Sulphone compounds and methods of making and using same

Abstract

The invention provides sulphone compounds and their use in treating medical disorders, such as obesity. Pharmaceutical compositions and methods of making various sulphone compounds are provided. The compounds are contemplated to have activity against methionyl aminopeptidase 2.

What is claimed is:  
     
         1 .- 39 . (canceled) 
     
     
         40 . A pharmaceutically acceptable composition comprising a compound represented by Formula IV: 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts and stereoisomers thereof, wherein 
         R 1  is selected from the group consisting of: 
         hydrogen, halogen, cyano, hydroxyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 alkenyloxy, C 3-6 alkynyloxy, C 3-6 cycloalkoxy, C 1-6 alkyl-S(O) w — wherein w is 0, 1 or 2, C 1-6 alkyl-N(R a )-carbonyl, R f R g N—, R f R g N-carbonyl, R f R g N-carbonyl-N(R a )—, R f R g NSO 2 —, C 1-6 alkyl-carbonyl-N(R a )—, C 1-6  alkoxy-carbonyl-N(R a )—, phenyl, phenyloxy, phenyl-C 1-6 alkyl-, phenyl-C 1-6 alkoxy, heteroaryl, heteroaryloxy, heteroaryl-C 1-6 alkyl, heteroaryl-C 1-6 alkoxy, heterocyclyl, heterocyclyloxy, heterocyclyl-C 1-6 alkyl, and heterocyclyl-C 1-6 alkoxy, wherein said heteroaryl is a 5-6 membered ring having one, two or three heteroatoms selected from O, S, or N, and wherein said phenyl or heteroaryl is optionally substituted with one or more substituents selected from R b ; wherein said heterocyclyl is a 4-7 membered ring optionally substituted by one or more substituents selected from R c  and wherein if said heterocyclyl contains a —NH moiety that nitrogen may be optionally substituted by one or more groups R d ; and wherein C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 alkenyloxy, and C 3-6 alkynyloxy may be optionally substituted by one or more substituents selected from R p , and wherein C 1-6 alkyl and C 1-6 alkoxy may be optionally substituted by one or more substituents selected from R p′  and wherein C 3-6 cycloalkyl and C 3-6 cycloalkoxy may be optionally substituted by one or more substituents selected from R p″ ; 
         R 2  is selected from the group consisting of: 
         halogen, hydroxyl, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 3-6 alkynyloxy, C 3-6 cycloalkyloxy, C 1-6 alkyl-S(O) 2 —, C 3-6 cycloalkylC 1-4 alkyl-, C 3-6 cycloalkylC 1-4 alkoxy-, R f R g N-carbonyl, phenyl-C 1-6 alkyl-, phenyl, phenyoxy, phenyl-C 1-6 alkoxy-, heteroaryl, heteroaryloxy, heteroaryl-C 1-6 alkyl, heteroaryl-C 1-6 alkoxy, heterocyclylC 1-6 alkyl-, and heterocyclyl-C 1-6 alkoxy, wherein said heteroaryl is a 5-6 membered monocyclic ring having one, two or three heteroatoms selected from O, S, or N, and optionally substituted with one or more substituents selected from R b ; wherein said heterocyclyl is a 4-7 membered ring optionally substituted by one or more substituents selected from R c  and wherein if said heterocyclyl contains a —NH moiety that nitrogen may be optionally substituted by one or more groups R d , and wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-6 alkenyloxy, or C 3-6 alkynyloxy may be optionally substituted by one or more substituents selected from halogen, hydroxyl, R a R a′ N—, or cyano, and wherein C 3-6 cycloalkyl and C 3-6 cycloalkoxy may be optionally substituted by one or more substituents selected from halogen, hydroxyl, R a R a′ N—, cyano and C 1-6 alkyl; or 
         R 1  and R 2  may be joined together with the carbons to which they are attached to form a 5-7 membered saturated, partially unsaturated, or unsaturated ring, optionally having 1, 2 or 3 heteroatom groups selected from O, NR h , or S(O) r  where r is 0, 1, or 2, wherein the formed 5-7 membered ring is optionally substituted on a carbon by one or more groups R e , and wherein the formed ring may be optionally bridged by a moiety selected from CH 2 , —(CH 2 ) 2 —, cis-CH═CH—, NR h ; or —CH 2 NR h —; and wherein if R 1  is hydrogen, R 2  may not be hydrogen; 
         R 5  is selected, independently for each occurrence, from the group consisting of hydrogen, hydroxyl, cyano, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 3-6 alkynyl, C 3-6 cycloalkyl, or C 1-6 alkoxy, or R f R g N—, wherein C 1-6 alkyl, C 2-6 alkenyl, C 3-6  alkynyl, C 3-6 cycloalkyl, or C 1-6 alkoxy may be optionally substituted with one or more halogens; 
         R 6  is selected from the group consisting of hydrogen, hydroxyl, cyano, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 alkenyloxy, C 3-6 alkynyloxy, C 3-6 cycloalkoxy, C 1-6 alkyl-S(O) w — wherein w is 0, 1 or 2, R f R g N—, R f R g N-carbonyl-, R f R g N-carbonyl-N(R a )—, RfRgN—SO 2 —, C 1-6 alkyl-carbonyl-N(R a )—, C 1-6 alkylsulphonylN(R a )—, C 1-6 alkoxycarbonyl-N(R a )—, phenyl, phenoxy, phenyl-C 1-6 alkyl-, phenyl-C 1-6 alkyoxy, heteroaryl, heteroaryloxy, heterocycloxy, heteroaryl-C 1-6 alkyl, heteroaryl-C 1-6 alkoxy-, heterocyclyl-C 1-6 alkyl-, and heterocyclyl-C 1-6 alkoxy-, wherein said heteroaryl is a 5-6 membered monocyclic ring having one, two or three heteroatoms selected from O, S, or N, and optionally substituted with one or more substituents selected from R b ; wherein said heterocyclyl is a 4-7 membered ring optionally substituted by one or more substituents selected from R c  and wherein if said heterocyclyl contains a —NH moiety that nitrogen may be optionally substituted by one or more groups R d , and, wherein C 1-6 alkyl and C 1-6 alkoxy may be optionally substituted by R p′ , wherein C 2-6 alkenyl, and C 2-6 alkynyl may be optionally substituted by one or more substituents selected from R p ; and wherein C 3-6 cycloalkyl or C 3-6  cycloalkoxy may be optionally substituted by one or more substituents selected from R p″ ; 
