Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
  • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
  • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
  • A61P31/18—Antivirals for RNA viruses for HIV
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/20—Antivirals for DNA viruses
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/20—Antivirals for DNA viruses
  • A61P31/22—Antivirals for DNA viruses for herpes viruses
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/04—Immunostimulants
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
  • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
  • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

• HPK1 Hematopoietic progenitor kinase 1
• HPK1 also known as mitogen-activated protein kinase kinase kinase kinase kinase (MAP4K1)
• MAP4K1 mitogen-activated protein kinase kinase kinase kinase
• HPK1 is mainly expressed in blood cells.
• HPK1 is a negative regulator of T cell receptor (TCR) signaling responsible for suppressing immune responses.
• TCR activation leads to the recruitment of HPK1 to the cell membrane, followed by activation through phosphorylation of Tyr281 ⁇ Serl71 ⁇ Thrl65 sites.
• Activated HPK1 destabilizes the TCR signaling complex by phosphorylating the Ser276 site of SLP76 protein, thereby inhibiting the activation and proliferation of T cells.
• HPK1 activation also inhibits the secretion of interferon gamma (IFN-Y).
• IFN-Y interferon gamma
• HPK1 knockout/knockdown In a series of tumor immune animal models, HPK1 knockout/knockdown, or the use of HPK1 inhibitors, can effectively prevent HPK1 from suppressing the immune system, improve the body's immunity, and thereby enhance the anti-tumor effect (Hernandez et al., Cell Reports, 2018).
• LCMV lymphocytic choriomeningitis virus
• HPK1 small molecule inhibitor may be an effective therapy for curing hepatitis B.
• HBV hepatitis B vaccine
• HPK1 small molecule inhibitors as broad-spectrum antiviral drugs alone or in combination (non-vaccine adjuvant) for viral infection. related disease treatment.
• the purpose of the present invention is to provide a series of novel HPK1 inhibitors, which can be used as therapeutic drugs for interferon-related diseases, especially viral infections.
• Zi is selected from N or C-RRi;
• z 2 and Z 3 are selected from N or C-RR2 respectively, wherein Z2 and Z 3 are not the same;
• RR1 is selected from hydrogen, halogen, alkenyl, hydroxyl, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C1-6 alkoxy, substituted or unsubstituted Substituted amino or substituted or unsubstituted amido;
• RR2 is selected from substituted or unsubstituted hydroxyl, substituted or unsubstituted amino, or substituted or unsubstituted group building;
• RR3 is selected from H, hydroxyl, halogen, alkenyl, substituted or unsubstituted C6 alkyl, substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted C1-6 alkoxy, substituted or unsubstituted A substituted amino group or a substituted or unsubstituted amido group;
• RR4, RR5 > RR6, RR7 are independently selected from H, hydroxyl, halogen, alkenyl, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted C1 -6 alkoxy, substituted or unsubstituted amino, substituted or unsubstituted amido, substituted or unsubstituted C5-10 heteroaryl or RR8-Z4-;
• RR8 is selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl or substituted or unsubstituted hydroxy;
• Z4 is selected from the group consisting of -0-, -NH-, -S-, -SO-, -SO2-, ethylene, benzoylamino or amino ethylene.
• the compound shown in formula I is the compound shown in the following formula 1-1:
• Re is selected from H, hydroxyl, halogen, alkenyl, substituted or unsubstituted Cl-6 alkyl, substituted or unsubstituted C3-8 cycloalkyl, or substituted or unsubstituted C-6 alkoxy;
• X' is selected from -0-, -NH-, -s-, -SO-, -SO2-, alkyl, benzylamino or amino alkyl;
• R 1 ' is a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group or R 14 -O-(CH 2 ) m -, wherein m is
• R14' is a substituted or unsubstituted C1-6 alkyl group or a substituted or unsubstituted C3-8 cycloalkyl group;
• the A' ring is a substituted or unsubstituted aryl group (preferably a substituted or unsubstituted phenyl group) or a substituted or unsubstituted 5-6 membered heteroaryl group, wherein the heteroaryl group has 1-4 members selected from 0 , S or N heteroatoms;
• Rb, RC, Rd, Re are each independently selected from H, hydroxyl, halogen, alkenyl, substituted or unsubstituted C1-6 In the formula, R ⁇ R°, Rd, R.
