Organic compounds and their uses

Abstract

The present application describes a method of treating an HCV-associated disorder by administering to a subject in need thereof a pharmaceutically effective amount of a compound of formula I in combination with an additional HCV-modulating compound.

What is claimed is: 
     
         1 . A method of treating an HCV-associated disorder, comprising:
 administering to a subject in need thereof a pharmaceutically effective amount of a compound of formula I:   
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salt thereof; 
       wherein
 y is 0 or 1; 
 n and p are each independently selected from 0, 1 or 2; 
 R 14  is C(O) or SO 2 ; 
 R 1 , R 2 , W, R 13  and V are each, independently, selected from hydrogen or from the group consisting of alkyl, alkyl-aryl, heteroalkyl, heterocyclyl, heteroaryl, aryl-heteroaryl, alkyl-heteroaryl, cycloalkyl, alkyloxy, alkyl-aryloxy, aryloxy, heteroaryloxy, heterocyclyloxy, cycloalkyloxy, amino, alkylamino, arylamino, alkyl-arylamino, arylamino, heteroarylamino, cycloalkylamino, carboxyalkylamino, mono- and di-alkylcarboxamide, aralkyloxy and heterocyclylamino; each of which may be further independently substituted one or more times with X 1  and X 2 ; wherein X 1  is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl, heterocyclylalkyl, aryl, alkylaryl, aralkyl, aryloxy, arylthio, arylheteroaryl, heteroaryl, heterocyclylamino, alkylheteroaryl, or heteroaralkyl; wherein X 1  can be independently substituted with one or more X 2  moieties which can be the same or different and are independently selected; wherein X 2  is hydroxy, oxo, alkyl, cycloalkyl, spirocycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aryloxy, thio, alkylthio, amino, mono- and di-alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, alkylsulfonamido, arylsulfonamido, carboxy, carbalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyl, alkoxycarbonyloxy, alkylureido, arylureido, halogen, cyano, or nitro; wherein each X 2  residue selected to be alkyl, alkoxy, and aryl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different and are independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl, heterocyclylalkyl, aryl, alkylaryl, aralkyl, arylheteroaryl, heteroaryl, heterocyclylamino, alkylheteroaryl and heteroaralkyl; 
 W is also selected from the group consisting of C(O)—C(O)H, C(═N—O—R 24 )—C(O)-amine, C(O)—C(O)-amine, C(O)NR 24 S(O) p R 24 , C(O)NR 24 S(O) p N(R 24 ) 2  and C(O)—[C(O)] a -heterocycle, wherein the heterocycle may be independently substituted one or more times with aryl, C 1-4 -alkyl, C 1-4 -alkyl substituted by one or more halogen atoms, and C 3-6 -cycloalkyl, wherein a is 0 or 1, wherein each R 24  is independently selected from hydrogen or the group consisting of C 1-4 -alkyl, C 3-6 -cycloalkylC 0-4 alkyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocycle, each of which may be independently substituted one or more times with a halogen atom or C 1-4 -alkyl; 
 V is also selected from the group consisting of -Q 1 -Q 2 , wherein Q 1  is absent, C(O), N(H), N(C 1-4 -alkyl), C═N(CN), C═N(SO 2 CH 3 ), C═N—COH—C 1-4 -alkyl, or C═N—COH, and Q 2  is hydrogen or is selected from the group consisting of C 1-4 -alkyl, O—C 1-4 -alkyl, NH 2 , N(H)—C 1-4 -alkyl, N(C 1-4 -alkyl) 2 , SO 2 -aryl, SO 2 —C 1-4 -alkyl, C 3-6 -cycloalkyl-C 0-4 -alkyl, aryl, heteroaryl and heterocycle, each of which may be independently substituted one or more times with a halogen atom, C 1-4 -alkyl, C 1-4 -alkyl substituted by one or more halogen atoms, or C 3-6 -cycloalkyl; 
 or R 1  and R 2  may together form a 3, 4, 5, 6 or 7-membered ring that is aromatic or non-aromatic and may contain one or more heteroatoms, wherein the ring may be further substituted one or more times; 
 R 3  is selected from the group consisting of hydrogen, C 1-4 -alkyl and C 3-6 cycloalkylC 0-4 alkyl; 
 X is O, S, N, NR 5 , CR 5  or CR 5 R 5a ; 
 R 4  represents 0-4 substituents, each of which is independently selected from hydrogen or from the group consisting of C 1-4 -alkyl, C 3-6 -cycloalkyl, aryl, heterocycle and heteroaryl, each of which may be independently substituted one or more times with a halogen atom or C 1-4 -alkyl; 