         R a  and R a′  are independently selected, for each occurrence, from the group consisting of hydrogen and C 1-6 alkyl, or R a  and R a′  when they occur together may form a 4-6 membered heterocyclic ring, wherein C 1-6 alkyl may be optionally substituted by one or more substituents selected from the group consisting of halogen, oxo and hydroxyl, and wherein the heterocyclic ring may be optionally substituted by one or more substituents selected from the group consisting of halogen, alkyl, oxo or hydroxyl; 
         R b  is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 3-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 alkenyloxy, C 3-6  alkynyloxy, C 3-6 cycloalkoxy, C 3-6 cycloalkyl, C 1-6 alkyl-S(O) w — wherein w is 0, 1 or 2, C 1-6 alkylN(R a )—, C 1-6 alkyl-N(R a )carbonyl, R a R a′ N—, R a R a′ N-carbonyl-, R a R a′ N-carbonyl-N(R a )—; R a R a′ N—SO 2 —, and C 1-6 alkyl-carbonyl-N(R a )—, wherein C 2-6 alkenyl, C 2-6 alkynyl, or C 1-6 alkoxy may be optionally substituted by one or more substituents selected from R p ; wherein C 3-6 cycloalkyl may be optionally substituted by one or more substituents selected from R p″ , and wherein C 1-6 alkyl may be optionally substituted by one or more substituents selected from R p′ ; 
         R c  for each occurrence is independently selected from the group consisting of, hydroxyl, cyano, oxo, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 3-6  alkynyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 alkyl-S(O) w —, wherein w is 0, 1 or 2, C 1-6 alkyl-NR a —, C 1-6 alkylC 3-6 cycloalkyl-, C 3-6 cycloalkylC 1-6 alkyl, R a R a′ N—, C 1-6 alkylcarbonyl-N(R a )—; C 1-6 alkoxycarbonyl-N(R a )—, R a R a′ N—SO 2 —, R a R a′ N-carbonyl-, R a R a′ N-carbonyl-N(R a )—, wherein C 1-6 alkyl, C 2-6 alkenyl, C 3-6 alkynyl, C 3-6 cycloalkyl, or C 1-6 alkoxy may be optionally substituted by R t ; 
         R d  is independently selected for each occurrence from the group consisting of C 1-6 alkyl, C 1-6 alkylcarbonyl or C 1-6 alkylsulphonyl, wherein C 1-6 alkyl is optionally substituted by one or more substituents selected from halogen, hydroxyl, and R a R a′ N—; 
         R e  is independently selected for each occurrence from the group consisting of hydroxyl, cyano, halogen, oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, C 1-4 alkoxy, C 3-6 alkenyloxy, C 3-6 alkynyloxy, C 3-6 cycloalkoxy, C 3-6 cycloalkyl-C 1-4 alkoxy-, C 1-4 alkyl-S(O) w — wherein w is 0, 1 or 2, R a R a′ N—, R a R a′ N-carbonyl, R a R a′ N-carbonyl-N(R a )—, R a R a′ N—SO 2 —, C 1-6 alkyl-carbonyl-N(R a )—, C 1-6 alkyl-SO 2 —N(R a )—, C 1-6 alkoxycarbonyl-, C 1-4 alkoxycarbonyl-N(R a )—, wherein C 2-4 alkenyl, and C 2-4 alkynyl may be optionally substituted by one or more substituents selected from R p ; wherein C 1-4 alkyl and C 1-4 alkoxy may optionally substituted by one or more substituents selected from R p′ ; and wherein C 3-6 cycloalkyl or C 3-6 cycloalkoxy may be optionally substituted by R p″ ; 
         R f  and R g , independently for each occurrence, are selected from group consisting of hydrogen, C 1-4 alkyl optionally substituted by one or more substituents selected from R p′ , and C 3-6 cycloalkyl optionally substituted by one or more substituents selected from R p″ , 
         or R f  and R g  taken together with the nitrogen to which they are attached form a 4-7 membered heterocyclyl, optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxyl, oxo, cyano, C 1-6 alkyl, C 1-6 alkoxy, R a R a′ N—, C 1-6 alkylcarbonyl-N(R a )—; C 1-6 alkoxycarbonyl-N(R a )—, R a R a′ N—SO 2 —, R a R a′ N-carbonyl-, R a R a′ N-carbonyl-N(R a ), and wherein C 1-6 alkyl or C 1-6 alkoxy may be optionally substituted by at least one or more substituent selected from the group consisting of R a R a′ N, halogen, hydroxy, and cyano, C 1-4 alkoxycarbonyl, R a R a′ N-carbonyl, R a R a′ N—SO 2 —, C 1-4 alkoxy, C 1-4 alkylS(O) w —, wherein w is 0, 1 or 2; 
         R p  is independently selected, for each occurrence, from the group consisting of R a R a′ N—, halogen, hydroxy, cyano, C 1-4 alkoxycarbonyl, R a R a′ N-carbonyl, R a R a′ N—SO 2 —, C 1-4 alkoxy, and C 1-4 alkylS(O) w —, wherein w is 0, 1 or 2; 
         R p′  is independently selected, for each occurrence, from the group consisting of R a R a′ N-halogen, hydroxy, cyano, C 1-4 alkoxycarbonyl, R a R a′ N-carbonyl, R a R a′ N—SO 2 —, C 1-4 alkoxy, C 1-4 alkylS(O) w — and C 3-6 cycloalkyl, wherein w is 0, 1 or 2 and wherein C 3-6 cycloalkyl is optionally substituted with R p″ ; 
         R p″  is independently selected, for each occurrence, from the group consisting of R a R a′ N—, halogen, hydroxy, cyano, C 1-4 alkoxycarbonyl, R a R a′ N-carbonyl, R a R a′ N—SO 2 —, C 1-4 alkoxy, C 1-4 alkylS(O) w  and C 1-6 alkyl, wherein w is 0, 1 or 2 and wherein C 1-6 alkyl is optionally substituted by one or more substituents selected from R p ; 
         R t  is independently selected from the group consisting of R f R g N—, halogen, cyano, hydroxyl and C 1-6 alkoxy; 
         R h  is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-6 alkenyl (wherein any unsaturated bond is not directly attached to a nitrogen), C 3-6 alkynyl(wherein any unsaturated bond is not directly attached to a nitrogen), C 3-6 cycloalkyl, C 1-6 alkyl-S(O) 2 —, and C 1-6 alkyl-N(R a )carbonyl, wherein C 1-6 alkyl is optionally substituted by one or more substituents selected from R p′ ; wherein C 3-6 alkenyl and C 3-6 alkynyl are optionally substituted by at least one substituent selected from R p , and wherein C 3-6 cycloalkyl is optionally substituted by at least one substituent selected from R p″ ; 
         and a pharmaceutically acceptable carrier. 
       
