Compounds and methods for treating inflammatory and fibrotic disorders

1. A method of treating an inflammatory condition, comprising administering to a patient in need thereof a compound of formula I

wherein

M is CR 1 ; A is CR 2 ; L is CR 3 ; B is CR 4 ; E is CX 4 ; G is CX 3 ; J is CX 2 ; K is CX 1 ;

wherein each dashed line is a double bond;

R 1 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, cyano, sulfonamido, halo, aryl, alkenylenearyl, and heteroaryl;

R 2 is selected from the group consisting of aryl; unsubstituted heteroaryl; heteroaryl substituted with one or more substituents selected from halo, alkyl, alkenyl, OCF 3 , NO 2 , OH, alkoxy, haloalkoxy, amino, CO 2 H, CO 2 alkyl, and heteroaryl; cycloalkyl; unsubstituted cycloheteroalkyl and cycloheteroalkyl substituted with one to three substituents independently selected from alkyleneOH, C(O)NH 2 , NH 2 , oxo (═O), aryl, haloalkyl, halo, and OH;

R 3 is selected from the group consisting of hydrogen, aryl, alkenylenearyl, heteroaryl, alkyl, alkenyl, haloalkyl, amino, and hydroxy;

R 4 is selected from the group consisting of hydrogen, alkyl, haloalkyl, alkoxy, aryl, alkenyl, alkenylenearyl, and heteroaryl; and

X 1 , X 2 , X 3 , X 4 , and X 5 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, halo, hydroxy, amino, aryl, cycloalkyl, thioalkyl, alkoxy, haloalkyl, haloalkoxy, alkoxyalkyl, cyano, aldehydo, alkylcarbonyl, amido, haloalkylcarbonyl, sulfonyl, and sulfonamide, or X 2 and X 3 together form a 5- or 6-membered ring comprising —O(CH 2 )O—, wherein n is 1 or 2, wherein at least one of X 1 , X 2 , X 3 , X 4 , and X 5 is not hydrogen; and

wherein at least one of (a) to (e) is satisfied:

(a) at least one of X 1 , X 2 , X 3 , X 4 , and X 5 is not selected from the group consisting of halo, alkoxy, and hydroxy; (b) R 1 is not selected from the group consisting of hydrogen, alkyl, alkenyl, phenyl, substituted phenyl and halo; (c) R 2 is not phenyl or substituted phenyl; (d) R 3 is not selected from the group consisting of hydrogen, alkyl, alkenyl, haloalkyl, hydroxy, phenyl and substituted phenyl; (e) R 4 is not selected from the group consisting of hydrogen, alkyl, haloalkyl, alkoxy, alkenyl, phenyl and substituted phenyl;

or a pharmaceutically acceptable salt, ester, or solvate thereof.

2. The method of claim 1 , wherein at least one of X 1 , X 2 , or X 3 is haloalkoxy.

3. The method of claim 1 , wherein

R 1 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, cyano, sulfonamido, halo, alkenylenearyl, and heteroaryl;

R 2 is selected from the group consisting of aryl; unsubstituted heteroaryl; heteroaryl substituted with one or more substituents selected from halo, unsubstituted alkyl, alkenyl, OCF 3 , NO 2 , OH, alkoxy, haloalkoxy, amino, CO 2 H, and CO 2 alkyl; cycloalkyl; unsubstituted cycloheteroalkyl and cycloheteroalkyl substituted with one to three substituents independently selected from alkyleneOH, C(O)NH 2 , NH 2 , aryl, haloalkyl, halo, and OH;

R 4 is selected from the group consisting of hydrogen, haloalkyl, alkoxy, alkenyl, and alkenylenearyl; and

X 5 is hydrogen.

4. The method of claim 1 , wherein one of X 1 , X 2 , and X 3 is not hydrogen.

5. The method of claim 4 , wherein R 2 is selected from the group consisting of aryl; unsubstituted heteroaryl; heteroaryl substituted with one or more substituents selected from halo, unsubstituted alkyl, alkenyl, OCF 3 , NO 2 , OH, alkoxy, haloalkoxy, amino, CO 2 H, and CO 2 alkyl; cycloalkyl; and unsubstituted cycloheteroalkyl.

6. The method of claim 5 , wherein the compound of formula I is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

7. The method of claim 1 , wherein R 2 is selected from the group consisting of 4-pyridyl, cyclopropanyl, 2-furanyl, 4-(3,5-dimethyl)-isoxazolyl, 4-pyrazolyl, 4-(1-methyl)-pyrazolyl, 5-pyrimidinyl, 2-imidazolyl, and thiazolyl.

