OA19424A - Inhibitors of Bruton's tyrosine kinase. - Google Patents

Abstract

The present invention relates to a new compound of formula I: or pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: V1 is C or N, V2 is C(R2) or N, whereby if V1 is C then V2 is N, if V1 is C then V2 is C(R2), or if V1 is N then V2 is C(R2); each n, k is independently 0, 1; each R2, R11 is independently H, D, Hal, CN, NR'R", C(O)NR'R", C1-C6 alkoxy; R3 is H, D, hydroxy, C(O)C1-C6 alkyl, C(O)C2-C6 alkenyl, C(O)C2-C6 alkynyl, C1-C6 alkyl; R4 is H, Hal, CN, CONR'R", hydroxy, C1-C6 alkyl, C1-C6 alkoxy; L is CH2, NH, O or chemical bond; R1 is selected from the group of the fragments, comprising: Fragment 1, Fragment 2, Fragment 3 each A1, A2, A3, A4 is independently CH, N, CHal; each A5, A6, A7, A8, A9 is independently C, CH or N; R5 is H, CN, Hal, CONR'R", C1-C6 alkyl, non-substituted or substituted by one or more halogens; each R' and R" is independently selected from the group, comprising H, C1-C6 alkyl, C1-C6 cycloalkyl, aryl; R6 is selected from the group:

Description

The présent invention relates to new inhibitors of Bruton’s tyrosine kinase, to their préparations, to pharmaceutical compositions containing such compounds, and to the use of such compounds or such compositions as pharmaceuticals for treatment of diseases and disorders.

Background of the invention

Bruton’s tyrosine kinase (Btk), a member of the Tec family of non-receptor tyrosine kinases, is a key signaling enzyme expressed in ail hematopoietic cells types except T lymphocytes and natural killer cells. Btk plays an essential rôle in the B-cell signaling pathway linking cell surface B-cell receptor (BCR) stimulation to downstream intracellular responses.

Btk is a key regulator of B-cell development, activation, signaling, and survival (Kurosaki, Curr. Op. Imm., 2000, 276-281; Schaeffer and Schwartzberg, Curr. Op. Imm. 2000, 282-288). In addition, Btk plays a rôle in a number of other hematopoetic cell signaling pathways, e.g., Toll like receptor (TLR) and cytokine receptor-mediated TNF-a production in macrophages, IgE receptor (FccRI) signaling in Mast cells, inhibition of Fas/APO-1 apoptotic signaling in B-lineage lymphoid cells, and collagen-stimulated platelet aggregation. See, e.g., Jeffries, et al., (2003), Journal of Biological Chemistry 278:26258-26264; Horwood, et al., (2003), The Journal of Experimental Medicine 197:1603-1611; Iwaki et al. (2005), Journal of Biological Chemistry 280(48):40261-40270; Vassilev et al. (1999), Journal of Biological Chemistry 274(3): 1646-1656, and Quek et al. (1998), Current Biology 8(20):1137-1140.

With the regulatory rôle reported for Btk in FccR-mediated mast cell activation, Btk inhibitors may also show potential in the treatment of allergie responses (Gilfillan et al (2009), Immunological Reviews 288:149- 169).

The reported rôle for Btk in the régulation of prolifération and apoptosis of B cells indicates the potential for Btk inhibitors in the treatment of tumors of blood

PA513904/OA/5118479.1 and lymphatic System, such as B-cell lymphomas. Inhibition of Btk seems to be relevant in particular for B-cell lymphomas due to chronic active BCR signaling (Davis et al (2010), Nature, 463:88-94).

Studies of ibrutinib, a covalent sélective inhibitor of Bruton’s tyrosine kinase, hâve demonstrated significant antitumor activity of the drug against mantle cell lymphoma and chronic lymphocytic leukemia, as well as acceptable tolerability (Robert Roskoski Jr. (2016), Pharmacol. Res., 113: 395-408; O. Foluso et al (2016), Clin. Lymphoma Myeloma Leuk., 16(2): 63-69). Also ibrutinib treats graft-versus-host disease (GVHD) (Miklos et al. (2017), Blood 2017:blood-201707-793786). However, off-target interactions of Ibrutinib with EGFR and other TEC family kinases can cause the adverse drug reactions (ADR), such as bleeding, rash, diarrhea and atrial fibrillation (Wu et al. (2016), Journal of Hematology & Oncology, 9:80). According to pharmacokinetic studies, Ibrutinib is prone to firstpass clearance to form a major métabolite, it is 15 times less active than the parent substance (Bose et al, (2016), Expert Opinion on Drug Metabolism & Toxicology).

Therefore, clinical need exists in new compounds affecting Bruton’s tyrosine kinase (Btk) with favorable characteristics of a potential médication.

Description of the invention

The ternis used in the description of this invention appear below.

Optionally substituted in one, two, three, or several positions means the specified group can be substituted by a radical or any combination of radicals in one, two, three, or from one to six positions.

“Alkyl” means an aliphatic straight chain or branched chain hydrocarbon group having from 1 to 12 carbon atoms, more preferably from 1 to 6 carbon atoms. Branched chain means alkyl chain having one or more “lower alkyl” substituents. Examples of alkyl groups include, but are not limited to, methyl, ethyl, w-propyl, Lo-propyl, n-butyl, zso-butyl, sec-butyl, terLbutyl, n-pentyl, 2pentyl, 3-pentyl, neo- pentyl, π-hexyl. Alkyl may hâve substituents which may be same or different structure.

“Cycloalkyl” means a saturated carbocyclic ring that contains from 3 to 10 carbon ring atoms. Examples of cycloalkyl groups include, but are not limited to, monocyclic groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, bicyclic groups, such as bicycloheptyl or bicyclooctyl. Cycloalkyl may hâve substituents which may be same or different structure.

“Alkenyl” means a straight chain or branched chain hydrocarbon group having from 2 to 12 carbon atoms, more preferably from 2 to 6 carbon atoms that contains one or more carbon-carbon double bound. Alkenyl may hâve substituents which may be same or different structure.

“Alkynyl” means a straight chain or branched chain hydrocarbon group having from 2 to 12 carbon atoms, more preferably from 2 to 6 carbon atoms that contains one or more carbon-carbon triple bound. Alkynyl may hâve substituents which may be same or different structure.

“Aryl” means an aromatic monocyclic or polycyclic system having from 6 to 14 carbon atoms, more preferably from 6 to 10 carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, phenylene, benzenetriyl, indanyl, naphthyl, naphthylene, naphthalenetriyl and anthrylene. Aryl may hâve cyclic system substituents which may be same or different structure. Aryl can be annelated with a nonaromatic cyclic system or heterocycle.

“Alkyloxy” or “Alkoxy” means an alkyl-O- group, wherein alkyl is defined in this section. Examples of alkoxy groups include, but are not limited to, methyloxy, ethyloxy, n-propyloxy, zso-propyloxy, n-butyloxy, terZ-butyloxy and Ao-butyloxy.

“Amino group” means R_kR_pN- group.

“Aminocarbonyl” means -C(=O)NR_kR_p group.

Examples of R_k and R_p include, but not limited to, substituents selected from the group containing hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or R_k and R_p together with nitrogen atom, to which they are attached, form a 4-7-membered heterocyclyl or heteroaryl.

“Lower alkyl” means a straight chain or branched chain alkyl having from 1 to 4 carbon atoms.

“Halo” or “Halogen” (Hal) means fluoro, chloro, bromo and iodo.

“Heterocycle”, “heterocyclyl”, “heterocyclic ring” means a monocyclic or polycyclic System having from 3 to 11 carbon atoms, of which one or more carbon atoms are substituted by one or more heteroatoms, such as nitrogen, oxygen, sulfur. Heterocycle may be fused with aryl or heteroaryl. Heterocycle may hâve one or more substituents which may be same or different structure. Nitrogen and sulfur atoms of heterocycle could be oxidized to N-oxide, S-oxide or S-dioxide. Heterocycle may be fully saturated, partially saturated and unsaturated. Examples of heterocycle include, but are not limited to, azetidine, pyrrolidine, piperidine, 2,8-diazaspiro[4.5]decane, piperazine, morpholine, and others.

“Heteroaryl” means an aromatic monocyclic or polycyclic System having from 5 to 11 carbon atoms, preferably from 5 to 10, of which one or more carbon atoms are substituted by one or more heteroatoms, such as nitrogen, sulfur or oxygen. Nitrogen atom of heterocycle could be oxidized to N-oxide. Heteroaryl may hâve one or more substituents which may be same or different structure. Examples of heteroaryl are pyrrolyl, furanyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isoxazolyl, isothiazolyl, tetrazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, triazolyl, 1,2,4-thiadiazolyl, quinoxalinyl, phthalazinyl, imidazo[l,2-a]pyridinyl, imidazo[2,l-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothiazenyl, quinolinyl, imidazolyl, pyrazolyl, thienopyridyl, quinazolinyl, naphthyridinyl, thienopyrimidinyl, pyrrolopyridinyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2,4-triazinyl, thienopyrrolyl, furopyrrolyl, and the like.

“Partially saturated” means a ring System including at least one double or triple bond. The term “partly saturated” relates to rings having many sites for saturation and does not include aryl and heteroaryl Systems as they defined above.

The term “oxo” used in this document relates to the radical =0.

“Substituent” means a Chemical radical attached to a scaffold (fragment).

“Solvaté” is a molecular aggregate that consists of the compound of the présent invention, or its pharmaceutically acceptable sait, with one or more solvent molécules. The solvent molécules are molécules of common pharmaceutical solvents, known to be safe for récipients, e.g. water, éthanol, ethylene glycol, etc. Other solvents, such as methanol, methyl-tert-butyl ether, ethyl acetate, methyl acetate, (R)-propylene glycol or (S)-propylene glycol, 1,4-butanediol, and the like, can be used to form intermediate solvatés for obtaining préférable solvatés.

“Hydrate” means a solvaté with water as the solvent.

Solvatés and/or hydrates preferably exist in crystalline form.

Terms “bond”, “chemical bond”, or “single bond” refer to a Chemical bonding of two atoms or two moieties (i.e., groups, fragments) when the atoms joined by the bond are considered to be part of larger substructure.

The terni “chiral” refers to molécules that hâve the property of being incompatible with their mirror image, whereas the terni “achiral” refers to molécules that hâve the property of being compatible with their mirror image.

The tenu “stereoisomers” refers to compounds that hâve identical Chemical composition and the same structure, but differ in the spatial arrangement of atoms or their groups. Stereoisomers may include géométrie isomers, enantiomers, diastereomers.

The tenu diastereomer refers to a stereoisomer with two or more centers of chirality, and such molécules are not mirror images of each other. Diastereomers hâve different physical properties, for example, melting points, boiling points, spectral properties and reactivity. Mixtures of diastereomers could be separated using high-resolution analytical techniques, such as electrophoresis and chromatography.

The terni “enantiomers” refers to two stereoisomers of a compound being mirror images of one another and not compatible in space.

The terms “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomers that are not optical active. Enantiomers can be isolated from the racemic mixture separately by chiral resolution, such as, for example, supercritical fluid chromatography (SFC).

The compounds of the invention may contain asymmetric or chiral centers and, therefore, exist in different stereoisomeric forms. It is contemplated that ail stereoisomeric forms of the compounds of the invention, including but not limited to diastereomers, enantiomers and atropisomers, as well as mixtures thereof, such as racemic mixtures, are part of the présent invention. Many organic compounds exist in optically active forms, i. e. they hâve the ability to rotate the plane of linearly polarized light. When describing an optically active compound, the préfixés R and S are used to designate the absolute configuration of the molécule with respect to its chiral center(s). A particular stereoisomer can also be defined as an enantiomer, and a mixture of such isomers is often referred to as an enantiomeric mixture.

The term “atropisomers” refers to compounds having spatial isomerism caused by the absence of rotation around a simple bond, for example, in diphenyls, dinaphthyls and others.

The term “excipient” is used herein to describe any ingrédient other than the compound(s) of the invention.

“Pharmaceutical composition” means a composition, comprising a compound of the invention and one or more pharmaceutically acceptable excipients. Examples of excipients include, but are not limited to, pharmaceutically acceptable and pharmacologically compatible fillers, solvents, diluents, carriers, auxiliary, distributing and sensing agents, delivery agents, such as preservatives, stabilizers, filler, disintegrators, moisteners, emulsifiers, suspending agents, thickeners, sweeteners, flavouring agents, aromatizing agents, antibacterial agents, fungicides, lubricants, and prolonged delivery controllers, the choice and suitable proportions of which dépend on the type and way of administration and dosage. Examples of suitable suspending agents are ethoxylated isostearyl alcohol, polyoxyethene, sorbitol and sorbitol ether, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacant and their mixtures as well.

Protection against action of microorganisms can be provided by varions antibacterial and antifungal agents, such as, for example, parabens, chlorobutanole, sorbic acid, and similar compounds. Composition may also contain isotonie agents, such as, for example, sugars, sodium chloride, and similar compounds. Prolonged action of composition may be achieved by agents slowing down absorption of active ingrédient, for example, aluminum monostearate and gélatine. Examples of suitable carriers, solvents, diluents and delivery agents include water, éthanol, polyalcohols and their mixtures, natural oils (such as olive oil) and organic esters (such as ethyl oleate) for injections. Examples of fillers are lactose, milk-sugar, sodium citrate, calcium carbonate, calcium phosphate and the like. Examples of disintegrators and distributors are starch, alginic acid and its salts, silicates and the like. Examples of suitable lubricants are magnésium stéarate, sodium lauryl sulfate, talc and polyethylene glycol of high molecular weight. Pharmaceutical composition for pérorai, sublingual, transdermal, intramuscular, intravenous, subeutaneous, local or rectal administration of active ingrédient, alone or in combination with another active compound may be administered to human and animais in a standard administration form, in a mixture with traditional pharmaceutical carriers. Suitable standard administration forms include pérorai forms such as tablets, gelatin capsules, pills, powders, granules, chewing-gums and pérorai solutions or suspensions; sublingual and transbuccal administration forms; aérosols; implants; local, transdermal, subeutaneous, intramuscular, intravenous, intranasal or intraocular forms and rectal administration forms.

“Pharmaceutically acceptable sait” means relatively nontoxic both organic and inorganic salts of acids and bases disclosed in this invention. These salts could be prepared in situ in the processes of synthesis, isolation or purification of compounds or they could be prepared specially. In particular, salts of bases specially could be prepared from purified base of the disclosed compound and suitable organic or minerai acid. Examples of salts prepared in this manner include hydrochlorides, hydrobromides, sulfates, bisulfates, phosphates, nitrates, acétates, oxalates, valeriates, oleates, palmitates, stéarates, laurates, borates, benzoates, lactates, p-toluenesulfonates, citrates, maleates, fumarates, succinates, tartrates, methane sulphonates, malonates, salicylates, propionates, ethane sulphonates, benzene sulfonates, sulfamates and the like (Detailed description of such salts properties is given in: Berge S.M., et al., “Pharmaceutical Salts” J. Pharm. Sci. 1977, 66: 1 - 19). Aminoacids may be selected from aminoacids—lysine, omithine and arginine.

“Médicament” - is a compound (or a mixture of compounds as a pharmaceutical composition) in the form of tablets, capsules, injections, ointments and other ready forms intended for restoration, improvement or modification of physiological functions in humans and animais, and for treatment and prophylaxis of diseases, for diagnostics, anesthésia, contraception, cosmetology and others.

“Treat”, “treating” and “treatment” refer to a method of alleviating or abrogating a biological disorder and/or at least one of its attendant symptoms. As used herein, to “alleviate” a disease, disorder or condition means reducing the severity and/or occurrence frequency of the symptoms of the disease, disorder, or condition. Further, référencés herein to “treatment” include référencés to curative, palliative and prophylactic treatment.

“Prophylaxis”, “prophylactic therapy” (“préventive therapy”) refers to a set of measures aimed at preventing the onset, eliminating risk factors, or early detecting a disease or disorder, its exacerbation, relapse, complications or other conséquences.

In one aspect, the subject of treatment, or patient, is a mammal, preferably a human subject. Said subject may be either male or female, of any âge.

“Disorder” means any condition that would benefit from treatment with the compound of the présent invention. This means chronic and acute disorders or diseases including those pathological conditions that prédisposé the mammal to the disorder in question. Non-limiting examples of disorders to be treated herein include benign and malignant tumors; leukemias and lymphoid malignancies; breast, ovarian, stomach, endométrial, salivary gland, lung, kidney, colon, thyroid, pancréas, prostate or bladder cancer; neuronal, glial, astrocytal, hypothalamic and other glandular, macrophagal, épithélial, stromal and blastocoelic disorders; inflammatory, angiogenic and immunologie disorders. Préférable disorders to be treated with the compound of the invention are tumors of blood and chronic lymphoproliférative diseases, cancer, autoimmune diseases.

“Therapeutically effective amount” refers to that amount of the therapeutic agent being administered which will relieve to some extent one or more of the symptoms of the disease/ disorder being treated.

The terms “inhibits”, “inhibiting”, or “inhibitor” of a kinase, as used herein, refer to suppression/ inhibition of enzymatic phosphotransferase activity.

The term “irréversible inhibitor”, as used herein, refers to a compound that, upon contact with a target protein (e.g., a kinase) causes the formation of a new covalent bond with or within the protein, whereby one or more of the target protein’s biological activities (e.g., phosphotransferase activity) is diminished or abolished notwithstanding the subséquent presence or absence of the irréversible inhibitor.

The term “irréversible Btk inhibitor”, as used herein, refers to an Btk inhibitor that can form a covalent bond with an amino acid residue of Btk.

The term biopharmaceutical, which may also be referred to as a biologie medical product or biologie, is intended to refer to any médicinal product manufactured in, extracted from, or semi-synthesized from biological sources. Exemplary biopharmaceuticals include vaccines, blood, or blood components, allergenics, somatic cells, gene thérapies, tissues, recombinant therapeutic protein, and living cells used in cell therapy. Biopharmaceuticals can comprise sugars, proteins, or nucleic acids, or be combinations of these substances, or may be living cells or tissues. They may be isolated from natural sources, such as human, animal, or microorganism, or produced by means of biological processes involving recombinant DNA technology. Non-limiting examples of the biopharmaceuticals include peptides, carbohydrates, lipids, monoclonal antibodies, biosimilars, biologies, non-IgG antibody-like structures such as but not limited to heterologous antibodies, diabodies, triabodies, and tetrabodies, other multivalent antibodies including scFv2/BITEs, streptabodies, and tandem diabodies, or combinations thereof. Optionally the biopharmaceuticals may be covalently linked to toxins, radioactive materials or another biological molécule, including proteins, peptides, nucleic acids, and carbohydrates. The aforementioned biological molécules include, but are not limited to, molécules of bacterial origin, viral origin, mammalian origin, or recombinant origin.

As used herein, the words “comprise,” “hâve,” “include,” or variations such as “comprises,” “comprising,” “has,” “having,” “includes” or “including”, and ail grammatical variations thereof will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.

Detailed description of the invention

The présent invention relates to a compound of Formula I:

ⁿ Formula I or pharmaceutically acceptable sait, solvaté or stereoisomer thereof, wherein:

Vi is C or N,

V₂ is C(R₂) or N, whereby if Vi is C then V₂ is N, if Vi is C then V₂ is C(R₂), or if Vi is N then V₂ is C(R₂);

each n, k is independently 0, 1;

each R₂, Ru is independently H, D, Hal, CN, NR’R”, C(O)NR’R”, Cj-C₆ alkoxy; R₃ is H, D, hydroxy, C(O)C_rC₆ alkyl, C(O)C₂-C₆ alkenyl, C(O)C₂-C₆ alkynyl, C_r C₆ alkyl;

R4 is H, Hal, CN, CONR’R”, hydroxy, C_rC₆ alkyl, Ci-C₆ alkoxy;

L is CH₂, NH, O or Chemical bond;

R! is selected from the group of the fragments, comprising:

Fragment 1, r₅ a/V^S

V^A^^{4 A9}Y^^{7 2 8} Fragment 2,

R₅ \a₆ ^{0 A}s\ ^A? _aî ^aYnY^{As 2} Fragment 3 each Ai, A₂, A₃, A₄ is independently CH, N, CHal;

each A₅, A_6j A₇, A₈, A₉ is independently C, CH or N;

R₅ is H, CN, Hal, CONR’R”, C_rC₆ alkyl, non-substituted or substituted by one or ίο more halogens;

each R’ and R” is independently selected from the group, comprising H, Ci-C₆ alkyl, C_rC₆ cycloalkyl, aryl;

R₆ is selected from the group:

each R₇, R₈, R₉, Rio is independently vinyl, methylacetylenyl; Hal is Cl, Br, I, F.

In another embodiment, the présent invention relates to a compound of Formula I wherein R_} is selected from the group including:

wherein R₅, Hal hâve the above meanings.

In another embodiment, the présent invention relates to a compound of

Formula II:

ⁿ Formula II, or pharmaceutically acceptable sait, solvaté or stereoisomer thereof, wherein:

Vi is C or N,

V₂ is C(R₂) or N, whereby if Vi is C then V₂ is N, if V! is C then V₂ is C(R₂), or ifVj isNthen V₂ is C(R₂);

each n, k is independently 0, 1 ;

R₂ is Hal, CN, NR’R”, C(O)NR’R”, C_rC₆ alkoxy;

Rh is H, Hal, CN, NR’R”, C(O)NR’R”, C_rC₆ alkoxy;

L is CH₂, NH, O or Chemical bond;

R₃ is H, hydroxy, C(O)Ci-C₆ alkyl, C(O)C₂-C₆ alkenyl, C(O)C₂-C₆ alkynyl, C_rC₆ alkyl;

R4 is H, Hal, CN, CONR’R”, hydroxy, C_rC₆ alkyl, C_rC₆ alkoxy;

Ri is selected from the group of the fragments, comprising:

each A_b A₂, A₃, A₄ is independently CH, N, CHal;

each A₅, A_6j A₇, A₈, A₉ is independently C, CH or N;

R₅ is H, CN, Hal, CONR’R”, C_rC₆ alkyl, , non-substituted or substituted by one or more halogens;

each R’ and R” is independently selected from the group, comprising H, C_rC₆ alkyl, Ci-C₆ cycloalkyl, aryl;

R₆ is selected from the group:

each R₇, R₈, R₉, Rio is independently vinyl, methylacetylenyl;

Hal is Cl, Br, I, F.

In another embodiment, the présent invention relates to a compound of Formula III:

Formula III, or pharmaceutically acceptable sait, solvaté or stereoisomer thereof, wherein:

Vi isCorN,

V₂ is C(R₂) or N, whereby if Vi is C then V₂ is N, if Vi is C then V₂ is C(R₂), or if Vi is N then V₂ is C(R₂);

each n, k is independently 0, 1 ;

R₂ is Hal, CN, NR’R”, C(O)NR’R”, C_rC₆ alkoxy;

R_h is H, Hal, CN, NR’R”, C(O)NR’R”, C_rC₆ alkoxy;

L is CH₂, NH, O or Chemical bond;

R₃ is H, hydroxy, C(O)Ci-C₆ alkyl, C(O)C₂-C₆ alkenyl, C(O)C₂-C₆ alkynyl, Ci-C₆ alkyl;

R4 is H, Hal, CN, CONR’R”, hydroxy, C_rC₆ alkyl, C_rC₆ alkoxy;

wherein if V) is C, V₂ is N, then at least one of R₃, R4, Ru is not H;

Ri is selected from the group of the fragments, comprising:

each Ai, A₂, A₃, A₄ is independently CH, N, CHal;

each A₅, A_6j A₇, A₈, A₉ is independently C, CH or N;

R₅ is H, CN, Hal, CONR’R”, Ci-C₆ alkyl, non-substituted or substituted by one or more halogens;

each R’ and R” is independently selected from the group, comprising H, Ci-C₆ alkyl, C_rC₆ cycloalkyl, aryl;

R₆ is selected from the group:

each R₇, R₈, R₉, Rio is independently vinyl, methylacetylenyl;

Hal is Cl, Br, I, F;

In another embodiment, the présent invention relates to a compound of

Formula IV:

Formula IV, or pharmaceutically acceptable sait, solvaté or stereoisomer thereof, wherein:

Vi is C or N,

V₂ is C(R₂) or N, whereby if Vi is C then V₂ is N, if Vi is C then V₂ is C(R₂), or if Vi is N then V₂ is C(R₂);

each n, k is independently 0, 1 ;

R₂ is Hal, CN, NR’R”, C(O)NR’R”, C_rC₆ alkoxy;

Rh is H, Hal, CN, NR’R”, C(O)NR’R”, C_rC₆ alkoxy;

L is CH₂, NH, O or Chemical bond;

R₃ is H, hydroxy, C(O)C_rC₆ alkyl, C(O)C₂-C₆ alkenyl, C(O)C₂-C₆ alkynyl, C_rC₆ alkyl;

R4 is H, Hal, CN, CONR’R”, hydroxy, Ci-C₆ alkyl, C_rC₆ alkoxy;

wherein if Vi is C, V₂ is N, then at least one of R₃, R4, Rh is not H;

Ri is selected from the group of the fragments, comprising:

each Ai, A₂, A₃, A₄ is independently CH, N, CHal;

each A₅, A_6j A₇, A₈, A₉ is independently C, CH or N, and at least one of A₅, A_6; A₇, A₈, A₉ is N;

R₅ is H, CN, Hal, CONR’R”, C_rC₆ alkyl, non-substituted or substituted by one or more halogens;

each R’ and R” is independently selected from the group, comprising H, C_rC₆ alkyl, C_rC₆ cycloalkyl, aryl;

R₆ is selected from the group:

each R₇, R₈, R₉, Rio is independently vinyl, methylacetylenyl;

Hal is Cl, Br, I, F;

In another embodiment, the présent invention relates to a compound of

Formula V:

or pharmaceutically acceptable sait, solvaté or stereoisomer thereof, wherein:

V[ is C or N, each n, k is independently 0, 1 ;

R₂ is H, Hal, CN, NR’R”, C(O)NR’R”, C_rC₆ alkoxy;

R₃ is H, hydroxy, C(O)C]-C6 alkyl, C(O)C₂-Cô alkenyl, C(O)C₂-Cô alkynyl, Cj-Cô alkyl;

R4 is H, Hal, CN, CONR’R”, hydroxy, C_rC₆ alkyl, C_rC₆ alkoxy;

L is CH₂, NH, O or Chemical bond;

Ri is selected from the group of the fragments, comprising:

each Ai, A₂, A₃, A₄ is independently CH, N, CHal;

each A₅, A_6j A₇, A₈, A₉ is independently C, CH or N;

R₅ is H, CN, Hal, CONR’R”, C_rC₆ alkyl, non-substituted or substituted by one or more halogens;

each R’ and R” is independently selected from the group, comprising H, C_rC₆ alkyl, Ci-C₆ cycloalkyl, aryl;

R₆ is selected from the group:

each R₇, R₈, R₉, Rio is independently vinyl, methylacetylenyl;

Rn is H, Hal, CN, NR’R”, C(O)NR’R”, C_rC₆ alkoxy;

Hal is Cl, Br, I, F;

In another embodiment, the présent invention relates to a compound of

Formula VI:

Formula VI, or pharmaceutically acceptable sait, solvaté or stereoisomer thereof , wherein:

R] is selected from the group of the fragments, comprising:

r₅ a₃ όΛ α₅ aA

A ^h

A ⁴

Fragment 1, r₅ \a₆

As Ag

A4 a₉^a₇ ⁸ Fragment 2

Fragment 3;

each Ai, A₂, A₃, A₄ is independently CH, N, CHal;

each A₅, A_6j A₇, A₈, A₉ is independently C, CH or N;

R₅ is H, CN, Hal, CONR’R”, C_rC₆ alkyl, , non-substituted or substituted by one or more halogens;

each R’ and R” is independently selected from the group, comprising H, C_rC₆ alkyl, Ci-C₆ cycloalkyl, aryl;

R₂ is Hal, CN, NR’R”, C(O)NR’R”, C_rC₆alkoxy;

R4 is H, Hal, CN, CONR’R”, hydroxy, C_rC₆ alkyl, Ci-C₆alkoxy;

n is 0, 1,2;

R₆ is selected from the group:

R₇ is vinyl, methylacetylenyl;

each R₈, R₉, Rio is independently methylacetylenyl

R_n is H, Hal, CN, NR’R”, C(O)NR’R”, C_rC₆alkoxy;

Hal is Cl, Br, I, F;

In another embodiment, the présent invention relates to a compound of

Formula VII:

Formula VII, or pharmaceutically acceptable salts or solvatés;

wherein:

Vi is C or N,

V₂ is C(R₂) or N, whereby if Vi is C then V₂ is N, if Vi is C then V₂ is C(R₂), or if Vi is N then V₂ is C(R₂);

k independently is 0, 1 ;

R₂ is H, D, Hal, CN, NR’R”, C(O)NR’R”;

R₃ is H, hydroxy, C(O)C_rC₆ alkyl, C(O)C₂-C₆ alkenyl, C(O)C₂-C₆ alkynyl, C_rC₆ alkyl;

R4 is H, Hal, CN, CONR’R”, hydroxy, C_rC₆ alkyl, C_rC₆ alkoxy;

L is CH₂, NH, O or Chemical bond;

Ri is selected from the group of the fragments, comprising:

each Ai, A₂, A₃, A₄ is independently CH, N, CHal;

each A₅, A_6j A₇, A₈, A₉ is independently C, CH or N;

R₅ is H, CN, Hal, CONR’R”, C_rC₆ alkyl, non-substituted or substituted by one or more halogens;

each R’ and R” is independently selected from the group, comprising H, C_rC₆ alkyl, C_rC₆ cycloalkyl, aryl;

Ru is H, Hal, CN, NR’R”, C(O)NR’R”, Ci-C₆alkoxy;

Hal is Cl, Br, I, F;

In another embodiment the présent invention relates to the compound of Formula II, compound of Formula III, compound of Formula IV, compound of Formula V, compound of Formula VI, compound of Formula VII, wherein Ri is selected from the group including:

wrehein R₅, Hal hâve the above meanings.

Compounds, described in the présent invention, may be formed as, and/or used as, pharmaceutically acceptable salts. The type of pharmaceutical acceptable salts, include, but are not limited to: acid addition salts, formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; or with an organic acid such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, benzoic acid, 3-(4hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfônic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 2-naphthalenesulfonic acid, 4methylbicyclo-[2.2.2]oct-2-ene-l-carboxylic acid, glucoheptonic acid, 4,4’methylenebis-3-hydroxy-2-ene-l-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like.

The corresponding counterions of the pharmaceutically acceptable salts may be analyzed and identified using various methods including, but not limited to, ion exchange chromatography, ion chromatography, capillary electrophoresis, inductively coupled plasma, atomic absorption spectroscopy, mass spectrometry, or any combination thereof.

The salts are recovered by using at least one of the following techniques: filtration, précipitation with a non-solvent followed by filtration, évaporation of the solvent, or, in the case of aqueous solutions, lyophilization. It should be understood that a reference to a pharmaceutically acceptable sait includes the solvent addition forms or crystal forms thereof, particularly solvatés or polymorphs. Solvatés contain either stoichiometric or non-stoichiometric amounts of a solvent, and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, éthanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvatés of compounds described herein can be conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered équivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.

Compounds described herein may be in various forms, including but not limited to, amorphous forms, milled forms and nano-particulate forms. In addition, compounds described herein include crystalline forms, also known as polymorphs. Polymorphs include the different crystal packing arrangements of the same elemental composition of a compound. Polymorphs usually hâve different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Various factors such as the recrystallization solvent, rate of crystallization, and storage température may cause one crystal form to dominate.

The screening and characterization of the pharmaceutically acceptable salts, polymorphs and/or solvatés may be accomplished using a variety of techniques including, but not limited to, thermal analysis, x-ray diffraction, spectroscopy, vapor sorption, and microscopy. Thermal analysis methods address to analysis of thermo Chemical dégradation or thermo physical processes including, but not limited to, polymorphie transitions, and such methods are used to analyze the relationships between polymorphie forms, to détermine weight loss, to fmd the glass transition température, or for excipient compatibility studies. Such methods include, but are not limited to, Differential scanning calorimetry (DSC), Modulated Differential Scanning Calorimetry (MDCS), Thermogravimetric analysis (TGA), Thermogravi-metric and Infrared analysis (TG/IR). X-ray diffraction methods include, but are not limited to, single crystal and powder diffractometers and synchrotron sources. The various spectroscopic techniques used include, but are not limited to, Raman, FTIR, UVIS, and NMR (liquid and solid State). The various microscopy techniques include, but are not limited to, polarized light microscopy, Scanning Electron Microscopy (SEM) with Energy Dispersive X-Ray Analysis (EDX), Environmental Scanning Electron Microscopy with EDX (in gas or water vapor atmosphère), IR microscopy, and Raman microscopy.

In another embodiment of the présent invention relates to the compounds selected from the group including:

Structure	Name	Compound No.
0 ό N' nh2 y-7 [ΛΗν cn /H o \ N-A	(R)-1 -( 1 -acryloylpiperidin-3-yl)-4amino-3 -(4-(4-oxopyridin-1 (4H)yl)phenyl)-1 H-pyrazolo[4,3c]pyridin-7-carbonitrile	BCD-BTK-4
0 N7 nh2 y-A ? ΛΗ ΥΝ h2n^o	(R)-1 -( 1 -acryloylpiperidin-3-yl)-4amino-3-(4-(4-oxopyridin-l(4H)yl)phenyl) -1 H-pyrazolo [4,3 c]pyridin-7-carboxamide	BCD-BTK-6
o ό nh2 W Cl Υγ	(R)-1 -(4-( 1 -( 1 -acryloylpiperidin-3yl)-4-amino-7-chloro-1Hpyrazolo[4,3-c]pyridin-3yl)phenyl)pyridin-4( 1 H)-one	BCD-BTK-9

Ο ô ι\Η ci HO. 7 Τ' /0 \ N—	(R)-1 -(4-( 1 -( 1 -acryloylpiperidin-3 yl)-4-chloro-5-hydroxy-1Hpyrazolo[3,4-b]pyridin-3-yl) phenyl)pyridin-4( 1 H)-one	BCD-BTK-13
0 ri N O HO. J ΎΓΧ5ν RN ^O	(R)-1 -( 1 -acryloylpiperidin-3 -yl)-5 hydroxy-3-(4-(4-oxopyridin-l(4H)yl)phenyl)-1 H-indazol-7carboxamide	BCD-BTK-18
Ois/5^ ' V Γζ\ \=Z ° CM r	(R)-1 -( 1 -acryloylpiperidin-3 -yl)-3 (4-(4-oxopyridin-1 (4H)-yl)phenyl)1 H-pyrazolo [4,3 -c]pyridin-7carboxamide	BCD-BTK-24
0 N^ O ϊΠγΑ ci Λ o \ Ν-γ	(R)-1-(4-(1-(1 -acryloylpiperidin-3 yl)-7-chloro-1 H-pyrazolo [4,3 -c] pyridin-3 -yl)phenyl)pyridin-4( 1H)- one	BCD-BTK-30

0 ό Ν-^ CN VA όΛ ΗΑ^θ 0^°	(R)-1 -( 1 -acryloylpiperidin-3-yl)-4cyano-3-(4-(4-oxopyridin-l(4H)yl)phenyl)-lH-indazol-7carboxamide	BCD-BTK-35
0 Ο Ν' νΑ / N νη2 VA Υ'Ν CN Λα ο \ Ν-γ	(R)-1 -( 1 -acryloylpiperidin-3-yl)-4amino-3 -(2-(4-oxopyridin-1 (4H)-yl) pyrimidm-5-yl)-lH-pyrazolo[4,3-c] pyridin-7-carbonitrile	BCD-BTK-36
0 ά νΑ. νη2 VA Ν/χ> CN Λα /0	(R)-1 -(1 -acryloylpiperidin-3-yl)-4amino-3 -(4-oxo-4H- [1,2’ -bipyridin]5’-yl)-lH-pyrazolo[4,3-c]pyridin-7carbonitrile	BCD-BTK-38
/ I '^ \ A /=¾ ζΑ ν'2 Λ y	(R)-1 -(5-( 1 -( 1 -acryloylpiperidin-3yl)-7-chloro-lH-pyrazolo[4,3-c] pyridin-3 -yl)pyrimidin-2-yl) pyridin4(lH)-one	BCD-BTK-54
ο ή Ν VA cx> ci Λ ο \ Ν-γ	(R)-5 ‘ -( 1 -( 1 -acryloylpiperidin-3 -yl) 7-chloro-lH-pyrazolo[4,3-c]pyridin- 3 -yl)-4H-[ 1,2 ’ -bipyridin]-4-one	BCD-BTK-56

0 ό N7 Ν=\ / Ν νη2\Α L Ρ Αν' d Λτ ο	(R)-1 -(5-(1 -(1 -acryloylpiperidin-3 yl)-4-amino-7-chloro-1Ηpyrazolo [4,3 -c]pyridin-3 -yl) pyrimidin-2-yl)pyridin-4( 1 H)-one	BCD-BTK-74
0 6 A Ν ΝΗ2ΧΑ Αν ci ζ^Α ο \__Ν-γ-	(R)-5 ’ -( 1 -( 1 -acryloylpiperidin-3 -yl)4-amino-7-chloro-lH-pyrazolo[4,3c]pyridin-3 -yl)-4H-[ 1,2 ’ -bipyridin]4-one	BCD-BTK-76
°Α^ ΟΑΑ 1 αΑ r\ « X J / ζ% / ζΆ τ /=\ Ρ Μ J-A Ζ-^ ζ <Ν I	(R)-1 -( 1 -acryloylpiperidin-3-yl)-4amino-3-(4-oxo-4H-[l,2’-bipyridin]5 ’-yl)- lH-pyrazolo[4,3-c]pyridin-7carboxamide	BCD-BTK-86
°Α^ οΑΑ X U*i A Χλ/χΑχ τ / \ P ΖΧ J\ CM τ	(R)-1 -( 1 -acryloylpiperidin-3-yl)-4amino-3-(4-oxo-4H-[l,2’-bipyridin]- 5 ’ -yl)-1 H-pyrazolo [4,3 -c]pyridin-7 carboxamide	BCD-BTK-88
0 Λ νΧ / Ν ΝΑ νΑν' Η2νΛ	(R)-1 -(1 -acryloylpiperidin-3 -yl)-3(2-(4-oxopyridin-1 (4H)-yl) pyrimidin-5 -yl)-1 H-pyrazolo [4,3 -c] pyridin-7-carboxamide	BCD-BTK-98

ο A Ν VA ΗζΝ^°	(R)-1 -( 1 -acryloylpiperidin-3-yl)-3(4oxo-4H[l ,2' -bipyridin]-5'-yl)-lHpyrazolo [4,3 -c]pyridin-7carboxamide	BCD-BTK-100
O-V ζ \__/ Cr^cx /ν / A/V Γ*0	(R)-1 -( 1 -acryloylpiperidin-3 -yl)-3 (4-(pyridin-4-yloxy)phenyl)-1Hpyrazolo [4,3 -c]pyridin-7-carbonitrile	BCD-BTK-104
z \_/ r^\^.Z V z/ z Z ^Z 7 C. / V/ ~O x°	(R)-1 -(1 -acryloylpiperidin-3 -yl)-3(2-(4-oxopyridin-1 (4H)-yl) pyrimidin-5-yl)-lH-pyrazolo[4,3-c] pyridin-7-carbonitrile	BCD-BTK-105
°\A °W A Xz% r\ VAj'V	(R)-1 -( 1 -acryloylpiperidin-3 -yl ) - 3 (4-oxo-4H[ 1,2' -bipyridin]-5 ' -yl)lH-pyrazolo[4,3-c]pyridin-7carbonitrile	BCD-BTK-107
0 A V Ο H / Xan \^N—^°	(R)-N-( 1 -( 1 -acryloylpiperidin-3 -yl)6-methyl-3 -(4-(4-oxopyridin-1 (4H)yl)phenyl)-1 H-pyrazolo [3,4-b] pyridin5-yl) acrylamide	BCD-BTK-117

0 Y Ο | |Γ% CN Λλ Ο \ Ν-%	(R)-l-(l-acryloylpiperidin-3-yl)-7- cyano-3-(4-(4-oxopyridin-l(4H)-yl) phenyl)-lH-indazol-5-yl acrylate	BCD-BTK-118
Γ ζ υ,/Ύ ζ\% Ο2 C\l τ	(R)-1 -(4-( 1 -( 1 -acryloylpiperidin-3yl)-5-amino-6-methyl-lHpyrazolo [3,4-b]pyridin-3 -yl) phenyl)pyridin-4( 1 H)-one	BCD-BTK-119
ο 4 Ν—7 Ν=Χ W ΗΟ. / W Η2Ν Yq ο	(R)-1 -( 1 -acryloylpiperidin-3 -yl) -5hydroxy-3 -(4-oxo-4H- [1,2’bipyridin]-5 ’ -yl)-1 H-indazol-7carboxamide	BCD-BTK-120
0 Ô ν^ν l// Ηογ^Ν Η2Λ° %3ν4	(R)-1 -( 1 -acryloylpiperidin-3 -yl)-5hydroxy-3-(2-(4-oxopyridin-l (4H)yl) pyrimidin-5-yl)-lH-indazol-7carboxamide	BCD-BTK-121
ο Ô |Ή Ο ΗΟ.^^ 7 Y J/ N :%''N cn /0 \ N-/'	(R)-1 -(1 -acryloylpiperidin-3-yl)-5hydroxy-3-(4-(4-oxopyridin-1 (4H)yl)phenyl)-lH-indazol-7-carbonitrile	BCD-BTK-122

N^\ Μ 0 ο CN Λλ η	(R)-1 -( 1 -acryloylpiperidin-3 -yl) -3(4 (pyridin-4-yloxy)phenyl)-lHpyrazolo[4,3-c]pyridin-7-carbonitrile	BCD-BTK-123
Ν=\ Μ ο Cl δδ ΓΓν /\ χθ \ Ν-^	(R)-1 -(1 -acryloylpiperidin-3-yl) -4chloro-3 -(4-(pyridin-4-yloxy) phenyl)-1 H-pyrazolo[3,4-b]pyridine	BCD-BTK-124
Ν^\ Μ ο ο Cl ζ°	(R) -1-(1-acryloylpiperidin-3-yl) -7chloro-3-(4-(pyridin-4-yloxy) phenyl)-lH-pyrazolo[4,3-c]pyridine	BCD-BTK-125
Ο ό Ν /^Ν ΗΟ. J χτ> 'γ'Ν CN /H 0 \ Ν~χ^	(R)-1 -( 1 -acryloylpiperidin-3 -yl)-5hydroxy-3 -(6-(4-oxopyridin-1 (4H)yl)pyridin-3 -yl)-1 H-indazol-7 carbonitrile	BCD-BTK-127
I ο ο δ	(R)-1 -( 1 -acryloylpiperidin-3 -yl)-5hydroxy-4-chloro-3-(4-(pyridin-4yloxy)phenyl)-1 H-pyrazolo[3,4b]pyridine	BCD-BTK-129

0 ό / Ν Τ £ \Ν χ/'-ν CN /S Ο \ Ny	(R)-1 -(1 -acryloylpiperidin-3-yl)-5hydroxy-3-(2-(4-oxopyridin-1 (4H)yl)pyrimidin-5 -yl)-1 H-indazol-7carbonitrile	BCD-BTK-130
ο O>/y / % 1 ΓΖ\ 5 Χϊ/	(R)-1 -(4-( 1 -( 1 -acryloylpiperidin-3 yl)-4-chloro-1 H-pyrazolo[3,4-b] pyridin-3 -yl)phenyl)pyridin-4( 1H)- one	BCD-BTK-131
Ν=\ ç? ο ο ΗΟ J ίοα Η^Ν ^?ν-/	(R)-1 -( 1 -acryloylpiperidin-3-yl)-5hydroxy-3 -(4-pyridin-4-yloxy) phenyl)-lH-indazol-7-carboxamide	BCD-BTK-133
Ν=\ Μ ο νη2 y-7 ΐ uA cn A ο \ N-y	(R)-1 -( 1 -acryloylpiperidin-3-yl)-4amino-3-(4-(pyridin-4-yloxy) phenyl)-lH-pyrazolo[4,3-c]pyridin7-carbonitrile	BCD-BTK-134
Z M O \=/ Z7-Z X? W-o Λ	(R)-1 -( 1 -acryloylpiperidin-3 -yl)-4amino-3-(4-(pyridin-4-yloxy) phenyl)-lH-pyrazolo[4,3-c]pyridin7-carboxamide	BCD-BTK-135

0 d Ç°C! W O. d YjT> Z\ o	(R)-1 -( 1 -acryloylpiperidin-3-yl)-4chloro-3-(4-(4-oxopyridin- 1 (4H)phenyl)-1 H-pyrazolo [3,4-b] pyridin-5-yl acrylate	BCD-BTK-136
N^\ 0 o HO. ^\d CïCN γ'Ν cn Λα o \ N~y	(R)-1 -( 1 -acryloylpiperidin-3-yl)-5hydroxy-3-(4-pyridin-4-yloxy) phenyl)-lH-indazol-7-carbonitrile	BCD-BTK-137
N^\ AJ o CN VA ΑΛ A^ N η2νΛ	(R)-1 -( 1 -acryloylpiperidin-3-yl)-4cyano-3-(4-(pyridin-4-yloxy) phenyl)-1 H-indazol-7-carboxamide	BCD-BTK-138
A 0 nh2 yd ΐ D Y^N' Cl λ~~\ \ ud 0	(R)-1 - ( 1 -acryloylpiperidin-3 -yl)-7chloro-3 -(4-(pyridin-4-yloxy) phenyl)-1 H-pyrazolo [4,3 -c]pyridin4-amine	BCD-BTK-139
N^\ M 0 O Γρ η2νΛο^Α o	(R)-1 -( 1 -acryloylpiperidin-3-yl) -3(4-(pyridin-4-yloxy)phenyl) -1Hpyrazolo[4,3-c]pyridin-7carboxamide	BCD-BTK-140

A ζ ΟΥΛ. A/ z / V Q-^	(R)-4-( 1-(1-(1 -acryloylpiperidin-3 yl)-7-chloro-lH-pyrazolo[4,3-c] pyridin-3-yl)-N-(pyridin-2-yl) benzamide	BCD-BTK-201
A'VCN VA O o îaa VS Cl A ζθ \ N-/	(R)-4-(4-( 1 -( 1 -acryloylpiperidin-3 yl)-7-chloro-lH-pyrazolo[4,3-c] pyridin-3-yl)phenoxy)nicotinonitrile	BCD-BTK-202
NH2 N=%/ 0 O Cl A ζθ \ N-A	(R)-4-(4-( 1 -( 1 -acryloylpiperidin-3yl)-7-chloro-lH-pyrazolo[4,3-c] pyridin-3-yl)phenoxy)nicotinamide	BCD-BTK-203
°V^ o^W u_ L Cz\ IAaAj	(R)-1-(4-(1-(1 -acryloylpiperidin-3 yl)-7-chloro-177-pyrazolo[4,3-c] pyridin-3-yl)-3-fluorophenyl) pyridin-4( l/7)-one	BCD-BTK-204

Ο ή ό' Ν ci X /Ο	(À)-1 -(4-( 1 -( 1 -acryloylpiperidin-3yl)-7-chloro-17i-pyrazolo[4,3-c] pyridin-3-yl)-2-fluorophenyl) pyridin-4( l//)-one	BCD-BTK-205
Ζ ιι οΑ5) Χ^ Ζ ) X	(R)-1 -(5-( 1 -(1 -acryloylpiperidin-3yl)-7-chloro-17/-pyrazolo[4,3-c] pyridin-3-yl)pyrimidin-2-yl)-4-oxo1,4-dihydropyridine-3 -carbonitrile	BCD-BTK-206
ω%3 ΑΑζ ΑΑ'ζ I / ζ γ \\ ^ζ X- Γό X. II ζ^ο I Μ	(R)-1-(5-(1-(1 -acryloylpiperidin-3 yl)-7-chloro-l//-pyrazolo[4,3-c] pyridin-3-yl)pyrimidin-2-yl)-4-oxo1,4-dihydropyridine-3 -carboxamide	BCD-BTK-207
ζ ιι χ ο,^ζ ι ζ-%^ r\ IXoZJ {Χδ	(R)-1-(4-(1-(1 -acryloylpiperidin-3 yl)-7-chloro-l//-pyrazolo[4,3-c] pyridin-3-yl)phenyl)-4-oxo-1,4dihydropyridine-3 -carbonitrile	BCD-BTK-208