• X is selected from -0-, -NH-, -S-, -SO-, -S02-, xyl, alkylamino or amino xyl; n is 1, 2, 3 or 4, m is 0, 1, 2, 3, 4 or 5,
• R 14 ' is a substituted or unsubstituted Ci-6 alkyl group or a substituted or unsubstituted C3-8 cycloalkyl group;
• the A' ring is a substituted or unsubstituted aryl group (preferably a substituted or unsubstituted phenyl group) or a substituted or unsubstituted 5-6 membered heteroaryl group, wherein the heteroaryl group has 1-4 members selected from 0 , S or N heteroatoms;
• R2' is selected from the following substituents:
• R1, R2, R3, & and R5 are each independently selected from: hydrogen, halogen, indenyl, hydroxyl, substituted or unsubstituted C "6 ii.
• Branched or straight-chain Cl-6 alkyl, C2-6 alkenyl or C2-6 block, the alkyl, alkenyl and block also contain various types of single or multiple substitutions, including hydrogen, hydroxyl , halogen, alkenyl, amino, -CHF2, -CF3, two (C1-6 alkyl) amino, single (C1-6 alkyl) amino, C3-6 cycloalkyl or C1-6 alkoxy; iii.
• Ri, R2, R and R8 are each as defined above.
• X is NH.
• Ri, R2, R8 and ring A are each as defined above.
• the A ring is selected from: In a preferred embodiment, the A ring and R7 together form an optionally substituted fused ring group, bridged ring group, heterobridged ring group, spirocyclic group or heterospirocyclic group:
• the Ri is an amino group, a hydroxyl group, an indenyl group, a methoxy group or a halogen substituent.
• R8 is methyl, ethyl, isopropyl, cyclopropyl, vinyl, ethyl or substituted or unsubstituted aryl (preferably phenyl) or 5-membered heteroaryl.
• R8 is methyl, ethyl, isopropyl, cyclopropyl, substituted or unsubstituted phenyl.
• the compound is selected from:
• the compound is In a specific embodiment, the virus is selected from the group consisting of Hepatitis B virus > Measles Virus > Sindbis Virus > West Nile Virus > Dengue Virus ) > Herpes Simplex Virus > Human Cytomegalovirus HCMV > Ebola Virus > Hepatitis C Virus (HCV), Influenza A Virus, Severe Acute Respiratory Syndrome Virus (SARS) -CoV), Zika Virus, HIV, Feline Infectious Peritonitis Virus, Mouse Hepatitis Virus > Canine Coronavirus, Feline Calicivirus (Feline Calicivirus), Feline Leukemia Virus, Feline Immunodeficiency Virus, Feline Panleukopenia Virus, Avian Infect
• the present invention provides a pharmaceutical composition
• a pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof , tautomers, prodrugs, metabolites or derivatives and one or more other antiviral drugs, and optional pharmaceutically acceptable excipients.
• the present invention provides the compound of the present invention for use as a drug for treating interferon-related diseases.
• the present invention provides a method for treating interferon-related diseases, comprising the step of administering a therapeutically effective amount of the compound or pharmaceutical composition of the present invention to a subject in need thereof.
• Figure 13 shows the synthetic route of compound D D02008H.
• Figure 14 shows the synthetic route of compound D D02015H.
• Figure 15 shows the synthetic route of compound D D02021H.
• Figure 16 shows the synthetic route of compound D D02018H.
• Figure 17 shows the synthetic route of compound D D02002H.
• Figure 18 shows the synthetic route of compound DD02019H.
• alkyl refers to branched and straight chain saturated aliphatic hydrocarbon groups containing, for example, 1 to 12, 1 to 6 or 1 to 4 carbon atoms.
