CN117447470A - Pyrrolopyridine derivative as HPK1 inhibitor, preparation method and application thereof - Google Patents

Pyrrolopyridine derivative as HPK1 inhibitor, preparation method and application thereof Download PDF

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CN117447470A
CN117447470A CN202311469918.6A CN202311469918A CN117447470A CN 117447470 A CN117447470 A CN 117447470A CN 202311469918 A CN202311469918 A CN 202311469918A CN 117447470 A CN117447470 A CN 117447470A
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compound
cancer
substituted
alkyl
unsubstituted
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曾申昕
黄文海
王尊元
潘有禄
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Hangzhou Medical College
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Hangzhou Medical College
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Abstract

The invention discloses a compound shown as a formula (I), a preparation method thereof and application thereof in pharmaceutical preparations. The compounds of formula (I) have excellent HPK1 and/or LCK kinase inhibiting activity and can significantly promote immune-related cytokinesRelease, improving T cell dysfunction, and treating related diseases caused by HPK1 and/or LCK kinase abnormality.

Description

Pyrrolopyridine derivative as HPK1 inhibitor, preparation method and application thereof
The application is a divisional application of an invention patent with the application date of 2023, 2-month and 20-date, the application number of 202310137749.X and the invention name of 'an HPK1 and/or LCK kinase regulator, a preparation method and application thereof'.
Technical Field
The invention belongs to the field of medicines, and relates to a pyrrolopyridine derivative serving as an HPK1 inhibitor, a preparation method and application thereof.
Background
The main therapeutic modalities used by oncologists to treat cancer are surgical excision, radiation therapy, and classical chemotherapeutic agents. Unfortunately, surgical resection is not a viable option for many forms of tumor or cancer. Furthermore, radiation therapy and chemotherapy drugs are not only targeted to diseased cells, thus ultimately damaging healthy cells. By exploiting tumor-specific antigen expression or inappropriate over-expression or inappropriate activation of specific proteins within tumor cells, therapies have been developed that more specifically target tumor cells, but tumor cells are prone to mutation and can be resistant to drugs that specifically target tumor cells.
The immune therapy can restart the immune system of the human body, so that the immune system can identify and kill tumor cells, and the novel anticancer strategy has become the most promising development direction in the development of novel antitumor drugs. However, only a small proportion of patients currently respond to treatment with an immunodetection agent, for example ipilimumab, pembrolizumab and nivolumab, only 5-15% of patients responding to ipilimumab (Nat Rev Drug Discov,2016, 15:235-247), while the proportion of patients responding to pembrolizumab and nivolumab is below 40% (Immunity, 2016, 44:1255-1269). The proportion of patients who respond continuously to immunotherapy is more rare, and most malignant patients cannot benefit from the immunotherapy, and can cause additional injury to the body due to toxic and side effects caused by the immunotherapy, so that how to lower the threshold value of the immunotherapy response and obtain a continuous effective response is a hot spot problem which is worth focusing on the current tumor immunotherapy.
Endogenous or adoptively transferred cytotoxic T cells are important mediators of anti-tumor immunity. Continued antigen exposure results in gradual loss of specific effector functions and proliferative capacity of T cells and significant transcriptional, epigenetic and metabolic changes, leading to T cell dysfunction. T cell depletion is characterized by significant changes in metabolic function, transcriptional programming, loss of effector function (e.g., cytokine secretion, killing capacity), and co-expression of multiple surface-inhibitory receptors. The root cause of T cell depletion is sustained antigen exposure, resulting in sustained TCR signaling. Prevention or reversal of T cell depletion has long been sought as a means of enhancing T cell effectiveness in cancer or chronically infected patients.
The hematopoietic progenitor cell kinase 1 (Hematopoietic progenitor kinase, HPK 1) kinase regulator has obvious synergistic anti-tumor effect with anti-tumor immune targets such as PD-1/PD-L1 monoclonal antibody, CTLA-4 monoclonal antibody, CAR-T and the like which are clinically researched or marketed, and is hopeful to be a key tool for solving the difficulty of the current anti-tumor immune treatment.
HPK1 is a negative regulator of T cell receptor, B cell receptor and dendritic cell, and can target and enhance anti-tumor immunity. HPK1 is expressed primarily by hematopoietic cells (including early progenitor cells). In T cells, HPK1 down regulates T Cell activation by phosphorylating SLP76 at Ser376 (J Exp Med,2007, 204:681-691) and Gads at Thr254 to reduce the persistence of the signaling micro-cluster, which results in recruitment of 14-3-3 protein binding to phosphorylated SLP76 and Gads, releasing SLP76-Gads-14-3-3 complex from LAT-containing micro-clusters (J Cell Biol,2011,195 (5): 839-853). HPK1 can also be activated in response to prostaglandin E2, which is normally secreted by tumors, which aids in the escape of tumor cells from the immune system. Loss of HPK1 kinase function increases cytokine secretion, enhancing T cell signaling, viral clearance, and tumor growth inhibition. Thus, HPK1 is considered a promising target for tumor immunotherapy.
Over a decade ago, research and development personnel have found that HPK1 is a potential cancer immunotherapy target, and several compounds have been put into clinical researches, such as CFI-402411, BGB-15025, PRJ1-3024, etc., but related drugs have not been marketed at present. The challenges faced in the development of HPK1 modulators are mainly the difference in HPK1 family member functions, and the difficulty in designing highly selective inhibitory compounds. Furthermore, inhibition of other related kinases involved in TCR signaling, such as Src and other Ste 20-like kinase families, is difficult to avoid.
Signaling of TCRs requires key protein kinases including protein kinases LCK and ZAP-70. LCK is a protein kinase that is necessary for T cell development, activation and initiation of T cell antigen receptor (TCR) -mediated signal transduction pathways specifically expressed by T lymphocytes. There are a number of literature reports that LCK modulators, typified by dasatinib, can be used in the treatment of acute T-lymphocyte leukemia, which by temporarily blocking CAR signals not only prevent the process of T-cell depletion but also reverse the phenotype of T-cell depletion. Indicating that the targeted LCK kinase is expected to become an important target of tumor immunity.
There is currently no report or patent application for dual-target modulators that target both HPK1 and LCK kinase.
Disclosure of Invention
In view of the shortcomings of the prior art, an object of the present invention is to provide a pyrrolopyridine derivative as an HPK1 inhibitor and a method for preparing the same; another object of the invention is to provide the use of the pyrrolopyridine derivatives for the preparation of a medicament for the prevention and/or treatment of cancer; it is another object of the present invention to provide the use of the pyrrolopyridine derivatives in combination with CAR-T, PD1-PDL1 for the manufacture of a medicament for the treatment of immune and cancer related diseases.
