Substituted pyrrolo[2,3-b]pyridine and pyrazolo[3,4-b]pyridine derivatives as protein kinase inhibitors

Abstract

This invention provides a class of BTK inhibitors, pharmaceutical compositions thereof, and methods of use thereof.

Description

Invention Field

[0001] This invention relates to a class of compounds that can inhibit the activity of Bruton's tyrosine kinase (BTK) or pharmaceutically acceptable salts thereof, and as medicines for treating hyperproliferative diseases such as cancer and inflammation, or immune and autoimmune diseases. Background of the Invention

[0003] Hyperproliferative disorders, such as cancer and inflammation, have attracted the attention of the academic community, who are striving to develop effective treatments. Efforts have been made in this regard, identifying and targeting specific mechanisms that play a role in proliferative disorders.

[0004] Bruton's tyrosine kinase (BTK) belongs to the Tec family of non-receptor tyrosine kinases. It is expressed in B cells and bone marrow cells and plays a key regulatory role in the B cell receptor (BCR) pathway. The B cell receptor pathway is involved in processes such as early B cell development, mature B cell activation, signal transduction, and survival.

[0005] X-linked agammaglobulinemia (XLA) is a known cause of human BTK functional mutations. It is a primary immunodeficiency disease in humans, characterized by a significant decrease or absence of serum immunoglobulins due to the failure to produce mature B cells caused by functional mutations. Furthermore, regulation of BTK can induce the production of pro-inflammatory cytokines and chemokines by B cells through the B cell receptor pathway, indicating the broad potential of BTK in the treatment of autoimmune diseases. The role of BTK in the treatment of autoimmune and inflammatory diseases has also been confirmed in BTK-deficient mouse models. Therefore, inhibiting BTK activity could be used to treat autoimmune and / or inflammatory diseases such as rheumatoid arthritis, multiple vasculitis, myasthenia gravis, and asthma.

[0006] Furthermore, BTK has been reported to play an important role in apoptosis. In some malignant tumors, BTK is overexpressed in B cells, which is associated with tumor cell proliferation and survival. Inhibition of BTK can prevent B cell activation and suppress the growth of malignant B cells by affecting B cell signaling pathways.

[0007] Therefore, inhibiting BTK activity can be used to treat cancers such as B-cell lymphoma, leukemia, and other hematologic malignancies. Numerous clinical trials have demonstrated the effectiveness of BTK inhibitors against cancer. Ibrutinib (PCI-32765) was the first BTK inhibitor approved by the U.S. Food and Drug Administration for the treatment of mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL), and Waldenström macroglobulinemia (WM). BTK inhibitors can also be used to treat other diseases, such as immune disorders and inflammation.

[0008] Therefore, compounds with BTK inhibitory activity are of great significance for the prevention and treatment of the aforementioned diseases. Although BTK inhibitors have been reported in the literature, such as WO 2008039218 and WO 2008121742, many have short half-lives or are toxic. Therefore, the need for novel BTK inhibitors remains urgent, which should offer advantages in at least one aspect of efficacy, stability, selectivity, safety, and pharmacodynamic characteristics in the treatment of hyperproliferative diseases. This invention relates to a novel class of BTK inhibitors. Summary of the Invention

[0009] This invention relates to a class of novel compounds, their pharmaceutically acceptable salts, and pharmaceutical compositions thereof, as well as their use as medicines.

[0010] In one aspect, the present invention provides compounds of formula (I):

[0011]

[0012] Or its pharmaceutically acceptable salt, wherein,

[0013] R 1 Selected from C 1-10 Alkyl and C 3-10 Cycloalkyl, wherein the alkyl group and the cycloalkyl group are either unsubstituted or selected independently from R. X Substituents of the substituents;

[0014] Each R 2 Independently selected from halogens and methyl groups;

[0015] Each R X Selected independently from C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 Alkyl, heterocyclic, heterocyclic-C 1-4 Alkyl, aryl, aryl-C 1-4 Alkyl, heteroaryl, heteroaryl-C 1-4 Alkyl, halogen, CN, -NO2, -NR a R b -OR a -SR a -S(O) r R a -S(O)2OR a -OS(O)2R b -S(O) r NR a R b -P(O)Ra R b 、-P(O)(OR a )(OR b )、-(CR c R d ) t NR a R b 、-(CR c R d ) t OR b 、-(CR c R d ) t SR b 、-(CR c R d ) t S(O) r R b 、-(CR c R d ) t P(O)R a R b 、-(CR c R d ) t P(O)(OR a )(OR b )、-(CR c R d ) t CO2R b 、-(CR c R d ) t C(O)NR a R b 、-(CR c R d ) t NR a C(O)R b 、-(CR c R d ) t NR a CO2R b 、-(CR c R d ) t OC(O)NR a R b 、-(CR c R d ) t NR a C(O)NR a R b 、-(CR c Rd ) t NR a SO2NR a R b 、-NR a (CR c R d ) t NR a R b 、-O(CR c R d ) t NR a R b 、-S(CR c R d ) t NR a R b 、-S(O) r (CR c R d ) t NR a R b 、-C(O)R a 、-C(O)(CR c R d ) t OR b 、-C(O)(CR c R d ) t NR a R b 、-C(O)(CR c R d ) t SR b 、-C(O)(CR c R d ) t S(O) r R b 、-CO2R b 、-CO2(CR c R d ) t C(O)NR a R b 、-OC(O)R a 、-C(O)NR a R b 、-NR a C(O)R b 、-OC(O)NR a R b 、-NR a C(O)OR b 、-NR aC(O)NR a R b -NR a S(O) r R b -CR a (=N-OR b -C (=NR) e )R a -C(=NR) e )NR a R b -NR a C(=NR e )NR a R b -CHF2, -CF3, -OCHF2, and -OCF3, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is unsubstituted or is selected independently from at least one hydroxyl, C, amino, halogen, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 1-10 Alkoxy, C 3-10 Cycloalkoxy, C 1-10 Alkylthio, C 3-10 Cycloalkylthio, C 1-10 Alkylamino, C 3-10 Cycloalkanes and di(C) 1-10 Substitution of alkyl)amino groups;

[0016] Each R a and R b Independently selected from hydrogen and C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 Alkyl, C 1-10 Alkoxy, C 3-10 Cycloalkoxy, C 1-10 Alkylthio, C 3-10 Cycloalkylthio, C 1-10 Alkylamino, C 3-10 Cycloalkylamino, di(C 1-10 Alkyl)amino, heterocyclic, heterocyclic-C 1-4 Alkyl, aryl, aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4Alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclic, aryl, and heteroaryl is unsubstituted or is selected independently from at least one halogen, C1, C2, C3, C4, C5, C6, C6, C7 ... 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 Cycloalkyl, hydroxyl, C 1-10 Alkoxy, C 3-10 Cycloalkoxy, C 1-10 Alkylthio, C 3-10 Cycloalkylthio, amino, C 1-10 Alkylamino, C 3-10 Cycloalkanes and di(C) 1-10 Substitution of alkyl)amino groups;

[0017] or R a and R b Together with the single or multiple atoms attached to them, they form a 4-12 membered heterocycle containing 0, 1, or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen, and phosphorus. The ring may optionally be composed of 1 or 2 heteroatoms independently selected from halogens, CN, C, and C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 Cycloalkyl, hydroxyl, C 1-10 Alkoxy, C 3-10 Cycloalkoxy, C 1-10 Alkylthio, C 3-10 Cycloalkylthio, amino, C 1-10 Alkylamino, C 3-10 Cycloalkanes and di(C) 1-10 Substitution of alkyl)amino groups;

[0018] Each R c and R d Independently selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 Alkyl, C 1-10 Alkoxy, C 3-10 Cycloalkoxy, C 1-10 Alkylthio, C 3-10 Cycloalkylthio, C 1-10 Alkylamino, C 3-10 Cycloalkylamino, di(C 1-10 Alkyl)amino, heterocyclic, heterocyclic-C 1-4 Alkyl, aryl, aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C1-4 Alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclic, aryl, and heteroaryl is unsubstituted or is selected independently from at least one halogen, C1, C2, C3, C4, C5, C6, C6, C7 ... 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 Cycloalkyl, hydroxyl, C 1-10 Alkoxy, C 3-10 Cycloalkoxy, C 1-10 Alkylthio, C 3-10 Cycloalkylthio, amino, C 1-10 Alkylamino, C 3-10 Cycloalkanes and di(C) 1-10 Substitution of alkyl)amino groups;

[0019] or R c and R d Together with the single or multiple carbon atoms attached to them, they form a 3-12 membered ring containing 0, 1, or 2 heteroatoms independently selected from oxygen, sulfur, and nitrogen. This ring may optionally be surrounded by 1 or 2 heteroatoms independently selected from halogens, CN, C, and C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 Cycloalkyl, hydroxyl, C 1-10 Alkoxy, C 3-10 Cycloalkoxy, C 1-10 Alkylthio, C 3-10 Cycloalkylthio, amino, C 1-10 Alkylamino, C 3-10 Cycloalkanes and di(C) 1-10 Substitution of alkyl)amino groups;

[0020] Each R e Independently selected from hydrogen, CN, NO2, C 1-10 Alkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 Alkyl, C 1-10 Alkoxy, C 3-10 Cycloalkoxy, -C(O)C 1-4 Alkyl, -C(O)C 3-10 Cycloalkyl, -C(O)OC 1-4 Alkyl, -C(O)OC 3-10 Cycloalkyl, -C(O)N(C 1-4 Alkyl)2、-C(O)N(C 3-10 cycloalkyl)2、-S(O)2C 1-4 Alkyl group, -S(O)2C 3-10Cycloalkyl, -S(O)2N(C 1-4 alkyl)2 and -S(O)2N(C 3-10 cycloalkyl)2;

[0021] m is selected from 0, 1, 2, 3, 4, and 5;

[0022] Each r is independently selected from 0, 1, and 2;

[0023] Each t is independently selected from 0, 1, 2, 3, and 4.

[0024] On the other hand, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or at least one pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0025] On the other hand, the present invention provides a method for regulating BTK, the method comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof to a system or individual in need, thereby regulating BTK.

[0026] On the other hand, the present invention also provides a method for treating, improving or preventing symptoms of BTK inhibition, comprising administering, to a desired systemic or individual effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof, or optionally in combination with another therapeutic agent, to treat the aforementioned symptoms.

[0027] Alternatively, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating BTK-mediated conditions. In certain embodiments, the compound may be used alone or in combination with another therapeutic agent to treat BTK-mediated conditions.

[0028] Alternatively, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment of BTK-mediated conditions.

[0029] Specifically, the conditions described include, but are not limited to, autoimmune diseases, xenoimmune diseases, allergic diseases, inflammatory diseases, or abnormal cell proliferation.

[0030] Furthermore, the present invention provides a method for treating BTK-mediated conditions, comprising administering, to a desired system or individual, an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutical composition thereof, or optionally in combination with another therapeutic agent, to treat the aforementioned conditions.

[0031] Alternatively, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt in the preparation of a medicament for treating BTK-mediated diseases. In certain embodiments, the compound may be used alone or in combination with a chemotherapeutic agent to treat the aforementioned cell proliferation abnormalities.

[0032] Specifically, the conditions mentioned include, but are not limited to, autoimmune diseases, xenoimmune diseases, allergic diseases, inflammatory diseases, or abnormal cell proliferation.

[0033] In some embodiments, the symptom is abnormal cell proliferation. In one embodiment, the abnormal cell proliferation is B-cell proliferation abnormality, including but not limited to B-cell malignancies, B-cell chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, multiple sclerosis, small lymphocytic lymphoma, mantle cell lymphoma, B-cell non-Hodgkin lymphoma, activated B-cell-like diffuse large B-cell lymphoma, multiple myeloma, diffuse large B-cell lymphoma, follicular lymphoma, primary exudative lymphoma, Burkitt lymphoma / leukemia, lymphomatoid granulomatosis, and plasmacytoma.

