GB2450771A - Heterocyclic compounds and their use as inhibitors of HCV polymersases for the treatment of HCV - Google Patents

Abstract

A compound of formula (I): <EMI ID=1.1 HE=28 WI=57 LX=867 LY=633 TI=CF> <PC>or a pharmaceutically acceptable salt thereof wherein A is a an optionally substituted 5 or 6 membered ring that may contain a nitrogen atom; the dotted line represents an optional bond; X is N, C or CH; R1 is selected from optionally substituted- alkyl, alkenyl, alkynyl group and an optionally substituted ring system; R2, R3, R4 and R5 are each independently selected from hydrogen or a substituent, or R2 and R3 and/or R3 and R4 are joined together to form an optionally substituted 5 or 6 membered ring that may contain a nitrogen atom. The compounds and their pharmaceutical compositions are inhibitors of viral polymerases, especially the hepatitis C virus (HCV) polymerase and are therefore useful in medicine for the treatment or prevention of HCV infections.

Description

Antiviral a2cnts This invention relates to compounds which can act as

inhibitors of viral polymerases, especially the hepatitis C virus (I ICV) polymerase, to uses of such compounds in the treatment and prevention of infection by hepatitis C virus, and to their preparation.

The hepatitis C virus (IICV) is the major causative agent of parenterally-transmitted and sporadic non-A, non-B hepatitis (NANB-ll). Some 1% of the human population of the planet is believed to be affected. Infection by the virus can result in chronic hepatitis and cirrhosis of the liver, and may lead to hepatocellular carcinoma. Currently no vaccine nor established therapy exists, although partial success has been achieved in a minority of cases by treatment with recombinant interferon-a, either alone or in combination with ribavirin. There is therefore a pressing need for new and broadly-effective therapeutics.

Several virally-encoded enzymes are putative targets for therapeutic intervention, including a metalloprotease (NS2-3), a serine protease (NS3), a helicase (NS3), and an RNA-dependent RNA polymerase (NS5B). Of these, the polymerase plays an essential role in replication of the virus and is therefore an important target in the fight against hepatitis C. Published International patent application WO 93/18766 (The Weilcome Foundation Limited) discloses indole derivatives of the following formula: I1 R13 N R14'I> (A) where R', R, R, R, R' and R' are defined therein, for use in the treatment or prophylaxis of viral infections, in particular retrovirus, herpesvirus, hepatitis, coxsackie virus and hepatitis C virus infections.

Published Japanese patent application JP270749 IA (Taiho Pharmaceuticals Co. Ltd.) discloses pyrroloimidazole derivatives of the following formula: R1 (B) X CH2COOH where R', R', R, X and Y are defined therein, as having an aldose reduction inhibitory effect and useful for therapy and prevention of various chronic symptoms and complications accompanying diabetes.

Katritzky ci a!. (J. Org. Chem. 2004, 69, 9313 9315) discloses the synthesis of pyrrolo[1,2-c]imidazoles (C) and imidazo[1,5-a]indoles (D): R-Nij R-Nj (C) (0) where X is 0 or S and R is defined therein.

Published international patent application WO 2004/078731 (Chemical Diversity Research Institute) discloses quinoline-carboxylic acids such as: (E) where R, R, R and W are delined therein, as Caspase enzyme inhibitors and useful for curing various diseases associated with increased apoptosis activity.

Published International patent application WO 2005/107742 (Yale University) discloses helioxanthin analogues of the following formula: R15 R13 /LL \-c I (F) ORb OR8 where X', X, Y, R' , R'', R and Rh are defined therein, for the treatment of hepadnaviruses, flaviviruses, herpesviruscs and human immunodeficiency virus, as well as prevention of tumours secondary to virus infection and other infections or disease states secondary to virus infection.

Nevertheless, there still remains the need for novel treatments against infection by hepatitis C virus.

It has now surprisingly been found that certain novel polycyclic imide derivatives can act as inhibitors of hepatitis C virus (I ICV) NS5b RNA dependent RNA polymerase enzyme.

Thus the present invention provides the compound of formula (I): 0 A N-R1 (I) R3X wherein Xis N, CII orC; the dotted line represents an optional bond; so that X is C when the doffed line represents a bond; and X is N or CII when the dotted line represents no bond; R' is Cialkyl, CaIkenyl, C2alkynyl, or (Cl l)(L;R, optionally substituted by Q' and Q; R' is Ccycloalkyl, Ilet, aryl or hcteroaryl, where C;cycloalkyl is optionally bridged by -(Cl I2)*-; Q1 and Q' are independently selected from halo, hydroxy, Cjalkyl, C1alkoxy, C2alkenyl, (CH2)C02R, (CH2)iC(O)NRS(O)R7, (CH2)C(O)NRR7 and oxo; R and R' are independently selected from hydrogen, Cioalkyl, (CH)oaryl, where (CH2)oaryl is optionally substituted by I to 3 halogen atoms; A is a 5-or 6-membered ring optionally containing one nitrogen atom; R is hydrogen, Cialkyl, halo or hydroxy, R is hydrogen, Cpalkyl, halo, hydroxy or C(O)C].)alkyl; or R2 and R are joined together to form a 5-or 6-membered ring optionally containing one nitrogen atom and optionally substituted by Q; Q is Cialkyl, C2(alkenyl, C2alkyny1, hydroxy, halo, (CH2)phenyl, 0(CH2)phenyl, NR1 R', NR' C(O)OCp)alkyl, C(O)OCialky1, C(O)NR R'2, N R' S(O)(Cfl2)1 C cycloalkyl, N R S(O)2C1 alkyl, NR S(O)2(CJ I 2)o;aryl or NR' S(0)2(Cl-i)4heteroaryl, optionally substituted by hydroxy, CO.2H, CO2Cialkyl or CN; Rr and R' are independently selected from hydrogen, Cialkyl, (CH2)!O(CI)alkyl), (CH2)C;cycloalkyl, (CH2) aryl, (CH2) Het and (CFI2)1 heteroaryl, optionally substituted by hydroxy, Cialkyl, (CH2)ophenyI and CO2H; or R'' and R'2, together with the nitrogen atom to which they are joined, form a 5-or 6-membered ring, optionally containing one oxygen atom or one further nitrogen atom, and optionally substituted by Cialkyl or (CI 12)l let; R is hydrogen, Cj.alkyl, halo, hydroxy, NR(Rr(J, NO2 or NR(Cll2)Ccycloalkyl; R and R' are independently selected from hydrogen and Ci4aIkyl; or R and R' are joined together to form a 5-or 6-membered ring optionally containing one nitrogen atom and optionally substituted by Cja1kyl, hydroxy, halo, Nil2, NO2 or CN; R is hydrogen, Cialkyl, C2alkcnyl, C1(alkynyl, hydroxy or halo; and pharmaceutically acceptable salts thereof.

Preferably, R' is C1 (alkyl, C2(alkenyl or (Cl l2)2R, optionally substituted by Q' and Q', where R', Q1 and Q are as hereinbefore defined. More preferably, R' is Ci4alkyl, C:aIkenyl or (CI-l)41 R optionally substituted by Qand Q, where R, Q1 and Q2 are as hcreinbefore defined.

Preferably, R is Ccycloalkyl, Het, aryl or heteroaryl, where Ccycloalkyl is optionally bridged by -(Cll)1. . Examples of suitable R' groups include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2. 1]hexyl, phenyl, thienyl, imidazo lyl, benzothienyl, piperidiriyl, azepinyl and tetrahydrobenzothienyl.

Preferably, Q' is halo, hydroxy, Ci,alkyl, (CH2)01 CO2 R, (CII C(0)N RS(O)2R, (C1l2)01C(O)NR R or oxo. More preferably, Q is halo, hydroxy, Calkyl, (CH2)01C02R (CH2)niC(0)Nl-IS(O)R', (CH2)oiC(O)NHR or oxo. Examples of suitable Q1 groups include fluoro, chloro, hydroxy, methyl, CO2H, CH2COII, CO2CH, CO2CH2CH, CH2C02CHCH, CO:CH2phenyl, CH 2C(O)N El S(O)CH CH2C(O)N HS(O)2C1 l2phenyl, CH2C(O)N HS(O)2CH2CII, C(O)NHCII, CH2C(O)NHCI-12-difluorophenyl and oxo.

Preferably, Q is halo, hydroxy, Ci,alky1, CI.(alkoxy or (Cl-l2)o;CO2R, where R' is as hereinbefore defined. More preferably, Q is halo, Cj4alkoxy or CO2R', where R is hydrogen or CH(alkyl. Examples of suitable Q2 groups include chioro, bromo, methoxy and CO2H.

Preferably, A is phenyl, pyridinyl, pyrrolyl and dihydropyrrolyl. Examples of suitable A groups, as illustrated in the compounds (I) below, include: R5 0 R3__JLN_R1 N'( R4 a R1 and R3_R1 Preferably, R2 is hydrogen, C11alky1, halo or hydroxy. More preferably, R is hydrogen, Calkyl, fluoro, chioro, bromo or hydroxy. Most preferably, R'is methyl, fluoro, chioro or hydroxy.

Preferably, R is hydrogen, CiialkyI, halo, hydroxy or C(O)Ci4alkyl. Examples of suitable R groups include hydrogen, methyl, fluorine, hydroxy and C(O)Cl I Preferably, R and R are joined to form either a 5-membered ring containing one nitrogen atom or a phenyl ring, both optionally substituted by Q, where Q is as hereinbefore defined. More preferably, R and R are joined to form a phenyl ring, optionally substituted by Qd Preferably, Q is CI.(alkyl, hydroxy, halo, (ClI2)ipheny1, O(CH2)iphenyI, NR1 Rfl, NHC(O)OC i4alkyl, C(O)0C1 alkyl, C(O)NR' R' , NHSO2(CH2)1 C)cycloalkyl, NHSO2C alkyl, NHSO2(CH2)o2phenyl or NI lSO2(CH2)2pyridyl, optionally substituted by hydroxy, COH, CO2CLlalkyl or CN, where R1 and Rare as hereinbefore defined. More preferably, Q' is Calkyl, hydroxy, fluoro, chloro, bromo, (ClI)12phenyl, O(CH2)2phenyl, NR' Rn, NI IC(O)OCalkyl, C(O)OC4aIkyl, C(O)NR' R' , N HSO2(CH2)1 2CS.)cycloalkyl, NI ISO2C1 -alkyl, NHSO2(CH2)i2phenyl or NHSO(CH2)i2pyridyl, optionally substituted by hydroxy, C021l, CO2C1ialkyl or CN, where R1 and RL are independently selected from hydrogen, Ci 4alkyI, O(C1 4alkyl), C cycloa1kyl, (CH2) 2phenyl, (CII:)2I-let and (CH2) i heteroaryl, optionally substituted by hydroxy, CialkyI, (C1I:)i2phenyl and CO2H. Examples of suitable Q groups include: methyl, 1propyl, hydroxy, bromo, -NH2, -OCH2phenyl, -CH2CH2phenyl, -CH2CII2CO2H, -CH2CH2CH2OH, -CE-I2CH2CH2CN, CO2CH3 H \7 OH o o z ZI ZI ZI ZI z ZI ZI zI 0

-I oO ZI (1

ZI

ZI ZI

ZI oo a Q O/

ZI

Q -u

I C-) s\ N)

I

ZI

o==< ZI ZI

ZI O/

ZI o o

Q

C oo d

I C,)

4. C) 0 C) Preferably, R is hydrogen, Cl)alkyl, NR R, NO2 or NR (Cll2)íCcycloalkyl, where and R are as hereinbcforc defined. More preferably, R1 is hydrogen, C_1alkyl, NIIR' , NO2 or NI-I(CH2)iCcycloalkyl, where R4 is as hereinbefore defined. Most preferably, R4 is hydrogen, Cjalkyl, NH, NO) or NlI(ClI)Ccycloalkyl. Especially, R is hydrogen, methyl, NI 12, NO2 or Ni I(Cl 12)cyclopropyl.

Preferably, R and R are joined to form a 6-membered ring optionally containing one nitrogen atom and optionally substituted by Cipalkyl, hydroxy or halo. More preferably, R' and are joined to Ibrm a phenyl ring optionally substituted by C1alkyl. Most preferably, R and are joined to form a phenyl ring.

Preferably, R is hydrogen, Ciialkyl, halo or hydroxy. More preferably, RC is hydrogen, CH2alkyl, fluoro, chioro, bromo or hydroxy. Most preferably, R' is methyl, fluoro, chioro or hydroxy.

In another embodiment of the present invention, there is provided the compounds of formula (Ia): R5 R4 II Nh-R1 (Ia) R3'( R2 0 or a pharmaceutically acceptable salt thereof, wherein R1, R2, R, R4 and R are as defined in relation to formula (I).

Preferably, R is Cialky1 or (CII2)R, optionally substituted by Q', where R and Q' are as defined in relation to formula (I). More preferably, R1 is Cialkyl or (CII2)1R, optionally substituted by Q', where R and Q' are as defined in relation to formula (I).

Preferably, R is Ccycloaikyl, optionally bridged by -(CIl2)1-. More preferably, R is C (cycloalky1, where cyclohexyl is optionally bridged by -CII-.

Preferably, Q' is (CII COCR, (CI12)1 C(O)NR(S(O)R or (CI I)( C(O)NRR1, where R and R are as defined in relation to formula (1). More preferably, Q' is (CII2)(ICO2R, CILC(O)NIIS(O)R7 or C(O)NIIR', where R( and R are as defined in relation to formula (I).

Most preferably, Q' is C011, CIlCOiI, COCIl, COCII7CII, CII2COCII2CIL, CTl.CC(O)NIIS(O)CI l Cl 12C(O)NI IS(O) Cl I phenyl or C(O)NIl(CII)).

Prcferably, R2 is hydrogen, alkyl, halo or hydroxy. More preferably, R2 is hydrogen, C 2alkyl, fluoro, chloro, bromo or hydroxy. Most preferably, R2 is methyl, fluoro, chloro or hydroxy.

Preferably, R is hydrogen, C14alkyl, halo or hydroxy. More preferably, R is hydrogen, methyl, fluoro, chloro or hydroxy.

Preferably, R2 and R arc joined to form a phenyl ring or a 5-membcrcd ring containing one nitrogen atom, which ring is optionally substituted by Q, where Q' is as defined in relation to formula (I).

Preferably, Q' is Cialkyl, hydroxy, (Cll2)phenyl or O(CI l2)n:phenyl, optionally substituted by hydroxy, COl!, CO'Cialkyl or CN. More preferably, Q' is C]Aalkyl, hydroxy, (CH2)iphenyl or OCH2phenyl, optionally substituted by hydroxy, CO2H, CO2CH; or CN.

