Glycolate oxidase inhibitors for the treatment of disease

Abstract

Described herein are compounds, methods of making such compounds, pharmaceutical compositions and medicaments containing such compounds, and methods of using such compounds to treat or prevent diseases or disorders associated with the enzyme glycolate oxidase (GO). Such diseases or disorders include, for example, disorders of glyoxylate metabolism, including primary hyperoxaluria, that are associated with production of excessive amounts of oxalate.

1 . A compound of Formula (I): 
       
         
           
           
               
               
           
         
         wherein: 
         ring C is selected from: 
       
       
         
           
           
               
               
           
         
         wherein the wavy lines ( ) indicate the points of attachment of the C 1  carbon to the carbonyl of C(O)—OR 1 , and the C 2  carbon to L; 
         L is a bond, CH 2 , CF 2 , O, NR L , S(═O), C(═O), CH 2 -Q, or Q-CH 2 ; wherein Q is O, NR L , or S; 
         R L  is hydrogen, C 1-4  alkyl, C 3-6  cycloalkyl, phenyl, or benzyl; wherein the C 1-4  alkyl is optionally substituted with hydroxycarbonyl, alkoxycarbonyl, hydroxycarbonylalkyl, or alkylcarbonyloxy; and the phenyl group alone or as a part of the benzyl group is optionally substituted with one or two groups selected from halo and haloalkoxy; 
         Ring A is C 3-8  cycloalkyl, C 8-11  spirocycloalkyl, 5-8 membered heterocycloalkyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, thienyl, phenyl, naphthyl, indanyl, tetrahydronaphthyl, dihydronaphthyl, pyridyl, indolyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, or tetrahydro-methanonaphthalenyl; 
         Ring B is present or not present; wherein:
 when Ring B is present, then Ring A is optionally substituted with one or two groups independently selected from halo, alkyl, alkoxy, cyano, hydroxy, haloalkoxy, (cycloalkyl)alkoxy, and cycloalkyl; 
 when Ring B is not present and Ring A is phenyl, then Ring A is substituted with:
 (i) one or two R AA  groups; 
 (ii) 2 halo groups when L is other than O; 
 (iii) 2 halo groups when L is O, and R 2  and R 3  are not hydrogen or alkyl; 
 (iv) one halo group when L is CH 2 NR L ; 
 (v) one halo group and one group selected from the group consisting of haloalkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, and (phenyl)alkoxy, when L is bond, O, or S(═O), wherein the phenyl is optionally substituted with halo, cyano, haloalkyl, or haloalkoxy; or 
 (vi) one cyano group and one (phenyl)alkoxy group, when L is bond or O, wherein the phenyl as part of the (phenyl)alkoxy group is optionally substituted with halo or haloalkoxy; 
 
 when Ring B is not present and Ring A is other than phenyl, then
 (i) Ring A is substituted with one or two R AB  groups or 
 (ii) Ring A is unsubstituted, wherein:
 1) when Ring A is unsubstituted tetrahydroquinolinyl, then L is a bond; 
 2) when Ring A is unsubstituted 2,3-dihydrobenzo[b][1,4]dioxinyl, then L is O; 
 3) when Ring A is unsubstituted tetrahydronaphthyl, then L is O, and R 1  is not hydrogen or ethyl; or 
 4) when Ring A is unsubstituted spirocycloalkyl, then L is O, or CH 2 S; 
 
 
 
