HK1195562B - Compounds for treating respiratory syncytial virus infections - Google Patents

Description

Compounds for the treatment of respiratory syncytial virus infection

Technical Field

The present invention relates to compounds useful in the treatment of viral infections, particularly Respiratory Syncytial Virus (RSV) infections. The invention also relates to processes for the preparation of said compounds and intermediates used in their preparation.

Background

Respiratory Syncytial Virus (RSV) is the leading cause of acute upper and Lower Respiratory Tract Infections (LRTI) in adults, young children and infants. Although risk groups include hospitalized, elderly and high-risk adults, RSV is primarily considered a pediatric disease due to the prevalence and severity of adverse outcomes in infants. Acute LRTI is a leading cause of death and morbidity in children worldwide. Serological evidence suggests that about 95% of all children in the western world are infected with RSV before the age of two and 100% of children are exposed to RSV before adulthood.

RSV is a seasonal infectious disease that typically prevails in the northern hemisphere from november to march/april. In more tropical climates, the annual epidemic is more variable, generally consistent with the rainy season. In most cases, RSV infection will cause only mild upper respiratory tract disease with symptoms similar to the common cold. However, severe infection with the virus can lead to bronchiolitis or pneumonia, which can lead to hospitalization or death. Furthermore, since the immune response to RSV infection is not protective, RSV infection recurs throughout adulthood. Annual reinfection rates in adults have been observed to be 3% to 6%.

RSV is a major cause of acute LRTI in infants. Symptoms of RSV infection include bronchiolitis, cough, wheezing, rale (creckling in the lungs), low fever (38.3 ℃), reduced oral intake and in more severe cases of infection cyanosis can develop and up to 20% of patients develop high temperatures. In one year, it is estimated that 4 to 5 million children under the age of four have acute RSV infection and more than 125,000 infants are hospitalized for RSV-related illness in the united states alone. 25% to 40% of RSV infected infants will show signs of pneumonia and bronchiolitis. The risk and severity of RSV infection is increased in infants with, for example, chronic coexisting medical conditions (e.g., chronic lung disease, congenital heart disease), those born prematurely, and those with immunodeficiency.

In adults and older children, RSV infection is associated with upper respiratory tract infections, tracheobronchitis and otitis media. However, RSV may be more severe in the treated (institutionalized) older population, characterized by severe pneumonia rates and mortality rates as high as 20% and 78%, respectively. Adults with a prior history of heart disease (e.g., congestive heart failure) or lung disease (e.g., Chronic Obstructive Pulmonary Disease (COPD), pneumonia, and asthma) are at high risk of RSV infection as are immunocompromised adults (e.g., those receiving hematopoietic stem cells or lung transplants and leukemia patients).

RSV infection places a significant burden on the medical system. This is particularly the case in infants, for example immunodeficient infants who spend twice the time in hospital on average (7 to 8 days compared to 3 to 4 days) as other RSV infected patients. Hospitalization of infants with acute RSV-associated bronchiolitis or RSV-associated pneumonia includes supportive care treatments of oxygen therapy, fluids to prevent dehydration, nasal inhalation, and respiratory support. There is also an economic impact associated with parents taking time to care for their children without working.

RSV is a member of the order Mononegavirales (Mononegavirales) and consists of non-segmented negative-strand RNA viruses in the Paramyxoviridae (Paramyxoviridae), Rhabdoviridae (Rhabdoviridae) and Filoviridae (Filoviridae) families. Human RSV (also commonly referred to as RSV or HRSV) is a member of the Pneumovirinae (Pneumovirinae) Pneumovirus genus (Pneumovirus) in the paramyxoviridae family. RSV is divided into two subgroups A and B based on genetic and antigenic variation in structural proteins (Mufson, M et al, J.Gen.Virol.66: 2111-2124). Other members of the pneumovirus genus include viruses such as bovine rsv (brsv), ovine rsv (orsv), and murine Pneumovirus (PVM), among others.

In addition to the genomic characteristics described above, family characteristics include a lipid envelope containing one or more glycoprotein species thought to be involved in attachment to and entry into the host cell. Entry is thought to require fusion of the viral envelope with the host cell membrane. In some cases, fusion of an infected cell with, for example, its neighboring cells can also result in the formation of fused multinucleated cells (known as syncytium). The fusion process is thought to be glycoprotein-mediated and is a property common to many enveloped viruses in other taxa. In the case of Paramyxoviridae, viruses of all genera characteristically express a fusion glycoprotein (F) that mediates membrane fusion.

The only small molecule drug currently approved for the treatment of severe RSV is an antiviral drug(ribavirin solution for inhalation). The agent is a broad-spectrum antiviral drug having a virus inhibitory action, and acts by inhibiting RSV replication. Unfortunately, due to their toxicity, the administration of such agents is limited to hospital settings. Strict procedures need to be followed when administering the agents in order to minimize the possibility of certain side effects occurring, making the administration of the agents more complicated. The agents have a number of side effects, including sudden decline in respiratory function (bronchospasm). Ribavirin (Virazole) is rarely prescribed due to its cost and potential toxicity. The efficacy of ribavirin remains controversial.

In the absence of an effective RSV antiviral treatment, a number of prophylactic strategies have been investigated. Although no vaccine has been approved for RSV, some success has been achieved in the area of preventing infants at high risk from developing severe lower respiratory tract disease caused by RSV and reducing LRTI. One immunoglobulin-based therapy that has been approved to protect high risk infants from severe LRTI is RSV-IGIV (intravenous RSV-immunoglobulin, also known as RespiGam)^TM). RespiGam was approved by the food and drug administration at 1 month 1996 for the prevention of Chronic Lung Disease (CLD) or a history of preterm birth (less than 35 weeks gestation)) And children of less than 24 months develop severe RSV lower respiratory tract disease.(palivizumab) is another immunoglobulin-based therapy, more specifically, it is a monoclonal antibody indicated for preventing RSV-related severe lower respiratory tract disease in high-risk pediatric patients. In 6 months 1998, the food and drug administration approved that Synagis started intramuscular administration every month before the onset of the RSV season and continued administration for a total of 5 doses. However, the difficulty of application and its high cost prevent its widespread use. Furthermore, the American Association of Pediatricians (AAP) has recently updated recommendations for the use of Synagis, further limiting its role to the use of infants at the highest risk of hospitalization according to the likely RSV spread. About 70% of the infant population hospitalized with severe RSV disease are term infants who, in the absence of approved treatment, are not receiving Synagis treatment.

Thus, there remains a continuing need for new compounds useful in the treatment of RSV infections.

Summary of The Invention

In a first aspect, there is provided a compound of formula (I) or a salt, racemate, isomer and/or prodrug thereof:

wherein

Represents a single bond or a double bond, as the case may be;

X₁is N, NR₃N-O (N-oxide), CHR₃Or CR₃；

X₂Is CR₁Or NR₁；

X₃Is CR₂Or NR₂；

R₁And R₂Together form an optionally substituted fused 5-membered ring or an optionally substituted fused 6-membered ring;

R₃is H or an optional substituent;

R₄is optionally substituted C_1-6Alkyl, optionally substituted C_2-6Alkenyl, optionally substituted C_2-6Alkynyl, optionally substituted C_3-8Cycloalkyl, optionally substituted heterocyclyl (including heteroaryl), or optionally substituted aryl;

R₅is R₆、C(＝O)R₆、C(＝S)R₆Or S (O)₂R₆；

R₆Selected from optionally substituted C_1-6Alkyl, optionally substituted C_2-6Alkenyl, optionally substituted C_2-6Alkynyl, optionally substituted C_3-8Cycloalkyl, optionally substituted heterocyclyl (including heteroaryl), optionally substituted aryl, N (R')₂Optionally substituted (NR')_q(R”’)_qC_3-8Cycloalkyl, optionally substituted (NR')_q(R”’)_qHeterocyclyl (including heteroaryl) and optionally substituted (NR')_q(R”’)_qAryl, wherein each R' is independently selected from H, optionally substituted C_1-6Alkyl, optionally substituted C_2-6Alkenyl, optionally substituted C_2-6Alkynyl, optionally substituted C_3-8Cycloalkyl, optionally substituted heterocyclyl (including heteroaryl), and optionally substituted aryl, and each R' "is independently selected from optionally substituted C_1-6Alkyl, optionally substituted C_2-6Alkenyl, optionally substituted C_2-6Alkynyl, optionally substituted C_3-8Cycloalkyl, optionally substituted heterocyclyl (including heteroaryl), and optionally substituted aryl, and eachQ is independently 0 or 1;

m is an integer selected from 1, 2, 3 and 4 (preferably 2), and each (CH)₂) May be optionally substituted.

The compounds of formula (I) or salts or prodrugs thereof may be in the form of the racemate or in the form of a single stereoisomer.

In one embodiment, the compound of formula (I) or a salt or prodrug thereof is in the form of a single stereoisomer, more particularly the R-or S-enantiomer.

The compounds of formula (I) are RSV antiviral agents and are useful in the treatment of RSV infections. Thus, the compounds of the invention are useful in the treatment of RSV diseases (e.g., bronchiolitis or pneumonia), or in the reduction of exacerbation of an underlying or pre-existing respiratory disease or condition in which RSV infection is a cause of said exacerbation. The potential or pre-existing respiratory disease or disorder may include asthma, Chronic Obstructive Pulmonary Disease (COPD), and immunosuppression (e.g., that experienced by bone marrow transplant recipients).

In a second aspect, there is provided an RSV antiviral agent comprising a compound of formula (I) as defined above or a salt, racemate, isomer or prodrug thereof.

The present invention also provides the use of a compound of formula (I) as defined above, or a salt, racemate, isomer or prodrug thereof, as an RSV antiviral agent.

The present invention also provides a compound of formula (I) as defined above, or a salt, racemate, isomer or prodrug thereof, for use as an RSV antiviral agent.

The compounds of formula (I) or salts, racemates, isomers or prodrugs thereof can also be administered in the form of a composition.

In a third aspect, there is provided a composition comprising a compound of formula (I) as defined above or a salt, racemate, isomer or prodrug thereof and a carrier.

In one embodiment, the composition is a pharmaceutical composition and the carrier is a pharmaceutically acceptable carrier.

In one embodiment, the medicament or composition as defined above further comprises one or more other RSV antiviral agents.

In a fourth aspect, there is provided a method of treating RSV infection comprising the step of administering to a subject in need thereof a compound of formula (I) as defined above or a salt, racemate, isomer or prodrug thereof or an agent or composition as defined above.

In a fifth aspect, there is provided a method of treating an RSV disease comprising the step of administering to a subject in need thereof a compound of formula (I) as defined above or a salt, racemate, isomer or prodrug thereof or an agent or composition as defined above. The present invention also provides a method of reducing exacerbation of an underlying or pre-existing respiratory disease wherein RSV infection is the cause of said exacerbation, comprising the step of administering to a subject in need thereof a compound of formula (I) as defined above or a salt, racemate, isomer or prodrug thereof or an agent or composition as defined above.

The present invention also provides the use of a compound of formula (I) as defined above or a salt, racemate, isomer or prodrug thereof, or a medicament or composition as defined above, in the manufacture of a medicament for the treatment of RSV infection or RSV disease or for reducing the exacerbation of an underlying or pre-existing respiratory disease wherein RSV infection is a cause of said exacerbation.

The present invention also provides the use of a compound of formula (I) or a salt, racemate, isomer or prodrug thereof, or a medicament or composition as defined above, for the treatment of RSV infection or RSV disease or to reduce exacerbation of an underlying or pre-existing respiratory disease wherein RSV infection is a cause of said exacerbation.

