TW201722956A - 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

Tetrahydropyranylamino-pyrrolopyrimidinone and method using same

The present invention relates to Bruton's tyrosine kinase (BTK) (including mutant BTK) inhibitors for use in the treatment of diseases or conditions associated with BTK kinase, including immune disorders, cancer, Cardiovascular disease, viral infection, inflammation, metabolic/endocrine dysfunction, and neurological disorders. In particular, the invention relates to compounds that inhibit BTK and compositions thereof, methods of treating diseases or conditions associated with BTK, and methods of synthesizing such 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 initiates many functional cellular processes 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 murine preclinical model of systemic lupus erythematosus (SLE) has been shown to result in significantly improved disease progression. In addition, BTK-deficient mice are resistant to the development of collagen-induced arthritis and less susceptible to staphylococcal-induced arthritis. Due to the role of BTK in B-cell activation, BTK inhibitors can also be used as inhibitors of pathogenic activity (such as autoantibody production) mediated by B-cells. BTK expression in osteoclasts, obese cells, and single cells has been shown to be important for the function of these cells. For example, IgE-mediated obese cell activation and reduced TNF-[alpha] production impaired by activated single cells have been associated with BTK deficiency in mice and humans. Thus, BTK inhibition can be used to treat allergic conditions and/or autoimmune and/or inflammatory diseases such as: SLE, rheumatoid arthritis, polyangiitis, 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 utility of BTK activity inhibition in the treatment of cancer, B-cell lymphoma, leukemia and other hematological malignancies. In addition, the role of BTK in osteoclast function is known to inhibit BTK activity and is useful in the treatment of bone disorders such as osteoporosis.

BTK inhibition with small molecule inhibitors thus has therapeutic immune disorders, cancer, cardiovascular disease, viral infection, inflammation, metabolism / The potential for endocrine dysfunction and neurological disorders. Therefore, there is still a considerable demand for small molecule inhibitors of BTK potency.

A first aspect of the application relates to a compound of formula (I): Or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof. As used herein, the terms 〞(I) compound 〞 and 〝 compound (I) 〞 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 thereof, analog thereof Or a derivative and a pharmaceutically acceptable diluent, excipient or carrier.

Another aspect of the present application relates to a method of treating a condition mediated by 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, in need of treatment A patient with a disease or condition associated with BTK kinase modulation.

Another aspect of the present application relates to a method of treating a condition mediated by BTK. The method comprises administering a therapeutically effective amount of a pharmaceutical composition There is a need for a condition for treating a disease or condition associated with BTK kinase modulation comprising a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite thereof, A crystalline form, analog or derivative and a pharmaceutically acceptable diluent, excipient or carrier.

Another aspect of the present application relates to a method of treating a cell proliferative disorder. 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, in need thereof The patient.

Another aspect of the present application relates to a method of treating a cell proliferative disorder. The method comprises administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolism thereof , a polymorph, an analog or derivative and a pharmaceutically acceptable diluent, excipient or carrier.

Another aspect of the present application relates to a method 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, in need thereof The patient.

Another aspect of the present application relates to a method of treating cancer. The method comprises administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolism thereof , a polymorph, an analog or derivative and a pharmaceutically acceptable diluent, excipient or carrier.

Another aspect of the present application relates to a method of modulating (e.g., 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, in need thereof The patient.

Another aspect of the present application relates to modulating (e.g., inhibiting) BTK. The method comprises administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolism thereof , a polymorph, an analog or derivative and a pharmaceutically acceptable diluent, excipient or carrier.

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

Another aspect of the present application relates to a pharmaceutical composition for treating a condition mediated by BTK, a cell proliferative disorder or cancer, or a method of modulating (e.g., 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 the present application relates to the manufacture of a compound of formula (I), or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof, for use in the manufacture of Use of a medicament for the treatment of a condition mediated by BTK, a cell proliferative disorder or cancer, or for modulating (e.g., inhibiting) BTK. A compound of formula (I), or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof, is administered in a therapeutically effective amount to a patient in need thereof .

Another aspect of the present application relates to the use of a pharmaceutical composition for the manufacture of a medicament for treating a BTK-mediated disorder, a cell proliferative disorder or cancer, or for modulating (e.g., inhibiting) BTK, the composition comprising Formula (I) A compound 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.

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

The present application provides BTK inhibitors, which are therapeutic agents for the treatment of 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 having improved potency and safety profiles relative to known BTK inhibitors. The present application also provides an agent for the novel mechanism of action of 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 ultimately provides a medical specialty with novel pharmacological strategies for treating diseases and conditions associated with BTK kinase.

Detailed description

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

In a first aspect of the application, which illustrates a 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 set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present application, the methods and materials are now illustrated. Other features, objects, and advantages of the present application will be apparent from the description of the invention and the appended claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. All technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art of the present application, unless otherwise defined. All patents and publications cited in this specification are hereby incorporated by reference in their entirety.

definition

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

The terms 〝 and/or 〞 used in this application mean 〝 and 〝 or 〝 or 〞 unless otherwise indicated.

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

The term "carrier" as used in this application includes carriers, excipients, and diluents that are involved in transporting or delivering a medicament from one organ or part of the body to another organ or part of the body, and means materials, A composition or vehicle such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material.

The compounds of formula (I) can form salts which are also within the scope of the present application. It is to be understood that the compounds of the formulae recited herein include the salts described herein, unless otherwise indicated.

Representative pharmaceutically acceptable salts include, for example, water soluble and water insoluble salts such as acetate, amsonate (4,4-diaminopurine-2,2-disulfonate) ), besylate, benzoate, hydrogencarbonate, hydrogen sulfate, hydrogen tartrate, borate, bromide, butyrate, calcium salt, calcium edetate, camphor sulfonate, carbonic acid Salt, chloride, citrate, clavulariate, dihydrochloride, ethylenediaminetetraacetate, ethanedisulfonate, estolate, ethanesulfonate, antibutene Fumerate, fiunarate, grape heptanoic acid, gluconic acid, glutamate, ethanol decyl p-aminobenzoate, hexafluorophosphate, hexylisophthalate ( Hexylresorcinate), hydrabamine salt, hydrobromine Acid salts, hydrochlorides, hydroxynaphthoates, iodides, isothionates, lactates, lactobions, laurates, magnesium salts, malates, maleates, almonds Acid salt, methanesulfonate, methyl bromide, methyl nitrate, methanesulfonate, pyrophosphate, naphthalenesulfonate, nitrate, N-methylglucamine ammonium salt, 3-hydroxyl -2-naphthoate, oleate, oxalate, palmitate, pamoate (1,1-methylene-bis-2-hydroxy-3-naphthoate, enwa Einbonate, pantothenate, phosphate/diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, secondary Acetate, succinate, sulfate, sulfosalicyrate, suramate, tannin, tartrate, teaclate, tosylate, triethyl Iodide and valerate.

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

〝 Solvate 〞 means a solvent addition form containing a stoichiometric or non-stoichiometric solvent. 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 an alcohol, the solvate formed is an alcoholate. Hydrates are formed by combining one or more water molecules with a molecular species, wherein water retains it as the molecular state of H ₂ O.

a compound of the invention (including salts, solvents of such compounds) All stereoisomers (eg, geometric isomers, optical isomers, and the like) of the compounds, esters, and prodrugs, as well as salts, solvates, and esters of prodrugs, such as those which may be due to various substituents Stereoisomers present on asymmetric carbon, including mirror image isomer forms (which may even exist in the absence of asymmetric carbon), rotamer forms, atropisomers, and non-mirrored Construct forms, as well as positional isomers such as 4-pyridyl and 3-pyridyl, are encompassed within the scope of the present application. For example, if a compound of formula (I) is incorporated into a double bond or a fused ring, both cis- and trans-forms, as well as mixtures, are included within the scope of the present application. Individual stereoisomers of the compounds of the present application may, for example, be substantially free of other isomers, or may be incorporated, for example, as racemates, or with all other or other selected stereoisomers. The chiral center of the present application may have an S or R configuration as defined by the IUPAC 1974 recommendation. The use of the terms sulfonium hydrazine, hydrazine hydrate, hydrazine oxime, ruthenium ruthenium ruthenium and the like is intended to apply equally to the mirror image isomers, stereoisomers, rotamers, tautomers of the compounds of the invention. Salts, solvates, esters and prodrugs of a conformation, positional isomer, racemate or prodrug.