In order to achieve the above object, the present invention provides a compound of formula (i) or a stereoisomer, tautomer, or pharmaceutically acceptable salt, hydrate, solvate, or PROTAC chimeric thereof;
wherein:
X 1 、X 2 and X 3 Is C;
X 4 and X 5 Each independently is CH or N, and X 4 And X 5 CH is not simultaneously present;
L 1 and L 2 Each independently selected from: none, NR, S, O, -NR-C (=O) R-, -NR-C (=O) NR-, -NR-C (=O) NR-, -NR-C (=S) NR-, -NR-C (=O) NRCH 2 -、-NR-C(＝S)NRCH 2 -wherein R is selected from: H. a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted 3-12 membered heterocyclic group having 1 to 3 heteroatoms selected from N, S and O;
ra is selected from: halogen, CN, CF 3 Substituted or unsubstituted C1-C6 alkyl, orWherein ring B is a C3-C8 cycloalkyl, 6-10 membered substituted or unsubstituted aryl, 5-10 membered substituted or unsubstituted heteroaryl, 3-10 membered substituted or unsubstituted heterocyclyl having 1-3 heteroatoms selected from N, S and O;
R 1 and R is 4 Each independently selected from: H. halogen, CN, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclyl having 1-3 heteroatoms selected from N, S and O, substituted or unsubstituted C6-C10 aryl;
R 2 selected from: unsubstituted, substituted or unsubstituted C1-C6 alkyl,Wherein L is 3 Is C1-C6 alkyl, 3-10 membered heterocyclic group, C1-C6 alkoxy, substituted amino, wherein the amino is substituted by C1-C6 alkyl, 3-10 membered heterocyclic group, R 5 Is NH 2 C1-C6 alkyl, 3-to 10-membered heterocyclyl, -, and->Wherein the X is H, CN, halogen; r is R 6 Is substituted or unsubstitutedSubstituted C1-C6 alkyl, 3-10 membered heterocyclyl, C1-C6 alkoxy, substituted amino wherein the amino substitution is C1-C6 alkyl, 3-10 membered heterocyclyl;
t is 0, 1,2 or 3;
s is 0, 1,2 or 3;
R 3 is halogen, -C1-8 alkyl, -C2-8 alkenyl, -C2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2 、-OR 3a 、-SO 2 R 3a 、-SO 2 NR 3a R 3b 、-COR 3a 、-CO 2 R 3a 、-CONR 3a R 3b 、-C(＝NR 3a )NR 3b R 3c 、-NR 3a R 3b 、-NR 3a COR 3b 、-NR 3a CONR 3b R 3c 、-NR 3a CO 2 R 3b 、-NR 3a SONR 3b R 3c 、-NR 3a SO 2 NR 3b R 3c or-NR 3a SO 2 R 3b the-C1-8 alkyl, -C2-8 alkenyl, -C2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups each optionally being substituted by at least one substituent R 3d Substitution;
R 3a 、R 3b and R is 3c Each independently is hydrogen, -C1-8 alkyl, -C2-8 alkenyl, -C2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, said-C1-8 alkyl, -C2-8 alkenyl, -C2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl each optionally being substituted with at least one substituent R 3e Substitution;
R 3d and R is 3e Each independently is hydrogen, halogen, -C1-8 alkyl, -C2-8 alkenyl, -C2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2 、-OR 3f 、-SO 2 R 3f 、-SO 2 NR 3f R 3g 、-COR 3f 、-CO 2 R 3f 、-CONR 3f R 3g 、-C(＝NR 3f )NR 3g R 3h 、-NR 3f R 3g 、-NR 3f COR 3g 、-NR 3f CONR 3g R 3h 、-NR 3f CO 2 R 3f 、-NR 3f SONR 3f R 3g 、-NR 3f SO 2 NR 3g R 3h or-NR 3f SO 2 R 3g the-C1-8 alkyl, -C2-8 alkenyl, -C2-8 alkynyl, cycloalkyl, heterocyclyl, aryl OR heteroaryl groups are each optionally substituted with at least one moiety selected from halogen, -C1-8 alkyl, -OR 3i 、-NR 3i R 3j Substituents for cycloalkyl, heterocyclyl, aryl or heteroaryl;
R 3f 、R 3g 、R 3h 、R 3i and R 3j Each independently is hydrogen, -C1-8 alkyl, -C1-8 alkoxy-C1-8 alkyl-, -C2-8 alkenyl, -C2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
ring a is selected from: a 6-to 10-membered substituted or unsubstituted aryl group, a 5-to 10-membered substituted or unsubstituted heteroaryl group.
Further, the compound as (I) is selected from the compounds in table 1:
TABLE 1
The invention also provides the use of a compound of formula (I) for the preparation of a modulator of HPK1 and/or LCK kinase.
The compound shown in the formula (I) can regulate HPK1 and/or LCK kinase and can be applied to preparing a double-target regulator targeting HPK1 and/or LCK kinase.
The invention also provides a method of inhibiting HPK1 and/or LCK comprising contacting an effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition, with HPK1 and/or LCK.
The invention also provides a preparation method of the compound shown as the formula (I), which comprises the following scheme:
wherein Pro is 1 And Pro 2 Is a conventional protecting group in organic synthesis, coupling 1 and coupling 2 are conventional C-C or C-N couplings in organic synthesis, and the other variables are as described in formula (I).
For example, compounds of formula (I) may be synthesized as shown in scheme I. Protecting the compound (1) to obtain a compound (2), and reacting the compound (2) with boric acid under palladium catalysis to obtain a compound (3); such as Pro 1 The protecting group does not fall off automatically, and Pro is not needed 2 Protection of (e.g. Pro) 1 The protecting group automatically falls off, pro is needed 2 The protection of the obtained compound (4); the compound (4) can be used under transition metal and with L which can be aryl, heterocycle, etc 1 The groups are subjected to the next coupling to give the compound of formula (I); such as Pro 2 Self-deprotection directly provides the compound of formula (I), whereas deprotection of Pro is required 2 To obtain the compound of the formula (I).
Pharmaceutically acceptable salts described herein include acid addition salts and base addition salts.
The acid addition salts include, but are not limited to, salts derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, and phosphonic acid, and salts derived from organic acids such as aliphatic monocarboxylic and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, and aliphatic and aromatic sulfonic acids. Thus, these salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, hydrochloride, hydrobromide, iodate, acetate, propionate, octanoate, isobutyrate, oxalate, malonate, succinate, suberic acid, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartaric acid, and methanesulfonate, salts further comprising amino acids such as arginine, gluconate, galacturonate, and the like. The acid addition salts may be prepared by contacting the free base form with a sufficient amount of the desired acid in a conventional manner to form the salt. The free base form can be regenerated by contacting the salt form with a base and isolating the free base in a conventional manner.
