Methods of treating cancer using pyrimidine and pyridine compounds having BTK inhibitory activity

Abstract

The present invention provides methods of treating cancer using pyrimidine and pyridine compounds that are useful as inhibitors of Bruton's tyrosine kinase (BTK).

Description

[0001] Related applications

[0002] This patent application claims priority to U.S. Provisional Patent Application No. 62 / 250,575, filed November 4, 2015; U.S. Provisional Patent Application No. 62 / 296,143, filed February 17, 2016; and U.S. Provisional Patent Application No. 62 / 341,189, filed May 25, 2016, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This invention relates to a series of pyrimidine and pyridine compounds that can be used as therapeutic agents to treat cancers in mammals. More specifically, embodiments of the invention describe irreversible kinase inhibitors, including but not limited to, Bruton's tyrosine kinase (hereinafter referred to as "BTK") inhibitors. Methods for preparing the above-described compounds and for formulating these compounds into pharmaceutical compositions containing said compounds are also disclosed herein. Background of the Invention

[0004] Protein kinases comprise a large family of structure-associated enzymes that control a variety of intracellular signal transduction processes (Hardie, G. and Hanks, S. (1995) The Protein Kinase Facts Book. I and II, Academic Press, San Diego, CA). Kinases can be further classified into multiple families based on their phosphorylated substrates (e.g., protein-tyrosine, protein-serine / threonine, lipids, etc.). Sequence motifs generally corresponding to these kinase families have been identified (e.g., Hanks, SK, 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)).

[0005] 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. A single protein kinase can be regulated by more than one mechanism.

[0006] By adding a phosphate group to a target protein, kinases can regulate many different cellular processes, including but not limited to proliferation, differentiation, apoptosis, motility, transcription, translation, and other signal transduction processes. These phosphorylation events act as molecular on / off switches that can regulate or modulate the biological function of target proteins. Target protein phosphorylation occurs in response to a variety of extracellular signals (hormones, neurotransmitters, growth and differentiation factors, etc.), cell cycle events, environmental or nutritional stress, etc. Suitable protein kinases function in signal transduction pathways to activate or deactivate (directly or indirectly) such as metabolic enzymes, regulatory proteins, receptors, cytoskeletal proteins, ion channels or pumps, or transcription factors. Uncontrolled signal transduction resulting from defects in protein phosphorylation control is involved in a variety of diseases, including, for example, inflammation, cancer, allergies / asthma, immune system diseases and conditions, central nervous system diseases and conditions, and angiogenesis.

[0007] BTK is a member of the Tec family of non-receptor tyrosine kinases and a signaling enzyme expressed in all hematopoietic cells except T lymphocytes and natural killer cells. BTK plays a crucial role in B-cell signaling pathways, which link stimulation of cell surface B-cell receptors to downstream intracellular responses. BTK is also a regulator of B-cell development, activation, signal transduction, and survival (Kurosaki, Curr Op Imm, 2000, 276-281; ​​Schaeffer and Schwartzberg, Curr Op Imm 2000, 282-288). Furthermore, BTK exerts physiological effects through other hematopoietic cell signaling pathways, such as Toll-like receptor (TLR) and cytokine receptor-mediated TNF-α production in macrophages, IgE receptor (Fcepsilon R1) signaling in mast cells, inhibition of Fas / APO-1 apoptosis signaling in B-cell lymphoid cells, and collagen-stimulated platelet aggregation. BTK possesses an ATP-binding capsule and is remarkably similar to Src-family kinases (such as lymphocyte-specific protein tyrosine kinases (Lck) and Lyn). Comparing BTK with other kinases reveals that 11 out of 491 kinases contain the conserved cysteine ​​residue Cys-481, particularly members of the Tec and EGFR (epidermal growth factor receptor) kinase families.

[0008] BTK plays a crucial role in the development, differentiation, activation, and proliferation of B cells, as well as the production of their antibodies and cytokines. Furthermore, BTK exerts a central influence on other immune processes, such as cytokine production, through the degranulation of neutrophils, mast cells, and monocytes, and the differentiation / activation of osteoclasts. B cell activation, tolerance disruption, and autoantibody production are exacerbated by the pro-inflammatory environment resulting from the activation of monocytes, neutrophils, and mast cells; these cells are also key pathogenic factors in autoimmune diseases (including but not limited to rheumatoid arthritis and systemic lupus erythematosus).

[0009] Current research has led to the development of reversible kinase inhibitors into therapeutic compounds. However, these reversible inhibitors have a critical drawback. Many reversible kinase inhibitors interact with ATP-binding sites. If the structure of the ATP-binding sites between kinases is highly conserved, it is difficult to develop a reversible inhibitor that can selectively inhibit the desired (e.g., target) kinase. Furthermore, if many reversible kinase inhibitors readily dissociate from their target peptides, it is difficult to maintain inhibitory activity over long periods. When using reversible kinase inhibitors as therapeutic agents, it often requires near-toxic doses and / or frequent dosing to achieve the desired biological effect.

[0010] Therefore, there is a need to provide irreversible kinase inhibitors that covalently bind to one or more target peptides but do not (essentially) bind to non-target peptides, thus avoiding undesirable off-target effects. Summary of the Invention

[0011] This invention relates to compounds of the general formula provided herein for the treatment and / or prevention of cancer, including non-Hodgkin's lymphoma mantle cell lymphoma and non-Hodgkin's lymphoma diffuse large B-cell lymphoma, including the abc subtype. Attached Figure Description

[0012] Figure 1 The mean percentage of inhibition of compound (2) at each dose level is shown in 11 primary CLL patient samples.

[0013] Figure 2 The inhibitory effect of compound (2) on six cell lines was shown in the ABC-DLBCL assay.

[0014] Figure 3 Compound (2) was shown to inhibit six cell lines in the MCL assay.

[0015] Figure 4aThis study demonstrates in vivo efficacy in an MCL model. The objective was to determine antitumor activity and dose-response. MCL cell line: Mino, a subcutaneous xenograft model. Mouse strain: nu / nu mice. Treatment began at 150-200 mmHg. 3 Tumor volume.

[0016] Figure 4b and 4c Mino: BTK inhibitors, tumor volume, and body weight in the MCL model.

[0017] Figure 4d and 4e Mino: BTK inhibitors, tumor volume, and body weight in the MCL model. Detailed Implementation

[0018] This invention provides a series of novel pyrimidine and pyridine kinase inhibitors. In some embodiments, the kinase inhibitors are irreversible inhibitors of tyrosine kinases. In a preferred embodiment, the irreversible inhibitor inhibits BTK. While not intended to limit the compounds of this invention to any particular mechanism of action, in some embodiments, the irreversible kinase inhibitors exert their physiological effects by forming a covalent bond with Cys481 of BTK. In particular, the Cys481 of BTK has homologues found in other kinases. Embodiments of the invention also describe methods for synthesizing the irreversible kinase inhibitors and methods for using the irreversible kinase inhibitors to treat diseases, including hyperproliferative diseases. Pharmaceutical formulations containing irreversible kinase inhibitors, including pharmaceutically acceptable salts, solvates, or prodrugs thereof, are also described as kinase inhibitors that can be used to treat the aforementioned diseases.

[0019] One aspect of the present invention provides a method for treating and / or preventing cancer, comprising administering a compound of general formula (I) to a subject:

[0020]

[0021] In the formula:

[0022] X represents CH or N.

[0023] R 1 It represents NH2, CONH2, or H.

[0024] R 2 Indicates Hal, Ar 1 Or Het 1 ,

[0025] R 3 Indicates 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 (CH2) p NR 5 R 6 O(CH2) p NR 5 R 6 Or NR 5 (CH2) p CR 7 R 8 NR 5 R 6 ,

[0026] R 4 It represents H, CH3, or NH2.

[0027] R 5 It represents H or an alkyl group containing 1, 2, 3, or 4 carbon atoms.

[0028] R 6 N(R 5 )2CH2CH=CHCONH、Het 3 CH2CH=CHCONH, CH2=CHCONH(CH2) n Het 4 (CH2) n COHet 3 -Dibase-CH2CH=CHCONH, HC≡CCO, CH3C≡CCO, CH2=CH-CO, CH2=C(CH3)CONH, CH3CH=CHCONH(CH2) n N≡CCR 7 R 8 CONH(CH2) n Het 4 NH(CH2) p COHet 3 -Dimethyl-CH2CH=CHCONH,Het 4 (CH2)p CONH(CH2CH2O) p (CH2) p COHet 3 -Dimethyl-CH2CH=CHCONH, CH2=CHSO2, ACH=CHCO, CH3CH=CHCO, Het 4 (CH2) p CONH(CH2) p Het 3 -Dimethyl-CH2CH=CHCONH, Ar 3 CH=CHSO2, CH2=CHSO2NH or N(R) 5 CH2CH=CHCO,

[0029] R 7 R 8 Together they represent alkylene groups containing 2, 3, 4, or 5 carbon atoms.

[0030] Ar 1 This indicates phenyl or naphthyl, where each of the above groups is unsubstituted or R-substituted. 6 Hal, (CH2) n NH2, CONHAr 3 (CH2) n NHCOA, O(CH2) n Ar 3 ,OCyc,A,COHet 3 OA and / or OHet 3 (CH2) monosubstituted, disubstituted, or trisubstituted

[0031] Ar 2 This indicates phenyl, naphthyl, or pyridyl, where each of these groups is unsubstituted or R-substituted. 6 Hal, OAr 3 (CH2) n NH2, (CH2) n NHCOA and / or Het 3 Mono- or di-substituted,

[0032] Ar 3 The term represents a phenyl group, wherein the phenyl group is unsubstituted or monosubstituted, disubstituted, or trisubstituted by OH, OA, Hal, CN, and / or A.

[0033] Het 1 This refers to a monocyclic or bicyclic saturated, unsaturated, or aromatic heterocycle containing 1-4 N, O, and / or S atoms, wherein the heterocycle is unsubstituted or modified by R. 6 O(CH2) nAr 3 And / or (CH2) n Ar 3 Mono- or di-substituted,

[0034] Het 2 This refers to a saturated heterocycle, either monocyclic or bicyclic, containing 1-4 N, O, and / or S atoms, wherein the heterocycle is unsubstituted or modified by R. 6 Het 3 , CycSO2, OH, Hal, COOH, OA, COA, COHet 3 CycCO, SO2 and / or =O mono-, di-, or tri-substituted.

[0035] Het 3 This refers to an unsaturated, saturated, or cyclic aromatic heterocycle containing 1-4 N, O, and / or S atoms, wherein the heterocycle is unsubstituted or monosubstituted, disubstituted, or trisubstituted by Hal, A, and / or =O.

[0036] Het 4 This refers to an unsaturated, saturated, or aromatic heterocycle containing 1-4 N, O, and / or S atoms, wherein the heterocycle is unsubstituted or monosubstituted, disubstituted, trisubstituted, or tetrasubstituted by A, NO2, Hal, and / or =O.

[0037] Cyc represents a cycloalkyl group containing 3, 4, 5, or 6 carbon atoms, wherein the cycloalkyl group is unsubstituted or R-substituted. 6 and / or OH mono- or di-substituted, and the cycloalkyl group may contain a double bond,

[0038] A represents a straight-chain or branched alkyl group containing 1-10 carbon atoms, wherein 1-7 hydrogen atoms may be substituted by F and / or Cl, and / or one or two non-adjacent CH2 and / or CH- groups may be substituted by O, NH and / or N.

[0039] Hal represents F, Cl, Br, or I.

[0040] n represents 0, 1, 2, 3, or 4.

[0041] p represents 1, 2, 3, 4, 5, or 6.

[0042] And its pharmaceutically available salts, tautomers and stereoisomers, including mixtures of all proportions thereof.

[0043] Generally, all residues appearing more than once can be the same or different, i.e., independent of each other. In other embodiments, unless explicitly stated otherwise, the meanings of residues and parameters are as indicated by general formula (I).