• alkyl groups include, but are not limited to, methyl, ethyl, propyl (such as n-propyl and isopropyl), T-groups (such as n-butyl, isobutyl, sec-butyl and tert-butyl), and pentyl (such as n-pentyl, isopentyl, neopentyl), n-hexyl, 2-methylpentyl, 2-ethylbutyl, 3-methylpentyl and 4-methylpentyl.
• C represents the number of carbon atoms a particular group may contain.
• C'6 alkyl represents straight and branched chain alkyl groups having 1 to 6 carbon atoms.
• alkenyl refers to a straight chain or branched alkenyl group having at least one double bond).
• the alkenyl group may be optionally substituted with one or more substituents, and includes groups with "cis” and “trans” orientations, or groups with "E” and “Z” orientations. Examples include, but are not limited to, vinyl, allyl, and the like.
• carboxylate as used herein generally refers to a branched or straight chain hydrocarbon group having at least one triple bond. Carboxyl can be optionally substituted.
• C2-3 carbinyl generally refers to a branched or straight chain hydrocarbon group having at least one triple bond. Carboxyl can be optionally substituted.
• C2-3 carbinyl generally refers to a carboxyl group containing at least 2, and at most 3, 4, 5, 6, 7 or 8 carbon atoms, respectively.
• Non-limiting examples of carboxanyl groups include ethylcanthyl, propanyl, butyryl, pentahanyl, hexanyl, hephanyl, octahanyl, nonanganyl, decanyl, and the like.
• cycloalkyl refers to a group resulting from the loss of a hydrogen atom from a cyclic cone molecule.
• Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclopentyl, and cyclohexyl.
• Examples of monocyclic cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
• heteroatom refers to oxygen (O), sulfur (S, or nitrogen (N).
• Halo and “halogen” refer to F, Cl, Br, or I.
• haloalkyl Refer to the alkyl substituted by one or more halogens.
• indenyl as used herein refers to the group-CN.
• amino refers to the group-NH2.
• heterocycloalkyl as used herein or "Heterocyclyl” means a ring containing 1-4 heteroatoms (if monocyclic), 1-6 heteroatoms (if bicyclic), or 1-9 heteroatoms (if tricyclic) Alkyl, the heteroatom is selected from O, S or N. Heterocycloalkyl can be optionally substituted by one or more substituents. In one embodiment, each ring of heterocycloalkyl. 2, 3 or 4 atoms may be substituted by substituents.
• heterocycloalkyl groups include piperazinyl, piperazinyl, tetrahydropyranyl, morphyl, thiomorphyl, 1,3 - dioxolyl, THF group, tetrahydroshenyl, shenyl, etc.
• aromatic ring or "aryl” as used herein refers to a monocyclic, bicyclic or tricyclic aromatic ring A group obtained by losing a hydrogen atom in the ring system.
• Aryl can be optionally substituted by one or more substituents. In one embodiment, 0, 1, 2, 3, 4 of each ring of aryl 1, 5 or 6 atoms can be substituted by substituents.
• aryl groups include phenyl, naphthyl, core group, drug base, anthracyl, molybdenum, etc.
• aromatic heterocyclic ring used herein " or “heteroaryl” means an “aromatic ring” or “aryl” having at least one heteroatom (0, S or N) in at least one ring, and the heteroatom-containing ring preferably has 1, 2 or 3 independently selected from 0, S or N heteroatoms.
• Each ring in a heteroatom-containing heteroaryl group may contain 1 or 2 oxygen or sulfur atoms and/or 1-4 nitrogen atoms, provided that the total number of heteroatoms in each ring is 4 or less And each ring has at least one carbon atom.
• a heteroaryl group can be attached to any available nitrogen or carbon atom of any ring.
• a heteroaryl ring system can be unsubstituted or can contain one or more substituents.
