TWI750645B - 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-pyrrolopyrimidone and methods of using the same

The present invention pertains to Bruton's tyrosine kinase (BTK) (including mutant BTK) inhibitors for use in the treatment of diseases or disorders associated with BTK kinase, including immune disorders, cancer, Cardiovascular disease, viral infections, inflammation, metabolic/endocrine dysfunction, and neurological disorders. In particular, the present invention relates to compounds that inhibit BTK and compositions thereof, methods of treating diseases or disorders 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 nascent B-cell development and mature B-cell activation and survival (Hunter, Cell, 1987 50, 823-829). BTK triggers many cellular processes downstream of the function of diverse receptors such as growth factors, B-cell antigens, chemokines and innate immune receptors, including cell proliferation, survival, differentiation, motility, angiogenesis, cytokine production and antigen presentation.

A BTK-deficient mouse model shows that BTK plays a role in allergic disorders and/or or autoimmune disease and/or inflammatory disease. 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. Furthermore, BTK-deficient mice may be resistant to developing collagen-induced arthritis and are less susceptible to staphylococcal-induced arthritis. Due to the role of BTK in B-cell activation, BTK inhibitors are also useful as inhibitors of B-cell mediated pathogenic activities such as autoantibody production. BTK expression in osteoclasts, adipocytes and single cells has been shown to be important for the function of these cells. For example, impaired IgE-mediated adipocyte activation and reduced TNF-[alpha] production by activated single cells have been associated with BTK deficiency in mice and humans. Thus, BTK inhibition is useful in the treatment of allergic disorders 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).

Furthermore, the role of BTK in apoptosis demonstrates the utility of inhibition of BTK activity for the treatment of cancer, B-cell lymphoma, leukemia and other hematological malignancies. Additionally, the role of BTK in osteoclast function is known, making BTK activity inhibition useful in the treatment of bone disorders, such as osteoporosis.

BTK inhibition with small molecule inhibitors thus has therapeutic potential for immune disorders, cancer, cardiovascular disease, viral infections, inflammation, metabolic// Potential for endocrine dysfunction and neurological disorders. Therefore, there is still a considerable need for potent small-molecule inhibitors of BTK.

The first aspect of this application relates to compounds of formula (I):

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

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

Another aspect of this application pertains to pharmaceutical compositions comprising a compound of formula (I), or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog thereof, or a pharmaceutically acceptable salt thereof Or derivatives and pharmaceutically acceptable diluents, excipients or carriers.

Another aspect of the present application pertains to methods of treating disorders mediated by BTK. The method comprises administering to a treatment in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof. A patient with a disease or disorder associated with BTK kinase modulation.

Another aspect of the present application pertains to methods of treating disorders mediated by BTK. The method comprises administering a therapeutically effective amount of a pharmaceutical composition A patient in need of treatment of a disease or condition associated with modulation of BTK kinase, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, poly Crystalline forms, analogs or derivatives and pharmaceutically acceptable diluents, excipients or carriers.

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

Another aspect of the present application pertains to methods of treating cell proliferative disorders. 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, metabolite, or compounds, polymorphs, analogs or derivatives and pharmaceutically acceptable diluents, excipients or carriers.

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

Another aspect of this application pertains to methods 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, metabolite, or compounds, polymorphs, analogs or derivatives and pharmaceutically acceptable diluents, excipients or carriers.

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

Another aspect of this application pertains to modulating (eg, 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, metabolite, or compounds, polymorphs, analogs or derivatives and pharmaceutically acceptable diluents, excipients or carriers.

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

Another aspect of this application relates to a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof for the manufacture of Use of an agent that modulates (eg inhibits) BTK for the treatment of a BTK-mediated disorder, cell proliferative disorder or cancer. Administration of a compound of formula (I), or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof, in a therapeutically effective amount to a patient in need thereof .

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

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

The present application provides BTK inhibitors that are therapeutic agents for the treatment of diseases, such as immune disorders, cancer, cardiovascular diseases, viral infections, inflammation, metabolic/endocrine dysfunction, neurological disorders and related Other diseases associated with BTK kinase regulation.

The present application further provides compounds and compositions with improved efficacy and safety profiles relative to known BTK inhibitors. The present application also provides agents directed toward novel mechanisms of action of BTK kinases for the treatment of various types of diseases, including immune disorders, cancer, cardiovascular disease, viral infections, inflammation, metabolic/endocrine dysfunction, and neurological disorders . The present application ultimately provides the medical profession with novel pharmacological strategies for the treatment of diseases and disorders associated with BTK kinases.

Detailed description

The present application relates to compounds and compositions capable of modulating Bruton's tyrosine kinase (BTK) activity. This 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, tautomer, The prodrug, solvate, metabolite, polymorph, analog or derivative is 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 disorders by inhibiting BTK kinase activity. Inhibition of BTK provides treatment, prevention or amelioration of diseases including, but not limited to, immune disorders, cancer, cardiovascular disease, viral infections, inflammation, metabolic/endocrine dysfunction, and neurological disorders.

In a first aspect of this application, it describes a compound of formula (I):

及其醫藥上可接受之鹽、互變異構物、前藥、溶劑合物、代謝物、多晶形物、類似物或衍生物。

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 the present 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, exemplified methods and materials are now described. Other features, objectives and advantages of this application will be apparent from the Summary of the Invention and the scope of the claims. In the specification and the appended claims, the singular also includes the plural unless the context clearly dictates otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. All patents and publications cited in this specification are incorporated herein 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" by way of example means an elements or more than one element.

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

This application also includes pharmaceutical compositions 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 involved in the transport or delivery of pharmaceutical agents from one organ or part of the body of an individual to another organ or part of the body, and means materials, Compositions or vehicles, such as liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials.

The compounds of formula (I) may form salts, which are also within the scope of this application. It is to be understood that the compounds of formula mentioned herein include the recited and salts thereof, unless otherwise indicated.

Representative "pharmaceutically acceptable salts" include, for example, water-soluble and water-insoluble salts such as acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate) ), benzenesulfonate, benzoate, bicarbonate, hydrogen sulfate, hydrogen tartrate, borate, bromide, butyrate, calcium salt, calcium EDTA, camphorsulfonate, carbonic acid Salt, chloride, citrate, clavulariate, dihydrochloride, EDTA, ethanedisulfonate, estolate, ethanesulfonate, fumarate Fumerate, fiunarate, glucoheptanoic acid, gluconic acid, glutamate, glycolate, hexafluorophosphate, hexylresorcinate ( hexylresorcinate), hydrabamine salt, hydrobromide Acid, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, magnesium salt, malate, maleate, almond acid salt, mesylate, methyl bromide, methyl nitrate, mesylate, pyromucate, naphthalene sulfonate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy -2-naphthoate, oleate, oxalate, palmitate, pamoate (1,1-methylene-bis-2-hydroxy-3-naphthoate, embolic acid) salt (einbonate), pantothenate, phosphate/diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, hypochlorite Acetate, succinate, sulfate, sulfosalicylate, suramate, tannin, tartrate, teoclate, tosylate, triethyl iodide and valerate.

The compounds of the present application (eg, including pharmaceutically acceptable salts, tautomers, prodrugs, and polymorphic forms of the compounds) can exist in solvated or desolvated forms with other solvent molecules.

"Solvate" means a solvent addition form containing a stoichiometric or non-stoichiometric amount of solvent. Some compounds or salts have a tendency to trap a fixed molar ratio of solvent in the crystalline solid state, thus forming solvates. If the solvent is water, the solvate formed is a hydrate; and if the solvent is an alcohol, the solvate formed is an alcoholate. Hydrate-based composition by one or more molecules of water with a molecular species is formed in which the water retains its molecular state as H ₂ O's.

