TWI694077B - Tetrahydropyranyl amino-pyrrolopyrimidinone and methods of use thereof - Google Patents

Abstract

The application relates to a compound of Formula (I): or a pharmaceutically acceptable salt thereof, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof, which modulates the activity of BTK, a pharmaceutical composition comprising the compound of Formula (I), and a method of treating or preventing a disease in which BTK plays a role.

Description

Tetrahydropiperanylamino-pyrrolopyrimidinone and method of using one

The present invention relates to Bruton's tyrosine kinase (BTK) (including mutant BTK) inhibitors for the treatment of diseases or disorders associated with BTK kinase, which include immune disorders, cancer, Cardiovascular diseases, viral infections, inflammation, metabolic/endocrine dysfunction and neurological disorders. In particular, the present invention relates to compounds and compositions that inhibit BTK, methods of treating diseases or conditions associated with BTK, and methods of synthesizing these compounds.

BTK is a member of the Tec family of tyrosine kinases and plays an important role in regulating early B-cell development and mature B-cell activation and survival (Hunter, Cell, 1987 50, 823-829). BTK triggers many cellular processes downstream of the functional downstream of diverse receptors (such as growth factors, B-cell antigens, chemokines, and innate immune receptors), including cell proliferation, survival, differentiation, activity, angiogenesis, and cytokine production And antigen presentation.

BTK-deficient mouse model shows BTK in allergic conditions and// Or play a role in autoimmune diseases and/or inflammatory diseases. For example, BTK deficiency in the standard preclinical murine model of systemic lupus erythematosus (SLE) has been shown to lead to significantly improved disease progression. In addition, BTK-deficient mice can be resistant to the development of collagen-induced arthritis and are less likely to acquire staphylococcus-induced arthritis. Due to the role of BTK in B-cell activation, BTK inhibitors can also be used as inhibitors of pathogenic activity mediated by B-cells, such as autoantibody production. BTK performance in osteoclasts, obese cells and single cells has been shown to be important for the function of these cells. For example, IgE-mediated obesity cell activation and reduced TNF-α production impaired by activated single cells have been associated with BTK defects in mice and humans. Therefore, BTK inhibition can be used to treat allergic disorders and/or autoimmune and/or inflammatory diseases such as: SLE, rheumatoid arthritis, multiple vasculitis, idiopathic thrombocytopenic purpura (ITP) , Myasthenia gravis, allergic rhinitis and asthma (DiPaolo et al. Nature Chem. Biol. 2011, 7(1): 41-50; Liu et al. Jour. Pharmacol. and Exp. Ther. 2011, 338 (1 ): 154-163).

Moreover, the role of BTK in apoptosis demonstrates the inhibitory effect of BTK activity on the treatment of cancer, B-cell lymphoma, leukemia and other hematological malignancies. In addition, the role of BTK in the function of osteoclasts is known, making inhibition of BTK activity useful in the treatment of bone disorders, such as osteoporosis.

BTK inhibition with small molecule inhibitors therefore has the treatment of immune disorders, cancer, cardiovascular diseases, viral infections, inflammation, metabolism/ Potential for endocrine dysfunction and neurological disorders. Therefore, there is still considerable demand for BTK effective small molecule inhibitors.

或其醫藥上可接受之鹽、互變異構物、前藥、溶劑合物、代謝物、多晶形物、類似物或衍生物。如本文所使用的用語〝式(I)化合物〞及〝化合物(I)〞係指相同的化合物且可交換使用。 The first aspect of the present application relates to the compound of formula (I):

Or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof. The terms "compound of formula (I)" and "compound (I)" as used herein refer to the same compound and are used interchangeably.

Another aspect of the present application relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, or the like Or derivatives and pharmaceutically acceptable diluents, excipients or carriers.

Another aspect of this application relates to a method of treating BTK-mediated disorders. The method comprises administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog, or derivative thereof to treatment in need Patients with diseases or disorders associated with BTK kinase regulation.

Another aspect of this application relates to a method of treating BTK-mediated disorders. The method includes administering a therapeutically effective amount of a pharmaceutical composition Patients in need of treatment for diseases or conditions associated with BTK kinase regulation, the composition comprises a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, and more Crystals, analogues or derivatives and pharmaceutically acceptable diluents, excipients or carriers.

Another aspect of this application relates to a method of treating cell proliferative disorders. The method comprises administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog, or derivative thereof Of patients.

Another aspect of this application relates to a method of treating cell proliferative disorders. The method comprises administering a therapeutically effective amount of a pharmaceutical composition to a patient in need thereof, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolism Substances, polymorphs, analogs or derivatives and pharmaceutically acceptable diluents, excipients or carriers.

Another aspect of this application relates to methods of treating cancer. The method comprises administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog, or derivative thereof Of patients.

Another aspect of this application relates to methods of treating cancer. The method comprises administering a therapeutically effective amount of a pharmaceutical composition to a patient in need thereof, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolism Substances, polymorphs, analogs or derivatives and pharmaceutically acceptable diluents, excipients or carriers.

Another aspect of this application relates to a method of regulating (eg, inhibiting) BTK. The method comprises administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog, or derivative thereof Of patients.

Another aspect of the present application relates to regulating (eg, inhibiting) BTK. The method comprises administering a therapeutically effective amount of a pharmaceutical composition to a patient in need thereof, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolism Substances, polymorphs, analogs or derivatives and pharmaceutically acceptable diluents, excipients or carriers.

Another aspect of the present application relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof in a method for treating BTK-mediated disorders, cell proliferative disorders, or cancer, or for modulating (eg, inhibiting) BTK , Tautomers, prodrugs, solvates, metabolites, polymorphs, analogs or derivatives. The compound of formula (I) or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof is administered to a patient in need thereof in a therapeutically effective amount .

Another aspect of the present application relates to a pharmaceutical composition in a method for treating a BTK-mediated disorder, cell proliferative disorder, or cancer, or modulating (eg, inhibiting) BTK, the composition comprising a compound of formula (I) Or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog, or derivative thereof, and a pharmaceutically acceptable diluent, excipient, or carrier. The composition is administered to a patient in need thereof in a therapeutically effective amount.

Another aspect of this application relates to the manufacture of compounds of formula (I) or pharmaceutically acceptable salts, tautomers, prodrugs, solvates, metabolites, polymorphs, analogs or derivatives thereof Use of agents to treat BTK-mediated disorders, cell proliferative disorders, or cancer, or to modulate (eg, inhibit) BTK. Administering a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog, or derivative thereof to a patient in need thereof in a therapeutically effective amount .

Another aspect of the present application relates to the use of a pharmaceutical composition to treat a BTK-mediated disorder, a cell proliferative disorder or cancer, or an agent that modulates (eg, inhibits) BTK, the composition comprising formula (I) Compounds or pharmaceutically acceptable salts, tautomers, prodrugs, solvates, metabolites, polymorphs, analogs or derivatives thereof, and pharmaceutically acceptable diluents, excipients or carriers. The composition is administered to a patient in need thereof in a therapeutically effective amount.

The present application further provides methods for treating diseases or disorders associated with BTK kinase regulation, including but not limited to immune disorders, cancer, cardiovascular diseases, viral infections, inflammation, metabolic/endocrine dysfunction, and nerves Sexual disorders, the method comprises administering a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog, or derivative thereof A patient suffering from at least one of a disease or condition.

The present application provides BTK inhibitors, which are therapeutic agents for treating diseases such as immune disorders, cancer, cardiovascular diseases, viral infections, inflammation, metabolic/endocrine dysfunction, neurological disorders and BTK kinase regulates other diseases associated with it.

The present application further provides compounds and compositions with improved efficacy and safety profile relative to known BTK inhibitors. The application of the present invention also provides a novel mechanism of action towards BTK kinase to treat various types of diseases including immune disorders, cancer, cardiovascular diseases, viral infections, inflammation, metabolic/endocrine dysfunction and neurological disorders . The present application finally provides a medical profession with a novel pharmacological strategy for treating diseases and disorders associated with BTK kinase.

Detailed description

The present application relates to compounds and compositions capable of modulating the activity of Bruton's tyrosine kinase (BTK). This application is characterized by a method of treating, preventing or ameliorating a disease or condition in which BTK plays a role by applying a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, Prodrugs, solvates, metabolites, polymorphs, analogs or derivatives are administered to patients in need thereof. The method of the present application can be used to treat various BTK-mediated diseases and conditions by inhibiting BTK kinase activity. Inhibition of BTK provides treatment, prevention, or improvement of diseases including, but not limited to, immune disorders, cancer, cardiovascular diseases, viral infections, inflammation, metabolic/endocrine dysfunction, and neurological disorders.

及其醫藥上可接受之鹽、互變異構物、前藥、溶劑合物、代謝物、多晶形物、類似物或衍生物。 In the first aspect of the present application, it illustrates the compound of formula (I):

And pharmaceutically acceptable salts, tautomers, prodrugs, solvates, metabolites, polymorphs, analogs or derivatives thereof.

In one embodiment, the compound of formula (I) is a pharmaceutically acceptable salt. In another embodiment, the compound of formula (I) is a hydrate. In yet another embodiment, the compound of formula (I) is a solvate.

The details of this application are described in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the implementation or testing of the present application, exemplified methods and materials will now be described. Other features, objectives and advantages of this application will be apparent from the content of the invention and the scope of patent application. In the description and the appended patent applications, the singular form also includes the plural, unless otherwise clearly stated in the context. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the technical field of the present application. All patents and publications cited in this specification are incorporated by reference in their entirety.

definition

The articles "a" and "an" used in this application refer to one or more than one (ie, at least one) grammatical object of the article. An "an element" illustrated by example means a Elements or more than one element.

The term "and/or" used in this application means "and" or "or" unless otherwise indicated.

The present application also includes a pharmaceutical composition comprising an effective amount of a compound of formula (I) and a pharmaceutically acceptable carrier.

The term "vehicle" as used in this application includes carriers, excipients and diluents involved in the transport or delivery of medicaments from one organ or part of the body of an individual to another organ or part of the body, and means materials, Compositions or vehicles, such as liquid or solid fillers, diluents, excipients, solvents or encapsulating materials.

Compounds of formula (I) may form salts, which are also within the scope of this application. It should be understood that the compounds of the chemical formula described herein include the salts mentioned and unless otherwise indicated.

Representative "pharmaceutically acceptable salts" include, for example, water-soluble and water-insoluble salts, such as acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate) ), benzenesulfonate, benzoate, bicarbonate, bisulfate, hydrogen tartrate, borate, bromide, butyrate, calcium salt, calcium ethylenediaminetetraacetate, camphorsulfonate, carbonic acid Salt, chloride, citrate, clavulariate, clavulariate, dihydrochloride, ethylenediaminetetraacetate, ethanedisulfonate, estolate, ethanesulfonate, fumarate Fumerate, fiunarate, glucoheptanoic acid, gluconic acid, glutamate, ethanol acetanilide, hexafluorophosphate, hexyl resorcinol salt ( hexylresorcinate), hydrabamine salt, hydrobromine Salt, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, magnesium salt, malate, maleate, almond Salt, methanesulfonate, methyl bromide, methyl nitrate, methyl sulfonate, pyrosilicate, naphthalene sulfonate, nitrate, N-methyl glucosamine ammonium salt, 3-hydroxyl -2-naphthoate, oleate, oxalate, palmitate, pamoate (1,1-methylene-bis-2-hydroxy-3-naphthoate, embolic acid (Einbonate)), pantothenate, phosphate/diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, inferior Acetate, succinate, sulfate, sulfosalicylate, suramate, tanninate, tartrate, tea chlorate (teoclate), tosylate, triethyl Iodide and valerate.

