CN110845500B

CN110845500B - Application of target BTK degradation compound in treatment of autoimmune system diseases

Info

Publication number: CN110845500B
Application number: CN201910954118.0A
Authority: CN
Inventors: 饶燏; 刘万里; 杨子默; 孙永汇; 朱璨; 杨冰; 李雨欣
Original assignee: Tsinghua University
Current assignee: Tsinghua University
Priority date: 2019-10-09
Filing date: 2019-10-09
Publication date: 2021-05-11
Anticipated expiration: 2039-10-09
Also published as: CN110845500A

Abstract

Use of a targeted BTK degrading compound in the treatment of an autoimmune disease. The invention provides application of a compound in preparing a medicament for treating or preventing autoimmune diseases, wherein the compound is a compound shown in a formula I or a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, and the compound has good treatment and prevention effects on the autoimmune diseases. X-Y-Z is formula I.

Description

Application of target BTK degradation compound in treatment of autoimmune system diseases

Technical Field

The invention relates to the field of biomedicine, in particular to application of a targeted BTK degradation compound in treating autoimmune system diseases.

Background

The protac (protein Targeting chiceras) technology, which is a protein Targeting degradation technology, is a chemical biological or drug discovery approach for inducing protein degradation by using the ubiquitin-proteasome system emerging in recent years. The function of the PROTAC small molecule is based on the process that E3 ubiquitin ligase performs ubiquitin ligation on a certain protein, one end of a PROTAC small molecule chimera can be specifically combined with a target protein, and the other end recruits E3 ubiquitin ligase to enable the PROTAC small molecule chimera to be close to the target protein, so that a subsequent degradation process occurs. The PROTAC chimera is synthesized on the basis of a selective small-molecule inhibitor, and the high homologous proteins can be distinguished through ingenious design, so that the PROTAC technology has certain advantages in the application of biological tools; in addition, the PROTAC molecules are non-covalently bound with the target protein, and can be dissociated after one molecule of protein is degraded to degrade another molecule of target protein, and the means for degrading the protein by the catalytic amount provides the possibility that the PROTAC technology is widely concerned and applied because of more directness and rapidness for the development of high-activity and low-toxicity medicine molecules.

The autoimmune disease refers to a disease caused by self-tissue damage due to the immune reaction of an organism to an autoantigen, and comprises organ-specific autoimmune diseases such as goodpasture's syndrome, pemphigus and the like, systemic autoimmune diseases such as arthritis, systemic lupus erythematosus and the like, the specific mechanism of the autoimmune disease is not completely clear, and one possible mechanism is that a large amount of BTK expression abnormally activates a BCR signal pathway, so that B cell dysfunction and immune tolerance state are changed, and the BTK is converted into autoreactive B cells, and a large amount of autoantibodies are secreted to induce the occurrence of the disease.

Based on the above mechanisms, BTK inhibitors are increasingly studied in autoimmune diseases (including rheumatoid arthritis) in recent years, BTK has become the most target of clinical drugs in the field of autoimmune diseases except TNF (tumor necrosis factor) and CD20, and is expected to become a new target for treating autoimmune diseases in the future, while ibrutinib is approved to be marketed by FDA in 2017 as an autoimmune disease (chronic graft versus host disease (cGVHD)), statistical data show that Rheumatoid Arthritis (RA) is a large class of autoimmune diseases, and is also the most resistant class of diseases to BTK inhibitors, and systemic lupus erythematosus is the second, psoriasis and urticaria can also be seen. Most studies of BTK inhibitors on autoimmune diseases are still in the first and second clinical stages but currently more than ten small molecule inhibitors are in the clinical stage and progress slowly, wherein the first BTK inhibitor exploring RA is a new group of spelrutinib, but the phase II trial in 2016 does not reach the main endpoint of ACR20 at week 4, and the clinical study of poselinb, which is mainly used for treating RA, has been terminated in 2018, and randomly and parallelly distributed clinical secondary studies in the usa, australia, argentina, mexico, japan, south africa, european union and the like, have been conducted, and the main endpoint of the study is ACR20 and drug-related and serious AEs, and patients 283 are recruited but fail to show curative effects. The results show that BTK is still in an exploration stage as a target point for treating autoimmune diseases, and a plurality of difficulties need to be overcome, and PROTAC is taken as a novel technology different from a small molecule inhibitor, and different forces are probably injected into the field. BTK has become the most target of clinical drugs in the field of autoimmune diseases except TNF (tumor necrosis factor) and CD20, is expected to become a new target for treating autoimmune diseases in the future, and provides opportunities and challenges for a PROTAC technology capable of efficiently degrading BTK protein.

Disclosure of Invention

The present invention is directed to solving, at least to some extent, one of the technical problems in the related art. Therefore, the inventor proposes a novel compound which adopts a double-target molecular structure, the structure of the compound is shown in figure 1, one end of the compound is targeted and combined with E3 ligase, the other end of the compound is targeted and combined with a target protein (BTK protein) to be degraded, and the structures at the two ends are connected through a chain (linker) to form a complete compound molecule. The compound has good treatment and prevention effects on autoimmune diseases.

To this end, in a first aspect of the invention, the invention proposes the use of a compound for the manufacture of a medicament for the treatment or prevention of an autoimmune disease, said compound being a compound of formula I or a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof:

X-Y-Z

formula I

Wherein:

y is

X is

Z is as follows:

wherein each L₁、L₂、L₃、L₄、L₅、L₆、L₇Independently is a bond, -O-, -S (═ O)_t1-，-S-，-N(R_a)-，-C(＝O)O-，-N(R_a)-C(＝O)-，-C(＝O)-(CH₂)_t2-，-CH₂-，-C(＝O)-，-OC(＝O)-，-C(＝S)-，-C(＝O)-N(R_a)-，-C(＝S)-N(R_a)-，-(CH₂)_t2-C (═ O) -or triazolyl;

each R_aIndependently hydrogen, C1-4 alkyl, haloC 1-4 alkyl, C1-4 alkanoyl or hydroxy;

each t2 is independently 0, 1,2,3, or 4;

each t1 is independently 0, 1 or 2;

each X₁、X₂、X₃、X₄、X₅、X₆、X₇、X₈、X₉、X₁₀Q, W independently represent CH, CH₂O, S, N, NH or Se;

each R₁、R₂、R₃、R₄、R₅、R₆B is independently H, deuterium, amino, C1-4 amido, C1-4 alkyl, C1-4 heteroalkyl, C3-8 cycloalkyl, C2-10 heterocyclyl, C6-10 aryl, C1-9 heteroaryl, C6-10 aryl, C1-4 alkoxy, C1-4 alkenyl, C1-4 alkynyl, wherein said C1-4 alkyl, C1-4 heteroalkyl, C3-8 cycloalkyl, C2-10 heterocyclyl, C6-10 aryl, C1-9 heteroaryl, C6-10 aryl, C1-4 alkoxy, C1-4 alkenyl, C1-4 alkynyl may optionally be substituted with one or more groups selected from deuterium, 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 alkylamino C1-6 alkyl, C6-10 aryl C1-6 alkyl, C1-9 heteroaryl C1-6 alkyl, C2-10 heterocyclyl C1-6 alkyl, C3-10 cycloalkyl C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C6-10 aryl, C6-10 aryloxy, C6-10 arylamino, C1-9 heteroaryl, C1-9 heteroaryloxy, C2-6 alkenyl, C3-10 cycloalkyl, halogen substituted C6-10 aryl, halogen substituted C1-9 heteroaryl, halogen substituted C2-10 heterocyclyl or C2-10 heterocyclyl;

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 alkylthio, C1-4 alkanoyl, C3-12 cycloalkyl, optionally substituted C3-9 heterocyclyl, optionally substituted C6-12 aryl, optionally substituted C1-9 heteroaryl;

each E is independently an amide group, an ester group, a carbamate group, a urea group, a guanidine group, a heterocyclic group, a cycloalkyl group, a spiroheterobicyclic group, a fused heterobicyclic group, a bridged heterobicyclic group, a C6-10 aryl group, or a C2-C10 heteroaryl group; each E is optionally substituted with 1,2,3 or 4 independent R_bSubstituted;

each R_bIndependently hydrogen, C1-4 alkyl, C1-4 haloalkyl, hydroxy, nitro, amino, cyano, halogen, carboxy, C1-4 alkoxy, C1-4 alkylamino, C1-4 alkylthio, C1-4 alkanoyl, C3-12 cycloalkyl, C3-9 heterocyclyl, C6-12 aryl, C1-9 heteroaryl, amino C1-4 alkyl, hydroxy C1-4 alkyl, sulfo, aminosulfonyl or aminoacyl;

each a, b, c, d, e, f is independently an integer between 0 and 30.

According to an embodiment of the present invention, the above-mentioned use may further include at least one of the following additional technical features:

according to an embodiment of the present invention, each L₁Independently a bond, -O-, -S-, -NH-,

each L₂Independently a bond, - (C ═ O) CH ═ CH₂-，-O-，-S-，-S(＝O)-，-S(＝O)₂-，-NRa-，-C(＝O)-，-C(＝O)O-，-N(R_a)-C(＝O)-，-CH₂-，-OC(＝O)-，-C(＝S)-，-C(＝O)-N(R_a)-，-C(＝S)-N(R_a) Or a group selected from the group consisting of a triazole group,

each R_aIndependently hydrogen, C1-2 alkyl, haloC 1-2 alkyl, C1-2 alkanoyl or hydroxy,

each R₁、R₂、R₃、R₄Independently H, amino, C1-4 alkyl, C1-4 heteroalkyl, C5-7 cycloalkyl, C5-7 heterocyclyl, C6-7 aryl, C5-7 heteroaryl, wherein said C1-4 alkyl, C1-4 heteroalkyl, C5-7 cycloalkyl, C5-7 heterocyclyl, C6-7 aryl, C5-7 heteroaryl may be optionally substituted with one or more substituents selected from deuterium, hydroxy, amino, oxo, F, Cl, Br, I, cyano.

