Mitogen-activated protein kinase inhibitors, methods of making, and methods of use thereof

A method for treating a respiratory disease in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of Formula I having the structure

• or a pharmaceutically acceptable salt or solvate thereof, wherein:
• A is hydrogen or —NH(CO)R2;
• R2 is selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, OR3, and NR4R4;
• R3 is selected from the group consisting of alkyl, cycloalkyl, and cycloalkylalkyl;
• each R4 is independently selected from the group consisting of H, alkyl, cycloalkyl, and cycloalkylalkyl;
• J1 is —CH2— and is substituted at position 4 on the pyridine;
• G1 is thiazole wherein L1 is CH, L2 is N, and L3 is S;
• Z1 and Z2 are each NH;
• G2 is pyrazole, isoxazole, or phenyl;
• E1 is CH or CR1 when G2 is phenyl, E1 is NR1 when G2 is pyrazole, or E1 is N or O when G2 is isoxazole;
• wherein R1 is selected from the group consisting of H, C1-8 alkyl, cycloalkyl, cycloalkylalkyl, and halogen;
• E2 is N when G2 is pyrazole, E2 is N or O when G2 is isoxazole, or E2 is CH—CH when G2 is phenyl;
• E3 is C when G2 is pyrazole, isoxazole, or phenyl;
• E4 is CH when G2 is pyrazole, isoxazole, or phenyl;
• and
• M1 is selected from the group consisting of C and Si;
• wherein if M1 is Si, each of M2 and M3 is methyl, R6 is methyl, and X is absent;
• wherein if M1 is C, each of M2 and M3 is selected from the group consisting of CH3 and CH2, R6 is selected from the group consisting of H and C1-8 alkyl, and X is selected from the group consisting of CH2, O, and S, or is absent;
• wherein if M1 is C and X is CH2, O, or S, then M1, M2, M3, and X together form a 4-member ring;
• wherein the respiratory disease is selected from the group consisting of asthma, rhinitis, sinusitis, COPD, pulmonary fibrosis, and a combination thereof.