WO2019127008A1 - Composé de dégradation ciblée de btk et son application - Google Patents

Composé de dégradation ciblée de btk et son application Download PDF

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Publication number
WO2019127008A1
WO2019127008A1 PCT/CN2017/118595 CN2017118595W WO2019127008A1 WO 2019127008 A1 WO2019127008 A1 WO 2019127008A1 CN 2017118595 W CN2017118595 W CN 2017118595W WO 2019127008 A1 WO2019127008 A1 WO 2019127008A1
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group
alkyl
compound
independently
integer
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PCT/CN2017/118595
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Chinese (zh)
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饶燏
刘万里
孙永汇
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清华大学
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    • 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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • 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

Definitions

  • the present invention relates to the field of biomedicine, and in particular, to a compound that targets degradation of BTK and uses thereof.
  • Non-Hodgkin's lymphoma is a blood system cancer that is a general term for all lymphomas except Hodgkin's lymphoma. In the United States, the lives of 2.1% of the population are affected. In 2015, 4.3 million people had non-Hodgkin's lymphoma and 23,400 were killed. Most clinical non-Hodgkin's lymphomas are B-cell type, accounting for 70%-85% of the total. Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin's lymphoma (NHL), with 7-8 out of 100,000 people per year in the United States and the United Kingdom.
  • DLBCL Diffuse large B-cell lymphoma
  • Ibrutinib is an FDA-approved drug for the treatment of chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and Walden's macroglobulinemia indication (WM). It has also been reported that ibrutinib can effectively inhibit the proliferation of some types of DLBCL.
  • the mechanism by which Ibrutinib plays a role is to covalently crosslink the thiol structure of the BTK protein at position 481 of the BTK protein in the cell, thereby depriving BTK of the function of phosphorylating the downstream signaling protein, thereby exerting anti-cell proliferation. The role.
  • ibrutinib shows a strong inhibitory activity against BTK kinase
  • the drug itself has a strong off-target effect and causes many side effects.
  • the IC 50 value for EGFR is 5.6 nM, which can cause severe diarrhea and rash
  • the IC 50 value for ITK is 10.7 nM, which can cause loss of natural killer cell function
  • the IC 50 value for TEC is 78 nM, which can cause coagulation defects.
  • BTK kinase C481S mutation can cause a significant decrease in the sensitivity of the cell line to ibrutinib.
  • BTK by Lu imatinib for their ability to inhibit autophosphorylation IC 50 decreased from 2.2nM to 1 ⁇ M.
  • the structures at both ends are linked by a linker to form a complete compound molecule.
  • the compound has strong anti-degradation effect on wild-type BTK, and has good degradation effect on BTK of C481S or C481A mutation (DC 50 ⁇ 30nM), and has no specificity or inhibition on other targets such as EGFR, ITK, TEC, etc.
  • the efficacy of targeting BTK proteins is not limited to EGFR, ITK, TEC, etc.
  • the invention proposes a compound.
  • the compound is a compound of the formula I or a stereoisomer, a geometric isomer, a tautomer, an oxynitride, a hydrate, a solvate, a metabolite, or a pharmaceutically Acceptable salts or prodrugs:
  • the X is
  • the Z is:
  • the Y is:
  • Each R a is independently hydrogen, C 1-4 alkyl, halo C 1-4 alkyl, C 1-4 alkyl acyl or hydroxy;
  • Each t2 is independently 0, 1, 2, 3 or 4;
  • Each t1 is independently 0, 1 or 2;
  • Each of X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , Q, W is independently C, O, S, N or Se;
  • Each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , B is independently H, hydrazine, C 1-4 alkyl, C 1-4 heteroalkyl, C 3-8 cycloalkyl, C 2-10 a heterocyclic group, a C6-10 aryl group, a C1-9 heteroaryl group, a C6-10 aryl group, a C1-4 alkoxy group, wherein the C1-4 alkyl group, the C1-4 heteroalkyl group, the C3- 8-cycloalkyl, C2-10 heterocyclyl, C6-10 aryl, C1-9 heteroaryl, C6-10 aryl C1-4 alkoxy, optionally optionally selected from hydrazine, Hydroxy, amino, oxo, F, Cl, Br, I, cyano, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 aminoalkyl, C1-6 alkoxy C1-6 alkyl, C1-6 al
  • Each A is independently hydrogen, C1-4 alkyl, C1-4 haloalkyl, hydroxy, nitro, amino, cyano, halogen, carboxy, C1-4 alkoxy, C1-4 alkylamino, C1-4 alkyl sulphide a C1-4 alkyl group, an optionally substituted C3-12 cycloalkyl group, an optionally substituted C3-9 heterocyclic group, an optionally substituted C6-12 aryl group, an optionally substituted C1-9 heteroaryl group base,
  • Each E is independently an amide group, an ester group, an aminomethyl group, a ureido group, a fluorenyl group, a heterocyclic group, a cycloalkyl group, a spiro heterobicyclic group, a fused heterobicyclic group, a bridged bicyclic group, and a C6-10 aryl group. Or a C2-C10 heteroaryl; each E is optionally substituted with 1, 2, 3 or 4 independent R b ;
  • Each R b is independently hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, hydroxy, nitro, amino, cyano, halo, carboxy, C 1-4 alkoxy, C 1-4 alkylamino, C 1-4 Alkylthio, C1-4 alkyl acyl, C3-12 cycloalkyl, C3-9 heterocyclic, C6-12 aryl, C1-9 heteroaryl, amino C1-4 alkyl, hydroxy C1-4 alkane a group, a sulfonic acid group, an aminosulfonyl group or an amino group;
  • Each of a, b, c, and d is independently an integer between 0 and 30.
  • the compounds according to the examples of the present invention have a strong effect on the degradation of wild-type BTK, and have a good degradation effect on BTK of C481S or C481A mutations (DC 50 ⁇ 30 nM), and have no inhibition or degradation to other targets such as EGFR, ITK, TEC, and the like. The effect is to specifically target the degradation of BTK protein.
  • the above compound may further include at least one of the following additional technical features:
  • each L 1 is independently a bond, -O-, -S-, -NH-,
  • Each R a is independently hydrogen, C 1-2 alkyl, halo C 1-2 alkyl, C 1-2 alkyl acyl or hydroxy,
  • Each of R 1 , R 2 , R 3 and R 4 is independently H, amino, C 1-4 alkyl, C 1-4 heteroalkyl, C 5-7 cycloalkyl, C 5-7 heterocyclyl, C 6-7 aryl. a C5-7 heteroaryl group, wherein the C1-4 alkyl group, the C1-4 heteroalkyl group, the C5-7 cycloalkyl group, the C5-7 heterocyclic group, the C6-7 aryl group, the C5-7 hetero
  • the aryl group can be optionally substituted with one or more substituents selected from the group consisting of hydrazine, hydroxy, amino, oxo, F, Cl, Br, I, cyano.
  • the X is a compound as shown below:
  • each A is independently hydrogen, optionally substituted C5-7 heterocyclyl, optionally substituted C5-7 cycloalkyl, optionally substituted C6-7 aryl, optionally substituted C5 -7 heteroaryl,
  • Each R 5 and B are independently H, amino, C 1-4 alkyl, C 1-4 heteroalkyl, C 5-7 cycloalkyl, C 5-7 heterocyclic, C 6-7 aryl, C 5-7 heteroaryl a group wherein the C1-4 alkyl group, C1-4 heteroalkyl group, C5-7 cycloalkyl group, C5-7 heterocyclic group, C6-7 aryl group, C5-7 heteroaryl group may be optionally One or more selected from the group consisting of hydrazine, hydroxy, amino, oxo, F, Cl, Br, I, cyano, C5-7 aryl, C5-7 heteroaryl, halogen substituted C5-7 aryl, halogen substituted C5 Substituent substitution of a -7heteroaryl, halogen-substituted C5-7 heterocyclyl;
  • Each R a is independently hydrogen, C 1-2 alkyl, halo C 1-2 alkyl, C 1-2 alkyl acyl or hydroxy,
  • Each R 6 is independently hydrogen, amino, hydroxy, nitro, amino, cyano, halogen, carboxy.