8. The method of claim 1 , wherein at least one of X 1 , X 2 , or X 3 is alkyl or cycloalkyl.

9. The method of claim 1 , wherein at least one of X 1 , X 2 , or X 3 is haloalkyl.

10. The method of claim 1 , wherein at least one of X 1 , X 2 , or X 3 is alkenyl.

11. The method of claim 1 , wherein at least one of X 1 , X 2 , or X 3 is amino.

12. A method of treating an inflammatory condition, comprising administering to a patient in need thereof a compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

13. The method of claim 1 , wherein the compound exhibits an IC 50 in a range of about 100 μM to about 1000 μM for inhibition of p38 MAPK.

14. The method of claim 13 , wherein the IC 50 is in the range of about 200 μM to about 800 μM.

15. The method of claim 1 , wherein the compound exhibits an EC 50 in the range of about 0.1 μM to about 1000 μM for inhibition of TNFα secretion in a bodily fluid in vivo.

16. The method of claim 1 , wherein the inflammatory condition is selected from the group consisting of fibrosis; chronic obstructive pulmonary disease; inflammatory pulmonary fibrosis; rheumatoid arthritis; rheumatoid spondylitis; osteoarthritis; gout; sepsis; septic shock; endotoxic shock; gram-negative sepsis; toxic shock syndrome; myofacial pain syndrome; Shigellosis; asthma; adult respiratory distress syndrome; inflammatory bowel disease; Crohn's disease; psoriasis; eczema; ulcerative colitis; glomerular nephritis; scleroderma; chronic thyroiditis; Grave's disease; Ormond's disease; autoimmune gastritis; myasthenia gravis; autoimmune hemolytic anemia; autoimmune neutropenia; thrombocytopenia; pancreatic fibrosis; chronic active hepatitis; hepatic fibrosis; renal disease; renal fibrosis; irritable bowel syndrome; pyresis; restenosis; cerebral malaria; stroke injury; ischemic injury; neural trauma; Alzheimer's disease; Huntington's disease; Parkinson's disease; acute pain; chronic pain; allergies; cardiac hypertrophy; chronic heart failure; acute coronary syndrome; cachexia; malaria; leprosy; leishmaniasis; Lyme disease; Reiter's syndrome; acute synoviitis; muscle degeneration; bursitis; tendonitis; tenosynoviitis; herniated, ruptured, or prolapsed intervertebral disk syndrome; osteopetrosis; thrombosis; silicosis; pulmonary sarcosis; bone resorption disease; cancer; Multiple Sclerosis; lupus; fibromyalgia; AIDS; Herpes Zoster; Herpes Simplex; influenza virus; Severe Acute Respiratory Syndrome; cytomegalovirus; diabetes mellitus and combinations thereof.

17. The method of claim 16 , wherein the inflammatory condition is fibrosis.

18. The method of claim 17 , wherein the fibrosis is pulmonary fibrosis.

19. A method of treating an inflammatory condition, comprising administering to a patient in need thereof a compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

20. The method of claim 19 , wherein the inflammatory condition is selected from the group consisting of fibrosis; chronic obstructive pulmonary disease; inflammatory pulmonary fibrosis; rheumatoid arthritis; rheumatoid spondylitis; osteoarthritis; gout; sepsis; septic shock; endotoxic shock; gram-negative sepsis; toxic shock syndrome; myofacial pain syndrome; Shigellosis; asthma; adult respiratory distress syndrome; inflammatory bowel disease; Crohn's disease; psoriasis; eczema; ulcerative colitis; glomerular nephritis; scleroderma; chronic thyroiditis; Grave's disease; Ormond's disease; autoimmune gastritis; myasthenia gravis; autoimmune hemolytic anemia; autoimmune neutropenia; thrombocytopenia; pancreatic fibrosis; chronic active hepatitis; hepatic fibrosis; renal disease; renal fibrosis; irritable bowel syndrome; pyresis; restenosis; cerebral malaria; stroke injury; ischemic injury; neural trauma; Alzheimer's disease; Huntington's disease; Parkinson's disease; acute pain; chronic pain; allergies; cardiac hypertrophy; chronic heart failure; acute coronary syndrome; cachexia; malaria; leprosy; leishmaniasis; Lyme disease; Reiter's syndrome; acute synoviitis; muscle degeneration; bursitis; tendonitis; tenosynoviitis; herniated, ruptured, or prolapsed intervertebral disk syndrome; osteopetrosis; thrombosis; silicosis; pulmonary sarcosis; bone resorption disease; cancer; Multiple Sclerosis; lupus; fibromyalgia; AIDS; Herpes Zoster; Herpes Simplex; influenza virus; Severe Acute Respiratory Syndrome; cytomegalovirus; diabetes mellitus and combinations thereof.

21. The method of claim 20 , wherein the inflammatory condition is fibrosis.

22. The method of claim 21 , wherein the fibrosis is idiopathic pulmonary fibrosis.