JP2007533693A - Acyl dihydropyrrole derivatives as HCV inhibitors - Google Patents

Abstract

［式中、Ａはヒドロキシを表し；Ｄはアリールまたはヘテロアリールを表し；Ｅは水素、Ｃ_1-6アルキル、アリール、ヘテロアリールまたはヘテロサイクリルを表し；Ｇは、水素、またはハロ、ＯＲ¹、ＳＲ¹、Ｃ(Ｏ)ＮＲ²Ｒ³、ＣＯ₂Ｈ、Ｃ(Ｏ)Ｒ⁴、ＣＯ₂Ｒ⁴、ＮＲ²Ｒ³、ＮＨＣ(Ｏ)Ｒ⁴、ＮＨＣＯ₂Ｒ⁴、ＮＨＣ(Ｏ)ＮＲ⁵Ｒ⁶、ＳＯ₂ＮＲ⁵Ｒ⁶、ＳＯ₂Ｒ⁴、ニトロ、シアノ、アリール、ヘテロアリールおよびヘテロサイクリルから選択される１つまたはそれ以上の置換基によって置換されていてもよいＣ_1-6アルキルを表し；Ｒ¹は水素、Ｃ_1-6アルキル、アリールアルキルまたはヘテロアリールアルキルを表し；Ｒ²およびＲ³は、独立して、水素、Ｃ_1-6アルキル、アリールおよびヘテロアリールから選択されるか；またはＲ²およびＲ³はそれらが結合している窒素原子と一緒になって５員または６員の飽和環状基を形成し；Ｒ⁴は、Ｃ_1-6アルキル、アリール、ヘテロアリール、アリールアルキルおよびヘテロアリールアルキルからなる群から選択され；Ｒ⁵およびＲ⁶は、独立して、水素、Ｃ_1-6アルキル、アリール、ヘテロアリール、アリールアルキルおよびヘテロアリールアルキルからなる群から選択されるか；またはＲ⁵およびＲ⁶はそれらが結合している窒素原子と一緒になって５員または６員の飽和環状基を形成し；Ｊは、Ｃ_1-6アルキル、ヘテロサイクリルアルキル、アリールアルキルまたはヘテロアリールアルキルを表す］で示されるで示される新規抗ウイルス薬ならびにその塩、溶媒和物およびエステル（ただし、Ａがエステル化されて−ＯＲ（ここで、Ｒは、直鎖または分枝鎖状のアルキル、アラルキル、アリールオキシアルキルまたはアリールから選択される）を形成する場合、Ｒはtert−ブチル以外である）；それらの製造方法、それらを含む医薬組成物、およびＨＣＶ治療におけるそれらの使用が提供される。Formula (I):

Wherein A represents hydroxy; D represents aryl or heteroaryl; E represents hydrogen, C _1-6 alkyl, aryl, heteroaryl or heterocyclyl; G represents hydrogen, halo, OR ¹ , SR ¹ , C (O) NR ² R ³ , CO ₂ H, C (O) R ⁴ , CO ₂ R ⁴ , NR ² R ³ , NHC (O) R ⁴ , NHCO ₂ R ⁴ , NHC (O) C ₁ optionally substituted by one or more substituents selected from NR ⁵ R ⁶ , SO ₂ NR ⁵ R ⁶ , SO ₂ R ⁴ , nitro, cyano, aryl, heteroaryl and heterocyclyl. _-6 alkyl; R ¹ is hydrogen, C _1-6 alkyl, arylalkyl or heteroarylalkyl; R ² and R ³ are independently hydrogen, C _1-6 alkyl, aryl and heteroaryl or is selected; or R ² And R ³ form a saturated cyclic group of 5-membered or 6-membered together with the nitrogen atom to which they are attached; R ⁴ is, C _1-6 alkyl, aryl, heteroaryl, arylalkyl and heteroaryl Selected from the group consisting of alkyl; R ⁵ and R ⁶ are independently selected from the group consisting of hydrogen, C _1-6 alkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl; or R ⁵ And R ⁶ together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated cyclic group; J is C _1-6 alkyl, heterocyclylalkyl, arylalkyl or heteroarylalkyl And the salts, solvates and esters thereof, provided that A is esterified to —OR (wherein R is selected from linear or branched alkyl, aralkyl, aryloxyalkyl or aryl), R is other than tert-butyl); their production method, pharmaceutical composition comprising them And their use in HCV treatment.

Description

  The present invention relates to a novel acyl dihydropyrrole derivative useful as an antiviral agent. Specifically, the present invention includes novel hepatitis C virus (HCV) inhibitors.

  Non-Patent Document 1, Non-Patent Document 2 and Non-Patent Document 3 disclose 4 ′, 5′-unsubstituted acylpyrrolidine compounds useful as reagents in the regioselective synthesis of bridged azabicyclo compounds; No medical use was disclosed for the compounds.

  Non-Patent Document 4, Non-Patent Document 5 and Non-Patent Document 6 disclose 4 ′, 5′-unsubstituted acylpyrrolidine compounds useful as reagents in the synthesis of tricyclic nitrogen-containing heterocycles; No medical use has been disclosed for pyrrolidine compounds. Non-Patent Document 7 discloses 4 ′, 5′-unsubstituted acylpyrrolidine compounds useful as reagents in the synthesis of non-peptide fibrinogen receptor antagonists; medical uses are disclosed for these acylpyrrolidine compounds. There wasn't.

  Non-Patent Document 8 discloses a 4 ′, 5′-unsubstituted acylpyrrolidine compound useful as a reagent in the synthesis of azomethine ylide; no medical use was disclosed for this acylpyrrolidine compound. Non-Patent Document 9 and Non-Patent Document 10 include 4 ′, 5′-unsubstituted acylpyrrolidine compounds useful as reagents in the synthesis of 7-spiroamine quinolones and spiro [indan-2,2′-pyrrolidine] compounds, respectively. No medical use has been disclosed for this acylpyrrolidine compound.

  Patent Document 1, Patent Document 2 and Patent Document 3 describe 4 ′, 5′-unsubstituted acyls useful as intermediates in the synthesis of indole carboxamide, N-aroyl amino acid amide and N-acyl-α-amino acid derivatives, respectively. A pyrrolidine compound has been disclosed; no medical use has been disclosed for this acylpyrrolidine compound.

  Non-Patent Document 11 discloses three types of pyrrolidinedicarboxylic acid derivatives useful as intermediates in the synthesis of pyrrolo [1,4] benzodiazepine compounds; no medical use is disclosed for these pyrrolidinedicarboxylic acid derivatives. It was.

  Patent Document 4 discloses an oxaazaheterocyclyl derivative having a factor Xa inhibitory activity, particularly a piperazinone compound. These derivatives can include certain acylpyrrolidine derivatives. There is no mention of HCV polymerase inhibitory activity for the disclosed compounds.

  HCV infection is a major cause of human liver disease worldwide. In the United States, an estimated 4.5 million Americans are chronically infected with HCV. Although only 30% of acute infections are manifest, more than 85% of infected individuals become chronic persistent infections. The cost of treating HCV infection in the United States in 1997 was estimated at $ 5,460 million. It is estimated that over 200 million people worldwide are chronically infected. 40-60% of all chronic liver diseases and 30% of all liver transplants are due to HCV infection. In the United States, cirrhosis, end-stage liver disease and 30% of all liver cancers are caused by chronic HCV infection. The CDC predicts that the number of deaths due to HCV will increase to a minimum of 38,000 per year by 2010.

  Due to the high variability of viral surface antigens, the presence of multiple viral genotypes and the revealed specificity of immunity, the potential for the development of effective vaccines in the near future is low. Alpha interferon (alone or in combination with ribavirin) has been widely used since it was approved for the treatment of chronic HCV infection. However, this treatment is generally accompanied by adverse side effects: influenza-like symptoms, leukopenia, thrombocytopenia, interferon depression and ribavirin-induced anemia (12). This therapy still has an effect on infections caused by HCV genotype 1 (which constitutes about 75% of all HCV infections in the developed market) compared to the effect on infections caused by the remaining 5 major HCV genotypes. Low. Unfortunately, only about 50-80% of patients respond to this treatment (measured by decreased serum HCV RNA levels and normalization of liver enzymes), and 50-70% of treated individuals Relapse within 6 months of discontinuing treatment. In recent years, with the introduction of pegylated interferon, both the initial response rate and the sustained response rate have been substantially improved, and the combination therapy of Peg-IFN and ribavirin is an excellent treatment level. However, side effects associated with combination therapy and response inhibition in patients with genotype 1 provide an opportunity for improved management of the disease.

  HCV was first identified by molecular cloning in 1989 (Non-Patent Document 13) and is now widely recognized as the most common virulence factor of post-transfusion non-A non-B hepatitis (NANBH) (Non-Patent Document 14). Yes. Due to its genomic structure and sequence homology, this virus has been assigned as a new genus in the Flaviviridae family. Flavivirus (eg yellow fever virus and dengue virus type 1 to 4) and pestivirus (eg bovine viral diarrhea virus, border disease virus and classical swine fever virus) (Non-patent Document 13; Like other members of the genus Flavivirus such as Non-Patent Document 15), HCV is an enveloped virus that contains a positive-polarity single-stranded RNA molecule. The HCV genome is about 9.6 kilobases (kb) with a long, highly conserved, 5 'untranslated region (NTR) without cap structure that functions as an in-sequence ribosome entry site (IRES). (Non-patent Document 16). Following this element is a region that encodes a single long open reading frame (ORF) that encodes a polypeptide of about 3000 amino acids, including both structural and non-structural viral proteins.

  Upon entry into the cell cytoplasm, this RNA is translated directly into a polypeptide of about 3000 amino acids, including both structural and nonstructural viral proteins. This large polypeptide is then processed into individual structural and non-structural proteins by a combination of proteinases encoded by the host and virus (Non-Patent Document 17). Next to the stop codon at the end of the long ORF, there are roughly three regions (about 40 base regions that are less conserved among the various genotypes, variable length poly (U) / polypyrimidine tract, and “3 ′ There is a 3′NTR consisting of a highly conserved 98 base element, also referred to as the “X-terminus” (Non-Patent Document 18; Non-Patent Document 19; Non-Patent Document 20; The 3 ′ NTR is predicted to form a stable secondary structure essential for HCV growth in chimpanzees and is thought to function in the initiation and regulation of viral RNA replication.

NS5B protein of HCV (591 amino acids, 65 kDa) (Non-Patent Document 22) encodes RNA-dependent RNA polymerase (RdRp) activity and contains a standard motif present in other RNA viral polymerases. The NS5B protein is approximately 85-85 amino acids within a type (about 95-98% amino acid (aa) identity across 1b isolates) and between types (between genotype 1a and genotype 1b isolates). % Aa identity) is very well preserved. The essentiality of HCV NS5B RdRp activity for the development of infectious progeny virions has been formally demonstrated in chimpanzees (23). Thus, inhibition of NS5B RdRp activity (inhibition of RNA replication) is expected to treat HCV infection.
WO2002 / 44168 WO96 / 33170 EP505868A2 WO99 / 37304 Ikeda et al, (1997) Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry 22: 3339-3344 Sato et al, (1995) Journal of the Chemical Society, Perkin Transactions 1, 14: 1801-1809 Sato et al, (1994) Heterocycles 37 (1): 245-248 Ikeda et al, (1996) Heterocycles 42 (1): 155-158 Confalone et al, (1988) Journal of Organic Chemistry 53 (3): 482-487 De Martino et al, (1976) Farmaco, Ed. Sci. 31 (11): 785-790 Alig et al, (1992) Journal of Medicinal Chemistry 35 (23): 4393-4407 Padwa et al, (1992) Journal of the American Chemical society 114 (2): 593-601 Culbertson et al, (1990) Journal of Medicinal Chemistry 33 (8): 2270-2275 Crooks et al, (1979) Journal of the Chemical Society, Perkins Transactions 1, 11: 2719-2726 De Caprariis et al, (1989) Journal of Heterocyclic Chemistry 26 (4): 1023-1027 Lindsay, KL (1997) Hepatology 26 (suppl 1): 71S-77S Choo, QL et al (1989) Science 244: 359-362 Kuo, G et al (1989) Science 244: 362-364 Miller, RH and RH Purcell (1990) Proc. Natl. Acad. Sci. USA 87: 2057-2061 Wang CY et al'An RNA pseudoknot is an essential structural element of the internal ribosome entry site located within the hepatitis C virus 5 'noncoding region' RNA- A Publication of the RNA Society. 1 (5): 526-537, 1995 Jul . Rice, CM (1996) in BN Fields, DMKnipe and PM Howley (eds) Virology 2nd Edition, p931-960; Raven Press, NY Kolykhalov, A. et al (1996) J. Virology 70: 3363-3371 Tanaka, T. et al (1995) Biochem Biophys. Res. Commun. 215: 744-749 Tanaka, T. et al (1996) J. Virology 70: 3307-3312 Yamada, N. et al (1996) Virology 223: 255-261 Behrens, SE et al (1996) EMBO J. 15: 12-22 AA Kolykhalov et al .. (2000) Journal of Virology, 74 (4), p.2046-2051

  According to the above, there is a great need to identify synthetic or biological compounds for their ability to inhibit HCV.

(Summary of Invention)
The present invention includes the acyl dihydropyrrole compounds shown below, pharmaceutical compositions containing such compounds and the use of such compounds in the treatment of viral infections, particularly HCV infections.

［式中、
Ａはヒドロキシを表し；
Ｄはアリールまたはヘテロアリールを表し；
Ｅは水素、Ｃ_1-6アルキル、アリール、ヘテロアリールまたはヘテロサイクリルを表し；
Ｇは、水素、またはハロ、ＯＲ¹、ＳＲ¹、Ｃ(Ｏ)ＮＲ²Ｒ³、ＣＯ₂Ｈ、Ｃ(Ｏ)Ｒ⁴、ＣＯ₂Ｒ⁴、ＮＲ²Ｒ³、ＮＨＣ(Ｏ)Ｒ⁴、ＮＨＣＯ₂Ｒ⁴、ＮＨＣ(Ｏ)ＮＲ⁵Ｒ⁶、ＳＯ₂ＮＲ⁵Ｒ⁶、ＳＯ₂Ｒ⁴、ニトロ、シアノ、アリール、ヘテロアリールおよびヘテロサイクリルから選択される１つまたはそれ以上の置換基によって置換されていてもよいＣ_1-6アルキルを表し；
Ｒ¹は水素、Ｃ_1-6アルキル、アリールアルキルまたはヘテロアリールアルキルを表し；
Ｒ²およびＲ³は、独立して、水素、Ｃ_1-6アルキル、アリールおよびヘテロアリールから選択されるか；またはＲ²およびＲ³はそれらが結合している窒素原子と一緒になって５員または６員の飽和環状基を形成し；
Ｒ⁴は、Ｃ_1-6アルキル、アリール、ヘテロアリール、アリールアルキルおよびヘテロアリールアルキルからなる群から選択され；
Ｒ⁵およびＲ⁶は、独立して、水素、Ｃ_1-6アルキル、アリール、ヘテロアリール、アリールアルキルおよびヘテロアリールアルキルからなる群から選択されるか；またはＲ⁵およびＲ⁶はそれらが結合している窒素原子と一緒になって５員または６員の飽和環状基を形成し；
ＪはＣ_1-6アルキル、ヘテロサイクリルアルキル、アリールアルキルまたはヘテロアリールアルキルを表す］
で示される化合物ならびにその塩、溶媒和物およびエステル（ただし、Ａがエステル化されて−ＯＲ（ここで、Ｒは、直鎖または分枝鎖状のアルキル、アラルキル、アリールオキシアルキルまたはアリールから選択される）を形成する場合、Ｒはtert−ブチル以外である）から選択される少なくとも１つの化学物質を提供する。 (Detailed description of the invention)
The present invention relates to a compound of formula (I):

[Where:
A represents hydroxy;
D represents aryl or heteroaryl;
E represents hydrogen, C _1-6 alkyl, aryl, heteroaryl or heterocyclyl;
G is hydrogen, or halo, OR ¹ , SR ¹ , C (O) NR ² R ³ , CO ₂ H, C (O) R ⁴ , CO ₂ R ⁴ , NR ² R ³ , NHC (O) R ⁴ One or more substitutions selected from NHCO ₂ R ⁴ , NHC (O) NR ⁵ R ⁶ , SO ₂ NR ⁵ R ⁶ , SO ₂ R ⁴ , nitro, cyano, aryl, heteroaryl and heterocyclyl _Represents C _1-6 alkyl _optionally substituted by a group;
R ¹ represents hydrogen, C _1-6 alkyl, arylalkyl or heteroarylalkyl;
R ² and R ³ are independently selected from hydrogen, C _1-6 alkyl, aryl and heteroaryl; or R ² and R ³ together with the nitrogen atom to which they are attached 5 Forming a 6-membered or 6-membered saturated cyclic group;
R ⁴ is selected from the group consisting of C _1-6 alkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl;
R ⁵ and R ⁶ are independently selected from the group consisting of hydrogen, C _1-6 alkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl; or R ⁵ and R ⁶ are attached to them. Together with the nitrogen atom forming a 5- or 6-membered saturated cyclic group;
J represents C _1-6 alkyl, heterocyclylalkyl, arylalkyl or heteroarylalkyl]
And the salts, solvates and esters thereof, wherein A is esterified to —OR (where R is selected from linear or branched alkyl, aralkyl, aryloxyalkyl or aryl And R is other than tert-butyl).