         each R AA  is independently alkyl; haloalkyl; haloalkoxy; cycloalkyloxy; (cycloalkyl)alkoxy; phenoxy optionally substituted with one or two halo groups; or alkylcarbonylaminoalkoxy; 
         each R AB  is independently halo; alkyl; hydroxy; alkoxy; haloalkyl; haloalkoxy; cycloalkyloxy; (cycloalkyl)alkoxy; or phenoxy optionally substituted with one or two halo groups; 
         Ring B, when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is optionally substituted with 1, 2, or 3 R B  groups; 
         each R B  is independently halo; cyano; alkyl; hydroxyalkyl; alkylsulfonyl; aminosulfonyl; alkylaminosulfonyl; dialkylaminosulfonyl; haloalkyl; alkoxy; aminoalkoxy; alkylaminoalkoxy; dialkylaminoalkoxy; hydroxyalkoxy; haloalkoxy; alkylcarbonyl; alkoxyalkoxy; aminocarbonyl; alkylaminocarbonyl; dialkylaminocarbonyl; alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkyl; cycloalkyloxy; (cycloalkyl)alkoxy wherein the cycloalkyl group is optionally substituted with hydroxyalkyl; cycloalkylcarbonyl; cycloalkylcarbonyloxy; heterocycloalkyl optionally substituted with one or two groups independently selected from halo, alkyl, and alkylcarbonyl; (5-6-membered heterocycloalkyl-one)alkyl; 5-6-membered heterocycloalkyl-one; (heterocycloalkyl)alkyl; heterocycloalkylcarbonyl; or 5-6-membered heteroaryl optionally substituted with one group selected from alkyl, hydroxyalkyl, (hydroxycycloalkyl)alkyl, alkoxyalkyl, and hydroxycycloalkyl; 
         R 1  is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; wherein W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, phenylcarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxycarbonyloxy, cycloalkylcarbonyloxy, —N(R 1A )C(O)R 1B , —N(R 1A )C(O)OR 1B , or —N(R 1A )C(O)NR 1B R 1C ; wherein R 1A , R 1B , and R 1C  are each independently hydrogen or C 1-6  alkyl; 
         R 2  and R 3  are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl; 
         provided:
 i. when L is CH 2 , and Ring A is phenyl other than phenyl substituted with (cycloalkyl)alkoxy, then Ring B cannot be halo-substituted phenyl; 
 ii. when L is O, Ring A is phenyl, and Ring B is not present, then R AA  cannot be alkyl; 
 iii. when L is O, Ring A is phenyl substituted with 1 R AA , and Ring B is not present, then R AA  cannot be meta-substituted trifluoromethyl; 
 iv. when L is O, Ring A is phenyl, Ring B is not present, and R 1  is ethyl, then R AA  cannot be trifluoromethoxy; 
 v. when L is bond, Ring A is other than phenyl, Ring B is not present, and R 1  is H, then R AB  cannot be methyl, and 
 vi. when L is NH, Ring A is pyridyl, indolyl, or indolinyl, and Ring B is not present, then R AB  cannot be alkyl; and 
 
         optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of  claim 1 , wherein
 L is a bond, CH 2 , CF 2 , O, NR L , C(═O), CH 2 -Q, or Q-CH 2 ; wherein Q is O, NR L , or S;   R L  is hydrogen or C 1-4  alkyl optionally substituted with hydroxycarbonyl, alkoxycarbonyl, hydroxycarbonylalkyl, or alkylcarbonyloxy;   Ring A is C 5-7  cycloalkyl, 5-6 membered heterocycloalkyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, phenyl, naphthyl, indanyl, tetrahydronaphthalinyl, dihydronaphthalinyl, pyridyl, indolyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, or tetrahydro-methanonaphthalenyl;   Ring B is present or not present; wherein:   when Ring B is present, then Ring A is optionally substituted with one or two halo, alkyl, alkoxy, or haloalkoxy;   when Ring B is not present and Ring A is phenyl, then Ring A is substituted with:
 (i) one or two R AA  groups, or (ii) 2 halo groups when L is other than O; 
   when Ring B is not present and Ring A is other than phenyl, then Ring A is substituted with one or two R AB  groups;   each R AA  is independently alkyl, haloalkyl, haloalkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, or phenoxy optionally substituted with one or two halo;   each R AB  is independently halo, alkyl, hydroxy, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, or phenoxy optionally substituted with one or two halo;   Ring B, when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is optionally substituted with one or two R B  groups;   each R B  is independently halo, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylcarbonyl, alkoxyalkoxy, alkylcarbonylaminoalkoxy, cycloalkyl, (cycloalkyl)alkyl, cycloalkyloxy, (cycloalkyl)alkoxy, cycloalkylcarbonyl, cycloalkylcarbonyloxy, heterocycloalkyl optionally substituted with alkyl or alkylcarbonyl, (5-6-membered heterocycloalkyl-one)alkyl, (heterocycloalkyl)alkyl, or heterocycloalkylcarbonyl;   R 1  is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; where W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, or phenylcarbonyloxy; and   R 2  and R 3  are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl.   
     