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

The term "isomers" refers to compounds having the same composition and molecular weight, but different physical and/or chemical properties. Structural differences may lie in configuration (geometric isomers) or in the ability to rotate the plane of polarized light (stereoisomers). With regard to stereoisomers, the compounds of formula (I) may have one or more asymmetric carbon atoms and may occur as racemates, racemic mixtures, or individual enantiomers or diastereomers.

In the specification of the present invention, the structural formula of the compound is represented by the formula Specific isomers are represented in some cases for convenience, but the present application includes all isomers, such as geometric isomers, optical isomers based on asymmetric carbons, stereoisomers, tautomers structures and the like.

"Isomerism" means compounds that have the same molecular formula, but differ in the bonding order of the atoms or the arrangement of the atoms in space. Isomers that differ in the arrangement of atoms in space are called "stereoisomers". Stereoisomers that are not mirror images of each other are referred to as "non-mirror images," and stereoisomers that are non-superimposable mirror images of each other are referred to as "enantiomers" or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is referred to as a "racemic mixture".

The compounds of this application may contain asymmetric or chiral centers, and therefore exist as different stereoisomers. All stereoisomeric forms of the compounds of this application, as well as mixtures thereof, including racemic mixtures, are intended to form part of this application. In addition, the present application includes all geometric and positional isomers. For example, if a compound of this application incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are included within the scope of this application. Each compound disclosed herein includes all enantiomers that conform to the compound's general structure. Compounds may be in racemic or enantiomeric pure form or any other form in terms of stereochemistry. Assay results may reflect data collected in racemic form, enantiomerically pure form, or any other form in terms of stereochemistry.

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

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

"Geometric isomer" means a mirror isomer that exists due to hindered rotation near a double bond. These configurations are given in their names by the prefixes cis and trans, or Z and E, indicating that the group is on the same or trans side of the molecule's double bond, according to the Cann-Inco-Prillot rule the difference.

In another aspect of the present application, the compound of formula (I) is a mirror isomer. In some embodiments, the compound is an ( S )-enantiomer. In other embodiments, the compound is a ( R )-enantiomer. In yet other embodiments, compounds of formula (I) may be (+) or (-) enantiomers. Compounds may contain more than one stereocenter.

In another aspect of this application, the compound of formula (I) The substance is a mirror image isomer. In some embodiments, the compound is an ipsilateral diastereoisomer. In other embodiments, the compound is a trans-diastereoisomer.

Aspiromeric mixtures can be separated into their individual non-spiroisomeric species on the basis of their physicochemical differences by methods well known to those skilled in the art, such as by chromatography and/or separation. segment crystallization. Enantiomers can be separated by converting the enantiomeric mixture to a non-enantiomer by reaction with a suitable optically active compound (eg, a chiral auxiliary such as a chiral alcohol or Mosher's yl chloride). Enantiomer mixtures, separation of diastereomers and conversion (eg hydrolysis) of individual diastereomers to the corresponding pure enantiomers. Enantiomers can also be separated using chiral HPLC columns.

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

A "tautomer" is one of two or more structural isomers that exist in equilibrium and can be readily converted from one isomeric form to another. This transformation results in the formal migration of hydrogen atoms with concomitant transformation of adjacent conjugated double bonds. Tautomers exist as mixtures of tautomer groups in solution. In solid form, often one tautomer predominates. In solutions where tautomerization is possible, tautomers reach chemical equilibrium. The exact ratio of tautomers depends on many factors, including temperature, solvent and pH. interconversion by tautomerization The concept of isomers is known as tautomerism.

Among the possible types of tautomerism, two types are often observed. In keto-enol tautomerism, electrons and hydrogen atoms move simultaneously. Ring-chain tautomerism occurs due to the reaction of the aldehyde group (-CHO) in the sugar chain molecule with one of the hydroxyl groups (-OH) in the same molecule, giving it a ring (ring-forming) as exhibited by glucose. shape) form.

Common tautomeric pairs are: keto-enol, amide-nitrile, lactamide-lactamide, amide-imine acid tautomerism in heterocycles (e.g. in nucleobases, such as guanine, thymine and cytosine), amine-enamines and enamine-imines. The (pyrrolopyrimidinyl)methanone-(pyrrolopyrimidinyl)methanol tautomer pair is included in the present application:

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

Another aspect of this application pertains to compounds of formula (I), wherein the compounds inhibit the kinase activity of mutant BTKs, such as drug-resistant mutant BTKs that conceal drug-resistance mutations (eg, the C481S mutation). In some embodiments, the patient or individual does not respond to a BTK inhibitor or relapses after BTK inhibitor treatment 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 at 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, the compound inhibits BTK activity at least more than 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 more active at inhibiting BTK containing one or more mutations as described herein (eg, C481S) 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, the activity of the compound against BTK containing one or more mutations as described herein is comparable to 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). Drug-resistant BTK mutants may have, without limitation, drug-resistant mutations comprising the C481S mutation.

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

Compounds of the present application can be converted to N-oxides by treatment with oxidizing agents such as 3-chloroperoxybenzoic acid (m-CPBA) and/or hydrogen peroxide to provide other compounds of the present application . Therefore, when the price and structure allows, consider all of the display and claimed nitrogen-containing compound is to include compounds and the N- oxide derivatives as shown in (which is may be N → O or N ⁺ -O ^- show )both. Furthermore, in other instances, nitrogen in the compounds of the present application can be converted to N-hydroxy or N-alkoxy compounds. For example, N-hydroxy compounds can be prepared by oxidizing a parent amine with an oxidizing agent such as m-CPBA. When valence and structure permit, all nitrogen-containing compounds shown and claimed are considered to encompass compounds as shown and their N-hydroxy (ie, N-OH) and N-alkoxy (ie, N-OR, wherein R is substituted or unsubstituted C ₁ -C ₆ alkyl, C ₁ -C ₆ alkenyl, C ₁ -C ₆ alkynyl, 3-14-membered carbocycle or 3-14-membered heterocycle) both derivatives.

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

Because prodrugs are known to enhance many desirable qualities of drug products (eg, solubility, bioavailability, manufacturing, etc.), compounds of formula (I) or pharmaceutically acceptable salts, tautomers, solvates, metabolites, etc. The compound, polymorph, analog or derivative can be delivered as a prodrug. Accordingly, the present application is intended to cover prodrugs of compounds of formula (I) or pharmaceutically acceptable salts, tautomers, solvates, metabolites, polymorphs, analogs or derivatives thereof, delivery of such prodrugs A method and a composition containing the prodrug. "Prodrug" is intended to include any covalently bonded carrier that, when administered to a mammalian subject, releases the active parent drug of the present application in vivo. Prodrugs can be made by modifying functional groups present in the compound in such a way that the modification is cleaved to the parent compound either in routine manipulation or in vivo. Prodrugs include compounds of the present application wherein a hydroxyl or amine group is bonded to any group that is cleaved to form a free hydroxyl or free amine group, respectively, when the prodrug of the present application is administered to a mammalian subject. Examples of prodrugs include, but are not limited to, a compound of each formula described herein, or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof. Alcohol and amine functional acetate, formate and benzoate derivatives.

The terms "crystalline polymorph," "polymorph," or "crystal form" mean a crystal structure in which a compound (or a salt or solvate thereof) crystallizes in different crystal packing arrangements, all arrangements having 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, rate of crystallization, storage temperature, and other factors may cause one crystalline form to prevail. Crystalline polymorphs of the compounds can be prepared by crystallization under various conditions.

