Methods for Treating Cancer Using Pyrimidine and Pyridine Compounds with BTK Inhibitory Activity

Abstract

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

What is claimed is: 
     
         1 . A method of treating or preventing cancer, comprising administering to a subject a therapeutically effective amount of a compound of formula I 
       
         
           
           
               
               
           
         
         wherein 
         X denotes CH or N, 
         R 1  denotes NH 2 , CONH 2  or H, 
         R 2  denotes Hal, Ar 1  or Het 1 , 
         R 3  denotes NR 5 [C(R 5 ) 2 ] n Het 2 , NR 5 [C(R 5 ) 2 ] n Cyc, Het 2 , O[C(R 5 ) 2 ] n Ar 2 , NR 5 [C(R 5 ) 2 ] n Ar 2 , O[C(R 5 ) 2 ] n Het 2 , NR 5 (CH 2 ) p NR 5 R 6 , O(CH 2 ) p NR 5 R 6  or NR 5 (CH 2 ) p CR 7 R 8 NR 5 R 6 , 
         R 4  denotes H, CH 3  or NH 2 , 
         R 5  denotes H or alkyl having 1, 2, 3 or 4 C atoms, 
         R 6  N(R 5 ) 2 CH 2 CH═CHCONH, Het 3 CH 2 CH═CHCONH, CH 2 ═CHCONH(CH 2 ), Het 4 (CH 2 ) n COHet 3 -diyl-CH 2 CH═CHCONH, HC≡CCO, CH 3 C≡CCO, CH 2 ═CH—CO, CH 2 ═C(CH 3 )CONH, CH 3 CH═CHCONH(CH 2 ), N≡CCR 7 R 8 CONH(CH 2 ) n , Het 4 NH(CH 2 ) p COHet 3 -diyl-CH 2 CH═CHCONH, Het 4 (CH 2 ) p CONH(CH 2 CH 2 O) p (CH 2 ) p COHet 3 -diyl-CH 2 CH═CHCONH, CH 2 ═CHSO 2 , ACH═CHCO, CH 3 CH═CHCO, Het 4 (CH 2 ) p CONH(CH 2 ) p Het 3 -diyl-CH 2 CH═CHCONH, Ar 3 CH═CHSO 2 , CH 2 ═CHSO 2 NH or N(R 5 )CH 2 CH═CHCO, 
         R 7 , R 8  denote together alkylene having 2, 3, 4, or 5 C atoms, 
         Ar 1  denotes phenyl or naphthyl, each of which is unsubstituted or mono-, di- or trisubstituted by R 6 , Hal, (CH 2 ) n NH 2 , CONHAr 3 , (CH 2 ) n NHCOA, O(CH 2 ) n Ar 3 , OCyc, A, COHet 3 , OA and/or OHet 3  (CH 2 ), 
         Ar 2  denotes phenyl, naphthyl or pyridyl each of which is unsubstituted or mono-, di- or trisubstituted by R 6 , Hal, OAr 3 , (CH 2 ) n NH 2 , (CH 2 ) n NHCOA and/or Het 3 , 
         Ar 3  denotes phenyl, which is unsubstituted or mono-, di- or trisubstituted by OH, OA, Hal, CN and/or A, 
         Het 1  denotes a mono- or bicyclic saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and/or S atoms, which may be unsubstituted or mono-, di- or trisubstituted by R 6 , O(CH 2 ) n Ar 3  and/or (CH 2 ) n Ar 3 , 
         Het 2  denotes a mono- or bicyclic saturated heterocycle having 1 to 4 N, O and/or S atoms, which may be unsubstituted or mono-, di- or trisubstituted by R 6 , Het 3 , CycSO 2 , OH, Hal, COOH, OA, COA, COHet 3 , CycCO, SO 2  and/or ═O, 
         Het 3  denotes a monocyclic unsaturated, saturated or aromatic heterocycle having 1 to 4 N, O and/or S atoms, which may be unsubstituted or mono-, di- or trisubstituted by Hal, A and/or ═O, 
         Het 4  denotes a bi- or tricyclic unsaturated, saturated or aromatic heterocycle having 1 to 4 N, O and/or S atoms, which may be unsubstituted or mono-, di-, tri- or tetrasubstituted by A, NO 2 , Hal and/or ═O, 
         Cyc denotes cyclic alkyl having 3, 4, 5 or 6 C atoms, which is unsubstituted, monosubstituted or disubstituted by R 6  and/or OH and which may comprise a double bond, 
         A denotes unbranched or branched alkyl having 1-10 C atoms, in which 1-7H atoms may be replaced by F and/or Cl and/or in which one or two non-adjacent CH 2  and/or CH-groups may be replaced by O, NH and/or by N, 
         Hal denotes F, Cl, Br or I, 
         n denotes 0, 1, 2, 3 or 4, 
         p denotes 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
 Het 1  denotes piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, benzimidazolyl, benzotriazolyl, indolyl, benzo-1,3-dioxolyl, indazolyl, azabicyclo[3.2.1]octyl, azabicyclo[2.2.2]octyl, imidazolidinyl, azetidinyl, azepanyl, benzo-2,1,3-thiadiazolyl, tetrahydrofuryl, dioxolanyl, tetrahydrothienyl, dihydropyrrolyl, tetrahydroimidazolyl, dihydropyrazolyl, tetrahydropyrazolyl, tetrahydropyridyl, dihydropyridyl or di hydrobenzodioxinyl, each of which is unsubstituted or mono-, di- or trisubstituted by R 6 , O(CH 2 ) n Ar 3  and/or (CH 2 ) n Ar 3 , and pharmaceutically usable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios. 
 