  As a further aspect of the invention, a compound of formula (I) or physiologically thereof for use in human or veterinary pharmacotherapy, in particular in the treatment or prevention of viral infections (especially HCV infection) Acceptable salts, solvates or esters are provided.

  It will be apparent that reference herein to treatment and / or prevention includes, but is not limited to, prevention, delay, prevention, treatment and cure of the disease. Furthermore, it will be apparent that references herein to treatment or prevention of HCV infection include treatment or prevention of HCV-related diseases such as liver fibrosis, cirrhosis and hepatocellular carcinoma.

  According to another aspect of the present invention, a compound of formula (I) or a physiologically acceptable salt, solvation thereof in the manufacture of a medicament for the treatment and / or prevention of viral infections (especially HCV infection) Use of the product or ester is provided.

  In a further or alternative embodiment, a method of treating a human or animal subject suffering from a viral infection (particularly an HCV infection), wherein the compound of formula (I) or A method is provided comprising administering an effective amount of a physiologically acceptable salt, solvate or ester thereof.

  It will be apparent that the compounds of the invention may contain one or more asymmetric carbon atoms and may exist in racemic, diastereoisomeric and optically active forms. These racemates, enantiomers and diastereoisomers are all considered to be within the scope of the invention.

［式中、Ａ、Ｄ、Ｅ、ＧおよびＪは式（Ｉ）についての上記定義と同じである］
で示される。 In one aspect of the invention, the relative stereochemistry of the compound of formula (I) is of formula (Ip):

[Wherein A, D, E, G and J are as defined above for formula (I)]
Indicated by

  The following aspects of the invention are applicable for each of Formula I and Formula Ip.

In one aspect of the invention, D represents optionally substituted phenyl; in another aspect, further substituted tert-butylphenyl; in a further aspect, D represents halo, C _{1 Represents} para-tert-butylphenyl which may be further substituted (in one embodiment, meta-substituted) by _-3 alkyl or C _1-3 alkoxy (eg, bromo, chloro, methyl or methoxy); , D represents meta-methoxy-para-tert-butylphenyl (3-methoxy-4-tert-butylphenyl).

  In one aspect, E represents an optionally substituted heteroaryl; in a further aspect, E represents thiazolyl or isoxazolyl, both of which may be substituted. In one aspect, E represents an optionally substituted thiazolyl. In another aspect, E represents an optionally substituted isoxazolyl. In another aspect E represents 1,3-thiazol-2-yl or 5-methyl-isoxazol-3-yl.

In one aspect G represents C _1-6 alkyl optionally substituted by OR ¹ , SR ¹ or SO ₂ R ⁴ ; in another aspect G is OR ¹ , SR ¹ or SO ₂ R Represents methyl optionally substituted by ⁴ ;

In one embodiment R ¹ represents C _1-3 alkyl; in another embodiment R ¹ represents methyl, ethyl or propyl; in a further embodiment methyl or ethyl.

In one embodiment R ⁴ represents C _1-3 alkyl; in another embodiment R ⁴ represents methyl, ethyl or propyl, in particular methyl.

In one aspect, J represents C _1-6 alkyl, arylalkyl or heteroarylalkyl. In another aspect J represents C _1-6 alkyl or heteroarylmethyl. In a further aspect, J represents isobutyl or 1,3-thiazol-4-ylmethyl. In one aspect, J represents isobutyl. In another aspect J represents 1,3-thiazol-4-ylmethyl.

  The present invention should be understood to encompass all combinations of the aspects of the invention described herein.

As used herein, unless otherwise stated, “alkyl” refers to an optionally substituted hydrocarbon group. Alkyl hydrocarbon groups can be straight chain, branched chain or cyclic and can be saturated or unsaturated. When the alkyl group is linear or branched, examples of such groups include methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, isobutyl, sec-butyl, tert-butyl. , N-pentyl, isopentyl, neopentyl, hexyl and the like. In one aspect, the alkyl moiety is C _1-4 alkyl. If an alkyl hydrocarbon group is unsaturated, it will be understood that there are at least two carbon atoms in the group (eg, an alkenyl or alkynyl group). If the alkyl hydrocarbon group is cyclic, it will be understood that there are at least 3 carbon atoms in the group. Cyclic alkyl groups can be saturated or unsaturated monocyclic or bridged bicyclic. When the cyclic alkyl group is saturated, examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. When the cyclic alkyl group is unsaturated, examples of such groups include cyclobutenyl, cyclopentenyl, cyclohexenyl and the like. In one aspect, the cyclic alkyl group has 3-6 carbon atoms. Unless otherwise specified, optional substituents include C _1-6 alkyl, halo, OR ¹ , SR ¹ , C (O) NR ² R ³ , C (O) R ⁴ , CO ₂ H, CO ₂ R ⁴ , NR ² R ³ , NHC (O) R ⁴ , NHCO ₂ R ⁴ , NHC (O) NR ⁵ R ⁶ , SO ₂ NR ⁵ R ⁶ , SO ₂ R ⁴ , nitro, cyano, oxo and heterocyclyl. .

  As used herein, the term “alkenyl” refers to a straight or branched chain hydrocarbon group containing one or more carbon-carbon double bonds. In one aspect, the alkenyl group has 2-6 carbon atoms. Examples of such groups include ethenyl, propenyl, butenyl, pentenyl or hexenyl.

  As used herein, the term “alkynyl” refers to a straight or branched chain hydrocarbon group containing one or more carbon-carbon triple bonds. In one aspect, the alkynyl group has 2-6 carbon atoms. Examples of such groups include ethynyl, propynyl, butynyl, pentynyl or hexynyl.

  As used herein, “alkoxy” (when used as a group or as part of a group) refers to an alkyl ether group, where the term “alkyl” is as defined above. The same. Examples of alkoxy as used herein include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, and the like.

As used herein, “aryl” refers to an optionally substituted aromatic having at least one ring having a conjugated π-electron system and containing up to two conjugated or fused ring systems. Refers to the group. “Aryl” includes carbocyclic aryl and biaryl groups, any of which may be substituted, such as phenyl, naphthyl or bi-phenyl. In one aspect, the “aryl” moiety is unsubstituted, monosubstituted, disubstituted or trisubstituted phenyl. In another aspect, the “aryl” substituent is C _1-6 alkyl, halo, OR ¹ , C (O) NR ² R ³ , C (O) R ⁴ , CO ₂ H, CO ₂ R ⁴ , NR ^2. R ³ , NHC (O) R ⁴ , NHCO ₂ R ⁴ , NHC (O) NR ⁵ R ⁶ , SO ₂ NR ⁵ R ⁶ , SO ₂ R ⁴ , nitro, cyano, oxo, heterocyclyl, CF ₃ and NO Selected from the group consisting of _two .

  As used herein, “arylalkyl” refers to an aryl group that is attached to the parent molecular moiety through an alkyl group.

As used herein, “heteroaryl” is selected from N, O, and S having at least one ring having a conjugated π-electron system and containing up to two conjugated or fused rings. Or an optionally substituted 5- or 6-membered aromatic group containing 1 to 4 heteroatoms. In one embodiment, the “heteroaryl” moiety is unsubstituted, monosubstituted or disubstituted thiazolyl. In another embodiment, the “heteroaryl” moiety is an unsubstituted, monosubstituted or disubstituted isoxazolyl. In another aspect, a “heteroaryl” substituent is a C _1-6 alkyl, halo, OR ¹ , C (O) NR ² R ³ , C (O) R ⁴ , CO ₂ H, CO ₂ R ⁴ , NR ² R ³ , NHC (O) R ⁴ , NHCO ₂ R ⁴ , NHC (O) NR ⁵ R ⁶ , SO ₂ NR ⁵ R ⁶ , SO ₂ R ⁴ , nitro, cyano, oxo, heterocyclyl, CF ₃ and Selected from the group consisting of NO ₂ .

  As used herein, “heteroarylalkyl” refers to a heteroaryl group that is attached to the parent molecular moiety through an alkyl group.

As used herein, “heterocycle” and “heterocyclyl” are substituted by hydrogen, C _1-6 alkyl, C (O) R ⁴ , SO ₂ R ⁴ , aryl or heteroaryl. Optionally substituted 5 or 6 membered containing 1 to 2 heteroatoms selected from N; O; and S optionally substituted by 1 or 2 carbon atoms A saturated cyclic hydrocarbon group.

  As used herein, “heterocyclylalkyl” refers to a heterocyclyl group attached to the parent molecular moiety through an alkyl group.

  As used herein, the term “pharmaceutically acceptable” refers to a compound that is suitable for pharmaceutical use. Salts and solvates of the compounds of the invention that are suitable for use in medicine are those in which the counterion or associated solvent is pharmaceutically acceptable. However, salts and solvates having a pharmaceutically unacceptable counterion or associating solvent may be used, for example, as intermediates in the preparation of other compounds of the invention and their pharmaceutically acceptable salts and solvates. Within the scope of the invention.

In one aspect, a chemical useful in the present invention can be at least one chemical selected from the group consisting of the following compounds:
rel- (2S, 5R) -2-isobutyl-1- (3-methoxy-4-tert-butylbenzoyl) -4-ethoxymethyl-5- (1,3-thiazol-2-yl) -2,5- Dihydro-1H-pyrrole-2-carboxylic acid;
rel- (2S, 5R) -2-isobutyl-1- (3-methoxy-4-tert-butylbenzoyl) -4-methoxymethyl-5- (1,3-thiazol-2-yl) -2,5- Dihydro-1H-pyrrole-2-carboxylic acid;
rel- (2S, 5R) -2-isobutyl-1- (3-methoxy-4-tert-butylbenzoyl) -4-n-propyloxymethyl-5- (1,3-thiazol-2-yl) -2 , 5-dihydro-1H-pyrrole-2-carboxylic acid;
rel- (2S, 5R) -2-isobutyl-1- (3-methoxy-4-tert-butylbenzoyl) -4-methylthiomethyl-5- (1,3-thiazol-2-yl) -2,5- Dihydro-1H-pyrrole-2-carboxylic acid;
rel- (2S, 5R) -2-isobutyl-1- (3-methoxy-4-tert-butylbenzoyl) -4-methylsulfonylmethyl-5- (1,3-thiazol-2-yl) -2,5 -Dihydro-1H-pyrrole-2-carboxylic acid;
rel- (2S, 5R) -1- (3-methoxy-4-tert-butylbenzoyl) -4- (methoxymethyl) -5- (5-methylisoxazol-3-yl) -2- (1,3 -Thiazol-4-ylmethyl) -2,5-dihydro-1H-pyrrole-2-carboxylic acid; and its salts, solvates and esters, and the individual enantiomers.

  In one aspect of the invention, a pharmaceutically acceptable salt complex is provided. The present invention also includes pharmaceutically acceptable salts of the compounds of formula (I). In one aspect, physiologically acceptable salts of the compounds of formula (I) include acid salts such as sodium, potassium, calcium, magnesium and tetraalkylammonium, or suitable acids such as acetic acid. Organic carboxylic acids such as lactic acid, tartaric acid, malic acid, isethionic acid, lactobionic acid and succinic acid; organic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid, and hydrochloric acid, Monobasic or dibasic salts with inorganic acids such as sulfuric acid, phosphoric acid and sulfamic acid.

In another aspect, the present invention also provides a pharmaceutically acceptable ester of a compound of formula (I), such as a carboxylic acid ester -COOR, wherein R is a linear or branched alkyl, For example, n-propyl, n-butyl, alkoxyalkyl (eg methoxymethyl), aralkyl (eg benzyl), aryloxyalkyl (eg phenoxymethyl), aryl (eg halogen, C _1-4 alkyl or C _{1 -4,} phenyl optionally substituted by alkoxy or amino). Unless otherwise stated, in one embodiment, any alkyl moiety present in such esters contains 1 to 18 carbon atoms, particularly 1 to 4 carbon atoms. In one aspect, any aryl moiety present in such esters comprises a phenyl group.

  In one aspect, the invention relates to compounds of formula (I) and salts and solvates thereof.

  In another aspect, the present invention relates to compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof.

  In one aspect, the invention relates to solvates, eg hydrates, of the compounds of formula (I).

  Furthermore, it will be apparent that certain compounds of the present invention may exist in various tautomeric forms. All tautomers are considered to be within the scope of the present invention.

［式中、Ａは保護ヒドロキシ基、例えば、アルコキシまたはシリルオキシ、例えば、トリ−(Ｃ_1-4アルキル)−シリルオキシ基であり、Ｄ、Ｅ、ＧおよびＪは、式（Ｉ）についての上記定義と同じである］で示される化合物から脱保護により製造され得る。適当な保護基は、T W Greene and P G M Wuts ‘Protective Groups in Organic Synthesis', 3^rd Ed (1999), J Wiley and Sonsに見られるが、該文献に記載されているものに限定されるものではない。 A compound of formula (I) wherein A is hydroxy is a compound of formula (II):

Wherein A is a protected hydroxy group such as alkoxy or silyloxy, such as a tri- (C _1-4 alkyl) -silyloxy group, and D, E, G and J are as defined above for formula (I) Can be produced by deprotection from a compound represented by Suitable protecting groups are found in TW Greene and PGM Wuts 'Protective Groups in Organic Synthesis', 3 ^rd Ed (1999), J Wiley and Sons, but are not limited to those described in the literature. .

  For example, when A is tert-butoxy and D, E, G and J are as defined above for formula (I), by treatment with a suitable acid (eg, trifluoroacetic acid). In one aspect, the reaction is performed in a solvent (eg, dichloromethane). In one embodiment, the temperature is in the range of 0-50 ° C, and in another embodiment, the temperature is in the range of 20-30 ° C.

  For example, when A is allyloxy and D, E, G and J are as defined above for formula (I), a suitable catalyst (eg, tetrakis (triphenylphosphine) palladium (0)) and a suitable By treatment with a proton source (eg, phenylsilane). The reaction is performed in a suitable solvent (eg, dichloromethane).

  For example, when A is tri (methyl) silyloxy and D, E, G and J are as defined above for formula (I), with an appropriate fluoride source (eg, tetrabutylammonium fluoride) By processing. The reaction is performed in a suitable solvent (eg, THF).

