THERAPEUTICALLY USEFUL SUBSTITUTED HYDROPYRIDO [3,2,1-ij] QUINOLINE COMPOUNDS

Abstract

Disclosed herein are compounds represented by the structural formula: therapeutic methods, compositions, and medicaments related thereto are also disclosed.

1 . A compound and salts and isomers thereof represented by the structural formula: 
     
       
         
         
             
             
         
       
       wherein each Y is independently C or N; 
       wherein m is an integer of 0, or 1; 
       n is an integer of 0, 1, 2, or 3; 
       Z and X are each independently selected from the group consisting of oxygen sulfur, and amine moiety NR N ; B is selected from the group consisting of hydrogen, hydrocarbyl, heterohydrocarbyl, substituted or unsubstituted aryl, halohydrocarbyl, hydroxyl, alkoxyl, hydroxyalkyl, alkylcarbonyl, carbonylalkyl, formyl, oxycarbonyl, aminocarbonyl, alkyl carboxyl, alkyl amide, amino, alkylamino, cyano and X—B together being a heterocyclic ring or ring system; 
       R and R 3  are each independently selected from the group consisting of hydrogen, hydrocarbyl, heterohydrocarbyl, substituted or unsubstituted aryl, halo, halohydrocarbyl, hydroxyl, alkoxyl, hydroxyalkyl, alkylcarbonyl, carbonylalkyl, formyl, oxycarbonyl, aminocarbonyl, alkyl carboxyl, alkyl amide, amino, alkylamino, and cyano; 
       each R 1  is independently selected from the group consisting of hydrogen, hydrocarbyl, heterohydrocarbyl, substituted or unsubstituted aryl, halo, halohydrocarbyl, hydroxyl, alkoxyl, hydroxyalkyl, alkylcarbonyl, formyl, oxycarbonyl, aminocarbonyl, aminocarbonxyl, alkylcarboxyl, alkyl alkylcarbonyl, formyl, oxycarbonyl, aminocarbonyl, aminocarbonxyl, alkylcarboxyl, alkyl amide, amino, alkylamino, and cyano; 
       each R 2  is independently selected from the group consisting of hydrocarbyl, heterohydrocarbyl, substituted or unsubstituted aryl, halo, halohydrocarbyl, hydroxyl, alkoxyl, hydroxyalkyl, alkylcarbonyl, formyl, oxo, oxycarbonyl, carboxyl, alkyl carboxylate, alkyl amide, aminocarbonyl, amino, alkylamino, and cyano; 
       each R N  is independently selected from the group consisting of hydrogen, hydrocarbyl, heterohydrocarbyl, substituted or unsubstituted aryl, halohydrocarbyl, hydroxyl, alkoxyl, hydroxyalkyl, alkylcarbonyl, carbonylalkyl, formyl, oxycarbonyl, aminocarbonyl, alkyl carboxyl, alkyl amide, amino, alkylamino, and cyano; including their alternate solid forms, tautomers, stereoisomers, enantiomers, diastereomers, prodrugs, and pharmaceutically acceptable salts, hydrates and solvates. 
     
   
   
       2 . The compound of  claim 1 , further represented by the compound selected from the group consisting of: 
     
       
         
         
             
             
         