     
     
         3 . The method according to  claim 1  wherein
 Het 1  denotes pyrazolyl, pyridyl, pyrimidinyl, dihydropyridyl or dihydrobenzodioxinyl, each of which is unsubstituted or mono-, di- or trisubstituted by R 6 , O(CH 2 ) n Ar 3  and/or (CH 2 ) n Ar 3 , and pharmaceutically usable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios. 
 
     
     
         4 . The method according to  claim 1  wherein
 Het 2  denotes piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, azabicyclo[3.2.1]octyl, azabicyclo[2.2.2]octyl, 2,7-diazaspiro[3.5]nonyl, 2,8-diazaspiro[4.5]decyl, 2,7-diazaspiro[4.4]nonyl, 3-azabicylo[3.1.0]hexyl, 2-azaspiro[3.3]heptyl, 6-azaspiro[3.4]octyl, 7-azaspiro[3.5]nonyl, 5-azaspiro[3.5]nonyl, imidazolidinyl, azetidinyl, azepanyl, tetrahydrofuryl, dioxolanyl, tetrahydrothienyl, tetrahydroimidazolyl, tetrahydropyrazolyl, tetrahydropyridyl, each of which is unsubstituted or mono-, di- or trisubstituted by R 6 , Het 3 , CycSO 2 , OH, OA, COA, COHet 3 , CycCO, SO 2  and/or ═O, and pharmaceutically usable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios. 
 
     
     
         5 . The method according to  claim 1  wherein
 Het 3  denotes piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, imidazolidinyl, azetidinyl, azepanyl, tetrahydrofuryl, dioxolanyl, tetrahydrothienyl, dihydropyrrolyl, tetrahydroimidazolyl, dihydropyrazolyl, tetrahydropyrazolyl, tetrahydropyridyl or dihydropyridyl, each of which may be unsubstituted or mono-, di- or trisubstituted by Hal, A and/or ═O,
 and pharmaceutically usable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios. 
 
 
     
     
         6 . The method according to  claim 1  wherein
 Het 3  denotes piperidinyl, pyrrolidinyl, morpholinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, dihydropyrrolyl, dihydropyrazolyl or dihydropyridyl, each of which may be unsubstituted or mono-, di- or trisubstituted by Hal, A and/or ═O, and pharmaceutically usable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios. 
 
     
     
         7 . The method according to  claim 1  wherein
 Het 4  denotes hexahydrothieno[3,4-d]imidazolyl, benzo[c][1,2,5]oxadiazolyl or 5H-dipyrrolo[1,2-c:2′,1′-f][1,3,2]diazaborinin-4-ium-uidyl, each of which may be unsubstituted or mono-, di-, tri- or tetrasubstituted by A, NO 2 , Hal and/or ═O, and pharmaceutically usable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios. 
 