The present invention also provides a compound of formula (I) as defined above or a salt, racemate, isomer or prodrug thereof or a medicament or composition as defined above for use in the treatment of RSV infection or RSV disease or for reducing the exacerbation of an underlying or pre-existing respiratory disease wherein RSV infection is the cause of said exacerbation.

In a sixth aspect, there is provided a process for the preparation of a compound of formula (I) as defined above which comprises reacting a compound of formula (II) with a general formula R '-C (═ O) R wherein R' is a leaving group or an activated ester group₆A step of reacting the compound of (1);

-----、X₁、X₂、X₃、R₁、R₂、R₃、R₄、R₆and m is as previously defined; and wherein the resulting compound of formula (I) is optionally converted into a salt or prodrug thereof.

The compounds of formula (II) are also considered novel. Thus, in a seventh aspect, there is provided a compound of formula (II) as defined above or a salt, racemate, isomer and/or prodrug thereof.

In one embodiment, the compound of formula (II) is in the form of a single stereoisomer, more particularly the R-or S-enantiomer.

In one embodiment, the compound of formula (II) is prepared by cyclization of a precursor compound of formula (III),

wherein R is H or C_1-6Alkyl (preferably C)_1-3Alkyl, more preferably ethyl or methyl); and- - - - - -, X₁、X₂、X₃、R₁、R₂、R₃And R₄As previously defined.

Detailed Description

The present invention relates to compounds of formula (I) as defined above which are RSV antiviral agents and are useful in the treatment of RSV infection or RSV disease or in the reduction of exacerbation of an underlying or pre-existing respiratory disease wherein RSV infection is a cause of said exacerbation.

Compound (I)

In one embodiment, the compound of formula (I) is a compound of formula (Ia) or a salt, racemate, isomer and/or prodrug thereof:

wherein

Represents a single bond or a double bond, as the case may be;

X₁is N, NR₃、N-O、CHR₃Or CR₃；

X₂Is CR₁Or NR₁；

X₃Is CR₂Or NR₂；

R₁And R₂Together form an optionally substituted fused 5-membered aryl or heteroaryl ring or an optionally substituted fused 6-membered aryl or heteroaryl ring;

R₃is H or an optional substituent;

R₄is an optionally substituted heterocyclic group (including heteroaryl) or an optionally substituted aryl group;

R₅is C (═ O) R₆Or S (O)₂R₆Preferably C (═ O) R₆；

R₆Selected from optionally substituted C_1-4Alkyl, optionally substituted C_3-6Cycloalkyl, optionally substituted heterocyclyl (including heteroaryl), optionally substituted aryl, optionally substituted (NR')_q(R”’)_qC_3-6Cycloalkyl radical, renOptionally substituted (NR')_q(R”’)_qHeterocyclyl (including heteroaryl) and optionally substituted (NR')_q(R”’)_qAryl, wherein R 'is H and R' is C_1-3Alkyl (preferably methylene, i.e., -CH)₂-) and each q is independently 0 or 1;

wherein each occurrence of aryl is preferably optionally substituted phenyl and each occurrence of heteroaryl is preferably an optionally substituted 5-membered heteroaryl comprising 1, 2 or 3 heteroatoms independently selected from O, N and S, or an optionally substituted 6-membered heteroaryl comprising 1 or 2 nitrogen atoms.

In one embodiment of the compounds of formula (I) or (Ia), R₁And R₂Together form an optionally substituted fused 5-membered heteroaryl or aryl ring or an optionally substituted fused 6-membered heteroaryl or aryl ring, and X₁Is N, N-O or CR₃Wherein R is₃Is H or an optional substituent including, but not limited to C_1-6Alkyl (preferably C)_1-3Alkyl, more preferably methyl), C_2-6Alkenyl (preferably C)_2-3Alkenyl), C_2-6Alkynyl (preferably C)_2-3Alkynyl), halogen, C_1-6Alkyl halogen (preferably C)_1-3Alkyl halogens, more preferably CHF₂And CF₃) Hydroxy, C_1-6Alkyl hydroxy (preferably C)_1-3Alkylhydroxy, more preferably CH₂OH)、C_1-6Alkoxy (preferably C)_1-3Alkoxy, more preferably methoxy), C_1-6Alkoxy halogen (preferably C)_1-3Alkoxy halogens, more preferably OCHF₂And OCF₃) Oxo, acyl, ketone (preferably C)_1-3Alkyl ketones), carboxylic acids (salts) (preferably CO)₂H) Ester (preferably C)_1-3Alkyl esters, more preferably CO₂Me and CO₂Et), cyano, nitro, amino, substituted amino (preferably C)_1-3Alkylamino group), disubstituted amino group (preferably di-C)_1-3Alkylamino group), amide group, aminoacyl group, substituted amide group (preferably C)_1-3Alkylamido), disubstituted amido (preferably di-C)_1-3Alkyl radicalAmide group), thiol, C_1-6Alkylthio, thio, sulfate (preferably C)_1-3Alkyl sulfates), sulfonates (preferably C)_1-3Alkyl sulfonate), sulfinyl, substituted sulfinyl (preferably C)_1-3Alkylsulfinyl), sulfonyl, substituted sulfonyl (preferably C)_1-3Alkylsulfonyl), sulfonamide group, substituted sulfonamide group (preferably C)_1-3Alkylsulfonamide group) and di-substituted sulfonamide group (preferably di-C)_1-3Alkylsulfonamido), wherein each alkyl, alkenyl, or alkynyl group, and groups comprising the same, may be further optionally substituted.

The fused 5-membered ring may be optionally substituted and includes, but is not limited to, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, triazolyl, triazol,Azolyl radical, isoAzolyl group,Oxadiazolyl, furanyl, thienyl, thiazolyl, isothiazolyl, and thiadiazolyl. In one embodiment, the fused 5-membered ring is selected from optionally substituted furyl, optionally substituted thienyl (thiophenyl), optionally substituted pyrrolyl, optionally substituted pyrazolyl, and optionally substituted imidazolyl. In another embodiment, the fused 5-membered ring is selected from the group consisting of optionally substituted furyl, optionally substituted thienyl, and optionally substituted imidazolyl. In one embodiment, the fused 5-membered ring is unsubstituted.

The fused 6-membered ring may be optionally substituted and includes, but is not limited to, phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl. In one embodiment, the fused 6 membered ring is optionally substituted phenyl. In another embodiment, the fused 6-membered ring is optionally substituted pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl, preferably optionally substituted pyridinyl. In one embodiment, the fused 6-membered ring is unsubstituted.

In one embodiment, X₁Is CR₃Wherein R is₃As previously defined. In a preferred embodiment, R₃Is H or C_1-3Alkyl (preferably H or methyl, most preferably H).

In another embodiment, X₁Is N.

In one embodiment, X₂Is CR₁And X₃Is CR₂。

In another embodiment, X₂Is NR₁And X₃Is CR₂。

In another embodiment, X₂Is CR₁And X₃Is NR₂。

In one embodiment, R₄Is an optionally substituted phenyl group or an optionally substituted 6-membered heteroaryl group, said 6-membered heteroaryl group being selected from the group consisting of pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl. In a preferred embodiment, R₄Is optionally substituted phenyl or optionally substituted pyridyl, more preferably optionally substituted phenyl and most preferably optionally substituted p-phenyl. Suitable optional substituents include, but are not limited to, C_1-6Alkyl (preferably C)_1-3Alkyl, more preferably methyl), C_2-6Alkenyl (preferably C)_2-3Alkenyl), C_2-6Alkynyl (preferably C)_2-3Alkynyl), C_3-6Cycloalkyl, 5-and 6-membered heterocyclyl (including heteroaryl), aryl (preferably phenyl), halogen, C_1-6Alkyl halogen (preferably C)_1-3Alkyl halogens, more preferably CHF₂And CF₃) Hydroxy, C_1-6Alkyl hydroxy (preferably C)_1-3Alkylhydroxy, more preferably CH₂OH)、C_1-6Alkoxy (preferably C)_1-3Alkoxy, more preferably methoxy), C_1-6Alkoxy halogen (preferably C)_1-3The halogen of an alkoxy group,more preferably OCHF₂And OCF₃) Oxo (═ O), acyl, ketone (preferably C)_1-3Alkyl ketones), carboxylic acids (salts) (preferably CO)₂H) Ester (preferably C)_1-3Alkyl esters, more preferably CO₂Me and CO₂Et), cyano, nitro, amino, substituted amino (preferably C)_1-3Alkylamino group), disubstituted amino group (preferably di-C)_1-3Alkylamino group), amide group, aminoacyl group, substituted amide group (preferably C)_1-3Alkylamido), disubstituted amido (preferably di-C)_1-3Alkylamido), mercaptans, C_1-6Alkylthio, thio, sulfate (preferably C)_1-3Alkyl sulfates), sulfonates (preferably C)_1-3Alkyl sulfonate), sulfinyl, substituted sulfinyl (preferably C)_1-3Alkylsulfinyl), sulfonyl, substituted sulfonyl (preferably C)_1-3Alkylsulfonyl), sulfonamide group, substituted sulfonamide group (preferably C)_1-3Alkylsulfonamide group) and di-substituted sulfonamide group (preferably di-C)_1-3Alkylsulfonamido), wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl (including heteroaryl), and aryl groups, and groups comprising the same, may be further optionally substituted. R₄Preferred optional substituents of (a) include 1, 2 or 3, preferably 1 or 2, and most preferably 1 optional substituent independently selected from: methyl, F, Cl, Br, CHF₂、CF₃OH, methoxy, OCHF₂And OCF₃And methyl, F and methoxy are particularly preferred.

In another embodiment, R₅Is C (═ O) R₆Wherein R is₆Is optionally substituted C_1-4Alkyl, optionally substituted C_3-6Cycloalkyl, optionally substituted heterocyclyl (including heteroaryl), optionally substituted aryl, optionally substituted NH-C_3-6Cycloalkyl, optionally substituted CH₂-C_3-6Cycloalkyl, optionally substituted NH-heteroaryl, optionally substituted CH₂-heteroaryl, optionally substituted NH-aryl and optionally substituted CH₂-aryl, or R₅Is S (O)₂R₆Wherein R is₆Is optionally substituted aryl or CH₂An aryl group;

further wherein each occurrence of aryl is preferably optionally substituted phenyl and each occurrence of heteroaryl is preferably optionally substituted 5-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from O, N and S, or optionally substituted 6-membered heteroaryl containing 1 or 2 nitrogen atoms.