Preferably, R is hydrogen, CI)alkyl, NO2 or NR(CH2)nCcycloalkyl, where and R' are defined in relation to formula (I). More preferably, R1 is hydrogen, Cjialkyl, NI-IR' , NO2 or Nll(CH)i2C;cycloalkyl, where R' is as hereinbefore defined. Most preferably, R4 is hydrogen, C1:alkyl, NH, NO or NlI(CH)C;(cycloalkyl. Especially, R4 is Nil2, NO2 or NH(Cl12)cyclopropyl.

Preferably, R and R4 are joined to form a 6-mcmbered ring optionally containing one nitrogen atom and optionally substituted by Ci4alkyl, hydroxy or halo. More preferably, R and are joined to form a phenyl ring optionally substituted by Ciialkyl. Most preferably, R and R4 are joined to form a pheriyl ring.

Preferably, R is hydrogen, Cialkyl, halo or hydroxy. More preferably, R is hydrogen, C2alkyl, fluoro, chloro, bromo or hydroxy. Most preferably, R is methyl, fluoro, chloro or hydroxy.

In another embodiment of the present invention, there is provided the compound of formula (Ib): R3_<JN_R1 ([b) R2 0 or a pharmaceutically acceptable salt thereof, wherein R, R2, R and R4 are as defined in relation to formula (I).

Preferably, R is C..a1kyl, C2alkenyl or Calkynyl, optionally substituted by Q1, where Q' is as defined in relation to formula (1). More preferably, R' is CI(alkyl, optionally substituted by halo, hydroxy, Calkyl, Cialkoxy or (Cil7)COR, where R' is as defined in relation to formula (I). Most preferably, R' is Cl)a1kyl, optionally substituted by (CH2)0..CO2Il. Examples of suitable R' groups include butyl, butyl, CO2H and Preferably, R' and R arc joined to form a 6-membered ring optionally containing one nitrogen atom and optionally substituted by Q, where Q is as defined in relation to formula (I).

More preferably, R and R are joined to form a phenyl ring optionally substituted by halo, hydroxy or C1 alkyl. Especially, R and W are joined to form an unsubstituted phenyl ring.

Preferably, R' is hydrogen or C]alkyl. More preferably, R1 is Cjalkyl. Most preferably, R1 is Ci4alkyl. Especially, R4 is methyl.

In another embodiment of the present invention, there is provided the compound of formula (Ic): R4 II N-R1 (Ic) R3'( R2 0 or a pharmaceutically acceptable salt thereof, wherein R1, R, R' and R4 are as defined in relation to formula (1).

Preferably, R1 is Cl.(alkyl, C2(,alkenyl or (CH2)0R, optionally substituted by Q' and Q, where R, Q' and Q are as defined in relation to formula (I). More preferably, R' is C1alkyl, Calkenyl or (Cl1)1R', optionally substituted by Q' and Q, where R, Q' and Q are as defined in relation to formula (I).

Preferably, R' is C cycloalkyl, liet, phenyl or heteroaryl, where cyclohexyl is optionally bridgedby**CH2-.

Preferably, Q' is CI.)alkyl, halo, hydroxy, (CH2)o1CO2R, (Cll2)4iC(O)NRR7 or oxo, where R' and R are as defined in relation to formula (I). More preferably, Q' is Ci4alkyl, halo, hydroxy, (CH2)) i C021-I, (CII 2)o1 CO2C] alkyl, (CH2)1 CO2(CH2)2phenyl, (Cl l:)o i C(O)N 11 R7 or oxo, where R is as defined in relation to formula (I). Most preferably, Q' is CLlalkyI, fluoro, chioro, bromo, hydroxy, (CH2) COH, (CH2) CO2C1 2alkyl, CO2CI l2phenyl, (CI-l)o C(O)NH(CH2)o2phenyl or oxo, where (CH2)oiC(O)NH(CFl2)2phenyl is optionally substituted by I to 3 halogen atoms.

Preferably, Q is halo, hydroxy, CialkyI or (CH2)CO2R, where is as defined in relation to formula (I). More preferably, Q' is halo, C021- l or CO2Ci4alkyl. Most preferably, Q is chloro, bromo or CO2H.

Preferably, R and R are joined to form a phenyl ring, optionally substituted by Q', where Q is as defined in relation to formula (1).

Preferably, Q is CI(,alkyl, hydroxy, halo, NR' R' or NR' C(O)CJ.alkyl, where R'' and R' are defined in relation to formula (I). More preferably, Q is CialkyI, halo, NHR' or NHC(O)OCialkyl, where R is as defined in relation to formula (1). Most preferably, Q is halo or NHR'2, where R' is as defined in relation to formula (I). Especially, Q is fluoro, chloro, bromo, NllR.

Preferably, R' is C (,alkyl, (Cl l2)( cycloalkyl or (Cl l) I let, optionally substituted by hydroxy, Cj.ia1kyl or (C112)uAphenyl. More preferably, R' is Cialkyl, Ccycloalkyl or (C112)o2pyridinyl or (Cl I)pyrrolidinyI, optionally substituted by hydroxy, methyl or CH:phenyl.

Preferably, R is hydrogen, CI)alkyl or C:,a1kenyl. More preferably, R is hydrogen or Calkyl. Most preferably, R4 is Calkyl. Especially, R4 is methyl.

In another embodiment of the present invention, there is provided the compound of formula (Id): R4 0 1L4 R-( N_R1 (Id) or a pharmaceutically acceptable salt thereof, wherein R', R2, R and R are as defined in relation to formula (I).

Preferably, R' is Cialkyl or (Cl-I)R', optionally substituted by Q', where R' and Q' arc as defined in relation to formula (I). More preferably, R is Ci ialkyl, optionally substituted by Q', where Q' is as defined in relation to formula (1). Most preferably, R' is butyl, optionally substituted by Q', where Q is as defined in relation to formula (I).

Preferably, Q1 is Cja1kyl or (CH2)oCO2R, where R is as defined in relation to formula (I). More preferably, Q' is Ci a&yl or (CH2)01 CO2R, where is as defined in relation to formula (I). Most preferably, Q' is (Cl-l2)41CO2H, (Cft).iCO:Ciialky1 or (C1-12), CO2(Cft)phcnyl. Especially, Q' is (CH2)1CO2H, CO2CH or (CH2)oiCO2CH2phenyl.

Preferably, R is hydrogen or Ci alkyl. More preferably, R is hydrogen or C1 4alkyl.

Most preferably, R2 is Ci 2aIkyl. Especially, R2 is methyl.

Preferably, R' is hydrogen, C1 alky1 or C(O)Ci alkyl. More preferably, R is C1 aIkyl or C(0)C.4alkyl. Most preferably, R is C1 alkyl or C(0)C1 2alkyl. Especially, R is C(O)CT-1.

Preferably, R2 and R' arc joined to form a phenyl ring, optionally substituted by Q, where Q is as defined in relation to formula (I).

Preferably, Q' is Cialkyl, hydroxy, halo, NR' R'2, NR' C(O)OCI(,alkyl, C(O)OC.

(alkyl, C(O)NR' Rn, NR' S(O)(C1i)()C;cycloalkyl or NR' S(O)2Cj.alkyl, where R1' and R1 are as defined in relation to formula (I). More preferably, Q' is halo, NR1 Rn, NHC(O)0C1 alkyl, C(O)OC.allcy1, C(O) N R R' 2, NHS(O)(CH2)(:C(cycloalkyl or N1-IS(O)2C1 a1kyl, where R' and 2 arc as defined in relation to formula (I). Most preferably, Q" is fluoro, chloro, bromo, NR' R' , NI lC(O)OC2alkyl, C(O)OC4alkyl, C(O)NR' R, NI IS(O)2(Cl l2)iC4 (cycloalkyl orNI1S(O)2Calkyl, where R' and R' are as defined in relation to formula (I).

Preferably, R1' and RI? are independently selected from hydrogen, C2calkyl, CL (cycloalkyl, (CI l2)(2phenyl, (CI I I let and (Cl l:)(heteroaryl, optionally substituted by hydroxy, C1.ialkyl, (CII)o iphenyl and CO-il; or R'' and R, together with the nitrogen atom to which they are joined, form a 6-membered ring, optionally containing one oxygen atom or one further nitrogen atom, and optionally substituted by C;alkyl or (Cl I;)2benzodioxolanyl. -I.

Preferably, R is hydrogen or Calkyl. More preferably, R is hydrogen or Calkyl.

Most preferably, R' is hydrogen or Ci2alkyl. Ispecially, R' is hydrogen or methyl.

When any variable occurs more than one time in formula (I) or in any substituent, its definition on each occurrence is independent of its delinition at every other occurrence.

As used herein, the term "alkyl" or "alkoxy" as a group or part of a group means that the group is straight or branched. Examples of suitable alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl and t-butyl. Examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy and t-butoxy.

The cycloalkyl groups referred to herein may represent, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

As used herein, the term "alkenyl" and "alkynyl" as a group or part of a group means that the group is straight or branched. Examples of suitable alkenyl groups include vinyl and allyl.

Suitable alkynyl groups are ethynyl and propargyl.

When used herein, the term "halogen" or "halo" as a group or part of a group means fluorine, chlorine, bromine and iodine.

When used herein, the term "aryl" as a group or part of a group means a carbocyclic aromatic ring. Examples of suitable aryl groups include phenyl and naphthyl.

When used herein, the term "heteroaryl" as a group or part of a group means a 5-to 10-membered heteroaromatic ring system containing I to 4 heteroatoms selected from N, 0 and S. Particular examples of such groups include pyrrolyl, furanyl, thienyl, pyridyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazolyl, oxadiazolyl, thiadiazolyl, triazinyl, tetrazolyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, benzofuranyl, benzothiazolyl, benzoxazolyl and quinolinyl.

When used herein, the term "Het" as a group or part of a group means a heteroaliphatic ring of 4 to 7 ring atoms, which ring may contain 1, 2 or 3 heteroatoms selected from N, 0 or S or a group S(O), S(O), NH or NCialkyl.

Where a compound or group is described as "optionally substituted", one or more substituents may be present. Optional substituents may be attached to the compounds or groups which they substitute in a variety of ways, either directly or through a connecting group of which the following are examples: amine, amide, ester, ether, thioether, sulfonamide, sulfamide, sulfoxide, urea, thiourea, urethane, acylsullonamide and acylsulfamide. As appropriate an -12 -optional substituent may itself be substituted by another substituent, the laffer being connected directly to the former or through a connecting group such as those exemplified above.

Specific compounds within the scope of this invention include the compounds named in the Examples and Tables below, and their pharmaceutically acceptable salts.

For use in medicine, the salts of the compounds of formula (I) will be non-toxic pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds according to the invention or of their non-toxic pharmaceutically acceptable salts.

Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, flimaric acid, p-toluencsulfonic acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid or sulfuric acid. Salts of amine groups may also comprise quatemary ammonium salts in which the amino nitrogen atom carries a suitable organic group such as an alkyl, alkenyl, alkynyl or aralkyl moiety. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include metal salts such as alkali metal salts, e.g. sodium or potassium salts; and alkaline earth metal salts, e.g. calcium or magnesium salts.

The salts may be formed by conventional means, such as by reacting the free base form of the product with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is removed in "aciio or by freeze drying or by exchanging the anions of an existing salt for another anion on a suitable ion exchange resin.

The present invention includes within its scope prodrugs of the compounds of formula (I) above. In general, such prodrugs will be functional derivatives of the compounds of formula (I) which are readily convertible in i/vu into the required compound of formula (t). Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. II. Bundgaard, Elsevier, 1985.

A prodrug may be a pharmacologically inactive derivative of a biologically active substance (the "parent drug" or "parent molecule") that requires transformation within the body in order to release the active drug, and that has improved delivery properties over the parent drug molecule. The transformation in i'ivo may be, for example, as the result of some metabolic process, such as chemical or enzymatic hydrolysis of a carboxylic, phosphoric or sulfate ester, or reduction or oxidation of a susceptible functionality.

The present invention includes within its scope solvates of the compounds of formula (I) and salts thereof, for example, hydrates.

The present invention also includes within its scope any enantiomers, diastereomers, geometric isomers and tautomers of the compounds of formula (I). It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the invention.

-13 -In another aspect of the invention, there is provided a pharmaceutical composition comprising a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier. The composition may be in any suitable form, depending on the intended method of administration. It may for example be in the form of a tablet, capsule or liquid for oral administration, or of a solution or suspension for administration parenterally. The composition may be prepared by admixing at least one active ingredient, or a pharmaceutically acceptable salt thereof, with one or more pharmaceutically acceptable adjuvants, diluents or carriers and/or with one or more other therapeutically or prophylactically active agents.

A further aspect of the invention provides a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof for use in therapy.

In another aspect of the invention, there is provided a method of inhibiting hepatitis C virus polymerase and/or of treating or preventing an illness due to hepatitis C virus, the method involving administering to a human or animal (preferably mammalian) subject suffering from the condition a therapeutically or prophylactically effective amount of the pharmaceutical composition described below or of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof. "Effective amount" means an amount sufficient to cause a benefit to the subject or at least to cause a change in the subject's condition.

A further aspect of the invention provides the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of infection by hepatitis C virus.

In a further embodiment of the present invention, there is provided the use of a compound of formula (I), as defined above, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of infection by hepatitis C virus, in combination with one or more other agents for the treatment of viral infections such as an antiviral agent, andlor an immunomodulatory agent such as a-, J3-. or y-interferon, particularly a-interferon. Suitable antiviral agents include ribavirin and inhibitors of hepatitis C virus (IICV) polymerase, such as inhibitors of metalloprotease (NS2-3), serine protcase (NS3), helicase (NS3) and RNA-dependent RNA polymerase (NS5B).

The dosage rate at which the compound is administered will depend on a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age of the patient, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition and the host undergoing therapy. For the treatment or prevention of infection by hepatitis C virus, suitable dosage levels may be of the order of 0.02 to 5 or 10 g per day, with oral dosages two to five times higher. For instance, administration of from 10 to 50 mg of the compound per kg of body weight from one to three times per day may be in order.

Appropriate values are selectable by routine testing. The compound may be administered alone -14-or in combination with other treatments, either simultaneously or sequentially. For instance, it may be administered in combination with effective amounts of antiviral agents, immunomodulators, anti-infectives or vaccines known to those of ordinary skill in the art. It may be administered by any suitable route, including orally, intravenously, cutaneously and subcutaneously. It may be administered directly to a suitable site or in a manner in which it targets a particular site, such as a certain type of cell. Suitable targeting methods are already known.

Compounds of general formula (1) may be prepared by methods disclosed in the documents hereinbefore referred to and by methods known in the artof organic synthesis as set forth below.

