Bumetanide, furosemide, piretanide, azosemide, and torsemide analogs, compositions and methods of use

Abstract

The present invention provides bumetanide, furosemide, piretanide, azosemide, and torsemide analogs and compositions comprising such analogs. The present invention also provides pharmaceutical compositions containing these bumetanide, furosemide, piretanide, azosemide, and torsemide analogs and methods for their use. All of these analogs are particularly useful for the treatment and/or prophylaxis of conditions that involve the Na + K + Cl − co-transporter or GABA A receptor including but not limited to addictive disorders, Alzheimer's Disease, anxiety disorders, ascites, autism, bipolar disorder, cancer, depression, endothelial corneal dystrophy, edema, epilepsy, glaucoma, Huntington's Disease, insomnia, ischemia, migraine, migraine with aura, neuropathic pain, nociceptive neuralgia, nociceptive pain, ocular diseases, pain, Parkinson's disease, personality disorders, postherpetic neuralgia, psychosis, schizophrenia, seizure disorders, tinnitus, and withdrawal syndromes.

1 - 191 . (canceled) 
     
     
         192 . A compound of the formula IX: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein: 
         Y is oxygen, sulfur, or selenium; 
         Z is oxygen, sulfur, or nitrogen; 
         R 6  is alkyl, alkylene, alkylcyano, alkylhalo, alkaryl, alkylheterocycloalkyl, or alkylaminodialkyl; 
         R 7  is hydrogen, alkyl, alkaryl, alkylaminodialkyl or alkylheterocycloalkyl; or 
         R 6  and R 7 , together with the atom to which they are attached, form a heterocycloalkyl group; 
         provided that:
 if Z is oxygen or sulfur, then R 7  is not present; 
 if Y is oxygen and Z is sulfur, then R 6  is not methyl; 
 if Y is sulfur and Z is sulfur, then R 6  is not methyl or alkylaminodialkyl; 
 if Y is oxygen and Z is oxygen, then R 6  is not methyl, ethyl, butyl, methylcyano, unsubstituted benzyl, chloromethyl, 2,2,2-trichloroethyl, ethyl-N-morpholinyl, N,N-dimethyl-2-ethylamino, N,N-dimethyl-3-propylamino or (CH 3 ) 2 C═CHCH 2 CH 2 -(E)-(CH 3 )C═CHCH 2 —; 
 if Y is oxygen, Z is nitrogen, and R 7  is hydrogen, then R 6  is not 2-(4-piperazin-1-yl)ethyl, 3-pyridylmethyl, unsubstituted benzyl, or n-butyl; 
 if Y is oxygen and Z is nitrogen, then R 6  and R 7  are not both unsubstituted benzyl or ethyl. 
 
       
     
     
         193 . A compound of the formula X: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein: 
         Y is oxygen, sulfur, or selenium; 
         Z is oxygen, sulfur, or nitrogen; 
         R 8  is hydrogen, alkyl, alkylene, alkylcyano, alkylhalo, alkaryl, alkylheterocycloalkyl, or alkylaminodialkyl; 
         R 9  is hydrogen, alkyl, alkaryl, alkylaminodialkyl or alkylheterocycloalkyl; or 
         R 8  and R 9 , together with the atom to which they are attached, form a heterocycloalkyl group; 
         R 10  is hydrogen or alkyl; 
         provided that:
 if Z is oxygen or sulfur, then R 9  is not present; 
 if Z is oxygen and R 8  is hydrogen, then R 10  is not hydrogen or methyl; 
 if Y is oxygen and Z is oxygen, then R 8  is not methyl, unsubstituted benzyl, butyl, or methylcyano; 
 if Y is oxygen, Z is nitrogen, and R 9  is hydrogen, then R 8  is not hydrogen, 2-(4-methylpiperazin-1-yl)ethyl, 3-(4-methylpiperazin-1-yl)propyl, 2-(N-morpholinyl)ethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-(4-(2-aminoethyl)piperazyn-1-yl)ethyl or a sultamyl group of the formula 
 
       
       
         
           
           
               
               
           
         
         
           if Y is oxygen and Z is nitrogen, then R 8  and R 9  are not both ethyl or benzyl; or 
           if Y is oxygen and Z is nitrogen, then R 8  and R 9 , together with the nitrogen atom to which they are attached, do not form a piperazin-1-yl group, a 4-methylpiperazin-1-yl group, or a N-morpholinyl group. 
         