［式中、Ａ、Ｅ、ＧおよびＪは式（Ｉ）についての上記定義と同じである］で示される化合物と適当なアシル化剤（例えば、Ｄ−Ｃ(Ｏ)−hal（ここで、halはハロ原子、例えば、クロロまたはブロモであり、Ｄは式（Ｉ）についての上記定義と同じである））との反応によって製造することもできる。一の態様では、該反応は、適当な塩基（例えば、トリエチルアミン）の存在下で、適当な溶媒（例えば、ジクロロメタン）中にて行われ、その後、いずれもの保護基を除去する。適当な保護基は、T W Greene and P G M Wuts ‘Protective Groups in Organic Synthesis', 3^rd Ed (1999), J Wiley and Sonsに見られるが、該文献に記載されているものに限定されるものではない。 A compound of formula (I) wherein A is hydroxy or a protected form thereof is also of formula (III):

Wherein A, E, G and J are as defined above for formula (I) and a suitable acylating agent (eg, DC (O) -hal (where hal is a halo atom, for example chloro or bromo, and D is as defined above for formula (I)))). In one embodiment, the reaction is performed in a suitable solvent (eg, dichloromethane) in the presence of a suitable base (eg, triethylamine), after which any protecting groups are removed. Suitable protecting groups are found in TW Greene and PGM Wuts 'Protective Groups in Organic Synthesis', 3 ^rd Ed (1999), J Wiley and Sons, but are not limited to those described in the literature. .

［式中、Ａはヒドロキシまたはアルコキシまたはトリ−(Ｃ_1-4アルキル)−シリルオキシ基であり、Ｄ、ＥおよびＪは式（Ｉ）についての上記定義と同じであり、Ｌは、ＣＯ₂ＹまたはＣＯＹを表し、ここで、Ｙは、水素またはアルキルを表す］で示される化合物の適当な操作によって製造することができる。 A compound of formula (I) or (II) in which G represents an optionally substituted alkyl is of formula (IIa):

Wherein A is a hydroxy or alkoxy or tri- (C _1-4 alkyl) -silyloxy group, D, E and J are as defined above for formula (I) and L is CO ₂ Y Or represents COY, where Y represents hydrogen or alkyl].

For example, the compound represented by formula (II) in which G represents hydroxyalkyl is converted into a suitable reducing agent (eg, lithium borohydride, hydrogenated) in a suitable solvent or a mixture thereof (eg, THF or methanol). Sodium boron, triacetoxy sodium borohydride, borane / dimethyl sulfide complex or lithium aluminum hydride, or a suitable combination thereof), L represents CO ₂ Y or COY and Y represents hydrogen or alkyl It can be produced by reducing the compound represented by the formula (IIa).

For example, a compound of formula (II) wherein G represents hydroxyalkyl may also be represented by the formula (L) representing CO ₂ Y or COY and Y representing hydrogen or alkyl in a suitable solvent (eg, THF). It can also be prepared by reacting the compound of IIa) with a suitable organometallic reagent (for example methylmagnesium bromide or methyllithium).

  For example, a compound represented by formula (II) in which G represents difluoroalkyl is represented by a compound represented by formula (IIa) in which L represents COY and Y represents alkyl in a suitable solvent (eg, dichloromethane). It can be prepared by reacting with a suitable fluorinating agent (eg, diethylaminosulfur trifluoride).

  For example, a compound of formula (II) wherein G represents alkenyl is a compound of formula (II) wherein L represents COY in the presence of a base (eg lithium bis (trimethylsilyl) amide) in a suitable solvent (eg THF) Compounds of formula (IIa) in which Y represents hydrogen or alkyl are converted to phosphonium salts (eg phosphonium such as methyltriphenylphosphonium bromide, methyltriphenylphosphonium chloride, methoxymethyltriphenylphosphonium bromide or methoxymethyltriphenylphosphonium chloride) (Halide salt).

  In a further aspect, a compound of formula (II) can be prepared by appropriate manipulation of another compound of formula (II). For example, converting a compound of formula (II) in which G represents hydroxyalkyl to a compound of formula (II) in which G represents an optionally substituted alkyl, such as alkyl, haloalkyl or alkoxyalkyl Can do.

  For example, a compound of formula (II) in which G represents alkoxyalkyl can be obtained by replacing a compound of formula (II) in which G represents hydroxyalkyl with a suitable base (eg sodium hydride) and a suitable alkylating agent. (E.g., methylated using methyl iodide or ethylated using ethyl iodide). it can. In one aspect, the reaction is performed in a suitable solvent (eg, DMF).

  For example, a compound of formula (II) in which G represents haloalkyl is prepared by halogenating a compound of formula (II) in which G represents hydroxyalkyl using an appropriate halogenating agent. For example, hydroxymethyl can be converted to fluoromethyl using a suitable fluorinating agent (eg, diethylaminosulfur trifluoride) in a suitable solvent (eg, dichloromethane).

For example, a compound of formula (II) in which G represents cyanomethyl is reacted with a compound of formula (II) in which G represents hydroxymethyl, for example with trifluoromethanesulfonic anhydride, and then the product Can be prepared by treatment with a nucleophile (eg, a cyanide salt such as tetrabutylammonium cyanide). Compound G is the formula (II) representing the C _1-4 alkylthiomethyl may be prepared similarly using the C _1-4 alkyl thiolate as nucleophile.

For example, a compound of formula (II) in which G represents C _1-4 alkylsulfonylmethyl can be prepared by using, for example, 3-chloroperbenzoic acid in a suitable solvent (eg, dichloromethane) and G is C It can be produced by oxidizing a compound represented by formula (II) representing _1-4 alkylthiomethyl.

  For example, a compound of formula (II) in which G represents alkyl can be prepared by deoxylation of a compound of formula (II) in which G represents hydroxyalkyl. In one embodiment, the deoxylation is performed in a two-step process: Step (i) A compound of formula (II) wherein G represents hydroxyalkyl is converted to a suitable chloroformate (eg 4-fluorophenylthio). Nochloroformate) to convert to thionocarbonate. In one embodiment, the reaction is performed in a suitable solvent (eg, dichloromethane) in the presence of a suitable base catalyst (eg, 4- (N, N-dimethylamino) pyridine). Step (ii) The thionocarbonate from step (i) is combined with a suitable radical initiator (eg, AIBN) and a suitable proton source (eg, tris (trimethylsilyl) in a suitable solvent (eg, dioxane). Silane). In one aspect, the temperature is in the range of 80-120 ° C.

  For example, a compound of formula (II) in which G represents an unsaturated alkyl group such as 1-methylethenyl or 2-methoxyethenyl can be prepared in the presence of a suitable catalyst (eg palladium-charcoal) in a suitable solvent ( For example, hydrogenation in ethanol) can be converted to compounds of formula (II) in which G represents a saturated alkyl group such as isopropyl or 2-methoxyethyl.

  For example, a compound of formula (II) in which G represents alkenyloxyalkyl or substituted alkenyloxyalkyl can be obtained by hydrogenation in a suitable solvent (eg ethanol) in the presence of a suitable catalyst (eg palladium-charcoal). Can be converted to a compound of formula (II) wherein G represents alkyloxyalkyl or substituted alkyloxyalkyl. For example, allyloxyalkyl or substituted allyloxyalkyl can be converted to propyloxyalkyl or substituted propyloxyalkyl.

A compound of formula (IIa) in which L represents CO ₂ Y and Y represents hydrogen can be prepared from a compound of formula (IIa) in which L represents CO ₂ Y and Y represents alkyl. . For example, the compound of formula (IIa), where L represents CO ₂ Me, can be hydrolyzed, eg, base-catalyzed hydrolysis using a suitable base such as sodium hydroxide in a suitable solvent such as methanol. Can be converted to a compound of formula (IIa) wherein L represents CO ₂ H.

［式中、Ｌは、ＣＯ₂ＹまたはＣＯＹを表し、Ｙは、水素またはアルキルを表し、Ａ、ＥおよびＪは、式（Ｉ）についての上記定義と同じである］で示される化合物から製造することができる。一の態様では、該反応は、適当な塩基（例えば、トリエチルアミン）の存在下、適当な溶媒（例えば、ジクロロメタン）中で行われる。 A compound of formula (IIa) in which L represents CO ₂ Y or COY and Y represents hydrogen or alkyl can be obtained by using a suitable acylating agent (eg, DC (O) -hal (where hal is halo An atom, for example chloro or bromo, and D is as defined above for formula (I)), using formula (IIIa):

[Wherein L represents CO ₂ Y or COY, Y represents hydrogen or alkyl, and A, E and J are as defined above for formula (I)]. can do. In one embodiment, the reaction is performed in a suitable solvent (eg, dichloromethane) in the presence of a suitable base (eg, triethylamine).

In a further aspect, the compound of formula (IIa), wherein L represents COY and Y represents hydrogen, is obtained from a compound of formula (IIa) wherein L represents CO ₂ Y and Y represents hydrogen or alkyl. It can be produced by a step method. In the first stage, the compound of formula (IIa), wherein L represents CO ₂ Y and Y represents hydrogen or alkyl, is treated with a suitable reducing agent (eg lithium aluminum hydride or sodium borohydride). In the second step, the resulting hydroxy group is oxidized with a suitable oxidizing agent (eg, a suitable mixture of oxalyl chloride, dimethyl sulfoxide and triethylamine) which can be selected from conventional oxidizing reagents known in the art. .

A compound of formula (IIa) wherein A is hydroxy can be converted to a compound of formula (IIa) wherein A is an alkoxy or silyloxy group by standard hydroxy protection techniques. Similarly, a compound of formula (IIa) wherein A is an alkoxy or silyloxy group can be converted to a compound of formula (IIa) wherein A is hydroxy by standard deprotection techniques. Suitable protecting groups are found in TW Greene and PGM Wuts 'Protective Groups in Organic Synthesis', 3 ^rd Ed (1999), J Wiley and Sons, but are not limited to those described in the literature. .

［式中、ＥおよびＪは、式（Ｉ）についての上記定義と同じであり、Ａは式（ＩＩ）についての上記定義と同じである］で示される化合物を式（Ｖ）：

［式中、Ｌは、ＣＯ₂ＹまたはＣＯＹを表し、Ｙは、水素またはアルキルを表す］で示される化合物と反応させることによって製造することができる。一の態様では、該反応は、臭化リチウムまたは酢酸銀のようなルイス酸触媒、およびトリエチルアミン、１,８−ジアザビシクロ[５,４,０]ウンデカ−７−エン（ＤＢＵ）またはテトラメチルグアニジンのような塩基の存在下であってもよい適当な溶媒（例えば、ＴＨＦまたはアセトニトリル）中で行われる。別法として、該反応は、酢酸のような酸の存在下、適当な溶媒（例えば、ＴＨＦまたはアセトニトリル）中で行われるか、または該反応は、触媒の不在下、適当な溶媒（例えば、トルエン、キシレンまたはアセトニトリル）中にて式（ＩＶ）で示される化合物および式（Ｖ）で示される化合物を加熱することによって行われ得る。 The compound represented by formula (IIIa) is represented by the formula (IV):

Wherein E and J are as defined above for formula (I) and A is as defined above for formula (II), wherein a compound of formula (V):

[Wherein L represents CO ₂ Y or COY, and Y represents hydrogen or alkyl]. In one embodiment, the reaction comprises a Lewis acid catalyst such as lithium bromide or silver acetate, and triethylamine, 1,8-diazabicyclo [5,4,0] undec-7-ene (DBU) or tetramethylguanidine. It is carried out in a suitable solvent (eg THF or acetonitrile) which may be in the presence of such a base. Alternatively, the reaction is carried out in a suitable solvent (eg THF or acetonitrile) in the presence of an acid such as acetic acid, or the reaction is carried out in the absence of a catalyst in a suitable solvent (eg toluene , Xylene or acetonitrile) and heating the compound of formula (IV) and the compound of formula (V).

The compound represented by the formula (III) in which G represents an optionally substituted alkyl is obtained by converting the compound represented by the formula (IIIa) into an N-protecting group (for example, benzyloxy After optionally protecting with carbonyl (CBZ) or tert-butoxycarbonyl), it can be prepared by appropriate operation. For example, a compound of formula (III) in which G represents hydroxyalkyl may be prepared using a suitable reducing agent (eg lithium borohydride or sodium borohydride) in a suitable solvent (eg THF). , L represents CO ₂ Y, and Y represents alkyl, and can be produced by reducing the compound represented by formula (IIIa). If protected prior to manipulation, deprotection of the N atom by standard methods yields compounds of formula (III). For example, when the N protecting group is tert-butoxycarbonyl, deprotection can be accomplished by treatment with a suitable acid (eg, trifluoroacetic acid).

  Similar to the method described above with respect to the compound of formula (II), the compound of formula (III) in which G represents hydroxyalkyl and the N atom is protected is an optionally substituted alkyl of G; For example, it represents an alkyl, haloalkyl or alkoxyalkyl, which can be converted to a compound of formula (III) in which the N atom is protected. Deprotection of the N atom by standard methods gives a new compound of formula (III).

［式中、Ｊは式（Ｉ）についての上記定義と同じであり、Ａは式（ＩＩ）についての上記定義と同じである］で示される化合物を式Ｅ−ＣＨＯで示される化合物と反応させることによって製造することができる。式（ＶＩ）で示される化合物の代わりに式（ＶＩ）で示される化合物の酸付加塩（例えば、塩酸塩）を使用する場合、該反応は、適当な塩基（例えば、トリエチルアミン）の存在下にて行うことができる。 The compound of formula (IV) is compounded with formula (VI): in a suitable solvent (eg dichloromethane) in the presence of any desiccant (eg magnesium sulfate).

[Wherein J is as defined above for formula (I) and A is as defined above for formula (II)] with a compound of formula E-CHO. Can be manufactured. When an acid addition salt (eg hydrochloride) of a compound of formula (VI) is used instead of a compound of formula (VI), the reaction is carried out in the presence of a suitable base (eg triethylamine). Can be done.

  Compounds of formula (VI) wherein J is other than heteroarylalkyl, acid addition salts of compounds of formula (VI) and E-CHO are known in the art or from standard literature It can be manufactured by a method.

［式中、Ｊは１,３−チアゾール−４−イルメチルのようなヘテロアリールアルキルであり、Ａは、アルコキシ、ベンジルオキシまたはトリ−(Ｃ_1-4アルキル)−シリルオキシ基である］で示される化合物を酸（例えば、１５％クエン酸）で処理することによって製造することができる。好ましくは、該反応は、適当な溶媒（例えば、ＴＨＦ）中にて行われる。 A compound of formula (VI) wherein J is a heteroarylalkyl such as 1,3-thiazol-4-ylmethyl and A is an alkoxy, benzyloxy or tri- (C _1-4 alkyl) -silyloxy group Formula (VII):

Wherein J is a heteroarylalkyl such as 1,3-thiazol-4-ylmethyl and A is an alkoxy, benzyloxy or tri- (C _1-4 alkyl) -silyloxy group. It can be prepared by treating a compound with an acid (eg, 15% citric acid). Preferably, the reaction is performed in a suitable solvent (eg, THF).

［式中、Ａはアルコキシ、ベンジルオキシまたはトリ−(Ｃ_1-4アルキル)−シリルオキシ基である］で示される化合物を式Ｊ−hal（式中、Ｊは１,３−チアゾール−４−イルメチルのようなヘテロアリールアルキルであり、halはハロ原子、好ましくは、クロロまたはブロモである）で示される化合物と反応させることによって製造することができる。好ましくは、該反応は、カリウムtert−ブトキシドのような適当な塩基の存在下にて行われる。好ましくは、該反応は、適当な溶媒（例えば、ＴＨＦ）中で行われる。好ましくは、該反応は、−１０〜１０℃の範囲の温度、より好ましくは、０℃の温度で行われる。 The compound represented by the formula (VII) is represented by the formula (VIII):

[Wherein A is an alkoxy, benzyloxy or tri- (C _1-4 alkyl) -silyloxy group] a compound represented by the formula J-hal (where J is 1,3-thiazol-4-ylmethyl) And hal is a halo atom, preferably chloro or bromo). Preferably, the reaction is carried out in the presence of a suitable base such as potassium tert-butoxide. Preferably, the reaction is performed in a suitable solvent (eg, THF). Preferably, the reaction is performed at a temperature in the range of −10 to 10 ° C., more preferably at a temperature of 0 ° C.

