	US 7,488,826 B2
	Substituted pyrroline kinase inhibitors
Han-Cheng Zhang, Landsale, Pa. (US); Bruce E. Maryanoff, Forest Grove, Pa. (US); and Hong Ye, Lansdale, Pa. (US)
Assigned to Janssen Pharmaceutica N.V., (Belgium)
Filed on Mar. 03, 2004, as Appl. No. 10/792,522.
Claims priority of provisional application 60/458127, filed on Mar. 27, 2003.
Prior Publication US 2004/0192718 A1, Sep. 30, 2004
Int. Cl. C07D 471/04 (2006.01)

U.S. Cl. 546—113

31 Claims

1. A compound of Formula (I):

wherein

R is selected from the group consisting of R_a, —C_1-8alkyl-R_a, —C_2-8alkenyl-R_a, —C_2-8alkynyl-R_aand cyano;

R_ais selected from the group consisting of dihydro-pyranyl, phenyl, naphthyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, azaindolyl, indazolyl, benzofuryl, benzothienyl, dibenzofuryl and dibenzothienyl;

R¹is selected from the group consisting of hydrogen, —C_1-8alkyl-R⁵, —C_2-8alkenyl-R⁵, —C_2-8alkynyl-R⁵, —C(O)—(C_1-8)alkyl-R⁹, —C(O)-aryl-R⁸, —C(O)—O—(C_1-8)alkyl-R⁹, —C(O)—O-aryl-R⁸, —C(O)—NH(C_1-8alkyl-R⁹), —C(O)—NH(aryl-R⁸), —C(O)—N(C_1-8alkyl-R⁹)₂, —SO₂—(C_1-8)alkyl-R⁹, —SO₂-aryl-R⁸, -cycloalkyl-R⁶, and aryl-R⁶;

R⁵is 1 to 2 substituents independently selected from the group consisting of hydrogen, —O—(C_1-8)alkyl, —O—(C_1-8)alkyl-OH, —O—(C_1-8)alkyl-O—(C_1-8)alkyl, —O—(C_1-8)alkyl-NH₂, —O—(C_1-8)alkyl-NH(C_1-8alkyl), —O—(C_1-8)alkyl-N(C_1-8alkyl)₂, —O—(C_1-8)alkyl-S—(C_1-8)alkyl, —O—(C_1-8)alkyl-SO₂—(C_1-8)alkyl, —O—(C_1-8)alkyl-SO₂—NH₂, —O—(C_1-8)alkyl-SO₂—NH(C_1-8alkyl), —O—(C_1-8)alkyl-SO₂—N(C_1-8alkyl)₂, —O—C(O)H, —O—C(O)—(C_1-8)alkyl, —O—C(O)—NH₂, —O—C(O)—NH(C_1-8alkyl), —O—C(O)—N(C_1-8alkyl)₂, —O—(C_1-8)alkyl-C(O)H, —O—(C_1-8)alkyl-C(O)—(C_1-8)alkyl, —O—(C_1-8)alkyl-CO₂H, —O—(C_1-8)alkyl-C(O)—O—(C_1-8)alkyl, —O—(C_1-8)alkyl-C(O)—NH₂, —O—(C_1-8)alkyl-C(O)—NH(C_1-8alkyl), —O—(C_1-8)alkyl-C(O)—N(C_1-8alkyl)₂, —C(O)H, —C(O)—(C_1-8)alkyl, —CO₂H, —C(O)—O—(C_1-8)alkyl, —C(O)—NH₂, —C(NH)—NH₂, —C(O)—NH(C_1-8alkyl), —C(O)—N(C_1-8alkyl)₂, —SH, —S—(C_1-8)alkyl, —S—(C_1-8)alkyl-S—(C_1-8)alkyl, —S—(C_1-8)alkyl-O—(C_1-8)alkyl, —S—(C_1-8)alkyl-O—(C_1-8)alkyl-OH, —S—(C_1-8)alkyl-O—(C_1-8)alkyl-NH₂, —S—(C_1-8)alkyl-O—(C_1-8)alkyl-NH(C_1-8alkyl), —S—(C_1-8)alkyl-O—(C_1-8)alkyl-N(C_1-8alkyl)₂, —S—(C_1-8)alkyl-NH(C_1-8alkyl), —SO₂—(C_1-8)alkyl, —SO₂—NH₂, —SO₂—NH(C_1-8alkyl), —SO₂—N(C_1-8alkyl)₂, —N—R⁷, cyano, (halo)_1-3, hydroxy, nitro, oxo, -cycloalkyl-R⁶, and -aryl-R⁶;

R⁶is 1 to 4 substituents attached to a carbon or nitrogen atom independently selected from the group consisting of hydrogen, —C_1-8alkyl, —C_2-8alkenyl, —C_2-8alkynyl, —C(O)H, —C(O)—(C_1-8)alkyl, —CO₂H, —C(O)—O—(C_1-8)alkyl, —C(O)—NH₂, —C(NH)—NH₂, —C(O)—NH(C_1-8alkyl), —C(O)—N(C_1-8)alkyl)₂, —SO₂—(C_1-8)alkyl, —SO₂—NH₂, —SO₂—NH(C_1-8alkyl), —SO₂—N(C_1-8alkyl)₂, —(C_1-8)alkyl-N—R⁷, —(C_1-8)alkyl-(halo)_1-3, —(C_1-8)alkyl-OH, -aryl-R⁸, and —(C_1-8)alkyl-aryl-R⁸;

with the proviso that, when R⁶is attached to a carbon atom, R⁶is further selected from the group consisting of —C_1-8alkoxy, —(C_1-8)alkoxy-(halo)_1-3, —SH, —S—(C_1-8)alkyl, —N—R⁷, cyano, halo, hydroxy, nitro and oxo;