Particularly preferred is R₅Is C (═ O) R₆。

Particularly preferred are optionally substituted 5-membered heterocyclic groups (including heteroaryl groups), including optionally substitutedAzolyl, optionally substituted isoacylAzolyl, optionally substituted furanyl and optionally substituted pyrazolyl, most preferably optionally substituted isoAn azole group. Suitable optional substituents include, but are not limited to, C_1-6Alkyl (preferably C)_1-4Alkyl, more preferably methyl), C_2-6Alkenyl (preferably C)_2-3Alkenyl), C_2-6Alkynyl (preferably C)_2-3Alkynyl), C_3-6Cycloalkyl, 5-and 6-membered heterocyclyl (including heteroaryl), aryl (preferably phenyl), halogen, C_1-6Alkyl halogen (preferably C)_1-3Alkyl halogens, more preferably CHF₂And CF₃) Hydroxy, C_1-6Alkyl hydroxy (preferably C)_1-3Alkylhydroxy, more preferably CH₂OH)、C_1-6Alkoxy (preferably C)_1-3Alkoxy, more preferably methoxy), C_1-6Alkoxy halogen (preferably C)_1-3Alkoxy halogens, more preferably OCHF₂And OCF₃) Oxo (═ O), acyl, ketone (preferably C)_1-3Alkyl ketones), carboxylic acids (salts) (preferably CO)₂H) Ester (preferably C)_1-3Alkyl esters, more preferably CO₂Me and CO₂Et), cyano, nitro, amino, substituted amino (preferably C)_1-3Alkylamino group), disubstituted amino group (preferably di-C)_1-3Alkylamino group), amide group, aminoacyl group, substituted amide group (preferably C)_1-3Alkylamido), disubstituted amido (preferably di-C)_1-3Alkylamido), mercaptans, C_1-6Alkylthio, thio, sulfate (preferably C)_1-3Alkyl sulfates), sulfonates (preferably C)_1-3Alkyl sulfonate), sulfinyl, substituted sulfinyl (preferably C)_1-3Alkylsulfinyl), sulfonyl, substituted sulfonyl (preferably C)_1-3Alkylsulfonyl), sulfonamide group, substituted sulfonamide group (preferably C)_1-3Alkylsulfonamide group) and di-substituted sulfonamide group (preferably di-C)_1-3Alkylsulfonamido), wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl (including heteroaryl), and aryl groups, and groups comprising the same, may be further optionally substituted. R₆Preferred optional substituents of (a) include 1, 2 or 3, preferably 1 or 2 optional substituents independently selected from: c_1-4Alkyl, halogen, nitro, C_1-3Alkyl halogen, C_1-3Alkoxy and C_1-3Alkoxy halogens, particularly preferably methyl, tert-butyl, nitro, F, Cl, Br, CHF₂、CF₃Methoxy group, OCHF₂And OCF₃And most preferably C_1-4Alkyl, in particular methyl.

In another embodiment, R₅Is C (═ O) R₆Wherein R is₆Is a 3-substituted heteroOxazol-4-yl, more preferably 3-methylisoOxazol-4-yl (also known as 3-methyl-1, 2-)Oxazol-4-yl).

In a particular embodiment, the present invention provides a compound of formula (Ib), or a salt, racemate, isomer and/or prodrug thereof,

wherein

Z₁、Z₂And Z₃Each independently selected from CHR₇、CR₇、N、NR₇N-O, S and O;

each R₇Independently selected from H or an optional substituent including, but not limited to C_1-6Alkyl (preferably C)_1-3Alkyl, more preferably methyl), C_2-6Alkenyl (preferably C)_2-3Alkenyl), C_2-6Alkynyl (preferably C)_2-3Alkynyl), halogen, C_1-6Alkyl halogen (preferably C)_1-3Alkyl halogen, CHF₂And CF₃) Hydroxy, C_1-6Alkyl hydroxy (preferably C)_1-3Alkylhydroxy, more preferably CH₂OH)、C_1-6Alkoxy (preferably C)_1-3Alkoxy, more preferably methoxy), C_1-6Alkoxy halogen (preferably C)_1-3Alkoxy halogen, OCHF₂And OCF₃) Oxo, acyl, ketone (preferably C)_1-3Alkyl ketones), carboxylic acids (salts) (preferably CO)₂H) Ester (preferably C)_1-3Alkyl esters, more preferably CO₂Me and CO₂Et), cyano, nitro, amino, substituted amino (preferably C)_1-3Alkylamino group), disubstituted amino group (preferably di-C)_1-3Alkylamino group), amide group, aminoacyl group, substituted amide group (preferably C)_1-3Alkylamido), disubstituted amido (preferably di-C)_1-3Alkylamido), mercaptans, C_1-6Alkylthio, thio, sulfate (preferably C)_1-3Alkyl sulfates), sulfonates (preferably C)_1-3Alkyl sulfonate), sulfinyl, substituted sulfinyl (preferably C)_1-3Alkyl radicalSulfinyl), sulfonyl, substituted sulfonyl (preferably C)_1-3Alkylsulfonyl), sulfonamide group, substituted sulfonamide group (preferably C)_1-3Alkylsulfonamide group) and di-substituted sulfonamide group (preferably di-C)_1-3Alkylsulfonamido), wherein each alkyl, alkenyl, or alkynyl group, and groups containing the same, may be further optionally substituted;

-----、X₁、R₃、R₄、R₅and R₆As previously defined.

In another particular embodiment, the present invention provides a compound of formula (Ic) or a salt, racemate, isomer and/or prodrug thereof,

wherein

Z’₁、Z’₂、Z’₃And Z'₄Each independently selected from CHR₇、CR₇、N、NR₇N-O, S and O, preferably CHR₇、CR₇、N、NR₇And N-O, more preferably CHR₇、CR₇N and NR₇；

R₇Independently selected from H or an optional substituent including, but not limited to C_1-6Alkyl (preferably C)_1-3Alkyl, more preferably methyl), C_2-6Alkenyl (preferably C)_2-3Alkenyl), C_2-6Alkynyl (preferably C)_2-3Alkynyl), halogen, C_1-6Alkyl halogen (preferably C)_1-3Alkyl halogen, CHF₂And CF₃) Hydroxy, C_1-6Alkyl hydroxy (preferably C)_1-3Alkylhydroxy, more preferably CH₂OH)、C_1-6Alkoxy (preferably C)_1-3Alkoxy, more preferably methoxy), C_1-6Alkoxy halogen (preferably C)_1-3Alkoxy halogen, OCHF₂And OCF₃) Oxo, acyl, ketone (preferably C)_1-3Alkyl ketones), carboxylic acids (salts) (preferably CO)₂H) Ester (preferably C)_1-3Alkyl esters, more preferably CO₂Me and CO₂Et), cyano, nitro, amino, substituted amino (preferably C)_1-3Alkylamino group), disubstituted amino group (preferably di-C)_1-3Alkylamino group), amide group, aminoacyl group, substituted amide group (preferably C)_1-3Alkylamido), disubstituted amido (preferably di-C)_1-3Alkylamido), mercaptans, C_1-6Alkylthio, thio, sulfate (preferably C)_1-3Alkyl sulfates), sulfonates (preferably C)_1-3Alkyl sulfonate), sulfinyl, substituted sulfinyl (preferably C)_1-3Alkylsulfinyl), sulfonyl, substituted sulfonyl (preferably C)_1-3Alkylsulfonyl), sulfonamide group, substituted sulfonamide group (preferably C)_1-3Alkylsulfonamide group) and di-substituted sulfonamide group (preferably di-C)_1-3Alkylsulfonamido), wherein each alkyl, alkenyl, or alkynyl group, and groups containing the same, may be further optionally substituted;

-----、X₁、R₃、R₄、R₅and R₆As previously defined.

Variable Z in formula (Ib)₁、Z₂And Z₃And the variable Z 'of formula (Ic)'₁、Z’₂、Z’₃And Z'₄In the case of each R₇When present, is preferably and independently selected from H, methyl, ethyl, propyl, ethenyl, propenyl, ethynyl, propynyl, F, Cl, Br, CHF₂、CF₃OH, methoxy, ethoxy, propoxy, OCHF₂、OCF₃Oxo, carboxy, CO₂Me、CO₂Et、CO₂Pr, cyano group, nitro group, amino group, methylamino group, ethylamino group, propylamino group, dimethylamino group, diethylamino group, dipropylamino group, aminoacyl group, acylamino group, methylamido group, ethylamido group, propylamido group, di-C_1-3Alkylamide, thiol, C_1-6Alkylthio, thio, SOMe, SOEt, SOPr, SO₂Me、SO₂Et、SO₂Pr、NHSO₂Me、NHSO₂Et、NHSO₂Pr、SO₂NHMe、SO₂NHEt、SO₂NHPr and SO₂N two C_1-3An alkyl group. H and methyl are particularly preferred R₇A group.

In another embodiment, the compound of formula (I) or (Ia) is selected from the following compounds or salts, racemates, isomers and/or prodrugs thereof:

wherein X₁、R₃、R₄、R₅、R₆And R₇As previously defined.

In another embodiment, the compound of formula (I) or (Ia) is selected from the following compounds or salts, racemates, isomers and/or prodrugs thereof:

wherein X₁、R₃、R₄、R₅、R₆And R₇As previously defined.

The compound of formula (I) or (Ia) may be selected from the following compounds or salts, racemates and enantiomers thereof:

in one embodiment, the compound of formula (I), (Ia), (Ib) or (Ic) is in the form of a single stereoisomer, more particularly the R-or S-enantiomer.

In a preferred embodiment, the single stereoisomeric form is an enantiomer represented by formula (I'):

wherein- - - - - - -, X₁、X₂、X₃、R₁、R₂、R₃、R₄、R₅、R₆As previously defined.

It is understood that references to isomers include stereoisomers (e.g., enantiomers) and structural isomers (e.g., tautomers). The term "tautomer" is used herein in its broadest sense and includes compounds of formula (I) that are in a state of rapid equilibrium between the two isomeric forms. The nature of the bond connecting two atoms or groups of such compounds and the position of these atoms or groups in the compounds may differ.

It will also be appreciated that reference to a compound of formula (I) or formula (II) and embodiments thereof may refer to the compound of formula (I) or (II) as such or a salt, racemate, isomer or prodrug thereof, if appropriate in context.

The term "C_1-6Alkyl "encompasses optionally having 1 to 6 carbon atomsSubstituted straight or branched chain hydrocarbon groups. Examples include methyl (Me), ethyl (Et), propyl (Pr), isopropyl (i-Pr), butyl (Bu), isobutyl (i-Bu), sec-butyl (s-Bu), tert-butyl (t-Bu), pentyl, neopentyl, hexyl and the like. Unless the context requires otherwise, the term "C" or "C" is used herein to describe a compound of formula_1-6Alkyl "also encompasses alkyl groups that contain one less hydrogen atom such that the group is attached through two positions (i.e., divalent). Such a group is also referred to as "C_1-6An alkylene group ". C_1-3Alkyl and C_1-3Alkylene groups are preferred.

The term "C_2-6Alkenyl "refers to an optionally substituted straight or branched chain hydrocarbon group having at least one double bond of E or Z stereochemistry (when applicable) and 2 to 6 carbon atoms. Examples include ethenyl, 1-propenyl, 1-and 2-butenyl, 2-methyl-2-propenyl, hexenyl, butadienyl, hexadienyl, hexantrienyl, and the like. Unless the context requires otherwise, the term "C" or "C" is used herein to describe a compound of formula_1-6Alkenyl "also encompasses alkenyl groups that contain one less hydrogen atom such that the group is attached through two positions (i.e., divalent). Such a group is also referred to as "C_2-6Alkenylene ". C_2-3Alkenyl and C_2-3Alkenylene groups are preferred.

The term "C_2-6Alkynyl "refers to an optionally substituted straight or branched chain hydrocarbon group having at least one triple bond and 2 to 6 carbon atoms. Examples include ethynyl, 1-propynyl, 1-and 2-butynyl, 2-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, and the like. Unless the context indicates otherwise, the term "C" is used_2-6Alkynyl "also encompasses alkynyl groups that contain one less hydrogen atom such that the group is linked through two positions (i.e., divalent). Such a group is also referred to as "C_2-6Alkynylene "groups. C_2-3Alkynyl and C_2-3Alkynylene groups are preferred.