Where a mixture of products is obtained from any of the processes described below for the preparation of compounds according to the invention, the desired product can be separated there from at an appropriate stage by conventional methods such as preparative I IPLC; or column chromatography utilising, for example, silica and/or alumina in conjunction with an appropriate solvent system.

During any of the synthetic sequences set out below it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Piotecti'' Groups in Oranu (77L'in/strl', ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, P/tL'clirc Groups in Oiaiiic S'iitJi'i.s', John Wiley & Sons, 3rd edition, 1999. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.

The following Schemes and Examples illustrate the invention.

The compounds of the invention were tested for inhibitory activity against the HCV RNA dependent RNA polymerase (NS5B) in an enzyme inhibition assay (example i) and a cell based HCV replication assay (example ii). The compounds in the Examples are all active against I ICV polymerase in the enzyme inhibition assay. Several of these compounds have shown activity in the cell based HCV replication assay with activities <50pM, and some with activities <I 0iM.

i) In-vitro HCV NS5B Enzyme Inhibition Assay The HCV-BK eDNA sequence coding for the NS5B protein lacking of the 21 C-terminal residues (residues 1-570) was cloned in the pT7.7 vector downstream of the T7 promoter and in frame with the first ATG of the gene 10 protein of the T7 phage. A C-terminal His Tag was added to simplify purification procedure. Expression in E.coli BL2I(DE3) was performed as described (Tomei ci al., JGV (2000), 81, 759). Bacteria were grown at 37 C in standard LB medium up to an absorbance of 0.8 at 600 nm. The temperature of the culture was then lowered to 18 C and expression induced with 0.4 mM IPTG for further 23 hrs. All the subsequent purification steps were performed at 4 C. Cells were harvested, washed with PBS (20 mM Na-phosphate [pH 7.5], 150 mM NaC1), resuspended in 100 ml of lysis buffer/liter of culture, and disruptcd with a model 11 OS Microfluidizer. Lysis buffer contained 10 mM Tris [pH 8.0], 1 mM EDTA, 0.5 M NaCI, 50% glycerol, 10 mM 3-mercaptoethanol, 0.1 % n-octyl-13-D-glucopyranoside (Inalco; n-OG), Complete' protease inhibitor cocktail (Roche). After addition of 10 mM MgCl, the extract was incubated with 0.5 units/mI of DNasel for 30 mm. The insoluble material was pelictied by centrifugation for 60 mm at 15,000 rpm in a Sorvall SS34 rotor. The clarified supernatant was incubated batchwisc for 45 mm with 50 mI/liter of culture of DEAE-Sepharose FF resin equilibrated in lysis buffer lacking glycerol. The flow-through from the I)EAE-Sepharose was diluted to 0.3 M NaCI and loaded on a Ni-NTA Superfiow column (Qiagen; 3 mI/liter of culture) equilibrated with A buffer + 10 mM Imidazole (A buffer: 10mM Tris [pH 8.0], 20% glycerol, 0.3 M NaCI, 0.1% n-OG, 10mM 3-mercaptoethanol) and eluted with a 50 to 500 mM imidazole gradient in A buffer. Peak fraction were collected, dialysed vs D buffer (10mM llepes [pH 8.0], 20% glycerol, 0.2% n-OG, 1 mM EDTA, 5 mM DTT) containing 0.15 M NaCI and loaded on HiTrap I tepariri column (Amersham) equilibrated with D buffer and eluted with a 0.15 to 0.8M NaCI gradient in D buffer. The protein was stored in aliquots in liquid nitrogen.

The purified enzyme was shown to possess in ritro RNA polymerase activity using RNA as template according to a description in Journal of General Virology 81:759-767 (2000). The reference describes a polymerisation assay using poly(A) and oligo(U) as a template/primer.

Incorporation of tritiated UTP is quantified by measuring acid-insoluble radioactivity. The present inventors have employed this assay to screen the various compounds described above as inhibitors of HCV RdRp.

Incorporation of radioactive UMP was measured as follows. The standard reaction (50 jil) was carried out in a buffer containing 20 mM Tris/HCJ pH 7.5, 5 mM MgCl2, 1 mM DTT, 10 mM NaCI, 0.0 1% Triton X-l0O, 1 pCi [H]-LJTP (40 Ci/mmol, NEN), 10 tM UTP and 10 j.ig/ml poly(A) /Oligo(U)12 (I ig/ml, Genset) as a template/primer. The final NS5B C2l enzyme concentration was 5 nM. The order of assembly was: I) compound, 2) enzyme, 3) template/primer, 4) NTP. After I h. incubation at 22 C the reaction was stopped by adding 50 tl of 20% TCA and applying samples to DE8I filters. The filters were washed thoroughly with 5% TCA containing I M Na21-1P04/NaHPO4, pH 7.0, rinsed with water and then ethanol, air dried, and the filter-bound radioactivity was measured in the scintillation counter. Carrying out this reaction in the presence of various concentrations of each compound set out above allowed determination of 1C values by utilising the formula: % Residual activity = l00/(l+[l]/lC.s))" where [I] is the inhibitor concentration and "s" is the slope of the inhibition curve.

(ii) Cell based DCV Replication Assay Ccli clones that stably maintain subgenomic IICV replicon were obtained by transfecting lIuh-7 cells with an RNA replicon identical to I77neo/NS3-3'/wt described by Lohmann c/al.

(1999) (EMBL-genbank No. AJ242652), followed by selection with neomycin sulfate (G4l8).

Viral replication was monitored by measuring the expression of the NS3 protein by an ELISA assay performed directly on cells grown in 96 wells microliter plates (Cell-ELISA) using the anti-NS3 monoclonal antibody 10E5/24 (as described in published International patent application WO 02/59321). Cells were seeded into 96 well plates at a density of 10' cells per well in a final volume of 0.1 ml of DMEM/lO% FCS. Two hours after plating, 50 Ill of l)MEM/l0% FCS containing a 3x concentration of inhibitor were added, cells were incubated for 96 hours and then fixed for 10' with ice-cold isopropanol. Each condition was tested in duplicate and average absorbance values were used for calculations. The cells were washed twice with PBS, blocked with 5% non-fat dry milk in PBS + 0.1% Triton X100 + 0.02% SDS (PBSTS) and then incubated o/n at 4U C with the I 0E5/24 mab diluted in Milk/PRSTS. After 1 5 washing 5 times with PI3STS, the cells were incubated for 3 hours at room temperature with Fe specific anti-mouse igG conjugated to alkaline phosphatase (Sigma), diluted in MiIkJPBSTS.

After washing again as above, the reaction was developed with p-nitrophenyl phosphate disodium substrate (Sigma) and the absorbance at 405/620 nm read at intervals. For calculations, we used data sets where samples incubated without inhibitors had absorbance values comprised between I and 1.5. The inhibitor concentration that reduced by 50% the expression of NS3 (IC)) was calculated by fitting the data to the Hill equation, Fraction inhibition = l-(Ai-b)/(A()-b) = [J]fl / ([J]11 + ICc0) where: -Al = absorbance value of HBI 10 cells supplemented with the indicated inhibitor concentration.

-A(J = absorbance value of HBE1O cells incubated without inhibitor.

-b absorbancc value of Huh-7 cells plated at the same density in the same microtiter plates and incubated without inhibitor.

-n = lull coefficient.

iii) General Procedures All solvents were obtained from commercial sources (Fluka, puriss.) and were used without further purification. With the exception of routine deprotection and coupling steps, reactions were carried out under an atmosphere of nitrogen in oven dried (110 C) glassware.

Organic extracts were dried over sodium sulfate, and were concentrated (after filtration of the drying agent) on rotary evaporators operating under reduced pressure. Flash chromatography was carried out on silica gel following published procedure (W.C. Still el a!., J. Org. Chem. 1978, 43, 2923) or on semi-automated flash chromatography systems utilising pre-packed columns.

Reagents were usually obtained directly from commercial suppliers (and used as supplied) but a limited number of compounds from in-house corporate collections were utilised.

In the latter case the reagents are readily accessible using routine synthetic steps that arc either reported in the scientific literature or are known to those skilled in the art.

H nmr spectra were recorded on Bruker AM series spectrometers operating at (reported) frequencies between 300 and 600 MI Iz. Chemical shifts () for signals corresponding to non-exchangeable protons (and exchangeable protons where visible) are recorded in parts per million (ppm) relative to tetramethylsilane and are measured using the residual solvent peak as reference. Signals are tabulated in the order: multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad, and combinations thereof); coupling constant(s) in hertz; number of protons. Mass spectral (MS) data were obtained on a Perkin Elmer API 100, or Waters Micromass ZQ, operating in negative (ES) or positive (ES) ionization mode and results are reported as the ratio of mass over charge (m/ ). Preparative scale HPLC separations were carried out on: I) Automated (mass-triggered) RP-HPLC Waters Micromass system, incorporating a 2525 pump module, a Micromass ZMD detector, and a 2767 collection module, operating under Fraction Lynx software. The mobile phase comprised a linear gradient of binary mixture of MeCN (containing 0.1% TFA) and water (containing 0.1% TEA). The flow rate was 20 mI/mm, -the stationary phase was Simmetry C, column (7 Jim, 19 x 300 mm); 2) Shimadzu LC-8A separation module, equipped with a Shimadzu SPDC-I OAV absorption detector. In all cases the mobile phase comprised a linear gradient of binary mixture of MeCN (containing 0.1 % TFA) and water (containing 0.1 % TFA), using flow rates between 15 and 25 mL/min.

The following abbreviations are used in the Schemes and Examples: AcOH: acetic acid; BINAP: 2,2 -bis(diphcnylphosphino)-1,1 -binaphthyl; I)BU: I,8-Diarabicyclo[5.4.0]undec-7-ene; DIPEA: diisopropylethyl amine; DMF: dimethylformamide; DMSO: dimethylsulfoxide; eq.: equivalent(s); Et20: diethyl ether; EtOAc: ethyl acetate; EtOH: ethanol; h: hour(s); HATU: O-(7-azabenzotriazol-I -yl)-N, N, N,N -tetramcthyluronium hexafluorophosphate; M: molar; MeCN: acetonitrile; Mel: iodomethane; MeOH: methanol; mm: minutes; NMP: I -methyl-2-pyrrolidinone; Pd(dba) : tris(dibenzylidencacetone)dipalladium; PE: petroleum ether; RP-HPLC: reversed phase high-pressure liquid chromatography; RT: room temperature; TEA: triethylamine; TEA: trifluoroacetic acid; THF: tetrahydrofuran.

Scheme 1 describes the synthesis of 2-(4,7-Dichloro-1,3-dioxo-l,3-dihydro-21J-isojndol-2-yl)pcntanoic acid (Entry 8, Table A) and related compounds 1-3. -18-

Imides 1-3 were obtained either by treatment of anhydrides 1-2 with the required amines under microwave irradiation, or by the above step followed by a thionyl chloride-promoted cyclisation.

Anhydrides 1-2 were in turn either commercially available or derived from dicarboxylic acids 1-I iiu trif'luoroacetic anhydride promoted dehydration. The required dicarboxylic acids 1-1 were commercially available unless otherwise stated. 4,7-E)imethylphthalic anhydride, required for the preparation of 2-(4,7-dimethyl-l,3-dioxo-I,3-dihydro-211-isoindol-2-yl)peritanoic acid (Entry 31, Table A), was prepared according to the literature procedure by Chan, T. c/a! I k'i,ulu'ilron, 1986, 42, 655.

O 0 R'-NH2, MW irradiation o --ROH TF -R or,--R ii I 0 ii N-R" -R iI OH R R' O o i) R -NH9, MW irradiation ii) SOCI2 1-2 1-3 Scheme I Compounds of general structure 1-3 can also be further functionalised by means of standard functional group manipulations to give amides 1-4, as depicted in Scheme la.

-RTJ<, RNH2, EDCI HCI, HOBI R_J_<)N_R \_\ R= Alk, AIkSO2 -R \_\ Scheme la Example 1 (Entry 8, Table A) 2-(4,7-Dichloro-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)pcntanoic acid 4,7-Dichlorophthalic anhydridc and norvalinc were dissolved in absolute EtOll, placed in a scaled tube and heated in a microwave oven at 150 C for 1 h. The mixture was cooled to RT and the solvent was evaporated under reduced pressure. The residue was purified by preparative FIPLC, cluting with MeCN/water containing 0. 1%TFA to give the title compound as a powder in 61% yield. ill NMR (300 MHz, DMSO-d(,, 300 K) ö 13.2 (bs, 111), 7.89 (s, 2H), 4.74 (dd, J 6.4, 111), 2.0 (m, 21-1), 1.3 (m, 211), 0.86 (t, J 7.3, 31-1); MS (ES) C1;lIi C12N04 requires 316, found: 314, 316 (M-l).

Example IA (Entry 37, Table A) 3-(1,3-Dioxo-1,3-dihydro-21-I-bcnzolel isoindol-2-yl)-IN-(ethylsulfonyl)hexanamidc Step I: 3-(l,3-Dioxo-1,3-dihydro-211-bcnzo[e]jsojndol-2-yI)-N-hexanojc acid The title compound was described as reported for Example 1, starting from naphtha[ I,2-c]furan-I,3-dione instead of 4,7-dichlorophthalic anhydride and from f3-norvaline instead of norvaline.

MS(ES) C1H17NO4 requires: 311, found: 312 (M+li).

Step 2: 3-( I,3-Dioxo-I,3-dihydro-21 1-benzofelisoindol-2-yl)-N-(ethylsulfonyl) hexanamide To a stirred solution of acid from Step I in DMF was added DMAP (1.8 eq), ethylsulfonamide (1.2 cq) and EDCI.1lCl (1.8 cq) and the reaction mixture was stirred at RT overnight. The mixture was then diluted with ltOAc, washed with I N aq. HCI, brine, dried (NaSO4) and the 1 0 volatiles were removed under reduced pressure. The residue was purified by preparative!-IPLC, eluting with MeCN/water containing 0.1 %TFA to give the title compound as a powder in 48% yield. II NMR (400 MHz, DMSO-d, 300K) 11.75 (s, 1H), 8.80 (d, J 7.8, III), 8.41 (d, J 8.1, 111,), 8.18 (d, J 8.3, 111), 7.89 (d, J 8.4, III), 7.84 (ddd, J 1.0, 6.8, 8.1, III), 7.77 (ddd, J 1.2, 6.8, 8.3, 111), 4.59 (m, IH), 3.24 (d, J 7.6, 1 H), 3.21 (d, J 7.3, IH), 3.08 (dd, J 8.8, 15.9, IH), 2.90 (dd, J 5.5, 15.9, 1 H), 1.98 (m, 111), 1.61 (m, I H), 1.26 (m, 211), 1.09 (t, J 7.3, 3H), 0.87 (t, J 7.3, 31-1). MS (ES) C2oH27NO,S requires 402, found: 403 (M+1).

