5b (1 g, 68% yield) as a yellow solid. ESI-MS (m/z): 345.3[ M+H ] ] ⁺ 。

And a second step of: compound 5b (1.0 g,2.90 mmol) was dissolved in dichloromethane (10 mL), and 1, 4-dioxane solution of hydrochloric acid (4M, 3.62 mL) was added dropwise and stirred overnight at room temperature. LCMS monitored the end of the reaction and the reaction concentrated to give 5c as a white solid (700 mg, 98% yield). ESI-MS (m/z): 245.4[ M+H ]] ⁺ 。

And a third step of: compound 5c (700 mg,2.86 mmol) and N, N-diisopropylethylamine (1.11 g,8.57mmol,1.49 mL) were dissolved in 1, 4-dioxane (10 mL) and stirred at 100deg.CMix overnight. LCMS monitored the end of the reaction, the reaction concentrated and the residue purified by silica gel column chromatography (dichloromethane/methanol=10/1) to give a yellow solid 5d (250 mg, 41% yield). ESI-MS (m/z): 209.4[ M+H ]] ⁺ 。

Fourth step: compound 5d (250 mg,1.20 mmol), methyl iodide (153 mg,1.08 mmol) and cesium carbonate (460 mg,1.44 mmol) were dissolved in N, N-dimethylformamide (2 mL) and stirred overnight at 80 ℃. LCMS monitored the end of the reaction, the reaction was diluted with ethyl acetate, washed sequentially with water and saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=20/1) to give 5e (150 mg, 56% yield) as a yellow solid. ESI-MS (m/z): 223.4[ M+H ] ] ⁺ 。

Fifth step: compound 5e (30 mg, 134. Mu. Mol), compound 2b (47 mg, 175. Mu. Mol) and trifluoroacetic acid (1.5 mg, 13. Mu. Mol) were dissolved in n-butanol (2 mL) and reacted at microwave 160℃for 2 hours. LCMS monitored the end of the reaction. The reaction solution was purified by reverse phase preparative HPLC to give 5 as a white solid (9.2 mg, 16% yield). ESI-MS (m/z): 419.4[ M+H ]] ⁺ ； ¹ H NMR(400MHz,DMSO-d6)δ8.39(d,J＝2.8Hz,1H),8.22(s,1H),7.84(d,J＝8.7Hz,1H),7.47(dd,J＝8.7,2.8Hz,1H),7.30(d,J＝2.8Hz,1H),6.74(br s,1H),6.04(d,J＝2.8Hz,1H),5.10-4.99(m,1H),4.51-4.45(m,1H),4.31-4.25(m,1H),3.64(d,J＝8.5Hz,1H),3.34-3.27(m,1H),3.05(s,3H),2.49-2.39(m,4H),1.42(d,J＝6.4Hz,3H)。

Example 6

(S) -4, 6-dimethyl-N- (trans-3- (3, 4, 5-trifluorophenoxy) cyclobutyl) -5, 6-dihydro-4H-pyrrolo [3,2, 1-des ] pteridin-2-amine

Compound 6 was prepared by the following steps:

the first step: compound 5e (30 mg, 134. Mu. Mol), compound 1e (44 mg, 175. Mu. Mol) and trifluoroacetic acid (1.5 mg, 13. Mu. Mol) were dissolved in n-butanol (2 mL) and reacted at microwave 160℃for 2 hours. LCMS monitored the end of the reaction. The reaction solution was purified by reverse phase preparative HPLC to give 6 as a white solid (17.84 mg, yield 32%). ESI-MS (m/z): 404.2[ M+H ]] ⁺ ； ¹ H NMR(400MHz, DMSO-d6)δ8.22(s,1H),7.31(d,J＝2.8Hz,1H),6.91-6.84(m,2H),6.05(d,J＝2.8Hz,1H),4.94-4.80(m,1H),4.45-4.40(m,1H),4.31-4.25(m,1H),3.68-3.63(m,1H),3.31(dd,J＝12.4,8.2Hz,1H),3.05(s,3H),2.47-2.29(m,4H),1.42(d,J＝6.4Hz,3H)。

Example 7

(S) -4, 5-dimethyl-2- ((cis-3- ((6- (trifluoromethyl) pyridin-3-yl) amino) cyclobutyl) amino) -4,5,9, 10-tetrahydro-6H, 8H-pyrido [3,2, 1-des ] pteridin-6-one

Compound 7 was prepared by the following steps:

the first step: 5-bromo-2-trifluoromethylpyridine 7a (457mg, 2.00 mmol), cis-3-amino-1-cyclobutyl carbamic acid tert-butyl ester 7b (372 mg,2.00 mmol), pd2 (dba) 3 (91.5 mg,0.10 mmol), xantphos (115.6 mg,0.20 mmol) and cesium carbonate (1.3 g,4.00 mmol) were dissolved in dioxane (10 mL) and stirred at 100℃overnight under nitrogen. TLC monitored the end of the reaction, the reaction cooled to room temperature, filtered, the filter cake washed twice with dichloromethane, the filtrate concentrated and the residue purified by silica gel column chromatography (dichloromethane/methanol=20/1) to give 7c as a white solid (580 mg, 87% yield). ESI-MS (m/z): 332.3[ M+H ] ] ⁺ 。

And a second step of:compound 7c (100 mg,0.3 mmol) was dissolved in methanol (5 mL), and a solution of hydrogen chloride-dioxane (4M, 0.75mL,3 mmol) was added dropwise at room temperature and stirred at room temperature for 2 hours. TLC monitored the end of the reaction and the reaction was spun dry to give 7d (80 mg, 99% yield) as a white solid. ESI-MS (m/z): 232.4[ M+H ]] ⁺ 。

And a third step of: compound 1i (76 mg, 0.30. Mu. Mol), compound 7d (80 mg,0.30 mol) and p-toluenesulfonic acid monohydrate (5.7 mg,0.03 mol) were dissolved in n-butanol (3 mL) and reacted at microwave 160℃for 2 hours. LCMS monitored the end of the reaction. The reaction solution was purified by reverse phase preparative HPLC to give 7 as a white solid (45 mg, yield 33%). ESI-MS (m/z): 448.5[ M+H ]] ⁺ ； ¹ H NMR(400MHz,DMSO-d ₆ )δ8.01(d,J＝2.7Hz,1H),7.51(d,J＝8.7Hz,1H),6.98-6.90(m,2H),6.81(d,J＝7.5Hz,1H),4.19-3.97(m,3H),3.58(q,J＝7.4Hz,1H),3.32-3.21(m,1H),2.96(s,3H),2.83-2.70(m,2H),2.55-2.52(m,2H),1.98-1.88(m,1H),1.86-1.73(m,3H),1.23(d,J＝6.8Hz,3H)。

Example 8

(S) -4, 5-dimethyl-2- ((trans-3- ((6- (trifluoromethyl) pyridin-3-yl) amino) cyclobutyl) amino) -4,5,9, 10-tetrahydro-6H, 8H-pyrido [3,2, 1-des ] pteridin-6-one

The first step 7b of example 7 was replaced with tert-butyl (trans-3-aminocyclobutyl) carbamate and a similar procedure and reaction procedure was used to give compound 8.ESI-MS (m/z): 448.5[ M+H ]] ⁺ ； ¹ H NMR(400MHz,DMSO-d ₆ )δ7.98(d,J＝2.7Hz,1H),7.53(d,J＝8.6Hz,1H),7.08(d,J＝5.5Hz,1H),6.92-6.80(m,2H),4.44(q,J＝7.3Hz,1H),4.12(q,J＝6.7Hz,1H),4.07-3.98(m,1H),3.96-3.86(m,1H),3.32-3.22(m,1H),2.95(s,3H),2.42-2.28(m,2H),2.25-2.14(m,2H),1.97-1.87(m,1H),1.85-1.72(m,1H),1.23(d,J＝6.8Hz,3H)。

Example 9

(S) -4, 5-dimethyl-2- ((trans-3- ((6- (trifluoromethyl) pyridin-3-yl) amino) cyclopentyl) amino) -4,5,9, 10-tetrahydro-6H, 8H-pyrido [3,2, 1-des ] pteridin-6-one

With N- [ trans-3-aminocyclopentyl groups ]Tert-butyl carbamate was used in place of the first step 7b of example 7, in a similar manner and reaction procedure to give compound 9.ESI-MS (m/z): 462.4[ M+H ]] ⁺ ； ¹ H NMR(400MHz,DMSO-d ₆ )δ8.04(d,J＝2.7Hz,1H),7.51(d,J＝8.7Hz,1H),6.98(dd,J＝8.7,2.8Hz,1H),6.74(d,J＝6.6Hz,1H),6.56(d,J＝7.6Hz,1H),4.29(q,J＝6.9Hz,1H),4.11(q,J＝6.7Hz,1H),4.03(dt,J＝13.0,4.7Hz,1H),3.92(q,J＝6.4Hz,1H),3.30-3.22(m,1H),2.93(s,3H),2.53(d,J＝5.0Hz,2H),2.19-2.02(m,2H),1.91(p,J＝6.9Hz,2H),1.80(dt,J＝12.7,6.7Hz,2H),1.58-1.41(m,2H),1.23(d,J＝6.8Hz,3H)。