The term "C_3-8Cycloalkyl "refers to a non-aromatic cyclic hydrocarbon group having 3 to 8 carbon atoms and includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloHeptyl, and the like. It is understood that a cycloalkyl group can be saturated (e.g., cyclohexyl) or unsaturated (e.g., cyclohexenyl). C_3-6Cycloalkyl groups are preferred.

The term "hydroxy" refers to the group-OH.

The term "C_1-6Alkylhydroxy "refers to C substituted with one or more hydroxy groups_1-6An alkyl group. C_1-3Alkylhydroxy groups are preferred, e.g., -CH₂OH。

The term "oxo" refers to the group ═ O.

The term "C_1-6Alkoxy "refers to a group that refers to the group OC_1-6An alkyl group. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, and the like. The oxygen atom may be located along the hydrocarbon chain and need not be an atom linking the group to the rest of the compound. C_1-3Alkoxy groups are preferred.

The term "aryloxy" refers to the group-oaryl and may include variations thereof (e.g., "alkoxyaryl"), wherein aryl is defined herein. Examples include, but are not limited to, phenoxy, naphthoxy, and benzyloxy.

The terms "halogen", "halo" and similar terms refer to fluorine, chlorine, bromine and iodine (F, Cl, Br, I).

The term "C_1-6Alkyl halogen "refers to C substituted by one or more halogens_1-6An alkyl group. C_1-3Alkyl halogen radicals are preferred, e.g., -CHF₂and-CF₃。

The term "C_1-6Alkoxy halogen "refers to C substituted with one or more halogens_1-6An alkoxy group. C_1-3Alkoxy halogen radicals are preferred, e.g., -OCHF₂and-OCF₃。

The term "carboxylic acid (salt)" or "carboxyl" refers to the group-COO^-or-COOH.

The term "ester" means that the hydrogen is replaced by, for example, C_1-6Alkyl ('CarboxyC') groups_1-6Alkyl "or" C_1-6Alkyl esters "), aryl or aralkyl (" aryl esters "or" aralkyl esters ") and the like. C_1-3Alkyl esters are preferred, for example, the methyl ester (-CO)₂Me), ethyl ester (-CO)₂Et) and propyl ester (-CO)₂Pr) and include reverse esters thereof (e.g., -OCOMe, -OCOEt, and-OCOPr).

The term "cyano" refers to the group-CN.

The term "nitro" refers to the group-NO₂。

The term "amino" refers to the group-NH₂。

The term "substituted amino" or "secondary amino" means that hydrogen is replaced by, for example, C_1-6Alkyl (' C)_1-6Alkylamino "), aryl or aralkyl (" arylamino "or" aralkylamino "), and the like. C_1-3Alkylamino groups are preferred, for example, methylamino (-NHMe), ethylamino (-NHEt), and propylamino (-NHPr).

The term "disubstituted amino" or "tertiary amino" means that two hydrogens are replaced by, for example, C_1-6Alkyl (which may be the same or different) ("di-C)_1-6Alkylamino "), aryl and C_1-6Alkyl ('aryl (C)')_1-6Alkyl) amino ") and the like. Di C_1-3Alkylamino groups are preferred, for example, dimethylamino (-NMe)₂) Diethylamino (-NEt)₂) Dipropylamino (-NPr)₂) And variants thereof (e.g., -N (Me) (Et), etc.).

The term "acyl" or "aldehyde" refers to the group-C (═ O) H.

The term "substituted acyl" or "ketone" means that hydrogen is replaced by, for example, C_1-6Alkyl radical (' C)_1-6Alkyl acyl radical "or" C_1-6Alkyl ketones "or" Ketone C_1-6Alkyl "), aryl groups (" aryl ketones ")"), aralkyl groups (" aralkyl ketones "), and the like. C_1-3Alkyl ketone groups are preferred.

The term "amido" or "amide" refers to the group-C (O) NH₂。

The term "aminoacyl" refers to the group-NHC (O) H.

The term "substituted amido" or "substituted amide" means that hydrogen is replaced by, for example, C_1-6Alkyl radical (' C)_1-6Alkylamido "or" C_1-6Alkylamides "), aryl (" arylamido "), arylalkyl (" aralkylamido "), and the like. C_1-3Alkylamide groups are preferred, for example, methylamides (-C (O) NHMe), ethylamides (-C (O) NHEt), and propylamides (-C (O) NHPr), and include the reverse amides thereof (e.g., -NHMeC (O) -, -NHEtC (O) -, and-NHPrC (O) -).

The term "disubstituted amido" or "disubstituted amide" means that two hydrogens are replaced with, for example, C_1-6Alkyl radicals (' Di C)_1-6Alkylamido "or" di-C_1-6Alkylamides "), aralkyls and C_1-6Alkyl radicals ('arylalkyl (C)')_1-6Alkyl) amido ") and the like. Di C_1-3Alkylamide groups are preferred, for example, dimethylamide (-C (O) NMe)₂) Diethyl amide (-C (O) NEt)₂) And dipropylamide (-C (O) NPr₂) And variants thereof (e.g., -C (O) N (Me) Et, etc.), and including the reverse amides thereof.

The term "thiol" refers to the group-SH.

The term "C_1-6Alkylthio "means hydrogen bonded by C_1-6An alkyl group substituted thiol group. C_1-3Alkylthio groups are preferred, for example, methylthio, ethylthio and propylthio.

The term "thio" refers to the group ═ S.

The term "sulfinyl" refers to the group-S (═ O) H.

The term "substituted sulfinyl" or "sulfoxide" means that the hydrogen is replaced by, for example, C_1-6Alkyl (' C)_1-6Alkylsulfinyl "or" C_1-6Alkyl sulfoxides "), aryl (" arylsulfinyl "), aralkyl (" aralkylsulfinyl "), and like substituted sulfinyl groups. C_1-3Alkylsulfinyl groups are preferred, such as, -SO methyl, -SO ethyl and-SO propyl.

The term "sulfonyl" refers to the group-SO₂H。

The term "substituted sulfonyl" means that hydrogen is substituted by, for example, C_1-6Alkyl ('Sulfonyl C')_1-6Alkyl "), aryl (" arylsulfonyl "), aralkyl (" aralkylsulfonyl "), and the like. Sulfonyl radical C_1-3Alkyl radicals are preferred, e.g. -SO₂Me、-SO₂Et and-SO₂Pr。

The term "sulfonamide" or "sulfonamide" refers to the group-SO₂NH₂。

The term "substituted sulfonamide" or "substituted sulfonamide" refers to a compound having a hydrogen atom replaced by, for example, C_1-6Alkyl ('sulfonamido' C)_1-6Alkyl "), aryl (" arylsulfonamides "), aralkyl (" aralkylsulfonamides "), and the like. Sulfonamide C_1-3Alkyl radicals are preferred, e.g. -SO₂NHMe、-SO₂NHEt and-SO₂NHPr, and including its inverse sulfonamide group (e.g., -NHSO₂Me、-NHSO₂Et and-NHSO₂Pr)。

The term "disubstituted sulfonamide" or "disubstituted sulfonamide" means that two hydrogens are replaced with, for example, C_1-6Alkyl groups (which may be the same or different) ("sulfonamidodiC)_1-6Alkyl "), aralkyl and C_1-6Alkyl groups (` sulfonamido (aralkyl) C `)_1-6Alkyl "), etc. Sulfonamide di C_1-3Alkyl radicals are preferred, e.g. -SO₂NMe₂、-SO₂NEt₂and-SO₂NPr₂And variants thereof (e.g., -SO)₂N (me) Et, etc.), and includes its reverse sulfonamide group.

The term "sulfate" refers to the group-OS (O)₂OH and containing hydrogen by, e.g., C_1-6Alkyl radical (' C)_1-6Alkyl sulfates "), aryl (" aryl sulfates "), aralkyl (" aralkyl sulfates "), and the like. C_1-3Alkyl sulfate groups are preferred, e.g. -OS (O)₂OMe、-OS(O)₂OEt and-OS (O)₂OPr。

The term "sulfonate" refers to the group-SO₃H and including hydrogen by e.g. C_1-6Alkyl radical (' C)_1-6Alkyl sulfonates "), aryl (" aryl sulfonates "), aralkyl (" aralkyl sulfonates "), and the like. C_1-3Alkyl sulfonate groups are preferred, e.g. -SO₃Me、-SO₃Et and-SO₃Pr。

The term "aryl" refers to any group comprising a carbocyclic (non-heterocyclic) aromatic ring, and may be a monocyclic, bicyclic or tricyclic ring system. The aromatic ring or ring system is generally composed of 6 to 10 carbon atoms. Such groups may comprise fused ring systems (e.g., naphthyl, tetrahydronaphthyl, fluorenyl, indenyl, azulenyl, anthracenyl, and the like), linked ring systems (e.g., biphenyl groups), and may be substituted or unsubstituted. Examples of aryl groups include, but are not limited to: phenyl, biphenyl, naphthyl, and tetrahydronaphthyl. Phenyl is preferred.

The term "aralkyl" refers to a substituted aryl group substituted by C_1-6An alkyl group substituted aryl group. Examples include benzyl and phenethyl.

The term "heterocyclyl" encompasses aromatic and non-aromatic heterocyclyl groups. Such groups may be substituted or unsubstituted. Particularly preferred optional substituents in the case of N-containing heterocycles include C_1-3Alkyl (especially N-C)_1-3Alkyl), more preferably methyl (especially N-methyl).

The term "aromatic heterocyclyl" may be used interchangeably with the term "heteroaromatic" or the term "heteroaryl" or "heteroaryl". The term "aromatic heterocyclyl" also encompasses pseudo-aromatic (pseudoaromatic) heterocyclyl groups. The term "pseudo-aromatic" refers to a ring system that is not strictly aromatic, but is stabilized by delocalization of electrons and exhibits behavior similar to aromatic rings.

The heteroatom in the aromatic heterocyclyl group may be selected from N, S and O.

The aromatic heterocyclyl group may be a 5-or 6-membered monocyclic aromatic ring system.

Examples of 5-membered monocyclic aromatic ring systems include furyl, thienyl, pyrrolyl,Azolyl group,Oxadiazolyl (including 1, 2, 3 and 1, 2, 4)Oxadiazolyl and furazanyl (i.e., 1, 2, 5-)Oxadiazolyl)), thiazolyl, isoxazolyl)Oxazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl (including 1, 2, 3, 1, 2, 4 and 1, 3, 4 triazolyl), tetrazolyl, thiadiazolyl (including 1, 2, 3 and 1, 3, 4 thiadiazolyl), and the like.

Examples of 6-membered monocyclic aromatic ring systems include pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl and the like. Examples of the 6-membered aromatic heterocyclic group containing 1 nitrogen include pyridyl. Examples of the 6-membered aromatic heterocyclic group containing 2 nitrogens include pyrazinyl, pyrimidinyl and pyridazinyl.

The aromatic heterocyclic group may also be a bicyclic or polycyclic heteroaromatic ring system such as a fused ring system (including purines, pteridinyl, naphthyridinyl, 1H thieno [2, 3-c ] pyrazolyl, thieno [2, 3-b ] furyl, and the like) or a linked ring system (e.g., oligothiophene (oligothiophene), polypyrrole, and the like). The fused ring system may also include aromatic 5-or 6-membered heterocyclic groups fused to carbocyclic aromatic rings (e.g., phenyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, and the like), such as nitrogen-containing 5-membered aromatic heterocyclic groups fused to a benzene ring, or l or 2 nitrogen-containing 5-membered aromatic heterocyclic groups fused to a benzene ring.

