Heterocyclic compounds as delta-5 desaturase inhibitors and methods of use

Abstract

The present disclosure provides compounds useful for the inhibition of Delta-5 Desaturase (“D5D”). The compounds have a general Formula Iwherein the variables of Formula I are defined herein. This disclosure also provides pharmaceutical compositions comprising the compounds, uses of the compounds, and compositions for treatment of, for example, a metabolic or cardiovascular disorder. Further, the disclosure provides intermediates useful in the synthesis of compounds of Formula I.

1 . A compound of Formula I 
       
         
           
           
               
               
           
         
         or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein 
       
       
         
           
           
               
               
           
         
         each R is independently selected from H, halogen, —OH, —CN, —CO(C 1-4 alkyl), —S(O) n (C 1-4 alkyl), —COOH, —COO(C 1-4 alkyl), —CONH 2 , —CONH(C 1-4 alkyl), —CO(diC 1-4 alkylamino), —NH 2 , C 1-4 alkylamino, diC 1-4 alkylamino, —NH(COC 1-4 alkyl), —N(C 1-4 alkyl)C(═O)F, C 1-4 alkyl, —(CH 2 ) m (C 3-5 cycloalkyl), —CH 2 (C 3-5 heterocycloalkyl), C 1-4 deuteroalkyl, C 3-5 cycloalkyl, C 3-4 heterocycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 deuteroalkoxy, phenyl, 5-membered heteroaryl, and 6-membered heteroaryl;
 wherein the C 1-4 alkyl group is optionally substituted with 1 to 4 F or optionally substituted with a substituent selected from —OH, —CN, C 1-4 alkoxy, —NH 2 , C 1-4 alkylamino, diC 1-4 alkylamino, and —S(O) n (C 1-4 alkyl); 
 wherein the C 1-4 alkoxy group is optionally substituted with 1 to 4 independently selected halogens or optionally substituted with a substituent selected from —OH, —CN, C 1-4 alkoxy, —NH 2 , C 1-4 alkylamino, diC 1-4 alkylamino, and —S(O) n (C 1-4 alkyl); 
 wherein the —CH 2 (C 3-5 cycloalkyl), C 3-4 heterocycloalkyl, phenyl, 5-membered heteroaryl, and 6-membered heteroaryl groups are optionally substituted with 1 to 4 substituents independently selected from halogen, —OH, —CN, C 1-4 alkoxy, C 1-4 alkyl, —NH 2 , C 1-4 alkylamino, diC 1-4 alkylamino, and —S(O) n (C 1-4 alkyl); and 
 wherein R of a first CR group and R of a second CR group, if present, together with the atoms to which they are attached, form a C 3-5 carbocycle; 
 
         R 1  is O, S, or NH; 
         R 2  is 
       
       
         
           
           
               
               
           
         
         wherein
 Ring A is a 5-membered heteroaryl containing one heteroatom selected from N, S, and O and optionally one or two further N atoms with the remaining ring atoms of the 5-membered heteroaryl being carbon, wherein 
 i) Ring A is attached via a C atom to the bicyclic core and R 3  is attached via an N atom; or 
 ii) Ring A is attached via an N atom to the bicyclic core and R 3  is attached via a C atom; or 
 iii) Ring A is attached via a C atom to the bicyclic core and R 3  is attached via a C atom; 
 and wherein the 
 
       
       
         
           
           
               
               
           
         
       
       portion of R 2  is further optionally substituted with one or two independently selected substituents R 3′ ;
 R 3  is C 1-6 alkyl, C 3-5 cycloalkyl, C 2-6 alkoxy, C 1-6 alkylamino, diC 1-6 alkylamino, —S(O) n (C 1-6 alkyl), —CH 2 (C 3-5 cycloalkyl), —OCH 2 (C 3-5 cycloalkyl), —NHCH 2 (C 3-5 cycloalkyl), —S(O) n CH 2 (C 3-5 cycloalkyl), —CH 2 (C 3-5 heterocycloalkyl), or phenyl; wherein the C 1-6 alkyl, C 3-5 cycloalkyl, C 2-6 alkoxy, C 1-6 alkylamino, diC 1-6 alkylamino, —S(O) n (C 1-6 alkyl), —CH 2 (C 3-5 cycloalkyl), —OCH 2 (C 3-5 cycloalkyl), —NHCH 2 (C 3-5 cycloalkyl), and —S(O) n CH 2 (C 3-5 cycloalkyl) groups are optionally substituted with 1-9 halogen atoms and are optionally substituted with —CN and wherein the phenyl is optionally substituted with 1-3 substituents selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy; 
 R 3′  is independently halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, or C 1-4 haloalkoxy; 
 R 4  is C 1-3 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-5 cycloalkyl, or C 3-5 cyclohaloalkyl; 
 n is 0, 1, or 2; and 
 m is 1 or 2; provided that 
 (4) if any of R is phenyl then R 3  is not an unsubstituted C 1-6 alkyl and R 3  is not C 1-2 alkoxy. 
 