     
     
         8 . The method according to  claim 1  wherein
 X denotes CH or N, 
 R 1  denotes NH 2 , CON H 2  or H, 
 R 2  denotes Hal, Ar 1  or Het 1 , 
 R 3  denotes NR 5 [C(R 5 ) 2 ] n Het 2 , NR 5 [C(R 5 ) 2 ] n Cyc, Het 2 , O[C(R 5 ) 2 ] n Ar 2 , NR 5 [C(R 5 ) 2 ] n Ar 2 , O[C(R 5 ) 2 ] n Het 2 , NR 5 (CH 2 ) p NR 5 R 6 , O(CH 2 ) p NR 5 R 6 NR 5 (CH 2 ) p CR 7 R 8 NR 5 R 6 , 
 R 4  denotes H, 
 R 5  denotes H or alkyl having 1, 2, 3 or 4 C atoms, 
 R 6  N(R 5 ) 2 CH 2 CH═CHCONH, Het 3 CH 2 CH═CHCONH, CH 2 ═CHCONH(CH 2 ), Het 4 (CH 2 ) n COHet 3 -diyl-CH 2 CH═CHCONH, HC≡CCO, CH 3 C≡CCO, CH 2 ═CH—CO, CH 2 ═C(CH 3 )CONH, CH 3 CH═CHCONH(CH 2 ) n , N≡CCR 7 R 8 CONH(CH 2 ) n , Het 4 NH(CH 2 ) p COHet 3 -diyl-CH 2 CH═CHCONH, Het 4 (CH 2 ) p CONH(CH 2 CH 2 O) p (CH 2 ) p COHet 3 -diyl-CH 2 CH═CHCONH, CH 2 ═CHSO 2 , ACH═CHCO, CH 3 CH═CHCO, Het 4 (CH 2 ) p CONH(CH 2 ) p Het 3 -diyl-CH 2 CH═CHCONH, Ar 3 CH═CHSO 2 , CH 2 ═CHSO 2 NH or N(R 5 )CH 2 CH═CHCO, 
 R 7 , R 8  denote together alkylene having 2, 3, 4, or 5 C atoms, 
 Ar 1  denotes phenyl or naphthyl, each of which is unsubstituted or mono-, di- or trisubstituted by R 6 , Hal, (CH 2 ) n NH 2 , CONHAr 3 , (CH 2 ) n NHCOA, O(CH 2 ) n Ar 3 , OCyc, A, COHet 3 , OA and/or OHet 3  (CH 2 ), 
 Ar 2  denotes phenyl or naphthyl, each of which is unsubstituted or mono-, di- or trisubstituted by R 6 , Hal, OAr 3 , (CH 2 ) n NH 2 , (CH 2 ) n NHCOA and/or Het 3 , 
 Ar 3  denotes phenyl, which is unsubstituted or mono-, di- or trisubstituted by OH, OA, Hal, CN and/or A, 
 Het 1  denotes piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, benzimidazolyl, benzotriazolyl, indolyl, benzo-1,3-dioxolyl, indazolyl, azabicyclo[3.2.1]octyl, azabicyclo[2.2.2]octyl, imidazolidinyl, azetidinyl, azepanyl, benzo-2,1,3-thiadiazolyl, tetrahydrofuryl, dioxolanyl, tetrahydrothienyl, dihydropyrrolyl, tetrahydroimidazolyl, dihydropyrazolyl, tetrahydropyrazolyl, tetrahydropyridyl, dihydropyridyl or di hydrobenzodioxinyl, each of which is unsubstituted or mono-, di- or trisubstituted by R 6 , O(CH 2 ) n Ar 3  and/or (CH 2 ) n Ar 3 , 
 Het 2  denotes piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, azabicyclo[3.2.1]octyl, azabicyclo[2.2.2]octyl, 2,7-diazaspiro[3.5]nonyl, 2,8-diazaspiro[4.5]decyl, 2,7-diazaspiro[4.4]nonyl, 3-azabicylo[3.1.0]hexyl, 2-azaspiro[3.3]heptyl, 6-azaspiro[3.4]octyl, 7-azaspiro[3.5]nonyl, 5-azaspiro[3.5]nonyl, imidazolidinyl, azetidinyl, azepanyl, tetrahydrofuryl, dioxolanyl, tetrahydrothienyl, tetrahydroimidazolyl, tetrahydropyrazolyl, tetrahydropyridyl, each of which is unsubstituted or mono-, di- or trisubstituted by R 6 , Het 3 , CycSO 2 , OH, OA, COA, COHet 3 , CycCO, SO 2  and/or ═O, 
 Het 3  denotes piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, imidazolidinyl, azetidinyl, azepanyl, tetrahydrofuryl, dioxolanyl, tetrahydrothienyl, dihydropyrrolyl, tetrahydroimidazolyl, dihydropyrazolyl, tetrahydropyrazolyl, tetrahydropyridyl or dihydropyridyl, each of which may be unsubstituted or mono-, di- or trisubstituted by Hal, A and/or ═O, 
 Het 4  denotes hexahydrothieno[3,4-d]imidazolyl, benzo[c][1,2,5]oxadiazolyl or 5H-dipyrrolo[1,2-c:2′,1′-f][1,3,2]diazaborinin-4-ium-uidyl, each of which may be unsubstituted or mono-, di-, tri- or tetrasubstituted by A, NO 2 , Hal and/or ═O, 
 Cyc denotes cyclic alkyl having 3, 4, 5 or 6 C atoms, which is unsubstituted or monosubstituted by R 6  and which may comprise a double bond, 
 A denotes unbranched or branched alkyl having 1-10 C atoms, in which 1-7H atoms may be replaced by F and/or Cl and/or in which one or two non-adjacent CH 2  and/or CH-groups may be replaced by O, NH and/or by N, 
 Hal denotes F, Cl, Br or I, 
 n denotes 0, 1, 2, 3 or 4, 
 p denotes 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 formula (II): 
       
