Substituted 6-methoxy-4-amino-n-phenyl-2-naphtamides as sphingosine receptor modulators

A method of treating a disorder associated with sphingosine-1-phosphate receptor modulation, which comprises administering to a mammal in need thereof, a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of Formula I

• wherein:
• R1 is H or optionally substituted C1-6 alkyl;
• R2 is H or optionally substituted C1-6 alkyl;
• R3 is H or optionally substituted C1-6 alkyl;
• R4 is H or optionally substituted C1-6 alkyl;
• R5 is H, optionally substituted C1-6 alkyl, halogen, —OR11, CN, NO2, C(O)R12 or NR13R14;
• R6 is H optionally substituted C1-6 alkyl, halogen, —OR11, CN, NO2, C(O)R12 or NR13R14;
• R7 is H, optionally substituted C1-6 alkyl, halogen, —OR11, CN, NO2, C(O)R12 or NR13R14;
• R8 is H, optionally substituted C1-6 alkyl, halogen, —OR11, CN, NO2, C(O)R12 or NR13R14;
• R9 is H or optionally substituted C1-6 alkyl;
• a is 1, 2 or 3;
• R10 is OPO3H2, carboxylic acid, PO3H2, P(O)MeOH, —P(O)(H)OH or OR15;
• R11 is H or optionally substituted C1-6 alkyl;
• R12 is H, OH or optionally substituted C1-6 alkyl;
• R13 is H or optionally substituted C1-6 alkyl;
• R14 is H or optionally substituted C1-6 alkyl;
• and
• R15 is H or optionally substituted C1-6 alkyl.

The method of claim, wherein the pharmaceutical composition is administered to the mammal to treat ocular diseases, wet and dry age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, retinal edema, geographic atrophy, glaucomatous optic neuropathy, chorioretinopathy, hypertensive retinopathy, ocular ischemic syndrome, prevention of inflammation-induced fibrosis in the back of the eye, various ocular inflammatory diseases including uveitis, scleritis, keratitis, and retinal vasculitis;

• or systemic vascular barrier related diseases, various inflammatory diseases, including acute lung injury, its prevention, sepsis, tumor metastasis, atherosclerosis, pulmonary edemas, and ventilation-induced lung injury;
• or autoimmune diseases and immunosuppression, rheumatoid arthritis, Crohn's disease, Graves' disease, inflammatory bowel disease, multiple sclerosis, Myasthenia gravis, Psoriasis, ulcerative colitis, autoimmune uveitis, renal ischemia perfusion injury, contact hypersensitivity, atopic dermatitis, and organ transplantation;
• or allergies and other inflammatory diseases, urticaria, bronchial asthma, and other airway inflammations including pulmonary emphysema and chronic obstructive pulmonary diseases;
• or cardiac protection, ischemia reperfusion injury and atherosclerosis;
• or wound healing such as but not limited to:
• scar-free healing of wounds from cosmetic skin surgery, ocular surgery, GI surgery, general surgery, oral injuries, various mechanical, heat and burn injuries, prevention and treatment of photoaging and skin ageing, and prevention of radiation-induced injuries;
• or bone formation, treatment of osteoporosis and various bone fractures including hip and ankles;
• or anti-nociceptive activity, visceral pain, pain associated with diabetic neuropathy, rheumatoid arthritis, chronic knee and joint pain, tendonitis, osteoarthritis, neuropathic pains;
• or central nervous system neuronal activity in Alzheimer's disease, age-related neuronal injuries;
• or organ transplant such as renal, corneal, cardiac or adipose tissue transplant.