RU2779287C2 - Methods for treatment of multiple sclerosis, using pyrimidine and pyridine compounds with btk-inhibiting activity - Google Patents

Abstract

FIELD: medicine; pharmaceutics.

SUBSTANCE: invention relates to the field of medicine and pharmaceutics, namely to the use of therapeutically effective amount of a compound selected from N-[(1-acryloylpiperidine-4-yl)methyl]-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine, its pharmaceutically suitable salts and tautomers, including tautomer mixtures in all ratios, and 1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidine-4-yl)amino)methyl)-4-fluoropiperidine-1-yl)prop-2-en-1-one, its pharmaceutically suitable salts and tautomers, including tautomer mixtures in all ratios, for the treatment or prevention of multiple sclerosis.

EFFECT: treatment or prevention of multiple sclerosis (hereinafter – MS), including relapsing MS (RMS), relapsing-remitting MS (RRMS), progressive MS (PMS), secondary progressive MS (SPMS), primary progressive MS (PPMS), and progressive-relapsing MS (PRMS), using compounds according to the invention.

4 cl, 21 dwg, 6 tbl, 3 ex

Description

Related Applications

This application claims priority in US Provisional Application No. 62/256,199, filed Nov. 17, 2015, the contents of which are hereby incorporated by reference in their entirety.

Field of invention

The invention relates to a number of compounds of pyrimidine and pyridine, which can be used as therapeutic agents in the treatment of multiple sclerosis (MS) in mammals. More specifically, embodiments of the present invention describe irreversible kinase inhibitors, including, but not limited to, inhibitors of Bruton's tyrosine kinase (hereinafter referred to as "BTK"). Methods for preparing the above compounds are disclosed in addition to including these compounds in pharmaceutical compositions that contain them.

Prerequisites

Protein kinases constitute a large family of structurally related enzymes that are responsible for directing a wide range of signal transduction processes in the cell (Hardie, G. and Hanks, S. (1995) Protein Kinase Facts Book. I and II, Academic Press, San Diego, CA). Kinases can be divided into families according to their substrates that they phosphorylate (eg, protein tyrosine, protein serine/threonine, lipids, etc.). Sequence motifs have been identified that broadly correspond to each of these families of kinases (e.g., Hanks, S.K., Hunter, T., FASEB J., 9:576-596 (1995); Knighton, et al., Science, 253:407- 414 (1991); Hiles, et al., Cell, 70:419-429 (1992); Kunz, et al., Cell, 73:585-596 (1993); Garcia-Bustos, et al., EMBO J. 13:2352-2361 (1994)).

Protein kinases can be characterized by their regulatory mechanisms. These mechanisms include, for example, autophosphorylation, transphosphorylation by other kinases, protein-protein interactions, protein-lipid interactions, and protein-polynucleotide interactions. An individual protein kinase may be regulated by more than one mechanism.

Kinases regulate many different cellular processes, including, but not limited to, proliferation, differentiation, apoptosis, motility, transcription, translation, and other signaling processes, by adding phosphate groups to target proteins. These phosphorylation events act as molecular switches that can modulate or regulate the biological function of the target protein. Phosphorylation of target proteins occurs in response to various extracellular signals (hormones, neurotransmitters, growth and differentiation factors, etc.), cell cycle events, environmental or nutritional stresses, etc. The respective functions of protein kinases in signaling pathways are to activate or inactivate (directly or indirectly), for example, a metabolic enzyme, regulatory protein, receptor, cytoskeletal protein, ion channel or pump or transcription factor. Uncontrolled signaling due to defective control of protein phosphorylation has been implicated in many diseases, including inflammation, cancer, allergy/asthma, immune system diseases and conditions, central nervous system diseases and conditions, and angiogenesis.

BTK, a member of the Tec family of non-receptor tyrosine kinases, is a signaling enzyme expressed in all hematopoietic cell types except T-lymphocytes and natural killer cells. BTK plays a well-described role in the B-cell signaling pathway linking stimulation of the cell-surface B-cell receptor to intracellular responses downstream. BTK is also a 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 ^exerts physiological effects through other hematopoietic cell signaling pathways, e.g. Fas/APO-1 apoptotic signals in lymphoid cells of the B-cell lineage and collagen-stimulated platelet aggregation. BTK has an ATP-binding pocket with high affinity for Src family kinases such as lymphocyte-specific protein tyrosine kinase (Lck) and Lyn. When comparing BTK with other kinases, a conserved cysteine residue, Cys-481, is found in 11 of 491 kinases, in particular among members of the Tec and EGFR (epidermal growth factor receptor) kinase families.

BTK plays important roles in the development, differentiation, activation and proliferation of B cells, as well as the formation of their antibodies and cytokines. In addition, Btk plays a central role in other immunological processes such as cytokine production by neutrophils, mast cells and monocytes, degranulation of neutrophils and mast cells, and differentiation/activation of osteoclasts. B-cell activation, tolerance disorder and autoantibody production on the one hand, and a pro-inflammatory environment resulting from increased activation of monocytes, neutrophils and mast cells on the other hand, are key in the etiology of autoimmune diseases, including (but not limited to) rheumatoid arthritis and systemic lupus erythematosus.

Therapeutic compounds of reversible kinase inhibitors have been developed. However, these reversible inhibitors have certain disadvantages. Many reversible kinase inhibitors interact with the ATP binding site. Given that the structure of ATP binding sites is very conserved among kinases, it is difficult to design a reversible inhibitor that selectively inhibits the desired kinase (ie, target). In addition, given that many reversible kinase inhibitors readily dissociate from their target polypeptide(s), maintaining inhibition for long periods of time can be difficult. Therefore, when reversible kinase inhibitors are used as therapeutic agents, near-toxic doses and/or frequent dosing are often necessary in order to achieve the intended biological effect.

Therefore, there is a need for irreversible kinase inhibitors that covalently bind to their target polypeptide(s) without (substantially) binding outside the target polypeptides and thus do not exhibit undesirable effects outside the targets.

The essence of the invention

The present invention is directed to compounds of the formulas provided herein for the treatment and/or prevention of multiple sclerosis (MS), including relapsing MS (RMS), relapsing-remitting MS (RRMS), progressive MS (PMS), secondary progressive MS (SPMS), primary progressive MS (PPMS), and progressive relapsing MS (PRMS).

Description of figures

Fig. 1: (a) prophylactic treatment using (1) delayed onset and reduced disease severity in SJL-EAE; (b) maximum clinical score at peak; (c) the onset of the disease; (d) cumulative clinical score.

Fig. 2: Prophylactic treatment using (1) reduced recurrence activity in SJL-EAE; (a) time to first relapse; (b) total number of relapses; (c) summary.

Fig. 3: (a) therapeutic treatment using (1) reduced disease severity in SJL-EAE; (b) cumulative EAE score.

Fig. 4: Therapeutic treatment using (1) reduced recurrence activity in SJL-EAE; (a) time to first relapse; (b) total number of relapses; (c) summary.

Fig. 5: summary table of clinical assessment data: compound (1).

Fig. 6: BTK filling after prophylactic treatment using (1) (24 hours after treatment); (a) the first dose; (b) last dose.

Fig. 7: (a) BTK filling after the first dose (1) (therapeutic study); (b) blood concentrations of BTK after the first dose (1) (therapeutic study).

Fig. 8: BTK filling after therapeutic treatment using (1) (24 hours after treatment).

Fig. 9: (a) Compound (2) significantly reduces disease severity when administered prophylactically; (b) cumulative EAE score.

Fig. 10: (a) Compound (2) reduced disease incidence and relapses in the EAE model; (b) summary.

Fig. 11: Schematic of the PK/PD experiment for compound (2).

Fig. 12: (a) BTK filling with compound (2) 2 hours after dosing; (b) BTK loading with compound (2) 24 hours post-dose (both measured by MSD streptavidin uptake assay).

Fig. 13: Plasma concentrations of free compound (2) 2 hours and 24 hours post-dose (measured by dry blood spot analysis).

Fig. 14: (a) therapeutic dosing of compound (2) reduced disease severity in SJL-EAE; (b) cumulative EAE score.

Fig. 15: (a) therapeutic dosing of compound (2) prolonged the time to first relapse and reduced relapses; (b) number of relapses; (c) summary.

Fig. 16: scheme of experiment with compound (2).

Fig. 17: (a) BTK filling with compound (2) 2 hours after dosing; (b) BTK loading with compound (2) 24 hours post-dose (measured by MSD streptavidin uptake assay).

Fig. 18: (a) therapeutic dosing of compound (2) reduced disease severity in SJL-EAE; (b) cumulative score.

Fig. 19: (a) therapeutic dosing of compound (2) reduced the number of relapses; (b) summary.

Fig. 20: (a) semi-therapeutic dosing of compound (2) reduced disease severity in SJL-EAE; (b) cumulative score.

Fig. 21: (a) therapeutic dosing of compound (2) reduced the number of relapses; (b) number of relapses; (c) summary.

Throughout the description and FIG., the terms compound (1) and compound (A250) are used interchangeably. Throughout the description and FIG., the terms compound (2) and compound (A225) are used interchangeably.

Description of the invention

The present invention provides a number of new pyrimidine and pyridine kinase inhibitors. In some embodiments, said kinase inhibitors are irreversible tyrosine kinase inhibitors. In preferred embodiments, said irreversible kinase inhibitors inhibit BTK. Although it is not intended that the compounds described in the present invention be limited to any particular mechanism of action, in some embodiments, these irreversible kinase inhibitors exhibit a physiological effect through the formation of a covalent bond with Cys 481 in BTK. Importantly, homologues of this Cys 481 in BTK are found in other kinases. Embodiments of the present invention also describe methods for synthesizing said irreversible inhibitors, methods for using said irreversible inhibitors in the treatment of diseases (including neurodegenerative diseases). In addition, pharmaceutical compositions are described that contain irreversible kinase inhibitors, including their pharmaceutically acceptable salts, solvates or prodrugs, which are kinase inhibitors and which can be used in the treatment of the above diseases.

In one aspect, the invention relates to a method for the treatment and/or prevention of multiple sclerosis (MS), including relapsing MS (RMS), relapsing-remitting MS (RRMS), progressive MS (PMS), secondary progressive MS (SPMS), primary progressive MS (PPMS) and progressive relapsing MS (PRMS) comprising administering to the subject a compound of formula (I):

wherein:

X stands for CH or N,

R ¹ is NH ₂ , CONH ₂ or H,

R ² is Hal, Ar ¹ or Het ¹ ,

R ³ is NR ⁵ [C(R ⁵ ) ₂ ] _n Het ² , NR ⁵ [C(R ⁵ ) ₂ ] _n Cyc, Het ² , O[C(R ⁵ ) ₂ ] _n Ar ² , NR ⁵ [C (R ⁵ ) ₂ ] _n Ar ² , O[C(R ⁵ ) ₂ ] _n Het ² , NR ⁵ (CH ₂ ) _p NR ⁵ R ⁶ , O(CH ₂ ) _p NR ⁵ R ⁶ or NR ⁵ (CH ₂ ) _p CR ⁷ R ⁸ NR ⁵ R ⁶ ,

R ⁴ is H, CH ₃ or NH ₂ ,

R ⁵ is H or alkyl having 1, 2, 3 or 4 C atoms,

R ⁶ N(R ⁵ ) ₂ CH ₂ CH=CHCONH, Het ³ CH ₂ CH=CHCONH, CH ₂ =CHCONH(CH ₂ ) _n , Het ⁴ (CH ₂ ) _n COHet ³ -diyl-CH ₂ CH=CHCONH, HC≡CCO, CH ₃ C≡CCO, CH ₂ =CH-CO, CH ₂ =C(CH ₃ )CONH, CH ₃ CH=CHCONH(CH ₂ ) _n , N≡CCR ⁷ R ⁸ CONH(CH ₂ ) _n , Het ⁴ NH (CH ₂ ) _p COHet ³ -diyl-CH ₂ CH \u003d CHCONH, Het ⁴ (CH ₂ ) _p CONH (CH ₂ CH ₂ O) _p (CH ₂ ) _p COHet ³ -diyl-CH ₂ CH \u003d CHCONH, CH ₂ \u003d CHSO ₂ , ACH \u003d CHCO, CH ₃ CH \u003d CHCO, Het ⁴ (CH ₂ ) _p CONH (CH ₂ ) _p Het ³ -diyl-CH ₂ CH \u003d CHCONH, Ar ³ CH \u003d CHSO ₂ , CH ₂ \u003d CHSO ₂ NH or N (R ⁵ )CH ₂ CH \u003d CHCO,

R ⁷ , R ⁸ together are alkylene having 2, 3, 4 or 5 C atoms,

Ar ¹ is phenyl or naphthyl, each of which is unsubstituted or mono-, di- or tri-substituted with R ⁶ , Hal, (CH ₂ ) _n NH ₂ , CONHAr ³ , (CH ₂ ) _n NHCOA, O(CH ₂ ) _n Ar ³ , OCyc, A, COHet ³ , OA and/or OHet ³ (CH ₂ ),

Ar ² is phenyl, naphthyl or pyridyl, each of which is unsubstituted or mono-, di- or tri-substituted with R ⁶ , Hal, OAr ³ , (CH ₂ ) _n NH ₂ , (CH ₂ ) _n NHCOA and/or Het ³ ,

Ar ³ is phenyl which is unsubstituted or mono-, di- or tri-substituted with OH, OA, Hal, CN and/or A,

Het ¹ is a mono- or bicyclic saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and/or S atoms, which may be unsubstituted or mono-, di- or tri-substituted with R ⁶ , O(CH ₂ ) _n Ar ³ and/or (CH ₂ ) _n Ar ³ ,

Het ² denotes a mono- or bicyclic saturated heterocycle having 1 to 4 N, O and/or S atoms, which may be unsubstituted or mono-, di- or tri-substituted with R ⁶ , Het ³ , CycSO ₂ , OH, Hal , COOH, OA, COA, COHet ³ , CycCO, SO ₂ and/or =O,

Het ³ denotes a monocyclic unsaturated, saturated or aromatic heterocycle having from 1 to 4 N, O and/or S atoms, which may be unsubstituted or mono-, di- or tri-substituted with Hal, A and/or =O,

Het ⁴ is a bi- or tricyclic unsaturated, saturated or aromatic heterocycle having 1 to 4 N, O and/or S atoms, which may be unsubstituted or mono-, di-, tri- or tetra-substituted with A, NO ₂ , Hal and/or =O,

Cyc is a cyclic alkyl having 3, 4, 5 or 6 C atoms which is unsubstituted, monosubstituted or disubstituted with R ⁶ and/or OH and which may contain a double bond,

A is straight or branched alkyl having 1-10 C atoms, in which 1-7 H atoms can be replaced by F and/or Cl and/or in which one or two non-adjacent CH ₂ and/or CH groups can be replaced by O, NH and/or N,

Hal is F, Cl, Br or I,

n is 0, 1, 2, 3 or 4,

p is 1, 2, 3, 4, 5 or 6,

and its pharmaceutically acceptable salts, tautomers and stereoisomers, including mixtures thereof in all proportions.