Example 2 (Entry I, Table B) 2-Butyl-4-methylpyrrolo(3,4-b)-indolc-1,3(211, 411)-dione To a solution of I -methyl-indole-2,3-dicarboxylic acid (Guven, A., Jones, R. A., ictrahedron, 1993, 49, 11145) in DCM was added TFAA (3 eq.). The reaction mixture was stirred for 3 hat RT, the volatiles were removed under reduced pressure and the pale yellow solid residue was triturated with Et20 and collected by filtration. The solid anhydride was then dissolved in butylamine, placed in a sealed tube and heated in a microwave oven at 150 C for 30 mm. The mixture was cooled to RT and the volatiles were removed under reduced pressure. The residue was dissolved in thionyl chloride and heated for 30 mm. Volatiles were then removed under reduced pressure to give the title compound. H NMR (400 MHz, I)MSO, 300 K) 7.77 (m, 211), 7.47 (t, J 7.3, 1H), 7.39 (t, J 7.4, IH), 4.02 (s, 3H), 3.52 (t, J 6.9, 2H), 1.59 (m, 211), 1.34 (m. 2H), 0.94 (t, J 7.3, 311); MS (ES') CIc1l](NO2requires 256, found: 257 (M+Hi.

Scheme 2 and Scheme 2a describe the synthesis of 3-[6-(butylamino)-4-methyl-1,3-dioxo-1,3-dihydro-2 II -pyrrolo[3,4-c]-quino lin-2-yljhexanoic acid (Entry 35, Table C) and related compounds 2-1 and 2-5.

Imides 2-1 can be obtained by further functionalisation of compounds of general formula 1-3 (see Scheme I) as reported in Scheme 2.

-20 -o o - R'NH2, Pd2(dba)3 --II N-R II N-R" > .2---i BINAP, Cs2CO > Br R \\ R"NH R o 0 1-3 2-1 Scheme 2 In particular, functionalised quinolines 2-5 can be prepared as described in Scheme 2a, whereby protection of carboxylic acid 2-2 as a Butyl ester is followed by Buchwald aminat ion to 2-4 and acid mediated ester hydrolysis to 2-5.

0Bu CO2tBu o N N R"NH2, Pd2(dba)3 BINAP. Cs2003 Br 2-2 CO Bu Br 2-3 CO2H TFNDCM/H20 R'NH 2-4 R NH 2-5 Scheme 2a Example 3 (Entry 35, Table C) 3-[6-(Butylamino)-4-methyl-1,3-dioxo-1,3-dihydro-2H-pyrrolo 13,4-cl -q u inolin-2-yljhcxanoic acid Step 1: 3-(6-Bromo-4-methyl-1,3-dioxo-1,3-dihydro-2//-pyrrolo[3,4-jguinolin-2-yl) hexanojc acid The title compound was prepared from 8-bromo-2-methylquinoline-3,4-dicarboxylic acid (Lyles, M. B.; Cameron, I. L.; Rawis, H. R., .Jot,rnuil!ticduinal (heinis'ir' 2001, 4649; Brown, R. F. C.; Coulston, K. J.; Eastwood, F. W.; Moffat, M. R., h'ira/wdro;i 1992, 7763) and 13-norvaline, according to the procedure described for Example 1. MS (ES) Ci li 7BrN2O requires 405, found: 405, 407 (M+H').

Step 2: rcii-Butyl 3-(6-bromo-4-methyl-1,3-dioxo-1,3-dihydro-2//-pyrrolo[3,4-clgujnoljn-2-yI) hcxanoate To a 0.04 M solution of acid from Step 1 in CH2C12 was added tcii-butyl N,V-diisopropylimidocarbamate (6 eq.). The mixture was stirred overnight at 45 C, cooled to RT, filtered and concentrated under reduced pressure. The residue was purified on a silica gel column (eluent: PE/EtOAc 12/I) to recover the title compound as a pale yellow oil (73%). MS (ES) C:H2cBrNOl requires 461, found: 461, 463 (M+Hi.

Step 3: tii-Butyl 3-[6-(butylamino)-4-methyl-1,3-dioxo-I,3-dihydro-2//-pyrrolol3, 4-clquinoliri- 2-yll hexanoate To 0.05 M solution of arylbromide from Step 2 in toluene were added BINAP (0.15 eq), Pd7(dba) (0.1 eq), butylamine (2 eq) and caesium carbonate (1.4 eq). The mixture was degassed under a stream of Argon for 5 mm and stirred at 80 C overnight. The orange mixture was cooled to RT, diluted with EtOAc, washed with water and brine, dried (NaSO), filtered and concentrated under reduced pressure. The residue was used in the next step without any further purification. MS (ES) CHN'O4 requires 453, found: 454 (M+1-J).

Step 4: 3-[6-(Butylamino)-4-methyl-l,3-dioxo-I,3-dihydro-2//-pyrrolo[3, 4-clguinolin-2-ylihexanoic acid.

A 0.025 M solution of arylamine from Step 3 in a mixture of trifluoroacetic acidJCll2Cb/water (30/65/5) was stirred at RT for I h. Volatiles were removed under reduced pressure and the residue was purified by preparative RP-HPLC eluting with MeCN/water containing 0.1% TFA to give the title compound as a purple solid (47 %). H NMR (DMSO-d(, 400 Ml lz, 300 K.) 7.76 (d, J 7.7, Ill), 7.55 (t, J 8.0, 111), 6.82 (d, J 7.5, 111), 4.57-4.59 (m, III), 3.3 (t, J 7.1, 211), 3.00 (dd, J 16.1, 8.4, 111), 2. 91 (s, 311), 2.80 (dd, J 16.2, 6.4, 111), 2.01-1.91 (m, Ill), 1.70-1.61 (m, 311), 1.42 (q, J 7.5, 211), 1.33-1.18 (m, 211), 0.95 (t, J 7.34, 311), 0.86 (t, J 7.34, 311). MS (ES) C221l7NO4 requires 397, found: 398 (M+li).

Scheme 3 describes the general synthetic route for of 2-16-(2-carboxycthyl)-1,3-dioxo-6-(2-phenetyl)-3,6-dihydropyrrolol3, 4-clindol-2(IH)-yllpentanoic acid (Entry 51, Table A) and related compounds 3-1.

R'Br. K2003 LL,NH 0 16-Crown-6 0 1 activated charcoal RBr, K2C03

-L ____ I NH -H NH I H N-R

or Mn02, then HE 16-Crown-6 --. -RBr, K2003 --0 --0 16-Crown-6 3-1 Scheme 3 In particular, functionalised pyrrolo[3,4-c]indole-1,3(211,611)-diones can be prepared as described in Scheme 3a for 2-16-(2-carboxyethyL)-1,3-dioxo-6-(2-phenctyl)-3,6-dihydropyrrolol3, 4-elindol-2(1 H)-yllpentanoic acid 3-8 (Entry 51, Table A).

-22 -Boc NH 0 BocN CO2Bn 3-2 0 K2C03, 18-crown-6 Activated Charcoal HN BrO MeO2CN MeO2CN Me3SnOH HO2CN Scheme 3a Example 4 (Entry 51. Table A) 2-16-(2-carboxyethyl)-1,3-dioxo-6-(2-phenetyl)-3,6- dihydropyrrolo 13,4-elindol-2(1 H)-ylipentanoic acid Step 1: tert-Butyl 1,3-dioxo-2,3,3a,4,5,8b-hexahydropyrroIof3,4-c indole-6( I /f)carboxylate A 0.1 M solution of icrI-butyl 2-vinyl-lI/-pyrrole-1-carboxylate (3-2, Scheme 3a; prepared according to the procedure described in Tietze, L. F.; Kettschau, G.; Heitmann, K., Si'iitIu'sis, 1996, 851) and 1I/-pyrrole-2,5-dione (1 eq) was stirred overnight at RT. The mixture was then concentrated under reduced pressure to give an oily residue. The latter was triturated with a Ill v/v mixture of CH2CI2/EtOAc to obtain the title compound as a yellow solid (77%). MS (E5) C,cHNO,requires: 290, found: 291(M+H).

Step 2: Benzyl-2-bromopentanoate To a 0.16 M solution of 2-bromopentanoic acid in l,2-dichloroethane were added benzyl alcohol (3 eq.), N,N'-dicyclohexylcarbodiimide (1 eq) and 4-dimethylaminopyridine (catalytic amount).

The mixture was stirred overnight at -78 C, and then it was allowed to reach RT, diluted with CHCI2, washed with ss NaHCO; and brine. The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified on a silica gel column (eluent: PE/EtOAc 12/2) to give the title compound as colorless oil (83%). H NMR (I)MSO-d(, -23 - 400 MHz, 300 K) 7.42-7.32 (m, 511), 5.20 (dd, J 14.5, 12.5, 2H), 4.60 (dd, J 7.8, 6.7, IH), 2.03- 1.95 (m, III), 1.92-1.83 (m, I H); 1.46-1.22 (m, 211), 0.88 (t, J 7.5, 3H).

Step 3: F3enzyl 2-( I,3-dioxo-3,6-dihydropyrrolo[3,4-]indo1-2( I IJ)-yI)pentanoate To a 0.1 M solution of compound from Step I in MeCN was added K2CO (2.14 eq), benzyl-2-bromopentanoate (1.1 eq), I 8-crown-6 (3% w/w) and activated charcoal (14% w/w). The mixture was refluxed overnight, cooled to RT, filtered and concentrated under reduced pressure.

Silica gel chromatography (eluent: PE/EtOAc 8/2) afforded the title compound as a yellow foam (38%). MS (ES) C22H20N204 requires: 376, found: 377 (M+lI').

Step 4: Benzyl 2-[6-(3 -methoxy-3-oxopropyl)-I,3 -dioxo-3,6-dihydropyrrolo[3.4-elindol-2( 1/I)-yl]pentanoate To a 0.03 M solution of compound from Step 3 in DMF at 0 C was added NaH (2 eq). The reaction mixture (which became red upon addition of NaH) was stirred at 0 C for 30 mm before adding 3-bromo methylpropanoate (2 eq). The resulting mixture was allowed to reach RT over a period of I h and quenched by addiction of ss NH CI and extracted with EtOAc. The organic phase was dried over NaSO4, filtered and concentrated under reduced pressure. The residue was purified on a silica gel column (eluent: PE/EtOAc 7/3) to recover the title compound as a yellow oil (65%). MS (ES) C2(H2(N2O( requires: 462, found: 463 (M+HD.

Step 5: 2-[6-(3-Methoxy-3-oxopropyfl-I,3-dioxo-3,6-dihydropyrrolo[3,4-('lindol-2( 1/f)-ylipentanoic acid To a 0.01 M solution of ester from Step 4 in EtOAc was added 10% Pd/C (10% w/w). The mixture was allowed to stir under H2 atmosphere for 2 h. The reaction mixture was then filtered through a pad of celite, concentrated under reduced pressure to obtain a yellow solid which was used in the next step without any further purification (quantitative yield). MS (ES) CJ-l20N2O, requires: 372, found: 373 (M+li).

Step 6: 2-[6-(2-Carboxyethyl)-1,3 -dioxo-3,6-dihydropyrrolo[3,4-clindol-2( 1 //)-yllpentanoic acid To a 0. 01 M solution of carboxylic acid from Step 5 in 1,2-dichioroethane was added trimethyltin hydroxide (10 eq). The mixture was refluxed overnight, cooled to RT and diluted with EtOAc. The organic phase was washed with lICI IN, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by preparative RP-IIPLC eluting with MeCN/water containing 0.1 %TFA to give the title compound as a white solid (31 %). 1-1 NMR (DMSO-d, 400 Mhz, 300 K) l3.01 (bs, lii), 12.40 (bs, lii), 8.00 (d, J 8.6, III), 7.83 (d, J 3.3, Ill), 7.61 (d, J 8.3, III), 6.82 (d, J 3.1, Ill), 4.71 (dd, iii, 4.6, III), 4.53 (t, J 6.7, 211), 2.80 (t, 36.7,211), 2.20-2.10 (m, ill), 2.07-199 (m, III), 1.30-1.21 (m, 211), 0. 87 (t, J 7.2,3 II); MS (ES) CI1lIN2O(rcquires: 358, found: 359 (M+li).

-24 - Scheme 4 describes the synthesis of 3-(9-methyl-I,3-dioxo-11 l-imidazo[ 1,5-a]indol-2(31 I)-yl)hexanoic acid (Entry 9, Table D) and related compounds 4-3. Carboxylic acids 4-1 were either commercially available or prepared according to literature procedures (sec Refs. below).

Carboxylic acids 4-1 were converted to the acylbenzotriazolyl derivatives 4-2 according to the method of Katrisky, A. R.; Singh, S., K.; Bobrov, S., I. Oi C/urn., 2004, 69, 93 13.

Intermediates 4-2 were then reacted with the required isocyanates to give compounds 4-3.

Et32CH3. :Bt R'"-NCO --R' 4-1 --R' 4-2 -43 Scheme 4 Alternatively, compounds 4-3 can also be obtained directly from indole 2-carboxylic acids 4-1 by reaction with the required isothiocyanatcs in the presence of silver trifluoroacetate and tricthylamine (Scheme 4a), according to the procedure reported by Shihuya. 1.: Goto, M. Shimizu, " anagisava. M Gama, Y., IIek'rocvclc's', 1999, 51, 2667.

R R"-NCS R

R NH R N-

r CF3CO2Ag r R 4-1 EtN 43 Scheme 4a Example 5 (Entry 9. Table D) 3-(9-Methyl-1,3-dioxo-1 H-imidazo 11,5-al indol-2(3 H)-yl)hexanoic acid Step 1: 1-1(3-Methyl-i H-indol-2-yl)carbonyll-11-1-1,2,3-bcnzotriazolc 3-Methyl-indole-2-carboxylic acid (prepared according to the procedure described by Liu, R.; Zhang, P.; Gan, T.; Cook, J. M., .1 Org C/win., 1997, 62, 7447), EtN (1 eq.) and 1-methylsulfonyl-1,2,3 -benzotriazolc (1 eq., prepared according to the procedure described by Katrisky, A. R.; Shobana, N.; Pernak, J.; Afridi, A. S.; Fan, W. Q., Tetrahedron, 1992, 37, 7817) were dissolved in THF and the resulting mixture was stirred at 75 C for 12 h. The mixture was allowed to cool to RT, the volatiles were removed under reduced pressure and the residue was taken up in CHCJ and washed with brine. The organic phase was dried (Na2 SO) and -25 -concentrated under reduced pressure. The residue was triturated with 1/1 v/v Et20/hexanc mixture to give the title compound as a yellow solid (41%). MS (ES) C1H12N Orequires: 276, found: 277 (M+H).