Example 10

(S) -4, 5-dimethyl-2- ((1- ((6- (trifluoromethyl) pyridin-3-yl) methyl) azetidin-3-yl) amino) -4,5,9, 10-tetrahydro-6H, 8H-pyrido [3,2, 1-des ] pteridin-6-one

Compound 10 was prepared by the following steps:

the first step: compound 1i (200 mg,791 umol) and compound 10a (457 mg,1.58 mmol) were dissolved in 10mL dioxane, pd was added ₂ dba ₃ (72 mg,79 mmole), S-Phos (65 mg,158 mmole) and sodium tert-butoxide (228 mg,2.37 mmole), under nitrogen at 100deg.C overnight, LCMS monitored complete reaction of the starting materials. Concentrating the reaction solution and introducing the residuePurification by preparative thin layer chromatography (dichloromethane/methanol=20/1) afforded compound 10b (90 mg, 29% yield) as a yellow oil. ESI-MS (m/z): 389.5[ M+H ]] ⁺ 。

And a second step of: compound 10b (90 mg,232 umol) was dissolved in 10mL of dichloromethane, trifluoroacetic acid (1 mL) was added, stirring was performed at room temperature for 4 hours, LCMS was monitored for complete reaction of the starting materials, and the reaction solution was concentrated to give compound 10c (90 mg), a yellow oil, which was directly used for the next reaction. ESI-MS (m/z): 289.4[ M+H ]] ⁺ 。

And a third step of: compounds 10c (90 mg) and 10d (53 mg, 279 umol) were dissolved in 10mL of acetonitrile, potassium carbonate (93 mg,673 umol) was added and reacted at 60℃for 4 hours, and LCMS monitored complete reaction of the starting materials. The reaction was concentrated, and the residue was purified by reverse phase preparative HPLC to give compound 10 (10 mg, yield 10.3%) as a white solid. ESI-MS (m/z): 448.5[ M+H ] ] ⁺ ； ¹ H NMR(500MHz,DMSO-d6)δ8.66(s,1H),7.96(d,J＝8.0Hz,1H),7.85(d,J＝8.0Hz,1H),6.89(d,J＝6.9Hz,1H),4.40(q,J＝7.0Hz,1H),4.12(q,J＝6.8Hz,1H),4.01(dt,J＝13.0,4.9Hz,1H),3.72(s,2H),3.59(t,J＝6.8Hz,2H),3.30-3.23(m,1H),2.95(d,J＝8.0Hz,5H),2.52(s,2H),1.92(d,J＝14.5Hz,1H),1.80(d,J＝3.9Hz,1H),1.23(d,J＝6.7Hz,3H)。

Example 11

(S) -4, 5-dimethyl-2- (((1S, 3 r) -3- (((6- (trifluoromethyl) pyridin-3-yl) oxo) methyl) cyclobutyl) amino) -4,5,9, 10-tetrahydro-6 h,8 h-pyrido [3,2, 1-des ] pteridin-6-one

Compound 11 was prepared by the following steps:

the first step: tert-butyl cis-3-hydroxymethyl cyclobutylcarbamate 11a (150 mg,0.745 mmol), methylsulfonic anhydride (259mg,1.49 mmol) and N, N-diisopropylethylamine (385 mg,2.98 mmol) were dissolved in dichloromethane (5 mL) and stirred overnight at room temperature. TLC monitored the end of the reaction, the reaction was diluted with dichloromethane, washed successively with water and saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give 11b as a yellow solid (204 mg, yield 98%). ¹ H NMR(500MHz,DMSO-d6)δ7.10(d,J＝8.1Hz,1H),4.11(d,J＝5.2Hz,2H),3.19(d,J＝1.6Hz,1H),3.16(d,J＝1.6Hz,3H),2.26(d,J＝5.9Hz,1H),1.68(d,J＝8.7Hz,2H),1.57-1.47(m,2H),1.37(s,9H)。

And a second step of: compound 11b (204 mg,731 mmol), compound 2a (131 mg,0.8 mmol) and cesium carbonate (480 mg,1.49 mmol) were dissolved in N, N-dimethylformamide (5 mL) and stirred overnight at 90 ℃. TLC monitored the end of the reaction, the reaction was diluted with water, extracted with ethyl acetate, washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=3/1) to give 11c (185 mg, yield 72%) as a yellow solid. ESI-MS (m/z): 347.2[ M+H ] ] ⁺ 。

And a third step of: compound 11c (120 mg, 346. Mu. Mol) was dissolved in methylene chloride (5 mL), and a 4M dioxane solution of hydrochloric acid (0.87 mL) was added at 0deg.C and stirred overnight. TLC monitored the end of the reaction and was directly spin-dried to give 11d (85 mg, 99% yield) as a white solid. ESI-MS (m/z): 247.4[ M+H ]] ⁺ 。

Fourth step: compound 11d (82 mg, 336. Mu. Mol), compound 1i (85 mg, 336. Mu. Mol) and p-toluenesulfonic acid monohydrate (5.7 mg, 33.6. Mu. Mol) were dissolved in n-butanol (3 mL) and reacted at microwave 160℃for 3 hours. LCMS monitored the end of the reaction. The reaction solution was purified by reverse phase preparative HPLC to give 11 as a white solid (25 mg, 16% yield). ESI-MS (m/z): 463.3[ M+H ]] ⁺ ； ¹ H NMR(500MHz,DMSO-d6)δ8.47(d,J＝3.0Hz,1H),7.85(d,J＝8.5Hz,1H),7.64(dd,J＝9.0,3.0Hz,1H),6.81(br s,1H),4.32-4.23(m,1H),4.16-4.09(m,3H),4.08-4.01(m,1H),3.30-3.24(m,2H),2.95(s,3H),2.48-2.38(m,3H),1.97-1.88(m,1H),1.86-1.73(m,3H),1.23(d,J＝7.0Hz,3H)。

Example 12

(S) -2- (((1S, 3 r) -3- (((1-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) oxy) methyl) cyclobutyl) amino) -4, 5-dimethyl-4, 5,9, 10-tetrahydro-6H, 8H-pyrido [3,2, 1-des ] pteridin-6-one

Compound 12 was prepared by the following steps:

the first step: ethyl trifluoroacetoacetate 12a (1.7 g,9.21 mmol) and cyclopropylhydrazine hydrochloride 12b (1.0 g,9.21 mmol) were dissolved in 20mL of ethanol and reacted overnight at 80 ℃. The reaction solution was concentrated, and the residue was slurried with petroleum ether and filtered to give compound 12c (800 mg, yield 45%) as a brown solid. ESI-MS (m/z): 193.2[ M+H ] ] ⁺ 。

And a second step of: compound 11b (872 mg,3.12 mmol), compound 12c (500 mg,2.61 mmol) and cesium carbonate (1.70 g,5.22 mmol) were dissolved in N, N-dimethylformamide (20 mL) and stirred overnight at 90 ℃. TLC monitored the end of the reaction, the reaction was diluted with water, extracted with ethyl acetate, washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=3/1) to give 12d (495 mg, yield 52%) as a yellow solid. ESI-MS (m/z): 362.6[ M+H ]] ⁺ 。

And a third step of: compound 12d (495mg, 1.1 mmol) was dissolved in dichloromethane (30 mL), and a 4M dioxane solution of hydrochloric acid (1.37 mL) was added at 0deg.C and stirred overnight. TLC monitored the end of the reaction and was directly spin-dried to give 12e as a white solid (231 mg, 80% yield). ESI-MS (m/z): 262.6[ M+H ]] ⁺ 。

Fourth step: compound 12e (26 mg,95 umol), compound 1i (20 mg,79 umol) and p-toluenesulfonic acid monohydrate (0.4 mg,7.9 umol) were dissolved in n-butanol (3 mL) at microwave 160 ℃The reaction was carried out for 3 hours. LCMS monitored the end of the reaction. The reaction solution was purified by reverse phase preparative HPLC to give 12 as a white solid (13 mg, yield 35%). ESI-MS (m/z): 492.4[ M+H ]] ⁺ ； ¹ H NMR(500MHz,DMSO-d6)δ6.67(br s,1H),6.17(s,1H),4.26-4.18(m,1H),4.15-4.06(m,2H),4.05-3.97(m,1H),3.54-3.21(m,5H),2.94(s,3H),2.60-2.50(m,2H),2.47-2.35(m,3H),1.96-1.86(m,1H),1.85-1.70(m,3H),1.21(d,J＝6.8Hz,3H),1.05-0.90(m,4H)。