[0034] In some embodiments, the condition is an autoimmune disease, including but not limited to rheumatoid arthritis, psoriatic arthritis, psoriasis, osteoarthritis, juvenile arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, myasthenia gravis, Hashimoto's thyroiditis, multiple sclerosis, acute disseminated encephalomyelitis, Addison's disease, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, Goodpasser syndrome, idiopathic thrombocytopenic purpura, scleroderma, primary biliary cirrhosis, Reiter's syndrome, psoriasis, autonomic dysfunction, neuromuscular rigidity, interstitial cystitis, lupus erythematosus, systemic lupus erythematosus, and lupus nephritis.

[0035] In some embodiments, the condition is a xenoimmune disease, including but not limited to graft-versus-host disease, transplantation, blood transfusion, anaphylaxis, allergy, type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, and allergic dermatitis.

[0036] In some embodiments, the condition is an inflammatory disease, including but not limited to asthma, appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, colitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, enteritis, hepatitis, and purulent hidradenitis. Inflammation, pharyngitis, mastitis, meningitis, inflammatory myocarditis, myositis, nephritis, orchitis, oophoritis, osteitis, otitis media, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, localized pneumonia, acute pneumonia, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, uveitis, vaginitis, vasculitis, and vulvitis.

[0037] In the above methods of using the compounds described in this invention, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered to a system comprising cells or tissues, or to an individual including a mammalian individual, such as a human or animal individual.

[0038] the term

[0039] Unless otherwise defined, all technical and scientific terms used in this patent have the same meaning as commonly understood by one of ordinary skill in the art. Unless otherwise stated, all patents, patent applications, publicly disclosed materials, etc., referenced in this patent are included in the full text of the references. If the same term has multiple definitions in this patent, the definition in this section shall prevail.

[0040] It is important to understand that the foregoing general description and the following detailed description are merely illustrative and do not impose any limitation on any of the claims. In this patent application, the singular includes the plural unless otherwise stated. It should be noted that in the specification and appended claims, singular forms such as “a,” “an,” and “this” include plural references unless otherwise stated. It should also be noted that “or” means “and / or” unless otherwise stated. Furthermore, terms such as “comprising,” “including,” and similar terms are not restrictive.

[0041] Unless otherwise stated, the mass spectrometry, nuclear magnetic resonance, high-performance liquid chromatography, infrared and ultraviolet / visible spectroscopy, and conventional pharmacological techniques used in this patent are prior art. Unless specifically defined, the nomenclature, experimental methods, and techniques involved in analytical chemistry, organic synthetic chemistry, pharmaceutical chemistry, and pharmaceutical chemistry described in this patent are known. Standard techniques can be used for chemical synthesis, chemical analysis, drug preparation, formulation and administration, and patient treatment. Reaction and purification techniques can be performed with reference to the manufacturer's instructions, known commonly used techniques, or the methods described in this patent. The above techniques and operations can be performed using methods known conventionally and those cited in the literature herein. In the specification, groups and substituents can be selected by those skilled in the art to form stable structures and compounds.

[0042] When using chemical formulas to refer to substituents, the substituents in the chemical formula are written from left to right in the same way as when written from right to left. For example, CH2O is the same as OCH2.

[0043] "Substitution" refers to the replacement of a hydrogen atom by a substituent. It is important to note that the substituent on a specific atom is restricted by its valence state.

[0044] The term "C" used in this article i-j "" or "ij element" refers to the part having ij carbon atoms or ij atoms. For example, "C 1-6 "Alkyl" refers to an alkyl group having 1-6 carbon atoms. Similarly, C 3-10Cycloalkyl means that the cycloalkyl group has 3 to 10 carbon atoms.

[0045] When any variable (such as R) appears more than once in the structure of a compound, it is defined independently in each case. Thus, for example, if a group is substituted by 0-2 Rs, that group can optionally be substituted by at most two Rs, and R has an independent choice in each case. Furthermore, combinations of substituents and / or their variants are permitted only if such combinations would produce a stable compound.

[0046] "One or more" or "at least one" means one, two, three, four, five, six, seven, eight, nine or more.

[0047] Unless otherwise stated, the term "heteroatom" refers to a heteroatom or heteroatom group (i.e., a group containing a heteroatom), that is, an atom other than carbon and hydrogen atoms or a group containing such atoms. Preferably, the heteroatom is independently selected from O, N, S, P, etc. In embodiments involving two or more heteroatoms, the two or more heteroatoms may be identical, or the two or more heteroatoms may be partially or completely different.

[0048] "Hydrogen" refers to 1 H, 2 H and 3 H.

[0049] Whether used alone or in combination with other terms, "alkyl" refers to a branched or straight-chain saturated aliphatic hydrocarbon group having a specific number of carbon atoms. Unless otherwise specified, "alkyl" refers to a C14-C14 hydrocarbon group. 1-10 Alkyl group. For example, "C 1-6 The "C" in "alkyl" 1-6 "" refers to a group consisting of a straight chain or branched arrangement of 1, 2, 3, 4, 5, or 6 carbon atoms. For example, "C 1-8 "Alkyl" includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, hexyl, heptyl, and octyl.

[0050] "Cycloalkyl," whether used alone or in combination with other terms, refers to a saturated monocyclic or polycyclic (e.g., bicyclic or tricyclic) hydrocarbon ring system, typically having 3 to 16 ring atoms. All ring atoms in a cycloalkyl group are carbon atoms, and the cycloalkyl group contains zero heteroatoms and zero double bonds. In polycyclic cycloalkyl groups, two or more rings may be fused, bridged, or spirofused together. Examples of monocyclic systems include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Bridged cycloalkyl groups are polycyclic systems containing 3-10 carbon atoms, which contain one or two alkylene bridges, each consisting of 1, 2, or 3 carbon atoms connecting two non-adjacent carbon atoms in the ring system. Cycloalkyl groups may be fused with aryl or heteroaryl groups. In some embodiments, the cycloalkyl group is benzofused. Representative examples of bridged cycloalkane systems include, but are not limited to, bicyclo[1.1.1]pentane, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, bicyclo[4.2.1]nonane, tricyclo[3.3.1.03,7]nonane, and tricyclo[3.3.1.13,7]decane (adamantane). The cycloalkyl group can be attached to the parent molecule via any substituted atom in the ring system.

[0051] "Alkenyl," whether used alone or in combination with other terms, refers to a non-aromatic straight-chain, branched, or cyclic hydrocarbon group containing 2-10 carbon atoms and at least one carbon-carbon double bond. In some embodiments, cyclic refers to monocyclic or polycyclic. In polycyclic alkenyl groups, two or more rings may be linked by fusion, bridging, or spirocyclic linkage. In some embodiments, one carbon-carbon double bond is present, and up to four non-aromatic carbon-carbon double bonds may be present. Therefore, "C 2－6 "Alkenyl" refers to an alkenyl group containing 2-6 carbon atoms. Alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, 2-methylbutenyl, cyclopentenyl, and cyclohexenyl. The straight-chain, branched, or cyclic portion of an alkenyl group may contain double bonds, and if a substituted alkenyl group is specified, it indicates that it may be substituted.

[0052] "Alkyne," whether used alone or in combination with other terms, refers to a straight-chain, branched, or cyclic hydrocarbon group containing 2-10 carbon atoms and at least one carbon-carbon triple bond. In some embodiments, up to three carbon-carbon triple bonds may be present. Therefore, "C 2-6 "Alynyl" refers to an alkynyl group containing 2-6 carbon atoms. Alynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, 3-methylbutynyl, etc. The straight-chain, branched, or cyclic portion of the alkynyl group may contain a triple bond. If a substituted alkynyl group is indicated, it means that it may be substituted.

[0053] "Halogens" refer to fluorine, chlorine, bromine, and iodine.

[0054] "Alkoxy," used alone or in combination with other terms, refers to an alkyl group as defined above, bonded to an oxygen atom by a single bond. The alkoxy group is linked to the molecule via an oxygen atom. Alkoxy groups can be represented as -O-alkyl. "C 1-10 "Alkoxy" refers to an alkoxy group containing 1-10 carbon atoms, which can be straight-chain or branched. Alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy, hexoxy, etc.

[0055] "Cycloalkoxy," used alone or in combination with other terms, refers to a cycloalkyl group as defined above, linked to an oxygen atom by a single bond. The cycloalkoxy group is linked to the molecule via an oxygen atom. Cycloalkoxy groups can be represented as -O-cycloalkyl. "C 3-10 "Cycloalkoxy" refers to a cycloalkoxy group containing 3-10 carbon atoms. Cycloalkoxy groups can be fused with aryl or heteroaryl groups. In some embodiments, the cycloalkoxy group is benzo-fused. Cycloalkoxy groups include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, etc.

[0056] "Alkylthio," used alone or in combination with other terms, refers to an alkyl group as defined above, linked to a sulfur atom by a single bond. The alkylthio group is attached to the molecule via a sulfur atom. Alkylthio can be represented as -S-alkyl. "C 1-10 "Alkylthio" refers to an alkylthio group containing 1-10 carbon atoms, which can be straight-chain or branched. Alkylthio groups include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, butylthio, and hexylthio.

[0057] "Cycloalkylthio," used alone or in combination with other terms, refers to a cycloalkyl group as defined above, linked to a sulfur atom by a single bond. The cycloalkylthio group is linked to the molecule via a sulfur atom. It can be represented as -S-cycloalkyl. "C 3-10 "Cyclothio" refers to a cyclothio group containing 3-10 carbon atoms. Cyclothio groups can be fused with aryl or heteroaryl groups. In some embodiments, the cyclothio group is benzo-fused. Cyclothio groups include, but are not limited to, cyclopropylthio, cyclobutyrio, and cyclohexylthio.

[0058] "Alkylamino," used alone or in combination with other terms, refers to an alkyl group as defined above, linked to a nitrogen atom by a single bond. An alkylamino group is linked to another molecule via a nitrogen atom. Alkylamino groups can be represented as -NH (alkyl). "C" 1-10 "Alkylamino" refers to an alkylamino group containing 1-10 carbon atoms, which can be straight-chain or branched. Alkylamino groups include, but are not limited to, methylamino, ethylamino, propylamino, isopropylamino, butylamino, and hexylamino.

[0059] "Cycloalkylamino," used alone or in combination with other terms, refers to a cycloalkyl group as defined above, linked to a nitrogen atom by a single bond. A cycloalkylamino group is linked to another molecule via a nitrogen atom. A cycloalkylamino group can be represented as -NH (cycloalkyl). "C 3-10 "Cycloalkylamino" refers to a cycloalkylamino group containing 3-10 carbon atoms. Cycloalkylamino groups can be fused with aryl or heteroaryl groups. In some embodiments, the cycloalkylamino group is benzo-fused. Cycloalkylamino groups include, but are not limited to, cyclopropylamino, cyclobutylamino, and cyclohexylamino.

[0060] "Di(alkyl)amino", used alone or in combination with other terms, refers to two alkyl groups as defined above, bonded by a single bond to a nitrogen atom. The di(alkyl)amino group is attached to the molecule via a nitrogen atom. Di(alkyl)amino can be represented as -N(alkyl)2. "Di(C 1-10 "alkyl)amino" refers to a di(C)amino group where each of the two alkyl groups contains 1-10 carbon atoms. 1-10 Alkyl)amino, which can be straight-chain or branched.

[0061] "Aryl", used alone or in combination with other terms, refers to an aryl group having 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms ("C4"). 6-14 Aromatic ring systems consisting of a monovalent, monocyclic, bicyclic, or tricyclic aryl group, particularly rings with 6 carbon atoms (“C6 aryl” groups), such as phenyl; or rings with 10 carbon atoms (“C6 aryl” groups). 10 Aryl groups), such as naphthyl; or rings having 14 carbon atoms ("C"). 14 Aryl groups, such as anthracene groups. Aryl groups can be fused with cycloalkyl or heterocyclic groups.

[0062] A divalent group formed from substituted benzene derivatives and possessing free valence electrons on a ring atom is named a substituted phenylene group. A divalent group derived from a monovalent polycyclic hydrocarbon group ending in "-" is obtained by removing a hydrogen atom from a carbon atom containing free valence electrons; its name is formed by adding "-idene" to the monovalent group name. For example, a naphthyl group with two linkage sites is called a naphthylene group.