F F F O >n Y-nh o τΠγν Cl	(Â)-4-( 1 -( 1 -acryloylpiperidin-3 -yl)7-chloro-17/-pyrazolo[4,3-c]pyridin3-yl)-A-(4-(trifluoromethyl)pyridin2-yl)benzamide	BCD-BTK-210
! N ο-χί O ϊπΑ F /0 \ N—	(R)-1 -(3-(7-fluoro-3-(4-(pyridin-4yloxy)phenyl)- l//-pyrazolo[4,3-c] pyridin-1 -yl)piperidin-1 -yl)prop-2en-l-one	BCD-BTK-211
Οχ \ 'L x v-^/^-z / Ύδ	(Â)-4-( 1 -( 1 -acryloylpiperidin-3 -yl)- 7-chloro-l//-pyrazolo[4,3-c]pyridin- 3-yl)-N-(5-fluoropyridin-2-yl) benzamide	BCD-BTK-212
dY? r o _/ z c°	(R)-1 -( 1 -acryloylpiperidin-3 -yl)-3 (4-(3-cyanopyridin-4-yloxy)phenyl)177-pyrazolo[4,3-c]pyridine-7carbonitrile	BCD-BTK-213
$ o >=N γ-ΝΗ O ^Y'N F z° \ N—	(A )-4 - ( 1 - ( 1 -acryloylpiperidin-3 -yl)7-fluoro- 1/7-pyrazolo [4,3 -c]pyridin3-yl)-Ar-(4-( 1,1 -difluoropropyl) pyridin-2-yl)benzamide	BCD-BTK-214

F. /— F \ o 2=N y-NH o Cl O \ N—	(Â)-4-( 1 -( 1 -acryloylpiperidin-3 -yl)7-chloro-1 H-pyrazolo [4,3 -c]pyridin3-yl)-7V-(4-(l, 1 -difluoropropyl) pyridin-2-yl)benzamide	BCD-BTK-215
r7W> f O Z P°	(R)-1 -( 1 -acryloylpiperidin-3 -yl ) - 3 (4-(2-cyanopyridin-3-yloxy)phenyl)1 H-pyrazolo [4,3 -c]pyridine-7carbonitrile	BCD-BTK-216
1 O Z r°	(A) - 4 - (4 - ( 1 - ( 1 -acryloylpiperidin-3 yl)-7-fluoro-lH-pyrazolo[4,3-c] pyridin-3 -yl)phenoxy) nicotinonitrile	BCD-BTK-217
H n-cn M o O ιπΑ AV'N Cl ,0 \	3-(4-{7-chloro-l-[l-(prop-2enoyl)piperidin-3-yl]- 1Hpyrazolo [4,3 -c]pyridin-3 -yl} phenoxy)pyridine-2-carbonitrile	BCD-BTK-218
0^7 Z \__/ A	4-{7-cyano-l-[l-(prop-2-enoyl) piperidin-3-yl]-lH-pyrazolo[4,3-c] pyridin-3 -yl} -TV- [4-( 1,1 difluoropropyl)pyridin-2-yl] benzamide	BCD-BTK-219

/ / z \ 1 z M k / A/50 //° O	3-(4- {7-chloro-1 -[(3Λ)-1 -(prop-2enoyl)piperidin-3-yl]-ÏHpyrazolo [4,3 -c]pyridin-3 -yl} phenoxy)pyridine-2-carboxamide	BCD-BTK-220
ο<> Z \__/ 1 1 4	4- {7-cyano-1 -[ 1 -(prop-2enoyl)piperidin-3-yl]- 1Hpyrazolo [4,3 -c]pyridin-3 -yl} -N- [4(trifluoromethyl)pyridin-2-yl] benzamide	BCD-BTK-221
0. ν-νη2 0-4 O ϊ'δΚΝ A/N Cl δ~^ ζθ \ Ν-γ	5 -(4- {7-chloro-1 -[(3Λ)-1 -(prop-2enoyl)piperidin- 3 -yl] -1Hpyrazolo[4,3-c]pyridin-3yl} phenoxy)pyridine-3 -carboxamide	BCD-BTK-222
ο/) z \__/ j zvv P6 TX?	4-{7-cyano-1-[(37?)-l-(prop-2enoyl)piperidin-3-yl]-1/7pyrazolo [4,3 -c]pyridin-3 -yl} -7V-(6fluoropyridin-2-yl)benzamide	BCD-BTK-223
o^f5 z \__/ Λ k	4- {7-cyano- 1-[(3À)-1 -(prop-2enoyl)piperidin-3-yl]-1//pyrazolo[4,3-c]pyridin-3-yl}-7V-[4(1,1 -difluoroethyl)pyridin-2yl]benzamide	BCD-BTK-224

\=N °y-NH o ü JL -N Cl z°	(A)-4 - ( 1 - ( 1 -acryloylpiperidin-3 -yl)7-chloro-l/7-pyrazolo[4,3-c]pyridin3 -yl)-A-(6-fluoropyridin-2yl)benzamide	BCD-BTK-225
fl- V \ \ yZ Ύ f Z*XX X3	(Λ)-4-( 1-(1 -acryloylpiperidin-3 -yl)7-chloro-l//-pyrazolo[4,3-c]pyridin3-yl)-A-(3-fluoropyridin-2yl)benzamide	BCD-BTK-226
Οχ JJ \ X t X>z^z 1 \ y^ Q--	(A )-4 - ( 1 - ( 1 -acryloylpiperidin-3 -yl)7-cyano-177-pyrazolo[4,3-c]pyridin3-yl)-7V-(5-fluoropyridin-2yl)benzamide	BCD-BTK-227
o-f\ z \__/ Λ ’ O	(A)-4-(l-(l -acryloylpiperidin-3 -yl)7-cyano-177-pyrazolo[4,3-c]pyridin3-yl)-7V-(pyridin-2-yl)benzamide	BŒ-BTK-228
A \==N o. / y-NH N=\ / N VA Oun %VN Cl <X zO \ N—ά	(À)-5-(l-(l-acryloylpiperidin-3-yl)7-chloro- 1/7-pyrazolo [4,3 -c]pyridin3-yl)-7V-(pyridin-2-yl)pyrimidine-2carboxamide	BCD-BTK-229

r o z P°	(A) - 3 - (4-( 1 - ( 1 -acryloylpiperidin-3yl)-7-fluoro-lH-pyrazolo[4,3-c] pyridin-3-yl)phenoxy)picolinonitrile	BCD-BTK-230
F0 F-X o \=N O. ' γΝΗ nh2 yA Cl Λα zo	(Λ)-4-( 1-(1 -acryloylpiperidin-3 -yl)4-amino-7-chloro-177-pyrazolo[4,3c]pyridin-3 -yl)-7V-(4-( 1,1difluoropropyl)pyridin-2-yl) benzamide	BCD-BTK-231
rVV l O z y	(Â)-4-(4-( 1 -( 1 -acryloylpiperidin-3 yl)-4-amino-7-chloro-l/7pyrazolo [4,3 -c]pyridin-3 yl)phenoxy)nicotinonitrile	BCD-BTK-232
f>n Οχ ' y-NH NH2 Ï^VN VA ci Λ^ z° \ N%	(À)-4-( 1 -( 1 -acryloylpiperidin-3 -yl)4-amino-7-chloro-177-pyrazolo[4,3c]pyridin-3 -yl)-7V-(3 -fluoropyridin2-yl)benzamide	BCD-BTK-233
ΓΛ An °%-νη nh2 y=A N N'A, u JL h CN ? X W	(Â)-4-( 1 -( 1 -acryloylpiperidin-3 -yl)4-amino-7-cyano-177-pyrazolo[4,3c]pyridin-3 -yl)-7V-(pyridine-2yl)benzamide	BCD-BTK-234

yNH F \yN CN X~\ /P CK»	4- {7-cyano-1 -[(3 A)-1 -(prop-2enoyl)piperidin-3 -yl] -1Hpyrazolo[4,3-c]pyridin-3-yl}-7V-(3fluoropyridin-2-yl)benzamide	BCD-BTK-235
NC 7= N ,°A7 nh2 \—/ U A ,N \yN ci	3 -(4- {4-amino-7-chloro-1 -[(3À)-1 (prop-2-enoyl)piperidin-3 -yl] -1Hpyrazolo[4,3-c]pyridin-3-yl} phenoxy)pyridine-2-carbonitrile	BCD-BTK-236
Cnh nh2 )—/ N U JL ,N \Cn ci	4- {4-amino-7-chloro-1 -[(3Λ)-1 (prop-2-enoyl)piperidin-3-yl]-lHpyrazolo[4,3-c]pyridin-3-yl}-7V-(5fluoropyridin-2-yl)benzamide	BCD-BTK-237
vNP yNH nh2 \—/ N^Vw, y d ,N CK Cl )-\ zP CNA=	4-{4-amino-7-chloro-l-[(3À)-l(prop-2-enoyl)piperidin-3-yl]-l/7pyrazolo[4,3-c]pyridin-3-yl}-7V(pyridin-2-yl)benzamide	BCD-BTK-238
Q y )-----( \ /“ ° Z=/ \	(R)-1 -( 1 -acryloylpiperidin-3-yl)- 4amine-7-methoxy-3-(4-(pyridin-4yloxy)phenyl)-lH-pyrazolo[4,3c]pyridine	BCD-BTK-239
o 0 )=N y—nh nh2 \—/ N y A n --° b<	(R)-4-( 1 -( 1 -acryloylpiperidin-3 -yl)4-amino-7-methoxy-1Hpyrazolo [4,3 -c]pyridin-3 -yl)-N (pyridin-2-yl)benzamide	BCD-BTK-240

nh2 \—/ Il J ,N	(R)-l- (1-acryloylpiperidin-3-yl)- 4amine-3-(4-(pyridin-4yloxy)phenyl)-1 H-pyrazolo [4,3 c]pyridine	BCD-BTK-241
0 Q %NH /Y NH2 \—/ N ΤΆ, u Y ,N Y-Y	(R)-4-( 1 -( 1 -acryloylpiperidin-3 -yl)4-amino-1 H-pyrazolo[4,3-c]pyridin3-yl)-N-(pyridin-2-yl)benzamide	BCD-BTK-242
ovQ YnH nYY, u Y -N Uji^N F Yy	(R)-4-( 1 -( 1 -acryloylpiperidin-3-yl)7-fluoro-1 H-pyrazolo [4,3 -c]pyridin3-yl)-N-(pyridin-2-yl)benzamide	BCD-BTK-243
F Y 0 )=N Ynh nYY, L Y ,N F YY	(R)-4-( 1 -( 1 -acryloylpiperidin-3 -yl)7-fluoro-lH-pyrazolo[4,3-c]pyridin3-yl)-N-(5-fluoropyridin-2yl)benzamide	BCD-BTK-244
E F O )=N %NH n^Y U Y h %N F YY	(R)-4-( 1 -( 1 -acryloylpiperidin-3 -yl)7-fluoro-l H-pyrazolo [4,3-c]pyridin3-yl)-N-(4-(trifluoromethyl)pyridin2-yl)benzamide	BCD-BTK-245

z. £ O °J (A	(R)-4-(4-( 1 -( 1 -acryloylpiperidin-3 yl)-7-fluoro-lH-pyrazolo[4,3c]pyridin-3yl)phenoxy)nicotinamide	BCD-BTK-246
n °j \ k x te AAz / te-V Xaa rz\ ? AyrU td	(R)-4-( 1 -( 1 -acryloylpiperidin-3 -yl)7-fluoro-1 H-pyrazolo [4,3 -c]pyridin3-yl)-N-(4-(l,ldifluorobutyl)pyridin-2yl)benzamide	BCD-BTK-247
LL Au M d	(R)-4-( 1 -( 1 -acryloylpiperidin-3 -yl)7-fluoro-lH-pyrazolo[4,3-c]pyridin3-yl)-N-(6-fluoropyridin-2yl)benzamide	BCD-BTK-248
dd fA=n °Anh O ûu V^N F A /0 \ NA	(R)-4-( 1 -( 1 -acryloylpiperidin-3 -yl)7-fluoro-1 H-pyrazolo [4,3 -c]pyridin3-yl)-N-(3-fluoropyridin-2yl)benzamide	BCD-BTK-249
Au M dXyO Ol )----( /^ü z—J	(R)-4-( 1 -( 1 -acryloylpiperidin-3 -yl)4-amino-7-chloro-l H-pyrazolo [4,3 c]pyridin-3-yl)-N-(6-fluoropyridin2-yl)benzamide	BCD-BTK-250

F F F \ A \=N °%-ΝΗ nh2 \A SA-n ci A z° \ Ν~γ	(R)-4-( 1 -( 1 -acryloylpiperidin-3 -yl)4-amino-7-chloro-lH-pyrazolo[4,3c]pyridin-3-yl)-N-(4- (trifluoromethyl)pyridin-2yl)benzamide	BCD-BTK-251
Aa An °%-ΝΗ o ϊπΑ SA-N Cl A z° \ N-V	(R)-4-( 1 -( 1 -acryloylpiperidin-3-yl)7-chloro-lH-pyrazolo[4,3-c]pyridin3-yl)-N-(4-(l,ldifluorobutyl)pyridin-2yl)benzamide	BCD-BTK-252
F S N=\ / N A ïAi N SA-n ci A /0 \ NA	(R)-5-( 1 -( 1 -acryloylpiperidin-3 -yl)7-chloro-lH-pyrazolo[4,3-c]pyridin3-yl)-N-(5-fluoropyridin-2yl)pyrimidine-2-carboxamide	BCD-BTK-253
^aJzF A^ An ox ' y-NH nh2 y- ΐ Αλ SA-n ci A z° VzN~~f	(R)-4-( 1 -( 1 -acryloylpiperidin-3 -yl)4-amino-7-chloro-lH-pyrazolo[4,3c]pyridin-3 -yl)-N-(4-( 1,1difluorobutyl)pyridin-2yl)benzamide	BCD-BTK-254

Ο ο ϊπΑ νΑν F /Ο \ Ν—ά	(R)-3 -(4-( 1 -( 1 -acryloylpiperidin-3 yl)-7-fluoro-l H-pyrazolo [4,3c]pyridin-3-yl) phenoxy)picolinamide	BCD-BTK-255
jp) fA=n °ανη A nh2 \a N AA, u JL <N VA cn zo \ N A	4- {4-amino-7-cyano-1 -[(3 R)-1 (prop-2-enoyl)piperidin-3 -yl]-1Hpyrazolo[4,3-c]pyridin-3-yl}-N-(3fluoropyridin-2-yl)benzamide	BCD-BTK-258
N=\ V< 0 o nAA U X ,N AA-n f '-n 0	(S)-1 -(2-((7-chloro-3-(4-(pyridin-4yloxy)phenyl)-1 H-pyrazolo [4,3c]pyridin-1 -yl)methyl)pyrrolidin-1 yl)but-2-yn-1 -one	BCD-BTK-259
ΓΧ \=N °N—nh O N AA l! A ,N AA-n ci ''XX F	(S)-4-( 1 -(( 1 -acryloylpyrrolidin-2yl)methyl)-7-chloro-1Hpyrazolo[4,3-c]pyridin-3-yl)-Nphenylbenzamide	BCD-BTK-260
/=z Ω r? /Ao J 6	1-(3-((7-chloro-3 -(4-(pyridin-4yloxy)phenyl)-1 H-pyrazolo [4,3 c]pyridin-1 -yl)methyl)azetidin-1 yl)but-2-yn-1 -one	BCD-BTK-261

X y—NH Ο il Λ ,Ν y^~N α χχ ο	(R)-4-( 1 -( 1 -(but-2-ynoyl)pyrrolidin3-yl)-7-chloro-lH-pyrazolo[4,3c]pyridin-3-yl)-N-(pyridin-2yl)benzamide	BCD-BTK-262
X \=Ν οχ ' y-NH ο Ά π R ,Ν ci /y 0	(S)-4-( 1 -( 1 -(but-2-ynoyl)pyrrolidin3 -yl)-7-chloro-1 H-pyrazolo[4,3 c]pyridin-3-yl)-N-(pyridin-2yl)benzamide	BCD-BTK-271
/ ' N p--\_y O νΆΧκ, U A ,N V% ci ''X? N—' H	(S)-1 -(2-((7-chloro-3-(4-(pyridin-4yloxy)phenyl)-1 H-pyrazolo[4,3 c]pyridin-1 -yl)methyl)pyrrolidin-1 yl)prop-2-en-1 -one	BCD-BTK-263
N oyy O n'Va, ü R ,n \yN ci	1 -(3 -((7-chloro-3 -(4-(pyridin-4yloxy)phenyl)-lH-pyrazolo[4,3c]pyridin-1 -yl)methyl)azetidin-1 yl)prop-2-en-1 -one	BCD-BTK-264
/ N p-yj/ O U A ,N o	(R)-1-(3-(7-chloro-3 -(4-(pyridin-4yloxy)phenyl)-lH-pyrazolo[4,3c]pyridin-1 -yl)pyrrolidin-1 -yl)but-2yn-l-one	BCD-BTK-265

/' N O u 7 ,N Cl /A 0	(S)-l-(3-(7-chloro-3-(4-(pyridin-4yloxy)phenyl)-l H-pyrazolo [4,3c]pyridin-1 -yl)pyrrolidin-1 -yl)but-2yn-l-one	BCD-BTK-270
J N oAj O nV!, l! 1 7 Cl o \^nyy o	(S)-l-(3-(7-chloro-3-(4-(pyridin-4yloxy)phenyl)- lH-pyrazolo[4,3c]pyridin-1 -yl)pyrrolidin-1 -yl)prop2-en-l-one	BCD-BTK-266
/N oAj O νΑά, n A ,N Cl Λί un o	(R)-1 -(3 -(7-chloro-3 -(4-(pyridin-4yloxy)phenyl)-l H-pyrazolo [4,3c]pyridin-1 -yl)pyrrolidin-1 -yl)prop2-en-l-one	BCD-BTK-272
ο, H / v-N ο θ U À ,N \V~N Ci ^'A/nV0 \	4-( 1 -(( 1 -(but-2-ynoyl)azetidin-3 yl)methyl)-7-chloro-1Hpyrazolo[4,3-c]pyridin-3-yl)-N(pyridin-2-yl)benzamide	BCD-BTK-267

fO F y-N HN y=o o N^Y^ u JL -N Y^N Il f\. z0 N YyNY	(R)-4-( 1 -( 1 -acryloylpiperidin-3-yl)7-cyano-1 H-pyrazolo [4,3 -c]pyridin3-yl)-N-(4-(l,ldifluorobutyl)pyridin-2yl)benzamide	BCD-BTK-268
FY N Y Y-NH O nYa, U Y F VF Cl αχ o	(R)-4-( 1 -(( 1 -(but-2-ynoyl)pyrrolidin2-yl)methyl)-7-chloro-lHpyrazolo [4,3 -c]pyridin-3 -yl)-N(pyridin-2-yl)benzamide	BCD-BTK-269
OU y/ °ΥΧλ-0 <Y z=y	(S)-4-(l-(l-acryloylpyrrolidin-3-yl)7-chloro-l H-pyrazolo [4,3-c]pyridin3-yl)-N-(pyridin-2-yl)benzamide	BCD-BTK-273
A y-NH O u JL -N ci A U-N^.0	(R)-4-( 1 -( 1 -acryloylpyrrolidin-3-yl)7-chloro-lH-pyrazolo[4,3-c]pyridin3-yl)-N-(pyridin-2-yl)benzamide	BCD-BTK-275

H2N 2 yo /°^N O U J h F	(R)-5-(4-(l-(l-acryloylpiperidin-3yl)-7-fluoro-lH-pyrazolo[4,3c]pyridin-3yl)phenoxy)nicotinamide	BCD-BTK-274
fX Οχ ' y-NH O nFÂ, ù JL h y^N c	4-(7-chloro-1 - {[ 1 -(prop-2enoyl)azetidin-3-yl]methyl} -1Hpyrazolo[4,3-c]pyridin-3-yl)-N(pyridin-2-yl)benzamide	BCD-BTK-276
rx \=N Οχ ' y-NH N=\ Z N VA i IL h V^n ci /0 \ N~y	(R)-5-(l-(l-acryloylpiperidin-3-yl)- 7-chloro-1 H-pyrazolo [4,3 -c]pyridin- 3-yl)-N-(6-fluoropyridin-2- yl)pyrimidine-2-carboxamide	BCD-BTK-277
A y-NH θ 5 Χν va /--¾¾ I V Z~~N d V2 \	(R)-4-( 1 -(( 1 -(but-2-ynoyl)piperidin3-yl)methyl)-7-chloro-1Hpyrazolo[4,3-c]pyridin-3-yl)-N(pyridin-2-yl)benzamide	BCD-BTK-278
fF 0 / N yNH (v ΐχΑι o ν^Ν /Vsj__ I \, /~~~N Cl ·( \	(5)-4-( 1 -(( 1 -(but-2-ynoyl)piperidin3-yl)methyl)-7-chloro-1/7pyrazolo[4,3-c]pyridin-3-yl)-7V(pyridin-2-yl)benzamide	BCD-BTK-283

44 \=N θΝ-ΝΗ O ÇÔ । W ZN Cl )	(R)-4-( 1 -(( 1 -acryloylpiperidin-3yl)methyl)-7-chloro-1Hpyrazolo[4,3-c]pyridin-3-yl)-N(pyridin-2-yl)benzamide	BCD-BTK-279
P N-nh O On 1 \, ZN Cl '/ \	(0)-4-(1-((1 -acryloylpiperidin-3 yl)methyl)-7-chloro-1Hpyrazolo[4,3-c]pyridin-3-yl)-7V(pyridin-2-yl)benzamide	BCD-BTK-290
ΓΝ N 4 Oy-NH O Nk^\, π N 7 ci N	4-(1-(1 -(but-2-ynoyl)azetidin-3 -yl)7-chloro-1 H-pyrazolo [4,3 -c]pyridin3-yl)-N-(pyridin-2-yl)benzamide	BCD-BTK-280
N o ÀJ 0 n'Va U d ,N Cl b N	1 -(3-(7-chloro-3-(4-(pyridin-4yloxy)phenyl)-lH-pyrazolo[4,3c]pyridin-1 -yl)azetidin-1 -yl)but-2yn-1 -one	BCD-BTK-281
/ N oAh O nNN π 4 τ Y'N Cl b N oO	1 -(3-(7-chloro-3-(4-(pyridin-4yloxy)phenyl)-177-pyrazolo[4,3c]pyridin-1 -yl)azetidin-1 -yl)prop-2en-l-one	BCD-BTK-282

Ο. Η Ο ο Τ^Ν A Cl	(Λ)-4-( 1-((1 -acryloylpyrrolidin-3 yl)methyl)-7-chloro-lApyrazolo[4,3-c]pyridin-3-yl)-7V(pyridin-2-yl)benzamide	BCD-BTK-284
Ο. Η y-N / y-N ό & ο% ο %V if Cl Α..^ν\^	(5)-4-(1-((1 -acryloylpyrrolidin-3 yl)methyl)-7-chloro-\Hpyrazolo[4,3-c]pyridin-3-yl)-7V(pyridin-2-yl)benzamide	BCD-BTK-285
Οχ Η y-N / VN Q θ W 7 ci Λαν>Λ\	(Â)-4-( 1-((1 -(but-2-ynoyl)pyrrolidin3-yl)methyl)-7-chloro-\Hpyrazolo[4,3-c]pyridin-3-yl)-7V(pyridin-2-yl)benzamide	BCD-BTK-286
Οχ H y-N A v OC~ 0 yv Ji Cl	( S)-4 - ( 1 - ( ( 1 -(but-2-ynoyl)pyrrolidin3-yl)methyl)-7-chloro- 1Hpyrazolo[4,3-c]pyridin-3-yl)-7V(pyridin-2-yl)benzamide	BCD-BTK-287
ΓΑ F'Vn Οχ ô y-NH N Αχ / N VA Ola wy-N Cl Λα /0 \ N-V	(À)-5-(l-(l-acryloylpiperidin-3-yl)7-chloro-lH-pyrazolo[4,3-c]pyridin3-yl)JV-(3-fluoropyridin-2-yl) pyrimidine-2-carboxamide	BCD-BTK-288
•A y-NH O ’l^T^N yA^N Cl Ôy	(Â)-4-( 1 -( 1 -(but-2-ynoyl)piperidin3-yl)-7-chloro-l/7-pyrazolo[4,3c]pyridin-3-yl)-7V-(pyridin-2yl)benzamide	BCD-BTK-289

~~0 r^\^z. À.Az ( j z Ί O 7/1 d°	(Â) - 5 - ( 1 - ( 1 -acryloylpiperidin-3 -yl)7-chloro- 177-pyrazolo [4,3 -c]pyridin3-yl)-2V-(4-(trifluoromethyl)pyridin2-yl)pyrimidine-2-carboxamide	BCD-BTK-291
ru M A ζά <z U. cy~P A z P 7 zAV 'ζΆΑ fVo zk	(Λ)-5 -(1-(1 -acryloylpiperidin-3 -yl)7-chloro-177-pyrazolo [4,3 -c]pyridin3-yl)-7V-(4-( 1,1 -difluorobutyl) pyridin-2-yl)pyrimidine-2carboxamide	BCD-BTK-292
Q^J AA.Z Aaz / r y ΑΆ3 71 Z-^ ^Ζ^ξ A/ A χΌ^	(À)-5-(l-(l-acryloylpiperidin-3-yl)7-chloro-l//-pyrazolo[4,3-c]pyridin3 -yl)-7V-(4-( 1,1 -difluoropropyl) pyridin-2-yl)pyrimidine-2carboxamide	BCD-BTK-293
V A nh2 \A l! JL <N \γ~Ν Cl 0 ν/ΝΎ \	(Â)-4-(4-amino-1 -( 1 -(but-2ynoyl)piperidin-3-yl)-7-chloro-l//pyrazolo[4,3-c]pyridin-3-yl)-7V(pyridin-2-yl)benzamide	BCD-BTK-295

In one aspect the présent invention relates to methods for préparation of compound of formula I:

or pharmaceutically accepted sait, solvaté or stereoisomer thereof;

wherein:

Vi is C or N,

V₂ is C(R₂) or N, whereby if Vi is C then V₂ is N, if Vi is C then V₂ is C(R₂), or if Vi is N then V₂ is C(R₂);

n, k independently is 0, 1;

R₂, R„ independently is H, D, Hal, CN, NR’R”, C(O)NR’R”, C_rC₆ alkoxy;

R₃ is H, D, hydroxy, C(O)C_rC₆ alkyl, C(O)C₂-C₆ alkenyl, C(O)C₂-C₆ alkynyl, C_r C₆ alkyl;

R4 is H, Hal, CN, CONR’R”, hydroxy, C_rC₆ alkyl, C_rC₆ alkoxy;

L is CH₂, NH, O or Chemical bond;

Ri is selected from the group of the fragments, comprising:

Fragment 1,

Fragment 3;

Ai, A₂, A₃, A₄ is independently CH, N, CHal;

A₅, A_6; A₇, A₈, A₉ is independently C, CH or N;

R₅ is H, CN, Hal, CONR’R”, Ci-C₆ alkyl, non-substituted or substituted by one or 5 more halogens;

R’ and R” is independently selected from the group, comprising H, Cj-C₆ alkyl, Ci-C₆ cycloalkyl, aryl;

R₆ is selected from the group:

R₇, R₈, R₉, Rio is independently vinyl, methylacetylenyl;

Hal is Cl, Br, I, F;

that includes:

1) interaction of compound of formula A

wherein V], V₂, L, R₃, R4, R] _b n, k hâve the same meanings as defined above, via the Suzuki-Miyaura reaction in an appropriate solvent, with compound of formula XI, X2, X3

Har^Rl

X1, X2, X3 wherein Ri has the meanings as defined above, in the presence of palladium salts, phosphorus-containing ligands, and inorganic or organic bases, which forms compound of formula B

wherein Vi, V₂, L, R], R₃, R4, Ru, n, k hâve the meanings as defined above, and

2) interaction of the resulting compound of formula B with inorganic or organic acid in an appropriate solvent, which forms a sait of compound of formula C

wherein Vi, V₂, L, R_b R₃, R₄, Ru, n, k hâve the meanings as defined above, and

3) interaction of the resulting sait of compound of formula C with an acylating agent in an appropriate solvent in the presence of organic base, which forms compound of formula I.

In yet another aspect the présent invention relates to methods for préparation of compound of formula III:

or pharmaceutically accepted sait, solvaté or stereoisomer thereof;

wherein:

Vj isCorN,

V₂ is C(R₂) or N, whereby if Vi is C then V₂ is N, if Vi is C then V₂ is C(R₂), or ifVi isNthen V₂ is C(R₂);

n, k independently is 0, 1 ;

R₂ is Hal, CN, NR’R”, C(O)NR’R”, C_rC₆ alkoxy;

Ru is H, Hal, CN, NR’R”, C(O)NR’R”, C_rC₆ alkoxy;

L is CH₂, NH, O or Chemical bond;

R₃ is H, hydroxy, C(O)C_rC₆ alkyl, C(O)C₂-C₆ alkenyl, C(O)C₂-C₆ alkynyl, C_rC₆ alkyl;

R4 is H, Hal, CN, CONR’R”, hydroxy, C_rC₆ alkyl, C_rC₆ alkoxy;

and if Vi is C, V₂ is N, then at least one of R₃, R4, Ri 1 is not H;

Ri is selected from the group of the fragments, comprising:

Ai, A₂, A₃, A₄ is independently CH, N, CHal;

A₅, A_6j A₇, A₈, A₉ is independently C, CH or N;

R₅ is H, CN, Hal, CONR’R”, Ci-C₆ alkyl, non-substituted or substituted by one or more halogens;

R’ and R” is independently selected from the group, comprising H, Ci-C₆ alkyl, 5 Ci-C₆ cycloalkyl, aryl;

R₆ is selected from the group:

R₇, R₈, R₉, Rio is independently vinyl, methylacetylenyl; Hal is Cl, Br, I, F.

that includes:

1) interaction of compound of formula D

wherein Vj, V₂, L, R₃, R4, Rn, n, k hâve the same meanings as defined above, via the Suzuki-Miyaura reaction in an appropriate solvent, with compound of formula XI, X2, X3

HaK^Rl

X1,X2, X3 wherein R, has the meanings as defined above, in the presence of palladium salts, phosphorus-containing ligands, and inorganic or organic bases, which forms compound of formula E

wherein V_b V₂, L, R_b R₃, R4, Ru, n, k hâve the meanings as defined above, and

2) interaction of the resulting compound of formula E with inorganic or organic acid in an appropriate solvent, which forms a sait of compound of formula F

wherein V_b V₂, L, R_b R₃, R4, Ru, n, k hâve the meanings as defined above, and

3) interaction of the resulting sait of compound of formula F with an acylating agent in an appropriate solvent in the presence of organic base, which forms compound of formula III.

The présent invention also relates to a method for inhibiting of biological activity of Bruton’s tyrosine kinase (Btk) in a subject, comprising contacting the Bruton’s tyrosine kinase with the compound described herein.

Irréversible Btk inhibitor compounds can be used for the manufacture of a 15 médicament for treating any of the foregoing conditions (e.g., autoimmune and inflammatory diseases, allergie disorders, immune disorders, tumors of blood and lymphatic System, cancer).

Generally, an irréversible Btk inhibitor compound used in the methods described herein is identified or characterized in an in vitro assay, e.g., an acellular biochemical assay or a cellular functional assay. Such assays are useful to détermine an in vitro IC₅₀ for an irréversible Btk inhibitor compound.

In some embodiments, the irréversible Btk inhibitor compound used for the methods described herein inhibits Btk or a Btk homolog kinase activity with an in vitro IC₅₀ of less than 10 μΜ (e.g., less than 1, less than 0.5, less than 0.4, less than 0.3, less than 0.1, less than 0.08, less than 0.06, less than 0.05, less than 0.04, less than 0.03, less than 0.02, less than 0.01, less than 0.008, less than 0.006, less than 0.005, less than 0.004, less than 0.003, less than 0.002, less than 0.001, less than 0.00099, less than 0.00098, less than 0.00097, less than 0.00096, less than 0.00095, less than 0.00094, less than 0.00093, less than 0.00092, or less than 0.00090 μΜ).

In one embodiment, the présent invention relates to a pharmaceutical composition that comprises a therapeutically effective amount of at least one of the compounds described herein, or pharmaceutically acceptable sait, solvaté thereof, and one or more pharmaceutically acceptable excipients. In another one embodiment, the pharmaceutical composition of the présent invention is intended to treat or prevent a disease or disorder mediated by Bruton’s tyrosine kinase (Btk).

In another one embodiment, the présent invention relates to a pharmaceutical composition for the prévention or treatment of a disease or disorder mediated by Bruton’s tyrosine kinase (Btk), that comprises a therapeutically effective amount of the compound described herein, or pharmaceutically acceptable sait thereof, and one or more pharmaceutically acceptable excipients.

In another one embodiment, the pharmaceutical composition of the présent invention is intended to treat or prevent tumors of blood and lymphatic System, immune disorders, cancer, autoimmune and inflammatory diseases, or allergie disorders. In some embodiments, pharmaceutical composition of the présent invention is intended to treat or prevent chronic lymphocytic leukemia, mantle cell lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, Waldenstrom macroglobulinemia, B-cell prolymphocytic leukemia, central nervous System lymphoma, multiple myeloma, pancreatic cancer, graft-versus-host disease, chronic graft-versus-host disease, rheumatoid arthritis, systemic lupus erythematosus, asthma, atopie dermatitis.

The pharmaceutical composition of the présent invention comprises, by way of example, from about 10% to about 100% of active ingrédients, preferably from about 20% to about 60% of active ingrédients. It is to be understood that each dosage unit may not comprise an effective amount of an active ingrédient or ingrédients, because the sufficient effective amount can be achieved by multiple dosing.

A typical composition is prepared by mixing the compound described herein with a carrier, diluent or excipient. Suitable carriers, diluents and excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water soluble and/or swellable polymers, hydrophilic or hydrophobie materials, gelatin, oils, solvents, water, and the like. The particular carrier, diluent or excipient used will dépend upon the means and purpose for which compound of the présent invention is being applied. Solvents are generally selected based on solvents recognized by persons skilled in the art as safe to be administered to a mammal. In general, safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, éthanol, propylene glycol, polyethylene glycols (e.g., PEG400, PEG300), etc. and mixtures thereof. The compositions may also include one or more buffers, stabilizing agents, surfactants, wefting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an élégant présentation of the drug (i.e., compound of the invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., médicament).

The pharmaceutical compositions also include solvatés and hydrates of compounds of the présent invention, or stabilized form of the compound (e.g., complex with a cyclodextrin dérivative or other known complexation agent).

The pharmaceutical compositions of the invention may be formulated for an oral route administration. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, and/or buccal, lingual, or sublingual administration by which the compound enters the blood stream directly from the mouth.

Formulations suitable for oral administration include solid, semi-solid and liquid Systems such as tablets; soft or hard capsules containing multi- or nanoparticulates, liquids, or powders; lozenges (including liquid-filled); chews; gels; fast dispersing dosage forms; films; ovules; sprays; and buccal/mucoadhesive patches. Formulations for oral administration preferably comprise tablets and capsules.

Liquid formulations include suspensions, solutions, syrups and élixirs. Such formulations may be employed as fillers in soft or hard capsules (made, for example, from gelatin or hydroxypropylmethylcellulose) and typically comprise a carrier, for example, water, éthanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.

The pharmaceutical compositions of the invention could be use for parentéral administration. As used herein, “parentéral administration” of a pharmaceutical composition includes any route of administration characterized by physical breaching of a tissue of a subject and administration of the pharmaceutical composition through the breach in the tissue, thus generally resulting in the direct administration into the blood stream, into muscle, or into an internai organ. Parentéral administration thus includes, but is not limited to, administration of a pharmaceutical composition by injection of the composition, by application of the composition through a surgical incision, by application of the composition through a tissue-penetrating non-surgical wound, and the like. In particular, parentéral administration is contemplated to include, but is not limited to, subeutaneous, intraperitoneal, intramuscular, intrastemal, intravenous, intraarterial, intrathecal, intraventricular, intraurethral, intracranial, intrasynovial injection or infusions; and kidney dialytic infusion techniques. Intratumoral delivery, e.g. intratumoral injection, may also be advantageous. Régional perfusion is also contemplated.

Formulations of a pharmaceutical composition suitable for parentéral administration typically comprise the active ingrédient combined with a pharmaceutically acceptable carrier, such as stérile water or stérile isotonie saline. Such formulations may be prepared, packaged, or sold in a form suitable for bolus administration or for continuous administration. Injectable formulations may be prepared, packaged, or sold in unit dosage form, such as in ampoules or in multi-dose containers containing a preservative. Formulations for parentéral administration include, but are not limited to, suspensions, solutions, émulsions in oily or aqueous vehicles, pastes, and the like.

The compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, or as a mixed component particle, for example, mixed with a suitable pharmaceutically acceptable excipient) from a dry powder inhaler, as an aérosol spray from a pressurised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, or as nasal drops.

The pressurised container, pump, spray, atomizer, or nebuliser generally contains a solution or suspension of a compound of the invention comprising, for example, a suitable agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent.

Prior to use in a dry powder or suspension formulation, the drug product is generally micronised to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogénisation, or spray drying.

Capsules, blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base and a performance modifier.

A suitable solution formulation for use in an atomiser using electrohydrodynamics to produce a fine mist may contain a suitable dose of the compound of the invention per actuation and the actuation volume may for example vary from 1 pL to 100 pL.

Suitable flavours, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled/intranasal administration.

In the case of dry powder inhalers and aérosols, the dosage unit is determined by means of a valve which delivers a metered amount. Units in accordance with the invention are typically arranged to administer a metered dose or “puff ’ of a compound of the invention. The overall daily dose will typically be administered in a single dose or, more usually, as divided doses throughout the day.

Formulations may be formulated to be immédiate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

In one embodiment, the présent invention relates to the method for treating diseases or disorders mediated by Bruton’s tyrosine kinase (Btk) that comprises the step of administering a therapeutically effective amount of any compound described above, or a pharmaceutical composition of the présent invention to a subject in need of such treatment.

In another one embodiment, the présent invention relates to the method for treating a disease or disorder mediated by Bruton’s tyrosine kinase (Btk), which is either a tumor of blood and lymphatic System, immune disorders, cancer, autoimmune and inflammatory disease, or allergie disorder, that comprises the step of administering a therapeutically effective amount of any compound described herein, or a pharmaceutical composition of the présent invention to a subject in need of such treatment.

In another one embodiment, the présent invention relates to the described above method for treating a subject with chronic lymphocytic leukemia, mantle cell lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, Waldenstrom macroglobulinemia, B cell prolymphocytic leukemia, central nervous System lymphoma, multiple myeloma, pancreatic cancer, graft-versus-host disease, chronic graft-versus-host disease, rheumatoid arthritis, systemic lupus erythematosus, asthma, atopie dermatitis.

The compounds of the invention may be administered alone or in combination with one or more other drugs or biopharmaceuticals (or as any combination thereof). The pharmaceutical compositions, methods and uses of the invention thus also encompass embodiments of combinations (co-administration) with other active agents.

As used herein, the tenus “co-administration”, “co-administered” and “in combination with” referring to the compounds with one or more other therapeutic agents, is intended to mean, and does refer to and include the foliowing:

• simultaneous administration of such combination of compound of the invention and therapeutic agent(s) to a patient in need of treatment, when such components are formulated together into a single dosage form which releases said components at substantially the same time to said patient, • substantially simultaneous administration of such combination of compound of the invention and therapeutic agent(s) to a patient in need of treatment, when such components are formulated apart from each other into separate dosage forms which are taken at substantially the same time by said patient, whereupon said components are released at substantially the same time to said patient, • sequential administration of such combination of compound of the invention and therapeutic agent(s) to a patient in need of treatment, when such components are formulated apart from each other into separate dosage forms which are taken at consecutive times by said patient with a significant time interval between each administration, whereupon said components are released at substantially different times to said patient; and • sequential administration of such combination of compound of the invention and therapeutic agent(s) to a patient in need of treatment, when such components are formulated together into a single dosage form which releases said components in a controlled manner whereupon they are concurrently, consecutively, and/or overlappingly released at the same and/or different times to said patient, where each part may be administered by either the same or a different route.

As well known to those skilled in the art, therapeutically effective dosages may vary when the drugs are used in combination treatment. Methods for experimentally determining therapeutically effective dosages of drugs and other agents for use in combination treatment regimens are described in the literature. For example, the use of metronomic dosing, i.e., providing more frequent, lower doses in order to minimize toxic side effects, has been described in the literature. Combination treatment further includes periodic treatments that start and stop at various times to assist with the clinical management of the patient. For combination thérapies described herein, dosages of the co-administered compounds will of course vary depending on the type of co-drug employed, on the spécifie drug employed, on the condition or disorder being treated and so forth.

In addition, compounds described herein may also be used in combination with procedures that may provide additional or synergistic benefit to the subject. By way of example only, subjects are expected to find therapeutic and/or prophylactic benefit in the methods described herein, wherein pharmaceutical composition of the présent invention and /or combinations with other therapeutics are combined with genetic testing to détermine whether that individual is a carrier of a mutant gene that is known to be correlated with certain diseases or conditions.

Where the subject is suffering from or at risk of suffering from an autoimmune disease, an inflammatory disease, or an allergy disorder, an irréversible Btk inhibitor compound of the présent invention can be used in with one or more of the following therapeutic agents in any combination: immunosuppressants (e.g., tacrolimus, rapamycin (sirolimus), everolimus, cyclosporin, methotrexate, cyclophosphamide, azathioprine, mercaptopurine, mycophenolate, or FTY720), glucocorticoids (e.g., prednisone, cortisone acetate, prednisolone, méthylprednisolone, dexamethasone, betamethasone, triamcinolone, beclometasone, fludrocortisone acetate, deoxycorticosterone acetate, aldostérone), non-steroidal anti-inflammatory drugs (e.g., salicylates, arylalkanoic acids, 2arylpropionic acids, N-arylanthranilic acids, oxicams, coxibs, or sulphonanilides), Cox-2-specific inhibitors (e.g., valdecoxib, celecoxib, or rofecoxib), leflunomide, gold thioglucose, gold thiomalate, aurofm, sulfasalazine, hydroxychloroquinine, minocycline, TNF-α binding proteins (e.g., infliximab, etanercept, or adalimumab), abatacept, anakinra, interferon-β, interferon-γ, interleukin-2, allergy vaccines, antihistamines, antileukotrienes, beta-agonists, theophylline, or anticholinergics.

Where the subject is suffering from or at risk of suffering from a tumor of blood and lymphatic system (e.g., chronic lymphocytic leukemia), the subject can be treated with an irréversible Btk inhibitor compound in any combination with one or more other anti-cancer agents. In some embodiments, one or more of the anti-cancer agents are proapoptotic agents. Examples of anti-cancer agents include, but are not limited to, any of the following: gossypol, genasense, polyphenol E, Chlorofusin, ail trans-retinoic acid (ATRA), bryostatin, tumor necrosis factorrelated apoptosis-inducing ligand (TRAIL), 5-aza-2’-deoxycytidine, doxorubicin, vincristine, etoposide, gemcitabine, imatinib, geldanamycin, 17-N-Allylamino-17Demethoxygeldanamycin (17-AAG), flavopiridol, LY294002, bortezomib, trastuzumab, BAY 11-7082, PKC412, or PDI 84352, paclitaxel, docetaxel, compounds that hâve the basic taxane skeleton as a common structure feature.

Further examples of anti-cancer agents for use in combination with an irréversible Btk inhibitor compound include inhibitors of mitogen-activated protein kinase signaling, e.g., UO 126, PD98059, PD 184352, PD0325901, ARRY142886, SB239063, SP600125, BAY 43-9006, wortmannin, or LY294002; Syk inhibitors; mTOR inhibitors; and antibodies (e.g., rituximab).

Other anti-cancer agents that can be employed in combination with an irréversible Btk inhibitor compound include Adriamycin, Dactinomycin, Bleomycin, Vinblastine, Cisplatin, acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutéthimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafïde dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin; cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflomithine hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine; fludarabine phosphate; fluorouracil; flurocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; iimofosine; interleukin II (including recombinant interleukin II, or rIL2), interferon alfa-2a; interferon alfa-2b; interferon alfa-nl; interferon alfa-n3; interferon beta-la; interferon gamma-1 b; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamme hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safmgol; safmgol hydrochloride; semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfui; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin hydrochloride.

Other anti-cancer agents that can be employed in combination with an irréversible Btk inhibitor compound include: 20-epi-l, 25 dihydroxyvitamin D3; 5ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amnibicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III dérivatives; balanol;

batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactam dérivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane; butbionine sulfoximine; calcipotriol; calphostin C; camptothecin dérivatives; canarypox IL-2; capecitabine; carboxamide-aminotriazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorhis; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A dérivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethymorspermine; dihydro-5-azacytidine; 9-dioxamycin; diphenyl spiromustine; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflomithine; elemene; emitefur; epirubicin; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; fmasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gélatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod; immunostimulant peptides; insulin-like growth factor-1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane;

iododoxorubicin; iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia 69 inhibiting factor; leukocyte alpha interferon; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilie disaccharide peptide; lipophilie platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone; mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonal antibody, human chorionic gonadotrophin; monophosphoryl lipid A+myobacterium cell wall sk; mopidamol; multiple drug résistance gene inhibitor; multiple tumor suppressor 1 -based therapy; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; palauamine; palinitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-triamine complex; porfimer sodium; porfiiomycin; prednisone; propyl bis-acridone; prostaglandin J2; protéasome inhibitors; protein A-based immune modulator; protein kinase C inhibitor; protein kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins;

pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylerie conjugale; raf antagonists; raltitrexed; ramosetron; ras famesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhénium Re 186 étidronate; rhizoxin; ribozymes; RII retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone Bl; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence derived inhibitor 1; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen-binding protein; sizofiran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-cell division inhibitors; stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; synthetic glycosaminoglycans; tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfm; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogénital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector System, érythrocyte gene therapy; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer; inhibitors of Bcl-2 protein family; phosphatidylinositol-3-kinase inhibitors; clarithromycin; erythromycin; azithromycin.

Yet other anticancer agents that can be employed in combination with an irréversible Btk inhibitor compound include alkylating agents, antimetabolites, natural products, or hormones, (e.g., nitrogen mustards, mechloroethamine, cyclophosphamide, chlorambucil, etc.), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne, etc.), or triazenes (dacarbazine, etc.).

Examples of antimetabolites include, but are not limited to, folie acid analog (e.g., methotrexate), or pyrimidine analogs (e.g., Cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin, fludarabine).

Ex amples of natural products useful in combination with an irréversible Btk inhibitor compound include, but are not limited to, vinca alkaloids (e.g., vinblastin, vincristine), epipodophyllotoxins (e.g., etoposide), antibiotics (e.g., daunorubicin, doxorubicin, bleomycin, clarithromycin), enzymes (e.g., L-asparaginase), or biological response modifiers (e.g., interferon alpha).

Examples of hormones and antagonists useful in combination with an irréversible Btk inhibitor compound include, but are not limited to, adrenocorticosteroids (e.g., prednisone, prednisolone), progestins (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethlystilbestrol, ethinyl estradiol), antiestrogen (e.g., tamoxifen), androgens (e.g., testosterone propionate, fluoxymesterone), antiandrogen (e.g., flutamide), gonadotropin releasing hormone analog (e.g., leuprolide), aromatase inhibitor (e.g., anastrozole). Other agents that can be used in the methods and compositions described herein for the treatment or prévention of cancer include platinum coordination complexes (e.g., cisplatin, carboplatin), anthracenedione (e.g., mitoxantrone), substituted urea (e.g., hydroxyurea), methyl hydrazine dérivative (e.g., procarbazine), adrenocortical suppressant (e.g., mitotane, aminoglutéthimide), growth hormone antagonist (e.g., octreotide).

