Azaindole derivatives

Abstract

Disclosed are compounds of Formula 1, and pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 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 immunological disorders, cardiovascular disease, cancer, and other diseases, disorders or conditions associated with PI3Kδ.

1 . A method of treating a disease, disorder or condition in a subject, the method comprising administering to the subject an effective amount of a compound of Formula 1, 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R 1  is selected from C 3-8  cycloalkyl, C 2-6  heterocyclyl, C 6-14  aryl, and C 1-9  heteroaryl, each optionally substituted with from one to five substituents independently selected from halo, oxo, —CN, R 11 , and R 12 ; 
         R 2 , R 4 , and R 5  are each independently selected from hydrogen, halo, —OH, —CN, C 1-3  alkyl, and C 1-3  haloalkyl; 
         R 3  is selected from hydrogen, C 1-3  alkyl, and C 1-3  haloalkyl; 
         R 6  and R 7  are each independently selected from hydrogen, C 1-3  alkyl, and C 1-3  haloalkyl; 
         R 8  is selected from hydrogen, methyl, and —NH 2 ; 
         R 9  is selected from hydrogen, halo, —CN, C 1-3  haloalkyl, —OR 16 , —C(O)R 16 , —C(O)OR 16 , —C(O)N(R 16 )R 17 , —C(O)N(R 16 )OR 17 , —C(O)N(R 16 )S(O) 2 R 18 , —SR 16 , —S(O)R 18 , —S(O) 2 R 18 , and —S(O) 2 N(R 16 )R 17 ; or 
         R 8  is selected from —NH— and —CH 2 —, and R 8  and R 9 , together with the carbon atoms to which they are attached, form a C 2-4  heteroarylene having 5 ring atoms and 1 to 3 heteroatoms, each of the heteroatoms being nitrogen, and wherein the C 2-4  heteroarylene is optionally substituted with R 12 ; 
         R 10  is selected from halo, —OH, C 1-3  alkyl, —NHR 16 , and —NHC(O)R 16 ; 
         each R 11  is independently selected from —OR 13 , —N(R 13 )R 14 , —NR 13 C(O)R 14 , —NHC(O)NR 13 R 14 , —NR 13 C(O)NHR 14 , —C(O)R 13 , —C(O)OR 13 , —C(O)N(R 13 )R 14 , —C(O)N(R 13 )OR 14 , —C(O)N(R 13 )S(O) 2 R 12 , —N(R 13 )S(O) 2 R 12 , —SR 13 , —S(O)R 12 , —S(O) 2 R 12 , and —S(O) 2 N(R 13 )R 14 ; 
         each R 12  is independently selected from C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-8  cycloalkyl-(CH 2 ) m —, C 6-14  aryl-(CH 2 ) m —, C 2-6  heterocyclyl-(CH 2 ) m —, and C 1-9  heteroaryl-(CH 2 ) m —, each optionally substituted with from one to five substituents independently selected from halo, oxo, —CN, C 1-6  alkyl, C 1-6  haloalkyl, and R 15 ; 
         each R 13  and R 14  is independently selected from
 (a) hydrogen; and 
 (b) C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-6  cycloalkyl-(CH 2 ) m —, C 6-14  aryl-(CH 2 ) m —, C 2-6  heterocyclyl-(CH 2 ) m —, and C 1-9  heteroaryl-(CH 2 ) m —, each optionally substituted with from one to five substituents independently selected from halo, oxo, —CN, C 1-6  alkyl, C 1-6  haloalkyl, and R′5; 
 
         each R 15  is independently selected
 from —OR 16 , —N(R 16 )R 17 , —N(R 16 )C(O)R 17 , —NHC(O)NR 16 R 17 , —NR 16 C(O)NHR 17 , —C(O)R 16 , —C(O)OR 16 , —C(O)N(R 16 )R 17 , —C(O)N(R 16 )OR 17 , —C(O)N(R 16 )S(O) 2 R 18 , —NR 16 S(O) 2 R 18 , —SR 16 , —S(O)R 18 , —S(O) 2 R 18 , and —S(O) 2 N(R 16 )R 17 ; 
 
         each R 16  and R 17  is independently selected from hydrogen, C 1-6  alkyl, and C 3-6  cycloalkyl; 
         each R 18  is independently selected from C 1-6  alkyl and C 3-6  cycloalkyl; 
         each m is independently selected from 0, 1, 2, 3, and 4; 
         wherein each of the aforementioned heteroaryl moieties independently has 1 to 4 heteroatoms independently selected from N, O, and S, and each of the aforementioned heterocyclyl moieties independently has 1 to 4 heteroatoms independently selected from N, O, and S; and 
         wherein the disease, disorder or condition is selected from allergic rhinitis, asthma, atopic dermatitis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, psoriasis, immune thrombocytopenic purpura, inflammatory bowel disease, behcet's disease, graft-versus-host disease (GVHD), chronic obstructive pulmonary disease, atherosclerosis, myocardial infarction, and thrombosis. 
       
     
     
         2 . A method according to  claim 1 , wherein R 1  is selected from pyrazolyl, thiazolyl, isoxazolyl, phenyl, pyridinyl, azetidinyl, 1,2-dihydropyridinyl, piperidinyl, tetrahydropyranyl, morpholinyl, and 2-oxa-6-azaspiro[3.3]heptanyl, each optionally substituted. 
     
     
         3 . A method according to  claim 1 , wherein R 1  is selected from pyrazolyl, thiazolyl, isoxazolyl, pyridinyl, azetidinyl, piperidinyl, tetrahydropyranyl, morpholinyl, and 2-oxa-6-azaspiro[3.3]heptanyl, each optionally substituted. 
     
     
         4 . A method according to  claim 1 , wherein R 1  is selected from pyrazolyl, pyridinyl, and morpholinyl, each optionally substituted. 
     
     
         5 . A method according to  claim 1 , wherein R 2 , R 4 , and R 5  are each independently selected from hydrogen and halo. 
     
     
         6 . A method according to  claim 1 , wherein (a) R 2 , R 4 , and R 5  are each hydrogen, (b) R 4  and R 5  are each hydrogen and R 2  is halo, (c) R 2  and R 5  are each hydrogen and R 4  is halo, or (d) R 2  and R 4  are each hydrogen and R 5  is halo. 
     
     
         7 . A method according to  claim 1 , wherein each of R 2  and R 4  is hydrogen. 
     
     
         8 . A method according to  claim 1 , wherein R 3  is C 1-3  alkyl or C 1-3  haloalkyl. 
     
     
         9 . A method according to  claim 8 , wherein R 3  is methyl. 
     
     
         10 . A method according to  claim 1 , wherein one of R 6  and R 7  is hydrogen. 
     
     
         11 . A method according to  claim 10 , wherein one of R 6  and R 7  is C 1-3  alkyl. 
     
     
         12 . A method according to  claim 1 , wherein R 8  is selected from methyl and —NH 2 . 
     
     
         13 . A method according to  claim 1 , wherein R 9  is selected from halo, —CN, and C 1-3  haloalkyl. 
     
     
         14 . A method according to  claim 13 , wherein R 9  is —CN. 
     
     
         15 . A method according to  claim 1 , wherein R 8  is —NH—, and R 8  and R 9 , together with the carbon atoms to which they are attached, form a 1H-imidazol-4,5-diyl or a 1H-pyrazol-4,5-diyl, each optionally substituted. 
     
     
         16 . A method according to  claim 1 , wherein R 10  is —NH 2 . 
     