     
     
         41 . The pharmaceutical composition of  claim 40 , wherein R 1  is selected from the group consisting of hydrogen, methoxy, ethoxy, O—CH 2 —CN, —O—(CH 2 ) 2 —NH 2 ; —NHCH 2 CN, or —O—(CH 2 ) 2 —OH. 
     
     
         42 . The pharmaceutical composition of  claim 40 , wherein R 2  is selected from the group consisting of halogen, cyano, methyl, ethyl, propyl, C 3-5 cycloalkyl, C 3-6 cycloalkyloxy, C 3-5 cycloalkyl-C 1-2 alkyl-, or a 5 membered heteraryl having one or two heteroatoms selected from O, N, and S. 
     
     
         43 . The pharmaceutical composition of  claim 40 , wherein R 2  is selected from the group consisting of furyl, thienyl, isothiazolyl, isoxazolyl, oxazolyl and pyrrolyl. 
     
     
         44 . The pharmaceutical composition of  claim 43 , wherein R 2  is selected from the group consisting of 3-furyl, and 5-isothiazolyl. 
     
     
         45 .- 47 . (canceled) 
     
     
         48 . A method of treating and/or controlling obesity, comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition of  claim 40 . 
     
     
         49 . A method of inducing weight loss in a patient in need thereof, comprising administering to said patient an effective amount of a pharmaceutical composition of  claim 40 . 
     
     
         50 . The method of  claim 48 , wherein the patient is a human. 
     
     
         51 . The method of  claim 48 , wherein the patient has a body mass index greater than or equal to about 30 kg/m 2  before the administration. 
     
     
         52 . The method of  claim 48 , wherein the compound is administered orally. 
     
     
         53 . (canceled) 
     
     
         54 . The composition of  claim 40 , wherein the composition is formulated as a unit dose. 
     
     
         55 . The composition of  claim 40 , wherein the composition is formulated for oral administration. 
     
     
         56 . The composition of  claim 40 , wherein the composition is formulated for intravenous or subcutaneous administration. 
     
     
         57 .- 58 . (canceled)