HK1179266A - Analogues for the treatment or prevention of flavivirus infections - Google Patents
Analogues for the treatment or prevention of flavivirus infections Download PDFInfo
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Description
This application is entitled to provisional application No. US61/316,988 filed 3/24/2010 as 35u.s.c. § 119(e), which is incorporated herein by reference in its entirety.
Technical Field
The present invention relates to novel compounds and methods of using the novel compounds to treat or prevent flavivirus infections.
Background
Hepatitis is a disease that exists throughout the world. It typically has viral properties, however, there are other known reasons. Viral hepatitis is by far the most common form of hepatitis. Approximately 750,000 americans are afflicted with hepatitis each year, with over 150,000 of them infected with the hepatitis c virus ("HCV").
HCV is a positive-stranded RNA virus belonging to the Flaviviridae family (Flaviviridae) and has close relationship with pestiviruses including cholera swine virus and Bovine Viral Diarrhea Virus (BVDV). HCV is thought to replicate by generating a complementary negative-strand RNA template. Without an effective culture replication system for this virus, HCV particles were isolated from pooled human plasma and shown to have a diameter of about 50-60nm by electron microscopy. The HCV genome is a single-stranded, sense RNA of about 9,600bp encoding a 3009-3030 amino acid polyprotein that is cleaved into mature viral proteins (nuclear, E1, E2, p7, NS2, NS3, NS4A, NS4B, NS5A, NS5B) simultaneously and after translation. The structural glycoproteins E1 and E2 are believed to be embedded in the lipid envelope of the virus and form stable heterodimers. It is also believed that the structural nucleoprotein interacts with the viral RNA genome to form the nucleocapsid. The nonstructural proteins designated NS2 to NS5 include proteins having enzymatic functions involved in viral replication and processing proteins including polymerase, protease and helicase.
The main source of contamination with HCV is blood. The significance of HCV infection as a health problem is demonstrated by the incidence of disease in high-risk groups. For example, in western countries, 60% to 90% of hemophiliacs and more than 80% of intravenous drug addicts are chronically infected with HCV. For intravenous drug users, the incidence varies from about 28% to 70% depending on the population studied. Due to advances in diagnostic tools for screening blood donors, the proportion of new HCV infections associated with post-transfusion has recently decreased dramatically.
Combinations of pegylated interferon with ribavirin are the treatment of choice for chronic HCV infection. This treatment does not provide a Sustained Viral Response (SVR) in most patients infected with the most prevalent genotypes (1a and 1 b). In addition, significant side effects prevent compliance with current therapies, and in some patients may require dose reduction or withdrawal.
Thus, there is a need for the development of antiviral agents for the treatment or prevention of flavivirus infections.
Disclosure of Invention
In one aspect, the present invention provides a compound of formula (I):
or a pharmaceutically acceptable salt thereof, wherein
A is each independently C6-14Aryl, 4-to 12-membered heterocyclic ring, C3-10Cycloalkyl or 5-12 membered heteroaryl;
b and B' are each independently absent, C1-6Alkyl radical, C2-6Alkenyl or C2-6An alkynyl group;
c and C' are each independently a 4-7 membered heterocyclic ring;
R1is halogen, -ORa、-NRaRb、-C(=O)ORa、-C(O)NRaRb、-C(=O)OH、-C(=O)Ra、-C(=NORc)Ra、-C(=NRc)NRaRb,-NRdC(=O)NRaRb、-NRbC(=O)Ra、-NRdC(=NRc)NRaRb、-NRbC(=O)ORa、-OC(=O)NRaRb、-OC(=O)Ra、-OC(=O)ORaHydroxy, nitro, azido, cyano, -S (O)0-3Ra、-SO2NRaRb、-NRbSO2Ra、-NRbSO2NRaRb、-P(=O)ORaORbUnsubstituted or substituted by R10Substituted one or more times by C1-6Alkyl, unsubstituted or substituted by R10Substituted one or more times by C2-6Alkenyl, unsubstituted or substituted by R10Substituted one or more times by C2-6Alkynyl, or any two occurrences of R1May form together with the atom to which they are attached unsubstituted or R115-7 cycloalkyl substituted once or more times, or unsubstituted or by R12A 5-7 membered heterocyclic ring substituted one or more times;
Ra-Rdeach independently is H, C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C6-12Aryl radical, C7-16Aralkyl, 5-12 membered heteroaryl, 6-18 memberedHeteroaralkyl, 3-12 membered heterocycle or 4-18 membered heterocycle-alkyl;
R2’is halogen, C1-10Alkyl radical, C1-6Haloalkyl, - (CH)2)1-6OH、-NRbC(=O)Ra,C6-12Aryl or 5-12 membered heteroaryl;
R2each independently is halogen, C1-10Alkyl radical, C1-6Haloalkyl, - (CH)2)1-6OH、-ORa、-C(=O)ORa,-NRaRb、-NRbC(=O)Ra,-C(O)NRaRb、-S(O)0-3Ra,C6-12Aryl, 5-12 membered heterocycle or 5-12 membered heteroaryl;
R3and R3' independently of each other is H, C1-6Alkyl, - (CH)2)1-6OH、C2-6Alkenyl or C2-6An alkynyl group;
R4and R4' independently of one another are halogen, -NRaRb,-C(O)NRaRb、-(CH2)1-6OH、C1-6Alkyl radical, C1-6Haloalkyl, hydroxy, C6-14Aryl or C1-6An alkoxy group; in which R appears twice4May form together with the atom to which they are attached an unsubstituted or substituted R10Substituted one or more times by C1-6Alkenyl, unsubstituted or substituted by R113-7 cycloalkyl substituted once or more times, or unsubstituted or substituted by R12A 4-7 membered heterocycle substituted one or more times; in which R appears twice4' may form together with the atom to which it is attached an unsubstituted or substituted R10Substituted one or more times by C1-6Alkenyl, unsubstituted or substituted by R113-7 cycloalkyl substituted once or more times, or unsubstituted or substituted by R12A 4-7 membered heterocycle substituted one or more times;
x and Y are each independently
Or a bond;
wherein the asterisk (—) indicates the point of attachment to the nitrogen of ring C or C';
R5and R5' independently of one another are H, unsubstituted or substituted by R10Substituted one or more times by C1-18Alkyl, unsubstituted or substituted by R10Substituted one or more times by C2-12Alkenyl, unsubstituted or substituted by R10Substituted one or more times by C2-12Alkynyl, unsubstituted or substituted by R11Substituted one or more times by C6-14Aryl, unsubstituted or substituted by R11Substituted one or more times by C7-16Aralkyl, unsubstituted or substituted by R115-12 membered heteroaryl, unsubstituted or substituted once or many times by R116-18 membered heteroaralkyl, unsubstituted or substituted once or many times by R123-12 membered heterocyclic ring substituted once or more times, or unsubstituted or substituted by R124-18 membered heterocyclyl-alkyl substituted one or more times;
R6is H, C1-6Alkyl or halo C1-6An alkyl group;
m and n are each independently 0,1, 2,3 or 4;
p is 0,1, 2,3 or 4;
q is 0,1 or 2;
u is 0 or 1;
s is 0,1, 2,3 or 4;
R10is halogen, -ORaOxo, -NRaRb,=NO-Rc、-C(=O)ORa、-C(O)NRaRb、-C(=O)OH、-C(=O)Ra、-C(=NORc)Ra,-C(=NRc)NRaRb,-NRdC(=O)NRaRb、-NRbC(=O)Ra、-NRdC(=NRc)NRaRb、-NRbC(=O)ORa、-OC(=O)NRaRb、-OC(=O)Ra、-OC(=O)ORaHydroxy, nitro, azido, cyano, -S (O)0-3Ra、-SO2NRaRb、-NRbSO2Ra、-NRbSO2NRaRbOR-P (= O) ORaORb；
R11Is halogen, -ORa、-NRaRb、-C(=O)ORa,-C(O)NRaRb、-C(=O)OH、-C(=O)Ra、-C(=NORc)Ra、-C(=NRc)NRaRb、-NRdC(=O)NRaRb、-NRbC(=O)Ra、-NRdC(=NRc)NRaRb、-NRbC(=O)ORa、-OC(=O)NRaRb、-OC(=O)Ra、-OC(=O)ORaHydroxy, nitro, azido, cyano, -S (O)0-3Ra、-SO2NRaRb、-NRbSO2Ra、-NRbSO2NRaRbOR-P (= O) ORaORb、C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C6-12Aryl radical, C7-16Aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl; and is
R12Is halogen, -ORaOxo, -NRaRb,=NO-Rc、-C(=O)ORa,-C(O)NRaRb、-C(=O)OH、-C(=O)Ra、-C(=NORc)Ra,-C(=NRc)NRaRb,-NRdC(=O)NRaRb、-NRbC(=O)Ra、-NRdC(=NRc)NRaRb、-NRbC(=O)ORa、-OC(=O)NRaRb、-OC(=O)Ra、-OC(=O)ORaHydroxy, nitro, azideRadical, cyano, -S (O)0-3Ra、-SO2NRaRb、-NRbSO2Ra、-NRbSO2NRaRbOR-P (= O) ORaORb、C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C6-12Aryl radical, C7-16Aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl.