[0044] In some embodiments, Het 1 The following are listed: piperidinyl, piperazinyl, pyrrolyl, morpholinyl, furanyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl, benzimidazolyl, benzotriazolyl, indolyl, benzo-1,3-dioxacyclopentenyl, inzolyl, and azirbicyclo[3]. 2.1] Octyl, aziridine [2.2.2] Octyl, imidazoalkyl, aziridine butyl, aziridine heptyl, benzo-2,1,3-thiadiazolyl, tetrahydrofuranyl, dioxacyclopentyl, tetrahydrothiophenyl, dihydropyrroleyl, tetrahydroimidazoyl, dihydropyrazolyl, tetrahydropyrazolyl, tetrahydropyridyl, dihydropyridyl or dihydrobenzodioxinyl, wherein each of the above groups is unsubstituted or R 6 O(CH2) n Ar 3 And / or (CH2) n Ar 3 Mono- or di-substituted.

[0045] In some embodiments, Het 1 The group represents pyrazolyl, pyridyl, pyrimidinyl, dihydropyridyl, or dihydrobenzodioxinyl, where each of these groups is unsubstituted or modified by R. 6 O(CH2) n Ar 3 And / or (CH2) n Ar 3 Mono- or di-substituted.

[0046] In some embodiments, Het 2 The following groups are indicated: piperidinyl, piperazinyl, pyrrolyl, 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-azabicyclo[3.1.0]hexyl, 2-azaspiro[3.3]heptyl, 6-azaspiro[3.4]octyl, 7-azaspiro[3.5]nonyl, 5-azaspiro[3.5]nonyl, imidazoalkyl, azacyclobutyl, azacycloheptyl, tetrahydrofuranyl, dioxacyclopentyl, tetrahydrothiophenyl, tetrahydroimidazoyl, tetrahydropyrazolyl, tetrahydropyridinyl, where each of the above groups is unsubstituted or R 6 Het 3 , CycSO2, OH, OA, COA, COHet 3 CycCO, SO2 and / or =O mono-, di-, or tri-substituted.

[0047] In some embodiments, Het 3 The following groups are indicated: piperidinyl, piperazine, pyrrolyl, morpholinyl, furanyl, thiophene, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, imidazolyl, aziridine, aziridine, heptyl, tetrahydrofuranyl, dioxacyclopentyl, tetrahydrothiophene, dihydropyrrolyl, tetrahydroimidazolyl, dihydropyrazolyl, tetrahydropyrazolyl, tetrahydropyridinyl, or dihydropyridinyl, wherein each of the above groups is unsubstituted or monosubstituted, disubstituted, or trisubstituted by Hal, A, and / or =O.

[0048] In some embodiments, Het 3 The group represents piperidinyl, pyrrolyl, morpholinyl, furanyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, dihydropyrrolyl, dihydropyrazolyl or dihydropyridinyl, where each of the above groups is unsubstituted or monosubstituted, disubstituted or trisubstituted by Hal, A and / or =O.

[0049] In some embodiments, Het 4 The expression represents hexahydrothiophene[3,4-d]imidazolyl, benzo[c][1,2,5]oxadiazolyl or 5H-dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-4-ium-uidyl, where each of the above groups is unsubstituted or monosubstituted, disubstituted, trisubstituted or tetrasubstituted by A, NO2, Hal and / or =O.

[0050] In some embodiments,

[0051] X represents CH or N.

[0052] R 1 It represents NH2, CONH2, or H.

[0053] R 2 Indicates Hal, Ar 1 Or Het 1 ,

[0054] R 3 Indicates 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 NR5 [C(R 5 )2] n Ar 2 、O[C(R 5 )2] n Het 2 NR 5 (CH2) p NR 5 R 6 O(CH2) p NR 5 R 6 Or NR 5 (CH2) p CR 7 R 8 NR 5 R 6 ,

[0055] R 4 H represents

[0056] R 5 It represents H or an alkyl group containing 1, 2, 3, or 4 carbon atoms.

[0057] R 6 N(R 5 )2CH2CH=CHCONH、Het 3 CH2CH=CHCONH, CH2=CHCONH(CH2) n Het 4 (CH2) n COHet 3 -Dibase-CH2CH=CHCONH, HC≡CCO, CH3C≡CCO, CH2=CH-CO, CH2=C(CH3)CONH, CH3CH=CHCONH(CH2) n N≡CCR 7 R 8 CONH(CH2) n Het 4 NH(CH2) p COHet 3 -Dimethyl-CH2CH=CHCONH,Het 4 (CH2) p CONH(CH2CH2O) p (CH2) p COHet 3 -Dimethyl-CH2CH=CHCONH, CH2=CHSO2, ACH=CHCO, CH3CH=CHCO, Het 4 (CH2) pCONH(CH2) p Het 3 -Dimethyl-CH2CH=CHCONH, Ar 3 CH=CHSO2, CH2=CHSO2NH or N(R) 5 CH2CH=CHCO,

[0058] R 7 R 8 Together they represent alkylene groups containing 2, 3, 4, or 5 carbon atoms.

[0059] Ar 1 This indicates phenyl or naphthyl, where each of the above groups is unsubstituted or R-substituted. 6 Hal, (CH2) n NH2, CONHAr 3 (CH2) n NHCOA, O(CH2) n Ar 3 ,OCyc,A,COHet 3 OA and / or OHet 3 (CH2) monosubstituted, disubstituted, or trisubstituted

[0060] Ar 2 This indicates phenyl or naphthyl, where each of the above groups is unsubstituted or R-substituted. 6 Hal, OAr 3 (CH2) n NH2, (CH2) n NHCOA and / or Het 3 Mono- or di-substituted,

[0061] Ar 3 The term represents a phenyl group, wherein the phenyl group is unsubstituted or monosubstituted, disubstituted, or trisubstituted by OH, OA, Hal, CN, and / or A.

[0062] Het 1The following are listed: piperidinyl, piperazinyl, pyrrolyl, morpholinyl, furanyl, thiophenyl, pyrroleyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl, benzimidazolyl, benzotriazolyl, indolyl, benzo-1,3-dioxacyclopentenyl, inzolyl, and azirbicyclo[3]. 2.1] Octyl, aziridine [2.2.2] Octyl, imidazoalkyl, aziridine butyl, aziridine heptyl, benzo-2,1,3-thiadiazolyl, tetrahydrofuranyl, dioxacyclopentyl, tetrahydrothiophenyl, dihydropyrroleyl, tetrahydroimidazoyl, dihydropyrazolyl, tetrahydropyrazolyl, tetrahydropyridyl, dihydropyridyl or dihydrobenzodioxinyl, wherein each of the above groups is unsubstituted or R 6 O(CH2) n Ar 3 And / or (CH2) n Ar 3 Mono- or di-substituted,

[0063] Het 2 The following groups are indicated: piperidinyl, piperazinyl, pyrrolyl, 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-azabicyclo[3.1.0]hexyl, 2-azaspiro[3.3]heptyl, 6-azaspiro[3.4]octyl, 7-azaspiro[3.5]nonyl, 5-azaspiro[3.5]nonyl, imidazoalkyl, azacyclobutyl, azacycloheptyl, tetrahydrofuranyl, dioxacyclopentyl, tetrahydrothiophenyl, tetrahydroimidazoyl, tetrahydropyrazolyl, tetrahydropyridinyl, where each of the above groups is unsubstituted or R 6 Het 3 , CycSO2, OH, OA, COA, COHet 3 CycCO, SO2 and / or =O mono-, di-, or tri-substituted.

[0064] Het 3 The following groups are indicated: piperidinyl, piperazine, pyrrolyl, morpholinyl, furanyl, thiophene, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, imidazolyl, aziridine, aziridine, heptyl, tetrahydrofuranyl, dioxacyclopentyl, tetrahydrothiophene, dihydropyrrolyl, tetrahydroimidazolyl, dihydropyrazolyl, tetrahydropyridinyl, tetrahydropyridinyl, or dihydropyridinyl, wherein each of the above groups is unsubstituted or monosubstituted, disubstituted, or trisubstituted by Hal, A, and / or =O.

[0065] Het 4 The expression represents hexahydrothiophene[3,4-d]imidazolyl, benzo[c][1,2,5]oxadiazolyl, or 5H-dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-4-ium-uidyl, wherein each of the above groups is unsubstituted or monosubstituted, disubstituted, trisubstituted, or tetrasubstituted by A, NO2, Hal, and / or =O.

[0066] Cyc represents a cycloalkyl group containing 3, 4, 5, or 6 carbon atoms, wherein the cycloalkyl group is unsubstituted or R-substituted. 6 Mono-substitution, and the cycloalkyl group may contain a double bond,

[0067] A represents a straight-chain or branched alkyl group containing 1-10 carbon atoms, wherein 1-7 hydrogen atoms may be substituted by F and / or Cl, and / or one or two non-adjacent CH2 and / or CH- groups may be substituted by O, NH and / or N.

[0068] Hal represents F, Cl, Br, or I.

[0069] n represents 0, 1, 2, 3, or 4.

[0070] p represents 1, 2, 3, 4, 5, or 6.

[0071] In some embodiments, the present invention provides a method for treating and / or preventing cancer, comprising administering to a subject a compound represented by general formula (II):

[0072]

[0073] and its pharmaceutically acceptable salts, solvates, salts of solvates, or prodrugs, wherein:

[0074] X is H, CH3, or NH2.

[0075] Y is H, Hal, or does not exist.

[0076] B is either N or CH.

[0077] E is NH2 or H.

[0078] W is NR, O, or a cyclic amine.

[0079] Z can be independently CH2, CH3, CH2-CH2, CH-CH2, H, NH, or it may not exist.

[0080] "Linker" is (CH2) nWherein: n is 1, 2, or 3, or optionally substituted groups, wherein the optionally substituted groups are selected from benzene rings, aromatic rings, heteroaromatic rings, branched or straight-chain alkyl groups, 5-6 membered monocyclic heteroaromatic rings containing 1-4 heteroatoms independently selected from nitrogen or oxygen, 4-7 membered saturated or partially unsaturated heterocycles containing 1-3 heteroatoms independently selected from nitrogen or oxygen, or 7-10 membered bicyclic saturated or partially unsaturated heterocycles containing 1-5 heteroatoms independently selected from nitrogen or oxygen, or 7-10 membered bicyclic saturated or partially unsaturated heterocycles containing 1-5 heteroatoms attached to a saturated heterocycle; linker may also be a cycloalkane optionally substituted with heteroatoms (independently selected from nitrogen or oxygen), a cycloalkane optionally substituted with -NH or OH, a cycloalkane containing a fused ring or a bridged ring, or a cycloalkane containing an optionally substituted spiro ring, wherein the spiro ring optionally contains heteroatoms.

[0081] A is a monocyclic or bicyclic aromatic carbocyclic ring or heterocyclic ring containing 0, 1, 2, 3, or 4 N and / or O atoms and 5, 6, 7, 8, 9, or 10 skeletal C atoms, wherein the carbocyclic or heterocyclic ring is unsubstituted or independently monosubstituted, disubstituted, or trisubstituted by Hal, OH, or OR.

[0082] Hal can be F, Cl, Br, or I.

[0083] R is independently hydrogen, oxygen, or an optionally substituted group, wherein the optionally substituted group is selected from C. 1-6 Straight-chain or cyclic aliphatic groups, benzyl, phenyl, phenyl optionally substituted with 1, 2 or 3 oxygen atoms, 4-7 membered heterocycles containing 1-2 heteroatoms independently selected from nitrogen or oxygen, or 5-6 membered monocyclic heteroaromatic rings containing 1-4 heteroatoms independently selected from nitrogen or oxygen, or monocyclic or bicyclic aromatic carbocyclic or heterocyclic rings containing 0, 1, 2, 3 or 4 nitrogen or oxygen atoms and 5, 6, 7 or 8 skeletal carbon atoms, wherein the carbocyclic or heterocyclic rings may be unsubstituted or mutually substituted. Independently mono-, di-, or tri-substituted by Hal, A, OH, NH2, nitriles, and / or CH(Hal)3, or a straight-chain or branched linear alkyl group containing 1, 2, 3, 4, 5, 6, 7, or 8 C atoms, wherein one or two CH2 groups may be substituted by an O atom or by –NH-, -CO-, -NHCOO-, -NHCONH-, -CONH-, -NHCO-, or –CH=CH-, and wherein 1-3 hydrogen atoms may be substituted by Hal.

[0084] R q Selected from -R, -A, halogens, -OR, -O(CH2) rOR, -R(NH), -NO2, -C(O)R, -CO2R, -C(O)N(R)2, -NRC(O)R, -NRC(O)NR2, -NRSO2R, or -N(R)2,

[0085] r is 1-4,

[0086] n is 0-4, and

[0087] Q are those electrophilic groups listed in Table 1, wherein the electrophilic groups may further include warheads.