       
     
     
         194 . A method for treating a condition selected from the group consisting of addictive disorders, Alzheimer's Disease, anxiety disorders, ascites, autism, bipolar disorder, cancer, depression, endothelial corneal dystrophy, edema, epilepsy, glaucoma, Huntington's Disease, insomnia, ischemia, migraine, migraine with aura, neuropathic pain, nociceptive neuralgia, nociceptive pain, ocular diseases, pain, Parkinson's disease, personality disorders, postherpetic neuralgia, psychosis, schizophrenia, seizure disorders, tinnitus, and withdrawal syndromes comprising administering:
 (i) an effective amount of a compound of the formula IX:   
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein: 
         Y is oxygen, sulfur or selenium; 
         Z is oxygen, sulfur or nitrogen; 
         R 6  is hydrogen, alkyl, alkylene, alkylcyano, alkylhalo, alkaryl, alkylheterocycloalkyl or alkylaminodialkyl; and 
         R 7  is hydrogen, alkyl, alkaryl, alkylaminodialkyl or alkylheterocycloalkyl; or 
         R 6  and R 7 , together with the atom to which they are attached, form a heterocycloalkyl group; 
         provided that if Z is oxygen or sulfur, then R 7  is not present; 
         (ii) an effective amount of a compound of the formula X: 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein: 
         Y is oxygen, sulfur, or selenium; 
         Z is oxygen, sulfur, or nitrogen; 
         R 8  is hydrogen, alkyl, alkylene, alkylcyano, alkylhalo, alkaryl, alkylheterocycloalkyl, or alkylaminodialkyl; 
         R 9  is hydrogen, alkyl, alkaryl, alkylaminoalkyl or alkylheterocycloalkyl; or 
         R 8  and R 9 , together with the atom to which they are attached, form a heterocycloalkyl group; and 
         R 10  is hydrogen or alkyl; 
         provided that if Z is oxygen or sulfur, then R 9  is not present; 
         (iii) an effective amount of a compound of the formulae XI-XIII: 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; 
         wherein: 
         Y is O, S, or Se; 
         R 11  is H, OR 12 , SR 12 , wherein R 12  is hydrogen, alkyl, aralkyl, aryl, alkylaminodialkyl, alkylcarbonylaminodialkyl, alkyloxycarbonylalkyl, alkylcarbonyloxyalkyl, alkylaldehyde, alkylketoalkyl, alkylamide, alkarylamide, arylamide, an alkylammonium group, alkylcarboxylic acid, alkylheteroaryl, alkylhydroxy, a biocompatible polymer such as alkyloxy(polyalkyloxy)alkylhydroxyl, a polyethylene glycol (PEG), a polyethylene glycol ester (PEG ester) and a polyethylene glycol ether (PEG ether), heteroaryl, methyloxyalkyl, methyloxyalkaryl, methylthioalkyl or methylthioalkaryl, unsubstituted or substituted, or 
         R 11  is N,N-dialkylamino, N,N-dialkarylamino, N,N-diarylamino, N-alkyl-N-alkarylamino, N-alkyl-N-arylamino, N-alkaryl-N-arylamino, unsubstituted or substituted; 
         R 13  is aryl, halo, heteroaryl, hydroxy, alkoxy, aryloxy, or heteroaryloxy, unsubstituted or substituted; and 
         R 14  and R 15  are each independently hydrogen, alkylaminodialkyl, carbonylalkyl, carbonylalkaryl, carbonylaryl, or carbonylheteroaryl; 
         (iv) an effective amount of a compound of the formula VII: 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein: 
         R 3  is selected from the group consisting of aryl, halo, heteroaryl, hydroxy, alkoxy, aryloxy, and heteroaryloxy, unsubstituted or substituted; 
         R 4  and R 5  are each independently selected from the group consisting of hydrogen, alkylaminodialkyl, carbonylalkyl, carbonylalkaryl, carbonylaryl, carbonylalkylheteroaryl, carbonylheteroaryl, and salts thereof; and 