The base addition salts are formed with metals or amines, such as alkali and alkaline earth metal hydroxides, or with organic amines. Examples of metals used as cations include, but are not limited to, sodium, potassium, magnesium, and calcium. Examples of suitable amines include, but are not limited to, N' -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine (ethane-1, 2-diamine), N-methylglucamine, and procaine. Base addition salts can be prepared by contacting the free acid form with a sufficient amount of the desired base in a conventional manner to form a salt. The free acid form can be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner.
Stereoisomers as described herein include enantiomers, diastereomers and geometric forms. Some compounds of the invention have cycloalkyl groups which may be substituted on more than one carbon atom, in which case all geometric forms thereof, including cis and trans, and mixtures thereof, are within the scope of the invention.
Solvates according to the present invention refer to the physical association of a compound of the present invention with one or more solvent molecules. The physical bonding includes various degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, the solvate may be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. "solvate" includes both solution phase and separable solvates. Representative solvates include ethanolates, methanolates, and the like. "hydrate" is where one or more solvent molecules are H 2 Solvates of O.
Prodrugs of the present invention are those compounds of formula (i) which are suitable for administration to a patient without undue toxicity, irritation, allergic response, and the like, and are effective for their intended use, and include acetal, ester, and zwitterionic forms. The prodrug is converted in vivo (e.g., by hydrolysis in blood) to the parent compound of the above formula.
The invention also provides a pharmaceutical composition, which comprises the compound shown as the formula (I) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt, hydrate or solvate thereof or a PROTAC chimeric thereof, and further comprises pharmaceutically acceptable auxiliary materials. The auxiliary materials are selected from the following components: carrier, diluent, binder, lubricant, wetting agent.
Preferably, the pharmaceutical composition further comprises a chemotherapeutic agent; wherein the chemotherapeutic agent is an immunotherapeutic agent.
Preferably, the pharmaceutical composition comprises a therapeutically effective amount of a compound of formula (I).
In certain embodiments, these pharmaceutical compositions are useful for treating disorders or conditions mediated by HPK1 and/or LCK kinase. The HPK1 and/or LCK kinase modulators of the invention may also be incorporated in pharmaceutical compositions that also include compounds useful in the treatment of cancer or other HPK1 and/or LCK kinase mediated disorders.
The compounds of the present invention of formula (i) may be formulated as pharmaceutical compositions in the form: syrups, elixirs, suspensions, powders, granules, tablets, capsules, troches, aqueous solutions, creams, ointments, lotions, gels, emulsions and the like.
The pharmaceutical formulation is preferably in unit dosage form. In this form, the formulation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form may be a packaged formulation containing discrete amounts of the formulation, such as tablets, capsules and powders packaged in vials or ampoules. In addition, the unit dosage form may be a capsule, a tablet or it may be an appropriate number of any of these dosage forms in packaged form.
The amount of active ingredient in the unit dosage formulation may vary or be adjusted from 0.1 mg to 1000 mg, depending upon the particular application and potency of the active ingredient. The composition may also contain other suitable therapeutic agents, if desired.
The pharmaceutically acceptable carrier will depend in part on the particular composition being administered and on the particular method of administration of the composition. Thus, the pharmaceutical compositions of the present invention exist in a variety of suitable formulations.
The compounds of the present invention, as represented by formula (i), alone or in combination with other suitable components, are formulated as aerosols (i.e., they may be "nebulized") for administration via inhalation. The aerosol may be placed in an acceptable pressurized propellant such as dichlorodifluorohexane, propane, nitrogen, and the like.
Formulations suitable for parenteral administration, such as, for example, by intravenous, intramuscular, intradermal and subcutaneous routes include aqueous and nonaqueous isotonic sterile injection solutions which may contain antioxidants, buffers, bacteriostats, and solutes which render the formulation isotonic with the blood of the recipient, and aqueous and nonaqueous sterile suspensions which may contain suspending agents, solubilizers, thickening agents, stabilizers and preservatives. In the practice of the invention, the compositions may be administered by, for example, intravenous infusion, oral, topical, intraperitoneal, intravesical and intrathecal administration. Formulations of the compounds may be presented in unit-dose or multi-dose sealed containers, such as ampules and vials. Solutions and suspensions for injection can be prepared from sterile powders, granules and tablets of the type previously described.
In the context of the present invention, the dosage administered to a subject should be sufficient to produce a beneficial therapeutic response in the subject over time. The dosage will depend on the potency of the particular compound used and the condition of the subject, as well as the body weight or body surface area of the subject to be treated. The size of the dose will depend on the presence, nature and extent of any adverse side effects associated with the administration of a particular compound in a particular subject. In determining an effective amount of a compound to be administered in the treatment or prevention of a condition being treated, a physician may evaluate factors such as circulating plasma levels of the compound, toxicity of the compound, and/or disease progression.
The invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate or deuterated compound thereof for the preparation of a medicament for the treatment, prevention or alleviation of a disease caused by overactivation of HPK1 and/or LCK kinase.
The invention also provides application of the compound shown in the formula (I) or pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate or deuterated compound thereof in preparing medicines for preventing and/or treating cancers.
The invention also provides the use of a compound of formula (i) or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate or deuterated compound thereof in combination with PD-1, PD-L1, CTLA-4, TIM-3, TGF- β and its receptor, LAG3 antagonist or TLR4, TLR7, TLR8, TLR9, STING agonist for the manufacture of a medicament for cancer immunotherapy.
The invention also provides the use of a compound of formula (i) or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate or deuterated compound thereof in combination with CAR-T for the manufacture of a medicament for use in cancer immunotherapy.
The invention also provides the use of a compound of formula (i) or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate or deuterated compound thereof in combination with CAR-T immunotherapy in cancer immunotherapy.
The CAR-T immunotherapy refers to: chimeric antigen receptor T cell immunotherapy is one of the more effective treatment modes of malignant tumors at present, and the basic principle is to utilize the immune cells of a patient to eliminate cancer cells, belonging to a cell therapy.
