CN112250666A

CN112250666A - Substituted pyrimidines and their use

Info

Publication number: CN112250666A
Application number: CN202011073228.5A
Authority: CN
Inventors: 金传飞; 钟文和; 陈康智; 许腾飞; 余天喜; 周克军
Original assignee: Sunshine Lake Pharma Co Ltd
Current assignee: Guangdong HEC Pharmaceutical
Priority date: 2020-10-09
Filing date: 2020-10-09
Publication date: 2021-01-22
Anticipated expiration: 2040-10-09
Also published as: CN112250666B

Abstract

The invention belongs to the technical field of medicines, and relates to substituted pyrimidine compounds, application thereof and pharmaceutical compositions containing the compounds, which can be used as Bruton's Tyrosine Kinase (BTK) inhibitors. The invention also relates to a method for preparing the compound and a pharmaceutical composition, and application of the compound and the pharmaceutical composition in preventing or treating diseases caused by over-activation of BTK, including but not limited to tumors, thromboembolism, inflammatory diseases, autoimmune diseases and other diseases, particularly tumors.

Description

Substituted pyrimidines and their use

Technical Field

The invention belongs to the technical field of medicines, and relates to a compound and a pharmaceutical composition serving as a Bruton's Tyrosine Kinase (BTK) inhibitor, and a using method and application thereof. In particular, the invention relates to substituted pyrimidine compounds and pharmaceutical compositions thereof, and also relates to methods for preparing the compounds and the pharmaceutical compositions, and application of the compounds and the pharmaceutical compositions in preventing or treating diseases caused by over-activation of BTK, including but not limited to tumors, thromboembolism, inflammatory diseases, autoimmune diseases and the like. In particular, the compound and the pharmaceutical composition thereof are used for preventing or treating tumors.

Background

Protein Kinases (PK) are enzymes that catalyze the process of protein phosphorylation. The phosphorylation process of proteins is the final link of the intracellular transmission of neural information, resulting in changes in the state of ion channel proteins and gates. The protein phosphorylation reaction is a sum of a type of covalent modification in which a phosphate at the terminal position (gamma position) of Adenosine Triphosphate (ATP) is transferred to a specific amino group of a substrate protein. The phosphate-accepting site in phosphorylation reactions, which are generally catalyzed by protein kinases, is the hydroxyl group of tyrosine, serine, or threonine.

More than about 400 protein kinases have been discovered, and a homologous catalytic domain (consisting of about 270 amino acid residues) exists in the molecule. Protein kinases form criss-cross networks in systems such as cell signaling and cell cycle regulation. Such enzymes alter the conformation and activity of proteins, enzymes by catalyzing the transfer of phosphate from ATP and covalently binding to the hydroxyl groups of certain tyrosine, serine or threonine residues in specific protein molecules.

Protein kinases can regulate many different cellular processes by adding phosphate groups to target proteins, for example: proliferation, differentiation, motility, apoptosis, transcription, translation and other signaling processes. These phosphorylation events act as molecular on-off switches that can modulate or modulate the biological function of the target protein. The phosphorylation response of a target protein occurs with a variety of extracellular signals (growth and differentiation factors, neurotransmitters, hormones, etc.), environmental or nutritional stresses, cell cycle events, etc. Suitable protein kinases function in signaling pathways to inactivate or activate (directly or indirectly) for example receptors, metabolic enzymes, regulatory proteins, cytoskeletal proteins, ion channels or pumps or transcription factors. Uncontrolled signaling due to defective control of protein phosphorylation is implicated in a variety of diseases including, for example, cancer, inflammation, allergy/asthma, angiogenesis, immune system diseases and disorders, and central nervous system diseases and disorders.

Protein kinases are numerous and constitute a large family of structurally related enzymes responsible for the control of various signal transduction processes in cells, and they are classified into 5 classes according to the kind of amino acid residues phosphorylated on their substrate proteins, namely: (1) serine/threonine (Ser/Thr) protein kinases: the hydroxyl groups of the protein are phosphorylated; (2) tyrosine (Tyr) protein kinase: the phenolic hydroxyl group of the protein acts as a phosphorus acceptor; (3) tryptophan protein kinase: the tryptophan residue of the protein is used as a phosphorus acceptor; (4) aspartyl/glutamyl protein kinase: using acyl of protein as phosphorus acceptor; (5) histidine protein kinase: the basic groups of lysine, arginine or histidine of proteins are phosphorylated, mainly in the "two-component signal system".

Among them, tyrosine protein kinases were discovered in the 80 s, and can catalyze autophosphorylation, and also phosphorylate other proteins. Its phosphorylation reaction occurs exclusively on the hydroxyl group of a particular tyrosine. The receptors for the allergenic proteins of certain oncoviruses, as well as for some growth factors, have tyrosine protein kinase activity.

Bruton's Tyrosine Kinase (BTK) is one of 5 members of the non-receptor tyrosine protein kinase Tec family, the others are Resting Lymphocyte Kinase (RLK), bone marrow kinase X (BMX), hepatocellular carcinoma-expressed tyrosine kinase (Tec) and interleukin-2-induced T-cell kinase (ITK). BTK consists of 659 amino acids, has a structure similar to that of TEC and ITK, and contains multiple domains, such as Plecktrin Homology (PH) domain, Tec Homology (TH) domain, Src homology 3(SH3) domain, SH2 domain, and SH1 domain (Future Med Chem,2014,6(6): 675) 695). BTK is normally present in the cytoplasm, but is transiently recruited to the cell membrane after its PH domain interacts with phosphatidylinositol 3,4, 5-triphosphate produced by phosphatidylinositol-3 kinase. The activation and recruitment of BTK to the cell membrane is accomplished in two steps: first, the BTK kinase domain Y551 site is phosphorylated by Syk or Src kinase (Rawlings DJ, Scharenberg AM, Park H, et al. activation of BTK by a phosphorylation mechanism in catalytic by SRC family kinases [ J ] Science,1996,271(5250):822-825), which phosphorylation increases the catalytic activity of BTK; subsequently, the Y223 site of the BTK SH3 domain is autophosphorylated, which is thought to stabilize the active conformation of BTK and to fully activate BTK (Marcotte DJ, Liu YT, Arduini RM, et al structure of human Bruton's tyrosine kinase in active and inactive conformations present. degustment a mechanism of activation for TEC fatigue kinases [ J ]. Protein Sci,2010,19(3): 429-.

BTK is a signaling enzyme expressed in all hematopoietic cells except natural killer cells and T lymphocytes. BTK plays a well-documented role in the B-cell signaling pathway that links cell surface B-cell receptor stimulation to downstream intracellular responses. BTK has been shown to play an extremely important role in a variety of physiological processes including development, maturation, differentiation and proliferation of B cells as an important component of the B Cell Receptor (BCR) signaling pathway (Nature,1993,361(6409): 226-233). In addition, BTK exerts physiological effects through other hematopoietic cell signaling pathways, such as Toll-like receptor (TLR) and cytokine receptor mediated TNF-a production in macrophages, inhibition of Fas/APO-1 apoptosis signaling in B-lineage lymphoid cells, IgE receptor (FcepsilonRl) signaling in mast cells, and collagen-stimulated platelet aggregation.

Precise regulation of BTK is critical to maintaining normal physiological function of B cells (Anticancer Agents Med Chem,2007,7(6): 624-. Over-activation of BTK causes a slowing of B cell apoptosis and is susceptible to autoimmune reactions, thereby inducing the development and progression of diseases such as B cell lymphoma and inflammation (Int Rev Immunol,2012,31(2): 119-132).

BTK has been shown to be overexpressed in a variety of B-cell lymphomas (Blood,2011,117(23): 6287-. Such as: in mantle cell lymphoma cells, BTK Tyr223 shows continuous autophosphorylation, which results in over-activation of BTK (Blood,2013,122(14): 2412-2424); in a mouse model of chronic lymphocytic leukemia, overexpression of BTK leads to an increase in both tumor incidence and mortality (Am J Blood Res,2013,3(1): 71-83). Over-activation by BTK gain-of-function mutations was also confirmed in acute myelogenous leukemia (Expert Opin Ther Patents,2010,20(11): 1457-. The level of anti-apoptotic proteins Mcl-1, Bcl-xL and Bcl-2 can be reduced by inhibiting the activity of BTK, thereby promoting B cell lymphoma apoptosis (Leuk Res,2013,37(10): 1271-.

BTK plays a key role in the generation and development of tumors and is important for the survival of various B cell malignant tumor cells such as leukemia and the like. The first finding in 1952 by the american pediatrician Ogdon Bruton was that BTK is abnormally expressed in a hereditary immunodeficiency disease X-linked agammaglobulinemia patient and is associated with recurrent bacterial infections in the patient (Vetrie D,

I,Sideras P,et al.The gene involved in X-linked agammaglobulinaemia is a member of the Src family of protein-tyrosine kinases.1993[J].J Immunol,2012,188(7):2948-2955；Tsukada S,Saffran DC,Rawlings DJ,et al.Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia[J]cell,1993,72(2): 279-290). BTK Small molecule inhibitors have been shown to have unexpectedly superior anti-tumor activity in clinical trials (Byrd JC, Furman RR, Costru SE, et al].N Engl J Med,2013,369(1):32-42；Byrd JC,Harrington B,O’Brien S,et al.Acalabrutinib(ACP-196)in relapsed chronic lymphocytic leukemia[J]N Engl J Med,2016,374(4): 323-. The BTK inhibitor ibrutinib (irutinib), which produces an enzyme inhibitory effect by forming a covalent bond with the cysteine residue of the active site of BTK kinase domain 481, was approved by the FDA in the united states for first-line treatment of Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL) in 2016, but patients treated with ibrutinib present a greater risk of bleeding or atrial fibrillation combined with a high risk of bleeding. Acatinib (acalaburtinib) obtained us FDA approval in 2017, becoming the 2 nd marketed BTK inhibitor. In 2019, sanbuctinib (zanubruntinib) developed by the pharmaceutical company of china, medicament qianjianshou was approved in the united states. In 2020, BTK inhibitors (tirabrutinib) developed by Xiaoye pharmaceutical Co were approved in Japan for the treatment of primary central nervous system lymphoma.

BTK inhibitors are currently being used not only for the treatment of B cell malignancies, but are also being clinically studied for the treatment of solid tumors, other hematological and immune system malignancies. However, currently, there are few BTK inhibitors with good drug properties and a single structure. Therefore, the development of new BTK inhibitors is of great importance.

Disclosure of Invention

The following is a summary of some aspects of the invention only and is not intended to be limiting. These aspects and others are described more fully below. All references in this specification are incorporated herein by reference in their entirety. When the disclosure of the present specification differs from the cited documents, the disclosure of the present specification controls.

The invention relates to a novel substituted pyrimidine compound, and experimental results show that: the compound has a remarkable inhibiting effect on BTK and has unexpected excellent BTK inhibiting activity. Therefore, the compound can be used as a BTK inhibitor and used for preventing or treating related diseases caused by over-activation of BTK, including but not limited to tumors, thromboembolism, inflammatory diseases, autoimmune diseases and other diseases, particularly tumors.

The compound has stable property, good safety and little toxic and side effect, and has the advantages of pharmacodynamics and pharmacokinetics, such as good brain/plasma ratio (brain plasma ratio), good bioavailability or good metabolic stability and the like, thereby having better clinical application prospect.

The invention also provides processes for the preparation of such compounds and pharmaceutical compositions containing them.

