FUSED HETEROAROMATIC PYRROLIDINONES
Disclosed are compounds of Formula 1, and pharmaceutically acceptable salts thereof, wherein G, L 1 , L 2 , R 1 , R 2 , R 3 , and R 4 are defined in the specification. This disclosure also relates to materials and methods for preparing compounds of Formula 1, pharmaceutical compositions containing them, and their use for treating disorders, diseases, and conditions involving the immune system and inflammation, including rheumatoid arthritis, hematological malignancies, epithelial cancers (i.e., carcinomas), and other disorders, diseases, and conditions for which inhibition of SYK is indicated.
1 . A compound of Formula 1,
or a pharmaceutically acceptable salt thereof, wherein:
G is selected from N and C(R 5 );
L 1 and L 2 are each independently selected from —NH— and a bond;
R 1 and R 2 are each independently selected from hydrogen, halo, C 1-3 alkyl, and C 1-3 haloalkyl, or R 1 and R 2 , together with the atom to which they are attached, form a C 3-6 cycloalkyl;
R 3 is selected from C 2-6 alkyl, C 3-8 cycloalkyl, C 2-5 heterocyclyl, and C 1-9 heteroaryl, each optionally substituted with from one to five substituents independently selected from halo, oxo, —NO 2 , —CN, R 6 , and R 7 ;
R 4 is selected from C 3-8 cycloalkyl, C 2-5 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 6 , and R 7 ;
R 5 is selected from hydrogen, halo, —CN, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 2-5 heterocyclyl, C 1-5 heteroaryl, and R 10 , wherein the alkyl, alkenyl, alkynyl moieties are each optionally substituted with from one to five substituents independently selected from halo, —CN, oxo, and R 10 , and wherein the heterocyclyl moiety has 3 to 6 ring atoms and the heteroaryl moiety has 5 or 6 ring atoms, and the heterocyclyl and heteroaryl moieties are each optionally substituted with from one to four substituents independently selected from halo, —NO 2 , —CN, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, and R 10 ;
each R 6 is independently selected from —OR 8 , —N(R 8 )R 9 , —NR 8 C(O)R 9 , —C(O)R 8 , —C(O)OR 8 , —C(O)N(R 8 )R 9 , —C(O)N(R 8 )OR 9 , —C(O)N(R 8 )S(O) 2 R 9 , —N(R 8 )S(O) 2 R 9 , —S(O) n R 8 , and —S(O) 2 N(R 8 )R 9 ;
each R 7 is independently selected from 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 2-5 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, —NO 2 , —CN, C 1-6 alkyl, C 1-6 haloalkyl, and R 10 ;
each R 8 and R 9 is independently selected from hydrogen or from 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 2-5 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, —NO 2 , —CN, C 1-6 alkyl, C 1-6 haloalkyl, and R 10 ;
each R 10 is independently selected from —OR 11 , —N(R 11 )R 12 , —N(R 11 )C(O)R 12 , —C(O)R 11 , —C(O)OR 11 , —C(O)N(R 11 )R 12 , —C(O)N(R 11 )OR 12 , —C(O)N(R 11 )S(O) 2 R 12 , —NR 11 S(O) 2 R 12 , —S(O) n R 11 , and —S(O) 2 N(R 11 )R 12 ;
each R 11 and R 12 is independently selected from hydrogen and C 1-6 alkyl;
each n is independently selected from 0, 1 and 2; and
each m is independently selected from 0, 1, 2, 3, and 4;
wherein each of the aforementioned heteroaryl moieties has one to four heteroatoms independently selected from N, O, and S, and each of the aforementioned heterocyclyl moieties is saturated or partially unsaturated and has one or two heteroatoms independently selected from N, O, and S.
2 - 35 . (canceled)
36 . A method of treating a disease or condition in a subject for which a SYK inhibitor is indicated, the method comprising administering to the subject an effective amount of a compound or pharmaceutically acceptable salt as defined in claim 1 .