 R 5  is selected from hydrogen or oxo or from the group consisting of hydroxyl, C 1-8 -alkyl, C 2-8 -alkenyl, C 2-8 -alkynyl, C 3-8 -cycloalkyl-C 0-4 -alkyl, aryl-C 0-4 -alkyl, heterocycle-C 0-4 -alkyl, heteroaryl-C 0-4 -alkyl, C 3-8 -cycloalkyloxy, aryloxy, and heteroaryloxy each of which may be independently substituted one or more times with a halogen atom, aryl, trihalomethyl, or C 1-4 -alkyl; 
 R 5a  is hydrogen or is selected from the group consisting of hydroxyl, C 1-8 -alkyl, C 2-8 -alkenyl, C 2-8 -alkynyl, C 3-8 -cycloalkyl-C 0-4 -alkyl, aryl-C 0-4 -alkyl and heteroaryl-C 0-4 -alkyl, 
 or R 4  and R 5  may together form a fused dimethyl cyclopropyl ring, a fused cyclopentane ring, a fused phenyl ring or a fused pyridyl ring, each of which may be substituted with a halogen atom, aryl, trihalomethyl, or C 1-4 -alkyl; 
 or R 5  and R 6  may together form a fused dimethyl cyclopropyl ring, a fused cyclopentane ring, a fused phenyl ring or a fused pyridyl ring, each of which may be substituted with a halogen atom, aryl, trihalomethyl, or C 1-4 -alkyl; 
 or R 5  and R 5a  may together form a spirocyclic ring having between 3 and 7 ring atoms and having 0, 1, or 2 ring heteroatoms, which is optionally substituted by 0-4 substituents selected from cyano, halogen, hydroxyl, amino, thiol, C 1-8 -alkyl, C 2-8 -alkenyl, C 2-8 -alkynyl, C 1-8 -alkoxy-C 0-4 alkyl, C 1-8 -haloalkyl, C 2-8 -haloalkenyl, C 2-8 -haloalkynyl, C 1-8 -haloalkoxy, C 1-8 -alkylthio, C 1-8 -alkylsulfonyl, C 1-8 -alkylsulfoxy, C 1-8 -alkanoyl, C 1-8 -alkoxycarbonyl, C 3-7 -cycloalkyl-C 0-4 -alkyl, aryl-C 0-4 -alkyl, heteroaryl-C 0-4 -alkyl, COOH, C(O)NH 2 , mono- and di-C 1-4 -alkyl-carboxamide, mono- and di-C 1-4 -alkyl-amino-C 0-4 alkyl, SO 3 H, SO 2 NH 2 , and mono- and di-C 1-4 -alkylsulfonamide, or two of said 0-4 substitutents taken together form a fused or spirocyclic 3 to 7 membered ring having 0, 1 or 2 ring heteroatoms selected from N, O and S, which fused or spirocyclic ring has 0 to 2 independently selected substituents selected from cyano, halogen, hydroxyl, amino, thiol, C 1-8 -alkyl, C 2-8 -alkenyl, C 2-8 -alkynyl, C 1-8 -alkoxy-C 0-4 alkyl, C 1-8 -haloalkyl, C 2-8 -haloalkenyl, C 2-8 -haloalkynyl, C 1-8 -haloalkoxy, C 1-8 -alkylthio, C 1-8 -alkylsulfonyl, C 1-8 -alkylsulfoxy, C 1-8 -alkanoyl, C 1-8 -alkoxycarbonyl, C 3-7 -cycloalkyl-C 0-4 -alkyl, aryl-C 0-4 -alkyl, heteroaryl-C 0-4 -alkyl, COOH, C(O)NH 2 , mono- and di-C 1-4 -alkyl-carboxamide, mono- and di-C 1-4 -alkyl-amino-C 0-4 alkyl, SO 3 H, SO 2 NH 2 , and mono- and di-C 1-4 -alkylsulfonamide; 
 R 6  and R 7  are each, independently, selected from the group consisting of hydrogen, hydroxy, amino, C 1-4 alkyl, C 1-4 alkoxy, and mono- and di-C 1-4 alkylamino, and C 3-6 cycloalkylC 0-4 alkyl; 
 R 8 , R 9 , R 10 , R 11  and R 12  are each, independently, selected from the group consisting of hydrogen, C 1-4 -alkyl and C 3-6 cycloalkylC 0-4 alkyl; 
 or R 6  and R 7  may together form a spirocyclic ring having between 3 and 7 ring atoms and having 0, 1, or 2 ring heteroatoms, which is optionally substituted by 0-4 substituents selected from cyano, halogen, hydroxyl, amino, thiol, C 1-8 -alkyl, C 2-8 -alkenyl, C 2-8 -alkynyl, C 1-8 -alkoxy-C 0-4 alkyl, C 1-8 -haloalkyl, C 2-8 -haloalkenyl, C 2-8 -haloalkynyl, C 1-8 -haloalkoxy, C 1-8 -alkylthio, C 1-8 -alkylsulfonyl, C 1-8 -alkylsulfoxy, C 1-8 -alkanoyl, C 1-8 -alkoxycarbonyl, C 3-7 -cycloalkyl-C 0-4 -alkyl, aryl-C 0-4 -alkyl, heteroaryl-C 0-4 -alkyl, COOH, C(O)NH 2 , mono- and di-C 1-4 -alkyl-carboxamide, mono- and di-C 1-4 -alkyl-amino-C 0-4 alkyl, SO 3 H, SO 2 NH 2 , and mono- and di-C 1-4 -alkylsulfonamide, or two substituents taken together form a fused or spirocyclic 3 to 7 membered ring having 0, 1 or 2 ring heteroatoms selected from N, O and S, which fused or spirocyclic ring has 0 to 2 independently selected substituents selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkanoyl, mono- and di-C 1-4 -alkylamino, mono- and di-C 1-4 -alkyl-carboxamide, C 1-4 -alkoxycarbonyl, and phenyl; 
 or R 3  and W may together form a 3, 4, 5, 6 or 7-membered ring that is aromatic or non-aromatic and may contain one or more heteroatoms, wherein the ring may be further substituted one or more times; and 
 or when y is 0, R 10  and V may together form a 3, 4, 5, 6 or 7-membered ring that is aromatic or non-aromatic and may contain one or more heteroatoms, wherein the ring may be further substituted one or more times; and 
 a pharmaceutically effective amount of an additional HCV-modulating compound, such that the HCV-associated disorder is treated. 
 