Example 13

(S) -2- (((1S, 3 r) -3- (((1-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) oxo) methyl) cyclobutyl) amino) -5- (hydroxymethyl) -4, 5-dimethyl-4, 5,9, 10-tetrahydro-6H, 8H-pyrido [3,2, 1-des ] pteridin-6-one

Compound 13 was prepared by the following steps:

the first step: 2, 4-dichloropyrido [3,2-d ]]Pyrimidine 1f (4.0 g,20.0 mmol) and 2-methyl-L-serine methyl ester hydrochloride 13a (4.07 g,24.0 mmol) were dissolved in dichloromethane (30 mL), N-diisopropylethylamine (7.75 g,59.99mmol,10.45 mL) was added, and stirred overnight at room temperature. LCMS monitored the end of the reaction, the reaction was diluted with dichloromethane, washed with water and saturated brine, respectively, the organic phase was dried over anhydrous sodium sulfate and concentrated by filtration to give 13b as a white solid (5.0 g, 84% yield). ESI-MS (m/z): 297.3[ M+H ]] ⁺ 。

And a second step of: compound 13b (5.0 g,16.85 mmol) was dissolved in tetrahydrofuran (50 mL), aqueous hydrochloric acid (6M, 5.62 mL) and platinum dioxide (382 mg,1.69 mmol) were added, the reaction system was replaced with hydrogen gas with a hydrogen balloon, and stirred at room temperature under hydrogen balloon pressure for 48 hours, and LCMS monitored the end of the reaction. The reaction solution was diluted with methanol and filteredThe filtrate was concentrated to give 13c (4.0 g, yield 88%) as a white solid. ESI-MS (m/z): 269.3[ M+H ]] ⁺ 。

And a third step of: compound 13c (1.5 g,5.58 mmol) and methyl iodide (1.58 g,11.16 mmol) were dissolved in acetonitrile (5 mL), cesium carbonate (3.64 g,11.16 mmol) was added, and the reaction mixture was stirred at room temperature for 48 hours. LCMS monitored the end of the reaction. The reaction solution was diluted with ethyl acetate, each of the solutions was washed with water and saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane/methanol=10/1) to give 13d (1.1 g, yield 69%) as a yellow solid. ESI-MS (m/z): 283.3[ M+H ] ] ⁺ 。

Fourth step: compound 12e (25 mg,84 umol), compound 13d (20 mg,70.7 umol) and p-toluenesulfonic acid monohydrate (0.4 mg,7.07 umol) were dissolved in n-butanol (3 mL) and reacted at microwave 160℃for 3 hours. LCMS monitored the end of the reaction. The reaction solution was purified by reverse phase preparative HPLC to give 13 as a white solid (13 mg, yield 35%). ESI-MS (m/z): 522.3[ M+H ]] ⁺ ； ¹ H NMR(500MHz,DMSO-d6)δ6.54(br s,1H),6.17(s,1H),5.06(t,J＝5.5Hz,1H),4.29-4.18(m,1H),4.10(d,J＝4.9Hz,2H),3.76-3.67(m,2H),3.65-3.58(m,1H),3.57-3.49(m,2H),2.97(s,3H),2.55-2.45(m,2H),2.44-2.32(m,3H),1.88-1.72(m,4H),1.33(s,3H),0.98(d,J＝7.8Hz,4H)。

Example 14

(S) -5- (hydroxymethyl) -4, 5-dimethyl-2- (((1S, 3R) -3- (((2-methyl-6- (trifluoromethyl) pyridin-3-yl) oxo) methyl) cyclobutyl) amino) -4,5,9, 10-tetrahydro-6H, 8H-pyrido [3,2, 1-des ] pteridin-6-one

Compound 14 was prepared by the following steps:

the first step: compound 2a (2.0 g,12.26 mmol), na ₂ CO ₃ (2.6 g,24.52 mmol) was added to water (60 mL), dissolved by stirring, and elemental iodine (3.11 g,12.26 mmol) was added to the reaction solution and stirred at room temperature for 3 hours. LCMS monitored the disappearance of starting material, pH of the reaction solution was adjusted to 5-6 with dilute hydrochloric acid and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated by filtration, and the residue was chromatographed on silica gel (ethyl acetate/petroleum ether=0-30% gradient elution) to give 14a as a white solid (1.5 g, yield 42%). ESI-MS (m/z): 290.2[ M+H ]] ⁺ 。

And a second step of: compound 14a (0.5 g,1.73 mmol) was dissolved in DMF (5 mL) and K was added ₂ CO ₃ (264 mg,2.64 mmol), stirred at 50℃for 2 hours, LCMS monitored translation for completion. The reaction solution was diluted with water, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography of the residue on silica gel (ethyl acetate/petroleum ether=0-15% gradient elution) gives 14b as a white solid (0.5 g, 76% yield). ESI-MS (m/z): 380.2[ M+H ]] ⁺ 。

And a third step of: compound 14b (412 mg,1.09 mmol), palladium acetate (24 mg, 109. Mu. Mol), trimethylcyclotriboroxine (682 mg,5.43 mmol), tricyclohexylphosphine (152 mg, 803. Mu. Mol), tripotassium phosphate (922 mg,4.35 mmol), water (3 mL), 1, 4-dioxane (30 mL) were added to a 100mL two-necked flask, after nitrogen substitution, stirring was carried out at 90℃overnight, TLC was monitored for the end of the reaction, the reaction solution was diluted with water, filtered with celite, extracted with ethyl acetate, and finally washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10/1) to give yellow liquid 14c (198 mg, yield 68%). ESI-MS (m/z): 268.2[ M+H ] +.

Fourth step: compound 14c (198mg, 741 umol) was dissolved in dichloromethane (10 mL), boron tribromide (928 mg,3.71 umol) was added dropwise at-78 ℃ and stirred for 1 hour, TLC monitored the end of the reaction, the reaction solution was diluted with water, extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to give yellow liquid 14d (143 mg, yield 91%). ESI-MS (m/z): 178.4[ M+H ] +.

Fifth step: compound 14d (120 mg,677 umol), compound 11b (208 mg,745 umol) and cesium carbonate (4471 mg,1.35 mmol) were dissolved in N, N-dimethylformamide (5 mL) and stirred overnight at 90 ℃. TLC monitored the end of the reaction, the reaction was diluted with water, extracted with ethyl acetate, washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=3/1) to give 14e (196 mg, yield 80%) as a yellow solid. ESI-MS (m/z): 361.4[ M+H ]] ⁺ 。

Sixth step: compound 14e (196 mg, 543. Mu. Mol) was dissolved in dichloromethane (10 mL), 4M hydrochloric acid (0.952 mL) was added at 0deg.C and stirred overnight. TLC monitored the end of the reaction and was directly spin-dried to give 14f as a white solid (112 mg, 79% yield). ESI-MS (m/z): 261.3[ M+H ]] ⁺ 。

Seventh step: compound 14f (27 mg,106 umol), compound 13d (20 mg,70.7 umol) and p-toluenesulfonic acid monohydrate (0.4 mg,7.07 umol) were dissolved in n-butanol (3 mL) and reacted at microwave 160℃for 3 hours. LCMS monitored the end of the reaction. The reaction solution was purified by reverse phase preparative HPLC to give 14 as a white solid (19 mg, yield 52%). ESI-MS (m/z): 507.3[ M+H ]] ⁺ ； ¹ H NMR(500MHz,DMSO-d6)δ7.67(d,J＝8.5Hz,1H),7.48(d,J＝8.5Hz,1H),6.54(br s,1H),5.06(t,J＝5.5Hz,1H),4.29-4.19(m,1H),4.05(d,J＝4.8Hz,2H),3.77-3.66(m,2H),3.65-3.60(m,1H),3.58-3.53(m,1H),2.98(s,3H),2.48-2.35(m,8H),1.90-1.74(m,4H),1.33(s,3H)。

Example 15

(S) -2- (((1S, 3 r) -3- (((2-cyclopropyl-6- (trifluoromethyl) pyridin-3-yl) oxo) methyl) cyclobutyl) amino) -5- (hydroxymethyl) -4, 5-dimethyl-4, 5,9, 10-tetrahydro-6 h,8 h-pyrido [3,2, 1-des ] pteridin-6-one

Compound 15 was prepared by the following steps:

the first step: compound 14b (300 mg,0.791 mmol), palladium acetate (18 mg,79 umol), cyclopropylboronic acid (399 mg,3.96 mmol), tricyclohexylphosphine (152 mg, 803 umol), tripotassium phosphate (67 mg,3.17 mmol), water (1 mL), 1, 4-dioxane (10 mL) were added to a 100mL two-necked flask, after nitrogen substitution, stirring overnight at 90℃was performed, TLC was monitored for the end of the reaction, the reaction solution was diluted with water, filtered with celite, extracted with ethyl acetate, and finally washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10/1) to give 15a (209 mg, yield 90%). ESI-MS (m/z): 294.3[ M+H ] +.