37 . A method of treating a disease or condition in a subject, the method comprising administering to the subject an effective amount of a compound or pharmaceutically acceptable salt as defined in claim 1 , wherein the disease or condition is selected from allergic rhinitis, allergic asthma, atopic dermatitis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, psoriasis, immune thrombocytopenic purpura, inflammatory bowel disease, chronic obstructive pulmonary disease, and thrombosis.
38 . A method of treating a disease or condition in a subject, the method comprising administering to the subject an effective amount of a compound or pharmaceutically acceptable salt as defined in claim 1 , wherein the disease or condition is selected from a hematological malignancy and an epithelial cancer.
39 - 43 . (canceled)
44 . A method of making a compound of Formula 9-5,
or a pharmaceutically acceptable salt thereof, the method comprising treating a compound of Formula 11-6,
with an acid to give a compound of Formula 9-5, and
optionally converting the compound of Formula 9-5 to a pharmaceutically acceptable salt, wherein:
R 3 is selected from C 2-6 alkyl, C 3-8 cycloalkyl, C 2-5 heterocyclyl, and C 1-9 heteroaryl, each optionally substituted with from one to five substituents independently selected from halo, oxo, —NO 2 , —CN, R 6 , and R 7 ;
R 4 is selected from C 3-8 cycloalkyl, C 2-5 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 6 , and R 7 ;
each R 6 is independently selected from —OR 8 , —N(R 8 )R 9 , —NR 8 C(O)R 9 , —C(O)R 8 , —C(O)OR 8 , —C(O)N(R 8 )R 9 , —C(O)N(R 8 )OR 9 , —C(O)N(R 8 )S(O) 2 R 9 , —N(R 8 )S(O) 2 R 9 , —S(O) n R 8 , and —S(O) 2 N(R 8 )R 9 ;
each R 7 is independently selected from 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 2-5 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, —NO 2 , —CN, C 1-6 alkyl, C 1-6 haloalkyl, and R 10 ;
each R 8 and R 9 is independently selected from hydrogen or from 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 2-5 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, —NO 2 , —CN, C 1-6 alkyl, C 1-6 haloalkyl, and R 10 ;
each R 10 is independently selected from —OR 11 , —N(R 11 )R 12 , —N(R 11 )C(O)R 12 , —C(O)R 11 , —C(O)OR 11 , —C(O)N(R 11 )R 12 , —C(O)N(R 11 )OR 12 , —C(O)N(R 11 )S(O) 2 R 12 , —NR 11 S(O) 2 R 12 , —S(O) n R 11 , and —S(O) 2 N(R 11 )R 12 ;
each R 11 and R 12 is independently selected from hydrogen and C 1-6 alkyl;
each n is independently selected from 0, 1 and 2; and
each m is independently selected from 0, 1, 2, 3, and 4;
wherein each of the aforementioned heteroaryl moieties has one to four heteroatoms independently selected from N, O, and S, and each of the aforementioned heterocyclyl moieties is saturated or partially unsaturated and has one or two heteroatoms independently selected from N, O, and S.
45 . The method according to claim 44 , wherein R 3 is 2-amino-cyclohex-1-yl optionally substituted with from one to four substituents independently selected from halo, oxo, —NO 2 , —CN, R 6 , and R 7 .
46 . The method according to claim 44 , wherein R 3 is 3-aminotetrahydro-2H-pyran-4-yl optionally substituted with from one to four substituents independently selected from halo, oxo, —NO 2 , —CN, R 6 , and R 7 .
47 . The method according to claim 44 , wherein R 4 is C 1-9 heteroaryl optionally substituted with from one to five substituents independently selected from halo, oxo, —CN, R 6 , and R 7 .
48 . The method according to claim 47 , wherein R 4 is selected from pyrrolyl, furanyl, thiopheneyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, and thiazolyl, each optionally substituted with from one to three substituents independently selected from halo, —CN, R 6 , and R 7 .
49 . The method according to claim 48 , wherein R 4 is pyrazol-4-yl optionally substituted with from one to three substituents independently selected from halo, —CN, R 6 , and R 7 .
50 . The method according to claim 49 , wherein R 4 is substituted with methyl, ethyl, cyclopropyl or C 1-2 haloalkyl.