         R 6  is selected from the group consisting of alkyloxycarbonylalkyl, alkylaminocarbonylalkyl, alkylaminodialkyl, alkylhydroxy, a biocompatible polymer such as alkyloxy(polyalkyloxy)alkylhydroxyl, a polyethylene glycol (PEG), a polyethylene glycol ester (PEG ester) and a polyethylene glycol ether (PEG ether), methyloxyalkyl, methyloxyalkaryl, methyloxyalkylheteroaryl, methylthioalkyl, methylthioalkaryl, and methylthioalkylheteroaryl, unsubstituted or substituted; 
         (v) an effective amount of a compound of the formula VIII: 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or a zwitterion thereof, 
         wherein: 
         R 7  is selected from the group consisting of hydrogen, alkyloxycarbonylalkyl, alkylaminocarbonylalkyl, alkylaminodialkyl, alkylhydroxy, a biocompatible polymer such as alkyloxy(polyalkyloxy)alkylhydroxyl, a polyethylene glycol (PEG), a polyethylene glycol ester (PEG ester) and a polyethylene glycol ether (PEG ether), methyloxyalkyl, methyloxyalkaryl, methyloxyalkylheteroaryl, methylthioalkyl, methylthioalkaryl, and methylthioalkylheteroaryl, unsubstituted or substituted; and 
         X −  is a halide or an anionic moiety; or 
         X −  is not present; 
         (vi) an effective amount of a compound of the formula XIV: 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein: 
         Y is oxygen, sulfur, or selenium; 
         Z is oxygen, sulfur, or nitrogen; 
         R 16  is hydrogen, alkyl, alkylene, alkylcyano, alkylhalo, aryl, heteroaryl, alkaryl, alkylheteroaryl, alkylheterocycloalkyl, or alkylaminodialkyl; 
         R 17  is hydrogen, alkyl, alkaryl, alkylheteroaryl, alkylaminodialkyl, or alkylheterocycloalkyl; or 
         R 16  and R 17 , together with the atom to which they are attached, form a heterocycloalkyl group; and 
         R 18  and R 19  are each independently hydrogen or alkyl; 
         provided that if Z is oxygen or sulfur, then R 9  is not present; 
         (vii) an effective amount of a compound of the formula XV: 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein: 
         Y is oxygen, sulfur, or selenium; 
         Z is oxygen, sulfur, or nitrogen; 
         R 20  is hydrogen, alkyl, alkylene, alkylcyano, alkylhalo, alkaryl, alkylheteroaryl, alkylheterocycloalkyl, or alkylaminodialkyl; 
         R 21  is hydrogen, alkyl, alkaryl, alkylheteroaryl, alkylaminodialkyl or alkylheterocycloalkyl; or 
         R 20  and R 21 , together with the atom to which they are attached, form a heterocycloalkyl group; and 
         R 22  and R 23  are each independently hydrogen, alkyl, alkenyl, alkoxy, alkaryloxyalkyl, alkaryl, or alkylheteroaryl; 
         (viii) an effective amount of a compound of the Formula XVI: 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; 
         (ix) an effective amount of a compound of the Formula XVII: 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein: 
         Y 1  is —(CH 2 ) x —, wherein x is either 0, 1, or 2; 
         R 60  is hydrogen, alkyl, aralkyl, or heteroarylalkyl; 
         R 61  is hydrogen, lower alkyl, lower alkenyl, alkaryl, alkylheteroaryl, aryl, cycloalkenyl, cycloalkyl, dialkylaminoalkyl, heterocycloalkyl, or heteroaryl; and 
         R 62  is hydrogen, lower alkyl, lower alkenyl, alkaryl, alkylheteroaryl, aryl, cycloalkenyl, cycloalkyl, dialkylaminoalkyl, heterocycloalkyl, or heteroaryl, or R 61  and R 62 , taken together with the nitrogen atom to which they are attached form a 4-8 member cycle which can be substituted or unsubstituted and can have one or more heteroatoms; 
         (x) an effective amount of a compound of the Formula XVIII: 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein: 
         Y 2  is —(CH 2 ) x —, wherein x is either 0, 1, or 2; 
         R 60  is hydrogen, alkyl, aralkyl, or heteroarylalkyl; 