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

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

Compounds of formula (I) or pharmaceutically acceptable salts, tautomers, prodrugs, solvates, metabolites, polymorphs, analogs or derivatives thereof containing the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the present application. Compounds (e.g., those compounds of incorporated radioactive isotopes such as ³ H, ¹⁴ C) application of the present invention, the isotopically labeled for drugs and / or by the interstitial tissue distribution assays. Tritiated (ie ³ H) and carbon-14 (ie ¹⁴ C) isotopes are useful for their ease of preparation and detectability. ¹¹ C and ¹⁸ F isotopes can be used in PET (positron emission tomography). PET can be used for brain imaging. Further, substitution with heavier isotopes (such as deuterium, i.e., ² H) may be substituted with therapeutic advantages due to the specific supplied from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements, and hence in some cases may be less Preferably, isotopically-labeled compounds of formula (I), or pharmaceutically acceptable salts, tautomers, prodrugs, solvates, metabolites, polymorphs, analogs or derivatives thereof, can generally be processed by The schemes described and/or the procedures disclosed in the Examples were prepared by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents. In one embodiment, the compound of formula (I), or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof, is not isotopically labeled.

The present application relates to compounds that are modulators of BTK. In one embodiment, the compounds of the present application are BTK inhibitors.

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

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

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

The term "treating" in reference to an individual refers to ameliorating at least one sign of the individual's disorder. Treatment includes curing, improving, 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 diseases, conditions or disorders. "Preventing or preventing" as used herein refers to reducing or eliminating the onset of signs or complications of a disease, condition or disorder.

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

The term "BTK-mediated" disease or disorder 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 aspect of the present application relates to treating or lessening the severity of one or more diseases in which BTK or mutants thereof are known to play a role. In particular, the present application relates to a method for the treatment or alleviation of the severity of a disease or condition selected from a proliferative disorder or an autoimmune disorder, wherein the method comprises adding a compound of formula (I) or A pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative or composition thereof is administered to a patient in need thereof.

The term "cell proliferative disorder" as used herein refers to a condition in which unregulated or abnormal growth of cells, or both, can contribute to the development of an unwanted condition or disease, which may or may not be cancerous . Exemplary cell proliferative disorders in the present application include various conditions in which cell division is deregulated. Exemplary cell proliferative disorders include, but are not limited to, neoplasms, benign tumors, malignant tumors, precancerous conditions, tumors in situ, enveloped tumors, metastatic tumors, liquid tumors, solid tumors, immune tumors, hematological tumors , cancers, tumors, 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 that expected or observed in adjacent or adjacent cells within the same tissue. Cell proliferative disorders include precancer or precancerous conditions. Cell proliferative disorders include cancer. The methods provided herein are preferably used to treat or slow the signs of cancer. The term "cancer" includes solid tumors, as well as hematological and/or malignant tumors. A "precancerous cell" or "precancerous cell" is a cell that manifests a cell proliferative disorder of a precancerous or precancerous condition. A "cancer cell" or "cancerous cell" is a cell that exhibits a cell proliferative disorder of cancer. Any reproducible measure can be used to identify cancer cells or precancerous cells. Cancer cells or precancerous cells can be identified by histological classification or grading of tissue samples (eg, biopsies). Cancer cells or precancerous cells can be identified through the use of appropriate molecular markers.

Exemplary noncancerous conditions or disorders include, but are not limited to, rheumatoid arthritis; inflammation; autoimmune diseases; lymphoproliferative conditions; acromegaly; rheumatoid spondylitis; osteoarthritis; gout; others Arthritis conditions; sepsis; septic shock; endotoxin shock; gram-negative sepsis; toxic shock syndrome; asthma; adult respiratory distress syndrome; chronic obstructive pulmonary disease; chronic lung inflammation; inflammatory bowel disease; Crohn's disease ); psoriasis; eczema; ulcerative colitis; pancreatic fibrosis; liver fibrosis; acute and chronic kidney disease; irritable bowel syndrome; fever; restenosis; cerebral malaria; stroke and ischemic injury; neurological Trauma; Alzheimer's disease; Huntington's disease; Parkinson's disease; acute and chronic pain; allergic rhinitis; allergic conjunctivitis; chronic heart failure; acute coronary Syndrome; cachexia; malaria; leprosy; kala-azar; Lyme disease; Reiter's syndrome; acute synovitis; muscle degeneration; bursitis; tendinitis; tenosynovitis; herniated, ruptured, or prolapsed intervertebral disc Syndrome; lithotripsy; thrombosis; restenosis; silicosis; pulmonary sarcoidosis; bone resorption diseases such as osteoporosis; graft-versus-host reaction; multiple sclerosis; lupus; fibromyalgia; AIDS and other viruses STDs such as herpes zoster, herpes simplex I or II, influenza virus and cytomegalovirus; and diabetes.

Exemplary cancers include, but are not limited to, adrenal cortical carcinoma, AIDS-related cancer, AIDS-related lymphoma, anal cancer, anorectal cancer, anal canal cancer, appendix cancer, childhood cerebellar astrocytoma, childhood cerebral astrocytoma, Basal cell carcinoma, skin cancer (non-melanoma), biliary tract cancer, extrahepatic cholangiocarcinoma, intrahepatic cholangiocarcinoma, bladder cancer, urethral bladder cancer, bone and joint cancer, osteosarcoma and malignant fibrous histiocytoma, brain cancer , brain tumor, brain stem glioma, cerebellar astrocytoma, cerebral astrocytoma/ Malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal tumor, optic pathway and hypothalamic glioma, breast cancer, tracheal adenoma/carcinoid, Cancer, Gastrointestinal Cancer, Nervous System Cancer, Nervous System Lymphoma, Central Nervous System Cancer, Central Nervous System Lymphoma, Cervical Cancer, Childhood Cancer, Chronic Lymphocytic Leukemia, Chronic Myeloid Leukemia, Chronic Myeloproliferative Disorders , colon cancer, colorectal cancer, cutaneous T-cell lymphoma, lymphoid neoplasms, mycosis fungoides, Seziary syndrome, endometrial cancer, esophageal cancer, extracranial germ cell tumors, extragonadal germ cell tumors Tumor (extragonadal germ cell tumor), extrahepatic cholangiocarcinoma, eye cancer, intraocular melanoma, retinocytoma, gallbladder cancer, gastric cancer (gastric, stomach cancer), gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), Germ cell tumor, ovarian germ cell tumor, gestational trophoblastic tumor glioma, head and neck cancer, hepatocellular (liver) cancer, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, eyeball cancer, Islet cell tumor (endocrine pancreatic cancer), Kaposi's sarcoma, kidney cancer (kidney cancer, renal cancer), kidney cancer (kidney cancer), throat cancer, acute lymphoblastic leukemia, acute myeloid leukemia, Chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, lip and oral cavity cancer, liver cancer, lung cancer, non-small cell lung cancer, small cell lung cancer, AIDS-related lymphoma, non-Hodgkin's lymphoma, primary Lymphoma of the central nervous system, Waldenstram's macroglobulinemia, medulloblastoma, melanoma, intraocular (ocular) melanoma, Merkel cells cancer, malignant mesothelioma, mesothelioma, metastatic squamous neck cancer, mouth cancer, tongue cancer, multiple endocrine neoplasia syndrome, mycosis fungoides, myelopoietic syndrome, myelopoietic/myeloproliferative disease, Chronic Myeloid Leukemia, Acute Myeloid Leukemia, Multiple Myeloma, Chronic Myeloproliferative Disorders, Nasopharyngeal Cancer, Neuroblastoma, Mouth Cancer, Oral Cancer, Oropharyngeal Cancer, Ovarian Cancer, Epithelial Ovarian Cancer, Ovarian Borderline Malignancy tumor (ovarian low malignant potential tumor), pancreatic cancer, islet cell pancreatic cancer, sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pineoblastoma and supratentorial primitive Neuroectodermal tumors, pituitary tumors, plasma cell neoplasia/multiple myeloma, pleuropulmonary blastoma, prostate cancer, rectal cancer, renal pelvis and ureteral transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, Ewing sarcoma family, Kaposi 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, gastric (stomach, gastric) carcinoma, supratentorial primitive neuroectodermal tumor, testicular carcinoma, laryngeal carcinoma, thymoma, thymoma and thymic carcinoma, thyroid carcinoma, transitional cell carcinoma of renal pelvis and ureter and other urinary organs, pregnancy Sexual trophoblastic tumor, urethral cancer, endometrial cancer, uterine sarcoma, uterine body cancer, vaginal cancer, vulvar cancer and Wilm's tumor.

Methods of preparing compounds

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

Compounds of formula (I) can be prepared by methods known in the art of organic synthesis, such as those described in part in the synthetic schemes below. In the schemes described below, it should be well understood that protecting groups for sensitive or reactive groups are used when necessary in accordance with general principles or chemistry. Protecting groups were manipulated according to standard organic synthesis methods (T.W. Greene and P.G.M. Wuts, Third Edition, "Protective Groups in Organic Synthesis", Wiley, New York 1999). These groups are removed at the appropriate stage of compound synthesis using methods readily apparent to those skilled in the art. The selection of the method as well as the reaction conditions and the order in which they are performed should be consistent with the method of preparation of the compounds of the present application.

Those skilled in the art will recognize the presence or absence of stereocenters in compounds of formula (I). Accordingly, the present application includes both possible stereoisomers (unless specified in the synthesis) and includes not only racemic compounds, but also individual enantiomers and/or diastereomers. When a compound is desired to be a single enantiomer or a non-spiroisomer, it can be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Elucidation of final products, intermediates or starting materials can be accomplished by any suitable method known in the art. See, eg, "Stereochemistry of Organic Compounds" by E.L. Eliel, S.H. Wilen and L.N. Mander (Wiley-Interscience, 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 obtained from those familiar with organic compounds prepared in many ways well known to those skilled in the art. By way of example, the compounds of the present application can be synthesized using the methods described below in conjunction with synthetic methods known in the art of synthetic organic chemistry or variations of those recognized by those skilled in the art. Preferred methods include, but are not limited to, those described below. Compounds of the present application (ie compounds of formula (I)) can be synthesized following the steps outlined in general scheme 1 comprising the sequence of compounding intermediates 2-a to 2-h. Starting materials can be obtained commercially or made in reported literature or by procedures known as exemplified.

A general manner 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. Nucleophilic addition of phenol 2-b to 2-chloro-4-fluorobenzene using a strong base such as sodium hydride (NaH) in a solvent such as N,N-dimethylformamide (DMF) carbonitrile 2-a to yield 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 converted to 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. Intermediate 2-f is acylated with 2-e using a strong base such as n-butyllithium (n-BuLi) in a solvent such as tetrahydrofuran (THF) to provide 2-g. Nucleophilic addition of the amine 2-h using a base such as N,N-diisopropylethylamine (DIPEA) and optionally in a solvent such as N,N-dimethylformamide (DMF) to aryl chloride 2-g to provide compounds of formula (I).

Mixtures of enantiomers, diastereomers, cis/trans isomers obtained from the methods described above can be separated by chiral salt techniques, using normal phase, reverse phase or chiral, depending on the nature of the separation Chromatography of the column separates into their single components.

Biological check

BTK kinase activity assay

Test inhibitors and controls were prepared in solvent (ie, DMSO) and added to each well of the reaction plate. Full-length active BTK was diluted in assay buffer and added to each well. Following pre-incubation, the kinase reaction was initiated by adding activation mix diluted in assay buffer containing biotinylated PLCy2 peptide and ATP. The plate was incubated and the reaction was then stopped in the dark by adding stop/detection mix prepared in assay buffer. The assay discs were incubated in the dark and the discs were read on a disc reader.

BTK C481S kinase activity assay

Test inhibitors and controls were prepared in solvent (ie DMSO) at the desired final concentrations and added to each well of the reaction plate middle. Full length BTKC481S was diluted in assay buffer and added to each well volume. Following pre-incubation, the kinase reaction was initiated by adding activation mix diluted in assay buffer containing biotinylated PLCy2 peptide and ATP. The plate was incubated and the reaction was then stopped in the dark by adding stop/detection mix prepared in assay buffer. The assay discs were incubated in the dark and the discs were read on a disc reader.

Antiproliferative assay

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

Methods of using compounds

Another aspect of the present application pertains to methods of treating, preventing, inhibiting or eliminating a disease or disorder associated with BTK modulation (eg, BTK inhibition). The method comprises adding 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) Pharmaceutical compositions of the compounds are administered to a patient in need of treatment of a disease or disorder associated with BTK modulation. In one embodiment, the BTK-mediated disorder is selected from the group consisting of immune disorders, cancer, cardiovascular disease, viral infections, inflammation, metabolic// Endocrine dysfunction and neurological disorders. In some embodiments, the method further comprises administering an additional therapeutic agent selected from an anti-inflammatory agent, an immunomodulatory agent, a chemotherapeutic agent, a neurotrophic factor, an agent for the treatment of cardiovascular disease, an agent for the treatment of liver disease, an anti-disease agent Poisons, blood disorders, diabetes, and immunodeficiency disorders. In some embodiments, the BTK is wild-type BTK. In other embodiments, the BTK is a mutant BTK (eg, a BTK C481S mutant).

Another aspect of this application relates to a method of treating, preventing, inhibiting or eliminating a cell proliferative disorder, the method comprising adding a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, A prodrug, solvate, metabolite, polymorph, analog or derivative, or pharmaceutical composition of a compound of formula (I) is 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 an anti-inflammatory agent, an immunomodulatory agent, a chemotherapeutic agent, a neurotrophic factor, an agent for the treatment of cardiovascular disease, an agent for the treatment of liver disease, an anti-disease agent Poisons, blood disorders, diabetes, and immunodeficiency disorders.

Another aspect of this application pertains to a method of modulating BTK, the method comprising adding a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite thereof , polymorphs, analogs or derivatives, or pharmaceutical compositions of compounds of formula (I) are administered to a patient in need thereof. In one embodiment, modulating BTK is inhibiting BTK. In some embodiments, the BTK is wild-type BTK. In other embodiments, the BTK is a mutant BTK (eg, the BTK C481S mutation body).

Another aspect of this application pertains to compounds of formula (I) or pharmaceutically acceptable salts, tautomers, prodrugs, solvates, metabolites thereof for use in methods of treating BTK mediated disorders , polymorphs, analogs or derivatives. In one embodiment, the disease or disorder is selected from the group consisting of immune disorders, cancer, cardiovascular disease, viral infections, inflammation, metabolic/endocrine dysfunction, and neurological disorders. In some embodiments, the method further comprises administering an additional therapeutic agent selected from an anti-inflammatory agent, an immunomodulatory agent, a chemotherapeutic agent, a neurotrophic factor, an agent for the treatment of cardiovascular disease, an agent for the treatment of liver disease, an anti-disease agent Poisons, blood disorders, diabetes, and immunodeficiency disorders. In some embodiments, the BTK is wild-type BTK. In other embodiments, the BTK is a mutant BTK (eg, a BTK C481S mutant).