     
     
         2 . The compound according to  claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein the compound is not
 2-[(methylamino)methyl]-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one.   
     
     
         3 - 7 . (canceled) 
     
     
         8 . The compound according to  claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein
 each R is independently selected from H, halogen, —COO(C 1-4 alkyl), C 1-4 alkyl, —(CH 2 ) m (C 3-5 cycloalkyl), —CH 2 (C 3-5 heterocycloalkyl), C 1-4 deuteroalkyl, C 3-5 cycloalkyl, C 3-4 heterocycloalkyl, C 2-4 alkynyl, C 1-4 alkoxy, phenyl, 5-membered heteroaryl, and 6-membered heteroaryl;
 wherein the C 1-4 alkyl group is optionally substituted with 1 to 4 F or optionally substituted with a substituent selected from —OH, —CN, C 1-4 alkoxy, C 1-4 alkylamino, and diC 1-4 alkylamino; and 
 wherein the —(CH 2 ) m (C 3-5 cycloalkyl), 5-membered heteroaryl, and 6-membered heteroaryl groups are optionally substituted with 1 to 4 substituents independently selected from halogen, —OH, and C 1-4 alkyl. 
   
     
     
         9 . The compound according to  claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein
 each R is independently selected from H, halogen, C 1-4 alkyl, C 1-4 deuteroalkyl, and C 1-4 alkoxy; wherein the C 1-4 alkyl group is optionally substituted with a substituent selected from —OH and —CN.   
     
     
         10 . The compound according to  claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein
 each R is independently selected from H and C 1-4 alkyl.   
     
     
         11 . The compound according to  claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein
 each R is independently selected from H, F, Cl, —COOMe, methyl, ethyl, isopropyl, fluoromethyl, trifluoromethyl, —CH 2 OH, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl, —CH 2 CN, 2-hydroxypropyl, —CH 2 OCH 3 , —CH 2 CH 2 OCH 3 , methylaminomethyl, dimethylaminomethyl, 2-(dimethylamino)ethyl, cyclopropylmethyl, (2,2-difluorocyclopropyl)methyl, (3,3-difluorocyclobutyl)methyl, (1-hydroxycyclopropyl)ethyl, —CD 3 , cyclopropyl, (oxetan-3-yl)methyl, oxetan-3-yl, prop-2-yn-1-yl, methoxy, phenyl, pyrazolyl, 1-methyl-pyrazol-4-yl, pyridinyl, pyrazinyl, pyrimidinyl, 6-methylpyridin-2-yl, and 6-chloropyridin-2-yl.   
     
     
         12 . The compound according to  claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein
 each R is independently selected from H, Cl, methyl, —CH 2 OH, 2-hydroxyethyl, —CH 2 CN, —CD 3 , and methoxy.   
     
     
         13 . The compound according to  claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein
 each R is independently selected from H and methyl.   
     
     
         14 - 20 . (canceled) 
     
     
         21 . The compound according to  claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein
 R 1  is O or S.   
     
     
         22 . The compound according to  claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein
 R 1  is O.   
     
     
         23 . The compound according to  claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein
 R 2  is   
       
         
           
           
               
               
           
         
       
     
     
         24 . The compound according to  claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein
 R 2  is   
       
         
           
           
               
               
           
         
       
     
     
         25 . The compound according to  claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein
 R 2  is   
       
         
           
           
               
               
           
         
       
       wherein A is a 5-membered heteroaryl containing two N atoms. 
     
     
         26 - 28 . (canceled) 
     
     
         29 . The compound according to  claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein
 R 2  is   
       
         
           
           
               
               
           
         
       
     
     
         30 . The compound according to  claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein
 R 2  is.   
       
