US2009232879A1PendingUtilityA1
Thyromimetics for the Treatment of Fatty Liver Diseases
Assignee: METABASIS THERAPEUTICS INCPriority: May 26, 2005Filed: May 26, 2006Published: Sep 17, 2009
Est. expiryMay 26, 2025(expired)· nominal 20-yr term from priority
A61P 5/14A61P 43/00A61P 3/06A61P 3/04A61P 3/00A61K 31/661A61K 31/665A61K 31/683A61P 1/16A61K 31/662
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Claims
Abstract
The present invention is directed toward the use of thyromimetic compounds that are thyroid receptor ligands, pharmaceutically acceptable salts thereof, and to prodrugs of these compounds for preventing, treating, or ameliorating fatty liver diseases such as steatosis, non-alcoholic fatty liver disease, and non-alcoholic steatohepatitis.
Claims
exact text as granted — not AI-modified1 . A method of decreasing fat content in the liver of an animal, comprising administering to said animal a therapeutically effective amount of a thyromimetic compound or a pharmaceutically acceptable salt thereof, wherein said compound binds to a thyroid receptor.
2 . A method of preventing, treating, or ameliorating a fatty liver disease in an animal, comprising administering to said animal a therapeutically effective amount of a thyromimetic compound or a pharmaceutically acceptable salt thereof, wherein said compound binds to a thyroid receptor.
3 . The method of claim 2 wherein said fatty liver disease is selected from the group consisting of steatosis, non-alcoholic fatty liver disease, and non-alcoholic steatohepatitis.
4 . The method of claim 1 or 2 wherein said compound binds to a thyroid receptor with a Ki of ≦1 μM.
5 . The method of claim 4 wherein said thyroid receptor is TRα1.
6 . The method of claim 4 wherein said thyroid receptor is TRβ1.
7 . The method of claim 4 wherein said compound binds to a thyroid receptor with a Ki of ≦100 nM.
8 . The method of claim 7 wherein said thyroid receptor is TRα1.
9 . The method of claim 7 wherein said thyroid receptor is TRβ1.
10 . The method of claim 1 or 2 , wherein said compound activates said thyroid receptor.
11 . The method of claim 10 wherein said thyroid receptor is TRα1.
12 . The method of claim 10 wherein said thyroid receptor is TRβ1.
13 . The method of claim 10 wherein said compound increases mRNA expression of a gene selected from the group consisting of LDL receptor, ACC, FAS, spot-14, CPT-1, CYP7A, apo AI, and mGPDH.
14 . The method of claim 1 or 2 wherein said compound reduces fat content in liver in the absence of any negative effects on the heart.
15 . The method of claim 14 wherein said negative effects include one or more of significant increase in heart rate, significant raising of blood pressure, significant increase in heart rate, significant increase in left ventricular contractility, significant increase in systolic blood pressure, and significant increase in diastolic blood pressure.
16 . The method of claim 1 or 2 wherein said compound reduces fat content in liver in the absence of any significant change in total body weight, significant change in TSH or TRH levels, significant change in liver enzymes, significant change in serum free fatty acid levels, or significant liver mitochondrial damage.
17 . The method of claim 1 or 2 wherein said thyromimetic compound is administered in the form of a pharmaceutical composition.
18 . The method of claim 17 , wherein said pharmaceutical composition is in the form of a controlled release composition, transdermal patch, tablet, hard capsule, or soft capsule.
19 . The method of claim 1 or 2 , wherein said thyromimetic compound is administered orally in a unit dose of about 0.375 μg/kg to 3.375 mg/kg.
20 . The method of claim 1 or 2 , wherein said thyromimetic compound is administered orally in a total daily dose of about 0.375 μg/kg/day to about 3.75 mg/kg/day, equivalent of the free acid.
21 . The method of claim 1 or 2 , wherein said thyromimetic compound is a compound of Formula I:
(Ar 1 )-G-(Ar 2 )-T-E wherein: Ar 1 and Ar 2 are substituted aryl groups; G is an atom or group of atoms that links Ar 1 and Ar 2 through a single C, S, Se, O, or N atom or CH 2 linked to C, S, Se, O, or N, wherein the C or N is substituted; T is an atom or group of atoms linking Ar 2 to E through 1-4 contiguous atoms or is absent; and E is a functional group or moiety with a pKa ≦7.4, a carboxylic acid or esters thereof, carboxylic acid amide, sulfonic acid, tetrazole, hydroxamic acid, oxamic acid, malonamic acid, 6-azauracil, thiazolidinedione, acylsulfonamide, other carboxylic acid surrogates, phosphonic acid, phosphonic acid monoester, phosphinic acid, or a prodrug thereof, or an atom or group of atoms containing an O or N that binds the thyroid hormone binding pocket of a TRα or TRβ.
22 . The method of claim 1 or 2 , wherein said thyromimetic compound is a compound of Formula II:
wherein:
G is selected from the group consisting of —O—, —S—, -Se-, —S(═O)—, —S(═O) 2 —, -Se-, —CH 2 —, —CF 2 —, —CHF—, —C(O)—, —CH(OH)—, —CH(C 1 -C 4 alkyl)-, CH(C 1 -C 4 alkoxy)-, —C(═CH 2 )—, —NH—, and —N(C 1 -C 4 alkyl)-, or CH 2 linked to any of the preceding groups;
or G is R 50 -R 51 wherein;
R 50 -R 51 together are —C(R 52 )═C(R 52 ) or alternatively R 50 and R 51 are independently selected from O, S and —CH(R 53 )—, with the provisos that at least one R 50 and R 51 is —CH(R 53 )—, and when one of R 50 and R 51 is O or S, then R 53 is R 54 ;
R 54 is hydrogen, halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, fluoromethyl, difluoromethyl, or trifluoromethyl;
R 53 is selected from hydrogen, halogen, hydroxyl, mercapto, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio, difluoromethylthio and trifluoromethylthio;
R 52 is selected from hydrogen, halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio, difluoromethylthio and trifluoromethylthio;
T is selected from the group consisting of —(CR a 2 ) k —, —CR b ═CR b —(CR a 2 ) n —, —(CR a 2 ) n —CR b ═CR b —, —(CR a 2 )—CR b ═CR b —(CR a 2 )—, —O(CR b 2 )(CR a 2 ) n —, —S(CR b 2 )(CR a 2 ) n —, —N(R c )(CR b 2 )(CR a 2 ) n —, —N(R b )C(O)(CR b 2 ) n —, —(CR a 2 ) m C(R b )(NR b R c )—, —C(O)(CR a 2 ) m —, —(CR a 2 ) m C(O)—, —(CR b 2 )—O—(CR b 2 )—(CR a 2 ) p —, —(CR b 2 )—S—(CR b 2 )—(CR b 2 ) p —, —(CR b 2 )—N(R c )—(CR b 2 )—(CR a 2 ) p —, —(CR a 2 ) p —(CR b 2 )—O—(CR b 2 )—, —(CR a 2 ) p —(CR b 2 )—S—(CR b 2 )—, —(CR a 2 ) p —(CR b 2 )—N(R c )—(CR b 2 )— and —(CH 2 ) p C(O)N(R b )C(R a 2 )—;
k is an integer from 0-4;
m is an integer from 0-3;
n is an integer from 0-2;
p is an integer from 0-1;
Each R a is independently selected from the group consisting of hydrogen, optionally substituted —C 1 -C 4 alkyl, halogen, —OH, optionally substituted —O—C 1 -C 4 alkyl, —OCF 3 , —OCHF 2 , —OCH 2 F, optionally substituted —S—C 1 -C 4 alkyl, —NR b R c , optionally substituted —C 2 -C 4 alkenyl, and optionally substituted —C 2 -C 4 alkynyl; with the proviso that when one R a is attached to C through an O, S, or N atom, then the other R a attached to the same C is a hydrogen, or attached via a carbon atom;
Each R b is independently selected from the group consisting of hydrogen and optionally substituted —C 1 -C 4 alkyl;
Each R c is independently selected from the group consisting of hydrogen and optionally substituted —C 1 -C 4 alkyl, optionally substituted —C(O)—C 1 -C 4 alkyl, and —C(O)H;
R 1 , R 2 , R 6 , and R 7 are each independently selected from the group consisting of hydrogen, halogen, optionally substituted —C 1 -C 4 alkyl, optionally substituted —S—C 1 -C 3 alkyl, optionally substituted —C 2 -C 4 alkenyl, optionally substituted —C 2 -C 4 alkynyl, —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , —OCH 2 F, optionally substituted —O—C 1 -C 3 alkyl, hydroxy and cyano; or
R 6 and T are taken together along with the carbons they are attached to form a ring of 5 to 6 atoms with 0-2 unsaturations, not including the unsaturation on the ring to which R 6 and T are attached, and 0 to 2 heteroatoms independently selected from —NR i —, —O—, and —S—, with the proviso that when there are 2 heteroatoms in the ring and both heteroatoms are different than nitrogen then both heteroatoms have to be separated by at least one carbon atom; and X is attached to this ring by a direct bond to a ring carbon, or by —(CR a 2 )— or —C(O)— bonded to a ring carbon or a ring nitrogen;
R i is selected from the group consisting of hydrogen, —C(O)C 1 -C 4 alkyl, —C 1 -C 4 alkyl, and —C 1 -C 4 -aryl; or
R 1 and R 7 are taken together along with the carbons to which they are attached to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations, not including the unsaturation on the ring to which R 1 and R 7 are attached, including 0 to 2 heteroatoms independently selected from —NR h —, —O—, and —S—, with the proviso that when there are 2 heteroatoms in the ring and both heteroatoms are different than nitrogen then both heteroatoms have to be separated by at least one carbon atom;
R 8 and R 9 are each independently selected from the group consisting of hydrogen, halogen, optionally substituted —C 1 -C 4 alkyl, optionally substituted —S—C 1 -C 3 alkyl, optionally substituted —C 2 -C 4 alkenyl, optionally substituted —C 2 -C 4 alkynyl, —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , —OCH 2 F, optionally substituted —O—C 1 -C 3 alkyl, hydroxy, —(CR a 2 )aryl, —(CR a 2 )cycloalkyl, —(CR a 2 )heterocycloalkyl, —C(O)aryl, —C(O)cycloalkyl, —C(O)heterocycloalkyl, —C(O)alkyl and cyano;
R 3 and R 4 are each independently selected from the group consisting of hydrogen, halogen, —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , —OCH 2 F, cyano, optionally substituted —C 1 -C 12 alkyl, optionally substituted —C 2 -C 12 alkenyl, optionally substituted —C 2 -C 12 alkynyl, optionally substituted —(CR a 2 ) m aryl, optionally substituted —(CR a 2 ) m cycloalkyl, optionally substituted —(CR a 2 ) m heterocycloalkyl, —C(R b )═C(R b )-aryl, —C(R b )═C(R b )— cycloalkyl, —C(R b )═C(R b )-heterocycloalkyl, —C≡C(aryl), —C≡C(cycloalkyl), —C≡C(heterocycloalkyl), —(CR a 2 ) n (CR b 2 )NR f R g , —OR d , —SR d , —S(═O)R e , —S(═O) 2 R e , —S(═O) 2 NR f R g , —C(O)NR f R g , —C(O)OR h , —C(O)R e , —N(R b )C(O)R e , —N(R b )C(O)NR f R g , —N(R b )S(═O) 2 R c , —N(R b )S(═O) 2 NR f R g , and —NR f R g ;
