CA2893318A1 - Thienopyridine derivatives for the treatment and prevention of dengue virus infections - Google Patents

Abstract

Methods and pharmaceutical compositions for treating viral infections, by administering certain thienopyridine derivative compounds in therapeutically effective amounts are disclosed. Methods of using the compounds and pharmaceutical compositions thereof are also disclosed. In particular, the treatment of viral infections such as caused by flavivirus is disclosed, i.e., including but not limited to, Dengue virus, West Nile virus, yellow fever virus, Japanese encephalitis virus, and tick-borne encephalitis virus.

Description

Thienopyridine Derivatives for the Treatment and Prevention of Dengue Virus Infections CROSS REFERENCE TO RELATED APPLICATIONS
[00001] This application claims priority to U.S. patent application 13/708,224, filed December 7, 2012, which is a continuation-in-part and claims priority to U.S. patent application No. 13/203,351, filed October 13, 2011, which is a national stage entry under U.S.C. 371(c), and claims priority to International Patent Application Number PCT/US10/25183, filed February 24, 2010, which in turn claims priority to and benefit of U.S. Provisional Application No. 61/156,132, filed February 27, 2009. All the applications are incorporated herein by reference in the entirety and for all purposes.
FIELD OF THE INVENTION

[00002] This invention relates to the use of thienopyridine derivatives and analogs, as well as compositions containing the same, for the treatment of viral diseases associated with the flavivirus family such as Dengue fever, Yellow fever, West Nile, St. Louis encephalitis, Hepatitis C, Murray Valley encephalitis, and Japanese encephalitis.
BACKGROUND OF THE INVENTION

[00003] Dengue fever (DF) is an acute febrile disease caused by one of four closely related virus serotypes (DEN-1, DEN-2, DEN-3, and DEN-4). Dengue fever is classified based on its clinical characteristics into classical dengue fever, or the more severe forms, dengue hemorrhagic fever syndrome (DHF), and dengue shock syndrome (DSS). Recovery from infection from one serotype produces life-long immunity to that particular serotype, but provides only short-lived and limited protection against any of the other serotypes (32). Dengue is a member of the Flaviviridae family which are enveloped, positive-sense RNA
viruses whose human pathogens also include West Nile virus (WNV), yellow fever virus (YFV), Japanese encephalitis virus (JEV), and tick-borne encephalitis virus (TBEV) among others.
Dengue transmission is via the bite of an infected Aedes aegypti mosquito which is found in tropical and sub-tropical regions around the world.

[00004] Each year regional epidemics of dengue cause significant morbidity and mortality, social disruption and substantial economic burden on the societies affected both in terms of hospitalization and mosquito control. Dengue is considered by the World Health Organization (WHO) to be the most important arthropod-borne viral disease with an estimated 50 million cases of dengue infection, including 500,000 DHF cases and 24,000 deaths worldwide each year (32, 33). WHO estimates that forty percent of the world's population (2.5 billion people) are at risk for DF, DHF, and DSS (32). Dengue is also a NIAID Category A pathogen and in terms of bio-defense, represents a significant threat to United States troops overseas. Dengue is an emerging threat to North America with a dramatic increase in severe disease in the past 25 years including major epidemics in Cuba and Venezuela, and outbreaks in Texas and Hawaii (4). Failure to control the mosquito vector and increases in long-distance travel have contributed to the increase and spread of dengue disease. The characteristics of dengue as a viral hemorrhagic fever virus (arthropod-borne, widely spread, and capable of inducing a great amount of cellular damage and eliciting an immune response that can result in severe hemorrhage, shock, and death) makes this virus a unique threat to deployed military personnel around the world as well as to travelers to tropical regions. Preparedness for both biodefense and for the public health challenges posed by dengue will require the development of new vaccines and antiviral therapeutics.

[00005] Dengue causes several illnesses with increasing severity being determined in part by prior infection with a different serotype of the virus. Classic dengue fever (DF) begins 3-8 days after the bite of an infected mosquito and is characterized by sudden onset of fever, headache, back pain, joint pain, a measles-like rash, and nausea and vomiting (20).
DF is frequently referred to as "breakbone" fever due to these symptoms. The disease usually resolves after two weeks but a prolonged recovery with weakness and depression is common. The more severe form of the disease, dengue hemorrhagic fever (DHF) has a similar onset and early phase of illness as dengue fever.
However, shortly after onset the disease is characterized by high fever, enlargement of the liver, and hemorrhagic phenomena such as bleeding from the nose, mouth, and internal organs due to vascular permeability (33). In dengue shock syndrome (DSS) circulatory failure and hypovolaemic shock resulting from plasma leakage occur and can lead to death in 12-24 hours without plasma replacement (33). The case fatality rate of DHF/DSS can be as high as 20% without treatment. DHF has become a leading cause of hospitalization and death among children in many countries with an estimated 500,000 cases requiring hospitalization each year and a case fatality rate of about 5%(32).

[00006] The pathogenesis of DHF/DSS is still being studied but is thought to be due in part to an enhancement of virus replication in macrophages by heterotypic antibodies, termed antibody-dependent enhancement (ADE) (8). During a secondary infection, with a different serotype of dengue virus, cross-reactive antibodies that are not neutralizing form virus-antibody complexes that are taken into monocytes and Langerhans cells (dendritic cells) and increase the number of infected cells (7). This leads to the activation of cytotoxic lymphocytes which can result in plasma leakage and the hemorrhagic features characteristic of DHF and DSS (20). This antibody-dependent enhancement of infection is one reason why the development of a successful vaccine has proven to be so difficult. Although less frequent, DHF/DSS can occur after primary infection (29), so virus virulence (15) and immune activation are also believed to contribute to the pathogenesis of the disease (25).

[00007] Dengue is endemic in more than 100 countries in Africa, the Americas, the Eastern Mediterranean, South-east Asia and the Western Pacific. During epidemics, attack rates can be as high as 80-90% of the susceptible population. All four serotypes of the virus are emerging worldwide, increasing the number of cases of the disease as well as the number of explosive outbreaks. In 2002 for example, there were 1,015,420 reported cases of dengue in the Americas alone with 14,374 cases of DHF, which is more than three times the number of dengue cases reported in the Americas in 1995 (23).

[00008] The dengue genome, approximately 11 kb in length, consists of a linear, single stranded, infectious, positive sense RNA that is translated as a single long polyprotein (reviewed in (27)). The genome is composed of seven nonstructural (NS) protein genes and three structural protein genes which encode the nucleocapsid protein (C), a membrane-associated protein (M), and an envelope protein (E). The nonstructural proteins are involved in viral RNA replication (31), viral assembly, and the inflammatory components of the disease (18). The structural proteins are involved mainly in viral particle formation (21). The precursor polyprotein is cleaved by cellular proteinases to separate the structural proteins (17), while a virus-encoded proteinase cleaves the nonstructural region of the polyprotein (6). The genome is capped and does not have a poly(A) tail at the 3' end but instead has a stable stem-loop structure necessary for stability and replication of the genomic RNA (3). The virus binds to cellular receptors via the E protein and undergoes receptor-mediated endocytosis followed by low-pH fusion in lysosomes (19). The viral genome is then uncoated and translated into the viral precursor polyprotein. Co- and posttranslational proteolytic processing separates the structural and nonstructural proteins. The RNA-dependent RNA polymerase along with cofactors synthesizes the minus-strand RNA which serves as a template for the synthesis of the progeny plus-strand RNA
(24). Viral replication is membrane associated (1, 30).
Following replication, the genome is encapsidated, and the immature virus, surrounded by a lipid envelope buds into the lumen (9). The envelope proteins become glycosylated and mature viruses are released outside the cell. Essential stages or process during the virus life cycle would be possible targets for inhibition from an antiviral drug and include binding of the virus to the cell through the E protein, uptake of the virus into the cell, the capping mechanism, the viral proteinase, the viral RNA-dependent RNA polymerase, and the viral helicase.

[00009] Current management of dengue virus-related disease relies solely on vector control. There are no approved antivirals or vaccines for the treatment or prevention of dengue. Ribavirin, a guanosine analogue, has been shown to be effective against a range of RNA virus infections and works against dengue in tissue culture by inhibiting the dengue 2'-C)-methyltransferase NS5 domain (2, 10). However, ribavirin did not show protection against dengue in a mouse model (14) or a rhesus monkey model (16), instead it induced anemia and thrombocytosis.
While there are no currently available approved vaccines, multivalent dengue vaccines have shown some limited potential in humans (5, 11, 12, 26). However, vaccine development is difficult due to the presence of four distinct serotypes of the virus which each cause disease. Vaccine development also faces the challenge of ADE where unequal protection against the different strains of the virus could actually increase the risk of more serious disease. Therefore there is a need for antiviral drugs that target all of the serotypes of dengue. An antiviral drug administered early during dengue infection that inhibits viral replication would prevent the high viral load associated with DHF and be an attractive strategy in the treatment and prevention of disease. An antiviral drug that inhibits viral replication could be administered prior to travel to a dengue endemic region to prevent acquisition of disease, or for those that have previously been exposed to dengue, could prevent infection by another serotype of virus and decrease the chance of life-threatening DHF and DSS. Having an antiviral drug would also aid vaccine development by having a tool at hand to treat complications that may arise due to unequal immune protection against the different serotypes. Although a successful vaccine could be a critical component of an effective biodefense, the typical delay to onset of immunity, potential side-effects, cost, and logistics associated with large-scale civilian vaccinations against a low-threat risk agent suggest that a comprehensive biodefense include a separate rapid-response element. Thus, there remains an urgent need to develop a safe and effective product to protect against flavivirus infection.
SUMMARY OF THE INVENTION

[000010] The present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound having the following general Formula I or a pharmaceutically acceptable salt thereof:
B
D A
I I
R
E , A
Formula I
wherein X is selected from the groups consisting of 0, S
and N-R', wherein R' is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, aryl, heteroaryl, acyl, arylacyl, heteroarylacyl, sulfonyl, aminosulfonyl, substituted aminosulfonyl, alkoxycarbonyl, cycloalkyloxycarbonyl, aryloxycarbonyl, carbamoyl and substituted carbamoyl;
R is selected from the group consisting of halogen, cyano, isocyano, nitro, amino, alkylamino, dialkylamino, cycloalkylamino, heterocycloalkylamino, arylamino, heteroarylamino, acylamino, arylacylamino, heteroarylacylamino, alkylsulfonylamino, arylsulfonylamino, hydroxysulfonyl, aminosulfonyl, substituted aminosulfonyl, acyl, arylacyl, heteroarylacyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl, aryloxycarbonyl, aminocarbonyl, and substituted aminocarbonyl, or R and R1 together with the carbons they are attached to may form a substituted or unsubstituted ring; and A, B, D, and E are independently N or C_R1, C-R2, C-R2 and C-R4, respectively, wherein R1, R2, R2 and R4 are independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, aryl, heteroaryl, hydroxy, alkyloxy, aryloxy, heteroaryloxy, acyloxy, arylacyloxy, heteroarylacyloxy, alkylsulfonyloxy, arylsulfonyloxy, thio, alkylthio, arylthio, amino, alkylamino, dialkylamino, cycloalkylamino, heterocycloalkylamino, arylamino, heteroarylamino, acylamino, arylacylamino, heteroarylacylamino, alkylsulfonylamino, arylsulfonylamino, acyl, arylacyl, heteroarylacyl, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, substituted aminosulfonyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl, aryloxycarbonyl, carbamoyl, substituted carbamoyl, halogen, cyano, isocyano and nitro; or R1 and R together with the carbons they are attached to may form a substituted or unsubstituted ring, or R2 and R2 or R2 and R4 together with the carbons they are attached to may form a substituted or unsubstituted ring, which may be aromatic or non-aromatic and may include one or more heteroatoms in the ring and may be fused with an aromatic or aliphatic ring. The pharmaceutical composition must be suitable for human or animal administration.

[000011] The present invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound having the following general Formula II or a pharmaceutically acceptable salt thereof:

\ R8 I
7,----...\,,.B...........:...... N
M 1 \ G R6 -NX Formula II
wherein X is selected from the groups consisting of 0, S or N-R', wherein R' is selected from the groups consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, aryl, heteroaryl, acyl, arylacyl, heteroarylacyl, sulfonyl, aminosulfonyl, substituted aminosulfonyl, alkoxycarbonyl, cycloalkyloxycarbonyl, aryloxycarbonyl, carbamoyl and substituted carbamoyl;
B is N or C-R2, wherein R2 is selected from the groups consisting of hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, aryl, heteroaryl, hydroxy, alkyloxy, aryloxy, heteroaryloxy, acyloxy, arylacyloxy, heteroarylacyloxy, alkylsulfonyloxy, arylsulfonyloxy, thio, alkylthio, arylthio, amino, alkylamino, dialkylamino, cycloalkylamino, heterocycloalkylamino, arylamino, heteroarylamino, acylamino, arylacylamino, heteroarylacylamino, alkylsulfonylamino, arylsulfonylamino, acyl, arylacyl, heteroarylacyl, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, substituted aminosulfonyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl, aryloxycarbonyl, carbamoyl, substituted carbamoyl, halogen, cyano, isocyano and nitro;
G is selected from the group consisting of -C(=0)-, -C(=S)-, -S(=0)2-, and -C(=NR5)-, wherein R5 is selected from the groups consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, aryl, heteroaryl, acyl, arylacyl, heteroarylacyl, sulfonyl, aminosulfonyl, substituted aminosulfonyl, alkoxycarbonyl, cycloalkyloxycarbonyl, aryloxycarbonyl, carbamoyl and substituted carbamoyl; or R5 and R6 or R7, together with the nitrogen atoms they are attached to, along with the carbon of G, or R5 and R8 or R9, together with the nitrogen atoms they are attached to, along with the carbon of G
and two carbons of the X-containing 5-membered ring, may form a substituted or unsubstituted ring, which may be fused with an aromatic or aliphatic ring;
R6, R7, R8, and R9 are independently selected from the groups consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, aryl, heteroaryl, acyl, arylacyl, heteroarylacyl, sulfonyl, aminosulfonyl, substituted aminosulfonyl, alkoxycarbonyl, cycloalkyloxycarbonyl, aryloxycarbonyl, carbamoyl and substituted carbamoyl; or R6 or R7 and R5, together with the nitrogen atoms they are attached to, along with the carbon of G, or R8 or R9 and R5, together with the nitrogen atoms they are attached to, along with the carbon of G
and two carbons of the X-containing 5-membered ring, or R6 or R7 and R8 or R9, together with the nitrogen atoms they are attached to, along with the carbon or sulfur of G and two carbons of the X-containing 5-membered ring, or R6 and R7, together with the nitrogen atom they are attached to, or R8 and R9, together with the nitrogen atom they are attached to, may form a substituted or unsubstituted ring, which may be fused with an aromatic or aliphatic ring; and cm M I
\---_,/
is a 7 or 8-membered ring which contains one or more heteroatoms selected from N, 0 and S, or a 4-membered ring which may optionally contain one or more heteroatoms selected from N, 0 and S. The ring may be substituted or unsubstituted, or fused with another ring, which may be aromatic or non-aromatic and may include one or more heteroatoms in the ring and may be fused with an aromatic or aliphatic ring. The pharmaceutical composition must be suitable for human or animal administration.

[000012] The present invention further provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound having the following general Formula III or a pharmaceutically acceptable salt thereof:
R"

X
N
Formula III
wherein X is selected from the groups consisting of: 0, S
and N-R', wherein R' is selected from the groups consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, aryl, heteroaryl, acyl, arylacyl, heteroarylacyl, sulfonyl, aminosulfonyl, substituted aminosulfonyl, alkoxycarbonyl, cycloalkyloxycarbonyl, aryloxycarbonyl, carbamoyl and substituted carbamoyl;
R is selected from the group consisting of halogen, cyano, isocyano, nitro, amino, alkylamino, dialkylamino, cycloalkylamino, heterocycloalkylamino, arylamino, heteroarylamino, acylamino, arylacylamino, heteroarylacylamino, alkylsulfonylamino, arylsulfonylamino, hydroxysulfonyl, aminosulfonyl, substituted aminosulfonyl, acyl, arylacyl, heteroarylacyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl, aryloxycarbonyl, aminocarbonyl, and substituted aminocarbonyl;
B, D, and E are independently N or C-R2, C-R3 and C-R4, respectively, wherein R2, R3 and R4 are independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, aryl, heteroaryl, hydroxy, alkyloxy, aryloxy, heteroaryloxy, acyloxy, arylacyloxy, heteroarylacyloxy, alkylsulfonyloxy, arylsulfonyloxy, thio, alkylthio, arylthio, amino, alkylamino, dialkylamino, cycloalkylamino, heterocycloalkylamino, arylamino, heteroarylamino, acylamino, arylacylamino, heteroarylacylamino, alkylsulfonylamino, arylsulfonylamino, acyl, arylacyl, heteroarylacyl, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, substituted aminosulfonyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl, aryloxycarbonyl, carbamoyl, substituted carbamoyl, halogen, cyano, isocyano and nitro; or R2 and R3 or R3 and R4 together with the carbons they are attached to may form a substituted or unsubstituted ring, which may be aromatic or non-aromatic and may include one or more heteroatoms in the ring and may be fused with an aromatic or aliphatic ring; and RI and Rfl are independently selected from the groups consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, aryl, heteroaryl, acyl, arylacyl, heteroarylacyl, sulfonyl, aminosulfonyl, substituted aminosulfonyl, alkoxycarbonyl, cycloalkyloxycarbonyl, aryloxycarbonyl, carbamoyl and substituted carbamoyl, provided that RI and Rfl can't both be hydrogen, wherein said pharmaceutical composition is suitable for human or animal administration.

[000013] The present invention further provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound selected from the group consisting of: 3-amino-N-cyclohexy1-6,7,8,9-tetrahydro-5H-cyclohepta[b]thieno[3,2-e]pyridine-2-carboxamide; 3-amino-N-buty1-6,7,8,9-tetrahydro-5H-cyclohepta[b]thieno[3,2-e]pyridine-2-carboxamide; 3-amino-N-(tert-buty1)-6,7,8,9-tetrahydro-5H-cyclohepta[b]thieno[3,2-e]pyridine-2-carboxamide; 3-amino-6-methyl-N-(5-pheny1-1,3,4-thiadiazol-2-yl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-5-methyl-N-(5-pheny1-1,3,4-thiadiazol-2-yl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-4-methoxy-N-(5-pheny1-1,3,4-thiadiazol-2-yl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-4-methyl-N-(5-pheny1-1,3,4-thiadiazol-2-yl)thieno[2,3-b]pyridine-2-carboxamide; 3,5-diamino-N-(5-phenyl-1,3,4-thiadiazol-2-yl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-2-((5-pheny1-1,3,4-thiadiazol-2-yl)carbamoyl)thieno[2,3-b]pyridine-5-carboxylic acid; 3-amino-6-chloro-N-(5-phenyl-1,3,4-thiadiazol-2-yl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-methyl-N-(5-pheny1-1,3,4-thiadiazol-2-y1)-7,8-dihydro-5H-thieno[2,3-b][1,6]naphthyridine-2-carboxamide; 2-(thiophen-2-y1)-10-(3-(trifluoromethyl)pheny1)-7,8-dihydro-5H-pyrido[3',2':4,5]thieno[3,2-b][1,5]diazonine-6,9,11(10H)-trione;
7-(thiophen-2-y1)-3-(3-(trifluoromethyl)phenyl)pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione; 3-amino-6-(trifluoromethyl)-N-[3-(trifluoromethyl)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-(2,4-dimethylthiazol-5-y1)-N-[3-(trifluoromethyl)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-(2-thieny1)-N-[3-(trifluoromethyl)phenyl]thieno[2,3-b]pyridine-2-carboxamidine; 8-(thiophen-2-y1)-4-(3-(trifluoromethyl)pheny1)-3,4-dihydro-1H-pyrido[3',2':4,5]thieno[3,2-e][1,4]diazepine-2,5-dione; 3-amino-N-methy1-6-(2-thieny1)-N-[3-(trifluoromethyl)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 3-amino-N-(2-dimethylaminoethyl)-6-(2-thieny1)-N-[3-(trifluoromethyl)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 6-acetamido-3-amino-N-(4-bromopheny1)-5-cyano-4-(2-furyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-N-(4-bromopheny1)-5-cyano-4-(2-fury1)-6-hydroxy-thieno[2,3-b]pyridine-2-carboxamide; 2-[N-[3-amino-6-(2-thienyl)thieno[2,3-b]pyridine-2-carbony1]-3-(trifluoromethyl)anilino]acetic acid;
3-[N-[3-amino-6-(2-thienyl)thieno[2,3-b]pyridine-2-carbony1]-3-(trifluoromethyl)anilino]propanoic acid; 3-amino-5-oxo-N-(5-pheny1-1,3,4-thiadiazol-2-y1)-6,7,8,9-tetrahydro-5H-cyclohepta[b]thieno[3,2-e]pyridine-2-carboxamide; 3-amino-5-hydroxy-N-(5-pheny1-1,3,4-thiadiazol-2-y1)-6,7,8,9-tetrahydro-5H-cyclohepta[b]thieno[3,2-e]pyridine-2-carboxamide; 3-amino-5-fluoro-N-(5-pheny1-1,3,4-thiadiazol-2-y1)-6,7,8,9-tetrahydro-5H-cyclohepta[b]thieno[3,2-e]pyridine-2-carboxamide; 3-amino-6-(4-chloropheny1)-N-[4-(trifluoromethoxy)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-[3-

14 (trifluoromethoxy)pheny1]-N-[4-(trifluoromethoxy)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 3-amino-N,6-bis(4-chlorophenyl)thieno[2,3-b]pyridine-2-carboxamide; 4-[[3-amino-6-(4-chlorophenyl)thieno[2,3-b]pyridine-2-carbonyl]amino]benzoic acid; 3-amino-N-(5-bromo-2-pyridy1)-6-(4-chlorophenyl)thieno[2,3-b]pyridine-2-carboxamide;
3-amino-N-(6-bromo-3-pyridy1)-6-(4-chlorophenyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-(4-chloropheny1)-N-[4-(difluoromethyl)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-(4-chloropheny1)-N-[4-(1,1-difluoroethyl)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-[3-(difluoromethoxy)pheny1]-N-[4-(trifluoromethoxy)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-(4-chloropheny1)-N-[4-(difluoromethoxy)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 3-amino-N-(2-bromopheny1)-6-(4-chlorophenyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-(4-chloropheny1)-N-(3,4-dichlorophenyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-(4-chloropheny1)-N-(2,3-dichlorophenyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-N-(3-chloropheny1)-6-(4-chlorophenyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-[3-(difluoromethoxy)pheny1]-N-[4-(difluoromethoxy)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 4-[[3-amino-6-(4-chlorophenyl)thieno[2,3-b]pyridine-2-carbonyl]amino]benzenesulfonic acid; 3-amino-6-(4-chloropheny1)-N-(2,5-dichlorophenyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-(4-chloropheny1)-N-(3,4-dimethylphenyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-N-(4-bromopheny1)-6-(5-chloro-2-pyridyl)thieno[2,3-b]pyridine-2-carboxamide; 3-(N-[3-amino-6-(4-chlorophenyl)thieno[2,3-b]pyridine-2-carbony1]-4-bromo-anilino)propanoic acid; 3-amino-6-(4-chloropheny1)-N-[4-(2,2,2-trifluoroacetyl)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-(4-chloropheny1)-N-(5-chloro-2-pyridyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-(4-chloropheny1)-N-(6-chloro-3-pyridyl)thieno[2,3-b]pyridine-2-carboxamide; 3-[N-[3-amino-6-(3-methoxyphenyl)thieno[2,3-b]pyridine-2-carbony1]-4-(trifluoromethoxy)anilino]propanoic acid; 3-(N-[3-amino-6-(4-chlorophenyl)thieno[2,3-b]pyridine-2-carbony1]-4-chloro-anilino)propanoic acid; 3-amino-6-(4-chloropheny1)-N-(4-hydroxyphenyl)thieno[2,3-b]pyridine-2-carboxamide; and 3-amino-N-(4-pyridy1)-6-(2-thienyl)thieno[2,3-b]pyridine-2-carboxamide, wherein said pharmaceutical composition is suitable for human or animal administration.
[000014] The present invention further provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of: 3-amino-N-(4-bromopheny1)-6-(4-chlorophenyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-(3-methoxypheny1)-N-[4-(trifluoromethoxy)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 3-amino-N-(2,5-dichloropheny1)-6-(2-thienyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-N-(2,3-dichloropheny1)-6-(2-thienyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-N-(4-bromopheny1)-6-(3-methoxyphenyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-(1,3-benzodioxo1-5-y1)-N-(2-bromo-4-methyl-phenyl)thieno[2,3-b]pyridine-2-carboxamide; and 3-amino-6-(3-methoxypheny1)-N-(2-phenoxyphenyl)thieno[2,3-b]pyridine-2-carboxamide, wherein said pharmaceutical composition is suitable for human or animal administration.

[000015] The present invention also provides a compound having the following general Formula II or a pharmaceutically acceptable salt thereof:

16 \ R8 B I
/---I N
M I G 'R6 ----e-----X Formula II
wherein X is selected from the groups consisting of 0, S or N-R', wherein R' is selected from the groups consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, aryl, heteroaryl, acyl, arylacyl, heteroarylacyl, sulfonyl, aminosulfonyl, substituted aminosulfonyl, alkoxycarbonyl, cycloalkyloxycarbonyl, aryloxycarbonyl, carbamoyl and substituted carbamoyl;
B is N or C-R2, wherein R2 is selected from the groups consisting of hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, aryl, heteroaryl, hydroxy, alkyloxy, aryloxy, heteroaryloxy, acyloxy, arylacyloxy, heteroarylacyloxy, alkylsulfonyloxy, arylsulfonyloxy, thio, alkylthio, arylthio, amino, alkylamino, dialkylamino, cycloalkylamino, heterocycloalkylamino, arylamino, heteroarylamino, acylamino, arylacylamino, heteroarylacylamino, alkylsulfonylamino, arylsulfonylamino, acyl, arylacyl, heteroarylacyl, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, substituted aminosulfonyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl, aryloxycarbonyl, carbamoyl, substituted carbamoyl, halogen, cyano, isocyano and nitro;

17 G is selected from the group consisting of -C(=0)-, -C(=S)-, -S(=0)2-, and -C(=NR5)-, wherein R5 is selected from the groups consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, aryl, heteroaryl, acyl, arylacyl, heteroarylacyl, sulfonyl, aminosulfonyl, substituted aminosulfonyl, alkoxycarbonyl, cycloalkyloxycarbonyl, aryloxycarbonyl, carbamoyl and substituted carbamoyl; or R5 and R6 or R7, together with the nitrogen atoms they are attached to, along with the carbon of G, or R5 and R8 or R9, together with the nitrogen atoms they are attached to, along with the carbon of G
and two carbons of the X-containing 5-membered ring, may form a substituted or unsubstituted ring, which may be fused with an aromatic or aliphatic ring;
R6, R7, R8, and R9 are independently selected from the groups consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, aryl, heteroaryl, acyl, arylacyl, heteroarylacyl, sulfonyl, aminosulfonyl, substituted aminosulfonyl, alkoxycarbonyl, cycloalkyloxycarbonyl, aryloxycarbonyl, carbamoyl and substituted carbamoyl; or R6 or R7 and R5, together with the nitrogen atoms they are attached to, along with the carbon of G, or R8 or R9 and R5, together with the nitrogen atoms they are attached to, along with the carbon of G
and two carbons of the X-containing 5-membered ring, or R6 or R7 and R8 or R9, together with the nitrogen atoms they are attached to, along with the carbon or sulfur of G and two carbons of the X-containing 5-membered ring, or R6 and R7, together with the nitrogen atom they are attached to, or R8 and R9, together with the nitrogen atom they are attached to, may form a substituted or unsubstituted ring, which may be fused with an aromatic or aliphatic ring; and

18 cm M I
\---_,/
is a 7 or 8-membered ring which contains one or more heteroatoms selected from N, 0 and S, or a 4-membered ring which may optionally contain one or more heteroatoms selected from N, 0 and S. The ring may be substituted or unsubstituted, or fused with another ring, which may be aromatic or non-aromatic and may include one or more heteroatoms in the ring and may be fused with an aromatic or aliphatic ring.
[000016] The present invention also provides a compound having the following general Formula III or a pharmaceutically acceptable salt thereof:
R"

X
N
Formula III
wherein X is selected from the groups consisting of: 0, S
and N-R', wherein R' is selected from the groups consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, aryl, heteroaryl, acyl, arylacyl, heteroarylacyl,

19 sulfonyl, aminosulfonyl, substituted aminosulfonyl, alkoxycarbonyl, cycloalkyloxycarbonyl, aryloxycarbonyl, carbamoyl and substituted carbamoyl;
R is selected from the group consisting of halogen, cyano, isocyano, nitro, amino, alkylamino, dialkylamino, cycloalkylamino, heterocycloalkylamino, arylamino, heteroarylamino, acylamino, arylacylamino, heteroarylacylamino, alkylsulfonylamino, arylsulfonylamino, hydroxysulfonyl, aminosulfonyl, substituted aminosulfonyl, acyl, arylacyl, heteroarylacyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl, aryloxycarbonyl, aminocarbonyl, and substituted aminocarbonyl;
B, D, and E are independently N or C-R2, C-R2 and C-R4, respectively, wherein R2, R2 and R4 are independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, aryl, heteroaryl, hydroxy, alkyloxy, aryloxy, heteroaryloxy, acyloxy, arylacyloxy, heteroarylacyloxy, alkylsulfonyloxy, arylsulfonyloxy, thio, alkylthio, arylthio, amino, alkylamino, dialkylamino, cycloalkylamino, heterocycloalkylamino, arylamino, heteroarylamino, acylamino, arylacylamino, heteroarylacylamino, alkylsulfonylamino, arylsulfonylamino, acyl, arylacyl, heteroarylacyl, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, substituted aminosulfonyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl, aryloxycarbonyl, carbamoyl, substituted carbamoyl, halogen, cyano, isocyano and nitro; or R2 and R2 or R2 and R4 together with the carbons they are attached to may form a substituted or unsubstituted ring, which may be aromatic or non-aromatic and may include one or more heteroatoms in the ring and may be fused with an aromatic or aliphatic ring; and RI and Rfl are independently selected from the groups consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, aryl, heteroaryl, acyl, arylacyl, heteroarylacyl, sulfonyl, aminosulfonyl, substituted aminosulfonyl, alkoxycarbonyl, cycloalkyloxycarbonyl, aryloxycarbonyl, carbamoyl and substituted carbamoyl, provided that RI and Rfl can't both be hydrogen.
[000017] The present invention also provides a compound selected from the group consisting of: 3-amino-N-cyclohexy1-6,7,8,9-tetrahydro-5H-cyclohepta[b]thieno[3,2-e]pyridine-2-carboxamide; 3-amino-N-buty1-6,7,8,9-tetrahydro-5H-cyclohepta[b]thieno[3,2-e]pyridine-2-carboxamide; 3-amino-N-(tert-buty1)-6,7,8,9-tetrahydro-5H-cyclohepta[b]thieno[3,2-e]pyridine-2-carboxamide; 3-amino-6-methyl-N-(5-pheny1-1,3,4-thiadiazol-2-yl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-5-methyl-N-(5-pheny1-1,3,4-thiadiazol-2-yl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-4-methoxy-N-(5-pheny1-1,3,4-thiadiazol-2-yl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-4-methyl-N-(5-pheny1-1,3,4-thiadiazol-2-yl)thieno[2,3-b]pyridine-2-carboxamide; 3,5-diamino-N-(5-pheny1-1,3,4-thiadiazol-2-yl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-2-((5-phenyl-1,3,4-thiadiazol-2-yl)carbamoyl)thieno[2,3-b]pyridine-5-carboxylic acid; 3-amino-6-chloro-N-(5-pheny1-1,3,4-thiadiazol-2-yl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-methyl-N-(5-pheny1-1,3,4-thiadiazol-2-y1)-7,8-dihydro-5H-thieno[2,3-b][1,6]naphthyridine-2-carboxamide; 2-(thiophen-2-y1)-10-(3-(trifluoromethyl)pheny1)-7,8-dihydro-5H-pyrido[3',2':4,5]thieno[3,2-b][1,5]diazonine-6,9,11(10H)-trione;

7-(thiophen-2-y1)-3-(3-(trifluoromethyl)phenyl)pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione; 3-amino-6-(trifluoromethyl)-N-[3-(trifluoromethyl)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-(2,4-dimethylthiazol-5-y1)-N-[3-(trifluoromethyl)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-(2-thieny1)-N-[3-(trifluoromethyl)phenyl]thieno[2,3-b]pyridine-2-carboxamidine; 8-(thiophen-2-y1)-4-(3-(trifluoromethyl)pheny1)-3,4-dihydro-1H-pyrido[3',2':4,5]thieno[3,2-e][1,4]diazepine-2,5-dione; 3-amino-N-methy1-6-(2-thieny1)-N-[3-(trifluoromethyl)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 3-amino-N-(2-dimethylaminoethyl)-6-(2-thieny1)-N-[3-(trifluoromethyl)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 6-acetamido-3-amino-N-(4-bromopheny1)-5-cyano-4-(2-furyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-N-(4-bromopheny1)-5-cyano-4-(2-fury1)-6-hydroxy-thieno[2,3-b]pyridine-2-carboxamide; 2-[N-[3-amino-6-(2-thienyl)thieno[2,3-b]pyridine-2-carbony1]-3-(trifluoromethyl)anilino]acetic acid;
3-[N-[3-amino-6-(2-thienyl)thieno[2,3-b]pyridine-2-carbony1]-3-(trifluoromethyl)anilino]propanoic acid; 3-amino-5-oxo-N-(5-pheny1-1,3,4-thiadiazol-2-y1)-6,7,8,9-tetrahydro-5H-cyclohepta[b]thieno[3,2-e]pyridine-2-carboxamide; 3-amino-5-hydroxy-N-(5-pheny1-1,3,4-thiadiazol-2-y1)-6,7,8,9-tetrahydro-5H-cyclohepta[b]thieno[3,2-e]pyridine-2-carboxamide; 3-amino-5-fluoro-N-(5-pheny1-1,3,4-thiadiazol-2-y1)-6,7,8,9-tetrahydro-5H-cyclohepta[b]thieno[3,2-e]pyridine-2-carboxamide; 3-amino-6-(4-chloropheny1)-N-[4-(trifluoromethoxy)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-[3-(trifluoromethoxy)pheny1]-N-[4-(trifluoromethoxy)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 3-amino-N,6-bis(4-chlorophenyl)thieno[2,3-b]pyridine-2-carboxamide; 4-[[3-amino-6-(4-chlorophenyl)thieno[2,3-b]pyridine-2-carbonyl]amino]benzoic acid; 3-amino-N-(5-bromo-2-pyridy1)-6-(4-chlorophenyl)thieno[2,3-b]pyridine-2-carboxamide;
3-amino-N-(6-bromo-3-pyridy1)-6-(4-chlorophenyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-(4-chloropheny1)-N-[4-(difluoromethyl)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-(4-chloropheny1)-N-[4-(1,1-difluoroethyl)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-[3-(difluoromethoxy)pheny1]-N-[4-(trifluoromethoxy)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-(4-chloropheny1)-N-[4-(difluoromethoxy)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 3-amino-N-(2-bromopheny1)-6-(4-chlorophenyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-(4-chloropheny1)-N-(3,4-dichlorophenyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-(4-chloropheny1)-N-(2,3-dichlorophenyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-N-(3-chloropheny1)-6-(4-chlorophenyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-[3-(difluoromethoxy)pheny1]-N-[4-(difluoromethoxy)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 4-[[3-amino-6-(4-chlorophenyl)thieno[2,3-b]pyridine-2-carbonyl]amino]benzenesulfonic acid; 3-amino-6-(4-chloropheny1)-N-(2,5-dichlorophenyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-(4-chloropheny1)-N-(3,4-dimethylphenyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-N-(4-bromopheny1)-6-(5-chloro-2-pyridyl)thieno[2,3-b]pyridine-2-carboxamide; 3-(N-[3-amino-6-(4-chlorophenyl)thieno[2,3-b]pyridine-2-carbony1]-4-bromo-anilino)propanoic acid; 3-amino-6-(4-chloropheny1)-N-[4-(2,2,2-trifluoroacetyl)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-(4-chloropheny1)-N-(5-chloro-2-pyridyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-(4-chloropheny1)-N-(6-chloro-3-pyridyl)thieno[2,3-b]pyridine-2-carboxamide; 3-[N-[3-amino-6-(3-methoxyphenyl)thieno[2,3-b]pyridine-2-carbony1]-4-(trifluoromethoxy)anilino]propanoic acid; 3-(N-[3-amino-6-(4-chlorophenyl)thieno[2,3-b]pyridine-2-carbony1]-4-chloro-anilino)propanoic acid; 3-amino-6-(4-chloropheny1)-N-(4-hydroxyphenyl)thieno[2,3-b]pyridine-2-carboxamide; and 3-amino-N-(4-pyridy1)-6-(2-thienyl)thieno[2,3-b]pyridine-2-carboxamide.
[000018] The present invention further provides a method for the treatment of at least one type of a Dengue virus infection or disease associated therewith, comprising administering in a therapeutically effective amount to a mammal in need thereof, a compound of Formula I, II or III as indicated above or a pharmaceutically acceptable salt thereof.
[000019] The present invention also provides a method for the treatment of at least one type of a Dengue infection or disease associated therewith, comprising administering in a therapeutically effective amount to a mammal in need thereof, a compound or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of: 3-amino-N-(4-bromopheny1)-6-(4-chlorophenyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-(3-methoxypheny1)-N-[4-(trifluoromethoxy)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 3-amino-N-(2,5-dichloropheny1)-6-(2-thienyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-N-(2,3-dichloropheny1)-6-(2-thienyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-N-(4-bromopheny1)-6-(3-methoxyphenyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-(1,3-benzodioxo1-5-y1)-N-(2-bromo-4-methyl-phenyl)thieno[2,3-b]pyridine-2-carboxamide; and 3-amino-6-(3-methoxypheny1)-N-(2-phenoxyphenyl)thieno[2,3-b]pyridine-2-carboxamide.

[000020] The present invention further provides novel intermediate compounds used in the synthesis of the compounds of the present invention. These intermediate compounds are selected from the group consisting of: tert-butyl (4E)-4-(hydroxymethylene)-5-oxoazepane-1-carboxylate; tert-butyl (3E)-3-(hydroxymethylene)-4-oxoazepane-1-carboxylate; tert-butyl 3-cyano-2-thioxo-1,2,5,6,8,9-hexahydro-7H-pyrido[2,3-d]azepine-7-carboxylate; tert-butyl 3-cyano-2-thioxo-1,2,5,7,8,9-hexahydro-6H-pyrido[3,2-c]azepine-6-carboxylate; and 3-amino-7-tert-butyloxycarbony1-6,7,8,9-tetrahydro-5H-1-thia-7,10-diaza-cyclohepta[f]indene-2-carboxylic acid (5-phenyl-[1,3,4]thiadiazol-2-y1)-amide; and 3-amino-6-tert-butyloxycarbony1-6,7,8,9-tetrahydro-5H-1-thia-6,10-diaza-cyclohepta[f]indene-2-carboxylic acid (5-phenyl-[1,3,4]thiadiazol-2-y1)-amide.

[000021] The present invention further provides a method for the preparation of a mixture of tert-butyl (4E)-4-(hydroxymethylene)-5-oxoazepane-1-carboxylate and tert-butyl (3E)-3-(hydroxymethylene)-4-oxoazepane-1-carboxylate, said method comprising reacting tert-butyl 4-oxoazepane-1-carboxylate with N-[tert-butoxy(dimethylamino)methy1]-N,N-dimethylamine.

[000022] The present invention also provides a method for the preparation of a mixture of tert-butyl 3-cyano-2-thioxo-1,2,5,6,8,9-hexahydro-7H-pyrido[2,3-d]azepine-7-carboxylate and tert-butyl 3-cyano-2-thioxo-1,2,5,7,8,9-hexahydro-6H-pyrido[3,2-c]azepine-6-carboxylate said method comprising reacting a mixture of tert-butyl (4E)-4-(hydroxymethylene)-5-oxoazepane-1-carboxylate and tert-butyl (3E)-3-(hydroxymethylene)-4-oxoazepane-1-carboxylate in the presence of 2-cyanoethanethioamide and piperidine acetate.

[000023] The present invention further provides a method for the preparation of 3-amino-7-tert-butyloxycarbony1-6,7,8,9-tetrahydro-5H-1-thia-7,10-diaza-cyclohepta[f]indene-2-carboxylic acid (5-phenyl-[1,3,4]thiadiazol-2-y1)-amide comprising reacting tert-butyl 3-cyano-2-thioxo-1,2,5,6,8,9-hexahydro-7H-pyrido[2,3-d]azepine-7-carboxylate with 2-chloro-N-(5-pheny1-1,3,4-thiadiazol-2-yl)acetamide.

[000024] The present invention also provides a method for the preparation of 3-amino-6,7,8,9-tetrahydro-5H-1-thia-7,10-diaza-cyclohepta[f]indene-2-carboxylic acid (5-phenyl-[1,3,4]thiadiazol-2-y1)-amide comprising reacting 3-amino-7-tert-butyloxycarbony1-6,7,8,9-tetrahydro-5H-1-thia-7,10-diaza-cyclohepta[f]indene-2-carboxylic acid (5-phenyl-[1,3,4]thiadiazol-2-y1)-amide with HC1.

[000025] The present invention further provides a method for the preparation of 3-amino-6-tert-butyloxycarbony1-6,7,8,9-tetrahydro-5H-1-thia-6,10-diaza-cyclohepta[f]indene-2-carboxylic acid (5-phenyl-[1,3,4]thiadiazol-2-y1)-amide comprising reacting tert-butyl 3-cyano-2-thioxo-1,2,5,7,8,9-hexahydro-6H-pyrido[3,2-c]azepine-6-carboxylate with 2-chloro-N-(5-pheny1-1,3,4-thiadiazol-2-yl)acetamide.

[000026] The present invention also provides a method for the preparation of 3-amino-6,7,8,9-tetrahydro-5H-1-thia-6,10-diaza-cyclohepta[f]indene-2-carboxylic acid (5-phenyl-[1,3,4]thiadiazol-2-y1)-amide comprising reacting 3-amino-6-tert-butyloxycarbony1-6,7,8,9-tetrahydro-5H-1-thia-6,10-diaza-cyclohepta[f]indene-2-carboxylic acid (5-phenyl-[1,3,4]thiadiazol-2-y1)-amide with HC1.

[000027] Other objects and advantages of the present invention will become apparent from the following description and appended claims.
DETAILED DESCRIPTION OF THE INVENTION

[000028] The compounds of the invention are of the following general Formula I:
B A
D
I I R
Eõ
A
Formula I
wherein X is selected from the groups consisting of 0, S
and N-R', wherein R' is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, aryl, heteroaryl, acyl, arylacyl, heteroarylacyl, sulfonyl, aminosulfonyl, substituted aminosulfonyl, alkoxycarbonyl, cycloalkyloxycarbonyl, aryloxycarbonyl, carbamoyl and substituted carbamoyl;
R is selected from the group consisting of halogen, cyano, isocyano, nitro, amino, alkylamino, dialkylamino, cycloalkylamino, heterocycloalkylamino, arylamino, heteroarylamino, acylamino, arylacylamino, heteroarylacylamino, alkylsulfonylamino, arylsulfonylamino, hydroxysulfonyl, aminosulfonyl, substituted aminosulfonyl, acyl, arylacyl, heteroarylacyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl, aryloxycarbonyl, aminocarbonyl, and substituted aminocarbonyl, or R and Rltogether with the carbons they are attached to may form a substituted or unsubstituted ring; and A, B, D, and E are independently N or C_R1, C-R2, C-R2 and C-R4, respectively, wherein R1, R2, R2 and R4 are independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, aryl, heteroaryl, hydroxy, alkyloxy, aryloxy, heteroaryloxy, acyloxy, arylacyloxy, heteroarylacyloxy, alkylsulfonyloxy, arylsulfonyloxy, thio, alkylthio, arylthio, amino, alkylamino, dialkylamino, cycloalkylamino, heterocycloalkylamino, arylamino, heteroarylamino, acylamino, arylacylamino, heteroarylacylamino, alkylsulfonylamino, arylsulfonylamino, acyl, arylacyl, heteroarylacyl, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, substituted aminosulfonyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl, aryloxycarbonyl, carbamoyl, substituted carbamoyl, halogen, cyano, isocyano and nitro; or R1 and R together with the carbons they are attached to may form a substituted or unsubstituted ring, or R2 and R2 or R2 and R4 together with the carbons they are attached to may form a substituted or unsubstituted ring, which may be aromatic or non-aromatic and may include one or more heteroatoms in the ring and may be fused with an aromatic or aliphatic ring.

[000029] Preferably, for the compound of Formula I, X is S; A
is C-NH2, B is C-R2 and R2 is fluoro substituted phenyl or B is C-H; D is a C-H; E is C-R4 and R4 is a thienyl or D is C-R2 and E
is C-R4, and R2 and R4 form a ring; and/or R is a substituted aminocarbonyl.

[000030] Preferably the compound of Formula I of the present invention is selected from the group consisting of: 3-amino-6,7,8,9-tetrahydro-5H-1-thia-10-aza-cyclohepta[f]indene-2-carboxylic acid (5-phenyl-[1,3,4]thiadiazol-2-y1)-amide; 1-amino-5-methy1-6,7,8,9-tetrahydro-thieno[2,3-c]isoquinoline-2-carboxylic acid (4-methyl-thiazol-2-y1)-amide; 3,6-diamino-5-cyano-4-furan-2-yl-thieno[2,3-b]pyridine-2-carboxylic acid (4-bromo-pheny1)-amide; 3-amino-6-ethy1-5,6,7,8-tetrahydro-thieno[2,3-b][1,6]naphthyridine-2-carboxylic acid (4-trifluoromethyl-pheny1)-amide; 4-[(3-amino-6-isopropy1-5,6,7,8-tetrahydro-thieno[2,3-b][1,6]naphthyridine-2-carbony1)-amino]-benzoic acid ethyl ester; and 3-amino-6-methy1-5,6,7,8-tetrahydro-thieno[2,3-b][1,6]naphthyridine-2-carboxylic acid (4-trifluoromethoxy-pheny1)-amide.

[000031] More preferably, the compound of Formula I of the present invention is 3-amino-6,7,8,9-tetrahydro-5H-1-thia-10-aza-cyclohepta[f]indene-2-carboxylic acid (5-phenyl-[1,3,4]thiadiazol-2-y1)-amide.

[000032] The compounds of the invention are also of the following general Formula II:

\ IR8 B I

---NX Formula II
wherein X is selected from the groups consisting of 0, S or N-R', wherein R' is selected from the groups consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, aryl, heteroaryl, acyl, arylacyl, heteroarylacyl, sulfonyl, aminosulfonyl, substituted aminosulfonyl, alkoxycarbonyl, cycloalkyloxycarbonyl, aryloxycarbonyl, carbamoyl and substituted carbamoyl;
B is N or C-R2, wherein R2 is selected from the groups consisting of hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, aryl, heteroaryl, hydroxy, alkyloxy, aryloxy, heteroaryloxy, acyloxy, arylacyloxy, heteroarylacyloxy, alkylsulfonyloxy, arylsulfonyloxy, thio, alkylthio, arylthio, amino, alkylamino, dialkylamino, cycloalkylamino, heterocycloalkylamino, arylamino, heteroarylamino, acylamino, arylacylamino, heteroarylacylamino, alkylsulfonylamino, arylsulfonylamino, acyl, arylacyl, heteroarylacyl, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, substituted aminosulfonyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl, aryloxycarbonyl, carbamoyl, substituted carbamoyl, halogen, cyano, isocyano and nitro;
G is selected from the group consisting of -C(=0)-, -C(=S)-, -S(=0)2-, and -C(=NR6)-, wherein R6 is selected from the groups consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, aryl, heteroaryl, acyl, arylacyl, heteroarylacyl, sulfonyl, aminosulfonyl, substituted aminosulfonyl, alkoxycarbonyl, cycloalkyloxycarbonyl, aryloxycarbonyl, carbamoyl and substituted carbamoyl; or R6 and R6 or R2, together with the nitrogen atoms they are attached to, along with the carbon of G, or R6 and R6 or R9f together with the nitrogen atoms they are attached to, along with the carbon of G
and two carbons of the X-containing 5-membered ring, may form a substituted or unsubstituted ring, which may be fused with an aromatic or aliphatic ring;

R6, R7, R8, and R9 are independently selected from the groups consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, aryl, heteroaryl, acyl, arylacyl, heteroarylacyl, sulfonyl, aminosulfonyl, substituted aminosulfonyl, alkoxycarbonyl, cycloalkyloxycarbonyl, aryloxycarbonyl, carbamoyl and substituted carbamoyl; or R6 or R7 and R5, together with the nitrogen atoms they are attached to, along with the carbon of G, or R8 or R9 and R5, together with the nitrogen atoms they are attached to, along with the carbon of G
and two carbons of the X-containing 5-membered ring, or R6 or R7 and R8 or R9, together with the nitrogen atoms they are attached to, along with the carbon or sulfur of G and two carbons of the X-containing 5-membered ring, or R6 and R7, together with the nitrogen atom they are attached to, or R8 and R9, together with the nitrogen atom they are attached to, may form a substituted or unsubstituted ring, which may be fused with an aromatic or aliphatic ring; and /---\1 M
\_) is a 7 or 8-membered ring which contains one or more heteroatoms selected from N, 0 and S, or a 4-membered ring which may optionally contain one or more heteroatoms selected from N, 0 and S. The ring may be substituted or unsubstituted, or fused with another ring, which may be aromatic or non-aromatic and may include one or more heteroatoms in the ring and may be fused with an aromatic or aliphatic ring.