[0088] As used herein, the term "warhead" refers to a portion of a functional group or substituent of a compound claimed in this invention, wherein the portion of the functional group or substituent is covalently bound to an amino acid (e.g., cysteine, lysine, or any other natural or modified amino acid capable of forming the covalent bond) in a binding region within a given ligand, wherein the warhead binds to the ligand, and wherein the covalent binding between the warhead and the binding region of the target protein occurs under conditions in which the physiological function of the protein is irreversibly inhibited.

[0089] While not intended to limit the invention to specific groups of substituent Q (as indicated under general formula (II) above), in some embodiments substituent Q is selected from the groups listed in Table 1. None of the compounds in the boxes in Table 1 are “warheads” as defined above.

[0090] Table 1

[0091]

[0092]

[0093]

[0094] In some embodiments, the present invention provides a method for treating and / or preventing cancer, comprising administering to a subject a compound represented by general formula (III):

[0095] ,

[0096] and its pharmaceutically acceptable salts, solvates, salts of solvates, or prodrugs, wherein:

[0097] X is O or NH.

[0098] Y is either N or CH.

[0099] W is H, NH2, or CONH2.

[0100] Q is either H or NH2.

[0101] R 1 It is L 1 –R 4 –L 2 –R 5 ,

[0102] R 2 It is M 1 -S 4 -M 2 -S 5

[0103] L 1 It is a single bond, a methylene group, or a ring A, wherein the ring A can be mono- or di-substituted by N or NH2.

[0104] R 4 It is Ar, A, or ring A, wherein ring A can be mono- or di-substituted by N, –O–, or Hal.

[0105] R 5 It is Ar, A, or ring A, wherein ring A can be substituted or disubstituted by N, –O–, or Hal, or is not present; in a preferred embodiment, R 5 Selected from the group consisting of 2-fluoropyridine, 1-methylpyridine-2(1H)-one, and 2-chloropyridine.

[0106] L 2 It is H, –O–, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 heteroalkyl, C1-C6 alkoxyalkyl, C1-C8 alkylaminoalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C4 alkyl (aryl), C1-C4 alkyl (heteroaryl), C1-C4 alkyl (C3-C8 cycloalkyl), or C1-C4 alkyl (C2-C8 heterocycloalkyl); in some embodiments, L 2 It is -CH2-O-(C1-C3 alkyl), -CH2-N(C1-C3 alkyl)2, C1-C4 alkyl (phenyl), or C1-C4 alkyl (5- or 6-membered heteroaryl); in some embodiments, L 2 Yes – A –; in some embodiments, L 2 It does not exist; in some preferred embodiments of the invention, L 2Select from the group consisting of but-3-en-2-one, prop-2-one, (E)-5-(dimethylamino)pent-3-en-2-one, (E)-pent-3-en-2-one, penta-3-yn-2-one, 1-chloroprop-2-one, (methanesulfonyl)ethane, (E)-5-((2-methoxyethyl)(methyl)amino)pent-3-en-2-one or (Z)-pent-3-en-2-one.

[0107] M 1 It's a single key.

[0108] S 4 It is Ar, A, or ring A, wherein ring A can be mono- or di-substituted by N, –O–, or Hal; in a preferred embodiment of the invention, S 4 It is a 5-6 quinary aromatic ring.

[0109] M 2 O, NH, CH2, or none at all.

[0110] S 5 It is H, Ar, A, or ring A, wherein ring A can be mono- or di-substituted by N, –O–, or Hal; in a preferred embodiment of the invention, S 5 The sample 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, S5 is absent.

[0111] Ar is a monocyclic or bicyclic aromatic carbocyclic or heterocyclic ring containing 0, 1, 2, 3, or 4 N and / or O atoms and 5, 6, 7, 8, 9, or 10 skeletal atoms, wherein the carbocyclic or heterocyclic ring is unsubstituted or independently monosubstituted, disubstituted, or trisubstituted by Hal, A, OH, OA, NH2, NHA, NA2, NO2, CN, OCN, COOH, COOA, CONH2, CONHA, CONA2, NHCOA, NHCONHA, NHCONH, CHO, and / or COA, wherein the nitrogen atom of the ring can be substituted by an oxygen atom to form an N-oxide group, and wherein, in the case of an aromatic bicyclic ring, one of the two rings can be partially saturated.

[0112] A is a straight-chain or branched linear alkyl group containing 1, 2, 3, or 4 carbon atoms, wherein 1, 2, or 3 hydrogen atoms may be substituted with Hal.

[0113] Hal can be F, Cl, Br, or I.

[0114] In some embodiments, the present invention provides a method for treating and / or preventing cancer, comprising administering a compound of formula (IV) to a subject:

[0115]

[0116] and its pharmaceutically acceptable salts, solvates, salts of solvates, or prodrugs, wherein:

[0117] Z is either N or CH.

[0118] X is O or NH, and

[0119] R 3 Selected from the group consisting of the following structures:

[0120]

[0121] Wherein, “R” represents the junction point with Z in general formula IV.

[0122] In some embodiments, the present invention provides a method for treating and / or preventing cancer, comprising administering a compound of general formula (V) to a subject:

[0123]

[0124] and its pharmaceutically acceptable salts, solvates, salts of solvates, or prodrugs, wherein:

[0125] X represents CH or N.

[0126] R 1 Indicates NR 5 [C(R 5 )2] n Het 2 ,

[0127] R 2 Indicates Hal, Ar 1 Or Het 1 ,

[0128] R 3 It represents NH2.

[0129] R 4 It represents H, CH3, or NH2.

[0130] R 5 It represents H or an alkyl group containing 1, 2, 3, or 4 carbon atoms.

[0131] R 6 N(R 5 )2CH2CH=CHCONH、Het 3CH2CH=CHCONH, CH2=CHCONH(CH2) n Het 4 (CH2) n COHet 3 -Dibase-CH2CH=CHCONH, HC≡CCO, CH3C≡CCO, CH2=CH-CO, CH2=C(CH3)CONH, CH3CH=CHCONH(CH2) n N≡CCR 7 R 8 CONH(CH2) n Het 4 NH(CH2) p COHet 3 -Dimethyl-CH2CH=CHCONH,Het 4 (CH2) p CONH(CH2CH2O) p (CH2) p COHet 3 -Dimethyl-CH2CH=CHCONH, CH2=CHSO2, ACH=CHCO, CH3CH=CHCO, Het 4 (CH2) p CONH(CH2) p Het 3 -Dimethyl-CH2CH=CHCONH, Ar 3 CH=CHSO2, CH2=CHSO2NH or N(R) 5 CH2CH=CHCO,

[0132] R 7 R 8 Together they represent alkylene groups containing 2, 3, 4, or 5 carbon atoms.

[0133] Ar 1 This indicates phenyl or naphthyl, where each of the above groups is unsubstituted or R-substituted. 6 Hal, (CH2) n NH2, CONHAr 3 (CH2) n NHCOA, O(CH2) n Ar 3 ,OCyc,A,COHet 3 OA and / or OHet 3 (CH2) monosubstituted, disubstituted, or trisubstituted

[0134] Ar 2This indicates phenyl, naphthyl, or pyridyl, where each of these groups is unsubstituted or R-substituted. 6 Hal, OAr 3 (CH2) n NH2, (CH2) n NHCOA and / or Het 3 Mono- or di-substituted,

[0135] Ar 3 The term represents a phenyl group, wherein the phenyl group is unsubstituted or monosubstituted, disubstituted, or trisubstituted by OH, OA, Hal, CN, and / or A.

[0136] Het 1 This refers to a monocyclic or bicyclic saturated, unsaturated, or aromatic heterocycle containing 1-4 N, O, and / or S atoms, wherein the heterocycle is unsubstituted or modified by R. 6 O(CH2) n Ar 3 And / or (CH2) n Ar can be mono-, di-, or tri-substituted.

[0137] Het 2 This refers to a saturated heterocycle, either monocyclic or bicyclic, containing 1-4 N, O, and / or S atoms, wherein the heterocycle is unsubstituted or modified by R. 6 Het 3 , CycSO2, OH, Hal, COOH, OA, COA, COHet 3 CycCO, SO2 and / or =O mono-, di-, or tri-substituted.

[0138] Het 3 This refers to an unsaturated, saturated, or aromatic heterocycle containing 1-4 N, O, and / or S atoms, wherein the heterocycle is unsubstituted or monosubstituted, disubstituted, or trisubstituted by Hal, A, and / or =O.

[0139] Het 4 This refers to an unsaturated, saturated, or aromatic heterocycle containing 1-4 N, O, and / or S atoms, wherein the heterocycle is unsubstituted or monosubstituted, disubstituted, trisubstituted, or tetrasubstituted by A, NO2, Hal, and / or =O.

[0140] Cyc represents a cycloalkyl group containing 3, 4, 5, or 6 carbon atoms, wherein the cycloalkyl group is unsubstituted or R-substituted. 6 and / or OH mono- or di-substituted, and the cycloalkyl group may contain a double bond,

[0141] A represents a straight-chain or branched alkyl group containing 1-10 carbon atoms, wherein 1-7 hydrogen atoms may be substituted by F and / or Cl, and / or one or two non-adjacent CH2 and / or CH- groups may be substituted by O, NH and / or N.

[0142] Hal represents F, Cl, Br, or I.

[0143] n represents 0, 1, 2, 3, or 4.

[0144] p represents 1, 2, 3, 4, 5, or 6.

[0145] And its pharmaceutically available salts, tautomers and stereoisomers, including mixtures of all proportions thereof.

[0146] In some embodiments, the present invention provides a method for treating and / or preventing cancer, comprising administering to a subject a compound selected from Table 2.

[0147] Table 2

[0148]

[0149]

[0150]

[0151]

[0152]

[0153]

[0154]

[0155]

[0156]

[0157]

[0158]

[0159]

[0160]

[0161]

[0162]

[0163] In some embodiments, the present invention provides a method for treating and / or preventing cancer, comprising administering to a subject a compound selected from: N-[(1-acryloylpiperidin-4-yl)methyl]-5-(4-phenoxyphenyl)pyrimidin-4,6-diamine (A250); and 1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-1-yl)prop-2-en-1-one (A225).

[0164] In some embodiments, the present invention provides a method as described above, wherein the compound is N-[(1-acryloylpiperidin-4-yl)methyl]-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine (A250).

[0165] In some embodiments, the present invention provides a method as described above, 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 (A225).

[0166] In some embodiments, the method of the present invention is used to treat or prevent conditions such as proliferative or hyperproliferative diseases, such as cancer.

[0167] In some embodiments, the present invention provides a method for treating, preventing, or reducing the severity of cancer in a patient by applying the compounds or compositions of the present invention.

[0168] In some embodiments, the present invention provides treatments for diseases, disorders, and conditions characterized by excessive or abnormal cell proliferation. These diseases include proliferative or hyperproliferative disorders. Examples of proliferative and hyperproliferative disorders include cancer and myeloproliferative disorders.

