Pyridinyl and fused pyridinyl triazolone derivatives

Abstract

or pharmaceutically acceptable salts thereof, wherein R1, R2, R3, and R4 are defined in the specification. This disclosure also relates to materials and methods for preparing compounds of Formula 1, to pharmaceutical compositions which contain them, and to their use for treating Type I hypersensitivity reactions, autoimmune diseases, inflammatory disorders, cancer, non-malignant proliferative disorders, and other conditions associated with BTK.

1 . A method of treating a disease, disorder or condition in a subject, the method comprising administering to the subject a compound of Formula 1, 
       
         
           
           
               
               
           
         
         a tautomer thereof or a pharmaceutically acceptable salt of the compound or tautomer, wherein: 
         R 1  is selected from hydrogen, halo, and C 1-4  alkyl; 
         R 2  and R 3  are each independently selected from hydrogen, halo, and C 1-6  alkyl, or R 2  and R 3 , together with carbon atoms to which they are attached, form a benzene ring or a pyridine ring in which the benzene ring is optionally substituted with from one to four substituents independently selected from halo, —CN, —OR 8 , and C 1-6  alkyl, and the pyridine ring is optionally substituted with from one to three substituents independently selected from halo, —CN, —OR 8 , and C 1-6  alkyl; 
         R 4  has the formula 
       
       
         
           
           
               
               
           
         
         
           in which   indicates a point of attachment; 
           L is selected from —O—, —CH 2 O—, and N(R 4e )—; 
           R 4a  is selected from —CH 2 R 5  and ethenyl optionally substituted with from one to three substituents independently selected from halo, cyano, and C 1-6  alkyl optionally substituted with —N(R 11 )R 12 ; and 
           (a) R 4c  is hydrogen, R 4e  is selected from hydrogen and C 1-4  alkyl when L is —N(R 4e )—, and R 4b  and R 4d , together with a nitrogen atom and carbon atoms to which R 4b , R 4c , and R 4d  are respectively attached, form a pyrrolidine ring or a piperidine ring, each ring optionally substituted with from one to six substituents independently selected from halo, C 1-4  alkyl, and C 1-4  haloalkyl; or 
           (b) R 4b  is selected from hydrogen and C 1-4  alkyl, R 4d  is hydrogen, L is —N(R 4e )—, and R 4c  and R 4e , together with the carbon atoms and a nitrogen atom to which R 4c , R 4d , and R 4e  are respectively attached, form a pyrrolidine ring or a piperidine ring, each ring optionally substituted with from one to six substituents independently selected from halo, C 1-4  alkyl, and C 1-4  haloalkyl; or 
           (c) R 4d  is hydrogen, R 4e  is selected from hydrogen and C 1-4  alkyl when L is —N(R 4e )—, and R 4b  and R 4c , together with the nitrogen and carbon atoms to which R 4b  and R 4c  are respectively attached, form pyrrolidine ring or a piperidine ring, each ring optionally substituted with from one to six substituents independently selected from halo, C 1-4  alkyl, and C 1-4  haloalkyl; 
         
         R 5  is selected from hydrogen, halo, and C 1-4  alkyl; 
         each R 8  is independently selected from
 hydrogen and 
 C 1-6  alkyl; and 
 
         each R 11  and R 12  is independently selected from
 hydrogen and 
 C 1-6  alkyl; 
 
         wherein the disease, disorder or condition is selected from allergic rhinitis, asthma, atopic dermatitis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, psoriasis, immune thrombocytopenic purpura, inflammatory bowel disease, chronic obstructive pulmonary disease, Sjögren's syndrome, ankylosing spondylitis, Behcet's disease, graft versus host disease, pemphigus vulgaris, idiopathic plasmacytic lymphadenopathy, atherosclerosis, myocardial infarction, and thrombosis. 
       
     
     
         2 - 24 . (canceled) 
     