In another aspect, the present application relates to a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, Pharmaceutical compositions of metabolites, polymorphs, analogs or derivatives. In one embodiment, the disease or disorder is selected from the group consisting of immune disorders, cancer, cardiovascular disease, viral infections, inflammation, metabolic/endocrine dysfunction, and neurological disorders. In some embodiments, the method further comprises administering an additional therapeutic agent selected from an anti-inflammatory agent, an immunomodulatory agent, a chemotherapeutic agent, a neurotrophic factor, an agent for the treatment of cardiovascular disease, an agent for the treatment of liver disease, an anti-disease agent Poisons, blood disorders, diabetes, and immunodeficiency disorders. In some embodiments, the BTK is wild-type BTK. In other In an embodiment of , the BTK is a mutant BTK (eg, a BTK C481S mutant).

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

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

Another aspect of the present invention pertains to compounds of formula (I) or pharmaceutically acceptable salts, tautomers, prodrugs, solvates, metabolites, polymorphs, analogs or derivatives thereof for use in modulating BTK thing. In one embodiment, modulating BTK is inhibiting BTK. In some embodiments, the BTK is wild-type BTK. In other embodiments, the BTK is a mutant BTK (eg, a BTK C481S mutant).

In another aspect, the present application relates to compounds of formula (I), or pharmaceutically acceptable salts, tautomers, prodrugs, solvates, metabolites, polymorphs, the like, for use in modulating BTK pharmaceutical compositions of substances or derivatives. In one embodiment, modulating BTK is inhibiting BTK. In some embodiments, the BTK is wild-type BTK. In other embodiments, the BTK is a mutant BTK (eg, the BTK C481S mutation body).

Another aspect of this 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 Use of an agent for the treatment of a BTK-mediated disease or disorder. In one embodiment, the disease or disorder is selected from the group consisting of immune disorders, cancer, cardiovascular disease, viral infections, inflammation, metabolic/endocrine dysfunction, and neurological disorders. In some embodiments, the treatment further comprises administering an additional therapeutic agent selected from the group consisting of anti-inflammatory agents, immunomodulatory agents, chemotherapeutic agents, neurotrophic factors, agents for the treatment of cardiovascular disease, agents for the treatment of liver disease, antiviral agents , Agents for the treatment of blood diseases, agents for the treatment of diabetes, and agents for the treatment of immunodeficiency disorders. In some embodiments, the BTK is wild-type BTK. In other embodiments, the BTK is a mutant BTK (eg, a BTK C481S mutant).

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

Another aspect of this 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 Use of an agent for the treatment, prevention, inhibition or elimination of a cell proliferative disorder. In one embodiment, the cell proliferative disorder is cancer.

In another aspect, the present application relates to compounds of formula (I) or pharmaceutically acceptable salts, tautomers, prodrugs, solvates, metabolites, polymorphs, analogs or derivatives thereof The pharmaceutical composition is used in the manufacture of medicaments for the treatment, prevention, inhibition or elimination of cell proliferative disorders. In one embodiment, the cell proliferative disorder is cancer.

Another aspect of this 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 Use of agents for regulating BTK. In one embodiment, modulating BTK is inhibiting BTK. In some embodiments, the BTK is wild-type BTK. In other embodiments, the BTK is a mutant BTK (eg, a BTK C481S mutant).

In another aspect, the present application relates to compounds of formula (I) or pharmaceutically acceptable salts, tautomers, prodrugs, solvates, metabolites, polymorphs, analogs or derivatives thereof Use of a pharmaceutical composition for the manufacture of a medicament for regulating BTK. In one embodiment, modulating BTK is inhibiting BTK. In some embodiments, the BTK is wild-type BTK. In other embodiments, the 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, glioblastoma 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, Adenocarcinoma tumor, pancreatic, adenocarcinoma, thyroid, follicular, anaplastic, papillary, seminoma, melanoma, sarcoma, bladder, liver and biliary tract, kidney, pancreas, myeloid Disorders, lymphoma, hair cell cancer, buccal space cancer, nasopharyngeal cancer, 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 cancer, thyroid cancer, liver and intrahepatic cholangiocarcinoma, hepatocellular carcinoma, gastric cancer, glioma/glioblastoma, endometrial cancer, melanoma, kidney and renal pelvis cancer , urinary bladder cancer, uterine body cancer, cervical cancer, multiple myeloma, acute myeloid leukemia, chronic myeloid leukemia, lymphocytic leukemia, chronic lymphocytic leukemia (CLL), myeloid leukemia, oral and laryngeal cancer , non-Hodgkin's lymphoma, melanoma and choriocolonic adenoma.

In any of the embodiments of the present application, the cancer can be any cancer in any organ, eg, 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 carcinoma, CNS cancer, ovarian cancer, endometrial cancer, prostate cancer, kidney 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 disorder is an immune disorder. In one embodiment, the immune disorder is rheumatoid arthritis.

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

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

The compounds disclosed in this application can be administered in amounts effective to treat or prevent and/or prevent the development of a disorder in an individual.

The compounds of the present application can be administered in combination therapy in therapeutically effective amounts with one or more therapeutic agents (pharmaceutical combinations) or modes (eg, non-drug therapy). For example, it can be combined with other antiproliferative, anticancer, immunomodulatory or Synergistic effect of anti-inflammatory substances. In some embodiments, the compound of formula (I) is administered in combination with an additional therapeutic agent selected from the group consisting of anti-inflammatory agents, immunomodulatory agents, chemotherapeutic agents, neurotrophic factors, agents for the treatment of cardiovascular disease, treatment of liver disease antiviral agents, agents for the treatment of blood disorders, agents for the treatment of diabetes, and agents for the treatment of immunodeficiency disorders. When the compounds of this application are administered in conjunction with other therapeutic agents, the dose of the co-administered compound will, of course, vary depending on the type of co-drug used, the particular drug used, the condition to be treated, and the like.

Combination therapy includes administration of the subject compound with other biologically active ingredients such as, but not limited to, anti-inflammatory agents, immunomodulatory agents, chemotherapeutic agents, neurotrophic factors, agents for the treatment of cardiovascular disease, agents for the treatment of liver disease, antiviral agents, therapeutic agents agents for blood disorders, agents for the treatment of diabetes, and agents for the treatment of immunodeficiency disorders) and additional combinations of non-drug therapies such as, but not limited to, surgery or radiation therapy. For example, the compounds of the present application may be used in combination with other pharmaceutically active compounds, preferably compounds capable of enhancing the effects of the compounds of the present application. The compounds of this application may be administered concurrently (as a single formulation or separate formulations) or sequentially with other drug therapies or treatment modalities. Combination therapy generally envisages the administration of two or more drugs during a single cycle or over the course of treatment.

Pharmaceutical composition

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

A "pharmaceutical composition" is a formulation containing a compound of the present application in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is in bulk or unit dosage form. The unit dosage form is any of a variety of forms including, for example, capsules, IV bags, lozenges, single pumps on an aerosol inhaler, or vials. An active ingredient (eg, of a disclosed compound or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof) in a unit dose composition The amount of formulation) is an effective amount and varies according to the particular treatment involved. It will be understood by those skilled in the art that routine changes in dosage may sometimes be necessary depending upon the age and condition of the patient. Dosage will also depend on the route of administration. Careful consideration of various routes including oral, transpulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal, sublingual, intrapleural, intrathecal, intranasal and similar. Dosage forms for topical or transdermal administration of the compounds of this application include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. In one embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and with any required preservatives, buffers or propellants.

