Amino Pyrimidine Derivatives

Abstract

The present invention describes new amino pyrimidine derivatives and pharmaceutically acceptable salts thereof which appear to interact with Bruton's tyrosine kinase (Btk). Accordingly, the novel amino pyrimidines may be effective in the treatment of autoimmune disorders, inflammatory diseases, allergic diseases, airway diseases, such as asthma and chronic obstructive pulmonary disease (COPD), transplant rejection, cancers e.g. of hematopoietic origin or solid tumors.

1 - 26 : (canceled) 
     
     
         27 . A method of treating a disease which is treated by the modulation of Bruton Tyrosine Kinase (BTK), comprising administration to a patient in need of such treatment, a therapeutically acceptable amount of a compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein, 
         R1 is hydrogen, C 1 -C 6  alkyl optionally substituted by hydroxy; 
         R2 is hydrogen or halogen; 
         R3 is hydrogen or halogen; 
         R4 is hydrogen; 
         R5 is hydrogen or halogen; 
         or R4 and R5 are attached to each other and stand for a bond, —CH 2 —, —CH 2 —CH 2 —, —CH═CH—, —CH═CH—CH 2 —; —CH 2 —CH═CH—; or —CH 2 —CH 2 —CH 2 —; 
         R6 and R7 stand independently from each other for H, C 1 -C 6  alkyl optionally substituted by hydroxyl, C 3 -C 6  cycloalkyl optionally substituted by halogen or hydroxy, or halogen; 
         R8, R9, R, R′, R10 and R11 independently from each other stand for H, or C 1 -C 6  alkyl optionally substituted by C1-C6 alkoxy; or any two of R8, R9, R, R′, R10 and R11 together with the carbon atom to which they are bound may form a 3-6 membered saturated carbocyclic ring; 
         R12 is hydrogen or C 1 -C 6  alkyl optionally substituted by halogen or C 1 -C 6  alkoxy; 
         or R12 and any one of R8, R9, R, R′, R10 or R11 together with the atoms to which they are bound may form a 4, 5, 6 or 7 membered azacyclic ring, which ring may optionally be substituted by halogen, cyano, hydroxyl, C 1 -C 6  alkyl or C 1 -C 6  alkoxy; 
         n is 0 or 1; and 
         R13 is C 2 -C 6  alkenyl optionally substituted by C 1 -C 6  alkyl, C 1 -C 6  alkoxy or N,N-di-C 1 -C 6  alkyl amino; C 2 -C 6  alkynyl optionally substituted by C 1 -C 6  alkyl or C 1 -C 6  alkoxy; or C 2 -C 6  alkylenyl oxide optionally substituted by C 1 -C 6  alkyl, or a pharmaceutically acceptable salt thereof. 
       
     
     
         28 . The method according to  claim 27 , comprising administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein
 R1 is hydrogen, or C 1 -C 6  alkyl optionally substituted by hydroxy;   R2 is halogen;   R3 is hydrogen;   R4 is hydrogen;   R5 is halogen;   or R4 and R5 are attached to each other and stand for a bond, —CH2-, —CH2-CH2-, —CH═CH—, —CH═CH—CH2-; —CH2-CH═CH—; or —CH2-CH2-CH2-;   R6 and R7 stand independently from each other for H, C 1 -C 6  alkyl optionally substituted by hydroxyl, C 3 -C 6  cycloalkyl optionally substituted by halogen or hydroxy, or halogen;   R8, R9, R10 and R11 independently from each other stand for H, or C 1 -C 6  alkyl; or any two of R8, R9, R10 and R11 together with the carbon atom to which they are bound may form a 3-6 membered saturated carbocyclic ring;   R and R′ are hydrogen;   R12 is hydrogen or C 1 -C 6  alkyl optionally substituted by halogen;   or R12 and any one of R8, R9, R, R′, R10 or R11 together with the atoms to which they are bound may form a 4, 5, 6 or 7 membered azacyclic ring, which ring may optionally be substituted by halogen, cyano, hydroxyl, C 1 -C 6  alkyl or C 1 -C 6  alkoxy;   n is 0 or 1; and   R13 is C 2 -C 6  alkenyl optionally substituted by C 1 -C 6  alkyl or C 1 -C 6  alkoxy; C 2 -C 6  alkynyl optionally substituted by C 1 -C 6  alkyl or C 1 -C 6  alkoxy; or C 2 -C 6  alkylenyl oxide optionally substituted by C 1 -C 6  alkyl.   
     