And a second step of: compound 15a (209 mg,712 umol) was dissolved in dichloromethane (10 mL), boron tribromide (829 mg,3.56 umol) was added dropwise at-78 ℃ and stirred for 1 hour, the reaction was monitored by TLC for the end of the reaction, the reaction solution was diluted with water, extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to give 15b (122 mg, yield 84%). ESI-MS (m/z): 204.4[ M+H ] +.

And a third step of: compound 15b (122 mg, 750 mol), compound 11b (211 mg,758 mol) and cesium carbonate (449 mg,1.38 mmol) were dissolved in N, N-dimethylformamide (5 mL) and stirred overnight at 90 ℃. TLC monitored the end of the reaction, the reaction was diluted with water, extracted with ethyl acetate, washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=3/1) to give 15c (152 mg, yield 66%) as a yellow solid. ESI-MS (m/z): 387.3[ M+H ]] ⁺ 。

Fourth step: compound 15c (152 mg,393 umol) was dissolved in dichloromethane (10 mL), 4M hydrochloric acid (0.706 mL) was added at 0deg.C and stirred overnight. TLC monitoring of the reaction was complete, straightSpin-drying afforded 15d (92 mg, 79% yield) as a white solid. ESI-MS (m/z): 287.3[ M+H ]] ⁺ 。

Fifth step: compound 15d (46 mg, 1592. Mu. Mol), compound 13d (30 mg, 106. Mu. Mol) and p-toluenesulfonic acid monohydrate (0.5 mg, 10.6. Mu. Mol) were dissolved in n-butanol (3 mL) and reacted at microwave 160℃for 3 hours. LCMS monitored the end of the reaction. The reaction solution was purified by reverse phase preparative HPLC to give 15 as a white solid (18 mg, yield 32%). ESI-MS (m/z): 533.1[ M+H ]] ⁺ ； ¹ H NMR(500MHz,DMSO-d6)δ7.56(dd,J＝8.5,3.8Hz,1H),7.45(d,J＝8.5Hz,1H),6.55(br s,1H),5.06(t,J＝5.7Hz,1H),4.30-4.18(m,1H),4.06(d,J＝5.1Hz,2H),3.77-3.66(m,2H),3.65-3.59(m,1H),3.57-3.52(m,1H),2.98(s,3H),2.52-2.45(m,2H),2.44-2.35(m,3H),1.87-1.75(m,4H),1.33(s,3H),1.02-0.97(m,2H),0.95-0.89(m,2H)。

Example 16

(S) -5- (methoxymethyl) -4- (methyl-d 3) -2- (((1S, 3 r) -3- (((6- (trifluoromethyl) pyridin-3-yl) oxo) methyl) cyclobutyl) amino) -4,5,9, 10-tetrahydro-6 h,8 h-pyrido [3,2, 1-des ] pteridin-6-one

Compound 16 was prepared by the following steps:

the first step: 2, 4-dichloropyrido [3,2-d ]]Pyrimidine 1f (2 g,10.00 mmol) and O-methyl-L-serine methyl ester hydrochloride 16a (2.45 g,15.00 mmol) were dissolved in tetrahydrofuran (20 mL), N-diisopropylethylamine (3.88 g,30.00mmol,5.22 mL) was added and stirred overnight at room temperature. LCMS monitored the end of the reaction, the reaction was concentrated and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to give 16b as a yellow oil (2.5 g, 84% yield). ESI-MS (m/z): 297.2[ M+H ]] ⁺ 。

And a second step of: compound 16b (2.5 g,8.43 mmol) was dissolved in tetrahydrofuran (30 mL), aqueous hydrochloric acid (6N, 1.40 mL) and platinum dioxide (191 mg,0.84 mmol) were added, the reaction system was replaced with hydrogen gas by hydrogen balloon, and stirring was carried out at room temperature under hydrogen balloon pressure for 48 hours, and LCMS monitored the end of the reaction. The reaction solution was diluted with methanol, filtered through celite, and the filtrate was concentrated and purified by silica gel column chromatography (dichloromethane/methanol=10/1) to give 16c (2.0 g, yield 88%) as a gray solid. ESI-MS (m/z): 269.3[ M+H ]] ⁺ 。

And a third step of: compound 16c (200 mg,0.74 mmol) and deuterated iodomethane (215 mg,1.49 mmol) were dissolved in acetonitrile (5 mL), cesium carbonate (480 mg,1.49 mmol) was added, and the mixture was reacted at 50℃for 2 hours. LCMS monitored the end of the reaction. The reaction solution was diluted with dichloromethane, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (dichloromethane/methanol=20/1) to give 16d (200 mg, yield 94%) of a yellow solid. ESI-MS (m/z): 286.3[ M+H ] ] ⁺ 。

Fourth step: compound 16d (25 mg,89 mol), compound 11c (32 mg,131 mol) and p-toluenesulfonic acid monohydrate (0.45 mg,8.9 mol) were dissolved in n-butanol (3 mL) and reacted at microwave 160℃for 3 hours. LCMS monitored the end of the reaction. The reaction solution was purified by reverse phase preparative HPLC to give 16 as a white solid (5 mg, yield 10%). ESI-MS (m/z): 496.4[ M+H ]] ⁺ ； ¹ H NMR(500MHz,DMSO-d6)δ8.43(d,J＝2.7Hz,1H),7.82(d,J＝8.7Hz,1H),7.59(dd,J＝8.8,2.8Hz,1H),6.60(br s,1H),4.32-4.20(m,2H),4.09(d,J＝5.0Hz,2H),4.03-3.94(m,1H),3.72-3.60(m,2H),3.16(s,3H),2.52-2.46(m,2H),2.45-2.32(m,3H),1.94-1.85(m,1H),1.84-1.69(m,3H)。

Example 17

(S) -5- (hydroxymethyl) -4, 5-dimethyl-2- (((1S, 3 r) -3- (((6- (trifluoromethyl) pyridin-3-yl) oxo) methyl) cyclobutyl) amino) -4,5,9, 10-tetrahydro-6 h,8 h-pyrido [3,2, 1-des ] pteridin-6-one

The fifth step starting material 14d in example 14 was replaced with 6- (trifluoromethyl) pyridin-3-ol 2a and the procedure was followed in a similar manner to the reaction step to give compound 17.ESI-MS (m/z): 493.3[ M+H ]] ⁺ ； ¹ H NMR(500MHz,DMSO-d6)δ8.43(d,J＝2.7Hz,1H),7.82(d,J＝8.7Hz,1H),7.59(dd,J＝8.6,2.8Hz,1H),6.53(br s,1H),5.06(t,J＝5.5Hz,1H),4.29-4.18(m,1H),4.10(d,J＝4.9Hz,2H),3.78-3.66(m,2H),3.65-3.58(m,1H),3.57-3.51(m,1H),2.98(s,3H),2.52-2.46(m,2H),2.45-2.34(m,3H),1.90-1.73(m,4H),1.33(s,3H)。

Example 18

(S) -4, 5-dimethyl-2- (((1S, 3 r) -3- (((2- (trifluoromethyl) pyrimidin-5-yl) oxy) methyl) cyclobutyl) amino) -4,5,9, 10-tetrahydro-6 h,8 h-pyrido [3,2, 1-des ] pteridin-6-one

Replacement of step 2a of example 11 with 2- (trifluoromethyl) pyrimidin-5-ol gave compound 18 in a similar manner and reaction procedure. ESI-MS (m/z): 464.3[ M+H ]] ⁺ ； ¹ H NMR(500MHz,DMSO-d6)δ8.76(s,2H),6.70(s,1H),4.28-4.17(m,3H),4.11(q,J＝6.8Hz,1H),4.11-4.39(m,1H),3.33(s,1H),3.30-3.22(m,2H),2.94(s,3H),2.52-2.46(m,2H),2.45-2.35(m,3H),1.95-1.86(m,1H),1.85-1.72(m,3H),1.21(d,J＝6.7Hz,3H)。

Example 19

(S) -5- (hydroxymethyl) -4, 5-dimethyl-2- (((1S, 3R) -3- ((3, 4, 5-trifluorophenoxy) methyl) cyclobutyl) amino) -4,5,9, 10-tetrahydro-6H, 8H-pyrido [3,2, 1-des ] pteridin-6-one

The fifth step starting material 14d in example 14 was replaced with 3,4, 5-trifluorophenol 1c and the procedure and reaction steps were similar to those described to give compound 19.ESI-MS(m/z):478.4[M+H] ⁺ ； ¹ H NMR(500MHz,DMSO-d6)δ7.10-6.95(m,2H),6.48(d,J＝7.8Hz,1H),5.06(br s,1H),4.24(q,J＝8.0Hz,1H),3.94(d,J＝5.9Hz,2H),3.81-3.70(m,2H),3.69-3.64(m,1H),3.57(d,J＝11.3Hz,1H),3.00(s,3H),2.52-2.45(m,2H),2.43-2.33(m,3H),1.90-1.80(m,2H),1.79-1.71(m,2H),1.35(s,3H)。