Each R d is selected from the group consisting of optionally substituted —C 2 -C 12 alkyl, optionally substituted —C 2 -C 12 alkenyl, optionally substituted —C 2 -C 12 alkynyl, optionally substituted —(CR b 2 ) n aryl, optionally substituted —(CR b 2 ) n cycloalkyl, optionally substituted —(CR b 2 ) n heterocycloalkyl, and —C(O)NR f R g ;
Each R e is selected from the group consisting of optionally substituted —C 1 -C 12 alkyl, optionally substituted —C 2 -C 12 alkenyl, optionally substituted —C 2 -C 12 alkynyl, optionally substituted —(CR a 2 ) n aryl, optionally substituted —(CR a 2 ) n cycloalkyl, and optionally substituted —(CR a 2 ) n heterocycloalkyl;
R f and R g are each independently selected from the group consisting of hydrogen, optionally substituted —C 1 -C 12 alkyl, optionally substituted —C 2 -C 12 alkenyl, optionally substituted —C 2 -C 12 alkynyl, optionally substituted —(CR b 2 ) n aryl, optionally substituted —(CR b 2 ) n cycloalkyl, and optionally substituted —(CR b 2 ) n heterocycloalkyl, or R f and R g may together form an optionally substituted heterocyclic ring of 3-8 atoms containing 0-4 unsaturations, said heterocyclic ring may contain a second heterogroup within the ring selected from the group consisting of O, NR c , and S, wherein said optionally substituted heterocyclic ring may be substituted with 0-4 substituents selected from the group consisting of optionally substituted —C 1 -C 4 alkyl, —OR b , oxo, cyano, —CF 3 , —CHF 2 , —CH 2 F, optionally substituted phenyl, and —C(O)OR h ;
Each R h is selected from the group consisting of optionally substituted —C 1 -C 12 alkyl, optionally substituted —C 2 -C 12 alkenyl, optionally substituted —C 2 -C 12 alkynyl, optionally substituted —(CR b 2 ) n aryl, optionally substituted —(CR b 2 ) n cycloalkyl, and optionally substituted —(CR b 2 ) n heterocycloalkyl; or
R 3 and R 8 are taken together along with the carbon atoms to which they are attached to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations, not including the unsaturation on the ring to which R 3 and R 8 are attached, including 0 to 2 heteroatoms independently selected from —NR h —, —O—, and —S—, with the proviso that when there are 2 heteroatoms in the ring and both heteroatoms are different than nitrogen then both heteroatoms have to be separated by at least one carbon atom; or
R 8 and G are taken together along with the carbon atoms to which they are attached to form an optionally substituted ring comprising —CH═CH—CH═, —N═CH—CH═, —CH═N—CH— or —CH═CH—N═;
R 5 is selected from the group consisting of —OH, optionally substituted —OC 1 -C 6 alkyl, —OC(O)R e , —OC(O)OR h , NHC(O)Olh, —OC(O)NH(R h ), —F, —NHC(O)R e , —NHS(═O)R e , —NHS(═O) 2 R e , —NHC(═S)NH(R h ), and —NHC(O)NH(R h ); or
R 3 and R 5 are taken together along with the carbons they are attached to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations, not including the unsaturation on the ring to which R 3 and R 5 are attached, including 0 to 2 heteroatoms independently selected from —NR h —, —O—, and —S—, with the proviso that when there are 2 heteroatoms in the ring and both heteroatoms are different than nitrogen then both heteroatoms have to be separated by at least one carbon atom; and
X is carboxylic acid or esters thereof, carboxylic acid amide, sulfonic acid, tetrazole, hydroxamic acid, oxamic acid, malonamic acid, 6-azauracil, thiazolidinedione, acylsulfonamide, other carboxylic acid surrogates, phosphonic acid, phosphonic acid monoester, phosphinic acid, or a prodrug thereof.
23 . The method of claim 1 or 2 , wherein said thyromimetic compound is a compound of Formula III:
wherein:
G is selected from the group consisting of —O—, —S—, -Se-, —S(═O)—, —S(═O) 2 —, -Se-, —CH 2 —, —CF 2 —, —CHF—, —C(O)—, —CH(OH)—, —CH(C 1 -C 4 alkyl)-, —CH(C 1 -C 4 alkoxy)-, —C(═CH 2 )—, —NH—, and —N(C 1 -C 4 alkyl)-, or CH 2 linked to any of the preceding groups;
or G is R 50 -R 51 wherein;
R 50 -R 51 together are —C(R 52 )═C(R 52 )— or alternatively R 50 and R 51 are independently selected from O, S and —CH(R 53 )—, with the provisos that at least one R 50 and R 51 is —CH(R 53 )—, and when one of R 50 and R 51 is O or S, then R 53 is R 54 ;
R 54 is hydrogen, halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, fluoromethyl, difluoromethyl, or trifluoromethyl;
R 53 is selected from hydrogen, halogen, hydroxyl, mercapto, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio, difluoromethylthio and trifluoromethylthio;
R 52 is selected from hydrogen, halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio, difluoromethylthio and trifluoromethylthio;
T is selected from the group consisting of —(CR a 2 ) k —, —CR b ═CR b —(CR a 2 ) n —, —(CR a 2 ) n —CR b ═CR b —, —(CR a 2 )—CR b ═CR b —(CR a 2 )—, —O(CR b 2 )(CR a 2 ) n —, —S(CR b 2 )(CR a 2 ) n —, —N(R c )(CR b 2 )(CR a 2 ) n —, —N(R b )C(O)(CR a 2 ) n —, —(CR a 2 ) m C(R b )(NR b R c )—, —C(O)(CR a 2 ) m —, —(CR a 2 ) m C(O)—, —(CR b 2 )—O—(CR b 2 )—(CR a 2 ) p —, —(CR b 2 )—S—(CR b 2 )—(CR a 2 ) p —, —(CR b 2 )—N(R c )—(CR b 2 )—(CR a 2 ) p —, —(CR a 2 ) p —(CR b 2 )—O—(CR b 2 )—, —(CR a 2 ) p —(CR b 2 )—S—(CR b 2 )—, —(CR a 2 ) p —(CR b 2 )—N(R c )—(CR b 2 ) and —(CH 2 ) p C(O)N(R b )C(R a 2 )—;
k is an integer from 0-4;
m is an integer from 0-3;
n is an integer from 0-2;
p is an integer from 0-1;
Each R a is independently selected from the group consisting of hydrogen, optionally substituted —C 1 -C 4 alkyl, halogen, —OH, optionally substituted —O—C 1 -C 4 alkyl, —OCF 3 , —OCHF 2 , —OCH 2 F, optionally substituted —S—C 1 -C 4 alkyl, —NR b R c , optionally substituted —C 2 -C 4 alkenyl, and optionally substituted —C 2 -C 4 alkynyl; with the proviso that when one R a is attached to C through an O, S, or N atom, then the other R a attached to the same C is a hydrogen, or attached via a carbon atom;
Each R b is independently selected from the group consisting of hydrogen and optionally substituted —C 1 -C 4 alkyl;
Each R c is independently selected from the group consisting of hydrogen and optionally substituted —C 1 -C 4 alkyl, optionally substituted —C(O)—C 1 -C 4 alkyl, and —C(O)H;
R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, optionally substituted —C 1 -C 4 alkyl, optionally substituted —S—C 1 -C 3 alkyl, optionally substituted —C 2 -C 4 alkenyl, optionally substituted —C 2 -C 4 alkynyl, —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , —OCH 2 F, optionally substituted —O—C 1 -C 3 alkyl, and cyano; with the proviso that at least one of R 1 and R 2 is not hydrogen;
R 3 and R 4 are each independently selected from the group consisting of hydrogen, halogen, —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , —OCH 2 F, cyano, optionally substituted —C 1 -C 12 alkyl, optionally substituted —C 2 -C 12 alkenyl, optionally substituted —C 2 -C 12 alkynyl, optionally substituted —(CR a 2 ) m aryl, optionally substituted —(CR a 2 ) m cycloalkyl, optionally substituted —(CR a 2 ) m heterocycloalkyl, —C(R b )═C(R b )-aryl, —C(R b )═C(R b )— cycloalkyl, —C(R b )═C(R b )-heterocycloalkyl, —C≡C(aryl), —C≡C(cycloalkyl), —C≡C(heterocycloalkyl), —(CR a 2 ) n (CR b 2 )NR f R g , —OR d , —SR d , —S(═O)R e , —S(═O) 2 R e , —S(═O) 2 NR f R g , —C(O)NR f R g , —C(O)OR h , —C(O)R e , N(R b )C(O)R e , —N(R b )C(O)NR f R g , —N(R b )S(═O) 2 R e , —N(R b )S(═O) 2 NR f R g , and —NR f R g ;
Each R d is selected from the group consisting of optionally substituted —C 1 -C 12 alkyl, optionally substituted —C 2 -C 12 alkenyl, optionally substituted —C 2 -C 12 alkynyl, optionally substituted —(CR b 2 ) n aryl, optionally substituted —(CR b 2 ) n cycloalkyl, optionally substituted —(CR b 2 ) n heterocycloalkyl, and —C(O)NR f R g ;
Each R e is selected from the group consisting of optionally substituted —C 1 -C 12 alkyl, optionally substituted —C 2 -C 12 alkenyl, optionally substituted —C 2 -C 12 alkynyl, optionally substituted —(CR a 2 ) n aryl, optionally substituted —(CR a 2 ) n cycloalkyl, and optionally substituted —(CR a 2 ) n heterocycloalkyl;
R f and R g are each independently selected from the group consisting of hydrogen, optionally substituted —C 1 -C 12 alkyl, optionally substituted —C 2 -C 12 alkenyl, optionally substituted —C 2 -C 12 alkynyl, optionally substituted —(CR b 2 ) n aryl, optionally substituted —(CR b 2 ) n cycloalkyl, and optionally substituted —(CR b 2 ) n heterocycloalkyl, or R f and R g may together form an optionally substituted heterocyclic ring of 3-8 atoms containing 0-4 unsaturations, said heterocyclic ring may contain a second heterogroup within the ring selected from the group consisting of O, NR c , and S, wherein said optionally substituted heterocyclic ring may be substituted with 0-4 substituents selected from the group consisting of optionally substituted —C 1 -C 4 alkyl, —OR b , oxo, cyano, —CF 3 , —CHF 2 , —CH 2 F, optionally substituted phenyl, and —C(O)OR h ;
Each R h is selected from the group consisting of optionally substituted —C 1 -C 12 alkyl, optionally substituted —C 2 -C 12 alkenyl, optionally substituted —C 2 -C 12 alkynyl, optionally substituted —(CR b 2 ) n aryl, optionally substituted —(CR b 2 ) n cycloalkyl, and optionally substituted —(CR b 2 ) n heterocycloalkyl;
R 5 is selected from the group consisting of —OH, optionally substituted —OC 1 -C 6 alkyl, —OC(O)R e , —OC(O)OR h , —NHC(O)OR h , —OC(O)NH(R h ), —F, —NHC(O)R e , —NHS(═O)R e , —NHS(═O) 2 R e , —NHC(═S)NH(R h ), and —NHC(O)NH(R h ); or
R 3 and R 5 are taken together along with the carbons they are attached to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations, not including the unsaturation on the ring to which R 3 and R 5 are attached, including 0 to 2 heteroatoms independently selected from —NR h —, —O—, and —S—, with the proviso that when there are 2 heteroatoms in the ring and both heteroatoms are different than nitrogen then both heteroatoms have to be separated by at least one carbon atom; and
X is carboxylic acid or esters thereof, carboxylic acid amide, sulfonic acid, tetrazole, hydroxamic acid, oxamic acid, malonamic acid, 6-azauracil, thiazolidinedione, acylsulfonamide, other carboxylic acid surrogates, phosphonic acid, phosphonic acid monoester, phosphinic acid, or a prodrug thereof.
