WO2019127008A1 - 一种靶向降解btk的化合物及其应用 - Google Patents

一种靶向降解btk的化合物及其应用 Download PDF

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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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English (en)
French (fr)
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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.

Abstract

本发明提出了化合物，该化合物其为X-Y-Z式（I）所示化合物或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药，该化合物针对野生型BTK降解作用效果强，且对C481S或C481A突变的BTK降解效果好(DC 50<30nM)，并且对其他靶点如EGFR、ITK、TEC等无抑制或降解作用，具有特异性靶向降解BTK蛋白的功效。

Description

一种靶向降解BTK的化合物及其应用 技术领域
本发明涉及生物医药领域，具体地，本发明涉及一种靶向降解BTK的化合物及其应用。
背景技术
非霍奇金淋巴瘤(NHL)是一种血液***癌症，是除霍奇金淋巴瘤外所有淋巴瘤的总称。在美国，2.1％人群的生活受到其影响。2015年，430万人群患有非霍奇金淋巴瘤，231400被夺去生命。临床大多数非霍奇金淋巴瘤为B细胞型，占总数70％～85％。弥漫大B细胞淋巴瘤(DLBCL)是最常见的非霍奇金淋巴瘤(NHL)，在美国和英国，每年10万人群中有7-8人发病。
依鲁替尼(Ibrutinib)是已经被FDA批准上市的用于治疗慢性淋巴细胞白血病(CLL)、套细胞淋巴瘤(MCL)以及华氏巨球蛋白血症适应症(WM)。并且有报道称，依鲁替尼可以有效抑制部分种类DLBCL的增殖。依鲁替尼发挥作用的机制是通过其丙烯酰胺结构与细胞中BTK蛋白481位半胱氨酸的巯基发生共价交联，从而使BTK失去磷酸化下游信号蛋白的功能，从而发挥抗细胞增殖的作用。
尽管依鲁替尼表现出来很强的针对BTK激酶的抑制活性，但是这种药物本身由于脱靶作用很强，会引起很多副作用。针对EGFR的IC 50值为5.6nM，能够引起严重腹泻和皮疹；针对ITK的IC 50值为10.7nM，能够引起自然杀伤细胞功能缺失；针对TEC的IC 50值为78nM，能够引起凝血缺陷。
有报道指出BTK激酶C481S突变能够引起细胞株对依鲁替尼敏感度大幅下降。依鲁替尼对于BTK自身磷酸化的抑制能力IC 50从2.2nM下降到1μM。
因此，BTK激酶的抑制剂和降解剂仍有待进一步开发和改进。
发明内容
本申请是基于发明人对以下事实和问题的发现和认识作出的：
现有技术中Ibrutinib可以抑制BTK激酶，但是文献(N.Engl.J.Med.370,2352-2254(2014).)报道Ibrutinib对C481S突变的BTK抑制能力IC50＝1μM，且该药物对于其他靶点，如EGFR、ITK、TEC也有不同程度的作用，副作用明显。基于上述问题的发现，发明人提出了一种新的化合物，该化合物采用的是双靶点分子结构，结构如图1所示，该类分子一端结构靶向结合E3连接酶，另一端结构靶向结合所要降解的目标蛋白(BTK蛋白)，这两端的结构通过链(linker)相连，形成一个完整的化合物分子。该化合物针对野生型BTK降 解作用效果强，且对C481S或C481A突变的BTK降解效果好(DC 50<30nM)，并且对其他靶点如EGFR、ITK、TEC等无抑制或降解作用，具有特异性靶向BTK蛋白的功效。
在本发明的第一方面，本发明提出了一种化合物。根据本发明的实施例，所述化合物其为式I所示化合物或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药：
X-Y-Z
式I
所述X为
Figure PCTCN2017118595-appb-000001
所述Z为：
Figure PCTCN2017118595-appb-000002
Figure PCTCN2017118595-appb-000003
所述Y为：
Figure PCTCN2017118595-appb-000004
其中，各L 1、L 2、L 3、L 4、L 5、L 6、L 7独立为键，-O-，-S(＝O) t1-，-S-，-N(R a)-，-C(＝O)O-，-N(R a)-C(＝O)-，-C(＝O)-(CH 2) t2-，-CH 2-，-C(＝O)-，-OC(＝O)-，-C(＝S)-，-C(＝O)-N(R a)-，-C(＝S)-N(R a)-，-(CH 2) t2-C(＝O)-或者三氮唑基；
各R a独立地为氢，C1-4烷基，卤代C1-4烷基，C1-4烷基酰基或羟基；
各t2独立地为0，1，2，3或4；
各t1独立地为0，1或2；
各X 1、X 2、X 3、X 4、X 5、X 6、X 7、X 8、X 9、X 10、Q、W独立地为C，O，S，N或Se；
各R 1、R 2、R 3、R 4、R 5、R 6、B独立地为H、氘、C1-4烷基、C1-4杂烷基、C3-8环烷基、C2-10杂环基、C6-10芳基、C1-9杂芳基、C6-10芳基、C1-4烷氧基，其中，所述的C1-4烷基、C1-4杂烷基、C3-8环烷基、C2-10杂环基、C6-10芳基、C1-9杂芳基、C6-10芳基C1-4烷氧基、可以任选地被一个或多个选自氘、羟基、氨基、氧代、F、Cl、Br、I、氰基、C1-6烷基、C1-6卤代烷基、C1-6羟基烷基、C1-6氨基烷基、C1-6烷氧基C1-6烷基、C1-6烷氨基C1-6烷基、C6-10芳基C1-6烷基、C1-9杂芳基C1-6烷基、C2-10杂环基C1-6烷基、C3-10环烷基C1-6烷基、C1-6烷氧基、C1-6烷氨基、C6-10芳基、C6-10芳氧基、C6-10芳氨基、C1-9杂芳基、C1-9杂芳氧基、C2-6烯基、C3-10环烷基、卤素取代C6-10芳基、卤素取代C1-9杂芳基、卤素取代C2-10杂环基或C2-10杂环基的取代基所取代，
各A独立为氢，C1-4烷基，C1-4卤代烷基，羟基，硝基，氨基，氰基，卤素，羧基，C1-4烷氧基，C1-4烷氨基，C1-4烷硫基，C1-4烷基酰基，任选取代的C3-12环烷基，任选取代的C3-9杂环基，任选取代的C6-12芳基，任选取代的C1-9杂芳基，
各E独立地为酰胺基，酯基，氨基甲酯基，脲基，胍基，杂环基，环烷基，螺杂双环基，稠合杂双环基，桥杂双环基，C6-10芳基或C2-C10杂芳基；各E任选地被1，2，3或4个独立的R b所取代；
各R b独立地为氢，C1-4烷基，C1-4卤代烷基，羟基，硝基，氨基，氰基，卤素，羧基，C1-4烷氧基，C1-4烷氨基，C1-4烷硫基，C1-4烷基酰基，C3-12环烷基，C3-9杂环基，C6-12芳基，C1-9杂芳基，氨基C1-4烷基，羟基C1-4烷基，磺酸基，氨基磺酰基或氨基酰基；
各a、b、c、d独立地为0～30之间的整数。根据本发明实施例的化合物针对野生型BTK降解作用效果强，且对C481S或C481A突变的BTK降解效果好(DC 50<30nM)，并且对其他靶点如EGFR、ITK、TEC等无抑制或降解作用，具有特异性靶向降解BTK蛋白的功效。
根据本发明的实施例，上述化合物还可以进一步包括如下附加技术特征至少之一：
根据本发明的实施例，各L 1独立地为键，-O-，-S-，-NH-，
各L 2独立地为键、-(C＝O)CH＝CH 2-，-O-，-S-，-S(＝O)-，-S(＝O) 2-，-NRa-，-C(＝O)-，-C(＝O)O-，-N(R a)-C(＝O)-，-CH 2-，-OC(＝O)-，-C(＝S)-，-C(＝O)-N(R a)-，-C(＝S)-N(R a)或者三氮唑基，
各R a独立地为氢，C1-2烷基，卤代C1-2烷基，C1-2烷基酰基或羟基，
各R 1、R 2、R 3、R 4独立地为H、氨基、C1-4烷基、C1-4杂烷基、C5-7环烷基、C5-7杂环基、C6-7芳基、C5-7杂芳基，其中，所述C1-4烷基、C1-4杂烷基、C5-7环烷基、C5-7杂环基、C6-7芳基、C5-7杂芳基可以任选地被一个或多个选自氘、羟基、氨基、氧代、F、Cl、Br、I、氰基取代基取代。
根据本发明的实施例，所述X为如下所示的化合物：
Figure PCTCN2017118595-appb-000005
Figure PCTCN2017118595-appb-000006
根据本发明的实施例，各A独立为氢，任选取代的C5-7杂环基，任选取代的C5-7环烷基，任选取代的C6-7芳基，任选取代的C5-7杂芳基，
各R 5、B独立地为H、氨基、C1-4烷基、C1-4杂烷基、C5-7环烷基、C5-7杂环基、C6-7芳基、C5-7杂芳基，其中，所述C1-4烷基、C1-4杂烷基、C5-7环烷基、C5-7杂环基、C6-7芳基、C5-7杂芳基可以任选地被一个或多个选自氘、羟基、氨基、氧代、F、Cl、Br、I、氰基、C5-7芳基、C5-7杂芳基、卤素取代C5-7芳基、卤素取代C5-7杂芳基、卤素取代C5-7杂环基的取代基取代；
各L 3、L 4、L 5独立地为键、-(C＝O)CH＝CH 2-，-O-，-S-，-S(＝O)-，-S(＝O) 2-，-NRa-，-C(＝O)-，-C(＝O)O-，-N(R a)-C(＝O)-，-CH 2-，-OC(＝O)-，-C(＝S)-，-C(＝O)-N(R a)-，-C(＝S)-N(R a)或者三氮唑基，
各R a独立地为氢，C1-2烷基，卤代C1-2烷基，C1-2烷基酰基或羟基，
各R 6独立地为氢，氨基，羟基，硝基，氨基，氰基，卤素，羧基。
根据本发明的实施例，所述A为
Figure PCTCN2017118595-appb-000007
Figure PCTCN2017118595-appb-000008
所述B为
Figure PCTCN2017118595-appb-000009
Figure PCTCN2017118595-appb-000010
其中，各R c独立地为H，C1-4烷基，卤代C1-4烷基，C1-4烷基酰基或羟基。
根据本发明的实施例，所述Z为如下所示的化合物：
Figure PCTCN2017118595-appb-000011
Figure PCTCN2017118595-appb-000012
根据本发明的实施例，各E独立为酰胺基，酯基，氨基甲酯基，脲基，胍基，杂环基，环烷基，C6-C8芳基或C5-C7杂芳基；各E任选地被1，2，3或4个独立的R b所取代，
各R b独立地为氢，C1-2烷基，C1-2卤代烷基，羟基，硝基，氨基，氰基，卤素，羧基，C1-2烷氧基，C1-2烷氨基，C1-2烷硫基，C1-2烷基酰基，C5-7环烷基，C5-7杂环基，C6-7芳基，C5-7杂芳基，氨基C1-2烷基，羟基C1-2烷基，磺酸基，氨基磺酰基或氨基酰基，
各a为0～10之间的整数，
各b为0～20之间的整数，
各c为0～20之间的整数，
各d为0～10之间的整数，
各L 6、L 7独立地为键、-(C＝O)CH＝CH 2-，-O-，-S-，-S(＝O)-，-S(＝O) 2-，-NRa-，-C(＝O)-，-C(＝O)O-，-N(R a)-C(＝O)-，-CH 2-，-OC(＝O)-，-C(＝S)-，-C(＝O)-N(R a)-，-C(＝S)-N(R a)或者三氮唑基，
各R a独立地为氢，C1-2烷基，卤代C1-,2烷基，C1-2烷基酰基或羟基。
根据本发明的实施例，所述Y为
Figure PCTCN2017118595-appb-000013
其中，各e、f独立地为0～30之间的整数；
各L 6、L 7独立为键，-O-，-S(＝O) t1-，-S-，-N(R a)-，-C(＝O)O-，-N(R a)-C(＝O)-，-C(＝O)-(CH 2) t2-，-CH 2-，-C(＝O)-，-OC(＝O)-，-C(＝S)-，-C(＝O)-N(R a)-，-C(＝S)-N(R a)-或者-(CH 2) t2-C(＝O)-，三氮唑基；
各R a独立地为氢，C1-2烷基，卤代C1-2烷基，C1-2烷基酰基或羟基；
各t2独立地为0，1，2，3或4；
各t1独立地为0，1或2。
根据本发明的实施例，所述X为
Figure PCTCN2017118595-appb-000014
所述Z为
Figure PCTCN2017118595-appb-000015
所述Y为
Figure PCTCN2017118595-appb-000016
Figure PCTCN2017118595-appb-000017
其中，n为0～2之间的整数；m1为1～6之间的整数，n1为0～6之间的整数；m2为0～26之间的整数，n2为0～6之间的整数；n3为1～26之间的整数；m3为2～20之间的整数，n4为0～6之间的整数。
根据本发明的实施例，包括式II～IX任一项所示化合物或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药，
Figure PCTCN2017118595-appb-000018
Figure PCTCN2017118595-appb-000019
其中，m1为1～6之间的整数，n1为0～6之间的整数，m2为0～26之间的整数，n2为0～6之间的整数，n3为1～26之间的整数，m3为2～20之间的整数，n4为0～6之间的整数。
在本发明的第二方面，本发明提出了一种化合物。根据本发明的实施例，其为式1～18任一项所示化合物或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂 化物、代谢产物、药学上可接受的盐或前药，
Figure PCTCN2017118595-appb-000020
Figure PCTCN2017118595-appb-000021
Figure PCTCN2017118595-appb-000022
Figure PCTCN2017118595-appb-000023
根据本发明实施例的化合物针对野生型BTK降解作用效果强，且对C481S或C481A突变的BTK降解效果好(DC 50<30nM)，并且对其他靶点如EGFR、ITK、TEC等无抑制或降解作用，具有特异性靶向降解BTK蛋白的功效。
在本发明的第三方面，本发明提出了一种药物组合物。根据本发明的实施例，所述药 物组合物包括前面所述的化合物。根据本发明实施例的药物组合物针对野生型BTK降解作用效果强，且对C481S或C481A突变的BTK降解效果好(DC 50<30nM)，并且对其他靶点如EGFR、ITK、TEC等无抑制或降解作用，具有特异性靶向降解BTK蛋白的功效。