     
     
         2 . The method of  claim 1 , wherein the additional HCV-modulating compound is selected from the group consisting of Sch 503034 and VX-950. 
     
     
         3 . The method of  claim 1 , wherein the additional HCV-modulating compound is interferon or derivatized interferon. 
     
     
         4 . The method of  claim 3 , wherein the interferon is selected from the group consisting of interferon alpha 2B, pegylated interferon alpha, consensus interferon, interferon alpha 2A, lymphoblastoid interferon, and interferon tau; and said compound having anti-hepatitis C virus activity is selected from the group consisting of interleukin 2, interleukin 6, interleukin 12, a compound that enhances the development of a type 1 helper T cell response, double stranded RNA, double stranded RNA complexed with tobramycin, Imiquimod, ribavirin, an inosine 5′-monophosphate dehydrogenase inhibitor, amantadine, and rimantadine. 
     
     
         5 . The method of  claim 1 , wherein the additional HCV-modulating compound is a cytochrome P450 monooxygenase inhibitor. 
     
     
         6 . The method of  claim 5 , wherein the cytochrome P450 inhibitor is selected from the group consisting of ritonavir, ketoconazole, troleandomycin, 4-methylpyrazole, cyclosporin, and clomethiazole. 
     
     
         7 . The method of  claim 1 , wherein the HCV-associated disorder is selected from the group consisting of HCV infection, liver cirrhosis, chronic liver disease, hepatocellular carcinoma, cryoglobulinaemia, non-Hodgkin's lymphoma, and a suppressed innate intracellular immune response. 
     