       
       wherein m is an integer of 0, or 1; 
       n is an integer of 0, 1, 2, or 3; 
       Z and X are each independently selected from the group consisting of oxygen sulfur, and amine moiety NR N ; B is selected from the group consisting of hydrogen, hydrocarbyl, heterohydrocarbyl, substituted or unsubstituted aryl, halohydrocarbyl, hydroxyl, alkoxyl, hydroxyalkyl, alkylcarbonyl, carbonylalkyl, formyl, oxycarbonyl, aminocarbonyl, alkyl carboxyl, alkyl amide, amino, alkylamino, cyano and X—B together being a heterocyclic ring or ring system; 
       R and R 3  are each independently selected from the group consisting of hydrogen, hydrocarbyl, heterohydrocarbyl, substituted or unsubstituted aryl, halo, halohydrocarbyl, hydroxyl, alkoxyl, hydroxyalkyl, alkylcarbonyl, carbonylalkyl, formyl, oxycarbonyl, aminocarbonyl, alkyl carboxyl, alkyl amide, amino, alkylamino, and cyano; 
       each R 1  is independently selected from the group consisting of hydrogen, hydrocarbyl, heterohydrocarbyl, substituted or unsubstituted aryl, halo, halohydrocarbyl, hydroxyl, alkoxyl, hydroxyalkyl, alkylcarbonyl, formyl, oxycarbonyl, aminocarbonyl, aminocarbonxyl, alkylcarboxyl, alkyl alkylcarbonyl, formyl, oxycarbonyl, aminocarbonyl, aminocarbonxyl, alkylcarboxyl, alkyl amide, amino, alkylamino, and cyano; 
       each R 2  is independently selected from the group consisting of hydrocarbyl, heterohydrocarbyl, substituted or unsubstituted aryl, halo, halohydrocarbyl, hydroxyl, alkoxyl, hydroxyalkyl, alkylcarbonyl, formyl, oxo, oxycarbonyl, carboxyl, alkyl carboxylate, alkyl amide, aminocarbonyl, amino, alkylamino, and cyano; each R N  is independently selected from the group consisting of hydrogen, hydrocarbyl, heterohydrocarbyl, substituted or unsubstituted aryl, halohydrocarbyl, hydroxyl, alkoxyl, hydroxyalkyl, alkylcarbonyl, carbonylalkyl, formyl, oxycarbonyl, aminocarbonyl, alkyl carboxyl, alkyl amide, amino, alkylamino, and cyano; including their alternate solid forms, tautomers, stereoisomers, enantiomers, diastereomers, prodrugs, and pharmaceutically acceptable salts, hydrates and solvates. 
     
   
   
       3 . The compound of  claim 1 , further represented by the structural formula: 
     
       
         
         
             
             
         
       
       wherein 
       m is 0, or 1; 
       n is 0, 1, 2, or 3; 
       Z is O, S, or NR N ; 
       X is O, S, or NR N ; 
       B is selected from the group consisting of hydrogen, hydrocarbyl, heterohydrocarbyl, substituted or unsubstituted aryl, halohydrocarbyl, hydroxyl, alkoxyl, hydroxyalkyl, alkylcarbonyl, carbonylalkyl, formyl, oxycarbonyl, aminocarbonyl, alkyl carboxyl, alkyl amide, amino, alkylamino, cyano and X—B together being a heterocyclic ring; 
       R and R 3  are each independently selected from the group consisting of hydrogen, hydrocarbyl, heterohydrocarbyl, substituted or unsubstituted aryl, halo, halohydrocarbyl, hydroxyl, alkoxyl, hydroxyalkyl, alkylcarbonyl, carbonylalkyl, formyl, oxycarbonyl, aminocarbonyl, alkyl carboxyl, alkyl amide, amino, alkylamino, and cyano; 
       each R 1  is independently selected from the group consisting of hydrogen, hydrocarbyl, heterohydrocarbyl, substituted or unsubstituted aryl, halo, halohydrocarbyl, hydroxyl, alkoxyl, hydroxyalkyl, alkylcarbonyl, formyl, oxycarbonyl, aminocarbonyl, aminocarbonxyl, alkylcarboxyl, alkyl amide, amino, alkylamino, and cyano; 
       each R 2  is independently selected from the group consisting of hydrocarbyl, heterohydrocarbyl, substituted or unsubstituted aryl, halo, halohydrocarbyl, hydroxyl, alkoxyl, hydroxyalkyl, alkylcarbonyl, formyl, oxo, oxycarbonyl, carboxyl, alkyl carboxylate, alkyl amide, aminocarbonyl, amino, alkylamino, and cyano; 
       each R N  is independently selected from the group consisting of hydrogen, hydrocarbyl, heterohydrocarbyl, substituted or unsubstituted aryl, halohydrocarbyl, hydroxyl, alkoxyl, hydroxyalkyl, alkylcarbonyl, carbonylalkyl, formyl, oxycarbonyl, aminocarbonyl, alkyl carboxyl, alkyl amide, amino, alkylamino, and cyano; including its alternate solid forms, tautomers, stereoisomers, enantiomers, diastereomers, prodrugs, and pharmaceutically acceptable salts, hydrates and solvates. 
     