In another aspect, there is provided a method for treating or preventing a flaviviridae viral infection in a patient, comprising administering to the patient a therapeutically effective amount of a compound, composition or combination of the invention.
In another aspect, there is provided a pharmaceutical composition comprising at least one compound of the invention and at least one pharmaceutically acceptable carrier or excipient.
In another aspect, there is provided a combination comprising a compound of the invention and one or more additional active agents selected from the group consisting of viral serine protease inhibitors, viral polymerase inhibitors, viral helicase inhibitors, immunomodulators, antioxidants, antibacterial agents, therapeutic vaccines, liver protective drugs, antisense drugs, inhibitors of HCV NS2/3 protease and inhibitors of the Internal Ribosome Entry Site (IRES).
In another aspect, there is provided the use of a compound, composition or combination of the invention in the treatment or prevention of a human flaviviridae virus infection.
In another aspect, there is provided the use of a compound, composition or combination of the invention in the manufacture of a medicament for the treatment or prevention of a flaviviridae infection in a human.
In one embodiment, the compounds of the present invention comprise compounds wherein the following forms of embodiments exist, either individually or in combination.
According to a further embodiment, the compound of the invention is represented by formula (II):
wherein the variables are each as defined herein.
According to a further embodiment, the compound of the invention is represented by formula (IIIA), (IIIB), (IV) or (V):
wherein the variables are each as defined herein.
According to a further embodiment, a is phenyl, thiophene, thieno [3,2-b ] thiophene, pyridine, pyrimidine, naphthyl, benzo [1,3] dioxole, benzoxazole or triazole.
According to a further embodiment, a is phenyl, thiophene, thieno [3,2-b ] thiophene, naphthyl, benzo [1,3] dioxole or benzoxazole.
According to a further embodiment, a is phenyl, thiophene, pyridine, pyrimidine or triazole.
According to a further embodiment, a is phenyl or thieno [3,2-b ] thiophene.
According to a further embodiment, a is phenyl or thiophene.
According to a further embodiment, A is
According to a further embodiment, A is
According to a further embodiment, A is
According to a further embodiment, A is
According to a further embodiment, a is a bond.
According to a further embodiment, B and B' are each independently C2-6Alkynyl or C1-6An alkyl group.
According to a further embodiment, B and B' are each independently- (C.ident.C) -or- (CH ≡ C) -or2)2-。
According to a further embodiment, B and B' are each- (CH)2)2-。
According to a further embodiment, B and B' are each- (C ≡ C) -.
In accordance with a further embodiment of the method,the method comprises the following steps:
according to a further embodiment, m or n is 2.
According to a further embodiment, m or n is 1.
According to a further embodiment, m and n are 1.
According to a further embodiment, one of m or n is 1 and the other m or n is 0.
According to a further embodiment, m and n are each independently 0 or 1, provided that at least one of m and n is 1.
According to a further embodiment, p is 2.
According to a further embodiment, p is 1.
According to a further embodiment, X and Y are each
According to a further embodiment, X and Y are each
Wherein bonds marked with an asterisk indicate nitrogen attachment to ring C or C'.
According to a further embodiment, R4And R4' independently of one another are H, halogen, C1-6Alkyl, hydroxy, phenyl or C1-4An alkoxy group.
According to a further embodiment, R4And R4' are each independently H, halogen, methyl, ethyl, tert-butoxy-or hydroxy.
According to a further embodiment, R4And R4' are each H.
According to a further embodiment, R4And R4Each' is fluorine.
According to a further embodiment, R4And R4Each' is methyl.
According to a further embodiment, at least one R4And R4' is methyl.
According to a further embodiment, R3And R3' are each H.
According to a further embodiment, R1Is H, halogen, -ORa、-NRaRb、-C(=O)ORa、-C(O)NRaRb、-C(=O)OH、-NRbC(=O)Ra-hydroxy, nitro, cyano, -S (O)0-3Ra、C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl or C1-6A haloalkyl group.
According to a further embodiment, R1Is halogen, C1-3Alkyl, hydroxy, cyano or C1-3An alkoxy group.
According to a further embodiment, R1Is chloro, fluoro, methyl, hydroxy, cyano or methoxy.
According to a further embodiment, R1Is methyl.
According to a further embodiment, R1Is H.
According to a further embodiment, R2And R2' independently of one another are H, halogen, C1-6Alkyl, - (CH)2)1-3OH、-ORa、-C(=O)ORa、-C(O)NRaRb、-C(=O)OH、C6-12Aryl or 5-12 membered heteroaryl, wherein Ra-RdEach independently is H, C1-12Alkyl radical, C6-12Aryl radical, C7-16Aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl.
According to a further embodiment, R2And R2' independently of one another are H, halogen, C1-6Alkyl, - (CH)2)1-3OH、-ORa、-C(=O)ORa,-C(O)NRaRb-C (= O) OH, phenyl or 5-6 membered heteroaryl, wherein Ra-RdEach independently is H, C1-12Alkyl radical, C6-12Aryl radical, C7-16Aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl.
According to a further embodiment, R2And R2Each' is methyl.
According to a further embodiment, R2And R2Each is iodine.
According to a further embodiment, R2And R2' are each H.
According to a further embodiment, R6Is H or C1-3An alkyl group.
According to a further embodiment, R5And R5' are each independently unsubstituted or substituted with R10Substituted one or more times by C1-8Alkyl, unsubstituted or substituted by R10Substituted one or more times by C2-8Alkenyl, unsubstituted or substituted by R10Substituted one or more times by C2-8Alkynyl, unsubstituted or substituted by R11Phenyl substituted once or many times, unsubstituted or by R11Substituted one or more times by C7-8Aralkyl, unsubstituted or substituted by R115-6 membered heteroaryl, unsubstituted or substituted once or many times by R116-8 membered heteroaralkyl, unsubstituted or substituted once or many times by R123-6 membered heterocyclic ring substituted once or more than once, or unsubstituted or substituted by R124-8 membered heterocyclyl-alkyl substituted one or more times.
According to a further embodiment, R5And R5' are each independently unsubstituted or substituted with R10Substituted one or more times by C1-6Alkyl, unsubstituted or substituted by R10Substituted one or more times by C2-6Alkenyl, unsubstituted or substituted by R10Substituted one or more times by C2-6Alkynyl, unsubstituted or substituted by R11Phenyl substituted once or many times, unsubstituted or by R11Benzyl substituted once or many times, unsubstituted or by R115-6 membered heteroaryl, unsubstituted or substituted once or many times by R116-7 membered heteroaralkyl, unsubstituted or substituted once or many times by R125-6 membered heterocycle substituted once or more than once, or unsubstituted or substituted by R126-7 membered heterocycle-alkyl substituted one or more times.
According to a further embodiment, R5And R5' are each independently unsubstituted or substituted with R10Substituted one or more times by C1-6Alkyl, unsubstituted or substituted by R10Substituted one or more times by C2-6Alkenyl, or unsubstituted or substituted by R10Substituted one or more times by C2-6Alkynyl.
According to a further embodiment, R5And R5' are each independently unsubstituted or substituted with R10Substituted one or more times by C1-12An alkyl group.