24 . The method of claim 1 or 2 , wherein said thyromimetic compound is a compound of Formula IV:
wherein:
A is selected from the group consisting of —NR i —, —O—, and —S—;
B is selected from the group consisting of —CR b —, and —N—;
R i is selected from the group consisting of hydrogen, —C(O)C 1 -C 4 alkyl, —C 1 -C 4 alkyl, and —C 1 -C 4 -aryl;
R b is selected from the group consisting of hydrogen and optionally substituted —C 1 -C 4 alkyl;
G is selected from the group consisting of —O—, —S—, -Se-, —S(═O)—, —S(═O) 2 —, —CH 2 —, —CF 2 —, —CHF—, —C(O)—, —CH(OH)—, —NH—, and —N(C 1 -C 4 alkyl)-, or CH 2 linked to any of the preceding groups;
or G is R 50 -R 51 wherein;
R 50 -R 51 together are —C 52 )═C(R 52 )— or alternatively R 50 and R 51 are independently selected from O, S and —CH(R 53 )—, with the provisos that at least one R 50 and R 51 is —CH(R 53 )—, and when one of R 50 and R 51 is O or S, then R 53 is R 54 ;
R 54 is hydrogen, halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, fluoromethyl, difluoromethyl, or trifluoromethyl;
R 53 is selected from hydrogen, halogen, hydroxyl, mercapto, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio, difluoromethylthio and trifluoromethylthio;
R 52 is selected from hydrogen, halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio, difluoromethylthio and trifluoromethylthio;
D is selected from the group consisting of a bond, —(CR a 2 )—, and —C(O)—;
n is an integer from 0-2;
Each R a is independently selected from the group consisting of hydrogen, optionally substituted —C 1 -C 4 alkyl, halogen, —OH, optionally substituted —O—C 1 -C 4 alkyl, —OCF 3 , —OCHF 2 , —OCH 2 F, optionally substituted —S—C 1 -C 4 alkyl, —NR b R c , optionally substituted —C 2 -C 4 alkenyl, and optionally substituted —C 2 -C 4 alkynyl, with the proviso that when one R a is attached to C through an O, S, or N atom, then the other R a attached to the same C is a hydrogen, or attached via a carbon atom;
R 1 and R 2 are each independently selected from the group consisting of halogen, optionally substituted —C 1 -C 4 alkyl, optionally substituted —S—C 1 -C 3 alkyl, optionally substituted —C 2 -C 4 alkenyl, optionally substituted —C 2 -C 4 alkynyl, —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , —OCH 2 F, optionally substituted —O—C 1 -C 3 alkyl, and cyano;
R 3 and R 4 are each independently selected from the group consisting of hydrogen, halogen, —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , —OCH 2 F, cyano, optionally substituted —C 1 -C 12 alkyl, optionally substituted —C 2 -C 12 alkenyl, optionally substituted —C 2 -C 12 alkynyl, optionally substituted —(CR a 2 ) m aryl, optionally substituted —(CR a 2 ) m cycloalkyl, optionally substituted —(CR a 2 ) m heterocycloalkyl, —C(R b )═C(R b )-aryl, —C(R b )═C(R b )— cycloalkyl, —C(R b )═C(R b )-heterocycloalkyl, —C≡C(aryl), —C≡C(cycloalkyl), —C≡C(heterocycloalkyl), —(CR a 2 ) n (CR b 2 )NR f R g , —OR d , —SR d , —S(═O)R e , —S(═O) 2 R e , —S(═O) 2 NR f R g , —C(O)NR f R g , —C(O)OR h , —C(O)R e , —N(R b )C(O)R e , —N(R b )C(O)NR f R g , —N(R b )S(O) 2 R e , —N(R b )S(═O) 2 NR f R g , and —NR f R g ;
Each R d is selected from the group consisting of optionally substituted —C 1 -C 12 alkyl, optionally substituted —C 2 -C 12 alkenyl, optionally substituted —C 2 -C 12 alkynyl, optionally substituted —(CR b 2 ) n aryl, optionally substituted —(CR b 2 ) n cycloalkyl, optionally substituted —(CR b 2 ) n heterocycloalkyl, and —C(O)NR f R g ;
Each R e is selected from the group consisting of optionally substituted —C 1 -C 12 alkyl, optionally substituted —C 2 -C 12 alkenyl, optionally substituted —C 2 -C 12 alkynyl, optionally substituted —(CR a 2 ) n aryl, optionally substituted —(CR a 2 ) n cycloalkyl, and optionally substituted —(CR a 2 ) n heterocycloalkyl;
R f and R g are each independently selected from the group consisting of hydrogen, optionally substituted —C 2 -C 12 alkyl, optionally substituted —C 2 -C 12 alkenyl, optionally substituted —C 2 -C 12 alkynyl, optionally substituted —(CR b 2 ) n aryl, optionally substituted —(CR b 2 ) n cycloalkyl, and optionally substituted —(CR b 2 ) n heterocycloalkyl, or R f and R g may together form an optionally substituted heterocyclic ring of 3-8 atoms containing 0-4 unsaturations, which may contain a second heterogroup selected from the group consisting of O, NR c , and S, wherein said optionally substituted heterocyclic ring may be substituted with 0-4 substituents selected from the group consisting of optionally substituted —C 1 -C 4 alkyl, —OR b , oxo, cyano, —CF 3 , —CHF 2 , —CH 2 F, optionally substituted phenyl, and —C(O)OR h ;
Each R h is selected from the group consisting of optionally substituted —C 1 -C 12 alkyl, optionally substituted —C 2 -C 12 alkenyl, optionally substituted —C 2 -C 12 alkynyl, optionally substituted —(CR b 2 ) n aryl, optionally substituted —(CR b 2 ) n cycloalkyl, and optionally substituted —(CR b 2 ) n heterocycloalkyl;
R 5 is selected from the group consisting of —OH, optionally substituted —OC 1 -C 6 alkyl, —OC(O)R e , —OC(O)OR h , —NHC(O)OR h , OC(O)NH(R h ), —F, —NHC(O)R e , —NHS(═O)R e , —NHS(═O) 2 R e , —NHC(═S)NH(R h ), and —NHC(O)NH(R h ); and
X is carboxylic acid or esters thereof, carboxylic acid amide, sulfonic acid, tetrazole, hydroxamic acid, oxamic acid, malonamic acid, 6-azauracil, thiazolidinedione, acylsulfonamide, other carboxylic acid surrogates, phosphonic acid, phosphonic acid monoester, phosphinic acid, or a prodrug thereof.
