JP2009543807A - Antiviral agent - Google Patents

Abstract

Disclosed are compounds and compositions of formula (I) and their use to treat viral infections of the Flaviviridae family.

Description

CROSS REFERENCE TO RELATED APPLICATIONS This application claims priority to co-pending US Provisional Patent Application No. 60 / 831,040 filed 14 July 2006, the contents of which are hereby incorporated by reference in their entirety.

The present invention relates to compounds, compositions and methods for treating viral infections in mammals mediated by medicinal chemistry, in particular, viruses of the Flaviviridae family at least in part.

BACKGROUND OF THE INVENTION Citations The following publications are cited in this application.
Szabo, E. et al., Pathol. Oncol. Res. 2003, 9: 215-221 (non-patent document 1)
Hoofnagle JH, Hepatology 1997, 26: 15S-20S (non-patent document 2)
Thomson BJ and Finch RG, Clin Microbial Infect. 2005, 11: 86-94 (Non-patent Document 3)
Moriishi K. and Matsuura Y., Antivir. Chem. Chemother. 2003, 14: 285-297 (non-patent document 4)
Fried, MW, et al. N. Engl. J Med 2002, 347: 975-982 (non-patent document 5)
Ni, ZJ and Wagman, AS Curr. Opin. Drug Discov. Devel. 2004, 7, 446-459 (non-patent document 6)
Beaulieu, PL and Tsantrizos, YS Curr. Opin. Investig. Drugs 2004, 5, 838-850 (Non-patent Document 7)
Griffith, RC et al., Ann. Rep. Med. Chem 39, 223-237, 2004 (non-patent document 8)
Watashi, K. et al., Molecular Cell, 19, 111-122, 2005 (Non-patent document 9)
Horsmans, Y. et al., Hepatology, 42, 724-731, 2005 (Non-patent Document 10)

Current status
Chronic infection with HCV is a major health problem associated with cirrhosis, hepatocellular carcinoma and liver dysfunction. An estimated 170 million chronic carriers worldwide are at risk of developing liver disease (Non-Patent Documents 1 and 2). In the United States alone, 2.7 million people are chronically infected with HCV, and the number of deaths associated with HCV in 2000 is estimated to be between 8,000 and 10,000, and this number is expected to increase significantly in recent years . Infection with HCV is latent in a high proportion of chronically infected (and infectious) carriers who do not seem to have experienced clinical symptoms for many years. Cirrhosis can ultimately cause liver dysfunction. Liver dysfunction due to chronic HCV infection is now recognized as the main cause of liver transplantation.

  HCV is a member of the Flaviviridae family of RNA viruses that affect animals and humans. The genome is a single-stranded RNA of about 9.6 kilobases, one open encoding a polyprotein of about 3000 amino acids flanked by untranslated regions (5'- and 3'-UTR) at both the 5 'and 3' ends It consists of a reading frame. The polyprotein serves as a precursor to at least 10 separate viral proteins critical to the replication and assembly of progeny viral particles. The structure of structural and nonstructural proteins in the HCV polyprotein is as follows: C-E1-E2-p7-NS2-NS3-NS4a-NS4b-NS5a-NS5b. HCV infection is theoretically curable because the HCV replication cycle does not require any DNA intermediates and the virus does not integrate into the host genome. Although the pathology of HCV infection mainly affects the liver, viruses have also been found in other cell types in the body including peripheral blood lymphocytes (Non-patent Documents 3 and 4).

  At present, the standard treatment for chronic HCV is the combination of interferon alpha (IFN-α) and ribavirin, which requires at least 6 months of treatment. IFN-α exhibits characteristic biological effects such as antiviral, immunomodulatory, and antitumor activity that are produced and secreted by most animal nucleated cells in response to several diseases, particularly viral infections. It belongs to a family of natural low molecular weight proteins. IFN-α is an important regulator of growth and differentiation that affects intercellular communication and immune regulation. Treatment of HCV with interferon was often accompanied by adverse side effects such as fatigue, fever, chills, headache, muscle pain, joint pain, mild hair loss, mental effects and related disorders, autoimmune phenomena and related disorders, and thyroid dysfunction . Ribavirin is an inhibitor of inosine 5 ′ monophosphate dehydrogenase (IMPDH) and enhances the efficacy of IFN-α in the treatment of HCV. Despite the introduction of ribavirin, more than 50% of patients do not clear the virus with current standard treatment of interferon alpha (IFN) and ribavirin. To date, the standard treatment for chronic hepatitis C has been changed to a combination of pegIFN-α and ribavirin. However, some patients still have significant side effects primarily related to ribavirin. Ribavirin causes significant hemolysis in 10-20% of patients treated at the current recommended dose, and the drug exhibits both teratogenic and embryotoxicity. Even with recent improvements, a significant proportion of patients do not respond with a sustained reduction in viral load (Non-Patent Document 5) and there is a clear need for more effective antiviral therapy for HCV infection .

  Several approaches to fighting viruses are being explored. They include, for example, the application of antisense oligonucleotides or ribozymes to inhibit HCV replication. In addition, low molecular weight compounds that directly inhibit HCV proteins and interfere with viral replication are considered attractive strategies for controlling HCV infection. Of the viral targets, NS3 / 4a protease / helicase and NS5b RNA-dependent RNA polymerase appear to be the most promising viral targets for new drugs (Non-Patent Documents 6-8).

  In addition to targeting viral genes and their transcripts and translation products, antiviral activity can also be achieved by targeting host cell proteins required for viral replication. For example, Watashi et al. (Non-Patent Document 9) show how antiviral activity can be achieved by inhibiting host cell cyclophilin. Alternatively, potent TLR7 agonists have been shown to lower HCV plasma levels in humans (Non-Patent Document 10).

  However, none of the aforementioned compounds exceeded the clinical trial stage (Non-Patent Documents 6 and 8).

  Given the global prevalence of HCV and other Flaviviridae members, and further considering limited treatment options, there is a strong need for new and effective drugs to treat infections caused by these viruses Yes.

Szabo, E. et al., Pathol. Oncol. Res. 2003, 9: 215-221 Hoofnagle J.H., Hepatology 1997, 26: 15S-20S Thomson B.J. and Finch R.G., Clin Microbial Infect. 2005, 11: 86-94 Moriishi K. and Matsuura Y., Antivir. Chem. Chemother. 2003, 14: 285-297 Fried, M.W., et al. N. Engl. J Med 2002, 347: 975-982 Ni, Z. J. and Wagman, A. S. Curr. Opin. Drug Discov. Devel. 2004, 7, 446-459 Beaulieu, P. L. and Tsantrizos, Y. S. Curr. Opin. Investig. Drugs 2004, 5, 838-850 Griffith, R. C. et al., Ann. Rep. Med. Chem 39, 223-237, 2004 Watashi, K. et al., Molecular Cell, 19, 111-122, 2005 Horsmans, Y. et al., Hepatology, 42, 724-731, 2005

式中：
Yはアリール、ヘテロアリール、置換アリール、および置換ヘテロアリールからなる群より選択され；
HETは、6員アリーレン環、NまたはOまたはSから選択される1個または2個または3個のヘテロ原子を含む6員ヘテロアリーレン環、および下記の式を有する二環式環からなる群より選択され、

式中、HETは(X)_tで置換されていてもよく、Xは、アルキル、置換アルキル、アルコキシ、置換アルコキシ、アミノ、置換アミノ、ハロ、ヒドロキシ、およびニトロからなる群より選択され；tは0、1または2に等しい整数であり；W¹、W⁴、およびW⁵は独立にNまたはCHであり；W³はNもしくはCHであるか、または、二環式環内の1個以下の窒素が酸化されてN-オキシドを生成してもよいとの条件で結合であり；かつ破線の一方が一重結合である場合、隣接する原子がそれぞれ1または2個の水素原子で置換されてその原子価を満たしているとの条件で、破線はそれぞれ独立に2個の隣接する原子間の一重結合または二重結合を表し；
DまたはEの一方はC-R^aであり、DまたはEの他方はSであり；
R^aおよびRは水素、アルキル、および置換アルキルからなる群より独立に選択され；
Qはシクロアルキル、置換シクロアルキル、シクロアルケニル、置換シクロアルケニル、複素環、置換複素環、アリール、置換アリール、ヘテロアリール、および置換ヘテロアリールからなる群より選択され；かつ
Zは以下からなる群より選択される：
（a）カルボキシおよびカルボキシエステル；
（b）-C(X⁴)NR⁸R⁹、式中、X⁴は=O、=NH、または=N-アルキルであり、R⁸およびR⁹は水素、アルキル、置換アルキル、アルケニル、置換アルケニル、アルキニル、置換アルキニル、アリール、置換アリール、ヘテロアリール、置換ヘテロアリール、複素環および置換複素環からなる群より独立に選択されるか、またはR⁸およびR⁹はそれらに結合している窒素原子と一緒になって複素環、置換複素環、ヘテロアリールもしくは置換ヘテロアリール環基を形成する；
（c）-C(X³)NR²¹S(O)₂R⁴、式中、X³は=O、=NR²⁴、および=Sから選択され、R²⁴は水素、アルキル、または置換アルキルであり；R⁴はアルキル、置換アルキル、アリール、置換アリール、ヘテロアリール、置換ヘテロアリール、複素環、置換複素環、およびNR²²R²³から選択され、R²¹、R²²およびR²³は独立に水素、アルキル、置換アルキル、シクロアルキル、もしくは置換シクロアルキルであるか；または、R²¹およびR²²もしくはR²²およびR²³はそれらに結合している原子と一緒になって置換されていてもよい複素環基を形成する；
（d）-C(X²)-N(R³)CR²R^2'C(=O)R¹、式中、X²は=O、=S、および=NR¹¹から選択され、R¹¹は水素またはアルキルであり、R¹は-OR⁷および-NR⁸R⁹から選択され、R⁷は水素、アルキル、置換アルキル、アルケニル、置換アルケニル、アルキニル、置換アルキニル、アリール、置換アリール、ヘテロアリール、置換ヘテロアリール、複素環および置換複素環から選択され；R⁸およびR⁹は前述の定義のとおりであり；
R²およびR^2'は水素、アルキル、置換アルキル、アルケニル、置換アルケニル、アルキニル、置換アルキニル、アリール、置換アリール、シクロアルキル、置換シクロアルキル、ヘテロアリール、置換ヘテロアリール、複素環、および置換複素環から独立に選択されるか；
または、定義のとおりのR²およびR^2'はそれらに結合している炭素原子と一緒になってシクロアルキル、置換シクロアルキル、複素環もしくは置換複素環基を形成するか、
さらにまたは、R²もしくはR^2'の一方は水素、アルキルもしくは置換アルキルであり、他方はそれに結合している炭素原子と一緒になって、R⁷およびそれに結合している酸素原子もしくはR⁸およびそれに結合している窒素原子のいずれかと共に複素環もしくは置換複素環基を形成し；
R³は水素およびアルキルから選択されるか、または、R²およびR^2'が一緒になって環を形成しない場合、ならびにR²もしくはR^2'およびR⁷もしくはR⁸が一緒になって複素環もしくは置換複素環基を形成しない場合、R³はそれに結合している窒素原子と一緒になって、R²およびR^2'の一方と一緒に複素環もしくは置換複素環基を形成してもよい；
（e）-C(X²)-N(R³)CR²⁵R²⁶R²⁷、式中、X²およびR³は上で定義されており、かつR²⁵、R²⁶およびR²⁷はアルキル、置換アルキル、アリール、置換アリール、複素環、置換複素環、ヘテロアリールおよび置換ヘテロアリールからなる群より独立に選択されるか、またはR²⁵およびR²⁶はそれらに結合している炭素原子と一緒になってシクロアルキル、置換シクロアルキル、複素環もしくは置換複素環基を形成する；および
（f）（a）〜（e）において定義したものではない、カルボン酸同配体。 SUMMARY OF THE INVENTION The present invention is directed to novel compounds, compositions and methods for treating mammalian viral infections mediated, at least in part, by Flaviviridae viruses such as HCV. In particular, the compounds of the invention are represented by formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, prodrug, or tautomer thereof:

In the formula:
Y is selected from the group consisting of aryl, heteroaryl, substituted aryl, and substituted heteroaryl;
HET is from the group consisting of a 6-membered arylene ring, a 6-membered heteroarylene ring containing 1 or 2 or 3 heteroatoms selected from N or O or S, and a bicyclic ring having the formula: Selected

Wherein HET may be substituted with (X) _t , wherein X is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, halo, hydroxy, and nitro; An integer equal to 0, 1 or 2; W ¹ , W ⁴ and W ⁵ are independently N or CH; W ³ is N or CH or no more than one in a bicyclic ring In the case that one of the broken lines is a single bond, each adjacent atom is replaced with 1 or 2 hydrogen atoms, respectively. Each dashed line independently represents a single or double bond between two adjacent atoms, provided that the valence is met;
One of D or E is CR ^a and the other of D or E is S;
R ^a and R are independently selected from the group consisting of hydrogen, alkyl, and substituted alkyl;
Q is selected from the group consisting of cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocycle, substituted heterocycle, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and
Z is selected from the group consisting of:
(A) carboxy and carboxy ester;
(B) —C (X ⁴ ) NR ⁸ R ⁹ , wherein X ⁴ is ═O, ═NH, or ═N-alkyl, and R ⁸ and R ⁹ are hydrogen, alkyl, substituted alkyl, alkenyl, substituted Independently selected from the group consisting of alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle, or R ⁸ and R ⁹ are bound to them Together with the atoms form a heterocyclic, substituted heterocyclic, heteroaryl or substituted heteroaryl ring group;
(C) —C (X ³ ) NR ²¹ S (O) ₂ R ⁴ , wherein X ³ is selected from ═O, ═NR ²⁴ , and ═S, and R ²⁴ is hydrogen, alkyl, or substituted alkyl Yes; R ⁴ is selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, and NR ²² R ²³ , R ²¹ , R ^22, and R ²³ are independently hydrogen , Alkyl, substituted alkyl, cycloalkyl, or substituted cycloalkyl; or R ²¹ and R ²² or R ²² and R ²³ are optionally substituted together with the atoms bonded to them. Forming a ring group;
(D) -C (X ² ) -N (R ³ ) CR ² R ^{2 '} C (= O) R ¹ , wherein X ² is selected from = O, = S, and = NR ¹¹ and R ¹¹ Is hydrogen or alkyl, R ¹ is selected from —OR ⁷ and —NR ⁸ R ⁹ , R ⁷ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl , Substituted heteroaryl, heterocycle and substituted heterocycle; R ⁸ and R ⁹ are as defined above;
R ² and R ^{2 ′} are hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle Selected independently from;
Or R ² and R ^{2 ′} as defined together with the carbon atom to which they are attached form a cycloalkyl, substituted cycloalkyl, heterocyclic or substituted heterocyclic group,
Additionally or alternatively, one of R ² or R ^{2 ′} is hydrogen, alkyl or substituted alkyl, and the other, together with the carbon atom bonded to it, is R ⁷ and the oxygen atom or R ⁸ and Forming a heterocyclic or substituted heterocyclic group with any of the nitrogen atoms bonded to it;
R ³ is selected from hydrogen and alkyl, or when R ² and R ^{2 ′} are not taken together to form a ring, and R ² or R ^{2 ′} and R ⁷ or R ⁸ are taken together to form a complex If not forming a ring or substituted heterocyclic group, R ³ may be taken together with the nitrogen atom bonded to it to form a heterocyclic or substituted heterocyclic group with one of R ² and R ^{2 ′.} Good;
(E) -C (X ² ) -N (R ³ ) CR ²⁵ R ²⁶ R ²⁷ , wherein X ² and R ³ are defined above, and R ²⁵ , R ²⁶ and R ²⁷ are alkyl, Independently selected from the group consisting of substituted alkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl and substituted heteroaryl, or R ²⁵ and R ²⁶ together with the carbon atom to which they are attached. And forms a cycloalkyl, substituted cycloalkyl, heterocyclic or substituted heterocyclic group; and (f) carboxylic acid isosteres not defined in (a)-(e).

DETAILED DESCRIPTION OF THE INVENTION Definitions It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the invention. In this specification and the appended claims, reference will be made to a number of terms that are defined to have the following meanings.

  As used herein, “alkyl” refers to a monovalent alkyl group having 1 to 10 carbon atoms, preferably 1 to 5 carbon atoms, more preferably 1 to 3 carbon atoms. . This term is exemplified by groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl and the like.

  “Substituted alkyl” means alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, halogen, hydroxy, nitro, carboxy, carboxy ester, 1 to 3, preferably 1 to 2 substituents selected from the group consisting of cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle An alkyl group having

  “Alkoxy” refers to the group “alkyl-O—” which includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, n-pentoxy and the like. included.

  “Substituted alkoxy” refers to the group “substituted alkyl-O—”.

  `` Acyl '' refers to HC (O)-, alkyl-C (O)-, substituted alkyl-C (O)-, alkenyl-C (O)-, substituted alkenyl-C (O)-, alkynyl-C ( O)-, substituted alkynyl-C (O)-, cycloalkyl-C (O)-, substituted cycloalkyl-C (O)-, aryl-C (O)-, substituted aryl-C (O)-, hetero Aryl-C (O)-, substituted heteroaryl-C (O)-, heterocyclic-C (O)-, and substituted heterocyclic-C (O)-are meant.

“Acylamino” refers to the group —C (O) NR ^f R ^g where R ^f and R ^g are hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl , Cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, wherein R ^f and R ^g together with the nitrogen atom are heterocycle or substituted heterocycle Form a ring.

  `` Acyloxy '' refers to alkyl-C (O) O-, substituted alkyl-C (O) O-, alkenyl-C (O) O-, substituted alkenyl-C (O) O-, alkynyl-C (O) O-, substituted alkynyl-C (O) O-, aryl-C (O) O-, substituted aryl-C (O) O-, cycloalkyl-C (O) O-, substituted cycloalkyl-C (O) Means the group O-, heteroaryl-C (O) O-, substituted heteroaryl-C (O) O-, heterocyclic-C (O) O-, and substituted heterocyclic-C (O) O- .

  “Alkenyl” has 2 to 10 carbon atoms, preferably 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms, and has at least 1 site, preferably 1 to 2 sites. An alkenyl group having alkenyl unsaturation is meant.

  “Substituted alkenyl” refers to alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, halogen, hydroxy, nitro, carboxy, carboxy ester, An alkenyl group having 1 to 3 substituents, preferably 1 to 2 substituents, selected from the group consisting of cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle Where any hydroxyl substitution is not attached to the vinyl carbon atom.

  “Alkynyl” has 2 to 10 carbon atoms, preferably 2 to 6 carbon atoms, more preferably 2 to 3 carbon atoms, and has at least 1 site, preferably 1 to 2 sites. An alkynyl group having alkynyl unsaturation is meant.

  “Substituted alkynyl” means alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, halogen, hydroxy, nitro, carboxy, carboxy ester, Alkynyl group having 1 to 3 substituents, preferably 1 to 2 substituents, selected from the group consisting of cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle Where any hydroxyl substituent is not attached to an acetylene carbon atom.

“Amino” refers to the group —NH ₂ .

“Substituted amino” refers to the group —NR ^h R ⁱ where R ^h and R ⁱ are hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl. Independently selected from the group consisting of substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, wherein R ^h and R ⁱ together with the nitrogen attached to them are heterocycles or Forms a substituted heterocyclic group, provided that R ^h and R ⁱ are not both hydrogen. When R ^h is hydrogen and R ⁱ is alkyl, the substituted amino group is sometimes referred to herein as alkylamino. When R ^h and R ⁱ are alkyl, the substituted amino group is sometimes referred to herein as dialkylamino.

The "amino acyl", -NR ^j C (O) alkyl, -NR ^j C (O) substituted alkyl, -NR ^j C (O) - cycloalkyl, -NR ^j C (O) substituted cycloalkyl, -NR ^j C (O) alkenyl, --NR ^j C (O) substituted alkenyl, --NR ^j C (O) alkynyl, --NR ^j C (O) substituted alkynyl, --NR ^j C (O) aryl, --NR ^j C (O ) Substituted aryl, -NR ^j C (O) heteroaryl, -NR ^j C (O) substituted heteroaryl, -NR ^j C (O) heterocycle, and -NR ^j C (O) substituted heterocycle Where R ^j is hydrogen or alkyl.

  “Aryl” or “Ar” means a monovalent aromatic carbocyclic group of 6 to 14 carbon atoms having one ring (eg, phenyl) or multiple condensed rings (eg, naphthyl or anthryl) The fused ring may or may not be aromatic provided that the point of attachment is an aromatic ring atom (eg, 2-benzoxazolinone, 2H-1,4-benzoxazin-3 (4H) -one- 7-Ile). Preferred aryl include phenyl and naphthyl.

  “Aralkyl” or “arylalkyl” refers to the group aryl-alkyl- and includes, for example, benzyl.

  The term “substituted aryl” refers to hydroxy, acyl, acylamino, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, substituted amino, aminoacyl, aryl, substituted aryl, aryloxy, Substituted aryloxy, cycloalkoxy, substituted cycloalkoxy, carboxy, carboxy ester, cyano, thiol, cycloalkyl, substituted cycloalkyl, halo, nitro, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, heteroaryloxy, substituted It means an aryl group substituted with 1 to 3, preferably 1 to 2 substituents selected from the group consisting of heteroaryloxy, heterocyclyloxy, and substituted heterocyclyloxy.

  “Arylene” and “substituted arylene” refer to the divalent aryl and substituted aryl groups defined above. “Phenylene” is a 6-membered optionally substituted arylene group, and includes, for example, 1,2-phenyle, 1,3-phenylene, and 1,4-phenylene.

  “Aryloxy” refers to the group aryl-O— that includes, for example, phenoxy, naphthoxy, and the like.

  “Substituted aryloxy” refers to substituted aryl-O— groups.

  “Carboxy” means —C (═O) OH or a salt thereof.

  `` Carboxyester '' refers to -C (O) O-alkyl, -C (O) O-substituted alkyl, -C (O) O-alkenyl, -C (O) O-substituted alkenyl, -C (O) O-alkynyl, -C (O) O-substituted alkynyl, -C (O) O-aryl, -C (O) O-substituted aryl, -C (O) O-heteroaryl, -C (O) O- It refers to the groups substituted heteroaryl, -C (O) O-heterocycle, and -C (O) O-substituted heterocycle. Preferred carboxy esters are —C (O) O-alkyl, —C (O) O-substituted alkyl, —C (O) O-aryl, and —C (O) O-substituted aryl.

  “Cycloalkyl” means a cyclic alkyl group of 3 to 10 carbon atoms having one or more rings that may contain 1 to 3 exocarbonyl or thiocarbonyl groups. Suitable cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, 3-oxocyclohexyl, and the like. In multiple condensed rings, one or more of the rings may be other than cycloalkyl (eg, aryl, heteroaryl or heterocycle), provided that the point of attachment is a carbocyclic atom of the cycloalkyl group. In one embodiment, the cycloalkyl group does not contain 1 to 3 exo carbonyl or thiocarbonyl groups. In another embodiment, the cycloalkyl group contains 1-3 exocarbonyl or thiocarbonyl groups. The term “exo” is understood to mean the attachment of a carbonyl or thiocarbonyl to a carbon ring atom of a cycloalkyl group.

  “Substituted cycloalkyl” refers to alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, halogen, hydroxy, nitro , Carboxy, carboxy ester, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle, and a cycloalkyl group having 1 to 5 substituents selected from the group consisting of substituted heterocycles.

  “Cycloalkenyl” means a cyclic alkenyl group of 5 to 10 carbon atoms having one or more rings that may contain 1 to 3 exocarbonyl or thiocarbonyl groups, wherein an aromatic group is I don't mean. Suitable cycloalkenyl groups include, for example, cyclopentyl, cyclohexenyl, cyclooctenyl, 3-oxocyclohexenyl and the like. In multiple condensed rings, one or more of the rings may be other than cycloalkenyl (eg, aryl, heteroaryl or heterocycle), provided that the point of attachment is a carbocyclic atom of the cycloalkyl group. In one embodiment, the cycloalkenyl group does not contain 1 to 3 exo carbonyl or thiocarbonyl groups. In another embodiment, the cycloalkenyl group contains 1-3 exocarbonyl or thiocarbonyl groups. The term “exo” is understood to mean the attachment of a carbonyl or thiocarbonyl to a carbon ring atom of a cycloalkenyl group.

  “Substituted cycloalkenyl” means alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, halogen, hydroxy, nitro, carboxy, carboxy ester Means a cycloalkenyl group having 1 to 5 substituents selected from the group consisting of cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle, except for hydroxyl substituent The bond point is not a vinyl carbon atom.

  “Cycloalkoxy” refers to —O-cycloalkyl groups.

  “Substituted cycloalkoxy” refers to —O-substituted cycloalkyl groups.

The term `` guanidino '' refers to the group --NHC (= NH) NH <sub>2 and the</sub> term `` substituted guanidino '' refers to --NR ^p C (= NR ^p ) N (R ^p ) ₂ where R Each ^p is independently hydrogen or alkyl.

  “Halo” or “halogen” means fluoro, chloro, bromo and iodo, preferably fluoro or chloro.

“Haloalkyl” means an alkyl group substituted with 1 to 5 halogen groups. An example of a haloalkyl is CF _3.

  “Heteroaryl” refers to an aromatic group having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the ring. means. Preferably, such heteroaryl groups have 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the ring. It is an aromatic group. Such heteroaryl groups can have one ring (eg, pyridyl or furyl) or multiple condensed rings (eg, indolizinyl or benzothienyl). Sulfur atoms in heteroaryl groups may be oxidized to sulfoxide and sulfone moieties.

  “Substituted heteroaryl” refers to heteroaryl groups that are substituted with from 1 to 3 substituents selected from the same group as defined for substituted aryl.

  When a particular heteroaryl is defined as “substituted”, eg, substituted quinoline, it is understood that such heteroaryl contains 1-3 of the aforementioned substituents.

  “Heteroarylene” and “substituted heteroarylene” mean the divalent heteroaryl and substituted heteroaryl groups defined above.

  “Heteroaryloxy” refers to the group —O-heteroaryl and “substituted heteroaryloxy” refers to the group —O-substituted heteroaryl.

  “Heterocycle” or “heterocycle” or “heterocyclyl” means 1 to 10 carbon atoms in the ring and 1 to 4 heteroatoms selected from the group consisting of nitrogen, sulfur or oxygen, A saturated or unsaturated group having one ring or a plurality of condensed rings is meant, and this ring may contain 1 to 3 exocarbonyl or thiocarbonyl groups. Preferably, such heterocyclic groups are a ring or multiple condensed rings having 1 to 10 carbon atoms in the ring and 1 to 4 heteroatoms selected from the group consisting of nitrogen, sulfur or oxygen. Is a saturated or unsaturated group having Sulfur atoms in heteroaryl groups may be oxidized to sulfoxide and sulfone moieties.

  In a plurality of fused rings, one or more of the rings may be other than a heterocycle (eg, aryl, heteroaryl or cycloalkyl), provided that the point of attachment is a heterocycle atom. In one embodiment, the heterocyclic group does not comprise 1 to 3 exo carbonyl or thiocarbonyl groups. In preferred embodiments, the heterocyclic group comprises 1 to 3 exo carbonyl or thiocarbonyl groups. The term “exo” is understood to mean the attachment of a carbonyl or thiocarbonyl to a carbon ring atom of a heterocyclic group.

  “Substituted heterocycle” refers to a heterocycle group that is substituted with from 1 to 3 of the same substituents as defined for substituted cycloalkyl. Preferred substituents for substituted heterocycles include alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, halogen, hydroxy, nitro, carboxy, Heterocyclic groups having 1 to 5 substituents selected from the group consisting of carboxyester, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are included.

  It is understood that where a particular heterocycle is defined as “substituted”, eg, substituted morpholino, such heterocycle includes 1-3 of the aforementioned substituents.

  Examples of heterocycles and heteroaryls include azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolidine, isoquinoline, quinoline, phthalazine, naphthyl Pyridine, quinoxaline, quinazoline, cinnoline, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3 , 4-Tetrahydro-isoquinoline, 4,5,6,7-tetrahydrobenzo [b] thiophene, thiazole, thiazolidine, thiophene, benzo [b] thio E down, morpholinyl, thiomorpholinyl (also referred to as thiamorpholinyl), piperidinyl, pyrrolidine, and the like tetrahydrofuranyl, but are not limited thereto.

  “Heterocyclyloxy” refers to the group —O-heterocycle and “substituted heterocyclyloxy” refers to the group —O-substituted heterocycle.

  “Thiol” refers to the group —SH.

式中、この環構造の原子は一つまたは複数の位置でR^kにより置換されていてもよい。本発明は、化学置換基をカルボン酸同配体に付加する場合、本発明の化合物がカルボン酸同配体の性質を保持することを企図する。本発明は、カルボン酸同配体がR^kから選択される一つまたは複数の部分で置換されていてもよい場合、置換が本発明の化合物のカルボン酸同配体の性質を除去しえないことを企図する。本発明は、カルボン酸同配体上の一つまたは複数のR^k置換基の置き換えが、そのような置換基が本発明の化合物のカルボン酸同配体の性質を破壊するであろう場合には、本発明の化合物のカルボン酸同配体の性質を維持する、またはその性質にとって絶対必要である一つまたは複数の原子では許容されないことを企図する。 “Isosteres” are different compounds that have different molecular formulas but exhibit the same or similar properties. For example, although tetrazole and carboxylic acid have very different molecular formulas, tetrazole is a conformation of carboxylic acid because it resembles the nature of carboxylic acid. Tetrazole is one of many possible isosteric substitutions for carboxylic acids. Other carboxylic acid isosteres contemplated by the present invention include -COOH, -SO ₃ H, -SO ₂ HNR ^k , -PO ₂ (R ^k ) ₂ , -CN, -PO ₃ (R ^k ) ₂ , -OR ^k , -SR ^k , -NHCOR ^k , -N (R ^k ) ₂ , -CON (R ^k ) ₂ , -CONH (O) R ^k , -CONHNHSO ₂ R ^k , -COHNSO ₂ R ^k , and -CONR ^k CN, where R ^k is hydrogen, hydroxy, halo, haloalkyl, thiocarbonyl, alkoxy, alkenoxy, alkylaryloxy, aryloxy, arylalkyloxy, cyano, nitro, imino, alkylamino, aminoalkyl , Thio, thioalkyl, alkylthio, sulfonyl, alkyl, alkenyl or alkynyl, aryl, aralkyl, cycloalkyl, heteroaryl, heterocycle and CO ₂ R ^m , where R ^m is hydrogen, alkyl or alkenyl. In addition, carboxylic acid isotopes include 5- to 7-membered carbocyclic or heterocyclic rings containing any combination of CH ₂ , O, S, or N in any chemically stable oxidation state, Any atom of the ring structure may include a ring that may be substituted at one or more positions. The following structures are non-limiting examples of preferred isotopes contemplated by the present invention:

Wherein the atoms of this ring structure may be substituted by R ^k at one or more positions. The present invention contemplates that when a chemical substituent is added to a carboxylic acid isostere, the compounds of the present invention retain the properties of the carboxylic acid isostere. In the present invention, when the carboxylic acid isotope may be substituted with one or more moieties selected from R ^k , the substitution cannot remove the carboxylic acid isotope properties of the compounds of the present invention. Contemplate that. The present invention relates to the case ^where replacement of one or more R ^k substituents on a carboxylic acid isostere will destroy the carboxylic acid isotope properties of the compounds of the present invention. It is contemplated that one or more atoms that maintain or are absolutely necessary for the carboxylic acid isotope properties of the compounds of the present invention are not permissible.

  A “carboxylic acid bioisostere” is a compound that behaves as an isostere of a carboxylic acid under biological conditions.

  Other carboxylic acid isosteres not specifically illustrated or described herein are also contemplated by the present invention.

  “Metabolite” means any derivative produced in a subject after administration of a parent compound. Metabolites can be produced from a parent compound by various biochemical transformations in a subject such as, for example, oxidation, reduction, hydrolysis, or conjugation. Metabolites include, for example, oxides and demethylated derivatives.

  “Thiocarbonyl” refers to the group —C (═S) —.

  “Pharmaceutically acceptable salt” means a pharmaceutically acceptable salt of a compound, which is derived from a variety of organic and inorganic counterions well known in the art, and by way of example only sodium, Potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc .; and if the molecule contains a basic functional group, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, etc. Organic or inorganic acid salts are included.

  "Prodrug" means an art-recognized modification to one or more functional groups that is metabolized in vivo to provide a compound of the present invention or an active metabolite thereof. Acyl groups for hydroxyl and / or amino substitution, esters of 1, 2 and 3 phosphates in which one or more side chain hydroxyl groups are converted to alkoxy, substituted alkoxy, aryloxy or substituted aryloxy groups, etc. Such functional groups, including, are known in the art.

  “Treating” or “treatment” of a disease means 1) preventing the disease from occurring in a patient who has a predisposition to the disease or has not yet shown its symptoms; 2) inhibits the disease, or Means to stop its development; or 3) to improve the disease or cause its regression. “Patient” means mammals, including human and non-human mammals.

  A “tautomer” is an enol-keto and imine-enamine tautomer, or a ring attached to a ring —NH— moiety and a ring = N— moiety such as pyrazole, imidazole, benzimidazole, triazole, and tetrazole. By means of a tautomer of heteroaryl groups containing atoms, it is meant that the interchangeable forms of the compound differing in proton position.

Unless stated otherwise, the naming of substituents not specifically defined herein is done by naming the terminal portion of the functional group, followed by the naming of the adjacent functional group toward the point of attachment. For example, the substituent “arylalkyloxycarbonyl” refers to the group (aryl)-(alkyl) -OC (O) —; the term “alkylaryloxy” refers to the group alkyl-aryl-O—. The term “arylalkyloxy” refers to the group aryl-alkyl-O—, “thioalkyl” refers to SH-alkyl-, “alkylthio” refers to alkyl-S—, and the like. The various substituents are alternative names, but can have equivalent names. For example, the terms 2-oxo-ethyl and the term carbonylmethyl both refer to the —C (O) CH ₂ — group.

  In all substituted groups as defined above, polymers resulting from defining substituents with further substituents to themselves (eg having substituted aryl groups as substituents that are themselves substituted with substituted aryl groups) It is understood that substituted aryl, where the first substituted aryl group is further substituted with a substituted aryl group, etc.) is not intended to be included herein. In such cases, the maximum number of such substitutions is three. For example, sequential substitution of a substituted aryl group with two other substituted aryl groups is limited to -substituted aryl- (substituted aryl) -substituted aryl.

  Similarly, it is understood that the above definitions are not intended to include unacceptable substitution patterns (eg, methyl substituted with 5 fluoro groups or an alpha hydroxyl group with respect to ethenyl or acetylenic unsaturation). . Such unacceptable substitution patterns are well known to those skilled in the art.

式中：
Yはアリール、ヘテロアリール、置換アリール、および置換ヘテロアリールからなる群より選択され；
HETは、6員アリーレン環、NまたはOまたはSから選択される1個または2個または3個のヘテロ原子を含む6員ヘテロアリーレン環、および下記の式を有する二環式環からなる群より選択され、

式中、HETは(X)_tで置換されていてもよく、Xは、アルキル、置換アルキル、アルコキシ、置換アルコキシ、アミノ、置換アミノ、ハロ、ヒドロキシ、およびニトロからなる群より選択され；tは0、1または2に等しい整数であり；W¹、W⁴、およびW⁵は独立にNまたはCHであり；W³はNもしくはCHであるか、または、二環式環内の1個以下の窒素が酸化されてN-オキシドを生成してもよいとの条件で結合であり；かつ破線の一方が一重結合である場合、隣接する原子がそれぞれ1または2個の水素原子で置換されてその原子価を満たしているとの条件で、破線はそれぞれ独立に2個の隣接する原子間の一重結合または二重結合を表し；
DまたはEの一方はC-R^aであり、DまたはEの他方はSであり；
R^aおよびRは水素、アルキル、および置換アルキルからなる群より独立に選択され；
Qはシクロアルキル、置換シクロアルキル、シクロアルケニル、置換シクロアルケニル、複素環、置換複素環、アリール、置換アリール、ヘテロアリール、および置換ヘテロアリールからなる群より選択され；かつ
Zは以下からなる群より選択される：
（a）カルボキシおよびカルボキシエステル；
（b）-C(X⁴)NR⁸R⁹、式中、X⁴は=O、=NH、または=N-アルキルであり、R⁸およびR⁹は水素、アルキル、置換アルキル、アルケニル、置換アルケニル、アルキニル、置換アルキニル、アリール、置換アリール、ヘテロアリール、置換ヘテロアリール、複素環および置換複素環からなる群より独立に選択されるか、またはR⁸およびR⁹はそれらに結合している窒素原子と一緒になって複素環、置換複素環、ヘテロアリールもしくは置換ヘテロアリール環基を形成する；
（c）-C(X³)NR²¹S(O)₂R⁴、式中、X³は=O、=NR²⁴、および=Sから選択され、R²⁴は水素、アルキル、または置換アルキルであり；R⁴はアルキル、置換アルキル、アリール、置換アリール、ヘテロアリール、置換ヘテロアリール、複素環、置換複素環、およびNR²²R²³から選択され、R²¹、R²²およびR²³は独立に水素、アルキル、置換アルキル、シクロアルキル、もしくは置換シクロアルキルであるか；または、R²¹およびR²²もしくはR²²およびR²³はそれらに結合している原子と一緒になって置換されていてもよい複素環基を形成する；
（d）-C(X²)-N(R³)CR²R^2'C(=O)R¹、式中、X²は=O、=S、および=NR¹¹から選択され、R¹¹は水素またはアルキルであり、R¹は-OR⁷および-NR⁸R⁹から選択され、R⁷は水素、アルキル、置換アルキル、アルケニル、置換アルケニル、アルキニル、置換アルキニル、アリール、置換アリール、ヘテロアリール、置換ヘテロアリール、複素環および置換複素環から選択され；R⁸およびR⁹は前述の定義のとおりであり；
R²およびR^2'は水素、アルキル、置換アルキル、アルケニル、置換アルケニル、アルキニル、置換アルキニル、アリール、置換アリール、シクロアルキル、置換シクロアルキル、ヘテロアリール、置換ヘテロアリール、複素環、および置換複素環から独立に選択されるか；
または、定義のとおりのR²およびR^2'はそれらに結合している炭素原子と一緒になってシクロアルキル、置換シクロアルキル、複素環もしくは置換複素環基を形成するか、
さらにまたは、R²もしくはR^2'の一方は水素、アルキルもしくは置換アルキルであり、他方はそれに結合している炭素原子と一緒になって、R⁷およびそれに結合している酸素原子もしくはR⁸およびそれに結合している窒素原子のいずれかと共に複素環もしくは置換複素環基を形成し；
R³は水素およびアルキルから選択されるか、または、R²およびR^2'が一緒になって環を形成しない場合、ならびにR²もしくはR^2'およびR⁷もしくはR⁸が一緒になって複素環もしくは置換複素環基を形成しない場合、R³はそれに結合している窒素原子と一緒になって、R²およびR^2'の一方と一緒に複素環もしくは置換複素環基を形成してもよい；
（e）-C(X²)-N(R³)CR²⁵R²⁶R²⁷、式中、X²およびR³は上で定義されており、かつR²⁵、R²⁶およびR²⁷はアルキル、置換アルキル、アリール、置換アリール、複素環、置換複素環、ヘテロアリールおよび置換ヘテロアリールからなる群より独立に選択されるか、またはR²⁵およびR²⁶はそれらに結合している炭素原子と一緒になってシクロアルキル、置換シクロアルキル、複素環もしくは置換複素環基を形成する；および
（f）（a）〜（e）において定義したものではない、カルボン酸同配体。 Accordingly, provided is a compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, prodrug, or tautomer thereof:

In the formula:
Y is selected from the group consisting of aryl, heteroaryl, substituted aryl, and substituted heteroaryl;
HET is from the group consisting of a 6-membered arylene ring, a 6-membered heteroarylene ring containing 1 or 2 or 3 heteroatoms selected from N or O or S, and a bicyclic ring having the formula: Selected

Wherein HET may be substituted with (X) _t , wherein X is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, halo, hydroxy, and nitro; An integer equal to 0, 1 or 2; W ¹ , W ⁴ and W ⁵ are independently N or CH; W ³ is N or CH or no more than one in a bicyclic ring In the case that one of the broken lines is a single bond, each adjacent atom is replaced with 1 or 2 hydrogen atoms, respectively. Each dashed line independently represents a single or double bond between two adjacent atoms, provided that the valence is met;
One of D or E is CR ^a and the other of D or E is S;
R ^a and R are independently selected from the group consisting of hydrogen, alkyl, and substituted alkyl;
Q is selected from the group consisting of cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocycle, substituted heterocycle, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and
Z is selected from the group consisting of:
(A) carboxy and carboxy ester;
(B) —C (X ⁴ ) NR ⁸ R ⁹ , wherein X ⁴ is ═O, ═NH, or ═N-alkyl, and R ⁸ and R ⁹ are hydrogen, alkyl, substituted alkyl, alkenyl, substituted Independently selected from the group consisting of alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle, or R ⁸ and R ⁹ are bound to them Together with the atoms form a heterocyclic, substituted heterocyclic, heteroaryl or substituted heteroaryl ring group;
(C) —C (X ³ ) NR ²¹ S (O) ₂ R ⁴ , wherein X ³ is selected from ═O, ═NR ²⁴ , and ═S, and R ²⁴ is hydrogen, alkyl, or substituted alkyl Yes; R ⁴ is selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, and NR ²² R ²³ , R ²¹ , R ^22, and R ²³ are independently hydrogen , Alkyl, substituted alkyl, cycloalkyl, or substituted cycloalkyl; or R ²¹ and R ²² or R ²² and R ²³ are optionally substituted together with the atoms bonded to them. Forming a ring group;
(D) -C (X ² ) -N (R ³ ) CR ² R ^{2 '} C (= O) R ¹ , wherein X ² is selected from = O, = S, and = NR ¹¹ and R ¹¹ Is hydrogen or alkyl, R ¹ is selected from —OR ⁷ and —NR ⁸ R ⁹ , R ⁷ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl , Substituted heteroaryl, heterocycle and substituted heterocycle; R ⁸ and R ⁹ are as defined above;
R ² and R ^{2 ′} are hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle Selected independently from;
Or R ² and R ^{2 ′} as defined together with the carbon atom to which they are attached form a cycloalkyl, substituted cycloalkyl, heterocyclic or substituted heterocyclic group,
Additionally or alternatively, one of R ² or R ^{2 ′} is hydrogen, alkyl or substituted alkyl, and the other, together with the carbon atom bonded to it, is R ⁷ and the oxygen atom or R ⁸ and Forming a heterocyclic or substituted heterocyclic group with any of the nitrogen atoms bonded to it;
R ³ is selected from hydrogen and alkyl, or when R ² and R ^{2 ′} are not taken together to form a ring, and R ² or R ^{2 ′} and R ⁷ or R ⁸ are taken together to form a complex If not forming a ring or substituted heterocyclic group, R ³ may be taken together with the nitrogen atom bonded to it to form a heterocyclic or substituted heterocyclic group with one of R ² and R ^{2 ′.} Good;
(E) -C (X ² ) -N (R ³ ) CR ²⁵ R ²⁶ R ²⁷ , wherein X ² and R ³ are defined above, and R ²⁵ , R ²⁶ and R ²⁷ are alkyl, Independently selected from the group consisting of substituted alkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl and substituted heteroaryl, or R ²⁵ and R ²⁶ together with the carbon atom to which they are attached. And forms a cycloalkyl, substituted cycloalkyl, heterocyclic or substituted heterocyclic group; and (f) carboxylic acid isosteres not defined in (a)-(e).

式中：
Yは置換アリールおよび置換ヘテロアリールからなる群より選択され；
Xはアミノ、ニトロ、アルキル、ハロアルキル、およびハロからなる群より独立に選択され；
tは0、1または2に等しい整数であり；
Qはシクロヘキシルおよびシクロペンチルからなる群より選択され；
R¹²およびR¹³は水素、アルキル、置換アルキル、アルケニル、置換アルケニル、アルキニル、置換アルキニル、アルコキシ、置換アルコキシ、-(CH₂)_0-3R¹⁶、および-NR¹⁷R¹⁸から独立に選択されるか、またはR¹²およびR¹³が両方とも水素であることはないとの条件で、R¹²およびR¹³ならびにそれらが結合している窒素原子が置換または非置換の複素環を形成し；ここでR¹⁶はアリール、ヘテロアリール、または複素環であり；かつR¹⁷およびR¹⁸は独立に水素もしくはアルキルであるか、またはR¹⁷およびR¹⁸はそれらが結合している窒素原子と一緒になって環原子4〜7個の複素環を形成し；
AまたはBの一方はC-R^aであり、AまたはBの他方はSであり；
R^aは水素、アルキル、および置換アルキルからなる群より選択され；かつ
Zはカルボキシ、カルボキシエステル、およびカルボン酸同配体からなる群より選択される。 In another embodiment, a compound having the formula (Ia) or a pharmaceutically acceptable salt or tautomer thereof is provided:

In the formula:
Y is selected from the group consisting of substituted aryl and substituted heteroaryl;
X is independently selected from the group consisting of amino, nitro, alkyl, haloalkyl, and halo;
t is an integer equal to 0, 1 or 2;
Q is selected from the group consisting of cyclohexyl and cyclopentyl;
R ¹² and R ¹³ are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, — (CH ₂ ) _0-3 R ¹⁶ , and —NR ¹⁷ R ¹⁸ Or R ¹² and R ¹³ and the nitrogen atom to which they are attached form a substituted or unsubstituted heterocycle, provided that R ¹² and R ¹³ are not both hydrogen; R ¹⁶ is aryl, heteroaryl, or heterocyclic; and R ¹⁷ and R ¹⁸ are independently hydrogen or alkyl, or R ¹⁷ and R ¹⁸ are taken together with the nitrogen atom to which they are attached. To form a heterocyclic ring of 4 to 7 ring atoms;
One of A or B is CR ^a and the other of A or B is S;
R ^a is selected from the group consisting of hydrogen, alkyl, and substituted alkyl; and
Z is selected from the group consisting of carboxy, carboxy ester, and carboxylic acid isosteres.

式中、Z、R^a、およびYは式（I）において先に定義したとおりであり、R¹²およびR¹³は式（Ia）において先に定義したとおりである。 In another embodiment, the present invention provides compounds of formula (Ib)-(Is):

Wherein Z, R ^a , and Y are as defined above in formula (I), and R ¹² and R ¹³ are as defined above in formula (Ia).

  In some embodiments of each of formulas (I) and (Ia), E is S. In other embodiments, D is CH and E is S.

In some embodiments of each of formulas (I) and (Ia)-(Is), where appropriate, R ^a is hydrogen. In other embodiments, R ^a is substituted alkyl, substituted amino, or substituted aminoalkyl. In some aspects, R ^a is selected from the following substituents.

  In some embodiments of each of formulas (I) and (Ia)-(Is), where appropriate, Q is cycloalkyl or substituted cycloalkyl. In some embodiments, Q is cycloalkyl. In other embodiments, Q is cycloalkenyl. In another embodiment, Q is cyclohexyl. In another embodiment, Q is cyclohexenyl. In yet another embodiment, T is cyclopentyl.

  In some embodiments of each of formulas (I) and (Ia)-(Is), where appropriate, Z is a carboxy or carboxy ester. In another embodiment, Z is selected from —C (═O) OH, and —C (═O) OR ″, where R ″ is alkyl. In another embodiment, Z is selected from carboxy, methyl carboxylate, and ethyl carboxylate. In yet another embodiment, Z is —C (═O) OH.

  In another embodiment, Z is a carboxylic acid isotope. In another embodiment, the carboxylic acid isostere is a carboxylic acid bioisostere. In another embodiment, the carboxylic acid isotope is selected from 1H-tetrazol-5-yl and 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl.

In another embodiment, Z is -C (= O) NR ⁸ R ⁹ where R ⁸ is hydrogen and R ⁹ is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl , A heterocyclic ring and a substituted heterocyclic ring. In another embodiment where Z is —C (═O) NR ⁸ R ⁹ and R ⁸ is hydrogen, R ⁹ is substituted alkyl. In another embodiment, where Z is —C (═O) NR ⁸ R ⁹ , R ⁸ is hydrogen, and R ⁹ is substituted alkyl, the substituted alkyl is sulfonic acid (SO ₃ H), carboxy, carboxy It includes 1 to 2 substituents selected from the group consisting of esters, amino, substituted amino, aryl, substituted aryl, heteroaryl and substituted heteroaryl. In another embodiment where Z is -C (= O) NR ⁸ R ⁹ , R ⁸ is hydrogen and R ⁹ is substituted alkyl, the substituted alkyl group is 3,4-dimethoxybenzyl, 3, 4, -Dihydroxybenzyl, 3-methoxy-4-hydroxybenzyl, 4-aminosulfonylbenzyl, 4-methylsulfonylbenzyl, (1-methyl-piperidin-3-yl) methyl, (1-methyl-pyrrolidin-3-yl) methyl , Fur-2-ylmethyl, 6-methylpyridin-2-ylmethyl, 2- (1-methyl-pyrrolidin-3-yl) ethyl, 1-phenylethyl, 1- (3-methoxyphenyl) -ethyl, 1- ( Selected from the group consisting of 4-methoxyphenyl) -ethyl, N ′, N′-dimethylaminoethyl, and 2- (1H-pyrazol-1-yl) ethyl.

  In another embodiment, Z is selected from N-methylcarboxamide, N, N-dimethylcarboxamide, N-isopropyl-carboxamide, N-allyl-carboxamide, and 5-hydroxy-tryptophan-carbonyl.

In another embodiment, Z is —C (═O) NR ⁸ R ⁹ , wherein R ⁹ is aryl or substituted aryl. In another embodiment where Z is —C (═O) NR ⁸ R ⁹ , R ⁹ is substituted aryl. In another embodiment, Z is -C (= O) NR ⁸ R ⁹ , R ⁹ is 7-hydroxynaphth-1-yl, 6-hydroxynaphth-1-yl, 5-hydroxynaphth-1-yl, 6 Karubokishinafuto 2-yl, (4-HOOCCH ₂ -) phenyl, selected from (3,4-dicarboxy) phenyl, 3-carboxyphenyl, the group consisting of 3-carboxy-4-hydroxyphenyl and 2-biphenyl Is done.

In another embodiment, Z is —C (═O) NR ⁸ R ⁹ , wherein R ⁹ is heteroaryl or substituted heteroaryl. In another embodiment wherein Z is —C (═O) NR ⁸ R ⁹ , R ⁹ is substituted heteroaryl. In another embodiment wherein Z is -C (= O) NR ⁸ R ⁹ and R ⁹ is substituted heteroaryl, the substituted heteroaryl is 4-methyl-2-oxo-2H-chromen-7-yl, Selected from the group consisting of 1-phenyl-4-carboxy-1H-pyrazol-5-yl, 5-carboxypyrid-2-yl, 2-carboxypyrazin-3-yl, and 3-carboxythien-2-yl The

In another embodiment, Z is —C (═O) NR ⁸ R ⁹ , wherein R ⁹ is a heterocycle. In another embodiment where Z is -C (= O) NR ⁸ R ⁹ and R ⁹ is a heterocyclic ring, the heterocyclic group is N-morpholino, tetrahydrofuranyl, and 1,1-dioxidetetrahydrothienyl. is there.

In another embodiment, Z is -C (= O) NR ⁸ R ⁹ , wherein R ⁸ and R ⁹ together with the nitrogen atom bonded to them form a heterocycle or substituted heterocycle To do. In another embodiment wherein Z is -C (= O) NR ⁸ R ⁹ and R ⁸ and R ⁹ together with the nitrogen atom bonded to them form a ring, The ring includes a 4-8 membered ring containing 1-3 heteroatoms. Another embodiment wherein Z is -C (= O) NR ⁸ R ⁹ and R ⁸ and R ⁹ together with the nitrogen atom bound to them form an optionally substituted heterocycle 1 to 3 heteroatoms contain 1 to 2 nitrogen atoms. Another embodiment wherein Z is -C (= O) NR ⁸ R ⁹ and R ⁸ and R ⁹ together with the nitrogen atom bound to them form an optionally substituted heterocycle Wherein the heterocycle or substituted heterocycle is selected from the group consisting of piperidine, substituted piperidine, piperazine, substituted piperazine, morpholino, substituted morpholino, thiomorpholino and substituted thiomorpholino, wherein the sulfur atom of the thiomorpholino or substituted thiomorpholino ring is Oxidized to provide sulfoxide and sulfone moieties. Another embodiment wherein Z is -C (= O) NR ⁸ R ⁹ and R ⁸ and R ⁹ together with the nitrogen atom bound to them form an optionally substituted heterocycle A heterocyclic ring or a substituted heterocyclic ring is 4-hydroxypiperidin-1-yl, 1,2,3,4-tetrahydro-3-carboxy-isoquinolin-2-yl, 4-methylpiperidin-1-yl, morpholine-4 Selected from the group consisting of -yl, thiomorpholin-4-yl, 4-methyl-piperazin-1-yl, and 2-oxo-piperazinyl.

In another embodiment, Z is —C (X) N (R ³ ) CR ² R ^{2 ′} C (═O) R ¹ .

In another embodiment, Z is —C (O) NHCHR ² C (═O) R ¹ .

In another embodiment, when Z is -C (X) N (R ³ ) CR ² R ^{2 '} C (= O) R ¹ or -C (O) NHCHR ² C (= O) R ^{1 2} is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl. In another embodiment where Z is -C (X) N (R ³ ) CR ² R ^{2 '} C (= O) R ¹ or -C (O) NHCHR ² C (= O) R ¹ , R ² is Selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, and substituted cycloalkyl. In another embodiment where Z is -C (X) N (R ³ ) CR ² R ^{2 '} C (= O) R ¹ or -C (O) NHCHR ² C (= O) R ¹ , R ² is Hydrogen, methyl, 1-methylprop-1-yl, sec-butyl, hydroxymethyl, 1-hydroxyeth-1-yl, 4-amino-n-butyl, 2-carboxyeth-1-yl, carboxymethyl, benzyl, (1H-imidazol-4-yl) methyl, (4-phenyl) benzyl, (4-phenylcarbonyl) benzyl, cyclohexylmethyl, cyclohexyl, 2-methylthioeth-1-yl, isopropyl, carbamoylmethyl, 2-carbamoylethanol Selected from the group consisting of 1-yl, (4-hydroxy) benzyl, and 3-guanidino-n-propyl.

In another embodiment, when Z is -C (X) N (R ³ ) CR ² R ^{2 '} C (= O) R ¹ or -C (O) NHCHR ² C (= O) R ^{1 1} is selected from the group consisting of hydroxy, alkoxy, amino (N-morpholino), amino, and substituted amino. In another embodiment wherein Z is -C (X) N (R ³ ) CR ² R ^{2 '} C (= O) R ¹ or -C (O) NHCHR ² C (= O) R ¹ , R ¹ is Selected from the group consisting of hydroxy, alkoxy, amino (N-morpholino), amino, and substituted amino, and R ² and R ³ together with a carbon atom and a nitrogen atom bonded to them, respectively, a heterocycle or Form a substituted heterocyclic group. In another embodiment wherein Z is -C (X) N (R ³ ) CR ² R ^{2 '} C (= O) R ¹ or -C (O) NHCHR ² C (= O) R ¹ , R ¹ is Selected from the group consisting of hydroxy, alkoxy, amino (N-morpholino), amino, and substituted amino, and R ² and R ³ together with a carbon atom and a nitrogen atom bonded to them, respectively, a heterocycle or Forming a substituted heterocyclic group, the heterocyclic and substituted heterocyclic groups being pyrrolidinyl, 2-carboxy-pyrrolidinyl, 2-carboxy-4-hydroxypyrrolidinyl, and 3-carboxy-1,2,3,4-tetrahydroisoquinoline Selected from the group consisting of -3-yl.

  In another embodiment, Z is 1-carboxamidocyclopent-1-ylaminocarbonyl, 1-carboxamido-1-methyl-eth-1-ylaminocarbonyl, 5-carboxy-1,3-dioxane-5-ylamino Carbonyl, 1- (N-methylcarboxamido) -1- (methyl) -eth-1-ylaminocarbonyl, 1- (N, N-dimethylcarboxamido) -1- (methyl) -eth-1-ylaminocarbonyl, 1-carboxy-1-methyl-eth-1-ylaminocarbonyl, 1- (N-methylcarboxamido) -cyclobutaneaminocarbonyl, 1-carboxamido-cyclobutaneaminocarbonyl, 1- (N, N-dimethylcarboxamido) -cyclobutaneamino Carbonyl, 1- (N-methylcarboxamido) -cyclopentaneaminocarbonyl, 1- (N, N-dimethylcarboxamido) -cyclopentaneaminocarbonyl, 1- (carboxamido) -cyclopentaneamino Carbonyl, 3- [N- (4- (2-aminothiazol-4-yl) phenyl) aminocarbonyl] -piperidin-3-ylaminocarbonyl, 3-carboxamido-pyrrolidin-3-ylaminocarbonyl, [1- ( 4- (acrylic acid) -phenyl) aminocarbonyl) -cyclobutan-1-yl] aminocarbonyl, and [1-methyl-1- (4- (acrylic acid) -phenyl) aminocarbonyl) -eth-1-yl] Selected from aminocarbonyl.

In another embodiment, Z is —C (O) NR ²¹ S (O) ₂ R ⁴ . In another embodiment wherein Z is —C (O) NR ²¹ S (O) ₂ R ⁴ , R ⁴ is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl . In another embodiment wherein Z is —C (O) NR ²¹ S (O) ₂ R ⁴ , R ⁴ is methyl, ethyl, isopropyl, propyl, trifluoromethyl, 2,2,2-trifluoroethyl, phenyl , Benzyl, phenethyl, 4-bromophenyl, 4-nitrophenyl or 4-methylphenyl, 4-methoxyphenyl, 2-aminoethyl, 2- (dimethylamino) ethyl, 2-N-benzyloxyaminoethyl, pyridinyl, thienyl 2-chlorothien-5-yl, 2-methoxycarbonylphenyl, naphthyl, 3-chlorophenyl, 2-bromophenyl, 2-chlorophenyl, 4-trifluoromethoxyphenyl, 2,5-difluorophenyl, 4-fluorophenyl, 2 -Methylphenyl, 6-ethoxybenzo [d] thiazo-2-yl, 4-chlorophenyl, 3-methyl-5-fluorobenzo [b] thiophen-1-yl, 4-acetylaminophenyl, quinoline-8- Yl, 4-t-butylphenyl, cyclopropyl, 2,5-dimethoxyphenyl, 2,5-dichloro-4-bromo-thien-3-yl, 2,5-dichloro-thien-3-yl, 2,6 -Dichlorophenyl, 1,3-dimethyl-5-chloro-1H-pyrazol-4-yl, 3,5-dimethylisoxazol-4-yl, benzo [c] [1,2,5] thiadiazol-4-yl 2,6-difluorophenyl, 6-chloro-imidazo [2,1-b] thiazol-5-yl, 2- (methylsulfonyl) phenyl, isoquinolin-8-yl, 2-methoxy-4-methylphenyl, 1 , 3,5-Trimethyl-1H-pyrazol-4-yl, 1-phenyl-5-methyl-1H-pyrazol-4-yl, 2,4,6-trimethylphenyl, and 2-carbamoyl-eth-1-yl It is.

  In another embodiment, Z is selected from hydrogen, halo, alkyl, alkoxy, amino, substituted amino, and cyano.

In another embodiment, Z is —C (X ² ) —N (R ³ ) CR ²⁵ R ²⁶ R ²⁷ , wherein X ² and R ³ are as defined above and R ²⁵ , R ²⁶ And R ²⁷ is alkyl, substituted alkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl and substituted heteroaryl, or R ²⁵ and R ²⁶ are taken together with the carbon atom to which they are attached. To form a cycloalkyl, substituted cycloalkyl, heterocyclic or substituted heterocyclic group.

  In another embodiment, Z is 1- (6- (3-carboxyprop-2-en-1-yl) -1H-benzo [d] imidazol-2-yl) cyclobutaneaminocarbonyl, 3- (6- ( 3-carboxyprop-2-en-1-yl) -1H-benzo [d] imidazol-2-yl) -1-methylpyrrolidine-3-aminocarbonyl, 1- (1-methyl-6- (3-carboxy Prop-2-en-1-yl) -1H-benzo [d] imidazol-2-yl) cyclobutaneaminocarbonyl, 1- (benzofuran-2-yl) -5-carboxy-cyclobutaneaminocarbonyl, 1- (2- Methylthiazol-4-yl) -cyclobutaneaminocarbonyl, 1- (2-acetylamino-thiazol-4-yl) -cyclobutaneamino, 1- (2-methylamino-thiazol-4-yl) -cyclobutaneaminocarbonyl, 1 From-(2-ethylthiazol-4-yl) -cyclobutaneaminocarbonyl and 1- (cyano) -cyclobutaneaminocarbonyl Be-option.

In still other embodiments of each of formulas (I) and (Ia)-(Is), where appropriate, Z is carboxy, a carboxy ester, a carboxylic acid isotope, —C (O) NR ⁸ R ⁹ , or —C (O) NHS (O) ₂ R ⁴ where R ⁸ and R ⁹ are as defined above and R ⁴ is alkyl or aryl. In other embodiments, Z is carboxy, methyl carboxylate, ethyl carboxylate, 6- (β-D-glucuronic acid) ester, 1H-tetrazol-5-yl, 5-oxo-4,5-dihydro-1,2 , 4-oxadiazol-3-yl, N-2-cyano-ethylamide, N-2- (1H-tetrazol-5-yl) ethylamide, methylsulfonylaminocarbonyl, trifluoromethylsulfonylaminocarbonyl, or phenylsulfonylamino Carbonyl. In yet other embodiments, Z is carboxy. In yet other embodiments, Z is —C (═O) OH.

In some embodiments of each of formulas (I) and (Ia)-(Is), where appropriate, Z ¹ is selected from the group consisting of hydrogen, halo, alkyl, and haloalkyl.

In some embodiments of each of formulas (I) and (Ia)-(Is), where appropriate, R is C _ν H _2ν -C (O) -OR ²³ , where ν is 1, 2 or 3 And R ²³ is hydrogen, alkyl or substituted alkyl. In another embodiment where R is C _ν H _2ν -C (O) -OR ²³ , ν is 1. In another embodiment R is _{C ν H 2ν -C (O)} -OR 23, R is carboxymethyl or methyl carboxymethyl.

  In another embodiment, R is hydrogen.

In another embodiment, R is C _ν H _2ν -C (O) -NR ¹² R ¹³ , where ν is 1, 2 or 3; R ¹² and R ¹³ are hydrogen, alkyl, substituted alkyl, Selected from alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy and — (CH ₂ ) _0-3 R ¹⁶ ; R ¹⁶ is aryl, heteroaryl, heterocycle, —NR ¹⁷ R ¹⁸ ; and R ¹⁷ and R ¹⁸ are independently selected from hydrogen and alkyl, or R ¹⁷ and R ¹⁸ together with the nitrogen atom to which they are attached form a 4-7 ring heterocycle; or in conditions of never R ¹² and R ¹³ are both alkoxy and / or substituted alkoxy, a nitrogen atom to which R ¹² and R ¹³ as well as they are attached to form a heterocyclic or substituted heterocyclic. In another embodiment, ν is 1. In another embodiment wherein R is C _ν H _2ν -C (O) -NR ¹² R ¹³ , the NR ¹² R ¹³ group is N, N-dimethylamino-carbonylmethyl, [N- (4-hydroxy-1, 1-dioxidetetrahydro-3-thienyl) amino] -carbonylmethyl, (cyclopropylmethylamino) -carbonylmethyl, (prop-2-yn-1-ylamino) -carbonylmethyl, (2- (morpholino) eta-1 -Ylamino) -carbonylmethyl, (phenylsulfonylamino) -carbonylmethyl, [N-benzylamino] -carbonylmethyl, (N- (4-methylsulfonyl-benzyl) amino) -carbonylmethyl, (tryptophanyl) -carbonylmethyl, (Tyrosine) -carbonylmethyl, (N- (1-carboxyprop-1-ylamino) -carbonylmethyl, (N- (2-carboxyeth-1-yl) -amino) -carbonylmethyl, (N- (4- Carboxybenzyl) -amino) -carbonylmethyl, N- [3- (N '-(4 -(Acrylic acid) -phenyl) carboxamido) pyrrolidin-3-yl] amino-carbonylmethyl, N- [4- (N '-(4- (acrylic acid) -phenyl) carboxamido) piperidin-4-yl] amino- Carbonylmethyl, [2- (N, N-dimethylamino) eth-1-ylamino] -carbonylmethyl, [(1- (5-methyl-4H-1,2,4-triazol-3-yl) ethyl) amino ] -Carbonylmethyl, (1-methyl-1- [N- (1-methyl-2-carboxy-1H-indol-5-yl) aminocarbonyl] eth-1-ylamino-carbonylmethyl, [N- (1- Methylpyrrolidin-3-yl-ethyl) -amino] -carbonylmethyl, (1-methyl-1- [N- (4- (acrylic acid) phenyl) aminocarbonyl] eth-1-ylamino-carbonylmethyl, (1- Methyl-1- [N- (4- (2-carboxy-furan-5-yl) phenyl) aminocarbonyl] eth-1-ylamino-carbonylmethyl, (1-methyl-1- [N- (4- (4 -Carboxy-thiazo Ru-2-yl) phenyl) aminocarbonyl] eth-1-ylamino-carbonylmethyl, (2- (4-methylpiperazin-1-yl) eth-1-ylamino) -carbonylmethyl, [(1-methylpyrrolidine- 3-yl) methylamino] -carbonylmethyl, [N- (1-methylpiperidin-3-yl-methyl) -amino] -carbonylmethyl, (1-piperidin-1-ylcyclopentyl) methylamino] -carbonylmethyl, (1- (acetyl) -pyrrolidin-2-ylmethyl) amino) -carbonylmethyl, [(2- (N, N-dimethylamino) -carbonyl) methylamino] -carbonylmethyl, [N- (1,1-di Oxidotetrahydro-3-thienyl) methylamino] -carbonylmethyl, (N-methyl-N-cyclohexyl-amino) -carbonylmethyl, (N-methyl-N-carboxymethyl-amino) -carbonylmethyl, [N-methyl- N-benzyl-amino] -carbonylmethyl, (N-methyl-N- (N ', N'-di Tilaminoacetyl) -amino) -carbonylmethyl, [N-methyl-N-phenyl-amino] -carbonylmethyl, (N-methyl-N-isopropyl-amino) -carbonylmethyl, (N-methyl-N- (N '-Methylpiperidin-4-yl) amino) -carbonylmethyl, [N-methyl-N- (1-methylpiperidin-4-yl) amino] -carbonylmethyl, [N-methyl-N- (1-methylpiperidine -4-yl-methyl) -amino] -carbonylmethyl, [N-methyl-N- (1-methylpiperidin-3-yl-methyl) -amino] -carbonylmethyl, [N-methyl-N- (1- Methylpyrazin-2-yl-methyl) -amino] -carbonylmethyl, [N-methyl-N- (5-methyl-1H-imidazol-2-ylmethyl) -amino] -carbonylmethyl, (N-methyl-N- [2- (hydroxy) eth-1-yl] amino) -carbonylmethyl, (N-methyl-N- [2- (N ′, N′-dimethylamino) eth-1-yl] amino) -carbonylmethyl, N-methyl-N- [2- ( N ′, N′-diethylamino) eth-1-yl] amino) -carbonylmethyl, (N-methyl-N- [2- (pyridin-2-yl) eth-1-yl] amino) -carbonylmethyl, N-methyl-N- [2- (pyridin-4-yl) eth-1-yl] amino) -carbonylmethyl, [N-methyl-N- (1- (1,3-thiazol-2-yl) ethyl ) -Amino] -carbonylmethyl, (N-methyl-N- [3- (N ', N'-dimethylamino) prop-1-yl] amino) -carbonylmethyl, (N-methyl-N- (1- Carboxy-2-methylprop-1-yl) -amino) -carbonylmethyl, (N-ethyl-N-propyl-amino) -carbonylmethyl, (N-ethyl-N- [2- (methoxy) eth-1-yl Amino) -carbonylmethyl, (N-ethyl-N- [2- (N ', N'-diethylamino) eth-1-yl] amino) -carbonylmethyl, [7-methyl-2,7-diazaspiro [4.4 ] Non-2-yl] -carbonylmethyl, (5-methyl-2,5-diazabicyclo [2.2.1] heptyl-2-yl) -carbonylmethyl (4-methyl-1,4-diazepan-1-yl) -carbonylmethyl, (piperidinyl) -carbonylmethyl, (4-carboxy-piperidinyl) -carbonylmethyl, (3-carboxypiperidinyl) -carbonylmethyl , (4-hydroxypiperidinyl) -carbonylmethyl, (4- (2-hydroxyeth-1-yl) piperidin-1-yl) -carbonylmethyl, [4- (N, N-dimethylamino) -piperidine- 1-yl] -carbonylmethyl, (3- (N, N-dimethylamino) -methylpiperidin-1-yl) -carbonylmethyl, (2- (2- (N, N-dimethylamino) -eth-1- Yl) piperidin-1-yl) -carbonylmethyl, [4- (4-methyl-4H-1,2,4-triazol-3-yl) piperidin-1-yl] -carbonylmethyl, (4-pyrrolidinyl-piperidinyl) ) -Carbonylmethyl, (3-pyrrolidinyl-piperidinyl) -carbonylmethyl, [4- (N, N-diethylamino) -piperidin-1-yl] -cal Nylmethyl, (4- (azetidin-1-yl) -piperidin-1-yl) -carbonylmethyl, (4- (piperidin-1-yl) -piperidin-1-yl) -carbonylmethyl, (hexahydropyrrolo [1 , 2-a] pyrazin-2 (1H) -yl) -carbonylmethyl, [(2- (N, N-dimethylamino) -methyl) morpholino] -carbonylmethyl, (3,5-dimethylmorpholino) -carbonylmethyl , (Thiomorpholino) -carbonylmethyl, morpholino-carbonylmethyl, (pyrrolidinyl) -carbonylmethyl, (2-carboxy-pyrrolidin-1-yl) -carbonylmethyl, (2- (carboxy) -4-hydroxy-pyrrolidine-1 -Yl) -carbonylmethyl, (2-carboxamido-pyrrolidin-1-yl) -carbonylmethyl, (2- (N, N-dimethylaminocarbonyl) -pyrrolidin-1-yl) -carbonylmethyl, (3- (N ', N'-dimethylamino) -pyrrolidin-1-yl) -carbonylmethyl, (3- (N', N ' -Diethylamino) -pyrrolidin-1-yl) -carbonylmethyl, (3- (pyridin-3-yl) -pyrrolidin-1-yl) -carbonylmethyl, (2-pyidin-4-ylpyrrolidin-1-yl)- Carbonylmethyl, piperazin-1-yl-carbonylmethyl, (4-methylpiperazinyl) -carbonylmethyl, (4- (carboxymethyl) -piperazin-1-yl) -carbonylmethyl, (4- (2-hydroxyeth -1-yl) piperazin-1-yl) -carbonylmethyl, (4- (isopropyl) piperazin-1-yl) -carbonylmethyl, (4- (2-methoxyeth-1-yl) piperazin-1-yl)- Carbonylmethyl, (4- (ethyl) piperazin-1-yl) -carbonylmethyl, (4- (N ', N'-dimethylaminoacetyl) -piperazin-1-yl) -carbonylmethyl, and (4- (6 -Methoxypyridin-2-yl) piperazin-1-yl) -carbonylmethyl.

  In another embodiment, R is selected from morpholinocarbonylmethyl, N, N-dimethylaminocarbonylmethyl, (4-pyrrolidinyl-piperidin-1-yl) carbonylmethyl, piperazinylcarbonylmethyl. In some aspects, R is an oxide of morpholinocarbonylmethyl, N, N-dimethylaminocarbonylmethyl, (4-pyrrolidinyl-piperidin-1-yl) carbonylmethyl, piperazinylcarbonylmethyl.

  In another embodiment, R is [(N, N-dimethylamino) prop-2-en-1-yl] -carbonylmethyl, (N, N-dimethylpiperidin-4-aminium trifluoroacetate) acetyl, 2- (N, N-dimethylpiperidine-4-aminium trifluoroacetate) morpholinoacetyl, (2- (diisopropyl) eth-1-yl) -carbonylmethyl, (pyridin-4-ylcarbonylhydrazino) -carbonyl Methyl, (N- (4-carboxybenzyl) -amino) carbonylhydrazino) -carbonylmethyl, (acetylhydrazino) -carbonylmethyl, ((N ', N'-dimethylaminomethyl-carbonyl) hydrazino) -carbonylmethyl Selected from.

In still other embodiments, R is substituted alkyl, wherein substituted alkyl is aminoalkyl, substituted aminoalkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heterocyclylalkyl, substituted heterocyclylalkyl, —CH ₂ COOH, and -CH ₂ CONR ¹² R ¹³ are selected from the group consisting of R ¹² and R ¹³ are hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy,-( CH _{2) 0-3} R ^16, and -NR ¹⁷ is selected from R ¹⁸ independently or under the conditions of the R ¹² and R ¹³ are not both hydrogen, R ¹² and R ¹³ as well as their There the nitrogen atom to which they are bonded form a substituted or unsubstituted heterocyclic; wherein R ¹⁶ is also aryl, heteroaryl, A heterocyclic; and R ¹⁷ and R ¹⁸ independently is hydrogen or alkyl, or R ¹⁷ and R ¹⁸ 4-7 taken together with the nitrogen atom to which they are attached a ring atom heterocycles Form.

In other embodiments, R is —CH ₂ CONR ¹² R ¹³ and at least one of R ¹² or R ¹³ is alkyl, substituted alkyl, or heteroaryl. In some aspects, at least one of R ¹² or R ¹³ is methyl, carboxymethyl, 2-hydroxyethyl, 2-morpholin-4-ylethyl, or tetrazoyl-5-yl. In other aspects, R is 1-methyl-piperidin-4-yl, 1-methyl-piperidin-3-ylmethyl, and thiazol-2-ylcarbamoylmethyl.

In yet other embodiments, R is —CH ₂ CONR ¹² R ¹³ , and R ¹² and R ¹³ and the nitrogen atom to which they are attached form a substituted or unsubstituted heterocycle. In some aspects, R ¹² and R ¹³ and the nitrogen atom to which they are attached form a substituted or unsubstituted morpholino ring, a substituted or unsubstituted piperidinyl ring, or a substituted or unsubstituted pyrrolidinyl ring. In other aspects, the substituted or unsubstituted morpholino ring, piperidinyl ring, or pyrrolidinyl ring is morpholino, 4-pyrrolidin-1-yl-piperidinyl, piperidinyl, 4-hydroxypiperidinyl, 4-carboxypiperidinyl, 4- Consists of dimethylaminopiperidinyl, 4-diethylaminopiperidinyl, 2-methylpyrrolidinyl, 4-morpholin-4-yl-piperidinyl, 3,5-dimethyl-morpholin-4-yl, 4-methylpiperidinyl Selected from the group.

In some embodiments, R ¹² and R ¹³ and the nitrogen atom to which they are attached are N, N-dimethylamino, N- (4-hydroxy-1,1-dioxidetetrahydro-3-thienyl) amino, cyclo Propylmethylamino, prop-2-yn-1-ylamino, 2- (morpholino) eth-1-ylamino, phenylsulfonylamino, N-benzylamino, N- (4-methylsulfonyl-benzyl) amino, tryptophanyl, tyrosine, N-1-carboxyprop-1-ylamino, N- (2-carboxyeth-1-yl) -amino, N- (4-carboxybenzyl) -amino, N- [3- (N ′-(4- ( Acrylic acid) -phenyl) carboxamido) pyrrolidin-3-yl] amino, N- [4- (N ′-(4- (acrylic acid) -phenyl) carboxamido) piperidin-4-yl] amino, 2- (N, N-dimethylamino) eth-1-ylamino, (1- (5-methyl-4H-1,2,4-triazol-3-yl) ethyl) amino, 1-methyl Ru-1- [N- (1-methyl-2-carboxy-1H-indol-5-yl) aminocarbonyl] eth-1-ylamino, N- (1-methylpyrrolidin-3-yl-ethyl) -amino, 1-methyl-1- [N- (4- (acrylic acid) phenyl) aminocarbonyl] eth-1-ylamino, 1-methyl-1- [N- (4- (2-carboxy-furan-5-yl) Phenyl) aminocarbonyl] eth-1-ylamino, 1-methyl-1- [N- (4- (4-carboxy-thiazol-2-yl) phenyl) aminocarbonyl] eth-1-ylamino, 2- (4- Methylpiperazin-1-yl) eth-1-ylamino, (1-methylpyrrolidin-3-yl) methylamino, N- (1-methylpiperidin-3-yl-methyl) -amino, (1-piperidin-1- Ylcyclopentyl) methylamino, 1- (acetyl) -pyrrolidin-2-ylmethyl) amino, (2- (N, N-dimethylamino) -carbonyl) methylamino, N- (1,1-dioxidetetrahydro-3- Thienyl) methylamino, N-methyl-N-cyclohexyl-amino, N-methyl-N-carboxymethyl-amino, N-methyl-N-benzyl-amino, N-methyl-N- (N ', N'-dimethylaminoacetyl) -amino N-methyl-N-phenyl-amino, N-methyl-N-isopropyl-amino, N-methyl-N- (N'-methylpiperidin-4-yl) amino, N-methyl-N- (1-methyl Piperidin-4-yl) amino, N-methyl-N- (1-methylpiperidin-4-yl-methyl) -amino, N-methyl-N- (1-methylpiperidin-3-yl-methyl) -amino, N-methyl-N- (1-methylpyrazin-2-yl-methyl) -amino, N-methyl-N- (5-methyl-1H-imidazol-2-ylmethyl) -amino, N-methyl-N- [ 2- (Hydroxy) eth-1-yl] amino, N-methyl-N- [2- (N ′, N′-dimethylamino) eth-1-yl] amino, N-methyl-N- [2- ( N ′, N′-diethylamino) eth-1-yl] amino, N-methyl-N- [2- (pyridin-2-yl) eth-1-yl] amino, N-methyl Ru-N- [2- (pyridin-4-yl) eth-1-yl] amino, N-methyl-N- (1- (1,3-thiazol-2-yl) ethyl) -amino, N-methyl -N- [3- (N ', N'-dimethylamino) prop-1-yl] amino, N-methyl-N- (1-carboxy-2-methylprop-1-yl) -amino, N-ethyl- N-propyl-amino, N-ethyl-N- [2- (methoxy) eth-1-yl] amino, N-ethyl-N- [2- (N ', N'-diethylamino) eth-1-yl] Amino, 7-methyl-2,7-diazaspiro [4.4] non-2-yl, 5-methyl-2,5-diazabicyclo [2.2.1] heptyl-2-yl, 4-methyl-1,4-diazepan- 1-yl, piperidinyl, 4-carboxy-piperidinyl, 3-carboxypiperidinyl, 4-hydroxypiperidinyl, 4- (2-hydroxyeth-1-yl) piperidin-1-yl, 4- (N, N -Dimethylamino) -piperidin-1-yl, 3- (N, N-dimethylamino) -methylpiperidin-1-yl, 2- (2- (N, N-dimethylamino) -eth-1-yl) pi Lysin-1-yl, 4- (4-methyl-4H-1,2,4-triazol-3-yl) piperidin-1-yl, 4-pyrrolidinyl-piperidinyl, 3-pyrrolidinyl-piperidinyl, 4- (N, N-diethylamino) -piperidin-1-yl, 4- (azetidin-1-yl) -piperidin-1-yl, 4- (piperidin-1-yl) -piperidin-1-yl, hexahydropyrrolo [1,2 -a] pyrazin-2 (1H) -yl, (2- (N, N-dimethylamino) -methyl) morpholino, 3,5-dimethylmorpholino, thiomorpholino, morpholino, pyrrolidinyl, 2-carboxy-pyrrolidine-1- 2- (carboxy) -4-hydroxy-pyrrolidin-1-yl, 2-carboxamido-pyrrolidin-1-yl, 2- (N, N-dimethylaminocarbonyl) -pyrrolidin-1-yl, 3- (N ', N'-dimethylamino) -pyrrolidin-1-yl, 3- (N', N'-diethylamino) -pyrrolidin-1-yl, 3- (pyridin-3-yl) -pyrrolidin-1-yl, 2 -Pydin-4-yl Pyrrolidin-1-i, piperazin-1-yl, 4-methylpiperazinyl, 4- (carboxymethyl) -piperazin-1-yl, 4- (2-hydroxyeth-1-yl) piperazin-1-yl, 4- (Isopropyl) piperazin-1-yl, 4- (2-methoxyeth-1-yl) piperazin-1-yl, 4- (ethyl) piperazin-1-yl, 4- (N ', N'-dimethylamino) Forms a group selected from acetyl) -piperazin-1-yl, 4- (6-methoxypyridin-2-yl) piperazin-1-yl, and 2-dimethylaminomethylmorpholin-4-yl.