The compounds of the present application (for example, including pharmaceutically acceptable salts, tautomers, prodrugs, and polymorphic forms of the compounds) may exist in a solvated form or in a subsolvated form with other solvent molecules.

"Solvate" means a solvent addition form containing stoichiometric or non-stoichiometric solvents. Some compounds or salts have a tendency to trap a fixed molar ratio of solvent in a crystalline solid state, thus forming a solvate. If the solvent is water, the solvate formed is a hydrate; and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by combining one or more water molecules with a molecular substance, where water retains its molecular state of H ₂ O.

Compounds of the invention (including salts and solvents of such compounds) Compounds, esters, and prodrugs, as well as all stereoisomers (eg, geometric isomers, optical isomers, and the like) of prodrugs, such as geometric isomers, optical isomers, and the like, such as those Stereoisomers that exist on asymmetric carbons on the surface, including mirror isomer forms (which may even exist in the absence of asymmetric carbon), rotamer forms, atropisomers, and non-mirror isomers Structural forms, as well as positional isomers (such as 4-pyridyl and 3-pyridyl) are encompassed within the scope of this application. For example, if the compound of formula (I) incorporates a double bond or a fused ring, both cis- and trans-forms and mixtures are included within the scope of this application. Individual stereoisomers of the compounds of this application may, for example, be substantially free of other isomers, or may be blended into, for example, racemates, or blended with all other or other selected stereoisomers. The chiral center of the present application may have the S or R configuration as defined by the IUPAC 1974 recommendation. The use of the terms "salt", "solvate", "ester", "prodrug" and the like is intended to apply equally to the mirror image isomers, stereoisomers, rotamers, and tautomers of the compounds of the invention Salts, solvates, esters and prodrugs of conformers, positional isomers, racemates or prodrugs.

The term "isomer" refers to compounds that have the same composition and molecular weight, but differ in physical and/or chemical properties. The structural difference may be in construction (geometric isomers) or in the ability to rotate the plane of polarized light (stereoisomers). With regard to stereoisomers, compounds of formula (I) may have one or more asymmetric carbon atoms and may occur as racemates, racemic mixtures or individual mirror isomers or diastereomers.

In the present specification, the structural formula of the compound is For the sake of convenience, in some cases, it represents a specific isomer, but the present application includes all isomers, such as geometric isomers, optical isomers based on asymmetric carbon, stereoisomers, and mutual variation Structures and the like.

"Isomerism" means compounds that have the same molecular formula but different bonding order of atoms or the arrangement of atoms in space. Isomers with different arrangement of atoms in space are called "stereoisomers". Stereoisomers that are not mirror images of each other are called "non-mirror isomers", and stereoisomers that are mirror images that cannot overlap with each other are called "mirror isomers" or sometimes optical isomers. A mixture containing equal amounts of individual chiral isomers of opposite chirality is called a "racemic mixture".

The compounds of this application may contain asymmetric or chiral centers and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the present application and mixtures thereof (including racemic mixtures) form part of the present application. In addition, the present application includes all geometric isomers and positional isomers. For example, if the compound of the present application incorporates a double bond or a fused ring, both cis- and trans-forms and mixtures are included within the scope of the present application. Each compound disclosed herein includes all mirror isomers that conform to the general structure of the compound. The compound may have a racemic or enantiomerically pure form or any other form in terms of stereochemistry. The test result may reflect the data collected in racemic form, pure form of mirror image isomerism, or any other form in terms of stereochemistry.

The carbon atoms bonded to four different substituents are called "chiral centers".

"Chiral isomer" means a compound having at least one chiral center. Compounds with more than one chiral center may exist as individual diastereomers or as a mixture of diastereomers called "diameric mixtures". When a chiral center exists, the stereoisomer can be characterized by the absolute configuration (R or S) of the chiral center. Absolute configuration refers to the spatial arrangement of substituents attached to the chiral center. The substituents attached to the chiral center under consideration are ordered according to the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al. Angew. Chem. Inter. Edit. 1966, 5,385; errata 511; Cahn et al. Angew. Chem. 1966, 78, 413; Cahn and Ingold J. Chem. Soc. 1951 (London), 612; Cahn Et al. Experientia 1956, 12, 81; Cahn J. Chem. Educ. 1964, 41, 116).

"Geometric isomer" means a non-mirror isomer that exists due to impeded rotation around the double bond. According to the Kan-Yingao-Pulillo rule, these configurations are given in their names to indicate that the group is prefixed with cis and trans forms on the same or opposite side of the double bond of the molecule, or Z and E the difference.

In another embodiment of the present application, the compound of formula (I) is a mirror image isomer. In some embodiments, the compound is ( S )-mirror. In other embodiments, the compound is ( R )-mirror. In still other embodiments, the compound of formula (I) may be a (+) or (-) enantiomer. The compound may contain more than one stereocenter.

In another embodiment of the present application, formula (I) is combined The object is a non-mirror isomer. In some embodiments, the compound is an ipsilateral diastereomer. In other embodiments, the compound is an anti diastereomer.

Diastereomer mixtures can be separated into their individual diastereomers based on their physical and chemical differences by methods well known to those skilled in the art, such as by chromatography and/or fractionation Segment crystallization. The enantiomers can be separated by reacting the enantiomeric mixture with an appropriate optically active compound (for example, a chiral auxiliary such as chiral alcohol or Mosher's acetyl chloride) to convert it into non- Mirror-isomer mixtures, separation of non-mirrors and conversion (eg hydrolysis) of individual non-mirrors to corresponding pure mirror isomers. The mirror image isomers can also be separated using chiral HPLC columns.

It is also possible that the compounds of the present application can exist in different tautomeric forms, and all such forms are included within the scope of the present application. For example, all keto-enol and imine-enamine forms of the compound are also included in this application.

A "tautomer" is one of two or more structural isomers that exist in equilibrium and can be easily converted from one isomeric form to another. This conversion leads to the formal migration of hydrogen atoms and is accompanied by the transformation of adjacent conjugated double bonds. Tautomers exist as a mixture of tautomers in solution. In solid form, a tautomer is often dominant. In solutions where tautomerization is possible, tautomers reach chemical equilibrium. The exact ratio of tautomers depends on many factors, including temperature, solvent and pH. Mutual conversion by mutual isomerization The concept of metamers is called tautomerism.

Among the possible types of tautomerism, two types are often observed. In the keto-enol tautomerism, electrons and hydrogen atoms move simultaneously. The ring-chain tautomerism is caused by the reaction of one of the aldehyde groups (-CHO) in the sugar chain molecule with one of the hydroxyl groups (-OH) in the same molecule, giving it a ring as shown by glucose (ring formation Shape) form.

Common tautomeric pairs are: keto-enol, amide-nitrile, amide-iminoimide, amide-imide acid tautomerism in heterocycles (eg in nucleobases, Such as guanine, thymine and cytosine), amine-enamine and enamine-imine. The (pyrrolopyrimidinyl)methanone-(pyrrolopyrimidinyl)methanol tautomer pair is included in the present application:

The application of the present invention relates to a compound of formula (I) capable of inhibiting BTK or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof, which is useful For the treatment of diseases and disorders associated with BTK kinase regulation. The present application further relates to compounds of formula (I) or pharmaceutically acceptable salts, tautomers, prodrugs, solvates, metabolites, polymorphs, analogs or derivatives thereof, which are useful for inhibiting BTK. In some embodiments, BTK is wild Raw BTK. In other embodiments, BTK is a mutant BTK.

Another aspect of the present application relates to a compound of formula (I), wherein the compound inhibits the kinase activity of a mutant BTK, such as a drug resistance mutant BTK (eg, C481S mutation) that conceals a drug resistance mutation. In some embodiments, the patient or individual does not respond to the BTK inhibitor or relapses after treatment with the BTK inhibitor, which is due to a mutation in the BTK kinase that prevents target inhibition (eg, the C481S mutation). In one embodiment, the BTK mutation is a C481S mutation.

In some embodiments, the present application provides a compound of formula (I), wherein the compound is more effective at inhibiting BTK activity than one or more of the following known BTK inhibitors: including but not limited to ibrutinib (Ibrutinib), GDC-0834, RN486, CGI-560, CGI-1746, HM-71224, CC-292, ONO-4059, CNX-774 and LFM-A13. For example, the compound may be more effective in inhibiting BTK activity than ibrutinib, GDC-0834, RN486, CGI-560, CGI-1746, HM-71224, CC-292, ONO-4059, CNX-774, and/or LFM-A13 Approximately 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or approximately 100-fold potency (as measured by IC ₅₀ ).

In some embodiments, the present application provides a compound of formula (I), wherein the compound is more active than one or more of the following known BTK inhibitors in inhibiting BTK containing one or more mutations (eg, C481S) as described herein More potent: including but not limited to ibrutinib, GDC-0834, RN486, CGI-560, CGI-1746, HM-71224, CC-292, ONO-4059, CNX-774, and LFM-A13. For example, the compounds are comparable to ibrutinib, GDC-0834, RN486, CGI-560, CGI-1746, HM-71224, CC-292, ONO-4059 in the activity of inhibiting BTK containing one or more mutations as described herein , CNX-774, and/or LFM-A13 are at least about 2 times, 3 times, 5 times, 10 times, 25 times, 50 times, or about 100 times more potent (e.g., measured by IC ₅₀ ). The drug-resistant BTK mutant may have, without limitation, a drug-resistant mutation that includes the C481S mutation.

Inhibitor efficacy IC ₅₀ value can be measured. The compound under substantially similar conditions as measured has a lower IC ₅₀ value are more potent than the compound having a higher IC ₅₀ values of.

The compounds of the present application can be converted into N-oxides by treatment with oxidizing agents (such as 3-chloroperoxybenzoic acid (m-CPBA) and/or hydrogen peroxide) to supply other compounds of the present application . Therefore, when the price and structure allows, consider all of the display and claimed nitrogen-containing compound is to include compounds and the N- oxide derivatives as shown in (which is may be N → O or N ⁺ -O ^- show )both. In addition, in other cases, the nitrogen in the compounds of the present application can be converted to N-hydroxyl or N-alkoxy compounds. For example, N-hydroxy compounds can be prepared by oxidizing a parent amine with an oxidizing agent such as m-CPBA. When the price and structure allow, all nitrogen compounds shown and claimed are considered to cover the compounds as shown and their N-hydroxyl groups (ie N-OH) and N-alkoxy groups (ie N-OR, (Wherein R is substituted or unsubstituted C ₁ -C ₆ alkyl, C ₁ -C ₆ alkenyl, C ₁ -C ₆ alkynyl, 3-14-membered carbocyclic ring or 3-14-membered heterocyclic ring) Both derivatives.

The term "prodrug" as used in this application means Compounds that can be converted into the disclosed compounds by metabolic means (such as hydrolysis) in vivo.

