Tetracyclic autotaxin inhibitors

Abstract

Described herein are compounds that are autotaxin inhibitors, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders associated with autotaxin activity.

What is claimed is: 
     
         1 . A compound having the structure of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof: 
       
         
           
           
               
               
           
         
         wherein, 
         R 1  is H, halogen, —CN, —OH, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, or C 1 -C 4 deuteroalkyl; 
         R 3  is H, F, C 1 -C 4 alkyl, or C 1 -C 4 fluoroalkyl; 
         R 4  is H, F, C 1 -C 4 alkyl, or C 1 -C 4 fluoroalkyl; 
         R 7  is H, or F; 
         each R A  substituent is independently H, halogen, OH, —O—C 1 -C 4 alkyl, —CN, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, or C 1 -C 6 deuteroalkyl;
 n is 0, or 1; 
 
         X is —CH═, —N═, or —CF═; and 
         W is —C(═O)—, —C(═S)—, or —CH 2 —. 
       
     
     
         2 . The compound of  claim 1 , or a pharmaceutically acceptable salt, or solvate thereof, wherein R 1  is H, F, Cl, —CN, —CH 3 , —CF 3 , or -CD 3 . 
     
     
         3 . The compound of  claim 1 , or a pharmaceutically acceptable salt, or solvate thereof, wherein R 1  is H or Cl. 
     
     
         4 . The compound of any one of  claims 1 - 3 , or a pharmaceutically acceptable salt, or solvate thereof, wherein R 3  is H or —CH 3 . 
     
     
         5 . The compound of any one of  claims 1 - 4 , or a pharmaceutically acceptable salt, or solvate thereof, wherein R 4  is H or —CH 3 . 
     
     
         6 . The compound of any one of  claims 1 - 5 , or a pharmaceutically acceptable salt, or solvate thereof, wherein X is —CH═ or —N═. 
     
     
         7 . The compound of any one of  claims 1 - 6 , or a pharmaceutically acceptable salt, or solvate thereof, wherein W is —C(═O)—, or —CH 2 —. 
     
     
         8 . The compound of any one of  claims 1 - 7 , or a pharmaceutically acceptable salt, or solvate thereof, wherein n is 0. 
     
     
         9 . The compound of  claim 1 , wherein the compound is:
 6-(4-fluorobenzyl)-5,6,11,11a-tetrahydro-1H-imidazo[1′,5′:1,6]pyrido[3,4-b]indol-3(2H)-one (compound no. 1-13);   6-(4-fluorobenzyl)-5,6,11,11a-tetrahydro-1H-imidazo[1′,5′:1,6]pyrido[3,4-b] indole-1,3(2H)-dione (compound no. 1-15);   (S)-6-(4-fluorobenzyl)-5,6,11,11a-tetrahydro-1H-imidazo[1′,5′:1,6]pyrido[3,4-b]indole-1,3(2H)-dione (compound no. 1-130);   8-[p-fluorophenyl)methyl]-6,8,11,13-tetrazatetracyclo[7.7.0.02, 7.011,15] hexadeca-1(9),2(7),3,5-tetraen-12,14-dione (compound no. C109);   6-(4-fluorobenzyl)-11,11-dimethyl-5,6,11,11a-tetrahydro-1H-imidazo[1′,5′:1,6]pyrido[3,4-b]indole-1,3(2H)-dione (compound no. A110);   6-(4-fluorobenzyl)-11,11-dimethyl-5,6,11,11a-tetrahydro-1H-imidazo[1′,5′:1,6]pyrido[3,4-b]indole-1,3(2H)-dione (compound no. A110 Enantiomer A); or   6-(4-fluorobenzyl)-11,11-dimethyl-5,6,11,11a-tetrahydro-1H-imidazo[1′,5′:1,6]pyrido[3,4-b]indole-1,3(2H)-dione (compound no. A110 Enantiomer B);   or a pharmaceutically acceptable salt, or solvate thereof of any of the preceding compounds.   
     