• Non-limiting examples of heteroaryl groups include pyryl, pyryl, phenenyl, pyrrolyl, fenyl, erlicyl, milyl, fenyl, isoamyl, wah ⁇ Linji, pirilyl, iso-n-sewa-based, pyridazinyl, succino-based, piperazinyl, triazinyl, iso-wakoulin-yl, ming-sui-based, etc.
• alkoxy refers to -O-alkyl.
• An alkoxy group can be optionally substituted with one or more substituents.
• residue moieties include, but are not limited to, ketone and aldehyde moieties.
• alkylamino refers to an amino group substituted with one or two alkyl groups.
• aminoalkyl refers to an alkyl group substituted with one or more amino groups.
• hydroxyalkyl refers to an alkyl group substituted with one or more hydroxy groups.
• the alkyl moiety optionally has one or more substituents.
• spirocyclyl denotes a polycyclic group in which two carbocyclic rings share one carbon atom.
• Heterospirocyclic group refers to a polycyclic group in which two monocyclic rings share one carbon atom, and the two rings may contain one or more heteroatoms.
• bridged ring group refers to any two carbon rings A ring group that shares two carbon atoms that are not directly connected can be divided into bicyclic, tricyclic, tetracyclic, etc. according to the number of rings.
• Heterobridged ring group refers to a polycyclic heterocyclic group, and the polycyclic There are two rings in the heterocyclic group that share two non-adjacent carbon atoms or heteroatoms.
• fused ring group used herein means a polycyclic ring formed by two or more carbon rings sharing ring edges Organic compound.
• Heterofused ring group refers to a polycyclic heterocyclic group, and in the polycyclic heterocyclic group, two rings share two adjacent carbon atoms or heteroatoms.
• the term “isomer” used herein " or “stereoisomer” refers to compounds that have the same chemical composition but differ in the arrangement of atoms or groups in space.
• tautomer or "tautomeric form” refers to compounds that have different energies Structural isomers, which are interconvertible via low energy barriers.
• proton tautomers also called prototropic isomers
• Valency tautomers include interconversion by recombination of some of the bonding electrons.
• diastereoisomer refers to those having two or more centers of asymmetry and whose molecules are not mutually Stereoisomers that are mirror images.
• prevention and/or treatment not only includes prevention and/or treatment of disease, but also generally includes prevention of disease onset, slowing or reversing the progression of disease, preventing or slowing down the disease-related reducing and/or alleviating one or more symptoms associated with the disease, reducing the severity and/or duration of the disease and/or any symptoms associated therewith and/or preventing the disease and /Or further increase in the severity of any symptoms associated with it, prevention, reduction or reversal of any physiological damage caused by the disease, and any pharmacological effects that are generally beneficial to the patient being treated.
• a therapeutic agent need not achieve a complete cure or eradicate any symptoms or manifestations of the disease.
• a drug used as a therapeutic agent can reduce the severity of a given disease state, but does not require Elimination of every manifestation of disease is considered a useful therapeutic agent.
• a treatment administered prophylactically need not be fully effective in preventing the onset of the disorder to constitute a viable prophylactic. Simply reducing the effects of disease in a subject (for example, by reducing the number or severity of its symptoms, or by increasing the effectiveness of another treatment, or by producing another beneficial effect), or reducing disease occurrence or The possibility of deterioration is enough.
• prevention and/or treatment includes the prevention and/or treatment of diseases achieved by various means, for example, the prevention and/or treatment of diseases is achieved by improving the immunity of the subject.
• administering or “administering” includes the means by which the compound is introduced into a subject to achieve its intended function. Examples of routes of administration that may be used include injection (subcutaneous, intravenous, parenteral, intraperitoneal, intrathecal), topical, oral, inhalation, rectal and transdermal.
• effective amount includes an amount effective to achieve the desired result, at dosages and for periods of time necessary.
• an effective amount of a compound can vary depending on factors such as the disease state, age and weight of the subject and the ability of the compound to elicit a desired response in the subject. Dosage regimens may be adjusted to provide the optimum therapeutic response.