Because prodrugs are known to improve many desirable qualities of drugs (eg, solubility, bioavailability, manufacturing, etc.), compounds of formula (I) or their pharmaceutically acceptable salts, tautomers, solvates, metabolism The substance, polymorph, analog or derivative can be delivered in the form of a prodrug. Therefore, the present application is intended to cover the prodrug of the compound of formula (I) or a pharmaceutically acceptable salt, tautomer, solvate, metabolite, polymorph, analog or derivative thereof, and delivery of the prodrug Method and composition containing the prodrug. "Prodrug" is intended to include any covalently bonded carriers. When these prodrugs are administered to a mammalian individual, they release the active parent drug of the present application in vivo. Prodrugs can be prepared by modifying the functional groups present in the compound, in such a way that the modified substance is cleaved into the parent compound by conventional operations or in vivo. Prodrugs include compounds of the present application in which a hydroxyl group or an amine group is bonded to any group, and when the drug is administered to a mammalian individual before the present application, the group is cleaved to form a free hydroxyl group or a free amine group, respectively. Examples of prodrugs include, but are not limited to, compounds of each formula described herein or pharmaceutically acceptable salts, tautomers, prodrugs, solvates, metabolites, polymorphs, analogs, or derivatives Acetate, formate and benzoate derivatives of alcohol and amine functional groups.

The term "crystalline polymorph", "polymorph" or "crystalline form" means a crystal structure in which a compound (or its salt or solvate) can be crystallized in different crystal stacks, all of which have the same elemental composition . Different crystal forms often have different X-ray diffraction patterns, Infrared spectrum, melting point, density and hardness, crystal shape, optical and electrical properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature and other factors may cause a crystalline form to dominate. The crystalline polymorph of the compound can be prepared by crystallization under different conditions.

The term "analog" as used herein refers to a compound that is structurally similar to another compound, but slightly different in composition (such as replacing an atom with an atom of a different element or having a special functional group, or with another One functional group replaces one functional group). Therefore, an analog is a compound that is similar or comparable in function and appearance, but is not the structure or origin of the reference compound.

This application also includes isotopically-labeled compounds that are the same as those cited in each formula described herein, but in fact one or more atoms have an atomic weight or mass number and the atomic weight most commonly found in nature Or substitution of atoms with different mass numbers. Examples of isotopes that can be incorporated into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, and fluorine, such as ³ H, ¹¹ C, ¹⁴ C, ² H, and ¹⁸ F.

Compounds of formula (I) or pharmaceutically acceptable salts, tautomers, prodrugs, solvates, metabolites, polymorphs, analogs or derivatives thereof containing the aforementioned isotopes and/or other isotopes of other atoms It is within the scope of the present application. The isotopically-labeled compounds of the present application (such as those incorporated into radioactive isotopes, such as ³ H and ¹⁴ C) are useful in the distribution of drugs and/or substrates. Tritiated (ie ³ H) and carbon-14 (ie ¹⁴ C) isotopes are useful for their ease of preparation and detectability. ¹¹ C and ¹⁸ F isotopes can be used in PET (positron emission tomography). PET can be used for brain imaging. Furthermore, substitution with heavier isotopes (such as deuterium, ie ² H) can provide specific therapeutic advantages due to greater metabolic stability, such as increased half-life in vivo or reduced dose requirements, and therefore may be more costly in some cases Preferably, isotope-labeled compounds of formula (I) or pharmaceutically acceptable salts, tautomers, prodrugs, solvates, metabolites, polymorphs, analogs or derivatives can generally be carried out by The described processes and/or the procedures disclosed in the examples are prepared with easily available isotopically labeled reagents instead of unisotopically labeled reagents. In one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog, or derivative thereof is not isotopically labeled.

The present application relates to compounds of BTK modulators. In one embodiment, the compound of the present application is a BTK inhibitor.

As used in this application, the term "administering (administer, administration, or administration)" refers to administering the disclosed compound or the pharmaceutically acceptable salt or composition of the disclosed compound directly to an individual, or administering the compound or A prodrug, derivative or analog of a pharmaceutically acceptable salt or composition of the compound is administered to an individual, and the prodrug, derivative or analog can form an equal amount of active compound in the individual.

"Patient" or "individual" is a mammal, such as a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human Primates, such as monkeys, chimpanzees, baboons, or gorillas.

When used in conjunction with a compound or pharmaceutical composition, an "effective amount" or "therapeutically effective amount" is an amount effective to treat or prevent a disease in an individual as described herein.

The term "treatment" with respect to an individual refers to improving at least one sign of the individual's condition. Treatment includes curing, improving, or at least partially ameliorating the condition.

The compounds of the present application or their pharmaceutically acceptable salts, tautomers, prodrugs, solvates, metabolites, polymorphs, analogs or derivatives can also be used to prevent diseases, conditions or disorders. As used herein, "preventing or preventing" refers to reducing or eliminating the onset of signs or complications of a disease, condition, or disorder.

The term "disorder" as used in this application means disease, condition or illness and is used interchangeably with these unless otherwise indicated.

The term "BTK-mediated" disease or disorder as used herein means any disease or other harmful condition in which BTK or its mutants are known to play a role. Accordingly, another embodiment of the present application relates to treating or reducing the severity of one or more diseases in which BTK or its mutants are known to play a role. In particular, the present application relates to a method of treating or reducing the severity of a disease or condition selected from a proliferative disorder or an autoimmune disorder, wherein the method comprises a compound of formula (I) according to the present application or Its pharmaceutically acceptable salts, tautomers, prodrugs, solvates, metabolites, polymorphs, analogues or derivatives or compositions are administered to patients in need thereof.

The term "cell proliferative disorder" as used herein refers to a condition in which unregulated or abnormally growing cells or both can cause an undesirable condition or the development of a disease, which may or may not be cancerous . The cell proliferative disorders exemplified in the present application include various conditions in which cell division is dysregulated. Exemplary cell proliferative disorders include but are not limited to neoplasms, benign tumors, malignant tumors, precancerous conditions, in situ tumors, coated tumors, metastatic tumors, liquid tumors, solid tumors, immune tumors, hematological tumors , Cancers (cancers), tumors (carcinomas), leukemia, lymphoma, sarcoma, and rapidly dividing cells. The term "rapidly dividing cells" as used herein is defined as any cell that divides at a rate that exceeds or is higher than expected or observed in neighboring or adjacent cells within the same tissue. Cell proliferative disorders include precancer or precancerous conditions. Cell proliferative disorders include cancer. The methods provided herein are preferably used to treat or slow the signs of cancer. The term "cancer" includes solid tumors, as well as hematological tumors and/or malignant tumors. "Primary cancer cells" or "precancerous cells" are cells that exhibit cell proliferative disorders of primary cancer or precancerous conditions. "Cancer cells" or "cancerous cells" are cells that exhibit cell proliferative disorders of cancer. Any reproducible measure can be used to identify cancer cells or precancerous cells. Cancer cells or precancerous cells can be identified by histological classification or grading of tissue samples (eg, biopsy samples). Cancer cells or precancerous cells can be identified by using appropriate molecular markers.

Exemplary non-cancerous conditions or disorders include but are not limited to rheumatoid arthritis; inflammation; autoimmune diseases; lymphoproliferative conditions; acromegaly; rheumatoid spondylitis; osteoarthritis; gout; other Arthritis conditions; Sepsis; Septic shock; Endotoxin shock; Gram-negative sepsis; Toxic shock syndrome; Asthma; Adult respiratory distress syndrome; Chronic obstructive pulmonary disease; Chronic lung inflammation; Inflammatory bowel disease; Cloning (Crohn )'S disease; psoriasis; eczema; ulcerative colitis; pancreatic fibrosis; liver fibrosis; acute and chronic kidney disease; irritability of the large intestine; fever; restenosis; cerebral malaria; stroke and ischemic injury; nerves Trauma; Alzheimer's disease; Huntington's disease; Parkinson's disease; acute and chronic pain; allergic rhinitis; allergic conjunctivitis; chronic heart failure; acute coronary Syndrome; cachexia; malaria; leprosy; kala-azar; Lyme disease; Reiter's syndrome; acute synovitis; muscle degeneration; bursitis; tendonitis; tenosynovitis; protrusion, rupture, or prolapsed intervertebral disc Syndrome; Stone osteosis; Thrombosis; Restenosis; silicosis; pulmonary sarcoma; bone resorption diseases, such as osteoporosis; graft-versus-host response; multiple sclerosis; lupus; fibromyalgia; AIDS and other viruses Sexual diseases such as herpes zoster, herpes simplex I or II, influenza virus and cytomegalovirus; and diabetes.

Exemplary cancers include, but are not limited to, adrenocortical carcinoma, AIDS-related cancer, AIDS-related lymphoma, anal cancer, anorectal cancer, anal canal cancer, appendic cancer, cerebellar astrocytoma in children, astrocytoma in children, Basal cell carcinoma, skin cancer (non-melanoma), biliary tract cancer, extrahepatic cholangiocarcinoma, intrahepatic cholangiocarcinoma, bladder cancer, urethral bladder cancer, bone and joint cancer, osteosarcoma and malignant fibrous histiocytoma, brain cancer , Brain tumor, brainstem glioma, cerebellar astrocytoma, cerebral astrocytoma/ Malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal tumor, visual pathway and hypothalamic glioma, breast cancer, tracheal adenoma/carcinoid Cancer, gastrointestinal cancer, nervous system cancer, nervous system lymphoma, central nervous system cancer, central nervous system lymphoma, cervical cancer, childhood cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic myeloproliferative disorders , Colon cancer, colorectal cancer, cutaneous T-cell lymphoma, lymphangioma, mycosis fungoides, Seziary syndrome, endometrial cancer, esophageal cancer, extracranial germ cell tumors, extragonadal germ cells Tumor (extragonadal germ cell tumor), extrahepatic cholangiocarcinoma, eye cancer, intraocular melanoma, retinoblastoma, gallbladder cancer, gastric cancer (gastric, stomach cancer), gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), Germ cell tumor, ovarian germ cell tumor, gestational trophoblastic tumor glioma, head and neck cancer, hepatocellular (liver) cancer, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, eye cancer, Islet cell tumor (endocrine pancreatic cancer), Kaposi sarcoma, kidney cancer, renal cancer, kidney cancer, larynx cancer, acute lymphoblastic leukemia, acute myeloid leukemia, Chronic lymphocytic leukemia, chronic myelogenous leukemia, hairy cell leukemia, lip and oral cancer, liver cancer, lung cancer, non-small cell lung cancer, small cell lung cancer, AIDS-related lymphoma, non-Hodgkin's lymphoma, primary Central nervous system lymphoma, Waldenstram's macroglobulinemia, medulloblastoma, melanoma, intraocular (eye) melanoma, merkel cells Cancer, malignant mesothelioma, mesothelioma, metastatic squamous neck cancer, mouth cancer, tongue cancer, multiple endocrine neoplasia syndrome, mycosis granulomatosis, bone marrow manufacturing syndrome, bone marrow manufacturing/myeloproliferative diseases, Chronic myelogenous leukemia, acute myelogenous leukemia, multiple myeloma, chronic myeloproliferative disorders, nasopharyngeal carcinoma, neuroblastoma, oral cancer, oral cancer, oropharyngeal cancer, ovarian cancer, ovarian epithelial cancer, ovarian critical malignancy Ovarian low malignant potential tumor, pancreatic cancer, pancreatic islet cell pancreatic cancer, sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pineal blastoma and superficial primitive Neuroectodermal tumors, pituitary tumors, plasmacytoma/multiple myeloma, pleural lung blastoma, prostate cancer, rectal cancer, renal pelvis and ureteral transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary adenocarcinoma, Ewing sarcoma family, Kaposi's sarcoma, soft tissue sarcoma, uterine cancer, uterine sarcoma, skin cancer (non-melanoma), skin cancer (melanoma), Merkel cell skin cancer, small intestine cancer, soft tissue sarcoma, squamous Cellular cancer, stomach (gastric) cancer, suprasuperior primitive neuroectodermal tumor, testicular cancer, laryngeal cancer, thymoma, thymoma and thymic cancer, thyroid cancer, renal pelvis and ureter and other urinary organs transitional cell cancer, pregnancy Trophoblastic tumor, urethral cancer, endometrial cancer, uterine sarcoma, uterine body cancer, vaginal cancer, vulvar cancer, and Wilm's tumor.