Examples of aromatic heterocyclic groups fused to a carbocyclic aromatic ring include benzothienyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzimidazolyl, indazolyl, benzofuranylAzolyl, benzisoylOxazolyl, benzothiazolyl, benzisothiazolyl, benzimidazolyl, indazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, cinnolinyl, benzotriazinyl, phthalazinyl, carbolinyl and the like.

It will be appreciated that suitable derivatives of the nitrogen-containing aromatic heterocyclic group include the N-oxides thereof.

The term "non-aromatic heterocyclyl" encompasses optionally substituted saturated and unsaturated rings comprising at least one heteroatom selected from N, S and O.

The non-aromatic heterocycle may be a 5-, 6-or 7-membered monocyclic ring.

Examples of 5-membered non-aromatic heterocyclyl rings include 2H-pyrrolyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrazolinyl, 2-pyrazolinyl, 3-pyrazolinyl, pyrazolinylAlkyl, 2-pyrazolidinyl, 3-pyrazolidinyl, imidazolidinyl, 3-dioxolanyl, thiazolidinyl, isovalerylOxazolidinyl, 2-imidazolinyl, and the like.

Examples of the 6-membered non-aromatic heterocyclic group include piperidyl, piperidinoyl (piperidinonyl), pyranyl, dihydropyranyl, tetrahydropyranyl, 2H pyranyl, 4H pyranyl, thianyl (thianyl), thiaalkyl oxide, thiaalkyl dioxide, piperazinyl, dioxanylAlkyl (dioxazinyl), 1, 4-dioxacyclohexyl (1, 4-dioxazinyl), 1, 4-dithianyl, 1, 3, 5-trithianylAlkyl (1, 3, 5-triozalanyl), 1, 3, 5-trithianyl, 1, 4-morpholinyl, thiomorpholinyl, 1, 4-oxathianyl (1, 4-oxathinyl), triazinyl, 1, 4-thiazinyl and the like.

Examples of 7-membered non-aromatic heterocycles include azepanyl, oxepinyl, thiepanyl, and the like.

The non-aromatic heterocyclyl ring may also be a bicyclic heterocyclyl ring, such as a linked ring system (e.g., uridine, etc.) or a fused ring system. Fused ring systems include non-aromatic 5-, 6-, or 7-membered heterocyclic groups fused to a carbocyclic aromatic ring (e.g., phenyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, and the like). Examples of non-aromatic 5-, 6-or 7-membered heterocyclic groups fused to a carbocyclic aromatic ring include indolinyl, benzodiazepineRadical, benzazepineAlkyl, dihydrobenzofuranyl, and the like.

As used herein, unless otherwise defined, the term "optionally substituted" or "optional substituent" refers to a group which may or may not be further substituted by 1, 2, 3, 4 or more, preferably 1, 2 or 3, more preferably 1 or 2 groups selected from: alkyl, alkenyl, alkynyl, cycloalkyl, hydroxy, alkylhydroxy, oxo, alkoxy, aryloxy, alkoxyaryl, halogen, alkylhalogen, alkoxyhalogen, carboxylic acid (salt), ester, cyano, nitro, amino, substituted amino, disubstituted amino, acyl, keto, amide, aminoacyl, substituted amide, disubstituted amide, thiol, alkylthio, thio, sulfate, sulfonate, sulfinyl, substituted sulfinyl, sulfonyl, substituted sulfonyl, sulfonamide, substituted sulfonamide, disubstituted sulfonamide, aryl, aralkyl, and heterocyclic (including heteroaryl), wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclic groups, and groups comprising the same, may be further optionally substituted.

The compounds of the present invention may also be prepared as pharmaceutically acceptable salts. It is to be understood that non-pharmaceutically acceptable salts also fall within the scope of the present invention, as they are useful as intermediates in the preparation of pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts include salts of pharmaceutically acceptable cations (e.g., sodium, potassium, lithium, calcium, magnesium, ammonium, alkylammonium, and the like); acid addition salts of pharmaceutically acceptable inorganic acids (e.g., hydrochloric acid, orthophosphoric acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid, boric acid, sulfamic acid, hydrobromic acid, and the like); and salts of pharmaceutically acceptable organic acids (e.g., acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulfonic, trihalomethanesulfonic, toluenesulfonic, benzenesulfonic, isethionic, salicylic, sulfanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic, valeric, orotic, and the like). Salts of amine groups may also include quaternary ammonium salts in which the amino nitrogen atom carries a suitable organic group (e.g., alkyl, alkenyl, alkynyl, aralkyl moieties, etc.).

Salts may be formed by conventional means, for example by reacting the free base form of the compound with one or more equivalents of the appropriate acid.

It will be understood that reference to pharmaceutically acceptable salts includes solvent addition forms or crystal forms thereof, particularly solvates or polymorphs. Solvates comprise stoichiometric or non-stoichiometric amounts of solvent and may be formed during crystallization with pharmaceutically acceptable solvents such as water, alcohols (e.g., methanol, ethanol, or isopropanol), DMSO, acetonitrile, Dimethylformamide (DMF), and the like, which solvates form part of the crystal lattice by non-covalently bonding to or occupying the pores in the lattice. When the solvent is water, hydrates are formed; alcoholates are formed when the solvent is an alcohol. Solvates of the compounds of the invention may be conveniently prepared or formed during the processes described herein. In addition, the compounds of the present invention may exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein.

In addition, the compounds of the present invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. Solvated forms of the compounds of the present invention are also considered disclosed herein.

It will be appreciated that the compounds of formula (I) have chiral centres and may therefore exist as racemates or as the R-or S-enantiomers. Thus, the compounds may be used as pure enantiomers or diastereomers, or as mixtures thereof in any proportion. In one embodiment, there is provided a single stereoisomeric form of a compound of formula (I) as defined above or a compound of formula (II) as defined above. Isomers may be separated conventionally by chromatographic methods or using resolving agents. Alternatively, the individual isomers may be prepared by asymmetric synthesis using chiral intermediates. When the compound has a carbon-carbon double bond, it may exist in Z-or E-form, and all isomeric forms of the compound are included in the present invention.

The invention also encompasses prodrugs of the compounds of formula (I).

The term "prodrug" is used herein in its broadest sense, including those compounds which are converted in vivo to compounds of formula (I). The use of this prodrug strategy can optimize the delivery of the drug to its site of action. Compounds having a free amino, amido, hydroxyl, or carboxylic acid group can be converted to prodrugs. Prodrugs may also include the N-oxide, the appropriate nitrogen atom in the compound of formula (I).

Pharmaceutical composition

The invention also provides a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier.

The pharmaceutical composition may also comprise one or more other RSV antiviral agents (e.g.) Or in combination therewith.

The term "composition" is intended to include the formulation of the active ingredient with conventional carriers and excipients, and encapsulating materials as carriers, to give capsules in which the active ingredient is surrounded by an encapsulating carrier, with or without other carriers. Any carrier must be "pharmaceutically acceptable," which means that it is compatible with the other ingredients of the composition and does not harm the subject. The compositions of the invention may contain other therapeutic agents as described above and may be formulated, for example, by employing conventional solid or liquid carriers or diluents and pharmaceutical additives of the appropriate type for the desired mode of administration (e.g., excipients, binders, preservatives, stabilizers, flavoring agents, and the like) in accordance with techniques such as those well known in the art of pharmaceutical formulation (see, for example, Remington: the science and practice of pharmacy, 21 st edition, 2005, lippincott williams & Wilkins).

The pharmaceutical compositions include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including intramuscular, subcutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation.

Thus, the compounds of the present invention may be placed in the form of pharmaceutical compositions and unit dosages thereof, together with conventional adjuvants, carriers or diluents, and in such form, the compounds of the present invention may be administered as: solid (e.g., as tablets or filled capsules), or liquid (e.g., solutions, suspensions, emulsions, elixirs) or capsules filled with the liquid, all for oral use; in the form of suppositories for rectal administration; or as sterile injectable solutions for parenteral (including subcutaneous) use.

Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles (principle), and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be administered.

For preparing pharmaceutical compositions from the compounds of the present invention, the pharmaceutically acceptable carrier may be solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.

Suitable carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term "formulation" is intended to encompass the formulation of an active compound with an encapsulating material as a carrier by providing a capsule in which the active component (with or without a carrier) is surrounded by, and thus associated with, the carrier. Similarly, cachets and lozenges (lozenes) are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid forms suitable for oral administration.

Liquid form preparations include solutions, suspensions and emulsions, for example, water or water-propylene glycol solutions. For example, parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solutions.

Sterile liquid form compositions include sterile solutions, suspensions, emulsions, syrups and elixirs. The active ingredient may be dissolved or suspended in a pharmaceutically acceptable carrier, such as sterile water, a sterile organic solvent, or a mixture of both.

Thus, compositions according to the invention may be formulated for parenteral administration (e.g. by injection, such as bolus injection (bolus injection) or continuous infusion) and may be presented in unit dosage form in ampoules, pre-filled syringes, small volume infusion containers or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle (e.g., sterile, pyrogen-free water) before use, by sterile isolation of a sterile solid or by lyophilization from solution.

Pharmaceutical forms suitable for injectable use include sterile injectable solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions. They should be stable under the conditions of manufacture and storage and be storable against oxidative and microbial (e.g., bacterial or fungal) contamination.

The solvent or dispersion medium for the injectable solutions or dispersions can comprise any conventional solvent or carrier system for compounds and may comprise, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.

Pharmaceutical forms suitable for injectable use may be delivered by any suitable route, including intravenous, intramuscular, intracerebral, intrathecal, epidural injection or infusion.

Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various other ingredients such as those enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. For sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying or freeze-drying the previously sterile-filtered solution of the active ingredient in combination with any additional desired ingredient.

When the active ingredient is suitably protected, it may be administered orally, e.g., with an inert diluent or with an ingestible support, or they may be enclosed in hard or soft shell gelatin capsules, or they may be compressed into tablets, or they may be incorporated directly into an edible food. For oral therapeutic administration, the active compound may be combined with excipients and used in the form of ingestible tablets, buccal tablets, troches (troche), capsules, elixirs, suspensions, syrups, wafers (wafers), and the like.

The amount of active compound in the therapeutically useful composition should be sufficient to obtain a suitable dosage.

Tablets, dragees, pills, capsules and the like may also comprise the following components: binders, such as gums, acacia, corn starch or gelatin; excipients, such as dicalcium phosphate; disintegrating agents, such as corn starch, potato starch, alginic acid, and the like; lubricants, such as magnesium stearate; and sweetening agents, such as sucrose, lactose or saccharin; or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier.

Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For example, tablets, pills, or capsules can be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts used. In addition, the active compounds may be incorporated into sustained release formulations and formulations, including those that permit the specific delivery of active peptides to specific regions of the intestine.

Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickeners as desired. Aqueous suspensions suitable for oral use can be prepared by dispersing the finely divided active component in water with a viscous material, for example, a natural or synthetic gum, resin, methylcellulose, sodium carboxymethylcellulose, or other known suspending agents.

Pharmaceutically acceptable carriers and/or diluents include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like.

Also included are solid form preparations which are intended to be converted, immediately prior to use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions and emulsions. In addition to the active ingredient, these formulations may contain coloring agents, flavoring agents, stabilizing agents, buffering agents, artificial and natural sweeteners, dispersing agents, thickening agents, solubilizing agents, and the like.

For topical application to the epidermis, the compounds according to the invention may be formulated as ointments, creams or lotions, or as transdermal patches. Ointments and creams may, for example, be formulated with the addition of suitable thickening and/or gelling agents to an aqueous or oily base. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents.

