Hydantoin compounds

Abstract

The invention relates to the use of hydantoin compounds useful for treating or preventing autoimmune disorders. The present invention also provides compositions and uses thereof.

1 . A compound of formula I: 
     
       
         
         
             
             
         
       
       wherein: 
       Q is methylene or ethylene; 
       R 1  is hydrogen, C 1-6  alkyl, C 1-6  alkoxy, C 1-8  hydroxyalkyl, (C 1-3  alkoxy)C 1-3  alkyl, C 1-3  alkylthio, C 2-5  alkenyl, phenyl, indolyl, quinolyl, pyrazolyl, pyrrolyl, pyridinyl, furyl, N-methylbenzotriazolyl, hydroxyethyl, propenyl, (ethoxycarbonyl)propyl, or tetrahydropyranyloxybutyl,
 wherein R 1  has 0-3 substituents independently selected from cyano, methyl, methoxy, pyrazolyl, furyl, hydroxyethyl, acetamido, pyrrolyl, and propenyl, and 0-1 substituents selected from benzotriazolyl, N-methyl-benzotriazolyl, and benzo[d][1,3]dioxolyl, 
 or Q and R 1  taken together are hydrogen; 
 
       T is C═O, —CH 2 —, —CH 2 —CH 2 —, —CH═CH— (cis or trans), propenylene, —CH═CH—CH 2 — (cis or trans), —CH 2 —CH═CH— (cis or trans), ethynylene, or vinylene; 
       R 2  is selected from C 2-6  alkenyl, C 1-12  alkyl, phenyl, phenoxy, benzyloxy, naphthyl, furyl, isoquinolinyl, quinolyl, indolyl, pyrazolyl, thiazolyl, anthryl, and benzothienyl,
 wherein R 2  is substituted with 0 to 2 substituents, wherein between 0 and 2 substituents are independently selected from methyl, methoxy, trifluoromethoxy, hydroxyl, hydroxymethyl, fluoro, chloro, bromo, dimethylamino, t-butyl, and isobutoxy; and between 0 and 1 substituents are selected from phenyl, pyridyl, pyrazolyl, furyl, benzoyl, pyrrolyl, pyridinyl, naphthyl, phenoxy, benzo[d][1,3]dioxolyl, cyclohexyl, cyclopentyl, cyclobutyl, and cyclopropyl; 
 
       X is a covalent bond, methylene, ethylene, or propenylene; and 
       R 3  is selected from phenyl, biphenylyl, thiophenyl, bithiophenylyl, diphenylmethanyl, triazolyl, thienyl, benzofuryl, phenanthryl, anthryl, fluorenyl, acenaphthyl, pyrenyl, indanyl, adamantyl, carbazolyl, N-methylcarbazolyl, indolyl, pyrrolidinyl, quinolyl, pyrrolyl, naphthyl, methylnaphthyl, methoxynaphthyl, dimethylthienyl, benzothiadiazolyl, benzimidazolyl, benzothienyl, benzodioxanyl, benzodioxepinyl, benzodioxocinyl, and benzo[d][1,3]dioxolyl,
 wherein R 3  is substituted with 0 to 4 substituents, wherein between 0 and 4 substituents are independently selected from methyl, trifluoromethyl, methoxy, trifluoromethoxy, chloro, fluoro, bromo, ethenyl, ethoxy, ethyl, isopropyl, t-butyl, propyloxy, amino, dimethylamino, methylamino, allyloxy, (methyl)(phenyl)amino, methanesulfonyl, t-butoxycarbonylmethylamino, t-butoxycarbonyl, boronic acid moiety, and methylcarbonylamino, and wherein between 0 and 2 substituents are independently selected from phenyl, phenoxy, benzyl, benzyloxy, benzoyl, (methyl)(phenyl)amino, N-morpholinyl, piperidyl, pyrrolidinyl, thienyl, furyl, hydroxyphenyl, naphthyl, methylnaphthyl, methoxynaphthyl, dimethylthienyl, benzimidazolyl, indolyl, isoquinolinyl, quinolinyl, dibenzofuranyl, benzofuranyl, biphenylyl, and benzo[d][1,3]dioxolyl; 
 
       or a pharmaceutically acceptable salt, C 1-6  alkyl ester or amide, or C 2-6  alkenyl ester or amide thereof. 
     
