IMIDAZOPYRIDAZINE JAK3 INHIBITORS AND THEIR USE FOR THE TREATMENT OF INFLAMMATORY AND AUTOIMMUNE DISEASES

摘要

The present invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof. The formula I compounds inhibit tyrosine kinase activity of JAK3, thereby making them useful for the treatment of inflammatory and autoimmune diseases.;

主权项

1. A compound having the formula I:or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
R1 is a 4- to 10-membered saturated or partially saturated heterocycle containing one heteroatom selected from 0 and NR1b, substituted with 0-5 R1a; R1a is selected independently at each occurrence from hydrogen, ═O, F, Cl, Br, C2D5, OCF3, CF3, CN, NO2, —(CH2)rORb, —(CH2)rSRb, —(CH2)rC(O)R1d, —(CH2)rC(O)ORb, —(CH2)rOC(O)Rb, —(CH2)rNRcRc, —(CH2)rC(O)NRcRc, —(CH2)rNRbC(O)R1c, —(CH2)rNRbC(O)ORc, —(CH2)rNRbC(O)NRcRc, —(CH2)rS(O)2NRcRc, —(CH2)rNRbS(O)2Rc, —(CH2)rS(O)Re, —(CH2)rS(O)2Re, C1-6 alkyl substituted with 0-5 Ra, C1-6 haloalkyl, —(CH2)r-3-14 membered carbocycle substituted with 0-2 Ra, or —(CH2)r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)p substituted with 0-2 Ra; R1b is hydrogen, CF3, —(CH2)rORb, —(CH2)rSRb, —(CH2)rC(O)R1d, —(CH2)rC(O)ORb, —(CH2)rOC(O)Rb, —(CH2)rNRcRc, —(CH2)rC(O)NRcRc, —(CH2)rNRbC(O)R1c, —(CH2)rNRbC(O)ORc, —(CH2)rNRbC(O)NRcRc, —(CH2)rS(O)2NRcRc, —S(O)2NRcRc, —(CH2)rNRbS(O)2Re, —(CH2)rS(O)Re, —(CH2)rS(O)2Rc, C1-6 alkyl substituted with 0-2 Ra, C1-6 haloalkyl, —(CH2)r-3-14 membered carbocycle substituted with 0-1 Ra, —(CH2)r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)p substituted with 0-2 Ra; or a —(CH2)r-5-7 membered heteroaryl comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S substituted with 0-2 Ra; R1c is independently at each occurrence hydrogen, C1-6 alkyl substituted with 0-3 Ra, C2-6 alkenyl substituted with 0-3 Ra, C3-10 cycloalkyl substituted with 0-3 Ra, C6-10 aryl substituted with 0-3 Ra, a 5- to 10-membered heterocycle containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 Ra, a 5- to 10-membered heteroaryl containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 Ra; R1d is independently at each occurrence hydrogen, C1-6 alkyl substituted with 0-2 Rd, C1-6 haloalkyl, C(O)NRcRc, C3-6 cycloalkyl substituted with 0-2 Rd, or (CH2)r-phenyl substituted with 0-2 Ra, a 4- to 10-membered heterocycle containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 Ra; R2 is —NRbC(O)NRcRc, —NRbC(O)R2b, —NRbC(O)OR2d, —NRbS(O)2R2b, —(CH2)r—C6-10 aryl substituted with 0-3 R2a, a —(CH2)r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)p substituted with 0-3 Ra or a —(CH2)r-4-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O, and S substituted with 0-3 R2a; R2a is selected independently at each occurrence from ═O, F, Cl, Br, OCF3, CF3, CN, CD3, NO2, —(CH2)rORb, —(CH2)rSRb, —(CH2)rC(O)Rb, —(CH2)rC(O)ORb, —(CH2)rOC(O)Rb, —(CH2)rNRcRc, —(CH2)rC(O)NRcRc, —(CH2)rNRbC(O)R2b, —(CH2)rNRbC(O)ORc, —NRbC(O)NRcRc, —S(O)2NRcRc, —NRbS(O)2Rc, —S(O)Re, —S(O)2Re, (CH2)rNH(C═NCN)NHR11, C1-6 alkyl substituted with 0-2 Ra, C2-6 alkenyl, C1-6 haloalkyl, —(CH2)r-3-14 membered carbocycle substituted with 0-2 Ra, and —(CH2)r-5-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)p substituted with 0-1 Ra; R2b is independently at each occurrence hydrogen, C1-6 alkyl substituted with 0-2 Ra, C1-6 haloalkyl, C3-6 cycloalkyl substituted with 0-2 Ra, or (CH2)r-phenyl substituted with 0-2 Ra, or —(CH2)r-5-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, 0, and S(O)p substituted with 0-1 Ra; R2d is independently at each occurrence C1-6 alkyl substituted with 0-2 Ra, C1-6 haloalkyl, C3-6 cycloalkyl substituted with 0-2 Ra, or (CH2)r-phenyl substituted with 0-2 Ra, or —(CH2)r-5-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)p substituted with 0-1 Ra; R3 is hydrogen, C1-6 alkyl substituted with 0-1 Ra, phenyl substituted with 0-1 Ra, or C3-6 cycloalkyl substituted with 0-1 Ra; Ra is independently at each occurrence hydrogen, ═O, D, F, Cl, Br, OCF3, CF3, CHF2, CN, NO2, —(CH2)rORb, —(CH2)rSRb, —(CH2)rC(O)Rb, —(CH2)rC(O)ORb, —(CH2)rOC(O)Rb, —(CH2)rNRcRc, —(CH2)rC(O)NRcRc, —(CH2)rNRbC(O)Rc, —(CH2)rNRbC(O)ORc, —NRbC(O)NRcRc, —S(O)2NRcRc, —NRbS(O)2Rc, —S(O)Rc, —S(O)2Rc, (CH2)rNH(C═NCN)NHRc, C1-6 alkyl substituted with 0-1 Rf, C1-6 haloalkyl, —(CH2)r-3-14 membered carbocycle substituted with 0-1 Rd, or —(CH2)r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)p substituted with 0-1 Rd, alternatively two Ra on adjacent or the same carbon atom form a cyclic acetal of the formula —O—(CH2)n—O—, or —O—CF2—O—, wherein n is selected from 1 or 2; Rb is independently at each occurrence hydrogen, C1-6 alkyl substituted with 0-2 Rd, C1-6 haloalkyl, C3-6 cycloalkyl substituted with 0-2 Rd, or (CH2)r-phenyl substituted with 0-2 Rd, or —(CH2)r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, 0, and S(O)p substituted with 0-1 Rd; Rc is independently at each occurrence hydrogen, C1-6 alkyl substituted with 0-1 Rf, C3-6 cycloalkyl, or (CH2)r-phenyl substituted with 0-1 Rf; Rd is independently at each occurrence hydrogen, F, Cl, Br, OCF3, CF3, CN, NO2, —ORc, —(CH2)rC(O)Rc, — NRcRc, —NRcC(O)ORc, —C(O)ORc, —SO2N(Rc)2, C1-6 alkyl, or (CH2)r-phenyl; Re is independently at each occurrence C1-6 alkyl, C3-6 cycloalkyl, or (CH2)r-phenyl; Rf is independently at each occurrence hydrogen, halo, CN, SO2-methyl, phenyl, NH2, NHCO-methyl, OH or OCH3; r is 0, 1, 2, 3, or 4; and p is 0, 1, or 2.