Method for preparing compound

The compounds of the present application can be prepared by various methods, including standard chemical methods. Suitable synthetic routes are described below In the process.

The compound of formula (I) can be prepared by methods known in organic synthesis techniques, such as the methods set forth in the following synthetic schemes. In the process described below, it should be fully understood that the protective groups of sensitive or reactive groups are used in accordance with general principles or chemical properties when necessary. The protecting group is operated according to standard organic synthesis methods (T.W. Greene and P.G.M. Wuts, Third Edition "Protective Groups in Organic Synthesis", Wiley, New York 1999). These groups are removed at a suitable compound synthesis stage using methods that are easily apparent to those skilled in the art. The selection method, reaction conditions and execution order should be consistent with the preparation method of the compound of the present application.

Those skilled in the art should recognize whether there is a stereo center in the compound of formula (I). Accordingly, the present application includes two possible stereoisomers (unless specified in the synthesis), and not only racemic compounds, but also individual mirror isomers and/or diastereomers. When the desired compound is a single enantiomer or diastereomer, it can be obtained by stereospecific synthesis or by resolution of the final product or any suitable intermediate. The resolution of the final product, intermediate or starting material can be achieved by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by E.L. Eliel, S.H. Wilen and L.N. Mander (Wiley-lnterscience, 1994).

The compounds described herein can be made from starting materials available on the market or synthesized using known organic, inorganic and/or enzymatic methods.

The compounds of the application of the present invention can be It is made in many ways well known to those skilled in the art. By way of example, the compounds of the present application can be synthesized using the methods described below in conjunction with synthetic methods known in synthetic organic chemistry techniques or variations of those recognized by those skilled in the art. Preferred methods include, but are not limited to those described below. The compound of the present application (that is, the compound of formula (I)) can be synthesized according to the steps outlined in the general scheme 1 including the order of the assembly intermediates 2-a to 2-h. Starting materials can be obtained on the market or made in reported literature or procedures known as examples.

The general method for preparing compounds of formula (I) using intermediates 2-a, 2-b, 2-c, 2-d, 2-e, 2-f, 2-g and 2-h is outlined in general scheme 1. Nucleophilic addition of phenol 2-b to 2-chloro-4-fluorobenzene using a strong base (such as sodium hydride (NaH)) in a solvent (such as N,N-dimethylformamide (DMF)) Formaldehyde 2-a to produce 2-c. 2-c is hydrolyzed using a base (eg potassium hydroxide (KOH)) in a solvent (eg ethanol) at elevated temperature to produce carboxylic acid 2-d. Use alkali (e.g. potassium carbonate (K ₂ CO ₃ ) or cesium carbonate (Cs ₂ CO ₃ )) in a solvent (e.g. N,N-dimethylformamide (DMF)) to make 2-d methyl iodide To provide 2-e. The intermediate 2-f is acetylated with 2-e in a solvent (such as tetrahydrofuran (THF)) using a strong base (such as n-BuLi) in a solvent (such as tetrahydrofuran (THF)) to provide 2-g. The amine 2-h is added nucleophilically using a base (e.g. N,N-diisopropylethylamine (DIPEA)) and optionally in a solvent (e.g. N,N-dimethylformamide (DMF)) To 2-g of aryl chloride to provide the compound of formula (I).

The mixture of enantiomers, diastereomers, cis/trans isomers obtained from the method described above may be chiral salt technology, using normal phase, reverse phase or chiral depending on the nature of the separation The column chromatography is separated into their single components.

Bioassay BTK kinase activity assay

The test inhibitor and control were prepared in a solvent (ie DMSO) and added to each well of the reaction plate. The full-length active BTK is diluted in assay buffer and added to each well. After pre-incubation, the kinase reaction is initiated by adding an activation mixture diluted in assay buffer containing biotinylated PLCγ2 peptide and ATP. The plate was incubated and then the reaction was stopped in the dark by adding the stop/detection mixture prepared in the assay buffer. Incubate the test disc in the dark and read the data on the disc reader.

BTK C481S kinase activity assay

The test inhibitor and control are prepared in the solvent (ie DMSO) at the desired final concentration and added to each well of the reaction plate in. Full-length BTKC481S was diluted in assay buffer and added to the volume of each well. After pre-incubation, the kinase reaction is initiated by adding an activation mixture diluted in assay buffer containing biotinylated PLCγ2 peptide and ATP. The plate was incubated and then the reaction was stopped in the dark by adding the stop/detection mixture prepared in the assay buffer. Incubate the test disc in the dark and read the data on the disc reader.

Anti-hyperplasia test

Cell survival rate is determined by MTS assay. Briefly, cells (ie TMD-8 cells or Rec-1 cells) were plated in 96-well plates, incubated in complete growth medium and then treated with various drugs and drug combinations. MTS/PMS was added and incubated, and then the cell survival rate was evaluated using a microplate reader. The data was normalized to the untreated control group and analyzed with Microsoft Excel.

How to use compounds

Another aspect of the present application relates to methods of treating, preventing, inhibiting, or eliminating diseases or conditions associated with BTK regulation (eg, BTK inhibition). The method comprises combining an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative or formula (I) The pharmaceutical composition of the compound is administered to patients in need of treatment for diseases or conditions associated with BTK regulation. In one embodiment, the BTK-mediated disorder is selected from immunological disorders, cancer, cardiovascular disease, viral infection, inflammation, metabolism/ Endocrine dysfunction and neurological disorders. In some embodiments, the method further comprises administering an additional therapeutic agent selected from the group consisting of anti-inflammatory agents, immunomodulators, chemotherapeutic agents, neurotrophic factors, cardiovascular disease treatment agents, liver disease treatment agents, disease resistance Toxic agents, agents for treating blood diseases, agents for treating diabetes, and agents for treating immune deficiency disorders. In some embodiments, BTK is wild-type BTK. In other embodiments, BTK is a mutant BTK (eg, BTK C481S mutant).

Another aspect of the present application relates to a method of treating, preventing, inhibiting or eliminating cell proliferative disorders, the method comprising applying a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, Prodrugs, solvates, metabolites, polymorphs, analogs or derivatives or pharmaceutical compositions of compounds of formula (I) are administered to patients in need thereof. In one embodiment, the cell proliferative disorder is cancer. In some embodiments, the method further comprises administering an additional therapeutic agent selected from the group consisting of anti-inflammatory agents, immunomodulators, chemotherapeutic agents, neurotrophic factors, cardiovascular disease treatment agents, liver disease treatment agents, disease resistance Toxic agents, agents for treating blood diseases, agents for treating diabetes, and agents for treating immune deficiency disorders.

Another aspect of the present application relates to a method for modulating BTK, which method comprises a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite , Polymorphs, analogs or derivatives, or pharmaceutical compositions of compounds of formula (I) are administered to patients in need thereof. In one embodiment, modulating the BTK line inhibits BTK. In some embodiments, BTK is wild-type BTK. In other embodiments, BTK is a mutant BTK (eg BTK C481S mutation body).

Another aspect of the present application relates to a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite thereof in a method for treating BTK-mediated disorders , Polymorphs, analogs or derivatives. In one embodiment, the disease or disorder is selected from immunological disorders, cancer, cardiovascular diseases, viral infections, inflammation, metabolic/endocrine dysfunction, and neurological disorders. In some embodiments, the method further comprises administering an additional therapeutic agent selected from the group consisting of anti-inflammatory agents, immunomodulators, chemotherapeutic agents, neurotrophic factors, cardiovascular disease treatment agents, liver disease treatment agents, disease resistance Toxic agents, agents for treating blood diseases, agents for treating diabetes, and agents for treating immune deficiency disorders. In some embodiments, BTK is wild-type BTK. In other embodiments, BTK is a mutant BTK (eg, BTK C481S mutant).

In another aspect, the present application relates to a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, or the like in a method for treating BTK-mediated disorders Pharmaceutical composition of metabolites, polymorphs, analogues or derivatives. In one embodiment, the disease or disorder is selected from immunological disorders, cancer, cardiovascular diseases, viral infections, inflammation, metabolic/endocrine dysfunction, and neurological disorders. In some embodiments, the method further comprises administering an additional therapeutic agent selected from the group consisting of anti-inflammatory agents, immunomodulators, chemotherapeutic agents, neurotrophic factors, cardiovascular disease treatment agents, liver disease treatment agents, disease resistance Toxic agents, agents for treating blood diseases, agents for treating diabetes, and agents for treating immune deficiency disorders. In some embodiments, BTK is wild-type BTK. In other In the embodiment, BTK is a mutant BTK (for example, BTK C481S mutant).

Another aspect of the present application relates to a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, prodrug, solvation thereof in a method for treating, preventing, inhibiting or eliminating cell proliferative disorders Substances, metabolites, polymorphs, analogs or derivatives. In one embodiment, the cell proliferative disorder is cancer.

In another aspect, the present application relates to a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, prodrug, or solvent thereof in a method of treating, preventing, inhibiting, or eliminating cell proliferative disorders Pharmaceutical composition of compound, metabolite, polymorph, analog or derivative. In one embodiment, the cell proliferative disorder is cancer.

Another aspect of the present invention relates to compounds of formula (I) or pharmaceutically acceptable salts, tautomers, prodrugs, solvates, metabolites, polymorphs, analogs or derivatives thereof used to modulate BTK Thing. In one embodiment, modulating the BTK line inhibits BTK. In some embodiments, BTK is wild-type BTK. In other embodiments, BTK is a mutant BTK (eg, BTK C481S mutant).

In another aspect, the application of the present invention relates to compounds of formula (I) or pharmaceutically acceptable salts, tautomers, prodrugs, solvates, metabolites, polymorphs, analogs, etc. for modulating BTK Pharmaceutical composition of substances or derivatives. In one embodiment, modulating the BTK line inhibits BTK. In some embodiments, BTK is wild-type BTK. In other embodiments, BTK is a mutant BTK (eg BTK C481S mutation body).

Another aspect of the present application relates to the manufacture of compounds of formula (I) or pharmaceutically acceptable salts, tautomers, prodrugs, solvates, metabolites, polymorphs, analogs or derivatives thereof Use of a medicament for the treatment of BTK-mediated diseases or conditions. In one embodiment, the disease or disorder is selected from immunological disorders, cancer, cardiovascular diseases, viral infections, inflammation, metabolic/endocrine dysfunction, and neurological disorders. In some embodiments, the treatment further comprises the administration of additional therapeutic agents selected from the group consisting of anti-inflammatory agents, immunomodulators, chemotherapeutic agents, neurotrophic factors, cardiovascular disease treatment agents, liver disease treatment agents, and antiviral agents , Agents for the treatment of blood diseases, agents for the treatment of diabetes and agents for the treatment of immune deficiency disorders. In some embodiments, BTK is wild-type BTK. In other embodiments, BTK is a mutant BTK (eg, BTK C481S mutant).