  • the A is a
  • the B is
  • each R c is independently H, C 1-4 alkyl, halo C 1-4 alkyl, C 1-4 alkyl acyl or hydroxy.
  • the Z is a compound as shown below:
  • each E is independently an amide group, an ester group, an aminomethyl group, a ureido group, a fluorenyl group, a heterocyclic group, a cycloalkyl group, a C6-C8 aryl group or a C5-C7 heteroaryl group; E is optionally replaced by 1, 2, 3 or 4 independent R b ,
  • Each R b is independently hydrogen, C 1-2 alkyl, C 1-2 haloalkyl, hydroxy, nitro, amino, cyano, halo, carboxy, C 1-2 alkoxy, C 1-2 alkylamino, C 1-2 Alkylthio, C1-2 alkyl acyl, C5-7 cycloalkyl, C5-7 heterocyclyl, C6-7 aryl, C5-7 heteroaryl, amino C1-2 alkyl, hydroxy C1-2 alkane Base, sulfonic acid group, aminosulfonyl group or aminoacyl group,
  • Each a is an integer between 0 and 10,
  • Each b is an integer between 0 and 20,
  • Each c is an integer between 0 and 20,
  • Each d is an integer between 0 and 10,
  • Each R a is independently hydrogen, C 1-2 alkyl, halo C 1 -, 2 alkyl, C 1-2 alkyl acyl or hydroxy.
  • the Y is
  • each e and f are independently an integer between 0 and 30;
  • Each R a is independently hydrogen, C 1-2 alkyl, halo C 1-2 alkyl, C 1-2 alkyl acyl or hydroxy;
  • Each t2 is independently 0, 1, 2, 3 or 4;
  • Each t1 is independently 0, 1, or 2.
  • the X is
  • the Z is
  • the Y is
  • the compound of any one of Formulas II to IX, or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmacy thereof, is included.
  • n1 is an integer between 1 and 6
  • n2 is an integer between 0 and 6
  • n3 is between 1 and 26.
  • An integer, m3 is an integer between 2 and 20, and n4 is an integer between 0 and 6.
  • the invention proposes a compound.
  • a compound which is a compound of any one of Formulas 1 to 18, or a stereoisomer, geometric isomer, tautomer, oxynitride, hydrate, solvate, metabolite thereof, a pharmaceutically acceptable salt or prodrug,
  • the compounds according to the examples of the present invention have a strong effect on the degradation of wild-type BTK, and have a good degradation effect on BTK of C481S or C481A mutations (DC 50 ⁇ 30 nM), and have no inhibition or degradation to other targets such as EGFR, ITK, TEC, and the like.
  • the effect is to specifically target the degradation of BTK protein.
  • the invention proposes a pharmaceutical composition.
  • the pharmaceutical composition comprises a compound as described above.
  • the pharmaceutical composition according to the embodiment of the present invention has a strong effect on degradation of wild-type BTK, and has good degradation effect on BTK of C481S or C481A mutation (DC 50 ⁇ 30 nM), and has no inhibition on other targets such as EGFR, ITK, TEC, and the like. Or degradation, with the specific ability to target the degradation of BTK protein.
  • the above pharmaceutical composition further comprises at least one of the following additional technical features:
  • the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or a combination thereof.
  • the pharmaceutical composition further includes other drugs for treating or preventing non-Hodgkin's lymphoma, and the other drug for treating or preventing non-Hodgkin's lymphoma includes ibrutinib.
  • the above pharmaceutical composition has a strong effect on the degradation of wild-type BTK, and has a good degradation effect on BTK of C481S or C481A mutation (DC50 ⁇ 30 nM), and has no inhibition or degradation to other targets such as EGFR, ITK, TEC, and the like. Role, with the specific ability to target BTK protein. And in combination, it is better for treating or preventing non-Hodgkin's lymphoma.
  • the invention provides the use of a compound as described above or a pharmaceutical composition as described above for the preparation of a medicament.
  • the medicament is for degrading BTK or inhibiting BTK.
  • the compound or pharmaceutical composition according to an embodiment of the present invention has a strong effect on degradation of wild-type BTK, and has a good degradation effect on BTK of C481S or C481A mutation (DC50 ⁇ 30 nM), and has no target for other targets such as EGFR, ITK, TEC, etc. Inhibition or degradation, with the specific ability to target BTK protein.
  • the invention provides the use of a compound as described above or a pharmaceutical composition as described above for the preparation of BTK.
  • the compound or pharmaceutical composition according to an embodiment of the present invention has a strong effect on degradation of wild-type BTK, and has a good degradation effect on BTK of C481S or C481A mutation (DC50 ⁇ 30 nM), and has no target for other targets such as EGFR, ITK, TEC, etc. Inhibition or degradation, with the specific targeting of the degradation of BTK protein.
  • the invention provides the use of a compound as described above or a pharmaceutical composition as described above for the preparation of a medicament.
  • the medicament is for the treatment or prevention of a BTK-related disease.
  • the compound or pharmaceutical composition according to an embodiment of the present invention has a strong effect on degradation of wild-type BTK, and has a good degradation effect on BTK of C481S or C481A mutation (DC50 ⁇ 30 nM), and has no target for other targets such as EGFR, ITK, TEC, etc. Inhibition or degradation, with the specific targeting of the degradation of BTK protein.
  • the above use further comprises at least one of the following additional technical features:
  • the BTK-related disease is non-Hodgkin's lymphoma.
  • the inventors have found that the above compounds or pharmaceutical compositions are more effective for non-Hodgkin's lymphoma of BTK-related diseases.
  • the invention provides the use of a compound as described above or a pharmaceutical composition as described above for anti-tumor.
  • a compound or pharmaceutical composition according to an embodiment of the present invention has a certain degree of prophylactic or therapeutic effect on a tumor.
  • the above use further comprises at least one of the following additional technical features:
  • the tumor is a lymphoma.
  • a compound or pharmaceutical composition according to an embodiment of the present invention is superior to other tumors in preventing or treating lymphoma.
  • the lymphoma is a non-Hodgkin's lymphoma.
  • the inventors have found that the compounds or pharmaceutical compositions described above are highly effective against wild-type BTK degradation and have a good degradation effect on BTK of C481S or C481A mutations (DC50 ⁇ 30 nM), and for other targets such as EGFR, ITK, TEC, etc. No inhibition or degradation, with the specific ability to target the degradation of BTK protein.
  • the compound or pharmaceutical composition according to an embodiment of the present invention is more effective in treating or preventing non-Hodgkin's lymphoma.
  • the invention provides a method of treating a tumor.
  • the compound described above or the pharmaceutical composition described above is administered to a patient.
  • a compound or pharmaceutical composition according to an embodiment of the present invention has a certain degree of prophylactic or therapeutic effect on a tumor.
  • the above method further comprises at least one of the following additional technical features:
  • the tumor is a lymphoma.
  • a compound or pharmaceutical composition according to an embodiment of the present invention is superior to other tumors in preventing or treating lymphoma.
  • the lymphoma is a non-Hodgkin's lymphoma.
  • the inventors have found that the compounds or pharmaceutical compositions described above are highly effective against wild-type BTK degradation and have a good degradation effect on BTK of C481S or C481A mutations (DC50 ⁇ 30 nM), and for other targets such as EGFR, ITK, TEC, etc. No inhibition or degradation, with the specific ability to target the degradation of BTK protein.
  • the compound or pharmaceutical composition according to an embodiment of the present invention is more effective in treating or preventing non-Hodgkin's lymphoma.
  • the invention provides a general procedure for the synthesis of a compound of formula I.
  • the compound of the formula I can be linked by a click reaction or an amide condensation reaction between a Pomalidomide or a Lenanidomide or an RG-7112-terminal derivative and an Ibrutinib-terminal derivative, as shown in FIG.
  • the preparation method of the Pomalidomide terminal derivative can be referred to the literature Chemistry & Biology 22, 755-763 (2015).
  • the preparation method of the Lenalidomide terminal derivative can be referred to J. Med. Chem (DOI: 10.1021/acs.jmedchem.
