Compounds for modulating s1p1 activity and methods of using the same

Abstract

The present embodiments are directed, in part, to compounds, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for modulating the activity of S1P1 receptor and methods of using the same.

1 - 124 . (canceled) 
     
     
         125 . A compound having Formula I, or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         AA is 
       
       
         
           
           
               
               
           
         
         W is O, S, or NR 1 ; 
         X is O, S, or NR 4 ; 
         Z is CHR 42  or NR 43 ; 
         n is 0, 1, 2, 3, or 4; 
         B 1  and D 1  together have a formula of 
       
       
         
           
           
               
               
           
         
         B 2 , B 3 , and B 4  are independently CR 38  or N; 
         D 1  is H, OH, NH 2 , NO 2 , optionally substituted carbocycle, optionally substituted heterocycle, optionally substituted heteroaryl, optionally substituted aryl group, branched or unbranched alkyl alcohol, halo, branched or unbranched alkyl, amide, cyano, alkoxy, haloalkyl, aklylsulfonyl, nitrite, or alkylsulfanyl; 
         R 2  and R 3  are independently H, optionally substituted C 1 -C 6  alkyl, optionally substituted C 1 -C 6  hydroxyalkyl, optionally substituted C 1 -C 6  alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl; or R 2  and R 3  are together optionally substituted cycloalkyl, or together form 
       
       
         
           
           
               
               
           
         
         R 1 , R 4 , R 38 , and R 43  are independently H, OH, NH 2 , optionally substituted C 1 -C 6  alkyl, optionally substituted C 1 -C 6  hydroxyalkyl, optionally substituted C 1 -C 6  alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl. 
         R 42  is independently Br, Cl, F, optionally substituted C 1 -C 6  alkyl, optionally substituted C 1 -C 6  hydroxyalkyl, optionally substituted C 1 -C 6  alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl. 
       
     
     
         126 . The compound of  claim 125 , or a pharmaceutically acceptable salt thereof, wherein AA is 
       
         
           
           
               
               
           
         
       
     
     
         127 . The compound of  claim 126 , or a pharmaceutically acceptable salt thereof, wherein AA is 
       
         
           
           
               
               
           
         
       
     
     
         128 . The compound of  claim 127 , or a pharmaceutically acceptable salt thereof, wherein both R 2  and R 3  are Et. 
     
     
         129 . The compound of  claim 126 , or a pharmaceutically acceptable salt thereof, wherein D 1  is 
       
         
           
           
               
               
           
         
       
       wherein:
 Z 6  is O, S, NR 40 , or CHR 37 ; 
 Z 7 , Z 8 , Z 9  and Z 10  are independently N or CR 41 ; 
 R 24 , R 25 , and R 26  are each independently H, OH, NH 2 , NO 2 , carbocycle, heterocycle, heteroaryl, aryl, branched or unbranched alkyl alcohol, halo, branched or unbranched alkyl, amide, cyano, alkoxy, haloalkyl, alkylsulfonyl, nitrite, alkylsulfanyl; or two of R 24 , R 25 , and R 26  together form a carbocycle, heterocycle, aryl, heteroaryl that is attached to one or more of the atoms of D 1 ; and 
 R 35 , R 36 , R 37 , R 40 , and R 41  are each independently H, OH, NH 2 , carbocycle, heterocycle, aryl, heteroaryl, branched or unbranched alkyl alcohol, halo, branched or unbranched alkyl, amide, cyano, alkoxy, haloalkyl, aklylsulfonyl, nitrite, or alkylsulfanyl; or R 35  and R 36  together form a carbocycle, heterocycle, aryl, or heteroaryl that is attached to one or more of the atoms of D 1 . 
 
     
     
         130 . The compound of  claim 129 , or a pharmaceutically acceptable salt thereof, wherein D 1  is 
       
         
           
           
               
               
           
         
       
     
     
         131 . The compound of  claim 126 , or a pharmaceutically acceptable salt thereof, wherein D 1  is 
       
         
           
           
               
               
           
         
       
       wherein R 21 , R 22 , R 23  are each independently optionally substituted C 1 -C 6  alkyl or H, OH, NH 2 , NO 2 , carbocycle, heterocycle, aryl, heteroaryl, branched or unbranched alkyl alcohol, halo, branched or unbranched alkyl, amide, cyano, alkoxy, haloalkyl, aklylsulfonyl, nitrite, or alkylsulfanyl; or two of R 21 , R 22 , and R 23  together form a carbocycle, heterocycle, aryl, or heteroaryl that is attached to one or more of the atoms of D 1 . 
     