     
         10 . A compound having the structure of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof: 
       
         
           
           
               
               
           
         
         wherein, 
         R 1  is H, halogen, —CN, C 1 -C 4 alkyl, —CF 3 , or C 1 -C 4 deuteroalkyl; 
         R 2  is H, halogen, —CN, —OH, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, C 1 -C 4 deuteroalkyl, C 1 -C 4 alkoxy, or C 1 -C 4 fluoroalkoxy; 
         R 3  is H, F, C 1 -C 4 alkyl, or C 1 -C 4 fluoroalkyl; 
         R 4  is H, F, C 1 -C 4 alkyl, or C 1 -C 4 fluoroalkyl; 
         R 5  is H, F, C 1 -C 4 alkyl, or C 1 -C 4 fluoroalkyl; 
         R 6  is H, F, C 1 -C 4 alkyl, or C 1 -C 4 fluoroalkyl; 
         R 7  is H, or F; 
         R 8  is independently selected from H, —OH, —OR 9 , C 1 -C 6 alkyl, and C 1 -C 6 fluoroalkyl; 
         L 1  is absent, substituted or unsubstituted C 1 -C 4 alkylene, or substituted or unsubstituted C 3 -C 7  cycloalkylene; 
         A is a substituted or unsubstituted aryl, substituted or unsubstituted monocyclic heteroaryl, substituted or unsubstituted bicyclic heteroaryl, substituted or unsubstituted monocyclic heterocycloalkyl, or substituted or unsubstituted bicyclic heterocycloalkyl; 
         each R A  substituent is independently H, halogen, OH, —OR 9 , —CN, —NO 2 , C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 heteroalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 2 -C 10 heterocycloalkyl, substituted or unsubstituted aryl, —C 1 -C 4 alkylene-substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —C 1 -C 4 alkylene-substituted or unsubstituted heteroaryl, —C(═O)R 9 , —S(═O) 2 R 9 , —S(═O)R 9 , —SR 9 , —S(═O) 2 N(R 10 ) 2 , —NR 10 S(═O) 2 R 9 , —OC(═O)R 9 , —CO 2 R 10 , —OCO 2 R 9 , —N(R 10 ) 2 , —C(═O)N(R 10 ) 2 , —OC(═O)N(R 10 ) 2 , —NHC(═O)R 9 , or —NHC(═O)OR 9 ;
 or two R A  groups may be taken together with the intervening atoms connecting the two R A  groups to form a substituted or unsubstituted ring containing 0-3 heteroatoms selected from —O—, —NR 11 — and —S—; 
 n is 0, 1, 2, 3, or 4; 
 
         X is —CH═, —N═, or —CF═; 
         W is —C(═O)—, —C(═S)—, or —CH 2 —; 
         Y is —C(═O)—, —C(═S)—, —CH 2 — or —CF 2 —; 
         Z is —CH 2 —, —O—, >N—(C 1 -C 6 alkyl), —Z′—, —Z′—NH— or —NH—Z′—;
 Z′ is >N-L 2 -B-L 3 -Q;
 L 2  is absent, substituted or unsubstituted C 1 -C 6 alkylene, substituted or unsubstituted C 1 -C 6 fluoroalkylene, or substituted or unsubstituted C 3 -C 6 cycloalkylene; 
 B is absent, —O—, —S—, —S(═O)—, —S(═O) 2 —, —NR 11 —, —C(═O)—, —C(═O)NR 10 —, or —NR 10 C(═O)—; 
 L 3  is absent, substituted or unsubstituted C 1 -C 6 alkylene, substituted or unsubstituted C 1 -C 6 fluoroalkylene, or substituted or unsubstituted C 3 -C 6 cycloalkylene; 
 Q is —CO 2 H, —CO 2 (C 1 -C 6 alkyl), —OH, —B(OH) 2 , —C(═O)NHSO 2 R 9 , —C(═O)N(R 10 ) 2 , —C(═O)NH—OH, —C(═O)NH—CN, —SO 2 NHC(═O)R 9 , —OP(═O)(OH) 2 , —P(═O)(OH) 2 , tetrazolyl, carboxylic acid bioisostere, substituted or unsubstituted monocyclic heterocycle, —S(═O) 2 R 9 , —S(═O)R 9 , —SR 9 , —S(═O) 2 N(R 10 ) 2 , —NR 10 S(═O) 2 R 9 , —OC(═O)R 9 , —OCO 2 R 9 , —N(R 10 ) 2 , —C(═O)N(R 10 ) 2 , —OC(═O)N(R 10 ) 2 , —NHC(═O)R 9 , or —NHC(═O)OR 9 ; 
 
