Pyrrolo[2,3-D]pyrimidine compounds
View Patent ↗A compound of the formula wherein R 1 , R 2 and R 3 are as defined above, which are inhibitors of the enzyme protein kinases such as Janus Kinase 3 and as such are useful therapy as immunosuppressive agents for organ transplants, xeno transplation, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type I diabetes and complications from diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer's disease, Leukemia and other autoimmune diseases.
1. A compound of the formula
or a pharmaceutically acceptable salt thereof; wherein
R 1 is a group of the formula
wherein y is 0, 1 or 2;
R 4 is selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfonyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl wherein the alkyl, alkenyl and alkynyl groups are optionally substituted by deuterium, hydroxy, amino, trifluoromethyl, (C 1 -C 4 )alkoxy, (C 1 -C 6 )acyloxy, (C 1 -C 6 )alkylamino, ((C 1 -C 6 )alkyl) 2 amino, cyano, nitro, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl or (C 1 -C 6 )acylamino; or R 4 is (C 3 -C 10 )cycloalkyl wherein the cycloalkyl group is optionally substituted by deuterium, hydroxy, amino, trifluoromethyl, (C 1 -C 6 )acyloxy, (C 1 -C 6 )acylamino, (C 1 -C 6 )alkylamino, ((C 1 -C 6 )alkyl) 2 amino, cyano, cyano(C 1 -C 6 )alkyl trifluoromethyl(C 1 -C 6 )alkyl, nitro, nitro(C 1 -C 6 )alkyl or (C 1 -C 6 )acylamino;
R 5 is a piperidinyl substituted by one to five carboxy, cyano, amino, deuterium, hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo, (C 1 -C 6 )acyl, (C 1 -C 6 )alkylamino, amino((C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy-CO—NH, (C 1 -C 6 )alkylamino-CO—, (C 2 -C 6 )alkenyl, (C 2 -C 6 ) alkynyl, (C 1 -C 6 )alkylamino, amino(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy((C 1 -C 6 )alkyl, (C 1 -C 6 )acyloxy((C 1 -C 6 )alkyl, nitro, cyano(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, nitro((C 1 -C 6 )alkyl, trifluoromethyl, trifluoromethyl(C 1 -C 6 )alkyl, (C 1 -C 6 )acylamino, (C 1 -C 6 )acylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )acylamino, amino(C 1 -C 6 )acyl, amino((C 1 -C 6 )acyl((C 1 -C 6 )alkyl, (C 1 -C 6 )alkylamino(C 1 -C 6 )acyl, ((C 1 -C 6 )alkyl) 2 amino(C 1 -C 6 )acyl, R 15 R 16 N—CO—O—, R 15 R 16 N—CO—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-S(O) m , R 15 R 16 NS(O) m , R 15 R 16 NS(O) m (C 1 -C 6 )alkyl, R 15 S(O) m R 16 N, R 15 S(O) m R 16 N(C 1 -C 6 )alkyl wherein m is 0, 1 or 2 and R 15 and R 16 are each independently selected from hydrogen or (C 1 -C 6 )alkyl; or a group of the formula
wherein a is 0, 1, 2, 3 or 4;
b, c, e, f and g are each independently 0 or 1;
d is 0, 1, 2, or 3;
X is S(O) n wherein n is 0, 1 or 2; oxygen, carbonyl or —C(═N-cyano)-;
Y is S(O) n wherein n is 0, 1 or 2; or carbonyl; and
Z is carbonyl, C(O)O—, C(O)NR— or S(O) n wherein n is 0, 1 or 2;
R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are each independently selected from the group consisting of hydrogen or (C 1 -C 6 )alkyl optionally substituted by deuterium, hydroxy, amino, trifluoromethyl, (C 1 -C 6 )acyloxy, (C 1 -C 6 )acylamino, (C 1 -C 6 )alkylamino, ((C 1 -C 6 )alkyl) 2 amino, cyano, cyano(C 1 -C 6 )alkyl, trifluoromethyl(C 1 -C 6 )alkyl, nitro, nitro(C 1 -C 6 )alkyl or (C 1 -C 6 )acylamino;
R 12 is carboxy, cyano, amino, oxo, deuterium, hydroxy, trifluoromethyl, (C 1 -C 6 )alkyl, trifluoromethyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo, (C 1 -C 6 )acyl, (C 1 -C 6 )alkylamino, ((C 1 -C 6 )alkyl) 2 amino, amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy-CO—NH, (C 1 -C 6 )alkylamino-CO—, (C 2 -C 6 )alkenyl, (C 2 -C 6 ) alkynyl, (C 1 -C 6 )alkylamino, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )acyloxy((C 1 -C 6 )alkyl, nitro, cyano(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, nitro( (C 1 -C 6 )alkyl, trifluoromethyl, trifluoromethyl(C 1 -C 6 )alkyl, (C 1 -C 6 )acylamino, (C 1 -C 6 )acylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )acylamino, amino(C 1 -C 6 )acyl, amino((C 1 -C 6 )acyl((C 1 -C 6 )alkyl, (C 1 -C 6 )alkylamino(C 1 -C 6 )acyl, ((C 1 -C 6 )alkyl) 2 amino(C 1 -C 6 )acyl, R 15 R 16 N—CO—O—, R 15 R 16 N—CO—(C 1 -C 6 )alkyl, R 15 C(O)NH, R 15 OC(O)NH, R 15 NHC(O)NH, (C 1 -C 6 )alkyl-S(O) m , (C 1 -C 6 )alkyl-S(O) m —(C 1 -C 6 )alkyl, R 15 R 16 NS(O) m , R 15 R 16 NS(O) m (C 1 -C 6 )alkyl, R 15 S(O) m R 16 N, R 15 S(O) m R 16 N(C 1 -C 6 )alkyl wherein m is 0, 1 or 2 and R 15 and R 16 are each independently selected from hydrogen or (C 1 -C 6 )alkyl;
R 2 and R 3 are each hydrogen.