Example 20

(S) -2- (((1S, 3 r) -3- ((4-fluoro-2- (trifluoromethyl) phenoxy) methyl) cyclobutyl) amino) -5- (hydroxymethyl) -4, 5-dimethyl-4, 5,9, 10-tetrahydro-6 h,8 h-pyrido [3,2, 1-des ] pteridin-6-one

The fifth step starting material 14d in example 14 was replaced with 4-fluoro-2- (trifluoromethyl) phenol and the procedure was followed in a similar manner to give compound 20.ESI-MS (m/z): 510.4[ M+H ]] ⁺ ； ¹ H NMR(500MHz,DMSO-d6)δ7.60-7.50(m,2H),7.34-7.27(m,1H),6.43(br s,1H),5.08(t,J＝5.6Hz,1H),4.22(q,J＝8.2Hz,1H),4.06(d,J＝5.2Hz,2H),3.77-3.68(m,2H),3.67-3.62(m,1H),3.61-3.55(m,1H),2.99(s,3H),2.51-2.45(m,2H),2.43-2.35(m,3H),1.90-1.83(m,2H),1.82-1.71(m,2H),1.34(s,3H)。

Example 21

(S) -5- (hydroxymethyl) -4, 5-dimethyl-2- (((1S, 3R) -3- (((2-phenyl-6- (trifluoromethyl) pyridin-3-yl) oxo) methyl) cyclobutyl) amino) -4,5,9, 10-tetrahydro-6H, 8H-pyrido [3,2, 1-des ] pteridin-6-one

Compound 21 was prepared by the following steps:

the first step: compound 21a (290 mg,1.46 mmol), compound 11b (193 mg,1.61 mmol) and cesium carbonate (191 mg,2.92 mmol) were dissolved in N, N-dimethylformamide (5 mL) and stirred overnight at 90 ℃. TLC monitored the end of the reaction, the reaction was diluted with water, extracted with ethyl acetate, washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=3/1) to give 21b (445 mg, yield 79%) as a yellow solid. ESI-MS (m/z): 381.3[ M+H ] ] ⁺ 。

And a second step of: compound 21b (158 mg,414 umol), [1,1' -bis (diphenylphosphine) ferrocene]Palladium dichloride dichloromethane complex (30 mg,41.4 umol), phenylboronic acid (101 mg,829 umol), cesium carbonate (405 mg,1.24 mmol), water (1 mL), dioxane (10 mL) were added to a 25mL two-necked flask, after nitrogen substitution, stirred overnight at 90 ℃, TLC monitored for reaction completion, the reaction solution was diluted with water, filtered with celite, extracted with ethyl acetate, and finally washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10/1) to give yellow liquid 21c (152 mg, yield 87%). ESI-MS (m/z): 423.4[ M+H ]] ⁺ 。

And a third step of: compound 21c (78 mg,164 umol) was dissolved in dichloromethane (5 mL), and a 4M dioxane hydrochloride solution (0.1 mL) was added at 0deg.C and stirred overnight. TLC monitored the end of the reaction and was directly spin-dried to give 21d (43 mg, 72% yield) as a white solid. ESI-MS (m/z): 323.7[ M+H ]] ⁺ 。

Fourth step: compound 21d (43 mg, 133. Mu. Mol), compound 13d (25 mg, 88.4. Mu. Mol) and p-toluenesulfonic acid monohydrate (1.31 mg, 13.3. Mu. Mol) were dissolved in n-butanol (3 mL) and reacted at microwave 160℃for 3 hours. LCMS monitored the end of the reaction. The reaction solution was purified by reverse phase preparative HPLC to give 21 as a white solid (14 mg, yield 27%). ESI-MS (m/z): 569.9[ M+H ] ] ⁺ ； ¹ H NMR(500MHz,DMSO-d6)δ7.92(d,J＝7.7Hz,2H),7.83(d,J＝8.6Hz,1H),7.74(d,J＝8.6Hz,1H),7.60-7.41(m,2H),7.44(d,J＝7.2Hz,1H),6.40(br s,1H),5.06(t,J＝5.6Hz,1H),4.23(p,J＝8.2Hz,1H),4.13(d,J＝5.3Hz,2H),3.79-3.68(m,2H),3.66-3.61(m,1H),3.58-3.52(m,1H),2.98(s,3H),2.52-2.35(m,5H),1.90-1.72(m,4H),1.33(s,2H)。

Example 22

(S) -5- (hydroxymethyl) -4, 5-dimethyl-2- (((1S, 3R) -3- (((2- (pyrrolidin-1-yl) -6- (trifluoromethyl) pyridin-3-yl) oxo) methyl) cyclobutyl) amino) -4,5,9, 10-tetrahydro-6H, 8H-pyrido [3,2, 1-des ] pteridin-6-one

Compound 22 was prepared by the following steps:

the first step: compound 14b (210 mg,554 umol), pd ₂ (dba) ₃ (50.7 mg, 55.4. Mu. Mol), tetrahydropyrrole (89 mg, 830. Mu. Mol), potassium t-butoxide (310 mg,2.77 mmol), 2-dicyclohexylphosphino-2' - (N, N-dimethylamine) -biphenyl (65 mg, 166. Mu. Mol) and toluene (8 mL) were added to a 50mL one-neck flask, the reaction system was stirred overnight at 80℃after nitrogen substitution, and LCMS showed complete reaction conversion. The reaction solution was filtered through celite, extracted with ethyl acetate and water, washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10/1) to give yellow liquid 22a (132 mg, yield 73%). ESI-MS (m/z): 323.3[ M+H ]]+。

And a second step of: compound 22a (132 mg,409 umol) was dissolved in dichloromethane (10 mL), boron tribromide (474 mg,1.89 umol) was added dropwise at-78 ℃ and stirred for 1 hour, the reaction was monitored by TLC for the end of the reaction, the reaction solution was diluted with water, extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to give yellow liquid 22b (65 mg, yield 73%). ESI-MS (m/z): 233.3[ M+H ] +.

And a third step of: compound 22b (65 mg,279 umol) and compound 11b (86 mg,307 umol) and cesium carbonate (189 mg,560 umol) were dissolved in N, N-dimethylformamide (5 mL), and stirred overnight at 90 ℃. TLC monitored the end of the reaction, the reaction was diluted with water, extracted with ethyl acetate, washed with saturated brine, the organic phase dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=3/1) to give 22c (78 mg, yield 67%) as a yellow solid. ESI-MS (m/z): 416.5[ M+H ]] ⁺ 。

Fourth step: compound 22c (78 mg, 87 umol) was dissolved in dichloromethane (5 mL), and a 4M dioxane solution of hydrochloric acid (0.1 mL) was added at 0deg.C and stirred overnight. TLC monitored the end of the reaction and was directly dried to give 22d as a white solid (45 mg, 76% yield). ESI-MS (m/z): 316.5[ M+H ]] ⁺ 。

Fifth step: compound 22d (40 mg,114 umol), compound 13d (25 mg,88.4 umol) and p-toluenesulfonic acid monohydrate (1.52 mg,8.82 umol) were dissolved in n-butanol (3 mL) and reacted at microwave 160℃for 3 hours. LCMS monitored the end of the reaction. The reaction solution was purified by reverse phase preparative HPLC to give 22 as a white solid (5 mg, yield 10%). ESI-MS (m/z): 562.4[ M+H ]] ⁺ ； ¹ H NMR(500MHz,DMSO-d6)δ7.12(d,J＝7.9Hz,1H),6.95(d,J＝7.9Hz,1H),6.50(br s,1H),5.07(t,J＝5.4Hz,1H),4.28-4.16(m,1H),3.93(d,J＝5.1Hz,2H),3.76-3.68(m,2H),3.65-3.53(m,6H),2.98(s,3H),2.51-2.45(m,2H),2.43-2.35(m,3H),1.92-1.68(m,8H),1.33(s,3H)。

Example 23

(S) -5- (hydroxymethyl) -4, 5-dimethyl-2- (((1 r, 3S) -3- (3, 4, 5-trifluorophenoxy) cyclobutyl) amino) -4,5,9, 10-tetrahydro-6H, 8H-pyrido [3,2, 1-des ] pteridin-6-one

Replacement of step 12e from example 13 with intermediate 1e gives compound 23 in a similar manner and reaction steps。ESI-MS(m/z):464.5[M+H] ⁺ ； ¹ H NMR(500MHz,DMSO-d6)δ6.90-6.80(m,2H),6.71(d,J＝6.9Hz,1H),5.07(d,J＝5.0Hz,1H),4.87-4.78(m,1H), 4.45-4.33(m,1H),3.78-3.68(m,2H),3.66-3.58(m,1H),3.57-3.50(m,1H),2.97(s,3H),2.52-2.37(m,4H),2.36-2.28(m,2H),1.90-1.75(m,2H),1.33(s,3H)。