[0063] "Heteroaryl," used alone or in combination with other terms, refers to a monovalent, monocyclic, bicyclic, or tricyclic aromatic ring system having 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms ("5- to 14-membered heteroaryl" groups), particularly 5, 6, 9, or 10 atoms, and containing at least one heteroatom, which may be the same or different, selected from N, O, and S. Heteroaryl groups can be fused with cycloalkyl or heterocyclic groups. In some embodiments, "heteroaryl" refers to...

[0064] Aromatic monocyclic rings ranging from 5 to 8 quinones, containing 1 to 4 heteroatoms selected from N, O, and S, and in some embodiments 1 to 3 heteroatoms, the remainder being carbon atoms; and

[0065] An 8- to 12-membered bicyclic ring containing 1 to 6 heteroatoms selected from N, O, and S, in some embodiments 1 to 4 heteroatoms, or in some embodiments 1 to 3 heteroatoms, the remainder being carbon atoms, with at least one heteroatom present in the aromatic ring; and

[0066] The 11- to 14-membered tricyclic ring contains 1 to 8 heteroatoms selected from N, O, and S, in some embodiments 1 to 6, in some embodiments 1 to 4, or in some embodiments 1 to 3, with the remainder being carbon atoms.

[0067] When the total number of S and O atoms in a heteroaryl group is greater than 1, these heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O atoms in a heteroaryl group is not greater than 2. In some embodiments, the total number of S and O atoms in a heteroaryl group is not greater than 1.

[0068] Examples of heteroaryl groups include, but are not limited to, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 3-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, pyridazinyl, triazinyl, pyrroleyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl, tetrazolyl, thiophenyl, and furanyl.

[0069] Furthermore, heteroaryl groups include, but are not limited to, indolyl, benzothiophene, benzofuranyl, benzimidazolyl, benzotriazolyl, quinoxalinyl, quinolinyl, and isoquinolinyl. "Heteroaryl" includes any nitrogen-containing heteroaryl derivative with N oxide.

[0070] Monovalent heteroaryl groups are named with the prefix "-aryl". The divalent groups derived from them are obtained by removing a hydrogen atom from a carbon atom that has a free valence electron. The divalent groups are named by adding "-idene" to the name of the monovalent group. For example, a pyridinyl group with two linkage sites is called a pyridinyl subunit.

[0071] "Heterocycle" (and its derivatives such as "heterocyclic" or "heterocyclic group") refers to a cyclic aliphatic hydrocarbon system that is saturated or unsaturated, monocyclic or polycyclic (e.g., bicyclic or tricyclic), typically having 3 to 16 ring atoms, and containing at least one (e.g., 2, 3, or 4) heteroatom independently selected from oxygen, sulfur, nitrogen, and phosphorus (preferably oxygen, sulfur, and nitrogen). In polycyclic systems, two or more rings can be linked by fusion, bridging, or spirocyclic linkages, and the heterocycle can be fused with an aryl or heteroaryl group. In some embodiments, the heterocycle is benzofused. Heterocycles also include cyclic systems partially substituted with one or more oxo or imino groups. In some embodiments, the C, N, S, and P atoms in the heterocycle are optionally oxo-substituted. In some embodiments, the C, S, and P atoms in the heterocycle are optionally substituted with imino groups, and the imino groups can be unsubstituted or substituted. Carbon atoms or heteroatoms on the heterocycle can be linking sites, provided that a stable structure is formed. When there is a substituent on a heterocycle, the substituent can be attached to any heteroatom or carbon atom on the heterocycle, provided that a stable chemical structure is formed.

[0072] Suitable heterocycles include, for example, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-imidazoyl, 2-imidazoyl, 3-imidazoyl, 4-imidazoyl, 5-imidazoyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 4-pyrrolyl, 5-pyrrolyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1-piperazinyl, 2-piperazinyl, 3-piperazinyl, 1-hexahydropyridazinyl, 3-hexahydropyridazinyl, 4-hexahydropyridazinyl, and tetrahydropyridinyl. Morpholinyl groups are also included, such as 1-morpholinyl, 2-morpholinyl, 3-morpholinyl, and 4-morpholinyl. Examples of heterocycles having one or more oxo moieties include, but are not limited to, piperidinyl-N-oxide, morpholinyl-N-oxide, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Bicyclic heterocyclic rings include, but are not limited to:

[0073]

[0074]

[0075] As used herein, "aryl-alkyl" refers to an aryl-substituted alkyl group as defined above. Example aryl alkyl groups include, but are not limited to, benzyl, phenethyl, and naphthylmethyl. In some embodiments, the aryl alkyl group contains 7-20 or 7-11 carbon atoms. When using "aryl C..." 1-4 When "alkyl" is used, "C" is used. 1-4 "" refers to the number of carbon atoms in the alkyl group, not the aryl group.

[0076] The term "heterocyclic-alkyl" as used here refers to a heterocyclic group that replaces an alkyl group as defined above. When using "heterocyclic C..." 1-4 When "alkyl" is used, "C" is used.1-4 "" refers to the number of carbon atoms in the alkyl group, not the heterocyclic group.

[0077] The term "cycloalkyl-alkyl" as used here refers to a cycloalkyl-substituted alkyl group as defined above. When using "C..." 3-10 cycloalkyl-C 1-4 When "alkyl" is used, "C" is used. 3-10 "" refers to the number of carbon atoms in the cycloalkyl moiety, not the alkyl moiety. Where "C" is... 1-4 "" refers to the number of carbon atoms in the alkyl group, not the cycloalkyl group.

[0078] The term "heteroaryl-alkyl" as used here refers to a heteroaryl-substituted alkyl group as defined above. When using "heteroaryl-C...", 1-4 When "alkyl" is used, "C" is used. 1-4 "" refers to the number of carbon atoms in the alkyl group, not the heteroaryl group.

[0079] To avoid ambiguity, for example, when referring to alkyl, cycloalkyl, heterocyclic alkyl, aryl, and / or heteroaryl substitutions, it means either that each of these groups is substituted individually or that these groups are substituted in combination. That is, if R is aryl-C 1-4 Alkyl groups, and may be unsubstituted or substituted with at least one substituent, such as 1, 2, 3 or 4 independently selected from R. X With respect to the substituents, it should be understood that the aryl moiety may be unsubstituted or replaced by at least one, such as 1, 2, 3, or 4, individually selected from R. X The substituents may be substituted, and the alkyl moiety may be unsubstituted or substituted by at least one, such as 1, 2, 3 or 4, individually selected from R. X Substituents are substituted.

[0080] "Pharmaceutically acceptable salts" refer to salts made from pharmaceutically acceptable, non-toxic bases or acids, including salts of inorganic or organic bases and inorganic or organic acids. Salts of inorganic bases can be selected from, for example, aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese, divalent manganese, potassium, sodium, and zinc salts. Further, salts of pharmaceutically acceptable inorganic bases can be selected from ammonium, calcium, magnesium, potassium, and sodium salts. Solid salts may exist in one or more crystalline forms, or polymorphs, and may also exist as solvates, such as hydrates. Pharmaceutically acceptable organic non-toxic base salts may be selected from, for example: primary amine, secondary amine and tertiary amine salts, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, heparin, isopropylamine, lysine, glucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine.

[0081] When the compound referred to in this patent is a base, its salt needs to be prepared with at least one pharmaceutically acceptable non-toxic acid, selected from inorganic and organic acids. For example, acids selected from acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, viscous acid, nitric acid, pyric acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, and p-toluenesulfonic acid. In some embodiments, these acids may be selected, such as citric acid, hydrobromic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, fumaric acid, and tartaric acid.

[0082] "Giving" or "administering" a compound or a pharmaceutically acceptable salt thereof means providing an individual in need of treatment with a compound or a pharmaceutically acceptable salt thereof from this invention.

[0083] "Effective dose" refers to the dose of a compound or its pharmaceutically acceptable salt that is capable of producing a biological or medical response in tissues, systems, animals, or humans that can be observed by researchers, veterinarians, clinicians, or other clinical personnel.

[0084] "Composition" includes: a product containing a specific amount of a specific ingredient, and a product formed by any combination of such specific amounts of the specific ingredients, directly or indirectly. A pharmaceutical composition includes: a product containing an active ingredient and an inert ingredient as a carrier, and a product made by any two or more ingredients directly or indirectly, through combination, compounding, or aggregation, or a product resulting from the decomposition of one or more ingredients, or a product resulting from other types of reactions or interactions between one or more ingredients.

[0085] "Pharmaceutical acceptable" means that it is compatible with other components in the formulation and poses no unacceptable toxicity to the user.

[0086] "Individual" refers to an individual suffering from a disease or ailment, including both mammals and non-mammals. Mammals include, but are not limited to, any member of the mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkeys; farm animals such as cattle, horses, sheep, goats, and pigs; livestock such as rabbits, dogs, and cats; and laboratory animals including rodents such as rats, mice, and guinea pigs. Non-mammalian animals include, but are not limited to, birds, fish, etc. In one embodiment of the invention, the mammal is a human.

[0087] "Treatment" includes relieving, reducing, or improving a disease or symptom; preventing other symptoms; improving or preventing underlying metabolic factors of symptoms; inhibiting a disease or symptom, for example, preventing the development of a disease or symptom; reducing a disease or symptom; promoting the remission of a disease or symptom; or causing the cessation of symptoms of a disease or symptom; and extends to include prevention. "Treatment" also includes achieving therapeutic and / or preventive benefits. A therapeutic benefit refers to the eradication or improvement of the treated condition. Furthermore, a therapeutic benefit is achieved by eradicating or improving one or more physical symptoms associated with an underlying disease, whereby an improvement in the patient's condition can be observed even though the patient may still have the underlying disease. A preventive benefit refers to the use of a composition by a patient to prevent a risk of a certain disease, or by the use of a composition by a patient when experiencing one or more physical symptoms of a disease, even though the disease has not yet been diagnosed.

[0088] A "protecting group" (Pg) is a substituent used to block or protect a specific functional group from reacting with other functional groups on a compound. For example, an "amino protecting group" is a substituent attached to an amino group to block or protect the amino functional group. Suitable amino protecting groups include acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ), and 9-fluorenylmethoxycarbonyl (Fmoc). Similarly, a "hydroxyl protecting group" is a substituent that effectively blocks or protects the function of a hydroxyl group. Suitable protecting groups include, but are not limited to, acetyl and silane. A "carboxyl protecting group" is a substituent that effectively blocks or protects the function of a carboxyl group. Commonly used carboxyl protecting groups include -CH2CH2SO2Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfinyl)ethyl, 2-(diphenylphosphine)-ethyl, nitroethyl, etc. For a general description and instructions for use of the protecting group, see the reference: TW Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

[0089] The term "NH protecting group" includes, but is not limited to, trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzylcarboxyl, o-bromobenzyloxycarbonyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl, benzoyl, tert-pentyloxycarbonyl, tert-butyloxycarbonyl, p-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4-(benzoazo)benzyloxycarbonyl, 2-furfuryloxycarbonyl, diphenylmethoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, phthaloyl, succinyl, alanyl, leucyl, 1-adamantaneoxycarbonyl, 8-quinolinyloxycarbonyl, and benzyl. Diphenylmethyl, triphenylmethyl, 2-nitrobenzyl, methanesulfonyl, p-toluenesulfonyl, N,N-dimethylaminomethylene, benzyl, 2-hydroxybenzyl, 2-hydroxy-5-chlorobenzyl, 2-hydroxy-1-naphthyl, 3-hydroxy-4-pyridyl, cyclohexyl, 2-ethoxycarbonylcyclohexyl, 2-ethoxycarbonylcyclopentyl, 2-acetylcyclohexyl, 3,3-dimethyl-5-oxocyclohexyl, diphenylphosphoyl, dibenzylphosphoyl, 5-methyl-2-oxy-2H-1,3-dioxocyclopenten-4-yl-methyl, trimethylsilyl, triethylsilyl, and triphenylsilyl.