Step 2: Benzyl 3-isocyanatohexanoate To a mixture of benzyl 3-aminohexanoate p-toluenesulphonate (prepared from (+/-)-3-norvaline and benzyl alcohol according to the procedure described by Chakravarty, P.K.; Carl, P.L.; Weber, M.J.; Katzcnellcnbogen, J.A., I i'J (7u'ni 1983, 26, 638) and pyridine (4 eq) in CII2CI2 at 0 C was added dropwise phosgene (20% solution in toluene, ca 1.9 M, 1.3 eq). The resulting mixture was stirred at 0 C for 2 h, diluted with CII2CI2 and the organic phase was washed with cold aq. 0.5 N 1-ICI, cold brine, dried (Na:S04) and concentrated under reduced pressure without heating. The title compound was obtained as a viscous yellow oil and was used without further purification in the next step.

1 5 Step 3: Benzyl 3-(9-methyl-I,3-dioxo-11 1-imidazo[ I,5-alindol-2(3 I 1)-yl)hexanoatc A mixture of compound from Step I, isocyanate from Step 2 (3.3 eu) and DBU (6.0 eq) in THF was stirred at 70 C for 12 h. The reaction mixture was allowed to cool to RT, the volatiles were then removed under reduced pressure and the residue was purified by Si02 gel chromatography (eluent: PE /EtOAc 95/5) and preparative RP-l-IPLC eluting with MeCN/water containing 0.1%TFA to give the title compound (15%). MS (ES) C24H:N:O4requires: 404, found: 405 (M+l1).

Step 4: 3-(9-Methyl-l,3-dioxo-lll-imidazof I,5-alindol-2(3H)-yl)hexanoic acid To a solution of benzyl ester from Step 3 in ethanol was added 10% Pd/C (10% w/w). The mixture was allowed to stir under H2 atmosphere for 12 h. The reaction mixture was then filtered, concentrated under reduced pressure and purified by preparative RP-HPLC eluting with MeCN/water containing 0.1% TFA to give the title compound (24%). H NMR (DMSO-d(,, 400 Ml-lz, 300 K) l2.37 (bs, III), 7.86 (d, J 7.7, ill), 7.80 (d, J 7.5, 111), 7.60 (t, J 7.6, III), 7.40 (t, J 6.9, III), 4.44 (m, III), 3.04 (m, 111), 2.79 (m, Ill), 1.98 (m, Ill), 1.66 (m, 111), 1.33 (m, 211), 0.91 (t, J 7.5, 311); MS (ES) C[7IlIN2Olrcquircs: 314, found: 313 (M-lI).

Compounds of structure 4-3 (Scheme 4) can be further functionalised employing standard functional group manipulations as reported in Schemes 5-a to 5-d. The required indolc-2-carboxylic acids were prepared from the appropriately substituted anilines according to the literature procedure reported by Liu, R.; Zhang, P.; Gan, T.; Cook, J. M., .1. Oi (iw,;i., 1997, 62, 7447.

N

i) I N -N' RNH2, Fd2dba3 HC H3C 0 Et3N SO2CH 0 )----"OH H) R-NCO, DBU N K2CO)"N_R N H N-B INAP (-N-i Br or Br RNH i) R-NCS, EtN CF300,Ag

N

i)fl',N

HC

EtN SO2CH H C 0 H)RR"NH LI1 fNH ii) R-NCO DBU I) TFA, H20 H C I BuO2tC or

H OBT

I) R-NCS, Et3N BuOC EDCI RR'N' CFCO2Ag o

N I) N H1C

OH Et3N SO,CH3 H3C H-C ii) R-NCO, DBU NR)TFA ButO2CHN ii) RSO2CI, EtN or Bu'O2CHN RSO2NH I) R-NCS, EI3N C FCO2Aq O 0 H33)I)TFA H1Cj \ N ii)RNH7, NaHB(OAc)3 \NR ButO,,CHN RNH Scheme 5a-5d Example 6 (Entry 22, Table D) 2-[9-Methyl-8-I(3-methylbutyl)aminoj -1,3-dioxo-1 H-imidazo 11,5-a] indol-2(3H)-ylipentanoic acid Step 1: 4-Bromo-3-methyl-1 H-indole-2-carboxylic acid The title compound was prepared according to the procedure reported by Liu, R.; Zhang, P.; Gan, T.; Cook, J. M., I. Oig Chc',,i., 1997, 62, 7447, employing 3-bromoaniline instead of aniline. MS (ES) CjHBrNO2 requires: 254, found: 253 (M-Hi.

-27 -Step 2: Bcnzyl N -(thioxomethylene)norvalinate The title compound was prepared from benzyl norvalinate p-toluensulphonate salt, following the procedure reported by Nowick, J. S. i a! ,J. Oi,' Chew., 1996, 6!, 3929 and used immediately without any further purification in the next step.

Step 3: Benzyl 2-(8-bromo-9-methyl-1,3-dioxo-11 l-imidazol I,5-a]indo 1-2(3 l)-yl)pentanoate To a solution of carboxylic acid from Step I in MeCN were added freshly prepared isothiocyanate from Step 2 (1. 2 eq), EtN (3.6 eq) and silver trifluoroacetate (2.4 eq) and the resulting mixture was stirred at 80 C for 12 h. The reaction mixture was allowed to cool to RT, the solids were filtered off through a pad of celitc and the filtrate was concentrated under reduced pressure. The residue was purified by Si02 gel chromatography (eluent: PE/EtOAc 95/5) to give the title compound as a pale yellow oil (21%). MS (ES) C2H2]BrN2O4requires: 468, found: 491, 493 (M+Na).

Step 4: 2-[9-methyl-8-[(3-methylbutyl)aminol-l.3-dioxo-1 11-imidazol I.5-alindol-2(3H)-ylipentanoic acid To a 0.03 M solution of benzyl ester from Step 3 in toluene were added 3-methylbutan-l-amine (2 eq), CsCO; (1.4 eq), BINAP (0.15 eq), and Pd2(dba) (0.1 eq). The resulting reaction mixture was heated to 110 C and stirred for 12 h. The mixture was allowed to cool to RT, diluted with EtOAc and washed twice with brine. The organic layer was dried (Na2SO), filtered and concentrated under reduced pressure. The residue was dissolved in ethanol and aq I N IICI (2 eq) was added followed by 10% PdJC (10% w/w). The mixture was stirred under H2 atmosphere for 3 h and the catalyst was then filtered off through a pad of celite. The filtrate was concentrated under reduced pressure and the crude residue was purified by preparative RP-HPLC eluting with MeCN/water containing 0.1%TFA to give the title compound as a yellow solid (45%). 11 NMR (CDCI,400 MlIz, 300K) p7.37-7.22 (m, 211), 6.56 (d, 111, .17.8), 5.89 (bs,l II) 4.81 (dd, III, 14.5, 11.1), 3.25 (t, 211, 1 7.2), 2.69 (s, 311), 2.37-2.23 (m, III), 2.19-2.06 (m l1l),1.78-l.67 (m, Ill), 1.65-1.56 (m, 211), 1.48-1.29 (m 211), 0.97 (d, 611,16.8), 0.93 (1, 311,17.2). MS (ES) C2]ll:7BNO4requires: 385, found: 386 (M+1i).

Fxample 7 (Entry 37, Table D) 2-17-{ I ( 1,3-bcnzodioxol-5-ylmcthyl)amino I carbonyl}-9-mcthyl-1,3-dioxo-1 11-imidazo 11,5-a indol-2(311)-yl Ipentanoic acid Step 1: 5-icri-Butyl 2-ethyl 3-methyl-lI l-indole-2,5-dicarboxylatc A mixture of 2-ethyl 3-methyl-I lJ-indolc-2,5-dicarboxylatc (prepared according to the procedure reported by Liu, R.; Zhang, P.; Gan, T.; Cook, i. M., I ()ig (/zc',n., 1997, 62, 7447, employing 4-aminobcnzoic acid instead of aniline) and tert-butyl N,V-diisopropylimidocarbamate (3 eq.) -28 -was stirred overnight at 45 C, cooled to RT, filtered and concentrated under reduced pressure.

The residue was purified on a silica gel column (eluent: PE/EtOAc 9/1) to give the title compound as a pale yellow solid (58%). MS (ES) C17H2,NO, requires: 303, found: 304 (M+H).

Step 2: 5-(teri-Butoxycarbonyl)-3-methyl-I l1-indole-2-carboxylic acid A solution olethyl ester from Step I and KOH (1.5 eq) in a E1OH/ HO mixture 1/I v/v was stirred at 80 C for 12 h. The volatiles were then removed under reduced pressure, the residue was diluted with EtOAc and cooled at 0 C. Aq. IN I IC1 was added dropwise to the biphasic mixture under vigorous stirring untill p11 =3 was reached. The organic layer was then separated, washed with brine, dried (INa2SO4) and concentrated under reduced pressure to give the title compound as a yellow solid (86%). MS (ES) C,Hj7NO4requires: 275, found: 274 (M-H).

Step 3: tert-Butyl 2-f I -[(benzyloxy)carbonyl]butyl} -9-methyl-i,3-dioxo-2,3-dihydro-I H -imidazo [1,5-alindole-7-carboxylate The title compound was prepared as described for bcnzyl 2-(8-bromo-9-methyl-I,3-dioxo-Ill- imidazo[l,5-a]indol-2(3H)-yl) pentanoate (Step 3, Example 6) employing 5-(ieributoxycarbonyl)-3-methyl-I H-indole-2-carboxylic acid from Step 2 instead of 4-bromo-3-methyl-I H-indole-2-carboxylic acid. The reaction progressed to completion in I h to give the title compound in 34% yield. MS (ES) CH;N2O(, requires: 490, found: 491 (M+H).

Step 4: 2-f I -[(Benzyloxy)carbonyl]butyl -9-methyl-I,3-dioxo-2,3-dihydro-II 1-imidazo [1,5-a] indo le-7-carboxyl ate A solution of'butyl carboxylate from step 3 in a TFAII)CM/H20 60/35/5 v/v/v mixture was stirred at RT for 2 h. The volatiles were then removed under reduced pressure and the residue azeotroped with toluene twice to give the title compound as an off-white solid (quantitative yield). MS (ES) C24H22N20, requires: 434, found: 435 (M+l-i).

Step 5: 2-17-f [(I,3-Benzodioxo l-5-ylmethyl)amino]carbonyfl -9-methyl-i,3-dioxo-Il-I-imidazoll,5-alindol-2(31 l)-yl]pentanoic acid To a solution of carboxylic acid from Step 4 in DCM was added i-(1,3-benzodioxol-5-yl)methanamine (1.1 eq), I IOBT (1.2 eq), EDCI.HC1 (1.2 eq) and DIPEA (1.5 eq) and the resulting mixture was stirred at RT for 48 h. The mixture was then diluted with EtOAc, washed with 1N aq. HCI, ss Nat lCO, brine, dried (Na2SO4) and concentrated under reduced pressure.

The residue was dissolved in EtOH, 10% Pd/C (10% w/w) was added and the resulting mixture was stirred under 112 atmosphere for 8 h. The catalyst was then filtered off, the filtrate was concentrated under reduced pressure and the residue was purified by preparative RP-HPLC eluting with MeCN/water containing 0.1%TFA to give the title compound (5 1%). H NMR -29 - (CDC1, 400 Mhz, 300K) ö8.17 (s, 111), 7.87 (s, 211), 6.89-6.80 (m, 311), 6.38 (m, 111) 5.97 (s, 211), 4.86 (dd, J 10.4, 4.5, III), 4.59 (d, J 5.7, 211), 2.58 (s, 311), 2.34 (m, 111), 2.18 (m, lii), 1.43 (m, 21!), 0.98 (t, J 7.1, 311); MS (ES) C2112NO7requires: 477, found: 478 (M+1i).

Example 8 (Entry 20, Table D) 2-17-I(Bcnzylsulfonyl)aminoj-9-methyl-1,3-dioxo-1 I I-imidazo 1,5-al indol-2(3H)-ylipentanoic acid Step 1: Ethyl 5-amino-3-methyl-I 1l-indole-2-carboxylate A mixture of ethyl 5-nitro-3-methyl-l1I-indole-2-carboxylate (prepared according to the procedure reported by Liu, R.; Zhang, P.; Gan, T.; Cook, J. M., .1. Oi, (.Iu',,i., 1997, 62, 7447, employing 4-nitroanilinc instead of aniline) and tin(1I)-chloride (5 eq.) in EtOhl/dioxanc 1/I v/v was stirred at 80 C for 12 h. The mixture was then cooled to RT, diluted with EtOAc and treated with ss NalICO, upon which an abundant precipitate was formed. The suspension was filtered through a pad of celite, the two layers were separated and the organic one was washed with brine, dried (Na2SO), filtered and concentrated under reduced pressure to give the title compound (95%). MS (ES) C121l14NO2 requires: 218, found: 219 (M+11).

Step 2: 5-[(ten-Butoxycarbonyl)amino]-3 -methyl-Ill -indolc-2-carboxylic acid Boc-anhydride (2.5 eq) was added to a solution of ethyl carboxylate from Step 1 in EtOAc. The resulting mixture was stirred at RT for 12 h, washed with brine, dried (Na:SOi), filtered and concentrated under reduced pressure. The residue was dissolved in a 3/I v/v EtOlI/1l20 mixture, KOIl (7.5 eq) was added and the mixture was stirred at 80 C for 12 h. Volatiles were partially removed under reduced pressure, the residue was diluted with EtOAc and cooled to 0 C. 1 N aq.

1 Id was added portionwise while maintaining vigorous stirring until p11 = 3 was reached. The aqueous phase was then discarded, the organic one was dried (Na2SO4), filtered and concentrated under reduced pressure to give the title compound (94%). 11 NMR (I)MSO-d), 300 Mhz, 300 K) 1 2.80 (bs, Ill), Il.23 (s, 111), 9.15 (s, Ill), 7.79 (s, 111), 7.28 (m, 211), 7.61 (d, J 8.3, III), 2.50 (s, 311), 1.52 (s, 911).

Step 3: Benzyl 2-[7-[(te,i-butoxycarbonyl)aminol-9-methyl-1,3-dioxo-lIl-imidazo[l, 5-alindole- 2(31 1)-yll-pentanoate The title compound was prepared as described for benzyl 2-(8-bromo-9-methyl-I,3-dioxo-lll-imidazo[1,5-a]indol-2(31 I)-yl)pentanoatc, Step 3, Example 6, employing 5-[(tcrtbutoxyearbonyl)amino]-3-methyl-I ll-indolc-2-carboxylic acid from Step 2 instead of 4-bromo- 3-methyl-Il l-indole-2-carboxylic acid. MS (ES) C2I I; N O) requires: 505, found: 506 (M+1 1).