In general, all residues that occur more than once can be identical or different, i.e. independent from each other. In other embodiments, the implementation of the residues and parameters have the meanings given for formula (I), unless explicitly stated otherwise.

In certain embodiments, Het ¹ is piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, benzimidazolyl , benzotriazolyl, indolyl, benzo-1,3-dioxolyl, indazolyl, azabicyclo[3.2.1]octyl, azabicyclo-[2.2.2]octyl, imidazolidinyl, azetidinyl, azepanyl, benzo-2,1,3-thiadiazolyl, tetrahydrofuryl, dioxolanyl, tetrahydrothienyl, dihydropyrrolyl, tetrahydroimidazolyl, dihydropyrazolyl, tetrahydropyrazolyl, tetrahydropyridyl, dihydropyridyl or dihydrobenzodioxinyl, each of which is unsubstituted or mono-, di- or tri-substituted with R ⁶ , O(CH ₂ ) _n Ar ³ and/or (CH ₂ ) _n Ar ³ .

In certain embodiments, Het ¹ is pyrazolyl, pyridyl, pyrimidinyl, dihydropyridyl, or dihydrobenzodioxinyl, each of which is unsubstituted or mono-, di-, or tri-substituted with R ⁶ , O(CH ₂ ) _n Ar ³ and/or (CH ₂ ) _n Ar ³ .

In certain embodiments, Het ² is piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, azabicyclo[3.2.1]octyl, azabicyclo[2.2.2]octyl, 2,7-diazaspiro[3.5]nonyl, 2,8-diazaspiro[4.5]decyl , 2,7-Diazaspiro[4.4]nonyl, 3-azabicylo[3.1.0]hexyl, 2-azaspiro[3.3]heptyl, 6-azaspiro[3.4]octyl, 7-azaspiro[3.5]nonyl, 5-azaspiro[3.5 ]nonyl, imidazolidinyl, azetidinyl, azepanyl, tetrahydrofuryl, dioxolanyl, tetrahydrothienyl, tetrahydroimidazolyl, tetrahydropyrazolyl, tetrahydropyridyl, each of which is unsubstituted or mono-, di- or tri-substituted with R ⁶ , Het ³ , CycSO ₂ , OH, OA, COA , COHet ³ , CycCO, SO ₂ and/or =O.

In certain embodiments, Het ³ is piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, imidazolidinyl , azetidinyl, azepanyl, tetrahydrofuryl, dioxolanyl, tetrahydrothienyl, dihydropyrrolyl, tetrahydroimidazolyl, dihydropyrazolyl, tetrahydropyrazolyl, tetrahydropyridyl, or dihydropyridyl, each of which may be unsubstituted or mono-, di-, or tri-substituted with Hal, A, and/or =O.

In certain embodiments, Het ³ is piperidinyl, pyrrolidinyl, morpholinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, dihydropyrrolyl, dihydropyrazolyl, or dihydropyridyl, each of which may be unsubstituted or mono-, di-, or tri-substituted with Hal , A and/or =O.

In certain embodiments, Het ⁴ is hexahydrothieno[3,4-d]imidazolyl, benzo[c][1,2,5]oxadiazolyl, or 5H-dipyrrolo[1,2-c:2',1'-f][1 ,3,2]diazaborinin-4-y-uidyl, each of which may be unsubstituted or mono-, di-, tri- or tetra-substituted with A, NO ₂ , Hal and/or =O.

In certain embodiments

X stands for CH or N,

R ¹ is NH ₂ , CONH ₂ or H,

R ² is Hal, Ar ¹ or Het ¹ ,

R ³ is NR ⁵ [C(R ⁵ ) ₂ ] _n Het ² , NR ⁵ [C(R ⁵ ) ₂ ] _n Cyc, Het ² , O[C(R ⁵ ) ₂ ] _n Ar ² , NR ⁵ [C (R ⁵ ) ₂ ] _n Ar ² , O[C(R ⁵ ) ₂ ] _n Het ² , NR ⁵ (CH ₂ ) _p NR ⁵ R ⁶ , O(CH ₂ ) _p NR ⁵ R ⁶ or NR ⁵ (CH ₂ ) _p CR ⁷ R ⁸ NR ⁵ R ⁶ ,

R ⁴ is H,

R ⁵ is H or alkyl having 1, 2, 3 or 4 C atoms,

R ⁶ is N(R ⁵ ) ₂ CH ₂ CH=CHCONH, Het ³ CH ₂ CH=CHCONH, CH ₂ =CHCONH(CH ₂ ) _n , Het ⁴ (CH ₂ ) _n COHet ³ -diyl-CH ₂ CH=CHCONH , HC≡CCO, CH ₃ C≡CCO, CH ₂ =CH-CO, CH ₂ =C(CH ₃ )CONH, CH ₃ CH=CHCONH(CH ₂ ) _n , N≡CCR ⁷ R ⁸ CONH(CH ₂ ) _n , Het ⁴ NH(CH ₂ ) _p COHet ³ -diyl-CH ₂ CH=CHCONH, Het ⁴ (CH ₂ ) _p CONH(CH ₂ CH ₂ O) _p (CH ₂ ) _p COHet ³ -diyl-CH ₂ CH \u003d CHCONH, CH ₂ \u003d CHSO ₂ , ACH \u003d CHCO, CH ₃ CH \u003d CHCO, Het ⁴ (CH ₂ ) _p CONH (CH ₂ ) _p Het ³ -diyl-CH ₂ CH \u003d CHCONH, Ar ³ CH \u003d CHSO ₂ , CH ₂ \u003d CHSO ₂ NH or N (R ⁵ )CH ₂ CH \u003d CHCO,

R ⁷ , R ⁸ together are alkylene having 2, 3, 4 or 5 C atoms,

Ar ¹ is phenyl or naphthyl, each of which is unsubstituted or mono-, di- or tri-substituted with R ⁶ , Hal, (CH ₂ ) _n NH ₂ , CONHAr ³ , (CH ₂ ) _n NHCOA, O(CH ₂ ) _n Ar ³ , OCyc, A, COHet ³ , OA and/or OHet ³ (CH ₂ ),

Ar ² is phenyl or naphthyl, each of which is unsubstituted or mono-, di- or tri-substituted with R ⁶ , Hal, OAr ³ , (CH ₂ ) _n NH ₂ , (CH ₂ ) _n NHCOA and/or Het ³ ,

Ar ³ is phenyl which is unsubstituted or mono-, di- or tri-substituted with OH, OA, Hal, CN and/or A,

Het ¹ is piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, benzimidazolyl, indolazolyl , benzo-1,3-dioxolyl, indazolyl, azabicyclo[3.2.1]octyl, azabicyclo[2.2.2]octyl, imidazolidinyl, azetidinyl, azepanyl, benzo-2,1,3-thiadiazolyl, tetrahydrofuryl, dioxolanyl, tetrahydrothienyl, dihydropyrrolyl , tetrahydroimidazolyl, dihydropyrazolyl, tetrahydropyrazolyl, tetrahydropyridyl, dihydropyridyl or dihydrobenzodioxinyl, each of which is unsubstituted or mono-, di- or tri-substituted with R ⁶ , O(CH ₂ ) _n Ar ³ and/or (CH ₂ ) _n Ar ³ ,

Het ² is piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, azabicyclo[3.2.1]octyl, azabicyclo[2.2.2]octyl, 2,7-diazaspiro[3.5]nonyl, 2,8-diazaspiro[4.5]decyl, 2.7 -diazaspiro[4.4]nonyl, 3-azabicylo[3.1.0]hexyl, 2-azaspiro[3.3]heptyl, 6-azaspiro[3.4]octyl, 7-azaspiro[3.5]nonyl, 5-azaspiro[3.5]nonyl, imidazolidinyl , azetidinyl, azepanyl, tetrahydrofuryl, dioxolanyl, tetrahydrothienyl, tetrahydroimidazolyl, tetrahydropyrazolyl, tetrahydropyridyl, each of which is unsubstituted or mono-, di- or tri-substituted with R ⁶ , Het ³ , CycSO ₂ , OH, OA, COA, COHet ³ , CycCO, SO ₂ and/or =O,

Het ³ is piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, imidazolidinyl, azazetidinyl , tetrahydrofuryl, dioxolanyl, tetrahydrothienyl, dihydropyrrolyl, tetrahydroimidazolyl, dihydropyrazolyl, tetrahydropyrazolyl, tetrahydropyridyl or dihydropyridyl, each of which may be unsubstituted or mono-, di- or tri-substituted with Hal, A and/or =O,

Het ⁴ is hexahydrothieno[3,4-d]imidazolyl, benzo[c][1,2,5]oxadiazolyl or 5H-dipyrrolo[1,2-c:2',1'-f][1,3,2 ]diazaborinin-4-u-uidyl, each of which may be unsubstituted or mono-, di-, tri- or tetra-substituted with A, NO ₂ , Hal and/or =O,

Cyc is a cyclic alkyl having 3, 4, 5 or 6 C atoms, which is unsubstituted or monosubstituted with R ⁶ and which may contain a double bond,

A is straight or branched alkyl having 1-10 C atoms, in which 1-7 H atoms can be replaced by F and/or Cl and/or in which one or two non-adjacent CH ₂ and/or CH groups can be replaced by O, NH and/or N,

Hal is F, Cl, Br or I,

n is 0, 1, 2, 3 or 4,

p stands for 1, 2, 3, 4, 5, or 6.

In certain embodiments, the invention relates to a method for the treatment and/or prevention of multiple sclerosis (MS), including relapsing MS (RMS), relapsing-remitting MS (RRMS), progressive MS (PMS), secondary progressive MS (SPMS), primary progressive MS (PPMS) and progressive relapsing MS (PRMS) comprising administering to the subject a compound of formula (II):

formula (II),

and its pharmaceutically acceptable salts, solvates, solvates of salts or prodrugs,

wherein:

X is H or CH ₃ or NH ₂ ,

Y is H, Hal or absent,

B is N or CH,

E is NH ₂ or H,

W is NR, O or cyclic amine,

Z is independently CH ₂ , CH ₃ , CH ₂ -CH ₂ , CH-CH ₂ , H, NH or absent,

"linker" is (CH ₂ ) _n in which: n is 1, 2 or 3, or an optionally substituted group selected from a phenyl ring, an aryl ring, a heteroaryl ring, a branched or straight chain alkyl group, a 5-6 membered a monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen or oxygen, a 4-7 membered saturated or partially unsaturated heterocycle having 1-3 heteroatoms independently selected from nitrogen or oxygen, or a 7-10 membered bicyclic saturated or a partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen or oxygen, or a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms attached to a heterosaturated ring. Linkers may also be cycloalkanes optionally substituted with heteroatoms (independently selected from nitrogen or oxygen), cycloalkanes optionally substituted with -NH or OH, fused or bridged rings, or optionally substituted spirocyclic rings which optionally contain heteroatoms,

A is a mono- or bicyclic aromatic homo- or heterocycle having 0, 1, 2, 3 or 4 N and/or O atoms and 5, 6, 7, 8, 9 or 10 C atoms, which may be unsubstituted or , independently of the other, mono-, di- or tri-substituted with Hal, OH or OR,

Hal is F, Cl, Br or I,

R is independently hydrogen, oxygen or an optionally substituted group selected from a C _1-6 linear or cyclic aliphatic, benzyl, phenyl group, a phenyl group optionally substituted with 1, 2 or 3 O atoms, a 4-7 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen or oxygen, or a mono- or bicyclic aromatic homo- or heterocycle having 0.1 , 2, 3 or 4 N, O and 5, 6, 7 or 8 skeletal C atoms, which may be unsubstituted or independently mono-, di- or tri-substituted with Hal, A, OH, NH ₂ , nitrile and/or CH(Hal) ₃ or is straight or branched linear alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 C atoms, in which one or two CH ₂ groups can be replaced by an O atom and /or a -NH-, -CO-, -NHCOO-, -NHCONH-, -CONH-, -NHCO- or -CH group =CH-, and in which 1-3 H atoms can be replaced by Hal,

R ^q is selected from --R, --A, halogen, --OR, --O(CH ₂ ) _r OR, --R(NH), --NO ₂ , --C(O)R, -- CO ₂ R, --C(O)N(R) ₂ , --NRC(O)R, --NRC(O)NR ² , --NRSO ₂ R or --N(R) ₂ ,

r is 1-4,

n is 0-4 and

Q is an electrophilic group such as those listed in Table 1, where said electrophilic groups may additionally contain a warhead.