  • the preparation method of the terminal derivative can be referred to Bioorg. Med. Chem. Lett. 18, 5904-5908 (2008). ACS Med. Chem. Lett. 4, 466-469 (2013).
  • the synthetic route of the Ibrutinib derivative can be referred to Patent PCT Int. Appl., 2013003629, 03Jan 2013.
  • the terminal alkyne required for Click chemistry is attached to the piperidine ring of the Ibrutinib core by an amide condensation reaction, and the preparation method can be referred to J. Chem. Inf. Model. 50, 446 (2010). PCT Int. Appl., 2013170115, 14Nov 2013.
  • FIG. 2 is a schematic view showing the construction of Formula I by a click reaction and an amide condensation reaction according to an embodiment of the present invention
  • Figure 3 is a graph showing the degradation of BTK by the compound of Formula 1 according to an embodiment of the present invention.
  • Figure 4 is a graph showing the degradation of BTK by the compounds of Formula 12 and Formula 13 according to an embodiment of the present invention
  • Figure 5 is a graph showing the degradation of BTK by the compounds of Formula 16 and Formula 17 according to an embodiment of the present invention.
  • Figure 6 is a graph showing the degradation of BTK by the compound of Formula 1 at different time of action according to an embodiment of the present invention
  • Figure 7 ( Figure 7-1, Figure 7-2, Figure 7-3) is the degradation of the compound BTK of Formula 1 according to an embodiment of the present invention affected by other compounds;
  • Figure 8 ( Figure 8-1, Figure 8-2, Figure 8-3) is a compound of Formula 1, Formula 2, Formula 3, and Formula 4 in different cell lines (HBL-1, IgE MM) according to an embodiment of the present invention. , Mino) degradation of BTK;
  • Figure 9 ( Figure 9-1, Figure 9-2, Figure 9-3) is a degradation of the C481S or C481A mutant BTK by a compound of Formula 1 according to an embodiment of the present invention
  • Figure 10 is a graph showing the degradation of other proteins (EGFR, FLT-3, ITK, TEC) by the compound of Formula 1 according to an embodiment of the present invention.
  • Figure 11 is a graph showing the inhibitory effect of the compound of Formula 1 on various proteins (BTK, EGFR, ITK) according to an embodiment of the present invention.
  • the term "administered to a patient as described above, or a stereoisomer, geometric isomer, tautomer, oxynitride, hydrate, solvate, metabolite, pharmaceutically acceptable, is pharmaceutically acceptable.
  • the salt or prodrug or the pharmaceutical composition described above means that a predetermined amount of the substance is introduced into the patient by some suitable means.
  • the composition can be administered by any conventional route as long as it can reach the intended tissue.
  • the invention is not limited to these exemplary modes of administration.
  • the active ingredient of the orally administered composition should be coated or formulated to prevent its degradation in the stomach.
  • the compounds of formula I of the invention or the pharmaceutical compositions can be administered using specific devices that deliver the active ingredients to target cells.
  • the frequency and dosage of the pharmaceutical composition of the present invention can be determined by a number of relevant factors including the type of disease to be treated, the route of administration, the age, sex, weight and severity of the disease as well as the active ingredient. Type of drug.
  • &quot refers to an amount of a compound that is sufficient to significantly ameliorate certain symptoms associated with a disease or condition, i.e., an amount that provides a therapeutic effect for a given condition and dosage regimen.
  • a therapeutically effective amount of a drug or compound does not require a cure for the disease or condition, but will provide a treatment for the disease or condition such that the onset of the disease or condition of the individual is delayed, prevented or prevented, or the symptoms of the disease or condition are alleviated, or the disease or The duration of the condition is altered, or for example the disease or condition becomes less severe, or the recovery is accelerated.
  • treatment is used to mean obtaining the desired pharmacological and/or physiological effect.
  • the effect may be prophylactic in terms of completely or partially preventing the disease or its symptoms, and/or may be therapeutic in terms of partially or completely curing the disease and/or the adverse effects caused by the disease.
  • treatment encompasses the treatment of a disease in a mammal, particularly a human, including: (a) preventing the occurrence of a disease or condition in an individual who is susceptible to the disease but has not yet been diagnosed; (b) inhibiting the disease; or (c) Relieve diseases, such as alleviating symptoms associated with the disease.
  • treatment encompasses any administration of a medicament or compound to an individual for the treatment, cure, amelioration, amelioration, alleviation or inhibition of a disease in an individual, including but not limited to the inclusion of a compound or combination of compounds of Formula I or Formula II described herein. The individual is given to the individual in need.
  • the excipients include pharmaceutically acceptable excipients, lubricants, fillers, diluents, disintegrants, stabilizers, preservatives, emulsifiers, solubilizers, colorants well known in the formulation arts. , sweetener, made into tablets, pills, capsules, injections and other different dosage forms.
  • a component refers to one or more components, that is, there may be more than one component contemplated for use or use in embodiments of the embodiments.
  • Stereoisomer refers to a compound that has the same chemical structure but differs in the way the atoms or groups are spatially aligned. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotomers), geometric isomers (cis/trans) isomers, atropisomers, etc. .
  • “Chirality” is a molecule that has properties that cannot overlap with its mirror image; “non-chiral” refers to a molecule that can overlap with its mirror image.
  • Enantiomer refers to two isomers of a compound that are not superimposable but are mirror images of each other.
  • Diastereomer refers to a stereoisomer that has two or more centers of chirality and whose molecules are not mirror images of each other. Diastereomers have different physical properties such as melting point, boiling point, spectral properties and reactivity. The mixture of diastereomers can be separated by high resolution analytical procedures such as electrophoresis and chromatography, such as HPLC.
  • optically active compounds Many organic compounds exist in optically active forms, i.e., they have the ability to rotate a plane of plane polarized light.
  • the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to one or more of its chiral centers.
  • the prefixes d and l or (+) and (-) are symbols for specifying the rotation of plane polarized light caused by the compound, wherein (-) or l indicates that the compound is left-handed.
  • Compounds prefixed with (+) or d are dextrorotatory.
  • a particular stereoisomer is an enantiomer and a mixture of such isomers is referred to as a mixture of enantiomers.
  • a 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.
  • any asymmetric atom (e.g., carbon, etc.) of the compounds disclosed herein may exist in racemic or enantiomerically enriched form, such as the (R)-, (S)- or (R, S)-configuration presence.
  • each asymmetric atom has at least 50% enantiomeric excess in the (R)- or (S)-configuration, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.
  • the compounds of the invention may be one of the possible isomers or mixtures thereof, such as racemates and mixtures of diastereomers (depending on the number of asymmetric carbon atoms) The form exists.
  • Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituent of the cycloalkyl group may have a cis or trans configuration.
  • the resulting mixture of any stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, for example, by chromatography, depending on the difference in physicochemical properties of the components. Method and / or step crystallization.
  • racemate of any of the resulting end products or intermediates can be resolved into the optical antipodes by methods known to those skilled in the art by known methods, for example, by obtaining the diastereomeric salts thereof. Separation. Racemic products can also be separated by chiral chromatography, such as high performance liquid chromatography (HPLC) using a chiral adsorbent.
  • HPLC high performance liquid chromatography
  • enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2 nd Ed. Robert) E.
  • tautomer or "tautomeric form” refers to structural isomers having different energies that are interconvertible by a low energy barrier. If tautomerism is possible (as in solution), the chemical equilibrium of the tautomers can be achieved.
  • proton tautomers also known as prototropic tautomers
  • Valence tautomers include interconversions by recombination of some bonding electrons.
  • keto-enol tautomerization is the interconversion of a pentane-2,4-dione and a 4-hydroxypent-3-en-2-one tautomer.
  • Another example of tautomerization is phenol-keto tautomerization.
  • a specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridine-4(1H)-one tautomers. All tautomeric forms of the compounds of the invention are within the scope of the invention unless otherwise indicated.
  • the compounds of the present invention may be optionally substituted with one or more substituents, such as the compounds of the above formula, or specific examples, subclasses, and inclusions of the present invention.
  • substituents such as the compounds of the above formula, or specific examples, subclasses, and inclusions of the present invention.
  • a class of compounds A class of compounds.
  • substituents such as the compounds of the above formula, or specific examples, subclasses, and inclusions of the present invention.