Step 4: Bcnzyl 2-(7-amino-9-methyl-l,3-dioxo-lIl-imidazo [1,5-alindole-2(3l1)-yll-pentanoate A solution of compound from Step 3 in a 1/9 v/v TFA/DCM mixture was stirred at RT for 3.5 h. The volatiles were removed under reduced pressure and the residue was used without further purification in the following step. MS (ES) C2HNO4requires: 405, found: 406 (M+H).

Step 5: 2-[7-[(Benzylsulfonyl)amjno]-9-methyl-I,3-dioxo-I lI-imidazo[ I,5-alindol-2(31-l)-yl]pentanoic acid To a solution of amine from Step 4 in DCM at 0 C were added Et;N (3 eq) and phenylmethansullonyl chloride (1.1 eq) and the resulting mixture was allowed to warm up to RT 1 0 while stirring for 12 h. The volatiles were then removed under reduced pressure and the residue was dissolved in a 1/1 v/v EtQH/EtOAc mixture. 10% Pd/C (10% w/w) was added to the above solution and the resulting mixture was stirred under 112 atmosphere for 12 h. The catalyst was filtered off, the filtrate was concentrated under reduced pressure and the residue was purified by preparative RP-UPLC eluting with MeCN/water containing 0.1%TFA to give the title compound. 1-I NMR (CD N, 400 MHz, 300K) p7.76 (d, J 8.6, III), 7.70 (bs, 111), 7.49 (d, J 1.5, III), 7.40-7.33 (m, 611), 4.78 (dd, J 10.9, 4.8, III), 4.43 (s, 211), 2.51 (s, 311), 1.41 (m, 211), 0.96 (t, J 7.3, 311); MS (ES) C2clI:NO(S requires: 469, found: 470 (M+ll').

Example 9 (Entry 29, Table D) 2-[9-Methyt-7-[(4-methylbenzyl)aminol -1,3-dioxo-1H-imidazo 11,5-alindol-2(3H)-ylipdntanoic acid To a solution of bcnzyl 2-(7-amino-9-mcthyl-l,3-dioxo -l Il-imidazo [1,5-a]indolc-2(3l1)-yl]-pcntanoate (Example 8, Step 4) in I,2-dichlorocthanc was added 4-methyl bcnzaldchydc (leq) and NaBI I(AcO) (1.6 cq) and the resulting mixture was stirred at RT for 12 h. The mixture was then diluted with EtOAc, washed with ss Nal ICth and brine. The organic phase was dried (Na2SO4), filtered and concentrated under reduced pressure and the residue dissolved in a 3/ v/v EtOl 1/EtOAc mixture. 10% Pd/C (10% w/w) was added to the above solution and the mixture was stirred under 112 atmosphere for 2 h. The catalyst was filtered off, the filtrate was concentrated under reduced pressure and the residue was dissolved in I,2-dichloroethanc and treated with 4-methyl benzaldchyde (lcq) and NaBll(AcO); (1.6 eq) as described above. After work-up (as described above) the residue was purified by preparative RP-IIPLC cluting with MeCN/water containing 0.1 %TFA to give the title compound. II NMR (CD N, 400 Mhz, 300K) p7.56 (d, J 8.8, 111), 7.31 (d, J 7.9, 211), 7.18 (d, J 7.9, 211), 6.96 (dd, J 8.8, 2.2, 111), 6.87 (d, J 1.7, 111), 4.72 (dd, J 11.0, 4.6, III), 4.36 (s, 211), 2.41 (s, 311), 2.32 (s, 311), 2.20 -2.06 (m, 411), 1.36 (m, 211), 0.94 (t, J 7.3, 311); MS (ES) C241I2cN;04 requires: 419, found: 420 (M+li).

1iI-NMR DATA: ENTRY 2, TABLE A: 4,7-dichloro-2-cyclopentyl-1 I1-isoindolc-1,3 (211)-dione H NMR (300 Ml Iz, DMSO-d(,, 300 K) 7.08 (s, 211), 4.51 (m, 1 H), 1.90-1.60 (m, 8H); ENTRY 5, TABLE A: (2S)-2-(4,7-dichloro-I,3-dioxo-1,3-dihyd ro-2H-isoindol-2-yI)pentanoic acid II NMR (300 M1-lz, DMSO-d,, 300 K) ö 13.2 (bs, I H), 7.89 (s, 211), 4.75 (dd, J 6.0, 1 H), 2.06- 2.01 (m, 211), 1.34-1.24 (m, 211), 0.87 (t, J 7.0, 3H); ENTRY 22, TABLE A: [1 -(4,7-dichloro-l,3-dioxo-1,3-dihyd ro-211-benzolelisoindol-2-yI)cyclopenlyll acetic acid 11 NMR (400 Mhz, DMSO-d(, 300 K) 12.15 (bs, 111), 8.81 (d, J 8.3, lii), 8.38 (d, J 8.1, IH), 8.17 (d, J 8.3, fl-I), 7.84-7.73 (m, 311), 2.68 (s, 2H), 2.39 (m, 411), 1.75-1.60 (m, 411); ENTRY 32, TABLE A: ethyl 3-(l,3-dioxo-1,3-dihydro-2H-benzo[elisoindol-2-yl)hexanoate H NMR (400 MHz, DMSO-d, 300K) ö 8.80 (d, J 7.8, IH), 8.41 (d, J 8.3, IH), 8.18 (d, J 8.3, III), 7.89 (d, J 8.1, IFI), 7.84 (ddd, J 1.2, 7.1, 8.3, III), 7.77 (ddd, J 1.2, 6.8, 8.1, IH), 4.55 (m, IH), 3.95 (q, J 7.1, 2H), 3.09 (dd, J 9.3, 15.6, III), 2.84 (dd, J 5.6, 15.7, 11-1), 2.00 (m, 111), 1.67 (m, III), 1.27 (m, 211), 1.00 (t, J 7.1, 31-1), 0.87 (t, J 7.3, 3H).

The following tables contain further examples: TABLE A: Phthalimides ___________________________ __________ _________ Observed Scheme Entry MOLSTRUCTURE NAME ______ ________________________ ____________________________ Mass no. I 2-butyl-4,7-dichloro-1 H- 1 c N o 272,274 isoindole-1,3(211)-dione 0 0 2 N-( 4,7-dichloro-2-cyclopenlyl-1Il-N/A isoindole-I,3(2H)-dione (1H-NMR) -32 -i? c;H 4,7-dichloro-2-(3-methylbutyl)-3 286,288 C CH, IH-lsolndole-1,3(2fl)-dionL (p (_) 4,7-dichloro-2- 4 (cyclopropylmethyl)I H-270,272 isoindole-I,3(21 1)-dione CF o 0 (hirI OH (2S)-2-(4,7-dichloro-1,3-dioxo-N/A 13hYtho2H:isoo12 (1II-NMR) yl) pcntanoic acid

CF

/C**-OH 1-(4 7-dichloro-1,3-dioxo-1,3- {j 326, 328 6 ç dihydro-21-I-isoindol-2-(fl) yI)cyclopentanecarboxylic acid 1IYN_J 2-(4,7-dichloro-1,3-dioxo-1,3-300, 302 7 dihydro-211-isoindol-2-(M-H) o HC yI)butanoic acid Cl OH 2-(4,7-dichloro-I,3-dioxo-1,3-N--< 314316 8 dihydro-2H-isoindol-2-(M11) yl)pcntanoic acid 1I-l 0OF1 (2S)-2-(4-methyl-1,3-dioxo-1,3- 9 dihydro-211-isoindol-2-262 CII yl)pentarioic acid CI Chir --LJ -0H (2S)-2-(4,7-dichloro-1,3-dioxo-N 300, -1 3-dihydro-211-isomdol-2-H 302(M-I-1) CI yI)butanoic acid CF ChrjI OH (2R)-2-(4,7-dichloro-1,3-dioxo-300 302 11 1,3-dihydro-211-isoindol-2- 0 HC (M-II) cI. yl)butanoic acid o 0 2-(4-chloro-1,3-dioxo-1,3- 12 dihydro-2H-isoindol-2-282 o CH yI)pcntanoic acid Ci 0 C) OH methyl 2-(4,7-dichloro-1,3-dioxo- 13 l,3-dihydro-211-isoindol-2-330,332 o OH. yl)pcntanoatc 000H 2-(1,3-dioxo-1,3-dihydro-2H- 14 iI benzo[e]isoindol-2-yI)pentanoic 298 acid 000H 2-(1,3-dioxo-1,3-dihydro-211-bcnzo[qisoindol-2-yl)pcntanoic 298 0 OH acid ci / 3-(4,7-dichloro-I,3-dioxo-1,3- 16 dihydro-2fl-isoindol-2-yl)-5-3,345 CI H,C OH. methyihexanoic acid [1-(1,3-dioxo-I,3-dihydro-211- 17 JN OH benzo[e]isoindol-2-338 0 yl)cyclohexyl]acetic acid J 3-(1,3-dioxo-1,3-dihydro-211- 18 benzo[e]isoindol-2-yl)-5-326 0 methylhexanoic acid methyl2-(1,3-dioxo-1,3-dihydro- 19 211-benzo[e]isoindol-2-312 0 CH yI)pentanoate -34 -

OH

J. (1 S,2R)-2-( 1,3-dioxo-I,3-dihydro- 2F1-benzo[e]isoindol-2-310 LL yI)cyclopcritanccarboxylic acid [1 -(1,3-dioxo-I,3-dihydro-2H-

NL OH

21 ( \ bcnzo[c]isodo1-2-324 O yl)cyclopcntyl]acetic acid ,,O [1-(4,7-dichloro-1,3-dioxo-1,3-N/A 22 [1 J OH dihydro-211-isoindol-2- *1 (1I1-NMR) a yl)cyclopcntyl]acctic acid -OH 2-( 1,3-dioxo-I,3-dihydro-21 I-23 Ott benzo[c]isoindol-2-yl)-3-312 OH mcthylpcntanoic acid 0 0 Chira ITN OH (2S,3 S)-2-( 1,3-dioxo-I,3-dihydro- 24 CH 2H-bdnzo[e]isoindol-2-yl)-3-312 OH, methylpentanoic acid ThN ***oH 3-(1,3-dioxo-I,3-dihydro-2H-bco[c]isoindo1-2-yI)hcxanoic 312 OH acid at i 3-( 1,3-dioxo-1,3 -dihydro-2H- 11 I bcnzo{c]isoindol-2-26 336 J yl)bicyclo[2.2.1]hcptanc-2-carboxylic acid 0 0 ChirI (2R)-2-( I,3-dioxo-1,3-dihydro- 27 2H-benzo[e]isoindol-2-298 CH yl)pentanoic acid 0 0 ChirI (2S)-2-(1,3-dioxo-1,3-dihydro- 28 ( UH 2H-bcnzo[c]isoindol-2-298 yI)pentanoic acid Ci C) 0 GIr (2R)-2-(4,7-dichloro-1,3-dioxo- 29 I,3-dihydro-211-isoindol-2-314, 316 ci yI)pentanoic acid

CH

N 3-(1,3-dioxo-1,3-dihydro-211- 0 bcnzo[c]isoindol-2-yl)-n-389 3a (methylsulfonyl)hexanamide COOH 2-(4,7-dimethyl-1,3-dioxo-1,3- 31 [ dihydro-211-isoindol-2-276 0 "ci, yI)pentanoic acid ethyl 3-(1,3-dioxo-1,3-dthydro-N/A 32 CH 211-benzo[e]isoindol-2- 0 OH, (lII-NMR) yl)hcxanoate

HG

33 2-buty1-6-mcthy1pro1o[3,4-257 3 elindole-1,3(21-1,6H)-dione H,C -2-buty1-6-cthy1pro1o[3,4-285 3 0 CH e]indole-1,3(211,611)-dione OH 0 2-butyl-4,9-dihydroxy-I h-I N-\ 314 , benzo[1]isoindole-I,3(2H)-dione N [ n-(bcnzylsulfonyl)-3-(1,3-dioxo- 36 I,3-dihydro-21 I-bcnzo[c]isoindol-465 la 2-yhcxamide / CH, N 3-(1,3-dioxo-I,3-dihydro-21 1- 37 (J1N ( benzo[e]isoindol-2-yI)-n-403 Ia (cthylsulfonyl)hcxanamidc 2-butyl-6-(3- 38 F4Q N' hydroxypropyl)pyrrolo[3,4-301 3 \_. e]indole-1,3(211,61 1)-dione

HC

ethyl 2-(6-mcthyl-1,3-dioxo-3,6- 39 dihydropyrrolo[3,4-e]indol-2(1II)-329 3 HCN\ CH yI)pcntanoate Oh o o NOH 3-(4-hydroxy-1,3-dioxo-1,3-dihydro-21-1-isomdol-2-278 yl)hexanoic acid N 2-butyl-5-chloro-6-nitro-I H- 41 rJ\ 283 CI isodo1e-I,3(2h)-dione 0 CH H N 5-amino-2-butyl-6-chloro-lh- 42 N isoindole-l,3(211)-dione 251 (ES-) o CH.

I 2-(6-mcthyl-1,3-dioxo-3,6- 43 --OH dihydropyrrolo[3,4-e]indol-2(1fl)-301 3 - yl)pentanoic acid o OH 7-_I n-mcthyl-2-(6-methyl-1,3-dioxo- N-( 3,6-dihydropyrrolo[3,4-e]indol-314 3 \J a 0 CH 2(11I)-yI)pentanamide 2-bulyl-5-chloro-6- \_ [(cyclopropylmcthyl)amino]-111-307 C) OIL isoindolc-1,3(2h)-dionc F o o 3-(4,7-difluoro-1,3-dioxo-1,3- 46) dihydro-2H-isoindol-2-298 F 0 yl)hcxanoic acid j o 3-[7-(ben1oxy)-1,3-dioxo-1,3 - 47 j j \ dihydro-2H-bcnzo[c]isoindol-2-418 3a yI]hexanoic acid _4 -3-(7-hydroxy-1,3-dioxo-1,3- 48 0H dihydro-211-benzo[e]isoindol-2-328 y1)hcxanoc acid

HC 0*-.