     
         8 . The method of  claim 1 , the compound of formula I, wherein
 y is 0 or 1;   n is 0 or 1;   R 14  is C(O) or SO 2      R 1  is selected from the group consisting of H and C 1-4 -alkyl;   R 2  is selected from the group consisting of C 1-4 -alkyl, C(O)C 1-4 -alkyl, C(O)OC 1-4 -alkyl, and C 3-6 cycloalkylC 0-4 alkyl;   or R 1  and R 2  together form a cyclopropane ring;   W is also selected from the group consisting of C(O)—C(O)H, C(═N—O—R 24 )—C(O)-amine, C(O)—C(O)-amine, C(O)NR 24 S(O) p R 24 , C(O)NR 24 S(O) p N(R 24 ) 2  and C(O)—[C(O)] a -heterocycle, wherein the heterocycle may be independently substituted one or more times with aryl, C 1-4 -alkyl, C 1-4 -alkyl substituted by one or more halogen atoms, and C 3-6 -cycloalkyl, wherein a is 0 or 1, wherein each R 24  is independently selected from hydrogen or from the group consisting of C 1-4 -alkyl, C 3-6 cycloalkylC 0-4 alkyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocycle, each of which may be independently substituted one or more times with a halogen atom or C 1-4 -alkyl;   p is 0, 1 or 2;   R 3  is selected from the group consisting of H and C 1-4 -alkyl;   X is O, NR 5  or CR 5 R 5a ;   R 4  is selected from hydrogen or from the group consisting of C 1-4 -alkyl, C 3-6 -cycloalkyl, aryl, heterocycle and heteroaryl, each of which may be independently substituted one or more times with a halogen atom or C 1-4 -alkyl;   R 5  is selected from hydrogen or oxo or from the group consisting of hydroxyl, C 1-8 -alkyl, C 2-8 -alkenyl, C 2-8 -alkynyl, C 3-8 -cycloalkyl-C 0-4 -alkyl, aryl-C 0-4 -alkyl, heterocycle-C 0-4 -alkyl and heteroaryl-C 0-4 -alkyl, each of which may be independently substituted one or more times with a halogen atom, aryl, trihalomethyl, or C 1-4 -alkyl;   R 5a  is selected from hydrogen or from the group consisting of hydroxyl, C 1-8 -alkyl, C 2-8 -alkenyl, C 2-8 -alkynyl, C 3-8 -cycloalkyl-C 0-4 -alkyl, aryl-C 0-4 -alkyl and heteroaryl-C 0-4 -alkyl,   or R 4  and R 5  may together form a fused dimethyl cyclopropyl ring, a fused cyclopentane ring, a fused phenyl ring or a fused pyridyl ring, each of which may be substituted with a halogen atom, aryl, trihalomethyl, or C 1-4 -alkyl;   or R 5  and R 5a  may together form a spirocyclic ring having between 3 and 7 ring atoms and having 0, 1, or 2 ring heteroatoms, which is optionally substituted by 0-4 substituents selected from cyano, halogen, hydroxyl, amino, thiol, C 1-8 -alkyl, C 2-8 -alkenyl, C 2-8 -alkynyl, C 1-8 -alkoxy-C 0-4 alkyl, C 1-8 -haloalkyl, C 2-8 -haloalkenyl, C 2-8 -haloalkynyl, C 1-8 -haloalkoxy, C 1-8 -alkylthio, C 1-8 -alkylsulfonyl, C 1-8 -alkylsulfoxy, C 1-8 -alkanoyl, C 1-8 -alkoxycarbonyl, C 3-7 -cycloalkyl-C 0-4 -alkyl, aryl-C 0-4 -alkyl, heteroaryl-C 0-4 -alkyl, COOH, C(O)NH 2 , mono- and di-C 1-4 -alkyl-carboxamide, mono- and di-C 1-4 -alkyl-amino-C 0-4 alkyl, SO 3 H, SO 2 NH 2 , and mono- and di-C 1-4 -alkylsulfonamide, or two substituents taken together form a fused or spirocyclic 3 to 7 membered ring having 0, 1 or 2 ring heteroatoms selected from N, O and S, which fused or spirocyclic ring has 0 to 2 independently selected substituents selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkanoyl, mono- and di-C 1-4 -alkylamino, mono- and di-C 1-4 -alkyl-carboxamide, C 1-4 -alkoxycarbonyl, and phenyl;   R 8 , R 10  and R 11  are each, independently, selected from the group consisting of H and C 1-4 -alkyl;   R 6  and R 7  are each, independently, selected from the group consisting of hydrogen, hydroxy, amino, C 1-4 alkyl, C 1-4 alkoxy, and mono- and di-C 1-4 alkylamino;   R 13  is H;   R 9  and R 12  are each, independently, selected from the group consisting of hydrogen, C 1-4 -alkyl and C 3-6 -cycloalkyl; and   V is also selected from the group consisting of -Q 1 -Q 2 , wherein Q 1  is absent, C(O), N(H), N(C 1-4 -alkyl), C═N(CN), C═N(SO 2 CH 3 ), C═N—COH—C 1-4 -alkyl, or C═N—COH, and Q 2  is hydrogen or is selected from the group consisting of C 1-4 -alkyl, O—C 1-4 -alkyl, NH 2 , N(H)—C 1-4 -alkyl, N(C 1-4 -alkyl) 2 , SO 2 -aryl, SO 2 —C 1-4 -alkyl, C 3-6 -cycloalkyl-C 0-4 -alkyl, aryl, heteroaryl and heterocycle, each of which may be independently substituted one or more times with a halogen atom, C 1-4 -alkyl, C 1-4 -alkyl substituted by one or more halogen atoms, or C 3-6 -cycloalkyl;   or R 3  and W can together form a 6-membered ring of the formula II:   
       