Examples of anti-cancer agents which act by arresting cells in the G2-M phases due to stabilized microtubules and which can be used in combination with an irréversible Btk inhibitor compound include without limitation the following marketed drugs and drugs in development: Erbulozole (also known as R-55104), Dolastatin 10 (also known as DLS-10 and NSC-376128), Mivobulin isethionate (also known as CI-980), Vincristine, NSC-639829, Discodermolide (also known as NVP-XX-A-296), ABT-751 (Abbott, also known as E-7010), Altorhyrtins (such as

Altorhyrtin A and Altorhyrtin C), Spongistatins (such as Spongistatin 1, Spongistatin 2, Spongistatin 3, Spongistatin 4, Spongistatin 5, Spongistatin 6, Spongistatin 7, Spongistatin 8, and Spongistatin 9), Cemadotin hydrochloride (also known as LU-103793 and NSC-D-669356), Epothilones (such as Epothilone A, Epothilone B, Epothilone C (also known as desoxyepothilone A or dEpoA), Epothilone D (also referred to as KOS-862, dEpoB, and desoxyepothilone B ), Epothilone E, Epothilone F, Epothilone B N-oxide, Epothilone A N-oxide, 16-azaepothilone B, 21-aminoepothilone B (also known as BMS-310705), 21hydroxyepothilone D (also known as Desoxyepothilone F and dEpoF), 26fluoroepothilone), Auristatin PE (also known as NSC-654663), Soblidotin (also known as TZT-1027), LS-4559-P (Pharmacia, also known as LS-4577), LS-4578 (Pharmacia, also known as LS-477-P), LS-4477 (Pharmacia), LS-4559 (Pharmacia), RPR-112378 (Aventis), Vincristine sulfate, DZ-3358 (Daiichi), FR182877 (Fujisawa, also known as WS-9885B), GS-164 (Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academy of Sciences), BSF-223651 (BASF, also known as ILX-651 and LU-223651), SAH-49960 (Lilly/Novartis), SDZ-268970 (Lilly/Novartis), AM-97 (Armad/Kyowa Hakko), AM-132 (Armad), AM-138 (Armad/Kyowa Hakko), IDN-5005 (Indena), Cryptophycin 52 (also known as LY355703), AC-7739 (Ajinomoto, also known as AVE-8063A and CS-39.HCI), AC7700 (Ajinomoto, also known as AVE-8062, AVE-8062A, CS-39-L-Ser.HCl, and RPR-258062A), Vitilevuamide, Tubulysin A, Canadensol, Centaureidin (also known as NSC-106969), T-138067 (Tularik, also known as T-67, TL-138067 and TI-13 8067), COBRA-I (Parker Hughes Institute, also known as DDE-261 and WHI-261), H1O (Kansas State University), H16 (Kansas State University), Oncocidin Al (also known as BTO-956 and DIME), DDE-313 (Parker Hughes Institute), Fijianolide B, Laulimalide, SPA-2 (Parker Hughes Institute), SPA-I (Parker Hughes Institute, also known as SPIKET-P), 3-IAABU (Cytoskeleton/Mt. Sinai School of Medicine, also known as MF-569), Narcosine (also known as NSC-5366), Nascapine, D-24851 (Asta Medica), A-105972 (Abbott), Hemiasterlin, 3-BAABU (Cytoskeleton/Mt. Sinai School of Medicine, also known as MF-191), TMPN (Arizona State University), Vanadocene acetylacetonate, T138026 (Tularik), Monsatrol, hianocine (also known as NSC-698666), 3-1AABE (Cytoskeleton/Mt. Sinai School of Medicine), A-204197 (Abbott), T-607 (Tularik, also known as T-900607), RPR-115781 (Aventis), Eleutherobins (such as Desmethyleleutherobin, Desaetyleleutherobin, Isoeleutherobin A, and ZEleutherobin), Caribaeoside, Caribaeolin, Halichondrin B, D-64131 (Asta Medica), D-68144 (Asta Medica), Diazonamide A, A-293620 (Abbott), NPI-2350 (Nereus), Taccalonolide A, TUB-245 (Aventis), A-259754 (Abbott), Diozostatin, (-)Phenylahistin (also known as NSCL-96F037), D-68838 (Asta Medica), D-68836 (Asta Medica), Myoseverin B, D-43411 (Zentaris, also known as D-81862), A289099 (Abbott), A-318315 (Abbott), HTI-286 (also known as SPA-110, trifluoroacetate sait) (Wyeth), D-82317 (Zentaris), D-82318 (Zentaris), SC-12983 (NCI), Resverastatin phosphate sodium, BPR-OY-007 (National Health Research Institutes), and SSR-250411 (Sanofi).

Where the subject is suffering from or at risk of suffering from a thromboembolie disorder (e.g., stroke), the subject can be treated with an irréversible Btk inhibitor compound in any combination with one or more other anti-thromboembolie agents. Examples of anti-thromboembolic agents include, but are not limited to, any of the following: thrombolytic agents (e.g., alteplase anistreplase, streptokinase, urokinase, or tissue plasminogen activator), heparin, tinzaparin, warfarin, dabigatran (e.g., dabigatran etexilate), factor Xa inhibitors (e.g., fondaparinux, draparinux, rivaroxaban, DX-9065a, otamixaban, LY517717, or YMI 50), ticlopidine, clopidogrel, CS-747 (prasugrel, LY640315), ximelagatran, or BIBR 1048.

It is understood that the compounds of the invention may be used in methods for treating, as described above, in treatment, as described above, and/or in the manufacture of a médicament for the therapeutic applications described above.

In one embodiment, the présent invention relates to use of the compound described herein or a pharmaceutical composition of the présent invention in the treatment of diseases or disorders mediated by Bruton’s tyrosine kinase (Btk) in a subject in need thereof.

In another one embodiment, the présent invention relates to the use of the compound described herein or a pharmaceutical composition of the invention in the treatment of a disease or disorder mediated by Bruton’s tyrosine kinase (Btk), which is either a tumor of blood and lymphatic System, immune disorders, cancer, autoimmune and inflammatory disease, or allergie disorder, that comprises the step of administering a therapeutically effective amount of any compound described herein, or a pharmaceutical composition of the présent invention to a subject in need thereof.

In another one embodiment, the présent invention relates to the use of the compound described herein or a pharmaceutical composition of the présent invention in the treatment of a subject with chronic lymphocytic leukemia, mantle cell lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, Waldenstrom macroglobulinemia, B cell prolymphocytic leukemia, central nervous System lymphoma, multiple myeloma, pancreatic cancer, graft-versus-host disease, chronic graft-versus-host disease, rheumatoid arthritis, systemic lupus erythematosus, asthma, atopie dermatitis. In ail of these embodiments, the subject may be human.

The compounds of the invention will be administered in an effective amount for treatment of the condition in question, i.e., at dosages and for periods of time necessary to achieve a desired resuit. A therapeutically effective amount may vary according to factors such as the particular condition being treated, the âge, sex and weight of the patient, and whether the compounds are being administered as a stand-alone treatment or in combination with one or more additional treatments.

Dosage regimens may be adjusted to provide the optimum desired response. For example, a single dose may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is especially 75 advantageous to formulate oral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form, as used herein, refers to physically discrète units suited as unitary dosages for the patients/subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The spécification for the dosage unit forms of the invention are generally dictated by and directly dépendent on (a) the unique characteristics of the agent and the particular therapeutic or prophylactic effect to be achieved, and (b) the limitations inhérent in the art of compounding such an active compound for the treatment of sensitivity in individuals.

Thus, the person skilled in the art would appreciate, based upon the disclosure provided herein, that the dose and dosing regimen is adjusted in accordance with methods well-known in the therapeutic arts. That is, the maximum tolerable dose can be readily established, and the effective amount providing a détectable therapeutic benefit to a patient may also be determined, as can the temporal requirements for administering each agent to provide a détectable therapeutic benefit to the patient. Accordingly, while certain dose and administration regimens are exemplified herein, these examples in no way limit the dose and administration regimen that may be provided to a patient in practicing the présent invention.

It is to be noted that dosage values may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. It is to be further understood that for any particular subject, spécifie dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the embodied composition. Further, the dosage regimen with the compositions of this invention may be based on a variety of factors, including the type of disease, the âge, weight, sex, medical condition of the patient, the severity of the condition, the route of administration, and the particular 76 compound employed. Thus, the dosage regimen can vary widely, but can be determined routinely using standard methods. For example, doses may be adjusted based on pharmacokinetic or pharmacodynamie parameters, which may include clinical effects such as toxic effects and/or laboratory values. Thus, the présent invention encompasses intra-patient dose-escalation as determined by the person skilled in the art. Determining appropriate dosages and regimens are well-known in the relevant art and would be understood to be encompassed by the person skilled in the art once provided the teachings disclosed herein.

Generally, standard daily dosage for an adult human is in the range from 0.02 mg to 5000 mg or from about 1 mg to about 1500 mg.

Once improvement of the patient’s conditions has occurred, a maintenance dose is administered, if necessary. Subsequently, the dosage or the frequency of administration, or both, can be reduced, as a fonction of the symptoms, to a level at which the improved disease or disorder is retained. Patients may be required periodic treatment on a long-term basis upon any relapse of symptoms.

The foregoing ranges are merely suggestive, as the number of variables in regard to an individual treatment régime is large, and considérable excursions from these recommended values are not uncommon. Such dosages may be altered depending on a number of variables, not limited to the activity of the compound used, the disorder or condition to be treated, the method of administration, the requirements of the individual subject, the severity of the disorder or condition being treated, and the judgment of the physician.

An effective amount for tumor therapy may be measured by its ability to slow down disease progression and/or ameliorate symptoms in a patient, and preferably to reverse disease progression. The ability of a compound of the présent invention to inhibit the foregoing diseases may be evaluated by in vitro assays, e.g. as described in the examples, as well as in suitable animal models that are prédictive of the efficacy in such disorders. Suitable dosage regimens will be selected in order to provide an optimum therapeutic response in each particular situation, for example, administered as a single tablet or capsule with possible adjustment of the dosage as indicated by the exigencies of each case.

In order that this invention may be better understood, the following examples are set forth. These examples are for purposes of illustration only and are not to be construed as limiting the scope of the invention in any manner.

Ail publications, patents, and patent applications cited in this spécification are incorporated herein by reference. Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended embodiments.

Examples

Abbreviations in this description, including those shown in illustrative schemes and the examples described below are well-know for an average person skilled in the art. Some of the abbreviations are as follows: XPhos - 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl DMF - dimethylformamide

HATU - l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium-3oxide hexafluorophosphate

DIPEA - diisopropylethylamine

BOC-anhydride - di-tert-butyldicarbonate

THF - tetrahydrofuran

DMSO - dimethylsulfoxide

Pd₂(dba)₃ - tris (dibenzylideneacetone) dipalladium (0)

Pd(dppf)Cl₂ - [l,r-bis(diphenylphosphino)ferrocene] dichloropalladium (II) TBDMSCl - tert-butyldimethylsilyl chloride

Pd(PPh₃)₄ - tetrakis (triphenylphosphine) palladium (0) ίο Example 1. General method for synthesis of compound of formula I.

wherein V_b V₂, L, R_b R₃, R4, R_lb n, k hâve the above meanings.

General method for synthesis of compound of formula III.

wherein V_b V₂, L, R_b R₃, R4, R_b, n, k hâve the above meanings.

Step 1: synthesis of compounds B (E). In a three-neck flask, equipped with a stirrer and thermometer, mix under nitrogen in the specified order: 20 mL of 1,4dioxane; (0.002 mol) of necessary compound XI, X2 or X3; 0.759 g (0.003 mol) of bis(pinacolato)diboron; 0.190 g (0.0004 mol) of XPhos; 0.588 g (0.006 mol) of dry potassium acetate; 0.067 g (0.0002 mol) of palladium(II) acetate. While stirring, pass an inert gas (argon or nitrogen) through the mixture for 15 minutes. Stir the resulting reaction mass under the inert gas at 80-90 °C for 3-5 hours; use the TLC method to ensure the completeness of the reaction. When the reaction is complété, cool the reaction mixture to 40 °C. Add a solution of 1.7 g (0.016 mol) of sodium carbonate in 10 mL of water, 0.231g (0.0002 mol) of tetrakis(triphenylphosphine)palladium, and 0.002 mol of a corresponding compound A(D). Stir the resulting mixture at 80-90 °C for 3-5 hours; use the TLC method to ensure the completeness of the reaction. When the reaction is complété, allow the mass to cool and filter it through celite; wash the celite with 10 mL of ethyl acetate and 10 mL of water; concentrate the filtrate under vacuum using a rotary evaporator. To the resulting residue add 30 mL of water and extract with 30 mL of ethyl acetate five times. Wash the organic layer with water and NaCl solution, dry with sodium sulfate, distill off the solvent. Purify the resulting product by column chromatography, eluent: from ethyl acetate to ethyl acetate : methanol (from 99:1 to 9:1) The resulting product is compound B(E) with 30% to 70% yield.

Step 2: synthesis of compounds C(F). In a three-neck flask, equipped with a stirrer and thermometer, mix under nitrogen in the specified order: 10 mL of 1,4dioxane, 0.002 mol of necessary compound B(E), and 4 mL of 4M hydrogen chloride in 1,4-dioxane. Allow the mixture to stand at room température. After 16 hours, distill off the solvent. The resulting residue is a hydrochloride of a corresponding compound C(F), which is taken to the next step without additional purification.

Step 3: synthesis of compounds of formula I and formula III.

Depending on the structure and physicochemical characteristics of the resulting compounds, the synthesis can be performed as follows:

Variation 1. In a three-neck flask, equipped with a stirrer and thermometer, mix under an inert gas in the specified order: 20 mL of dry dichloromethane (or dimethylformamide (DMF)), 0.0005 mol of compound C(F) hydrochloride, and (0.0015 mol) of diisopropylethylamine. Cool the mixture to -30 °C and add at this température 0.00051 mol of acryloyl chloride. Allow the reaction mass to stand at room température. After 1 hour, concentrate the solvent under vacuum using a rotary evaporator; add 50 mL of ethyl acetate and 50 mL of water. Separate the ethyl acetate from the aqueous layer; wash the aqueous layer once again with ethyl acetate, and combine the ethyl acetate extracts. After that, wash it with 10% citric acid and NaCl solution. Dry the ethyl acetate with sodium sulfate and distill off the solvent. Purify the resulting product by column chromatography, eluent hexane : ethyl acetate (from 3:7 to 0:100). The resulting product is compound of formulai with 5% to 50% yield. Final purification is performed using Akta Explorer 100 with the Inertsil ODS-3 column, R - 10 pm, L*d - 250*30 mm. The compound III is synthetized in a similar manner.

Variation 2. In a three-neck flask, equipped with a stirrer and thermometer, mix under an inert gas in the specified order: 20 mL of dry dichloromethane (or DMF), 0.0005 mol of compound C(F) hydrochloride respectively, and (0.004 mol) of diisopropylethylamine. Cool the mixture to -20 °C and add at this température 0.00205 mol of acryloyl chloride. Allow the reaction mass to stand at room température. After 1 hour, remove the solvent under vacuum; add 50 mL of ethyl acetate and 50 mL of water. Separate ethyl acetate from the aqueous layer; wash the aqueous layer once again with ethyl acetate, and combine the ethyl acetate extracts. After that, wash it with 10% citric acid and NaCl solution. Dry the ethyl acetate with sodium sulfate and distill off the solvent. Purify the resulting product by column chromatography, eluent hexane : ethyl acetate (from 3:7 to 0:90). The resulting product is compound of formula I with 5% to 60% yield. The compound III is synthetized in a similar manner with 5% to 60% yield.

Variation 3. Add HATU 0.55 mmol, and DIPEA 0.73 mmol to a suspension of tetrolic acid 0.38 mmol in dry methylene chloride (20 ml). Cool the reaction mass to 0°C and add a suspension of 0.38 mmol of the hydrochloride of compound C (F) in dry methylene chloride, if the solubility allows, so that the température of the mixture does not exceed 5°C. After the addition, leave the reaction mixture at room température for 1 hour, then remove the solvent under vacuum and add 50 ml of ethyl acetate and 50 ml of water. Separate ethyl acetate from the aqueous layer, wash the aqueous layer again with ethyl acetate, and combine ethyl acetate, then wash with 10% citric acid solution and NaCl solution. Dry the ethyl acetate over sodium sulfate and distill off the solvent. Isolate the final product by column chromatography, eluent: hexane: ethyl acetate (3:7 to 1:9). A compound of formula I is obtained with 5% to 60% yield. In case of précipitation, filter it off, otherwise wash the reaction mixture with water and NaCl, distill off the solvent. The product is purified by column chromatography. Compound III is synthesized in a similar manner with 5 to 60% yield.

Example 2. General method for synthesis of compounds XI, X2, X3.

r₅R ^ai“^a3

Hal—Hal + HoY N ----- Hal—(^z /~N>=O

Α2^ςα₄ ^A2^A4 ' \ r₅R

X1-2 X1-1X1 r₅ ^αγ^α3 a₅zA₆

Hal—/-OH . Hal-7 7% ^A2 ^A4 Ag'Ag R₅ Hal^A| ⁴ Yf ⁷

X2-2 X2-1 X2

X3-2 X3-1 X3

Hal = Br, I, Cl or OMs, OTs wherein A_b A₂, A₃, A4, A₅, A₆, A₇, A₈, A₉, R₅ hâve the foregoing meanings.

Compounds XI. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix in the specified order: 200 mL of DMF, 0.1 mol of a corresponding phenyl dihalide Xl-2, 0.1 mol of a corresponding hydroxypyridine Xl-1, and 0.2 mol of césium or potassium carbonate. Stir the mixture at 100 °C under an inert gas for 2-6 hours; use the TLC method to ensure the completeness of the reaction. After that, distill off most of the solvent using a rotary evaporator; add 200 mL of ethyl acetate, and fîlter the resulting suspension through celite. Evaporate the filtrate. Purify the resulting product by column chromatography, eluent ethyl acetate: methanol (9:1). The resulting product is compound XI with 60% to 80% yield.

Compounds X2. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix in the specified order: 10 mL of dry DMF, 0.01 mol of a corresponding pyridine halide X2-1, 0.011 mol of a corresponding phénol halide X2-2, and 0.012 mol of césium or potassium carbonate. Heat the mixture to 40-80 °C, allow to stand at this température for 18 hours; use the TLC method to ensure the completeness of the reaction. After that, fîlter the reaction mass through celite. Add the filtrate to 100 mL of water, and fîlter the precipitate. Wash the fîlter cake twice with 20 mL of water, and allow to dry in air. The resulting product is compound X2 with 80% to 95% yield.

Compounds X3. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix in the specified order: 20 mL of dichloromethane, 0.0106 mol of a corresponding halogen benzoic acid X3-2, and 0.02 mol of thionyl chloride. Add 2-3 drops of DMF to the mixture and boil it for 1.5 hours until the precipitate is dissolved. After that, distill off the solvent; reevaporate with 20 mL of toluene, and dissolve the resulting solid precipitate in 10 mL of dichloromethane. With constant stirring, add the resulting solution at 0 °C to a pre-prepared solution of a corresponding aminopyridine X3-1 in 10 mL of pyridine. Stir the mixture for another 1 hour, distill off the solvent, and treat the residue with water. Fîlter the precipitate, wash with 20 mL of water, and allow to dry in air. The resulting product is compound X3 with 40% to 80% yield.

Example 3. Methods for synthesis of intermediates.

O

chloropyridine in tert-butanol, add 38.5 g (0.175 mol) of BOC anhydride. Stir the mixture for 5 hours at 40 °C. Remove excess solvent by distillation in a rotary evaporator at 40 °C; treat the residue with hexane. Cool the resulting suspension to 0 °C, and filter the precipitate. Yield: 28 g (77%).

BCD-BTK-4-10. Τη a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix in the specifïed order: 135 mL of dry tetrahydrofuran (THF), 20 g (0.169 mol) of Ν,Ν,Ν',Ν'-tetramethylethylenediamine, and 15.7 g (0.068 mol) of BCD-BTK-4-11. Cool the resulting mixture to -78 °C; add, dropwise, 68 mL of 2.5M n-butyllithium in hexane, maintaining the température. After that, allow the reaction mass to stand for another 30 minutes. Add 15 g (0.2 mol) of DMF, maintaining the température at -78 °C. After 1 hour, stop the cooling and allow the reaction mixture to warm to room température. Allow to stand for another hour. Add, while cooling, 30 mL of methanol and 150 mL of NH₄C1 aqueous solution. Allow to stand for 30 minutes. To the reaction mass add 1000 mL of water, 500 mL of dichloromethane, and transfer the resulting mixture to a separatory funnel. Separate the organic layer; re-extract the aqueous layer using 200 mL of dichloromethane. Combine the organic layers, wash with water, and dry with sodium sulfate. Distill off dichloromethane using a rotary evaporator; dissolve the residue in 200 mL of dichloromethane. To the resulting mixture add 50 mL of 4M HCl in 1,4-dioxane, while stirring and cooling. Allow the mixture to stand at room température for 5 hours; use the TLC method to ensure the completeness of the reaction. Add another 200 mL of dichloromethane, and neutralize excess acid with 2M NaOH. Separate dichloromethane, wash with water, and dry with sodium sulfate. Purify the resulting product by column chromatography, eluent dichloromethane. Yield: 9.6 g (55%).

BCD-BTK-4-9. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix in the specifïed order: 40 mL of dry dichloroethane, 6 g (0.037 mol) of BCD-BTK-4-10, and 7.5 g (0.0417 mol) of Nbromosuccinimide. Stir the mixture under nitrogen at 50-60 °C for 2 hours; use the TLC method to ensure the completeness of the reaction. When the reaction is complété, cool the mixture to -10 °C, and filter the precipitate. Wash the filter cake once with cooled dichloroethane and three times with 50 mL of water. Allow the washed precipitate to dry in air until the mass is constant. Yield: 7.1g (79%).

BCD-BTK-4-8. In a thick walled flask with a threaded neck, mix 150 mL of DMSO, 14.5 g (0.062 mol) of BCD-BTK-4-9, and 12.5 g (0.248 mol) of hydrazine hydrate. Screw the cap on tightly, and heat the flask to 130-140 °C for 4 hours. After that, concentrate the reaction mass using a rotary evaporator. To the residue add 100 mL of water and cool to -5 °C. Filter the precipitate with chilled water, and allow to dry in air. Yield: 10.8 g (81%).

BCD-BTK-9-6. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix in the specified order: 40 mL of dry dichloroethane, 6 g (0.037 mol) of BCD-BTK-4-10, and 5.56 g (0.0417 mol) ofNchlorosuccinimide. Stir the mixture under nitrogen at 50-60 °C for 3 hours; use the TLC method to ensure the completeness of the reaction. When the reaction is complété, cool the mixture to -10 °C, and filter the precipitate. Wash the filter cake once with cooled dichloroethane and three times with 50 mL of water. Allow the washed precipitate to dry in air until the mass is constant. Yield: 5 g (71%).

BCD-BTK-9-5. In a thick walled flask with a threaded neck, mix 150 mL of DMSO, 5 g (0.026 mol) of BCD-BTK-4-9, and 5.23 g (0.105 mol) of hydrazine hydrate. Screw the cap on tightly, and heat the flask to 130-140 °C for 4 hours. After that, distill off the solvent using a rotary evaporator. To the residue add 100 mL of water and cool to -5 °C. Filter the precipitate with chilled water, and allow to dry in air. Yield: 3.54 g (81%).

BCD-BTK-9-5a. In a round-bottom flask mix in the specified order: 4.4 g (44 mmol) of succinic anhydride and 3.36 g (20 mmol) of the compound BCDBTK-9-5. Stir the mixture at 160°C for 20 minutes and add to the mixture 6 g of ice and 30 ml of water. Filter the precipitate, wash with water and dry under vacuum at 40°C. Yield: 3.5 g (70%).

BCD-BTK-9-4a. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix under nitrogen in the specified order: 25 ml of DMF, 3.5 g (0.014 mol) of the compound BCD-BTK-9-5a and 3.6 g (0.016 mol) N-iodosuccinimide. Mix at 40°C for 5 hours, use the TLC method to ensure the completeness of the reaction. When the reaction is complété, pour 100 ml of water and filter the precipitate; wash it two times and dry at 40°C under vacuum. Yield: 4.00 g (77%).

BCD-BTK-9-3a. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix under nitrogen in the specified order: 25 ml of dry THF, 2.52 g (0.0067 mol) of the compound BCD-BTK-9-4a, 3.93 g (0.015 mol) of triphenylphosphine and 3.0 g (0.015 mol) of (S)-3-hydroxy-l-(tbutoxycarbonyl)-piperidine and mix for 15 minutes. Then cool the mixture to 0°C and add dropwise 3.0 g (0.015 mol) of diisopropyl azodicarboxylate keeping the température at 0°C. After that warm the mixture up to 20°C and mix for 6 hours, use the TLC method to ensure the completeness of the reaction. When the reaction is complété, distill off the solvent. The product is purified by column chromatography, eluent: ethyl acetate-hexane 8:2. Yield: 2.5 g (67%).

BCD-BTK-9-4. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix in the specified order: 150 mL of 1,4dioxane, 7 g (0.04118 mol) of BCD-BTK-9-5, and 10.039 g (0.152 mol) of KOH. Add, while cooling with water, 21g (0.0822 mol) of iodine. Stop cooling, and stir the mixture at 70-75 °C for 3 hours; use the TLC method to ensure the completeness of the reaction. When the reaction is complété, add the reaction mass to 600 mL of water, and extract with 100 mL of ethyl acetate fïve times. Wash the organic layer with 200 mL of water and dry with sodium sulfate. Remove the solvent; purify the resulting product by column chromatography, eluent dichloromethane : ethyl acetate (from 98:2 to 9:1). Concentrate the resulting product with pooled fractions; wash the residue three times with 50 mL of hexane. Yield: 1.2 g (10%).

BCD-BTK-9-3. Variation 1. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix under nitrogen in the specified order: 25 mL of dry methanol, 2.06 g (0,0037 mol) of BCD-BTK-9-3a and 1 ml of hydrazine-hydrate and mix for 6 hours, use the TLC method to ensure the completeness of the reaction. When the reaction is complété, distill off the solvent at room température and add 20 ml of water. Filter the precipitate, wash with water and dry. Yield: 1.76 g (79%).

Variation 2. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix in the specified order: 20 mL of dry THF, 0.55 g (0.00177 mol) of BCD-BTK-9-4, 0.624 g (0.00355 mol) of triphenylphosphine, and 0.721 (0.00355 mol) of (S)-3-hydroxy-l-(tert-butoxycarbonyl)piperidine. Stir under nitrogen for 15 minutes. Cool the reaction mass to 0 °C; add, dropwise, 0.624 g (0.00355 mol) of diethyl azodicarboxylate, maintaining the température. After that, allow the reaction mass to warm to room température, and stir for 1.5 hours; use the TLC method to ensure the completeness of the reaction. When the reaction is complété, distill off the solvent, and treat the residue with a mixture of hexane/ethyl acetate (7:3). Filter off and discard the resulting precipitate; concentrate the mother liquor, and purify the resulting residue by column chromatography, eluent hexane : ethyl acetate (from 95:5 to 7:3). Yield: 0.58 g (68%).

BCD-BTK-241-3. In a Steel autoclave mix in the specified order: 15 ml of methanol, 0.2 ml of aqueous ammonia, 1.06 g (0.0022 mol) of BCD-BTK-9-3 and 0.05 g of 10% palladium-on-carbon and hydrogenize at 2-3 atm. for 6 hours. After the reaction is complété, distill off the solvent at room température and add 20 ml of water. Filtrate the precipitate, wash with water and dry. Yield: 0.88 g (89%).

BCD-BTK-4-7a and BCD-BTK-4-7b. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix under nitrogen in the specified order: 120 mL of dry THF, 7 g (0.0325 mol) of BCD-BTK-4-8, 12.066 g (0.0455 mol) of triphenylphosphine, and 4.767 g (0.0342 mol) of p-methoxybenzyl alcohol. Stir for 15 minutes. Cool the reaction mass to 0 °C; add, dropwise, 6.867 g (0.39 mol) of diethyl azodicarboxylate, maintaining the température. After that, allow the reaction mass to warm to room température, and stir for 2 hours; use the TLC method to ensure the completeness of the reaction. When the reaction is complété, distill off the solvent; purify the resulting product by column chromatography, eluent dichloromethane : ethyl acetate (from 9:1 to 1:1). BCD89

BTK-4-7a is purified first (yield: 4,53 g (41.8%)), BCD-BTK-4-7b is purified after that (yield: 2.3 g (21.2%)).

BCD-BTK-4-6a. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix under nitrogen in the specified order: 20 mL of dry DMF, 4.375 g (0.013 mol) of BCD-BTK-4-7a, 2 g (0.0168 mol) of zinc cyanide, and 0.759 g (0.00065 mol) of tetrakis(triphenylphosphine)palladium. Heat the mixture to 130 °C for 5 hours; use the TLC method to ensure the completeness of the reaction. When the reaction is complété, cool the mixture, filter through celite, and distill off the solvent. To the residue add a 1:1 mixture of acetone/hexane, boil for 5-10 minutes, and cool to -10 °C. Filter the suspension, wash the precipitate with hexane, and allow to dry in air. Yield: 2.7 g (75%).

BCD-BTK-4-6b. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix in the specified order: 10 mL of dry DMF, 2.3 g (0.0068 mol) of BCD-BTK-4-7b, 1.054 g (0.00888 mol) of zinc cyanide, and 0.399 g (0.00034 mol) of tetrakis(triphenylphosphine)palladium. Heat the reaction mixture to 130 °C under nitrogen for 3 hours; use the TLC method to ensure the completeness of the reaction. When the reaction is complété, cool the mixture, filter through celite, and distill off the solvent. To the residue add a 1:1 mixture of acetone/hexane, boil for 5-10 minutes, and cool to -10 °C. Filter the suspension, wash with hexane, and allow to dry in air. Yield: 1.5 g (79%).

BCD-BTK-4-5. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix in the specified order: 20 mL of trifluoroacetic acid, 2.7 g (0.00918 mol) of BCD-BTK-4-6a, and 1.5 g (0.0051 mol) of BCD-BTK-4-6b. Allow the mixture to stand at 60 °C for 3-5 hours. Distill off trifluoroacetic acid as completely as possible, and dissolve the residue in 100 mL of water. Extract the aqueous solution containing small amount of precipitate with hexane; discard the organic layer; neutralize the aqueous layer to pH 6-7. Filter the resulting precipitate, and wash it once with 50 mL of a 1:1 mixture of acetone : hexane, twice with 20 mL of water; allow to dry in air. Yield: 2.1 g (92%).

BCD-BTK-4-4. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix in the specified order: 20 mL of DMF, 2.1 g (0.011 mol) of BCD-BTK-4-5, and 3 g (0.013 mol) of N-iodosuccinimide. Heat the mixture to 70 °C and allow to stand at this température for 2 hours; use the TLC method to ensure the completeness of the reaction. When the reaction is complété, add the mixture to 100 mL of water; filter the suspension, wash the filter cake with water and a 1:1 mixture of acetone/water. Allow to dry in air. Yield: 3 g (93%).

BCD-BTK-4-3. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix in the specified order: 15 mL of dry THF, 1 g (0.00333 mol) of BCD-BTK-4-4, 1.766 g (0.0066 mol) of triphenylphosphine, and 1.355 (0.0066 mol) of (S)-3-hydroxy-l-(tert-butoxycarbonyl)piperidine. Stir under nitrogen for 15 minutes. Cool the reaction mass to 0 °C; add, dropwise, 1.173 g (0.0066 mol) of diethyl azodicarboxylate, maintaining the température. After that, allow the reaction mass to warm to room température, and stir for 3 hours; use the TLC method to ensure the completeness of the reaction. When the reaction is complété, distill off the solvent, and treat the residue with a mixture of hexane/ethyl acetate (7:3). Filter off and discard the resulting precipitate; concentrate the mother liquor, and purify the resulting product by column chromatography, eluent dichloromethane : ethyl acetate (from 9:1 to 7:3). Yield: 0.61 g (39%).

BCD-BTK-6-3. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix in the specified order: 5 mL of DMSO, 0.6 g (0.00128 mol) of BCD-BTK-4-3, 0.355 g (0.00257 mol) of potassium carbonate, and 0.845 g (0.0076 mol) of 30% hydrogen peroxide in water. Stir the mixture at 30 °C for 4 hours; use the TLC method to ensure the completeness of the reaction. When the reaction is complété, add 25 mL of water to the reaction mass, and extract with 20 mL of ethyl acetate five times. Combine the organic extracts, wash them with NaCl solution, dry with sodium sulfate, and distill off the solvent. Purify the resulting product by column chromatography, eluent ethyl acetate. Yield: 0.55 g (90%).

2)

BCDBTK-211-7

BCDBTK-211-5

BCD-BTK-211-6. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, add under nitrogen 50 ml of dry THF, cool to -78°C and add dropwise in the specified order: 9.57 ml of 2.5M butyl lithium in hexane, 2.42 g (0.02 mol) diisopropylamine and a solution of 3 g (0.022 mol) of the compound BCD-BTK-211-7 in 20ml of dry THF. Keep the mixture at -78°C for 5.5 hours. Then add 1.75 g (0.023 mol) of DMF maintaining the température. After that keep the mixture at room température for 1 hour. Then add while cooling the reaction mixture 10 ml of methanol and 30 ml of aqueous NH₄C1 and keep for 30 minutes. Add 200 ml of water, 120 ml of dichloromethane and transfer the émulsion into a séparation tunnel. Separate the organic layer, re-extract the water layer with 60 ml of dichloromethane. Combine the organic layers, wash with water and dry with sodium sulfate. Distill off dichloromethane. Purify the resulting product by column chromatography, eluent hexane : ethyl acetate (95:5). Yield: 1.8 g (50%).

BCD-BTK-211-5. In a thick-walled flask with a threaded neck, mix 25 mL of DMSO, 1.6 g (0.0099 mol) of BCD-BTK-211-6, and 2 g (0.039 mol) of hydrazine hydrate and heat up to 130-140°C for 6 hours. After that distill off the solvent using a rotary evaporator. Add 50 ml of water and 25 ml of ethyl acetate to the residue and transfer the émulsion into a séparation funnel. Separate the organic layer, re-extract the water layer with 25 ml of ethylacetate. Combine the organic layers, wash with water and dry with sodium sulfate. Distill off ethyl acetate.

Purify the resulting product by column chromatography, eluent hexane : ethyl acetate (7:3). Yield: 0.85 g (62%).

BCD-BTK-211-4. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix under nitrogen in the specified order: 10 mL of DMF, 0.81 g (0.0059 mol) of BCD-BTK-211-5 and 1.6 g (0.07 mol) of N-iodosuccinimide. Stir at 80°C for 3 hours, use the TLC method to ensure the completeness of the reaction. When the reaction is complété, add 80 ml of water and filtrate the precipitate, wash it with water 2 times and dry at 40°C under vacuum. Yield: 1.3 g (85%).

BCD-BTK-211-3. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix under nitrogen in the specified order: 25 mL of dry THF, 1.25 mL (0.0047 mol) of BCD-BTK-211-4, 2.5 g (0.0094 mol) of triphenylphosphine and 1.19 g (0.0094 mol) of (S)-3-hydroxy-l-(tertbutoxycarbonyl)piperidine and stir for 15 minutes. Then cool the reaction mass to 0°C and add, dropwise, 1.93 g (0.0094 mol) of diisopropylazodicarboxylate keeping that température. After that heat the reaction mass to room température and stir for 10 hours, use the TLC method to ensure the completeness of the reaction. When the reaction is complété, distill of the solvent, treat the residue with a mixture of hexane - ethyl acetate 9:1. Filter and discard the resulting precipitate; concentrate the mother liquor. Purify the resulting product by column chromatography, eluent hexane : ethyl acetate (from 9:1 to 8:2). Yield: 1.18 g (56%).

BCD-BTK-30-6. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix under nitrogen in the specified order: 200 mL of dry THF and 12.308 g (0.12 mol) of diisopropylamine. Cool the resulting mixture to -40 °C; add, dropwise, 48.7 mL of 2.5M butyllithium in hexane. Allow the mixture to stand at this température. After 30 minutes, cool the mixture to -78 °C; add, dropwise, solution of 15.7 g (0.068 mol) of BCD-BTK-307 in 100 mL of dry THF. After that, allow the reaction mass to stand for 2.5 hours. Add 15 g (0.2 mol) of DMF, maintaining the température at -78 °C. Stop the cooling and allow the reaction mixture to warm to room température. Allow to stand for another hour. Add, while cooling the reaction mixture, 30 mL of methanol and 150 mL of NH₄C1 aqueous solution. Allow to stand for 30 minutes. To the reaction mass add 1000 mL of water, 500 mL of dichloromethane, and transfer the émulsion to a separatory tunnel. Separate the organic layer; re-extract the aqueous layer using 200 mL of dichloromethane. Combine the organic layers, wash with water, and dry with sodium sulfate. Distill off dichloromethane. Yield: 17 g (96%).

BCD-BTK-30-5. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix under nitrogen in the specified order: 20 mL of éthanol, 2.7 g (0.0152 mol) of BCD-BTK-30-6, and 3.07 g (0.06 mol) of hydrazine hydrate. Stir the mixture while boiling for 4 hours; use the TLC method to ensure the completeness of the reaction. When the reaction is complété, pour the mixture into 100 mL of water and cool it to 0 °C. Filter the resulting precipitate, wash twice with 20 mL of water, and dry under vacuum at 40 °C. Yield: 1 g (43%).

BCD-BTK-30-4. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix under nitrogen in the specified order: 10 mL of DMF, 1 g (0.0064 mol) of BCD-BTK-30-5, and 1.9 g (0.0083 mol) of N-iodosuccinimide. Stir the mixture at 80 °C for 3 hours; use the TLC method to ensure the completeness of the reaction. When the reaction is complété, pour the mixture into 100 mL of water; filter the resulting precipitate, wash twice with water, and dry under vacuum at 40 °C. Yield: 1.75 g (94%).

BCD-BTK-30-3. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix under nitrogen in the specified order:

mL of dry THF, 1 g (0.00956 mol) of BCD-BTK-30-4, 5.064 g (0.01912 mol) of triphenylphosphine, and 3.889 g (0.01912 mol) of (S)-3-hydroxy-l-(tertbutoxycarbonyl)piperidine. Stir for 15 minutes. Cool the reaction mass to 0 °C; add, dropwise, 3.907 g (0.01912 mol) of diisopropyl azodicarboxylate, maintaining the température. After that, allow the reaction mass to warm to room température, and stir for 10 hours; use the TLC method to ensure the completeness of the reaction. When the reaction is complété, distill off the solvent, and treat the residue with a mixture of hexane/ethyl acetate (9:1). Fîlter and discard the resulting precipitate; concentrate the mother liquor. Purify the resulting product by column îo chromatography, eluent hexane : ethyl acetate (from 9:1 to 7:3). Yield: 1.8 g (41%).

4)

BCDBTK-104-4

BCD-BTK-104-9. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix under nitrogen in the specified order: 500 mL of tetrachloromethane, 23.75 g (250 mmol) of 4-hydroxypyridine, and 89 g (500 mmol) of N-bromosuccinimide. Stir at 25 °C for 30 hours. Fîlter the precipitate, wash with 50 mL of tetrachloromethane; stir the precipitate in a mixture of 500 mL of acetone and 150 mL of methanol for 15 minutes. Filter the suspension; stir the precipitate in a mixture of 400 mL of acetone and 400 mL of dichloromethane for 15 minutes. Filter the suspension; mix the precipitate vigorously in 400 mL of acetonitrile for 20 minutes. Filter the suspension; dry the precipitate under vacuum at 40 °C. Yield: 56 g (88%).

BCD-BTK-104-8. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix under nitrogen in the specified order: 120 mL of phosphoryl chloride and 38 g (150 mmol) of BCD-BTK-104-9. Stir the reaction mass at 70 °C for 3 hours, cool it to 40 °C, and pour on ice, while stirring vigorously. Filter the precipitate, wash with water, and dry under vacuum at 40 °C. Yield: 36.7 g (91%).

BCD-BTK-104-7. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix under nitrogen in the specified order: 200 mL of dry THF and 30 g (110 mmol) of BCD-BTK-104-8. Cool the mixture in the ice bath; add, dropwise, 2M z-PrMgCl in THF (60 mL, 120 mmol). Stir the suspension at 20 °C for 1 hour, cool in the ice bath; add, dropwise, 17 mL (16 g, 220 mmol) of dimethylformamide, while stirring vigorously. Stir the reaction mass at 20 °C for 4 hour, cool in the ice bath; add 15 mL of 15% NH₄C1 and 50 mL of water, while stirring vigorously. To the reaction mass add 100 mL of ethyl acetate; separate the organic layer, extract the aqueous layer with 70 mL of ethyl acetate twice. Wash the combined organic layers with 30 mL of water twice, and then with saturated NaCl solution; dry with anhydrous sodium sulfate. Distill off the solvent; treat the residue with 30 mL of hexane, filter, and dry under vacuum at 40 °C. Yield: 20 g (60%).

BCD-BTK-104-6. In a thick walled flask with a threaded neck, mix 30 mL of DMSO, 1.7 g (0.00723 mol) of BCD-BTK-104-7, and 1.3 g (0.025 mol) of hydrazine hydrate. Screw the cap on tightly, and heat the flask to 130-140 °C for 16 hours. After that, transfer the reaction mass to a flask, and distill off the solvent using a rotary evaporator. To the residue add 100 mL of water and cool to +5 °C.

Filter the resulting precipitate, wash twice with chilled water, and allow to dry in air. Yield: 1.2 g (86%).

BCD-BTK-104-lla, BCD-BTK-104-llb. Add 170 ml of DMSO, then add 2.18 g (54.5 mmol) of sodium hydride (60% suspension in paraffm oil) to a 500 ml round-bottom flask. Stir the mixture at room température under nitrogen for 15 min. Add successively 9.00 g (45.4 mmol) BCD-BTK-104-6 and 8.17 g (52.2 mmol) 4-methoxybenzyl chloride to the mixture. Stir the mixture at room température for 20 h, add 900 ml of water, extract water phase with ethyl acetate (3 x 400 ml), wash the combined organic layers with water (3 x 300 ml), dry with Na₂SO₄. Purify the resulting product (as two isomers) by chromatography. Yield: 12 g (86%) of isomer mixture.

BCD-BTK-104-12a, BCD-BTK-104-12b. Add the mixture of 12 g, (37.7 mmol) of BCD-BTK-104-lla and BCD-BTK-104-llb, 6.60 g, (56.6 mmol) of Zn(CN)₂, 0.86 g, (0.94 mmol) of Pd₂(dba)₃, 0.69 g, (0.94 mmol) of Pd(dppf)Cl₂ and 120 ml of DMF to a 500 ml round-bottom flask. Pass intensive stream of nitgoren for 5 minutes, heat at 120°C for 2.5 hours. Distill off 4/5 of DMF volume under reduced pressure, add 200 ml of water, 400 ml of ethyl acetate to the residue, separate the organic layer, extract the water layer with ethyl acetate (2 x 100 ml), wash the combined organic layers with water (2 x 100 ml) and the saturated NaCl solution, dry with Na₂SO₄. Purify the resulting product by chromatography, eluent dichloromethane-ethyl acetate (1:1). Yield: 9.2 g (93%) of isomer mixture.

BCD-BTK-104-5. Add the mixture of 9.2 g (35.0 mmol) of BCD-BTK-10412a and BCD-BTK-104-12b to a 250 ml round-bottom flask. Add 59.6 g (522 mmol) of trifluoroacetic acid and heat the intensively boiling reaction mass for 3.5 h, cool to room température, distill off trifluoroacetic acid under reduced pressure in a rotary film evaporator to 1/5 of the initial volume. Pour into water, bring to pH=7, extract the water layer by ethyl acetate, wash the combined organic extracts with water, dry with Na₂SO₄. Purify the resulting product by column chromatography, eluent ethyl acetate - hexane (7:3). Boil the resulting 4 g of solid mass (80%) in 50 ml of methylene chloride, cool to 0°C, filter, wash with methylene chloride (10 ml) and dry. Yield: 2.9 g (58%).

BCD-BTK-104-5. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix under nitrogen in the specified order: 70 mL of dry DFM, 7.0 g (35.4 mmol) of BCD-BTK-104-6, 0.05 g of [1,1'bis(diphenylphosphino)ferrocene]dichloropalladium (II), 0.7 g (10.8 mmol) of zinc dust, and 4.9 g (41 mmol) of zinc cyanide. Stir the mixture under nitrogen at 100 °C for 3 hours; allow to cool, filter through celite; wash the celite with DFM (2 x 20 mL), and concentrate the filtrate. Purify the resulting product by column chromatography, eluent ethyl acetate. Yield: 3.0 g (59%).

BCD-BTK-104-4. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix under nitrogen in the specified order: 10 mL of DMF, 3 g (0.021 mol) of BCD-BTK-104-5, and 5.7 g (0.025 mol) of Niodosuccinimide. Stir the mixture at 40 °C for 5 hours; use the TLC method to ensure the completeness of the reaction. When the reaction is complété, pour the mixture into 100 mL of water; filter the resulting precipitate, wash twice with water, and dry under vacuum at 40 °C. Yield: 4.8 g (85%).

BCD-BTK-104-3. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix under nitrogen in the specified order: 25 mL of dry THF, 4.8 g (0.018 mol) of BCD-BTK-104-4, 9.4 g (0.036 mol) of triphenylphosphine, and 7.2 g (0.036 mol) of (S)-3-hydroxy-l-(tertbutoxycarbonyl)piperidine. Stir for 15 minutes. Cool the reaction mass to 0 °C; add, dropwise, 7.3 g (0.036 mol) of diisopropyl azodicarboxylate, maintaining the température. After that, heat the reaction mass to 40 °C, and stir for 6 hours; use the TLC method to ensure the completeness of the reaction. When the reaction is complété, distill off the solvent; purify the resulting product by column chromatography, eluent dichloromethane. Yield: 3.3 g (40%).

BCD-BTK-24-3. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix in the specified order: 5 mL of DMSO, 0.6 g (0.00128 mol) of BCD-BTK-104-3, 0.355 g (0.00257 mol) of potassium carbonate, and 0.845 g (0.0076 mol) of 30% hydrogen peroxide in water. Stir the mixture at 30 °C for 4 hours; use the TLC method to ensure the completeness of the reaction. When the reaction is complété, add 25 mL of water to the reaction mass, and extract with 20 mL of ethyl acetate five times. Wash the organic layer 5 with NaCl solution and water, dry with sodium sulfate, and distill off the solvent.

Purify the resulting product by column chromatography, eluent dichloromethane : ethyl acetate (9:1). Yield: 0.55 g (90%).

BCD-BTK-239-16

BCD-BTK-239-15 BCD-BTK-239-14

BCD-BTK-239-4

BCD-BTK-239-15. In a round-bottom flask, mix in the specifïed order:

solution of 2.17 g (38.3 mmol) of KOH in 22 ml of water and 5.00 g (34.8 mmol) of BCD-BTK-239-16. Stir the reaction mass at 20°C for 20 minutes, cool in an ice bath to 5°C and add while stirring dropwise 4.44 g (34.8 mmol) of dimethyl sulfate. Stir the reaction mass at 20°C for 3 h, allow it to stand at 4°C for 20 h. Filter the precipitate, wash with water, dry under vacuum at 40°C. Yield: 6.04 g (90%).

BCD-BTK-239-14. In a round-bottom flask, mix in the specified order: 6.80 g (43.6 mmol) of BCD-BTK-239-15 and 70.0 ml (930 mmol) of aqueous ammonia. Stir the reaction mass at 90°C for 2.5 h, cool down, distill off the solvent under reduced pressure, dissolve the residue in 100 ml of methanol, add 1 g of activated carbon, boil for 30 minutes, cool down, filter through celite and distill off the solvent to dryness. Yield: 6.50 g (96%).

BCD-BTK-239-13. In a round-bottom flask, mix in the specified order: a mixture of 1 ml of 98% nitric acid and 5 ml of 70% nitric acid and 1 g (6.44 mmol) of BCD-BTK-239-14. Stir the reaction mass at 20°C, pour a mixture of 6 g of ice and 30 ml of water into the reaction mass. Filter the precipitate, wash with water, dry under vacuum at 40°C. Yield: 0,96 g (89%).

BCD-BTK-239-12. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix in the specified order: 26.2 g (220 mmol) of thionyl chloride and 7.60 g (44.9 mmol) of BCD-BTK-239-13. Boil the mixture with the reflux condenser and a calcium chloride tube for 5 h. Distill the solvent off to dryness under reduced pressure, add to the residue successively 30 g of ice and 70 ml of water and bring pH to 8 with solid Na₂CO₃. Stir the reaction mass for 20 h, bring pH to 7 with 2 N hydrochloric acid, filtrate the precipitate, wash with water, dry under vacuum at 40°C for 24 h. Yield: 4.8 g (58%).

BCD-BTK-239-11. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix in the specified order: 130 ml of tertbutanol, 4.32 g (23.0 mmol) of BCD-BTK-239-12 and 6.42 g (23.0 mmol) of DPPA and add while stirring dropwise 2.33 g (23.0 mmol) of triethylamine. Boil the reaction mass while stirring under nitrogen for 16 h, distill off the solvent. Purify the product by column chromatography on silicagel, eluent ethyl acetate: hexane (1:9). Yield: 4.35 g (73%).

BCD-BTK-239-10. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix in the specified order: 2.00 g (7.73 mmol) of BCD-BTK-239-11, 2.24 g (19.3 mmol) of Ν,Ν,Ν',Ν'tetramethylethylenediamine and 90 ml of dry THF. Cool the reaction mass to

100

-78°C while constant stirring under nitrogen. Add to the reaction mass with a syringe 7.72 ml (19.3 mmol) of 2.5M of a solution of n-butyllithium in hexane for 5 minutes, continue stirring at the same température for 1 h; add 1.68 g (23.0 mmol) of DMF to the reaction mass, continue stirring at -78°C for another hour, then add to the reaction mass a saturated solution of NH₄C1 (20 ml), heat to 20°C and add 100 ml of ethyl acetate, separate the organic layer, extract the water layer with ethyl acetate (2 x 50 ml), wash the combined organic layers with a saturated solution of NaCl, dry with Na₂SO₄. Distill off the solvent under reduced pressure, purify the product by column chromatography on silicagel, eluent ethyl acetate: hexane (2:8). Yield: 1.53 g (70%).