     
         3 . The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of  claim 1 , wherein
 Ring B is present; wherein Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is optionally substituted with one or two R B  groups;   each R B  is independently halo, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylcarbonyl, alkoxyalkoxy, alkylcarbonylaminoalkoxy, cycloalkyl, (cycloalkyl)alkyl, cycloalkyloxy, (cycloalkyl)alkoxy, cycloalkylcarbonyl, cycloalkylcarbonyloxy, heterocycloalkyl optionally substituted with alkyl or alkylcarbonyl, (5-6-membered heterocycloalkyl-one)alkyl, (heterocycloalkyl)alkyl, or heterocycloalkylcarbonyl; provided that when L is S and Ring A is phenyl, then Ring B is not halo-substituted phenyl.   
     
     
         4 . The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of  claim 1 , wherein
 Ring A is C 3-7  cycloalkyl, C 8-11  spirocycloalkyl, 5-8 membered heterocycloalkyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, thienyl, phenyl, naphthyl, indanyl, tetrahydronaphthyl, dihydronaphthyl, pyridyl, indolyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, or tetrahydro-methanonaphthalenyl;   Ring B is present or not present; wherein:   when Ring B is present, then Ring A is optionally substituted with one or two groups selected from halo, alkyl, alkoxy, haloalkoxy, (cycloalkyl)alkoxy, and cycloalkyl;   when Ring B is not present and Ring A is other than phenyl, then
 (i) Ring A is substituted with one or two R AB  groups or 
 (ii) Ring A is unsubstituted, wherein:
 1) when Ring A is unsubstituted tetrahydroquinolinyl, then L is bond; 
 2) when Ring A is unsubstituted 2,3-dihydrobenzo[b][1,4]dioxinyl, then L is O; 
 3) when Ring A is unsubstituted tetrahydronaphthyl, then L is O, and R 1  is not hydrogen or ethyl; or 
 4) when Ring A is unsubstituted spirocycloalkyl, then L is O; 
 
   each R B  is independently halo; cyano; alkyl; alkylsulfonyl; aminosulfonyl; alkylaminosulfonyl; dialkylaminosulfonyl; haloalkyl; alkoxy; haloalkoxy; alkylcarbonyl; alkoxyalkoxy; aminocarbonyl; alkylaminocarbonyl; dialkylaminocarbonyl; alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkyl; cycloalkyloxy; (cycloalkyl)alkoxy; cycloalkylcarbonyl; cycloalkylcarbonyloxy; heterocycloalkyl optionally substituted with one or two groups independently selected from halo, alkyl, and alkylcarbonyl; (5-6-membered heterocycloalkyl-one)alkyl; 5-6-membered heterocycloalkyl-one; (heterocycloalkyl)alkyl; heterocycloalkylcarbonyl; or 5-6 membered heteroaryl.   
     
     
         5 . The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of  claim 1 , wherein
 Ring B is not present;   L is a bond, CH 2 , CF 2 , O, NR L , C(═O), CH 2 -Q, or Q-CH 2 ; wherein Q is O, NR L , or S;   R L  is hydrogen or C 1-4  alkyl optionally substituted with hydroxycarbonyl, alkoxycarbonyl, hydroxycarbonylalkyl, or alkylcarbonyloxy;   Ring A is C 5-7  cycloalkyl, 5-6 membered heterocycloalkyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, phenyl, naphthyl, indanyl, tetrahydronaphthalinyl, dihydronaphthalinyl, pyridyl, indolyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, or tetrahydro-methanonaphthalenyl;   wherein:
 when Ring A is phenyl, then Ring A is substituted with:
 (i) one or two R AA  groups, or (ii) 2 halo groups when L is other than O; 
 