In another aspect, the present application relates to compounds of formula (I) or pharmaceutically acceptable salts, tautomers, prodrugs, solvates, metabolites, polymorphs, analogs or derivatives thereof The use of a pharmaceutical composition for the manufacture of a medicament for the treatment of BTK-mediated diseases or conditions. In one embodiment, the disease or disorder is selected from immunological disorders, cancer, cardiovascular diseases, viral infections, inflammation, metabolic/endocrine dysfunction, and neurological disorders. In some embodiments, the treatment further comprises the administration of additional therapeutic agents selected from the group consisting of anti-inflammatory agents, immunomodulators, chemotherapeutic agents, neurotrophic factors, cardiovascular disease treatment agents, liver disease treatment agents, and antiviral agents , Agents for the treatment of blood diseases, agents for the treatment of diabetes and agents for the treatment of immune deficiency disorders. In some embodiments, BTK is wild type BTK. In other embodiments, BTK is a mutant BTK (eg, BTK C481S mutant).

Another aspect of the present application relates to the manufacture of compounds of formula (I) or pharmaceutically acceptable salts, tautomers, prodrugs, solvates, metabolites, polymorphs, analogs or derivatives thereof Use of agents for treating, preventing, inhibiting or eliminating cell proliferative disorders. In one embodiment, the cell proliferative disorder is cancer.

In another aspect, the present application relates to compounds of formula (I) or pharmaceutically acceptable salts, tautomers, prodrugs, solvates, metabolites, polymorphs, analogs or derivatives thereof The use of the pharmaceutical composition to manufacture, treat, prevent, inhibit or eliminate cell proliferative disorders. In one embodiment, the cell proliferative disorder is cancer.

Another aspect of the present application relates to the manufacture of compounds of formula (I) or pharmaceutically acceptable salts, tautomers, prodrugs, solvates, metabolites, polymorphs, analogs or derivatives thereof Regulate the use of BTK agents. In one embodiment, modulating the BTK line inhibits BTK. In some embodiments, BTK is wild-type BTK. In other embodiments, BTK is a mutant BTK (eg, BTK C481S mutant).

In another aspect, the present application relates to compounds of formula (I) or pharmaceutically acceptable salts, tautomers, prodrugs, solvates, metabolites, polymorphs, analogs or derivatives thereof The use of pharmaceutical compositions to manufacture agents for regulating BTK. In one embodiment, modulating the BTK line inhibits BTK. In some embodiments, BTK is wild type BTK. In other embodiments, BTK is a mutant BTK (eg, BTK C481S mutant).

In some embodiments of the methods and uses described herein, the cancer is selected from breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, genitourinary tract cancer, esophageal cancer, laryngeal cancer, glioma cells Tumor, neuroblastoma, gastric cancer, skin cancer, keratoacanthoma, lung cancer, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer (NSCLC), small cell carcinoma, lung adenocarcinoma, bone cancer, colon cancer, gland Tumor, pancreatic cancer, adenocarcinoma, thyroid cancer, follicular cancer, undifferentiated cancer, papillary cancer, seminoma, melanoma, sarcoma, bladder cancer, liver cancer and biliary tract cancer, kidney cancer, pancreatic cancer, bone marrow Disease, lymphoma, hair cell cancer, buccal space cancer, nasopharyngeal cancer, pharyngeal cancer, lip cancer, tongue cancer, mouth cancer, small intestine cancer, colorectal cancer, colorectal cancer, rectal cancer, brain cancer and central nervous system cancer , Hodgkin's lymphoma, bronchial cancer, thyroid cancer, liver and intrahepatic cholangiocarcinoma, hepatocellular carcinoma, gastric cancer, glioma/glioblastoma, endometrial cancer, melanoma, kidney and renal pelvis cancer , Urethral bladder cancer, endometrial cancer, cervical cancer, multiple myeloma, acute myelogenous leukemia, chronic myelogenous leukemia, lymphocytic leukemia, chronic lymphocytic leukemia (CLL), myeloid leukemia, oral and larynx cancer , Non-Hodgkin's lymphoma, melanoma and villous colon adenoma.

In any of the embodiments of the present application, the cancer may be any cancer in any organ, for example, the cancer is selected from the group consisting of glioma, thyroid cancer, breast cancer, small cell lung cancer , Non-small cell carcinoma, gastric cancer, colon cancer, gastrointestinal stromal tumor, pancreatic cancer, bile duct Cancer, CNS cancer, ovarian cancer, endometrial cancer, prostate cancer, kidney cancer, large cell lymphoma, leukemia, multiple myeloma, mesothelioma, melanoma, and combinations thereof.

In some embodiments of the methods and uses described herein, the disease or disorder is an immune disorder. In one embodiment, the immune disorder is rheumatoid arthritis.

In some embodiments of the methods and uses described herein, the disease or disorder is systemic and local inflammation, arthritis, inflammation associated with immunosuppression, organ transplant rejection, allergy, ulcerative colitis, Crohn's disease, Dermatitis, asthma, systemic lupus erythematosus, Sjogren's syndrome, multiple sclerosis, scleroderma/systemic sclerosis, idiopathic thrombocytopenic purpura (ITP), antineutrophils Cytoplasmic antibody (ANCA) vasculitis, chronic obstructive pulmonary disease (COPD), psoriasis.

In one embodiment, a method of treating a disease or disorder associated with BTK regulation (including immune disorders, cancer, cardiovascular diseases, viral infections, inflammation, metabolic/endocrine dysfunction, and neurological disorders) includes formula ( I) The compound is administered to patients suffering from at least one of these diseases or conditions.

The compounds disclosed in the present application can be administered in an amount effective to treat or prevent a disorder in an individual and/or prevent its development.

The compounds of the present application can be administered in combination therapy with a therapeutically effective amount in combination with one or more therapeutic agents (pharmaceutical combinations) or modalities (eg, non-pharmaceutical therapies). For example, it can be combined with other anti-proliferative, anti-cancer, immunomodulatory or Anti-inflammatory substances have a synergistic effect. In some embodiments, the compound of formula (I) is administered in combination with an additional therapeutic agent selected from the group consisting of anti-inflammatory agents, immunomodulators, chemotherapeutic agents, neurotrophic factors, cardiovascular disease treatment agents, liver disease treatment Agents, antiviral agents, agents for treating blood diseases, agents for treating diabetes, and agents for treating immune deficiency disorders. When the compound of the present application is administered together with other therapeutic agents, the dose of the co-administered compound will of course vary depending on the type of common drug used, the specific drug used, the condition to be treated, and so on.

Combination therapy includes administration of the subject compound and other biologically active ingredients (such as, but not limited to, anti-inflammatory agents, immunomodulators, chemotherapeutic agents, neurotrophic factors, cardiovascular disease treatment agents, liver disease treatment agents, antiviral agents, treatment Additional combinations of agents for blood diseases, agents for treating diabetes, and agents for treating immunodeficiency disorders) and non-pharmacological therapies (such as but not limited to surgery or radiation therapy). For example, the compound of the present application can be used in combination with other pharmaceutically active compounds, preferably a compound capable of increasing the effect of the compound of the present application. The compound of the present application can be administered simultaneously with other drug therapies or treatment modes (being a single preparation or separate preparations) or sequentially. Combination therapy usually envisages the administration of two or more drugs during a single cycle or during the course of treatment.

Pharmaceutical composition

The present application also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof With A combination of at least one pharmaceutically acceptable excipient or carrier.

"Pharmaceutical composition" is a formulation containing the compound of the present application in a form suitable for administration to an individual. In one embodiment, the pharmaceutical composition is in bulk form or unit dosage form. The unit dosage form is any of various forms, including, for example, capsules, IV bags, lozenges, single pumps or vials on an aerosol inhaler. Active ingredients in a unit-dose composition (e.g. the disclosed compounds or pharmaceutically acceptable salts, tautomers, prodrugs, solvates, metabolites, polymorphs, analogs or derivatives The amount of formulation) is an effective amount and varies according to the particular treatment involved. Those skilled in the art should understand that it is sometimes necessary to routinely vary the dosage depending on the age and condition of the patient. The dose also depends on the route of administration. Carefully consider various routes including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, transbuccal, sublingual, intrapleural, intrathecal, intranasal and Similar. Dosage forms for topical or transdermal administration of the compounds of this application include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. In one embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any desired preservatives, buffers, or propellants.

As used herein, the phrase "pharmaceutically acceptable" refers to those compounds, materials, compositions, carriers, and/or dosage forms that are suitable for use in contact with human and animal tissues within a reasonable range of medical judgment, without excessive Toxicity, irritation, allergic reactions or other problems or complications, and there is a corresponding reasonable benefit/risk ratio.

"Pharmaceutically acceptable excipient" means an excipient that is used to prepare a pharmaceutical composition that is generally safe, non-toxic, and is not biologically or otherwise undesirable, and includes veterinary uses and human medicine For use, it is an acceptable excipient. "Pharmaceutically acceptable excipients" as used in the specification and the scope of patent applications also include one or more of these excipients.

The pharmaceutical composition of this application is formulated to be compatible with the intended route of administration. Examples of administration routes include parenteral, such as intravenous, intradermal, subcutaneous, oral (eg, inhalation), percutaneous (topical), and transmucosal administration. Solutions or suspensions for parenteral, intradermal or subcutaneous administration may include the following components: sterile diluents such as water for injection, saline solution, fixed oil, polyethylene glycol, glycerin, propylene glycol or other synthetic solvents; Antibacterial agents, such as benzyl alcohol or methylparaben; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; buffers, such as acetate, citrate, or phosphate; And agents used to adjust tension, such as sodium chloride or glucose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

The compound or pharmaceutical composition of the present application can be administered to an individual in many well-known methods currently used for chemotherapy treatment. For example, the compounds of the present application for the treatment of cancer can be injected directly into the tumor, into the blood stream or into the body cavity or orally or applied through the skin as a patch. The dose chosen should be sufficient to constitute an effective treatment, but not so high as to cause unacceptable side effects. Preferably during the treatment and within a reasonable period after treatment Monitor the patient's disease (such as cancer, primary cancer and the like) and health status closely.

The term "therapeutically effective amount" as used in the present invention refers to the amount of a pharmaceutical agent used to treat, ameliorate or prevent an identified disease or condition or exhibit a detectable therapeutic or inhibitory effect. This effect can be detected by any verification method known in the art. The amount effective for an individual will depend on the individual's weight, size, and health; the nature and extent of the condition; and the treatment or combination of treatments selected for administration. The therapeutically effective amount for a particular situation can be determined by routine experimentation within the skills and judgment of the clinician. In one embodiment, the disease or disorder is selected from immunological disorders, cancer, cardiovascular diseases, viral infections, inflammation, metabolic/endocrine dysfunction, and neurological disorders. In another embodiment, the disease or condition to be treated is cancer. In another embodiment, the disease or condition to be treated is a cell proliferative disorder.