As used herein, the term "warhead" refers to a moiety, functional group, or substituent of compounds as claimed in the present invention, wherein said moiety, functional group, or substituent is covalently bound to an amino acid (such as cysteine, lysine, or any other amino acid native to or modified that can form said covalent bond) that is present, for example, at a binding site in a given ligand where said warhead binds to said ligand, where covalent bonding between said warhead and the binding site of said target protein occurs under conditions in which there is an irreversible inhibition of the physiological function of the specified protein.

Although the present invention is not intended to be limited to a specific group for the Q substituent as set forth above in formula (II), in certain embodiments, the Q substituent is selected from the groups shown in Table 1. All compounds in Table 1 shown in a box are not "warheads" as defined above.

Table 1

» обозначает точку связывания Q с Z в формуле (II).where "

" denotes the point of binding Q to Z in the formula (II).

In certain embodiments, the invention relates to a method for the treatment and/or prevention of multiple sclerosis (MS), including relapsing MS (RMS), relapsing-remitting MS (RRMS), progressive MS (PMS), secondary progressive MS (SPMS), primary progressive MS (PPMS); and progressive relapsing MS (PRMS), which comprises administering to a subject a compound of formula (III):

formula (III),

and its pharmaceutically acceptable salts, solvates, solvates of salts or prodrugs,

where

X is O or NH,

Y is N or CH,

W is H, NH ₂ or CONH ₂ ,

Q is H or NH ₂ ,

R ¹ is L ¹ -R ⁴ -L ² -R ⁵ ,

R ² is M ¹ -S ⁴ -M ² -S ⁵

L ¹ is a single bond, methylene or cyclic A, which can be mono- or disubstituted using N or NH ₂ ,

R ⁴ is Ar, A or cyclic A, which may be mono- or disubstituted using N, -O- or Hal,

R ⁵ is Ar, A or cyclic A, which may be mono- or disubstituted using N, -O- or Hal, or may be absent. In preferred embodiments, R ⁵ is selected from the group consisting of 2-fluoropyridine, 1-methylpyridin-2(1H)-one, and 2-chloropyridine,

L ² is H, -O-, substituted or unsubstituted C ₁ -C ₄ alkyl, substituted or unsubstituted C ₁ -C ₄ heteroalkyl, C ₁ -C ₆ alkoxyalkyl, C ₁ -C ₈ alkylaminoalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C ₁ -C ₄ alkyl (aryl), C ₁ -C ₄ alkyl (heteroaryl), C ₁ -C ₄ alky (C ₃ -C ₈ cycloalkyl) or C ₁ -C ₄ alkyl (C ₂ -C ₈ heterocycloalkyl). In some embodiments, L ² is --CH ₂ --O--(C ₁ -C ₃ alkyl), --CH ₂ --N(C ₁ -C ₃ alkyl) ₂ , C ₁ -C ₄ alkyl( phenyl) or C ₁ -C ₄ alkyl (5- or 6-membered heteroaryl). In some embodiments, L ² is -A-. In some embodiments, L ² is absent. In preferred embodiments of the present invention, L ² is selected from the group consisting of but-3-en-2-one, propan-2-one, (E)-5-(dimethylamino)pent-3-en-2-one, ( E)-pent-3-en-2-one, pent-3-in-2-one, 1-chloropropan-2-one, (methylsulfonyl)ethane, (E)-5-((2-methoxyethyl)(methyl )amino)pent-3-en-2-one or (Z)-pent-3-en-2-one,

M ¹ is a single bond,

S ⁴ is Ar, A or cyclic A which may be mono- or disubstituted using N, -O- or Hal. In preferred embodiments of the present invention, S ⁴ is a heteroaromatic 5-6 membered ring,

M ² is O, NH, CH ₂ or absent,

S ⁵ is H, Ar, A, or cyclic A, which may be mono- or disubstituted using N, -O-, Hal. In certain embodiments of the present invention, S ⁵ is selected from the group consisting of but-3-en-2-one, benzene, (E)-5-(dimethylamino)pent-3-en-2-one, ethylbenzene, 1-ethyl -2-methoxybenzene, aniline and (E)-5-morpholinopent-3-en-2-one. In some embodiments of the present invention, S ⁵ is absent,

Ar is a mono- or bicyclic aromatic homo- or heterocycle having 0, 1, 2, 3 or 4 N and/or O atoms and 5, 6, 7, 8, 9 or 10 backbone atoms which may be unsubstituted or, independently of each other, mono-, di- or tri-substituted with Hal, A, OH, OA, NH ₂ , NHA, NA ₂ , NO ₂ , CN, OCN, COOH, COOA, CONH ₂ , CONHA, CONA ₂ , NHCOA , NHCONHA, NHCONH, CHO and/or COA, and in which the N-atom of the ring can be substituted with an O-atom to form an N-oxide group, and in which, in the case of a bicyclic aromatic ring, one of the two rings can be partially rich,

A is a straight or branched linear or cyclic alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 C atoms, in which one or two CH ₂ groups can be replaced by an O atom and/or by a group - NH-, -CO-, -NHCOO-, -NHCONH-. -N(LA)-, -CONH-, -NHCO- or -CH=CH-,

LA is straight or branched linear alkyl having 1, 2, 3 or 4 C atoms, in which 1, 2 or 3 H atoms can be replaced by Hal,

Hal is F, Cl, Br, or I.

In certain embodiments, the invention relates to a method for the treatment and/or prevention of multiple sclerosis (MS), including relapsing MS (RMS), relapsing-remitting MS (RRMS), progressive MS (PMS), secondary progressive MS (SPMS), primary progressive MS (PPMS); and progressive relapsing MS (PRMS), comprising administering to the subject a compound of formula (IV):

formula (IV)

and its pharmaceutically acceptable salts, solvates, solvates of salts or prodrugs,

where

Z is N or CH,

X is O or NH, and

R ³ is selected from the group consisting of the following structures:

where "R" denotes the point of attachment to Z in the formula IV.

In certain embodiments, the invention relates to a method for the treatment and/or prevention of multiple sclerosis (MS), including relapsing MS (RMS), relapsing-remitting MS (RRMS), progressive MS (PMS), secondary progressive MS (SPMS), primary progressive MS (PPMS) and progressive relapsing MS (PRMS) comprising administering to the subject a compound of formula (V):

and its pharmaceutically acceptable salts, solvates, solvates of salts or prodrugs,

where

X stands for CH or N,

R ¹ is NR ⁵ [C(R ⁵ ) ₂ ] _n Het ² ,

R ² is Hal, Ar ¹ or Het ¹ ,

R ³ is NH ₂ ,

R ⁴ is H, CH ₃ or NH ₂ ,

R ⁵ is H or alkyl having 1, 2, 3 or 4 C atoms,

R ⁶ is N(R ⁵ ) ₂ CH ₂ CH=CHCONH, Het ³ CH ₂ CH=CHCONH, CH ₂ =CHCONH(CH ₂ ) _n , Het ⁴ (CH ₂ ) _n COHet ³ -diyl-CH ₂ CH=CHCONH , HC≡CCO, CH ₃ C≡CCO, CH ₂ =CH-CO, CH ₂ =C(CH ₃ )CONH, CH ₃ CH=CHCONH(CH ₂ ) _n , N≡CCR ⁷ R ⁸ CONH(CH ₂ ) _n , Het ⁴ NH(CH ₂ ) _p COHet ³ -diyl-CH ₂ CH=CHCONH, Het ⁴ (CH ₂ ) _p CONH(CH ₂ CH ₂ O) _p (CH ₂ ) _p COHet ³ -diyl-CH ₂ CH \u003d CHCONH, CH ₂ \u003d CHSO ₂ , ACH \u003d CHCO, CH ₃ CH \u003d CHCO, Het ⁴ (CH ₂ ) _p CONH (CH ₂ ) _p Het ³ -diyl-CH ₂ CH \u003d CHCONH, Ar ³ CH \u003d CHSO ₂ , CH ₂ \u003d CHSO ₂ NH or N (R ⁵ )CH ₂ CH \u003d CHCO,

R ⁷ , R ⁸ together are alkylene having 2, 3, 4 or 5 C atoms,

Ar ¹ is phenyl or naphthyl, each of which is unsubstituted or mono-, di- or tri-substituted with R ⁶ , Hal, (CH ₂ ) _n NH ₂ , CONHAr ³ , (CH ₂ ) _n NHCOA, O(CH ₂ ) _n Ar ³ , OCyc, A, COHet ³ , OA and/or OHet ³ (CH ₂ ),

Ar ² is phenyl, naphthyl or pyridyl, each of which is unsubstituted or mono-, di- or tri-substituted with R ⁶ , Hal, OAr ³ , (CH ₂ ) _n NH ₂ , (CH ₂ ) _n NHCOA and/or Het ³ ,

Ar ³ is phenyl which is unsubstituted or mono-, di- or tri-substituted with OH, OA, Hal, CN and/or A,

Het ¹ is a mono- or bicyclic saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and/or S atoms, which may be unsubstituted or mono-, di- or tri-substituted with R ⁶ , O(CH ₂ ) _n Ar ³ and/or (CH ₂ ) _n Ar ³ ,

Het ² denotes a mono- or bicyclic saturated heterocycle having 1 to 4 N, O and/or S atoms, which may be unsubstituted or mono-, di- or tri-substituted with R ⁶ , Het ³ , CycSO ₂ , OH, Hal , COOH, OA, COA, COHet ³ , CycCO, SO ₂ and/or =O,

Het ³ denotes a monocyclic unsaturated, saturated or aromatic heterocycle having from 1 to 4 N, O and/or S atoms, which may be unsubstituted or mono-, di- or tri-substituted with Hal, A and/or =O,

Het ⁴ is a bi- or tricyclic unsaturated, saturated or aromatic heterocycle having 1 to 4 N, O and/or S atoms, which may be unsubstituted or mono-, di-, tri- or tetra-substituted with A, NO ₂ , Hal and/or =O,

Cyc is a cyclic alkyl having 3, 4, 5 or 6 C atoms which is unsubstituted, monosubstituted or disubstituted with R ⁶ and/or OH and which may contain a double bond,

A is straight or branched alkyl having 1-10 C atoms, in which 1-7 H atoms can be replaced by F and/or Cl and/or in which one or two non-adjacent CH ₂ and/or CH groups can be replaced by O, NH and/or N,

Hal is F, Cl, Br or I,

n is 0, 1, 2, 3 or 4,

p is 1, 2, 3, 4, 5 or 6,

and its pharmaceutically acceptable salts, tautomers and stereoisomers, including mixtures thereof in all proportions.

In certain embodiments, the invention relates to a method for the treatment and/or prevention of multiple sclerosis (MS), including relapsing MS (RMS), relapsing-remitting MS (RRMS), progressive MS (PMS), secondary progressive MS (SPMS), primary progressive MS (PPMS) and progressive relapsing MS (PRMS) comprising administering to the subject a compound selected from Table 2:

table 2

No. chemical name "A1" (R)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one "A2" (R)-1-(3-((6-Amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)piperidin-1-yl)prop-2-en-1-one A3 N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)phenyl)acrylamide A4 (R)-1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)pyrrolidin-1-yl)prop-2-en-1-one "A5" N-((1-(6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)pyrrolidin-3-yl)methyl)acrylamide "A6" 1-(4-(((5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)piperidin-1-yl)prop-2-en-1-one "A7" N-((1-(6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)piperidin-4-yl)methyl)acrylamide "A8" 4-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidine-1-carbonyl)-1-methylpyridin-2(1H)-one "A9" 1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)piperidin-1-yl)but-2-yn-1-one "A10" 5-(4-Phenoxyphenyl)-N4-((1-(vinylsulfonyl)piperidin-4-yl)methyl)pyrimidine-4,6-diamine "A11" (E)-1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-4-((2-methoxyethyl)(methyl )amino)but-2-en-1-one "A12" (4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)(2-fluoropyridin-3-yl)methanone A13 (E)-1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)but-2-en-1-one A14 N4-((1-(cyclopropylsulfonyl)piperidin-4-yl)methyl)-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine A15 (Z)-1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)but-2-en-1-one A16 1-(4-(2-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)ethyl)piperidin-1-yl)prop-2-en-1-one A17 1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)piperidin-1-yl)prop-2-en-1-one "A18" N-(2-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)ethyl)acrylamide A19 (R)-1-(3-((6-Amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one "A20" N-(1-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)cyclopentyl)acrylamide "A21" 1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)pyrrolidin-1-yl)prop-2-en-1-one "A22" 1-(4-(((5-fluoro-3-(4-phenoxyphenyl)pyridin-2-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one A23 1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)ethanone "A24" (E)-7-(3-(4-(4-((3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)amino)-4-oxobut-2 -en-1-yl)piperazin-1-yl)-3-oxopropyl)-5,5-difluoro-1,3-dimethyl-5H-dipyrrolo[1,2-c:2',1'-f][ 1,3,2]diazaborinin-4-y-5-uid A25 1-(4-(((2-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one A26 (S)-1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)pyrrolidin-1-yl)prop-2-en-1-one A27 N-(2-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)ethyl)acrylamide "A28" (S)-1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)pyrrolidin-1-yl)prop-2-en-1-one A29 1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-2-methylprop-2-en-1-one A30 (4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)(cyclohex-1-en-1-yl)methanone A31 1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-3-methylbut-2-en-1-one A32 (4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)(cyclopent-1-en-1-yl)methanone A33 1-(4-(((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1 -he A34 1-(4-(((6-amino-5-(4-(3-fluorophenoxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one A35 (E)-7-(3-((2-(4-(4-((3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)amino)-4 -oxobut-2-en-1-yl)piperazin-1-yl)ethyl)amino)-3-oxopropyl)-5,5-difluoro-1,3-dimethyl-5H-dipyrrolo[1,2-c:2 ',1'-f][1,3,2]diazaborinin-4-th-5-uid A36 1-(4-(((6-amino-2-methyl-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one A37 1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-hydroxypiperidin-1-yl)prop-2-en-1-one "A38" (R)-1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)pyrrolidin-1-yl)prop-2-en-1-one A39 1-(4-(((6-amino-5-(4-(phenylamino)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one A40 1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)-1H-pyrrol-2(5H)-one A41 1-(4-(((6-amino-5-(4-benzylphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one "A42" (4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)(cyclobut-1-en-1-yl)methanone A43 (Z)-1-(4-(((6-Amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)piperidin-1-yl)but-2-en-1-one A44 1-(4-(((6-amino-2-methyl-5-(4-phenoxyphenyl)pyrimidin-4-yl)(methyl)amino)methyl)piperidin-1-yl)prop-2-en-1- he A45 1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-2-chloroethanone A46 1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-in-1-one A47 1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)(methyl)amino)methyl)piperidin-1-yl)prop-2-en-1-one A48 1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-8-azabicyclo[3.2.1]octan-8-yl)prop-2-en- 1-he A49 N-((1S,3S)-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclopentyl)acrylamide "A50" N-(4-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)butyl)acrylamide "A51" N-(cis-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)acrylamide "A52" 1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)azepan-1-yl)prop-2-en-1-one "A53" N-(trans-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)acrylamide "A54" (E)-5-(4-phenoxyphenyl)-N4-((1-(styrylsulfonyl)piperidin-4-yl)methyl)pyrimidin-4,6-diamine "A55" N4-((1-(methylsulfonyl)piperidin-4-yl)methyl)-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine "A56" 1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-2,3-dihydroxypropan-1-one "A57" 4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-2-one "A58" N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)ethensulfonamide "A59" N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)propyl)acrylamide A60 N-(5-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)pyridin-3-yl)acrylamide "A61" (R)-1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)pyrrolidin-1-yl)prop-2-in-1-one A62 (R,E)-1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)pyrrolidin-1-yl)-4-(dimethylamino)but-2 -en-1-he A63 (E)-N-(cis-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)-4-(dimethylamino)but-2-enamide A64 N-(cis-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)propiolamide A65 (S)-1-(2-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)morpholino)prop-2-en-1-one A66 (R)-1-(2-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)morpholino)prop-2-en-1-one A67 N-(3-((6-amino-5-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide "A68" 1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-8-azabicyclo[3.2.1]octan-8-yl)prop-2-in- 1-he A69 N-(3-((6-amino-5-(1-(4-cyanobenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide A70 N-(3-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)phenyl)acrylamide A71 (E)-1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-8-azabicyclo[3.2.1]octan-8-yl)-4 -(dimethylamino)but-2-en-1-one A72 N-(3-((6-amino-5-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide "A73" (R,E)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)pyrrolidin-1-yl)-4-(dimethylamino)but-2-en- 1-he A74 (R,E)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)piperidin-1-yl)-4-(dimethylamino)but-2-en- 1-he A75 1-(trans-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-4-hydroxypyrrolidin-1-yl)prop-2-en-1-one "A76" 1-(4-(((2-amino-3-(4-phenoxyphenyl)pyridin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one A77 1-(4-(((6-amino-5-(4-fluorophenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one "A78" 1-(4-(((6-amino-5-(4-(trifluoromethoxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one A79 1-(4-(((6-amino-5-(4-(4-(trifluoromethyl)phenoxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1 -he "A80" 1-(4-(((6-amino-5-(4-(4-(fluorophenoxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one "A81" 1-(4-(((6-amino-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one "A82" 1-(4-(((6-amino-5-(3,4-dimethoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one A83 1-(4-(((6-amino-5-(3,4,5-trimethoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one "A84" 1-(4-(((6-amino-5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl) prop-2-en-1-one A85 1-(4-(((6-amino-5-(4-methoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one "A86" 4-(4-(4-(((1-acryloylpiperidin-4-yl)methyl)amino)-6-aminopyrimidin-5-yl)phenoxy)benzonitrile "A87" 1-(4-(((6-amino-5-(2,5-difluoro-4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one "A88" 1-(4-(((6-amino-5-(2,3-difluoro-4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one A89 1-(4-(((6-amino-5-(4-((1-methylpiperidin-4-yl)oxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2 -en-1-he A90 1-(4-(((6-amino-5-(4-phenoxy-2-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1- he A91 1-(2-(6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)prop-2-en-1-one A92 1-(8-(6-Amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)prop-2-en-1-one A93 1-(7-(6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)prop-2-en-1-one A94 1-(4-(((6-amino-5-(4-(4-hydroxyphenoxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one A95 1-(4-(((6-amino-5-(4-(3-(trifluoromethyl)phenoxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1 -he A96 1-(4-(((6-amino-5-(4-(pyridin-3-yloxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1- he A97 1-(4-(((6-amino-5-(4-(pyridin-4-yloxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1- he "A98" 1-(4-(((6-amino-5-(4-(p-tolyloxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one "A99" 1-(4-(((6-amino-5-(4-(cyclohexyloxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one A100 N4-((1R,5S,6r)-3-azabicyclo[3.1.0]hexan-6-ylmethyl)-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine hydrochloride "A101" (3S,4S)-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-3-ol hydrochloride "A102" (E)-1-(6-((6-Amino-5-chloropyrimidin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)-4-(dimethylamino)but-2-en- 1-he "A103" 1-(3-(2-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)ethyl)azetidin-1-yl)prop-2-en-1-one "A104" 1-(3-(2-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)ethyl)azetidin-1-yl)prop-2-in-1-one "A105" (E)-1-(6-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)-4-(dimethylamino)but -2-en-1-he "A106" 1-(6-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)prop-2 -en-1-he "A107" 1-(6-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-2-azaspiro[3.3]heptan-2-yl)prop-2 -en-1-he "A108" 1-(6-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-2-azaspiro[3.3]heptan-2-yl)but-2-yn-1-one "A109" 1-((3S,4S)-4-(((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1- yl)prop-2-en-1-one A110 1-((3S,4S)-4-(((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1- silt) prop-2-in-1-one A111 1-(6-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-2-azaspiro[3.3]heptan-2-yl)prop-2 -in-1-he "A112" 1-(6-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)prop-2 -in-1-he A113 1-(2-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-6-azaspiro[3.4]octan-6-yl)prop-2-en-1-one A114 1-(6-((6-amino-5-(4-(pyridin-4-yloxy)phenyl)pyrimidin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)prop-2- en-1-he A115 1-(2-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-6-azaspiro[3.4]octan-6-yl)prop-2-in-1-one "A116" 1-(6-((6-amino-5-(1-(pyridin-4-ylmethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-2-azaspiro[3.3]heptan-2 -yl)prop-2-en-1-one A117 N-(1,3-trans-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclobutyl)acrylamide A118 N-((1,3-cis-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclobutyl)acrylamide A119 N4-(2-((2-chloroethyl)sulfonyl)-2-azaspiro[3.3]heptan-6-yl)-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine A120 1-(6-((6-Amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one A121 1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-methoxypiperidin-1-yl)prop-2-en-1-one "A122" N-(6-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)spiro[3.3]heptan-2-yl)acrylamide A123 1-(1-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-7-azaspiro[3.5]nonan-7-yl)prop-2-en-1-one A124 1-(6-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one A125 1-(8-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-5-azaspiro[3.5]nonan-5-yl)prop-2-en-1-one A126 (E)-1-((3S,4S)-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-4 -(dimethylamino)but-2-en-1-one A127 (E)-1-(6-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-2-azaspiro[3.3]heptan-2-yl)-4-(dimethylamino)but -2-en-1-he A128 3-((6-Amino-5-chloro-pyrimidin-4-ylamino)-methyl)-benzoic acid methyl ester A129 trans-3-(6-amino-5-chloro-pyrimidin-4-ylamino)-cyclohexanecarboxylic acid methyl ester A130 (1R,3S)-3-(6-amino-5-chloro-pyrimidin-4-ylamino)-cyclohexanecarboxylic acid methyl ester A131 3-((6-Amino-5-(4-phenoxy-phenyl)-pyrimidin-4-ylamino)-methyl)-benzoic acid methyl ester A132 trans-3-(6-Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexanecarboxylic acid methyl ester A133 (1R,3S)-3-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexanecarboxylic acid methyl ester A134 -((6-amino-5-(4-phenoxy-phenyl)-pyrimidin-4-ylamino)-methyl)-benzoic acid A135 (1S,3S)-3-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexanecarboxylic acid A136 (1R,3S)-3-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexanecarboxylic acid A137 (4-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-phenyl)-N-methoxy-N-methyl-acetamide A138 3-((6-amino-5-(4-phenoxy-phenyl)-pyrimidin-4-ylamino)-methyl)-N-methoxy-N-methyl-benzamide A139 (1S,3S)-3-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexanecarboxylic acid methoxy-methyl-amide A140 (1R,3S)-3-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexanecarboxylic acid methoxy-methyl-amide A141 1-(3-((6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-methyl)-phenyl)-but-2-in-1-one A142 1-(3-((6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-methyl)-phenyl)-but-2-en-1-one A143 1-((1S,3S)-3-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexyl)-propenone A144 1-((1S,3S)-3-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexyl)-but-2-en-1-one A145 1-((1S,3S)-3-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexyl)-but-2-yn-1-one A146 1-((1S,3R)-3-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexyl)-but-2-en-1-one A147 1-((1S,3R)-3-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexyl)-but-2-yn-1-one A148 (S)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one A149 N-(3-((2-amino-3-(4-(benzyloxy)phenyl)pyridin-4-yl)oxy)phenyl)acrylamide A150 1-(3-((2-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one A151 (E)-N-(3-((2-amino-3-(4-phenoxyphenyl)pyridin-4-yl)oxy)phenyl)-4-(dimethylamino)but-2-enamide A152 (E)-N-(3-((2-amino-3-(4-(benzyloxy)phenyl)pyridin-4-yl)oxy)phenyl)-4-(dimethylamino)but-2-enamide A153 (E)-1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-4-(dimethylamino)but-2-ene -1-he A154 N-cis-4-((6-amino-5-(4-(benzyloxy)phenyl)pyrimidin-4-yl)amino)cyclohexyl)acrylamide A155 4-(4-(((1-acryloylpyrrolidin-3-yl)methyl)amino)-6-aminopyrimidin-5-yl)-N-phenylbenzamide A156 1-(3-(((6-amino-5-(4-(benzyloxy)phenyl)pyrimidin-4-yl)amino)methyl)pyrrolidin-1-yl)prop-2-en-1-one A157 4-(4-(((1-acryloylpiperidin-4-yl)methyl)amino)-6-aminopyrimidin-5-yl)-N-phenylbenzamide A158 N-(3-((2-amino-3-(4-phenoxyphenyl)pyridin-4-yl)oxy)-4-fluorophenyl)acrylamide A159 4-(4-((cis-4-acrylamidocyclohexyl)amino)-6-aminopyrimidin-5-yl)-N-phenylbenzamide A160 (E)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)piperidin-1-yl)-4-(dimethylamino)but-2-ene-1- he A161 N-(3-((6-amino-5-(6-phenoxypyridin-3-yl)pyrimidin-4-yl)oxy)-4-fluorophenyl)acrylamide A162 N-(3-((6-amino-5-(4-(pyridin-2-yloxy)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide A163 N-(3-((6-amino-5-(3-sulfamoylphenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide A164 N-(3-((6-amino-5-(3-(trifluoromethoxy)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide A165 N-(3-((6-amino-5-(6-(2-fluorophenoxy)pyridin-3-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide A166 N-(3-((6-amino-5-(6-(4-fluorophenoxy)pyridin-3-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide A167 N-(6-((5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)pyridin-2-yl)acrylamide A168 1-(4-(((6-amino-5-(6-phenoxypyridin-3-yl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one A169 1-(4-(((6-amino-5-(4-(3-(trifluoromethyl)phenoxy)phenyl)pyrimidin-4-yl)amino)methyl)-4-hydroxypiperidin-1-yl)prop-2- en-1-one A170 1-((3S,4S)-4-(((6-amino-5-(4-(3-(trifluoromethyl)phenoxy)phenyl)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1- yl)prop-2-en-1-one A171 