 
         each R 9  is independently C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 1 -C 6 deuteroalkyl, C 3 -C 6 cycloalkyl, a substituted or unsubstituted phenyl, —C 1 -C 4 alkylene-substituted or unsubstituted aryl, a substituted or unsubstituted monocyclic heteroaryl, —C 1 -C 4 alkylene-substituted or unsubstituted monocyclic heteroaryl, or a substituted or unsubstituted bicyclic heteroaryl; 
         each R 10  is independently H, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 1 -C 6 deuteroalkyl, C 3 -C 6 cycloalkyl, a substituted or unsubstituted phenyl, —C 1 -C 4 alkylene-substituted or unsubstituted aryl, a substituted or unsubstituted monocyclic heteroaryl, or —C 1 -C 4 alkylene-substituted or unsubstituted monocyclic heteroaryl;
 or two R 10  groups attached to the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted heterocycle; 
 
         R 11  is H, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 1 -C 6 deuteroalkyl, C 3 -C 6 cycloalkyl, a substituted or unsubstituted phenyl, —C 1 -C 4 alkylene-substituted or unsubstituted aryl, a substituted or unsubstituted monocyclic heteroaryl, —C 1 -C 4 alkylene-substituted or unsubstituted monocyclic heteroaryl, —S(═O) 2 R 9 , —C(═O)R 9 , —CO 2 R 10 , or —C(═O)N(R 10 ) 2 ; 
         t is 0 or 1; and 
         u is 0 or 1. 
       
     
     
         11 . The compound of  claim 10 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 Z is —CH 2 —, —O—, >N—(C 1 -C 6 alkyl), or —Z′—;   Z′ is >N-L 2 -B-L 3 -Q;   L 2  is absent, substituted or unsubstituted C 1 -C 6 alkylene, substituted or unsubstituted C 1 -C 6 fluoroalkylene, or substituted or unsubstituted C 3 -C 6 cycloalkylene;   B is absent, —O—, —S—, —S(═O)—, —S(═O) 2 —, —NR 11 —, —C(═O)—, —C(═O)NR 10 —, or —NR 10 C(═O)—;   L 3  is absent, substituted or unsubstituted C 1 -C 6 alkylene, substituted or unsubstituted C 1 -C 6 fluoroalkylene, or substituted or unsubstituted C 3 -C 6 cycloalkylene; and   Q is —CO 2 H, —CO 2 (C 1 -C 6 alkyl), —OH, —B(OH) 2 , —C(═O)NHSO 2 R 9 , —C(═O)N(R 10 ) 2 , —C(═O)NH—OH, —C(═O)NH—CN, —SO 2 NHC(═O)R 9 , —OP(═O)(OH) 2 , —P(═O)(OH) 2 , tetrazolyl, or carboxylic acid bioisostere.   
     
     
         12 . The compound of  claim 10  or  claim 11 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 Z is —Z′—. 
 
     
     
         13 . The compound of any one of  claims 10 - 12 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 L 2  is C 1 -C 6 alkylene, or C 3 -C 6 cycloalkylene;   B is absent; and   L 3  is absent.   
     
     
         14 . The compound of any one of  claims 10 - 12 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 L 2  is C 1 -C 6 alkylene;   B is absent; and   L 3  is absent or C 3 -C 6 cycloalkylene.   
     