The phrase "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions, carriers and/or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with human and animal tissue without excessive toxicity, irritation, allergic reaction or other problems or complications with a reasonable benefit/risk ratio.

"Pharmaceutically acceptable excipient" means an excipient useful in the preparation of pharmaceutical compositions that are generally safe, non-toxic, and biologically or otherwise undesired, and includes those for veterinary use as well as for human medicine Excipients acceptable for use. As used in the description and the scope of the patent application, "pharmaceutically acceptable excipients" also include one or more than one of these excipients.

The pharmaceutical compositions of the present application are formulated to be compatible with their intended route of administration. Examples of routes of administration include parenteral, eg, intravenous, intradermal, subcutaneous, oral (eg, inhalation), transdermal (topical), and transmucosal administration. Solutions or suspensions for parenteral, intradermal or subcutaneous administration may include the following components: sterile diluents such as water for injection, saline solution, fixed oils, polyethylene glycol, glycerol, propylene glycol or other synthetic solvents; Antibacterial agents such as benzyl alcohol or methylparaben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as EDTA; buffers such as acetate, citrate or phosphate; and tonicity-adjusting agents such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

The compounds or pharmaceutical compositions of the present application can be administered to an individual by many of the well-known methods currently used for chemotherapy treatment. For example, the compounds of the present application for use in the treatment of cancer can be injected directly into a tumor, into the blood stream or into a body cavity or administered orally or through the skin in a patch. The dose selected should be sufficient to constitute an effective treatment, but not so high as to cause unacceptable side effects. Preferably during treatment and for a reasonable period after treatment Patients are closely monitored for disease (eg, cancer, precancer, and the like) and health status.

The term "therapeutically effective amount" as used herein refers to the amount of a pharmaceutical agent that is used to treat, ameliorate or prevent an identified disease or condition or to exhibit a detectable therapeutic or inhibitory effect. This effect can be detected by any assay method known in the art. A clearly effective amount for an individual will depend on the individual's weight, size, and health; the nature and extent of the condition; and the treatment or combination of treatments selected for administration. A therapeutically effective amount for a particular situation can be determined by routine experimentation, which is within the skill and judgment of the clinician. In one embodiment, the disease or disorder is selected from the group consisting of immune disorders, cancer, cardiovascular disease, viral infections, inflammation, metabolic/endocrine dysfunction, and neurological disorders. In another aspect, 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 estimated initially in cell culture assays (eg, neoplastic cells) or in animal models (often rats, mice, rabbits, dogs, or pigs). Animal models can also be used to determine the appropriate range and route of administration. Such information can then be used to determine useful doses and routes of administration 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 compared LD ₅₀ / ED ₅₀ of FIG. A pharmaceutical composition exhibiting a high therapeutic index is preferred. The dosage may vary within this range depending upon the dosage form employed, the sensitivity of the patient, and the route of administration.

Dosage and administration are adjusted to provide adequate concentrations of active agent or to maintain the desired effect. Factors that may be taken into consideration include the severity of the disease state, the general health of the individual, the age, weight and sex of the individual, diet, time and frequency of administration, drug combination, response sensitivity, and tolerance/response to treatment . Long-acting pharmaceutical compositions can be administered every 3-4 days, weekly, or biweekly, depending on the half-life and clearance of the particular formulation.

Pharmaceutical compositions containing the active compounds of the present application (ie compounds of formula (I)) can be produced in a generally known manner, for example by means of conventional mixing, dissolving, granulating, dragee-making, grinding, emulsifying, Encapsulation, entrainment or freezing methods. Pharmaceutical compositions can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers including excipients and/or adjuvants which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Of course, the appropriate formulation will depend on the route of administration chosen.

Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where soluble in water) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. Carriers suitable for intravenous administration include physiological saline, bacteriostatic water, Cremophor EL ^™ (BASF, Parsippany, NJ) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringability occurs. It must be stable under 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 coatings 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, such as parabens, chlorobutanol, phenol, ascorbic acid, mercuric thiosalate, and the like. In many instances, it is preferred that the composition include isotonic agents (eg, sugars), polyols (eg, mannitol, sorbitol), sodium chloride. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

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

Oral compositions usually include an inert diluent or a pharmaceutically acceptable edible carrier. The composition can be enclosed in gelatin capsules or compressed into lozenges. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of troches, lozenges, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the fluid carrier is The compound in the dose is administered orally and rinsed in the mouth and expectorated or swallowed. Pharmaceutically compatible binder and/or adjuvant materials may be included as part of the composition. Tablets, pills, capsules, lozenges and the like may contain any of the following ingredients or a compound of similar nature: binders such as microcrystalline cellulose, tragacanth or gelatin; excipients such as starch or lactose ; disintegrants such as alginic acid, Primogel or corn starch; lubricants such as magnesium stearate or Sterotes; glidants such as colloidal silica; sweeteners such as sucrose or saccharin; or flavoring agents such as Peppermint, methyl salicylate or orange flavoring.

Compounds for administration by inhalation are delivered as an aerosol spray from a pressurized container or dispenser containing a suitable propellant, eg, a gas such as carbon dioxide, or a nebulizer.

Systemic administration can also be by transmucosal or transdermal means. Penetrating agents suitable for the penetration barrier are used in formulations for transmucosal or transdermal administration. Such penetrants are generally known in the art and include, for example, cleansers for transmucosal administration, bile salts and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. The active compounds for transdermal administration are formulated as ointments, salves, gels or creams as generally known in the art.

The active compounds can be prepared from pharmaceutically acceptable carriers that eliminate the compounds rapidly from the body, 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. Methods of making these formulations It is understood by those skilled in the art. Materials are also commercially available from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions, including liposomes targeted to infected cells with monoclonal antibodies to viral antigens, can also be used as pharmaceutically acceptable carriers. Such materials can be prepared according to methods known to those skilled in the art, eg, as described in US Pat. No. 4,522,811.

It is especially advantageous to formulate oral or parenteral compositions in unit dosage form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suitable as unitary dosages for the subjects to be treated; each unit contains a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specifications for the unit dosage forms of the present application are dictated by, or directly dependent on, the unique characteristics of the active compound and the particular therapeutic effect to be achieved.

In therapeutic applications, the dosage of a pharmaceutical composition used in accordance with the present application will depend, among other factors affecting the dosage chosen, on the agent, the age, weight, and clinical condition of the patient being administered, and the clinical conditions for which the treatment is administered. The experience and judgment of a physician or practitioner. The dose should generally be sufficient to cause a reduction in tumor growth and preferably regression, and preferably also complete regression of the cancer. Dosages may range from about 0.01 mg/kg per day to about 5000 mg/kg per day. An effective amount of a pharmaceutical agent is that amount that provides an objectively identifiable improvement as noted by clinicians and other qualified observers. For example, tumor regression in a patient can be measured with reference to the diameter of the tumor. Reduction in tumor diameter indicates regression. Regression was also indicated by the tumor no longer reappearing after treatment was discontinued. The term "dose-effective manner" as used herein means The amount of active compound that produces the desired biological effect in an individual or cell.

The pharmaceutical composition can be incorporated into a container, pack or dispenser with instructions for administration.

