Phosphatidylinositol 3 kinase inhibitors

A novel quinoline compound according to Formula(I)

• or stereoisomers, prodrugs, or pharmaceutically acceptable salt forms thereof, wherein:
• X is NR2 or CR2, forming a 5 or 6 membered quinoline-fused heterocycle;
• Y is NR3, CR3, or O, forming a 5 or 6 membered quinoline-fused heterocycle;
• with the proviso that in said 5-membered quinoline fused heterocyle X cannot be NR2;
• R1 is H, OH, or O(C1-C8)R1a,
• C1-C8 alkyl substituted with 0-3 R1a,
• C2-C8 alkenyl substituted with 0-3 R1a,
• C2-C8 alkynyl substituted with 0-3 R1a,
• C2-C8 alkoxy substituted with 0-3 R1a,
• C3-C10 carbocycle substituted with 0-3 R1b,
• C1-C4 sulfonamido substituted with 0-3 R1b,
• C6-C10 aryl substituted with 0-3 R1b, or
• 5 to 10 member heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, wherein said 5 to 10 member heterocycle is substituted with 0-3 R1b;
• R1a, at each occurrence, is independently selected from is H, Cl, F, Br, I, CN, NO2, NR12R13, OR5, SR4, C(═O)R4, NR14R15, S(═O)R6, S(═O)2R15,
• C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
• C1-C4 haloalkoxy, C1-C4 haloalkyl-S—,
• C3-C10 carbocycle substituted with 0-3 R1b,
• C1-C4 sulfonamido substituted with 0-3 R1b,
• C6-C10 aryl substituted with 0-3 R1b, and
• 5 to 10 member heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R1b;
• with the proviso that said heterocycle is not imidazo
• R1b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR12R13, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3,
• C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
• C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
• with the proviso that R1 is not
• where A is B—(CH2)n—R1c,
• B is —CONH—, —SO2— or —CO—,
• n is 1-6, and
• R1c is C1-C14 alkyl,
• phenyl,
• unsaturated 5-member heterocycle containing 2 or 3 heteroatoms selected from nitrogen, oxygen, and sulfur,
• wherein the phenyl and the unsaturated 5-member heterocycle are substituted with
• 0-2 substituents selected independently from halogen, CF3, hydroxyl, nitro, amino, formylamino, C1-C6 alkyl, C1-C6 alkoxy, C2-C8 alkanoylamino and C2-C8 alkanoyloxy;
• R2 is H,
• C1-C8 alkyl substituted with 0-3 R2a,
• C2-C8 alkenyl substituted with 0-3 R2a,
• C2-C8 alkynyl substituted with 0-3 R2a,
• C3-C10 carbocycle substituted with 0-3 R2b,
• C1-C4 sulfonamido substituted with 0-3 R2b,
• C6-C10 aryl substituted with 0-3 R2b, or
• 5 to 10 member heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, wherein said 5 to 10 member heterocycle is substituted with 0-3 R2b,
• R2a, at each occurrence, is independently selected from is H, Cl, F, Br, I, CN, NO2, NR12R13, OR5, SR4, C(═O)R4, NR14R15, S(═O)R6, S(═O)2R15,
• C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
• C1-C4 haloalkoxy, C1-C4 haloalkyl-S—,
• C3-C10 carbocycle substituted with 0-3 R2b,
• C1-C4 sulfonamido substituted with 0-3 R2b,
• aryl, arylamine, or allyloxy, at each occurrence substituted with 0-3 R2b, and 5 to 10 member heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 member heterocycle is substituted with 0-3 R2b;
• R2b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, thiazole, NR12R13, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, H2N—C(═O)—,
• C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C6 cyanoalkyl,
• C1-C4 haloalkoxy, C1-C4 cyanoalkoxy, and C1-C4 haloalkyl-S—;
• R3 is H, O, or S,
• C1-C8 alkyl substituted with 0-3 R3a,
• C2-C8 alkenyl substituted with 0-3 R3a,
• C2-C8 alkynyl substituted with 0-3 R3a,
• C2-C8 alkoxy substituted with 0-3 R3a,
• C3-C10 carbocycle substituted with 0-3 R3b,
• C1-C4 sulfonamido substituted with 0-3 R3b,
• C6-C10 aryl substituted with 0-3 R3b, or
• 5 to 10 member heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, wherein said 5 to 10 member heterocycle is substituted with 0-3 R3b,
• R3a, at each occurrence, is independently selected from is H, Cl, F, Br, I, CN, NO2, NR12R13, OR5, SR4, C(═O)R4 providing the NR2 is not substituted by R2a being C(═O)R4,
• NR14R15, S(═O)R6, S(═O)2R15,
• C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
• C1-C4 haloalkoxy, C1-C4 haloalkyl-S—,
• C3-C10 carbocycle substituted with 0-3 R3b,
• C1-C4 sulfonamido substituted with 0-3 R3b,
• C6-C10 aryl substituted with 0-3 R3b, and
• 5 to 10 member heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 member heterocycle is substituted with 0-3 R3b;
• R3b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR12R13, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, H2N—C(═O)—,