     
         29 . The method according to  claim 27 , comprising administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein
 R1 is hydrogen, or C 1 -C 6  alkyl optionally substituted by hydroxy;   R2 is halogen;   R3 is hydrogen;   R4 is hydrogen;   R5 is halogen;   R6 and R7 stand independently from each other for H, C 1 -C 6  alkyl optionally substituted by hydroxyl, C 3 -C 6  cycloalkyl optionally substituted by halogen or hydroxy, or halogen;   R8, R9, R10 and R11 independently from each other stand for H, or C 1 -C 6  alkyl; or any two of R8, R9, R10 and R11 together with the carbon atom to which they are bound may form a 3-6 membered saturated carbocyclic ring;   R and R′ are hydrogen;   R12 is hydrogen or C 1 -C 6  alkyl optionally substituted by halogen;   or R12 and any one of R8, R9, R, R′, R10 or R11 together with the atoms to which they are bound may form a 4, 5, 6 or 7 membered azacyclic ring, which ring may optionally be substituted by halogen, cyano, hydroxyl, C 1 -C 6  alkyl or C 1 -C 6  alkoxy;   n is 0 or 1; and   R13 is C 2 -C 6  alkenyl optionally substituted by C 1 -C 6  alkyl or C 1 -C 6  alkoxy; C 2 -C 6  alkynyl optionally substituted by C 1 -C 6  alkyl or C 1 -C 6  alkoxy; or C 2 -C 6  alkylenyl oxide optionally substituted by C 1 -C 6  alkyl.   
     
     
         30 . The method according to  claim 27 , comprising administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein
 R1 is hydrogen, C 1 -C 6  alkyl optionally substituted by hydroxy;   R2 is hydrogen or halogen;   R3 is hydrogen or halogen;   R4 and R5 are attached to each other and stand for a bond, —CH 2 —, —CH 2 —CH 2 —, —CH═CH—, —CH═CH—CH 2 —; —CH 2 —CH═CH—; or —CH 2 —CH 2 —CH 2 —;   R6 and R7 stand independently from each other for H, C 1 -C 6  alkyl optionally substituted by hydroxyl, C 3 -C 6  cycloalkyl optionally substituted by halogen or hydroxy, or halogen;   R8, R9, R10 and R11 independently from each other stand for H, or C 1 -C 6  alkyl; or any two of R8, R9, R10 and R11 together with the carbon atom to which they are bound may form a 3-6 membered saturated carbocyclic ring;   R and R′ are hydrogen;   R12 is hydrogen or C 1 -C 6  alkyl optionally substituted by halogen;   or R12 and any one of R8, R9, R, R′, R10 or R11 together with the atoms to which they are bound may form a 4, 5, 6 or 7 membered azacyclic ring, which ring may optionally be substituted by halogen, cyano, hydroxyl, C 1 -C 6  alkyl or C 1 -C 6  alkoxy;   n is 0 or 1; and   R13 is C 2 -C 6  alkenyl optionally substituted by C 1 -C 6  alkyl or C 1 -C 6  alkoxy; C 2 -C 6  alkynyl optionally substituted by C 1 -C 6  alkyl or C 1 -C 6  alkoxy; or C 2 -C 6  alkylenyl oxide optionally substituted by C 1 -C 6  alkyl.   
     