BCD-BTK-239-8. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix in the specified order: 1.25 g (4.36 mmol) of BCD-BTK-239-10 and 20.0 ml (80.0 mmol) of 4N HCl solution in dioxane at 20°C and stir for 18 h. Distill off the solvent to dryness at reduced pressure, dissolve the residue in 5 ml of water, extract the water layer with 5 ml of methyl-tbutyl ether, separate the water layer, bring pH to 8 with 3N solution of KOH, Filtrate the precipitate, wash with water, dry under vacuum at 40°C for 24 h. Yield: 0.75 g (93%).

BCD-BTK-239-7. Dissolve 0.70 g (3.75 mmol) of BCD-BTK-239-8 in 5 ml of DMSO, add to 0.28 g (5.63 mmol) of hydrazine hydrate. Place the reaction mass into a flask under pressure and heat at 120°C while stirring for 15 h, distill off the solvent at reduced pressure, purify the product by column chromatography on silicagel, eluent ethyl acetate and then ethyl acetate/methanol (7:3). Yield: 0.59 g (96%).

BCD-BTK-239-6. In a round-bottom flask, mix in the specified order: 4.4 g (44 mmol) of succinic anhydride and 3.28 g (20 mmol) of BCD-BTK-239-7. Mix the reaction mass at 160 °C for 20 min, pour into the reaction mass 6 g of ice and 30 ml of water. Filtrate the precipitate, wash with water, dry under vacuum at 40°C. Yield: 3.1 g (62%).

101

BCD-BTK-239-5. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix under nitrogen in the specified order: 25 ml of DMF, 3 g (0.012 mol) of BCD-BTK-239-6 and 3.2 g (0.014 mol) of Niodosuccinimide. Stir the mixture at 40°C for 5 h; use the TLC method to ensure the completeness of the reaction. When the reaction is complété, pour 100 ml of water and filtrate the precipitate, wash with water (2 times) and dry at 40°C under vacuum. Yield: 2.86 g (77%).

BCD-BTK-239-4. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix under nitrogen in the specified order: 25 ml of dry THF, 2.86 g (0.0067 mol) of BCD-BTK-239-5, 3.93 g (0.015 mol) of triphenylphosphine and 3.0 g (0.015 mol) of (S)-3-hydroxy-l-(t-butoxycarbonyl) piperidine, and mix for 15 minutes. Then cool the reaction mass to 0°C and add dropwise 3.0 g (0.015 mol) diisopropyl azodicarboxylate, keeping the température at the same level. After that, heat the reaction mass to 20°C and mix for 6 hours; use the TLC method to ensure the completeness of the reaction. When the reaction is complété, distill off the solvent, purify the product by column chromatography, eluent: ethyl acetate - hexane (8:2). Yield: 2.08 g (56%).

BCD-BTK-239-3. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix under nitrogen in the specified order: 25 ml of dry methanol, 2.08 g (0.0037 mol) of BCD-BTK-239-4 and 1 ml of hydrazine hydrate, stir for 6 h; use the TLC method to ensure the completeness of the reaction. When the reaction is complété, distill off the solvent at room température and add 20 ml of water. Filter the precipitate, wash with water and dry. Yield: 1.45 g (79%).

6)

102

BTK-130-12

BCDBTK-130-11

BCDBTK-130-10

Br

BCDBTK-130-13

^Br BTK-130-7

BCDBTK-130-9

BCD-BTK-130-12. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix under nitrogen in the specified order: 300 mL of acetic acid and 20 g (0.131 mol) of 2-amino-5-nitrotoluene. To the 5 resulting mixture add a solution of 31 g of bromine in 20 mL of acetic acid. After that, allow the reaction mass to stand for 1 hour and pour it into 2 L of water, add 20 g of sodium hydrogen sulfite, and stir for 30 minutes. Filter the precipitate, wash with water, and re-crystallize from 1 L of éthanol. Yield: 26 g (86%).

BCD-BTK-130-11. In a round-bottom flask, equipped with a stirrer, 10 thermometer and reflux condenser, mix under nitrogen in the specified order: 190 mL of acetic acid and 26 g (0.113 mol) of BCD-BTK-130-12. Stir the mixture for 2 hours, cool to 15 °C, and add, dropwise, a solution of 20 g (0.29 mol) of sodium nitrite in water. Stir the reaction mass for 24 hours at room température. Then pour it into 1 L of water; filter the precipitate, wash with 20 mL of water 15 twice. Re-crystallize the precipitate from 200 mL of éthanol. Yield: 17.3 g (63%).

BCD-BTK-130-10. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix under nitrogen in the specified order: 40 mL of éthanol, 2.3 g (0.04 mol) of iron powder, 4.1 g (0.076 mol) of NH₄C1,

103 and 1 g (0.00413 mol) of BCD-BTK-130-11. Stir the resulting mixture for 3 hours at boiling température; use the TLC method to ensure the completeness of the reaction. When the reaction is complété, fîlter the mixture through celite, concentrate the solvent and residue. Fîlter the precipitate, wash with 30 mL of water, and allow to dry in air. Yield: 0.8 g (91%).

BCD-BTK-130-9. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix under nitrogen in the specified order: 20 mL of water, 5 mL of concentrated hydrochloric acid, and 3 g (0.0144 mol) of BCD-BTK-130-10. Cool the mixture to 0 °C, and add, dropwise, a solution of 1.19 g (0.0173 mol) of sodium nitrite in 5 mL of water, maintaining the température (0 °C). Allow the reaction mass to stand for another hour, and add a solution of 11.9 g (0.072 mol) of potassium iodide in water. Allow the resulting mixture to stand at room température. After 3 hours, neutralize to pH 6-7 with sodium bicarbonate, and extract three times with 30 mL of ethyl acetate. Wash the organic layer with water, dry with sodium sulfate, and distill off the solvent. Purify the resulting product by column chromatography, eluent hexane : ethyl acetate (from 1:1 to 2:8). Yield: 2.76 g (60%).

BCD-BTK-130-8. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix under nitrogen in the specified order: 60 mL of dry THF, 2.1 g (0.0065 mol) of BCD-BTK-130-9, 3.4 g (0.013 mol) of triphenylphosphine, and 1.373 g (0.00975 mol) of p-methoxybenzyl alcohol. Stir for 15 minutes. Cool the reaction mass to 0 °C; add, dropwise, 2.333 g (0.013 mol) of diethyl azodicarboxylate, maintaining the température. After that, allow the reaction mass to warm to room température, and stir for 1.5 hours; use the TLC method to ensure the completeness of the reaction. When the reaction is complété, distill off the solvent; purify the residue by column chromatography, eluent hexane : ethyl acetate (9:1). Yield: 1.72 g (60%).

BCD-BTK-130-7. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix under nitrogen in the specified order: 120 mL of dry THF and 2.7 g (0.0061 mol) of BCD-BTK-130-8. Cool the

104 suspension to 6 °C, and add, dropwise, 1.6 mL (0.0079 mol) of 2M z-PrMgCl in THF. Stir the mixture at 5 °C. After 1 hour, add 1.84 g (0.0098 mol) of triisopropyl borate, stir for 10 hours at room température, and cool again to 5 °C. To the resulting mixture add 6 mL (0.061 mol) of 30% hydrogen peroxide, 0.244 g (0.0061 mol) of solid NaOH, and stir for another hour at room température. After that, add a solution of 9.6 g (0.076 mol) of sodium sulfite in 30 mL of water, stir, and extract with ethyl acetate. Wash the organic layer with water, dry with sodium sulfate, and distill off the solvent. Purify the resulting product by column chromatography, eluent hexane : ethyl acetate (2:3). Yield: 1.3 g (63%).

BCD-BTK-130-6. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix under nitrogen in the specified order: 20 mL of dry DMF, 0.62 g (0.00186 mol) of BCD-BTK-130-7, 0.13 g (0.00112 mol) of zinc cyanide, and 0.09 g (0.000079 mol) of tetrakis(triphenylphosphine)palladium. Heat the mixture to 80 °C for 10 hours; use the TLC method to ensure the completeness of the reaction. When the reaction is complété, cool the mixture, filter through celite, and distill off the solvent. Purify the residue by column chromatography, eluent hexane : ethyl acetate (8:2). Yield: 0.46 g (90%). Dissolve the resulting product in 20 mL of trifluoroacetic acid and stir at 60 °C for 1 hour. Distill off the excess acid, neutralize the residue with a solution of sodium bicarbonate; distill off water. Purify the resulting product by column chromatography, eluent ethyl acetate. Yield: 0.23 g (56%).

BCD-BTK-130-5. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix under nitrogen in the specified order: 10 mL of dry DMF, 1.1g (0.0069 mol) of BCD-BTK-130-6, and 0.71g (0.0104 mol) of imidazole. Cool the mixture to 0 °C and add 1.56 g (0.0104 mol) of TBDMSC1. Allow to stand at this température for 30 minutes. When the reaction is complété, pour the reaction mass into water, and extract with 20 mL of ethyl acetate three times. Wash the ethyl acetate with 30 mL of water twice, dry with sodium sulfate, and distill off the solvent. Purify the resulting product by column chromatography, eluent hexane : ethyl acetate (8:2). Yield: 1.2 g (63%).

105

BCD-BTK-130-4. Τη a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix in the specified order: 3 mL of DMF, 0.3 g (0.0011 mol) of BCD-BTK-130-5, and 0.36 g (0.00165 mol) of Niodosuccinimide. Stir the mixture at 20 °C for 18 hours; use the TLC method to ensure the completeness of the reaction. When the reaction is complété, pour the reaction mass into water, and extract with 20 mL of ethyl acetate three times. Wash the organic layer with 30 mL of water twice, dry with sodium sulfate, and distill off the solvent. Purify the resulting product by column chromatography, eluent hexane : ethyl acetate (8:2). Yield: 0.36 g (82%).

BCD-BTK-130-3. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix under nitrogen in the specified order: 10 mL of dry THF, 0.36 g (0.0009 mol) of BCD-BTK-130-4, 0.470 g (0.0018 mol) of triphenylphosphine, and 0.37 g (0.0018 mol) of (S)-3-hydroxy-l(tert-butoxycarbonyl)piperidine. Stir for 15 minutes. Cool the reaction mass to 0 °C; add, dropwise, 0.370 g (0.0018 mol) of diisopropyl azodicarboxylate, maintaining the température. After that, allow the reaction mass to warm to room température, and stir for 30 hours; use the TLC method to ensure the completeness of the reaction. When the reaction is complété, distill off the solvent, and treat the residue with a mixture of hexane/ethyl acetate (9:1). Filter off and discard the resulting precipitate; concentrate the mother liquor, and purify the resulting product by column chromatography, eluent dichloromethane (from 9:1 to 7:3). Yield: 0.33 g (63%).

BCD-BTK-18-3. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix in the specified order: 5 mL of DMSO, 0.6 g (0.00128 mol) of BCD-BTK-130-3, 0.355 g (0.00257 mol) of potassium carbonate, and 0.845 g (0.0076 mol) of 30% hydrogen peroxide in water. Stir the mixture at 20 °C for 14 hours; use the TLC method to ensure the completeness of the reaction. When the reaction is complété, add 25 mL of water to the reaction mass, and extract with 20 mL of ethyl acetate five times. Wash the organic layer with NaCl solution and water, dry with sodium sulfate, and distill off the solvent.

106

Purify the resulting product by column chromatography, eluent ethyl acetate : hexane (1:1). Yield: 0.55 g (90%).

BCD-BTK-35-9. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix under nitrogen in the specified order: 60 mL of dry THF and 3.067 g (0.0217 mol) of 2,2,6,6-tetramethylpiperidine. Cool the mixture to -78 °C, add 8.69 mL (0.0217 mol) of 2.5M butyllithium in hexane, and allow to stand. After 20 minutes, add a solution of 6 g (0.01974 mol) of 3fluoro-4-iodobromobenzene in 6 mL of THF, maintaining the température -78 °C. Allow the mixture to stand for 1 hour and add 4.56 mL (0.059 mol) of DFM. Stop cooling and allow the mixture to warm to room température. Allow to stand for another hour. Add, while cooling the reaction mixture, 3 mL of methanol and 15 mL of NH₄C1 aqueous solution. Allow to stand for 30 minutes. To the reaction mass add 100 mL of water, 50 mL of dichloromethane, and transfer to a separatory funnel. Separate the organic layer; re-extract the aqueous layer twice using 25 mL of dichloromethane. Combine the organic layers, wash with water, dry with sodium sulfate, and distill off the solvent. Purify the resulting product by column chromatography, eluent hexane : dichloromethane (9:1). Yield: 3.1 g (47%).

BCD-BTK-35-8. In a thick walled flask with a threaded neck, mix 150 mL of DMSO, 3.1g (0.00933 mol) of BCD-BTK-35-9, and 3.5 g (0.0699 mol) of hydrazine hydrate. Heat the flask to 130-140 °C for 16 hours. After that, distill off the solvent using a rotary evaporator. To the residue add 100 mL of water and cool

107 to 5 °C. Filter the precipitate with chilled water, and allow to dry in air. Yield: 2.4 g (81%).

BCD-BTK-35-7. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix under nitrogen in the specified order: 10 mL of dry DMF, 4.375 g (0.00654 mol) of BCD-BTK-35-8, 0.461 g (0.00393 mol) of zinc cyanide, and 0.378 g (0.00032 mol) of tetrakis(triphenylphosphine)palladium. Heat the mixture to 100 °C for 1.5 hours; use the TLC method to ensure the completeness of the reaction. When the reaction is complété, cool the mixture, filter through celite, and distill off the solvent as completely as possible. Add 20 mL of water and extract three times with 20 mL of ethyl acetate. Wash the organic layer three times with water, dry with sodium sulfate, and distill off the solvent. Purify the resulting product by column chromatography, eluent hexane : ethyl acetate (9:1). Yield: 1.35 g (92%).

BCD-BTK-35-6. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix under nitrogen in the specified order: 10 mL of 95% sulfuric acid and 1.35 g (0.00599 mol) of BCD-BTK-35-7. Stir the resulting mixture for 2 hours at room température, and pour into 200 mL of iced water. Filter the resulting precipitate, wash with 20 mL of water twice, and allow to dry in air. Yield: 1.35 g (93%).

BCD-BTK-35-5. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix under nitrogen in the specified order: 10 mL of dry DMF, 1.35 g (0.00556 mol) of BCD-BTK-35-6, 0.461 g (0.00393 mol) of zinc cyanide, and 0.643 g (0.00055 mol) of tetrakis(triphenylphosphine)palladium. Heat the reaction mixture to 110°C for 2 hours; use the TLC method to ensure the completeness of the reaction. After that, pour the reaction mass into 200 mL of iced water, filter the resulting precipitate, wash twice with 20 mL of water, and allow to dry in air. Purify the resulting product by column chromatography, eluent ethyl acetate : methanol (9:1). Yield: 1 g (96%).

108

BCD-BTK-35-4. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix under nitrogen in the specified order: 10 mL of DMF, 1 g (0.00558 mol) of BCD-BTK-35-5, and 1.5 g (0.0067 mol) of N-iodosuccinimide. Stir the mixture at 60 °C for 3 hours; use the TLC method to ensure the completeness of the reaction. When the reaction is complété, pour the mixture into 100 mL of water; filter the resulting precipitate, wash twice with 20 mL of water, and dry under vacuum at 40 °C. Yield: 1.15 g (66%).

BCD-BTK-35-3. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix under nitrogen in the specified order: 25 mL of dry THF, 1.15 g (0.00365 mol) of BCD-BTK-35-4, 1.916 g (0.0073 mol) of triphenylphosphine, and 1.468 g (0.0073 mol) of (S)-3-hydroxy-1(tert-butoxycarbonyl)piperidine. Stir for 15 minutes. Cool the reaction mass to 0 °C; add, dropwise, 1.271 g (0.0073 mol) of diethyl azodicarboxylate, maintaining the température. After that, allow the reaction mass to warm to room température, and stir for 6 hours; use the TLC method to ensure the completeness of the reaction. When the reaction is complété, distill off the solvent; purify the resulting product by column chromatography, eluent ethyl acetate : hexane (1:1). Yield: 0.65 g (36%).

8)

109

BCD-BTK-13-14. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix under nitrogen in the specified order: 120 mL of éthanol and 23.4 g (0.436 mol) of acrylonitrile. Cool the mixture to 0 °C; add, dropwise, 21g (0.414 mol) of hydrazine hydrate, maintaining the température. Stir the mixture for 24 hours at room température. Cool the reaction mass to 0 °C, add 60 g (0.436 mol) of para-methoxybenzaldehyde, and stir at room température for 24 hours. After that, distill off the solvent, dissolve the residue in 130 mL of 2-propanol, add 9.2 g (0.23 mol) ofNaOH, and boil for 2.5 hours. After that, concentrate the reaction mass, dissolve the residue in water, and extract with 125 mL of ethyl acetate four times. Combine the organic layers and wash with 200 mL of 2M hydrochloric acid. Separate the aqueous layer. Neutralize the no aqueous layer with 2M NaOH and extract the product with 100 mL of dichloromethane four times. Wash the organic layer with water, dry with sodium sulfate, and distill off the solvent. Purify the resulting product by column chromatography, eluent hexane : ethyl acetate (1:1). Yield: 10.58 g (12.8%).

BCD-BTK-13-13. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix under nitrogen in the specified order: 1 g (0.0048 mol) of BCD-BTK-13-14 and 1.17 g (0.0051 mol) of diethyl ethoxymethylenemalonate. Heat the mixture for 2 hours at 125-130 °C. Distill off the solvent using a rotary evaporator. Take the mixture to the next step without additional purification. Yield: 1.88 g (99%).

BCD-BTK-13-12. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix under nitrogen in the specified order: 1.88 g (0.005 mol) of raw compound BCD-BTK-13-13 obtained from the previous step and 10 mL of diphenyl ether. Stir the mixture for 3 hours at 250 °C; use the TLC method to ensure the completeness of the reaction. Allow the reaction mass to cool and add 30 mL of hexane. Filter the resulting precipitate, wash with 30 mL of hexane twice, and allow to dry in air. Yield: 1.55 g (92%).

BCD-BTK-13-11. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix under nitrogen in the specified order: 10 mL of éthanol, 1.55 g (0.0046 mol) of BCD-BTK-13-12, and 10 mL of 10% NaOH. Stir the resulting mixture at boiling température; use the TLC method to ensure the completeness of the reaction. When the reaction is complété, acidify the mixture to pH 1-2 with IM hydrochloric acid, filter the resulting precipitate. Wash the precipitate twice with 10 mL of water, allow to dry in air, and take to the next step without additional purification. Yield: 1.394 g (79%).

BCD-BTK-13-10. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix under nitrogen in the specified order: 2 g (0.005 mol) of raw compound BCD-BTK-13-11 obtained from the previous step and 12 mL of diphenyl ether. Stir the resulting mixture for 1 hour at 120 °C; use the TLC method to ensure the completeness of the reaction. Allow the reaction ni mass to cool and add 30 mL of hexane. Filter the resulting precipitate, wash with 30 mL of hexane twice, and allow to dry in air. Yield: 1.45 g (84%).

BCD-BTK-13-9. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix in the specified order: 100 mL of DMF, 10 g (0.038 mol) of BCD-BTK-13-10, and 9.6 g (0.042 mol) of Niodosuccinimide. Stir the mixture at 80 °C for 2 hours; use the TLC method to ensure the completeness of the reaction. When the reaction is complété, pour the mixture into 100 mL of water; filter the resulting precipitate, wash twice with water, and dry under vacuum at 40 °C. Yield: 10.2 g (71%).

BCD-BTK-13-8. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix under nitrogen in the specified order: 30 mL of phosphoryl chloride and 3.67 g (0.0095 mol) of BCD-BTK-13-9. Stir the mixture at 60 °C. After 1 hour, pour the mixture on ice while stirring. Filter the resulting precipitate and wash three times with 30 mL of water. Yield: 2.66 g (70%).

BCD-BTK-13-7. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix under nitrogen in the specified order: 120 mL of dry THF and 4.778 g (0.0118 mol) of BCD-BTK-13-8. Cool the suspension to 0 °C, and add, dropwise, 3.6 mL (0.0177 mol) of 2M LPrMgCl in THF. Stir the mixture at 0 °C. After 1 hour, add 5.622 g (0.02959 mol) of triisopropyl borate, stir for 16 hours at room température, and cool again to 0 °C. To the resulting mixture add 16.97 g (0.1183 mol) of 30% hydrogen peroxide, 0.478 g (0.0118 mol) of solid NaOH, and stir for another hour at room température. After that, add 15.07 g (0.1183 mol) of sodium sulfite, stir, and extract three times with 100 mL of ethyl acetate. Wash combined organic layer with water, dry with sodium sulfate, and distill off the solvent using a rotary evaporator. Purify the resulting product by column chromatography, eluent hexane : ethyl acetate (from 9:1 to 8:2). Yield: 1.13 g (33%).

BCD-BTK-13-6. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix under nitrogen in the specified order:

112 mL of trifluoroacetic acid and 2 g (0.0068 mol) of BCD-BTK-13-7. Boil the resulting mixture for 1 hour; use the TLC method to ensure the completeness of the reaction. After that, distill off most of the trifluoroacetic acid using a rotary evaporator; neutralize the residue to pH 7 with a solution of sodium bicarbonate. Concentrate the mixture to dryness. Purify the resulting product by column chromatography, eluent hexane : ethyl acetate (from 9:1 to 8:2). Yield: 0.63 g (55%).

BCD-BTK-13-5. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix under nitrogen in the specified order: 10 mL of dry DMF, 0.6 g (0.0035 mol) of BCD-BTK-13-6, and 0.36 g (0.0053 mol) of imidazole. Cool the mixture to 0 °C, add 0.8 g (0.0053 mol) of TBDMSC1, and allow to stand at this température for 30 minutes. When the reaction is complété, pour the reaction mass into water, and extract with 20 mL of ethyl acetate three times. Wash the combined extract with water, dry with sodium sulfate, and distill off the solvent. Take the resulting product to the next step without additional purification. Yield: 0.7 g (75%).

BCD-BTK-13-4. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix in the specified order: 10 mL of DMF, 0.6 g (0.0021 mol) of raw compound BCD-BTK-13-5 obtained from the previous step and 0.7 g (0.0031 mol) of N-iodosuccinimide. Stir the mixture at 50 °C for 3 hours; use the TLC method to ensure the completeness of the reaction. When the reaction is complété, pour the mixture into 100 mL of water; filter the resulting precipitate, wash twice with 20 mL of water, and dry under vacuum at 40 °C. Yield: 0.73 g (85%).

BCD-BTK-13-3. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix under nitrogen in the specified order: 25 mL of dry THF, 2.71g (0.00956 mol) of BCD-BTK-13-4, 5.064 g (0.01912 mol) of triphenylphosphine, and 3.889 g (0.01912 mol) of (S)-3-hydroxyl-(tert-butoxycarbonyl)piperidine. Stir under nitrogen for 15 minutes. Cool the reaction mass to 0 °C; add, dropwise, 3.907 g (0.01912 mol) of diisopropyl

113 azodicarboxylate, maintaining the température. After that, allow the reaction mass to warm to room température, and stir for 10 hours; use the TLC method to ensure the completeness of the reaction. Purify the resulting product by column chromatography, eluent hexane : ethyl acetate (from 9:1 to 7:3). Yield: 1.8 g (41%).

BCD-BTK-124-6. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix under nitrogen in the specified order: 20 mL of phosphoryl chloride and 2.42 g (0.0095 mol) of BCD-BTK-13-10. Stir the mixture at 60 °C. After 2 hours, pour the mixture on ice while stirring. Fîlter the resulting precipitate, wash three times with 30 mL of water, and allow to dry in air. Yield: 2.0 g (77%).

BCD-BTK-124-5. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix under nitrogen in the specified order: 20 mL of trifluoroacetic acid and 4.923 g (0.0178 mol) of BCD-BTK-124-6. Boil the resulting mixture for 2 hours; use the TLC method to ensure the completeness of the reaction. After that, distill off most of the trifluoroacetic acid using a rotary evaporator; neutralize the residue to pH 7 with a solution of sodium bicarbonate. Extract the aqueous solution with 20 mL of ethyl acetate three times; wash the combined extract with water, dry with sodium sulfate, and distill off the solvent. Purify the resulting product by column chromatography, eluent hexane : ethyl acetate (from 9:1 to 8:2). Yield: 0.63 g (55%).

BCD-BTK-124-4. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix under nitrogen in the specified order: 10 mL of DMF, 1 g (0.0064 mol) of BCD-BTK-30-5, and 1.9 g (0.0083 mol) of N-iodosuccinimide. Stir the mixture at 80 °C for 3 hours; use the TLC method to ensure the completeness of the reaction. When the reaction is complété, pour the mixture into 100 mL of water; fîlter the resulting precipitate, wash twice with 20 mL of water, and dry under vacuum at 40 °C. Yield: 1.75 g (94%).

BCD-BTK-124-3. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix under nitrogen in the specified order:

114 mL of dry THF, 2.67 g (0.00956 mol) of BCD-BTK-30-4, 5.064 g (0.01912 mol) of triphenylphosphine, and 3.889 g (0.01912 mol) of (S)-3-hydroxyl-(tert-butoxycarbonyl)piperidine. Stir under nitrogen for 15 minutes. Cool the reaction mass to 0 °C; add, dropwise, 3.907 g (0.01912 mol) of diisopropyl azodicarboxylate, maintaining the température. After that, allow the reaction mass to warm to room température, and stir for 10 hours. When the reaction is complété, distill off the solvent; purify the residue by column chromatography, eluent hexane : ethyl acetate (from 9:1 to 7:3). Yield: 2 g (44%).

9)

BCDBTK-13-14

BCD-BTK-117-12. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix under nitrogen in the specified order: 1 g (0.0048 mol) of BCD-BTK-13-14 and 1.18 g (0.0051 mol) of diethyl-2-(lethoxyethylidene)malonate. Heat the mixture for 2 hours at 125-130 °C. Distill off the residual solvent using a rotary evaporator. Take the mixture to the next step without additional purification. Yield: 1.88 g (99%).

BCD-BTK-117-11. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix under nitrogen in the specified order: 8.25 g (0.0213 mol) of raw compound BCD-BTK-117-12 obtained from the

115 previous step and 50 mL of diphenyl ether. Stir the mixture at 120 °C for 3 hours. After that, allow the reaction mass to cool and add 110 mL of hexane. Filter the resulting precipitate, wash with 30 mL of hexane twice, and allow to dry in air. Purify the resulting product by column chromatography, eluent hexane : ethyl acetate (from 95:5 to 7:3). Yield: 5.54 g (76%).

BCD-BTK-117-10. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix under nitrogen in the specified order: 30 mL of phosphoryl chloride and 5.5 g (0.0095 mol) of BCD-BTK-117-11. Stir the mixture at 100 °C. After 3 hours, distill off most of the phosphoryl chloride, and pour the residue on ice while stirring. Extract the resulting product with 30 mL of ethyl acetate three times. Wash the combined organic extract with water and NaCl solution, dry with sodium sulfate, and distill off the solvent using a rotary evaporator. Yield: 5.74 g (93%).

BCD-BTK-117-9. In a stainless Steel autoclave equipped with a stirrer and thermometer, place in the specified order: 100 mL of éthanol, 5.7 g (0.0159 mol) of BCD-BTK-117-10, 3.3 mL of triethylamine, and 1 g of 10% Pd/C. Close the autoclave lid, blow with nitrogen, and then introduce hydrogen at room température for 3 hours at 5 bar pressure. When the reaction is complété, filter the reaction mass through celite, and distill off the solvent. Yield: 4.79 g (93%).

BCD-BTK-117-8. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix under nitrogen in the specified order: 33 mL of methanol, 3.28 g (0.0105 mol) of BCD-BTK-117-9, and 33 mL of 10% NaOH. Stir the mixture at the boiling température. When the reaction is complété, acidify the mixture to pH 1-2 with 2M hydrochloric acid, and filter the resulting precipitate. Wash the precipitate twice with 10 mL of water, allow to dry in air, and take to the next step without additional purification. Yield: 3.2 g (96%).

BCD-BTK-117-7. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix under nitrogen in the specified order: 150 mL of absolute tert-butanol, 5 g (0.017 mol) of raw compound BCD-BTK117-9 obtained from the previous step, and 2.4 mL of triethylamine (0.017 mol).

116

After that, add 3.7 g (0.017 mol) of DPPA, and stir the mixture at the boiling température for 12 hours. When the reaction is complété, distill off the solvent; purify the resulting product by column chromatography, eluent hexane : ethyl acetate (from 99:1 to 7:3). Yield: 5.25 g (85%).

BCD-BTK-117-6. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix under nitrogen in the specifïed order: 20 mL of trifluoroacetic acid and 3.5 g (0.0068 mol) of BCD-BTK-117-7. Allow the resulting mixture to stand at 80 °C for 2 hours. After that, distill off most of the trifluoroacetic acid using a rotary evaporator; neutralize the residue to pH 7 with 5% sodium bicarbonate. Extract the resulting solution three times with 30 mL of ethyl acetate, wash twice with 30 mL of water, and distill off the solvent. Purify the resulting product by column chromatography, eluent hexane : ethyl acetate (2:3). Yield: 0.63 g (55%).

BCD-BTK-117-5. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix under nitrogen in the specifïed order: 10 mL of DMF, 2.44 g (0.01 mol) of BCD-BTK-117-6, and 2.5 g (0.011 mol) of N-iodosuccinimide. Stir the mixture at 60 °C for 5 hours. When the reaction is complété, pour the mixture into 100 mL of water; filter the resulting precipitate, wash twice with 20 mL of water, and dry under vacuum at 40 °C. Yield: 3 g (82%).

BCD-BTK-117-4. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix under nitrogen in the specifïed order: 40 mL of 2-propanol, 2 g (0.0054 mol) of BCD-BTK-117-5, and 0.756 g (0.0135 mol) of NaOH. Stir the mixture at the boiling température. When the reaction is complété, acidify the mixture to pH 7-8 with IM hydrochloric acid. Extract the resulting solution five times with 30 mL of ethyl acetate, wash the organic extract twice with 30 mL of water, and distill off the solvent. Purify the resulting product by column chromatography, eluent hexane : ethyl acetate (1:1). Yield: 0.96 g (64%).

117

BCD-BTK-117-3. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix under nitrogen in the specified order: 10 mL of dry THF, 0.4 g (0.00146 mol) of BCD-BTK-117-4, 0.78 g (0.003 mol) of triphenylphosphine, and 0.6 g (0.003 mol) of (S)-3-hydroxy-l-(tertbutoxycarbonyl)piperidine, and 0.25 mL (0.0015 mol) of diisopropylethylamine. Stir under nitrogen for 15 minutes. Cool the reaction mass to 0 °C; add, dropwise, 0.6 g (0.003 mol) of diisopropyl azodicarboxylate, maintaining the température. After that, stir the reaction mass at 0 °C for 4 hours. When the reaction is complété, distill off the solvent; purify the resulting product by column chromatography, eluent hexane : ethyl acetate (from 9:1 to 7:3). Yield: 0.34 g (50%).

Example 4. Methods for synthesis of intermediates Xl(a-h), X2(a-i), X3(am).

1)

X1a

XIa. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix in the specified order: 200 mL of DFM, 24 g (0.1 mol) of pdibromobenzene, 9.675 g (0.1 mol) 4-hydroxypyridine, 66.3 g (0.2 mol) of césium carbonate, and 1.94 g (0.01 mol) of copper(I) iodide. Stir the mixture at 120 °C under nitrogen for 6 hours; use the TLC method to ensure the completeness of the reaction. Distill off most of the solvent, add 200 mL of ethyl acetate, and filter the suspension through celite. Concentrate the fïltrate. Purify the resulting product by column chromatography, eluent ethyl acetate: methanol (9:1). Yield: 11.74g (61%). Similarly synthesize the compounds Xl(b-h). Their structures are presented in the table below.

Xlb

Xlc

Xld

Xle

Xlf

Xlg

Xlh

118

X2a. In a round-bottom flask, equipped with a stirrer, thermometer and 5 reflux condenser, mix in the specified order: 10 mL of dry DFM, 1.0 g (0.0048 mol) of 4-iodopyridine, 1.26 g (0.00725 mol) of p-bromophenol, 0.093 g (0.00048 mol) of copper(I) iodide, 3.17 g (0.00965 mol) of césium carbonate, and 0.89 g (0.0048 mol) of 2,2,6,6-tetramethyl-3,5-heptanedione. Heat the mixture to 60 °C, and allow to stand at this température for 8 hours. Filter the reaction mass 10 through celite, dilute the filtrate with water, and extract the product with ethyl acetate. Wash the combined extract with 50 mL of NaCl solution and 50 mL of water, dry with sodium sulfate, and distill off. Purify the resulting product by column chromatography, eluent ethyl acetate : hexane (2:8). Yield: 0.7 g (58%).

3)

X2b-2 X2b-1 X2b X2e

X2b-2. In a round-bottom flask, mix 1.8 g (0.015 mol) of 3-hydroxypridine-2carbonitrile, 30 ml of DMF, 9.77 g (0.30 mol) of Cs₂CO₃ and 2.54 g (0.018 mol) of l-fluoro-4-nitrobenzene. Heat the reaction mass to 140°C and stir at this température for 4 h; use the TLC method to ensure the completeness of the

119 reaction. Distill off the solvent under redused pressure and add 40 mL of water. Filter the precipitate, wash with 15 ml of water and 15 ml of hexane. Yield: 2.86 g (79%).

X2b-1. In a round-bottom flask, mix 3 g (0.012 mol) of the compound 3, 45 ml of éthanol, 5 ml of water, 0.32 g (0.006 mol) of NH₄C1, 3.35 g (0.06 mol) of Fe. Heat the reaction mass to 120°C and stir at this température for 2 h; use the TLC method to ensure the completeness of the reaction. Distill off the solvent under redused pressure and add 30 mL of water. Filter the precipitate, wash with 10 ml of water. Yield: 2.21 g (87%).

X2b. Add 7ml of 33% solution of HBr in acetic acid to a solution of 2.7 g (0.013 mol) of 3-(4-aminophenoxy)pyridine-2-carbonitrile in 50 ml of water, cooled to 0°C. Stir the reaction mass at this température for 1 h. Add to the reaction mass 1 g (0.014 mol) of NaNO₂ dissolved in 10 ml of water and mix for 2 h. Add 1.86 g (0.013 mol) of preliminary cruched CuBr and a solution of 26.8 g (0.26 mol) of NaBr in 20 ml of water; stir the mixture for another hour, then heat to room température; use the TLC method to ensure the completeness of the reaction. Add 25 ml of saturated solution of NaHCO₃ to pH 8, extract the water layer with 20 ml of ethyl acetate thrice. Dry the combined organic layers with Na₂SO₄, distill off the solvent under reduced pressure. Purify the resulting product (3-(4-bromophenoxy)pyridine-2-carbonitrile) by column chromatography, eluent ethyl acetate : hexane (1:9). Yield: 2.65 g (74%).

X2e. Add 2.21 g (0.016 mol) of K₂CO₃ to a solution of 1.10 g (0.004 mol) of 3-(4-bromophenoxy)pyridine-2-carbonitrile in 10 ml of DMSO, stir the reaction mass for 20 min. Add 0.27 g (0.008 mol) of H₂O₂ and stir for 2 h; use the TLC method to ensure the completeness of the reaction. Add 40 ml of water, mix the reaction mass for 20 min, filtrate the resulting precipitate, wash with 10 ml of water. Yield: 0.72 g (62%).

4)

120

X2c-3. In a round-bottom flask, mix 4.2 g (0.02 mol) of methyl 5hydroxypyridine-3-carboxylate, 50 ml of DMF, 13 g (0.04 mol) of Cs₂CO₃ and 4.44 g (0.022 mol) of 1 -bromo-4-nitrobenzene. Heat the reaction mass to 140°C and stir at this température for 4 h; use the TLC method to ensure the completeness of the reaction. Distill off the solvent under the reduced pressure, add 50 ml of water. Filter the resulting precipitate, wash with 15 ml of water and 15 ml of hexane. Yield: 4.66 g (85%).

X2c-2. In a round-bottom flask, mix 4.66 g (0.017 mol) of the compound 3, 45 ml of éthanol, 5 ml of water, 0.45 g (0.008 mol) of NH₄C1, 4.75 g (0.085 mol) of Fe. Heat the reaction mass to 120°C and stir at this température for 2 h; use the TLC method to ensure the completeness of the reaction. Distill off the solvent under the reduced pressure, add 30 ml of water. Filter the resulting precipitate, wash with 10 ml of water. Yield: 3.07 g (74%).

X2c-1. Add 7 ml of 33% solution of HBr in acetic acid to 3.18 g (0.013 mol) of methyl 5-(4-aminophenoxy)pyridine-3-carboxylate in 50 ml of water. Stir the reaction mass at this température for 1 h. Then add 1 g (0.014 mol) of NaNO₂ in 10 ml of water and stir for 2 h. Then add 1.86 g (0.013 mol) of preliminary crushed CuBr and a solution of 26.8 g (0.26 mol) of NaBr in 20 ml of water, stir the mixture for 1 h, then heat to room température; use the TLC method to ensure the completeness of the reaction. Add 25 ml of a saturated solution of NaHCO₃ to pH 8, extract the water layer with 20 ml of ethyl acetate thrice. Dry the combined organic layers with Na₂SO₄. Distill off the solvent under reduced pressure. Purify the resulting product by column chromatography, eluent ethyl acetate : hexane (1:9) Yield: 0.6 g (15%).

121

X2c. Add 5 ml of a methanol solution of NH₃ to a methanol solution of 0.2 g (0.0006 mol) of 5-methyl-(4-bromophenoxy)pyridine-3-carboxylate). Stir the reaction mass at room température for 24 h; use the TLC method to ensure the completeness of the reaction. Distill off the extra solvent under reduced pressure. Yield: 0.16 g (91%).

5)

X2d-3 X2d-2 X2d-1

X2d X2f

X2d-3. Add 10.6 g (0.10 mol) of Na₂CO₃ and 12.7 g (0.05 mol) of I₂ to a solution of 4.76 g (0.05 mol) pyridin-4-ol in 200 ml of water. Stir the reaction mass at room température for 12 h; use the TLC method to ensure the completeness of the reaction. Add 12 ml of HCl to pH=5, Na₂S₂O₃ till color removal. Fïltrate the resulting precipitate, mix the precipitate with 200 ml of boiling éthanol and fïltrate one more time. Concentrate the fïltrate under reduced pressure, re-crystallize residue from methanol. Yield: 3.4 g (31%).

X2d-2. Add 1.41 g (0.012 mol) of Zn(CN)₂ and 1.15 g (0.001 mol) of Pd(PPh₃)₄ to a solution of 2.21 g (0.01 mol) of 3-iodopyridin-4-ol in 20 ml of DMF. Heat the reaction mass to 100°C and stir at this température for 2 h; use the TLC method to ensure the completeness of the reaction. Fïltrate the resulting precipitate and wash it with DMF. Concentrate the fïltrate under reduced pressure. Purify the resulting product by column chromatography, eluent ethyl acetate : methanol (9:1) Yield: 1.1g (92%).

X2d-1. Add 2.46 g (0.016 mol) of POC1₃ to 0.24 g (0.002 mol) of 4hydroxypyridine-3-carbonitrile. Stir the reaction mass for 1 h at room température, heat to 70°C and mix for 1.5 h; use the TLC method to ensure the completeness of the reaction. Pour the mixture into ice, extract with 10 ml of ethyl acetate twice. Wash the combined organic extracts with 10 ml of NaHCO₃ and 10 ml of water,

122 dry with Na₂SO₄, distill off the solvent under reduced pressure. Yield: 0.25 g (90%).

X2d. Add 0.11 g (0.00077 mol) of K₂CO₃ and 0.12 g (0.0007 mol) of 4bromophenol to a solution of 0.1 g (0.0007 mol) of 4-chloropyridine-3-carbonitrile in 1 ml of DMF. Stir the reaction mass under reactionless gas at 70°C for 2.5 h; use the TLC method to ensure the completeness of the reaction. Add 20 ml of water, stir the reaction mass while colling down in an ice bath for 10 min. Filter the precipitate. Yield: 0.155 g (78%).

X2f. Add 2.21 g (0.016 mol) K₂CO₃ to a solution of 1.10 g (0.004 mol) of 4(4-bromophenoxy)pyridine-3-carbonitrile in 10 ml of DMSO. Add 0.27 g (0.008 mol) of H₂O₂ and stir for 2 h; use the TLC method to ensure the completeness of the reaction. Add 40 ml of water, stir the reaction mass for 20 minutes, filter the precipitate, wash with 10 ml of water. Yield: 0.96 g (82%).

X3a. In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix in the specified order: 20 mL of dichloromethane, 2.1 g (0.0106 mol) of p-bromobenzoic acid, and 1 g (0.0106 mol) of oxalyl chloride. Boil the mixture for 1 hour, distill off the solvent, and dissolve the resulting solid residue in 10 mL of dichloromethane. With constant stirring, add the resulting solution at 5 °C to a pre-prepared solution of 2-aminopyridine in 10 mL of pyridine. Stir the mixture for 1 hour, distill off the solvent, and treat the residue with water. Filter the resulting precipitate, wash with 20 mL of water, and allow to dry in air. Yield: 2.3 - 2.5 g (80-86%).Similarly synthesize the compounds X3(bo) shown in the table below:

X3b

X3c

X3d

X3e

X3f

X3g

X3h

123

Br	Br y	Br	Br	Br	Br	Br
ΝγΝ	7	ΝγΝ	δ	δ	L ü	ΝγΝ
HN^O i^N	HN^O 7n L	HN <3 L Ij	HN^O L il	HN^O L if	HN^O 7 n	hnSd
L IJ	F	F	^^F		^^F	^^F
X3i	X3j	X3k	X31	X3m	X3n	X3o
Br	Br	Br	Br	Br	Br	Br
c y o CO U_	7=\ O 4- '—A LL y u_	O 5=/	ΝγΝ HN^O Y	=\ o 1 V. LL V LL	ΝγΝ HN^O l FF	Π Cû o 5=,

Example 5. Methods for synthesis of compounds BCD-BTK-4, BCD-BTK6, BCD-BTK-9, BCD-BTK-13, BCD-BTK-18, BCD-BTK-24, BCD-BTK-30, BCD-BTK-35, BCD-BTK-36, BCD-BTK-38, BCD-BTK-54, BCD-BTK-56, BCD-BTK-74, BCD-BTK-76, BCD-BTK-86, BCD-BTK-88, BCD-BTK-98, BCD-BTK-100, BCD-BTK-104, BCD-BTK-105, BCD-BTK-107, BCD-BTK10 117, BCD-BTK-118, BCD-BTK-119, BCD-BTK-120, BCD-BTK-121, BCDBTK-122, BCD-BTK-127, BCD-BTK-130, BCD-BTK-131, BCD-BTK-136. BCD-BTK-204, BCD-BTK-205, BCD-BTK-206, BCD-BTK-207, BCD-BTK208.

124

BCD-BTK-4-Boc BCD-BTK-4-H

BCD-BTK-4-Boc. In a three-neck flask, equipped with a stirrer and thermometer, mix under nitrogen in the specified order: 20 mL of 1,4-dioxane, 0.5 g (0.002 mol) of compound Xla, 0.8 g (0.003 mol) of bis(pinacolato)diboron, 0.05 g of XPhos (2-dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl), 0.588 g (0.006 mol) of dry potassium acetate, 0.07 g of palladium(II) acetate. Pass nitrogen through the mixture while stirring. Stir the reaction mass under nitrogen at 90 °C for 3 hours. When the reaction is complété, cool the mixture to 40 °C; add a solution of 1.7 g (0.016 mol) of sodium carbonate in 10 mL of water, 0.231 g (0.0002 mol) of tetrakis(triphenylphosphine)palladium, and 0.2 g of BCD-BTK-43. Stir the mixture at 80 °C for 5 hours. When the reaction is complété, allow the mixture to cool, filter through celite; wash the celite with 15 mL of ethyl acetate and 10 mL of water. Concentrate the filtrate under vacuum in a rotary evaporator. To the resulting residue add 40 mL of water, and extract the product with 30 mL of ethyl acetate five times. Wash the combined organic extract with water and NaCl solution, dry with sodium sulfate, and distill off the solvent. Purify the resulting product by column chromatography, eluent ethyl acetate : methanol (from 99:1 to 9:1). 0.1 g of BCD-BTK-4-Boc is obtained (yield 50%).

BCD-BTK-4-H. In a three-neck flask, equipped with a stirrer and thermometer, mix under nitrogen in the specified order: 10 mL of 1,4-dioxane, 0.1 g of BCD-BTK-4-Boc obtained from the previous step, and 3 mL of 4M hydrogen chloride in 1,4-dioxane. Allow the mixture to stand at room température.

125

After 6 hours, distill off the solvent. 0.15 g of light yellow powder is obtained. Take it to the next step without additional purification.

BCD-BTK-4. In a three-neck flask, equipped with a stirrer and thermometer, mix under an inert gas in the specified order: 15 mL of dry DMF, 0.15 g of BCDBTK-4-H obtained from the previous step, and 0.3 mL of diisopropylethylamine. Cool the mixture to -30 °C and add at this température 0.03 g of acryloyl chloride. Allow the reaction mass to stand at room température. After 1 hour, concentrate the solvent under vacuum using a rotary evaporator; add 20 mL of ethyl acetate and 60 mL of water. Separate ethyl acetate from the aqueous layer, and wash the aqueous layer with ethyl acetate one more time. Wash the combined organic extract with saturated NaCl solution, dry with sodium sulfate, and distill off the solvent. Purify the resulting product by column chromatography, eluent hexane : ethyl acetate (from 3:7 to 0:100). 0.07 g of BCD-BTK-4 is obtained (yield 45%). Final purification is performed using Akta Explorer 100 with an Inertsil ODS-3 column, R - 10 pm, L*d - 250*30 mm.

The synthesis of compounds BCD-BTK-6, BCD-BTK-9, BCD-BTK-13, BCD-BTK-18, BCD-BTK-24, BCD-BTK-30, BCD-BTK-35, BCD-BTK-36, BCD-BTK-38, BCD-BTK-54, BCD-BTK-56, BCD-BTK-74, BCD-BTK-76, BCD-BTK-86, BCD-BTK-88, BCD-BTK-98, BCD-BTK-100, BCD-BTK-104, BCD-BTK-105, BCD-BTK-107, BCD-BTK-117, BCD-BTK-118, BCD-BTK119, BCD-BTK-120, BCD-BTK-121, BCD-BTK-122, BCD-BTK-127, BCDBTK-130, BCD-BTK-131, BCD-BTK-136 BCD-BTK-204, BCD-BTK-205, BCD-BTK-206, BCD-BTK-207, BCD-BTK-208 is performed in the same manner from the corresponding compounds BCD-BTK-4-3, BCD-BTK-6-3, BCD-BTK-9-3, BCD-BTK-13-3, BCD-BTK-18-3, BCD-BTK-24-3, BCD-BTK30-3, BCD-BTK-35-3, BCD-BTK-104-3, BCD-BTK-211-3 , BCD-BTK-239-3, BCD-BTK-241-3 and conpounds Xla, Xlb, Xlc, Xld, Xle, Xlf, Xlg, Xlh.

Example 6. Methods for synthesis of compounds BCD-BTK-123, BCDBTK-123, BCD-BTK-124, BCD-BTK-125, BCD-BTK-129, BCD-BTK-133,

126

BCD-BTK-134, BCD-BTK-135, BCD-BTK-137, BCD-BTK-138, BCD-BTK139, BCD-BTK-140, BCD-BTK-202, BCD-BTK-203, BCD-BTK-211, BCDBTK-213, BCD-BTK-216, BCD-BTK-217, BCD-BTK-218, BCD-BTK-220,

BCD-BTK-222, BCD-BTK-230, BCD-BTK-232, BCD-BTK-236, BCD-BTK239, BCD-BTK-241, BCD-BTK-246, BCD-BTK-255, BCD-BTK-259, BCDBTK-261, BCD-BTK-263, BCD-BTK-264, BCD-BTK-265, BCD-BTK-266, BCD-BTK-270, BCD-BTK-272, BCD-BTK-274, BCD-BTK-281, BCD-BTK282.