[0090] The “C(O)OH” protecting group includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, 1,1-dimethylpropyl, n-butyl, tert-butyl, phenyl, naphthyl, benzyl, diphenylmethyl, triphenylmethyl, p-nitrobenzyl, p-methoxybenzyl, bis(p-methoxyphenyl)methyl, acetylmethyl, benzoylmethyl, p-nitrobenzoylmethyl, p-bromobenzoylmethyl, p-methanesulfonylbenzoylmethyl, 2-tetrahydropyranyl, 2-tetrahydrofuranyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, acetoxymethyl, propionyloxymethyl, neopentyloxymethyl, o- Phthalimide methyl, succinimide methyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxymethyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, benzyloxymethyl, methylthiomethyl, 2-methylthioethyl, phenylthiomethyl, 1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl, and tert-butylmethoxyphenylsilyl.

[0091] The “OH or SH” protecting group includes, but is not limited to, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, isobutoxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, and 2,2,2-tribromoethoxycarbonyl. 2-(trimethylsilane)ethoxycarbonyl, 2-(benzenesulfonyl)ethoxycarbonyl, 2-(triphenylphosphonium)ethoxycarbonyl, 2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, 4-ethoxy-1-naphthyloxycarbonyl, 8-quinolinyloxycarbonyl, acetyl, formic acid, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl Phenoxyacetyl, pivaloyl, benzoyl, methyl, tert-butyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, benzyl (phenylmethyl), p-methoxybenzyl, 3,4-dimethoxybenzyl, diphenylmethyl, triphenylmethyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiaranyl, methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloro-ethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, 1-ethoxyethyl, methanesulfonyl, p-toluenesulfonyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl and tert-butylmethoxyphenylsilyl.

[0092] Geometric isomers may exist in the compounds of this invention. The compounds of this invention may contain E or Z configurations of carbon-carbon or carbon-nitrogen double bonds, where “E” indicates that, according to the Cahn-Ingold-Prelog preference rule, the preferred substituent is on the opposite side of the carbon-carbon or carbon-nitrogen double bond, and “Z” indicates that the preferred substituent is on the same side of the carbon-carbon or carbon-nitrogen double bond. The compounds of this invention may also exist as mixtures of “E” and “Z” isomers. Substituents around cycloalkyl or heterocyclic groups may be designated as cis or trans configurations. Furthermore, this invention includes different isomers and mixtures thereof formed by different arrangements of substituents around the adamantane ring system. Two substituents around a monocycle in the adamantane ring system are designated as Z or E relative configurations. See, for example, C.D. Jones, M. Kaselj, R.N. Salvatore, W.J. Le Noble J. Org. Chem. 1998, 63, 2758-2760.

[0093] The compounds of this invention may contain asymmetrically substituted carbon atoms in the R or S configuration, the definitions of which are given in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13-10. Compounds containing asymmetrically substituted carbon atoms are racemic if the R and S configurations are present in equal amounts. If one configuration is present in greater quantity than the other, the configuration of the chiral carbon atom is indicated by the more abundant configuration, preferably an enantiomeric excess of about 85-90%, more preferably about 95-99%, and further about 99% or more. Therefore, this invention comprises racemic mixtures, relative and absolute stereoisomers, and mixtures of relative and absolute stereoisomers.

[0094] Isotope enrichment or labeling of compounds

[0095] The compounds of this invention may exist in isotopically labeled or enriched forms, comprising one or more atoms with masses and mass numbers different from the most common atomic masses and mass numbers found in nature. The isotopes may be radioactive or non-radioactive. Isotopes of atoms such as hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine are included, but not limited to, these isotopes. 2 H, 3 H, 13 C 14 C 15 N、 18 O、 32 P, 35 S, 18 F, 36 Cl and 125 I. Other isotopes and / or other atoms containing these atoms are also within the scope of this invention.

[0096] In another embodiment, the isotope-labeled compound contains deuterium (… 2 H), tritium ( 3 H) or 14 C isotopes. The isotope-labeled compounds of the present invention can be obtained using methods well known to those skilled in the art. These isotope-labeled compounds can be obtained by replacing the unlabeled reagent with an isotope-labeled reagent, referring to the embodiments and reaction diagrams of the present invention. In some examples, the compound can be treated with an isotope-labeled reagent to replace atoms with isotope atoms; for example, replacing hydrogen with deuterium can be achieved through the action of a deuterated acid such as D₂SO₄ / D₂O.

[0097] The isotope-labeled compounds of this invention can serve as a standard for BTK inhibitor pharmacodynamic binding assays. Isotope-containing compounds can be used in pharmaceutical research to evaluate the mechanisms of action and metabolic pathways of non-isotope-labeled parent compounds, and to study the in vivo metabolic fate of the compounds (Blake et al. J. Pharm. Sci. 64, 3, 367-391 (1975)). Such metabolic studies are crucial for designing safe and effective therapeutic drugs, as they can determine whether the in vivo active compound used by the patient or the metabolites of the parent compound are toxic or carcinogenic (Foster et al., Advances in Drug Research Vol. 14, pp. 2-36, Academic press, London, 1985; Kato et al. J. Labelled Compounds. Radiopharmaceuticals, 36(10): 927-932 (1995); Kushner et al., Can. J. Physiol. Pharmacology, 77, 79-88 (1999)).

[0098] In addition, drugs containing non-reflective active isotopes, such as deuterated drugs, are called "heavy drugs" and can be used to treat diseases and conditions associated with BTK activity. When the proportion of a certain isotope in a compound exceeds its natural abundance, it is called enrichment. The amount of enrichment includes, but is not limited to, for example, from about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 21, 25, 29, 33, 37, 42, 46, 50, 54, 58, 63, 67, 71, 75, 79, 84, 88, 92, 96 to about 100 mol%.

[0099] Stable isotopic labeling of drugs can alter their physicochemical properties, such as pKa and liquid solubility. If isotopic substitution affects regions associated with ligand-receptor interactions, these effects and alterations can influence the pharmacodynamic response of drug molecules. While some physical properties of stable isotopically labeled molecules differ from unlabeled molecules, their chemical and biological properties are the same. However, there is an important distinction: due to the increased mass of the heavy isotope, any chemical bond containing the heavy isotope and another atom is stronger than that of the light isotope. Consequently, the presence of the isotope at metabolic or enzyme conversion sites slows down the reaction, potentially altering the pharmacokinetic characteristics or efficacy compared to unlabeled compounds.

[0100] In embodiment (1), the present invention provides a compound represented by formula (I):

[0101]

[0102] Or its pharmaceutically acceptable salt, wherein,

[0103] R 1 Selected from C 1-10 Alkyl and C 3-10 Cycloalkyl, wherein the alkyl group and the cycloalkyl group are either unsubstituted or selected independently from R. X Substituents of the substituents;

[0104] Each R 2 Independently selected from halogens and methyl groups;

[0105] Each R X Selected independently from C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 Alkyl, heterocyclic, heterocyclic-C 1-4 Alkyl, aryl, aryl-C 1-4 Alkyl, heteroaryl, heteroaryl-C 1-4 Alkyl, halogen, CN, -NO2, -NR a R b -OR a -SR a -S(O) r R a -S(O)2OR a -OS(O)2R b -S(O) r NR a R b -P(O)R a R b -P(O)(OR) a (OR) b ), -(CR c R d ) t NR a R b 、-(CR c R d ) t OR b 、-(CR c R d ) t SR b 、-(CR c R d ) t S(O) r R b 、-(CR c R d )t P(O)R a R b 、-(CR c R d ) t P(O)(OR a )(OR b )、-(CR c R d ) t CO2R b 、-(CR c R d ) t C(O)NR a R b 、-(CR c R d ) t NR a C(O)R b 、-(CR c R d ) t NR a CO2R b 、-(CR c R d ) t OC(O)NR a R b 、-(CR c R d ) t NR a C(O)NR a R b 、-(CR c R d ) t NR a SO2NR a R b 、-NR a (CR c R d ) t NR a R b 、-O(CR c R d ) t NR a R b 、-S(CR c R d ) t NR a R b 、-S(O) r (CR c R d ) t NRa R b -C(O)R a -C(O)(CR) c R d ) t OR b -C(O)(CR) c R d ) t NR a R b -C(O)(CR) c R d ) t SR b -C(O)(CR) c R d ) t S(O) r R b -CO2R b -CO2(CR) c R d ) t C(O)NR a R b -OC(O)R a -C(O)NR a R b -NR a C(O)R b -OC(O)NR a R b -NR a C(O)OR b -NR a C(O)NR a R b -NR a S(O) r R b -CR a (=N-OR b -C (=NR) e )R a -C(=NR) e )NR a R b -NR a C(=NR e )NR a R b -CHF2, -CF3, -OCHF2, and -OCF3, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is unsubstituted or is selected independently from at least one hydroxyl, C, amino, halogen, C 1-10 Alkyl, C 2-10 alkenyl, C2-10 alkynyl group, C 3-10 cycloalkyl, C 1-10 Alkoxy, C 3-10 Cycloalkoxy, C 1-10 Alkylthio, C 3-10 Cycloalkylthio, C 1-10 Alkylamino, C 3-10 Cycloalkanes and di(C) 1-10 Substitution of alkyl)amino groups;

[0106] Each R a and R b Independently selected from hydrogen and C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 Alkyl, C 1-10 Alkoxy, C 3-10 Cycloalkoxy, C 1-10 Alkylthio, C 3-10 Cycloalkylthio, C 1-10 Alkylamino, C 3-10 Cycloalkylamino, di(C 1-10 Alkyl)amino, heterocyclic, heterocyclic-C 1-4 Alkyl, aryl, aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 Alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclic, aryl, and heteroaryl is unsubstituted or is selected independently from at least one halogen, C1, C2, C3, C4, C5, C6, C6, C7 ... 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 Cycloalkyl, hydroxyl, C 1-10 Alkoxy, C 3-10 Cycloalkoxy, C 1-10 Alkylthio, C 3-10 Cycloalkylthio, amino, C 1-10 Alkylamino, C 3-10 Cycloalkanes and di(C) 1-10 Substitution of alkyl)amino groups;

[0107] or R a and R b Together with the single or multiple atoms attached to them, they form a 4-12 membered heterocycle containing 0, 1, or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen, and phosphorus. The ring may optionally be composed of 1 or 2 heteroatoms independently selected from halogens, CN, C, and C. 1-10 Alkyl, C 2-10 alkenyl, C2-10 alkynyl group, C 3-10 Cycloalkyl, hydroxyl, C 1-10 Alkoxy, C 3-10 Cycloalkoxy, C 1-10 Alkylthio, C 3-10 Cycloalkylthio, amino, C 1-10 Alkylamino, C 3-10 Cycloalkanes and di(C) 1-10 Substitution of alkyl)amino groups;

[0108] Each R c and R d Independently selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 Alkyl, C 1-10 Alkoxy, C 3-10 Cycloalkoxy, C 1-10 Alkylthio, C 3-10 Cycloalkylthio, C 1-10 Alkylamino, C 3-10 Cycloalkylamino, di(C 1-10 Alkyl)amino, heterocyclic, heterocyclic-C 1-4 Alkyl, aryl, aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 Alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclic, aryl, and heteroaryl is unsubstituted or is selected independently from at least one halogen, C1, C2, C3, C4, C5, C6, C6, C7 ... 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 Cycloalkyl, hydroxyl, C 1-10 Alkoxy, C 3-10 Cycloalkoxy, C 1-10 Alkylthio, C 3-10 Cycloalkylthio, amino, C 1-10 Alkylamino, C 3-10 Cycloalkanes and di(C) 1-10 Substitution of alkyl)amino groups;

[0109] or R c and R d Together with the single or multiple carbon atoms attached to them, they form a 3-12 membered ring containing 0, 1, or 2 heteroatoms independently selected from oxygen, sulfur, and nitrogen. This ring may optionally be surrounded by 1 or 2 heteroatoms independently selected from halogens, CN, C, and C. 1-10 Alkyl, C 2-10alkenyl, C 2-10 alkynyl group, C 3-10 Cycloalkyl, hydroxyl, C 1-10 Alkoxy, C 3-10 Cycloalkoxy, C 1-10 Alkylthio, C 3-10 Cycloalkylthio, amino, C 1-10 Alkylamino, C 3-10 Cycloalkanes and di(C) 1-10 Substitution of alkyl)amino groups;

[0110] Each R e Independently selected from hydrogen, CN, NO2, C 1-10 Alkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 Alkyl, C 1-10 Alkoxy, C 3-10 Cycloalkoxy, -C(O)C 1-4 Alkyl, -C(O)C 3-10 Cycloalkyl, -C(O)OC 1-4 Alkyl, -C(O)OC 3-10 Cycloalkyl, -C(O)N(C 1-4 Alkyl)2、-C(O)N(C 3-10 cycloalkyl)2、-S(O)2C 1-4 Alkyl group, -S(O)2C 3-10 Cycloalkyl, -S(O)2N(C 1-4 alkyl)2 and -S(O)2N(C 3-10 cycloalkyl)2;

[0111] m is selected from 0, 1, 2, 3, 4, and 5;

[0112] Each r is independently selected from 0, 1, and 2;

[0113] Each t is independently selected from 0, 1, 2, 3, and 4.