     
         15 . The compound of any one of  claims 10 - 14 , or a pharmaceutically acceptable salt, or solvate thereof, wherein
 L 2  is C 1 -C 6 alkylene; and   Q is —CO 2 H, —CO 2 (C 1 -C 6 alkyl), —B(OH) 2 , —C(═O)NHSO 2 R 9 , —C(═O)N(R 10 ) 2 , tetrazolyl, or carboxylic acid bioisostere.   
     
     
         16 . The compound of any one of  claims 10 - 12 , or a pharmaceutically acceptable salt, or solvate thereof, wherein:
 L 2  is absent, —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, or —CH 2 CH 2 CH 2 CH 2 —; and   Q is —CO 2 H, or —CO 2 (C 1 -C 6 alkyl).   
     
     
         17 . The compound of any one of  claims 10 - 16 , or a pharmaceutically acceptable salt, or solvate thereof, wherein:
 R 3  is H, F, Cl, Br, —CN, —OH, —CH 3 , or —CF 3 ; and   R 4  is H, F, Cl, Br, —CN, —OH, —CH 3 , or —CF 3 .   or R 3  and R 4  are taken together with the carbon atom to which they are attached to form —C(═O)— or cyclopropyl.   
     
     
         18 . The compound of any one of  claims 10 - 17 , or a pharmaceutically acceptable salt, or solvate thereof, wherein:
 R 5  is H, F, Cl, —CH 3 , or —CF 3 ; and   R 6  is H, F, Cl, —CH 3 , or —CF 3 .   
     
     
         19 . The compound of any one of  claims 10 - 18 , or a pharmaceutically acceptable salt, or solvate thereof, wherein:
 R 7  is H, F, Cl, —CH 3 , or —CF 3 .   
     
     
         20 . The compound of any one of  claims 10 - 19 , or a pharmaceutically acceptable salt, or solvate thereof, wherein:
 L 1  is a absent or C 1-4 alkylene; and   A is phenyl, naphthyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, indolyl, indazolyl, benzoxazolyl, benzisoxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzimidazolyl, purinyl, cinnolinyl, phthalazinyl, pteridinyl, pyridopyrimidinyl, pyrazolopyrimidinyl, or azaindolyl.   
     
     
         21 . The compound of any one of  claims 10 - 20 , or a pharmaceutically acceptable salt, or solvate thereof, wherein:
 L 1  is absent, —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, or —CH 2 CH 2 CH 2 CH 2 —.   
     
     
         22 . The compound of any one of  claims 10 - 21 , or a pharmaceutically acceptable salt, or solvate thereof, wherein:
 A is phenyl.   
     
     
         23 . The compound of any one of  claims 10 - 21 , or a pharmaceutically acceptable salt, or solvate thereof, wherein:
 A is pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl.   
     
     
         24 . The compound of any one of  claims 10 - 21 , or a pharmaceutically acceptable salt, or solvate thereof, wherein:
 A is pyridinyl.   
     
     
         25 . The compound of any one of  claims 10 - 21 , or a pharmaceutically acceptable salt, or solvate thereof, wherein:
 A is furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl.   
     
     
         26 . The compound of any one of  claims 10 - 25 , or a pharmaceutically acceptable salt, or solvate thereof, wherein:
 R 1  is H, halogen, —CN, —OH, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, C 1 -C 4 deuteroalkyl, C 1 -C 4 alkoxy, C 1 -C 4 fluoroalkoxy, or C 1 -C 4 hydroxyalkyl.   
     
     
         27 . The compound of any one of  claims 10 - 26 , or a pharmaceutically acceptable salt, or solvate thereof, wherein:
 R 1  is H, F, Cl, Br, —CN, —OH, —CH 3 , —CF 3 , —CD 3 , —OCH 3 , —OCH 2 CH 3 , —OCF 3 , —OCH 2 CF 3 , or —CH 2 OH.   
     