         
           
           
               
               
           
         
       
       wherein formula II may be further substituted;
 or when y is 0, R 10  and V can form a cyclopropyl ring that may be further substituted by an amide group. 
 
     
     
         9 . The method of  claim 1 , the compound of formula I, wherein R 14  is C(O). 
     
     
         10 . The method of  claim 1 , the compound of formula I, wherein y is 0, and R 10  and V form a cyclopropyl ring that is substituted with C(O)N(H)-pyrazine. 
     
     
         11 . The method of  claim 1 , the compound of formula I, wherein R 4 , R 6  and R 7  are hydrogen, and R 5  is arylC 0-3 alkyl, heteroaryloxy, or heteroarylC 0-3 alkyl, wherein aryl and heteroaryl may be independently substituted one or more times with a halogen atom, aryl, trihalomethyl, C 3-6 -cycloalkyl or C 1-4 -alkyl. 
     
     
         12 . The method of  claim 1 , the compound of formula I, wherein R 1  and R 2 , are independently selected from hydrogen or from the group consisting of C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkylC 0-4 alkyl, C 3-6 cycloalkenylC 0-4 alkyl, C 1-4 alkoxyC 0-4 alkyl, and heterocycloalkylC 0-4 alkyl, each of which is unsubstituted or substituted with one or more groups selected from fluoro, chloro, hydroxy, C 1-2 alkylS, C 1-2 alkylS(O), and C 1-2 alkylS(O) 2 , and wherein the heterocycloalkyl is a 3 to 6 membered ring having one or two N, O or S ring atoms. 
     
     
         13 . The method of  claim 1 , the compound of formula I, wherein R 1  is hydrogen and R 2  is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, allyl, propargyl, 3-fluoro-n-propyl, n-butyl, n-pentyl, iso-propyl, sec-butyl, iso-butyl, 3-methyl-n-butyl, 3,3,3-trifluoro-n-propyl, 2,2-difluoroethyl, trifluoromethyl, 1,1-difluoro-n-propyl, 2,2,2-trifluoroethyl, 2,2-difluoro-n-but-3-enyl, 4-pentenyl, 3,3-difluoro-allyl, 2-methyl-allyl, 3-butenyl, 2-cyanoethyl, 3,3-difluoropropyl, 2,2-difluoro-3-butenyl, 2,2-difluoro-n-propyl, 4,4,4-trifluorobutyl, C 3-6 cycloalkyl, oxetan-2-ylmethyl, thietan-2-ylmethyl, 3-fluorocyclobutylmethyl, 3-hydroxycyclobutylmethyl, 3-butynyl, methoxymethyl, 2-methoxyethyl, methyl-S(O) 0-2 C 1-2 alkyl, 3,3-difluorocyclobutylmethyl, oxetan-3-ylmethyl, C 3-6 cycloalkylmethyl, 1-methylcyclopropylmethyl, C 3-6 cycloalkyl-difluoromethyl, C 3-6 cycloalkylethyl, thietan-3-ylmethyl, 1-fluorocyclobutylmethyl, 1-fluorocyclopropylmethyl, 2,2-difluorocyclopropylmethyl, and cyclopenten-2-ylmethyl. 
     
     
         14 . The method of  claim 1 , the compound of formula I, wherein n is 1, and R 4  and R 5  together form a fused ring system selected from: 
       
         
           
           
               
               
           
         
       
       wherein R 18  is selected from the group consisting of hydrogen, a halogen atom, aryl, trihalomethyl, and C 1-4 -alkyl. 
     