According to a further embodiment, R5And R5' are each independently methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, 2-methylbutane, 3-methylbutane, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or Cyclohexyl (CH)2) -, in each case they are each unsubstituted or substituted by R10One or more substitutions.
According to a further embodiment, R5And R5' are each independently methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, 2-methylbutane, 3-methylbutane, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or Cyclohexyl (CH)2)-。
According to a further embodiment, R5And R5' are each independently unsubstituted or substituted with R10Isopropyl substituted one or more times.
According to a further embodiment, R5And R5' independently of each other is isopropyl, unsubstituted or substituted by-OCH3One or more substitutions.
According to a further embodiment, R5And R5' each is isopropyl.
According to a further embodiment, R5And R5' are each H or tert-butyl.
According to a further embodiment, R5And R5' are each independently unsubstituted or substituted with R11Phenyl substituted one or more times.
According to a further embodiment, R5And R5' are each independently unsubstituted or substituted with R11Benzyl substituted one or more times.
According to a further embodiment, R10Is halogen, -ORaOxo, -NRaRb、=NO-Rc、-C(=O)ORa、-C(O)NRaRb、-C(=O)OH、-C(=O)Ra、-C(=NORc)Ra、-C(=NRc)NRaRb、-NRdC(=O)NRaRb、-NRbC(=O)Ra、-NRdC(=NRc)NRaRb、-NRbC(=O)ORa、-OC(=O)NRaRb、-OC(=O)Ra、-OC(=O)ORaHydroxy, nitro, azido, cyano, -S (O)0-3Ra、-SO2NRaRb、-NRbSO2Raor-NRbSO2NRaRbWherein R isa-RdEach independently is H, C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C6-12Aryl radical, C7-16Aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl.
According to a further embodiment, R10is-NRaRb、-NRdC(=O)NRaRb、-NRbC(=O)Ra、-NRdC(=NRc)NRaRb、-NRbC(=O)ORa、-NRbSO2Raor-NRbSO2NRaRbWherein R isa-RdEach independently is H, C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C6-12Aryl radical, C7-16Aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl.
According to a further embodiment, R10is-NRaRb,-NRdC(=O)NRaRb、-NRbC(=O)Ra、-NRbC(=O)ORaor-NRbSO2RaWherein R isa,RbAnd RdEach independently is H, C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C6-12Aryl radical, C7-16Aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl.
According to a further embodiment, R10is-NRaRbor-NRdC(=O)NRaRbWherein R isaAnd RbEach independently is H, C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C6-12Aryl radical, C7-16Aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl.
According to a further embodiment, R10is-NRdC(=O)NRaRbWherein R isa,RbEach independently is H, C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C6-12Aryl radical, C7-16Aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl.
According to a further embodiment, R10Is halogen, -ORaOxo, -C (= O) ORa、-C(O)NRaRb、-C(=O)OH、-C(=O)Ra、-OC(=O)NRaRb、-OC(=O)Ra、-OC(=O)ORaHydroxy, cyano, wherein R isa-RbEach independently is H, C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C6-12Aryl radical, C7-16Aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl.
According to a further embodiment, R10Is halogen, -ORaOxo, -C (= O) ORa、-C(O)NRaRb、-C(=O)OH、-OC(=O)NRaRbHydroxy or cyano, wherein R isa-RbEach independently is H, C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C6-12Aryl radical, C7-16Aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl.
According to a further embodiment, R10Is halogen, C1-6Alkoxy, hydroxy or NH2。
According to a further embodiment, R10Is halogen, hydroxy or NH2。
According to a further embodiment, R10Is a halogen.
According to a further embodiment, R11Is halogen, -ORa、-NRaRb、-C(=O)ORa、-C(O)NRaRb、-C(=O)OH、-C(=O)Ra、-C(=NORc)Ra、-C(=NRc)NRaRb,-NRdC(=O)NRaRb、-NRbC(=O)Ra、-NRdC(=NRc)NRaRb、-NRbC(=O)ORa、-OC(=O)NRaRb、-OC(=O)Ra、-OC(=O)ORaHydroxy, nitro, azido, cyano, -S (O)0-3Ra、-SO2NRaRb、-NRbSO2Raor-NRbSO2NRaRb,C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C6-12Aryl radical, C7-16Aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle or 4-18 membered heterocycle-alkyl, wherein R isa-RdEach independently is H, C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C6-12Aryl radical, C7-16Aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl.
According to a further embodiment, R11Is halogen, -ORa、-NRaRb、-C(=O)ORa、-C(O)NRaRb、-C(=O)OH、-C(=O)Ra、-NRdC(=O)NRaRb、-NRbC(=O)Ra、-NRbC(=O)ORa、-OC(=O)NRaRb、-OC(=O)Ra、-OC(=O)ORaHydroxy, cyano, -SO2NRaRb、-NRbSO2Ra、C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, phenyl, C7-8Aralkyl, 5-6 membered heteroaryl, 6-8 membered heteroaralkyl, 5-6 membered heterocycle, or 6-8 membered heterocycle-alkyl, wherein R isa、RbAnd RdEach independently is H, C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C6-12Aryl radical, C7-16Aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl.
According to a further embodiment, R11Is halogen, -ORa、-NRaRb、-C(O)NRaRb、-C(=O)OH、-C(=O)Ra、-NRdC(=O)NRaRb、-NRbC(=O)Ra、-NRbC(=O)ORa、-OC(=O)NRaRbHydroxy, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, phenyl, C7-8Aralkyl, 5-6 membered heteroaryl, 6-8 membered heteroaralkyl, 5-6 membered heterocycle, or 6-8 membered heterocycle-alkyl, wherein R isa、RbAnd RdEach independently is H, C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C6-12Aryl radical, C7-16Aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl.
According to a further embodiment, R11Is halogen, -ORa、-NRaRbHydroxy, cyano or C1-6Alkyl radical, wherein Ra-RbEach independently is H, C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C6-12Aryl radical, C7-16Aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl.
According to a further embodiment, R11Is halogen, hydroxy, cyano or NH2。
According to a further embodiment, R11Is a halogen.
According to a further embodiment, R12Is halogen, -ORaOxo, -NRaRb、=NO-Rc、-C(=O)ORa、-C(O)NRaRb、-C(=O)OH、-C(=O)Ra、-C(=NORc)Ra、-C(=NRc)NRaRb、-NRdC(=O)NRaRb、-NRbC(=O)Ra、-NRdC(=NRc)NRaRb、-NRbC(=O)ORa、-OC(=O)NRaRb、-OC(=O)Ra、-OC(=O)ORaHydroxy, nitro, azido, cyano, -S (O)0-3Ra、-SO2NRaRb、-NRbSO2Ra、-NRbSO2NRaRb、C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C6-12Aryl radical, C7-16Aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl, wherein R isa-RdEach independently is H, C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C6-12Aryl radical, C7-16Aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl.
According to a further embodiment, R12Is halogen, -ORaOxo, -NRaRb、-C(=O)ORa、-C(O)NRaRb、-C(=O)OH、-C(=O)Ra、-NRdC(=O)NRaRb、-NRbC(=O)Ra、-NRbC(=O)ORa、-OC(=O)NRaRb、-OC(=O)Ra、-OC(=O)ORaHydroxy, cyano, -SO2NRaRb、-NRbSO2Ra,C1-6Alkyl radical, C2-6Alkenyl radical、C2-6Alkynyl, phenyl, C7-8Aralkyl, 5-6 membered heteroaryl, 6-8 membered heteroaralkyl, 5-6 membered heterocycle, or 6-8 membered heterocycle-alkyl, wherein R isa、RbAnd RdEach independently is H, C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C6-12Aryl radical, C7-16Aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl.
According to a further embodiment, R12Is halogen, -ORaOxo, -NRaRb、-C(O)NRaRb、-C(=O)OH、-C(=O)Ra,-NRdC(=O)NRaRb、-NRbC(=O)Ra、-NRbC(=O)ORa、-OC(=O)NRaRbHydroxy, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, phenyl, C7-8Aralkyl, 5-6 membered heteroaryl, 6-8 membered heteroaralkyl, 5-6 membered heterocycle, or 6-8 membered heterocycle-alkyl, wherein R isa,RbAnd RdEach independently is H, C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C6-12Aryl radical, C7-16Aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl.
According to a further embodiment, R12Is halogen, -ORaOxo, -NRaRbHydroxy, cyano or C1-6Alkyl radical, wherein Ra-RbEach independently is H, C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C6-12Aryl radical, C7-16Aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl.
According to a further embodiment, R12Is a halogen.
According to a further embodiment, Ra-RdEach independently is H, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, phenyl, C7-8Aralkyl, 5-6 membered heteroaryl, 6-8 membered heteroaralkyl, 5-6 membered heterocycle, or 6-8 membered heterocycle-alkyl.
According to a further embodiment, RaAnd RcEach independently is H, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, phenyl, C7-8Aralkyl, 5-6 membered heteroaryl, 6-8 membered heteroaralkyl, 5-6 membered heterocycle or 6-8 membered heterocycle-alkyl, RbAnd RdEach independently is H or C1-3An alkyl group.
According to a further embodiment, RaAnd RcEach independently is H, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, phenyl, benzyl, 5-6 membered heteroaryl, 6-8 membered heteroaralkyl, 5-6 membered heterocycle or 6-8 membered heterocycle-alkyl, RbAnd RdEach independently is H or C1-3An alkyl group.
According to a further embodiment, Ra-RdEach independently is H or C1-3An alkyl group.
According to a further embodiment, the compounds of the invention are represented by formula (IV):
according to a further embodiment, R8And R8' each independently is-NRaRb、-NRbC(=O)Raor-NRbC(=O)ORaWherein R isa-RbEach independently is H, C1-6Alkyl, phenyl, benzyl, 5-6 membered heteroaryl, 6-8 membered heteroaralkyl, 5-6 membered heterocycle, or 6-8 membered heterocycle-alkyl.
According to a further embodiment, R8And R8' each independently is-NRaRbor-NRbC(=O)ORaWherein R isa-RbEach independently is H, C1-6Alkyl, phenyl, benzyl, 5-6 membered heteroaryl, 6-8 membered heteroaralkyl, 5-6 membered heterocycle, or 6-8 membered heterocycle-alkyl.
According to a further embodiment, R8And R8' each independently is-NRbC(=O)ORaWherein R isa-RbEach independently is H, C1-6Alkyl, phenyl, benzyl, 5-6 membered heteroaryl, 6-8 membered heteroaralkyl, 5-6 membered heterocycle, or 6-8 membered heterocycle-alkyl.
According to a further embodiment, R in formula (IV)8And R8' each independently is-NRbC(=O)ORaWherein R isa-RbEach independently is H, C1-6Alkyl, phenyl, tetrahydrofuran or benzyl.
According to a further embodiment, R in formula (IV)8And R8' each independently is-NRbC(=O)ORaWherein R isaIs C1-6Alkyl radical, RbIs H or methyl.
According to a further embodiment, R in formula (IV)8And R8' each independently is-NRbC(=O)ORaWherein R isaIs C1-6Alkyl radical, RbIs H.
According to a further embodiment, R in formula (IV)8And R8' each independently is-NRbC(=O)ORaWherein R isaIs methyl, RbIs H.
According to a further embodiment, R7And R7' each independently is C1-8Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl, phenyl, benzyl, 5-6 membered heteroaryl, 6-7 membered heteroaralkyl, 3-6 membered heterocycle, or 4-7 membered heterocycle-alkyl;
according to a further embodiment, R7And R7' are each independently phenyl.
According to a further embodiment, R7And R7' each independently is C1-6An alkyl group.
According to a further embodiment, R7And R7' are each independently methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, 2-methylbutane, 3-methylbutane, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
According to a further embodiment, R7And R7' each is isopropyl.
According to a further embodiment, the compounds of the invention are represented by formula (V):
according to a further embodiment, B, B', R are allowed as valenciesa-Rd、R1、R2、R2’、R3、R3’、R4、R4’、R10、R11And R12The alkyl, alkenyl, alkynyl, alkoxy, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycle OR heterocycle-alkyl of (A) are each independently unsubstituted OR substituted by halogen, -ORa’、-NRa’Rb’、C(=O)ORa’、-C(O)NRa’Rb’-C (= O) OH, hydroxy, nitro, azido or cyano, wherein R is substituted one or more timesa’-Rd’Each independently is H, C1-12An alkyl group.
According to a further embodiment, B, B', R are allowed as valenciesa-Rd、R1、R2、R2’、R3、R3’、R4、R4’、R10、R11And R12The alkyl, alkenyl, alkynyl, alkoxy, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycle or heterocycle-alkyl of (a) is each independently unsubstituted or substituted once by halogen.
According to a further embodiment, B, B', R are allowed as valenciesa-Rd、R1、R2、R2’、R3、R3’、R4、R4’、R10、R11And R12The alkyl, alkenyl, alkynyl, alkoxy, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycle or heterocycle-alkyl of (a) is each independently unsubstituted or substituted once with fluorine.
According to a further embodiment, the compound is selected from compounds as defined in the general formula (la), wherein:
a is C6-14Aryl, 5-12 membered heteroaryl, or a bond;
b and B' are each independently- (C.ident.C) -or- (CH)2)2-；
R1Is H, halogen, -ORa、-NRaRb、-C(=O)ORa、-C(O)NRaRb、-C(=O)OH、-NRbC(=O)RaHydroxy, nitro, cyano, -S (O)0-3Ra、-C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl or C1-6A haloalkyl group;
R2and R2' are each independently H, methyl or iodo;
m and n are each independently 0,1 or 2;
p is 0,1 or 2;
R3and R3' is H;
R4and R4' independently of one another are H, halogen, C1-6Alkyl, hydroxy, phenyl or C1-4An alkoxy group;
x and Y are
R5And R5' are each independently unsubstituted or substituted with R10Substituted one or more times by C1-12An alkyl group.
According to a further embodiment, the compound is selected from compounds as defined in the general formula (la), wherein:
a is C6-14Aryl, 5-12 membered heteroaryl, or a bond;
b and B' are each independently- (C.ident.C) -or- (CH)2)2-；
R1Is H or methyl;
R2and R2' are each independently H, methyl or iodo;
m and n are each independently 0,1 or 2;
p is 0,1 or 2;
R3and R3' is H;
R4and R4' independently of one another are H, halogen, C1-6Alkyl, hydroxy, phenyl or C1-4An alkoxy group;
x and Y are
R5And R5' are each independently unsubstituted or substituted with R10Substituted one or more times by C1-12An alkyl group.
According to a further embodiment, the compound is selected from compounds as defined in the general formula (la), wherein:
a is phenyl, thiophene, thieno [3,2-b ] thiophene, pyridine, pyrimidine, naphthyl, benzo [1,3] dioxole, benzoxazole or triazole;
b and B' are each independently- (C.ident.C) -or- (CH)2)2-；
R1Is H or methyl;
R2and R2' are each independently H, methyl or iodo;
m and n are each independently 0,1 or 2;
p is 0,1 or 2;
R3and R3' is H;
R4and R4' independently of one another are H, halogen, C1-6Alkyl, hydroxy, phenyl or C1-4An alkoxy group;
x and Y are
R5And R5' are each independently unsubstituted or substituted with R10Substituted one or more times by C1-12An alkyl group.
According to a further embodiment, the compound is selected from compounds as defined in the general formula (la), wherein:
a is phenyl, thiophene, thieno [3,2-b ] thiophene, naphthyl, benzo [1,3] dioxole or benzoxazole;
b and B' are each independently- (C.ident.C) -or- (CH)2)2-；
R1Is H, halogen, -ORa、-NRaRb、-C(=O)ORa、-C(O)NRaRb、-C(=O)OH、-NRbC(=O)RaHydroxy, nitro, cyano, -S (O)0-3Ra、-C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl or C1-6A haloalkyl group;
R2and R2' are each independently H, methyl or iodo;
m and n are each independently 0,1 or 2;
p is 0,1 or 2;
R3and R3' is H;
R4and R4' independently of one another are H, halogen, C1-6Alkyl, hydroxy, phenyl or C1-4An alkoxy group;
x and Y are each
R5And R5' are each independently unsubstituted or substituted with R10Substituted one or more times by C1-12An alkyl group;
R7and R7' are each independently unsubstituted or substituted with R10Substituted one or more times by C1-8Alkyl, unsubstituted or substituted by R10Substituted one or more times by C2-8Alkenyl, unsubstituted or substituted by R10Substituted one or more times by C2-8Alkynyl, unsubstituted or substituted by R11Phenyl substituted once or many times, unsubstituted or by R11Benzyl substituted once or many times, unsubstituted or by R115-6 membered heteroaryl, unsubstituted or substituted once or many times by R116-7 membered heteroaralkyl, unsubstituted or substituted once or many times by R123-6 membered heterocyclic ring substituted once or more times or unsubstituted or substituted by R124-7 membered heterocyclyl-alkyl substituted one or more times; and is
R8And R8' each independently is-NRaRb、-NRdC(=O)NRaRb、-NRbC(=O)Ra、-NRdC(=NRc)NRaRb、-NRbC(=O)ORa、-NRbSO2Ra、-NRbSO2NRaRbWherein R isa-RdEach independently is H, C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C6-12Aryl radical, C7-16Aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl.