[000033] Preferably, for the compound of Formula II, X is S; B
is CH; each of R8 and R9 is H; G is -C(=0)-; R6 is a hydrogen; R7 is a heteroaryl; and is a 7-membered ring which contains N as a heteroatom.

[000034] Preferably, the compound of Formula II of the present invention is 3-amino-6,7,8,9-tetrahydro-5H-1-thia-6,10-diaza-cyclohepta[f]indene-2-carboxylic acid (5-phenyl-[1,3,4]thiadiazol-2-y1)-amide.

[000035] Also preferably, the compound of Formula II of the present invention is 3-amino-6,7,8,9-tetrahydro-5H-1-thia-7,10-diaza-cyclohepta[f]indene-2-carboxylic acid (5-phenyl-[1,3,4]thiadiazol-2-y1)-amide.

[000036] The compounds of the present invention are also of the following general Formula III:

N.00.000õRio D./13:2)c, R
EN x Formula III
wherein X is selected from the groups consisting of: 0, S
and N-R', wherein R' is selected from the groups consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, aryl, heteroaryl, acyl, arylacyl, heteroarylacyl, sulfonyl, aminosulfonyl, substituted aminosulfonyl, alkoxycarbonyl, cycloalkyloxycarbonyl, aryloxycarbonyl, carbamoyl and substituted carbamoyl;
R is selected from the group consisting of halogen, cyano, isocyano, nitro, amino, alkylamino, dialkylamino, cycloalkylamino, heterocycloalkylamino, arylamino, heteroarylamino, acylamino, arylacylamino, heteroarylacylamino, alkylsulfonylamino, arylsulfonylamino, hydroxysulfonyl, aminosulfonyl, substituted aminosulfonyl, acyl, arylacyl, heteroarylacyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl, aryloxycarbonyl, aminocarbonyl, and substituted aminocarbonyl;
B, D, and E are independently N or C-R2, C-R3 and C-R4, respectively, wherein R2, R3 and R4 are independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, aryl, heteroaryl, hydroxy, alkyloxy, aryloxy, heteroaryloxy, acyloxy, arylacyloxy, heteroarylacyloxy, alkylsulfonyloxy, arylsulfonyloxy, thio, alkylthio, arylthio, amino, alkylamino, dialkylamino, cycloalkylamino, heterocycloalkylamino, arylamino, heteroarylamino, acylamino, arylacylamino, heteroarylacylamino, alkylsulfonylamino, arylsulfonylamino, acyl, arylacyl, heteroarylacyl, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, substituted aminosulfonyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl, aryloxycarbonyl, carbamoyl, substituted carbamoyl, halogen, cyano, isocyano and nitro; or R2 and R3 or R3 and R4 together with the carbons they are attached to may form a substituted or unsubstituted ring, which may be aromatic or non-aromatic and may include one or more heteroatoms in the ring and may be fused with an aromatic or aliphatic ring; and RI and Rfl are independently selected from the groups consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, aryl, heteroaryl, acyl, arylacyl, heteroarylacyl, sulfonyl, aminosulfonyl, substituted aminosulfonyl, alkoxycarbonyl, cycloalkyloxycarbonyl, aryloxycarbonyl, carbamoyl and substituted carbamoyl, provided that RI and Rfl can't both be hydrogen.

[000037] Preferably, for the compound of Formula III, X is S; B
is C-H; D is C-H; and E is C-R4 and R4 is a heteroaryl. Also preferably, D is C-R3 and E is C-R4, and R3 and R4 form a ring.
Again preferably, R is a substituted aminocarbonyl.

[000038] Preferably, the compound of Formula III of the present invention is 3-[N-[3-amino-6-(2-thienyl)thieno[2,3-b]pyridine-2-carbony1]-3-(trifluoromethyl)anilino]propanoic acid.

[000039] The compounds of the present invention also include compounds or a pharmaceutically acceptable salt thereof selected from the group consisting of: 3-amino-N-cyclohexy1-6,7,8,9-tetrahydro-5H-cyclohepta[b]thieno[3,2-e]pyridine-2-carboxamide;
3-amino-N-buty1-6,7,8,9-tetrahydro-5H-cyclohepta[b]thieno[3,2-e]pyridine-2-carboxamide; 3-amino-N-(tert-buty1)-6,7,8,9-tetrahydro-5H-cyclohepta[b]thieno[3,2-e]pyridine-2-carboxamide;
3-amino-6-methyl-N-(5-pheny1-1,3,4-thiadiazol-2-yl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-5-methyl-N-(5-pheny1-1,3,4-thiadiazol-2-yl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-4-methoxy-N-(5-pheny1-1,3,4-thiadiazol-2-yl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-4-methyl-N-(5-pheny1-1,3,4-thiadiazol-2-yl)thieno[2,3-b]pyridine-2-carboxamide; 3,5-diamino-N-(5-phenyl-1,3,4-thiadiazol-2-yl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-2-((5-pheny1-1,3,4-thiadiazol-2-yl)carbamoyl)thieno[2,3-b]pyridine-5-carboxylic acid; 3-amino-6-chloro-N-(5-phenyl-1,3,4-thiadiazol-2-yl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-methyl-N-(5-pheny1-1,3,4-thiadiazol-2-y1)-7,8-dihydro-5H-thieno[2,3-b][1,6]naphthyridine-2-carboxamide; 2-(thiophen-2-y1)-10-(3-(trifluoromethyl)pheny1)-7,8-dihydro-5H-pyrido[3',2':4,5]thieno[3,2-b][1,5]diazonine-6,9,11(10H)-trione;
7-(thiophen-2-y1)-3-(3-(trifluoromethyl)phenyl)pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione; 3-amino-6-(trifluoromethyl)-N-[3-(trifluoromethyl)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-(2,4-dimethylthiazol-5-y1)-N-[3-(trifluoromethyl)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-(2-thieny1)-N-[3-(trifluoromethyl)phenyl]thieno[2,3-b]pyridine-2-carboxamidine; 8-(thiophen-2-y1)-4-(3-(trifluoromethyl)pheny1)-3,4-dihydro-1H-pyrido[3',2':4,5]thieno[3,2-e][1,4]diazepine-2,5-dione; 3-amino-N-methy1-6-(2-thieny1)-N-[3-(trifluoromethyl)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 3-amino-N-(2-dimethylaminoethyl)-6-(2-thieny1)-N-[3-(trifluoromethyl)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 6-acetamido-3-amino-N-(4-bromopheny1)-5-cyano-4-(2-furyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-N-(4-bromopheny1)-5-cyano-4-(2-fury1)-6-hydroxy-thieno[2,3-b]pyridine-2-carboxamide; 2-[N-[3-amino-6-(2-thienyl)thieno[2,3-b]pyridine-2-carbony1]-3-(trifluoromethyl)anilino]acetic acid;
3-[N-[3-amino-6-(2-thienyl)thieno[2,3-b]pyridine-2-carbony1]-3-(trifluoromethyl)anilino]propanoic acid; 3-amino-5-oxo-N-(5-pheny1-1,3,4-thiadiazol-2-y1)-6,7,8,9-tetrahydro-5H-cyclohepta[b]thieno[3,2-e]pyridine-2-carboxamide; 3-amino-5-hydroxy-N-(5-pheny1-1,3,4-thiadiazol-2-y1)-6,7,8,9-tetrahydro-5H-cyclohepta[b]thieno[3,2-e]pyridine-2-carboxamide; 3-amino-5-fluoro-N-(5-pheny1-1,3,4-thiadiazol-2-y1)-6,7,8,9-tetrahydro-5H-cyclohepta[b]thieno[3,2-e]pyridine-2-carboxamide; 3-amino-6-(4-chloropheny1)-N-[4-(trifluoromethoxy)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-[3-(trifluoromethoxy)pheny1]-N-[4-(trifluoromethoxy)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 3-amino-N,6-bis(4-chlorophenyl)thieno[2,3-b]pyridine-2-carboxamide; 4-[[3-amino-6-(4-chlorophenyl)thieno[2,3-b]pyridine-2-carbonyl]amino]benzoic acid; 3-amino-N-(5-bromo-2-pyridy1)-6-(4-chlorophenyl)thieno[2,3-b]pyridine-2-carboxamide;
3-amino-N-(6-bromo-3-pyridy1)-6-(4-chlorophenyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-(4-chloropheny1)-N-[4-(difluoromethyl)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-(4-chloropheny1)-N-[4-(1,1-difluoroethyl)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-[3-(difluoromethoxy)pheny1]-N-[4-(trifluoromethoxy)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-(4-chloropheny1)-N-[4-(difluoromethoxy)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 3-amino-N-(2-bromopheny1)-6-(4-chlorophenyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-(4-chloropheny1)-N-(3,4-dichlorophenyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-(4-chloropheny1)-N-(2,3-dichlorophenyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-N-(3-chloropheny1)-6-(4-chlorophenyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-[3-(difluoromethoxy)pheny1]-N-[4-(difluoromethoxy)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 4-[[3-amino-6-(4-chlorophenyl)thieno[2,3-b]pyridine-2-carbonyl]amino]benzenesulfonic acid; 3-amino-6-(4-chloropheny1)-N-(2,5-dichlorophenyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-(4-chloropheny1)-N-(3,4-dimethylphenyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-N-(4-bromopheny1)-6-(5-chloro-2-pyridyl)thieno[2,3-b]pyridine-2-carboxamide; 3-(N-[3-amino-6-(4-chlorophenyl)thieno[2,3-b]pyridine-2-carbony1]-4-bromo-anilino)propanoic acid; 3-amino-6-(4-chloropheny1)-N-[4-(2,2,2-trifluoroacetyl)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-(4-chloropheny1)-N-(5-chloro-2-pyridyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-(4-chloropheny1)-N-(6-chloro-3-pyridyl)thieno[2,3-b]pyridine-2-carboxamide; 3-[N-[3-amino-6-(3-methoxyphenyl)thieno[2,3-b]pyridine-2-carbony1]-4-(trifluoromethoxy)anilino]propanoic acid; 3-(N-[3-amino-6-(4-chlorophenyl)thieno[2,3-b]pyridine-2-carbony1]-4-chloro-anilino)propanoic acid; 3-amino-6-(4-chloropheny1)-N-(4-hydroxyphenyl)thieno[2,3-b]pyridine-2-carboxamide; and 3-amino-N-(4-pyridy1)-6-(2-thienyl)thieno[2,3-b]pyridine-2-carboxamide.
Preferred among said compounds are 3-amino-N,6-bis(4-chlorophenyl)thieno[2,3-b]pyridine-2-carboxamide and 3-amino-6-[3-(difluoromethoxy)pheny1]-N-[4-(difluoromethoxy)phenyl]thieno[2,3-b]pyridine-2-carboxamide.

[000040] The compounds of the present invention also includea compound or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of: 3-amino-N-(4-bromopheny1)-6-(4-chlorophenyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-(3-methoxypheny1)-N-[4-(trifluoromethoxy)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 3-amino-N-(2,5-dichloropheny1)-6-(2-thienyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-N-(2,3-dichloropheny1)-6-(2-thienyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-N-(4-bromopheny1)-6-(3-methoxyphenyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-(1,3-benzodioxo1-5-y1)-N-(2-bromo-4-methyl-phenyl)thieno[2,3-b]pyridine-2-carboxamide; and 3-amino-6-(3-methoxypheny1)-N-(2-phenoxyphenyl)thieno[2,3-b]pyridine-2-carboxamide. Preferably said compound is 3-amino-N-(4-bromopheny1)-6-(4-chlorophenyl)thieno[2,3-b]pyridine-2-carboxamide or 3-amino-6-(3-methoxypheny1)-N-[4-(trifluoromethoxy)phenyl]thieno[2,3-b]pyridine-2-carboxamide.

[000041] The method of the present invention is for the treatment of at least one type of a Dengue virus infection or disease associated therewith (each type of Dengue virus infection being caused by a Dengue virus serotype), comprising administering in a therapeutically effective amount to a mammal in need thereof, a compound of Formula I, Formula II, Formula III or other compounds of the present invention as described above.

[000042] Preferably, the mammal is a human and the viral infection is a flavivirus infection. More preferably, the flavivirus is selected from the group consisting of Dengue virus, West Nile virus, yellow fever virus, Japanese encephalitis virus, and tick-borne encephalitis virus. Most preferably, the flavivirus is a Dengue virus selected from the group consisting of DEN-1, DEN-2, DEN-3, and DEN-4.

[000043] Preferably, the viral infection is associated with a condition selected from the group consisting of Dengue fever, Yellow fever, West Nile, St. Louis encephalitis, Hepatitis C, Murray Valley encephalitis, and Japanese encephalitis. Most preferably, the viral infection is associated with Dengue fever wherein said Dengue fever is selected from the group consisting of classical dengue fever and dengue hemorrhagic fever.

[000044] The method of the present invention may also comprise co-administration of: a) other antivirals; b) vaccines; and/or c) interferons or pegylated interferons.

[000045] The present invention also provides for methods of synthesis of compounds of the present invention, in particular 3-amino-6,7,8,9-tetrahydro-5H-1-thia-7,10-diaza-cyclohepta[f]indene-2-carboxylic acid (5-phenyl-[1,3,4]thiadiazol-2-y1)-amide and 3-amino-6,7,8,9-tetrahydro-5H-1-thia-6,10-diaza-cyclohepta[f]indene-2-carboxylic acid (5-phenyl-[1,3,4]thiadiazol-2-y1)-amide. These methods of synthesis are provided below in Examples 14 and 15.

[000046] Novel Intermediates in the synthesis of the compounds of the present invention include but are not limited to each of tert-butyl (4E)-4-(hydroxymethylene)-5-oxoazepane-1-carboxylate;
tert-butyl (3E)-3-(hydroxymethylene)-4-oxoazepane-1-carboxylate;
tert-butyl 3-cyano-2-thioxo-1,2,5,6,8,9-hexahydro-7H-pyrido[2,3-d]azepine-7-carboxylate; tert-butyl 3-cyano-2-thioxo-1,2,5,7,8,9-hexahydro-6H-pyrido[3,2-c]azepine-6-carboxylate; and 3-amino-7-tert-butyloxycarbony1-6,7,8,9-tetrahydro-5H-1-thia-7,10-diaza-cyclohepta[f]indene-2-carboxylic acid (5-phenyl-[1,3,4]thiadiazol-2-y1)-amide; and 3-amino-6-tert-butyloxycarbony1-6,7,8,9-tetrahydro-5H-1-thia-6,10-diaza-cyclohepta[f]indene-2-carboxylic acid (5-phenyl-[1,3,4]thiadiazol-2-y1)-amide.
DEFINITIONS

[000047] In accordance with this detailed description, the following abbreviations and definitions apply. It must be noted that as used herein, the singular forms "a", "an", and "the"

include plural referents unless the context clearly dictates otherwise.

[000048] The publications discussed herein are provided solely for their disclosure. Nothing herein is to be construed as an admission regarding antedating the publications. Further, the dates of publication provided may be different from the actual publications dates, which may need to be independently confirmed.

[000049] Where a range of values is provided, it is understood that each intervening value is encompassed. The upper and lower limits of these smaller ranges may independently be included in the smaller, subject to any specifically-excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either both of those included limits are also included in the invention. Also contemplated are any values that fall within the cited ranges.

[000050] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Any methods and materials similar or equivalent to those described herein can also be used in practice or testing. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.

[000051] By "patient" or "subject" is meant to include any mammal. A "mammal", for purposes of treatment, refers to any animal classified as a mammal, including but not limited to, humans, experimental animals including rats, mice, and guinea pigs, domestic and farm animals, and zoo, sports, or pet animals, such as dogs, horses, cats, cows, and the like.

[000052] The term "efficacy" as used herein refers to the effectiveness of a particular treatment regime. Efficacy can be measured based on change of the course of the disease in response to an agent.

[000053] The term "success" as used herein in the context of a chronic treatment regime refers to the effectiveness of a particular treatment regime. This includes a balance of efficacy, toxicity (e.g., side effects and patient tolerance of a formulation or dosage unit), patient compliance, and the like.
For a chronic administration regime to be considered "successful" it must balance different aspects of patient care and efficacy to produce a favorable patient outcome.

[000054] The terms "treating", "treatment", and the like are used herein to refer to obtaining a desired pharmacological and physiological effect. The effect may be prophylactic in terms of preventing or partially preventing a disease, symptom, or condition thereof and/or may be therapeutic in terms of a partial or complete cure of a disease, condition, symptom, or adverse effect attributed to the disease. The term "treatment", as used herein, covers any treatment of a disease in a mammal, such as a human, and includes: (a) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it, i.e., causing the clinical symptoms of the disease not to develop in a subject that may be predisposed to the disease but does not yet experience or display symptoms of the disease; (b) inhibiting the disease, i.e., arresting or reducing the development of the disease or its clinical symptoms; and (c) relieving the disease, i.e., causing regression of the disease and/or its symptoms or condition. Treating a patient's suffering from disease related to a pathological inflammation is contemplated. Preventing, inhibiting, or relieving adverse effects attributed to pathological inflammation over long periods of time and/or are such caused by the physiological responses to inappropriate inflammation present in a biological system over long periods of time are also contemplated.

[000055] As used herein, "acyl" refers to the groups H-C(0)-, alkyl-C(0)-, substituted alkyl-C(0)-, alkenyl-C(0)-, substituted alkenyl-C(0)-, alkynyl-C(0)-, substituted alkynyl-C(0)-, cycloalkyl-C(0)-, substituted cycloalkyl-C(0)-, aryl-C(0)-, substituted aryl-C(0)-, heteroaryl-C(0)-, substituted heteroaryl-C(0)-, heterocyclic-C(0)-, and substituted heterocyclic-C(0)- wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

[000056] "Alkylamino" refers to the group -NRR where each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and where each R is joined to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

[000057] "Alkenyl" refers to alkenyl group preferably having from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-2 sites of alkenyl unsaturation.

[000058] "Alkoxy" refers to the group "alkyl-O-" which includes, by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.

[000059] "Alkyl" refers to linear or branched alkyl groups having from 1 to 10 carbon atoms, alternatively 1 to 6 carbon atoms. This term is exemplified by groups such as methyl, t-butyl, n-heptyl, octyl and the like.

[000060] "Amino" refers to the group -NH2.

[000061] "Aryl" or "Ar" refers to an unsaturated aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) which condensed rings may or may not be aromatic (e.g., 2-benzoxazolinone, 2H-1,4-benzoxazin-3(4H)-one, and the like) provided that the point of attachment is through an aromatic ring atom.

[000062] "Substituted aryl" refers to aryl groups which are substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amidino, alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, carboxylamido, cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thioheteroaryl, substituted thioheteroaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic, substituted thioheterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, halo, nitro, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -S(0)2-alkyl, -S(0)2-substituted alkyl, -S(0)2-cycloalkyl, -S(0)2-substituted cycloalkyl, -S(0)2-alkenyl, -S(0)2-substituted alkenyl, -S(0)2-aryl, -S(0)2-substituted aryl, -S(0)2-heteroaryl, -S(0)2-substituted heteroaryl, -S(0)2-heterocyclic, -S(0)2-substituted heterocyclic, -0S(0)2-alkyl, -05(0)2-substituted alkyl, -0S(0)2-aryl, -0S(0)2-substiruted aryl, -0S(0)2-heteroaryl, -05(0)2-substituted heteroaryl, -05(0)2-heterocyclic, -0S(0)2-substituted heterocyclic, -0S(0)2-NRR where R is hydrogen or alkyl, -NRS(0)2-alkyl, -NRS(0)2-substituted alkyl, -NRS(0)2-aryl, -NRS(0)2-substituted aryl, -NRS(0)2-heteroaryl, -NRS(0)2-substituted heteroaryl, -NRS(0)2-heterocyclic, -NRS(0)2-substituted heterocyclic, -NRS(0)2-NR-alkyl, -NRS(0)2-NR-substituted alkyl, -NRS(0)2-NR-aryl, -NRS(0)2-NR-substiruted aryl, -NRS(0)2-NR-heteroaryl, -NRS(0)2-NR-substituted heteroaryl, -NRS(0)2-NR-heterocyclic, -NRS(0)2-NR-substiruted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono-and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and amino groups on the substituted aryl blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or substituted with -SO2NRR where R is hydrogen or alkyl.

[000063] "Cycloalkyl" refers to cyclic alkyl groups of from 3 to 8 carbon atoms having a single cyclic ring including, by way of example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl and the like. Excluded from this definition are multi-ring alkyl groups such as adamantanyl, etc.

[000064] "Halo" or "halogen" refers to fluoro, chloro, bromo and iodo.

[000065] "Heteroaryl" refers to an aromatic carbocyclic group of from 2 to 10 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur within the ring or oxides thereof. Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl) wherein one or more of the condensed rings may or may not be aromatic provided that the point of attachment is through an aromatic ring atom.
Additionally, the heteroatoms of the heteroaryl group may be oxidized, i.e., to form pyridine N-oxides or 1,1-dioxo-1,2,5-thiadiazoles and the like. Additionally, the carbon atoms of the ring may be substituted with an oxo (=0). The term "heteroaryl having two nitrogen atoms in the heteroaryl, ring" refers to a heteroaryl group having two, and only two, nitrogen atoms in the heteroaryl ring and optionally containing 1 or 2 other heteroatoms in the heteroaryl ring, such as oxygen or sulfur.

[000066] "Substituted heteroaryl" refers to heteroaryl groups which are substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amidino, alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, carboxylamido, cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thioheteroaryl, substituted thioheteroaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic, substituted thioheterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, halo, nitro, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -S(0)2-alkyl, -S(0)2-substituted alkyl, -S(0)2-cycloalkyl, -S(0)2-substituted cycloalkyl, -S(0)2-alkenyl, -S(0)2-substituted alkenyl, -S(0)2-aryl, -S(0)2-substituted aryl, -S(0)2-heteroaryl, -S(0)2-substituted heteroaryl, -S(0)2-heterocyclic,-S(0)2-substituted heterocyclic, -0S(0)2-alkyl, -OS(0)2-substituted alkyl, -0S(0)2-aryl, -0S(0)2-substituted aryl, -0S(0)2-heteroaryl, -0S(0)2-substituted heteroaryl, -05(0)2-heterocyclic, -0S(0)2-substituted heterocyclic, -0S02-NRR where R
is hydrogen or alkyl, -NRS(0)2-alkyl, -NRS(0)2-substituted alkyl, -NRS(0)2-aryl, -NRS(0)2-substituted aryl, -NRS(0)2-heteroaryl, -NRS(0)2-substituted heteroaryl, -NRS(0)2-heterocyclic, -NRS(0)2-substituted heterocyclic, -NRS(0)2-NR-alkyl, -NRS(0)2-NR-substiruted alkyl, -NRS(0)2-NR-aryl, -NRS(0)2-NR-substituted aryl, -NRS(0)2-NR-heteroaryl, -NRS(0)2-NR-substituted heteroaryl, -NRS(0)2-NR-heterocyclic, -NRS(0)2-NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono-and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and amino groups on the substituted aryl blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or substituted with -SO2NRR where R is hydrogen or alkyl.

[000067] "Sulfonyl" refers to the group -S(0)2R where R is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

[000068] "Optionally substituted" means that the recited group may be unsubstituted or the recited group may be substituted.

[000069] "Pharmaceutically-acceptable carrier" means a carrier that is useful in preparing a pharmaceutical composition or formulation that is generally safe, non-toxic, and neither biologically nor otherwise undesirable, and includes a carrier that is acceptable for veterinary use as well as human pharmaceutical use.

[000070] "Pharmaceutically-acceptable cation" refers to the cation of a pharmaceutically-acceptable salt.

[000071] "Pharmaceutically-acceptable salt" refers to salts which retain the biological effectiveness and properties of compounds which are not biologically or otherwise undesirable.
Pharmaceutically-acceptable salts refer to pharmaceutically-acceptable salts of the compounds, which salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like;
and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.

[000072] Pharmaceutically-acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines, di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenyl amines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines, di(substituted alkenyl) amines, tri(substituted alkenyl) amines, cycloalkyl amines, di(cycloalkyl) amines, tri(cycloalkyl) amines, substituted cycloalkyl amines, disubstituted cycloalkyl amine, trisubstituted cycloalkyl amines, cycloalkenyl amines, di(cycloalkenyl) amines, tri(cycloalkenyl) amines, substituted cycloalkenyl amines, disubstituted cycloalkenyl amine, trisubstituted cycloalkenyl amines, aryl amines, diaryl amines, triaryl amines, heteroaryl amines, diheteroaryl amines, triheteroaryl amines, heterocyclic amines, diheterocyclic amines, triheterocyclic amines, mixed di- and tri-amines where at least two of the substituents on the amine are different and are selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic, and the like. Also included are amines where the two or three substituents, together with the amino nitrogen, form a heterocyclic or heteroaryl group.

[000073] Examples of suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine, purines, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like. It should also be understood that other carboxylic acid derivatives would be useful, for example, carboxylic acid amides, including carboxamides, lower alkyl carboxamides, dialkyl carboxamides, and the like.

[000074] Pharmaceutically-acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like.

[000075] A compound may act as a pro-drug. Pro-drug means any compound which releases an active parent drug in vivo when such pro-drug is administered to a mammalian subject. Pro-drugs are prepared by modifying functional groups present in such a way that the modifications may be cleaved in vivo to release the parent compound. Pro-drugs include compounds wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, or sulfhydryl group, respectively. Examples of pro-drugs include, but are not limited to esters (e.g., acetate, formate, and benzoate derivatives), carbamates (e.g., N,N-dimethylamino-carbonyl) of hydroxy functional groups, and the like.

[000076] "Treating" or "treatment" of a disease includes:
(1) preventing the disease, i.e. causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease, (2) inhibiting the disease, i.e., arresting or reducing the development of the disease or its clinical symptoms, or (3) relieving the disease, i.e., causing regression of the disease or its clinical symptoms.

[000077] A "therapeutically-effective amount" means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease.
The "therapeutically-effective amount" will vary depending on the compound, the disease, and its severity and the age, weight, etc., of the mammal to be treated.
Pharmaceutical Formulations of the Compounds

[000078] "Pharmaceutical composition" refers to a composition intended and suitable for human or animal administration. A
composition containing a compound of the present invention dissolved in a solvent such as water, organic solvent, alcohol or DMSO for the intended purpose of in-vitro testing or for any type of testing outside of an animal or human body is not considered a pharmaceutical composition as defined herein.

[000079] In general, compounds will be administered in a therapeutically-effective amount by any of the accepted modes of administration for these compounds. The compounds can be administered by a variety of routes, including, but not limited to, oral, parenteral (e.g., subcutaneous, subdural, intravenous, intramuscular, intrathecal, intraperitoneal, intracerebral, intraarterial, or intralesional routes of administration), topical, intranasal, localized (e.g., surgical application or surgical suppository), rectal, and pulmonary (e.g., aerosols, inhalation, or powder). Accordingly, these compounds are effective as both injectable and oral compositions. The compounds can be administered continuously by infusion or by bolus injection.

[000080] The actual amount of the compound, i.e., the active ingredient, will depend on a number of factors, such as the severity of the disease, i.e., the condition or disease to be treated, age, and relative health of the subject, the potency of the compound used, the route and form of administration, and other factors.

[000081] Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50/ED50.

[000082] The data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of such compounds lies within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. For any compound used, the therapeutically-effective dose can be estimated initially from cell culture assays. A
dose may be formulated in animal models to achieve a circulating plasma concentration range which includes the IC50 (i.e., the concentration of the test compound which achieves a half-maximal inhibition of symptoms) as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Levels in plasma may be measured, for example, by high performance liquid chromatography.

[000083] The amount of the pharmaceutical composition administered to the patient will vary depending upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, the state of the patient, the manner of administration, and the like. In therapeutic applications, compositions are administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. An amount adequate to accomplish this is defined as "therapeutically-effective dose." Amounts effective for this use will depend on the disease condition being treated as well as by the judgment of the attending clinician depending upon factors such as the severity of the inflammation, the age, weight, and general condition of the patient, and the like.

[000084] The compositions administered to a patient are in the form of pharmaceutical compositions described supra. These compositions may be sterilized by conventional sterilization techniques, or may be sterile filtered. The resulting aqueous solutions may be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.

[000085] The active compound is effective over a wide dosage range and is generally administered in a pharmaceutically- or therapeutically-effective amount. The therapeutic dosage of the compounds will vary according to, for example, the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. For example, for intravenous administration, the dose will typically be in the range of about 0.5 mg to about 100 mg per kilogram body weight. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems. Typically, the clinician will administer the compound until a dosage is reached that achieves the desired effect.

[000086] When employed as pharmaceuticals, the compounds are usually administered in the form of pharmaceutical compositions.
Pharmaceutical compositions contain as the active ingredient one or more of the compounds above, associated with one or more pharmaceutically-acceptable carriers or excipients. The excipient employed is typically one suitable for administration to human subjects or other mammals. In making the compositions, the active ingredient is usually mixed with an excipient, diluted by an excipient, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container.
When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier, or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

[000087] In preparing a formulation, it may be necessary to mill the active compound to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it ordinarily is milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size is normally adjusted by milling to provide a substantially uniform distribution in the formulation, e.g., about 40 mesh.

[000088] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents;
emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents. The compositions of the invention can be formulated so as to provide quick, sustained, or delayed-release of the active ingredient after administration to the patient by employing procedures known in the art.

[000089] The quantity of active compound in the pharmaceutical composition and unit dosage form thereof may be varied or adjusted widely depending upon the particular application, the manner or introduction, the potency of the particular compound, and the desired concentration. The term "unit dosage forms"
refers to physically-discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.

[000090] The compound can be formulated for parenteral administration in a suitable inert carrier, such as a sterile physiological saline solution. The dose administered will be determined by route of administration.

[000091] Administration of therapeutic agents by intravenous formulation is well known in the pharmaceutical industry. An intravenous formulation should possess certain qualities aside from being just a composition in which the therapeutic agent is soluble. For example, the formulation should promote the overall stability of the active ingredient(s), also, the manufacture of the formulation should be cost-effective. All of these factors ultimately determine the overall success and usefulness of an intravenous formulation.

[000092] Other accessory additives that may be included in pharmaceutical formulations and compounds as follow: solvents:
ethanol, glycerol, propylene glycol; stabilizers: EDTA (ethylene diamine tetraacetic acid), citric acid; antimicrobial preservatives: benzyl alcohol, methyl paraben, propyl paraben;
buffering agents: citric acid/sodium citrate, potassium hydrogen tartrate, sodium hydrogen tartrate, acetic acid/sodium acetate, maleic acid/sodium maleate, sodium hydrogen phthalate, phosphoric acid/potassium dihydrogen phosphate, phosphoric acid/disodium hydrogen phosphate; and tonicity modifiers: sodium chloride, mannitol, dextrose.

[000093] The presence of a buffer is necessary to maintain the aqueous pH in the range of from about 4 to about 8. The buffer system is generally a mixture of a weak acid and a soluble salt thereof, e.g., sodium citrate/citric acid; or the monocation or dication salt of a dibasic acid, e.g., potassium hydrogen tartrate; sodium hydrogen tartrate, phosphoric acid/potassium dihydrogen phosphate, and phosphoric acid/disodium hydrogen phosphate.

[000094] The amount of buffer system used is dependent on (1) the desired pH; and (2) the amount of drug. Generally, the amount of buffer used is able to maintain a formulation pH in the range of 4 to 8. Generally, a 1:1 to 10:1 mole ratio of buffer (where the moles of buffer are taken as the combined moles of the buffer ingredients, e.g., sodium citrate and citric acid) to drug is used.

[000095] A useful buffer is sodium citrate/citric acid in the range of 5 to 50 mg per ml. sodium citrate to 1 to 15 mg per ml.
citric acid, sufficient to maintain an aqueous pH of 4-6 of the composition.

[000096] The buffer agent may also be present to prevent the precipitation of the drug through soluble metal complex formation with dissolved metal ions, e.g., Ca, Mg, Fe, Al, Ba, which may leach out of glass containers or rubber stoppers or be present in ordinary tap water. The agent may act as a competitive complexing agent with the drug and produce a soluble metal complex leading to the presence of undesirable particulates.

[000097] In addition, the presence of an agent, e.g., sodium chloride in an amount of about of 1-8 mg/ml, to adjust the tonicity to the same value of human blood may be required to avoid the swelling or shrinkage of erythrocytes upon administration of the intravenous formulation leading to undesirable side effects such as nausea or diarrhea and possibly to associated blood disorders. In general, the tonicity of the formulation matches that of human blood which is in the range of 282 to 288 mOsm/kg, and in general is 285 mOsm/kg, which is equivalent to the osmotic pressure corresponding to a 0.9%
solution of sodium chloride.

[000098] An intravenous formulation can be administered by direct intravenous injection, i.v. bolus, or can be administered by infusion by addition to an appropriate infusion solution such as 0.9% sodium chloride injection or other compatible infusion solution.

[000099] The compositions are preferably formulated in a unit dosage form, each dosage containing from about 5 to about 100 mg, more usually about 10 to about 30 mg, of the active ingredient. The term "unit dosage forms" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.

[0000100] The active compound is effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0000101] For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention.
When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, 0.1 to about 2000 mg of the active ingredient.

[0000102] The tablets or pills may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A
variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.

[0000103] The liquid forms in which the novel compositions may be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[0000104] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically-acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
The liquid or solid compositions may contain suitable pharmaceutically-acceptable excipients as described supra.
Compositions in pharmaceutically-acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device may be attached to a face masks tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered from devices which deliver the formulation in an appropriate manner.

[0000105] The compounds can be administered in a sustained release form. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the compounds, which matrices are in the form of shaped articles, e.g., films, or microcapsules.
Examples of sustained-release matrices include polyesters, hydrogels (e.g., poly(2- hydroxyethyl-methacrylate) as described by Langer et al., J. Biomed. Mater. Res. 15: 167-277 (1981) and Langer, Chem. Tech. 12: 98-105 (1982) or poly(vinyl alcohol)), polylactides (U.S. Patent No. 3,773,919), copolymers of L-glutamic acid and gamma ethyl-L-glutamate (Sidman et al., Biopolymers 22: 547-556, 1983), non-degradable ethylene-vinyl acetate (Langer et al., supra), degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOTTm (i.e., injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid (EP
133,988).

[0000106] The compounds can be administered in a sustained-release form, for example a depot injection, implant preparation, or osmotic pump, which can be formulated in such a manner as to permit a sustained-release of the active ingredient. Implants for sustained-release formulations are well-known in the art. Implants may be formulated as, including but not limited to, microspheres, slabs, with biodegradable or non-biodegradable polymers. For example, polymers of lactic acid and/or glycolic acid form an erodible polymer that is well-tolerated by the host.

[0000107] Transdermal delivery devices ("patches") may also be employed. Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Patent No. 5,023,252, issued June 11, 1991, herein incorporated by reference. Such patches may be constructed for continuous, pulsatile, or on-demand delivery of pharmaceutical agents.

[0000108] Direct or indirect placement techniques may be used when it is desirable or necessary to introduce the pharmaceutical composition to the brain. Direct techniques usually involve placement of a drug delivery catheter into the host's ventricular system to bypass the blood-brain barrier.
One such implantable delivery system used for the transport of biological factors to specific anatomical regions of the body is described in U.S. Patent No. 5,011,472, which is herein incorporated by reference.

[0000109] Indirect techniques usually involve formulating the compositions to provide for drug latentiation by the conversion of hydrophilic drugs into lipid-soluble drugs. Latentiation is generally achieved through blocking of the hydroxy, carbonyl, sulfate, and primary amine groups present on the drug to render the drug more lipid-soluble and amenable to transportation across the blood-brain barrier. Alternatively, the delivery of hydrophilic drugs may be enhanced by intra-arterial infusion of hypertonic solutions which can transiently open the blood-brain barrier.

[0000110] In order to enhance serum half-life, the compounds may be encapsulated, introduced into the lumen of liposomes, prepared as a colloid, or other conventional techniques may be employed which provide an extended serum half-life of the compounds. A variety of methods are available for preparing liposomes, as described in, e.g., Szoka et al., U.S. Patent Nos.
4,235,871, 4,501,728 and 4,837,028 each of which is incorporated herein by reference.

[0000111] Pharmaceutical compositions are suitable for use in a variety of drug delivery systems. Suitable formulations for use in the present invention are found in Remington's Pharmaceutical Sciences, Mace Publishing Company, Philadelphia, PA, 17th ed.
(1985).

[0000112] In the examples below, if an abbreviation is not defined above, it has its generally accepted meaning. Further, all temperatures are in degrees Celsius (unless otherwise indicated). The following Methods were used to prepare the compounds set forth below as indicated.
Example 1 ¨ Formulation 1

[0000113] Hard gelatin capsules containing the following ingredients are prepared:
Quantity Ingredient (mg/capsule) Active Ingredient 30.0 Starch 305.0 Magnesium stearate 5.0

[0000114] The above ingredients are mixed and filled into hard gelatin capsules in 340 mg quantities.
Example 2- Formulation 2

[0000115] A tablet formula is prepared using the ingredients below:
Quantity Ingredient (mg/capsule) Active ingredient 25.0 Cellulose, microcrystalline 200.0 Colloidal silicon dioxide 10.0 Stearic acid 5.0

[0000116] The components are blended and compressed to form tablets, each weighing 240 mg.
Example 3 ¨ Formulation 3

[0000117] A dry powder inhaler formulation is prepared containing the following components:
Ingredient Weight%
Active Ingredient 5 Lactose 95

[0000118] The active mixture is mixed with the lactose and the mixture is added to a dry powder inhaling appliance.
Example 4 ¨ Formulation 4

[0000119] Tablets, each containing 30 mg of active ingredient, are prepared as follows:
Quantity Ingredient (mg/capsule) Active Ingredient 30.0 mg Starch 45.0 mg Microcrystalline cellulose 35.0 mg Polyvinylpyrrolidone (as 10% solution in water) 4.0 mg Sodium Carboxymethyl starch 4.5 mg Magnesium stearate 0.5 mg Talc 1.0 mg Total 120mg

[0000120] The active ingredient, starch, and cellulose are passed through a No. 20 mesh U.S. sieve and mixed thoroughly.
The solution of polyvinyl-pyrrolidone is mixed with the resultant powders, which are then passed through a 16 mesh U.S.
sieve. The granules so produced are dried at 50 to 60 C and passed through a 16 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No. 30 mesh U.S. sieve, are then added to the granules, which after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.
Example 5 ¨ Formulation 5

[0000121]
Capsules, each containing 40 mg of medicament, are made as follows:
Quantity Ingredient (mg/capsule) Active Ingredient 40.0 mg Starch 109.0 mg Magnesium stearate 1.0 mg Total 150.0 mg

[0000122] The active ingredient, cellulose, starch, an magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 150 mg quantities.

Example 6 ¨ Formulation 6

[0000123] Suppositories, each containing 25 mg of active ingredient, are made as follows:
Ingredient Amount Active Ingredient 25 mg Saturated fatty acids glycerides to 2,000 mg

[0000124] The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2.0 g capacity and allowed to cool.
Example 7 ¨ Formulation 7

[0000125] Suspensions, each containing 50 mg of medicament per 5.0 ml dose, are made as follows:
Ingredient Amount Active Ingredient 50.0 mg Xanthan gum 4.0 mg Sodium carboxymethyl cellose (11%) Microcrystalline cellulose (89%) 500 mg Sucrose 1.75 g Sodium benzoate 10.0 mg Flavor and color q.v.
Purified water to 5.0 ml

[0000126] The medicament, sucrose, and xanthan gum are blended, passed through a NO. 10 mesh U.S. sieve, and then mixed with a previously made solution of the microcrystalline cellulose and sodium carboxymethyl cellulose in water. The sodium benzoate, flavor, and color are diluted with some of the water and added with stirring. Sufficient water is then added to produce the required volume.
Example 8 ¨ Formulation 8

[0000127] Hard gelatin tablets, each containing 15 mg of active ingredient, are made as follows:
Quantity Ingredient (mg/capsule) Active Ingredient 15.0 mg Starch 407.0 mg Magnesium stearate 3.0 mg Total 425.0 mg

[0000128] The active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S.
sieve, and filled into hard gelatin capsules in 560 mg quantities.
Example 9 ¨ Formulation 9

[0000129] An intravenous formulation may be prepared as follows:

Ingredient (mg/capsule) Active Ingredient 250.0 mg Isotonic saline 1000 ml

[0000130] Therapeutic compound compositions generally are placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle or similar sharp instrument.
Example 10 ¨ Formulation 10

[0000131] A topical formulation may be prepared as follows:
Ingredient Quantity Active Ingredient 1-10 g Emulsifying Wax 30 g Liquid Paraffin 20 g White Soft Paraffin to 100 g

[0000132] The white soft paraffin is heated until molten. The liquid paraffin and emulsifying wax are incorporated and stirred until dissolved. The active ingredient is added and stirring is continued until dispersed. The mixture is then cooled until solid.
Example 11 ¨ Formulation 11

[0000133] An aerosol formulation may be prepared as follows: A
solution of the candidate compound in 0.5% sodium bicarbonate/saline (w/v) at a concentration of 30.0 mg/mL is prepared using the following procedure:

[0000134] Preparation of 0.5% Sodium Bicarbonate / Saline Stock Solution: 100.0mL
Ingredient Gram/100.0 mL Final Concentration Sodium Bicarbonate 0.5 g 0.5%
Saline q.s. ad 100.0 mL q.s. ad 100%
Procedure:
1. Add 0.5g sodium bicarbonate into a 100 mL volumetric flask.
2. Add approximately 90.0 mL saline and sonicate until dissolved.
3. Q.S. to 100.0 mL with saline and mix thoroughly.

[0000135] Preparation of 30.0 mg/mL Candidate Compound: 10.0 mL
Ingredient Gram/100.0 mL Final Concentration Candidate Compound 0.300 g 30.0 mg/mL
.05% Sodium q.s. ad 10.0 mL q.s. ad 100%
Bicarbonate/Saline Stock Solution Procedure:
1. Add 0.300 g of the candidate compound into a 10.0 mL
volumetric flask.
2. Add approximately 9.7 mL of 0.5% sodium bicarbonate / saline stock solution.

3. Sonicate until the candidate compound is completely dissolved.
4. Q.S. to 10.0 mL with 0.5% sodium bicarbonate / saline stock solution and mix.
Example 12 ¨ Development of a high-throughput screening assay for measurement of dengue virus-induced cytopathic effect.

[0000136] A sensitive and reproducible high-throughput screening (HIS) assay has been established to measure dengue virus-induced cytopathic effect (CPE). To determine the amount of dengue virus stock required to produce complete CPE in 5 days, Vero cell monolayers were seeded on 96-well plates and infected with 10-fold serial dilutions of the dengue virus stock representing a multiplicity of infection (MOI) of approximately 0.001 PFU/cell to 0.1 PFU/cell. At 5 days post-infection, the cultures were fixed with 5% glutaraldehyde and stained with 0.1%
crystal violet. Virus-induced CPE was quantified spectrophotometrically at 0D570. From this analysis, an MOI of 0.1 PFU/cell of dengue virus stock was chosen for use in the HIS
assay. To establish the signal-to-noise ratio (S/N) of the 96-well assay and evaluate the well-to-well and assay-to-assay variability, five independent experiments were performed. Vero cell monolayers were infected with 0.1 PFU/cell of dengue virus stock. Each plate contained the following controls:
quadruplicate virus-infected wells, quadruplicate uninfected cell wells and a dose response curve in duplicate for ribavirin at 500, 250, 125 and 62 pM, as reference standards. At day 5 post-infection, the plates were processed as described above.

[0000137] The dengue virus CPE assay was used to evaluate compounds from the SIGA chemical library for those that inhibit dengue virus-induced CPE. Each evaluation run consisted of 48 96-well plates with 80 compounds per plate to generate 4,608 data points per run. At this throughput we are capable of evaluating 200,000 compounds in about 52 weeks. Compounds were dissolved in DMSO and diluted in medium such that the final concentration in each well was 5 pM compound and 0.5% DMSO. The compounds were added robotically to the culture medium using the PerkinElmer MultiPROBEO II HT PLUS robotic system. Following compound addition, cultures were infected with dengue virus (DEN-2 strain New Guinea C). After 5 days incubation, plates were processed and CPE quantified on a PerkinElmer EnVision II
plate reader system.

[0000138] The results of these experiments indicated that the 96-well assay format is robust and reproducible. The S/N ratio (ratio of signal of cell control wells (signal) to virus control wells (noise)) was 5.0 1.2. The well-to-well variability was determined for each individual plate and found to have a coefficient of variance of less than 10% for both positive control and negative control wells, and overall assay-to-assay variability was less than15%. Using this assay, the EC50 values for ribavirin were determined to be 125 25 pM, respectively.
The effectiveness of ribavirin against dengue varies with the cell type used, but the values we obtained were within the range of published values for this compound (2, 13, 28). Taken together, these results show that a sensitive and reproducible HTS assay has been successfully developed to evaluate our compound library for inhibitors of dengue virus replication.
Example 13 ¨ Determining Anti-Dengue-2 Activity of Compounds of the Invention:

[0000139] The assay described in Example 12 was the basis of a high-throughput screen for dengue virus inhibitors, against which a library of 210,000 compounds was tested. Compounds that inhibited dengue virus induced CPE by at least 50% were further investigated for chemical tractability, potency, and selectivity.

[0000140] Initially, the chemical structures of the hit compounds were examined for chemical tractability. A chemically tractable compound is defined as one that is synthetically accessible using reasonable chemical methodology, and which possesses chemically stable functionalities and potential drug-like qualities. Hits that passed this medicinal chemistry filter were evaluated for their potency. Compound potency was determined by evaluating inhibitory activity across a broad range of concentrations. Nonlinear regression was used to generate best-fit inhibition curves and to calculate the 50%
effective concentration (EC50). The selectivity or specificity of a given compound is typically expressed as a ratio of its cytotoxicity to its biological effect. A cell proliferation assay is used to calculate a 50% cytotoxicity concentration (CC50); the ratio of this value to the EC50 is referred to as the therapeutic index (T.I. = CC50/EC50). Two types of assays have been used to determine cytotoxicity, both of which are standard methods for quantitating the reductase activity produced in metabolically active cells (22). One is a colorimetric method that measures the reduction of 3-(4,5-dimethylthiazol-2-y1)-2,5-diphenyl-tetrazolium bromide (MIT), and the other uses fluorimetry to measure the reduction of resazurin (Alamar Blue).
Selectivity could be further characterized by assessing the inhibitory action against viruses from unrelated virus families.
Sixteen quality dengue hits were discovered in the pool of initial hits from the HIS screening, all with EC50 values below 25 M. Verification that these compounds act against each of the four serotypes of dengue was done with yield assays carried out at several drug concentrations, and the titer determined for each.

[0000141] Compounds that were active in the primary screen were tested for activity in viral yield assays. Table 1 shows some of the compounds that were tested for activity against Dengue-2 (Strain New Guinea C) in a viral yield assay at a range of concentrations. Vero cells in 12-well plates were infected with dengue-2 virus at a multiplicity of infection (MOI) of 0.1, treated with compound (or DMSO as a control), incubated at 37 C, harvested 48 hours post infection and titered on Vero cells as described above. The EC50 was calculated through ExcelFit.
Activities against other serotypes of dengue virus were determined in a similar way.

[0000142] Compound 1 was identified as one of the most potent and selective compounds from within the pool of the initial quality hits, with activity against all four serotypes of dengue. Chemical analogs of this compound were obtained, and these analogs were tested as described in order to define the relationship between chemical structure and biological activity (see Table 1). All of the compounds in Table 1, labeled A or B, are active against dengue with EC50 values at or below 25 M.

Table 1: Compounds active against Dengue-2 Virus in Vero cells Activity A: EC5ri <5 uM;
Compound Chemical Structure Molecular Formula Chemical Name B: 5<EC5 0 <25 uM;
C: EC5ri >25 uM
' NH 3-Amino-6,7,8,9-tetrahydro-\ o 5H-1-thia-10-aza-1 \ N-N
1 S N4 I C21 H19 N5 0 S2 cyclohepta[f]indene-2- A
S 40 carboxylic acid (5-phenyl-[1,3,4]thiadiazol-2-yl)-amide F
410 3-Amino-4-(4-fluoro-phenyly6-thiophen-2-yl-thieno[2,3-b]pyridine-2-carboxylic acid N S NH2 amide --\ S 0 p NH 3-Amino-6-thiophen-2-yl-1 LN F F thieno[2,3-b]pyridine-2-\
3 N Ns-T (10 o F
carboxylic acid (3- s trifluoromethyl-phenyl)-amide ' 1-Amino-5-methy1-6,7,8,9-tetrahydro-thieno[2,3-ql) 4i2 c]isoquinoline-2-carboxylic A
I-13C Nr S y 3 acid (4-methyl-thiazol-2-y1)-0 S2/ amide 3-Amino-6-thiophen-2-y1-4-F F
trifluoromethyl-thieno[2,3-¨ FNH, N-N 021 H12 F3 N5 0 S3 b]pyridine-2-carboxylic acid A
\ /
S N ' S (5-pheny141,3,4]thiadiazol-2-s o ylyamide P
\ 0 3,6-Diamino-5-cyano-4-furan-N . Br 019 H12 Br N5 02 S 2-yl-thieno[2,3-b]pyridine-2-A
1 \ carboxylic acid (4-bromo-H2N N S 0 phenyI)-amide , H3c..0 40 3-Amino-6-cyclopropy1-4-(4-methoxy-phenyl)-thieno[2,3-o b]pyridine-2-carboxylic acid , 1 \ amide N s N1-12 V
' 0 3-Amino-6-cyclopropy1-4-8 NH2 017 H15 N3 0 S phenyl-thieno[2,3-b]pyridine-2- A
_-_-NH2 \ carboxylic acid amide A I \

/ r 3-Amino-4,6-dimethyl-F , thieno[2,3-b]pyridine-2-9 I jcN r C17 H14 F3 N3 0 S A
H3C N S carboxylic acid (3-trifluoromethyl-phenyI)-amide t.- b=
140 3-Amino-4-(2-chloro-phenyl)-CI NH2 5,6,7,8-tetrahydro-thieno[2,3-OI \ N b]quinoline-2-carboxylic acid N S N¨) thiazol-2-ylamide S
_ 0 3-Amino-4-furan-2-y1-5,6,7,8-NH2 tetrahydro-thieno[2,3-S I o C16 H15 N3 02 S
b]quinoline-2-carboxylic acid A
\ amide , -o NH 3-Amino-5-oxo-5,6,7,8-I \

S b]quinoline-2-carboxylic acid A
(3-trifluoromethyl-phenyl)-F F
F amide :.= :.=
3-Amino-6-methyl-5,6,7,8-3 . N tetrahydro-thieno[2,3-13 L1JIII, li CI C18 H17 CI N4 0 S
b][1,6]naphthyridine-2- A
o carboxylic acid (4-chloro-phenyl)-amide P P
3-Amino-6-methyl-5,6,7,8-NH2 F tetrahydro-thieno[2,3-14 H30.N 0 4 I \ C19 H19 F N4 0 S b][1,6]naphthyridine-2- A
., N ,D IN carboxylic acid 4-fluoro-benzylamide p p 1-13C.N 0 3-Amino-6-methyl-5,6,7,8-I \ tetrahydro-thieno[2,3-N 0 ,N¨\ C16 H22 N4 0 S
C
b][1,6]naphthyridine-2- A

CH3 carboxylic acid diethylamide .., ..-3-Amino-6-methyl-5,6,7,8-F
NH tetrahydro-thieno[2,3-16 H3c,N N * F C18 H16 F2 N4 0 S b][1,6]naphthyridine-2- A
I \
N s carboxylic acid (3,4-difluoro-phenyI)-amide P P
3-Amino-6-methyl-5,6,7,8-NH2 tetrahydro-thieno[2,3-17 I \ C20 H22 N4 0 S b][1,6]naphthyridine-2- A
N S N . CH3 carboxylic acid (2,4-dimethyl-phenyl)-amide 3-Amino-6-methy1-5,6,7,8-H3C.N 0 CI tetrahydro-thieno[2,3-18 1 \ 018 H17 CI N4 0 S b][1,6]naphthyridine-2-A
'N S N li carboxylic acid (3-chloro-phenylyamide y , 3-Amino-6-methy1-5,6,7,8-CI
NH2 tetrahydro-thieno[2,3-19 H3c.N N * C18 H17 CI N4 0 S b][1,6]naphthyridine-2- A
1 \
. carboxylic acid (2-chloro-phenylyamide 3-Amino-6-methy1-5,6,7,8-NH2 * p1-13 tetrahydro-thieno[2,3-20 H3c..õ...N 1 \ N N'CH3 020 H23 N5 0 S
b][1,6]naphthyridine-2- A
N S 0 carboxylic acid (4-dimethylamino-phenylyamide , .
3-Amino-6-ethy1-5,6,7,8-cH3 NH i, 2 F tetrahydro-thieno[2,3-21 N I \ N * F F 020 H19 F3 N4 0 S b][1,6]naphthyridine-2- A
N S o carboxylic acid (4-trifluoromethyl-phenylyamide . , (3-Amino-6-ethy1-5,6,7,8-CI-13 NH 2 . tetrahydro-thieno[2,3-22 LN N 022 H24 N4 0 S b][1,6]naphthyridin-2-yI)-(3,4- A
1 \ dihydro-1H-isoquinolin-2-yI)-.
N S 0 methanone t, p 3-Amino-6-isopropy1-5,6,7,8-X3 NH _ pH3 tetrahydro-thieno[2,3-23 H3C N .1... 1 \ N W 021 H24 N4 02 S
b][1,6]naphthyridine-2- A
N S 0 carboxylic acid (4-methoxy-pheny1)-amide 3-Amino-6-isopropy1-5,6,7,8-cH3 NH2 . tetrahydro-thieno[2,3-_ 24 H3eLN / 1 \ N 020 H21 F N4 0 S b][1,6]naphthyridine-2- A
N S 0 F carboxylic acid (3-fluoro-pheny1)-amide 4-[(3-Amino-6-isopropyl-cH3 (o 5,6,7,8-tetrahydro-thieno[2,3-25 r3 NH2 023 H26 N4 03 S b][1,6]naphthyridine-2- A
H3c N ....--.0 NW o carbonyl)-amino]-benzoic acid ethyl ester , .
3-Amino-6-isopropy1-5,6,7,8-1H3 NH2 tetrahydro-thieno[2,3-b][1,6Thaphthyridine-2-A
N carboxylic acid , I
N S 0 (benzo[1,3]dioxo1-5-ylmethyly amide _ 3-Amino-6-methy1-4-thiophen-s H3C 2-y1-5,6,7,8-tetrahydro-27H3C.N NH2 N =
023 H22 N4 0 S2 thieno[2,3- A
I\ b][1,6Thaphthyridine-2-'N S 0 carboxylic acid o-tolylamide y , 3-Amino-6-methy1-4-thiophen--s 2-y1-5,6,7,8-tetrahydro-28 H3c,N 1 \ o 023 H22 N4 02 S2 thieno[2,3-A
N e N b][1,6Thaphthyridine-2-- * 0 CH, carboxylic acid (4-methoxy-phenylyamide 3-Amino-6-methy1-5,6,7,8-NH2 tetrahydro-thieno[2,3-29 1 \ 018 H17 F N4 0 S b][1,6Thaphthyridine-2-A
'NI S =N If F carboxylic acid (4-fluoro-phenylyamide , .
3-Amino-6-methy1-5,6,7,8-tetrahydro-thieno[2,3-. 1 ''', 1 F).4 b][1,6Th Naphthyridine-2-30 . Nr S . N . o 019 H17 F3 N4 02 S A
carboxylic acid (4-o trifluoromethoxy-phenyI)-amide . , NH2 3-Amino-6-benzy1-5,6,7,8-N
o a tetrahydro-thieno[2,3-1 `=== \
31 Si ' Nj S N-0 025 H23 CI N4 02 S b][1,6]naphthyridine-2- A

carboxylic acid (5-chloro-2-methoxy-phenylyamide t, p 3-Amino-6-methy1-5,6,7,8-NH2 / N tetrahydro-thieno[2,3-32 H,C, N .. C22 H23 N5 0 S
N 1 "=== \ b][1,6]naphthyridine-2- A
Nj S 0 carboxylic acid [2-(1H-indo1-3-ylyethyl]-amide 3-Amino-6-methy1-5,6,7,8-H3c, 0 tetrahydro-thieno[2,3-N 1 \
33 Nj S N I/ 0 019 H18 N4 03 S b][1,6]naphthyridine-2- A
o..i carboxylic acid benzo[1,3]dioxo1-5-ylamide _ 3-Amino-6-methy1-4-thiophen-s 2-y1-5,6,7,8-tetrahydro-34 H C NH2 *
N 022 H20 N4 0 S2 thieno[2,3- A
b][1,6Thaphthyridine-2-N S 0 carboxylic acid phenylamide , .
3-Amino-6-methy1-5,6,7,8-tetrahydro-thieno[2,3-H3C.
35 N IN 0 022 H26 N4 0 S b][1,6Thaphthyridine-2- A
o cH3 carboxylic acid (4-tert-butyl-ce3 phenyI)-amide 3-Amino-6-methy1-4-thiophen-_ N s 2-y1-5,6,7,8-tetrahydro-36 H3C,N i_NI Fi thieno[2,3-r: 022 H19 CI N4 0 S2 A
I I
b][1,6]naphthyridine-2-NI' S N 411' ci carboxylic acid (4-chloro-phenylyamide y , NH2 3-Amino-6-methyl-5,6,7,8-H3oN. 1 0 a tetrahydro-thieno[2,3-\
37-'NS N II 019 H19 CI N4 02 S
b][1,6]naphthyridine-2- A
carboxylic acid (5-chloro-2-H3c-o methoxy-phenylyamide NH2 3-Amino-6-methyl-5,6,7,8-1-1,C.IN ,,, 1\ 10 tetrahydro-thieno[2,3-38 Nj S N Ilk 018 H17 F N4 0 S
b][1,6]naphthyridine-2- A
carboxylic acid (2-fluoro-F phenylyamide , .
3-Amino-6-methy1-5,6,7,8-NH2 N tetrahydro-thieno[2,3-39 ,CH3 H3C.N N4 , I \ S¨j 016 H17 N5 0 S2 b][1,6]naphthyridine-2- A
N S 0 carboxylic acid (4-methyl-thiazol-2-yl)-amide . , 3-Amino-6-ethyl-5,6,7,8-NH2 = tetrahydro-thieno[2,3-LN N
40 . I \ 020 H19 F3 N4 02 S
b][1,6]naphthyridine-2-A
N S 0 0 carboxylic acid (2-)r trifluoromethoxy-phenyI)-F
amide t, p 3-Amino-6-ethy1-5,6,7,8-CI
CH3tetrahydro-thieno[2,3-b][1,6Thaphthyridine-2- A
I \NH2 ..¨ Nµ\
N'S carboxylic acid (2-chloro-pyridin-3-yI)-amide 3-Amino-6-methy1-5,6,7,8-NH2 F tetrahydro-thieno[2,3-42 H,C,N / 1 \ N * :F 019 H17 F3 N4 0 S
b][1,6]naphthyridine-2- A
N S 0 carboxylic acid (4-trifluoromethyl-phenylyamide 3-Amino-6-methy1-5,6,7,8-NH2CH3 tetrahydro-thieno[2,3-43 H3c,N ,. 1 \ N =
0 020 H20 N4 02 S b][1,6]naphthyridine-2- A
N S 0 carboxylic acid (4-acetyl-phenylyamide , .
3-Amino-6-methy1-5,6,7,8-a NH tetrahydro-thieno[2,3-44 H3C,N , N 018 H16 012 N4 0 S
b][1,6Thaphthyridine-2- A
1 . ' carboxylic acid (2,5-dichloro-N S 0 a phenylyamide / r 3-Amino-6-methyl-5,6,7,8-CI
tetrahydro-thieno[2,3-45 H3c,N s NH2 N lik CH3 C19 H19 CI N4 0 S
b][1,6]naphthyridine-2- A
, I ' N S 0 carboxylic acid (3-chloro-4-methyl-pheny1)-amide t.- b=
3-Amino-6-methyl-5,6,7,8-CI
NH2 _ 46 H3C,N N6 tetrahydro-thieno[2,3-' \ C17 H16 CI N5 0 S
b][1,6]naphthyridine-2- A
N1S \ _ . carboxylic acid (2-chloro-pyridin-3-yI)-amide H 3-Amino-6-methyl-5,6,7,8-H' tetrahydro-thieno[2,3-47 NH2 H C24 H32 N4 0 S b][1,6]naphthyridine-2- A
H3C.N N-i%' I \ CH3 carboxylic acid (1-adamantan-N S 0 1-yl-ethyl)-amide NH 3-Amino-6-methyl-5,6,7,8-H,C,N 0 tetrahydro-thieno[2,3-48 I \ C18 H18 N4 0 S A
N S N
b][1,6]naphthyridine-2-carboxylic acid phenylamide :.= :.=

3-Amino-6-methyl-4-phenyl-49 H3C,N NH C24 H22 N4 0 S 5,6,7,8-tetrahydro-thieno[2,3-A
I I b][1,6]naphthyridine-2-. N
N S
IW carboxylic acid phenylamide P
40 3-Amino-6-methy1-4-phenyl-5,6,7,8-tetrahydro-thieno[2,3-NH
50 H3c..N 2 ...... C25 H24 N4 02 S
b][1,6]naphthyridine-2- A
, I I N
N S carboxylic acid (4-methoxy-o 40 0..CH3 .. phenyl)-amide p s=
40 3-Amino-6-methy1-4-phenyl-5,6,7,8-tetrahydro-thieno[2,3-H3c.N ...., NH2 51 I C26 H24 N4 02 S b][1,6]naphthyridine-2- A
Nr s N Ali cH3 carboxylic acid (4-acetyl-pheny1)-amide o .., ..-3-Amino-6,7,8,9-tetrahydro-H¨CI
NH 5H-1-thia-6,10-diaza-/ , \
I s N--N cyclohepta[f]indene-2-¨ 1 C20H18N60S2 . HCI
carboxylic acid (5-phenyl- A

s os[1,3,4]thiadiazol-2-y1)-amide hydrochloride P P
NH
3-Amino-5,6,7,8-tetrahydro-I \ ,N-- C20 H17 N5 0 S2 N thieno[2,3-b]quinoline-2-N s N¨ i A
s it carboxylic acid (5-phenyl-[1,3,4]thiadiazol-2-y1)-amide 0,CH, 0 3-Amino-4-(3,4-dimethoxy-H3c- so 54 NH, 022 H18 F N3 03 S phenyI)-6-(4-fluoro-phenyly A
.....
NH2 thieno[2,3-b]pyridine-2-I , \
0 s o carboxylic acid amide F
Is s 3-Amino-6-thiophen-2-yl-..-= )\1 S N4 1 thieno[2,3-b]pyridine-2-0 C16 H12 N4 0 S3 carboxylic acid (4-methyl-NH2 thiazol-2-yl)-amide 6-Acety1-3-amino-4-F
CH3 F , trifluoromethy1-5,6,7,8-,- NI-12 56 J.
0 N ""..
I \ 0 CH6H C24 H25 F3 N4 02 S tetrahydro-thieno[2,3-A
Nj S N 41 3 b][1,6]naphthyridine-2-cH3 carboxylic acid (4-tert-butyl-phenyl)-amide 2-[(3-Amino-6-methyl-5,6, 7,8-NH tetrahydro-thieno[2,3-b][1,6]naphthyridine-2-N' s N N C23 H26 N4 03 S2 A
carbony1)-amino]-4,5,6,7-o o'cH3 tetrahydro-benzo[b]thiophene-3-carboxylic acid ethyl ester . , 3-Amino-6-methyl-5,6,7,8-tetrahydro-thieno[2,3-NH2 N . C19 H20 N4 02 S b][1,6]naphthyridine-2- A
H30 ,2õ.. .,N
1 \ carboxylic acid (2-methoxy-.
N S 0 phenylyamide t, p 3-Amino-6-isopropy1-5,6,7,8-CH Fµ..õF tetrahydro-thieno[2,3-b][1,6]naphthyridine-2-59 H3c-I-N / 1 \ N
Nit * 0r-F 021 H21 F3 N4 02 S A
carboxylic acid (4-'N S o trifluoromethoxy-phenyI)-amide 3-Amino-6-isopropy1-5,6,7,8-CH3tetrahydro-thieno[2,3-N
'NS60 H3C).' N / 1 \ * FF 021 H21 F3 N4 0 S
b][1,6]naphthyridine-2- A

N carboxylic acid (4-trifluoromethyl-phenylyamide 3-Amino-6-methy1-5,6,7,8-NH2 . tetrahydro-thieno[2,3-61 H3C.N 1 N 019 H19 F N4 0 S
b][1,6]naphthyridine-2- A
\
0 F carboxylic acid (5-fluoro-2-N S
methyl-phenylyamide 3-Amino-6-methy1-5,6,7,8-NH2 N . tetrahydro-thieno[2,3-62H3C.N N4 I \ s 019 H17 N5 0 S2 b][1,6]naphthyridine-2- A
'NI S 0 carboxylic acid benzothiazol-2-ylamide . ,.
H3c.r\j, NH2 3-Amino-6-methyl-5,6,7,8-Br I cN tetrahydro-thieno[2,3-63 N S 01 018 H16 Br2 N4 0 S b][1,6Thaphthyridine-2- A
0 carboxylic acid (2,5-dibromo-Br phenyl)-amide y ' 0 3-Amino-6-methy1-4-phenyl-5,6,7,8-tetrahydro-thieno[2,3-64 H3C,N NH2 024 H21 CI N4 0 S b][1,6]naphthyridine-2-A

. N carboxylic acid (4-chloro-N S
0 Ir phenyl)-amide ci F
3-Amino-6-methyl-4-F F
NH2 trifluoromethyl-thieno[2,3-nHC S jcN N,N 014 H12 F3 N5 0 S2 b]pyridine-2-carboxylic acid B
, N (5-ethyl-[1,3,4]thiadiazol-2-y1)-o SiLCH, amide 1.1 NH2 3-Amino-4,6-diphenyl-66\ N /I 026 H19 N3 0 S
thieno[2,3-b]pyridine-2- B
1 -...
N carboxylic acid phenylamide s r s 0 I. 3-Amino-6-(2-methoxy-67 .CH
0 NH2 024 H21 N3 02 S phenyly4-phenyl-thieno[2,3-B
I I b]pyridine-2-carboxylic acid 40 N s 0 NV cyclopropylamide t, p 3-Amino-6-methoxymethy1-4-68 I \ 011 H13 N3 02 S methyl-thieno[2,3-b]pyridine-2-B
H3C N S NI-12 carboxylic acid amide y y N
NH
1 1 0 3,6-Diamino-5-cyano-69 H2N NS 021 H15 N5 0 S thieno[2,3-b]pyridine-2-B
N
10 110 carboxylic acid diphenylamide NH

N.....
i ) 1 3,6-Diamino-5-cyano-H2N NS N . 0 -> 019 H19 N5 02 S
thieno[2,3-b]pyridine-2-carboxylic acid (4-butoxy-pheny1)-amide B
H,C
NH
0 3-Amino-6-propyl-thieno[2,3-I 011 H13 N3 0 S b]pyridine-2-carboxylic acid B
H3C 'N B NH2 amide 0 CH, NH2 0 3-Amino-4,6-dimethy1-5-(2-oxo-2-phenyl-ethylythieno[2,3-72 .--- \ 018 H17 N3 02 S B
0 I b]pyridine-2-carboxylic acid H,C N- s NH2 amide y , 3-Amino-6-propyl-thieno[2,3-___ nl X _I NH2 F F
73 H3 c--s T
N )\I 017 H14 CI F3 N4 0 b]pyridine-2-carboxylic acid I F S (3-chloro-6-trifluoromethyl- B
o ci pyridin-2-y1)-amide H,CAT 1 2 3-Amino-4-methoxymethy1-6-NH . methyl-thieno[2,3-b]pyridine-2-H3C N s-crN =C21 H19 N3 02 S carboxylic acid naphthalen-1-ylamide , .
o 3,6-Diamino-2-(3-H3C...--- 10 ."- NH
1 trifluoromethyl-75 H2N NI' S F
018 H15 F3 N4 03 S phenylcarbamoy1)-thieno[2,3- B
N F..
IW F b]pyridine-5-carboxylic acid ethyl ester . , .0 H3C 1\4 9-Methoxymethy1-7-methyl-76 I jc 1\11\11 C11 H10 N4 02S 3H-pyrido[3',2':4,5]thieno[3,2- B
H3C N S d][1,2,3]triazin-4-one t, p H3C õ C H33-Amino-4-dimethylamino-77 N NH2 017 H18 N4 0 S thieno[2,3-b]pyridine-2- B
N carboxylic acid benzylamide I \

NH2 3-Amino-5,6,7,8-tetrahydro-0 F thieno[2,3-b]quinoline-2-78 I \ 018 H16 F N3 0 S B
r\I S N 411 carboxylic acid (2-fluoro-phenylyamide 3-Amino-6,7,8,9-tetrahydro-0 F 5H-1-thia-10-aza-79 I \ 019 H18 F N3 0 S cyclohepta[f]indene-2- B
S N . carboxylic acid (2-fluoro-phenylyamide , .
3-Amino-6,7,8,9-tetrahydro-5H-1-thia-10-aza-I \
80 C19 H20 N4 03 S2 cyclohepta[f]indene-2- B
N S N 41 V=0 NH, carboxylic acid (4-sulfamoyl-pheny1)-amide . ,.
y-I3 0 3-Amino-4-methoxymethy1-6-NH methyl-thieno[2,3-b]pyridine-2-\ 2 N . a C17 H16 CI N3 02 S
1 \ carboxylic acid (4-chloro-H30 Nr S 0 phenyI)-amide y , NH 3-Amino-6,7,8,9-tetrahydro-82\ 0 I 013 H15 N3 0 S 5H-1-thia-10-aza-B
cyclohepta[f]indene-2-N S NH2 carboxylic acid amide ai3 NH 3-Amino-4,6-dimethyl-thieno[2,3-b]pyridine-2-carboxylic acid naphthalen-2-H3C I\J S N Mr- ylamide HC. 0 ,CH3 ._ 0 r 3,6-Diamino-5-cyano-4-(3,4-84401 40 dimethoxy-phenyI)-thieno[2,3-I\1 b]pyridine-2-carboxylic acid N
, I s (4-fluoro-phenyI)-amide F
F F NH 3-Amino-6-thiophen-2-y1-4-0 trifluoromethyl-thieno[2,3-85 ..--- , \
I s b]pyridine-2-carboxylic acid , ,N¨\ diethylamide \ S H3C¨I CH3 t, -X 0 3-Amino-4-furan-2-y1-5,6,7,8-NH tetrahydro-thieno[2,3-N-fl C19 H16 N4 02 S2 B
86 N_ b]quinoline-2-carboxylic acid O I \ S'"'.
thiazol-2-ylamide NH 3-Amino-5,6,7,8-tetrahydro-87 r...0 1 \ C22 H19 N3 0 S thieno[2,3-b]quinoline-2-B
>N1'1s/--µN 4.W carboxylic acid naphthalen-2-ylamide NH 3-Amino-6,7-dihydro-5H-,N-N cyclopenta[b]thieno[3,2-88 i\J S N¨ I 019 H15 N5 0 S2 e]pyridine-2-carboxylic acid B
S 40 (5-phenyl-[1,3,4]thiadiazol-2-yI)-amide F
F F NH2 (3-Amino-6-phenyl-4-o trifluoromethyl-thieno[2,3-' b]pyridin-2-yI)-morpholin-4-yl- B
0 1\1 S
N_¨ methanone o F 3-Amino-6-thiophen-2-y1-4-F F NH2 trifluoromethyl-thieno[2,3-90 ...- \
, 1 s 1\1--N C17 H12 F3 N5 0 S3 b]pyridine-2-carboxylic acid B
(5-ethyl-[1,3,4]thiadiazol-2-y1)-\ s amide y , NH2 3-Amino-6,7-dihydro-5H-91 cincie flit C21 H17 N3 0 S cyclopenta[b]thieno[3,2-B
e]pyridine-2-carboxylic acid N S N
naphthalen-2-ylamide NH2 3-Amino-5,6,7,8-tetrahydro-92 1 \ ,N-N 016 H17 N5 0 S2 thieno[2,3-b]quinoline-2-B
N S N¨ '-' II'CH3 carboxylic acid (5-ethyl-s [1,3,4]thiadiazol-2-yl)-amide , .
NH 3-Amino-6-ethy1-5-methyl-H3C 2 N * F C18 H16 F3 N3 0 S thieno[2,3-b]pyridine-2-93 1 \ B
H3C s 0 carboxylic acid (3-F F
trifluoromethyl-phenylyamide . , 0 NH, CH3 3-Amino-5-oxo-5,6,7,8-94 1 \ N 0 C21 H21 N3 02 S tetrahydro-thieno[2,3-B
OH3 b]quinoline-2-carboxylic acid Hp (2,4,6-trimethyl-phenyl)-amide t, p 0 3-Amino-7,7-dimethy1-5-oxo-95 H3C1 \ 5,6,7,8-tetrahydro-thieno[2,3-H3C b]quinoline-2-carboxylic acid /
(furan-2-ylmethylyamide a cH3 NH2 5-AllyI-3-amino-4,6-dimethyl-96 H2c 411 , 1 \ N
C19 H18 CI N3 0 S thieno[2,3-b]pyridine-2-carboxylic acid (3-chloro-Hp s o B
phenylyamide , -yH3 o CI 3-Amino-4-methoxymethy1-6-NH methyl-thieno[2,3-b]pyridine-2-97 2 N * C17 H16 CI N3 02 S B
carboxylic acid (3-chloro-H3C S 0 phenyl)-amide , .
I
F
0 F 3-Amino-4-methoxymethy1-6-N C18 H16 F3 N3 02 S methyl-thieno[2,3-b]pyridine-,c.... . B

1 \ µ carboxylic acid (3-I-13C S 0 trifluoromethyl-phenylyamide ¨ 3-Amino-4-furan-2-y1-6,7-\ 0 dihydro-5H-99 015 H13 N3 02 S cyclopenta[b]thieno[3,2-B

aI \ e]pyridine-2-carboxylic acid N S NH2 amide y 0> 2,2-Dimethy1-5-morpholin-4-yl-r 9-o-tolyI-1,4-dihydro-2H,9H-3-I ) NI' B
oxa-7-thia-6,9,11-triaza-rN I\I'SThrN . benzo[c]fluoren-8-one o,) o NH2 3-Amino-6-(4-methoxy-o ..--- µ
phenylythieno[2,3-b]pyridine-101 , I ' CH C18 H19 N3 02 S B
a N s N¨( 0182-carboxylic acid H3c.0 =WI' isopropylamide 0 3-Amino-4,6-dimethyl-I \ thieno[2,3-b]pyridine-2-H3C S N carboxylic acid ethyl-phenyl-amide( . , 3-Amino-6-methy1-4-thiophen-_ . s 2-y1-5,6,7,8-tetrahydro-NH2 thieno[2, 103 Fl3c'N 3-B

I, N SrN¨c-j jc ,N-o b][1,6Thaphthyridine-2-\- carboxylic acid (5-methyl-0 cH3 isoxazol-3-yl)-amide t, p 3-Amino-6-methy1-5,6,7,8-F
NH tetrahydro-thieno[2,3-104H3c- N 41 0I-13 019 H19 F N4 0 S
b][1,6]naphthyridine-2- B
N s 0 carboxylic acid (2-fluoro-4-methyl-phenylyamide 3-Amino-6-methy1-5,6,7,8-NH, .<1 tetrahydro-thieno[2,3-H3 CI - N¨ , \ /
1 % 015 H18 N4 0 S b][1,6Thaphthyridine-2- B
.
N S 0 carboxylic acid cyclopropylamide NH 3-Amino-6-methyl-5,6,7,8-H3C,N o . tetrahydro-thieno[2,3-106 I \ C19 H20 N4 0 S B
b][1,6]naphthyridine-2-N' S N
carboxylic acid benzylamide NH 3-Amino-6-methyl-5,6,7,8-H3C,N 0 tetrahydro-thieno[2,3-. I \ 3 N S N¨FCH3 016 H22 N4 0 S b][1,6]naphthyridine-2-B
carboxylic acid tart-butylamide / r 3-Amino-6-methyl-5,6,7,8-NH 2 OH3 tetrahydro-thieno[2,3-H3c..,,, , o o¨i 108 - I - \ 020 H22 N4 02 S
b][1,6]naphthyridine-2- B
Nj S N¨L carboxylic acid (3-ethoxy-pheny1)-amide t.- b=
NH2 3-Amino-6-methyl-5,6,7,8-H .
3 N CI tetrahydro-thieno[2,3-c I I
4.
109 N s 018 H16 012 N4 0 S
b][1,6]naphthyridine-2- B
N
o carboxylic acid (2,6-dichloro-CI phenyI)-amide 3-Amino-6-methyl-5,6,7,8-NH2 tetrahydro-thieno[2,3-H3c .õ,..N N II F
110 I \ 018 H16 CI F N4 0 S
b][1,6]naphthyridine-2- B
0 CI carboxylic acid (3-chloro-4-fluoro-pheny1)-amide 3-Amino-6-methyl-5,6,7,8-F
NH2 tetrahydro-thieno[2,3-111 H3c.N N 411 F 018 H16 F2 N4 OS b][1,6]naphthyridine-2- B
I \
. carboxylic acid (2,4-difluoro-phenyI)-amide :.= :.=
3-Amino-6-methyl-5,6,7,8-tetrahydro-thieno[2,3-H3C,N ...... N
.
112 , I \ 019 H17 N5 0 S
b][1,6]naphthyridine-2- B
N S 0 \\ carboxylic acid (3-cyano-N
phenyI)-amide P P
3-Amino-6-methyl-5,6,7,8-tetrahydro-thieno[2,3-H3c,N N 01 113 I \ 019 H19 CI N4 0 S
b][1,6]naphthyridine-2- B
carboxylic acid 2-chloro-benzylamide p P
Ns 3-Amino-6-methyl-5,6,7,8-tetrahydro-thieno[2,3-114 H3c..N ,, N cH3 019 H19 N5 0 S2 b][1,6]naphthyridine-2- B
NH2 z 1 I \ s cH3 carboxylic acid (3-cyano-4,5-'NI S o dimethyl-thiophen-2-yI)-amide .., ..-H¨CI 3-Amino-6,7,8,9-tetrahydro-NH, 5H-1-thia-7,10-diaza-...- cyclohepta[f]indene-2-N I \
N.--N 020H18N6052 . HCI B
S N- carboxylic acid (5-phenyl-s 0 [1,3,4]thiadiazol-2-y1)-amide hydrochloride P P
3-Amino-6,7,8,9-tetrahydro-5H-1-thia-10-aza-116 I \ 019 H18 F N3 0 S
cyclohepta[f]indene-2- C
N S N . F carboxylic acid (4-fluoro-pheny1)-amide NH 3-Amino-6,7,8,9-tetrahydro-0 01-13 5H-1-thia-10-aza-117 I \ C20 H21 N3 0 S C
1\1 S N li cyclohepta[f]indene-2-carboxylic acid m-tolylamide y , 3-Amino-6,7,8,9-tetrahydro-5H-1-thia-10-aza-1 \ o cyclohepta[f]indene-2- C
N 8 N . q CFI3 carboxylic acid (4-methoxy-phenylyamide F
F F NH2 3-Amino-6-phenyl-o trifluoromethyl-thieno[2,3-119 1 \ C22 H16 F3 N3 02 S C
0 --,,, S N 11 s b]pyridine-2-carboxylic acid CH3 (4-methoxy-phenylyamide , .
CH3 NH2 o 3-Amino-4,6-dimethyl-120 I \ µN 41 thieno[2,3-b]pyridine-2-C
carboxylic acid (4-acetyl-phenyl)-am0ide . , CH3 NH2 ¨ 3-Amino-4,6-dimethyl-N\ 1 thieno[2,3-b]pyridine-2-121 I \ C19 H16 N4 0 S C
H3C N S N 11 carboxylic acid quinolin-8-ylamide t, p CH3 NH2 3-Amino-4,6-dimethyl-thieno[2,3-b]pyridine-2-122 \ N _6 020 H25 N3 0 S C

carboxylic acid adamantan-1-ylamide F
3-Amino-6-methyl-4-F F NH
trifluoromethyl-thieno[2,3-,C1-c¨e 017 H13 F3 1 N3 0 S b]pyridine-2-carboxylic acid C
H3C S N 41 I (4-iodo-2-methyl-phenyI)-H3o amide ?it o 3-Amino-4-methoxymethy1-6-124 017 H17 N3 02 S methyl-thieno[2,3-b]pyridine-2- C

H3o NsI N carboxylic acid phenylamide , .
H3c,0 03-Amino-4-(4-methoxy-phenyly6-phenyl-thieno[2,3-b]pyridine-2-carboxylic acid I \
40 N- s NH2 amide / W
H3C,0 03-Amino-4-(4-methoxy-pheny1)-6-phenyl-thieno[2,3-I
b]pyridine-2-carboxylic acid \
00) ni S N-0. phenylamide b-CH3 3,6-Diamino-5-cyano-thieno[2,3-b]pyridine-2-127 H2N Nr S N * 017 H15 N5 0 S
carboxylic acid (2,6-dimethyl-phenyI)-amide b, F
F F
NH 3-Amino-6-methyl-4-128 trifluoromethyl-thieno[2,3-H3c N s N w b]pyridine-2-carboxylic acid lik naphthalen-1-ylamide 3,6-Diamino-5-cyano-o I \thieno[2,3-b]pyridine-2-C15 H9 Cl2 N5 0 S C

H2N Nr S N . CI carboxylic acid (3,4-dichloro-CI phenyI)-amide b= b N-.. NH2 3,6-Diamino-5-cyano-I , <
130 H2N )1\1)--S thieno[23-b]pyridine-2-1 , carboxylic acid (2-F
trifluoromethyl-phenyI)-amide F F
P P

NH2 3-Amino-4-methyl-6-I

C16 H11 F3 I N3 0 S trifluoromethyl-thieno[2,3-C
, b]pyridine-2-carboxylic acid N S y F F (2-iodo-phenyI)-amide p F
F F 3-Amino-6-methy1-4-NH2 trifluoromethyl-thieno[2,3-132 r f _N C16 H13 F3 N4 0 S C
b]pyridine-2-carboxylic acid H3C NS" y NO, (5-methyl-pyridin-2-yI)-amide ..- ..-I \ 2-[(3,6-Diamino-5-cyano-thieno[2,3-b]pyridine-2-133 H2N Nr S N II 017 H13 N5 03 S C
carbonyI)-amino]-benzoic p acid methyl ester P
N. NH
..... 2 \ 0 3,6-Diamino-5-cyano-, \ thieno[2,3-b]pyridine-2-134 H2N N . C15 H10 Br N5 0 S C
S N carboxylic acid (2-bromo-Br pheny1)-amide . ,.
N= NH2 3,6-Diamino-5-cyano-JU thieno[2,3-b]pyridine-2-H2N N ScN s 015 H10 F N5 0 S C
carboxylic acid (2-fluoro-0 phenyI)-amide F
y y N.
NH 3,6-Diamino-5-cyano-I , I N thieno[2,3-b]pyridine-2-ci2 015 H12 N6 03 S2 carboxylic acid (4-sulfamoyl- C
,NH
phenyl)-amide yH3 o 3-Amino-4-methoxymethy1-6-NH2 methyl-thieno[2,3-b]pyridine-2-137 0.--= \
I ' o s,CI-13 015 H17 N5 02 S2 C
carboxylic acid (5-ethyl-H3c N S [1,3,4]thiadiazol-2-y1)-amide NN
CH3 3-Amino-6,7-dihydro-5H-_ NHµ CH3 138 \ / \ N¨ C15 H19 N3 0 S cyclopenta[b]thieno[3,2-C
e]pyridine-2-carboxylic acid N
S 0 diethylamide NH2 0 (3-Amino-6,7,8,9-tetrahydro-5H-1-thia-10-aza-139 CI)Y1 N 017 H21 N3 02 S C
i cyclohepta[f]inden-2-yI)-NN S c0 morpholin-4-yl-methanone . .
NH
p 0 3-Amino-4-methoxymethy1-6-\
I-13C / \ methyl-thieno[2,3-b]pyridine-2-140 \ S N . C23 H21 N3 02 S C
carboxylic acid 3 ¨N 6 H C diphenylamide NH
P \ o 3-Amino-4-methoxymethy1-6-H3 C methyl-thieno[2,3-b]pyridine-2-/ \
S N 410. C19 H19 N3 03 S C
¨N CH, carboxylic acid (4-acetyl-H3c phenyl)-amide 142 NH 5-Acetyl-3-amino-6-methyl-_6024 C21 H25 N3 02 thieno[2,3-b]pyridine-2-I , S C
carboxylic acid adamantan-1-H3Cr\r¨S N
ylamide 3,6-Diamino-5-cyano-4-(4-14340 H3O OH3 C26 H25 N5 0 S isopropyl-phenyI)-thieno[2,3-C
N., NH2 _b b]pyridine-2-carboxylic acid N..., k , I \ (2,3-dimethyl-phenyl)-amide . ,.
NH2 3-Amino-6,7-dihydro-5H-o o cyclopenta[b]thieno[3,2-C
144 -\N . -NH, C17 H16 N4 03 S2 / s g ii e]pyridine-2-carboxylic acid N o (4-sulfamoyl-phenyl)-amide y y ¨ NH2 j (3-Am ino-4,6-dimethyl-145 H3C \ / \ N C14 H17 N3 02 S
thieno[2,3-b]pyridin-2-yI)- C
N morpholin-4-yl-methanone :..

3-Amino-4-methoxymethy1-6-p 0 N \ /
H C \ methyl-thieno[2,3-b]pyridine-2-146 3 020 H17 Br N4 02 S C
carboxylic acid (6-bromo--N
H3C Br quinolin-8-ylyamide 3-Amino-4-methoxymethy1-6-H,CP o j-cH3 \ methyl-thieno[2,3-b]pyridine-2-147 / \ s N-01 018 H26 N4 02 S C
carboxylic acid (1-ethyl--N
H3C piperidin-3-yI)-amide ,o1-13 \ 2-[(3,6-Diamino-5-cyano-0 thieno[2,3-b]pyridine-2-148 1\1:, NH2 020 H19 N5 03 S2 carbonyl)-amino]-4,5,6,7- C
H 0 / A tetrahydro-benzo[b]thiophene-s NIP 3-carboxylic acid ethyl ester F 3-Amino-6-methyl-4-F F
trifluoromethyl-thieno[2,3-NH
r I 2 F F 017 H11 F6 N3 0 S b]pyridine-2-carboxylic acid C

I-13C -,N.----...S N

(3-trifluoromethyl-phenyly amide y y N= N .
9-Methoxymethy1-7-methy1-3-\ naphthalen-1-y1-3H-150 H3C / , ` S 0 # 021 H16 N4 02 S
pyrido[3',2':4,5]thieno[3,2--N
d][1,2,3]triazin-4-one :..

cH3 3-(2,4-Dimethyl-phenyl)-9-d 151 - N=N * C19 H18 N4 02 S methoxymethy1-7-methyl-3H-C
F-13o \ / N =CH3 pyrido[3',2':4,5]thieno[3,2-N
S 0 d][1,2,3]triazin-4-one N NH2 3,6-Diamino-5-cyano-ro thieno[2,3-b]pyridine-2-H2N iv S N 40 =N carboxylic acid (4-cyano-phenyl)-amide S
N HC 3 2,7,9-Trimethy1-3H-153 H3CN 1 cy, 012 H11 N3 0 S
pyrido[3',2':4,5]thieno[3,2- C
d]pyrimidin-4-one y , N CH
2,7-Dimethy1-3H-pyrido[3',2':4,5]thieno[3,2- C
N S
d]pyrimidin-4-one 9-130.cH3 o o 3,6-Diamino-5-cyano-4-(3,4,5-0 ci_13 trimethoxy-phenyI)-thieno[2,3-N-.. b]pyridine-2-carboxylic acid . o I \ amide H2 N ...'N S NH2 N= N = CH3 3-(4-Acetyl-phenyl)-9-\ methoxymethy1-7-methy1-3H-156 / \ s o o C19 H16 N4 03 S C
pyrido[3',2':4,5]thieno[3,2--N
H3C d][1,2,3]triazin-4-one . , 9H3 NH2 3-Amino-4,5,6-trimethyl-157 017 H16 Br N3 H3C N . Br thieno[2,3-b]pyridine-2-I \

. carboxylic acid (4-bromo-phenylyamide t, p 3-Amino-4-phenylamino-il NH
158 014 H12 N4 0 S thieno[2,3-b]pyridine-2- C

I \ carboxylic acid amide H3C,N.CH3N\ .
9-Dimethylamino-3-pheny1-3H-N
159 V I \ 017 H14 N4 0 S
pyrido[3',2':4,5]thieno[3,2- C
N ID
d]pyrimidin-4-one ' S

H30 3-Amino-5-ethy1-4,6-dimethyl-160 0 012 H15 N3 0 S thieno[2,3-b]pyridine-2-C
H30 N S carboxylic acid amide , .

-.., \ 0 3-Amino-6-phenyl-thieno[2,3-161 I , 014 H11 N3 0 S b]pyridine-2-carboxylic acid C
40 N S NH2 amide . ,.
F
3-Amino-6-methyl-4-trifluoromethyl-thieno[2,3-o 1 \ ,GH3 C17 H14 F3 N3 02 S
b]pyridine-2-carboxylic acid H3C Nr S N . o (4-methoxy-phenylyamide y .
CH3 3-Amino-4,6-dimethyl-163 C17 H17 N3 02 S thieno[2,3-b]pyridine-2-C
H3C carboxylic acid (4-methoxy-o 0 O.CH3 phenylyamide , NH
\ \ 3-Amino-6-pyridin-3-yl-I ' NH2 164 C13 H10 N4 0 S thieno[2,3-b]pyridine-2- C

I 0 carboxylic acid amide F
3-Amino-6-methyl-4-F F NH
165 o 1 \ 017 H14 F3 N3 0 S trifluoromethyl-thieno[2,3-b]pyridine-2-carboxylic acid p- C
H3C NrS N.0 H3 tolylamide H3C.õ,-CH3 " NH2 3-Amino-4-dimethylamino-thieno[2,3-b]pyridine-2- C
NlS 0 I \ carboxylic acid amide t, p OH3 NH2( 3-Amino-4,6-dimethyl-/ , \
I N¨\
C14 H19 N3 0 S thieno[2,3-b]pyridine-2-carboxylic acid diethylamide C

H3C cH3 o 2,2-Dimethy1-5-morpholin-4-yl-N=\ 1,4-dihydro-2H,9H-3-oxa-7--- , , / \ thia-6,9,11-triaza-N N S 0 benzo[c]fluoren-8-one 0, ,,. :=,.
HO
CH3 1-Amino-8,8-dimethy1-5-0 NH2 morpholin-4-y1-8,9-dihydro-6H-...-- µ
C17 H22 N4 03 S 7-oxa-3-thia-4-aza- C
rThl N S NH2 cyclopenta[a]naphthalene-2-0,) carboxylic acid amide o-oH3 .o H3c io 3,6-Diamino-5-cyano-4-(3,4-dimethoxy-phenyI)-thieno[2,3-N b]pyridine-2-carboxylic acid 1 \ amide H2N 'N S 0 . ,.
NH2 1-Amino-5-morpholin-4-yl--... \ 0 6,7,8,9-tetrahydro-thieno[2, I , C16 H20 c]isoquinoline-2-carboxylic 3-r-N N S NH2 o) acid amide y y CH, NH2 3-Amino-4,6-dimethyl-172 I \ e 016 H14 Br N3 0 S thieno[2,3-b]pyridine-2-C
H3C N S N Br carboxylic acid (4-bromo-*
phenylyamide :..
NH 3-Amino-6,7-dihydro-5H-173 I \ 017 H15 N3 0 S
cyclopenta[b]thieno[3,2-C
S N = e]pyridine-2-carboxylic acid phenylamide 2-Benzy1-8,8-dimethy1-8,9-H3CCI 1% if 021 H19 N3 02S dihydro-2H,6H-7-oxa-11-thia-C
N S" T
CH, 2,4,10-triaza-benzo[b]fluoren-o 1-one NH 3-Amino-6,7,8,9-tetrahydro-1 \ im\ 5H-1-thia-10-aza-N s NwcH3 cyclohepta[f]indene-2-carboxylic acid p-tolylamide o 3-Amino-4-methoxymethy1-6-176 NH2 _0.
N 017 H23 N3 02S methyl-thieno[2,3-b]pyridine-2-C
I \ carboxylic acid H3CN S 0 cyclohexylamide y y NH 3-Amino-6,7-dihydro-5H-177 I \ 017 H14 F N3 0 S
cyclopenta[b]thieno[3,2-C
N S N * F e]pyridine-2-carboxylic acid (4-fluoro-phenyl)-amide :..
CH3 NH 3-Amino-4,6-dimethyl-xii--y_e F thieno[2,3-b]pyridine-2-I \
C N S N C
carboxylic acid (2-fluoro-phenyI)-amide NH 3-Amino-6,7-dihydro-5H-µ 0 CH3 CH3 cyclopenta[b]thieno[3,2-I \ C
N S N II C19 H19 N3 0 S e]pyridine-2-carboxylic acid (2,3-dimethyl-pheny1)-amide . ,.
NH 3-Amino-6,7-dihydro-5H-i x 0 F cyclopenta[b]thieno[3,2-I
e]pyridine-2-carboxylic acid (2-fluoro-phenyl)-amide y y CH3 NH2 3-Amino-4,6-dimethyl-1 \ e CH, CH3 thieno[2,3-b]pyridine-2-I-13C N .
carboxylic acid (2,3-dimethyl-1\1 S
phenylyamide :..
5-Morpholin-4-y1-1,2,3,4-182I I C17 H18 N4 02 S tetrahydro-9H-7-thia-6,9,11-C
(NN s N triaza-benzo[c]fluoren-8-one 0,) 0 ci-13 NH 3-Amino-4,6-dimethyl-thieno[2,3-b]pyridine-2-N3c N S N w S=o carboxylic acid (4-sulfamoyl-niN2 phenyl)-amide NH 3-Amino-6,7-dihydro-5H-o cla-- cyclopenta[b]thieno[3,2-N S N . 0. e]pyridine-2-carboxylic acid ci-13 (4-methoxy-phenylyamide o CI 3-Amino-4-methoxymethy1-6-NH methyl-thieno[2,3-b]pyridine-2-185 N * C17 H16 CI N3 02 S

carboxylic acid (2-chloro-I \ phenyl)-amide y ' CH3 NH2 ,r0C1 3-Amino-4,6-dimethyl-1 \ I* C17 H13 CI F3 N3 0 thieno[2,3-b]pyridine-2-S carboxylic acid (2-chloro-5-F trifluoromethyl-phenylyamide F
F

I\ (3-Amino-5,6,7,8-tetrahydro-187 C16 H19 N3 02 S thieno[2,3-b]quinolin-2-yly C
N S 71¨

morpholin-4-yl-methanone \-0 NH
(3-Amino-6,7-dihydro-5H-188 . I µ C16 H19 N3 0 S cyclopenta[b]thieno[3,2-C
N S NO e]pyridin-2-ylypiperidin-1-yl-methanone . ' F

S2 (3-Amino-6-thiophen-2-y1-4-o trifluoromethyl-thieno[2,3-1 \
b]pyridin-2-yl)-piperidin-1-yl- c CrN S N¨\
\ S / methanone y y 3-Amino-6,7-dihydro-5H-cyclopenta[b]thieno[3,2-190 Cncce N_N 015 H15 N5 0 S2 e]pyridine-2-carboxylic acid c N S N4s Jc,CI-13 (5-ethyl-[1,3,4]thiadiazol-2-yly amide , NH
(3-Amino-6,7,8,9-tetrahydro-191 C18 H23 N3 0 S 5H-1-thia-10-aza- C
N S NO cyclohepta[flinden-2-yly piperidin-1-yl-methanone ' F
F F NH2 3-Amino-6-phenyl-4-o trifluoromethyl-thieno[2,3----= \
1 ' N C18 H11 F3 N4 0 S2 b]pyridine-2-carboxylic acid c 0 -N S N¨ thiazol-2-ylamide S
NH
OCI 3-Amino-5,6,7,8-tetrahydro-1 \
. 019 H15 CI F3 N3 0 thieno[2,3-b]quinoline-2-N S N c S carboxylic acid (2-chloro-5-F
trifluoromethyl-phenylyamide F F
p F 3-Amino-6-phenyl-4-F F NH' trifluoromethyl-thieno[2,3-o 194 --- .
, 1 ' õN-N 019 H14 F3 N5 0 S2 b]pyridine-2-carboxylic acid c 0 N s N-%=k,c1-13 (5-ethyl-[1,3,4]thiadiazol-2-yl)-amide y y ¨
\ S 3-Amino-4-thiophen-2-yl-NH2 5,6,7,8-tetrahydro-thieno[2,3-0 I C16 H15 N3 0 S2 c o b]quinoline-2-carboxylic acid \ amide F
F F NH2 3-Amino-6-pheny1-4-0 trifluoromethyl-thieno[2,3-196 =-==== µ
1 ' 019 H18 F3 N3 0 S
C
b]pyridine-2-carboxylic acid 0 1\1 S N¨\
diethylamide H3C¨/ CH, 0 CI 3-Amino-4-methoxymethy1-6-NH . 017 H15 Br CI N3 02 methyl-thieno[2,3-b]pyridine-N Br c S carboxylic acid (4-bromo-3-\
H3C Nr S 0 chloro-phenylyamide CH, 7,9-Dimethy1-3-(3-F , trifluoromethyl-phenyly3H-198 I i _1\11 r 018 H12 F3 N3 0 S C
H3C NS T = - 0 F pyrido[3',2':4,5]thieno[3,2-0 cl]pyrimidin-4-one y , CH, NH2 0 [(3-Amino-4,6-dimethyl-199 I c ,) 012 H13 N3 03 S thieno[2,3-b]pyridine-2- C
H3C Nn S NJ OH carbonyl)-amino]-acetic acid o CH, 3-Amino-4,6-dimethyl-200 I I thieno[2,3-b]pyridine-2-C
o I-13C N S N a C16 H13 CI F N3 0 S
1. carboxylic acid (3-chloro-4-F fluoro-phenyl)-amide , .
Nr---\
2,8,8-Trimethy1-8,9-dihydro-201 H3C....) I 015 H15 N3 02S 2H,6H-7-oxa-11-thia-2,4,10- C
N S 0 triaza-benzo[b]fluoren-1-one . , 2-Ally1-8,8-dimethy1-8,9-H3C 1 I -IN_ , dihydro-2H,6H-7-oxa-11-thia-202 Nr S 'CH, C17 H17 N3 02 S C
CH3 2,4,10-triaza-benzo[b]fluoren-o 1-one t, p CH 8,8-Dimethy1-2-(2-methyl-1 2 ally1)-8,9-dihydro-2H,6H-7-oxa-203 !torn i N,>L 018 H19 N3 02S C
N S CH3 11-thia-2,4,10-triaza-H3c o benzo[b]fluoren-1-one Cln64) 3-Amino-5,6,7,8-tetrahydro-N S N thieno[2,3-b]quinoline-2-carboxylic acid (4-o)_NO
acetylamino-phenyI)-amide ., ., 3-Amino-6,7,8,9-tetrahydro-I \ 5H-1-thia-10-aza-cyclohepta[f]indene-2- C
carboxylic acid phenethyl-41 amide , .
NH

CH3 n----c e 3-Amino-6-isobutyl-thieno[2,3-b]pyridine-2-carboxylic acid C

phenylamide I \ 3-Amino-6,7-dihydro-5H-cyclopenta[b]thieno[3,2-6 e]pyridine-2-carboxylic acid diphenylamide y , 0 `= 3-Amino-4-ethyl-7,7-dimethyl-2-(morcholine-4-carbonyl)-7 8-208 4_N\ s CID 020 H25 N3 03 S s = -' ' C
dihydro-6H-thieno[2,3-H3C b]quinolin-5-one -.... 3-Amino-4-methoxymethy1-6-NH2 ¨ C16 H17 N3 03 S methyl-thieno[2,3-b]pyridine-2-N C

1 -. \ carboxylic acid (furan-2-ylmethyl)-amide o H3c NH 3-Amino-4-methoxymethy1-6-210 N * 018 H19 N3 02 S methyl-thieno[2,3-b]pyridine-2-C
I \ carboxylic acid o-tolylamide . ,.

0 CI 3-Amino-4-methoxymethy1-6-NH
N * 017 H15 012 N3 02 methyl-thieno[2,3-b]pyridine-2-I S carboxylic acid (2,5-dichloro-H3C S 0 CI phenyl)-amide . .
¨ 3-Amino-4-furan-2-y1-6,7-NH, dihydro-5H-aI 0 021 H16 N4 04 S cyclopenta[b]thieno[3,2- C
\
r\J S N . if e]pyridine-2-carboxylic acid 0 (4-nitro-phenylyamide _ o 3-Amino-4-furan-2-y1-5,6,7,8-NH2 tetrahydro-thieno[2,3-213 o C22 H18 N4 04 S C
0 I \ 43 b]quinoline-2-carboxylic acid N S N 41 N. (4-nitro-phenylyamide o-0 NH2 3-Amino-7,7-dimethyl-5-oxo-214 I \ n C20 H18 N4 04 S
5,6,7,8-tetrahydro-thieno[2,3-C
Hgc N s N ii N7_ b]quinoline-2-carboxylic acid o (4-nitro-phenylyamide NH2 3-Amino-6,7-dihydro-5H-CnC--e cyclopenta[b]thieno[3,2-215 p C17 H14 N4 03 S C
N S N 4/ N. e]pyridine-2-carboxylic acid 0- (4-nitro-phenylyamide . ,.
CH3 NH2 5-AllyI-3-amino-4,6-dimethyl-thieno[2,3-b]pyridine-2-216 I \ N 110 Br 019 H18 Br N3 0 S c H2c, S o carboxylic acid (4-bromo-H3c 'N
phenyl)-amide y y NH 3-Amino-6,7,8,9-tetrahydro-0 5H-1-thia-10-aza-217 I \ C19 H19 N3 0 S c cyclohepta[f]indene-2-carboxylic acid phenylamide :y _ N o 3-Amino-4-furan-2-y1-5,6,7,8-o 218 O 1 \ 023 H21 N3 02 S tetrahydro-thieno[2,3-N S N
b]quinoline-2-carboxylic acid C
*
o-tolylamide 3-Amino-4-furan-2-y1-6,7-\ o NH2 dihydro-5H-o 219 a, I \ 023 H21 N3 02 S cyclopenta[b]thieno[3,2-C
N S N . e]pyridine-2-carboxylic acid (2-ethyl-phenyl)-amide H3c 103-Amino-4-p-tolyI-6,7,8,9-tetrahydro-5H-1-thia-10-aza-220 NH2 020 H21 N3 0 S c cyclohepta[f]indene-2-410- I \ carboxylic acid amide t, p F
3-Amino-6-thiophen-2-y1-4-F F NH
-0- µ
, I ' o 019 H11 F3 N4 03 trifluoromethyl-thieno[2,3- c 41N4), S2 b]pyridine-2-carboxylic acid \ s o (4-nitro-phenylyamide yy ...)30 I\J I S\
N .C20 H18 N4 04S3-Amino-7,7-dimethy1-5-oxo-5,6,7,8-tetrahydro-thieno[2,3-c b]quinoline-2-carboxylic acid O-N: (2-nitro-phenylyamide _ 3-Amino-4-thiophen-2-yl-S
NH2 6,7,8,9-tetrahydro-5H-1-thia-223 o C20 H18 N4 0 S3 10-aza-cyclohepta[flindene-2- c sm carboxylic acid thiazol-2-N S N4N) ylamide CI
0 3-Amino-4-(4-chloro-phenyly 5,6,7,8-tetrahydro-thieno[2,3-224 NH2 018 H16 CI N3 0 S c b]quinoline-2-carboxylic acid o S I \ amide 5-AllyI-3-amino-4,6-dimethyl-225 411 e C19 H18 N4 03 S
I-12C ..õ thieno[2,3-b]pyridine-2-H3C I \ N S 0 N C
o- carboxylic acid (4-nitro-phenyI)-amide y , o NH2 3-Amino-7,7-dimethy1-5-oxo-1 \
226 H3c I\I s N . 0 C21 H19 N3 04 S 5,6,7,8-tetrahydro-thieno[2,3-C
H3c b]quinoline-2-carboxylic acid o...1 benzo[1,3]clioxo1-5-ylamide 140 3-Amino-4-p-tolyI-5,6,7,8-tetrahydro-thieno[2,3-b]quinoline-2-carboxylic acid O1 \ amide NH 3-Amino-5,6,7,8-tetrahydro-1 \ thieno[2,3-b]quinoline-2-NN S N II iv, carboxylic acid (4-nitro-0 phenylyamide . , yH3 me a 3-Amino-4-methoxymethy1-6-NH thyl-thieno[2,3-b]pyridine-2-229 2 N * CH3 018 H18 CI N3 02 S C
1 \ carboxylic acid (3-chloro-4-H3C Nr S 0 methyl-phenylyamide t, p N CH 3,8,8-Trimethy1-2-phenethyl-y3 H3C I 1 C23 H23 N3 02 S 8,9-dihydro-2H,6H-7-oxa-11-cH3 thia-2,4,10-triaza-o benzo[b]fluoren-1-one 3,8,8-Trimethy1-2-(2-morpholin-H3c i 1 4-yl-ethyl)-8,9-dihydro-2H,6H-231 Nr S 1\1..N," C21 H26 N4 03 S C
cH3 7-oxa-11-thia-2,4,10-triaza-0 c,(5 benzo[b]fluoren-1-one N
H3CM I 8,8-Dimethy1-8,9-dihydro-232 N C14 H13 N3 0 S2 2H,6H-7,11-dithia-2,4,10- C
S
CH3 triaza-benzo[b]fluoren-1-one , 0> 3 2,2-Dimethy1-5-morpholin-4-yl-9-pheny1-1,4-dihydro-2H,9H-3-oxa-7-thia-6,9,11-triaza- C

r-N Nr S N
benzo[c]fluoren-8-one H3C'õCH3 (1-Amino-8,8-dimethy1-5-c:, morpholin-4-y1-8,9-dihydro-6H-I 1 /¨\ 021 H28 N4 04 S 7-oxa-3-thia-4-aza- C
ri\I 1\( S N\ /0 cyclopenta[a]naphthalen-2-yI)-0,) o morpholin-4-yl-methanone y , CH, 3-Ethyl-2-furan-2-ylmethy1-8,8-, rN,I) dimethy1-8,9-dihydro-2H,6H-7-H3CCa I jt j C
Nr SIYI 0 oxa-11-thia-2,4,10-triaza-CH3 0 benzo[b]fluoren-1-one ,cy,,. j__ThH 3,8,8-Trimethy1-2-(tetrahydro-H,C li() furan-2-ylmethyl)-8,9-dihydro-236 Nr s N 0 C20 H23 N3 03 S C
cH 2H,6H-7-oxa-11-thia-2,4,10-o triaza-benzo[b]fluoren-1-one CH, 0 C H3cN 3-Acetylamino-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-¨14 N
b]thieno[3,2-e]pyridine-2-0 "-- \ 0 H3C 1 1 carboxylic acid butylamide Nj S

0_CH3 1101 3-Amino-4-(4-methoxy-pheny1)-6-thiophen-2-yl-NH2 thieno[2,3-b]pyridine-2-I \
...... Ni.' s 0 carboxylic acid amide \ s t, p yH3 4-[(3-Amino-4-methoxymethyl-o 239 NI-12 . 0 N 019 H19 N3 04 S 6-methyl-thieno[2,3-b]pyridine-C
1 , o-cH3 2-carbonylyamino]-benzoic H3c N s o acid methyl ester yH3 o 1-0H3 5-[(3-Amino-4-methoxymethyl-o o NH2 6-methyl-thieno[2,3-b]pyridine-II CI C20 H20 Cl N3 04 S C
1 \ 2-carbonylyamino]-2-chloro-H3c..r i\f÷ s o benzoic acid ethyl ester ci,H03 3-Amino-4-(4-ethoxy-phenyly 241 4 023 H22 N4 02 S2 5,6,7,8-tetrahydro-thieno[2,3-C
NH2 b]quinoline-2-carboxylic acid CI \ -õ, thiazol-2-ylamide N s N¨eN .3 ,S' 6 9H, 0 F 3-Amino-4-methoxymethy1-6-methyl-thieno[2,3-b]pyridine-2-I \ carboxylic acid (2-fluoro-5-H,C * C18 H18 F N3 02 S S 0 CH, methyl-phenylyamide yH3 3-Amino-4-methoxymethy1-6-o NH2 t--\ methyl-thieno[2,3-b]pyridine-2-243 , \ N II
N
1 carboxylic acid (4-morpholin-H3c N-- S 0 4-yl-phenyl)-amide y , 1-Amino-8,8-dimethy1-5-H3c cH3 o morpholin-4-y1-8,9-dihydro-6H-NH2 C24 H28 N4 04 S 7-oxa-3-thia-4-aza-N cyclopenta[a]naphthalene-2-rN
0,) 0 IIPI 00H3 carboxylic acid (4-methoxy-pheny1)-amide H3C CH3 9-(3,4-Dichloro-phenyl)-2,2-o dimethy1-5-morpholin-4-y1-1,4-ci C24 H22 012 N4 03 245 dihydro-2H,9H-3-oxa-7-thia- C
S
\ N * CI 6,9,11-triaza-benzo[c]fluoren-oN,... j N S 0 8-one , .

0 CH 1-Amino-8,8-dimethy1-5-,L.LNH2JJr morpholin-4-y1-8,9-dihydro-6H-246 C25 H38 N4 03 S 7-oxa-3-thia-4-aza- C
r-N N S
0,) 0 cyclopenta[a]naphthalene-2-carboxylic acid dibutylamide cH3 . , HC 01-13 1-Amino-8,8-dimethy1-5-...... NH2 morpholin-4-y1-8,9-dihydro-6H-247 r^ N ' / \ C24 H28 N4 04 S 7-oxa-3-thia-4-aza-C
0,....iNsN cyclopenta[a]naphthalene-2-0-9 carboxylic acid (2-methoxy-0H3 phenyl)-amide t, p H,C CH, 2,2,9a-Trimethy1-5-(4-0 0 morpholinyI)-1,4,9,9a,10,11-hexahydro-2H-pyrano[4",3":4',5']pyrido[3',2':4 nr\N = i N
s-,_/ N s\ ,5]thieno[2,3-e]pyrrolo[1,2-0 a]pyrimidine-8,12-dione H3q o NH2 N 40 (3-Amino-4-methoxymethy1-6-methyl-thieno[2,3-b]pyridin-2-249 ...... 019 H19 N3 02 S C
0 y1)-(2,3-dihydro-indo1-1-y1)-\ / S
N methanone H3c ?H3 0, 3-Amino-4-methoxymethy1-6-NH2 methyl-thieno[2,3-b]pyridine-2-250 0, 018 H17 N3 04 S C

I \ I . 0 carboxylic acid benzo[1,3]dioxo1-5-ylamide N S N
dCH, (3-Amino-4-methoxymethy1-6-251 H3c / \ NH2 o 015 H19 N3 03 S methyl-thieno[2,3-b]pyridin-2- C
, r yI)-morpholin-4-yl-methanone s o 2-(2,4-Dichloro-benzyI)-8,8-H3c ¨
µ z CI 0 ci 021 H17 012 N3 02 dimethy1-8,9-dihydro-2H,6H-7-N I S oxa-11-thia-2,4,10-triaza-s N
benzo[b]fluoren-1-one y , NH 3-Amino-7,7-dimethy1-7,8-o dihydro-5H-1,6-dithia-9-aza-s \
C16 H21 N3 02 S2 cyclopenta[b]naphthalene-2- C
253 H,C , I s ..
I-13C N "-\__\ carboxylic acid (3-hydroxy-OH propyI)-amide F F
3-Amino-5,6,7,8-tetrahydro-NH2 F thieno[2,3-b]quinoline-2-C

N
I \ * carboxylic acid (2-trifluoromethyl-phenylyamide S
, .
CH3 NH 3-Amino-4,5,6-trimethyl-H3C C 2 0 thieno[2,3-b]pyridine-2-255 1 \ õ....../...... CH3 015 H16 carboxylic acid (5-methyl-Nr Nr isoxazol-3-yl)-amide . , 3-Amino-4,6-dimethyl-H3C / \ NH2 thieno[2,3-b]pyridine-2-256 N¨ 1 N CH3 C18 H17 N3 02 S C
s 140 o carboxylic acid (3-acetyl-o phenyl)-amide t, p 3-Amino-4,6-dimethyl-I \ thieno[2,3-b]pyridine-2-C
H3C Nr S N . carboxylic acid phenethyl-amide H3C .,.._ N0µ 3-Amino-4,6-dimethyl-thieno[2,3-b]pyridine-2-258 S 11-.._, 015 H15 N3 02 S C
\ / carboxylic acid (furan-2-N ylmethyl)-amide ,CH3 0 3-Amino-4,6-dimethyl-thieno[2,3-b]pyridine-2-I \ 2 N =carboxylic acid (2-methoxy-5-H3C 1\( S =

0 CH3 methyl-phenylyamide , .

NH
3-Amino-4,6-dimethyl-260 1 \ 411 017 H17 N3 0 S
thieno[2,3-b]pyridine-2- C
H3C S N carboxylic acid benzylamide CH, CH, 2-Ethy1-2-methy1-5-morpholin-o 261 N=\ C19 H22 N4 03 S 4-y1-1,4-dihydro-2H,9H-3-oxa-C
N 7-thia-6,9,11-triaza--- 1 \
r--- N S 0 benzo[c]fluoren-8-one o,J
y , 6-Acetyl-3-amino-4-F FF trifluoromethy1-5,6,7,8-CH tetrahydro-thieno[2,3-, C' 22 H21 F3 N4 03 S c H3AN 0 b][1,6]naphthyridine-2-carboxylic acid 4-methoxy-benzylamide H3c, 2-[(3-Amino-6-methyl-5,6,7,8-o tetrahydro-thieno[2,3-NH2 ,cH3 b][1,6Thaphthyridine-2-263 H3c..N ,... N 11 0 C22 H24 N4 05 S c , 1 \ carbonyl)-amino]-4,5-N s o s, dimethoxy-benzoic acid H3c methyl ester 3-Amino-6-methy1-5,6,7,8-NH 2 CH, tetrahydro-thieno[2,3-I \ N¨Cir O'N C16 H17 N5 02 S b][1,6Thaphthyridine-2- c 2 H3C,N
, N S o carboxylic acid (3-methyl-isoxazol-5-yl)-amide . , 3-Amino-6-methy1-5,6,7,8-H3c tetrahydro-thieno[2,3-265 H3C,N I \ N * F C19 H19 F N4 0 S b][1,6Thaphthyridine-2- c . carboxylic acid (4-fluoro-2-N S o methyl-phenylyamide t, p 3-Amino-6-methy1-5,6,7,8-NH2 0-CH tetrahydro-thieno[2,3-266 H3C. N \
, I 0 ilk 020 H22 N4 02 S
b][1,6]naphthyridine-2- c N S N carboxylic acid 4-methoxy-benzylamide 3-Amino-6-methy1-5,6,7,8-H3C-N 0 tetrahydro-thieno[2,3-267 . 1 \ 020 H22 N4 0 S b][1,6]naphthyridine-2- C
N S N *
carboxylic acid phenethyl-amide 3-Amino-6-methy1-5,6,7,8-NH2 tetrahydro-thieno[2,3-H3C,N 0 268 1 \
N S N- i s-...i,---at 016 H18 N6 0 S2 b][1,6Thaphthyridine-2- c ' N-N carboxylic acid (5-ethyl-[1,3,4]thiadiazol-2-yl)-amide 3-Amino-6-methy1-5,6,7,8-0tetrahydro-thieno[2,3-NH2 0=

269 H3cN 1, . o \ C20 H20 N4 03 S b][1,6Thaphthyridine-2-carboxylic acid C
Nj S N (benzo[1,3]clioxo1-5-ylmethyl)-amide 3-Amino-6-methy1-5,6,7,8-NH2 CH, tetrahydro-thieno[2,3-H3C,N N¨( 270 I \ µ CH3 015 H20 N4 0 S
b][1,6]naphthyridine-2- C
N'S 0 carboxylic acid isopropylamide y , CH, 3-Amino-6-isopropy1-5,6,7,8-CH3 NH2( ¨1 CH, / \ /N
I ' C18 H26 N4 0 S tetrahydro-thieno[2,3-b][1,6Thaphthyridine-2- C

S 0 carboxylic acid diethylamide 3-Amino-6-isopropy1-5,6,7,8-r13 NH, õN"N tetrahydro-thieno[2,3-272 H3C N 1 \ N-\s-k,CH, 018 H22 N6 0 S2 b][1,6]naphthyridine-2- C
N S 0 carboxylic acid (5-ethyl-[1,3,4]thiadiazol-2-yl)-amide ¨ 3-Amino-6-methy1-4-thiophen-s z 2-y1-5,6,7,8-tetrahydro-273 I-13C,N NH2 019 H22 N4 0 S2 thieno[2,3-C
I S I b][1,6Thaphthyridine-2-N
NõCH3 1 carboxylic acid 0 cH3 isopropylamide . , (3-Amino-6-methyl-5,6,7,8-NH2 o tetrahydro-thieno[2,3-H3c.N __.
=

-..N 023 H26 N4 03 S
b][1,6]naphthyridin-2-y1)-(6,7- C
o cH3 dimethoxy-3,4-dihydro-1H-isoquinolin-2-y1)-methanone t, p 4-[(3-Amino-6-ethyl-5,6, 7,8-OH ( tetrahydro-thieno[2,3-275 LN NI-12 N_cN_µ0 021 H29 N5 03 S b][1,6]naphthyridine-2- C
I \ o 0 carbonyl)-piperidine-1-N S
carboxylic acid ethyl ester 3-Amino-6-methy1-5,6,7,8-NH2 . /-CH, tetrahydro-thieno[2,3-276 H3C.N ' i \ N N\- C22 H27 N5 0 S
cH3 b][1,6Thaphthyridine-2- C
`N s o carboxylic acid (4-diethylamino-pheny1)-amide 3-Amino-6-methy1-5,6,7,8-F
NH2 . tetrahydro-thieno[2,3-277 H3C-N N 018 H16 F2 N4 0 S b][1,6]naphthyridine-2-C
I \
0 F carboxylic acid (2,6-difluoro-N S
phenylyamide , .
3-Amino-6-methy1-5,6,7,8-NH2 N, N tetrahydro-thieno[2,3-N-1-13C.

N ii 278 b][1,6Thaphthyridine-2- C
, I \ -' N S 0 carboxylic acid [1,3,4]thiadiazol-2-ylamide R.
NH 2 3-Amino-6-methyl-5,6,7,8-H3C õ..,N N
,.. I \ * ,CH3 tetrahydro-thieno[2,3-b][1,6]naphthyridine-2- C
,o carboxylic acid 3,4-H3c dimethoxy-benzylamide y , 3-Amino-6-methyl-5,6,7,8-H3C.N .2õ, S I
I
F tetrahydro-thieno[2,3-280 -N N 401 F 019 H17 F3 N4 0 S b][1,6Thaphthyridine-2-C
F
0 carboxylic acid (3-trifluoromethyl-phenylyamide Table 2 - Novel Compounds of Formula III of the present invention.
Molecular Cmpd Chemical Structure Analytical Data Chemical Name Formula 3-benzamido-N-(5-o 1H NMR in THF-d8: S 8.46 (s, 1H), 8.16- phenyl-1,3,4-8.19 (m, 2H), 7.95-7.98 (m, 2H), 7.48-7.62 thiadiazol-2-y1)-285 NH oN4 IN 0 C28 H23 (m, 6H), 3.15 (d, 2H), 2.93 (d, 2H), 1.90 6,7,8,9-tetrahydro-5H-1101 :, s\ N5 02 S2 (s, 2H), 1.72 (s, 4H); Mass Spec: 526.2 cyclohepta[b]thieno[3, " - (M+H)+ 2-e]pyridine-2-carboxamide 3-(butylamino)-N-(5-1H NMR in THF-d8: S 7.83-7.91 (m, 3H), phenyl-1,3,4-7.48-7.50 (m, 3H), 6.91 (s, 2H), 4.47-4.52 . .
tluadiazol-2-y1)-289 /pi \ 0 el C25 H27 (m, 2H), 3.11 (d, 2H), 2.89 (d, 2H), 1.88-N5 0S2 2.00 (m, 4H), 1.72 (s, 4H), 1.43-1.50 (m, 6,7,8,9-tetrahydro-5H-nr s N4N L.
2H), 1.03 (t, 3H); Mass Spec: 478.2 cyclohepta[b]thieno[3, 2-e]pyridine-2-(M+H)+
carboxamide 2-((2-((5-pheny1-1,3,4-HO
"NH
1H NMR in DMSO-d6: S 8.18 (s, 1H), thiadiazol-2-, 0 C23 H21 293 101 ' 41 7.87 (d, 2H), 7.57 (s, 3H), 7.37 (s, 2H), 4.67 (s, 2H), 3.08 (d, 2H), 2.84 (d, 2H), yl)carbamoy1)-6,7,8,9-tetrahydro-5H-nr s 11 ¨ µ1,1 _IN N5 03 S2 1.84 (s, 2H), 1.65 (s, 4H); Mass Spec: cyclohepta[b]thieno[3, 480.1 (M+H)+ 2-e]pyridin-3-yl)amino)acetic acid 3-((2-1H NMR in DMSO-d6: S 8.32 (s, 1H), aminoethyl)amino)-N-\...---\ 8.21 (s, 2H), 7.90-7.92 (m, 2H), 7.58-7.60 (5-phenyl-1,3,4-NH

294 C23 H24 (m, 3H), 4.69 (t, 2H), 3.46-3.52 (m, 2H), thiadiazol-2-y1)-1111 = \ N6 0 S2 3.02-3.11 (m, 4H), 2.88 (d, 2H), 1.86 (s, 6,7,8,9-tetrahydro-5H-N s ri4N-IN 2H), 1.67 (s, 4H); Mass Spec: 465.2 cyclohepta[b]thieno[3, (M+H)+ 2-e]pyridine-2-carboxamide o 3-oxo-3-((2-((5-H 0--(i43 phenyl-1,3,4-N H 1H NMR in DMS0-d6: S 7.98 (s, 1H), thiadiazol-2-o 01 \ .
C24 H21 7.89 (d, 2H), 7.37-7.50 (m, 3H), 3.26 (s, yl)carbamoy1)-6,7,8,9-295 N S ril ¨ cr IN N5 04 S2 2H), 3.08 (d, 2H), 2.85 (d, 2H), 1.85 (s, tetrahydro-5H-2H), 1.66 (s, 4H); Mass Spec: 508.1 cyclohepta[b]thieno[3, (M+H)+ 2-e]pyridin-3-yl)amino)propanoic acid H2N 3-(2-aminoacetamido)-N H
O 1H NMR in DMSO-d6: S 11.02(s, 1H), N-(5-phenyl-1,3,4-'N

01 \ s 010 8.39 (s, 3H), 8.11 (s, 1H), 7.93-7.96 (m, thiadiazol-2-y1)-296 ni s N4 I
H N.-N C23 H22 2H), 7.57-7.61 (m, 3H), 4.04 (d, 2H), 3.13 6,7,8,9-tetrahydro-5H-(d, 2H), 2.90 (d, 2H), 1.87 (s, 2H), 1.67 (s, cyclohepta[b]thieno[3, 4H); Mass Spec: 479.1 (M+H)+ 2-e]pyridine-2-carboxamide 7 -\ 1?
3-(nicotinamido)-N-µN H 1H NMR in DMSO-d6: S 11.33(s, 1H), o (5-pheny1-1,3,4-N <\
401 \ di 9.46 (s, 1H), 9.03 (d, 1H), 8.82 (d, 1H), thiadiazol-2-y1)-297 S N¨ I
H N.-N C27 H22 8.13 (s, 1H), 7.92-8.03 (m, 3H), 7.54-7.56 N6 02 S2 (m, 3H), 3.15 (d, 2H), 2.93 (d, 2H), 1.86 6,7,8,9-tetrahydro-5H-cyclohepta[b]thieno[3, (s, 2H), 1.68 (s, 4H); Mass Spec: 527.1 (M+H)+
2-e]pyridine-2-carboxamide o (isonicotinamido)-N
O 1H NMR in DMSO-d6: S 11.40(s, 1H), N-(5-phenyl-1,3,4-N \ S N¨<\ I di 9.09 (d, 2H), 8.36 (d, 2H), 8.12 (s, 1H), thiadiazol-2-y1)-H N.-N C27 H22 7.95 (d, 2H), 7.56-7.58 (m, 3H), 3.16 (s, 6,7,8,9-tetrahydro-5H-2H), 2.94 (s, 2H), 1.88 (s, 2H), 1.69 (s, cyclohepta[b]thieno[3, 4H); Mass Spec: 527.1 (M+H)+ 2-e]pyridine-2-carboxamide HO
"NH
0 2-[[6-chloro-2-[(5-I \ S 41 C18 H12 1H NMR in DMSO-d6: S 8.53 (d, 1H), phenyl-1,3,4-' s thiadiazol-2-299 CI N N¨ I
H N....N Cl N5 03 7.88 (s, 2H), 7.50-7.58 (m, 5H), 4.68 (s, yl)carbamoyl]thieno[2, S2 2H); Mass Spec: 446.0 (M+H)+
3-b]pyridin-3-yl]amino]acetic acid \----\
3-(2-NH

4 1H NMR in DMSO-d6:
N., \
S 8.61 (d, 1H), aminoethylamino)-6-I , chloro-N-(5-phenyl-300 01 N S N-eN__IN C18 H15 8.30 (s, 2H), 7.89-7.92 (m, 2H), 7.54-7.60 Cl N6 0 S2 (m, 3H), 4.69-4.73 (m, 2H), 3.46-3.49 (m, 1,3,4.-thiadiazol-2-yl)tlueno[2,3-2H); Mass Spec: 431.1 (M+H)+
b]pyridine-2-carboxamide 3-oxo-3-[[6-(2-NH OH 1H NMR in DMSO-d6: thieny1)-24[3-S 8.35 (s, 2H), (trifluoromethyl)pheny I 7.80-7.86 (m, 3H), 7.68 (d, 1H), 7.47 (t, 302 "--= N S N F3 N3 04 S2 1]carbamoyl]thieno[2,3 2H);
\ .0 F 1H), 7.18-7.25 (m, 2H), 3.28-3.60 (bs, s o -b]pyridin-3-yl]amino]propanoic acid 2-[[6-methyl-2-[[4-HI..õ1 1H NMR in CD30D: S 8.44 (s, 1H), 7.73 (trifluoromethoxy)phe C21 H19 (d, 2H), 7.48 (dd, 1H), 7.25 (d, 2H), 6.41 nyl]carbamoy1]-7,8-NH
303 NN , \ , FZF F3 N4 04 (d, 1H), 5.61 (d, 1H), 3.81 (s, 2H), 3.12 (s, dihydro-5H-1 , N I H=

0\/
N S W S 2H), 2.32 (s, 3H); Mass Spec: 481.1 thieno[2,3-o (M+H)+
b][1,6]naphthyridin-3-yl]amino]acetic acid NcNEI2 3-(2-I rEl F F
aminoethylamino)-6-N
0 C21 H17 (2-thieny1)-N43-[3 F
304 s o F3 N4 0 Mass Spec: 463.1 (M+H)+
(trifluoromethyl)pheny S2 1]thieno[2,3-b]pyridine-2-carboxamide OH
NH 1H NMR in DMSO-d6: S 12.80 (s, 1H), 24[6-(2-thieny1)-24[3-I , jcH
305 F F C21 H14 8.23-8.42 (m, 2H), 7.95-8.07 (m, 3H), 7.74 (trifluoromethyl)pheny N N S F3 N3 03 (d, 1H), 7.55 (t, 1H), 7.38 (d, 1H), 7.21 (s, 1]carbamoyl]thieno[2,3 \
S 0 1401 F S2 1H), 6.89 (s, 1H), 3.88 (s, 2H); Mass Spec: -b]pyridin-3-478.1 (M+H)+ yl]amino]acetic acid 3-[[2-N H H 1H NMR in DMSO-d6: S 11.59 (s, 1H), (methylamino)acetyl]a I
307 \ N rEl F F C22 H17 10.89 (s, 1H), 9.12 (s, 2H), 8.45 (d, 1H), mino]-6-(2-thieny1)-N-N
o lµr 0 F 8.31 (s, 1H), 8.14 (d, 1H), 8.03-8.07 (m, [3-s s S2 2H), 7.78 (d, 1H), 7.62 (t, 1H), 7.50 (d, (trifluoromethyl)pheny 1H), 7.23-7.26 (m, 1H), 4.13 (s, 2H), 2.59 1]thieno[2,3-(s, 3H); Mass Spec: 491.1 (M+H)+ b]pyridine-2-carboxamide 3-[[2-1H NMR in DMSO-d6: S 11.44 (s, 1H), (dimethylamino)acetyl nri 111 10.85 (s, 1H), 9.95 (s, 1H), 8.44 (d, 1H), ]amino]-6-(2-thieny1)-I H F F C23 H19 8.26 (s, 1H), 8.16 (d, 1H), 7.97-8.03 (m, N-[3-N N s \ F S2 2H), 7.78 (d, 1H), 7.62 (t, 1H), 7.49 (d, (trifluoromethyl)pheny 01011 1H), 7.25 (t, 1H), 4.32 (d, 2H), 2.83 (d, 1]thieno[2,3-s o 6H); Mass Spec: 505.1 (M+H)+ b]pyridine-2-carboxamide N,N,N-trimethy1-2-I 1H NMR in DMSO-d6: S 11.12 (s, 1H), oxo-2((6-(thiophen-2-NH Nr C24 H22 10.79 (s, 1H), 8.39 (d, 1H), 8.16-8.22 (m, y1)-2-03-2H), 8.02 (d, 1H), 7.93 (d, 1H), 7.79 (d, (trifluoromethyl)pheny 309 1 ' rii F F F3 N4 02 N 1H), 7.63 (t, 1H), 7.51 (d, 1H), 7.25 (t, 1)carbamoyl)thieno[2,3 N rsr S 0 \
F S2 s o 1H), 4.49 (s, 2H), 3.28 (s, 9H); Mass Spec: -b]pyridin-3-519.1 (M+H)+
yl)amino)ethanaminiu m 1H NMR in DMSO-d6: S 10.67 (s, 1H), o o--/ 10.56 (s, 1H), 8.25 (d, 1H), 8.21 (s, 1H), ethyl 4-oxo-4-[[6-(2-.---/-10 C25 H20 8.11 (d, 1H), 7.97-8.01 (m, 2H), 7.77 (d, thieny1)-24[3-N H -(trifluoromethyl)pheny 310 F F3 N3 04 1H), 7.62 (t, 1H), 7.49 (d, 1H), 7.22-7.25 F
S2 (m, 1H), 3.96-4.03 (m 2H) 2.74-2.78 (m l]carbamoyl]thieno[2,3 \ Ns N S 40 m, , , -, " -b]pyridin-3-F
0 2H), 2.59-2.63 (m, 2H), 1.14 (t, 3H); Mass yl]amino]butanoate Spec: 548.1 (M+H)+

OH 4-oxo-4-[[6-(2-1H NMR in CD30D: S 8.32 (s, 1H), 8.11 thieny1)-24[3-NV-7---( F C23 H16 (d, 1H), 7.77-7.79 (m, 2H), 7.69 (d, 1H), (trifluoromethyl)pheny 311 I jcri F F3 N3 04 7.53-7.57 (m, 2H), 7.36 (d, 1H), 7.16 (t, 1]carbamoyl]thieno[2,3 ' S 0 100 F S2 1H), 2.82-2.87 (m, 2H), 2.71-2.76 (m, -b]pyridin-3-2H); Mass Spec: 520.0 (M+H)+
yl]amino]butanoic acid 3-[[2-(dimethylamino)acetyl 1H NMR in CD3OD: S 8.04 (s, 1H), 7.76 ]amino]-6-methyl-N-µ,...e C23 H24 (d, 2H), 7.28 (d, 2H), 3.79 (s, 2H), 3.25 (s, NH [4-312 Nni F\ FF F3 N5 03 2H), 3.19 (s, 2H), 2.92 (s, 2H), 2.52 (s, (trifluoromethoxy)phe I N 11:11 41 s, I 0/¨
S 3H), 2.41 (s, 6H); Mass Spec: 508.2 ny1]-7,8-dihydro-5H-o (M+H)+
thieno[2,3-b][1,6]naphthyridine-2-carboxamide 3#3-H2N---N.õ...\ 1H NMR in DMSO-d6: S 8.36 (s, 1H), aminopropyl)amino)-N H 8.05 (s, 3H), 7.89-7.91 (m, 2H), 7.58-7.60 N-(5-phenyl-1,3,4-o 313 4101 \ 001 C24 H26 (m, 3H), 4.48-4.59 (m, 2H), 3.13 (s, 2H), thiadiazol-2-y1)-N.' S N- I H N-N N6 0 S2 2.94-2.99 (m, 2H), 2.87-2.92 (m, 2H), 6,7,8,9-tetrahydro-5H-2.21-2.30 (m, 2H), 1.86 (s, 2H), 1.68 (s, cyclohepta[b]thieno[3, 4H); 2-e]pyridine-2-carboxamide 3-(N-(2-N----\ NO 1H NMR in DMSO-d6: S 10.34 (s, 1H), aminoethyl)acetamido) o s 0 C25 H26 8.30 (s, 3H), 7.96 (d, 2H), 7.92 (s, 1H), 1101 \
7.60-7.62 (m, 3H), 4.80 (t, 2H), 3.48-3.55 -N-(5-phenyl-1,3,4-thiadiazol-2-y1)-N.' S N¨ I N6 02 S2 6,7,8,9-tetrahydro-5H-H N.--N (m, 2H), 3.13 (d, 2H), 2.91 (d, 2H), 2.25 cyclohepta[b]thieno[3, (s, 3H), 1.86 (s, 2H), 1.67 (s, 4H);
2-e]pyridine-2-carboxamide _.--Isil 3-((2-\.....--\
N H 1H NMR in CDC13: S 7.84-7.86 (m, 2H), (dimethylamino)ethyl) amino)-N-(5-phenyl-=1o 7.60 (s, 1H), 7.48-7.49 (s, 3H), 4.60 (t, 315 \ 010 C25 H28 2H), 3.14-3.16 (m, 2H), 2.88-2.92 (m, 1,3,4-thiadiazol-2-y1)-INr. S N_e I N6 0 S2 6,7,8,9-tetrahydro-5H-H N-N 4H), 2.39 (s, 6H), 1.88-1.93 (m, 2H), 1.69-cyclohepta[b]thieno[3, 1.19 (m, 4H);
2-e]pyridine-2-carboxamide 3-(ethylamino)-6-(2-11_ - 1H NMR in DMSO-d6: S 9.93 (s, 1H), ...õ ,.....- thienyl)-N-[3-H F F C21 H16 8.57 (d, 1H), 8.17 (s, 1H), 7.95-8.08 (m, (trifluoromethyl)pheny 321 N N S 0 F F3 N3 0 4H), 7.77 (d, 1H), 7.58 (t, 1H), 7.44 (d, 1]thieno[2,3-\ s o S2 1H), 7.24 (t, 1H), 3.65-3.71 (m, 2H), 1.28 b]pyridine-2-(t, 3H); Mass Spec: 448.0 (M+H)+
carboxamide ) 3-acetamido-N-(5-NH phenyl-1,3,4-o 1H NMR in CDC13: S 7.83 (d, 2H), 7.46-N, N4s I 6,7,8,9-tetrahydro-5H-140 C23 H21 7.53 (m, 4H), 6.88 (s, 2H), 3.13 (d, 2H), thiadiazol-2-y1)-H N--N N5 02 S2 2.82-2.88 (m, 5H), 1.90 (s, 2H), 1.73 (s, cyclohepta[b]thieno[3, 4H); Mass Spec: 464.1 (M+H)+
2-e]pyridine-2-carboxamide \N H 3-(methylamino)-N-o 1101 \
C22 H21 1H NMR in DMSO-d6: S 8.16 (s, 1H), (5-phenyl-1,3,4-7.85-7.88 (m, 2H), 7.55-7.57 (m, 3H), 7.32 thiadiazol-2-y1)-359 N s N¨eN _IN N5 0 S2 (s, 2H), 4.01 (s, 3H), 3.06 (d, 2H), 2.86 (d, 6,7,8,9-tetrahydro-5H-2H), 1.84 (s, 2H), 1.66 (s, 4H); Mass Spec: cyclohepta[b]thieno[3, 436.2 (M+H)+ 2-e]pyridine-2-carboxamide N-(5-pheny1-1,3,4-z¨N, p 1H NMR in DMSO-d6: S 12.04 (s, 1H)' thiadiazol-2-y1)-3-N H 8.89-8.92 (m, 1H), 8.25-8.28 (m, 2H), 360 101 \ o 0 C27 H22 8.14-8.18 (m, 1H), 7.93-7.95 (m, 2H), (picolinamido)-S
N6 02 S2 7.77-7.81 (m, 1H), 7.56-7.59 (m, 3H), 3.15 6,7,8,9-tetrahydro-5H-' S N4 I cyclohepta[b]thieno[3, H N-N (s, 2H), 2.92 (s, 2H), 1.87 (s, 2H), 1.69 (s, 2-e]pyridine-2-4H); Mass Spec: 527.1 (M+H)+
carboxamide 3-[(2-aminoacetyl)amino]-6-1H NMR in DMSO-d6: S 11.08 (s, 1H), N H C18 H13 chloro-N-(5-phenyl-8 32 (s 3H) 7.93 (s 2H) 7.59-7.70 (m 361 N. \ 0 0110 Cl N6 02 ' " " ' 1,3,4-thiadiazol-2-I , 4H), 4.05 (s, 2H); Mass Spec: 445.1 S2 yl)thieno[2,3-CI hi S N4 I (M+H)+
H N-N b]pyridine-2-carboxamide 0 ju 3-[[6-chloro-2-[(5-HO c/ phenyl-1,3,4-C19 H12 1H NMR in DMSO-d6: S 8.35 (s, 1H), thiadiazol-2-NH
362 o 4 Cl N5 04 7.90 (s, 2H), 7.50 (s, 4H), 3.24 (s, 2H); yl)carbamoyl]thieno[2, N. \
I ,S2 Mass Spec: 474.0 (M+H)+ 3-b]pyridin-3-ci N- s N4 I
H N-N yl]amino]-3-oxo-propanoic acid OH

0.---j) i -0 H 2-[carboxymethyl-[6-4 1H NMR in D20: S 8.50 (d, 1H), 8.22 (s, (2-thieny1)-24[3-[[3 , I I H F F 1H), 7.96 (d, 1H), 7.83 (d, 1H), 7.76 (d, (trifluoromethyl)pheny s \ F S2 1H), 7.54-7.68 (m, 3H), 7.09 (t, 1H), 3.99 1]carbamoyl]thieno[2,3 40 (s, 4H); Mass Spec: 536.0 (M+(M+H)+-b]pyridin-3-o yl]amino]acetic acid Table 3 - Novel Compounds of Formula III activity against Dengue Virus in Vero cells.
Activity (EC50 in n1V1) A: EC50<5 M; B: 5<EC50<25 M; C: EC50>25 M; n.d.:
Cmpd not determined 299 B B n.d. B

308 n.d. A n.d. n.d.

313 n.d. A n.d. n.d.
314 n.d. A n.d. n.d.
315 n.d. A n.d. n.d.

Table 4 - Novel compounds of the present invention outside the scope of Formula III.
Molecular Cmpd Chemical Structure Analytical Data Chemical Name Formula 3-amino-N-1H NMR in DMSO-d6: S 8.11 (s, 1H), cyclohexy1-6,7,8,9-0 C19 H25 7.32 (d, 1H), 7.05 (s, 2H), 3.72-3.74 (m, tetrahydro-5H-281 4101 \ N3 0 S 1H), 3.06 (dd, 2H), 2.86 (dd, 2H), 1.64- cyclohepta[b]thieno[3, Nr S N-0 1.84 (m, 11H), 1.20-1.41 (m, 3H), 1.03- 2-etyridine-2-H
1.15 (m, 2H); Mass Spec: 344.2 (M+H)+ carboxamide 1H NMR in DMSO-d6: S 8.08 (s, 1H), 3-amino-N-butyl-NH2 7.58 (t, 1H), 7.02 (s, 2H), 3.14-3.20 (m, o 6,7,8,9-tetrahydro-5H-282 1111 ' \ / C17 H23 2H), 3.02 (d, 2H), 2.81 (s, 2H), 1.80 (s, cyclohepta[b]thieno[3, lc S N-/ N3 OS 2H), 1.60(s, 4H), 1.41-1.48 (m, 2H), 1.24-H 1.31 (m, 2H), 0.87 (t, 3H); Mass Spec:
2-e]pyridine-2-carboxamide 318.1 (M+H)+
3-amino-N-(tert-N H 2 1H NMR in DMSO-d6: S 8.09 (s, 1H), buty1)-6,7,8,9-0 C17 H23 6.95 (s, 2H), 6.55 (s, 1H), 3.03 (d, 2H), tetrahydro-5H-. \
N3 0 S 2.83 (d, 2H), 1.81 (s, 2H), 1.63 (s, 4H), cyclohepta[b]thieno[3, Nj S N ( 1.36 (s, 9H); Mass Spec:
318.2 (M+H)+ 2-e]pyridine-2-H
carboxamide 3-amino-6-methyl-N-1H NMR in DMSO-d6: S 8.18 (d, 1H), (5-phenyl-1,3,4-284 I 'en. s 1 1401 C17 H13 7.85 (d, 2H), 7.37-7.49 (m, 4H), 7.23 (d, thiadiazol-2-N H "¨'N--N . N5 0 S2 1H), 7.10 (s, 2H), 2.57 (s, 3H); Mass Spec: yl)thieno[2,3-368.1 (M+H)+ b]pyridine-2-carboxamide 3-amino-5-methyl-N-NH2 1H NMR in DMSO-d6: S 8.39 (s, 1H), (5-phenyl-1,3,4-o 286 I \ s el C17 H13 8.10 (s, 1H), 7.83-7.85 (m, 2H), 7.33-7.47 thiadiazol-2-'sr s N¨ I N5 0 S2 (m, 3H), 7.05 (s, 2H), 2.41 (s, 3H);
Mass yl)thieno[2,3-H N¨N
Spec: 368.1 (M+H)+ b]pyridine-2-carboxamide ,-, `-' NH2 0 3-amino-4-methoxy-S el 1H NMR in DMSO-d6: S 8.37 (d, 1H), N-(5-phenyl-1,3,4-NS N¨ 1 C17 H13 7.85 (d, 2H), 7.34-7.48(m, 3H), 6.90 (s, thiadiazol-2-N5 02 S2 3H), 4.00 (s, 3H); Mass Spec: 384.1 yl)thieno[2,3-(M+H)+ b]pyridine-2-carboxamide I IN H2 3-amino-4-methyl-N-0 1H NMR in DMSO-d6: S 8.33 (d, 1H), (5-phenyl-1,3,4-Cn s 1 C 17 H13 7.85 (d, 2H), 7.36-7.48 (m, 3H), 7.06 (d, thiadiazol-2-288 hr. S N¨ I
N5 0 S2 1H), 6.84 (s, 2H), 2.79 (s, 3H); Mass Spec:
yl)thieno[2,3-368.1 (M+H)+ b]pyridine-2-carboxamide 3,5-diamino-N-(5-NH2 1H NMR in DMSO-d6: S 8.02 (d, 1H), phenyl-1,3,4-1 S\ . i\sN I 0 C16 H12 7.83 (d, 2H), 7.32-7.47 (m, 4H), 6.89 (s, thiadiazol-2-N6 0S2 2H), 5.28 (s, 2H); Mass Spec: 369.1 ypthieno[2,3-11¨C _N
(M+H)+ b]pyridine-2-carboxamide H2 3-amino-2-((5-phenyl-o 0 C17 H11 1H NMR in DMSO-d6: S 12.81 (s, 1H), 1,3,4-thiadiazol-2----- \
291 rsj S N¨e I 8.13 (d, 2H), 7.91 (s, 3H), 7.49-7.56 (m, yl)carbamoyl)thieno[2, 5H); Mass Spec: 398.0 (M+H)+ 3-b]pyridine-5-carboxylic acid 3-amino-6-chloro-N-o 1H NMR in DMSO-d6: S 8.57 (s, 1H), I \ 101 (5-pheny1-1,3,4-C16 H10 thiadiazol-2-292 N¨e I Cl N5 0 S2 7.91 (s, 2H), 7.56 (s, 5H); Mass Spec:
yl)thieno[2,3-CI nr s H N¨N 388.0 (M+H)+
b]pyridine-2-carboxamide 3-amino-6-methyl-N-H2 1H NMR in DMSO-d6: S 7.99 (s, 1H), (5-pheny1-1,3,4-7.83-7.85 (m, 2H), 7.33-7.47 (m, 3H), 7.09 thiadiazol-2-y1)-7,8-301 C20 H18 S N4 1 (s, 2H), 3.63 (s, 2H), 3.01 (s, 2H), 2.74 (s, dihydro-5H-H s 010 N6 0 S2 2H), 2.40 (s, 3H); Mass Spec: 423.2 thieno[2,3-(M+H)+
b][1,6]naphthyridine-2-carboxamide 2-(thiophen-2-y1)-10-1H NMR in DMSO-d6: S 10.81 (s' 1H), o 8.28 (d, 1H), 8.16 (d, 1H), 8.10 (s, 1H), (3-(trifluoromethyl)pheny 8.04 (d, 1H), 7.91 (d, 1H), 7.80 (d, 1H), 306 ,,..._ F F3 N3 03 1)-7,8-dihydro-I 7.62 (t, 1H), 7.52 (d, 1H), 7.25 (t, 1H), F
jcN S2 pyrido[3',2':4,5]thieno[
2.81-3.03 (m, 4H); Mass Spec: 502.0 s o 0 F 3,2-b][1,5]diazonine-(M+H)+
6,9,11(10H)-trione [ul o I cr F F 1H NMR in DMSO-d6: S 8.35 (d, 1H), 7-(thiophen-2-y1)-3-(3-NN, S
so F C20 H10 8.01 (d, 1H), 7.95 (d, 1H), 7.74 (d, 1H), (trifluoromethyl)pheny 316 \ s o F3 N3 02 1)pyrido[3',2':4,5]thien 7.63-7.68 (m, 2H), 7.50-7.53 (m, 2H), 7.23 S2 o[3,2-d]pyrimidine-(t, 1H); Mass Spec: 446.0 (M+H)+
2,4(1H,3H)-dione NH2 F F 3-amino-6-(trifluoromethyl)-N-F
F 1H NMR in DMSO-d6: S 9.97 (s, 1H), [3-317 F>,---re----s ri . C16 H9 F6 8.83 (d, 1H), 8.22 (s, 1H), 7.98-8.02 (m, F N3 0 S 2H), 7.55-7.63 (m, 3H), 7.43 (d, 1H);
(trifluoromethyl)pheny 1]thieno[2,3-Mass Spec: 406.0 (M+H)+
b]pyridine-2-carboxamide 3-amino-6-(2,4-)7a jcrrsji F F 1H NMR in DMSO-d6: S 9.76 (s, 1H), dimethylthiazol-5-y1)-C20 H15 8.59 (d, 1H), 8.23 (s, 1H), 8.00 (d, 1H), N-[3-318 2¨s o 01 F
F3 N4 0 7.75 (d, 1H), 7.55-7.60 (m, 3H), 7.72 (d, (trifluoromethyl)pheny S2 1H), 2.65-2.66 (m, 6H); Mass Spec: 449.1 1]thieno[2,3-(M+H)+ b]pyridine-2-carboxamide NH2 3-amino-6-(2-thieny1)-I F F 1H NMR in DMSO-d6: S 8.44 (d, 1H), N-[3-F C19 H13 8.01 (d, 1H), 7.93 (dd, 1H), 7.72 (d, 1H), (trifluoromethyl)pheny 319 \ s NH 7.54 (t, 1H), 7.39 (s, 2H), 7.32 (d, 1H), F3 N4 S2 l]thieno[2,3-7.20-7.23 (m, 3H), 6.20 (s, 2H); Mass b]pyridine-2-Spec: 419.0 (M+H)+
carboxamidine 8-(thiophen-2-y1)-4-(3-HO 1H NMR in DMSO-d6: S 8.62 (d, 1H), N-8 C21 H12 8.17 (d, 1H), 8.03 (dd, 1H), 7.95 (s, 1H), (trifluoromethyl)pheny 320 I jcN) F F F3 N3 02 7.79-7.82 (m, 2H), 7.71-7.78 (m, 2H), 1 -3,4-dih. dro-1H-) Y
pyrido[3',2':4,5]thieno[
F S2 7.23-7.26 (m, 1H), 4.56 (s, 2H); Mass 3,2-e][1,4]diazepine-Spec: 460.0 (M+H)+
o 2,5-dione 3-amino-N-methy1-6-NH2 1H NMR in DMSO-d6: S 8.50 (d, 1H), (2-thieny1)-N[3-I ili F C20 H14 7.95 (d, 1H), 7.90 (d, 1H), 7.85 (s, 1H), (trifluoromethyl)pheny 322 \ " 5 0 0F F F3 N3 0 7.78-7.81 (m, 1H), 7.69-7.70 (m, 3H), 7.54 1]thieno[2,3-S2 (s, 2H), 7.16-7.19 (m, 1H), 3.35 (s, 3H);
b]pyridine-2-Mass Spec: 434.0 (M+H)+
carboxamide `..N., NH* 3-amino-N-(2-I crN F F F C23 H21 dimethylaminoethyl)-\ ' s 101 1H NMR in DMSO-d6: S 8.53 (d, 1H), 6-(2-thieny1)-N[3-o 7.69-8.01 (m, 7H), 7.18 (t, 1H), 6.69 (bs, (trifluoromethyl)pheny 2H), 4.18 (t, 2H), 3.29 (q, 2H), 2.85-2.86 S2 1]thieno[2,3-(m, 6H); Mass Spec: 491.1 (M+H)+
b]pyridine-2-carboxamide Co N
NH2 ..
6-acetamido-3-amino-.
Br 1 1H NMR in DMSO-d6: S 11.09 (s, 1H), N-(4-bromopheny1)-5-C21 H14 10.37 (s, 1H), 8.23 (d, 1H), 7.49-7.57 (m, cyano-4-(2-324 HNrNS \ 0 Br N5 03 S 5H), 6.91-6.92 (m, 1H), 4.28 (s, 2H), 2.17 furyl)thieno[2,3-(s, 3H); Mass Spec: 497.0 (M+H)+ b]pyridine-2-carboxamide eo N., NH2 H .
3-amino-N-(4-/ N=Br I \ 1H NMR in DMSO-d6: S 9.50 (s, 1H), bromopheny1)-5-.,....
HO N o 0 C19 H11 8.09 (t, 1H), 7.47-7.65 (m, 5H), 7.13 (d, cyano-4-(2-fury1)-6-Br N4 03 S 1H), 6.85 (d, 1H), 6.35 (s, 2H); Mass hydroxy-thieno[2,3-Spec: 456.0 (M+2H)+ b]pyridine-2-carboxamide NH2 OH 1H NMR in DMSO-d6: S 8.26 (d, 1H), 2-[N-[3-amino-6-(2-thienyl)thieno[2,3-1 F-40 F F C21 H14 7.87-7.90 (m, 2H), 7.68-7.70 (m, 2H), N b]pyridine-2-326 s F3 N3 03 7.44-7.53 (m, 3H), 7.31 (s, 2H), 7.16-7.19 (M+H)+
\ o VI F
S2 (m, 1H), 4.07 (s, 2H); Mass Spec: 478.0 carbony1]-3-(trifluoromethypanilin o]acetic acid o 3-[N-[3-amino-6-(2-NH2r)..-oH F 1H NMR in DMSO-d6: S 8.44 (d, 1H), N
thienyl)thieno[2,3-C22 H16 7.88-7.94 (m, 2H), 7.82 (s, 1H), 7.76-7.77 I sc F b]pyridine-2-327 F3 N3 03 0 (m, 1H), 7.66-7.69 (m, 3H), 7.52 (s, 2H), \ F
(trifluoromethypanilin o S2 7.15-7.18 (m, 1H), 3.90 (t, 2H), 2.17 (t, carbony1]-3-2H); Mass Spec: 492.1 (M+H)+
o]propanoic acid o NH2 o 1110' I \ N"--N 3-amino-5-oxo-N-(5-N S [qi-, 1H NMR in DMSO-d6: S 8.58 (s, 1H), phenyl-1,3,4-s 40 C21 H17 7.83-7.86 (m, 2H), 7.43-7.48 (m, 2H), thiadiazol-2-y1)-328 7.34-7.39 (m, 1H), 7.29 (s, 2H), 3.22 (t, 6,7,8,9-tetrahydro-5H-2H), 2.82 (t, 2H), 1.91 (t, 2H), 1.74-1.82 cyclohepta[b]thieno[3, (m, 2H); Mass Spec: 436.1 (M+H)+ 2-e]pyridine-2-carboxamide OH 3-amino-5-hydroxy-N-0 1H NMR in DMSO-d6: S 8.53 (s, 1H), (5-phenyl-1,3,4-4. I \ N¨tr C21 H19 7.91-7.93 (m, 2H), 7.55-7.57 (m, 3H), 5.62 thiadiazol-2-y1)-329 "
14 s 1-1 S 40 N5 02 S2 (d, 1H), 4.88-4.90 (m, 1H), 2.96-3.11 (m, 6,7,8,9-tetrahydro-5H-2H), 1.81-2.02 (m, 4H), 1.35-1.58 (m, cyclohepta[b]thieno[3, 2H); Mass Spec: 438.1 (M+H)+ 2-e]pyridine-2-carboxamide 3-amino-5-fluoro-N-F

NH2 (5-phenyl-1,3,4-0 - I \ j4.--N C21 H18 F thiadiazol-2-y1)-330 'Isi S N¨ I Mass Spec: 440.0 (M+H)+ 6,7,8,9-tetrahydro-5H-cyclohepta[b]thieno[3, 2-e]pyridine-2-carboxamide 3-amino-6-(4-1H NMR in DMSO-d6: S 9.69 (s, 1H), chloropheny1)-I \ 8.61 (d, 1H), 8.24 (d, 2H), 8.12 (d, 1H), (trifluoromethoxy)phe 0 ---N S HN =

F F Cl F3 N3 CI * 0XF 02 S 7.83 (d, 2H), 7.61 (d, 2H), 7.48 (s, 2H), nyl]thieno[2,3-7.35 (d, 2H); Mass Spec: 463.8 (M+H)+ b]pyridine-2-carboxamide NH2 3-amino-6-[3-I \ 1H NMR in DMSO-d6: S 9.70 (s, 1H), (trifluoromethoxy)phe , F F C22 H13 ny1]-N44-HN . oXF
F6 N3 03 8.64 (d, 2H), 8.17-8.27 (m, 3H), 7.83 (d, (trifluoromethoxy)phe 2H), 7.69 (t, 1H), 7.49-7.53 (m, 3H), 7.35 nyl]th .
S
ieno[2,3-o)<FF
(d, 2H); Mass Spec: 513.8 (M+H)+
b]pyridine-2-carboxamide .õ. NH2 1H NMR in DMSO-d6: S 9.62 (s, 1H), 3-amino-N,6-bis(4-II rj C20 H13 8.61 (d, 1H), 8.23 (d, 2H), 8.12 (d, 1H), chlorophenyl)thieno[2, , 0 io C12 N3 0 S 7.76 (d, 2H), 7.60 (d, 2H), 7.47 (s, 2H), 3-b]pyridine-2-ci ci 7.39 (d, 2H); Mass Spec: 413.8 (M+H)+
carboxamide ,_. NH2 I I rj 1H NMR in DMS0-d6: S 9.77 (s, 1H), 4-[[3-amino-6-(4-s o 101 0 .63 (d, 1H), 8.24 (d, 2H), 8.12 (d, 1H), chlorophenyl)thieno[2, 334 ci = 3-b]pyridine-2-ON Cl N3 03 S 7.86-7.94 (m, 4H), 7.55-7.62 (m, 4H);
carbonyl]amino]benzo Mass Spec: 423.9 (M+H)+
ic acid I I H
NN.y..,..)õ, CI 0 ' ,--- Br 3-amino-N-(5-bromo-1H NMR in DMSO-d6: S 9.99 (s, 1H), C19 H12 2-pyridy1)-6-(4-8.62 (d, 1H), 8.48 (d, 1H), 8.23 (d, 2H), 335 Br C1N4 0 chlorophenyl)thieno[2, 8.11 (d, 1H), 8.01-8.06 (m, 2H), 7.54-7.61 S 3-b]pyridine-2-(m, 4H); Mass Spec: 460.8 (M+H)+
carboxamide ,,,... NH2 I , I N0 H
110 N S ,1 CI ---- Br 3-amino-N-(6-bromo-1H NMR in DMSO-d6: S 9.82 (s, 1H), C19 H12 3-pyridy1)-6-(4-8.77 (d, 1H), 8.63 (d, 1H), 8.24 (d, 2H), 336 Br C1N4 0 chlorophenyl)thieno[2, 8.09-8.14 (m, 2H), 7.56-7.63 (m, 5H);
S 3-b]pyridine-2-Mass Spec: 460.8 (M+H)+
carboxamide NH 3-amino-6-(4-I I 0 C21 H14 1H NMR in DMSO-d6: S 9.69 (s, 1H), chloropheny1)-N44-337 0 N' S 0 0 a F Cl F2 N3 0 8.61 (d, 1H), 8.23 (d, 2H), 8.11 (d, 1H), (difluoromethyflpheny 'IP' 7.87 (d, 2H), 7.52-7.61 (m, 6H), 6.99 (t, 1]thieno[2,3-H
F S
1H); Mass Spec: 429.9 (M+H)+ b]pyridine-2-carboxamide 3-amino-6-(4-I I 1 1H NMR in DMSO-d6: S 9.67 (s, 1H), chloropheny1)-N44-338 s 0 lip F Cl F2 N3 0 8.62 (d, 1H), 8.24 (d, 2H), 8.12 (d, 1H), (1,1-so N-ci =7.85 (d, 2H), 7.50-7.62 (m, 6H), 1.98 (t, difluoroethyl)phenyl]t F S
3H); Mass Spec: 443.9 (M+H)+ hieno[2,3-b]pyridine-2-carboxamide 3-amino-6-[3-I \ 1H NMR in DMSO-d6: S 9.69 (s, 1H), (difluoromethoxy)phe 40 ' N B FXF
HN C22 H14 8.63 (d, 1H), 8.08-8.17 (m, 2H), 7.99 (s, ny1]-N44-339 F5 N3 03 1H), 7.83 (d, 2H), 7.62 (d, 1H), 7.48 (s, (trifluoromethoxy)phe , S 2H), 7.34-7.39 (m, 4H); Mass Spec: 495.9 nyl]thieno[2,3-7 (M+H)+ b]pyridine-2-carboxamide NH, 3-amino-6-(4-. C21 H14 1H NMR in DMSO-d6: S 9.59 (s, 1H), chloropheny1)-N44-340 ci 0 N s 0 lel ojeF Cl F2 N3 8.60 (d, 1H), 8.24 (d, 2H), 8.12 (d, 1H), (difluoromethoxy)phe 7.75 (d, 2H), 7.61 (d, 2H), 6.94-7.45 (m, nyl]thieno[2,3-5H); Mass Spec: 445.8 (M+H)+ b]pyridine-2-carboxamide \ Br is Isr S

o 1H NMR in DMS0-d6: S 9.19 (s, 1H), 3-amino-N-(2-C20 H13 8.60 (d, 1H), 8.23 (d, 2H), 8.12 (d, 1H), bromopheny1)-6-(4-341 Br Cl N3 0 7.59-7.72 (m, 4H), 7.38-7.46 (m, 3H), chlorophenyl)thieno[2, S 7.16-7.22 (m, 1H); Mass Spec: 457.7 3-b]pyridine-2-(M+H)+ carboxamide 3-amino-6-(4-NH2 1H NMR in DMSO-d6: S 9.74 (s, 1H), chloropheny1)-N-(3,4-I I " GI C20 H12 8.62 (d, 1H), 8.24 (d, 2H), 8.11-8.14 (m, 342 s , di 0 N
dichlorophenyl)thieno[
C13 N3 0 S 2H), 7.73 (dd, 1H), 7.55-7.62 (m, 5H);
CI 4111147 'IP.' ci Mass Spec: 447.8 (M+H)+ 2,3-b]pyridine-carboxamide 3-amino-6-(4-1H NMR in DMSO-d6: S 9.46 (s, 1H), chloropheny1)-N-(2,3-NH2CI C13 N3 0 S C20 H12 8.61 (d, 1H), 8.24 (d, 2H), 8.13 (d, 1H), dichlorophenyl)thieno[
11 c, 7.53-7.62 (m, 4H), 7.37-7.46 (m, 3H);
40 N s 0 40 Mass Spec: 447.8 (M+H)+ 2,3-b]pyridine-carboxamide GI
._,., NH2 1H NMR in DMSO-d6: S 9.63 (s, 1H), 3-amino-N-(3-I , I HCI C20 H13 8.60 (d, 1H), 8.22 (d, 2H), 8.10 (d, 1H), chloropheny1)-6-(4-0 IW C12 N3 0 S 7.92 (s, 1H), 7.49-7.66 (m, 5H), 7.34 (t, chlorophenyl)thieno[2, Cl 1H), 7.12 (d, 1H); Mass Spec: 413.8 3-b]pyridine-2-(M+H)+ carboxamide 3-amino-6-[3-(difluoromethoxy)phe 1H NMR in DMSO-d6: S 9.59 (s, 1H), I \ o C22 H15 ny1]-N44-8.62 (d, 1H), 8.15 (d, 1H), 8.09 (d, 1H), 345 0 --N s HN = oF><HF F4 N3 03 (difluoromethoxy)phe 7.99 (s, 1H), 7.75 (d, 2H), 6.94-7.64 (m, S nyl]thieno[2,3-8H); Mass Spec: 477.9 (M+H)+
o.õ,Fr.F b]pyridine-2-carboxamide ...õ..
NH2 4-[[3-amino-6-(4-I , I 0 C20 H14 1H NMR in DMSO-d6: S 9.54 (s, 1H), chlorophenyl)thieno[2, 346 di N- s 0 di 8.59 (d, 1H), 8.22 (d, 2H), 8.09 (d, 1H), 3-b]pyridine-2-CI "gow" 'W s-OH C1N3 04 S2 7.53-7.66 (m, 6H); Mass Spec: 459.8 (M+H)+
carbonyl]amino]benze nesulfonic acid ci I I H
N 1H NMR in DMS0-d6: S 9.27 (s, 1H), 3-amino-6-(4-0 N' s 0 0 8.61 (d, 1H), 8.23 (d, 2H), 8.13 (d, 1H), chloropheny1)-N-(2,5-347 CI 7.84 (s, 1H), 7.58-7.62 (m, 3H), 7.44 (s, dichlorophenyl)thieno[
ci C13 N3 0 S
2H), 7.34 (dd, 1H); Mass Spec: 447.8 2,3-b]pyridine-(M+H)+ carboxamide 1H NMR in DMS0-d6: S 9.32 (s, 1H), 3-amino-6-(4-.._, NH2 I I rEl 8.57 (d, 1H), 8.21 (d, 2H), 8.09 (d, 1H), chloropheny1)-N-(3,4-348 a N s 0 0 7.58 (d, 2H), 7.48 (s, 1H), 7.38-7.40 (m, dimethylphenyl)thieno Cl N3 05 ci 'IP' 3H), 7.06 (d, 1H), 2.20 (s, 3H), 2.17 (s, [2,3-b]pyridine-2-3H); Mass Spec: 407.9 (M+H)+ carboxamide 3-amino-N-(4-4H.,2 IR1 C19 H12 1H NMR in DMS0-d6: S 9.64 (s, 1H), bromopheny1)-6-(5-349 I -, N S Br Cl N4 0 Br S 8.78 (s, 1H), 8.65 (d, 1H), 8.40-8.48 (m, chloro-2-CI
2H), 8.11 (d, 1H), 7.70 (d, 2H), 7.48-7.52 pyridyl)thieno[2,3-(m, 4H); Mass Spec: 458.8 (M+H)+ b]pyridine-2-carboxamide N,OH
I I
NH

Hiti) Br Cl N3 C23 H17 1H NMR in DMSO-d6: S 8.51 (d, 1H), 3-(N-[3-amino-6-(4-chlorophenyl)thieno[2, 8.13 (d, 2H), 8.00 (d, 1H), 7.66 (d, 2H), 0 ' 0 ift 3-b]pyridine-2-350 N s 7.51 (d, 2H), 7.35 (d, 2H), 3.92 (t, 2H), CI 411111-47 "4111-Vr Br 03 S
carbony1]-4-bromo-2.53 (t, 2H); Mass Spec: 529.8 (M+H)+
anilino)propanoic acid 3-amino-6-(4-I 1H NMR in DMSO-d6: S 10.05 (s, 1H), chloropheny1)-N44-351 N s Cl F3 N3 8'64 (d' 1H)' 8.23 (d, 2H), 8.06-8.13 (m, (2,2,2-so - 0 0 F F
CI F
02 S 5H), 7.59-7.65 (m, 4H); Mass Spec: 475.8 trifluoroacetyl)phenyl]
o (M+H)+ thieno[2,3-b]pyridine-2-carboxamide NH2 3-amino-6-(4-I - I rE,1 1H NMR in DMSO-d6: S 10.00 (s, 1H), chloropheny1)-N-(5-ci 401 352 " s 0 C19 H12 8.61 (d, 1H), 8.41 (s, 1H), 8.23 (d, 2H), chloro-2-c' C12 N4 OS 8.11 (d, 2H), 7.93 (d, 1H), 7.54-7.60(m, pyridy1)t1ieno[2,3-4H); Mass Spec: 414.9 (M+H)+ b]pyridine-2-carboxamide 3-amino-6-(4-I
"
1H NMR in DMSO-d6: S 9.83 (s, 1H), chloropheny1)-N-(6-I
, illii N s0 rt-a-ci C19 H12 8.77 (s, 1H), 8.62 (d, 1H), 8.10-8.24 (m, chloro-3-CI 41111111-4P C12 N4 0 S 4H), 7.48-7.61 (m, 5H); Mass Spec: 414.8 pyridy1)t1ieno[2,3-(M+H)+ b]pyridine-2-carboxamide NH2 7 1H NMR in CD3OD: S 8.28 (d, 1H), 7.78 3-[N-[3-amino-6-(3-methoxyphenyl)thieno , I \ Nal C25 H20 (d, 1H), 7.48-7.54 (m, 3H), 7.33-7.29 (m, 0 N S 0 glir 0 F---\--F F3 N3 05 4H), 6.98 (d, 1H), 4.09 (t, 2H), 3.85 (s, [2,3-b]pyridine-2-S 3H), 2.67 (t, 2H); Mass Spec: 531.9 carbonyl]-4-(trifluoromethoxy)anili 0 F (M+H)+
no]propanoic acid 1H NMR in DMSO-d6: S 8.50 (d, 1H), 3-(N-[3-amino-6-(4-chlorophenyl)thieno[2, 1101 ' s o 0 C12 N3 03 8.12 (d, 2H), 8.00 (d, 1H), 7.49-7.54 (m, 6H), 7.42 (d, 2H), 3.92 (t, 2H), 2.52 (t, 3-b]pyridine-2-CI CI S carbony1]-4-chloro-2H); Mass Spec: 485.8 (M+H)+
anilino)propanoic acid 3-amino-6-(4-I I H
N 1H NMR in DMSO-d6: S 9.27 (d, 2H), chloropheny1)-N-(4-0 N' s 0 a C20 H14 8.57 (d, 1H), 8.23 (d, 2H), 8.10 (d, 1H), hydroxyphenyl)thieno[
ci 41101-P OH Cl N3 02 S 7.60 (d, 2H), 7.42 (d, 2H), 7.34 (s, 2H), 2,3-b]pyridine-2-6.72 (d, 2H); Mass Spec: 395.9 (M+H)+
carboxamide NH2 1H NMR in CDC13: S 8.54 (d, 2H), 7.92 3-amino-N-(4-1 1 H C17 H12 (d, 1H), 7.69-7.73 (m, 2H), 7.57 (d, 2H), pyridy1)-6-(2-N Isr S.rN
357 thienyl)thieno[2,3-s \ 1 N4 0 S2 7.48 (d, 1H), 7.24 (s, 1H), 7.15 (t, 1H), 0 ,-Isl 6.25 (s, 2H); b]pyridine-2-carboxamide Table 5 - Activity against Dengue virus of novel compounds of the present invention outside the scope of Formula III.
Activity (EC50 in nM) A: EC50<5 M; B: 5<EC50<25 M; C: EC50>25 M; n.d.:
Cmpd not determined 281 n.d. B n.d. n.d.
282 n.d. B n.d. n.d.
283 n.d. A n.d. n.d.

286 n.d. A n.d. n.d.
287 n.d. B n.d. n.d.

290 n.d. A n.d. n.d.
291 n.d. B n.d. n.d.

316 n.d. A n.d. n.d.
317 n.d. A n.d. n.d.
318 n.d. A n.d. n.d.
319 n.d. A n.d. n.d.
320 n.d. A n.d. n.d.

323 n.d. A n.d. n.d.
324 n.d. A n.d. n.d.

326 n.d. A n.d. n.d.

334 n.d. A n.d. n.d.

346 n.d. A n.d. n.d.
347 n.d. A n.d. n.d.
348 n.d. A n.d. n.d.

351 n.d. A n.d. n.d.

354 n.d. B md. n.d.
355 n.d. A n.d. n.d.
356 n.d. B md. n.d.
357 n.d. A n.d. n.d.
Table 6 - Compounds of the present invention.
Molecular Cmpd Chemical Structure Chemical Name Formula F

F
3-amino-8-methyl-N-(3-(trifluoromethy1)pheny1)thieno[2,3-b]quino1ine-2-H S
carboxamide /
I \
, 3-amino-N-(naphthalen-2-y1)-6,7,8,9-tetrahydro-S N
365 H C23 H21 N3 0 S 5H-cyclohepta[b]thieno[3,2-e]pyridine-2-carboxamide 0 ' 1 \ N 3-amino-N-(thiazol-2-y1)-6,7,8,9-tetrahydro-5H-N S N¨ 3 C16 H16 N4 0 S2 cyclohepta[b]thieno[3,2-e]pyridine-2-carboxamide H S

F
0 C16 H12 F3 N3 0 3-amino-6-methyl-N-(3-367 I \ l< F
S (trifluoromethyl)phenyl)thieno[2,3-b]pyridine-2-NS N . carboxamide H

F
F
F
NH2 H 41 3-amino-N-(3-(trifluoromethyl)pheny1)-6,7,8,9-368 0 1 \ S tetrahydro-5H-cyclohepta[b]thieno[3,2-e]pyridine-N S 0 2-carboxamide NH2 F\,F 3-amino-N-(4-(trifluoromethoxy)pheny1)-6,7,8,9-369 0 1 I 1-,11 0, or 02 S -F C20 H18 F3 N3 N S
tetrahydro-5H-cyclohepta[b]thieno[3,2-e]pyridine-2-carboxamide F F 3-amino-N-(3-(trifluoromethyl)pheny1)-370 NH2 H 4i S F C21 H20 F3 N3 0 5,6,7,8,9,10-hexahydrocycloocta[b]thieno[3,2-S i etyridine-2-carboxamide ...... N \
s F
NH2 0)4 3-amino-N-(2-(trifluoromethoxy)pheny1)-6,7,8,9-371 tetrahydro-5H-cyclohepta[b]thieno[3,2-e]pyridine-N I . 02 S
2-carboxamide S

\
=I I H C20 H18 F3 N3 0 3-amino-N-(2-(trifluoromethyl)pheny1)-6,7,8,9-372 N S N tetrahydro-5H-cyclohepta[b]thieno[3,2-e]pyridine-S
0 0 2-carboxamide 373 \
\ , S N . C25 H23 N3 0 S 3-amino-N,N-dipheny1-6,7,8,9-tetrahydro-5H-cyclohepta[b]thieno[3,2-e]pyridine-2-carboxamide N e5 40 3-amino-N-(naphthalen-l-y1)-6,7,8,9-tetrahydro-374 NH2 H afr C23 H21 N3 0 S 5H-cyclohepta[b]thieno[3,2-e]pyridine-2-11110 I \ N carboxamide 'isi S 0 CO
NI-, NH2 N 41 \ N 3,6-diamino-5-cyano-4-(2-fury1)-N-phenyl-1 s thieno[2,3-b]pyridine-2-carboxamide "-s'---"

ci co N-(4-chloropheny1)-3-[(3,4-o 02 S
dichlorophenyl)methoxy]thieno[2,3-b]pyridine-2-H carboxamide N * CI
I \
NSO
CI
CO

F 3-[(3,4-dichlorophenyl)methoxy]-N-[3-: N2 02 S (trifluoromethyl)phenyl]thieno[2,3-b]pyridine-2-carboxamide N-.--s 0 ci cio 3-[(3,4-dichlorophenyl)methoxy]-N-[4-N2 03 S (trifluoromethoxy)phenyl]thieno[2,3-b]pyridine-2-o I'll 410 o carboxamide NSO F
F
Cl 41, CI
0 C21 H14 C12 N2 3-[(3,4-dichlorophenyl)methoxy]-N-phenyl-379 o --- , \
I s 02 S thieno[2,3-b]pyridine-2-carboxamide H
CI
. CI
N-(3-chloropheny1)-3-[(3,4-380 dichlorophenyl)methoxy]thieno[2,3-b]pyridine-2-p CI carboxamide .,._/
N S N
H
HO

381= N / I C14 H9 Cl N2 02 N-(3-chloropheny1)-3-hydroxy-thieno[2,3-S b]pyridine-2-carboxamide S"--N
H
HO
C), z 1 C14 H9 Cl N2 02 N-(2-chloropheny1)-3-hydroxy-t1ieno[2,3-= N S Nj S b]pyridine-2-carboxamide H
CI

c\c) NH2 NFiN 1 411 3,6-diamino-5-cyano-4-(2-fury1)-N-(4-N
phenylthiazol-2-ypthieno[2,3-b]pyridine-2-.-- \
1 ' s S2 carboxamide ,--;.õ. ....., OH

,..-"
384 I \
C21 H18 N4 03 3-hydroxy-6-morpholino-4-phenyl-N-thiazol-2-yl-Oa NS r114s3 S2 thieno[2,3-b]pyridine-2-carboxamide ell /

.--I \
3-hydroxy-N-(2-methoxypheny1)-6-morpho1ino-4-385 s C25 H23 N3 04 S
oa ' S 11 . phenyl-thieno[2,3-b]pyridine-2-carboxamide o s NJI
s rrs \ , 386 ;
[1.... 3-methy1-N-t1iazo1-2-y1-6-(2-thieny1)-4-N \H

(trifluoromethyl)thieno[2,3-b]pyridine-2-F carboxamide ___F__\.14 F N s [5-hydroxy-3-methy1-5-(trifluoromethyl)-4H-F OH \ I ,..., / C19 H13 F6 N3 pyrazol-1-3/1]-[3-methy1-6-(2-thieny1)-4-F F
02 S2 (trifluoromethyl)thieno[2,3-b]pyridin-2-yl]methanone F
m I) (:\ sõ.----s N-tert-buty1-3-methy1-6-(2-t1ieny1)-4-388 H F F S2 (trifluoromethyl)thieno[2,3-b]pyridine-2-carboxamide F

\ I
HN N-(2-furylmethyl)-3,4,6-trimethyl-thieno[2,3-b]pyridine-2-carboxamide d N Sj-N
C24 H22 N2 02 5-acetyl-3-methyl-N-phenethyl-N-(2-390 thienylmethypthieno[2,3-b]pyridine-. S2 carboxamide F 0õ / 1 0 391 40 N S---N C17 H13 F N2 02 5-acety1-N-(3-fluoropheny1)-3-methy1-thieno[2,3-H S b]pyridine-2-carboxamide H N
N¨ I 0 ' 1 \ s 392 -retS 0 C18 H15 N3 0 S2 N-(1,3-benzothiazol-2-y1)-3,4,6-trimethyl-----"'"'----thieno[2,3-b]pyridine-2-carboxamide o s N, 393 1 .¨Ill . N
H \ I
C21 H21 N3 02 S N44-(cyclopropanecarbonylamino)pheny1]-3,4,6-trimethyl-thieno[2,3-b]pyridine-2-carboxamide 0, .......y......

N-(1-cyclopropylethyl)-3,4,6-trimethyl-thieno[2,3-N b]pyridine-2-carboxamide N S
N-isobuty1-3,4,6-trimethyl-thieno[2,3-b]pyridine-_ 2-carboxamide (:) al HN "III 0) N-(2,3-dihydro-1,4-benzodioxin-6-y1)-3,4,6-C's trimethy1-thieno[2,3-b]pyridine-2-carboxamide ¨N

F C22 H15 F2 N3 N2,N5-bis(4-fluoropheny1)-3-methyl-thieno[2,3-F ii til 02 S b]pyridine-2,5-dicarboxamide =
(2-methylindolin-1-y1)-(3,4,6-trimethylthieno[2,3-N s_.....N b]pyridin-2-yl)methanone O \ I
F\ _F
O S N'c N,3-dimethyl-N-(3-methylcyclohexyl)-6-399 p¨N \ I F(trifluoromethyl)thieno[2,3-b]pyridine-2-S
\ carboxamide o S N
\ I
5-acetyl-N[[4-I/ o C21 H23 N3 02 S
(dimethylaminomethyl)phenyl]methyl]-3-methyl-thieno[2,3-b]pyridine-2-carboxamide N¨

/
¨0 0\ S-...(N./
3,4,6-trimethyl-N-(3,4,5-401 \O = NI. C20 H22 N2 04 S trimethoxyphenyl)thieno[2,3-b]pyridine-2-H carboxamide ¨0 Os S...õN
\ 1 . 11 N43-(ethylcarbamoyl)pheny1]-3,4,6-trimethyl-0 thieno[2,3-b]pyridine-2-carboxamide NH
K

\ I

= 11 C17 H16 N2 02 5 N-(2-hydroxypheny1)-3,4,6-trimethyl-thieno[2,3-b]pyridine-2-carboxamide 0 s N, \ I
404 C) C19 H21 N5 0 S (4-pyrazin-2-y1piperazin-l-y1)-(3,4,6-N trimethylthieno[2,3-b]pyridin-2-yl)methanone --- NLNI..D 3,4,6-trimethyl-N-(3-oxo-3-pyrrolidin-l-yl-405 / \S H C18 H23 N3 02 S
propyl)thieno[2,3-b]pyridine-2-carboxamide -N

4* N
, \ I H17 F3 N2 0 S N-ethyl-3,6-dimethyl-N-phenyl-4-(trifluoromethyl)thieno[2,3-b]pyridine-2-) F F carboxamide F

. N-\
0 [442,5-dimethoxypheny1)methy1tiperazin-l-y1]-\ ¨ri s /4õ, \ I C24 H29 N3 03 S (3,4,6-trimethylthieno[2,3-b]pyridin-2-o yl)methanone ¨
3,4-dihydro-1H-isoquinolin-2-y1-(3,4,6-408 \N / 1 N 110 C20 H20 N2 0 S
trimethy1t1ieno[2,3-b]pyridin-2-y1)methanone S

409 \ C21 H24 N2 02 S N-[1-(2-methoxyphenypethy1]-N,3,4,6-0 N tetramethy1-thieno[2,3-b]pyridine-2-carboxamide \ \
F
H H
F
410 F.,.....T.) .1õ, ", N-Ny" =C22 H17 F3 N4 0 1[[3-methy1-6-(2-thieny1)-4-(trifluoromethyl)thieno[2,3-b]pyridine-2-¨N carbony1]amino]-3-(p-to1y1)thiourea s \

411 /N S = C18 H13 N3 0 S2 3-amino-N-pheny1-6-(2-t1ieny1)thieno[2,3-µ¨g b]pyridine-2-carboxamide NH

7-(thiophen-2-y1)pyrido[3',2':4,5]t1ieno[3,2-d]pyrimidin-4(3H)-one S
NH2 H =
CI
N
413 C18 H11 C12 N3 3-amino-N-(3,4-dichloropheny1)-6-(2-N S 0 CI 0 S2 thienyl)thieno[2,3-b]pyridine-2-carboxamide S

414 \ Ns N= C20 H17 N3 0 S2 3-amino-N-(3,4-dimethylpheny1)-6-(2-thienyl)thieno[2,3-b]pyridine-2-carboxamide s 0 0-\

C20 H15 N3 03 3-amino-N-(2,3-dihydro-1,4-benzodioxin-6-3/1)-6-\ Ns N 1 S2 (2-thienyl)thieno[2,3-b]pyridine-2-carboxamide \ S

C19 H13 Br N4 0 3-amino-N-(4-bromopheny1)-6-(4-416 s 11113 Br pyridyl)thieno[2,3-b]pyridine-2-carboxamide /

I
3-amino-6-(4-pyridy1)-1\1[4-417 I oXF 02 S (trifluoromethoxy)phenyl]t1ieno[2,3-b]pyridine-2-carboxamide \ 3-amino-6-methyl-N-[2-(trifluoromethyl)phenyl]thieno[2,3-b]pyridine-2-S
carboxamide _,.....,....,....... ,õNH2 1 1 H 3-amino-N-(m-toly1)-6-(2-thienyl)thieno[2,3-NS.rN /40 b]pyridine-2-carboxamide \µ¨g 0 C15 H10 F3 N3 0 3-amino-N4 \ 3-(trifluoromethyl)phenyl]thieno[2,3-N . S b]pyridine-2-carboxamide H

421 0 Br C14 H10 Br N3 0 3-amino-N-(3-bromophenyl)thieno[2,3-b]pyridine-I \ S 2-carboxamide N7.----S N .
H
NH2 _ C14 H10 Br N3 0 3-amino-N-(2-bromophenyl)thieno[2,3-b]pyridine-422 NI' S N1 S 2-carboxamide Br 423 I \ C14 H10 Br N3 0 3-amino-N-(4-bromopheny1)t1ieno[2,3-b]pyridine-NS N 441 Br S 2-carboxamide H
F
F
NH FH C15 H10 F3 N3 0 3-amino-N42-(trifluoromethyl)phenyl]thieno[2,3-424 N 4.
($ µ S b]pyridine-2-carboxamide isj S 0 I I H C20 H13 Br Cl N3 3-amino-N-(4-bromopheny1)-6-(4-425a N N S 0 0 0 S chlorophenyl)thieno[2,3-b]pyridine-carboxamide CI 411111127 41111127 Br S S N
N-(1-adamanty1)-3-amino-6-(2-thienypthieno[2,3-b]pyridine-2-carboxamide I I H
C19 H15 N3 02 3-amino-N-(4-methoxypheny1)-6-(2-427 C/Nsn":1N
S2 thienyl)thieno[2,3-b]pyridine-2-carboxamide \

3-amino-6-(2-thieny1)-N[4-NI

(trifluoromethoxy)phenyl]thieno[2,3-b]pyridine-2-\ s 02 S2 carboxamide N H2 H *

/ \ C20 H15 N3 02 N-(4-acetylpheny1)-3-amino-6-(2-S2 thienyl)thieno[2,3-b]pyridine-2-carboxamide s 3-amino-6-(3-methoxypheny1)-N[4-430 (trifluoromethoxy)phenyl]thieno[2,3-b]pyridine-2-OFXFF carboxamide o / \ C18 H11 C12 N3 3-amino-N-(3,5-dichloropheny1)-6-(2-431 s 0 S2 thienyl)thieno[2,3-b]pyridine-2-carboxamide CI
\ S

/<0 0 C20 H17 N3 03 3-amino-N-(2,4-dimethoxypheny1)-6-(2-yN S S2 thienyl)thieno[2,3-b]pyridine-2-carboxamide µ-g 0 Ci N
/ \ C18 H11 C12 N3 3-amino-N-(2,5-dichloropheny1)-6-(2-433 s N 40 ¨N H 0 S2 thienyl)thieno[2,3-b]pyridine-2-carboxamide ¨

\ S

N
C18 H11 C12 N3 3-amino-N-(2,3-dichloropheny1)-6-(2-S 0 CI CI 0 S2 thienyl)thieno[2,3-b]pyridine-2-carboxamide ¨N
¨
\ S

N Br ..--- \
I\

N
C19 H13 Br N4 0 3-amino-N-(4-bromopheny1)-6-(3-435 j N S pyridyl)thieno[2,3-b]pyridine-2-carboxamide , 1 \ N
N S N¨ I 40I
436 \ S H s C19 H12 N4 0 S3 3-amino-N-(1,3-benzothiazol-2-y1)-6-(2-thienyl)thieno[2,3-b]pyridine-2-carboxamide NH2 H 4.
N
/ \ NS S C19 H12 F3 N3 0 3-amino-6-(2-thieny1)-N42-437 --/s1 F F
S2 (trifluoromethyl)phenyl]thieno[2,3-b]pyridine-2-¨ carboxamide \ s \
/ \ 3-amino-N-(2,5-dimethylpheny1)-6-(2-438 s N . C20 H17 N3 0 S2 ¨N H thienyl)thieno[2,3-b]pyridine-2-carboxamide ¨
\ s \
439 1 \ C18 H12 Br N3 3-amino-N-(4-bromopheny1)-6-(2--, N-- S N 411 Br 02 S furypthieno[2,3-b]pyridine-2-carboxamide H
\ 0 F
I \ o F
C20 H13 F3 N4 0 3-amino-6-(4-pyridy1)-1\1[3-440 ' -----S N
(trifluoromethyl)phenyl]thieno[2,3-b]pyridine-2-S
eN H II
carboxamide N

/ \ N

441 ¨ ¨N H C20 H17 N3 03 3-amino-N-(2,5-dimethoxypheny1)-6-(2-0 S2 thienyl)thieno[2,3-b]pyridine-2-carboxamide \S /

I \
3-amino-N-[2-methoxy-5-\ S
442 F C20 H14 F3 N3 (trifluoromethyl)pheny1]-6-(2-thienyl)thieno[2,3-F b]pyridine-2-carboxamide F
/ \ N
¨N H
C19 H11 Cl F3 N3 3-amino-N44-ch1oro-3-(trifluoromethy1)pheny1]-443 ¨
\ s 0 S2 6-(2-thienyl)thieno[2,3-b]pyridine-2-carboxamide NH2 H= /

..--- \ C20 H17 N3 03 3-amino-N-(3,4-dimethoxypheny1)-6-(2-444 1 \
---- N
S 0 0 S2 thienyl)thieno[2,3-b]pyridine-2-carboxamide /
\ S

/ \ N
C18 H12 Cl N3 0 3-amino-N-(3-chloropheny1)-6-(2-445 S N .
¨N H S2 thienyl)thieno[2,3-b]pyridine-2-carboxamide ¨
CI
\ s \ 0 I 3-amino-N-(4-bromopheny1)-6-(3-446 0 -,,, s vi .
Br C21 H16 Br N3 02 S methoxyphenyl)thieno[2,3-b]pyridine-carboxamide o I \ 3-amino-N-(3-bromopheny1)-6-(3-C21 H16 Br N3 447 le N S
HN * 02 S methoxyphenyl)thieno[2,3-b]pyridine-carboxamide o Br H
/
I \ N 10 F
0 'N S o F 3-amino-6-(3-methoxypheny1)-N44-02 S (trifluoromethyl)phenyl]thieno[2,3-b]pyridine-2-o carboxamide NH2 H 4.
N
/ \Ns (5 -NI
F F 3-amino-6-(3-methoxypheny1)-N[2-(trifluoromethyl)phenyl]thieno[2,3-b]pyridine-2-carboxamide 0.-o / \Ns N . C22 H16 F3 N3 3-amino-6-(3-methoxypheny1)-N[3-450 -N H (trifluoromethyl)phenyl]thieno[2,3-b]pyridine-2-*

F
carboxamide 0-.-s .'"' \ 0 I 3-amino-N-(4-bromopheny1)-6-(3,4-451 0 N S vi .
Br C22 H18 Br N3 dimethoxyphenyl)thieno[2,3-b]pyridine-2-o 03 S
carboxamide o H2N H F4.
F
/ \ F

3-amino-6-(1,3-benzodioxo1-5-y1)-N[4-452 -N (trifluoromethyl)phenyl]thieno[2,3-b]pyridine-2-carboxamide o \õ....o o / \ Ns N 11 3-amino-6-(1,3-benzodioxo1-5-y1)-N43-[3 (trifluoromethyl)phenyl]thieno[2,3-b]pyridine-2-carboxamide o \õ..0 ---- I \ 0 ifin '14 HN *
C21 H16 Br N3 3-amino-N-(3-bromopheny0-6-(4-454 o methoxyphenyOthieno[2,3-b]pyridine-\ 02S
Br carboxamide N F
/ \ N IDS 0 F
--14 3-amino-6-(4-fluorophenyB-N44-S (trifluoromethyDphenyl]thieno[2,3-b]pyridine-2-carboxamide F

/ \ Ns NC21 H13 F4 N3 41 3-amino-6-(4-fluorophenyB-N43-[3 456 'MI H * (trifluoromethyDphenyl]thieno[2,3-b]pyridine-2-F
F F S
carboxamide F

H
_ \ aim F
3-amino-6-methyl-N-[4-(N
41110Cl H12 F3 N3 0,..li (trifluoromethoxy)phenyl]thieno[2,3-b]pyridine-2-carboxamide / \ N
C19 H14 F N3 0 3-amino-N-(3-fluoro-4-methyl-phenyl)-6-(2-458 s N .
H S2 thienAthieno[2,3-b]pyridine-2-carboxamide -N
-N S

/ \ N F 3-amino-6-(2-thienyB-N44-459 s 0 (trifluoromethyBphenyl]thieno[2,3-b]pyridine-2-¨ carboxamide N s O Ci / \ N
S N li ---N H
C19 H14 Cl N3 3-amino-N-(5-chloro-2-methoxy-phenyB-6-(2-460 ¨

\ S \ 02 S2 thienAthieno[2,3-b]pyridine-2-carboxamide F

0 is F
N
H
-11 C18 H11 F2 N3 0 3-amino-N-(3,4-difluoropheny0-6-(2-461 ¨
S2 thienAthieno[2,3-b]pyridine-2-carboxamide \ s o / \ N
462 C18 H12 Br N3 0 3-amino-N-(2-bromopheny0-6-(2--N H S2 thienAthieno[2,3-b]pyridine-2-carboxamide ¨
Br \ S

N
/ \
463S2 thienAthieno[2,3-b]pyridine-2-carboxamide s N 40 C19 H14 F N3 0 3-amino-N-(5-fluoro-2-methyl-pheny0-6-(2-H
..."-N
¨
F
\ S

N
/ \ C18 H12 F N3 0 3-amino-N-(3-fluoropheny0-6-(2-464 S N .
"---N H F S2 thienAthieno[2,3-b]pyridine-2-carboxamide ¨
\ S

N 3-amino-6-(4-pyridy0-N-[4-/ \ C20 H13 F3 N4 0 465 s 0 (trifluoromethyDphenyl]thieno[2,3-b]pyridine-2---N S
carboxamide / \
N---N
/ \
466 S N = C19 H13 Br N4 0 3-amino-N-(2-bromopheny1)-6-(4-H
---hl S pyridy1)thieno[2,3-b]pyridine-2-carboxamide / \ Br N¨

/ \ NS N I/
¨N H
3-amino-N-(2-bromopheny1)-6-(3-02 S Br C21 H16 Br N3 methoxyphenyl)thieno[2,3-b]pyridine-2-carboxamide o / \ Ns N . C21 H16 Br N3 3-amino-N-(2-bromopheny1)-6-(4-468 -1,1 H
02 S methoxyphenyl)thieno[2,3-b]pyridine-* Br carboxamide o \

IL Br / \ N 3-amino-N-(4-bromopheny1)-6-(4-S H tillii C21 H16 Br N3 469 ---N methoxyphenyl)thieno[2,3-b]pyridine-411 carboxamide o \

OF
/ \ N C18 H11 F2 N3 0 3-amino-N-(2,5-difluoropheny1)-6-(2-S2 thienyl)thieno[2,3-b]pyridine-2-carboxamide ¨
F
\ S

/ \ N
F C18 H11 F2 N3 0 3-amino-N-(2,4-difluoropheny1)-6-(2-¨
F S2 thienyl)thieno[2,3-b]pyridine-2-carboxamide \ s o / \ Ns N 4I 3-amino-6-(4-methoxypheny1)-1\143-[3 (trifluoromethyl)phenyl]thieno[2,3-b]pyridine-2-* F

carboxamide o \
\o NH2 H 473 3-amino-6-(2-thieny1)-N-(3,4,5-\ C21 H19 N3 04 trimethoxyphenyl)thieno[2,3-b]pyridine-2-* 0 carboxamide --1,1 ----\ S

Br IL
/ \ N
S [µii II" 3-amino-6-(1,3-benzodioxo1-5-y1)-N-(4---N C21 H14 Br N3 . 03 S bromophenyl)thieno[2,3-b]pyridine-2-carboxamide o \.....0 / *
F
N F
\ 0 C23 H18 F3 N3 3-amino-6-(3,4-dimethoxypheny1)-1\144-[4 475 --N (trifluoromethyl)phenyl]thieno[2,3-b]pyridine-2-¨ilo carboxamide o¨

o 3-amino-6-(3,4-dimethoxypheny1)-1\143-[3 / \ Ns Fri 41 C23 H18 F3 N3 476 ---N (trifluoromethyl)phenyl]thieno[2,3-b]pyridine-2-carboxamide ¨0 o¨

........õ-..õ, ........NH2 I I H
CNSrN 0 3-amino-N-(o-toly1)-6-(2-thienyl)thieno[2,3-477 \ S 0 b]pyridine-2-carboxamide Br NN
I N 3-(2-bromopheny1)-7-478 C15 H9 Br N4 OS
methylpyrido[3',2':4,5]thieno[3,2-d][1,2,3]triazin-4(3H)-one Br \
3-(3-bromopheny1)-7-S
479 C15 H9 Br N4 OS
methylpyrido[3',2':4,5]thieno[3,2-d][1,2,3]triazin-4(3H)-one / \F 3-amino-6-(4-pyridy1)-1\1[2-s 0 C20 H13 F3 N4 0 480 (trifluoromethy1)pheny1]thieno[2,3-b]pyridine-2-¨N
/ carboxamide N-S N
/ Br C19 H13 Br N4 0 3-amino-N-(3-bromopheny1)-6-(4-N- pyridyl)thieno[2,3-b]pyridine-2-carboxamide NIS N F
3-amino-6-(dimethoxymethyl)-N-[4-482 (trifluoromethyl)phenyl]thieno[2,3-b]pyridine-2-carboxamide N
C17 H12 F3 N3 6-acetyl-3-amino-N-[4-02 S (trifluoromethyl)phenyl]thieno[2,3-b]pyridine-2-carboxamide C17 H15 N3 03 1-[3-amino-6-(2-thienyl)thieno[2,3-b]pyridine-2-S2 carbonyl]pyrrolidine-2-carboxylic acid C21 H16 Br N3 0 3-amino-N-(4-bromopheny1)-6-(p-toly0thieno[2,3-S N Br S b]pyridine-2-carboxamide (NE)-3-amino-N-(3H-1,3-benzothiazol-2-ylidene)-S NN= 6-(2-thienyl)thieno[2,3-b]pyridine-2-carboxamide S
N V
H2, 0 r s 3-amino-6-(4-pyridy0-1\1[2-487 (trifluoromethoxy)phenyflthieno[2,3-b]pyridine-2-carboxamide s CrNs 3-amino-N-(5-pheny1-1,3,4-thiadiazol-2-34)-6-(2-thienyl)thieno[2,3-b]pyridine-2-carboxamide I H
N S
0 = F
C20 H13 F2 N3 0 3-amino-N-(3-fluoropheny0-6-(4-489 fluorophenyOthieno[2,3-b]pyridine-2-carboxamide I I H

N N S

F
490 F C20 H13 F2 N3 0 3-amino-N,6-bis(4-fluoropheny1)thieno[2,3-S b]pyridine-2-carboxamide 0 N s N

? riliF C21 H16 F N3 02 3-amino-N-(4-fluoropheny1)-6-(4-491 methoxyphenyl)thieno[2,3-b]pyridine-S
carboxamide H 3-amino-6-(4-methoxypheny1)-N[4-492 7 I \ " * F C22 H16 F3 N3 (trifluoromethyl)phenyl]thieno[2,3-b]pyridine-2-0 'N S 0 F 02S
F carboxamide o \

7 I \ 0 3-amino-N-(4-chloropheny1)-6-(4-0 `ni S C21 H16 Cl N3 HN tair 02 S methoxyphenyl)thieno[2,3-b]pyridine-o illW ci carboxamide \

H
----. \ N
I
111# N-(4-acetylpheny1)-3-amino-6-(4-494 0 '1,1 S 0 0 C23 H19 N3 03 S methoxyphenyl)thieno[2,3-b]pyridine-2-o carboxamide \

---- 1 \ 0 ci C21 H15 C12 N3 3-amino-N-(2,5-dichloropheny1)-6-(3-495 40/ 'N S
HN .
02 S methoxyphenyl)thieno[2,3-b]pyridine-carboxamide 1:) CI

0, S
HN
3-amino-N-(2,5-dimethoxypheny1)-6-(3-o C23 H21 N3 04 S methoxyphenyOthieno[2,3-b]pyridine-2-carboxamide \ 0 S
HN
497s$ Br 03 S C22 H16 Br N3 3-amino-6-(1,3-benzodioxo1-5-y1)-N-(4-bromo-2-methyl-phenyl)thieno[2,3-b]pyridine-2-carboxamide \ 0 F F
3-amino-N[4-chloro-3-(trifluoromethyDphenyl]-HN F
CI C22 H15 Cl F3 N3 6-(3-methoxyphenyOthieno[2,3-b]pyridine-2-carboxamide o \ 0 3-amino-N-(2,3-dihydro-1,4-benzodioxin-6-y0-6-C23 H19 N3 04 S (3-methoxyphenyl)thieno[2,3-b]pyridine-2-o carboxamide \ o 3-amino-6-(3,4-dimethoxypheny1)-N-(4-methoxy-500 S N S HN to, C24 H23 N3 04 S 2-methyl-phenyl)thieno[2,3-b]pyridine-2-carboxamide \ 0 40/ /%1 S
HN sap 3-amino-N-(2-ethoxypheny1)-6-(3-501 C23 H21 N3 03 S methoxyphenyOthieno[2,3-b]pyridine-2-carboxamide s HN
3-amino-N-(2,4-difluoropheny1)-6-(3-methoxyphenyl)thieno[2,3-b]pyridine-2-carboxamide , o S HN
3-amino-N,6-bis(3-methoxyphenyl)thieno[2,3-oN
zo b]pyridine-2-carboxamide / \ 3-amino-N-(2-methoxypheny1)-6-(3-C22 H19 N3 03 S methoxyphenyl)thieno[2,3-b]pyridine-2-carboxamide 0-__ /C; N
/S C22 H19 N3 02 3-amino-6-(3-methoxypheny1)-N-(3-505 methylsulfanylphenyl)thieno[2,3-b]pyridine-2-carboxamide N 3-amino-6-(3-methoxypheny1)-N-(4-506 \ s N * C22 H19 N3 03 S methoxyphenyl)thieno[2,3-b]pyridine-2-¨N
carboxamide 0-__ / \ 3-amino-N-(4-methoxy-2-methyl-pheny1)-6-(3-C23 H21 N3 03 S methoxyphenyl)thieno[2,3-b]pyridine-2-carboxamide

143 NH2 H o N=
\
\ Ns 0 0¨ 3-amino-N-(3,4-dimethoxypheny1)-6-(3-508 N C23 H21 N3 04 S methoxyphenyl)thieno[2,3-b]pyridine-2-. carboxamide \ Ns N

3-amino-6-(3,4-dimethoxypheny1)-N-(2-C24 H23 N3 04 S ethoxyphenyl)thieno[2,3-b]pyridine-2-o. carboxamide \ Ns N =F
C21 H16 F N3 02 3-amino-N-(4-fluoropheny1)-6-(3-= methoxyphenyl)thieno[2,3-b]pyridine-2-carboxamide 0 0., /
S H 3-amino-N-(1,3-benzodioxo1-5-y1)-6-(3-511 C22 H17 N3 04 S methoxyphenyl)thieno[2,3-b]pyridine-2-* carboxamide \ Ns *
3-amino-N-(2,4-dimethoxypheny1)-6-(3-C23 H21 N3 04 S methoxyphenyl)thieno[2,3-b]pyridine-2-carboxamide \ Ns 0 N-(4-acetylpheny1)-3-amino-6-(3-513 C23 H19 N3 03 S methoxyphenyl)thieno[2,3-b]pyridine-2-. carboxamide o-

144 o I \
0 'N s [µii *
C22 H16 Br N3 3-amino-6-(1,3-benzodioxo1-5-3/1)-N-(2-bromo-4-Br 03 S methyl-phenyl)thieno[2,3-b]pyridine-\--o carboxamide H F
".-- 1 \ N

0 , s 0 3-amino-N-(3-fluoro-2-methy1-pheny0-6-(3-515 methoxyphenyOthieno[2,3-b]pyridine-o S
carboxamide OF
/ \ NS N II

516 N H C21 H15 F2 N3 3-amino-N-(2,5-difluoropheny0-6-(3----methoxyphenyOthieno[2,3-b]pyridine-2-carboxamide 0.-_ I \
o 3-amino-6-(1,3-benzodioxo1-5-3/0-N-(2-517 a '11 S Eri . C23 H19 N3 04 S ethoxyphenyl)thieno[2,3-b]pyridine-2-carboxamide o o \--o ) NH2 i / \ Ns N .
--N H 3-amino-N-(2,5-dimethoxypheny1)-6-(3,4-illi i C24 H23 N3 05 S dimethoxyphenyOthieno[2,3-b]pyridine-2-carboxamide ¨o o / \ Ns H * CI C21 H15 Cl F N3 3-amino-N-(4-chloro-2-fluoro-phenyl)-6-(3---N

. F 02 S methoxyphenyOthieno[2,3-b]pyridine-carboxamide a....

145 \c) NH H = 0 \

--- N 3-amino-6-(3-methoxypheny1)-N-(3,4,5-520 4111 C24 H23 N3 05 S trimethoxyphenyl)thieno[2,3-b]pyridine-2-carboxamide 0¨

o / \N s N =
--N H
521 . C22 H19 N3 02 S 3-amino-6-(3-methoxypheny1)-N-(o-tolypthieno[2,3-b]pyridine-2-carboxamide 0-....

o / \ Ns N . 3-amino-6-(3-methoxypheny1)-N-(2---N H
41 o C27 H21 N3 03 S phenoxyphenyl)thieno[2,3-b]pyridine-2-carboxamide / \ NS N 411 C22 H18 F N3 02 3-amino-N-(3-fluoro-4-methyl-pheny1)-6-(3-523 H methoxyphenyl)thieno[2,3-b]pyridine---N S
11 carboxamide 0.....

N
/ \ 3-amino-6-(3,4-dimethoxypheny1)-N-(2,5-524 S N 41 C24 H23 N3 03 S dimethylphenyl)thieno[2,3-b]pyridine-2-¨N H
carboxamide 0-..._ F
NH2 0 Ali, F
/ \ N N 41111j 3-amino-N-(3,4-difluoropheny1)-6-(3-525 ¨1,1 methoxyphenyl)thieno[2,3-b]pyridine-. 02 S
carboxamide 0_

146 o N
/ \ s N li F
---N H
CI C21 H15 Cl F N3 3-amino-N-(3-chloro-4-fluoro-phenyl)-6-(3-526 #
02 S methoxyphenyl)thieno[2,3-b]pyridine-o-..., carboxamide o ---- , µ
I ' \

Fl CI Si N 3-amino-6-(4-chloropheny1)-N-(4-527 methoxyphenyl)thieno[2,3-b]pyridine-carboxamide / \Ns N Ok 3-amino -6-( 1 ,3 -benzodioxo1-5 -y1)-N-(3,4-528 ""---N H
C23 H19 N3 03 S dimethylphenyl)thieno[2,3-b]pyridine-2-itcarboxamide O\_0 / \ NS N 411 C22 H16 Cl N3 3-amino -6-( 1 ,3 -benzodioxo1-5 -y1)-N-(3 -chloro -4-529 -Thl H methyl-phenypthieno[2,3-b]pyridine-* 03 S
carboxamide o \0...o o / \ N *
H 3-amino-6-(3,4-dimethoxypheny1)-N-(2,4--N

* C24 H23 N3 03 S dimethylphenyl)thieno[2,3-b]pyridine-2-carboxamide o¨

NH2 _ ,c, "
N
..-- 0 N S

? 3-amino-6-(3,4-dimethoxypheny1)-N42-methoxy-5-(trifluoromethyl)phenyl]thieno[2,3-b]pyridine-2-carboxamide

147 o H
N
,=== 0 N S
w C23 H20 Cl N3 3-amino-N-(5-chloro-2-methoxy-phenyl)-6-(3,4-532 CI dimethoxyphenyl)thieno[2,3-b]pyridine-2-carboxamide .---. \ 0 , I F
illh )4 S H *
0 3-amino-6-(3,4-dimethoxypheny1)-N-(3-fluoro-4-o C23 H20 F N3 03 533 methyl-phenyl)thieno[2,3-b]pyridine-S
carboxamide / F
I I H

N
.... 0 N S

C22 H17 Cl F N3 3-amino-N-(4-chloro-2-fluoro-phenyl)-6-(3,4-534 dimethoxyphenyl)thieno[2,3-b]pyridine-2-carboxamide NH2 H = /

I ' di "N S 0 F 411111111kP C21 H16 F N3 02 3-amino-6-(4-fluoropheny1)-N-(4-535 methoxyphenyl)thieno[2,3-b]pyridine-S
carboxamide I \
, s *o/ 3-amino-N-(2,4-dimethoxypheny1)-6-(3,4-536 H C24 H23 N3 05 S dimethoxyphenyl)thieno[2,3-b]pyridine-2-o 101 carboxamide o s o I \ 3-amino-6-(1,3-benzodioxo1-5-y1)-N-(2,4-537 <o0 0 'N S ,ri . ci C21 H13 C12 N3 03S dichlorophenyl)thieno[2,3-b]pyridine-2-ci carboxamide

148 I ' <0 OCN s ri 4.
0 F C21 H14 F N3 03 3-amino-6-(1,3-benzodioxo1-5-y1)-N-(2-538 S fluorophenyl)thieno[2,3-b]pyridine-2-carboxamide ci 1,1 I sI 11 ... 400 w O ? F
C22 H17 Cl F N3 3-amino-N-(2-chloro-4-fluoro-phenyl)-6-(3,4-539 dimethoxyphenyl)thieno[2,3-b]pyridine-2-carboxamide o / \ Ns N 41C22 H18 N3 3-amino-N-(3-chloropheny1)-6-(3,4-540 -1,1 H Cl dimethoxyphenyl)thieno[2,3-b]pyridine-2-41 ci 03 S
carboxamide NH2 H =
I ---- , \ N F
I ' o a C22 H18 F N3 03 3-amino-6-(3,4-dimethoxypheny1)-N-(4-0 S fluorophenyl)thieno[2,3-b]pyridine-2-carboxamide o / \ Ns N H = s C24 H21 N3 02 N-(4-allylsulfanylpheny1)-3-amino-6-(3----N

it S2 methoxyphenyl)thieno[2,3-b]pyridine-carboxamide o-__ H
N . C22 H18 Cl N3 3-amino-N-(3-chloro-2-methyl-phenyl)-6-(3-543 N S 0 02S methoxyphenyl)thieno[2,3-b]pyridine-ci carboxamide o

149 \
I
el 'NI s ri /I
3-amino-N-(3-chloro-4-methyl-phenyl)-6-(3-oi C22 H18 Cl N3 02 S methoxyphenyOthieno[2,3-b]pyridine-carboxamide o / \ Ns N 411 ci --N H
CI C21 H15 C12 N3 3-amino-N-(2,4-dichloropheny0-6-(3-545 = methoxyphenyOthieno[2,3-b]pyridine-a__ carboxamide / \N
S N 41 3-amino-N-(3,4-dimethylpheny1)-6-(3-546 ---N H C23 H21 N3 02 S methoxyphenyOthieno[2,3-b]pyridine-2-. carboxamide 0.¨

/ \N 3-amino-6-(3-methoxypheny1)-N-(m----N H tolypthieno[2,3-b]pyridine-2-carboxamide 0-....
NH2 \
o o 3-amino-N-(2-chloro-5-methoxy-phenyl)-6-(3-...-- , C22 H18 Cl N3 B [1 03 S 0 548 , I ' methoxyphenyOthieno[2,3-b]pyridine-carboxamide ci / \ Ns N 4. Br ---N H
549 C22 H18 Br N3 3-amino-N-(4-bromo-2-methyl-phenyl)-6-(3-=

methoxyphenyOthieno[2,3-b]pyridine-2-o-..... carboxamide

150 o / \ Ns N 41 Br --/%1 H
550 C22 H18 Br N3 3-amino-N-(4-bromo-3-methyl-phenyl)-6-(3-methoxyphenyOthieno[2,3-b]pyridine-2-O- carboxamide o / \ Ns H . F
---N

3-amino-N-(4-fluoro-2-methyl-phenyl)-6-(3-methoxyphenyOthieno[2,3-b]pyridine-2-S
carboxamide o-...

o / \ N
S N . 3-amino-N-(3-ethoxypheny1)-6-(3-H
552 ¨N C23 H21 N3 03 S methoxyphenyOthieno[2,3-b]pyridine-2-* o carboxamide 0-....

o / \ Ns N II 3-amino-6-(3-methoxypheny1)-N-(p-. tolypthieno[2,3-b]pyridine-2-carboxamide la._ N
/ \
s N . 3-amino-N-(2,4-dimethylpheny1)-6-(3-H
554 ---N C23 H21 N3 02 S methoxyphenyOthieno[2,3-b]pyridine-2-itcarboxamide 0-..._ / C; 0 . C25 H25 N3 02 S 3-amino-6-(3-methoxypheny1)-N-(4-sec-butylphenyOthieno[2,3-b]pyridine-2-carboxamide 0....._

151 NH2 H .
N Br / \

SI

C21 H15 Br F N3 3-amino-N-(4-bromo-2-fluoro-pheny1)-6-(3-556 methoxyphenyl)thieno[2,3-b]pyridine-carboxamide /N F
I \ lik 557 140 , 02 S 3-amino-N-(2-chloro-4-fluoro-phenyl)-6-(3-methoxyphenyl)thieno[2,3-b]pyridine-2-carboxamide ¨o NH2 H .
N
..., , \ 3-amino-6-(3-methoxypheny1)-N42-[2-558 F (trifluoromethyl)phenyl]thieno[2,3-b]pyridine-2-40 -,..,N I s o 03 S
F F carboxamide o Br I
N C22 H18 Br N3 3-amino-N-(3-bromo-4-methyl-pheny1)-6-(3-\ =

N B 0 02 S methoxyphenyl)thieno[2,3-b]pyridine-carboxamide o / \ NSC22 N 11 H15 F3 N3 3-amino-N42-chloro-5-(trifluoromethyl)phenyfl-Cl 560 6-(3-methoxyphenyl)thieno[2,3-b]pyridine-2-it F

carboxamide o-...

o / \ xsC21 N . H16 N3 3-amino-N-(3-chloropheny1)-6-(3-Cl 561 methoxyphenyl)thieno[2,3-b]pyridine-0 ci 02 S
carboxamide 0...._

152 / \ N 3-amino-N-(2,3-dimethylpheny1)-6-(3-562 s N
C23 H21 N3 02 S methoxyphenyl)thieno[2,3-b]pyridine-2---N
carboxamide N; 0 CI CI C21 H15 C12 N3 3-amino-N-(2,3-dichloropheny1)-6-(3-563 N02S methoxyphenyl)thieno[2,3-b]pyridine-* carboxamide o o ci = \ NsN 3-amino-N-(3,5-dichloropheny1)-6-(3-methoxyphenyl)thieno[2,3-b]pyridine-2-ci 02 S
carboxamide / \ 3-amino-N-(5-fluoro-2-methyl-phenyl)-6-(3-565 s H C22 H18 F N3 02 methoxyphenypthieno[2,3-b]pyridine-2-41 carboxamide \ Ns N 3-amino-6-(3-methoxypheny1)-N-(4-methy1sulfany1pheny1)t1ieno[2,3-b]pyridine-2-* S2 carboxamide / \N
_ s H 411 N C24 H20 N4 02 3-amino-N-(2-ethylsulfany1-1,3-benzothiazol-6-S3 y1)-6-(3-methoxyphenypthieno[2,3-b]pyridine-2-carboxamide 0._

153 o /___ \ Ns HN 41 ry N
s),T C25 3-amino-6-(3-methoxypheny1)-N-(2-S3 propylsulfany1-1,3-benzothiazol-6-ypthieno[2,3-o¨, b]pyridine-2-carboxamide o / \S Fri . ti ¨NI
s.--,Li . C25 H20 N4 02 N-(2-allylsulfany1-1,3-benzothiazol-6-y1)-3-569 amino-6-(3-methoxypheny1)thieno[2,3-b]pyridine-o¨ 1 S3 2-carboxamide o / \ is ti C26 H24 N4 02 410. N 3-amino-N-(2-butylsulfany1-1,3-benzothiazol-6--"N

0 s--1L-s S3 y1)-6-(3-methoxyphenyl)thieno[2,3-b]pyridine-2-carboxamide o¨

o / \S NC25 441 H25 N3 02 3-amino-N-(2-isobutylsulfanylpheny1)-6-(3-571 ¨NJ H methoxyphenyl)thieno[2,3-b]pyridine-. s\ /
--\ S2 carboxamide 0-._ o /\ N's rp C25 H25 N3 02 3-amino-N-(2-butylsulfanylpheny1)-6-(3-S2 methoxyphenyl)thieno[2,3-b]pyridine-* s carboxamide o.....

N
/ \ Ns 0 CI C23 H20 Cl N3 3-amino-N-(3-chloro-2-methyl-pheny1)-6-(3,4-573 "--N 03 S dimethoxyphenyl)thieno[2,3-b]pyridine-2-. carboxamide ¨0 a¨.

154 o ci / \ Ns N 41.
H
574 4 C23 H20 Cl N3 03 S 3-amino-N-(3-chloro-4-methyl-phenyl)-6-(3,4-dimethoxyphenypthieno[2,3-b]pyridine-2---0 carboxamide 0-.._ / \ NS N 40.
-N H
575 411 ci C22 H17 C12 N3 3-amino-N-(2,5-dichloropheny1)-6-(3,4-dimethoxyphenyl)thieno[2,3-b]pyridine-2-¨o 03 S
o¨ carboxamide 0 Br / \ NS N . 3-amino-N-(2-bromo-4-methyl-phenyl)-6-(3,4-H C23 H20 Br N3 -N
dimethoxyphenyl)thieno[2,3-b]pyridine-2-. 03 S
carboxamide ¨0 o¨

o / \ Ns N 41 3-amino-6-(3,4-dimethoxypheny1)-N-(3,4-577 -N H C24 H23 N3 03 S dimethylphenyl)thieno[2,3-b]pyridine-2-* carboxamide ¨0 0¨.

o / \S N * Br 3-amino-N-(4-bromo-2-methyl-phenyl)-6-(3,4-0 -N H C23 H20 Br N3 03 S dimethoxyphenyl)thieno[2,3-b]pyridine-2-carboxamide ¨0 o¨

NH2 H =
N Br C23 H20 Br N3 3-amino-N-(4-bromo-3-methyl-phenyl)-6-(3,4---- , µ
579 I s dimethoxyphenyl)thieno[2,3-b]pyridine-2-op `N S 0 03 S
carboxamide ? 0

155 a"--7 NH2 H li / \
I
9 si 's o 3-amino-N-(1,3-benzodioxo1-5-y1)-6-(3,4-580 1 0 C23 H19 N3 05 S dimethoxyphenyl)thieno[2,3-b]pyridine-2-carboxamide / \N H
S *
---N
581 0 C23 H21 N3 03 S 3-amino-6-(3,4-dimethoxypheny1)-N-(o--o tolypthieno[2,3-b]pyridine-2-carboxamide o-...

o / \Ns N 410 3-amino-6-(3,4-dimethoxypheny1)-N-(3-582 ---N H C24 H23 N3 04 S ethoxyphenyl)thieno[2,3-b]pyridine-2-carboxamide ¨0 F

/ N
F 3-amino-N-[4-bromo-3-(trifluoromethyDpheny1]-\ s N

. Br C23 H17 Br F3 ---N3 03S 6-(3,4-dimethoxyphenyl)thieno[2,3-b]pyridine-2-411 carboxamide ¨0 a¨

o F.,,./..%
/ \Ns ti fit =0 3-amino-6-(3,4-dimethoxypheny1)-N-[4-0 -1,1 04 S (trifluoromethoxy)phenyl]thieno[2,3-b]pyridine-2-carboxamide ¨o 0¨

, \ F
, . ' s [1 . CI C23 H17 Cl F3 N3 3-amino-N-[4-chloro-3-(trifluoromethyDpheny1]-585 --1,/ 6-(3,4-dimethoxyphenyl)thieno[2,3-b]pyridine-2-411 carboxamide ¨o 0_

156 H2N H .
N
/ \ NS 0 CI
¨N
586 C22 H16 N3 3-amino-6-(1,3-benzodioxo1-5-y1)-N-(3-chloro-2-* Cl 03 S methyl-phenyl)thieno[2,3-b]pyridine-carboxamide \,0 ,-- . \
, I s 00 -N S ri 11 3-amino-6-(1,3-benzodioxo1-5-y1)-N-(2,5-587 0 ci C21 H13 C12 N3 \-0 dichlorophenyl)thieno[2,3-b]pyridine-2-carboxamide ....., . \
I s 3-amino-6-(1,3-benzodioxo1-5-y1)-N-(2,5-588 ei Ikl S El 4. C23 H19 N3 03 S
dimethylphenyl)thieno[2,3-b]pyridine-2-carboxamide \---0 -O CI
1 \ 3-amino-6-(1,3-benzodioxo1-5-y1)-N-(2-chloro-5-589 40) Ns ri 41 C22 H16 Cl N3 methoxy-phenyl)thieno[2,3-b]pyridine-2-carboxamide \--0 /

N . Br C22 H16 BrN3 3-amino-6-(1,3-benzodioxo1-5-y1)-N-(4-bromo-3-590 I \

N S 0 03 S methyl-phenyl)thieno[2,3-b]pyridine-2-carboxamide o\_0 , I 0 \
3-amino-N,6-bis(1,3-benzodioxo1-5-yl)thieno[2,3-o o-j b]pyridine-2-carboxamide

157 \ Ns N 411 592 4 C23 H19 N3 03 S 3-amino-6-(1,3-benzodioxo1-5-y1)-N-(3-ethylphenyl)thieno[2,3-b]pyridine-2-carboxamide SNF
0 C22 H16 F N3 03 3-amino-6-(1,3-benzodioxo1-5-y1)-N-(4-fluoro-2-593 \--0 methyl-phenyl)thieno[2,3-b]pyridine-S
carboxamide 0 ci 0 I 3-amino-6-(1,3-benzodioxo1-5-y1)-N-(5-chloro-2-594 <0 "*-1,1 s C22 H16 Cl N3 04 S methoxy-phenyl)thieno[2,3-b]pyridine-2-¨0 carboxamide \ 0 3-amino-6-(1,3-benzodioxo1-5-y1)-N-(3-chloro-4-595 , s HN * C21 H13 Cl F N3 03S fluoro-phenyl)thieno[2,3-b]pyridine-0 carboxamide \--o ci , 0 3-amino-6-(1,3-benzodioxo1-5-y1)-N-(2,4-596 N S N C23 H19 N3 03 S dimethylphenyl)thieno[2,3-b]pyridine-2-H
carboxamide s3-amino-6-(1,3-benzodioxo1-5-y1)-N-(3,4-010 s HN C21 H13 F2 N3 03 S difluorophenyl)thieno[2,3-b]pyridine-2-0 carboxamide \-0

158 --- , \ 0 0 -N s HN .
C21 H13 Cl F N3 3-amino-6-(1,3-benzodioxo1-5-y1)-N-(4-chloro-2-\-0 F 03 S
oi 598 fluoro-phenyl)thieno[2,3-b]pyridine-carboxamide , I s 0 Iki s is141 F 3-amino-6-(1,3-benzodioxo1-5-y1)-N42-methoxy-C23 H16 F3 N3 \(:) F

(trifluoromethyl)phenyl]thieno[2,3-b]pyridine-2-carboxamide I\ 0 F F 3-amino-6-(1,3-benzodioxo1-5-y1)-N44-chloro-3-C22 H13 Cl F3 N3 600 001 S HN . F
03 S (trifluoromethyl)phenyl]thieno[2,3-b]pyridine-2-0 =oi carboxamide 1 \ 0 1 3-amino-6-(1,3-benzodioxo1-5-y1)-N-(4-HN . C21 H14 Cl N3 03S chlorophenypthieno[2,3-b]pyridine-2-0 oi carboxamide I ' OS N s 11.
0 F C21 H14 F N3 03 3-amino-6-(1,3-benzodioxo1-5-y1)-N-(3-602 S fluorophenyl)thieno[2,3-b]pyridine-2-carboxamide o ...-- , \
, I ' <:S -N s NF
C21 H14 F N3 03 3-amino-6-(1,3-benzodioxo1-5-y1)-N-(4-603 S fluorophenyl)thieno[2,3-b]pyridine-2-carboxamide

159 N
/ \ N

¨14 . C21 H15 Cl F N3 3-amino-N-(3-chloro-2-methyl-pheny1)-6-(4-0 S fluorophenypthieno[2,3-b]pyridine-2-carboxamide F

N
---N H
605 . a C20 H12 C12 F N3 3-amino-N-(2,5-dichloropheny1)-6-(4-F 0 S fluorophenypthieno[2,3-b]pyridine-2-carboxamide / \N

S N II C22 H18 F N3 02 3-amino-N-(2-ethoxypheny1)-6-(4-\_ S fluorophenypthieno[2,3-b]pyridine-2-carboxamide F

/ \N s N .
607 ¨N H C22 H18 F N3 0 3-amino-N-(3,4-dimethylpheny1)-6-(4-41 S fluorophenypthieno[2,3-b]pyridine-2-carboxamide F

0 0,1 /_._ \ NS N= 0 N C21 H14 F N3 03 3-amino-N-(1,3-benzodioxo1-5-y1)-6-(4-S fluorophenypthieno[2,3-b]pyridine-2-carboxamide F

/ \N

S N 40 C22 H18 F N3 0 3-amino-N-(3-ethylpheny1)-6-(4---N H
0 S fluorophenypthieno[2,3-b]pyridine-2-carboxamide F

160 o 610 40 C21 H16 F N3 0 3-amino-6-(4-fluoropheny1)-N-(o-tolypthieno[2,3-F S b]pyridine-2-carboxamide o /
S N 4.
H
--N

C22 H18 F N3 02 3-amino-N-(3-ethoxypheny1)-6-(4-F S fluorophenyl)thieno[2,3-b]pyridine-2-carboxamide / \ is N . C21 H15 F2 N3 0 3-amino-N-(3-fluoro-4-methyl-phenyl)-6-(4-H
---N S fluorophenyl)thieno[2,3-b]pyridine-2-carboxamide *
F

N

/ \ S N F C20 H12 Cl F2 N3 3-amino-N-(3-ch1oro-4-fluoro-pheny1)-6-(4---NI H 0 S fluorophenyl)thieno[2,3-b]pyridine-2-carboxamide * CI
F

/\N

S N ''H C22 H18 F N3 0 3-amino-N-(2,4-dimethylpheny1)-6-(4-* S fluorophenyl)thieno[2,3-b]pyridine-2-carboxamide F
F

615 / \ NS N C20 H12 F3 N3 0 3-amino-N-(3,4-difluoropheny1)-6-(4----N S fluorophenyl)thieno[2,3-b]pyridine-2-carboxamide *
F

161 / \
s N Br 616 411 C20 H12 Br F2 3-amino-N-(4-bromo-2-fluoro-phenyB-6-(4-N3 0 S fluorophenyBthieno[2,3-b]pyridine-2-carboxamide \ NS N CI
¨N
617 C20 H12 Cl F2 N3 3-amino-N-(4-chloro-2-fluoro-pheny1)-6-(4-S fluorophenyBthieno[2,3-b]pyridine-2-carboxamide /\N S N
618 C20 H12 Cl F2 N3 3-amino-N-(2-chloro-4-fluoro-pheny0-6-(4-41 ci 0 S fluorophenyBthieno[2,3-b]pyridine-2-carboxamide NH2 H 0\
s 0¨ C22 H18 F N3 03 3-amino-N-(3,4-dimethoxyphenyB-6-(4-619 fluorophenyBthieno[2,3-b]pyridine-2-carboxamide 620 \ Ns N ci C20 H13 Cl F N3 3-amino-N-(4-ch1oropheny0-6-(4-H
¨N 0 S fluorophenyBthieno[2,3-b]pyridine-2-carboxamide /
S

H C21 H15 Cl F N3 3-amino-N-(5-chloro-2-methyl-phenyl)-6-(4-ci 0 S fluorophenyBthieno[2,3-b]pyridine-2-carboxamide

162 o ci / \ Ns N ilk -N H
622 4114 c, C20 H12 C12 F N3 3-amino-N-(3,5-dichloropheny1)-6-(4-0 S fluorophenyl)thieno[2,3-b]pyridine-2-carboxamide F

N
-N H
623 . F C21 H15 F2 N3 0 3-amino-N-(5-fluoro-2-methyl-pheny1)-6-(4-S fluorophenyl)thieno[2,3-b]pyridine-2-carboxamide F

/ \ N /
S N . 0 3-amino-6-(4-fluoropheny1)-N-(4-methoxy-2-624 -N methyl-phenyl)thieno[2,3-b]pyridine-* S
carboxamide F

N
/ \ S N 411 s/ C21 H16 F N3 0 3-amino-6-(4-fluoropheny1)-N-(4-methylsulfanylphenyl)thieno[2,3-b]pyridine-2-. S2 carboxamide F

----- i \ 0 I
401 S H N iii 3-amino-N-(2,5-dimethylpheny1)-6-(3-626 C23 H21 N3 02 S methoxyphenyl)thieno[2,3-b]pyridine-2-carboxamide o 1 \ 0 Br N S HN 41 C22 H18 Br N3 02 S 3-amino-N-(2-bromo-4-methyl-phenyl)-6-(3-methoxyphenyl)thieno[2,3-b]pyridine-2-carboxamide o

163 F
H
-- I I
N 3-amino-N-(4-bromo-2-fluoro-pheny1)-6-(3,4-.00 ,N S
0 VI C22 H17 Br F N3 dimethoxyphenyl)thieno[2,3-b]pyridine-2-? Br 03S

carboxamide CI "=-= F
I I Il 0 Nr S 0 0 3-amino-6-(2,5-dichloropheny1)-N-(2,5-629 CI F difluorophenyl)thieno[2,3-b]pyridine-2-carboxamide oi --, H 3-amino-6-(2,5-dichloropheny1)-N-(3,4-N s F
630 difluorophenyl)thieno[2,3-b]pyridine-2-carboxamide CI

"....
I \, 401 N- S N *
C20 H14 Cl N3 0 3-amino-6-(4-chloropheny1)-N-phenyl-thieno[2,3-631 0i S b]pyridine-2-carboxamide 0 1,1 S ti C21 H16 Cl N3 0 3-amino-6-(4-chloropheny1)-N-(m-CI S tolypthieno[2,3-b]pyridine-2-carboxamide o ---- \
I' i& 1,1 S [1 633 C23 H21 N3 03 S =
3-amino-6-(3,4-dimethoxypheny1)-N-(m-'o IW
tolypthieno[2,3-b]pyridine-2-carboxamide ...-- \
I' ...0 dab ---N s ti, =
3-amino-6-(3,4-dimethoxypheny1)-N-phenyl-634 =,0 RP C22 H19 N3 03 S
thieno[2,3-b]pyridine-2-carboxamide

164 Ø." s I \ 3-amino-6-(3,4-dimethoxypheny1)-N-(4-635,o Agit. --Isi s H = \¨ C24 H23 N3 04 S ethoxyphenyl)thieno[2,3-b]pyridine-2-o II" carboxamide ..., µ
3-amino-N,6-bis(p-tolyl)thieno[2,3-b]pyridine-2-636 I \ S N C22 H19 N3 0 S
0 .
H carboxamide ..--- \
637 3-amino-N-(o-toly1)-6-(p-tolyl)thieno[2,3-I
0 N S N411 C22 H19 N3 0 5 b]pyridine-2-carboxamide o ..--I \
o 0 rsi S
H 11 0¨\
ethyl 44[3-amino-6-(p-tolypthieno[2,3-b]pyridine-2-carbonyl]amino]benzoate o -0- µ

I \ 3-amino-N-(2-nitropheny1)-6-(p-tolypthieno[2,3-40 N S ri . C21 H16 N4 03 S b]pyridine-2-carboxamide 0-.N:
o---.... \
I
640 10/ rkr s vi = F C21 H16 F N3 0 3-amino-N-(4-fluoropheny1)-6-(p-tolypthieno[2,3-S b]pyridine-2-carboxamide ",.... \
I C22 H18 Cl N3 3-amino-N-(5-chloro-2-methoxy-pheny1)-6-(p-641 0 Nr s N .
02 S tolyl)thieno[2,3-b]pyridine-2-carboxamide

165 S Fri 3-amino-N-phenyl-6-(p-tolyl)thieno[2,3-b]pyridine-2-carboxamide 0 0 3-amino-N-(2-methoxypheny1)-6-(p-I
S tolyl)thieno[2,3-b]pyridine-2-carboxamide 644 S Fri C22 H19 N3 0 S 3-amino-N-(m-toly1)-6-(p-tolyl)thieno[2,3-b]pyridine-2-carboxamide I
645 CI = \
S *
C22 H16 Cl N3 methyl 44[3-amino-6-(4-chlorophenypthieno[2,3-03 S b]pyridine-2-carbonyl]amino]benzoate \
F C20 H13 Cl F N3 3-amino-6-(4-chloropheny1)-N-(4-646 S H 0 S fluorophenyl)thieno[2,3-b]pyridine-2-carboxamide ci 411134-1.

\
647 N s ri41 C23 H21 N3 02 S 3-amino-N-(2-ethoxypheny1)-6-(p-tolyl)thieno[2,3-b]pyridine-2-carboxamide C21 H16 Cl N3 0 3-amino-N-(4-chloropheny1)-6-(p-tolypthieno[2,3-648 isr s ci b]pyridine-2-carboxamide

166 ...-- \
1 C21 H16 F N3 0 3-amino-N-(2-fluoropheny1)-6-(p-tolyl)thieno[2,3-649 SI Isl S [I . S b]pyridine-2-carboxamide F

/
650 I \ C21 H16 Cl N3 0 3-amino-N-(2-chloropheny1)-6-(p-tolyl)thieno[2,3-0 iki S ri * S b]pyridine-2-carboxamide ci N II o\ 3-amino -6-(1,3-benzodioxo1-5-y1)-N-(2,4-1 \
<
651 , s C23 H19 N3 05 S dimethoxyphenyl)thieno[2,3-b]pyridine-2-0 so 0 carboxamide o/
NH2 H . 0 3-amino-6-(4-chloropheny1)-N-(2,4-652 N \
C22 H18 Cl N3 I \
03 S dimethoxyphenyl)thieno[2,3-b]pyridine-2-ii ri" s o carboxamide CI 411111kilil ..---- \
S C20 H13 F3 N4 0 3-amino-N-(4-pyridy1)-643-[3 653 ao ti l¨ /7 S (trifluoromethyl)phenyl]thieno[2,3-b]pyridine-2-N
carboxamide F F
F

41 Br , I 3-amino-N-(4-bromopheny1)-6-(2,4-654 ith -Ni s o C20 H12 Br C12 dichlorophenyl)thieno[2,3-b]pyridine-2-CI gl(111111P carboxamide

167 F

, s'====
I I
di N' S 2 ¨ 0 Cc'?

3-amino-N-(1,3-benzodioxo1-5-y1)-6-(2,4-difluorophenyl)thieno[2,3-b]pyridine-2-carboxamide Table 7 ¨ Activity against Dengue virus of compounds of the present invention.
Activity (EC50 in nM) A: EC50<5 M; B: 5<EC50<25 M; C: EC50>25 M; n.d.: not Cmpd determined 366 n.d. A n.d. n.d.
367 n.d. A n.d. n.d.

370 n.d. A n.d. n.d.
371 n.d. A n.d. n.d.
372 n.d. A n.d. n.d.

374 n.d. A n.d. n.d.
375 n.d. B n.d. n.d.
376 n.d. B n.d. n.d.
377 n.d. A n.d. n.d.
378 n.d. A n.d. n.d.

168 379 n.d. A n.d. n.d.
380 n.d. A n.d. n.d.
381 n.d. B n.d. n.d.
382 n.d. B n.d. n.d.
383 n.d. A n.d. n.d.
384 n.d. B n.d. n.d.
385 n.d. B n.d. n.d.
386 n.d. A n.d. n.d.
387 n.d. B n.d. n.d.
388 n.d. A n.d. n.d.
389 n.d. B n.d. n.d.
390 n.d. A n.d. n.d.
391 n.d. A n.d. n.d.
392 n.d. B n.d. n.d.
393 n.d. B n.d. n.d.
394 n.d. A n.d. n.d.
395 n.d. B n.d. n.d.
396 n.d. B n.d. n.d.
397 n.d. A n.d. n.d.
398 n.d. B n.d. n.d.
399 n.d. A n.d. n.d.
400 n.d. A n.d. n.d.
401 n.d. C n.d. n.d.
402 n.d. C n.d. n.d.

169 403 n.d. A n.d. n.d.
404 n.d. A n.d. n.d.
405 n.d. A n.d. n.d.
406 n.d. A n.d. n.d.
407 n.d. C n.d. n.d.
408 n.d. C n.d. n.d.
409 n.d. C n.d. n.d.
410 n.d. A n.d. n.d.

412 n.d. B n.d. n.d.

416 n.d. A n.d. n.d.

418 n.d. B n.d. n.d.
419 n.d. A n.d. n.d.
420 n.d. A n.d. n.d.
421 n.d. B n.d. n.d.
422 n.d. A n.d. n.d.
423 n.d. A n.d. n.d.
424 n.d. B n.d. n.d.

426 n.d. A n.d. n.d.

170 432 n.d. B n.d. n.d.

435 n.d. A n.d. n.d.
436 n.d. A n.d. n.d.

440 n.d. B n.d. n.d.

442 n.d. A n.d. n.d.
443 n.d. A n.d. n.d.
444 n.d. A n.d. n.d.

171 451 n.d. A n.d. n.d.

456 n.d. A n.d. n.d.
457 n.d. B n.d. n.d.

460 n.d. A n.d. n.d.

463 n.d. A n.d. n.d.

466 n.d. B n.d. n.d.
467 n.d. A n.d. n.d.

474 n.d. A n.d. n.d.

172 477 n.d. A n.d. n.d.
478 n.d. B n.d. n.d.
479 n.d. A n.d. n.d.
480 n.d. A n.d. n.d.
481 n.d. B n.d. n.d.

484 n.d. A n.d. n.d.

487 n.d. A n.d. n.d.

496 n.d. A n.d. n.d.

173 499 n.d. A n.d. n.d.
500 n.d. A n.d. n.d.
501 n.d. A n.d. n.d.
502 n.d. A n.d. n.d.
503 n.d. A n.d. n.d.
504 n.d. A n.d. n.d.
505 n.d. A n.d. n.d.

508 n.d. A n.d. n.d.
509 n.d. A n.d. n.d.

511 n.d. A n.d. n.d.

513 n.d. A n.d. n.d.

515 n.d. A n.d. n.d.
516 n.d. A n.d. n.d.
517 n.d. A n.d. n.d.
518 n.d. A n.d. n.d.
519 n.d. A n.d. n.d.
520 n.d. A n.d. n.d.
521 n.d. A n.d. n.d.

174 523 n.d. A n.d. n.d.
524 n.d. A n.d. n.d.
525 n.d. A n.d. n.d.
526 n.d. A n.d. n.d.
527 n.d. A n.d. n.d.
528 n.d. A n.d. n.d.

531 n.d. A n.d. n.d.

536 n.d. A n.d. n.d.
537 n.d. A n.d. n.d.
538 n.d. A n.d. n.d.
539 n.d. A n.d. n.d.
540 n.d. A n.d. n.d.
541 n.d. A n.d. n.d.

544 n.d. A n.d. n.d.
545 n.d. A n.d. n.d.

175 548 n.d. A n.d. n.d.
549 n.d. A n.d. n.d.

551 n.d. A n.d. n.d.
552 n.d. A n.d. n.d.
553 n.d. A n.d. n.d.
554 n.d. A n.d. n.d.

556 n.d. A n.d. n.d.
557 n.d. A n.d. n.d.
558 n.d. A n.d. n.d.
559 n.d. A A A
560 n.d. A n.d. n.d.

562 n.d. A n.d. n.d.
563 n.d. A n.d. n.d.
564 n.d. A n.d. n.d.
565 n.d. A n.d. n.d.

567 n.d. A n.d. n.d.
568 n.d. A n.d. n.d.

176 573 n.d. A n.d. n.d.

578 n.d. A n.d. n.d.
579 n.d. A n.d. n.d.
580 n.d. A n.d. n.d.
581 n.d. A n.d. n.d.
582 n.d. A n.d. n.d.

584 n.d. A n.d. A
585 n.d. A n.d. n.d.
586 n.d. A n.d. n.d.
587 n.d. A n.d. n.d.
588 n.d. A n.d. n.d.
589 n.d. A n.d. n.d.
590 n.d. A n.d. n.d.

592 n.d. A n.d. n.d.
593 n.d. A n.d. n.d.
594 n.d. A n.d. n.d.

177 595 n.d. A n.d. n.d.

601 n.d. A n.d. n.d.

603 n.d. A n.d. A
604 n.d. A n.d. n.d.
605 n.d. A n.d. n.d.
606 n.d. A n.d. n.d.
607 n.d. A n.d. n.d.
608 n.d. A n.d. n.d.

610 n.d. A n.d. n.d.
611 n.d. A n.d. n.d.

613 n.d. A n.d. n.d.
614 n.d. A n.d. n.d.

618 A A n.d. n.d.

178 619 n.d. A n.d. n.d.

621 n.d. A n.d. n.d.
622 n.d. A n.d. n.d.
623 n.d. A n.d. n.d.
624 n.d. A n.d. n.d.

626 n.d. A n.d. n.d.
627 n.d. A n.d. n.d.

629 n.d. A n.d. n.d.

632 n.d. A n.d. n.d.
633 n.d. A n.d. n.d.
634 n.d. A n.d. n.d.

637 n.d. A n.d. n.d.

639 n.d. A n.d. n.d.
640 n.d. A n.d. n.d.
641 n.d. A n.d. n.d.
642 n.d. A n.d. n.d.

179 643 n.d. A n.d. n.d.
644 n.d. A n.d. n.d.

647 n.d. A n.d. n.d.

649 n.d. A n.d. n.d.

653 n.d. A n.d. n.d.
654 n.d. A n.d. n.d.
655 n.d. A n.d. n.d.
Example 14 - Synthesis of 3-Amino-6,7,8,9-tetrahydro-5H-1-thia-7,10-diaza-cyclohepta[f]indene-2-carboxylic acid (5-phenyl-[1,3,4]thiadiazol-2-y1)-amide hydrochloride (C12 or Compound 115 in Table 1) N-N Clj N.-N
H2N4 j K2CO3, DMF, rt N ¨( S 4 + CI
CI __________________________________________ 76% a S mli Cl C2 C3

180 0 H0)40 THF, 65 C + C540¨ OH H2NkeCN C8 0 + Me 2 No k`'' .__)...
N Me2N 91% µ41s1"1 N Piperidine acetate I I I
Boc Boc Boc H20, relux 25%
C4 C5 C6 (Major) C7 (Minor) Boc N
atICN
CN
Boc ¨N I + Oci N S N S

aNrICN Na0Ac, Et0H, reflux Boc ¨N I + N.-CljN4 ,N ___________ )..
S S 4 39%

Boc 4M HCI in 1,4-dioxane S = __________________________________________________________ S 4 76% HCI

Step A - Synthesis of 2-chloro-N-(5-pheny1-1,3,4-thiadiazol-2-yl)acetamide (C3) [0000143] To a mixture of 5-phenyl-1,3,4-thiadiazol-2-amine (Cl, 1.06 g, 6 mmol) and K2003 (0.83 g, 6 mmol) in anhydrous DMF (20 mL), was added chloroacetyl chloride (C2, 0.48 mL, 6 mmol). The mixture was stirred at room temperature for 4 h. The reaction mixture was then poured into ice-water (100 mL), stirred, and then filtered. The resulting solid was washed with water, and then dried in the oven under vacuum to afford compound C3 (1.15 g, 76%) as a white solid.

181 Step B - Synthesis of tert-butyl (4E)-4-(hydroxymethylene)-5-oxoazepane-1-carboxylate (C6) and tert-butyl (3E)-3-(hydroxymethylene)-4-oxoazepane-1-carboxylate (C7) [0000144] A solution of tert-butyl 4-oxoazepane-1-carboxylate (C4, 2.56 g, 12.0 mmol) and N-[tert-butoxy(dimethylamino)methy1]-N,N-dimethylamine (C5, 2.97 mL, 14.4 mmol) in THF (30 mL) was refluxed for 8 h. After cooling, the reaction mixture was treated with water (20 mL), stirred at room temperature for 15 min, and then extracted with Et0Ac. The organic layer was dried over Na2SO4, and concentrated under reduced pressure to give C6 (major) and C7 (minor) as a colorless oil (2.63g, 91%), which was used as a mixture in the next step reaction directly.
Step C - Synthesis of tert-butyl 3-cyano-2-thioxo-1,2,5,6,8,9-hexahydro-7H-pyrido[2,3-d]azepine-7-carboxylate (C9) and tert-butyl 3-cyano-2-thioxo-1,2,5,7,8,9-hexahydro-6H-pyrido[3,2-c]azepine-6-carboxylate (C10) [0000145] A solution of a mixture of C6 and C7 (2.36 g, 9.8 mmol), 2-cyanoethanethioamide (C8, 0.98 g, 9.8 mmol) and piperidine acetate (10 mL) [prepared from glacial acetic acid (4.2 mL), water (10 mL) and piperidine (7.2 mL)] in H20 (50 mL) was refluxed for 2 h. After cooling, the reaction mixture was extracted with Et0Ac. The combined organic layer was dried over Na2SO4, and concentrated under reduced pressure. The given residue was purified through silica gel chromatography (Et0Ac/Hexane 60:40) to afford the desired compound C9, a yellow solid (0.75 g, 25%) as the major product. MS: MH+ = 306 and C10 (0.188g, 6.3%) as the minor product. MS: MH+ = 306.
Step D - Synthesis of 3-amino-7-tert-butyloxycarbony1-6,7,8,9-tetrahydro-5H-1-thia-7,10-diaza-cyclohepta[f]indene-2-carboxylic acid (5-phenyl-[1,3,4]thiadiazol-2-y1)-amide (C11)

182 [0000146] A mixture of C9 (750 mg, 2.46 mmol), C3 (623 mg, 2.46 mmol) and sodium acetate (302 mg, 3.68 mmol) in Et0H (20 mL) was refluxed for 4 h. After cooling, the reaction mixture was poured into water (100 mL), stirred, and then filtered. The given solid was dried in the oven under vacuum, and then recrystallized in Et0Ac to afford compound Cll (500 mg, 39%) as a yellow solid. MS: MNa+ = 545.
Step E - Synthesis of 3-Amino-6,7,8,9-tetrahydro-5H-1-thia-7,10-diaza-cyclohepta[f]indene-2-carboxylic acid (5-phenyl-[1,3,4]thiadiazol-2-y1)-amide hydrochloride (C12, Compound 115 in the Table) [0000147] The Boc-protected amine Cll (150 mg, 0.29 mmol) was stirred in a solution of 4 M HC1 in 1,4-dioxane (5 mL) at room temperature for 2 h. Then the mixture was concentrated under reduced pressure and the product was precipitate out in hexane.
The given solid was further purified by recrystallization from Me0H/CH2C12 to afford the target compound C12 (100mg, 76%) as a red solid. HPLC: purity > 97%. MS: MH+ = 423. IH NMR (DMSO-d6 +
D20): 6 8.02 (s, 1H), 7.60 (d, 2H), 7.42 (m, 3H), 4.26 (s, 2H), 3.45 (s, 2H), 3.12 (m, 2H), 1.96 (s, 2H).
Example 15 - Synthesis of 3-Amino-6,7,8,9-tetrahydro-5H-1-thia-6,1C
diaza-cyclohepta[f]indene-2-carboxylic acid (5-phenyl-[1,3,4]thiadiazol-2-y1)-amide hydrochloride (C14 or Compound 52 in Table 1)

183 Boc (1,2X4X7 +
Na0Ac, Et0H, reflux CIA 41-1s1 N , _______________ )...
N S S 4 30%

Boc NH2 NH2 NO:144 ..N
4M HCI in N S N¨il 1,4-dioxane Cc$140_40 N--N

70%

[0000148] The compound C14 was synthesized in a manner similar to Compound 115 (C12) by utilizing isolated tert-butyl 3-cyano-2-thioxo-1,2,5,7,8,9-hexahydro-6H-pyrido[3,2-c]azepine-6-carboxylate (C10). The compound 3-amino-6-tert-butyloxycarbony1-6,7,8,9-tetrahydro-5H-1-thia-6,10-diaza-cyclohepta[f]indene-2-carboxylic acid (5-phenyl-[1,3,4]thiadiazol-2-y1)-amide (C13) was confirmed with mass spectroscopy. C14 was obtained as a yellow solid. MS: MH+ =
423. 1H NMR (DMSO-d6 + D20): 6 8.24 (s, 1H), 7.86 (s, 2H), 7.53 (s, 3H), 3.36 (s, 2H), 3.28 (s, 4H), 3.17 (s, 2H).
Example 16 - Synthesis of Compounds 281, 282 and 283 CN
Br\ 0 NI-12 0 HO n \
C, CN µ
Ethyl Formate 1 - SN H2 Cr:HN-R 4101 \ 0 LHMDS, THF 1. .
_____________ 1. Piperdine Acetate N SH
r Na0Et/Et0H N
S HN-R
water 1-3 1-1 1-2 281, 282, 283 Synthesis of 2-(hydroxymethylene)cycloheptanone (1-2):
[0000149] A solution of 1-1 (19.04 g, 169.7 mmol) in anhydrous THF (50 mL) was cooled to 0 C. A solution of LHMDS (1.0 M in THF, 190 mL, 190 mmol) was added dropwise, followed by ethyl

184 formate (13.8 g, 186.3 mmol). The resulting mixture was stirred for 3 h at 0 C under N2 and quenched by slow addition of water (300 mL) and hexanes (200 mL). The layers were separated, the aqueous layer was neutralized with 5% citric acid (350 mL), followed by extraction with ethyl acetate (300 mL x 2). Organic layers were combined, washed with water (300 mL), brine (300 mL) and dried (Na2SO4). The solvent was removed under reduced pressure and 1-2 was obtained as an oil (20.0 g, 84% yield).
This was used in the next step without further purification.
Synthesis of 2-sulfany1-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-carbonitrile (1-3):
[0000150] A mixture of 1-2 (18.0 g, 128.6 mmol), 2-cyanothioacetamide (12.9 g, 128.6 mmol) and a piperidine solution (122 mL, prepared from piperidine (90 mL) and AcOH (53 mL) in water (125 mL)) in water (643 mL) was heated to reflux for 15 minutes. Additional AcOH (193 mL) was added and the reaction mixture was allowed to cool to room temperature slowly, when compound 1-3 precipitated out as a red solid. The reaction mixture was filtered and the cake was washed with water (100 mL) and dried under vacuum (18.5 g, 70% yield).
General procedure for the preparation of 2-bromoacetoamide

185 [0000151] To a solution of the corresponding primary amine (25 mmol) in anhydrous DCM (100 mL) was added a mixture of 2-bromoacetyl bromide (25 mmol) and triethylamine (30 mmol) in anhydrous DCM (20 mL) at -30 C under N2. After the addition, the reaction mixture was stirred at room temperature for 1.5 h and then concentrated. The residue was re-dissolved in acetone (50 mL), precipitated triethylamine hydrobromide was removed by filtration, and the filtrate was evaporated to yield the product. The product was further purified by trituration with diethyl ether.
General procedure for the preparation of final products [0000152] To a slurry of compound 1-3 (1 mmol, 204 mg) in anhydrous Et0H (5 mL) was added the corresponding 2-bromoacetamide (1 mmol), followed by a solution of sodium ethoxide in Et0H (2.6 M solution, 1.5 mmol, 0.58 mL) at room temperature under N2. The reaction was heated to reflux for 2 hours and during that time, the desired product precipitated out. The mixture was cooled to room temperature and filtered.
The solid was washed by Et0H (2 mL), diethyl ether (5 mL) and dried under vacuum to yield the final products.
Example 17 - Synthesis of Compounds 284, 286, 287 and 288 RI RI R
/ __ /0 s S R2CN Na0Et/Et0H R2 µ 0 Br HN-- /

1\1-"N R3e----S HN¨(\ /

284,286,287,288 [0000153] To a slurry of 1-5 (100 mg, 0.333 mmol) in anhydrous Et0H (2.5 mL) was added the corresponding sulfanylpyridine carbonitrile (1-7) followed by a solution of sodium ethoxide in

186 Et0H (2.6 M solution, 0.2 mL, 0.56 mmol) at room temperature under N2. The reaction was heated to reflux for 2 hours and during that time, the desired product precipitated out. The mixture was cooled to room temperature and filtered. The solid was washed with Et0H (2 mL) and ether (5 mL), and dried under vacuum to give the final compounds.
Example 18 - Synthesis of Compounds 285, 289, 293 and 294, 295, 296, 297, 298, 358, 359 and 360 OCN

/ N SH
S 0 Br Br b0 / __________________________ 4( S 40 -H2N- I ------. Br HN-- I J.
N-N Et3N/DCM N-NI Na0Et/Et0H

R

0 \ S 0 .. , s 0 ________ I'. Nj S HN-N S
N---N
285,289,293,294,295,296,297,298,358,359,360 Synthesis of 2-bromo-N-(5-pheny1-1,3,4-thiadiazol-2-yl)acetamide (1-5):
[0000154] A slurry of 1-4 (4.0 g, 22.57 mmol) and TEA (4.55 g, 45.14 mmol) in anhydrous DCM (400 mL) was cooled to 10 C
followed by the dropwise addition of 2-bromoacetyl bromide (9.12 g, 45.14 mmol). After the addition was complete, the mixture was stirred at room temperature overnight under N2 and then filtered. The cake was washed with DCM (100 mL), aqueous saturated NaHCO3 (100 mL), diethyl ether (100 mL) and dried under vacuum to give 1-5 (4.85 g, yield 72%).
Synthesis of 3-amino-N-(5-pheny1-1,3,4-thiadiazol-2-y1)-6,7,8,9-tetrahydro-5H-cyclohepta[b]thieno[3,2-e]pyridine-2-carboxamide (1-6):
[0000155] To a slurry of 1-3 (2.04 g, 10 mmol) in anhydrous Et0H (100 mL) was added 1-5 (2.99 g, 10 mmol), followed by a

187 solution of sodium ethoxide in Et0H (2.6 M solution, 5.8 mL, 15 mmol,) at room temperature under N2. The reaction was heated to reflux for 2 hours and during that time, the desired product precipitated out. The mixture was cooled to room temperature and filtered. The solid was washed with Et0H (20 mL), diethyl ether (50 mL), and dried under vacuum to give 1-6 (3.30 g, yield 78%).
Synthesis of 3-benzamido-N-(5-pheny1-1,3,4-thiadiazol-2-y1)-6,7,8,9-tetrahydro-5H-cyclohepta[b]thieno[3,2-e]pyridine-2-carboxamide (285):
[0000156] To a solution of 1-6 (500 mg, 1.18 mmol) in anhydrous DMF (5 mL) was added pyridine (0.15 mL) at room temperature under N2, followed by benzoic anhydride (401 mg, 1.77 mmol). Then the mixture was stirred at 50 C overnight.
HPLC revealed about 60% conversion. More benzoic anhydride (267 mg) and pyridine (0.15 mL) were added and the mixture was stirred at 50 C for another 5 hours. DCM (100 mL) was added and the mixture was washed with water (10 mL), aqueous saturated NaHCO3 (10 mL), brine (10 mL) and dried (Na2SO4). The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to give 285 (35 mg, yield 7%).
Synthesis of 3-(butylamino)-N-(5-pheny1-1,3,4-thiadiazol-2-y1)-6,7,8,9-tetrahydro-5H-cyclohepta[b]thieno[3,2-e]pyridine-2-carboxamide (289):
[0000157] To a solution of 1-6 (200 mg, 0.475 mmol) in anhydrous NMP (2 mL) was added n-BuI (131 mg, 0.713 mmol) and the mixture was stirred at room temperature for 1 h under N2.
Then, DCM (100 mL) was added and the mixture was washed with water (10 mL), aqueous saturated NaHCO3 (10 mL), brine (10 mL) and dried (Na2SO4). Most of the solvent was removed under reduced pressure and the precipitated solid was filtered. The

188 cake was washed with diethyl ether (10 mL) and dried under vacuum to yield 289 (70 mg, 31% yield).
Synthesis of 2-((2-((5-pheny1-1,3,4-thiadiazol-2-yl)carbamoy1)-6,7,8,9-tetrahydro-5H-cyclohepta[b]thieno[3,2-e]pyridin-3-yl)amino)acetic acid (293):
[0000158] To a mixture of intermediate 1-6 (0.63 g, 1.5 mmol) and TEA (0.9 mL, 6.0 mmol, 4.0 eq) in anhydrous THF (20 mL) was slowly added ethyl bromoacetate (0.4 mL, 3.0 mmol, 2.0 eq) and the contents were stirred overnight at room temperature. The volatiles were removed under vacuum and the residue was purified by flash chromatography on silica gel eluting 0-5%
Me0H/DCM affording the desired intermediate. This material was treated with aqueous 1M LiOH (4 mL) in THF-H20 (3:1, 20 mL) at room temperature overnight. Most of the THF was removed under vacuum and the aqueous layer was washed with MTBE:Et0Ac (1:1, mL) and acidified to pH= 3-5 using acetic acid. The free acid obtained was stirred with sodium methoxide (1 eq) in MTBE
to give the desired sodium salt of 293 (0.12 g, 9% overall yield) as a solid.
Synthesis of 3-((2-aminoethyl)amino)-N-(5-pheny1-1,3,4-thiadiazol-2-y1)-6,7,8,9-tetrahydro-5H-cyclohepta[b]thieno[3,2-e]pyridine-2-carboxamide (294):
[0000159] To a solution of intermediate 1-6 (0.42 g, 1 mmol) and triethylamine (2 mL) in N-methylpyrrolidinone (20 mL) was added N(Boc)-2-bromoethylamine (1.8 g, 8.0 mmol) and the contents were heated at 100 C for 16 h. The reaction mixture was cooled to room temperature and poured into ice-cold water.
The solid obtained was filtered and air-dried to give the free base (0.23 g). Treatment of the free base with 2M HC1 in diethyl ether (10 mL) at room temperature overnight followed by filtration afforded 294 in the HC1 salt form (0.19 g, 38%
overall yield).

189 Synthesis of 3-oxo-3-((2-((5-pheny1-1,3,4-thiadiazol-2-yl)carbamoy1)-6,7,8,9-tetrahydro-5H-cyclohepta[b]thieno[3,2-e]pyridin-3-yl)amino)propanoic acid (295):
[0000160] To a solution of intermediate 1-6 (0.63 g, 1.5 mmol) and TEA (1 mL) in anhydrous DCM (30 mL) at 0 C was added methylmalonyl chloride (0.4 g, 3.0 mmol, 2.0 eq) dropwise and the contents were slowly warmed to room temperature and stirred for 24 h. The organic portion was washed with 1M NaOH, brine, dried (Na2SO4), filtered and concentrated. The crude methyl ester was stirred with 1M LiOH (4 mL) in THF (12 mL) and water (4 mL) at room temperature overnight. Most of the THF was removed under vacuum and the solid obtained was filtered, dried and treated with sodium methoxide (1.0 eq) in MTBE at room temperature overnight. The solid obtained was filtered and dried under vacuum to give the sodium salt of 295 (0.3 g, 38%
overall yield) as a brown solid.
Synthesis of 3-(2-aminoacetamido)-N-(5-pheny1-1,3,4-thiadiazol-2-y1)-6,7,8,9-tetrahydro-5H-cyclohepta[b]thieno[3,2-e]pyridine-2-carboxamide (296):
[0000161] To a solution of intermediate 1-6 (1.26 g, 3.0 mmol) and Boc-glycine (1.05 g, 6.0 mmol, 2.0 eq) in anhydrous DMF (30 mL) at room temperature was sequentially added HBTU (2.27 g, 6.0 mmol, 2.0 eq) and DIEA (2.6 mL, 15 mmol, 5.0e q). The contents were stirred at room temperature for 36 h. The reaction mixture was poured into ice-cold water and the solid obtained was filtered, and dried under vacuum. The solid was dissolved in TFA (10 mL) and DCM (20 mL) and stirred overnight.
The volatiles were removed under vacuum. The residue obtained was stirred in 2M HC1 in diethyl ether (20 mL) at room temperature overnight and the solid was filtered, dried under vacuum to yield 296 as the HC1 salt (0.6 g, 39% overall yield).

190 Synthesis of 3-acetamido-N-(5-pheny1-1,3,4-thiadiazol-2-y1)-6,7,8,9-tetrahydro-5H-cyclohepta[b]thieno[3,2-e]pyridine-2-carboxamide (358):
[0000162] To a solution of 1-6 (200 mg, 0.475 mmol) in anhydrous DMF (2 mL) was added pyridine (0.05 mL) followed by acetic anhydride (60 mg, 0.57 mmol). The reaction mixture was stirred at room temperature overnight and then DCM (100 mL) was added. The mixture was washed with water (10 mL), aqueous saturated NaHCO3 (10 mL), brine (10 mL) and dried (Na2SO4). The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to give 358 (40 mg, yield 19%).
Synthesis of 3-(methylamino)-N-(5-pheny1-1,3,4-thiadiazol-2-y1)-6,7,8,9-tetrahydro-5H-cyclohepta[b]thieno[3,2-e]pyridine-2-carboxamide (359):
[0000163] To a solution of 1-6 (200 mg, 0.475 mmol) in anhydrous NMP (2 mL) was added CH3I (102 mg, 0.712 mmol) and stirred for 1 hour at room temperature under N2. Then, DCM
(100 mL) was added and the mixture was washed with water (10 mL), saturated aqueous NaHCO3 (10 mL), brine (10 mL) and dried (Na2SO4). Most of the solvent was removed under reduced pressure and the precipitated solid was filtered. The cake was washed with diethyl ether (10 mL) and dried under vacuum to give 359 (95 mg, 48% yield).
General procedure for compounds 297, 298 and 360 [0000164] To a solution of intermediate 1-6 (0.84 g, 2.0 mmol) and the corresponding pyridine carboxylic acid (0.49 g, 4.0 mmol, 2.0 eq) in anhydrous DMF (25 mL) at room temperature was sequentially added HBTU (1.52 g, 4.0 mmol, 2.0 eq) and DIEA
(3.5 mL, 20 mmol, 10 eq) and the contents were stirred at room temperature overnight. The reaction mixture was poured into ice-cold water and the solid obtained was filtered and dried

191 under vacuum. The free base obtained above was stirred in 2M
HC1 in diethyl ether (10 mL), filtered and dried to give the appropriate HC1 salt form of the final compounds.
Example 19 - Synthesis of Compound 290 0 0 02N, s KSAc ,S
CN Na0Et Br FN¨µ I ¨3. AcS/ _____ HN¨c\ / Et0H

02N, 0 H2N 0 ,) s Pt02/1-12 /S
/
290a N-N 290 N-N
Synthesis of S-[2-oxo-2-[(5-pheny1-1,3,4-thiadiazol-2-yl)amino]ethyl] ethanethioate (1-8):
[0000165] To a slurry of 1-5 (300 mg, 1 mmol) in anhydrous DCM
(30 mL) was added potassium thioacetate (171 mg, 1.5 mmol) and the mixture was stirred at room temperature overnight. The precipitate was filtered, the filter cake was washed with diethyl ether (30 mL), and dried under vacuum to give intermediate 1-8 (287 mg, yield 95%).
Synthesis of 3-amino-5-nitro-N-(5-pheny1-1,3,4-thiadiazol-2-yl)thieno[2,3-b]pyridine-2-carboxamide (290a):
[0000166] To a slurry of 1-8 (100 mg, 0.34 mmol) in anhydrous Et0H (5 mL) was added a solution of Na0Et in Et0H (2.6 M
solution, 0.2 mL, 0.52 mmol) at room temperature under N2 for 1 h. Then, 1-9 (62 mg, 0.34 mmol) was added to the mixture and the reaction was heated to reflux for 2 hours. During that time, the desired product precipitated out. The mixture was cooled to room temperature and filtered. The solid was washed with Et0H (10 mL) and diethyl ether (15 mL), and dried under vacuum to give 290a (53 mg, 39% overall yield).
Synthesis of 3,5-diamino-N-(5-pheny1-1,3,4-thiadiazol-2-yl)thieno[2,3-b]pyridine-2-carboxamide (290):

192 [0000167] To a slurry of 17 (280 mg, 0.704 mmol) in anhydrous Et0H (60 mL) was added Pt02 (28 mg), and the mixture was hydrogenated at 30 psi for 3 days. The mixture was filtered through Celite, the filtrate was concentrated and the resulting residue was recrystallized with Me0H/diethyl ether (1:4, 5 mL) to give 290 (45 mg, 18% yield).
Example 20 - Synthesis of Compound 291 H2N1(CN e s so Th\lj"0EtO / CN Na0Et/Et0H
), N NSH 3. + HN--µ /
N-N

Et0 0 s LiOH \ s HN¨µ THF/H HO20 /
N-N N-N

Synthesis of Ethyl 5-cyano-6-sulfanyl-pyridine-3-carboxylate (1-12):
[0000168] To a solution of 1-11 (500 mg, 3.00 mmol) and 2-cyanothioacetamide (1.0 g, 10.0 mmol) in anhydrous Et0H (36 mL) was added a solution of Na0Et in Et0H (2.6 M solution, 4.0 mL, 1.04 mmol) at room temperature and then the mixture was heated to reflux for 1 hour. The mixture was cooled to room temperature, concentrated and the residue was dissolved in water (20 mL). Concentrated HC1 was added dropwise to adjust the pH to 8-9 when a solid precipitated out. The precipitate was collected by filtration and filter cake was washed with water and dried under vacuum to yield 1-12 (212 mg, 34% yield).
Synthesis of Ethyl 3-amino-2-[(5-pheny1-1,3,4-thiadiazol-2-yl)carbamoyl]thieno[2,3-b]pyridine-5-carboxylate (1-13):
[0000169] To a slurry of compound 1-12 (150 mg, 0.721 mmol) in anhydrous Et0H (5 mL) was added 1-5 (216 mg, 0.721 mmol), followed by a solution of Na0Et in Et0H (2.6 M solution, 0.5

193 mL, 1.3 mmol) at room temperature under N2. The reaction was heated to reflux for 2 hours and during that time, the desired product precipitated out. The mixture was cooled to room temperature and filtered. The solid was washed with Et0H (2 mL), diethyl ether (5 mL), and dried under vacuum to give 1-13 (230 mg, 75% yield).
Synthesis of 3-amino-2-[(5-pheny1-1,3,4-thiadiazol-2-yl)carbamoyl]thieno[2,3-b]pyridine-5-carboxylic acid (291):
[0000170] To a slurry of compound 1-13 (230 mg, 0.54 mmol) in THF (5 mL) was added a solution of LiOH in water (1 M solution, 1.35 mL, 1.35 mmol). The reaction was stirred at room temperature for 2 hours and during that time the desired product precipitated out. After filtration, the solid was washed with Et0H (2 mL) and diethyl ether (5 mL), and dried under vacuum to give 291 (48 mg, 22% yield).
Example 21 - Synthesis of Compound 292 Na0Et --C S 40 1 a Et0H _,.. 0 AcS/ S
HN----,/ + Cle CI e.--S HN- i lei \\ /
N-N N-N

[0000171] To a slurry of 1-8 (200 mg, 0.669 mmol) in anhydrous Et0H (10 mL) was added a solution of Na0Et in Et0H (2.6 M
solution, 0.4 mL, 1.04 mmol) at room temperature under nitrogen for one hour. Then, 1-10 (116 mg, 0.669 mmol) was added to the mixture and the reaction was heated to reflux for 2 hours.
During that time, the desired product precipitated out. The mixture was cooled to room temperature and filtered. The solid was washed with Et0H (10 mL), diethyl ether (15 mL), and dried under vacuum to yield 292 (35 mg, 15% overall yield).
Example 22 - Synthesis of Compounds 299, 300, 361 and 362

194 1-.-- __ e s 0 _... r--.0) s 0 CII\r N-N N-N
CIN,r S HN¨ /

299, 300, 361, 362 Synthesis of 2-[[6-chloro-2-[(5-pheny1-1,3,4-thiadiazol-2-yl)carbamoyl]thieno[2,3-b]pyridin-3-yl]amino]acetic acid (299):
[0000172] A solution of 292 (200 mg, 1 eq), TEA (0.32 mL, 6 eq) in DMF (3 ml) with ethyl bromoacetate (172 mg, 2 eq) was stirred at room temperature for 2 h. The reaction was poured into ice water (10 mL), filtered, and dried to afford the ethyl ester intermediate. This material was dissolved in 3:1 THF/H20 (10 mL) and 1M NaOH (1.5 mL, 3 eq) and stirred at room temperature for 2 h. Following removal of THF, the resulting solid was collected by filtration and dried under vacuum to afford product 299 as the sodium salt (105 mg, 43% overall yield).
Synthesis of 3-(2-aminoethylamino)-6-chloro-N-(5-pheny1-1,3,4-thiadiazol-2-yl)thieno[2,3-b]pyridine-2-carboxamide (300):
[0000173] A solution of 292 (350 mg, 1 eq), TEA (2 ml), and N-(Boc)-2-bromoethylamine (1 g, 5 eq) in NMP (20 mL) was heated at 100 C for 16 h. The reaction mixture was cooled to room temperature, poured into ice water (60 mL), and the solid was filtered and dried to give the Boc-protected intermediate.
This solid dissolved in 10% HC1 in Me0H (20 mL) and stirred at room temperature for 3 h. The volume of the reaction mixture was reduced to 3 mL, the solid was collected by filtration and washed by diethyl ether (3 x 3 mL) to afford product 300 (85 mg, 20% yield) as a light-yellow powder.
Synthesis of 3-[(2-aminoacetyl)amino]-6-chloro-N-(5-pheny1-1,3,4-thiadiazol-2-yl)thieno[2,3-b]pyridine-2-carboxamide (361):
[0000174] A solution of 292 (200 mg, 1 eq), Boc-glycine (180 mg, 2 eq), HBTU (390 mg, 2 eq) and DIPEA (0.447 mL, 5 eq) in

195 DMF (5 mL) were stirred at room temperature for 3 days. The reaction was poured into ice water (20 mL), filtered, and dried to isolate the Boc-protected intermediate. This material was dissolved in 10% HC1 in Me0H (10 mL) and the reaction was stirred at room temperature for 2 h. After removing solvents, the resulting solid was washed with Et0H (3 x 10 mL) and DCM
(3x10 mL) to afford 361 as the HC1 salt (30 mg, 12% overall yield).
Synthesis of 3-[[6-chloro-2-[(5-pheny1-1,3,4-thiadiazol-2-yl)carbamoyl]thieno[2,3-b]pyridin-3-yl]amino]-3-oxo-propanoic acid (362):
[0000175] A mixture of 292 (1 g, 1 eq) and TEA (3.33 ml) in anhydrous DCM (100 mL) was stirred at 0 C, then methyl malonyl chloride (0.833 mL, 3 eq) was added slowly. After stirring at room temperature for 18 h, DMF (5 mL) was added and the reaction was stirred for an additional 6 h in attempt to drive to completion. The mixture was concentrated to dryness, triturated in water (500 mL) for 1 h, filtered, and the solid was washed by MTBE (3 x 30 mL). This crude ester intermediate was purified by silica gel column chromatography using 0-5%
Me0H/DCM to give pure material (385 mg, 31% yield). The hydrolysis reaction was performed with the purified ester intermediate (386 mg, 1 eq) in 3:1 THF/H20 (30 mL) and 1M NaOH
(3.4 mL, 4.3 eq). The reaction was stirred at room temperature and then concentrated to dryness. The resulting solid was collected by filtration, washed by MTBE (3 x 50 mL), and dried to give 362 as a light-yellow solid (215 mg, 17% overall yield).
Example 23 - Synthesis of Compound 301

196 CN
0 1\1y0Me OMe 1-12eN m\ION

Na0Et N SH
1-12 Toluene Et0H

Reflux Reflux Na0Et \ s Brf s = + "
Et0H
N S
N SH
-N
1-5 N¨N

Synthesis of 3-(dimethylaminomethylene)-1-methyl-piperidin-4-one (1-13):
[0000176] A mixture of 1-12 (25 mL, 203 mmol, 1.0 eq), and N,N-dimethylformamide dimethylacetal (30 mL, 223.3 mmol, 1.1 eq) in toluene (200 mL) was heated to reflux for 12 h.
Additional N,N-dimethylformamide dimethylacetal (30 mL, 223.3 mmol, 1.1 eq) was added and the heating was continued for another 24 h. Volatiles were removed under reduced pressure and N,N-dimethylformamide dimethylacetal (60 mL, 446.6 mmol, 2.2 eq) was added to the residue yet again and it was heated at 100 C overnight. The reaction mixture was evaporated under reduced pressure, and twice azeotroped toluene twice to afford 48 g (-70% purity by LC-MS) of crude 1-13 as a dark brown liquid.
Synthesis of 6-methy1-2-sulfany1-7,8-dihydro-5H-1,6-naphthyridine-3-carbonitrile (1-14):
[0000177] To a mixture of crude compound 1-13 (15 g, 89 mmol, 1.3 eq) and 2-cyanothioacetamide (6.9 g, 68.5 mmol, 1 eq) in anhydrous Et0H (150 mL) at room temperature, was added Na0Et (21 wt% in Et0H, 55 mL, 144 mmol, 2.1 eq) and the reaction mixture was heated to reflux overnight. The reaction mixture was cooled to room temperature, poured into ice water and acidified with aqueous HC1 (2N) to pH - 2. The mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was triturated with Me0H, filtered and

197 dried under vacuum to afford 12 g (66% yield, >85% purity by LC-MS) of crude compound 1-14 as a yellow solid.
Synthesis of 3-amino-6-methyl-N-(5-pheny1-1,3,4-thiadiazol-2-y1)-7,8-dihydro-5H-thieno[2,3-b][1,6]naphthyridine-2-carboxamide (301):
[0000178] See procedure used for the synthesis of 1-6.
Example 24 - Synthesis of Compounds 302, 304-311, 321 and 363 Br\ 0 + H2N
Br Et3N 0 C - r t CH2022 h ON Br \ e CF3 N OMe I CN
OMe H2N HN =

Cz-r0 \ 0 s N SH
Xylene \ s Pipendine Na0Et 1-21 Reflux 1-22 Et0H
1-23 Et0H
24 h Reflux Reflux ______________ / H ____________________________ /
I I I

__________________________________ )0- N= CF3 302, 304, 305, 306, 307, 308, 309, 310, 311, 321, 363 Synthesis of 3-(dimethylamino)-1-(2-thienyl)prop-2-en-1-one (1-22):
[0000179] See procedure used for the synthesis of 1-13.
Synthesis of 2-sulfany1-6-(2-thienyl)pyridine-3-carbonitrile (1-23):
[0000180] See procedure used for the synthesis of 1-14.
Synthesis of 2-bromo-N-[3-(trifluoromethyl)phenyl]acetamide (1-24):
[0000181] See procedure used for the synthesis of 1-5.
Synthesis of 3-amino-6-(2-thieny1)-N-[3-(trifluoromethyl)phenyl]thieno[2,3-b]pyridine-2-carboxamide (1-25):

198 [0000182] See procedure used for the synthesis of 1-6.
Synthesis of 3-oxo-3-[[6-(2-thieny1)-2-[[3-(trifluoromethyl)phenyl]carbamoyl]thieno[2,3-b]pyridin-3-yl]amino]propanoic acid (302):
[0000183] See procedure used for the synthesis of compound 295.
Synthesis of 3-(2-aminoethylamino)-6-(2-thieny1)-N-[3-(trifluoromethyl)phenyl]thieno[2,3-b]pyridine-2-carboxamide (304):
[0000184] See procedure used for the synthesis of compound 294.
Synthesis of 2-[[6-(2-thieny1)-2-[[3-(trifluoromethyl)phenyl]carbamoyl]thieno[2,3-b]pyridin-3-yl]amino]acetic acid (305):
[0000185] See procedure used for the synthesis of compound 299.
Synthesis of 2-[carboxymethyl-[6-(2-thieny1)-2-[[3-(trifluoromethyl)phenyl]carbamoyl]thieno[2,3-b]pyridin-3-yl]amino]acetic acid (363):
[0000186] By-product resulting from disubstitution of the glycine reagent during the synthesis of compound 305.
Synthesis of 2-(thiophen-2-y1)-10-(3-(trifluoromethyl)pheny1)-7,8-dihydro-5H-pyrido[3',2':4,5]thieno[3,2-b][1,5]diazonine-6,9,11(10H)-trione (306):
[0000187] By-product resulting from intramolecular cyclization of the bromoacetyl intermediate used for the synthesis of compounds 307, 308, and 309.
Synthesis of 3-[[2-(methylamino)acetyl]amino]-6-(2-thieny1)-N-[3-(trifluoromethyl)phenyl]thieno[2,3-b]pyridine-2-carboxamide (307):
[0000188] A solution of 1-25 (500 mg) in 1,4-dioxane was reacted with bromoacetyl bromide and TEA. After stirring at room temperature for 20 minutes, the reaction mixture was poured into cold diethyl ether, stirred for 10 min, filtered, washed with diethyl ether and dried in vacuo to afford 760 mg

199 (quantitative yield) of the bromoacetyl intermediate as the hydrobromide salt. On 200 mg scale, this bromoacetyl intermediate was reacted with a methylamine solution (33% wt.
solution in Et0H) for 2 hours at room temperature. The reaction mixture was evaporated to dryness and triturated with DCM to afford pure compound. This material was treated with 1.25M HC1 in Me0H and stirred for 2 hours. Following evaporation in vacuo and trituration with diethyl ether, 75 mg of compound 307 was isolated as the HC1 salt (44% yield).
Synthesis of 3-[[2-(dimethylamino)acetyl]amino]-6-(2-thieny1)-N-[3-(trifluoromethyl)phenyl]thieno[2,3-b]pyridine-2-carboxamide (308):
[0000189] On 200 mg scale, the bromoacetyl intermediate used for the synthesis of compound 307 was reacted with a 2M
dimethylamine solution in THF for 1 hour at room temperature.
The reaction mixture was evaporated to dryness and treated with 2M HC1 in diethyl ether and stirred for 1 hour. The reaction mixture was filtered and triturated with DCM to afford 135 mg of 308 as the HC1 salt (79% yield).
Synthesis of Trimethyl-[2-oxo-2-[[6-(2-thieny1)-2-[[3-(trifluoromethyl)phenyl]carbamoyl]thieno[2,3-b]pyridin-3-yl]amino]ethyl]ammonium (309):
[0000190] On 150 mg scale, the bromoacetyl intermediate used for the synthesis of compound 307 was mixed with a 25%
trimethylamine in Me0H solution for 1 hour at room temperature.
The reaction mixture was evaporated to dryness and triturated with DCM to afford 100 mg of 309 (71% yield).
Synthesis of Ethyl 4-oxo-4-[[6-(2-thieny1)-2-[[3-(trifluoromethyl)phenyl]carbamoyl]thieno[2,3-b]pyridin-3-yl]amino]butanoate (310):
[0000191] A solution of compound 1-25 (0.71 g, 1.69 mmol, 1.0 equiv) in 1,4-dioxane (20 mL) was treated with succinyl chloride (5.0 mL, excess) at room temperature under N2. The reaction mixture was stirred for 2 h. The reaction mixture was

200 poured into cold diethyl ether and the resulting solid was filtered, washed with diethyl ether and dried to afford 0.9 g, (99% yield) of 310 as a pale yellow solid.
Synthesis of 4-oxo-4-[[6-(2-thieny1)-2-[[3-(trifluoromethyl)phenyl]carbamoyl]thieno[2,3-b]pyridin-3-yl]amino]butanoic acid (311):
[0000192] Compound 310 (0.548 g, 1.0 mmol, 1.0 equiv) was dissolved in THF/H20 (3:1; 120 mL) and treated with sodium hydroxide (0.4 g, 10 mmol, 10 equiv) at room temperature for 2 h. The reaction mixture was evaporated to reduce the volume.
The resulting precipitate was filtered and washed with DCM and hexanes. After drying, 0.44 g (81% yield) of the sodium salt of 311 was isolated as a yellow solid.
Synthesis of 3-(ethylamino)-6-(2-thieny1)-N-[3-(trifluoromethyl)phenyl]thieno[2,3-b]pyridine-2-carboxamide (321):
[0000193] To a solution of compound 1-25 (0.5 g, 1.2 mmol, 1 eq) in anhydrous 1,4-dioxane (30 mL) was added dropwise triethyloxonium tetrafluoroborate (0.29 g, 1.55 mmol, 1.3 eq) in DCM (5 mL) at 5 C. The reaction mixture was allowed to warm to room temperature and stir overnight. The reaction mixture was evaporated in vacuo, triturated with diethyl ether, filtered and washed with diethyl ether. This crude material was purified by trituration with Me0H to afford 70 mg of 321 (13% yield) as a bright yellow solid.
Example 25 - Synthesis of Compounds 303 and 312 Br 0 CF 3 NH2 NHR
= 1 _O OCF3 HN 1-24 P OCF3 -N SH N S N S N
Na0Et Et0H 303,312 Ref lux

201 Synthesis of 3-amino-6-methyl-N-[4-(trifluoromethoxy)pheny1]-7,8-dihydro-5H-thieno[2,3-b][1,6]naphthyridine-2-carboxamide (1-26):
[0000194] See procedure used for the synthesis of 1-6.
Synthesis of 2-[[6-methy1-2-[[4-(trifluoromethoxy)phenyl]carbamoy1]-7,8-dihydro-5H-thieno[2,3-b][1,6]naphthyridin-3-yl]amino]acetic acid (303):
[0000195] See procedure used for the synthesis of compound 299.
Synthesis of 3-[[2-(dimethylamino)acetyl]amino]-6-methyl-N-[4-(trifluoromethoxy)pheny1]-7,8-dihydro-5H-thieno[2,3-b][1,6]naphthyridine-2-carboxamide (312):
[0000196] See procedure used for the synthesis of compound 308.
Example 26 - Synthesis of Compound 316 NH
________ / 2 HNI).LOCI
I H
____________________________________________ I H
10/ CF3 _______________________ 0 1,4-clioxane N SN CF3 OH
I NI
NHCbz .2003 0 Synthesis of Chloromethyl N-[6-(2-thieny1)-2-[[3-(trifluoromethyl)phenyl]carbamoyl]thieno[2,3-b]pyridin-3-yl]carbamate (1-32):
[0000197] To a solution of intermediate 1-25 (1.26 g, 3 mmol) in anhydrous 1,4-dioxane (60 mL) at room temperature was added chloromethyl chloroformate (1 mL, 12 mmol) and the contents were stirred overnight. The solid obtained was filtered, triturated with MTBE (2 x 20 mL) and dried to afford the desired intermediate 1-32 (1 g) as the HC1 salt.

202 Synthesis of 7-(thiophen-2-y1)-3-(3-(trifluoromethyl)phenyl)pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione (316):
[0000198] To a solution of (L)-Cbz-valine (2.5 g, 10 mmol) in anhydrous DMF (100 mL) at room temperature was added cesium carbonate (3.3 g, 10 mmol) and the mixture was stirred for 1 h.
To the reaction flask was added the intermediate 1-32 (1 g) and the contents were stirred at room temperature overnight. The reaction mixture was added to ice-cold water and the precipitate obtained was filtered, washed with MTBE (2 x 30 mL) and dried to afford 316 as a yellow solid (0.5 g).
Example 27 - Synthesis of Compound 317 ON
(0F300)20 ___________________________________ F30NSH

____________________________ /NH2 Na0Et F30 Ns,r1\1 0F3 Synthesis of 4-ethoxy-1,1,1-trifluoro-but-3-en-2-one (1-34):
[0000199] To a solution of trifluoroacetic anhydride (8.6 mL, 61.9 mmol, 1.05 eq) and N,N-dimethylamino pyridine (0.43 g, 3.54 mmol, 0.06 eq) in DCM (90 mL) at - 10 C was added dropwise methyl vinyl ether (5.6 mL, 59 mmol, 1 eq). The reaction mixture was stirred at - 10 C and warmed to room temperature overnight. GC-MS analysis of the reaction mixture showed completion of reaction. The reaction mixture was poured into a cold saturated sodium bicarbonate solution and extracted with DCM. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated to afford 8.5 g (85%
yield) of compound 1-34 as a dark brown liquid.
Synthesis of 2-sulfany1-6-(trifluoromethyl)pyridine-3-carbonitrile (1-35):

203 [0000200] To a mixture of 1-34 (3 g, 17.8 mmol, 1 eq) and 2-cyanothioacetamide (2.7 g, 26.8 mmol, 1.5 eq) in ethanol (30 mL) was added N-methylmorpholine (2.5 mL) and refluxed for 24 h. The reaction mixture was evaporated in vacuo to afford 7 g of crude 1-35 which was used in the next step without purification.
Synthesis of 3-amino-6-(trifluoromethyl)-N-[3-(trifluoromethyl)phenyl]thieno[2,3-b]pyridine-2-carboxamide (317):
[0000201] See procedure used for the synthesis of 1-6.
Example 28 - Synthesis of Compound 318 , I NN CN
I :

H2N,.S
1\l/r--'" 0 N \ NSH
1. 1\1)--4)0 . L
)\--S

reflux, 18 h 1-37 ,---S / -S 1-38 , ________________________________ /NH2 I I H
1-24NSi N CF3 '--- N
_______________ 1.
Na0Et "-S 318 0 io Et0H, reflux Synthesis of 3-(dimethylamino)-1-(2,4-dimethylthiazol-5-yl)prop-2-en-1-one (1-37):
[0000202] A solution of 1-acetyl-2,4-dimethyl-thiazole (10 g, 64 mmol) in N,N-dimethylformamide dimethylacetal (100 mL) was refluxed overnight. GC/MS analysis showed completion. The contents were cooled to room temperature and poured into ice-cold water. The solid 1-37 obtained (10 g, 80%) was dried and used in the next step as such.
Synthesis of 6-(2,4-dimethylthiazol-5-y1)-2-sulfanyl-pyridine-3-carbonitrile (1-38):
[0000203] To a mixture of 1-37 (10 g, 48 mmol) and 2-cyanothioacetamide (10 g, 100 mmol) in Et0H (200 mL) was added NMP (10 mL) and the contents were heated at 80 C overnight.
The volatiles were removed under vacuum and the residue was

204 triturated with a 2:1 mixture of hexane/Et0Ac affording the desired intermediate 1-38 (7.2 g, 60% yield) as an orange solid, which was used in the next step as such.
Synthesis of 3-amino-6-(2,4-dimethylthiazol-5-y1)-N-[3-(trifluoromethyl)phenyl]thieno[2,3-b]pyridine-2-carboxamide (318):
[0000204] See procedure used for the synthesis of 1-6.
Example 29 - Synthesis of Compound 319 H NH2 .
HN
H2N 401 CF3 CICNis CF3 CIN 1-23 I \ __ \( NH ee---S NH
1-39 1-40 ...-- 319 Synthesis of 2-chloro-N-[3-(trifluoromethyl)phenyl]acetamidine (1-40):

[0000205] Chloroacetonitrile (2.0 g, 26.7 mmol) and 3-(trifluoromethyl)benzenamine (4.20 g, 26.7 mmol) was treated with 4N HC1 in 1,4-dioxane (50 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum and crude 1-40 was used for next step without further purification.
Synthesis of 3-amino-6-(2-thieny1)-N-[3-(trifluoromethyl)phenyl]thieno[2,3-b]pyridine-2-carboxamidine (319):

[0000206] See procedure used for the synthesis of 1-6.
Example 30 - Synthesis of Compound 326 CI
H2N CF3 >)ci 0,LNH cF3 0 Cr __________________________________________________ >10)N

CI OH
cr0 (0 HO) 010 CF3 1-23 TFA

"5 326 Synthesis of tert-butyl 2-[3-(trifluoromethyl)anilino]acetate (1-41):

[0000207] 3-(trifluoromethyl)benzenamine (5.0 g, 31 mmol), tert-butyl 2-chloroacetate (33 g, 172 mmol) and K2CO3 (35 g.
253 mmol) in acetone (200 mL) was heated to 60 C overnight and then the solid was removed by filtration. The filtrate was concentrated and the residue was purified by silica gel column chromatography eluting 5:1 hexane/MTBE to yield 10g of 1-41 as a yellowish oil (quantitative yield).
Synthesis of tert-butyl 2-[N-(2-chloroacety1)-3-(trifluoromethyl)anilino]acetate (1-42):

[0000208] To compound 1-41 (5 g, 18 mmol) and 2-chloroacetyl chloride (3.0 g, 27 mmol) in DCM (100 mL) was added a catalytic amount of tetrabutylammonium hydrosulfate followed by a solution of K2CO3 ( 5 g, 36 mmol) in water (100 mL). The reaction mixture was stirred at room temperature for 40 min and the organic portion was isolated and concentrated which was combined with another reaction product done on the same scale.
The residue was purified via silica gel column chromatography eluting with 5:1 hexanes/MTBE to give 8g of 1-42 as a yellowish oil (62% yield).
Synthesis of 2-[N-(2-chloroacety1)-3-(trifluoromethyl)anilino]acetic acid (1-43):

[0000209] To a solution of compound 1-42 (1.0 g, 2.8 mmol) in DCM was added 10 mL of TFA. The resulting mixture was stirred at room temperature for 2 h and then the solvents were removed.
The crude mixture was used for the next step directly.
Synthesis of 2-[N-[3-amino-6-(2-thienyl)benzothiophene-2-carbony1]-3-(trifluoromethyl)anilino]acetic acid (326):

[0000210] To a crude mixture of compound 1-43, compound 1-23 (0.4 g, 1.8 mmol), K2003 ( 8 g, 58 mmol), was added DMF (20 mL). The reaction mixture was stirred at 50 C for 1 h, then diluted with water (200 mL) and acidified with 2N HC1 to pH 2.
The solid was collected, triturated with of 1:1 THF/MTBE (40 mL) to give 120 mg of 326 as the potassium salt (14% yield).
Synthesis of 8-(2-thieny1)-4-[3-(trifluoromethyl)pheny1]-1,3-dihydrobenzothiopheno[3,2-e][1,4]diazepine-2,5-dione (320):

[0000211] This was a by-product formed resulting from intramolecular cyclization of the ethyl ester version of compound 326. After performing base catalyzed hydrolysis of the ester group of this intermediate, compound 320 was the major product isolated. Note: originally this was an alternate scheme to synthesize compound 326.
Example 31 - Synthesis of Compound 322 1-23 ,N

Synthesis of 2-chloro-N-methyl-N-[3-(trifluoromethyl)phenyl]acetamide (1-49):

[0000212] 3-(trifluoromethyl)-N-methylbenzenamine (3.0 g, 28 mmol) and 2-chloroacetyl chloride (12.6 g, 112 mmol) in 30 mL
of DCM was added a catalytic amount of tetrabutylammonium hydrosulfate, followed by a solution of K2003 ( 15 g, 112 mmol) in 100 mL of water. The reaction mixture was stirred at room temperature for 40 min and the DCM layer was collected and combined with another same scale reaction. The residue was purified through a silica gel column eluting with 5:1 hexane/MTBE to give 2.7 g of 1-49 as a yellowish oil (38%
yield).
Synthesis of 3-amino-N-methy1-6-(2-thieny1)-N-[3-(trifluoromethyl)phenyl]thieno[2,3-b]pyridine-2-carboxamide (322):

[0000213] To a mixture of compound 1-49 (2.7 g, 10.7 mmol) and 1-23 (1.5 g, 7.2 mmol) in 20 mL of Et0H was added 15 mL of 21%
Na0Et in Et0H. The reaction mixture was heated for 2 h and then filtered. The solid was washed 20 mL of Et0H and dried to give 1.8 g of 322 (58% yield).
Example 32 - Synthesis of Compound 323 CF3 CF=3 CF3 I (F?
HN LiAIH4 HN
Br Br TEA 1-50 ¨N
1-51 TEA, DCM
¨N1 Th\I
/NH2?CF3 Br/ NJ \ 1) 1-23, K2003, DMF ' Nsj-.(1\1= CF3 S\ 0 1-52 2) 4M HCI in dioxane 323 ¨N
Synthesis of 2-(dimethylamino)-N-[3-(trifluoromethyl)phenyl]acetamide (1-50):

[0000214] To a solution of 2-(N,N-dimethylamino)-acetylchloride (25 g, 160 mmol) and TEA (14 mL, 100 mmol) in anhydrous DCM (100 mL) at 0 C was added dropwise 3-(trifluoromethyl)-aniline (15 g, 93 mmol). The contents were slowly warmed to room temperature while stirring overnight. The reaction mixture was washed with water (2 x 20 mL), a saturated sodium bicarbonate solution, dried (Na2SO4), filtered and concentrated. Crude 1-50 (20 g) was obtained and used in the next step as such.
Synthesis of N',N'-dimethyl-N-[3-(trifluoromethyl)phenyl]ethane-1,2-diamine (1-51):

[0000215] To a solution of crude 1-50 (20 g) in anhydrous THF
(200 mL) at 0 C was added dropwise a solution of LiA1H4 (1M
solution in THF, 186 mL, 186 mmol) and the contents were slowly warmed to 70 C and refluxed overnight. The contents were cooled to 0 C, quenched with the addition of a saturated sodium potassium tartrate solution and filtered through a pad of Celite. The clear solution was concentrated and the residue was partitioned between Et0Ac (500 mL) and water (100 mL). The layers were separated and the organic layer was washed with a saturated NaHCO3 solution, dried (Na2SO4), filtered and concentrated. The residue obtained was left at high-vacuum overnight affording the desired intermediate 1-51 (8 g) as a brown oil.
Synthesis of 2-bromo-N-(2-dimethylaminoethyl)-N-[3-(trifluoromethyl)phenyl]acetamide (1-52):

[0000216] See procedure used for the synthesis of 1-5.
Synthesis of 3-amino-N-(2-dimethylaminoethyl)-6-(2-thieny1)-N-[3-(trifluoromethyl)phenyl]thieno[2,3-b]pyridine-2-carboxamide (323):

[0000217] To a mixture of 1-23 and 1-52 in anhydrous DMF (30 mL) at room temperature was added K2003 (13.8 g, 100 mmol) and the contents were stirred at 90 C for 2 days. The contents were cooled to room temperature and poured into ice-cold water.
The solid obtained was filtered, washed with MTBE (3 x 50 mL) and dried. The orange solid obtained (1.5 g) was treated with 4M HC1 in dioxane (20 mL) at room temperature for 5 h and filtered. The orange solid was dried under high-vacuum affording 323 as the HC1 salt (1.2 g).
Example 33 - Synthesis of Compound 324 NC"(NH2 co NCCN Ac20 NCrCN

1-53 H2N N SH AcHN N SH

Br Br NH2 1-56 NC HN Br AcHN N 0 Synthesis of 2-amino-4-(2-fury1)-6-sulfanyl-pyridine-3,5-dicarbonitrile (1-54):

[0000218] Fufural (3.0 g, 31mmol), 2-cyanoethanethioamide (6.0 g, 60 mmol) and 5 mL of 4-methylmorpholine in 50 mL of Et0H was heated at 80 C for 6 h. The reaction mixture was added to water (200 mL) and acidified with 2N HC1 to pH 2. The resulting solid was collected, washed with water (20 mL), and dried to afford 3.3 g of 1-54 (44% yield).
Synthesis of N-[3,5-dicyano-4-(2-fury1)-6-sulfany1-2-pyridyl]acetamide (1-55):

[0000219] To a suspension of compound 1-54 (3.3 g, 13 mmol) in 50 mL of DCM was added 5 mL of pyridine followed by 3 mL of acetic anhydride. The reaction mixture was stirred for 2 h and filtered. The solid was collected and triturated with Et0H (50 mL) at 60 C for 30 minutes. The solid was collected and dried to give 2.5 g of 1-55 (67% yield).
Synthesis of 6-acetamido-3-amino-N-(4-bromopheny1)-5-cyano-4-(2-furyl)thieno[2,3-b]pyridine-2-carboxamide (324):

[0000220] To a solution of 2-bromo-N-(4-bromophenyl)acetamide (1 g, 3.52 mmol, 2 eq) and 1-55 (0.5 g, 1.76 mmol, 1 eq) in anhydrous DMF (20 mL), was added K2CO3 (0.36 g, 2.64 mmol, 1.5 eq) at room temp. The reaction mixture was heated at 80 'C for 2 h and then evaporated in vacuo. The residue was treated with ice water, stirred and the solid was collected by filtration.

The solid was triturated with Et0Ac to afford 95 mg of compound 324 (11% yield) as a light brown solid.