[0169] In some embodiments, the term "cancer" includes, but is not limited to, the following cancers. Oral cancer: Head and neck, including buccal cavity, lip, tongue, mouth, and pharynx; Cardiac cancer: Sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma; Lung cancer: Non-small cell lung cancer, including adenocarcinoma (acini, bronchoalveolar carcinoma [non-mucinous, mucinous, mixed], papillary, solid adenocarcinoma, clear cell, mucinous [colloid] adenocarcinoma, mucinous cystadenocarcinoma, signet ring, well-differentiated fetus), bronchoalveolar, squamous cell carcinoma (basal cell, clear cell, papillary cell, small cell), large cell (undifferentiated) carcinoma (giant cell, basal cell, clear cell, large cell [with rhabdomyosarcoma phenotype], large cell neuroendocrine carcinoma [LCNEC], combined LCNEC); Small cell lung cancer, including small cell (oat cell) carcinoma, combined small cell; Adenoid cystic carcinoma; Hamartoma; Lymphoma; Neuroendocrine / carcinoid; Sarcoma. Gastrointestinal cancers: esophagus (squamous cell carcinoma, laryngeal carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (cancer, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, hemangioma), small intestine (adenocarcinoma, lymphoma, carcinoid, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villonoma, hamartoma, leiomyoma). ), colon, colon-rectum, colorectal, rectum; urogenital tract cancers: kidney (adenocarcinoma, Wilm's tumor [nephroblastoma], lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminomatous sarcoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); liver cancer: Hepatocellular carcinoma (HCC), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, bile duct; Bone cancer: osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteoporosis), benign chondroma, chondrocyte tumor, chondrosarcoma, osteofibroma, osteoid osteoma, and giant cell tumor. Cancers of the nervous system: Skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningeal sarcoma, glioma), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor [pineal tumor], glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal neurofibroma, meningioma, glioma, sarcoma);Women / Gynecological Cancers: Uterus (Endometrial Cancer), Cervix (Cervical Cancer, Pretumoral Cervical Dysplasia), Ovary (Ovarian Cancer [Seroid Cystic Adenocarcinoma, Mucinous Cystic Adenocarcinoma, Unclassified Cancer], Granular Cell Tumor, Sertoli-Leydig Cell Tumor, Dysgerminoma, Malignant Teratoma), Vulva (Squamous Cell Carcinoma, Intraepithelial Carcinoma, Adenocarcinoma, Fibrosarcoma, Melanoma), Vagina (Clear Cell Carcinoma, Squamous Cell Carcinoma, Uveal Sarcoma (Embryosarcoma)) Fallopian tube (cancer), breast cancer; hematologic cancers: blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma [malignant lymphoma] hairy cell; lymphocytic lesions; skin cancers: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, carracic sarcoma, keratoacanthoma, moles dysplasticnevi, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; thyroid cancers: papillary thyroid carcinoma, follicular thyroid carcinoma, undifferentiated thyroid carcinoma, medullary thyroid carcinoma, type 2A multiple endocrine tumor, type 2B multiple endocrine tumor, familial medullary thyroid carcinoma, pheochromocytoma, paraganglioma; and adrenal cancers: neuroblastoma.

[0170] In some embodiments, the cancer is selected from non-Hodgkin's lymphoma mantle cell lymphoma and non-Hodgkin's lymphoma diffuse large B-cell lymphoma, including the ABC subtypes. In some embodiments, the cancer is non-Hodgkin's lymphoma mantle cell lymphoma. In some embodiments, the cancer is non-Hodgkin's lymphoma diffuse large B-cell lymphoma. In some embodiments, the cancer is non-Hodgkin's lymphoma diffuse large B-cell lymphoma, including the ABC subtypes.

[0171] In some embodiments, the cancer is selected from non-Hodgkin's lymphoma mantle cell lymphoma and non-Hodgkin's lymphoma diffuse large B-cell lymphoma, including the ABC subtype, and the compound is A250 or A225. In some embodiments, the compound is A250. In some embodiments, the compound is A225. In some embodiments, the cancer is non-Hodgkin's lymphoma mantle cell lymphoma, and the compound is A250 or A225. In some embodiments, the compound is A250. In some embodiments, the compound is A225. In some embodiments, the cancer is non-Hodgkin's lymphoma diffuse large B-cell lymphoma, and the compound is A250 or A225. In some embodiments, the compound is A250. In some embodiments, the compound is A225. In some embodiments, the cancer is non-Hodgkin's lymphoma diffuse large B-cell lymphoma, including the ABC subtype, and the compound is A250 or A225. In some embodiments, the compound is A250. In some embodiments, the compound is A225.

[0172] Generally, all groups appearing more than once can be the same or different, i.e., independent of each other. In this context, unless otherwise explicitly stated, each group and parameter has the meaning specified for general formulas (I), (II), (III), (IV), and (V). Therefore, the present invention relates particularly to compounds of general formulas (I), (II), (III), (IV), and (V), wherein at least one of the groups has the preferred meaning shown below.

[0173] Unless otherwise stated, the term "substituted" preferably means substituted by the aforementioned substituents, which may involve various degrees of substitution.

[0174] All physiologically acceptable salts, derivatives, solvates, salt solvates, and stereoisomers of these compounds, including mixtures thereof in all proportions, are also conforming to this invention.

[0175] Compounds of general formulas (I), (II), (III), (IV), and (V) may have one or more chiral centers. Therefore, these compounds may occur in various enantiomeric forms and may be racemic or optical. Consequently, the present invention also relates to optical (stereoisomers), enantiomers, racemates, diastereomers, hydrates, and solvates of these compounds.

[0176] Because the pharmaceutical activities of racemic or stereoisomers of the compounds of this invention may differ, enantiomers may be required. In these cases, chemical or physical methods known to those skilled in the art, or even directly employed in synthesis, can be used to resolve the final product or even intermediates into enantiomers.

[0177] In the case of racemic amines, the mixture can form diastereomers with optically active resolving agents. Examples of suitable resolving agents are optically active acids such as R- or S-type tartaric acid, diacetyl tartaric acid, dibenzoyl tartaric acid, mandelic acid, malic acid, and lactic acid; suitable N-protected amino acids (e.g., N-benzoylproline or N-benzenesulfonylproline); or various optically active camphorsulfonic acids. Chromatographic resolution of enantiomers using optically active resolving agents (e.g., dinitrobenzoylphenylglycine immobilized on silica gel, cellulose triacetate, or other derivatives of carbohydrates or chiral derivatized methacrylic acid polymers) is also advantageous. Suitable eluents used for this purpose are aqueous or alcoholic solvent mixtures, such as ethane / isopropanol / nitriles, for example, in a ratio of 82:15:3. A clever method for resolving racemic compounds containing ester groups (e.g., acetyl esters) is the use of enzymes, particularly esterases.

[0178] It is also conceivable that compounds of general formulas (I), (II), (III), (IV), and (V) include their isotopic notation forms. The isotopic notation forms of compounds having general formulas (I), (II), (III), (IV), and (V) are identical to those of the compounds, differing only in that one or more atoms of the compound are replaced by one or more atoms with atomic weights or mass numbers different from those of naturally occurring atoms. Examples of commercially available isotopes that can be incorporated into compounds of general formula I by known methods include hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, for example, respectively. 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. Compounds of general formula I containing one or more of the aforementioned isotopes and / or other atoms, their prodrugs, or pharmaceutically acceptable salts of any of them should be understood as part of this invention. Isotope-labeled compounds of general formula I can be used in a variety of advantageous ways. For example, in combination with, etc. 3 H or 14 Compounds of general formula 1, labeled with radioactive isotopes of tritium (C), can be used for drug and / or substrate tissue distribution assays. These two radioactive isotopes are particularly preferred due to their ease of preparation and good detectability. 3 H) and carbon-14 ( 14 C). Due to substances such as deuterium ( 2 Heavier isotopes of H exhibit higher metabolic stability, and incorporating such isotope-labeled compounds into compounds of general formula I is therapeutically beneficial. This higher metabolic stability directly leads to a longer in vivo half-life or a reduced dosage, which in most cases represents a preferred embodiment of the invention. Isotope-labeled compounds of general formula I are typically prepared by performing the synthetic schemes and steps disclosed in the Examples and Preparation sections of this text, replacing non-isotope-labeled reactants with readily available isotope-labeled reactants.

[0179] In other embodiments, deuterium ( 2H) is incorporated into compounds of general formulas (I), (II), (III), (IV), and (V). Such deuterium-containing compounds can undergo oxidative metabolic modification via a first-order kinetic isotope effect. The first-order kinetic isotope effect is a change in chemical reaction rate due to the substitution of the isotopic nucleus, resulting from the change in the ground-state energy required to form a covalent bond after the isotopic substitution. Substitution with a heavier isotope typically leads to a decrease in the ground-state energy of the chemical bond, thereby causing a rate-limiting decrease in the rate of bond-breaking reactions. If bond breaking occurs in or near a saddle point along the coordinates of a multi-product reaction, the product distribution ratio can be significantly altered. This is explained as follows: if deuterium is bonded to a non-substitutable position on a carbon atom, the rate difference k is typically... m / k d =2-7. If this rate difference is successfully applied to compounds of general formulas (I), (II), (III), (IV), and (V) that are easily oxidized, the properties of the compound in vivo can be significantly altered, thereby improving its pharmacokinetic properties.

[0180] In the discovery and development of therapeutics, those skilled in the art attempt to optimize pharmacokinetic parameters while maintaining favorable in vitro properties. It is reasonable to assume that many compounds with poor pharmacokinetic properties are readily metabolized by oxidation. Existing in vitro liver microsomal assays provide valuable information about this type of oxidative metabolism, enabling the rational design of deuterium-containing compounds of general formulas (I), (II), (III), (IV), and (V) to improve their stability due to antioxidant metabolism. Consequently, the pharmacokinetic properties of compounds of general formulas (I), (II), (III), (IV), and (V) have been significantly improved, an improvement that can be attributed to a prolonged in vivo half-life (t / 2) and a peak efficacy concentration (C2). max The dose-response curve area (AUC) and F can be used to quantitatively represent the results, or they can be expressed quantitatively by the reduction in clearance, dose, and material cost.

[0181] While not intended to limit the invention to any deuterium-containing motif, the following is an example. Compounds of general formulas (I), (II), (III), (IV), and (V) have multiple sites that may be attacked by oxidative metabolism, such as benzyl hydrogen atoms and hydrogen atoms bonded to nitrogen atoms, in which various combinations of hydrogen atoms are replaced by deuterium atoms, thus some, most, or all of the hydrogen atoms are replaced by deuterium atoms. Determining the half-life allows for the advantageous and accurate determination of the degree of improvement in resistance to oxidative metabolism. In this way, it has been determined that the half-life of the parent compound can be increased by up to 100% due to this type of deuterium-hydrogen substitution.

[0182] Deuterium-hydrogen substitution in compounds of general formulas (I), (II), (III), (IV), and (V) can also be used advantageously to alter the metabolite profile of the starting compound to reduce or eliminate undesirable toxic metabolites. For example, if a toxic metabolite is generated via oxidative carbon-hydrogen (CH) bond cleavage, it is reasonable to assume that a deuterium-containing analogue will significantly reduce or eliminate the formation of undesirable metabolites, even if the specific oxidation reaction is not a rate-determining step. For more information on deuterium-hydrogen substitution in existing technologies, see, for example, Hanzlik et al., J. Org. Chem. 55, 3992-3997, 1990; Reider et al., J. Org. Chem. 52, 3326-3334, 1987; Foster, Adv. Drug Res. 14, 1-40, 1985; Gillette et al., Biochemistry 33(10) 2927-2937, 1994; and Jarman et al., Carcinogenesis 16(4), 683-688, 1993.

[0183] The compounds of this invention may be in the form of prodrug compounds. A "prodrug compound" refers to a derivative that, under physiological conditions in an organism, can be converted into the biologically active compounds of this invention through reactions such as oxidation, reduction, and hydrolysis, each reaction occurring with or without the participation of an enzyme. Examples of prodrugs are compounds in which: the amino group of the compound of this invention is acylated, alkylated, or phosphorylated, for example, eicosylamino, alanylamino, neopentanoyloxymethylamino; or the hydroxyl group is acylated, alkylated, phosphorylated, or converted to a borate ester, for example, acetyloxy, palmitoyloxy, neopentanoyloxy, succinyloxy, fumaroxy, alanyloxy; or the carboxyl group is esterified or amidated; or the thiohydroxy group forms a disulfide bridge with a carrier molecule (e.g., a peptide), which selectively delivers the drug to the target site and / or to the cytosol. These compounds can be prepared from the compounds of this invention according to known methods. Other examples of prodrugs are compounds in which the carboxylic acid esters in the compounds of the present invention are, for example, converted to alkyl-, aryl-, choline-, amino-, acyloxymethyl esters, or linol-esters.

[0184] Metabolites of the compounds of this invention are also within the scope of this invention.

[0185] When tautomerism (e.g., keto-enol tautomerism) occurs in the compounds of the present invention or their prodrugs, protection is required both for their individual forms (e.g., ketone or enol forms) and for mixtures thereof in any proportion. This also applies to their stereoisomers, such as enantiomers, cis / trans isomers, conformational isomers, etc. If necessary, isomers can be separated according to methods known in the art (e.g., liquid chromatography). This also applies to their enantiomers, for example, separation using a chiral stationary phase. Furthermore, enantiomers can be separated by conversion to diastereomers, i.e., coupling with an enantiomerically pure auxiliary compound, followed by separation of the resulting diastereomer and cleavage of the auxiliary residues. Alternatively, any enantiomer of the compounds of the present invention can be obtained stereoselectively from optically pure starting materials.