According to an embodiment of the invention, each X is independently a compound as shown below:

according to an embodiment of the invention, each A is independently hydrogen, optionally substituted C5-7 heterocyclyl, C5-7 cycloalkyl, optionally substituted C6-7 aryl, optionally substituted C5-7 heteroaryl;

each R₅B is independently H, amino, C1-4 alkyl, C1-4 heteroalkyl, C5-7 cycloalkyl, C5-7 heterocyclyl, C6-7 aryl, C5-7 heteroaryl, wherein said C1-4 alkyl, C1-4 heteroalkyl, C5-7 cycloalkyl, C5-7 heterocyclyl, C6-7 aryl, C5-7 heteroaryl may optionally be substituted with one or more groups selected from deuterium, hydroxy, amino, oxo, F, Cl, Br, I, cyano, C5-7 aryl, C5-7 heteroaryl, halogen substituted C5-7 aryl, halogen substituted C5-7 heteroaryl, and halogen substituted C5-7 heterocyclic group;

each L₃、L₄、L₅Independently a bond, - (C ═ O) CH ═ CH₂-，-O-，-S-，-S(＝O)-，-S(＝O)₂-，-NRa-，-C(＝O)-，-C(＝O)O-，-N(R_a)-C(＝O)-，-CH₂-，-OC(＝O)-，-C(＝S)-，-C(＝O)-N(R_a)-，-C(＝S)-N(R_a) Or a triazole group;

each R_aIndependently hydrogen, C1-2 alkyl, haloC 1-2 alkyl, C1-2 alkanoyl or hydroxy;

each R₆Independently hydrogen, amino, hydroxyl, nitro, amino, cyano, halogen, carboxyl.

According to an embodiment of the invention, each A is independently

Each R_cIndependently hydrogen or C1-2 alkyl;

in some embodiments, B is

According to an embodiment of the invention, each Z is independently a compound as shown below:

according to an embodiment of the invention, each E is independently an amide group, an ester group, a carbamate group, a urea group, a guanidine group, a heterocyclic group, a cycloalkyl group, a C6-C8 aryl group or a C5-C7 heteroaryl group; each E is optionally substituted with 1,2,3 or 4 independent R_bThe substitution is carried out on the raw materials,

each R_bIndependently hydrogen, C1-2 alkyl, C1-2 haloalkyl, hydroxy, nitro, amino, cyano, halogen, carboxy, C1-2 alkoxy, C1-2 alkylamino, C1-2 alkylthio, C1-2 alkanoyl, C5-7 cycloalkyl, C5-7 heterocyclyl, C6-7 aryl, C5-7 heteroaryl, amino C1-2 alkyl, hydroxy C1-2 alkyl, sulfo, aminosulfonyl or aminoacyl,

each a is an integer of 0 to 10,

each b is an integer of 0 to 20,

each c is an integer of 0 to 20,

each d is an integer of 0 to 10,

each e is an integer of 0 to 10,

each f is an integer of 0 to 10,

each L₆、L₇Independently a bond, - (C ═ O) CH ═ CH₂-，-O-，-S-，-S(＝O)-，-S(＝O)₂-，-NRa-，-C(＝O)-，-C(＝O)O-，-N(R_a)-C(＝O)-，-CH₂-，-OC(＝O)-，-C(＝S)-，-C(＝O)-N(R_a)-，-C(＝S)-N(R_a) Or a group selected from the group consisting of a triazole group,

each R_aIndependently hydrogen, C1-2 alkyl, haloC 1-2 alkyl, C1-2 alkanoyl or hydroxy.

According to an embodiment of the invention, said Y is

According to an embodiment of the invention, X is

In some embodiments, Z is

In some embodiments, the Y is

Wherein m1 is an integer between 1 and 10, and n1 is an integer between 0 and 10; m2 is an integer of 0-10, n2 is an integer of 0-10; n3 is an integer between 1 and 10; m3 is an integer of 2 to 10, and n4 is an integer of 0 to 10.

According to an embodiment of the present invention, the compound includes a compound represented by any one of formulas (1) to (23) or a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug thereof,

wherein m1 is an integer between 1 and 10, n1 is an integer between 0 and 10, m2 is an integer between 0 and 10, n2 is an integer between 0 and 10, n3 is an integer between 1 and 10, m3 is an integer between 2 and 10, and n4 is an integer between 0 and 10.

In a second aspect of the present invention, the present invention provides a use of a compound for the preparation of a medicament for treating or preventing an autoimmune disease, the compound being a compound represented by any one of formulae 1 to 36, or a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug thereof,

the compounds according to the embodiments of the present invention have excellent therapeutic and prophylactic effects on autoimmune diseases.

According to an embodiment of the invention, the autoimmune disease is arthritis, pulmonary hemorrhage, systemic lupus erythematosus, pemphigus, chronic lymphocytic thyroiditis, hyperthyroidism, insulin dependent diabetes mellitus, myasthenia gravis, chronic ulcerative colitis, pernicious anemia with chronic atrophic gastritis, primary biliary cirrhosis, multiple sclerosis or acute idiopathic polyneuritis.

According to an embodiment of the invention, the autoimmune disease is arthritis or pulmonary hemorrhage. The inventors have found that the compounds described above are superior in the therapeutic and prophylactic effects on arthritis and pulmonary hemorrhage.

In a third aspect of the invention, the invention proposes the use of a pharmaceutical composition comprising a compound as described hereinbefore in the manufacture of a medicament for the treatment or prevention of an autoimmune disease. The pharmaceutical composition according to the embodiment of the present invention has a good therapeutic and prophylactic effect on autoimmune diseases.

according to an embodiment of the present invention, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or combination thereof.

According to an embodiment of the invention, the pharmaceutical composition further comprises other drugs for treating or preventing autoimmune diseases. The inventor finds that the combined drug has better effect on treating or preventing autoimmune diseases.

According to an embodiment of the invention, the autoimmune disease is arthritis, pulmonary hemorrhage, systemic lupus erythematosus, pemphigus, chronic lymphocytic thyroiditis, hyperthyroidism, insulin dependent diabetes mellitus, myasthenia gravis, chronic ulcerative colitis, pernicious anemia with chronic atrophic gastritis, primary biliary cirrhosis, multiple sclerosis or acute idiopathic polyneuritis. In some embodiments, the autoimmune disease is arthritis or pulmonary hemorrhage.

According to an embodiment of the invention, the other medicament for treating or preventing autoimmune diseases comprises ibrutinib.

In yet another aspect of the invention, the invention features general procedures for the synthesis of compounds of formula I. According to the embodiment of the invention, the compound shown in formula I can be connected through click reaction or amide condensation reaction between Pomalidomide or Lenanidomide or RG-7112 terminal derivatives and Ibrutinib terminal derivatives, as shown in FIG. 2, wherein the Pomalidomide terminal derivatives can be prepared by reference to Chemistry & Biology 22,755 763(2015), the Lenalidomide terminal derivatives can be prepared by reference to J.Med.chem (DOI:10.1021/ACS. jmedchem.6b01816), the RG-7112 terminal derivatives can be prepared by reference to bioorg.Med.chem.Lett.18,5904-5908(2008). ACS.Med.chem.Lett.4,466-469 (2013), the Ibrinib terminal derivatives can be synthesized by reference to Jaorg.Chem.29, PCT 3603, and PCT. The terminal alkyne required by Click chemistry is linked to the piperidine ring of the ibbrutinib parent nucleus by amide condensation, as described in j.chem.inf.model.50,446(2010). PCT int.appl.,2013170115,14Nov 2013.

Drawings

FIG. 1 is a basic technical scheme of PROTACs according to an embodiment of the present invention;

FIG. 2 is a schematic illustration of the construction of formula I by a click reaction and an amide condensation reaction according to an embodiment of the present invention;

FIG. 3 shows the results of inhibition of LPS-stimulated release of THP-1 cytokines by compounds according to examples of the present invention;

FIG. 4 shows the results of a compound according to an embodiment of the present invention on the treatment of arthritis in mice;

FIG. 5 shows the results of a compound according to an embodiment of the present invention on treatment of pulmonary hemorrhage in mice;

FIG. 6 shows the results of a compound according to an embodiment of the present invention on treatment of pulmonary hemorrhage in mice;

FIG. 7 shows the results of a compound according to an embodiment of the present invention on treatment of mouse systemic lupus erythematosus;

FIG. 8 shows the results of a compound according to an embodiment of the present invention on the treatment of mouse systemic lupus erythematosus.

Detailed Description

Reference will now be made in detail to embodiments of the present invention, examples of which are illustrated in the accompanying drawings. The embodiments described below with reference to the drawings are illustrative and intended to be illustrative of the invention and are not to be construed as limiting the invention.

As used herein, the term "administering to a patient a previously described compound, or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, or a previously described pharmaceutical composition" refers to introducing a predetermined amount of a substance into the patient by some suitable means. The compound of formula I of the present invention, or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, or pharmaceutical composition thereof, may be administered by any common route, as long as it reaches the intended tissue. Various modes of administration are contemplated, including peritoneal, intravenous, intramuscular, subcutaneous, cortical, oral, topical, nasal, pulmonary and rectal, but the invention is not limited to these exemplified modes of administration. However, because of oral administration, the active ingredients of orally administered compositions should be coated or formulated to prevent degradation in the stomach. Furthermore, the compounds of formula I according to the invention or the pharmaceutical compositions can be administered using specific devices for delivering the active ingredient to the target cells.

The administration frequency and dose 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 administration route, the age, sex, body weight and severity of the disease of the patient and the type of drug as an active ingredient.