2. A compound of the formula
or a pharmaceutically acceptable salt thereof wherein
R 1 is a group of the formula
wherein y is 0;
R 4 is (C 1 -C 6 )alkyl;
R 5 is piperidinyl substituted by one to five carboxy, cyano, amino, deuterium, hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo, (C 1 -C 6 )acyl, (C 1 -C 6 )alkylamino, amino( (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy-CO—NH, (C 1 -C 6 )alkylamino-CO—, (C 2 -C 6 )alkenyl, (C 2 -C 6 ) alkynyl, (C 1 -C 6 )alkylamino, amino(C 1 -C 6 )alkyl, hydroxy( (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )acyloxy( (C 1 -C 6 )alkyl, nitro, cyano(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, nitro(C 1 -C 6 )alkyl, trifluoromethyl, trifluoromethyl(C 1 -C 6 )alkyl, (C 1 -C 6 )acylamino, (C 1 -C 6 )acylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )acylamino, amino(C 1 -C 6 )acyl, amino(C 1 -C 6 )acyl((C 1 -C 6 )alkyl, (C 1 -C 6 )alkylamino( (C 1 -C 6 )acyl, ((C 1 -C 6 )alkyl) 2 amino(C 1 -C 6 )acyl, R 15 R 16 N—CO—O—, R 15 R 16 N—CO—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-S(O) m , R 15 R 16 NS(O) m , R 15 R 16 NS(O) m( (C 1 -C 6 )alkyl, R 15 S(O) m R 16 N, R 15 S(O) m R 16 N(C 1 -C 6 )alkyl, or a group of the formula
wherein:
m is 0, 1 or 2;
R 15 and R 16 are each independently selected from hydrogen or (C 1 -C 6 )alkyl;
d is 1;
R 9 and R 10 are each independently selected from the group consisting of hydrogen or (C 1 -C 6 )alkyl optionally substituted by deuterium, hydroxy, amino, trifluoromethyl, (C 1 -C 6 )acyloxy, (C 1 -C 6 )acylamino, (C 1 -C 6 )alkylamino, ((C 1 -C 6 )alkyl) 2 amino, cyano, cyano( (C 1 -C 6 )alkyl, trifluoromethyl(C 1 -C 6 )alkyl, nitro, nitro(C 1 -C 6 )alkyl or (C 1 -C 6 )acylamino;
R 12 is cyano, trifluoromethyl, (C 1 -C 6 )alkyl, trifluoromethyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylamino, ((C 1 -C 6 )alkyl) 2 amino, (C 2 -C 6 )alkynyl, cyano(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-S(O) m wherein m is 0, 1 or 2; and
R 2 and R 3 are each H.
3. A compound selected from the group consisting of:
Methyl-[4-methyl-1-(propane-1-sulfonyl)-piperidin-3-yl]-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine;
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid methyl ester;
3,3,3-Trifluoro-1-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-propan-1-one;
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid dimethylamide;
3-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile;
3,3,3-Trifluoro-1-{4-methyl-3-[methyl-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-propan-1-one;
1-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-but-3-yn-1-one;
1-{3-[(5-Chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-methyl-amino]-4-methyl-piperidin-1-yl}-propan-1-one; and
1-{3-[(5-Fluoro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-methyl-amino]-4-methyl-piperidin-1-yl}-propan-1-one.
4. A compound of claim 3 , wherein said compound is 3-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile, or a pharmaceutically acceptable salt thereof.