  The compounds of formula (VIII) and J-hal are known in the art or can be prepared by standard literature methods.

  Compounds of formula (I) in which A is an ester can be prepared by esterifying a compound of formula (I) in which A is hydroxy by standard literature methods for esterification. .

  Compounds of formula (I), (II), (IIa), (III) and / or (IIIa) present as diastereoisomers can be converted by techniques well known in the art (eg by column chromatography). It will be clear that it may be sorted.

  It will be apparent that the racemates of formula (I), (II), (IIa), (III) and / or (IIIa) may be resolved into their individual enantiomers. Such a division can conveniently be performed by standard methods known in the art. For example, racemic compounds of formula (I), (II), (IIa), (III) and / or (IIIa) can be resolved by chiral preparative HPLC. Alternatively, racemic compounds of formula (I), (II), (IIa), (III) and / or (IIIa) containing a suitable acidic or basic group such as a carboxylic acid group or an amine group Compounds can be separated by standard diastereoisomeric salt formation using a chiral base or acid reagent, respectively, as required. Such techniques are well established in the art.

Each of the enantiomeric compounds represented by the formula (III) and / or (IIIa) can be subjected to a general asymmetric synthesis method using a chiral auxiliary or a chiral catalyst reagent, if necessary, It will be apparent that it can be prepared by performing any suitable functional group interconversion as described above, including the addition or removal of chiral auxiliaries. Such general asymmetric synthesis methods are well known in the art and include those described in “Asymmetric Synthesis,” Academic Press, 1984 and / or “Chiral Auxiliaries and Ligands in Asymmetric Synthesis”, Wiley, 1995. However, it is not limited to these. For example, suitable common chiral auxiliaries include chiral alcohols such as menthol or 1-phenylethanol; chiral oxazolidinones such as 4-benzyloxazolidin-2-one or 4-isopropyloxazolidine-2-one; Chiral sultams such as tam; or chiral amines such as 1-phenylethylamine or 2-amino-2-phenylethanol. Suitable general chiral catalyst reagents include metal salts such as M _m X _x (where M is silver, cobalt, zinc, titanium, magnesium or manganese, and X is a halide (eg, chloride or Bromide), acetate, trifluoroacetate, p-toluenesulfonate, trifluoromethylsulfonate, hexafluorophosphate or nitrate, and m and x are 1, 2, 3 or 4. Chiral basic amines and chiral ligands, such as N-methylephedrine, 1-phenyl-2- (1-pyrrolidinyl) -1-propanol, 3- (dimethyl, which may be in the presence of a base (eg triethylamine) Amino) -1,7,7-trimethylbicyclo [2.2.1] -heptan-2-ol, 3,4 Bis (diphenylphosphanyl) -1- (phenylmethyl) - pyrrolidine, Kinkonin (Chinchonine), Kinkonijin (Chinchonidine), sparteine, hydroquinine or quinine, include BINAP or chiral bis (oxazoline) (BOX) ligands and derivatives. All of these chiral auxiliaries or chiral catalyst reagents are well described in the art. General examples of the preparation of various chiral pyrrolidines by asymmetric synthesis using chiral auxiliaries or chiral catalyst reagents include Angew. Chem. Int. Ed., (2002), 41: 4236; Chem. Rev., (1998), 98: 863; J. Am. Chem. Soc., (2002), 124: 13400; J. Am. Chem. Soc., (2003), 125: 10175; Org. Lett., (2003) , 5, 5043; Tetrahedron, (1995), 51: 273; Tetrahedron: Asymm., (1995), 6: 2475; Tetrahedron: Asymm., (2001), 12: 1977; Tetrahedron: Asymm., (2002), 13: 2099 and Tet. Lett., (1991), 41: 5817, but are not limited thereto.

The synthesis of compounds of formula (I) is carried out by methods analogous to those described in the methods and experimental sections above, with appropriate manipulation and protection of any chemical functional group. Suitable protecting groups are found in TW Greene and PGM Wuts 'Protective Groups in Organic Synthesis', 3 ^rd Ed (1999), J Wiley and Sons, but are not limited to those described in the literature. .

Abbreviations In the description of the present invention, chemical elements are identified according to the periodic table of elements. Abbreviations and symbols used herein are in accordance with the common usage of such abbreviations and symbols by those skilled in the chemical arts. The following abbreviations are used herein:

２−アミノ−４−メチル−ペンタン酸tert−ブチルエステル・塩酸塩（５.００ｇ、２２.３ｍｍｏｌ）、１,３−チアゾール−２−カルボキシアルデヒド（２.５３ｇ、２２.４ｍｍｏｌ）およびトリエチルアミン（３.１０ｍＬ、２２.２ｍｍｏｌ）のジクロロメタン（６０ｍＬ）中撹拌混合物を窒素下にて還流させながら１９時間加熱した。反応混合物を室温に冷却させ、水で２回洗浄し、Ｎａ₂ＳＯ₄で乾燥させ、蒸発させて、油状物として標記化合物を得た。
¹Ｈ ＮＭＲ（ＣＤＣｌ₃）：δ ８.４６（ｓ，１Ｈ）、７.９４（ｄ，１Ｈ）、７.４４（ｄｄ，１Ｈ）、４.０７（ｄｄ，１Ｈ）、１.８９−１.７４（ｍ，２Ｈ）、１.６４−１.５２（ｍ，１Ｈ）、１.４８（ｓ，９Ｈ）、０.９６（ｄ，３Ｈ）および０.９０（ｄ，３Ｈ）。 Intermediate 1
2- [N- (1,3-thiazol-2-ylmethylene) amino] -4-methylpentanoic acid tert-butyl ester

2-Amino-4-methyl-pentanoic acid tert-butyl ester hydrochloride (5.00 g, 22.3 mmol), 1,3-thiazole-2-carboxaldehyde (2.53 g, 22.4 mmol) and triethylamine (3 (10 mL, 22.2 mmol) in dichloromethane (60 mL) was heated at reflux under nitrogen for 19 hours. The reaction mixture was allowed to cool to room temperature, washed twice with water, dried over Na ₂ SO ₄ and evaporated to give the title compound as an oil.
¹ H NMR (CDCl ₃ ): δ 8.46 (s, 1H), 7.94 (d, 1H), 7.44 (dd, 1H), 4.07 (dd, 1H), 1.89-1 .74 (m, 2H), 1.64-1.52 (m, 1H), 1.48 (s, 9H), 0.96 (d, 3H) and 0.90 (d, 3H).

中間体１（０.２５０ｇ、０.８８ｍｍｏｌ）の窒素下での無水ＴＨＦ（５ｍＬ）中冷却（０℃）撹拌溶液にトリエチルアミン（０.１２３ｍＬ、０.８８ｍｍｏｌ）を添加し、次いで、臭化リチウム（０.０７７ｇ、０.８８ｍｍｏｌ）およびメチルプロピオレート（０.０８ｍＬ、０.９０ｍｍｏｌ）を添加した。該混合物を０℃で５分間撹拌し、次いで、氷／水浴を取り外し、周囲温度で２時間撹拌を続けた。高速撹拌しながら塩化アンモニウム水溶液を添加し、得られた混合物を酢酸エチルで２回抽出した。合わせた有機層を硫酸ナトリウムで乾燥させ、蒸発させた。残留物を、溶離液としてシクロヘキサン−酢酸エチル（８：２、ｖ／ｖ）を使用してシリカゲルクロマトグラフィーにより精製して、油状物として標記化合物を得た。
(Ｃ₁₈Ｈ₂₆Ｎ₂Ｏ₄Ｓ ＋ Ｈ)⁺についてのＭＳ計算値：３６７。
ＭＳ（エレクトロスプレー）：測定値(Ｍ＋Ｈ)⁺＝３６７。 Intermediate 2
rel- (2S, 5R) -2-isobutyl-5- (1,3-thiazol-2-yl) -2,5-dihydro-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4- Methyl ester

Triethylamine (0.123 mL, 0.88 mmol) was added to a cooled (0 ° C.) stirred solution of intermediate 1 (0.250 g, 0.88 mmol) in anhydrous THF (5 mL) under nitrogen, followed by lithium bromide. (0.077 g, 0.88 mmol) and methyl propiolate (0.08 mL, 0.90 mmol) were added. The mixture was stirred at 0 ° C. for 5 minutes, then the ice / water bath was removed and stirring was continued at ambient temperature for 2 hours. Aqueous ammonium chloride was added with rapid stirring, and the resulting mixture was extracted twice with ethyl acetate. The combined organic layers were dried with sodium sulfate and evaporated. The residue was purified by silica gel chromatography using cyclohexane-ethyl acetate (8: 2, v / v) as eluent to give the title compound as an oil.
_{(C 18 H 26 N 2 O} 4 S + H) + MS calcd for: 367.
MS (electrospray): found (M + H) ⁺ = 367.

窒素下での中間体２（１.０ｇ、２.７３ｍｍｏｌ）の無水ジクロロメタン（２０ｍＬ）中溶液にトリエチルアミン（０.５ｍＬ、３.５８ｍｍｏｌ）を添加し、次いで、３−メトキシ−４−tert−ブチルベンゾイルクロリド^*（０.７９ｇ、３.４８ｍｍｏｌ）を添加し、該混合物を室温で一夜撹拌した。該反応物を水の添加によりクエンチし、ジクロロメタンで抽出した。有機フラクションを蒸発させ、シリカゲルクロマトグラフィーに付してシクロヘキサン−酢酸エチル（９：１、ｖ／ｖ）で溶離することにより精製して、固体として標記化合物を得た。
^* ３−メトキシ−４−tert−ブチル安息香酸（J. Org. Chem.(1961), 26, 1732）から製造した。
(Ｃ₃₀Ｈ₄₀Ｎ₂Ｏ₆Ｓ ＋ Ｈ)⁺についてのＭＳ計算値：５５７。
ＭＳ（エレクトロスプレー）：測定値(Ｍ＋Ｈ)⁺＝５５７。 Intermediate 3
rel- (2S, 5R) -2-isobutyl-1- (3-methoxy-4-tert-butylbenzoyl) -5- (1,3-thiazol-2-yl) -2,5-dihydro-1H-pyrrole -2,4-dicarboxylic acid 2-tert-butyl ester 4-methyl ester

To a solution of intermediate 2 (1.0 g, 2.73 mmol) in anhydrous dichloromethane (20 mL) under nitrogen was added triethylamine (0.5 mL, 3.58 mmol) and then 3-methoxy-4-tert-butyl. Benzoyl chloride ^* (0.79 g, 3.48 mmol) was added and the mixture was stirred overnight at room temperature. The reaction was quenched by the addition of water and extracted with dichloromethane. The organic fraction was evaporated and purified by silica gel chromatography eluting with cyclohexane-ethyl acetate (9: 1, v / v) to give the title compound as a solid.
^* Prepared from 3-methoxy-4-tert-butylbenzoic acid (J. Org. Chem. (1961), 26, 1732).
_{(C 30 H 40 N 2 O} 6 S + H) + MS calcd for: 557.
MS (electrospray): found (M + H) ⁺ = 557.

窒素下での中間体３（０.６９７ｇ、１.２５ｍｍｏｌ）の乾燥ＴＨＦ（５０ｍＬ）中溶液に水素化アルミニウムリチウム（エーテル中１Ｍ溶液１.２５ｍＬ）を添加した。２０分後、該反応物を炭酸ナトリウム溶液（１Ｍ）の添加によりクエンチし、酢酸エチルで抽出した。有機フラクションを蒸発させ、シリカゲルカラムクロマトグラフィーに付してシクロヘキサン−酢酸エチル勾配液（７：３（ｖ／ｖ）、次いで、６：４（ｖ／ｖ））で溶離することにより精製して、固体として標記化合物を得た。
(Ｃ₂₉Ｈ₄₀Ｎ₂Ｏ₅Ｓ ＋ Ｈ)⁺についてのＭＳ計算値：５２９。
ＭＳ（エレクトロスプレー）：測定値(Ｍ＋Ｈ)⁺＝５２９。 Intermediate 4
rel- (2S, 5R) -2-isobutyl-1- (3-methoxy-4-tert-butylbenzoyl) -4-hydroxymethyl-5- (1,3-thiazol-2-yl) -2,5- Dihydro-1H-pyrrole-2-carboxylic acid 2-tert-butyl ester

To a solution of intermediate 3 (0.697 g, 1.25 mmol) in dry THF (50 mL) under nitrogen was added lithium aluminum hydride (1.25 mL of a 1M solution in ether). After 20 minutes, the reaction was quenched by the addition of sodium carbonate solution (1M) and extracted with ethyl acetate. The organic fraction was evaporated and purified by silica gel column chromatography eluting with a cyclohexane-ethyl acetate gradient (7: 3 (v / v) then 6: 4 (v / v)) The title compound was obtained as a solid.
_{(C 29 H 40 N 2 O} 5 S + H) + MS calcd for: 529.
MS (electrospray): found (M + H) ⁺ = 529.

窒素下にて−１０℃での中間体４（０.１１３ｇ、０.２１ｍｍｏｌ）の乾燥ＤＭＦ（４ｍＬ）中溶液に水素化ナトリウム（９ｍｇ、油中６０％分散体、０.２３ｍｍｏｌ）を添加した。この温度で２０分後、ヨウ化メチル（０.０２７ｍＬ、０.４３ｍｍｏｌ）を添加し、該混合物を室温にし、一夜撹拌した。メタノールを添加し、溶媒を真空除去した。残留物を水と酢酸エチルとの間で分配させ、有機層を分取し、硫酸ナトリウムで乾燥させ、蒸発させた。溶離液としてシクロヘキサン−酢酸エチル（９：１（ｖ／ｖ））を使用してシリカゲルクロマトグラフィーにより精製して、標記化合物を得た。
¹Ｈ ＮＭＲ（ＣＤ₃ＯＤ）：δ ７.５１（ｄ，１Ｈ）、７.３２（ｄ，１Ｈ）、７.２２（ｄ，１Ｈ）、６.８４（ｄ，１Ｈ）、６.５０（ｄ，１Ｈ）、６.１７（ｄ，１Ｈ）、５.８９（ｄ，１Ｈ）、３.６２−３.７５（ｍ，５Ｈ）、３.２３（ｓ，３Ｈ）、２.５６−２.６８（ｍ，１Ｈ）、２.０５−２.１５（ｍ，１Ｈ）、１.７０−１.８５（ｍ，１Ｈ）、１.６０（ｓ，９Ｈ）、１.３４（ｓ，９Ｈ）および１.０８（２ｄ，６Ｈ）。 Intermediate 5
rel- (2S, 5R) -2-isobutyl-1- (3-methoxy-4-tert-butylbenzoyl) -4-methoxymethyl-5- (1,3-thiazol-2-yl) -2,5- Dihydro-1H-pyrrole-2-carboxylic acid 2-tert-butyl ester

To a solution of intermediate 4 (0.113 g, 0.21 mmol) in dry DMF (4 mL) at −10 ° C. under nitrogen was added sodium hydride (9 mg, 60% dispersion in oil, 0.23 mmol). . After 20 minutes at this temperature, methyl iodide (0.027 mL, 0.43 mmol) was added and the mixture was allowed to reach room temperature and stirred overnight. Methanol was added and the solvent was removed in vacuo. The residue was partitioned between water and ethyl acetate and the organic layer was separated, dried over sodium sulfate and evaporated. Purification by silica gel chromatography using cyclohexane-ethyl acetate (9: 1 (v / v)) as eluent gave the title compound.
¹ H NMR (CD ₃ OD): δ 7.51 (d, 1H), 7.32 (d, 1H), 7.22 (d, 1H), 6.84 (d, 1H), 6.50 ( d, 1H), 6.17 (d, 1H), 5.89 (d, 1H), 3.62-3.75 (m, 5H), 3.23 (s, 3H), 2.56-2 .68 (m, 1H), 2.05-2.15 (m, 1H), 1.70-1.85 (m, 1H), 1.60 (s, 9H), 1.34 (s, 9H) ) And 1.08 (2d, 6H).