The term "therapeutically effective amount" refers to an amount of a compound sufficient to significantly ameliorate some of the symptoms associated with a disease or condition, i.e., to provide a therapeutic effect for a given condition and administration regimen. A therapeutically effective amount of a drug or compound need not cure a disease or condition, but will provide treatment for a disease or condition such that the onset of the disease or condition in an individual is delayed, prevented or prevented, or the symptoms of the disease or condition are alleviated, or the duration of the disease or condition is altered, or the disease or condition becomes less severe, or recovery is accelerated, for example.

The term "treatment" is used to refer to obtaining a desired pharmacological and/or physiological effect. The effect may be prophylactic in terms of complete or partial prevention of the disease or symptoms thereof, and/or may be therapeutic in terms of a partial or complete cure for the disease and/or adverse effects resulting from the disease. As used herein, "treatment" encompasses treatment of a disease in a mammal, particularly a human, including: (a) preventing the occurrence of a disease or disorder in an individual who is susceptible to the disease but has not yet been diagnosed with the disease; (b) inhibiting the disease; or (c) alleviating the disease, e.g., alleviating symptoms associated with the disease. As used herein, "treatment" encompasses any administration of a drug or compound to a subject to treat, cure, alleviate, ameliorate, reduce or inhibit a disease in the subject, including, but not limited to, administration of a composition comprising a compound of formula I or formula II as described herein to a subject in need thereof.

According to the embodiment of the invention, the auxiliary materials comprise medicinal excipients, lubricants, fillers, diluents, disintegrating agents, stabilizers, preservatives, emulsifiers, cosolvents, colorants and sweeteners which are well known in the field of preparation, and are prepared into different dosage forms such as tablets, pills, capsules, injections and the like.

Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ or contradict this application (including but not limited to defined terminology, application of terminology, described techniques, and the like), this application controls.

It will be further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.

The following definitions as used herein should be applied, unless otherwise indicated. For the purposes of the present invention, the chemical elements are in accordance with the CAS version of the periodic Table of the elements, and the handbook of chemistry and Physics, 75 th edition, 1994. In addition, general principles of Organic Chemistry can be referred to as described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausaltito: 1999, and "March's Advanced Organic Chemistry" by Michael B.Smith and Jerry March, John Wiley & Sons, New York:2007, the entire contents of which are incorporated herein by reference.

The articles "a," "an," and "the" as used herein are intended to include "at least one" or "one or more" unless otherwise indicated or clearly contradicted by context. Thus, as used herein, the articles refer to articles of one or more than one (i.e., at least one) object. For example, "a component" refers to one or more components, i.e., there may be more than one component contemplated for use or use in embodiments of the described embodiments.

The term "comprising" is open-ended, i.e. includes the elements indicated in the present invention, but does not exclude other elements.

"stereoisomers" refers to compounds having the same chemical structure but differing in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans), atropisomers, and the like.

"chiral" is a molecule having the property of not overlapping its mirror image; and "achiral" refers to a molecule that can overlap with its mirror image.

"enantiomer" refers to two isomers of a compound that are not overlapping but are in mirror image relationship to each other.

"diastereomer" refers to a stereoisomer having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may be separated by high resolution analytical procedures such as electrophoresis and chromatography, e.g., HPLC.

The stereochemical definitions and rules used in the present invention generally follow the general definitions of 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.

Many organic compounds exist in an optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of a molecule with respect to one or more of its chiral centers. The prefixes d and l or (+) and (-) are the symbols used to specify the rotation of plane polarized light by the compound, where (-) 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 an enantiomeric mixture. A50: 50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in the chemical reaction or process.

Any asymmetric atom (e.g., carbon, etc.) of a compound disclosed herein can exist in racemic or enantiomerically enriched forms, such as the (R) -, (S) -or (R, S) -configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, 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 in the (R) -or (S) -configuration.

Depending on the choice of starting materials and methods, the compounds of the invention may exist as one of the possible isomers or as mixtures thereof, for example as racemates and diastereomeric mixtures (depending on the number of asymmetric carbon atoms). 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 substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituents of the cycloalkyl group may have cis or trans configuration.

Any resulting mixture of stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, depending on differences in the physicochemical properties of the components, for example, by chromatography and/or fractional crystallization.

The racemates of any of the resulting end products or intermediates can be resolved into the optical enantiomers by known methods using methods familiar to those skilled in the art, e.g., by separation of the diastereomeric salts obtained. The racemic product can also be separated by chiral chromatography, e.g., High Performance Liquid Chromatography (HPLC) using a chiral adsorbent. In particular, Enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al, Enantiomers, racemes and solutions (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)。

The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that can interconvert by a low energy barrier (low energy barrier). If tautomerism is possible (e.g., in solution), then the chemical equilibrium of the tautomer can be reached. For example, proton tautomers (also known as proton transfer tautomers) include interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers (valenctautomers) include interconversion by recombination of some of the bonding electrons. A specific example of keto-enol tautomerism is the tautomerism of the pentan-2, 4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenol-ketone tautomerism. One specific example of phenol-ketone tautomerism is the tautomerism of pyridin-4-ol and pyridin-4 (1H) -one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

The compounds of the invention may be optionally substituted with one or more substituents, as described herein, in compounds of the general formula above, or as specifically exemplified, sub-classes, and classes of compounds encompassed by the invention. It is understood that the term "optionally substituted" may be used interchangeably with the term "substituted or unsubstituted". In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced with a particular substituent. Unless otherwise indicated, an optional substituent group may be substituted at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents may be substituted at each position, identically or differently.

In addition, unless otherwise explicitly indicated, the descriptions of the terms "… independently" and "… independently" and "… independently" used in the present invention are interchangeable and should be understood in a broad sense to mean that the specific items expressed between the same symbols do not affect each other in different groups or that the specific items expressed between the same symbols in the same groups do not affect each other.

In the various parts of this specification, substituents of the disclosed compounds are disclosed in terms of group type or range. It is specifically intended that the invention includes each and every independent subcombination of the various members of these groups and ranges. For example, the term "C1-6 alkyl" refers specifically to independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

Each a, b, c, d, e, f, m1, m2, m3, n1, n2, n3 and n4 is independently an integer of 0 to 30. In one embodiment, each a, b, c, d, e, f, m1, m2, m3, n1, n2, n3, n4 is independently an integer between 0 and 25. In another embodiment, each a, b, c, d, e, f, m1, m2, m3, n1, n2, n3, n4 is independently an integer between 0 and 20. In another embodiment, each a, b, c, d, e, f, m1, m2, m3, n1, n2, n3, n4 is independently an integer between 0 and 15. In another embodiment, each a, b, c, d, e, f, m1, m2, m3, n1, n2, n3, n4 is independently an integer between 0 and 10. In another embodiment, each a, b, c, d, e, f, m1, m2, m3, n1, n2, n3, n4 is independently an integer between 0 and 5.

In each of the parts of the invention, linking substituents are described. Where the structure clearly requires a linking group, the markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for the variable recites "alkyl" or "aryl," it is understood that the "alkyl" or "aryl" represents an attached alkylene group or arylene group, respectively.

The term "alkyl" or "alkyl group" as used herein, denotes a saturated, straight or branched chain monovalent hydrocarbon radical containing from 1 to 20 carbon atoms, wherein the alkyl group may be optionally substituted with one or more substituents as described herein. Unless otherwise specified, alkyl groups contain 1-20 carbon atoms. In one embodiment, the alkyl group contains 1 to 12 carbon atoms; in another embodiment, the alkyl group contains 1 to 6 carbon atoms; in yet another embodiment, the alkyl group contains 1 to 4 carbon atoms; in yet another embodiment, the alkyl group contains 1 to 3 carbon atoms.

Examples of 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 (-CH2CH2CH2CH 3), 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), 3-methyl-2-butyl (-CH2CH 3-3 CH3)2CH2CH 3-2 CH), 2-methyl-1-butyl (-CH2CH 3), n-hexyl (-CH2CH2CH2CH2CH3), 2-hexyl (-CH (CH3) CH2CH2CH3), 3-hexyl (-CH (CH2CH3) (CH2CH2CH3)), 2-methyl-2-pentyl (-C (CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH (CH3) CH (CH3) CH2CH3), 4-methyl-2-pentyl (-CH (CH3) CH2CH (CH3)2), 3-methyl-3-pentyl (-C (CH3) (CH2CH3)2), 2-methyl-3-pentyl (-CH (CH2CH3) CH (CH3)2), 2, 3-dimethyl-2-butyl (-C (CH 2) 2 (-CH 69556), 2-dimethyl-3-butyl (-CH 8653) 2CH 8653), n-heptyl, n-octyl, and the like.

The term "alkylene" refers to a saturated divalent hydrocarbon radical resulting from the removal of two hydrogen atoms from a saturated straight or branched chain hydrocarbon radical. Unless otherwise specified, the alkylene group contains 1 to 12 carbon atoms. In one embodiment, the alkylene group contains 1 to 6 carbon atoms; in another embodiment, the alkylene group contains 1 to 4 carbon atoms; in yet another embodiment, the alkylene group contains 1 to 3 carbon atoms; in yet another embodiment, the alkylene group contains 1 to 2 carbon atoms. Examples of such include methylene (-CH2-), ethylene (-CH2CH2-), isopropylidene (-CH (CH3) CH2-), and the like.

The term "alkenyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e., one carbon-carbon sp2 double bond, wherein the alkenyl radical may be optionally substituted with one or more substituents described herein, including the positioning of "cis" and "tans", or the positioning of "E" and "Z". In one embodiment, the alkenyl group contains 2 to 8 carbon atoms; in another embodiment, the alkenyl group contains 2 to 6 carbon atoms; in yet another embodiment, the alkenyl group contains 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (-CH ═ CH2), allyl (-CH2CH ═ CH2), and the like.