根据本发明的实施例，上述药物组合物进一步包括如下附加技术特征至少之一：
根据本发明的实施例，所述药物组合物进一步包含药学上可接受的载体、赋形剂、稀释剂、辅剂、媒介物或其组合。
根据本发明的实施例，所述药物组合物进一步包括其他治疗或预防非霍奇金淋巴瘤的药物，所述其他治疗或预防非霍奇金淋巴瘤的药物包括依鲁替尼。发明人发现，上述药物组合物针对野生型BTK降解作用效果强，且对C481S或C481A突变的BTK降解效果好(DC50<30nM)，并且对其他靶点如EGFR、ITK、TEC等无抑制或降解作用，具有特异性靶向BTK蛋白的功效。并且联合用药，其治疗或预防非霍奇金淋巴瘤的效果更好。
在本发明的第四方面，本发明提出了前面所述的化合物或前面所述的药物组合物在制备药物中的用途。根据本发明的实施例，所述药物用于降解BTK或抑制BTK。根据本发明实施例的化合物或者药物组合物针对野生型BTK降解作用效果强，且对C481S或C481A突变的BTK降解效果好(DC50<30nM)，并且对其他靶点如EGFR、ITK、TEC等无抑制或降解作用，具有特异性靶向BTK蛋白的功效。
在本发明的第五方面，本发明提出了前面所述的化合物或前面所述的药物组合物在制备BTK中的用途。根据本发明实施例的化合物或药物组合物针对野生型BTK降解作用效果强，且对C481S或C481A突变的BTK降解效果好(DC50<30nM)，并且对其他靶点如EGFR、ITK、TEC等无抑制或降解作用，具有特异性靶向降解BTK蛋白的功效。
在本发明的第六方面，本发明提出了前面所述的化合物或前面所述的药物组合物在制备药物中的用途。根据本发明的实施例，所述药物用于治疗或预防BTK相关性疾病。根据本发明实施例的化合物或药物组合物针对野生型BTK降解作用效果强，且对C481S或C481A突变的BTK降解效果好(DC50<30nM)，并且对其他靶点如EGFR、ITK、TEC等无抑制或降解作用，具有特异性靶向降解BTK蛋白的功效。
根据本发明的实施例，上述用途进一步包括如下附加技术特征至少之一：
根据本发明的实施例，所述BTK相关性疾病为非霍奇金淋巴瘤。发明人发现，上述化合物或药物组合物对于BTK相关性疾病的非霍奇金淋巴瘤的疗效更好。
在本发明的第七方面，本发明提出了前面所述的化合物或前面所述的药物组合物在抗肿瘤中的用途。根据本发明实施例的化合物或药物组合物对肿瘤有一定程度的预防或治疗的效果。
根据本发明的实施例，上述用途进一步包括如下附加技术特征至少之一：
根据本发明的实施例，所述肿瘤为淋巴瘤。根据本发明实施例的化合物或药物组合物对淋巴瘤预防或治疗的效果优于其他肿瘤。
根据本发明的实施例，所述淋巴瘤为非霍奇金淋巴瘤。发明人发现，前面所述化合物或药物组合物针对野生型BTK降解作用效果强，且对C481S或C481A突变的BTK降解效果好(DC50<30nM)，并且对其他靶点如EGFR、ITK、TEC等无抑制或降解作用，具有特异性靶向降解BTK蛋白的功效。根据本发明实施例的化合物或药物组合物对非霍奇金淋巴瘤的治疗或者预防效果更佳。
在本发明的第八方面，本发明提出了一种***的方法。根据本发明的实施例，给予患者前面所述的化合物或前面所述的药物组合物。根据本发明实施例的化合物或药物组合物对肿瘤有一定程度的预防或治疗的效果。
根据本发明的实施例，上述方法进一步包括如下附加技术特征至少之一：
根据本发明的实施例，所述肿瘤为淋巴瘤。根据本发明实施例的化合物或药物组合物对淋巴瘤预防或治疗的效果优于其他肿瘤。
根据本发明的实施例，所述淋巴瘤为非霍奇金淋巴瘤。发明人发现，前面所述化合物或药物组合物针对野生型BTK降解作用效果强，且对C481S或C481A突变的BTK降解效果好(DC50<30nM)，并且对其他靶点如EGFR、ITK、TEC等无抑制或降解作用，具有特异性靶向降解BTK蛋白的功效。根据本发明实施例的化合物或药物组合物对非霍奇金淋巴瘤的治疗或者预防效果更佳。
在本发明的又一方面，本发明提出了式I所示化合物的合成一般步骤。根据本发明的实施例，式I所示化合物可通过Pomalidomide或Lenanidomide或RG-7112端衍生物和Ibrutinib端衍生物之间的click反应或酰胺缩合反应连接而成，如图2所示，其中，Pomalidomide端衍生物的制备方法可参考文献Chemistry&Biology 22,755-763(2015).，Lenalidomide端衍生物的制备方法可参考文献J.Med.Chem(DOI:10.1021/acs.jmedchem.6b01816).，RG-7112端衍生物的制备方法可参考文献Bioorg.Med.Chem.Lett.18,5904-5908(2008).ACS Med.Chem.Lett.4,466-469(2013).，Ibrutinib端衍生物的合成路线可参考专利PCT Int.Appl.,2013003629,03Jan 2013。Click chemistry所需的端炔烃则通过酰胺缩合反应连接到Ibrutinib母核的哌啶环上，制备方法可参考文献J.Chem.Inf.Model.50,446(2010).PCT Int.Appl.,2013170115,14Nov 2013。
附图说明
图1是根据本发明实施例的PROTACs的基本技术路线；
图2是根据本发明实施例的通过click反应和酰胺缩合反应构建式I所示的示意图；
图3是根据本发明实施例的式1所示化合物对BTK的降解作用；
图4是根据本发明实施例的式12、式13所示化合物对BTK的降解作用；
图5是根据本发明实施例的式16、式17所示化合物对BTK的降解作用；
图6是根据本发明实施例的式1所示化合物在不同作用时间对BTK的降解作用；
图7(图7-1、图7-2、图7-3)是根据本发明实施例的式1所示化合物BTK降解作用受其他化合物的影响；
图8(图8-1、图8-2、图8-3)是根据本发明实施例的式1、式2、式3、式4所示化合物在不同细胞系(HBL-1、IgE MM、Mino)对BTK的降解作用；
图9(图9-1、图9-2、图9-3)是根据本发明实施例的式1所示化合物在对C481S或C481A突变BTK的降解作用；
图10是根据本发明实施例的式1所示化合物在对其他蛋白(EGFR、FLT-3、ITK、TEC)的降解作用；
图11是根据本发明实施例的式1所示化合物在对多种蛋白(BTK、EGFR、ITK)的抑制作用。
具体实施方式
下面详细描述本发明的实施例，所述实施例的示例在附图中示出。下面通过参考附图描述的实施例是示例性的，旨在用于解释本发明，而不能理解为对本发明的限制。
在本文中所使用的术语“给予患者前面所述的化合或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药或前面所述的药物组合物”指将预定量的物质通过某种适合的方式引入病人。本发明的式I所述化合物或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药或者药物组合物可以通过任何常见的途径被给药，只要它可以到达预期的组织。给药的各种方式是可以预期的，包括腹膜，静脉，肌肉，皮下，皮层，口服，局部，鼻腔，肺部和直肠，但是本发明不限于这些已举例的给药方式。然而，由于口服给药时，口服给药的组合物的活性成分应该被包被或被配制以防止其在胃部被降解。此外，本发明的式I所述化合物或者所述药物组合物可以使用将活性成分传送到靶细胞的特定器械来给药。
本发明的药物组合物的给药频率和剂量可以通过多个相关因素被确定，该因素包括要被治疗的疾病类型，给药途径，病人年龄，性别，体重和疾病的严重程度以及作为活性成分的药物类型。
术语“治疗有效量”是指化合物足以显著改善某些与疾病或病症相关的症状的量，也即为 给定病症和给药方案提供治疗效果的量。治疗有效量的药物或化合物不需要治愈疾病或病症，但将为疾病或病症提供治疗，使得个体的疾病或病症的发作被延缓、阻止或预防，或者疾病或病症的症状得以缓解，或者疾病或病症的期限被改变，或者例如疾病或病症变得不严重，或者加速康复。
术语“治疗”用于指获得期望的药理学和/或生理学效果。所述效果就完全或部分预防疾病或其症状而言可以是预防性的，和/或就部分或完全治愈疾病和/或疾病导致的不良作用而言可以是治疗性的。本文使用的“治疗”涵盖哺乳动物、特别是人的疾病的治疗，包括：(a)在容易患病但是尚未确诊得病的个体中预防疾病或病症发生；(b)抑制疾病；或(c)缓解疾病，例如减轻与疾病相关的症状。本文使用的“治疗”涵盖将药物或化合物给予个体以治疗、治愈、缓解、改善、减轻或抑制个体的疾病的任何用药，包括但不限于将含本文所述式I或式II化合物或药物组合物的给予有需要的个体。
根据本发明的实施例，所述辅料包括制剂领域公知的可药用的赋形剂、润滑剂、填充剂、稀释剂、崩解剂、稳定剂、防腐剂、乳化剂、助溶剂、着色剂、甜味剂，制成片剂、丸剂、胶囊剂、注射剂等不同剂型。
现在详细描述本发明的某些实施方案，其实例由随附的结构式和化学式说明。本发明意图涵盖所有的替代、修改和等同技术方案，它们均包括在如权利要求定义的本发明范围内。本领域技术人员应认识到，许多与本文所述类似或等同的方法和材料能够用于实践本发明。本发明绝不限于本文所述的方法和材料。在所结合的文献、专利和类似材料的一篇或多篇与本申请不同或相矛盾的情况下(包括但不限于所定义的术语、术语应用、所描述的技术，等等)，以本申请为准。
应进一步认识到，本发明的某些特征，为清楚可见，在多个独立的实施方案中进行了描述，但也可以在单个实施例中以组合形式提供。反之，本发明的各种特征，为简洁起见，在单个实施方案中进行了描述，但也可以单独或以任意适合的子组合提供。
除非另外说明，本发明所使用的所有科技术语具有与本发明所属领域技术人员的通常理解相同的含义。本发明涉及的所有专利和公开出版物通过引用方式整体并入本发明。
除非另外说明，应当应用本文所使用得下列定义。出于本发明的目的，化学元素与元素周期表CAS版，和《化学和物理手册》，第75版，1994一致。此外，有机化学一般原理可参考"Organic Chemistry",Thomas Sorrell,University Science Books,Sausalito:1999,和"March's Advanced Organic Chemistry”by Michael B.Smith and Jerry March,John Wiley&Sons,New York:2007中的描述，其全部内容通过引用并入本文。
除非另有说明或者上下文中有明显的冲突，本文所使用的冠词“一”、“一个(种)”和“所述”旨在包括“至少一个”或“一个或多个”。因此，本文所使用的这些冠词是指一个或多于一 个(即至少一个)宾语的冠词。例如，“一组分”指一个或多个组分，即可能有多于一个的组分被考虑在所述实施方案的实施方式中采用或使用。
术语“包含”为开放式表达，即包括本发明所指明的内容，但并不排除其他方面的内容。
“立体异构体”是指具有相同化学构造，但原子或基团在空间上排列方式不同的化合物。立体异构体包括对映异构体、非对映异构体、构象异构体(旋转异构体)、几何异构体(顺/反)异构体、阻转异构体，等等。
“手性”是具有与其镜像不能重叠性质的分子；而“非手性”是指与其镜像可以重叠的分子。
“对映异构体”是指一个化合物的两个不能重叠但互成镜像关系的异构体。
“非对映异构体”是指有两个或多个手性中心并且其分子不互为镜像的立体异构体。非对映异构体具有不同的物理性质，如熔点、沸点、光谱性质和反应性。非对映异构体混合物可通过高分辨分析操作如电泳和色谱，例如HPLC来分离。
本发明所使用的立体化学定义和规则一般遵循S.P.Parker，Ed.，McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company，New York；and Eliel，E.and Wilen，S.，“Stereochemistry of Organic Compounds”，John Wiley&Sons，Inc.，New York，1994。
许多有机化合物以光学活性形式存在，即它们具有使平面偏振光的平面发生旋转的能力。在描述光学活性化合物时，使用前缀D和L或R和S来表示分子关于其一个或多个手性中心的绝对构型。前缀d和l或(+)和(-)是用于指定化合物所致平面偏振光旋转的符号，其中(-)或l表示化合物是左旋的。前缀为(+)或d的化合物是右旋的。一种具体的立体异构体是对映异构体，这种异构体的混合物称作对映异构体混合物。对映异构体的50:50混合物称为外消旋混合物或外消旋体，当在化学反应或过程中没有立体选择性或立体特异性时，可出现这种情况。
本发明公开化合物的任何不对称原子(例如，碳等)都可以以外消旋或对映体富集的形式存在，例如(R)-、(S)-或(R,S)-构型形式存在。在某些实施方案中，各不对称原子在(R)-或(S)-构型方面具有至少50％对映体过量，至少60％对映体过量，至少70％对映体过量，至少80％对映体过量，至少90％对映体过量，至少95％对映体过量，或至少99％对映体过量。
依据起始物料和方法的选择，本发明化合物可以以可能的异构体中的一个或它们的混合物，例如外消旋体和非对映异构体混合物(这取决于不对称碳原子的数量)的形式存在。光学活性的(R)-或(S)-异构体可使用手性合成子或手性试剂制备，或使用常规技术拆分。如果化合物含有一个双键，取代基可能为E或Z构型；如果化合物中含有二取代的环烷基，环烷基的取代基可能有顺式或反式构型。
所得的任何立体异构体的混合物可以依据组分物理化学性质上的差异被分离成纯的或 基本纯的几何异构体，对映异构体，非对映异构体，例如，通过色谱法和/或分步结晶法。
可以用已知的方法将任何所得终产物或中间体的外消旋体通过本领域技术人员熟悉的方法拆分成光学对映体，如，通过对获得的其非对映异构的盐进行分离。外消旋的产物也可以通过手性色谱来分离，如，使用手性吸附剂的高效液相色谱(HPLC)。特别地，对映异构体可以通过不对称合成制备，例如，可参考Jacques,et al.,Enantiomers,Racemates and Resolutions(Wiley Interscience,New York,1981)；Principles of Asymmetric Synthesis(2 nd Ed.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,2007)。
术语“互变异构体”或“互变异构形式”是指具有不同能量的可通过低能垒(low energy barrier)互相转化的结构异构体。若互变异构是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(protontautomer)(也称为质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键互变异构体(valence tautomer)包括通过一些成键电子的重组来进行的互相转化。酮-烯醇互变异构的具体实例是戊烷-2,4-二酮和4-羟基戊-3-烯-2-酮互变异构体的互变。互变异构的另一个实例是酚-酮互变异构。酚-酮互变异构的一个具体实例是吡啶-4-醇和吡啶-4(1H)-酮互变异构体的互变。除非另外指出，本发明化合物的所有互变异构体形式都在本发明的范围之内。