         
           
           
               
               
           
         
         wherein:
 X is H or CH 3  or NH 2 , 
 Y is H, Hal or is absent, 
 B is N or CH, 
 E is NH 2  or H, 
 W is NR, O or a cyclic amine, 
 Z is, independently, CH 2 , CH 3 , CH 2 —CH 2 , CH—CH 2 , H, NH or is absent, 
 “linker” is (CH 2 ) n , wherein: n is 1, 2 or 3 or an optionally substituted group selected from a phenyl ring, an aryl ring, heteroaryl ring, branched or unbranched alkyl group, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, or oxygen, a 4-7 membered saturated or partially unsaturated heterocycle having 1-3 heteroatoms independently selected from nitrogen, or oxygen, or a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, or oxygen, or a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms attached to a hetero saturated ring. Linkers may also be cycloalkanes optionally substituted by heteroatoms (independently selected from nitrogen, or oxygen), cycloalkanes optionally substituted with —NH or OH, fused or bridged rings or optionally substituted spirocyclic rings that optionally contain heteroatoms, 
 A is a mono- or bicyclic aromatic homo- or heterocycle having 0, 1, 2, 3 or 4 N, and/or O atoms and 5, 6, 7, 8, 9, or 10 skeleton C atoms, which may be unsubstituted or, independently of one another, mono-, di- or trisubstituted by 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 cyclic aliphatic, benzyl, phenyl, a phenyl group optionally substituted with 1, 2 or 3 O atoms, a 4-7 membered heterocylic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, or oxygen or a mono- or bicyclic aromatic homo- or heterocycle having 0, 1, 2, 3 or 4 N, O atoms and 5, 6, 7, or 8 C skeleton atoms, which may be unsubstituted or, independently of one another, mono-, di- or trisubstituted by Hal, A, OH, NH 2 , nitrile, and/or CH(Hal) 3  or is an unbranched or branched linear alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 C atoms, in which one or two CH 2  groups may be replaced by an O atom and/or by an —NH—, —CO—, —NHCOO—, —NHCONH—, —CONH—, —NHCO— or —CH═CH-group, and in which 1-3H atoms may be replaced by Hal, 
 R q  is selected from —R, --A, halogen, —OR, —O(CH 2 ) r OR, —R(NH), —NO 2 , —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)NR 2 , —NRSO 2 R, or —N(R) 2 , 
 r is 1-4, 
 n is 0-4, and 
 Q is an electrophilic group. 
 
       
     
     
         10 . The method according to  claim 1 , wherein the compound is selected from Table 2, and pharmaceutically usable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios. 
     
     
         11 . The method according to  claim 10 , 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); and pharmaceutically usable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios. 
     
     
         12 . The method according to  claim 1 , wherein the cancer is selected from Non-Hodgkin's Lymphoma mantle cell lymphoma and Non-Hodgkins's Lymphoma diffuse large b-cell lymphoma, including abc subtype. 
     