25 . The method of claim 1 or 2 , wherein said thyromimetic compound is a compound of Formula V:
wherein:
G is selected from the group consisting of —O—, —S—, -Se-, —S(═O)—, —S(═O) 2 —, —CH 2 —, —CF 2 —, —CHF—, —C(O)—, —CH(OH)—, —NH—, and —N(C 1 -C 4 alkyl)-, or CH 2 linked to any of the preceding groups;
or G is R 50 -R 51 wherein;
R 50 -R 51 together are —C(R 52 )═C(R 52 )— or alternatively R 50 and R 51 are independently selected from O, S and —CH(R 53 )—, with the provisos that at least one R 50 and R 51 is —CH(R 53 )—, and when one of R 50 and R 51 is O or S, then R 53 is R 54 ;
R 54 is hydrogen, halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, fluoromethyl, difluoromethyl, or trifluoromethyl;
R 53 is selected from hydrogen, halogen, hydroxyl, mercapto, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio, difluoromethylthio and trifluoromethylthio;
R 52 is selected from hydrogen, halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio, difluoromethylthio and trifluoromethylthio;
T is selected from the group consisting of —(CR a 2 ) k —, —CR b ═CR b —(CR a 2 ) n —, —(CR a 2 ) n —CR b ═CR b —, (CR a 2 )—CR b ═CR b —(CR a 2 )—, —O(CR b 2 )(CR a 2 ) n —, —S(CR b 2 )(CR a 2 ) n , —N(R c )(CR b 2 )(CR a 2 ) n —, —N(R b )C(O)(CR a 2 ) n —, —(CR a 2 ) m C(R b )(NR b R c )—, —C(O)(CR a 2 ) m —, —(CR a 2 ) m C(O)—, —(CR b 2 )—O—(CR b 2 )—(CR a 2 ) p —, —(CR b 2 )—S—(CR b 2 )—(CR a 2 ) p —, —(CR b 2 )—N(CR b 2 )—S—(CR b 2 )—(CR a 2 ) p —, —(CR a 2 ) p —(CR b 2 )—O—(CR b 2 )—), —(CR a 2 ) p —(CR b 2 )—S—(CR b 2 )—, —(CR a 2 ) p —(CR b 2 )—N(R c )—(CR b 2 )— and —(CH 2 ) p C(O)N(R b )C(R a 2 )—;
k is an integer from 0-4;
m is an integer from 0-3;
n is an integer from 0-2;
p is an integer from 0-1;
Each R a is independently selected from the group consisting of hydrogen, optionally substituted —C 1 -C 4 alkyl, halogen, —OH, optionally substituted —O—C 1 -C 4 alkyl, —OCF 3 , —OCHF 2 , —OCH 2 F, optionally substituted —S—C 1 -C 4 alkyl, —NR b R c , optionally substituted —C 2 -C 4 alkenyl, and optionally substituted —C 2 -C 4 alkynyl; with the proviso that when one R a is attached to C through an O, S, or N atom, then the other R a attached to the same C is a hydrogen, or attached via a carbon atom;
Each R b is independently selected from the group consisting of hydrogen and optionally substituted —C 1 -C 4 alkyl;
Each R c is independently selected from the group consisting of hydrogen and optionally substituted —C 1 -C 4 alkyl, optionally substituted —C(O)—C 1 -C 4 alkyl, and —C(O)H;
R 1 and R 2 are each independently selected from the group consisting of halogen, optionally substituted —C 1 -C 4 alkyl, optionally substituted —S—C 1 -C 3 alkyl, optionally substituted —C 2 -C 4 alkenyl, optionally substituted —C 2 -C 4 alkynyl, —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , —OCH 2 F, optionally substituted —O—C 1 -C 3 alkyl, and cyano;
R 8 is selected from the group consisting of hydrogen, halogen, optionally substituted —C 1 -C 4 alkyl, optionally substituted —S—C 1 -C 3 alkyl, optionally substituted —C 2 -C 4 alkenyl, optionally substituted —C 2 -C 4 alkynyl, —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCHF2, —OCH 2 F, optionally substituted —O—C 1 -C 3 alkyl, hydroxy, —(CR a 2 )aryl, —(CR a 2 )cycloalkyl, —(CR a 2 )heterocycloalkyl, —C(O)aryl, —C(O)cycloalkyl, —C(O)heterocycloalkyl, —C(O)alkyl and cyano;
R 3 and R 4 are each independently selected from the group consisting of hydrogen, halogen, —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , —OCH 2 F, cyano, optionally substituted —C 1 -C 12 alkyl, optionally substituted —C 2 -C 12 alkenyl, optionally substituted —C 2 -C 12 alkynyl, optionally substituted —(CR a 2 ) m aryl, optionally substituted —(CR a 2 ) m cycloalkyl, optionally substituted —(CR a 2 ) m heterocycloalkyl, —C(R b )═C(R b )-aryl, —C(R b )═C(R b )— cycloalkyl, —C(R b )═C(R b )-heterocycloalkyl, —C≡C(aryl), —C≡C(cycloalkyl), —C≡C(heterocycloalkyl), —(CR a 2 ) n (CR b 2 )NR f R g , —OR d , —SR d , —S(═O)R e , —S(═O) 2 R e , —S(═O) 2 N f R g , —C(O)NR f R g , —C(O)OR h , —C(O)R e , —N(R b )C(O)R e , —N(R b )C(O)NR f R g , —N(R b )S(O) 2 R e , —N(R b )S(═O) 2 NR f R g , and —NR f R g ;
Each R d is selected from the group consisting of optionally substituted —C 1 -C 12 alkyl, optionally substituted —C 2 -C 12 alkenyl, optionally substituted —C 2 -C 12 alkynyl, optionally substituted —(CR b 2 ) n aryl, optionally substituted —(CR b 2 ) n cycloalkyl, optionally substituted —(CR b 2 ) n heterocycloalkyl, and —C(O)NR f R g ;
Each R e is selected from the group consisting of optionally substituted —C 1 -C 12 alkyl, optionally substituted —C 2 -C 12 alkenyl, optionally substituted —C 2 -C 12 alkynyl, optionally substituted —(CR a 2 ) n aryl, optionally substituted —(CR a 2 ) n cycloalkyl, and optionally substituted —(CR a 2 ) n heterocycloalkyl;
R f and R g are each independently selected from the group consisting of hydrogen, optionally substituted —C 1 -C 12 alkyl, optionally substituted —C 2 -C 12 alkenyl, optionally substituted —C 2 -C 12 alkynyl, optionally substituted —(CR b 2 ) n aryl, optionally substituted —(CR b 2 ) n cycloalkyl, and optionally substituted —(CR b 2 ) n heterocycloalkyl, or R f and R g may together form an optionally substituted heterocyclic ring of 3-8 atoms containing 0-4 unsaturations, which may contain a second heterogroup selected from the group consisting of O, NR c , and S, wherein said optionally substituted heterocyclic ring may be substituted with 0-4 substituents selected from the group consisting of optionally substituted —C 1 -C 4 alkyl, —OR b , oxo, cyano, —CF 3 , —CHF 2 , —CH 2 F, optionally substituted phenyl, and —C(O)OR h ;
Each R h is selected from the group consisting of optionally substituted —C 1 -C 12 alkyl, optionally substituted —C 2 -C 12 alkenyl, optionally substituted —C 2 -C 12 alkynyl, optionally substituted —(CR b 2 ) n aryl, optionally substituted —(CR b 2 ) n cycloalkyl, and optionally substituted —(CR b 2 ) n heterocycloalkyl;
R 3 and R 8 are taken together along with the carbon atoms to which they are attached to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations, not including the unsaturation on the ring to which R 3 and R 8 are attached, including 0 to 2 heteroatoms independently selected from —NR—, —O—, and —S—, with the proviso that when there are 2 heteroatoms in the ring and both heteroatoms are different than nitrogen then both heteroatoms have to be separated by at least one carbon atom; or
R 8 and G are taken together along with the carbon atoms to which they are attached to form an optionally substituted ring comprising —CH═CH—CH═, —N═CH—CH═, —CH═N—CH═ or —CH═CH—N═;
R 5 is selected from the group consisting of —OH, optionally substituted —OC 1 -C 6 alkyl, —OC(O)R e , —OC(O)OR h , —NHC(O)OR h , —OC(O)NH(R h ), —F, —NHC(O)R e , —NHS(═O)R e , —NHS(═O) 2 R e , —NHC(═S)NH(R h ), and —NHC(O)NH(R h ); or
R 3 and R 5 are taken together along with the carbons they are attached to form a ring of 5 to 6 atoms with 0-2 unsaturations, not including the unsaturation on the ring to which R 3 and R 5 are attached, including 0 to 2 heteroatoms independently selected from —NR i —, —O—, and —S—, with the proviso that when there are 2 heteroatoms in the ring and both heteroatoms are different than nitrogen then both heteroatoms have to be separated by at least one carbon atom;
R 7 is selected from the group consisting of hydrogen, halogen, amino, hydroxyl, —O—C 1 -C 4 alkyl, —OCF 3 , —OCHF 2 , —OCH 2 F, —CF 3 , —CHF 2 , —CH 2 F, cyano, —SH and —S—C 1 -C 4 alkyl; and
X is carboxylic acid or esters thereof, carboxylic acid amide, sulfonic acid, tetrazole, hydroxamic acid, oxamic acid, malonamnic acid, 6-azauracil, thiazolidinedione, acylsulfonamide, other carboxylic acid surrogates, phosphonic acid, phosphonic acid monoester, phosphinic acid, or a prodrug thereof.