BCD-BTK-104-3 + X2a

Step 1

BCD-BTK-123

BCD-BTK-104-Boc BCD-BTK-104-H

BCD-BTK-104-Boc. In a three-neck flask, equipped with a stirrer and thermometer, mix under nitrogen in the specified order: 10 mL of 1,4-dioxane,

0.3 g (0.0012 mol) of compound X2a, 0.3 g (0.00132 mol) of bis(pinacolato)diboron, 0.02 g of XPhos, 0.23 g (0.0024 mol) of dry potassium acetate, 0.03 g of palladium(II) acetate. Stir the reaction mass under nitrogen at 90 °C for 2 hours. When the reaction is complété, cool the mixture to 20 °C; add a solution of 0.3 g (0.003 mol) of sodium carbonate in 10 mL of water, 0.03 g of tetrakis(triphenylphosphine)palladium, and 0.48 g (0.00108 mol) of BCD-BTK104-3. Stir the mixture at 80 °C for 5 hours. When the reaction is complété, allow the mixture to cool, filter through celite; wash the celite with 10 mL of ethyl acetate and 30 mL of water. Concentrate the filtrate under vacuum in a rotary evaporator. To the resulting residue add 60 mL of water, and extract the product with 20 mL of ethyl acetate five times. Wash the combined organic extract with water and NaCl solution, dry with sodium sulfate, and distill off the solvent. Purify

127 the resulting product by column chromatography, eluent ethyl acetate : methanol (from 99:1 to 8:2). 0.3 g of BCD-BTK-104-Boc is obtained (yield 55%).

BCD-BTK-104-H. In a three-neck flask, equipped with a stirrer and thermometer, mix under nitrogen in the specified order: 15 mL of 1,4-dioxane, 0.3 g of BCD-BTK-104-Boc obtained from the previous step, and 6 mL of 4M hydrogen chloride in 1,4-dioxane. Allow the mixture to stand at room température. After 8 hours, distill off the solvent. 0.4 g of BCD-BTK-104-H is obtained. Take it to the next step without additional purification.

BCD-BTK-123. In a three-neck flask, equipped with a stirrer and thermometer, mix under an inert gas in the specified order: 20 mL of dry dichloromethane, 0.4 g of BCD-BTK-104-H obtained from the previous step, and 0.5 mL of diisopropylethylamine. Cool the mixture to -30 °C and add at this température 0.09 g of acryloyl chloride. Allow the reaction mass to stand at room température. After 1.5 hour, concentrate the solvent under vacuum in a rotary evaporator; add 20 mL of ethyl acetate and 60 mL of water. Separate ethyl acetate from the aqueous layer, and wash the aqueous layer with ethyl acetate one more time. Wash the combined organic extract with saturated NaCl solution, dry with sodium sulfate, and distill off the solvent. Purify the resulting product by column chromatography, eluent hexane : ethyl acetate (from 3:7 to 1:9). 0.27 g of the product is obtained (yield 71%). Final purification is performed using Akta Explorer 100 with the Inertsil ODS-3 column, R - 10 pm, L*d - 250*30 mm.

The synthesis of compounds BCD-BTK-123, BCD-BTK-124, BCD-BTK125, BCD-BTK-129, BCD-BTK-133, BCD-BTK-134, BCD-BTK-135, BCDBTK-137, BCD-BTK-138, BCD-BTK-139, BCD-BTK-140, BCD-BTK-202, BCD-BTK-203, BCD-BTK-211, BCD-BTK-213, BCD-BTK-216, BCD-BTK217, BCD-BTK-218, BCD-BTK-220, BCD-BTK-222, BCD-BTK-230, BCDBTK-232, BCD-BTK-236, BCD-BTK-239, BCD-BTK-241, BCD-BTK-246, BCD-BTK-255, BCD-BTK-259, BCD-BTK-261, BCD-BTK-263, BCD-BTK264, BCD-BTK-265, BCD-BTK-266, BCD-BTK-270, BCD-BTK-272, BCDBTK-274, BCD-BTK-281, BCD-BTK-282 is performed in the same manner from

128 the corresponding compounds BCD-BTK-4-3, BCD-BTK-9-3, BCD-BTK-30-3, BCD-BTK-104-3, BCD-BTK-211-3, BCD-BTK-239-3, BCD-BTK-241-3 and compounds X2a, X2b, X2c, X2d, X2e, X2f.

Example 7. Methods for synthesis of compounds BCD-BTK-201, BCDBTK-210, BCD-BTK-212, BCD-BTK-214, BCD-BTK-215, BCD-BTK-219, BCD-BTK-221, BCD-BTK-223, BCD-BTK-224, BCD-BTK-225, BCD-BTK226, BCD-BTK-227, BCD-BTK-228, BCD-BTK-229, BCD-BTK-231, BCDBTK-233, BCD-BTK-234, BCD-BTK-235, BCD-BTK-237, BCD-BTK-238, BCD-BTK-240, BCD-BTK-242, BCD-BTK-243, BCD-BTK-244, BCD-BTK245, BCD-BTK-247, BCD-BTK-248, BCD-BTK-249, BCD-BTK-250, BCDBTK-251, BCD-BTK-252, BCD-BTK-253, BCD-BTK-254, BCD-BTK-258, BCD-BTK-260, BCD-BTK-262, BCD-BTK-267, BCD-BTK-268, BCD-BTK269, BCD-BTK-271, BCD-BTK-273, BCD-BTK-275, BCD-BTK-276, BCDBTK-277, BCD-BTK-278, BCD-BTK-279, BCD-BTK-280, BCD-BTK-283, BCD-BTK-284, BCD-BTK-285, BCD-BTK-286, BCD-BTK-287, BCD-BTK288, BCD-BTK-289, BCD-BTK-290, BCD-BTK-291, BCD-BTK-292, BCDBTK-293, BCD-BTK-295.

Step 1

BCD-BTK-30-3 + X3a----

BCD-BTK-201

BCD-BTK-289

BCD-BTK-30-Boc BCD-BTK-30-H

129

BCD-BTK-30-Boc. In a three-neck flask, equipped with a stirrer and thermometer, mix under nitrogen in the specifïed order: 10 mL of 1,4-dioxane, 0.2 g (0.0007 mol) of compound X3a, 0.2 g (0.00079 mol) of bis(pinacolato)diboron, 0.015 g of XPhos, 0.1 g (0.0008 mol) of dry potassium acetate, 0.02 g of palladium(II) acetate. Stir the reaction mass under nitrogen at 90 °C for 2 hours. When the reaction is complété, cool the mixture to 20 °C; add a solution of 0.17 g (0.00165 mol) of sodium carbonate in 10 mL of water, 0.04 g of tetrakis(triphenylphosphine)palladium, and 0.29 g (0.00063 mol) of BCD-BTK30-3. Stir the mixture at 70 °C for 8 hours. When the reaction is complété, allow the mixture to cool, filter through celite; wash the celite with 20 mL of ethyl acetate and 50 mL of water. Concentrate the filtrate under vacuum in a rotary evaporator. To the resulting residue add 50 mL of water and extract the product with 20 mL of ethyl acetate three times. Wash the combined organic extract with water and NaCl solution, dry with sodium sulfate, and distill off the solvent. Purify the resulting product by column chromatography, eluent ethyl acetate : methanol (from 100:0 to 95:5). 0.16 g of BCD-BTK-30-Boc is obtained (yield 47%).

BCD-BTK-30-H. In a three-neck flask, equipped with a stirrer and thermometer, mix under nitrogen in the specifïed order: 8 mL of 1,4-dioxane, 0.16 g of the compound obtained from the previous step, and 3 mL of 4M hydrogen chloride in 1,4-dioxane. Allow the mixture to stand at room température. After 4 hours, distill off the solvent. 0.23 g of BCD-BTK-30-H is obtained. Take it to the next step without additional purification.

BCD-BTK-201. In a three-neck flask, equipped with a stirrer and thermometer, mix under an inert gas in the specifïed order: 20 mL of dry dichloromethane, 0.23 g of BCD-BTK-30-H obtained from the previous step, and 0.2 mL of diisopropylethylamine. Cool the mixture to -30 °C and add at this température 0.03 g of acryloyl chloride. Allow the reaction mass to stand at room température. After 30 minutes, concentrate the solvent under vacuum using a rotary evaporator; add 10 mL of ethyl acetate and 30 mL of water. Separate ethyl acetate from the aqueous layer, and extract the product from the aqueous layer with

130 ethyl acetate one more time. Wash the combined organic extract with saturated NaCl solution, dry with sodium sulfate, and distill off the solvent. Purify the resulting product by column chromatography, eluent hexane : ethyl acetate (from 3:7 to 1:9). 0.074 g of the product is obtained (yield 34%). Final purification is performed using Akta Explorer 100 with the Inertsil ODS-3 column, R - 10 μm, L*d - 250*30 mm.

BCD-BTK-289. Add 0.2 g (0.00052 mol) of HATU and 0.094 g (0.0012 mol) of diisopropylethylamine to a suspension of 0.032 g (0.00038 mol) of tetrolic acid in dry methylene chloride (20 ml). Cool the reaction mass to 0°C and add a solution of 0.164 g (0.00038 mol) of amine BCD-BTK-30-H in dry methylene chloride if the solubility allows in such a way that the température of the mixture would not exceed 5°C. Afterwards, allow the reaction mass stand at room température for 1 h, then distill off the solvent under vacuum, add 50 ml of ethyl acetate and 50 ml of water. Separate ethyl acetate from the water layer, wash the water layer with etyl acetate one more time and combine the ethyl acetate layers. Then wash them with 10% solution of citric acid and a solution of NaCl. Dry ethyl acetate layer with sodium sulphate and distill off the solvent. Yield 0.08 g (47%). Final purification is performed using Akta Explorer 100 with the Inertsil ODS-3 column, R - 10 pm, L*d - 250*30 mm.

Compounds BCD-BTK-210, BCD-BTK-212, BCD-BTK-214, BCD-BTK215, BCD-BTK-219, BCD-BTK-221, BCD-BTK-223, BCD-BTK-224, BCDBTK-225, BCD-BTK-226, BCD-BTK-227, BCD-BTK-228, BCD-BTK-229, BCD-BTK-231, BCD-BTK-233, BCD-BTK-234, BCD-BTK-235, BCD-BTK237, BCD-BTK-238, BCD-BTK-240, BCD-BTK-242, BCD-BTK-243, BCDBTK-244, BCD-BTK-245, BCD-BTK-247, BCD-BTK-248, BCD-BTK-249, BCD-BTK-250, BCD-BTK-251, BCD-BTK-252, BCD-BTK-253, BCD-BTK254, BCD-BTK-258, BCD-BTK-260, BCD-BTK-262, BCD-BTK-267, BCDBTK-268, BCD-BTK-269, BCD-BTK-271, BCD-BTK-273, BCD-BTK-275, BCD-BTK-276, BCD-BTK-277, BCD-BTK-278, BCD-BTK-279, BCD-BTK280, BCD-BTK-283, BCD-BTK-284, BCD-BTK-285, BCD-BTK-286, BCD131

BTK-287, BCD-BTK-288, BCD-BTK-290, BCD-BTK-291, BCD-BTK-292, BCD-BTK-293, BCD-BTK-295 are synthesized similarly from the corresponding compounds BCD-BTK-4-3, BCD-BTK-9-3, BCD-BTK-30-3, BCD-BTK-104-3, BCD-BTK-211-3, BCD-BTK-239-3, BCD-BTK-241-3 and compounds X3a, 5 X3b, X3c, X3d, X3e, X3f, X3g, X3h, X3i, X3j, X3k, X31, X3m, X3n, X3o.

Example 8. Analysis of the obtained compounds.

To confirm the purity and structure of the obtained compounds, liquid chromatography-mass spectrometry (LC/MS) and ’H NMR were used (Table 1).

Equipment characteristics:

Liquid chromatography-mass spectrometry

Name	Manufacturer, country
Agilent Triple Quad LC/MS System	Agilent, USA
Agilent 1200 Autosampler
Agilent 1200 Column Thermostat
Agilent 1200 Degasser
Agilent 1200 Autosampler Thermostat
Agilent 6410 QQQ MS Detector
Agilent 1200 UV-detector
Agilent 1200 Pump

NMR Spectrometer

Name	Manufacturer, country	Model, main characteristics
NMR Spectrometer	Germany	AVANCE III, 400 MHz

132

Table 1. Analytical characteristics for example compounds

Compound	ESI-MS, [M+H]+	NMR Ή (DMSO-d6), δ, ppm
BCD-BTK-4	466,2	8.33 (s, 1H), 8.07 (d, J = 7.8 Hz, 2H), 7.89 - 7.73 (m, 4H), 6.82 (dd, J = 24.1, 13.9 Hz, 3H), 6.29 (d, J = 7.8 Hz, 2H), 6.10 (dd, J = 30.5, 16.4 Hz, 1H), 5.66 (dd, J = 49.4, 10.0 Hz, 1H), 4.91 (d, J = 33.2 Hz, 1H), 4.63 (d, J = 11.1 Hz, 1H), 4.41-4.21 (m, 1H), 4.12-4.02 (m, 1H), 3.73 (d, J = 11.4 Hz, 1H), 3.47 (s, 1H), 2.99 (s, 1H), 2.35-2.08 (m, 2H), 1.96 (d, J = 31.8 Hz, 1H), 1.57 (s, 1H)
BCD-BTK-6	484,2	8.04 (t, J = 18.8 Hz, 4H), 7.76 (dd, J = 26.5, 8.3 Hz, 5H), 7.39 (s, 1H), 6.82 (dd, J = 16.5, 10.6 Hz, 1H), 6.29 (d, J = 7.7 Hz, 2H), 6.10 (dd, J = 34.5, 19.6 Hz, 2H), 5.64 (dd, J = 44.7, 10.1 Hz, 1H), 5.07 (s, 1H), 4.56 (s, 1H), 4.39 - 4.24 (m, 1H), 4.04 (s, 1H), 3.51 (d, J = 11.8 Hz, 1H), 2.82 (s, 1H), 2.22 (dd, J = 70.7, 23.5 Hz, 3H), 1.93 (d, J = 13.4 Hz, 1H), 1.50 (s, 1H)
BCD-BTK-9	475,0	8.08 (d, J = 7.7 Hz, 2H), 7.87 - 7.65 (m, 5H), 6.93 6.66 (m, 1H), 6.30 (d, J = 7.7 Hz, 2H), 6.21 - 5.97 (m, 3H), 5.78 - 5.54 (m, 2H), 5.20 (s, 1H), 4.72 (d, J = 10.0 Hz, 1H), 4.34 (d, J = 11.3 Hz, 1H), 4.193.94 (m, 1H), 3.76-3.53 (m, 1H), 2.92 (s, J = 88.1 Hz, 1H), 2.26 (s, 2H), 1.96 (dd, J = 22.5, 8.8 Hz, 1H), 1.62 (s, 1H)
BCD-BTK13	476,1	10.48 (s, 1H), 8.39 (s, 1H), 8.18 - 8.02 (m, 2H), 7.85 (d, J = 8.1 Hz, 2H), 7.73 - 7.62 (m, 2H), 6.92 - 6.54 (m, 1H), 6.36 - 6.22 (m, 2H), 6.10 (dd, J = 35.2, 16.7 Hz, 1H), 5.64 (dd, J = 61.5, 10.5 Hz, 1H), 4.88 (s, 1H), 4.61 (d, J = 12.5 Hz, 1H), 4.20 (s, 1H), 4.09 (d, J = 13.7 Hz, 1H), 3.75 (t, J= 11.4 Hz, 1H), 3.12 (d, J = 11.3 Hz, 1H), 2.40-2.14 (m, 2H), 1.99 (d, J= 13.2 Hz, 1H), 1.65 (s, 1H)
BCD-BTK18	484,3	9.60 (s, 1H), 8.25 (s, 1H), 8.12 - 8.05 (m, 3H), 8.02 (d, J= 8.3 Hz, 3H), 7.80 (d, J= 39.7 Hz, 1H), 7.74 7.67 (m, 2H), 7.39 (d, J= 22 Hz, 1H), 7.08 (d, J= 22 Hz, 1H), 6.80 (dd, J= 16.8, 10.9 Hz, 1H), 6.33 6.25 (m, 2H), 6.09 (dd, J= 34.7, 16.6 Hz, 1H), 5.64 (dd, J= 56.9, 10.4 Hz, 1H), 4.81 (s, 1H), 4.65 - 3.99 (m, 2H), 3.60 (t, J= 11.5 Hz, 1H), 3.25 - 2.83 (m, 1H), 2.37 - 1.88 (m, 2H), 1.48 (s, 1H)

133

Compound	ESI-MS, [M+H]+	NMR XH (DMSO-d6), δ, ppm
BCD-BTK- 24	469,4	9.50 (s, 1H), 8.55 (s, 1H), 8.42 (s, 1H), 8.27 - 8.18 (m, 2H), 8.12 - 8.04 (m, 2H), 7.96 (d, J= 35.8 Hz, 1H), 7.78 - 7.71 (m, 2H), 6.93 - 6.73 (m, 1H), 6.32 6.25 (m, 2H), 6.10 (dd, J= 32.1, 16.7 Hz, 1H), 5.64 (dd, J= 59.2, 10.5 Hz, 1H), 4.97 (s, 1H), 4.65 - 3.98 (m, 2H), 3.75 - 3.39 (m, 1H), 2.97 (t, J= 12.2 Hz, 1H), 2.41 - 2.09 (m, 2H), 2.04 - 1.93 (m, 1H), 1.53 (s, 1H)
BCD-BTK- 30	460,1	9.40 (s, 1H), 8.50 (d, J = 2.1 Hz, 1H), 8.26 - 8.16 (m, 2H), 8.13 - 8.04 (m, 2H), 7.74 (d, J= 8.6 Hz, 2H), 6.95 - 6.71 (m, 1H), 6.35 - 6.25 (m, 2H), 6.12 (dd, J - 24.6, 16.6 Hz, 1H), 5.66 (dd, J = 53.2, 10.5 Hz, 1H), 5.28 (d, J= 22.4 Hz, 1H), 4.56 (dd, J= 123.2, 13.0 Hz, 1H), 4.19 (dd, J= 82.3, 13.4 Hz, 1H), 3.59 (dt, J= 130.4, 11.4 Hz, 1 H), 3.04 (t, J = 12.7 Hz, 1H), 2.44 - 2.26 (m, 2H), 2.01 (d, J= 13.4 Hz, 1H), 1.66 (s, 1H)
BCD-BTK- 35	493,2	8.52 (d, J= 9.3 Hz, 1H), 8.13 (dd, J= 6.6, 3.8 Hz, 4H), 7.98 - 7.76 (m, 5H), 6.69 (ddd, J= 70.9, 16.6, 10.5 Hz, 1H), 6.39 - 6.23 (m, 2H), 6.06 (dd, J= 34.2, 16.6 Hz, 1H), 5.64 (dd, J= 32.8, 10.5 Hz, 1H), 4.69 - 4.20 (m, 3H), 4.14 - 3.75 (m, 1H), 3.51 - 2.88 (m, 1H), 2.46-2.29 (m, 1H), 2.20 (s, 1H), 1.97-1.82 (m, 1H), 1.47 (s, 1H)
BCD-BTK- 36	468,3	9.04 (s, 2H), 8.98 - 8.88 (m, 2H), 8.37 (s, 1H), 7.31 (s, 2H), 6.82 (dd, J= 2^2, 14.3 Hz, 1H), 6.38 (d, J= 7.9 Hz, 2H), 6.10 (dd, J= 26.5, 16.5 Hz, 1H), 5.66 (dd, J= 46.7, 10.5 Hz, 1H), 4.94 (d, J= 35.4 Hz, 1H), 4.49 (dd, J= 108.4, 13.1 Hz, 1H), 4.30 - 3.99 (m, 1H), 3.76 - 3.44 (m, 1H), 3.03 (s, 1H), 2.32 2.10 (m, 2H), 1.98 (s, 1H), 1.56 (s, 1H)
BCD-BTK- 38	467,3	8.72 (d, J= 22 Hz, 1H), 8.63 - 8.52 (m, 2H), 8.34 (s, 1H), 8.22 (dd, J- 8.6, 2.3 Hz, 1H), 7.98 (d, J= 8.5 Hz, 1H), 7.16 (s, 2H), 6.95 - 6.76 (m, 1H), 6.41 6.29 (m, 2H), 6.09 (td, J= 18.3, 17.6, 8.6 Hz, 1H), 5.66 (dd, J= 48.7, 10.5 Hz, 1H), 4.92 (d, J= 34.6 Hz, 1H), 4.48 (dd, J = 107.8, 13.0 Hz, 1H), 4.15 (dd, J =78.7, 13.2 Hz, 1 H), 3.62 (dt, J= 100.0, 11.4 Hz, 1H), 3.00 (d, J= 12.5 Hz, 1H), 2.28 (dq, J= 9.7, 4.8 Hz, 2H), 1.98 (s, 1H), 1.57 (s, 1H)
BCD-BTK-	462,2	9.51 (d, J= 3.2 Hz, 3H), 8.96 - 8.83 (m, 2H), 8.54 (s, 1H), 7.04 - 6.67 (m, 1H), 6.45 - 6.32 (m, 2H), 6.22 -

134

Compound	ESI-MS, [M+H]+	NMR Ή (DMSO-d6), δ, ppm
54		6.01 (m, 1H), 5.66 (dd, J= 57.4, 10.5 Hz, 1H), 5.33 (d, 7=28.0 Hz, 1H), 4.53 (dd, J= 118.6, 13.1 Hz, 1H), 4.30 - 3.97 (m, 1H), 3.66 (dt, J= 128.7, 11.3 Hz, 1H), 3.22 - 3.03 (m, 1H), 2.34 (d, J= 4.4 Hz, 2H), 2.00 (s, 1H), 1.67 (s, 1H)
BCD-BTK- 56	461,1	9.46 (s, 1H), 9.19 (d, J= 2.3 Hz, 1H), 8.72 - 8.47 (m, 4H), 8.01 (d, J = 8.7 Hz, 1H), 6.83 (dt, J= 39.5, 13.5 Hz, 1H), 6.39 - 6.25 (m, 2H), 6.21 - 6.01 (m, 1H), 5.65 (dd, J= 55.9, 10.5 Hz, 1H), 5.31 (d, J= 26.0 Hz, 1H), 4.54 (dd, J= 114.0, 12.9 Hz, 1H),4.15 (d, J = 70.2 Hz, 1H), 3.79 - 3,10 m, 1H), 3.10 (s, OH), 2.33 (s, 2H), 1.95 (d, 31.0 Hz, 1H), 1.65 (s, 1H)
BCD-BTK- 74	477,1	9.05 (s, 2H), 8.93 (d, J-7.9 Hz, 2H), 7.84 (s, 1H), 6.94 - 6.69 (m, 1H), 6.44 - 6.30 (m, 5H), 6.23 - 6.02 (m, 1H), 5.67 (dd, J= 42.5, 10.6 Hz, 1H), 5.23 (d, J = 24.7 Hz, 1H), 4.52 (dd, J = 140.7, 13.6 Hz, 1H), 4.18 (dd, 7=81.4, 14.7 Hz, 1H), 3.69 (t, 7= 11.9 Hz, 1H), 2.98 (s, 1H), 2.30 (d, 7= 26.1 Hz, 3H), 1.97 (d, 7= 13.4 Hz, 1H), 1.61 (s, 1H)
BCD-BTK- 76	476,2	8.74 (d, 7= 2.2 Hz, 1H), 8.64 - 8.51 (m, 2H), 8.24 (d, 7 = 8.5 Hz, 1H), 7.98 (d, 7= 8.5 Hz, 1H), 7.82 (s, 1H), 6.82 (ddd, J= 32.7, 17.1, 10.9 Hz, 1H), 6.40 6.26 (m, 2H), 6.25 - 6.03 (m, 3H), 5.82 - 5.55 (m, 1H), 5.22 (d, J= 22.6 Hz, 1H), 4.83 - 4.32 (m, 1H), 4.31-4.01 (m, 1H), 3.67 (t, 7= 11.8 Hz, 1H), 2.95 (t, J= 12.0 Hz, 1H), 2.30 (d, J= 26.3 Hz, 2H), 2.06 1.90 (m, 1H), 1.61 (s, 1H)
BCD-BTK- 86	486,2	9.04 (d, 7= 3.2 Hz, 2H), 8.99 - 8.89 (m, 2H), 8.10 (d, 7 = 8.7 Hz, 2H), 7.48 (d, 7 = 26.5 Hz, 1H), 6.90 6.72 (m, 3H), 6.41 - 6.32 (m, 2H), 6.09 (dd, 7= 29.1, 16.6 Hz, 1H), 5.65 (dd, J= 46.4, 10.6 Hz, 1H), 5.10 (d, 7= 8.0 Hz, 1H), 4.31 (s, 1H), 4.29 (s, 1H), 3.58 (dd, 7= 13.1, 9.8 Hz, 1H), 2.96 - 2.80 (m, 1H), 2.38 - 2.04 (m, 2H), 2.02 - 1.88 (m, 1H), 1.50 (s, 1H)
BCD-BTK- 88	485,2	8.74 (s, 1H), 8.57 (d, 7= 7.9 Hz, 2H), 8.23 (d, 7= 8.5 Hz, 1H), 8.15 - 7.93 (m, 3H), 7.39 (d, 7= 39.9 Hz, 1H), 6.83 (dd, J= 16.7, 10.5 Hz, 1H), 6.33 (t, 7= 6.2 Hz, 4H), 6.09 (dd, 7= 30.2, 16.7 Hz, 1H), 5.64 (dd, 7 = 46.0, 10.4 Hz, 1H), 5.09 (td, 7= 10.4, 5.0 Hz, 1H),

135

Compound	ESI-MS, [M+H]+	NMR Ή (DMSO-d6), δ, ppm
		4.63 - 3.97 (m, 2H), 3.55 (t, J= 11.6 Hz, 1H), 2.87 (dd, J= 24.5, 13.0 Hz, 1H), 2.29 (dd, J= 24.0, 12.3 Hz, 1H), 2.20-2.03 (m, 1H), 1.99- 1.82 (m, 1H), 1.48 (d, J= 14.3 Hz, 1H)
BCD-BTK98	471,2	9.59 (s, 1H), 9.52 (s, 2H), 8.94 - 8.87 (m, 2H), 8.59 (s, 1H), 8.45 (s, 1H), 7.98 (d, J= 33.3 Hz, 1H), 6.82 (ddd, J= 33.8, 16.5, 10.5 Hz, 1H), 6.44 - 6.33 (m, 2H), 6.10 (dd, J=31.1, 16.5 Hz, 1 H), 5.64 (dd,J= 62.6, 10.5 Hz, 1H), 5.17 - 4.97 (m, 1H), 4.64 - 4.30 (m, 1H), 4.28 - 4.00 (m, 1H), 3.78 - 3.48 (m, 1H), 3.03 (td, J= 10.8, 9.1, 5.9 Hz, 1H), 2.39 - 2.13 (m, 2H), 1.99 (tq, 8.5, 4.6 Hz, 1H), 1.61 - 1.44 (m, 1H)
BCD-BTK100	4701,2	9.56 (s, 1H), 9.21 (d, J= 2.4 Hz, 1H), 8.68 (dd, J= 8.6, 2.4 Hz, 1H), 8.63 - 8.54 (m, 3H), 8.46 (s, 1H), 8.01 (q, J= 10.8, 8.5 Hz, 2H), 6.84 (ddd, J = 37.1, 16.6, 10.5 Hz, 1H), 6.48 - 6.29 (m, 2H), 6.09 (dd, J= 31.0, 16.5 Hz, 1H), 5.64 (dd, J=63.1, 10.5 Hz, 1H), 4.99 (s, 1H), 4.74 - 3.98 (m, 2H), 3.61 (dt, J= 80.9, 11.3 Hz, 1H), 3.03 (m, 1H), 2.42 - 2.14 (m, 2H), 1.97 (dt, 13.5, 3.8 Hz, 1H), 1.51 (s, 1H)
BCD-BTK104	451,2	9.75 (s, 1H), 9.01 (s, 1H), 8.27 - 8.18 (m, 2H), 8.12 8.04 (m, 2H), 7.78 - 7.71 (m, 2H), 6.93 - 6.73 (m, 1H), 6.35 - 6.32 (m, 2H), 6.15 (t, 2H), 5.64 (dd, J= 59.2, 10.5 Hz, 1H), 5.12 (d, 1H), 4.65-3.98 (m, 2H), 3.75 - 3.39 (m, 1H), 2.97 (t, J= 12.2 Hz, 1H), 2.41-2.09 (m, 2H), 2.04- 1.93 (m, 1H), 1.53 (s, 1H)
BCD-BTK105	453,2	9.79 (s, 1H), 9.53 (s, 2H), 9.03 (s, 1H) 8.94 - 8.87 (d, 2H), 6.88 (ddd, J= 33.8, 16.5, 10.5 Hz, 1H), 6.33 6.30 (d, 2H), 6.12 (t, 16.5 Hz, 1H), 5.64 (dd, J= 62.6, 10.5 Hz, 1H), 5.10 (d, 1H), 4.63-4.31 (m, 1H), 4.27 - 4.01 (m, 1H), 3.78 - 3.48 (m, 1H), 3.03 (td, J= 10.8, 9.1, 5.9 Hz, 1H), 2.39 - 2.13 (m, 2H), 1.99 (tq, .7=8.5, 4.6 Hz, 1H), 1.61-1.44 (m, 1H)
BCD-BTK- 107	452,1	9.77 (s, 1H), 9.22 (d, J= 2.3 Hz, 1H), 9.01 (s, 1H), 8.69 (dd, J= 8.7, 2.4 Hz, 1H), 8.63 - 8.55 (m, 2H), 8.02 (d, J= 8.6 Hz, 1H), 6.81 (dd, J= 29.3, 15.6 Hz,

136

Compound	ESI-MS, [M+H]+	NMR Ή (DMSO-d6), δ, ppm
		1H), 6.41 - 6.26 (m, 2H), 6.11 (t, J= 17.8 Hz, 1H), 5.65 (dd, J= 60.8, 10.5 Hz, 1H), 5.10 (d, J= 26.3 Hz, 1H), 4.43 (d, J= 13.8 Hz, 1H), 4.27 - 3.98 (m, 1H), 3.92 - 3.60 (m, 1H), 2.35 (t, J= 4.4 Hz, 1H), 2.05 (d,7= 14.7 Hz, 1H), 1.86- 1.44 (m, 2H)
BCD-BTK- 117	509,3	9.87 (s, 1H), 8.61 (s, 1H), 8.10 (dd, J= 21.9, 7.9 Hz, 4H), 7.70 (d, J= 8.4 Hz, 2H), 6.95 - 6.67 (m, 1H), 6.60 (dd, J= 17.0, 10.2 Hz, 1H), 6.39 - 6.25 (m, 3H), 6.12 (dd, J= 30.2, 16.5 Hz, 1H), 5.82 (dd, J= 10.1, 2.0 Hz, 1H), 5.78 - 5.53 (m, 1H), 4.92 (d, J= 12.8 Hz, 1H), 4.68 - 4.24 (m, 1H), 4.21 - 3.73 (m, 1H), 3.26 - 3.09 (m, 1H), 2.60 (s, 3H), 2.40 - 2.13 (m, 2H), 2.07 - 1.95 (m, 1H), 1.67 (s, 1H)
BCD-BTK- 118	520,3	8.06 (dd, J= 11.0, 7.7 Hz, 4H), 7.70 (d, J= 8.4 Hz, 2H), 7.64 (s, 1H), 6.97 - 6.61 (m, 1H), 6.32 - 6.25 (m, 2H), 6.21 - 6.02 (m, 1H), 5.65 (dd, J= 59.6, 10.5 Hz, 1H), 5.03 (s, 2H), 4.82 (s, 1H), 4.62 - 4.05 (m, 2H), 3.76 (s, 1H), 3.16 (d, J= 11.3 Hz, 1H), 2.48 (s, 3H), 2.36-2.25 (m, 1H), 2.16 (s, 1H), 1.96 (s, 1H)
BCD-BTK- 119	455,3	8.06 (dd, J= 11.0, 7.7 Hz, 4H), 7.70 (d, J= 8.4 Hz, 2H), 7.64 (s, 1H), 6.96 - 6.60 (m, 1H), 6.34 - 6.24 (m, 2H), 6.10 (dd, 7=31.8, 16.6 Hz, 1H), 5.65 (dd,7 = 59.6, 10.5 Hz, 1H), 5.03 (s, 2H), 4.82 (s, 1H), 4.66 -4.19(m, 1H), 4.17-3.67 (m, 1H), 3.16 (d, J= 11.3 Hz, 1H), 2.48 (s, 3H), 2.39-2.23 (m, 1H), 2.16 (s, 1H), 1.96 (s, 1H), 1.64 (s, 1H)
BCD-BTK- 120	485,3	9.67 (s, 1H), 9.01 (d, J= 2.2 Hz, 1H), 8.60 - 8.52 (m, 2H), 8.47 (dd, J= 8.7, 2.3 Hz, 1H), 8.28 (s, 1H), 7.97 (d, J= 8.6 Hz, 1H), 7.83 (d, J= 36.7 Hz, 1H), 7.40 (d, 7 = 2.2 Hz, 1H), 7.11 (d, J= 22 Hz, 1H), 6.95 6.73 (m, 1H), 6.46 - 6.28 (m, 2H), 6.09 (dd, 7= 34.6, 16.6 Hz, 1H), 5.64 (dd, 7= 60.0, 10.6 Hz, 1H), 4.84 (s, 1H), 4.26 (s, 2H), 3.64 (t,7= 11.5 Hz, 1H), 2.97 (t, 7= 12.1 Hz, 1H), 2.40-2.00 (m, 2H), 1.92 (s, OH), 1.48 (s, 1H)
BCD-BTK121	486,3	9.33 (s, 2H), 8.88 (d, 7= 7.8 Hz, 2H), 8.29 (d, 7= 7.4 Hz, 1H), 7.84 (d, 7 = 35.2 Hz, 1H), 7.42 (s, 1H), 7.14 (s, 1H), 6.98 - 6.59 (m, 1H), 6.37 (d, 7= 7.7 Hz,

137

Compound	ESI-MS, [M+H]+	NMR Ή (DMSO-d6), δ, ppm
		2H), 6.09 (dd, J= 34.5, 16.7 Hz, 1H), 5.64 (dd, J= 61.2, 10.5 Hz, 1H), 4.86 (s, 1H), 4.69-3.96 (m, 2H), 3.66 (t, J= 11.5 Hz, 1H), 3.01 (d, J= 13.3 Hz, 1H), 2.41-1.85 (m, 3H), 1.48 (s, 1H)
BCD-BTK- 122	466,4	10.08 (s, 1H), 8.20 - 7.98 (m, 4H), 7.87 - 7.68 (m, 3H), 7.55 (d, J= 2.1 Hz, 1H), 6.84 (dd, J= 29.3, 14.4 Hz, 1H), 6.42 - 6.23 (m, 2H), 6.09 (dd, J= 30.4, 16.7 Hz, 1H), 5.65 (dd, J= 61.2, 10.4 Hz, 1H), 5.05 (d, J = 33.0 Hz, 1H), 4.83 - 4.35 (m, 1H), 4.16 (d, J= 63.9 Hz, 1H), 3.87 - 3.50 (m, 1H), 3.13 (d, J = 40.9 Hz, 1H), 2.41 - 1.95 (m, 3H), 1.58 (s, 1H)
BCD-BTK- 123	451,3	9.68 (s, 1H), 8.98 (s, 1H), 8.55 (s, 2H), 8.21 - 8.14 (m, 2H), 7.43 - 7.34 (m, 2H), 7.15 - 6.80 (m, 3H), 6.11 (t, J= 16.8 Hz, 1H), 5.65 (dd,J=52.7, 10.5 Hz, 1H), 5.08 (s, 1H), 4.75 - 4.00 (m, 2H), 3.88 - 3.52 (m, 1H), 3.07 (s, 1H), 2.34 (q, J= 6.1, 4.6 Hz, 2H), 2.03 (s, 1H), 1.62 (s, 1H)
BCD-BTK124	460,2	8.56 (d, J= 5.0 Hz, 1H), 8.54 - 8.44 (m, 2H), 7.82 (d, J= 8.2 Hz, 2H), 7.43 (d, J= 4.9 Hz, 1H), 7.34 7.26 (m, 2H), 7.09 - 6.96 (m, 2H), 6.92 - 6.58 (m, 1H), 6.11 (dd, J=33.3, 16.8 Hz, 1H), 5.64 (dd, J= 61.7, 10.5 Hz, 1H), 4.98 (s, 1H), 4.63 (d, J= 12.4 Hz, 1H), 4.11 (d, J= 13.7 Hz, 1 H), 3.77 (d, J= 12.4 Hz, 1H), 3.08 (d, J= 4.1 Hz, 1H), 2.43 - 2.29 (m, 1H), 2.24 (s, 1H), 2.01 (d, J= 13.4 Hz, 1H), 1.67 (s, 1H)
BCD-BTK- 125	460,1	9.39 (s, 1H), 8.61 - 8.39 (m, 3H), 8.17 (d, J= 8.4 Hz, 2H), 7.59 - 7.28 (m, 2H), 7.18 - 7.04 (m, 2H), 6.85 (ddd, J=28.2, 16.5, 10.3 Hz, 1H), 6.11 (t, J= 18.9 Hz, 1H), 5.66 (dd, J= 49.2, 10.5 Hz, 1H), 5.29 (s, 1H), 4.85-4.39 (m, 1H), 4.18 (dd, J= 85.1, 13.4 Hz, 1H), 3.70 (dd, J= 24.1, 12.6 Hz, 1H), 3.02 (t, J= 12.3 Hz, 1H), 2.47-2.24 (m, 3H), 1.99 (d,J= 13.4 Hz, 1H), 1.64 (s, 1H)
BCD-BTK- 127	467,2	10.10 (s, 1H), 9.02 (d, J = 22 Hz, 1H), 8.56 (d, J= 7.9 Hz, 2H), 8.49 (dd, J= 8.7, 2.3 Hz, 1H), 7.98 (d, J = 8.7 Hz, 1H), 7.72 (d, J= 2.2 Hz, 1H), 7.57 (d, J= 2.1 Hz, 1H), 6.83 (dd, J= 32.0, 15.5 Hz, 1H), 6.47 -

138

Compound	ESI-MS, [M+H]+	NMR Ή (DMSO-d6), δ, ppm
		6.28 (m, 2H), 6.09 (dd, J= 27.7, 16.4 Hz, 1H), 5.64 (dd, J= 62.0, 10.4 Hz, 1H), 5.07 (d, J = 32.4 Hz, 1H), 4.71-4.31 (m, 1H), 4.29-3.96 (m, 1H), 3.71 (d, J= 92.2 Hz, 1H), 3.16 (d, J= 16.8 Hz, 1H), 2.35 -2.10 (m, 1H), 1.99 (s, 1H), 1.59 (s, 1H)
BCD-BTK- 129	476,1	10.42 (s, 1H), 8.50 (d, J= 5.4 Hz, 2H), 8.38 (d, J= 2.0 Hz, 1H), 7.78 (d, J= 8.1 Hz, 2H), 7.28 (dd, J= 8.6, 2.1 Hz, 2H), 7.01 (d, J= 5.5 Hz, 2H), 6.92 6.60 (m, 1H), 6.14 (d, J= 16.6 Hz, 1H), 5.65 (dd, J = 57.3, 10.5 Hz, 1H), 4.87 (s, 1H), 4.70 - 4.01 (m, 2H), 3.74 (t, J= 11.4 Hz, OH), 3.06 (s, OH), 2.39-2.15 (m, 2H), 1.99 (d, J= 13.5 Hz, 1H), 1.64 (s, 1H)
BCD-BTK- 130	468,2	10.13 (s, 1H), 9.35 (s, 2H), 9.13 - 8.63 (m, 2H), 7.75 (d, J= 2.2 Hz, 1H), 7.57 (d, J = 2.2 Hz, 1H), 6.98 6.72 (m, 1H), 6.45 - 6.33 (m, 2H), 6.10 (dd, J= 29.4, 16.6 Hz, 1H), 5.56 (d, J = 10.6 Hz, 1H), 4.49 (dd, J= 100.7, 13.2 Hz, 1H), 4.25 - 3.99 (m, 1H), 3.96 - 3.54 (m, 1 H), 3.16 (s, 1H), 2.40 - 2.15 (m, 2H), 2.04 (d, J = 29.0 Hz, 1H), 1.61 (s, 1H)
BCD-BTK131	460,1	8.56 (d, J= 5.0 Hz, 1H), 8.15 - 7.99 (m, 2H), 7.89 (d, J= 8.1 Hz, 2H), 7.78 - 7.64 (m, 2H), 7.43 (d, J= 5.0 Hz, 1H), 6.95 - 6.55 (m, 1H), 6.42 - 6.23 (m, 2H), 6.11 (dd, J=34.9, 16.6 Hz, 1H), 5.64 (dd, J= 63.0, 10.5 Hz, 1H), 5.00 (s, 1H), 4.18 (m, 2H), 3.79 (t, J= 11.5 Hz, 1H), 3.21-3.00 (m, 1H), 2.35 (dd, J = 11.2, 3.9 Hz, 1H), 2.24 (s, 1H), 2.02 (d,J = 13.4 Hz, 1H), 1.68 (s, 1H)
BCD-BTK- 133	484,2	9.47 (s, 1H), 8.50 (s, 2H), 8.24 (d, J= 23.6 Hz, 1H), 7.96 (d, J= 8.2 Hz, 2H), 7.72 (d, J= 48.2 Hz, 1H), 7.40 - 7.28 (m, 3H), 7.07 (d, J = 2.1 Hz, 1H), 7.02 (d, J= 5.3 Hz, 2H), 6.82 (dd, J= 16.7, 10.0 Hz, 1H), 6.10 (dd, J= 32.9, 16.7 Hz, 1H), 5.64 (dd, J = 49.1, 10.5 Hz, 1H), 5.46 - 4.55 (m, 2H), 4.33 (dd, J= 40.9, 12.9 Hz, 1H), 3.83 (dt, J= 216.9, 12.6 Hz, 1H), 2.84 (t, J= 12.2 Hz, 1H), 2.31 (d, J =22.6 Hz, 1 H), 2.19 (s, 1H), 1.93 (d, J =9.9 Hz, 1H), 1.51 (s, 1H)
BCD-BTK134	466,2	8.52 (s, 2H), 8.30 (s, 1H), 7.71 (d, J= 8.2 Hz, 2H), 7.47 - 7.28 (m, 2H), 7.12 (d, J= 5.2 Hz, 2H), 6.79

139

Compound	ESI-MS, [M+H]+	NMR *H (DMSO-d6), ô, ppm
		(d, J= 26.2 Hz, 2H), 6.10 (dd, J= 29.8, 16.7 Hz, 1H), 5.66 (dd, J= 45.8, 10.6 Hz, 1H), 4.90 (d, J= 33.0 Hz, 2H), 4.35 (d, J= 16.0 Hz, 1H), 3.69 (d, J = 11.9 Hz, 1H), 2.95 (s, 1H), 2.34 - 2.11 (m, 2H), 1.95 (d, 7=27.1 Hz, 1H), 1.58 (s, 1H)
BCD-BTK- 135	484,2	8.50 (s, 2H), 8.35 (s, 1H), 8.04 (s, 1H), 7.71 (d, J= 8.2 Hz, 2H), 7.46 - 7.25 (m, 3H), 7.11 (d, J= 5.2 Hz, 2H), 6.77 (d, 7 = 26.2 Hz, 2H), 6.11 (dd, J= 29.8, 16.7 Hz, 1H), 5.65 (dd, J= 45.8, 10.6 Hz, 1H), 4.97 (s , 1H), 4.34 (d, J= 16.0 Hz, 1H), 3.68 (d, J= 11.9 Hz, 1H), 2.94 (s, 1H), 2.34-2.11 (m, 2H), 1.93 (d,7 = 27.1 Hz, 1H), 1.59 (s, 1H)
BCD-BTK- 136	530,2	8.69 (d, 7= 3.7 Hz, 1H), 8.14 (d, J= 7.3 Hz, 2H), 7.89 (d, J = 8.1 Hz, 2H), 7.72 (d, J= 8.4 Hz, 2H), 6.88 (dd, J= 16.5, 10.4 Hz, 1H), 6.68 (d, J= 17.2 Hz, 1H), 6.55 (dd, 7=17.4, 10.3 Hz, 1H), 6.31 (dd,7 = 11.7, 9.0 Hz, 3H), 6.10 (dd, J = 39.7, 16.7 Hz, 1H), 5.64 (dd, J=68.0, 10.6 Hz, 1H), 4.99 (d, J= 16.7 Hz, 1H), 4.46 (dd, J= 137.7, 13.0 Hz, 1H), 4.09 (d, J = 13.4 Hz, 1H), 3.80 (s, 1H), 3.16 (d, J= 16.1 Hz, 1H), 2.41-2.18 (m, 2H), 2.00 (d, J= 13.1 Hz, 1H), 1.66 (s, 1H)
BCD-BTK- 137	466,2	10.02 (s, 1H), 8.51 (d, J= 5.5 Hz, 2H), 7.97 (d, J = 8.4 Hz, 2H), 7.69 (d, J= 2.3 Hz, 1H), 7.53 (d, J= 2.2 Hz, 1H), 7.44 - 7.26 (m, 2H), 7.16 - 6.96 (m, 2H), 6.98-6.69 (m, 1H), 6.10 (dd, J = 29.7, 16.6 Hz, 1H), 5.65 (dd, J= 55.4, 10.5 Hz, 1H), 5.03 (d, J= 33.8 Hz, 1H), 4.80 - 3.93 (m, 2H), 3.62 (dt, J= 99.7, 11.5 Hz, 1H), 3.02 (t,7=12.1Hz, 1H), 2.41-2.16 (m, 2H), 1.95 (d, 7= 30.0 Hz, 1H), 1.59 (s, 1H)
BCD-BTK- 138	493,1	8.53 (d, J= 13.5 Hz, 3H), 8.24 - 8.05 (m, 2H), 7.83 (dd, 7=7.3, 1.1 Hz, 1H), 7.75 (s, 2H), 7.41 (d, J= 8.0 Hz, 2H), 7.03 (d, J= 12.5 Hz, 2H), 6.70 (ddd, J= 79.3, 16.6, 10.6 Hz, 1H), 6.06 (dd, J= 33.1, 16.6 Hz, 1H), 5.64 (dd, J= 47.6, 10.6 Hz, 1H), 4.73 - 3.94 (m, 3H), 3.80 (t, 7=11.9 Hz, 1H), 3.03 (d, J= 12.4 Hz, 1H), 2.43 (s, 1H), 2.23 (s, 1H), 2.02 - 1.79 (m, 1H), 1.52 (s, 1H)

140

Compound	ESI-MS, [M+H]+	NMR Ή (DMSO-d6), δ, ppm
BCD-BTK- 139	475,2	8.54 (s, 2H), 7.78 (s, 1H), 7.72 (d, J= 8.1 Hz, 2H), 7.41 - 7.29 (m, 2H), 7.10 (s, 2H), 6.80 (td, J= 16.7, 8.3 Hz, 1H), 6.13 (d, J= 32.6 Hz, 3H), 5.67 (dd, J= 38.0, 10.6 Hz, 1H), 4.85 - 3.97 (m, 2H), 2.88 (t, J= 12.4 Hz, 1H), 2.38-2.14 (m, 3H), 1.97 (dt, J= 13.6, 3.6 Hz, 1H), 1.61 (s, 1H)
BCD-BTK- 140	469,2	9.46 (s, 1H), 8.47 (d, J= 50.3 Hz, 4H), 8.14 (d, J= 8.5 Hz, 2H), 7.97 (t, J= 26.1 Hz, 1H), 7.35 (d, J= 8.6 Hz, 2H), 7.02 (d, J= 5.1 Hz, 2H), 6.91 - 6.73 (m, 1H), 6.10 (dd, J= 30.2, 16.6 Hz, 1H), 5.64 (dd, J= 53.7, 10.0 Hz, 1H), 4.96 (s, 1H), 4.60 (d, J= 10.4 Hz, 1H), 4.33 (s, 1H), 4.07 (d, J= 12.9 Hz, 1H), 3.67 - 3.57 (m, 1H), 2.97 - 2.84 (m, 1H), 2.12 (tt, J = 22.9, 16.5 Hz, 4H), 1.53 (s, 1H)
BCD-BTK- 201	487,1	10.86 (s, 1H), 9.42 (s, 1H), 8.49 (s, 1H), 8.40 (d, J= 3.6 Hz, 1H), 8.28 - 8.09 (m, 5H), 7.90 - 7.79 (m, 1H), 7.18 (dd,/= 6.9, 5.1 Hz, 1H), 6.91-6.71 (m, 1H), 6.13 (s, 1H), 5.78 - 5.54 (m, 1H), 5.39 - 5.17 (m, 1H), 4.81 - 4.66 (m, 1H), 4.50-4.27 (m, 1H), 4.16 - 4.02 (m, 1H), 3.81 - 3.67 (m, 1H), 3.48 - 3.37 (m, 1H), 3.05 - 2.94 (m, 1H), 2.33 (s, 3H), 2.00 (s, 1H), 1.77- 1.55 (m, 1H)
BCD-BTK- 202	485,2	9.39 (s, 1H), 9.00 (s, 1H), 8.67 (d, J= 6.0 Hz, 1H), 8.50 (s, 1H), 8.21 (d, J= 8.6 Hz, 2H), 7.50 (d, J= 8.6 Hz, 2H), 6.95 (d, J= 6.0 Hz, 1H), 6.85 (d, / = 11.6 Hz, 1H), 6.22 - 5.99 (m, 1H), 5.66 (dd, / = 48.4, 9.9 Hz, 1H), 5.31 (s, 1H), 4.70 (s, 1H), 4.47-4.22 (m, 1H), 4.16-4.02 (m, 1 H), 3.73 (s, 1H), 3.01 (s, 1H), 2.32 (d, J= 4.4 Hz, 2H), 2.00 (d, J= 11.3 Hz, 1H), 1.65 (s, 1H)
BCD-BTK- 203	503,0	9.37 (s, 1H), 8.78 (s, 1H), 8.49 (d, J= 4.0 Hz, 2H), 8.16 (d, /= 8.6 Hz, 2H), 7.79 (d, J= 24.6 Hz, 2H), 7.49 - 7.34 (m, 2H), 6.81 (d, J= 5.8 Hz, 2H), 6.12 (s, 1H), 5.79 - 5.51 (m, 1H), 5.38 - 5.15 (m, 1H), 4.79 4.65 (m, 1H), 4.48 - 4.26 (m, 1 H), 4.17 - 4.02 (m, 1H), 3.80 - 3.66 (m, 1H), 3.08 - 2.89 (m, 1H), 2.32 (d, J= 4.9 Hz, 2H), 1.99 (s, 1H), 1.65 (s, 1H)
BCD-BTK- 204	478,00	δ = 9.07 (s, 1H), 8.51 (s, 1H), 8.18 - 8.09 (m, 2H), 8.00 (t,/=8.2 Hz, 1H), 7.83 (dd,/= 11.6, 1.8 Hz,