The term "alkynyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e. a carbon-carbon sp triple bond, wherein said alkynyl radical may optionally be substituted with one or more substituents as described herein. In one embodiment, alkynyl groups contain 2-8 carbon atoms; in another embodiment, alkynyl groups contain 2-6 carbon atoms; in yet another embodiment, alkynyl groups contain 2-4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C.ident.CH), propargyl (-CH2℃ ident.CH), 1-propynyl (-C.ident.C-CH 3), and the like.

The term "heteroalkyl" denotes an alkyl chain interrupted by one or more heteroatoms, wherein the alkyl group and the heteroatoms have the meaning as described herein. Unless otherwise specified, the heteroalkyl group has from 2 to 10 carbon atoms, in other embodiments the heteroalkyl group has from 2 to 8 carbon atoms, in other embodiments the heteroalkyl group has from 2 to 6 carbon atoms, in other embodiments the heteroalkyl group has from 2 to 4 carbon atoms, and in other embodiments the heteroalkyl group has from 2 to 3 carbon atoms. Examples include, but are not limited to, CH3OCH2-, CH3CH2OCH2-, CH3SCH2-, (CH3)2NCH2-, (CH3)2CH2OCH2-, CH3OCH2CH2-, CH3CH2OCH2CH2-, and the like.

The term "alkenylene" denotes an alkenyl group derived from a straight or branched chain alkene by the removal of two hydrogen atoms. And the alkenylene group may be substituted or unsubstituted, wherein the substituent may be, but is not limited to, deuterium, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkyl, alkenyl, alkynyl, heterocyclic, mercapto, nitro, or aryloxy. Examples include, but are not limited to, ethenylene (-CH ═ CH-), isopropenylene (-C (CH3) ═ CH-), 3-methoxypropene-1, 1-diyl, 2-methylbutene-1, 1-diyl, and the like.

The term "carbocyclylene" ("cycloalkylene") denotes a saturated divalent hydrocarbon ring obtained by removing two hydrogen atoms from a monocyclic ring having 3 to 12 carbon atoms or a bicyclic ring having 7 to 12 carbon atoms, wherein carbocyclyl or cycloalkyl have the meaning as defined in the present invention, and examples thereof include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, 1-cyclopent-1-enylene, 1-cyclopent-2-enylene and the like.

The term "heterocyclylene" denotes a monocyclic, bicyclic or tricyclic ring system wherein one or more atoms in the ring are independently selected from heteroatoms and may be fully saturated or contain one or more unsaturations, but not belonging to the aromatic class, having two points of attachment to the rest of the molecule, wherein the heterocyclyl group has the meaning as described herein. Examples include, but are not limited to, piperidine-1, 4-diyl, piperazine-1, 4-diyl, tetrahydrofuran-2, 4-diyl, tetrahydrofuran-3, 4-diyl, azetidine-1, 3-diyl, pyrrolidine-1, 3-diyl, and the like.

The term "alkoxy" means an alkyl group attached to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains 1 to 12 carbon atoms. In one embodiment, the alkoxy group contains 1 to 6 carbon atoms; in another embodiment, the alkoxy group contains 1 to 4 carbon atoms; in yet another embodiment, the alkoxy group contains 1 to 3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents described herein.

Examples of 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-1-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-pentoxy (n-pentoxy, n-pentoxy, -OCH2CH3), 2-pentyloxy (-OCH (CH3) CH2CH3), 3-pentyloxy (-OCH (CH2CH3)2), 2-methyl-2-butoxy (-OC (CH3)2CH 3), 3-methyl-2-butoxy (-OCH (CH3) CH (CH3)2), 3-methyl-1-butoxy (-OCH2CH2CH (CH3)2), 2-methyl-l-butoxy (-OCH2CH (CH3) CH2CH3), and the like.

The terms "haloalkyl", "haloalkenyl" or "haloalkoxy" denote alkyl, alkenyl or alkoxy groups substituted with one or more halogen atoms, examples of which include, but are not limited to, trifluoromethyl, trifluoromethoxy and the like.

The term "hydroxyalkyl" or "hydroxy-substituted alkyl" means that the alkyl group is substituted with one or more hydroxy groups, wherein the alkyl group has the meaning described herein. Examples include, but are not limited to, hydroxymethyl, hydroxyethyl, 1, 2-dihydroxyethyl, and the like.

The term "carbocyclyl" or "carbocycle" denotes a monovalent or multivalent, non-aromatic, saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system containing 3 to 12 carbon atoms. Carbobicyclic groups include spirocarbocyclic and fused carbocyclic groups, and suitable carbocyclic groups include, but are not limited to, cycloalkyl, cycloalkenyl and cycloalkynyl groups. Examples of carbocyclyl groups further include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like.

The term "cycloalkyl" denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic ring system containing from 3 to 12 carbon atoms. In one embodiment, the cycloalkyl group contains 3 to 12 carbon atoms; in another embodiment, cycloalkyl contains 3 to 8 carbon atoms; in yet another embodiment, the cycloalkyl group contains 3 to 6 carbon atoms. The cycloalkyl groups may be independently unsubstituted or substituted with one or more substituents described herein.

The terms "heterocyclyl" and "heterocycle" are used interchangeably herein and refer to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring containing 3 to 12 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur and oxygen atoms. Unless otherwise indicated, heterocyclyl groups may be carbon-or nitrogen-based, and the-CH 2-group may optionally be replaced by-c (o) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of heterocyclyl groups include, but are not limited to: oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl, tetrahydropyridinylPyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiaxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepanyl, oxa

Radical, diaza

Radical, S-N-aza

Radicals, indolinyl, 1,2,3, 4-tetrahydroisoquinolinyl, 1, 3-benzodioxolyl, 2-oxa-5-azabicyclo [2.2.1]Hept-5-yl. Examples of substitutions of the-CH 2-group by-C (O) -in the heterocyclic group include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidinonyl, 3, 5-dioxopiperidinyl and pyrimidinedione. Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, sulfolane group, 1-dioxothiomorpholinyl group. The heterocyclyl group may be optionally substituted with one or more substituents as described herein.

In one embodiment, heterocyclyl is a 4-7 atom heterocyclyl and refers to a saturated or partially unsaturated monocyclic ring containing 4-7 ring atoms in which at least one ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen atoms. Unless otherwise indicated, a heterocyclic group of 4-7 atoms may be carbon-or nitrogen-based, and the-CH 2-group may optionally be replaced by-c (o) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of heterocyclic groups consisting of 4 to 7 atoms include, but are not limited to: azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranylA group selected from the group consisting of tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiaxalyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepanyl

Radical, diaza

Radical, S-N-aza

And (4) a base. Examples of substitutions of the-CH 2-group by-C (O) -in the heterocyclic group include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidinonyl, 3, 5-dioxopiperidinyl and pyrimidinedione. Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, sulfolane group, 1-dioxothiomorpholinyl group. Said heterocyclyl group of 4 to 7 atoms may be optionally substituted by one or more substituents as described herein.

In another embodiment, heterocyclyl is a 4-atom heterocyclyl and refers to a saturated or partially unsaturated monocyclic ring containing 4 ring atoms in which at least one ring atom is substituted by a member selected from the group consisting of nitrogen, sulfur, and oxygen atoms. Unless otherwise indicated, a heterocyclic group consisting of 4 atoms may be carbon-or nitrogen-based, and the-CH 2-group may optionally be replaced by-c (o) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of heterocyclic groups consisting of 4 atoms include, but are not limited to: azetidinyl, oxetanyl, thietanyl. The 4-atom heterocyclyl group may be optionally substituted with one or more substituents described herein.

In another embodiment, heterocyclyl is a 5 atom heterocyclyl 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. Unless otherwise indicated, a heterocyclic group consisting of 5 atoms may be carbon-or nitrogen-based, and the-CH 2-group may optionally be replaced by-c (o) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of 5-atom heterocyclic groups include, but are not limited to: pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl. Examples of the-CH 2-group substituted by-C (O) -in the heterocyclic group 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, sulfolane group. The 5-atom heterocyclyl group may be optionally substituted with one or more substituents described herein.

In another embodiment, heterocyclyl is a 6 atom heterocyclyl 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. Unless otherwise indicated, a heterocyclic group of 6 atoms may be carbon-or nitrogen-based, and the-CH 2-group may optionally be replaced by-c (o) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of heterocyclic groups consisting of 6 atoms include, but are not limited to: tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl. Examples of substitutions of the-CH 2-group in the heterocyclyl by-C (O) -include, but are not limited to, 2-piperidinonyl, 3, 5-dioxopiperidinyl and pyrimidinedione. Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, 1, 1-dioxothiomorpholinyl. The 6-atom heterocyclyl group may be optionally substituted with one or more substituents described herein.

In yet another embodiment, heterocyclyl is a 7-12 atom heterocyclyl and refers to a saturated or partially unsaturated spiro-or fused-bicyclic ring containing 7-12 ring atoms in which at least one ring atom is selected from the group consisting of nitrogen, sulfur and oxygen atoms. Unless otherwise indicated, a heterocyclic group of 7-12 atoms may be carbon-or nitrogen-based, and the-CH 2-group may optionally be replaced by-c (o) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of heterocyclic groups consisting of 7 to 12 atoms include, but are not limited to: indolinyl, 1,2,3, 4-tetrahydroisoquinolinyl, 1, 3-benzodioxolyl, 2-oxa-5-azabicyclo [2.2.1] hept-5-yl. Said heterocyclyl group of 7 to 12 atoms may be optionally substituted by one or more substituents as described herein.

The terms "fused bicyclic ring," "fused bicyclic group," and "fused ring group" are used interchangeably herein and all refer to a monovalent or multivalent saturated or partially unsaturated bridged ring system, which refers to a non-aromatic bicyclic ring system. Such systems may contain independent or conjugated unsaturated systems, but the core structure does not contain aromatic or heteroaromatic rings (although aromatic groups may be substituted thereon).