 when Ring A is other than phenyl, then Ring A is substituted with one or two R AB  groups; 
   each R AA  is independently alkyl, haloalkyl, haloalkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, or phenoxy optionally substituted with one or two halo;   each R AB  is independently halo, alkyl, hydroxy, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, or phenoxy optionally substituted with one or two halo;   R 1  is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; where W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, or phenylcarbonyloxy; and   R 2  and R 3  are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl.   
     
     
         6 . The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of  claim 5 , wherein
 Ring A is phenyl, naphthyl, indanyl, tetrahydronaphthalinyl, dihydronaphthalinyl, pyridyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, or dihydroisoquinolinyl;   wherein:
 when Ring A is phenyl, then Ring A is substituted with:
 (i) one or two R AA  groups, or (ii) 2 halo groups when L is other than O; 
 
 when Ring A is other than phenyl, then Ring A is substituted with one or two R AB  groups; 
   each R AA  is independently haloalkoxy, cycloalkyloxy, or phenoxy optionally substituted with one or two halo;   each R AB  is independently halo, alkyl, alkoxy, or haloalkoxy;   R 1  is hydrogen, alkyl, cycloalkyl, or W; where W is alkyl substituted with alkylcarbonyloxy; and   R 2  and R 3  are independently hydrogen or alkyl; wherein the alkyl is optionally substituted with alkylcarbonyloxy.   
     
     
         7 . The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of  claim 1 , wherein
 Ring B is not present;   Ring A is C 3-7  cycloalkyl, C 8-11  spirocycloalkyl, 5-6 membered heterocycloalkyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, phenyl, naphthyl, indanyl, tetrahydronaphthyl, dihydronaphthyl, pyridyl, indolyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, or tetrahydro-methanonaphthalenyl;   wherein:
 when Ring A is phenyl, then Ring A is substituted with:
 (i) one or two R AA  groups, 
 (ii) 2 halo groups when L is other than O; 
 (iii) 2 halo groups when L is O, and R 2  and R 3  are not hydrogen or alkyl, 
 (iv) one halo group when L is CH 2 NR L , or 
 (v) one halo group and one group selected from the group consisting of haloalkoxy, (cycloalkyl)alkoxy, and (phenyl)alkoxy, when L is bond or O, wherein the phenyl is optionally substituted with halo; 
 
 when Ring A is other than phenyl, then
 (i) Ring A is substituted with one or two R AB  groups; or 
 (ii) Ring A is unsubstituted, wherein:
 1) when Ring A is unsubstituted tetrahydroquinolinyl, then L is bond; 
 2) when Ring A is unsubstituted 2,3-dihydrobenzo[b][1,4]dioxinyl, then L is O; 
 3) when Ring A is unsubstituted tetrahydronaphthyl, then L is O, and R 1  is not hydrogen or ethyl; or 
 4) when Ring A is unsubstituted spirocycloalkyl, then L is O. 
 
 
   
     
     
         8 . The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of  claim 7 , wherein
 Ring A is piperidinyl, phenyl, naphthyl, indanyl, tetrahydronaphthyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, pyridyl, quinolinyl, isoquinolynyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, spiro[2.5]octane, spiro[4.5]decane, or spiro[5.5]undecane;   when Ring A is phenyl, then Ring A is substituted with:
 (i) one or two R AA  groups, 
 (ii) 2 halo groups when L is other than O; 
 (iii) 2 halo groups when L is O, and R 2  and R 3  are not hydrogen or alkyl, 
 (iv) one halo group when L is CH 2 NR L , or 
 (v) one halo group and one group selected from the group consisting of haloalkoxy and (cycloalkyl)alkoxy, when L is bond or O; 
   each R AA  is independently haloalkyl, cycloalkyloxy, (cycloalkyl)alkoxy, or alkylcarbonylaminoalkoxy;   each R AB  is independently halo, alkyl, haloalkyl, or haloalkoxy;   R 1  is hydrogen, alkyl or W; wherein W is alkyl substituted with alkylcarbonyloxy;   R 2  and R 3  are independently hydrogen or alkyl; wherein the alkyl is optionally substituted with cycloalkylcarbonyloxy or heterocycloalkylcarbonyloxy, wherein the heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl.   
     
