US 2010/0249126 A1Published application

Pyrimidine derivatives used as pi-3-kinase inhibitors

AssigneeNovartis Vaccines and Diagnostics, Inc.

InventorsMatthew Burger, Zhi-Jie Ni, Sabina Pecchi, Gordana Atallah, Sarah Bartulis, Kelly Frazier, Aaron Smith, Joelle Verhagen, Yanchen Zhang, Allan Wagman, Simon Ng, Keith Pfister, Daniel J. Poon, Alicia Louie, Teresa Pick, Paul Barsanti, Edwin Iwanowicz, Wendy Fantl, Thomas Hendrickson, Mark Knapp, Hanne Meritt, Charles Voliva, Marion Wiesmann, Xiahua Xin

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Abstract

Phosphatidylinositol (PI) 3-kinase inhibitor compounds (I), their pharmaceutically acceptable salts, and prodrugs thereof; compositions of the new compounds, either alone or in combination with at least one additional therapeutic agent, with a pharmaceutically acceptable carrier; and uses of the new compounds, either alone or in combination with at least one additional therapeutic agent, in the prophylaxis or treatment of proliferative diseases characterized by the abnormal activity of growth factors, protein serine/threonine kinases, and phospholipid kinases.

Claims53

Dependent claims

A compound having Formula I:

or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein, W is CRw or N, wherein Rw is selected from the group consisting of
(1) hydrogen,
(2) cyano,
(3) halogen,
(4) methyl,
(5) trifluoromethyl,
(6) sulfonamido;
R1 is selected from the group consisting of
(1) hydrogen,
(2) cyano,
(3) nitro,
(4) halogen,
(5) substituted and unsubstituted alkyl,
(6) substituted and unsubstituted alkenyl,
(7) substituted and unsubstituted alkynyl,
(8) substituted and unsubstituted aryl,
(9) substituted and unsubstituted heteroaryl,
(10) substituted and unsubstituted heterocyclyl,
(11) substituted and unsubstituted cycloalkyl,
(12) —COR1a,
(13) —CO2R1a,
(14) —CONR1aR1b,
(15) —NR1aR1b,
(16) —NR1aCOR1b,
(17) —NR1aSO2R1b,
(18) —OCOR1a,
(19) —OR1a,
(20) —SR1a,
(21) —SOR1a,
(22) —SO2R1a, and
(23) —SO2NR1aR1b,
wherein R1a, and R1b are independently selected from the group consisting of
(a) hydrogen,
(b) substituted or unsubstituted alkyl,
(c) substituted and unsubstituted aryl,
(d) substituted and unsubstituted heteroaryl,
(e) substituted and unsubstituted heterocyclyl, and
(f) substituted and unsubstituted cycloalkyl;
R2 is selected from the group consisting
(1) hydrogen,
(2) cyano,
(3) nitro,
(4) halogen,
(5) hydroxy,
(6) amino,
(7) substituted and unsubstituted alkyl,
(8) —COR2a, and
(9) —NR2aCOR2b,
wherein R2a, and R2b are independently selected from the group consisting of
(a) hydrogen, and
(b) substituted or unsubstituted alkyl;
R3 is selected from the group consisting of
(1) hydrogen,
(2) cyano,
(3) nitro,
(4) halogen,
(5) substituted and unsubstituted alkyl,
(6) substituted and unsubstituted alkenyl,
(7) substituted and unsubstituted alkynyl,
(8) substituted and unsubstituted aryl,
(9) substituted and unsubstituted heteroaryl,
(10) substituted and unsubstituted heterocyclyl,
(11) substituted and unsubstituted cycloalkyl,
(12) —COR3a,
(13) —NR3aR3b,
(14) —NR3aCOR3b,
(15) —NR3aSO2R3b,
(16) —OR3a,
(17) —SR3a,
(18) —SOR3a,
(19) —SO2R3a, and
(20) —SO2NR3aR3b,
wherein R3a, and R3b are independently selected from the group consisting of
(a) hydrogen,
(b) substituted or unsubstituted alkyl,
(c) substituted and unsubstituted aryl,
(d) substituted and unsubstituted heteroaryl,
(e) substituted and unsubstituted heterocyclyl, and
(f) substituted and unsubstituted cycloalkyl;
and
R4 is selected from the group consisting of
(1) hydrogen, and
(2) halogen.