     
         13 . A pharmaceutical composition comprising at least one compound of formula I or formula II: 
       
         
           
           
               
               
           
         
         wherein 
         X denotes CH or N, 
         R 1  denotes NH 2 , CON H 2  or H, 
         R 2  denotes Hal, Ar 1  or Het 1 , 
         R 3  denotes NR 5 [C(R 5 ) 2 ] n Het 2 , NR 5 [C(R 5 ) 2 ] n Cyc, Het 2 , O[C(R 5 ) 2 ] n Ar 2 , NR 5 [C(R 5 ) 2 ] n Ar 2 , O[C(R 5 ) 2 ] n Het 2 , NR 5 (CH 2 ) p NR 5 R 6 , O(CH 2 ) p NR 5 R 6  or NR 5 (CH 2 ) p CR 7 R 8 NR 5 R 6 , 
         R 4  denotes H, CH 3  or NH 2 , 
         R 5  denotes H or alkyl having 1, 2, 3 or 4 C atoms, 
         R 6  N(R 5 ) 2 CH 2 CH═CHCONH, Het 3 CH 2 CH═CHCONH, CH 2 ═CHCONH(CH 2 ), Het 4 (CH 2 ) n COHet 3 -diyl-CH 2 CH═CHCONH, HC≡CCO, CH 3 C≡CCO, CH 2 ═CH—CO, CH 2 ═C(CH 3 )CONH, CH 3 CH═CHCONH(CH 2 ) n , N≡CCR 7 R 8 CONH(CH 2 ) n , Het 4 NH(CH 2 ) p COHet 3 -diyl-CH 2 CH═CHCONH, Het 4 (CH 2 ) p CONH(CH 2 CH 2 O) p (CH 2 ) p COHet 3 -diyl-CH 2 CH═CHCONH, CH 2 ═CHSO 2 , ACH═CHCO, CH 3 CH═CHCO, Het 4 (CH 2 ) p CONH(CH 2 ) p Het 3 -diyl-CH 2 CH═CHCONH, Ar 3 CH═CHSO 2 , CH 2 ═CHSO 2 NH or N(R 5 )CH 2 CH═CHCO, 
         R 7 , R 8  denote together alkylene having 2, 3, 4, or 5 C atoms, 
         Ar 1  denotes phenyl or naphthyl, each of which is unsubstituted or mono-, di- or trisubstituted by R 6 , Hal, (CH 2 ) n NH 2 , CONHAr 3 , (CH 2 ) n NHCOA, O(CH 2 ) n Ar 3 , OCyc, A, COHet 3 , OA and/or OHet 3  (CH 2 ), 
         Ar 2  denotes phenyl, naphthyl or pyridyl each of which is unsubstituted or mono-, di- or trisubstituted by R 6 , Hal, OAr 3 , (CH 2 ) n NH 2 , (CH 2 ) n NHCOA and/or Het 3 , 
         Ar 3  denotes phenyl, which is unsubstituted or mono-, di- or trisubstituted by OH, OA, Hal, CN and/or A, 
         Het 1  denotes a mono- or bicyclic saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and/or S atoms, which may be unsubstituted or mono-, di- or trisubstituted by R 6 , O(CH 2 ) n Ar 3  and/or (CH 2 ) n Ar 3 , 
         Het 2  denotes a mono- or bicyclic saturated heterocycle having 1 to 4 N, O and/or S atoms, which may be unsubstituted or mono-, di- or trisubstituted by R 6 , Het 3 , CycSO 2 , OH, Hal, COOH, OA, COA, COHet 3 , CycCO, SO 2  and/or ═O, 
         Het 3  denotes a monocyclic unsaturated, saturated or aromatic heterocycle having 1 to 4 N, O and/or S atoms, which may be unsubstituted or mono-, di- or trisubstituted by Hal, A and/or ═O, 
         Het 4  denotes a bi- or tricyclic unsaturated, saturated or aromatic heterocycle having 1 to 4 N, O and/or S atoms, which may be unsubstituted or mono-, di-, tri- or tetrasubstituted by A, NO 2 , Hal and/or ═O, 
         Cyc denotes cyclic alkyl having 3, 4, 5 or 6 C atoms, which is unsubstituted, monosubstituted or disubstituted by R 6  and/or OH and which may comprise a double bond, 
         A denotes unbranched or branched alkyl having 1-10 C atoms, in which 1-7H atoms may be replaced by F and/or Cl and/or in which one or two non-adjacent CH 2  and/or CH-groups may be replaced by O, NH and/or by N, 
         Hal denotes F, Cl, Br or I, 
         n denotes 0, 1, 2, 3 or 4, 
         p denotes 1, 2, 3, 4, 5 or 6; 
       