         
           
           
               
               
           
         
       
     
     
         31 - 33 . (canceled) 
     
     
         34 . The compound according to  claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein
 R 3  is C 1-6 alkyl, C 2-6 alkoxy, —CH 2 (C 3-5 cycloalkyl), —OCH 2 (C 3-5 cycloalkyl), —CH 2 (C 3-5 heterocycloalkyl), or phenyl; wherein the C 1-6 alkyl, C 2-6 alkoxy, —CH 2 (C 3-5 cycloalkyl), and —OCH 2 (C 3-5 cycloalkyl) groups are optionally substituted with 1-9 halogen atoms and are optionally substituted with —CN and wherein the phenyl is optionally substituted with one halogen substituent.   
     
     
         35 . The compound according to  claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein
 R 3  is C 1-6 alkyl, C 2-6 alkoxy, —CH 2 (C 3-5 cycloalkyl), or —CH 2 (C 3-5 heterocycloalkyl); wherein the C 1-6 alkyl, C 2-6 alkoxy, and —CH 2 (C 3-5 cycloalkyl) groups are optionally substituted with 1-9 halogen atoms.   
     
     
         36 . The compound according to  claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein
 R 3  is C 1-6 alkyl, C 2-6 alkoxy, —CH 2 (C 3-5 cycloalkyl), or —CH 2 (C 3-5 heterocycloalkyl); wherein the C 1-6 alkyl, C 2-6 alkoxy, and —CH 2 (C 3-5 cycloalkyl) groups are substituted with 2-5 halogen atoms.   
     
     
         37 . The compound according to  claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein
 R 3  is 2,2,2-trifluoroethyl, propyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, 2,2,3,3,3-pentafluoropropyl, —OCH 2 CN, —OC(CH 3 ) 2 CN, difluoromethoxy, trifluoromethoxy, —OCH(CN)CH 3 , 2-fluoroethoxy, 2,2,-difluoroethoxy, 2,2,2-trifluoroethoxy, 2,2-difluoropropoxy, 2,2,3,3-tetrafluoropropoxy, 2,2,3,3,3-pentafluoropropoxy, cyclopropylmethyl, (2,2-difluorocyclopropyl)methyl, (3,3-difluorocyclobutyl)methyl, cyclopropylmethoxy, (2,2-difluorocyclopropyl)methoxy, (oxetan-3-yl)methyl, phenyl, 3-fluorophenyl, or 4-fluorophenyl.   
     
     
         38 - 40 . (canceled) 
     
     
         41 . The compound according to  claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein
 R 4  is C 1-3 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, or C 3-5 cycloalkyl.   
     
     
         42 . The compound according to  claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein
 R 4  is C 1-4 haloalkyl.   
     
     
         43 . The compound according to  claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein
 R 4  is methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, or cyclopropyl.   
     
     
         44 - 49 . (canceled) 
     
     
         50 . The compound according to  claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein the compound is
 2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one;   2-(methoxymethyl)-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one;   2-cyclopropyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one;   2-cyclopropyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one;   7-ethyl-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one;   2-methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one;   6-{1-[(2,2-difluorocyclopropyl)methyl]-1H-pyrazol-4-yl}-2-methyl-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one;   2-methyl-6-{1-[(oxetan-3-yl)methyl]-1H-pyrazol-4-yl}-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one;   2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-3-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one;   2-methyl-6-[4-(2,2,2-trifluoroethoxy)phenyl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one;   7-ethoxy-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one;   2-(methoxymethyl)-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one;   2-methoxy-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one;   2-(hydroxymethyl)-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one;   2-(hydroxymethyl)-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one;   2-(fluoromethyl)-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one;   2-[(dimethylamino)methyl]-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one;   6-(1-{[(1R)-2,2-difluorocyclopropyl]methyl}-1H-pyrazol-4-yl)-2-methyl-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one; or   6-(1-{[(1S)-2,2-difluorocyclopropyl]methyl}-1H-pyrazol-4-yl)-2-methyl-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one.   
     
     
         51 . The compound according to  claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein the compound is
 2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one;   2-methoxy-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one; or   2-(hydroxymethyl)-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one.   
     
     
         52 . The compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
         53 . The compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
         54 . The compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
         55 - 67 . (canceled) 
     
     
         68 . A pharmaceutical composition comprising the compound according to  claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, and a pharmaceutically acceptable excipient. 
     
     
         69 - 80 . (canceled) 
     
     
         81 . A method of reducing the body weight or the body-mass-index of a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound according to  claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer. 
     
     
         82 . A method of treating a metabolic or cardiovascular disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound according to  claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer. 
     
     
         83 . A method of treating diabetes, obesity, dyslipidemia, or non-alcoholic steatohepatitis (NASH) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound according to  claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer. 
     
     
         84 - 104 . (canceled)