Substituted heteroaryl compounds and methods of use
The present invention provides novel heteroaryl compounds, pharmaceutical acceptable salts and formulations thereof useful in preventing, managing, treating or lessening the severity of a protein kinase-mediated disease. The invention also provides pharmaceutically acceptable compositions comprising such compounds and methods of using the compositions in the treatment of protein kinase-mediated disease.
1. A compound having Formula (I):
or a stereoisomer, a tautomer, an N-oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,
wherein:
W is
wherein W is optionally substituted by 1, 2, or 3 R 2 groups;
Ar is phenyl or 5-6 membered heteroaryl, wherein Ar is optionally substituted by 1, 2, 3, 4 or 5 R 8 groups;
Z is H or C1-C6 alkyl;
B is pyrazolyl, imidazolyl or indazolyl, wherein B is optionally substituted by 1, 2, 3, 4 or 5 R 4 groups;
R 1 is H, F, Cl, Br, I, NO 2 , N 3 , CN or C 1 -C 6 alkyl; and
each R 2 , R 4 and R 8 is independently F, Cl, Br, I, NO 2 , N 3 , CN, C 1 -C 12 alkyl, or C 1 -C 12 , hydroxyalkyl.
2. The compound according to claim 1 , wherein Ar is phenyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyridyl, pyridonyl, pyrimidinyl, pyrimidonyl, pyridazinyl, thiazolyl, isothiazolyl, tetrazolyl, triazolyl, thienyl, pyrazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl or triazinyl, wherein Ar is optionally substituted by 1, 2 or 3 R 8 groups.
3. The compound according to claim 1 , wherein Z is H, methyl, ethyl, n-propyl, or i-propyl.
4. The compound according to claim 1 , wherein IV is H, F, Cl, Br, CN, methyl, ethyl, n-propyl, or i-propyl.
5. The compound according to claim 1 , wherein each R 2 , R 4 and R 8 is independently F, Cl, Br, CN, N 3 , NO 2 , C 1 -C 6 alkyl or C 1 -C 6 hydroxyalkyl.
6. The compound according to claim 1 , wherein each R 2 , R 4 and R 8 is independently F, Cl, CN, methyl, ethyl, n-propyl, i-propyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 2-hydroxy-2-methylpropyl, or 2-hydroxypropan 2 yl.
7. The compound according to claim 1 , wherein B is:
and wherein B is optionally substituted by 1, 2 or 3 R 4 groups.
8. The compound according to claim 1 having one of the following structures:
or a stereoisomer, a tautomer, an N-oxide, a solvate, or a pharmaceutically acceptable salt thereof.
9. A pharmaceutical composition comprising the compound of claim 1 , and a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle or a combination thereof.
10. The pharmaceutical composition of claim 9 further comprising a therapeutic agent selected from the group consisting of chemotherapeutic agents, anti-proliferative agents, phosphodiesterase 4 (PDE4) inhibitors, β 2 -adrenoreceptor agonists, corticosteroids, non-steroidal GR agonists, anticholinergic agents, antihistamines, anti-inflammatory agents, immunosuppressants, immunomodulators, agents for treating atherosclerosis, agents for treating pulmonary fibrosis and combinations thereof.