Cancers described herein include lymphomas, blastomas, medulloblastomas, retinoblastomas, sarcomas, liposarcomas, synovial cell sarcomas, neuroendocrine tumors, carcinoid tumors, gastrinomas, islet cell carcinomas, mesotheliomas, schwannomas, auditory neuroma, meningiomas, adenocarcinomas, melanomas, leukemias or lymphoid malignancies, squamous cell carcinomas, epithelial squamous cell carcinomas, lung carcinomas, small cell lung carcinomas, non-small cell lung carcinomas, adenocarcinoma lung carcinomas, lung squamous cell carcinomas, peritoneal carcinomas, hepatocellular carcinomas, stomach carcinomas, intestinal carcinomas, pancreatic carcinomas, glioblastomas, cervical carcinomas, ovarian carcinomas, liver carcinomas, bladder carcinomas, liver carcinomas, breast carcinomas, metastatic breast carcinomas, colon carcinomas, rectal carcinomas, colorectal carcinomas, uterine carcinomas, salivary gland carcinomas, kidney carcinomas, prostate carcinomas, vulval carcinomas, thyroid carcinomas, liver carcinomas, anal carcinomas, penile carcinomas, merkel cell carcinomas, esophageal carcinomas, biliary tract tumors, head and neck carcinomas, and hematological malignancies.
Hematological malignancies described herein include, but are not limited to, acute T-lymphoblastic leukemia (T-ALL), chronic T-lymphoblastic leukemia, acute B-lymphoblastic leukemia, chronic B-lymphoblastic leukemia, plasma cell neoplasms, multiple myeloma, macroglobulinemia, jetty lymphoma, non-hodgkin's lymphoma, primary thrombocythemia, polycythemia vera.
Compared with the prior art, the invention has the following advantages:
the invention combines immunotherapy, targets HPK1 and/or LCK kinase, can obviously promote the release of cytokines and obviously shakes T cell functions. The targeted HPK1 and/or LCK kinase compound (such as a compound shown in the formula (I)) provided by the invention has better immune factor release activity, so that the targeted HPK1 and/or LCK kinase compound can be used for preparing, treating, preventing and relieving diseases caused by excessive activation of HPK1 and/or LCK kinase or used as a lead compound for designing candidate molecules with higher activity. In addition, the synthesis method of the HPK1 and/or LCK kinase regulator provided by the invention has the advantages of low-cost and easily available raw materials, mild reaction conditions, simple and convenient operation, high regioselectivity and high yield, and is beneficial to industrial production.
Detailed Description
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
Example 1: synthesis of Compound 1
Step 1: synthesis of intermediate 1-1
To 5-bromo-3-iodo-7-azaindole (3.21 g,1.0 eq.) and di-tert-butyl dicarbonate (6.54 g,3.0 eq.) in tetrahydrofuran (100 mL) was added triethylamine (5.05 g,5.0 eq.). The reaction mixture was stirred at 50℃for 6h. The mixture was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate=20:1) to give compound 1-1 (3.4 g, 81%).
Step 2: synthesis of intermediate 1-2
To a mixture of compound 1-1 (3 g,1.0 eq.) and 3, 4-dimethoxyphenylboronic acid (1.30 g,1.0 eq.) in dioxane (100 mL) and water (50 mL) was added K 2 CO 3 (4.14 g,3.0 eq.) and Pd (dppf) Cl 2 (365.5 mg,0.015 eq.). The reaction mixture was stirred under nitrogen at 110 ℃ for 12h. The mixture was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: meoh=20:1) to give compound 1-2 (1.8 mg, 78%).
Step 3: synthesis of intermediates 1-3
Compounds 1-3 were prepared from compounds 1-2 in a similar manner to that described in example 1, step 1.
Step 4: synthesis of Compound 1
To a mixture of compounds 1-3 (1.5 g,1.0 eq.) and (4- (4- (tert-butoxycarbonyl) piperazin-1-yl) phenyl) boronic acid (1.38 g,1.0 eq.) in dioxane (30 mL) and water (6 mL) was added K 2 CO 3 (245.04 mg,3.0 eq.) and Pd (dppf) Cl 2 (21.95 mg,0.015 eq.). The reaction mixture is reactedStirred under nitrogen at 110℃for 12h. The mixture was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: meoh=50:1) to give compound 1 (1.5 g, 65%).
ESI + -MS(m/z)：515.36.11[M+H] + 。 1 H NMR(400MHz,DMSO)δ11.85(s,1H),8.51(d,J＝2.0Hz,1H),8.32(d,J＝1.9Hz,1H),7.82(d,J＝2.5Hz,1H),7.62(d,J＝8.7Hz,2H),7.35–7.26(m,2H),7.05(dd,J＝8.4,6.9Hz,3H),3.86(s,3H),3.79(s,3H),3.54–3.44(m,4H),3.20–3.09(m,4H),1.43(s,9H).
Example 2: synthesis of Compound 2
To compound 1 (200 mg,1.0 eq.) was added 100mL of ethyl acetate as a solvent, 20mL of ethyl acetate solution of saturated hydrogen chloride was added, and the reaction was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, 100mL of methanol was added, 10mL of triethylamine was added, and the mixture was stirred for 1 hour and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: meoh=5:1) to give compound 2 (150 mg, 93%).
ESI + -MS(m/z)：415.36[M+H] + 。 1 H NMR(400MHz,DMSO)δ11.86(s,1H),8.51(d,J＝1.7Hz,1H),8.31(d,J＝1.6Hz,1H),7.82(s,1H),7.62(d,J＝8.6Hz,2H),7.34–7.24(m,2H),7.10–7.00(m,3H),3.86(s,3H),3.79(s,3H),3.26–3.15(m,4H),3.03–2.90(m,4H).
Example 3: synthesis of Compound 3
Compound 3 (160 mg, 80%) was prepared from compounds 1-3 (200 mg,1.0 eq.) and 4- (4-methyl-1-piperazinyl) phenylboronic acid (101.85 mg,1.0 eq.) in a similar manner as described in example 1 step 4. ESI+ -MS (m/z): 429.34[ M+H ]] + 。 1 H NMR(400MHz,DMSO)δ11.84(s,1H),8.50(d,J＝1.3Hz,1H),8.31(d,J＝1.0Hz,1H),7.82(d,J＝2.0Hz,1H),7.60(d,J＝8.5Hz,2H),7.34–7.25(m,2H),7.04(dd,J＝8.1,4.9Hz,3H),3.86(s,3H),3.79(s,3H),3.21–3.13(m,4H),2.49–2.41(m,J＝3.9Hz,4H),2.23(s,3H).
Example 4: synthesis of Compound 4
Compound 4 (170 mg, 85%) was prepared from compounds 1-3 (200 mg,1.0 eq.) and (6- (4-methylpiperazin-1-yl) pyridin-3-yl) boronic acid (102.31 mg,1.0 eq.) in a similar manner as described in example 1 step 4. ESI+ -MS (m/z): 430.36[ M+H ]] + 。 1 H NMR(400MHz,DMSO)δ11.93(s,1H),8.51(dd,J＝3.6,2.5Hz,2H),8.34(d,J＝1.9Hz,1H),7.94(dd,J＝8.8,2.5Hz,1H),7.83(d,J＝2.4Hz,1H),7.37–7.25(m,2H),7.03(d,J＝8.3Hz,1H),6.93(d,J＝8.9Hz,1H),3.86(s,3H),3.79(s,3H),3.58–3.50(m,4H),2.47–2.36(m,4H),2.22(s,3H).
