Substituted spirocyclic inhibitors of autotaxin

Abstract

The present invention relates to compounds according to Formula 1 and pharmaceutically acceptable salts, synthesis, intermediates, formulations, and methods of disease treatment therewith, including cancer, lymphocyte homing, chronic inflammation, neuropathic pain, fibrotic diseases, thrombosis, and cholestatic pruritus, mediated at least in part by ATX.

1 . A compound having the structure: 
       
         
           
           
               
               
           
         
       
       wherein R 1  is aryl substituted with one or more independent G 1  substituents;
 R 2  is C 1-12  alkyl or C 3-12 cycloalkyl; 
 R 3  is C 1-12  alkyl; and 
 R 4  is aryl or heteroaryl optionally substituted with one or more independent G 4  substituents, 
 G 1  and G 4  are each, independently, selected from one or more of H, D, halo, —CN, —CD 3 , —OCD 3 , -oxo-, —CF 3 , —OCF 3 , —OCHF 2 , —NR 5 R 6 , —NO 2 , —B(OH) 2 , —PO(OR 12 ) 2 , —PO(OR 12 )R 13 , —CONR 12 OH, —C 0-12 alkyl, —C 2-12 alkenyl, —C 2-12 alkynyl, C 3-12 cycloalkyl-C 0-12 alkyl-, C 3-12 heterocycloalkyl-C 0-12 alkyl-, aryl-C 0-12 alkyl-, heteroaryl-C 0-12 alkyl-, —OC 0-12 alkyl, —S(O) n1 R 12 , —C(O)R 12 , —C(O)NR 12 R 13 , —C(O)—C(O)NR 12 R 13 , —C(O)OR 12 , —C(O)—C(O)OR 12 , —OC(O)R 12 , —NR 12 C(O)R 13 , —NR 12 C(O)OR 13 , —NR 12 S(O) 2 R 13 , —(CR 14 R 15 )C(O)R 13 , —(CR 14 R 15 )C(O)OR 12 , —(CR 14 R 15 )C(O)NR 12 R 13 , —(CR 14 R 15 ) n1 S(O) 2 NR 12 R 13 , —(CR 14 R 15 ) n1 NR 12 R 13 , —(CR 14 R 15 ) n1 OR 12 , —(CR 14 R 15 ) n1 S(O) n2 R 12 , —NR 16 C(O)NR 12 R 13 , —NR 16 S(O) 2 NR 12 R 13  or —NR 16 S(O)NR 12 R 13 , any of which is optionally substituted with one or more independent Q 1  substituents; 
 Q 1  is selected from H, D, halo, —CN, —CD 3 , —OCD 3 , -oxo-, —CF 3 , —OCF 3 , —OCHF 2 , —NO 2 , —B(OH) 2 , —PO(OR 17 ) 2 , —PO(OR 17 )R 18 , NR 17 R 18 , —CONR 17 OH, C 0-12 alkyl-, —C 2-12  alkenyl, —C 2-12 alkynyl, aryl-C 0-12 alkyl-, heteroaryl-C 0-12 alkyl-, C 3-12 cycloalkyl-C 0-12 alkyl-, C 3-12 heterocycloalkyl-C 0-12 alkyl-, aryl-C 0-12 cycloalkyl-, heteroaryl-C 3-12 cycloalkyl-, C 3-12 heterocycloalkyl-C 3-12 cycloalkyl-, C 3-12 cycloalkyl-C 3-12 cycloalkyl-, C 1-12 alkyl-C 3-12 heterocycloalkyl-, C 3-12 heterocycloalkyl-C 3-12 heterocycloalkyl-, aryl-C 3-12 heterocycloalkyl-, heteroaryl-C 3-12 heterocycloalkyl-, —OC 0-12 alkyl, —C(O)—C(O)NR 17 R 18 , —C(O)—C(O)OR 17 , —OC(O)R 17 , —NR 17 C(O)R 18 , —NR 17 S(O) 2 R 18 , —(CR 19 R 20 ) n3 C(O)R 17 , —(CR 19 R 20 ) n3 C(O)OR 17 , —(CR 19 R 20 ) n3 C(O)NR 17 R 18 , —(CR 19 R 20 ) n3 S(O) 2 NR 17 R 18 , —(CR 19 R 20 ) n3 NR 17 R 18 , —(CR 19 R 20 ) n3 OR 17 , —(CR 19 R 20 ) n3 S(O) n4 R 17 , —NR 21 C(O)NR 17 R 18 , —NR 21 S(O) 2 NR 17 R 18  or —NR 21 S(O)NR 17 R 18 , any of which is optionally substituted with one or more independent Q 2  substituents; and 
 Q 2  is selected from one or more of H, D, halo, —CN, -oxo-, —CD 3 , —OCD 3 , —CF 3 , —OCF 3 , —OCHF 2 , —NO 2 , —B(OH) 2 , —PO(OR 27 ) 2 , —PO(OR 27 )R 28 , —CONR 27 OH, —CONR 27 R 28 C 0-12 alkyl-, —C 2-12  alkenyl, —C 2-12  alkynyl, —OC 0-12 alkyl, aryl-C 0-12 alkyl-, heteroaryl-C 0-12 alkyl-, C 3-12 cycloalkyl-C 0-12 alkyl-, C 3-12 heterocycloalkyl-C 0-12 alkyl-, aryl-C 0-12 cycloalkyl-, heteroaryl-C 3-12 cycloalkyl-, C 3-12 heterocycloalkyl-C 3-12 cycloalkyl-, C 3-12 cycloalkyl-C 3-12 cycloalkyl-, C 1-12 alkyl-C 3-12 heterocycloalkyl-, C 3-12 heterocycloalkyl-C 3-12 heterocycloalkyl-, aryl-C 3-12 heterocycloalkyl-, heteroaryl-C 3-12 heterocycloalkyl-, —C(O)—C(O)NR 27 R 28 , —C 0-12 alkylC(O)OR 27 , —C(O)—C(O)OR 27 , —OC(O)R 27 , —NR 27 C(O)R 28 , —NR 27 C(O)OR 28 , —NR 27 S(O) 2 R 28 , —(CR 29 R 30 ) n5 C(O)R 27 , —(CR 29 R 30 ) n5 C(O)OR 27 , —(CR 29 R 30 ) n5 C(O)NR 27 R 28 , —(CR 29 R 30 ) n5 S(O) 2 NR 27 R 28 , —(CR 29 R 30 ) n5 NR 27 R 28 , —(CR 29 R 30 ) n5 OR 27 , —(CR 29 R 30 ) n5 S(O) n6 R 27 , —NR 30 C(O)NR 27 R 28 , —NR 30 S(O) 2 NR 27 R 28  or —NR 30 S(O)NR 27 R 28  substituents, any of which may be optionally substituted 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         2 . The compound of  claim 1 , wherein R 2  is C 1-12  alkyl. 
     
