Substituted pyrroline kinase inhibitors

A compound of Formula (I):

• wherein
• R is a 6-membered heterocyclyl;
• R1 is selected from the group consisting of hydrogen, —C1-8alkyl-R5, —C2-8alkenyl-R5, —C2-8alkynyl-R5, —C(O)—(C1-8)alkyl-R9, —C(O)-aryl-R8, —C(O)—O—(C1-8)alkyl-R9, —C(O)—O-aryl-R8, —C(O)—NH(C1-8alkyl-R9), —C(O)—NH(aryl-R8), —C(O)—N(C1-8alkyl-R9)2, —SO2—(C1-8)alkyl-R9, —SO2-aryl-R8, -cycloalkyl-R6, -heterocyclyl-R6, -aryl-R6 and -heteroaryl-R6;
• wherein heterocyclyl and heteroaryl are attached to the azaindole nitrogen atom in the one position via a heterocyclyl or heteroaryl ring carbon atom;
• R2 is one substituent attached to a carbon or nitrogen atom selected from the group consisting of hydrogen, —C1-8alkyl-R5, —C2-8alkenyl-R5, —C1-8alkynyl-R5, —C(O)H, —C(O)—(C1-8)alkyl-R9, —C(O)—NH2, —C(O)—NH(C1-8alkyl-R9), —C(O)—N(C1-8alkyl-R9)2, —C(O)—NH(aryl-R8), —C(O)-cycloalkyl-R8, —C(O)-heterocyclyl-R8, —C(O)-aryl-R8, —C(O)-heteroaryl-R8, —CO2H, —C(O)—O—(C1-8)alkyl-R9, —C(O)—O-aryl-R8, —SO2—(C1-8)alkyl-R9, —SO2-aryl-R8, -cycloalkyl-R6, -aryl-R6 and —(C1-8)alkyl-N—R7;
• with the proviso that, when R2 is attached to a carbon atom, R2 is further selected from the group consisting of —C1-8alkoxy-R5, —N—R7, cyano, halogen, hydroxy, nitro, oxo, -heterocyclyl-R6 and -heteroaryl-R6;
• R3 is 1 to 3 substituents attached to a carbon atom independently selected from the group consisting of hydrogen, —C1-8alkyl-R10, —C2-8alkenyl-R10, —C2-8alkynyl-R10, —C1-8alkoxy-R10, —C(O)H, —C(O)—(C1-8)alkyl-R9, —C(O)—NH2, —C(O)—NH(C1-8alkyl-R9), —C(O)—N(C1-8alkyl-R9)2, —C(O)-cycloalkyl-R8, —C(O)-heterocyclyl-R8, —C(O)-aryl-R8, —C(O)-heteroaryl-R8, —C(NH)—NH2, —CO2H, —C(O)—O—(C1-8)alkyl-R9, —C(O)—O-aryl-R8, —SO2-(C1-8)alkyl-R9, —SO2-aryl-R8, —N—R7, cyano, halogen, hydroxy, nitro, -cycloalkyl-R8, -heterocyclyl-R8, -aryl-R8 and -heteroaryl-R8;
• R4 is 1 to 4 substituents attached to a carbon atom independently selected from the group consisting of hydrogen, —C1-8alkyl-R10, —C2-8alkenyl-R10, —C2-8alkynyl-R10, —C1-8alkoxy-R10, —C(O)H, —C(O)—(C1-8)alkyl-R9, —C(O)—NH2, —C(O)—NH(C1-8alkyl-R9), —C(O)—N(C1-8alkyl-R9)2, —C(O)-cycloalkyl-R8, —C(O)-heterocyclyl-R8, —C(O)-aryl-R8, —C(O)-heteroaryl-R8, —C(NH)—NH2, —CO2H, —C(O)—O—(C1-8)alkyl-R9, —C(O)—O-aryl-R8, —SH, —S—(C1-8)alkyl-R10, —SO2—(C1-8)alkyl-R9, —SO2-aryl-R8, —SO2—NH2, —SO2—NH(C1-8alkyl-R9), —SO2—N(C1-8alkyl-R9)2, —N—R7, cyano, halogen, hydroxy, nitro, -cycloalkyl-R8, -heterocyclyl-R8, -aryl-R8 and -heteroaryl-R8;
• R5 is 1 to 2 substituents independently selected from the group consisting of