Aza-indole pi3kδ inhibitors, methods of making and using the same

Abstract

This invention discloses a class of indole derivatives containing or without heteroatoms (such as nitrogen heteroatoms) and their pharmaceutical compositions that can be used as PI3Kδ kinase inhibitors, and can be used to treat diseases, conditions or symptoms related to PI3Kδ inhibition, including immune disorders, cancer and cardiovascular diseases.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, specifically to a class of azaindole compounds, their preparation methods, and applications. Background Technology

[0002] Malignant tumors have long posed a serious threat to human health, especially B-cell malignancies, including chronic lymphocytic leukemia, acute lymphoblastic leukemia, non-Hodgkin's lymphoma, and follicular lymphoma. Early treatments primarily involved alleviating symptoms through traditional cytotoxic drugs. However, with in-depth research into the mechanisms of tumor formation, various physiological processes within tumor cells, such as signal transduction, cell cycle regulation, apoptosis, and angiogenesis, have become increasingly understood. Among these, the PI3K / Akt signaling pathway is a crucial signaling pathway in mammals, and its abnormal activation is considered closely related to tumor development and progression.

[0003] Phosphatidylinositol-3-kinase (PI3K) is a member of the lipokinase family and an important component of the PI3K / AKT / mTOR signaling pathway. It mediates phosphorylation processes within the cell, thus influencing a series of processes including cell growth, proliferation, differentiation, migration, and apoptosis. Studies have found that abnormal activation of the PI3K pathway is closely related to the occurrence and development of various diseases, with different types of PI3K playing different functions. Type I PI3K mainly includes PI3Kα, PI3Kβ, PI3Kγ, and PI3Kδ. Mutations in PI3Kα are associated with tumor development and progression; PI3Kβ can activate platelets and is associated with the development of thrombotic diseases; in PTEN-deficient tumors, PI3Kγ promotes tumor malignancy; PI3Kγ and PI3Kδ are mainly related to the immune and hematopoietic systems, and are closely related to the occurrence of immune disorders, hematologic malignancies, and inflammation. Type II PI3K mainly affects membrane transport. Type III PI3K member Vps34 can affect endocytosis and vesicle transport, regulate autophagy, and also mediate cellular signal transduction through mTOR.

[0004] While PI3Kα and PI3Kβ are expressed in many tissue types, PI3Kγ and PI3Kδ are primarily expressed in leukocytes and are therefore considered attractive targets for treating inflammatory conditions and other immune system-related diseases. Studies have also shown that targeting one or more of the four type I PI3K subtypes can produce applicable therapies for cancer. The gene encoding P110α is frequently mutated in common cancers, including breast cancer, brain cancer, prostate cancer, colon cancer, stomach cancer, lung cancer, and endometrial cancer. Mutations in these subtypes have not been identified in other PI3K subtypes, but there is evidence that they promote the development and progression of malignancies. PI3Kδ is consistently overexpressed in acute myeloid leukemia, and inhibitors of PI3Kδ can prevent the growth of leukemia cells.

[0005] The patent specification with publication number CN104619708A discloses an azaindole compound. Using azaindole as the structural core, a series of small molecule PI3Kδ inhibitors were designed and synthesized. The PI3Kδ kinase inhibitory activity of this compound was tested, showing good kinase subtype selectivity and better in vitro proliferation inhibitory activity against tumor cell lines.

[0006] The patent specification with publication number CN112794851A discloses a 3-(pyridin-3-yl)-7-azaindole derivative PI3Kδ inhibitor, which can inhibit the activity of PI3Kδ kinase and has potential therapeutic applications for diseases, symptoms and conditions related to PI3Kδ kinase overexpression. Summary of the Invention

[0007] This invention provides a class of indole derivatives, with or without heteroatoms (such as nitrogen heteroatoms), and pharmaceutical compositions thereof that can be used as PI3Kδ kinase inhibitors, for the treatment of diseases, conditions or symptoms related to PI3Kδ inhibition, including immune disorders, cancer and cardiovascular diseases.

[0008] In a first aspect, the present invention provides compounds having the structure shown in formula (I), or pharmaceutically acceptable salts thereof, or racemic mixtures thereof, hydrates, solvates, prodrugs, enantiomers, diastereomers, or tautomers thereof:

[0009]

[0010] In formula (1):

[0011] * indicates chiral carbon;

[0012] W, X, Y and Z are all carbon atoms, or at least one of W, X, Y and Z is a nitrogen atom and the others are carbon atoms;

[0013] R 1H, halogen, nitro, cyano, amino, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, carboxyl, ester, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 cycloalkyl, substituted or unsubstituted C 1-6 Heterocyclic alkyl, substituted or unsubstituted C 4-10 aryl, substituted or unsubstituted C 1-8 heteroaryl, C 2-10 alkenyl, C 2-10 The group consisting of one or more of the following: alkynyl, alkyl monosubstituted amino, alkyl disubstituted amino, alkoxy, alkyl carbonyloxy, cycloalkyl carbonyloxy, heteroaryl carbonyloxy, alkoxy carbonyl, cycloalkoxy carbonyl, heteroaryloxy carbonyl, alkyl carbonylamine, cycloalkyl carbonylamine, heteroaryl carbonylamine, amino carbonyl, alkoxyformamide, alkimidyl, hydroxyalkoxy, sugar residue, sulfonic acid group, phosphoric acid group, polyhydroxyalkoxy carbonyl, carboxyalkoxy, and carboxyalkylformyloxy.

[0014] R 2 Selected from aryl, heteroaryl and C 3-6 Heterocyclic alkyl groups; each of which is optionally and independently substituted with one or more groups selected from halogens, hydroxyl groups, amino groups, nitro groups, cyano groups, amino groups, hydroxyl groups, hydroxymethyl groups, hydroxyethyl groups, mercapto groups, carboxyl groups, ester groups, substituted or unsubstituted C groups. 1-6 Alkyl, C 2-10 alkenyl, C 2-10 Alkyne group, substituted or unsubstituted C 4-10 aryl, substituted or unsubstituted C 1-8 Heteroaryl, alkoxycarbonyl, cycloalkylcarbonylamine, alkimidyl, hydroxyalkoxy, sugar residue, sulfonic acid group, phosphoric acid group, polyhydroxyalkoxycarbonyl, carboxylalkoxy;

[0015] R 3 Selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 cycloalkyl, substituted or unsubstituted C 1-6 Heterocyclic alkyl groups;

[0016] R 4 A monocyclic or bicyclic system comprising at least two single atoms, wherein at least one ring in the ring system is an aromatic ring, and the aromatic ring may be unsubstituted or substituted, for example, by one or more of the following, particularly 1-3 of the following substituents: halogen, hydroxyl, amino, nitro, cyano, amino, hydroxyl, hydroxymethyl, hydroxyethyl, mercapto, carboxyl, ester, substituted or unsubstituted C 1-6 Alkyl, C 2-10 alkenyl, C 2-10 Alkyne group, substituted or unsubstituted C 4-10 aryl, substituted or unsubstituted C1-8 Heteroaryl, alkoxycarbonyl, cycloalkylcarbonylamine, alkimidyl, hydroxyalkoxy, sugar residue, sulfonic acid group, phosphoric acid group, polyhydroxyalkoxycarbonyl, carboxyalkoxy; its monocyclic or bicyclic forms include, but are not limited to, phenyl, naphthyl, indene, azulel, fluorenyl and anthracene, furanyl, thiophene, pyridyl, pyrrole, oxazolyl, thiazolyl, imidazole, pyrazolyl, pyrazolylalkyl, isoxazolyl, isotriazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5- Triazinyl, 1,3,5-trithiaalkyl, indoleyl, indolyl, isozinyl, dihydroindolyl, benzo[b]furanyl, benzo[b]thiophenyl, 1H-indazolyl, benzimidazolyl, benzothiazolyl, purinyl, 4H-quinazinyl, quinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, porphyrinyl, 2,3-diazanaphthyl, quinazolinyl, quinoxalinyl, 1,8-diazanaphthyl, pteridinyl, carbazoyl, acridineyl, phenazinyl, phenothiazinyl, and phenotoxazinyl.