     
         3 . The compound of  claim 2 , wherein R 2  is iso-propyl. 
     
     
         4 . The compound of  claim 1 , wherein the compound has the structure: 
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound of  claim 1 , wherein R 3  is methyl. 
     
     
         6 . The method of  claim 1 , wherein R 4  is aryl optionally substituted with one or more independent G 4  substituents. 
     
     
         7 . The method of  claim 6 , wherein R 4  is phenyl, 4-methoxy-phenyl, 3-fluoro-4-methoxy-phenyl, 4-cyano-phenyl, 3-cyano-phenyl, 3-methoxy-phenyl, 4-trifluoromethoxy-phenyl, 3-chloro-phenyl, 3-bromo-phenyl, 4-deutero-phenyl, 4-trifluoromethyl-phenyl, 4-carboxy-phenyl, 4-chloro-phenyl, 4-fluoro-phenyl, 4-methyl-phenyl, 3,4-dichloro-phenyl, 4-ethoxy-phenyl, 4-trideuteromethoxy-phenyl, 4-carboxymethyl-phenyl, 4-(oxetan-3-ylmethoxy)-phenyl,4-(2-hydroxyethoxy)-phenyl, 4-boronic acid-phenyl, 3-methoxy-4-carboxy-phenyl, 3-chloro-4-carboxy-phenyl, 4-carboxamide-phenyl, 4-oxyacetic acid-phenyl, 4-oxyacetamide-phenyl, 4-cyanomethyl-phenyl, 4-(2-dimethylamino-ethoxy)-phenyl, 4-acetamido-phenyl, 4-methyl-sulfnamido-phenyl, 4-methylcarbamate-phenyl, benzo[d][1,3]-dioxol-5-yl, 2-chloro-phenyl, 4-methylsulfonyl-phenyl, 3-methyl-1-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl, 4-(oxetan-3-ylamino)-phenyl, 4-(1H-1,2,4-triazol-3-yl)-phenyl, or 4-(2H-tetrazol-5-yl)-phenyl. 
     
     
         8 . The method of  claim 1 , wherein R 4  is heteroaryl optionally substituted with one or more independent G 4  substituents. 
     