The terms "spirocyclic", "spiro", "spirobicyclic" or "spirobicyclic" are used interchangeably herein to refer to a monovalent or multivalent saturated or partially unsaturated ring system in which one ring is derived from a specific ring carbon atom on another ring. For example, as described below, one saturated bridged ring system (rings B and B') is referred to as "fused bicyclic ring", while ring a and ring B share one carbon atom in two saturated ring systems, referred to as "spiro" or "spirobicyclic ring". Each ring in the fused bicyclic and spirobicyclic groups may be a carbocyclic or heterocyclic group, and each ring is optionally substituted with one or more substituents described herein.

The term "heterocycloalkyl" refers to a monovalent or polyvalent saturated monocyclic, bicyclic, or tricyclic ring system containing 3 to 12 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur, or oxygen atoms.

The term "n-atomic" where n is an integer typically describes the number of ring-forming atoms in a molecule in which the number of ring-forming atoms is n. For example, piperidinyl is a heterocycloalkyl group of 6 atoms, while 1,2,3, 4-tetrahydronaphthalene is a cycloalkyl group of 10 atoms.

The term "unsaturated" as used herein means that the group contains one or more unsaturations.

The term "heteroatom" refers to O, S, N, P and Si, including N, S and any oxidation state form of P; primary, secondary, tertiary amines and quaternary ammonium salt forms; or a form in which a hydrogen on a nitrogen atom in the heterocycle is substituted, for example, N (like N in 3, 4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like NR in N-substituted pyrrolidinyl).

The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

The term "aryl" denotes monocyclic, bicyclic and tricyclic carbon ring systems containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, wherein at least one ring system is aromatic, wherein each ring system comprises a ring of 3 to 7 atoms with one or more attachment points to the rest of the molecule. The term "aryl" may be used interchangeably with the term "aromatic ring". Examples of the aryl group may include phenyl, naphthyl, and anthracene. The aryl group may independently be optionally substituted with one or more substituents described herein.

The term "heteroaryl" denotes monocyclic, bicyclic and tricyclic ring systems containing 5 to 12 ring atoms, or 5 to 10 ring atoms, or 5 to 6 ring atoms, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms, wherein each ring system contains a ring of 5 to 7 atoms with one or more attachment points to the rest of the molecule. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound". The heteroaryl group is optionally substituted with one or more substituents described herein. In one embodiment, a heteroaryl group of 5-10 atoms contains 1,2,3, or 4 heteroatoms independently selected from O, S, and N.

Examples of 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 (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), and the like, 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2, 3-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 3-triazolyl, 1,2, 3-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, pyrazinyl, 1,3, 5-triazinyl; the following bicyclic rings are also included, but are in no way limited to these: benzimidazolyl, benzofuranyl, benzothienyl, indolyl (e.g., 2-indolyl), purinyl, quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, or 4-isoquinolyl), imidazo [1,2-a ] pyridyl, pyrazolo [1,5-a ] pyrimidinyl, imidazo [1,2-b ] pyridazinyl, [1,2,4] triazolo [4,3-b ] pyridazinyl, [1,2,4] triazolo [1,5-a ] pyrimidinyl, [1,2,4] triazolo [1,5-a ] pyridyl, and the like.

The term "carboxy", whether used alone or in combination with other terms, such as "carboxyalkyl", denotes-CO₂H; the term "carbonyl", whether used alone or in combination with other terms, such as "aminocarbonyl" or "acyloxy", denotes- (C ═ O) -.

The term "alkylamino" includes "N-alkylamino" and "N, N-dialkylamino" in which the amino groups are each independently substituted with one or two alkyl groups. In some of these embodiments, the alkylamino group is one or two C_1-6Lower alkylamino groups in which the alkyl group is attached to the nitrogen atom. In other embodiments, the alkylamino group is C_1-3Lower alkylamino groups of (a). Suitable alkanesThe alkylamino group may be monoalkylamino or dialkylamino, and such examples include, but are not limited to, N-methylamino, N-ethylamino, N-dimethylamino, N-diethylamino, and the like.

The term "arylamino" denotes an amino group substituted with one or two aryl groups, examples of which include, but are not limited to, N-phenylamino. In some embodiments, the aromatic ring on the arylamino group may be further substituted.

The term "aminoalkyl" includes C substituted with one or more amino groups_1-10A straight or branched alkyl group. In some of these embodiments, aminoalkyl is C substituted with one or more amino groups_1-6Examples of "lower aminoalkyl" radicals include, but are not limited to, aminomethyl, aminoethyl, aminopropyl, aminobutyl, and aminohexyl.

The term "prodrug", as used herein, represents a compound that is converted in vivo to a compound of formula (I). Such conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrug compound of the invention can be ester, and in the prior invention, the ester can be used as the prodrug and comprises phenyl ester and aliphatic (C)_1-24) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxy group, i.e., it can be acylated to provide the compound in prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a hydroxyl group on the parent. For a complete discussion of prodrugs, reference may be made to the following: T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems, Vol.14of the A.C.S.Symphosis Series, Edward B.Roche, ed., Bioreversible Carriers in Drug designs, American Pharmaceutical Association and Pergamon Press,1987, J.Rautio et al, Prodrugs in Design and Clinical Applications, Nature Review Delivery, 2008,7,255 and 270, S.J.Herer et al, Prodrugs of pharmaceuticals and pharmaceuticals, Journal of chemical Chemistry,2008,51,2328 and 5.

"metabolite" refers to the product of a particular compound or salt thereof obtained by metabolism in vivo. Metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by assay methods as described herein. Such products may be obtained by administering the compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.

As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as are: berge et al, description of the scientific acceptable salts in detail in J. pharmaceutical Sciences,1977,66:1-19. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, salts of inorganic acids formed by reaction with amino groups such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and salts of organic acids such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or those obtained by other methods described in the literature above, such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, cyclopentylpropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxy-ethanesulfonates, lactobionates, lactates, laurates, malates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, palmitates, pamoates, pectinates, persulfates, 3-phenylpropionates, picrates, pivalates, propionates, stearates,thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts obtained with appropriate bases include alkali metals, alkaline earth metals, ammonium and N⁺(C_1-4Alkyl radical)₄A salt. The present invention also contemplates quaternary ammonium salts formed from compounds containing groups of N. Water-soluble or oil-soluble or dispersion products can be obtained by quaternization. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations resistant to formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C_1-8Sulfonates and aromatic sulfonates.

"solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association of solvent molecules that is water.

The term "treating" or "treatment" as used herein refers, in some embodiments, to ameliorating a disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" or "treatment" refers to moderating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" or "treatment" refers to modulating the disease or disorder, either physically (e.g., stabilizing a perceptible symptom) or physiologically (e.g., stabilizing a parameter of the body), or both. In other embodiments, "treating" or "treatment" refers to preventing or delaying the onset, occurrence, or worsening of a disease or disorder.

Pharmaceutically acceptable acid addition salts may be formed with inorganic and organic acids, for example, acetate, aspartate, benzoate, benzenesulfonate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlorotheophylline, citrate, edisylate, fumarate, glucoheptonate, gluconate, glucuronate, hippurate, hydroiodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, methanesulfonate, methylsulfate, naphthoate, naphthalenesulfonate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/biphosphate/dihydrogen phosphate, dihydrogenphosphate, Polysilonolactates, propionates, stearates, succinates, sulfosalicylates, tartrates, tosylates and trifluoroacetates.

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 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. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include 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. Some organic amines include, for example, isopropylamine, benzathine (benzathine), choline salts (cholinate), diethanolamine, diethylamine, lysine, meglumine (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. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of the appropriate base (e.g., Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, etc.), or by reacting the free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are usually carried out in water or an organic solvent or a mixture of both. Generally, where appropriate, it is desirable to use a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile. In, for example, "Remington's Pharmaceutical Sciences", 20 th edition, Mack Publishing Company, Easton, Pa., (1985); and "handbook of pharmaceutically acceptable salts: properties, Selection and application (Handbook of Pharmaceutical Salts: Properties, Selection, and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) may find some additional lists of suitable Salts.

In addition, the compounds disclosed herein, including their salts, may also be obtained in the form of their hydrates or in the form of solvents containing them (e.g., ethanol, DMSO, etc.), for their crystallization. The compounds disclosed herein may form solvates with pharmaceutically acceptable solvents (including water), either inherently or by design; thus, the present invention is intended to include both solvated and unsolvated forms.

Any formulae given herein are also intended to represent the non-isotopically enriched forms as well as the isotopically enriched forms of these compounds. Isotopically enriched compounds have the structure depicted by the formulae given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as²H，³H，¹¹C，¹³C，¹⁴C，¹⁵N，¹⁷O，¹⁸O，¹⁸F，³¹P，³²P，³⁵S，³⁶Cl and¹²⁵I。

in another aspect, the compounds of the invention include isotopically enriched compounds as defined herein, e.g. wherein a radioisotope, e.g. is present³H，¹⁴C and¹⁸those compounds of F, or in which a non-radioactive isotope is present, e.g.²H and¹³C. the same asThe site-enriched compound can be used for metabolism research (using)¹⁴C) Reaction kinetics study (using, for example²H or³H) Detection or imaging techniques such as Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT) including drug or substrate tissue distribution determination, or may be used in radiotherapy of a patient.¹⁸F-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 known to those skilled in the art or by the procedures and examples described in the present specification using a suitable isotopically labelled reagent in place of the original used unlabelled reagent.

In addition, heavier isotopes are, in particular, deuterium (i.e.,²substitution of H or D) may provide certain therapeutic advantages resulting from greater metabolic stability. For example, increased in vivo half-life or decreased dosage requirements or improved therapeutic index. The concentration of such heavier isotopes, particularly deuterium, can be defined by isotopic enrichment factors. If a substituent of a compound of the invention is designated as deuterium, the compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Pharmaceutically acceptable solvates of the invention include those in which the crystallization solvent may be isotopically substituted, e.g. D₂O, acetone-d₆、DMSO-d₆Those solvates of (a).