The term "oxime isomer" refers to a compound having the same composition and molecular weight but differing in physical and/or chemical properties. Structural differences can lie in the configuration (geometric isomers) or in the ability to rotate the plane of polarized light (stereoisomers). With respect to stereoisomers, the compounds of formula (I) may have one or more asymmetric carbon atoms and may be present as racemates, racemic mixtures or individual mirror image or non-image isomers.

In the specification of the present invention, the structural formula of the compound is It is intended to represent a particular isomer in some cases, but the present application includes all isomers such as geometric isomers, optical isomers based on asymmetric carbons, stereoisomers, tautomers. Structure and the like.

〝 Isomerism 〞 means a compound having the same molecular formula, but the order of bonding of atoms or the arrangement of atoms in space is different. The isomers in which atoms are arranged in space are called 〝 stereoisomers. Stereoisomers that are not mirror images of each other are referred to as non-mirromeric isomers, and stereoisomers that are non-superimposable mirror images of each other are referred to as quinone mirror isomers or sometimes optical isomers. A mixture of individual mirror image isomer forms containing equal amounts of opposite chirality is referred to as a racemic mixture.

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

A carbon atom bonded to four different substituents is referred to as a chiral center enthalpy.

By chiral isomer 〞 is meant a compound having at least one chiral center. Compounds having more than one chiral center may be present as individual non-image isomers or as a mixture of non-image isomers known as quinone non-image isomer mixtures. When a chiral center is present, 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 a chiral center. 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; Experientia 1956, 12, 81; Cahn J. Chem. Educ. 1964, 41, 116).

〝Geometric isomer 〞 means a non-image isomer that exists due to resistance to rotation near the double bond. According to the Can-Ingone-Pullo rule, these configurations are in their names to indicate that the group is prefixed cis and trans, or Z and E, on the ipsilateral or opposite side of the double bond of the molecule. 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 a ( S )-mirromer. In other embodiments, the compound is a ( R )-mirromer. In still other embodiments, the compound of formula (I) can be a (+) or (-) mirror image isomer. The compound may contain more than one stereocenter.

In another embodiment of the present application, the formula (I) is combined The substance is a non-image isomer. In some embodiments, the compound is an ipsilateral non-image isomer. In other embodiments, the compound is a reverse non-image isomer.

Non-imagewise isomer mixtures can be separated into their individual non-image isomers based on their physical chemical differences by methods well known to those skilled in the art, such as by chromatography and/or fractionation. Segmental crystallization. The mirror image isomers can be isolated by reacting a mirror image isomerization mixture with a suitable optically active compound, such as a chiral auxiliary such as a chiral alcohol or Mosher's mercapto chloride. The mixture of mirror images isomerized, the non-image isomers are separated and the individual non-image isomers are converted (eg, hydrolyzed) to the corresponding pure mirror image isomers. The mirror image isomers can also be separated using a chiral HPLC column.

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

The oxime tautomer is one of two or more structural isomers present in equilibrium and can be readily converted from one isomeric form to another. This conversion results in a formal migration of hydrogen atoms accompanied by a transformation of adjacent conjugated double bonds. Tautomers are present as a mixture of tautomeric groups in solution. In solid form, it is often dominated by one tautomer. The tautomer reaches a chemical equilibrium in a solution that may have tautomerization. The exact ratio of tautomers depends on many factors including temperature, solvent and pH. Mutual conversion of each other by tautomerization The concept of an isomer is called tautomerism.

Of the various types of tautomerism that may be observed, two types are often observed. In the keto-enol tautomerism, electrons and hydrogen atoms move simultaneously. The cyclo-chain tautomerism occurs due to the reaction of an aldehyde group (-CHO) in a sugar chain molecule with one of the hydroxyl groups (-OH) in the same molecule, giving it a ring as shown by glucose (looping) Form).

Common tautomer pairs are: keto-enol, guanamine-nitrile, indoleamine-nitriene, guanamine-imidic tautomerism in heterocycles (eg in nucleobases, Such as guanine, thymine and cytosine, amine-enamine and enamine-imine. (Pyroropyrimidinyl)methanone-(pyrrolopyrimidinyl)methanol tautomer pairs are included in the present application:

The present application relates to a compound of formula (I), or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof, which is capable of inhibiting BTK, useful For the treatment of diseases and conditions associated with BTK kinase regulation. The application further relates to a compound of formula (I), or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof, for use in inhibiting BTK. In some implementations, BTK is wild Raw BTK. In other embodiments, BTK is a mutant BTK.

Another aspect of the present application pertains to compounds of formula (I), wherein the compound inhibits the kinase activity of the mutant BTK, such as a drug resistant mutant BTK (e.g., a C481S mutation) that occludes 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 due to a BTK kinase mutation (eg, a C481S mutation) that prevents target inhibition. In one embodiment, the BTK mutation is a C481S mutation.

In some embodiments, the application provides a compound of formula (I), wherein the compound is more potent in inhibiting BTK activity than one or more of the following known BTK inhibitors: 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, a compound may inhibit at least BTK activity more than at least ibrutinib, GDC-0834, RN486, CGI-560, CGI-1746, HM-71224, CC-292, ONO-4059, CNX-774, and/or LFM-A13. about 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or about 100 times the potency (e.g., the IC ₅₀ measured in a).

In some embodiments, the application provides a compound of formula (I), wherein the compound is less active against BTK comprising one or more mutations (eg, C481S) as described herein than one or more of the following known BTK inhibitors 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, a compound can inhibit the activity of BTK containing one or more mutations as described herein, such as Ibrutinib, GDC-0834, RN486, CGI-560, CGI-1746, HM-71224, CC-292, ONO-4059 , CNX-774, and / or LFM-A13 plurality of at least about 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or about 100 times the potency (e.g., the IC ₅₀ measured in a). A drug resistant BTK mutant can have, without limitation, a drug resistance mutation comprising a 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 compound of the present application can be converted to an N-oxide by treatment with an oxidizing agent 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 allow, all nitrogen compounds shown and claimed are considered to include the compounds as shown and their N-oxide derivatives (which may be indicated by N→O or N ⁺ -O ^- )both. Further, in other instances, the nitrogen in the compounds of the present application can be converted to N-hydroxy or N-alkoxy compounds. For example, an N-hydroxy compound can be prepared by oxidizing a nucleophilic amine with an oxidizing agent such as m-CPBA. When the price and structure permit, all nitrogen compounds shown and claimed are considered to cover the compounds as shown and their N-hydroxy groups (ie N-OH) and N-alkoxy groups (ie N-OR, Wherein R is a substituted or unsubstituted C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkenyl group, a C ₁ -C ₆ alkynyl group, a 3-14 member carbon ring or a 3-14 member heterocyclic ring) Both derivatives.

The term "prodrug" as used in this application means A metabolically (eg, hydrolyzed) compound that can be converted to the disclosed compound in vivo.

Because prodrugs are known to enhance many of the desired qualities of a drug (eg, solubility, bioavailability, manufacture, etc.), the compound of formula (I) or a pharmaceutically acceptable salt, tautomer, solvate, metabolism thereof The substance, polymorph, analog or derivative can be delivered as a prodrug. Accordingly, the present application is intended to encompass a prodrug of a compound of formula (I), or a pharmaceutically acceptable salt, tautomer, solvate, metabolite, polymorph, analog or derivative thereof, for delivery of the prodrug And a composition comprising the prodrug. The prodrug is intended to include any covalently bonded carrier which, when administered to a mammalian subject, releases 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 manner that the modifications are cleaved into the parent compound in a conventional manner or in vivo. Prodrugs include the compounds of the present application wherein a hydroxy or amine group is bonded to any group which, upon administration of a drug to a mammalian subject prior to the present application, 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 of the formulae described herein, or pharmaceutically acceptable salts, tautomers, prodrugs, solvates, metabolites, polymorphs, analogs or derivatives thereof. Acetate, formate and benzoate derivatives of alcohol and amine functional groups.