• “Therapeutically effective amount” refers to the amount of the compound of the present application, which amount (i) treats or prevents a specific disease, condition or disorder, (ii) weakens, improves or eliminates one or more symptoms of a specific disease, condition or disorder, or (iii) preventing or delaying the onset of one or more symptoms of a particular disease, condition or disorder described herein.
• subject or “patient” as used herein refers to animals, such as mammals, including but not limited to primates (such as humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats , mice, etc. In certain embodiments, the subject is a human.
• inhibitor as used herein means to reduce the activity of the enzyme of interest as compared to the activity of the enzyme in the absence of the inhibitor.
• the term "inhibition" means that HPK1 activity is reduced by at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least about 50%, at least about 60%, at least about 70%, At least about 80%, at least about 90%, or at least about 95%; or about 5% to about 25%, about 25% to about 50%, about 50% to about 75%, or about 75% to 100% reduction in CO activity %; or 15-10 activity is reduced by about 95% to 100%, for example, the activity is reduced by 95%, 96%, 97%, 98%, 99% or 100%.
• Compounds of the Invention The present invention provides a series of compounds having HPK1 inhibitory activity.
• the compound of the present invention can increase or restore the expression or production of interferon in the subject, thereby enhancing the immunity of the subject, and then treating and/or preventing diseases.
• the HPK1 inhibitory compound of the present invention can enhance the antiviral effect mediated by IFN- ⁇ and/or enhance the activation of T cells mediated by IFN- ⁇ , thereby being able to treat and/or prevent viral infection.
• the HPK1 inhibitory active compounds of the present invention can also be used to enhance the immunity of a subject.
• the present invention provides the compound shown in formula I, Each substituent in the formula is as described above.
• the compound of the present invention may be a compound represented by formula 1-2-1, formula 1-2-2 or formula 1-2-3:
• the compounds of the present invention may form pharmaceutically acceptable salts, such as organic or inorganic salts formed by the compounds of the present invention.
• Exemplary salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate , Lactate, Salicylate, Acid Citrate, Tartrate, Oleate, Tannin, Pantothenate, Bitartrate, Ascorbate, Succinate, Maleate, Gentiana salt, fumarate, gluconate, glucuronate, sugar salt, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, bishydroxyl catalate (i.e.
• I,r-methylene-bis-(2-hydroxy-3-carboxylate) salt alkali metal (e.g. sodium and potassium) salts, alkaline earth metal (e.g. Magnesium) salt and Hyun salt.
• a pharmaceutically acceptable salt may involve the inclusion of another molecule such as acetate, succinate or other counterion.
• the counterion can be any organic or inorganic moiety which stabilizes the charge on the parent compound.
• pharmaceutically acceptable salts can have more than one charged atom in their structure. In instances where multiple charged atoms are part of a pharmaceutically acceptable salt, the salt can have multiple counterions. Thus, a pharmaceutically acceptable salt may have one or more charged atoms and/or one or more counterions.
• the compounds of the invention may also form solvates (eg, hydrates).
• solvate refers to the physical association of a compound with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In some cases, solvates will be capable of isolating, for example when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. Exemplary solvates include hydrates, ethanolates, methanolates, isopropanolates, acetonitrile solvates, and ethyl acetate solvates. Solvation methods are known in the art. The compounds of the present invention are metabolized in vivo.
• metabolites that is, products produced by metabolizing specific compounds or their salts in vivo should also be included in the protection scope of the present invention.
• the compound of the present invention can also be made into a “prodrug” or “prodrug”, that is, a compound of a drug precursor, which, when administered to a subject, undergoes a chemical transformation through a metabolic or chemical process to obtain a compound of formula I or a salt thereof .
• Prodrugs are well known in the art (see, e.g., Berge et al. (1977) "Pharmaceutical Salts w , J. Pharm. Sci.
• esters of the present invention may also form esters and esters are therefore also within the scope of this application within.
• Representative examples of specific esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates, and ethyl succinates.
• the compounds of the present application are intended to include those present in the compounds of the present application All isotopes of the atoms.
• the isotopes of hydrogen include S (D) and Ni (T).