In some embodiments, the compounds of the present invention are represented in table 1A. In some embodiments, the variables used herein are as defined in the specific embodiments shown in table 1A.
In some embodiments, the compounds of the present invention are represented in table 1B. In some embodiments, the variables used herein are as defined in the specific embodiments shown in table 1B.
In one embodiment of the compounds of the invention, R1Is halogen, -ORa、-NRaRb、-C(=O)ORa、-C(O)NRaRb、-C(=O)OH、-C(=O)Ra、-C(=NORc)Ra、-C(=NRc)NRaRb,-NRdC(=O)NRaRb、-NRbC(=O)Ra、-NRdC(=NRc)NRaRb、-NRbC(=O)ORa、-OC(=O)NRaRb、-OC(=O)Ra、-OC(=O)ORaHydroxy, nitro, azido, cyano, -S (O)0-3Ra、-SO2NRaRb、-NRbSO2Ra、-NRbSO2NRaRb、-P(=O)ORaORbUnsubstituted or substituted by R10Substituted one or more times by C1-6Alkyl, unsubstituted or substituted by R10Substituted one or more times by C2-6Alkenyl, unsubstituted or substituted by R10Substituted one or more times by C2-6Alkynyl.
In one embodiment of the compounds of the present inventionIn the case, B, B' and R are allowed as valences hereina-Rd、R1、R2、R2’、R3、R3’、R4、R4’、R10、R11And R12The alkyl, alkenyl, alkynyl, alkoxy, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycle OR heterocycle-alkyl of (A) are each independently unsubstituted OR substituted by halogen, -ORa’Oxo, -NRa’Rb’,=NO-Rc’、-C(=O)ORa’、-C(O)NRa’Rb’、-C(=O)OH、-C(=O)Ra’、-C(=NORc’)Ra’、-C(=NRc’)NRa’Rb’、-NRd’C(=O)NRa’Rb’、-NRb’C(=O)Ra’、-NRd’C(=NRc’)NRa’Rb’、-NRb’C(=O)ORa’、-OC(=O)NRa’Rb’、-OC(=O)Ra’、-OC(=O)ORa’Hydroxy, nitro, azido, cyano, -S (O)0-3Ra’、-SO2NRa’Rb’、-NRb’SO2Ra’One or more substitutions; wherein R isa’-Rd’Each independently is H, C1-12An alkyl group.
In one embodiment of the compounds of the invention, p is 0,1 or 2,
In one embodiment of the compounds of the invention, p is 0 or 1.
In one embodiment of the compounds of the present invention, p is 0.
In one embodiment of the compounds of the invention, p is 2.
In one embodiment of the compounds of the invention, R4And R4' is H.
In one embodiment of the compounds of the invention, R1Is halogen, C1-3Alkyl, hydroxy, cyano or C1-3An alkoxy group.
In one embodiment of the compounds of the invention, R1Is chloro, fluoro, methyl, hydroxy, cyano or methoxy.
In one embodiment of the compounds of the present invention, n R1Is H.
In one embodiment of the compounds of the invention, R10Is halogen, -ORaOxo, -C (= O) ORa、-C(O)NRaRb、-C(=O)OH、-C(=O)Ra、-OC(=O)NRaRb、-OC(=O)Ra、-OC(=O)ORaHydroxy, cyano, wherein R isa-RbEach independently is H, C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C6-12Aryl radical, C7-16Aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl.
In one embodiment of the compounds of the invention, R11Is halogen, -ORa、-NRaRb、-C(=O)ORa、-C(O)NRaRb、-C(=O)OH、-C(=O)Ra、-C(=NORc)Ra、--C(=NRc)NRaRb、-NRdC(=O)NRaRb、-NRbC(=O)Ra、-NRdC(=NRc)NRaRb、-NRbC(=O)ORa、-OC(=O)NRaRb、-OC(=O)Ra、-OC(=O)ORaHydroxy, nitro, azido, cyano, -S (O)0-3Ra、-SO2NRaRb、-NRbSO2Raor-NRbSO2NRaRb、C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C6-12Aryl radical, C7-16Aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl, wherein R isa-RdEach independently is H, C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C6-12Aryl radical, C7-16Aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl.
In one embodiment of the compounds of the invention, R11Is halogen, -ORa、-NRaRb、-C(=O)ORa、-C(O)NRaRb、-C(=O)OH、-C(=O)Ra、-NRdC(=O)NRaRb、-NRbC(=O)Ra、-NRbC(=O)ORa、-OC(=O)NRaRb、-OC(=O)Ra、-OC(=O)ORaHydroxy, cyano, -SO2NRaRb、-NRbSO2Ra、C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, phenyl, C7-8Aralkyl, 5-6 membered heteroaryl, 6-8 membered heteroaralkyl, 5-6 membered heterocycle, or 6-8 membered heterocycle-alkyl, wherein R isa,RbAnd RdEach independently is H, C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C6-12Aryl radical, C7-16Aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl.
In one embodiment of the compounds of the invention, R11Is halogen, -ORa、-NRaRb、-C(O)NRaRb、-C(=O)OH、-C(=O)Ra、-NRdC(=O)NRaRb、-NRbC(=O)Ra、-NRbC(=O)ORa、-OC(=O)NRaRbHydroxy, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, phenyl, C7-8Aralkyl, 5-6 membered heteroaryl, 6-8 membered heteroaralkyl, 5-6 membered heterocycle, or 6-8 membered heterocycle-alkyl, wherein R isa,RbAnd RdEach independently is H, C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, alkynyl,C6-12Aryl radical, C7-16Aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl.
In one embodiment of the compounds of the invention, R11Is halogen, -ORa、-NRaRbHydroxy, cyano, C1-6Alkyl radical, wherein Ra-RbEach independently is H, C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C6-12Aryl radical, C7-16Aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl.
In one embodiment of the compounds of the invention, R12Is halogen, -ORaOxo, -NRaRb,=NO-Rc、-C(=O)ORa、-C(O)NRaRb、-C(=O)OH、-C(=O)Ra、-C(=NORc)Ra、-C(=NRc)NRaRb、-NRdC(=O)NRaRb、-NRbC(=O)Ra、-NRdC(=NRc)NRaRb、-NRbC(=O)ORa、-OC(=O)NRaRb、-OC(=O)Ra、-OC(=O)ORaHydroxy, nitro, azido, cyano, -S (O)0-3Ra、-SO2NRaRb、-NRbSO2Ra、-NRbSO2NRaRb、C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C6-12Aryl radical, C7-16Aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl, wherein R isa-RdEach independently is H, C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C6-12Aryl radical, C7-16Aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl.
In one of the compounds of the present inventionIn one embodiment, R12Is halogen, -ORaOxo, -NRaRb、-C(=O)ORa、-C(O)NRaRb、-C(=O)OH、-C(=O)Ra、-NRdC(=O)NRaRb、-NRbC(=O)Ra、-NRbC(=O)ORa、-OC(=O)NRaRb、-OC(=O)Ra、-OC(=O)ORaHydroxy, cyano, -SO2NRaRb、-NRbSO2Ra、C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, phenyl, C7-8Aralkyl, 5-6 membered heteroaryl, 6-8 membered heteroaralkyl, 5-6 membered heterocycle, or 6-8 membered heterocycle-alkyl, wherein R isa,RbAnd RdEach independently is H, C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C6-12Aryl radical, C7-16Aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl.
In one embodiment of the compounds of the invention, R12Is halogen, -ORaOxo, -NRaRb、-C(O)NRaRb、-C(=O)OH、-C(=O)Ra、-NRdC(=O)NRaRb、-NRbC(=O)Ra、-NRbC(=O)ORa、-OC(=O)NRaRbHydroxy, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, phenyl, C7-8Aralkyl, 5-6 membered heteroaryl, 6-8 membered heteroaralkyl, 5-6 membered heterocycle, or 6-8 membered heterocycle-alkyl, wherein R isa,RbAnd RdEach independently is H, C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C6-12Aryl radical, C7-16Aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl.
In one embodiment of the compounds of the invention, R12Is halogen, -ORaOxo, -NRaRbHydroxy, cyano, C1-6Alkyl radical, wherein Ra-RbEach independently is H, C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C6-12Aryl radical, C7-16Aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl.
In one embodiment of the compounds of the invention, wherein B, B', R are allowed as valenciesa-Rd、R1、R2、R2’、R3、R3’、R4、R4’、R10、R11And R12The alkyl, alkenyl, alkynyl, alkoxy, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycle OR heterocycle-alkyl of (A) are each independently unsubstituted OR substituted by halogen, -ORa’、-NRa’Rb’、C(=O)ORa’、-C(O)NRa’Rb’-C (= O) OH, hydroxy, nitro, azido, cyano substituted one or more times; wherein R isa’-Rd’Each independently is H, C1-12An alkyl group.
In one embodiment of the compounds of the invention, wherein B, B', R are allowed as valenciesa-Rd、R1、R2、R2’、R3、R3’、R4、R4’、R10、R11And R12The alkyl, alkenyl, alkynyl, alkoxy, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycle or heterocycle-alkyl of (a) is each independently unsubstituted or substituted once by halogen.
In one embodiment of the compounds of the invention, wherein B, B', R are allowed as valenciesa-Rd、R1、R2、R2’、R3、R3’、R4、R4’、R10、R11And R12Alkyl, alkenyl, alkynyl, alkoxy, aryl, aralkyl, heteroaryl, heteroaralkyl in (1)Ring or heterocycle-alkyl is each independently unsubstituted or substituted once by fluorine.
In one embodiment, the compounds of the invention are represented by formula (VI):
or a pharmaceutically acceptable salt thereof, wherein
Ra-RdEach independently is H, C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C6-12Aryl radical, C7-16Aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl;
R1is halogen, -ORa、-NRaRb、-C(=O)ORa、-C(O)NRaRb、-C(=O)OH、-C(=O)Ra、-C(=NORc)Ra、-C(=NRc)NRaRb、-NRdC(=O)NRaRb、-NRbC(=O)Ra、-NRdC(=NRc)NRaRb、-NRbC(=O)ORa、-OC(=O)NRaRb、-OC(=O)Ra、-OC(=O)ORaHydroxy, nitro, azido, cyano, -S (O)0-3Ra、-SO2NRaRb、-NRbSO2Ra、-NRbSO2NRaRb、-P(=O)ORaORbUnsubstituted or substituted by R10Substituted one or more times by C1-6Alkyl, unsubstituted or substituted by R10Substituted one or more times by C2-6Alkenyl, unsubstituted or substituted by R10Substituted one or more times by C2-6Alkynyl or any two occurrences of R1May form together with the atom to which they are attached an unsubstituted or substituted R115-7 cycloalkyl substituted once or more times, orUnsubstituted or substituted by R12A 5-7 membered heterocyclic ring substituted one or more times;
R2' is halogen, C1-10Alkyl radical, C1-6Haloalkyl, - (CH)2)1-6OH、-NRbC(=O)Ra、C6-12Aryl or 5-12 membered heteroaryl;
R2each independently is halogen, C1-10Alkyl radical, C1-6Haloalkyl, - (CH)2)1-6OH、-ORa、-C(=O)ORa、-NRaRb、-NRbC(=O)Ra,-C(O)NRaRb、-S(O)0-3Ra,C6-12Aryl, 5-12 membered heterocycle or 5-12 membered heteroaryl;
R4and R4' each independently is C1-6An alkyl group;
x and Y are each independently
Or key
Wherein the asterisk (—) indicates the point of attachment of the nitrogen of the pyrrolidine ring;
R5and R5' independently of one another are H, unsubstituted or substituted by R10Substituted one or more times by C1-18Alkyl, unsubstituted or substituted by R10Substituted one or more times by C2-12Alkenyl, unsubstituted or substituted by R10Substituted one or more times by C2-12Alkynyl, unsubstituted or substituted R11Substituted once or more times C6-14Aryl, unsubstituted or substituted by R11Substituted one or more times by C7-16Aralkyl, unsubstituted or substituted by R115-12 membered heteroaryl, unsubstituted or substituted once or many times by R116-18 membered heteroaralkyl, unsubstituted or substituted once or many times by R123-12 membered heterocyclic ring substituted once or more times, or unsubstituted or substituted by R12Is substituted for one4-18 membered heterocycle-alkyl, one or more times;
R6is H, C1-6Alkyl or halo C1-6An alkyl group;
m and n are each independently 0,1 or 2, provided that at least one of m and n is 1;
p is 0,1, 2,3 or 4;
q is 1 or 2;
u is 0 or 1;
s is 0,1, 2,3 or 4;
R10is halogen, -ORaOxo, -NRaRb、=NO-Rc、-C(=O)ORa、-C(O)NRaRb、-C(=O)OH、-C(=O)Ra、-C(=NORc)Ra、-C(=NRc)NRaRb、-NRdC(=O)NRaRb、-NRbC(=O)Ra、-NRdC(=NRc)NRaRb、-NRbC(=O)ORa、-OC(=O)NRaRb、-OC(=O)Ra、-OC(=O)ORaHydroxy, nitro, azido, cyano, -S (O)0-3Ra、-SO2NRaRb、-NRbSO2Ra、-NRbSO2NRaRbOR-P (= O) ORaORb；
R11Is halogen, -ORa、-NRaRb、-C(=O)ORa、-C(O)NRaRb、-C(=O)OH、-C(=O)Ra、-C(=NORc)Ra、-C(=NRc)NRaRb,-NRdC(=O)NRaRb、-NRbC(=O)Ra、-NRdC(=NRc)NRaRb、-NRbC(=O)ORa、-OC(=O)NRaRb、-OC(=O)Ra、-OC(=O)ORaHydroxy, nitroAzido, cyano, -S (O)0-3Ra、-SO2NRaRb、-NRbSO2Ra、-NRbSO2NRaRbOR-P (= O) ORaORb、C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C6-12Aryl radical, C7-16Aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl; and is
R12Is halogen, -ORaOxo, -NRaRb,=NO-Rc、-C(=O)ORa、-C(O)NRaRb、-C(=O)OH、-C(=O)Ra、-C(=NORc)Ra、-C(=NRc)NRaRb、-NRdC(=O)NRaRb、-NRbC(=O)Ra、-NRdC(=NRc)NRaRb、-NRbC(=O)ORa、-OC(=O)NRaRb、-OC(=O)Ra、-OC(=O)ORaHydroxy, nitro, azido, cyano, -S (O)0-3Ra、-SO2NRaRb、-NRbSO2Ra、-NRbSO2NRaRbOR-P (= O) ORaORb,C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C6-12Aryl radical, C7-16Aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl.
In one embodiment, the compounds of the present invention are represented by formula (VI) wherein R is1Is halogen, unsubstituted or substituted by R10Substituted one or more times by C1-4Alkyl, -C (= O) ORa、-C(O)NRaRbHydroxy, cyano or C1-3An alkoxy group.
In one embodiment, the compounds of the present invention are represented by formula (VI) wherein at least one R is4And R4' is methyl.
In one embodiment, the compounds of the present invention are represented by formula (VI) wherein R is4And R4' is methyl.
In one embodiment, the compounds of the invention are represented by formula (VI) wherein one of m and n is 1 and the other is 0.
In one embodiment, the compounds of the invention are represented by formula (VI) wherein m and n are 1.
In one embodiment, the compounds of the present invention are represented by formula (VI) wherein X and Y are
In one embodiment, the compounds of the present invention are represented by formula (VI) wherein q is 2.