         R 61  is hydrogen, lower alkyl, lower alkenyl, alkaryl, alkylheteroaryl, aryl, cycloalkenyl, cycloalkyl, dialkylaminoalkyl, heterocycloalkyl, or heteroaryl; and 
         R 62  is hydrogen, lower alkyl, lower alkenyl, alkaryl, alkylheteroaryl, aryl, cycloalkenyl, cycloalkyl, dialkylaminoalkyl, heterocycloalkyl, or heteroaryl, or R 61  and R 62 , taken together with the nitrogen atom to which they are attached form a 4-8 member cycle which can be substituted or unsubstituted and can have one or more heteroatoms; 
         (xi) an effective amount of a compound of the Formula XIX: 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein: 
         R 61  is hydrogen, lower alkyl, lower alkenyl, alkaryl, alkylheteroaryl, aryl, cycloalkenyl, cycloalkyl, dialkylaminoalkyl, heterocycloalkyl, or heteroaryl; 
         R 62  is hydrogen, lower alkyl, lower alkenyl, alkaryl, alkylheteroaryl, aryl, cycloalkenyl, cycloalkyl, dialkylaminoalkyl, heterocycloalkyl, or heteroaryl, or R 61  and R 62 , taken together with the nitrogen atom to which they are attached form a 4-8 member cycle which can be substituted or unsubstituted and can have one or more heteroatoms; and 
         R 63  is alkyl, alkylcyano, aryl, heteroaryl, —CH 2 —C(O)—N(R 64 )—R 65 , or —CH 2 —O—C(O)—R 66 , wherein R 64 , R 65 , and R 66  are each independently alkyl; 
         (xii) an effective amount of a compound of the Formula XX: 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein: 
         R 60  is hydrogen, alkyl, aralkyl, or heteroarylalkyl; 
         R 61  is hydrogen, lower alkyl, lower alkenyl, alkaryl, alkylheteroaryl, aryl, cycloalkenyl, cycloalkyl, dialkylaminoalkyl, heterocycloalkyl, or heteroaryl; 
         R 62  is hydrogen, lower alkyl, lower alkenyl, alkaryl, alkylheteroaryl, aryl, cycloalkenyl, cycloalkyl, dialkylaminoalkyl, heterocycloalkyl, or heteroaryl, or R 61  and R 62 , taken together with the nitrogen atom to which they are attached form a 4-8 member cycle which can be substituted or unsubstituted and can have one or more heteroatoms; and 
         R 67  is hydrogen, hydroxy, or amino; 
         (xiii) an effective amount of a compound of the Formula XXI: 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein: 
         R 60  is hydrogen, alkyl, aralkyl, or heteroarylalkyl; 
         R 68  is —SO 2 -alkyl or —N(R 69 )—R 70 ; 
         R 69  is hydrogen, aryl, heteroaryl, cycloalkenyl, cycloalkyl, heterocycloalkyl, alkylcycloalkenyl, alkylcycloalkyl, alkylaryl, alkylheteroaryl or alkylheterocycloalkyl; and 
         R 70  is hydrogen or R 69  and R 70 , together with the nitrogen atom to which they are attached, form a heterocycloalkyl; 
         (xiv) an effective amount of a compound of the Formula XXII: 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein: 
         R 60  is hydrogen, alkyl, aralkyl, or heteroarylalkyl; 
         R 61  is hydrogen, lower alkyl, lower alkenyl, alkaryl, alkylheteroaryl, aryl, cycloalkenyl, cycloalkyl, dialkylaminoalkyl, heterocycloalkyl, or heteroaryl; 
         R 62  is hydrogen, lower alkyl, lower alkenyl, alkaryl, alkylheteroaryl, aryl, cycloalkenyl, cycloalkyl, dialkylaminoalkyl, heterocycloalkyl, or heteroaryl, or R 61  and R 62 , taken together with the nitrogen atom to which they are attached form a 4-8 member cycle which can be substituted or unsubstituted and can have one or more heteroatoms; 
         R 71  is hydroxy or —N(R 73 )—R 74 ; 
         R 72  is halo, aryl, arylamino, heteroarylamino, heterocycloalkyl, heteroaryl, heteroaryloxy, heterocycloalkoxy, or alkylthio; and 
         R 73  and R 74  are each independently alkyl; 
         (xv) an effective amount of a compound of the Formula XXIII: 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein: 