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

The term "anthraquinone analog" as used herein refers to a compound that is structurally similar to another compound but differs slightly in composition (eg, one atom or a particular functional group is present with an atom of a different element, or A functional group replaces a functional group). Thus, an analog is a compound that is similar or comparable in function and appearance, but is not a reference to the structure or origin of the compound.

The present application also encompasses isotopically labeled compounds which are identical to those recited in each of the formulae described herein, but in fact one or more atoms have atomic mass or mass number and the most commonly found atomic mass in nature. Or atomic substitution with different mass numbers. Examples of isotopes that may be incorporated into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, fluorine, such as ³ H, ¹¹ C, ¹⁴ C, ² H, and ¹⁸ F.

a compound of formula (I), or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof, containing the aforementioned isotopes and/or other isotopes of other atoms It is within the scope of the present invention. Isotopically labeled compounds of the present application (such as those incorporating radioactive isotopes, such as ³ H, ¹⁴ C) are useful in drug and/or matrix distribution assays. Deuterated (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 (positive emission tomography). PET can be used for brain imaging. Furthermore, substitution with heavier isotopes such as deuterium, i.e., ² H, may provide specific therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and thus may in some cases be more Preferably, the isotope-labeled compound of formula (I) or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof is generally The procedures disclosed in the schemes and/or examples are prepared by substituting an isotopically labeled reagent with an easily available isotopically labeled reagent. 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 invention is directed to a compound of a BTK modulator. In one embodiment, the compound of the present application is a BTK inhibitor.

The term "administer, administration" or "administration" as used in this application refers to the direct administration of a compound or a pharmaceutically acceptable salt or composition of the disclosed compound to an individual, or a compound or A pharmaceutically acceptable salt or composition of a compound is administered to an individual, a prodrug, derivative or analog which forms an equivalent amount of the active compound in the subject.

A sputum sputum or sputum 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, the guanidine effective amount 〝 or 〝 therapeutically effective amount 〞 is an amount effective to treat or prevent the disease in an individual as described herein.

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

The compounds of the present application, or pharmaceutically acceptable salts, tautomers, prodrugs, solvates, metabolites, polymorphs, analogs or derivatives thereof, may also be used to prevent a disease, condition or condition. Preventing or prevention as used herein means reducing or eliminating the onset of signs or complications of a disease, condition or condition.

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

The term "disease or condition" as mediated by BTK as used herein means any disease or other deleterious condition in which BTK or a mutant thereof is known to play a role. Accordingly, another embodiment of the present invention is directed to treating or ameliorating the severity of one or more diseases in which BTK or a mutant thereof is known to play a role. In particular, the present application relates to a method of treating or ameliorating the severity of a disease or condition selected from a proliferative disorder or an autoimmune disorder, wherein the method comprises administering a compound of formula (I) according to the present application or Pharmaceutically acceptable salts, tautomers, prodrugs, solvates, metabolites, polymorphs, analogs or derivatives or compositions thereof are administered to a patient in need thereof.

The term "cell proliferative disorder" as used herein refers to a condition in which cells that are unregulated or abnormally grown or both may cause an undesired condition or progression of the disease, which may or may not be cancerous. . Exemplary cell proliferative disorders of the present application encompass a variety of conditions in which cell division is dysregulated. Exemplary cell proliferative disorders include, but are not limited to, neoplasms, benign tumors, malignant tumors, precancerous conditions, orthotopic tumors, encapsulated tumors, metastatic tumors, liquid tumors, solid tumors, immune tumors, hematological tumors , cancers, carcinomas, leukemias, lymphomas, sarcomas, and rapidly dividing cells. The term "rapidly dividing cell" as used herein is defined as any cell that divides at a rate that exceeds or exceeds the rate expected or observed in adjacent or contiguous 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 and/or malignant tumors. The cancer cells or the precancerous cells are cells of a cell proliferative disorder that exhibits a primary cancer or a precancerous condition. A cancer cell or a cancer cell is a cell that exhibits a cell proliferative disorder of cancer. Any measure of reproducibility 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 conditions include, but are not limited to, rheumatoid arthritis; inflammation; autoimmune diseases; lymphoproliferative conditions; acromegaly; rheumatoid spondylitis; osteoarthritis; gout; Arthritic condition; 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; ); psoriasis; eczema; ulcerative colitis; pancreatic fibrosis; liver fibrosis; acute and chronic kidney disease; large intestine acute disease; fever; restenosis; cerebral malaria; stroke and ischemic injury; Trauma; Alzheimer's disease; Huntington's disease; Parkinson's disease; acute and chronic pain; allergic rhinitis; allergic conjunctivitis; chronic heart failure; Syndrome; cachexia; malaria; leprosy; kala-azar; Lyme disease; Reiter's syndrome; acute synovitis; muscle degeneration; bursitis; tendonitis; tenosynovitis; herniated, ruptured or prolapsed intervertebral disc Syndrome; osteopetrosis; thrombosis; restenosis; silicosis; pulmonary sarcoma; bone resorption diseases, such as osteoporosis; graft versus host response; Sclerosing disease; lupus; fibromyalgia; AIDS and other viral 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, appendical cancer, cerebellar astrocytoma in children, cerebral astrocytoma in children, Basal cell carcinoma, skin cancer (non-melanoma), biliary tract cancer, extrahepatic cholangiocarcinoma, intrahepatic cholangiocarcinoma, bladder cancer, urinary bladder cancer, bone and joint cancer, osteosarcoma and malignant fibrous histiocytoma, brain cancer , brain tumor, brain stem neuroglioma, cerebellar astrocytoma, cerebral astrocytoma / Malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal tumor, visual pathway and hypothalamic neuroma, breast cancer, tracheal adenoma/carcinoid, class Carcinoma, 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, lymphoma, verrucous granuloma, Seziary syndrome, endometrial cancer, esophageal cancer, extracranial germ cell tumor, extragonadal germ cell Extendary germ cell tumor, extrahepatic cholangiocarcinoma, eye cancer, intraocular melanoma, retinoblastoma, gallbladder carcinoma, gastric cancer, stomach cancer, gastrointestinal carcinoma, gastrointestinal stromal tumor (GIST), Germ cell tumor, ovarian germ cell tumor, gestational trophoblastic tumor neuroglioma, head and neck cancer, hepatocyte (liver) cancer, Hodgkin lymph Tumor, hypopharyngeal carcinoma, intraocular melanoma, eyeball cancer, pancreatic islet cell tumor (endocrine pancreatic cancer), Kaposi sarcoma, kidney cancer, renal cancer, kidney cancer, throat 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 Lymphoma, non-Hodgkin's lymphoma, primary central nervous system lymphoma, Waldenstram's macroglobulinemia, medulloblastoma, melanoma, intraocular (ocular) melanin Tumor, merkel cell Cancer, malignant mesothelioma, mesothelioma, metastatic squamous cell carcinoma, mouth cancer, tongue cancer, multiple endocrine neoplasia syndrome, verrucous granuloma, bone marrow malnutrition syndrome, poor bone marrow production/myeloproliferative disease, Chronic myelogenous leukemia, acute myeloid 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 cancer, parathyroid cancer, penile cancer, pharyngeal carcinoma, pheochromocytoma, pineal blastoma, and supratentorial Neuroectodermal tumor, pituitary tumor, plasma cell tumor/multiple myeloma, pleural pulmonary blastoma, prostate cancer, rectal cancer, renal pelvic and ureteral transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, 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 bowel cancer, soft tissue sarcoma, squamous cell carcinoma, stomach, gastric cancer, supratentorial primitive neuroectodermal tumor, testicular cancer, laryngeal cancer, thymoma, thymoma and thymic carcinoma, thyroid cancer Transitional cell carcinoma of the renal pelvis and ureter and other urinary organs, gestational trophoblastoma, urinary tract cancer, endometrial cancer, uterine sarcoma, endometrial cancer, vaginal cancer, genital cancer, and Wilm's tumor.

Method of preparing a compound

The compounds of the present application can be made in a variety of ways, including standard chemical methods. Suitable synthetic pathways are described below In the process.

The compound of formula (I) can be prepared by methods known in the art of organic synthesis, as described in the section of the synthetic scheme below. In the schemes described below, it is to be fully understood that a protecting group of a sensitive or reactive group is used, if necessary, in accordance with general principles or chemical properties. The protecting group is operated according to standard organic synthesis methods (T. W. Greene and P. G. M. Wuts, 3rd edition "Protective Groups in Organic Synthesis", Wiley, New York 1999). Such groups are removed at a suitable stage of compound synthesis using methods that are readily apparent to those skilled in the art. The method of selection, as well as the reaction conditions and the order of their execution, should be in accordance with the process for the preparation of the compounds of the present application.

Those skilled in the art will recognize the presence of a stereocenter in the compound of formula (I). Accordingly, the present application includes two possible stereoisomers (unless specified in the synthesis) and includes not only racemic compounds, but also individual mirror image isomers and/or non-image isomers. When the compound is desired to be a single mirror image or a non-image isomer, it can be obtained by stereospecific synthesis or by resolution of the final product or any suitable intermediate. Resolution of the final product, intermediate or starting material can be accomplished 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 prepared from commercially available starting materials or synthesized using known organic, inorganic and/or enzymatic methods.

The compounds of the present application can be synthesized by those skilled in the art. It is made in many ways that are 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 the art of synthetic organic chemistry or by variations of synthetic methods recognized by those skilled in the art. Preferred methods include, but are not limited to, those described below. The compounds of the present application (i.e., the compounds of formula (I)) can be synthesized according to the procedures outlined in General Scheme 1 containing the order of the intermediates 2-a to 2-h. Starting materials can be made commercially or in the literature reported or as known by way of example.

A general procedure for the preparation of 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. The phenol 2-b is added nucleophilically 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 such as potassium hydroxide (KOH) in a solvent such as ethanol at elevated temperature to yield the carboxylic acid 2-d. 2-d is methyl iodide using a base such as potassium carbonate (K ₂ CO ₃ ) or cesium carbonate (Cs ₂ CO ₃ ) in a solvent such as N,N-dimethylformamide (DMF) To provide 2-e. The intermediate 2-f is deuterated with 2-e using a strong base such as n-butyllithium (n-BuLi) in a solvent such as tetrahydrofuran (THF) to afford 2-g. The amine 2-h is nucleophilic plus using a base such as N,N-diisopropylethylamine (DIPEA) and optionally in a solvent such as N,N-dimethylformamide (DMF). The aryl chloride 2-g is formed to provide a compound of formula (I).

The mixture of the mirror image isomer, the non-image isomer, and the cis/trans isomer obtained from the above process may be a chiral salt technique, a normal phase, a reverse phase or a chiral depending on the nature of the separation. The column chromatography is separated into a single component of each other.

Biological test BTK kinase activity assay

Test inhibitors and controls were prepared in solvent (i.e., DMSO) and added to each well of the reaction disk. The full length active BTK was diluted in assay buffer and added to each well. After pre-incubation, the kinase reaction is initiated by the addition of an activation mixture diluted in assay buffer containing biotinylated PLC[gamma]2 peptide and ATP. The dish is incubated and then the reaction is terminated in the dark by the addition/detection mixture prepared in assay buffer. The assay disk is incubated in the dark and the disk is read on the disk reader.

BTK C481S kinase activity assay

The test inhibitor and the control are prepared in a solvent (ie DMSO) at the desired final concentration and added to each well of the reaction disk. in. The full length BTKC481S was diluted in assay buffer and added to each well volume. After pre-incubation, the kinase reaction is initiated by the addition of an activation mixture diluted in assay buffer containing biotinylated PLC[gamma]2 peptide and ATP. The dish is incubated and then the reaction is terminated in the dark by the addition/detection mixture prepared in assay buffer. The assay disk is incubated in the dark and the disk is read on the disk reader.

Anti-hyperplasia test

Cell viability was determined by MTS assay. Briefly, cells (i.e., 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 cell viability was then assessed using a microplate reader. Data were normalized to untreated control and analyzed in Microsoft Excel.

Method of using a compound

Another aspect of the present application relates to a method of treating, preventing, inhibiting or ameliorating a disease or condition associated with BTK modulation (e.g., BTK inhibition). The method comprises an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof or formula (I) The pharmaceutical composition of the compound is administered to a patient in need of treatment for a disease or condition associated with BTK modulation. In one embodiment, the condition mediated by BTK is selected from the group consisting of an immune disorder, 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 an anti-inflammatory agent, an immunomodulatory agent, a chemotherapeutic agent, a neurotrophic factor, a agent for treating cardiovascular disease, a agent for treating liver disease, and a disease resistance agent. A poison, an agent for treating blood diseases, an agent for treating diabetes, and an agent for treating an immunodeficiency disorder. In some embodiments, the BTK is wild-type BTK. In other embodiments, BTK is a mutant BTK (eg, a BTK C481S mutant).

A further aspect of the present application relates to a method of treating, preventing, inhibiting or ameliorating a cell proliferative disorder, the method comprising administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, tautomer thereof, Prodrugs, solvates, metabolites, polymorphs, analogs or derivatives or pharmaceutical compositions of the compounds of formula (I) are administered to a patient 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 an anti-inflammatory agent, an immunomodulatory agent, a chemotherapeutic agent, a neurotrophic factor, a agent for treating cardiovascular disease, a agent for treating liver disease, and a disease resistance agent. A poison, an agent for treating blood diseases, an agent for treating diabetes, and an agent for treating an immunodeficiency disorder.

Another aspect of the present application relates to a method of modulating BTK, which comprises a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite thereof A pharmaceutical composition of a polymorph, analog or derivative or a compound of formula (I) is administered to a patient in need thereof. In one embodiment, the BTK system is modulated to inhibit BTK. In some embodiments, the 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, for use in a method of treating a condition mediated by BTK , a polymorph, an analog or a derivative. In one embodiment, the disease or condition is selected from the group consisting of an immune condition, a cancer, a cardiovascular disease, a viral infection, inflammation, a metabolic/endocrine dysfunction, and a neurological disorder. In some embodiments, the method further comprises administering an additional therapeutic agent selected from the group consisting of an anti-inflammatory agent, an immunomodulatory agent, a chemotherapeutic agent, a neurotrophic factor, a agent for treating cardiovascular disease, a agent for treating liver disease, and a disease resistance agent. A poison, an agent for treating blood diseases, an agent for treating diabetes, and an agent for treating an immunodeficiency disorder. In some embodiments, the BTK is wild-type BTK. In other embodiments, BTK is a mutant BTK (eg, a BTK C481S mutant).

In another aspect, the present application is directed to a compound of formula (I), or a pharmaceutically acceptable salt, tautomer, prodrug, solvate thereof, for use in a method of treating a condition mediated by BTK, A pharmaceutical composition of a metabolite, polymorph, analog or derivative. In one embodiment, the disease or condition is selected from the group consisting of an immune condition, a cancer, a cardiovascular disease, a viral infection, inflammation, a metabolic/endocrine dysfunction, and a neurological disorder. In some embodiments, the method further comprises administering an additional therapeutic agent selected from the group consisting of an anti-inflammatory agent, an immunomodulatory agent, a chemotherapeutic agent, a neurotrophic factor, a agent for treating cardiovascular disease, a agent for treating liver disease, and a disease resistance agent. A poison, an agent for treating blood diseases, an agent for treating diabetes, and an agent for treating an immunodeficiency disorder. In some embodiments, the BTK is wild-type BTK. In other In an embodiment, BTK is a mutant BTK (eg, a BTK C481S mutant).

Another aspect of the present application relates to a compound of formula (I), or a pharmaceutically acceptable salt, tautomer, prodrug, solvate thereof, for use in a method for treating, preventing, inhibiting or ameliorating a cell proliferative disorder A substance, metabolite, polymorph, analog or derivative. In one embodiment, the cell proliferative disorder is cancer.

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

Another aspect of the invention pertains to a compound of formula (I), or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof, for use in modulating BTK Things. In one embodiment, the BTK system is modulated to inhibit BTK. In some embodiments, the BTK is wild-type BTK. In other embodiments, BTK is a mutant BTK (eg, a BTK C481S mutant).

In another aspect, the present application is directed to a compound of formula (I), or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph thereof, or the like, for use in modulating BTK. a pharmaceutical composition of a substance or derivative. In one embodiment, the BTK system is modulated to inhibit BTK. In some embodiments, the 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 a compound of formula (I), or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof, for use in the manufacture of Use of a medicament for treating a disease or condition mediated by BTK-. In one embodiment, the disease or condition is selected from the group consisting of an immune condition, a cancer, a cardiovascular disease, a viral infection, inflammation, a metabolic/endocrine dysfunction, and a neurological disorder. In some embodiments, the treatment further comprises administering an additional therapeutic agent selected from the group consisting of an anti-inflammatory agent, an immunomodulatory agent, a chemotherapeutic agent, a neurotrophic factor, a agent for treating cardiovascular diseases, a agent for treating liver diseases, and an antiviral agent. An agent for treating blood diseases, an agent for treating diabetes, and an agent for treating an immunodeficiency disorder. In some embodiments, the BTK is wild-type BTK. In other embodiments, BTK is a mutant BTK (eg, a BTK C481S mutant).

In another aspect, the present application is directed to a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof The use of a pharmaceutical composition for the manufacture of a medicament for the treatment of a BTK-mediated disease or condition. In one embodiment, the disease or condition is selected from the group consisting of an immune condition, a cancer, a cardiovascular disease, a viral infection, inflammation, a metabolic/endocrine dysfunction, and a neurological disorder. In some embodiments, the treatment further comprises administering an additional therapeutic agent selected from the group consisting of an anti-inflammatory agent, an immunomodulatory agent, a chemotherapeutic agent, a neurotrophic factor, a agent for treating cardiovascular diseases, a agent for treating liver diseases, and an antiviral agent. An agent for treating blood diseases, an agent for treating diabetes, and an agent for treating an immunodeficiency disorder. In some embodiments, BTK is wild type BTK. In other embodiments, BTK is a mutant BTK (eg, a BTK C481S mutant).

Another aspect of the present application relates to the manufacture of a compound of formula (I), or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof, for use in the manufacture of Use of a medicament for treating, preventing, inhibiting or eliminating a cell proliferative disorder. In one embodiment, the cell proliferative disorder is cancer.

In another aspect, the present application is directed to a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof The use of a pharmaceutical composition for the manufacture of a medicament for the treatment, prevention, inhibition or elimination of a cell proliferative disorder. In one embodiment, the cell proliferative disorder is cancer.

Another aspect of the present application relates to the manufacture of a compound of formula (I), or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof, for use in the manufacture of The use of a BTK-adjusting agent. In one embodiment, the BTK system is modulated to inhibit BTK. In some embodiments, the BTK is wild-type BTK. In other embodiments, BTK is a mutant BTK (eg, a BTK C481S mutant).

In another aspect, the present application is directed to a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof The use of a pharmaceutical composition to manufacture a medicament for modulating BTK. In one embodiment, the BTK system is modulated to inhibit BTK. In some embodiments, BTK is wild type BTK. In other embodiments, BTK is a mutant BTK (eg, a BTK C481S mutant).

In some embodiments of the methods and uses described herein, the cancer is selected from the group consisting of breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, genitourinary tract cancer, esophageal cancer, laryngeal cancer, and glial cell. 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 carcinoma, undifferentiated carcinoma, mastoid carcinoma, spermatoma, melanoma, sarcoma, bladder cancer, liver cancer and biliary tract cancer, kidney cancer, pancreatic cancer, bone marrow Disease, lymphoma, hair cell carcinoma, buccal carcinoma, nasopharyngeal carcinoma, 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 carcinoma, thyroid cancer, liver and intrahepatic cholangiocarcinoma, hepatocellular carcinoma, gastric cancer, glioma/glioma, endometrial cancer, melanoma, kidney and renal pelvic cancer Urethral bladder cancer, uterine body cancer, cervical cancer, and more Myeloma, acute myeloid leukemia, chronic myelogenous leukemia, lymphocytic leukemia, chronic lymphocytic leukemia (CLL), myeloid leukemia, oral and laryngeal cancer, non-Hodgkin's lymphoma, melanoma and villus 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, renal cancer, large cell lymphoma, leukemia, multiple myeloma, mesothelioma, and melanoma, and combinations thereof.

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

In some embodiments of the methods and uses described herein, the disease or condition 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), anti-neutrophils Cytoplasmic antibodies (ANCA) vasculitis, chronic obstructive pulmonary disease (COPD), psoriasis.

In one embodiment, a method of treating a disease or condition associated with BTK modulation, including an immune disorder, cancer, cardiovascular disease, viral infection, inflammation, metabolic/endocrine dysfunction, and a neurological disorder, comprises formula I) The compound is administered to a patient suffering from at least one of the diseases or conditions.

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

The compounds of the present application can be administered in a therapeutically effective amount in combination therapy with one or more therapeutic agents (pharmaceutical combinations) or modes (e.g., non-pharmacological therapy). For example, with other anti-proliferation, anti-cancer, immune regulation 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 an anti-inflammatory agent, an immunomodulator, a chemotherapeutic agent, a neurotrophic factor, a agent for treating cardiovascular diseases, and a liver disease treatment. Agents, antiviral agents, agents for treating blood diseases, agents for treating diabetes, and agents for treating immunodeficiency disorders. When a compound of the present application is administered together with other therapeutic agents, the dosage of the co-administered compound will of course vary depending on the type of co-drug used, the particular drug employed, the condition being treated, and the like.

Combination therapies include administering a subject compound with other biologically active ingredients (such as, but not limited to, anti-inflammatory agents, immunomodulators, chemotherapeutic agents, neurotrophic factors, agents for treating cardiovascular diseases, agents for treating liver diseases, antiviral agents, treatments) Additional combinations of agents for blood disorders, agents for treating diabetes and agents for treating immunodeficiency disorders, and non-drug therapies such as, but not limited to, surgery or radiation therapy. For example, the compounds of the present application can be used in combination with other pharmaceutically active compounds, preferably compounds which increase the effect of the compounds of the present application. The compounds of the present application can be administered simultaneously (either as a single formulation or as separate formulations) or sequentially with other pharmaceutical therapies or modes of treatment. Combination therapies typically envisage administration of two or more drugs during a single cycle or during a 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 And to There is one less pharmaceutically acceptable excipient or combination of carriers.

The pharmaceutical composition is a formulation containing a 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 in unit dosage form. Unit dosage forms can be in any of a variety of forms including, for example, capsules, IV bags, lozenges, single pumps or vials on an aerosol inhaler. An active ingredient (e.g., a disclosed compound, or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof) in a unit dosage composition. The amount of the formulation) is an effective amount and varies depending on the particular treatment involved. It will be understood by those skilled in the art 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, transpulmonary, rectal, parenteral, percutaneous, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal, sublingual, intrapleural, intrathecal, intranasal and Similar. Dosage forms for topical or transdermal administration of a compound of the present 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 preservative, buffer or propellant required.

The phrase "pharmaceutically acceptable" as used herein refers to such compounds, materials, compositions, carriers and/or dosage forms suitable for use in contact with human and animal tissues within the scope of sound medical judgment, without undue excess. Toxicity, irritation, allergic reactions or other problems or complications, and a reasonable benefit/risk ratio.

"Pharmaceutically acceptable excipient" means an excipient for the preparation of a pharmaceutical composition which is generally safe, non-toxic and which is not biologically or otherwise undesirable, and includes both veterinary use and human medicine. An acceptable excipient for use. The pharmaceutically acceptable excipients, as used in the specification and claims, include one or more such excipients.

The pharmaceutical compositions of the present application are formulated to be compatible with the intended route of administration. Examples of routes of administration include parenteral, such as intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), and transmucosal administration. Solutions or suspensions for parenteral, intradermal or subcutaneous administration may include the following ingredients: sterile diluents, such as water for injection, aqueous saline, fixed oil, polyethylene glycol, glycerol, propylene glycol or other synthetic solvents; An antibacterial agent such as benzyl alcohol or methylparaben; an antioxidant such as ascorbic acid or sodium hydrogen sulfite; a chelating agent such as ethylenediaminetetraacetic acid; a buffer such as acetate, citrate or phosphate; And an agent for adjusting the tension, such as sodium chloride or glucose. The pH can be adjusted with an acid or a base 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 compounds or pharmaceutical compositions of the present application can be administered to an individual in a number of well known methods currently used in the treatment of chemotherapy. For example, a compound of the present application for treating cancer can be injected directly into a tumor, injected into the bloodstream or into a body cavity, or administered orally or as a patch through the skin. 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 period and within a reasonable period of time after treatment Monitor patients' diseases (such as cancer, primary cancer, and the like) and their health status closely.

The term "therapeutically effective amount" as used herein, refers to an 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 assay known in the art. The amount that is clearly effective for an individual will depend on the individual's weight, size, and health; the nature and extent of the condition; and the combination of treatments or treatments selected for administration. The therapeutically effective amount for a particular situation can be determined by routine experimentation within the skill and judgment of the clinician. In one embodiment, the disease or condition is selected from the group consisting of an immune condition, a cancer, a cardiovascular disease, a viral infection, inflammation, a metabolic/endocrine dysfunction, and a neurological disorder. 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.

A therapeutically effective amount of any compound can be initially estimated in a cell culture assay (e.g., a tumor cell) or in an animal model (often a rat, mouse, rabbit, dog, or pig). Animal models can also be used to determine the appropriate concentration range and path of administration. This information can then be used to determine the useful dose and route to humans. Therapeutic / prophylactic efficacy and toxicity in a standard pharmaceutical procedures determined in cell cultures or experimental animals, e.g. ED ₅₀ (dose at 50% of the group in the therapeutically effective) and LD ₅₀ (so that 50% of the groups lethal dose ). The dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the ratio LD ₅₀ /ED ₅₀ . A pharmaceutical composition exhibiting a high therapeutic index is preferred. The dosage may vary within this range depending on the dosage form employed, the sensitivity of the patient, and the route of administration.

Adjust the dose and dose to provide sufficient active agent concentration or to maintain the desired effect. Factors that may be considered include the severity of the disease state, the general health of the individual, the age, weight and sex of the individual, the diet, the time and frequency of administration, the combination of drugs, the sensitivity of the response, and the tolerance/response to the treatment. . The long-acting pharmaceutical composition can be administered every 3 to 4 days, every week, or every two weeks, depending on the half-life and clearance rate of the particular formulation.

Pharmaceutical compositions containing the active compounds of the present application (i.e., compounds of formula (I)) can be prepared in a generally known manner, for example by conventional mixing, dissolving, granulating, making sugar-coated tablets, grinding, emulsifying, Encapsulation, entrainment or freezing method. The pharmaceutical compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers, including excipients and/or adjuvants which facilitate the processing of the active compounds into preparations which are pharmaceutically acceptable. Of course, the appropriate formulation will depend on the route of administration chosen.

Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where they are soluble in water) or dispersions and sterile powders for the preparation of injectable solutions or dispersions. Carriers suitable for intravenous administration include physiological saline, bacteriostatic water, Cremophor EL ^(TM) (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 the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, sodium thiomersate and the like. In many instances, it is preferred that the composition include an isotonic agent (e.g., a sugar), a polyol (such as mannitol, sorbitol), sodium chloride. Prolonged absorption of the injectable compositions can be brought about by including agents which delay absorption, such as aluminum monostearate and gelatin, in the composition.

Sterile injectable solutions can be prepared by incorporating the active compound in the required compositions in a liquid or a combination of the ingredients or ingredients listed above in a suitable solvent, if desired, followed by filtration. Dispersions are generally prepared by incorporating the active compound into a sterile vehicle which contains a base dispersion medium and other optional ingredients selected from those listed above. In the case of a sterile powder for the preparation of a sterile injectable solution, the preparation process is vacuum drying and lyophilization, from the previously sterilely filtered solution, the active ingredient plus any additional ingredients of the desired ingredients.

Oral compositions typically include an inert diluent or a pharmaceutically acceptable edible carrier. The composition can be encapsulated in a gelatin capsule or compressed into a tablet. For the purpose of oral administration, the active compound may be combined with excipients and employed in the form of lozenges, lozenges or capsules. The oral composition can also be prepared using a fluid carrier for use as a mouthwash in which the fluid is loaded The compound in the agent is administered orally and rinsed and spit or swallowed in the mouth. Pharmaceutically compatible binders and/or adjuvant materials can be included as part of the composition. Tablets, pills, capsules, throat lozenges and the like may contain any of the following ingredients or compounds of similar nature: binders such as microcrystalline cellulose, tragacanth or gelatin; excipients such as starch or lactose a disintegrant such as alginic acid, Primogel or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal cerium oxide; a sweetener such as sucrose or saccharin; or a flavoring agent such as Peppermint, methyl salicylate or orange flavoring.

The compounds for administration by inhalation are delivered in the form of an aerosol spray from a pressurized container or dispenser containing a suitable propellant, such as a gas, such as carbon dioxide, or a nebulizer.

Systemic administration can also be carried out by mucosal or transdermal means. A penetrating agent suitable for permeating the barrier is used in a formulation 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 by the use of nasal sprays or suppositories. The active compounds for transdermal administration are formulated into ointments, salves, gels or creams as generally known in the art.

The active compounds can be prepared by avoiding the 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. Method for preparing such formulations It is understood by those skilled in the art. Materials are also available commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells having monoclonal antibodies to 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, for example, as described in U.S. Patent No. 4,522,811.

It is especially advantageous to formulate oral or parenteral compositions in unit dosage forms that are easy to administer and that are homogeneous in dosage. Dosage unit form, as used herein, refers to a physically discrete unit that is suitable as a unit dosage of the individual to be treated; each unit comprises a predetermined amount of active compound calculated to bind to 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 particular therapeutic effect desired or directly dependent on such characteristics and therapeutic effects.

In therapeutic applications, the dosage of the pharmaceutical composition used in accordance with the present application depends, in addition to other factors affecting the selected dosage, on the agent, the age, weight and clinical condition of the patient being treated, and the clinical circumstances in which the treatment is administered. The experience and judgment of a physician or practicing physician. The dosage should generally be sufficient to cause a slowing of the tumor growth and preferably to resolve, and preferably also cause complete regression of the cancer. Dosages can range from about 0.01 mg/kg per day to about 5000 mg/kg per day. An effective amount of a pharmaceutical agent is an amount that provides an objectively identifiable improvement as noted by a clinician and other qualified observers. For example, tumor regression in a patient can be measured with reference to the diameter of the tumor. A reduction in tumor diameter indicates regression. The regression is also indicated by the tumor no longer appearing after stopping treatment. The term 〝 dose effective mode as used herein refers to The amount of active compound that produces a desired biological effect in an individual or cell.

The pharmaceutical composition can be incorporated into the container, package or dispenser together with the indication of administration.

As used herein, pharmaceutically acceptable salt hydrazine refers to a derivative of a compound of the present application wherein the nucleophilic compound is modified by making an acid or base salt thereof. 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, the non-toxic salts or quaternary ammonium salts of the 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 acids and organic acids selected from the group consisting of 2-ethyloxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonate. Acid, benzoic acid, acid carbonic acid, carbonic acid, citric acid, ethylenediaminetetraacetic acid, ethane disulfonic acid, 1,2-ethanesulfonic acid, fumaric acid, grape heptanoic acid, gluconic acid, glutamine Acid, glycolic acid, ethanol thiol-aminobenzoic acid, hexylresorcinol, hydrabamic, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxy fumaric acid, hydroxynaphthoic acid , isethionethane, lactic acid, lactobionic acid, lauryl sulfonic 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, methic acid, succinic acid, amine sulfonic acid, p-aminobenzenesulfonic acid, sulfuric acid, tannic acid, tartaric acid, toluenesulfonic acid and Common amino acids such as glycine, alanine, phenylalanine, arginine and the like.

Other examples of pharmaceutically acceptable salts include caproic acid, rings Pentylpropionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzhydryl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonate 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 proton present in the parent compound is replaced by a metal ion (such as an alkali metal ion, an alkaline earth metal ion or an ammonium ion); or with an organic base (such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N) When the methyl-reductive glucosamine and the like are coordinated, the present invention also encompasses the salt formed.