141

Compound	ESI-MS, [M+H]+	NMR *H (DMSO-d6), δ, ppm
		1H), 7.63 (d, J= 8.4 Hz, 1H), 6.94 - 6.71 (m, 1H), 6.32 - 6.27 (m, 2H), 6.18 - 6.01 (m, 1H), 5.72, 5.57 (2d, J= 10.0 Hz, 1H, rotamers), 5.32 (s, 1H), 4.70, 4.42 (2d, J = 11.9 Hz, 1 H, rotamers), 4.27, 4.06 (2d, J= 13.2 Hz, 1H, rotamers), 3.76 - 3.38 (m, 1H), 3.33 - 3.01 (m, 1H), 2.32 (s, 2H), 2.06 - 1.93 (m, 1H), 1.63 (s, 1H)
BCD-BTK- 205	478,10	δ = 9.42 (s, 1H), 8.48 (s, 1H), 8.12 - 8.03 (m, 2H), 7.85 (dd, J= Ί.Ί, 1.5 Hz, 2H), 7.77 (t, J= 8.4 Hz, 1H), 6.90 - 6.67 (m, 1H), 6.31 - 6.22 (m, 2H), 6.19 6.04 (m, 1H), 5.71, 5.58 (2d, J = 10.1 Hz, 1H, rotamers), 5.27 (s, 1H), 4.69, 4.37 (2d, J- 12.2 Hz, 1H, rotamers), 4.27, 4.07 (2d, J = 12.9 Hz, 1H, rotamers), 3.82 - 3.40 (m, 1H), 3.33 - 3.06 (m, 1H), 2.33 (s, 2H), 2.06 - 1.94 (m, 1H), 1.67 (s, 1H)
BCD-BTK- 206	-	δ = 9.56 (s, 1H), 9.52 - 9.49 (m, 1H), 8.98 (dd, J = 8.3, 2.4 Hz, 1H), 8.54 (s, 1H), 6.94 - 6.69 (m, 1H), 6.19 - 6.02 (m, 1H), 5.72, 5.57 (2d, J= 10.1 Hz, 1H, rotamers), 5.42 - 5.24 (m, 1H), 4.67, 4.37 (2d, J= 13.0 Hz, 1H, rotamers), 4.19, 4.06 (2d, J= 13.1 Hz, 1H, rotamers), 3.87 - 3.46 (m, 1 H), 3.33 - 3.10 (m, 1H), 2.40 - 2.29 (m, 1H), 2.06 - 1.96 (m, 1H), 1.66 (s, 1H)
BCD-BTK- 207	-	δ = 9.75 (d, J= 2.4 Hz, 1H), 9.57 (s, 2H), 9.51 (s, 1H), 9.17 (d, J= 4.2 Hz, 1H), 8.98 (dd, J- 8.0, 2.5 Hz, 1H), 8.53 (s, 1H), 7.69 (d, J= 4.1 Hz, 1H), 6.94 - 6.72 (m, 1H), 6.65 (d, J= 8.0 Hz, 1H), 6.18 - 6.04 (m, 1H), 5.72, 5.58 (2d, J= 10.5 Hz, 1H, rotamers), 5.42 - 5.23 (m, 1H), 4.68, 4.39 (2d, J= 11.1 Hz, 1H, rotamers), 4.22, 4.06 (2d, J = 13.0 Hz, 1H, rotamers), 3.86 - 3.45 (m, 1H), 3.33 - 3.09 (m, 1H), 2.41 - 2.27 (m, 2H), 2.00 (s, 1H), 1.65 (s, 1H)
BCD-BTK- 208	-	δ = 9.46 (s, 1H), 8.86 (s, 1H), 8.52 (s, 1H), 8.17 8.05 (m, 3H), 7.90 (t, J= 8.2 Hz, 1H), 6.93 - 6.70 (m, 1H), 6.50 (d, J= 7.9 Hz, 1H), 6.20 - 6.03 (m, 1H), 5.72, 5.57 (2d, J= 10.1 Hz, 1H, rotamers), 5.39 - 5.23 (m, 1H), 4.66, 4.38 (2d, J= 12.1 Hz, 1H), 4.22, 4.05 (d, J= 12.7 Hz, 1H, rotamers), 3.83 - 3.44

142

Compound	ESI-MS, [M+H]+	NMR 'il (DMSO-d6), δ, ppm
		(m, 1H), 3.33 - 3.06 (m, 1H), 2.40 - 2.27 (m, 2H), 2.04 - 1.94 (m, 1H), 1.65 (s, 1H)
BCD-BTK- 210	555,20	δ = 11.43 (s, 1H), 9.46 (s, 1H), 8.71 (d, <7=5.1 Hz, 1H), 8.58 (s, 1H), 8.54 (s, 1H), 8.27 - 8.19 (m, 4H), 7.57 (d,J=5.0 Hz, 1H), 6.94-6.78 (m, 1H), 6.186.05 (m, 1H), 5.72, 5.60 (2d, J= 10.1 Hz, 1H, rotamers), 5.31 (s, 1H), 4.69, 4.43 (2d, J= 11.7 Hz, 1H, rotamers), 4.28, 4.07 (2d, J= 10.1 Hz, 1H, rotamers), 3.80 - 3.41 (m, 1H), 3.33 - 2.99 (m, 1H), 2.41-2.27 (m, 2H), 1.98 (s, 1H), 1.63 (s, 1H)
BCD-BTK211	444,10	δ = 9.29 (d, J= 1.9 Hz, 1H), 8.51 (d, .7=6.0 Hz, 2H), 8.47 (d, J = 3.6 Hz, 1 H), 8.15 (d, J = 8.3 Hz, 2H), 7.36 (d, J= 8.7 Hz, 2H), 7.03 (dd, J=4.8, 1.4 Hz, 2H), 6.92 - 6.73 (m, 1H), 6.17 - 6.03 (m, 1H), 5.71, 5.59 (2d, J= 10.4 Hz, 1H, rotamers), 4.78 (s, 1H), 4.63, 4.40 (2d, J= 12.9 Hz, 1H, rotamers), 4.21, 4.04 (2d, J = 12.9 Hz, 1H, rotamers), 3.75 - 3.46 (m, 1H), 3.33 - 3.02 (m, 1H), 2.39 - 2.26 (m, 2H), 1.97 (s, 1H), 1.62 (s, 1H)
BCD-BTK212	505,10	δ = 11.01 (s, 1H), 9.42 (s, 1H), 8.49 (s, 1H), 8.39 (d, J= 3.0 Hz, 1H), 8.27 (dd, J = 9.2, 4.2 Hz, 1H), 8.19 (q, J = 8.5 Hz, 4H), 7.78 (td, J= 8.7, 3.1 Hz, 1H), 6.94 - 6.72 (m, 1H), 6.21 - 6.03 (m, 1H), 5.72, 5.60 (2d, J= 10.2 Hz, 1H, rotamers), 5.29 (s, 1H), 4.72, 4.42 (2d, J= 11.2 Hz, 1H, rotamers), 4.32, 4.08 (d, J = 12.2 Hz, 1H, rotamers), 3.81 - 3.36 (m, 1H), 3.33 2.94 (m, 1H), 2.43-2.26 (m, 2H), 1.99 (s, 1H), 1.65 (s, 1H)
BCD-BTK- 213	476,20	δ = 9.71 (s, 1H), 9.02 (d, J= 8.0 Hz, 2H), 8.68 (d, J= 6.0 Hz, 1H), 8.23 (d, J= 8.6 Hz, 2H), 7.53 (d, J= 8.6 Hz, 2H), 6.96 (d, J = 6.0 Hz, 1H), 6.94 - 6.78 (m, 1H), 6.16 - 6.03 (m, 1H), 5.71, 5.58 (2d, J= 10.2 Hz, 1H, rotamers), 5.08 (s, 1H), 4.62, 4.46 (2d, J= 11.8 Hz, 1H, rotamers), 4.26, 4.04 (d, J= 12.8 Hz, 1H, rotamers), 3.84 - 3.58 (m, 1H), 3.33 - 3.01 (m, 1H), 2.38-2.19 (m, 2H), 2.01 (s, 1H), 1.59 (s, 1H)
BCD-BTK214	549,20	δ = 11.22 (s, 1H), 9.37 (d,J=2.0 Hz, 1H), 8.56 (d,J = 5.1 Hz, 1H), 8.50 (d, J= 3.6 Hz, 1H), 8.39 (s, 1H),

143

Compound	ESI-MS, [M+H]+	NMR Ί1 (DMSO-d6), δ, ppm
		8.22 (s, 4H), 7.33 (d, J= 5.1 Hz, 1H), 6.95 - 6.75 (m, 1H), 6.17 - 6.05 (m, 1H), 5.72, 5.59 (2d, J= 10.1 Hz, 1H, rotamers), 4.80 (s, 1H), 4.63, 4.41 (2d, J= 10.1 Hz, 1H, rotamers), 4.21, 4.05 (2d, J= 12.3 Hz, 1H, rotamers), 3.79 - 3.39 (m, 2H), 3.33 - 3.06 (m, 1H), 2.39 - 2.16 (m, 4H), 1.99 (s, 1H), 1.64 (s, 1H), 0.96 (t, 7=7.4 Hz, 3H)
BCD-BTK215	565,20	δ = 11.22 (s, 1H), 9.46 (s, 1H), 8.58 - 8.52 (m, 2H), 8.40 (s, 1H), 8.25 - 8.17 (m, 4H), 7.33 (dd, 7= 5.1, 1.2 Hz, 1H), 6.95 - 6.77 (m, 1H), 6.21 - 6.05 (m, 1H), 5.72, 5.60 (2d, 7= 10.4 Hz, 1H, rotamers), 5.32 (s, 1H), 4.69, 4.44 (2d, 7= 12.6 Hz, 1H, rotamers), 4.29, 4.07 (d, J= 12.6 Hz, 1H), 3.79 - 3.41 (m, 1H), 3.33 -2.99 (m, 1H), 2.41-2.16 (m, 4H), 1.99 (s, 1H), 1.63 (s, 1H), 0.96 (t, 7 = 7.4 Hz, 3H)
BCD-BTK- 216	476,30	δ = 9.68 (s, 1H), 9.00 (s, 1H), 8.55 (dd, 7= 4.5, 1.0 Hz, 1H), 8.18 (d, 7=8.7 Hz, 2H), 7.76 (dd,7=8.7, 4.5 Hz, 1H), 7.67 - 7.63 (m, 1H), 7.46 - 7.40 (m, 2H), 6.96 - 6.78 (m, 1H), 6.19 - 6.02 (m, 1H), 5.71, 5.58 (2d, 7= 9.8, 1H, rotamers), 5.08 (s, 1H), 4.62, 4.46 (2d, 7= 11.2 Hz, 1H, rotamers), 4.26, 4.04 (d, 7 = 12.7 Hz, 1H, rotamers), 3.82 - 3.57 (m, 1H), 3.33 3.02 (m, 1H), 2.38-2.16 (m, 2H),2.01 (s, 1H), 1.58 (s, 1H)
BCD-BTK- 217	469,20	δ = 9.32 (s, 1H), 9.02 (s, 1H), 8.68 (d, 7= 6.0 Hz, 1H), 8.49 (d, 7= 3.6 Hz, 1H), 8.22 (d, 7= 8.2 Hz, 2H), 7.52 (d, J= 8.6 Hz, 2H), 6.96 (d, J= 6.0 Hz, 1H), 6.94-6.72 (m, 1H), 6.17-6.03 (m, 1H), 5.72, 5.59 (2d, 7= 10.2 Hz, 1H, rotamers), 4.79 (s, 1H), 4.63, 4.41 (2d, 7= 11.5 Hz, 1H, rotamers), 4.21, 4.05 (2d, 7= 10.5 Hz, 1H, rotamers), 3.77 - 3.40 (m, 1H), 3.35 - 3.09(m, 1H), 2.39 - 2.27 (m, 2H), 1.99 (s, 1H), 1.63 (s, 1H), 1.24 (s, 1H)
BCD-BTK218	485,20	δ = 9.38 (s, 1H), 8.57 - 8.53 (m, 1H), 8.51 (s, 1H), 8.15 (d, J= 8.5 Hz, 2H), 7.76 (dd, 7= 8.7, 4.5 Hz, 1H), 7.65 (d, 7= 8.7 Hz, 1H), 7.42 (d, 7= 8.7 Hz, 2H), 6.95 - 6.75 (m, 1H), 6.17 - 6.04 (m, 1H), 5.71, 5.59 (2d,7= 10.3 Hz, 1H, rotamers), 5.30 (s, 1H),

144

Compound	ESI-MS, [M+H]+	NMR Ή (DMSO-d6), δ, ppm
		4.68, 4.41 (2d, 7= 12.2 Hz, 1H, rotamers), 4.28, 4.07 (2d, 7= 11.0 Hz, 1H, rotamers), 3.75 - 3.39 (m, 1H), 3.31-2.97 (m, 1H), 2.31 (s, 2H), 1.96 (s, 1H), 1.62 (s, 1H)
BCD-BTK- 219	556,30	δ = 11.24 (s, 1H), 9.77 (s, 1H), 9.02 (s, 1H), 8.56 (d, 7 = 5.1 Hz, 1H), 8.40 (s, 1H), 8.23 (s, 4H), 7.33 (dd, 7 = 5.1, 1.2 Hz, 1H), 6.95 - 6.79 (m, 1H), 6.16 - 6.04 (m, 1H), 5.72, 5.59 (2d, 7= 9.8 Hz, 1H, rotamers), 5.09 (s, 1H), 4.62, 4.47 (2d, 7= 12.3 Hz, 1H, rotamers), 4.27, 4.04 (2d, 7 = 13.2 Hz, 1H, rotamers), 3.85 - 3.62 (m, 1H), 3.33 - 3.05 (m, 1H), 2.39 - 2.17 (m, 4H), 2.02 (s, 1H), 1.59 (s, 1H), 0.96 (t,7= 7.4 Hz, 3H)
BCD-BTK- 220	503,20	δ = 9.34 (s, 1H), 8.49 (s, J= 8.2 Hz, 1H), 8.46 (dd, 7 = 4.0, 1.3 Hz, 1H), 8.03 (d, 7= 8.6 Hz, 2H), 7.96 (s, 1H), 7.65 - 7.50 (m, 3H), 7.13 (d, J= 8.7 Hz, 2H), 6.92 - 6.77 (m, 1H), 6.18 - 6.03 (m, 1H), 5.71, 5.59 (2d, 7= 10.5 Hz, 1H, rotamers), 5.27 (s, 1H), 4.67, 4.41 (2d, 7= 11.5 Hz, 1H, rotamers), 4.29, 4.06 (2d, 7= 12.9 Hz, 1H, rotamers), 3.74 - 3.40 (m, 1H), 3.33 - 2.94 (m, 2H), 2.35 - 2.26 (m, 2H), 1.96 (s, 1H), 1.61 (s, 1H)
BCD-BTK- 221	546,30	δ = 11.46 (s, 1H), 9.77 (s, 1H), 9.02 (s, 1H), 8.71 (d, 7 = 5.1 Hz, 1H), 8.58 (s, 1H), 8.24 (s, 4H), 7.57 (d, 7 = 4.8 Hz, 1H), 6.97-6.77 (m, 1H), 6.17-6.03 (m, 1H), 5.72, 5.59 (2d, 7= 10.0 Hz, 1H, rotamers), 5.09 (s, 1H), 4.62, 4.47 (2d, 7= 11.4 Hz, 1H, rotamers), 4.26, 4.03 (2d, 7= 12.2 Hz, 1H, rotamers), 3.87 3.59 (m, 1H), 3.33 - 3.03 (m, 1H), 2.34 (s, 2H), 2.02 (s, 1H), 1.59 (s, 1H)
BCD-BTK- 222	503,20	δ = 9.34 (s, 1H), 8.86 (s, 1H), 8.55 (d, 7= 2.6 Hz, 1H), 8.46 (s, 1H), 8.16 (s, 1H), 8.08 (d, 7= 8.7 Hz, 2H), 7.90 - 7.86 (m, 1H), 7.59 (s, 1H), 7.26 (d, 7 = 8.7 Hz, 2H), 6.90 - 6.69 (m, 1 H), 6.18 - 6.05 (m, 1H), 5.71, 5.59 (2d, 7= 9.7 Hz, 1H, rotamers), 5.27 (s, 1H), 4.77 - 4.36 (m, 1H), 4.36 - 4.06 (m, 1H), 3.38-3.34 (m, 1H), 3.30 - 2.91 (m, 1H), 2.31 (s, 2H), 1.99 (s, 1H), 1.66 (s, 1H)

145

Compound	ESI-MS, [M+H]+	NMR Ίΐ (DMSO-d6), δ, ppm
BCD-BTK- 223	496,20	δ = 11.15 (s, 1H), 9.76 (s, 1H), 9.02 (s, 1H), 8.278.14 (m, 5H), 8.05 (q, J= 8.2 Hz, 1H), 6.95 (dd, J= 7.9, 2.3 Hz, 1H), 6.92-6.78 (m, 1H), 6.17-6.04 (m, 1H), 5.72, 5.59 (2d, J= 9.8 Hz, 1H, rotamers), 5.09 (s, 1H), 4.63, 4.47 (2d, J= 13.3 Hz, 1H, rotamers), 4.27, 4.03 (2d, J= 11.6 Hz, 1H, rotamers), 3.86 3.60 (m, 1H), 3.33 - 3.02 (m, 1H), 2.34 (s, 1H), 2.01 (s, 1H), 1.59 (s, 1H)
BCD-BTK- 224	542,20	δ = 11.24 (s, 1H), 9.77 (s, 1H), 9.02 (s, 1H), 8.56 (d, J = 5.1 Hz, 1H), 8.43 (s, 1H), 8.23 (s, 4H), 7.37 (d, J = 3.8 Hz, 1H), 6.96 - 6.79 (m, 1H), 6.17 - 6.05 (m, 1H), 5.72, 5.59 (2d, J= 10.4 Hz, 1H, rotamers), 5.09 (s, 1H), 4.62, 4.47 (2d, J= 11.0 Hz, 1H, rotamers), 4.27, 4.03 (2d, J= 12.9 Hz, 1H, rotamers), 3.86 3.61 (m, 1H), 3.39 - 3.04 (m, 1H), 2.39 - 2.23 (m, 2H), 2.09 - 1.94 (m, 4H), 1.60 (s, 1H)
BCD-BTK- 225	505,20	δ = 11.13 (s, 1H), 9.47 (s, 1H), 8.55 (s, 1H), 8.25 8.14 (m, 5H), 8.05 (q, J= 8.2 Hz, 1H), 6.94 (dd, J = 8.0, 2.5 Hz, 1H), 6.91 - 6.78 (m, 1H), 6.18 - 6.05 (m, 1H), 5.72, 5.60 (2d, J= 10.4 Hz, 1H, rotamers), 5.37 - 5.21 (m, 1H), 4.69, 4.44 (2d, J= 13.0 Hz, 1H, rotamers), 4.29, 4.07 (2d, J= 13.3 Hz, 1H, rotamers), 3.71 - 3.40 (m, 1H), 3.39 - 2.94 (m, 1H), 2.41 - 2.27 (m, 2H), 1.98 (s, 1H), 1.63 (s, 1H)
BCD-BTK- 226	505,30	δ = 10.87 (s, 1H), 9.43 (s, 1H), 8.49 (s, 1H), 8.32 (d, J = 4.6 Hz, 1H), 8.20 (s, 4H), 7.84 - 7.76 (m, 1H), 7.45 - 7.38 (m, 2H), 6.91 - 6.73 (m, 1H), 6.20 - 6.05 (m, 1H), 5.72, 5.60 (2d, J= 9.8 Hz, 1H, rotamers), 5.30 (s, 1H), 4.73,4.42 (2d, J= 11.8 Hz, 1H, rotamers), 4.34, 4.09 (2d, J= 12.9 Hz, 1H), 3.81 3.34 (m, 1H), 3.33 - 2.95 (m, 1H), 2.33 (s, 2H), 2.00 (s, 1H), 1.66 (s, 1H)
BCD-BTK- 227	496,30	δ = 11.00 (s, 1H), 9.72 (s, 1H), 8.95 (s, 1H), 8.36 (d, J= 3.1 Hz, 1H), 8.29 (dd, J= 9.2, 4.2 Hz, 1H), 8.24 - 8.17 (m, 4H), 7.75 (td, J= 8.6, 3.1 Hz, 1H), 6.92 6.73 (m, 1H), 6.20 - 6.02 (m, 1H), 5.71, 5.58 (2d, J = 10.1 Hz, 1H, rotamers), 5.18 - 4.97 (m, 1H), 4.67, 4.45 (2d, J= 11.7 Hz, 1H, rotamers), 4.32, 4.07 (2d,

146

Compound	ESI-MS, [M+H]+	NMR ‘11 (DMSO-d6), δ, ppm
		J= 11.9 Hz, 1H, rotamers), 3.89-3.56 (m, 1H), 3.33 - 2.98 (m, 1H), 2.40 - 2.23 (m, 2H), 2.04 (s, 1H), 1.65 (s, 1H)
BCD-BTK- 228	478,30	J = 11.06 (s, 1H), 9.77 (s, 1H), 9.02 (s, 1H), 8.43 (d, J= 3.Ί Hz, 1H), 8.27 - 8.17 (m, 4H), 7.95 - 7.89 (m, 1H), 7.26 - 7.20 (m, 1H), 6.98 - 6.77 (m, 1H), 6.16 6.04 (m, 1H), 5.72, 5.59 (2d, 7 = 9.7 Hz, 1H, rotamers), 5.09 (s, 1H), 4.62, 4.48 (2d, 7= 13.3 Hz, 1H, rotamers), 4.27 (m, 1H), 3.80 - 3.62 (m, 1H), 3.46 - 3.01 (m, 1H), 2.40 - 2.21 (m, 2H), 2.02 (s, 1H), 1.59 (s, 1H)
BCD-BTK- 229	489,20	δ = 10.55 (s, 1H), 9.67 (s, 2H), 9.57 (s, 1H), 8.58 (s, 1H), 8.43 (d, 7= 4.0 Hz, 2H), 8.30 (d, 7= 8.2 Hz, 1H), 7.98 - 7.88 (m, 1H), 7.24 (dd, 7= 6.9, 5.2 Hz, 2H), 6.94 - 6.78 (m, 2H), 6.21 - 6.02 (m, 1H), 5.72, 5.60 (2d, J= 10.5 Hz, 1H, rotamers), 5.42 - 5.24 (m, 1H), 4.66, 4.42 (2d, 7= 10.8 Hz, 1H, rotamers), 4.22, 4.05 (2d, 7= 11.7 Hz, 1H, rotamers), 3.88 - 3.49 (m, 1H), 3.33-3.07 (m, 1H), 2.43 - 2.28 (m, 2H), 1.99 (s, 1H), 1.64 (s, 1H)
BCD-BTK- 230	444,20	δ = 9.29 (d, 7= 1.9 Hz, 1H), 8.56 - 8.53 (m, 1H), 8.48 (d, J= 3.6 Hz, 1H), 8.16 (d, 7= 8.2 Hz, 2H), 7.76 (dd, 7 = 8.7, 4.5 Hz, 1H), 7.68 - 7.62 (m, 1H), 7.42 (d, 7=8.7 Hz, 1H), 6.95-6.71 (m, 1H), 6.186.03 (m, 1H), 5.71, 5.58 (2d,7= 10.1 Hz, 1H, rotamers), 4.78 (s, 1H), 4.63, 4.40 (2d, 7= 11.6 Hz, 1H, rotamers), 4.21, 4.05 (2d, 7= 13.6 Hz, 1H, rotamers), 3.78 - 3.33 (m, 1H), 3.29-3.01 (m, 1H), 2.39-2.28 (m, 2H), 1.99 (s, 1H), 1.61 (s, 1H).
BCD-BTK- 231	580,20	δ = 11.20 (s, 1H), 8.56 (d,7=5.1 Hz, 1H), 8.39 (s, 1H), 8.22 (d, 7= 8.3 Hz, 2H), 7.90 (s, 1H), 7.79 (d, 7 = 8.0 Hz, 2H), 7.33 (d, J = 5.1 Hz, 1H), 6.94-6.76 (m, 1H), 6.65 - 6.46 (m, 2H), 6.18 - 6.03 (m, 1H), 5.72, 5.62 (2d, 7= 10.3 Hz, 1H, rotamers), 5.20 (s, 1H), 4.68, 4.38 (2d,7= 11.9 Hz, 1H, rotamers), 4.31, 4.06 (2d, J = 12.8 Hz, 1H, rotamers), 3.72 - 3.28 (m, 1H), 3.28 - 2.85 (m, 1H), 2.37 - 2.16 (m, 4H), 1.93 (s, 1H), 1.59 (s, 1H), 0.96 (t, J = 7.4 Hz, 3H)

147

Compound	ESI-MS, [M+H]+	NMR Ή (DMSO-d6), δ, ppm
BCD-BTK- 232	500,10	δ = 8.92 (s, 1H), 8.65 (d, J= 6.0 Hz, 1H), 7.80 - 7.71 (m, 3H), 7.50 - 7.39 (m, 2H), 7.09 (d, J= 6.0 Hz, 1H), 6.90 - 6.66 (m, 1H), 6.21 - 6.05 (m, 1H), 6.01 (s, 2H), 5.70, 5.61 (2d, J = 10.6 Hz, 1H, rotamers), 5.19 (s, 1H), 4.81-4.35 (m, 1H), 4.37 - 4.05 (m, 1H), 3.69 - 3.10 (m, 1H), 2.94 - 2.78 (m, 1H), 2.41 2.21 (m, 2H), 2.05 - 1.92 (m, 1H), 1.62 (m, 1H)
BCD-BTK- 233	520,20	δ = 10.90 (s, 1H), 8.35 (dt, 7 = 4.7, 1.3 Hz, 1H), 8.23 - 8.17 (m, 2H), 7.93 - 7.76 (m, 4H), 7.45 (ddd, J = 8.3, 4.7, 3.8 Hz, 1H), 6.94 - 6.75 (m, 1H), 6.46 (s, 2H), 6.19 - 6.04 (m, 1H), 5.72, 5.62 (2d, J = 10.6 Hz, 1H, rotamers), 5.22 (s, 1H), 4.69, 4.38 (2d, J= 12.9 Hz, 1H, rotamers), 4.31, 4.06 (2d, J= 13.3 Hz, 1H, rotamers), 3.73 - 3.29 (m, 1H), 3.28 - 2.87 (m, 1H), 2.31-2.21 (m, 2H), 1.94 (s, 1H), 1.60 (s, 1H)
BCD-BTK- 234	493,20	δ = 10.79 (s, 1H), 8.38 (d, J= 3.9 Hz, 2H), 8.32 8.17 (m, 4H), 7.87 - 7.78 (m, 2H), 7.74 (d, J= 8.2 Hz, 2H), 7.21 - 7.11 (m, 1H), 6.79 (s, 3H), 6.11 (m, 1H), 5.65 (m, 1H), 4.91 (m, 1H), 4.73 - 4.33 (m, 1H), 4.35 - 4.02 (m, 1H), 3.59 (m, 1H), 3.33 - 2.94 (m, 1H), 2.28 (s, 2H), 1.99 (s, 1H), 1.62 (s, 1H)
BCD-BTK- 235	496,20	δ = 10.95 (s, 1H), 9.77 (s, 1H), 9.02 (s, 1H), 8.35 (d, J = 4.7 Hz, 1H), 8.23 (q, J= 8.5 Hz, 4H), 7.92 - 7.78 (m, 1H), 7.45 (dt, J = 8.3, 4.1 Hz, 1H), 6.98 - 6.72 (m, 1H), 6.16 - 6.03 (m, 1H), 5.72, 5.59 (2d, J= 10.1 Hz, 1H, rotamers), 5.10 (s, 1H), 4.63, 4.48 (2d, J = 12.2 Hz, 1H, rotamers), 4.28, 4.03 (2d, J = 11.7 Hz, 1H, rotamers), 3.85 - 3.59 (m, 1H), 3.16 - 3.02 (m, 1H), 2.43-2.19 (m, 2H), 2.01 (s, 1H), 1.59 (s, 1H)
BCD-BTK- 236	500,20	δ = 8.53 (dd, J= 4.3, 1.5 Hz, 1H), 7.81 (s, 1H), 7.78 - 7.69 (m, 4H), 7.44 - 7.39 (m, 2H), 6.92 - 6.75 (m, 1H), 6.24 - 6.03 (m, 3H), 5.71, 5.61 (2d, J= 10.2 Hz, 1H, rotamers), 5.18 (s, 1H), 4.71-4.34 (m, 1H), 4.34 - 4.04 (m, 1H), 3.69 - 3.25 (m, 1H), 3.24 - 2.86 (m, 1H), 2.24 (s, 2H), 1.94 (m, 1H), 1.58 (s, 1H)
BCD-BTK- 237	520,10	δ = 11.02 (s, 1H), 8.42 (d, J =3.1 Hz, 1H), 8.26 (dd, J= 9.2, 4.2 Hz, 1H), 8.20 (d, J = 8.3 Hz, 2H), 7.86 7.75 (m, 4H), 6.92 - 6.76 (m, 1H), 6.19 - 5.98 (m, 3H), 5.71, 5.62 (2d, J= 10.4 Hz, 1H, rotamers), 5.19

148

Compound	ESI-MS, [M+H]+	NMR Ή (DMSO-d6), δ, ppm
		(s, 1H), 4.69, 4.37 (2d, J = 12.7 Hz, 1H, rotamers), 4.31, 4.07 (2d, J = 11.9 Hz, 1H, rotamers), 3.70 3.26 (m, 1H), 3.26 - 2.86 (m, 1H), 2.25 (s, 2H), 1.94 (s, 1H), 1.58 (s, 1H)
BCD-BTK- 238	502,10	δ = 10.90 (s, 1H), 8.44 - 8.39 (m, 1H), 8.22 (dd, J = 8.4, 2.0 Hz, 3H), 7.92 - 7.84 (m, 2H), 7.78 (d, J= 8.1 Hz, 2H), 7.23 - 7.17 (m, 1H), 6.92 - 6.76 (m, 1H), 6.62 - 6.44 (m, 2H), 6.20 - 6.04 (m, 1H), 5.71, 5.62 (2d, 7 = 10.2 Hz, 1H, rotamers), 5.21 (s, 1H), 4.69, 4.38 (2d, J = 12.4 Hz, 1H, rotamers), 4.31, 4.06 (2d, 7= 13.0 Hz, 1H, rotamers), 3.71 - 3.29 (m, 1H), 3.27 - 2.88 (m, 1H), 2.36 - 2.20 (m, 2H), 1.93 (s, 1H), 1.59 (s, 1H)
BCD-BTK- 239	471,20	δ = 8.56 - 8.50 (m, 2H), 7.73 (d, 7 = 8.3 Hz, 2H), 7.50 (s, 1H), 7.40 - 7.33 (m, 2H), 7.14 - 7.01 (m, 4H), 6.92 - 6.70 (m, 1H), 6.14, 6.10 (2d, 7 = 7.3 Hz, 1H, rotamers), 5.72, 5.65 (2d, J = 10.8 Hz, 1H, rotamers), 5.02 (s, 1H), 4.64, 4.33 (2d, 7= 13.5 Hz, 1H, rotamers), 4.28, 4.05 (2d, 7 = 12.2 Hz, 1H, rotamers), 3.62 - 3.28 (m, 1H), 3.28 - 2.84 (m, 1H), 2.37-2.16 (m, 2H), 1.94 (s, 1H), 1.57 (s, 1H)
BCD-BTK- 240	498,20	δ = 10.87 (s, 1H), 8.41 (dd, 7= 5.2, 1.8 Hz, 1H), 8.26 - 8.15 (m, 3H), 7.89 - 7.84 (m, 1H), 7.79 (d, 7= 8.0 Hz, 2H), 7.51 (s, 1H), 7.21 - 7.17 (m, 1H), 6.93 6.73 (m, 1H), 6.18 - 6.06 (m, 1H), 5.71, 5.65 (2d, 7 = 10.6 Hz, 1H, rotamers), 5.52 (s, 2H), 4.97 (s, 1H), 4.66, 4.34 (2d, J = 12.5 Hz, 1H, rotamers), 4.31, 4.06 (2d, 7= 13.7 Hz, 1H, rotamers), 3.91 (s, 3H), 3.58 3.31 (m, 1H), 3.25 - 2.81 (m, 1H), 2.39 - 2.17 (m, 2H), 1.97- 1.88 (m, 1H), 1.56 (s, 1H)
BCD-BTK- 241	441,20	δ = 8.54 - 8.47 (m, 2H), 7.81 - 7.72 (m, 3H), 7.37 7.30 (m, 2H), 7.09 - 7.04 (m, 2H), 6.97 (s, 1H), 6.93 - 6.68 (m, 1H), 6.15, 6.06 (2d, J= 16.4 Hz, 1H, rotamers), 5.88 (s, 2H), 5.72, 5.59 (2d, 7= 10.3 Hz, 1H, rotamers), 4.73 - 4.49 (m, 2H), 4.34 - 4.03 (m, 2H), 3.70 - 3.32 (m, 1H), 3.23 - 2.91 (m, 1H), 2.16 (s, 2H), 1.99 - 1.85 (m, 1H), 1.62 (s, 1H)
BCD-BTK-	468,20	δ = 10.86 (s, 1H), 8.43 - 8.40 (m, 1H), 8.24 - 8.18

149

Compound	ESI-MS, [M+H]+	NMR 'il (DMSO-d6), δ, ppm
242		(m, 3H), 7.89 - 7.84 (m, 1H), 7.83 - 7.77 (m, 3H), 7.21 - 7.16 (m, 1H), 7.03 - 6.97 (m, 1H), 6.93 - 6.70 (m, 1H), 6.20 - 6.03 (m, 1H), 5.91 (s, 2H), 5.73, 5.60 (2d, J= 10.2 Hz, 1H, rotamers), 4.75 - 4.51 (m, 2H), 4.34 - 4.05 (m, 2H), 3.73 - 3.32 (m, 1H), 3.26 - 2.87 (m, 1H), 2.27 - 2.09 (m, 2H), 1.91 (s, 1H), 1.63 (s, 1H)
BCD-BTK- 243	471,20	δ = 10.90 (s, 1H), 9.38 (s, 1H), 8.60 - 8.35 (m, 2H), 8.31-8.15 (m, 5H), 7.87 (t, J = 7.9 Hz, 1H), 7.24 7.15 (m, 1H), 6.94 - 6.74 (m, 1H), 6.17 - 6.05 (m, 1H), 5.72, 5.59 (2d, J = 10.5 Hz, 1H, rotamers), 4.79 (s, 1H), 4.64, 4.42 (2d, J = 12.6 Hz, 1H, rotamers), 4.22, 4.04 (2d, J = 13.3 Hz, 1H, rotamers), 3.82 3.37 (m, 1H), 3.33 - 3.03 (m, 1H), 2.42 - 2.26 (m, 2H), 1.99 (s, 1H), 1.63 (s, 1H)
BCD-BTK- 244	489,20	δ= 11.05 (s, 1H), 9.36 (d, J =2.2 Hz, 1H), 8.49 (d, J = 3.6 Hz, 1H), 8.43 (d, J= 3.1 Hz, 1H), 8.26 (dd, J= 9.2, 4.2 Hz, 1H), 8.20 (s, 4H), 7.82 (td, J= 8.7, 3.1 Hz, 1H), 6.94 - 6.74 (m, 1H), 6.17 - 6.00 (m, 1H), 5.72, 5.59 (2d, J - 10.4 Hz, 1H, rotamers), 4.80 (s, 1H), 4.64, 4.22 (2d, J = 12.7 Hz, 1H, rotamers), 4.42, 4.04 (2d, J = 13.7 Hz, 1H, rotamers), 3.80 - 3.37 (m, 1H), 3.33 - 3.05 (m, 1H), 2.43 - 2.27 (m, 2H), 1.99 (s, 1H), 1.63 (s, 1H)
BCD-BTK- 245	539,10	δ = 11.42 (s, 1H), 9.37 (d, J=2.2 Hz, 1H), 8.70 (d, J = 5.2 Hz, 1H), 8.58 (s, 1H), 8.50 (d, J= 3.6 Hz, 1H), 8.23 (s, 4H), 7.56 (dd, J = 5.1, 1.6 Hz, 1H), 6.92 6.75 (m, 1H), 6.16 - 6.05 (m, 1H), 5.72, 5.59 (2d, J = 10.3 Hz, 1H, rotamers), 4.80 (s, 1H), 4.63, 4.21 (2d, J = 12.6 Hz, 1H, rotamers), 4.42, 4.04 (2d, J = 13.6 Hz, 1H, rotamers), 3.81 - 3.38 (m, 1H), 3.33 - 3.02 (m, 1H), 2.41 - 2.27 (m, 2H), 1.99 (s, 1H), 1.64 (s, 1H)
BCD-BTK- 246	487,20	δ = 9.30 (d, J= 2.3 Hz, 1H), 8.77 (s, 1H), 8.50 (d, J= 5.7 Hz, 1H), 8.47 (d, J= 3.6 Hz, 1H), 8.17 (d, J= 8.5 Hz, 2H), 7.86 (s, 1H), 7.77 (s, 1H), 7.44 - 7.35 (m, 2H), 6.93 - 6.73 (m, 2H), 6.17 - 6.02 (m, 1H), 5.71, 5.59 (2d, J = 10.4 Hz, 1H, rotamers), 4.77 (s, 1H),

150

Compound	ESI-MS, [M+H]+	NMR 'il (DMSO-d6), δ, ppm
		4.63, 4.22 (d, J = 12.7 Hz, 1H, rotamers), 4.40, 4.05 (2d, J= 13.6 Hz, 1H, rotamers), 3.76 - 3.35 (m, 1H), 3.14 - 3.03 (m, 1H), 2.41 - 2.24 (m, 2H), 1.98 (s, 1H), 1.63 (s, 1H)
BCD-BTK- 247	563,20	δ= 11.20 (s, 1H), 9.37 (d, J-2.2 Hz, 1H), 8.55 (d, J = 5.1 Hz, 1H), 8.50 (d, J= 3.6 Hz, 1H), 8.39 (s, 1H), 8.22 (s, 4H), 7.32 (dd, J = 5.2, 1.5 Hz, 1H), 6.93 6.75 (m, 1H), 6.19 - 6.02 (m, 1H), 5.72, 5.59 (2d, J= 10.5 Hz, 1H, rotamers), 4.80 (s, 1H), 4.63, 4.22 (2d, J = 12.6 Hz, 1H, rotamers), 4.42, 4.04 (2d, J = 13.6 Hz, 1H, rotamers), 3.81 - 3.37 (m, 1H), 3.33 - 3.05 (m, 1H), 2.41 - 2.29 (m, 2H), 2.29 - 2.13 (m, 2H), 1.99 (s, 1H), 1.63 (s, 1H), 1.47 - 1.34 (m, 2H), 0.94 (t, J=1A Hz, 3H)
BCD-BTK- 248	489,20	δ = 11.11 (s, 1H), 9.37 (d, J= 2.2 Hz, 1H), 8.50 (d, J = 3.6 Hz, 1H), 8.20 (s, 4H), 8.17 (dd, J= 8.1, 2.4 Hz, 1H), 8.05 (q, J = 8.2 Hz, 1H), 6.94 (dd, J= 8.0, 2.5 Hz, 1H), 6.94 - 6.74 (m, 1 H), 6.19 - 6.02 (m, 1H), 5.72, 5.59 (2d, J = 10.5 Hz, 1H, rotamers), 4.79 (s, 1H), 4.64, 4.22 (2d, J= 12.6 Hz, 1H, rotamers), 4.42, 4.04 (d, J = 13.6 Hz, 1H, rotamers), 3.80 - 3.37 (m, 1H), 3.33 - 3.00 (m, 1H), 2.44 - 2.26 (m, 2H), 1.99 (s, 1H), 1.63 (s, 1H)
BCD-BTK- 249	489,20	δ - 10.91 (s, 1H), 9.38 (d, J= 2.2 Hz, 1H), 8.50 (d, J = 3.6 Hz, 1H), 8.35 (dt, J= 4.7, 1.3 Hz, 1H), 8.27 8.18 (m, 4H), 7.88 - 7.82 (m, 1H), 7.47 - 7.41 (m, 1H), 6.93 - 6.74 (m, 1H), 6.17 - 6.05 (m, 1H), 5.72, 5.59 (2d, J = 10.4 Hz, 1H, rotamers), 4.80 (s, 1H), 4.64, 4.23 (2d, J= 12.7 Hz, 1H, rotamers), 4.42, 4.05 (2d, J= 13.6 Hz, 1H, rotamers), 3.79 - 3.36 (m, 1H), 3.32 - 3.04 (m, 1H), 2.42 - 2.27 (m, 2H), 1.99 (s, 1H), 1.64 (s, 1H)
BCD-BTK- 250	520,20	δ = 11.39 (s, 1H), 8.70 (d, 5.1 Hz, 1H), 8.58 (s, 1H), 8.24 - 8.20 (m, 2H), 7.82 (s, 1H), 7.79 (d, J = 8.1 Hz, 2H), 7.56 (dd, J = 5.2, 1.5 Hz, 1H), 6.92 6.76 (m, 1H), 6.17 - 6.01 (m, 3H), 5.71, 5.62 (2d, J= 10.4 Hz, 1H, rotamers), 5.20 (s, 1H), 4.68, 4.31 (2d, J = 12.5 Hz, 1H, rotamers), 4.37, 4.07 (2d, J= 13.5

151

Compound	ESI-MS, [M+H]+	NMR Ή (DMSO-d6), δ, ppm
		Hz, 1H, rotamers), 3.70 - 3.33 (m, 1H), 3.27 - 2.86 (m, 1H), 2.35 - 2.21 (m, 2H), 1.98 - 1.87 (m, 1H), 1.59 (s, 1H)
BCD-BTK251	570,20	δ = 11.09 (s, 1H), 8.22 - 8.15 (m, 3H), 8.05 (q, J = 8.2 Hz, 1H), 7.82 (s, 1H), 7.77 (d, J = 8.0 Hz, 2H), 6.94 (dd, J = 8.0, 2.5 Hz, 1H), 6.92 - 6.76 (m, 1H), 6.18 - 5.99 (m, 3H), 5.71, 5.62 (d, J = 10.5 Hz, 1H, rotamers), 5.20 (s, 1H), 4.69, 4.31 (2d, J = 12.6 Hz, 1H, rotamers), 4.37, 4.06 (2d, J = 13.6 Hz, 1H, rotamers), 3.68 - 3.33 (m, 1H), 3.27 - 2.83 (m, 1H), 2.35-2.20 (m, 2H), 1.92 (s, 1H), 1.59 (s, 1H)
BCD-BTK- 252	579,20	δ = 11.20 (s, 1H), 9.46 (s, 1H), 8.58 - 8.50 (m, 2H), 8.39 (s, 1H), 8.25 - 8.17 (m, 4H), 7.32 (d, J= 5.1 Hz, 1H), 6.94 - 6.75 (m, 1H), 6.20 - 6.03 (m, 1H), 5.72, 5.60 (2d, J = 10.4 Hz, 1H, rotamers), 5.29 (s, 1H), 4.69, 4.29 (2d, J= 12.2 Hz, 1H, rotamers), 4.43, 4.06 (2d, J = 13.4 Hz, 1H), 3.81 - 3.41 (m, 1H), 3.30 2.98 (m, 1H), 2.40 - 2.12 (m, 6H), 1.98 (s, 1H), 1.64 (s, 1H), 1.48 - 1.33 (m, 2H), 0.94 (t, J= 7.4 Hz, 3H)
BCD-BTK- 253	507,10	δ = 10.69 (s, 1H), 9.67 (s, 2H), 9.57 (s, 1H), 8.59 (s, 1H), 8.45 (d, J = 2.8 Hz, 1H), 8.34 (dd, J = 8.8, 3.7 Hz, 1H), 7.90 (td, J = 8.7, 3.0 Hz, 1H), 6.96 - 6.71 (m, 1H), 6.19 - 5.99 (m, 1H), 5.72, 5.59 (2d, J= 10.4 Hz, 1H, rotamers), 5.37 (s, 1H), 4.66, 4.19 (2d, J = 11.8 Hz, 1H, rotamers), 4.42, 4.04 (2d, J = 14.2 Hz, 1H, rotamers), 3.86 - 3.47 (m, 1H), 3.33 - 3.04 (m, 1H), 2.40-2.28 (m, 2H), 1.99 (s, 1H), 1.65 (s, 1H)
BCD-BTK- 254	594,10	δ = 11.17 (s, 1H), 8.55 (d, J = 5.1 Hz, 1H), 8.39 (s, 1H), 8.21 (d, J = 8.4 Hz, 2H), 7.84 - 7.75 (m, 3H), 7.32 (dd, J = 5.1, 1.4 Hz, 1H), 6.93 - 6.74 (m, 1H), 6.19 - 5.98 (m, 3H), 5.71, 5.62 (2d, J = 10.3 Hz, 1H, rotamers), 5.19 (s, 1H), 4.68, 4.31 (2d, J = 12.2 Hz, 1H, rotamers), 4.37, 4.07 (2d, J = 13.3 Hz, 1H, rotamers), 3.68 - 3.25 (m, 1H), 3.26 - 2.87 (m, 1H), 2.34 - 2.14 (m, 4H), 1.92 (d, J= 7.4 Hz, 1H), 1.58 (s, 1H), 1.46 - 1.35 (m, 2H), 0.93 (t, J= 7.4 Hz, 3H)
BCD-BTK- 255	487,20	δ = 9.24 (d, J = 22 Hz, 1H), 8.48 - 8.43 (m, 2H), 8.04 (d, J= 8.6 Hz, 2H), 7.94 (s, 1H), 7.64 - 7.54 (m,