[0017] Furthermore, the absolute configuration of the chiral carbon in equation (1) can be the S configuration, as shown in equation (2):

[0018]

[0019] In some preferred embodiments, one of W, X, Y, and Z is a nitrogen atom, and the other three are carbon atoms. For example, W or Z is a nitrogen atom, and the rest are carbon atoms.

[0020] In some preferred solutions, R 1 It is H or a halogen (e.g., Cl).

[0021] In some preferred solutions, R 2 The substituent may be a substituted or unsubstituted C1-C6 alkyl, pyridyl, phenyl, pyrazolyl, or thiophene group, wherein the substituent is one or more of pyridyl, C1-C6 alkyl, (C1-C6 alkyl)sulfonyl, hydroxyl, or halogen (e.g., F).

[0022] In some preferred solutions, R 3 It is a C1-C6 alkyl chain or a C3-C6 cycloalkyl chain.

[0023] In some preferred solutions, R 4 for Specifically, the compound may be a compound having any of the following structures:

[0024]

[0025]

[0026]

[0027] Secondly, the present invention provides a method for preparing compounds 12-41, wherein compounds 12-41 are synthesized using reaction route I;

[0028] Reaction route I includes the following processes:

[0029]

[0030] Compound 1 reacts with aluminum trichloride and acetyl chloride in anhydrous dichloromethane to generate 3-acetyl-azaindole, i.e., compound 2. Then, through a Ullmann coupling reaction catalyzed by cuprous iodide, compound 3 is formed. Next, it condenses with S-tert-butylsulfinamide to form an imine intermediate 4, which is then reduced in the presence of diisobutylaluminum hydride (DIBAL-H) ​​to generate the S-configuration compound 5. Finally, it is hydrolyzed under hydrochloric acid conditions to give compound 6. Compound 6 reacts with chlorinated compound R... 4 The target compound was obtained by nucleophilic substitution of -Cl.

[0031] Furthermore, when R 4 for At that time, chlorinated compound R 4 -Cl can be synthesized using reaction route II; reaction route II includes the following process:

[0032]

[0033] Compound 7 reacts with phosphorus oxychloride in N,N-dimethylformamide (DMF) to generate compound 8. Compound 8 reacts with hydroxylamine hydrochloride, and the aldehyde group reacts to generate an oxime, giving compound 9. Then, it reacts with thionyl chloride in anhydrous dichloromethane (DCM) to dehydrate and form a cyano group, giving compound 10. Compound 10 reacts with ammonia in 1,4-dioxane to generate the target compound 11.

[0034] The compounds prepared according to the above preparation method, their pharmaceutically acceptable salts, hydrates, solvates, polymorphs or prodrugs can be purified by column chromatography, high performance liquid chromatography, crystallization or other appropriate methods.

[0035] The compounds described in the first aspect can exhibit tautomerism, structural isomerism, and stereoisomerism. The present invention includes any tautomerism, structural isomerism, or stereoisomerism thereof, and mixtures thereof, which have the ability to modulate kinase activity, and this ability is not limited to any single isomer or mixture thereof.

[0036] Thirdly, the present invention provides a pharmaceutical composition comprising the compound described in the first aspect, or a pharmaceutically acceptable salt thereof, or a racemic mixture thereof, hydrate, solvate, prodrug, enantiomer, diastereomer, tautomer, and at least one of a pharmaceutically acceptable carrier, diluent, and excipient.

[0037] A pharmaceutically acceptable carrier (i.e., a pharmaceutically acceptable carrier) is a carrier that is compatible with (and in some embodiments, stabilizes) the active ingredient in the composition and is harmless to the individual being treated. Pharmaceutical carriers and / or excipients can be selected from fillers, salts, disintegrants, binders, lubricants, flow aids, wetting agents, controlled-release matrices, colorants, flavoring agents, buffers, stabilizers, solubilizers, and combinations thereof.

[0038] Pharmaceutical compositions comprising the compounds described in the first aspect of this document and / or their pharmaceutically acceptable salts may be administered in a variety of known manners, such as oral, topical, rectal, parenteral, inhalation, or implantation.

[0039] Depending on the therapeutic purpose, drug compositions can be formulated into various types of dosage forms, such as tablets, pills, powders, liquid preparations, suspensions, emulsions, granules, capsules, suppositories, and injections (solutions and suspensions).

[0040] To form a pharmaceutical composition in tablet form, any excipient known and widely used in the art may be used, such as carriers, including lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, and silica; binders, including water, ethanol, propanol, common syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, and polyvinylpyrrolidone; disintegrants, including dry starch, sodium alginate, agar powder, and kelp powder, sodium bicarbonate, calcium carbonate, fatty acid esters of polyvinyl sorbitol, sodium lauryl sulfate, monoglyceride stearate, starch, and lactose; disintegration inhibitors, including white sugar, glyceryl tristearate, coconut oil, and hydrogenated oil; adsorption promoters, including quaternary ammonium base and sodium lauryl sulfate; wetting agents, including glycerin and starch; adsorbents, including starch, lactose, kaolin, bentonite, and colloidal silica; and lubricants, including pure talc, stearates, boric acid powder, and polyethylene glycol. It can also be made into sugar-coated tablets, gelatin-coated tablets, sausage-coated tablets, coated tablets, double-layered tablets and multilayered tablets by selecting common coating materials as needed.

[0041] To form a pharmaceutical composition in pellet form, any excipient known and widely used in the art may be used, such as carriers, like lactose, starch, coconut oil, hardened vegetable oil, kaolin, and talc; binders, like gum arabic, tragacanth, gelatin, and ethanol; and disintegrants, like agar and kelp powder.

[0042] To form a pharmaceutical composition in suppository form, any excipient known and widely used in the art may be used, such as polyethylene glycol, coconut oil, higher alcohols, esters of higher alcohols, gelatin, and semi-synthetic glycerides.

[0043] To prepare pharmaceutical compositions in injectable form, solutions or suspensions can be sterilized (preferably with the addition of appropriate amounts of sodium chloride, glucose, or glycerol) to create an isotonic injection similar to blood. Any commonly used carrier in the art can be used in the preparation of the injection, such as water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and fatty acid esters of polyvinyl sorbitol. Furthermore, common solvents, buffers, and analgesics can be added.

[0044] In this invention, there are no particular limitations on the method of administration of the pharmaceutical composition. Various dosage forms can be selected for administration based on the patient's age, gender, other conditions, and symptoms. For example, tablets, pills, solutions, suspensions, emulsions, granules, or capsules can be administered orally; injections can be administered alone or mixed with an injection delivery solution (such as glucose solution and amino acid solution) for intravenous injection; suppositories are administered rectally.

[0045] Fourthly, the present invention provides a method for inhibiting PI3K activity in vivo or in vitro, comprising contacting PI3K with an effective amount of one of the compounds described in the first aspect and / or a pharmaceutically acceptable salt thereof.

[0046] Fifthly, the present invention provides a method for inhibiting PI3K activity in vivo or in vitro, comprising contacting an amount of a pharmaceutical composition capable of effectively inhibiting PI3K activity with PI3K, said pharmaceutical composition comprising a compound described in the first aspect and / or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0047] In a sixth aspect, the present invention provides a method for treating a disease in an individual that responds to inhibition of PI3K, comprising administering to the individual in need of the compound described in the first aspect and / or a pharmaceutically acceptable salt thereof that effectively inhibits the amount of PI3K in the individual.

[0048] In a seventh aspect, the present invention provides a method for treating a disease in an individual that responds to inhibition of PI3K, comprising administering to the individual in need a pharmaceutical composition capable of effectively inhibiting an amount of PI3K in the individual, the pharmaceutical composition comprising a compound as described in the first aspect and / or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0049] Eighthly, the present invention provides the use of the compound described in the first aspect, or a pharmaceutically acceptable salt thereof, or a racemic mixture thereof, hydrate, solvate, prodrug, enantiomer, diastereomer, tautomer, or pharmaceutical composition described in the third aspect, in the preparation of a PI3Kδ kinase inhibitor.