         R 60  is hydrogen, alkyl, aralkyl, or heteroarylalkyl; 
         R 61  is hydrogen, lower alkyl, lower alkenyl, alkaryl, alkylheteroaryl, aryl, cycloalkenyl, cycloalkyl, dialkylaminoalkyl, heterocycloalkyl, or heteroaryl; 
         R 62  is hydrogen, lower alkyl, lower alkenyl, alkaryl, alkylheteroaryl, aryl, cycloalkenyl, cycloalkyl, dialkylaminoalkyl, heterocycloalkyl, or heteroaryl, or R 61  and R 62 , taken together with the nitrogen atom to which they are attached form a 4-8 member cycle which can be substituted or unsubstituted and can have one or more heteroatoms; 
         R 75  is alkyl, aryl, cycloalkenyl, cycloalkyl, heteroaryl, heterocycloalkyl, cycloalkylalkyl, heteroarylalkyl, or dialkylaminoalkyl; and 
         R 76  is hydrogen, alkyl, aralkyl, or heteroarylalkyl; 
         (xvi) an effective amount of a compound of the Formula XXIV: 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein: 
         R 61  is hydrogen, lower alkyl, lower alkenyl, alkaryl, alkylheteroaryl, aryl, cycloalkenyl, cycloalkyl, dialkylaminoalkyl, heterocycloalkyl, or heteroaryl; 
         R 62  is hydrogen, lower alkyl, lower alkenyl, alkaryl, alkylheteroaryl, aryl, cycloalkenyl, cycloalkyl, dialkylaminoalkyl, heterocycloalkyl, or heteroaryl, or R 61  and R 62 , taken together with the nitrogen atom to which they are attached form a 4-8 member cycle which can be substituted or unsubstituted and can have one or more heteroatoms; 
         R 77  is hydroxy or —N(R 79 )—R 80 ; 
         R 78  is —N(R 81 )—R 82  or heterocycloalkyl; 
         R 79  is alkyl, alkaryl, or alkylheteroaryl; 
         R 80  and R 81  are each independently hydrogen, alkyl, alkaryl, or alkylheteroaryl; and 
         R 82  is hydrogen, alkyl, aryl or R 81  and R 82 , together with the nitrogen atom to which they are attached, form a heterocycloalkyl; 
         (xvii) an effective amount of a compound of the Formula XXV: 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein: 
         R 60  is hydrogen, alkyl, aralkyl, or heteroarylalkyl; and 
         R 83  is halo, aryl, heteroaryl, arylamino, heteroarylamino, aryloxy, heteroaryloxy, arylthio, or heteroarylthio; or 
         (xviii) an effective amount of a compound of the Formula XXVI: 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein: 
         Y is oxygen, sulfur, or selenium; 
         Z is oxygen, sulfur, or nitrogen; 
         R 61  is hydrogen, lower alkyl, lower alkenyl, alkaryl, alkylheteroaryl, aryl, cycloalkenyl, cycloalkyl, dialkylaminoalkyl, heterocycloalkyl, or heteroaryl; 
         R 62  is hydrogen, lower alkyl, lower alkenyl, alkaryl, alkylheteroaryl, aryl, cycloalkenyl, cycloalkyl, dialkylaminoalkyl, heterocycloalkyl, or heteroaryl, or R 61  and R 62 , taken together with the nitrogen atom to which they are attached form a 4-8 member cycle which can be substituted or unsubstituted and can have one or more heteroatoms; 
         R 72  is halo, aryl, arylamino, heteroarylamino, heterocycloalkyl, heteroaryl, heteroaryloxy, heterocycloalkoxy, or alkylthio; 
         R 84  is alkenyl, alkyl, alkylcyano, alkylhalo, alkaryl, alkylheteroaryl, alkylcycloalkenyl, alkylcycloalkyl, alkylheterocycloalkyl, or alkylaminodialkyl; 
         R 85  is hydrogen, alkenyl, alkyl, alkylcyano, alkylhalo, alkaryl, alkylheteroaryl, alkylcycloalkenyl, alkylcycloalkyl, alkylheterocycloalkyl, or alkylaminodialkyl; 
         R 86  is —N(R 87 )—R 88 , cycloalkenyl, cycloalkyl, or heterocycloalkyl; and 
         R 87  and R 88  are each independently hydrogen, alkyl, alkaryl, or alkylheteroaryl, or R 87  and R 88 , together with the nitrogen atom to which they are attached, form a heterocycloalkyl, 
         provided that if Z is oxygen or sulfur, R 85  is not present. 
       