ヨウ化メチルの代わりにヨウ化エチルを使用して、中間体５について記載した方法と同様にこれを製造した。粗製物質を、溶離液としてシクロヘキサン−酢酸エチル（６：４（ｖ／ｖ））を使用して分取ＴＬＣプレートでのクロマトグラフィーにより精製して、標記化合物を得た。
¹Ｈ ＮＭＲ（ＣＤ₃ＯＤ）：δ ７.４８（ｄ，１Ｈ）、７.２８（ｄ，１Ｈ）、７.１９（ｄ，１Ｈ）、６.８０（ｄ，１Ｈ）、６.４６（ｓ，１Ｈ）、６.１４（ｓ，１Ｈ）、５.８５（ｄ，１Ｈ）、３.６−３.７５（ｍ，２Ｈ）、３.６７（ｓ，３Ｈ）、３.２５−３.４１（ｑ，２Ｈ）、２.５５−２.６５（ｍ，１Ｈ）、２.０２−２.１２（ｍ，１Ｈ）、１.７０−１.８５（ｍ，１Ｈ）、１.５７（ｓ，９Ｈ）、１.３１（ｓ，９Ｈ）および０.９５−１.１（ｍ，９Ｈ）。 Intermediate 6
rel- (2S, 5R) -2-isobutyl-1- (3-methoxy-4-tert-butylbenzoyl) -4-ethoxymethyl-5- (1,3-thiazol-2-yl) -2,5- Dihydro-1H-pyrrole-2-carboxylic acid 2-tert-butyl ester

This was prepared in a manner similar to that described for Intermediate 5 using ethyl iodide instead of methyl iodide. The crude material was purified by chromatography on a preparative TLC plate using cyclohexane-ethyl acetate (6: 4 (v / v)) as eluent to give the title compound.
¹ H NMR (CD ₃ OD): δ 7.48 (d, 1H), 7.28 (d, 1H), 7.19 (d, 1H), 6.80 (d, 1H), 6.46 ( s, 1H), 6.14 (s, 1H), 5.85 (d, 1H), 3.6-3.75 (m, 2H), 3.67 (s, 3H), 3.25-3 .41 (q, 2H), 2.55-2.65 (m, 1H), 2.02-2.12 (m, 1H), 1.70-1.85 (m, 1H), 1.57 (S, 9H), 1.31 (s, 9H) and 0.95-1.1 (m, 9H).

ヨウ化メチルの代わりにヨウ化ｎ−プロピルを使用して、中間体５について記載した方法と同様にこれを製造した。粗製物質を、溶離液としてシクロヘキサン−酢酸エチル（６：４（ｖ／ｖ））を使用して分取ＴＬＣプレートによるクロマトグラフィーにより精製して、標記化合物を得た。
(Ｃ₃₂Ｈ₄₆Ｎ₂Ｏ₅Ｓ ＋ Ｈ)⁺についてのＭＳ計算値：５７１。
ＭＳ（エレクトロスプレー）：測定値(Ｍ＋Ｈ)⁺＝５７１。 Intermediate 7
rel- (2S, 5R) -2-isobutyl-1- (3-methoxy-4-tert-butylbenzoyl) -4-n-propyloxymethyl-5- (1,3-thiazol-2-yl) -2 , 5-Dihydro-1H-pyrrole-2-carboxylic acid 2-tert-butyl ester

This was prepared in the same manner as described for Intermediate 5 using n-propyl iodide instead of methyl iodide. The crude material was purified by chromatography on a preparative TLC plate using cyclohexane-ethyl acetate (6: 4 (v / v)) as eluent to give the title compound.
_{(C 32 H 46 N 2 O} 5 S + H) + MS calcd for: 571.
MS (electrospray): found (M + H) ⁺ = 571.

メタンスルホニルクロリド（０.０４４ｍＬ、０.５７ｍｍｏｌ）を乾燥ジクロロメタン（３ｍＬ）で希釈した。この溶液にトリエチルアミン（０.０８ｍＬ、０.５７ｍｍｏｌ）を添加し、次いで、中間体４（０.３ｇ、０.５７ｍｍｏｌ）を乾燥ジクロロメタン（３ｍＬ）中溶液として添加し、該混合物を室温で一夜撹拌した。さらにそれぞれ同量のメタンスルホニルクロリドおよびトリエチルアミンを添加し、１時間後、該反応を水（５ｍＬ）でクエンチした。疎水性フリットを使用して相を分取し、溶媒を蒸発させて、標記化合物を得た。
(Ｃ₃₀Ｈ₄₂Ｎ₂Ｏ₇Ｓ₂ ＋ Ｈ)⁺についてのＭＳ計算値：６０７。
ＭＳ（エレクトロスプレー）：測定値(Ｍ＋Ｈ)⁺ ６０７。 Intermediate 8
rel- (2S, 5R) -2-isobutyl-1- (3-methoxy-4-tert-butylbenzoyl) -4-[(methanesulfonyloxy) -methyl] -5- (1,3-thiazole-2- Yl) -2,5-dihydro-1H-pyrrole-2-carboxylic acid 2-tert-butyl ester

Methanesulfonyl chloride (0.044 mL, 0.57 mmol) was diluted with dry dichloromethane (3 mL). To this solution was added triethylamine (0.08 mL, 0.57 mmol), then Intermediate 4 (0.3 g, 0.57 mmol) was added as a solution in dry dichloromethane (3 mL) and the mixture was stirred at room temperature overnight. did. Further equal amounts of methanesulfonyl chloride and triethylamine were added respectively and after 1 hour the reaction was quenched with water (5 mL). The phases were separated using a hydrophobic frit and the solvent was evaporated to give the title compound.
_{(C 30 H 42 N 2 O} 7 S 2 + H) + MS calcd for: 607.
MS (electrospray): found (M + H) ⁺ 607.

ナトリウムメタンスルフィド（０.０４５ｇ、０.６４ｍｍｏｌ）を乾燥ＤＭＦ（４ｍＬ）に溶解した。この溶液に中間体８（０.１２６ｇ、０.２１ｍｍｏｌ）を乾燥ジクロロメタン（０.５ｍＬ）中溶液として添加し、該混合物を窒素雰囲気下にて室温で一夜撹拌した。該反応をブライン（５ｍＬ）でクエンチした。相を分取し、水性層をジクロロメタン（２×１０ｍＬ）で抽出した。有機層を合わせ、Ｎａ₂ＳＯ₄で乾燥させ、濾過し、溶媒を真空除去した。得られた油状物を、（Ａ）０.１％（ｖ／ｖ）ギ酸を含有する水および（Ｂ）０.０５％（ｖ／ｖ）ギ酸を含有するアセトニトリル−水（９５：５（ｖ／ｖ））を含む二溶媒勾配溶離を用いてＣ₁₈カラムによる逆相ＨＰＬＣにより精製し、エレクトロスプレー質量分析法によりフラクションの分析をした。Ｔｈｅｒｍｏ−Ｆｌｕｏｐｈａｓｅカラム（１００×２０ｍｍ、粒径５μ）を使用して分析ＨＰＬＣに付し、水性アセトニトリル（１：１（ｖ／ｖ））で溶離し、保持時間２９分のフラクションを回収することよりさらに精製して、固体として標記化合物を得た。
(Ｃ₃₀Ｈ₄₂Ｎ₂Ｏ₄Ｓ₂ ＋ Ｈ)⁺についてのＭＳ計算値：５５９。
ＭＳ（エレクトロスプレー）：測定値(Ｍ＋Ｈ)⁺＝５５９。 Intermediate 9
rel- (2S, 5R) -2-isobutyl-1- (3-methoxy-4-tert-butylbenzoyl) -4-methylthiomethyl-5- (1,3-thiazol-2-yl) -2,5- Dihydro-1H-pyrrole-2-carboxylic acid 2-tert-butyl ester

Sodium methane sulfide (0.045 g, 0.64 mmol) was dissolved in dry DMF (4 mL). To this solution was added Intermediate 8 (0.126 g, 0.21 mmol) as a solution in dry dichloromethane (0.5 mL) and the mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was quenched with brine (5 mL). The phases were separated and the aqueous layer was extracted with dichloromethane (2 × 10 mL). The organic layers were combined, dried over Na ₂ SO ₄ , filtered and the solvent removed in vacuo. The resulting oil was purified from (A) water containing 0.1% (v / v) formic acid and (B) acetonitrile-water containing 95% (v / v) formic acid (95: 5 (v / V)) and purified by reverse phase HPLC on a _C18 column using a dual solvent gradient elution and fractions analyzed by electrospray mass spectrometry. By subjecting to analytical HPLC using a Thermo-Fluophase column (100 × 20 mm, particle size 5 μ), eluting with aqueous acetonitrile (1: 1 (v / v)) and collecting fractions with a retention time of 29 minutes. Further purification gave the title compound as a solid.
_{(C 30 H 42 N 2 O} 4 S 2 + H) + MS calcd for: 559.
MS (electrospray): found (M + H) ⁺ = 559.

ナトリウムメタンスルフィン酸（０.０６５ｇ、０.６４ｍｍｏｌ）を乾燥ＤＭＦ（４ｍＬ）に溶解した。この溶液に中間体８（０.１２６ｇ、０.２１ｍｍｏｌ）を乾燥ジクロロメタン（０.５ｍＬ）中溶液として添加し、該混合物を窒素雰囲気下にて室温で一夜撹拌した。該反応をブライン（５ｍＬ）でクエンチし、相を分取し、水性層をジクロロメタン（１０ｍＬ×２）で抽出した。有機層を合わせ、Ｎａ₂ＳＯ₄で乾燥させ、濾過し、真空中にて減少させた。得られた油状物を、（Ａ）０.１％（ｖ／ｖ）ギ酸を含有する水および（Ｂ）０.０５％（ｖ／ｖ）ギ酸を含有するアセトニトリル−水（９５：５（ｖ／ｖ））を含む二溶媒勾配溶離を用いてＣ₁₈カラムによる逆相ＨＰＬＣにより精製し、エレクトロスプレー質量分析法によってフラクションを分析した。シリカゲルカラムクロマトグラフィーに付し、シクロヘキサン／酢酸エチル（８：２（ｖ／ｖ））で溶離することによりさらに精製して、標記化合物を得た。
(Ｃ₃₀Ｈ₄₂Ｎ₂Ｏ₆Ｓ₂ ＋ Ｈ)⁺についてのＭＳ計算値： ５９１。
ＭＳ（エレクトロスプレー）：測定値(Ｍ＋Ｈ)⁺ ５９１。 Intermediate 10
rel- (2S, 5R) -2-isobutyl-1- (3-methoxy-4-tert-butylbenzoyl) -4-[(methylsulfonyl) -methyl] -5- (1,3-thiazol-2-yl ) -2,5-dihydro-1H-pyrrole-2-carboxylic acid 2-tert-butyl ester

Sodium methanesulfinic acid (0.065 g, 0.64 mmol) was dissolved in dry DMF (4 mL). To this solution was added Intermediate 8 (0.126 g, 0.21 mmol) as a solution in dry dichloromethane (0.5 mL) and the mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was quenched with brine (5 mL), the phases were separated and the aqueous layer was extracted with dichloromethane (10 mL × 2). The organic layers were combined, dried over Na ₂ SO ₄ , filtered and reduced in vacuo. The resulting oil was purified from (A) water containing 0.1% (v / v) formic acid and (B) acetonitrile-water containing 95% (v / v) formic acid (95: 5 (v / V)) and purified by reverse phase HPLC on a _C18 column using a two solvent gradient elution and fractions were analyzed by electrospray mass spectrometry. Further purification by silica gel column chromatography eluting with cyclohexane / ethyl acetate (8: 2 (v / v)) gave the title compound.
MS calculated for (C ₃₀ H ₄₂ N ₂ O ₆ S ₂ + H) ⁺ : 591.
MS (electrospray): found (M + H) ⁺ 591.

中間体６のエナンチオマーを、Ｗｈｅｌｋ Ｏ−１カラム（２インチ×２０ｃｍ、流速７０ｍＬ／分）を使用してキラルＨＰＬＣに付し、ヘプタン−エタノール（９５：５（ｖ／ｖ））で溶離することにより分離した。２番目に溶離するエナンチオマー（保持時間１０分）を回収してエナンチオマーＡを得た。 Intermediate 11
rel- (2S, 5R) -2-isobutyl-1- (3-methoxy-4-tert-butylbenzoyl) -4-ethoxymethyl-5- (1,3-thiazol-2-yl) -2,5- Enantiomer A of dihydro-1H-pyrrole-2-carboxylic acid 2-tert-butyl ester

The enantiomer of intermediate 6 is subjected to chiral HPLC using a Whelk O-1 column (2 inches × 20 cm, flow rate 70 mL / min) and eluted with heptane-ethanol (95: 5 (v / v)). Separated by. The second eluting enantiomer (retention time 10 minutes) was recovered to give enantiomer A.

Intermediate 12
2- [N- (diphenylmethylene) amino] -3- (1,3-thiazol-4-yl) propanoic acid tert-butyl ester

Process A
Cooling (ice bath) solution of 2- [N- (diphenylmethylene) amino] ethanoic acid tert-butyl ester (99.26 g, 336 mmol) in dry THF (600 mL) under nitrogen atmosphere in THF with potassium tert-butoxide in THF A 1M solution (341 mL) was added dropwise over 1 hour (an addition funnel). The addition funnel was rinsed with additional dry THF (150 mL), it was added to the reaction, and the mixture was stirred in an ice bath for an additional hour.

Process B
Independently, during this time, 4- (chloromethyl) -1,3-thiazole hydrochloride (59.84 g, 352 mmol) was newly converted to the free base as follows: 750 mL) and water (300 mL) and the pH of the aqueous layer was adjusted to pH 9 with solid sodium bicarbonate. The organic layer was separated, dried over sodium sulfate and carefully evaporated at 80 torr to give the free base.

Process C
4- (Chloromethyl) -1,3-thiazole (formed in Step B) was dissolved in THF (400 mL) and added dropwise over 45 minutes to the reaction mixture from Step A while maintaining the reaction at ice bath temperature. (Drip funnel). Solid lithium iodide (0.47 g, 3.5 mmol) was added directly to the reaction mixture 5 minutes after the addition of the alkylating agent began. The addition funnel was rinsed with additional dry THF (100 mL) and added to the reaction. The reaction was warmed to room temperature over 1 hour and stirred at room temperature for an additional 2 hours before being partitioned between a mixture of saturated brine (1 L) and water (500 mL) and ethyl acetate (1.5 L). . The organic layer was separated and the aqueous layer was re-extracted with additional ethyl acetate (2 × 500 mL). The combined organic layers were dried over sodium sulfate and evaporated to give the title compound (141.5 g, crude), which was used in the following step without further purification.
¹ H NMR (CDCl ₃ ): δ 8.65 (d, 1H), 7.55-7.62 (m, 2H), 7.2-7.55 (m, 6H), 7.05 (d, 1H), 6.78-6.87 (m, 2H), 4.36-4.41 (m, 1H), 3.47-3.54 (m, 1H), 3.36-3.44 ( m, 1H) and 1.44 (s, 9H).