152

Compound	ESI-MS, [M+H]+	NMR Ή (DMSO-d6), δ, ppm
		2H), 7.52 (s, 1H), 7.16 - 7.10 (m, 2H), 6.92 - 6.72 (m, 1H), 6.17 - 6.03 (m, 1H), 5.71, 5.58 (2d, J= 10.4 Hz, 1H, rotamers), 4.74 (s, 1H), 4.62, 4.22 (2d, J = 12.5 Hz, 1H, rotamers), 4.39, 4.04 (d, J = 13.6 Hz, 1H, rotamers), 3.76 - 3.32 (m, 1H), 3.29 - 2.98 (m, 1H), 2.39 - 2.24 (m, 2H), 1.97 (s, 1H), 1.61 (s, 1H)
BCD-BTK- 258	511,10	δ = 10.89 (s, 1H), 8.38 - 8.32 (m, 2H), 8.22 - 8.18 (m, 2H), 7.88 - 7.82 (m, 1H), 7.79 (2d, J = 8.1 Hz, 2H), 7.47 - 7.42 (m, 1H), 7.29 - 6.62 (m, 2H), 6.19 6.00 (m, 1H), 5.72, 5.61 (2d, J = 10.5 Hz, 1H, rotamers), 5.02 - 4.82 (m, 1H), 4.62, 4.29 (2d, J = 12.7 Hz, 1H, rotamers), 4.39, 4.05 (2d, J = 13.4 Hz, 1H, rotamers), 3.78 - 3.43 (m, 1H), 3.33 - 2.85 (m, 1H), 2.31-2.10 (m, 2H), 1.96 (s, 1H), 1.55 (s, 1H)
BCD-BTK- 259	472,20	Ή NMR (400 MHz, DMSO, mixture of amide rotamers 60/40): δ = 9.39, 9.35 (2s, 1H, rotamers), 8.53 (s, 1H), 8.52 (s, 1H), 8.48 (s, 1H), 8.17 - 8.11 (m, 2H), 7.37 (dd, J= 8.7, 1.8 Hz, 2H), 7.08 - 7.03 (m, 2H), 4.97 - 4.88 (m, 1H), 4.85 - 4.50 (m, 2H), 3.68 - 3.39 (m, 2H), 2.12 - 1.88 (m, 3H), 1.87 - 1.69 (m, 1H), 1.99, 1.32 (2s, 3H, rotamers)
BCD-BTK- 260	487,20	'H NMR (400 MHz, DMSO, mixture of amide rotamers 60/40): δ = 10.92 (s, 1H), 9.42, 9.37 (2s, 1H), 8.50, 8.49 (2s, 1H), 8.43 - 8.40 (m, 1H), 8.25 8.19 (m, 3H), 8.16 (d, J = 8.5 Hz, 2H), 7.90 - 7.84 (m, 1H), 7.22 - 7.16 (m, 1H), 6.60 - 6.48, 5.91 5.82 (2m, 1H), 6.03 - 5.96, 5.63 - 5.55 (2m, 1H), 5.03 - 4.94 (m, 1H) 5.63 - 5.55, 5.03 - 4.94 (2m, 1H), 4.87 - 4.79 (m, 1H), 4.74 - 4.65 (m, 1H), 3.64 3.48 (m, 2H), 2.11-1.77 (m, 4H)
BCD-BTK- 261	458,20	δ = 9.38 (s, 1H), 8.54 - 8.49 (m, 3H), 8.19 - 8.10 (m, 2H), 7.37 (d, J= 8.7 Hz, 2H), 7.07 - 7.01 (m, 2H), 5.06 - 4.97 (m, 2H), 4.32 - 4.19 (m, 1H), 4.14 - 4.06 (m, 1H), 4.05 - 3.96 (m, 1H), 3.89 - 3.81 (m, 1H), 3.31-3.20 (m, 1H), 1.97 (s, 3H)
BCD-BTK- 262	485,20	δ = 10.91 (s, 1H), 9.46 (d, J= 5.2 Hz, 1H), 8.54 (d, J = 2.6 Hz, 1H), 8.43 - 8.39 (m, 1H), 8.24 - 8.15 (m, 5H), 7.90 - 7.83 (m, 1H), 7.22 - 7.16 (m, 1H), 6.09 -

153

Compound	ESI-MS, [M+H]+	NMR XH (DMSO-d6), δ, ppm
		6.04 (m, 1H), 4.27 - 4.14 (m, 1H), 4.02 - 3.83 (m, 2H), 3.73 - 3.53 (m, 1H), 2.61 - 2.53 (m, 2H), 2.05, 1.98 (2s, 3H, rotamers)
BCD-BTK- 263	460,10	*H NMR (400 MHz, DMSO, mixture of amide rotamers 60/40): δ = 9.35, 9.30 (2s, 1H, rotamers), 8.57 - 8.49 (m, 2H), 8.47 (d, J= 5.1 Hz, 1H), 8.15 8.09 (m, 2H), 7.40 - 7.32 (m, 2H), 7.09 - 7.01 (m, 2H), 6.60 - 6.49, 5.92 - 5.82 (2m, 1H, rotamers), 6.05 - 5.95, 5.05 - 5.01 (2m, 1H, rotamers), 5.66 5.57 (m, 1H), 5.00 - 4.91, 4.82 - 4.75 (2m, 2H, rotamers), 4.73 - 4.61 (m, 1H), 3.63 - 3.47 (m, 2H), 2.09- 1.75 (m, 4H)
BCD-BTK- 264	446,20	δ = 9.38 (s, 1H), 8.54-8.49 (m, 3H), 8.18 - 8.11 (m, 2H), 7.40 - 7.33 (m, 2H), 7.07 - 7.02 (m, 2H), 6.39 6.25 (m, 1H), 6.13 - 6.04 (m, 1H), 5.64 (dd, J= 10.3, 2.3 Hz, 1H), 5.03 (d, J= 7.3 Hz, 2H), 4.35 (t, 7= 8.6 Hz, 1H), 4.22 - 4.14 (m, 1H), 4.08 - 3.99 (m, 1H), 3.90 (dd, 7= 10.2, 5.6 Hz, 1H), 3.35 - 3.21 (m, 1H)
BCD-BTK- 265	458,20	δ = 9.39 (d, 7= 5.2 Hz, 1H), 8.55 - 8.48 (m, 3H), 8.17 - 8.08 (m, 2H), 7.43 - 7.30 (m, 2H), 7.07 - 7.00 (m, 2H), 6.10 - 5.97 (m, 1H), 4.27 - 4.11 (m, 1H), 4.03 - 3.77 (m, 2H), 3.75 - 3.51 (m, 1H), 2.63 - 2.51 (m, 2H), 2.03, 1.97 (2s, 3H, rotamers)
BCD-BTK- 266	446,20	δ = 9.39 (d, 7 = 2.6 Hz, 1H), 8.57 - 8.46 (m, 3H), 8.18 - 8.04 (m, 2H), 7.39 - 7.30 (m, 2H), 7.08 - 6.97 (m, 2H), 6.75 - 6.50 (m, 1H), 6.22 - 5.95 (m, 2H), 5.75 - 5.58 (m, 1H), 4.22 - 4.10 (m, 1H), 4.05 - 3.56 (m, 3H), 2.71-2.51 (m, 2H)
BCD-BTK- 267	485,30	δ = 10.92 (s, 1H), 9.45 (s, 1H), 8.54 (s, 1H), 8.45 8.37 (m, 1H), 8.26 - 8.13 (m, 5H), 7.91 - 7.81 (m, 1H), 7.23 - 7.15 (m, 1H), 5.05 (d, 7= 7.2 Hz, 2H), 4.28-4.19 (m, 1H), 4.11 (dd, 7= 9.2, 5.4 Hz, 1H), 4.05 - 3.98 (m, 1H), 3.87 (dd, 7= 10.2, 5.5 Hz, 1H), 3.39-3.23 (m, 1H), 1.98 (s, 3H)
BCD-BTK- 268	570,30	δ = 11.22 (s, 1H), 9.76 (s, 1H), 9.02 (s, 1H), 8.55 (d, J= 5.1 Hz, 1H), 8.39 (d, 7 = 1.4 Hz, 1H), 8.23 (s, 4H), 7.33 (dd, 7= 5.2, 1.6 Hz, 1H), 6.96 - 6.76 (m, 1H), 6.18 - 6.02 (m, 1H), 5.72, 5.59 (2d, 7= 10.5 Hz,

154

Compound	ESI-MS, [M+H]+	NMR Ή (DMSO-d6), δ, ppm
		1H, rotamers), 5.09 (s, 1H), 4.62, 4.27 (2d, J = 12.9 Hz, 1H, rotamers), 4.47, 4.03 (2d, J = 13.4 Hz, 1H, rotamers), 3.87-3.61 (m, 1H), 3.47-3.01 (m, 1H), 2.40 - 2.31 (m, 2H), 2.30 - 2.13 (m, 2H), 2.01 (s, 1H), 1.60 (s, 1H), 1.49 - 1.34 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H)
BCD-BTK- 269	499,20	’H NMR (400 MHz, DMSO, mixture of amide rotamers 60/40): δ = 10.91 (s, 1H), 9.46, 9.42 (2s, 1H, rotamers), 8.54, 8.51 (2s, 1H, rotamers), 8.42 (dd, 7=4.9, 1.8 Hz, 1H), 8.25-8.11 (m, 5H), 7.917.82 (m, 1H), 7.19 (dd, 7= 7.3, 4.9 Hz, 1H), 5.01 4.89 (m, 1H), 4.89 - 4.73 (m, 1H), 4.70 - 4.50 (m, 1H), 3.70 - 3.40 (m, 2H), 2.16 - 1.68 (m, 4H), 2.00, 1.31 (2s, 3H, rotamers)
BCD-BTK- 270	458,20	!H NMR (400 MHz, DMSO, mixture of amide rotamers 50/50): δ = 9.41, 9.39 (2s, 1H, rotamers), 8.61 - 8.55 (m, 2H), 8.53 (d, 7= 2.8 Hz, 1H), 8.18 8.12 (m, 2H), 7.44 - 7.38 (m, 2H), 7.19 - 7.11 (m, 2H), 6.11-6.00 (m, 1H), 4.26-4.11 (m, 1H),4.O23.81 (m, 2H), 3.74 - 3.52 (m, 1H), 2.65 - 2.50 (m, 2H), 2.03, 1.97 (2s, 3H, rotamers)
BCD-BTK- 271	485,20	‘H NMR (400 MHz, DMSO, mixture of amide rotamers 50/50): δ = 10.91 (s, 1H), 9.47, 9.45 (2s, 1H, rotamers), 8.55, 8.54 (2s, 1H, rotamers), 8.43 8.40 (m, 1H), 8.25 - 8.14 (m, 5H), 7.90 - 7.84 (m, 1H), 7.24-7.16 (m, 1H), 6.15-6.01 (m, 1H),4.294.11 (m, 1H), 4.07 - 3.80 (m, 2H), 3.75 - 3.51 (m, 1H), 2.63 - 2.53 (m, 2H), 2.05, 1.98 (2s, 3H, rotamers)
BCD-BTK- 272	446,20	δ = 9.39, 9.38 (2s, 1H, rotamers), 8.56 - 8.49 (m, 3H), 8.15 - 8.10 (m, 2H), 7.41 - 7.26 (m, 2H), 7.10 7.01 (m, 2H), 6.75 - 6.45 (m, 1H), 6.23 - 6.11 (m, 1H), 6.12 - 5.97 (m, 1H), 5.75 - 5.59 (m, 1H), 4.19 4.13 (m, 1H), 4.05 - 3.82 (m, 2H), 3.79 - 3.59 (m, 1H), 2.65-2.56 (m, 2H)
BCD-BTK- 273	473,20	δ = 10.91 (s, 1H), 9.46 (d, 7= 2.3 Hz, 1H), 8.55 (s, 1H), 8.43 - 8.39 (m, 1H), 8.26 - 8.11 (m, 5H), 7.91 7.82 (m, 1H), 7.23 - 7.16 (m, 1H), 6.75 - 6.57 (m,

155

Compound	ESI-MS, [M+H]+	NMR Ή (DMSO-d6), δ, ppm
		1H), 6.23 - 6.14 (m, 1H), 6.13 - 5.99 (m, 1H), 5.75 5.63 (m, 1H), 4.26 - 4.12 (m, 1H), 4.08 - 3.82 (m, 2H), 3.82 - 3.59 (m, 1H), 2.71 - 2.52 (m, 2H)
BCD-BTK- 274	487,20	δ = 9.28 (d, 7= 2.2 Hz, 1H), 8.88 (d, 7= 1.7 Hz, 1H), 8.62 (d, 7= 2.7 Hz, 1H), 8.46 (d, 7 = 3.7 Hz, 1H), 8.21 (s, 1H), 8.12 (d, 7= 8.4 Hz, 2H), 7.88 (dd, 7 = 2.8, 1.8 Hz, 1H), 7.68 (s, 1H), 7.32 - 7.24 (m, 2H), 6.95 - 6.73 (m, 1H), 6.18 - 6.02 (m, 1H), 5.71, 5.59 (2d, 7= 10.4 Hz, 1H, rotamers), 4.76 (s, 1H), 4.63, 4.22 (2d, 7= 12.8 Hz, 1H, rotamers), 4.40, 4.04 (2d, J= 13.8 Hz, 1H, rotamers), 3.77 - 3.35 (m, 1H), 3.27 - 2.99 (m, 1H), 2.41 - 2.17 (m, 2H), 1.97 (s, 1H), 1.62 (s, 1H)
BCD-BTK- 275	473,20	δ = 10.91 (s, 1H), 9.46 (d, 7 = 2.4 Hz, 1H), 8.55 (s, 1H), 8.41 (dd, 7= 4.9, 1.8 Hz, 1H), 8.24 - 8.12 (m, 5H), 7.91 - 7.83 (m, 1H), 7.23 - 7.15 (m, 1H), 6.74 6.55 (m, 1H), 6.22 - 6.14 (m, 1H), 6.13 - 5.99 (m, 1H), 5.77-5.63 (m, 1H), 4.29-4.11 (m, 1H), 4.073.83 (m, 2H), 3.81 - 3.60 (m, 1H), 2.69 - 2.53 (m, 2H)
BCD-BTK- 276	473,20	δ = 10.92 (s, 1H), 9.45 (s, 1H), 8.54 (s, 1H), 8.45 8.39 (m, 1H), 8.25 - 8.16 (m, 5H), 7.92 - 7.81 (m, 1H), 7.24 - 7.14 (m, 1H), 6.39 - 6.24 (m, 1H), 6.13 6.04 (m, 1H), 5.68 - 5.62 (m, 1H), 5.05 (d, 7= 7.3 Hz, 2H), 4.39 - 4.31 (m, 1H), 4.23 - 4.16 (m, 1H), 4.10 - 4.00 (m, 1H), 3.97 - 3.83 (m, 1H), 3.38 - 3.25 (m, 1H)
BCD-BTK- 277	507,10	δ = 10.70 (s, 1H), 9.67 (s, 2H), 9.57 (s, 1H), 8.59 (s, 1H), 8.20 (dd, 7= 7.9, 2.2 Hz, 1H), 8.12 (q, 7= 8.1 Hz, 1H), 7.01 (dd, 7= 7.9, 2.2 Hz, 1H), 6.95 - 6.75 (m, 1H), 6.19 - 6.03 (m, 1H), 5.72, 5.59 (2d, 7= 10.4 Hz, 1H, rotamers), 5.42 - 5.24 (m, 1H), 4.66, 4.20 (2d, 7= 12.6 Hz, 1H, rotamers), 4.41, 4.04 (2d, J = 13.8 Hz, 1H, rotamers), 3.89 - 3.48 (m, 1H), 3.33 3.09 (m, 1H), 2.41 - 2.29 (m, 2H), 1.99 (s, 1H), 1.65 (s, 1H)
BCD-BTK- 278	513,30	Ή NMR (400 MHz, DMSO, mixture of amide rotamers 50/50): δ = 10.93, 10.92 (2s, 1H, rotamers),

156

Compound	ESI-MS, [M+H]+	NMR Ή (DMSO-d6), δ, ppm
		9.48, 9.45 (2s, 1H, rotamers), 8.56, 8.53 (2s, 1H, rotamers), 8.44 - 8.37 (m, 1H), 8.29 - 8.16 (m, 5H), 7.90 - 7.83 (m, 1H), 7.26 - 7.12 (m, 1H), 4.83 - 4.66 (m, 2H), 4.15 - 3.90 (m, 2H), 3.25 - 3.10 (m, 1H), 2.95 - 2.73 (m, 1H), 2.26 - 2.03 (m, 1H), 2.00, 1.54 (2s, 3H, rotamers), 1.87 - 1.62 (m, 2H), 1.52 - 1.26 (m, 2H)
BCD-BTK- 279	501,20	δ = 10.95 (s, 1H), 9.46 (s, 1H), 8.54 (s, 1H), 8.44 8.39 (m, 1H), 8.25 - 8.16 (m, 5H), 7.92 - 7.84 (m, 1H), 7.23 - 7.17 (m, 1H), 6.82 - 6.65 (m, 1H), 6.05, 6.00 (2d, J = 2.5 Hz, 1H, rotamers), 5.69 - 5.54 (m, 1H), 4.86 - 4.63 (m, 2H), 4.26 - 3.85 (m, 2H), 3.24 3.04 (m, 1H), 3.02 - 2.71 (m, 1H), 2.25 - 2.06 (m, 1H), 1.81-1.60 (m, 2H), 1.50- 1.27 (m, 2H)
BCD-BTK280	471,10	δ = 10.94 (s, 1H), 9.46 (s, 1H), 8.54 (s, 1H), 8.46 8.37 (m, 1H), 8.27 - 8.17 (m, 5H), 7.96 - 7.79 (m, 1H), 7.27 - 7.13 (m, 1H), 6.27 (p, J= 6.4 Hz, 1H), 4.74 (d, J = 6.6 Hz, 2H), 4.52 (d, J = 6.5 Hz, 2H), 2.03 (s, 3H)
BCD-BTK281	444,10	δ = 9.39 (s, 1H), 8.54 - 8.50 (m, 3H), 8.22 - 8.17 (m, 2H), 7.42 - 7.35 (m, 2H), 7.08 - 7.01 (m, 2H), 6.32 6.18 (m, 1H), 4.79 - 4.66 (m, 2H), 4.56 - 4.43 (m, 2H), 2.02 (s, 3H)
BCD-BTK- 282	432,20	δ = 9.39 (s, 1H), 8.55 - 8.48 (m, 3H), 8.23 - 8.16 (m, 2H), 7.42 - 7.35 (m, 2H), 7.08 - 7.01 (m, 2H), 6.46 6.35 (m, 1H), 6.31 - 6.22 (m, 1H), 6.21 - 6.12 (m, 1H), 5.77 - 5.68 (m, 1H), 4.88 - 4.76 (m, 2H), 4.58 4.50 (m, 2H)
BCD-BTK- 283	513,20	'H NMR (400 MHz, DMSO, mixture of amide rotamers 50/50): δ = 10.93, 10.92 (2s, 1H, rotamers), 9.48, 9.45 (2s, 1H, rotamers), 8.56, 8.53 (2s, 1H, rotamers), 8.43 - 8.39 (m, 1H), 8.25 - 8.17 (m, 5H), 7.90 - 7.84 (m, 1H), 7.21 - 7.17 (m, 1H), 4.78 - 4.66 (m, 2H), 4.13-3.92 (m, 2H), 3.25 - 3.10 (m, 1H), 2.90 - 2.75 (m, 1H), 2.23 - 2.06 (m, 1H), 2.00, 1.54 (2s, 3H, rotamers), 1.86 - 1.65 (m, 2H), 1.52 - 1.27 (m, 2H)
BCD-BTK-	487,20	<5 = 10.92 (s, 1H), 9.45 (s, 1H), 8.53 (s, 1H), 8.42 (dd, J= 4.9, 1.9 Hz, 1H), 8.29 - 8.12 (m, 5H), 7.93 - 7.81

157

Compound	ESI-MS, [M+H]+	NMR Ή (DMSO-d6), δ, ppm
284		(m, 1H), 7.19 (dd, 7 = 7.3, 4.9 Hz, 1H), 6.63 - 6.45 (m, 1H), 6.19 - 6.06 (m, 1H), 5.70 - 5.61 (m, 1H), 4.90 - 4.79 (m, 2H), 3.78 - 3.66 (m, 1H), 3.62 - 3.43 (m, 2H), 3.41 - 3.34 (m, 1H), 3.30 - 3.20 (m, 1H), 3.05 - 2.80 (m, 1H), 2.09 - 1.93 (m, 1H), 1.91 - 1.72 (m, 1H)
BCD-BTK- 285	487,20	δ = 10.92 (s, 1H), 9.45 (s, 1H), 8.54 (s, 1H), 8.45 8.39 (m, 1H), 8.27 - 8.13 (m, 5H), 7.92 - 7.82 (m, 1H), 7.25-7.11 (m, 1H), 6.62-6.45 (m, 1H), 6.196.06 (m, 1H), 5.69 - 5.59 (m, 1H), 4.93 - 4.79 (m, 2H), 3.78 - 3.66 (m, 1H), 3.63 - 3.43 (m, 2H), 3.43 3.32 (m, 1H), 3.28 - 3.25 (m, 1H), 3.03 - 2.78 (m, 1H), 2.14-1.70 (m, 2H)
BCD-BTK- 286	499,20	’H NMR (400 MHz, DMSO, mixture of amide rotamers 50/50): δ = 10.93, 10.92 (2s, 1H, rotamers), 8.55, 8.54 (2s, 1H, rotamers), 8.42, 8.41 (2s, 1H, rotamers), 8.26 - 8.13 (m, 5H), 7.91 - 7.83 (m, 1H), 7.19 (dd, 7= 7.3, 4.8 Hz, 1H), 4.92 - 4.75 (m, 2H), 3.80 - 3.63 (m, 1H), 3.59 - 3.41 (m, 2H), 3.31 - 3.17 (m, 1H), 2.99 - 2.82 (m, 1H), 2.03 - 1.92 (m, 1H), 2.00, 1.94 (2s, 3H, rotamers), 1.88 - 1.75 (m, 1H)
BCD-BTK- 287	499,30	*H NMR (400 MHz, DMSO, mixture of amide rotamers 50/50): δ = 10.92 (2s, 1H, rotamers), 9.46, 9.45 (2s, 1H, rotamers), 8.54, 8.53 (2s, 1H, rotamers), 8.42 (dd, 7= 5.1, 1.8 Hz, 1H), 8.27 - 8.15 (m, 5H), 7.93 - 7.82 (m, 1H), 7.23 - 7.14 (m, 1H), 4.94 - 4.75 (m, 2H), 3.85 - 3.64 (m, 1H), 3.60 - 3.41 (m, 2H), 3.43 - 3.33 (m, 1 H), 3.27 - 3.17 (m, 1H), 2.96 - 2.85 (m, 1H), 2.05 - 1.96 (m, 1H), 2.00, 1.94 (2s, 3H, rotamers), 1.89 - 1.76 (m, 1H)
BCD-BTK- 288	507,20	δ = 11.01 (s, 1H), 9.64 (s, 2H), 9.56 (s, 1H), 8.59 (s, 1H), 8.34 (s, 1H), 7.93 - 7.82 (m, 1H), 7.51 - 7.41 (m, 1H), 6.97 - 6.71 (m, 1H), 6.18 - 6.02 (m, 1H), 5.78 - 5.54 (m, 1H), 5.42 - 5.26 (m, 1H), 4.66, 4.19 (2s, 1H, rotamers) 4.41, 4.04 (2s, 1Ή, rotamers), 3.88 - 3.44 (m, 1H), 3.33 - 3.09 (m, 1H), 2.34 (s, 2H), 1.99 (s, 1H), 1.65 (s, 1H)
BCD-BTK- 289	499,20	lH NMR (400 MHz, DMSO, mixture of amide rotamers 50/50): δ = 10.93 (s, 1H), 9.47, 9.45 (2s, 1H, rotamers), 8.56, 8.53 (2s, 1H, rotamers), 8.44 -

158

Compound	ESI-MS, [M+H]+	NMR Ή (DMSO-d6), δ, ppm
		8.39 (m, 1H), 8.25 - 8.14 (m, 5H), 7.91 - 7.84 (m, 1H), 7.24 - 7.16 (m, 1H), 5.48 - 5.32, 5.30 - 5.20 (2m, 1H, rotamers), 4.60 - 4.43 (m, 1H), 4.26 - 3.97 (m, 1H), 3.95 - 3.84, 3.54 - 3.47 (2m, 1H, rotamers), 3.33-3.15 (m, 1H), 2.47-2.25 (m, 1H), 2.11-1.98 (m, 1H), 2.07, 1.79 (2s, 3H, rotamers), 1.72 - 1.55 (m, 1H)
BCD-BTK- 290	501,20	δ = 10.92 (s, 1H), 9.46 (s, 1H), 8.53 (s, 1H), 8.43 8.40 (m, 1H), 8.25 - 8.16 (m, 5H), 7.90 - 7.84 (m, 1H), 7.21 - 7.17 (m, 1H), 6.82 - 6.66 (m, 1H), 6.05, 6.00 (2d, J = 2.5 Hz, 1H, rotamers), 5.66 - 5.54 (m, 1H), 4.82 - 4.62 (m, 2H), 4.25 - 3.87 (m, 2H), 3.24 2.72 (m, 2H), 2.27 - 2.07 (m, 1H), 1.77 - 1.64 (m, 2H), 1.38 (s, 2H)
BCD-BTK- 291	557,20	δ = 10.96 (s, 1H), 9.69 (s, 2H), 9.58 (s, 1H), 8.73 (d, J= 5.1 Hz, 1H), 8.59 (d, J= 2.1 Hz, 2H), 7.63 (dd, J = 5.2, 1.6 Hz, 1H), 6.94 - 6.76 (m, 1H), 6.25 - 6.02 (m, 1H), 5.72, 5.59 (2d, J = 10.5 Hz, 1H, rotamers), 5.45 - 5.20 (m, 1H), 4.66, 4.21 (2d, J = 12.7 Hz, 1H, rotamers), 4.41, 4.04 (2d, J= 13.8 Hz, 1H, rotamers), 3.91 - 3.49 (m, 1H), 3.33 - 3.09 (m, 1H), 2.42 - 2.28 (m, 2H), 2.00 (s, 1H), 1.65 (s, 1H)
BCD-BTK- 292	581,30	δ = 10.77 (s, 1H), 9.68 (s, 2H), 9.58 (s, 1H), 8.59 8.54 (m, 2H), 8.43 (s, 1H), 7.39 (dd, J = 5.2, 1.5 Hz, 1H), 7.02 - 6.63 (m, 1H), 6.22 - 5.99 (m, 1H), 5.72, 5.59 (2d, J = 10.4 Hz, 1H, rotamers), 5.43 - 5.22 (m, 1H), 4.66, 4.21 (2d, J= 12.6 Hz, 1H, rotamers), 4.42, 4.04 (2d, J= 13.7 Hz, 1H, rotamers), 3.91 - 3.48 (m, 1H), 3.33 - 3.03 (m, 1H), 2.44 - 2.30 (m, 2H), 2.29 2.14 (m, 2H), 1.99 (s, 1H), 1.65 (s, 1H), 1.49 - 1.34 (m, 2H), 0.94 (t, J= 7.4 Hz, 3H)
BCD-BTK- 293	567,30	δ = 10.78 (s, 1H), 9.69 (s, 2H), 9.58 (s, 1H), 8.61 8.55 (m, 2H), 8.43 (s, 1H), 7.39 (dd, J= 5.2, 1.6 Hz, 1H), 6.97 - 6.70 (m, 1H), 6.23 - 6.01 (m, 1H), 5.72, 5.59 (2d, J= 10.4 Hz, 1H, rotamers), 5.45 - 5.25 (m, 1H), 4.66, 4.21 (2d, J= 12.6 Hz, 1H, rotamers), 4.42, 4.04 (2d, J = 13.9 Hz, 1 H, rotamers), 3.89 - 3.47 (m, 1H), 3.33 - 3.08 (m, 1H), 2.39 - 2.19 (m, 4H), 1.99

159

Compound	ESI-MS, [M+H]+	NMR '11 (DMSO-d6), δ, ppm
		(s, 1H), 1.65 (s, 1H), 0.97 (t, 7=7.5 Hz, 3H)
BCD-BTK- 295	514,30	’H NMR (400 MHz, DMSO, mixture of amide rotamers 70/80): δ = 10.88 (s, 1H), 8.45 - 8.37 (m, 1H), 8.27 - 8.16 (m, 3H), 7.93 - 7.84 (m, 1H), 7.84, 7.82 (2s, 1H, rotamers), 7.78 (dd, J = 8.4, 1.7 Hz, 2H), 7.23 - 7.16 (m, 1H), 6.04, 6.05 (2d, 2H, rotamers), 5.29, 5.15 (2tt, J = 9.0, 4.4 Hz, 1H, rotamers), 4.54, 4.45 (2dd, J = 13.0, 4.1 Hz, 1H, rotamers), 4.21, 4.03 (2d, J = 13.0 Hz, 1H, rotamers), 3.78, 3.35 (2dd, J= 12.7, 10.1 Hz, 1H), 3.33 - 3.06 (m, 1H), 2.41 - 2.19 (m, 2H), 2.06, 1.84 (2s, 3H, rotamers), 2.04 - 1.94 (m, 1H), 1.70 - 1.46 (m, 1H)

Example 9. Metabolic stability assay.

Assessment of the metabolic stability of candidate compounds allows to evaluate the résistance of the compounds to the action of biotransformation 5 enzymes. To assess the metabolic stability of the drug candidates, we used pooled human liver S9 fraction.

1) Metabolic stability in human liver S 9 fractions

The rate of enzymatic décomposition of a compound was detected by incubating the reaction mixture in a dry block heater at 37 °C; the reaction mixture 10 contained 0.5 mg/mL of pooled human liver S9 fraction (XenoTech, USA, cat# H0610), 10 mM of a drug candidate, 2 mM β-nicotinamide adenine dinucleotide (Carbosynth, UK, cat#NN10871) and 4 mM of magnésium chloride in 0.1M sodium phosphate buffer pH=7.4. The reaction was terminated by adding 100 pL of acetonitrile for each 100 pL of the reaction mixture. After the reaction was 15 terminated, the samples were centrifuged for 10 min at 10000 rpm. The supematant was chromatographed using Agilent 1200 chromatograph (Agilent, USA). We used gradient elution (1 mL/min flow rate). We plotted a calibration curve of the logarithm of the peak area vs. time. The gradient of the line corresponded to the élimination rate constant k. Based on the constant, determined

160 using the curve, we calculated the drug’s half-life (Ti/₂) and metabolism rate (CL_int).

The results characterized S9 stability of the drug candidates. The compounds demonstrate sufficient S 9 stability. The results are provided in Table 2 and Table 3.

2) Metabolic stability in human liver microsomes

The rate of enzymatic décomposition of a compound was detected by incubating the reaction mixture in a dry block heater at 37 °C; the reaction mixture contained 0.5 mg/mL of pooled human liver microsomes (XenoTech, USA, cat# H6010), 10 mM of a drug candidate, 2 mM β-nicotinamide adenine dinucleotide (Carbosynth, UK, cat#NN10871) and 4 mM of magnésium chloride in 0.1M sodium phosphate buffer pH=7.4. The reaction was terminated by adding 100 pL of acetonitrile for each 100 pL of the reaction mixture. After the reaction was terminated, the samples were centrifuged for 10 min at 10000 rpm. The supematant was chromatographed using Agilent 1200 chromatograph (Agilent, USA). We used gradient elution (1 mL/min flow rate). We plotted a calibration curve of the logarithm of the peak area vs. time. The gradient of the line corresponded to the élimination rate constant k. Based on the constant, determined using the curve, we calculated the drug’s half-life (Ti_/2) and metabolism rate (CL_int).

Elimination rate constant (k) — (—gradient) , . . 0.693

Half life fiiU (min) = —-—

161

V(pL mg) = volume of incubation (pL) protein in the incubation (mg)

Vx 0.693

Intrinsic Clearance (CL^OfuLinin⁷^ protein) --------The results characterized microsomal stability of the drug candidates. The compounds demonstrate sufficient microsomal stability and their rate of enzymatic 5 décomposition Cl_int is less than 47 pL/min/mg. The results are provided in Table 2 and Table 4.

Table 2. Results of metabolic stability.

Candidate No.	Stability
S9, Clint pL/min/mg	Microsomes, Clint pL/min/mg
Ibrutinib	15.8	111.8
BCD-BTK-123	6.64	51.0
BCD-BTK-125	3.12	22.8
BCD-BTK-134	7.56	32.2
BCD-BTK-139	11.04	31.6

Table 3. Results of S9 metabolic stability.

Candidate No.	Clint pL/min/mg	Candidate No.	Clint pL/min/mg
BCD-BTK-13	3,32	BCD-BTK-124	4,0
BCD-BTK-30	3,48	BCD-BTK-128	6,68
BCD-BTK-56	1,7	BCD-BTK-129	1,44
BCD-BTK-74	2,6	BCD-BTK-131	1,16
BCD-BTK-76	1,48	BCD-BTK-132	13,0
BCD-BTK-104	1,92	BCD-BTK-137	3,32
BCD-BTK-117	1,4	BCD-BTK-140	2,28
BCD-BTK-118	3,32	BCD-BTK-119	0,92
BCD-BTK-204	1.98	BCD-BTK-230	10.5
BCD-BTK-201	5.44	BCD-BTK-235	8.1

162

BCD-BTK-205	1.76	BCD-BTk-232	14
BCD-BTK-202	6.8	BCD-BTK-233	3.1
BCD-BTK-203	2.96	BCD-BTK-236	12.4
BCD-BTK-206	1.64	BCD-BTK-238	13
BCD-BTK-207	1.16	BCD-BTK-240	4.8
BCD-BTK-208	3.16	BCD-BTK-242	14.1
BCD-BTK-215	9.3	BCD-BTK-243	12
BCD-BTK-218	7.6	BCD-BTK-244	9.6
BCD-BTK-220	4.8	BCD-BTK-258	11.2
BCD-BTK-228	7.9	BCD-BTK-269	10
BCD-BTK-229	5.4	BCD-BTk-292	1.9

Table 4. Results of microsome metabolic stability.

Candidate No.	Cljnt pL/min/mg	Candidate No.	Clint pL/min/mg
BCD-BTK-204	30.4	BCD-BTK-244	39.2
BCD-BTK-205	31.1	BCD-BTK-245	32.8
BCD-BTK-206	24.1	BCD-BTK -241	27.4
BCD-BTK-207	33.1	BCD-BTK -247	42.2
BCD-BTK-210	3.0	BCD-BTK -252	11.2
BCD-BTK-212	11.2	BCD-BTK-258	39
BCD-BTK-215	24.2	BCD-BTK-261	41
BCD-BTK-223	26	BCD-BTK-262	16.8
BCD-BTK-227	18.4	BCD-BTK-264	18.2
BCD-BTK-228	10	BCD-BTK-265	37.6
BCD-BTK-229	3.5	BCD-BTK-266	37.6
BCD-BTK-233	36	BCD-BTK-268	7.4
BCD-BTK-239	27.3	BCD-BTK-269	41.8
BCD-BTK-240	24.5	BCD-BTK-272	28.6
BCD-BTK-242	12.4	BCD-BTK-273	16

163

BCD-BTK-243

21.4

BCD-BTK -292

12.2

Example 10. Stability in human blood plasma.

Assessment of the stability of candidate compounds in human blood plasma allows to evaluate the résistance of the compounds to the action of blood plasma enzymes, for example, esterases.

To assess the blood plasma stability of the drug candidates, we used pooled human blood plasma taken from ten healhy donors. The initial solution (10 Mm in DMSO) was diluted with pooled blood plasma to ΙΟμΜ (test solution). The test solution had been incubated for 4 hours in a dry block heater at 37 °C. We determined peak areas of the compounds corresponding to the start of the test (before incubating) and the end of the test (after incubating in a dry block heater at 37 °C) by HPLC using Agilentl200 chromatograph (Agilent, USA) with preliminary protein précipitation with acetonitrile. We used gradient elution (1 mL/min flow rate). We determined amount of substance in the sample in % after incubation.

We evaluated the stability of the compounds. Compounds described herein hâve the stability level in plasma more than 80%. Enzymes of blood plasma potentially will not reduce the concentration of compounds in the bloodstream and thus will not influence the effectiveness in vivo. The results are presented in table 5.

Table 5. Results of stability in human blood plasma.

Candidate No.	Amount of substance in the sample, %	Candidate No.	Amount of substance in the sample, %
BCD-BTK-204	91.9	BCD-BTK -241	80.6
BCD-BTK-205	88.6	BCD-BTK -247	87.3
BCD-BTK-203	84.7	BCD-BTK -250	84.5

164

BCD-BTK-206	87.6	BCD-BTK -251	89.2
BCD-BTK-207	82.6	BCD-BTK -252	85.2
BCD-BTK-208	91.4	BCD-BTK -254	93.0
BCD-BTK-211	94.8	BCD-BTK-259	90.7
BCD-BTK-212	90.8	BCD-BTK-260	83.2
BCD-BTK-216	80.4	BCD-BTK-261	100.0
BCD-BTK-217	90.8	BCD-BTK-263	86.7
BCD-BTK-218	92.0	BCD-BTK-265	81.7
BCD-BTK-220	90.2	BCD-BTK-266	87.2
BCD-BTK-221	80.5	BCD-BTK-268	91.0
BCD-BTK-222	100.0	BCD-BTK-269	95.4
BCD-BTK-226	84.5	BCD-BTK-267	100.0
BCD-BTK-228	85.2	BCD-BTK-274	91.3
BCD-BTK-229	83.5	BCD-BTK-278	96.2
BCD-BTK-230	93.3	BCD-BTK-283	97.4
BCD-BTK-231	93.1	BCD-BTK-289	100.0
BCD-BTK-234	83.5	BCD-BTK-290	100.0
BCD-BTk-232	88.6	BCD-BTK -292	93.3
BCD-BTK-236	96.8	BCD-BTK -293	85.7
BCD-BTK-239	80.3	BCD-BTK -295	100.0
BCD-BTK-240	100.0	BCD-BTK -125	97.8
BCD-BTK-242	100.0	BCD-BTK -134	89.7
BCD-BTK -237	95.5	BCD-BTK -139	87.1

Example 11. Chemical stability.

Assessment of Chemical stability of the compounds allows to assess their stability in gastric fluid.

A concentrate of SGF without enzymes, pH=1.4 (Sigma Ireland, cat#01651) was used as artificial gastric fluid. The initial candidate solution (10 mM in

165

DMSO) was diluted with the working solution of SGF to the concentration of 10 μηι (test solution). The test solution was incubated in a dry block heater at 37 °C. We determined peak areas of the compounds corresponding to the start of the test (before incubating) and the end of the test (after incubating in a dry block 5 heater at 37 °C) by HPLC using Agilentl200 chromatograph (Agilent, USA). We used gradient elution (1 mL/min flow rate). We determined amount of substance in the sample in % after incubation.

We evaluated the stability of the compounds. Compounds described herein are chemically stable in acidic environment of artificial gastric fluid. The results ίο are presented in table 6.

Table 6. The results of Chemical stability.

Candidate No.	Amount of substance in the sample in %	Candidate No.	Amount of substance in the sample in %
BCD-BTK-9	100,0	BCD-BTK-122	97,5
BCD-BTK-13	91,0	BCD-BTK-124	95,8
BCD-BTK-30	97,7	BCD-BTK-128	100,0
BCD-BTK-56	99,0	BCD-BTK-129	97,8
BCD-BTK-74	98,7	BCD-BTK-131	97,7
BCD-BTK-76	99,7	BCD-BTK-132	97,6
BCD-BTK-104	99,4	BCD-BTK-133	100,0
BCD-BTK-117	99,7	BCD-BTK-136	89,9
BCD-BTK-118	95,4	BCD-BTK-137	94,3
BCD-BTK-119	100,0	BCD-BTK-140	99,4
BCD-BTK -204	100	BCD-BTK -248	100
BCD-BTK -201	100	BCD-BTK -249	100
BCD-BTK -205	100	BCD-BTK -250	100
BCD-BTK -202	95.5	BCD-BTK -251	100
BCD-BTK -203	100	BCD-BTK -252	94.4

166

BCD-BTK -206	100	BCD-BTK -254	100
BCD-BTK -207	100	BCD-BTK -255	100
BCD-BTK -208	100	BCD-BTK-258	100
BCD-BTK -210	96.1	BCD-BTK-259	100
BCD-BTK -211	100	BCD-BTK-260	100
BCD-BTK -212	100	BCD-BTK-261	100
BCD-BTK -213	97.4	BCD-BTK-262	100
BCD-BTK -214	100	BCD-BTK-263	100
BCD-BTK -215	100	BCD-BTK-264	97.8
BCD-BTK -216	96.3	BCD-BTK-265	94.8
BCD-BTK -217	95.3	BCD-BTK-266	100
BCD-BTK -218	96	BCD-BTK-268	99.3
BCD-BTK-219	96.7	BCD-BTK-269	100
BCD-BTK-220	100	BCD-BTK-270	99.1
BCD-BTK-221	91.3	BCD-BTK-271	100
BCD-BTK-222	100	BCD-BTK-267	100
BCD-BTK-223	96.7	BCD-BTK-272	100
BCD-BTK-224	100	BCD-BTK-273	100
BCD-BTK-225	100	BCD-BTK-274	100
BCD-BTK-226	100	BCD-BTK-275	100
BCD-BTK-227	100	BCD-BTK-276	100
BCD-BTK-228	99.9	BCD-BTK-277	99.8
BCD-BTK-229	99.8	BCD-BTK-278	100
BCD-BTK-230	99.9	BCD-BTK-279	100
BCD-BTK-231	100	BCD-BTK-283	100
BCD-BTK-234	100	BCD-BTK-284	100
BCD-BTK-235	100	BCD-BTK-285	100
BCD-BTk-232	95.9	BCD-BTK-289	100
BCD-BTK-233	100	BCD-BTK-290	100

167

BCD-BTK-236	100	BCD-BTK -281	100
BCD-BTK-238	100	BCD-BTK -282	100
BCD-BTK-239	100	BCD-BTK -286	100
BCD-BTK-240	100	BCD-BTK -287	100
BCD-BTK-242	100	BCD-BTK -292	100
BCD-BTK-243	99.6	BCD-BTK -293	98.4
BCD-BTK-244	100	BCD-BTK -294	100
BCD-BTK-245	100	BCD-BTK -295	89.5
BCD-BTK-246	100	BCD-BTK -123	97
BCD-BTK -237	100	BCD-BTK -125	100
BCD-BTK -241	100	BCD-BTK -134	100
BCD-BTK -247	100	BCD-BTK -139	100

Example 12. Permeability through the monolayer of Caco-2 cells.

Assessment of permeability through the monolayer of Caco-2 cells allows to evaluate the ability of the candidate compounds to penetrate through biological membranes by active and passive transport.

Caco-2, the cells of the intestinal epithelium, had been cultured in transwell plate înserts with the filters (with pores of 0.4 pm, BD Falcon with High Density, ίο #353495) for 21 days, and then the integrity of the monolayer were estimated with Lucifer Yellow dye (Sigma-Aldrich, USA) by standard protocol. When setting the A—*B transfer, solutions of test substances were added in a buffer with pH 6.5 (Hanks solution, 10 mM HEPES, 15 mM glucose solution) with the concentration of 10 μΜ into the upper chamber; the lower chamber was filled with a buffer with 15 pH 7.4 (Hanks solution, 10 mM HEPES, 15 mM glucose solution, 1% BSA).

When setting B^A transfer, the upper chamber was filled with the buffer with pH 6.5, and solutions of the test substances were added in the buffer with pH 7.4 at the

168 concentration of 10 μΜ in the lower chamber. Propranolol was used as a control substance (as it has high permeability).

After incubating for 2 h at 37°C under 5% CO₂, the amounts of test compounds were determined in the upper and lower chambers by HPLC using Agilent 1200 chromatograph (Agilent, USA) with preliminary protein précipitation with acetonitrile. We used gradient elution (1 mL/min flow rate). We determined the areas of peaks corresponding to the compounds. On the basis of peak areas in the calibration standards we determined the concentration of compound in the initial solution and in the samples from the wells of the upper and lower chambers.

P_app, permeability through the cell layer, was calculated using the following formula:

Papp = (p * V)/ (C_(o) * t * Area), where P_app is the effective constant of permeability, m/s V is the volume of solution (0.8 ml in A^B test, 0.2 ml in B^A test), ml Area is the surface area of the membrane (0.33 cm ), cm t is the time of incubation (7200 sec), sec

C(₀) is the concentration of the initial solution, μΜ is the concentration of the solution after 2 hours (the concentration in the sample from the well of the lower chamber in A^B test; the concentration in the sample from the well of the top chamber in in B^A test), μΜ

The efflux coefficient shows the ability of cells to eliminate the substance from the bloodstream. The value was calculated with the following formula:

efflux Papp B—a/ Papp A—b ? where

Papp a-b i^s the value of the permeability in the direct test (A—>B);

Papp b-a i^s the value of the permeability in the backward test in (B—>A).

The compounds described herein show a high rate of the direct transport A^B Przpp>5*10^A(-6)cm/s, (the lumen of the intestine - bloodstream), while the efflux coefficient does not exceed 2, which indicates that efflux (driven by such

169 transporters as Pgp, BCRP) does not impose any restrictions on bioavailability of the compounds. The results are presented in table 7.

Table 7. Results of the assessment of permeability through the monolayer of

Caco-2 cells

Candidate No.	Caco-2, Papp, 10A(-6)cm/s	efflux
A -► B	Β Λ
BCD-BTK-123	14.8	7.4	0.5
BCD-BTK-125	21.0	13.2	0.6
BCD-BTK-134	25.8	12	0.4
BCD-BTK-139	52.2	5.7	0.1
BCD-BTK-202	20.3	1.91	0.09
BCD-BTK-203	9.31	8.4	0.9
BCD-BTK-210	11.88	0.21	0.02
BCD-BTK-211	19.21	3.55	0.18
BCD-BTK-213	8.39	5.17	0.62
BCD-BTK-214	17.81	0.87	0.05
BCD-BTK-216	29.64	8.72	0.29
BCD-BTK-217	37.26	18.94	0.51
BCD-BTK-218	20.2	17.38	0.86
BCD-BTK-222	5.06	6.97	1.38
BCD-BTK-223	5.9	0.3	0.05
BCD-BTK-226	12.1	5.5	0.45
BCD-BTK-228	8.0	1.4	0.17
BCD-BTK-229	10.7	12.2	1.14
BCD-BTK-230	26.5	2.68	0.1
BCD-BTK-231	9.8	1.84	0.19
BCD-BTK-234	8.2	9.2	1.1
BCD-BTk-232	6.27	3.58	0.57
BCD-BTK-236	6.51	2.87	0.44

170

Candidate No.	Caco-2, Papp, 10A(-6)cm/s	efflux
Λ Β	B , A
BCD-BTK-238	6.75	4.78	0.71
BCD-BTK-240	18.2	11.1	0.61
BCD-BTk-237	6.9	3.5	0.5
BCD-BTk-251	8.3	1.5	0.2
BCD-BTK-261	8.3	0.95	0.11
BCD-BTK-266	9.5	2.2	0.23
BCD-BTK-272	6.3	1.1	0.18
BCD-BTK-292	11.6	0.07	0.006
BCD-BTK-293	6.17	0.37	0.06

Example 13. In vitro inhibition of kinase activity.

To assess Btk kinase activity described herein, SignalChem kinase System was used. Btk kinase activity was determined in the reaction between recombinant Btk kinase enzyme (SignalChem #B10-10H) and Poly (4:1 Glu, Tyr) peptide to substrate in the presence of the inhibitor.

The measurements were carried out in a 25 pL reaction volume using a 96well plate (Corning, #3642). The kinase enzyme and inhibitor were pre-incubated for 10 minutes in the reaction buffer containing 25 mM of MOPS (pH 7.2), 12.5 mM of β-glycerophosphate, 27 mM of MgCl₂, 2 mM of MnCl₂, 5 mM of 15 EGTA, 2 mM of EDTA, 0.3 mM of DTT, and 1.2mg/mL of bovine sérum albumin. Staurosporine (Abcam Biochemicals, abl46588) was used as a reference inhibitor and 0.1% DMSO in the reaction buffer - as a négative control. The solution of 0.5 mg/mL peptide substrate and 50 pM ATP in the same buffer were

171 added; the solution was incubated for 180 minutes at 37 °C. To detect the amount of ATP taken up during the kinase reaction, the équivalent amount of ADP ( from the ADP Glo Détection Kit (Promega, #V9101)) was used according to the protocol. The reaction mixture was equilibrated to room température. 25 pL of 5 ADP-Glo Reagent were added into each well; the plate was incubated for 40 minutes. 50 pL of Kinase Détection Reagent were added; the plate was incubated for 30 minutes. The luminescence was measured with multimode plate reader (Tecan Infinité M200Pro, Switzerland). IC₅₀ values were calculated using Magellan 7.2 software (Tecan, Switzerland) approximating experimental points by 10 four-parameter logistic model with the optimization by Levenberg-Marquardt. The results are presented in the tables 8, 9 and 11.

For active compounds selected by screening using the target enzyme BTK, the values of IC₅₀ were determined on a kinase panel: EGFR (SignalChem, #E1011G), ITK (SignalChem, #I13-10G) and TEC (SignalChem, #T03-10G). The 15 results are presented in the table 9.