In one aspect, the invention relates to a compound that is a compound of formula (I) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt of a compound of formula (I) or a prodrug thereof,

wherein R is¹、R²、R³、R⁴、R⁵、U、V、W、X₁、X₂、Y₁And Y₂Have the meaning as described in the present invention.

In some embodiments of the present invention, the substrate is,

is a heterocyclic group consisting of 3 to 8 atoms, wherein x represents the end attached to U.

In some embodiments, U is-NH-or-O-.

In some embodiments, V is-CH₂-、-CH₂CH₂-or-C (═ O) -.

In some embodiments, W is-NH-, -O-, -CH₂-、-CH₂CH₂-、-CH₂O-、-OCH₂-, -C (═ O) NH — or-NHC (═ O) -.

In some embodiments, X₁And X₂Each independently is CH or N.

In some embodiments, Y is₁And Y₂Each independently is CH or N.

In some embodiments, R¹、R²And R³Each independently is H, D, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-SH、-COOH、-C(＝O)NH₂、-C(＝O)NHCH₃、-C(＝O)N(CH₃)₂、-C(＝O)-(C₁-C₆Alkyl), -C (═ O) - (C)₁-C₆Alkoxy), -S (═ O)₂C₁-C₆Alkyl radical, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆Haloalkyl, C₁-C₆Alkoxy radical, C₁-C₆Haloalkoxy, C₁-C₆Alkylthio radical, C₁-C₆Alkylamino or hydroxy substituted C₁-C₆An alkyl group.

In some embodiments, R⁴And R⁵Each independently is H, D, -OH, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆Haloalkyl, C₁-C₆Alkoxy or C₁-C₆A haloalkoxy group; or R⁴、R⁵And the nitrogen atom to which they are attached, together form a heterocyclic group of 3 to 8 atoms.

In some embodiments of the present invention, the substrate is,

is a heterocyclic group consisting of 3 to 6 atoms, wherein x represents the end attached to U.

In yet other embodiments of the present invention, the substrate is,

is composed of

Wherein denotes the end connected to U.

In some embodiments, R¹、R²And R³Each independently is H, D, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-SH、-COOH、-C(＝O)NH₂、-C(＝O)NHCH₃、-C(＝O)N(CH₃)₂、-C(＝O)-(C₁-C₄Alkyl), -C (═ O) - (C)₁-C₄Alkoxy), -S (═ O)₂C₁-C₄Alkyl radical, C₁-C₄Alkyl radical, C₂-C₄Alkenyl radical, C₂-C₄Alkynyl, C₁-C₄Haloalkyl, C₁-C₄Alkoxy radical, C₁-C₄Haloalkoxy, C₁-C₄Alkylthio radical, C₁-C₄Alkylamino or hydroxy substituted C₁-C₄An alkyl group.

In other embodiments, R¹、R²And R³Each independently is H, D, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-SH、-COOH、-C(＝O)NH₂、-C(＝O)NHCH₃、-C(＝O)N(CH₃)₂、-C(＝O)-CH₃、-C(＝O)-OCH₃、-S(＝O)₂CH₃Methyl, ethyl, n-propyl, isopropyl, tert-butyl, vinyl, -CHF₂、-CF₃Methoxy, -OCF₃Methylamino, dimethylamino or hydroxymethyl.

In some casesIn the embodiment, R⁴And R⁵Each independently is H, D, -OH, C₁-C₄Alkyl radical, C₂-C₄Alkenyl radical, C₂-C₄Alkynyl, C₁-C₄Haloalkyl, C₁-C₄Alkoxy or C₁-C₄A haloalkoxy group; or R⁴、R⁵And the nitrogen atom to which they are attached, together form a heterocyclic group of 3 to 6 atoms.

In other embodiments, R⁴And R⁵Each independently H, D, -OH, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, 2-methylpropyl, 1-methylpropyl, ethenyl, propenyl, allyl, ethynyl, propynyl, propargyl, -CHF₂、-CF₃Methoxy, ethoxy, isopropoxy or-OCF₃(ii) a Or R⁴、R⁵And the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl group.

In some embodiments, the compound of the present invention, which is a compound of formula (II) or a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt of a compound of formula (II), or a prodrug thereof,

wherein R is¹、R²、R³、R⁴、R⁵、U、V、X₁、X₂、Y₁And Y₂Have the meaning as described in the present invention.

In other embodiments, the compound of the present invention, which is a compound of formula (II ') or a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt of a compound of formula (II'), or a prodrug thereof,

In still other embodiments, the compound of the present invention, which is a compound of formula (III) or a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt of a compound of formula (III), or a prodrug thereof,

In some embodiments, the compound of the present invention is a compound having one of the following structures or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt of the compound having one of the following structures, or a prodrug thereof:

in another aspect, the present invention relates to a pharmaceutical composition comprising a compound disclosed herein.

In some embodiments, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable excipient, carrier, adjuvant, or any combination thereof.

In yet another aspect, the invention relates to the use of a compound or pharmaceutical composition disclosed herein for the preparation of a medicament for the prevention or treatment of a disease associated with over-activation of BTK.

In some embodiments, the related disease caused by over-activation of BTK according to the present invention is a tumor, thromboembolism, inflammatory disorder, and/or autoimmune disease.

In some embodiments, the disease associated with over-activation of BTK according to the invention is a tumor.

In some embodiments, the tumor of the invention is a B cell lymphoma, a solid tumor, and/or a hematologic and immune system tumor.

In some embodiments, the B cell lymphoma of the present invention is diffuse large B cell lymphoma, small lymphocytic tumor, mantle cell lymphoma, multiple myeloma, and/or chronic lymphocytic leukemia.

In other embodiments, the solid tumor according to the invention is a cancer of the stomach, intestine, liver, kidney, lung, brain, larynx, oesophagus, head and neck, squamous epithelium, lymphatic system, thyroid, bladder, cervix, prostate, genitourinary tract, breast, small cell lung, pancreas, colon, glioblastoma and/or monocytic leukaemia.

In still other embodiments, the hematologic and immune system tumors of the present invention are acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, and/or chronic myeloid leukemia.

In some embodiments, the inflammatory disorder or autoimmune disease described herein is asthma, psoriasis, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, a heteroimmune disease, idiopathic thrombocytopenic purpura, immune complex-mediated vasculitis, and/or autoimmune-mediated hemolytic anemia.

In a further aspect, the invention relates to the use of a compound or pharmaceutical composition disclosed herein for the manufacture of a medicament for inhibiting the activity of bruton's tyrosine kinase.

In yet another aspect, the invention relates to a process for the preparation, isolation and purification of a compound of formula (I), formula (II') or formula (III).

Biological test results show that the compound provided by the invention has unexpectedly excellent anti-novel coronavirus activity, so that the compound provided by the invention can be used as a better novel coronavirus inhibitor.

Any embodiment of any aspect of the invention may be combined with other embodiments, as long as they do not contradict. Furthermore, in any embodiment of any aspect of the invention, any feature may be applicable to that feature in other embodiments, so long as they do not contradict.

Detailed description of the invention

Definitions and general terms

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. One 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.

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 one or to more than one (i.e., to at least one) of the objects. 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 "patient" as used herein refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to a human.

The term "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 (cis/trans) isomers, atropisomers, and the like.

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.

When tautomerism (e.g., keto-enol tautomerism) of the compounds of the present invention or prodrugs thereof exists, it is intended to claim both their individual forms (e.g., keto or enol forms), respectively, and mixtures thereof in any proportion. The same applies to their stereoisomers, e.g., enantiomers, diastereomers, conformers (rotamers), geometric (cis/trans) isomers, atropisomers, and the like.

If desired, the tautomers can be separated according to methods known in the art (e.g., liquid chromatography). The same applies to their enantiomers, for example, using chiral stationary phase separation. Furthermore, enantiomers can be separated by conversion to diastereomers, i.e. coupling with enantiomerically pure auxiliary compounds, followed by separation of the resulting diastereomers and cleavage of the auxiliary residues. Alternatively, any enantiomer of a compound of the invention may be obtained by stereoselective synthesis using optically pure starting materials.

"pharmaceutically acceptable" refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio, and which are effective for their intended use.

The term "optionally substituted with … …" is used interchangeably with the term "unsubstituted or substituted with …", i.e., the structure is unsubstituted or substituted with one or more substituents described herein, including but not limited to D, F, Cl, Br, I, N₃，-CN，-NO₂，-NH₂，-OH，-SH，-COOH，-C(＝O)NH₂，-C(＝O)NHCH₃，-C(＝O)N(CH₃)₂-C (═ O) -alkyl, -C (═ O) -alkoxy, -NHS (═ O)₂-alkyl, -N (alkyl) S (═ O)₂-alkyl, -S (═ O)₂Alkyl, alkoxy, alkylthio, alkylamino, alkenyl, alkynyl, haloalkyl, haloalkoxy, hydroxy-substituted alkyl, cyano-substituted alkyl, amino-substituted alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyl-alkylene, heterocyclyl-alkylene, aryl-alkylene, heteroaryl-alkylene, and the like.

In the description of the parts, the invention discloses the substituents of the compounds according to the group type orThe scope is disclosed. 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-C₆Alkyl "means in particular independently disclosed methyl, ethyl, C₃Alkyl radical, C₄Alkyl radical, C₅Alkyl and C₆An alkyl group.

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 terms "halogen" and "halo" are used interchangeably herein to refer to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

The term "alkyl" or "alkyl group" as used herein, denotes a saturated, straight or branched chain, monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may be optionally substituted with one or more substituents as described herein. In some embodiments, the alkyl group contains 1 to 6 carbon atoms; in other embodiments, the alkyl group contains 1 to 4 carbon atoms; in still other embodiments, the alkyl group contains 1 to 3 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH)₃) Ethyl group (Et, -CH)₂CH₃) N-propyl (n-Pr, -CH)₂CH₂CH₃) Isopropyl group (i-Pr, -CH (CH)₃)₂) N-butyl (n-Bu, -CH)₂CH₂CH₂CH₃) Isobutyl (i-Bu, -CH)₂CH(CH₃)₂(2-methylpropyl)), sec-butyl (s-Bu, -CH (CH)₃)CH₂CH₃(1-methylpropyl)), tert-butyl (t-Bu, -C (CH)₃)₃) And so on.

The term "alkylene" refers to a saturated divalent hydrocarbon radical obtained by removing two hydrogen atoms from a saturated straight or branched chain hydrocarbonA group. Unless otherwise specified, the alkylene group contains 1 to 10 carbon atoms. In some embodiments, the alkylene group contains 1 to 6 carbon atoms; in other embodiments, the alkylene group contains 1 to 4 carbon atoms; in still other embodiments, the alkylene group contains 1 to 2 carbon atoms. Examples include, but are not limited to, methylene (-CH)₂-) ethylene (-CH₂CH₂-) propylene (-CH)₂CH₂CH₂-) isopropylidene (-CH (CH)₃)CH₂-) and the like. The alkylene group is optionally substituted with one or more substituents described herein.

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 sp²A double bond, wherein the alkenyl group may be optionally substituted with one or more substituents described herein, including the positioning of "cis" and "trans", 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 ═ CH)₂) Allyl (-CH)₂CH＝CH₂) 1-propenyl (i.e., propenyl, -CH ═ CH-CH)₃) And so on.

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 (-CH)₂C.ident.CH), 1-propynyl (i.e., propynyl, -C.ident.C-CH)₃) And so on.