     
         28 . The compound of any one of  claims 10 - 27 , or a pharmaceutically acceptable salt, or solvate thereof, wherein:
 R 2  is H, halogen, —CN, —OH, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, C 1 -C 4 deuteroalkyl, C 1 -C 4 alkoxy, or C 1 -C 4 fluoroalkoxy.   
     
     
         29 . The compound of any one of  claims 10 - 28 , or a pharmaceutically acceptable salt, or solvate thereof, wherein:
 R 2  is H, F, Cl, Br, I, —CN, —OH, —CH 3 , —CF 3 , —CD 3 , —OCH 3 , —OCH 2 CH 3 , —OCF 3 , or —OCH 2 CF 3 .   
     
     
         30 . The compound of any one of  claims 10 - 29 , or a pharmaceutically acceptable salt, or solvate thereof, wherein:
 t is 0; and   u is 0   
     
     
         31 . The compound of any one of  claims 10 - 30 , or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the following structure of Formula (II): 
       
         
           
           
               
               
           
         
       
     
     
         32 . The compound of any one of  claims 10 - 31 , or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the following structure of Formula (III), Formula (IV), or Formula (V): 
       
         
           
           
               
               
           
         
       
     
     
         33 . A compound of  claim 10 , wherein the compound is:
 4-(6-(4-fluorobenzyl)-1,3-dioxo-11,11a-dihydro-1H-imidazo[1′,5′:1,6]pyrido[3,4-b]indol-2(3H,5H,6H)-yl)butanoic acid (compound no. 1-1);   (S)-4-(6-(4-fluorobenzyl)-1,3-dioxo-11,11a-dihydro-1H-imidazo[1′,5′:1,6]pyrido[3,4-b]indol-2(3H,5H,6H)-yl)butanoic acid (compound no. 1-2);   (R)-4-(6-(4-fluorobenzyl)-1,3-dioxo-11,11a-dihydro-1H-imidazo[1′,5′:1,6]pyrido[3,4-b] indol-2(3H,5H,6H)-yl)butanoic acid (compound no. 1-3);   3-(6-(4-fluorobenzyl)-1,3-dioxo-11,11a-dihydro-1H-imidazo[1′,5′:1,6]pyrido[3,4-b]indol-2(3H,5H,6H)-yl)propanoic acid (compound no. 1-4);   3-(6-(4-fluorobenzyl)-1,3-dioxo-11,11a-dihydro-1H-imidazo[1′,5′:1,6]pyrido[3,4-b]indol-2(3H,5H,6H)-yl)propanoic acid (compound no. 1-5; Enantiomer A);   3-(6-(4-fluorobenzyl)-1,3-dioxo-11,11a-dihydro-1H-imidazo[1′,5′:1,6]pyrido[3,4-b]indol-2(3H,5H,6H)-yl)propanoic acid (compound no. 1-6; Enantiomer B);   4-(1,3-dioxo-6-(3-phenylpropyl)-11,11a-dihydro-1H-imidazo[1′,5′:1,6]pyrido[3,4-b] indol-2(3H,5H,6H)-yl)butanoic acid (compound no. 1-7);   6-(4-fluorobenzyl)-5,6,11,11a-tetrahydrooxazolo[3′,4′:1,6]pyrido[3,4-b]indol-3(1H)-one (compound no. 1-8);   (S)-6-(4-fluorobenzyl)-5,6,11,11a-tetrahydrooxazolo[3′,4′:1,6] pyrido[3,4-b]indol-3(1H)-one (compound no. 1-9);   (R)-6-(4-fluorobenzyl)-5,6,11,11a-tetrahydrooxazolo[3′,4′:1,6] pyrido[3,4-b]indol-3(1H)-one (compound no. 1-10);   (S)-4-(6-((6-methoxypyridin-3-yl)methyl)-1,3-dioxo-11,11a-dihydro-1H-imidazo[1′,5′:1,6]pyrido[3,4-b]indol-2(3H,5H,6H)-yl)butanoic acid (compound no. 1-11);   (S)-3-(6-((6-methoxypyridin-3-yl)methyl)-1,3-dioxo-11,11a-dihydro-1H-imidazo[1′,5′:1,6]pyrido[3,4-b]indol-2(3H,5H,6H)-yl)propanoic acid (compound no. 1-12);   6-(4-fluorobenzyl)-2-methyl-5,6,11,11a-tetrahydro-1H-imidazo[1′,5′:1,6]pyrido[3,4-b]indol-3(2H)-one (compound no. 1-14);   6-(4-fluorobenzyl)-2-methyl-5,6,11,11a-tetrahydro-1H-imidazo[1′,5′:1,6]pyrido[3,4-b]indole-1,3(2H)-dione (compound no. 1-129);   6-(4-fluorobenzyl)-2-(2-hydroxyethyl)-5,6,11,11a-tetrahydro-1H-imidazo[1′,5′:1,6]pyrido[3,4-b]indole-1,3(2H)-dione (compound no. 1-121);   2-(6-(4-fluorobenzyl)-1,3-dioxo-5,6,11,11a-tetrahydro-1H-imidazo[1′,5′:1,6] pyrido[3,4-b]indol-2(3H)-yl)acetonitrile (compound no. 1-139);   2-(6-(4-fluorobenzyl)-1,3-dioxo-5,6,11,11a-tetrahydro-1H-imidazo[1′,5′:1,6]pyrido[3,4-b]indol-2(3H)-yl)acetic acid (compound no. 1-19);   7-(4-fluorobenzyl)-2,3,6,7,12,12a-hexahydropyrazino[1′,2′:1,6]pyrido[3,4-b]indole-1,4-dione (compound no. 1-16);   2-(7-(4-fluorobenzyl)-1,4-dioxo-3,4,6,7,12,12a-hexahydropyrazino [1′,2′:1,6]pyrido[3,4-b]indol-2(1H)-yl)acetic acid (compound no. 1-23);   3-(7-(4-fluorobenzyl)-1,4-dioxo-3,4,6,7,12,12a-hexahydropyrazino [1′,2′:1,6]pyrido[3,4-b]indol-2(1H)-yl)propanoic acid (compound no. 1-24);   (S)-4-(6-(4-fluorobenzyl)-1,3-dioxo-5,6,11,11a-tetrahydro-1H-imidazo[1′,5′:1,6]pyrido[3,4-b]indol-2(3H)-yl)-2,2-dimethylbutanoic acid (compound no. 1-39);   (S)-4-(6-(4-fluorobenzyl)-1,3-dioxo-5,6,11,11a-tetrahydro-1H-imidazo[1′,5′:1,6]pyrido[3,4-b]indol-2(3H)-yl)-3,3-dimethylbutanoic acid (compound no. 1-42);   (S)-4-(8-chloro-6-(4-fluorobenzyl)-1,3-dioxo-5,6,11,11a-tetrahydro-1H-imidazo[1′,5′:1,6]pyrido[3,4-b]indol-2(3H)-yl)butanoic acid (compound no. 1-27);   (S)-8-chloro-6-(4-fluorobenzyl)-5,6,11,11a-tetrahydro-1H-imidazo[1′,5′:1,6] pyrido[3,4-b]indole-1,3(2H)-dione (compound no. 1-26);   (S)-3-(6-((6-chloropyridin-3-yl)methyl)-1,3-dioxo-5,6,11,11a-tetrahydro-1H-imidazo[1′,5′:1,6]pyrido[3,4-b]indol-2(3H)-yl)propanoic acid (compound no. 1-84);   (S)-1-((6-((6-methoxypyridin-3-yl)methyl)-1,3-dioxo-5,6,11,11a-tetrahydro-1H-imidazo[1′,5′:1,6]pyrido[3,4-b]indol-2(3H)-yl)methyl)cyclopropane-1-carboxylic acid (compound no. 1-18);   (S)-3-(6-(4-fluorobenzyl)-1,3-dioxo-5,6,11,11a-tetrahydro-1H-imidazo [1′,5′:1,6]pyrido[3,4-b]indol-2(3H)-yl)-2,2-dimethylpropanoic acid (compound no. 1-30);   (S)-1-((6-(4-fluorobenzyl)-1,3-dioxo-5,6,11,11a-tetrahydro-1H-imidazo[1′,5′:1,6]pyrido[3,4-b]indol-2(3H)-yl)methyl)cyclopropane-1-carboxylic acid (compound no. 1-34);   3-{8-[(4-fluorophenyl)methyl]-12,14-dioxo-6,8,11,13-tetraazatetracyclo [7.7.0.02, 7.011,15]hexadeca-1(9),2(7),3,5-tetraen-13-yl}propionic acid (compound no. C114) 3-{8-[(4-fluorophenyl)methyl]-12,14-dioxo-6,8,11,13-tetraazatetracyclo [7.7.0.02, 7.011,15]hexadeca-1(9),2(7),3,5-tetraen-13-yl}propionic acid (compound no. C114 Enantiomer A);   3-{8-[(4-fluorophenyl)methyl]-12,14-dioxo-6,8,11,13-tetraazatetracyclo [7.7.0.02, 7.011,15]hexadeca-1(9),2(7),3,5-tetraen-13-yl} propionic acid (compound no. C114 Enantiomer B);   (S)-3-(6-(4-fluorobenzyl)-1-oxo-3-thioxo-5,6,11,11a-tetrahydro-1H-imidazo [1′,5′:1,6]pyrido[3,4-b]indol-2(3H)-yl)propanoic acid (compound no. E1);   3-(6-(4-fluorobenzyl)-11,11-dimethyl-1,3-dioxo-5,6,11,11a-tetrahydro-1H-imidazo[1′,5′:1,6]pyrido[3,4-b]indol-2(3H)-yl)propanoic acid (compound no. A11);   2-(6-(4-fluorobenzyl)-3-oxo-11,11a-dihydro-1H-imidazo[1′,5′:1,6] pyrido[3,4-b]indol-2(3H,5H,6H)-yl)acetic acid (compound no. 1-20);   3-(6-(4-fluorobenzyl)-3-oxo-11,11a-dihydro-1H-imidazo[1′,5′:1,6]pyrido[3,4-b]indol-2(3H,5H,6H)-yl)propanoic acid (compound no. 1-21);   (S)-3-(1,3-dioxo-6-((2-(trifluoromethyl)thiazol-5-yl)methyl)-11,11a-dihydro-1H-imidazo[1′,5′:1,6]pyrido[3,4-b]indol-2(3H,5H,6H)-yl)propanoic acid (compound no. 1-102);   (S)-3-(6-(4-methoxybenzyl)-1,3-dioxo-11,11a-dihydro-1H-imidazo[1′,5′:1,6]pyrido[3,4-b]indol-2(3H,5H,6H)-yl)propanoic acid (compound no. 1-131);   (S)-3-(6-(2,4-dichlorobenzyl)-1,3-dioxo-11,11a-dihydro-1H-imidazo[1′,5′:1,6]pyrido[3,4-b]indol-2(3H,5H,6H)-yl)propanoic acid (compound no. 1-132);   (S)-3-(6-(4-chloro-2-fluorobenzyl)-1,3-dioxo-11,11a-dihydro-1H-imidazo[1′,5′:1,6]pyrido[3,4-b]indol-2(3H,5H,6H)-yl)propanoic acid (compound no. 1-133);   (S)-3-(6-(2,4-difluorobenzyl)-1,3-dioxo-11,11a-dihydro-1H-imidazo[1′,5′:1,6]pyrido[3,4-b]indol-2(3H,5H,6H)-yl)propanoic acid (compound no. 1-134);   (S)-3-(6-((6-fluoropyridin-3-yl)methyl)-1,3-dioxo-11,11a-dihydro-1H-imidazo[1′,5′:1,6]pyrido[3,4-b]indol-2(3H,5H,6H)-yl)propanoic acid (compound no. 1-135);   (S)-6-(4-fluorobenzyl)-3-thioxo-2,3,5,6,11,11a-hexahydro-1H-imidazo[1′,5′:1,6]pyrido[3,4-b]indol-1-one (compound no. E2);   (S)-3(6-(4-fluorobenzyl)-3-oxo-1-thioxo-5,6,11,11a-tetrahydro-1H-imidazo [1′,5′:1,6]pyrido[3,4-b]indol-2(3H)-yl)propanoic acid (compound no. 1-141);   3-{8-[(p-fluorophenyl)methyl]-12,14-dioxo-6,8,11,13-tetrazatetracyclo [7.7.0.02,7.011,15]hexadeca-1(9),2(7),3,5-tetraene-13-yl}-2,2-dimethyl