Table 8. Results of in vitro tests of inhibition of BTK kinase activity

Candidate No.	IC5o kinase BTK, nM	Candidate No.	IC50 kinase BTK, nM
BCD-BTK-135	6.28	BCD-BTK-242	1.77
BCD-BTK-128	4.94	BCD-BTK-243	29.31
BCD-BTK-201	19.06	BCD-BTK-244	55.74
BCD-BTK-202	74.56	BCD-BTK-237	12.65
BCD-BTK-203	1103.50	BCD-BTK-241	10.01
BCD-BTK-214	34.34	BCD-BTK-247	14.70
BCD-BTK-215	35.78	BCD-BTK-250	15.26
BCD-BTK-218	55.46	BCD-BTK-251	2.71
BCD-BTK-220	53.55	BCD-BTK-252	14.55

172

BCD-BTK-228	38.91	BCD-BTK-254	11.24
BCD-BTK-229	43.95	BCD-BTK-258	1.17
BCD-BTK-230	10.51	BCD-BTK-260	17.65
BCD-BTK-234	1.17	BCD-BTK-266	13.15
BCD-BTK-235	13.89	BCD-BTK-272	54.75
BCD-BTK-233	11.47	BCD-BTK-273	26.08
BCD-BTK-236	17.38	BCD-BTK-290	19.60
BCD-BTK-238	18.89	BCD-BTK-292	7.34
BCD-BTK-239	2.38	BCD-BTK-295	65.21
BCD-BTK-240	2.25	-	-

Table 9. Results of in vitro tests on the kinase panel

Candidate No.	IC50 kinase BTK, nM	IC5o kinase EGFR, nM	IC50 kinase ITK, nM	IC50 kinase TEC, nM
BCD-BTK-125	108.74	>1000	>1000	-
BCD-BTK-134	1.16	127.1	300	-
BCD-BTK-139	0.85	48.83	200	-
BCD-BTK-201	19.06	172.41	>300	55.22
BCD-BTK-202	74.56	>500	>500	>500
BCD-BTK-220	53.55	820.3	>300	>100
BCD-BTK-230	10.51	>500	>1000	>200
BCD-BTK-234	1.17	1.8	25.44	14.82
BCD-BTK-239	2.38	10.48	24.95	6
BCD-BTK-240	2.25	2.41	7.78	3.81
BCD-BTK-241	10.01	25.23	-	-
BCD-BTK-242	1.77	1.32	11.03	6.61
BCD-BTK-251	2.71	8.83	10.1	7.21
BCD-BTK-252	14.55	>500	>1000	>100
BCD-BTK-258	1.17	18.6	33.32	2.92

173

BCD-BTK-292 7.34 >500 63.45 77.85

These compounds are effective inhibitors of the kinase activity of Btk. Several compounds described herein show a high selectivity to the kinases EGFR, ITK, and TEC similar in structure.

Example 14. Antiproliférative activity against BTK-sensitive cell lines in vitro.

Antiproliférative activity of BTK inhibitors was measured in cell-based bioassay on B-cells cultures: Mino (mantle cell lymphoma, ATCC® CRL3000™), Z-138 (mantle cell lymphoma, ATCC® CRL-3001™) and DOHH2 (follicular lymphoma, Creative Bioarray CSC-C0219) using cell viability reagent Alamar Blue (Invitrogen, #DAL1100). Cells were cultured in 10% FBSsupplemented (HyClone, #SH3008803 / Gibco, #16140-071) RPMI-1640 (PanEco, #S330p) for at least 1 passage after thawing, washed with PBS andpassaged in 96well culture plates (Coming, #3599) with growth medium with 10% FBS (HyClone, #SH3008803 / Gibco, #16140-071) and antibiotic (50 pg/ml of gentamicin (Biolot, #1.3.16)) = 3*10⁴ cells in 50 μΐ of medium per well.

The compounds were dissolved in DMSO and diluted with the assay medium to final concentrations ranging from 0 to 100 pm. 150 μΐ of each diluted compound were then added to each well (final concentration of DMSO was less than 1%) and incubated at 37°C in an incubator under 5% of CO2 for 72 h. After incubation, 20 μΐ of Alamar Blue reagent (Invitrogen, #DAL1100) were added to each well. The plates were shaked on an orbital shaker (Biosan, Latvia) and then incubated for 14-16 hours at 37°C in the incubator.

The number of living cells were estimated, measuring the fluorescence signal at the excitation wavelength (λΕχ) of 540 nm and the émission wavelength (XEm) of 590 nm on a microplate reader (Tecan Infinité M200Pro, Switzerland).

For each compound, IC₅₀ was calculated using Magellan 7.2 software (Tecan, Switzerland) approximating experimental points by four-parameter logistic

174 model with the optimization by Levenberg-Marquardt. The results are presented in the tables 10 and 11.

The CC₅₀ values were determined in the test for General cytotoxicity on HepG2 cells (hepatocellular carcinoma, ATCC® HB-8065™). 2*10⁴ cells (in 50 5 μΐ) per well were seeded in 96-well plates (Corning, #3599) in DMEM medium (PanEco, #S420p), after 24 h of incubation 150 μΐ of candidate compounds were added to each well in the range of final concentrations from 200 μΜ to 4 μΜ and the plate was incubated in a total volume of 200 μΐ for 72 hours. Viability of the cells was assessed using Alamar Blue dye (Invitrogen, #DAL1100). CC₅₀ was 10 determined similarly (table 10).

The relationship between toxic (CC₅₀) and a therapeutic (IC₅₀) effects of the dose is the therapeutic index, which can be expressed as the ratio between CC₅₀ (HepG2) (general cytotoxicity of the candidate) and IC₅₀ (Mino) (antiproliférative activity on the target cells):

CC₅₀(HepG2)

Terapeutic index = —ÇMino~)

Table 10. The results of the assessment of the spécifie activity of the compounds in the cell-based antiproliférative test using the cell line panel (Mino, Z-138, DOHH2) and the results of the assessment of the general toxicity using HepG2 cell line are presented as average values of activity obtained in several tests.

Candidate No.	IC50 Mino, mkM	IC50 DOHH2, mkM	IC50 Z- 138, mkM	CC50 HepG2, mkM	CC50 (HepG2) / IC50 (Mino)
BCD-BTK-9	23.53	-	44.05	>100	>4.25
BCD-BTK-13	37.09	-	>50	>100	>2.70
BCD-BTK-30	15.62	-	22.7	61.49	3.94
BCD-BTK-56	32.51	-	30.51	>50	>1.54
BCD-BTK-74	21.9	-	17.62	100	4.57

175

Candidate No.	IC50 Mino, mkM	IC50 DOHH2, mkM	IC50 Z- 138, mkM	CC50 HepG2, mkM	CC50 (HepG2) / IC50 (Mino)
BCD-BTK-76	15.96	-	19.63	>100	>6.27
BCD-BTK-104	20.16	-	32.62	>100	>4.96
BCD-BTK-117	13.29	-	23.37	>50	>3.76
BCD-BTK-118	13.71	-	7.84	66.151	4.83
BCD-BTK-119	12.26	-	25.48	>100	>8.16
BCD-BTK-122	35.57	-	36.45	>100	>2.81
BCD-BTK-124	5.22	-	17.23	36.67	7.02
BCD-BTK-128	19.1	-	28.82	>100	>5.24
BCD-BTK-129	29.23	-	27.73	63.83	2.18
BCD-BTK-131	5.42	-	13.01	28.6	5.28
BCD-BTK-132	18.65	-	>100	57.65	3.09
BCD-BTK-133	19.75	-	38.25	99.67	5.05
BCD-BTK-136	12.54	-	>50	>100	>7.97
BCD-BTK-137	11.55	-	25.6	65.87	5.70
BCD-BTK-140	16.85	-	>50	>100	>5.93
BCD-BTK-201	11.90	7.97	6.54	>50	>4.20
BCD-BTK-202	7.79	8.87	12.64	31.99	4.10
BCD-BTK-203	13.61	13.97	16.01	61.88	4.55
BCD-BTK-204	21.04	23.50	20.94	62.04	2.95
BCD-BTK-205	16.58	20.18	24.89	57.16	3.45
BCD-BTK-208	21.50	-	32.22	111.97	5.21
BCD-BTK-211	5.67	23.01	17.28	45.23	7.97
BCD-BTK-212	3.50	-	14.81	28.05	8.01
BCD-BTK-213	3.19	19.72	9.70	>100	>31.3
BCD-BTK-214	1.28	>100	89.37	>100	>77.94
BCD-BTK-215	2.93	>100	8.00	>100	>34.11

176

Candidate No.	IC50 Mino, mkM	IC50 DOHH2, mkM	IC50 Z- 138, mkM	CC50 HepG2, mkM	CC50 (HepG2) / IC50 (Mino)
BCD-BTK-216	2.14	9.52	12.12	40.15	18.77
BCD-BTK-217	17.37	16.06	13.87	40.15	2.31
BCD-BTK-218	1.10	3.55	8.58	26.21	23.92
BCD-BTK-219	10.05	-	~50	>100	>9.95
BCD-BTK-220	10.51	9.46	14.18	>50	>9.51
BCD-BTK-221	10.46	3.05	4.98	5.32	0.51
BCD-BTK-222	19.35	26.30	26.29	50.25	2.60
BCD-BTK-224	11.03		>50	73.14	6.63
BCD-BTK-226	5.97	8.05	7.24	19.04	3.19
BCD-BTK-229	36.34	41.23	77.11	>100	>2.75
BCD-BTK-230	9.81	14.93	14.41	57.60	5.87
BCD-BTK-231	2.26	-	3.39	9.08	4.01
BCD-BTK-234	9.60	8.87	16.84	36.56	3.81
BCD-BTK-235	18.64	>100	>100	>100	>5.37
BCD-BTK-232	15.26	-	10.75	31.07	2.04
BCD-BTK-233	5.44	1.11	4.11	18.44	3.39
BCD-BTK-236	8.93	3.79	11.10	27.07	3.03
BCD-BTK-238	10.58	4.05	9.44	24.80	2.34
BCD-BTK-239	14.21	8.18	15.97	60.22	4.24
BCD-BTK-240	14.07	2.00	10.49	>100	>7.11
BCD-BTK-242	17.33	8.38	16.49	52.53	3.03
BCD-BTK-246	32.38	-	23.74	>100	>3.09
BCD-BTK-237	6.25	3.25	6.99	28.35	4.54
BCD-BTK-241	21.32	11.53	15.49	45.36	2.13
BCD-BTK-247	5.81	>100	>50	>100	>17.21
BCD-BTK-249	28.83	-	>50	-100	>3.47

177

Candidate No.	IC50 Mino, mkM	IC50 DOHH2, mkM	IC50 Z- 138, mkM	CC50 HepG2, mkM	CC50 (HepG2) / IC50 (Mino)
BCD-BTK-250	2.38	-	3.26	12.21	5.13
BCD-BTK-251	3.65	3.38	4.46	>50	>13.70
BCD-BTK-252	4.46	19.60	14.89	>100	>22.43
BCD-BTK-254	2.95	-	6.65	12.34	4.18
BCD-BTK-258	17.31	15.09	35.80	>50	>2.89
BCD-BTK-259	16.34	16.96	27.47	47.61	2.91
BCD-BTK-260	49.87	>100	>100	>100	>2.00
BCD-BTK-261	4.27	-	5.01	8.33	1.95
BCD-BTK-263	20.64	-	35.24	>50	>2.42
BCD-BTK-264	4.92	-	14.32	10.47	2.13
BCD-BTK-265	7.91	-	16.57	16.54	2.09
BCD-BTK-266	3.61	4.99	12.64	12.01	3.33
BCD-BTK-268	10.32	26.63	78.29	>100	>9.69
BCD-BTK-270	6.79	-	14.32	23.42	3.45
BCD-BTK-272	6.83	5.23	14.93	17.55	2.57
BCD-BTK-274	40.10	-	>100	38.01	0.95
BCD-BTK-277	17.95	20.58	30.05	41.87	2.33
BCD-BTK-284	27.88	-	114.98	>100	>3.59
BCD-BTK-285	10.09	-	>34.6	>100	>9.91
BCD-BTK-289	10.18	-	8.29	18.83	1.85
BCD-BTK-281	5.63	-	4.67	15.82	2.81
BCD-BTK-282	4.02	-	4.30	9.45	2.35
BCD-BTK-292	3.35	20.66	>50	>100	>29.81
BCD-BTK-293	4.30	>100	>50	>100	>23.23
BCD-BTK-295	2.00	1.94	1.19	32.53	16.23

178

Table 11. Results of the inhibition of BTK kinase activity in vitro and cell tests results

Candidate	ic50 kinase, nM	IC50 Mino, mkM	IC5O z138, mkM	cc50 HepG2, mkM	cc50 (HepG2)/IC50 (Mino)
Ibrutinib	1.73	9.18	15.124	54.89	5.98
BCD-BTK-125	108.74	7.297	14.62	27.13	4.18
BCD-BTK-134	1.16	11.586	21.18	63.99	5.80
BCD-BTK-139	0.85	10.22	21.13	39.65	3.88
BCD-BTK-123	1512.1	13.22	28.03	50.35	3.81

179

Claims (13)

1. A compound of Formula I:

Formula I or pharmaceutically acceptable sait, solvaté or stereoisomer thereof,

5 wherein:

Vi is C or N,

V₂ is C(R₂) or N, whereby if Vi is C then V₂ is N, if Vi is C then V₂ is C(R₂), or to if Vi is N then V₂ is C(R₂);

each n, k is independently 0, 1 ;

each R₂, R_n is independently H, D, Hal, CN, NR’R”, C(O)NR’R”, C_rC₆ alkoxy;

R₃ is H, D, hydroxy, C(O)Ci-C₆ alkyl, C(O)C₂-C₆ alkenyl, C(O)C₂-C₆ alkynyl, C_r C₆ alkyl;

15 R4 is H, Hal, CN, CONR’R”, hydroxy, Ci-Cô alkyl, Cj-C₆ alkoxy;

L is CH₂, NH, O or Chemical bond;

Ri is selected from the group of the fragments, consisting of:

180 each Ai, A₂, A₃, A₄ is independently CH, N, CHal;

each A₅, A_6j A₇, A₈, A₉ is independently C, CH or N;

R₅ is H, CN, Hal, CONR’R”, C_rC₆ alkyl, non-substituted or substituted by one or more halogens;

5 each R’ and R” is independently selected from the group, comprising H, Ci-C₆ alkyl, Ci-C₆ cycloalkyl, aryl;

R₆ is selected from the group:

each R₇, R₈, R₉, Rio is independently vinyl, methylacetylenyl;

10 Hal is Cl, Br, I, F.

2. The compound according to claim 1, wherein Ri is selected from the group including:

181

wherein R₅, Hal hâve the above meanings.

3. The compound according to daims 1-2, selected from the group

10 including:

(R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(4-oxopyridin-1 (4H)-yl)phenyl)-

1 H-pyrazolo[4,3-c]pyridin-7-carbonitrile (BCD-BTK-4) (R)-1 -( 1 -acryloylpiperidin-3-yl)-4-amino-3-(4-(4-oxopyridin-1 (4H)-yl)phenyl)-

1 H-pyrazolo[4,3-c]pyridin-7-carboxamide (BCD-BTK-6)

15 (R)-1 -(4-( 1 -( 1 -acryloylpiperidin-3 -yl)-4-amino-7-chloro-1 H-pyrazolo[4,3-c] pyridin-3-yl)phenyl)pyridin-4(lH)-one (BCD-BTK-9)

182 (R)-1 -(4-( 1 -( 1 -acryloylpiperidin-3-yl)-4-chloro-5-hydroxy-1 H-pyrazolo[3,4-b] pyridin-3-yl)phenyl)pyridin-4(lH)-one (BCD-BTK-13) (R)-1 -( 1 -acryloylpiperidin-3-yl)-5-hydroxy-3-(4-(4-oxopyridin-1 (4H)-yl)phenyl)-

1 H-indazol-7-carboxamide (BCD-BTK-18) (R)-1 -( 1 -acryloylpiperidin-3-yl)-3-(4-(4-oxopyridin-1 (4H)-yl)phenyl)- 1Hpyrazolo[4,3-c]pyridin-7-carboxamide (BCD-BTK-24) (R)-1 -(4-( 1 -( 1 -acryloylpiperidin-3 -yl)-7-chloro-1 H-pyrazolo [4,3 -c]pyridin-3-yl) phenyl)pyridin-4( 1 H)-one (BCD-BTK-30) (R)-1 -( 1 -acryloylpiperidin-3-yl)-4-cyano-3-(4-(4-oxopyridin-1 (4H)-yl)phenyl)- 1Hindazol-7-carboxamide (BCD-BTK-35) (R)-1 -( 1 -acryloylpiperidin-3-yl)-4-amino-3-(2-(4-oxopyridin-1 (4H)-yl)pyrimidin5-yl)-lH-pyrazolo[4,3-c]pyridin-7-carbonitrile (BCD-BTK-36) (R)-1 -( 1 -acryloylpiperidin-3-yl)-4-amino-3-(4-oxo-4H-[ 1,2 ’-bipyridin]-5 ’-yl)-1Hpyrazolo[4,3-c]pyridin-7-carbonitrile (BCD-BTK-38) (R)-1 -(5-( 1 -( 1 -acryloylpiperidin-3 -yl)-7-chloro-1 H-pyrazolo [4,3-c]pyridin-3-yl) pyrimidin-2-yl)pyridin-4( 1 H)-one (BCD-BTK-54) (R)-5'-(l-(l-acryloylpiperidin-3-yl)-7-chloro-lH-pyrazolo[4,3-c]pyridin-3-yl)-4H[ 1,2'-bipyridin]-4-one (BCD-BTK-56) (R)-1-(5-(1-(1 -acryloylpiperidin-3 -yl)-4-amino-7-chloro-1 H-pyrazolo [4,3 -c] pyridin-3-yl)pyrimidin-2-yl)pyridin-4( 1 H)-one (BCD-BTK-74) (R)-5 ’-(l-( 1 -acryloylpiperidin-3-yl)-4-amino-7-chloro-1 H-pyrazolo[4,3-c]pyridin3 -yl)-4H-[1,2’ -bipyridin]-4-one (BCD-BTK-76) (R)-1 -( 1 -acryloylpiperidin-3-yl)-4-amino-3-(2-(4-oxopyridin-1 (4H)-yl)pyrimidin5-yl)-1 H-pyrazolo[4,3-c]pyridine-7-carboxamide (BCD-BTK-86) (R)-1 -( 1 -acryloylpiperidin-3-yl)-4-amino-3-(4-oxo-4H-[ 1,2 ’ -bipyridin]-5 ’-yl)- 1Hpyrazolo[4,3 -c]pyridin-7-carboxamide (BCD-BTK-88) (R)-1 -( 1 -acryloylpiperidin-3 -yl)-3 -(2-(4-oxopyridin-1 (4H)-yl)pyrimidin-5 -yl)-1Hpyrazolo[4,3-c]pyridin-7-carboxamide (BCD-BTK-98) (R)-1 -( 1 -acryloylpiperidin-3 -yl)-3 -(4oxo-4H[ 1,2' -bipyridin]-5 ' -yl)-1 H-pyrazolo [4,3-c]pyridin-7-carboxamide (BCD-BTK-100)

183 (R)-l-(l-acryloylpiperidin-3-yl)-3-(4-(pyridin-4-yloxy)phenyl)-lH-pyrazolo[4,3-c] pyridin-7-carbonitrile (BCD-BTK-104) (R)-1 -( 1 -acryloylpiperidin-3 -yl)-3 -(2-(4-oxopyridin-1 (4H)-yl)pyrimidin-5-yl)-1Hpyrazolo[4,3-c]pyridin-7-carbonitrile (BCD-BTK-105) (R)-1 -( 1 -acryloylpiperidin-3 -yl)-3 -(4-oxo-4H[ 1,2' -bipyridin] -5 ' -yl)-1 H-pyrazolo [4,3-c]pyridin-7-carbonitrile (BCD-BTK-107) (R)-N-( 1 -( 1 -acryloylpiperidin-3 -yl)-6-methyl-3-(4-(4-oxopyridin-1 (4H)-yl) phenyl)-lH-pyrazolo[3,4-b]pyridin5-yl) acrylamide (BCD-BTK-117) (R)-1 -( 1 -acryloylpiperidin-3-yl)-7-cyano-3-(4-(4-oxopyridin-1 (4H)-yl)phenyl)-1Hindazol-5-yl acrylate (BCD-BTK-118) (R)-1-(4-(1-(1 -acryloylpiperidin-3 -yl)-5 -amino-6-methyl-1 H-pyrazolo [3,4-b] pyridin-3-yl)phenyl)pyridin-4( 1 H)-one (BCD-BTK-119) (R)-1 -( 1 -acryloylpiperidin-3-yl)-5-hydroxy-3-(4-oxo-4H-[ 1,2 ’ -bipyridin]-5 ’-yl)1 H-indazol-7-carboxamide (BCD-BTK-120) (R)-1 -(1 -acryloylpiperidin-3-yl)-5-hydroxy-3-(2-(4-oxopyridin-1 (4H)-yl) pyrimidin-5-yl)-lH-indazol-7-carboxamide (BCD-BTK-121) (R)-1 -( 1 -acryloylpiperidin-3-yl)-5-hydroxy-3-(4-(4-oxopyridin-1 (4H)-yl)phenyl)lH-indazol-7-carbonitrile (BCD-BTK-122) (R)-1 -( 1 -acryloylpiperidin-3-yl)-3-(4-(pyridin-4-yloxy)phenyl)-1 H-pyrazolo[4,3 -c] pyridin-7-carbonitrile (BCD-BTK-123) (R)-l-(l-acryloylpiperidin-3-yl)-4-chloro-3-(4-(pyridin-4-yloxy)phenyl)-lHpyrazolo[3,4-b]pyridine (BCD-BTK-124) (R)-1 -( 1 -acryloylpiperidin-3 -yl)-7-chloro-3-(4-(pyridin-4-yloxy)phenyl)-1Hpyrazolo [4,3-c]pyri dîne (BCD-BTK-125) (R)-l-(l-acryloylpiperidin-3-yl)-5-hydroxy-3-(6-(4-oxopyridin-l(4H)-yl)pyridin3-yl)-lH-indazol-7-carbonitrile (BCD-BTK-127) (R)-1-(1-acryloylpiperidin-3-yl)-5-hydroxy-4-chloro-3-(4-(pyridin-4-yloxy) phenyl)-1 H-pyrazolo[3,4-b]pyridine (BCD-BTK-129) (R)-1 -( 1 -acryloylpiperidin-3-yl)-5-hydroxy-3-(2-(4-oxopyridin-1 (4H)-yl) pyrimidin-5-yl)-lH-indazol-7-carbonitrile (BCD-BTK-130)

184 (R)-1 -(4-( 1-(1 -acryloylpiperidin-3 -yl)-4-chloro-1 H-pyrazolo [3,4-b]pyridin-3 -yl) phenyl)pyridin-4( 1 H)-one (BCD-BTK-131) (R)-l-(l-acryloylpiperidin-3-yl)-5-hydroxy-3-(4-pyridin-4-yloxy)phenyl)-lHindazol-7-carboxamide (BCD-BTK-133) (R)-1 -( 1 -acryloylpiperidin-3-yl)-4-amino-3-(4-(pyridin-4-yloxy)phenyl)-1Hpyrazolo[4,3-c]pyridin-7-carbonitrile (BCD-BTK-134) (R)-l-(l-acryloylpiperidin-3-yl)-4-amino-3-(4-(pyridin-4-yloxy)phenyl)-lHpyrazolo[4,3-c]pyridin-7-carboxamide (BCD-BTK-135) (R)-1 -( 1 -acryloylpiperidin-3 -yl)-4-chloro-3-(4-(4-oxopyridin-1 (4H)phenyl)-1Hpyrazolo[3,4-b]pyridin-5-yl acrylate (BCD-BTK-136) (R)-1 -( 1 -acryloylpiperidin-3-yl)-5-hydroxy-3-(4-pyridin-4-yloxy)phenyl)-1Hindazol-7-carbonitrile (BCD-BTK-137) (R)-1-(1-acryloylpiperidin-3-yl)-4-cyano-3-(4-(pyridin-4-yloxy)phenyl)-lHindazol-7-carboxamide (BCD-BTK-138) (R)-l-(l-acryloylpiperidin-3-yl)-7-chloro-3-(4-(pyridin-4-yloxy)phenyl)-lHpyrazolo[4,3-c]pyridin-4-amine (BCD-BTK-139) (R)-1 -( 1 -acryloylpiperidin-3-yl)-3-(4-(pyridin-4-yloxy)phenyl)- lH-pyrazolo[4,3-c] pyridin-7-carboxamide (BCD-BTK-140) (R)-4-(l-(1-(1 -acryloylpiperidin-3-yl)-7-chloro-l H-pyrazolo [4,3-c]pyridin-3-yl)N-(pyridin-2-yl)benzamide (BCD-BTK-201) (R)-4-(4-( 1 -( 1 -acryloylpiperidin-3 -yl)-7-chloro-1 H-pyrazolo [4,3 -c]pyridin-3 -yl) phenoxy)nicotinonitrile (BCD-BTK-202) (R)-4-(4-( 1 -( 1 -acryloylpiperidin-3 -yl)-7-chloro-1 H-pyrazolo [4,3 -c]pyridin-3 -yl) phenoxy)nicotinamide (BCD-BTK-203) (Λ)-1-(4-(1-(1-acryloylpiperidin-3-yl)-7-chloro-l/7-pyrazolo[4,3-c]pyridin-3-yl)-3fluorophenyl)pyridin-4( 177)-one (BCD-BTK-204) (R)-1-(4-(1-(1 -acryloylpiperidin-3 -yl)-7-chloro- l//-pyrazolo [4,3 -c]pyridin-3 -yl)-2fluorophenyl)pyridin-4( 117)-one (BCD-BTK-205) (R) -1 - ( 5 - ( 1 - ( 1 -acryloylpiperidin-3 -yl)-7-chloro- 127-pyrazolo [4,3 -c]pyridin-3 -yl) pyrimidin-2-yl)-4-oxo-1,4-dihydropyridine-3-carbonitrile (BCD-BTK-206)

185 (R)-1-(5-(1 -(1 -acryloylpiperidin-3-yl)-7-chloro-l/7-pyrazolo[4,3-c]pyridin-3-yl) pyrimidin-2-yl)-4-oxo-1,4-dihydropyridine-3-carboxamide (BCD-BTK-207) (Λ)-1 -(4-( 1 -( 1 -acryloylpiperidin-3 -yl)-7-chloro- 1 H-pyrazol o [4,3 -c]pyridin-3 -yl) phenyl)-4-oxo-1,4-dihydropyridine-3 -carbonitrile (BCD-BTK-208) (/?)-4-(l-(l-acryloylpiperidin-3-yl)-7-chloro-l/7-pyrazolo[4,3-c']pyridin-3-yl)-A-(4(trifluoromethyl)pyridin-2-yl)benzamide (BCD-BTK-210) (Â)-l-(3-(7-fluoro-3-(4-(pyridin-4-yloxy)phenyl)-l/7-pyrazolo[4,3-c]pyridin-l-yl) piperidin-1 -yl)prop-2-en-1 -one (BCD-BTK-211) (7?)-4-( 1 -( 1 -acryloylpiperidin-3 -yl)-7-chloro- 177-pyrazolo [4,3 -c]pyridin-3 -yl)-N(5-fluoropyridin-2-yl)benzamide (BCD-BTK-212) (À)-l-(l-acryloylpiperidin-3-yl)-3-(4-(3-cyanopyridin-4-yloxy)phenyl)-l/7pyrazolo[4,3-c]pyridine-7-carbonitrile (BCD-BTK-213) (À)-4-(l-(l-acryloylpiperidin-3-yl)-7-fluoro-l/7-pyrazolo[4,3-c]pyridin-3-yl)-7V-(4(1,1 -difluoropropyl)pyridin-2-yl)benzamide (BCD-BTK-214) (À)-4-(l-(l-acryloylpiperidin-3-yl)-7-chloro-l/7-pyrazolo[4,3-c]pyridin-3-yl)-7V-(4(1,1 -difluoropropyl)pyridin-2-yl)benzamide (BCD-BTK-215) (R)-1 -(1 -acryloylpiperidin-3-yl)-3-(4-(2-cyanopyridin-3-yloxy)phenyl)- 1Hpyrazolo[4,3-c]pyridine-7-carbonitrile (BCD-BTK-216) (J?)-4-(4-(l-(l-acryloylpiperidin-3-yl)-7-fluoro-l//-pyrazolo[4,3-c]pyridin-3-yl) phenoxy)nicotinonitrile (BCD-BTK-217) (R)-3 -(4-( 1 -( 1 -acryloylpiperidin-3 -yl)-7-chloro-1 H-pyrazolo [4,3 -c]pyridin-3 -yl) phenoxy)picolinonitrile (BCD-BTK-218) (R)-4-(l-(l-acryloylpiperidin-3-yl)-7-cyano-lH-pyrazolo[4,3-c]pyridin-3-yl)-N-(4(1,1 -difluoropropyl)pyridin-2-yl)benzamide (BCD-BTK-219)

3-(4-(7-chloro-l-[(3À)-l-(prop-2-enoyl)piperidin-3-yl]-17/-pyrazolo[4,3-c]pyridin3 -yl)phenoxy)pyridine-2-carboxamide (BCD-BTK-220) (R)-4-( 1 -( 1 -acryloylpiperidin-3 -yl)-7-cyano-1 H-pyrazolo [4,3 -c]pyridin-3 -yl)-N-(4(trifluoromethyl)pyridin-2-yl)benzamide (BCD-BTK-221)

5-(4-(7-chloro-1 -[(3À)-1 -(prop-2-enoyl)piperidin-3-yl]- l/7-pyrazolo[4,3-c]pyridin3-yl)phenoxy)pyridine-3-carboxamide (BCD-BTK-222)

186

4-(7-cyano-l-[(3À)-l-(prop-2-enoyl)piperidin-3-yl]-177-pyrazolo[4,3-c]pyridin-3yl)-V(641uoropyridin-2-yl)benzamide (BCD-BTK-223)

4-(7-cyano-1 - [(3 R ) -1 -(prop-2-enoyl)piperidin-3 -yl]-1 //-pyrazolo [4,3 -c]pyridin-3 yl)-A-[4-(l,l-difluoroethyl)pyridin-2-yl]benzamide (BCD-BTK-224) (Â)-4-(l-(l-acryloylpiperidin-3-yl)-7-chloro-l/7-pyrazolo[4,3-c]pyridin-3-yl)-7V-(6fluoropyridin-2-yl)benzamide (BCD-BTK-225) (À)-4-(l-(l-aciyloylpiperidin-3-yl)-7-chloro-lH-pyrazolo[4,3-c]pyridin-3-yl)-7V-(3fluoropyridin-2-yl)benzamide (BCD-BTK-226) (À)-4-(l-(l-acryloylpiperidin-3-yl)-7-cyano-lA-pyrazolo[4,3-c]pyridin-3-yl)-7V-(5fluoropyridin-2-yl)benzamide (BCD-BTK-227) (^)-4-(l-(l-acryloylpiperidin-3-yl)-7-cyano-l/7-pyrazolo[4,3-c]pyridin-3-yl)-2V(pyridin-2-yl)benzamide (BCD-BTK-228) (À)-5-(l-(l-acryloylpiperidin-3-yl)-7-chloro-l/7-pyrazolo[4,3-c]pyridin-3-yl)-7V(pyridin-2-yl)pyrimidine-2-carboxamide (BCD-BTK-229) (7?)-3-(4-(1-(1-acryloylpiperidin-3-yl)-7-fluoro-177-pyrazolo [4,3-c]pyridin-3-yl) phenoxy)picolinonitrile (BCD-BTK-230) (/?)-4-(l-(l-acryloylpiperidin-3-yl)-4-amino-7-chloro-l//-pyrazolo[4,3-c]pyridin3-yl)-W(4-(l,l-difluoropropyl)pyridin-2-yl)benzamide (BCD-BTK-231) (À)-4-(4-(l-(l-acryloylpiperidin-3-yl)-4-amino-7-chloro-l/7-pyrazolo[4,3-c] pyridin-3-yl)phenoxy)nicotinonitrile (BCD-BTK-232) (Â)-4-(l-(l-acryloylpiperidin-3-yl)-4-amino-7-chloro-177-pyrazolo[4,3-c]pyridin3-yl)-7V-(3-fluoropyridin-2-yl)benzamide (BCD-BTK-233) (À)-4-(l-(l-acryloylpiperidin-3-yl)-4-amino-7-cyano-lH-pyrazolo[4,3-c]pyridin-3yl)-7V-(pyridine-2-yl)benzamide (BCD-BTK-234)

4-(7-cyano-l-[(3Â)-l-(prop-2-enoyl)piperidin-3-yl]-l/7-pyrazolo[4,3-c]pyridin-3yl)-7V-(3-fluoropyridin-2-yl)benzamide (BCD-BTK-235)

3-(4-(4-amino-7-chloro-1 -[(3Â)-1 -(prop-2-enoyl)piperidin-3-yl]- l//-pyrazolo[4,3c]pyridin-3-yl)phenoxy)pyridine-2-carbonitrile (BCD-BTK-236)

4-(4-amino-7-chloro-l-[(3À)-l-(prop-2-enoyl)piperidin-3-yl]-17/-pyrazolo[4,3-c] pyridin-3-yl)-7V-(5-fluoropyridin-2-yl)benzamide (BCD-BTK-237)

187

4-(4-amino-7-chloro-l-[(3Â)-l-(prop-2-enoyl)piperidin-3-yl]-l//-pyrazolo[4,3-c] pyridin-3 -yl)-A-(pyridin-2-yl)benzamide (BCD-BTK-238) (R)-1 -( 1 -acryloylpiperidin-3 -yl)-4-amine-7-methoxy-3 -(4-(pyridin-4-yloxy) phenyl)-lH-pyrazolo[4,3-c]pyridine (BCD-BTK-239) (R)-4-( 1 -( 1 -acryloylpiperidin-3 -yl)-4-amino-7-methoxy-1 H-pyrazolo [4,3 -c] pyridin-3-yl)-N-(pyridin-2-yl)benzamide (BCD-BTK-240) (R)-l-(l-acryloylpiperidin-3-yl)-4-amine-3-(4-(pyridin-4-yloxy)phenyl)-lHpyrazolo[4,3-c]pyridine (BCD-BTK-241) (R)-4-(l-(l-acryloylpiperidin-3-yl)-4-amino-lH-pyrazolo[4,3-c]pyridin-3-yl)-N(pyridin-2-yl)benzamide (BCD-BTK-242) (R)-4-(l-(l-acryloylpiperidin-3-yl)-7-fluoro-lH-pyrazolo[4,3-c]pyridin-3-yl)-N(pyridin-2-yl)benzamide (BCD-BTK-243) (R)-4-(l-(l -acryloylpiperidin-3 -yl)-7-fluoro-l H-pyrazolo [4,3-c]pyridin-3-yl)-N-(5fluoropyridin-2-yl)benzamide (BCD-BTK-244) (R)-4-(l-(l-acryloylpiperidin-3-yl)-7-fluoro-lH-pyrazolo[4,3-c]pyridin-3-yl)-N-(4(trifluoromethyl)pyridin-2-yl)benzamide (BCD-BTK-245) (R)-4-(4-( 1 -( 1 -acryloylpiperidin-3 -yl)-7-fluoro-1 H-pyrazolo [4,3-c]pyridin-3-yl) phenoxy)nicotinamide (BCD-BTK-246) (R)-4-( 1 -( 1 -acryloylpiperidin-3 -yl)-7-fluoro-1 H-pyrazolo [4,3 -c]pyridin-3 -yl)-N-(4(1,1 -difluorobutyl)pyridin-2-yl)benzamide (BCD-BTK-247) (R)-4-( 1 -( 1 -acryloylpiperidin-3 -yl)-7-fluoro-1 H-pyrazolo [4,3 -c]pyridin-3 -yl)-N-(6fluoropyridin-2-yl)benzamide (BCD-BTK-248) (R)-4-(l-(l-acryloylpiperidin-3-yl)-7-fluoro-lH-pyrazolo[4,3-c]pyridin-3-yl)-N-(3fluoropyridin-2-yl)benzamide (BCD-BTK-249) (R)-4-(l-(l-acryloylpiperidin-3-yl)-4-amino-7-chloro-lH-pyrazolo[4,3-c]pyridin3-yl)-N-(6-fluoropyridin-2-yl)benzamide (BCD-BTK-250) (R)-4-( 1 -( 1 -acryloylpiperidin-3 -yl)-4-amino-7-chloro-1 H-pyrazolo[4,3 -c]pyridin3-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide (BCD-BTK-251) (R)-4-(l-(l-acryloylpiperidin-3-yl)-7-chloro-lH-pyrazolo[4,3-c]pyridin-3-yl)-N(4-( 1,1 -difluorobutyl)pyridin-2-yl)benzamide (BCD-BTK-252)

188 (R)-5-(l-(l-acryloylpiperidin-3-yl)-7-chloro-lH-pyrazolo[4,3-c]pyridin-3-yl)-N(5-fluoropyridin-2-yl)pyrimidine-2-carboxamide (BCD-BTK-253)

R)-4-(l-(l-acryloylpiperidin-3-yl)-4-amino-7-chloro-lH-pyrazolo[4,3-c]pyridin-3yl)-N-(4-( 1,1 -difluorobutyl)pyridin-2-yl)benzamide (BCD-BTK-254) (R)-3-(4-(l-(l-acryloylpiperidin-3-yl)-7-fluoro-lH-pyrazolo[4,3-c]pyridin-3-yl) phenoxy)picolinamide (BCD-BTK-255)

4-(4-amino-7-cyano-1 - [(3R)-1 -(prop-2-enoyl)piperidin-3 -yl] -1 H-pyrazolo [4,3 -c] pyridin-3-yl)-N-(3-fluoropyridin-2-yl)benzamide (BCD-BTK-258) (S)-1 -(2-((7-chloro-3-(4-(pyridin-4-yloxy)phenyl)-1 H-pyrazolo [4,3-c]pyridin-1 -yl) methyl)pyrrolidin-1 -yl)but-2-yn-1 -one (BCD-BTK-259) (S)-4-( 1 -(( 1 -acryloylpyrrolidin-2-yl)methyl)-7-chloro-1 H-pyrazolo[4,3-c]pyridin3-yl)-N-phenylbenzamide (BCD-BTK-260)

1-(3-((7-chloro-3 -(4-(pyridin-4-yloxy)phenyl)-1 H-pyrazolo [4,3 -c]pyridin-1 -yl) methyl)azetidin-l-yl)but-2-yn-l-one (BCD-BTK-261) (R)-4-( 1 -( 1 -(but-2-ynoyl)pyrrolidin-3-yl)-7-chloro-1 H-pyrazolo[4,3-c]pyridin-3yl)-N-(pyridin-2-yl)benzamide (BCD-BTK-262) (S)-1 -(2-((7-chloro-3-(4-(pyridin-4-yloxy)phenyl)-1 H-pyrazolo [4,3-c]pyridin-1 -yl) methyl)pyrrolidin-1 -yl)prop-2-en-1 -one (BCD-BTK-263)

1 -(3-((7-chloro-3-(4-(pyridin-4-yloxy)phenyl)-l H-pyrazolo [4,3-c]pyridin-1-yl) methyl)azetidin-1 -yl)prop-2-en-1 -one (BCD-BTK-264) (R)-1-(3-(7-chloro-3 -(4-(pyridin-4-yloxy)phenyl)-1 H-pyrazolo[4,3 -c]pyridin-1 -yl) pyrrolidin-1 -yl)but-2-yn-1 -one (BCD-BTK-265) (S)-1 -(3-(7-chloro-3-(4-(pyridin-4-yloxy)phenyl)-1 H-pyrazolo[4,3-c]pyridin-1 -yl) pyrrolidin-1 -yl)prop-2-en-1 -one (BCD-BTK-266)

4-(1-((1 -(but-2-ynoyl)azetidin-3 -yl)methyl)-7-chloro-1 H-pyrazolo [4,3 -c]pyridin-3 yl)-N-(pyridin-2-yl)benzamide (BCD-BTK-267) (R)-4-(l-(l-acryloylpiperidin-3-yl)-7-cyano-lH-pyrazolo[4,3-c]pyridin-3-yl)-N-(4(1,1 -difluorobutyl)pyridin-2-yl)benzamide (BCD-BTK-268) (R)-4-( 1 -(( 1 -(but-2-ynoyl)pyrrolidin-2-yl)methyl)-7-chloro-1 H-pyrazolo [4,3-c] pyridin-3-yl)-N-(pyridin-2-yl)benzamide (BCD-BTK-269)

189 (S)-1 -(3-(7-chloro-3-(4-(pyridin-4-yloxy)phenyl)-1 H-pyrazolo[4,3-c]pyridin-1 -yl) pyrrolidin-1 -yl)but-2-yn-1 -one (BCD-BTK-270) (S)-4-(l-(l-(but-2-ynoyl)pyrrolidin-3-yl)-7-chloro-lH-pyrazolo[4,3-c]pyridin-3yl)-N-(pyridin-2-yl)benzamide (BCD-BTK-271) (R)-1-(3-(7-chloro-3 -(4-(pyridin-4-yloxy)phenyl)-1 H-pyrazolo [4,3 -c]pyridin-1 -yl) pyrrolidin-1 -yl)prop-2-en-1 -one (BCD-BTK-272) (S)-4-(l-(l-acryloylpyTrolidin-3-yl)-7-chloro-lH-pyrazolo[4,3-c]pyridin-3-yl)-N(pyridin-2-yl)benzamide (BCD-BTK-273) (R)- 5-(4-( 1 -( 1 -acryloylpiperidin-3 -yl)-7-fluoro-1 H-pyrazolo [4,3 -c]pyridin-3 yl)phenoxy)nicotinamide (BCD-BTK-274) (R)-4-( 1 -( 1 -acryloylpyrrolidin-3 -yl)-7-chloro-1 H-pyrazolo [4,3 -c]pyridin-3 -yl)-N(pyridin-2-yl)benzamide (BCD-BTK-275)

4-(7-chloro-l-([l-(prop-2-enoyl)azetidin-3-yl]methyl)-lH-pyrazolo[4,3-c]pyridin3-yl)-N-(pyridin-2-yl)benzamide (BCD-BTK-276) (R)-5-(l-(l-acryloylpiperidin-3-yl)-7-chloro-lH-pyrazolo[4,3-c]pyridin-3-yl)-N(6-fluoropyridin-2-yl)pyrimidine-2-carboxamide (BCD-BTK-277) (R)-4-( 1-((1 -(but-2-ynoyl)piperidin-3 -yl)methyl)-7-chloro-1 H-pyrazolo [4,3 -c] pyridin-3-yl)-N-(pyridin-2-yl)benzamide (BCD-BTK-278) (R)-4-( 1-((1 -acryloylpiperidin-3 -yl)methyl)-7-chloro-1 H-pyrazolo [4,3 -c]pyridin-3 yl)-N-(pyridin-2-yl)benzamide (BCD-BTK-279)

4-(l-(l-(but-2-ynoyl)azetidin-3-yl)-7-chloro-lH-pyrazolo[4,3-c]pyridin-3-yl)-N(pyridin-2-yl)benzamide (BCD-BTK-280) l-(3-(7-chloro-3-(4-(pyridin-4-yloxy)phenyl)-lH-pyrazolo[4,3-c]pyridin-l-yl) azetidin-1 -yl)but-2-yn-1 -one (BCD-BTK-281) l-(3-(7-chloro-3-(4-(pyridin-4-yloxy)phenyl)-177-pyrazolo[4,3-c]pyridin-l-yl) azetidin-1 -yl)prop-2-en-1 -one (BCD-BTK-282) (5’)-4-(l-((l-(but-2-ynoyl)piperidin-3-yl)methyl)-7-chloro-177-pyrazolo[4,3-c] pyridin-3 -yl)-7V-(pyridin-2-yl)benzamide (BCD-BTK-283) (Â)-4-(l-((l-acryloylpynOlidin-3-yl)methyl)-7-chloro-177-pyrazolo[4,3-c]pyridin3 -yl)-7V-(pyridin-2-yl)benzamide (BCD-BTK-284)

190 (5)-4-(1-((1-acryloylpyrrolidin-3-yl)methyl)-7-chloro-l/7-pyrazolo[4,3-c]pyridin3-yl)-W(pyridin-2-yl)benzamide (BCD-BTK-285) (Â)-4-(l-((l-(but-2-ynoyl)pyrrolidin-3-yl)methyl)-7-chloro-l/7-pyrazolo[4,3-c] pyridin-3-yl)-A-(pyridin-2-yl)benzamide (BCD-BTK-286) (5)-4-(1 -((l-(but-2-ynoyl)pyrrolidin-3-yl)methyl)-7-chloro-l//-pyrazolo[4,3-c] pyridin-3 -yl)-A-(pyridin-2-yl)benzamide (BCD-BTK-287) (À)-5-(l-(l-acryloylpiperidin-3-yl)-7-chloro-177-pyrazolo[4,3-c]pyridin-3-yl)-A-(3fluoropyridin-2-yl)pyrimidine-2-carboxamide (BCD-BTK-288) (Â)-4-(l-(l-(but-2-ynoyl)piperidin-3-yl)-7-chloro-l/7-pyrazolo[4,3-c]pyridin-3-yl)W(pyridin-2-yl)benzamide (BCD-BTK-289) (5)-4-(1-((1 -acryloylpiperidin-3 -yl)methyl)-7-chloro-177-pyrazolo [4,3 -c]pyridin-3 yl)-A-(pyridin-2-yl)benzamide (BCD-BTK-290) (/?)-5-(l-(l-acryloylpiperidin-3-yl)-7-chloro-l//-pyrazolo[4,3-c]pyridin-3-yl)-A-(4(trifluoromethyl)pyridin-2-yl)pyrimidine-2-carboxamide (BCD-BTK-291) (Â)-5-(l-(l-acryloylpiperidin-3-yl)-7-chloro-l//-pyrazolo[4,3-c]pyridin-3-yl)-A-(4(1,1 -difluorobutyl)pyridin-2-yl)pyrimidine-2-carboxamide (BCD-BTK-292) (Â)-5-(l-(l-acryloylpiperidin-3-yl)-7-chloro-177-pyrazolo[4,3-c]pyridin-3-yl)-7V-(4(1,1 -difluoropropyl)pyridin-2-yl)pyrimidine-2-carboxamide (BCD-BTK-293) (À)-4-(4-amino-l-(l-(but-2-ynoyl)piperidin-3-yl)-7-chloro-l/f-pyrazolo[4,3-c] pyridin-3-yl)-A-(pyridin-2-yl)benzamide (BCD-BTK-295)

4. A method for inhibiting biological activity of Bruton’s tyrosine kinase (Btk) in a subject, comprising contacting the tyrosine kinase with the compound according to any daims 1 to 3.

5. A pharmaceutical composition for the prévention or treatment of a disease or disorder mediated by Bruton’s tyrosine kinase (Btk), comprising a therapeutically effective amount of the compound according to any daims 1 to 3, or pharmaceutically acceptable sait thereof, and one or more pharmaceutically acceptable excipients.

6. The pharmaceutical composition according to claim 5, wherein the disease or disorder mediated by Bruton’s tyrosine kinase (Btk) is tumors of blood

191 and lymphatic System, immune disorders, cancer, autoimmune and inflammatory diseases, or allergie disorders.

7. The pharmaceutical composition according to claim 6, wherein tumors of blood and lymphatic System are selected from the group comprising chronic lymphocytic leukemia, mantle cell lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, Waldenstrom macroglobulinemia, B-cell prolymphocytic leukemia, central nervous System lymphoma, multiple myeloma; immune disorders are selected from the group comprising graft-versus-host disease, chronic graftversus-host disease; cancer is pancreatic cancer; autoimmune diseases are selected from the group comprising rheumatoid arthritis, systemic lupus erythematosus; inflammatory disease is asthma; allergie disorder is atopie dermatitis.

8. A method for treating a disease or disorder mediated by Bruton’s tyrosine kinase (Btk) comprising administering a therapeutically effective amount of the compound according to any claims 1 to 3, or pharmaceutically acceptable sait thereof, or the pharmaceutical composition according to claim 5 in a subject in need thereof.

9. The method for treating according to claim 8, wherein the disease or disorder mediated by Bruton’s tyrosine kinase (Btk) is tumors of blood and lymphatic System, immune disorders, cancer, autoimmune and inflammatory diseases, or allergie disorders.

10. The method for treating according to claim 9, wherein tumors of blood and lymphatic System are selected from the group comprising chronic lymphocytic leukemia, mantle cell lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, Waldenstrom macroglobulinemia, B-cell prolymphocytic leukemia, central nervous System lymphoma, multiple myeloma; immune disorders are selected from the group comprising graft-versus-host disease, chronic graft-versushost disease; cancer is pancreatic cancer; autoimmune diseases are selected from the group comprising rheumatoid arthritis, systemic lupus erythematosus; inflammatory disease is asthma; allergie disorder is atopie dermatitis.

192

11. Use of the compound according to any daims 1 to 3, or pharmaceutically acceptable sait thereof, or a pharmaceutical composition according to claim 5 for the prévention or treatment of a disease or disorder mediated by Bruton’s tyrosine kinase (Btk) in a subject in need thereof.

5

12. The use according to claim 11, wherein the disease or disorder mediated by Bruton’s tyrosine kinase (Btk) is tumors of blood and lymphatic System, immune disorders, cancer, autoimmune and inflammatory diseases, or allergie disorders.

13. The use according to claim 12, wherein tumors of blood and lymphatic

10 System are selected from the group comprising chronic lymphocytic leukemia, mantle cell lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, Waldenstrom macroglobulinemia, B-cell prolymphocytic leukemia, central nervous System lymphoma, multiple myeloma; immune disorders are selected from the group comprising graft-versus-host disease, chronic graft-versus-host disease;

15 cancer is pancreatic cancer; autoimmune diseases are selected from the group comprising rheumatoid arthritis, systemic lupus erythematosus; inflammatory disease is asthma; allergie disorder is atopie dermatitis.