The therapeutically effective amount of any compound can be estimated initially from cell culture assays (eg neoplastic cells) or in animal models (often rats, mice, rabbits, dogs or pigs). The animal model can also be used to determine the appropriate concentration range and route of administration. These data can then be used to determine useful doses and routes to humans. Therapeutic/preventive efficacy and toxicity can be determined in cell cultures or laboratory animals using standard medical procedures, such as ED ₅₀ (dose effective for treatment in 50% of the population) and LD ₅₀ (dose lethal to 50% of the population ). The dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the ratio LD ₅₀ /ED ₅₀ . Pharmaceutical compositions that exhibit a high therapeutic index are preferred. The dosage can vary within this range depending on the dosage form used, the sensitivity of the patient, and the route of administration.

Adjust the dosage and administration to provide sufficient active agent concentration or maintain the desired effect. Factors that can be considered include the severity of the disease state, the individual's general health status, the individual's age, weight and gender, diet, time and frequency of administration, drug combination, response sensitivity and tolerance/response to treatment . The long-acting pharmaceutical composition may be administered every 3 to 4 days, weekly, or biweekly depending on the half-life and clearance rate of the specific formulation.

The pharmaceutical composition containing the active compound of the present application (that is, the compound of formula (I)) can be manufactured in a generally known manner, for example, by means of conventional mixing, dissolving, granulating, manufacturing sugar-coated tablets, grinding, emulsifying, Encapsulation, entrainment or freezing methods. The pharmaceutical composition can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers (including excipients and/or adjuvants that facilitate processing of the active compound into pharmaceutically usable preparations). Of course, the appropriate formulation depends on the chosen route of administration.

Pharmaceutical compositions suitable for injection include sterile aqueous solutions (when soluble in water) or dispersions and sterile powders for the immediate preparation of sterile injectable solutions or dispersions. Carriers suitable for intravenous administration include physiological saline, bacteriostatic water, Cremophor EL ^™ (BASF, Parsippany, NJ) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringability occurs. It must be stable under manufacturing and storage conditions and must be preserved to resist the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or a dispersion medium containing, for example, water, ethanol, polyol (for example, glycerin, propylene glycol, and liquid polyethylene glycol and the like), and suitable mixtures thereof. Appropriate fluidity can be maintained, for example, by using a coating (such as lecithin), by maintaining the required particle size in the case of dispersions, and by using surfactants. The antimicrobial effect can be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid, sodium thiomersal, and the like. In many cases, it is preferred that the composition includes isotonic agents (eg, sugar), polyhydric alcohols (such as mannitol, sorbitol), and sodium chloride. Prolonged absorption of the injectable composition can be achieved by including in the composition an agent that delays absorption (for example, aluminum monostearate and gelatin).

Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Dispersions are usually prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and other required ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the method of preparation is vacuum drying and freeze drying, from which the previously sterilized filtered solution yields the active ingredient plus any additional powder of the desired ingredient.

Oral compositions generally include an inert diluent or a pharmaceutically acceptable edible carrier. The composition can be encapsulated in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be combined with excipients and used in the form of troches, throat lozenges, or capsules. The oral composition can also be prepared using a fluid carrier and used as a mouthwash, in which the fluid carrier The compound in the agent is administered orally and rinsed and spit out or swallowed in the mouth. Pharmaceutically compatible adhesives and/or adjuvant materials can be included as part of the composition. Lozenges, pills, capsules, throat lozenges and the like may contain any of the following ingredients or compounds of similar properties: binders such as microcrystalline cellulose, tragacanth or gelatin; excipients such as starch or lactose ; Disintegrants such as alginic acid, Primogel or corn starch; lubricants such as magnesium stearate or Sterotes; glidants such as colloidal silica; sweeteners such as sucrose or saccharin; or flavoring agents such as Mint, methyl salicylate or orange flavoring.

The compound for administration by inhalation is delivered in the form of an aerosol spray from a pressurized container or dispenser (which contains a suitable propellant, such as a gas, such as carbon dioxide) or a nebulizer.

Systemic administration can also be performed by transmucosal or transdermal means. Use penetrants suitable for penetrating barriers in formulations for transmucosal or transdermal administration. Such penetrants are generally known in the art and include, for example, detergents for transmucosal administration, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. The active compounds for transdermal administration are formulated into ointments, ointments, gels or creams as generally known in the art.

Active compounds can avoid the preparation of pharmaceutically acceptable carriers for rapid elimination of the compound itself, such as controlled release formulations, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Preparation method of these formulations It is understood by those skilled in the art. Materials can also be obtained from Alza Corporation and Nova Pharmaceuticals, Inc. on the market. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies against viral antigens) can also be used as pharmaceutically acceptable carriers. Such materials can be made according to methods known to those skilled in the art, such as described in US Patent No. 4,522,811.

It is particularly advantageous to formulate oral or parenteral compositions in unit dosage form for ease of administration and uniformity of dosage. Unit dosage form as used herein refers to physically discrete units suitable as unit dosages for the individual to be treated; each unit contains a predetermined amount of active compound calculated to associate with the desired pharmaceutical carrier to produce the desired therapeutic effect. The specification of the unit dosage form of the present application is specified by the unique characteristics of the active compound and the specific therapeutic effects to be achieved or directly depending on these characteristics and therapeutic effects.

In therapeutic applications, the dosage of the pharmaceutical composition used in accordance with this application, in addition to other factors affecting the selected dosage, also depends on the medicament, the age, weight, and clinical condition of the patient receiving the drug, and the clinical treatment administered The experience and judgment of a physician or practicing physician. The dose should generally be sufficient to cause tumor growth to slow down and preferably regress, and also preferably cause cancer to completely regress. The dosage can range from about 0.01 mg/kg per day to about 5000 mg/kg per day. The effective amount of the medicinal agent is to provide an objectively identifiable improvement as indicated by clinicians and other qualified observers. For example, tumor regression in a patient can be measured with reference to the diameter of the tumor. The reduction in tumor diameter indicates regression. Regression is also indicated by the fact that the tumor no longer appears after stopping treatment. The term "dose effective way" as used herein refers to The amount of active compound that produces the desired biological effect in the individual or cell.

The pharmaceutical composition can be included in a container, package or dispenser together with instructions for administration.

"Pharmaceutically acceptable salt" as used herein refers to a derivative of the compound of the present application, wherein the parent compound is modified by making its acid or base salt. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues (such as amines), basic or organic salts of acidic residues (such as carboxylic acids), and the like. Pharmaceutically acceptable salts include, for example, non-toxic salts or quaternary ammonium salts known from parent compounds formed from non-toxic inorganic or organic acids. For example, such conventional toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, and benzenesulfonate Acid, benzoic acid, acid carbonic acid, carbonic acid, citric acid, ethylenediaminetetraacetic acid, ethanedisulfonic acid, 1,2-ethanesulfonic acid, fumaric acid, grape heptanoic acid, gluconic acid, glutamine Acid, Glycolic Acid, Ethyl Acetylp-Arsanilic Acid, Hexyl Resorcinic Acid, Hydrabamic, Hydrobromic Acid, Hydrochloric Acid, Hydroiodic Acid, Hydroxy Fumaric Acid, Hydroxy Naphthoic Acid , Isethionate, lactic acid, lactobionic acid, laurylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, napsylic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, benzene Acetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, hypoacetic acid, succinic acid, sulfamic acid, p-aminobenzenesulfonic acid, sulfuric acid, tannic acid, tartaric acid, toluenesulfonic acid and Common amino acids, such as glycine, alanine, phenylalanine, spermine, etc.

Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclic Pentanepropionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid Acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, muconic acid and the like. When the acidic protons present in the parent compound are replaced by metal ions (such as alkali metal ions, alkaline earth metal ions or ammonium ions); or with organic bases (such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N -When the methyl-reduced glucosamine and the like are coordinated, the application of the present invention also includes the formed salt.

It should be understood that all the pharmaceutically acceptable salts mentioned include solvent addition forms (solvates) or crystalline forms (polymorphs) of the same salts as defined herein.

The compounds of the present application can also be prepared as esters, such as pharmaceutically acceptable esters. For example, the carboxylic acid functional group in the compound can be converted to its corresponding ester, such as methyl ester, ethyl ester, or other ester. Moreover, the alcohol group in the compound can be converted into its corresponding ester, such as acetate, propionate or other ester.

The compounds of the present application can also be prepared as prodrugs, such as pharmaceutically acceptable prodrugs. The terms "pro-drug and prodrug" are used interchangeably herein and refer to any compound that releases the active parent drug in vivo. Because prodrugs are known to improve many desirable qualities of drugs (eg, solubility, bioavailability, manufacturing, etc.), the compounds of the present application can be delivered as prodrugs. Therefore, the present application is intended to cover the prodrugs of the currently applied compounds, their delivery methods and Contains its composition. "Prodrug" is intended to include any covalently bonded carriers. When these prodrugs are administered to an individual, they release the active parent drug of the present application in vivo. The prodrugs in the present application are prepared by modifying the functional groups present in the compound, in this way the modifier is cleaved into the parent compound by conventional operations or in vivo. Prodrugs include compounds of the present application wherein the hydroxyl, amine, sulfhydryl, carboxyl, or carbonyl groups are bonded to any group that cleaves in vivo to form free hydroxyl groups, free amine groups, free thiol groups, free carboxyl groups, respectively Or free carbonyl.

Examples of prodrugs include, but are not limited to, esters of hydroxy functional groups in the compounds of the present application (e.g. acetate, dialkylaminoacetate, formate, phosphate, sulfate and benzoate derivatives ) And carbamates (eg N,N-dimethylaminocarbonyl); esters of carboxyl functional groups (eg ethyl esters, morpholine ethanolate); N-acyl derivatives of amino functional groups (eg N-acetyl) N-Mannich base, Schiff base and enamine; oxime, acetal, ketal and enol esters of ketone and aldehyde functional groups; and the like, see Bundegaard , H. Design of Prodrugs, p1-92, Elsevier, New York-Oxford (1985).

The compound or its pharmaceutically acceptable salts, tautomers, prodrugs, solvates, metabolites, polymorphs, analogs or derivatives are oral, nasal, transdermal, pulmonary, inhalation, Buccal, sublingual, intraperitoneal, subcutaneous, intramuscular, intravenous, rectal, intrapleural, intrathecal, and parenteral administration. In one embodiment, the compound or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog, or derivative thereof is administered orally. Those skilled in the art should recognize The advantages of a specific investment path.

The dosage regimen of the compound is selected based on various factors, including the type, species, age, weight, sex, and medical condition of the patient; the severity of the condition to be treated; the route of administration; the kidney and liver function of the patient; and The specific compound used or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof. Clinicians or veterinarians who are generally familiar with this technique can easily determine and prescribe the effective amount of drugs required to prevent, counter or suppress the progression of the condition.

The compounds disclosed techniques for formulation and administration may be found in the present application Remington: the Science and Practice of Pharmacy , 19 th edition, Mack Publishing Co., Easton, PA (1995). In one embodiment, the compounds described herein and their pharmaceutically acceptable salts, tautomers, prodrugs, solvates, metabolites, polymorphs, analogs or derivatives are pharmaceutically acceptable The carrier or diluent combination is used in pharmaceutical preparations. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The compound or its pharmaceutically acceptable salts, prodrugs, solvates, metabolites, polymorphs, analogs or derivatives are present in an amount sufficient to provide the desired dosage within the scope described herein In pharmaceutical composition.

All percentages and ratios used herein are by weight unless otherwise indicated. Other features and advantages of the application of the present invention are apparent from different embodiments. The examples provided illustrate different components and methods for implementing the present application. The examples do not limit the application Application. Those skilled in the art can build on the application of the present invention to identify and use other components and methods for implementing the application of the present invention.