[0050] Ninthly, the present invention provides the use of the compound described in the first aspect, or a pharmaceutically acceptable salt thereof, or a racemic mixture thereof, hydrate, solvate, prodrug, enantiomer, diastereomer, tautomer, or pharmaceutical composition described in the third aspect, in the preparation of a medicament for treating diseases responsive to inhibition of PI3Kδ. The diseases include inflammatory diseases, autoimmune diseases, cancer, infectious diseases, and cardiovascular diseases.

[0051] The inflammatory diseases and autoimmune diseases mentioned are rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), allergic rhinitis, asthma, lupus erythematosus, psoriasis, and multiple sclerosis.

[0052] The cancer mentioned is a solid tumor or a hematologic malignancy, selected from leukemia, multiple myeloma (MM), and lymphoma; the leukemia mentioned is acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML); the lymphoma mentioned is Hodgkin lymphoma, non-Hodgkin lymphoma (NHL), mantle cell lymphoma (MCL), follicular lymphoma, B-cell lymphoma, cellular lymphoma, and diffuse large B-cell lymphoma (DLBCL).

[0053] The infectious diseases mentioned include bacterial infections, fungal infections, viral infections, and parasitic infections.

[0054] The cardiovascular and cerebrovascular diseases mentioned include acute heart failure, hypotension, hypertension, angina pectoris, myocardial infarction, cardiomyopathy, congestive heart failure, atherosclerosis, coronary heart disease, restenosis and vascular stenosis, as well as traumatic brain injury, stroke, ischemia-reperfusion injury and arterial lesions.

[0055] Furthermore, the compounds and / or their pharmaceutically acceptable salts described in the first aspect of this document can be used in combination with other active ingredients for the treatment of inflammatory diseases, autoimmune diseases, cancer, infectious diseases, or cardiovascular diseases. The compounds and / or their pharmaceutically acceptable salts described in the first aspect can also be used separately with other active ingredients or formulated into compound preparations. Other active ingredients refer to those known to be effective in treating PI3K-mediated diseases.

[0056] definition

[0057] The term "alkyl" refers to a straight-chain or branched saturated alkyl group containing 1-18 carbon atoms, for example 1-12 carbon atoms, further for example 1-6 carbon atoms, and still for example 1-4 carbon atoms. For example, "C1-C6 alkyl" within the range of "alkyl" indicates the alkyl group having 1-6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl ("Me"), ethyl ("Et"), n-propyl ("n-Pr"), isopropyl ("i-Pr"), n-butyl ("n-Bu"), isobutyl ("i-Bu"), sec-butyl ("s-Bu"), and tert-butyl ("t-Bu").

[0058] The term "halogen" (or "halogenated") refers to fluorine, chlorine, bromine, and iodine (or fluorinated (F), chlorinated (Cl), brominated (Br), and iodinated (I)).

[0059] The term "alkoxy" refers to the -O-alkyl group, where the alkyl group is as defined above. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy, and hexoxy, including their isomers.

[0060] The term "aryl" refers to a carbocyclic hydrocarbon group consisting of 6-14 ring carbon atoms, for example 6-12 ring carbon atoms, formed by the fusion of one or more rings, wherein at least one ring is an aromatic ring and the other rings are not heteroaryl as defined below, and the bonding point may be on an aromatic ring or on other rings. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indenyl, indenyl, olyl, with phenyl being preferred.

[0061] The term "heteroaryl" or "heteroary" refers to a monocyclic, bicyclic, or tricyclic, saturated or partially unsaturated ring selected from 4 to 12 members, containing at least one carbon atom in addition to at least one, for example, 1-4, again for example, 1-3, or again for example, 1 or 2 heteroatoms selected from O, S, and N. The bonding point of the heteroaryl group can be on the heteroatom or on the carbon atom. "Heteroaryl" or "heteroary" also refers to a monocyclic ring containing at least one heteroatom selected from O, S, and N; or a fused ring, wherein at least one ring contains at least one heteroatom selected from O, S, and N and the other rings are not heteroaryl or aryl, and the bonding point can be on the heteroaryl group or on other rings.

[0062] If a structural formula in this article contains an asterisk "*", then the compound represented by that structural formula is a racemic mixture.

[0063] The term "substituted by one or more substituents" means that one or more hydrogen atoms on a given atom or group are independently replaced by one or more substituents selected from the given group. In some embodiments, "substituted by one or more substituents" means that a given atom or group is replaced by 1, 2, 3 or 4 substituents independently selected from the given group.

[0064] The term "pharmaceutically acceptable salt" refers to a derivative of the disclosed compound, wherein the parent compound is modified by converting an existing acid or base moiety into its salt form. Pharmaceutically acceptable salts include, but are not limited to, acid addition salts formed by the compounds described in the first aspect with inorganic or organic acids, and base addition salts formed by the compounds described in the first aspect with an acidic group and a pharmaceutically acceptable cation. The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing a basic or acidic moiety using conventional chemical methods. Generally, these salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture thereof.

[0065] The term "solvent" refers to a solvent addition form containing stoichiometric or non-stoichiometric amounts of solvent. If the solvent is water, the resulting solvate is a hydrate; when the solvent is ethanol, the resulting solvate is an ethanol compound.

[0066] The term "prodrug" refers to a non-active precursor of a compound that is converted into its active form in vivo through normal metabolic pathways. For illustration, a prodrug can be converted into its pharmacologically active form by hydrolysis (e.g.) of ester or amide bonds, thereby introducing or exposing functional groups on the resulting product.

[0067] Undefined technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which this invention pertains.

[0068] Compared with the prior art, the present invention has the following advantages: The present invention provides a class of indole derivatives containing or without heteroatoms (such as nitrogen heteroatoms) and their pharmaceutical compositions that can be used as PI3Kδ kinase inhibitors, which can be used to treat diseases, symptoms or conditions related to PI3Kδ inhibition, including immune diseases, cancer and cardiovascular diseases. Detailed Implementation

[0069] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Operating methods not specifically specified in the following embodiments are generally performed under conventional conditions or as recommended by the manufacturer.

[0070] Preparation Example 1

[0071]

[0072] 4-Chloro-7-azaindole (2 g, 13.11 mmol) and aluminum trichloride (8.74 g, 65.55 mmol) were placed in a two-necked flask, purged with argon gas three times, and anhydrous dichloromethane was added. After reacting at room temperature for 30 min, acetyl chloride (4.67 mL, 65.55 mmol) was slowly added dropwise at 0 °C. After the addition was complete, the mixture was allowed to return to room temperature for 3 h. Acetyl chloride was then quenched by slowly adding methanol dropwise at 0 °C. The reaction solution was concentrated, water was added to the residue, and the pH of the reaction solution was adjusted to approximately 4 with an aqueous sodium hydroxide solution. The mixture was extracted three times with ethyl acetate, the organic layers were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was recrystallized from PE / EA and filtered to obtain a yellow-green solid 2 (2 g, 78%).

[0073] Preparation Example 2

[0074]

[0075] Compound 2 (2 g, 10.28 mmol), cuprous iodide (392 mg, 2.06 mmol), (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (587 g, 4.12 mmol), and potassium carbonate (2.84 g, 20.56 mmol) were weighed and added to a two-necked flask. Dimethyl sulfoxide was added under argon protection, and 3-bromopyridine (2.44 g, 15.42 mmol) was added at room temperature. The mixture was heated to 90 °C and reacted for 2 h. After the reaction was completed, the mixture was cooled to room temperature, ethyl acetate was added, and the mixture was stirred for 30 min. The insoluble matter was removed by filtration. The filtrate was extracted three times with water, and the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by column chromatography using PE / EA (v / v, 5:1) to obtain pure product 3 (2.24 g, 80%).