26 . The method of claim 1 or 2 , wherein said thyromimetic compound is a compound of Formula VI:
wherein:
T is selected from the group consisting of —(CR a 2 ) k —, —CR b ═CR b —(CR 2 ) n —, —(CR a 2 ) n —CR b ═CR b —, —(CR a 2 )—CR b ═CR b —(CR a 2 )—, —O(CR b 2 )(CR a 2 ) n —, —S(CR b 2 )(CR a 2 ) n —, —N(R c )(CR b 2 )(CR a 2 ) n —, —N(R b )C(O)(CR a 2 ) n —, —(CR a 2 ) m C(R b )(NR b R c )—, —C(O)(CR a 2 ) m —, (CR a 2 ) m C(O)—, —(CR b 2 )—O—(CR b 2 )—(CR a 2 ) p —, —(CR b 2 )—S—(CR b 2 )—(CR a 2 ) p —, —(CR b 2 )—N(R c )—(CR b 2 )—(CR a 2 ) p —, —(CR a 2 ) p —(CR b 2 )—O—(CR b 2 )—, —(CR a 2 ) p —(CR b 2 )—S—(CR b 2 )—, —(CR a 2 ) p —(CR b 2 )—N(R c )—(CR b 2 )— and —(CH 2 ) p C(O)N(R b )C(R a 2 )—;
k is an integer from 0-4;
m is an integer from 0-3;
n is an integer from 0-2;
p is an integer from 0-1;
Each R a is independently selected from the group consisting of hydrogen, optionally substituted —C 1 -C 4 alkyl, halogen, —OH, optionally substituted —O—C 1 -C 4 alkyl, —OCF 3 , —OCHF 2 , —OCH 2 F, optionally substituted —S—C 1 -C 4 alkyl, —NR b R c , optionally substituted —C 2 -C 4 alkenyl, and optionally substituted —C 2 -C 4 alkynyl; with the proviso that when one R a is attached to C through an O, S, or N atom, then the other R a attached to the same C is a hydrogen, or attached via a carbon atom;
Each R b is independently selected from the group consisting of hydrogen and optionally substituted —C 1 -C 4 alkyl;
Each R c is independently selected from the group consisting of hydrogen and optionally substituted —C 1 -C 4 alkyl, optionally substituted —C(O)—C 1 -C 4 alkyl, and —C(O)H;
R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, optionally substituted —C 1 -C 4 alkyl, optionally substituted —S—C 1 -C 3 alkyl, optionally substituted —C 2 -C 4 alkenyl, optionally substituted —C 2 -C 4 alkynyl, —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , —OCH 2 F, optionally substituted —O—C 1 -C 3 alkyl, and cyano; with the proviso that at least one of R 1 and R 2 is not hydrogen;
R 3 is selected from the group consisting of hydrogen, halogen, —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , —OCH 2 F, cyano, optionally substituted —C 1 -C 12 alkyl, optionally substituted —C 2 -C 12 alkenyl, optionally substituted —C 2 -C 12 alkynyl, optionally substituted —(CR a 2 ) m aryl, optionally substituted —(CR a 2 ) m cycloalkyl, optionally substituted —(CR a 2 ) m heterocycloalkyl, —C(R b )═C(R b )-aryl, —C(R b )═C(R b )— cycloalkyl, —C(R b )═C(R b )-heterocycloalkyl, —C≡C(aryl), —C≡C(cycloalkyl), C≡C(heterocycloalkyl), —(CR a 2 ) n (CR b 2 )NR f R g , —OR d , —SR d , —S(═O)R e , —S(═O) 2 R e , —S(═O) 2 NR f R g , —C(O)NR f R g , —C(O)OR h , —C(O)R e , —N(R b )C(O)R e , —N(R b )C(O)NR f R g , —N(R b )S(═O) 2 R e , —N(R b )S(═O) 2 N f R g , and —NR f R g ;
Each R d is selected from the group consisting of optionally substituted —C 1 -C 12 alky, optionally substituted —C 2 -C 12 alkenyl, optionally substituted —C 2 -C 12 alkynyl, optionally substituted —(CR b 2 ) n aryl, optionally substituted —(CR b 2 ) n cycloalkyl, optionally substituted —(CR b 2 ) n heterocycloalkyl, and —C(O)NR f R g ;
Each R e is selected from the group consisting of optionally substituted —C 1 -C 12 alkyl, optionally substituted —C 2 -C 12 alkenyl, optionally substituted —C 2 -C 12 akynyl, optionally substituted —(CR a 2 ) n aryl, optionally substituted —(CR a 2 ) n cycloalkyl, and optionally substituted —(CR a 2 ) n heterocycloalkyl;
R f and R g are each independently selected from the group consisting of hydrogen, optionally substituted —C 1 -C 12 alkyl, optionally substituted —C 2 -C 12 alkenyl, optionally substituted —C 2 -C 12 alkynyl, optionally substituted —(CR b 2 ),aryl, optionally substituted —(CR b 2 ) n cycloalkyl, and optionally substituted —(CR b 2 ) n heterocycloalkyl, or R f and R g may together form an optionally substituted heterocyclic ring of 3-8 atoms containing 0-4 unsaturations, said heterocyclic ring may contain a second heterogroup within the ring selected from the group consisting of O, NR c , and S, wherein said optionally substituted heterocyclic ring may be substituted with 0-4 substituents selected from the group consisting of optionally substituted —C 1 -C 4 alkyl, —OR b , oxo, cyano, —CF 3 , optionally substituted phenyl, and —C(O)OR h ;
Each R h is selected from the group consisting of optionally substituted —C 1 -C 12 alkyl, optionally substituted —C 2 -C 12 alkenyl, optionally substituted —C 2 -C 12 alkynyl, optionally substituted —(CR b 2 ) n aryl, optionally substituted -(Cle2),cycloalkyl, and optionally substituted —(CR b 2 ) n heterocycloalkyl;
R 5 is selected from the group consisting of —OH, optionally substituted —OC 1 -C 6 alkyl, —OC(O)R e , —OC(O)OR h , —NHC(O)OR h , —OC(O)NH(R h ), —F, —NHC(O)R e , —NHS(═O)R e , —NHS(═O) 2 R e , —NHC(═S)NH(R h ), and —NHC(O)NH(R h ); and
X is carboxylic acid or esters thereof, carboxylic acid amide, sulfonic acid, tetrazole, hydroxamic acid, oxamic acid, malonamic acid, 6-azauracil, thiazolidinedione, acylsulfonamide, other carboxylic acid surrogates, phosphonic acid, phosphonic acid monoester, phosphinic acid, or a prodrug thereof.
27 . The method of claim 1 or 2 , wherein said thyromimetic compound is a compound of Formula VII:
wherein:
G is selected from the group consisting of —O—, —S—, -Se-, —S(═O)—, —S(═O) 2 —, —CH 2 —, —CF 2 —, —CHF—, —C(O)—, —CH(OH)—, —NH—, and —N(C 1 -C 4 alkyl)-, or CH 2 linked to any of the preceding groups;
or G is R 50 -R 51 wherein;
R 50 -R 51 together are —C(R 52 )═C(R 52 )— or alternatively R 50 and R 51 are independently selected from O, S and —CH(R 53 )—, with the provisos that at least one R 50 and R 51 is —CH(R 53 )—, and when one of R 50 and R 51 is O or S, then R 53 is R 54 ;
R 54 is hydrogen, halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, fluoromethyl, difluoromethyl, or trifluoromethyl;
R 53 is selected from hydrogen, halogen, hydroxyl, mercapto, C 2 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio, difluoromethylthio and trifluoromethylthio;
R 52 is selected from hydrogen, halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio, difluoromethylthio and trifluoromethylthio;
T is selected from the group consisting of —(CR a 2 ) k —, —CR b ═CR b —(CR a 2 ) n —, —(CR a 2 ) n —CR b ═CR b —, —(CR a 2 )—CR b ═CR b —(CR a 2 )—, —O(CR b 2 )(CR a 2 ) n —, —S(CR b 2 )(CR a 2 ) n —, —N(R c )(CR b 2 )(CR a 2 ) n —, —N(R b )C(O)(CR a 2 ) n —, —(CR a 2 ) m C(R b )(NR b R c )—, —C(O)(CR a 2 ) m —, —(CR a 2 ) m C(O)—, —(CR b 2 )—O—(CR b 2 )—(CR a 2 ) p —, —(CR b 2 )—S—(CR b 2 )—(CR a 2 ) p —, —(CR b 2 )—N(R c )—(CR b 2 )—(CR a 2 ) p —, —(CR a 2 ) p —(CR b 2 )—O—(CR b 2 )—, —(CR a 2 ) p —(CR b 2 )—S—(CR b 2 )—, —(CR a 2 ) p —(CR b 2 )—N(R c )—(CR b 2 )— and —(CH 2 ) p C(O)N(R b )C(R a 2 )—;
k is an integer from 0-4;
m is an integer from 0-3;
n is an integer from 0-2;
p is an integer from 0-1;
Each R a is independently selected from the group consisting of hydrogen, optionally substituted —C 1 -C 4 alkyl, halogen, —OH, optionally substituted —O—C 1 -C 4 alkyl, —OCF 3 , —OCHF 2 , —OCH 2 F, optionally substituted —S—C 1 -C 4 alkyl, —NR b R c , optionally substituted —C 2 -C 4 alkenyl, and optionally substituted —C 2 -C 4 alkynyl; with the proviso that when one R a is attached to C through an O, S, or N atom, then the other R a attached to the same C is a hydrogen, or attached via a carbon atom;
Each R b is independently selected from the group consisting of hydrogen and optionally substituted —C 1 -C 4 alkyl;
Each R c is independently selected from the group consisting of hydrogen and optionally substituted —C 1 -C 4 alkyl, optionally substituted —C(O)—C 1 -C 4 alkyl, and —C(O)H;
R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, optionally substituted —C 1 -C 4 alkyl, optionally substituted —S—C 1 -C 3 alkyl, optionally substituted —C 2 -C 4 alkenyl, optionally substituted —C 2 -C 4 alkynyl, —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , —OCH 2 F, optionally substituted —O—C 1 -C 3 alkyl, and cyano; with the proviso that at least one of R 1 and R 2 is not hydrogen;
R 3 is selected from the group consisting of hydrogen, halogen, —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , —OCH 2 F, cyano, optionally substituted —C 1 -C 12 alkyl, optionally substituted —C 2 -C 12 alkenyl, optionally substituted —C 2 -C 12 alkynyl, optionally substituted —(CR a 2 ) m aryl, optionally substituted —(CR a 2 ) m cycloalkyl, optionally substituted —(CR a 2 ) m heterocycloalkyl, —C(R b )═C(R b )-aryl, —C(R b )═C(R b )— cycloalkyl, —C(R b )═C(R b )-heterocycloalkyl, —C≡C(aryl), —C≡C(cycloalkyl), —C≡C(heterocycloalkyl), —(CR a 2 ) n (CR b 2 ) f R 9 , —OR d , —SR d , —S(═O)R e , —S(═O) 2 R e , —S(═O) 2 NR f R g , —C(O)NR f R g , —C(O)OR h , —C(O)R e , —N(R b )C(O)R e , —N(R b )C(O)NR f R g , —N(R b )S(═O) 2 R e , —N(R b )S(═O) 2 NR f R g , and —NR f R g ;
Each R d is selected from the group consisting of optionally substituted —C 1 -C 12 alkyl, optionally substituted —C 2 -C 12 alkenyl, optionally substituted —C 2 -C 12 alkynyl, optionally substituted —(CR b 2 ) n aryl, optionally substituted —(CR b 2 )ncycloalkyl, optionally substituted —(CR b 2 ) n heterocycloalkyl, and —C(O)NR f R g ;
Each R e is selected from the group consisting of optionally substituted —C 1 -C 12 alkyl, optionally substituted —C 2 -C 12 alkenyl, optionally substituted —C 2 -C 12 alkynyl, optionally substituted —(CR a 2 ) n aryl, optionally substituted —(CR a 2 ) n cycloalkyl, and optionally substituted —(CR a 2 ) n heterocycloalkyl;
R f and R g are each independently selected from the group consisting of hydrogen, optionally substituted —C 1 -C 12 alkyl, optionally substituted —C 2 -C 12 alkenyl, optionally substituted —C 2 -C 12 alkynyl, optionally substituted —(CR b 2 ) n aryl, optionally substituted —(CR b 2 ) n cycloalkyl, and optionally substituted —(CR b 2 ) n heterocycloalkyl, or R f and R g may together form an optionally substituted heterocyclic ring of 3-8 atoms containing 0-4 unsaturations, said heterocyclic ring may contain a second heterogroup within the ring selected from the group consisting of O, NR c , and S, wherein said optionally substituted heterocyclic ring may be substituted with 0-4 substituents selected from the group consisting of optionally substituted —C 1 -C 4 alkyl, —OR b , oxo, cyano, —CF 3 , —CHF 2 , —CH 2 F, optionally substituted phenyl, and —C(O)OR h ;