[0114] In another embodiment (2), the present invention provides the compound of embodiment (1) or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from -CD3, methyl, ethyl, isopropyl, and cyclopropyl, wherein methyl, ethyl, isopropyl, and cyclopropyl are either unsubstituted or substituted with at least one, and are independently selected from R X The substituent is replaced. In another embodiment, R is... 1 Selected from methyl, ethyl, isopropyl, and cyclopropyl, wherein methyl, ethyl, isopropyl, and cyclopropyl are either unsubstituted or substituted with at least one, and are independently selected from R. X Substituents are substituted.

[0115] In another embodiment (3), the present invention provides the compound of embodiment (2) or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from -CD3, methyl, ethyl, isopropyl, and cyclopropyl. In another embodiment, R 1 Selected from methyl, ethyl, isopropyl and cyclopropyl.

[0116] In another embodiment (4), the present invention provides the compound of embodiment (2) or a pharmaceutically acceptable salt thereof, wherein each R X Independently selected from halogens, CN, -NO2, -NR a R b -OR a -SR a -S(O) r R a -S(O)2OR a -OS(O)2R b -S(O) r NR a R b 、-(CR c R d ) t NR a R b 、-(CR c R d ) t OR b 、-(CR c R d ) t SR b 、-(CR c R d ) t S(O) r R b 、-(CR c R d ) t CO2R b -C(O)R a -C(O)(CR) c R d ) t SR b -CO2R b -OC(O)R a -C(O)NR a R b -NR a C(O)R b -OC(O)NR a R b -NR a C(O)ORb -NR a S(O) r R b -CHF2, -CF3, -OCHF2 and -OCF3.

[0117] In another embodiment (5), the present invention provides the compound of embodiment (4) or a pharmaceutically acceptable salt thereof, wherein each R X It is independently selected from halogens, CN, -NO2, -NH2, -OH, CHF2, -CF3, -OCHF2 and -OCF3.

[0118] In another embodiment (6), the present invention provides a compound of any one of embodiments (1)-(5) or a pharmaceutically acceptable salt thereof, wherein m is selected from 0, 1, 2, 3 and 4.

[0119] In another embodiment (7), the present invention provides the compound of embodiment (6) or a pharmaceutically acceptable salt thereof, wherein m is selected from 0, 1 and 2.

[0120] In another embodiment (8), the present invention provides a compound of any one of embodiments (1)-(7) or a pharmaceutically acceptable salt thereof, wherein each R 2 It is independently selected from F, Cl, Br and methyl.

[0121] In another embodiment (9), the present invention provides the compound of embodiment (8) or a pharmaceutically acceptable salt thereof, wherein each R 2 It is independently selected from F, Cl and methyl.

[0122] In another embodiment (10), the present invention provides the compound of embodiment (9) or a pharmaceutically acceptable salt thereof, wherein R 2 It is F.

[0123] In another embodiment (11), the present invention provides a compound of any one of embodiments (1)-(9) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) Some of the structures are selected from phenyl, In another implementation, wherein formula (I) Some of the structures are selected from phenyl,

[0124] In another embodiment (12), the present invention provides the compound of embodiment (11) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) Some of the structures are selected from phenyl,

[0125] In another embodiment (13), the compound provided by the present invention is selected from:

[0126]

[0127]

[0128] And its pharmaceutically acceptable salts.

[0129] In another embodiment (14), the present invention provides a pharmaceutical composition comprising a compound of any one of embodiments (1)-(13) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.

[0130] In another embodiment (15), the present invention provides a method for treating, improving or preventing conditions that inhibit BTK response, comprising administering to an individual in need an effective amount of any one of the compounds of embodiments (1)-(13) or a pharmaceutically acceptable salt thereof, or at least one of their pharmaceutical compositions, optionally in combination with a second therapeutic agent.

[0131] In another embodiment (16), the present invention provides the use of any compound of embodiments (1)-(13) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating diseases of abnormal cell proliferation.

[0132] In another embodiment (17), the present invention provides the compound of embodiment (16) or a pharmaceutically acceptable salt thereof, wherein the cell proliferation disorder is a B cell proliferation disorder.

[0133] In another embodiment (18), the present invention provides the compound of embodiment (17) or a pharmaceutically acceptable salt thereof, wherein B-cell proliferative disorders include, but are not limited to, B-cell malignancies, B-cell chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, multiple sclerosis, small lymphocytic lymphoma, mantle cell lymphoma, B-cell non-Hodgkin lymphoma, activated B-cell-like diffuse large B-cell lymphoma, multiple myeloma, diffuse large B-cell lymphoma, follicular lymphoma, primary exudative lymphoma, Burkitt lymphoma / leukemia, lymphomatoid granulomatosis, and plasmacytoma.

[0134] In another aspect, the present invention provides a kit comprising the compounds disclosed herein or pharmaceutically acceptable salts thereof; and a specification including one or more of the following information: the disease state to which the ingredient is applied, storage information of the ingredient, dosage information, and instructions on how to use the ingredient. In a particular variant, the kit comprises the compound in multiple dosage forms.

[0135] In another aspect, the present invention provides articles comprising the compounds disclosed herein or pharmaceutically acceptable salts thereof; and packaging materials. In one variation, the packaging material comprises a container. In a particular variation, the container comprises a label indicating one or more of the following: the disease state to which the compound is applied, storage information, dosage information, and / or instructions on how to use the compound. In another variation, the articles comprise compounds in multiple dosage forms.

[0136] In another aspect, the present invention provides a treatment method comprising administering to an individual a compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0137] In another aspect, the present invention provides a method for inhibiting BTK by contacting a compound disclosed herein or a pharmaceutically acceptable salt thereof with BTK.

[0138] In another aspect, the present invention provides a method for inhibiting BTK, comprising bringing the disclosed compound or a pharmaceutically acceptable salt thereof into an individual to inhibit BTK activity in vivo.

[0139] In another aspect, the present invention provides a method for inhibiting BTK, comprising administering a first compound to an individual, the compound being converted in vivo into a second compound, wherein the second compound inhibits BTK activity in vivo, and the second compound is a compound and a variant thereof from any of the above embodiments.

[0140] In another aspect, the present invention provides a method for treating a disease state in which BTK activity causes the pathology and / or symptoms of the disease state, the method comprising bringing into an individual a therapeutically effective amount of the disclosed compound or a pharmaceutically acceptable salt thereof.

[0141] In another aspect, the present invention provides a method for treating a disease state in which BTK activity causes the pathology and / or symptoms of the disease state, the method comprising administering a first compound to an individual, the first compound being converted in vivo into a second compound, wherein the second compound inhibits BTK activity in vivo. It is noteworthy that the compound described in the present invention can be a pre-conversion or post-conversion compound.

[0142] In each of the above variations, the disease state is selected from: cancerous proliferative diseases (e.g., brain, lung, squamous cell, bladder, stomach, pancreas, breast, head, neck, renal region, kidney, ovary, prostate, colorectal, epidermal, esophageal, testicular, gynecological, or thyroid cancer); non-cancerous proliferative diseases (e.g., benign skin hyperplasia (such as psoriasis), restenosis, and benign prostatic hyperplasia (BPH)); pancreatitis; kidney disease; pain; prevention of blastocyst implantation; treatment of diseases related to angiogenesis or vascularization (e.g., tumor angiogenesis, acute and chronic inflammatory diseases such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema, and scleroderma). Diabetes mellitus, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma, and ovarian cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, colon cancer, and epidermoid carcinoma; asthma; neutrophil chemotaxis (e.g., reperfusion injury from myocardial infarction and stroke, and inflammatory arthritis); septic shock; T-cell-mediated diseases in which immunosuppression is valuable (e.g., prevention of organ transplant rejection, graft-versus-host disease, lupus, multiple sclerosis, and rheumatoid arthritis); atherosclerosis; inhibition of keratinocytes responding to a mixture of growth factors; chronic obstructive pulmonary disease (COPD) and other diseases.

[0143] On the other hand, the present invention provides a method for treating a disease state in which BTK gene mutations cause the pathology and / or symptoms of the disease state, such as melanoma, lung cancer, colon cancer and other types of tumors.

[0144] In another aspect, the present invention relates to the use of compounds and variants of any of the above embodiments as pharmaceuticals. In yet another aspect, the present invention relates to the use of compounds and variants of any of the above embodiments for the preparation of BTK inhibitory drugs.

[0145] In another aspect, the present invention relates to the use of compounds and variants of any of the above embodiments for the preparation of medicaments for treating disease states of pathology and / or symptoms caused by BTK activity.

[0146] Dosage and pharmaceutical composition

[0147] Generally, the compounds described in this invention will be administered in therapeutically effective amounts, alone or in combination with one or more therapeutic agents, via any common and acceptable method known in the art. Therapeutically effective amounts can vary widely depending on the severity of the subject's disease, age, and relative health condition, the efficacy of the compound used, and other factors known in the art. For example, for the treatment of neoplastic diseases and immune system diseases, the required dose will vary depending on the administration regimen, the specific condition to be treated, and the desired effect.

[0148] Generally, satisfactory results are achieved with daily doses ranging from 0.001 to 100 mg / kg body weight, specifically from about 0.03 to 2.5 mg / kg body weight. Daily doses for larger mammals, such as humans, can range from about 0.5 mg to about 2000 mg, or more specifically, from 0.5 mg to 1000 mg, administered in convenient forms, such as in fractions up to four times daily or in a sustained-release form. Suitable oral doses contain about 1 to 50 mg of the active ingredient per unit dose.

[0149] The compounds of the present invention can be administered in the form of pharmaceutical compositions via any conventional route; for example, enterically, orally, in tablet or capsule form, parenterally, in injectable solutions or suspensions; or topically, in the form of lotions, gels, ointments or creams, or in the form of nasal or suppositories.

[0150] Pharmaceutical compositions comprising a compound of the present invention in the form of a free base or pharmaceutically acceptable salt, and at least one pharmaceutically acceptable carrier or diluent, can be manufactured in a conventional manner via mixing, granulation, coating, dissolving, or freeze-drying processes. For example, a pharmaceutical composition comprising a compound of the present invention combined with at least one pharmaceutically acceptable carrier or diluent can be prepared in a conventional manner by mixing with a pharmaceutically acceptable carrier or diluent. Unit-dose formulations for oral administration comprise, for example, from about 0.1 mg to about 500 mg of the active substance.

[0151] In one embodiment, the pharmaceutical composition is a solution of the active ingredient, including a suspension or dispersion, such as an isotropic aqueous solution. In the case of a lyophilized composition containing only the active ingredient or mixed with a carrier such as mannitol, the dispersion or suspension may be prepared prior to use. The pharmaceutical composition may be sterilized and / or contain adjuvants such as preservatives, stabilizers, wetting agents or emulsifiers, solubilizers, salts and / or buffers that regulate osmotic pressure. Suitable preservatives include, but are not limited to, antioxidants such as ascorbic acid, and antimicrobial agents such as sorbic acid or benzoic acid. The solution or suspension may also contain thickeners, including but not limited to sodium carboxymethyl cellulose, carboxymethyl cellulose, dextran, polyvinylpyrrolidone, gelatin, or solubilizers such as Tween 80 (polyoxyethylene (20) sorbitan monooleate).