[0076] Preparation Example 3

[0077]

[0078] In a two-necked flask, starting material 3 (2.24 g, 8.26 mmol) and S-tert-butylsulfinamide (2.00 g, 16.52 mmol) were added. The mixture was evacuated and purged with argon gas three times. Anhydrous tetrahydrofuran was added, followed by tetraethyl titanate (3.77 g, 16.52 mmol) at room temperature. The mixture was then heated to 80 °C and refluxed overnight. After the reaction was complete, the mixture was cooled to room temperature, and ethyl acetate was added and stirred for 30 min. The mixture was filtered to remove insoluble matter, and the filtrate was extracted three times with water. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography using PE / EA (v / v, 1:1) eluent to obtain a pale yellow solid 4 (2.17 g, 70%).

[0079] Preparation Example 4

[0080]

[0081] Raw material 4 (2.17 g, 5.79 mmol) was added to two flasks, evacuated and purged with argon gas three times, anhydrous toluene was added, and DIBAL-H (11.58 mL, 11.58 mmol) was slowly added dropwise at -78 °C. After the addition was complete, the reaction was carried out at -78 °C for 4 h. After the reaction was complete, saturated NH4Cl was added at low temperature and stirred for 30 min. The insoluble matter was removed by filtration, the filtrate was extracted three times with water, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by column chromatography using PE / EA (v / v, 1:1) to obtain white solid 5 (1.79 g, 82%).

[0082] Preparation Example 5

[0083]

[0084] Raw material 5 (1.79 g, 4.76 mmol) was added to a single-necked flask, dissolved in methanol, and then reacted with 4N HCl at room temperature for 1 h. After the reaction was complete, the reaction solution was concentrated, water was added to the residue, and the pH of the reaction solution was adjusted to alkaline with sodium hydroxide aqueous solution. The mixture was extracted three times with dichloromethane, the organic layers were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was recrystallized from DCM / MeOH and filtered to obtain white solid 6 (1.29 g, 100%).

[0085] Preparation Example 6

[0086]

[0087] Additive 6 (1.29 g, 4.76 mmol), additive 11 (887 mg, 5.24 mmol), and DIPEA (921 mg, 7.14 mmol) to a pressure-resistant tube, dissolve in n-butanol, and react overnight at 140 °C. After the reaction is complete, cool to room temperature, dilute with water, extract three times with ethyl acetate, combine the organic layers, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, concentrate, and elute with DCM / MeOH (v / v, 50:1) by column chromatography to obtain white solid 12 (960 mg, 50%).

[0088] 1H NMR (400MHz, DMSO-d6) δ9.10(d,J=2.4Hz,1H),8.59(dd,J=4.8,1.6Hz,1H),8.30(ddd,J=8.4,2.8,1.6Hz,1H),8.27(d,J=5.2Hz,1H),8.11(s,1H),7. 62(ddd,J=8.4,4.8,0.8Hz,1H),7.36(d,J=5.2Hz,1H),6.58(d,J=8.0Hz,1 H),6.54(s,2H),6.41(s,2H),5.96(p,J=6.8Hz,1H),1.64(d,J=6.8Hz,3H). 13 C NMR(100MHz,DMSO-d6)δ170.54,168.32,167.89,153.25,152.53,149.87,149.20,140.47 ,139.47,136.37,132.35,129.28,123.80,123.29,123.11,122.71,65.14,47.31,26.79.

[0089] Preparation Example 7 (S)-2,4-diamino-6-((1-(1-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl)amino)pyrimidin-5-nitrile 13

[0090]

[0091] The preparation method is similar to that in Scheme 1-6, except that the reactants are changed. The same applies below. Column chromatography yielded a white solid 13, with a yield of 53%.

[0092] 1 H NMR(500MHz,DMSO-d6)δ9.17(d,J=2.5Hz,1H),8.53(dd,J=4.5,1.5Hz,1H),8.38( ddd,J=8.5,2.5,1.5Hz,1H),8.32(dd,J=4.5,1.5Hz,1H),8.14(dd,J=8.0,1.5Hz,1 H),7.98(s,1H),7.59(ddd,J=8.5,4.5,1.0Hz,1H),7.23(dd,J=8.0,4.5Hz,1H),6 .82(d,J=8.5Hz,1H),6.58–6.44(m,4H),5.82–5.75(m,1H),1.66(d,J=7.0Hz,3H). 13C NMR(100MHz,DMSO-d6)δ165.96,163.54,163.21,147.57,146.96,144.33,143.90,135.24 ,130.60,129.11,125.33,124.47,120.71,119.95,118.23,117.52,60.09,41.96,20.79.

[0093] Preparation Example 8 (S)-2,4-diamino-6-((1-(6-chloro-1-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl)amino)pyrimidine-5-nitrile 14

[0094]

[0095] The preparation method is similar to that in Examples 1-6. Column chromatography yielded a white solid 14, with a yield of 57%.

[0096] 1 H NMR (400MHz, Methanol-d4) δ9.10(m,1H),8.51(m,1H),8.34(ddd,J=8.4,2.8,1.2Hz,1H),8.11(d,J=8.4Hz,1 H),7.79(s,1H),7.61(dd,J=8.4,4.8Hz,1H),7.20(d,J=8.4Hz,1H),5.91–5.80(m,1H),1.71(d,J=6.8Hz,3H). 13 C NMR (100MHz, Methanol-d4) δ164.87,162.59,162.25,145.60,145.35,144.26,142.74,140. 79,134.39,130.38,130.28,123.58,119.42,118.43,116.02,115.88,44.45,41.23,18.47.

[0097] Preparation Example 9 (S)-2,4-diamino-6-((1-(6-chloro-1-(3-(methanesulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl)amino)pyrimidine-5-nitrile 15

[0098]

[0099] The preparation method is similar to that in Examples 1-6. Column chromatography yielded a white solid 15, with a yield of 60%.

[0100] 1H NMR (500MHz, DMSO-d6) δ8.37–8.33(m,1H),8.28(dd,J=8.0,2.0Hz,1H),8.20(d,J=8.0Hz,1H),8.05(s,1H),7.94–7.90(m,1H),7.89–7 .83(m,1H),7.32(d,J=8.5Hz,1H),6.91(d,J=8.5Hz,1H),6.65–6.35(m,4H),5.78(p,J=7.0Hz,1H),3.32(s,3H),1.66(d,J=7.0Hz,3H). 13 C NMR(100MHz,DMSO-d6)δ165.97,163.52,163.19,146.09,144.32,142.46,138.53,132.29,131.1 0,128.39,126.34,124.92,121.60,120.43,119.81,118.19,117.52,60.13,44.01,41.72,20.80.

[0101] Preparation Example 10 (S)-2,4-diamino-6-((1-(1-(pyridin-3-yl)-1H-pyrrolo[3,2-b]pyridin-3-yl)ethyl)amino)pyrimidin-5-nitrile 16

[0102]

[0103] The preparation method is similar to that in Examples 1-6. Column chromatography yielded a white solid 16 with a yield of 55%.

[0104] 1 H NMR (600MHz, DMSO-d6) δ8.88(d,J=2.4Hz,1H),8.62(dd,J=4.8,1.2Hz,1H),8.47(dd,J=4.8,1.2Hz,1H),8.09(ddd,J=8.4,2.4,1.8Hz,1H),8.01–7.95 (m,2H),7.66–7.59(m,1H),7.27(dd,J=8.4,4.8Hz,1H),7.02(d,J=8.4Hz,1 H), 6.55 (s, 2H), 6.46 (s, 2H), 5.80 (p, J = 7.2Hz, 1H), 1.64 (d, J = 7.2Hz, 3H). 13C NMR(150MHz,DMSO-d6)δ165.61,163.59,163.34,148.03,145.64,145.06,143.78,135.56 ,131.53,129.04,128.76,125.06,120.49,118.66,118.24,118.17,60.23,42.97,23.11.

[0105] Preparation Example 11 (S)-2,4-diamino-6-((1-(1-(pyridin-3-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)ethyl)amino)pyrimidine-5-nitrile 17

[0106]

[0107] The preparation method is similar to that in Examples 1-6. Column chromatography yielded a white solid 17, with a yield of 77%.

[0108] 1 H NMR(600MHz,Chloroform-d)δ8.89(s,1H),8.86(d,J=2.4Hz,1H),8.70(dd,J=4.8,1.8Hz,1H),8.35(d,J=5.4Hz,1H),7.90–7.84(m,1H),7.63–7.5 8(m,1H),7.54(dd,J=8.4,4.8Hz,1H),7.40(s,1H),5.80(p,J=7.2Hz,1H) ,5.23(d,J=8.4Hz,1H),5.07(s,2H),4.98(s,2H),1.73(d,J=7.2Hz,3H). 13 C NMR(150MHz,Chloroform-d)δ165.10,163.04,162.96,148.60,145.59,145.59,140.00,135 .20,133.53,133.53,132.62,131.53,127.84,124.37,120.41,114.45,62.35,42.44,20.97.

[0109] Preparation Example 12 (S)-2,4-diamino-6-((1-(1-(pyridin-3-yl)-1H-pyrrolo[3,2-c]pyridin-3-yl)ethyl)amino)pyrimidine-5-nitrile 18

[0110]

[0111] The preparation method is similar to that in Examples 1-6. Column chromatography yielded a white solid 18, with a yield of 61%.

[0112] 1 H NMR(600MHz,DMSO-d6)δ9.00(d,J=1.2Hz,1H),8.87(dd,J=2.4,1.2Hz,1H),8.6 4(dd,J=4.8,1.2Hz,1H),8.29(d,J=5.4Hz,1H),8.09(ddd,J=8.4,2.4,1.8Hz,1H ),7.79(s,1H),7.64(ddd,J=8.4,4.8,1.2Hz,1H),7.54(dd,J=5.4,1.2Hz,1H),6 .86(d,J=8.4Hz,1H),6.51(s,4H),5.86(p,J=7.2Hz,1H),1.67(d,J=7.2Hz,3H). 13 C NMR(150MHz,DMSO-d6)δ165.94,163.52,163.15,148.31,145.21,143.58,142.33,139.47 ,135.28,131.77,127.23,125.06,124.74,121.42,118.17,106.11,60.07,41.72,21.09.

[0113] Preparation Example 13 (S)-2,4-diamino-6-((1-(5-chloro-1-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl)amino)pyrimidine-5-nitrile 19

[0114]

[0115] The preparation method is similar to that in Examples 1-6. Column chromatography yielded a white solid 19, with a yield of 63%.

[0116] 1 H NMR(500MHz,DMSO-d6)δ9.11(dd,J=2.5,1.0Hz,1H),8.56(dd,J=4.5,1.5Hz,1H),8.36–8.30(m,3H),8.08(s,1H),7.6 0(ddd,J=8.5,4.5,1.0Hz,1H),6.96(d,J=8.5Hz,1H),6.64–6.35(m,4H),5.71(p,J=7.0Hz,1H),1.66(d,J=7.0Hz,3H). 13CNMR(100MHz,DMSO-d6)δ166.03,163.45,163.18,147.44,145.81,144.51,141.93,134.7 5,130.89,128.44,127.75,124.51,124.26,121.50,119.65,118.18,60.12,42.06,20.68.

[0117] Preparation Example 14 (S)-N-(1-(4-chloro-1-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl)-9H-purine-6-amine 20

[0118]

[0119] The preparation method is similar to that in Examples 1-6. Column chromatography yielded 20 white solids, with a yield of 64%.

[0120] 1 H NMR (400MHz, DMSO-d6) δ12.94(s,1H),9.07(s,1H),8.57(d,J=4.8Hz,1H),8.32–8.20(m,3H),8.13(d,J=17.6Hz ,2H),7.80(s,1H),7.60(dd,J=8.4,4.8Hz,1H),7.34(dd,J=5.2,2.0Hz,1H),6.22(s,1H),1.71(d,J=6.8Hz,3H). 13 C NMR(100MHz,DMSO-d6)δ152.90,148.51,147.91,147.77,145.29,145.06,144.51,139.34 ,139.32,135.76,134.76,131.95,131.56,127.18,124.56,118.52,117.95,52.52,22.59.

[0121] Preparation Example 15(S)-N 6 -(1-(4-chloro-1-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl)-9H-purine-2,6-diamine 21

[0122]

[0123] The preparation method is similar to that in Examples 1-6. Column chromatography yielded a white solid 21, with a yield of 52%.

[0124] 1H NMR (600MHz, DMSO-d6) δ12.41(m,3H),9.09(d,J=2.4Hz,1H),8.59(dd,J=4.8,1.2Hz,1H),8.32–8.26(m,2H),8.22 (s,1H),7.79(s,1H),7.62(dd,J=8.4,4.8Hz,1H),7.35(d,J=5.4Hz,1H),6.17–6.02(m,2H),1.71(d,J=7.2Hz,3H). 13 C NMR(150MHz,DMSO-d6)δ160.62,148.45,147.82,147.69,144.99,144.78,144.37,135.75 ,134.75,131.48,124.49,124.49,118.47,118.44,118.44,117.91,117.90,55.38,49.07.

[0125] Preparation Example 16 (S)-4-amino-6-((1-(4-chloro-1-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl)amino)pyrimidin-5-nitrile 22

[0126]

[0127] The preparation method is similar to that in Examples 1-6. Column chromatography yielded a white solid 22, with a yield of 49%.

[0128] 1 H NMR (600MHz, DMSO-d6) δ9.08(d,J=2.4Hz,1H),8.58(dd,J=4.8,1.2Hz,1H),8.29(ddd,J=8.4,2.4,1.8Hz,1H),8.26(d,J=5.4Hz,1H),8.11(s,1H), 8.07(s,1H),7.61(dd,J=8.4,4.8Hz,1H),7.38(d,J=7.8Hz,1H),7.35(d, J=5.4Hz,1H),7.21(s,2H),6.03(p,J=7.2Hz,1H),1.65(d,J=7.2Hz,3H). 13C NMR(150MHz,DMSO-d6)δ164.90,161.93,160.22,148.46,147.75,145.04,144.46,135.61 ,134.66,131.56,127.43,124.49,118.76,118.49,117.92,116.10,68.31,43.16,21.79.

[0129] Preparation Example 17 (S)-2,4-diamino-6-((1-(4-chloro-1-(4-hydroxyphenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl)amino)pyrimidine-5-nitrile 23

[0130]

[0131] The preparation method is similar to that in Examples 1-6. Column chromatography yielded a white solid 23, with a yield of 64%.

[0132] 1 H NMR (600MHz, DMSO-d6) δ9.69(s,1H),8.19(d,J=5.4Hz,1H),7.84(s,1H),7.52(d,J=9.0Hz,2H),7.27(d,J=5.4Hz,1H) ,6.93(d,J=9.0Hz,2H),6.57(d,J=8.4Hz,1H),6.52(s,2H),6.38(s,2H),5.97(p,J=7.2Hz,1H),1.62(d,J=7.2Hz,3H). 13 CNMR(150MHz,DMSO-d6)δ165.75,163.54,163.10,156.64,148.43,143.95,135.22,12 9.63,128.35,126.15,118.33,117.60,117.47,117.15,116.06,60.30,42.52,22.29.

[0133] Preparation Example 18 (S)-2,4-diamino-6-((1-(4-chloro-1-(3-hydroxyphenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl)amino)pyrimidine-5-nitrile 24

[0134]

[0135] The preparation method is similar to that in Examples 1-6. Column chromatography yielded a white solid 24, with a yield of 66%.

[0136] 1H NMR(600MHz, DMSO-d6)δ9.80(s,1H),8.24(d,J=5.4Hz,1H),7.93(s,1H),7.40–7.27(m,3H),7.26–7.17(m,1H),6.79( dd,J=8.4,2.4Hz,1H),6.66(d,J=8.4Hz,1H),6.54(s,2H),6.39(s,2H),5.98(p,J=7.2Hz,1H),1.63(d,J=7.2Hz,3H). 13 C NMR(100MHz,DMSO-d6)δ170.56,168.32,167.89,163.19,153.06,148.86,143.83,140.17,13 5.23,132.62,123.11,123.09,122.81,122.50,119.42,118.79,116.13,65.09,47.26,27.07.

[0137] Preparation Example 19 (S)-2,4-diamino-6-((1-(4-chloro-1-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl)amino)pyrimidine-5-nitrile 25

[0138]

[0139] The preparation method is similar to that in Examples 1-6. Column chromatography yielded a white solid 25, with a yield of 68%.