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

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

The compounds of the present application may 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 liberates an active parent drug in vivo. Because prodrugs are known to enhance many of the desired qualities of a drug (e.g., solubility, bioavailability, manufacturing, etc.), the compounds of the present application can be delivered in prodrug form. Accordingly, the present application is intended to cover prodrugs of currently applied compounds, methods of delivery thereof, and Contains its constituents. The prodrug is intended to include any covalently bonded carrier which, when administered to an individual, releases 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 such a manner that the modifications are cleaved into the parent compound in a conventional manner or in vivo. Prodrugs include the compounds of the present application wherein a hydroxy, amine, thiol, carboxy or carbonyl group is bonded to any group which is cleaved in vivo to form free hydroxyl groups, free amine groups, free sulfhydryl 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, dialkylamino acetate, formate, phosphate, sulfate, and benzoate derivatives) And a carbamate (for example, N,N-dimethylaminocarbonyl); an ester of a carboxyl functional group (e.g., ethyl ester, morpholinoethanol ester); an N-mercapto derivative of an amine functional group (e.g. N-Ethyl)N-Mannich bases, Schiff bases and enaminones; oximes, acetals, ketals and enol esters of ketone and aldehyde functional groups; and similar, see Bundegaard , H. Design of Prodrugs, p1-92, Elsevier, New York-Oxford (1985).

A compound, or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof, is orally, nasally, transdermally, pulmonaryly, inhaled, orally 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 particular route of administration.

Dosage regimens utilizing the compound are selected according to a variety of factors, including the type, species, age, weight, sex, and medical condition of the patient; the severity of the condition being treated; the route of administration; the kidney and liver function of the patient; The particular compound used, or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof. An effective amount of the drug required to prevent, counter or arrest the progression of the condition can be readily determined and opened by a clinician or veterinarian who is familiar with the art.

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 pharmaceutically acceptable salts, tautomers, prodrugs, solvates, metabolites, polymorphs, analogs or derivatives thereof, are pharmaceutically acceptable A carrier or diluent combination is used in the pharmaceutical preparation. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The compound or a pharmaceutically acceptable salt, prodrug, solvate, metabolite, polymorph, analog or derivative thereof is present in an amount sufficient to provide a desired dosage within the ranges described herein. In pharmaceutical compositions.

All percentages and ratios used herein are by weight unless otherwise indicated. Other features and advantages of the present invention will become apparent from the various embodiments. The examples provided are illustrative of different components and methods for practicing the present invention. The embodiment does not limit the application Application. Those skilled in the art can use the present invention to identify and use other components and methods for practicing the present invention.

Example

The present application is further exemplified by the following examples and synthetic procedures, which are not to be construed as limiting the scope and spirit of the application to the specific procedures described herein. The examples are provided to illustrate specific embodiments and are not intended to limit the scope of the application. It should be further appreciated that various other embodiments, modifications, and equivalents may be made by those skilled in the art, without departing from the spirit of the invention and/or the scope of the appended claims.

Analytical methods, materials and instruments

Use reagents and solvents received from market suppliers unless otherwise noted. Proton nuclear magnetic resonance (NMR) spectroscopy was obtained on a Bruker or Varian spectrometer at 400 MHz. The spectroscopy is given in ppm (δ) and the coupling constant J is recorded in Hertz. Tetramethyl decane (TMS) was used as an internal standard. Mass spectra were collected using a Waters ZQ Single Quad mass spectrometer (Ion Trap ESI). Purity and low-resolution mass spectrometry data using 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. Data was obtained using Waters MassLynx 4.1 software and the purity was UV The wavelength is 220 nm, ELSD and ESI are characterized. Column: Acquity UPLC BEH C18 1.7μm 2.1 X 50mm; Flow rate: 0.6 ml/min; Solvent A (95 mM ammonium citrate/acetonitrile/formic acid 95/5/0.1), solvent B (95/5/0.09 acetonitrile/water) / Formic acid); Gradient: 5-100% B from 0 to 2 minutes, 100% B to 2.2 minutes, followed by 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)

The 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 the evolution of the gas ceased. The reaction mixture was stirred at room temperature for 10 min then 2-chloro-4-fluorobenzonitrile (2-A, 5.0 g, 32.5 mmol). 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 brine solution, dried over Na ₂ SO _4. A concentrate of 7.5 g of an off-white solid was supplied. 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) The material is consumed until the start. The mixture was allowed to cool to room temperature and the mixture was slowly acidified with concentrated HCl. The precipitate was filtered and dried to give a beige solid (2- C, 7.. NMR (400 MHz, DMSO-d ₆ ) δ 13.22 (s, 1H), 7.78 (d, J = 8.7 Hz, 1H), 7.48 (t, J = 7.8 Hz, 2H), 7.27 (t, J = 7.4 Hz, 1H), 7.16 (d, J = 8.0 Hz, 2H), 7.08 (d, J = 2.2 Hz, 1H), 6.97 (dd, J = 8.7, 2.3 Hz, 1H); MS m/z 249 [M+H ] ⁺ .

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

2-Chloro-4-phenoxy-benzoic acid (2-C, 5.0 g, 20.2 mmol) was dissolved in DMF (50 mL) was added and the solid K ₂ CO ₃ (4.15 g, 30.1 mmol). The reaction mixture was cooled to 0 ° C and methyl iodide (1.4 mL, 22.2 mmol) was then added dropwise. The mixture was allowed to warm to room temperature over 1 hour. The starting materials are all consumed during this period. The mixture was diluted with water and extracted with Et ₂ O to. It was dried and concentrated in vacuo to give EtOAc (EtOAc md. NMR (400 MHz, DMSO-d ₆ ) δ 7.89 (d, J = 8.7 Hz, 1H), 7.49 (t, J = 7.9 Hz, 2H), 7.29 (t, J = 7.4 Hz, 1H), 7.17 (d, J=7.9 Hz, 2H), 7.12 (d, J=2.4 Hz, 1H), 6.99 (dd, J=8.7, 2.4 Hz, 1H), 3.84 (s, 3H); MS m/z 263 [M+H ] ⁺ .

Example 2: (2-Chloro-4-phenoxyphenyl)(4-((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-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) with N-bromosuccinimide (26.7 g) , 149.8 millimolar) batch processing while maintaining a temperature of about 25-30 ° C. The reaction mixture was stirred at room temperature overnight. Water (500 ml) was added and the phases were separated. The dried organic phase was ₂ SO ₄ Na, filtered, and concentrated in vacuo. The crude product was triturated in Et ₂ O and filtered to give 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (2-F, 22.43 g, 74%) 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 , 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 (2.69 M in hexanes, 23.2 mL, 62.3 mmol) was added dropwise at -78 ° C under an inert atmosphere to 5-bromo-4-chloro-7H in THF (200 mL) A stirred solution of pyrrolo[2,3-d]pyrimidine (2-F, 6.90 g, 29.7 mmol). The reaction mixture was maintained at -78 ° C for 1 hour and then added to a solution of methyl 2-chloro-4-phenoxybenzoate (2-D, 8.19 g, 31.2 mmol) in THF (80 mL) Cool (to -78 ° C) in solution. The reaction mixture was stirred at -78 <0>C for 1 h then quenched with EtOAc EtOAc. The mixture was allowed to warm to room temperature and then extracted with EtOAc (3 X 100 mL). The combined extracts were washed with brine, dried over Na ₂ SO ₄ dried and concentrated in vacuo. The crude product was purified by column chromatography technique (SiO _2, hexanes / EtOAc) to to give a white solid becomes (2-chloro-4-phenoxyphenyl) (4-chloro--7H- pyrrolo [ 2,3-d]pyrimidin-5-yl)methanone (2-G, 4.73 g, 41%). ^{1 H NMR (400MHz, DMSO-} d 6) δ 13.426 (s, 1H), 8.75 (s, 1H), 8.14 (s, 1H), 7.60 (d, J = 8.5Hz, 1H), 7.49 (t, J = 7.9 Hz, 2H), 7.26 (t, J = 7.4 Hz, 1H), 7.23 - 7.12 (m, 3H), 7.01 (dd, J = 8.5, 2.3 Hz, 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-piperid-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) a mixture of ((2S,5R)-5-aminotetrahydro-2H-piperidin-2-yl)methanol (72 mg, 0.54 mmol) with DIPEA (272 μL, 1.56 mmol) The mixture was stirred at 160 ° C for 1 hour under microwave irradiation. The volatiles were removed in vacuo and the residue was purified by column chromatography technique _{(NH 2 -SiO 2, DCM /} MeOH), to give an off-white solid becomes (2-chloro-4-phenoxyphenyl) (4-((3R,6S)-6-(Hydroxymethyl)tetrahydro-2H-piperid-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl ) ketone ((I), 175 mg, 70%). ^{1 H NMR (400MHz, DMSO-} d 6) δ12.76 (s, 1H), 8.60 (d, J = 7.1Hz, 1H), 8.25 (s, 1H), 7.64 (s, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.48 (t, J = 7.6 Hz, 2H), 7.26 (t, J = 7.2 Hz, 1H), 7.18-7.20 (m, 3H), 7.02 (d, J = 8.3 Hz, 1H), 4.67 (s, 1H), 4.16 (d, J = 7.7 Hz, 2H), 3.49-3.27 (m, 3H), 3.12 (t, J = 11.2 Hz, 1H), 2.19 (d, J = 11.4) Hz, 1H), 1.78 (d, J = 12.9 Hz, 1H), 1.67-1.49 (m, 1H), 1.39 (d, J = 12.3 Hz, 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 a reaction disk (Corning 96 - a white disk with a solid surface that was not connected to the solid half of the slot). 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-glycerophosphate and Diluted in 0.2 mM NaF) and added to each well in a volume of 17.5 microliters, a final concentration of 0.08 nM in a 25 microliter reaction. After pre-incubation for 30 minutes at room temperature, the kinase reaction was initiated by the addition of 5 μl of the activation mixture diluted in assay buffer containing biotinylated PLCγ2 peptide and ATP to a final concentration of 150 nM biotinylated PLCγ2 and 180 μM ATP. . The plates were incubated for 60 minutes at room temperature. In the dark by the addition of EDTA and containing AlphaScreen ^TM biotin streptavidin donor beads and anti -pTYR100 assay buffer acceptor beads prepared in 10 microliter stop / detection mixture to terminate the reaction. Final concentration of 10mM EDTA and both 500 ng / AlphaScreen ^TM slots of donor beads and acceptor beads. The assay plate was incubated for 60 minutes at room temperature in the dark and the plate 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