像本发明所描述的，本发明的化合物可以任选地被一个或多个取代基所取代，如上面的通式化合物，或者像实施例里面特殊的例子，子类，和本发明所包含的一类化合物。应了解“任选取代的”这个术语与“取代或非取代的”这个术语可以交换使用。一般而言，术语“取代的”表示所给结构中的一个或多个氢原子被具体取代基所取代。除非其他方面表明，一个任选的取代基团可以在基团各个可取代的位置进行取代。当所给出的结构式中不只一个位置能被选自具体基团的一个或多个取代基所取代，那么取代基可以相同或不同地在各个位置取代。
另外，需要说明的是，除非以其他方式明确指出，在本发明中所采用的描述方式“各…独立地为”与“…各自独立地为”和“…独立地为”可以互换，均应做广义理解，其既可以是指在不同基团中，相同符号之间所表达的具体选项之间互相不影响，也可以表示在相同的基团中，相同符号之间所表达的具体选项之间互相不影响。
在本说明书的各部分，本发明公开化合物的取代基按照基团种类或范围公开。特别指出，本发明包括这些基团种类和范围的各个成员的每一个独立的次级组合。例如，术语“C1-6 烷基”特别指独立公开的甲基、乙基、C3烷基、C4烷基、C5烷基和C6烷基。
在本发明的各部分，描述了连接取代基。当该结构清楚地需要连接基团时，针对该基团所列举的马库什变量应理解为连接基团。例如，如果该结构需要连接基团并且针对该变量的马库什基团定义列举了“烷基”或“芳基”，则应该理解，该“烷基”或“芳基”分别代表连接的亚烷基基团或亚芳基基团。
本发明使用的术语“烷基”或“烷基基团”，表示含有1至20个碳原子，饱和的直链或支链一价烃基基团，其中，所述烷基基团可以任选地被一个或多个本发明描述的取代基所取代。除非另外详细说明，烷基基团含有1-20个碳原子。在一实施方案中，烷基基团含有1-12个碳原子；在另一实施方案中，烷基基团含有1-6个碳原子；在又一实施方案中，烷基基团含有1-4个碳原子；还在一实施方案中，烷基基团含有1-3个碳原子。
烷基基团的实例包含，但并不限于，甲基(Me、-CH3)，乙基(Et、-CH2CH3)，正丙基(n-Pr、-CH2CH2CH3)，异丙基(i-Pr、-CH(CH3)2)，正丁基(n-Bu、-CH2CH2CH2CH3)，异丁基(i-Bu、-CH2CH(CH3)2)，仲丁基(s-Bu、-CH(CH3)CH2CH3)，叔丁基(t-Bu、-C(CH3)3)，正戊基(-CH2CH2CH2CH2CH3)，2-戊基(-CH(CH3)CH2CH2CH3)，3-戊基(-CH(CH2CH3)2)，2-甲基-2-丁基(-C(CH3)2CH2CH3)，3-甲基-2-丁基(-CH(CH3)CH(CH3)2)，3-甲基-1-丁基(-CH2CH2CH(CH3)2)，2-甲基-1-丁基(-CH2CH(CH3)CH2CH3)，正己基(-CH2CH2CH2CH2CH2CH3)，2-己基(-CH(CH3)CH2CH2CH2CH3)，3-己基(-CH(CH2CH3)(CH2CH2CH3))，2-甲基-2-戊基(-C(CH3)2CH2CH2CH3)，3-甲基-2-戊基(-CH(CH3)CH(CH3)CH2CH3)，4-甲基-2-戊基(-CH(CH3)CH2CH(CH3)2)，3-甲基-3-戊基(-C(CH3)(CH2CH3)2)，2-甲基-3-戊基(-CH(CH2CH3)CH(CH3)2)，2,3-二甲基-2-丁基(-C(CH3)2CH(CH3)2)，3,3-二甲基-2-丁基(-CH(CH3)C(CH3)3)，正庚基，正辛基，等等。
术语“亚烷基”表示从饱和的直链或支链烃基中去掉两个氢原子所得到的饱和的二价烃基基团。除非另外详细说明，亚烷基基团含有1-12个碳原子。在一实施方案中，亚烷基基团含有1-6个碳原子；在另一实施方案中，亚烷基基团含有1-4个碳原子；在又一实施方案中，亚烷基基团含有1-3个碳原子；还在一实施方案中，亚烷基基团含有1-2个碳原子。这样的实例包括亚甲基(-CH2-)，亚乙基(-CH2CH2-)，亚异丙基(-CH(CH3)CH2-)等等。
术语“烯基”表示含有2-12个碳原子的直链或支链一价烃基，其中至少有一个不饱和位点，即有一个碳-碳sp2双键，其中，所述烯基基团可以任选地被一个或多个本发明所描述的取代基所取代，其包括“cis”和“tans”的定位，或者"E"和"Z"的定位。在一实施方案中，烯基基团包含2-8个碳原子；在另一实施方案中，烯基基团包含2-6个碳原子；在又一实施方案中，烯基基团包含2-4个碳原子。烯基基团的实例包括，但并不限于，乙烯基(-CH＝CH2)、烯丙基(-CH2CH＝CH2)等等。
术语“炔基”表示含有2-12个碳原子的直链或支链一价烃基，其中至少有一个不饱和位点，即有一个碳-碳sp三键，其中，所述炔基基团可以任选地被一个或多个本发明所描述的取代基所取代。在一实施方案中，炔基基团包含2-8个碳原子；在另一实施方案中，炔基基团包含2-6个碳原子；在又一实施方案中，炔基基团包含2-4个碳原子。炔基基团的实例包括，但并不限于，乙炔基(-C≡CH)、炔丙基(-CH2C≡CH)、1-丙炔基(-C≡C-CH3)等等。
术语“杂烷基”表示烷基链中***一个或多个杂原子，其中烷基基团和杂原子具有如本发明所述的含义。除非另外详细说明，杂烷基基团含有2-10个碳原子，另外一些实施方案是，杂烷基基团含有2-8个碳原子，另外一些实施方案是，杂烷基基团含有2-6个碳原子，另外一些实施方案是，杂烷基基团含有2-4个碳原子，另外一些实施方案是，杂烷基基团含有2-3个碳原子。这样的实例包括，但并不限于，CH3OCH2-，CH3CH2OCH2-，CH3SCH2-，(CH3)2NCH2-，(CH3)2CH2OCH2-，CH3OCH2CH2-，CH3CH2OCH2CH2-等。
术语“亚烯基”表示从直链或支链的烯烃中去掉两个氢原子所得到的烯烃基基团。并且所述亚烯基可以是取代或非取代的，其中取代基可以是，但并不限于，氘、羟基、氨基、卤素、氰基、芳基、杂芳基、烷氧基、烷基、烯基、炔基、杂环基、巯基、硝基或芳氧基。这样的实例包括，但并不限于，亚乙烯基(-CH＝CH-)、亚异丙烯基(-C(CH3)＝CH-)、3-甲氧基丙烯-1,1-二基、2-甲基丁烯-1,1-二基等等。
术语“亚碳环基”(“亚环烷基”)表示含有3-12个碳原子的单环或7-12个碳原子的双环去掉两个氢原子所得到的饱和二价碳氢环，其中碳环基或环烷基具有如本发明所述的含义，这样的实例包括，但并不限于，亚环丙基、亚环丁基、亚环戊基、1-环戊-1-亚烯基、1-环戊-2-亚烯基等。
术语“亚杂环基”表示单环、双环或三环体系，其中环上一个或多个原子独立地选自杂原子，并且可以是完全饱和的或包含一个或多个不饱和度，但不属于芳香族类，具有两个连接点与分子其余部分相连，其中杂环基基团具有如本发明所述的含义。这样的实例包括，但并不限于，哌啶-1,4-二基、哌嗪-1,4-二基、四氢呋喃-2,4-二基、四氢呋喃-3,4-二基、氮杂环丁烷-1,3-二基、吡咯烷-1,3-二基等。
术语“烷氧基”表示烷基基团通过氧原子与分子其余部分相连，其中烷基基团具有如本发明所述的含义。除非另外详细说明，所述烷氧基基团含有1-12个碳原子。在一实施方案中，烷氧基基团含有1-6个碳原子；在另一实施方案中，烷氧基基团含有1-4个碳原子；在又一实施方案中，烷氧基基团含有1-3个碳原子。所述烷氧基基团可以任选地被一个或多个本发明描述的取代基所取代。
烷氧基基团的实例包括，但并不限于，甲氧基(MeO、-OCH3)，乙氧基(EtO、-OCH2CH3)，1-丙氧基(n-PrO、n-丙氧基、-OCH2CH2CH3)，2-丙氧基(i-PrO、i-丙氧基、 -OCH(CH3)2)，1-丁氧基(n-BuO、n-丁氧基、-OCH2CH2CH2CH3)，2-甲基-l-丙氧基(i-BuO、i-丁氧基、-OCH2CH(CH3)2)，2-丁氧基(s-BuO、s-丁氧基、-OCH(CH3)CH2CH3)，2-甲基-2-丙氧基(t-BuO、t-丁氧基、-OC(CH3)3)，1-戊氧基(n-戊氧基、-OCH2CH2CH2CH2CH3)，2-戊氧基(-OCH(CH3)CH2CH2CH3)，3-戊氧基(-OCH(CH2CH3)2)，2-甲基-2-丁氧基(-OC(CH3)2CH2CH3)，3-甲基-2-丁氧基(-OCH(CH3)CH(CH3)2)，3-甲基-l-丁氧基(-OCH2CH2CH(CH3)2)，2-甲基-l-丁氧基(-OCH2CH(CH3)CH2CH3)，等等。
术语“卤代烷基”，“卤代烯基”或“卤代烷氧基”表示烷基，烯基或烷氧基基团被一个或多个卤素原子所取代，这样的实例包含，但并不限于，三氟甲基、三氟甲氧基等。
术语“羟烷基”卓“羟基取代的烷基”表示烷基基团被一个或多个羟基基团所取代，其中烷基基团具有本发明所述的含义。这样的实例包含，但并不限于羟甲基、羟乙基、1,2-二羟基乙基等。
术语“碳环基”或“碳环”表示含有3-12个碳原子的，单价或多价的非芳香性的饱和或部分不饱和单环、双环或者三环体系。碳双环基包括螺碳双环基和稠合碳双环基，合适的碳环基基团包括，但并不限于，环烷基、环烯基和环炔基。碳环基基团的实例进一步包括，环丙基、环丁基、环戊基、1-环戊基-1-烯基、1-环戊基-2-烯基、1-环戊基-3-烯基、环己基、1-环己基-1-烯基、1-环己基-2-烯基、1-环己基-3-烯基、环己二烯基、环庚基、环辛基、环壬基、环癸基、环十一烷基、环十二烷基，等等。
术语“环烷基”表示含有3-12个碳原子的，单价或多价的饱和单环，双环或三环体系。在一实施方案中，环烷基包含3-12个碳原子；在另一实施方案中，环烷基包含3-8个碳原子；在又一实施方案中，环烷基包含3-6个碳原子。所述环烷基基团可以独立地未被取代或被一个或多个本发明所描述的取代基所取代。
术语“杂环基”和“杂环”在此处可交换使用，都是指包含3-12个环原子的饱和或部分不饱和的单环、双环或三环，其中至少一个环原子选自氮、硫和氧原子。除非另外说明，杂环基可以是碳基或氮基，且-CH2-基团可以任选地被-C(O)-替代。环的硫原子可以任选地被氧化成S-氧化物。环的氮原子可以任选地被氧化成N-氧化合物。杂环基的实例包括，但不限于：环氧乙烷基、氮杂环丁基，氧杂环丁基，硫杂环丁基，吡咯烷基，2-吡咯啉基，3-吡咯啉基，吡唑啉基，吡唑烷基，咪唑啉基，咪唑烷基，四氢呋喃基，二氢呋喃基，四氢噻吩基，二氢噻吩基，1,3-二氧环戊基，二硫环戊基，四氢吡喃基，二氢吡喃基，2H-吡喃基，4H-吡喃基，四氢噻喃基，哌啶基，吗啉基，硫代吗啉基，哌嗪基，二噁烷基，二噻烷基，噻噁烷基，高哌嗪基，高哌啶基，氧杂环庚烷基，硫杂环庚烷基，氧氮杂
Figure PCTCN2017118595-appb-000024
基，二氮杂
Figure PCTCN2017118595-appb-000025
基，硫氮杂
Figure PCTCN2017118595-appb-000026
基，吲哚啉基，1,2,3,4-四氢异喹啉基、1,3-苯并二噁茂基、2-氧杂-5-氮杂双环[2.2.1]庚-5-基。杂环基中-CH2-基团被-C(O)-取代的实例包括，但不限于，2-氧代吡咯烷 基、氧代-1,3-噻唑烷基、2-哌啶酮基、3,5-二氧代哌啶基和嘧啶二酮基。杂环基中硫原子被氧化的实例包括，但不限于，环丁砜基、1,1-二氧代硫代吗啉基。所述的杂环基基团可以任选地被一个或多个本发明所描述的取代基所取代。
在一实施方案中，杂环基为4-7个原子组成的杂环基，是指包含4-7个环原子的饱和或部分不饱和的单环，其中至少一个环原子选自氮、硫和氧原子。除非另外说明，4-7个原子组成的杂环基可以是碳基或氮基，且-CH2-基团可以任选地被-C(O)-替代。环的硫原子可以任选地被氧化成S-氧化物。环的氮原子可以任选地被氧化成N-氧化合物。4-7个原子组成的杂环基的实例包括，但不限于：氮杂环丁基，氧杂环丁基，硫杂环丁基，吡咯烷基，2-吡咯啉基，3-吡咯啉基，吡唑啉基，吡唑烷基，咪唑啉基，咪唑烷基，四氢呋喃基，二氢呋喃基，四氢噻吩基，二氢噻吩基，1,3-二氧环戊基，二硫环戊基，四氢吡喃基，二氢吡喃基，2H-吡喃基，4H-吡喃基，四氢噻喃基，哌啶基，吗啉基，硫代吗啉基，哌嗪基，二噁烷基，二噻烷基，噻噁烷基，高哌嗪基，高哌啶基，氧杂环庚烷基，硫杂环庚烷基，氧氮杂
Figure PCTCN2017118595-appb-000027
基，二氮杂
Figure PCTCN2017118595-appb-000028
基，硫氮杂
Figure PCTCN2017118595-appb-000029
基。杂环基中-CH2-基团被-C(O)-取代的实例包括，但不限于，2-氧代吡咯烷基、氧代-1,3-噻唑烷基、2-哌啶酮基、3,5-二氧代哌啶基和嘧啶二酮基。杂环基中硫原子被氧化的实例包括，但不限于，环丁砜基、1,1-二氧代硫代吗啉基。所述的4-7个原子组成的杂环基基团可以任选地被一个或多个本发明所描述的取代基所取代。
在另一实施方案中，杂环基为4个原子组成的杂环基，是指包含4个环原子的饱和或部分不饱和的单环，其中至少一个环原子选自氮、硫和氧原子所取代。除非另外说明，4个原子组成的杂环基可以是碳基或氮基，且-CH2-基团可以任选地被-C(O)-替代。环的硫原子可以任选地被氧化成S-氧化物。环的氮原子可以任选地被氧化成N-氧化合物。4个原子组成的杂环基的实例包括，但不限于：氮杂环丁基，氧杂环丁基，硫杂环丁基。所述的4个原子组成的杂环基基团可以任选地被一个或多个本发明所描述的取代基所取代。
在另一实施方案中，杂环基为5个原子组成的杂环基，是指包含5个环原子的饱和或部分不饱和的单环，其中至少一个环原子选自氮、硫和氧原子。除非另外说明，5个原子组成的杂环基可以是碳基或氮基，且-CH2-基团可以任选地被-C(O)-替代。环的硫原子可以任选地被氧化成S-氧化物。环的氮原子可以任选地被氧化成N-氧化合物。5个原子组成的杂环基的实例包括，但不限于：吡咯烷基，2-吡咯啉基，3-吡咯啉基，吡唑啉基，吡唑烷基，咪唑啉基，咪唑烷基，四氢呋喃基，二氢呋喃基，四氢噻吩基，二氢噻吩基，1,3-二氧环戊基，二硫环戊基。杂环基中-CH2-基团被-C(O)-取代的实例包括，但不限于，2-氧代吡咯烷基、氧代-1,3-噻唑烷基。杂环基中硫原子被氧化的实例包括，但不限于，环丁砜基。所述的5个原子组成的杂环基基团可以任选地被一个或多个本发明所描述的取代基所取代。