Each R h is selected from the group consisting of optionally substituted —C 1 -C 12 alkyl, optionally substituted —C 2 -C 12 alkenyl, optionally substituted —C 2 -C 12 alkynyl, optionally substituted —(CR b 2 ) n aryl, optionally substituted —(CR b 2 ) n cycloalkyl, and optionally substituted —(CR b 2 ) n heterocycloalkyl;
R 5 is selected from the group consisting of —OH, optionally substituted —OC 1 -C 6 alkyl, —OC(O)R e , —OC(O)OR h , —NHC(O)OR h , —OC(O)NH(R h ), —F, —NHC(O)R e , —NHS(═O)R e , —NHS(═O) 2 R e , —NHC(═S)NH(R h ), and —NHC(O)NH(R h ); or
R 3 and R 5 are taken together along with the carbons they are attached to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations, not including the unsaturation on the ring to which R 3 and R 5 are attached, including 0 to 2 heteroatoms independently selected from —NR h —, —O—, and —S—, with the proviso that when there are 2 heteroatoms in the ring and both heteroatoms are different than nitrogen then both heteroatoms have to be separated by at least one carbon atom;
R 9 is selected from the group consisting of hydrogen, halogen, optionally substituted —C 1 -C 4 alkyl, optionally substituted —S—C 1 -C 3 alkyl, optionally substituted —C 2 -C 4 alkenyl, optionally substituted —C 2 -C 4 alkynyl, —CF 3 , —OCF 3 , optionally substituted-O—C 1 -C 3 alkyl, hydroxy, (CR a 2 )aryl, C(O)aryl, C(O)alkyl and cyano; and
X is carboxylic acid or esters thereof, carboxylic acid amide, sulfonic acid, tetrazole, hydroxamic acid, oxamic acid, malonamic acid, 6-azauracil, thiazolidinedione, acylsulfonamide, other carboxylic acid surrogates, phosphonic acid, phosphonic acid monoester, phosphinic acid, or a prodrug thereof.
28 . The method of claim 1 or 2 , wherein said thyromimetic compound is a compound of Formula VIII:
wherein:
G is selected from the group consisting of —O—, —S—, -Se-, —S(═O)—, —S(═O) 2 —, -Se-, —CH 2 —, —CF 2 —, —CHF—, —C(O)—, —CH(OH)—, —CH(C 1 -C 4 alkyl)-, —CH(C 1 -C 4 alkoxy)-, —C(—CH 2 )—, —NH—, and —N(C 1 -C 4 alkyl)-, or CH 2 linked to any of the preceding groups;
or G is R 50 -R 51 wherein;
R 50 -R 51 together are —C(R 52 )═C(R 52 )— or alternatively R 50 and R 51 are independently selected from O, S and —CH(R 53 )—, with the provisos that at least one R 50 and R 51 is —CH(R 53 )—, and when one of R 50 and R 51 is O or S, then R 53 is R 54 ;
R 54 is hydrogen, halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, fluoromethyl, difluoromethyl, or trifluoromethyl;
R 53 is selected from hydrogen, halogen, hydroxyl, mercapto, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio, difluoromethylthio and trifluoromethylthio;
R 52 is selected from hydrogen, halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio, difluoromethylthio and trifluoromethylthio;
A and T are each independently selected from the group consisting of —(CR a 2 )—, —(CR a 2 ) 2 —, —O(CR b 2 )—, —S(CR b 2 )—, —N(R c )(CR b 2 )—, —N(R b )C(O)—, —C(O)(CR a 2 )—, —(CR a 2 )C(O)—, —(CR b 2 )O—, —(CR b 2 )S—, and —(CR b 2 )N(R c )—;
Each R a is independently selected from the group consisting of hydrogen, optionally substituted —C 1 -C 4 alkyl, halogen, —OH, optionally substituted —O—C 1 -C 4 alkyl, —OCF 3 , —OCHF 2 , —OCH 2 F, optionally substituted —S—C 1 -C 4 alkyl, —NR b R c , optionally substituted —C 2 -C 4 alkenyl, and optionally substituted —C 2 -C 4 alkynyl; with the proviso that when one R a is attached to C through an O, S, or N atom, then the other R a attached to the same C is a hydrogen, or attached via a carbon atom;
Each R b is independently selected from the group consisting of hydrogen and optionally substituted —C 1 -C 4 alkyl;
Each R c is independently selected from the group consisting of hydrogen and optionally substituted —C 1 -C 4 alkyl, optionally substituted —C(O)—C 1 -C 4 alkyl, and —C(O)H;
R 1 , R 2 , and R 7 , are each independently selected from the group consisting of hydrogen, halogen, optionally substituted —C 1 -C 4 alkyl, optionally substituted —S—C 1 -C 3 alkyl, optionally substituted —C 2 -C 4 alkenyl, optionally substituted —C 2 -C 4 alkynyl, —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , —OCH 2 F, optionally substituted —O—C 1 -C 3 alkyl, and cyano; with the proviso that at least one of R 1 and R 2 is not hydrogen;
R 8 and R 9 are each independently selected from the group consisting of hydrogen, halogen, optionally substituted —C 1 -C 4 alkyl, optionally substituted —S—C 1 -C 3 alkyl, optionally substituted —C 2 -C 4 alkenyl, optionally substituted —C 2 -C 4 alkynyl, —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , —OCH 2 F, optionally substituted —O—C 1 -C 3 alkyl, hydroxy, —(CR a 2 )aryl, —(CRhu a 2 )cycloalkyl, —(CR a 2 )heterocycloalkyl, —C(O)aryl, —C(O)cycloalkyl, —C(O)heterocycloalkyl, —C(O)alkyl and cyano;
R 3 and R 4 are each independently selected from the group consisting of hydrogen, halogen, —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , —OCH 2 F, cyano, optionally substituted —C 1 -C 12 alkyl, optionally substituted —C 2 -C 12 alkenyl, optionally substituted —C 2 -C 12 alkynyl, optionally substituted —(CR a 2 ) m aryl, optionally substituted —(CR a 2 ) m cycloalkyl, optionally substituted —(CR a 2 ) m heterocycloalkyl, —C(R b )═C(R b )-aryl, —C(R b )═C(R b )—cycloalkyl, —C(R b )═C(R b )-heterocycloalkyl, —C≡C(aryl), —C≡C(cycloalkyl), —C≡C(heterocycloalkyl), —(CR a 2 ) n (CR b 2 )NR f R g , —OR d , —SR d , —S(═O)R e , —S(═O) 2 R e , —S(═O) 2 NR f R g , —C(O)NR f R g , —C(O)OR h , —C(O)R e , —N(R b )C(O)R e , —N(R b )C(O)NR f R g , —N(R b )S(═O) 2 R e , —N(R b )S(═O) 2 NR f R g , and —NR f R g ;
Each R d is selected from the group consisting of optionally substituted —C 1 -C 12 alkyl, optionally substituted —C 2 -C 12 alkenyl, optionally substituted —C 2 -C 12 alkynyl, optionally substituted —(CR b 2 ) n aryl, optionally substituted —(CR b 2 ) n cycloalkyl, optionally substituted —(CR b 2 ) n heterocycloalkyl, and —C(O)NR f R g ;
Each R e is selected from the group consisting of optionally substituted —C 1 -C 12 alkyl, optionally substituted —C 2 -C 12 alkenyl, optionally substituted —C 2 -C 12 alkynyl, optionally substituted —(CR a 2 ) n aryl, optionally substituted —(CR e 2 ) n cycloalkyl, and optionally substituted —(CR a 2 ) n heterocycloalkyl;
R f and R g are each independently selected from the group consisting of hydrogen, optionally substituted —C 1 -C 12 alkyl, optionally substituted —C 2 -C 12 alkenyl, optionally substituted —C 2 -C 12 alkynyl, optionally substituted —(CR b 2 ) n aryl, optionally substituted —(CR b 2 ) n cycloalkyl, and optionally substituted —(CR b 2 ) n heterocycloalkyl, or R f and R g may together form an optionally substituted heterocyclic ring of 3-8 atoms containing 0-4 unsaturations, said heterocyclic ring may contain a second heterogroup within the ring selected from the group consisting of O, NR c , and S, wherein said optionally substituted heterocyclic ring may be substituted with 0-4 substituents selected from the group consisting of optionally substituted —C 1 -C 4 alkyl, —OR b , oxo, cyano, —CF 3 , —CHF 2 , —CH 2 F, optionally substituted phenyl, and —C(O)OR h ;
Each R h is selected from the group consisting of optionally substituted —C 1 -C 12 alkyl, optionally substituted —C 2 -C 12 alkenyl, optionally substituted —C 2 -C 12 alkynyl, optionally substituted —(CR b 2 ) n aryl, optionally substituted —(CR b 2 ) n cycloalkyl, and optionally substituted —(CR b 2 ) n heterocycloalkyl;
R 3 and R 8 are taken together along with the carbon atoms to which they are attached to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations, not including the unsaturation on the ring to which R 3 and R 8 are attached, including 0 to 2 heteroatoms independently selected from —NR h —, —O—, and —S—, with the proviso that when there are 2 heteroatoms in the ring and both heteroatoms are different than nitrogen then both heteroatoms have to be separated by at least one carbon atom; or
R 8 and G are taken together along with the carbon atoms to which they are attached to form an optionally substituted ring of formula —CH═CH—CH═, —N═CH—CH═, —CH═N—CH═ or —CH═CH—N═;
R 5 is selected from the group consisting of —OH, optionally substituted —OC 1 -C 6 alkyl, —OC(O)R e , —OC(O)OR h , —NHC(O)OR h , —OC(O)NH(R h ), —F, —NHC(O)R e , —NHS(═O)R e , —NHS(═O) 2 R e , —NHC(═S)NH(R h ), and —NHC(O)NH(R h ); or
R 3 and R 1 are taken together along with the carbons they are attached to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations, not including the unsaturation on the ring to which R 3 and R 5 are attached, including 0 to 2 heteroatoms independently selected from —NR h —, —O—, and —S—, with the proviso that when there are 2 heteroatoms in the ring and both heteroatoms are different than nitrogen then both heteroatoms have to be separated by at least one carbon atom;
Y is selected from the group consisting of —O—, and —NR v —;
when Y is —O—, R 11 attached to —O— is independently selected from the group consisting of —H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH 2 -heterocycloakyl wherein the cyclic moiety contains a carbonate or thiocarbonate, optionally substituted -alkylaryl, —C(R z ) 2 OC(O)NR z 2 , —NR z —C(O)—R y , —C(R z ) 2 —OC(O)R y , —C(R z ) 2 —O—C(O)OR y , —C(R z ) 2 OC(O)SR y , -alkyl-S—C(O)R y , -alkyl-S—S-alkylhydroxy, and -alkyl-S—S—S-alkylhydroxy;
when Y is —NR v —, then R 11 attached to —NR v — is independently selected from the group consisting of —H, —[C(R z ) 2 ] q —C(O)OR y , —C(R x ) 2 C(O)OR y , —[C(R z ) 2 ] q —C(O)SR y , and -cycloalkylene-C(O)OR y ;
q is an integer 2 or 3;
Each R z is selected from the group consisting of R y and —H;
Each R y is selected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl;
Each R x is independently selected from the group consisting of —H, and alkyl, or together R x and R x form a cycloalkyl group;
Each R V is selected from the group consisting of —H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl;
and pharmaceutically acceptable salts and prodrugs thereof and pharmaceutically acceptable salts of said prodrugs.