As used herein, "pharmaceutically acceptable salts" refer to derivatives of the compounds of the present application wherein the parent compound is modified by making acid or base salts 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 conventional nontoxic or quaternary ammonium salts of parent compounds formed from nontoxic inorganic or organic acids. For example, such conventionally toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from the group consisting of: 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid Acid, benzoic acid, acid carbonic acid, carbonic acid, citric acid, ethylenediaminetetraacetic acid, ethanedisulfonic acid, 1,2-ethanesulfonic acid, fumaric acid, grape heptanoic acid, gluconic acid, glutamine Acid, glycolic acid, glycolic acid, hexylresorcinolic acid, hydrabamic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxyfumaric acid, hydroxynaphthoic acid , isethionic acid, 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 Glycolic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, hypoacetic acid, succinic acid, sulfamic acid, p-aminobenzenesulfonic acid, sulfuric acid, tannic acid, tartaric acid, toluenesulfonic acid and Common amino acids such as glycine, alanine, phenylalanine, arginine, etc.

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

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

The compounds of the present application can also be prepared as esters, such as pharmaceutically acceptable esters. For example, carboxylic acid functional groups in compounds can be converted to their corresponding esters, such as methyl esters, ethyl esters, or other esters. Furthermore, alcohol groups in compounds can be converted to their corresponding esters, such as acetate, propionate, or other esters.

The compounds of the present application may also be prepared as prodrugs, eg, pharmaceutically acceptable prodrugs. The terms "pro-drug and prodrug" are used interchangeably herein and refer to any compound that releases the active parent drug in vivo. Because prodrugs are known to enhance many desirable qualities of a drug product (eg, 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 the presently claimed compounds, methods of delivery thereof, and composition containing it. "Prodrug" is intended to include any covalently bonded carrier that, 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 way that the modification is cleaved to the parent compound either routinely or in vivo. Prodrugs include compounds of the present application wherein a hydroxyl, amine, sulfhydryl, carboxyl or carbonyl group is bonded to any group that is cleaved in vivo to form free hydroxyl, free amine, free sulfhydryl, free carboxyl, respectively or free carbonyl.

Examples of prodrugs include, but are not limited to, esters of hydroxy functional groups in the compounds of this application (eg acetate, dialkylaminoacetate, formate, phosphate, sulfate, and benzoate derivatives) compounds) and carbamates (such as N,N-dimethylaminocarbonyl); esters of carboxyl functional groups (such as ethyl ester, morpholinoethanol ester); N-acyl derivatives of amino functional groups (such as N-Acetyl) N-Mannich bases, Schiff bases and enaminones; oximes, acetals, ketals and enol esters of ketone and aldehyde functions; and the like, see Bundegaard , H. Design of Prodrugs, p1-92, Elsevier, New York-Oxford (1985).

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

The dosage regimen utilizing the compound is 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 to be treated; the route of administration; the patient's renal and hepatic function; and The particular compound used, or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof. A clinician or veterinarian of ordinary skill in the art can readily determine and prescribe an effective amount of the drug needed to prevent, counteract, or arrest the progression of the condition.

The compounds disclosed techniques for formulation and administration may be found in the present application Remington: the Science and Practice of Pharmacy , 19 th edition, Mack Publishing Co., Easton, PA (1995). In one embodiment, the compounds described herein, and pharmaceutically acceptable salts, tautomers, prodrugs, solvates, metabolites, polymorphs, analogs or derivatives thereof, and pharmaceutically acceptable salts, tautomers, prodrugs, solvates, metabolites, polymorphs, analogs or derivatives thereof The carrier or diluent combination is used in pharmaceutical preparations. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The compounds or pharmaceutically acceptable salts, prodrugs, solvates, metabolites, polymorphs, analogs or derivatives thereof are present in amounts sufficient to provide the 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 application are apparent from the various embodiments. The provided examples illustrate different components and methods for practicing the present application. The examples do not limit the applied application. Those skilled in the art can build upon the present application to identify and use other components and methods useful in practicing the present application.

Example

The application is further exemplified by the following examples and synthetic schemes, which are not to be construed to limit the scope and spirit of the application to the specific schemes described herein. It should be understood that the examples are provided to illustrate particular implementation aspects and are not intended to limit the scope of the application thereby. It should be further understood that various other embodiments, modifications and their equivalents that may be suggested by those skilled in the art may be resorted to without departing from the spirit of the present application and/or the scope of the appended claims.

Analytical methods, materials and instruments

Unless otherwise noted, reagents and solvents received from commercial suppliers were used. Proton nuclear magnetic resonance (NMR) spectra were acquired on Bruker or Varian spectrometers at 400 MHz. Spectra are given in ppm ([delta]) and coupling constants, J, are reported in Hertz. Tetramethylsilane (TMS) was used as 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 were obtained using Waters MassLynx 4.1 software and purity was in UV 220 nm wavelength, ELSD and ESI characterization. Column: Acquity UPLC BEH C18 1.7 μm 2.1 X 50 mm; flow rate: 0.6 ml/min; solvent A (95/5/0.1 in 10 mM ammonium formate/acetonitrile/formic acid), solvent B (95/5/0.09 in acetonitrile/water /formic acid); gradient: 5-100% B from 0 to 2 minutes, hold 100% B to 2.2 minutes, then 5% B at 2.21 minutes.

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 parts per million

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

Step 1: 2-Chloro-4-phenoxybenzonitrile (Intermediate 2-B)

Phenol (3.66 g, 39 mmol) dissolved in DMF (30 mL) was treated in small portions with 60% NaH in oil (1.56 g, 39 mmol) until evolution of gas ceased. The reaction mixture was stirred at room temperature for 10 minutes, followed by the addition of 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 partitioned in DCM/water. The organic phase was separated and washed with saturated brine solution, dried over Na ₂ SO _4. 7.5 g of an off-white solid was provided as concentration. ¹ H NMR (400MHz, 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=2.3Hz, 1H), 7.20 (d, J=7.9Hz, 2H), 7.04 (dd, J=8.7, 2.3Hz, 1H); MS m/z 230[M+H] ⁺ .

Step 2: 2-Chloro-4-phenoxybenzoic acid (Intermediate 2-C)

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

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

2-Chloro-4-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 added dropwise. The mixture was allowed to warm to room temperature over 1 hour. The starting material was completely consumed during this period. The mixture was diluted with water and extracted with Et ₂ O to. Dried and concentrated in vacuo to give a yellow oil (2-D, 4.15 g, 79%) which was used without further purification. NMR(400MHz, DMSO-d ₆ )δ 7.89(d,J=8.7Hz,1H), 7.49(t,J=7.9Hz,2H), 7.29(t,J=7.4Hz,1H), 7.17(d, J=7.9Hz,2H), 7.12(d,J=2.4Hz,1H), 6.99(dd,J=8.7,2.4Hz,1H), 3.84(s,3H); MS m/z 263[M+H ] ⁺ .

Example 2: (2-Chloro-4-phenoxyphenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-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) was dissolved in N-bromosuccinimide (26.7 g) , 149.8 mmol) in batches 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, after filtration fed into a white solid, 5-bromo-4-chloro -7H- pyrrolo [2,3-d] pyrimidine (2-F, 22.43 g, 74%) . Melting point: 242-244°C; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.96 (s, 1H), 8.61 (s, 1H), 7.94 (s, 1H); MS m/z 232 [M( ³⁵ Cl , ⁷⁹ Br)+H] ⁺ , 234[M( ³⁵ Cl, ⁸¹ Br)+H] ⁺ , 234[M( ³⁷ Cl, ⁷⁹ Br)+H] ⁺ , 236[M( ³⁷ Cl, ⁸¹ Br)+ H] ⁺ .