在另一实施方案中，杂环基为6个原子组成的杂环基，是指包含6个环原子的饱和或 部分不饱和的单环，其中至少一个环原子选自氮、硫和氧原子。除非另外说明，6个原子组成的杂环基可以是碳基或氮基，且-CH2-基团可以任选地被-C(O)-替代。环的硫原子可以任选地被氧化成S-氧化物。环的氮原子可以任选地被氧化成N-氧化合物。6个原子组成的杂环基的实例包括，但不限于：四氢吡喃基，二氢吡喃基，2H-吡喃基，4H-吡喃基，四氢噻喃基，哌啶基，吗啉基，硫代吗啉基，哌嗪基，二噁烷基，二噻烷基，噻噁烷基。杂环基中-CH2-基团被-C(O)-取代的实例包括，但不限于，2-哌啶酮基、3,5-二氧代哌啶基和嘧啶二酮基。杂环基中硫原子被氧化的实例包括，但不限于，1,1-二氧代硫代吗啉基。所述的6个原子组成的杂环基基团可以任选地被一个或多个本发明所描述的取代基所取代。
还在一实施方案中，杂环基为7-12个原子组成的杂环基，是指包含7-12个环原子的饱和或部分不饱和的螺双环或稠合双环，其中至少一个环原子选自氮、硫和氧原子。除非另外说明，7-12个原子组成的杂环基可以是碳基或氮基，且-CH2-基团可以任选地被-C(O)-替代。环的硫原子可以任选地被氧化成S-氧化物。环的氮原子可以任选地被氧化成N-氧化合物。7-12个原子组成的杂环基的实例包括，但不限于：吲哚啉基，1,2,3,4-四氢异喹啉基、1,3-苯并二噁茂基、2-氧杂-5-氮杂双环[2.2.1]庚-5-基。所述的7-12个原子组成的杂环基基团可以任选地被一个或多个本发明所描述的取代基所取代。
术语“稠合双环”，“稠环”，“稠合双环基”和“稠环基”在此处可交换使用，都是指单价或多价的饱和或部分不饱和的桥环体系，所述桥环体系是指非芳香族的双环体系。这样的体系可以包含独立的或共轭的不饱和体系，但其核心结构不包含芳香环或芳杂环(但是芳香族基团可以作为其上的取代基)。
术语“螺环基”，“螺环”，“螺双环基”或“螺双环”在此处可交换使用，是指单价或多价的饱和或部分不饱和环体系，其中一个环起源于另一个环上特定的环碳原子。例如，像下面所描述的，一个饱和的桥环体系(环B和B’)被称为“稠合双环”，而环A和环B在两个饱和的环体系中共享一个碳原子，被称为“螺环”或“螺双环”。稠合双环基和螺双环基中的每个环都可以是碳环基或杂环基，并且每个环任选地被一个或多个本发明所描述的取代基所取代。
Figure PCTCN2017118595-appb-000030
术语“杂环烷基”是指含有3-12个环原子的单价或多价的饱和单环、双环或者三环体系，其中至少一个环原子选自氮、硫或氧原子。
术语“n个原子组成的”，其中n是整数，典型地描述分子中成环原子的数目，在所述分 子中成环原子的数目是n。例如，哌啶基是6个原子组成的杂环烷基，而1,2,3,4-四氢萘是10个原子组成的环烷基基团。
在本发明中所使用的术语“不饱和的”表示基团中含有一个或多个不饱和度。
术语“杂原子”是指O、S、N、P和Si，包括N、S和P任何氧化态的形式；伯、仲、叔胺和季铵盐的形式；或者杂环中氮原子上的氢被取代的形式，例如，N(像3,4-二氢-2H-吡咯基中的N)，NH(像吡咯烷基中的NH)或NR(像N-取代的吡咯烷基中的NR)。
术语“卤素”是指氟(F)、氯(Cl)、溴(Br)或碘(I)。
术语“芳基”表示含有6-14个环原子，或6-12个环原子，或6-10个环原子的单环、双环和三环的碳环体系，其中，至少一个环体系是芳香族的，其中每一个环体系包含3-7个原子组成的环，且有一个或多个附着点与分子的其余部分相连。术语“芳基”可以和术语“芳香环”交换使用。芳基基团的实例可以包括苯基、萘基和蒽。所述芳基基团可以独立任选地被一个或多个本发明所描述的取代基所取代。
术语“杂芳基”表示含有5-12个环原子，或5-10个环原子，或5-6个环原子的单环、双环和三环体系，其中至少一个环体系是芳香族的，且至少一个环体系包含一个或多个杂原子，其中每一个环体系包含5-7个原子组成的环，且有一个或多个附着点与分子其余部分相连。术语“杂芳基”可以与术语“杂芳环”或“杂芳族化合物”交换使用。所述杂芳基基团任选地被一个或多个本发明所描述的取代基所取代。在一实施方案中，5-10个原子组成的杂芳基包含1，2，3或4个独立选自O，S和N的杂原子。
杂芳基基团的实例包括，但并不限于，2-呋喃基、3-呋喃基、N-咪唑基、2-咪唑基、4-咪唑基、5-咪唑基、3-异噁唑基、4-异噁唑基、5-异噁唑基、2-噁唑基、4-噁唑基、5-噁唑基、N-吡咯基、2-吡咯基、3-吡咯基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-嘧啶基、哒嗪基(如3-哒嗪基)、2-噻唑基、4-噻唑基、5-噻唑基、四唑基(如5-四唑基)、***基(如2-***基和5-***基)、2-噻吩基、3-噻吩基、吡唑基(如2-吡唑基)、异噻唑基、1,2,3-噁二唑基、1,2,5-噁二唑基、1,2,4-噁二唑基、1,2,3-***基、1,2,3-硫代二唑基、1,3,4-硫代二唑基、1,2,5-硫代二唑基、吡嗪基、1,3,5-三嗪基；也包括以下的双环，但绝不限于这些双环：苯并咪唑基、苯并呋喃基、苯并噻吩基、吲哚基(如2-吲哚基)、嘌呤基、喹啉基(如2-喹啉基，3-喹啉基，4-喹啉基)、异喹啉基(如1-异喹啉基、3-异喹啉基或4-异喹啉基)、咪唑并[1,2-a]吡啶基、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,2-b]哒嗪基、[1,2,4]***并[4,3-b]哒嗪基、[1,2,4]***并[1,5-a]嘧啶基、[1,2,4]***并[1,5-a]吡啶基，等等。
术语“羧基”，无论是单独使用还是和其他术语连用，如“羧烷基”，表示-CO 2H；术语“羰基”，无论是单独使用还是和其他术语连用，如“氨基羰基”或“酰氧基”，表示-(C＝O)-。
术语“烷基氨基”包括“N-烷基氨基”和“N,N-二烷基氨基”，其中氨基基团分别独立地被一个或两个烷基基团所取代。其中一些实施例是，烷基氨基是一个或两个C 1-6烷基连接到氮原子上的较低级的烷基氨基基团。另外一些实施例是，烷基氨基是C 1-3的较低级的烷基氨基基团。合适的烷基氨基基团可以是单烷基氨基或二烷基氨基，这样的实例包括，但并不限于，N-甲氨基，N-乙氨基，N,N-二甲氨基，N,N-二乙氨基等等。
术语“芳氨基”表示氨基基团被一个或两个芳基基团所取代，这样的实例包括，但并不限于N-苯氨基。其中一些实施例是，芳氨基上的芳环可以进一步被取代。
术语“氨基烷基”包括被一个或多个氨基所取代的C 1-10直链或支链烷基基团。其中一些实施例是，氨基烷基是被一个或多个氨基基团所取代的C 1-6“较低级的氨基烷基”，这样的实例包括，但并不限于，氨甲基，氨乙基，氨丙基，氨丁基和氨己基。
本发明所使用的术语“前药”，代表一个化合物在体内转化为式(I)所示的化合物。这样的转化受前体药物在血液中水解或在血液或组织中经酶转化为母体结构的影响。本发明前体药物类化合物可以是酯，在现有的发明中酯可以作为前体药物的有苯酯类，脂肪族(C 1-24)酯类，酰氧基甲基酯类，碳酸酯，氨基甲酸酯类和氨基酸酯类。例如本发明里的一个化合物包含羟基，即可以将其酰化得到前体药物形式的化合物。其他的前体药物形式包括磷酸酯，如这些磷酸酯类化合物是经母体上的羟基磷酸化得到的。关于前体药物完整的讨论可以参考以下文献：T.Higuchi and V.Stella,Pro-drugs as Novel Delivery Systems,Vol.14of the A.C.S.Symposium Series,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al.,Prodrugs:Design and Clinical Applications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al.,Prodrugs of Phosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51,2328-2345。
“代谢产物”是指具体的化合物或其盐在体内通过代谢作用所得到的产物。一个化合物的代谢产物可以通过所属领域公知的技术来进行鉴定，其活性可以通过如本发明所描述的那样采用试验的方法进行表征。这样的产物可以是通过给药化合物经过氧化，还原，水解，酰氨化，脱酰氨作用，酯化，脱脂作用，酶裂解等等方法得到。相应地，本发明包括化合物的代谢产物，包括将本发明的化合物与哺乳动物充分接触一段时间所产生的代谢产物。
本发明所使用的“药学上可接受的盐”是指本发明的化合物的有机盐和无机盐。药学上可接受的盐在所属领域是为我们所熟知的，如文献：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,1977,66:1-19.所记载的。药学上可接受的无毒的酸形成的盐包括，但并不限于，与氨基基团反应形成的无机酸盐有盐酸盐，氢溴酸盐，磷酸盐，硫酸盐，高氯酸盐，和有机酸盐如乙酸盐，草酸盐，马来酸盐，酒石酸盐， 柠檬酸盐，琥珀酸盐，丙二酸盐，或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。其他药学上可接受的盐包括己二酸盐，藻酸盐，抗坏血酸盐，天冬氨酸盐，苯磺酸盐，苯甲酸盐，重硫酸盐，硼酸盐，丁酸盐，樟脑酸盐，樟脑磺酸盐，环戊基丙酸盐，二葡萄糖酸盐，十二烷基硫酸盐，乙磺酸盐，甲酸盐，反丁烯二酸盐，葡庚糖酸盐，甘油磷酸盐，葡萄糖酸盐，半硫酸盐，庚酸盐，己酸盐，氢碘酸盐，2-羟基-乙磺酸盐，乳糖醛酸盐，乳酸盐，月桂酸盐，月桂基硫酸盐，苹果酸盐，丙二酸盐，甲磺酸盐，2-萘磺酸盐，烟酸盐，硝酸盐，油酸盐，棕榈酸盐，扑酸盐，果胶酸盐，过硫酸盐，3-苯基丙酸盐，苦味酸盐，特戊酸盐，丙酸盐，硬脂酸盐，硫氰酸盐，对甲苯磺酸盐，十一酸盐，戊酸盐，等等。通过适当的碱得到的盐包括碱金属，碱土金属，铵和N +(C 1-4烷基) 4的盐。本发明也拟构思了任何所包含N的基团的化合物所形成的季铵盐。水溶性或油溶性或分散产物可以通过季铵化作用得到。碱金属或碱土金属盐包括钠，锂，钾，钙，镁，等等。药学上可接受的盐进一步包括适当的、无毒的铵，季铵盐和抗平衡离子形成的胺阳离子，如卤化物，氢氧化物，羧化物，硫酸化物，磷酸化物，硝酸化物，C 1-8磺酸化物和芳香磺酸化物。
本发明的“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括，但并不限于，水，异丙醇，乙醇，甲醇，二甲亚砜，乙酸乙酯，乙酸和氨基乙醇。术语“水合物”是指溶剂分子是水所形成的缔合物。
如本发明所使用的术语“治疗”任何疾病或病症，在其中一些实施方案中指改善疾病或病症(即减缓或阻止或减轻疾病或其至少一种临床症状的发展)。在另一些实施方案中，“治疗”指缓和或改善至少一种身体参数，包括可能不为患者所察觉的身体参数。在另一些实施方案中，“治疗”指从身体上(例如稳定可察觉的症状)或生理学上(例如稳定身体的参数)或上述两方面调节疾病或病症。在另一些实施方案中，“治疗”指预防或延迟疾病或病症的发作、发生或恶化。
可药用的酸加成盐可与无机酸和有机酸形成，例如乙酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、溴化物/氢溴酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、樟脑磺酸盐、氯化物/盐酸盐、氯茶碱盐、柠檬酸盐、乙二磺酸盐、富马酸盐、葡庚糖酸盐、葡糖酸盐、葡糖醛酸盐、马尿酸盐、氢碘酸盐/碘化物、羟乙基磺酸盐、乳酸盐、乳糖醛酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、扁桃酸盐、甲磺酸盐、甲基硫酸盐、萘甲酸盐、萘磺酸盐、烟酸盐、硝酸盐、十八酸盐、油酸盐、草酸盐、棕榈酸盐、扑酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、聚半乳糖酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、磺基水杨酸盐、酒石酸盐、甲苯磺酸盐和三氟乙酸盐。
可以由其衍生得到盐的无机酸包括例如盐酸、氢溴酸、硫酸、硝酸、磷酸等。
可以由其衍生得到盐的有机酸包括例如乙酸、丙酸、羟基乙酸、草酸、马来酸、丙二 酸、琥珀酸、富马酸、酒石酸、柠檬酸、苯甲酸、扁桃酸、甲磺酸、乙磺酸、对甲苯磺酸、磺基水杨酸等。
可药用碱加成盐可与无机碱和有机碱形成。
可以由其衍生得到盐的无机碱包括，例如铵盐和周期表的I族至XII族的金属。在某些实施方案中，该盐衍生自钠、钾、铵、钙、镁、铁、银、锌和铜；特别适合的盐包括铵、钾、钠、钙和镁盐。
可以由其衍生得到盐的有机碱包括伯胺、仲胺和叔胺，取代的胺包括天然存在的取代的胺、环状胺、碱性离子交换树脂等。某些有机胺包括，例如，异丙胺、苄星青霉素(benzathine)、胆碱盐(cholinate)、二乙醇胺、二乙胺、赖氨酸、葡甲胺(meglumine)、哌嗪和氨丁三醇。
本发明的可药用盐可以用常规化学方法由母体化合物、碱性或酸性部分来合成。一般而言，该类盐可以通过使这些化合物的游离酸形式与化学计量量的适宜碱(如Na、Ca、Mg或K的氢氧化物、碳酸盐、碳酸氢盐等)反应，或者通过使这些化合物的游离碱形式与化学计量量的适宜酸反应来进行制备。该类反应通常在水或有机溶剂或二者的混合物中进行。一般地，在适当的情况中，需要使用非水性介质如***、乙酸乙酯、乙醇、异丙醇或乙腈。在例如“Remington′s Pharmaceutical Sciences”，第20版，Mack Publishing Company，Easton，Pa.，(1985)；和“药用盐手册：性质、选择和应用(Handbook of Pharmaceutical Salts：Properties，Selection，and Use)”，Stahl and Wermuth(Wiley-VCH，Weinheim，Germany，2002)中可找到另外一些适宜盐的列表。
另外，本发明公开的化合物，包括它们的盐，也可以以它们的水合物形式或包含其溶剂(例如乙醇、DMSO，等等)的形式得到，用于它们的结晶。本发明公开化合物可以与药学上可接受的溶剂(包括水)固有地或通过设计形成溶剂化物；因此，本发明旨在包括溶剂化的和未溶剂化的形式。
本发明给出的任何结构式也意欲表示这些化合物未被同位素富集的形式以及同位素富集的形式。同位素富集的化合物具有本发明给出的通式描绘的结构，除了一个或多个原子被具有所选择原子量或质量数的原子替换。可引入本发明化合物中的示例性同位素包括氢、碳、氮、氧、磷、硫、氟和氯的同位素，如 2H， 3H， 11C， 13C， 14C， 15N， 17O， 18O， 18F， 31P， 32P， 35S， 36Cl和 125I。
另一方面，本发明所述化合物包括同位素富集的本发明所定义的化合物，例如，其中存在放射性同位素，如 3H， 14C和 18F的那些化合物，或者其中存在非放射性同位素，如 2H和 13C。该类同位素富集的化合物可用于代谢研究(使用 14C)、反应动力学研究(使用例如 2H或 3H)、检测或成像技术，如正电子发射断层扫描术(PET)或包括药物或底物组织分布 测定的单光子发射计算机断层成像术(SPECT)，或可用于患者的放疗中。 18F富集的化合物对PET或SPECT研究而言是特别理想的。同位素富集的式I或式II所示化合物可以通过本领域技术人员熟悉的常规技术或本发明中的实施例和制备过程所描述使用合适的同位素标记试剂替代原来使用过的未标记试剂来制备。