     
         9 . The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of  claim 1 , wherein
 Ring B is present;   Ring A is C 3-7  cycloalkyl, C 8-11  spirocycloalkyl, 5-6 membered heterocycloalkyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, thienyl, phenyl, naphthyl, indanyl, tetrahydronaphthyl, dihydronaphthyl, pyridyl, indolyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, or tetrahydro-methanonaphthalenyl; wherein Ring A is optionally substituted with one or two groups selected from halo, alkyl, alkoxy, and haloalkoxy;   Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is optionally substituted with one or two R B  groups;   each R B  is independently halo; cyano; alkyl; haloalkyl; alkoxy; haloalkoxy; alkylcarbonyl; alkoxyalkoxy; aminocarbonyl; alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkyl; cycloalkyloxy; (cycloalkyl)alkoxy; cycloalkylcarbonyl; cycloalkylcarbonyloxy; heterocycloalkyl optionally substituted with 1 or 2 alkyl, alkylcarbonyl or a halo; (5-6-membered heterocycloalkyl-one)alkyl; (heterocycloalkyl)alkyl; or heterocycloalkylcarbonyl.   
     
     
         10 . The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of  claim 9 , wherein
 L is bond, CH 2 , CF 2 , O, NR L , CH 2 -Q, or Q-CH 2 ; wherein Q is O, NR L , or S;   R L  is hydrogen, C 1-4  alkyl, or benzyl, wherein the phenyl, as part of the benzyl group, is optionally substituted with haloalkoxy;   Ring A is C 3-7  cycloalkyl, 5-6 membered heterocycloalkyl, phenyl, or naphthyl, wherein Ring A is optionally substituted with halo or haloalkoxy;   Ring B is cycloalkyl, heterocycloalkyl, phenyl, tetrahydronaphthyl, tetrahydroquinolinyl, quinolinyl, or, isoquinolinyl; wherein each Ring B is optionally substituted with one or two R B  groups;   each R B  is independently halo; cyano; haloalkyl; haloalkoxy; alkoxyalkoxy; aminocarbonyl; alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkoxy; heterocycloalkyl optionally substituted with 1 or 2 alkyl, alkylcarbonyl or halo; or (5-6-membered heterocycloalkyl-one)alkyl; and   R 1  is hydrogen or W; wherein W is alkyl substituted with alkylcarbonyloxy, dialkylaminocarbonyloxy cycloalkylcarbonyloxy, or phenylcarbonyloxy.   
     
     
         11 . The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of  claim 1 , wherein L is a bond, O, NR L , CH 2 -Q, or Q-CH 2 ; wherein Q is O, NR L , or S. 
     
     
         12 - 13 . (canceled) 
     
     
         14 . A compound of Formula (IV): 
       
         
           
           
               
               
           
         
         wherein: 
         Ring C is selected from: 
       
       
         
           
           
               
               
           
         
         wherein the wavy lines ( ) indicate the points of attachment of the C 1  carbon to the carbonyl of C(O)—OR 1 , and the C 2  carbon to N of NR L ; 
         R L  is hydrogen, C 1-4  alkyl, C 3-6  cycloalkyl, phenyl, or benzyl; wherein the C 1-4  alkyl is optionally substituted with hydroxycarbonyl, alkoxycarbonyl, hydroxycarbonylalkyl, or alkylcarbonyloxy; and the phenyl group alone or as a part of the benzyl group is optionally substituted with one or two groups selected from halo and haloalkoxy; 
         Ring A is C 3-7  cycloalkyl, C 8-11  spirocycloalkyl, 5-6 membered heterocycloalkyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, phenyl, naphthyl, indanyl, tetrahydronaphthyl, dihydronaphthyl, pyridyl, indolyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, or tetrahydro-methanonaphthalenyl; 
         Ring B is present or not present; wherein: 
         when Ring B is present, then Ring A is optionally substituted with one or two groups selected from halo, alkyl, alkoxy, and haloalkoxy; 
         when Ring B is not present and Ring A is phenyl, then Ring A is substituted with:
 (i) one or two R AA  groups, or 
 (ii) 2 halo groups; 
 