Examples

This application is further exemplified by the following examples and synthetic procedures, which are not to be construed as limiting the scope and spirit of this application to the specific procedures described herein. It should be understood that the examples are provided to illustrate specific implementation aspects and are not intended to limit the scope of the application. It should be further understood that various other implementations, modifications, and equivalents that may be resorted to by those skilled in the art may be resorted to without departing from the spirit of the present application and/or the scope of the appended patent application.

Analysis methods, materials and instruments

Unless otherwise noted, use reagents and solvents received from market suppliers. Proton nuclear magnetic resonance (NMR) spectroscopy was obtained at 400 MHz on a Bruker or Varian spectrometer. The spectrum is given in ppm (δ) and the coupling constant J is recorded in Hertz. Tetramethylsilane (TMS) was used as the internal standard. The mass spectrum was collected using a Waters ZQ Single Quad mass spectrometer (ion trap ESI). Purity and low-resolution mass spectrometry data are Waters Acquity i-class ultra-high performance liquid chromatography (UPLC) with Acquity photodiode array detector, Acquity evaporative light scattering detector (ELSD) and Waters ZQ mass spectrometer System measurement. The data is obtained using Waters MassLynx 4.1 software and the purity is based on UV Wavelength 220 nm, ELSD and ESI characterization. Column: Acquity UPLC BEH C18 1.7μm 2.1 X 50mm; flow rate: 0.6 ml/min; solvent A (95/5/0.1 of 10 mM ammonium formate/acetonitrile/formic acid), solvent B (95/5/0.09 of acetonitrile/water / Formic acid); gradient: 5-100% B from 0 to 2 minutes, hold 100% B to 2.2 minutes, then 5% B at 2.21 minutes.

The abbreviations used in the following examples and elsewhere herein are: DCM dichloromethane

DIEA N,N-diisopropylethylamine

DIPEA N,N-diisopropylethylamine

DMF N,N-dimethylformamide

DMSO dimethyl sulfoxide

DTT dithiothreitol

EDTA ethylenediaminetetraacetic acid

EGTA ethylene glycol tetraacetic acid

Et ₂ O diethyl ether

EtOAc ethyl acetate

EtOH ethanol

LCMS liquid chromatography-mass spectrometry

MeOH methanol

MS mass spectrometry

NMR nuclear magnetic resonance

ppm million points

Example 1: Methyl 2-chloro-4-phenoxybenzoate (intermediate 2-D)

Step 1: 2-chloro-4-phenoxybenzonitrile (intermediate 2-B)

Phenol (3.66 g, 39 mmol) dissolved in DMF (30 mL) was treated with 60% NaH (1.56 g, 39 mmol) dispersed in oil in small portions until gas evolution ceased. The reaction mixture was stirred at room temperature for 10 minutes, and then 2-chloro-4-fluorobenzonitrile (2-A, 5.0 g, 32.5 mmol) was added. The mixture was stirred at room temperature for 3 hours until completion (LCMS). The volatiles were removed in vacuo and the crude product was dissolved in DCM/water. The organic phase was separated and washed with saturated saline solution, and dried over Na ₂ SO ₄ . 7.5 g of off-white solid was supplied by concentration. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.96 (d, J=8.7 Hz, 1H), 7.51 (t, J=7.9 Hz, 2H), 7.33 (d, J=7.4 Hz, 1H), 7.30 ( d, J=2.3 Hz, 1H), 7.20 (d, J=7.9 Hz, 2H), 7.04 (dd, J=8.7, 2.3 Hz, 1H); MS m/z 230[M+H] ⁺ .

Step 2: 2-chloro-4-phenoxybenzoic acid (intermediate 2-C)

2-chloro-4-phenoxybenzonitrile (2-B, 7.0 g, 30.6 mmol), potassium hydroxide 5M (100 mL) and EtOH (20 mL) were stirred under reflux for 6 hours (until Starting material consumption). The mixture was allowed to cool to room temperature and the mixture was slowly acidified with concentrated HCl. The precipitate was filtered off and dried to give a beige solid (2-C, 7.15 g, 94%). NMR (400MHz, DMSO-d ₆ ) δ 13.22 (s, 1H), 7.88 (d, J=8.7Hz, 1H), 7.48 (t, J=7.8Hz, 2H), 7.27 (t, J=7.4Hz, 1H), 7.16 (d, J=8.0Hz, 2H), 7.08 (d, J=2.2Hz, 1H), 6.97 (dd, J=8.7, 2.3Hz, 1H); MS m/z 249[M+H ] ⁺ .

Step 3: Methyl 2-chloro-4-phenoxybenzoate (intermediate 2-D)

2-chloro-4-phenoxybenzoic acid (2-C, 5.0 g, 20.2 mmol) was dissolved in DMF (50 mL) and solid K ₂ CO ₃ (4.15 g, 30.1 mmol) was added. The reaction mixture was cooled to 0°C and methyl iodide (1.4 mL, 22.2 mmol) was added dropwise. The mixture was allowed to warm to room temperature over 1 hour. The starting material is completely consumed during this period. The mixture was diluted with water and extracted with Et ₂ O. Dry and concentrate in vacuo to provide a yellow oil (2-D, 4.15 g, 79%), which was used without further purification. _{NMR (400MHz, DMSO-d 6} ) δ 7.89 (d, J = 8.7Hz, 1H), 7.49 (t, J = 7.9Hz, 2H), 7.29 (t, J = 7.4Hz, 1H), 7.17 (d, J=7.9Hz, 2H), 7.12(d, J=2.4Hz, 1H), 6.99(dd, J=8.7, 2.4Hz, 1H), 3.84(s, 3H); MS m/z 263[M+H ] ⁺ .

Example 2: (2-chloro-4-phenoxyphenyl) (4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-piperan-3-yl)amino) -7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Compound (I))

Step 1: 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (intermediate 2-F)

4-chloro-7H-pyrrolo[2,3-d]pyrimidine (2-E, 20.0 g, 130.7 mmol) dissolved in DCM (800 mL) was taken as N-bromosuccinimide (26.7 g) , 149.8 millimoles) in batches while maintaining the temperature at about 25-30°C. The reaction mixture was stirred at room temperature overnight. Water (500 mL) was added and the phases were separated. The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was wet-milled in Et ₂ O, and after filtration, 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (2-F, 22.43 g, 74%) was supplied as a white solid. . Melting point: 242-244°C; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.96 (s, 1H), 8.61 (s, 1H), 7.94 (s, 1H); MS m/z 232 [M ( ³⁵ Cl , ⁷⁹ Br)+H] ⁺ ,234[M( ³⁵ Cl, ⁸¹ Br)+H] ⁺ ,234[M( ³⁷ Cl, ⁷⁹ Br)+H] ⁺ ,236[M( ³⁷ Cl, ⁸¹ Br)+ H] ⁺ .

Step 2: (2-chloro-4-phenoxyphenyl) (4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (intermediate 2-G)

N-BuLi (2.69M in hexane, 23.2 mL, 62.3 mmol) was added dropwise to 5-bromo-4-chloro-7H- in THF (200 mL) under -78°C and inert atmosphere Pyrrolo[2,3-d]pyrimidine (2-F, 6.90 g, 29.7 mmol) in a stirred solution. The reaction mixture was kept at -78°C for 1 hour and then pre-added with methyl 2-chloro-4-phenoxybenzoate (2-D, 8.19 g, 31.2 mmol) in THF (80 mL) Cool (to -78°C) the solution. The reaction mixture was stirred at -78°C for 1 hour, and then quenched with the addition of HCl 1N (65 mL). The mixture was allowed to warm to room temperature and then extracted with EtOAc (3×100 mL). The combined extracts were washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The crude product was purified by column chromatography (SiO ₂ , hexane/EtOAc) to give (2-chloro-4-phenoxyphenyl)(4-chloro-7H-pyrrolo[ 2,3-d]pyrimidin-5-yl)methanone (2-G, 4.73 g, 41%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.426 (s, 1H), 8.75 (s, 1H), 8.14 (s, 1H), 7.60 (d, J=8.5 Hz, 1H), 7.49 (t, J =7.9Hz, 2H), 7.26(t, J=7.4Hz, 1H), 7.23-7.12(m, 3H), 7.01(dd, J=8.5, 2.3Hz, 1H); MS m/z 384[M( ³⁵ Cl, ³⁵ Cl)+H] ⁺ ,386[M( ³⁵ Cl, ³⁷ Cl)+H] ⁺ ,388[M( ³⁷ Cl, ³⁷ Cl)+H] ⁺ .

Step 3: (2-chloro-4-phenoxyphenyl) (4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-piperan-3-yl)amino)- 7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (I)

(2-chloro-4-phenoxyphenyl) (4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (2-G, 200 mg, 0.52 mmol ), ((2S,5R)-5-aminotetrahydro-2H-piperan-2-yl)methanol (72 mg, 0.54 mmol) and DIPEA (272 μL, 1.56 mmol) at Stir at 160°C for 1 hour under microwave irradiation. The volatiles were removed in vacuo and the residue was purified by column chromatography (NH ₂ -SiO ₂ , DCM/MeOH) to give (2-chloro-4-phenoxyphenyl) as an off-white solid (4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-piperan-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl ) Ketone ((I), 175 mg, 70%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.76 (s, 1H), 8.60 (d, J=7.1 Hz, 1H), 8.25 (s, 1H), 7.64 (s, 1H), 7.58 (d, J=8.4Hz, 1H), 7.48(t, J=7.6Hz, 2H), 7.26(t, J=7.2Hz, 1H), 7.18-7.20(m, 3H), 7.02(d, J=8.3Hz, 1H), 4.67(s,1H), 4.16(d,J=7.7Hz,2H), 3.49-3.27(m,3H), 3.12(t,J=11.2Hz,1H), 2.19(d,J=11.4 Hz,1H), 1.78(d,J=12.9Hz,1H),1.67-1.49(m,1H), 1.39(d,J=12.3Hz,1H); MS m/z 479[M( ³⁵ Cl)+ H] ⁺ ,481[M( ³⁷ Cl)+H] ⁺ .

Example 3: BTK kinase activity assay

Test inhibitors and controls (CGI-1746, GDC-0834, PCI-32765, Dasatinib, and R-406) were prepared in 10% DMSO at 10 times the desired final concentration and at 2.5 A microliter volume was added to each well of the reaction disk (the white disk with the solid surface of Corning 96-well half-area unconnected). Combine full-length active BTK in assay buffer (50 mM Tris, pH 8.0, 0.02 mg/ml BSA, 10 mM MgCl ₂ , 1 mM EGTA, 10% glycerol, 0.2 mM Na ₃ VO ₄ , 1 mM DTT, 0.1 mM β-glycerol phosphate and 0.2 mM NaF) and added to each well in a volume of 17.5 microliters to a final concentration of 0.08 nM in a 25 microliter reaction. After pre-incubation at room temperature for 30 minutes, the kinase reaction was initiated by adding 5 μl of the activation mixture diluted in assay buffer containing biotinylated PLCγ2 peptide and ATP, with final concentrations of 150 nM biotinylated PLCγ2 and 180 μM ATP . The dish was incubated at room temperature for 60 minutes. The reaction was stopped in the dark by adding 10 μl stop/detection mixture prepared in assay buffer containing EDTA and AlphaScreen ^™ streptavidin donor beads and anti-pTYR100 acceptor beads. The final concentration is 10 mM EDTA and 500 ng/well of AlphaScreen ^™ donor and acceptor beads. The assay disc was incubated in the dark at room temperature for 60 minutes and the disc was read on a Perkin Elmer Envision Multilabel plate reader (excitation wavelength: 640 nm, emission wavelength: 570 nm). The results are shown in Table 1.