     
         17 . A method according to  claim 1 , wherein the compound is selected from the following compounds:
 (S)-5-Chloro-N 4 -(1-(1-methyl-6-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)pyrimidine-2,4-diamine;   (S)-2,4-Diamino-6-((1-(1-methyl-6-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-2-Amino-4-methyl-6-((1-(1-methyl-6-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-2-Amino-4-((1-(1-methyl-6-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-5-Chloro-N 4 -(1-(1-methyl-6-morpholino-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)pyrimidine-2,4-diamine;   4-Amino-2-methyl-6-((1-(1-methyl-6-morpholino-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-5-Fluoro-N 4 -(1-(1-methyl-6-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)pyrimidine-2,4-diamine;   (S)-4-Amino-2-hydroxy-6-((1-(1-methyl-6-morpholino-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-2-Amino-4-methyl-6-((1-(1-methyl-6-morpholino-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-Diamino-6-((1-(1-methyl-6-morpholino-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-4-Amino-2-hydroxy-6-((1-(1-methyl-6-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-Diamino-6-((1-(1-methyl-6-(pyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-Diamino-6-((1-(1-methyl-6-(1H-pyrazol-5-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)pyrimidine-5-carbonitrile;   2,4-Diamino-6-(((1S)-1-(6-(3,5-dimethyl-1H-pyrazol-4-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-Diamino-6-((1-(6-(2-hydroxypyridin-4-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)—N 6 -(1-(1-Methyl-6-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)-9H-purine-2,6-diamine;   (S)-2,4-Diamino-6-((1-(1-methyl-6-(thiazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)—N 4 -(1-(1-Methyl-6-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine;   (S)-2-Amino-4-methyl-6-((1-(1-methyl-6-(3-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)pyrimidine-5-carbonitrile;   2,4-Diamino-6-((1-(6-(4-hydroxy-4-methylpiperidin-1-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-Diamino-6-((1-(6-(4-hydroxy-4-methylpiperidin-1-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (R)-2,4-Diamino-6-((1-(6-(4-hydroxy-4-methylpiperidin-1-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-2-Amino-4-((1-(6-(2-hydroxypyridin-4-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)-6-methylpyrimidine-5-carbonitrile;   (S)-2-Amino-4-methyl-6-((1-(1-methyl-6-(pyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-2-Amino-4-methyl-6-((1-(1-methyl-6-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-Diamino-6-((1-(1-methyl-6-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)—N 6 -(1-(1-Methyl-6-morpholino-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)-9H-purine-2,6-diamine;   (S)-5-Chloro-N 4 -(1-(1-methyl-6-morpholino-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)pyrimidine-2,4,6-triamine;   2,4-Diamino-6-(((1S)-1-(6-(3,5-dimethylisoxazol-4-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)pyrimidine-5-carbonitrile;   2-Amino-4-(((1S)-1-(6-(3,5-dimethylisoxazol-4-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)-6-methylpyrimidine-5-carbonitrile;   (S)-2,4-Diamino-6-((1-(6-(1-(difluoromethyl)-1H-pyrazol-5-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-5-Chloro-N 4 -(1-(1-methyl-6-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)pyrimidine-2,4,6-triamine;   (S)—N 6 -(1-(1-Methyl-6-(pyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)-9H-purine-2,6-diamine;   (S)-2,4-Diamino-6-((1-(6-(1-cyclopropyl-1H-pyrazol-5-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)—N 6 -(1-(6-(1-Cyclopropyl-1H-pyrazol-5-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)-9H-purine-2,6-diamine;   (S)—N 6 -(1-(6-(1-(Difluoromethyl)-1H-pyrazol-5-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)-9H-purine-2,6-diamine;   5-Chloro-N 4 -(1-(6-(3,3-difluoroazetidin-1-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)pyrimidine-2,4,6-triamine;   2,4-Diamino-6-((1-(6-(3-hydroxyazetidin-1-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)pyrimidine-5-carbonitrile;   1-(5-(1-((2,6-Diamino-5-chloropyrimidin-4-yl)amino)ethyl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)azetidin-3-ol;   (S)-2,4-Diamino-6-((1-(6-(3-methoxyazetidin-1-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)pyrimidine-5-carbonitrile;   2,4-Diamino-6-((1-(6-(3,3-difluoroazetidin-1-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (R)-2,4-Diamino-6-((1-(6-(3,3-difluoroazetidin-1-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-Diamino-6-((1-(6-(3,3-difluoroazetidin-1-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)pyrimidine-5-carbonitrile;   2,4-Diamino-6-((1-(1-methyl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (R)-2,4-Diamino-6-((1-(1-methyl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-Diamino-6-((1-(1-methyl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (R)-2,4-Diamino-6-((1-(1-methyl-6-morpholino-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)pyrimidine-5-carbonitrile;   (S)-2,4-Diamino-6-((1-(3-hydroxy-1-methyl-6-morpholino-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)pyrimidine-5-carbonitrile;   a stereoisomer of any of the aforementioned compounds; and   a pharmaceutically acceptable salt of any of the aforementioned compounds or stereoisomers.   
     