Example 5: synthesis of Compound 5
Compound 5 (200 mg, 74%) was prepared from compound 1-3 (200 mg,1.0 eq.) and 1-methyl-4- ((4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) sulfonyl) piperazine (169.44 mg,1.0 eq.) in a similar manner as described in example 1 step 4. ESI (electronic service provider interface) + -MS(m/z)：493.25[M+H] + 。 1 H NMR(400MHz,DMSO)δ12.05(s,1H),8.66(s,1H),8.52(s,1H),8.06(d,J＝7.8Hz,2H),7.95–7.87(m,1H),7.81(d,J＝7.8Hz,2H),7.43–7.25(m,2H),7.05(d,J＝8.0Hz,1H),3.87(s,3H),3.80(s,3H),3.02–2.84(m,4H),2.44–2.32(m,4H),2.14(s,3H).
Example 6: synthesis of Compound 6
Compound 6 (150 mg, 65%) was prepared from compounds 1-3 (200 mg,1.0 eq.) and 4- (4-tetrahydropyranyl) phenylboronic acid pinacol ester (133.33 mg,1.0 eq.) in a similar manner as described in example 1 step 4. ESI+ -MS (m/z): 415.35[ M+H ]] + 。 1 H NMR(400MHz,DMSO)δ11.91(s,1H),8.55(d,J＝1.2Hz,1H),8.38(s,1H),7.85(d,J＝2.0Hz,1H),7.68(d,J＝8.0Hz,2H),7.41–7.27(m,4H),7.04(d,J＝8.2Hz,1H),4.01–3.93(m,J＝10.7Hz,2H),3.86(s,3H),3.80(s,3H),3.45(td,J＝11.0,5.4Hz,2H),2.88–2.74(m,1H),1.77–1.64(m,4H).
Example 7: synthesis of Compound 7
Compound 7 (160 mg, 70%) was prepared from compounds 1-3 (200 mg,1.0 eq.) and (6-morpholinopyridin-3-yl) boronic acid (96.23 mg,1.0 eq.) in a similar manner as described in example 1 step 4. ESI+ -MS (m/z): 417.21[ M+H ]] + 。 1 H NMR(400MHz,DMSO)δ11.90(s,1H),8.54(dd,J＝11.0,2.1Hz,2H),8.36(d,J＝1.8Hz,1H),7.98(dd,J＝8.8,2.5Hz,1H),7.84(d,J＝2.5Hz,1H),7.37–7.26(m,2H),7.04(d,J＝8.3Hz,1H),6.94(d,J＝8.8Hz,1H),3.87(s,3H),3.80(s,3H),3.77–3.68(m,4H),3.55–3.45(m,4H).
Example 8: synthesis of Compound 8
Compound 8 (200 mg, 83%) was prepared from compounds 1-3 (200 mg,1.0 eq.) and 6- (4-Boc-1-piperazinyl) pyridine-3-boronic acid pinacol ester (180.09 mg,1.0 eq.) in a similar manner as described in example 1 step 4. ESI+ -MS (m/z): 516.32[ M+H ]] + 。 1 H NMR(400MHz,DMSO)δ11.88(s,1H),8.52(dd,J＝9.4,1.4Hz,2H),8.35(s,1H),7.97(dd,J＝8.8,1.9Hz,1H),7.83(d,J＝2.0Hz,1H),7.37–7.25(m,2H),7.03(d,J＝8.2Hz,1H),6.96(d,J＝8.8Hz,1H),3.86(s,3H),3.79(s,3H),3.59–3.51(m,J＝5.0Hz,4H),3.50–3.41(m,4H),1.44(s,9H).
Example 9: synthesis of Compound 9
Compound 9 (140 mg, 87%) was prepared from compound 8 (200 mg,1.0 eq.) in a similar manner as described in example 2. ESI+ -MS (m/z): 416.37[ M+H ]] + 。1H NMR(400MHz,DMSO)δ11.90(s,1H),8.52(d,J＝4.6Hz,2H),8.35(s,1H),7.96(dd,J＝8.5,1.7Hz,1H),7.83(s,1H),7.38–7.22(m,2H),7.04(d,J＝8.1Hz,1H),6.94(d,J＝8.8Hz,1H),3.87(s,3H),3.80(s,3H),3.57–3.52(m,4H),2.97–2.81(m,4H).
Example 10: synthesis of Compound 10
Compound 10 (120 mg, 64%) was prepared from compounds 1-3 (200 mg,1.0 eq.) and 4- (dimethylcarbamoyl) phenylboronic acid (89.35 mg,1.0 eq.) in a similar manner as described in example 1 step 4. ESI+ -MS (m/z): 402.27[ M+H ]] + 。 1 H NMR(400MHz,DMSO)δ11.97(s,1H),8.61(d,J＝1.9Hz,1H),8.45(d,J＝1.7Hz,1H),7.85(dd,J＝13.9,5.3Hz,3H),7.52(d,J＝8.2Hz,2H),7.34(dd,J＝8.2,1.8Hz,1H),7.30(d,J＝1.6Hz,1H),7.05(d,J＝8.3Hz,1H),3.87(s,3H),3.80(s,3H),3.00(s,6H).
Example 11: synthesis of Compound 11
Compound 11 (150 mg, 77%) was prepared from compound 1-3 (200 mg,1.0 eq.) and 1-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) piperidine (134.72 mg,1.0 eq.) in a similar manner as described in example 1 step 4. ESI+ -MS (m/z): 418.34[ M+H ]] + 。 1 H NMR(400MHz,DMSO)δ11.80(s,1H),8.55(d,J＝1.8Hz,1H),8.36(s,2H),8.00(s,1H),7.78(d,J＝2.4Hz,1H),7.32–7.24(m,2H),7.04(d,J＝8.3Hz,1H),4.23–4.13(m,1H),3.88(s,3H),3.80(s,3H),3.01–2.94(m,J＝11.5Hz,2H),2.32(s,3H),2.25(t,J＝9.3Hz,2H),2.11–2.02(m,4H).