1-(4-(((6-amino-2'-phenoxy-[5,5'-bipyrimidin]-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one A172 N-(3-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide A173 N-((1S,3R)-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)acrylamide A174 N-((1R,3S)-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)acrylamide A175 N-((1R,3R)-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)acrylamide A176 N-((1S,3S)-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)acrylamide A177 N-(4-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)bicyclo[2.1.1]hexan-1-yl)acrylamide A178 (R)-N4-(1-((Perfluorophenyl)sulfonyl)pyrrolidin-3-yl)-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine A179 (R)-N4-(1-((Perfluorophenyl)sulfonyl)piperidin-3-yl)-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine A180 (R)-1-(3-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en- 1-he A181 N-(cis-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclopentyl)acrylamide A182 N-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)cyclobutyl)acrylamide A183 N-(3-((6-amino-5-(1-(3,5-difluorobenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide A184 N-(3-((6-amino-5-(1-(2-fluorobenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide A185 1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)azetidin-1-yl)prop-2-en-1-one A186 N-(5-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)pyridin-3-yl)acrylamide A187 N-(3-((6-amino-5-(1-(4-fluorobenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide A188 N-((1R,3S,5R)-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-5-hydroxycyclohexyl)acrylamide (racemic) A189 N-(5-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)pyridin-3-yl)acrylamide A190 N-(3-((6-amino-5-(1-(3-methylbenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide A191 N-(3-((6-amino-5-(1-(3-chlorobenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide A192 (R)-1-(2-(((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)methyl)morpholino)prop-2-en-1 -he A193 (S)-1-(2-(((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)methyl)morpholino)prop-2-en-1 -he A194 N-(3-((6-amino-5-(1-(2-cyanobenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide A195 N-(3-((6-amino-5-(1-(3-(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide A196 (R)-1-(3-(((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)methyl)pyrrolidin-1-yl)prop-2 -en-1-he A197 N-(5-((6-amino-5-(4-(4-cyanophenoxy)phenyl)pyrimidin-4-yl)oxy)pyridin-3-yl)acrylamide A198 N-(3-((6-amino-5-(1-(3-methoxybenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide A199 4-(4-(4-((((3S,4S)-1-acryloyl-3-hydroxypiperidin-4-yl)methyl)amino)-6-aminopyrimidin-5-yl)phenoxy)benzonitrile A200 (R)-4-(4-(4-((4-acryloylmorpholin-2-yl)methoxy)-6-aminopyrimidin-5-yl)phenoxy)benzonitrile "A201" (R)-4-(4-(4-((1-acryloylpyrrolidin-3-yl)methoxy)-6-aminopyrimidin-5-yl)phenoxy)benzonitrile "A202" 4-(4-(4-((2-acryloyl-2-azaspiro[3.3]heptan-6-yl)oxy)-6-aminopyrimidin-5-yl)phenoxy)benzonitrile "A203" N-(3-((6-amino-5-(1-(3-cyanobenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide "A204" 1-((3S,5S)-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-5-fluoropiperidin-1-yl)prop-2-en-1-one "A205" 1-((3R,5R)-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-5-fluoropiperidin-1-yl)prop-2-en-1-one "A206" methyl 3-((4-(4-(3-acrylamidophenoxy)-6-aminopyrimidin-5-yl)-1H-pyrazol-1-yl)methyl)benzoate "A207" 4-(4-(4-((2-acryloyl-2-azaspiro[3.3]heptan-6-yl)amino)-6-aminopyrimidin-5-yl)phenoxy)benzonitrile "A208" 4-(4-(4-(((8-acryloyl-8-azabicyclo[3.2.1]octan-3-yl)methyl)amino)-6-aminopyrimidin-5-yl)phenoxy)benzonitrile "A209" 1-(3-(((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8- yl)prop-2-en-1-one A210 1-((3R,4R)-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-4-hydroxypiperidin-1-yl)prop-2-en-1-one (racemic) A211 N-(3-((6-amino-5-(1-(3-(methylsulfonyl)benzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide A212 N-(3-((6-amino-5-(1-(3-(dimethylamino)benzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide A213 N-(3-((6-amino-5-(4-(3-cyanophenoxy)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide A214 3-(4-(4-(((1-acryloylpiperidin-4-yl)methyl)amino)-6-aminopyrimidin-5-yl)phenoxy)benzonitrile A215 1-((3S,4S)-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)but-2-yn- 1-he A216 1-acryloyl-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidine-4-carboxylic acid A217 (E)-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-1-(4-(dimethylamino)but-2-enoyl)piperidine-4-carboxylic acid acid A218 (E)-1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-4-(3-fluoroazetidin-1-yl )but-2-en-1-one A219 (E)-1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-4-(3,3-difluoroazetidine-1 -yl)but-2-en-1-one A220 (E)-1-(4-(((6-Amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-4-(pyrrolidin-1-yl)but -2-en-1-he "A221" 1-(6-((6-amino-5-(4-(pyridin-3-yloxy)phenyl)pyrimidin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)prop-2- en-1-he "A222" (E)-1-(6-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)-4-(3-fluoroazetidine -1-yl)but-2-en-1-one A223 (E)-1-(6-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)-4-(3-fluoroazetidine -1-yl)but-2-en-1-one A224 (E)-N-(1,3-cis-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclobutyl)-4-(dimethylamino)but-2-enamide "A225" 1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-1-yl)prop-2-en-1-one (2) A226 (E)-1-(2-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-6-azaspiro[3.4]octan-6-yl)-4-(dimethylamino)but -2-en-1-he A227 (E)-1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-1-yl)-4-(dimethylamino)but- 2-en-1-he A228 (E)-N-(1,3-trans-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclobutyl)-4-(dimethylamino)but-2-enamide A229 N-(1,3-cis-3-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)cyclobutyl)acrylamide A230 (E)-N-(1,3-cis-3-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)cyclobutyl)-4-( dimethylamino)but-2-enamide A231 (E)-1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-3-phenylprop-2-en-1- he A232 1-((3S,4S)-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-3-(dimethylamino) propane-1-he A233 1-((3S,4S)-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-3-(piperidin- 1-yl) propane-1-one "A234" 1-((3S,4S)-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-3-morpholinopropan-1 -he A235 1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-1-yl)-3-(piperidin-1-yl)propan- 1-he A236 (E)-N-(1,3-cis-3-((6-amino-5-(4-(3-(trifluoromethyl)phenoxy)phenyl)pyrimidin-4-yl)amino)cyclobutyl)-4-( dimethylamino)but-2-enamide A237 N-(1,3-trans-3-((6-amino-5-(4-(3-(trifluoromethyl)phenoxy)phenyl)pyrimidin-4-yl)amino)cyclobutyl)acrylamide A238 N-(1,3-cis-3-((6-amino-5-(4-(3-(trifluoromethyl)phenoxy)phenyl)pyrimidin-4-yl)amino)cyclobutyl)acrylamide A239 1-acryloyl-4-(((6-amino-5-(4-(3-(trifluoromethyl)phenoxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidine-4-carboxylic acid A240 N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)-2-fluorophenyl)acrylamide A241 N-(3-(4-amino-6-((4-phenoxyphenyl)amino)pyrimidin-5-yl)phenyl)acrylamide A242 N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide A243 N-(3-(2-amino-4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)acrylamide A244 N-(3-((2-amino-3-(4-phenoxyphenyl)pyridin-4-yl)oxy)phenyl)acrylamide A245 N-(3-(4-amino-6-(4-phenoxyphenoxy)pyrimidin-5-yl)phenyl)acrylamide A246 N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)-4-fluorophenyl)acrylamide A247 (R)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one A248 (E)-N-(3-(4-amino-6-(4-phenoxyphenoxy)pyrimidin-5-yl)phenyl)-4-(dimethylamino)but-2-enamide A249 N-(3-((6-amino-5-(4-(benzyloxy)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide A250 1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one (1) A251 N-(5-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)-2,4-difluorophenyl)acrylamide A252 (E)-N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)-4-(dimethylamino)but-2-enamide A253 1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one A254 N-(3-((6-amino-5-(4-((2-methoxybenzyl)oxy)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide A255 N-(3-((5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide A256 N-(3-((6-amino-5-(4-(benzyloxy)-3-methoxyphenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide A257 N-(3-((6-amino-5-(4-(benzyloxy)-2,3-difluorophenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide A258 4-(4-(3-acrylamidophenoxy)-6-aminopyrimidin-5-yl)-N-phenylbenzamide A259 N-(3-((6-amino-5-(6-(benzyloxy)pyridin-3-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide A260 N-(3-((6-amino-5-(4-((3-fluorobenzyl)oxy)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide A261 N-(3-((6-amino-2'-(benzyloxy)-[5,5'-bipyrimidin]-4-yl)oxy)phenyl)acrylamide A262 1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)pyrrolidin-1-yl)prop-2-en-1-one A263 1-(4-(4-Amino-6-(4-phenoxyphenoxy)pyrimidin-5-yl)-5,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one A264 N-(3-((6-amino-5-(4-((4-methoxybenzyl)oxy)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide A265 (E)-N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)-4-morpholinobut-2-enamide A266 N-((1s,4s)-4-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)acrylamide A267 N-(3-(4-((4-phenoxyphenyl)amino)pyridin-3-yl)phenyl)acrylamide A268 N-(3-((6-amino-5-(6-phenoxypyridin-3-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide A269 1-(3-((6-amino-5-(4-(benzyloxy)phenyl)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one A270 N-(3-((3-(4-phenoxyphenyl)pyridin-4-yl)oxy)phenyl)acrylamide A271 N-(3-((2-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide A272 3-(3-acrylamidophenyl)-4-(4-phenoxyphenoxy)picolinamide A273 1-(3-(4-amino-6-((4-phenoxyphenyl)amino)pyrimidin-5-yl)-5,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one A274 (E)-N-(3-(4-amino-6-(4-phenoxyphenoxy)pyrimidin-5-yl)phenyl)-4-morpholinobut-2-enamide A275 (S)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one A276 N-((1r,4r)-4-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)acrylamide A277 N-(3-((6-amino-5-(4-fluoro-3-methoxyphenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide A278 N-(3-((6-amino-5-(4-(2-hydroxypropan-2-yl)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide A279 1-(3-(4-amino-6-(4-phenoxyphenoxy)pyrimidin-5-yl)-5,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one A280 N-(4-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide A281 N-(4-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)acrylamide A282 (E)-4-(dimethylamino)-N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)but-2-enamide A283 N-(3-(4-((4-phenoxyphenyl)amino)pyrimidin-5-yl)phenyl)acrylamide "A284" 1-(3-((5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one A285 N-(3-((6-amino-5-(4-(pyrrolidin-1-carbonyl)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide A286 1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one A287 N-(4-(4-(4-phenoxyphenoxy)pyridin-3-yl)benzyl)acrylamide A288 1-(4'-(4-phenoxyphenoxy)-5,6-dihydro-[3,3'-bipyridin]-1(2H)-yl)prop-2-en-1-one A289 N-(3-((6-amino-5-(4-isopropoxyphenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide A290 (E)-N-(4-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)-4-(dimethylamino)but-2-enamide A291 N-(3-((6-amino-5-(5-methoxypyridin-3-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide A292 1-(4-(((6-amino-5-(4-(benzyloxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one A293 (E)-4-morpholino-N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)but-2-enamide A294 N-(3-((6-amino-5-(4-(benzyloxy)-2,6-difluorophenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide A295 (E)-N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)-4-(4-(5-((4S)-2-oxohexahydro- 1H-thieno[3,4-d]imidazol-4-yl)pentanoyl)piperazin-1-yl)but-2-enamide A296 N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)but-2-inamide A297 N-(4-((3-(4-phenoxyphenyl)pyridin-4-yl)oxy)phenyl)acrylamide A298 N-(1-(6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)piperidin-3-yl)acrylamide A299 1-(4-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one A300 3-(3-aminophenyl)-4-(4-phenoxyphenoxy)pyridine-2-amine "A301" (E)-N-(3-(4-amino-6-(4-phenoxyphenoxy)pyrimidin-5-yl)phenyl)-4-(3,3-difluoropiperidin-1-yl)but-2-enamide "A302" N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)benzyl)acrylamide "A303" 6-(4-aminophenoxy)-5-(4-phenoxyphenyl)pyrimidine-4-amine "A304" N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)benzyl)but-2-inamide A305 6-(3-aminophenoxy)-5-(4-phenoxyphenyl)pyrimidine-4-amine "A306" N-(3-(2-amino-4-(4-phenoxyphenoxy)pyrimidin-5-yl)phenyl)acrylamide A307 (E)-N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)but-2-enamide A308 N-(4-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)propionamide A309 N-((1-(6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)piperidin-3-yl)methyl)acrylamide A310 N-(3-(2-amino-4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)propionamide A311 (R)-N-(3-(4-amino-6-((1-phenylethyl)amino)pyrimidin-5-yl)phenyl)acrylamide A312 3-(4-(4-phenoxyphenoxy)pyridin-3-yl)aniline "A313" 4-(3-aminophenoxy)-3-(4-phenoxyphenyl)pyridine-2-amine A314 4-(4-(4-phenoxyphenoxy)pyridin-3-yl)aniline A315 (4-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)methanamine A316 (3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)methanamine A317 5-(3-aminophenyl)-6-(4-phenoxyphenoxy)pyrimidine-4-amine A318 N-(3-((3-(4-phenoxyphenyl)pyridin-4-yl)oxy)phenyl)propionamide A319 N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)propionamide A320 N-(4-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)propionamide A321 N-(4-((3-(4-phenoxyphenyl)pyridin-4-yl)oxy)phenyl)propionamide "A322" N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)methacrylamide A323 N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)benzyl)propionamide A324 N-(4-(4-(4-phenoxyphenoxy)pyridin-3-yl)benzyl)propionamide A325 N-(3-(4-amino-6-(4-phenoxyphenoxy)pyrimidin-5-yl)phenyl)propionamide A326 N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)propionamide A327 (E)-N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)benzyl)but-2-enamide "A328" 3-(4-phenoxyphenyl)-4-(3-propionamidophenoxy)picolinamide "A329" N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)-1-cyanocyclopropanecarboxamide A330 N-(3-(4-amino-6-(4-phenoxyphenoxy)pyrimidin-5-yl)phenyl)-1-cyanocyclopropanecarboxamide A331 (E)-3-(7-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)naphthalen-2-yl)-N,N-dimethylacrylamide A332 1-(4-(1-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)ethyl)piperidin-1-yl)prop-2-en-1-one A333 1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)propan-1-one A334 1-(4-(((5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one A335 1-(4-(((6-amino-5-(4-(pyridin-2-yloxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1- he A336 1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)but-2-yn-1-one A337 N4-((1-(6-chloropyridin-2-yl)piperidin-4-yl)methyl)-5-(4-phenoxyphenyl)pyrimidin-4,6-diamine A338 1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)piperidin-1-yl)prop-2-en-1-one A339 N-(3-((6-amino-5-(4-(benzyloxy)-2,5-difluorophenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide A340 N-(3-((2-amino-3-(4-phenoxyphenyl)pyridin-4-yl)oxy)phenyl)but-2-inamide A341 (R)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)pyrrolidin-1-yl)but-2-yn-1-one A342 N-{3-[6-amino-5-(4-phenoxy-phenyl)-pyrimidin-4-yloxy]-phenyl}-2-chloroacetamide A343 N-(3-{6-amino-5-[4-(2-fluoro-benzyloxy)-phenyl]-pyrimidin-4-yloxy}-phenyl)-acrylamide A344 N-(3-{6-amino-5-[4-(4-fluoro-benzyloxy)-phenyl]-pyrimidin-4-yloxy}-phenyl)-acrylamide A345 N-(3-{6-amino-5-[4-(3-fluoro-benzyloxy)-phenyl]-pyrimidin-4-yloxy}-phenyl)-2-chloroacetamide A346 N-{3-[6-amino-5-(4-benzyloxy-phenyl)-pyrimidin-4-yloxy]-phenyl}-propionamide A347 N-{3-[6-amino-5-(4-benzyloxy-phenyl)-pyrimidin-4-yloxy]-phenyl}-2-chloroacetamide A348 N-{3-[6-amino-5-(4-benzyloxy-3-fluoro-phenyl)-pyrimidin-4-yloxy]-phenyl}-acrylamide A349 N-{3-[6-amino-5-(4-benzyloxy-2-fluoro-phenyl)-pyrimidin-4-yloxy]-phenyl}-acrylamide A350 N-{3-(6-amino-5-(4-benzyloxy-2-fluoro-phenyl)-pyrimidin-4-yloxy}-phenyl)-2-chloroacetamide A351 N-{3-[6-amino-5-(4-benzyloxy-3-fluoro-phenyl)-pyrimidin-4-yloxy]-phenyl}-2-chloroacetamide A352 N-{4-[4-(3-acryloylamino-phenoxy)-6-amino-pyrimidin-5-yl]-phenyl}-benzamide