[0140] 1 H NMR (400MHz, DMSO-d6) δ13.09(s,1H),8.38(s,1H),8.26(d,J=5.2Hz,1H),8.09(s,1H),7.95(s,1H),7.27(d, J=5.2Hz,1H),6.56(d,J=8.0Hz,1H),6.51(s,2H),6.39(s,2H),5.92(p,J=6.8Hz,1H),1.62(d,J=6.8Hz,3H). 13 C NMR(100MHz,DMSO-d6)δ165.77,163.57,163.13,148.00,144.28,135.40,132.37 ,127.61,121.71,121.35,118.37,117.75,117.66,117.20,60.38,42.56,22.03.

[0141] Preparation Example 20 (S)-2,4-diamino-6-((1-(4-chloro-1-(1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl)amino)pyrimidine-5-nitrile 26

[0142]

[0143] The preparation method is similar to that in Examples 1-6. Column chromatography yielded a white solid 26, with a yield of 62%.

[0144] 1 H NMR (400MHz, DMSO-d6) δ12.87(s,1H),8.28(d,J=5.2Hz,1H),8.05(s,1H),7.87(t,J=2.0Hz,1H),7.31(d,J=5.2Hz,1H) ,7.00(t,J=2.0Hz,1H),6.89(d,J=8.4Hz,1H),6.52(s,2H),6.34(s,2H),5.98(p,J=6.8Hz,1H),1.60(d,J=6.8Hz,3H). 13 CNMR(100MHz,DMSO-d6)δ165.86,163.53,163.20,147.80,146.26,144.43,135.4 6,130.64,125.27,119.05,118.34,117.97,117.58,97.33,60.37,42.48,22.53.

[0145] Preparation Example 21 (S)-2,4-diamino-6-((1-(4-chloro-1-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl)amino)pyrimidine-5-nitrile 27

[0146]

[0147] The preparation method is similar to that in Examples 1-6. Column chromatography yielded a white solid 27, with a yield of 59%.

[0148] 1 H NMR (400MHz, DMSO-d6) δ8.73–8.68(m,2H),8.33(d,J=5.2Hz,1H),8.22(s,1H),8.16–8.12(m,2H),7.41(d,J =5.2Hz,1H),6.66(d,J=8.0Hz,1H),6.52(s,2H),6.39(s,2H),5.95(p,J=6.8Hz,1H),1.64(d,J=6.8Hz,3H). 13C NMR(100MHz,DMSO-d6)δ166.30,164.18,164.04,163.64,151.85,149.24,145.20,145.07 ,142.12,136.41,126.90,120.74,119.61,119.52,118.82,117.14,60.93,43.00,22.44.

[0149] Preparation Example 22 (S)-2,4-diamino-6-((1-(4-chloro-1-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl)amino)pyrimidine-5-nitrile 28

[0150]

[0151] The preparation method is similar to that in Examples 1-6. Column chromatography yielded a white solid 28, with a yield of 55%.

[0152] 1 H NMR(400MHz,Methanol-d4)δ8.27(d,J=2.4Hz,1H),8.22(dd,J=5.2,2.0Hz,1H),7.96(s,1H),7 .81–7.71(m,1H),7.22(d,J=5.2Hz,1H),6.10–5.73(m,1H),3.97(s,3H),1.73(d,J=6.8Hz,3H). 13 C NMR(150MHz,Methanol-d4)δ164.87,162.69,161.99,147.78,144.35,135.36,131.70, 131.68,127.67,123.90,121.42,117.77,117.22,115.84,77.68,60.81,43.60,21.18.

[0153] Preparation Example 23 (S)-2,4-diamino-6-((1-(4-chloro-1-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl)amino)pyrimidin-5-nitrile 29

[0154]

[0155] The preparation method is similar to that in Examples 1-6. Column chromatography yielded 29g of white solid, with a yield of 57%.

[0156] 1H NMR (600MHz, DMSO-d6) δ8.79(d,J=8.4Hz,1H),8.55(ddd,J=4.8,1.8,1.2Hz,1H),8.45(s,1H),8.33(d,J=5.4Hz,1H),8.03(ddd,J=8.4,7.2,2.4Hz,1H), 7.38(d,J=5.4Hz,1H),7.35(ddd,J=7.2,4.8,1.2Hz,1H),6.97(d,J=8.4Hz, 1H), 6.52 (s, 2H), 6.32 (s, 2H), 6.00 (p, J = 7.2Hz, 1H), 1.61 (d, J = 7.2Hz, 3H). 13 C NMR(150MHz,DMSO-d6)δ165.85,163.46,163.16,149.85,148.89,148.20,144.21,139.38 ,135.68,125.01,121.78,120.03,119.19,118.76,118.28,116.09,60.40,42.53,22.47.

[0157] Preparation Example 24 (S)-2,4-diamino-6-((1-(4-chloro-1-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl)amino)pyrimidine-5-nitrile 30

[0158]

[0159] The preparation method is similar to that in Examples 1-6. Column chromatography yielded a white solid 30, with a yield of 61%.

[0160] 1 H NMR (600MHz, DMSO-d6) δ8.27(d,J=5.4Hz,1H),8.07(s,1H),7.86(dt,J=10.8,2.4Hz,1H),7.76(ddd,J=8.4,2.4,1.2Hz,1H),7.60(td,J=8.4,6.6Hz,1 H),7.35(d,J=5.4Hz,1H),7.22(td,J=8.4,2.4Hz,1H),6.56(d,J=7.8Hz,1 H), 6.52 (s, 2H), 6.38 (s, 2H), 5.96 (p, J = 7.2Hz, 1H), 1.63 (d, J = 7.2Hz, 3H). 13C NMR (150MHz, DMSO-d6) δ165.76, 163.53, 163.12, 162.63 (d, J = 241.5Hz), 148.37, 144.32, 139.50 (d, J = 12.0Hz), 135.62, 131.38 (d, J = 9. 0Hz), 127.65, 119.65 (d, J = 3.0Hz), 118.88, 118.47, 118.30, 118.08, 113.44 (d, J = 21.0Hz), 111.09 (d, J = 25.5Hz), 60.38, 42.50, 22.08.

[0161] Preparation Example 25 (S)-2,4-diamino-6-((1-(4-chloro-1-(3,5-difluorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl)amino)pyrimidine-5-nitrile 31

[0162]

[0163] The preparation method is similar to that in Examples 1-6. Column chromatography yielded a white solid 31, with a yield of 63%.

[0164] 1 H NMR (600MHz, DMSO-d6) δ8.31(d,J=5.4Hz,1H),8.16(s,1H),7.89–7.82(m,2H),7.37(d,J=5.4Hz,1H),7. 26(tt,J=9.0,2.4Hz,1H),6.55–6.47(m,3H),6.39(s,2H),5.94(p,J=6.6Hz,1H),1.63(d,J=6.6Hz,3H). 13 C NMR(150MHz,DMSO-d6)δ165.75,163.53,163.11,162.95(dd,J=243.0,15.0Hz),148.47,144.46,140.21(t,J=15.0Hz),1 35.79,127.42,119.35,118.85,118.51,118.28,106.74(dd,J=22.5,6.0Hz),101.80(t,J=25.5Hz),60.42,42.49,21.92.

[0165] Preparation Example 26 (S)-2,4-diamino-6-((1-(4-chloro-1-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl)amino)pyrimidine-5-nitrile 32

[0166]

[0167] The preparation method is similar to that in Examples 1-6. Column chromatography yielded a white solid 32, with a yield of 66%.

[0168] 1 H NMR (600MHz, DMSO-d6) δ8.28(d,J=5.4Hz,1H),8.06(s,1H),8.04(dd,J=3.6,1.2Hz,1H),7.79(dd,J=5.4,1.8Hz,1H),7.73(dd,J=5. 4,3.6Hz,1H),7.31(d,J=5.4Hz,1H),6.57(d,J=8.4Hz,1H),6.51(s,2H),6.37(s,2H),5.94(p,J=7.2Hz,1H),1.63(d,J=7.2Hz,3H). 13 C NMR(150MHz,DMSO-d6)δ165.76,163.53,163.12,148.04,144.29,136.35,135.48,12 7.60,126.80,123.01,118.29,118.19,118.09,117.60,114.11,60.39,42.52,22.07.