[0152] The suspension in oil may contain vegetable oil, synthetic or semi-synthetic oil as the oily component, often for injection purposes. Examples include liquid fatty acid esters containing long-chain fatty acids having 8 to 22 carbon atoms, or in some embodiments, 12 to 22 carbon atoms, as the acid component. Suitable liquid fatty acid esters include, but are not limited to, lauric acid, tridecanoic acid, myristic acid, pentadecanoic acid, palmitic acid, heptadecanoic acid, stearic acid, arachidic acid, benzyl acid, or corresponding unsaturated acids such as oleic acid, transoleic acid, erucic acid, brassinolic acid, and linoleic acid, and may contain antioxidants such as vitamin E, 3-carotene, or 3,5-di-tert-butyl-hydroxytoluene if desired. The alcohol component of these fatty acid esters may have six carbon atoms and may be monovalent or polyvalent, such as mono-, di-, or trivalent alcohols. Suitable alcohol components include, but are not limited to, methanol, ethanol, propanol, butanol, or pentanol or their isomers, ethylene glycol, and glycerol.

[0153] Other suitable fatty acid esters include, but are not limited to, ethyl oleate, isopropyl myristate, and isopropyl palmitate. M2375 (polyoxyethylene glycerin), M1944CS (unsaturated polyethylene glycol-modified glycerol esters prepared by alcoholysis of almond oil, containing glycerol esters and polyethylene glycol esters), LABRASOL TM (Saturated polyethylene glycol-modified glycerol esters prepared by alcoholysis of TCM, comprising glycerol esters and polyethylene glycol esters; both available from GaKefosse, France), and / or 812 (a saturated fatty acid triglyceride with a chain length of C8 to C12 from Hüls AG, Germany), and vegetable oils such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil, or peanut oil.

[0154] Pharmaceutical compositions for oral administration can be prepared, for example, by mixing the active ingredient with one or more solid carriers, granulating the resulting mixture if desired, and processing the mixture or granules by adding additional excipients to form tablets or tablet cores.

[0155] Suitable carriers include, but are not limited to, fillers such as sugars, such as lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, such as tricalcium phosphate or dicalcium phosphate, and binders such as starches, such as corn, wheat, rice or potato starch, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, and / or, if desired, disintegrants such as the aforementioned starches, carboxymethyl starch, croscarmellose, alginate or its salts, such as sodium alginate. Additional excipients include flow conditioners and lubricants such as silica, talc, stearic acid or its salts, such as magnesium stearate or calcium stearate, and / or polyethylene glycol or its derivatives.

[0156] Suitable, optional enteric coatings can be provided for tablet cores by using, in particular, concentrated sugar solutions, which may include gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol, and / or titanium dioxide, or coating solutions dissolved in suitable organic solvents or solvent mixtures; or, for enteric coatings, solutions of suitable cellulose formulations, such as cellulose acetate phthalate or hydroxypropyl methylcellulose phthalate solutions. Dyes or pigments may be added to the tablets or tablet coatings, for example, for identification purposes or to indicate different dosages of the active ingredient.

[0157] Pharmaceutical compositions for oral administration may also include hard capsules, including gelatin or soft-sealable capsules containing gelatin and plasticizers such as glycerin or sorbitol. Hard capsules may contain the active ingredient in particulate form, for example, mixed with fillers such as corn starch, binders and / or flow aids such as talc or magnesium stearate, and optionally, stabilizers. In soft capsules, the active ingredient may be dissolved or suspended in a suitable liquid excipient such as fatty oil, paraffin oil, or liquid polyethylene glycol or fatty acid esters of ethylene glycol or propylene glycol, and stabilizers and detergents, such as fatty acid esters of polyoxyethylene sorbitol, may also be added.

[0158] Pharmaceutical compositions suitable for rectal administration, such as suppositories, comprise a combination of an active ingredient and a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycol, or higher alkanols.

[0159] Pharmaceutical compositions suitable for parenteral administration may contain the active ingredient in a water-soluble form, such as a water-soluble salt or an aqueous injectable suspension containing a substance that increases viscosity, such as sodium carboxymethyl cellulose, an aqueous solution of sorbitol and / or dextran, and, if desired, a stabilizer. The active ingredient, optionally with excipients, may also be in a lyophilized form and can be prepared as a solution by adding a suitable solvent prior to parenteral administration. Solutions used, for example, for parenteral administration, can also be used as infusion solutions. Injectable formulations are typically prepared under aseptic conditions, filled into, for example, ampoules or vials, and sealed in a container.

[0160] The present invention also provides pharmaceutical combinations, such as a pillbox comprising a) a compound disclosed herein, which may be in free form or in a pharmaceutically acceptable salt form, and b) at least one adjuvant. The pillbox may include instructions for use.

[0161] combination therapy

[0162] The compounds or pharmaceutically acceptable salts described in this patent may be used alone or in combination with other therapeutic agents.

[0163] For example, the use of adjuvants can enhance the therapeutic effect of the compounds of this invention (e.g., the therapeutic benefit of using an adjuvant alone is minimal, but when used in combination with another drug, it can enhance the individual's therapeutic benefit), or, for example, the combination of the compounds of this invention with another equally effective therapeutic agent can enhance the individual's therapeutic benefit. For example, in the treatment of gout, using the compounds of this invention in combination with another drug for treating gout may enhance clinical benefit. Or, for example, if the adverse reaction of using the compounds of this invention is nausea, then an antinausea drug can be used in combination. Alternatively, combined therapies may include, but are not limited to, physical therapy, psychotherapy, radiation therapy, compression therapy of the affected area, rest, dietary improvements, etc. Regardless of the disease, symptom, or condition, the therapeutic benefit of the two therapies should have an additive or synergistic effect on the individual's therapeutic benefit.

[0164] When this patented compound is used in combination with other therapeutic agents, the route of administration of the pharmaceutical composition may be the same as that of the other drugs, or it may be different due to differences in physical and chemical properties. For example, oral administration of this patented compound can produce and maintain good blood drug levels, while another therapeutic agent may require intravenous administration. Therefore, this patented compound and another therapeutic agent may be administered simultaneously, sequentially, or separately. Example

[0165] There are various methods for synthesizing compounds of formula (I) or their pharmaceutically acceptable salts; the methods described in this example are representative. However, it should be noted that compounds of formula (I) or their pharmaceutically acceptable salts may also be obtained through other synthetic methods.

[0166] In a compound of formula (I), the bonding between atoms may result in the presence of specific stereoisomers (such as chiral centers). The synthesis of compounds of formula (I) or their pharmaceutically acceptable salts may produce mixtures of different isomers (enantiomers, diastereomers). Unless otherwise specified, the listed compounds include all possible stereoisomers.

[0167] Compounds of formula (I) can also be prepared as pharmaceutically acceptable acid addition salts, for example, by reacting the free base form of the compound of the present invention with a pharmaceutically acceptable inorganic or organic acid. Alternatively, a compound of formula (I) can be prepared as a pharmaceutically acceptable base addition salt by reacting it in its free acid form with a pharmaceutically acceptable inorganic or organic base. Suitable inorganic and organic acids and bases for preparing pharmaceutically acceptable salts of compounds of formula (I) have been described in the definition section of this application. Furthermore, salts of compounds of formula (I) can also be prepared by using salts of starting materials or intermediates.

[0168] The free acid or free base of the compound of formula (I) can be prepared by its corresponding base addition salt or acid addition salt. The acid addition salt form of the compound of formula (I) can be converted into the corresponding free base, for example by treatment with a suitable base (such as ammonium hydroxide solution, sodium hydroxide, etc.). The base addition salt form of the compound of formula (I) can be converted into the corresponding free acid, for example by treatment with a suitable acid (such as hydrochloric acid, etc.).

[0169] The N-oxide of a compound of formula (I) or a pharmaceutically acceptable salt thereof may be prepared by methods known in the art. For example, the N-oxide may be prepared by reacting the non-oxidized form of a compound of formula (I) with an oxidizing agent (such as trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, and m-chloroperbenzoic acid) in an inert organic solvent (such as a halogenated hydrocarbon such as dichloromethane) at 0–80 °C. Alternatively, the N-oxide of a compound of formula (I) may also be prepared from the N-oxide of a starting material.

[0170] The non-oxidized form of compound (I) can be prepared by reacting its N-oxide with a reducing agent (such as sulfur, sulfur dioxide, triphenylphosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, and phosphorus tribromide) in a corresponding inert organic solvent (such as acetonitrile, ethanol, and aqueous dioxane) at 0–80 °C.

[0171] Protected derivatives of the compound of formula (I) can be prepared by methods well known to those skilled in the art. For a detailed technical description of the addition and removal of protecting groups, see: TW Greene, Protecting Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, Inc. 1999.

[0172] The notation and common sense used in these methods, routes, and examples are consistent with current scientific literature, such as the Journal of the American Chemical Society or the Journal of Biochemistry. Unless otherwise stated, standard single-letter or three-letter abbreviations generally refer to L-type amino acid residues. Unless otherwise stated, all starting materials used were purchased from commercial suppliers and were not further purified before use. For example, the following abbreviations will be used in the examples and throughout the instructions: g (gram), mg (milligram), L (liter), mL (milliliter), μL (microliter), psi (pounds per square inch), M (molar), mM (millimole), iv (intravenous injection), Hz (hertz), MHz (megahertz), mol (molar), mmol (millimole), RT (ambient temperature), min (minute), h (hour), mp (melting point), TLC (thin-layer chromatography), Rt (retention time), RP (reversed phase), MeOH (methanol), i-PrOH (isopropanol), TEA (triethylamine), TFA (trifluoroacetic acid), TFAA (trifluoroacetic anhydride), THF (tetrahydrofuran), DMSO (dimethyl sulfoxide), EtOAc (ethyl acetate), DME (1,2-dimethoxyethane), DCM (dichloromethane), DCE (dichloroethane), DMF (N,N-dimethylformamide), DMPU (N,N'-dimethylpropenylurea), CDI (1 ,1-carbonyldiimidazole), IBCF (isobutyl chloroformate), HOAc (acetic acid), HOSu (N-hydroxysuccinimide), HOBT (1-hydroxybenzotriazole), Et2O (diethyl ether), EDCI (1-(3-dimethylaminopropyl)3-ethylcarbodiimide hydrochloride), BOC (tert-butyloxycarbonyl), FMOC (9-fluorenylmethoxycarbonyl), DCC (dicyclohexylcarbodiimide), CBZ (benzyloxycarbonyl), Ac (acetyl), atm (atmospheric pressure) ), TMSE (2-(trimethsilyl)ethyl), TMS (trimethsilyl), TIPS (triisopropylsilyl), TBS (tert-butyldimethsilyl), DMAP (4-dimethylaminopyridine), Me (methyl), OMe (methoxy), Et (ethyl), tBu (tert-butyl), HPLC (high performance liquid chromatography), BOP (bis(2-oxo-3-oxazolyl)phosphine chloride), TBAF (tetra-n-butylammonium fluoride), mCPBA (m-chloroperoxybenzoic acid).

[0173] Ether or Et2O refers to diethyl ether; salt water refers to a saturated aqueous solution of NaCl. Unless otherwise stated, all temperatures refer to °C (degrees Celsius), and all reactions are carried out in an inert atmosphere at room temperature.

[0174] 11H NMR spectra were recorded using a Varian Mercury Plus 400 NMR spectrometer. Chemical shifts are expressed in ppm. Coupling constants are expressed in Hertz (Hz). Apparent diversity was described using segmentation modes, defined as s (singleton), d (doublet), t (triplet), q (quartet), m (multiplet), and br (broad peak).