     
     
         195 . A method of making furosemide N-morpholinyl amide comprising:
 (a) combining furosemide and at least two coupling agents to give a reactive intermediate; and   (b) reacting the reactive intermediate with morpholine to give furosemide N-morpholinyl amide.   
     
     
         196 . A compound of the Formula XVI: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         197 . A method for antagonizing GABA A  receptors comprising administering a composition comprising an effective amount of a compound of the Formula XVI: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         198 . A compound of the formula XVII: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein: 
         Y 1  is —(CH 2 ) x —, wherein x is either 0, 1, or 2; 
         R 60  is hydrogen, alkyl, aralkyl, or heteroarylalkyl; 
         R 61  is hydrogen, lower alkyl, lower alkenyl, alkaryl, alkylheteroaryl, aryl, cycloalkenyl, cycloalkyl, dialkylaminoalkyl, heterocycloalkyl, or heteroaryl; and 
         R 62  is hydrogen, lower alkyl, lower alkenyl, alkaryl, alkylheteroaryl, aryl, cycloalkenyl, cycloalkyl, dialkylaminoalkyl, heterocycloalkyl, or heteroaryl, or R 61  and R 62 , taken together with the nitrogen atom to which they are attached form a 4-8 member cycle which can be substituted or unsubstituted and can have one or more heteroatoms. 
       
     
     
         199 . A compound of the formula XVIII: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein: 
         Y 2  is —(CH 2 ) x —, wherein x is either 0, 1, or 2; 
         R 60  is hydrogen, alkyl, aralkyl, or heteroarylalkyl; 
         R 61  is hydrogen, lower alkyl, lower alkenyl, alkaryl, alkylheteroaryl, aryl, cycloalkenyl, cycloalkyl, dialkylaminoalkyl, heterocycloalkyl, or heteroaryl; and 
         R 62  is hydrogen, lower alkyl, lower alkenyl, alkaryl, alkylheteroaryl, aryl, cycloalkenyl, cycloalkyl, dialkylaminoalkyl, heterocycloalkyl, or heteroaryl, or R 61  and R 62 , taken together with the nitrogen atom to which they are attached form a 4-8 member cycle which can be substituted or unsubstituted and can have one or more heteroatoms. 
       