• C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C6 cyanoalkyl,
• C1-C4 haloalkoxy, C1-C4 cyanoalkoxy, and C1-C4 haloalkyl-S—;
• R4 is H, phenyl, benzyl, C1-C4 alkyl, C3-C8 cycloalkyl substituted with 0-3 R1b, or
• a 5 to 10 member heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 member heterocycle is substituted with 0-3 R1b;
• R5 is H, phenyl, benzyl, or C1-C4 alkyl;
• R6 is H,
• C1-C8 alkyl substituted with 0-3 R6a,
• C2-C8 alkenyl substituted with 0-3 R6a,
• C2-C8 alkynyl substituted with 0-3 R6a,
• C3-C10 carbocycle substituted with 0-3 R6b,
• C1-C4 sulfonamido substituted with 0-3 R6b,
• aryl, arylamine, or alkyloxy, at each occurrence substituted with 0-3 R6b, or
• 5 to 10 member heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, wherein said 5 to 10 member heterocycle is substituted with 0-3 R6b,
• except where R6 is in the form of —C(R6c)(R6d)—NH—CH(R6e)(R6f),
• wherein R6c and R6d are independently H, C1-4 haloalkyl or C1-8 alkyl, and
• R6e is a C1-8alkyl or C1-8 alkyl or C1-4 haloalkyl, and
• R6f is phenyl, benzyl, naphthyl or saturated or unsaturated 5- or 6-membered heterocycle containing 1, 2 or 3 atoms selected from nitrogen, oxygen and sulphur with no more than two substituent atoms selected from oxygen and sulphur, and
• wherein said phenyl, benzyl or heterocycle contain 0-3 substituents selected from C1-6 alkyl, C1-4 haloalkyl, —OC1-6alkyl, halogen, cyano and nitro;
• R6a, at each occurrence, is independently selected from is H, Cl, F, Br, I, CN, NO2, NR12R13, OR5, SR4, C(═O)R4, NR14R15, S(═O)R6, S(═O)2R15, C(═O)NH2,
• C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
• C1-C4 haloalkoxy, C1-C4 haloalkyl-S—,
• C3-C10 carbocycle substituted with 0-3 R1b,
• C1-C4 sulfonamido substituted with 0-3 R1b,
• C6-C10 aryl substituted with 0-3 R1b, and
• 5 to 10 member heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 member heterocycle is substituted with 0-3 R1b;
• R6b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR12R13, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3,
• C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
• C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
• R7 is C1-C4 alkyl, C2-C4 alkenyl, or C3-C4 alkynyl;
• R8 is H,
• C1-C8 alkyl substituted with 0-3 R8a,
• C2-C8 alkenyl substituted with 0-3 R8a,
• C2-C8 alkynyl substituted with 0-3 R8a
• C3-C10 carbocycle substituted with 0-3 R8b,
• C1-C4 sulfonamido substituted with 0-3 R8b,
• C6-C10 aryl substituted with 0-3 R8b, or
• 5 to 10 member heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, wherein said 5 to 10 member heterocycle is substituted with 0-3 R8b,
• R8a, at each occurrence, is independently selected from is H, Cl, F, Br, I, CN, NO2, NR12R13, OR5, SR4, C(═O)R4, NR14R15, S(═O)R6, S(═O)2R15,
• C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
• C1-C4 haloalkoxy, C1-C4 haloalkyl-S—,
• C3-C10 carbocycle substituted with 0-3 R8b,
• C1-C4 sulfonamido substituted with 0-3 R8b,
• C6-C10 aryl substituted with 0-3 R8b, and
• 5 to 10 member heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 member heterocycle is substituted with 0-3 R8b;
• R8b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR12R13, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3,
• C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
• C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
• R12, at each occurrence, is independently selected from H, C1-C6 alkyl, benzyl, phenethyl,
• (C1-C6 alkyl)-C(═O)—, (C1-C6 alkyl)-OC(═O)—, (C1-C6 alkyl)-S(═O)2—, and piperdinyl C(═O)—;
• R13, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, benzyl, phenethyl,
• (C1-C6 alkyl)-C(═O)—, and (C1-C6 alkyl)-S(═O)2—;
• alternatively, R12 and R13 together with the nitrogen to which they are attached, may combine to form a 4-7 member ring wherein said 4-7 member ring optionally contains an additional heteroatom selected from O and NH;
• R14, at each occurrence, is independently selected from H, C1-C6 alkyl, benzyl, phenethyl, (C1-C6 alkyl)-C(═O)—, and (C1-C6 alkyl)-S(═O)2—;
• R15, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, benzyl, phenethyl, (C1-C6 alkyl)-OC(═O)—,
• (C1-C6 alkyl)-C(═O)—, and (C1-C6 alkyl)-S(═O)2—;
• and
• alternatively, R14 and R15, may combine together with the nitrogen to which they are attached, to form a 4-7 member ring,
• wherein said 4-7 member ring optionally contains an heteroatom selected from O and NH.