• the isotopes of carbon include 13C and 14C.
• the compound of the application of isotope labeling can usually be passed through conventional techniques known to those skilled in the art or by Similar to the method described in this application, it is prepared by using an appropriate isotope-labeled reagent instead of an unlabeled reagent used in other cases.
• the term "derivative" refers to an atom or atomic group in the molecule of the parent compound that is replaced by other atoms or atomic groups. Substitute the resulting compound.
• Interferon-Related Diseases as described herein refer to diseases that can be treated and/or prevented by increasing or restoring interferon expression or production in a subject by administering the compounds of the present invention.
• the interferon is IFN- ⁇ and/or IFN- ⁇ ; therefore, the compound of the present invention can be used as an enhancer of IFN- ⁇ and/or IFN- ⁇ signaling pathway, while the "Interferon-associated disease" also includes all viral infections to which IFN-p/IFN- ⁇ has a therapeutic and/or preventive effect.
• the interferon-associated disease is a viral infection including but not limited to hepatitis B Virus
• Hepatitis B virus Measles Virus > Sindbis Virus > West Nile Virus, Dengue Virus Herpes Simplex Virus Human Cytomegalovirus Cytomegalovirus (HCMV) > Ebola Virus, Hepatitis C Virus (HCV), Influenza A Virus > Severe Acute Respiratory Syndrome Virus (SARS-CoV), Zika Virus > HIV ( HIV), Feline Infectious Peritonitis Virus > Mouse Hepatitis Virus > Canine Coronavirus, Feline Calicivirus, Feline Leukemia Virus, Feline Immunodeficiency Virus, Feline Panleukopenia Virus, Avian Infectious Bronchitis Virus, Transmissible Gastroenteritis Virus, Porcine Epidemic Diarrhea virus (Porcine Epidemic Diarrhea Virus), porcine hemagglutinating encephalomyelitis virus (Porcine Hemagglutinating Encephalomyelitis Virus), bovine
• compositions Given that the compounds of the present invention can treat interferon-related diseases, the compounds of the present invention can be formulated into pharmaceutical compositions.
• the compound of the present invention or its pharmaceutically acceptable salt, solvate, stereoisomer, tautomer, prodrug, metabolite or derivative and optionally pharmaceutically acceptable excipients.
• pharmaceutically acceptable means that the described compound, substance, composition and/or dosage form are suitable for use in contact with human and animal tissues without causing excessive toxicity, irritation, allergy reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
• excipient refers to a carrier, excipient or stabilizer that is nontoxic to cells or mammals at the dosages and concentrations employed.
• Non-limiting examples include buffers, such as phosphate, citrate, and other organic acids; antioxidants, including ascorbic acid; low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins proteins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides and other carbohydrates (including glucose , mannose or dextrin); chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and/or nonionic surfactants such as TWEEWM, polyethylene glycol (PEG) and PLURONICSTM o
• the pharmaceuticallycerolidone such as
• the compounds of the present invention can treat interferon-related diseases, especially viral infections. Therefore, in addition to the compound of the present invention, the pharmaceutical composition of the present invention may also contain one or more other antiviral drugs, so as to enhance the curative effect of the pharmaceutical composition. Advantages of the present invention:
• the present invention provides a novel highly active and highly selective HPK1 small molecule inhibitor
• the present invention clarifies for the first time the internal mechanism connection between HPK1 kinase and viral infection
• HPK1 small-molecule inhibitor of the present invention can be used as a monotherapy to exhibit antiviral effects at the level of cells and animal models, thereby laying a new material foundation for the development of interferon-related diseases, especially drugs for viral infections;
• HPK1 small molecule inhibitor of the present invention can be used as an adjuvant/combined drug to improve immunity and exhibit antiviral effects at the level of cells and animal models, thus laying a new foundation for the development of interferon-related diseases, especially drugs for viral infections material basis.
• the technical solutions of the present invention are further described below in conjunction with specific implementation cases, but the following implementation cases do not constitute limitations to the present invention, and all the various application methods adopted according to the principles and technical means of the present invention belong to the scope of the present invention.