Test inhibitors and controls (Starosporine) were prepared in 10% DMSO at 10 times the desired final concentration and added to the reaction disk in a volume of 2.5 microliters (Corning 96-slot half zone) In the slots of the solid disc that are not connected to the white disc). 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) at 17.5 μm A liter volume was added to each well and a final concentration of 10 nM in a 25 microliter reaction. After pre-incubation for 30 minutes at room temperature, the kinase reaction was initiated by the addition of 5 μL of the activation mixture diluted in assay buffer containing biotinylated PLCγ2 peptide and ATP to a final concentration of 125 nM biotinylated PLCγ2 and 60 μM ATP. . The plates were incubated for 60 minutes at room temperature. In the dark by the addition of assay buffer containing -pTYR100 acceptor beads prepared in 10 microliter stop / detection mixture of streptavidin donor beads and anti-EDTA, staurosporine and chain terminated AlphaScreen ^TM reaction. Final concentration of 15mM EDTA, both 1μM staurosporine and 500 ng / slots of AlphaScreen ^TM (Augmented proximal homogeneous fluorescence assay (Amplified Luminescent Proximity Homogeneous Assay)) technology donor beads and acceptor beads . The assay plate was incubated for 60 minutes at room temperature in the dark and the plate 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 with various drugs. And the drug combination treatment for 72 hours. MTS/PMS was added and incubated for 4 hours, followed by cell viability using a microplate reader (absorption wavelength 490 nm). Compare data to unprocessed The control group was standardized and analyzed by 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 embodiments described herein. It is intended that such equivalents be included within the scope of the following claims.

Claims (11)

A compound of formula (I): Or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof. A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof And a pharmaceutically acceptable diluent, excipient or carrier. A compound according to claim 1 or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof, or according to the scope of the patent application The use of two pharmaceutical compositions for the manufacture of a medicament for the treatment of a condition mediated by BTK. The use according to claim 3, wherein the BTK-mediated condition is selected from the group consisting of an immune condition, a cancer, a cardiovascular disease, a viral infection, inflammation, a metabolic/endocrine dysfunction, and a neurological condition. According to the use of the fourth aspect of the patent application, wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, genitourinary tract cancer, esophageal cancer, laryngeal cancer, glioblastoma, and nerve Germ cell tumor, 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, adenoma, pancreatic cancer, adenocarcinoma, thyroid cancer, follicular carcinoma, undifferentiated carcinoma, mastoid cancer, fine Cell tumor, melanoma, sarcoma, bladder cancer, liver cancer and biliary tract cancer, kidney cancer, pancreatic cancer, myeloid disease, lymphoma, hair cell cancer, buccal carcinoma, nasopharyngeal carcinoma, pharyngeal cancer, lip cancer, Tongue cancer, mouth cancer, small bowel cancer, colorectal cancer, colorectal cancer, rectal cancer, brain cancer and central nervous system cancer, Hodgkin's lymphoma, bronchial carcinoma, thyroid cancer, liver and intrahepatic cholangiocarcinoma , hepatocellular carcinoma, gastric cancer, glioma/glioma, endometrial cancer, melanoma, renal and renal pelvic cancer, urinary bladder cancer, endometrial cancer, cervical cancer, multiple myeloma, acute myeloid Leukemia, chronic myelogenous leukemia, lymphocytic leukemia, chronic lymphocytic leukemia (CLL), myelogenous leukemia, oral and laryngeal cancer, non-Hodgkin's lymphoma, melanoma, and villus adenoma. According to the use of claim 4, wherein the condition is rheumatoid arthritis, systemic and local inflammation, arthritis, inflammation associated with immunosuppression, organ transplant rejection, allergy, ulcerative colitis, cloning (Crohn ), dermatitis, asthma, systemic lupus erythematosus, Sjogren's syndrome, multiple sclerosis, scleroderma/systemic sclerosis, idiopathic thrombocytopenic purpura (ITP), resistance Neutrophil cytoplasmic antibody (ANCA) vasculitis, chronic obstructive pulmonary disease (COPD) or psoriasis. A compound according to claim 1 or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite thereof, The use of a polymorph, an analogue or derivative thereof, or a pharmaceutical composition according to item 2 of the scope of the patent application for the manufacture of a medicament for the regulation of BTK. A compound according to claim 1 or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof, for use in the treatment of A condition mediated by BTK or a method of modulating BTK. The compound according to claim 8 wherein the BTK-mediated disorder is selected from the group consisting of an immune disorder, a cancer, a cardiovascular disease, a viral infection, inflammation, a metabolic/endocrine dysfunction, and a neurological disorder. A compound according to claim 9 wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, genitourinary tract cancer, esophageal cancer, laryngeal cancer, glioblastoma, and nerve Germ cell tumor, 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, adenoma, pancreas Cancer, adenocarcinoma, thyroid cancer, follicular carcinoma, undifferentiated carcinoma, mastoid carcinoma, spermatoma, melanoma, sarcoma, bladder cancer, liver cancer and biliary tract cancer, kidney cancer, pancreatic cancer, bone marrow disease, lymph Tumor, hair cell carcinoma, buccal carcinoma, nasopharyngeal carcinoma, pharyngeal cancer, lip cancer, tongue cancer, mouth cancer, small intestine cancer, colorectal cancer, colorectal cancer, rectal cancer, brain cancer and central nervous system cancer, Hodge Lymphoma, bronchial carcinoma, thyroid cancer, liver and intrahepatic cholangiocarcinoma, hepatocellular carcinoma, gastric cancer, glioma/glioma, endometrial cancer, melanoma, renal and renal pelvic 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 laryngeal cancer, non-Hodgkin's lymphoma, melanoma, and villus adenoma. A compound according to claim 9 wherein the condition is rheumatoid arthritis, systemic and local inflammation, arthritis, inflammation associated with immunosuppression, organ transplant rejection, allergy, ulcerative colitis, Crohn's disease , dermatitis, asthma, systemic lupus erythematosus, Hugh's syndrome, multiple sclerosis, scleroderma/systemic sclerosis, idiopathic thrombocytopenic purpura (ITP), anti-neutrophil cytoplasm Antibody (ANCA) vasculitis, chronic obstructive pulmonary disease (COPD) or psoriasis.