     
         25 . The method according to  claim 1 , wherein the compound is selected from the following compounds:
 (R)-3-(1-((1-methacryloylpyrrolidin-3-yl)oxy)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one;   (R)-3-(1-((1-acryloylpyrrolidin-3-yl)oxy)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one;   (R,E)-3-(1-((1-(but-2-enoyl)pyrrolidin-3-yl)oxy)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one;   N-(1-(3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)isoquinolin-1-yl)pyrrolidin-3-yl)acrylamide;   (S)-3-(1-(1-acryloylpyrrolidin-3-yl)oxy)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one;   (S)-3-(14(1-acryloylpyrrolidin-2-yl)methyl)amino)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one;   (S)-3-(1-(((1-acryloylpyrrolidin-2-yl)methoxy)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one;   (S)-3-(1-((1-acryloylpyrrolidin-3-yl)amino)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one;   (R)-3-(1-((1-acryloylpyrrolidin-2-yl)methoxy)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one;   (S)-3-(1-((1-methacryloylpyrrolidin-3-yl)amino)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one;   (S)-3-(1-((1-acryloylpyrrolidin-3-yl)(methyl)amino)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one;   (S)-3-(1-((1-methacryloylpyrrolidin-3-yl)oxy)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one;   (S)-3-(1-((1-acryloylpyrrolidin-3-yl)oxy)methyl)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one;   (S,E)-5-(1-((1-(4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl)oxy)isoquinolin-3-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one;   (S,E)-3-(1-((1-(but-2-enoyl)pyrrolidin-3-yl)amino)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one;   (S)-3-(8-((1-acryloylpyrrolidin-3-yl)oxy)-1,7-naphthyridin-6-yl)-1H-1,2,4-triazol-5(4H)-one;   (S)-3-(8-((1-acryloylpyrrolidin-3-yl)amino)-1,7-naphthyridin-6-yl)-1H-1,2,4-triazol-5(4H)-one;   (S)-3-(1-((1-acryloylpyrrolidin-3-yl)oxy)-7-fluoroisoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one;   3-(1-((trans-1-acryloyl-4-methylpyrrolidin-3-yl)oxy)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one;   3-(1-(((3R,4S)-1-acryloyl-4-methylpyrrolidin-3-yl)oxy)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one;   3-(1-(((3S,4R)-1-acryloyl-4-methylpyrrolidin-3-yl)oxy)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one;   (S)-3-(1-((1-acryloylpyrrolidin-3-yl)oxy)-8-fluoroisoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one;   (S)-3-(1-((1-acryloylpyrrolidin-3-yl)amino)-8-fluoroisoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one;   (S)-3-(1-((1-acryloylpyrrolidin-3-yl)oxy)-7-chloroisoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one;   (S)-3-(1-((1-acryloylpyrrolidin-3-yl)amino)-7-fluoroisoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one;   (S)-3-(1-((1-acryloylpyrrolidin-3-yl)amino)-7-chloroisoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one;   (S)-3-(1-((1-acryloylpyrrolidin-3-yl)oxy)-8-chloroisoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one;   (S)-3-(1-((1-acryloylpyrrolidin-3-yl)amino)-8-chloroisoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one;   (S)-3-(1-((1-acryloylpyrrolidin-3-yl)amino)-8-methoxyisoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one;   (S)-3-(6-((1-acryloylpyrrolidin-3-yl)oxy)-4-methylpyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one;   (S)-3-(6-((1-acryloylpyrrolidin-3-yl)oxy)pyridin-2-yl)-1H-1,2,4-triazol-5 (4H)-one;   (S)-3-(6-((1-acryloylpyrrolidin-3-yl)oxy)-5-methylpyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one;   (S)-5-(1-((1-(2-chloroacetyl)pyrrolidin-3-yl)oxy)isoquinolin-3-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one;   (S)-5-(1-((1-(2-chloroacetyl)pyrrolidin-3-yl)amino)isoquinolin-3-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one;   (S)-5-(1-((1-acryloylpiperidin-3-yl)oxy)isoquinolin-3-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one;   (S)-5-(14(1-acetylpyrrolidin-3-yl)oxy)isoquinolin-3-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one;   (S)-5-(1-((1-propionylpyrrolidin-3-yl)oxy)isoquinolin-3-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one;   a tautomer of any one of the aforementioned compounds;   a stereoisomer of any one of the aforementioned compounds or tautomers; and   a pharmaceutically acceptable salt of any one of the aforementioned compounds, tautomers or stereoisomers.   
     
     
         26 - 32 . (canceled) 
     
     
         33 . The method according to  claim 1 , further comprising administering to the subject at least one additional pharmacologically active agent. 
     
     
         34 - 35 . (canceled) 
     
     
         36 . The method according to  claim 1 , wherein the compound is (S)-3-(1-((1-acryloylpyrrolidin-3-yl)oxy)isoquinolin-3-yl)-1H-1,2,4-triazol-5 (4H)-one, a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer. 
     
     
         37 . The method according to  claim 1 , wherein the compound is (S)-3-(1-((1-acryloylpyrrolidin-3-yl)amino)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one, a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer. 
     
     
         38 . The method according to  claim 1 , wherein the compound is (S)-3-(8-((1-acryloylpyrrolidin-3-yl)oxy)-1,7-naphthyridin-6-yl)-1H-1,2,4-triazol-5(4H)-one, a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer. 
     
     
         39 . The method according to  claim 1 , wherein the compound is (S)-3-(8-((1-acryloylpyrrolidin-3-yl)amino)-1,7-naphthyridin-6-yl)-1H-1,2,4-triazol-5(4H)-one, a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer. 
     
     
         40 . The method according to  claim 1 , wherein the compound is (S)-3-(1-((1-acryloylpyrrolidin-3-yl)oxy)-8-fluoroisoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one, a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer. 
     
     
         41 . The method according to  claim 1 , wherein the compound is (S)-3-(1-((1-acryloylpyrrolidin-3-yl)amino)-8-fluoroisoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one, a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer. 
     
     
         42 . The method according to  claim 1 , wherein the compound is (S)-3-(1-((1-acryloylpyrrolidin-3-yl)oxy)-7-chloroisoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one, a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer. 
     
     
         43 . The method according to  claim 1 , wherein the compound is (S)-3-(1-((1-acryloylpyrrolidin-3-yl)amino)-7-chloroisoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one, a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer. 
     
     
         44 . The method according to  claim 1 , wherein the compound is (S)-3-(1-((1-acryloylpyrrolidin-3-yl)oxy)-8-chloroisoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one, a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer. 
     
     
         45 . The method according to  claim 1 , wherein the compound is (S)-3-(1-((1-acryloylpyrrolidin-3-yl)amino)-8-chloroisoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one, a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer.