WO2007002051A1

WO2007002051A1 - Carboline derivatives and their use as inhibitors of flaviviridae infections

Info

Publication number: WO2007002051A1
Application number: PCT/US2006/023928
Authority: WO
Inventors: Kristjan Gudmundsson
Original assignee: Smithkline Beecham Corporation
Priority date: 2005-06-22
Filing date: 2006-06-19
Publication date: 2007-01-04

Abstract

The present invention relates to compounds that are useful in the treatment or prophylaxis of viruses belonging to Flaviviridae, such as a flavivirus, a pestivirus, or a hepacivirus, particularly dengue fever, yellow fever, West Nile virus, or HCV.

Description

CARBOLINE DERIVATIVES AND THEIR USE AS INHIBITORS OF FLAVIVIRIDAE INFECTIONS

FIELD OF THE INVENTION

The present invention relates to compounds useful as anti-viral agents. The present invention relates to compounds that are useful in the treatment of viruses belonging to Flaviviridae, including flaviviruses, pestiviruses, and hepaciviruses. The invention includes compounds useful for the treatment or prophylaxis of dengue fever, yellow fever, West Nile virus, and HCV.

BACKGROUND OF THE INVENTION

Infection with HCV is a major cause of human liver disease throughout the world. In the US, an estimated 4.5 million Americans are chronically infected with HCV. Although only 30% of acute infections are symptomatic, greater than 85% of infected individuals develop chronic, persistent infection. Treatment costs for HCV infection have been estimated at $5.46 billion for the US in 1997. Worldwide over 200 million people are estimated to be infected chronically. HCV infection is responsible for 40-60% of all chronic liver disease and 30% of all liver transplants. Chronic HCV infection accounts for 30% of all cirrhosis, end-stage liver disease, and liver cancer in the U.S. The CDC estimates that the number of deaths due to HCV will minimally increase to 38,000/year by the year 2010.

Due to the high degree of variability in the viral surface antigens, existence of multiple viral genotypes, and demonstrated specificity of immunity, the development of a successful vaccine in the near future is unlikely. Alpha-interferon (alone or in combination with ribavirin) has been widely used since its approval for treatment of chronic HCV infection. However, adverse side effects are commonly associated with this treatment: flu-like symptoms, leukopenia, thrombocytopenia, depression from interferon, as well as anemia induced by ribavirin (Lindsay, K.L. (1997) Hepatology 26 (suppl 1): 71S-77S). This therapy remains less effective against infections caused by HCV genotype 1 (which constitutes -75% of all HCV infections in the developed markets) compared to infections caused by the other 5 major HCV genotypes. Unfortunately, only -50-80% of the patients respond to this treatment (measured by a reduction in serum HCV RNA levels and normalization of liver enzymes) and, of those treated, 50-70% relapse within 6 months of cessation of treatment. Recently, with the introduction of pegylated interferon, both initial and sustained response rates have improved substantially, and combination treatment of Peg-IFN with ribavirin constitutes the gold standard for therapy. However, the side effects associated with combination therapy and the impaired response in patients with genotype 1 present opportunities for improvement in the management of this disease. First identified by molecular cloning in 1989 (Choo, Q-L et al (1989) Science 244:359- 362), hepatitis C virus (HCV) is now widely accepted as the most common causative agent of post-transfusion non A, non-B hepatitis (NANBH) (Kuo, G et al (1989) Science 244:362-364). Due to its genome structure and sequence homology, this virus was assigned as a new genus in the Flaviviridae family. Like the other members of the Flaviviridae, such as flaviviruses (e.g. yellow fever virus and Dengue virus types 1-4) and pestiviruses (e.g. bovine viral diarrhea virus, border disease virus, and classic swine fever virus) (Choo, Q-L et al (1989) Science 244:359-3; Miller, R.H. and R.H. Purcell (1990) Proc. Natl. Acad. Sci. USA 87:2057-2061), HCV is an enveloped virus containing a single strand RNA molecule of positive polarity. The HCV genome is approximately 9.6 kilobases (kb) with a long, highly conserved, noncapped 5¹ nontranslated region (NTR) of approximately 340 bases which functions as an internal ribosome entry site (IRES) (Wang CY et al 'An RNA pseudoknot is an essential structural element of the internal ribosome entry site located within the hepatitis C virus 5' noncoding region' RNA- A Publication of the RNA Society. 1 (5): 526-537, 1995 JuI.). This element is followed by a region which encodes a single long open reading frame (ORF) encoding a polypeptide of -3000 amino acids comprising both the structural and nonstructural viral proteins.

Upon entry into the cytoplasm of the cell, this RNA is directly translated into a polypeptide of -3000 amino acids comprising both the structural and nonstructural viral proteins. This large polypeptide is subsequently processed into the individual structural and nonstructural proteins by a combination of host and virally-encoded proteinases (Rice, CM. (1996) in B.N. Fields, D.M.Knipe and P.M. Howley (eds) Virology 2^nd Edition, p931-960; Raven Press, N.Y.). Following the termination codon at the end of the long ORF, there is a 3¹ NTR which roughly consists of three regions: an ~ 40 base region which is poorly conserved among various genotypes, a variable length poly(U)/polypyrimidine tract, and a highly conserved 98 base element also called the "3¹ X-tail" (Kolykhalov, A. et al (1996) J. Virology 70:3363-3371 ; Tanaka, T. et al (1995) Biochem Biophys. Res. Commun. 215:744-749; Tanaka, T. et al (1996) J. Virology 70:3307-3312; Yamada, N. et al (1996) Virology 223:255-261). The 3¹ NTR is predicted to form a stable secondary structure which is essential for HCV growth in chimps and is believed to function in the initiation and regulation of viral RNA replication.

Based on the foregoing, there exists a significant need to identify synthetic or biological compounds for their ability to inhibit HCV. SUMMARY OF THE INVENTION

The present invention includes a method for the treatment or prophylaxis of Flaviviridae viruses through administration of a compound of formula (I):

wherein: each R¹ independently is halogen, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, -R¹⁰cycloalkyl, Ay, AyR⁴, AyOR⁴ -NHR¹⁰Ay, Het, HetR⁴, HetOR⁴, -

NHHet, -NHR¹⁰Het, -OR⁴, -OAy, -OHet, -R¹⁰OR⁴, -NR⁴R⁵, -NR⁴Ay, -R¹⁰NR⁴R⁵, -

R¹⁰NR⁴Ay, -R¹⁰C(O)R⁴, -C(O)R⁴, -CO₂R⁴, -R¹⁰CO₂R⁴, -C(O)NR⁴R⁵, -C(O)Ay, -C(O)NR⁴Ay, -

C(O)Het, -C(O)NHR¹⁰Het, -R¹⁰C(O)NR⁴R⁵, -C(S)NR⁴R⁵, -R¹⁰C(S)NR⁴R⁵, -

R¹⁰NHC(NH)NR⁴R⁵, -C(NH)NR⁴R⁵, -R¹⁰C(NH)NR⁴R⁵, -S(O)₂NR⁴R⁵, -S(O)₂NR⁴Ay, -

R¹⁰SO₂NHCOR⁴, -R¹⁰SO₂NR⁴R⁵, -R¹⁰SO₂R⁴, -S(O)₁₇₁R⁴, cyano, nitro, or azido; p is 0, 1 , 2, 3, or 4; n is O or 1 ; m is 0, 1 , or 2;

X is selected from a group consisting of C(O), C(O)O, C(O)Y, S(O), SO₂, S(O)Y, SO₂Y,

C(O)OY, C(O)NHY, C(O)YN(H)C(O)OY; each Y independently is optionally substituted alkylene, optionally substituted cycloalkylene, optionally substituted alkenylene, optionally substituted cycloalkenylene, or optionally substituted alkynylene;

R² is -Ay or -Het, each optionally substituted with one or more halogen, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, -R¹⁰cycloalkyl, Ay, AyR⁴, AyOR⁴ -NHR¹⁰Ay, Het,

HetR⁴, HetOR⁴, -NHHet, -NHR¹⁰Het, -OR⁴, -OAy, -OHet, -R¹⁰OR⁴, -NR⁴R⁵, -NR⁴Ay, -R¹⁰NR⁴R⁵,

-R¹⁰NR⁴Ay, -R¹⁰C(O)R⁴, -C(O)R⁴, -CO₂R⁴, -R¹⁰CO₂R⁴, -C(O)NR⁴R⁵, -C(O)Ay₁ -C(O)NR⁴Ay, -

C(O)Het, -C(O)NHR¹⁰Het, -R¹⁰C(O)NR⁴R⁵, -C(S)NR⁴R⁵, -

R¹⁰C(S)NR⁴R⁵, -R¹⁰NHC(NH)NR⁴R⁵, -C(NH)NR⁴R⁵, -R¹⁰C(NH)NR⁴R⁵, -S(O)₂NR⁴R⁵, -

S(O)₂NR⁴Ay₁ -R¹⁰SO₂NHCOR⁴, -R¹⁰SO₂NR⁴R⁵, -R¹⁰SO₂R⁴, -S(O)_mR⁴, cyano, nitro, or azido;

R³ is alkyl, -Ay or -Het, where Ay or Het may each be optionally substituted with one or more halogen, haloalkyi, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, -R¹⁰cycloalkyl, Ay, AyR⁴,

AyOR⁴ -NHR¹⁰Ay, Het, HetR⁴, HetOR⁴, -NHHet, -NHR¹⁰Het, -OR⁴, -OAy, -OHet, -R¹⁰OR⁴, -

NR⁴R⁵, -NR⁴Ay, -R¹⁰NR⁴R⁵, -R¹⁰NR⁴Ay, -R¹⁰C(O)R⁴, -C(O)R⁴, -CO₂R⁴, -R¹⁰CO₂R⁴, -C(O)NR⁴R⁵, -C(O)Ay, -C(O)NR⁴Ay, -C(O)Het, -C(O)NHR¹⁰Het, -R¹⁰C(O)NR⁴R⁵, -C(S)NR⁴R⁵, -

S(O)₂NR⁴Ay, -R¹⁰SO₂NHCOR⁴, -R¹⁰SO₂NR⁴R⁵, -R¹⁰SO₂R⁴, -S(0)_mR⁴, cyano, nitro, or azido; each of R⁴ and R⁵ is independently selected from H or alkyl; each R¹⁰ is an optionally substituted alkylene;

Ay represents an aryl group;

Het represents a 5- or 6-membered heterocyclyl or heteroaryl group; the method including administration of pharmaceutically acceptable salts, solvates, and physiologically functional derivatives thereof.

Preferably, the Flaviviridae virus is a flavivirus, a pestivirus, or a hepacivirus. More particularly, the virus is associated with a human disease selected from dengue fever, yellow fever, west nile virus, and HCV. Further, preferably the method is for the treatment or prophylaxis of HCV infection.

In one embodiment of the present invention, R¹ is selected from halogen, alkyl, cyano, nitro, -OR⁴, Het, -NR⁴R⁵, or -CONR⁴R⁵. Preferably R¹ is halogen or alkyl. Preferably R¹ is F, Cl, Br, or I. More preferably R¹ is Cl or Br.

In one embodiment p is 1 and R¹ is substituted para to the depicted indole nitrogen atom.

In one embodiment R² is Ay. Preferably Ay is phenyl substituted with one or two substituents. Preferably Ay is phenyl optionally substituted with halogen, alkyl, cyano, nitro, -OR⁴, Het, -NR⁴R⁵, or -CONR⁴R⁵. Preferably Ay is phenyl optionally substituted with halogen, alkyl, cyano, -OR⁴, -NR⁴R⁵, Or -CONR⁴R⁵.

In one embodiment R² is Het. Preferably Het is dihydrobenzofuran or piperonyl.

In one embodiment n is 1 and X is selected from C(O), C(O)O, C(O)Y, C(O)OY, C(O)NHY, or SO₂Y. Preferably X is selected from C(O)Y, C(O)O, C(O)OY, or C(O)NHY. Preferably, further, R³ is alkyl, Ay, or Het. Preferably R³ is alkyl or Ay.

In one embodiment n is O and R³ is Het. Preferably R³ is Het optionally substituted with one or more of halogen, alkyl, cyano, nitro, -OR⁴, Het, Ay, -NR⁴R⁵, or -CONR⁴R⁵.

The present invention includes embodiments in which each variable in Formula (I) is selected from the groups particularly identified herein.

Particularly preferred compounds include:

Methyl 6-chloro-1 -(4-methylphenyl)-1 ,3,4,9-tetrahydro-2H-β-carboline-2-carboxylate; 6-Chloro-1-(4-methylphenyl)-2-(3-phenylpropanoyl)-2,3,4,9-tetrahydro-1 H-β-carboline; Phenylmethyl 6-chloro-1 -(4-methylphenyl)-1 ,3,4,9-tetrahydro-2H-β-carboline-2-carboxylate; Methyl 6-f luoro-1 -(4-methylphenyl)-1 ,3,4,9-tetrahydro-2H-β-carboline-2-carboxylate; 6-Fluoro-1-(4-methylphenyl)-2-(3-phenylpropanoyl)-2,3,4,9-tetrahydro-1H-β-carboline; Phenylmethyl 6-f luoro-1 -(4-methylphenyl)-1.SAΘ-tetrahydro^H-β-carboline^-carboxylate; Methyl 6-bromo-1 -(4-methylphenyl)-1 ,3,4,9-tetrahydro-2H-β-carboline-2-carboxylate; 6-Bromo-1-(4-methylphenyl)-2-(3-phenylpropanoyl)-2,3,4,9-tetrahydro-1 H-β-carboline; Phenylmethyl 6-bromo-1 -(4~methylphenyl)-1 ,3,4,9-tetrahydro-2H-β-carboline-2-carboxylate; (1 R)-6-Chloro-1 -(4-methylphenyl)-2-(3-phenylpropanoyl)-2₎3,4,9-tetrahydro-1 H-β-carboline; (1 S)-6-Chloro-1 -(4-methylphenyl)-2-(3-phenylpropanoyl)-2,3,4,9-tetrahydro-1 H-β-carboline; 1-(4-Methylphenyl)-2-[(phenylmethyl)sulfonyl]-2,3,4,9-tetrahydro-1 H-β-carboline; 1-(4-Methylphenyl)-2-(methylsulfonyl)-2,3,4,9-tetrahydro-1 H-β-carboline; (4-{[1-(4-Methylphenyl)-1 ,3,4,9-tetrahydro-2H-b-carbolin-2-yl]sulfonyl}phenyl)amine. 2-Acetyl-1-(4-methylphenyl)-2,3,4,9-tetrahydro-1 H-β-carboline; 1-(4-Methylphenyl)-2-(3-phenylpropanoyl)-2,3,4,9-tetrahydro-1 H-β-carboline; 1-(4-Methylphenyl)-2-(3-phenyl-2-propynoyl)-2,3,4,9-tetrahydro-1 H-b-carboline; 1-(4-Methylphenyl)-2-[3-(3-pyridinyl)propanoyl]-2,3,4,9-tetrahydro-1 H-β-carboline; Phenylmethyl {2-[1 -(4-methylphenyl)-1 ,3,4,9-tetrahydro-2H-b-carbolin-2-yl]-2- oxoethyl}carbamate;

6-(Methyloxy)-1-(4-methylphenyl)-2-(3-phenylpropanoyl)-2,3,4,9-tetrahydro-1 H-β-carboline; 8-Methyl-1-(4-methylphenyl)-2-(3-phenylpropanoyl)-2,3,4,9-tetrahydro-1 H-β-carboline; 6-Methyl-1-(4-methylphenyl)-2-(3-phenylpropanoyl)-2,3,4,9-tetrahydro-1 H-β-carboline; 7-Fluoro-1-(4-methylphenyl)-2-(3-phenylpropanoyl)-2,3,4,9-tetrahydro-1 H-β-carboline; 7-(Methyloxy)-1-(4-methylphenyl)-2-(3-phenylpropanoyl)-2,3,4,9-tetrahydro-1 H-β-carboline; (1 R/1 S)-1 -(2,3-dihydro-1 -benzof uran-5-yl)-2-[(2E)-3-phenyl-2-propenoyl]-2,3,4,9-tetrahydro-1 H- β-carboline;

(1 R)-1 -(2,3-dihydro-1 -benzof uran-5-yl)-2-[(2E)-3-phenyl-2-propenoyl]-2,3,4,9-tetrahydro-1 H-β- carboline;

(1 S)-1 -(2,3-dihydro-1 -benzof uran-5-yl)-2-[(2E)-3-phenyl-2-propenoyl]-2,3,4,9-tetrahydro-1 H-β- carboline;

1 -(1 ,3-benzodioxol-5-yl)-2-{4-[4-(methyloxy)phenyl]-2-pyrimidinyl}-2,3,4,9-tetrahydro-1 H-β- carboline;

1 -(1 ,3-benzodioxol-5-yl)-2-(2-pyrimidinyl)-2,3,4,9-tetrahydro-1 H-β-carboline; 1 -(1 ,3-benzodioxol-5-yl)-2-(4-phenyl-2-pyrimidinyl)-2,3,4,9-tetrahydro-1 H-β-carboline; 1-phenyl-2-(4-phenyl-2-pyrimidinyl)-2,3,4,9-tetrahydro-1 H-β-carboline; 1-(2,3-dihydro-1-benzofuran-5-yl)-2-(4-phenyl-2-pyrimidinyl)-2,3,4,9-tetrahydro-1 H-β-carboline; 1-(2,3-dihydro-1-benzofuran-5-yl)-2-[4-(3-pyridinyl)-2-pyrimidinyl]-2,3,4,9-tetrahyclro-1 H-β- carboline;

1 -(2,3-dihydro-1 -benzof uran-5-yl)-2-[4-(1 H-imidazol-1 -yl)-2-pyrimidinyl]-2,3,4,9-tetrahydro-1 H-β- carboline;

1 -(2,3-dihydro-1 -benzof uran-5-yl)-2-[4-(4-methyl-1 H-imidazol-1 -yl)-2-pyrimidinyl]-2,3,4,9- tetrahydro-1 H-β-carboline;

1 -(2,3-dihydro-1 -benzof uran-5-yl)-2-[4-(4-methyl-1 H-imidazol-1 -yl)-2-pyrimidinyl]-2,3,4,9- tetrahydro-1 W-β-carboline, including pharmaceutically acceptable salts, solvates, and physiologically functional derivatives thereof.

Further, preferred compounds include:

Methyl 6-chloro-1 -(4-methylphenyl)-1 ,3,4,9-tetrahydro-2H-β-carboline-2-carboxylate; 6-Chloro-1-(4-methylphenyl)-2-(3-phenylpropanoyl)-2,3,4,9-tetrahydro-1H-β-carboline; Phenylmethyl 6-chloro-1 -(4-methylphenyl)-1 ,3,4,9-tetrahydro-2H-β-carboline-2-carboxylate; Methyl 6-f luoro-1 -(4-methylphenyl)-1 ,3,4,9-tetrahydro-2H-β-carboline-2-carboxylate; 6-Fluoro-1-(4-methylphenyl)-2-(3-phenylpropanoyl)-2,3,4,9-tetrahydro-1 H-β-carboline; Phenylmethyl 6-fluoro-1 -(4-methylphenyl)-1 ,3,4,9-tetrahydro-2H-β-carboline-2-carboxylate; Methyl 6-bromo-1 -(4-methylphenyl)-1 ,3,4,9-tetrahydro-2H-β-carboline-2-carboxylate; 6-Bromo-1-(4-methylphenyl)-2-(3-phenylpropanoyl)-2,3,4,9-tetrahydro-1 H-β-carboline; Phenylmethyl 6-bromo-1 -(4-methylphenyl)-1 ,3,4,9-tetrahydro-2H-β-carboline-2-carboxylate; (1 S)-6-Chloro-1 -(4-methylphenyl)-2-(3-phenylpropanoyl)-2,3,4,9-tetrahydro-1 H-β-carboline; 6-(Methyloxy)-1-(4-methylphenyl)-2-(3-phenylpropanoyl)-2,3,4,9-tetrahydro-1H-β-carboline; and 6-Methyl-1-(4-methylphenyl)-2-(3-phenylpropanoyl)-2,3,4,9-tetrahydro-1 H-β-carboline, including pharmaceutically acceptable salts, solvates, and physiologically functional derivatives thereof.

Still further, preferred compounds include:

Methyl 6-chloro-1 -(4-methylphenyl)-1 ,3,4,9-tetrahydro-2H-β-carboline-2-carboxylate; 6-Chloro-1-(4-methylphenyl)-2-(3-phenylpropanoyl)-2,3,4,9-tetrahydro-1 H-β-carboline; Phenylmethyl 6-chloro-1 -(4-methylphenyl)-1 ,3,4,9-tetrahydro-2H-β-carboline-2-carboxylate; Methyl 6-bromo-1 -(4-methylphenyl)-1 ,3,4,9-tetrahydro-2H-β-carboline-2-carboxylate; 6-Bromo-1-(4-methylphenyl)-2-(3-phenylpropanoyl)-2,3,4,9-tetrahydro-1 H-β-carboline; Phenylmethyl 6-bromo-1-(4-methylphenyl)-1 ,3,4,9-tetrahydro-2H-β-carboline-2-carboxylate; and (1 S)-6-Chloro-1 -(4-methylphenyl)-2-(3-phenylpropanoyl)-2,3,4,9-tetrahydro-1 H-β-carboline, including pharmaceutically acceptable salts, solvates, and physiologically functional derivatives thereof.

One aspect of the present invention includes a method for the treatment or prophylaxis of viruses belonging to Flaviviridae. Preferably the virus is a flavivirus, a pestivirus, or a hepacivirus. Further preferably the disease or condition is dengue fever, yellow fever, west nile virus, or HCV. Still further preferably the condition or disorder is HCV.

Another aspect of the present invention includes the use of a compound of formula (I):

R¹⁰SO₂NHCOR⁴, -R¹⁰SO₂NR⁴R⁵, -R¹⁰SO₂R⁴, -S(O)_mR⁴, cyano, nitro, or azido; p is 0, 1 , 2, 3, or 4; n is O or 1 ; m is 0, 1 , or 2;

HetR⁴, HetOR⁴, -NHHet, -NHR¹⁰HeI, -OR⁴, -OAy, -OHet, -R¹⁰OR⁴, -NR⁴R⁵, -NR⁴Ay, -R¹⁰NR⁴R⁵,

-R¹⁰NR⁴Ay, -R¹⁰C(O)R⁴, -C(O)R⁴, -CO₂R⁴, -R¹⁰CO₂R⁴, -C(O)NR⁴R⁵, -C(O)Ay, -C(O)NR⁴Ay, -

C(O)Het, -C(O)NHR¹⁰Het, -R¹⁰C(O)NR⁴R⁵, -C(S)NR⁴R⁵, -

S(O)₂NR⁴Ay, -R¹⁰SO₂NHCOR⁴, -R¹⁰SO₂NR⁴R⁵, -R¹⁰SO₂R⁴, -S(O)_mR⁴, cyano, nitro, or azido; R³ is alkyl, -Ay or -Het, where Ay or Het may each be optionally substituted with one or more halogen, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, -R¹⁰cycloalkyl, Ay, AyR⁴, AyOR⁴ -NHR¹⁰Ay, Het, HetR⁴, HetOR⁴, -NHHet, -NHR¹⁰Het, -OR⁴, -OAy, -OHet, -R¹⁰OR⁴, - NR⁴R⁵, -NR⁴Ay, -R¹⁰NR⁴R⁵, -R¹⁰NR⁴Ay, -R¹⁰C(O)R⁴, -C(O)R⁴, -CO₂R⁴, -R¹⁰CO₂R⁴, -C(O)NR⁴R⁵, -C(O)Ay, -C(O)NR⁴Ay, -C(O)Het, -C(O)NHR¹⁰HeI, -R¹⁰C(O)NR⁴R⁵, -C(S)NR⁴R⁵, - R¹⁰C(S)NR⁴R⁵, -R¹⁰NHC(NH)NR⁴R⁵, -C(NH)NR⁴R⁵, -R¹⁰C(NH)NR⁴R⁵, -S(O)₂NR⁴R⁵, - S(O)₂NR⁴Ay, -R¹⁰SO₂NHCOR⁴, -R¹⁰SO₂NR⁴R⁵, -R¹⁰SO₂R⁴, -S(O)_mR⁴, cyano, nitro, or azido; each of R⁴ and R⁵ is independently selected from H or alkyl; each R¹⁰ is an optionally substituted alkylene; Ay represents an aryl group;

Het represents a 5- or 6-membered heterocyclyl or heteroaryl group; including pharmaceutically acceptable salts, solvates, and physiologically functional derivatives thereof, in the manufacture of a medicament for the treatment or prophylaxis of viruses belonging to Flaviviridae. Preferably the virus is a flavivims, a pestivirus, or a hepacivirus. Further preferably the disease or condition is dengue fever, yellow fever, west nile virus, or HCV. Still further preferably the condition or disorder is HCV.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

Terms are used within their accepted meanings. The following definitions are meant to clarify, but not limit, the terms defined.

As used herein the term "alkyl" refers to a straight or branched chain hydrocarbon, preferably having from one to twelve carbon atoms, which may be optionally substituted. Examples of "alkyl" as used herein include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, n-butyl, tert-butyl, isopentyl, n-pentyl, and the like.

As used throughout this specification, the preferred number of atoms, such as carbon atoms, will be represented by, for example, the phrase "C_x-C_y alkyl," which refers to an alkyl group, as herein defined, containing the specified number of carbon atoms. Similar terminology will apply for other preferred terms and ranges as well.

As used herein the term "alkenyl" refers to a straight or branched chain aliphatic hydrocarbon containing one or more carbon-to-carbon double bonds that may be optionally substituted. Examples include, but are not limited to, vinyl, allyl, and the like.

As used herein the term "alkynyl" refers to a straight or branched chain aliphatic hydrocarbon containing one or more carbon-to-carbon triple bonds that may be optionally substituted. Examples include, but are not limited to, ethynyl and the like.

As used herein, the term "alkylene" refers to a straight or branched chain divalent hydrocarbon radical, preferably having from one to ten carbon atoms. Alkylene groups as defined herein may optionally be substituted. Examples of "alkylene" as used herein include, but are not limited to, methylene, ethylene, n-propylene, n-butylene, and the like.

As used herein, the term "alkenylene" refers to a straight or branched chain divalent hydrocarbon radical, preferably having from one to ten carbon atoms, containing one or more carbon-to-carbon double bonds that may be optionally substituted. Examples include, but are not limited to, vinylene, allylene or 2-propenylene, and the like.

As used herein, the term "alkynylene" refers to a straight or branched chain divalent hydrocarbon radical, preferably having from one to ten carbon atoms, containing one or more carbon-to-carbon triple bonds that may be optionally substituted. Examples include, but are not limited to, ethynylene and the like.

As used herein, the term "cycloalkyl" refers to an optionally substituted non-aromatic cyclic hydrocarbon ring, which optionally includes an alkylene linker through which the cycloalkyl may be attached. Exemplary "cycloalkyl" groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. As used herein, the term "cycloalkyl" includes an optionally substituted fused polycyclic hydrocarbon saturated ring and aromatic ring system, namely polycyclic hydrocarbons with less than maximum number of non-cumulative double bonds, for example where a saturated hydrocarbon ring (such as a cyclopentyl ring) is fused with an aromatic ring (herein "aryl," such as a benzene ring) to form, for example, groups such as indane.

As used herein, the term "cycloalkenyl" refers to an optionally substituted non-aromatic cyclic hydrocarbon ring containing one or more carbon-to-carbon double bonds which optionally includes an alkylene linker through which the cycloalkenyl may be attached. Exemplary "cycloalkenyl" groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like.

As used herein, the term "cycloalkylene" refers to a divalent, optionally substituted non- aromatic cyclic hydrocarbon ring. Exemplary "cycloalkylene" groups include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, including fused systems with reference to the above definition for cycloalkyl.

As used herein, the term "cycloalkenylene" refers to a divalent optionally substituted non-aromatic cyclic hydrocarbon ring containing one or more carbon-to-carbon double bonds. Exemplary "cycloalkenylene" groups include, but are not limited to, cyclopropenylene, cyclobutenylene, cyclopentenylene, cyclohexenylene, cycloheptenylene, and the like. As used herein, the term "heterocycle" or "heterocyclyl" refers to an optionally substituted mono- or polycyclic ring system containing one or more degrees of unsaturation and also containing one or more heteroatoms. Preferred heteroatoms include N, O, and/or S, including N-oxides, sulfur oxides, and dioxides. Preferably the ring is three to twelve- membered and is either fully saturated or has one or more degrees of unsaturation. Such rings may be optionally fused to one or more of another "heterocyclic" ring(s) or cycloalkyl ring(s). Examples of "heterocyclic" groups include, but are not limited to, tetrahydrofuran, pyran, 1 ,4- dioxane, 1 ,3-dioxane, piperidine, pyrrolidine, morpholine, tetrahydrothiopyran, and tetrahydrothiophene.

As used herein, the term "aryl" refers to an optionally substituted benzene ring or to an optionally substituted fused benzene ring system, for example anthracene, phenanthrene, or naphthalene ring systems. Examples of "aryl" groups include, but are not limited to, phenyl, 2- naphthyl, and 1-naphthyl.

As used herein, the term "heteroaryl" refers to an optionally substituted monocyclic five to seven membered aromatic ring, or to an optionally substituted fused bicyclic aromatic ring system comprising two of such aromatic rings. These heteroaryl rings contain one or more nitrogen, sulfur, and/or oxygen atoms, where N-oxides, sulfur oxides, and dioxides are permissible heteroatom substitutions. Additionally, the term is meant to encompass heterocycles fused with aromatic ring systems. Examples of "heteroaryl" groups used herein include, but should not be limited to, furan, thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole, oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole, pyridine, pyridazine, pyrazine, pyrimidine, quinoline, isoquinoline, benzofuran, dihydrobenzofuran, piperonyl (benzodioxolyl), benzothiophene, indole, indazole, benzimidizole, imidazopyridine, pyrazolopyridine, pyrazolopyrimidine, and substituted versions thereof.

As used herein the term "halogen" refers to fluorine, chlorine, bromine, or iodine.

As used herein the term "haloalkyl" refers to an alkyl group, as defined herein, which is substituted with at least one halogen. Examples of branched or straight chained "haloalkyl" groups useful in the present invention include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, and t-butyl substituted independently with one or more halogens, e.g., fluoro, chloro, bromo, and iodo. The term "haloalkyl" should be interpreted to include such substituents as perfluoroalkyl groups and the like.

As used herein the term "alkoxy" refers to the group -OR, where R is alkyl as defined above.

As used herein the term "alkoxycarbonyl" refers to groups such as:

where the R represents an alkyl group as herein defined. As used herein the term "aryloxycarbonyl" refers to groups such as:

where the Ay represents an aryl group as herein defined.

As used herein the term "heteroaryloxycarbonyl" refers to groups such as:

where the Het represents a heteroaryl group as herein defined.

As used herein the term "nitro" refers to the group -NO₂.

As used herein the term "cyano" refers to the group -CN.

As used herein the term "azido" refers to the group -N₃.

As used herein the term "acyl" refers to the group RC(O)-, where R is alkyl, aryl, heteroaryl, or heterocyclyl, as each is defined herein.

As used herein the term "oxo" refers to the group =0.

As used herein throughout the present specification, the phrase "optionally substituted" or variations thereof denote an optional substitution, including multiple degrees of substitution, with one or more substituent group. The phrase should not be interpreted so as to be imprecise or duplicative of substitution patterns herein described or depicted. Rather, those of ordinary skill in the art will appreciate that the phrase is included to provide for obvious modifications, which are encompassed within the scope of the appended claims.

The compounds of formulas (I) may crystallize in more than one form, a characteristic known as polymorphism, and such polymorphic forms ("polymorphs") are within the scope of formula (I). Polymorphism generally can occur as a response to changes in temperature, pressure, or both. Polymorphism can also result from variations in the crystallization process. Polymorphs can be distinguished by various physical characteristics known in the art such as x- ray diffraction patterns, solubility, and melting point.

Certain of the compounds described herein contain one or more chiral centers, or may otherwise be capable of existing as multiple stereoisomers. The scope of the present invention includes mixtures of stereoisomers as well as purified enantiomers or enantiomerically/diastereomerically enriched mixtures. Also included within the scope of the invention are the individual isomers of the compounds represented by formula (I), as well as any wholly or partially equilibrated mixtures thereof. The present invention also includes the individual isomers of the compounds represented by the formulas above as mixtures with isomers thereof in which one or more chiral centers are inverted.

T r,vipi No.: Typically, but not absolutely, the salts of the present invention are pharmaceutically acceptable salts. Salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of this invention. Salts of the compounds of the present invention may comprise acid addition salts.

Representative pharmaceutically acceptable salts include, but should not be considered limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, calcium edetate, camsylate, carbonate, clavulanate, citrate, dihydrochloride, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylsulfate, monopotassium maleate, mucate, napsylate, nitrate, N-methylglucamine, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, potassium, salicylate, sodium, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate, tosylate, triethiodide, trimethylammonium, and valerate salts. Other salts, which are not pharmaceutically acceptable, may be useful in the preparation of compounds of this invention and these should be considered to form a further aspect of the invention.

As used herein, the term "solvate" refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of Formula I, or a salt or physiologically functional derivative thereof) and a solvent. Such solvents, for the purpose of the invention, should not interfere with the biological activity of the solute. Non-limiting examples of suitable solvents include, but are not limited to water, methanol, ethanol, and acetic acid. Preferably the solvent used is a pharmaceutically acceptable solvent. Non-limiting examples of suitable pharmaceutically acceptable solvents include water, ethanol, and acetic acid. Most preferably the solvent used is water.

As used herein, the term "physiologically functional derivative" refers to any pharmaceutically acceptable derivative of a compound of the present invention that, upon administration to a mammal, is capable of providing (directly or indirectly) a compound of the present invention or an active metabolite thereof. Such derivatives, for example, esters and amides, will be clear to those skilled in the art, without undue experimentation. Reference may be made to the teaching of Burger's Medicinal Chemistry And Drug Discovery, 5^th Edition, VoI 1 : Principles and Practice, which is incorporated herein by reference to the extent that it teaches physiologically functional derivatives.

As used herein, the term "effective amount" means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought, for instance, by a researcher or clinician. The term "therapeutically effective amount" means any amount which, as compared to a corresponding

T αVip.1 No.: subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function. For use in therapy, therapeutically effective amounts of a compound of formula (I), as well as salts, solvates, and physiological functional derivatives thereof, may be administered as the raw chemical. Additionally, the active ingredient may be presented as a pharmaceutical composition.

Accordingly, the invention further provides pharmaceutical compositions that include effective amounts of compounds of the formula (I) and salts, solvates, and physiological functional derivatives thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients. The compounds of formula (I) and salts, solvates, and physiologically functional derivatives thereof, are as herein described. The carrier(s), diluent(s) or excipient(s) must be acceptable, in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient of the pharmaceutical composition.

In accordance with another aspect of the invention there is also provided a process for the preparation of a pharmaceutical formulation including admixing a compound of the formula (I) or salts, solvates, and physiological functional derivatives thereof, with one or more pharmaceutically acceptable carriers, diluents or excipients.

A therapeutically effective amount of a compound of the present invention will depend upon a number of factors. For example, the species, age, and weight of the recipient, the precise condition requiring treatment and its severity, the nature of the formulation, and the route of administration are all factors to be considered. The therapeutically effective amount ultimately should be at the discretion of the attendant physician or veterinarian. Regardless, an effective amount of a compound of formula (I) for the treatment of humans suffering from frailty, generally, should be in the range of 0.1 to 100 mg/kg body weight of recipient (mammal) per day. More usually the effective amount should be in the range of 1 to 10 mg/kg body weight per day. Thus, for a 70 kg adult mammal the actual amount per day would usually be from 70 to 700 mg. This amount may be given in a single dose per day or in a number (such as two, three, four, five, or more) of sub-doses per day such that the total daily dose is the same. An effective amount of a salt, solvate, or physiologically functional derivative thereof, may be determined as a proportion of the effective amount of the compound of formula (I) perse. Similar dosages should be appropriate for treatment of the other conditions referred to herein.

Pharmaceutical formulations may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Such a unit may contain, as a non- limiting example, 0.5 mg to 1g of a compound of the formula (I), depending on the condition being treated, the route of administration, and the age, weight, and condition of the patient. Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient. Such pharmaceutical formulations may be prepared by any of the methods well known in the pharmacy art.

Pharmaceutical formulations may be adapted for administration by any appropriate route, for example by an oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route. Such formulations may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s) or excipient(s). By way of example, and not meant to limit the invention, with regard to certain conditions and disorders for which the compounds of the present invention are believed useful certain routes will be preferable to others. Based upon the physical manifestations that are often associated with HPV infection, rectal, topical, or vaginal routes of administration may be preferable. As one example, for the treatment or prophylaxis of cervical dysplasia the preferred route may be a vaginal route.

Pharmaceutical formulations adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions, each with aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil liquid emulsions. For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Generally, powders are prepared by comminuting the compound to a suitable fine size and mixing with an appropriate pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavorings, preservatives, dispersing agents, and coloring agents can also be present.

Capsules are made by preparing a powder, liquid, or suspension mixture and encapsulating with gelatin or some other appropriate shell material. Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate, or solid polyethylene glycol can be added to the mixture before the encapsulation. A disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Examples of suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants useful in these dosage forms include, for example, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.

Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant, and pressing into tablets. A powder mixture may be prepared by mixing the compound, suitably comminuted, with a diluent or base as described above. Optional ingredients include binders such as carboxymethylcellulose, aliginates, gelatins, or polyvinyl pyrrolidone, solution retardants such as paraffin, resorption accelerators such as a quaternary salt, and/or absorption agents such as bentonite, kaolin, or dicalcium phosphate. The powder mixture can be wet-granulated with a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials, and forcing through a screen. As an alternative to granulating, the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules. The granules can be lubricated to prevent sticking to the tablet-forming dies by means of the addition of stearic acid, a stearate salt, talc or mineral oil. The lubricated mixture is then compressed into tablets. The compounds of the present invention can also be combined with a free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps. A clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material, and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different unit dosages.

Oral fluids such as solutions, syrups, and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound. Syrups can be prepared, for example, by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle. Suspensions can be formulated generally by dispersing the compound in a non-toxic vehicle. Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives; flavor additives such as peppermint oil, or natural sweeteners, saccharin, or other artificial sweeteners; and the like can also be added.

Where appropriate, dosage unit formulations for oral administration can be microencapsulated. The formulation can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax or the like.

The compounds of formula (I) and salts, solvates, and physiological functional derivatives thereof, can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines. The compounds of formula (I) and salts, solvates, and physiologically functional derivatives thereof may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.

The compounds may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone (PVP), pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethyl-aspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues. Furthermore, the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug; for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels.

Pharmaceutical formulations adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. For example, the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3(6), 318 (1986), incorporated herein by reference as related to such delivery systems.

Pharmaceutical formulations adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, or oils.

For treatments of the eye or other external tissues, for example mouth and skin, the formulations may be applied as a topical ointment or cream. When formulated in an ointment, the active ingredient may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with an oil-in-water cream base or a water-in-oil base.

Pharmaceutical formulations adapted for topical administrations to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.

Pharmaceutical formulations adapted for topical administration in the mouth include lozenges, pastilles, and mouthwashes.

Pharmaceutical formulations adapted for nasal administration, where the carrier is a solid, include a coarse powder having a particle size for example in the range 20 to 500 microns. The powder is administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose. Suitable formulations wherein the carrier is a liquid, for administration as a nasal spray or as nasal drops, include aqueous or oil solutions of the active ingredient. Pharmaceutical formulations adapted for administration by inhalation include fine particle dusts or mists, which may be generated by means of various types of metered dose pressurized aerosols, nebulizers, or insufflators.

Pharmaceutical formulations adapted for rectal administration may be presented as suppositories or as enemas.

Pharmaceutical formulations adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulations.

Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.

In addition to the ingredients particularly mentioned above, the formulations may include other agents conventional in the art having regard to the type of formulation in question. For example, formulations suitable for oral administration may include flavoring or coloring agents.

The compounds of the present invention and their salts, solvates, and physiologically functional derivatives thereof, may be employed alone or in combination with other therapeutic agents. The compound(s) of formula (I) and the other pharmaceutically active agent(s) may be administered together or separately and, when administered separately, administration may occur simultaneously or sequentially, in any order. The amounts of the compound(s) of formula (I) and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect. The administration in combination of a compound of formula (I) salts, solvates, or physiologically functional derivatives thereof with other treatment agents may be in combination by administration concomitantly in: (1 ) a unitary pharmaceutical composition including both compounds; or (2) separate pharmaceutical compositions each including one of the compounds. Alternatively, the combination may be administered separately in a sequential manner wherein one treatment agent is administered first and the other second or vice versa. Such sequential administration may be close in time or remote in time.

The compounds of the present invention may be used in the treatment of a variety of disorders and conditions and, as such, the compounds of the present invention may be used in combination with a variety of other suitable therapeutic agents useful in the treatment or prophylaxis of those disorders or conditions. Treatment will depend upon the nature and type of viral infection.

Alternatively, the present invention may be combined with other medical therapies including a variety of cytotoxic or antiviral agents. For example, and not meant to limit the invention, the compounds of the present invention may be combined with other therapeutic agents such as immune therapies (such as interferon), therapeutic vaccines, antifibrotic agents, anti-inflammatory agents (such as corticosteroids or NSAIDs), bronchodilators such as beta-2 adrenergic agonists and xanthines (such as theophylline), mucolytic agents, anti-muscarinics, anti-leukotrienes, inhibitors of cell adhesion (such as ICAM antagonists), anti-oxidants (such as N-acetylcysteine), cytokine agonists, cytokine antagonists, lung surfactants and/or antimicrobial and anti-viral agents (such as ribavirin and amantidine). The compositions according to the invention may also be used in combination with gene replacement therapy.

The compounds of this invention may be made by a variety of methods, including well- known standard synthetic methods. Illustrative general synthetic methods are set out below and then specific compounds of the invention are prepared in the working Examples.

In all of the examples described below, protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles of synthetic chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Green and P. G. M. Wuts (1991) Protecting Groups in Organic Synthesis, John Wiley & Sons, incorporated by reference with regard to protecting groups). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection of processes as well as the reaction conditions and order of their execution shall be consistent with the preparation of compounds of formula (I).

Those skilled in the art will recognize if a stereocenter exists in compounds of formula (I). Accordingly, the present invention includes all possible stereoisomers and includes not only racemic compounds but the individual enantiomers as well. When a compound is desired as a single enantiomer, such may be obtained by stereospecific synthesis, by resolution of the final product or any convenient intermediate, or by chiral chromatographic methods as are known in the art. Resolution of the final product, an intermediate, or a starting material may be effected by any suitable method known in the art. See, for example, Stereochemistry of Organic Compounds by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-lnterscience, 1994), incorporated by reference with regard to stereochemistry. EXPERIMENTAL SECTION

As used herein the symbols and conventions used in these processes, schemes and examples, regardless of whether a particular abbreviation is specifically defined, are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry. Specifically, but without limitation, the following abbreviations may be used in the examples and throughout the specification: g (grams); mg (milligrams);

L (liters); mL (milliliters); μl_ (microliters); psi (pounds per square inch);

M (molar); mM (millimolar);

Hz (Hertz); MHz (megahertz); mol (moles); mmol (millimoles);

RT (room temperature); h (hours); min (minutes); TLC (thin layer chromatography); mp (melting point); RP (reverse phase);

T_r (retention time); TFA (trifluoroacetic acid);

TEA (triethylamine); THF (tetrahydrofuran);

TFAA (trifluoroacetic anhydride); CD₃OD (deuterated methanol);

CDCI₃ (deuterated chloroform); DMSO (dimethylsulfoxide);

SiO₂ (silica); atm (atmosphere);

EtOAc (ethyl acetate); CHCI₃ (chloroform);

HCI (hydrochloric acid); Ac (acetyl);

DMF (Λ/,Λ/-dimethylformamide); Me (methyl);

Cs₂CO₃ (cesium carbonate); EtOH (ethanol);

Et (ethyl); tBu (tert-butyl);

MeOH (methanol).

Unless otherwise indicated, all temperatures are expressed in ⁰C (degrees Centigrade). All reactions conducted at room temperature unless otherwise noted.

¹H NMR spectra were recorded on a Varian VXR-300, a Varian Unity-300, a Varian Unity-400 instrument, or a General Electric QE-300. Chemical shifts are expressed in parts per million (ppm, δ units). Coupling constants are in units of hertz (Hz). Splitting patterns describe apparent multiplicities and are designated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), or br (broad). Mass spectra were obtained on Micromass Platform or ZMD mass spectrometers from Micromass Ltd., Altricham, UK, using either Atmospheric Chemical Ionization (APCI) or Electrospray Ionization (ESI).

Analytical thin layer chromatography was used to verify the purity of intermediate(s) which could not be isolated or which were too unstable for full characterization as well as to follow the progress of reaction(s).

The absolute configuration of compounds were assigned by Ab lnitio Vibrational Circular Dichroism (VCD) Spectroscopy¹'². The experimental VCD spectrum were acquired in CDCI₃ using a Bomem ChirallR™ VCD spectrometer operating between 2000 and 800 cm^"1. The Gaussian 98 suite of computational programs were used to calculate model VCD spectrums³. The stereochemical assignment were made by comparing this experimental spectrum to the VCD spectrum calculated for a model structure with (R) or (S)-configuration.

1. J. R. Chesseman, et al, Chem. Phys. Lett. 252 (1996) 211.

2. PJ. Stephens and FJ. Devlin, Chirality 12 (2000) 172.

3. Gaussian 98, Revision A.11.4, M.J. Frisch, et al, Gaussian, Inc., Pittsburgh PA, 2002.

Compounds of formula (I) can be prepared by any suitable method known to one skilled in the art or by the process outlined below:

reagent

A compound of formula (IV) can be prepared by a Pictet-Spangler type reaction between a tryptamine of formula (II) and a benzaldehyde of formula (III). The reaction can be performed in a suitable solvent in the presence of an acid and optionally with heating. Suitable solvents include halogenated hydrocarbon solvents (e.g. dichloromethane), aromatic hydrocarbon solvents (e.g. toluene) and the like. Suitable acids include hydrochloric acid, trifluoroacetic acid. This reaction can also be run under conditions that facilitate removal of water, e.g. in toluene using a Dean Stark apparatus. Compounds of formula Il and formula III are commercially available or can be prepared as described in known literature.

Compound of formula (I) can be prepared by condensation of compound of formula (IV) and compound of formula (V) in a suitable solvent optionally in the presence of base, optionally with heating. Suitable solvents include halogenate solvents (e.g. dichloromethane), aromatic hydrocarbon solvents (e.g. toluene), N,N-dimethylformamide, dimethylsulfoxide, acetonitrile, nitromethane and the like. Suitable bases include triethylamine, diisopropylethylamine, dimethylaminopyridine, pyridine and the like.

Alternatively, compounds of formula (I) can be prepared by reaction of compound of formula (IV) and compound of formula (VI). The reaction can be carried out in the presence of suitable copling reagents, such as 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1 -hydroxybenzotriazole in a suitable solvent. Suitable solvents include dimethylformamide, dichloromethane, and the like.

EXAMPLES

Example 1 : 6-Chloro-1 -(4-methylphenyl)-2.3 ,4,9-tetrahvdro-1 H-β-carboline.

A suspension of 5-chlorotryptamine hydrochloride (3.70 g, 16.0 mmol) and p-tolualdehyde (1.80 ml_, 15.2 mmol) in glacial acetic acid (50 mL) was heated at 8O⁰C overnight. The resulting precipitate was collected by filtration, rinsed with hexane and dried briefly. The solid was then stirred with dichloromethane and 10% aqueous sodium carbonate until all of the solids had dissolved. The layers were separated, and the aqueous layer was washed again with dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated to afford 6-chloro-1-(4-methylphenyl)-2,3,4,9-tetrahydro-1 H-β- carboline (4.37 g, 92% yield) as a white solid. ¹H NMR (DMSO-d₆): δ 10.60 (s, 1 H), 7.46 (d, 1 H), 7.25 - 7.17 (m, 5H), 7.01 (dd, 1 H), 5.06 (s, 1H), 3.09 (m, 1H), 2.94 (m, 1 H), 2.71 (m, 3H)₁ 2.32 (s, 3H); MS m/z 297 (M+1).

Example 2: Methyl 6-chloro-1-ta-methylphenylH ,3,4.9-tetrahvdro-2H-β-carboline-2- carboxylate.

To a solution of 6-chloro-1-(4-methylphenyl)-2,3,4,9-tetrahydro-1 H-β-carboline (87 mg, 0.29 mmol) and 4-(dimethylamino)pyridine (54 mg, 0.44 mmol) in dichloromethane (3 mL) was added methyl chloroformate (23 μl_, 0.29 mmol). After stirring at room temperature for 3 h, the reaction was diluted with aqueous sodium bicarbonate and stirred for 15 min, then filtered through a hydrophobic frit. The aqueous layer was stirred with additonal dichloromethane and the filtration was repeated. The combined organic layers were concentrated and purified by silica gel chromatography using a gradient of 0 to 40% ethyl acetate in hexane to afford methyl 6-chloro-1-(4-methylphenyl)-1 ,3,4,9-tetrahydro-2H-β-carboline-2-carboxylate (102 mg, 98%) as a white solid. ¹H NMR (DMSO-d₆): δ 11.12 (bs, 1H), 7.51 (d, 1H), 7.30 (d, 1H), 7.17 (m, 2H), 7.11 - 7.06 (m, 3H), 6.35 (br, 1H), 4.15 (br, 1 H), 3.69 (s, 3H), 3.04 (m, 1 H), 2.77 (m, 2H), 2.28 (s, 3H); MS m/z 355 (M+1).

Example 3: 6-Chloro-1-(4-methylphenyl)-2-(3-phenylpropanoyl)-2.3,4,9-tetrahvdro-1 H-β- carboline.

6-Chloro-1 -(4-methylphenyl)-2-(3-phenylpropanoyl)-2,3,4,9-tetrahydro-1 H-β-carboline was prepared from 6-chloro-1-(4-methylphenyl)-2,3,4,9-tetrahydro-1 H-β-carboline (87 mg, 0.29 mmol) and hydrocinnamoyl chloride in a similar manner as described above to give a white solid (115 mg, 91%). ¹H NMR (DMSOd₆): δ 11.18 and 10.95 (s, 1 H, major and minor conformers), 7.50 (d, 1 H), 7.31 - 7.21 (m, 5H), 7.16 - 7.06 (m, 6H), 6.85 and 6.24 (s, 1 H, major and minor conformers), 4.71 and 4.00 (m, 1 H, minor and major conformers), 3.14 (m, 1H), 2.91 - 2.67 (m, 6H), 2.28 (s, 3H); MS m/z 429 (M+1).

Example 4: Phenylmethyl 6-chloro-1-(4-methylphenyl)-1 ,3,4,9-tetrahvdro-2H-β-carboline-2- carboxylate.

Phenylmethyl 6-chloro-1 -(4-methylphenyl)-1 ,3,4,9-tetrahydro-2H-β-carboline-2-carboxylate was prepared from 6-chloro-1-(4-methylphenyl)-2,3,4,9-tetrahydro-1 H-β-carboline (87 mg, 0.29 mmol) and benzyl chloroformate in a similar manner as described above to give an off-white solid (93 mg, 74%). ¹H NMR (DMSOd₆): δ 11.10 (br, 1 H), 7.52 (d, 1 H), 7.39 - 7.06 (m, 11 H), 6.35 (br, 1H), 5.22 - 5.12 (m, 2H), 4.21 (br, 1 H), 3.07 (m, 1 H), 2.79 (m, 2H), 2.28 (s, 3H); MS m/z 431 (M+1).

Example 5: 6-Fluoro-1 -(4-methvlphenvO-2.3,4,9-tetrahvdro-1 H-β-carboline.

6-Fluoro-1-(4-methylphenyl)-2,3,4,9-tetrahydro-1H-β-carboline was prepared from 5- fluorotryptamine hydrochloride (0.52 g, 2.44 mmol) in a similar manner as described above to give a white solid (0.53 g, 78%). ¹H NMR (DMSO-d₆): δ 10.42 (s, 1 H), 7.17 - 7.13 (m, 6H), 6.82 - 6.77 (m, 1 H), 5.00 (s, 1 H), 3.02 (m, 1 H), 2.89 (m, 1 H), 2.65 (m, 3H), 2.27 (s, 3H); MS m/2281 (M+1).

Example 6: Methyl 6-fluoro-1-(4-methylphenyl)-1 ,3,4,9-tetrahvdro-2H-β-carboline-2- carboxylate.

Methyl 6-fluoro-1-(4-methylphenyl)-1 ,3,4,9-tetrahydro-2H-β-carboline-2-carboxylate was prepared from 6-fluoro-1-(4-methylphenyl)-2,3,4,9-tetrahydro-1 H-β-carboline (63 mg, 0.20 mmol) and methyl chloroformate in a similar manner as described above to give a white solid (48 mg, 63%). ¹H NMR (DMSOd₆): δ 11.01 (bs, 1H), 7.29 - 7.06 (m, 6H), 6.91 (m, 1H), 6.35 (br, 1H), 4.15 (br, 1H), 3.69 (s, 3H), 3.04 (m, 1H), 2.75 (m, 2H), 2.28 (s, 3H); MS m/z 339 (M+1).

Example 7: 6-Fluoro-1 -(4-methylphenylV2-(3-phenylpropanoyl)-2,3,4,9-tetrahvdro-1 H-β- carboline.

6-Fluoro-1 -(4-methylphenyl)-2-(3-phenylpropanoyl)-2,3,4,9-tetrahydro-1 H-β-carboline was prepared from 6-fluoro-1-(4-methylphenyl)-2,3,4,9-tetrahydro-1 H-β-carboline (63 mg, 0.20 mmol) and hydrocinnamoyl chloride in a similar manner as described above to give a white foam (85 mg, 91%). ¹H NMR (DMSOd₆): δ 11.07 and 10.84 (s, 1H, major and minor conformers), 7.30 - 7.03 (m, 11 H), 6.91 (m, 1H), 6.84 and 6.23 (s, 1H, major and minor conformers), 4.71 and 4.03 (m, 1 H, minor and major conformers), 3.14 (m, 1 H), 2.89 - 2.67 (m, 6H), 2.28 (s, 3H); MS m/z 413 (M+1).

Example 8: Phenylmethyl 6-fluoro-1-(4-methylphenylH ,3.4.9-tetrahvdro-2H-β-carboline-2- carboxylate.

Phenylmethyl 6-fluoro-1-(4-methylphenyl)-1 ,3,4,9-tetrahydro-2H-β-carboline-2-carboxylate was prepared from 6-fluoro-1-(4-methylphenyl)-2,3,4,9-tetrahydro-1H-β-carboline (63 mg, 0.20 mmol) and benzyl chloroformate in a similar manner as described above to give a white foam (83 mg, 89%). ¹H NMR (DMSOd₆): δ 10.98 (br, 1 H), 7.39 - 7.10 (m, 11H), 6.91 (m, 1 H), 6.34 (br, 1 H), 5.22 - 5.10 (m, 2H), 4.21 (br, 1 H), 3.07 (m, 1 H), 2.76 (s, 2H), 2.28 (s, 3H); MS m/z 415 (M+1).

Example 9: 6-Bromo-1 -(4-methylphenyl)-2,3 A9-tetrahydro-1 H-β-carboline.

6-Bromo-1 -(4-methylphenyl)-2,3,4,9-tetrahydro-1 H-β-carboline was prepared from 5- bromotryptamine hydrochloride (0.47 g, 1.78 mmol) in a similar manner as described above to give a white solid (0.49 g, 80%). ¹H NMR (DMSOd₆): δ 10.59 (s, 1 H), 7.57 (d, 1 H), 7.18 - 7.08 (m, 6H), 5.03 (s, 1 H), 3.05 (m, 1 H), 2.91 (m, 1 H), 2.68 (m, 3H), 2.29 (s, 3H); MS m/z 341 (M+1).

Example 10: Methyl 6-bromo-1-(4-methylphenyl'>-1.3,4,9-tetrahvdro-2H-β-carboline-2- carboxylate.

Methyl 6-bromo-1-(4-methylphenyl)-1 ,3,4,9-tetrahydro-2H-β-carboline-2-carboxylate was prepared from 6-bromo-1-(4-methylphenyl)-2,3,4,9-tetrahydro-1H-β-carboline (60 mg, 0.18 mmol) and methyl chloroformate in a similar manner as described above to give a white foam (49 mg, 70%). ¹H NMR (DMSOd₆): δ 11.14 (s, 1H), 7.65 (d, 1 H), 7.26 (m, 1 H), 7.20 - 7.16 (m, 3H), 7.10 (m, 2H), 6.30 (br, 1 H), 4.14 (br, 1 H), 3.69 (s, 3H)₁ 3.04 (m, 1 H), 2.78 (m, 2H), 2.28 (s, 3H); MS m/z 399 (M+1).

Example 11 : 6-Bromo-1 -(4-methylphenylV2-(3-phenylpropanoylV2.3,4,9-tetrahvdro-1 H-β- carboline.

6-Bromo-1 -(4-methylphenyl)-2-(3-phenylpropanoyl)-2,3,4,9-tetrahydro-1 H-β-carboline was prepared from 6-bromo-1-(4-methylphenyl)-2,3,4,9-tetrahydro-1 H-β-carboline (60 mg, 0.18 mmol) and hydrocinnamoyl chloride in a similar manner as described above to give a white solid (71 mg, 86%). ¹H NMR (DMSO-d₆): δ 11.19 and 10.96 (s, 1H, major and minor conformers), 7.64 (d, 1H), 7.29 - 7.10 (m, 9H), 7.06 (m, 2H), 6.84 and 6.24 (s, 1 H, major and minor conformers), 4.70 and 4.03 (m, 1 H, minor and major conformers), 3.14 (m, 1 H), 2.89 - 2.68 (m, 6H), 2.28 (s, 3H); MS m/z 473 (M+1).

Example 12: Phenylmethyl 6-bromo-1-(4-methylphenylM .3,4,9-tetrahvdro-2H-B-carboline-2- carboxylate.

Phenylmethyl 6-bromo-1-(4-methylphenyl)-1 ,3,4,9-tetrahydro-2H-β-carboline-2-carboxylate was prepared from 6-bromo-1-(4-methylphenyl)-2,3,4,9-tetrahydro-1 H-β-carbo[ine (60 mg, 0.18 mmol) and benzyl chloroformate in a similar manner as described above to give a white foam (83 mg, 99%). ¹H NMR (DMSOd₆): δ 11.11 (br, 1 H), 7.66 (s, 1 H), 7.48 - 7.09 (m, 11 H), 6.35 (br, 1 H), 5.22 - 5.12 (m, 2H), 4.21 (br, 1H), 3.07 (m, 1H), 2.78 (m, 2H), 2.28 (s, 3H); MS m/z 475 (M+1).

Example 13: (1 R)-6-Chloro-1 -(4-methy|phenyl)-2-(3-phenylpropanoyl)-2.3,4,9-tetrahvdro-1 H-B- carboline.

(1 R)-6-Chloro-1-(4-methylphenyl)-2-(3-phenylpropanoyl)-2,3,4,9-tetrahydro-1 H-β-carboline was prepared by separation of (1 R/1S)-6-chloro-1-(4-methylphenyl)-2-(3-phenylpropanoyl)-2,3,4,9- tetrahydro-1 H-β-carboline by supercritical fluid chromatography (Diacel OD-H, 30% methanol, 1500 psi, 40⁰C, 2 mL/min, retention time 10.0 min). Stereochemistry was assigned by vibrational circular dichroism. Example 14: (1 SV6-Chloro-1 -f4-methylDhenyl)-2-(3-phenylpropanoyl)-2.3.4.9-tetrahvdro-1 H-B- carboline.

(1 S)-6-Chloro-1 -(4-methylphenyl)-2-(3-phenylpropanoyl)-2,3,4,9-tetrahydro-1 H-β-carboline was prepared by separation of (1 R/1 S)-6-chloro-1-(4-methylphenyl)-2-(3-phenylpropanoyl)-2,3,4,9- tetrahydro-1 H-β-carboline by supercritical fluid chromatography (Diacel OD-H, 30% methanol, 1500 psi, 40⁰C, 2 mlJmin, retention time 13.0 min). Stereochemistry was assigned by vibrational circular dichroism.

Example 15; 1-(4-Methylphenyl)-2-r(phenylmethyl)sulfonyll-2,3A9-tetrahvdro-1 H-3-carboline.

¹H NMR (DMSOd₆): δ 10.82 (s, 1 H), 7.47 (d, 1 H), 7.28 (m, 2 H), 7.21 - 7.00 (m, 10H), 5.96 (s, 1H), 4.29 (s, 2H), 3.78 (dd, 1H), 3.13 (m, 1H), 2.87 (m, 1H), 2.75 (m, 1H), 2.29 (s, 3H); MS m/z 417 (M+1). Example 16: 1 -(4-Methvlphenvn-2-(methvlsulfonvπ-2,3.4.9-tetrahvdro-1 H-β-carboline.

¹H NMR (DMSO-Cl₆): δ 10.89 (s, 1H), 7.48 (d, 1H), 7.29 (d, 1H), 7.20 - 6.98 (m, 6H), 6.02 (s, 1H), 3.87 (dd, 1H), 3.18 (m, 1H), 2.97 (m, 1H), 2.80 (m, 1H), 2.78 (s, 3H), 2.29 (s, 3H); MS m/z341 (M+1).

Example 17: (4-([1-(4-Methylphenvn-1 ,3,4.9-tetrahvdro-2H-b-carbolin-2- yllsulfonvDphenvπamine.

¹H NMR (DMSOd₆): δ 10.78 (s, 1H), 7.34 (m, 3H), 7.24 (d, 1H), 7.14 (d, 2H), 7.03 (m, 3H), 6.93 (m, 1H), 6.43 (d, 2H), 6.09 (s, 1H), 5.88 (br, 2H), 3.80 (dd, 1H)₁3.10 (m, 1H), 2.59-2.39 (m, 2H), 2.28 (s, 3H); MS m/z 418 (M+1).

Example 18: 2-Acetyl-1-(4-methylphenvO-2,3A9-tetrahvdro-1 H-β-carboline.

¹H NMR (DMSO-Cl₆): δ 10.94 and 10.79 (s, 1 H, major and minor conformers), 7.46 (d, 1 H), 7.28 (d, 1 H), 7.20 - 6.97 (m, 6H), 6.80 and 6.14 (s, 1 H, major and minor conformers), 4.68 and 3.94 (m, 1 H, minor and major conformers), 3.21 (m, 1 H), 2.91 - 2.72 (m, 2H), 2.27 (s, 3H), 2.13 (s, 3H); MS m/z 305 (M+1).

Example 19: 1-(4-Methvlphenvl)-2-(3-phenvlpropanovl)-2.3.4.9-tetrahydro-1 H-β-carboline.

¹H NMR (CDCI₃): δ 7.88 (s, 1 H), 7.52 (d, 1 H), 7.29 - 7.09 (m, 11 H), 7.02 and 5.92 (s, 1 H, major and minor conformers), 4.95 and 3.87 (m, 1 H, minor and major conformers), 3.36 (m, 1H), 3.00 (m, 2H), 2.83 (d, 2H), 2.71 (m, 2H), 2.33 (s, 3H); MS m/z 395 (M+1).

Example 20: 1 -(4-Methylphenyl)-2-(3-phenyl-2-propynoyl)-2,3,4,9-t.etrahvdro-1 H-b-carboline.

¹H NMR (CDCI₃): δ 7.75 (s, 1 H), 7.63 - 7.55 (m, 2H), 7.46 - 7.13 (m, 10H), 6.96 and 6.78 (s, 1 H, major and minor conformers), 4.83 and 4.62 (dd, 1 H, minor and major conformers), 3.56 (m, 1 H), 3.13 - 2.86 (m, 2H), 2.34 (s, 3H); MS m/z 391 (M+1 ).

Example 21 : 1 -(4-Methylphenyl)-2-r3-(3-pyridinyltoropanoyll-2.3 A9-tetrahvdro-1 H-B-carboline.

¹H NMR (DMSOd₆): δ 10.95 and 10.75 (s, 1 H, major and minor conformers), 8.50 (s, 1 H), 8.38 (d, 1 H), 7.69 (d, 1 H), 7.45 (d, 1 H), 7.27 (m, 2H), 7.15 (m, 2H), 7.08 (m, 3H), 6.99 (t, 1 H), 6.83 and 6.23 (s, 1 H, major and minor conformers), 4.72 and 4.03 (m, 1 H, minor and major conformers), 3.17 (m, 1 H), 2.92 - 2.73 (m, 6H), 2.27 (s, 3H); MS m/z 396 (M+1).

Example 22: Phenylmethyl (2-H-(4-methylphenylH .3A9-tetrahvdro-2H-b-carbolin-2-yl1-2- oxoethvDcarbamate.

¹H NMR (DMSO-d₆): δ 10.96 and 10.81 (s, 1H₁ major and minor conformers), 7.47 (d, 1H), 7.42 - 7.28 (m, 6H), 7.16 - 6.99 (m, 6H), 6.75 and 6.21 (s, 1H, major and minor conformers), 5.04 (m, 2H), 4.01 - 3.96 (m, 3H), 3.21 (m, 1 H), 2.85 (m, 2H), 2.27 (s, 3H); MS m/z 454 (M+1).

Example 23: 6-(Methyloxy)-1 -(4-methylphenyl)-2-(3-phenylpropanovn-2.3.4.9-tetrahvdro-1 H-B- carboline.

¹H NMR (DMSOd₆): δ 10.77 and 10.56 (s, 1 H, major and minor conformers), 7.26 - 7.21 (m, 4H), 7.18 - 7.13 (m, 4H), 7.07 (m, 2H), 6.94 (d, 1 H), 6.82 and 6.20 (s, 1 H, major and minor conformers), 6.71 (dd, 1H), 4.72 and 4.00 (m, 1H, minor and major conformers), 3.76 (s, 3H), 3.15 (m, 1H), 2.90 - 2.68 (m, 6H)₁ 2.28 (s, 3H); MS m/z 425 (M+1). Example 24: 8-Methyl-1 -(4-methylphenvn-2-(3-phenylpropanovn-2.3,4,9-tetrahvdro-1 H-B- carboline.

¹H NMR (DMSOd₆): δ 10.86 and 10.73 (s, 1 H, major and minor conformers), 7.28 - 7.22 (m, 5H), 7.18 - 7.07 (m, 5H), 6.93 - 6.86 (m, 3H), 6.17 (s, 1 H, minor conformer), 4.60 and 3.99 (m, 1 H₁ minor and major conformers), 3.14 (m, 1 H), 2.90 - 2.67 (m, 6H), 2.39 (s, 3H), 2.28 (s, 3H); MS m/z 409 (M+1).

Example 25: 6-Methyl-1 -(4-methylphenylV2-(3-phenylpropanovn-2,3.4.9-tetrahvdro-1 H-B- carboline.

¹H NMR (DMSO-d₆): δ 10.80 and 10.60 (s, 1 H, major and minor conformers), 7.25 - 7.12 (m, 9H), 7.07 (m, 2H), 6.89 (d, 1 H), 6.82 and 6.20 (s, 1 H, major and minor conformers), 4.71 and 4.00 (m, 1H, minor and major conformers), 3.14 (m, 1H), 2.90 - 2.67 (m, 6H), 2.37 (s, 3H), 2.27 (s, 3H); MS m/z 409 (M+1). Exam^ple 26: 7-Fluoro-1-(4-methylphenvB-2-(3-phenylpropanovn-2,3,4,9-tetrahvdro-1 H-B- carboline.

¹H NMR (DMSO-Cl₆): δ 11.07 and 10.83 (s, 1H, major and minor conformers), 7.43 (m, 1H), 7.26 - 7.04 (m, 10H), 6.86 (m, 1 H), 6.82 and 6.21 (s, 1 H, major and minor conformers), 4.73 and 4.00 (m, 1 H, minor and major conformers), 3.14 (m, 1 H), 2.89 - 2.68 (m, 6H), 2.28 (s, 3H); MS m/z 413 (M+1).

Example 27: 7-(MethyloxyH -(4-methylphenyl)-2-(3-phenylpropanoylV2,3.4,9-tetrahvdro-1 H-β- carboline.

¹H NMR (DMSOd₆): δ 10.77 and 10.55 (s, 1 H, major and minor conformers), 7.31 (d, 1 H), 7.24 (m, 4H), 7.19 - 7.07 (m, 5H), 6.80 (s, 2H), 6.65 (dd, 1 H), 6.17 (s, 1 H, minor conformer), 4.69 and 3.98 (m, 1 H, minor and major conformers), 3.75 (s, 3H), 3.12 (m, 1 H), 2.89 - 2.67 (m, 6H), 2.28 (s, 3H); MS m/z 425 (M+1). Exam^ple 28: (1 R/1 SV 1 -(2,3-dihvdro-1 -benzof uran-5-vn-2.3.4,9-tetrahvdro-1 H-β-carboline.

A solution of tryptamine (0.325 g, 2.03 mmol) and 2,3-dihydro-1 -benzof uran-5-carbaldehyde (0.250 g, 1.69 mmol) in glacial acetic acid (10 mL) was heated to 100⁰C with stirring. After 2.5 h the solution was treated with an additional portion of 2,3-dihydro-1 -benzofuran-5- carbaldehyde (0.062 g, 0.418 mmol) and stirred at O⁰C for an additional 3 h. The dark brown solution was cooled to RT and stirred overnight. The solvent was removed by concentration at reduced pressure and the residue dissolved in dichlorom ethane. The solution was washed twice with 10% aqueous sodium bicarbonate followed by aqueous brine. The solution was then treated with magnesium sulfate and a small portion of activated charcoal and heated to boiling for 5 minutes. After cooling to RT, the mixture was filtered through celite and the filtrate evaporated to dryness to afford 0.590 g of a yellow-brown foam. The crude product was purified by flash chromatography (silica gel, 95:5 dichloromethane/2M ammonia in methanol) to give (1 R/1 S)-1-(2,3-dihydro-1 -benzof uran-5-yl)-2,3,4,9-tetrahydro-1 H-β-carboline (0.460 g, 94%) as a yellow powder. ¹H NMR (DMSOd₆): δ 10.32 (s, 1 H), 7.36 (d,1 H), 7.20 (d, 1 H), 7.09 (S, 1H), 7.01-6.88 (m, 3H), 6.69 (d, 1H), 4.99 (s, 1H), 4.49 (t, 2H), 3.17-3.00 (m, 3H), 2.90 (m, 1 H), 2.79-2.58 (m, 3H). MS m/z 291 (M+1).

Example 29: (1 R/1 SV1-(2,3-dihvdro-1 -benzof υran-5-yl)-2-f(2EV3-phenyl-2-propenoyll-2.3.4,9- tetrahvdro-1 H-β-carboline

Example 30: (1 RH-(2.3-dihvdro-1 -benzof uran-5-yl)-2-r(2E)-3-phenyl-2-propenoyll-2.3.4.9- tetrahvdro-1 H-β-carboline Example 31 : (1 SV1 -(2,3-dihvdro-1 -benzof uran-5-vO-2-r(2E)-3-phenyl-2-propenovπ-2,3.4.9- tetrahvdro-1 H-β-carboline

A solution of (1 R/1 S)-1-(2,3-dihydro-1 -benzof uran-5-yl)-2,3,4,9-tetrahydro-1 H-β-carboline (0.250 g, 0.861 mmol) and N,N-diisopropylethylamine (0.300 mL, 1.72 mmol) in 10 mL of anhydrous dichloromethane was treated with cinnamoyl chloride (0.159 g, 0.947 mmol) and the resulting solution was stirred at RT. After 2.5 h, the solution was diluted with dichloromethane, washed with 5% aqueous citric acid (2x), 10% aqueous sodium bicarbonate (2x), dried over magnesium sulfate and concentrated to dryness at reduced pressure. The crude product was subjected to flash chromatography (silica gel, 97:3 dichloromethane/methanol) to afford 0.330 g (91%) (1 R/1 S)-1 -(2,3-dihydro-1 -benzof uran-5-yl)-2-[(2E)-3-phenyl-2-propenoyl]-2,3,4,9-tetrahydro-1 H- β-carboline (compound 2) as a light yellow foam. ¹H NMR (DMSOd₆, 95⁰C): δ 10.63 (br s, 1 H), 7.69 (d, 2H), 7.54 (d, 1 H), 7.49-7.22 (m, 5H), 7.14 (s, 1 H), 7.08 (t, 1 H), 7.03-6.97 (m, 2H), 6.84 (br s, 1 H), 6.70 (d, 1 H), 5.67 (s, 1 H), 4.49 (t, 2H), 4.43 (m, 1 H), 3.32 (m, 1H), 3.13 (t, 2H), 2.87 (m, 2H). MS m/z 421 (M+1). A 223 mg portion of the racemic product was subjected to supercritical fluid chiral chromatography (Chiralpak AS-H 5μM column, 3:1 MeOH/CHCI₃ mobile phase, 40⁰C, 180 bars, flow rate=180 g/minute) to afford 105 mg of (1 R)-1 -(2,3-dihydro-1- benzofuran-5-yl)-2-[(2E)-3-phenyl-2-propenoyl]-2,3,4,9-tetrahydro-1 H-β-carboline (Example 30) eluting at 1.14 minutes and 99 mg of (1S)-1-(2,3-dihydro-1 -benzof uran-5-yl)-2-[(2E)-3-phenyl-2- propenoyl]-2,3,4,9-tetrahydro-1 H-β-carboline (Example 31) eluting at 1.88 minutes. Both compounds were determined to be enantiomerically pure by analytical chiral SFC (ChiralCel OJ column, 30% MeOH mobile phase, 3000 psi, 40⁰C, flow rate=3 ml_/minute). The retention times were 11.7 and 20.2 minutes for compounds 30 and 31 respectively. The absolute configurations were assigned using VCD spectroscopy. Additionally, the following compounds may be prepared as described in Bioorg. Med. Chem. Lett, 2003, 13, 761-765 and WO 02/064590 A2:

Example Compound Name Structure

33 1 -(1 ,3-benzodioxol-5-yl)-2- (2-pyrimidinyl)-2,3,4,9-

tetrahydro-1 fy-β-carboline

1 -(1 ,3-benzodioxol-5-yl)-2- (4-phenyl-2-pyrimidinyl)-

34 2,3,4,9-tetrahydro-1 H-β- carboline

1 -phenyl-2-(4-phenyl-2- pyrimidinyl)-2,3,4,9-

35 tetrahydro-1 H-β-carboline

1 -(2,3-dihydro-1 -benzof uran- 5-yl)-2-(4-phenyl-2-

36 pyrimidinyl)-2,3,4,9- tetrahydro-1 H-β-carboline

1 -(2,3-dihydro-1 -benzof uran- 5-yl)-2-[4-(3-pyridinyl)-2-

37 pyrimidinyl]-2,3,4,9- tetrahydro-1 H-β-carboline

1 -(2,3-dihydro-i -benzof uran- 5-yl)-2-[4-(1 H-imidazol-1 -yl)-

38 2-pyrimidinyl]-2,3,4,9- tetrahydro-1 H-β-carboline

1 -(2,3-dihydro-1 -benzof uran- 5-yl)-2-[4-(4-methyl-1 H- imidazol-1 -yl)-2-pyrimidinyl]-

39 2,3,4,9-tetrahydro-1 H-β- carboline

40 2,3,4,9-tetrahydro-1 H-β- carboline

BIOLOGICAL EXPERIMENTALS AND DATA

Compounds of the current invention are believed useful in the treatment and/or prophylaxis of conditions and diseases associated with HcV infection. Activity mediated through HCV was determined using an ET replicon line.

The Materials used include a Medium comprised of DMEM (^"IX liquid, high glucose); Invitrogen cat# 11965-092; 100 x Penicillin/Streptomycin solution (10, 000 Units/mL); Invitrogen cat# 15140-122; 100 x Non-essential amino acid solution (10 mM); Invitrogen cat# 11140-050; Fetal bovine serum; JRH Biosciences cat# 12107-500M; Geneticin (50 mg/mL); Invitrogen cat# 10131-035

The Luciferase assay reagents include Steady-Glo Luciferase assay system, cat# E2550 (Promega)

The ET replicon line (see Lohmann et al. (1999), Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line. Science 285: 110-113; Krieger et al. (2001), Enhancement of hepatitis C virus RNA replication by cell culture-adaptive mutations. J. Virol. 75: 4614-4624; and Vrolijk et al. (2003), A replicon-based bioassay for the measurement of interferons in patients with chronic hepatitis C. J. Virol. Meth. 110: 201-209, each herein incorporated by reference with regard to the ET replicon line), includes Huh7 cells stably transfected with HCV genotype 1 b strain Con1 replicon. This replicon expresses the firefly luciferase, has the coding region for ubiquitin inserted upstream of the neomycin gene, and carries three cell culture- adaptive mutations that enhance RNA replication cooperatively (E1202G, T1280I, and S2197P). The ET cell line was obtained under licence from: ReBLikon GmbH, Nach dem alten Schloss 22, 55239 Gau-Odernheim, Germany.

Cells are maintained at 37⁰C, 5% CO₂, in DMEM with 10% FCS, 1 x penicillin/streptomycin, 1 x non-essential amino acids, 0.5 mg/mL Geneticin. For passage, cells are washed once with PBS, and incubated at 37°C with sufficient trypsin (0.05%) / versene to cover the monolayer. Once detached from the flask, cells are mixed with several mLs of DMEM + 10% FBS to inactivate the trypsin, then diluted appropriately (usually 1 in 5 or 1 in 10) with sufficient medium to pass to a new flask. For a T225 flask, 40-50 mLs total volume of cells + medium is typically used. To prevent the density dependent drop in replicon RNA, the ET cell line is maintained at sub-confluent (60-80%) levels.

Compounds are diluted in DMSO across the first 10 wells of a Costar V-bottom 96-well plate using a Biomek 2000 Workstation (Beckman-Coulter), with 0.5 log₁₀ dilution intervals. DMSO only is added to the last two columns of the plate. The top concentration of drug in this master plate is typically 2.5 mM. A 1/5 dilution of the compounds is made by adding DMEM + 10% FBS with a multichannel pipettor, giving a top concentration of 500 μM. 5 μL of diluted compounds is transferred into black Costar flat bottom 96-well daughter plates using a RapidPlate workstation (Zymark).

Cells are grown to approximately 80% confluency and trypsinised as described above. Cells are counted in a Levy Hemocytometer and diluted to 20,000 cells/ml in DMEM containing 10% FBS, 1 x penicillin/streptomycin, 1x NEAAs. (Note: Geneticin is omitted for the assay).

245 μL cell suspension is added to the first 11 columns of the daughter plates prepared as above using a Multidrop dispenser (Titertek). Thus, 5,000 cells are added per well, and the final top concentration of each compound is 10 μM. The twelfth column of each plate is used to generate background readings for the assay. Plates are incubated at 37°C, 5% CO₂ for 72 hours.

Luciferase assay

Steady-Glo reagent is prepared according to the manufacturer's instructions, by mixing the Steady-Glo Buffer and Steady-Glo substrate Buffer at room temperature. Medium is removed from the 96-well plates containing ET cells treated with compound using a multichannel aspirator. 100 μl of Steady-Glo reagent is added to each well using a multichannel pipettor or Multidrop dispensor. Plates are incubated at room temperature for 5 minutes to ensure complete lysis, and mixed by gentle shaking. Luciferase activity is read using a Topcount (PE Biosystems), with a 1 -second read-time per well. Data are analyzed and IC₅₀ curves generated using RoboFit software.

The compounds herein described are believed to exhibit useful Luciferase activity. Although specific IC₅₀ values are given for certain of the present compounds, these values should be considered exemplary. Those skilled in the art will appreciate the variability in performing and recording data using the biological activity assays that are herein described.

Table 1

Example HCV fnM) E Exxaammppllee H HCCVV ((nnMWn) Example HCV OnM)

2 10 25 151

3 22 26 1099

4 11 27 10000

6 430 29 5470

7 1098 30 10000

8 177 31 2315

11 16

12 5

13 10000

14 16

19 2695

23 125

24 5975

Test compounds were employed in free or salt form.

All research complied with the principles of laboratory animal care (NIH publication No. 85-23, revised 1985) and GlaxoSmithKline policy on animal use.

Although specific embodiments of the present invention are herein illustrated and described in detail, the invention is not limited thereto. The above detailed descriptions are provided as exemplary of the present invention and should not be construed as constituting any limitation of the invention. Modifications will be obvious to those skilled in the art, and all modifications that do not depart from the spirit of the invention are intended to be included with the scope of the appended claims

Claims

What is claimed is:

1. A method for the treatment or prophylaxis of Flaviviridae viruses through administration of a compound of formula (I):

wherein: each R¹ independently is halogen, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycioalkenyl, -R¹⁰cydoalkyl, Ay, AyR⁴, AyOR⁴ -NHR¹⁰Ay, Het, HetR⁴, HetOR⁴, -NHHet, -NHR¹⁰Het, -OR⁴, -OAy, -OHet, -R¹⁰OR⁴, -NR⁴R⁵, -NR⁴Ay, -R¹⁰NR⁴ R⁵, -R¹⁰NR⁴Ay, -R¹⁰C(O)R⁴, -C(O)R⁴, -CO₂R⁴, -R¹⁰CO₂R⁴, -C(O)NR⁴R⁵, -C(O)Ay, -C(O)NR⁴Ay, -C(O)Het, -C(O)NHR¹⁰Het, -R¹⁰C(O)NR⁴R⁵, -C(S)NR⁴R⁵, -R¹⁰C(S)NR⁴R

5 >

-R¹⁰NHC(NH)NR⁴R⁵, -C(NH)NR⁴R⁵, -R¹⁰C(NH)NR⁴R⁵, -S(O)₂NR⁴R⁵, -S(O)₂NR⁴Ay, -R¹⁰SO₂NHCOR⁴, -R¹⁰SO₂NR⁴R⁵, -R¹⁰SO₂R⁴, -S(0)_mR⁴, cyano, nitro, or azido; p is 0, 1 , 2, 3, or 4; n is O or 1 ; m is 0, 1 , or 2;

X is selected from a group consisting of C(O), C(O)O, C(O)Y, S(O), SO₂, S(O)Y, SO₂Y, C(O)OY, C(O)NHY, C(O)YN(H)C(O)OY; each Y independently is optionally substituted alkylene, optionally substituted cycloalkylene, optionally substituted alkenylene, optionally substituted cycloalkenylene, or optionally substituted alkynylene;

R² is -Ay or -Het, each optionally substituted with one or more halogen, haloalkyl, al kyl, alkenyl, alkynyl, cycloalkyl, cycioalkenyl, -R¹⁰cycloalkyl, Ay, AyR⁴, AyOR⁴ -NHR¹⁰ Ay, Het, HetR⁴, HetOR⁴, -NHHet, -NHR¹⁰Het, -OR⁴, -OAy, -OHet, -R¹⁰OR⁴, -NR⁴R⁵, -NR⁴Ay,

-R¹⁰NR⁴R⁵, -R¹⁰NR⁴Ay, -R¹⁰C(O)R⁴, -C(O)R⁴, -CO₂R⁴, -R¹⁰CO₂R⁴, -C(O)NR⁴R⁵, -C(O) Ay, -C(O)NR⁴Ay, -C(O)Het, -C(O)NHR¹⁰Het, -R¹⁰C(O)NR⁴R⁵, -C(S)NR⁴R⁵, -R¹⁰C(S)N R⁴R⁵, -R¹⁰NHC(NH)NR⁴R⁵, -C(NH)NR⁴R⁵, -R¹⁰C(NH)NR⁴R⁵, -S(O)₂NR⁴R⁵, -S(O)₂NR⁴

Ay,

-R¹⁰SO₂NHCOR⁴, -R¹⁰SO₂NR⁴R⁵, -R¹⁰SO₂R⁴, -S(O)_mR⁴, cyano, nitro, or azido;

R³ is alkyl, -Ay or -Het, where Ay or Het may each be optionally substituted with one or more halogen, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, -R¹⁰cycloalkyl, Ay, AyR⁴, AyOR⁴ -NHR¹⁰Ay, Het, HetR⁴, HetOR⁴, -

R¹⁰NR⁴Ay, -R¹⁰C(O)R⁴, -C(O)R⁴, -CO₂R⁴, -R¹⁰CO₂R⁴, -C(O)NR⁴R⁵, -C(O)Ay, -

C(O)NR⁴Ay, -C(O)Het, -C(O)NHR¹⁰Het, -R¹⁰C(O)NR⁴R⁵, -C(S)NR⁴R⁵, -

S(O)₂NR⁴Ay, -R¹⁰SO₂NHCOR⁴, -R¹⁰SO₂NR⁴R⁵, -R¹⁰SO₂R⁴, -S(O)_mR⁴, cyano, nitro, or azido; each of R⁴ and R⁵ is independently selected from H or alkyl; each R¹⁰ is an optionally substituted alkylene;

Ay represents an aryl group;

2. The method of claim 1 wherein the virus is a flaviviruses, a pestiviruses, or a hepaciviruses.

3. The method of claim 2 wherein the virus is associated with a human disease selected from dengue fever, yellow fever, west nile virus, and HCV.

4. The method of claim 3 wherein method is for the treatment or prophylaxis of HCV infection.

5. The method of claim 1 wherein R¹ is selelcted from halogen, alkyl, cyano, nitro, -OR⁴, Het, -NR⁴R⁵, Or -CONR⁴R⁵.

6. The method of claim 5 wherein R¹ is halogen or alkyl.

7. The method of claim 6 wherein R¹ is F, Cl, Br, or I.

8. The method of claim 7 wherein R¹ is Cl or Br.

9. The method of claim 1 wherein p is 1 and R¹ is substituted para to the depicted indole nitrogen atom.

10. The method of claim 1 wherein R² is Ay.

11. The method of claim 10 wherein Ay is phenyl substituted with one or two substituents.

12. The method of claim 11 wherein Ay is phenyl optionally substituted with halogen, alkyl, cyano, nitro, -OR⁴, Het, -NR⁴R⁵, or -CONR⁴R⁵.

13. The method of claim 12 wherein Ay is phenyl optionally substituted with halogen, alkyl, cyano, -OR⁴, -NR⁴R⁵, Or -CONR⁴R⁵.

14. The method of claim 1 wherein R² is Het.

15. The method of claim 14 wherein Het is dihydrobenzofuran or piperonyl.

16. The method of claim 1 wherein n is 1 and X is selected from C(O), C(O)O, C(O)Y, C(O)OY, C(O)NHY₁ or SO₂Y.

17. The method of claim 16 wherein X is selected from C(O)Y, C(O)O, C(O)OY, or C(O)NHY.

18. The method of claim 13 wherein R³ is alkyl, Ay, or Het.

19. The method of claim 18 wherein R³ is alkyl or Ay.

20. The method of claim 1 wherein n is 0 and R³ is Het.

21. The method of claim 20 wherein R³ is Het optionally substituted with one or more of halogen, alkyl, cyano, nitro, -OR⁴, Het, Ay, -NR⁴R⁵, or -CONR⁴R⁵.

22. The method of claim 1 wherein the compound is

Methyl 6-chloro-1 -(4-methylphenyl)-1 ,3 ,4,9-tetrahydro-2H-β-carboline-2-carboxylate;

6-Chloro-1-(4-methylphenyl)-2-(3-phenylpropanoyl)-2,3,4,9-tetrahydro-1 H-β- carboline;

Phenylmethyl 6-chloro-1 -(4-methylphenyl)-1 ,3,4,9-tetrahydro-2H-β-carboline-2- carboxylate;

Methyl 6-f luoro-1 -(4-methylphenyl)-1 ,3,4,9-tetrahydro-2H-β-carboline-2-carboxylate;

6-Fluoro-1-(4-methylphenyl)-2-(3-phenylpropanoyl)-2,3,4,9-tetrahydro-1 H-β- carboline;

Phenylmethyl 6-f luoro-1 -(4-methylphenyl)-1 ,3,4,9-tetrahydro-2H-β-carboline-2- carboxylate;

Methyl 6-bromo-1 -(4-methylphenyl)-1 ,3,4,9-tetrahydro-2H-β-carboline-2-carboxylate;

6-Bromo-1-(4-methylphenyl)-2-(3-phenylpropanoyl)-2,3,4,9-tetrahydro-1 H-β- carboline;

Phenylmethyl 6-bromo-1 -(4-methylphenyl)-1 ,3,4,9-tetrahydro-2H-β-carboline-2- carboxylate;

(1 R)-6-Chloro-1 -(4-methylphenyl)-2-(3-phenylpropanoyl)-2,3,4,9-tetrahydro-1 H-β- carboline;

(1 S)-6-Chloro-1 -(4-methylphenyl)-2-(3-phenylpropanoyl)-2,3,4,9-tetrahydro-1 H-β- carboline;

1-(4-Methylphenyl)-2-[(phenylmethyl)sulfonyl]-2,3,4,9-tetrahydro-1 H-β-carboline;

1-(4-Methylphenyl)-2-(methylsulfonyl)-2,3,4,9-tetrahydro-1 H-β-carboline;

(4-{[1-(4-Methylphenyl)-1 ,3,4,9-tetrahydro-2H-b-carbolin-2-yl]sulfonyl}phenyl)amine.

2-Acetyl-1-(4-methylphenyl)-2,3,4,9-tetrahydro-1H-β-carboline;

1-(4-Methylphenyl)-2-(3-phenylpropanoyl)-2,3,4,9-tetrahydro-1 H-β-carboline; 1-(4-Methylphenyl)-2-(3-phenyl-2-propynoyl)-2,3,4,9-tetrahydro-1 H-b-carboline; 1-(4-Methylphenyl)-2-[3-(3-pyridinyl)propanoyl]-2,3,4,9-tetrahydro-1H-β-carboline; Phenylmethyl {2-[1 -(4-methylphenyl)-1 ,3,4,9-tetrahydro-2H-b-carbolin-2-yl]-2- oxoethyljcarbamate;

6-(Methyloxy)-1-(4-methylphenyl)-2-(3-phenylpropanoyl)-2,3,4,9-tetrahydro-1H-β- carboline;

8-Methyl-1-(4-methylphenyl)-2-(3-phenyIpropanoyl)-2,3,4,9-tetrahydro-1 H-β- carboline;

6-Methyl-1-(4-methylphenyl)-2-(3-phenylpropanoyl)-2,3,4,9-tetrahydro-1 H-β- carboline;

7-Fluoro-1-(4-methylphenyl)-2-(3-phenylpropanoyl)-2,3,4,9-tetrahydro-iH-β- carboline;

7-(Methyloxy)-1-(4-methylphenyl)-2-(3-phenylpropanoyl)-2,3,4,9-tetrahydro-1 H-β- carboline;

(1 R/1 S)-1 -(2,3-dihydro-1 -benzof uran-5-yl)-2-[(2E)-3-phenyl-2-propenoyl]-2,3,4,9- tetrahydro-1 H-β-carboline;

(1 R)-1 -(2,3-dihydro-1 -benzof uran-5-yl)-2-[(2E)-3-phenyl-2-propenoyl]-2,3,4,9- tetrahydro-1 H-β-carboline;

(1 S)-1 -(2,3-dihydro-1 -benzof uran-5-yl)-2-[(2E)-3-phenyl-2-propenoyl]-2,3,4,9- tetrahydro-1 H-β-carboline;

1-(1,3-benzodioxol-5-yl)-2-{4-[4-(methyloxy)phenyl]-2-pyrimidinyl}-2,3,4,9-tetrahydro- 1 H-β-carboline;

1 -(1 ,3-benzodioxol-5-yl)-2-(2-pyrimidinyl)-2,3,4,9-tetrahydro-1 H-β-carboline; 1 -(1 ,3-benzodioxol-5-yl)-2-(4-phenyl-2-pyrimidinyl)-2,3,4,9-tetrahydro-1 H-β-carboline; 1-phenyl-2-(4-phenyl-2-pyrimidinyl)-2,3,4,9-tetrahydro-1 H-β-carboline; 1 -(2,3-dihydro-1 -benzof uran-5-yl)-2-(4-phenyl-2-pyrimidinyl)-2,3,4,9-tetrahydro-1 H-β- carboline;

1-(2,3-dihydro-1-benzofuran-5-yl)-2-[4-(3-pyridinyl)-2-pyrimidinyl]-2,3,4,9-tetrahydro- 1 H-β-carboline;

1 -(2,3-dihydro-1 -benzof uran-5-yl)-2-[4-(1 H-imidazol-1 -yl)-2-pyrimidinyl]-2,3,4,9- tetrahydro-1 H-β-carboline;

1 -(2,3-dihydro-1 -benzofuran-5-yl)-2-[4-(4-methyl-1 H-imidazol-1 -yl)-2-pyrimidinyl]- 2,3,4,9-tetrahydro-1 H-β-carboline; 1 -(2,3-dihydro-i -benzof uran-5-yl)-2-[4-(4-methyl-1 H-imidazoI-1 -yl)-2-pyrimidinyl]-

2,3,4,9-tetrahydro-1 W-β-carboIine, including pharmaceutically acceptable salts, solvates, and physiologically functional derivatives thereof.

23. The method of claim 1 wherein the compound is

Methyl 6-chloro-1 -(4-methylphenyl)-1 ,3,4,9-tetrahydro-2H-β-carboline-2-carboxylate; 6-Chloro-1-(4-methylphenyl)-2-(3-phenylpropanoyl)-2,3,4,9-tetrahydro-1H-β- carboline;

Methyl 6-fluoro-1-(4-methylphenyl)-1 ,3,4,9-tetrahydro-2H-β-carboline-2-carboxylate; 6-Fluoro-1-(4-methylphenyl)-2-(3-phenylpropanoyl)-2,3,4,9-tetrahydro-1 H-β- carboline;

Phenylmethyl 6-fluoro-1 -(4-methylphenyl)-1 ,3,4,9-tetrahydro-2H-β-carboline-2- carboxylate;

Methyl 6-bromo-1 -(4-methylphenyl)-1 ,3,4,9-tetrahydro-2H-β-carboline-2-carboxylate; 6-Bromo-1-(4-methylphenyl)-2-(3-phenylpropanoyl)-2,3,4,9-tetrahydro-1 H-β- carboline;

6-(Methyloxy)-1-(4-methylphenyl)-2-(3-phenylpropanoyl)-2,3,4,9-tetrahydro-1H-β- carboline; and

6-Methyl-1-(4-methylphenyl)-2-(3-phenylpropanoyl)-2,3,4,9-tetrahydro-1 H-β- carboline, including pharmaceutically acceptable salts, solvates, and physiologically functional derivatives thereof.

24. The method of claim 1 wherein the compound is

Methyl 6-chloro-1 -(4-methylphenyl)-1 ,3,4,9-tetrahydro-2H-β-carboline-2-carboxylate;

Phenylmethyl 6-chloro-1 -(4-methylphenyl)-1 ,3,4,9-tetrahydro-2H-β-carboline-2- carboxylate; Methyl 6-bromo-1 -(4-methylphenyl)-1 ,3,4,9-tetrahydro-2H-β-carboline-2-carboxylate; 6-Bromo-1-(4-methylphenyl)-2-(3-phenylpropanoyl)-2,3,4,9-tetrahydro-1 H-β- carboline;

Phenylmethyl 6-bromo-1 -(4-methylphenyl)-1 ,3,4,9-tetrahydro-2H-β-carboline-2- carboxylate; and

(1 S)-6-Chloro-1 -(4-methylphenyl)-2-(3-phenylpropanoyl)-2,3,4,9-tetrahydro-1 H-β- carboline, including pharmaceutically acceptable salts, solvates, and physiologically functional derivatives thereof.

25. Use of a compound according to claims 1 to 24 in the manufacture of a medicament for use in the treatment or prophylaxis of viruses belonging to Raviviridae.

26. The use of claim 25 wherein the virus is a flavivirus, a pestivirus, or a hepacivirus.

27. The use of claim 25 wherein the disease or condition is dengue fever, yellow fever, West Nile virus, or HCV.

28. The use of claim 27 wherein the condition or disorder is HCV.