80 more elements

A compound having Formula II:

or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein, W is CRw or N, wherein Rw is selected from the group consisting of
(1) hydrogen,
(2) cyano,
(3) halogen,
(4) methyl,
(5) trifluoromethyl, and
(6) sulfonamido;
X is O, S, NH, or a direct bond;
R2 is selected from the group consisting
(1) hydrogen,
(2) cyano,
(3) nitro,
(4) halogen,
(5) hydroxy,
(6) amino,
(7) substituted and unsubstituted alkyl,
(8) —COR2a, and
(9) —NR2aCOR2b,
wherein R2a, and R2b are independently selected from the group consisting of
(a) hydrogen, and
(b) substituted or unsubstituted alkyl;
R3 is selected from the group consisting of
(1) hydrogen,
(2) cyano,
(3) nitro,
(4) halogen,
(5) substituted and unsubstituted alkyl,
(6) substituted and unsubstituted alkenyl,
(7) substituted and unsubstituted alkynyl,
(8) substituted and unsubstituted aryl,
(9) substituted and unsubstituted heteroaryl,
(10) substituted and unsubstituted heterocyclyl,
(11) substituted and unsubstituted cycloalkyl,
(12) —COR3a,
(13) —NR3aR3b,
(14) —NR3aCOR3b,
(15) —NR3aSO2R3b,
(16) —OR3a,
(17) —SR3a,
(18) —SOR3a,
(19) —SO2R3a, and
(20) —SO2NR3aR3b,
wherein R3a, and R3b, are independently selected from the group consisting of
(a) hydrogen,
(b) substituted or unsubstituted alkyl,
(c) substituted and unsubstituted aryl,
(d) substituted and unsubstituted heteroaryl,
(e) substituted and unsubstituted heterocyclyl, and
(f) substituted and unsubstituted cycloalkyl;
R4 is selected from the group consisting of
(1) hydrogen, and
(2) halogen;
and
R5 is selected from the group consisting of
(1) substituted and unsubstituted cycloalkyl,
(2) substituted and unsubstituted heterocyclyl,
(3) substituted and unsubstituted aryl, and
(4) substituted and unsubstituted heteroaryl.

55 more elements

A compound having Formula III:

or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein, W is CRw or N, wherein Rw is selected from the group consisting of
(1) hydrogen,
(2) cyano,
(3) halogen,
(4) methyl,
(5) trifluoromethyl, and
(6) sulfonamido;
R2 is selected from the group consisting
(1) hydrogen,
(2) cyano,
(3) nitro,
(4) halogen,
(5) hydroxy,
(6) amino,
(7) substituted and unsubstituted alkyl,
(8) —COR2a, and
(9) —NR2aCOR2b,
wherein R2a, and R2b are independently selected from the group consisting of
(a) hydrogen, and
(b) substituted or unsubstituted alkyl;
R3 is selected from the group consisting of
(1) hydrogen,
(2) cyano,
(3) nitro,
(4) halogen,
(5) substituted and unsubstituted alkyl,
(6) substituted and unsubstituted alkenyl,
(7) substituted and unsubstituted alkynyl,
(8) substituted and unsubstituted aryl,
(9) substituted and unsubstituted heteroaryl,
(10) substituted and unsubstituted heterocyclyl,
(11) substituted and unsubstituted cycloalkyl,
(12) —COR3a,
(13) —NR3aR3b,
(14) —NR3aCOR3b,
(15) —NR3aSO2R3b,
(16) —OR3a,
(17) —SR3a,
(18) —SOR3a,
(19) —SO2R3a, and
(20) —SO2NR3aR3b,
wherein R3a, and R3b are independently selected from the group consisting of
(a) hydrogen,
(b) substituted or unsubstituted alkyl,
(c) substituted and unsubstituted aryl,
(d) substituted and unsubstituted heteroaryl,
(e) substituted and unsubstituted heterocyclyl, and
(f) substituted and unsubstituted cycloalkyl;
R4 is selected from the group consisting of
(1) hydrogen, and
(2) halogen;
and
R6 is selected from the group consisting of
(1) hydrogen,
(2) substituted and unsubstituted alkyl, and
(3) substituted and unsubstituted cycloalkyl.

53 more elements

Dependencies are inferred from the claim text.