[0186] The compounds of this invention may be in the form of pharmaceutically acceptable salts or solvates. The term "pharmaceutically acceptable salt" (also referred to as "pharmaceutically acceptable salt") refers to a salt prepared from a pharmaceutically acceptable non-toxic alkali or acid (including inorganic bases or acids and organic bases or acids). Where the compounds of this invention contain one or more acidic or basic groups, this invention also includes their corresponding pharmaceutically or toxicologically acceptable salts, especially those that are pharmaceutically usable. Thus, compounds of this invention containing acidic groups may exist in salt form and, according to the invention, may be used as, for example, alkali metal salts, alkaline earth metal salts, or ammonium salts. More precise examples of such salts include: sodium salts, potassium salts, calcium salts, magnesium salts, or salts containing ammonia or organic amines (e.g., ethylamine, ethanolamine, triethanolamine, or amino acids). Compounds of this invention containing one or more basic groups (i.e., protonable groups) may exist in salt form and, according to the invention, may exist in the form of addition salts formed with inorganic or organic acids. Examples of suitable acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, neopentanoic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, aminosulfonic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known in the art. If the compounds of the present invention contain both acidic and basic groups in the molecule, then the present invention also contains an internal salt or internal ammonium salt (zwitterion) in addition to the salt form described herein. These salts can be prepared by conventional methods known to those skilled in the art, for example, by contacting them in a solvent or dispersant with an organic or inorganic acid or base, or by exchanging anions or cations with other salts. The present invention also includes salts of all the compounds of the present invention that are unsuitable for direct use in pharmaceuticals due to low physiological compatibility, but can be used, for example, as intermediates in chemical reactions or in the preparation of pharmaceutically acceptable salts.

[0187] In addition, the present invention relates to pharmaceutical compositions comprising the present invention compound or its prodrug compound or its pharmaceutically acceptable salt or its solvate as an active ingredient, and comprising a pharmaceutically acceptable carrier.

[0188] "Pharmaceutical composition" refers to one or more active ingredients and one or more inert components constituting a carrier, as well as any product obtained directly or indirectly from: any combination, compounding, aggregation, or dissociation of any two or more components, or other types of reactions or interactions of one or more components. Therefore, the pharmaceutical compositions of the present invention include any compositions prepared by mixing the compounds of the present invention with a pharmaceutically acceptable carrier.

[0189] The pharmaceutical compositions of the present invention may additionally contain one or more other compounds as active ingredients, such as one or more other compounds of the present invention, prodrug compounds, or other BTK inhibitors. The pharmaceutical compositions include suitable compositions for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular, pulmonary (nasal or buccal inhalation), or nasal administration, the most suitable route of administration depending on the nature and severity of the condition being treated and the nature of the active ingredient in any known manner. They can be conveniently present in unit dose form and prepared using any method known in the pharmaceutical art.

[0190] In one embodiment, the compound and pharmaceutical composition, or a pharmaceutically acceptable salt, prodrug, or hydrate thereof, and a pharmaceutically acceptable carrier, are used to treat cancer.

[0191] The present invention also relates to the use of the compounds of the present invention in the preparation of medicaments for treating cancer.

[0192] In practical applications, according to conventional pharmaceutical formulation techniques, the compounds of the present invention, as active ingredients, can be bound to a pharmaceutical carrier to form a tight mixture. The carrier can take various forms depending on the desired formulation for administration (e.g., oral or parenteral (including intravenous)). In preparing oral dosage forms, any conventional pharmaceutical medium can be used, such as water, ethylene glycol, oils, alcohols, flavoring agents, preservatives, coloring agents, etc. In the case of oral liquid dosage forms, any conventional pharmaceutical medium can be used, such as suspensions, elixirs, and solutions; or carriers such as starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrants, etc. In the case of oral solid dosage forms, the composition can exist as, for example, powders, hard and soft capsules, and tablets; solid oral dosage forms are preferred over liquid dosage forms.

[0193] Because tablets and capsules are easy to administer, they represent the most beneficial oral unit dosage forms, in which case a solid drug carrier is clearly preferable. If desired, tablets can be coated using standard aqueous or anhydrous techniques. The compositions and formulations should contain at least 0.1% of the active compound. Of course, the percentage of the active compound in these compositions can vary, and can advantageously range from about 2% to about 60% by weight. The amount of the active compound in the therapeutically useful compositions is an amount sufficient to obtain an effective dose. The active compound can also be administered intranasally, for example, as liquid drops or sprays.

[0194] Tablets, pills, capsules, etc., may also contain: binders, such as gum arabic, gum arabic, corn starch, or gelatin; excipients, such as dicalcium phosphate; disintegrants, such as corn starch, potato starch, or alginate; lubricants, such as magnesium stearate; and sweeteners, such as sucrose, lactose, or saccharin. When the unit dosage form is a capsule, it may contain a liquid carrier other than the above-mentioned types of materials, such as fatty oils.

[0195] Various other substances can be present as coating materials or used to alter the physical form of a unit dose. For example, tablets can be coated with shellac, sugar coating, or both. In addition to the active ingredient, syrups or elixirs may also contain: sucrose as a sweetener, methylparaben and propylparaben as preservatives, colorants, and flavoring agents (e.g., cherry or orange flavor).

[0196] The compounds of this invention can also be administered parenterally. Solutions or suspensions of these active compounds can be prepared by suitably mixing them in water with a surfactant (e.g., hydroxypropyl cellulose). Dispersions can be prepared from glycerol, liquid polyethylene glycol, and mixtures thereof in oil. Under normal storage and use conditions, these formulations may contain preservatives to prevent microbial growth.

[0197] Suitable drug forms for injection include sterile aqueous solutions or dispersions and sterile powders for immediate preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must have sufficient fluidity to facilitate injection. During preparation and storage, the form must be stable and resistant to contamination by microorganisms such as bacteria and fungi. The carrier may include solvents or dispersion media such as water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

[0198] Any suitable route of administration can provide an effective dose of the compounds of the present invention for mammals (especially humans). For example, administration can be made orally, rectally, topically, parenterally, through the eyes, lungs, nose, etc. Dosage forms include tablets, sublingual tablets, dispersants, suspensions, solutions, capsules, creams, ointments, aerosols, etc. Oral administration of the compounds of the present invention is preferred.

[0199] The effective amount of the applied active ingredient may depend on the specific compound being applied, the mode of application, the condition to be treated, and the severity of the condition. The dosage can be readily determined by those skilled in the art.

[0200] Certain aspects of the present invention provide capsules comprising the compounds described above. In some embodiments, the capsules comprise about 20 mg to about 100 mg of the compound of the present invention. In some embodiments, the capsules comprise about 80 mg of the compound of the present invention. In some embodiments, the capsules comprise about 160 mg of the compound of the present invention. In some embodiments, the capsules comprise about 600 mg of the compound of the present invention. In some embodiments, the capsules comprise about 900 mg of the compound of the present invention. In some embodiments, the compound is N-[(1-acryloylpiperidin-4-yl)methyl]-5-(4-phenoxyphenyl)pyrimidin-4,6-diamine (A250) or 1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-1-yl)prop-2-en-1-one (A225). In some embodiments, the compound is N-[(1-acryloylpiperidin-4-yl)methyl]-5-(4-phenoxyphenyl)pyrimidin-4,6-diamine (A250). In some embodiments, the compound is 1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-1-yl)prop-2-en-1-one (A225).

[0201] Certain aspects of this invention relate to a method of treating cancer as described herein, including the step of administering a capsule as described above to a subject once daily. In some embodiments, the cancer is a relapsed / refractory B-cell malignancy. In some embodiments, the cancer is selected from non-Hodgkin's lymphoma mantle cell lymphoma and non-Hodgkin's lymphoma diffuse large B-cell lymphoma, including the ABC subtypes.

[0202] This invention also relates to a medicine box (casing) comprising the following individually packaged components:

[0203] a) An effective amount of the compound of the present invention or a physiologically acceptable salt, solvate, or prodrug thereof; and

[0204] b) An effective amount of another active pharmaceutical ingredient.

[0205] The medicine box comprises a suitable container, such as a box, individual bottle, bag, or ampoule. The medicine box may include, for example, individual ampoules, each containing an effective amount of the compound of the present invention and / or its pharmaceutically available derivatives, solvates, and stereoisomers (including mixtures thereof in all proportions) and an effective amount of additional pharmaceutically active ingredient in dissolved or lyophilized form.

[0206] Experimental Section

[0207] As described in the examples below, compounds are prepared according to the following general procedure in some exemplary embodiments. It should be understood that although the general method describes the synthesis of certain compounds of the present invention, the general method below, as well as other methods known to those skilled in the art, are also applicable to the synthesis of all compounds described herein and the subclasses and types of each compound.

[0208] The compound numbers used in the following examples correspond to the compound numbers mentioned above.

[0209] Example 1

[0210] Mosaic dot test (CLL patient sample)

[0211] Mosaic spot assays were performed according to standard operating procedures of Mosaic Laboratories. Mosaic spot medium (X-Vivo 10 medium [Lonza, Fisher Scientific, Carlsbad, CA] + 10% FBS [Life Technologies, Carlsbad, CA]) was placed in 96-well plates containing the compound and two controls: 1) a cytotoxic dose of cisplatin as a positive control; and 2) no treatment as a reference and negative control. The viability and cell count of blood and bone marrow mononuclear cells from chronic lymphocytic leukemia (CLL) were evaluated before seeding with the above-mentioned mosaic spot medium. Tumor cells were placed in a medium containing 5% CO2. 2 Cells were incubated in a humidified 37°C incubator for 4 days. At the end of incubation, cells were removed and centrifuged onto positively charged slides (Superfrost+, VWR, Radnor, PA). The slides were stained with Wright Giemsa according to standard operating procedures in the Mosaic laboratory. Cell growth was measured by a hematologist. Results are shown in [link to results]. Figure 1 .

[0212] Example 2

[0213] MCL / ABC-DLBCL cell line

[0214] Cell lines stored in liquid nitrogen were thawed and expanded in growth medium containing whole serum. Once the desired fold increase in cell number was achieved, screening began. Cells were seeded into growth medium in black 384-well plates treated with tissue culture medium. Cells were equilibrated in the plates by centrifugation and placed in a 37°C incubator (attached to the drug delivery module) for 24 hours prior to treatment. At treatment, a set of untreated plates was collected and ATPLite (PerkinElmer) was added to measure ATP levels. These Tzero (T0) plates were read using the ultrasensitive fluorescence of an Envision plate reader. The plates were incubated with the compound for 72 hours and analyzed using ATPLite. All data points were collected via an automated workflow and quality controlled using Horizon proprietary software. Plates were accepted if they met the following quality control criteria: consistent relative to the original values ​​throughout the experiment, a Z-factor score greater than 0.6, and consistent performance of the untreated / vector control on the plates.

[0215] Horizon uses growth inhibition (GI) as a measure of cell growth. The percentage of GI is calculated using the following tests and equations:

[0216]

[0217] Where T is the signal measurement of the test item after 72 hours, and V is the control measurement of untreated / medium-treated material. o This is the measurement of the untreated / medium-treated control at time zero (commonly known as the T0 plate). The formula is derived from the growth inhibition calculation used in the National Cancer Institute's NCI-60 high-throughput screening.

[0218] A GI reading of 0% represents no growth inhibition, occurring when the 72-hour T reading is comparable to the corresponding V reading. A GI reading of 100% represents complete growth inhibition (cell inhibition), in which case cells treated with the compound for 72 hours have the same endpoint reading as T0 control cells. A GI reading of 200% represents complete cell death in all culture wells (cytotoxicity), in which case the 72-hour T reading is lower than the T0 control (value close to or equal to zero). These GI calculations were used for the analysis of all single-reagent and combined-reagent data; results are shown in [link to results]. Figure 2 and Figure 3 .