  In some embodiments, HET is selected from quinolinylene and substituted quinolinylene. In another embodiment, HET is selected from quinolinylene, isoquinolinylene, 7-methyl-quinolinylene, 7-trifluoromethyl-quinolinylene, 8-fluoro-quinolinylene and 7-fluoro-quinolinylene. In yet another embodiment, HET is 2- [substituted] -quinolin-6-yl, 2- [substituted] -7-methyl-quinolinyl, 2- [substituted] -7-fluoro-quinolinyl, 2- [substituted] -7-trifluoromethyl-quinolinyl, and 2- [substituted] -8-fluoro-quinolinyl.

であり、ここでX、t、W¹、W³、W⁴、およびW⁵は先に定義している。いくつかの態様において、W¹は窒素である。他の局面において、HETは

からなる群より選択される。 In some embodiments, HET may be substituted with (X) _t

Where X, t, W ¹ , W ³ , W ⁴ , and W ⁵ are defined above. In some embodiments, W ¹ is nitrogen. In other aspects, HET

Selected from the group consisting of

In some embodiments, HET is 1,4-phenylene optionally substituted with (X) _t , wherein X and t are defined above.

  In some embodiments, t is 0.

  In another embodiment, t is 1 and X is amino, nitro, methyl, or halo.

In other embodiments, HET is selected from the following group.

  In some embodiments, Y is substituted aryl or substituted heteroaryl.

  In some embodiments, Y is selected from the group consisting of: substituted biphenyl; substituted phenyl; one which may be fused to the phenyl ring and independently selected from the group consisting of N or O or S or A substituted 6-membered heteroaryl ring having 2 or 3 heteroatoms, wherein the heteroatom N or S may be oxidized; and a fused to phenyl ring And a substituted 5-membered heteroaryl ring having one, two or three heteroatoms independently selected from the group consisting of N or O or S, wherein the heteroatoms N or S are oxidized Optionally substituted 5-membered heteroaryl ring. In some embodiments, Y may be fused to a phenyl ring and has 1 or 2 or 3 heteroatoms independently selected from the group consisting of N or O or S, substituted 5-membered A heteroaryl ring, wherein the heteroatom N or S is an optionally oxidized substituted 5-membered heteroaryl ring.

In another embodiment, -Y is -Ar ¹ - is a (G ¹⁾ _q, wherein Ar ¹ is selected from arylene and heteroarylene, G ¹ is halo, hydroxy, nitro, cyano, alkyl, substituted alkyl, Selected from alkoxy, substituted alkoxy, acyl, acylamino, aminoacyl, amino, substituted amino, carboxy and carboxy ester; and q is an integer from 1 to 3. In another embodiment wherein -Y is -Ar ^1- (G ¹ ) _q , Ar ¹ is selected from phenyl, thiazolyl, furanyl, thienyl, pyridinyl, pyrazinyl, oxazolyl, isoxazolyl, pyrrolyl, imidazolyl, and pyrrolidinyl. In another embodiment wherein -Y is -Ar ^1- (G ¹ ) _q , G ¹ is selected from bromo, chloro, methyl, hydroxy, methoxy, ethoxy, acetyl, acetamide, carboxy, and amino. In another embodiment Y is 2,4-dimethylthiazol-5-yl, 3-bromo-4-aminophenyl, 3-amido-4-hydroxy-phenyl, 2-hydroxy-6-methoxy-phenyl, 4- Selected from (acetylamino) -phenyl, 2,4-dihydroxyphenyl, 2,4-dimethoxy-6-hydroxyphenyl, and 7-hydroxybenzofuranyl.

In another embodiment, Y is —Ar ¹ —Ar ² —, wherein the —Ar ¹ Ar ² — group is -aryl-aryl, -aryl-substituted aryl, -substituted aryl-aryl, -substituted aryl-substituted. Aryl, -aryl-heteroaryl, -aryl-substituted heteroaryl, -substituted aryl-heteroaryl, -substituted aryl-substituted heteroaryl, heteroaryl-aryl, heteroaryl-substituted aryl, substituted heteroaryl-aryl, substituted heteroaryl -Substituted aryl, -aryl-cycloalkyl, -aryl-substituted cycloalkyl, -substituted aryl-cycloalkyl, -substituted aryl-substituted cycloalkyl, -aryl-heterocycle, aryl-substituted heterocycle, substituted aryl-heterocycle, And selected from the group consisting of substituted aryl-substituted heterocycles.

In another embodiment wherein Y is -Ar ¹ -Ar ^2- , the -Ar ¹ -Ar ² -group is 4'-chloro-4-methoxybiphen-2-yl, biphen-2-yl, biphen-4 -Yl, 4-amino-4'-chlorobiphen-2-yl, 4'-aminomethyl-4-methoxybiphen-2-yl, 4-carbamoyl-4'-methoxybiphen-2-yl, 4-carbamoyl -4'-fluorobiphen-2-yl, 4-carbamoyl-4'-methoxybiphen-2-yl, 4-carbamoyl-4'-nitrobiphen-2-yl, 4- (carbamoylmethyl-carbamoyl) biphen- 2-yl, 4- (carbamoylmethylcarbamoyl) -4'-chlorobiphen-2-yl, 4-carboxy-4'-chlorobiphen-2-yl, 3-carboxy-4'-methoxybiphen-2-yl, 4 -Carboxy-4'-methoxybiphen-2-yl, 4'-carboxy-4- (pyrrolidin-1-ylcarbonyl) biphen-2-yl, 4-carboxymethoxybiphen-2-yl, 4-cal Boxymethoxy-4'-chlorobiphen-2-yl, 4'-chlorobiphen-2-yl, 4'-chloro-4-chlorobiphen-2-yl, 4'-chloro-4- (dimethylaminoethylcarbamoylbiphen-2- 4'-chloro-4- (2-ethoxyethoxy) biphen-2-yl, 3'-chloro-4'-fluoro-4-methoxybiphen-2-yl, 4'-chloro-4-fluorobi Fen-2-yl, 4'-chloro-4-hydroxybiphen-2-yl, 3'-chloro-4-methoxybiphen-2-yl, 4'-chloro-4-methylcarbamoylbiphen-2- 4'-chloro-4- (2-methoxyethoxy) biphen-2-yl, 4'-chloro-4-nitrobiphen-2-yl, 4'-chloro-4- (2-oxo-2-pyrrolidine- 1-ylethoxy) biphen-2-yl, 4'-chloro-4- (pyrrolidin-1-ylcarbonyl) biphen-2-yl, 4'-chloro-4- (3-pyrrolidin-1-ylpropoxy) biphen- 2-yl, 4'-cyano-4-methoxybiphen-2-yl 3 ', 4'-dichloro-4-methoxybiphen-2-yl, 4,4'-dimethoxybiphen-2-yl, 3', 4'-dimethoxy-4- (pyrrolidin-1-ylcarbonyl) Biphen-2-yl, 4'-dimethylamino-4-methoxybiphen-2-yl, 4- (2-dimethylaminoethylcarbamoyl) biphen-2-yl, 4'-ethoxy-4-methoxybiphen-2 -Yl, 4'-fluoro-4-methoxybiphen-2-yl, 4-hydroxybiphenyl, 4-methoxybiphenyl, 4-methoxy-4'-hydroxybiphen-2-yl, 4- (2-methoxyethoxy ) Biphen-2-yl, 4-methoxy-4'-methylbiphen-2-yl, 4-methoxy-3'-nitrobiphen-2-yl, 4-methoxy-4'-nitrobiphen-2-yl, 4-methylcarbamoyl Biphen-2-yl, 3'-methyl-4-methoxybiphen-2-yl, 4'-nitro-4- (pyrrolidin-1-ylcarbonyl) biphen-2-yl, 4- (2-oxo- 2-pyrrolidin-1-yl Selected from the group consisting of (ethoxy) biphen-2-yl, 4- (3-pyrrolidin-1-ylpropoxy) biphen-2-yl, and 4'-trifluoromethyl-4-methoxybiphen-2-yl .

In another embodiment wherein Y is -Ar ¹ -Ar ^2- , the -Ar ¹ -Ar ² -group is 4- (1H-imidazol-1-yl) phenyl, 2-furan-2-yl-5-methoxy Phenyl, 5-methoxy-2-thiophen-2-ylphenyl, 2- (2,4-dimethoxypyrimidin-5-yl) -4-methoxyphenyl, 2- (pyrid-4-yl) phenyl, 3-amino- 5-phenylthiophen-2-yl, 5- (4-chlorophenyl) -2-methylfuran-2-yl, 3- (4-chlorophenyl) -5-methylisoxazol-4-yl, 2- (4- Chlorophenyl) -4-methylthiazol-5-yl, 3- (3,4-dichloro-phenyl) isoxazol-5-yl, 3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl, 5-methyl Selected from the group consisting of 2-phenylthiophen-3-yl and 1-phenyl-1H-pyrazol-4-yl.

In another embodiment a, -Ar ¹ -Ar ² - - Y is -Ar ¹ -Ar ² group 2-cyclohexyl -N, N-dimethylamino - carbonyl methyl-5-methoxyphenyl, and 4-morpholinophenyl Selected from the group consisting of

  In still other embodiments, Y is substituted quinolyl, substituted benzofuryl, substituted thiazolyl, substituted furyl, substituted thienyl, substituted pyridinyl, substituted pyrazinyl, substituted oxazolyl, substituted isoxazolyl, substituted pyrrolyl, substituted imidazolyl, substituted pyrrolidinyl, substituted pyrazolyl, substituted isothiazolyl, Substituted 1,2,3-oxadiazolyl, substituted 1,2,3-triazolyl, substituted 1,3,4-thiadiazolyl, substituted pyrimidinyl, substituted 1,3,5-triazinyl, substituted indolizinyl, substituted indolyl, substituted isoindolyl, substituted indazolyl , Substituted benzothienyl, substituted benzthiazolyl, substituted prynyl, substituted quinolidinyl, substituted quinolinyl, substituted isoquinolinyl, substituted cinnolinyl, substituted phthalazinyl, substituted quinazolinyl, substituted quinoxalinyl, substituted 1,8-naphthyridinyl, and substituted pteri It is selected from the group consisting of nil. In some embodiments, Y is independently selected from the group consisting of alkyl, haloalkyl, halo, hydroxy, nitro, cyano, alkoxy, substituted alkoxy, acyl, acylamino, aminoacyl, amino, substituted amino, carboxy, and carboxy ester. Substituted with 1 to 3 substituents. In yet another aspect, Y is 2,4-dimethylthiazol-5-yl.

  In some embodiments, Y is selected from the corresponding Y group of Table 1.

In some embodiments, -Het-Y is:

  Preferred compounds of the present invention or pharmaceutically acceptable salts, partial salts, or tautomers thereof include those shown in Table 1 below.

  The present invention further provides metabolites of any of the compounds of formula (I), (Ia)-(Is), or the compounds of Table 1. In some aspects, the metabolite is an oxide.

  The present invention is also directed to pharmaceutical compositions comprising a pharmaceutically acceptable diluent and a therapeutically effective amount of one of the compounds described herein or a mixture of one or more of such compounds. .

  The present invention further provides a method for treating a viral infection mediated by a virus of the Flaviviridae family, such as HCV, in a mammal, wherein the viral infection is diagnosed or the viral infection A pharmaceutical comprising a pharmaceutically acceptable diluent and a therapeutically effective amount of one of the compounds described herein or a mixture of one or more of such compounds in a mammal at risk of developing the disease Also contemplated is a method comprising administering a pharmaceutical composition. In another aspect, the present invention provides the use of a compound for preparing a medicament for treating or preventing an infection. In other aspects, the mammal is a human.

  In yet another embodiment of the invention, a method of treating or preventing a viral infection in a mammal, in combination with administration of a therapeutically effective amount of one or more agents active against HCV. A method of administering a compound is provided. Active agents against HCV include ribavirin, levovirin, viramidine, inhibitors of thymosin alpha-1, NS3 serine protease, and inhibitors of inosine monophosphate dehydrogenase, either alone or in combination with ribavirin or viramidine. Is included. Preferably, the additional agent active against HCV is interferon alpha or pegylated interferon alpha, alone or in combination with ribavirin or viramidine.

General Synthetic Methods The compounds of the present invention can be prepared from readily available starting materials using the following general methods and procedures. Where typical or preferred process conditions (ie, reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are indicated, it is understood that other process conditions may be used unless otherwise specified. I will. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

  In addition, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesirable reactions. Suitable protecting groups for various functional groups, as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, many protecting groups are described in T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999, and references cited therein.

  Where a compound of the invention contains one or more chiral centers, such compounds are prepared as pure stereoisomers, ie as individual enantiomers or diastereomers, or as stereoisomer-rich mixtures. Or it can be isolated. All such stereoisomers (and mixtures rich in stereoisomers) are included within the scope of the invention unless otherwise indicated. Pure stereoisomers (or stereoisomer-rich mixtures) can be prepared, for example, using optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, and the like.

一つの態様において、式（I）の化合物を上のスキーム1に示すとおり遷移金属触媒クロスカップリング反応により調製し、ここで、LおよびL'は適当なクロスカップリング置換基であり、P'は水素、窒素保護基、またはRであり、かつZ、D、E、R、Q、HET、およびYは先に定義したとおりである。典型的には、LまたはL'の一方はSn、B、Zr、またはZn系の金属（例えば-BOH₂、Sn(CH₃)₃など）であり、LまたはL'の他方はハロゲンまたはスルホン酸エステルなどの脱離基である。適当なハロゲンおよびスルホン酸エステルには、Cl、Br、I、-OSO₂CF₃、および-OSO₂CH₃が含まれる。適当な遷移金属触媒にはPdおよびNi系触媒（例えばPd(PPh₃)₂Cl₂、Pd[P(Ph₃)]₄など）が含まれる。一つの態様において、1.1または1.2の一方は-B(OH)₂であるLを有し、LまたはL'がハロゲンである1.1または1.2の化合物を触媒量の二塩化トリフェニルホスフィンパラジウム（II）存在下、過剰のビス(ネオペンチルグリコラト)ジボロンで処理することにより調製する。得られたボロン酸をLがハロゲンまたはスルホン酸エステルである1.1または1.2の他方と、鈴木カップリング条件下でカップリングさせて式（I）の化合物または中間体1.3を生成する。適当なカップリング条件には、Pd[P(Ph)₃]₄およびNaHCO₃を含む還流メタノール中、10〜20時間の1.1および1.2の反応が含まれる。P'がHまたは保護基である場合、保護基を除去し、続いて得られたNH基を官能基化して化合物（I）を得る。この変換の具体例をスキーム5に示す。 Scheme 1

In one embodiment, a compound of formula (I) is prepared by a transition metal catalyzed cross-coupling reaction as shown in Scheme 1 above, where L and L ′ are suitable cross-coupling substituents and P ′ Is hydrogen, a nitrogen protecting group, or R, and Z, D, E, R, Q, HET, and Y are as defined above. Typically, one of L or L ′ is Sn, B, Zr, or a Zn-based metal (eg, —BOH ₂ , Sn (CH ₃ ) ₃ etc.), and the other of L or L ′ is halogen or sulfone A leaving group such as an acid ester. Suitable halogen and sulfonate esters include Cl, Br, I, -OSO ₂ CF ₃ , and -OSO ₂ CH ₃ . Suitable transition metal catalysts include Pd and Ni based catalysts (eg, Pd (PPh ₃ ) ₂ Cl ₂ , Pd [P (Ph ₃ )] _4, etc.). In one embodiment, one of 1.1 or 1.2 has L which is —B (OH) ₂ and a compound of 1.1 or 1.2 wherein L or L ′ is halogen is a catalytic amount of triphenylphosphine palladium (II) dichloride. Prepare by treatment with excess bis (neopentylglycolato) diboron in the presence. The resulting boronic acid is coupled with the other of 1.1 or 1.2, where L is a halogen or sulfonate ester, under Suzuki coupling conditions to produce the compound of formula (I) or intermediate 1.3. Suitable coupling conditions include reactions of 1.1 and 1.2 in refluxing methanol containing Pd [P (Ph) ₃ ] ₄ and NaHCO ₃ for 10-20 hours. When P ′ is H or a protecting group, the protecting group is removed, and then the resulting NH group is functionalized to give compound (I). A specific example of this transformation is shown in Scheme 5.

一つの態様において、化合物1.1はスキーム2に示すとおりに合成することができ、ここで例示のために、DはCHであり、EはSであり、ZはCOOPであり、Qはシクロヘキシルであり、Pはアルキルなどのヒドロキシ保護基であり、P'は窒素保護基であり、かつLはハロゲンである。チオフェン2.1を硝酸および硫酸の混合物で処理してニトロ化合物2.2を生成する。ニトロ化合物を還元し、続いて得られたアミンをt-ブチルオキシカルボニルなどの保護基P'で保護して、化合物2.3を得る。チオフェン2.3をN-ブロモスクシンイミド（NBS）などのハロゲン化剤で処理して臭化物2.4を生成することができる。2.4をトリメチルシリルアセチレン、CuI、およびPdCl₂(PPh₃)₂に曝露することによりアセチレン2.5を得、これを次いでn-Bu₄NFで処理し、マイクロ波照射して2.6を生成する。化合物2.6を次にシクロヘキサノンおよびナトリウムエトキシドと、エタノール中、還流条件下で反応させて、シクロヘキセン2.7を生成し、これを次いでH₂およびPd(OH)₂/Cまたはトリエチルシランなどの還元剤で還元してシクロヘキサン2.8とする。化合物2.8を次いで官能基化してR基を導入することもでき、または環窒素を保護した後にNBSなどのハロゲン化剤で処理してカップリング相手2.9を生成することもできる。 Scheme 2

In one embodiment, compound 1.1 can be synthesized as shown in Scheme 2, where for purposes of illustration, D is CH, E is S, Z is COOP, and Q is cyclohexyl. , P is a hydroxy protecting group such as alkyl, P ′ is a nitrogen protecting group, and L is a halogen. Thiophene 2.1 is treated with a mixture of nitric acid and sulfuric acid to produce nitro compound 2.2. Reduction of the nitro compound and subsequent protection of the resulting amine with a protecting group P ′ such as t-butyloxycarbonyl gives compound 2.3. Thiophene 2.3 can be treated with a halogenating agent such as N-bromosuccinimide (NBS) to produce bromide 2.4. Exposure of 2.4 to trimethylsilylacetylene, CuI, and PdCl ₂ (PPh ₃ ) ₂ yields acetylene 2.5, which is then treated with n-Bu ₄ NF and microwave irradiated to produce 2.6. Compound 2.6 is then reacted with cyclohexanone and sodium ethoxide in ethanol under reflux conditions to produce cyclohexene 2.7, which is then reacted with a reducing agent such as H ₂ and Pd (OH) ₂ / C or triethylsilane. Reduce to cyclohexane 2.8. Compound 2.8 can then be functionalized to introduce the R group, or the ring nitrogen can be protected and then treated with a halogenating agent such as NBS to produce the coupling partner 2.9.

スキーム1に記載のL'-HET-Y基1.2は、当技術分野において周知の通常の方法により調製することができる。スキーム3は、そのような収束合成において用いるのに適したHET-Y基を調製するための一つの一般的方法を例示する。スキーム3はブロモおよびヒドロキシル置換アリールまたはヘテロアリール化合物3.1を用い、これは一つまたは複数のX基でさらに置換してもよい（示していない）。必要があれば、ヒドロキシル基を通常の保護基Pgで保護することができ、これらは当技術分野において周知である。化合物3.3は、3.1を通常の鈴木条件下でボロン酸3.2と反応させることによって生成し、3.2は上のスキーム1に記載の様式で、対応するY-Br化合物から調製することができる。Pgが水素ではないとき、保護基を通常の方法で除去することができる。得られた化合物3.3のヒドロキシル基を次に通常の条件下で、スキーム1のカップリング段階で用いるための化合物1.2に変換することができる。 Scheme 3

The L′-HET-Y group 1.2 described in Scheme 1 can be prepared by conventional methods well known in the art. Scheme 3 illustrates one general method for preparing HET-Y groups suitable for use in such convergent synthesis. Scheme 3 uses bromo and hydroxyl substituted aryl or heteroaryl compounds 3.1, which may be further substituted with one or more X groups (not shown). If necessary, the hydroxyl group can be protected with the usual protecting group Pg, which are well known in the art. Compound 3.3 is produced by reacting 3.1 with boronic acid 3.2 under normal Suzuki conditions and 3.2 can be prepared from the corresponding Y-Br compound in the manner described in Scheme 1 above. When Pg is not hydrogen, the protecting group can be removed by conventional methods. The resulting hydroxyl group of compound 3.3 can then be converted to compound 1.2 for use in the coupling step of Scheme 1 under normal conditions.

  Scheme 4 below illustrates the preparation of a quinolinyl HET-Y group with a bromo group suitable for Suzuki coupling with compound 1.1. It is understood that this quinolinyl group is shown for illustrative purposes only.

スキーム4において、市販のアミノ2-メチル-4-ニトロベンゼン、化合物4.1を対応するブロモ-2-メチル-ニトロベンゼン、化合物4.2に、等モル量の亜硝酸ナトリウム、過剰のHBｒおよび触媒量の臭化銅（II）を用いての通常の条件下で変換する。反応は好ましくは化合物4.1を不活性溶媒中、約-10〜10℃の温度で過剰の臭化水素水溶液（例えば、48％HBr）と混合することにより行う。水に溶解した等モル量の亜硝酸ナトリウムを反応混合物に、反応温度を維持しながらゆっくり加える。次いで触媒量の固体臭化銅（I）を反応混合物に加え、これを室温よりもわずかに低い温度まで昇温させる。反応完了を示す窒素発生の停止まで反応を監視する。その後、得られた生成物、ブロモ-2-メチル-ニトロベンゼン、化合物4.2を蒸発、抽出、沈澱、ろ過、クロマトグラフィーなどの通常の技術により単離することもでき；または精製および/または単離せずに次の段階で用いることもできる。 Scheme 4

In Scheme 4, commercially available amino 2-methyl-4-nitrobenzene, compound 4.1 to the corresponding bromo-2-methyl-nitrobenzene, compound 4.2 to equimolar amount of sodium nitrite, excess HBr and catalytic amount of copper bromide Convert under normal conditions using (II). The reaction is preferably carried out by mixing compound 4.1 with an excess of aqueous hydrogen bromide solution (eg 48% HBr) in an inert solvent at a temperature of about -10 to 10 ° C. An equimolar amount of sodium nitrite dissolved in water is slowly added to the reaction mixture while maintaining the reaction temperature. A catalytic amount of solid copper (I) bromide is then added to the reaction mixture, which is allowed to warm to a temperature slightly below room temperature. The reaction is monitored until nitrogen evolution ceases indicating completion of the reaction. The resulting product, bromo-2-methyl-nitrobenzene, compound 4.2 can then be isolated by conventional techniques such as evaporation, extraction, precipitation, filtration, chromatography; or without purification and / or isolation It can also be used in the next stage.

  Suitable examples of compound 4.1 include 2-nitro-3-methylaniline, 4-methyl-3-nitroaniline (both commercially available from Aldrich Chemical Company, Milwaukee, Wisconsin, USA) and 3-methyl-4 -Commercial variants such as nitroaniline (commercially available from Lancaster Synthesis Inc.) are included.