Example 12: synthesis of Compound 12
Compound 12 (120 mg, 62%) was prepared from compounds 1-3 (200 mg,1.0 eq.) and 4- (4-morpholinyl) phenylboronic acid (95.83 mg,1.0 eq.) in a similar manner as described in example 1 step 4. ESI+ -MS (m/z): 416.31[ M+H ]] + 。 1 H NMR(400MHz,DMSO)δ11.85(s,1H),8.52(d,J＝2.0Hz,1H),8.32(d,J＝1.8Hz,1H),7.82(d,J＝2.5Hz,1H),7.62(d,J＝8.7Hz,2H),7.35–7.26(m,2H),7.10–7.00(m,3H),3.86(s,3H),3.80(s,3H),3.78–3.71(m,4H),3.18–3.10(m,4H).
Example 13: synthesis of Compound 13
Compound 13 (135 mg, 73%) was prepared from compounds 1-3 (200 mg,1.0 eq.) and 4- (2H-tetrazol-5-yl) phenylboronic acid pinacol ester (125.92 mg,1.0 eq.) in a similar manner as described in example 1 step 4. ESI+ -MS (m/z): 399.28[ M+H ]] + 。 1 H NMR(400MHz,DMSO)δ12.01(s,1H),8.69(d,J＝1.1Hz,1H),8.53(s,1H),8.17(d,J＝8.1Hz,2H),8.05(d,J＝8.1Hz,2H),7.89(d,J＝1.3Hz,1H),7.36(dd,J＝8.2,1.2Hz,1H),7.32(s,1H),7.06(d,J＝8.3Hz,1H),3.89(s,3H),3.81(s,3H).
Example 14: synthesis of Compound 14
To correspond to the procedure in example 1Compound 14 (170 mg, 83%) was prepared from compounds 1-3 (200 mg,1.0 eq.) and 4- (4-methyl-1-piperazinomethyl) phenylboronic acid pinacol (146.41 mg,1.0 eq.) in a similar manner as described in 4. ESI (electronic service provider interface) + -MS(m/z)：443.39[M+H] + 。 1 H NMR(400MHz,DMSO)δ11.92(s,1H),8.56(d,J＝1.6Hz,1H),8.39(d,J＝1.3Hz,1H),7.85(d,J＝2.1Hz,1H),7.70(d,J＝8.0Hz,2H),7.39(d,J＝7.9Hz,2H),7.35–7.26(m,2H),7.04(d,J＝8.2Hz,1H),3.86(s,3H),3.80(s,3H),3.49(s,2H),3.44–3.34(m,4H),2.41–2.32(m,4H),2.16(s,3H).
Example 15: synthesis of Compound 15
Compound 15 (155 mg, 78%) was prepared from compounds 1-3 (200 mg,1.0 eq.) and 4-morpholinomethylphenylboronic acid (102.31 mg,1.0 eq.) in a similar manner as described in example 1 step 4. ESI (electronic service provider interface) + -MS(m/z)：430.30[M+H] + 。 1 H NMR(400MHz,DMSO)δ11.92(s,1H),8.56(d,J＝2.0Hz,1H),8.39(d,J＝2.0Hz,1H),7.85(s,1H),7.71(d,J＝8.1Hz,2H),7.41(d,J＝8.1Hz,2H),7.36–7.23(m,2H),7.04(d,J＝8.3Hz,1H),3.86(s,3H),3.80(s,3H),3.65–3.54(m,4H),3.50(s,2H),2.45–2.30(m,4H).
Example 16: synthesis of Compound 16
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Compound 16 (160 mg, 80%) was prepared from compounds 1-3 (200 mg,1.0 eq.) and 4- (1-methyl-4-piperidinyl) phenylboronic acid pinacol ester (139.35 mg,1.0 eq.) in a similar manner as described in example 1 step 4. ESI (electronic service provider interface) + -MS(m/z)：428.33[M+H] + 。 1 H NMR(400MHz,DMSO)δ11.92(s,1H),8.54(s,1H),8.37(s,1H),7.84(s,1H),7.67(d,J＝5.5Hz,2H),7.31(dd,J＝19.0,5.5Hz,4H),7.04(d,J＝7.0Hz,1H),3.86(s,3H),3.79(s,3H),3.09–2.93(m,J＝7.1Hz,2H),2.62–2.54(m,J＝0.7Hz,1H),2.33(s,3H),2.27–2.14(m,2H),1.87–1.68(m,4H).
Example 17: synthesis of Compound 17
Compound 17 (145 mg, 72%) was prepared from compounds 1-3 (200 mg,1.0 eq.) and (2- (4-methylpiperazin-1-yl) pyrimidin-5-yl) boronic acid (102.78 mg,1.0 eq.) in a similar manner as described in example 1 step 4. ESI (electronic service provider interface) + -MS(m/z)：431.26[M+H] + 。 1 H NMR(400MHz,DMSO)δ11.93(s,1H),8.78(s,2H),8.51(d,J＝1.7Hz,1H),8.40(s,1H),7.84(d,J＝2.2Hz,1H),7.32(dd,J＝12.2,3.9Hz,2H),7.02(d,J＝8.3Hz,1H),3.87(s,3H),3.83–3.75(m,7H),2.45–2.34(m,4H),2.23(s,3H).
Example 18: synthesis of Compound 18
Compound 18 (150 mg, 81%) was prepared from compound 1-3 (200 mg,1.0 eq.) and 2- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -1,3, 4-oxadiazole (125.92 mg,1.0 eq.) in a similar manner as described in example 1 step 4. ESI (electronic service provider interface) + -MS(m/z)：399.36[M+H] + 。 1 H NMR(400MHz,DMSO)δ12.01(s,1H),9.37(s,1H),8.66(s,1H),8.51(s,1H),8.12(d,J＝8.0Hz,2H),8.02(d,J＝8.1Hz,2H),7.88(s,1H),7.37–7.26(m,2H),7.05(d,J＝8.2Hz,1H),3.87(s,3H),3.80(s,3H).
Example 19: synthesis of Compound 19
To compound 9 (200 mg,1.0 eq.) and 1-iodo-2-methoxyethane (44.82 mg,0.5 eq.) were added K in acetonitrile (30 mL) 2 CO 3 (245.04 mg,3.0 eq.). The reaction mixture was stirred under nitrogen at 60 ℃ for 4h. Cooling the mixtureCooled to room temperature and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: meoh=10:1) to give compound 19 (80 mg, 70%). ESI (electronic service provider interface) + -MS(m/z)：443.39[M+H] + 。 1 H NMR(400MHz,DMSO)δ11.88(d,J＝1.7Hz,1H),8.51(dd,J＝3.6,2.4Hz,2H),8.34(d,J＝1.8Hz,1H),7.94(dd,J＝8.8,2.5Hz,1H),7.83(d,J＝2.4Hz,1H),7.37–7.26(m,2H),7.03(d,J＝8.3Hz,1H),6.93(d,J＝8.9Hz,1H),3.86(s,3H),3.79(s,3H),3.53(s,4H),3.40–3.28(m,6H),3.25(s,3H),1.17(t,J＝7.1Hz,2H).