       
         
           
           
               
               
           
         
         wherein:
 X is H or CH 3  or NH 2 , 
 Y is H, Hal or is absent, 
 B is N or CH, 
 E is NH 2  or H, 
 W is NR, O or a cyclic amine, 
 Z is, independently, CH 2 , CH 3 , CH 2 —CH 2 , CH—CH 2 , H, NH or is absent, 
 “linker” is (CH 2 ) n , wherein:  n  is 1, 2 or 3 or an optionally substituted group selected from a phenyl ring, an aryl ring, heteroaryl ring, branched or unbranched alkyl group, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, or oxygen, a 4-7 membered saturated or partially unsaturated heterocycle having 1-3 heteroatoms independently selected from nitrogen, or oxygen, or a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, or oxygen, or a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms attached to a hetero saturated ring. Linkers may also be cycloalkanes optionally substituted by heteroatoms (independently selected from nitrogen, or oxygen), cycloalkanes optionally substituted with —NH or OH, fused or bridged rings or optionally substituted spirocyclic rings that optionally contain heteroatoms, 
 A is a mono- or bicyclic aromatic homo- or heterocycle having 0, 1, 2, 3 or 4 N, and/or O atoms and 5, 6, 7, 8, 9, or 10 skeleton C atoms, which may be unsubstituted or, independently of one another, mono-, di- or trisubstituted by 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 cyclic aliphatic, benzyl, phenyl, a phenyl group optionally substituted with 1, 2 or 3 O atoms, a 4-7 membered heterocylic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, or oxygen or a mono- or bicyclic aromatic homo- or heterocycle having 0, 1, 2, 3 or 4 N, O atoms and 5, 6, 7, or 8 C skeleton atoms, which may be unsubstituted or, independently of one another, mono-, di- or trisubstituted by Hal, A, OH, NH 2 , nitrile, and/or CH(Hal) 3  or is an unbranched or branched linear alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 C atoms, in which one or two CH 2  groups may be replaced by an O atom and/or by an —NH—, —CO—, —NHCOO—, —NHCONH—, —CONH—, —NHCO— or —CH═CH-group, and in which 1-3H atoms may be replaced by Hal, 
 R q  is selected from —R, --A, halogen, —OR, —O(CH 2 ) r OR, —R(NH), —NO 2 , —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)NR 2 , —NRSO 2 R, or —N(R) 2 , 
 r is 1-4, 
 n is 0-4, and 
 Q is an electrophilic group; 
 
         and/or pharmaceutically usable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios, and optionally excipients and/or adjuvants. 
       
     
     
         14 . The pharmaceutical composition according to  claim 13  and/or pharmaceutically usable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios, and at least one further medicament active ingredient. 
     
     
         15 . The pharmaceutical composition according to  claim 13 , wherein the compound is selected from Table 2. 
     
     
         16 . The pharmaceutical composition according to  claim 13 , 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). 
     
     
         17 . The method according to  claim 1 , wherein the cancer is selected from Non-Hodgkin's Lymphoma mantle cell lymphoma and Non-Hodgkins's Lymphoma diffuse large b-cell lymphoma, including abc subtype, and 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); and pharmaceutically usable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios. 
     
     
         18 . The method according to  claim 1 , wherein the cancer is selected from Non-Hodgkin's Lymphoma mantle cell lymphoma and Non-Hodgkins's Lymphoma diffuse large b-cell lymphoma, including abc subtype, and the compound is N-[(1-acryloylpiperidin-4-yl)methyl]-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine (A250); and pharmaceutically usable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios. 
     
     
         19 . The method according to  claim 1 , wherein the cancer is selected from Non-Hodgkin's Lymphoma mantle cell lymphoma and Non-Hodgkins's Lymphoma diffuse large b-cell lymphoma, including abc subtype, and 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); and pharmaceutically usable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.