  • a class of compounds A class of compounds.
  • substituents such as the compounds of the above formula, or specific examples, subclasses, and inclusions of the present invention.
  • a class of compounds A class of compounds.
  • C1-6 alkyl specifically refers to independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.
  • linking substituents are described.
  • the Markush variable recited for that group is understood to be a linking group.
  • the definition of the Markush group for the variable is "alkyl” or "aryl”
  • the “alkyl” or “aryl” respectively represent the attached An alkylene group or an arylene group.
  • alkyl or "alkyl group” as used herein, denotes a saturated straight or branched monovalent hydrocarbon group containing from 1 to 20 carbon atoms, wherein the alkyl group may be optionally selected The ground is replaced by one or more substituents described herein. Unless otherwise specified, an alkyl group contains from 1 to 20 carbon atoms. In one embodiment, the alkyl group contains from 1 to 12 carbon atoms; in another embodiment, the alkyl group contains from 1 to 6 carbon atoms; in yet another embodiment, the alkyl group contains 1 - 4 carbon atoms; also in one embodiment, the alkyl group contains 1-3 carbon atoms.
  • alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr) , -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3) CH2CH3), tert-butyl (t-Bu, -C(CH3)3), n-pentyl (-CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3) 2) 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2)
  • alkylene means a saturated divalent hydrocarbon group derived by removing two hydrogen atoms from a saturated linear or branched hydrocarbon group. Unless otherwise specified, an alkylene group contains from 1 to 12 carbon atoms. In one embodiment, the alkylene group contains 1-6 carbon atoms; in another embodiment, the alkylene group contains 1-4 carbon atoms; in yet another embodiment, the alkylene group The group contains 1-3 carbon atoms; also in one embodiment, the alkylene group contains 1-2 carbon atoms. Examples of such include methylene (-CH2-), ethylene (-CH2CH2-), isopropylidene (-CH(CH3)CH2-) and the like.
  • alkenyl denotes a straight or branched chain monovalent hydrocarbon radical containing from 2 to 12 carbon atoms, wherein at least one site of unsaturation, i.e., has a carbon-carbon sp2 double bond, wherein the alkenyl group It may optionally be substituted by one or more of the substituents described herein, including the positioning of "cis” and “tans", or the positioning of "E” and "Z”.
  • the alkenyl group contains 2-8 carbon atoms; in another embodiment, the alkenyl group contains 2-6 carbon atoms; in yet another embodiment, the alkenyl group comprises 2 - 4 carbon atoms.
  • alkynyl means a straight or branched chain monovalent hydrocarbon radical containing from 2 to 12 carbon atoms, wherein at least one site of unsaturation, i.e., has a carbon-carbon sp triple bond, wherein the alkynyl group It may be optionally substituted with one or more of the substituents described herein.
  • the alkynyl group contains 2-8 carbon atoms; in another embodiment, the alkynyl group contains 2-6 carbon atoms; in yet another embodiment, the alkynyl group comprises 2 - 4 carbon atoms.
  • alkynyl groups include, but are not limited to, ethynyl (-C ⁇ CH), propargyl (-CH2C ⁇ CH), 1-propynyl (-C ⁇ C-CH3), and the like.
  • heteroalkyl denotes the insertion of one or more heteroatoms in the alkyl chain, wherein the alkyl group and heteroatom have the meaning as described herein.
  • a heteroalkyl group contains 2-10 carbon atoms, in other embodiments, a heteroalkyl group contains 2-8 carbon atoms, and in other embodiments, a heteroalkyl group contains 2 -6 carbon atoms, in other embodiments, the heteroalkyl group contains 2-4 carbon atoms, and in other embodiments, the heteroalkyl group contains 2-3 carbon atoms.
  • Such examples include, but are not limited to, CH3OCH2-, CH3CH2OCH2-, CH3SCH2-, (CH3)2NCH2-, (CH3)2CH2OCH2-, CH3OCH2CH2-, CH3CH2OCH2CH2-, and the like.
  • alkenylene means an alkene group derived by removing two hydrogen atoms from a linear or branched olefin. And the alkenylene group may be substituted or unsubstituted, wherein the substituent may be, but not limited to, anthracene, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkyl, Alkenyl, alkynyl, heterocyclyl, fluorenyl, nitro or aryloxy.
  • carbocyclylene denotes a saturated divalent hydrocarbon ring obtained by removing a single ring of 3 to 12 carbon atoms or a double ring of 7 to 12 carbon atoms by removing two hydrogen atoms.
  • carbocyclyl or cycloalkyl has the meaning as described herein, such examples include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, 1-cyclopent-1-ene Alkenyl, 1-cyclopent-2-enyl and the like.
  • heterocyclylene means a monocyclic, bicyclic or tricyclic ring system wherein one or more atoms on the ring are independently selected from heteroatoms and may be fully saturated or contain one or more unsaturations, but not It belongs to the class of aromatics and has two points of attachment to the rest of the molecule, wherein the heterocyclyl group has the meaning as described herein.
  • Such examples include, but are not limited to, piperidine-1,4-diyl, piperazine-1,4-diyl, tetrahydrofuran-2,4-diyl, tetrahydrofuran-3,4-diyl, aza Cyclobutane-1,3-diyl, pyrrolidine-1,3-diyl and the like.
  • alkoxy denotes an alkyl group attached to the remainder of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains from 1 to 12 carbon atoms. In one embodiment, the alkoxy group contains from 1 to 6 carbon atoms; in another embodiment, the alkoxy group contains from 1 to 4 carbon atoms; in yet another embodiment, the alkoxy group The group contains 1-3 carbon atoms. The alkoxy group can be optionally substituted with one or more substituents described herein.
  • alkoxy groups include, but are not limited to, methoxy (MeO, -OCH3), ethoxy (EtO, -OCH2CH3), 1-propoxy (n-PrO, n-propoxy, -OCH2CH2CH3), 2-propoxy (i-PrO, i-propoxy, -OCH(CH3)2), 1-butoxy (n-BuO, n-butoxy, -OCH2CH2CH2CH3), 2- Methyl-l-propoxy (i-BuO, i-butoxy, -OCH2CH(CH3)2), 2-butoxy (s-BuO, s-butoxy, -OCH(CH3)CH2CH3) , 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH3)3), 1-pentyloxy (n-pentyloxy, -OCH2CH2CH2CH2CH3), 2-pentyloxy (-OCH(CH3)CH2CH3
  • haloalkyl denotes an alkyl, alkenyl or alkoxy group substituted by one or more halogen atoms, examples of which include, but are not limited to, Trifluoromethyl, trifluoromethoxy, and the like.
  • hydroxyalkyl "hydroxy substituted alkyl” means that the alkyl group is substituted by one or more hydroxy groups, wherein the alkyl group has the meanings indicated herein. Such examples include, but are not limited to, hydroxymethyl, hydroxyethyl, 1,2-dihydroxyethyl, and the like.
  • Carbocyclyl or “carbocyclic” refers to a monovalent or polyvalent, non-aromatic, saturated or partially unsaturated monocyclic, bicyclic or tricyclic system containing from 3 to 12 carbon atoms.
  • Carbon bicyclic groups include spirocarbon bicyclic groups and fused carbon bicyclic groups, and suitable carbocyclic groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl.
  • Examples of the carbocyclic group further include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a 1-cyclopentyl-1-alkenyl group, a 1-cyclopentyl-2-alkenyl group, a 1-cyclopentyl group- 3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, cycloheptyl, cyclooctyl Base, cyclodecyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like.
  • cycloalkyl denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic system containing from 3 to 12 carbon atoms. In one embodiment, the cycloalkyl group contains 3 to 12 carbon atoms; in another embodiment, the cycloalkyl group contains 3 to 8 carbon atoms; in yet another embodiment, the cycloalkyl group contains 3 to 6 carbon atom.
  • the cycloalkyl group can be independently unsubstituted or substituted with one or more substituents described herein.
  • heterocyclyl and “heterocycle” are used interchangeably herein to refer to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring containing from 3 to 12 ring atoms, wherein at least one ring atom is selected from Nitrogen, sulfur and oxygen atoms.