     
     
         200 . A compound of the formula XIX: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein: 
         R 61  is hydrogen, lower alkyl, lower alkenyl, alkaryl, alkylheteroaryl, aryl, cycloalkenyl, cycloalkyl, dialkylaminoalkyl, heterocycloalkyl, or heteroaryl; 
         R 62  is hydrogen, lower alkyl, lower alkenyl, alkaryl, alkylheteroaryl, aryl, cycloalkenyl, cycloalkyl, dialkylaminoalkyl, heterocycloalkyl, or heteroaryl, or R 61  and R 62 , taken together with the nitrogen atom to which they are attached form a 4-8 member cycle which can be substituted or unsubstituted and can have one or more heteroatoms; and 
         R 63  is alkyl, alkylcyano, aryl, heteroaryl, —CH 2 —C(O)—N(R 64 )—R 65 , or —CH 2 —O—C(O)—R 66 , wherein R 64 , R 65 , and R 66  are each independently alkyl. 
       
     
     
         201 . A compound of the formula XX: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein: 
         R 60  is hydrogen, alkyl, aralkyl, or heteroarylalkyl; 
         R 61  is hydrogen, lower alkyl, lower alkenyl, alkaryl, alkylheteroaryl, aryl, cycloalkenyl, cycloalkyl, dialkylaminoalkyl, heterocycloalkyl, or heteroaryl; 
         R 62  is hydrogen, lower alkyl, lower alkenyl, alkaryl, alkylheteroaryl, aryl, cycloalkenyl, cycloalkyl, dialkylaminoalkyl, heterocycloalkyl, or heteroaryl, or R 61  and R 62 , taken together with the nitrogen atom to which they are attached form a 4-8 member cycle which can be substituted or unsubstituted and can have one or more heteroatoms; and 
         R 67  is hydrogen, hydroxy, or amino. 
       
     
     
         202 . A compound of the formula XXI: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein: 
         R 60  is hydrogen, alkyl, aralkyl, or heteroarylalkyl; 
         R 68  is —SO 2 -alkyl or —N(R 69 )—R 70 ; 
         R 69  is hydrogen, aryl, heteroaryl, cycloalkenyl, cycloalkyl, heterocycloalkyl, alkylcycloalkenyl, alkylcycloalkyl, alkylaryl, alkylheteroaryl or alkylheterocycloalkyl; and 
         R 70  is hydrogen or R 69  and R 70 , together with the nitrogen atom to which they are attached, form a heterocycloalkyl. 
       
     
     
         203 . A compound of the formula XXII: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein: 
         R 60  is hydrogen, alkyl, aralkyl, or heteroarylalkyl; 
         R 61  is hydrogen, lower alkyl, lower alkenyl, alkaryl, alkylheteroaryl, aryl, cycloalkenyl, cycloalkyl, dialkylaminoalkyl, heterocycloalkyl, or heteroaryl; 
         R 62  is hydrogen, lower alkyl, lower alkenyl, alkaryl, alkylheteroaryl, aryl, cycloalkenyl, cycloalkyl, dialkylaminoalkyl, heterocycloalkyl, or heteroaryl, or R 61  and R 62 , taken together with the nitrogen atom to which they are attached form a 4-8 member cycle which can be substituted or unsubstituted and can have one or more heteroatoms; 
         R 71  is hydroxy or —N(R 73 )—R 74 ; 
         R 72  is halo, aryl, arylamino, heteroarylamino, heterocycloalkyl, heteroaryl, heteroaryloxy, heterocycloalkoxy, or alkylthio; and 
         R 73  and R 74  are each independently alkyl. 
       
     
     
         204 . A compound of the formula XXIII: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein: 
         R 60  is hydrogen, alkyl, aralkyl, or heteroarylalkyl; 
         R 61  is hydrogen, lower alkyl, lower alkenyl, alkaryl, alkylheteroaryl, aryl, cycloalkenyl, cycloalkyl, dialkylaminoalkyl, heterocycloalkyl, or heteroaryl; 
         R 62  is hydrogen, lower alkyl, lower alkenyl, alkaryl, alkylheteroaryl, aryl, cycloalkenyl, cycloalkyl, dialkylaminoalkyl, heterocycloalkyl, or heteroaryl, or R 61  and R 62 , taken together with the nitrogen atom to which they are attached form a 4-8 member cycle which can be substituted or unsubstituted and can have one or more heteroatoms; 
         R 75  is alkyl, aryl, cycloalkenyl, cycloalkyl, heteroaryl, heterocycloalkyl, cycloalkylalkyl, heteroarylalkyl, or dialkylaminoalkyl; and 
         R 76  is hydrogen, alkyl, aralkyl, or heteroarylalkyl. 
       