propionic acid (compound no. C111);   8-[p-fluorophenyl)methyl]-12-thioxo-6,8,11,13-tetrazatetracyclo [7.7.0.02,7.011,15]hexadeca-1(9),2(7),3,5-tetraen-14-one (compound no. E3);   3-{8-[(p-fluorophenyl)methyl]-16,16-dimethyl-12,14-dioxo-6,8,11,13-tetrazatetracyclo[7.7.0.02,7.011,15]hexadeca-1 (9),2(7),3,5-tetraene-13-yl}propionic acid (compound no. C11);   (S)-3-(6-(4-fluorobenzyl)-1,3-dioxo-11,11a-dihydro-1H-imidazo[1′,5′:1,6]pyrido[3,4-b] indol-2(3H,5H,6H)-yl)-N-(methylsulfonyl)propanamide (compound no. 1-142);   (S)-3-(6-(4-fluorobenzyl)-1,3-dioxo-11,11a-dihydro-1H-imidazo[1′,5′:1,6]pyrido[3,4-b]indol-2(3H,5H,6H)-yl)-N-(phenylsulfonyl)propanamide (compound no. 1-143);   3-(6-(4-fluorobenzyl)-11a-methyl-1,3-dioxo-11,11a-dihydro-1H-imidazo[1′,5′:1,6]pyrido[3,4-b]indol-2(3H,5H,6H)-yl)propanoic acid (compound no. A113);   2-((2H-tetrazol-5-yl)methyl)-6-(4-fluorobenzyl)-5,6,11,11a-tetrahydro-1H-imidazo[1′,5′:1,6]pyrido[3,4-b]indole-1,3(2H)-dione (compound no. 1-140); or   3-{8-[(p-fluorophenyl)methyl]-16,16-dimethyl-12,14-dioxo-6,8,11,13-tetrazatetracyclo[7.7.0.02,7.011,15]hexadeca-1 (9),2(7),3,5-tetraene-13-yl}-2,2-dimethylpropionic acid (compound no. C13);   or a pharmaceutically acceptable salt, or solvate thereof of any one of the preceding compounds.   
     
     
         34 . A pharmaceutical composition comprising a compound of any one of  claims 1 - 33 , or a pharmaceutically acceptable salt, or solvate thereof, and at least one pharmaceutically acceptable excipient. 
     
     
         35 . A method for treating or preventing cancer in a mammal comprising administering a therapeutically effective amount of a compound of any one of  claims 1 - 33 , or a pharmaceutically acceptable salt, or solvate thereof, to the mammal in need thereof. 
     
     
         36 . The method of  claim 35 , wherein the cancer is amenable to treatment with an autotaxin inhibitor. 
     
     
         37 . A method for the treatment or prevention of fibrosis in a mammal comprising administering a therapeutically effective amount of a compound of any one of  claims 1 - 33 , or a pharmaceutically acceptable salt, or solvate thereof, to the mammal in need thereof. 
     
     
         38 . The method of  claim 37 , wherein the fibrosis is amenable to treatment with an autotaxin inhibitor. 
     
     
         39 . The method of any one of  claims 35 - 38 , further comprising administering a second therapeutic agent to the mammal in addition to the compound of any one of  claims 1 - 33 , or a pharmaceutically acceptable salt, or solvate thereof.