  • a heterocyclic group can be a carbyl or a nitrogen group, and a -CH2- group can be optionally substituted with -C(O)-.
  • the sulfur atom of the ring can be optionally oxidized to an S-oxide.
  • the nitrogen atom of the ring can be optionally oxidized to an N-oxygen compound.
  • heterocyclic groups include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrroline, 3-pyrrolyl , pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothienyl, 1,3-dioxocyclopentyl, disulfide Pentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl , dioxoalkyl, dithiaalkyl, thiamethane, homopiperazinyl,
  • Examples of the -CH2- group in the heterocyclic group substituted by -C(O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidinyl , 3,5-dioxopiperidinyl and pyrimidindione.
  • Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, a sulfolane group and a 1,1-dioxothiomorpholinyl group.
  • the heterocyclyl group can be optionally substituted with one or more substituents described herein.
  • a heterocyclic group is a heterocyclic group consisting of 4-7 atoms, and refers to a saturated or partially unsaturated monocyclic ring containing 4-7 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen and sulfur. And oxygen atoms.
  • a heterocyclic group consisting of 4-7 atoms may be a carbon or a nitrogen group, and the -CH2- group may be optionally substituted by -C(O)-.
  • the sulfur atom of the ring can be optionally oxidized to an S-oxide.
  • the nitrogen atom of the ring can be optionally oxidized to an N-oxygen compound.
  • heterocyclic group consisting of 4-7 atoms include, but are not limited to, azetidinyl, oxetanyl, thioheterobutyl, pyrrolidinyl, 2-pyrroline, 3-pyrroline , pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothienyl, 1,3-dioxocyclopentyl, disulfide Cyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine Base, dioxoalkyl, dithiaalkyl, thiamethane, homopiperidine
  • Examples of the -CH2- group in the heterocyclic group substituted by -C(O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidinyl , 3,5-dioxopiperidinyl and pyrimidindione.
  • Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, a sulfolane group and a 1,1-dioxothiomorpholinyl group.
  • the heterocyclyl group of 4-7 atoms may be optionally substituted with one or more substituents described herein.
  • the heterocyclic group is a heterocyclic group consisting of 4 atoms, and refers to a saturated or partially unsaturated monocyclic ring containing 4 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur and oxygen atoms.
  • a heterocyclic group consisting of 4 atoms may be a carbon group or a nitrogen group, and a -CH2- group may be optionally substituted with -C(O)-.
  • the sulfur atom of the ring can be optionally oxidized to an S-oxide.
  • the nitrogen atom of the ring can be optionally oxidized to an N-oxygen compound.
  • heterocyclic group consisting of 4 atoms examples include, but are not limited to, azetidinyl, oxetanyl, thietanyl.
  • the heterocyclic group consisting of 4 atoms may be optionally substituted by one or more substituents described herein.
  • the heterocyclic group is a heterocyclic group consisting of 5 atoms, and refers to a saturated or partially unsaturated monocyclic ring containing 5 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur and oxygen atoms. .
  • a heterocyclic group consisting of 5 atoms may be a carbon group or a nitrogen group, and a -CH2- group may be optionally substituted by -C(O)-.
  • the sulfur atom of the ring can be optionally oxidized to an S-oxide.
  • the nitrogen atom of the ring can be optionally oxidized to an N-oxygen compound.
  • Examples of the 5-atomic heterocyclic group include, but are not limited to, pyrrolidinyl group, 2-pyrroline group, 3-pyrroline group, pyrazolinyl group, pyrazolidinyl group, imidazolinyl group, imidazolidinyl group, Tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothienyl, 1,3-dioxocyclopentyl, dithiocyclopentyl.
  • Examples of the -CH2- group in the heterocyclic group substituted by -C(O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl.
  • Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, a sulfolane group.
  • the heterocyclic group consisting of 5 atoms may be optionally substituted by one or more substituent
  • the heterocyclic group is a 6 atom heterocyclic group, and refers to a saturated or partially unsaturated monocyclic ring containing 6 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen atoms. .
  • a heterocyclic group consisting of 6 atoms may be a carbyl group or a nitrogen group, and the -CH2- group may be optionally substituted by -C(O)-.
  • the sulfur atom of the ring can be optionally oxidized to an S-oxide.
  • the nitrogen atom of the ring can be optionally oxidized to an N-oxygen compound.
  • heterocyclic group consisting of 6 atoms include, but are not limited to, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, Morpholinyl, thiomorpholinyl, piperazinyl, dioxoalkyl, dithiaalkyl, thiamethane.
  • Examples of the -CH2- group substituted by -C(O)- in the heterocyclic group include, but are not limited to, 2-piperidinone, 3,5-dioxopiperidinyl and pyrimidinone.
  • Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, a 1,1-dioxothiomorpholinyl group.
  • the 6 atomic heterocyclyl group may be optionally substituted with one or more substituents described herein.
  • the heterocyclic group is a heterocyclic group of 7 to 12 atoms, and refers to a saturated or partially unsaturated spirobicyclic or fused bicyclic ring containing 7 to 12 ring atoms, wherein at least one ring atom Selected from nitrogen, sulfur and oxygen atoms.
  • a heterocyclic group consisting of 7-12 atoms may be a carbon or a nitrogen group, and a -CH2- group may be optionally substituted by -C(O)-.
  • the sulfur atom of the ring can be optionally oxidized to an S-oxide.
  • the nitrogen atom of the ring can be optionally oxidized to an N-oxygen compound.
  • heterocyclic group consisting of 7 to 12 atoms examples include, but are not limited to, porphyrin group, 1,2,3,4-tetrahydroisoquinolyl group, 1,3-benzodioxanyl group, 2- Oxa-5-azabicyclo[2.2.1]hept-5-yl.
  • the heterocyclic group consisting of 7-12 atoms may be optionally substituted by one or more substituents described herein.
  • fused bicyclic fused ring
  • fused bicyclic fused bicyclic
  • fused ring refers to a non-aromatic bicyclic system. Such a system may comprise an independent or conjugated unsaturated system, but the core structure does not comprise an aromatic ring or an aromatic heterocyclic ring (but an aromatic group may serve as a substituent thereon).
  • spirocyclyl spirocyclic
  • spirobicyclo spirobicyclic
  • spirobicyclic a saturated bridged ring system in which one ring originates from another A specific ring of carbon atoms on a ring.
  • a saturated bridged ring system rings B and B'
  • ring A and ring B share a carbon atom in two saturated ring systems
  • spiral ring or "spiral double ring.
  • Each of the fused bicyclic and spiro bicyclic groups may be a carbocyclic or heterocyclic group, and each ring is optionally substituted with one or more substituents described herein.
  • heterocycloalkyl refers to a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic ring system containing from 3 to 12 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur or oxygen atoms.
  • n typically describes the number of ring-forming atoms in the molecule in which the number of ring-forming atoms is n.
  • piperidinyl is a heterocycloalkyl group consisting of 6 atoms
  • 1,2,3,4-tetrahydronaphthalene is a cycloalkyl group composed of 10 atoms.
  • unsaturated as used in the present invention means that the group contains one or more unsaturations.
  • heteroatom refers to O, S, N, P, and Si, including any form of oxidation states of N, S, and P; forms of primary, secondary, tertiary, and quaternary ammonium salts; or nitrogen atoms in heterocycles. a form in which hydrogen is substituted, for example, N (like N in 3,4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like in N-substituted pyrrolidinyl) NR).
  • halogen means fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
  • aryl denotes a monocyclic, bicyclic and tricyclic carbocyclic ring system containing from 6 to 14 ring atoms, or from 6 to 12 ring atoms, or from 6 to 10 ring atoms, wherein at least one ring system is aromatic Of the family, wherein each ring system comprises a ring of 3-7 atoms and one or more attachment points are attached to the remainder of the molecule.
  • aryl can be used interchangeably with the term "aromatic ring”. Examples of the aryl group may include a phenyl group, a naphthyl group, and an anthracene. The aryl group may be independently and optionally substituted with one or more substituents described herein.