[0175] Low-resolution mass spectrometry (MS) and compound purity data were obtained from a Shimadzu LC / MS single quadrupole system equipped with an electrospray ionization detector (ESI), UV detectors (220 and 254 nm), and evaporative light scattering detector (ELSD). Thin-layer chromatography was performed using 0.25 mm Asahi Pogyi silica gel plates (60F-254), 5% phosphomolybdic acid in ethanol, ninhydrin or p-methoxybenzaldehyde solution, and observed under UV light. Rapid column chromatography was performed using silica gel (200-300 mesh, Qingdao Ocean Chemical Co., Ltd.).

[0176] Synthesis scheme

[0177] Compounds of Formula I or pharmaceutically acceptable salts thereof can be synthesized by various methods, some exemplary methods of which are provided below and in examples. Other synthetic methods can be readily devised by those skilled in the art based on the information disclosed herein.

[0178] In the reactions described below, it may be necessary to protect the active groups to prevent them from participating in other undesirable reactions. These groups include hydroxyl, amino, imine, thiol-containing, or carboxyl groups, which may be present in the final product. Commonly used protecting groups can be found in TW Greene and PGM Uts in "Protective Groups in Organic Chemistry," John Wiley and Sons, 1991.

[0179] The synthetic schemes for all compounds of this invention are illustrated by the following schemes and examples. The starting materials used are derived from commercially available products or can be prepared according to existing processes or the methods exemplified herein.

[0180] The intermediates listed in the following synthesis schemes were obtained from literature or synthesized using existing similar synthesis methods.

[0181] As an illustration of the preparation method of compound I, one synthetic method for compound I is shown in Scheme 1. The NH group in nitrogen-indole compound II-A (commercially available) is protected, and then fluorinated with N-fluorobis(benzenesulfonamide) to obtain fluorinated compound II-C. Difluorinated compound II-D can be prepared by directional ortho-metallization (DoM) as shown in Scheme 2 via II-C. The protecting group in II-D leaves, and then it undergoes a bromination reaction with NBS to convert II-D into bromide II, which is then combined with intermediate III to prepare IV under n-butyllithium (n-BuLi) conditions. The reaction of amine V with aryl fluoride IV under the action of a base (such as N,N-diisopropylethylamine (DIPEA)) yields the compound of formula I.

[0182]

[0183] Synthesis Scheme 1

[0184] As a further illustration of the preparation of intermediate V, one synthetic route for V is shown in Scheme 2. Commercially available VA is used as the starting material. Sulfonate VB can be prepared by methanesulfonation and amino protection. Primary amine VD can be prepared by reacting sulfonate VB with a reagent such as NaN3, followed by reduction with PPh3. Sulfonation of amine VD and the departure of the Boc group yield a compound of formula V.

[0185]

[0186] Synthesis Scheme 2

[0187] In some cases, the order of the above synthesis scheme can be adjusted to promote the reaction or avoid the formation of unwanted reaction products. The following embodiments are provided to enable a fuller understanding of the invention. These embodiments are merely examples and should not be construed as limiting the invention.

[0188] Intermediate A

[0189] (3R,6S)-6-(methylsulfonamide methyl)tetrahydro-2H-pyran-3-ammonium chloride (A)

[0190]

[0191] (3R,6S)-6-(((tert-butyldimethylsilyl) ) (Oxy)methyl)tetrahydro-2H-pyran-3-amine (A-1)

[0192] (3R,6S)-6-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-3-amine (A-1) was prepared according to the method described in patent WO2018 / 69863.

[0193] tert-butyl((3R,6S)-6-(((tert-butyldimethylsilyl) ) (Oxy)methyl)tetrahydro-2H-pyran-3-yl ) amino Formate (A-2)

[0194] TEA (3.10 g, 30.6 mmol) was added to a DCM (150 mL) solution of (3R,6S)-6-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-3-yl)amine (A-1) (5.00 g, 20.4 mmol) under ice bath conditions, followed by the dropwise addition of (Boc)₂O (5.10 g, 23.5 mmol). The resulting solution was stirred at RT for 18 h. The mixture was then washed with 2% citric acid (2×), H₂O, and saturated brine, dried over Na₂SO₄, and concentrated to obtain crude tert-butyl((3R,6S)-6-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-3-yl)carbamate (A-2), which could be directly used in the next step. MS-ESI (m / z): 346 [M+1] + .

[0195] tert-butyl ((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)carbamate (A-3)

[0196] A solution of TBAF (1.0 M in THF) (61.0 mL, 61.2 mmol) was added dropwise to a THF solution of tert-butyl((3R,6S)-6-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-3-yl)carbamate (A-2) (7.00 g, 20.4 mmol) at 0 °C and stirred at RT for 2.5 h. After concentration and dissolution in EtOAc, the solution was washed successively with H2O, 5% NaOH, 5% citric acid, and brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluting with 10–50% EtOAc in n-hexane to give the title compound tert-butyl((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)carbamate (A-3). MS-ESI (m / z): 232 [M+1] + .

[0197] ((2S,5R)-5-((tert-Butoxycarbonyl)amino)tetrahydro-2H-pyran-2-yl)methylmethanesulfonate (A-4)

[0198] TEA (9.90 g, 97.4 mmol) was added to a DCM (150 mL) solution of tert-butyl((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)carbamate (A-3) (15.0 g, 64.9 mmol) under ice bath conditions, followed by dropwise addition of MsCl (8.93 g, 77.9 mmol). The resulting solution was stirred at 0 °C for 1 h. The mixture was diluted with water and washed with 5% citric acid and saturated brine, dried over Na₂SO₄, and concentrated to obtain a crude product of ((2S,5R)-5-((tert-butyloxycarbonyl)amino)tetrahydro-2H-pyran-2-yl)methylmethanesulfonate (A-4), which could be directly used in the next step. MS-ESI (m / z): 310 [M+1]+ .

[0199] tert-butyl((3R,6S)-6-(azidomethyl)tetrahydro-2H-pyran-3-yl) ) Carbamate (A-5)

[0200] To a DMSO (150 mL) solution of ((2S,5R)-5-((tert-butyloxycarbonyl)amino)tetrahydro-2H-pyran-2-yl)methyl methanesulfonate (A-4) (19.1 g, 61.9 mmol), NaN3 (28.2 g, 433 mmol) was added and the mixture was stirred at 100 °C for 6 h. The mixture was cooled to RT, diluted with EtOAc, washed with H2O and saturated brine, dried over Na2SO4, and concentrated to obtain crude tert-butyl((3R,6S)-6-(azidomethyl)tetrahydro-2H-pyran-3-yl)carbamate (A-5), which could be used directly in the next step. MS-ESI (m / z): 257 [M+1] + .

[0201] tert-butyl ((3R,6S)-6-(aminomethyl)tetrahydro-2H-pyran-3-yl)carbamate (A-6)

[0202] PPh3 (48.2 g, 184 mmol) and H2O (11.0 g, 613 mmol) were added to a THF (150 mL) solution of tert-butyl((3R,6S)-6-(aminomethyl)tetrahydro-2H-pyran-3-yl)carbamate (A-5) (15.7 g, 61.3 mmol). The mixture was stirred at 45 °C for 6 h. After cooling to RT, the mixture was concentrated. The residue was extracted with HCl (0.5 M, 150 mL) and EtOAc (2×). The aqueous phase was adjusted to pH ≈ 8-9 with Na2CO3 and then extracted with DCM / MeOH (10:1, 3×). The solution was dried over Na2SO4 and concentrated to obtain crude tert-butyl((3R,6S)-6-(aminomethyl)tetrahydro-2H-pyran-3-yl)carbamate (A-6), which could be directly used in the next step. MS-ESI(m / z): 231[M+1] + .

[0203] tert-Butyl ((3R,6S)-6-(methylsulfonamidomethyl)tetrahydro-2H-pyran-3-yl)carbamate (A-7)

[0204] TEA (2.97 g, 29.6 mmol) was added to a DCM (100 mL) solution of tert-butyl((3R,6S)-6-(aminomethyl)tetrahydro-2H-pyran-3-yl)carbamate (A-6) (4.50 g, 19.6 mmol) in an ice bath, followed by the dropwise addition of MsCl (2.69 g, 23.5 mmol). The solution was stirred at 0 °C for 0.5 h. The mixture was diluted with water and washed with 5% citric acid and saturated brine, dried over Na₂SO₄, and concentrated. The residue was purified by silica gel column chromatography, eluting with 50–70% EtOAc in n-hexane to give the title compound tert-butyl((3R,6S)-6-(methylsulfonamidomethyl)tetrahydro-2H-pyran-3-yl)carbamate (A-7). MS-ESI (m / z): 309 [M+1] + .

[0205] (3R,6S)-6-(methylsulfonamide methyl)tetrahydro-2H-pyran-3-ammonium chloride (A)

[0206] The compound consisting of tert-butyl ((3R,6S)-6-(methylsulfonamidomethyl)tetrahydro-2H-pyran-3-yl)carbamate (A-7) (4.00 g, 12.9 mmol) and HCl (4.0 M in dioxane) (25 mL) was stirred in DCM (15 mL) for 2 h at RT. The mixture was concentrated to give a crude product of (3R,6S)-6-(methylsulfonamidomethyl)tetrahydro-2H-pyran-3-ammonium chloride (A) that can be used directly in the next step. MS-ESI (m / z): 209 [M+1] + .

[0207] Intermediate B

[0208] 4,5-Difluoro-1H-pyrrolo[2,3-b]pyridine (B)

[0209]

[0210] 4-Bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (B-1)

[0211] NaH (60% dispersed in mineral oil) (4.87 g, 122 mmol) was added to a THF (400 mL) solution of 4-bromo-1H-pyrrolo[2,3-b]pyridine (20.0 g, 102 mmol) in an ice bath and stirred at 0–5 °C for 0.5 h. Then, TIPSCl (23.1 g, 120 mmol) was added dropwise and stirred at RT for 0.5 h. The mixture was quenched with H₂O, extracted with EtOAc (2×), washed with H₂O and saturated brine, dried over Na₂SO₄ and concentrated. The residue was purified by silica gel column chromatography, eluting with n-hexane to give the title compound 4-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (B-1). MS-ESI (m / z): 353 / 355 (1:1) [M+1] + .

[0212] 4-Fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (B-2)

[0213] A solution of 4-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (B-1) (20.0 g, 56.7 mmol) in THF (300 mL) was added dropwise to n-BuLi (2.5 M in n-hexane, 45 mL, 113 mmol), and the mixture was stirred at this temperature for 0.5 h. Then, a solution of NFSI (21.4 g, 68.0 mmol) in THF (100 mL) was added dropwise, and the mixture was stirred at -78 °C for 1 h. The mixture was then quenched with sat.NH4Cl (aq), extracted with EtOAc (3×), washed with H2O and saturated brine, dried over Na2SO4, and concentrated to obtain crude 4-fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (B-2), which could be directly used in the next step. MS-ESI (m / z): 293 [M+1] + .

[0214] 4,5-Difluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (B-3)

[0215] A solution of 4-fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (B-2) (27.9 g, 95.5 mmol) in THF (360 mL) was added dropwise to s-BuLi (1.3 M in n-hexane, 162 mL, 210 mmol), and the mixture was stirred at this temperature for 0.5 h. Then, a solution of NFSI (75.2 g, 239 mmol) in THF (230 mL) was added dropwise, and the mixture was stirred at -78 °C for 1 h. The mixture was then quenched with sat.NH4Cl (aq), extracted with EtOAc (3×), washed with H2O and saturated brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography and eluted with n-hexane to give the title compound 4,5-difluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (B-3). MS-ESI(m / z): 311[M+1] + .

[0216] 4,5-Difluoro-1H-pyrrolo[2,3-b]pyridine (B)

[0217] 4,5-Difluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (B-3) (20.0 g, 64.5 mmol) and HCl (4.0 M in EtOAc) (66 mL) were stirred in DCM (134 mL) for 4 h at RT. The mixture was concentrated and quenched with sat. NaHCO3 (aq), extracted with EtOAc (3×), washed with H2O and saturated brine, dried over Na2SO4 and concentrated to obtain crude 4,5-difluoro-1H-pyrrolo[2,3-b]pyridine (B) which could be directly used in the next step. MS-ESI (m / z): 155 [M+1] + .