[0169] Preparation Example 27 (S)-2,4-diamino-6-((1-(4-chloro-1-(pyridin-2-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl)amino)pyrimidine-5-nitrile 33

[0170]

[0171] The preparation method is similar to that in Examples 1-6. Column chromatography yielded a white solid 33, with a yield of 65%.

[0172] 1 H NMR (400MHz, Methanol-d4) δ8.48(d,J=4.8Hz,1H),8.12(d,J=5.2Hz,1H),7.72(td,J=7.6,1.6Hz,1H),7.57(s,1H),7.33–7. 26(m,1H),7.16(d,J=5.2Hz,1H),7.04(d,J=7.6Hz,1H),5.92(q,J=6.8Hz,1H),5.60(d,J=3.6Hz,2H),1.67(d,J=6.8Hz,3H). 13C NMR(150MHz,Methanol-d4)δ165.09,163.07,162.68,156.69,149.54,149.06,143.64,137.12, 136.01,126.58,122.78,121.94,117.17,117.16,116.73,116.33,62.29,50.01,43.47,21.76.

[0173] Preparation Example 28 (S)-2,4-diamino-6-((1-(4-chloro-1-(thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl)amino)pyrimidine-5-nitrile 34

[0174]

[0175] The preparation method is similar to that in Examples 1-6. Column chromatography yielded a white solid 34, with a yield of 59%.

[0176] 1 H NMR (400MHz, DMSO-d6) δ8.31(d,J=5.2Hz,1H),8.05(s,1H),7.45(dd,J=3.6,1.6Hz,1H),7.41(dd,J=5.6,1.2Hz,1H),7.35(d,J=5.2 Hz,1H),7.09(dd,J=5.6,3.6Hz,1H),6.70(d,J=8.0Hz,1H),6.51(s,2H),6.37(s,2H),5.94(p,J=7.2Hz,1H),1.62(d,J=7.2Hz,3H). 13 C NMR(150MHz,DMSO-d6)δ165.79,163.51,163.12,147.72,144.45,138.86,135.75,12 7.67,125.88,121.91,119.26,118.46,118.27,117.70,117.60,60.42,42.44,22.03.

[0177] Preparation Example 29 (S)-2,4-diamino-6-((1-(4-chloro-1-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl)amino)pyrimidine-5-nitrile 35

[0178]

[0179] The preparation method is similar to that in Examples 1-6. Column chromatography yielded a white solid 35, with a yield of 55%.

[0180] 1 H NMR(400MHz, DMSO-d6)δ8.24(d,J=5.2Hz,1H),7.99(s,1H),7.86–7.80(m,2H),7.64–7.53(m,2H),7.44–7.37(m,1H), 7.32(d,J=5.2Hz,1H),6.61(d,J=8.0Hz,1H),6.52(s,2H),6.39(s,2H),5.98(p,J=6.8Hz,1H),1.64(d,J=6.8Hz,3H). 13 C NMR(150MHz,DMSO-d6)δ165.77,163.54,163.12,148.35,144.15,138.05,135.44,12 9.71,127.90,126.97,124.30,118.37,118.32,118.08,117.70,60.35,42.53,22.21.

[0181] Preparation Example 30 (S)-2,4-diamino-6-((1-(4-chloro-1-(m-tolyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl)amino)pyrimidine-5-nitrile 36

[0182]

[0183] The preparation method is similar to that in Examples 1-6. Column chromatography yielded a white solid 36, with a yield of 51%.

[0184] 1 H NMR (400MHz, DMSO-d6) δ8.23(d,J=5.2Hz,1H),7.96(s,1H),7.66–7.59(m,2H),7.47–7.40(m,1H),7.30(d,J=5.2Hz,1H),7.20 (d,J=7.6Hz,1H),6.59(d,J=8.0Hz,1H),6.52(s,2H),6.38(s,2H),5.98(p,J=6.8Hz,1H),2.41(s,3H),1.63(d,J=6.8Hz,3H). 13 CNMR(100MHz,DMSO-d6)δ165.80,163.57,163.15,148.39,144.16,139.25,138.04,135.43,129.5 2,128.02,127.68,124.79,121.56,118.37,118.27,118.04,117.69,60.38,42.56,22.26,21.55.

[0185] Preparation Example 31 (S)-2,4-diamino-6-((1-(4-chloro-1-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl)amino)pyrimidine-5-nitrile 37

[0186]

[0187] The preparation method is similar to that in Examples 1-6. Column chromatography yielded a white solid 37, with a yield of 62%.

[0188] 1 H NMR(400MHz, DMSO-d6)δ8.29(dd,J=4.8,1.6Hz,1H),8.11(dd,J=8.0,1.6Hz,1H),7.93–7.91(m,1H),7.84(s,1H),7.43–7.35(m ,2H),7.20(dd,J=8.0,4.8Hz,1H),6.78(d,J=8.4Hz,1H),6.50(d,J=14.4Hz,4H),5.79(p,J=7.2Hz,1H),1.65(d,J=7.2Hz,3H). 13 C NMR (150MHz, DMSO-d6) δ165.92, 164.88, 163.52, 163.17, 162.70, 160.28 (d, J = 241.5Hz), 147.41, 143.67, 134.97 (d, J = 3. 0Hz), 128.84, 125.83, 125.48 (d, J = 7.5Hz), 120.38, 119.04, 118.19, 117.09, 116.36 (d, J = 22.5Hz), 60.05, 41.89, 20.84.

[0189] Preparation Example 32 (S)-2,4-diamino-6-((1-(4-chloro-1-(3-(methanesulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl)amino)pyrimidine-5-nitrile 38

[0190]

[0191] The preparation method is similar to that in Examples 1-6. Column chromatography yielded a white solid 38, with a yield of 63%.

[0192] 1H NMR (400MHz, DMSO-d6) δ8.41(s,1H),8.29(d,J=5.6Hz,2H),8.16(s,1H),7.94(d,J=7.6Hz,1H),7.86(t,J=8.0Hz,1H),7.37( d,J=5.2Hz,1H),6.67(d,J=8.0Hz,1H),6.53(s,2H),6.39(s,2H),6.00(p,J=6.8Hz,1H),3.32(s,3H),1.65(d,J=6.8Hz,3H). 13 CNMR(100MHz,DMSO-d6)δ165.81,163.56,163.14,148.38,144.47,142.34,138.64,135.77,130.9 9,128.90,127.66,125.08,122.04,119.31,118.69,118.36,118.12,60.40,44.03,42.50,22.16.

[0193] Preparation Example 33 (S)-2,4-diamino-6-((1-(4-chloro-1-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)propyl)amino)pyrimidine-5-nitrile 39

[0194]

[0195] The preparation method is similar to that in Examples 1-6. Column chromatography yielded a white solid 39, with a yield of 61%.

[0196] 1 H NMR(600MHz,DMSO-d6)δ9.07(d,J=2.4Hz,1H),8.58(dd,J=4.8,1.2Hz,1H),8.33–8.22(m,2H),8.10(s,1H),7.61(dd,J=8.4,4.8 Hz,1H),7.36(d,J=5.4Hz,1H),6.57–6.43(m,3H),6.31(s,2H),5.83(q,J=7.2Hz,1H),2.10–1.92(m,2H),0.98(t,J=7.2Hz,3H). 13C NMR(150MHz,DMSO-d6)δ165.78,163.67,163.41,148.35,147.72,145.01,144.33,135.57,13 4.68,131.52,127.41,124.49,118.66,118.52,118.28,117.96,60.38,48.46,29.93,11.75.

[0197] Preparation Example 34 (S)-2,4-diamino-6-((4-chloro-1-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)(cyclopropyl)methyl)amino)pyrimidine-5-nitrile 40

[0198]

[0199] The preparation method is similar to that in Examples 1-6. Column chromatography yielded a white solid 40, with a yield of 51%.