  • heteroaryl denotes a monocyclic, bicyclic and tricyclic ring system containing from 5 to 12 ring atoms, or from 5 to 10 ring atoms, or from 5 to 6 ring atoms, wherein at least one ring system is aromatic, And at least one ring system comprises one or more heteroatoms, wherein each ring system comprises a ring of 5-7 atoms and one or more attachment points are attached to the remainder of the molecule.
  • heteroaryl can be used interchangeably with the terms “heteroaryl ring” or “heteroaromatic compound”.
  • the heteroaryl group is optionally substituted with one or more substituents described herein.
  • a heteroaryl group of 5-10 atoms comprises 1, 2, 3 or 4 heteroatoms independently selected from O, S and N.
  • heteroaryl groups include, but are not limited to, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl , 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2- Pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (eg 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (such as 2-thi
  • alkylamino includes “N-alkylamino” and "N,N-dialkylamino” wherein the amino groups are each independently substituted with one or two alkyl groups.
  • the alkylamino group is a lower alkylamino group having one or two C1-6 alkyl groups attached to the nitrogen atom.
  • the alkylamino group is a lower alkylamino group of C1-3 .
  • Suitable alkylamino groups may be monoalkylamino or dialkylamino, examples of which include, but are not limited to, N-methylamino, N-ethylamino, N,N-dimethylamino, N, N - Diethylamino and the like.
  • arylamino means that the amino group is substituted by one or two aryl groups, examples of which include, but are not limited to, N-phenylamino. In some of these embodiments, the aromatic ring on the arylamino group can be further substituted.
  • aminoalkyl includes C1-10 straight or branched alkyl groups substituted with one or more amino groups.
  • the aminoalkyl group is a C1-6 "lower aminoalkyl group” substituted with one or more amino groups, examples of which include, but are not limited to, aminomethyl, ammonia Ethyl, aminopropyl, aminobutyl and aminohexyl.
  • prodrug denotes a compound which is converted in vivo to a compound of formula (I). Such transformation is affected by the hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue.
  • the prodrug-like compound of the present invention may be an ester.
  • the ester may be used as a prodrug such as a phenyl ester, an aliphatic (C 1-24 ) ester, an acyloxymethyl ester, or a carbonate. , carbamates and amino acid esters.
  • a compound of the invention comprises a hydroxyl group, i.e., it can be acylated to give a compound in the form of a prodrug.
  • Other prodrug forms include phosphates, such as those obtained by phosphorylation of a hydroxy group on the parent.
  • Metal product refers to a product obtained by metabolism of a specific compound or a salt thereof in vivo. Metabolites of a compound can be identified by techniques well known in the art, and the activity can be characterized by experimental methods as described herein. Such a product may be obtained by administering a compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage and the like. Accordingly, the invention includes metabolites of a compound, including metabolites produced by intimate contact of a compound of the invention with a mammal for a period of time.
  • the "pharmaceutically acceptable salt” as used in the present invention means an organic salt and an inorganic salt of the compound of the present invention.
  • Pharmaceutically acceptable salts are well known in the art, as described in the literature: SMBerge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19.
  • Salts formed by pharmaceutically acceptable non-toxic acids include, but are not limited to, mineral acid salts formed by reaction with amino groups, hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, And organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or by other methods described in the literature, such as ion exchange These salts.
  • salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, disulfate, borate, butyrate, camphoric acid Salt, camphor sulfonate, cyclopentylpropionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate Salt, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, Malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulphate, 3 -Phenylpropionate
  • Salts obtained by appropriate bases include the alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • the present invention also contemplates quaternary ammonium salts formed from any of the compounds comprising a group of N. Water soluble or oil soluble or dispersed products can be obtained by quaternization.
  • Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Pharmaceutically acceptable salts further comprise suitable amine cation nontoxic ammonium, quaternary ammonium, and the counterion, such as halide, hydroxide, carboxylate, sulfated, phosphorylated compounds, nitrate compounds, C 1 -8 sulfonate and aromatic sulfonate.
  • suitable amine cation nontoxic ammonium, quaternary ammonium, and the counterion such as halide, hydroxide, carboxylate, sulfated, phosphorylated compounds, nitrate compounds, C 1 -8 sulfonate and aromatic sulfonate.
  • Solvent-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol.
  • hydrate means that the solvent molecule is an association formed by water.
  • any disease or condition as used in the present invention refers to ameliorating a disease or condition (ie, slowing or preventing or alleviating the progression of a disease or at least one of its clinical symptoms).
  • “treating” refers to alleviating or ameliorating at least one physical parameter, including physical parameters that may not be perceived by the patient.
  • “treating” refers to modulating a disease or condition from the body (eg, stabilizing a detectable symptom) or physiologically (eg, stabilizing the body's parameters) or both.
  • “treating” refers to preventing or delaying the onset, onset, or exacerbation of a disease or condition.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids, such as acetate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/ Carbonate, hydrogen sulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlorophylline, citrate, ethanedisulfonate, fumarate, glucoheptonate, Portuguese Saccharate, glucuronate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, Malay Acid salt, malonate, mandelic acid salt, methanesulfonate, methyl sulfate, naphthoate, naphthalene sulfonate, nicotinate, nitrate, octadecanoate, oleate, oxalic acid Salt, palmitate
  • Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid. , ethanesulfonic acid, p-toluenesulfonic acid, sulfosalicylic acid, and the like.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic bases and organic bases.
  • Inorganic bases from which salts can be derived include, for example, ammonium salts and metals of Groups I to XII of the Periodic Table.
  • the salt is derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include the ammonium, potassium, sodium, calcium, and magnesium salts.
  • Organic bases from which salts can be derived include primary, secondary and tertiary amines, and substituted amines include naturally occurring substituted amines, cyclic amines, basic ion exchange resins and the like.
  • Certain organic amines include, for example, isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine. .
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, basic or acidic moiety by conventional chemical methods.
  • such salts can be obtained by reacting the free acid form of these compounds with a stoichiometric amount of a suitable base such as a hydroxide, carbonate, bicarbonate, or the like of Na, Ca, Mg or K.
  • a suitable base such as a hydroxide, carbonate, bicarbonate, or the like of Na, Ca, Mg or K.
  • the free base form of these compounds is prepared by reaction with a stoichiometric amount of a suitable acid. This type of reaction is usually carried out in water or an organic solvent or a mixture of the two.
  • a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile.
  • a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile.
  • the compounds disclosed in the present invention may also be obtained in the form of their hydrates or in the form of their solvents (e.g., ethanol, DMSO, etc.) for their crystallization.
  • solvents e.g., ethanol, DMSO, etc.
  • the compounds disclosed herein may form solvates either intrinsically or by design with pharmaceutically acceptable solvents, including water; thus, the invention is intended to include both solvated and unsolvated forms.
  • any structural formula given by the present invention is also intended to indicate that these compounds are not isotopically enriched and isotopically enriched.
  • Isotopically enriched compounds have the structure depicted by the general formula given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • Exemplary isotopes that may be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O , 18 O, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I.
  • the compounds of the invention include isotopically enriched compounds of the invention, for example, those in which a radioisotope such as 3 H, 14 C and 18 F is present, or in which a non-radioactive isotope is present, such as 2 H and 13 C.
  • a radioisotope such as 3 H, 14 C and 18 F
  • a non-radioactive isotope such as 2 H and 13 C.
  • isotopically enriched compounds can be used for metabolic studies (using 14 C), reaction kinetic studies (using, for example, 2 H or 3 H), detection or imaging techniques such as positron emission tomography (PET) or including drugs or Single photon emission computed tomography (SPECT) of substrate tissue distribution assays, or may be used in patient radiation therapy.
  • 18 F enriched compounds are particularly desirable for PET or SPECT studies.
  • Isotopically enriched compounds of Formula I or Formula II can be prepared by conventional techniques familiar to those skilled in the art or by the use of suitable isotopically labeled reagents in place of the previously used unlabeled reagents as described in the Examples and Preparations of the Invention. .
  • substitution of heavier isotopes may provide certain therapeutic advantages resulting from higher metabolic stability. For example, increased in vivo half-life or reduced dose requirements or improved therapeutic index.
  • Isotopic enrichment factors can be used to define the concentration of such heavier isotopes, particularly ruthenium.