  Compound 4.2 is then converted to (E) -2- (bromo-2-nitrophenyl) vinyldimethylamine, compound 4.4 by reaction with excess N, N-dimethylformamide dimethyl acetal, compound 4.3. The reaction is typically carried out in an appropriate solvent, such as DMF, under an inert atmosphere. Preferably, the reaction is carried out at an elevated temperature of about 100 ° C to 160 ° C. The reaction is continued until it is substantially complete, but typically is completed within about 1-6 hours. After the reaction is complete, the resulting product can be isolated by conventional techniques such as evaporation, extraction, precipitation, filtration, chromatography, etc .; or can be used in the next step without purification and / or isolation. .

  Oxidation of (E) -2- (bromo-2-nitrophenyl) vinyldimethylamine, compound 4.4 proceeds upon contact with a large excess of sodium periodate to yield bromo-2-nitrobenzaldehyde. This reaction is typically carried out in an inert diluent such as tetrahydrofuran, an aqueous mixture of dioxane. Preferably, the reaction is conducted at ambient temperature and continues until it is substantially complete, but typically is completed within about 0.5-6 hours. After completion of the reaction, the resulting product, bromo 2-nitrobenzaldehyde, compound 4.5 can also be isolated by conventional techniques such as evaporation, extraction, precipitation, filtration, chromatography, etc .; or without purification and / or isolation It can also be used in the next stage.

  Normal reduction of compound 4.5 yields the corresponding bromo 2-aminobenzaldehyde, compound 4.10.

  Separately, bromo-5-methoxybenzoyl chloride, compound 4.7 (available from Maybridge) is converted to the corresponding bromo-3-acetyl-methoxybenzene, compound 4.8, by reaction with dimethylzinc. The reaction is typically carried out in a suitable inert diluent such as benzene, toluene, xylene. Since dimethylzinc is pyrophoric, preferably dimethylzinc is placed in a solvent prior to addition of compound 4.7. Preferably, the reaction is initially performed at a temperature of about -10 to about 10 ° C and then slowly returned to room temperature. The reaction is continued until it is substantially complete, but typically is completed within about 0.2 to 2 hours. After completion of the reaction, the resulting product, bromo-3-acetyl-methoxy-benzene (compound 4.8), can also be isolated by conventional techniques such as evaporation, extraction, precipitation, filtration, chromatography; or purification and It can also be used in the next step without isolation.

  Alternatively, bromo-5-methoxybenzoyl chloride, compound 4.7 can be obtained from the corresponding commercially available bromo-5-methoxybenzoic acid such as 2-bromo-5-methoxybenzoic acid (available from Aldrich Chemical Company, Milwaukee, Wisconsin, USA). Can be prepared by conversion to acid halides. The acid halide can be prepared by contacting the carboxylic acid with an inorganic acid halide such as thionyl chloride, phosphorus trichloride, phosphorus tribromide or phosphorus pentachloride, or preferably with oxalyl chloride under normal conditions. it can. Generally, this reaction uses about 1 to 5 molar equivalents of an inorganic acid halide or oxalyl chloride, either neat or in an inert solvent such as dichloromethane or carbon tetrachloride, and ranges from about 0 ° C to about 80 ° C. Perform at temperature for about 1 to about 48 hours. In this reaction, a catalyst such as DMF may be used.

  Commercially available chlorophenylboronic acid, compound 4.9, is coupled with compound 4.8 under normal Suzuki conditions to produce chlorophenyl substituted 3-acetylmethoxybenzene, compound 4.6. 2-, 3- and 4-chlorophenylboronic acid are commercially available from Aldrich Chemical Company, supra.

  Compound 4.6 is then coupled with compound 4.10 under condensation conditions to give 2-biaryl-6-bromoquinoline, compound 4.11. This reaction is preferably carried out by mixing approximately stoichiometric amounts of both compounds 4.6 and 4.10 in an appropriate inert solvent such as ethanol, isopropanol, etc., in the presence of a suitable base such as potassium hydroxide, under an inert atmosphere. To do. Preferably, the reaction is conducted at a temperature of about 70 ° C. to about 100 ° C. and proceeds to substantial completion, but is typically complete within about 2-16 hours. After completion of the reaction, the resulting product, compound 4.11, can also be isolated by conventional techniques such as evaporation, extraction, precipitation, filtration, chromatography; or used in the next step without purification and / or isolation You can also.

スキーム1に記載の合成に加えて、式（I）の化合物を他の方法で調製することもできる。スキーム5は一つのそのような方法を示しており、ここで例示のために、ZはCOOHであり、DはCHであり、EはSであり、Qはシクロヘキシルであり、かつR^a、およびHET-Y基は化合物5.14において示すとおりである。化合物5.1を市販（Aldrich）の5.2と、フリードランダーの条件を用いて縮合させ、キノリン5.3を生成する。そのような条件の例を以下の実施例2に示す。化合物5.3を、水素化リチウムアルミニウムなどの公知の方法を用いて対応するアルコール5.4に変換し、続いてデス・マーチン試薬を用いて再酸化して、アルデヒド5.5を得ることができる。市販のチオフェン5.6を硝酸/硫酸での処理により5.7に変換する。次いで、化合物5.7および5.5をMeOH中、触媒量のピロリジン存在下で一緒に還流し、ニトロ-オレフィン5.8を生成する。次に、化合物5.8を亜リン酸トリエチルと共に還流してチエノ-ピロール誘導体5.9を得る。5.9をシクロヘキサノンと共に、酢酸、無水酢酸、およびリン酸存在下で加熱することにより、スキーム2のとおりにシクロヘキシル環を導入し、5.10を得る。化合物5.10をトリエチルシランで還元して5.11とする。5.11を市販の5.12とDMF中、標準のアルキル化条件を用いて反応させ、アセトアミド部分を導入して5.13を生成し、これをLiOH水溶液でけん化して所望の生成物5.14を得る。 Scheme 5

In addition to the synthesis described in Scheme 1, compounds of formula (I) can also be prepared by other methods. Scheme 5 illustrates one such method, where for purposes of illustration, Z is COOH, D is CH, E is S, Q is cyclohexyl, and R ^a , and The HET-Y group is as shown in compound 5.14. Compound 5.1 is condensed with commercially available (Aldrich) 5.2 using the conditions of a free drander to produce quinoline 5.3. Examples of such conditions are shown in Example 2 below. Compound 5.3 can be converted to the corresponding alcohol 5.4 using known methods such as lithium aluminum hydride, followed by reoxidation using Dess-Martin reagent to give aldehyde 5.5. Commercially available thiophene 5.6 is converted to 5.7 by treatment with nitric acid / sulfuric acid. Compounds 5.7 and 5.5 are then refluxed together in MeOH in the presence of a catalytic amount of pyrrolidine to produce nitro-olefin 5.8. Compound 5.8 is then refluxed with triethyl phosphite to give thieno-pyrrole derivative 5.9. Heating 5.9 with cyclohexanone in the presence of acetic acid, acetic anhydride, and phosphoric acid introduces the cyclohexyl ring as in Scheme 2 to give 5.10. Compound 5.10 is reduced to 5.11 with triethylsilane. Reaction of 5.11 with commercially available 5.12 in DMF using standard alkylation conditions, introducing the acetamide moiety to yield 5.13, which is saponified with aqueous LiOH to give the desired product 5.14.

もう一つの態様において、式（I）の化合物をスキーム6に示すとおりに合成し、スキーム中、例示のために、DはSであり、EはCHであり、ZはCOOPであり、Qはシクロヘキシルであり、Pはアルキルなどのヒドロキシ保護基であり、P'は窒素保護基であり、L'はハロゲンなどの脱離基であり、かつHETおよびYは先に定義したとおりである。化合物6.1をシアノ酢酸メチルと、ジイソプロピルエチルアミンなどの塩基存在下で反応させてアルキル化生成物6.2を生成する。6.2をHClガスに曝露してピロール6.3を得、これを次いで臭化ベンジルおよびNaHとの反応により、P'がベンジルである6.4などの保護ピロールに変換することができる。次に、6.4を水素化ジイソブチルアルミニウムで還元して対応するアルコールとし、続いて(n-Pr)₄NRuO₄/N-メチルモルホリンN-酸化物などの酸化剤により酸化してアルデヒド6.5とする2段階法などにより、エステル6.4をアルデヒド6.5に変換する。THF中、アルデヒド6.5のチオグリコール酸メチルおよびカリウムtert-ブトキシドとの反応により化合物6.6を得、これをシクロヘキシル部分を導入するためのスキーム5と同様の様式で官能基化して6.7を得ることができる。同様に、P'保護基を6.7から除去することができ、R基をスキーム5に記載のとおりに導入して、式（I）の化を得ることができる。 Scheme 6

In another embodiment, compounds of formula (I) are synthesized as shown in Scheme 6, in which, for the sake of illustration, D is S, E is CH, Z is COOP, and Q is Cyclohexyl, P is a hydroxy protecting group such as alkyl, P ′ is a nitrogen protecting group, L ′ is a leaving group such as halogen, and HET and Y are as defined above. Compound 6.1 is reacted with methyl cyanoacetate in the presence of a base such as diisopropylethylamine to produce alkylated product 6.2. 6.2 can be exposed to HCl gas to give pyrrole 6.3, which can then be converted to a protected pyrrole such as 6.4 where P ′ is benzyl by reaction with benzyl bromide and NaH. Next, 6.4 is reduced with diisobutylaluminum hydride to the corresponding alcohol, followed by oxidation with an oxidizing agent such as (n-Pr) ₄ NRuO ₄ / N-methylmorpholine N-oxide to give aldehyde 6.5 Ester 6.4 is converted to aldehyde 6.5, such as by a step method. Reaction of aldehyde 6.5 with methyl thioglycolate and potassium tert-butoxide in THF gives compound 6.6, which can be functionalized in a manner similar to Scheme 5 for introducing a cyclohexyl moiety to give 6.7. . Similarly, the P ′ protecting group can be removed from 6.7 and the R group can be introduced as described in Scheme 5 to give the formula (I).

スキーム7は、ニトロ化合物7.3とアルデヒド7.6とのカップリングから生成した中間体7.8の合成を例示している。チオフェン7.1を、無水酢酸および硝酸の溶液への添加などによる適当なニトロ化条件下でニトロ化して酸7.2を生成し、次いでこれをエステル化して中間体エステル7.3を得る。カップリング相手7.6を2-クロロ-6-メチルキノリン7.4から出発して調製する。7.4をNBS（N-ブロモスクシンイミド）などの適当なハロゲン化試薬で処理してハロゲン化し、一および二臭化物の混合物7.5を得る。次いで、混合物を50％水性エタノールなどの水性溶媒中、ヘキサメチレンテトラミンなどのアミン存在下で還流し、酸による後処理後にアルデヒド7.6を得る。ニトロ化合物7.3およびアルデヒド7.6をメタノールなどのアルコール系溶媒中で一緒に還流し、これに触媒量のピロリジンなどのアミンを加えてオレフィン7.7を得、次いでこれを亜リン酸トリエチルで処理して環化チエノピロール7.8を生成する。7.8の調製の詳細を実施例4に示す。 Scheme 7

Scheme 7 illustrates the synthesis of intermediate 7.8 generated from the coupling of nitro compound 7.3 and aldehyde 7.6. Thiophene 7.1 is nitrated under appropriate nitrating conditions, such as by addition of acetic anhydride and nitric acid to the solution to produce acid 7.2, which is then esterified to give intermediate ester 7.3. Coupling partner 7.6 is prepared starting from 2-chloro-6-methylquinoline 7.4. 7.4 is treated with a suitable halogenating reagent such as NBS (N-bromosuccinimide) to give a mixture 7.5 of mono and dibromide. The mixture is then refluxed in an aqueous solvent such as 50% aqueous ethanol in the presence of an amine such as hexamethylenetetramine to give aldehyde 7.6 after workup with acid. Nitro compound 7.3 and aldehyde 7.6 are refluxed together in an alcoholic solvent such as methanol, and a catalytic amount of an amine such as pyrrolidine is added to give olefin 7.7, which is then treated with triethyl phosphite to cyclize. This produces thienopyrrole 7.8. Details of the preparation of 7.8 are given in Example 4.

スキーム8は、スキーム5に記載の方法に従って化合物8.2〜8.6を調製するための中間体7.8の使用を例示する。 Scheme 8

Scheme 8 illustrates the use of intermediate 7.8 to prepare compounds 8.2-8.6 according to the method described in Scheme 5.

スキーム8は、上のスキームに記載の方法に従っての、9.3などの化合物の調製を例示する。R'およびR''が一緒になって環式基を形成する、化合物9.3の合成例を実施例9および10に示す。 Scheme 9

Scheme 8 illustrates the preparation of compounds such as 9.3 according to the methods described in the above scheme. Synthetic examples of compound 9.3, in which R ′ and R ″ together form a cyclic group, are shown in Examples 9 and 10.

Administration and Pharmaceutical Compositions The present invention provides novel compounds having antiviral activity, including Flaviviridae viruses such as hepatitis C virus. The compounds of the present invention inhibit viral replication by inhibiting enzymes involved in replication, including RNA-dependent RNA polymerase. They can also inhibit other enzymes used in the activity or propagation of Flaviviridae viruses.

  In general, the compounds of the invention will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that provide similar utilities. The actual amount of the compound of the invention, i.e., active ingredient, depends on many factors, such as the severity of the disease being treated, the age and relative health of the subject, the potency of the compound used, the route and mode of administration, and other factors. Will depend. The drug can be administered multiple times a day, preferably once or twice a day.

  The therapeutically effective amount of the compound of the present invention is in the range of about 0.01-50 mg / kg of recipient body weight per day; preferably about 0.01-25 mg / kg / day, more preferably about 0.1-10 mg / kg / day. sell. Thus, for administration to a 70 kg person, the dosage range will most preferably be about 7-70 mg per day.

  The present invention is not limited to any particular composition or pharmaceutical carrier and can thus vary. In general, the compounds of the invention will be administered as a pharmaceutical composition by any one of the following routes: oral, systemic (eg, transdermally, intranasally or via suppositories), or parenteral (eg, Intramuscular, intravenous or subcutaneous administration. The preferred manner of administration is oral using a convenient daily dosage regimen that can be adjusted according to the degree of affliction. The composition can take the form of tablets, pills, capsules, semi-solids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other suitable composition. Another preferred mode of administration of the compounds of the present invention is inhalation.

  The choice of formulation depends on various factors such as the mode of administration of the drug and the bioavailability of the drug. For delivery by inhalation, the compounds can be formulated as solutions, suspensions, aerosol propellants or dry powder and filled into a suitable dispenser for administration. There are several types of pharmaceutical inhalation devices—nebulizer inhalers, metered dose inhalers (MDI) and dry powder inhalers (DPI). Nebulizer devices produce a stream of high velocity air that causes the therapeutic agent (formulated in a liquid) to spray as a mist that is carried into the patient's respiratory tract. An MDI is a formulation that is typically packaged with compressed gas. After activation, the device releases a measured amount of therapeutic agent by compressed gas, thus providing a reliable method of administering a certain amount of agent. DPI administers a therapeutic agent in the form of a flowable powder that can be dispersed in the patient's inspiratory flow during breathing by the device. In order to obtain a free flowing powder, the therapeutic agent is formulated with an excipient such as lactose. A measured amount of the therapeutic agent is stored in capsule form and administered at each actuation.

  Recently, pharmaceutical formulations have been developed, especially for drugs with low bioavailability, based on the principle that bioavailability can be increased by increasing the surface area, ie by decreasing the particle size. For example, US Pat. No. 4,107,288 describes a pharmaceutical formulation having particles with a particle size in the range of 10-1,000 nm, wherein the active material is supported on a polymeric cross-linked matrix. US Pat. No. 5,145,684 describes a pharmaceutical formulation in which a drug is pulverized into nanoparticles (average particle size 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to obtain a pharmaceutical formulation that exhibits significantly higher bioavailability. The manufacture of the formulation is described.

  The composition usually consists of a combination of a compound of the invention and at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the claimed compound. Such excipients can be gas excipients commonly available to those skilled in the art for any solid, liquid, semi-solid, or aerosol composition.

  Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, Includes nonfat dry milk. Liquid and semi-solid excipients are selected from a variety of oils including those of glycerol, propylene glycol, water, ethanol and petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. sell. Particularly preferred liquid carriers for injectable solutions include water, saline, aqueous dextrose, and glycols.

  A compressed gas may be used to disperse the compounds of the present invention in the form of an aerosol. Inert gases suitable for this purpose are nitrogen, carbon dioxide and the like. Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 18th ed., 1990).

  The amount of the compound in the formulation can vary within the full range used by those skilled in the art. Typically, the formulation will contain from about 0.01 to 99.99% by weight of the total formulation of the compound on a weight percent (% by weight) basis, with the remainder being one or more suitable pharmaceutical excipients It is an agent. Preferably, the compound is present at a level of about 1-80% by weight. Representative pharmaceutical formulations are described in the Formulation Examples section below.

The present invention is also directed to a pharmaceutical composition comprising a combination of a therapeutically effective amount of a compound of the present invention and a therapeutically effective amount of another active agent against an RNA-dependent RNA virus, particularly HCV. Agents active against HCV include ribavirin, levovirin, viramidine, thymosin alpha-1, inhibitors of HCV NS3 serine protease, or inhibitors of inosine monophosphate dehydrogenase, interferon-alpha, pegylated interferon-alpha (pegylated Interferon-α), interferon-α and ribavirin combination, peginterferon-α and ribavirin combination, interferon-α and levovirin combination, and peginterferon-α and levovirin combination. is not. Interferon-α includes recombinant interferon-α2a (such as ROFERON interferon available from Hoffman-LaRoche, Nutley, NJ) and interferon-α2b (Intron-A interferon available from Schering Corp., Kenilworth, New Jersey, USA). Etc.), consensus interferon, and purified interferon-α product. For a discussion of ribavirin and its activity against HCV, see JO Saunders and SA Raybuck, "Inosine Monophosphate Dehydrogenase: Consideration of Structure, Kinetics and Therapeutic Potential," Ann. Rep. Med. Chem., 35 : 201-210 (2000). .

  Agents active against hepatitis C virus inhibit HCV protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV release, HCV NS5A protein, and inosine 5 'monophosphate dehydrogenase Drugs are also included. Other drugs include nucleoside analogs for the treatment of HCV infection. Still other compounds include those disclosed in International Publication No. 2004/014313 and International Publication No. 2004/014852, and references cited therein. Patent application WO 2004/014313 and WO 2004/014852 are hereby incorporated by reference in their entirety.

  Specific antiviral agents include Omega IFN (BioMedicines Inc.), BILN-2061 (Boehringer Ingelheim), Summetrel (Endo Pharmaceuticals Holdings Inc.), Roferon A (F. Hoffman-La Roche), Pegasys (F. Hoffman) -La Roche), Pegasys / Ribaravin (F. Hoffman-La Roche), CellCept (F. Hoffman-La Roche), Wellferon (GlaxoSmithKline), Albuferon-α (Human Genome Sciences Inc.), Levovirin (ICN Pharmaceuticals), IDN -6556 (Idun Pharmaceuticals), IP-501 (Indevus Pharmaceuticals), Actimmune (InterMune Inc.), Infergen A (InterMune Inc.), ISIS 14803 (ISIS Pharamceuticals Inc.), JTK-003 (Japan Tobacco Inc.), Pegasys / Ceplene (Maxim Pharmaceuticals), Ceplene (Maxim Pharmaceuticals), Civacir (Nabi Biopharmaceuticals Inc.), Intron A / Zadaxin (RegeneRx), Levovirin (Ribapharm Inc.), Viramidine (Ribapharm Inc.), Heptazyme (Ribozyme Pharmaceuticals), Intron A (Schering-Plough), PEG-Intron (Schering-Plough), Rebetron (Sche ring-Plough), Ribavirin (Schering-Plough), PEG-Intron / Ribavirin (Schering-Plough), Zadazim (SciClone), Rebif (Serono), IFN-β / EMZ701 (Transition Therapeutics), T67 (Tularik Inc.), VX-497 (Vertex Pharmaceuticals Inc.), VX-950 / LY-570310 (Vertex Pharmaceuticals Inc.), Omniferon (Viragen Inc.), XTL-002 (XTL Biopharmaceuticals), SCH 503034 (Schering-Plough), isatoribine and its The prodrugs ANA971 and ANA975 (Anadys), R1479 (Roche Biosciences), Valopicitabine (Idenix), NIM811 (Novartis), and Actilon (Coley Pharmaceuticals) are included.

  In some embodiments, the compositions and methods of the present invention comprise a compound of the present invention and an interferon. In some aspects, the interferon is selected from the group consisting of interferon alpha 2B, pegylated interferon alpha, consensus interferon, interferon alpha 2A, and lymphoblastic interferon tau.

  In other embodiments, the compositions and methods of the invention comprise a compound of the invention, and the compound having anti-HCV activity enhances the development of interleukin 2, interleukin 6, interleukin 12, type 1 helper T cell responses Selected from the group consisting of a compound, interfering RNA, antisense RNA, imiquimod, ribavirin, inosine 5 'monophosphate dehydrogenase inhibitor, amantadine, and rimantadine.

  In still other embodiments, the compound having anti-HCV activity is ribavirin, levovirin, viramidine, an inhibitor of thymosin alpha-1, NS3 serine protease, and an inhibitor of inosine monophosphate dehydrogenase, alone or in combination with ribavirin or viramidine -α or pegylated interferon-α.

  In another embodiment, the compound having anti-HCV activity is interferon-α or peginterferon-α, alone or in combination with ribavirin or viramidine.

Examples In the examples below and the synthetic schemes described above, the following abbreviations have the following meanings. If an abbreviation is not defined, it has its generally accepted meaning.
μL = microliter μM = micromolar concentration μg = microgram
NMR = Nuclear magnetic resonance
br = wide
d = double line δ = chemical shift
dd = double wire double wire
DMEM = Dulbecco's modified Eagle medium
DMF = N, N-dimethylformamide
DMSO = dimethyl sulfoxide
DTT = Dithiothreitol
EDTA = ethylenediaminetetraacetic acid
ESI = electrospray ionization
g = grams
h or hr = hour
HCV = Hepatitis C virus
HPLC = high performance liquid chromatography
Hz = Hertz
IPTG = Isopropyl-β-D-thiogalactopyranoside
IU = international unit
IC ₅₀ = inhibition concentration at 50% inhibition
J = Coupling constant (expressed in Hz unless otherwise specified)
m = Multiple line
M = Molar concentration
M + H ⁺ = parent mass spectral peak + H ⁺
mg = milligram
mL = milliliter
mM = mmol concentration
mmol = mmol
MS = mass spectrum
nm = nanometer
nM = nanomolar concentration
ng = nanogram
NTA = nitrilotriacetic acid
NTP = Nucleoside triphosphate
PCR = polymerase chain reaction
ppm = parts per million
psi = pounds per square inch
Rp-HPLC = reversed-phase high-performance liquid chromatography
s = single line
t = triple line
TC ₅₀ = toxic concentration at 50% cytotoxicity
tetrakis or tetrakis palladium = tetrakis (triphenylphosphine) palladium (0)
TFA = trifluoroacetic acid
THF = tetrahydrofuran
Tris = Tris (hydroxymenthyl) aminomethane
UTP = uridine triphosphate

  The following examples illustrate compounds and intermediates useful for preparing the compounds of the present invention. A summary of the synthetic protocols used to prepare these compounds is given above.

Example 1
6-Bromo-2- (4'-chloro-4-methoxy-biphenyl-2-yl) -quinoline 4.11
Stage 1. 4-Bromo-2-methyl-1-nitro-benzene (4.2):
To an ice-cold solution of 3-methyl-4-nitro-phenylamine (10.0 g, 65.7 mmol) in acetone (200 mL) was added 48% HBr (21 mL, 197.2 mmol). NaNO ₂ (4.54 g, 65.7 mmol) was dissolved in water (20 mL) and added dropwise to the amine solution at a rate that kept the temperature below 5 ° C. The mixture was stirred at this temperature for an additional 10 minutes and then solid CuBr (1.5 g, 10 mmol) was added in portions at a rate that kept the temperature below 15 ° C. The reaction was complete when no more nitrogen was observed (approximately 15 minutes). The reaction mixture was evaporated to dryness and the residue was dissolved in a mixture of water (500 mL) and ethyl acetate (750 mL). The organic phase was separated, washed with water (2 ×), saturated NaCl (2 ×) and dried (Na ₂ SO ₄ ). It was then evaporated to dryness to give the crude product as a yellow solid which was purified by filtration through a silica gel pad (400 mL) eluting with toluene.
Yield: 10.45 g (73%);

Step 2. [(E) -2- (5-Bromo-2-nitro-phenyl) -vinyl] -dimethyl-amine (4.4):
A mixture of compound 4.2 (9.26 g, 42.9 mmol), N, N-dimethylformamide dimethyl acetal 4.3 (14.3 mL, 107.2 mmol) and DMF (11 mL) was heated at 145 ° C. (bath) for 2 hours under a slow stream of argon. . The reaction mixture was then evaporated to dryness. The dark pink product crystallized on standing.

Step 3. 5-Bromo-2-nitro-benzaldehyde (4.5):
Compound 4.4 (11.63 g, 42.9 mmol) was dissolved in a 1: 1 mixture of THF and water (500 mL). To this solution was added NaIO ₄ (34.3 g, 160 mmol) and the mixture was stirred at room temperature for 1 hour, during which time the dark solution became light yellow and a large amount of precipitate formed. The solid material was filtered off and washed twice with ethyl acetate (100 mL), the organic phase was collected and evaporated to dryness. The residue was passed through a silica gel pad (400 mL) and filtered using toluene for elution to give the title compound (7.08 g, 71%).

Step 4. 2-Amino-5-bromo-benzaldehyde (4.10):
Compound 4.10 was synthesized from compound 4.5 (5.45 g, 23.7 mmol) using the method of LI Smith and JW Opie (Org. Synth. Coll. Vol. 3, 56) in a yield of 55% (2.6 g).