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 some embodiments, alkoxy groups contain 1 to 6 carbon atoms; in other embodiments, the alkoxy group contains 1 to 4 carbon atoms; in still other embodiments, alkoxy groups contain 1-3 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, -OCH)₃) Ethoxy (EtO, -OCH)₂CH₃) 1-propoxy (n-propoxy, n-PrO, n-propoxy, -OCH₂CH₂CH₃) 2-propoxy (isopropoxy, i-PrO, i-propoxy, -OCH (CH)₃)₂) 1-butoxy (n-BuO, n-butoxy, -OCH)₂CH₂CH₂CH₃) 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH)₂CH(CH₃)₂) 2-butoxy (s-BuO, s-butoxy, -OCH (CH)₃)CH₂CH₃) 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH)₃)₃) And so on.

The term "alkylthio" means an alkyl group attached to the rest of the molecule through a sulfur atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkylthio group contains 1 to 12 carbon atoms. In some embodiments, the alkylthio group contains 1 to 6 carbon atoms; in other embodiments, the alkylthio group contains 1 to 4 carbon atoms; in still other embodiments, the alkylthio group contains 1 to 3 carbon atoms. The alkylthio group may be optionally substituted with one or more substituents described herein. Examples of alkylthio groups include, but are not limited to, methylthio (MeS, -SCH)₃) Ethylthio (EtS, -SCH)₂CH₃) And so on.

The term "alkylamino" or "alkylamino" denotes an amino group independently substituted with one or two alkyl groups, respectively, including "N-alkylamino" and "N, N-dialkylamino" wherein the alkyl groups have the meaning as described herein. Suitable alkylamino groups can be monoalkylamino or dialkylamino, and such examples include, but are not limited to, N-methylamino (methylamino), N-ethylamino (ethylamino), N-dimethylamino (dimethylamino), N-diethylamino (diethylamino), and the like. The alkylamino group is optionally substituted with one or more substituents described herein.

The term "hydroxy-substituted alkyl" means that the alkyl group is substituted with one or more hydroxy groups (-OH), wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the hydroxy-substituted alkyl group contains 1 to 12 carbon atoms. In some embodiments, the hydroxy-substituted alkyl group contains 1 to 6 carbon atoms, e.g., hydroxy-substituted C₁-C₆An alkyl group; in other embodiments, the hydroxy-substituted alkyl group contains 1 to 4 carbon atoms, e.g., hydroxy-substituted C₁-C₄An alkyl group; in still other embodiments, the hydroxy-substituted alkyl group contains 1 to 3 carbon atoms, e.g., hydroxy-substituted C₁-C₃An alkyl group. Examples include, but are not limited to, hydroxymethyl, hydroxyethyl (e.g., 2-hydroxyethyl), 2-hydroxy-1-propyl, 3-hydroxy-1-propyl, 2, 3-dihydroxypropyl, and the like.

The term "haloalkyl" or "haloalkoxy" means an alkyl or alkoxy group substituted with one or more halogen atoms, wherein the alkyl and alkoxy groups have the meaning as described herein, examples of which include, but are not limited to, -CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂、-OCHF₂、-OCF₃、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂And the like. In some embodiments, C₁-C₆The haloalkyl group containing a fluorine-substituted C₁-C₆An alkyl group; in other embodiments, C₁-C₄The haloalkyl group containing a fluorine-substituted C₁-C₄An alkyl group; in still other embodiments, C₁-C₂The haloalkyl group containing a fluorine-substituted C₁-C₂An alkyl group.

The term "cycloalkyl" denotes a saturated monocyclic, bicyclic or tricyclic ring system containing from 3 to 12 ring carbon atoms. In some embodiments, cycloalkyl groups contain 3 to 10 ring carbon atoms, e.g., C_3-10A cycloalkyl group; in other embodiments, cycloalkyl groups contain 3 to 8 ring carbon atoms, e.g., C_3-8A cycloalkyl group; in still other embodiments, cycloalkyl groups contain 3-6 ring carbon atoms, e.g., C_3-6A cycloalkyl group. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. Wherein, as described in the present invention, C_3-8Cycloalkyl radicals including C_3-6A cycloalkyl group; said C_3-6Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The cycloalkyl group may be optionally substituted with one or more substituents described herein.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic ring system containing 3 to 12 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen atoms; wherein the heterocyclic group is non-aromatic and does not contain any aromatic ring. Unless otherwise specified, heterocyclyl may be carbon-or nitrogen-based, and-CH₂-the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atoms of the ring may optionally be oxidized to the N-oxide. The term "heterocyclyl" may be used interchangeably with the term "heterocycle". As described herein, the heterocyclyl group may consist of 3 to 8 atoms or 3 to 6 atoms, optionally selected from C, N, O or S and at least one atom being N, O or S; wherein the heterocyclic group consisting of 3 to 8 atoms includes a heterocyclic group consisting of 3 to 6 atoms; the heterocyclic group consisting of 3 to 6 atoms includes a heterocyclic group consisting of 3 to 5 atoms. Specifically, the heterocyclic group consisting of 3 to 6 atoms includes, but is not limited toIn the above examples, the alkylene oxide group may be an ethylene oxide group, an aziridine group, an azetidine group, an oxetane group, a pyrrolidinyl group, a tetrahydrofuranyl group, a tetrahydrothienyl group, a thiazolidine group, a pyrazolidinyl group, a pyrazolinyl group, an oxazolidinyl group, an imidazolidinyl group, a piperidyl group, a piperazinyl group, or a morpholinyl group. The heterocyclyl group may be optionally substituted with one or more substituents described herein.

The term "aryl" denotes a monocyclic, bicyclic and tricyclic carbocyclic ring system containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, wherein at least one ring is aromatic and has one or more attachment points to the rest of the molecule. The term "aryl" may be used interchangeably with the terms "aromatic ring" or "aromatic ring". Examples of the aryl group may include phenyl, indenyl, 2, 3-dihydro-1H-indenyl, naphthyl and anthryl. The aryl group may be optionally substituted with one or more substituents described herein. Unless otherwise stated, the group "C_6-10Aryl "represents an aryl group containing from 6 to 10 ring carbon atoms.

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 is aromatic and at least one ring contains 1, 2,3 or 4 ring heteroatoms selected from nitrogen, oxygen, sulfur, and wherein the heteroaryl has one or more attachment points to the rest of the molecule. when-CH is present in the heteroaryl group₂When it is a group, -CH₂-the group may optionally be replaced by-C (═ O) -. Unless otherwise indicated, the heteroaryl group may be attached to the rest of the molecule (e.g., the main structure in the formula) via any reasonable site, which may be C or N. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound". The heteroaryl group may be optionally substituted with one or more substituents described herein. In some embodiments, heteroaryl is 5-10 atom consisting of heteroaryl, meaning that heteroaryl contains 1-9 ring carbon atoms and 1, 2,3, or 4 ring heteroatoms selected from O, S and N; in other embodiments, heteroaryl is heteroaryl of 5 to 6 atomsRepresents a heteroaryl group containing 1 to 5 ring carbon atoms and 1, 2,3 or 4 ring heteroatoms selected from O, S and N; examples of heteroaryl groups consisting of 5 to 6 atoms include, but are not limited to, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, thiazolyl, triazolyl, tetrazolyl, and the like.

The term "j-k atoms" means that the cyclic group consists of j-k ring atoms including carbon atoms and/or heteroatoms such as O, N, S, P; j and k are each independently any non-zero natural number, and k > j; the term "j-k" includes j, k and any natural number therebetween. For example, "3 to 8 atoms", "3 to 6 atoms", "5 to 10 atoms" or "5 to 6 atoms" means that the cyclic group consists of 3 to 8 (i.e., 3,4,5, 6, 7 or 8), 3 to 6 (i.e., 3,4,5 or 6), 5 to 10 (i.e., 5, 6, 7, 8, 9 or 10) or 5 to 6 (i.e., 5 or 6) ring atoms including carbon atoms and/or heteroatoms such as O, N, S, P.

The terms "cycloalkylalkylene", "heterocyclylalkylene", "arylalkylene", "heteroarylalkylene" mean that the cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each independently attached to the rest of the molecule through an alkylene group, wherein the cycloalkyl, heterocyclyl, aryl, heteroaryl and alkylene groups all have the meaning described herein. For example, examples of arylalkylene groups include, but are not limited to, phenylmethylene, phenylethylene, phenylpropylene, and the like. The cycloalkylalkylene, heterocyclylalkylene, arylalkylene, heteroarylalkylene are each independently optionally substituted with one or more substituents described herein.

The term "prodrug", as used herein, represents a compound that is converted in vivo to a compound of formula (I), formula (II') or formula (III). 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 the ester can be used as prodrug in the prior inventionWith benzoates, 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.

"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. 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. The 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, phosphatesCompound, nitrate, C₁-C₈Sulfonates 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, ethanolamine, or mixtures thereof. The term "hydrate" refers to an association of solvent molecules that is water.

When the solvent is water, the term "hydrate" may be used. In one embodiment, a molecule of a compound of the present invention may be associated with a molecule of water, such as a monohydrate; in another embodiment, one molecule of the compound of the present invention may be associated with more than one molecule of water, such as a dihydrate; in yet another embodiment, one molecule of the compound of the present invention may be associated with less than one molecule of water, such as a hemihydrate. It should be noted that the hydrates of the present invention retain the biological effectiveness of the compound in its non-hydrated form.

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.

The term "prevent" or "prevention" refers to a reduction in the risk of acquiring a disease or disorder (i.e., arresting the development of at least one clinical symptom of a disease in a subject that may be facing or predisposed to facing such a disease, but who has not yet experienced or exhibited symptoms of the disease).

The term "therapeutically effective amount" means an amount of a compound that, when administered to a subject to treat a disease, is sufficient to effect treatment of the disease. The "therapeutically effective amount" may vary with the compound, the disease and the severity, as well as the condition, age, weight, sex, etc., of the subject to be treated.

Unless otherwise indicated, all suitable isotopic variations, stereoisomers, tautomers, solvates, metabolites, pharmaceutically acceptable salts and prodrugs thereof, of the compounds of the present invention are encompassed within the scope of the present invention.

In the structures disclosed herein, when the stereochemistry of any particular chiral atom is not specified, then all stereoisomers of that structure are contemplated as within this invention and are included as disclosed compounds in this invention. When stereochemistry is indicated by a solid wedge (solid wedge) or dashed line representing a particular configuration, then the stereoisomers of the structure are so well-defined and defined.

Nitroxides of the compounds of the present invention are also included within the scope of the present invention. The nitroxides of the compounds of the present invention may be prepared by oxidation of the corresponding nitrogen-containing basic species using a common oxidizing agent (e.g. hydrogen peroxide) in the presence of an acid such as acetic acid at elevated temperature, or by reaction with a peracid in a suitable solvent, for example peracetic acid in dichloromethane, ethyl acetate or methyl acetate, or 3-chloroperoxybenzoic acid in chloroform or dichloromethane.

The compounds of formula (I), formula (II') or formula (III) may be present in the form of a salt. In some embodiments, the salt refers to a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal being treated therewith. In other embodiments, the salt need not be a pharmaceutically acceptable salt, and may be an intermediate useful in the preparation and/or purification of a compound of formula (I), formula (II ') or formula (III) and/or in the isolation of an enantiomer of a compound of formula (I), formula (II') or formula (III).

Any formulae given herein are also intended to represent theseNon-isotopically enriched forms of the compounds and isotopically enriched forms. 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 invention relates to intermediates for the preparation of compounds of formula (I), formula (II') or formula (III).