  • a substituent of a compound of the invention is designated as hydrazine
  • the compound has at least 3500 for each of the specified hydrazine atoms (52.5% of ruthenium incorporation at each of the specified ruthenium atoms), at least 4,000 (60% of ruthenium incorporation), At least 4,500 (67.5% of cerium incorporation), at least 5,000 (75% of cerium incorporation), at least 5,500 (82.5% of cerium incorporation), at least 6,000 (90% of cerium incorporation), at least 6333.3 (95%) Iridium enrichment factor with at least 6466.7 (97% cerium incorporation), at least 6600 (99% cerium incorporation) or at least 6633.3 (99.5% cerium incorporation).
  • the present invention can include pharmaceutically acceptable solvates wherein the solvent of crystallization may be isotopically substituted, for example D 2 O, acetone -d 6, DMSO-d 6 solvate of those.
  • the invention relates to intermediates for the preparation of compounds of Formula I or Formula II.
  • the invention relates to a process for the preparation, isolation and purification of a compound encompassed by Formula I or Formula II.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention, a pharmaceutically acceptable carrier, an excipient, a diluent, an adjuvant, a vehicle, or a combination thereof.
  • the pharmaceutical composition can be in the form of a liquid, solid, semi-solid, gel or spray.
  • “Combination” means a fixed combination in a single dosage unit form or a kit for a portion to be administered in combination, wherein the compounds and combination partners disclosed herein may be administered separately at the same time or may be administered separately at intervals of time, In particular, the joint partners are shown to cooperate, such as synergy.
  • the terms "co-administered” or “co-administered” and the like are intended to encompass the administration of a selected combination partner to a single individual (eg, a patient) in need thereof, and is intended to include a treatment regimen in which the substance does not have to be administered by the same route of administration or simultaneously. .
  • pharmaceutical combination denotes a product obtained by mixing or combining more than one active ingredient, and includes both fixed and non-fixed combinations of the active ingredients.
  • fixed combination means that the active ingredient, such as a compound of the present invention and a combination partner, is administered to a patient simultaneously in the form of a single entity or dosage.
  • non-fixed combination means that the active ingredient, such as a compound of the present invention and a combination partner, are administered to a patient as a separate entity simultaneously, together or without specific time constraints, wherein the administration provides a therapeutically effective level of both compounds in the patient. .
  • the Pomalidomide terminal derivative used in the following examples was prepared according to the method disclosed in the literature Chemistry & Biology 22, 755-763 (2015).
  • the Lenalidomide terminal derivative is prepared according to the method disclosed in the literature J. Med. Chem (DOI: 10.1021/acs. jmedchem. 6b01816).
  • the RG-7112 terminal carboxylic acid derivative is according to the literature Bioorg. Med. Chem. Lett. 18, 5904 -5908 (2008). and ACS Med. Chem. Lett. 4, 466-469 (2013).
  • the Ibrutinib-end derivative used in the following examples was prepared as follows: The terminal alkyne required for Click chemistry was attached to the Ibrutinib intermediate (cas: 1022150-12-4) by an amide condensation reaction.
  • the specific preparation process is as follows: (1) Preparation of intermediate 1a
  • the obtained product 230 mg, 5 mL of dichloromethane and 0.5 mL of trifluoroacetic acid were added to a 25 mL round bottom flask, and stirred at room temperature for 6 hours. Add 15 mL of toluene, spin dry the solvent, and use a 200-300 mesh silica gel column to separate and purify.
  • the obtained product 800 mg, 15 mL of dichloromethane and 1.5 mL of trifluoroacetic acid was added to a 25 mL round bottom flask, and stirred at room temperature for 2 hours. After adding 25 mL of toluene, the solvent was evaporated, and the mixture was separated and purified using a 200-300 mesh silica gel column.
  • the compound of the formula 2, the formula 9, the formula 11 and the formula 13-formula 18 was prepared according to the above production method.
  • the dry solvent is separated and purified using a 200-300 mesh silica gel column.
  • the compound of the formula 8 was prepared according to the above preparation method.
  • Opti-MEM medium containing PEI and plasmid The preparation method of Opti-MEM medium containing PEI and plasmid is as follows), mix well, replace the normal culture solution after 8 hours and add the compound for 48 hours; replace the culture solution and add the compound, and then treat the cells after 48 hours. .
  • the cells were collected: the treated cells were scraped off in the culture medium, fully suspended, and collected by centrifugation at 300 g for 5 minutes. After washing with PBS, the PBS was discarded.
  • Lysis cells Add 150 ⁇ l of 2 ⁇ Loading Buffer to each sample, mix well, shake at 95 °C for 15 minutes, mix and store at -20 °C or directly for Western Blot.
  • 5 ⁇ Loading Buffer 250 mM Tris-HCl (pH 6.8), 10% (W/V) SDS, 0.5% (W/V) bromophenol blue, 50% (V/V) glycerol, 5% ( W/V) ⁇ -mercaptoethanol (2-ME).
  • 2 ⁇ Loading Buffer is prepared by adding 1.5 times the volume of dd water to the 5 ⁇ Loading Buffer.
  • Protein samples were prepared according to the experimental requirements, denatured at 95 ° C for 15 minutes, centrifuged, mixed and loaded onto SDS-PAGE gel loading wells. The loading volume was adjusted according to the protein quantification results, usually 4 ⁇ l per well.
  • Electrophoresis When the power is turned on, the protein sample has a voltage of 83 volts in the concentrated gel. When the protein sample enters the separation gel, we adjust the voltage to 110 volts to continue the electrophoresis. Electrophoresis was terminated when bromophenol blue almost completely ran out of PAGE gel.
  • the degradation activity of the compounds according to the examples of the present invention on BTK is as follows:
  • Jurkat cell line 1.5 ⁇ 10 6 cells per well (6-well plate), incubation at 37 ° C 5% CO 2 for 48 hours The final concentration of DMSO was 1%.
  • Jurkat cell line 1.5 ⁇ 10 6 cells per well (6-well plate), incubated at 37 ° C 5% CO 2 for 48 hours; DMSO final concentration 1%).
  • the compounds represented by Formula 1, Formula 16, and Formula 17 have the strongest degradation (both of which can degrade about 80% or more of BTK at a concentration of 10 nM).
  • the compound of Formula 1 is capable of degrading about 60% or more of C481S or C481A mutant BTK at a concentration of 30 nM.
  • the compound of Formula 1 was free of off-target and could not degrade EGFR, FLT-3, ITK and TEC at a concentration of 2000 nM.
  • the enzyme was added to 1x kinase matrix buffer.
  • FAM-labeled peptide and ATP were added to 1x kinase matrix buffer.
  • the enzyme plate already contains 5 microliters of compound in 10% DMSO.
  • the reaction was stopped by the addition of 25 microliters of stop buffer.
  • Inhibition rate (max-conversion value) / (max-min) * 100.
  • the results of inhibition of different kinases by the compounds of the invention as determined by the methods described above are shown in FIG.
  • the inhibitory activity of the compound of Formula 1 on BTK kinase has an IC 50 of 95 nM
  • the inhibitory activity of Ibrutinib on BTK has an IC 50 of 1.4 nM
  • the inhibitory activity of Ibrutinib on ITK has an IC 50 of 34 nM
  • the inhibitory activity against EGFR has an IC 50 of 1.3 nM.
  • the compound of formula 1 50 values ITK, EGFR IC is higher than 1000nM. It is indicated that the compound according to an embodiment of the present invention has no significant inhibitory effect on the target of side effects of Ibrutinib.
  • Reagents RPIM 1640medium; DMEM medium; 100 ⁇ non-essential amino acids (NEAA); 100 ⁇ streptomycin mixture; 50 mM ⁇ -mercaptoethanol; calf serum (FBS, previously inactivated).
  • a medium 500 ml: RPIM 1640medium (450 ml) + 100 x NEAA (5 ml) + 100 x streptomycin mixture (5 ml) + calf serum (50 ml) + 50 mM ⁇ -mercaptoethanol (0.5 ml).