29 . The method of claim 1 or 2 , wherein said thyromimetic compound is a compound of Formula IX:
wherein:
G is selected from the group consisting of —O—, —S—, -Se-, —S(═O)—, —S(═O) 2 —, -Se-, —CH 2 —, —CF 2 —, —CHF—, —C(O)—, —CH(OH)—, —CH(C 1 -C 4 alkyl)-, —CH(C 1 -C 4 alkoxy)-, —C(═CH 2 )—, —NH—, and —N(C 1 -C 4 alkyl)-, or CH 2 linked to any of the preceding groups;
or G is R 50 -R 51 wherein;
R 50 -R 51 together are —C(R 52 )═C(R 52 )— or alternatively R 50 and R 51 are independently selected from O, S and —CH(R 53 )—, with the provisos that at least one R 50 and R 51 is —CH(R 53 )—, and when one of R 50 and R 51 is O or S, then R 53 is R 54 ;
R 54 is hydrogen, halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, fluoromethyl, difluoromethyl, or trifluoromethyl;
R 53 is selected from hydrogen, halogen, hydroxyl, mercapto, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio, difluoromethylthio and trifluoromethylthio;
R 52 is selected from hydrogen, halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio, difluoromethylthio and trifluoromethylthio;
T is selected from the group consisting of —(CR a 2 ) n C(R b 2 )O—, —(CR a 2 ) n C(R b 2 )N(R b )—, —(CR a 2 ) n C(R b 2 )S—, —C(O)(CR a 2 ) p C(R b 2 )O—, —C(O)(CR a 2 ) p C(R b 2 )N(R b )—, —C(O)(CR a 2 ) p C(R b 2 )S—, —(CR a 2 ) p C(O)C(R b 2 )O—, —(CR a 2 ) p C(O)C(R b 2 )N(R b )—, and —(CR a 2 ) p C(O)C(R b 2 )S—,
k is an integer from 0-4;
m is an integer from 0-3;
n is an integer from 0-2;
p is an integer from 0-1;
Each R a is independently selected from the group consisting of hydrogen, optionally substituted —C 1 -C 4 alkyl, halogen, —OH, optionally substituted —O—C 1 -C 4 alkyl, —OCF 3 , —OCHF 2 , —OCH 2 F, optionally substituted —S—C 1 -C 4 alkyl, —NR b R c C, optionally substituted —C 2 -C 4 alkenyl, and optionally substituted —C 2 -C 4 alkynyl; with the proviso that when one R a is attached to C through an O, S, or N atom, then the other R a attached to the same C is a hydrogen, or attached via a carbon atom;
Each R b is independently selected from the group consisting of hydrogen and optionally substituted —C 1 -C 4 alkyl;
Each R c is independently selected from the group consisting of hydrogen and optionally substituted —C 1 -C 4 alkyl, optionally substituted —C(O)—C 1 -C 4 alkyl, and —C(O)H;
R 1 , R 2 , R 6 , and R 7 are each independently selected from the group consisting of hydrogen, halogen, optionally substituted —C 1 -C 4 alkyl, optionally substituted —S—C 1 -C 3 alkyl, optionally substituted —C 2 -C 4 alkenyl, optionally substituted —C 2 -C 4 alkynyl, —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , —OCH 2 F, optionally substituted —O—C 1 -C 3 alkyl, and cyano; with the proviso that at least one of R 1 and R 2 is not hydrogen;
R 8 and R 9 are each independently selected from the group consisting of hydrogen, halogen, optionally substituted —C 1 -C 4 alkyl, optionally substituted —S—C 1 -C 3 alkyl, optionally substituted —C 2 -C 4 alkenyl, optionally substituted —C 2 -C 4 alkynyl, —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , —OCH 2 F, optionally substituted-O—C 1 -C 3 alkyl, hydroxy, —(CR a 2 )aryl, —(CR a 2 )cycloalkyl, —(CR a 2 )heterocycloalkyl, —C(O)aryl, —C(O)cycloalkyl, —C(O)heterocycloalkyl, —C(O)alkyl and cyano; or
R 1 and R 7 are taken together along with the carbon atoms to which they are attached to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations, not including the unsaturation on the ring to which R 1 and R 7 are attached, including 0 to 2 heteroatoms independently selected from —NR h —, —O—, and —S—, with the proviso that when there are 2 heteroatoms in the ring and both heteroatoms are different than nitrogen then both heteroatoms have to be separated by at least one carbon atom;
R 3 and R 4 are each independently selected from the group consisting of hydrogen, halogen, —CF 3 , —CH 2 , —CH 2 F, —OCF 3 , —OCHF 2 , —OCH 2 F, cyano, optionally substituted —C 1 -C 12 alkyl, optionally substituted —C 2 -C 12 alkenyl, optionally substituted —C 2 -C 12 alkynyl, optionally substituted —(CR a 2 ) m aryl, optionally substituted —(CR a 2 ) m cycloalkyl, optionally substituted —(CR a 2 ) m heterocycloalkyl, —C(R b )═C(R b )-aryl, —C(R b )═C(R b )— cycloalkyl, —C(R b )═C(R b )-heterocycloalkyl, —C≡C(aryl), —C≡C(cycloalkyl), —C≡-C(heterocycloalkyl), —(CR a 2 ) n (CR b 2 )NR f R g , —OR d , SR d , —S(═O)R e , —S(═O) 2 R e , —S(—O) 2 NR f R g , —C(O)NR f R g , —C(O)OR h , —C(O)R e , —N(R b )C(O)R e , —N(R b )C(O)NR f R g , —N(R b )S(═O) 2 NR f R g , —N(R h )S(═O) 2 R e , —(R b )S(═O) 2 NR f N g , and —NR f R g ;
Each R d is selected from the group consisting of optionally substituted —C 1 -C 12 alkyl, optionally substituted —C 2 -C 12 alkenyl, optionally substituted —C 2 -C 12 alkynyl, optionally substituted —(CR b 2 ) n aryl, optionally substituted —(CR b 2 ) n cycloalkyl, optionally substituted —(CR b 2 ) n heterocycloalkyl, and —C(O)NR f R g ;
Each R e is selected from the group consisting of optionally substituted —C 1 -C 12 alkyl, optionally substituted —C 2 -C 12 alkenyl, optionally substituted —C 2 -C 12 alkynyl, optionally substituted —(CR a 2 ) n aryl, optionally substituted —(CR a 2 ) n cycloalkyl, and optionally substituted —(CR a 2 ) n heterocycloalkyl;
R f and R g are each independently selected from the group consisting of hydrogen, optionally substituted —C 1 -C 12 alkyl, optionally substituted —C 2 -C 12 alkenyl, optionally substituted —C 2 -C 12 alkynyl, optionally substituted —(CR b 2 ) n aryl, optionally substituted —(CR b 2 ) n cycloalkyl, and optionally substituted —(CR b 2 ) n heterocycloalkyl, or R f and R g may together form an optionally substituted heterocyclic ring of 3-8 atoms containing 0-4 unsaturations, said heterocyclic ring may contain a second heterogroup within the ring selected from the group consisting of O, NR c , and S, wherein said optionally substituted heterocyclic ring may be substituted with 0-4 substituents selected from the group consisting of optionally substituted —C 1 -C 4 alkyl, —OR b , oxo, cyano, —CF 3 , optionally substituted phenyl, and —C(O)OR h ;
Each R h is selected from the group consisting of optionally substituted —C 1 -C 12 alkyl, optionally substituted —C 2 -C 12 alkenyl, optionally substituted —C 2 -C 12 alkynyl, optionally substituted —(CR b 2 ) n aryl, optionally substituted —(CR b 2 ) n cycloalkyl, and optionally substituted —(CR b 2 ) n heterocycloalkyl; or
R 3 and R 8 are taken together along with the carbon atoms to which they are attached to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations, not including the unsaturation on the ring to which R 3 and R 1 are attached, including 0 to 2 heteroatoms independently selected from —NR h —, —O—, and —S—, with the proviso that when there are 2 heteroatoms in the ring and both heteroatoms are different than nitrogen then both heteroatoms have to be separated by at least one carbon atom; or
R 8 and G are taken together along with the carbon atoms to which they are attached to form an optionally substituted ring of formula —CH═CH—CH═, —N═CH—CH═, —CH═N—CH═ or —CH═CH—N═;
R 5 is selected from the group consisting of —OH, optionally substituted —OC 1 -C 6 alkyl, —OC(O)R e , —OC(O)OR h , —NHC(O)OR h , —OC(O)N—H(R h ), —F, —NHC(O)R e , —NHS(═O)R e , —NHS(═O) 2 R e , —NHC(═S)NH(R h ), and —NHC(O)NH(R h ); or
R 3 and R 5 are taken together along with the carbons they are attached to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations not including the unsaturation on the ring to which R 3 and R 5 are attached, including 0 to 2 heteroatoms independently selected from —NR h —, —O—, and —S—, with the proviso that when there are 2 heteroatoms in the ring and both heteroatoms are different than nitrogen then both heteroatoms have to be separated by at least one carbon atom;