Example 4: BTK C481S kinase activity assay

The test inhibitor and the control (staurosporine) were prepared in 10% DMSO at 10 times the desired final concentration and added to the reaction plate (Corning 96-well half) in a volume of 2.5 μl The solid surface is not connected to the white plate) in each slot. Full-length BTKC481S was diluted in assay buffer (50 mM Tris, pH 8.0, 0.02 mg/ml BSA, 10 mM MgCl ₂ , 1 mM EGTA, 10% glycerol, 1 mM DTT, 1 mM β-glycerophosphate, and 1 mM NaF) and diluted at 17.5 μM One liter volume is added to each well, and the final concentration is 10 nM in a 25 microliter reaction. After pre-incubation at room temperature for 30 minutes, the kinase reaction was initiated by adding 5 μl of the activation mixture diluted in assay buffer containing biotinylated PLCγ2 peptide and ATP, with final concentrations of 125 nM biotinylated PLCγ2 and 60 μM ATP . The dish was incubated at room temperature for 60 minutes. Stop in the dark by adding 10 μl stop/detection mixture prepared in assay buffer containing EDTA, staurosporine and AlphaScreen ^™ streptavidin donor beads and anti-pTYR100 acceptor beads reaction. Both AlphaScreen ^TM (Amplified Luminescent Proximity Homogeneous Assay) technology donor beads and acceptor beads with a final concentration of 15mM EDTA, 1 μM staurosporine, and 500 ng/well . The assay disc was incubated in the dark at room temperature for 60 minutes and the disc was read on a Perkin Elmer Envision Multilabel plate reader (excitation wavelength: 640 nm, emission wavelength: 570 nm). The results are shown in Table 1.

Example 5: Anti-hyperplasia assay

Cell survival was determined by MTS assay. Briefly, cells (ie TMD-8 cells or Rec-1 cells) were plated in 96-well plates at 2,000-10,000 cells/well, incubated in complete growth medium for 24 hours and then treated with various drugs And drug combination treatment for 72 hours. MTS/PMS was added and incubated for 4 hours, and then the cell survival rate was evaluated using a microplate reader (absorption wavelength of 490 nm). Compare data to unprocessed The control group was standardized and analyzed with Microsoft Excel. The results are shown in Table 1.

Equivalent

Those skilled in the art will recognize or be able to determine many equivalents of the specific implementations specifically described herein using routine experimentation. It is intended that these equivalents be included within the scope of the following patent applications.

Claims (49)

A compound of formula (I):

Or its pharmaceutically acceptable salts or tautomers. A pharmaceutical composition comprising a compound according to item 1 of the patent application, or a pharmaceutically acceptable salt or tautomer thereof, and a pharmaceutically acceptable diluent, excipient or carrier. The use of a compound according to item 1 of the patent application or its pharmaceutically acceptable salt or tautomer or a pharmaceutical composition according to item 2 of the patent application in the manufacture of a medicament, which is used to treat BTK Mediated illness. Use of a compound according to item 1 of the patent application, or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition according to item 2 of the patent application in the manufacture of a medicament, which is used to regulate BTK. The compound according to item 1 of the patent application or its pharmaceutically acceptable salt or tautomer is a method for treating BTK-mediated disorders or modulating BTK. A compound of formula (I):

Or a pharmaceutically acceptable salt thereof. A compound of formula (I):

A pharmaceutical composition comprising a compound according to item 6 of the patent application or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent, excipient or carrier. A pharmaceutical composition comprising a compound according to item 7 of the patent application scope and a pharmaceutically acceptable diluent, excipient or carrier. The use of a compound according to item 6 of the patent application or a pharmaceutically acceptable salt thereof or a compound according to item 7 of the patent application or a pharmaceutical composition according to item 8 or 9 of the patent application for the manufacture of a medicament, the medicament It is used to treat BTK-mediated disorders or regulate BTK. The compound according to item 6 of the patent application or its pharmaceutically acceptable salt or the compound according to item 7 of the patent application is a method for treating BTK-mediated disorders or modulating BTK. Use according to item 3 or 10 of the patent application scope, wherein the BTK-mediated disorder is selected from immune disorders, cancer, cardiovascular diseases Diseases, viral infections, inflammation, metabolic/endocrine dysfunction, and neurological disorders. Use according to item 12 of the patent application scope, wherein the cancer is selected from breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, esophageal cancer, laryngeal cancer, gastric cancer, skin cancer, lung cancer, bone cancer, colon cancer , Pancreatic cancer, thyroid cancer, hair cell cancer, buccal space cancer, pharyngeal cancer, lip cancer, tongue cancer, mouth cancer, small intestine cancer, colorectal cancer, colorectal cancer, rectal cancer, brain cancer, central nervous system cancer, nose Pharyngeal cancer, liver cancer, intrahepatic cholangiocarcinoma, bronchial cancer, endometrial cancer, renal cancer, renal pelvis cancer, urethral bladder cancer, endometrial cancer, oral cancer, throat cancer, glioblastoma, glioblastoma, Keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer (NSCLC), small cell carcinoma, lung adenocarcinoma, adenoma, adenocarcinoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma , Melanoma, sarcoma, bladder cancer, liver tumor, nephroma, myeloid disease, lymphoma, Hodgkin's lymphoma, hepatocellular carcinoma, glioma, multiple myeloma, acute myeloid leukemia, chronic Myeloid leukemia, lymphocytic leukemia, chronic lymphocytic leukemia (CLL), myeloid leukemia, non-Hodgkin's lymphoma, and villous colon adenoma. The use according to item 12 of the patent application scope, wherein the cancer is chronic lymphocytic leukemia. The use according to item 12 of the patent application scope, wherein the cancer is lymphoma. The use according to item 15 of the patent application scope, wherein the lymphoma is non-Hodgkin's lymphoma. The use according to item 15 of the patent application scope, wherein the lymphoma is a B-cell lymphoma. The use according to item 17 of the patent application scope, wherein the B-cell lymphoma is B-cell non-Hodgkin's lymphoma. The use according to item 15 of the patent application scope, wherein the lymphoma is a degeneratively changed large cell lymphoma. The use according to item 15 of the patent application scope, wherein the lymphoma is a central nervous system (CNS) lymphoma. The use according to item 20 of the patent application scope, wherein the CNS lymphoma is a primary CNS lymphoma. The use according to item 15 of the patent application scope, wherein the lymphoma is Waldenstram's macroglobulinemia. The use according to item 12 of the patent application scope, wherein the cancer is a bone marrow disorder. The use according to item 12 of the patent application scope, wherein the cancer is myeloid leukemia. The use according to item 12 of the patent application scope, wherein the cancer is acute myeloid leukemia. The use according to item 12 of the patent application scope, wherein the cancer is multiple myeloma. The use according to item 12 of the patent application scope, wherein the cancer is lymphocytic leukemia. The use according to item 12 of the patent application scope, wherein the cancer is a sarcoma. According to the use in item 12 of the patent application scope, the cancer is brain cancer. Use according to item 12 of the patent application scope, wherein the BTK-mediated condition is rheumatoid arthritis, systemic and local inflammation, arthritis, inflammation related to immunosuppression, organ transplant rejection, allergy, ulcerative colon Inflammation, Crohn's disease, dermatitis, asthma, systemic lupus erythematosus, Sjogren's syndrome, multiple sclerosis, scleroderma/systemic sclerosis, idiopathic thrombocytopenic purpura (ITP), anti-neutrophil cytoplasmic antibody (ANCA) vasculitis, chronic obstructive pulmonary disease (COPD) or psoriasis. The compound according to claim 5 or 11, wherein the BTK-mediated disorder is selected from immunological disorders, cancer, cardiovascular diseases, viral infections, inflammation, metabolic/endocrine dysfunction, and neurological disorders. The compound according to item 31 of the patent application scope, wherein the cancer is selected from breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, esophageal cancer, laryngeal cancer, gastric cancer, skin cancer, lung cancer, bone cancer, colon cancer , Pancreatic cancer, thyroid cancer, hair cell cancer, buccal space cancer, pharyngeal cancer, lip cancer, tongue cancer, mouth cancer, small intestine cancer, colorectal cancer, colorectal cancer, rectal cancer, brain cancer, central nervous system cancer, nose Pharyngeal cancer, liver cancer, intrahepatic cholangiocarcinoma, bronchial cancer, endometrial cancer, renal cancer, renal pelvis cancer, urethral bladder cancer, endometrial cancer, oral cancer, throat cancer, glioblastoma, glioblastoma, Keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer (NSCLC), small cell carcinoma, lung adenocarcinoma, adenoma, adenocarcinoma, follicle Carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder cancer, liver tumor, nephroma, myeloid disorder, lymphoma, Hodgkin's lymphoma, hepatocellular carcinoma, glioma Neoplasms, multiple myeloma, acute myeloid leukemia, chronic myelogenous leukemia, lymphocytic leukemia, chronic lymphocytic leukemia (CLL), myeloid leukemia, non-Hodgkin's lymphoma, and villous colon adenoma. According to the compound of claim 31, the cancer is chronic lymphocytic leukemia. The compound according to item 31 of the patent application scope, wherein the cancer is lymphoma. According to the compound of claim 34, the lymphoma is non-Hodgkin's lymphoma. The compound according to item 34 of the patent application scope, wherein the lymphoma is a B-cell lymphoma. The compound according to item 36 of the patent application range, wherein the B-cell lymphoma is B-cell non-Hodgkin's lymphoma. The compound according to item 34 of the patent application scope, wherein the lymphoma is a degeneratively changed large cell lymphoma. The compound according to claim 34, wherein the lymphoma is a central nervous system (CNS) lymphoma. The compound according to item 39 of the patent application scope, wherein the CNS lymphoma is a primary CNS lymphoma. The compound according to item 34 of the patent application scope, wherein the lymphoma is Waldenstram's macroglobulinemia. The compound according to claim 31, wherein the cancer is a bone marrow disorder. The compound according to item 31 of the patent application scope, wherein the cancer is myeloid leukemia. The compound according to item 31 of the patent application scope, wherein the cancer is acute myeloid leukemia. The compound according to item 31 of the patent application scope, wherein the cancer is multiple myeloma. The compound according to item 31 of the patent application scope, wherein the cancer is lymphocytic leukemia. The compound according to item 31 of the patent application scope, wherein the cancer is a sarcoma. According to the compound of claim 31, the cancer is brain cancer. The compound according to item 31 of the patent application scope, wherein the condition is rheumatoid arthritis, systemic and local inflammation, arthritis, inflammation related to immunosuppression, organ transplant rejection, allergy, ulcerative colitis, clone (Crohn ), dermatitis, asthma, systemic lupus erythematosus, Sjogren syndrome, multiple sclerosis, scleroderma/systemic sclerosis, idiopathic thrombocytopenic purpura (ITP), anti Neutrophil cytoplasmic antibody (ANCA) vasculitis, chronic obstructive pulmonary disease (COPD) or psoriasis.