Example 24

(S) -5- (hydroxymethyl) -4-methyl-2- (((1 r, 3S) -3- (3, 4, 5-trifluorophenoxy) cyclobutyl) amino) -4,5,9, 10-tetrahydro-6H, 8H-pyrido [3,2, 1-des ] pteridin-6-one

Compound 24 was prepared by the following steps:

the first step: compound 16c (500 mg,1.86 mmol) and methyl iodide (343 mg,2.42 mmol) were dissolved in acetonitrile (10 mL), cesium carbonate (1.21 g,372 mmol) was added, and the mixture was reacted at 50℃for 2 hours. LCMS monitored the end of the reaction. The reaction solution was diluted with dichloromethane, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (dichloromethane/methanol=20/1) to give 24a (350 mg, yield 66%) as a white solid. ESI-MS (m/z): 283.3[ M+H ]] ⁺ 。

And a second step of: 24a (250 mg,0.88 mmol) was dissolved in dichloromethane (2 mL) and boron tribromide (2.21 g,8.84mmol,0.85 mL) was added dropwise at 0deg.C, and the reaction was continued at 0deg.C for two hours after the addition was completed. LCMS monitored the end of the reaction. The reaction solution was carefully quenched with sodium bicarbonate solution, extracted with dichloromethane, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=10/1) to give 24b (100 mg, yield 42%) as a white solid. ESI-MS (m/z): 269.3[ M+H ] ] ⁺ 。

Third step: compound 24b (30 mg,111 umol), compound 1e (42 mg,167 umol) and p-toluenesulfonic acid monohydrate (1.92 mg,11.1 umol) were dissolved in n-butanol (3 mL) and reacted at microwave 160℃for 3 hours. LCMS monitored the end of the reaction. The reaction solution was purified by reverse phase preparative HPLC to give 24 as a white solid (16 mg, yield 32%). ESI-MS (m/z): 450.3[ M+H ]] ⁺ ； ¹ H NMR(500MHz,DMSO-d6)δ6.91-6.79(m,2H),6.76-6.69(m,1H),5.01-4.95(m,1H),4.87-4.81(m,1H),4.45-4.33(m,1H),4.16-3.94(m,2H),3.80-3.63(m,2H),2.97(s,3H),2.51-2.44(m,2H),2.41-2.35(m,2H),1.95-1.85(m,1H),1.81-1.69(m,1H)。

Example 25

(S) -4, 5-dimethyl-2- (((1 r, 3S) -3- ((2-methyl-6- (trifluoromethyl) pyridin-3-yl) oxo) cyclobutyl) amino) -4,5,9, 10-tetrahydro-6H, 8H-pyrido [3,2, 1-des ] pteridin-6-one

The intermediate 14d was used in place of the first step 2a of example 2, and in a similar manner and reaction procedure, compound 25 was obtained. ESI-MS (m/z): 463.5[ M+H ]] ⁺ ； ¹ H NMR(500MHz,DMSO-d6)δ7.66(d,J＝8.5Hz,1H),7.25(d,J＝8.5Hz,1H),6.88(d,J＝6.8Hz,1H),4.97(br s,1H), 4.50-4.36(m,1H),4.11(q,J＝6.8Hz,1H),4.04-3.98(m,1H),3.35-3.29(m,2H),2.94(s,3H),2.60-2.30(m,9H),2.00-1.88(m,1H),1.85-1.75(m,1H),1.23(d,J＝6.6Hz,3H)。

Example 26

(S) -4, 5-dimethyl-2- (((1 r, 3S) -3- ((4-methyl-2- (trifluoromethyl) pyrimidin-5-yl) oxy) cyclobutyl) amino) -4,5,9, 10-tetrahydro-6H, 8H-pyrido [3,2, 1-des ] pteridin-6-one

Compound 26 was prepared by the following steps:

the first step: ethyl formate (3.17 g,42.73 mmol) was added sequentially to dry tetrahydrofuran (140 mL) as solid sodium ethoxide (3.49 g,50.50 mmol). After addition of compound 26a (7 g,38.85 mmol) at 5-10℃the reaction was warmed to 50℃and stirred for 2 hours with incubation, and HPLC monitored for disappearance of starting material. Tetrahydrofuran was distilled off under reduced pressure to give 26b as a yellow oil which was used directly in the next step.

And a second step of: the oily substance 26b obtained in the previous step was added with 150ml of absolute ethanol, stirred at room temperature for dissolution, and trifluoroacetamidine (4.35 g,33.01mmol, purity 85%) was added dropwise, stirred at 30℃for 5 hours while maintaining the temperature, then heated to 80℃and stirred for 2 hours, and HPLC was monitored for disappearance of starting material. The reaction solution was cooled, then, ethanol (about 100 ml) was distilled off under reduced pressure, the remaining residual liquid was added to 300ml of ice water, the pH was adjusted to 3 with concentrated hydrochloric acid, and the mixture was stirred for 0.5 hour, suction filtration and drying of the cake gave compound 26c (4.37 g, yield 41%, purity 99%) as a yellow solid. ESI-MS (m/z): 271.4[ M+H ]] ⁺ 。

And a third step of: compound 26c (4.0 g,14.80 mmol) was added to 60ml acetonitrile, phosphorus oxychloride (6.81 g,44.41 mmol) was added dropwise, and after the addition was completed, the mixture was stirred for 10 minutes, warmed to 80℃and stirred for 2 hours at a constant temperature, and HPLC was monitored to complete the conversion of the starting material. Acetonitrile was removed under reduced pressure, and the residue was added to 200mL of ice water, stirred for 0.5 hour, and suction-filtered to give 26d (3.9 g, yield 86%, purity 95%) as a yellow solid.

Fourth step: compound 26d (2.0 g,6.93 mmol), trimethylboroxine (2.61 g,20.79 mmol), palladium acetate (155 mg,0.69 mol), potassium phosphate (2.94 g,13.86 mmol) were added sequentially to 1, 4-dioxane (150 mL), water (15 mL) was added, the mixture was stirred at 90℃under nitrogen protection for 17 hours, HPLC was monitored for complete conversion of the starting material, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/9) to give 26e (1.86 g, yield 50%, purity 99%) as a white solid. ESI-MS (m/z): 269.1[ M+H ] ] ⁺ 。

Fifth step: compound 26e (280 mg,1.04 mmol) was dissolved in methanol (10 mL), palladium on carbon (13 mg,104 umol) was added thereto, the reaction system was replaced with hydrogen, the reaction was monitored by TLC for 5 hours, the reaction solution was filtered through celite, and the filtrate was concentrated to give 26f (170 mg, yield 91%) as a yellow liquid. ESI-MS (m/z): 177.5[ M-H ]] ^- 。

Sixth step: compound 26f (120 mg,673 umol) and compound 1b (268 mg,1.01 mmol) and cesium carbonate (268 mg,1.68 mmol) were dissolved in N, N-dimethylformamide (5 mL) and stirred overnight at 90 ℃. TLC monitored the end of the reaction, the reaction was diluted with water, extracted with ethyl acetate, washed with saturated brine, the organic phase dried over anhydrous sodium sulfate, concentrated by filtration, and the residue purified by silica gel column chromatography (petroleum ether/ethyl acetate=3/1) to give 26g (148 mg, yield 62%) of a yellow solid. ESI-MS (m/z): 348.5[ M+H ]] ⁺ 。

Seventh step: 26g (148 mg,340 mol) of the compound was dissolved in methylene chloride (5 mL), 4M hydrochloric acid (0.4 mL) was added at 0deg.C and stirred overnight. TLC monitored the end of the reaction and was directly spin-dried to give a white solid 26h (84 mg, 86% yield). ESI-MS (m/z): 284.4[ M+H ]] ⁺ 。

Eighth step: compound 26h (30 mg,118 umol), compound 1i (35 mg,142 umol) and p-toluenesulfonic acid monohydrate (2 mg,11.8 umol) were dissolved in n-butanol (3 mL) and reacted at microwave 160℃for 3 hours. LCMS monitored the end of the reaction. The reaction solution was purified by reverse phase preparative HPLC to give 26 as a white solid (14 mg, yield 25%). ESI-MS (m/z): 464.5[ M+H ] ] ⁺ ； ¹ H NMR(500MHz,DMSO-d6)δ8.34(s,1H),6.87(d,J＝6.9Hz,1H),5.19-5.08(m,1H),4.52-4.41(m,1H),4.12(q,J＝6.9Hz,1H),4.08-3.99(m,1H),3.29-3.24(m,2H),2.95(s,3H),2.58-2.41(m,9H),2.00-1.90(m,1H),1.86-1.73(m,1H),1.23(d,J＝6.8Hz,3H)。

The following examples can be obtained according to the synthetic routes and synthetic methods of intermediates described in the above examples.