     
         18 - 23 . (canceled) 
     
     
         24 . A method according to  claim 1 , further comprising administering to the subject at least one additional pharmacologically active agent. 
     
     
         25 . (canceled) 
     
     
         26 . A method according to  claim 1 , wherein the compound is (S)-2,4-Diamino-6-((1-(1-methyl-6-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)pyrimidine-5-carbonitrile or a pharmaceutically acceptable salt thereof. 
     
     
         27 . A method according to  claim 1 , wherein the compound is (S)-2-Amino-4-methyl-6-((1-(1-methyl-6-morpholino-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)pyrimidine-5-carbonitrile or a pharmaceutically acceptable salt thereof. 
     
     
         28 . A method according to  claim 1 , wherein the compound is (S)-2,4-Diamino-6-((1-(1-methyl-6-morpholino-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)pyrimidine-5-carbonitrile or a pharmaceutically acceptable salt thereof. 
     
     
         29 . A method according to  claim 1 , wherein the compound is (S)-2,4-Diamino-6-((1-(1-methyl-6-(pyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)pyrimidine-5-carbonitrile or a pharmaceutically acceptable salt thereof. 
     
     
         30 . A method according to  claim 1 , wherein the compound is (S)-2,4-Diamino-6-((1-(1-methyl-6-(1H-pyrazol-5-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)pyrimidine-5-carbonitrile or a pharmaceutically acceptable salt thereof. 
     
     
         31 . A method according to  claim 1 , wherein the compound is (S)-2,4-Diamino-6-((1-(6-(2-hydroxypyridin-4-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)pyrimidine-5-carbonitrile or a pharmaceutically acceptable salt thereof. 
     
     
         32 . A method according to  claim 1 , wherein the compound is (S)-2,4-Diamino-6-((1-(1-methyl-6-(thiazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)pyrimidine-5-carbonitrile or a pharmaceutically acceptable salt thereof. 
     
     
         33 . A method according to  claim 1 , wherein the compound is (S)-2-Amino-4-((1-(6-(2-hydroxypyridin-4-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)-6-methylpyrimidine-5-carbonitrile or a pharmaceutically acceptable salt thereof. 
     
     
         34 . A method according to  claim 1 , wherein the compound is (S)-2-Amino-4-methyl-6-((1-(1-methyl-6-(pyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)pyrimidine-5-carbonitrile or a pharmaceutically acceptable salt thereof. 
     
     
         35 . A method according to  claim 1 , wherein the compound is (S)-2-Amino-4-methyl-6-((1-(1-methyl-6-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)pyrimidine-5-carbonitrile or a pharmaceutically acceptable salt thereof. 
     
     
         36 . A method according to  claim 1 , wherein the compound is (S)-2,4-Diamino-6-((1-(1-methyl-6-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)pyrimidine-5-carbonitrile or a pharmaceutically acceptable salt thereof. 
     
     
         37 . A method according to  claim 1 , wherein the compound is 2,4-Diamino-6-(((1S)-1-(6-(3,5-dimethylisoxazol-4-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)pyrimidine-5-carbonitrile or a pharmaceutically acceptable salt thereof. 
     
     
         38 . A method according to  claim 1 , wherein the compound is (S)-2,4-Diamino-6-((1-(6-(1-(difluoromethyl)-1H-pyrazol-5-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)pyrimidine-5-carbonitrile or a pharmaceutically acceptable salt thereof. 
     
     
         39 . A method according to  claim 1 , wherein the compound is (S)-2,4-Diamino-6-((1-(6-(3-methoxyazetidin-1-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)pyrimidine-5-carbonitrile or a pharmaceutically acceptable salt thereof. 
     
     
         40 . A method according to  claim 1 , wherein the compound is (S)-2,4-Diamino-6-((1-(6-(3,3-difluoroazetidin-1-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)pyrimidine-5-carbonitrile or a pharmaceutically acceptable salt thereof.