Pharmaceutical compositions, formulations and administration of the compounds of the invention

The invention provides a pharmaceutical composition, which comprises a compound shown as a formula (I), a formula (II') or a formula (III) or individual stereoisomers, racemic or non-racemic mixtures of isomers or pharmaceutically acceptable salts or solvates thereof. In some embodiments of the invention, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier, adjuvant or vehicle, and optionally, other therapeutic and/or prophylactic ingredients.

Suitable carriers, adjuvants and excipients are well known to those skilled in the art and are described in detail, for example, in Ansel h.c.et al, Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems (2004) Lippincott, Williams & Wilkins, philidelphia; gennaro a.r.et al, Remington: the Science and Practice of Pharmacy (2000) Lippincott, Williams & Wilkins, Philadelphia; and Rowe R.C., Handbook of Pharmaceutical Excipients (2005) Pharmaceutical Press, Chicago.

It will also be appreciated that certain compounds of the invention may be present in free form or, if appropriate, in the form of a pharmaceutically acceptable derivative thereof, when used in therapy. Some non-limiting embodiments of pharmaceutically acceptable derivatives include pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any additional adduct or derivative that upon administration to a patient in need thereof provides, directly or indirectly, a compound of the present invention or a metabolite or residue thereof.

As used herein, "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, mixture or vehicle that is compatible with the dosage form or pharmaceutical composition to be administered. Each excipient, when mixed, must be compatible with the other ingredients of the pharmaceutical composition in order to avoid interactions that would substantially reduce the efficacy of the compounds of the invention when administered to a patient and interactions that would result in a pharmaceutical composition that is not pharmaceutically acceptable. Furthermore, each excipient must be pharmaceutically acceptable, e.g., of sufficiently high purity.

Suitable pharmaceutically acceptable excipients will vary depending on the particular dosage form selected. In addition, pharmaceutically acceptable excipients may be selected for their specific function in the composition. For example, certain pharmaceutically acceptable excipients may be selected to aid in the production of a uniform dosage form. Certain pharmaceutically acceptable excipients may be selected to aid in the production of stable dosage forms. Certain pharmaceutically acceptable excipients may be selected to facilitate carrying or transporting a compound of the invention from one organ or portion of the body to another organ or portion of the body when administered to a patient. Certain pharmaceutically acceptable excipients may be selected that enhance patient compliance.

Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants and buffers. The skilled artisan will recognize that certain pharmaceutically acceptable excipients may provide more than one function, and provide alternative functions, depending on how many such excipients are present in the formulation and which other excipients are present in the formulation.

The pharmaceutical compositions disclosed herein are prepared using techniques and methods known to those skilled in the art. Some commonly used methods in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).

Thus, in another aspect, the invention relates to a process for preparing a pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle or combination thereof, which process comprises admixing the ingredients. Pharmaceutical compositions comprising the disclosed compounds may be prepared by mixing, for example, at ambient temperature and atmospheric pressure.

The compounds disclosed herein are generally formulated in a dosage form suitable for administration to a patient by a desired route. For example, dosage forms include those suitable for the following routes of administration: (1) oral administration, such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets and cachets; (2) parenteral administration, such as sterile solutions, suspensions, and reconstituted powders; (3) transdermal administration, such as transdermal patches; (4) rectal administration, e.g., suppositories; (5) inhalation, such as aerosols, solutions, and dry powders; and (6) topical administration, such as creams, ointments, lotions, solutions, pastes, sprays, foams and gels. The compounds of the invention are preferably administered orally.

In some embodiments, the compounds disclosed herein can be formulated in oral dosage forms. In other embodiments, the compounds disclosed herein may be formulated in an inhalation dosage form. In other embodiments, the compounds disclosed herein can be formulated for nasal administration. In still other embodiments, the compounds disclosed herein can be formulated for transdermal administration. In still other embodiments, the compounds disclosed herein may be formulated for topical administration.

In practice, the compounds of the present invention may be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). In preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed, such as water, glycols, alcohols, oils, preservatives, flavoring agents, coloring agents and the like. In the case of oral liquid preparations, any conventional pharmaceutical media can be used, for example, elixirs, solutions and suspensions; or carriers such as sugars, starches, diluents, disintegrating agents, lubricants, granulating agents, binders, microcrystalline cellulose and the like. In the case of oral solid preparations, the compositions may be presented, for example, as powders, hard and soft capsules, and as tablets. Solid oral dosage forms are preferred over liquid dosage forms.

The pharmaceutical compositions provided by the present invention may be provided as compressed tablets, milled tablets, chewable lozenges, fast-dissolving tablets, double-compressed tablets, enteric-coated tablets, sugar-coated or film-coated tablets.

The pharmaceutical composition provided by the present invention may be provided in soft or hard capsules, which may be prepared from gelatin, methylcellulose, starch or calcium alginate.

The pharmaceutical compositions provided by the present invention may be administered parenterally by injection, infusion or implantation for local or systemic administration. Parenteral administration as used herein includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous administration.

The pharmaceutical compositions provided herein can be formulated in any dosage form suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems and solid forms suitable for solution or suspension in a liquid prior to injection. Such dosage forms may be prepared according to conventional methods known to those skilled in The art of pharmaceutical Science (see Remington: The Science and Practice of Pharmacy, supra).

In another aspect, the disclosed pharmaceutical compositions may be formulated in any dosage form suitable for administration to a patient by inhalation, such as a dry powder, aerosol, suspension, or solution composition.

Pharmaceutical compositions suitable for transdermal administration may be prepared as discrete patches intended to remain in intimate contact with the epidermis of the patient for an extended period of time. For example, the active ingredient may be delivered from a patch agent by iontophoresis, as generally described in Pharmaceutical Research,3(6),318 (1986).

Pharmaceutical compositions suitable for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.

In one embodiment, a compound of the invention or a pharmaceutical composition comprising a compound of the invention may be administered once or several times at different time intervals over a specified period of time according to a dosing regimen. For example, once, twice, three times or four times daily. In one embodiment, the administration is once daily. In yet another embodiment, the administration is twice daily. The administration may be carried out until the desired therapeutic effect is achieved or the desired therapeutic effect is maintained indefinitely. Suitable dosing regimens for the compounds of the invention or pharmaceutical compositions comprising the compounds of the invention depend on the pharmacokinetic properties of the compound, such as absorption, distribution and half-life, which can be determined by the skilled person. In addition, the appropriate dosage regimen, including the duration of the regimen, of the compound of the invention or of the pharmaceutical composition containing the compound of the invention depends on the condition being treated, the severity of the condition being treated, the age and physical condition of the patient being treated, the medical history of the patient being treated, the nature of concurrent therapy, the desired therapeutic effect, and other factors within the knowledge and experience of the skilled artisan. Such a skilled artisan will also appreciate that appropriate dosage regimens may be required to be adjusted for the individual patient's response to the dosage regimen, or as the individual patient needs to change over time.

The compounds of the present invention may be administered simultaneously, or before or after one or more other additional therapeutic agents. The compounds of the invention may be administered separately from other additional therapeutic agents, by the same or different routes of administration, or in the same pharmaceutical composition.

The present invention also relates to a compound or pharmaceutical composition for inhibiting abnormal cell growth in a mammal comprising an amount of a compound of the present invention or a pharmaceutically acceptable salt or solvate or prodrug thereof and an amount of an additional anticancer therapeutic, wherein the amount of the compound, salt, solvate or prodrug together with the amount of the additional anticancer therapeutic is effective to inhibit abnormal cell growth. Many anti-cancer therapeutic agents are currently known in the art. In one embodiment, the anti-cancer therapeutic is an antibody selected from the group consisting of: zaolizumab, trastuzumab, bevacizumab, disitumumab, lintuzumab, ibritumomab, rituximab, cetuximab, tiximumab, IGF 1R-specific antibody, CD 40-specific antibody, WX G250, and chTNT-1/B. In another embodiment, the anti-cancer therapeutic is a chemotherapeutic agent selected from the group consisting of: enzymes, alkylating agents, anti-hormones, anti-androgens, anti-metabolites, intercalating antibiotics (intercalating antibiotics), mitotic inhibitors, growth factor inhibitors, topoisomerase inhibitors, cell cycle inhibitors, angiogenesis inhibitors, and biological response modifiers. In yet another embodiment, the anti-cancer therapeutic is an inhibitor of another protein kinase, such as Vegfr1, Vegfr2, Vegfr3 (also known as Flt-4), Flt-3, Akt, Axl, Aurora A, Aurora B, dyrk2, epha2, fgfr3, igf1r, IKK2, JNK3, KDR, MEK, MET, Plk1, PDK1, RSK1, TAK1, Src, ZA, Zap70, cKit, bRaf, EGFR, PDGFR, Jak2, PI3K, NPM-Alk, c-Abl, BTK, FAK, LimK, and Erk.

The term "therapeutically effective amount" as used herein refers to the total amount of each active ingredient sufficient to show meaningful patient benefit. When the active ingredient alone is used for separate administration, the term refers only to that ingredient. When used in combination, the term refers to the combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, sequentially or simultaneously. By this is meant that, when properly administered, any amount of the compound is sufficient to achieve the desired prophylactic or therapeutic effect in the patient to which it is administered. Generally, it will depend on the condition to be prevented or treated and the route of administration. Substantially satisfactory results are obtained when a daily dose of from about 0.01mg to about 100mg per kg of animal body weight is administered, preferably a single daily dose. For large mammals, the total daily dosage is from about 0.1mg to about 1000mg, preferably from about 0.2mg to about 50 mg. In the case of a 70kg adult, the total daily dose is approximately about 0.2mg to 200 mg. The dosage regimen may be adjusted to provide the optimum therapeutic response. The amount administered, the route of administration and further treatment regimens may be determined by the treating clinician, depending on, for example: age, sex, general condition of the patient, and the nature and severity of the disease/condition to be treated.

Use of the Compounds and pharmaceutical compositions of the invention

The compounds and pharmaceutical compositions provided by the present invention have excellent BTK inhibitory activity and low toxicity (e.g., acute toxicity, chronic toxicity, genetic toxicity, reproductive toxicity, cardiotoxin, drug interactions, and carcinogenicity). Also, the compound or the pharmaceutical composition is excellent in oral absorbability, action sustainability, stability and pharmacokinetics. Furthermore, the compounds or pharmaceutical compositions are less affected by plasma components. Therefore, the compound or the pharmaceutical composition of the present invention can be safely used in mammals (e.g., human, monkey, cow, horse, dog, cat, rabbit, rat, mouse, etc.), and can be used for preventing and/or treating diseases related to over-activation of BTK.

In addition to being beneficial for human therapy, the compounds and pharmaceutical compositions of the present invention may also find application in veterinary therapy for pets, animals of the introduced species and mammals in farm animals. Examples of other animals include horses, dogs, and cats. Herein, the compound of the present invention includes pharmaceutically acceptable derivatives thereof.

General synthetic procedure

To illustrate the invention, the following examples are set forth. It is to be understood that the invention is not limited to these embodiments, but is provided as a means of practicing the invention.

In general, the compounds of the invention can be prepared by the processes described herein, wherein the substituents are as defined for formula (I), formula (II') or formula (III), unless otherwise specified. The following reaction schemes and examples serve to further illustrate the context of the invention.

Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare a number of other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art by modification, such as appropriate protection of interfering groups, by the use of other known reagents in addition to those described herein, or by some routine modification of reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized as being applicable to the preparation of other compounds of the present invention.

