Provided herein are compounds of formula (I) or pharmaceutically acceptable salts, solvates or prodrugs thereof, or mixtures thereof, wherein Z1, Z2, X1, X2, X3, R1, R2, R3, m and n are defined herein. Also provided are pharmaceutically acceptable compositions that include a compound of formula I an
Provided herein are compounds of formula (I) or pharmaceutically acceptable salts, solvates or prodrugs thereof, or mixtures thereof, wherein Z1, Z2, X1, X2, X3, R1, R2, R3, m and n are defined herein. Also provided are pharmaceutically acceptable compositions that include a compound of formula I and a pharmaceutically acceptable excipient. Also provided are methods for treating FAAH-mediated disorders comprising administering to a subject in need thereof a therapeutically effective amount of a compound or composition of the present invention.
대표청구항▼
1. A method of treating an FAAH-mediated disorder comprising administering to a subject in need thereof a therapeutically effective amount of compound of formula I: or a pharmaceutically acceptable salt, solvate or prodrug thereof, or mixture thereof, wherein: is selected from a single bond and a do
1. A method of treating an FAAH-mediated disorder comprising administering to a subject in need thereof a therapeutically effective amount of compound of formula I: or a pharmaceutically acceptable salt, solvate or prodrug thereof, or mixture thereof, wherein: is selected from a single bond and a double bond;when is a single bond, X1 is selected from CR4R5 and NR6, and X2 is selected from CR7R8 and NR9;when is a double bond, X1 is selected from CR4 and N, and X2 is selected from CR7 and N;X3 is selected from CR10R11 and NR12;provided that at least one of X1, X2 and X3 is selected from N, NR6, NR9, and N′2;m is 0 or 1;Z1 is selected from —OR13 and C1-6 alkyl;Z2 is selected from —OR14 and C1-6 alkyl;or alternatively, Z1 and Z2, together with the B to which they are bound, form an 5- to 8-membered ring having at least one O atom directly attached to B, wherein the ring is comprised of carbon atoms and optionally one or more additional heteroatoms independently selected from the group consisting of N, S, and O;n is 0, 1, 2 or 3;R1 and R2 each independently is selected from hydrogen, halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 perhaloalkyl, —CN and —OR15;or alternatively, R1 and R2, taken together with the carbon to which they are bound, form a carbonyl group;R3, at each occurrence, independently is selected from halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 perhaloalkyl, —OH, C1-6 alkoxy and —CN;R4, R5, R7, R8, R10, and R11 each independently is selected from hydrogen, halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 perhaloalkyl, —CN, —OR16, —NR17R18, —C(O)R19, C3-10, carbocyclyl, C6-10 aryl, C7-12 aralkyl, 3-10 membered heterocyclyl, and 5-10 membered heteroaryl;R6, R9, and R12 each independently is selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, —C(O)R20, —C(O)OR21, ═S(O)2R22, C3-10 carbocyclyl, C6-10 aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, and —(CR27R28)p—R23;R13 and R14, at each occurrence, each independently is selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl;R15 and R16, at each occurrence, each independently is selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocyclyl, C6-10 aryl, C7-12 aralkyl, 3-10 membered heterocyclyl, and 5-10 membered heteroaryl;R17 and R18, at each occurrence, each independently is selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, —C(O)R24, —C(O)OR25, C3-10 carbocyclyl, C6-10 aryl, C7-12 aralkyl, 3-10 membered heterocyclyl, and 5-10 membered heteroaryl;R19, R20 and R21, at each occurrence, each independently is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocyclyl, C6-10 aryl, C7-12 aralkyl, 3-10 membered heterocyclyl, and 5-10 membered heteroaryl;R22 is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocyclyl, C6-10 aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, and —(CR29R30)qR26;R23, at