         when Ring B is not present and Ring A is 5-6 membered heterocycloalkyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, naphthyl, indanyl, tetrahydronaphthyl, dihydronaphthyl, benzothiazolyl, quinolinyl, isoquinolinyl, isoindolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, or 2,3-dihydrobenzo[b][1,4]dioxinyl, then Ring A is substituted with one or two R AB  groups; 
         when Ring B is not present and Ring A is C 3-7  cycloalkyl or C 8-11  spirocycloalkyl, then Ring A is optionally substituted with one or two R AB  groups; 
         when Ring B is not present and Ring A is pyridyl, indolyl, or indolinyl, then Ring A is substituted with one or two R AC  groups; 
         each R AA  is independently alkyl; haloalkyl; haloalkoxy; cycloalkyloxy; (cycloalkyl)alkoxy; phenoxy optionally substituted with one or two halo; or alkylcarbonylaminoalkoxy; 
         each R AB  is independently halo; alkyl; hydroxy; alkoxy; haloalkyl; haloalkoxy; cycloalkyloxy; (cycloalkyl)alkoxy; or phenoxy optionally substituted with one or two halo; 
         each R AC  is independently halo; hydroxy; alkoxy; haloalkyl; haloalkoxy; cycloalkyloxy; (cycloalkyl)alkoxy; or phenoxy optionally substituted with one or two halo; 
         Ring B, when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is optionally substituted with one or two R B  groups; 
         each R B  is independently halo; cyano; alkyl; haloalkyl; alkoxy; haloalkoxy; alkylcarbonyl; alkoxyalkoxy; aminocarbonyl; alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkyl; cycloalkyloxy; (cycloalkyl)alkoxy; cycloalkylcarbonyl; cycloalkylcarbonyloxy; heterocycloalkyl optionally substituted with 1 or 2 alkyl, alkylcarbonyl or halo; (5-6-membered heterocycloalkyl-one)alkyl; (heterocycloalkyl)alkyl; or heterocycloalkylcarbonyl; 
         R 1  is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; wherein W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, phenylcarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxycarbonyloxy, cycloalkylcarbonyloxy, —N(R 1A )C(O)R 1B , —N(R 1A )C(O)OR 1B , or —N(R 1A )C(O)NR 1B R 1C ; wherein R 1A , R 1B , and R 1C  are each independently hydrogen or C 1-6  alkyl; 
         R 2  and R 3  are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl; and 
         optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof. 
       
     
     
         15 . The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of  claim 14 , wherein R L  is hydrogen or C 1-4  alkyl. 
     
     
         16 - 18 . (canceled) 
     
     
         19 . A compound of Formula (V): 
       
         
           
           
               
               
           
         
         wherein: 
         Ring C is selected from: 
       
       
         
           
           
               
               
           
         
         wherein the wavy lines ( ) indicate the points of attachment of the C 1  carbon to the carbonyl of C(O)—OR 1 , and the C 2  carbon to O; 
         Ring A is cycloalkyl, C 8-11  spirocycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each is substituted with one or two R AB  groups; 
         Ring B is present or not present; wherein 
         when Ring B is present, then Ring A is optionally substituted with a group selected from halo, alkyl, alkoxy, cyano, hydroxy, and (cycloalkyl)alkoxy; 
         when Ring B is not present and Ring A is phenyl, then Ring A is substituted with:
 (i) one or two R AD  groups; 
 (ii) two groups selected from chloro or bromo; or 
 (iii) one halo group and one group selected from the group consisting of haloalkoxy, (cycloalkyl)alkoxy, and (phenyl)alkoxy, wherein the phenyl is optionally substituted with halo; 
 (iv) one cyano group and one (phenyl)alkoxy group, wherein the phenyl as part of the (phenyl)alkoxy group is optionally substituted with halo or haloalkoxy; 
 
         or Ring A is unsubstituted C 8-11  spirocycloalkyl; unsubstituted dihydroxybenzodioxynyl; or unsubstituted tetrahydronaphthalene when R 1  is not hydrogen or ethyl; 
         each R AB  is independently halo; alkyl; hydroxy; alkoxy; haloalkyl; haloalkoxy; cycloalkyloxy; (cycloalkyl)alkoxy; phenoxy optionally substituted with one or two halo; or (phenyl)alkoxy, wherein the phenyl is optionally substituted with halo; 
         each R AD  is independently hydroxy; alkoxy; haloalkyl; cycloalkyloxy; (cycloalkyl)alkoxy; or phenoxy optionally substituted with one or two halo; 
         Ring B, when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is optionally substituted with one or two R B  groups; 
         each R B  is independently halo; cyano; alkyl; hydroxyalkyl; alkylsulfonyl; aminosulfonyl; alkylaminosulfonyl; dialkylaminosulfonyl; haloalkyl; alkoxy; aminoalkoxy; alkylaminoalkoxy; dialkylaminoalkoxy; hydroxyalkoxy; haloalkoxy; alkylcarbonyl; alkoxyalkoxy; aminocarbonyl; alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkyl; cycloalkyloxy; (cycloalkyl)alkoxy wherein cycloalkyl group is optionally substituted with hydroxyalkyl; cycloalkylcarbonyl; cycloalkylcarbonyloxy; heterocycloalkyl optionally substituted with 1 or 2 alkyl, alkylcarbonyl or halo; (5-6-membered heterocycloalkyl-one)alkyl; (heterocycloalkyl)alkyl; or heterocycloalkylcarbonyl; or 5-6 membered heteroaryl optionally substituted with alkyl wherein alkyl is optionally substituted with 1 or 2 groups independently selected from cycloalkyl and hydroxy; alkoxyalkyl; hydroxyalkyl; or hydroxycycloalkyl; 
         R 1  is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; wherein W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, phenylcarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxycarbonyloxy, cycloalkylcarbonyloxy, —N(R 1A )C(O)R 1B , —N(R 1A )C(O)OR 1B , or —N(R 1A )C(O)NR 1B R 1C ; wherein R 1A , R 1B , and R 1C  are each independently hydrogen or C 1-6  alkyl; 
         R 2  and R 3  are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl; 
         provided:
 (i) when Ring A is phenyl, Ring B is not present, and R 1  is ethyl, then Ring A cannot be substituted with trifluoromethoxy; and 
 (ii) when Ring A is phenyl substituted with 1 R AD , then R AD  cannot be meta-substituted trifluoromethyl; and 
 
         optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof. 
       
     
     
         20 - 22 . (canceled) 
     
     
         23 . The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of  claim 1 , wherein Ring A is C 3-7  cycloalkyl, 5-6 membered heterocycloalkyl, or phenyl. 
     
     
         24 - 26 . (canceled) 
     
     
         27 . The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of  claim 1 , wherein R 1  is hydrogen or W. 
     
     
         28 - 29 . (canceled) 
     
     
         30 . The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of  claim 1 , wherein R 2  and R 3  are independently hydrogen. 
     
     
         31 . The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of  claim 1 , wherein ring C is: 
       
         
           
           
               
               
           
         
       
     
     
         32 . The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of  claim 1 , wherein ring C is: 
       
         
           
           
               
               
           
         
       
     
     
         33 - 40 . (canceled) 
     
     
         41 . A pharmaceutical composition comprising the compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of  claim 1  and a pharmaceutically acceptable excipient. 
     
     
         42 - 46 . (canceled)