The examples described below, unless otherwise indicated, are all temperatures set forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and were used without further purification unless otherwise indicated. General reagents were purchased from Shantou Wen Long chemical reagent factory, Guangdong Guanghua chemical reagent factory, Guangzhou chemical reagent factory, Tianjin Haojian Yunyu chemical Co., Ltd, Tianjin Shucheng chemical reagent factory, Wuhan Xin Huayuan scientific and technological development Co., Ltd, Qingdao Tenglong chemical reagent Co., Ltd, and Qingdao Kaolingyi factory.

The anhydrous tetrahydrofuran, dioxane, toluene and ether are obtained through reflux drying of metal sodium. The anhydrous dichloromethane and chloroform are obtained by calcium hydride reflux drying. Ethyl acetate, petroleum ether, N-hexane, N, N-dimethylacetamide and N, N-dimethylformamide were used as they were previously dried over anhydrous sodium sulfate.

The following reactions are generally carried out under positive pressure of nitrogen or argon or by sleeving a dry tube over an anhydrous solvent (unless otherwise indicated), the reaction vial being stoppered with a suitable rubber stopper and the substrate being injected by syringe. The glassware was dried.

The column chromatography is performed using a silica gel column. Silica gel (300 and 400 meshes) was purchased from Qingdao oceanic chemical plants.

¹H NMR spectra were recorded using a Bruker 400MHz or 600MHz NMR spectrometer.¹H NMR Spectrum in CDC1₃、DMSO-d₆、CD₃OD or acetone-d₆TMS (0ppm) or chloroform (7.26ppm) was used as a reference standard for the solvent (in ppm). When multiple peaks occur, the following reduction will be usedWriting: s (singlets, singlet), d (doublets ), t (triplets, triplet), q (quatets, quartets), m (multiplets ), br (broadended, broad), brs (broadended singlets, broad singlet), dd (doublets ), ddd (doublets, doublets), ddles of doublets), ddt (doublets of doublets, doublets), dt (doublets ), dq (doublets of doublets, doublets), td (triplets of doublets, triplet), tt (triplet of triplets). Coupling constant J, expressed in Hertz (Hz).

The conditions for determining low resolution Mass Spectrometry (MS) data were: agilent 6120 four-stage rod HPLC-M (column model: Zorbax SB-C18, 2.1X 30mm,3.5 micron, 6min, flow rate 0.6 mL/min. mobile phase 5% -95% (CH with 0.1% formic acid)₃CN) in (H containing 0.1% formic acid)₂O) by electrospray ionization (ESI) at 210nm/254nm, with UV detection.

Pure compounds were detected by UV at 210nm/254nm using Agilent 1260pre-HPLC or Calesep pump 250pre-HPLC (column model: NOVASEP 50/80mm DAC).

The following acronyms are used throughout the invention:

the following synthetic schemes describe the steps for preparing the compounds of the present disclosure, unless otherwise indicated, wherein,

X₁、X₂、Y₁、Y₂and W has the definition set forth herein.

Synthesis scheme 1

Formula (A), (B) and11) The compound shown can be prepared by the following steps: formula (A), (B) and1) The compound is subjected to esterification reaction to obtain a compound of the formula (I)2) A compound shown in the specification; then formula (A), (B), (C), (2) The ester group of the compound is alsoObtaining from (A) to3) The compounds shown. Formula (A), (B) and3) A compound of the formula4) Reacting the compound shown in the formula (A) to obtain a compound shown in the formula (B)5) The compounds shown. Formula (A), (B) and5) The alcohol group of the compound is oxidized to obtain a compound represented by the formula (A)6) A compound shown in the specification; formula (A), (B) and6) A compound of the formula7) Reacting the compound shown in the formula (A) to obtain a compound shown in the formula (B)8) The compounds shown. Formula (A), (B) and8) The compound shown is subjected to Boc protection group removal to obtain a compound shown as a formula (I) (II) ((III))9) The compounds shown. Formula (A), (B) and9) A compound of the formula10) The compound shown in the formula (I) is reacted to obtain11) The target product shown.

Synthesis scheme 2

Formula (A), (B) and15) The compound shown can be prepared by the following steps: formula (A), (B) and1) A compound of the formula7) Reacting the compound shown in the formula (A) to obtain a compound shown in the formula (B)12) A compound shown in the specification; then formula (A), (B), (C), (12) A compound of the formula4) Reacting the compound shown in the formula (A) to obtain a compound shown in the formula (B)13) The compounds shown. Formula (A), (B) and13) The compound shown is subjected to Boc protection group removal to obtain a compound shown as a formula (I) (II) ((III))14) The compounds shown. Formula (A), (B) and14) A compound of the formula10) The compound shown in the formula (I) is reacted to obtain15) The target product shown.

The compounds, pharmaceutical compositions and uses thereof provided by the present invention are further illustrated below in connection with the examples.

Examples

Example 11- (4- (((6-amino-5- (4-phenoxyphenyl) pyrimidin-4-yl) methyl) amino) piperidin-1-yl) prop-2-en-1-one

Step 1) Synthesis of methyl 6-amino-5-chloropyrimidine-4-carboxylate

Methanol (200mL) was added to a 1L single-neck round-bottom flask, thionyl chloride (11mL) was added dropwise, and then 6-amino-5-chloropyrimidine-4-carboxylic acid (20.0g,115.6mmol) was added and reacted at 70 ℃ for 23 hours; the reaction was stopped, cooled to room temperature, spin-dried under reduced pressure, and purified by column chromatography (dichloromethane/methanol (v/v) ═ 30/1) to give the title compound as a white solid (12.5g, 58%).

MS(ESI,pos.ion)m/z:188.1[M+H]⁺.

Step 2) (Synthesis of 6-amino-5-chloropyrimidin-4-yl) methanol

Methyl 6-amino-5-chloropyrimidine-4-carboxylate (10.05g,53.7mmol) and methanol (100mL) were added at 25 ℃ to a 250mL single neck round bottom flask, sodium borohydride (3.1g,81.9mmol) was added in portions, and the reaction was allowed to continue stirring for 1 hour; the reaction was stopped, quenched by addition of ethyl acetate hydrogen chloride solution to pH 7, filtered, the filtrate collected and dried under reduced pressure to give the title compound as a white solid (7.09g, 83%).

MS(ESI,pos.ion)m/z:160.1[M+H]⁺.

Step 3) (6-amino-5- (4-phenoxyphenyl) pyrimidin-4-yl) methanol synthesis

(6-amino-5-chloropyrimidin-4-yl) methanol (7.09g,44.6mmol), 4-phenoxyphenylboronic acid (11.8g,55.1mmol), palladium acetate (0.51g,2.27mmol), X-Phos (2.16g,4.53mmol), potassium carbonate (15.5g,112.3mmol), and 1, 4-dioxane (100mL) and water (10mL) were charged into a 250mL single neck round bottom flask and reacted in an oil bath at 110 ℃ for 2.5 hours; the reaction was stopped, cooled to room temperature, filtered, the filtrate was collected, spin-dried under reduced pressure, and then dichloromethane (100mL) and water (50mL) were added, liquid-separated, the organic phase was collected, spin-dried under reduced pressure, and column chromatography purification (dichloromethane/methanol (v/v) ═ 30/1) gave the title compound as a white solid (9.76g, 75%).

MS(ESI,pos.ion)m/z:294.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)8.56(s,1H),7.42(t,J＝7.9Hz,2H),7.26–7.17(m,3H),7.17–7.07(m,4H),4.36(s,2H).

Step 4) synthesis of 6-amino-5- (4-phenoxyphenyl) pyrimidine-4-formaldehyde

(6-amino-5- (4-phenoxyphenyl) pyrimidin-4-yl) methanol (2.0g,6.82mmol) and dichloromethane (30mL) were added to a 100mL single neck round bottom flask at 25 deg.C, dess-martin oxidant (4.38g,10.3mmol) was added and the reaction was allowed to continue stirring for 1 hour; the reaction was stopped, saturated sodium bicarbonate solution (30mL) was added, the organic phase was separated, the organic phase was collected, spin-dried under reduced pressure, and purified by column chromatography (dichloromethane/methanol (v/v) ═ 30/1) to give the title compound as a white solid (1.46g, 74%).

MS(ESI,pos.ion)m/z:292.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)9.89(s,1H),8.73(s,1H),7.46–7.39(m,2H),7.32–7.26(m,3H),7.19–7.11(m,4H).

Step 5) tert-butyl 4- (((6-amino-5- (4-phenoxyphenyl) pyrimidin-4-yl) methyl) amino) piperidine-1-carboxylic acid Synthesis of esters

6-amino-5- (4-phenoxyphenyl) pyrimidine-4-carbaldehyde (526mg,1.8mmol), 4-amino-1-Boc-piperidine (443mg,2.2mmol), and dichloromethane (10mL) were added to a 100mL single-neck round-bottom flask at 25 deg.C, sodium triacetoxyborohydride (592mg,2.79mmol) was added, and the reaction was continued for 2 hours; the reaction was stopped, dichloromethane (20mL) and saturated sodium bicarbonate solution (30mL) were added, and the organic phase was separated, collected, dried under reduced pressure, and purified by column chromatography (dichloromethane/methanol (v/v) ═ 30/1) to give the title compound as a white solid (513mg, 60%). MS (ESI, pos.ion) M/z 476.8[ M + H ]]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)8.53(s,1H),7.42(t,J＝7.9Hz,2H),7.24–7.17(m,3H),7.14–7.08(m,4H),3.58(s,2H),2.84–2.67(m,2H),2.60–2.52(m,1H),1.77–1.66(m,2H),1.45(s,9H),1.33–1.21(m,2H).

Step 6) Synthesis of 5- (4-phenoxyphenyl) -6- ((piperidin-4-ylamino) methyl) pyrimidin-4-amine hydrochloride

Tert-butyl 4- (((6-amino-5- (4-phenoxyphenyl) pyrimidin-4-yl) methyl) amino) piperidine-1-carboxylate (403mg,0.85mmol) and dichloromethane (4mL) were added to a 50mL single-neck round bottom flask at 25 deg.C, a solution of hydrochloric acid in ethyl acetate (5mL,4M) was added, and the reaction was stirred for 6 hours; the reaction was stopped and the residue was spin-dried under reduced pressure to give the title compound as a white solid (349mg, 99%).

MS(ESI,pos.ion)m/z:376.1[M+H]⁺.

Step 7)1- (4- (((6-amino-5- (4-phenoxyphenyl) pyrimidin-4-yl) methyl) amino) piperidin-1-yl) propan- 2-en-1-ones

5- (4-phenoxyphenyl) -6- ((piperidin-4-ylamino) methyl) pyrimidin-4-amine hydrochloride (349mg,0.85mmol), DIPEA (0.3mL,1.72mmol) and methanol (5mL) were added to a 50mL single neck round bottom flask at 25 deg.C, acryloyl chloride (0.07mL,0.87mmol) was slowly added dropwise, and the reaction was allowed to continue stirring for 10 minutes; the reaction was stopped, dichloromethane (30mL) and saturated sodium bicarbonate solution (30mL) were added, and the organic phase was separated, collected, dried under reduced pressure, and purified by column chromatography (dichloromethane/methanol (v/v) ═ 20/1) to give the title compound as a white solid (165mg, 45%).

MS(ESI,pos.ion)m/z:430.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)8.54(s,1H),7.43(dd,J＝11.2,4.8Hz,2H),7.26–7.18(m,3H),7.15–7.05(m,4H),6.56(dt,J＝16.9,10.3Hz,1H),6.25(dd,J＝16.8,1.9Hz,1H),5.67(dd,J＝10.6,1.9Hz,1H),4.49–4.25(m,1H),3.90(d,J＝13.6Hz,1H),3.57(s,2H),3.10(t,J＝11.7Hz,1H),2.99–2.55(m,4H),1.42–1.18(m,2H).

EXAMPLE 2 Synthesis of (S) -1- (3- (((6-amino-5- (4-phenoxyphenyl) pyrimidin-4-yl) methyl) amino) pyrrolidin-1-yl) prop-2-en-1-one

Step 1) (S) -tert-butyl 3- (((6-amino-5- (4-phenoxyphenyl) pyrimidin-4-yl) methyl) amino) pyrrolidine- Synthesis of 1-carboxylic acid esters

6-amino-5- (4-phenoxyphenyl) pyrimidine-4-carbaldehyde (1.46g,5.0mmol), (S) -1-Boc-3-aminopyrrolidine (1.07g,5.75mmol), and dichloromethane (20mL) were charged at 25 ℃ into a 100mL single-neck round bottom flask, sodium triacetoxyborohydride (1.64g,7.73mmol) was added, and the reaction was continued for 0.5 h; the reaction was stopped, dichloromethane (20mL) and saturated sodium bicarbonate solution (30mL) were added, the layers were separated, the organic phase was collected, spin-dried under reduced pressure, and purified by column chromatography (dichloromethane/methanol (v/v) ═ 30/1) to give the title compound as a white solid (1.32g, 57%). MS (ESI, pos.ion) m/z:462.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)8.54(s,1H),7.42(t,J＝7.6Hz,2H),7.27–7.17(m,3H),7.17–7.08(m,4H),3.51–3.39(m,2H),3.38–3.29(m,1H),3.28–3.20(m,1H),3.05(ddd,J＝15.9,10.7,4.7Hz,1H),1.81–1.56(m,2H),1.45(s,9H).

Step 2 Synthesis of (S) -5- (4-phenoxyphenyl) -6- ((pyrrolidin-3-ylamino) methyl) pyrimidin-4-amine hydrochloride Become into

(S) -tert-butyl 3- (((6-amino-5- (4-phenoxyphenyl) pyrimidin-4-yl) methyl) amino) pyrrolidine-1-carboxylic acid ester (800mg,1.73mmol) and dichloromethane (10mL) were added to a 100mL single neck round bottom flask at 25 deg.C, a solution of hydrochloric acid in ethyl acetate (4mL,4M) was added, and the reaction was stirred for 7 hours; the reaction was stopped and spin dried under reduced pressure to give the title compound as a white solid (689mg, 99%).

MS(ESI,pos.ion)m/z:362.2[M+H]⁺.

Step 3) (S) -1- (3- (((6-amino-5- (4-phenoxyphenyl) pyrimidin-4-yl) methyl) amino) pyrrolidine-1- Synthesis of Yl) prop-2-en-1-one

(S) -5- (4-phenoxyphenyl) -6- ((pyrrolidin-3-ylamino) methyl) pyrimidin-4-amine hydrochloride (689mg,1.73mmol), DIPEA (0.609mL,3.49mmol) and methanol (8mL) were added to a 50mL single neck round bottom flask at 25 deg.C, acryloyl chloride (0.144mL,1.79mmol) was slowly added dropwise, and the reaction was allowed to continue stirring for 1 hour; the reaction was stopped, dichloromethane (30mL) and saturated sodium bicarbonate solution (30mL) were added, and the organic phase was separated, collected, dried under reduced pressure, and purified by column chromatography (dichloromethane/methanol (v/v) ═ 10/1) to give the title compound as a white solid (423mg, 59%).

MS(ESI,pos.ion)m/z:416.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)8.54(s,1H),7.47–7.38(m,2H),7.26–7.18(m,3H),7.17–7.09(m,4H),6.49–6.31(m,2H),5.69–5.62(m,1H),4.90(d,J＝9.8Hz,2H),3.75–3.49(m,5H),3.38–3.21(m,2H),1.91–1.81(m,1H),1.77–1.62(m,1H).

EXAMPLE 3 Synthesis of (R) -1- (3- (((6-amino-5- (4-phenoxyphenyl) pyrimidin-4-yl) methyl) amino) pyrrolidin-1-yl) prop-2-en-1-one

Step 1) (R) -tert-butyl 3- (((6-amino-5- (4-phenoxyphenyl) pyrimidin-4-yl) methyl) amino) pyrrolidine- Synthesis of 1-carboxylic acid esters

6-amino-5- (4-phenoxyphenyl) pyrimidine-4-carbaldehyde (1.83g,6.27mmol), (R) -1-Boc-3-aminopyrrolidine (1.35g,7.25mmol) and dichloromethane (40mL) were charged at 25 ℃ into a 100mL single neck round bottom flask, sodium triacetoxyborohydride (2.06g,9.71mmol) was added and the reaction was continued for 0.5 h; the reaction was stopped, dichloromethane (30mL) and saturated sodium bicarbonate solution (30mL) were added, the organic phase was separated, collected, dried under reduced pressure, and purified by column chromatography (dichloromethane/methanol (v/v) ═ 30/1) to give the title compound as a white solid (1.48g, 51%).

MS(ESI,pos.ion)m/z:462.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)8.54(s,1H),7.42(t,J＝7.7Hz,2H),7.26–7.17(m,3H),7.16–7.08(m,4H),3.53(s,2H),3.49–3.39(m,2H),3.33(dd,J＝15.5,8.8Hz,1H),3.24(dt,J＝11.3,5.8Hz,1H),3.12–2.98(m,1H),1.79–1.52(m,2H),1.45(s,9H).

Step 2 Synthesis of (R) -5- (4-phenoxyphenyl) -6- ((pyrrolidin-3-ylamino) methyl) pyrimidin-4-amine hydrochloride Become into

(R) -tert-butyl 3- (((6-amino-5- (4-phenoxyphenyl) pyrimidin-4-yl) methyl) amino) pyrrolidine-1-carboxylic acid ester (800mg,1.73mmol) and dichloromethane (10mL) were added to a 100mL single neck round bottom flask at 25 deg.C, a solution of hydrochloric acid in ethyl acetate (4mL,4M) was added and the reaction stirred for 7 hours; the reaction was stopped and spin-dried under reduced pressure to give the title compound as a white solid (690mg, 100%).

MS(ESI,pos.ion)m/z:362.2[M+H]⁺.

Step 3) (R) -1- (3- (((6-amino-5- (4-phenoxyphenyl) pyrimidin-4-yl) methyl) amino) pyrrolidine-1- Synthesis of Yl) prop-2-en-1-one

(R) -5- (4-phenoxyphenyl) -6- ((pyrrolidin-3-ylamino) methyl) pyrimidin-4-amine hydrochloride (690mg,1.73mmol), DIPEA (0.61mL,3.5mmol) and methanol (8mL) were added to a 50mL single neck round bottom flask at 25 deg.C, acryloyl chloride (0.144mL,1.79mmol) was slowly added dropwise, and the reaction was allowed to continue stirring for 1 hour; the reaction was stopped, dichloromethane (30mL) and saturated sodium bicarbonate solution (30mL) were added, and the organic phase was separated, collected, dried under reduced pressure, and purified by column chromatography (dichloromethane/methanol (v/v) ═ 10/1) to give the title compound as a white solid (527mg, 73%).

MS(ESI,pos.ion)m/z:415.9[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)8.54(s,1H),7.48–7.38(m,2H),7.26–7.18(m,3H),7.16–7.09(m,4H),6.49–6.30(m,2H),5.69–5.61(m,1H),4.90(d,J＝10.3Hz,2H),3.73–3.50(m,5H),3.38–3.21(m,2H),2.11–2.02(m,1H),1.74–1.63(m,1H).

EXAMPLE 4 Synthesis of N- (1-acryloylpiperidin-4-yl) -6-amino-5- (4-phenoxyphenyl) pyrimidine-4-carboxamide

Step 1) Synthesis of t-butyl 4- (6-amino-5-chloropyrimidine-4-carboxamido) piperidine-1-carboxylate

6-amino-5-chloropyrimidine-4-carboxylic acid (5.0g,28.9mmol), 4-amino-1-tert-butoxycarbonyl-piperidine (8.8g,44mmol), HOBt (6.0g,44.4mmol), EDCI (8.4g,43.8mmol) and DMF (60mL) were charged into a 250mL single neck round bottom flask, triethylamine (14.3mL,101.9mmol) was added dropwise, and the reaction was carried out at 60 ℃ for 22 hours; the reaction was stopped, cooled to room temperature, and then dichloromethane (100mL) and water (100mL) were added, followed by liquid separation, and the organic phase was collected, dried under reduced pressure, and purified by column chromatography (dichloromethane/methanol (v/v) ═ 20/1) to give the title compound as a white solid (7.81g, 76%).

MS(ESI,pos.ion)m/z:300.2[M+H-56]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)8.39(s,1H),7.84(d,J＝7.7Hz,1H),4.17–3.95(m,3H),2.98–2.90(m,2H),2.05–1.95(m,2H),1.68(s,2H),1.48(s,9H).

Step 2) Synthesis of t-butyl 4- (6-amino-5- (4-phenoxyphenyl) pyrimidine-4-carboxamido) piperidine-1-carboxylate Become into

Tert-butyl 4- (6-amino-5-chloropyrimidine-4-carboxamido) piperidine-1-carboxylate (4.02g,11.3mmol), 4-phenoxyphenylboronic acid (3.74g,17.5mmol), palladium acetate (0.259g,1.15mmol), X-Phos (1.1g,2.31mmol), potassium carbonate (4.73g,34.2mmol), and 1, 4-dioxane (50mL) and water (5mL) were charged to a 250mL single neck round bottom flask and reacted for 4.5 hours at 110 deg.C in an oil bath; the reaction was stopped, cooled to room temperature, filtered, the filtrate was collected, spin-dried under reduced pressure, and then dichloromethane (100mL) and water (50mL) were added, liquid-separated, the organic phase was collected, spin-dried under reduced pressure, and column chromatography purification (dichloromethane/methanol (v/v) ═ 30/1) gave the title compound as a white solid (3.89g, 70%).

MS(ESI,pos.ion)m/z:490.4[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)8.52(s,1H),7.98(d,J＝8.5Hz,1H),7.40(t,J＝7.9Hz,2H),7.26–7.02(m,7H),4.11–3.88(m,3H),2.85(t,J＝11.9Hz,2H),1.90(d,J＝9.8Hz,2H),1.65(d,J＝4.3Hz,2H),1.47(s,9H).

Step 3) Synthesis of 6-amino-5- (4-phenoxyphenyl) -N- (piperidin-4-yl) pyrimidine-4-carboxamide hydrochloride

Tert-butyl 4- (6-amino-5- (4-phenoxyphenyl) pyrimidine-4-carboxamido) piperidine-1-carboxylate (3.42g,6.98mmol) and dichloromethane (20mL) were added to a 100mL single-neck round-bottom flask at 25 deg.C, a solution of hydrochloric acid in ethyl acetate (5mL,4M) was added, and the reaction was stirred for 5 hours; the reaction was stopped and spin dried under reduced pressure to give the title compound as a white solid (2.96g, 99%).

MS(ESI,pos.ion)m/z:390.3[M+H]⁺.

Step 4) Synthesis of N- (1-acryloylpiperidin-4-yl) -6-amino-5- (4-phenoxyphenyl) pyrimidine-4-carboxamide Become into

6-amino-5- (4-phenoxyphenyl) -N- (piperidin-4-yl) pyrimidine-4-carboxamide hydrochloride (2.66g,6.24mmol), triethylamine (1.72mL,12.3mmol) and methanol (50mL) were added to a 100mL single neck round bottom flask at 25 deg.C, acryloyl chloride (0.608mL,7.56mmol) was slowly added dropwise, and the reaction was allowed to continue stirring for 1 hour; the reaction was stopped, dichloromethane (50mL) and saturated sodium bicarbonate solution (50mL) were added, and the organic phase was separated, collected, dried under reduced pressure, and purified by column chromatography (dichloromethane/methanol (v/v) ═ 10/1) to give the title compound as a white solid (2.01g, 73%).

MS(ESI,pos.ion)m/z:444.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)8.50(s,1H),8.01(d,J＝8.4Hz,1H),7.39(t,J＝7.9Hz,2H),7.25–7.03(m,7H),6.58(dd,J＝16.8,10.6Hz,1H),6.27(dd,J＝16.8,1.7Hz,1H),5.69(dd,J＝10.6,1.8Hz,1H),4.57(d,J＝12.7Hz,1H),4.15–3.85(m,2H),3.16(t,J＝12.1Hz,1H),2.82(t,J＝12.0Hz,1H),1.98(d,J＝13.6Hz,2H),1.64–1.37(m,2H).

EXAMPLE 5 Synthesis of (S) -N- (1-acryloylpyrrolidin-3-yl) -6-amino-5- (4-phenoxyphenyl) pyrimidine-4-carboxamide

Step 1) Synthesis of (S) -tert-butyl 3- (6-amino-5-chloropyrimidine-4-carboxamido) pyrrolidine-1-carboxylate

6-amino-5-chloropyrimidine-4-carboxylic acid (5.0g,28.9mmol), (S) -1-tert-butoxycarbonyl-3-aminopyrrolidine (7.7mL,43.9mmol), HOBt (6.0g,44.4mmol), EDCI (8.4g,43.8mmol) and DMF (60mL) were added to a 250mL single neck round bottom flask, triethylamine (14.3mL,101.9mmol) was added dropwise and reacted at 60 ℃ for 6 hours; the reaction was stopped, cooled to room temperature, and dichloromethane (100mL) and water (100mL) were added to separate the phases, the organic phase was collected, dried under reduced pressure, and purified by column chromatography (dichloromethane/methanol (v/v) ═ 20/1) to give the title compound as a white solid (8.28g, 84%).

MS(ESI,pos.ion)m/z:286.2[M+H-56]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)8.37(s,1H),8.02(s,1H),4.58(dq,J＝11.8,5.9Hz,1H),3.72(dd,J＝11.4,6.3Hz,1H),3.63–3.41(m,2H),3.41–3.21(m,1H),2.24(dt,J＝13.5,6.7Hz,1H),1.98(s,1H),1.47(s,9H).

Step 2) (S) -tert-butyl 3- (6-amino-5- (4-phenoxyphenyl) pyrimidine-4-carboxamido) pyrrolidine-1-carboxylic acid Synthesis of esters

(S) -tert-butyl 3- (6-amino-5-chloropyrimidine-4-carboxamido) pyrrolidine-1-carboxylate (8.0g,23.5mmol), 4-phenoxyphenylboronic acid (7.7g,36mmol), palladium acetate (0.27g,1.2mmol), X-Phos (1.1g,2.31mmol), potassium carbonate (9.8g,71mmol), and 1, 4-dioxane (80mL) and water (8mL) were charged into a 250mL single neck round bottom flask and reacted for 2 hours at 110 ℃ in an oil bath; the reaction was stopped, cooled to room temperature, filtered, the filtrate was collected, spin-dried under reduced pressure, and then dichloromethane (100mL) and water (50mL) were added, liquid-separated, the organic phase was collected, spin-dried under reduced pressure, and column chromatography purification (dichloromethane/methanol (v/v) ═ 30/1) gave the title compound as a white solid (7.98g, 72%).

MS(ESI,pos.ion)m/z:476.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)8.51(s,1H),8.16(d,J＝4.2Hz,1H),7.40(t,J＝7.9Hz,2H),7.20(t,J＝8.1Hz,3H),7.16–7.08(m,4H),4.48(dq,J＝11.8,5.8Hz,1H),3.63(dd,J＝11.3,6.3Hz,1H),3.57–3.38(m,2H),3.26(dd,J＝40.5,8.3Hz,1H),2.16(td,J＝13.4,7.2Hz,1H),1.96–1.82(m,1H),1.47(s,9H).

Step 3 preparation of hydrochloride salt of (S) -6-amino-5- (4-phenoxyphenyl) -N- (pyrrolidin-3-yl) pyrimidine-4-carboxamide Synthesis of

(S) -tert-butyl 3- (6-amino-5- (4-phenoxyphenyl) pyrimidine-4-carboxamido) pyrrolidine-1-carboxylate (6.0g,12.6mmol) and dichloromethane (40mL) were added to a 100mL single-neck round bottom flask at 25 deg.C, a solution of hydrochloric acid in ethyl acetate (20mL,4M) was added, and the reaction was stirred for 3 hours; the reaction was stopped and spin dried under reduced pressure to give the title compound as a white solid (5.19g, 100%).

MS(ESI,pos.ion)m/z:376.3[M+H]⁺.

Step 4) (S) -N- (1-acryloylpyrrolidin-3-yl) -6-amino-5- (4-phenoxyphenyl) pyrimidine-4-carboxylic acid Synthesis of amines

(S) -6-amino-5- (4-phenoxyphenyl) -N- (pyrrolidin-3-yl) pyrimidine-4-carboxamide hydrochloride (5.19g,12.6mmol), triethylamine (3.5mL,24.9mmol) and methanol (80mL) were added to a 250mL single neck round bottom flask at 25 deg.C, acryloyl chloride (1.25mL,15.5mmol) was slowly added dropwise, and the reaction was allowed to continue stirring for 0.5 h; the reaction was stopped, dried under reduced pressure, dichloromethane (100mL) and saturated sodium bicarbonate solution (50mL) were added, separated, the organic phase was collected, dried under reduced pressure, and purified by column chromatography (dichloromethane/methanol (v/v) ═ 10/1) to give the title compound as a white solid (3.4g, 63%).

MS(ESI,pos.ion)m/z:430.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)8.51(s,1H),8.21(dd,J＝22.7,7.4Hz,1H),7.40(t,J＝7.8Hz,2H),7.25–7.17(m,3H),7.17–7.07(m,4H),6.53–6.42(m,1H),6.41–6.35(m,1H),5.71(ddd,J＝17.3,8.6,3.6Hz,1H),4.54(dt,J＝11.9,6.0Hz,1H),3.84(ddd,J＝19.2,11.7,6.2Hz,1H),3.77–3.62(m,2H),3.52(ddd,J＝15.2,11.8,4.3Hz,1H),2.35–2.15(m,1H),2.12–1.90(m,1H).

EXAMPLE 6 Synthesis of (R) -N- (1-acryloylpyrrolidin-3-yl) -6-amino-5- (4-phenoxyphenyl) pyrimidine-4-carboxamide

Step 1 synthesis of (R) -tert-butyl 3- (6-amino-5-chloropyrimidine-4-carboxamido) pyrrolidine-1-carboxylate

6-amino-5-chloropyrimidine-4-carboxylic acid (5.0g,28.9mmol), (R) -1-tert-butoxycarbonyl-3-aminopyrrolidine (7.7mL,43.9mmol), HOBt (6.0g,44.4mmol), EDCI (8.4g,43.8mmol) and DMF (60mL) were charged into a 250mL single neck round bottom flask, triethylamine (14.3mL,101.9mmol) was added dropwise, and the reaction was carried out at 60 ℃ for 2 hours; the reaction was stopped, cooled to room temperature, and then dichloromethane (100mL) and water (100mL) were added, followed by liquid separation, and the organic phase was collected, dried under reduced pressure, and purified by column chromatography (dichloromethane/methanol (v/v) ═ 20/1) to give the title compound as a white solid (7.27g, 74%).

MS(ESI,pos.ion)m/z:286.0[M+H-56]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)8.38(s,1H),8.02(s,1H),4.59(dq,J＝11.8,5.9Hz,1H),3.72(dd,J＝11.4,6.3Hz,1H),3.50(d,J＝17.9Hz,2H),3.34(dd,J＝30.2,9.1Hz,1H),2.25(td,J＝13.5,7.3Hz,1H),1.98(s,1H),1.48(s,9H).

Step 2) (R) -tert-butyl 3- (6-amino-5- (4-phenoxyphenyl) pyrimidine-4-carboxamido) pyrrolidine-1-carboxylic acid Synthesis of esters

(R) -tert-butyl 3- (6-amino-5-chloropyrimidine-4-carboxamido) pyrrolidine-1-carboxylate (6.0g,17.6mmol), 4-phenoxyphenylboronic acid (5.81g,27.2mmol), palladium acetate (0.201g,0.93mmol), X-Phos (854mg,0.78mmol), potassium carbonate (7.35g,53.3mmol), and 1, 4-dioxane (60mL) and water (6mL) were added to a 250mL single neck round bottom flask and reacted for 1.5 hours at 110 deg.C in an oil bath; the reaction was stopped, cooled to room temperature, filtered, the filtrate was collected, spin-dried under reduced pressure, and then dichloromethane (100mL) and water (50mL) were added, liquid-separated, the organic phase was collected, spin-dried under reduced pressure, and column chromatography purification (dichloromethane/methanol (v/v) ═ 30/1) gave the title compound as a white solid (6.13g, 73%).

MS(ESI,pos.ion)m/z:476.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)8.52(s,1H),8.16(d,J＝3.5Hz,1H),7.40(t,J＝7.9Hz,2H),7.19(dd,J＝15.5,8.0Hz,3H),7.16–7.08(m,4H),4.48(dq,J＝11.7,5.9Hz,1H),3.64(dd,J＝11.3,6.3Hz,1H),3.47(dt,J＝14.4,7.4Hz,2H),3.26(dd,J＝42.4,8.5Hz,1H),2.17(td,J＝13.4,7.2Hz,1H),1.88(dd,J＝10.9,5.7Hz,1H),1.63(d,J＝2.6Hz,2H),1.48(s,9H).

Step 3 preparation of hydrochloride salt of (R) -6-amino-5- (4-phenoxyphenyl) -N- (pyrrolidin-3-yl) pyrimidine-4-carboxamide Synthesis of

(R) -tert-butyl 3- (6-amino-5- (4-phenoxyphenyl) pyrimidine-4-carboxamido) pyrrolidine-1-carboxylate (0.5g,1.05mmol) and dichloromethane (8mL) were added to a 100mL single-neck round bottom flask at 25 deg.C, a solution of hydrochloric acid in ethyl acetate (2mL,4M) was added, and the reaction was stirred for 1.5 hours; the reaction was stopped and spin dried under reduced pressure to give the title compound as a white solid (394mg, 99%).

MS(ESI,pos.ion)m/z:376.3[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm)9.63–9.29(m,3H),8.73(s,1H),7.44(t,J＝7.9Hz,2H),7.37(d,J＝8.5Hz,2H),7.19(t,J＝7.4Hz,1H),7.09(dd,J＝8.2,3.5Hz,4H),4.27(td,J＝11.6,6.5Hz,1H),3.32–3.11(m,4H),2.91(dt,J＝11.4,5.6Hz,1H),2.07–1.95(m,1H),1.64(td,J＝12.1,6.3Hz,1H).