     
         9 . The method of  claim 8 , wherein R 4  is 4-pyridyl, 1-methyl-1H-indazol-5-yl, 2-methyl-2H-indazoyl-5-yl, 1-imidazo[1,2a]pyridine-6-yl, 3-methylimidazo[1,5a]pyridine-6-yl, 1H-pyrrolo[2,3b]pyridine-5-yl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl, 1-methyl-6-oxo-1,6-dihydropyridin-3-yl, 5-benzofuranyl, 2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl, 1H-benzo[d][1,2,3]triazol-5-yl, 1H-indazoyl-5-yl, 1H-indol-5-yl, or 3-pyridyl. 
     
     
         10 . The method of  claim 1 , wherein the compound has the structure: 
       
         
           
           
               
               
           
         
       
     
     
         11 . The method of  claim 10 , wherein R 4  is aryl optionally substituted with one or more independent G 4  substituents. 
     
     
         12 . The method of  claim 11 , wherein R 4  is phenyl, 4-methoxy-phenyl, 3-fluoro-4-methoxy-phenyl, 4-cyano-phenyl, 3-cyano-phenyl, 3-methoxy-phenyl, 4-trifluoromethoxy-phenyl, 3-chloro-phenyl, 3-bromo-phenyl, 4-deutero-phenyl, 4-trifluoromethyl-phenyl, 4-carboxy-phenyl, 4-chloro-phenyl, 4-fluoro-phenyl, 4-methyl-phenyl, 3,4-dichloro-phenyl, 4-ethoxy-phenyl, 4-trideuteromethoxy-phenyl, 4-carboxymethyl-phenyl, 4-(oxetan-3-ylmethoxy)-phenyl,4-(2-hydroxyethoxy)-phenyl, 4-boronic acid-phenyl, 3-methoxy-4-carboxy-phenyl, 3-chloro-4-carboxy-phenyl, 4-carboxamide-phenyl, 4-oxyacetic acid-phenyl, 4-oxyacetamide-phenyl, 4-cyanomethyl-phenyl, 4-(2-dimethylamino-ethoxy)-phenyl, 4-acetamido-phenyl, 4-methyl-sulfnamido-phenyl, 4-methylcarbamate-phenyl, benzo[d][1,3]-dioxol-5-yl, 2-chloro-phenyl, 4-methylsulfonyl-phenyl, 3-methyl-1-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl, 4-(oxetan-3-ylamino)-phenyl, 4-(1H-1,2,4-triazol-3-yl)-phenyl, or 4-(2H-tetrazol-5-yl)-phenyl. 
     
     
         13 . The method of  claim 10 , wherein R 4  is heteroaryl optionally substituted with one or more independent G 4  substituents. 
     
     
         14 . The method of  claim 13 , wherein R 4  is 4-pyridyl, 1-methyl-1H-indazol-5-yl, 2-methyl-2H-indazoyl-5-yl, 1-imidazo[1,2a]pyridine-6-yl, 3-methylimidazo[1,5a]pyridine-6-yl, 1H-pyrrolo[2,3b]pyridine-5-yl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl, 1-methyl-6-oxo-1,6-dihydropyridin-3-yl, 5-benzofuranyl, 2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl, 1H-benzo[d][1,2,3]triazol-5-yl, 1H-indazoyl-5-yl, 1H-indol-5-yl, or 3-pyridyl. 
     
     
         15 . A pharmaceutical composition comprising the compound of  claim 1  and one or more pharmaceutically acceptable carriers. 
     
     
         16 . A method for inhibiting autotaxin comprising administering to a subject in need thereof an effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         17 . The method of  claim 16 , wherein the compound binds to autotaxin providing a reduction in lysophosphatidic acid levels. 
     
     
         18 . The method of  claim 16 , wherein the method further comprises administering one or more additional therapeutically active agents. 
     
     
         19 . The method of  claim 18 , wherein the one or more additional therapeutically active agents is a corticosteroid, an immunosuppressant, an analgesic, an anti-cancer agent, an anti-inflammatory agent, a non-steroidal anti-inflammatory agent, a dual cyclooxygenase-1 and -2 inhibitor, a cyclooxygenase-2 selective inhibitor, a TNFα blocker, a kinase inhibitor, a chemokine receptor antagonist, a bronchodilator, a leukotriene receptor antagonist, a leukotriene formation inhibitor, a prostaglandin receptor antagonist, a prostaglandin formation inhibitor, a monoacylglycerol kinase inhibitor, a phospholipase A1 inhibitor, a phospholipase A2 inhibitor, a lysophospholipase D inhibitor, an autotaxin inhibitor, and a lysophosphatidic acid receptor antagonist.