     
         15 . The method of  claim 1 , the compound of formula I, wherein X is CR 5 R 5a , R 5a  is hydrogen, and R 5  is selected from the group consisting of piperidine, phenyl, pyridinyl, pyridinyloxy and pyridinylmethyl, wherein the phenyl and pyridinyl groups may be independently substituted one or more times with a halogen atom or C 1-4 -alkyl. 
     
     
         16 . The method of  claim 15 , the compound of formula I, wherein X is CR 5 R 5a , R 5a  is hydrogen, and R 5  is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
       wherein R 21  is independently selected from the group consisting of C 1-4 -alkyl and aryl. 
     
     
         17 . The method of  claim 1 , the compound of formula I, wherein X is CR 5 R 5a , R 4  is hydrogen, and R 5  and R 5a  taken in combination form a 3 to 6 member spirocyclic carbocycle substituted with 0-2 substituents selected from halogen, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 1-6 -alkoxy, C 3-7 -cycloalkyl-C 0-4 -alkyl, phenyl-C 0-4 -alkyl, naphthyl-C 0-4 -alkyl, heteroaryl-C 0-4 -alkyl, or two substituents taken together form a fused or spirocyclic 3 to 7 membered carbocyclic ring, each of which is substituted with 0-3 independently selected halogen atoms or C 1-4 -alkyl groups. 
     
     
         18 . The method of  claim 1 , the compound of formula, 
       
         
           
           
               
               
           
         
       
       wherein
 k 1  and k 2  are 0 or 1 such that a sum of k 1  and k 2  equals 1 or 2; 
 R a  is hydrogen, C 1-4 alkyl, or phenyl; 
 R b  is hydrogen, C 1-4 alkyl, C 1-4 alkoxy-C 0-4 alkyl, mono- and di-C 1-4 alkylaminoC 0-4 alkyl, mono- and di-C 1-4 alkyl carboxamide, C 1-4 alkanoyl, C 1-4 alkoxycarbonyl, or phenyl; 
 or R a  and R b , taken together, form a spirocyclic 3 to 6 membered ring having 0, 1 or 2 ring heteroatoms selected from N, O and S, which fused or spirocyclic ring has 0 to 2 independently selected substituents selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkanoyl, and phenyl; 
 R c  represents 0 to 4 substituents which are independently selected at each occurrence of R c  from the group consisting of halogen, C 1-4 alkyl, and phenyl, or two geminal R c  substituents, taken in combination form a 3 to 6 member spirocyclic ring; 
 R 4  represents 0, 1, or 2 substituents each of which is independently selected from H and C 1-4 -alkyl; and 
 R 6  is hydrogen or C 1-4 alkyl. 
 
     
     
         19 . The method of  claim 1 , the compound of formula I, wherein the divalent residue: 
       
         
           
           
               
               
           
         
       
       is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein R e  is absent, C(O), or S(O) 2 ; and R g  is selected hydrogen or selected from the group consisting of C 1-6 alkyl, arylC 0-4 alkyl, heteroarylC 0-4 alkyl, heterocyclylC 0-4 alkyl, and C 3-7 cycloalkylC 0-4 alkyl, each of which is substituted with 0 to 4 independently selected substituents selected from the group consisting of cyano, halogen, hydroxyl, amino, thiol, C 1-8 -alkyl, C 2-8 -alkenyl, C 2-8 -alkynyl, C 1-8 -alkoxy-C 0-4 alkyl, C 1-8 -haloalkyl, C 2-8 -haloalkenyl, C 2-8 -haloalkynyl, C 1-8 -haloalkoxy, C 1-8 -alkylthio, C 1-8 -alkylsulfonyl, C 1-8 -alkylsulfoxy, C 1-8 -alkanoyl, C 1-8 -alkoxycarbonyl, C 3-7 -cycloalkyl-C 0-4 -alkyl, aryl-C 0-4 -alkyl, heteroaryl-C 0-4 -alkyl, COOH, C(O)NH 2 , mono- and di-C 1-4 -alkyl-carboxamide, mono- and di-C 1-4 -alkyl-amino-C 0-4 alkyl, SO 3 H, SO 2 NH 2 , and mono- and di-C 1-4 -alkylsulfonamide.