     
         132 . The compound of  claim 131 , or a pharmaceutically acceptable salt thereof, wherein D 1  is 
       
         
           
           
               
               
           
         
       
     
     
         133 . The compound of  claim 129 , or a pharmaceutically acceptable salt thereof, wherein D 1  is 
       
         
           
           
               
               
           
         
         wherein: 
         Z 6  is O, S, NR 40 , or CHR 37 ; 
         Z 7 , Z 8 , Z 9 , and Z 10  are independently N or CR 41 ; 
         R 35 , R 36 , R 37 , R 40 , and R 41  are each independently H, OH, NH 2 , carbocycle, heterocycle, heteroaryl, aryl, branched or unbranched alkyl alcohol, halo, branched or unbranched alkyl, amide, cyano, alkoxy, haloalkyl, aklylsulfonyl, nitrite, or alkylsulfanyl; or R 35  and R 36  together form an aryl, carbocycle, heterocycle, or heteroaryl that is attached to one or more of the atoms of D 1 . 
       
     
     
         134 . The compound of  claim 129 , or a pharmaceutically acceptable salt thereof, wherein D 1  is 
       
         
           
           
               
               
           
         
       
     
     
         135 . The compound of  claim 125  having the formula of: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         136 . A pharmaceutical composition comprising a compound of  claim 125 , or a pharmaceutically acceptable salt thereof. 
     
     
         137 . A method of treating or preventing neuropathy, pain, inflammatory pain, cancer pain, bone cancer pain, tumor pain, pain or neuropathy resulting from disorders of the central or peripheral nervous system, neuropathic pain, pain associated with dysesthesia, allodynia or hypersensitivity, chemotherapy induced neuropathic pain, chemotherapy induced peripheral neuropathy, diabetic neuropathy or pain associated with diabetic neuropathy, post herpetic neuralgia or pain associated with post herpetic neuralgia, HIV-related neuropathy or pain associated with HIV-related neuropathy, pain or neuropathy resulting from spinal chord injury, nerve lesions, tissue injury, MS, stroke, nutritional deficiencies, or toxins, fibromyalgia or pain associated with fibromyalgia, phantom limb pain, complex region pain syndrome, carpal tunnel syndrome, sciatica, pudendal neuralgia, back or neck pain, including those resulting from degenerative disk disease, trigeminal neuralgia, headache disorders including, but not limited to migraine and cluster headache, orofacial pain, odontalgia, temporomandibular joint pain, endometrial pain, osteoarthritis, rheumatoid arthritis, atypical odontalgia, interstitial cystitis, uveitis, or any combination thereof in a subject comprising administering to the subject a compound of any one of  claim 125 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. 
     
     
         138 . A method of treating or preventing neuropathy, chemotherapy induced neuropathic pain, chemotherapy induced peripheral neuropathy, diabetic neuropathy or pain associated with diabetic neuropathy in a subject in need thereof, the method comprising administering to the subject a compound of  claim 125  or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. 
     
     
         139 . A method of treating or preventing chemotherapy induced neuropathic pain in a subject in need thereof, the method comprising administering to the subject a compound of  claim 125  or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. 
     
     
         140 . A method of treating or preventing cancer in a subject, the method comprising administering to the subject a compound of  claim 125 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. 
     
     
         141 . The method of  claim 140 , wherein the cancer is ovarian, breast, lung, brain, colon, prostate, esophageal, pancreatic, brain, glioblastoma, leukemia, multiple myeloma, lymphoma, skin cancer, acute Lymphoblastic Leukemia, acute myeloid leukemia, basal cell cancer, bile duct cancer, bladder cancer, bone cancer (Ewing sarcoma, osteosarcoma), CLL, CML, uterine cancer, cervical cancer, hairy cell leukemia, melanoma, thyroid cancer, rectal cancer, renal cell cancer, small cell lung cancer, non-small cell lung cancer, or stomach cancer.