此外，较重同位素特别是氘(即， 2H或D)的取代可提供某些治疗优点，这些优点是由代谢稳定性更高带来的。例如，体内半衰期增加或剂量需求降低或治疗指数得到改善带来的。可以用同位素富集因子来定义该类较重同位素特别是氘的浓度。如果本发明化合物的取代基被指定为氘，该化合物对各指定的氘原子而言具有至少3500(各指定氘原子处52.5％的氘掺入)、至少4000(60％的氘掺入)、至少4500(67.5％的氘掺入)，至少5000(75％的氘掺入)，至少5500(82.5％的氘掺入)、至少6000(90％的氘掺入)、至少6333.3(95％的氘掺入)、至少6466.7(97％的氘掺入)、至少6600(99％的氘掺入)或至少6633.3(99.5％的氘掺入)的同位素富集因子。本发明可药用的溶剂化物包括其中结晶溶剂可以是同位素取代的例如D 2O、丙酮-d 6、DMSO-d 6的那些溶剂化物。
另一方面，本发明涉及制备式I或式II所包含的化合物的中间体。
另一方面，本发明涉及式I或式II所包含的化合物的制备、分离和纯化的方法。
另一方面，本发明提供一种药物组合物，所述药物组合物包含本发明化合物，药学上可接受的载体，赋形剂，稀释剂，辅剂，溶媒，或它们的组合。在一些实施方案，药物组合物可以是液体，固体，半固体，凝胶或喷雾剂型。
“联合”表示在单个剂量单位形式中的固定组合或用于组合施用的部分的药盒，其中本发明公开的化合物和组合伴侣可以在同一时间独立施用或者可以在一定的时间间隔内分别施用，特别是使联合伴侣表现出合作、例如协同作用。如术语“共同给药”或“联合给药”等意欲囊括将所选的组合伴侣施用于需要其的单个个体(例如患者)，并且意欲包括其中物质不必通过相同施用途径或同时施用的治疗方案。如本文所用的术语“药物组合”表示将一种以上活性成分混合或组合所得到的产品，并且既包括活性成分的固定组合也包括非固定组合。术语“固定联合”表示活性成分如本发明公开化合物和组合伴侣以单一实体或剂量的形式同时施用于患者。术语“非固定联合”表示活性成分如本发明公开化合物和组合伙伴均作为单独实体同时、共同或无特定时间限制地先后施用于患者，其中该施用在患者体内提供了两种化合物的治疗有效水平。
下述实施例中所使用的实验方法如无特殊说明，均为常规方法。
下述实施例中所用的材料、试剂等，如无特殊说明，均可从商业途径得到。
下述实施例中使用的Pomalidomide端衍生物根据文献Chemistry&Biology 22,755-763(2015).中公开的方法制备。Lenalidomide端衍生物根据文献J.Med.Chem(DOI: 10.1021/acs.jmedchem.6b01816).中公开的方法制备，RG-7112端羧酸衍生物根据文献Bioorg.Med.Chem.Lett.18,5904-5908(2008).及ACS Med.Chem.Lett.4,466-469(2013).中公开的方法制备。
下述实施例中使用的Ibrutinib端衍生物按照如下方法制备：Click chemistry所需的端炔烃通过酰胺缩合反应连接到Ibrutinib中间体(cas：1022150-12-4)上。具体制备过程如下：(1)中间体1a的制备
Figure PCTCN2017118595-appb-000031
在25mL圆底烧瓶中加入193mg Ibrutinib中间体(cas：1022150-12-4)、3mL无水氯仿和31μL丙炔酸。将103mg DCC溶解于2mL无水氯仿中，保持反应液在0摄氏度的搅拌条件下，将DCC的无水氯仿溶液缓慢加入到上述反应液中，保持0摄氏度搅拌1小时。将反应液冷却至-20度，过滤后保留滤液，重复过滤两次，将滤液旋干后使用200-300目硅胶色谱柱进行分离纯化，流动相为二氯甲烷：甲醇＝60：1，即得中间体1a，产率72％。
中间体1b的制备
Figure PCTCN2017118595-appb-000032
在25mL圆底烧瓶中加入193mg Ibrutinib中间体(cas：1022150-12-4)、3mL无水氯仿和42mg丙炔酸。将103mg DCC溶解于2mL无水氯仿中，保持反应液在0摄氏度的搅拌条件下，将DCC的无水氯仿溶液缓慢加入到上述反应液中，保持0摄氏度搅拌1小时。将反应液冷却至-20度，过滤后保留滤液，重复过滤两次，将滤液旋干后使用200-300目硅胶色谱柱进行分离纯化，流动相为二氯甲烷：甲醇＝60：1，即得中间体1b，产率62％。
中间体1c的制备
Figure PCTCN2017118595-appb-000033
在25mL圆底烧瓶中加入193mg Ibrutinib中间体(cas：1022150-12-4)、3mL无水DMF、75mg HOBT、106mg EDCI、49mg戊炔酸、77μL三乙胺和10mg DMAP。保持反应液在室温的条件下搅拌24小时。加入15mL饱和氯化钠水溶液猝灭反应，将混合物用15mL×3乙酸乙酯萃取三遍，将有机相合并，使用无水硫酸钠干燥，旋干溶剂，使用200-300目硅胶色谱柱进行分离纯化，流动相为二氯甲烷：甲醇＝40：1，即得中间体1c，产率61％。
中间体1d的制备
Figure PCTCN2017118595-appb-000034
在25mL圆底烧瓶中加入193mg Ibrutinib中间体(cas：1022150-12-4)、3mL无水DMF、75mg HOBT、106mg EDCI、56mg己炔酸、77μL三乙胺和10mg DMAP。保持反应液在室温的条件下搅拌24小时。加入15mL饱和氯化钠水溶液猝灭反应，将混合物用15mL×3乙酸乙酯萃取三遍，将有机相合并，使用无水硫酸钠干燥，旋干溶剂，使用200-300目硅胶色谱柱进行分离纯化，流动相为二氯甲烷：甲醇＝40：1，即得中间体1d，产率71％。
(2)中间体2a的制备
Figure PCTCN2017118595-appb-000035
在100mL圆底烧瓶中加入2.67mL 3-aminopropan-1-ol、50mL无水二氯甲烷，将反应液冷却至0摄氏度，加入6.8mL三乙胺和9.7mL Boc 2O。将反应液在搅拌的条件下自然回升到在室温，继续搅拌12小时。加入100mL饱和碳酸氢钠水溶液猝灭反应，将混合物用50mL×3二氯甲烷萃取三遍，将有机相合并，使用无水硫酸钠干燥，旋干溶剂，使用200-300目硅胶色谱柱进行分离纯化，流动相为二氯甲烷：甲醇＝20：1，即得中间体2a，产率72％。
中间体2b的制备
Figure PCTCN2017118595-appb-000036
在100mL圆底烧瓶中加入3.22mL 4-aminobutan-1-ol、50mL无水二氯甲烷，将反应液冷却至0摄氏度，加入6.8mL三乙胺和9.7mL Boc 2O。将反应液在搅拌的条件下自然回升到在室温，继续搅拌12小时。加入100mL饱和碳酸氢钠水溶液猝灭反应，将混合物用50mL×3二氯甲烷萃取三遍，将有机相合并，使用无水硫酸钠干燥，旋干溶剂，使用200-300目硅胶色谱柱进行分离纯化，流动相为二氯甲烷：甲醇＝20：1，即得中间体2b，产率81％。
中间体2c的制备
Figure PCTCN2017118595-appb-000037
在100mL圆底烧瓶中加入1.6g叠氮化钠和25mL水，加入4.9g 2-(2-hydroxyethoxy)ethyl-4-methylbenzenesulfonate。将反应液在90摄氏度搅拌24小时。加入50mL饱和碳酸氢钠水溶液猝灭反应，将混合物用40mL×3二氯甲烷萃取三遍，将有机相合并，使用无水硫酸钠干燥，旋干溶剂，即得中间体，产率46％。在50mL圆底烧瓶中加入所得的产品787mg，8mL无水二氯甲烷和1.67mL三乙胺，在搅拌的条件下将1.72g TsCl的无水二氯甲烷溶液缓慢加入到上述反应液中，室温搅拌24小时。加入100mL饱和碳酸氢钠水溶液猝灭反应，将混合物用50mL×3二氯甲烷萃取三遍，将有机相合并，使用无水硫酸钠干燥，旋干溶剂，使用200-300目硅胶色谱柱进行分离纯化，流动相为石油醚：乙酸乙酯＝5：1，即得中间体2c，产率67％。
中间体2d的制备
Figure PCTCN2017118595-appb-000038
在50mL圆底烧瓶中加入526mg中间体2a和15mL无水THF，在0摄氏度搅拌的条件下缓慢加入150mg NaH(60％，分散在矿物油中)，将反应液在0摄氏度搅拌1小时，将285mg中间体2c的无水THF溶液缓慢加入到上述反应液中，将反应液在搅拌的条件下自然回升到在室温，继续搅拌15小时。在反应液中滴加入甲醇猝灭反应，旋干溶剂，使用200-300目硅胶色谱柱进行分离纯化，流动相为石油醚：乙酸乙酯＝6：1，即得中间体，产率26％。在25mL圆底烧瓶中加入所得的产品230mg，5mL二氯甲烷和0.5mL三氟乙酸，室温搅拌6小时。加入15mL甲苯，旋干溶剂，使用200-300目硅胶色谱柱进行分离纯化，流动相为二氯甲烷：甲醇＝10：1，即得中间体2d，产率62％。
中间体2e的制备
Figure PCTCN2017118595-appb-000039
Figure PCTCN2017118595-appb-000040
在100mL圆底烧瓶中加入2.8g中间体2b和50mL无水THF，在0摄氏度搅拌的条件下缓慢加入800mg NaH(60％，分散在矿物油中)，将反应液在0摄氏度搅拌1小时，将1.43g中间体2c的无水THF溶液缓慢加入到上述反应液中，将反应液在搅拌的条件下自然回升到在室温，继续搅拌15小时。在反应液中滴加入甲醇猝灭反应，旋干溶剂，使用200-300目硅胶色谱柱进行分离纯化，流动相为石油醚：乙酸乙酯＝6：1，即得中间体，产率22％。在25mL圆底烧瓶中加入所得的产品800mg，15mL二氯甲烷和1.5mL三氟乙酸，室温搅拌2小时。加入25mL甲苯，旋干溶剂，使用200-300目硅胶色谱柱进行分离纯化，流动相为二氯甲烷：甲醇＝10：1，即得中间体2e，产率66％。
(3)中间体3a的制备
Figure PCTCN2017118595-appb-000041
在5mL圆底烧瓶中加入13.3mg RG-7112端羧酸衍生物、9.2mg HATU、0.5mL DMF和12μL DIEA。保持反应液在室温的条件下搅拌0.5小时，在搅拌的条件下加入4.4mg2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethan-1-amine的DMF溶液0.5mL。保持反应液在室温的条件下搅拌2小时。加入5mL饱和氯化钠水溶液猝灭反应，将混合物用5mL×3乙酸乙酯萃取三遍，将有机相合并，使用无水硫酸钠干燥，旋干溶剂，使用200-300目硅胶色谱柱进行分离纯化，流动相为二氯甲烷：甲醇＝40：1，即得中间体3a，产率53％。
中间体3b的制备
Figure PCTCN2017118595-appb-000042
在5mL圆底烧瓶中加入13.3mg RG-7112端羧酸衍生物、9.2mg HATU、0.5mL DMF 和12μL DIEA。保持反应液在室温的条件下搅拌0.5小时，在搅拌的条件下加入5.3mg14-azido-3,6,9,12-tetraoxatetradecan-1-amine的DMF溶液0.5mL。保持反应液在室温的条件下搅拌2小时。加入5mL饱和氯化钠水溶液猝灭反应，将混合物用5mL×3乙酸乙酯萃取三遍，将有机相合并，使用无水硫酸钠干燥，旋干溶剂，使用200-300目硅胶色谱柱进行分离纯化，流动相为二氯甲烷：甲醇＝40：1，即得中间体3a，产率51％。
(4)中间体4a的制备
Figure PCTCN2017118595-appb-000043
在5mL圆底烧瓶中加入24mg 8-aminooctanoic acid、70μL DIEA、0.3mL DMF和35mg2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione。保持反应液在90摄氏度的条件下搅拌3小时。加入5mL饱和氯化钠水溶液猝灭反应，将混合物用5mL×3乙酸乙酯萃取三遍，将有机相合并，使用无水硫酸钠干燥，旋干溶剂，使用200-300目硅胶色谱柱进行分离纯化，流动相为二氯甲烷：甲醇＝40：1，即得中间体4a，产率22％。
(5)中间体5a的制备
Figure PCTCN2017118595-appb-000044
在100mL圆底烧瓶中加入3g octane-1,8-diol、20mL无水THF和1.3g叔丁醇钾。保持反应液在氩气保护室温的条件下搅拌15分钟，滴加入1.2g 3-溴丙炔。保持反应液在氩气保护室温的条件下搅拌12小时。旋干溶剂，加入30mL饱和氯化钠水溶液猝灭反应，采用1M HCl将pH值调至3-5，将混合物用30mL×3二氯甲烷萃取三遍，将有机相合并，使用无水硫酸钠干燥，旋干溶剂，使用200-300目硅胶色谱柱进行分离纯化，流动相为石油醚：乙酸乙酯＝3：1，即得中间体5a，产率55％。
中间体5b的制备
Figure PCTCN2017118595-appb-000045
在100mL圆底烧瓶中加入12.6g 2,2'-(ethane-1,2-diylbis(oxy))bis(ethan-1-ol)、50mL无水THF和5g叔丁醇钾。保持反应液在氩气保护室温的条件下搅拌15分钟，滴加入3.5mL3-溴丙炔。保持反应液在氩气保护室温的条件下搅拌12小时。旋干溶剂，加入30mL饱和氯化钠水溶液猝灭反应，采用1M HCl将pH值调至3-5，将混合物用30mL×3二氯甲烷萃 取三遍，将有机相合并，使用无水硫酸钠干燥，旋干溶剂，使用200-300目硅胶色谱柱进行分离纯化，流动相为石油醚：乙酸乙酯＝3：1，即得中间体5b，产率77％。
中间体5c的制备
Figure PCTCN2017118595-appb-000046
在100mL圆底烧瓶中加入4.4mL pentane-1,5-diol、30mL无水THF和2.5g叔丁醇钾。保持反应液在氩气保护室温的条件下搅拌15分钟，滴加入1.73mL 3-溴丙炔。保持反应液在氩气保护室温的条件下搅拌12小时。旋干溶剂，加入30mL饱和氯化钠水溶液猝灭反应，采用1M HCl将pH值调至3-5，将混合物用30mL×3二氯甲烷萃取三遍，将有机相合并，使用无水硫酸钠干燥，旋干溶剂，使用200-300目硅胶色谱柱进行分离纯化，流动相为石油醚：乙酸乙酯＝3：1，即得中间体5c，产率74％。
实施例1、式1-式18所示化合物的制备
Figure PCTCN2017118595-appb-000047