each occurrence, independently is selected from C3-10 carbocyclyl, C6-10 aryl, 3-10 membered heterocyclyl, and 5-10 membered heteroaryl;R24 and R25, at each occurrence, each independently is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocyclyl, C6-10 aryl, C7-12 aralkyl, 3-10 membered heterocyclyl, and 5-10 membered heteroaryl;R26, at each occurrence, independently is selected from C3-10 carbocyclyl, C6-10 aryl, 3-10 membered heterocyclyl, and 5-10 membered heteroaryl;R27, R28, R29 and R30, at each occurrence, each independently is selected from hydrogen and C1-6 alkyl; andp, and q, at each occurrence, each independently is selected from 1, 2, 3, 4, 5 and;wherein the FAAH-mediated disorder is a pain disorder, or an inflammatory disorder. 2. The method of claim 1, wherein m is 1 and X3 is NR12. 3. The method of claim 2, wherein is a double bond. 4. The method of claim 3, wherein X1 is CR4. 5. The method of claim 4, wherein X2 is CR7. 6. The method of claim 5, wherein R7 is selected from hydrogen, C1-6 alkyl and C7-10 aralkyl. 7. The method of claim 4, wherein X2 is N. 8. The method of claim 4, wherein R4 is selected from hydrogen, C1-6 alkyl and C7-10 aralkyl. 9. The method of claim 3, wherein X1 is N. 10. The method of claim 9, wherein X2 is CR7. 11. The method of claim 10, wherein R7 is selected from hydrogen, C1-6 alkyl and C7-10 aralkyl. 12. The method of claim 2, wherein is a single bond. 13. The method of claim 12, wherein X1 is CR4R5. 14. The method of claim 12, wherein X2 is CR7R8. 15. The method of claim 14, wherein R7 is hydrogen and R8 is hydrogen. 16. The method of claim 13, wherein R4 is hydrogen and R5 is hydrogen. 17. The method claim 2, wherein R12 is selected from hydrogen, C1-6 alkyl and —(CR27R28)p—R23. 18. The method of claim 1, wherein m is 0. 19. The method of claim 18, wherein is a single bond. 20. The method of claim 19, wherein X2 is NR9. 21. The method of claim 20, wherein R9 is selected from hydrogen, C1-6 alkyl and —(CR27R28)p—R23. 22. The method of claim 19, wherein X1 is CR4R5. 23. The method of claim 22, wherein R4 is hydrogen and R5 is hydrogen. 24. The method of claim 1, wherein R1 and R2, taken together with the carbon to which they are bound, form a carbonyl group. 25. The method of claim 1, wherein n is 0. 26. The method claim 1, wherein the compound is of the formula Ia: or a pharmaceutically acceptable salt, solvate or prodrug thereof, or mixture thereof. 27. The method of claim 1, wherein the compound is of the formula Ib: or a pharmaceutically acceptable salt, solvate or prodrug thereof, or mixture thereof. 28. The method of claim 1, wherein the compound is of the formula V: or a pharmaceutically acceptable salt, solvate or prodrug thereof, or mixture thereof. 29. The method of claim 28, wherein the compound is of the formulae Va or Vb: or a pharmaceutically acceptable salt, solvate or prodrug thereof, or mixture thereof. 30. The method of claim 1, wherein the compound is of the formula IX: or a pharmaceutically acceptable salt, solvate or prodrug thereof, or mixture thereof. 31. The method of claim 30, wherein the compound is of the formulae IXa or IXb: or a pharmaceutically acceptable salt, solvate or prodrug thereof, or mixture thereof. 32. The method of claim 1, wherein the compound is of the formula XI: or a pharmaceutically acceptable salt, solvate or prodrug thereof, or mixture thereof. 33. The method of claim 32, wherein the compound is of the formulae XIa or XIb: or a pharmaceutically acceptable salt, solvate or prodrug thereof, or mixture thereof. 34. The method of claim 1, wherein the compound is of the formula VII: or a pharmaceutically acceptable salt, solvate or prodrug thereof, or mixture thereof. 35. The method of claim 34, wherein the compound is of the formulae VIIa or VIIb: or a pharmaceutically acceptable salt, solvate or prodrug thereof, or mixture thereof. 36. The method of claim 1, wherein R12 is selected from hydrogen, C1-6 alkyl and —(CH2)p—R23. 