Formulations suitable for topical administration in the mouth include lozenges comprising: active pharmaceutical agents in a flavored base, typically sucrose and acacia or tragacanth; pastilles (pastilles) comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

The solution or suspension is applied directly to the nasal cavity by conventional means, such as with a dropper, pipette or nebulizer. The formulations may be provided in single or multiple dose forms. In the case of a dropper or pipette in multi-dose form, this may be achieved by administering an appropriate, predetermined volume of solution or suspension to the patient.

In the case of a nebulizer, this can be achieved, for example, by a metered nebulization spray pump. To improve nasal delivery and retention (retention), the compounds according to the invention may be encapsulated with cyclodextrins, or formulated with other agents intended to enhance delivery and retention in the nasal mucosa.

Administration to the respiratory tract may also be achieved by aerosol formulations in which the active ingredient is provided in pressurized packaging with a suitable propellant, such as a chlorofluorocarbon (CFC) (e.g. dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane), a Hydrofluorocarbon (HFC) (e.g. Hydrofluorocarbon (HFA)), carbon dioxide or other suitable gas.

The aerosol may also conveniently comprise a surfactant, such as lecithin. The dose of medicament may be controlled by providing a metering valve.

Alternatively, the active ingredient may be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP). Conveniently, the powder carrier will form a gel within the nasal cavity. The powder compositions may be presented in unit dosage form, for example in capsules or cartridges of, for example, gelatin, or in a blister pack (from which the powder may be administered using an inhaler).

In formulations intended for administration to the respiratory tract, including intranasal formulations, the compounds may generally have a small particle size, for example on the order of 5 to 10 microns or less. Such particle sizes may be obtained by methods known in the art, for example by micronization.

When desired, formulations suitable for providing sustained release of the active ingredient may be employed.

The pharmaceutical formulation is preferably in unit dosage form. In this form, the formulation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of the preparation, such as packeted tablets, capsules, and powders in vials or ampoules. In addition, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

It is particularly advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suitable for single dose administration to a subject to be treated; each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The instructions for the new dosage unit forms of the present invention are subject to and directly depend on: (a) the unique characteristics of the active substance and the specific therapeutic effect to be achieved, and (b) the inherent limitations in the art of formulating the active substance for the treatment of viral infections in subjects with a disease condition in which physical health is impaired as disclosed in detail herein.

The invention also includes a compound that is free of a carrier, wherein the compound is in unit dosage form.

Liquids or powders for intranasal administration, tablets or capsules for oral administration, and liquids for intravenous administration are preferred compositions.

Method of treatment

The compounds of formula (I) have demonstrated efficacy as RSV inhibitors, thus providing a method of treating RSV infections. The compounds of formula (I) are also useful in treating RSV disease or reducing exacerbation of an underlying or pre-existing respiratory disease wherein RSV infection is a cause of said exacerbation. The RSV disease may include bronchiolitis and pneumonia. Potential or pre-existing respiratory diseases or conditions may include asthma, Chronic Obstructive Pulmonary Disease (COPD), and immunosuppression (e.g., that experienced by bone marrow transplant recipients).

The treatment may be therapeutic treatment or prophylactic treatment. Generally, the term "treating" refers to affecting a subject, tissue or cell to obtain a desired pharmacological and/or physiological effect and includes: (a) inhibiting viral infection or RSV disease, e.g., by preventing its development or further development; (b) reducing or ameliorating the effects of viral infection or RSV disease, e.g., by causing regression of the effects of viral infection or RSV disease; (c) reducing the incidence of a viral infection or an RSV disease, or (d) preventing the occurrence of a viral infection or an RSV disease in a subject, tissue or cell that is predisposed to, or at risk of, a RSV disease but has not yet been diagnosed, by a protective pharmacological and/or physiological effect such that the viral infection or RSV disease does not develop or occur in the subject, tissue or cell.

The term "subject" refers to any animal, particularly a mammal (e.g., a human), having a disease for which treatment with a compound of formula (I) is indicated. Particularly preferred treatment groups include populations at risk, such as hospitalized subjects, elderly people, high risk adults, and infants.

The term "administering" is understood to mean providing a compound or pharmaceutical composition of the invention to a subject suffering from, or at risk of, a disease or condition to be treated or prevented.

Although the invention has been described in relation to the treatment of RSV infections and diseases, more particularly RSV infections or diseases in humans and animals, it will be appreciated that the invention may also be used to treat other viruses of the pneumovirinae, more particularly the pneumovirus genus and Metapneumovirus genus. Dosage form

The term "therapeutically effective amount" refers to the amount of a compound of formula (I) that elicits the biological or medical response in a subject, tissue or cell that is being sought by a researcher, veterinarian, medical doctor or other clinician.

In the treatment of RSV infections or diseases, suitable dosage levels are generally from about 0.01 to about 500mg/kg of subject body weight per day, which can be administered in single or multiple doses. For the purpose of therapeutic efficacy and/or symptom modulation of the dose to the subject to be treated, the dose can be selected, for example, as any dose within any of these ranges.

It will be understood that the specific dose level and frequency of dosage for any particular subject may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the subject being treated.

Preparation method

The compounds of the present invention can be prepared generally by the following methods. Unless otherwise indicated, the groups of each compound are as previously defined.

Step (a): synthesis of the precursor (Compound of the formula (III))

In general, 1 equivalent of the appropriate bicyclic ester, e.g., 6H-thieno [2, 3-b ], is treated with 1 to 2 equivalents of the appropriate base (e.g., sodium hydride, potassium carbonate, or cesium carbonate) in a suitable organic solvent (e.g., DMF) at 0 deg.C]Pyrrole-5-carboxylic acid methyl ester or 2-methyl-1- [2- (trimethylsilyl) ethoxy]-1, 4-dihydropyrrolo [2, 3-d]Imidazole-5-carboxylic acid methyl ester (prepared by reaction of Zarghi, A.; Ebrahimabadi, A.H.; Hassanzadeh, F.; Heydari, M.R.; Shafiee, A.BollettinoCh)imicoFarmaceutico，2003，Vo]142, No. 6p.251-254). Deprotonation was carried out by stirring at room temperature for about 1 hour. Then 1 to 2 equivalents of the appropriate bromoketone are added at 0 ℃ and the reaction is allowed to proceed at room temperature for at least 30 minutes. With water or saturated NH₄The reaction was diluted with aqueous Cl and the resulting precipitated product was collected by filtration and used as such in the next step. If no precipitate forms, the mixture is extracted with a suitable organic solvent (e.g., ethyl acetate or dichloromethane), and the organic layer is dried (MgSO)₄Or Na₂SO₄) And concentrated under vacuum. The residue was purified by flash chromatography.

Step (b): synthesis of intermediates (Compounds of formula (II))

In general, 1 equivalent of the appropriate ketoester or keto acid is reacted with 3 to 40 equivalents of ethylenediamine. Acetic acid may also be added in catalytic amounts. The mixture was heated at reflux in an inert solvent (e.g. chloroform, 1, 2-dichloroethane or 1, 4-dioxane) and monitored by LCMS. After completion the reaction was cooled to room temperature and then concentrated in vacuo. The residue can be purified directly by flash chromatography or it can be suspended/dissolved in water and extracted with a suitable organic solvent (e.g. dichloromethane). The organic layer was dried (MgSO₄Or Na₂SO₄) And concentrated under vacuum. The residue was then purified by flash chromatography.

Step (c): synthesis of the end product (Compound of formula (I))

In general, 1 equivalent of the appropriate cyclic amine in pyridine is added to 2.5 to 5 equivalents of the appropriate acid chloride in pyridine at 0 ℃. The acid chloride is initially prepared by reacting the corresponding acid with thionyl chloride or oxalyl chloride and a catalytic amount of DMF in dichloromethane. In some embodiments, the acid chloride may be prepared in situ in methylene chloride using cyanuric chloride and triethylamine. Alternatively, a solution of a cyclic amine in a suitable organic solvent (e.g., dichloromethane) is treated with a suitable base (e.g., triethylamine) and then treated with 2 to 5 equivalents of the appropriate isocyanate or acid chloride at 0 ℃.

The reaction was allowed to warm to room temperature and monitored by LCMS. After completion with water or saturated NaHCO₃The reaction mixture is quenched with aqueous solution and extracted with an organic solvent (e.g., ethyl acetate or dichloromethane). The organic layer was dried (MgSO₄Or Na₂SO₄) And concentrated under vacuum. The residue was then purified by flash chromatography.

Step (d): optional protection/deprotection

It will be appreciated that reaction intermediates may optionally be protected with one or more appropriately selected protecting groups during the course of the reaction and subsequently deprotected. Suitable protecting groups are known to those skilled in the art and are also described in protective group in organic synthesis, 3 rd edition 1999greene t.w. and wutsp.g.m., john wiley & Sons, Inc (see also 4 th edition, 2007john wiley & Sons, Inc).

In general, appropriately protected fused ring systems are dissolved in a solvent mixture (e.g., trifluoroacetic acid/dichloromethane in a ratio of 1: 1 to 4: 1), where PG represents a protecting group, which can be, but is not limited to, (2-ethoxyethyl) (trimethyl) silane groups. The reaction mixture was stirred at room temperature and monitored by LCMS. Upon completion the mixture was concentrated under vacuum and the resulting residue was purified by flash chromatography.

General procedure for the separation of stereoisomers by chiral chromatography

Selected compounds of the invention can be separated into individual stereoisomers by HPLC using a chromatographic column with a chiral stationary phase. Suitable conditions for separating the racemic compound into enantiomers may include the conditions detailed below.

Column: chiracecell OD-H (250 mm. times.4.6 mm) 5. mu.M,

isocratic elution: hexane: ethanol (90: 10v/v)

Detection wavelength: 220nm

Flow rate: 1.2 mL/min

Concentration: 1.0mg/mL

Sample introduction volume: 10 μ L

Column temperature: 25 deg.C

In one embodiment, the compounds of formula (I) may be prepared by a process which comprises reacting a compound of formula (II) as defined above with a compound of formula R '-C (═ O) R wherein R' is a leaving group or an activated ester group₆The step of reacting the compound of (1). The compounds of formula (II) may be in the form of racemates or single stereoisomers (e.g. enantiomers). Thus, a process for preparing a compound of formula (I) may comprise forming and/or separating a stereoisomer (e.g. an enantiomer) of a compound of formula (II) and reacting it with a compound of formula R' -C (═ O) R₆And (3) other steps of the reaction of the compound (1).

The leaving group may be of any suitable known type, for example j. march, advanced organic chemistry: the disclosures of Reactions, MechanismandsStructure, 4 th edition, pp.352-357, John Wiley & Sons, New York, 1992, are incorporated herein by reference (see also 5 th edition, John Wiley & Sons, New York2001 and 6 th edition, John Wiley & Sons, New Jersey, 2007). Preferably, the leaving group is halogen, more preferably chlorine.

Activated ester groups are known to those skilled in the art, for example as Montalbetti, c.a.g.n. and Falque, v., Tetrahedron (2005) 61: 10827, and 10852.

Examples

In order to illustrate the nature of the invention so that it may be more clearly understood, the following non-limiting examples are provided. However, it will be appreciated by persons skilled in the art that the invention described herein is susceptible to variations and modifications other than those specifically described below.