Claims

1. A method for the treatment or prevention of cancer, which method comprises administering to a subject a therapeutically effective amount of a compound of general formula (I): ###0001### (I) wherein: X represents CH or N, A represents a straight-chain or branched alkyl group containing 1-10 C atoms, wherein 1-7 hydrogen atoms can be replaced by F and / or Cl, and / or wherein one or two non-adjacent CH2 and / or CH- groups can be replaced by O, NH and / or by N, Hal represents F, Cl, Br or I, n represents 0, 1, 2, 3 or 4, p represents 1, 2, 3, 4, 5 or 6, and pharmaceutically usable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

2. The method according to claim 1, wherein the compound is of general formula (Ia): ###0002### (Ia) wherein: X represents CH or N, A represents a straight-chain or branched alkyl group containing 1-10 C atoms, wherein 1-7 hydrogen atoms can be replaced by F and / or Cl, and / or wherein one or two non-adjacent CH2 and / or CH- groups can be replaced by O, NH and / or by N, Hal represents F, Cl, Br or I, n represents 0, 1, 2, 3 or 4, p represents 1, 2, 3, 4, 5 or 6, and pharmaceutically usable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

3. The method according to claim 1 or 2, wherein the compound is of general formula (Ib): ###0003### (Ib) wherein: X represents CH or N, A represents a straight-chain or branched alkyl group containing 1-10 C atoms, wherein 1-7 hydrogen atoms can be replaced by F and / or Cl, and / or wherein one or two non-adjacent CH2 and / or CH- groups can be replaced by O, NH and / or by N, Hal represents F, Cl, Br or I, n represents 0, 1, 2, 3 or 4, p represents 1, 2, 3, 4, 5 or 6, and pharmaceutically usable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios. R 1 represents NH2, CONH2or H, R 2 represents Hal, Ar 1 or Het 1 , R 3 represents 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 (CH2) p NR 5 R 6 , O(CH2) p NR 5 R 6 or NR 5 (CH2) p CR 7 R 8 NR 5 R 6 , R 4 represents H, CH3or NH2, R 5 represents H or alkyl containing 1, 2, 3 or 4 C atoms, R 6 N(R 5 )2CH2CH=CHCONH, Het 3 CH2CH=CHCONH, CH2=CHCONH(CH2) n , Het 4 (CH2) n COHet 3 - diyl-CH2CH=CHCONH, HC≡CCO, CH3C≡CCO, CH2=CH-CO, CH2=C(CH3)CONH, CH3CH=CHCONH(CH2) n , N≡CCR 7 R 8 CONH(CH2) n , Het 4 NH(CH2) p COHet 3 - diyl-CH2CH=CHCONH, Het 4 (CH2) p CONH(CH2CH2O) p (CH2) p COHet 3 - diyl-CH2CH=CHCONH, CH2=CHSO2, ACH=CHCO, CH3CH=CHCO, Het 4 (CH2) p CONH(CH2) p Het 3 - diyl-CH2CH=CHCONH, Ar 3 CH=CHSO2, CH2=CHSO2NH or N(R 5 )CH2CH=CHCO, R 7 , R 8 together represent alkylene containing 2, 3, 4, or 5 C atoms, Ar 1 represents phenyl or naphthyl, each of the above-mentioned radicals being unsubstituted or substituted by R 6 , Hal, (CH2) n NH2, CONHAr 3 , (CH2) n NHCOA, O(CH2) n Ar 3 , OCyc, A, COHet 3 , OA and / or OHet 3 (CH2) mono-, di- or trisubstituted, Ar 2 represents phenyl, naphthyl or pyridyl, each of the above groups being unsubstituted or substituted by R 6 , Hal, OAr 3 , (CH2) n NH2, (CH2) n NHCOA and / or Het 3 one, two or three substituents, Ar 3 represents phenyl, which is unsubstituted or mono-, di- or trisubstituted by OH, OA, Hal, CN and / or A, Het 1 represents a monocyclic or bicyclic, saturated, unsaturated or aromatic heterocycle containing 1 to 4 N, O and / or S atoms, which is unsubstituted or substituted by R 6 , O(CH2) n Ar 3 and / or (CH2) n Ar 3 one-, two- or three-substituted, Het 2 represents a monocyclic or bicyclic, saturated heterocycle containing 1 to 4 N, O and / or S atoms, which is unsubstituted or mono-, di- or trisubstituted by R 6 , Het 3 , CycSO2, OH, Hal, COOH, OA, COA, COHet 3 , CycCO, SO2and / or =O, Het 3 Het denotes a monocyclic, unsaturated, saturated or ring aromatic heterocycle which contains 1 to 4 N, O and / or S atoms, which is unsubstituted or mono-, di- or trisubstituted by Hal, A and / or =0, Het 4 represents an unsaturated, saturated or aromatic heterocyclic ring, which is mono-, di-, tri- or tetra- substituted by A, NO2, Hal and / or =0, Cyc denotes cycloalkyl having 3, 4, 5 or 6 C atoms, which is unsubstituted or substituted by R 6 and / or OH mono- or disubstituted, and which can contain double bonds, 4. The method according to any one of claims 1 to 3, wherein the compound is of general formula (Ic): ###0004### (Ic) wherein: X represents CH or N, A represents a straight-chain or branched alkyl group containing 1-10 C atoms, wherein 1-7 hydrogen atoms can be replaced by F and / or Cl, and / or wherein one or two non-adjacent CH2 and / or CH- groups can be replaced by O, NH and / or by N, Hal represents F, Cl, Br or I, n represents 0, 1, 2, 3 or 4, p represents 1, 2, 3, 4, 5 or 6, and pharmaceutically usable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

5. The method according to any one of claims 1 to 4, wherein the compound is of general formula (Id): ###0005### (Id) wherein: X represents CH or N, A represents a straight-chain or branched alkyl group containing 1-10 C atoms, wherein 1-7 hydrogen atoms can be replaced by F and / or Cl, and / or wherein one or two non-adjacent CH2 and / or CH- groups can be replaced by O, NH and / or by N, Hal represents F, Cl, Br or I, n represents 0, 1, 2, 3 or 4, p represents 1, 2, 3, 4, 5 or 6, and pharmaceutically usable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

6. The method according to any one of claims 1 to 5, wherein the compound is of general formula (Ie): ###0006### (Ie) wherein: X represents CH or N, A represents a straight-chain or branched alkyl group containing 1-10 C atoms, wherein 1-7 hydrogen atoms can be replaced by F and / or Cl, and / or wherein one or two non-adjacent CH2 and / or CH- groups can be replaced by O, NH and / or by N, Hal represents F, Cl, Br or I, n represents 0, 1, 2, 3 or 4, p represents 1, 2, 3, 4, 5 or 6, and pharmaceutically usable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

7. The method according to any one of claims 1 to 6, wherein the compound is of general formula (If): ###0007### (If) wherein: X represents CH or N, A represents a straight-chain or branched alkyl group containing 1-10 C atoms, wherein 1-7 hydrogen atoms can be replaced by F and / or Cl, and / or wherein one or two non-adjacent CH2 and / or CH- groups can be replaced by O, NH and / or by N, Hal represents F, Cl, Br or I, n represents 0, 1, 2, 3 or 4, p represents 1, 2, 3, 4, 5 or 6, and pharmaceutically usable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

8. The method according to any one of claims 1 to 7, wherein the compound is of general formula (Ig): ###0008### (Ig) wherein: X represents CH or N, A represents a straight-chain or branched alkyl group containing 1-10 C atoms, wherein 1-7 hydrogen atoms can be replaced by F and / or Cl, and / or wherein one or two non-adjacent CH2 and / or CH- groups can be replaced by O, NH and / or by N, Hal represents F, Cl, Br or I, n represents 0, 1, 2, 3 or 4, p represents 1, 2, 3, 4, 5 or 6, and pharmaceutically usable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