2-[6-[4- \/ OH (mcthoxycarbony1)bcn1]-1,3-435 3 \ dioxo-3,6-dihydropyrrolo[3,4-a e]indol-2(1H)-yl]penianoic acid HN N 2-(5-amino-6-chloro-1,3-dioxo-I,3-dihydro-211-isoindol-2-297 0 CH yI)pcntanoic acid C) HO -.]/ o 2-[6-(2-carboxyethyl)-1,3-dioxo- 51 HO 3,6-dihydropoIo[3,4-e]indoI-359 3a CH, 2(11 I)-yl]pentanoic acid C) F-IC) 2-[6-(3-cyanopropyl)-l,3-dioxo- 52 N 3,6-dihydropo1o[3,4-E]indo1-354 3a CH 2(11 1)-yl]pentanoic acid 0 HO /J ç> 2-[1,3-dioxo-6-(2-phcnylcthyl)- \ /-----</ \ 53 N] \) 3,6-dihydropyrrolo[3,4-c]indol-391 3a 2(1I-I)-yl]pentanoic acid

Table B: Indoics

Observed Entry MOLSTRUCTURE NAME Scheme Mass

OH

2-buty1-4-mcthy1pro1o[3,4-257 b] indole-I,3(21I,4H)-dionc

OH

4-methyl-2-(1- 2 mcthylbutyl)pyrrolo[3,4-271 b]indole-1,3(211,411)-dione 0 HO

HO

GH, 2-tert-butyl-4-o methylpyrrolo[3,4-b]indole-257 I,3(2H,41-1)-dione H C N 2-(4-mcthyl-1,3-dioxo-3,4- 4 dihydropyrrolo[3,4-b]indol-301 2(111)-yl)pentanoic acid

Table C: Quinolines

Observed Entry MOLSTRUCTURE NAME Scheme ______ _________________________ __________________________ Mass ________

OH

000FI 2-(4-methyl-1 3-dioxo-1 3- 1 dihydro-2H-pyo1o[3,4-313 0 CH c]quinolin-2-yI)pcntanoic acid OH, o N 3-(4-mcthyl-1,3-dioxo-1,3- 2 N coN dihydro-2H-pynolo{3,4-327 0 Oft c]quinolin-2-yl)hcxanoic acid cii Br 3-bromo-5-(4-mcthyl-I 3- 3 dioxol,3dihytho2ll 411,413 pyrrolo[3,4-C]quinolin-2- 0 yI)benzoic acid cii 0 Ci 4-chloro-3-(4-methyl-1,3- dioxo-1,3-dihydro-211-367 0 oo pyrrolo[3,4-c]quinolin-2- 0 yl)bcnzoic acid methyl 3-(4-methyl-l,3-dioxo-5. 1,3-dihydro-2H-pyrrolo[3,4-353 OH, c]quinolin-2-yl)thiophene-2-S-' N OH, carboxylate 6 2-(2-acetyh3-thieny-4-337 L' N OH c]quinoline-1,3(2F1)-dione -40 - o -H 3-(4-methyl-1,3-dioxo-1,3- -N dihydro-2H-pyrrolo[3,4-339 x yI)cyclohcxanccarboxylic acid 3-(6-bromo-4-methyl-1,3- N--k OH dioxo-1 3-dihydro-211-8 405,407 K pyrrolo[3,4-c]quinolin-2-

OH

______ ___________________________ yl)hexanoic acid -( <OH 3-{6-{(1-ben1pipedin-4- 1) yl)amino]-4-methyl-1,3-dioxo- 9 --515 2a f CH 1,3 -dihydro-21 I-pyrrolo[3,4-c]quinolin-2-yl}hexanoic acid HO1CH (2S)-4-methyl-2-(4-mcthyl- 1,3-dioxo-1,3-dihydro-211-327 I pyrrolo[3,4-c]quinolin-2- NCH yl)pentanoic acid HO-jL 3-(1 I I-imidazol-4-yl)-2-(4- methyl-I,3-dioxo-I,3-dihydro-11 351 o 21 I-pyrrolo[3,4-c]quino lin-2- NOH yl)propanoic acid (Br o 2-(3-bromophenyl)-4-methyl-

N

12 11I-pyrrolo[3,4-c]qurnoline-367, 369 OH 1,3(211)-dione 2-[(1S,4S)-bicyclo{2.2. 1]hept- 13 2-yl]-4-methyl-111-pyrrolo[3,4-307 c]quinoline-1,3(21 I)-dione

N CH -41 -

) . benzyl 4-(4-methyl-1,3-dioxo- 14 1,3-dihydro-21-l-pyrrolo[3,4-430 c]quinolin-2-yl)piperidine-1-carboxylate N(H

N

4-methyl-2-[(3S)-2-oxoazepan- -N 3-yI]-lll-pyrrolo[3,4-324 c]quinoline-1,3(2H)-dione (2S)-3-cyclohexyl-2-(4-

OH

methyl-I,3-dioxo-1,3-dihydro-16 367 N 2II-polo[3,4-c]quinoI-2-yl)propanoic acid O 4-methyl-2-[(3S)-2-oxotetrahydro-3-thienyl]-1Il-17 313 pyrrolo[3,4-c]quinoline- CH 1,3(21I)-dione (2S)-2-(4-methyl-1,3-dioxo- 18 N OH 1,3-dihydro-211-pyrrolo[3,4-327 CH c]quinolin-2-yl)hexanoic acid

OH

2-(4-methyl-1,3-dioxo-1,3- 19 CH, dihydro-2H-pyrrolo[3,4-311 J/o c]qumolin-2-yI)pent-4-enoic N (N acid -42 -i 0

-CFI

methyl (2S)-4-rnethyl-2-(4--ON methyl 1,3 dioxo 1,3 dihydro / OH 341 211-pyrrolo[3,4-c]quinolin-2-yl)pcntanoate

H

2-( I -ethylpropyl)-4-methyl- 21 I1l-pyrrolo[3,4-c]quinoline-283 N OH 1,3(211)-dione o 2-cycloheptyl-4-methyl-1 H- 22 N pyrrolo[3,4-c]quinoline-309 1,3(211)-dione 2-cyc1ooc1-4-methy1-1 H- 23 N pyrrolo[3,4-c]quinoline-323 CH 1,3(2H)-dione

CH

I (2S)-3-methyl-2-(4-methyl- 24 -N0H 1,3-dioxo-1,3-dihydro-211-313 pyrrolo[3,4-c]quinolin-2-yl)butanoic acid (4-methyl-l,3-dioxo-1,3-dihydro-211-pynolo[3,4- - o c]quinolin-2-yl)(2NXCH thienyl)acetic acid -N -. CH, 4-methyl-2-( 1 -methylbutyl)- 26 11I-pyrrolo[3,4-c]quinolinc-283 N OH 1,3(211)-dione -43 - o 2-(3-chlorophenyl)-4-methyl- 27 N 1lI-pyrrolo[3,4-c]quinoline-323 I 1,3(211)-dione ethyl 2-(4-methyl-l,3-dioxo- 1,3-dihydro-211-pyrrolo[3,4-0 / 28 -N c]quinolin-2-yl)-4,5,6,7-421 j tetrahydro-1 -bcnzothiophenc- N c1, 3-carboxylate 4-methyl-2-(4- 29 -N mcthylcyclohexyl)-1Il-309 pyrrolo[3,4-c]quinolinc- 1,3(211)-dione

HO

(2R)-2-(4-methyl-1,3-dioxo- 1,3-dihydro-21-I-pyrrolo[3,4-313 N (H c]quinolin-2-yl)pent.anoic acid

HO-K

0 -(2S)-2-(4-mcthyl-1,3-dioxo- 31 1,3-dihydro-211-pyrrolo{3,4-313 [1' j c]quinolin-2-yl)pcntanoic acid

N CH OH 0

HO-K 4-methyl-2-(4-methyl-1,3- 32 O,J' dioxo-l,3-dihydro-211-327 pyrrolo[3,4-c]quinolin-2-yI)pentanoic acid C) 0 (2R)-2-(4-methyl-1,3-dioxo- 33 1,3-dihydro-211-pyrrolo[3,4-327 N (H, c]quinolin-2-yI)hexanoic acid

OH

(2S)-2-(4-mcthyl-1,3-dioxo- / "N -c I,3-dihydro-211-pyrrolo[3,4-311 c]qurnolin-2-yl)pcnt-4-enoic N CH acid 3-[6-(butylamino)-4-methyl-1,3-dioxo-1,3-diliydro-21 I-H,C *N,, ***V< 398 2a \ pyrrolo[3,4-c]quinolin-2-OH yl]hexanoic acid CH o H 3-{6-[(3- ( hydroxypropyl)amino]-4- 36 CH methyl-1,3-dioxo-1,3-dihydro-400 2a 21 1-pyrrolo[3,4-c]quinolin-2-yI}hexanoic acid o o 3-(4-methyl-6-{[2-(1- OH, mcthy1po1idin-2- 37 yl)cthyl]amino}-1,3-dioxo-1,3-453 2a OH, dihydro-211-pyrrolo[3,4- ______ __________________________ cjquinolin-2-yl)hcxanoic_acid __________ _________ OH, j,? /) N-(2,6-difluorobenzyl)-3-(4- 38 /F methyl-1,3-dioxo-1,3-dihydro-452 Ia ftJ \ ( F / 211-pyrrolo[3,4-c]quinolin-2-CH yl)hexanamide CN, 3-[6-(cyclopentylamino)-4- N-foH methyl-1,3-dioxo-1,3-dihydro-N 211-pyrrolo[3,4-c]quinolin-2-410 2a OH, yl]hexanoic acid CH o ci N 2-(5-chloro-2-mcthoxyphenyl)- / 4-methyl-Il l-pyrrolo{3,4-353 c]quinolinc-1,3(211)-dione 2-[ 1 -(hydroxethyl)buty1J-4- 41 -{ methyl-111-pyrrolo[3,4-299 o c]quinoline-l,3(211)-dione Table D: imidazoindoles and pyrroles Observed Entry MOLSTRUCTURE NAME Scheme Mass _________ 2-buiyl-1Il-imidazo[1,5- _NNNcH a]indole-1,3(2H)-dione 1 243 4 o 6-acetyl-2-butyl-5,7-dimcthyl-

HG

*-N\ 1F1-pro1o[1,2-c]idazo1e- 2 cII 1,3(2H)-dione 263 4 HC CH, o 2-butyl-9-methyl-111- H C imidazo[ 1,5-a]indole-1,3(211)- 3 dionc 257 4 OH methyl 2-(9-methyl.-I,3-dioxo- J IH-imidazo[1,5-ajindol-2(3H)- 4 OH. yI)pentanoate 315 4 -46 - bcnzyl 2-(9-methyl-1,3-dioxo-1I1-imidazo[1,5-a]indol-2(311)--o o yl)pcntanoatc HC 391 4

CH

N--

o 2-(9-mcthyl-I,3-dioxo-1H- imidazo[1,5-a]indol-2(311)-

OH

6. N-yl)pentanoic acid 301 4 7-bromo-2-butyl-9-mcthyl-111- HCN imidazo[1,5-A]indole-1,3(21 1)-a dionc 3' 4 bcnzyl 3-(9-mcthyl-1,3-dioxoo 1II-imid2zo[1,5-a]mdol-2(311)- 8 yl)hexanoatc 405 4 3-(9-methyl-1,3-dioxo-1 H- o OH imidazo[1,5-A]indol-2(311)- 9 CH yI)hcxanoic acid 313 (M-1) 4 CH 6-bromo-2-butyl-9-mcthyl-1H-imidazo[1,5-a]indolc-1,3(2H)-dione 335,337 4 -47 - 6-[(1-bcn1pipcdin-4-yl)amino]-2-butyi-9-mcihyl- ii 1I1-imidazo[1,5-a]indole-I,3(211)-dione H 7-[(1-bcnzyipiperidin-4- 12 H yI)amino]-2-butyl-9-mcthyi-446 5a 11I-imidazo[1,5-a]thdoic- _______ ___________________________ 1,3(21 1)-dionc ___________ _________ bcnzyi 3-(6-acctyl-5,7-dimethyl-1,3-dioxo-111-IC II / 0 \ 13 pyrrolo[i,2-cjimidazol-2(311)-411 4 CH\. yl)hcxanoatc Cl-I 3 -(6-acctyl-5,7-dimcthyl-1,3- a dioxo-1l1-pyrrolo[1,2-HO H / o 14,, c]imidazol-2(311)-yl)hcxanoic 321 4 acid HC OH, H - 8-[( I -benzylpiperidin-4-- ( CII yl)amino]-2-butyl-9-methyl-446 5a K-11I-imidazo[l,5-a]indole- _______ ______________________________ I,3(21 1)-dione ____________ ___________ 2-[8-(cyciopentylamino)-9- HC.< N CH methyl-i,3-dioxo-I H- 16 imidazo[ I,5-a]indol-2(3 II)-384 5a yl]pentanoic acid 0. OH 2-[7-[(tert- ftC -butoxycarbonyi)amino]-9- 17 N--' mcthyl-1,3-dioxo-1II-416 5c )J1JJ imidazo[ 1,5-a]indol-2(311)-yl] pcntanoic acid O OH 2-(7-amino-9-mcthyl-1,3dioxo-1I1-imidazo[I,5-a]indol- 18 2(3I1)-y1)pcnnoic acid 316 5c

HN

2-[7-I N\CH { [(cyclohexylmcthyl)sulfonyl] 19 arnino}-9-rncthyl-1,3-dioxo-476 5c 1I1-imidazo[1,5-a]hdol-2(3II)- ______ ________________________ yl]pentanoic acid o OoH 2-[7-[(bcnzylsulfonyl)amino]- I N'CH 9-methyl-I,3-dioxo-III-imidazo[l,5-a]indol-2(311)-470 5c yl]pentanoic acid 2-[9-methyl-I,3-dioxo-7- {[(pidin-4- 21 /N ylmethyl)sulfonyl]amino}-1II-471 5c "IP'N imidazo[I,5-a]indol-2(31 I)-______ ________________________ yl]pentanoic acid _________ _________ .OH 2-[9-methyl-8-[(3- HG HC)N--methylbutyl)amino] -I,3 -dioxo- 22 -N, CH, 1t-1-imidazo[1,5-a]indol-2(3H)-386 5a C) yl]pentanoic acid o OH 2-[9-mcthyl-1,3-dioxo-8- O --[(pyridin-2-ylmcthyl)amino]- 23,N--CH 11I-imidazo[1,5-a]indol-2(311)-407 5a 0 yI]pcntanoic acid 2-[8-[(3- H (_\ C),,JN isopropoxypropyl)amino]-9- 24):H methyl-1,3-dioxo-1II-416 5a imidazo[ 1,5-a]indol-2(311)- ______ __________________________ yI]pcntanoic acid __________ _________ 0H 2-[9-methyl-8-[(I-H methylpipedin-4-y1)amino]-413 5a NN() 1,3-dioxo-1 H-imidazo[ 1,5-