[0000221] The intermediate 2-bromo-N-(4-bromophenyl)acetamide was prepared as follows: To a solution of 4-bromo aniline (20 g, 116.3 mmol, 1 eq) in anhydrous DCM (200 mL) and TEA (24.3 mL, 174.5 mmol, 1.5 eq) at 0 C, was added bromoacetyl bromide (11.1 mL, 127.9 mmol, 1.1 eq) dropwise over 30 min. The reaction mixture was stirred at room temperature for 2 h.
Volatiles were removed under reduced pressure and the residue was partitioned between Et0Ac and water. The layers were separated and the organic layer was washed with brine, dried (Na2SO4), filtered and concentrated to afford 24 g of 2-bromo-N-(4-bromophenyl)acetamide as a dark brown solid.
Example 34 - Synthesis of Compound 325 o o s Co NO / ). 2N CN
)./ ......ir H Et0 CN Et0 1 CN H
________________ ).- I > Nr 1 CO
1-56 NH2 =
_,.. NC HN=

Br I , \
HO-----.N..------s \o Synthesis of Ethyl 2-cyano-3-(2-furyl)prop-2-enoate (1-57):

[0000222] To a mixture of fufural (5 g, 52 mmol) and ethyl 2-cyanoacetate (5 g, 44 mmol) in Et0H (50 mL) was added TEA (0.5 mL). The reaction mixture was stirred for 30 minutes. The resulting white solid was collected and dried to give 6 g of 1-57 (71% yield).
Synthesis of 4-(2-fury1)-2-hydroxy-6-thioxo-1H-pyridine-3,5-dicarbonitrile (1-58):

[0000223] See procedure for 1-54.
Synthesis of 3-amino-N-(4-bromopheny1)-5-cyano-4-(2-fury1)-6-hydroxy-thieno[2,3-b]pyridine-2-carboxamide (325):

[0000224] To a mixture of 1-58 (750 mg, 3.0 mmol), 1-56 (1.0 g. 4.0 mmol), K2003(2.1 g, 15 mmol) was added DMF (15 mL). The resulting mixture was stirred at 50 C for 2 h, diluted with water (1000 mL) and acidified to a pH 2. The solid was collected and dried to give 250 mg of 325 as brown solid (18%
yield).
Example 35 - Synthesis of Compound 327 CI

H2N CF3 EtO)Br Et0 N CF3 CI). Et0 N CF3 CO2Et CO2H
/NH2.) NH2?
1-23 r NaOH I N CF3 io c3 S
µ-6 Synthesis of Ethyl 3-[3-(trifluoromethyl)anilino]propanoate (1-59):

[0000225] To a solution of ethyl 3-bromopropanoate (10 g, 60 mmol) and 3-(trifluoromethyl)benzenamine (5 g, 31 mmol) in DMF
(100 mL) was added K2003 (10 g, 77 mmol). The resulting mixture was heated to 120 C for 2 days. The solid was removed by filtration, washed with MTBE (200 mL), and the filtrate was diluted with water (1000 mL). The organic layer was collected, dried, filtered, and concentrated. The crude mixture was purified by silica gel column chromatography eluting 15:1 hexanes/MTBE to give 2 g of 1-59 as a yellow oil (25% yield).
Synthesis of ethyl 3-[N-(2-chloroacety1)-3-(trifluoromethyl)anilino]propanoate (1-60):

[0000226] To a solution of 1-59 (2 g, 7.6 mmol), 2-chloroacetyl chloride (3.4 g, 30 mmol), a catalytic amount of tetrabutylammonium hydrosulfate in 40 mL of DCM was added a solution of K2CO3 (4.0 g, 30 mmol) in water (40 mL). The resulting mixture was stirred at room temperature for 40 min and then the organic layer was collected and concentrated. The crude mixture was purified through silica gel column chromatography eluting 4:1 hexanes/MTBE to give 2.8 g of 1-60 as a yellow oil in quantitative yield.
Synthesis of Ethyl 3-[N-[3-amino-6-(2-thienyl)thieno[2,3-b]pyridine-2-carbony1]-3-(trifluoromethyl)-anilino]propanoate (1-61):

[0000227] To a mixture of 1-60 (2.8 g, 8.3 mmol), 1-23 (1.5 g, 6.9 mmol), and K2003 (11.5 g, 83 mmol) was added 25 mL of DMF.
The resulting mixture was stirred at 50 C for 2 h and then diluted with water (1000 mL). Following extraction with Et0Ac (1000 mL), the combined organic layers were dried, filtered, and concentrated. The crude mixture was triturated with MTBE to give 2 g of 1-61 as a yellow solid (56% yield).
Synthesis of 3-[N-[3-amino-6-(2-thienyl)thieno[2,3-b]pyridine-2-carbony1]-3-(trifluoromethyl)-anilino]propanoic acid (327):

[0000228] To solution of 1-61 (500 mg, 0.96 mmol) in THF was added 40 a 4N NaOH solution (40 mL). The resulting mixture was stirred at room temperature overnight. Solvents were removed and the solid was collected, washed with water (50 mL), THF (5 mL), and dried to give 400 mg of 327 as yellow solid (85%
yield).
Example 36 - Synthesis of Compounds 329 and 330 Pd(PPh3)4 DMFDMA
HO/ NaOH 0 dppe ' eX,Xs 0 .CN -\\ NH

H2N) CN 0 N-N
, _____________________________________ õ, = N-N

OH

H S DAST H S
NaB1-14 \ I N I
N-N N-N

Synthesis of 8-oxabicyclo[5.1.0]octan-6-one (1-63):

[0000229] To a solution of cyclohept-2-enone (6.0 g, 45.5 mmol) in Me0H (40 mL) was added 13.6 ml of H202 at -4 C, followed by 7 mL of 10% NaOH solution. The resulting mixture was stirred at room temperature for 1 h, diluted with brine (1000 mL), and extracted with MTBE (2 x 200 mL). The combined organic layers were dried, filtered, concentrated and the crude material was purified by silica gel column chromatography eluting 15:1 hexanes/MTBE to give 5.5 g of 1-63 as a yellowish oil (96% yield).
Synthesis of Cycloheptane-1,3-dione (1-64):

[0000230] To a solution of 1-63 (6.0 g, 47 mmol) in toluene (18 mL) was added Pd(PPh3)4 (2.7 g, 2.35 mmol) and 1,2-bis(diphenylphosphino)ethane (1.0 g, 2.35 mmol). The reaction was bubbled with N2 for 10 min, sealed in a 75 mL pressure tube and heated at 100 C overnight. The reaction was cooled to room temperature and the solid was filtered off. The filtrate was collected, concentrated and purified by silica gel column chromatography eluting 1:10 hexanes/diethyl ether to give 5.0 g of crude product. This material was distilled to give 3.0 g of 1-64 as a yellowish oil which was used in the next step directly.
Synthesis of 2-(dimethylaminomethylene)cycloheptane-1,3-dione (1-65):

[0000231] A solution of 1-64 (3.0 g, 23.8 mmol) in N,N-dimethylformamide dimethyl acetal (30 mL) was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo, the solid was collected and washed with 1:1 of hexane/diethyl ether (50 mL) to give 3.4 g of 1-65 as a yellowish solid (79% yield).
Synthesis of 5-oxo-2-thioxo-6,7,8,9-tetrahydro-1H-cyclohepta[b]pyridine-3-carbonitrile (1-66):

[0000232] See procedure used for the synthesis of 1-14.
Synthesis of 3-[N-[3-amino-6-(2-thienyl)thieno[2,3-b]pyridine-2-carbony1]-3-(trifluoromethyl)anilino]propanoic acid (328):

[0000233] See procedure used for the synthesis of 1-6.
Synthesis of 3-amino-5-oxo-N-(5-pheny1-1,3,4-thiadiazol-2-y1)-6,7,8,9-tetrahydro-5H-cyclohepta[b]thieno[3,2-e]pyridine-2-carboxamide (329):

[0000234] To a solution of 328 (100 mg, 0.23 mmol) in Et0H was added NaBH4 (100 mg, 2.6 mmol) and the reaction mixture was stirred at room temperature for 40 min and then quenched with a saturated NH4C1 solution (20 mL). The solid was collected, washed with water (20 mL), and dried to give 110 mg of 329 as a yellow solid in quantitative yield.
Synthesis of 3-amino-5-hydroxy-N-(5-pheny1-1,3,4-thiadiazol-2-y1)-6,7,8,9-tetrahydro-5H-cyclohepta[b]thieno[3,2-e]pyridine-2-carboxamide (330):

[0000235] To a solution of 329 (640 mg, 1.47 mmol) in DCM (60 mL) was added XtalFluor-E (503 mg, 2.2 mmol). The resulting mixture was stirred at room temperature for 40 min and then concentrated. The crude material was purified by silica gel column chromatography eluting DCM/THF to give 30 mg of 330 as a yellow solid (5% yield).
Example 37 - Synthesis of Compounds 331, 333-338, 340-344, 347-349, 351-353 and 356 0 OMe 1) Piperidine CN
N
,z,,"I I
) I 1 2) CCN Z
OMe f N SH
CI 1_67CI 1-68 H2N's ci 1-69 Z=CorN Z=CorN AcOH, Et0H Z=CorN

R5, R

X,Y=CorN NH2 Br.)(N) R2 y.

\ X,Y=CorN
Na0Et, Et0H f CI Z=CorN R1 R2 331, 333, 334, 335, 336, 337, 338, 340, 341, 342, 343, 344, 347, 348, 349, 351, 352, 353, 356 Synthesis of 1-(4-chloropheny1)-3-(dimethylamino)prop-2-en-1-one (1-68):

[0000236] See procedure used for intermediate 1-37.
Synthesis of 6-(4-chloropheny1)-2-sulfanyl-pyridine-3-carbonitrile (1-69):

[0000237] A solution of compound 1-68 (5 g, 23.84 mmol, 1.0 equiv.) in piperidine (18 mL) was refluxed for 2 h. The reaction mixture was cooled to ambient temp, concentrated under vacuum, and azeotroped with Et0H. To the crude intermediate was added Et0H (100 mL), 2-cyanothioacetamide (2.9 g, 28.6 mmol, 1.2 equiv.), and AcOH (1.7 mL). The mixture was refluxed for 16 h, cooled to room temperature, poured into an ice/water mixture (200 mL) and stirred for 15 minutes. Solids were removed by filtration, washed with water, and triturated with Et0H (50 mL) followed by 1:1 Et0Ac/Hex mixture. The solids were dried under vacuum to give 4.3 g of compound 1-69 (73% overall yield).

General procedure for compounds 331, 333, 334, 335, 336, 337, 338, 340, 341, 342, 343, 344, 347, 348, 349, 351, 352, 353, 356

[0000238] For the synthesis of final compounds see the procedure used for intermediate 1-6. Compound 334 required an additional step involving hydrolysis of the ester following the cyclization reaction. Note: The bromoacetamide intermediate used in the final reaction was synthesized using the same procedure used for the synthesis of 1-24. Please note some compounds required reduction of the parent nitro moiety to the corresponding amine and was based upon commercial availability of the starting materials.
Example 38 - Synthesis of Compounds 332, 339 and 345 N OMe / 1\1 , ,r H2N,S I , 0 OMe 1... 410 0 DI. SI
Piperidine N SH

OR OR Et0H OR
R = CHF2 or CF3 R = CHF2 or CF3 R = CHF2 or CF3 Br 0 \
\ ______ l< 1 0 N S 4. OR' 332, 339, 345 _____________________ a-Na0Et, Et0H OR R = CHF2 or CF3 The same experimental procedures used for the compounds above (i.e., 331, 333, 334, etc.) were used for the synthesis of compounds 332, 339, and 345.
Example 39 - Synthesis of Compound 346 02N 40 ON H2N 5 Br(Br ,CI OH Fe/NH4CI 0 S
N a H CO
1-73 0* PyTrHidFine //sµµ0 1-75 Et0H/H20 3 ON

Br.rp N SH

HN N S
CI

1-76 s Na0Et 1-77 //S\\

C/1"0 DOH

i) NaOH, H20, Me0H I I H

____________________ 71- 01 N S
ii) neutralize with HCI 0 101 ,OH

'µ.

Synthesis of p-tolyl 4-nitrobenzenesulfonate (1-74):

[0000239] To a solution of compound 1-73 (4 g, 37 mmol), pyridine (4.5 mL) and THF (50 mL) was added a solution of p-cresol (9.8 g) in THF (25 mL) slowly over 10 min at 0 C. The reaction mixture was allowed to reach ambient temp and then heated to 65 C for 48 h. The reaction was stopped by adding a saturated aqueous NH4C1 solution and extracted with Et0Ac. The organic layer was washed with brine, dried over Na2SG4, filtered and concentrated under vacuum to give a residue. The residue was purified by silica gel column chromatography eluting with 0-50% Et0Ac/Hexanes to give 7.7 g of compound 1-74.
Synthesis of p-tolyl 4-aminobenzenesulfonate (1-75):

[0000240] To a mixture of compound 1-74 (2 g, 6.8 mmol, 1.0 equiv.) in EtGH (40 mL) was added a solution of NH4C1 (1.5 g, 27 mmol, 4.0 equiv.) in 10 mL of water followed by iron (1.5 g, 27 mmol, 4.0 equiv.). The reaction mixture was heated to 80 C
for 20 min, cooled to ambient temp, filtered through a pad of Celite, and then washed with MeGH and DCM. The combined filtrates were concentrated under vacuum and extracted with DCM. The organic portion was washed with water, dried (Na2SO4), filtered and concentrated under vacuum to give crude material.
The crude product was purified by silica gel column chromatography to give 1.1 g of compound 1-75 (61% yield).
Synthesis of p-tolyl 4-[(2-bromoacetyl)amino]benzenesulfonate (1-76):

[0000241] To a solution of compound 1-75 (1.1 g, 4.2 mmol, 1.0 equiv.) in THF (100 mL) was added NaHCO3 (5.3 g, 6.3 mmol, 1.5 equiv.) and bromoacetyl bromide (0.44 mL, 5.02 mmol, 1.2 equiv.) at 0 C. The reaction mixture was warmed to ambient temp and stirred for 16 h. The reaction mixture was filtered through a pad of Celite, washed with DCM, and the combined filtrates were concentrated under vacuum to give crude compound 1-76. This material was carried to next step without further purification.
Synthesis of p-tolyl 4-[[3-amino-6-(4-chlorophenyl)thieno[2,3-b]pyridine-2-carbonyl]amino]-benzenesulfonate (1-77):

[0000242] See procedure used for the synthesis of 1-6.
Synthesis of 4-[[3-amino-6-(4-chlorophenyl)thieno[2,3-b]pyridine-2-carbonyl]amino]benzenesulfonic acid (346):

[0000243] A mixture of compound 1-77 (425 mg), 10 mL of 20%
NaOH in water and Me0H (10 mL) was heated to 80 C for 14 h.
The mixture was cooled to ambient temperature and the solids were removed by filtration, washed with water, DCM, hexanes and dried under vacuum. The solids were suspended in water (5 mL) and acidified with 3N HC1 to adjust the pH to 2-3 and stirred for 30 min. The solids were filtered, washed with water, DCM
and hexanes. The solids were dried under vacuum at 35 C for 14 h to give 210 mg of 346 (59% overall yield).
Example 40 - Synthesis of Compounds 350, 354 and 355 CI
ce H
H2N 0 Et0 N 0 CI )-CI Et0 N 0 EtO)Br ____________________________ 0 _),..

R = Br, CI, or OCF3 R = Br, Cl, or OCF3 R = Br, Cl, or CO2Et CO2H
......CN NH2 ? NH2 ?
I, I \ " NaOH 0 N 0 -)... I
R' R'CI or OCH3 N S 0 R 0 N S 0 R
=
_______ 1.-R 1-81 R = Br, CI, or OCF3 CI 350, 354, 355 R = Br, CI, or OCF3

[0000244] The same experimental procedures used for the compound 327 were used for the synthesis of compounds 350, 354, and 355.

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[0000245] All references cited herein are herein incorporated by reference in their entirety for all purposes.

[0000246] The invention has been described in terms of preferred embodiments thereof, but is more broadly applicable as will be understood by those skilled in the art. The scope of the invention is only limited by the following claims.

Claims (57)

WHAT IS CLAIMED IS:

1. A
compound having the following general Formula III or a pharmaceutically acceptable salt thereof:
wherein X is selected from the groups consisting of:
O, S and N-R', wherein R' is selected from the groups consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, aryl, heteroaryl, acyl, arylacyl, heteroarylacyl, sulfonyl, aminosulfonyl, substituted aminosulfonyl, alkoxycarbonyl, cycloalkyloxycarbonyl, aryloxycarbonyl, carbamoyl and substituted carbamoyl;
R is selected from the group consisting of halogen, cyano, isocyano, nitro, amino, alkylamino, dialkylamino, cycloalkylamino, heterocycloalkylamino, arylamino, heteroarylamino, acylamino, arylacylamino, heteroarylacylamino, alkylsulfonylamino, arylsulfonylamino, hydroxysulfonyl, aminosulfonyl, substituted aminosulfonyl, acyl, arylacyl, heteroarylacyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl, aryloxycarbonyl, aminocarbonyl, and substituted aminocarbonyl;

B, D, and E are independently N or C-R2, C-R3 and C-R4, respectively, wherein R2, R3 and R4 are independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, aryl, heteroaryl, hydroxy, alkyloxy, aryloxy, heteroaryloxy, acyloxy, arylacyloxy, heteroarylacyloxy, alkylsulfonyloxy, arylsulfonyloxy, thio, alkylthio, arylthio, amino, alkylamino, dialkylamino, cycloalkylamino, heterocycloalkylamino, arylamino, heteroarylamino, acylamino, arylacylamino, heteroarylacylamino, alkylsulfonylamino, arylsulfonylamino, acyl, arylacyl, heteroarylacyl, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, substituted aminosulfonyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl, aryloxycarbonyl, carbamoyl, substituted carbamoyl, halogen, cyano, isocyano and nitro;
or R2 and R3 or R3 and R4 together with the carbons they are attached to may form a substituted or unsubstituted ring, which may be aromatic or non-aromatic and may include one or more heteroatoms in the ring and may be fused with an aromatic or aliphatic ring; and R10 and R11 are independently selected from the groups consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, aryl, heteroaryl, acyl, arylacyl, heteroarylacyl, sulfonyl, aminosulfonyl, substituted aminosulfonyl, alkoxycarbonyl, cycloalkyloxycarbonyl, aryloxycarbonyl, carbamoyl and substituted carbamoyl, provided that R10 and R11 can't both be hydrogen.

2. The compound of claim 1, wherein X is S.

3. The compound of claim 1, wherein B is C-H.

4. The compound of claim 1, wherein D is a C-H.

5. The compound of claim 1, wherein E is C-R4 and R4 is a heteroaryl.

6. The compound of claim 1, wherein D is C-R3 and E is C-R4, and R3 and R4 form a ring.

7. The compound of claim 1, wherein R is a substituted aminocarbonyl.

8. The compound of claim 1 being 3-[N-[3-amino-6-(2-thienyl)thieno[2,3-b]pyridine-2-carbonyl]-3-(trifluoromethyl)anilino]propanoic acid.

9. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound having the following general Formula III or a pharmaceutically acceptable salt thereof:
wherein X is selected from the groups consisting of:
O, S and N-R', wherein R' is selected from the groups consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, aryl, heteroaryl, acyl, arylacyl, heteroarylacyl, sulfonyl, aminosulfonyl, substituted aminosulfonyl, alkoxycarbonyl, cycloalkyloxycarbonyl, aryloxycarbonyl, carbamoyl and substituted carbamoyl;
R is selected from the group consisting of halogen, cyano, isocyano, nitro, amino, alkylamino, dialkylamino, cycloalkylamino, heterocycloalkylamino, arylamino, heteroarylamino, acylamino, arylacylamino, heteroarylacylamino, alkylsulfonylamino, arylsulfonylamino, hydroxysulfonyl, aminosulfonyl, substituted aminosulfonyl, acyl, arylacyl, heteroarylacyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl, aryloxycarbonyl, aminocarbonyl, and substituted aminocarbonyl;
B, D, and E are independently N or C-R2, C-R3 and C-R4, respectively, wherein R2, R3 and R4 are independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, aryl, heteroaryl, hydroxy, alkyloxy, aryloxy, heteroaryloxy, acyloxy, arylacyloxy, heteroarylacyloxy, alkylsulfonyloxy, arylsulfonyloxy, thio, alkylthio, arylthio, amino, alkylamino, dialkylamino, cycloalkylamino, heterocycloalkylamino, arylamino, heteroarylamino, acylamino, arylacylamino, heteroarylacylamino, alkylsulfonylamino, arylsulfonylamino, acyl, arylacyl, heteroarylacyl, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, substituted aminosulfonyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl, aryloxycarbonyl, carbamoyl, substituted carbamoyl, halogen, cyano, isocyano and nitro;
or R2 and R3 or R3 and R4 together with the carbons they are attached to may form a substituted or unsubstituted ring, which may be aromatic or non-aromatic and may include one or more heteroatoms in the ring and may be fused with an aromatic or aliphatic ring; and R10 and R11 are independently selected from the groups consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, aryl, heteroaryl, acyl, arylacyl, heteroarylacyl, sulfonyl, aminosulfonyl, substituted aminosulfonyl, alkoxycarbonyl, cycloalkyloxycarbonyl, aryloxycarbonyl, carbamoyl and substituted carbamoyl, provided that R10 and R11 can't both be hydrogen, wherein said composition is suitable for human or animal administration.

10. The composition of claim 9, wherein X is S.

11. The composition of claim 9, wherein B is C-H.

12. The composition of claim 9, wherein D is a C-H.

13. The composition of claim 9, wherein E is C -R4 and R4 is a heteroaryl.

14. The composition of claim 9, wherein D is C-R3 and E is C-R4, and R3 and R4 form a ring.

15. The composition of claim 9, wherein R is a substituted aminocarbonyl.

16. The composition of claim 9, wherein said compound is 3-[N-[3-amino-6-(2-thienyl)thieno[2,3-b]pyridine-2-carbonyl]-3-(trifluoromethyl)anilino]propanoic acid.

17. A method for the treatment of at least one type of a Dengue virus infection or disease associated therewith, comprising administering in a therapeutically effective amount to a mammal in need thereof, a compound of Formula III below or a pharmaceutically acceptable salt thereof:
wherein X is selected from the groups consisting of:
O, S and N-R', wherein R' is selected from the groups consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, aryl, heteroaryl, acyl, arylacyl, heteroarylacyl, sulfonyl, aminosulfonyl, substituted aminosulfonyl, alkoxycarbonyl, cycloalkyloxycarbonyl, aryloxycarbonyl, carbamoyl and substituted carbamoyl;

R is selected from the group consisting of halogen, cyano, isocyano, nitro, amino, alkylamino, dialkylamino, cycloalkylamino, heterocycloalkylamino, arylamino, heteroarylamino, acylamino, arylacylamino, heteroarylacylamino, alkylsulfonylamino, arylsulfonylamino, hydroxysulfonyl, aminosulfonyl, substituted aminosulfonyl, acyl, arylacyl, heteroarylacyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl, aryloxycarbonyl, aminocarbonyl, and substituted aminocarbonyl;
B, D, and E are independently N or C -R2, C-R3 and C-R4, respectively, wherein R2, R3 and R4 are independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, aryl, heteroaryl, hydroxy, alkyloxy, aryloxy, heteroaryloxy, acyloxy, arylacyloxy, heteroarylacyloxy, alkylsulfonyloxy, arylsulfonyloxy, thio, alkylthio, arylthio, amino, alkylamino, dialkylamino, cycloalkylamino, heterocycloalkylamino, arylamino, heteroarylamino, acylamino, arylacylamino, heteroarylacylamino, alkylsulfonylamino, arylsulfonylamino, acyl, arylacyl, heteroarylacyl, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, substituted aminosulfonyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl, aryloxycarbonyl, carbamoyl, substituted carbamoyl, halogen, cyano, isocyano and nitro;
or R2 and R3 or R3 and R4 together with the carbons they are attached to may form a substituted or unsubstituted ring, which may be aromatic or non-aromatic and may include one or more heteroatoms in the ring and may be fused with an aromatic or aliphatic ring; and R10 and R11 are independently selected from the groups consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, aryl, heteroaryl, acyl, arylacyl, heteroarylacyl, sulfonyl, aminosulfonyl, substituted aminosulfonyl, alkoxycarbonyl, cycloalkyloxycarbonyl, aryloxycarbonyl, carbamoyl and substituted carbamoyl,provided that R10 and R11 can't both be hydrogen.

18. The method of claim 17, wherein X is S.

19. The method of claim 17, wherein B is C-H.

20. The method of claim 17, wherein D is a C-H.

21. The method of claim 17, wherein E is C -R4 and R4 is a heteroaryl.

22. The method of claim 17, wherein D is C-R3 and E is C-R4, and R3 and R4 form a ring.

23. The method of claim 17, wherein R is a substituted aminocarbonyl.

24. The method of claim 17, wherein said compound is 3-[N-[3-amino-6-(2-thienyl)thieno[2,3-b]pyridine-2-carbonyl]-3-(trifluoromethyl)anilino]propanoic acid.

25. The method of claim 17, wherein the mammal is a human.

26. The method of claim 17, wherein said Dengue virus is selected from the group consisting of DEN-1, DEN-2, DEN-3, and DEN-4.

27. The method of claim 17, wherein said viral infection is associated with Dengue fever.

28. The method of claim 27, wherein said Dengue fever is selected from the group consisting of classical dengue fever and dengue hemorrhagic fever.

29. The method of claim 17, which further comprises co-administration of at least one agent selected from the group consisting of antiviral agent, vaccine, and interferon.

30. The method of claim 29, wherein said interferon is pegylated.

31. A compound selected from the group consisting of: 3-amino-N-cyclohexyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]thieno[3,2-e]pyridine-2-carboxamide; 3-amino-N-butyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]thieno[3,2-e]pyridine-2-carboxamide; 3-amino-N-(tert-butyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]thieno[3,2-e]pyridine-2-carboxamide; 3-amino-6-methyl-N-(5-phenyl-1,3,4-thiadiazol-2-yl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-5-methyl-N-(5-phenyl-1,3,4-thiadiazol-2-yl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-4-methoxy-N-(5-phenyl-1,3,4-thiadiazol-2-yl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-4-methyl-N-(5-phenyl-1,3,4-thiadiazol-2-yl)thieno[2,3-b]pyridine-2-carboxamide; 3,5-diamino-N-(5-phenyl-1,3,4-thiadiazol-2-yl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-2-((5-phenyl-1,3,4-thiadiazol-2-yl)carbamoyl)thieno[2,3-b]pyridine-5-carboxylic acid; 3-amino-6-chloro-N-(5-phenyl-1,3,4-thiadiazol-2-yl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-methyl-N-(5-phenyl-1,3,4-thiadiazol-2-yl)-7,8-dihydro-5H-thieno[2,3-b][1,6]naphthyridine-2-carboxamide; 2-(thiophen-2-yl)-10-(3-(trifluoromethyl)phenyl)-7,8-dihydro-5H-pyrido[3',2':4,5]thieno[3,2-b][1,5]diazonine-6,9,11(10H)-trione; 7-(thiophen-2-yl)-3-(3-(trifluoromethyl)phenyl)pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione; 3-amino-6-(trifluoromethyl)-N-[3-(trifluoromethyl)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-(2,4-dimethylthiazol-5-yl)-N-[3-(trifluoromethyl)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-(2-thienyl)-N-[3-(trifluoromethyl)phenyl]thieno[2,3-b]pyridine-2-carboxamidine; 8-(thiophen-2-yl)-4-(3-(trifluoromethyl)phenyl)-3,4-dihydro-1H-pyrido[3',2':4,5]thieno[3,2-e][1,4]diazepine-2,5-dione; 3-amino-N-methyl-6-(2-thienyl)-N-[3-(trifluoromethyl)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 3-amino-N-(2-dimethylaminoethyl)-6-(2-thienyl)-N-[3-(trifluoromethyl)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 6-acetamido-3-amino-N-(4-bromophenyl)-5-cyano-4-(2-furyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-N-(4-bromophenyl)-5-cyano-4-(2-furyl)-6-hydroxy-thieno[2,3-b]pyridine-2-carboxamide; 2-[N-[3-amino-6-(2-thienyl)thieno[2,3-b]pyridine-2-carbonyl]-3-(trifluoromethyl)anilino]acetic acid; 3-[N-[3-amino-6-(2-thienyl)thieno[2,3-b]pyridine-2-carbonyl]-3-(trifluoromethyl)anilino]propanoic acid; 3-amino-5-oxo-N-(5-phenyl-1,3,4-thiadiazol-2-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]thieno[3,2-e]pyridine-2-carboxamide; 3-amino-5-hydroxy-N-(5-phenyl-1,3,4-thiadiazol-2-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]thieno[3,2-e]pyridine-2-carboxamide; 3-amino-5-fluoro-N-(5-phenyl-1,3,4-thiadiazol-2-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]thieno[3,2-e]pyridine-2-carboxamide; 3-amino-6-(4-chlorophenyl)-N-[4-(trifluoromethoxy)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-[3-(trifluoromethoxy)phenyl]-N-[4-(trifluoromethoxy)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 3-amino-N,6-bis(4-chlorophenyl)thieno[2,3-b]pyridine-2-carboxamide; 4-[[3-amino-6-(4-chlorophenyl)thieno[2,3-b]pyridine-2-carbonyl]amino]benzoic acid; 3-amino-N-(5-bromo-2-pyridyl)-6-(4-chlorophenyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-N-(6-bromo-3-pyridyl)-6-(4-chlorophenyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-(4-chlorophenyl)-N-[4-(difluoromethyl)phenyl]thieno[2,3-b]pyridine-2-carboxamide;
3-amino-6-(4-chlorophenyl)-N-[4-(1,1-difluoroethyl)phenyl]thieno[2,3-b]pyridine-2-carboxamide;
3-amino-6-[3-(difluoromethoxy)phenyl]-N-[4-(trifluoromethoxy)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-(4-chlorophenyl)-N-[4-(difluoromethoxy)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 3-amino-N-(2-bromophenyl)-6-(4-chlorophenyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-(4-chlorophenyl)-N-(3,4-dichlorophenyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-(4-chlorophenyl)-N-(2,3-dichlorophenyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-N-(3-chlorophenyl)-6-(4-chlorophenyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-[3-(difluoromethoxy)phenyl]-N-[4-(difluoromethoxy)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 4-[[3-amino-6-(4-chlorophenyl)thieno[2,3-b]pyridine-2-carbonyl]amino]benzenesulfonic acid; 3-amino-6-(4-chlorophenyl)-N-(2,5-dichlorophenyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-(4-chlorophenyl)-N-(3,4-dimethylphenyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-N-(4-bromophenyl)-6-(5-chloro-2-pyridyl)thieno[2,3-b]pyridine-2-carboxamide; 3-(N-[3-amino-6-(4-chlorophenyl)thieno[2,3-b]pyridine-2-carbonyl]-4-bromo-anilino)propanoic acid; 3-amino-6-(4-chlorophenyl)-N-[4-(2,2,2-trifluoroacetyl)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-(4-chlorophenyl)-N-(5-chloro-2-pyridyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-(4-chlorophenyl)-N-(6-chloro-3-pyridyl)thieno[2,3-b]pyridine-2-carboxamide; 3-[N-[3-amino-6-(3-methoxyphenyl)thieno[2,3-b]pyridine-2-carbonyl]-4-(trifluoromethoxy)anilino]propanoic acid; 3-(N-[3-amino-6-(4-chlorophenyl)thieno[2,3-b]pyridine-2-carbonyl]-4-chloro-anilino)propanoic acid; 3-amino-6-(4-chlorophenyl)-N-(4-hydroxyphenyl)thieno[2,3-b]pyridine-2-carboxamide; and 3-amino-N-(4-pyridyl)-6-(2-thienyl)thieno[2,3-b]pyridine-2-carboxamide.

32. The compound of claim 31 being 3-amino-N,6-bis(4-chlorophenyl)thieno[2,3-b]pyridine-2-carboxamide.

33. The compound of claim 31 being 3-amino-6-[3-(difluoromethoxy)phenyl]-N-[4-(difluoromethoxy)phenyl]thieno[2,3-b]pyridine-2-carboxamide.

34. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound selected from the group consisting of: 3-amino-N-cyclohexyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]thieno[3,2-e]pyridine-2-carboxamide; 3-amino-N-butyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]thieno[3,2-e]pyridine-2-carboxamide; 3-amino-N-(tert-butyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]thieno[3,2-e]pyridine-2-carboxamide; 3-amino-6-methyl-N-(5-phenyl-1,3,4-thiadiazol-2-yl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-5-methyl-N-(5-phenyl-1,3,4-thiadiazol-2-yl)thieno[2,3-b]pyridine-2-carboxamide;
3-amino-4-methoxy-N-(5-phenyl-1,3,4-thiadiazol-2-yl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-4-methyl-N-(5-phenyl-1,3,4-thiadiazol-2-yl)thieno[2,3-b]pyridine-2-carboxamide; 3,5-diamino-N-(5-phenyl-1,3,4-thiadiazol-2-yl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-2-((5-phenyl-1,3,4-thiadiazol-2-yl)carbamoyl)thieno[2,3-b]pyridine-5-carboxylic acid; 3-amino-6-chloro-N-(5-phenyl-1,3,4-thiadiazol-2-yl)thieno[2,3-b]pyridine-2-carboxamide;
3-amino-6-methyl-N-(5-phenyl-1,3,4-thiadiazol-2-yl)-7,8-dihydro-5H-thieno[2,3-b][1,6]naphthyridine-2-carboxamide;
2-(thiophen-2-yl)-10-(3-(trifluoromethyl)phenyl)-7,8-dihydro-5H-pyrido[3',2':4,5]thieno[3,2-b][1,5]diazonine-6,9,11(10H)-trione; 7-(thiophen-2-yl)-3-(3-(trifluoromethyl)phenyl)pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione; 3-amino-6-(trifluoromethyl)-N-[3-(trifluoromethyl)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-(2,4-dimethylthiazol-5-yl)-N-[3-(trifluoromethyl)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-(2-thienyl)-N-[3-(trifluoromethyl)phenyl]thieno[2,3-b]pyridine-2-carboxamidine; 8-(thiophen-2-yl)-4-(3-(trifluoromethyl)phenyl)-3,4-dihydro-1H-pyrido[3',2':4,5]thieno[3,2-e][1,4]diazepine-2,5-dione; 3-amino-N-methyl-6-(2-thienyl)-N-[3-(trifluoromethyl)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 3-amino-N-(2-dimethylaminoethyl)-6-(2-thienyl)-N-[3-(trifluoromethyl)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 6-acetamido-3-amino-N-(4-bromophenyl)-5-cyano-4-(2-furyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-N-(4-bromophenyl)-5-cyano-4-(2-furyl)-6-hydroxy-thieno[2,3-b]pyridine-2-carboxamide; 2-[N-[3-amino-6-(2-thienyl)thieno[2,3-b]pyridine-2-carbonyl]-3-(trifluoromethyl)anilino]acetic acid; 3-[N-[3-amino-6-(2-thienyl)thieno[2,3-b]pyridine-2-carbonyl]-3-(trifluoromethyl)anilino]propanoic acid; 3-amino-5-oxo-N-(5-phenyl-1,3,4-thiadiazol-2-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]thieno[3,2-e]pyridine-2-carboxamide; 3-amino-5-hydroxy-N-(5-phenyl-1,3,4-thiadiazol-2-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]thieno[3,2-e]pyridine-2-carboxamide; 3-amino-5-fluoro-N-(5-phenyl-1,3,4-thiadiazol-2-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]thieno[3,2-e]pyridine-2-carboxamide; 3-amino-6-(4-chlorophenyl)-N-[4-(trifluoromethoxy)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-[3-(trifluoromethoxy)phenyl]-N-[4-(trifluoromethoxy)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 3-amino-N,6-bis(4-chlorophenyl)thieno[2,3-b]pyridine-2-carboxamide; 4-[[3-amino-6-(4-chlorophenyl)thieno[2,3-b]pyridine-2-carbonyl]amino]benzoic acid; 3-amino-N-(5-bromo-2-pyridyl)-6-(4-chlorophenyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-N-(6-bromo-3-pyridyl)-6-(4-chlorophenyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-(4-chlorophenyl)-N-[4-(difluoromethyl)phenyl]thieno[2,3-b]pyridine-2-carboxamide;

3-amino-6-(4-chlorophenyl)-N-[4-(1,1-difluoroethyl)phenyl]thieno[2,3-b]pyridine-2-carboxamide;
3-amino-6-[3-(difluoromethoxy)phenyl]-N-[4-(trifluoromethoxy)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-(4-chlorophenyl)-N-[4-(difluoromethoxy)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 3-amino-N-(2-bromophenyl)-6-(4-chlorophenyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-(4-chlorophenyl)-N-(3,4-dichlorophenyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-(4-chlorophenyl)-N-(2,3-dichlorophenyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-N-(3-chlorophenyl)-6-(4-chlorophenyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-[3-(difluoromethoxy)phenyl]-N-[4-(difluoromethoxy)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 4-[[3-amino-6-(4-chlorophenyl)thieno[2,3-b]pyridine-2-carbonyl]amino]benzenesulfonic acid; 3-amino-6-(4-chlorophenyl)-N-(2,5-dichlorophenyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-(4-chlorophenyl)-N-(3,4-dimethylphenyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-N-(4-bromophenyl)-6-(5-chloro-2-pyridyl)thieno[2,3-b]pyridine-2-carboxamide; 3-(N-[3-amino-6-(4-chlorophenyl)thieno[2,3-b]pyridine-2-carbonyl]-4-bromo-anilino)propanoic acid; 3-amino-6-(4-chlorophenyl)-N-[4-(2,2,2-trifluoroacetyl)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-(4-chlorophenyl)-N-(5-chloro-2-pyridyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-(4-chlorophenyl)-N-(6-chloro-3-pyridyl)thieno[2,3-b]pyridine-2-carboxamide; 3-[N-[3-amino-6-(3-methoxyphenyl)thieno[2,3-b]pyridine-2-carbonyl]-4-(trifluoromethoxy)anilino]propanoic acid; 3-(N-[3-amino-6-(4-chlorophenyl)thieno[2,3-b]pyridine-2-carbonyl]-4-chloro-anilino)propanoic acid; 3-amino-6-(4-chlorophenyl)-N-(4-hydroxyphenyl)thieno[2,3-b]pyridine-2-carboxamide; and 3-amino-N-(4-pyridyl)-6-(2-thienyl)thieno[2,3-b]pyridine-2-carboxamide, wherein said composition is suitable for human or animal administration .

35. The composition of claim 34, wherein said compound is 3-amino-N,6-bis(4-chlorophenyl)thieno[2,3-b]pyridine-2-carboxamide.

36. The composition of claim 34, wherein said compound is 3-amino-6-[3-(difluoromethoxy)phenyl]-N-[4-(difluoromethoxy)phenyl]thieno[2,3-b]pyridine-2-carboxamide.

37. A method for the treatment of at least one type of a Dengue virus infection or disease associated therewith, comprising administering in a therapeutically effective amount to a mammal in need thereof, a compound or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of: 3-amino-N-cyclohexyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]thieno[3,2-e]pyridine-2-carboxamide; 3-amino-N-butyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]thieno[3,2-e]pyridine-2-carboxamide; 3-amino-N-(tert-butyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]thieno[3,2-e]pyridine-2-carboxamide; 3-amino-6-methyl-N-(5-phenyl-1,3,4-thiadiazol-2-yl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-5-methyl-N-(5-phenyl-1,3,4-thiadiazol-2-yl)thieno[2,3-b]pyridine-2-carboxamide;
3-amino-4-methoxy-N-(5-phenyl-1,3,4-thiadiazol-2-yl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-4-methyl-N-(5-phenyl-1,3,4-thiadiazol-2-yl)thieno[2,3-b]pyridine-2-carboxamide; 3,5-diamino-N-(5-phenyl-1,3,4-thiadiazol-2-yl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-2-((5-phenyl-1,3,4-thiadiazol-2-yl)carbamoyl)thieno[2,3-b]pyridine-5-carboxylic acid; 3-amino-6-chloro-N-(5-phenyl-1,3,4-thiadiazol-2-yl)thieno[2,3-b]pyridine-2-carboxamide;
3-amino-6-methyl-N-(5-phenyl-1,3,4-thiadiazol-2-yl)-7,8-dihydro-5H-thieno[2,3-b][1,6]naphthyridine-2-carboxamide;
2-(thiophen-2-yl)-10-(3-(trifluoromethyl)phenyl)-7,8-dihydro-5H-pyrido[3',2':4,5]thieno[3,2-b][1,5]diazonine-6,9,11(10H)-trione; 7-(thiophen-2-yl)-3-(3-(trifluoromethyl)phenyl)pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione; 3-amino-6-(trifluoromethyl)-N-[3-(trifluoromethyl)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-(2,4-dimethylthiazol-5-yl)-N-[3-(trifluoromethyl)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-(2-thienyl)-N-[3-(trifluoromethyl)phenyl]thieno[2,3-b]pyridine-2-carboxamidine; 8-(thiophen-2-yl)-4-(3-(trifluoromethyl)phenyl)-3,4-dihydro-1H-pyrido[3',2':4,5]thieno[3,2-e][1,4]diazepine-2,5-dione; 3-amino-N-methyl-6-(2-thienyl)-N-[3-(trifluoromethyl)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 3-amino-N-(2-dimethylaminoethyl)-6-(2-thienyl)-N-[3-(trifluoromethyl)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 6-acetamido-3-amino-N-(4-bromophenyl)-5-cyano-4-(2-furyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-N-(4-bromophenyl)-5-cyano-4-(2-furyl)-6-hydroxy-thieno[2,3-b]pyridine-2-carboxamide; 2-[N-[3-amino-6-(2-thienyl)thieno[2,3-b]pyridine-2-carbonyl]-3-(trifluoromethyl)anilino]acetic acid; 3-[N-[3-amino-6-(2-thienyl)thieno[2,3-b]pyridine-2-carbonyl]-3-(trifluoromethyl)anilino]propanoic acid; 3-amino-5-oxo-N-(5-phenyl-1,3,4-thiadiazol-2-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]thieno[3,2-e]pyridine-2-carboxamide; 3-amino-5-hydroxy-N-(5-phenyl-1,3,4-thiadiazol-2-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]thieno[3,2-e]pyridine-2-carboxamide; 3-amino-5-fluoro-N-(5-phenyl-1,3,4-thiadiazol-2-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]thieno[3,2-e]pyridine-2-carboxamide; 3-amino-6-(4-chlorophenyl)-N-[4-(trifluoromethoxy)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-[3-(trifluoromethoxy)phenyl]-N-[4-(trifluoromethoxy)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 3-amino-N,6-bis(4-chlorophenyl)thieno[2,3-b]pyridine-2-carboxamide; 4-[[3-amino-6-(4-chlorophenyl)thieno[2,3-b]pyridine-2-carbonyl]amino]benzoic acid; 3-amino-N-(5-bromo-2-pyridyl)-6-(4-chlorophenyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-N-(6-bromo-3-pyridyl)-6-(4-chlorophenyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-(4-chlorophenyl)-N-[4-(difluoromethyl)phenyl]thieno[2,3-b]pyridine-2-carboxamide;
3-amino-6-(4-chlorophenyl)-N-[4-(1,1-difluoroethyl)phenyl]thieno[2,3-b]pyridine-2-carboxamide;
3-amino-6-[3-(difluoromethoxy)phenyl]-N-[4-(trifluoromethoxy)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-(4-chlorophenyl)-N-[4-(difluoromethoxy)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 3-amino-N-(2-bromophenyl)-6-(4-chlorophenyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-(4-chlorophenyl)-N-(3,4-dichlorophenyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-(4-chlorophenyl)-N-(2,3-dichlorophenyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-N-(3-chlorophenyl)-6-(4-chlorophenyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-[3-(difluoromethoxy)phenyl]-N-[4-(difluoromethoxy)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 4-[[3-amino-6-(4-chlorophenyl)thieno[2,3-b]pyridine-2-carbonyl]amino]benzenesulfonic acid; 3-amino-6-(4-chlorophenyl)-N-(2,5-dichlorophenyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-(4-chlorophenyl)-N-(3,4-dimethylphenyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-N-(4-bromophenyl)-6-(5-chloro-2-pyridyl)thieno[2,3-b]pyridine-2-carboxamide; 3-(N-[3-amino-6-(4-chlorophenyl)thieno[2,3-b]pyridine-2-carbonyl]-4-bromo-anilino)propanoic acid; 3-amino-6-(4-chlorophenyl)-N-[4-(2,2,2-trifluoroacetyl)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-(4-chlorophenyl)-N-(5-chloro-2-pyridyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-(4-chlorophenyl)-N-(6-chloro-3-pyridyl)thieno[2,3-b]pyridine-2-carboxamide; 3-[N-[3-amino-6-(3-methoxyphenyl)thieno[2,3-b]pyridine-2-carbonyl]-4-(trifluoromethoxy)anilino]propanoic acid; 3-(N-[3-amino-6-(4-chlorophenyl)thieno[2,3-b]pyridine-2-carbonyl]-4-chloro-anilino)propanoic acid; 3-amino-6-(4-chlorophenyl)-N-(4-hydroxyphenyl)thieno[2,3-b]pyridine-2-carboxamide; and 3-amino-N-(4-pyridyl)-6-(2-thienyl)thieno[2,3-b]pyridine-2-carboxamide.

38. The method of claim 37, wherein said compound is 3-amino-N,6-bis(4-chlorophenyl)thieno[2,3-b]pyridine-2-carboxamide.

39. The method of claim 37, wherein said compound is 3-amino-6-[3-(difluoromethoxy)phenyl]-N-[4-(difluoromethoxy)phenyl]thieno[2,3-b]pyridine-2-carboxamide.

40. The method of claim 37, wherein the mammal is a human.

41. The method of claim 37, wherein said Dengue virus is selected from the group consisting of DEN-1, DEN-2, DEN-3, and DEN-4.

42. The method of claim 37, wherein said viral infection is associated with Dengue fever.

43. The method of claim 42, wherein said Dengue fever is selected from the group consisting of classical dengue fever and dengue hemorrhagic fever.

44. The method of claim 37, which further comprises co-administration of at least one agent selected from the group consisting of antiviral agent, vaccine, and interferon.

45. The method of claim 44, wherein said interferon is pegylated.

46. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of: 3-amino-N-(4-bromophenyl)-6-(4-chlorophenyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-(3-methoxyphenyl)-N-[4-(trifluoromethoxy)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 3-amino-N-(2,5-dichlorophenyl)-6-(2-thienyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-N-(2,3-dichlorophenyl)-6-(2-thienyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-N-(4-bromophenyl)-6-(3-methoxyphenyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-(1,3-benzodioxol-5-yl)-N-(2-bromo-4-methyl-phenyl)thieno[2,3-b]pyridine-2-carboxamide; and 3-amino-6-(3-methoxyphenyl)-N-(2-phenoxyphenyl)thieno[2,3-b]pyridine-2-carboxamide, wherein said composition is suitable for human or animal administration.

47. The composition of claim 46, wherein said compound is 3-amino-N-(4-bromophenyl)-6-(4-chlorophenyl)thieno[2,3-b]pyridine-2-carboxamide.

48. The composition of claim 46, wherein said compound is 3-amino-6-(3-methoxyphenyl)-N-[4-(trifluoromethoxy)phenyl]thieno[2,3-b]pyridine-2-carboxamide.

49. A method for the treatment of at least one type of a Dengue virus infection or disease associated therewith, comprising administering in a therapeutically effective amount to a mammal in need thereof, a compound or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of: 3-amino-N-(4-bromophenyl)-6-(4-chlorophenyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-(3-methoxyphenyl)-N-[4-(trifluoromethoxy)phenyl]thieno[2,3-b]pyridine-2-carboxamide; 3-amino-N-(2,5-dichlorophenyl)-6-(2-thienyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-N-(2,3-dichlorophenyl)-6-(2-thienyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-N-(4-bromophenyl)-6-(3-methoxyphenyl)thieno[2,3-b]pyridine-2-carboxamide; 3-amino-6-(1,3-benzodioxol-5-yl)-N-(2-bromo-4-methyl-phenyl)thieno[2,3-b]pyridine-2-carboxamide; and 3-amino-6-(3-methoxyphenyl)-N-(2-phenoxyphenyl)thieno[2,3-b]pyridine-2-carboxamide.

50. The method of claim 49, wherein said compound is 3-amino-N-(4-bromophenyl)-6-(4-chlorophenyl)thieno[2,3-b]pyridine-2-carboxamide.

51. The method of claim 49, wherein said compound is 3-amino-6-(3-methoxyphenyl)-N-[4-(trifluoromethoxy)phenyl]thieno[2,3-b]pyridine-2-carboxamide.

52. The method of claim 49, wherein the mammal is a human.

53. The method of claim 49, wherein said Dengue virus is selected from the group consisting of DEN-1, DEN-2, DEN-3, and DEN-4.

54. The method of claim 53, wherein said viral infection is associated with Dengue fever.

55. The method of claim 54, wherein said Dengue fever is selected from the group consisting of classical dengue fever and dengue hemorrhagic fever.

56. The method of claim 49, which further comprises co-administration of at least one agent selected from the group consisting of antiviral agent, vaccine, and interferon.

57. The method of claim 56, wherein said interferon is pegylated.