   
   
       4 . The compound of  claim 1 , provided that when Z and X are both oxygen, R 2  is not oxo, or R 1  and R 2  are not both phenyl or both methyl at the same time. 
   
   
       5 . The compound of  claim 1 , further represented by the structural formula: 
     
       
         
         
             
             
         
       
       wherein 
       n is 0, 1, 2, or 3; 
       o is 0, 1, 2, or 3; 
       Z is O or S; 
       X is O, S, or NR N ; 
       B is selected from the group consisting of hydrogen, a substituent having a formula C 0-12 H 0-30 N 0-3 O 0-5 P 0-2 S 0-3 F 0-6 Cl 0-3 Br 0-3 I 0-3 , C 1-6  alkyl, C 1-6  alkenyl, C 1-6  alkynyl, C 1-6  haloalkyl, hydroxyalkyl, phenyl, benzyl, furylmethyl, or wherein X—B is morpholino and X—B being a heterocyclic ring; 
       R and R 3  are each independently selected from the group consisting of hydrogen and a substituent having a formula
   C 0-12 H 0-30 N 0-3 O 0-5 P 0-2 S 0-3 F 0-6 Cl 0-3 Br 0-3 I 0-3 ; 
 
       each R 1  is independently selected from the group consisting of hydrogen, hydrocarbyl, heterohydrocarbyl, substituted or unsubstituted aryl, halo, halohydrocarbyl, hydroxyl, alkoxyl, hydroxyalkyl, alkylcarbonyl, formyl, oxycarbonyl, aminocarbonyl, aminocarbonxyl, alkylcarboxyl, alkyl amide, amino, alkylamino, and cyano; 
       each R N  is independently selected from the group consisting of hydrogen and C 1-12  hydrocarbyl; 
       each R A  is independently selected from the group consisting of hydrogen, alkyl, hydrocarbyl, C 1-12  alkyl, C 1-12  alkenyl, C 1-12  alkynyl, halo, C 1-12  halohydrocarbyl, C 1-12  hydroxyalkyl, C 3-12  cyclic hydrocarbyl, heteroaryl, heterohydrocarbyl, substituted or unsubstituted aryl, alkoxyl, hydroxyalkyl, alkylcarbonyl, carbonylalkyl, formyl, oxycarbonyl, aminocarbonyl, alkyl carboxyl, alkyl amide, amino, alkylamino, and cyano; 
       including its alternate solid forms, tautomers, stereoisomers, enantiomers, diastereomers, prodrugs, and pharmaceutically acceptable salts, hydrates and solvates. 
     
   
   
       6 . The compound of  claim 5  wherein X is O. 
   
   
       7 . The compound of  claim 5  wherein Z is O. 
   
   
       8 . The compound of  claim 5  wherein B is selected from the group consisting of C 1-6  alkyl, C 1-6  alkenyl, C 1-6  alkynyl, C 1-6  haloalkyl, hydroxyalkyl, phenyl, benzyl, furylmethyl, or wherein X—B is morpholino. 
   
   
       9 . The compound of  claim 5  wherein each R A  is independently hydrogen, C 1-12  alkyl, C 1-12  alkenyl, C 1-12  alkynyl, halo, C 1-12  halohydrocarbyl, C 1-12  hydroxyalkyl, C 3-12  cyclic hydrocarbyl, or heteroaryl. 
   
   
       10 . The compound of  claim 5  wherein X is NR N . 
   
   
       11 . The compound of  claim 5 , wherein B is selected from the group consisting of C 1-6  alkyl, C 1-6  alkenyl, C 1-6  alkynyl, C 1-6  haloalkyl, hydroxyalkyl, phenyl, benzyl, furylmethyl, or wherein X—B is morpholino. 
   