[0218] Intermediate C

[0219] Methyl 4-(2,6-difluorophenoxy)-2-fluorobenzoate (C)

[0220]

[0221] A compound consisting of methyl 2,4-difluorobenzoate (5.00 g, 29.1 mmol), 2,6-difluorophenol (4.53 g, 34.9 mmol), and Cs₂CO₃ (19 g, 858 mmol) was stirred in DMSO (80 mL) for 4 h at 55 °C. The mixture was cooled to RT, diluted with H₂O, and extracted with MTBE (3×). The mixture was washed with H₂O and saturated brine, dried over Na₂SO₄, and concentrated. The residue was purified by silica gel column chromatography, eluting with 0–1% EtOAc in n-hexane to give the title compound methyl 4-(2,6-difluorophenoxy)-2-fluorobenzoate (C). MS-ESI (m / z): 283 [M+1] + .

[0222] Example 1

[0223] N-(((2S,5R)-5-((3-(4-(2,6-difluorophenoxy)-2-fluorobenzoyl)-5-fluoro-1H-pyrrolo[2, [3-b]pyridin-4-yl)amino)tetrahydro-2H-pyran-2-yl)methyl)methanesulfonamide (1)

[0224]

[0225] 3-Bromo-4,5-difluoro-1H-pyrrolo[2,3-b]pyridine (1a)

[0226] NBS (5.37 g, 30.2 mmol) was added to a DMF (50 mL) solution of 4,5-difluoro-1H-pyrrolo[2,3-b]pyridine (B) (4.74 g, 30.8 mmol) at room temperature, and the mixture was stirred at room temperature for 0.5 h. The mixture was poured into water (150 mL), and the precipitated solid was collected by filtration, washed with water, and dried in air to give 3-bromo-4,5-difluoro-1H-pyrrolo[2,3-b]pyridine (1a). MS-ESI (m / z): 233 / 235 (1:1) [M+1] + .

[0227] (4,5-Difluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)(4-(2,6-difluorophenoxy)-2-fluorophenyl)methyl ketone (1b)

[0228] A solution of 3-bromo-4,5-difluoro-1H-pyrrolo[2,3-b]pyridine (1a) (500 mg, 2.15 mmol) in 12 mL of THF was added dropwise to n-BuLi (2.5 M in n-hexane, 2.0 mL, 4.94 mmol). The mixture was stirred at this temperature for 20 minutes, followed by dropwise addition of a solution of methyl 4-(2,6-difluorophenoxy)-2-fluorobenzoate (C) (728 mg, 2.58 mmol) in 5 mL of THF. The mixture was reacted at -78 °C for another 1 hour. At this temperature, 1 N HCl (15 mL) was slowly added to restore the reaction temperature to RT. The mixture was diluted with water (10 mL) and extracted with EtOAc (2×). The extract was washed with saturated brine and dried over Na2SO4. The solvent residue was removed by vacuum distillation and purified by silica gel column chromatography. Elution with 20-70% EtOAc in n-hexane gave (4,5-difluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)(4-(2,6-difluorophenoxy)-2-fluorophenyl)methyl ketone (1b). MS-ESI (m / z): 404 [M+1] + .

[0229] N-(((2S,5R)-5-((3-(4-(2,6-difluorophenoxy)-2-fluorobenzoyl)-5-fluoro-1H-pyrrolo[2, [3-b]pyridin-4-yl ) (1)Tetrahydro-2H-pyran-2-yl)methyl)methanesulfonamide

[0230] DIPEA (1.55 g, 12.0 mmol) was added to a solution of (3R,6S)-6-(methylsulfonamidomethyl)tetrahydro-2H-pyran-3-ammonium chloride (A) (586 mg, 2.40 mmol) and (4,5-difluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)(4-(2,6-difluorophenoxy)-2-fluorophenyl) methyl ketone (1b) (486 mg, 1.20 mmol) in n-BuOH (10 mL) and stirred at 115 °C for 16 h. After cooling and concentration, the mixture was diluted with water and extracted with EtOAc (2×). The extract was dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography and eluted with 1–3% MeOH in DCM to give the title compound N-(((2S,5R)-5-((3-(4-(2,6-difluorophenoxy)-2-fluorobenzoyl)-5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)tetrahydro-2H-pyran-2-yl)methyl)methanesulfonamide (1). MS-ESI (m / z): 593 [M+1] + .

[0231] Table 1 lists Examples 2-8, which were prepared using essentially the same method as Example 1, with commercially available starting materials or those prepared according to literature methods. Table 1 also provides the names and structures of Examples 2-8.

[0232] Table 1

[0233]

[0234]

[0235] Reference compound 1

[0236] (5-ethoxy-4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-1H-pyrrolo[2, [3-b]pyridin-3-yl)(2-fluoro-4-(2-fluorophenoxy)phenyl)methyl ketone (control compound 1)

[0237] Control compound 1 was prepared according to the method described in reference WO 2020239124.

[0238] kinase assay

[0239] The kinase activity of BTK(C481S) was determined at Reaction Biology Corporation. The BTK(C481S) reaction substrate pEY (poly[Glu:Tyr](4:1)) (Sigma, Cat.#P7244-250MG) was prepared in fresh reaction buffer (20 mM Hepes (pH 7.5), 10 mM MgCl2, 1 mM EGTA, 0.02% Brij35, 0.02 mg / ml BSA, 0.1 mM Na3VO4, 2 mM DTT, 1% DMSO). BTK(C481S) (SignalChem, Cat.#B10-12CH) was added to the substrate solution and gently mixed. The final concentrations of BTK(C481S) and the substrate were 6 nM and 0.2 mg / ml, respectively. The test compound was serially diluted 3-fold starting from 1 μM in 10 concentration / response modes.

[0240] The test compound dissolved in 100% DMSO was added to the kinase reaction system via an ultrasonic fluid handling system (Echo 550; nanoliter range) and incubated at room temperature for 20 minutes. 10 μM of […] 33 P]-ATP (ATP: Sigma, Cat.#A7699; [ 33 [P]-ATP: Hartmann Analytic (Cat.#SCF-301-12) was added to the reaction solution to initiate the reaction, and incubated at room temperature for 120 minutes. Fluorescence intensity was detected using a specific affinity assay. The percentage inhibition rate of the compound at each concentration was calculated by comparing the fluorescence intensity ratio with that of the control group (DMSO), and the IC50 of the compound was obtained using GraphPad Prism software. 50 value.

[0241] The selected compounds were determined using the biological methods described herein. The results are shown in Table 2:

[0242] Table 2

[0243] Example BTK(C481S)IC50(nM) 1 1.5 2 0.66

[0244] Cell proliferation assay

[0245] The inhibitory effect of the compound on the proliferation of DOHH2 (DSMZ catalog#:ACC47) cells was investigated to determine whether the compound could inhibit BTK activity in the cells. In this experiment, the inhibitory activity of the compound on BTK was detected by inhibiting the proliferation of DOHH2 cells. Cells were digested and seeded at a concentration of 5000 cells / well in 96-well plates, and incubated at 37°C with 5% CO2 for 4 h. Different concentrations (final concentrations of 10000, 3333.3, 1111.1, 270.4, 123.5, 41.2, 13.7, 4.6, and 1.5 nM) of the compound were added to three parallel wells of the 96-well cell culture plate, and incubated at 37°C with 5% CO2 for 120 h. MTS was added to each well at a concentration of 20 μL MTS per 100 μL of culture medium. After 2 h of incubation, 25 μL of 10% SDS was added to each well to terminate the reaction. The absorbance at 490 nm and 650 nm was measured using a microplate reader. Calculate IC using GraphPad Prism 5.0 50 .

[0246] The selected compounds were determined using the biological methods described herein. The results are shown in Table 3:

[0247] Table 3

[0248]

[0249] Pharmacokinetic experiments

[0250] This study aimed to investigate the pharmacokinetic properties of Examples 1 and 2 in male Sprague-Dawley (SD) rats (provided by Beijing Vital River Laboratory Animal Technology Co., Ltd.).

[0251] Animals were administered 5 mg / kg of the solutions from Examples 1 and 2 via single gavage. The solvent for the administration was 10% DMSO (Sigma, batch number: STBJ2353): 60% PEG400 (PanReac AppliChem, batch number: 1480132): 30% water, which could form a solution at a concentration of 2 mg / mL. Plasma samples were collected before administration and at 0.083, 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours after administration. The concentrations of the solutions from Examples 1 and 2 in the plasma samples were determined using LC / MS / MS (Liquid chromatography: Waters UPLC; Mass spectrometry: API4000). The results are shown in Table 4.

[0252] Table 4

[0253] Example 1 Example 2 route of administration Gavage Gavage Dosage (mg / kg) 5 5 <![CDATA[T 1 / 2 (h)]]> 3.69 3.08 <![CDATA[AUC last (h.ng / mL)]]> 4953 8338 F(％) 24.9 31

[0254] This study aimed to investigate the pharmacokinetic properties of Example 1 in male beagle dogs (provided by Beijing Mars Biotechnology Co., Ltd.).

[0255] Animals were administered solutions of Compound 1 (Example 1) and Reference Compound 1, respectively, via single gavage at concentrations of 3 mg / kg and 5 mg / kg, respectively. The solvent for the administration was 10% dimethyl sulfoxide (Sigma, batch number: STBJ2353): 60% polyethylene glycol 400 (PanReac AppliChem, batch number: 1480132): 30% water, which could form a solution at a concentration of 5 mg / mL. Plasma samples were collected before administration and at 0.083, 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours after administration. The concentrations of Compound 1 (Example 1) and Reference Compound 1 in the plasma samples were determined using LC / MS / MS (Liquid chromatography: Waters; Mass spectrometry: API4000). The results are shown in Table 5.

[0256] Table 5

[0257] Example 1 Reference compound 1 route of administration Gavage Gavage Dosage (mg / kg) 3 5 <![CDATA[T 1 / 2 (h)]]> 15.6 3.39 <![CDATA[AUC last (h.ng / mL)]]> 3824 200 F(％) 26.0 9.82

Claims

1. The compound represented by formula (I): (I) Or its pharmaceutically acceptable salt, wherein, R 1 Selected from C 1-10 Alkyl and C 3-10 cycloalkyl; Each R 2 Independently selected from halogens; m is selected from 1 and 2.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 It is selected from methyl, ethyl, isopropyl and cyclopropyl.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein each R 2 It is independently selected from F, Cl and Br.

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 It is F.

5. The compound of any one of claims 1-4 or a pharmaceutically acceptable salt thereof, wherein formula (I) Some of the structures are selected from phenyl, , , , , , , and .

6. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein formula (I) Some of the structures are selected from phenyl, and .

7. Compounds, selected from: 、 、 、 、 、 、 、 ， And its pharmaceutically acceptable salts.

8. A pharmaceutical composition comprising a compound of any one of claims 1-7 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

9. Use of any compound of claims 1-7 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating diseases of B-cell proliferation disorders.

10. The use of claim 9, wherein the B-cell proliferation disorder is a B-cell malignancy.

11. The use of claim 9, wherein the B-cell proliferation disorder is selected from B-cell prolymphocytic leukemia and B-cell non-Hodgkin lymphoma.

12. The use of claim 11, wherein the B-cell non-Hodgkin lymphoma is selected from lymphoplasmacytic lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, primary exudative lymphoma, Burkitt lymphoma, lymphomatoid granulomatosis, and B-cell chronic lymphocytic lymphoma.

13. The use of claim 12, wherein the diffuse large B-cell lymphoma is an activated B-cell-like diffuse large B-cell lymphoma.

14. The use of claim 12, wherein the B-cell chronic lymphocytic lymphoma is selected from chronic lymphocytic leukemia and small lymphocytic lymphoma.

15. The use of claim 9, wherein the B-cell proliferation disorder is selected from plasmacytoma and multiple myeloma.

16. The use of claim 9, wherein the B-cell proliferation disorder is Burkitt leukemia.

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