In certain embodiments, the invention relates to a method for the treatment and/or prevention of multiple sclerosis (MS), including relapsing MS (RMS), relapsing-remitting MS (RRMS), progressive MS (PMS), secondary progressive MS (SPMS), primary progressive MS (PPMS) and progressive relapsing MS (PRMS) comprising administering to the subject a compound selected from:

N-[(1-acryloylpiperidin-4-yl)methyl]-5-(4-phenoxyphenyl)pyrimidin-4,6-diamine (1); and

1-(4-(((6-Amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-1-yl)prop-2-en-1-one (2) .

In certain embodiments, the invention relates to a process as described above, wherein the compound is N-[(1-acryloylpiperidin-4-yl)methyl]-5-(4-phenoxyphenyl)pyrimidin-4,6-diamine (1).

In certain embodiments, the invention relates to a process as described above wherein the compound is 1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidine -1-yl) prop-2-en-1-one (2).

In certain embodiments, the invention relates to a method for the treatment and/or prevention of multiple sclerosis (MS) comprising administering compound (1) to a subject.

In certain embodiments, the invention relates to a method for the treatment and/or prevention of multiple sclerosis (MS) comprising administering compound (2) to a subject.

In certain embodiments, the invention relates to a method for treating and/or preventing relapsing MS (RMS) comprising administering compound (1) to a subject.

In certain embodiments, the invention relates to a method for treating and/or preventing relapsing MS (RMS) comprising administering compound (2) to a subject.

In certain embodiments, the invention relates to a method for treating and/or preventing relapsing-remitting MS (RRMS) comprising administering compound (1) to a subject.

In certain embodiments, the invention relates to a method for treating and/or preventing relapsing-remitting MS (RRMS) comprising administering compound (2) to a subject.

In certain embodiments, the invention relates to a method for the treatment and/or prevention of progressive MS (PMS) comprising administering a compound (1) to a subject.

In certain embodiments, the invention relates to a method for the treatment and/or prevention of progressive MS (PMS) comprising administering compound (2) to a subject.

In certain embodiments, the invention relates to a method for treating and/or preventing secondary progressive MS (SPMS) comprising administering compound (1) to a subject.

In certain embodiments, the invention relates to a method for treating and/or preventing secondary progressive MS (SPMS) comprising administering compound (2) to a subject.

In certain embodiments, the invention relates to a method for treating and/or preventing primary progressive MS (PPMS) comprising administering compound (1) to a subject.

In certain embodiments, the invention relates to a method for treating and/or preventing primary progressive MS (PPMS) comprising administering compound (2) to a subject.

In certain embodiments, the invention relates to a method for the treatment and/or prevention of progressive relapsing MS (PRMS) comprising administering compound (1) to a subject.

In certain embodiments, the invention relates to a method for the treatment and/or prevention of progressive relapsing MS (PRMS) comprising administering compound (2) to a subject.

In general, all residues that occur more than once can be identical or different, i.e. independent of each other. Before and after, the residues and parameters have the meanings given for formula (I), formula (II), formula (III), formula (IV) and formula (V), unless expressly stated otherwise. Accordingly, the invention particularly relates to compounds of formula (I), formula (II), formula (III), formula (IV) and formula (V), in which at least one of these residues has one of the preferred meanings, indicated below.

The term "substituted" preferably refers to substitution with the above substituents, where many different degrees of substitution are possible, unless otherwise indicated.

All physiologically acceptable salts, derivatives, solvates, solvates of salts and stereoisomers of these compounds, including mixtures thereof in all proportions, are also in accordance with the invention.

Compounds of formula (I), (II), (III), (IV) and (V) may have one or more centers of chirality. Accordingly, they may occur in various enantiomeric forms and be either racemic or optically active. Therefore, the invention also relates to the optically active forms (stereoisomers), enantiomers, racemates, diastereomers and hydrates and solvates of these compounds.

Since the pharmaceutical activity of the racemates or stereoisomers of the compounds according to the invention may vary, it may be desirable to use the enantiomers. In these cases, the final product or even intermediates can be separated into enantiomeric compounds by chemical or physical measures known to the person skilled in the art, or even used as such in the synthesis.

In the case of racemic amines, the formation of diastereomers occurs in mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids such as the R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitably N-protected amino acids (e.g. N-benzoylproline or N-benzenesulfonylproline ), or various optically active camphorsulfonic acids. Also advantageous is the chromatographic resolution of the enantiomers with an optically active resolving agent (eg dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chiral derivatives of methacrylate polymers immobilized on silica gel). Suitable eluents for this purpose are mixtures of aqueous or alcoholic solvents such as, for example, hexane/isopropanol/acetonitrile, for example in a ratio of 82:15:3. An elegant way to resolve racemates containing ester groups (eg acetyl esters) is to use enzymes, in particular esterases.

It is also contemplated that the compounds of formula (I), formula (II), formula (III), formula (IV) and formula (V) include their isotopically labeled forms. The isotopically labeled form of a compound of formula (I), formula (II), formula (III), formula (IV) and formula (V) is identical to this compound, except for the fact that one or more atoms of the compound are replaced by an atom or atoms, having an atomic mass or mass number that is different from the atomic mass or mass number of an atom that normally occurs in nature. Examples of isotopes which are readily commercially available and which can be incorporated into a compound of formula I by conventional methods include the isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N , ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, and ³⁶ CI, respectively. It is also contemplated that a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of any of them containing one or more of the above isotopes and/or other isotopes of other atoms are embodiments of the present invention. The isotopically labeled compound of Formula I can be used in many useful ways. For example, an isotopically labeled compound of formula I in which, for example, a radioisotope such as ³ H or ¹⁴ C is incorporated is suitable for drug and/or substrate distribution in tissue analysis. These radioisotopes, i.e. tritium ( ³ H) and carbon-14 ( ¹⁴ C) are particularly preferred due to their ease of preparation and excellent detectability. Incorporation of heavier isotopes, eg deuterium ( ² H), into a compound of formula I may have therapeutic advantages due to the higher metabolic stability of this isotopically labeled compound. The higher metabolic stability is directly reflected in increased in vivo half-life or lower doses, which under some circumstances would represent a preferred embodiment of the present invention. An isotopically labeled compound of formula I can be adapted to the procedures disclosed in the synthetic schemes and the associated description, in the exemplary part and in the preparation part of this text, by replacing the non-isotopically labeled reagent with a readily available isotopically labeled reagent.

In other embodiments, it is contemplated that deuterium ( ² H) can be incorporated into a compound of formula (I), formula (II), formula (III), formula (IV), and formula (V). Such deuterated compounds can modify the oxidative metabolism of said deuterated compound through a primary effect of the isotope on kinetics. The primary effect of an isotope on kinetics is a change in the rate of a chemical reaction, which is the result of a change in isotopic nuclei, which in turn is due to a change in the ground state energy required to form a covalent bond after this isotopic change. Substitution of a heavier isotope generally results in a decrease in the ground state energy for the chemical bond and thus causes a reduction in the rate of bond breaking which limits the rate. If bond breaking occurs at or near the saddle point around the multi-product reaction coordinates, the distribution ratios of the products can essentially be changed. To explain: if deuterium is bonded to a carbon atom in a non-replaceable position, the kM/kD rate difference is typically 2-7. If this difference in rates is observed in any compounds of formula (I), formula (II), formula (III), formula (IV) and formula (V) subject to oxidation, the in vivo profile of this compound can be significantly modified, resulting in improved pharmacokinetics. properties.

In research and development of therapeutic agents, one skilled in the art will attempt to optimize pharmacokinetic parameters while maintaining desirable in vitro properties. It is reasonable to assume that many compounds with poor pharmacokinetic profiles are subject to oxidative metabolism. An in vitro liver microsome assay, known in the art, can provide useful information on the course of this type of oxidative metabolism, which in turn allows rational development of deuterated compounds of formula (I), formula (II), formula (III), formula (IV) and formula (V) with improved stability through resistance to the specified oxidative metabolism. Thus, a significant improvement in the pharmacokinetic profiles of the compounds of the formula can be achieved, and can be quantified in terms of increased in vivo half-life (t/2), concentration at maximum therapeutic effect (C _max ), area under the dose-response curve (AUC), and F; and in relation to reduced clearance, dose cost and materials.

Although the present invention is not intended to be limited to any deuterated motif, the following is an example. A compound of formula (I), formula (II), formula (III), formula (IV), and formula (V) which has several potential sites of attack for oxidative metabolism, such as benzyl hydrogen atoms and nitrogen bonded hydrogen atoms, obtained as a series of analogs in which various combinations of hydrogen atoms are replaced by deuterium atoms so that some, most or all of these hydrogen atoms are replaced by deuterium atoms. The determination of the half-life makes it possible to favorably and accurately determine the extent to which improvement in resistance to oxidative metabolism occurs. Thus, it can be determined that the half-life of the parent compound can be increased by up to 100% as a result of this type of deuterium-hydrogen replacement.

Deuterium-hydrogen substitution in a compound of formula (I), formula (II), formula (III), formula (IV), and formula (V) can also be used to achieve a beneficial modification of the parent compound's metabolite spectrum to reduce or eliminate unwanted toxic metabolites. For example, if a toxic metabolite is generated via oxidative cleavage of a carbon-hydrogen (C-H) bond, it can reasonably be assumed that the deuterated analog will significantly reduce or eliminate the formation of the undesired metabolite, even if the specific oxidation is not a rate-determining step. Further information on the state of the art regarding deuterium-hydrogen replacement can be found, for example, in Hanzlik et al., J. Org. Chem. 55, 3992-3997, 1990, Reider et al., J. Org. Chem. 52, 3326-3334, 1987, Foster, Adv. DrugRes. 14, 1-40, 1985, Gillette et al, Biochemistry 33(10) 2927-2937, 1994, and Jarman et al. Carcinogenesis 16(4), 683-688, 1993.