   
       12 . The compound of  claim 3 , further represented by the structural formula: 
     
       
         
         
             
             
         
       
       wherein 
       n is 0, 1, 2, or 3; 
       o is 0, 1, 2, or 3; 
       Z is O or S; 
       X is O, S, or NR N ; 
       B is selected from the group consisting of hydrogen, a substituent having a formula C 0-12 H 0-30 N 0-3 O 0-5 P 0-2 S 0-3 F 0-6 Cl 0-3 Br 0-3 I 0-3 , and X—B being a heterocyclic ring; 
       each R 3  is independently selected from the group consisting of hydrogen and a substituent having a formula
   C 0-12 H 0-30 N 0-3 O 0-5 P 0-2 S 0-3 F 0-6 Cl 0-3 Br 0-3 I 0-3 ; 
 
       each R N  is independently selected from the group consisting of hydrogen and C 1-12  hydrocarbyl; 
       each R A  is independently selected from the group consisting of hydrogen, C 1-12  alkyl, C 1-12  alkenyl, C 1-12  alkynyl, halo, C 1-12  halohydrocarbyl, C 1-12  hydroxyalkyl, C 3-12  cyclic hydrocarbyl, and substituted or unsubstituted aryl; 
       including its alternate solid forms, tautomers, stereoisomers, enantiomers, diastereomers, prodrugs, and pharmaceutically acceptable salts, hydrates and solvates. 
     
   
   
       13 . The compound of  claim 1 , further represented by the structural formula: 
     
       
         
         
             
             
         
       
       wherein 
       n is 0, 1, 2, or 3; 
       Z is O, S, or NR N ; 
       X is O, S, or NR N ; 
       B is selected from the group consisting of hydrogen, hydrocarbyl, heterohydrocarbyl, substituted or unsubstituted aryl, halohydrocarbyl, hydroxyl, alkoxyl, hydroxyalkyl, alkylcarbonyl, carbonylalkyl, formyl, oxycarbonyl, aminocarbonyl, alkyl carboxyl, alkyl amide, amino, alkylamino, cyano and X—B together being a heterocyclic ring; 
       R and R 3  are each independently selected from the group consisting of hydrogen, hydrocarbyl, heterohydrocarbyl, substituted or unsubstituted aryl, halo, halohydrocarbyl, hydroxyl, alkoxyl, hydroxyalkyl, alkylcarbonyl, carbonylalkyl, formyl, oxycarbonyl, aminocarbonyl, alkyl carboxyl, alkyl amide, amino, alkylamino, and cyano; 
       each R 1  is independently selected from the group consisting of hydrogen, hydrocarbyl, heterohydrocarbyl, substituted or unsubstituted aryl, halo, halohydrocarbyl, hydroxyl, alkoxyl, hydroxyalkyl, alkylcarbonyl, formyl, oxycarbonyl, aminocarbonyl, aminocarbonxyl, alkylcarboxyl, alkyl amide, amino, alkylamino, and cyano; 
       each R 2  is independently selected from the group consisting of hydrocarbyl, heterohydrocarbyl, substituted or unsubstituted aryl, halo, halohydrocarbyl, hydroxyl, alkoxyl, hydroxyalkyl, alkylcarbonyl, formyl, oxo, oxycarbonyl, carboxyl, alkyl carboxylate, alkyl amide, aminocarbonyl, amino, alkylamino, and cyano; 
       including its alternate solid forms, tautomers, stereoisomers, enantiomers, diastereomers, prodrugs, and pharmaceutically acceptable salts, hydrates and solvates. 
     
   
   
       14 . The compound of  claim 1 , further represented by the structural formula: 
     
       
         
         
             