在5mL圆底烧瓶中加入48mg Pomalidomide端衍生物、44mg中间体1a、18mg CuSO 4、60mg抗坏血酸钠、0.1mL水和1mL叔丁醇。在氩气的保护下70摄氏度搅拌6小时后，加入15mL饱和碳酸氢钠水溶液猝灭反应，将混合物用15mL×3二氯甲烷萃取三遍，将有机相合并，使用无水硫酸钠干燥，旋干溶剂，使用200-300目硅胶色谱柱进行分离纯化，流动相为二氯甲烷：甲醇＝30：1，即得式1所示化合物，产率61％。 1H-NMR(400MHz,CDCl 3/CD 3OD＝3:1,ppm):8.27-8.23(m,2H),7.60(t,J＝9.1Hz,2H),7.45(dd,J＝8.4Hz,J＝7.3Hz,1H),7.39-7.34(m,2H),7.16-7.02(m,6H),6.91(d,J＝8.5Hz,1H),5.16(dd,J＝48Hz,J＝12.8Hz,1H),4.91-4.46(m,5H),4.01-3.03(m,16H),2.80-2.70(m,3H),2.36-2.21(m,2H),2.07-1.98(m,2H),1.84-1.79(m,1H)； 13C-NMR(100MHz,CDCl 3/CD 3OD＝3:1,ppm):172.7,169.5,169.3,168.0,160.7,158.6,158.1,156.2,155.2,153.8,146.7,136.0,132.4,130.0,129.9,129.3,129.2,127.3,124.1,119.5,119.0,116.9,111.4,110.0,70.5,70.5,70.4,69.4,68.9,53.4,52.8,50.6,50.3,49.5,46.9,46.7,43.0,42.1,31.3,30.3,30.2,25.2,23.9,22.7；LR-MS:calculated for C 46H 49N 12O 9[M+H] +,913.37；found,913.66.
按照上述制备方法制备式2-式6、式9-式11、式13-式18所示化合物。
Figure PCTCN2017118595-appb-000048
1H-NMR(400MHz,CDCl 3/CD 3OD＝3:1,ppm):8.27(d,J＝12.4Hz,1H),7.78(d,J＝17.6Hz,1H),7.60(dd,J＝8.4Hz,J＝6.0Hz,2H),7.48-7.37(m,3H),7.17-7.02(m,6H),6.88(dd,J＝8.4Hz,J＝3.6Hz,1H),4.90-4.49(m,5H),5.16(dd,J＝36.8Hz,J＝14.4Hz,1H),3.88-3.33(m,15H),2.83-2.70(m,3H),2.25-1.96(m,6H),1.75-1.51(m,2H)；LR-MS:calculated for C 47H 51N 12O 8[M+H] +,911.39；found,911.64.
Figure PCTCN2017118595-appb-000049
1H-NMR(400MHz,CDCl 3/CD 3OD＝3:1,ppm):8.17(s,1H),7.51-7.49(m,3H),7.36(t,J＝8.1,1H),7.29-7.26(m,3H),7.07-6.93(m,5H),6.80(d,J＝8.6Hz,1H),4.81-4.34(m,5H),3.97-3.72(m,3H),3.52-3.46(m,6H),3.28-2.89(m,7H),2.72-2.60(m,4H),2.24-1.77(m,6H),1.55-1.50(m,2H)；LR-MS:calculated for C 47H 51N 12O 8[M+H] +,911.39；found,911.91.
Figure PCTCN2017118595-appb-000050
1H-NMR(400MHz,CDCl 3,ppm):8.37-8.33(m,1H),7.65-7.62(m,2H),7.55-7.36(m,4H),7.18-7.06(m,6H),6.90(d,J＝8.5Hz,1H),6.55-6.45(m,1H),5.77(s,1H),4.92-4.50(m,4H),4.42(s,1H),4.02-3.44(m,11H),3.30-3.05(m,1H),2.88-2.69(m,5H),2.50-1.94(m,11H),1.75-1.62(m,1H)；LR-MS:calculated for C 47H 51N 12O 8[M+H] +,911.39；found,911.83.
Figure PCTCN2017118595-appb-000051
1H-NMR(400MHz,CDCl 3,ppm):8.38(s,1H),7.63-7.61(m,2H),7.53-7.36(m,4H),7.18-7.06(m,6H),6.90(d,J＝8.5Hz,1H),6.52-6.48(m,1H),5.85(s,1H),4.92-4.40(m,5H),4.04-3.44(m,15H),3.24-3.07(m,1H),2.87-2.73(m,5H),2.46-1.93(m,11H),1.75-1.62(m,1H)；LR-MS:calculated for C 49H 55N 12O 9[M+H] +,955.41；found,955.80.
Figure PCTCN2017118595-appb-000052
1H-NMR(400MHz,CDCl 3,ppm):8.36-8.26(m,2H),7.68(t,2H),7.49-7.45(m,1H),7.38-7.34(m,2H),7.15-6.96(m,7H),6.54(s,1H),6.44(s,2H),5.17-4.49(m,6H),4.08-3.05(m,20H),2.91-2.72(m,4H),2.35-1.78(m,5H)；LR-MS:calculated for C 48H 53N 12O 10[M+H] +,957.39；found,957.65.
Figure PCTCN2017118595-appb-000053
1H-NMR(400MHz,CDCl 3,ppm):8.36-8.22(m,2H),7.66-7.51(m,3H),7.41-7.07(m,17H),6.89(s,1H),5.57(s,2H),5.57-5.30(m,1H),4.98-4.47(m,3H),4.07-3.79(m,4H),3.65-3.46(m,10H),3.32-3.05(m,4H),2.96-2.51(m,4H),2.50-2.28(m,4H),2.05-1.50(m,9H),1.47(s,3H),1.35-1.31(m,10H),1.25(s,3H)；LR-MS:calculated for C 69H 81Cl 2N 14O 8[M+H] +,1303.57；found,1303.66.
Figure PCTCN2017118595-appb-000054
1H-NMR(400MHz,CDCl 3,ppm):8.34-8.22(m,2H),7.63-7.55(m,3H),7.41-7.03(m,17H),6.90(s,1H),5.60(s,2H),5.47-5.30(m,1H),4.95-4.50(m,3H),4.10-3.83(m,4H),3.65-3.10(m,18H),3.02-2.88(m,2H),2.72(s,2H),2.50-2.28(m,4H),2.05-1.50(m,9H),1.47(s,3H),1.35-1.31(m,10H),1.25(s,3H)；LR-MS:calculated for C 71H 85Cl 2N 14O 9[M+H] +,1347.59；found,1347.76.
Figure PCTCN2017118595-appb-000055
1H-NMR(400MHz,CDCl 3/CD 3OD＝3:1,ppm):8.26(d,J＝17.2Hz,1H),8.13(d,J＝11.2Hz,1H),7.61(t,J＝10.7Hz,2H),7.48(dd,J＝15.8Hz,J＝8.0Hz,1H),7.39-7.35(m,3H),7.18-7.05(m,5H),6.87(t,J＝10.5Hz,1H),5.28-5.13(m,1H),4.93-4.56(m,3H),4.39(dt,J＝28.4Hz,J＝6.9Hz,2H),3.55-3.51(m,1H),3.37-3.22(m,2H),3.15-2.65(m,3H),2.39-1.47(m,12H)；LR-MS:calculated for C 43H 43N 12O 6[M+H] +,823.34；found,823.64.
Figure PCTCN2017118595-appb-000056
1H-NMR(400MHz,CDCl 3/CD 3OD＝3:1,ppm):8.26(d,J＝7.8Hz,1H),7.65(d,J＝7.3Hz,1H),7.58(d,J＝8.0Hz,2H),7.41-7.32(m,5H),7.15-7.02(m,5H),5.15(dd,J＝13.3Hz,J＝4.7 Hz,1H),4.77-4.21(m,6H),4.03-3.81(m,1H),3.81-3.34(m,1H),2.83-2.05(m,13H),1.96-1.75(m,5H),1.70-1.55(m,3H),1.45-1.21(m,4H)；LR-MS:calculated for C 47H 52N 11O 5[M+H] +,850.41；found,850.68.
Figure PCTCN2017118595-appb-000057
1H-NMR(400MHz,CDCl 3/CD 3OD＝3:1,ppm):8.35-8.20(m,1H),8.09(d,J＝13.6Hz,1H),7.68(d,J＝6.8Hz,1H),7.62-7.59(m,2H),7.43-7.32(m,4H),7.16-7.04(m,5H),5.31-4.83(m,4H),4.58-3.97(m,6H),3.66-3.33(m,3H),3.10-2.60(m,6H),2.38-1.86(m,12H),1.65-1.45(m,3H),1.35-1.22(m,4H)；LR-MS:calculated for C 49H 56N 11O 6[M+H] +,894.43；found,894.70.
Figure PCTCN2017118595-appb-000058
1H-NMR(400MHz,CDCl 3/CD 3OD＝3:1,ppm):8.29-8.26(m,1H),7.68(dd,J＝7.0Hz,J＝1.3Hz,1H),7.61(dd,J＝8.6Hz,J＝2.2Hz,2H),7.45-7.35(m,5H),7.18-7.05(m,5H),5.17(dd,J＝13.4Hz,J＝5.0Hz,1H),4.79-4.23(m,6H),4.00-3.51(m,2H),3.41-3.15(m,6H),2.86-2.19(m,13H),2.02-1.87(m,7H),1.54-1.49(m,3H),1.35-1.25(m,6H)；LR-MS:calculated for C 52H 62N 11O 6[M+H] +,936.48；found,936.80.
Figure PCTCN2017118595-appb-000059
1H-NMR(400MHz,CDCl 3/CD 3OD＝3:1,ppm):8.20-8.15(m,2H),7.61(d,J＝6.6Hz,1H),7.54(t,J＝8.1Hz,2H),7.34-7.28(m,4H),7.10-7.05(m,3H),6.99(d,J＝8.0Hz,2H),5.23-4.77 (m,3H),4.50-4.24(m,5H),3.95-3.75(m,2H),3.54-3.30(m,10H),2.96-2.55(m,5H),2.34-1.71(m,9H)；LR-MS:calculated for C 47H 52N 11O 8[M+H] +,898.39；found,898.68.
Figure PCTCN2017118595-appb-000060
1H-NMR(400MHz,CDCl 3/CD 3OD＝3:1,ppm):8.28-8.12(m,2H),7.67-7.61(m,3H),7.43-7.36(m,4H),7.14-7.06(m,5H),5.24-5.15(m,2H),4.93-4.24(m,6H),4.05-3.83(m,1H),3.65-3.50(m,1H),3.07-2.84(m,3H),2.62-1.55(m,12H),1.38-1.24(m,3H),；LR-MS:calculated for C 44H 46N 11O 5[M+H] +,808.36；found,808.64.
Figure PCTCN2017118595-appb-000061
1H-NMR(400MHz,CDCl 3/CD 3OD＝3:1,ppm):8.27(d,J＝8.6Hz,1H),7.61(d,J＝7.1Hz,2H),7.50-7.35(m,4H),7.18-7.05(m,6H),6.87(dd,J＝8.5Hz,J＝3.1Hz,1H),4.93-4.48(m,3H),4.36-4.28(m,2H),4.10-3.87(m,1H),3.71-3.15(m,4H),2.81-2.69(m,5H),2.47-1.90(m,10H),1.71-1.39(m,5H)；LR-MS:calculated for C 46H 49N 12O 6[M+H] +,865.38；found,865.65.
式7-式8所示化合物的制备
Figure PCTCN2017118595-appb-000062
在5mL圆底烧瓶中加入19mg Pomalidomide端衍生物、18mg中间体1a和0.2mL无水二氧六环，在氩气保护下加入2.8mg RuCp*Cl(PPh 3) 2的无水二氧六环溶液0.2mL。在氩气的保护下60摄氏度搅拌12小时后，加入15mL饱和碳酸氢钠水溶液猝灭反应，将混合 物用15mL×3二氯甲烷萃取三遍，将有机相合并，使用无水硫酸钠干燥，旋干溶剂，使用200-300目硅胶色谱柱进行分离纯化，流动相为二氯甲烷：甲醇＝25：1，得到式1和式7同分异构体混合物，再使用200-300目硅胶色谱柱进行分离纯化，流动相为乙酸乙酯：甲醇＝15：1，即得式7所示化合物，产率23％。 1H-NMR(400MHz,(CD 3) 2CO,ppm):10.01(s,1H),8.29(s,1H),7.96-7.74(m,3H),7.55(t,J＝8.0Hz,1H),7.43(t,J＝8.0Hz,2H),7.21-7.01(m,6H),6.58(s,1H),6.48(s,2H),5.35(t,J＝4.8Hz,1H),5.08-5.00(m,2H),4.69-4.53(m,3H),4.21-4.06(m,1H),4.04-3.49(m,12H),3.15-2.69(m,4H),2.52-1.79(m,6H)；LR-MS:calculated for C 46H 49N 12O 9[M+H] +,913.37；found,913.45.