In one embodiment, the compounds of the invention are represented by formula (VIA):
or a pharmaceutically acceptable salt thereof, wherein the variables are each as defined herein, and
p' is each independently 0,1 or 2;
R7and R7' are each independently unsubstituted or substituted with R10Substituted one or more times by C1-8Alkyl, unsubstituted or substituted by R10Substituted one or more times by C2-8Alkenyl, unsubstituted or substituted by R10Substituted one or more times by C2-8Alkynyl, unsubstituted or substituted by R11Phenyl substituted once or many times, notSubstituted or by R11Benzyl substituted once or many times, unsubstituted or by R115-6 membered heteroaryl, unsubstituted or substituted once or many times by R116-7 membered heteroaralkyl, unsubstituted or substituted once or many times by R123-6 membered heterocyclic ring substituted once or more than once, or unsubstituted or substituted by R124-7 membered heterocyclyl-alkyl substituted one or more times; and is
R8And R8' each independently is-NRaRb、-NRdC(=O)NRaRb、-NRbC(=O)Ra、-NRdC(=NRc)NRaRb、-NRbC(=O)ORa、-NRbSO2Raor-NRbSO2NRaRbWherein R isa-RdEach independently is H, C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C6-12Aryl radical, C7-16Aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl.
In one embodiment, the compound of the invention is represented by a compound of formula (VIB):
or a pharmaceutically acceptable salt thereof, wherein the variables are each as defined herein, and
R7and R7' are each independently unsubstituted or substituted with R10Substituted one or more times by C1-8Alkyl, unsubstituted or substituted by R10Substituted one or more times by C2-8Alkenyl, unsubstituted or substituted by R10Substituted one or more times by C2-8Alkynyl, unsubstituted or substituted by R11Phenyl substituted once or many times, unsubstituted or by R11Benzyl substituted once or many times, unsubstituted or by R11Substituted one or more times5-6 membered heteroaryl, unsubstituted or substituted by R116-7 membered heteroaralkyl, unsubstituted or substituted once or many times by R123-6 membered heterocyclic ring substituted once or more than once, or unsubstituted or substituted by R124-7 membered heterocyclyl-alkyl substituted one or more times; and is
R8And R8' each independently is-NRaRb、-NRdC(=O)NRaRb、-NRbC(=O)Ra、-NRdC(=NRc)NRaRb、-NRbC(=O)ORa、-NRbSO2Raor-NRbSO2NRaRbWherein R isa-RdEach independently is H, C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C6-12Aryl radical, C7-16Aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle or 4-18 membered heterocycle-alkyl,
in one embodiment, the compounds of the invention are represented by formula (VI IA):
or a pharmaceutically acceptable salt thereof, wherein the variables are each as defined herein, and
p' is each independently 0,1 or 2;
R7and R7' are each independently unsubstituted or substituted with R10Substituted one or more times by C1-8Alkyl, unsubstituted or substituted by R10Substituted one or more times by C2-8Alkenyl, unsubstituted or substituted by R10Substituted one or more times by C2-8Alkynyl, unsubstituted or substituted by R11Phenyl substituted once or many times, unsubstituted or by R11Benzyl substituted once or many times, unsubstituted or by R11Substituted once or more than once by a 5-6 membered heteroaryl group,Unsubstituted or substituted by R116-7 membered heteroaralkyl, unsubstituted or substituted once or many times by R123-6 membered heterocyclic ring substituted once or more than once, or unsubstituted or substituted by R124-7 membered heterocyclyl-alkyl substituted one or more times; and is
R8And R8' each independently is-NRaRb、-NRdC(=O)NRaRb、-NRbC(=O)Ra、-NRdC(=NRc)NRaRb、-NRbC(=O)ORa、-NRbSO2Raor-NRbSO2NRaRbWherein R isa-RdEach independently is H, C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C6-12Aryl radical, C7-16Aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl.
In one embodiment, the compounds of the invention are represented by formula (VI IB):
or a pharmaceutically acceptable salt thereof, wherein the variables are each as defined herein, and
R7and R7' are each independently unsubstituted or substituted with R10Substituted one or more times by C1-8Alkyl, unsubstituted or substituted by R10Substituted one or more times by C2-8Alkenyl, unsubstituted or substituted by R10Substituted one or more times by C2-8Alkynyl, unsubstituted or substituted by R11Phenyl substituted once or many times, unsubstituted or by R11Benzyl substituted once or many times, unsubstituted or by R115-6 membered heteroaryl, unsubstituted or substituted once or many times by R116-7 membered heteroaralkyl, unsubstituted or substituted once or many times by R12SubstitutionOne or more times of a 3-to 6-membered heterocyclic ring, or unsubstituted or substituted by R124-7 membered heterocyclyl-alkyl substituted one or more times; and is
R8And R8' each independently is-NRaRb、-NRdC(=O)NRaRb、-NRbC(=O)Ra、-NRdC(=NRc)NRaRb、-NRbC(=O)ORa、-NRbSO2Raor-NRbSO2NRaRbWherein R isa-RdEach independently is H, C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C6-12Aryl radical, C7-16Aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl.
In one embodiment, the compounds of the present invention are represented by compounds of formula (VIA), (VIB), (VIIA) or (VI IB), wherein R is8And R8' each independently is-NRaRb、-NRbC(=O)Ra、-NRbC(=O)ORaWherein R isa-RbEach independently is H, C1-6Alkyl, phenyl, benzyl, 5-6 membered heteroaryl, 6-8 membered heteroaralkyl, 5-6 membered heterocycle, or 6-8 membered heterocycle-alkyl.
In one embodiment, the compounds of the present invention are represented by compounds of formula (VIA), (VIB), (VIIA) or (VIIB) wherein s and u are 0.
In one embodiment, the compounds of the invention are represented by compounds of formula (VIA), (VIB), (VIIA) or (VIIB), wherein R in formula (IV) is8And R8' each independently is-NRbC(=O)ORaWherein R isa-RbEach independently is H, C1-6Alkyl, phenyl, tetrahydrofuran or benzyl.
In one embodiment, the compounds of the present invention are represented by compounds of formula (VIA), (VIB), (VIIA), or (VIIB), wherein R is7And R7' are each independently unsubstituted or substituted with R11Phenyl substituted one or more times.
In one embodiment, the compounds of the present invention are represented by compounds of formula (VIA), (VIB), (VIIA), or (VIIB), wherein R is7And R7' are each independently unsubstituted or substituted with R10Substituted one or more times by C1-6An alkyl group.
In one embodiment, the compounds of the present invention are represented by compounds of formula (VIA), (VIB), (VIIA) or (VI IB), wherein R is7And R7' are each independently methyl, ethyl, propyl, isopropyl, methoxyisopropyl, butyl, sec-butyl, tert-butyl, pentyl, 2-methylbutane, 3-methylbutane, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
In one embodiment, the compounds of the present invention are represented by compounds of formula (VIA), (VIB), (VIIA), or (VIIB), wherein R is7And R8Or R7’And R8’Together with the attached carbon are each independently:
the use of the compounds of the invention in the treatment of human hepatitis c virus infection. The use of a compound of the invention in a composition further comprising the administration of at least one additional active agent. Use of a compound of the invention, wherein the at least one additional active agent is selected from the group consisting of viral serine protease inhibitors, viral polymerase inhibitors, viral helicase inhibitors, immunomodulators, antioxidants, antibacterial agents, therapeutic vaccines, hepatoprotectants, antisense agents, inhibitors of HCV NS2/3 protease and inhibitors of the Inner Ribosome Entry Site (IRES).
Use of a compound of the invention wherein said at least one additional active agent is selected from ribavirin and interferon- α.
The use of a compound of the invention for the manufacture of a medicament.
A pharmaceutical formulation comprising at least one compound of the invention and at least one pharmaceutically acceptable carrier or excipient.
The use of the compounds of the invention in the treatment of human hepatitis c virus infection. The use of a compound of the invention in a composition further comprising the administration of at least one additional active agent. Use of a compound of the invention, wherein the at least one additional active agent is selected from the group consisting of viral serine protease inhibitors, viral polymerase inhibitors, viral helicase inhibitors, immunomodulators, antioxidants, antibacterial agents, therapeutic vaccines, hepatoprotectants, antisense agents, inhibitors of HCV NS2/3 protease and inhibitors of the Inner Ribosome Entry Site (IRES). Use of a compound of the present invention wherein said at least one additional active agent is selected from ribavirin and interferon- α.