X is P(O)(YR 11 )Y″;
Y″ is selected from the group consisting of hydrogen, optionally substituted —C 1 -C 6 -alkyl, —CF 3 , —CHF 2 , —CH 2 F, —CH 2 OH, optionally substituted —C 2 -C 6 alkenyl, optionally substituted —C 2 -C 6 alkynyl, optionally substituted —(CR a 2 ) n cycloalkyl, optionally substituted (CR a 2 ) n heterocycloalkyl, —(CR a 2 ) k S(═O)R e , —(CR a 2 ) k S(═O) 2 R e , —(CR a 2 ) k S(═O) 2 NR f N g , —(CR a 2 ) k C(O)NR f R g , and —(CR a 2 ) k C(O)R e ;
Y is selected from the group consisting of —O—, and —NR v —;
when Y is —O—, R 11 attached to —O— is independently selected from the group consisting of —H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH 2 -heterocycloakyl wherein the cyclic moiety contains a carbonate or thiocarbonate, optionally substituted -alkylaryl, —C(R z ) 2 OC(O)NR z 2 , —NR z —C(O)—R y , —C(R z ) 2 —OC(O)R y , —C(R z ) 2 —O—C(O)OR y , —C(R z ) 2 OC(O)SR y , -alkyl-S—C(O)R y , -alkyl-S—S-alkylhydroxy, and -alkyl-S—S—S-alkylhydroxy;
when Y is —NR v —, then R 11 attached to —NR v — is independently selected from the group consisting of —H, —[C(R z ) 2 ] q —C(O)OR y , —C(R x ) 2 C(O)OR y , —[C(R z ) 2 ] q —C(O)SR y , and -cycloalkylene-C(O)OR y ;
q is an integer 2 or 3;
Each R z is selected from the group consisting of R y and —H;
Each R y is selected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl;
Each R x is independently selected from the group consisting of —H, and alkyl, or together R x and R x form a cycloalkyl group;
Each R v is selected from the group consisting of —H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl;
and pharmaceutically acceptable salts and prodrugs thereof and pharmaceutically acceptable salts of said prodrugs.
30 . The method of any one of claims 22 - 29 , wherein:
X is P(O)(YR 11 )(Y′R 11 ) or P(O)(YR 11 )Y″; Y″ is selected from the group consisting of hydrogen, optionally substituted —C 1 -C 6 -alkyl, —CF 3 , —CHF 2 , —CH 2 F, —CH 2 OH, optionally substituted —C 2 -C 6 alkenyl, optionally substituted —C 2 -C 6 alkynyl, optionally substituted —(CR a 2 ) n cycloalkyl, optionally substituted (CR a 2 ) n heterocycloalkyl, —(CR a 2 ) k S(═O)R e , —(CR a 2 ) k S(═O) 2 R e , —(CR a 2 ) k S(═O) 2 NR f R g , —(CR a 2 ) k C(O)NR f R g , and —(CR a 2 ) k C(O)R e ;; Y and Y′ are each independently selected from the group consisting of —O—, and —NR v —; when Y is —O— and Y″ is hydrogen, optionally substituted —C 1 -C 6 -alkyl, —CF 3 , —CHF 2 , —CH 2 F, —CH 2 OH, optionally substituted —C 2 -C 6 alkenyl, optionally substituted —C 2 -C 6 alkynyl, optionally substituted —(CR a 2 ) n cycloalkyl, optionally substituted —(CR a 2 ) n heterocycloalkyl, —(CR a 2 ) k S(═O)R e , —(CR a 2 ) k S(═O) 2 R e , —(CR a 2 ) k S(═O) 2 NR f R g , —(CR a 2 ) k C(O)NR f R g , or —(CR a 2 ) k C(O)R e , or when Y and Y′ are both —O—, R 11 attached to —O— is independently selected from the group consisting of —H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH 2 -heterocycloakyl wherein the cyclic moiety contains a carbonate or thiocarbonate, optionally substituted -alkylaryl, —C(R z ) 2 OC(O)NR z 2 , —NR z —C(O)—R y , —C(R z ) 2 —OC(O)R y , —C(R z ) 2 —O—C(O)OR y , —C(R z ) 2 OC(O)SR y , -alkyl-S—C(O)R y , -alkyl-S—S-alkylhydroxy, and -alkyl-S—S—S-alkylhydroxy; when Y is —NR v — and Y″ is hydrogen, optionally substituted —C 1 -C 6 -alkyl, —CF 3 , —CHF 2 , —CH 2 F, —CH 2 OH, optionally substituted —C 2 -C 6 alkenyl, optionally substituted —C 2 -C 6 alkynyl, optionally substituted —(CR a 2 ) n cycloalkyl, optionally substituted —(CR a 2 ) n heterocycloalkyl, —(CR a 2 ) k S(═O)R e , —(CR a 2 ) k S(═O) 2 R e , —(CR a 2 ) k S(═O) 2 NR f R g , —(CR a 2 ) k C(O)NR f R g , or —(CR a 2 ) k C(O)R e , or when Y and Y′ are both —NR v —, then R 11 attached to —NR v — is independently selected from the group consisting of —H, —[C(R z ) 2 ] q —C(O)OR y , —C(R x ) 2 C(O)OR y , —[C(R z ) 2 ], —C(O)SR y , and -cycloalkylene-C(O)OR y ; when Y is —O— and Y 1 is NR v , then R 11 attached to —O— is independently selected from the group consisting of —H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH 2 -heterocycloakyl wherein the cyclic moiety contains a carbonate or thiocarbonate, optionally substituted -alkylaryl, —C(R z ) 2 OC(O)NR z 2 , —NR z —C(O)—R y , —C(R z ) 2 —OC(O)R y , —C(R z ) 2 —O—C(O)OR y , —C(R z ) 2 OC(O)SR y , -alkyl-S—C(O)R y , -alkyl-S—S-alkylhydroxy, and -alkyl-S—S—S-alkylhydroxy; and R 11 attached to —NR v — is independently selected from the group consisting of —H, —[C(R z ) 2 ] q —C(O)OR y , (R x ) 2 C(O)OR y , —[C(R z ) 2 ] q —C(O)SR y , and -cycloalkylene-C(O)OR y ; or when Y and Y′ are independently selected from —O— and —NR v —, then R 11 and R 11 together form a cyclic group comprising -alkyl-S—S-alkyl-, or R 11 and R 11 together form the group:
wherein:
V, W, and W′ are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aralkyl, heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally substituted I-alkenyl, and optionally substituted I-alkynyl; or
together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, substituted with hydrogen, hydroxy, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both Y groups attached to the phosphorus; or
together V and Z are connected via an additional 3-5 atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon or carbon substituted by hydrogen, that is fused to an aryl group at the beta and gamma position to the Y attached to the phosphorus; or
together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms or carbon substituted by hydrogen and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from a Y attached to the phosphorus; or
together Z and W are connected via an additional 3-5 atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon or carbon substituted by hydrogen, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or
together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, wherein 0-2 atoms are heteroatoms and the remaining atoms are carbon or carbon substituted by hydrogen, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
Z is selected from the group consisting of —CHR z OH, —CHR z OC(O)R y , —CHR z OC(S)R y , —CHR z OC(S)OR y , —CHR z OC(O)SR y , —CHR z OCO 2 R y , —OR z , —SR z , —CHR z N 3 , —CH 2 aryl, —CH(aryl)OH, —CH(CH═CR z 2 )OH, —CH(C≡C z )OH, —R z , —NR z 2 , —OCOR y , —OCO 2 R y , —SCOR y , —SCO 2 R y , —NHCOR z , —NHCO 2 R y , —CH 2 NHaryl, —(CH 2 ) q —OR z , and —(CH 2 ) q —SR z ;
q is an integer 2 or 3;
Each R z is selected from the group consisting of R y and —H;
Each R y is selected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl;
Each R x is independently selected from the group consisting of —H, and alkyl, or together R x and R x form a cycloalkyl group;
Each R v is selected from the group consisting of —H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl;
with the provisos that:
a) V, Z, W, W′ are not all —H; and
b) when Z is —R z , then at least one of V, W, and W′ is not —H, alkyl, aralkyl, or heterocycloalkyl;
and pharmaceutically acceptable salts and prodrugs thereof and pharmaceutically acceptable salts of said prodrugs.
31 . The method of claim 1 or 2 , wherein said compound is selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
32 . The method of claim 1 or 2 , wherein said compound is selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
33 . The method of claim 1 or 2 , wherein said compound is selected from the group consisting of:
and pharmaceutically acceptable salts thereof.Join the waitlist — get patent alerts
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