按照上述制备方法制备式8所示化合物。
Figure PCTCN2017118595-appb-000063
1H-NMR(400MHz,(CD 3) 2CO,ppm):10.15-10.01(m,1H),8.30(s,1H),7.94-7.74(m,3H),7.56(t,J＝8.2Hz,1H),7.43(t,J＝7.4Hz,2H),7.21-7.02(m,6H),6.60(s,1H),6.42(s,2H),5.08-4.99(m,2H),4.69-4.53(m,3H),4.21-4.06(m,1H),4.04-3.49(m,16H),3.15-2.69(m,4H),2.54-1.77(m,6H)；LR-MS:calculated for C 48H 53N 12O 10[M+H] +,957.39；found,957.70.
式12所示化合物的制备
Figure PCTCN2017118595-appb-000064
在5mL圆底烧瓶中加入7mg Ibrutinib中间体(cas：1022150-12-4)、0.15mL无水DMF、2.8mg HOBT、4mg EDCI、7mg中间体4a、4μL三乙胺和1mg DMAP。保持反应液在室温的条件下搅拌24小时。加入5mL饱和氯化钠水溶液猝灭反应，将混合物用5mL×3乙酸乙酯萃取三遍，将有机相合并，使用无水硫酸钠干燥，旋干溶剂，使用200-300目硅胶色谱柱进行分离纯化，流动相为二氯甲烷：甲醇＝40：1，即得式12所示化合物，产率61％。 1H-NMR(400MHz,CDCl 3/CD 3OD＝3:1,ppm):8.27-8.23(m,1H),7.57(d,J＝8.4Hz,2H),7.44(dd,J＝ 15.5Hz,J＝7.7Hz,1H),7.34(t,J＝7.7Hz,2H),7.15-7.00(m,6H),6.84(t,J＝9.6Hz,1H),4.86-4.46(m,3H),4.02-3.83(m,1H),3.35-3.11(m,3H),2.81-2.70(m,3H),2.36-1.90(m,6H),1.62-1.29(m,12H)；LR-MS:calculated for C 43H 46N 9O 6[M+H] +,784.35；found,784.64.
实施例2、式1-式18所示化合物在Western Blot水平的生物活性测试
细胞处理(野生型细胞)：
Set up对数生长期的Ramos或HBL-1或Mino或IgE MM或Jurkat或HeLa细胞于6孔板里，加化合物处理；48h后收细胞。
细胞处理(C481S或C481A突变BTK质粒瞬转细胞)：
Set up对数生长期的293T或HeLa细胞于6孔板里，18小时后待细胞贴壁后更换培养液，1.5小时后每孔加入新制的含有PEI和质粒的Opti-MEM培养基500微升(含有PEI和质粒的Opti-MEM培养基制备方法如下所示)，混匀，8小时后更换正常培养液并加化合物，处理48小时；更换培养液并加化合物，再处理48小时后收细胞。
含有PEI和质粒的Opti-MEM培养基制备方法：
将0.2微克或0.5微克质粒加到250微升预热的Opti-MEM培养基，轻摇混匀后静置5分钟；将0.6微克或1.5微克PEI加到250微升预热的Opti-MEM培养基，轻摇混匀后静置5分钟；将含有PEI的Opti-MEM培养基缓慢加入到含有质粒的Opti-MEM培养基中，边加边轻摇混匀，静置30分钟即得。
细胞全蛋白抽提：
收集细胞：将处理后的细胞于培养基中刮下，充分混悬后300g离心5分钟收集，PBS洗一遍后，弃去PBS。
裂解细胞：每一样品加入150μl的2×Loading Buffer，充分震荡混匀，95℃变性15分钟，混匀后于-20℃保存或直接用于Western Blot检测。
5×Loading Buffer的配方为：250mM Tris-HCl(pH6.8)，10％(W/V)SDS，0.5％(W/V)溴酚蓝，50％(V/V)甘油，5％(W/V)β-巯基乙醇(2-ME)。2×Loading Buffer的制备是将1.5倍体积的dd水加入到5×Loading Buffer中即得。
Western Blot检测的具体步骤如下：
1)配制合适浓度的SDS-PAGE胶。参考《分子克隆实验指南》(科学出版社，第二版)第883页表18.3制备合适浓度的分离胶，参考第883页表18.4制备浓度为4％的浓缩胶。
2)制备样品。根据实验要求制备蛋白样品，95℃变性15分钟，离心、混匀并上样于SDS-PAGE胶上样孔中。根据蛋白定量结果适量调整上样体积，通常每个孔上样量为4μl。
3)电泳。接通电源，蛋白样品在浓缩胶中电压为83伏特，待蛋白样品进入分离胶时， 我们把电压调整为110伏特继续电泳。待溴酚蓝几乎完全跑出PAGE胶时终止电泳。
4)转膜。电泳结束后取下凝胶，按下列顺序安装转膜装置：(负极)、滤纸、凝胶、活化的PVDF膜、滤纸、(正极)。切记凝胶和PVDF膜之间绝对不能气泡。然后夹紧转移装置置于转膜缓冲液中，最后放入冰盒，置于4℃冷库100V恒压通电1.5小时。
5)封闭。转膜结束后，取出PVDF膜，将膜浸没在含5％的脱脂奶粉的TBST缓冲液里，室温下摇床振荡1小时。
6)一抗孵育。封闭结束后，用TBST缓冲液荡洗3次，然后加入适度稀释比例的一抗，4℃过夜。回收一抗，将PVDF膜用TBST缓冲液荡洗3次，每次振荡10分钟。
7)二抗孵育。弃去TBST缓冲液，加入一定稀释比(通常是1：3000～1：5000)的二抗(鼠抗或者兔抗，由一抗决定)，室温下摇床振荡1小时。弃去二抗，将PVDF膜用TBST缓冲液荡洗3次，每次振荡10分钟。最后用TBST缓冲液荡洗10分钟。
8)显色并压片。将ECL显色底物均匀覆盖在PVDF膜上，室温显色0.5～15分钟。
根据本发明实施例的化合物对BTK的降解活性如下：
在Ramos细胞系中，在蛋白免疫印迹实验(WB)结果中可以明显观察到在不同剂量下，式1所示化合物对BTK的降解作用如图3所示(Ramos细胞系:2×10 6细胞每孔(6孔板),37℃ 5％CO 2培养48小时；DMSO终浓度为1％)，式12和式13所示化合物对BTK的降解作用如图4所示(Ramos细胞系:2×10 6细胞每孔(6孔板),37℃ 5％CO 2培养48小时；DMSO终浓度为1％)，式16和式17所示化合物对BTK的降解作用如图5所示(Ramos细胞系:2×10 6细胞每孔(6孔板),37℃ 5％CO 2培养48小时；DMSO终浓度为1％)；在HBL-1细胞系中，在蛋白免疫印迹实验(WB)结果中可以明显观察到在不同剂量下，式1所示化合物对BTK的降解作用如图8-1所示(HBL-1细胞系:2×10 6细胞每孔(6孔板),37℃ 5％CO 2培养48小时；DMSO终浓度为1％)，图8-2所示(IgE MM细胞系:2×10 6细胞每孔(6孔板),37℃ 5％CO 2培养48小时；DMSO终浓度为1％)，图8-3所示(Mino细胞系:2×10 6细胞每孔(6孔板),37℃5％CO 2培养48小时；DMSO终浓度为1％)，在相同剂量不同时间下，式1所示化合物对BTK的降解作用如图6所示(HBL-1细胞系:2×10 6细胞每孔(6孔板),37℃ 5％CO 2培养；DMSO终浓度为1％)；在IgE MM细胞系中，在蛋白免疫印迹实验(WB)结果中可以明显观察到在不同剂量下，式1所示化合物对BTK的降解作用如图8(图8-1～图8-3)所示；在Mino细胞系中，在蛋白免疫印迹实验(WB)结果中可以明显观察到在不同剂量下，式1所示化合物对BTK的降解作用如图8(图8-1～图8-3)所示。
在Rescue实验中，在Ramos细胞系中，在蛋白免疫印迹实验(WB)结果中可以明显观察到式1所示化合物对BTK的降解作用，受到依鲁替尼、泊马度胺、MG-132、MLN4924的影响结果如图7-1所示(Pom＝泊马度胺,Ib＝依鲁替尼,M＝MLN4924；式1所示化合物浓 度为100nM,M浓度为400nM；依鲁替尼、泊马度胺浓度为1μM；Ramos细胞系:2×10 6细胞每孔(6孔板),37℃ 5％CO 2培养48小时；DMSO终浓度为1％)；图7-2所示(Pom＝泊马度胺,Ib＝
依鲁替尼,
Figure PCTCN2017118595-appb-000065
式1,L-1和L-2浓度为100nM；Ib和Pom浓度为1μM；Ramos细胞系:2×10 6细胞每孔(6孔板),37℃ 5％CO 2培养48小时；DMSO终浓度为1％)；图7-3所示(MG＝MG-132；式1浓度为100nM；MG浓度为400nM；Ramos细胞系:2×10 6细胞每孔(6孔板),37℃ 5％CO 2，加入MG-132预先孵育4小时,然后加入式1,37℃ 5％CO 2孵育12小时；DMSO终浓度为1％)；在蛋白免疫印迹实验(WB)结果中可以明显观察到依鲁替尼、泊马度胺、MG-132、MLN4924、L-1、L-2对BTK无降解作用，如图7(图7-1～图7-3)所示。
在HeLa和293T细胞中，在蛋白免疫印迹实验(WB)结果中可以明显观察到在不同剂量下，式1所示化合物对C481S或C481A突变BTK的降解作用如图9-1所示(HeLa细胞系:1×10 6细胞每孔(6孔板),37℃5％CO 2孵育4天，0.5μg质粒用PEI方法瞬转入细胞，-/+意思是未经瞬转/经过瞬转)，图9-2所示(293T细胞系:1×10 6细胞每孔(6孔板),37℃5％CO 2孵育4天.0.2μg质粒用PEI方法瞬转入细胞.)，图9-3所示(HeLa细胞系:1×10 6细胞每孔(6孔板),37℃5％CO 2孵育4天.0.5μg质粒用PEI方法瞬转入细胞)；在蛋白免疫印迹实验(WB)结果中可以明显观察到Ibrutinib对C481S或C481A突变BTK无降解作用，如图9(图9-1～图9-3)所示。
在化合物脱靶作用实验中，在HeLa、HBL-1、Jurkat细胞系中，在蛋白免疫印迹实验(WB)结果中可以明显观察到式1所示化合物对EGFR、FLT-3、ITK、TEC无降解作用，如图10(HeLa细胞系:1×10 6细胞每孔(6孔板),37℃ 5％CO 2孵育48小时；DMSO终浓度1％。HBL-1细胞系:2×10 6细胞每孔(6孔板),37℃ 5％CO 2孵育24小时；DMSO终浓度1％。Jurkat细胞系:1.5×10 6细胞每孔(6孔板),37℃ 5％CO 2孵育48小时；DMSO终浓度1％。Jurkat细胞系:1.5×10 6细胞每孔(6孔板),37℃5％CO 2孵育48小时；DMSO终浓度1％)。
由上述测试结果可以看出，式1、式16和式17所示化合物降解作用最强(两者在10nM的浓度下可降解约80％以上的BTK)。式1所示化合物能在30nM的浓度下可降解约60％以上的C481S或C481A突变BTK。式1所示化合物不存在脱靶作用，在2000nM的浓度下不能降解EGFR、FLT-3、ITK和TEC。
实施例3、式1所示化合物对BTK、ITK、EGFR的抑制
1.准备1x激酶基质缓冲液和终止缓冲液。
1)1x激酶基质缓冲液
50mM HEPES,pH 7.5
0.01％Brij-35
2)终止缓冲液
100mM HEPES,pH 7.5
0.015％Brij-35
0.2％Coating Reagent#3
50mM EDTA
2.准备化合物。
1)使用100％DMSO稀释化合物，到达反应中最终所需抑制剂最高浓度的50X。如果化合物在1μM测试，在这一步骤中制备化合物50μM的DMSO溶液。
2)以3倍的梯度连续稀释化合物，得到总共10个浓度。
3)在96孔板的2个空孔中加入100微升100％DMSO作为无化合物对照和无酶对照。
4)准备中间板。
将10微升化合物从源板转移到一块新的96孔板，作为中间板。
在中间板的每个孔里加入90微升1x激酶缓冲液。
在振动器上将中间板中化合物混匀10分钟
3.准备酶联板。
1)将96孔中间板每个孔取5微升转移到384孔板，一式两份。例如，96孔板A1转移到384孔板A1和A2，96孔板A2转移到384孔板A3和A4，以此类推。
4.激酶反应。
1)准备2.5x酶溶液
将酶加入到1x激酶基质缓冲液。
2)准备2.5x肽溶液
将FAM标记的肽和ATP加入到1x激酶基质缓冲液。
3)将2.5x酶溶液转移到酶联板。
4)酶联板已经包含5微升化合物在10％DMSO里。
5)在384孔酶联板的每个孔里加入10微升2.5x酶溶液。
6)室温孵育10分钟。
7)将2.5x肽溶液转移到酶联板。
在384孔酶联板的每个孔里加入10微升2.5x肽溶液。
8)激酶反应及停止
在28摄氏度孵育指定的时间。
加入25微升终止缓冲液终止反应。
9)在Caliper上收集数据。
5.曲线拟合
1)从Caliper程序拷贝转换数据。
2)将转换值转变成抑制值。
抑制率＝(max-转换值)/(max-min)*100.
“max”代表DMSO对照；“min”代表low control.