hydrogen, —O—(C1-8)alkyl, —O-aryl-R6, —O—(C1-8)alkyl-OH, —O—(C1-8)alkyl-O—(C1-8)alkyl, —O—(C1-8)alkyl-NH2, —O—(C1-8)alkyl-NH(C1-8alkyl), —O—(C1-8)alkyl-N(C1-8)alkyl)2, —O—(C1-8)alkyl-S—(C1-8)alkyl, —O—(C1-8)alkyl-SO2—(C1-8)alkyl, —O—(C1-8)alkyl-SO2—NH2, —O—(C1-8)alkyl-SO2—NH(C1-8alkyl), —O—(C1-8)alkyl-SO2—N(C1-8alkyl)2, —O—C(O)H, —O—C(O)—(C1-8)alkyl, —O—C(O)—NH2, —O—C(O)—NH(C1-8alkyl), —O—C(O)—N(C1-8alkyl)2, —O—(C1-8)alkyl-C(O)H, —O—(C1-8)alkyl-C(O)—(C1-8)alkyl, —O—(C1-8)alkyl-CO2H, —O—(C1-8)alkyl-C(O)—O—(C1-8)alkyl, —O—(C1-8)alkyl-C(O)—NH2, —O—(C1-8)alkyl-C(O)—NH(C1-8alkyl), —O—(C1-8)alkyl-C(O)—N(C1-8alkyl)2, —C(O)H, —C(O)—(C1-8)alkyl, —CO2H, —C(O)—O—(C1-8)alkyl, —C(O)—NH2, —C(NH)—NH2, —C(O)—NH(C1-8alkyl), —C(O)—N(C1-8alkyl)2, —SH, —S—(C1-8)alkyl, —S—(C1-8)alkyl-S—(C1-8)alkyl, —S—(C1-8)alkyl-O—(C1-8)alkyl, —S—(C1-8)alkyl-O—(C1-8)alkyl-OH, —S—(C1-8)alkyl-O—(C1-8)alkyl-NH2, —S—(C1-8)alkyl-O—(C1-8)alkyl-NH(C1-8alkyl), —S—(C1-8)alkyl-O—(C1-8)alkyl-N(C1-8alkyl)2, —S—(C1-8)alkyl-NH(C1-8alkyl), —SO2—(C1-8)alkyl, —SO2—NH2, —SO2—NH(C1-8alkyl), —SO2—N(C1-8alkyl)2, —N—R7, cyano, (halo)1-3, hydroxy, nitro, oxo, -cycloalkyl-R6, -heterocyclyl-R6, -aryl-R6 and -heteroaryl-R6;
• R6 is 1 to 4 substituents attached to a carbon or nitrogen atom independently selected from the group consisting of hydrogen, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, —C(O)H, —C(O)—(C1-8)alkyl, —CO2H, —C(O)—O—(C1-8)alkyl, —C(O)—NH2, —C(NH)—NH2, —C(O)—NH(C1-8alkyl), —C(O)—N(C1-8)alkyl)2, —SO2—(C1-8)alkyl, —SO2—NH2, —SO2—NH(C1-8alkyl), —SO2—N(C1-8alkyl)2, —(C1-8)alkyl-N—R7, —(C1-8)alkyl-(halo)1-3, —(C1-8)alkyl-OH, -aryl-R8, —(C1-8)alkyl-aryl-R8 and —(C1-8)alkyl-heteroaryl-R8;
• with the proviso that, when R6 is attached to a carbon atom, R6 is further selected from the group consisting of —C1-8alkoxy, —(C1-8)alkoxy-(halo)1-3, —SH, —S—(C1-8)alkyl, —N—R7, cyano, halo, hydroxy, nitro, oxo and -heteroaryl-R8;
• R7 is 2 substituents independently selected from the group consisting of hydrogen, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, —(C1-8)alkyl-OH, —(C1-8)alkyl-O—(C1-8)alkyl, —(C1-8)alkyl-NH2, —(C1-8)alkyl-NH(C1-8alkyl), —(C1-8)alkyl-N(C1-8alkyl)2, —(C1-8)alkyl-S—(C1-8)alkyl, —C(O)H, —C(O)—(C1-8)alkyl, —C(O)—O—(C1-8)alkyl, —C(O)—NH2, —C(O)—NH(C1-8alkyl), —C(O)—N(C1-8alkyl)2, —SO2—(C1-8)alkyl, —SO2—NH2, —SO2—NH(C1-8alkyl), —SO2—N(C1-8alkyl)2, —C(N)—NH2, -cycloalkyl-R8, —(C1-8)alkyl-heterocyclyl-R8, -aryl-R8, —(C1-8)alkyl-aryl-R8 and —(C1-8)alkyl-heteroaryl-R8;
• R8 is 1 to 4 substituents attached to a carbon or nitrogen atom independently selected from the group consisting of hydrogen, —C1-8alkyl, —(C1-8)alkyl-(halo)1-3 and —(C1-8)alkyl-OH;
• with the proviso that, when R8 is attached to a carbon atom, R8 is further selected from the group consisting of —C1-8alkoxy, —NH2, —NH(C1-8alkyl), —N(C1-8alkyl)2, cyano, halo, —(C1-8)alkoxy-(halo)1-3, hydroxy and nitro;
• R9 is 1 to 2 substituents independently selected from the group consisting of hydrogen, —C1-8alkoxy, —NH2, —NH(C1-8alkyl), —N(C1-8alkyl)2, cyano, (halo)1-3, hydroxy and nitro;
• R10 is 1 to 2 substituents independently selected from the group consisting of hydrogen, —NH2, —NH(C1-8alkyl), —N(C1-8alkyl)2, cyano, (halo)1-3, hydroxy, nitro and oxo;
• and
• Y and Z is each O;
• and pharmaceutically acceptable salts thereof.