Synthesis of compounds

In Bruker Ultrashield^TMRecording on 400 or AM300 spectrometer¹HNMR spectra. Residual solvent peak as reference in CDCl₃、d₆-acetone, CD₃CN、CD₃OD or d₆Spectra were recorded in DMSO. Chemical shifts are reported on a parts per million (ppm) scale, and diversity is expressed using the following convention: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet) and the prefix br (broad).

Mass spectra (ESI) were recorded on a ThermoFinnigan LCQAdvantage or LCQDeca mass spectrometer coupled to a ThermoFinnigan SurveyorHPLC system. Unless otherwise stated, chromatography was performed using phenomenex C8(2) or C18(2) columns. The separation was performed at acidic pH using water containing 0.1% formic acid (solvent a) and acetonitrile containing 0.1% formic acid (solvent B). The separation was performed using ammonium acetate (5mM, solvent A) and methanol (solvent B) at neutral pH.

On 100 to 200 mesh silica gel or using biotage sp4(grace resolution v)^TMSilica flash column or C18 silica-filled column).

Abbreviations used in the examples, unless otherwise indicated, are as follows:

DMF: n, N-dimethylformamide

DMSO, DMSO: dimethyl sulfoxide

ESI: electrospray ionization

MS: mass spectrometry

LCMS: liquid chromatography-mass spectrometry

HPLC: high performance liquid chromatography

NMR: nuclear magnetic resonance

min: minute (min)

h: hour(s)

Example (b):

synthesis of 11a- (4-methoxyphenyl) -1- [ (3-methyl-1, 2- Oxazol-4-yl) carbonyl]-2, 3, 11, 11 a-tet Hydrogen-1H, 5H-imidazo [1, 2-a ]]Thieno [3 ', 2': 4,5]Pyrrolo [1, 2-d]Pyrazine-5-ones (1)

Step (a): to a solution of methyl 6H-thieno [2, 3-b ] pyrrole-5-carboxylate (100mg, 0.55mmol) in DMF (2mL) at 0 deg.C was added sodium hydride (15mg, 0.63 mmol). The reaction mixture was stirred at 0 ℃ for 1 hour and then 2-bromo-1- (4-methoxyphenyl) ethanone (251mg, 1.1mmol) was added. After 5 minutes the reaction was warmed to room temperature and stirred for 1 hour. The mixture was then poured into ice water, and the resulting precipitate was collected by filtration and washed with hexane to give methyl 6- [2- (4-methoxyphenyl) -2-oxoethyl ] -6H-thieno [2, 3-b ] pyrrole-5-carboxylate (100mg, 55% yield) as a white solid.

ESI-MIm/z[M+H]⁺330.15.¹HNMR(400MHz，CDCl₃)8.02(d，J＝8.8Hz，2H)，7.25(s，1H)，7.02(d，J＝5.3Hz，1H)，6.99(d，J＝8.8Hz，2H)，6.91(d，J＝5.3Hz，1H)，5.84(s，2H)，3.90(s，3H)，3.78(s，3H).

Step (b): to a solution of methyl 6- [2- (4-methoxyphenyl) -2-oxoethyl ] -6H-thieno [2, 3-b ] pyrrole-5-carboxylate (100mg, 0.30mmol) in 1, 4-dioxane (10mL) was added ethylenediamine (0.78mg, 12mmol) and the mixture was heated at reflux. The reaction was monitored by LCMS. Upon completion, the reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography (1% to 6% methanol-dichloromethane) to give 11a- (4-methoxyphenyl) -2, 3, 11, 11 a-tetrahydro-1H, 5H-imidazo [1, 2-a ] thieno [3 ', 2': 4, 5] pyrrolo [1, 2-d ] pyrazin-5-one (75mg, 73% yield).

ESI-MIm/z[M+H]⁺340.25.¹HNMR(400MHz，CDCI₃)7.31(d，J＝8.7Hz，2H)，7.14(s，1H)，6.96(d，J＝5.3Hz，1H)，6.82(d，J＝5.3Hz，1H)，6.78(d，J＝8.7Hz，2H)，4.52(d，J＝11.7Hz，1H)，4.25(d，J＝11.7Hz，1H)，4.02-3.89(m，1H)，3.73(s，3H)，3.64-3.51(m，1H)，3.37-3.26(m，1H)，3.08-2.94(m，1H).

Step (c): to produce the acid chloride: to 3-methylisoTo a cooled (ice-bath) suspension of oxazole-4-carboxylic acid (140mg, 1.1mmol) in dichloromethane (3mL) was added oxalyl chloride (0.23mL, 2.7mmol) followed by DMF (1 drop, catalytic). The mixture was allowed to warm to room temperature and stirred until the reaction was complete (suspension dissolved). The resulting solution was concentrated in vacuo and further dried under a stream of nitrogen to give the crude acid chloride.

To a cooled (ice-bath) suspension of the acid chloride (generated as above, 1.1mmol) in pyridine (2.4mL) was added 11a- (4-methoxyphenyl) -2, 3, 11, 11 a-tetrahydro-1H, 5H-imidazo [1, 2-a ]]Thieno [3 ', 2': 4,5]Pyrrolo [1, 2-d]Pyrazine-5-one (75mg, 0.22mmol) in pyridine (3mL) suspension after the mixture was warmed to room temperature for 2 hours LCMS indicated complete reaction, so the mixture was diluted with water and extracted with ethyl acetate (× 3). The extracts were combined, washed with brine and dried (Na)₂SO₄) Filtering and in vacuumThe filtrate was concentrated. The residue was purified by flash chromatography using biotage sp4 (0% to 10% methanol-ethyl acetate). The resulting material was dissolved in ethyl acetate and saturated NaHCO was used₃And (4) washing with an aqueous solution. The organic layer was concentrated in vacuo and the resulting solid was triturated with ethyl acetate-hexane to give 11a- (4-methoxyphenyl) -1- [ (3-methyl-1, 2-Oxazol-4-yl) carbonyl]-2, 3, 11, 11 a-tetrahydro-1H, 5H-imidazo [1, 2-a]Thieno [3 ', 2': 4,5]Pyrrolo [1, 2-d]Pyrazin-5-one (1) (44mg, 44% yield).

ESI-MIm/z[M+H]⁺449.16.¹HNMR(400MHz，CDCl₃)8.54(s，1H)，7.35(d，J＝9.0Hz，2H)，7.14(s.1H)，6.98(d，J＝5.3Hz，1H)，6.90(d，J＝5.3Hz，1H)，6.78(d，J＝9.0Hz，2H)，5.71(d，J＝12.6Hz，1H)，4.62(d，J＝12.6Hz，1H)，4.44-4.30(m，1H)，4.09-4.01(m，1H)，3.94-3.79(m，2H)，3.73(s，3H)，2.46(s，3H).

Synthesis of 5a- (4-methoxyphenyl) -2-methyl-6- [ (3-methyl-1, 2-) Oxazol-4-yl) carbonyl]5a, 6, 7, 8-tetra Hydrogen-5H-imidazo [1, 2-a ]]Imidazo]4′，5′：4，5]Pyrrolo [1, 2-d]-pyrazine-10 (1H) -one (2)

(5aS) -5a- (4-methoxyphenyl) -2-methyl-6- [ (3-methyl-1, 2-Oxazol-4-yl) carbonyl]-1- { [2- (trimethylsilyl) ethoxy]Methyl } -5a, 6, 7, 8-tetrahydro-5H-imidazo [1, 2-a ]]Imidazo [4 ', 5':4，5]pyrrolo [1, 2-d]-pyrazin-10 (1H) -one or its regioisomer (5aS) -5a- (4-methoxyphenyl) -6- [ (3-methyl-1, 2-Oxazol-4-yl) carbonyl]-3- { [2- (trimethylsilyl) ethoxy]Methyl } -5a, 6, 7, 8-tetrahydro-5H-imidazo [1, 2-a ]]Imidazo [4 ', 5': 4,5]Pyrrolo [1, 2-d]-pyrazin-10 (3H) -one (27mg, 0.048mmol) was dissolved in dichloromethane (0.9mL) and treated with trifluoroacetic acid (2.1 mL). The mixture was stirred at room temperature. LCMS indicated complete deprotection after 1 hour. The mixture was then concentrated in vacuo and the resulting residue was purified by flash chromatography using biotageSP4 (0% to 5% MeOH gradient in EtOAc) to give 5a- (4-methoxyphenyl) -2-methyl-6- [ (3-methyl-1, 2-Oxazol-4-yl) carbonyl]-5a, 6, 7, 8-tetrahydro-5H-imidazo [1, 2-a ]]Imidazo [4 ', 5': 4,5]Pyrrolo [1, 2-d]-pyrazin-10 (1H) -one (2) or its regioisomer 5a- (4-methoxyphenyl) -2-methyl-6- [ (3-methyl-1, 2-Oxazol-4-yl) carbonyl]-5a, 6, 7, 8-tetrahydro-5H-imidazo [1, 2-a ]]Imidazo [4 ', 5': 4,5]Pyrrolo [1, 2-d]-pyrazin-10 (3H) -one (8.5mg, 40% yield).

ESI-MIm/z[M+H]⁺447.09.¹HNMR(400MHz，CDCl₃)8.53(brs，1H)，8.46(brs，1H)，7.43(brd，J＝8.9Hz，2H)，6.82-6.73(m，2H)，6.69(s，1H)，6.05(d，J＝13.1Hz，1H)，4.46(d，J＝12.8Hz，1H)，4.35(ddd，J＝10.7，8.8，4.6Hz，1H)，4.00(td，J＝8.9，5.6Hz，1H)，3.83(tdd，J＝13.2，9.8，6.6Hz，2H)，3.72(s，3H)，2.52(s，3H)，2.42(d，J＝0.5Hz，3H).

The compounds in table 1 were prepared analogously with reference to the general methods and/or the synthesis examples.

Table 1: characterization of the Compound examples

Biological data

The following methods can be used to determine the antiviral activity of the compounds of the invention in vivo and in vitro.

RSV antiviral assay protocol

The compounds of the invention were tested for antiviral activity against respiratory syncytial virus. cytopathic effect (CPE) assays were performed essentially as described in the literature (see, e.g., Watanabe et al, 1994, J. virological methods, 48: 257.) Serial dilutions of the test compounds were prepared in 96-well plates, HEp2 cells (1.0 × 10) were infected with RSV at low multiplicity of infection (e.g., moi of RSVA2 is-0.01)⁴Individual cells/well) and added to the plate to assess antiviral activity. Uninfected HEp2 cells were used to assess compound cytotoxicity. At 5% CO₂The assay was incubated at 37 ℃ for 5 days in an atmosphere. By means of the vital dye 3- (4, 5-dimethylthiazol-2-yl) -2, 5-diphenyltetrazoleMetabolism of bromide (MTT) to determine the extent of CPE. MTT (1mg/ml) was added to each well and the plates were incubated at 37 ℃ for 2 hours. The wells were aspirated, isopropanol (200 μ L) was added and the absorbance values were read at 540/650 nm. CPE 50% inhibition calculated using non-linear regression analysis (EC)₅₀) And the production of cytotoxicity (CC)₅₀) The concentration of the compound (c).

Representative activity ranges for the compounds of the invention against RSVA2 are shown in table 2, where RSVA2EC₅₀The average values lie in the following ranges, a: less than or equal to 0.049 mu M, B: 0.05 to 0.099 μ M, C: 0.10 μ M to 0.499 μ M, D: 0.5-10.0. mu.M and E: > 10.0. mu.M. Reproduced EC in the experience of the present inventors₅₀Values typically fall within three standard deviations of the mean.