3)在XLfit excel add-in version 5.4.0.8拟合数据得到IC 50值。
采用的方程式为
Y＝Bottom+(Top-Bottom)/(1+(LogIC 50/X)*HillSlope))
通过上述方法测得本发明化合物对不同激酶抑制结果如图11中所示。式1所示化合物对BTK激酶的抑制活性IC 50为95nM，Ibrutinib对BTK的抑制活性IC 50为1.4nM；Ibrutinib的对ITK的抑制活性IC 50为34nM，对EGFR的抑制活性IC 50为1.3nM。式1所示化合物对ITK、EGFR的IC 50值均高于1000nM。说明根据本发明实施例的化合物对Ibrutinib存在副作用的靶点无明显抑制作用。
实施例4、式1-式18所示化合物对细胞增殖的抑制
MTT实验试剂：
试剂：RPIM 1640medium；DMEM medium；100×非必需氨基酸(NEAA)；100×青链霉素混合液；50mMβ巯基乙醇；小牛血清(FBS，事先经过失活处理)。
A培养基(500ml)：RPIM 1640medium(450ml)+100×NEAA(5ml)+100×青链霉素混合液(5ml)+小牛血清(50ml)+50mMβ巯基乙醇(0.5ml)。
B培养基(500ml)：DMEM medium(450ml)+100×NEAA(5ml)+100×青链霉素混合液(5ml)+小牛血清(50ml)+50mMβ巯基乙醇(0.5ml)。。
CCK-8试剂盒(Cell Counting Kit-8)
MTT实验流程(Ramos cell与HBL-1cell)：
1)收集对数期细胞，用A培养基调节细胞悬液浓度6.6×10 4/ml。
2)用A培养基2倍梯度稀释小分子浓度为100nM至2nM。配置成小分子溶液。
3)将45μL的细胞悬液加入到96孔板(边缘孔用灭菌PBS填充，3000个细胞/孔)。每板设阴性对照(45μL细胞悬液和45μL的A培养基)，每组设定3复孔。
4)置37℃，5％CO 2孵育1小时后，在96孔板的每个孔中加入45μL对应的小分子溶液。然后再在37℃，5％CO 2孵育72-96小时。体系中，小分子浓度呈2倍梯度稀释，浓度从50nM至1nM。
每孔加入10μl cck-8溶液，继续培养4h。直接酶联免疫检测仪OD490nm测量各孔的吸光值。
通过上述方法测得本发明化合物对细胞增殖抑制结果如表1中所示。
表1：式1-式18所示化合物对HBL-1细胞系和Ramos细胞系抑制能力的MTT实验(GI50值)：
Figure PCTCN2017118595-appb-000066
Figure PCTCN2017118595-appb-000067
Figure PCTCN2017118595-appb-000068
其中，N.D表示未检测抑制活性。
在HBL-1细胞中，式1、式2、式3、式4、式16、式17所示化合物活性与阳性对照化合物Ibrutinib接近，GI 50均在5nM左右；在Ramos细胞中，式1-式18所示化合物与阳性对照化合物Ibrutinib的GI 50值均高于1000nM，说明根据本发明的实施例的化合物对于HBL-1细胞增殖的抑制能力与Ibrutinib相当。
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术 人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。

Claims (24)

  1. 一种化合物，其为式I所示化合物或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药：
    X-Y-Z
    式I
    所述X为
    Figure PCTCN2017118595-appb-100001
    所述Z为：
    Figure PCTCN2017118595-appb-100002
    Figure PCTCN2017118595-appb-100003
    所述Y为
    Figure PCTCN2017118595-appb-100004
    其中，各L 1、L 2、L 3、L 4、L 5、L 6、L 7独立为键，-O-，-S(＝O) t1-，-S-，-N(R a)-，-C(＝O)O-，-N(R a)-C(＝O)-，-C(＝O)-(CH 2) t2-，-CH 2-，-C(＝O)-，-OC(＝O)-，-C(＝S)-，-C(＝O)-N(R a)-，-C(＝S)-N(R a)-，-(CH 2) t2-C(＝O)-或者三氮唑基；
    各R a独立地为氢，C1-4烷基，卤代C1-4烷基，C1-4烷基酰基或羟基；
    各t2独立地为0，1，2，3或4；
    各t1独立地为0，1或2；
    各X 1、X 2、X 3、X 4、X 5、X 6、X 7、X 8、X 9、X 10、Q、W独立地为C，O，S，N或Se；
    各R 1、R 2、R 3、R 4、R 5、R 6、B独立地为H、氘、氨基、C1-4酰胺基、C1-4烷基、C1-4杂烷基、C3-8环烷基、C2-10杂环基、C6-10芳基、C1-9杂芳基、C6-10芳基、C1-4烷氧基、C1-4烯基、C1-4炔基，其中，所述的C1-4烷基、C1-4杂烷基、C3-8环烷基、C2-10杂环基、C6-10芳基、C1-9杂芳基、C6-10芳基、C1-4烷氧基、C1-4烯基、C1-4炔基可以任选地被一个或多个选自氘、羟基、氨基、氧代、F、Cl、Br、I、氰基、C1-6烷基、C1-6卤代烷基、C1-6羟基烷基、C1-6氨基烷基、C1-6烷氧基C1-6烷基、C1-6烷氨基C1-6烷基、C6-10芳基C1-6烷基、C1-9杂芳基C1-6烷基、C2-10杂环基C1-6烷基、C3-10环烷基C1-6烷基、C1-6烷氧基、C1-6烷氨基、C6-10芳基、C6-10芳氧基、C6-10芳氨基、C1-9杂芳基、C1-9杂芳氧基、C2-6烯基、C3-10环烷基、卤素取代C6-10芳基、卤素取代C1-9杂芳基、卤素取代C2-10杂环基或C2-10杂环基的取代基所取代，
    各A独立为氢，C1-4烷基，C1-4卤代烷基，羟基，硝基，氨基，氰基，卤素，羧基，C1-4烷氧基，C1-4烷氨基，C1-4烷硫基，C1-4烷基酰基，任选取代的C3-12环烷基，任选取代的C3-9杂环基，任选取代的C6-12芳基，任选取代的C1-9杂芳基，
    各E独立地为酰胺基，酯基，氨基甲酯基，脲基，胍基，杂环基，环烷基，螺杂双环基，稠合杂双环基，桥杂双环基，C6-10芳基或C2-C10杂芳基；各E任选地被1，2，3或4个独立的R b所取代；
    各R b独立地为氢，C1-4烷基，C1-4卤代烷基，羟基，硝基，氨基，氰基，卤素，羧基，C1-4烷氧基，C1-4烷氨基，C1-4烷硫基，C1-4烷基酰基，C3-12环烷基，C3-9杂环基，C6-12芳基，C1-9杂芳基，氨基C1-4烷基，羟基C1-4烷基，磺酸基，氨基磺酰基或氨基酰基；
    各a、b、c、d独立地为0～30之间的整数。
  2. 根据权利要求1所述的化合物，其特征在于，
    各L 1独立地为键，-O-，-S-，-NH-，
    各L 2独立地为键、-(C＝O)CH＝CH 2-，-O-，-S-，-S(＝O)-，-S(＝O) 2-，-NRa-，-C(＝O)-，-C(＝O)O-，-N(R a)-C(＝O)-，-CH 2-，-OC(＝O)-，-C(＝S)-，-C(＝O)-N(R a)-，-C(＝S)-N(R a)或者三氮唑基，
    各R a独立地为氢，C1-2烷基，卤代C1-2烷基，C1-2烷基酰基或羟基，
    各R 1、R 2、R 3、R 4独立地为H、氨基、C1-4烷基、C1-4杂烷基、C5-7环烷基、C5-7杂环基、C6-7芳基、C5-7杂芳基，其中，所述C1-4烷基、C1-4杂烷基、C5-7环烷基、C5-7杂环基、C6-7芳基、C5-7杂芳基可以任选地被一个或多个选自氘、羟基、氨基、氧代、F、Cl、Br、I、氰基取代基取代。
  3. 根据权利要求2所述的化合物，其特征在于，所述X为如下所示的化合物：
    Figure PCTCN2017118595-appb-100005
  4. 根据权利要求1所述的化合物，其特征在于，
    各A独立为氢，任选取代的C5-7杂环基，任选取代的C5-7环烷基，任选取代的C6-7芳基，任选取代的C5-7杂芳基，
    各R 5、B独立地为H、氨基、C1-4烷基、C1-4杂烷基、C5-7环烷基、C5-7杂环基、C6-7芳基、C5-7杂芳基，其中，所述C1-4烷基、C1-4杂烷基、C5-7环烷基、C5-7杂环基、C6-7芳基、C5-7杂芳基可以任选地被一个或多个选自氘、羟基、氨基、氧代、F、Cl、Br、I、氰基、C5-7芳基、C5-7杂芳基、卤素取代C5-7芳基、卤素取代C5-7杂芳基、卤素取代C5-7杂环基的取代基取代；
    各L 3、L 4、L 5独立地为键、-(C＝O)CH＝CH 2-，-O-，-S-，-S(＝O)-，-S(＝O) 2-，-NRa-，-C(＝O)-，-C(＝O)O-，-N(R a)-C(＝O)-，-CH 2-，-OC(＝O)-，-C(＝S)-，-C(＝O)-N(R a)-，-C(＝S)-N(R a)或者三氮唑基，
    各R a独立地为氢，C1-2烷基，卤代C1-2烷基，C1-2烷基酰基或羟基，
    各R 6独立地为氢，氨基，羟基，硝基，氨基，氰基，卤素，羧基。
  5. 根据权利要求4所述的化合物，其特征在于，所述A为
    Figure PCTCN2017118595-appb-100006
    Figure PCTCN2017118595-appb-100007
    所述B为
    Figure PCTCN2017118595-appb-100008
    Figure PCTCN2017118595-appb-100009
    其中，各R c独立地为H，C1-4烷基，卤代C1-4烷基，C1-4烷基酰基或羟基。
  6. 根据权利要求5所述的化合物，其特征在于，所述Z为如下所示的化合物：
    Figure PCTCN2017118595-appb-100010
  7. 根据权利要求1所述的化合物，其特征在于，
    各E独立为酰胺基，酯基，氨基甲酯基，脲基，胍基，杂环基，环烷基，C6-C8芳基或C5-C7杂芳基；各E任选地被1，2，3或4个独立的R b所取代，
    各R b独立地为氢，C1-2烷基，C1-2卤代烷基，羟基，硝基，氨基，氰基，卤素，羧基， C1-2烷氧基，C1-2烷氨基，C1-2烷硫基，C1-2烷基酰基，C5-7环烷基，C5-7杂环基，C6-7芳基，C5-7杂芳基，氨基C1-2烷基，羟基C1-2烷基，磺酸基，氨基磺酰基或氨基酰基，
    各a为0～10之间的整数，
    各b为0～20之间的整数，
    各c为0～20之间的整数，
    各d为0～10之间的整数，
    各L 6、L 7独立地为键、-(C＝O)CH＝CH 2-，-O-，-S-，-S(＝O)-，-S(＝O) 2-，-NRa-，-C(＝O)-，-C(＝O)O-，-N(R a)-C(＝O)-，-CH 2-，-OC(＝O)-，-C(＝S)-，-C(＝O)-N(R a)-，-C(＝S)-N(R a)或者三氮唑基，
    各R a独立地为氢，C1-2烷基，卤代C1-,2烷基，C1-2烷基酰基或羟基。
  8. 根据权利要求7所述的化合物，其特征在于，所述Y为
    Figure PCTCN2017118595-appb-100011
    其中，各e、f独立地为0～30之间的整数；
    各L 6、L 7独立为键，-O-，-S(＝O) t1-，-S-，-N(R a)-，-C(＝O)O-，-N(R a)-C(＝O)-，-C(＝O)-(CH 2) t2-，-CH 2-，-C(＝O)-，-OC(＝O)-，-C(＝S)-，-C(＝O)-N(R a)-，-C(＝S)-N(R a)-或者-(CH 2) t2-C(＝O)-，三氮唑基；
    各R a独立地为氢，C1-2烷基，卤代C1-2烷基，C1-2烷基酰基或羟基；
    各t2独立地为0，1，2，3或4；
    各t1独立地为0，1或2。
  9. 根据权利要求1所述的化合物，其特征在于，所述X为
    Figure PCTCN2017118595-appb-100012
    所述Z为
    Figure PCTCN2017118595-appb-100013
    所述Y为
    Figure PCTCN2017118595-appb-100014
    Figure PCTCN2017118595-appb-100015
    其中，n为0～2之间的整数；m1为1～6之间的整数，n1为0～6之间的整数；m2为0～26之间的整数，n2为0～6之间的整数；n3为1～26之间的整数；m3为2～20之间的整数，n4为0～6之间的整数。
  10. 根据权利要求1-9任一项所述的化合物，其特征在于：包括式II～IX任一项所示化合物或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药，
    Figure PCTCN2017118595-appb-100016
    Figure PCTCN2017118595-appb-100017
    其中，m1为1～6之间的整数，n1为0～6之间的整数，m2为0～26之间的整数，n2为0～6之间的整数，n3为1～26之间的整数，m3为2～20之间的整数，n4为0～6之间的整数。
  11. 一种化合物，其特征在于，其为式1～18任一项所示化合物或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前 药，
    Figure PCTCN2017118595-appb-100018
    Figure PCTCN2017118595-appb-100019
    Figure PCTCN2017118595-appb-100020
    Figure PCTCN2017118595-appb-100021
  12. 一种药物组合物，其特征在于，包括权利要求1～11任一项所述的化合物。
  13. 根据权利要求12所述的药物组合物，其特征在于，进一步包含药学上可接受的载体、赋形剂、稀释剂、辅剂、媒介物或其组合。
  14. 根据权利要求12所述的药物组合物，其特征在于，进一步包括其他治疗或预防非霍奇金淋巴瘤的药物，所述其他治疗或预防非霍奇金淋巴瘤的药物包括依鲁替尼。
  15. 权利要求1-11任一项所述化合物或权利要求12～14任一项所述的药物组合物在制备药物中的用途，所述药物用于降解BTK或抑制BTK。
  16. 权利要求1-11任一项所述化合物或权利要求12～14任一项所述的药物组合物在降解BTK中的用途。
  17. 权利要求1-11任一项所述化合物或权利要求12～14任一项所述的药物组合物在制备药物中的用途，所述药物用于治疗或预防BTK相关性疾病。
  18. 根据权利要求17所述的用途，其特征在于，所述BTK相关性疾病为非霍奇金淋巴瘤。
  19. 权利要求1-11任一项所述化合物或权利要求12～14任一项所述的药物组合物在抗肿瘤中的用途。
  20. 根据权利要求19所述的用途，其特征在于，所述肿瘤为淋巴瘤。
  21. 根据权利要求20所述的用途，其特征在于，所述淋巴瘤为非霍奇金淋巴瘤。
  22. 一种***的方法，其特征在于，给予患者权利要求1-11任一项所述的化合物或权利要求12-14任一项所述的药物组合物。
  23. 根据权利要求22所述的方法，其特征在于，所述肿瘤为淋巴瘤。
  24. 根据权利要求23所述的方法，其特征在于，所述淋巴瘤为非霍奇金淋巴瘤。
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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
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WO2022007824A1 (zh) * 2020-07-07 2022-01-13 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
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WO2022052950A1 (zh) * 2020-09-09 2022-03-17 海思科医药集团股份有限公司 一种降解btk化合物的盐及其晶型和在医药上的用途
WO2022089400A1 (zh) * 2020-10-26 2022-05-05 上海美志医药科技有限公司 靶向降解Btk的化合物及其抗肿瘤用途
WO2022111449A1 (zh) * 2020-11-25 2022-06-02 四川海思科制药有限公司 一种btk降解剂的制备方法
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