• the experimental methods in the following examples that do not specify specific conditions are generally in accordance with conventional conditions, or in accordance with the conditions suggested by the manufacturer. Percentages and parts are by weight unless otherwise indicated. Examples Example 1. Synthesis of compounds of the present invention
• the target compound DD02008H was obtained as a yellow solid (71.94 mg, 183 umoh 40.9% yield, 98.6% purity), the structure was confirmed by XH NMR, Confirmed by LCMS and HPLC.
• the mixture was slowly poured into 40.0 mL H 2 O with stirring, the pH was adjusted to about 8 with saturated NaHCCh, and then extracted with DCM ( 80.0 mL*3 ), and the organic layer was washed with brine ( 50.0 mL*2) , dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, the obtained crude product was purified by preparative high-performance liquid chromatography, the obtained material was adjusted to about pH 8 with saturated NaHCO 3 , extracted with DCM (40.0 mL*4), and washed with brine ( 40.0 mL*3) The organic layer was washed, dried over anhydrous Na 2 SO 4 , filtered, and concentrated to obtain the target product DD02018H (17.1 mg, 35.13 umol, 5.31% yield, 97.7% purity) as a light yellow solid with the structure Confirmed by XH NMR, LCMS and HPLC.
• % inhibition 100-(Signal cm pd-SignalAve_PC)/(SignalAve_vc-SignalAve_PC) x 100
• cmpd refers to the test compound
• PC refers to the positive control
• VC refers to the negative control.
• the positive control used in the HPK1 experiment was Sunitinib.
• Table 2. has listed the inhibitory ability of the compound described in each embodiment to HPK1 kinase activity
• LCMS showed that the compound 7_Cis was completely consumed, and the molecular weight of the target product was detected.
• Staurosporine MCE HY-15141 The initial concentration of all compounds tested was 10 pM, three-fold concentration serial dilution, a total of 10 concentration points, and each concentration was repeated once.
• % inhibition 100-(Signal cm pd-SignalAve_PC)/(SignalAve_vc-SignalAve_PC) x 100
• cmpd refers to the test compound
• PC refers to the positive control
• VC refers to the negative control.
• DD02001A_trans is effective against most kinases, such as AKT1, HER2, EGFR, ERK1/2, ZAP70, IGF1R, ATR, MNK1/2, R0S1, CDK4, CDK7, CDK12, p38-alpha, IKK-beta, CKlgammal, etc. at 10 pM No obvious inhibitory effect was shown at the concentration (inhibition rate ⁇ 40%), but highly selective inhibition of immune-related protein kinases shown in Table 6, indicating that compound DD02001A_trans has excellent kinase inhibitory selectivity.
• DD02001A_trans 2000 > 1500, 1000, 500 mg/kg
• mice purchased from Guangdong Experimental Animal Center, license number: SCXK (Guangdong) 2018-0002), 10 mice, half male and half male. After the mice weighing 18-22 g o were purchased, the mice were reared for three days to adapt to the environment. Mice were housed in indoor cages at a room temperature of 23 ⁇ 1 °C, relative humidity of 40%-60%, and free access to food and drink.
• mice were fasted without food and water for 10 hours before the experiment. Give the mice a one-time gavage of the test drug (0.1ml/10g) at each concentration, observe continuously for 14 days, and record in detail the poisoning symptoms of the animals after administration, the time of occurrence and duration of poisoning, and the death of the animals; Carry out autopsy in time and record the pathological changes. If obvious changes are observed with the naked eye, pathological biopsy should be performed. According to the results of acute toxicity experiments, the maximum tolerated dose of DD02001A_trans administered to mice is in the range of 1000-1500 mg/kg. Example 2.
• Interferon P is a protein encoded by the IFNB1 gene. Natural or recombinant IFN- ⁇ protein has antiviral, antibacterial and anticancer activities.