Biological screening and results of Wnt pathway inhibitors

Test example 1: construction of Colo205-LUC-TCF/LEF-M1 reporter cell line

Colo205 cell line (Proc. Natl. Acad. Sci. Cell bank, cat#TCHu102) was purchased from Proc. Natl. Acad. Sci. Cell bank, amplified and subcultured, and then transfected with a luciferase reporter plasmid (Promega) driven by TCF/LEF transcription factor by lipo3000 liposome transfection in the exponential growth phase of cells. The plasmid carries a resistance gene, and can be used for resistance screening. Transfection was performed in 10cm dishes using conventional complete medium without resistance. After 2 days, the medium with resistance was changed and the culture was continued. The resistant medium was then changed every 2 days and the suspension cells were discarded, and the original medium was centrifuged to remove cells and debris and was then retained as an adaptive medium. After the cells had grown up the dishes, the cells were digested, counted and passaged into 96-well plates to average the number of cells contained in each well to 1.5 cells/well, using adaptation medium at the time of passaging. The remaining cells were frozen. After 4 hours of culture after passage, the cells were allowed to adhere, and then the cell numbers of each well were observed under a microscope. Only 1 cell per well was labeled, which was a monoclonal well. Then, the culture medium was changed every 2 days for normal culture, and observation was performed. The pre-monoclonal cells have wells that continue to grow, and are labeled 2 times, and can be replaced with normal medium with resistance. When cells in a monoclonal well grow to a 96-well plate well, they are digested and passaged to a 24-well culture plate, and after the 24-well plate grows to a full, passaged to 1 96-well plate and 1 6-well plate, wherein 96-well plate cells are passaged to at least 6-well plates, wherein 3-well plates are added with a known Wnt inhibitor, and the other 3-well plates are not treated. After 24 hours, the 96-well plate cells were added with a fluorescent detection reagent to detect the fluorescence intensity. Cell lines in which fluorescence expression was not present in the treatment and post-fluorescence reduction was inhibited were selected and further cultured. The Colo205-LUC-TCF/LEF-M1 cell line is one of the cell lines screened by the screening method, the growth curve, the cell morphology and the cell growth state of the cell line are similar to those of original Colo205 cells, the ratio of the fluorescent signals treated by adding the inhibitor to the fluorescent signals not treated by the inhibitor is large in all the cell lines, and the ratio can be inhibited by 4-5 times at 4h, so that the cell line is completely suitable for screening Wnt inhibitors in the later period.

Test example 2: detection of Colo205-LUC-TCF/LEF M1 reporter cell line inhibition Capacity by Compounds

The Colo205-LUC-TCF/LEF M1 cell strain is a report tool cell for stably transfecting pGL4.49-LUC2-TCF/LEF vectors, the beta-catenin Wnt channel is continuously activated, after an inhibitor is added, the Wnt channel is inhibited, the expression level of firefly luciferase regulated by TCF/LEF cis elements on the vectors is reduced, and after a detection substrate is added subsequently, the detected optical signal is correspondingly reduced, so that the inhibition effect of the compound is detected.

100. Mu.L of compound was added to each well of a 96-well cell culture plate at a maximum concentration of 20. Mu.M, and the compound concentration was diluted 3-fold in a gradient. 10000 stably reporter-transfected colo205 cells and 100. Mu.L medium were then inoculated into each well, with corresponding treatments as positive and negative control wells. Placing the cells into 5% CO ₂ After 4 hours of incubation at 37℃in a cell incubator for 4 hours, the culture medium was removed, 100. Mu.L of a reagent (Promega) containing a corresponding firefly luciferase substrate was added to each well, and the luciferase reporter gene activity was measured. The luminescence intensity was read in full wavelength mode with SpectraMax. The IC of each compound was calculated from the light signal intensity of DMSO-treated cells alone as positive control and the light signal intensity of cell-free wells as negative control ₅₀ Is a concentration of (3). The Colo205 reporter assay data are summarized in Table 1 below.

IC of the Table 1 Compounds against Colo205-LUC-TCF/LEF reporter inhibition ₅₀ Value of

Test example 3: proliferation inhibition assay of compounds on Wnt mutant cell lines (Colo 205, DU4475, NCI-H929 and HepG 2) and non-Wnt mutant cell lines (Hela and RKO)

The cell lines used in the experiments were those in which the Wnt pathway was continuously activated and which proliferated as Wnt pathway dependent Colo205, DU4475, NCI-H929 and HepG2 cell lines; whereas normally Wnt pathway is not activated and HELA and RKO cell lines whose proliferation is independent of Wnt pathway are used as control cell lines, it was judged that the inhibition of Wnt dependent proliferation by the compounds of the invention is not due to other non-specific toxicities.

Colo205, du4475, NCI-H929, hepG2, HELA and RKO cell lines cultured in the respective media were treated in the logarithmic phase, and after collecting the cells, a uniform cell suspension of known concentration was prepared, and then the cell suspension was added to a 96-well cell culture plate so that 1000 cells were contained in each well. Placing 5% CO ₂ The cells are cultured in a cell incubator at 37 ℃ for 20-24 hours. The following day, the 3-fold gradient of the compound which had been completely dissolved was added to each cell culture well to give a final maximum concentration of 20. Mu.M in the cell culture well, and the culture was continued for 96 hours. The assay was performed using a Promega cell viability assay, the more cell proliferation the stronger the final signal intensity. The detection instrument is in SpectraMax, full wavelength mode. Wells with DMSO alone served as positive control wells and wells without cells inoculated served as negative control wells, and IC of each compound for Wnt continuous activation or proliferation inhibition of proliferation dependent cells was calculated ₅₀ Value, and IC for proliferation inhibition of Wnt-unactivated or proliferation-independent cells ₅₀ The inhibition of Wnt pathway and the toxic effect on normal cells were evaluated. The results are shown in Table 2 below.

IC of the compounds of Table 2 for inhibition of proliferation of Wnt mutant cell lines ₅₀ Value of

27	378.5	NT	NT	460.15	NT	>10000
28	88.91	NT	NT	120.27	NT	>10000
29	355.77	NT	1027.91	746.64	NT	>10000
30	271.79	NT	431.55	340.16	NT	>10000

The above results indicate that the compounds of the present invention have significant inhibitory activity against mutant cell lines Colo205, DU4475, NCI-H929 and HepG2, while having substantially no significant inhibitory activity against Hela and RKO cell lines, indicating that the compounds of the present invention have significant and selective inhibition of the Wnt pathway.

Claims (20)

1. A compound having the structure of formula (I) or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof:

   wherein:

   represents the presence or absence of a single bond;

   R ¹ represent C ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl, 3-6 membered heterocycloalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, and said R1 may optionally be selected from 0, 1, 2, 3: hydrogen, halogen, OR ^a Nitro, (C) ₁ -C ₆ ) Alkyl, (C) ₁ -C ₆ ) Alkoxy, (C) ₁ -C ₆ ) Haloalkyl, (C) ₃ -C ₆ ) Cycloalkyl, halo (C) ₃ -C ₆ ) Cycloalkyl, 3-6 membered heterocycloalkyl, halo 3-6 membered heterocycloalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, cyano, SR ^a Halo (C) ₁ -C ₆ ) Alkoxy, halo (C) ₃ -C ₆ ) Cycloalkoxy, halo (C) ₁ -C ₆ ) Alkylthio, (C) ₃ -C ₆ ) Cycloalkyloxy, (C) ₃ -C ₆ ) Cycloalkylthio, halo (C) ₃ -C ₆ ) A substituent of a cycloalkylthio group;

   x represents a covalent bond or- (CR) ^a R ^a’ ) _m -、-(CR ^a R ^a’ ) _m -O-(CR ^a R ^a’ ) _n -、-(CR ^a R ^a’ ) _m -N(R ^b )-(CR ^a R ^a’ ) _n -、-(CR ^a R ^a’ ) _m -S-(CR ^a R ^a’ ) _n -、-(CR ^a R ^a’ ) _m C(O)(CR ^a R ^a’ ) _n -、-(CR ^a R ^a’ ) _m S(O) ₂ (CR ^a R ^a’ ) _n -、-(CR ^a R ^a’ ) _m C(O)N(R ^b )(CR ^a R ^a’ ) _n -、-(CR ^a R ^a’ ) _m S(O) ₂ N(R ^b )(CR ^a R ^a’ ) _n -、-(CR ^a R ^a’ ) _m N(R ^b )C(O)(CR ^a R ^a’ ) _n -、-(CR ^a R ^a’ ) _m N(R ^b )S(O) ₂ (CR ^a R ^a’ ) _n -、-(CR ^a R ^a’ ) _m OC(O)N(R ^b )(CR ^a R ^a’ ) _n -、-(CR ^a R ^a’ ) _m N(R ^b )C(O)O(CR ^a R ^a’ ) _n -、-(CR ^a R ^a ’) _m N(R ^b )C(O)N(R ^b’ )(CR ^a R ^a’ ) _n -、-(CR ^a R ^a’ ) _m N(R ^b )S(O) ₂ N(R ^b’ )(CR ^a R ^a’ ) _n -；