  • B medium 500 ml: DMEM medium (450 ml) + 100 x NEAA (5 ml) + 100 x streptomycin mixture (5 ml) + calf serum (50 ml) + 50 mM ⁇ -mercaptoethanol (0.5 ml). .
  • the small molecule concentration was diluted by a 2-fold gradient from A medium to 100 nM to 2 nM. Configured as a small molecule solution.
  • Table 1 MTT assay (GI50 value) of the inhibitory ability of the compounds of Formula 1 - Formula 18 against HBL-1 cell line and Ramos cell line:
  • N.D indicates that the inhibitory activity was not detected.
  • the activity of the compound represented by Formula 1, Formula 2, Formula 3, Formula 4, Formula 16, and Formula 17 is similar to that of the positive control compound Ibrutinib, and the GI 50 is about 5 nM; in Ramos cells, Formula 1- GI 50 values shown in the formula 18 compound with a positive control compound were Ibrutinib than 1000nM, and instructions for the ability to inhibit proliferation Ibrutinib HBL-1 cells are relatively compound of Example of the present invention.

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Abstract

La présente invention concerne un composé, qui est un composé de X-Y-Z formule I ou un stéréoisomère, un isomère géométrique, un tautomère, un oxynitrure, un hydrate, un solvate, un métabolite, un sel pharmaceutiquement acceptable ou un promédicament de celui-ci. Le composé a une activité de dégradation puissante sur BTK de type sauvage et une bonne activité de dégradation sur C481S ou BTK à mutation C481A (DC 50<30nM), sans inhibition ni activité de dégradation sur d'autres cibles telles que EGFR, ITK, TEC, etc, et a ainsi un effet de dégradation ciblée spécifique de la protéine BTK.
PCT/CN2017/118595 2017-12-26 2017-12-26 Composé de dégradation ciblée de btk et son application WO2019127008A1 (fr)

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CN110724143A (zh) * 2019-10-09 2020-01-24 清华大学 一种靶向btk蛋白降解化合物的制备及其在治疗自身免疫系统疾病与肿瘤中的应用
CN110845500A (zh) * 2019-10-09 2020-02-28 清华大学 靶向btk降解化合物在治疗自身免疫系统疾病中的应用
WO2020177657A1 (fr) * 2019-03-02 2020-09-10 上海美志医药科技有限公司 Composé chimique ayant une activité de dégradation de btk
CN112812100A (zh) * 2019-11-18 2021-05-18 四川海思科制药有限公司 一种具有降解btk激酶的化合物及其制备方法和药学上的应用
CN112979656A (zh) * 2019-12-12 2021-06-18 上海美志医药科技有限公司 一类靶向降解btk蛋白的化合物
CN113544130A (zh) * 2019-05-31 2021-10-22 四川海思科制药有限公司 一种btk抑制剂环衍生物及其制备方法和药学上的应用
US11155561B2 (en) * 2017-09-03 2021-10-26 Shanghai Meizer Pharmaceuticals Co., Ltd. Substituted glutarimides as Btk inhibitors
WO2022007824A1 (fr) * 2020-07-07 2022-01-13 四川海思科制药有限公司 Composé ayant une activité de dégradation de la kinase btk, son procédé de préparation et son utilisation pharmaceutique
WO2022052950A1 (fr) * 2020-09-09 2022-03-17 海思科医药集团股份有限公司 Sel d'un composé destiné à dégrader la btk, forme cristalline de ce sel, et son utilisation en médecine
WO2022089400A1 (fr) * 2020-10-26 2022-05-05 上海美志医药科技有限公司 Composé pour la dégradation ciblée de btk et son utilisation antitumorale
WO2022111449A1 (fr) * 2020-11-25 2022-06-02 四川海思科制药有限公司 Procédé de préparation d'un agent de dégradation de btk
CN115304606A (zh) * 2021-06-21 2022-11-08 清华大学 一种同时靶向btk和gspt1蛋白的降解剂
WO2022253250A1 (fr) * 2021-06-01 2022-12-08 正大天晴药业集团股份有限公司 Dégradation de la tyrosine kinase de bruton contenant un cycle fusionné ou un cycle spiro
WO2023125907A1 (fr) * 2021-12-30 2023-07-06 Beigene, Ltd. Dégradation de la tyrosine kinase de bruton (btk) par conjugaison d'inhibiteurs de btk avec un ligand de ligase e3 et méthodes d'utilisation
US11760761B2 (en) 2020-08-17 2023-09-19 Aligos Therapeutics, Inc. Methods and compositions for targeting PD-L1

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WO2016106381A1 (fr) * 2014-12-23 2016-06-30 Pharmacyclics Llc Combinaisons d'inhibiteurs de btk et régime de dosage
CN107406454A (zh) * 2015-03-19 2017-11-28 浙江导明医药科技有限公司 优化的联合用药及其治疗癌症和自身免疫疾病的用途
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Cited By (19)

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US11155561B2 (en) * 2017-09-03 2021-10-26 Shanghai Meizer Pharmaceuticals Co., Ltd. Substituted glutarimides as Btk inhibitors
WO2020177657A1 (fr) * 2019-03-02 2020-09-10 上海美志医药科技有限公司 Composé chimique ayant une activité de dégradation de btk
CN113544130A (zh) * 2019-05-31 2021-10-22 四川海思科制药有限公司 一种btk抑制剂环衍生物及其制备方法和药学上的应用
CN113544130B (zh) * 2019-05-31 2024-01-09 西藏海思科制药有限公司 一种btk抑制剂环衍生物及其制备方法和药学上的应用
WO2021068380A1 (fr) * 2019-10-09 2021-04-15 清华大学 Préparation d'un composé de dégradation ciblant la protéine btk, et utilisation de celui-ci dans le traitement de maladies et de tumeurs auto-immunes
CN110724143A (zh) * 2019-10-09 2020-01-24 清华大学 一种靶向btk蛋白降解化合物的制备及其在治疗自身免疫系统疾病与肿瘤中的应用
CN110724143B (zh) * 2019-10-09 2021-03-23 清华大学 一种靶向btk蛋白降解化合物的制备及其在治疗自身免疫系统疾病与肿瘤中的应用
CN110845500A (zh) * 2019-10-09 2020-02-28 清华大学 靶向btk降解化合物在治疗自身免疫系统疾病中的应用
CN112812100A (zh) * 2019-11-18 2021-05-18 四川海思科制药有限公司 一种具有降解btk激酶的化合物及其制备方法和药学上的应用
CN112979656A (zh) * 2019-12-12 2021-06-18 上海美志医药科技有限公司 一类靶向降解btk蛋白的化合物
WO2022007824A1 (fr) * 2020-07-07 2022-01-13 四川海思科制药有限公司 Composé ayant une activité de dégradation de la kinase btk, son procédé de préparation et son utilisation pharmaceutique
US11760761B2 (en) 2020-08-17 2023-09-19 Aligos Therapeutics, Inc. Methods and compositions for targeting PD-L1
WO2022052950A1 (fr) * 2020-09-09 2022-03-17 海思科医药集团股份有限公司 Sel d'un composé destiné à dégrader la btk, forme cristalline de ce sel, et son utilisation en médecine
WO2022089400A1 (fr) * 2020-10-26 2022-05-05 上海美志医药科技有限公司 Composé pour la dégradation ciblée de btk et son utilisation antitumorale
WO2022111449A1 (fr) * 2020-11-25 2022-06-02 四川海思科制药有限公司 Procédé de préparation d'un agent de dégradation de btk
WO2022253250A1 (fr) * 2021-06-01 2022-12-08 正大天晴药业集团股份有限公司 Dégradation de la tyrosine kinase de bruton contenant un cycle fusionné ou un cycle spiro
CN115304606A (zh) * 2021-06-21 2022-11-08 清华大学 一种同时靶向btk和gspt1蛋白的降解剂
CN115304606B (zh) * 2021-06-21 2024-04-19 清华大学 一种同时靶向btk和gspt1蛋白的降解剂
WO2023125907A1 (fr) * 2021-12-30 2023-07-06 Beigene, Ltd. Dégradation de la tyrosine kinase de bruton (btk) par conjugaison d'inhibiteurs de btk avec un ligand de ligase e3 et méthodes d'utilisation

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