Step 4) (R) -N- (1-acryloylpyrrolidin-3-yl) -6-amino-5- (4-phenoxyphenyl) pyrimidine-4-carboxylic acid Synthesis of amines

(R) -6-amino-5- (4-phenoxyphenyl) -N- (pyrrolidin-3-yl) pyrimidine-4-carboxamide hydrochloride (320mg,0.78mmol), triethylamine (0.273mL,1.69mmol) and methanol (5mL) were added to a 50mL single neck round bottom flask at 25 deg.C, acryloyl chloride (0.077mL,0.95mmol) was slowly added dropwise, and the reaction was allowed to continue stirring for 0.5 h; the reaction was stopped, spin-dried under reduced pressure, dichloromethane (30mL) and saturated sodium bicarbonate solution (30mL) were added, separated, the organic phase was collected, spin-dried under reduced pressure, and purified by column chromatography (dichloromethane/methanol (v/v) ═ 10/1) to give the title compound as a white solid (249mg, 75%).

MS(ESI,pos.ion)m/z:430.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)8.51(s,1H),8.20(dd,J＝22.6,7.4Hz,1H),7.40(t,J＝7.8Hz,2H),7.24–7.16(m,3H),7.12(t,J＝9.5Hz,4H),6.53–6.42(m,1H),6.42–6.36(m,1H),5.71(ddd,J＝17.2,8.6,3.7Hz,1H),4.61–4.46(m,1H),3.84(ddd,J＝19.1,11.7,6.2Hz,1H),3.77–3.61(m,2H),3.61–3.43(m,1H),2.35–2.16(m,1H),2.13–1.90(m,1H).

Biological assay

EXAMPLE A test for the inhibitory Effect of the Compounds of the present invention on BTK

Purpose of experiment

Determination of BTK inhibition IC of compound by using Mobility shift assay method₅₀The compounds of the present invention were evaluated for their ability to inhibit BTK.

Experimental procedure

1X kinase base buffer (50mM HEPES, pH 7.5, 0.01% Brij-35) and 1X stop buffer (100mM HEPES, pH 7.5, 0.015% Brij-35, 0.2% Coating Reagent #3,50mM EDTA) were prepared. The starting well concentration of 50x compound (e.g. starting well reaction concentration 10 μ M, 500 μ M compound) was prepared in DMSO, and diluted in 4-fold gradient to 10-fold total gradient. Two wells containing only 100% DMSO were prepared simultaneously, followed by a negative control well without BTK and a positive control well without compound. Transferring more than 20 μ LTo a 96-well plate, 180. mu.L of 1x kinase base buffer was added per well and mixed well. Then, 5. mu.L of each of the samples was transferred to 384-well plates at 2-well per concentration. A2.5 XBTK solution and a FAM-labeled substrate Peptide (Peptide FAM-P2) solution were prepared. mu.L of 1x kinase base buffer was added to the wells except the negative control, and 10. mu.L of BTK solution (2.5X) was added to the remaining wells and incubated at room temperature for 10 min. Then 10. mu.L of FAM-labeled substrate peptide solution (2.5X) was added to each well, and after incubation at 28 ℃ for a specified time, 25. mu.L of 1X stop buffer was added to each well to terminate the reaction. The Caliper instrument is used for detecting and acquiring data values read by the instrument. The kinase inhibition rate is expressed by the formula: (max-sample)/(max-min) × 100, where max represents the data value for the positive control group, min represents the data value for the negative control group, and sample represents the data value for different concentrations of compound. Then, the equation Y is equal to Bottom + (Top-Bottom)/(1+ (IC)₅₀Fitting data with/X) HillSlope and calculating IC₅₀The value is obtained. See table a for experimental results.

TABLE A results of the BTK inhibition experiments with the compounds of the present invention

Example numbering	IC₅₀(μM)
		Example 2	5.89
Example 3	6.04
		Example 4	4.87
Example 5	2.97
		Example 6	2.38

The experimental results show that: the compound has a remarkable inhibiting effect on BTK and has unexpected excellent BTK inhibiting activity. Example B pharmacokinetic evaluation of the Compounds of the invention after intravenous injection or gavage in rats and dogs

The present invention evaluates the pharmacokinetic studies of the compounds of the invention in rats and/or dogs for details in the animals shown in table 1.

Table 1 information sheet of the subject animals of the present invention

Test method

The compounds of the invention were administered to the animals in the form of 10% DMSO + 10% Kolliphor HS15+ 78% Saline + 2% (2% HCl) solution or 78% Saline + 2% (2% HCl) + 20% PEG400 solution, and the animals were fasted for 12h before administration and allowed free access to water. For the group administered by intravenous injection, the dose was 1mg/kg (rat) or 0.5mg/kg (dog), and blood was taken intravenously (blood volume taken was about 0.2mL) at the following time points after administration: 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24h (dog) or 0.083, 0.25, 0.5, 1.0, 2.0, 5.0, 7.0 and 24h (rat), EDTA-K is added into the blood sampling tube in advance₂Can be used as anticoagulant. For the gavage group, 5mg/kg (rat) or 2.5mg/kg (dog) was administered, and intravenous blood sampling (blood volume taken about 0.2mL) was performed at the following time points after administration: 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24h (dog) or 0.25, 0.5, 1.0, 2.0, 5.0, 7.0 and 24h (rat), EDTA-K is added into the blood sampling tube in advance₂Can be used as anticoagulant. Blood samples were centrifuged at 12,000rpm for 2 minutes, plasma was collected and stored at-20 ℃ or-70 ℃. .

The plasma samples collected above were processed (frozen plasma was thawed at room temperature, vortexed for 15s, 10-20. mu.L of plasma was taken, 120-150. mu.L of acetonitrile solution containing the internal standard was added, vortexed for 5min, centrifuged at 4,000rpm for 5min, 100. mu.L of supernatant was taken, and 120-150. mu.L of methanol/water (v/v. 1/1) was added and mixed) and then the concentration of the compounds in the plasma was analyzed by LC/MS/MS.

The analysis result shows that the compound of the invention has better pharmacokinetic property in rats and/or dogs. The compound of the invention has good drug property and good clinical application prospect.

In the description herein, references to the description of the term "one embodiment," "an embodiment," "some embodiments," "an example," "a specific example" or "some examples" or the like are intended to 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, a schematic representation of the above terms does not necessarily refer to the same embodiment, implementation, or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments, implementations, or examples. Furthermore, the various examples, embodiments, or examples described in this specification, as well as features of various examples, embodiments, or examples, may 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. A compound which is a compound represented by 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,

wherein:

is a heterocyclic group consisting of 3 to 8 atoms, wherein denotes the end attached to U;

u is-NH-or-O-;

v is-CH₂-、-CH₂CH₂-or-C (═ O) -;

w is-NH-, -O-, -CH₂-、-CH₂CH₂-、-CH₂O-、-OCH₂-, -C (═ O) NH — or-NHC (═ O) -;

X₁and X₂Each independently is CH or N;

Y₁and Y₂Each independently is CH or N;

R¹、R²and R³Each independently is H, D, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-SH、-COOH、-C(＝O)NH₂、-C(＝O)NHCH₃、-C(＝O)N(CH₃)₂、-C(＝O)-(C₁-C₆Alkyl), -C (═ O) - (C)₁-C₆Alkoxy), -S (═ O)₂C₁-C₆Alkyl radical, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆Haloalkyl, C₁-C₆Alkoxy radical, C₁-C₆Haloalkoxy, C₁-C₆Alkylthio radical, C₁-C₆Alkylamino or hydroxy substituted C₁-C₆An alkyl group;

R⁴and R⁵Each independently is H, D, -OH, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆Haloalkyl, C₁-C₆Alkoxy or C₁-C₆A haloalkoxy group; or R⁴、R⁵And the nitrogen atom to which they are attached, together form a heterocyclic group of 3 to 8 atoms.

2. The compound of claim 1, wherein,

3. The compound according to claim 1 or 2, wherein,

is composed of

Wherein denotes the end connected to U.

4. The compound of claim 1, wherein R¹、R²And R³Each independently is H, D, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-SH、-COOH、-C(＝O)NH₂、-C(＝O)NHCH₃、-C(＝O)N(CH₃)₂、-C(＝O)-(C₁-C₄Alkyl), -C (═ O) - (C)₁-C₄Alkoxy), -S (═ O)₂C₁-C₄Alkyl radical, C₁-C₄Alkyl radical, C₂-C₄Alkenyl radical, C₂-C₄Alkynyl, C₁-C₄Haloalkyl, C₁-C₄Alkoxy radical, C₁-C₄Haloalkoxy, C₁-C₄Alkylthio radical, C₁-C₄Alkylamino or hydroxy substituted C₁-C₄An alkyl group;

R⁴and R⁵Each independently is H, D, -OH, C₁-C₄Alkyl radical, C₂-C₄Alkenyl radical, C₂-C₄Alkynyl, C₁-C₄Haloalkyl, C₁-C₄Alkoxy or C₁-C₄A haloalkoxy group; or R⁴、R⁵And the nitrogen atom to which they are attached, together form a heterocyclic group of 3 to 6 atoms.

5. A compound according to claim 1 or 4, wherein R¹、R²And R³Each independently is H, D, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-SH、-COOH、-C(＝O)NH₂、-C(＝O)NHCH₃、-C(＝O)N(CH₃)₂、-C(＝O)-CH₃、-C(＝O)-OCH₃、-S(＝O)₂CH₃Methyl, ethyl, n-propyl, isopropyl, tert-butyl, vinyl, -CHF₂、-CF₃Methoxy, -OCF₃Methylamino, dimethylamino, or hydroxymethyl;

R⁴and R⁵Each independently H, D, -OH, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, 2-methylpropyl, 1-methylpropyl, ethenyl, propenyl, allyl, ethynyl, propynyl, propargyl, -CHF₂、-CF₃Methoxy, ethoxy, isopropoxy or-OCF₃(ii) a Or R⁴、R⁵And the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl group.

6. The compound of claim 1, which is a compound of formula (II), formula (II ') or formula (III) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of a compound of formula (II), formula (II') or formula (III),

7. the compound according to claim 1 or 6, which is a compound having one of the following structures 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 of the compound having one of the following structures:

8. a pharmaceutical composition comprising a compound of any one of claims 1-7; and

the pharmaceutical composition optionally further comprises a pharmaceutically acceptable excipient, carrier, adjuvant, or any combination thereof.

9. Use of a compound according to any one of claims 1 to 7 or a pharmaceutical composition according to claim 8 for the manufacture of a medicament for the prophylaxis or treatment of a tumour.

10. The use according to claim 9, wherein the tumor is a B-cell lymphoma, a solid tumor and/or a tumor of the blood and immune system;

wherein the B cell lymphoma is diffuse large B cell lymphoma, small lymphocytic tumor, mantle cell lymphoma, multiple myeloma and/or chronic lymphocytic leukemia;

wherein the solid tumor is gastric cancer, intestinal cancer, liver cancer, kidney cancer, lung cancer, brain cancer, laryngeal cancer, esophageal cancer, head and neck cancer, squamous carcinoma, lymphatic system cancer, thyroid cancer, bladder cancer, cervical cancer, prostate cancer, genitourinary tract cancer, breast cancer, small cell lung cancer, lung adenocarcinoma, pancreatic cancer, colon cancer, glioblastoma and/or monocytic leukemia;

wherein the blood and immune system tumor is acute lymphatic leukemia, chronic lymphatic leukemia, acute myelogenous leukemia and/or chronic myelogenous leukemia.

11. Use of a compound according to any one of claims 1 to 7 or a pharmaceutical composition according to claim 8 in the manufacture of a medicament for inhibiting the activity of bruton's tyrosine kinase.