THIAZOLE-SUBSTITUTED AMINOHETEROARYLS AS SPLEEN TYROSINE KINASE INHIBITORS

摘要

The invention provides certain thiazole-substituted aminoheteroaryl compounds of the Formula (I) (I), or pharmaceutically acceptable salts thereof, wherein ring R1, R2, R3, R4, ring A, and the subscripts n1, n2, and r are as defined herein. The invention also provides pharmaceutical compositions comprising such compounds, and methods of using the compounds for treating diseases or conditions mediated by Spleen Tyrosine Kinase (Syk).;

主权项

1. A compound of the Formula (I) or a pharmaceutically acceptable salt thereof, wherein ring A is a 9- or 10-membered bicyclic heteroaryl or heterocyclyl ring containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; the subscripts n1 and n2 are independently 0 or 1; R1 is selected from the group consisting of:
(a) C1-C3 alkyl;(b) C1-C3 fluoroalkyl;(c) C1-C3 alkoxy; and(d) C3-C6 cycloalkyl; R2 is selected from the group consisting of H and halo; or R1 and R2 when substituted on a common carbon atom, together with the carbon atom, form a carbonyl; R3 is selected from the group consisting of
(a) C1-C3 alkyl;(b) C1-C3 alkoxy; and(c) halo; X is N or C(H); the subscript r is 0 or 1; R4 is selected from the group consisting of: ring Cy is a mono- or bicyclic carbocyclic ring system containing 4 to 12 carbon atoms; ring CA is phenyl or C3-C6 cycloalkyl; R5 is —C(O)ORA or —C(O)NH2; R6 is C1-C3 alkyl or halo; R7 is H or C1-C3 alkyl; R8 is H or F; R9 is H or OH; the subscript s is 0 or 1; the subscript t is 0, 1, 2, 3, 4, or 5; RA is independently selected from the group consisting of:
(a) H;(b) C1-C8 alkyl;(c) a group of the formula -M-RCH, wherein
M is a bond or —(CH2)n3—, wherein the subscript n3 is 1 or 2;RCH is (a) aryl or C3-C6 cycloalkyl optionally substituted with 1-3 groups independently selected from halo, C1-C4 alkyl, or C1-C4 alkoxy; or (b) a 5- to 6-membered monocyclic heterocycle containing 1 or 2 heteroatoms independently selected from the group consisting of N and O, wherein said heterocycle of RCH is optionally substituted with 1 or 2 groups independently selected from the group consisting of oxo and C1-3 alkyl;(d) a group of the formula —(CH2)n3—Rm or —(CH2)2—O—(CH2)2—Rm wherein
Rm is —CO2Rm1, —C(O)N(Rm2)2, or —O(CO)Rm1;
Rm1 is C1-C4 alkyl; andRm2 is H or C1-C4 alkyl;(e) a group of the formula —(CH2)2—Rn,
Rn is —OH, —O—(C1-C4 alkyl), —O—(CH2)2—O—(C1-C4 alkyl), —NH2, —N(H)(C1-C4 alkyl) or —N(C1-C4 alkyl)2;(f) a group of the formulawherein
Ro is H or C1-C4 alkyl; andRp is C1-C4 alkyl, C3-C6 cycloalkyl, or phenyl; and,(g) a group of the formulawherein Ro and Rp are as set forth above.