             
         
       
       wherein 
       n is 0, 1, 2, or 3; 
       o is 0, 1, 2, or 3; 
       X is O, S, or NR N ; 
       B is selected from the group consisting of hydrogen, C 1-6  alkyl, C 1-6  alkenyl, C 1-6  alkynyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, phenyl, benzyl, furylmethyl, hydrocarbyl, heterohydrocarbyl, substituted or unsubstituted aryl, halohydrocarbyl, hydroxyl, alkoxyl, hydroxyalkyl, alkylcarbonyl, carbonylalkyl, formyl, oxycarbonyl, aminocarbonyl, alkyl carboxyl, alkyl amide, amino, alkylamino, cyano and X—B together being morpholino or a heterocyclic ring; 
       R and R 3  are each independently selected from the group consisting of hydrogen, hydrocarbyl, heterohydrocarbyl, substituted or unsubstituted aryl, halo, halohydrocarbyl, hydroxyl, alkoxyl, hydroxyalkyl, alkylcarbonyl, carbonylalkyl, formyl, oxycarbonyl, aminocarbonyl, alkyl carboxyl, alkyl amide, amino, alkylamino, and cyano; 
       each R 1  is independently selected from the group consisting of hydrogen, hydrocarbyl, heterohydrocarbyl, substituted or unsubstituted aryl, halo, halohydrocarbyl, hydroxyl, alkoxyl, hydroxyalkyl, alkylcarbonyl, formyl, oxycarbonyl, aminocarbonyl, aminocarbonxyl, alkylcarboxyl, alkyl amide, amino, alkylamino, and cyano; 
       each R A  is independently selected from the group consisting of hydrogen, C 1-12  alkyl, C 1-12  alkenyl, C 1-12  alkynyl, halo, C 1-12  halohydrocarbyl, C 1-12  hydroxyalkyl, C 3-12  cyclic hydrocarbyl, heteroaryl, hydrocarbyl, heterohydrocarbyl, substituted or unsubstituted aryl, halo, halohydrocarbyl, hydroxyl, alkoxyl, hydroxyalkyl, alkylcarbonyl, carbonylalkyl, formyl, oxycarbonyl, aminocarbonyl, alkyl carboxyl, alkyl amide, amino, alkylamino, and cyano; 
       including its alternate solid forms, tautomers, stereoisomers, enantiomers, diastereomers, prodrugs, and pharmaceutically acceptable salts, hydrates and solvates. 
     
   
   
       15 . The compound of  claim 14  wherein X is O. 
   
   
       16 . The compound of  claim 14 , wherein B is C 1-6  alkyl, C 1-6  alkenyl, C 1-6  alkynyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, phenyl, benzyl, furylmethyl, or wherein X—B is morpholino. 
   
   
       17 . The compound of  claim 14  wherein X is NR N . 
   
   
       18 . The compound of  claim 14 , wherein B is C 1-6  alkyl, C 1-6  alkenyl, C 1-6  alkynyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, phenyl, and benzyl. 
   
   
       19 . The compound of  claim 14  wherein each R A  is independently hydrogen, C 1-12  alkyl, C 1-12  alkenyl, C 1-12  alkynyl, halo, C 1-12  halohydrocarbyl, C 1-12  hydroxyalkyl, C 3-12  cyclic hydrocarbyl, or heteroaryl. 
   
   
       20 . A compound of  claim 1  selected from the group consisting of: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       21 . A compound of  claim 1  selected from the group consisting of: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       22 . Use of a compound according to  claim 1  in the manufacture of a medicament for the treatment of a disease or condition mediated by sphingosine-1-phosphate 3 (S1P3) receptor in a mammal. 
   
   
       23 . The use of  claim 22 , wherein the disease or condition is selected from the group consisting of glaucoma, elevated intraocular pressure, ischemic neuropathies, optic neuropathy, pain, visceral pain, corneal pain, headache pain, migraine, cancer pain, back pain, irritable bowel syndrome pain, muscle pain and pain associated with diabetic neuropathy, diabetic retinopathy, retinal degenerative conditions, dry eye, angiogenesis, retinopathy of prematurity, diabetic retinopathy, optic neuropathy, glaucomatous retinopathy, macular degeneration, choroidal neovascularization, ocular wound healing, retinal edema, congestive heart failure, cardiac arrhythmia, atherosclerosis, bradycardia, asthma, chronic obstructive pulmonary disease, acute lung injury, acute respiratory distress syndrome, idopathic pulmonary fibrosis, ventilation-induced lung injury, scar-less wound healing, scar-less skin-wound and cosmetic healing. 
   
   
       24 . The use of  claim 22  wherein the mammal is a human.