窒素下での中間体１２（１４１.４ｇ、粗製生成物）のＴＨＦ（７５０ｍＬ）中溶液を氷浴中にて冷却した。撹拌しながらクエン酸水溶液（１５％（ｗ／ｖ）、７５０ｍＬ）を２５分間にわたって添加した。該混合物を１時間にわたって室温に加温し、さらに５時間撹拌し、一夜放置し、さらに２時間撹拌した。ＴＨＦを２５℃で減圧除去し、１Ｍ塩酸水溶液（３７５ｍＬ）を添加した。該混合物をジエチルエーテル（２×１Ｌ）で抽出し、合わせたエーテル抽出物を水（２００ｍＬ）で抽出した。合わせた水性層をさらなるジエチルエーテル（５００ｍＬ）で抽出した。これらのエーテル層を廃棄した。次いで、水性層を新たなジエチルエーテル（１Ｌ）の存在下にて注意深くｐＨ９.５に調整した。このエーテル層を分取し、維持した。該水性層に飽和ブライン（４００ｍＬ）を添加し、この層をさらなるジエチルエーテル（３×６００ｍＬ）で抽出した。４つのエーテル層を合わせ、硫酸ナトリウムで乾燥させた。溶媒を蒸発させて、標記化合物（油状物）を得た。
¹Ｈ ＮＭＲ（ＣＤＣｌ₃）：δ ８.７７（ｄ，１Ｈ）、７.０８（ｄ，１Ｈ）、３.７７−３.８５（ｍ，１Ｈ）、３.２２−３.３２（ｍ，１Ｈ）、３.０２−３.１３（ｍ，１Ｈ）および１.４２（ｓ，９Ｈ）。 Intermediate 13
2-Amino-3- (1,3-thiazol-4-yl) propanoic acid tert-butyl ester

A solution of intermediate 12 (141.4 g, crude product) in THF (750 mL) under nitrogen was cooled in an ice bath. While stirring, aqueous citric acid (15% (w / v), 750 mL) was added over 25 minutes. The mixture was warmed to room temperature over 1 hour, stirred for an additional 5 hours, allowed to stand overnight, and stirred for an additional 2 hours. THF was removed under reduced pressure at 25 ° C., and 1M aqueous hydrochloric acid solution (375 mL) was added. The mixture was extracted with diethyl ether (2 × 1 L) and the combined ether extracts were extracted with water (200 mL). The combined aqueous layers were extracted with additional diethyl ether (500 mL). These ether layers were discarded. The aqueous layer was then carefully adjusted to pH 9.5 in the presence of fresh diethyl ether (1 L). The ether layer was separated and maintained. To the aqueous layer was added saturated brine (400 mL) and this layer was extracted with additional diethyl ether (3 × 600 mL). The four ether layers were combined and dried over sodium sulfate. The solvent was evaporated to give the title compound (oil).
¹ H NMR (CDCl ₃ ): δ 8.77 (d, 1H), 7.08 (d, 1H), 3.77-3.85 (m, 1H), 3.22-3.32 (m, 1H), 3.02-3.13 (m, 1H) and 1.42 (s, 9H).

中間体１３（０.９６ｇ、４.２０ｍｍｏｌ）および５−メチルイソオキサゾール−３−カルボキシアルデヒド（０.９３ｇ、８.３７ｍｍｏｌ）のジクロロメタン（１５ｍＬ）中混合物を４０℃で３時間加熱し、室温に冷却し、一夜放置した。反応混合物を減圧下にて蒸発させて、２−[[Ｎ−(５−メチルイソオキサゾール−３−イル)メチレン]アミノ]−３−(１,３−チアゾール−４−イル)プロパン酸tert−ブチルエステルおよび中間体１３の混合物（３：１比）を得た。この混合物を乾燥ＴＨＦ（１５ｍＬ）に溶解し、臭化リチウム（０.３５５ｇ、４.０９ｍｍｏｌ）を添加し、該混合物を窒素下にて０℃で撹拌した。トリエチルアミン（０.５７ｍＬ、４.０９ｍｍｏｌ）を添加し、次いで、メチルプロピオレート（０.３ｍＬ、３.３７ｍｍｏｌ）を添加し、得られた混合物を０℃で２０分間撹拌し、室温に加温した。２時間後、飽和塩化アンモニウム溶液（４０ｍＬ）を添加し、該混合物を酢酸エチルで抽出した。有機層を硫酸マグネシウムで乾燥させ、蒸発させた。残留物を、溶離液として酢酸エチル−シクロヘキサン（１：２（ｖ／ｖ））を使用してシリカゲルクロマトグラフィーにより精製して、油状物として標記化合物を得、これは放置後に固化した。
(Ｃ₁₉Ｈ₂₃Ｎ₃Ｏ₅Ｓ ＋ Ｈ)⁺についてのＭＳ計算値：４０６。
ＭＳ測定値（エレクトロスプレー）：（Ｍ＋Ｈ)⁺＝４０６ Intermediate 14
rel- (2S, 5R) -5- (5-methylisoxazol-3-yl) -2- (1,3-thiazol-4-ylmethyl) -2,5-dihydro-1H-pyrrole-2,4- Dicarboxylic acid 2-tert-butyl ester 4-methyl ester

A mixture of intermediate 13 (0.96 g, 4.20 mmol) and 5-methylisoxazole-3-carboxaldehyde (0.93 g, 8.37 mmol) in dichloromethane (15 mL) was heated at 40 ° C. for 3 hours and brought to room temperature. Cooled and left overnight. The reaction mixture was evaporated under reduced pressure to give 2-[[N- (5-methylisoxazol-3-yl) methylene] amino] -3- (1,3-thiazol-4-yl) propanoic acid tert- A mixture of butyl ester and intermediate 13 (3: 1 ratio) was obtained. This mixture was dissolved in dry THF (15 mL), lithium bromide (0.355 g, 4.09 mmol) was added and the mixture was stirred at 0 ° C. under nitrogen. Triethylamine (0.57 mL, 4.09 mmol) was added, followed by methylpropiolate (0.3 mL, 3.37 mmol) and the resulting mixture was stirred at 0 ° C. for 20 minutes and warmed to room temperature. did. After 2 hours, saturated ammonium chloride solution (40 mL) was added and the mixture was extracted with ethyl acetate. The organic layer was dried with magnesium sulfate and evaporated. The residue was purified by silica gel chromatography using ethyl acetate-cyclohexane (1: 2 (v / v)) as eluent to give the title compound as an oil which solidified after standing.
_{(C 19 H 23 N 3 O} 5 S + H) + MS calcd for: 406.
MS measurement (electrospray): (M + H) ⁺ = 406

中間体１４（０.９７４ｇ、２.４０ｍｍｏｌ）、３−メトキシ−４−tert−ブチルベンゾイルクロリド（０.６５２ｇ、２.８８ｍｍｏｌ）およびトリエチルアミン（０.４ｍＬ、２.８７ｍｍｏｌ）の混合物を窒素下にて室温で一夜撹拌した。該混合物を水およびブラインで洗浄し、硫酸マグネシウムで乾燥させ、蒸発させた。残留物を、溶離液としてシクロヘキサン−酢酸エチル（３：１（ｖ／ｖ））を使用してシリカゲルクロマトグラフィーにより精製して、泡沫体として標記化合物を得た。
(Ｃ₃₁Ｈ₃₇Ｎ₃Ｏ₇Ｓ ＋ Ｈ)⁺についてのＭＳ計算値：５９６。
ＭＳ測定値（エレクトロスプレー）：（Ｍ＋Ｈ)⁺＝５９６ Intermediate 15
rel- (2S, 5R) -1- (3-methoxy-4-tert-butylbenzoyl) -5- (5-methylisoxazol-3-yl) -2- (1,3-thiazol-4-ylmethyl) -2,5-dihydro-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-methyl ester

A mixture of intermediate 14 (0.974 g, 2.40 mmol), 3-methoxy-4-tert-butylbenzoyl chloride (0.652 g, 2.88 mmol) and triethylamine (0.4 mL, 2.87 mmol) under nitrogen. And stirred at room temperature overnight. The mixture was washed with water and brine, dried over magnesium sulphate and evaporated. The residue was purified by silica gel chromatography using cyclohexane-ethyl acetate (3: 1 (v / v)) as eluent to give the title compound as a foam.
_{(C 31 H 37 N 3 O} 7 S + H) + MS calcd for: 596.
MS measurement (electrospray): (M + H) ⁺ = 596

中間体１５（０.７１６ｇ、１.２０ｍｍｏｌ）の乾燥ＴＨＦ（１３ｍＬ）中溶液を窒素下にて撹拌し、−４３℃に冷却した。水素化アルミニウムリチウムのジエチルエーテル中１.０Ｍ溶液（１.３２ｍＬ）を滴下した。添加終了後、該混合物を−３８℃に加温し、その温度で２.２５時間保持した。該混合物を１Ｍ炭酸カリウム水溶液（１２ｍＬ）でクエンチし、室温に加温し、酢酸エチルで抽出した。抽出物を硫酸マグネシウムで乾燥させ、蒸発させた。残留物を、溶離液としてシクロヘキサン−酢酸エチル（初めに２：１（ｖ／ｖ）、次いで、１：１（ｖ／ｖ））およびメタノールを使用してシリカゲルクロマトグラフィーにより精製して、泡沫体として標記化合物を得た。
(Ｃ₃₀Ｈ₃₇Ｎ₃Ｏ₆Ｓ ＋ Ｈ)⁺についてのＭＳ計算値：５６８。
ＭＳ測定値（エレクトロスプレー）：（Ｍ＋Ｈ)⁺＝５６８ Intermediate 16
rel- (2S, 5R) -4- (hydroxymethyl) -1- (3-methoxy-4-tert-butylbenzoyl) -5- (5-methylisoxazol-3-yl) -2- (1,3 -Thiazol-4-ylmethyl) -2,5-dihydro-1H-pyrrole-2-carboxylic acid tert-butyl ester

A solution of intermediate 15 (0.716 g, 1.20 mmol) in dry THF (13 mL) was stirred under nitrogen and cooled to -43 ° C. A 1.0 M solution of lithium aluminum hydride in diethyl ether (1.32 mL) was added dropwise. After the addition was complete, the mixture was warmed to -38 ° C and held at that temperature for 2.25 hours. The mixture was quenched with 1M aqueous potassium carbonate (12 mL), warmed to room temperature and extracted with ethyl acetate. The extract was dried over magnesium sulfate and evaporated. The residue was purified by silica gel chromatography using cyclohexane-ethyl acetate (first 2: 1 (v / v) then 1: 1 (v / v)) and methanol as eluent to give a foam To give the title compound.
_{(C 30 H 37 N 3 O} 6 S + H) + MS calcd for: 568.
MS measurement (electrospray): (M + H) ⁺ = 568

中間体１６（０.３４５ｇ、０.６１ｍｍｏｌ）のＤＭＦ（２０ｍＬ）中溶液を窒素下にて撹拌し、−１０℃に冷却した。水素化ナトリウムの鉱油中６０％分散体（４０ｍｇ、１.００ｍｍｏｌ）を添加し、得られた混合物を０℃以下で３０分間撹拌した。ヨードメタン（０.１８９ｍＬ、３.０４ｍｍｏｌ）を−１０℃で添加し、該混合物を室温に一夜加温した。該混合物をメタノール（１５ｍＬ）でクエンチし、減圧下にて蒸発させた。残留物を水と酢酸エチルとの間で分配させた。有機層を回収し、水およびブラインで洗浄し、硫酸マグネシウムで乾燥させ、蒸発させた。残留物を、溶離液としてシクロヘキサン−酢酸エチル（３：１（ｖ／ｖ））を使用してシリカゲルクロマトグラフィーにより精製して、泡沫体として標記化合物を得た。
(Ｃ₃₁Ｈ₃₉Ｎ₃Ｏ₆Ｓ ＋ Ｈ)⁺についてのＭＳ計算値：５８２。
ＭＳ測定値（エレクトロスプレー）：（Ｍ＋Ｈ)⁺＝５８２ Intermediate 17
rel- (2S, 5R) -1- (3-methoxy-4-tert-butylbenzoyl) -4- (methoxymethyl) -5- (5-methylisoxazol-3-yl) -2- (1,3 -Thiazol-4-ylmethyl) -2,5-dihydro-1H-pyrrole-2-carboxylic acid tert-butyl ester

A solution of intermediate 16 (0.345 g, 0.61 mmol) in DMF (20 mL) was stirred under nitrogen and cooled to −10 ° C. A 60% dispersion of sodium hydride in mineral oil (40 mg, 1.00 mmol) was added and the resulting mixture was stirred at 0 ° C. or lower for 30 minutes. Iodomethane (0.189 mL, 3.04 mmol) was added at −10 ° C. and the mixture was warmed to room temperature overnight. The mixture was quenched with methanol (15 mL) and evaporated under reduced pressure. The residue was partitioned between water and ethyl acetate. The organic layer was collected, washed with water and brine, dried over magnesium sulfate and evaporated. The residue was purified by silica gel chromatography using cyclohexane-ethyl acetate (3: 1 (v / v)) as eluent to give the title compound as a foam.
_{(C 31 H 39 N 3 O} 6 S + H) + MS calcd for: 582.
MS measurement (electrospray): (M + H) ⁺ = 582

中間体６（０.０２１ｇ、０.０３８ｍｍｏｌ）のトリフルオロ酢酸（２ｍＬ）中溶液を２０℃で３時間撹拌した。該混合物を蒸発させ、残留物を、エーテルを用いてトリチュレートして、固体として標記化合物を得た。
¹Ｈ ＮＭＲ（ＣＤ₃ＯＤ）：δ ７.６５（ｍ，１Ｈ）、７.５０（ｍ，１Ｈ）、７.２５（ｄ，１Ｈ）、６.８８（ｄ，１Ｈ）、６.４５（ｓ，１Ｈ）、６.３（ｓ，１Ｈ）、５.９（ｓ，１Ｈ）、３.８２（ｄｄ，２Ｈ）、３.６９（ｓ，３Ｈ）、３.３０−３.４５（ｍ，２Ｈ）、２.５０−２.６５（ｍ，１Ｈ）、２.１５−２.２５（ｍ，１Ｈ）、１.７５−１.９０（ｍ，１Ｈ）、１.３４（ｓ，９Ｈ）および０.９５−１.１５（ｍ，９Ｈ）。カルボン酸プロトンは溶媒と交換できる。
相対立体化学は、ＮＭＲ ｎＯｅ実験により(２Ｓ,５Ｒ)であることが確認された。 Example 1
rel- (2S, 5R) -2-isobutyl-1- (3-methoxy-4-tert-butylbenzoyl) -4-ethoxymethyl-5- (1,3-thiazol-2-yl) -2,5- Dihydro-1H-pyrrole-2-carboxylic acid

A solution of Intermediate 6 (0.021 g, 0.038 mmol) in trifluoroacetic acid (2 mL) was stirred at 20 ° C. for 3 hours. The mixture was evaporated and the residue was triturated with ether to give the title compound as a solid.
¹ H NMR (CD ₃ OD): δ 7.65 (m, 1H), 7.50 (m, 1H), 7.25 (d, 1H), 6.88 (d, 1H), 6.45 ( s, 1H), 6.3 (s, 1H), 5.9 (s, 1H), 3.82 (dd, 2H), 3.69 (s, 3H), 3.30-3.45 (m , 2H), 2.50-2.65 (m, 1H), 2.15-2.25 (m, 1H), 1.75-1.90 (m, 1H), 1.34 (s, 9H) ) And 0.95-1.15 (m, 9H). Carboxylic acid protons can be exchanged for solvents.
The relative stereochemistry was confirmed to be (2S, 5R) by NMR nOe experiments.