[0200] 1 H NMR(400MHz,DMSO-d6)δ9.10(d,J=2.4Hz,1H),8.59(dd,J=4.8,1.2Hz,1H),8.32(ddd, J=8.4,2.4,1.6Hz,1H),8.29(s,1H),8.26(d,J=5.2Hz,1H),7.66–7.57(m,1H),7.35(d, J=5.2Hz,1H),6.57–6.51(m,3H),6.36(s,2H),5.49(t,J=8.4Hz,1H),1.60(qt,J=8.4,4 .8Hz,1H),0.68(dq,J=9.2,4.8Hz,1H),0.63–0.47(m,2H),0.30(dq,J=9.6,4.8Hz,1H). 13 C NMR (100MHz, DMSO-d6) δ165.71,163.37,148.25,148.24,147.76,145.04,144.27,135.59,134. 68,131.59,128.62,124.51,118.60,118.32,118.06,117.60,60.19,49.60,17.11,4.58,3.52.

[0201] Preparation Example 35 (S)-2,4-diamino-6-((1-(6-chloro-1-(pyridin-3-yl)-1H-pyrrolo[3,2-b]pyridin-3-yl]ethyl)amino)pyrimidine-5-nitrile 41

[0202]

[0203] The preparation method is similar to that in Examples 1-6. Column chromatography yielded a white solid 41, with a yield of 58%.

[0204] 1 H NMR (400MHz, DMSO-d6) δ8.89(d,J=2.8Hz,1H),8.65(dd,J=4.8,1.2Hz,1H),8.48(d,J=2.0Hz,1H),8.16–8.13(m,1H),8.11(d,J=2.0Hz,1H ),8.06(s,1H),7.63(dd,J=8.4,4.8Hz,1H),6.84(d,J=8.4Hz,1H),6.58(s,2H),6.48(s,2H),5.81(p,J=6.8Hz,1H),1.63(d,J=6.8Hz,3H). 13 C NMR(100MHz,DMSO-d6)δ165.61,163.52,163.33,148.45,145.31,144.12,142.36,135.15 ,131.88,130.48,129.17,125.55,125.13,120.80,118.47,118.20,60.30,42.49,22.65.

[0205] Biological Experiment Example 1: Inhibition of PI3Kδ Enzyme Activity IC 50 Evaluation test

[0206] Adopting ADP-Glo TMThe kinase assay was used to determine the inhibitory effect of the test compound on PI3Kδ enzyme activity. First, the test compound was diluted according to a specific concentration gradient, and then 50 nL of each concentration solution was transferred to a 384-well plate. Negative control wells and positive control wells were set up in the 384-well plate. 50 nL of dimethyl sulfoxide (DMSO) (solvent control) was added to the negative control wells, and 50 nL of DMSO and a drug known to effectively inhibit PI3Kδ enzyme activity were added to the positive control wells. Next, the PI3Kδ enzyme was diluted to a working concentration of 1.25 nM with kinase buffer, and then 2 μL was added to each of the 384 wells, including the control wells. Subsequently, 2.5 μL of the corresponding control reagent was added to each of the negative and positive control wells. After centrifugation for 30 seconds and vortexing to mix, the plates were incubated at room temperature for 10 minutes. Subsequently, 2.5 μL of a pre-prepared ATP (adenosine triphosphate) and PIP2 (phosphatidylinositol diphosphate) mixture was added to each well. After repeated centrifugation and mixing, the mixture was incubated at room temperature for 2 hours to simulate the enzymatic reaction process under physiological conditions. After incubation, 5 μL of ADP-Glo ​​reagent was added to each well, mixed again, and incubated for 3 hours to consume the remaining ATP and convert the generated ADP into a luminescent signal. Immediately afterwards, 10 μL of enzyme detection reagent was added, mixed, and incubated for another hour to fully detect enzyme activity. After a series of incubations and centrifugation processes, the RLU (relative light units) value of each well was read using an Enspire microplate reader, and the enzyme activity inhibition rate corresponding to different concentrations of the test compound was calculated.

[0207] Finally, using the log value of the compound concentration on the X-axis and the corresponding percentage inhibition rate on the Y-axis, a dose-response curve was plotted using the log(inhibitor) vs. response-variable slope module in the analysis software GraphPad Prism 5, thereby accurately determining the half-maximal inhibitory concentration (IC50) of each test compound on the activity of PI3Kδ enzyme.

[0208] Table 1 shows the IC50 values ​​of compound 12-41 of the present invention and the positive control drug edralin against PI3Kδ activity. 50 value.

[0209] Table 1

[0210] Compound numbering <![CDATA[ΡΙ3KδIC 50 (nM)]]> Compound numbering <![CDATA[ΡΙ3KδIC 50 (nM)]]> 12 11 27 32.3 13 64 28 103 14 11 29 116 15 17 30 895 16 5.82 31 641 17 537 32 393 18 146 33 93.2 19 120 34 448 20 1351 35 435 21 1014 36 1550 22 257 37 434 23 447 38 66.4 24 742 39 11.1 25 73.7 40 47.2 26 210 41 13.6 Edrani 3

[0211] Furthermore, it should be understood that after reading the above description of the present invention, those skilled in the art can make various alterations or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A compound having the structure shown in formula (2) or a pharmaceutically acceptable salt thereof: （2）； One of W, X, Y, and Z is a nitrogen atom, and the other three are carbon atoms; R 1 It is H or halogen; R 2 The C1-C6 alkyl, pyridyl, phenyl, pyrazolyl, or thiophene group is substituted or unsubstituted, wherein the substituent of the C1-C6 alkyl group is pyridyl, and the substituent of the pyridyl, phenyl, pyrazolyl, or thiophene group is one or more of the following: C1-C6 alkyl, (C1-C6 alkyl)sulfonyl, hydroxyl, or halogen. R 3 It is a C1-C6 alkyl chain or a C3-C6 cycloalkyl chain; R 4 for , , or .

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, R 1 The selected halogen is Cl; R 2 The halogen selected from the upper substituent is F.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, The compound is a compound having any of the following structures: 。 4. The method for preparing the compound according to claim 3, characterized in that, The compound was synthesized using reaction route I; Reaction route I The process includes the following: Compound 1 reacts with aluminum trichloride and acetyl chloride in anhydrous dichloromethane to generate 3-acetyl-azaindole, i.e., compound 2. Then, through a Ullmann coupling reaction catalyzed by cuprous iodide, compound 3 is formed. Next, it condenses with S-tert-butylsulfinamide to form an imine intermediate 4, which is then reduced in the presence of diisobutylaluminum hydride (DIBAL-H) ​​to generate the S-configuration compound 5. Finally, it is hydrolyzed under hydrochloric acid conditions to give compound 6. Compound 6 reacts with chlorinated compound R... 4 The target compound was obtained by nucleophilic substitution of -Cl.

5. The preparation method according to claim 4, characterized in that, R 4 for At that time, chlorinated compound R 4 -Cl was synthesized using reaction route II; Reaction route II includes the following processes: Compound 7 reacts with phosphorus oxychloride in N,N-dimethylformamide (DMF) to generate compound 8. Compound 8 reacts with hydroxylamine hydrochloride, and the aldehyde group reacts to generate an oxime, giving compound 9. Then, it reacts with thionyl chloride in anhydrous dichloromethane (DCM) to dehydrate and form a cyano group, giving compound 10. Compound 10 reacts with ammonia in 1,4-dioxane to generate the target compound 11.

6. A pharmaceutical composition, characterized in that, It comprises the compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

7. A pharmaceutical composition, characterized in that, It comprises the compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, and a diluent.

8. A pharmaceutical composition, characterized in that, It comprises the compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, and an excipient.

9. The use of the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of claims 6 to 8, in the preparation of a PI3Kδ kinase inhibitor.

10. The use of the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of claims 6 to 8, in the preparation of a medicament for treating a disease responsive to inhibition of PI3Kδ, characterized in that, The disease in question is an inflammatory disease, an autoimmune disease, cancer, or an infectious disease.