   
   
       2 . The compound of  claim 1 , wherein R 1  is hydrogen, methyl, hydroxymethyl, methoxy, methoxymethyl, methylthio, isopropyl, phenyl, indolyl, pyrazolyl, pyrrolyl, pyridinyl, furyl, N-methylbenxotriazolyl, or hydroxyethyl; and wherein R 1  has 0 to 2 substituents. 
   
   
       3 . The compound of  claim 1 , wherein R 2  is selected from C 2-4  alkenyl, phenyl, naphthyl, furyl, isoquinolinyl, quinolyl, indolyl, pyrazolyl, thiazolyl, and benzothienyl, wherein R 2  is substituted with 0 to 2 groups, wherein between 0 and 2 substituents are independently selected from methyl, methoxy, trifluoromethoxy, hydroxyl, fluoro, and hydroxymethyl. 
   
   
       4 . The compound of  claim 1 , wherein X is methylene, ethylene, or propenylene. 
   
   
       5 . The compound of  claim 1 , wherein X is methylene. 
   
   
       6 . The compound of  claim 1 , wherein T is —CH 2 —, —CH═CH— (cis or trans —CH═CH—CH 2 — (cis or trans), —CH 2 —CH═CH— (cis or trans), ethynylene, or vinylene. 
   
   
       7 . The compound of  claim 5 , wherein T is methylene, —CH═CH—CH 2 — (trans), or —CH 2 —CH═CH— (trans). 
   
   
       8 . The compound of  claim 1 , wherein Q is methylene. 
   
   
       9 . The compound of  claim 1 , wherein Q is ethylene. 
   
   
       10 . The compound of  claim 1 , wherein:
 R 3  is selected from phenyl, biphenylyl, thiophenyl, bithiophenylyl, triazolyl, thienyl, benzofuryl, phenanthryl, indolyl, pyrrolidinyl, quinolyl, pyrrolyl, naphthyl, methylnaphthyl, methoxynaphthyl, dimethylthienyl, benzothiadiazolyl, benzimidazolyl, benzothiophenyl, benzodioxanyl, benzodioxepinyl, benzodioxocinyl, and benzo[d][1,3]dioxolyl;
 wherein R 3  is substituted with between 0 and 3 substituents, wherein between 0 and 3 substituents are independently selected from methyl, trifluoromethyl, methoxy, trifluoromethoxy, chloro, fluoro, bromo, ethenyl, ethoxy, ethyl, isopropyl, t-butyl, propyloxy, amino, dimethylamino, methylamino, allyloxy, (methyl)(phenyl)amino, methanesulfonyl, t-butoxycarbonylmethylamino, t-butoxycarbonyl, boronic acid moiety, and methylcarbonylamino; and wherein between 0 and 1 substituents is independently selected from phenyl, phenoxy, benzyl, benzyloxy, benzoyl, (methyl)(phenyl)amino, N-morpholinyl, piperidyl, pyrrolidinyl, thienyl, furyl, hydroxyphenyl, naphthyl, methylnaphthyl, methoxynaphthyl, dimethylthienyl, benzimidazolyl, indolyl, quinolinyl, dibenzofuranyl, benzofuranyl, biphenylyl, and benzo[d][1,3]dioxolyl. 
   
   
   
       11 . The compound of  claim 8 , wherein R 3  is phenyl, naphthyl, anthryl, biphenylyl, fluorenyl, or acenapthyl with between 0 and 3 substituents independently selected from fluoro, bromo methyl, methoxy, and hydroxymethyl. 
   
   
       12 . The compound of  claim 1 , wherein R 1  is methoxymethyl, hydroxymethyl, or methyl. 
   
   
       13 . The compound of  claim 1 , wherein R 1  is hydrogen, C 1-4  alkyl, C 1-4  hydroxyalkyl, (C 1-3  alkoxy)C 1-3  alkyl, C 1-3  alkylthio, C 2-5  alkenyl, hydroxyethyl, propenyl, or (ethoxycarbonyl)propyl; wherein R 1  has 0-3 substituents independently selected from cyano, methyl, methoxy, hydroxyethyl, acetamido, and propenyl. 
   
   
       14 . The compound of  claim 1 , wherein R 2  is a phenyl group with between 0 and 3 substituents independently selected from methoxy, trifluoromethoxy, fluoro, and methyl. 
   
   
       15 . The compound of  claim 1 , wherein:
 R 1  is hydrogen, methyl, hydroxymethyl, methoxy, methoxymethyl, methylthio, phenyl, pyrazolyl, pyrrolyl, pyridinyl, furyl, or N-methylbenzotriazolyl; or R 1  is phenyl independently substituted with methyl, methoxy, pyrazolyl, furyl, benzotriazolyl, N-methyl-benzotriazolyl, or pyrrolyl;   T is —CH 2 —, —CH 2 —CH 2 —, —CH═CH—CH 2 — (trans), ethynylene, or allyl;   R 2  is selected from phenyl, naphthyl, furyl, quinolyl, indolyl, pyrazolyl, thiazolyl, and benzothienyl, wherein R 2  is substituted with 0-2 groups, wherein between 0 and 2 substituents are independently selected from methyl, methoxy, trifluoromethoxy, hydroxyl, and hydroxymethyl; and   R 3  is selected from phenyl, naphthyl, thienyl, benzofuryl, indolyl, isoquinolinyl, quinolyl, pyridinyl, pyrrolyl, benzothiadiazolyl, and benzimidazolyl,
 wherein R 3  is substituted with between 0 and 2 substituents, wherein between 0 and 2 substituents are independently selected from methyl, trifluoromethyl, methoxy, trifluoromethoxy, chloro, fluoro, bromo, ethenyl, ethoxy, ethyl, dimethylamino, and methylamino. 
   
   
   
       16 . The compound of  claim 1 , wherein:
 R 1  is hydrogen, methyl, hydroxymethyl, methoxy, methoxymethyl, methylthio, phenyl, pyrazolyl, pyrrolyl, pyridinyl, furyl, C 1-8  hydroxyalkyl, or N-methylbenzotriazolyl;
 or R 1  is substituted with 0 to 1 substituents selected from methyl, methoxy, pyrazolyl, furyl, pyridinyl, benzotriazolyl, N-methyl-benzotriazolyl, and pyrrolyl; 
   T is —CH 2 —, —CH 2 —CH 2 —, —CH═CH—CH 2 — (trans), ethynylene, or allyl;   R 2  is selected from phenyl, naphthyl, furyl, quinolyl, indolyl, pyrazolyl, benzo[d][1,3]dioxolyl, thiazolyl, and benzothienyl,
 wherein R 2  is substituted with 0-3 groups, wherein between 0 and 3 substituents are independently selected from methyl, methoxy, trifluoromethoxy, hydroxyl, and hydroxymethyl; 
   X is methylene;   R 3  is selected from phenyl, naphthyl, thienyl, benzofuryl, indolyl, pyrrolidinyl, isoquinolyl, quinolyl, pyrrolyl, benzothiadiazolyl, benzimidazolyl, and benzothiophenyl;
 wherein R 3  is substituted with between 0 and 2 substituents, wherein between 0 and 2 substituents are independently selected from methyl, trifluoromethyl, methoxy, trifluoromethoxy, chloro, fluoro, bromo, ethenyl, ethoxy, ethyl, dimethylamino, and methylamino. 
   
   
   
       17 . The compound of  claim 1 , selected from ER 818561, ER 817135, ER 813508, ER 813509, ER 813493, ER 813510, ER 813511, ER 817118, ER 817137, ER 817119, ER 818573, ER 818567, ER 818550, and ER 813512. 
   
   
       18 . The compound of  claim 1 , selected from ER 813499, ER 813081, ER813077, ER 818528, ER 818574, ER 813411, ER 813078, ER 813521, ER 817116, ER 813080, ER 813519, ER 813492, ER813452, ER 813410, and ER 812605. 
   
   
       19 . The compound of  claim 1 , selected from ER 818568, ER 813091, ER 813075, ER 818562, ER 813096, ER 819695, ER 813092, ER 813082, ER 820087, ER 813079, ER 813089, ER 813529, ER 813414, and ER 813516. 
   
   
       20 . The compound of  claim 1 , selected from ER 818558, ER 818559, ER 818560, ER 818554, ER 818535, ER 818564, ER 818524, and ER 817117. 
   
   
       21 . A compound of formula II: 
     
       
         
         
             
             
         
       
       wherein: 
       Q is a straight or branched, saturated or unsaturated C 1-6  alkylene chain; 
       R 1  is an optionally substituted phenyl ring or an optionally substituted 6-membered heteroaryl ring having 1-2 nitrogens; 
       T is a straight or branched, saturated or unsaturated C 1-6  alkylene chain; 
       R 2  is an optionally substituted phenyl or naphthyl ring, or an optionally substituted 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 
       X is a straight or branched, saturated or unsaturated C 1-4 alkylene chain; and 
       R 3  is phenyl, naphthyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, thienyl, furyl, pyrazolyl, triazolyl, isoxazolyl, or thiazolyl; wherein R 3  is optionally substituted with pyrrolidinyl, morpholinyl, piperidinyl, furyl, thienyl, phenyl, —N(Me)phenyl, dimethylamino, methoxy, ethoxy, methyl, t-butyl, pyridyl, -methylamino, —C(═O)OMe, —C(═O)OCH 2 phenyl, amino, hydroxyl, hydroxyethoxy, trifluoromethoxy, trifluoromethyl, or —SO 2 phenyl; 
       or a pharmaceutically acceptable salt, C 1-6  alkyl ester or amide, or C 2-6  alkenyl ester or amide thereof. 
     
   
   
       22 . A compound of formula III: 
     
       
         
         
             
             
         
       
       wherein: 
       Q is —CH 2 O—, —(CH 2 ) 2 O—, —(CH 2 ) 3 O—, —(CH 2 ) 4 O—, —(CH 2 ) 6 O—, —CH 2 OCH 2 —, —(CH 2 ) 2 OCH 2 —, —(CH 2 ) 3 OCH 2 —, —(CH 2 ) 4 OCH 2 —, —(CH 2 ) 6 OCH 2 —, —(CH 2 ) 2 S—, —CH 2 —, —(CH 2 ) 2 —, —(CH 2 ) 3 —, —(CH 2 ) 4 —, —CH 2 CH═CH—, —CH 2 C(═CH 2 )CH 2 —, —CH 2 CH 2 CH═CH—, —CH 2 CH(CH 3 )CH 2 —, —CH 2 C(═O)OCH 2 —, —CH 2 CH═C(CH 3 )CH 2 CH 2 CH═C(CH 3 )—, —CH 2 C≡CCH 2 CH 2 —, —CH 2 C(═O)CH 2 —, —(CH 2 ) 4 C(═O)OCH 2 CH 2 —, —(CH 2 ) 5 C(═O)OCH 2 CH 2 —, —(CH 2 ) 6 C(═O)OCH 2 CH 2 —CH 2 C(═O)N(Et)CH 2 CH 2 —, or —CH 2 CH 2 N(CH 3 )CH 2 —; 
       R 1  is CN, pyridyl, thiazolyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, phenyl, isoxazolyl, pyrrolyl, benztriazolyl, cyclohexyl, cyclopropyl, or thienyl; 
       T is —CH 2 O—, —(CH 2 ) 2 O—, —(CH 2 ) 3 O—, —(CH 2 ) 4 O—, —(CH 2 ) 6 O—, —CH 2 OCH 2 —, —(CH 2 ) 2 OCH 2 —, —(CH 2 ) 3 OCH 2 —, —(CH 2 ) 4 OCH 2 —, —(CH 2 ) 6 OCH 2 —, —(CH 2 ) 2 S—, —CH 2 —, —(CH 2 ) 2 —, —(CH 2 ) 3 —, —(CH 2 ) 4 —, —CH 2 CH═CH—, —CH 2 CH═CHCH 2 —, —CH 2 C(═CH 2 )CH 2 —, —CH 2 CH 2 CH═CH—, —CH 2 CH(CH 3 )CH 2 —, —CH 2 C(═O)OCH 2 —, —CH 2 CH═C(CH 3 )CH 2 CH 2 CH═C(CH 3 )—, —CH 2 C≡C— or —CH 2 C≡CCH 2 CH 2 —; 
       R 2  is optionally substituted phenyl, naphthyl, quinolinyl, phthalimidyl, isoquinolinyl, indolyl, thienyl, furyl, isoxazolyl, or thiazolyl; 
       X is —CH 2 —, —CH 2 CH 2 —, —CH 2 CH═CH—, —CH 2 C(CH 3 )—CH— or —CH 2 CH(CH 3 )—; and 
       R 3  is phenyl or naphthyl; wherein R 3  is optionally substituted with pyrrolidinyl, morpholinyl, piperidinyl, furyl, thienyl, phenyl, —N(Me)phenyl, dimethylamino, methoxy, ethoxy, methyl, t-butyl, pyridyl, methylamino, —C(═O)OMe, —C(═O)OCH 2 phenyl, amino, hydroxyl, hydroxyethoxy, trifluoromethoxy, trifluoromethyl, or —SO 2 phenyl; 
       or a pharmaceutically acceptable salt, C 1-6  alkyl ester or amide, or C 2-6  alkenyl ester or amide thereof. 
     
   
   
       23 . A compound of formula IV: 
     
       
         
         
             
             
         
       
       wherein: 
       Q is —CH 2 O—, —(CH 2 ) 2 O—, —(CH 2 ) 3 O—, —(CH 2 ) 4 O—, —(CH 2 ) 6 O—, —CH 2 OCH 2 —, —(CH 2 ) 2 OCH 2 —, —(CH 2 ) 3 OCH 2 —, —(CH 2 ) 4 OCH 2 —, —(CH 2 ) 6 OCH 2 —, or —(CH 2 ) 2 S—; 
       R 1  is hydrogen; 
       T is —CH 2 —, —(CH 2 ) 2 —, —(CH 2 ) 3 —, —(CH 2 ) 4 —, —CH 2 CH═CH—, —CH 2 CH═CHCH 2 —, —CH 2 C(═CH 2 )CH 2 —, —CH 2 CH 2 CH═CH—, —CH 2 CH(CH 3 )CH 2 —, —CH 2 C(═O)OCH 2 —, —CH 2 CH═C(CH 3 )CH 2 CH 2 CH═C(CH 3 )—, —CH 2 C≡C— or —CH 2 C═CCH 2 CH 2 —; 
       R 2  is optionally substituted phenyl or naphthyl; 
       X is CH 2 —; and 
       R 3  is a phenyl or naphthyl ring; wherein R 3  is optionally substituted with pyrrolidinyl, morpholinyl, piperidinyl, furyl, thienyl, phenyl, —N(Me)phenyl, dimethylamino, methoxy, ethoxy, methyl, t-butyl, pyridyl, —NHMe, —C(═O)OMe, —C(═O)OCH 2 phenyl, amino, hydroxyl, hydroxyethoxy, trifluoromethoxy, trifluoromethyl, or —SO 2 phenyl; 
       or a pharmaceutically acceptable salt, C 1-6  alkyl ester or amide, or C 2-6  alkenyl ester or amide thereof. 
     
   
   
       24 . A pharmaceutical composition comprising a compound of  claim 1 ,  15 ,  16 ,  17 ,  18 ,  19 , or  20 . 
   
   
       25 . A method for treating rheumatoid arthritis in a patient, comprising the step of administering to a patient in need of treatment a pharmaceutical composition comprising a compound of  claim 1 . 
   
   
       26 . A method for treating multiple sclerosis in a patient, comprising the step of administering to a patient in need of treatment a pharmaceutical composition comprising a compound of  claim 1 . 
   
   
       27 . A method for treating an autoimmune disease, comprising the step of administering to a patient in need of treatment a pharmaceutical composition comprising a compound of  claim 1 .