HC -49 -

a]indol-2(31 l)-yI]pcntanoic acid o OH 2-[8-[(2-furylmethyl)amino]-9-HG -methyl-i,3-dioxo-1I1- 26 CH imidazo[1,5-a]indol-2(311)-394 (M-1) 5a 1LX yI]pentanoic acid o 0OH cis-4-{ [2-( 1 -carboxybutyl)-9- <N methyl-i,3-dioxo-2,3-dihydro- 27 1 H-irnidazo[ I,5-a]indol-8-442 5a C) yl]amino} cyclohcxanecarboxyl ic acid .OH 2-[9-methyl-I,3-dioxo-7- N NCH [(propylsulfonyl)amino] -111- 28 imidazo[1,5-a]indol-2(311)-422 5c yl]pentanoic acid o C.OH 2-[9-methyl-7-[(4-ic methylbenzyl)amino]-I,3- 29 dioxo-IH-imidazo[1,5-420 5d a] indo L-2(3 H)-yI]pentanoic IC acid OH 2-[8-(4-isopropylpipcra.zin-I - HCN H yl)-9-mcthyl-1,3-dioxo-1 11-OH imidazo[1,5-a]indol-2(3H)-427 5a yl]pentanoic acid O OH 2-[7-(tert-butoxycarbonyl)-9- H methyl-I,3-dioxo-ill- 31 imidazo[1,5-a]indol-2(311)-401 5b HCO.-1J yI]pentanoic acid H,C ii OH 0 0 -OH (1117 2-[7- [(cyclopcntylamino)carbonyl] - 9-methyl-i,3 -dioxo-ill-32 412 5b imidazo{i,5-a]indol-2(311)-yljpentanoic acid 0 2-[7-(([l-> H L (hydroxymethyl)butyljamino}c arbonyl)-9-methyl-1,3-dioxo- 33 (H N f 1I1-imidazo[1,5-a]indol-2(311)-430 5b yI]pcntanoic acid 2-[9-methyl-7-{[(1- H <iN methyIpipedin-4- 34 N yl)amino]carbonyl}-1,3-dioxo-i 5b 11I-imidazo[1,5-a]indol-2(311)-H C yl]pentanoic acid (H 2-[7-{ [4-( I,3-bcnzodioxol-5- y1mcthy1)piperaz-1 -N yl]carbonyl} -9-methyl-1,3 -547 5b dioxo-1II-imidazo{1,5-a]indol- ______ __________________________ 2(311)-yl]pentanoic acid __________ _________ OOH 2-[9-methyl-7-{ [(2-morpholin- ftC -CH 4-ylethyl)amino]carbonyl} -I,3 - 36 0 dioxo-1l-l-imidazo[1,5-a]indol-457 5b 0 2(3H)-yI]pentanoic acid 2-[7-{[(l,3-bcnzodioxol-5- HC <Li. ylmethyl)amino]carbonyl}-9-methyl-1,3-dioxo-I 1-1- 37 / ( 0 478 5b -imidazo[ I,5-a]indol-.2(3 11)- 0 yI]pentanoic acid -51 - O OH 2-[7-[(bcnzylamino)carbonyl]- N 9-methyl-1,3 -dioxo-111- 38 imidazo[1,5-a]indol-2(311)-434 5b yl]pcntanoic acid 3-[8-(cyclopentylamino)-9- H C OH methyl-1,3-dioxo-1 II-N (H imida'o[I,5-a]indol-2(311)-398 5a \. / ftJ U yl]hexanoic acid 3-[8-(4-isopropylpiperazin-1- OH yl)-9-methyl-1,3-dioxo-IH-HC N imidazo[15a]indol2(3H) 441 5a yl]hexanoic acid 3-[8-[(l -benzylpiperidin-4-

OF I

yI)amino]-9-methyl-1,3-dioxo- 41 1II-imidazo[1,5-a]indol-2(3H)-503 5a yI]hexanoic acid o 2-[8-[(1 -benzylpiperidin-4- 1yl)aminoj-9-methyl-1,3-dioxo- 42 N 489 5a 11 I-imidazo[1,5-a]indol-2(31 I)- ______ _________________________ yl]pentanoic acid __________ _________

Claims (18)

1. -52 -Claims 1) A compound of formula (I): 0 A N-R1 (I) R3 R2 wherein X

   is N, CII or C; the dotted line represents an optional bond; so that X is C when the dotted line represents a bond; and X is N or CII when the dotted line represents no bond; R' is C1alkyl, Calkenyl, C2alkynyl, or (Cll:)oR, optionally substituted by Q' and Q2; R is C)cycloalkyl, I let, aryl or heteroaryl, where C;Mcycloalkyl is optionally bridged by -(ClI)1:.

   Q' and Q2 are independently selected from halo, hydroxy, C] )alkyl, CI)alkoxy, C2alkenyl, (CH2)0 CO2R', (CH2)( C(O)N ROS(O)2R7, (Cl l2)C(O)N RR' and oxo; R and R' are independently selected from hydrogen, Cl.)alkyl, (C112)o..;aryl, where (CH2){aryl is optionally substituted by 1 to 3 halogen atoms; A is a 5-or 6-membered ring optionally containing one nitrogen atom; R is hydrogen, Cialkyl, halo or hydroxy, R is hydrogen, C1(alkyl, halo, hydroxy or C(O)C1(alkyl; or R2 and R are joined together to form a 5-or 6-membered ring optionally containing one nitrogen atom and optionally substituted by Q; Q is C..alkyI, C2 (alkenyl, C2alkynyl, hydroxy, halo, (CH2)I) phenyl, O(CH2)0 phenyl, NR' R' 2, NR' C(O)OC)a1kyl, C(O)OCalkyl, C(O)NR1 R' NR' S(O)2(CI I2)oC;cycIoalkyl, NR' S(O)2C1,alkyl, NR' S(O)2(CI-I2)oaryl or NR' S(O)2(C112)o;heteroaryl, optionally substituted by hydroxy, C021-I, CO2Cialkyl or CN; R' and RL are independently selected from hydrogen, Cl)alkyI, (CFI2)iO(Cialkyl), (CH2)( C;cycloalkyl, (C I12)0 aryl, (CH 2)0-;Het and (CH2)0;heteroaiyl, optionally substituted by hydroxy, C1ialkyl, (Cl I:)ophenyl and CO2H; or R and R 2 together with the nitrogen atom to which they are joined, form a 5-or 6-membered ring, optionally containing one oxygen atom or one further nitrogen atom, and optionally substituted by alkyl or (CH2) ;Het; R4 is hydrogen, Cia1ky1, halo, hydroxy, NRR'1, NO2 or NR0(CH2)oCcycloa1kyl; -53 -9 II) R and R are independently selected from hydrogen and C14alkyl; or R and R are joined together to form a 5-or 6-membered ring optionally containing one nitrogen atom and optionally substituted by Ci4alkyl, hydroxy, halo, Nil2, NO2 or CN; R is hydrogen, Ci4alkyl, C2alkenyl, C2alkynyl, hydroxy or halo; and pharmaceutically acceptable salts thereof.
2. 2) A compound according to claim I wherein R1 is Cialkyl, C2 alkenyl or (C112)nIR optionally substituted by Q' and Q, wherein R is cyclopropyl, cyclopentyl, cyciohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2. I]hexyl, phenyl, thienyl, imidazolyl, benzothienyl, piperidinyl, azepinyl or tetrahydrobenzothienyl; Q1 is halo, hydroxy, C14alkyl, (Cl12)o}CO:R6, (C117)()1C(O)NIIS(O)2R, (Cl 12)01C(O)NIIR or oxo and Q is halo, C1alkoxy or CO2R, where R4 is hydrogen or C) .a1kyl.
3. 3) A compound according to either claim I or 2 wherein A is phenyl, pyridinyl, pyrrolyl or dihydropyrrolyl.
4. 4) A compound according to any one of claims 1 to 3 wherein R2 is hydrogen, C11alkyl, halo or hydroxyl; R is hydrogen, Cia1kyl, halo, hydroxy or C(O)C)lalkyl; or R2 and R are joined to form either a 5-membered ring containing one nitrogen atom or a phenyl ring, both optionally substituted by Q, wherein Q' is C1alkyl, hydroxy, fluoro, chloro, bromo, (C112)1 2phenyl, O(Cl 12) 2phenyl, N R' R'2 NI lC(O)OC2alkyl, C(O)OC24alkyl, C(O)N R' R'2 NI ISO2(CI 12)) Cc4,cyc1oa1ky1, Ni ISO2C aIkyI, NI 1S02(Cl 12)) 2phenyl or NI 1S02(Cl 12)1 2pyridyl, optionally substituted by hydroxy, C02l I, CO2C alkyl or CN, where R" and R) 2 are independently selected from hydrogen, C) -ialkyl, O(C1 4alkyl), C (cycloa1kyl, (Cl 12)) 2phenyl, (Cl12)o2IIet and (C112))2heteroaryl, optionally substituted by hydroxy, Ci4alkyl, (C112)12phenyl and CO2I I.
5. 5) A compound according to any one of claims I to 4 wherein R' is hydrogen, C1(,alkyl, NR9R' , NO2 or NR9(C1l2)o;Ccycloalkyl, where R9 and R' are as defined in relation to claim 1 or R and R4 are joined to form a 6membered ring optionally containing one nitrogen atom and optionally substituted by C1a1kyl, hydroxy or halo.
6. 6) A compound according to any one of claims I to 5 wherein R is hydrogen, Ci4alkyl, halo or hydroxy. More preferably, R is hydrogen, C)2alkyl, fluoro, chloro, bromo or hydroxy.
7. 7) A compound according to any one of claims I to 6 of formula (Ia): -54 -R5 R4 II f N-R (Ia) R3(( R2 or a pharmaceutically acceptable salt thereof, wherein R, R, R, R1 and R arc as defined in relation to claims Ito 6.
8. 8) A compound according to claim 7 wherein R' is C1aIkyl or (CH-pR, optionally substituted by Q', where R is CcycloaIkyl, where cyclohexyl is optionally bridged by-Cll-; Q is (CH COR', Cli C(O)NIlS(O) R1 or C(O)NIIR7, where R and R7 are as delmed in relation to claim I; R is hydrogen, C1alkyl, Iluoro, chloro, bromo or hydroxyl; R is hydrogen, methyl, Iluoro, chioro or hydroxyl or R and R are joined to form a phenyl ring or a 5-membered ring containing one nitrogen atom, which ring is optionally substituted by Q, where Q' is as defmed in relation to claim 1; Q is C1.a1kyI, hydroxy, (CH2)ipheny1 or OCFI2phenyl, optionally substituted by hydroxy, COFl, CO CH or CN; R4 is hydrogen, C1 alky1, NI IR NO or NH(CH)iCcycloa1kyl, where R' is as defined in relation to claim 1 or R and R are joined to form a phenyl ring optionally substituted by Cialkyl and R is hydrogen, C1alkyl, fluoro, chloro, bromo or hydroxy.
9. 9) A compound according to any one of claims I to 6 of formula (Ib): R3_KN__R1 (th) or a pharmaceutically acceptable salt thereof, wherein R1, R2, R and R' arc as defined in relation claims 1 to 6.
10. 10) A compound according to claim 9 wherein R' is C)a1ky1, optionally substituted by halo, hydroxy, C1.,aIkyl, Ci a1koxy or (CI l) -CO2R, where R is as defined in relation to formula (I); R2 and R are joined to form a phenyl ring optionally substituted by halo, hydroxy or Ci ,aIky1; and R4 is Ci)alkyl.
11. 11) A compound according to any one of claims 1 to 6 of formula (Ic): -55 -R31' (Ic) or a pharmaceutically acceptable salt thereof, wherein R, R, R and R are as defined in relation to any one of claims I to 6.
12. 12) A compound according to claim ii wherein R' is Cicalkyl, C14alkenyl or (Cll2)o2R, optionally substituted by Q' and Q, where R' is C;cycloalkyl, I let, phenyl or heteroaryl, where cyclohexyl is optionally bridged by -C112-,Q' is C1alkyl, halo, hydroxy, (Cll2)1CO2l I, (Cil)o CO2C14alkyl, (CIl2)4iCO2(Cll2)o2phenyl, (Cll2)1iC(O)NllR7 or oxo, where R7 is as defined in relation claim 1; Q is halo, C021 I or CO2C alkyi; R and R are joined to form a phenyl ring, optionally substituted by Q, where Q is C1alkyl, halo, NIIR' or NJlC(O)OCia1kyl, where R is Calky1, C,cycloalky1 or (C112)o2pyridinyl or (C112)o2pyrroiidinyl, optionally substituted by hydroxy, methyl or Cll:phenyl; and R4 is hydrogen or Ci4alkyl.
13. 13) A compound according to any one of claims ito 6 of formula (Id): R3N_R1 d) or a pharmaceutically acceptable salt thereof, wherein R', R2, R' and R1 are as defined in relation to any one of claims 1 to 6.
14. 14) A compound according to claim 13 wherein R1 is C alkyl, optionally substituted by Q, where Q' is C 4alkyl or (CI 12)0-CO2R, where is as defined in relation to claim 1; R2 is hydrogen or Ci4alkyl; R is C1 4aikyl or C(O)Calkyl or R and R arc joined to form a phenyl ring, optionally substituted by Q where Q" is halo, NR R' , NIIC(O)OC1 alky1, C(O)OC1 25,alkyl, C(O)NR R'2, NIIS(O)2(CII2)o2C,cycloa1kyl or NIIS(O)2Ci4alkyl, where R'' and R'2 are independently selected from hydrogen, C:alky1, C(,cycloa1kyl, (C112)02phenyl, (ClI)o:IIet and (C112)o2hcteroaryl, optionally substituted by hydroxy, Ci 4alkyI, (C1I2)oiphenyl and C0211; or R! I and R1 2, together with the nitrogen atom to which they are joined, form a 6-membered -56 -ring, optionally containing one oxygen atom or one further nitrogen atom, and optionally substituted by C_ialky1 or (Clh)obenzodioxolanyl; and R4 is hydrogen or C14alkyl.
15. 15) A compound according to any one olclaims I to 14 for use in medicine.
16. 16) A pharmaceutical composition comprising a compound of formula (1) according to any one of claims I to 14 or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier.
17. 17) A method of inhibiting hepatitis C virus polymerase andlor of treating or preventing an illness due to hepatitis C virus, the method involving administering to a human or animal (preferably mammalian) subject suffering from the condition a therapeutically or prophylactically effective amount of the pharmaceutical composition described below or of a compound of formula (1) according to any one of claims I to 14, or a pharmaceutically 1 5 acceptable salt thereof.
18. 18) A further aspect of the invention provides the use of a compound of formula (1) according to any one of claims I to 14, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of infection by hepatitis C virus.