Step 5. 1- (2-Bromo-5-methoxy-phenyl) -ethanone (4.8):
To an ice-cold solution of 2-bromo-5-methoxy-benzoyl chloride (8.75 g, 35 mmol) in toluene (40 mL) was added 2M toluene solution of dimethylzinc (9.63 mL, 19.25 mmol) under an argon atmosphere (dimethylzinc zinc). Is pyrophoric-contact with air should be avoided!) The ice bath was removed and the mixture was allowed to warm slowly to room temperature. Once the reaction starts, it proceeds rapidly, producing a turbid solution. The reaction was complete in 30 minutes. The reaction mixture was then re-cooled to 0 ° C. and quenched with ethanol (10 mL). The mixture was evaporated to dryness and the residue was dissolved in a mixture of 1M HCl (50 mL) and ethyl acetate (100 mL). The organic phase was separated, washed with water (2 × 50 mL), brine (2 ×) and dried (Na ₂ SO ₄ ). The final solution was evaporated and the oil was dried under high vacuum overnight to give the title compound as a colorless liquid (7.96 g, 99%).

Step 6. 1- (4′-Chloro-4-methoxy-biphenyl-2-yl) -ethanone (4.6):
Compound 4.8 (6.0 g, 26.19 mmol), 4-chlorobenzeneboronic acid (4.51 g, 28.81 mmol) and Pd (PPh ₃ ) ₄ (0.303 g) in toluene (250 mL), MeOH (60 mL) and 2M NaHCO ₃ (25 mL). , 0.262 mmol) was stirred at 80 ° C. for 16 hours under an argon atmosphere. After removal of the solvent, the dry residue was dissolved in CHCl ₃ (150 mL) and filtered. The solvent was evaporated and the residue was purified by chromatography using CHCl ₃ -MeOH (70: 1) as eluent to give the title compound (6.33 g, 93%).

Step 7. 6-Bromo-2- (4′-chloro-4-methoxy-biphenyl-2-yl) -quinoline (4.11):
Compound 4.11 (100 mg, 0.5 mmol) and compound 4.6 (130 mg, 0.5 mmol) are dissolved in ethanol (5 mL), 10% KOH (800 μL, 1.5 mmol) is added and the mixture is placed in a 90 ° C. bath under an argon atmosphere. Maintained overnight. The solvent was evaporated and the residue was triturated with water. Semi-solid compound 4.11 was purified on a silica gel pad (400 mL) eluting with toluene to give a yellow gum (2.03 g, 44%).

Example 2
Step 1. 6-Bromo-2- (2,4-dimethyl-thiazol-5-yl) -quinoline To a solution of KOH (10.32 (85%) g, 156.27 mmol) in anhydrous EtOH (700 mL) was added 2-amino- 5-Bromobenzaldehyde (10.42 g, 52.09 mmol) and 5-acetyl-2,4-dimethylthiazole (8.16 mL, 60.42 mmol) were added. The mixture was stirred at 78 ° C. for 16 hours under Ar atmosphere and then cooled in an ice bath. This was neutralized with 5N HCl to pH 7 and then evaporated to about 60 mL. Water (500 mL) was added. The resulting precipitate was collected by filtration, washed thoroughly with water, and dried to give 6-bromo-2- (2,4-dimethyl-thiazol-5-yl) -quinoline (15.62 g, 94%). .

Step 2. 2- (2,4-Dimethyl-thiazol-5-yl) -quinolin-6-boronic acid 6-Bromo-2- (2,4-dimethyl-thiazol-5-yl in anhydrous DMSO (260 mL) ) -Quinoline (15 g, 46.99 mmol), bis (neopentylglucolato) diboron (31.83 g, 141 mmol), bis (triphenylphosphine) chloride-palladium (II) (1.65 g, 2.35 mmol), and potassium acetate (13.81) g, 141 mmol) was stirred at 90 ° C. under Ar atmosphere for 2 hours and then cooled to room temperature. The mixture was poured into water (1.2 L) and the precipitate was collected by filtration, washed with water and dried. EtOAc (600 mL) was added to the dried solid and the insoluble solid was removed by filtration. The filtrate was evaporated and the product was adsorbed onto silica gel and purified by elution with EtOAc-hexane (5: 2) on a short silica pad to give 2- (2,4-dimethyl-thiazol-5-yl) -quinoline. -6-boronic acid was obtained (16.4 g, still containing about 30% bis (neopentylglucolato) diboron by NMR-yield 94%).

Example 3
2- (2,4-Dimethyl-thiazol-5-yl) -8-fluoro-quinoline-6-boronic acid Step 1. 4-Amino-3-fluoro-boronic acid
Commercially available 4-bromo-2-fluoroaniline (500 mg, 2.6 mmol), potassium acetate (764 mg, 7.8 mmol), [P (Ph ₃ )] ₂ Pd (II) Cl ₂ (18 mg, 0.026) in DMSO (13 mL) mmol) and bis (neopentylglycolato) diboron (1.76 g, 7.8 mmol) were heated at 60 ° C. overnight under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried (sodium sulfate) and concentrated. The crude product was purified using RP-HPLC to give 4-amino-3-fluoro-boronic acid.

Step 2. 4-Amino-3-fluoro-5-iodo-boronic acid
4-Amino-3-fluoro-boronic acid is treated with N-iodosuccinimide in acetic acid. The reaction mixture is diluted with ethyl acetate, washed with water and brine, dried (sodium sulfate) and concentrated to give 4-amino-3-fluoro-5-iodo-boronic acid.

Step 3. 4-Amino-3-fluoro-5-furomyl-boronic acid
4-Amino-3-fluoro-5-iodo-boronic acid is dissolved in THF, during which time CO bubbles from the reaction vessel. Tetrakis (triphenylphosphino) palladium is added and the reaction mixture is heated to 50 ° C. Add tributyltin hydride. The reaction mixture is diluted with ethyl acetate, washed with water and brine, dried (sodium sulfate), concentrated and purified to give 4-amino-3-fluoro-5-formyl-boronic acid.

Step 4. 2- (2,4-Dimethyl-thiazol-5-yl) -8-fluoro-quinoline-6-boronic acid Compound 4-amino-3-fluoro-5-formyl-boronic acid in ethanol, 5- Reflux overnight with a mixture of acetyl-2,4-dimethylthiazole and 10% KOH / ethanol. The reaction mixture is concentrated, triturated with water and purified to give 2- (2,4-dimethyl-thiazol-5-yl) -8-fluoro-quinoline-6-boronic acid.

Example 4
5- (2-Chloro-quinolin-6-yl) -4H-thieno [3,2-b] pyrrole-2-carboxylic acid methyl ester (7.8)
Step 1. 5-Methyl-4-nitro-thiophene-2-carboxylic acid (7.2)
Acetic anhydride (17 mL, 176 mmol, 5 eq) is cooled to −78 ° C. in a dry ice / acetone bath, fuming nitric acid (6 mL, 113 mmol, 3.2 eq) is slowly added and the mixture is allowed to warm to −20 ° C. 5-Methyl-thiophene-2-carboxylic acid 7.1 (5 g, 35.2 mmol, 1 eq) was slowly added in small portions (rapid exotherm). The temperature rose between -20 ° C and + 10 ° C and then stabilized at -20 ° C. The reaction mixture was stirred at −20 ° C. for 10 minutes. Then, the reaction was quenched with ice water to form a precipitate, which was collected by filtration and washed with ice water. The pink solid was recrystallized from EtOH / H ₂ O. The collected crystals were washed with ice water, air dried, and dried under reduced pressure to give 5-methyl-4-nitro-thiophene-2-carboxylic acid 7.2 as a peach brown solid (3.24 g, 50%). The reaction was repeated on a 15 gram scale (yield 9.82 g, 50%).

Step 2. 5-Methyl-4-nitro-thiophene-2-carboxylic acid methyl ester (7.3)
Compound 7.2 (10 g, 53.4 mmol, 1 eq) in MeOH (100 mL) was treated with sulfuric acid (10 mL, 19 mmol, 3.5 eq) and refluxed for 1 day. After cooling the reaction mixture to ambient temperature, the solvent was evaporated. The residue was dissolved in EtOAc, quenched with saturated NaHCO ₃ and then the layers were separated. The organic layer was washed with brine, dried (Na ₂ SO ₄ ), filtered, concentrated and dried under reduced pressure to give 5-methyl-4-nitro-thiophene-2-carboxylic acid methyl ester 7.3 as a pale salt. Obtained as a brown solid (9.95 g, 93%).

2-クロロ-6-ジブロモメチル-キノリン：

Step 3. 2-Chloro-6-bromomethyl-quinoline and 2-chloro-6-dibromomethyl-quinoline (7.5)
A solution of 2-chloro-6-methylquinoline 7.4 (2 g, 11.3 mmol, 1 eq) in benzene (13 mL) was added NBS (4 g, 23 mmol, 2 eq) followed by benzoyl peroxide (0.365 g) under an argon atmosphere. 1.13 mmol, 0.10 equiv). The mixture was heated to reflux for 4 hours. After cooling to room temperature, the solvent was evaporated and the residue was dissolved in DCM and washed with saturated NaHCO ₃ . The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated. The crude product was purified by ISCO (DCM: Hex = 4: 1) to give 2-chloro-6-bromomethyl-quinoline and 2-chloro-6-dibromomethyl-quinoline 7.5 as white solids (3 g, 80%) This consisted of monobromoquinoline: dibromoquinoline in a ratio of 1: 8 as judged by HPLC. TLC gradient DCM: Hex = 4: 1. 2-chloro-6-bromomethyl-quinoline:

2-Chloro-6-dibromomethyl-quinoline:

Step 4. 2-Chloro-quinoline-6-carbaldehyde (7.6)
A 1: 8 mixture of brominated quinoline 7.5 (3 g, 9.24 mmol, 1 eq) and hexamethylenetetramine (3.89 g, 28 mmol, 3 eq) were heated to reflux in 50% aqueous ethanol (16 mL) for 1 h. After cooling to room temperature, water (10 mL) was added followed by 12N HCl (1.50 mL) slowly over 5 minutes. The reaction mixture was heated to reflux for 0.5 hours and then cooled to room temperature. The reaction mixture was added to brine and extracted four times with DCM. The collected organics were washed twice with brine, dried (Na ₂ SO ₄ ), filtered and concentrated. The solid was dried under reduced pressure to give 2-chloro-quinoline-6-carbaldehyde 7.6 as a white solid (1.63 g, 92%), which was used without further purification.

Step 5. 5-[(E) -2- (2-Chloro-quinolin-6-yl) -vinyl] -4-nitro-thiophene-2-carboxylic acid methyl ester (7.7)
A solution of compound 7.3 (1.71 g, 8.51 mmol, 1 eq) in MeOH (35 mL) was treated with compound 7.6 (1.63 g, 8.51 mmol, 1 eq). The reaction mixture was heated to reflux until a solution was obtained. Then a catalytic amount of pyrrolidine (70 μL, 0.0605 g, 0.851 mmol, 0.10 equiv) was added. The reaction mixture was heated to reflux overnight. After cooling to room temperature, the solvent was evaporated to give a residue which was purified by ISCO (gradient Hex: EtOAc = 100: 0 to 0: 100) to give 5-[(E) -2- (2-chloro-quinoline). -6-yl) -vinyl] -4-nitro-thiophene-2-carboxylic acid methyl ester 7.7 was obtained as an orange-red solid (2.62 g, 82%). TLC gradient Hex: EtOAc = 1: 1.

Step 6. 5- (2-Chloro-quinolin-6-yl) -4H-thieno [3,2-b] pyrrole-2-carboxylic acid methyl ester (7.8)
A solution of compound 7.7 (2.62 g, 7.00 mmol, 1 eq) in triethyl phosphite (7 mL) was heated to reflux (160 ° C.) for 2 hours. After cooling to room temperature, the solvent [P (OEt) ₃ bp: 153-157 ° C .; OP (OEt) ₃ bp: 215 ° C.] was evaporated using a water bath maintained at 70 ° C. under high vacuum. The residue was dissolved in EtOAc and precipitated with n-hexane. The solid was collected by filtration and washed with 5% EtOAc / n-hexane. After air drying for several minutes, the solid was dried under reduced pressure to give the target compound 7.8 as a brown yellow solid (960 mg, 40%). TLC gradient Hex: EtOAc = 1: 1.

Example 5
6-Cyclohex-1-enyl-5- [2- (2-fluoro-phenyl) -quinolin-6-yl] -4- (2-morpholin-4-yl-2-oxo-ethyl) -4H-thieno [ 3,2-b] pyrrole-2-carboxylic acid (Compound 186)
Step 1. 5- [2- (2-Fluoro-phenyl) -quinolin-6-yl] -4H-thieno [3,2-b] pyrrole-2-carboxylic acid methyl ester (8.2a)
Compound 7.8 (Example 4, 387 mg, 1.13 mmol), 2-fluorophenylboronic acid (237 mg, 1.69 mmol, 1.5 eq) and Pd (PPh ₃ ) ₄ (65 mg, 0.057 mmol, 0.05 eq) in a microwave reaction vessel. added. To this was added dioxane (12 mL) and 1M K ₃ PO ₄ aqueous solution (4 mL). The reaction vessel was sealed followed by degassing and Ar purging (x2). The reaction mixture was then heated by microwave at 120 ° C. for 10 minutes. HPLC analysis confirmed complete consumption of compound 7.8. The reaction mixture was cooled to room temperature during which time precipitation occurred. The precipitate was filtered off, washed with cold H ₂ O and dried under reduced pressure to give 5- [2- (2-fluoro-phenyl) -quinolin-6-yl] -4H-thieno [3,2-b ] Pyrrole-2-carboxylic acid methyl ester 8.2a was obtained as a yellow powder (399 mg, 88%). MS: 403.1 (M + H ⁺ ).

Step 2. 6-cyclohex-1-enyl-5- [2- (2-fluoro-phenyl) -quinolin-6-yl] -4H-thieno [3,2-b] pyrrole-2-carboxylic acid methyl ester ( 8.3a)
Compound 8.2a (245 mg, 0.61 mmol), cyclohexanone (947 μL, 9.15 mmol, 15 eq), acetic anhydride (500 μL), 85% H ₃ PO ₄ (500 μL), and acetic acid (4 mL) were added to the microwave reaction vessel. . The reaction vessel was sealed and heated by microwave at 180 ° C. for 75 minutes. HPLC analysis confirmed complete consumption of compound 8.2a. The reaction mixture was poured into NH ₄ OH (concentrated aqueous solution, 50 mL) at 0 ° C. The aqueous mixture was further diluted with H ₂ O and extracted with ethyl acetate (× 3). The combined extracts were then washed with HCl (1M aqueous solution), NaHCO ₃ (saturated aqueous solution) and brine. The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated to give 6-cyclohex-1-enyl-5- [2- (2-fluoro-phenyl) -quinolin-6-yl] -4H-thieno [ 3,2-b] pyrrole-2-carboxylic acid methyl ester 8.3a was obtained. The crude residue was dried under reduced pressure and used without further purification. MS: 483.1 (M + H ⁺ ).

Step 3. 6-Cyclohex-1-enyl-5- [2- (2-fluoro-phenyl) -quinolin-6-yl] -4- (2-morpholin-4-yl-2-oxo-ethyl) -4H -Thieno [3,2-b] pyrrole-2-carboxylic acid (Compound 186)
Compound 8.3a (75 mg, 0.16 mmol) was added to the reaction vessel and dissolved with DMF (8 mL). NaH (67% in mineral oil, 11 mg, 0.31 mmol, 2 eq) was then added and the reaction mixture was stirred at room temperature. After 15 minutes, 2-chloro-1-morpholin-4-yl-ethanone (36 μL, 0.31 mmol, 2 eq) was added in one portion and the reaction mixture continued to stir at room temperature. After 3 hours, complete consumption of compound 8.3a was confirmed by HPLC and LC-MS analysis. The reaction mixture was quenched with H ₂ O (0.1 mL), transferred to a 50 mL flask and concentrated. The crude residue was then added with cold H ₂ O to precipitate the methyl ester as a dark powder. The solid was collected by centrifugation and washed once more with H ₂ O. The methyl ester was then transferred to a reaction vial and dissolved with THF (3 mL), MeOH (1 mL) and LiOH (1M aqueous solution, 1 mL). The reaction mixture was then heated to 50 ° C. and carefully monitored by HPLC and LC-MS analysis. After complete conversion, the reaction mixture was neutralized with HCl (2M aqueous solution, 0.5 mL) and concentrated. The crude residue was then dissolved in DMF and acidified with TFA. The mixture was filtered and purified by reverse phase HPLC to give 6-cyclohex-1-enyl-5- [2- (2-fluoro-phenyl) -quinolin-6-yl] -4- (2-morpholine-4- (Il-2-oxo-ethyl) -4H-thieno [3,2-b] pyrrole-2-carboxylic acid (Compound 186) was obtained as an orange powder (35 mg, 37%).

Example 6
6-Cyclohex-1-enyl-5- [2- (2,4-dimethyl-thiazol-5-yl) -quinolin-6-yl] -4- (2-morpholin-4-yl-2-oxo-ethyl ) -4H-thieno [3,2-b] pyrrole-2-carboxylic acid (Compound 187)
Step 1. 5- [2- (2,4-Dimethyl-thiazol-5-yl) -quinolin-6-yl] -4H-thieno [3,2-b] pyrrole-2-carboxylic acid methyl ester (8.2b )
Compound 7.8 (Example 4, 500 mg, 1.46 mmol), 2,4-dimethyl-thiazole-5-boronic acid pinacol ester (436 mg, 1.82 mmol, 1.25 eq) and Pd (PPh ₃ ) ₄ (84 mg in a microwave reaction vessel. 0.073 mmol, 0.05 equivalents) was added. To this was added dioxane (12 mL) and K ₃ PO ₄ (1M aqueous solution, 4 mL). The reaction vessel was sealed followed by degassing and Ar purging (x2). The reaction mixture was then heated by microwave at 120 ° C. for 10 minutes. HPLC analysis confirmed complete consumption of compound 7.8. The reaction mixture was cooled to room temperature during which time precipitation occurred. The precipitate was filtered off, washed with cold H ₂ O, dried under reduced pressure, and 5- [2- (2,4-dimethyl-thiazol-5-yl) -quinolin-6-yl] -4H-thieno [3,2-b] pyrrole-2-carboxylic acid methyl ester 8.2b was obtained as a yellow powder (506 mg, 81%). MS: 420.1 (M + H ⁺ ).

Step 2. 6-Cyclohex-1-enyl-5- [2- (2,4-dimethyl-thiazol-5-yl) -quinolin-6-yl] -4H-thieno [3,2-b] pyrrole-2 -Carboxylic acid methyl ester (8.3b)
Compound 8.2b (200 mg, 0.48 mmol), cyclohexanone (740 μL, 7.16 mmol, 15 eq), acetic anhydride (400 μL), 85% H ₃ PO ₄ (400 μL), and acetic acid (4 mL) were added to the microwave reaction vessel. . The reaction vessel was sealed and heated by microwave at 150 ° C. for 100 minutes. HPLC analysis confirmed complete consumption of compound 8.2b. The reaction mixture was poured into NH ₄ OH (concentrated aqueous solution, 50 mL) at 0 ° C. The aqueous mixture was further diluted with H ₂ O and extracted with ethyl acetate (× 3). The combined extracts were then washed with HCl (1M aqueous solution), NaHCO ₃ (saturated aqueous solution) and brine. The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated to 6-cyclohex-1-enyl-5- [2- (2,4-dimethyl-thiazol-5-yl) -quinolin-6-yl. ] -4H-thieno [3,2-b] pyrrole-2-carboxylic acid methyl ester 8.3b was obtained. The crude residue was dried under reduced pressure and used without further purification. MS: 500.1 (M + H ⁺ ).

Step 3. 6-Cyclohex-1-enyl-5- [2- (2,4-dimethyl-thiazol-5-yl) -quinolin-6-yl] -4- (2-morpholin-4-yl-2- Oxo-ethyl) -4H-thieno [3,2-b] pyrrole-2-carboxylic acid (Compound 187)
Compound 8.3b (56 mg, 0.11 mmol) was added to the reaction vessel and dissolved with DMF (4 mL). NaH (60% in mineral oil, 9 mg, 0.22 mmol, 2 eq) was then added and the reaction mixture was stirred at room temperature. After 15 minutes, 2-chloro-1-morpholin-4-yl-ethanone (26 μL, 0.22 mmol, 2 eq) was added in one portion and the reaction mixture continued to stir at room temperature. After 6 hours, complete consumption of compound 8.3b was confirmed by HPLC and LC-MS analysis. The reaction mixture was quenched with H ₂ O (0.1 mL), transferred to a 50 mL flask and concentrated. The crude residue was then added with cold H ₂ O to precipitate the methyl ester as a dark powder. The solid was collected by centrifugation and washed once more with H ₂ O. The methyl ester was then transferred to a reaction vial and dissolved with THF (3 mL), MeOH (1 mL) and LiOH (1M aqueous solution, 1 mL). The reaction mixture was then heated to 50 ° C. and carefully monitored by HPLC and LC-MS analysis. After complete conversion, the reaction mixture was neutralized with HCl (2M aqueous solution, 0.5 mL) and concentrated. The crude residue was then dissolved in DMF and acidified with TFA. The mixture was filtered and purified by reverse phase HPLC to give 6-cyclohex-1-enyl-5- [2- (2,4-dimethyl-thiazol-5-yl) -quinolin-6-yl] -4- ( 2-Morpholin-4-yl-2-oxo-ethyl) -4H-thieno [3,2-b] pyrrole-2-carboxylic acid (Compound 187) was obtained as an orange powder (15 mg, 22%).

Example 7
6-Cyclohexyl-5- [2- (2-fluoro-phenyl) -quinolin-6-yl] -4- (2-morpholin-4-yl-2-oxo-ethyl) -4H-thieno [3,2- b] pyrrole-2-carboxylic acid (Compound 188)
Step 1. 6-Cyclohexyl-5- [2- (2-fluoro-phenyl) -quinolin-6-yl] -4H-thieno [3,2-b] pyrrole-2-carboxylic acid methyl ester (8.4a)
To a microwave reaction vessel was added compound 8.3a (Example 5, Step 2, 235 mg, 0.49 mmol), triethylsilane (116 μL, 0.73 mmol, 1.5 eq) and TFA (5 mL). The reaction vessel was sealed and heated by microwave at 70 ° C. for 5 minutes. LC-MS analysis confirmed complete consumption of compound 8.3a. The reaction mixture is poured into 50 mL and concentrated to give 6-cyclohexyl-5- [2- (2-fluoro-phenyl) -quinolin-6-yl] -4H-thieno [3,2-b] pyrrole-2-carboxylic acid. The acid methyl ester 8.4a was obtained as a red powder. The crude residue was dried under reduced pressure and used without further purification. MS: 485.1 (M + H ⁺ ).

Step 2. 6-Cyclohexyl-5- [2- (2-fluoro-phenyl) -quinolin-6-yl] -4- (2-morpholin-4-yl-2-oxo-ethyl) -4H-thieno [3 , 2-b] pyrrole-2-carboxylic acid (Compound 188)
Compound 8.4a (307 mg, 0.63 mmol) was added to the reaction vessel and dissolved with DMF (20 mL). NaH (60% in mineral oil, 50 mg, 1.26 mmol, 2 eq) was then added and the reaction mixture was stirred at room temperature. After 15 minutes, 2-chloro-1-morpholin-4-yl-ethanone (146 μL, 1.26 mmol, 2 eq) was added in one portion and the reaction mixture continued to stir at room temperature. After 75 minutes, complete consumption of compound 8.4a was confirmed by HPLC and LC-MS analysis. The reaction mixture was quenched with H ₂ O (0.5 mL), transferred to a 50 mL flask and concentrated. The crude residue was then added with cold H ₂ O to precipitate the methyl ester as a dark powder. The solid was collected by centrifugation and washed once more with H ₂ O. The methyl ester was then transferred to a reaction vial and dissolved with THF (6 mL), MeOH (2 mL) and LiOH (1M aqueous solution, 2 mL). The reaction mixture was then heated to 50 ° C. and carefully monitored by HPLC and LC-MS analysis. After complete conversion, the reaction mixture was neutralized with HCl (2M aqueous solution, 1 mL) and concentrated. The crude residue was then dissolved in DMF and acidified with TFA. The mixture was filtered and purified by reverse phase HPLC to give 6-cyclohexyl-5- [2- (2-fluoro-phenyl) -quinolin-6-yl] -4- (2-morpholin-4-yl-2- Oxo-ethyl) -4H-thieno [3,2-b] pyrrole-2-carboxylic acid (Compound 188) was obtained as an orange powder (107 mg, 28%).

Example 8
6-Cyclohexyl-5- [2- (2,4-dimethyl-thiazol-5-yl) -quinolin-6-yl] -4- (2-morpholin-4-yl-2-oxo-ethyl) -4H- Thieno [3,2-b] pyrrole-2-carboxylic acid (Compound 189)
Step 1. Methyl 6-cyclohexyl-5- [2- (2,4-dimethyl-thiazol-5-yl) -quinolin-6-yl] -4H-thieno [3,2-b] pyrrole-2-carboxylate Ester (8.4b)
To a 100 mL round bottom flask was added compound 8.3b (Example 6, Step 2, 360 mg, 0.72 mmol), triethylsilane (172 μL, 1.08 mmol, 1.5 eq) and TFA (7 mL). The reaction mixture was capped and stirred at room temperature for 1 hour. LC-MS analysis confirmed complete consumption of compound 8.3b. The reaction mixture was concentrated to give 6-cyclohexyl-5- [2- (2,4-dimethyl-thiazol-5-yl) -quinolin-6-yl] -4H-thieno [3,2-b] pyrrole-2 -Carboxylic acid methyl ester 8.4b was obtained. The crude residue was dried under reduced pressure and used without further purification. MS: 502.1 (M + H ⁺ ).