     
         31 . The method according to  claim 27 , comprising administering a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein
 R1 is hydrogen, C 1 -C 6  alkyl optionally substituted by hydroxy;   R2 is hydrogen or halogen;   R3 is hydrogen or halogen;   R4 and R5 are attached to each other and stand for a —CH 2 —CH 2 —, or —CH═CH—;   R6 and R7 stand independently from each other for H, C 1 -C 6  alkyl optionally substituted by hydroxyl, C 3 -C 6  cycloalkyl optionally substituted by halogen or hydroxy, or halogen;   R8, R9, R10 and R11 independently from each other stand for H, or C 1 -C 6  alkyl; or any two of R8, R9, R10 and R11 together with the carbon atom to which they are bound may form a 3-6 membered saturated carbocyclic ring;   R and R′ are hydrogen;   R12 is hydrogen or C 1 -C 6  alkyl optionally substituted by halogen;   or R12 and any one of R8, R9, R, R′, R10 or R11 together with the atoms to which they are bound may form a 4, 5, 6 or 7 membered azacyclic ring, which ring may optionally be substituted by halogen, cyano, hydroxyl, C 1 -C 6  alkyl or C 1 -C 6  alkoxy;   n is 0 or 1; and   R13 is C 2 -C 6  alkenyl optionally substituted by C 1 -C 6  alkyl or C 1 -C 6  alkoxy; C 2 -C 6  alkynyl optionally substituted by C 1 -C 6  alkyl or C 1 -C 6  alkoxy; or C 2 -C 6  alkylenyl oxide optionally substituted by C 1 -C 6  alkyl.   
     
     
         32 . The method according to  claim 27 , comprising administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein
 R1 is hydrogen, or C 1 -C 6  alkyl optionally substituted by hydroxy;   R2 is halogen;   R3 is hydrogen;   R4 is hydrogen;   R5 is halogen;   R6 and R7 stand independently from each other for H, C 1 -C 6  alkyl optionally substituted by hydroxyl, C 3 -C 6  cycloalkyl optionally substituted by halogen or hydroxy, or halogen;   R8, R9, R10 and R11 independently from each other stand for H, or C 1 -C 6  alkyl;   R and R′ are hydrogen;   R12 is hydrogen or C 1 -C 6  alkyl optionally substituted by halogen;   n is 0 or 1; and   R13 is C 2 -C 6  alkenyl optionally substituted by C 1 -C 6  alkyl or C 1 -C 6  alkoxy; C 2 -C 6  alkynyl optionally substituted by C 1 -C 6  alkyl or C 1 -C 6  alkoxy; or C 2 -C 6  alkylenyl oxide optionally substituted by C 1 -C 6  alkyl.   
     
     
         33 . The method according to  claim 27 , comprising administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein
 R1 is hydrogen, or C 1 -C 6  alkyl optionally substituted by hydroxy;   R2 is halogen;   R3 is hydrogen;   R4 is hydrogen;   R5 is halogen;   R6 and R7 stand independently from each other for H, C 1 -C 6  alkyl optionally substituted by hydroxyl, C 3 -C 6  cycloalkyl optionally substituted by halogen or hydroxy, or halogen;   R8 and R9, independently from each other stand for H, or C 1 -C 6  alkyl;   R and R′ are hydrogen;   R12 and any one of R10 or R11 together with the atoms to which they are bound may form a 4, 5, 6 or 7 membered azacyclic ring, which ring may optionally be substituted by halogen, cyano, hydroxyl, C 1 -C 6  alkyl or C 1 -C 6  alkoxy;   n is 0 or 1; and   R13 is C 2 -C 6  alkenyl optionally substituted by C 1 -C 6  alkyl or C 1 -C 6  alkoxy; C 2 -C 6  alkynyl optionally substituted by C 1 -C 6  alkyl or C 1 -C 6  alkoxy; or C 2 -C 6  alkylenyl oxide optionally substituted by C 1 -C 6  alkyl.   
     
     
         34 . The method according to  claim 27 , comprising administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein
 R1 is hydrogen, or C 1 -C 6  alkyl optionally substituted by hydroxy;   R2 is halogen;   R3 is hydrogen;   R4 is hydrogen;   R5 is halogen;   R6 and R7 stand independently from each other for H, C 1 -C 6  alkyl optionally substituted by hydroxyl, C 3 -C 6  cycloalkyl optionally substituted by halogen or hydroxy, or halogen;   R8, R9, R10 and R11 independently from each other stand for H, or C 1 -C 6  alkyl;   R and R′ are hydrogen;   R12 is hydrogen or C 1 -C 6  alkyl optionally substituted by halogen;   n is 0 or 1; and   R13 is C 2 -C 6  alkenyl optionally substituted by C 1 -C 6  alkyl or C 1 -C 6  alkoxy.   
     