Example 20: synthesis of Compound 20
Compound 20 (95 mg, 81%) was prepared from compound 9 (200 mg,1.0 eq.) and dimethylcarbamoyl chloride (25.78 mg,0.5 eq.) in a similar manner as described in example 19. ESI (electronic service provider interface) + -MS(m/z)：487.35[M+H] + 。 1 H NMR(400MHz,DMSO)δ11.89(s,1H),8.52(d,J＝8.9Hz,2H),8.35(s,1H),7.97(d,J＝8.7Hz,1H),7.83(s,1H),7.43–7.23(m,2H),6.99(dd,J＝33.6,8.3Hz,2H),3.86(s,3H),3.79(s,3H),3.60–3.51(m,4H),3.28–3.19(m,4H),2.79(s,6H).
Example 21: synthesis of Compound 21
Compound 21 (90 mg, 84%) was prepared from compound 9 (200 mg,1.0 eq.) and acryloyl chloride (21.69 mg,0.5 eq.) in a similar manner as described in example 19. ESI (electronic service provider interface) + -MS(m/z)：443.39[M+H] + 。 1 H NMR(400MHz,DMSO)
Example 22: synthesis of Compound 22
As in example 19Compound 22 (80 mg, 71%) was prepared from compound 2 (200 mg,1.0 eq.) and dimethylcarbamoyl chloride (24.71 mg,0.5 eq.) in a similar manner as described. ESI (electronic service provider interface) + -MS(m/z)：486.25[M+H] + 。 1 H NMR(400MHz,DMSO)δ11.85(d,J＝1.7Hz,1H),8.51(d,J＝2.0Hz,1H),8.32(d,J＝1.8Hz,1H),7.82(d,J＝2.4Hz,1H),7.62(d,J＝8.7Hz,2H),7.37–7.25(m,2H),7.05(dd,J＝8.5,2.5Hz,3H),3.86(s,3H),3.79(s,3H),3.30–3.23(m,4H),3.21–3.13(m,J＝4.9Hz,4H),2.78(s,6H).
Other compounds of the invention are worth referring to the synthetic preparation methods exemplified above.
Biological Activity assay
Experimental example 1: inhibition assay for HPK1 and LCK kinase
1. Compounds were 3-fold diluted with DMSO in dilution plates at initial concentrations of 1-10. Mu.M.
2. The compound was 50-fold diluted into 1x kinase reaction buffer and shaken on a shaker for 20 minutes.
3. Preparation of 2x kinase with lx enzyme reaction buffer.
4. mu.L of kinase (formulated in step 3) was added to each well of the reaction plate.
5. To each well, 1. Mu.L of the diluted compound in buffer was added, and the plate was sealed with a sealing plate membrane and centrifuged at 1000g for 30 seconds and left at room temperature for 10 minutes.
6. A mixture of 4xM BP Protein and ATP (final ATP concentration of 10. Mu.M) was prepared with lx enzyme reaction buffer, and 1. Mu.L of a 4 xMBP Protein/ATP mixture was added to the reaction plate.
7. 1000g of the plate is sealed by a sealing plate membrane and centrifuged for 30 seconds, and the reaction is carried out for 60 minutes at room temperature.
8. Transfer 4. Mu.L ADP-Glo to 384 reaction plates at 1000rpm/min, centrifuge 1min, incubate at 25℃for 40min.
9. Transfer 8uL Detection solution to 384 reaction plates 1000rpm/min, centrifuge lmin, incubate 40min at 25 ℃.
10. The RLU (Relative luminescence unit) signal was read using a Biotek multifunctional reader. The intensity of the signal is used to characterize the extent of kinase activity.
(3) Data processing
The inhibition rate per well was calculated as follows:
the Lum positive control is the average of RLU readings for all positive controls and the Lum negative control is the average of RLU readings for all negative controls in empty DMSO.
Computing IC 50 And plotting inhibition curves of the compounds:
ICso (half inhibition concentration) of the compounds was obtained using the following nonlinear fitting formula, data analysis was performed using Graphpad 9.3 software.
Y＝Bottom+(Top-Bottom)/(1+10^((L ogIC 50 -X)*Hill Slope))
X is the log value of the compound concentration; y, inhibition (% inhibition).
(4) Experimental results
Inhibition of HPK 1/LCK enzyme and stimulation of IL-2 by the compounds of the invention:
experimental results:
TABLE 2
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Wherein IC 50 Middle a=<100nM；B＝100～500nM；C＝500～1000nM；D＝>A=in the stimulation fold of 1000nM IL-2>2；B＝1～2；C＝<1
Some of the compounds of the invention have better inhibition effect on HPK1, some have better inhibition effect on LCK, some can inhibit HPK1 and LCK at the same time, and some of the compounds show obvious stimulation effect on cytokine IL-2, so that tumor immunity can be improved, and the compounds of the invention have better application potential on diseases caused by HPK1 and/or LCK kinase.
The HPK1 and/or LCK modulators, their preparation and their use provided by the present invention are described in detail above.
The principles and embodiments of the present invention have been described herein with reference to specific examples, the description of which is intended only to aid in the understanding of the method of the present invention and its central ideas. It should be noted that it will be apparent to those skilled in the art that the present invention may be modified and practiced in several ways without departing from the principles of the present invention, and these modifications and adaptations are also within the scope of the appended claims.
Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be apparent to those skilled in the art that certain minor changes and modifications may be practiced. Accordingly, the description and examples should not be construed as limiting the scope of the invention.