R⁷is 2 substituents independently selected from the group consisting of hydrogen, —C_1-8alkyl, —C_2-8alkenyl, —C_2-8alkynyl, —(C_1-8)alkyl-OH, —(C_1-8)alkyl-O—(C_1-8)alkyl, —(C_1-8)alkyl-NH₂, —(C_1-8)alkyl-NH(C_1-8alkyl), —(C_1-8)alkyl-N(C_1-8alkyl)₂, —(C_1-8)alkyl-S—(C_1-8)alkyl, —C(O)H, —C(O)—(C_1-8)alkyl, —C(O)—O—(C_1-8)alkyl, —C(O)—NH₂, —C(O)—NH(C_1-8alkyl), —C(O)—N(C_1-8alkyl)₂, —SO₂—(C_1-8)alkyl, —SO₂—NH₂, —SO₂—NH(C_1-8alkyl), —SO₂—N(C_1-8alkyl)₂, —C(N)—NH₂, -cycloalkyl-R⁸, -aryl-R⁸and —(C_1-8)alkyl-aryl-R⁸;

R⁸is 1 to 4 substituents attached to a carbon or nitrogen atom independently selected from the group consisting of hydrogen, —C_1-8alkyl, —(C_1-8)alkyl-(halo)_1-3and —(C_1-8)alkyl-OH;

with the proviso that, when R⁸is attached to a carbon atom, R⁸is further selected from the group consisting of —C_1-8alkoxy, —NH₂, —NH(C_1-8alkyl), —N(C_1-8alkyl)₂, cyano, halo, —(C_1-8)alkoxy-(halo)_1-3, hydroxy and nitro;

R⁹is 1 to 2 substituents independently selected from the group consisting of hydrogen, —C_1-8alkoxy, —NH₂, —NH(C_1-8alkyl), —N(C_1-8alkyl)₂, cyano, (halo)_1-3, hydroxy and nitro;

R²is one substituent attached to a carbon or nitrogen atom selected from the group consisting of hydrogen, —C_1-8alkyl-R⁵, —C_2-8alkenyl-R⁵, —C_2-8alkynyl-R⁵, —C(O)H, —C(O)—(C_1-8)alkyl-R⁹, —C(O)—NH₂, —C(O)—NH(C_1-8alkyl-R⁹), —C(O)—N (C_1-8alkyl-R⁹)₂, —C(O)—NH(aryl-R⁸), —C(O)-cycloalkyl-R⁸, —C(O)-aryl-R⁸, —CO₂H, —C(O)—O—(C_1-8)alkyl-R⁹, —C(O)-aryl-R⁸, —SO₂—(C_1-8)alkyl-R⁹, —SO₂-aryl-R⁸, -cycloalkyl-R⁶, -aryl-R⁶and —(C_1-8)alkyl-N—R⁷;

with the proviso that, when R²is attached to a carbon atom, R²is further selected from the group consisting of —C_1-8alkoxy-R⁵, —N—R⁷, cyano, halogen, hydroxy, nitro and oxo;

R³is 1 to 3 substituents attached to a carbon atom independently selected from the group consisting of hydrogen, —C_1-8alkyl-R¹⁰, —C_2-8alkenyl-R¹⁰, —C_2-8alkynyl-R¹⁰, —C_1-8alkoxy-R¹⁰, —C(O)H, —C(O)—(C_1-8)alkyl-R⁹, —C(O)—NH₂, —C(O)—NH(C_1-8alkyl-R⁹), —C(O)—N(C_1-8alkyl-R⁹)₂, —C(O)-cycloalkyl-R⁸, —C(O)-aryl-R⁸, —C(NH)—NH₂, —CO₂H, —C(O)—O—(C_1-8)alkyl-R⁹, —C(O)—O-aryl-R⁸, —SO₂—(C_1-8)alkyl-R⁹, —SO₂-aryl-R⁸, —N—R⁷, cyano, halogen, hydroxy, nitro, -cycloalkyl-R⁸and -aryl-R⁶;

R⁴is 1 to 4 substituents attached to a carbon atom independently selected from the group consisting of hydrogen, —C_1-8alkyl-R¹⁰, —C_2-8alkenyl-R¹⁰, —C_2-8alkynyl-R¹⁰, —C_1-8alkoxy-R¹⁰, —C(O)H, —C(O)—(C_1-8)alkyl-R⁹, —C(O)—NH₂, —C(O)—NH(C_1-8alkyl-R⁹), —C(O)—N(C_1-8alkyl-R⁹)₂, —C(O)-cycloalkyl-R⁸, —C(O)-aryl-R⁸, —C(NH)—NH₂, —CO₂H, —C(O)—O—(C_1-8)alkyl-R⁹, —C(O)—O-aryl-R⁸, —SH, —S—(C_1-8)alkyl-R¹⁰, —SO₂—(C_1-8)alkyl-R⁹, —SO₂-aryl-R⁸, —SO₂—NH₂, —SO₂—NH(C_1-8alkyl-R⁹), —SO₂—N(C_1-8alkyl-R⁹)₂, —N—R⁷, cyano, halogen, hydroxy, nitro, -cycloalkyl-R⁸, and -aryl-R⁶;

R¹⁰is 1 to 2 substituents independently selected from the group consisting of hydrogen, —NH₂, —NH(C_1-8alkyl), —N(C_1-8alkyl)₂, cyano, (halo)_1-3, hydroxy, nitro and oxo; and,

Y and Z are independently selected from the group consisting of O, S, (H,OH) and (H,H); with the proviso that one of Y and Z is O and the other is selected from the group consisting of O, S, (H,OH) and (H,H);

or a pharmaceutically acceptable salt thereof.