     
         35 . The method according to  claim 27 , comprising administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein
 R1 is hydrogen, or C 1 -C 6  alkyl optionally substituted by hydroxy;   R2 is fluoro;   R3 is hydrogen;   R4 is hydrogen;   R5 is halogen;   R6 and R7 stand independently from each other for H, C 1 -C 6  alkyl optionally substituted by hydroxyl, C 3 -C 6  cycloalkyl optionally substituted by halogen or hydroxy, or halogen;   R8 and R9 independently from each other stand for H, or C 1 -C 6  alkyl;   R12 and any one of R10 or R11 together with the atoms to which they are bound may form a 4, 5, 6 or 7 membered azacyclic ring, which ring may optionally be substituted by halogen, cyano, hydroxyl, C 1 -C 6  alkyl or C 1 -C 6  alkoxy;   n is 0; and   R13 is C 2 -C 6  alkenyl optionally substituted by C 1 -C 6  alkyl or C 1 -C 6  alkoxy; or C 2 -C 6  alkynyl optionally substituted by C 1 -C 6  alkyl or C 1 -C 6  alkoxy.   
     
     
         36 . The method according to  claim 27 , comprising administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein
 R1 is C 1 -C 6  alkyl;   R2 is fluoro;   R3 is hydrogen;   R4 is hydrogen;   R5 is fluoro;   R6 and R7 stand independently from each other for H, C 3 -C 6  cycloalkyl, or halogen;   R8, R9, R10 and R11 stand for H;   R12 is hydrogen;   n is 0; and   R13 is C 2 -C 6  alkenyl optionally substituted by C 1 -C 6  alkyl.   
     