The compounds of the present invention may be in the form of a prodrug. "Prodrug compound" means a derivative, the conversion of which into a biologically active compound according to the present invention occurs under physiological conditions in a living body, for example, through oxidation, reduction, hydrolysis or the like, each of which occurs enzymatically or without the involvement of an enzyme. Examples of prodrugs are compounds in which the amino group in the compound of the present invention is acylated, alkylated or phosphorylated, e.g. , succinyloxy, fumaryloxy, alanyloxy, or in which the carboxyl group is esterified or amidated, or in which the sulfhydryl group forms a disulfide bridge with a carrier molecule, such as a peptide, which delivers the drug selectively to the target and/or to the cytosol of the cell. These compounds can be obtained from the compounds of the present invention in accordance with well-known methods. Other examples of prodrugs are compounds in which the carboxylate in the compound of the present invention is, for example, converted to alkyl, aryl, choline, amino, acyloxymethyl ester, linolenoyl ester.

Metabolites of the compounds of the present invention are also within the scope of the present invention.

Where tautomerism, eg keto-enol tautomerism, of the compounds of the present invention or their prodrugs may occur, the individual forms, eg the ketone or enol form, are claimed separately and together as mixtures in any ratio. The same applies to stereoisomers, eg enantiomers, cis/trans isomers, conformers, and the like.

If desired, the isomers can be separated by methods well known in the art, for example by means of liquid chromatography. The same applies to enantiomers, for example using chiral stationary phases. Additionally, enantiomers can be isolated by converting them to diastereomers, i.e. conjugation with an enantiomerically pure auxiliary compound, followed by separation of the resulting diastereomers and elimination of the remainder of the auxiliary agent. Alternatively, any enantiomer of a compound of the present invention can be obtained by stereoselective synthesis using optically pure starting materials.

The compounds of the present invention may be in the form of a pharmaceutically acceptable salt or solvate. The term "pharmaceutically acceptable salts" refers to salts derived from pharmaceutically acceptable non-toxic bases or acids, including inorganic bases or acids and organic bases or acids. In cases where the compounds of the present invention contain one or more acidic or basic groups, the invention also includes their respective pharmaceutically or toxicologically acceptable salts, in particular their pharmaceutically acceptable salts. Thus, compounds of the present invention which contain acidic groups may be present in the form of a salt and may be used in accordance with the invention, for example, as alkali metal salts, alkaline earth metal salts, or as ammonium salts. More specific examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts or ammonia salts or organic amines such as ethylamine, ethanolamine, triethanolamine or amino acids. Compounds of the present invention which contain one or more basic groups, i. groups that can be protonated can be present in the form of a salt, and they can be used in accordance with the invention in the form of their addition salts with inorganic or organic acids. Examples of suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalene disulfonic acids, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propanoic acid. acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropanoic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid and other acids, known to the person skilled in the art. If the compounds of the present invention simultaneously contain acidic and basic groups in the molecule, the invention also includes, in addition to the indicated salt forms, internal salts or betaines (zwitterions). The corresponding salts can be obtained by conventional methods known to the person skilled in the art, for example by bringing them into contact with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange with other salts. The present invention also relates to all salts of the compounds of the present invention which, due to low physiological compatibility, are not directly suitable for use in pharmaceuticals, but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.

In addition, the present invention relates to pharmaceutical compositions containing a compound of the present invention, or a prodrug thereof, or a pharmaceutically acceptable salt or solvate thereof, as an active ingredient, together with a pharmaceutically acceptable carrier.

"Pharmaceutical composition" means one or more active ingredients and one or more inert ingredients that make up the carrier, as well as any product that is the direct or indirect result of the combination, complexation or aggregation of any two or more ingredients, or the dissociation of one or more ingredients, or other types of reactions or interactions of one or more ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition obtained by mixing a compound of the present invention and a pharmaceutically acceptable carrier.

The pharmaceutical composition of the present invention may further contain one or more other compounds as active ingredients, such as one or more additional compounds of the present invention or a prodrug or other BTK inhibitors.

Pharmaceutical compositions include compositions suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular and intravenous), ocular (ophthalmic), pulmonary (nasal or buccal inhalation), or nasal administration, whatever the most appropriate route in any given case depends on the nature and severity of the conditions being treated and on the nature of the active ingredient. For convenience, they may be presented in unit dosage form and prepared by any of the methods well known in the pharmaceutical art.

In one embodiment, said compounds and pharmaceutical composition, or a pharmaceutically acceptable salt, prodrug or hydrate thereof, and a pharmaceutically acceptable carrier, are for the treatment of multiple sclerosis (MS), including relapsing MS (RMS), relapsing-remitting MS (RRMS) , progressive MS (PMS), secondary progressive MS (SPMS), primary progressive MS (PPMS), and progressive relapsing MS (PRMS).

The invention also relates to the use of compounds according to the invention for the preparation of a medicament for the treatment of multiple sclerosis (MS), including relapsing MS (RMS), relapsing-remitting MS (RRMS), progressive MS (PMS), secondary progressive MS (SPMS ), primary progressive MS (PPMS) and progressive relapsing MS (PRMS).

In practice, the compounds of the present invention can be combined as an active ingredient in a homogeneous mixture with a pharmaceutical carrier in accordance with standard methods of pharmaceutical compounding. The carrier may take a wide variety of forms, depending on the form of preparation desired for administration, for example, oral or parenteral (including intravenous). Any of the usual pharmaceutical vehicles, such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like, may be used in preparing compositions for oral dosage form. In the case of oral liquid preparations, any of the usual pharmaceutical media may be used, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binding agents, disintegrating agents, and the like. In the case of oral solid preparations, the composition may take forms such as, for example, powders, hard and soft capsules and tablets, with solid oral preparations being preferred over liquid preparations.

Because of their ease of administration, tablets and capsules represent the most favorable form of oral dosage unit, in which case pharmaceutical carriers are obviously used. If desired, tablets can be coated using standard aqueous or non-aqueous methods. Such compositions and formulations should contain at least 0.1 percent active compound. The percentage of active compound in these compositions, of course, may vary and may conveniently be between about 2 percent and about 60 percent by weight of the unit. The amount of active compound in such therapeutically effective compositions is such that an effective dose is obtained. The active compounds can also be administered intranasally, for example as liquid drops or spray.

Tablets, pills, capsules, etc. may also contain a binder such as gum tragacanth, gum arabic, cornstarch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetener such as sucrose, lactose or saccharin. When the dosage unit is in the form of a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as fatty oil.

Various other materials may be present as coatings or to modify the physical form of the dosage unit. For example, tablets can be coated with shellac, sugar, or both. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propyl parabens as preservatives, a coloring agent, and a flavoring such as cherry or orange flavor.

The compounds of the present invention can also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxypropyl cellulose. Dispersions can also be obtained in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under normal conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and fluid to the extent that easy passage through the needle occurs. It must be stable under the conditions of manufacture and storage and must be protected from the contaminating action of microorganisms such as bacteria and fungi. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (eg glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

Any suitable route of administration may be used to provide a mammal, in particular a human, with an effective dose of a compound of the present invention. For example, oral, rectal, topical, parenteral, ophthalmic, pulmonary, nasal, and the like can be used. Dosage forms include tablets, lozenges, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like. Preferably, the compounds of the present invention are administered orally.

The effective dose of the active ingredient used may vary depending on the particular compound used, the route of administration, the condition being treated and the severity of the condition being treated. Such a dose can be easily determined by a person skilled in the art.

The invention also relates to a set consisting of individual packages

a) an effective amount of a compound according to the invention, or a physiologically acceptable salt, solvate or prodrug thereof, and

b) an effective amount of the additional active ingredient of the medicinal product.

The kit contains suitable containers such as boxes, individual bottles, bags or ampoules. The kit may contain, for example, individual ampoules, each containing an effective amount of a compound according to the invention and/or its pharmaceutically acceptable derivatives, solvates and stereoisomers, including mixtures thereof in all proportions, and an effective amount of an additional active ingredient of the drug in dissolved or lyophilized form.

Experimental section

Effect of compound (1) on PLP _139-151 induced EAE in SJL mice (relapsing relapsing-remitting MS mouse model)

Compound (1) was administered prophylactically in EAE-induced PLP _{139-151 to} female SJL mice. Treatment started on day 0 after induction: vehicle, 0.3 mg/kg, 1.0 mg/kg and 3 mg/kg and FTY-720 at 3 mg/kg. The inventors also determined PK/PD (receptor filling) at the first dose and at the end of the study. The results are shown in FIG. 1 and 2.

Animals: 75 female SJL mice from Jax (10 weeks old on arrival), at least 18 g on arrival.

Treatment groups

Group Treatment Dose Scheme Path N A Imitation no data no data no data 5 B Carrier no data Preventive, QD PO fifteen C one 0.3 mg/kg Preventive, QD PO fifteen D one 1 mg/kg Preventive, QD PO fifteen E one 3 mg/kg Preventive, QD PO fifteen F FTY-720 3 mg/kg Preventive, QD PO ten

Getting solutions:

Getting CFA: required total volume: 10 ml; 2 mg/ml M.T. was added to IFA to give a total concentration of 2 mg/ml M.T. in CFA (added 100 mg M.T. in 50 ml IFA).

Preparation of PLP _139-151 : 100 μg PLP _139-151 : concentration: 1 mg/ml; 25 mg PLP in 25 ml PBS. PLP/CFA was emulsified at a ratio of 1:1 using the homogenizer method.

Preparation of PTX: stock solution: 1 ml of PBS was added to a 50 μg vial (stored in the refrigerator); 60 ng/mouse (0.2 ml/mouse)=0.3 µg/ml (1:167 diluted stock, 210 µl in 35 ml PBS).

Effect of compound (1) on PLP _139-151 induced EAE in SJL mice (BTKi in a mouse relapsing-remitting MS model - therapeutic dosing)

Compound (1) was administered at PLP _139-151 EAE-induced female SJL mice in a prophylactic (treatment start at induction) and therapeutic (treatment start at remission) dosing regimen. The study was dose dependent: 0.3, 1 and 3 mg/kg for the prophylactic dosing regimen and 1, 3 and 10 mg/kg for the therapeutic dosing. In addition, the inventors determined the PK/PD after the first and last dose to allow modeling of the effect depending on the filling of the receptors. See fig. 3-5.

Animals: 145 female SJL mice from Jax (10 weeks old on arrival), at least 18 g on arrival.

Treatment groups

Group Treatment Dose Scheme Path N A Imitation no data no data no data 5 B Carrier no data Preventive, QD PO fifteen C (one) 0.3 mg/kg Preventive, QD PO fifteen D (one) 1 mg/kg Preventive, QD PO fifteen E (one) 3 mg/kg Preventive, QD PO fifteen F FTY-720 1 mg/kg Preventive, QD PO ten G Carrier no data Therapeutic, QD PO fifteen H (one) 1 mg/kg Therapeutic, QD PO fifteen I (one) 3 mg/kg Therapeutic, QD PO fifteen J (one) 10 mg/kg Therapeutic, QD PO fifteen K FTY-720 1 mg/kg Therapeutic, QD PO ten

EAE induction in SJL mice:

PLP139-15 was dissolved in PBS and emulsified with an equal volume of CFA supplemented with 2mg/ml Mycobacterium tuberculosis (M.T.) (CFA already contains 1mg/ml MT, so another 1mg/ml was added for a final concentration of 2mg/ml). Mice were injected with s.c. 0.2 ml of peptide emulsion in the abdominal part of the side (0.1 ml on each side). On the same day and 48 hours later, mice were injected with i.p. 200 µl (60 ng) Bordetella Pertussis toxin in saline.

Getting solutions

Getting CFA: required total volume: 10 ml; 2 mg/ml M.T. was added to IFA to give a total concentration of 2 mg/mL M.T. in CFA (added 100 mg M.T. in 50 ml IFA).

Preparation of PLP _139-151 : 100 μg PLP _139-151 : concentration: 1 mg/ml; 25 mg PLP in 25 ml PBS; PLP/CFA was emulsified at a ratio of 1:1 using the homogenizer method.

Preparation of PTX: stock solution: 1 ml of PBS was added to a 50 μg vial (stored in the refrigerator); 60 ng/mouse (0.2 ml/mouse)=0.3 µg/ml (1:167 diluted stock, 210 µl in 35 ml PBS).

BTK filling in mouse blood (compounds 1 and 2)

In order to calculate the amount of Btk fill that was achieved after dosing the Btk inhibitor, samples were collected from mice treated with vehicle. Vehicle group samples were considered to have 0% occupancy and % occupancy in Btk inhibitor treated mice was calculated relative to this 0% value. Blood was collected and placed in anticoagulant-coated tubes. Acceptable anticoagulants were EDTA or heparin. The collected blood was kept at room temperature (20-24°C) until processing. Blood (80 μl) was transferred to a 1.5 ml Eppendorf snap cap tube using a pipette. 800 μl room temperature red blood cell lysing buffer was added, the tube was capped and inverted 3 times to mix. The mixture was incubated for 5 minutes at room temperature. Cells were pelleted by centrifugation for 5 minutes at 600×g at room temperature and then aspirated without disturbing the cell pellet. Cells were washed by resuspension in 400 μl of RBC lysis buffer using a pipette, followed by centrifugation for 5 minutes at 600 xg (room temperature) and gentle aspiration of the liquid. Stock incubation media were created by combining RPMI1640 and connecting a Btk fill probe. No FBS or Pen/Strep was added to the media. The probe compound was pre-dissolved in DMSO to 10 mM and stored in aliquots at -80°C. 1 μl of 10 mM probe compound was added per 10 ml of RPMI1640 to obtain stock incubation media containing a total of 1 μM probe. The pelleted cells were resuspended in 1 ml of incubation media containing the probe. Cells were incubated with the probe for 1 hour at 37° C. in a tissue culture incubator with controlled CO ₂ with tube lids open. Lysis buffer was prepared within 1 hour of incubation (add 10 μl of HALT protease and phosphatase inhibitor cocktail per ml of MPER lysis buffer. Chill mixed buffer on ice at least 10 minutes before use). After 1 hour of incubation, cells were pelleted by centrifugation at room temperature for 5 minutes at 600×g. The media were aspirated and the cells were resuspended in 120 µl of chilled MPER lysis buffer. Incubated on ice after addition of lysis buffer and subsequently stored samples at -80° C. prior to use in MSD fill assay.

