AR102263A1 - COMPOUNDS AND COMPOSITIONS FOR THE MODULATION OF THE KINASA ACTIVITIES OF THE RECEIVER OF EGF MUTANTE - Google Patents

Abstract

The present application provides a group of protein kinase inhibitors, aminopyrimidine derivatives and their pharmaceutically acceptable salts that are useful for treating cell proliferative diseases and disorders, such as cancer and immune diseases. This provides methods for synthesizing and administering protein kinase inhibitor compounds. Also, it provides pharmaceutical formulations comprising at least one of the protein kinase inhibitor compounds together with a pharmaceutically acceptable carrier, diluent or excipient thereof and useful intermediates that are generated during the synthesis of aminopyrimidine derivatives. Claim 1: A compound of the formula (1) wherein: X is CH or N; R¹ is H, R⁸ or -OR⁸; R² is hydrogen, C₁₋₆ alkyl, 6 to 10 membered monocyclic or bicyclic aryl, or 5 to 10 membered heteroaryl comprising 1-4 heteroatoms that are selected from N, O and S, where the heteroaryl or aryl is optional and independently substituted on one or more carbon atoms with R¹³; and where the heteroaryl having one or more nitrogen atoms is optionally and independently substituted on one or more nitrogen atoms with R⁸; R³ is hydrogen, 4 to 7 membered monocyclic heterocyclyl comprising 1 to 2 heteroatoms selected from N, O and S, and is optionally substituted with oxo, 5 to 6 membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O and S, NR⁹R¹⁰, NR¹¹R¹², or phenyl, where the heteroaryl or phenyl is optional and independent substituted on one or more carbon atoms with R¹³; and where the heterocyclyl or heteroaryl having one or more nitrogen atoms is optionally and independently substituted on one or more nitrogen atoms with R⁸; R⁴ is hydrogen, C₁₋₄ alkyl, C₃₋₅ cycloalkyl, F, Cₗ, Bʳ, CN ₒ CF₃; R⁵ is hydrogen, CF₃, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl comprising 1 to 3 heteroatoms that are selected from N, O and S, or 6 to 10 membered monocyclic or bicyclic aryl, where the heteroaryl or aryl is optionally and independently substituted on one or more carbon atoms with R¹³; R⁶ is hydrogen or C₁₋₆ alkyl; R⁷ is hydrogen, -CH₂OH, -CH₂OR⁸, C₁₋₃ alkyl, (CH₂) ₙNR⁹R¹⁰, (CH₂) ₙNR¹¹R¹², C (O) NR⁹R¹⁰, or C (O) NR¹¹R¹², where each n is independently 1 or 2; R⁸ is selected from C₁₋₆ alkyl or C₃₋₇ cycloalkyl; R⁹ is selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl or 4-7 membered heterocyclyl comprising 1-2 heteroatoms that are selected from N, O and S, where the C₁₋₆ alkyl or C₃₋₇ cycloalkyl is optionally substituted with halogen or -OR⁸, and where the 4- to 7-membered heterocyclyl having a nitrogen atom is optionally and independently substituted with -R⁸, -C (O) R⁸, -C (O) OR⁸, or C (O) NHR⁸ ; R¹⁰ is C₁₋₆ alkyl, C₃₋₇ cycloalkyl, or (CH₂) ₙNR⁹R⁹, where each n is -independently- 1 or 2; R¹¹ and R¹² taken together with the nitrogen atom to which they are attached form, independently for each occurrence: i) a saturated or partially saturated monocyclic group of 3 to 8 members that does not have a heteroatom outside the nitrogen atom to which R¹¹ and R¹² are attached, wherein said saturated or partially saturated monocyclic group of 3 to 8 members is optionally and independently substituted on one or more carbons with halogen, hydroxyl, -OR⁸, -NR⁹R¹⁰, or -NR¹¹R¹²; or ii) a 5 to 8-membered saturated or partially saturated monocyclic group having 1 or 2 heteroatoms, in addition to the nitrogen atom to which R¹¹ and R¹² are attached, where said heteroatoms are independently selected from nitrogen, oxygen, sulfur, sulfone or sulfoxide, wherein said saturated or partially saturated monocyclic group of 5 to 8 members having 1 or 2 nitrogen atoms is optionally substituted in one or more carbon or nitrogen atoms with -R⁸, -C (O) R⁸, -C (O) OR⁸, -C (O) NHR⁸, -SO₂R⁸, -SO₂NH₂, or SO₂NR⁸₂; and R¹³ is selected from halogen, CN, CF₃, R⁸, -OR⁸ or C₂₋₄ alkenyl; or one of its pharmaceutically acceptable salts.