37. The method of claim 36, wherein R23 is phenyl. 38. The method of claim 1, wherein the compound is of the formula XV: or a pharmaceutically acceptable salt, solvate or prodrug thereof, or mixture thereof. 39. The method of claim 38, wherein the compound is of the formulae XVa or XVb: or a pharmaceutically acceptable salt, solvate or prodrug thereof, or mixture thereof. 40. The method of claim 38, wherein R9 is selected from hydrogen, C1-6 alkyl and —(CH2)p—R23. 41. The method of claim 40, wherein R23 is phenyl. 42. The method of claim 1, wherein Z1 is —OR13 and Z2 is —OR14. 43. The method of claim 42, wherein R13 is hydrogen and R14 is hydrogen. 44. The method of claim 1, wherein the compound is selected from: or a pharmaceutically acceptable salt, solvate or prodrug thereof, or mixture thereof. 45. The method of claim 1, wherein the FAAH-mediated disorder is a pain disorder. 46. The method of 45, wherein the pain disorder is selected from neuropathic pain, central pain, deafferentiation pain, chronic pain, stimulus of nociceptive receptors, acute pain, non-inflammatory pain, inflammatory pain, pain associated with cancer, preoperative pain, arthritic pain, lumbosacral pain, musculo-skeletal pain, headache, migraine, muscle ache, lower back and neck pain, and toothache. 47. The method of claim 45, wherein the pain disorder is neuropathic pain. 48. The method of claim 45, wherein the pain disorder is arthritic pain. 49. The method of claim 46, wherein the arthritic pain is osteoarthritic pain. 50. The method of claim 46, wherein the arthritic pain is rheumatoid arthritic pain. 51. The method of claim 46, wherein the inflammatory pain is associated with an inflammatory disorder. 52. The method of claim 1, wherein the FAAH-mediated disorder is an inflammatory disorder. 53. The method of claim 52, wherein the inflammatory disorder is irritable bowel disease. 54. The method of claim 47, wherein the neuropathic pain is diabetic retinopathy; sciatica; non-specific lower back pain; multiple sclerosis pain; fibromyalgia; HIV-related neuropathy; neuralgia; or pain resulting from physical trauma, amputation, cancer, chemotherapy, surgery, invasive medical procedures, toxins, burns, infection, chronic inflammatory condition, peripheral nerve disorder, nerve crush, nerve stretch, incomplete nerve transsection, mononeuropathy, polyneuropathy, dorsal root ganglion compression, inflammation of the spinal cord, contusion, tumor or hemisection of the spinal cord, tumor of the brainstem, thalamus, or cortex, or trauma to the brainstem, thalamus, or cortex. 55. The method of claim 46, wherein the pain disorder is a non-inflammatory pain. 56. The method of claim 55, wherein the non-inflammatory pain is peripheral neuropathic pain, central pain, deafferentation pain, chronic noiceptive pain, phantom pain, pain felt by psychiatric patients, or wandering pain. 57. The method of claim 52, wherein the inflammatory disorder is inflammation affecting blood vessels, joints, gastrointestinal tract, skin, multiple organs and tissues; inflammation associated with vascular disease, migraine headache, tension headache, arteritis, thyroiditis, asplastic anemia, Hodgkin's disease, scleroderma, rheumatic fever, type I diabetes, myasthenia gravis, sarcoidosis, nephrotic syndrome, Behcet's syndrome, polymyostis, gingivitis, hypersensitivity, conjunctivitis, multiple sclerosis, or ischemia; neuroinflammation associated with brain disorders; chronic inflammation associated with cranial radiation injury; inflammation associated with trauma; or inflammation that is acute, adhesive, atrophic, catarrhal, chronic, cirrhotic, diffuse, disseminated, exudative, fibrinous, fibrosing, focal, granulomatous, hyperplastic, hypertrophic, interstitial, metastatic, necrotic, obliterative, parenchymatous, plastic, productive, proliferous, pseudomenbranous, purulent, sclerosing, seroplastic, serous, simple, specific, subacute, supporative, toxic, traumatic, or ulcerative.
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