In another aspect, the invention relates to intermediates for the preparation of compounds encompassed by formula I or formula II.

In another aspect, the invention relates to a process for the preparation, isolation and purification of a compound encompassed by formula I or formula II.

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention, a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or combination thereof. In some embodiments, the pharmaceutical composition may be in a liquid, solid, semi-solid, gel, or spray dosage form.

"combination" means a fixed combination or a kit of parts for combined administration in the form of a single dosage unit, wherein a compound disclosed in the invention and a combination partner may be administered separately at the same time or may be administered separately within certain time intervals, in particular such that the combination partners show a cooperative, e.g. synergistic, effect. Such as the terms "co-administration" or "co-administration" and the like are intended to encompass administration of the selected combination partners to a single individual in need thereof (e.g., a patient), and are intended to encompass treatment regimens in which the substances are not necessarily administered by the same route of administration or simultaneously. The term "pharmaceutical combination" as used herein denotes a product resulting from mixing or combining more than one active ingredient and includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that the active ingredients, such as the compounds disclosed herein and the combination partners, are administered to the patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients, such as the disclosed compounds and combination partners, are both administered to a patient as separate entities simultaneously, jointly or sequentially with no specific time limits, wherein the administration provides therapeutically effective levels of both compounds in the patient.

The experimental procedures used in the following examples are all conventional procedures unless otherwise specified.

Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.

The Pomalidomide terminal derivatives used in the following examples were prepared according to the methods disclosed in the literature Chemistry & Biology 22, 755-. Lenalidomide terminal derivatives were prepared according to the method disclosed in document j.med.chem (DOI:10.1021/acs.jmedchem.6b01816) and RG-7112 terminal carboxylic acid derivatives were prepared according to the methods disclosed in documents bioorg.med.chem.lett.18,5904-5908(2008) and ACS med.chem.lett.4,466-469(2013).

The Ibrutinib terminal derivatives used in the following examples were prepared as follows: the terminal alkynes required for Click chemistry were attached to Ibrutinib intermediate (cas: 1022150-12-4) by amide condensation. The preparation process comprises the following steps:

(1) preparation of intermediate 1a

A25 mL round bottom flask was charged with 193mg Ibrutinib intermediate (cas: 1022150-12-4), 3mL anhydrous chloroform and 31. mu.L propiolic acid. 103mg of DCC was dissolved in 2mL of anhydrous chloroform, and the reaction solution was stirred at 0 ℃ while the anhydrous chloroform solution of DCC was slowly added to the reaction solution, and stirred at 0 ℃ for 1 hour. Cooling the reaction solution to-20 ℃, filtering, keeping the filtrate, repeating the filtering twice, spin-drying the filtrate, and separating and purifying by using a 200-mesh and 300-mesh silica gel chromatographic column, wherein the mobile phase is dichloromethane: methanol 60: 1, obtaining the intermediate 1a with the yield of 72 percent.

Preparation of intermediate 1b

A25 mL round bottom flask was charged with 193mg Ibrutinib intermediate (cas: 1022150-12-4), 3mL anhydrous chloroform and 42mg propiolic acid. 103mg of DCC was dissolved in 2mL of anhydrous chloroform, and the reaction solution was stirred at 0 ℃ while the anhydrous chloroform solution of DCC was slowly added to the reaction solution, and stirred at 0 ℃ for 1 hour. Cooling the reaction solution to-20 ℃, filtering, keeping the filtrate, repeating the filtering twice, spin-drying the filtrate, and separating and purifying by using a 200-mesh and 300-mesh silica gel chromatographic column, wherein the mobile phase is dichloromethane: methanol 60: 1, obtaining an intermediate 1b with the yield of 62 percent.

Preparation of intermediate 1c

A25 mL round bottom flask was charged with 193mg Ibrutinib intermediate (cas: 1022150-12-4), 3mL anhydrous DMF, 75mg HOBT, 106mg EDCI, 49mg pentynoic acid, 77. mu.L triethylamine and 10mg DMAP. The reaction solution was stirred at room temperature for 24 hours. The reaction was quenched by addition of 15mL of saturated aqueous sodium chloride solution, the mixture was extracted three times with 15mL of × 3 ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was dried, and the separation and purification were carried out using a 200-mesh 300-mesh silica gel column, the mobile phase was dichloromethane: 40 parts of methanol: 1, obtaining an intermediate 1c with the yield of 61%.

Preparation of intermediate 1d

A25 mL round bottom flask was charged with 193mg Ibrutinib intermediate (cas: 1022150-12-4), 3mL anhydrous DMF, 75mg HOBT, 106mg EDCI, 56mg hexynoic acid, 77. mu.L triethylamine and 10mg DMAP. The reaction solution was stirred at room temperature for 24 hours. The reaction was quenched by addition of 15mL of saturated aqueous sodium chloride solution, the mixture was extracted three times with 15mL of × 3 ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was dried, and the separation and purification were carried out using a 200-mesh 300-mesh silica gel column, the mobile phase was dichloromethane: 40 parts of methanol: 1, obtaining an intermediate 1d with the yield of 71 percent.

(2) Preparation of intermediate 2a

In a 100mL round bottom flask were placed 2.67mL of 3-aminopropan-1-ol and 50mL of anhydrous dichloromethane, the reaction was cooled to 0 ℃ and 6.8mL of triethylamine and 9.7mL of Boc were added₂And O. The reaction solution was allowed to spontaneously return to room temperature with stirring, and stirring was continued for 12 hours. The reaction was quenched by the addition of 100mL of saturated aqueous sodium bicarbonate solution, the mixture was extracted three times with 50mL × 3 dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was dried,separating and purifying by using a 200-mesh 300-mesh silica gel chromatographic column, wherein the mobile phase is dichloromethane: methanol 20: 1, obtaining the intermediate 2a with the yield of 72 percent.

Preparation of intermediate 2b

In a 100mL round bottom flask was added 3.22mL of 4-aminobutan-1-ol and 50mL of anhydrous dichloromethane, the reaction was cooled to 0 ℃ and 6.8mL of triethylamine and 9.7mL of Boc were added₂And O. The reaction solution was allowed to spontaneously return to room temperature with stirring, and stirring was continued for 12 hours. The reaction was quenched by addition of 100mL of saturated aqueous sodium bicarbonate, the mixture was extracted three times with 50mL × 3 dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was dried, and the separation and purification were performed using a 200-: methanol 20: 1, obtaining the intermediate 2b with the yield of 81 percent.

Preparation of intermediate 2c

A100 mL round bottom flask was charged with 1.6g of sodium azide and 25mL of water, and 4.9g of 2- (2-hydroxyethoxy) ethyl-4-methylbenzenesulfonate was added. The reaction was stirred at 90 ℃ for 24 hours. The reaction was quenched by the addition of 50mL of saturated aqueous sodium bicarbonate, the mixture was extracted three times with 40mL × 3 dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was spin dried to give the intermediate in 46% yield. A50 mL round-bottom flask was charged with 787mg of the obtained product, 8mL of anhydrous dichloromethane and 1.67mL of triethylamine, and a solution of 1.72g of TsCl in anhydrous dichloromethane was slowly added to the above reaction solution with stirring, followed by stirring at room temperature for 24 hours. Quenching the reaction by adding 100mL of saturated aqueous sodium bicarbonate solution, extracting the mixture with 50mL × 3 dichloromethane for three times, combining the organic phases, drying with anhydrous sodium sulfate, spin-drying the solvent, and separating and purifying by using a 200-mesh 300-mesh silica gel chromatographic column, wherein the mobile phase is petroleum ether: ethyl acetate ═ 5: 1, obtaining the intermediate 2c with the yield of 67%.

Preparation of intermediate 2d

526mg of intermediate 2a and 15mL of anhydrous THF were added to a 50mL round-bottom flask, 150mg of NaH (60% dispersed in mineral oil) was slowly added with stirring at 0 deg.C, the reaction solution was stirred at 0 deg.C for 1 hour, 285mg of intermediate 2c in anhydrous THF was slowly added to the reaction solution, the reaction solution was naturally warmed to room temperature with stirring, and stirring was continued for 15 hours. Dropwise adding methanol into the reaction solution for quenching reaction, spin-drying the solvent, and separating and purifying by using a 200-plus-300-mesh silica gel chromatographic column, wherein the mobile phase is petroleum ether: ethyl acetate ═ 6:1, obtaining the intermediate with the yield of 26 percent. In a 25mL round-bottom flask, 230mg of the obtained product, 5mL of dichloromethane and 0.5mL of trifluoroacetic acid were added, and the mixture was stirred at room temperature for 6 hours. Adding 15mL of toluene, spin-drying the solvent, and separating and purifying by using a 200-mesh 300-mesh silica gel chromatographic column, wherein the mobile phase is dichloromethane: methanol 10: 1, obtaining the intermediate 2d with the yield of 62 percent.

Preparation of intermediate 2e

A100 mL round bottom flask was charged with 2.8g of intermediate 2b and 50mL of anhydrous THF, 800mg of NaH (60% dispersed in mineral oil) was added slowly with stirring at 0 deg.C, the reaction was stirred at 0 deg.C for 1 hour, 1.43g of intermediate 2c in anhydrous THF was added slowly to the reaction, the reaction was allowed to spontaneously warm to room temperature with stirring, and stirring was continued for 15 hours. Dropwise adding methanol into the reaction solution for quenching reaction, spin-drying the solvent, and separating and purifying by using a 200-plus-300-mesh silica gel chromatographic column, wherein the mobile phase is petroleum ether: ethyl acetate ═ 6:1, obtaining the intermediate with the yield of 22 percent. In a 25mL round bottom flask, 800mg of the resulting product, 15mL of dichloromethane and 1.5mL of trifluoroacetic acid were added and stirred at room temperature for 2 hours. Adding 25mL of toluene, spin-drying the solvent, and separating and purifying by using a 200-mesh 300-mesh silica gel chromatographic column, wherein the mobile phase is dichloromethane: methanol 10: 1, obtaining the intermediate 2e with the yield of 66 percent.