Probe:

Lysates of probed cells were thawed and biotinylated Btk was quantified using the streptavidin uptake assay performed on the MSD platform. Streptavidin-coated MSD microtiter plates were blocked by incubation with 200 µl/well casein containing blocking buffer from Pierce for 1 h. microtiter plate shaker and the plate was closed using a plastic adhesive sealing film. After blocking, the plates were washed with 1×200 µl/well (PBS/0.05% Tween 20). Standards were added at 100 µl/well. Prior to addition, cell lysates were diluted (10 µl+200 µl) in blocking buffer in a separate dilution plate. 50 μl of diluted cell lysate was added to 50 μl of blocking buffer per well to a final volume of 100 μl/well. It was left to incubate for 1.5-2 hours at room temperature. Standards were analyzed in duplicate, as well as unknown samples. The plate was washed (3×200 µl/well (PBS/0.05% Tween 20)) and rabbit anti-Btk antibody (100 µl/well) diluted to 1 µg/ml (1:1000) in blocking buffer was added. The solution was incubated for 1.5-2 hours at room temperature with shaking. The plate was washed (3 x 200 µl/well (PBS/0.05% Tween 20)) and SULFO labeled goat anti-rabbit (100 µl/well) diluted to 1 µg/ml (1:500) in blocking buffer was added . The solution was incubated for 1.5-2 hours at room temperature with shaking. The plate was washed (3×200 µl/well) (PBS/0.05% Tween 20), then diluted (4×MSD Read Buffer) to 2× concentration with water and then added at 150 µl/well. The plate was immediately read using an MSD Sector Imager 600. Data was processed using the MSD Discovery Workbench software program.

A calibration curve using recombinant Btk pretreated with an in vitro biotinylated probe was used for quantitation. In order to create a stock standard, recombinant Btk was treated in vitro at 2 ng/µl in PBS containing 1 mg/ml BSA with 1 µM probe for 1 h at 37°C and then frozen in aliquots at -80°C.

In order to create a calibration curve, an aliquot of stock standard recombinant Btk was diluted with 5 µl + 245 µl of blocking buffer. The diluted standard was then further diluted in blocking buffer with 1:2 serial dilutions (70 µl + 140 µl blocking buffer). Standards were prepared in 96 dilution plates, as well as samples. The values of the calibration curve for Btk-biotin ranged from 40 to 0.02 ng/ml. Curve fitting was performed using four parameter fitting in the MSD Discovery Workbench software program.

In the assay described above, probe binding to Btk is measured where the inhibitors are not covalently bound to the active site and therefore unoccupied Btk is detected. Thus, samples taken from vehicle-treated mice contain cells completely empty of Btk, and the amount of Btk-biotin found in these samples was taken as 0% fill. Cells from a white blood cell sample that were incubated ex vivo with 1 μM compound (1) for 10 min before probe treatment were taken as 100% completion. The percent fill in all samples was calculated relative to the carrier group value, which was taken as 0% fill. See fig. 6-8, 12, 13 and 17.

Effect of compound (2) on PLP _139-151 induced EAE in SJL mice (BTKi in a mouse model of relapsing-remitting MS)

Compound 2 was administered prophylactically (starting on the day of induction) in EAE-induced PLP _{139-151 to} female SJL mice. 3 mg/kg PO, for which the publication shows efficacy in RA models. Treatment was started on day 0 after induction: vehicle, 0.3 mg/kg, 1.0 mg/kg, and 3 mg/kg PO QD. Endpoints included clinical score and body weight, receptor occupancy, and CD69 expression at the end of the study (2 and 24 hours after administration). Fig. 9-11.

Animals: 90 female SJL mice from Jax (10 weeks old on arrival), at least 18 g on arrival.

Treatment groups

90 mice were induced with PLP/CFA/PTX. Prophylactic treatment was started on the same day as EAE induction (before induction).

Group Treatment Dose Scheme Path N A Imitation no data no data no data 3 B Carrier no data Preventive, QD PO fifteen C RN486 30 mg/kg Preventive, QD PO fifteen D 2 0.3 mg/kg Preventive, QD PO fifteen E 2 1 mg/kg Preventive, QD PO fifteen F 2 3 mg/kg Preventive, QD PO fifteen G FTY-720 1 mg/kg Preventive, QD PO 7 H Against CD20 250 µg/mouse Preventive (once a day 0) IV 5

EAE induction in SJL mice

PLP _{139-15 was} dissolved in PBS and emulsified in an equal volume of CFA with the addition of 2 mg/ml Mycobacterium tuberculosis (MT) (CFA already contains 1 mg/ml MT, so another 1 mg/ml was added for a final concentration of 2 mg/ml) . Mice were injected sc with 0.2 ml of the peptide emulsion into the ventral flank (0.1 ml on each side). On the same day and 48 hours later, mice were injected ip with 200 μl (60 ng) of Bordetella Pertussis toxin in saline.

Getting solutions:

Getting CFA: required total volume: 10 ml; 2 mg/ml M.T. was added to IFA to give a total concentration of 2 mg/mL M.T. in CFA (added 100 mg M.T. in 50 ml IFA).

Preparation of PLP _139-151 : 100 μg PLP _139-151 : concentration: 1 mg/ml; 15 mg PLP in 15 ml PBS. PLP/CFA at a ratio of 1:1 was emulsified using the homogenizer method.

Preparation of PTX: stock solution: 1 ml of PBS was added to a 50 μg vial (stored in the refrigerator)

60 ng/mouse (0.2 ml/mouse)=0.3 µg/ml (1:100 diluted stock, 150 µl in 25 ml PBS).

The effect of therapeutic treatment using BTKi on PLP _139-151 induced EAE in SJL mice

Compound 2 was administered therapeutically in EAE-induced PLP _{139-151 to} female SJL mice. Dosing was started on day 9 post-induction: vehicle, 1.0 mg/kg, 3 mg/kg, 10 mg/kg PO QD. Endpoints included clinical score, receptor occupancy, and CD69 expression at the end of the study (2 hours and 24 hours after administration). Fig. 14-16. B-cell depleting antibody was used as a reference (against CD20).

Animals: 100 female SJL mice from Jax (10 weeks old on arrival), at least 18 g on arrival.

Treatment groups

100 mice were induced with PLP/CFA/PTX. At the first sign of disease, mice were randomized to different treatment groups according to their clinical judgment.

Group Treatment Dose Scheme Path N A Imitation no data no data no data 5 B Carrier no data Therapeutic, QD PO fifteen C RN486 30 mg/kg Therapeutic, QD PO fifteen D 2 1 mg/kg Therapeutic, QD PO fifteen E 2 3 mg/kg Therapeutic, QD PO fifteen F 2 10 mg/kg Therapeutic, QD PO fifteen G isotypic 250 µg/mouse Therapeutic IV ten H Against CD20 250 µg/mouse Therapeutic IV ten

EAE induction in SJL mice

PLP139-15 was dissolved in PBS and emulsified using an equal volume of CFA supplemented with 2mg/ml Mycobacterium tuberculosis (M.T.) (CFA already contains 1mg/ml MT so another 1mg/ml was added for a final concentration of 2mg/ml) . Mice were injected with s.c. 0.2 ml of peptide emulsion in the abdominal part of the side (0.1 ml on each side). On the same day and 48 hours later, mice were injected with i.p. 200 µl (60 ng) Bordetella Pertussis toxin in saline.

Getting solutions:

Getting CFA: required total volume: 10 ml; added 2 mg/ml M.T. in IFA to give a total concentration of 2 mg/mL M.T. in CFA (added 100 mg M.T. in 50 ml IFA).

Preparation of PLP _139-151 : 100 μg PLP _139-151 : concentration: 1 mg/ml; 20 mg PLP in 20 ml PBS; PLP/CFA was emulsified at a ratio of 1:1 using the homogenizer method.

Preparation of PTX: stock solution: 1 ml of PBS was added to a 50 μg vial (stored in the refrigerator)

60 ng/mouse (0.2 ml/mouse)=0.3 µg/ml (1:100 diluted stock, 150 µl in 25 ml PBS).

PLP-induced EAE in SJL mice

EAE (experimental autoimmune encephalomyelitis) is an animal model of multiple sclerosis (MS). This model reflects certain aspects of the pathology seen in MS, including inflammation and demyelination. Compound 2 was administered therapeutically in EAE-induced PLP _{139-151 to} female SJL mice. Dosing was started on day 17 after induction: vehicle, 1.0 mg/kg and 10 mg/kg PO QD. The endpoint included clinical evaluation. Fig. 18-19. Compound 2 was administered therapeutically in EAE-induced PLP _{139-151 to} female SJL mice. Dosing was started on day 7 post-induction (before starting EAE): vehicle, 1.0 mg/kg and 10 mg/kg PO QD. The endpoint included clinical evaluation. Fig. 20-21.

Animals: Mice are female SJL mice from Jackson Laboratories. SJL mice were ordered at 8-10 weeks and used between 9 and 11 weeks. During the experiment, the animals were kept in the agricultural boardroom.

Procedure

1) Preparation of PLP _139-151 : a solution of PLP _139-151 peptide was prepared at a concentration of 1-2 mg/ml in PBS.

2) Preparation of IFA+MT: OFA supplemented with M. tuberculosis H37RA was prepared as follows: IFA (10 ml/vial) was poured into a 50 ml Falcon tube (50 ml for each 100 mg vial of dehydrated TM H37RA). 100 mg TM H37RA was added to 50 ml CFA and rapidly homogenized (~1 minute).

3) Preparation of the emulsion: Equal amounts of IFA/TM and PLP _139-151 were used for the emulsion. IFA/TM was added to a sterile beaker. The contents were emulsified by adding the PLP _139-151 solution dropwise with a transfer pipette while homogenizing at low speed. After cooling on ice every few minutes to prevent heating of the emulsion (heating of peptides can cause denaturation), the PLP _139-151 solution was added and the procedure was repeated until the emulsion had a uniform consistency. The emulsion was homogenized at high speed for a few seconds (15-30 seconds) to provide a homogeneous emulsion. The stability of the emulsion was tested by extruding a droplet onto the surface of 50 ml of PBS in a reservoir or in a 100 ml beaker. The emulsion droplet was retained without dispersion. The emulsion was kept on ice until use.

4) PLP _139-151 Injection: A 1 ml Luer lock syringe was filled with the emulsion. A 15 gauge animal feeding needle was attached, the feeding needle was dipped into the emulsion and the needle was filled. When the needle was filled, air was expelled from the syringe. 0.2 ml of PLP _139-151 emulsion was injected into the ventral flank of each mouse (0.1 ml at 2 sites close to the lymph nodes) using a 27 gauge needle.

5) Preparation of PTX: 1 ml of sterile PBS was added to 50 μg of PTX (1 vial) and mixed gently. The stock was kept at 4° C. and a fresh solution was obtained for injection 48 hours later from the stock. Prior to use, PTX was diluted in PBS to the desired concentration (0.25-1 μg/ml or 50-100 ng/mouse).

6) PTX injection: SJL mice were injected with 200 μl i.p. using a 25 gauge needle.

One injection was performed on the same day as the injection of MOG _35-55 and repeated again 48 hours later.

7) Body weight and clinical score: SJL mice were weighed and determined by clinical score according to the scoring system at least 3 times a week. At the peak of the disease (approximately 10-15 days), they were evaluated every day. The duration of the study was up to 10 weeks.

Claims (4)

1. Use of a therapeutically effective amount of a compound selected from N-[(1-acryloylpiperidin-4-yl)methyl]-5-(4-phenoxyphenyl)pyrimidin-4,6-diamine, pharmaceutically acceptable salts and tautomers thereof, including mixtures of tautomers in all ratios, and -1-one, its pharmaceutically acceptable salts and tautomers, including mixtures of tautomers in all ratios, for the treatment or prevention of multiple sclerosis. 2. Use according to claim 1, wherein the compound is N-[(1-acryloylpiperidin-4-yl)methyl]-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine, its pharmaceutically acceptable salts and tautomers, in including mixtures of tutomers in all proportions. 3. Use according to claim 1, wherein the compound is 1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-1-yl) prop-2-en-1-one, its pharmaceutically acceptable salts, tautomers, including mixtures of tautomers in all proportions. 4. Use according to any one of claims 1 to 3, wherein the multiple sclerosis (MS) is selected from relapsing multiple sclerosis (RMS), relapsing-remitting multiple sclerosis (RRMS), progressive multiple sclerosis (PMS), secondary progressive multiple sclerosis ( SPMS), primary progressive multiple sclerosis (PPMS) and progressive relapsing multiple sclerosis (PRMS).

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