   Cy represents C ₃ -C ₅ Cycloalkyl OR 4-5 membered cycloheteroalkyl, and which may optionally be substituted with 0, 1 OR 2 groups selected from hydrogen, halogen, -OR ^a 、(C ₁ -C ₆ ) Alkyl, (C) ₁ -C ₆ ) Haloalkyl, (C) ₃ -C ₆ ) Cycloalkyl, cyano and hydroxy (C) ₁ -C ₆ ) Substituted by alkyl;

   R ² represents hydrogen, (C) ₁ -C ₆ ) Alkyl, (C) ₁ -C ₆ ) Haloalkyl, (C) ₃ -C ₆ ) Cycloalkyl or hydroxy (C) ₁ -C ₆ ) An alkyl group;

   R ³ and R is ^3’ Each independently represents hydrogen, halogen, OR ^a 、(C ₁ -C ₆ ) Alkyl, (C) ₃ -C ₆ ) Cycloalkyl, hydroxy C ₁ -C ₆ Alkyl or (C) ₁ -C ₆ ) Alkoxy (C) ₁ -C ₆ ) An alkyl group;

   or R is ³ And R is ^3’ Together with the carbon atoms to which they are attached form a 3-to 6-membered saturated or unsaturated ring which may optionally contain 1 or 2 heteroatoms selected from O, S and N and which may optionally be substituted with 0, 1 or 2 heteroatoms selected from halogen, hydroxy and C ₁ -C ₆ Substituted by alkyl;

   or R is ² 、R ³ Or R is ² 、R ^3’ Together with the atoms to which they are attached form a 4-6 membered saturated or unsaturated ring which may optionally contain 1 or 2 heteroatoms selected from O, S and N and which may optionally be substituted with 0, 1 or 2 heteroatoms selected from halogen, hydroxy and C ₁ -C ₆ Substituted by alkyl;

   R ⁴ and R is ^4’ Each independently represents hydrogen, C ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl, hydroxy C ₁ -C ₆ Alkyl, halogenated C ₁ -C ₆ Alkyl, (C) ₁ -C ₆ ) Alkoxy (C) ₁ -C ₆ ) An alkyl group;

   or R is ⁴ And R is R ^4’ Together form = O;

   R ^T and R is ^T’ Each independently represents hydrogen, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, hydroxy C ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl, halogen, OR ^a ；

   Or R is ^T And R is ^T’ Together with the atoms to which they are attached form a 3-6 membered ring;

   wherein whenWhen a single bond is not present, A represents (CR ^L R ^L’ ) _p Wherein R is ^L And R is ^L’ Each independently represents hydrogen, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, hydroxy C ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl, halogen, OR ^a Or R ^L And R is ^L’ Together with the carbon atoms to which they are attached, form a 3-6 membered ring which may optionally contain 0, 1 or 2 heteroatoms selected from O, S and N, and which may optionally be substituted with 0, 1 or 2 substituents selected from halogen and hydroxy;

   wherein whenWhen a single bond is present, A represents CR ^H Wherein R is ^H Represents hydrogen, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, hydroxy C ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl, halogen, OR ^a ；

   Wherein R is ^a 、R ^a’ 、R ^b 、R ^b’ Each independently represents hydrogen or C ₁ -C ₆ An alkyl group;

   wherein m, n, p each independently represent 0, 1 or 2.
2. The compound of claim 1, or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof, having the structure of formula (II):

   Wherein R is ¹ 、R ² 、R ³ 、R ^3’ 、R ⁴ 、R ^4’ X, cy have the definition as in claim 1.
3. The compound of claim 1, or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof, having the structure of formula (III):

   wherein R is ¹ 、R ² 、R ³ 、R ^3’ 、R ⁴ 、R ^4’ 、R ^T 、R ^T’ 、R ^L 、R ^L’ X, cy have the definition as in claim 1.
4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof, wherein R ² Represents hydrogen, C ₁ -C ₆ Alkyl, hydroxy (C) ₁ -C ₆ Alkyl) or C ₃ -C ₆ Cycloalkyl groups.
5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof, wherein R ³ ，R ^3’ Each independently represents hydrogen, C ₁ -C ₆ Alkyl or hydroxy (C) ₁ -C ₆ Alkyl).
6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof, wherein R ⁴ ，R ^4’ Each independently represents hydrogen, C ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl, or R ⁴ And R is R ^4’ Together form =o.
7. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof, wherein Cy represents C ₃ -C ₅ Cycloalkyl or 4-5 membered cycloheteroalkyl, preferably Cy represents
8. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof, wherein X represents a covalent bond or- (CR) ^a R ^a’ ) _m -、-(CR ^a R ^a’ ) _m -O-(CR ^a R ^a’ ) _n -、-(CR ^a R ^a’ ) _m -N(R ^b )-(CR ^a R ^a’ ) _n -、-(CR ^a R ^a’ ) _m -S-(CR ^a R ^a’ ) _n -、-(CR ^a R ^a’ ) _m C(O)N(R ^b )(CR ^a R ^a’ ) _n -、-(CR ^a R ^a’ ) _m S(O) ₂ N(R ^b )(CR ^a R ^a’ ) _n -、-(CR ^a R ^a’ ) _m N(R ^b )C(O)(CR ^a R ^a’ ) _n -、-(CR ^a R ^a’ ) _m N(R ^b )S(O) ₂ (CR ^a R ^a’ ) _n -、-(CR ^a R ^a’ ) _m OC(O)N(R ^b )(CR ^a R ^a’ ) _n -、-(CR ^a R ^a’ ) _m N(R ^b )C(O)O(CR ^a R ^a’ ) _n -、-(CR ^a R ^a ’) _m N(R ^b )C(O)N(R ^b’ )(CR ^a R ^a’ ) _n -、-(CR ^a R ^a’ ) _m N(R ^b )S(O) ₂ N(R ^b’ )(CR ^a R ^a’ ) _n -。
9. A compound according to claim 8, wherein X represents-O-, -NR, or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof ^b -、-CR ^a R ^a’ -、-OCR ^a R ^a’ -、-CR ^a R ^a’ O-、-C(O)-、-C(O)NR ^b -、-NR ^b C(O)-、-NR ^b -C(O)-NR ^b -、-CR ^a R ^a’ -C(O)NR ^b -、-CR ^a R ^a’ -NR ^b C(O)-、-S-、-NR ^b S(O) ₂ -、-SO ₂ NR ^b 、-OC(O)NR ^b -、-S(O) ₂ 、-C(O)NR ^b -、-C(O)CR ^a R ^a’ -、-CR ^a R ^a’ C(O)NR ^b -、-NR ^b C(O)CR ^a R ^a’ -、-NR ^b C (O) O-; wherein R is ^a 、R ^a’ 、R ^b Each independently represents hydrogen or C ₁ -C ₆ An alkyl group.
10. A compound according to claim 9, wherein X represents- (CR), or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof ^a R ^a’ ) _m -O-(CR ^a R ^a’ ) _n -, preferably-O-, -OCR ^a R ^a’ -、-CR ^a R ^a’ O-, more preferably-O-or-O-CH ₂ -。
11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof, wherein R ^T And R is ^T’ Represents hydrogen.
12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof, wherein R ^L And R is ^L’ Represents hydrogen.
13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof, wherein R ^H Represents hydrogen.
14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof, wherein R ¹ Represents C substituted by 0, 1, 2 or 3 substituents ₃ -C ₆ Cycloalkyl, 3-6 membered heterocycloalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, wherein the substituents are selected from halogen, (C) ₁ -C ₆ ) Alkyl, (C) ₁ -C ₆ ) Haloalkyl, (C) ₃ -C ₆ ) Cycloalkyl, halo (C) ₃ -C ₆ ) Cycloalkyl, 3-6 membered heterocycloalkyl, halo 3-6 membered heterocycloalkyl, C ₆ -C ₁₀ Aryl and 5-10 membered heteroaryl.
15. The compound of claim 14, or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof, wherein R ¹ Represent C ₃ -C ₆ Cycloalkyl, 3-6 membered heterocycloalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, and R as described ¹ Can be optionally selected from 0, 1, 2 and 3: hydrogen, halogen, (C) ₁ -C ₆ ) Alkyl, (C) ₁ -C ₆ ) Haloalkyl, (C) ₃ -C ₆ ) Cycloalkyl, halo (C) ₃ -C ₆ ) The substituents of cycloalkyl groups are substituted.
16. The compound of claim 14, or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof, wherein R ¹ Selected from:
17. the compound of claim 15, or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof, wherein R ¹ Selected from:
18. a compound having the structure:
19. a pharmaceutical composition comprising a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof.
20. Use of a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof, or a pharmaceutical composition according to claim 19 for the manufacture of a medicament for the prevention and/or treatment of cancer, tumour, inflammatory diseases, autoimmune diseases or immune mediated diseases.