(3) Preparation of intermediate 4a

A5 mL round bottom flask was charged with 24mg of 8-aminoctanoic acid, 70. mu.L of DIEA, 0.3mL of DMF, and 35mg of 2- (2, 6-diozoperidin-3-yl) -4-fluorooisolinone-1, 3-dione. The reaction solution was stirred for 3 hours at 90 ℃. The reaction was quenched by addition of 5mL of saturated aqueous sodium chloride, the mixture was extracted three times with 5mL of × 3 ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was dried, and the separation and purification were carried out using a 200-: 40 parts of methanol: 1, obtaining the intermediate 4a with the yield of 22 percent.

Preparation of intermediate 4b

A5 mL round bottom flask was charged with 26mg of 9-aminoctanoic acid, 70. mu.L of DIEA, 0.3mL of DMF, and 35mg of 2- (2, 6-diozoperidin-3-yl) -4-fluorooisolinone-1, 3-dione. The reaction solution was stirred for 3 hours at 90 ℃. The reaction was quenched by addition of 5mL of saturated aqueous sodium chloride, the mixture was extracted three times with 5mL of × 3 ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was dried, and the separation and purification were carried out using a 200-: 40 parts of methanol: 1, obtaining the intermediate 4b with the yield of 31 percent.

(4) Preparation of intermediate 5a

A100 mL round bottom flask was charged with 3g octane-1,8-diol, 20mL anhydrous THF, and 1.3g potassium tert-butoxide. The reaction mixture was stirred for 15 minutes under argon atmosphere at room temperature, and 1.2g of 3-bromopropyne was added dropwise. The reaction solution was stirred for 12 hours while maintaining the room temperature under argon atmosphere. Spin-drying the solvent, adding 30mL of saturated aqueous sodium chloride solution to quench the reaction, adjusting the pH to 3-5 with 1M HCl, extracting the mixture with 30mL × 3 dichloromethane three times, combining the organic phases, drying with anhydrous sodium sulfate, spin-drying the solvent, and separating and purifying with a 200-mesh 300-mesh silica gel chromatography column, wherein the mobile phase is petroleum ether: ethyl acetate ═ 3: 1, obtaining the intermediate 5a with the yield of 55 percent.

Preparation of intermediate 5b

A100 mL round bottom flask was charged with 12.6g of 2, 2' - (ethane-1,2-diylbis (oxy)) bis (ethane-1-ol), 50mL of anhydrous THF, and 5g of potassium tert-butoxide. The reaction mixture was stirred for 15 minutes under argon atmosphere at room temperature, and 3.5mL of 3-bromopropyne was added dropwise. The reaction solution was stirred for 12 hours while maintaining the room temperature under argon atmosphere. Spin-drying the solvent, adding 30mL of saturated aqueous sodium chloride solution to quench the reaction, adjusting the pH to 3-5 with 1M HCl, extracting the mixture with 30mL × 3 dichloromethane three times, combining the organic phases, drying with anhydrous sodium sulfate, spin-drying the solvent, and separating and purifying with a 200-mesh 300-mesh silica gel chromatography column, wherein the mobile phase is petroleum ether: ethyl acetate ═ 3: 1, obtaining the intermediate 5b with the yield of 77%.

Preparation of intermediate 5c

A100 mL round-bottom flask was charged with 4.4mL pentane-1,5-diol, 30mL anhydrous THF, and 2.5g potassium tert-butoxide. The reaction mixture was stirred for 15 minutes under argon atmosphere at room temperature, and 1.73mL of 3-bromopropyne was added dropwise. The reaction solution was stirred for 12 hours while maintaining the room temperature under argon atmosphere. Spin-drying the solvent, adding 30mL of saturated aqueous sodium chloride solution to quench the reaction, adjusting the pH to 3-5 with 1M HCl, extracting the mixture with 30mL × 3 dichloromethane three times, combining the organic phases, drying with anhydrous sodium sulfate, spin-drying the solvent, and separating and purifying with a 200-mesh 300-mesh silica gel chromatography column, wherein the mobile phase is petroleum ether: ethyl acetate ═ 3: 1, obtaining the intermediate 5c with the yield of 74 percent.

(4) Preparation of intermediate 6a

276mg of acetylene lithium ethylenediamine complex is added into a 25mL round-bottom flask, dissolved in 8mLDMSO, placed into an ice bath to be cooled to 0 ℃, 6-bromohexanoic acid is dissolved in 8mLDMSO, slowly dripped into the reaction solution, stirred in the ice bath for 10 minutes continuously, slowly heated to room temperature and stirred for 2 hours. Pouring the reaction solution into ice water, acidifying with 1M hydrochloric acid, extracting the mixture for three times with 30mL multiplied by 3 dichloromethane, combining the organic phases, drying by using anhydrous sodium sulfate, spin-drying the solvent, and separating and purifying by using a 200-plus-300-mesh silica gel chromatographic column, wherein the mobile phase is petroleum ether: ethyl acetate 10: 1, obtaining the intermediate 6a with the yield of 35%.

Preparation of intermediate 6b

In a 250mL round bottom flask, 7.3g of methyl 3-bromoo-2-methylbenezoate, 6.5g of NBS and 529mg of AIBN were added, dissolved in 100mL of dry chloroform, and then refluxed at 90 ℃ for 5 hours. After the solvent was spin-dried, 60mL of saturated aqueous sodium chloride solution was added to quench the reaction, the mixture was extracted three times with 60mL of × 3 dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was spin-dried to obtain an intermediate. 7.6g of the intermediate obtained were mixed with 5.3g of 2, 6-dioxolane-3-ammonium chloride, 4.6mL Et₃N, 90mL of dry acetonitrile was added, and the reaction mixture was stirred at 80 ℃ for 10 hours. Spin-drying the solvent, and separating and purifying by using a 200-mesh 300-mesh silica gel chromatographic column, wherein the mobile phase is dichloromethane: methanol 20: 1-5: 1Obtaining the intermediate 6b with the yield of 60 percent.

Preparation of intermediate 6c

A25 mL round bottom flask was charged with 35mg of intermediate 6b, 30mg of intermediate 6a, 5mg of cuprous iodide, 15mg of Pd (dppf)₂Cl₂6mL DMF and 3mL Et₃And N, reacting for 3 hours at 80 ℃ under the protection of nitrogen. Spin-drying the solvent, and separating and purifying by using a 200-mesh 300-mesh silica gel chromatographic column, wherein the mobile phase is dichloromethane: 25 parts of methanol: 1, obtaining the intermediate 6c with the yield of 82%.

Preparation of intermediate 6d

A25 mL round bottom flask was charged with 35mg of intermediate 6b, 30mg of intermediate 6a, 5mg of cuprous iodide, 15mg of Pd (dppf)₂Cl₂6mL DMF and 3mL Et₃And N, reacting for 3 hours at 80 ℃ under the protection of nitrogen. Spin-drying the solvent, and separating and purifying by using a 200-mesh 300-mesh silica gel chromatographic column, wherein the mobile phase is dichloromethane: 25 parts of methanol: 1, obtaining the intermediate 6d with the yield of 81 percent.

Example 1 preparation of Compounds represented by formula 19 to formula 36

A10 mL round bottom flask was charged with 50mg of Ibrutinib intermediate (cas: 1022150-12-4), 56mg of intermediate 4b, 21mg of HOBT, 30mg of EDCI, 20. mu.l of Et₃N, 2mg DMAP and 2ml DMF were dissolved and stirred at room temperature for 12 hours. 10mL of saturated aqueous sodium chloride solution was added to the reaction solution, the mixture was extracted with 10mL of X3 ethyl acetate three times, the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was dried by spinning, and the separation and purification were carried out using a 200-mesh 300-mesh silica gel column, and the mobile phase was dichloromethane: 40 parts of methanol: 1, the formula28, yield 85%.

A10 mL round bottom flask was charged with 50mg of Ibrutinib intermediate (cas: 1022150-12-4), 54mg of intermediate 4a, 21mg of HOBT, 30mg of EDCI, 20. mu.l of Et₃N, 2mg DMAP and 2ml DMF were dissolved and stirred at room temperature for 12 hours. 10mL of saturated aqueous sodium chloride solution was added to the reaction solution, the mixture was extracted with 10mL of X3 ethyl acetate three times, the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was dried by spinning, and the separation and purification were carried out using a 200-mesh 300-mesh silica gel column, and the mobile phase was dichloromethane: 40 parts of methanol: 1, obtaining the formula 12 with the yield of 86%.

A10 mL round bottom flask was charged with 30mg of Ibrutinib intermediate (cas: 1022150-12-4), 30mg of intermediate 6d, 13mg of HOBT, 18mg of EDCI, 15. mu.l of Et₃N, 6mg DMAP and 2ml DMF were dissolved and stirred at room temperature for 12 hours. 10mL of saturated aqueous sodium chloride solution was added to the reaction solution, the mixture was extracted with 10mL of X3 ethyl acetate three times, the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was dried by spinning, and the separation and purification were carried out using a 200-mesh 300-mesh silica gel column, and the mobile phase was dichloromethane: methanol 30: 1, obtaining an intermediate, dissolving the intermediate in 4mL of methanol and 1mL of DMF, adding 20mg of palladium carbon, and reacting for 8 hours at 38 ℃ in hydrogen. Filtering the reaction solution by using kieselguhr, spin-drying the solvent, and separating and purifying by using a 200-mesh and 300-mesh silica gel chromatographic column, wherein the mobile phase is dichloromethane: methanol 30: 1, obtaining the formula 34 with the yield of 72 percent.