     
         37 . The method of  claim 27 , comprising administering a therapeutically effective amount of a compound selected from:
 N-(3-(5-((1-Acryloylazetidin-3-yl)oxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;   (E)-N-(3-(6-Amino-5-((1-(but-2-enoyl)azetidin-3-yl)oxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;   N-(3-(6-Amino-5-((1-propioloylazetidin-3-yl)oxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;   N-(3-(6-Amino-5-((1-(but-2-ynoyl)azetidin-3-yl)oxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;   N-(3-(5-((1-Acryloylpiperidin-4-yl)oxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;   N-(3-(6-Amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;   (E)-N-(3-(6-Amino-5-(2-(N-methylbut-2-enamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;   N-(3-(6-Amino-5-(2-(N-methylpropiolamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;   (E)-N-(3-(6-Amino-5-(2-(4-methoxy-N-methylbut-2-enamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;   N-(3-(6-Amino-5-(2-(N-methylbut-2-ynamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;   N-(2-((4-Amino-6-(3-(4-cyclopropyl-2-fluorobenzamido)-5-fluoro-2-methylphenyl)pyrimidin-5-yl)oxy)ethyl)-N-methyloxirane-2-carboxamide;   N-(2-((4-Amino-6-(3-(6-cyclopropyl-8-fluoro-1-oxoisoquinolin-2(1H)-yl)phenyl)pyrimidin-5-yl)oxy)ethyl)-N-methylacrylamide;   N-(3-(5-(2-Acrylamidoethoxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;   N-(3-(6-Amino-5-(2-(N-ethylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;   N-(3-(6-Amino-5-(2-(N-(2-fluoroethyl)acrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;   N-(3-(5-((1-Acrylamidocyclopropyl)methoxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;   (S)—N-(3-(5-(2-Acrylamidopropoxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;   (S)—N-(3-(6-Amino-5-(2-(but-2-ynamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;   (S)—N-(3-(6-Amino-5-(2-(N-methylacrylamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;   (S)—N-(3-(6-Amino-5-(2-(N-methylbut-2-ynamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;   N-(3-(6-Amino-5-(3-(N-methylacrylamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;   (S)—N-(3-(5-((1-Acryloylpyrrolidin-2-yl)methoxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;   (S)—N-(3-(6-Amino-5-((1-(but-2-ynoyl)pyrrolidin-2-yl)methoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;   (S)-2-(3-(5-((1-Acryloylpyrrolidin-2-yl)methoxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-(hydroxymethyl)phenyl)-6-cyclopropyl-3,4-dihydroisoquinolin-1(2H)-one;   N-(2-((4-Amino-6-(3-(6-cyclopropyl-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-5-fluoro-2-(hydroxymethyl)phenyl)pyrimidin-5-yl)oxy)ethyl)-N-methylacrylamide;   N-(3-(5-(((2S,4R)-1-Acryloyl-4-methoxypyrrolidin-2-yl)methoxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;   N-(3-(6-Amino-5-(((2S,4R)-1-(but-2-ynoyl)-4-methoxypyrrolidin-2-yl)methoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;   2-(3-(5-(((2S,4R)-1-Acryloyl-4-methoxypyrrolidin-2-yl)methoxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-(hydroxymethyl)phenyl)-6-cyclopropyl-3,4-dihydroisoquinolin-1(2H)-one;   N-(3-(5-(((2S,4S)-1-Acryloyl-4-methoxypyrrolidin-2-yl)methoxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;   N-(3-(6-Amino-5-(((2S,4S)-1-(but-2-ynoyl)-4-methoxypyrrolidin-2-yl)methoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;   N-(3-(5-(((2S,4R)-1-Acryloyl-4-fluoropyrrolidin-2-yl)methoxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;   N-(3-(6-Amino-5-(((2S,4R)-1-(but-2-ynoyl)-4-fluoropyrrolidin-2-yl)methoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;   (S)—N-(3-(5-((1-Acryloylazetidin-2-yl)methoxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;   (S)—N-(3-(6-Amino-5-((1-propioloylazetidin-2-yl)methoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;   (S)-2-(3-(5-((1-Acryloylazetidin-2-yl)methoxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-(hydroxymethyl)phenyl)-6-cyclopropyl-3,4-dihydroisoquinolin-1(2H)-one;   (R)—N-(3-(5-((1-Acryloylazetidin-2-yl)methoxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;   (R)—N-(3-(5-((1-Acryloylpiperidin-3-yl)methoxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;   N-(3-(5-(((2R,3S)-1-Acryloyl-3-methoxypyrrolidin-2-yl)methoxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;   N-(3-(5-(((2S,4R)-1-Acryloyl-4-cyanopyrrolidin-2-yl)methoxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;   and   N-(3-(5-(((2S,4S)-1-Acryloyl-4-cyanopyrrolidin-2-yl)methoxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, or a pharmaceutically acceptable salt thereof.   
     
     
         38 . The method according to  claim 27  wherein the disease which is treated by the modulation of BTK is selected from an autoimmune disorder, an inflammatory disease and an allergic disease. 
     
     
         39 . The method according to  claim 27  wherein the disease which is treated by the modulation of BTK is selected from asthma and chronic obstructive pulmonary disease (COPD), transplant rejection; rheumatoid arthritis, systemic onset juvenile idiopathic arthritis (SOJIA), gout, pemphigus vulgaris, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, Sjögren's syndrome, autoimmune hemolytic anemia, anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitides, cryoglobulinemia, thrombotic thrombocytopenic purpura, chronic autoimmune urticaria, atopic dermatitis, contact dermatitis, allergic rhinitis, atherosclerosis, type 1 diabetes, type 2 diabetes, inflammatory bowel disease, ulcerative colitis, morbus Crohn, pancreatitis, glomerolunephritis, Goodpasture's syndrome, Hashimoto's thyroiditis, Grave's disease, antibody-mediated transplant rejection (AMR), graft versus host disease, B cell-mediated hyperacute, acute and chronic transplant rejection; thromboembolic disorders, myocardial infarct, angina pectoris, stroke, ischemic disorders, pulmonary embolism; multiple myeloma; leukemia; acute myelogenous leukemia; chronic myelogenous leukemia; lymphocytic leukemia; myeloid leukemia; non-Hodgkin lymphoma; lymphomas; polycythemia vera; essential thrombocythemia; myelofibrosis with myeloid metaplasia; and Waldenstroem disease.