• HPK1 and IFN- ⁇ Luciferase Reporter plasmids were overexpressed in HEK293 cells, the cells were stimulated with Sendai virus (SeV) 24 hours after transfection, and harvested 12 hours later Cells were collected for IFN-P Luciferase activity test.
• Sendai virus Sendai virus
• ISRE IFN-stimulated response elements
• IFN-stimulated response elements can be combined with phosphorylated IRF3 to mediate IFN-P transcription, which is another important indicator of the antiviral pathway.
• Different doses of HPK1 and ISRE Luciferase Reporter plasmids were overexpressed in HEK293 cells, the cells were stimulated with Sendai virus (SeV) 24 hours after transfection, and the cells were collected 12 hours later for ISRE Luciferase activity test.
• SeV Sendai virus
• compound C2 exhibited a dose-dependent restoration of HPK1-inhibited IFN-8 expression ( Figure 5) o Example 5.
• the oral maximum tolerated dose of the compound of the present invention The inventors tested the oral maximum tolerance of representative compounds in mice received dose. The test results showed that the maximum tolerated oral dose of compound C1 in a single administration was 337.5 mg/kg (Table 2), and the maximum tolerated oral dose of compound C3 was 225 mg/kg (Table 3). Table 2. Oral acute toxicity test results of small molecule compound C1 in mice. Table 3. Oral acute toxicity test results of small molecule compound C3 in mice. Example 6.
• mice of the present invention effectively treat mouse MHV models
• MHV mouse Hepatitis virus
• MHV is a mouse coronavirus that easily infects the liver and nervous system. 8-week-old female C57 mice, 3 mice in each group, were orthotopically injected with 4*10 4 pfu virus in the liver. After the virus was inoculated, the mice were administered orally (10 mg/kg, BID ) . Three days after the virus infection, the virus content in the liver tissue was detected by qPCR.
• Example 7 The compounds of the present invention are effective in the treatment of Feline Infectious Peritonitis (FIP), referred to as Feline Infectious Peritonitis (FIP), which is a fatal abnormal immune response in cats, and is caused by feline coronaviruses carried by cats.
• FIP Feline Infectious Peritonitis
• FIP farnesoid fever
• wet FIP wet FIP
• dry FIP dry FIP Symptoms in cats with FIP vary, depending on the type of organ affected by the virus. As of 2011, FIP has ranked first among pet cat fatal infectious diseases in developed countries.
• HPK1 inhibitors can carry out anti-infection treatment from the two dimensions of IFN- ⁇ -mediated antiviral effect and IFN- ⁇ -mediated T cell activation. Therefore, HPK1 inhibitors have therapeutic effects on human or animal diseases caused by all viruses with IFN-B/IFN-v effects, including but not limited to: Hepatitis B virus, Measles Virus > Sindbis Virus > West Nile Virus > Dengue Virus > Herpes Simplex Virus > Human Cytomegalovirus HCMV, Ebola Virus ), Hepatitis C Virus (HC V) > Influenza A Virus. Severe Acute Respiratory Syndrome Virus (SARS-CoV).
• SARS-CoV Severe Acute Respiratory Syndrome Virus
• Zika Virus Zika Virus (Zika Virus), HIV (HIV), Feline Infectious Virus (Feline Infectious Peritonitis Virus > Mouse Hepatitis Virus > Canine Coronavirus, Feline Calicivirus, Feline Leukemia Virus, Feline Immunodeficiency Virus, Cat Feline Panleukopenia Virus, Avian Infectious Bronchitis Virus, Transmissible Gastroenteritis Virus, Porcine Epidemic Diarrhea Virus, Porcine Hemagglutinating Encephalomyelitis Virus (Porcine Hemagglutinating Encephalomyelitis Virus), Bovine Coronavirus (Bovine Coronavirus), etc.
• HPK1 inhibitors are expected to be used as a new type of broad-spectrum antiviral therapy for the treatment of the above-mentioned virus-induced diseases. All documents mentioned in this application are incorporated by reference in this application as if each were individually incorporated by reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art may make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

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