中間体６の代わりに中間体５を使用して、実施例１について記載した方法と同様に、標記化合物を製造した。
¹Ｈ ＮＭＲ（ＣＤ₃ＯＤ）：δ ７.６４（ｄ，１Ｈ）、７.５１（ｄ，１Ｈ）、７.２５（ｄ，１Ｈ）、６.８９（ｄ，１Ｈ）、６.４５（ｓ，１Ｈ）、６.２８（ｓ，１Ｈ）、５.９１（ｓ，１Ｈ）、３.７７（ｄ，２Ｈ）、３.６８（ｓ，３Ｈ）、３.２３（ｓ，３Ｈ）、２.５０−２.６５（ｍ，２Ｈ）、２.１５−２.３０（ｍ，１Ｈ）、１.７５−１.９０（ｍ，１Ｈ）、１.３４（ｓ，９Ｈ）および１.０８（２×ｄ，６Ｈ）。カルボン酸プロトンは溶媒と交換されていると考えられる。
相対立体化学は、ＮＭＲ ｎＯｅ実験により(２Ｓ,５Ｒ)であることが確認された。 Example 2
rel- (2S, 5R) -2-isobutyl-1- (3-methoxy-4-tert-butylbenzoyl) -4-methoxymethyl-5- (1,3-thiazol-2-yl) -2,5- Dihydro-1H-pyrrole-2-carboxylic acid

The title compound was prepared in a manner similar to that described for Example 1 using Intermediate 5 instead of Intermediate 6.
¹ H NMR (CD ₃ OD): δ 7.64 (d, 1H), 7.51 (d, 1H), 7.25 (d, 1H), 6.89 (d, 1H), 6.45 ( s, 1H), 6.28 (s, 1H), 5.91 (s, 1H), 3.77 (d, 2H), 3.68 (s, 3H), 3.23 (s, 3H), 2.50-2.65 (m, 2H), 2.15-2.30 (m, 1H), 1.75-1.90 (m, 1H), 1.34 (s, 9H) and 1. 08 (2 × d, 6H). Carboxylic acid protons are thought to be exchanged for solvents.
The relative stereochemistry was confirmed to be (2S, 5R) by NMR nOe experiments.

中間体６の代わりに中間体７を使用して、実施例１について記載した方法と同様に、標記化合物を製造した。
(Ｃ₂₈Ｈ₃₈Ｎ₂Ｏ₅Ｓ ＋ Ｈ)⁺についてのＭＳ計算値：５１５。
ＭＳ（エレクトロスプレー）：測定値(Ｍ＋Ｈ)⁺ ５１５。
相対立体化学は、ＮＭＲ ｎＯｅ実験により(２Ｓ,５Ｒ)であることが確認された。 Example 3
rel- (2S, 5R) -2-isobutyl-1- (3-methoxy-4-tert-butylbenzoyl) -4-n-propyloxymethyl-5- (1,3-thiazol-2-yl) -2 , 5-Dihydro-1H-pyrrole-2-carboxylic acid

The title compound was prepared in a manner similar to that described for Example 1 using Intermediate 7 instead of Intermediate 6.
_{(C 28 H 38 N 2 O} 5 S + H) + MS calcd for: 515.
MS (electrospray): found (M + H) ⁺ 515.
The relative stereochemistry was confirmed to be (2S, 5R) by NMR nOe experiments.

中間体６の代わりに中間体９を使用して、実施例１について記載した方法と同様に、標記化合物を製造した。
(Ｃ₂₆Ｈ₃₄Ｎ₂Ｏ₄Ｓ₂ ＋ Ｈ)⁺についてのＭＳ計算値：５０３。
ＭＳ（エレクトロスプレー）：測定値(Ｍ＋Ｈ)⁺＝５０３。 Example 4
rel- (2S, 5R) -2-isobutyl-1- (3-methoxy-4-tert-butylbenzoyl) -4-methylthiomethyl-5- (1,3-thiazol-2-yl) -2,5- Dihydro-1H-pyrrole-2-carboxylic acid

The title compound was prepared in a manner similar to that described for Example 1 using Intermediate 9 instead of Intermediate 6.
MS calculated for (C ₂₆ H ₃₄ N ₂ O ₄ S ₂ + H) ⁺ : 503.
MS (electrospray): found (M + H) ⁺ = 503.

中間体６の代わりに中間体１０を使用して、実施例１について記載した方法と同様に、標記化合物を製造した。
¹Ｈ ＮＭＲ（ＣＤ₃ＯＤ）：δ ７.６５（ｄ，１Ｈ）、７.５１（ｄ，１Ｈ）、７.２２（ｄ，１Ｈ）、６.８３（ｄ，１Ｈ）、６.４９（ｍ，２Ｈ）、６.２１（ｓ，１Ｈ）、４.１１（ｄ，１Ｈ）、３.６８（ｓ，３Ｈ）、３.４５（ｄ，１Ｈ）、２.９９（ｓ，３Ｈ）、２.５０−２.６３（ｍ，１Ｈ）、２.２２−２.３４（ｍ，１Ｈ）、１.７５−１.９０（ｍ，１Ｈ）、１.３２（ｓ，９Ｈ）および１.０８（２×ｄ，６Ｈ）。酸プロトンは溶媒と交換されていると考えられる。 Example 5
rel- (2S, 5R) -2-isobutyl-1- (3-methoxy-4-tert-butylbenzoyl) -4-methylsulfonylmethyl-5- (1,3-thiazol-2-yl) -2,5 -Dihydro-1H-pyrrole-2-carboxylic acid

The title compound was prepared in a manner similar to that described for Example 1 using Intermediate 10 instead of Intermediate 6.
¹ H NMR (CD ₃ OD): δ 7.65 (d, 1H), 7.51 (d, 1H), 7.22 (d, 1H), 6.83 (d, 1H), 6.49 ( m, 2H), 6.21 (s, 1H), 4.11 (d, 1H), 3.68 (s, 3H), 3.45 (d, 1H), 2.99 (s, 3H), 2.50-2.63 (m, 1H), 2.22-2.34 (m, 1H), 1.75-1.90 (m, 1H), 1.32 (s, 9H) and 1. 08 (2 × d, 6H). It is thought that the acid proton is exchanged with the solvent.

中間体１１（０.０２６ｇ、０.０４７ｍｍｏｌ）のトリフルオロ酢酸（２ｍＬ）中溶液を２０℃で３時間撹拌した。混合物を蒸発させ、残留物を、エーテルを用いてトリチュレートして、固体として標記化合物を得た。
¹Ｈ ＮＭＲ（ＣＤ₃ＯＤ）：δ ７.６１（ｄ，１Ｈ）、７.４７（ｄ，１Ｈ）、７.２２（ｄ，１Ｈ）、６.８６（ｄ，１Ｈ）、６.４３（ｓ，１Ｈ）、６.２６（ｓ，１Ｈ）、５.８７（ｓ，１Ｈ）、３.８０（ｄｄ，２Ｈ）、３.６６（ｓ，３Ｈ）、３.２５−３.５０（ｍ，２Ｈ）、２.４８−２.６０（ｍ，１Ｈ）、２.１５−２.２５（ｍ，１Ｈ）、１.７０−１.８５（ｍ，１Ｈ）、１.３１（ｓ，９Ｈ）および１.００−１.１０（ｍ，９Ｈ）。酸プロトンは溶媒と交換されていると考えられる。 Example 6
rel- (2S, 5R) -2-isobutyl-1- (3-methoxy-4-tert-butylbenzoyl) -4-ethoxymethyl-5- (1,3-thiazol-2-yl) -2,5- Enantiomer A of dihydro-1H-pyrrole-2-carboxylic acid

A solution of intermediate 11 (0.026 g, 0.047 mmol) in trifluoroacetic acid (2 mL) was stirred at 20 ° C. for 3 hours. The mixture was evaporated and the residue was triturated with ether to give the title compound as a solid.
¹ H NMR (CD ₃ OD): δ 7.61 (d, 1H), 7.47 (d, 1H), 7.22 (d, 1H), 6.86 (d, 1H), 6.43 ( s, 1H), 6.26 (s, 1H), 5.87 (s, 1H), 3.80 (dd, 2H), 3.66 (s, 3H), 3.25-3.50 (m 2H), 2.48-2.60 (m, 1H), 2.15-2.25 (m, 1H), 1.70-1.85 (m, 1H), 1.31 (s, 9H) ) And 1.00-1.10. (M, 9H). It is thought that the acid proton is exchanged with the solvent.

中間体１７（０.２５６ｇ、０.４４ｍｍｏｌ）のジクロロメタン（３ｍＬ）中溶液をトリフルオロ酢酸（３ｍＬ）で室温にて一夜処理した。混合物を蒸発させ、残留物をトルエンと一緒に共蒸発させ、メタノールを用いてトリチュレートして、白色固体として標記化合物を得た。
(Ｃ₂₇Ｈ₃₁Ｎ₃Ｏ₆Ｓ ＋ Ｈ)⁺についてのＭＳ計算値：５２６。
ＭＳ測定値（エレクトロスプレー）：（Ｍ＋Ｈ)⁺＝５２６
¹Ｈ ＮＭＲ（ＣＤＣｌ₃）：δ ８.８８（ｄ，１Ｈ）、７.２２（ｄ，１Ｈ）、７.１４（ｄ，１Ｈ）、６.６６（ｄｄ，１Ｈ）、６.６３（ｄ，１Ｈ）、５.９２（ｓ，１Ｈ）、５.６０（ｓ，１Ｈ）、５.３５（ｓ，１Ｈ）、４.２８（ｄ，１Ｈ）、３.７２（ｓ，３Ｈ）、３.８７−３.６０（ｍ，３Ｈ）、３.１０（ｓ，３Ｈ）、２.２４（ｓ，３Ｈ）および１.３１（ｓ，９Ｈ）。酸プロトンは見られなかった。 Example 7
rel- (2S, 5R) -1- (3-methoxy-4-tert-butylbenzoyl) -4- (methoxymethyl) -5- (5-methylisoxazol-3-yl) -2- (1,3 -Thiazol-4-ylmethyl) -2,5-dihydro-1H-pyrrole-2-carboxylic acid

A solution of intermediate 17 (0.256 g, 0.44 mmol) in dichloromethane (3 mL) was treated with trifluoroacetic acid (3 mL) at room temperature overnight. The mixture was evaporated and the residue was coevaporated with toluene and triturated with methanol to give the title compound as a white solid.
_{(C 27 H 31 N 3 O} 6 S + H) + MS calcd for: 526.
MS measurement (electrospray): (M + H) ⁺ = 526
¹ H NMR (CDCl ₃ ): δ 8.88 (d, 1H), 7.22 (d, 1H), 7.14 (d, 1H), 6.66 (dd, 1H), 6.63 (d , 1H), 5.92 (s, 1H), 5.60 (s, 1H), 5.35 (s, 1H), 4.28 (d, 1H), 3.72 (s, 3H), 3 .87-3.60 (m, 3H), 3.10 (s, 3H), 2.24 (s, 3H) and 1.31 (s, 9H). No acid protons were seen.

  The compounds of the present invention can be formulated for administration in any convenient manner, and therefore the present invention also provides a compound of formula (I) or a physiologically acceptable salt or solvate thereof, Included within the scope are therapeutic pharmaceutical compositions comprising admixture with further physiologically acceptable diluents or carriers.

  The compounds of the present invention can be administered by a variety of routes including intravenous, intraperitoneal, subcutaneous, intramuscular, oral, topical, transdermal or transmucosal administration. For systemic administration, oral administration is preferred. For oral administration, for example, the compounds can be formulated into conventional oral dosage forms such as capsules, tablets and liquid preparations (eg, syrups, elixirs and concentrated drops).

  Alternatively, injection (parenteral administration) (eg, intramuscular injection, intravenous injection, intraperitoneal injection and subcutaneous injection) can be used. For injection, the compounds of the invention are formulated into liquid solutions in physiologically compatible buffers or solutions such as saline, Hank's solution, or Ringer's solution. In addition, the compounds can be formulated into solid dosage forms and can be dissolved or suspended again immediately before use. It can also be prepared in a lyophilized dosage form.

  Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art and include, for example, bile salts and fusidic acid derivatives for transmucosal administration. In addition, surfactants can be used to facilitate penetration. Transmucosal administration can be, for example, nasal sprays, rectal suppositories, or vaginal suppositories.

  For topical administration, the compounds of the invention can be formulated into ointments, salves, gels, or creams as generally known in the art.

The dosage of the various compounds depends on the potency (IC ₅₀ ), efficacy (EC ₅₀ ) and biological half-life (of the compound) of the compound, the age, size and weight of the patient, and the disease or disorder associated with the patient. It can be determined by a standard method in consideration of factors such as The importance of these and other factors to consider is known to those skilled in the art.

  The dosage will also depend on the route of administration and the degree of oral bioavailability. For example, compounds with low oral bioavailability must be administered at relatively high doses. Oral administration is the preferred method of administration of the compounds of the present invention.

  In one aspect, the composition is in unit dosage form. For oral administration, for example, tablets or capsules can be administered, for nasal administration, metered aerosols can be administered, and for transdermal administration, topical formulations or patches can be administered. For transmucosal delivery, buccal patches can be administered. In either case, the dosage is such that the patient can administer a single dose.

  Each dosage unit for oral administration is a compound of formula (I) calculated as the free base or a pharmaceutically acceptable salt thereof, in one aspect 0.01 to 500 mg / Kg, in another aspect, Contains 0.1 to 50 mg / Kg. The daily dosage for the parenteral, nasal, oral inhalation, transmucosal or transdermal routes comprises the compound of formula (I), in one embodiment from 0.01 mg to 100 mg / Kg. To do. In one aspect, the topical formulation contains 0.01-5.0% of a compound of formula (I). As will be readily apparent to those skilled in the art, sufficient active ingredient to exhibit the desired activity can be administered from 1 to 6 times, preferably once a day.

  Compositions of formula (I) and their pharmaceutically acceptable salts that are active when administered orally can be formulated as syrups, tablets, capsules, and lozenges. A syrup formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier (eg, ethanol, peanut oil, olive oil, glycerin or water) containing flavors or colorants. When the composition is in the form of a tablet, any pharmaceutical carrier commonly used to prepare solid formulations can be used. Examples of such carriers include magnesium stearate, clay, talc, gelatin, acacia, stearic acid, starch, lactose and sucrose. When the composition is in a capsule dosage form, any conventional encapsulation using, for example, the above carrier in a hard gelatin capsule shell is suitable. Where the composition is a soft gelatin shell capsule, any pharmaceutical carrier commonly used to prepare dispersions or suspensions, such as aqueous gums, celluloses, silicates or oils, is contemplated and placed in the soft gelatin shell. It is done.

  A typical parenteral composition is a compound in a sterile aqueous or non-aqueous carrier, which may contain a parenterally acceptable oil (eg, polyethylene glycol, polyvinylpyrrolidone, lecithin, peanut oil or sesame oil) or It consists of a salt solution or suspension.

  Typical inhalable compositions are in the form of solutions, suspensions or emulsions that can be administered as a dry powder or use a conventional propellant such as dichlorodifluoromethane or trichlorofluoromethane. Aerosol dosage form.

  A typical suppository formulation comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof that is active when administered in this manner, and a binder and / or lubricant, such as a polymeric glycol, gelatin. , Cocoa butter or other low melting vegetable waxes or fats or synthetic analogs thereof.

  Typical skin or transdermal formulations include conventional aqueous or non-aqueous vehicles such as creams, ointments, lotions or pastes, or are in the form of pharmaceutical plasters, patches or films.

  When the compounds of the present invention are administered according to the present invention, unacceptable toxic effects are not considered.

Assay The ability of the compounds of the invention to inhibit NS5B wild type HCV polymerase activity can be demonstrated, for example, using the following in vitro assay:

In vitro detection of inhibitors of HCV RNA-dependent RNA polymerase activity
After incorporating [ ³³ P] -GMP into RNA, biotin-labeled RNA polymer was adsorbed by streptavidin-containing SPA beads. A synthetic template consisting of biotinylated 13mer oligo G hybridized with poly rC was used as a homopolymer substrate.