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

n-BuLi (2.69M in hexanes, 23.2 mL, 62.3 mmol) was added dropwise to 5-bromo-4-chloro-7H- in THF (200 mL) at -78°C under inert atmosphere pyrrolo[2,3-d]pyrimidine (2-F, 6.90 g, 29.7 mmol) in a stirred solution. The reaction mixture was kept at -78 °C for 1 h and then a pre-preparation of methyl 2-chloro-4-phenoxybenzoate (2-D, 8.19 g, 31.2 mmol) in THF (80 mL) was added. Cool (to -78°C) the solution. The reaction mixture was stirred at -78°C for 1 hour, then quenched with the addition of HCl IN (65 mL). The mixture was allowed to warm to room temperature and then extracted with EtOAc (3×100 mL). The combined extracts were washed with brine, dried over Na ₂ SO ₄ 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 =7.9Hz,2H), 7.26(t,J=7.4Hz,1H), 7.23-7.12(m,3H), 7.01(dd,J=8.5,2.3Hz,1H); MS m/z 384[M( ^{35 Cl, 35 Cl) + H} ] +, 386 [M (35 Cl, 37 Cl) + H] +, 388 [M (37 Cl, 37 Cl) + H] +.

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

(2-Chloro-4-phenoxyphenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (2-G, 200 mg, 0.52 mmol) ), ((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methanol (72 mg, 0.54 mmol) and a mixture of DIPEA (272 μl, 1.56 mmol) in Stir 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-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl ) ketone ((I), 175 mg, 70%). ¹ H NMR (400MHz, DMSO-d ₆ ) δ 12.76(s, 1H), 8.60(d, J=7.1Hz, 1H), 8.25(s, 1H), 7.64(s, 1H), 7.58(d, J=8.4Hz,1H), 7.48(t,J=7.6Hz,2H), 7.26(t,J=7.2Hz,1H), 7.18-7.20(m,3H), 7.02(d,J=8.3Hz, 1H), 4.67(s, 1H), 4.16(d, J=7.7Hz, 2H), 3.49-3.27(m, 3H), 3.12(t, J=11.2Hz, 1H), 2.19(d, J=11.4 Hz,1H), 1.78(d,J=12.9Hz,1H), 1.67-1.49(m,1H), 1.39(d,J=12.3Hz,1H); MS m/z 479[M( ³⁵ Cl)+ H] ⁺ , 481[M( ³⁷ Cl)+H] ⁺ .

Example 3: BTK kinase activity assay

Test inhibitors and controls (CGI-1746, GDC-0834, PCI-32765, Dasatinib and R-406) were prepared in 10% DMSO at 10-fold the desired final concentrations and at 2.5 A microliter volume was added to each well of a reaction plate (Corning 96 - solid white plate with unconnected surface of well half). Full-length active BTK was prepared 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 0.2 mM NaF) and added to each well in a 17.5 microliter volume for a final concentration of 0.08 nM in a 25 microliter reaction. After a 30 min pre-incubation at room temperature, the kinase reaction was initiated by adding 5 microliters of activation mix 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 at room temperature for 60 minutes. Reactions were stopped in the dark by adding 10 microliters of stop/detection mix prepared in assay buffer ^{containing EDTA and AlphaScreen™ streptavidin donor beads and anti-pTYR100 acceptor beads.} Final concentrations were 10 mM EDTA and 500 ng/well of both AlphaScreen ^™ donor and acceptor beads. The assay disks were incubated in the dark at room temperature for 60 minutes and the disks were 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 (Staurosporine) were prepared at 10 times the desired final concentration in 10% DMSO and added to the reaction plate (Corning 96-well half-space) in a 2.5 microliter volume. solid surface unconnected white disc) in each slot. Full-length BTKC481S was diluted in assay buffer (50 mM Tris, pH 8.0, BSA at 0.02 mg/ml, 10 mM MgCl ₂ , 1 mM EGTA, 10% glycerol, 1 mM DTT, 1 mM β-glycerophosphate and 1 mM NaF) and added to 17.5 μm Liter volumes were added to each well for a final concentration of 10 nM in a 25 microliter reaction. After a 30 min pre-incubation at room temperature, the kinase reaction was initiated by adding 5 microliters of activation mix 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 at room temperature for 60 minutes. Stop in the dark by adding 10 microliters of stop/detection mix prepared in assay buffer containing EDTA, staurosporine and AlphaScreen ^{™ streptavidin donor beads and anti-pTYR100 acceptor beads} reaction. ^{AlphaScreen™} (Amplified Luminescent Proximity Homogeneous Assay) technology both donor and acceptor beads at final concentrations of 15 mM EDTA, 1 μM staurosporine and 500 ng/well . The assay disks were incubated in the dark at room temperature for 60 minutes and the disks were 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-proliferative assay

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

equivalent

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments described herein. It is intended that such equivalents be included within the scope of the following claims.

Claims (18)

Use of a compound of formula (I), or a pharmaceutically acceptable salt, tautomer, ester, hydrate or stereoisomer thereof, in the manufacture of a medicament for the treatment of cancer in a subject,

Wherein the mutant BTK was detected in the sample of the individual. The use according to claim 1, wherein the mutant BTK comprises a drug resistance mutation. According to the use of item 2 of the claimed scope, the drug resistance mutation is a mutation in amino acid 481. According to the use of item 2 of the patented scope of application, the drug resistance mutation is C481S. The use according to claim 1, wherein the cancer exhibits resistance to a BTK inhibitor. The use according to the 5th patent application scope, wherein the BTK inhibitor is ibrutinib. Use according to item 1 of the patented scope, wherein the cancer is selected from breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, esophagus cancer, laryngeal cancer, stomach cancer, skin cancer, lung cancer, bone cancer, and pancreatic cancer , colon cancer, thyroid cancer, biliary tract cancer, hair cell cancer, buccal space cancer, nasopharyngeal cancer, Lip cancer, tongue cancer, mouth cancer, colorectal cancer, small bowel cancer, colorectal cancer, rectal cancer, brain cancer, central nervous system cancer, bronchial cancer, liver cancer, intrahepatic bile duct cancer, urethra and bladder cancer, uterine body cancer, kidney cancer carcinoma, renal pelvis, oral cavity, throat, glioblastoma, glioblastoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer (NSCLC), small cell carcinoma, lung adenocarcinoma , Adenoma, Adenocarcinoma, Follicular Carcinoma, Undifferentiated Carcinoma, Mastoid Carcinoma, Seminoma, Melanoma, Sarcoma, Bladder Cancer, Hepatoma, Nephroma, Myeloid Disorders, Lymphoma, Hodgkin lymphoma, hepatocellular carcinoma, glioma, endometrial cancer, multiple myeloma, acute myeloid leukemia, chronic myeloid leukemia, lymphocytic leukemia, chronic lymphocytic leukemia (CLL), myeloid leukemia, non- Hodgkin's lymphoma and choriocolonic adenoma. According to the use according to the first item of the patent application, wherein the cancer is chronic lymphocytic leukemia. According to the use of item 1 of the scope of application, wherein the cancer is lymphoma. According to the use of item 9 of the scope of the application, wherein the lymphoma is non-Hodgkin's lymphoma. Use according to item 9 of the scope of the application, wherein the lymphoma is a B-cell lymphoma. The use according to claim 9, wherein the lymphoma is degenerative large cell lymphoma, central nervous system (CNS) lymphoma or Waldenstram's macroglobulinemia. According to the use according to item 1 of the scope of application, wherein the cancer is Myeloid disorder or myeloid leukemia. According to the use according to item 1 of the claimed scope, the cancer is acute myeloid leukemia. Use according to item 1 of the application scope, wherein the cancer is multiple myeloma. According to the use according to item 1 of the scope of application, wherein the cancer is lymphocytic leukemia. According to the use according to item 1 of the claimed scope, the cancer is sarcoma or brain cancer. According to the use according to item 1 of the scope of the application, wherein the sample is a tissue or a biopsy of the individual.