     
     
         205 . A compound of the formula XXIV: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein: 
         R 61  is hydrogen, lower alkyl, lower alkenyl, alkaryl, alkylheteroaryl, aryl, cycloalkenyl, cycloalkyl, dialkylaminoalkyl, heterocycloalkyl, or heteroaryl; 
         R 62  is hydrogen, lower alkyl, lower alkenyl, alkaryl, alkylheteroaryl, aryl, cycloalkenyl, cycloalkyl, dialkylaminoalkyl, heterocycloalkyl, or heteroaryl, or R 61  and R 62 , taken together with the nitrogen atom to which they are attached form a 4-8 member cycle which can be substituted or unsubstituted and can have one or more heteroatoms; 
         R 77  is hydroxy or —N(R 79 )—R 80 ; 
         R 78  is —N(R 81 )—R 82  or heterocycloalkyl; 
         R 79  is alkyl, alkaryl, or alkylheteroaryl; 
         R 80  and R 81  are each independently hydrogen, alkyl, alkaryl, or alkylheteroaryl; and 
         R 82  is hydrogen, alkyl, aryl or R 81  and R 82 , together with the nitrogen atom to which they are attached, form a heterocycloalkyl. 
       
     
     
         206 . A compound of the formula XXV: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein: 
         R 60  is hydrogen, alkyl, aralkyl, or heteroarylalkyl; and 
         R 83  is halo, aryl, heteroaryl, arylamino, heteroarylamino, aryloxy, heteroaryloxy, arylthio, or heteroarylthio. 
       
     
     
         207 . A compound of the formula XXVI: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein: 
         Y is oxygen, sulfur, or selenium; 
         Z is oxygen, sulfur, or nitrogen; 
         R 61  is hydrogen, lower alkyl, lower alkenyl, alkaryl, alkylheteroaryl, aryl, cycloalkenyl, cycloalkyl, dialkylaminoalkyl, heterocycloalkyl, or heteroaryl; 
         R 62  is hydrogen, lower alkyl, lower alkenyl, alkaryl, alkylheteroaryl, aryl, cycloalkenyl, cycloalkyl, dialkylaminoalkyl, heterocycloalkyl, or heteroaryl, or R 61  and R 62 , taken together with the nitrogen atom to which they are attached form a 4-8 member cycle which can be substituted or unsubstituted and can have one or more heteroatoms; 
         R 72  is halo, aryl, arylamino, heteroarylamino, heterocycloalkyl, heteroaryl, heteroaryloxy, heterocycloalkoxy, or alkylthio; 
         R 84  is alkenyl, alkyl, alkylcyano, alkylhalo, alkaryl, alkylheteroaryl, alkylcycloalkenyl, alkylcycloalkyl, alkylheterocycloalkyl, or alkylaminodialkyl; 
         R 85  is hydrogen, alkenyl, alkyl, alkylcyano, alkylhalo, alkaryl, alkylheteroaryl, alkylcycloalkenyl, alkylcycloalkyl, alkylheterocycloalkyl, or alkylaminodialkyl; 
         R 86  is —N(R 87 )—R 88 , cycloalkenyl, cycloalkyl, or heterocycloalkyl; and 
         R 87  and R 88  are each independently hydrogen, alkyl, alkaryl, or alkylheteroaryl, or R 87  and R 88 , together with the nitrogen atom to which they are attached, form a heterocycloalkyl, 
         provided that if Z is oxygen or sulfur, R 85  is not present.