The reaction conditions were 0.5 μM [ ³³ P] -GTP (0.2 Ci / mMol), 1 mM dithiothreitol, 20 mM MgCl ₂ , 5 mM MnCl ₂ , 20 mM Tris-HCl, pH 7.5, 1.6 μg / mL poly C. /0.256 μM biotinylated oligo G13, 10% glycerol, 0.01% NP-40, 0.2 u / μL RNasin and 50 mM NaCl.

  HCV RNA polymerase (recombinant full-length NS5B expressed in baculovirus and purified to homogeneity (Lohmann et al, J. Virol. 71 (11), 1997, 8416 'Biochemical properties of hepatitis C virus NS5B RNA-dependent RNA Polymerase and identification of amino acid sequence motifs essential for cyclic activity ')) were added to a final concentration of 10 nM.

A 5 × concentrated assay buffer mixture was prepared using 1M MnCl ₂ (0.25 mL), glycerol (4 mL), 10% NP-40 (0.025 mL) and water (7.225 mL), 10 mL total.

The 2-fold concentrated enzyme buffer was 1M-Tris-HCl, pH 7.5 (0.4 mL), 5M NaCl (0.2 mL), 1M-MgCl ₂ (0.4 mL), glycerol (1 mL), 10% NP- 40 (10 μL), 1 M DTT (20 μL) and water (7.97 mL), total volume 10 mL.

The substrate mixture was 5 × concentrated assay buffer mixture (4 μL), [ ³³ P] -GTP (10 μCi / μL, 0.02 μL), 25 μM GTP (0.4 μL), 0.4 u / μL RNasin (0.04 μL). , 20 μg / mL poly rC / biotinylated oligo rG (1.6 μL) and water (3.94 μL), total volume 10 μL.

  The enzyme mixture was prepared by adding 1 mg / ml full length NS5B polymerase (1.5 μL) to 2.811 mL of 2 × concentrated enzyme buffer.

  The assay was set up with compound (1 μL), substrate mixture (10 μL) and enzyme mixture (added to start reaction last) (10 μL), total volume 21 μL.

  The reaction was performed in a U-bottom white 96 well plate. After the enzyme was added, the reaction was mixed on a plate shaker and incubated at 22 ° C. for 1 hour. Following this, the reaction was stopped by the addition of 40 μL of 1.875 mg / ml streptavidin SPA beads in 0.1 M EDTA. After incubating the beads with the reaction mixture for 1 hour at 22 ° C., 120 μL of 0.1 M EDTA in PBS was added. The plates were sealed, mixed, centrifuged, and incorporated radioactivity was measured by counting in a Trilux (Wallac) or Topcount (Packard) Scintillation Counter.

After subtracting the background level without the enzyme, the decrease in the amount of radioactivity incorporated in the presence of the compound relative to the amount of radioactivity incorporated in the absence of the compound is a measure of the level of inhibition. It was said. Ten concentrations of compound were tested at 3-fold or 5-fold dilutions. From these counts, the percentage inhibition or IC ₅₀ at the highest concentration tested for the compound was calculated using the Grafit3 or Grafit4 software package.

All exemplified compounds had an IC ₅₀ of <50 μM in the above assay. Accordingly, the compounds of the present invention have potential therapeutic utility in the treatment and prevention of HCV. Preferred compounds had an IC ₅₀ of <10 μM.

  The pharmaceutical composition of the present invention may comprise other therapeutic agents such as immunotherapeutic agents (eg, interferons such as interferon α-2a (Roferon-A; Hoffmann-La Roche), interferon α-2b (Intron-A; Schering). -Plough), interferon alphacon-1 (Infergen; Intermune), pegylated interferon α-2b (Peg-Intron; Schering-Plough) or pegylated interferon α-2a (Pegasys; Hoffmann-La Roche)), therapeutic vaccine, anti Fibrotic drugs, anti-inflammatory drugs (eg, corticosteroids or NSAIDs), bronchodilators (eg, beta-2 adrenergic drugs and xanthines (eg, theophylline)), mucolytic drugs, antimuscarinic drugs, anti-leukotrienes Cell adhesion inhibitors (eg, ICAM Drugs), antioxidants (eg, N-acetylcysteine), cytokine agonists, cytokine antagonists, lung surfactants and / or antimicrobial and antiviral agents (eg, ribavirin and amantidine) You can also The composition of the present invention can also be used in combination with gene replacement therapy.

  Thus, the present invention, in a further aspect, comprises a compound of formula (I) or a physiologically acceptable salt or solvate thereof together with another therapeutically active agent, in particular interferon and / or ribavirin. Provide a combination.

  Combinations as defined above can be conveniently provided for use in the form of pharmaceutical formulations, thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier provide a further aspect of the invention To do.

  The individual components of such a combination can be administered separately or combined in a pharmaceutical formulation, either sequentially or simultaneously. Appropriate doses of known therapeutic agents will be readily apparent to those skilled in the art.

  All publications, including, but not limited to, patents and patent applications cited herein are hereby expressly incorporated by reference specifically and individually as if each individual publication was fully disclosed. Is hereby incorporated by reference as if explicitly stated as part of the specification.

Claims (23)

Formula (I):

[Where:
A represents hydroxy;
D represents aryl or heteroaryl;
E represents hydrogen, C _1-6 alkyl, aryl, heteroaryl or heterocyclyl;
G is hydrogen, or halo, OR ¹ , SR ¹ , C (O) NR ² R ³ , CO ₂ H, C (O) R ⁴ , CO ₂ R ⁴ , NR ² R ³ , NHC (O) R ⁴ One or more substitutions selected from NHCO ₂ R ⁴ , NHC (O) NR ⁵ R ⁶ , SO ₂ NR ⁵ R ⁶ , SO ₂ R ⁴ , nitro, cyano, aryl, heteroaryl and heterocyclyl _Represents C _1-6 alkyl _optionally substituted by a group;
R ¹ represents hydrogen, C _1-6 alkyl, arylalkyl or heteroarylalkyl;
R ² and R ³ are independently selected from hydrogen, C _1-6 alkyl, aryl and heteroaryl; or R ² and R ³ together with the nitrogen atom to which they are attached 5 Forming a 6-membered or 6-membered saturated cyclic group;
R ⁴ is selected from the group consisting of C _1-6 alkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl;
R ⁵ and R ⁶ are independently selected from the group consisting of hydrogen, C _1-6 alkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl; or R ⁵ and R ⁶ are attached to them. Together with the nitrogen atom forming a 5- or 6-membered saturated cyclic group;
J represents C _1-6 alkyl, heterocyclylalkyl, arylalkyl or heteroarylalkyl]
And the salts, solvates and esters thereof, wherein A is esterified to —OR (where R is selected from linear or branched alkyl, aralkyl, aryloxyalkyl or aryl Wherein R is other than tert-butyl). The at least one chemical entity of claim 1 selected from the group consisting of:
rel- (2S, 5R) -2-isobutyl-1- (3-methoxy-4-tert-butylbenzoyl) -4-ethoxymethyl-5- (1,3-thiazol-2-yl) -2,5- Dihydro-1H-pyrrole-2-carboxylic acid;
rel- (2S, 5R) -2-isobutyl-1- (3-methoxy-4-tert-butylbenzoyl) -4-methoxymethyl-5- (1,3-thiazol-2-yl) -2,5- Dihydro-1H-pyrrole-2-carboxylic acid;
rel- (2S, 5R) -2-isobutyl-1- (3-methoxy-4-tert-butylbenzoyl) -4-n-propyloxymethyl-5- (1,3-thiazol-2-yl) -2 , 5-dihydro-1H-pyrrole-2-carboxylic acid;
rel- (2S, 5R) -2-isobutyl-1- (3-methoxy-4-tert-butylbenzoyl) -4-methylthiomethyl-5- (1,3-thiazol-2-yl) -2,5- Dihydro-1H-pyrrole-2-carboxylic acid;
rel- (2S, 5R) -2-isobutyl-1- (3-methoxy-4-tert-butylbenzoyl) -4-methylsulfonylmethyl-5- (1,3-thiazol-2-yl) -2,5 -Dihydro-1H-pyrrole-2-carboxylic acid;
rel- (2S, 5R) -1- (3-methoxy-4-tert-butylbenzoyl) -4- (methoxymethyl) -5- (5-methylisoxazol-3-yl) -2- (1,3 -Thiazol-4-ylmethyl) -2,5-dihydro-1H-pyrrole-2-carboxylic acid; and its salts, solvates and esters, and the individual enantiomers.   2. At least one chemical entity according to claim 1, wherein D represents phenyl which may be substituted. 4. At least one chemical entity according to claim 3, wherein D represents para-tert-butylphenyl, which may be further substituted by halo, _C1-3 alkyl or _C1-3 alkoxy.   The at least one chemical entity of claim 1 wherein E represents an optionally substituted heteroaryl.   6. At least one chemical entity according to claim 5, wherein E represents thiazolyl or isoxazolyl, both of which may be substituted. The at least one chemical entity of claim 1 wherein G represents C _1-6 alkyl optionally substituted by OR ¹ , SR ¹ or SO ₂ R ⁴ . G is, OR ^1, SR ¹ or SO ₂ R ⁴ represents methyl optionally substituted by at least one chemical entity of claim 7 wherein. _{9. At} least one chemical entity according to claim 7 or 8, wherein R ¹ represents C _1-3 alkyl. R ⁴ represents C _1-3 alkyl, at least one chemical entity of claim 7 wherein. J represents C _1-6 alkyl, arylalkyl or heteroarylalkyl, at least one chemical entity of claim 1, wherein.   2. At least one chemical selected from the compounds of formula (I) according to claim 1 and pharmaceutically acceptable salts and solvates thereof. A subject in need of treatment or prevention of a viral infection has the formula (I):

[Where:
A represents hydroxy;
D represents aryl or heteroaryl;
E represents hydrogen, C _1-6 alkyl, aryl, heteroaryl or heterocyclyl;
G is hydrogen, or halo, OR ¹ , SR ¹ , C (O) NR ² R ³ , CO ₂ H, C (O) R ⁴ , CO ₂ R ⁴ , NR ² R ³ , NHC (O) R ⁴ One or more substitutions selected from NHCO ₂ R ⁴ , NHC (O) NR ⁵ R ⁶ , SO ₂ NR ⁵ R ⁶ , SO ₂ R ⁴ , nitro, cyano, aryl, heteroaryl and heterocyclyl _Represents C _1-6 alkyl _optionally substituted by a group;
R ¹ represents hydrogen, C _1-6 alkyl, arylalkyl or heteroarylalkyl;
R ² and R ³ are independently selected from hydrogen, C _1-6 alkyl, aryl and heteroaryl; or R ² and R ³ together with the nitrogen atom to which they are attached 5 Forming a 6-membered or 6-membered saturated cyclic group;
R ⁴ is selected from the group consisting of C _1-6 alkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl;
R ⁵ and R ⁶ are independently selected from the group consisting of hydrogen, C _1-6 alkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl; or R ⁵ and R ⁶ are attached to them. Together with the nitrogen atom forming a 5- or 6-membered saturated cyclic group;
J represents C _1-6 alkyl, heterocyclylalkyl, arylalkyl or heteroarylalkyl]
And the salts, solvates and esters thereof, wherein A is esterified to —OR (where R is selected from linear or branched alkyl, aralkyl, aryloxyalkyl or aryl Wherein R is other than tert-butyl). A method of treating or preventing a viral infection comprising administering an effective amount of at least one chemical selected from:   14. The method of claim 13, comprising inhibiting HCV replication.   14. The method of claim 13, wherein at least one chemical is administered in an oral dosage form. Formula (I) for use in drug therapy:

[Where:
A represents hydroxy;
D represents aryl or heteroaryl;
E represents hydrogen, C _1-6 alkyl, aryl, heteroaryl or heterocyclyl;
G is hydrogen, or halo, OR ¹ , SR ¹ , C (O) NR ² R ³ , CO ₂ H, C (O) R ⁴ , CO ₂ R ⁴ , NR ² R ³ , NHC (O) R ⁴ One or more substitutions selected from NHCO ₂ R ⁴ , NHC (O) NR ⁵ R ⁶ , SO ₂ NR ⁵ R ⁶ , SO ₂ R ⁴ , nitro, cyano, aryl, heteroaryl and heterocyclyl _Represents C _1-6 alkyl _optionally substituted by a group;
R ¹ represents hydrogen, C _1-6 alkyl, arylalkyl or heteroarylalkyl;
R ² and R ³ are independently selected from hydrogen, C _1-6 alkyl, aryl and heteroaryl; or R ² and R ³ together with the nitrogen atom to which they are attached 5 Forming a 6-membered or 6-membered saturated cyclic group;
R ⁴ is selected from the group consisting of C _1-6 alkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl;
R ⁵ and R ⁶ are independently selected from the group consisting of hydrogen, C _1-6 alkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl; or R ⁵ and R ⁶ are attached to them. Together with the nitrogen atom forming a 5- or 6-membered saturated cyclic group;
J represents C _1-6 alkyl, heterocyclylalkyl, arylalkyl or heteroarylalkyl]
And the salts, solvates and esters thereof, wherein A is esterified to —OR (where R is selected from linear or branched alkyl, aralkyl, aryloxyalkyl or aryl Wherein R is other than tert-butyl).   17. At least one chemical entity according to claim 16 wherein the drug therapy is treatment of a viral infection.   18. At least one chemical entity according to claim 17, wherein the viral infection is HCV. Formula (I) in the manufacture of a medicament for the treatment of viral infections:

[Where:
A represents hydroxy;
D represents aryl or heteroaryl;
E represents hydrogen, C _1-6 alkyl, aryl, heteroaryl or heterocyclyl;
G is hydrogen, or halo, OR ¹ , SR ¹ , C (O) NR ² R ³ , CO ₂ H, C (O) R ⁴ , CO ₂ R ⁴ , NR ² R ³ , NHC (O) R ⁴ One or more substitutions selected from NHCO ₂ R ⁴ , NHC (O) NR ⁵ R ⁶ , SO ₂ NR ⁵ R ⁶ , SO ₂ R ⁴ , nitro, cyano, aryl, heteroaryl and heterocyclyl _Represents C _1-6 alkyl _optionally substituted by a group;
R ¹ represents hydrogen, C _1-6 alkyl, arylalkyl or heteroarylalkyl;
R ² and R ³ are independently selected from hydrogen, C _1-6 alkyl, aryl and heteroaryl; or R ² and R ³ together with the nitrogen atom to which they are attached 5 Forming a 6-membered or 6-membered saturated cyclic group;
R ⁴ is selected from the group consisting of C _1-6 alkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl;
R ⁵ and R ⁶ are independently selected from the group consisting of hydrogen, C _1-6 alkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl; or R ⁵ and R ⁶ are attached to them. Together with the nitrogen atom forming a 5- or 6-membered saturated cyclic group;
J represents C _1-6 alkyl, heterocyclylalkyl, arylalkyl or heteroarylalkyl]
And the salts, solvates and esters thereof, wherein A is esterified to —OR (where R is selected from linear or branched alkyl, aralkyl, aryloxyalkyl or aryl Wherein R is other than tert-butyl).   20. Use according to claim 19, wherein the viral infection is HCV.   A pharmaceutical composition comprising at least one chemical substance selected from the compound represented by formula (I) according to claim 1 and salts, solvates and esters thereof, and a pharmaceutically acceptable diluent or carrier. Formula (II):

[Wherein A is alkoxy and D, E, G and J are as defined for formula (I)]
A method for producing a compound represented by the formula (I) according to claim 1, comprising treating the compound represented by formula (I) with an acid.   23. The method of claim 22, wherein A is tert-butoxy.