Step 2. 6-Cyclohexyl-5- [2- (2,4-dimethyl-thiazol-5-yl) -quinolin-6-yl] -4- (2-morpholin-4-yl-2-oxo-ethyl) -4H-thieno [3,2-b] pyrrole-2-carboxylic acid (Compound 189)
Compound 8.4b (361 mg, 0.72 mmol) was added to the reaction vessel and dissolved with DMF (20 mL). NaH (60% in mineral oil, 58 mg, 1.44 mmol, 2 eq) was then added and the reaction mixture was stirred at room temperature. After 15 minutes, 2-chloro-1-morpholin-4-yl-ethanone (167 μL, 1.44 mmol, 2 eq) was added in one portion and the reaction mixture continued to stir at room temperature. After 60 minutes, complete consumption of compound 8.4b was confirmed by HPLC and LC-MS analysis. The reaction mixture was quenched with H ₂ O (0.5 mL), transferred to a 50 mL flask and concentrated. The crude residue was then added with cold H ₂ O to precipitate the methyl ester as a dark powder. The solid was collected by centrifugation and washed once more with H ₂ O. The methyl ester was then transferred to a reaction vial and dissolved with THF (6 mL), MeOH (2 mL) and LiOH (1M aqueous solution, 2 mL). The reaction mixture was then heated to 50 ° C. and carefully monitored by HPLC and LC-MS analysis. After complete conversion, the reaction mixture was neutralized with HCl (2M aqueous solution, 1 mL) and concentrated. The crude residue was then dissolved in DMF and acidified with TFA. The mixture was filtered and purified by reverse phase HPLC to give 6-cyclohexyl-5- [2- (2,4-dimethyl-thiazol-5-yl) -quinolin-6-yl] -4- (2-morpholine- 4-yl-2-oxo-ethyl) -4H-thieno [3,2-b] pyrrole-2-carboxylic acid (Compound 189) was obtained as an orange powder (178 mg, 39%).

Example 9
6-Cyclohexyl-5- [2- (2,4-dimethyl-thiazol-5-yl) -quinolin-6-yl] -4- (2-oxo-2-thiomorpholin-4-yl-ethyl) -4H -Thieno [3,2-b] pyrrole-2-carboxylic acid (compounds 44 and 190)
Step 1. 4-tert-Butoxycarbonylmethyl-6-cyclohexyl-5- [2- (2,4-dimethyl-thiazol-5-yl) -quinolin-6-yl] -4H-thieno [3,2-b ] Pyrrole-2-carboxylic acid methyl ester (9.1)
Compound 8.4b (Example 8, Step 1, 191 mg, 0.38 mmol) was added to the reaction vessel and dissolved in DMF (15 mL). NaH (60% in mineral oil, 30 mg, 0.76 mmol, 2 eq) was then added and the reaction mixture was stirred at room temperature. After 15 minutes, 2-tert-butyl bromoacetate (112 μL, 0.76 mmol, 2 eq) was added in one portion and the reaction mixture continued to stir at room temperature. The reaction was monitored by HPLC and LC-MS analysis. After complete conversion of compound 8.4b, the reaction mixture was quenched with H ₂ O (0.5 mL), which was transferred to a 50 mL flask and concentrated. The crude residue was then added with cold H ₂ O to precipitate the methyl ester as a dark powder. The solid was collected by centrifugation and washed once more with H ₂ O. Then crude 4-tert-butoxycarbonylmethyl-6-cyclohexyl-5- [2- (2,4-dimethyl-thiazol-5-yl) -quinolin-6-yl] -4H-thieno [3,2-b The pyrrole-2-carboxylic acid methyl ester 9.1 was dried under reduced pressure and used without further purification. MS: 616.1 (M + H ⁺ ).

Step 2. 4-Carboxymethyl-6-cyclohexyl-5- [2- (2,4-dimethyl-thiazol-5-yl) -quinolin-6-yl] -4H-thieno [3,2-b] pyrrole- 2-Carboxylic acid methyl ester (9.2)
Compound 9.1 (234 mg, 0.38 mmol) was added to a 50 mL flask and dissolved in 4M HCl in dioxane (5 mL). Anisole (250 μL, 5% v / v) was then added and the reaction mixture was stirred at room temperature. After HPLC and LC-MS analysis showed complete conversion of compound 9.1, the reaction mixture was concentrated. Then crude 4-carboxymethyl-6-cyclohexyl-5- [2- (2,4-dimethyl-thiazol-5-yl) -quinolin-6-yl] -4H-thieno [3,2-b] pyrrole- 2-Carboxylic acid methyl ester 9.2 was briefly dried under reduced pressure and used without further purification. MS: 560.1 (M + H ⁺ ).

Step 3. 6-Cyclohexyl-5- [2- (2,4-dimethyl-thiazol-5-yl) -quinolin-6-yl] -4- (2-oxo-2-thiomorpholin-4-yl-ethyl ) -4H-thieno [3,2-b] pyrrole-2-carboxylic acid (Compound 190)
Compound 9.2 (107 mg, 0.19 mmol) was added to the reaction vessel and dissolved with DMF (3 mL). HBTU (86 mg, 0.23 mmol, 1.2 eq) and DIEA (73 μL, 0.42 mmol, 2.2 eq) were then added and the reaction mixture was stirred at room temperature. After 15 minutes, thiomorpholine (24 μL, 0.24 mmol, 1.25 equiv) was added in one portion and the reaction mixture continued to stir at 35 ° C. After confirming complete consumption of compound 9.2 by HPLC and LC-MS analysis, the reaction mixture was concentrated by high speed vacuum. The crude residue was then added with cold H ₂ O to precipitate the methyl ester. The solid was collected by centrifugation and washed once more with H ₂ O. The methyl ester was then transferred to a reaction vial and dissolved with THF (3 mL), MeOH (1 mL) and LiOH (1M aqueous solution, 1 mL). The reaction mixture was then heated to 50 ° C. and carefully monitored by HPLC and LC-MS analysis. After complete conversion, the reaction mixture was neutralized with HCl (2M aqueous solution, 0.5 mL) and concentrated. The crude residue was then dissolved in DMF and acidified with TFA. The mixture was filtered and purified by reverse phase HPLC to give 6-cyclohexyl-5- [2- (2,4-dimethyl-thiazol-5-yl) -quinolin-6-yl] -4- (2-oxo- 2-Thiomorpholin-4-yl-ethyl) -4H-thieno [3,2-b] pyrrole-2-carboxylic acid (Compound 190) was obtained as an orange powder (24 mg, 20%).

Example 10
6-Cyclohexyl-5- [2- (2,4-dimethyl-thiazol-5-yl) -quinolin-6-yl] -4- (2-oxo-2-piperidin-1-yl-ethyl) -4H- Thieno [3,2-b] pyrrole-2-carboxylic acid (compounds 35 and 191)
Compound 9.2 (Example 9, Step 2, 107 mg, 0.19 mmol) was added to the reaction vessel and dissolved in DMF (3 mL). HBTU (86 mg, 0.23 mmol, 1.2 eq) and DIEA (73 μL, 0.42 mmol, 2.2 eq) were then added and the reaction mixture was stirred at room temperature. After 15 minutes, piperidine (24 μL, 0.24 mmol, 1.25 equiv) was added in one portion and the reaction mixture continued to stir at 35 ° C. After confirming complete consumption of compound 9.2 by HPLC and LC-MS analysis, the reaction mixture was concentrated by high speed vacuum. The crude residue was then added with cold H ₂ O to precipitate the methyl ester. The solid was collected by centrifugation and washed once more with H ₂ O. The methyl ester was then transferred to a reaction vial and dissolved with THF (3 mL), MeOH (1 mL) and LiOH (1M aqueous solution, 1 mL). The reaction mixture was then heated to 50 ° C. and carefully monitored by HPLC and LC-MS analysis. After complete conversion, the reaction mixture was neutralized with HCl (2M aqueous solution, 0.5 mL) and concentrated. The crude residue was then dissolved in DMF and acidified with TFA. The mixture was filtered and purified by reverse phase HPLC to give 6-cyclohexyl-5- [2- (2,4-dimethyl-thiazol-5-yl) -quinolin-6-yl] -4- (2-oxo- 2-Piperidin-1-yl-ethyl) -4H-thieno [3,2-b] pyrrole-2-carboxylic acid (Compound 191) was obtained as an orange powder (24 mg, 21%).

  Prophetic compounds 1-34, 36-43, and 45-185 of Table 1 can be similarly prepared according to the general synthetic methods and examples described above.

Biological Examples Biological Example 1. Anti-Hepatitis C Activity A compound can be anti-C by inhibiting HCV polymerase, by inhibiting other enzymes required in the replication cycle, or by other pathways. Can exhibit hepatitis B activity. Several assays have been published to assess these activities. A general method for assessing the total increase in HCV virus in culture was disclosed in US Pat. No. 5,738,985 to Miles et al. In vitro assays are described in Ferrari et al. Jnl. Of Vir., 73: 1649-1654, 1999; Ishii et al., Hepatology, 29: 1227-1235, 1999; Lohmann et al., Jnl of Bio. Chem., 274: 10807-10815, 1999; and Yamashita et al., Jnl. Of Bio. Chem., 273: 15479-15486, 1998.

  International Publication No. 97/12033, filed Sep. 27, 1996, by C. Hagedorn and A. Reinoldus as the inventor, by Emory University, is US Provisional Patent Application No. 60 filed Sep. 1995. An HCV polymerase assay has been described which claims priority to / 004,383 and can be used to assess the activity of the compounds described herein. Another HCV polymerase assay is reported by Barthholomeusz, et al., Hepatitis C Virus (HCV) RNA polymerase assay using cloned HCV non-structural proteins; Antiviral Therapy 1996: 1 (Supp 4) 18-24.

  Evaluation methods for determining reduced kinase activity from HCV drugs were disclosed in Katze et al. US Pat. No. 6,030,785, Delvecchio US Pat. No. 6,228,576, and Jubin et al. US Pat. No. 5,759,795. Evaluation methods for examining the protease inhibitory activity of the proposed HCV drug were disclosed in US Pat. No. 5,861,267 to Su et al., US Pat. No. 5,739,002 to De Francesco et al., And US Pat. No. 5,597,691 to Houghton et al.

Biological Example 2. Replicon Assay
The cell line ET (Huh-lucubineo-ET) was used to screen compounds for HCV RNA-dependent RNA polymerase inhibition. An ET cell line, EMCV- containing I ₃₈₉ luc-ubi-neo / NS3-3 ′ / ET, a firefly luciferase-ubiquitin-neomycin phosphotransferase fusion protein, and a cell culture adaptive mutation (E1202G; T1280I; K1846T) RNA transcripts with a replicon containing an IRES-driven NS3-5B polyprotein were stably transfected (Krieger at al, 2001 and unpublished). ET cells are cultured in DMEM supplemented with 10% fetal bovine serum, 2 mM glutamine, penicillin (100 IU / mL) / streptomycin (100 μg / mL), 1 × nonessential amino acids, and 250 μg / mL G418 (“Geneticin”) did. These are all available from Life Technologies (Bethesda, MD). Cells were seeded in 96-well plates at 0.5-1.0 × 10 ⁴ cells / well and incubated for 24 hours before adding the test compound. Compounds were added to the cells to a final concentration of 0.1 nM to 50 μM and a final DMSO concentration of 0.5%. Luciferase activity was measured 48-72 hours later with the addition of lysis buffer and substrate (Catalog Number Glo-lysis buffer E2661 and Bright-Glo luciferase system E2620 Promega, Madison, Wis.). Cells should not be too confluent during the assay. Percent inhibition of replication data was plotted against the no compound control. Under the same conditions, the cytotoxicity of the compounds was evaluated using the cell proliferation reagent, WST-1 (Roche, Germany). Compounds showing antiviral activity but no significant cytotoxicity were selected to determine the effective and toxic concentrations at which EC ₅₀ and TC ₅₀ , ie 50% of maximal inhibition, were observed. For these evaluations, 10-point 2-fold serial dilutions are used for each compound, which spans a 1000-fold concentration range. EC ₅₀ and similarly TC ₅₀ values were calculated by fitting the% inhibition at each concentration to the following formula:
% Inhibition = 100% / [(EC ₅₀ / [I]) ^b +1]
In the formula, b is a Hill coefficient.

In some aspects, a compound of formula (I) will have an EC ₅₀ of ₅₀ μM or less when tested according to the assay of Example 2. In other aspects, the EC ₅₀ is 10 μM or less. In yet another aspect, the EC ₅₀ is 5 μM or less.

  When tested at 6.25 μM, compounds 186-191 were found to each have the following percent inhibition: 75, 63, 99, 100, 98, and 97.

Biological Example 3. Cloning and expression of recombinant HCV-NS5b
The coding sequence of NS5b protein, as described in Lohmann, V., et al. (1999) Science 285, 110-113, using primers shown on page 266 of WO 2005/012288, It was cloned from pFKI ₃₈₉ luc / NS3-3 ′ / ET by PCR.

  The cloned fragment lacks the C-terminal 21 amino acid residues. The cloned fragment was inserted into an IPTG inducible expression plasmid that provides an epitope tag (His) 6 at the carboxy terminus of the protein.

  Recombinant enzyme was expressed in XL-1 cells, and after expression induction, the protein was purified using affinity chromatography on a nickel-NTA column. The storage conditions are 10 mM Tris-HCl pH 7.5, 50 mM NaCl, 0.1 mM EDTA, 1 mM DTT, 20% glycerol at −20 ° C.

Biological Example 4. HCV-NS5b Enzyme Assay Polymerase activity is assayed by measuring the incorporation of radiolabeled UTP into the RNA product using a biotinylated heteropolymer template containing a portion of the HCV genome. did. Typically, the assay mixture (50 μL) is 10 mM Tris-HCl (pH 7.5), 5 mM MgCl ₂ , 0.2 mM EDTA, 10 mM KCl, 1 unit / μL RNAsin, 1 mM DTT, 10 μM each [ ³ H] -UTP Containing NTP, and 10 ng / μL heteropolymer template. Test compounds were first dissolved in 100% DMSO and further diluted in aqueous buffer containing 5% DMSO. Typically, compounds were tested at concentrations between 1 nM and 100 μM. The reaction was started by addition of enzyme and continued for 2 hours at 37 ° C. The reaction was stopped with 100 mM EDTA (8 μL) and the reaction mixture (30 μL) was transferred to a streptavidin-coated scintillation proximity microtiter plate (FlashPlates) and incubated at 4 ° C. overnight. Radioactivity uptake was quantified by scintillation counting.

Formulation Examples The following are representative pharmaceutical formulations containing a compound of formula (I).

Formulation Example 1
Tablet formulation The following ingredients are intimately mixed and compressed into a single scored tablet.

Formulation Example 2
Capsule formulation The following ingredients are mixed intimately and filled into hard gelatin capsules.

Formulation Example 3
Suspension formulation The following ingredients are mixed to form a suspension for oral administration.

Formulation Example 4
Injectable formulation The following ingredients are mixed to produce an injectable formulation.

Formulation Example 5
Suppository Formulation A suppository with a total weight of 2.5 g is prepared by mixing a compound of the invention with Witepsol® H-15 (triglycerides of saturated plant fatty acids; Riches-Nelson, Inc., New York) It has the following composition.

Claims (53)

A compound of formula (I) or a pharmaceutically acceptable salt or tautomer thereof:

In the formula:
Y is selected from the group consisting of aryl, heteroaryl, substituted aryl, and substituted heteroaryl;
HET is from the group consisting of a 6-membered arylene ring, a 6-membered heteroarylene ring containing 1 or 2 or 3 heteroatoms selected from N or O or S, and a bicyclic ring having the formula: Selected

Wherein HET may be substituted with (X) _t , wherein X is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, halo, hydroxy, and nitro; An integer equal to 0, 1 or 2; W ¹ , W ⁴ and W ⁵ are independently N or CH; W ³ is N or CH or no more than one in a bicyclic ring In the case that one of the broken lines is a single bond, each adjacent atom is replaced with 1 or 2 hydrogen atoms, respectively. Each dashed line independently represents a single or double bond between two adjacent atoms, provided that the valence is met;
One of D or E is CR ^a and the other of D or E is S;
R ^a and R are independently selected from the group consisting of hydrogen, alkyl, and substituted alkyl;
Q is selected from the group consisting of cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocycle, substituted heterocycle, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and
Z is selected from the group consisting of:
(A) carboxy and carboxy ester;
(B) —C (X ⁴ ) NR ⁸ R ⁹ , wherein X ⁴ is ═O, ═NH, or ═N-alkyl, and R ⁸ and R ⁹ are hydrogen, alkyl, substituted alkyl, alkenyl, substituted Independently selected from the group consisting of alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle, or R ⁸ and R ⁹ are bound to them Together with the atoms form a heterocyclic, substituted heterocyclic, heteroaryl or substituted heteroaryl ring group;
(C) —C (X ³ ) NR ²¹ S (O) ₂ R ⁴ , wherein X ³ is selected from ═O, ═NR ²⁴ , and ═S, and R ²⁴ is hydrogen, alkyl, or substituted alkyl Yes; R ⁴ is selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, and NR ²² R ²³ , R ²¹ , R ^22, and R ²³ are independently hydrogen , Alkyl, substituted alkyl, cycloalkyl, or substituted cycloalkyl; or R ²¹ and R ²² or R ²² and R ²³ are optionally substituted together with the atoms bonded to them. Forming a ring group;
(D) -C (X ² ) -N (R ³ ) CR ² R ^{2 '} C (= O) R ¹ , wherein X ² is selected from = O, = S, and = NR ¹¹ and R ¹¹ Is hydrogen or alkyl, R ¹ is selected from —OR ⁷ and —NR ⁸ R ⁹ , R ⁷ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl , Substituted heteroaryl, heterocycle and substituted heterocycle; R ⁸ and R ⁹ are as defined above;
R ² and R ^{2 ′} are hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle Selected independently from;
Or R ² and R ^{2 ′} as defined together with the carbon atom to which they are attached form a cycloalkyl, substituted cycloalkyl, heterocyclic or substituted heterocyclic group,
Additionally or alternatively, one of R ² or R ^{2 ′} is hydrogen, alkyl or substituted alkyl, and the other, together with the carbon atom bonded to it, is R ⁷ and the oxygen atom or R ⁸ and Forming a heterocyclic or substituted heterocyclic group with any of the nitrogen atoms bonded to it;
R ³ is selected from hydrogen and alkyl, or when R ² and R ^{2 ′} are not taken together to form a ring, and R ² or R ^{2 ′} and R ⁷ or R ⁸ are taken together to form a complex If not forming a ring or substituted heterocyclic group, R ³ may be taken together with the nitrogen atom bonded to it to form a heterocyclic or substituted heterocyclic group with one of R ² and R ^{2 ′.} Good;
(E) -C (X ² ) -N (R ³ ) CR ²⁵ R ²⁶ R ²⁷ , wherein X ² and R ³ are defined above, and R ²⁵ , R ²⁶ and R ²⁷ are alkyl, Independently selected from the group consisting of substituted alkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl and substituted heteroaryl, or R ²⁵ and R ²⁶ together with the carbon atom to which they are attached. And forms a cycloalkyl, substituted cycloalkyl, heterocyclic or substituted heterocyclic group; and (f) carboxylic acid isosteres not defined in (a)-(e). 2. The compound of claim 1, wherein Y is selected from the group consisting of:
Substituted biphenyl; substituted phenyl; substituted 6-membered heteroaryl ring which may be fused to a phenyl ring and has 1 or 2 or 3 heteroatoms independently selected from the group consisting of N or O or S A substituted 6-membered heteroaryl ring in which the heteroatom N or S may be oxidized; and may be fused to a phenyl ring and is independently selected from the group consisting of N or O or S A substituted 5-membered heteroaryl ring having 1 or 2 or 3 heteroatoms, wherein the heteroatom N or S may be oxidized.   Y is 4′-chloro-4-methoxybiphen-2-yl, biphen-2-yl, biphen-4-yl, 4-amino-4′-chlorobiphen-2-yl, 4′-aminomethyl-4 -Methoxybiphen-2-yl, 4-carbamoyl-4'-methoxybiphen-2-yl, 4-carbamoyl-4'-fluorobiphen-2-yl, 4-carbamoyl-4'-methoxybiphen- 2-yl, 4-carbamoyl-4'-nitrobiphen-2-yl, 4- (carbamoylmethyl-carbamoyl) biphen-2-yl, 4- (carbamoylmethylcarbamoyl) -4'-chlorobiphen-2-yl, 4- Carboxy-4'-chlorobiphen-2-yl, 3-carboxy-4'-methoxybiphen-2-yl, 4-carboxy-4'-methoxybiphen-2-yl, 4'-carboxy-4- (pyrrolidine -1-ylcarbonyl) biphen-2-yl, 4-carboxymethoxybiphen-2-yl, 4-carboxymethoxy-4'-chlorobiphen-2-yl, 4'-chlorobi -2-yl, 4'-chloro-4-chlorobiphen-2-yl, 4'-chloro-4- (dimethylaminoethylcarbamoylbiphen-2-yl, 4'-chloro-4- (2-ethoxy Ethoxy) biphen-2-yl, 3'-chloro-4'-fluoro-4-methoxybiphen-2-yl, 4'-chloro-4-fluorobiphen-2-yl, 4'-chloro-4- Hydroxybiphen-2-yl, 3'-chloro-4-methoxybiphen-2-yl, 4'-chloro-4-methylcarbamoylbiphen-2-yl, 4'-chloro-4- (2-methoxy Ethoxy) biphen-2-yl, 4′-chloro-4-nitrobiphen-2-yl, 4′-chloro-4- (2-oxo-2-pyrrolidin-1-ylethoxy) biphen-2-yl, 4′- Chloro-4- (pyrrolidin-1-ylcarbonyl) biphen-2-yl, 4′-chloro-4- (3-pyrrolidin-1-ylpropoxy) biphen-2-yl, 4′-cyano-4-methoxybiphenyl Fen-2-yl, 3 ', 4'-dichloro-4-methoxybiphen-2-yl, 4,4'-dimethyl Xibiphen-2-yl, 3 ′, 4′-dimethoxy-4- (pyrrolidin-1-ylcarbonyl) biphen-2-yl, 4′-dimethylamino-4-methoxybiphen-2-yl, 4- (2 -Dimethylaminoethylcarbamoyl) biphen-2-yl, 4'-ethoxy-4-methoxybiphen-2-yl, 4'-fluoro-4-methoxybiphen-2-yl, 4-hydroxybiphen-2-yl 4-methoxybiphen-2-yl, 4-methoxy-4'-hydroxybiphen-2-yl, 4- (2-methoxyethoxy) biphen-2-yl, 4-methoxy-4'-methylbiphen- 2-yl, 4-methoxy-3'-nitrobiphen-2-yl, 4-methoxy-4'-nitrobiphen-2-yl, 4-methylcarbamoylbiphen-2-yl, 3'-methyl-4-methoxybi Phen-2-yl, 4′-nitro-4- (pyrrolidin-1-ylcarbonyl) biphen-2-yl, 4- (2-oxo-2-pyrrolidin-1-ylethoxy) biphen-2-yl, 4- (3-pyrrolidine-1- Rupuropokishi) biphen-2-yl, and 4'-trifluoromethyl-4 is selected from methoxy group consisting bi phen-2-yl The compound of claim 2, wherein.   The substituted phenyl is selected from the group consisting of halo, heteroaryl, hydroxy, nitro, cyano, alkyl, substituted alkyl, alkenyl, alkoxy, substituted alkoxy, acyl, acylamino, aminoacyl, amino, substituted amino, carboxy, and carboxy ester 3. A compound according to claim 2, which is substituted with 1 to 3 substituents.   Y is substituted quinolyl, substituted benzofuryl, substituted thiazolyl, substituted furyl, substituted thienyl, substituted pyridinyl, substituted pyrazinyl, substituted oxazolyl, substituted isoxazolyl, substituted pyrrolyl, substituted imidazolyl, substituted pyrrolidinyl, substituted pyrazolyl, substituted isothiazolyl, substituted 1,2, 3-oxadiazolyl, substituted 1,2,3-triazolyl, substituted 1,3,4-thiadiazolyl, substituted pyrimidinyl, substituted 1,3,5-triazinyl, substituted indolizinyl, substituted indolyl, substituted isoindolyl, substituted indazolyl, substituted benzothienyl, Selected from the group consisting of substituted benzthiazolyl, substituted purinyl, substituted quinolidinyl, substituted quinolinyl, substituted isoquinolinyl, substituted cinnolinyl, substituted phthalazinyl, substituted quinazolinyl, substituted quinoxalinyl, substituted 1,8-naphthyridinyl, and substituted pteridinyl It is the compound of claim 2, wherein.   1 to 3 Y independently selected from the group consisting of alkyl, haloalkyl, halo, hydroxy, nitro, cyano, alkoxy, substituted alkoxy, acyl, acylamino, aminoacyl, amino, substituted amino, carboxy, and carboxy ester 6. The compound according to claim 5, which is substituted with a substituent.   7. A compound according to claim 6, wherein Y is 2,4-dimethylthiazol-5-yl.   2. The compound of claim 1, wherein Q is cycloalkyl or cycloalkenyl.   9. A compound according to claim 8, wherein Q is cyclohexyl or cyclohexenyl. Z is carboxy, carboxy ester, carboxylic acid isotope, -C (O) NR ⁸ R ⁹ , or -C (O) NHS (O) ₂ R ⁴ , wherein R ⁸ and R ⁹ are defined in claim 1. it is as defined, and R ⁴ is alkyl or aryl the compound of claim 1, wherein.   Z is carboxy, methyl carboxylate, ethyl carboxylate, 6- (β-D-glucuronic acid) ester, 1H-tetrazol-5-yl, 5-oxo-4,5-dihydro-1,2,4-oxa Diazol-3-yl, N-2-cyano-ethylamide, N-2- (1H-tetrazol-5-yl) ethylamide, methylsulfonylaminocarbonyl, trifluoromethylsulfonylaminocarbonyl, or phenylsulfonylaminocarbonyl, 11. A compound according to claim 10.   12. A compound according to claim 11 wherein Z is carboxy.   2. The compound of claim 1, wherein D is CH and E is S. R is a substituted alkyl, the substituted alkyl, aminoalkyl, substituted aminoalkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heterocyclylalkyl, substituted heterocyclylalkyl, -CH ₂ COOH, and -CH ₂ CONR ¹² R ¹³ is selected from the group consisting of R ¹² and R ¹³ are hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, — (CH ₂ ) _0-3 R ¹⁶ , and -NR ¹⁷ is selected from R ¹⁸ independently, or in terms of both of R ¹² and R ¹³ are not both hydrogen, R ¹² and R ¹³ as well as they are attached The nitrogen atom forms a substituted or unsubstituted heterocycle; R ¹⁶ is aryl, heteroaryl, or heterocycle; and R ¹⁷ and R The compound of claim 1, wherein ¹⁸ is independently hydrogen or alkyl, or R ¹⁷ and R ¹⁸ together with the nitrogen atom to which they are attached form a heterocyclic ring of 4 to 7 ring atoms. . _2. The compound of claim 1, wherein R is —CH ₂ CONR ¹² R ¹³ and at least one of R ¹² or R ¹³ is alkyl, substituted alkyl, or heteroaryl. At least one of methyl R ¹² or R ^13, carboxymethyl, 2-hydroxyethyl, 2-morpholin-4-ylethyl or tetrazolyl-5-yl, compound according to claim 15, wherein. 15. The compound according to claim 14, wherein R is —CH ₂ CONR ¹² R ¹³ , and R ¹² and R ¹³ and the nitrogen atom to which they are attached form a substituted or unsubstituted heterocycle. R ¹² and R ¹³ as well as they are bonded to the nitrogen atom is substituted or unsubstituted morpholino ring, form a substituted or unsubstituted piperidinyl ring or a substituted or unsubstituted pyrrolidinyl ring, according to claim 17 A compound according.   Substituted or unsubstituted morpholino ring, piperidinyl ring, or pyrrolidinyl ring is morpholino, 4-pyrrolidin-1-yl-piperidinyl, piperidinyl, 4-hydroxypiperidinyl, 4-carboxypiperidinyl, 4-dimethylaminopiperidinyl , 4-diethylaminopiperidinyl, 2-methylpyrrolidinyl, 4-morpholin-4-yl-piperidinyl, 3,5-dimethyl-morpholin-4-yl, 4-methylpiperidinyl 19. A compound according to claim 18.   R is N, N-dimethylamino-carbonylmethyl, [N- (4-hydroxy-1,1-dioxidetetrahydro-3-thienyl) amino] -carbonylmethyl, (cyclopropylmethylamino) -carbonylmethyl, ( (Prop-2-yn-1-ylamino) -carbonylmethyl, (2- (morpholino) eth-1-ylamino) -carbonylmethyl, (phenylsulfonylamino) -carbonylmethyl, [N-benzylamino] -carbonylmethyl, N- (4-methylsulfonyl-benzyl) amino) -carbonylmethyl, (tryptophanyl) -carbonylmethyl, (tyrosine) -carbonylmethyl, (N- (1-carboxyprop-1-ylamino) -carbonylmethyl, (N- (2-carboxyeth-1-yl) -amino) -carbonylmethyl, (N- (4-carboxybenzyl) -amino) -carbonylmethyl, N- [3- (N ′-(4- (acrylic acid)- Phenyl) carboxamide) pyrrolidin-3-yl] ami No-carbonylmethyl, N- [4- (N '-(4- (acrylic acid) -phenyl) carboxamido) piperidin-4-yl] amino-carbonylmethyl, [2- (N, N-dimethylamino) ethanol 1-ylamino] -carbonylmethyl, [(1- (5-methyl-4H-1,2,4-triazol-3-yl) ethyl) amino] -carbonylmethyl, (1-methyl-1- [N- ( 1-methyl-2-carboxy-1H-indol-5-yl) aminocarbonyl] eth-1-ylamino-carbonylmethyl, [N- (1-methylpyrrolidin-3-yl-ethyl) -amino] -carbonylmethyl, (1-methyl-1- [N- (4- (acrylic acid) phenyl) aminocarbonyl] eth-1-ylamino-carbonylmethyl, (1-methyl-1- [N- (4- (2-carboxy-furan -5-yl) phenyl) aminocarbonyl] eth-1-ylamino-carbonylmethyl, (1-methyl-1- [N- (4- (4-carboxy-thiazol-2-yl) phenyl) aminocarbonyl] eta- 1-ylamino-carbo Nylmethyl, (2- (4-methylpiperazin-1-yl) eth-1-ylamino) -carbonylmethyl, [(1-methylpyrrolidin-3-yl) methylamino] -carbonylmethyl, [N- (1-methyl Piperidin-3-yl-methyl) -amino] -carbonylmethyl, (1-piperidin-1-ylcyclopentyl) methylamino] -carbonylmethyl, (1- (acetyl) -pyrrolidin-2-ylmethyl) amino) -carbonylmethyl , [(2- (N, N-dimethylamino) -carbonyl) methylamino] -carbonylmethyl, [N- (1,1-dioxidetetrahydro-3-thienyl) methylamino] -carbonylmethyl, (N-methyl -N-cyclohexyl-amino) -carbonylmethyl, (N-methyl-N-carboxymethyl-amino) -carbonylmethyl, [N-methyl-N-benzyl-amino] -carbonylmethyl, (N-methyl-N- ( N ', N'-dimethylaminoacetyl) -amino) -carbonylmethyl, (N-methyl-N- Enyl-amino] -carbonylmethyl, (N-methyl-N-isopropyl-amino) -carbonylmethyl, (N-methyl-N- (N'-methylpiperidin-4-yl) amino) -carbonylmethyl, [N- Methyl-N- (1-methylpiperidin-4-yl) amino] -carbonylmethyl, [N-methyl-N- (1-methylpiperidin-4-yl-methyl) -amino] -carbonylmethyl, [N-methyl -N- (1-methylpiperidin-3-yl-methyl) -amino] -carbonylmethyl, [N-methyl-N- (1-methylpyrazin-2-yl-methyl) -amino] -carbonylmethyl, [N -Methyl-N- (5-methyl-1H-imidazol-2-ylmethyl) -amino] -carbonylmethyl, (N-methyl-N- [2- (hydroxy) eth-1-yl] amino) -carbonylmethyl, (N-methyl-N- [2- (N ', N'-dimethylamino) eth-1-yl] amino) -carbonylmethyl, N-methyl-N- [2- (N', N'-diethylamino) [Eta-1-yl] amino) -carbonylmethyl, (N- Methyl-N- [2- (pyridin-2-yl) eth-1-yl] amino) -carbonylmethyl, (N-methyl-N- [2- (pyridin-4-yl) eth-1-yl] amino ) -Carbonylmethyl, [N-methyl-N- (1- (1,3-thiazol-2-yl) ethyl) -amino] -carbonylmethyl, (N-methyl-N- [3- (N ', N '-Dimethylamino) prop-1-yl] amino) -carbonylmethyl, (N-methyl-N- (1-carboxy-2-methylprop-1-yl) -amino) -carbonylmethyl, (N-ethyl-N -Propyl-amino) -carbonylmethyl, (N-ethyl-N- [2- (methoxy) eth-1-yl] amino) -carbonylmethyl, (N-ethyl-N- [2- (N ', N' -Diethylamino) eth-1-yl] amino) -carbonylmethyl, [7-methyl-2,7-diazaspiro [4.4] non-2-yl] -carbonylmethyl, (5-methyl-2,5-diazabicyclo [2.2 .1] heptyl-2-yl) -carbonylmethyl, (4-methyl-1,4-diazepan-1-yl) -carbonylmethyl, (pipe (Lidinyl) -carbonylmethyl, (4-carboxy-piperidinyl) -carbonylmethyl, (3-carboxypiperidinyl) -carbonylmethyl, (4-hydroxypiperidinyl) -carbonylmethyl, (4- (2-hydroxyeta- 1-yl) piperidin-1-yl) -carbonylmethyl, [4- (N, N-dimethylamino) -piperidin-1-yl] -carbonylmethyl, (3- (N, N-dimethylamino) -methylpiperidine -1-yl) -carbonylmethyl, (2- (2- (N, N-dimethylamino) -eth-1-yl) piperidin-1-yl) -carbonylmethyl, [4- (4-methyl-4H- 1,2,4-triazol-3-yl) piperidin-1-yl] -carbonylmethyl, (4-pyrrolidinyl-piperidinyl) -carbonylmethyl, (3-pyrrolidinyl-piperidinyl) -carbonylmethyl, [4- (N, N-diethylamino) -piperidin-1-yl] -carbonylmethyl, (4- (azetidin-1-yl) -piperidin-1-yl) -carbo Nylmethyl, (4- (piperidin-1-yl) -piperidin-1-yl) -carbonylmethyl, (hexahydropyrrolo [1,2-a] pyrazin-2 (1H) -yl) -carbonylmethyl, [(2 -(N, N-dimethylamino) -methyl) morpholino] -carbonylmethyl, (3,5-dimethylmorpholino) -carbonylmethyl, (thiomorpholino) -carbonylmethyl, morpholino-carbonylmethyl, (pyrrolidinyl) -carbonylmethyl, (2-carboxy-pyrrolidin-1-yl) -carbonylmethyl, (2- (carboxy) -4-hydroxy-pyrrolidin-1-yl) -carbonylmethyl, (2-carboxamido-pyrrolidin-1-yl) -carbonylmethyl (2- (N, N-dimethylaminocarbonyl) -pyrrolidin-1-yl) -carbonylmethyl, (3- (N ', N'-dimethylamino) -pyrrolidin-1-yl) -carbonylmethyl, (3 -(N ', N'-diethylamino) -pyrrolidin-1-yl) -carbonylmethyl, (3- (pi Gin-3-yl) -pyrrolidin-1-yl) -carbonylmethyl, (2-piidin-4-ylpyrrolidin-1-yl) -carbonylmethyl, piperazin-1-yl-carbonylmethyl, (4-methylpiperazini ) -Carbonylmethyl, (4- (carboxymethyl) -piperazin-1-yl) -carbonylmethyl, (4- (2-hydroxyeth-1-yl) piperazin-1-yl) -carbonylmethyl, (4- (Isopropyl) piperazin-1-yl) -carbonylmethyl, (4- (2-methoxyeth-1-yl) piperazin-1-yl) -carbonylmethyl, (4- (ethyl) piperazin-1-yl) -carbonylmethyl , (4- (N ′, N′-dimethylaminoacetyl) -piperazin-1-yl) -carbonylmethyl and (4- (6-methoxypyridin-2-yl) piperazin-1-yl) -carbonylmethyl 15. A compound according to claim 14, which is selected.   2. The compound according to claim 1, wherein t is 0.   2. The compound of claim 1, wherein t is 1 and X is amino, nitro, methyl or halo. 23. A compound according to any one of claims 1 to 22, wherein HET is 1,4-phenylene optionally substituted with (X) _t , wherein X and t are defined in claim 1.   24. The compound of claim 23, wherein t is 0. HET may be substituted with (X) _t

In ^{and, X, t, W 1,} W 3, W 4, and W ⁵ are as defined in claim 1, a compound of any one of claims 1 to 22. W ¹ is nitrogen, 25. A compound according. 27. The compound of claim 26, wherein HET is selected from the group consisting of:

Where X and t are defined in claim 1. A compound having the formula (Ia) or a pharmaceutically acceptable salt or tautomer thereof:

In the formula:
Y is selected from the group consisting of substituted aryl and substituted heteroaryl;
X is independently selected from the group consisting of amino, nitro, alkyl, haloalkyl, and halo;
t is an integer equal to 0, 1 or 2;
Q is selected from the group consisting of cyclohexyl and cyclopentyl;
R ¹² and R ¹³ are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, — (CH ₂ ) _0-3 R ¹⁶ , and —NR ¹⁷ R ¹⁸ R ¹² and R ¹³ and the nitrogen atom to which they are attached form a substituted or unsubstituted heterocycle, provided that both R ¹² and R ¹³ are not hydrogen. R ¹⁶ is aryl, heteroaryl, or heterocycle; and R ¹⁷ and R ¹⁸ are independently hydrogen or alkyl, or R ¹⁷ and R ¹⁸ are together with the nitrogen atom to which they are attached. Form a heterocyclic ring of 4 to 7 ring atoms;
One of A or B is CR ^a and the other of A or B is S;
R ^a is selected from the group consisting of hydrogen, alkyl, and substituted alkyl; and
Z is selected from the group consisting of carboxy, carboxy ester, and carboxylic acid isosteres. 29. The compound of claim 28, wherein Y is selected from the group consisting of:
Substituted biphenyl; substituted phenyl; substituted 6-membered heteroaryl ring which may be fused to a phenyl ring and has 1 or 2 or 3 heteroatoms independently selected from the group consisting of N or O or S The heteroatom N or S may be oxidized, substituted 6-membered heteroaryl ring; and may be fused to a phenyl ring and independently selected from the group consisting of N or O or S A substituted 5-membered heteroaryl ring having 1 or 2 or 3 heteroatoms, wherein the heteroatom N or S may be oxidized.   Y is 4′-chloro-4-methoxybiphen-2-yl, biphen-2-yl, biphen-4-yl, 4-amino-4′-chlorobiphen-2-yl, 4′-aminomethyl-4 -Methoxybiphen-2-yl, 4-carbamoyl-4'-methoxybiphen-2-yl, 4-carbamoyl-4'-fluorobiphen-2-yl, 4-carbamoyl-4'-methoxybiphen- 2-yl, 4-carbamoyl-4'-nitrobiphen-2-yl, 4- (carbamoylmethyl-carbamoyl) biphen-2-yl, 4- (carbamoylmethylcarbamoyl) -4'-chlorobiphen-2-yl, 4- Carboxy-4'-chlorobiphen-2-yl, 3-carboxy-4'-methoxybiphen-2-yl, 4-carboxy-4'-methoxybiphen-2-yl, 4'-carboxy-4- (pyrrolidine -1-ylcarbonyl) biphen-2-yl, 4-carboxymethoxybiphen-2-yl, 4-carboxymethoxy-4'-chlorobiphen-2-yl, 4'-chlorobi -2-yl, 4'-chloro-4-chlorobiphen-2-yl, 4'-chloro-4- (dimethylaminoethylcarbamoylbiphen-2-yl, 4'-chloro-4- (2-ethoxy Ethoxy) biphen-2-yl, 3'-chloro-4'-fluoro-4-methoxybiphen-2-yl, 4'-chloro-4-fluorobiphen-2-yl, 4'-chloro-4- Hydroxybiphen-2-yl, 3'-chloro-4-methoxybiphen-2-yl, 4'-chloro-4-methylcarbamoylbiphen-2-yl, 4'-chloro-4- (2-methoxy Ethoxy) biphen-2-yl, 4′-chloro-4-nitrobiphen-2-yl, 4′-chloro-4- (2-oxo-2-pyrrolidin-1-ylethoxy) biphen-2-yl, 4′- Chloro-4- (pyrrolidin-1-ylcarbonyl) biphen-2-yl, 4′-chloro-4- (3-pyrrolidin-1-ylpropoxy) biphen-2-yl, 4′-cyano-4-methoxybiphenyl Fen-2-yl, 3 ', 4'-dichloro-4-methoxybiphen-2-yl, 4,4'-dimethyl Xibiphen-2-yl, 3 ′, 4′-dimethoxy-4- (pyrrolidin-1-ylcarbonyl) biphen-2-yl, 4′-dimethylamino-4-methoxybiphen-2-yl, 4- (2 -Dimethylaminoethylcarbamoyl) biphen-2-yl, 4'-ethoxy-4-methoxybiphen-2-yl, 4'-fluoro-4-methoxybiphen-2-yl, 4-hydroxybiphen-2-yl 4-methoxybiphen-2-yl, 4-methoxy-4'-hydroxybiphen-2-yl, 4- (2-methoxyethoxy) biphen-2-yl, 4-methoxy-4'-methylbiphen- 2-yl, 4-methoxy-3'-nitrobiphen-2-yl, 4-methoxy-4'-nitrobiphen-2-yl, 4-methylcarbamoylbiphen-2-yl, 3'-methyl-4-methoxybi Phen-2-yl, 4′-nitro-4- (pyrrolidin-1-ylcarbonyl) biphen-2-yl, 4- (2-oxo-2-pyrrolidin-1-ylethoxy) biphen-2-yl, 4- (3-pyrrolidine-1- Rupuropokishi) biphen-2-yl, and 4'-trifluoromethyl-4 is selected from methoxy group consisting bi phen-2-yl, 29. A compound according.   The substituted phenyl is selected from the group consisting of halo, heteroaryl, hydroxy, nitro, cyano, alkyl, substituted alkyl, alkenyl, alkoxy, substituted alkoxy, acyl, acylamino, aminoacyl, amino, substituted amino, carboxy, and carboxy ester 30. The compound of claim 29, substituted with 1 to 3 substituents.   Y is substituted quinolyl, substituted benzofuryl, substituted thiazolyl, substituted furyl, substituted thienyl, substituted pyridinyl, substituted pyrazinyl, substituted oxazolyl, substituted isoxazolyl, substituted pyrrolyl, substituted imidazolyl, substituted pyrrolidinyl, substituted pyrazolyl, substituted isothiazolyl, substituted 1,2, 3-oxadiazolyl, substituted 1,2,3-triazolyl, substituted 1,3,4-thiadiazolyl, substituted pyrimidinyl, substituted 1,3,5-triazinyl, substituted indolizinyl, substituted indolyl, substituted isoindolyl, substituted indazolyl, substituted benzothienyl, Selected from the group consisting of substituted benzthiazolyl, substituted purinyl, substituted quinolidinyl, substituted quinolinyl, substituted isoquinolinyl, substituted cinnolinyl, substituted phthalazinyl, substituted quinazolinyl, substituted quinoxalinyl, substituted 1,8-naphthyridinyl, and substituted pteridinyl It is the claim 29 A compound according.   1 to 3 Y independently selected from the group consisting of alkyl, haloalkyl, halo, hydroxy, nitro, cyano, alkoxy, substituted alkoxy, acyl, acylamino, aminoacyl, amino, substituted amino, carboxy, and carboxy ester 40. The compound of claim 32, substituted with a substituent.   34. The compound of claim 33, wherein Y is 2,4-dimethylthiazol-5-yl.   29. The compound of claim 28, wherein Q is cyclohexyl or cyclohexenyl.   Z is methyl carboxylate, ethyl carboxylate, 6- (β-D-glucuronic acid) ester, 1H-tetrazol-5-yl, 5-oxo-4,5-dihydro-1,2,4-oxadiazole 3. 3-yl, N-2-cyano-ethylamide, N-2- (1H-tetrazol-5-yl) ethylamide, methylsulfonylaminocarbonyl, trifluoromethylsulfonylaminocarbonyl, or phenylsulfonylaminocarbonyl. 35. The compound according to 35.   40. The compound of claim 36, wherein Z is carboxy. At least one of alkyl of R ¹² or R ^13, substituted alkyl or heteroaryl, claim 28 A compound according. At least one of R ¹² or R ¹³ is methyl, carboxymethyl, 2-hydroxyethyl, 2-morpholin-4-ylethyl or tetrazolyl-5-yl, 38. A compound according. Nitrogen atom to which R ¹² and R ¹³ as well as they are attached, form a substituted or unsubstituted heterocyclic, claim 28 A compound according. 41. The compound of claim 40, wherein R ¹² and R ¹³ and the nitrogen atom to which they are attached form a substituted or unsubstituted morpholino ring, a substituted or unsubstituted piperidinyl ring, or a substituted or unsubstituted pyrrolidinyl ring. .   A substituted or unsubstituted morpholino ring, piperidinyl ring, or pyrrolidinyl ring is morpholino, 4-pyrrolidin-1-yl-piperidinyl, piperidinyl, 4-hydroxypiperidinyl, 4-carboxypiperidinyl, 4-dimethylaminopiperidinyl Selected from the group consisting of nyl, 4-diethylaminopiperidinyl, 2-methylpyrrolidinyl, 4-morpholin-4-yl-piperidinyl, 3,5-dimethyl-morpholin-4-yl, 4-methylpiperidinyl 42. The compound of claim 41. R ¹² and R ¹³ and the nitrogen atom to which they are attached are both N, N-dimethylamino, N- (4-hydroxy-1,1-dioxidetetrahydro-3-thienyl) amino, cyclopropylmethylamino, Prop-2-yn-1-ylamino, 2- (morpholino) eth-1-ylamino, phenylsulfonylamino, N-benzylamino, N- (4-methylsulfonyl-benzyl) amino, tryptophanyl, tyrosine, N-1- Carboxyprop-1-ylamino, N- (2-carboxyeth-1-yl) -amino, N- (4-carboxybenzyl) -amino, N- [3- (N ′-(4- (acrylic acid)- Phenyl) carboxamido) pyrrolidin-3-yl] amino, N- [4- (N '-(4- (acrylic acid) -phenyl) carboxamido) piperidin-4-yl] amino, 2- (N, N-dimethylamino) ) Eta-1-ylamino, (1- (5-methyl-4H-1,2,4-triazol-3-yl) ethyl) amino, 1-methyl-1- [N- (1-methyl-2-carboxyl) Ruboxy-1H-indol-5-yl) aminocarbonyl] eth-1-ylamino, N- (1-methylpyrrolidin-3-yl-ethyl) -amino, 1-methyl-1- [N- (4- (acrylic) Acid) phenyl) aminocarbonyl] eth-1-ylamino, 1-methyl-1- [N- (4- (2-carboxy-furan-5-yl) phenyl) aminocarbonyl] eth-1-ylamino, 1-methyl -1- [N- (4- (4-carboxy-thiazol-2-yl) phenyl) aminocarbonyl] eth-1-ylamino, 2- (4-methylpiperazin-1-yl) eth-1-ylamino, 1-methylpyrrolidin-3-yl) methylamino, N- (1-methylpiperidin-3-yl-methyl) -amino, (1-piperidin-1-ylcyclopentyl) methylamino, 1- (acetyl) -pyrrolidine- 2-ylmethyl) amino, (2- (N, N-dimethylamino) -carbonyl) methylamino, N- (1,1-dioxidetetrahydro-3-thienyl) methylamino, N-methyl-N-cyclohexane Sil-amino, N-methyl-N-carboxymethyl-amino, N-methyl-N-benzyl-amino, N-methyl-N- (N ', N'-dimethylaminoacetyl) -amino, N-methyl-N -Phenyl-amino, N-methyl-N-isopropyl-amino, N-methyl-N- (N'-methylpiperidin-4-yl) amino, N-methyl-N- (1-methylpiperidin-4-yl) Amino, N-methyl-N- (1-methylpiperidin-4-yl-methyl) -amino, N-methyl-N- (1-methylpiperidin-3-yl-methyl) -amino, N-methyl-N- (1-methylpyrazin-2-yl-methyl) -amino, N-methyl-N- (5-methyl-1H-imidazol-2-ylmethyl) -amino, N-methyl-N- [2- (hydroxy) ethane -1-yl] amino, N-methyl-N- [2- (N ', N'-dimethylamino) eth-1-yl] amino, N-methyl-N- [2- (N', N'- Diethylamino) eth-1-yl] amino, N-methyl-N- [2- (pyridin-2-yl) eth-1-yl] amino, N-methyl-N- [2- (pyridin-4- Yl) eth-1-yl] amino, N-methyl-N- (1- (1,3-thiazol-2-yl) ethyl) -amino, N-methyl-N- [3- (N ', N' -Dimethylamino) prop-1-yl] amino, N-methyl-N- (1-carboxy-2-methylprop-1-yl) -amino, N-ethyl-N-propyl-amino, N-ethyl-N- [2- (Methoxy) eth-1-yl] amino, N-ethyl-N- [2- (N ′, N′-diethylamino) eth-1-yl] amino, 7-methyl-2,7-diazaspiro [ 4.4] non-2-yl, 5-methyl-2,5-diazabicyclo [2.2.1] heptyl-2-yl, 4-methyl-1,4-diazepan-1-yl, piperidinyl, 4-carboxy-piperidinyl, 3-carboxypiperidinyl, 4-hydroxypiperidinyl, 4- (2-hydroxyeth-1-yl) piperidin-1-yl, 4- (N, N-dimethylamino) -piperidin-1-yl, 3 -(N, N-dimethylamino) -methylpiperidin-1-yl, 2- (2- (N, N-dimethylamino) -eth-1-yl) piperidin-1-yl, 4- (4 -Methyl-4H-1,2,4-triazol-3-yl) piperidin-1-yl, 4-pyrrolidinyl-piperidinyl, 3-pyrrolidinyl-piperidinyl, 4- (N, N-diethylamino) -piperidin-1-yl 4- (azetidin-1-yl) -piperidin-1-yl, 4- (piperidin-1-yl) -piperidin-1-yl, hexahydropyrrolo [1,2-a] pyrazin-2 (1H)- Yl, (2- (N, N-dimethylamino) -methyl) morpholino, 3,5-dimethylmorpholino, thiomorpholino, morpholino, pyrrolidinyl, 2-carboxy-pyrrolidin-1-yl, 2- (carboxy) -4- Hydroxy-pyrrolidin-1-yl, 2-carboxamido-pyrrolidin-1-yl, 2- (N, N-dimethylaminocarbonyl) -pyrrolidin-1-yl, 3- (N ', N'-dimethylamino) -pyrrolidine -1-yl, 3- (N ′, N′-diethylamino) -pyrrolidin-1-yl, 3- (pyridin-3-yl) -pyrrolidin-1-yl, 2-pyidin-4-ylpyrrolidin-1- Lee, Pi Perazin-1-yl, 4-methylpiperazinyl, 4- (carboxymethyl) -piperazin-1-yl, 4- (2-hydroxyeth-1-yl) piperazin-1-yl, 4- (isopropyl) piperazine -1-yl, 4- (2-methoxyeth-1-yl) piperazin-1-yl, 4- (ethyl) piperazin-1-yl, 4- (N ', N'-dimethylaminoacetyl) -piperazine-1 29. The compound of claim 28, forming a group selected from -yl and 4- (6-methoxypyridin-2-yl) piperazin-1-yl.   30. The compound of claim 28, wherein t is 0.   29. The compound of claim 28, wherein t is 1 and X is amino, nitro, methyl or halo.   29. The compound of claim 28, wherein D is CH and E is S.   A compound selected from Table 1, or a tautomer, pharmaceutically acceptable salt, or partial salt thereof.   48. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of any one of claims 1, 28, or 47.   48. Any one of claims 1, 28, or 47 for preparing a medicament for treating or preventing a mammalian viral infection mediated at least in part by a virus of the Flaviviridae family. Use of the described compounds.   49. A method for treating or preventing a mammalian viral infection mediated, at least in part, by a virus of the Flaviviridae family, comprising administering to said mammal a composition according to claim 48. Including methods.   51. The method of claim 50, wherein the viral infection is mediated by hepatitis C virus.   51. The method of claim 50, in combination with a therapeutically effective amount of one or more agents active against hepatitis C virus.   Active agents against hepatitis C virus include HCV protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV invasion, HCV-constructed, HCV release, HCV NS5A protein, or inosine 5 ' 53. The method of claim 52, wherein the method is an inhibitor of monophosphate dehydrogenase.