Table 2: RSVA2 antiviral data for compounds

Numbering	Range of activity	Numbering	Range of activity	Numbering	Range of activity
						1	A	2	A	3	B
4	A	5	C	6	A
						7	A	8	A	9	C
10	A	11	A	12	C
						13	A	14	E	15	E
16	E	17	E	18	E
						19	E	20	E	21	C
22	E	23	E	24	E
						25	E	26	E	27	D

RSV fusion assay

Selected compounds of the invention can be tested for their ability to inhibit the basic fusion process of respiratory syncytial virus.

Generation of RSV-F constructs

Single-stranded synthetic DNA oligonucleotides encoding a portion of the RSVA2F glycoprotein comprising optimal codons and no potential poly (a) additions or splice sites were produced by synthesis (Mason et al, WO 02/42326). Basically, the methods described above and Morton et al, 2003, Virology, 311: 275 to yield a membrane anchored full length F.

Syncytial formation assay

The fusion activity of the RSV-F construct was measured in 293 cells essentially according to the method described in Morton et al. For example: by adding plasmid DNA carrying the construct of interest (0.5. mu.g/well to 1.5. mu.g/well) to CaPO₄Cells with approximately 80% confluence in 6-well plates were transfected in solution for 2 hours. After glycerol shock and washing, the transfected cells were digested with trypsin,and 4 × 10⁴To 10 × 10⁴Individual cells/well were added to 96-well plates containing 2-fold or 3-fold serial dilutions of the test compound. Syncytia formation was assessed by visual inspection and quantified at 42 hours post-transfection by addition of 20 μ LCellTiter96OneSolution (Promega) followed by incubation at 37 ℃ for 2 hours. The absorbance values were read at 490/690 nm. Non-linear regression analysis was used to calculate the concentration of compound (EC) that reduced absorbance by 50% relative to untreated control cultures₅₀)。

RSV cotton rat model

Cotton rat models can be established essentially as described in the literature (Wyde et al, 2003, Antiviralres, 60: 221). Briefly, cotton rats weighing 50g to 100g were lightly anesthetized with isoflurane and orally administered either compound or vehicle control at 100 mg/kg/day. By intranasal instillation of approximately 1000TCID per animal in anesthetized-like rats₅₀RSVA2, 2 hours later, and then infected with the virus. 4 days after virus inoculation, each cotton rat was sacrificed, lungs removed and RSV titers determined by plaque assay.

RSVBalb/c mouse model

Can be prepared essentially according to Cianci et al, 2004, Antichronobial Agentsan and Chemotherapy, 48: 413 to establish a mouse model. Briefly, 8-week-old female Balb/c mice were weighed,

using Avertin^TMIntraperitoneal anesthesia, and the compound or vehicle is administered orally prior to infection, followed by once daily or twice daily administration. About 10000TCID for mice₅₀RSVA 2/animal was inoculated intranasally. 3 days after virus inoculation, each mouse was sacrificed, lungs were removed and RSV titers were determined by plaque assay. Body weight, spleen and liver weight can also be assessed. In addition, the ability of the test compounds to reduce the number of total and differentiated (macrophages, neutrophils and lymphocytes) inflammatory cells in bronchoalveolar lavage fluid (BALF) was also measured. This enables studies to improve the inflammatory response to RSV infection in animals treated with the test compounds as compared to those vaccinated with RSV aloneThe ability to respond.

Throughout the specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

The reference in this specification to any prior publication, or information derived from it, or to any matter which is known in the art, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that prior publication, or information derived from it, or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

It will be understood by those skilled in the art that many modifications may be made without departing from the spirit and scope of the invention.

Claims (10)

1. A compound of formula (I) or a salt thereof:

wherein

Represents a single bond or a double bond;

X₁is CHR₃Or CR₃；

X₂Is CR₁；

X₃Is CR₂；

R₁And R₂Together form an optionally substituted fused 5-or 6-membered heteroaromatic ring, said 5-or 6-membered heteroaromatic ring selected from the group consisting of phenyl, pyridyl, imidazolyl, furyl, and thienyl;

R₃is H;

R₄is para-substituted phenyl, wherein the substituents are selected from methyl, F;

R₅is C (═ O) R₆Or S (O)₂R₆；

When R is₅Is C (═ O) R₆When R is₆Selected from: 3-methylisoOxazol-4-yl; c_3-8A cycloalkyl group; a furyl group; c_1-6Alkyl optionally substituted by C_3-6Cycloalkyl, furyl; substitutedOxazolyl, wherein the substituent is methyl; substituted pyrazolyl, in which the substituent is C_1-6An alkyl group; n (R')₂Wherein each R' is independently selected from H, C_3-8Cycloalkyl, C substituted by phenyl_1-6An alkyl group;

when R is₅Is S (O)₂R₆When R is₆Selected from aryl or CH₂Aryl, wherein said aryl is phenyl, or R₆Selected from aryl, which is optionally substituted phenyl, wherein the optional substituent is nitro; and is

m is 2.

2. The compound of claim 1, wherein R₅Is C (═ O) R₆。

3. The compound according to claim 1, which is selected from the following compounds or salts thereof:

1)11a- (4-methoxyphenyl) -1- [ (3-methyl-1, 2-Oxazol-4-yl) carbonyl]-2, 3, 11, 11 a-tetrahydro-1H, 5H-imidazo [1, 2-a]Thieno [3 ', 2': 4,5]Pyrrolo [1, 2-d]Pyrazin-5-one;

2)5a- (4-methoxyphenyl) -2-methyl-6- [ (3-methyl-1, 2-)Oxazol-4-yl) carbonyl]-5a, 6, 7, 8-tetrahydro-5H-imidazo [1, 2-a ]]Imidazo [4 ', 5': 4,5]Pyrrolo [1, 2-d]Pyrazin-10 (1H) -one;

3)5a- (4-methoxyphenyl) -6- [ (3-methyl-1, 2-Oxazol-4-yl) carbonyl]-5a, 6, 7, 8-tetrahydro-5H, 10H-furo [2 ', 3': 4,5]Pyrrolo [1, 2-a]Imidazo [1, 2-d ] s]Pyrazin-10-one;

4)12a- (4-methoxyphenyl) -1- [ (3-methyl-1, 2-Oxazol-4-yl) carbonyl]-2, 3, 12, 12 a-tetrahydro-1H, 5H-imidazo [1 ', 2': 4,5]Pyrazino [1, 2-a ] s]Indol-5-one;

5)5a- (4-methoxyphenyl) -6- [ (3-methyl-1, 2-Oxazol-4-yl) carbonyl]-5a, 6, 7, 8-tetrahydro-5H, 10H-imidazo [1, 2-a [ ]]Thieno [2 ', 3': 4,5]Pyrrolo [1, 2-d]Pyrazin-10-one;

6)11a- (4-fluorophenyl) -1- [ (3-methyl-1, 2-)Oxazol-4-yl) carbonyl]-2, 3, 11, 11 a-tetrahydro-1H, 5H-imidazo [1, 2-a]Thieno [3 ', 2': 4,5]Pyrrolo [1, 2-d]Pyrazin-5-one;

7)1- [ (3-methyl-1，2-Oxazol-4-yl) carbonyl]-11a- (4-methylphenyl) -2, 3, 11, 11 a-tetrahydro-1H, 5H-imidazo [1, 2-a]Thieno [3 ', 2': 4,5]Pyrrolo [1, 2-d]Pyrazin-5-one;

8)12a- (4-methoxyphenyl) -1- [ (3-methyl-1, 2-Oxazol-4-yl) carbonyl]-2, 3, 12, 12 a-tetrahydro-1H, 5H-imidazo [1, 2-a]Pyrido [3 ', 2': 4,5]Pyrrolo [1, 2-d]Pyrazin-5-one;

9)12a- (4-methoxyphenyl) -1- [ (3-methyl-1, 2-Oxazol-4-yl) carbonyl]-2, 3, 12, 12 a-tetrahydro-1H, 5H-imidazo [1, 2-a]Pyrido [2 ', 3': 4,5]Pyrrolo [1, 2-d]Pyrazin-5-one;

10)1- [ (3-methyl-1, 2-)Oxazol-4-yl) carbonyl]-12a- (4-methylphenyl) -2, 3, 12, 12 a-tetrahydro-1H, 5H-imidazo [1, 2-a]Pyrido [3 ', 2': 4,5]Pyrrolo [1, 2-d]Pyrazin-5-one;

11)12a- (4-fluorophenyl) -1- [ (3-methyl-1, 2-Oxazol-4-yl) carbonyl]-2, 3, 12, 12 a-tetrahydro-1H, 5H-imidazo [1, 2-a]Pyrido [3 ', 2': 4,5]Pyrrolo [1, 2-d]Pyrazin-5-one;

12)12a- (4-fluorophenyl) -1- [ (3-methyl-1, 2-Oxazol-4-yl) carbonyl]-2, 3, 12, 12 a-tetrahydro-1H, 5H-imidazo [1, 2-a]Pyrido [2 ', 3': 4,5]Pyrrolo [1, 2-d]Pyrazin-5-one;

13)1- [ (3-methyl-1, 2-)Oxazol-4-yl) carbonyl]-11a- (6-methylpyridin-3-yl) -2, 3, 11, 11 a-tetrahydro-1H, 5H-imidazo [1, 2-a]Thieno [3 ', 2': 4,5]Pyrrolo [1, 2-d]Pyrazin-5-one;

14)11a- (4-fluorophenyl) -1- [ (5-methyl-1, 3-)Oxazol-4-yl) carbonyl]-2, 3, 11, 11 a-tetrahydro-1H, 5H-imidazo [1, 2-a]Thieno [3 ', 2': 4,5]Pyrrolo [1, 2-d]Pyrazin-5-one; and

15)11a- (4-fluorophenyl) -1- [ (4-nitrophenyl) sulfonyl ] -2, 3, 11, 11 a-tetrahydro-1H, 5H-imidazo [1, 2-a ] thieno [3 ', 2': 4, 5] pyrrolo [1, 2-d ] pyrazin-5-one.

An RSV antiviral agent comprising a compound as defined in any one of claims 1 to 3 or a salt thereof.

5. A pharmaceutical composition comprising a compound or salt thereof as defined in any one of claims 1 to 3 and a pharmaceutically acceptable carrier.

6. Use of a compound or salt thereof as defined in any one of claims 1 to 3 in the manufacture of a medicament for the treatment of an RSV infection or to reduce exacerbation of an underlying or pre-existing respiratory disease wherein an RSV infection is a cause of said exacerbation.

7. Use of the pharmaceutical composition of claim 5 in the manufacture of a medicament for treating an RSV infection or reducing exacerbation of an underlying or pre-existing respiratory disease, wherein RSV infection is a cause of said exacerbation.

8. By usingIn the preparation of a compound as defined in any one of claims 1 to 3, wherein R₅Is C (═ O) R₆A compound of formula (II) with a compound of formula R '-C (═ O) R wherein R' is a leaving group or an activated ester group₆A step of reacting the compound of (1);

wherein the resulting compound of formula (I) is optionally converted into a salt thereof;

and wherein- - - - - - -, X₁、X₂、X₃、R₄、R₆And m is as defined in claim 1.

A compound of (II):

wherein- - - - - - -, X₁、X₂、X₃、R₄And m is as defined in claim 1.

10. A process as defined in claim 8, comprising the step of cyclizing the precursor compound of formula (III),

wherein R is H or C_1-6An alkyl group; and is

-----、X₁、X₂、X₃And R₄As defined in claim 1.