Claims (10)

1. A compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt, hydrate, solvate, or PROTAC chimera thereof;
wherein:
X 1 、X 2 and X 3 Is C;
X 4 and X 5 Each independently is CH or N, and X 4 And X 5 CH is not simultaneously present;
L 1 and L 2 Each independently selected from: none, NR, S, O, -NR-C (=O) R-, -NR-C (=O) NR-, -NR-C (=O) NR-, -NR-C (=S) NR-, -NR-C (=O) NRCH 2 -、-NR-C(＝S)NRCH 2 -wherein R is selected from: H. a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted 3-12 membered heterocyclic group having 1 to 3 heteroatoms selected from N, S and O;
ra is selected from: halogen, CN, CF 3 Substituted or unsubstituted C1-C6 alkyl, orWherein ring B is a C3-C8 cycloalkyl, 6-10 membered substituted or unsubstituted aryl, 5-10 membered substituted or unsubstituted heteroaryl, 3-10 membered substituted or unsubstituted heterocyclyl having 1-3 heteroatoms selected from N, S and O;
R 1 and R is 4 Each independently selected from: H. halogen, CN, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclyl having 1-3 heteroatoms selected from N, S and O, substituted or unsubstituted C6-C10 aryl;
R 2 selected from: unsubstituted, substituted or unsubstituted C1-C6 alkyl,Wherein L is 3 Is C1-C6 alkyl, 3-10 membered heterocyclic group, C1-C6 alkoxy, substituted amino, wherein the amino is substituted by C1-C6 alkyl, 3-10 membered heterocyclic group, R 5 Is NH 2 C1-C6 alkyl, 3-to 10-membered heterocyclyl, -, and->Wherein the X is H, CN, halogen; r is R 6 Is a substituted or unsubstituted C1-C6 alkyl, 3-10 membered heterocyclic group, C1-C6 alkoxy, substituted amino, wherein the amino is substituted by C1-C6 alkyl, 3-10 membered heterocyclic group;
t is 0, 1,2 or 3;
s is 0, 1,2 or 3;
R 3 is halogen, -C1-8 alkyl, -C2-8 alkenyl, -C2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2 、-OR 3a 、-SO 2 R 3a 、-SO 2 NR 3a R 3b 、-COR 3a 、-CO 2 R 3a 、-CONR 3a R 3b 、-C(＝NR 3a )NR 3b R 3c 、-NR 3a R 3b 、-NR 3a COR 3b 、-NR 3a CONR 3b R 3c 、-NR 3a CO 2 R 3b 、-NR 3a SONR 3b R 3c 、-NR 3a SO 2 NR 3b R 3c or-NR 3a SO 2 R 3b the-C1-8 alkyl, -C2-8 alkenyl, -C2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups each optionally being substituted by at least one substituent R 3d Substitution;
R 3a 、R 3b and R is 3c Each independently is hydrogen, -C1-8 alkyl, -C2-8 alkenyl, -C2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, said-C1-8 alkyl, -C2-8 alkenyl, -C2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl each optionally being substituted with at least one substituent R 3e Substitution;
R 3d and R is 3e Each independently is hydrogen, halogen, -C1-8 alkyl, -C2-8 alkenyl, -C2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2 、-OR 3f 、-SO 2 R 3f 、-SO 2 NR 3f R 3g 、-COR 3f 、-CO 2 R 3f 、-CONR 3f R 3g 、-C(＝NR 3f )NR 3g R 3h 、-NR 3f R 3g 、-NR 3f COR 3g 、-NR 3f CONR 3g R 3h 、-NR 3f CO 2 R 3f 、-NR 3f SONR 3f R 3g 、-NR 3f SO 2 NR 3g R 3h or-NR 3f SO 2 R 3g the-C1-8 alkyl, -C2-8 alkenyl, -C2-8 alkynyl, cycloalkyl, heterocyclyl, aryl OR heteroaryl groups are each optionally substituted with at least one moiety selected from halogen, -C1-8 alkyl, -OR 3i 、-NR 3i R 3j Substituents for cycloalkyl, heterocyclyl, aryl or heteroaryl;
R 3f 、R 3g 、R 3h 、R 3i and R 3j Each independently is hydrogen, -C1-8 alkyl, -C1-8 alkoxy-C1-8 alkyl-, -C2-8 alkenyl, -C2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
ring a is selected from: a 6-to 10-membered substituted or unsubstituted aryl group, a 5-to 10-membered substituted or unsubstituted heteroaryl group.
2. The compound of claim 1, wherein said compound is selected from the group consisting of the compounds in table 1;
TABLE 1
3. A process for the preparation of a compound according to claim 1, comprising: protecting the compound (1) to obtain a compound (2), and reacting the compound (2) with boric acid under palladium catalysis to obtain a compound (3); such as Pro 1 The protecting group does not fall off automatically, and Pro is not needed 2 Protection of (e.g. Pro) 1 The protecting group automatically falls off, pro is needed 2 The protection of the obtained compound (4); the compound (4) reacts with L under the action of transition metal 1 The group is coupled in the next step; such as Pro 2 Self-deprotection directly provides the compound of formula (I), whereas deprotection of Pro is required 2 Obtaining the compound of formula (I); the reaction process is as follows:
4. a pharmaceutical composition, which is characterized in that the pharmaceutical composition comprises the compound shown as the formula (I) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt, hydrate or solvate thereof or a PROTAC chimeric thereof, and further comprises pharmaceutically acceptable auxiliary materials.
5. A modulator of HPK1 and/or LCK kinase, comprising said compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt, hydrate, solvate, or PROTAC chimeric thereof.
6. Use of a compound of formula (i) as defined in claim 1 or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate or deuterated compound thereof for the preparation of a medicament for the treatment, prophylaxis and alleviation of diseases which are caused by overactivation of HPK1 and/or LCK kinase.
7. Use of a compound of formula (i) as defined in claim 1 or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate or deuterated compound thereof for the preparation of a medicament for the prophylaxis and/or treatment of cancer.
8. Use of a compound of formula (i) as described in claim 1 or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate or deuterated compound thereof in combination with PD-1, PD-L1, CTLA-4, TIM-3, TGF- β and its receptor, LAG3 antagonist or TLR4, TLR7, TLR8, TLR9, STING agonist for the manufacture of a medicament for cancer immunotherapy.
9. Use of a compound of formula (i) as described in claim 1, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate or deuterated compound thereof, in combination with CAR-T for the manufacture of a medicament for cancer immunotherapy.
10. The use according to claim 8 or 9, wherein said cancer comprises lymphoma, blastoma, medulloblastoma, retinoblastoma, sarcoma, liposarcoma, synovial cell sarcoma, neuroendocrine tumor, carcinoid tumor, gastrinoma, islet cell carcinoma, mesothelioma, schwannoma, acoustic neuroma, meningioma, adenocarcinoma, melanoma, leukemia or lymphoid malignancy, squamous cell carcinoma, epithelial squamous cell carcinoma, lung cancer, small cell lung cancer, non-small cell lung cancer, adenocarcinoma lung cancer, lung squamous carcinoma, peritoneal carcinoma, hepatocellular carcinoma, gastric cancer, intestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, liver cancer, breast cancer, metastatic breast cancer, colon cancer, rectal cancer, colorectal cancer, uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal cancer, penile carcinoma, mecholly cell carcinoma, esophageal cancer, biliary tract tumor, head and neck cancer and hematological malignancy.
CN202311469918.6A 2023-02-20 2023-02-20 Pyrrolopyridine derivative as HPK1 inhibitor, preparation method and application thereof Pending CN117447470A (en)

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