9. The method according to claim 1, wherein the compound is of general formula (II): ###0009### (II) wherein: X is H or CH3 or NH2, Y is H, Hal or is absent, B is N or CH, E is NH2 or H, W is NR, O or cyclic amine, Z is independently CH2, CH3, CH2-CH2, CH-CH2, H, NH or is absent, Het 1 represents piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, furanyl, 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, tetrahydrofuranyl, dioxolanyl, tetrahydrothienyl, dihydropyrrolyl, tetrahydroimidazolyl, dihydropyrazolyl, tetrahydropyrazolyl, tetrahydropyridyl, dihydropyridyl or dihydrobenzodioxinyl, each of which is unsubstituted or substituted by R 6 , O(CH2) n Ar 3 and / or (CH2) n Ar 3 one, two or three substituents, and pharmaceutically usable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios. ​ Het 1 represents pyrazolyl, pyridyl, pyrimidinyl, dihydropyridyl or dihydrobenzodioxinyl, each of which is unsubstituted or substituted by R 6 , O(CH2) n Ar 3 and / or (CH2) n Ar 3 substituted, di-substituted or tri-substituted, and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios. ​ Het 2 represents piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, azabicyclo[3.2.1]octyl, azabicyclo[2.2.2]octyl, 2,7- diazaspiro[3.5]nonanyl, 2,8-diazaspiro[4.5]decanyl, 2,7- diazaspiro[4.4]nonanyl, 3-azabicyclo[3.1.0]hexanyl, 2- azaspiro[3.3]heptanyl, 6-azaspiro[3.4]octanyl, 7-azaspiro[3.5]nonanyl, 5-azaspiro[3.5]nonanyl, imidazolidinyl, azetidinyl, azepanyl, tetrahydrofuranyl, dioxolanyl, tetrahydrothiophenyl, tetrahydroimidazolyl, tetrahydropyrazolyl, tetrahydropyridinyl, each of which is unsubstituted or mono-, di- or trisubstituted by R 6 , Het 3 , CycSO2, OH, OA, COA, COHet 3 , CycCO, SO2and / or =O, and pharmaceutically usable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios. ​ Het 3 represents piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, imidazolidinyl, azetidinyl, azepanyl, tetrahydrofuranyl, dioxolanyl, tetrahydrothienyl, dihydropyrrolyl, tetrahydroimidazolyl, dihydropyrazolyl, tetrahydropyrazolyl, tetrahydropyridyl or dihydropyridyl, each of which is unsubstituted or mono-, di- or trisubstituted by Hal, A and / or =0, ​ ​ Het 3 represents piperidinyl, pyrrolidinyl, morpholinyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, dihydropyrrolyl, dihydropyrazolyl or dihydropyridyl, each of which is unsubstituted or mono-, di- or trisubstituted by Hal, A and / or =0, ​ ​ Het 4 represents hexahydrothieno[3,4-d]imidazolyl, benzo[c][l,2,5]oxadiazolyl or 5H- dipyrrolo[l,2-c:2',l'-f][l,3,2]diazaborinin-4-ium-yl, each of the above-mentioned radicals being unsubstituted or one-, two-, three- or four- substituted by A, NO2, Hal and / or =0, and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios. ​ ​ R 1 represents NH2, CONH2or H, R 2 represents Hal, Ar 1 or Het 1 , R 3 represents 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 (CH2) p NR 5 R 6 , O(CH2) p NR 5 R 6 or NR 5 (CH2) p CR 7 R 8 NR 5 R 6 , R 4 represents H, R 5 represents H or alkyl containing 1, 2, 3 or 4 C atoms, R 6 N(R 5 )2CH2CH=CHCONH, Het 3 CH2CH=CHCONH, CH2=CHCONH(CH2) n , Het 4 (CH2) n COHet 3 - diyl - CH2CH=CHCONH, HC≡CCO, CH3C≡CCO, CH2=CH-CO, CH2=C(CH3)CONH, CH3CH=CHCONH(CH2) n , N≡CCR 7 R 8 CONH(CH2) n , Het 4 NH(CH2) p COHet 3 - diyl - CH2CH=CHCONH, Het 4 (CH2) p CONH(CH2CH2O) p (CH2) p COHet 3 - diyl - CH2CH=CHCONH, CH2=CHSO2, ACH=CHCO, CH3CH=CHCO, Het 4 (CH2) p CONH(CH2) p Het 3 - diyl - CH2CH=CHCONH, Ar 3 CH=CHSO2, CH2=CHSO2NH or N(R 5 )CH2CH=CHCO, R 7 , R 8 together represent alkylene containing 2, 3, 4, or 5 C atoms, Ar 1 represents phenyl or naphthyl, each of the above mentioned radicals being unsubstituted or substituted by R 6 , Hal, (CH2) n NH2, CONHAr 3 , (CH2) n NHCOA, O(CH2) n Ar 3 , OCyc, A, COHet 3 , OA and / or OHet 3 (CH2) mono-, di- or trisubstituted, Ar 2 represents phenyl or naphthyl, each of the above mentioned radicals being unsubstituted or substituted by R 6 , Hal, OAr 3 , (CH2) n NH2, (CH2) n NHCOA and / or Het 3 one, two or three substituents, Ar 3 represents phenyl, which is unsubstituted or mono-, di- or trisubstituted by OH, OA, Hal, CN and / or A, Het 1 represents piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, furanyl, 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, tetrahydrofuranyl, dioxolanyl, tetrahydrothienyl, dihydropyrrolyl, tetrahydroimidazolyl, dihydropyrazolyl, tetrahydropyrazolyl, tetrahydropyridyl, dihydropyridyl or dihydrobenzodioxinyl, each of which is unsubstituted or substituted by R 6 , O(CH2) n Ar 3 and / or (CH2) n Ar 3 one-, two- or three-substituted, Het 2 represents piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, azabicyclo[3.2.1]octyl, azabicyclo[2.2.2]octyl, 2,7- diazaspiro[3.5]nonanyl, 2,8-diazaspiro[4.5]decanyl, 2,7- diazaspiro[4.4]nonanyl, 3-azabicyclo[3.1.0]hexanyl, 2- azaspiro[3.3]heptanyl, 6-azaspiro[3.4]octanyl, 7-azaspiro[3.5]nonanyl, 5-azaspiro[3.5]nonanyl, imidazolidinyl, azetidinyl, azepanyl, tetrahydrofuranyl, dioxolanyl, tetrahydrothiophenyl, tetrahydroimidazolyl, tetrahydropyrazolyl, tetrahydropyridinyl, each of which is unsubstituted or monosubstituted, disubstituted or trisubstituted by R 6 , Het 3 , CycSO2, OH, OA, COA, COHet 3 , CycCO, SO2and / or =O, Het 3 represents piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, imidazolidinyl, azetidinyl, azepanyl, tetrahydrofuranyl, dioxolanyl, tetrahydrothienyl, dihydropyrrolyl, tetrahydroimidazolyl, dihydropyrazolyl, tetrahydropyrazolyl, tetrahydropyridyl or dihydropyridyl, each of which is unsubstituted or monosubstituted, disubstituted or trisubstituted by Hal, A and / or =0, Het 4 represents hexahydrothieno[3,4-d]imidazolyl, benzo[c][l,2,5]oxadiazolyl or 5H- dipyrrolo[l,2-c:2',l'-f][l,3,2]diazaborinin-4-ium-yl, each of the above-mentioned radicals being unsubstituted or one-, two-, three- or four- substituted by A, NO2, Hal and / or =0, Cyc denotes cycloalkyl having 3, 4, 5 or 6 C atoms, which is unsubstituted or is substituted by R 6 one substituent, and the cycloalkyl group can comprise a double bond, ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ "linker" is (CH2) n wherein: n is 1, 2 or 3 or is an optionally substituted group selected from a phenyl ring, an aromatic ring, a heteroaromatic ring, a branched or straight chain alkyl group, a 5-6 membered monocyclic heteroaromatic ring containing 1-4 heteroatoms independently selected from nitrogen or oxygen, a 4-7 membered saturated or partially unsaturated heterocyclic ring containing 1-3 heteroatoms independently selected from nitrogen or oxygen, or a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring containing 1-5 heteroatoms independently selected from nitrogen or oxygen, or a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring containing 1-5 heteroatoms attached to a saturated heterocyclic ring, or a cycloalkane optionally substituted with a heteroatom (independently selected from nitrogen or oxygen), a cycloalkane optionally substituted with -NH or OH, a cycloalkane containing a fused or bridged ring, or a cycloalkane containing an optionally substituted spirocyclic ring, wherein the spirocyclic ring optionally contains a heteroatom, A is a monocyclic or bicyclic aromatic carbocycle or heterocycle containing 0, 1, 2, 3 or 4 N and / or O atoms and 5, 6, 7, 8, 9 or 10 skeletal C atoms, which is unsubstituted or mono-, di- or trisubstituted independently of one another by Hal, OH or OR, Hal is F, CI, Br or I, R is independently hydrogen, oxygen or an optionally substituted group selected from C 1-6 linear or branched alkyl, alkenyl or alkynyl group having 1 to 6 carbon atoms, which is unsubstituted or independently mono-, di- or trisubstituted by Hal, A, OH, NH2, nitrile, and / or CH(Hal)3, or a straight-chain or branched linear alkenyl group having 2 to 6 carbon atoms, which is unsubstituted or independently mono-, di- or trisubstituted by Hal, A, OH, NH2, nitrile, and / or CH(Hal)3, or a straight-chain or branched linear alkynyl group having 2 to 6 carbon atoms, which is unsubstituted or independently mono-, di- or trisubstituted by Hal, A, OH, NH2, nitrile, and / or CH(Hal)3, or a straight-chain or branched linear alkoxy group having 1 to 6 carbon atoms, which is unsubstituted or independently mono-, di- or trisubstituted by Hal, A, OH, NH2, nitrile, and / or CH(Hal)3, or a straight-chain or branched linear alkenyloxy group having 2 to 6 carbon atoms, which is unsubstituted or independently mono-, di- or trisubstituted by Hal, A, OH, NH2, nitrile, and / or CH(Hal)3, or a straight-chain or branched linear alkynyloxy group having 2 to 6 carbon atoms, which is unsubstituted or independently mono-, di- or trisubstituted by Hal, A, OH, NH2, nitrile, and / or CH(Hal)3, or a straight-chain or branched linear alkylthio group having 1 to 6 carbon atoms, which is unsubstituted or independently mono-, di- or trisubstituted by Hal, A, OH, NH2, nitrile, and / or CH(Hal)3, or a straight-chain or branched linear alkenylthio group having 2 to 6 carbon atoms, which is unsubstituted or independently mono-, di- or trisubstituted by Hal, A, OH, NH2, nitrile, and / or CH(Hal)3, or a straight-chain or branched linear alkynylthio group having 2 to 6 carbon atoms, which is unsubstituted or independently mono-, di- or trisubstituted by Hal, A, OH, NH2, nitrile, and / or CH(Hal)3, R q selected from -R, -A, halogen, -OR, -O(CH2) r OR, -R(NH), -NO2, -C(O)R, -CO2R, -C(O)N(R)2, -NRC(O)R, -NRC(O)NR2, -NRSO2R, or -N(R)2, r is 1-4, n is 0-4, and Q is an electrophilic group.

10. The method of claim 1, wherein the compound is selected from those listed in Table 2, and pharmaceutically acceptable salts, tautomers, and stereoisomers thereof, including mixtures thereof in all ratios.

11. The method of claim 10, wherein the compound is selected from: N-[(l-acryloylpiperidin-4-yl)methyl]-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine (A250); and l-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-l-yl)prop-2-en-l-one (A225); and pharmaceutically acceptable salts, tautomers, and stereoisomers thereof, including mixtures thereof in all ratios.

12. The method of any one of claims 1 to 11, wherein the cancer is selected from non-Hodgkin lymphoma mantle cell lymphoma and non-Hodgkin lymphoma diffuse large b-cell lymphoma, including the abc subtype.

13. A medicament comprising at least one compound of the general formula I or of the general formula II: in which: X denotes CH or N, R 1 represents NH2, CONH2or H, R 2 represents Hal, Ar 1 or Het 1 , R 3 represents 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 (CH2) p NR 5 R 6 , O(CH2) p NR 5 R 6 or NR 5 (CH2) p CR 7 R 8 NR 5 R 6 , R 4 represents H, CH3or NH2, R 5 represents H or alkyl containing 1, 2, 3 or 4 C atoms, R 6 N(R 5 )2CH2CH=CHCONH, Het 3 CH2CH=CHCONH, CH2=CHCONH(CH2) n , Het 4 (CH2) n COHet 3 - diyl-CH2CH=CHCONH, HC≡CCO, CH3C≡CCO, CH2=CH-CO, CH2=C(CH3)CONH, CH3CH=CHCONH(CH2) n , N≡CCR 7 R 8 CONH(CH2) n , Het 4 NH(CH2) p COHet 3 - diyl-CH2CH=CHCONH, Het 4 (CH2) p CONH(CH2CH2O) p (CH2) p COHet 3 - diyl-CH2CH=CHCONH, CH2=CHSO2, ACH=CHCO, CH3CH=CHCO, Het 4 (CH2) p CONH(CH2) p Het 3 - diyl-CH2CH=CHCONH, Ar 3 CH=CHSO2, CH2=CHSO2NH or N(R 5 )CH2CH=CHCO, R 7 , R 8 together represent alkylene containing 2, 3, 4, or 5 C atoms, Ar 1 represents phenyl or naphthyl, each of the above mentioned radicals being unsubstituted or substituted by R 6 , Hal, (CH2) n NH2, CONHAr 3 , (CH2) n NHCOA, O(CH2) n Ar 3 , OCyc, A, COHet 3 , OA and / or OHet 3 (CH2) mono-, di- or trisubstituted, Ar 2 represents phenyl, naphthyl or pyridyl, each of the above groups being unsubstituted or substituted by R 6 , Hal, OAr 3 , (CH2) n NH2, (CH2) n NHCOA and / or Het 3 one, two or three substituents, Ar 3 represents phenyl, which is unsubstituted or mono-, di- or trisubstituted by OH, OA, Hal, CN and / or A, Het 1 represents a monocyclic or bicyclic, saturated, unsaturated or aromatic heterocycle containing 1 to 4 N, O and / or S atoms, which is unsubstituted or substituted by R 6 , O(CH2) n Ar 3 and / or (CH2) n Ar 3 one-, two- or three-substituted, Het 2 represents a monocyclic or bicyclic, saturated heterocycle containing 1 to 4 N, O and / or S atoms, which is unsubstituted or monosubstituted, disubstituted or trisubstituted by R 6 , Het 3 , CycSO2, OH, Hal, COOH, OA, COA, COHet 3 , CycCO, SO2and / or =O, Het 3 Het denotes a monocyclic, unsaturated, saturated or ring aromatic heterocycle, which contains 1 to 4 N, O and / or S atoms, which is unsubstituted or mono-, di- or trisubstituted by Hal, A and / or =0, Het 4 represents an unsaturated, saturated or aromatic heterocyclic ring, which is mono-, di-, tri- or tetra- substituted by A, NO2, Hal and / or =0, Cyc denotes cycloalkyl having 3, 4, 5 or 6 C atoms, which is unsubstituted or substituted by R 6 and / or OH mono- or disubstituted, and which can contain double bonds, A denotes a straight-chain or branched alkyl group having 1-10 C atoms, wherein 1-7 hydrogen atoms can be replaced by F and / or CI, and / or wherein one or two non-adjacent CH2and / or CH- groups can be replaced by O, NH and / or by N, Hal denotes F, CI, Br or I, n denotes 0, 1, 2, 3 or 4, p denotes 1, 2, 3, 4, 5 or 6; of the general formula (II), in which: X is H or CH3 or NH2, Y is H, Hal or is absent, B is N or CH, E is NH2 or H, W is NR, O or a cyclic amine, Z is independently CH2, CH3, CH2-CH2, CH-CH2, H, NH or nothing, "linker" is (CH2) n wherein: n is 1, 2 or 3 or is an optionally substituted group selected from a phenyl ring, an aromatic ring, a heteroaromatic ring, a branched or straight chain alkyl group, a 5-6 membered monocyclic heteroaromatic ring containing 1-4 heteroatoms independently selected from nitrogen or oxygen, a 4-7 membered saturated or partially unsaturated heterocyclic ring containing 1-3 heteroatoms independently selected from nitrogen or oxygen, or a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring containing 1-5 heteroatoms independently selected from nitrogen or oxygen, or a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring containing 1-5 heteroatoms attached to a saturated heterocyclic ring, a cycloalkane optionally substituted with a heteroatom (independently selected from nitrogen or oxygen), a cycloalkane optionally substituted with -NH or OH, a cycloalkane containing a fused or bridged ring, or a cycloalkane containing an optionally substituted spirocyclic ring, wherein the spirocyclic ring optionally contains a heteroatom, A is a monocyclic or bicyclic aromatic carbocyclic or heterocyclic ring containing 0, 1, 2, 3 or 4 N and / or O atoms and 5, 6, 7, 8, 9 or 10 skeletal C atoms, which is unsubstituted or mono-, di- or tri-substituted independently of one another with Hal, OH or OR, Hal is F, CI, Br or I, R is independently hydrogen, oxygen or an optionally substituted group selected from C 1-6 linear or branched alkyl, alkenyl or alkynyl group having 1 to 8 C atoms, which can be unsubstituted, partially or fully halogenated, or in which one or more H atoms can be replaced by A, OH, CN, NH2, or in which one or more non-adjacent CH2groups can be replaced by a group -O-, -NR'-, -C(O)-, -C(O)NR'-, -NR'C(O)-, -NR'C(O)NR'-, -CH=CH-, -C≡C-, -C(O)C(O)-, -C(O)CH2-, or -CH2C(O)-, or in which one or more H atoms can be replaced by a group -O-, -S-, -NR'-, -SiR'R"-, -GER'-, -O-C(O)-, -NR'C(O)-, -C(O)NR'-, -NR'C(O)NR'-, -CH=CH-, -C≡C-, -C(O)C(O)-, -C(S)C(O)-, -C(O)CH2-, -CH2C(O)-, -CH2CH2-, -CH2CH2CH2-, -CH=CHCH2-, -C(O)CH=CH-, -S(O)2-, -S(O)-, -NHC(O)-, -C(O)NH-, -N(Ph)2-, -CH=NOH, -CH=NCN, -CH=NH-, -O-CH2-, -CH2O-, -NH-CH2-, -CH2NH-, -CH2NH-CH2-, -CH2NH-C(O)-, -C(O)NH-CH2-, -CH2C(O)H-, -CH2CH2-, -CH2CH2CH2-, -CH=CHCH2-, -C(O)CH=CH-, -S(O)2-, -S(O)-, -NHC(O)-, -C(O)NH-, -N(Ph)2-, -CH=NOH, -CH=NCN, -CH=NH-, -O-CH2-, -CH2O-, -NH-CH2-, -CH2NH-, -CH2NH-CH2-, -CH2NH-C(O)-, -C(O)NH-CH2-, -CH2C(O)H-, -CH=CH-, -C≡C-, -CN, -OH, -NH2, -NO2, -N3, -CN, -OH, -NH2, -NO2, -N3, -SH, -OCH3, -S(C1-C4alkyl), -NH(C1-C4alkyl), -N(C1-C4alkyl)2, -CH3, -CH2CH3, -CH=CH2, -C≡CCH3, -CN, -OH, -NH2, -NO2, -N3, -SH, -OCH3, -S(C1-C4alkyl), -NH(C1-C4alkyl), -N(C1-C4alkyl)2, -CH R q selected from -R, -A, halogen, -OR, -O(CH2) r OR, -R(NH), -NO2, -C(O)R, -CO2R, -C(O)N(R)2, -NRC(O)R, -NRC(O)NR2, -NRSO2R, or -N(R)2, r is 1-4, n is 0-4, and Q is an electrophilic group; and / or pharmaceutically usable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios, and optionally containing excipients and / or adjuvants.

14. The medicaments as claimed in claim 13, comprising at least one further pharmaceutically active ingredient, and / or pharmaceutically usable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

15. The medicaments as claimed in claim 13 or 14, wherein the compounds are selected from those listed in Table 2.

16. The medicaments as claimed in claim 13 or 14, wherein the compounds are selected from: N-[(1 -acryloylpiperidin-4-yl)methyl]-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine (A250); and 1 -(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4- fluoropiperidin-1 -yl)prop-2-en-1 -one (A225).

17. Use of a compound of the general formula I or of the general formula II and pharmaceutically usable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios, for the manufacture of a medicament for the treatment of cancer, in which formulae: X denotes CH or N, R 1 represents NH2, CONH2or H, R 2 represents Hal, Ar 1 or Het 1 , R 3 represents 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 (CH2) p NR 5 R 6 , O(CH2) p NR 5 R 6 or NR 5 (CH2) p CR 7 R 8 NR 5 R 6 , R 4 represents H, CH3or NH2, R 5 represents H or alkyl containing 1, 2, 3 or 4 C atoms, R 6 N(R 5 )2CH2CH=CHCONH, Het 3 CH2CH=CHCONH, CH2=CHCONH(CH2) n , Het 4 (CH2) n COHet 3 - diyl - CH2CH=CHCONH, HC≡CCO, CH3C≡CCO, CH2=CH-CO, CH2=C(CH3)CONH, CH3CH=CHCONH(CH2) n , N≡CCR 7 R 8 CONH(CH2) n , Het 4 NH(CH2) p COHet 3 - diyl - CH2CH=CHCONH, Het 4 (CH2) p CONH(CH2CH2O) p (CH2) p COHet 3 - diyl - CH2CH=CHCONH, CH2=CHSO2, ACH=CHCO, CH3CH=CHCO, Het 4 (CH2) p CONH(CH2) p Het 3 - diyl - CH2CH=CHCONH, Ar 3 CH=CHSO2, CH2=CHSO2NH or N(R 5 )CH2CH=CHCO, R 7 , R 8 together represent alkylene containing 2, 3, 4, or 5 C atoms, Ar 1 represents phenyl or naphthyl, each of the above mentioned radicals being unsubstituted or substituted by R 6 , Hal, (CH2) n NH2, CONHAr 3 , (CH2) n NHCOA, O(CH2) n Ar 3 , OCyc, A, COHet 3 , OA and / or OHet 3 (CH2) mono-, di- or trisubstituted, Ar 2 represents phenyl, naphthyl or pyridyl, each of the above groups being unsubstituted or substituted by R 6 , Hal, OAr 3 , (CH2) n NH2, (CH2) n NHCOA and / or Het 3 one, two or three substituents, Ar 3 represents phenyl, which is unsubstituted or mono-, di- or trisubstituted by OH, OA, Hal, CN and / or A, Het 1 represents a monocyclic or bicyclic, saturated, unsaturated or aromatic heterocycle containing 1 to 4 N, O and / or S atoms, which is unsubstituted or substituted by R 6 , O(CH2) n Ar 3 and / or (CH2) n Ar 3 one-, two- or three-substituted, Het 2 represents a monocyclic or bicyclic, saturated heterocycle containing 1 to 4 N, O and / or S atoms, which is unsubstituted or monosubstituted, disubstituted or trisubstituted by R 6 , Het 3 , CycSO2, OH, Hal, COOH, OA, COA, COHet 3 , CycCO, SO2and / or =O, Het 3 Het denotes a monocyclic, unsaturated, saturated or ring aromatic heterocycle, which contains 1 to 4 N, O and / or S atoms, which is unsubstituted or mono-, di- or trisubstituted by Hal, A and / or =0, Het 4 represents an unsaturated, saturated or aromatic heterocyclic ring, which is mono-, di-, tri- or tetra- substituted by A, NO2, Hal and / or =0, Cyc denotes cycloalkyl having 3, 4, 5 or 6 C atoms, which is unsubstituted or substituted by R 6 and / or OH mono- or disubstituted, and which can contain double bonds, A denotes a straight-chain or branched alkyl group having 1-10 C atoms, in which 1-7 hydrogen atoms can be replaced by F and / or CI, and / or in which one or two non-adjacent CH2and / or CH- groups can be replaced by O, NH and / or by N, Hal denotes F, CI, Br or I, n denotes 0, 1, 2, 3 or 4, p denotes 1, 2, 3, 4, 5 or 6; of the general formula (II), in which formulae: X is H or CH3or NH2, Y is H, Hal or is absent, B is N or CH, E is NH2or H, W is NR, O or cyclic amine, Z is independently CH2, CH3, CH2-CH2, CH-CH2, H, NH or is absent, "linker" is (CH2) n wherein: n is 1, 2 or 3 or is an optionally substituted group selected from a phenyl ring, an aromatic ring, a heteroaromatic ring, a branched or straight chain alkyl group, a 5-6 membered monocyclic heteroaromatic ring containing 1-4 heteroatoms independently selected from nitrogen or oxygen, a 4-7 membered saturated or partially unsaturated heterocyclic ring containing 1-3 heteroatoms independently selected from nitrogen or oxygen, or a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring containing 1-5 heteroatoms independently selected from nitrogen or oxygen, or a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring containing 1-5 heteroatoms attached to a saturated heterocyclic ring; the linker can also be a cycloalkane optionally substituted with a heteroatom (independently selected from nitrogen or oxygen), a cycloalkane optionally substituted with -NH or OH, a cycloalkane containing fused or bridged rings, or a cycloalkane containing an optionally substituted spirocyclic ring, wherein the spirocyclic ring optionally contains a heteroatom, A is a monocyclic or bicyclic aromatic carbocyclic or heterocyclic ring containing 0, 1, 2, 3 or 4 N and / or O atoms and 5, 6, 7, 8, 9 or 10 skeletal C atoms, which is unsubstituted or mono-, di- or trisubstituted, independently of one another, with Hal, OH or OR, Hal is F, Cl, Br or I, R is independently hydrogen, oxygen or an optionally substituted group selected from C 1-6 linear or branched alkyl, alkenyl or alkynyl group having 1 to 8 C atoms, which can be unsubstituted, partially or fully halogenated, or in which one or more H atoms can be replaced by A, OH, CN, NH2, or in which one or more non-adjacent CH2groups can be replaced by a group -O-, -NR'-, -C(O)-, -C(O)NR'-, -NR'C(O)-, -NR'C(O)NR'-, -CH=CH-, -C≡C-, -C(O)C(O)-, -C(O)CH2-, or -CH2C(O)-, or in which one or more H atoms can be replaced by a group -O-, -S-, -NR'-, -SiR'R"-, -GER'-, -O-C(O)-, -NR'C(O)-, -C(O)NR'-, -NR'C(O)NR'-, -CH=CH-, -C≡C-, -C(O)C(O)-, -C(S)C(O)-, -C(O)CH2-, -CH2C(O)-, -CH2CH2-, -CH2CH2CH2-, -CH=CH-CH2-, -NHC(O)-, -C(O)NHNH-, -CH2SiR'R"-, -CH2SnR'R"-, -CH2PdR'R"-, -CH2PtR'R"-, -CH2RhR'R"-, -CH2RuR'R"-, -CH2OsR'R"-, -CH2IrR'R"-, -CH2ReR'R"-, -CH2RfR'R"-, -CH2RgR'R"-, -CH2RmR'R"-, -CH2RnR'R"-, -CH2RrR'R"-, -CH2RwR'R"-, -CH2RxR'R"-, -CH2RyR'R"-, -CH2RzR'R"-, -CH2RbR'R"-, -CH2RcR'R"-, -CH2RdR'R"-, -CH2ReR'R"-, -CH2RfR'R"-, -CH2RgR'R"-, -CH2RhR'R"-, -CH2RiR'R"-, -CH2RjR'R"-, -CH2RkR'R"-, -CH2RlR'R"-, -CH2RmR'R"-, -CH2RnR'R"-, -CH2RoR'R"-, -CH2RpR'R"-, -CH2RqR'R"-, -CH2RrR'R"-, -CH2RsR'R"-, -CH2RtR'R"-, -CH2RuR'R"-, -CH2RvR'R"-, -CH2RwR'R"-, -CH2RyR'R"-, -CH2RzR'R"-, -CH2RbR'R"-, -CH2RcR'R"-, -CH2RdR'R"- R q selected from -R, -A, halogen, -OR, -O(CH2) r OR, -R(NH), -NO2, -C(O)R, -CO2R, -C(O)N(R)2, -NRC(O)R, -NRC(O)NR2, -NRSO2R, or -N(R)2, r is 1-4, n is 0-4, and Q is an electrophilic group.

18. The use according to claim 17 for the manufacture of a medicament for the treatment of non-Hodgkin lymphoma mantle cell lymphoma or non-Hodgkin lymphoma diffuse large B-cell lymphoma, including the abc subtype.

19. The use according to claim 16 or 17, wherein the compound is selected from those listed in Table 2.

20. The use according to claim 16 or 17, wherein the compound is selected from: N-[(1-acryloylpiperidin-4-yl)methyl]-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine (A250); and 1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-1-yl)prop-2-en-1-one (A225).

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