A10 mL round bottom flask was charged with 30mg of Ibrutinib intermediate (cas: 1022150-12-4), 30mg of intermediate 6d, 13mg of HOBT, 18mg of EDCI, 15. mu.l of Et₃N, 6mg DMAP and 2ml DMF were dissolved and stirred at room temperature for 12 hours. 10mL of saturated aqueous sodium chloride solution was added to the reaction solution, the mixture was extracted with 10mL of X3 ethyl acetate three times, the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was dried by spinning, and the separation and purification were carried out using a 200-mesh 300-mesh silica gel column, and the mobile phase was dichloromethane: methanol 30: 1, obtaining an intermediate, dissolving the intermediate in 4mL of methanol and 1mL of DMF, adding 20mg of palladium carbon, and reacting for 8 hours at 38 ℃ in hydrogen. Filtering the reaction solution by using kieselguhr, spin-drying the solvent, and separating and purifying by using a 200-mesh and 300-mesh silica gel chromatographic column, wherein the mobile phase is dichloromethane: methanol 30: 1, obtaining the formula 36 with the yield of 69%.

EXAMPLE 2 inhibition of THP-1 Release of inflammatory factors upon LPS stimulation by Compounds

1. LPS was prepared.

Adding RPMI1640 medium without FBS into LPS solid powder to a final concentration of 1mg/ml, and subpackaging and storing.

2. Compounds (see table 1 for compound structures and numbers) were prepared.

1) Compounds were diluted with 100% DMSO to reach 100X of the highest concentration of inhibitor ultimately desired in the reaction. If compounds were tested at 100nM, a 10. mu.M DMSO solution of compound was prepared in this step.

2) The compounds were diluted 100-fold in the medium.

3. The cells are treated with a drug.

1) THP-1 cells were diluted to the required concentration and six well plates were seeded with 1X10^6 cells per well supplemented to 2ml medium.

2) Diluted drugs and DMSO controls were dispensed into corresponding wells at 500ul, while blank controls without drug and DMSO were placed and incubated in an incubator at 37 ℃ for 24 h. Each group was repeated 3 times.

LPS stimulation.

The corresponding volume of 1mg/ml LPS solution was taken, the medium was diluted and added to a six-well plate with a constant concentration of 0.5ug/ml, and incubated for 24 hours.

RT-PCR detection of inflammatory factor levels

1) The treated THP-1 cells were collected, centrifuged at 100g for 5 min, washed 2 times with PBS, and total RNA was extracted from the cells using Trizol method, followed by cDNA synthesis using CWBIO easy quick RT MasterMix as a template for qPCR.

2) PCR primers for detecting IL-1 beta, TNF alpha, IL-6, IL-10 and internal reference GAPDH were designed based on the gene sequence of human proinflammatory cytokine, and fluorescent quantitative PCR was performed using the designed primers (see Table 2 for specific conditions).

The results of the inhibition of the release of the inflammatory cytokines by the compounds of the present invention measured by the above methods are shown in fig. 3 and table 3, and the exemplified compounds down-regulate the RNA levels of IL-1 β, TNF α, IL-6, IL-10 in the cells to different degrees, wherein the inhibition of the release of the inflammatory cytokines by the compounds of formula 28 is most significant, which indicates that the compounds of the present invention can inhibit the BTK pathway and thus the release of the inflammatory cytokines.

Table 1: exemplary Compound structures and numbering

Table 2: RT-PCR

Wherein, target gene refers to target gene, species, primer name refers to primer name, sequence guide sequence.

Table 3: modulation of inflammatory factor mRNA levels by compounds

Wherein down means down and up means up.

EXAMPLE 3 Effect of Compounds in mouse models of arthritis, pulmonary hemorrhage, systemic lupus erythematosus

In the following experiments, the inventors examined the effect of compounds in the treatment of arthritis, pulmonary hemorrhage and systemic lupus erythematosus, using formula 16 as an example.

1. Arthritis (arthritis)

The experimental scheme is as follows: bovine type II Collagen (CII) was thoroughly emulsified with equal volume of Freund's complete adjuvant (CFA) to make an emulsion containing CII 1.5 mg/mL. Each group of mice was injected intradermally with 150. mu.L of dorsal skin at the root of the tail under sterile conditions. After 21 days, bovine type II Collagen (CII) was thoroughly emulsified with an equal volume of Incomplete Freund's Adjuvant (IFA) to prepare an emulsion containing 1.5mg/mL of CII. Each group of mice was injected intradermally with 80. mu.L of dorsal skin at the root of the tail under sterile conditions. The disease is developed 3-4 days after the second immunization. Then, mice with similar degrees of morbidity are randomly divided into 4 groups, namely a control group, an ibrutinib group, a 1650 mg/kg formula group and a 16100 mg/kg formula group, and corresponding medicines are respectively injected into the abdominal cavity. Each group of mice was scored daily for Arthritis (AI): score 0, normal; if so: 1 point for ankle joint red swelling, 1 point for palm red swelling, 1 point for 1-2 toe red swelling, and 2 points for more than 2 toe red swelling; each foot was scored once, each mouse was scored as the sum of the four-footed scores, and the maximum score was 16.

The experimental results are as follows: as shown in fig. 4, ibrutinib significantly improved the symptoms of swelling of the mouse feet, and the high dose group of formula 16 also improved the symptoms of arthritis compared to the blank group.

2. Pulmonary hemorrhage

The experimental scheme is as follows: b6 mice were divided into healthy group (3), blank group (7), ibrutinib group (7) and formula 8 group (7), except healthy group, 1ml of norphytane was intraperitoneally injected uniformly, blank group, ibrutinib group and PROTAC group were injected with solvent, ibrutinib and formula 16 respectively one week before norphytane injection, 100mg/kg per day, mice were sacrificed after continuous injection for 18 days after norphytane injection, lungs and spleens were removed, weighed and observed for bleeding in lungs.

The experimental results are as follows: as shown in fig. 5 and fig. 6, in the mouse pulmonary hemorrhage model, with ibrutinib as a control, formula 16 can effectively improve the symptoms of pulmonary hemorrhage, and the lung weight and spleen weight are also significantly lower than those of the control group of ibrutinib.

3. Systemic Lupus Erythematosus (SLE)

The experimental scheme is as follows: using 6-8 week-old bm12 mice (JAX1162), spleens were ground to obtain total splenic cells, and after a sufficient red blood cell lysis procedure, the total splenic cells were washed 2 times with PBS to prepare cell suspensions, and each mouse was transfused 1x10 through the caudal vein⁷Bm12 spleen cells and were induced continuously for two weeks using the same method. Intravenous blood was collected the day before injection as a pre-induction control. Blood was taken weekly after injection. One week after the second injection, the induced mice were divided into vehicle group, ibrutinib group and formula 16 group, and 50mg/kg or 100mg/kg of ibrutinib or formula 16 was intraperitoneally injected daily, and the non-induced mice were taken as healthy controls. Two weeks after consecutive injections, spleens and kidneys were taken for relevant phenotypic analysis.

The experimental results are as follows: as shown in fig. 7 and 8, the bm12 lymphocyte-induced SLE mouse model was successfully modeled, and the induced mice could produce autoantibodies specific for anti-dsDNA, but in the ibrutinib group and formula 16 group, the anti-dsDNA antibodies in serum were significantly lower than in the vehicle group. After 3 weeks of induction, antinuclear antibodies (ANA) were detected in mouse serum and it was found that both the ibrutinib group and formula 16 group produced lower levels of ANA after induction of bm12 lymphocytes. The deposition of immune complexes in the glomerulus is an important index for evaluating the mouse autoimmune phenotype, and the kidney of the mouse is taken to be frozen tissue section, and the immunofluorescence staining result shows that the Illustranib group and the formula 16 group have less antibody deposition.

In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.

Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.

Claims

1. Use of a compound for the preparation of a medicament for the treatment or prevention of an autoimmune disease, said compound being a compound of formula 28 or a stereoisomer, tautomer, pharmaceutically acceptable salt thereof,

2. use according to claim 1, wherein the autoimmune disease is arthritis, pulmonary hemorrhage, systemic lupus erythematosus, pemphigus, chronic lymphocytic thyroiditis, hyperthyroidism, insulin dependent diabetes mellitus, myasthenia gravis, chronic ulcerative colitis, pernicious anemia with chronic atrophic gastritis, primary biliary cirrhosis, multiple sclerosis or acute idiopathic polyneuritis.

3. The use according to claim 1, wherein the autoimmune disease is arthritis or pulmonary hemorrhage.

4. Use of a pharmaceutical composition for the preparation of a medicament for the treatment or prevention of an autoimmune disease, the pharmaceutical composition comprising a compound of formula 28, or a stereoisomer, tautomer, pharmaceutically acceptable salt thereof,

5. the use according to claim 4, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or combination thereof.

6. The use according to claim 4, wherein the pharmaceutical composition further comprises other drugs for treating or preventing autoimmune diseases.

7. Use according to claim 6, wherein the autoimmune disease is arthritis, pulmonary hemorrhage, systemic lupus erythematosus, pemphigus, chronic lymphocytic thyroiditis, hyperthyroidism, insulin dependent diabetes mellitus, myasthenia gravis, chronic ulcerative colitis, pernicious anemia with chronic atrophic gastritis, primary biliary cirrhosis, multiple sclerosis or acute idiopathic polyneuritis.

8. Use according to claim 6, wherein the autoimmune disease is arthritis or pulmonary hemorrhage.

9. The use according to claim 6, wherein the other medicament for the treatment or prevention of autoimmune disease comprises ibrutinib.