The use of a compound of the invention for the manufacture of a medicament.
A pharmaceutical formulation comprising at least one compound of the invention and at least one pharmaceutically acceptable carrier or excipient.
In one embodiment, the present invention provides a method of treating or preventing an HCV viral infection comprising contacting a biological sample or administering to a patient in need thereof an amount of a compound disclosed herein effective to treat or prevent the infection.
In one embodiment of the method, the HCV has genotype 1. In yet another embodiment, HCV can be of genotype 1a, genotype 1b, or a combination thereof.
According to one aspect of the invention, the compounds of the invention are selected from table 1A.
TABLE 1A
And pharmaceutically acceptable salts thereof.
According to one aspect of the invention, the compounds of the invention are selected from table 1B.
TABLE 1B
And pharmaceutically acceptable salts thereof.
In one embodiment, the invention is one or more compounds of table 1A or a pharmaceutically acceptable salt thereof.
In one embodiment, the invention is one or more compounds of table 1B or a pharmaceutically acceptable salt thereof.
In one embodiment, the present invention provides a compound of the invention described herein for use in the treatment or prevention of a flaviviridae infection in a host.
In one embodiment, the present invention provides a pharmaceutical composition comprising at least one compound of the invention described herein and at least one pharmaceutically acceptable carrier or excipient.
In one embodiment, the present invention provides a pharmaceutical composition for treating or preventing a flaviviridae viral infection in a host, comprising at least one compound of the present invention described herein and at least one pharmaceutically acceptable carrier or excipient.
In one embodiment, the present invention provides a pharmaceutical composition comprising at least one compound of the invention described herein, and further comprising at least one additional active agent selected from the group consisting of serine protease inhibitors, viral polymerase inhibitors, viral helicase inhibitors, immunomodulators, antioxidants, antibacterial agents, therapeutic vaccines, hepatoprotectants, antisense drugs, inhibitors of HCV NS2/3 protease, and inhibitors of the ribosome entry site (IRES).
In another embodiment, a combination is provided comprising at least one compound of the invention described herein and one or more additional active agents.
In another embodiment, a combination is provided comprising at least one compound of the invention described herein and one or more additional active agents selected from the group consisting of serine protease inhibitors, viral polymerase inhibitors, viral helicase inhibitors, immunomodulators, antioxidants, antibacterial agents, therapeutic vaccines, hepatoprotectants, antisense drugs, inhibitors of HCV NS2/3 protease and inhibitors of the Inner Ribosome Entry Site (IRES).
In one combined embodiment, the compound and the additional active agent are administered sequentially.
In a combined embodiment, the compound and the additional active agent are administered simultaneously.
The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier are encompassed by another aspect of the present invention.
Additional active agents for use in the compositions and combinations include, for example, ribavirin, amantadine, mepodib, ribavirin, viramidine, and histamine dihydrochloride.
The term "viral serine protease inhibitor" as used herein refers to an agent that is effective in inhibiting mammalian viral serine proteases, including HCV serine protease. HCV serine protease inhibitors include, for example, those compounds described in the following references: WO 99/07733(Boehringer Ingelheim), WO 99/07734(Boehringer Ingelheim), WO00/09558(Boehringer Ingelheim), WO 00/09543(Boehringer Ingelheim), WO 00/59929(Boehringer Ingelheim), WO 02/060926(BMS), WO 2006039488(Vertex), WO 2005077969(Vertex), WO2005035525(Vertex), WO 2005028502(Vertex) WO 2005007681(Vertex), WO 2004092162(Vertex), WO 2004092161(Vertex), WO2003035060(Vertex), WO 03/087092(Vertex), WO 02/18369(Vertex) or WO98/17679 (Vertex).
In one embodiment, the present invention provides a pharmaceutical composition comprising at least one compound of the invention described herein, and further comprising one or more additional active agents selected from the group consisting of viral serine protease inhibitors, viral polymerase inhibitors, viral helicase inhibitors, immunomodulators, antioxidants, antibacterial agents, therapeutic vaccines, hepatoprotective agents, antisense drugs, inhibitors of HCV NS2/3 protease, and inhibitors of the ribosome entry site (IRES).
In another embodiment, there is provided a combination therapy of at least one compound of the invention described herein with one or more additional active agents selected from the group consisting of viral serine protease inhibitors, viral polymerase inhibitors, viral helicase inhibitors, immunomodulators, antioxidants, antibacterial agents, therapeutic vaccines, hepatoprotectants, antisense drugs, inhibitors of HCV NS2/3 protease and inhibitors of the ribosome entry site (IRES).
Additional active agents for use in the compositions and combinations include, for example, ribavirin, amantadine, mepodib, ribavirin, viramidine, and histamine dihydrochloride.
In one combined embodiment, the compound and the additional active agent are administered sequentially.
In a combined embodiment, the compound and the additional active agent are administered simultaneously. The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier are encompassed by another aspect of the present invention.
The term "viral serine protease inhibitor" as used herein refers to an agent that is effective in inhibiting mammalian viral serine proteases, including HCV serine protease. HCV serine protease inhibitors include, for example, those compounds described in the following references: WO 99/07733(Boehringer Ingelheim), WO 99/07734(Boehringer Ingelheim), WO00/09558(Boehringer Ingelheim), WO 00/09543(Boehringer Ingelheim), WO 00/59929(Boehringer Ingelheim), WO 02/060926(BMS), WO 2006039488(Vertex), WO 2005077969(Vertex), WO2005035525(Vertex), WO 2005028502(Vertex) WO 2005007681(Vertex), WO 2004092162(Vertex), WO 2004092161(Vertex), WO2003035060(Vertex), WO 03/087092(Vertex), WO 02/18369(Vertex) or WO98/17679 (Vertex).
Specific examples of viral serine protease inhibitors include telaprevir (VX-950, Vertex), VX-500(Vertex), TMC435350(Tibotec/Medivir), MK-7009(Merck), ITMN-191(R7227, InterMune/Roche), and Boceprevir (SCH503034, Schering).
The term "viral polymerase inhibitor" as used herein refers to an agent that is effective in inhibiting mammalian viral polymerases, including HCV polymerase. HCV polymerase inhibitors include non-nucleosides, such as those described in the following references:
WO 03/010140(Boehringer inner lheim), WO 03/026587(Br i s to l Myers Squibb); WO 02/100846A1, WO 02/100851A2, WO 01/85172A1(GSK), WO 02/098424A1(GSK), WO 00/06529(Merck), WO 02/06246A1(Merck), WO 01/47883(Japan Tobacco), WO 03/000254(Japan Tobacco) and EP 1256628A2 (Agouron).
In addition, other inhibitors of HCV polymerase also include nucleoside analogs, such as those described in the following references: WO 01/90121A2(Idenix), WO 02/069903A2(Bi ocrys t Pharmaceut i ca l Inc.) and WO 02/057287A2(Merck/Isis) and WO 02/057425A2 (Merck/Isis).
Specific examples of HCV polymerase inhibitors include VCH-759(ViroChem Pharma), VCH-916(ViroChem Pharma), VCH-222(ViroChem Pharma), R1626(Roche), R7128(Roche/Pharmas set), PF-868554(Pfizer), MK-0608(Merck/Isis), MK-3281(Merck), A-837093(Abbott), GS 9190(Gilead), ana598(Anadys), HCV-796(Viropharma), and GSK625433 (GlaxoSmithline), R1479 (Klche), MK-0608(Merck), R1656(Roche-Pharmas set), and Valopicitabine (Idenix). Specific examples of HCV polymerase inhibitors include JTK-002/003 and JTK-109(Japan Tobacco), HCV-796(Viropharma), GS-9190(Gilead), and PF-868,554 (Pfizer).
The term "viral helicase inhibitor" as used herein refers to an agent effective to inhibit the function of mammalian viral helicases, including those of the flaviviridae family.
The term "immunomodulator" as used herein refers to an agent which is effective in increasing or enhancing the immune system response of a mammal. Immunomodulators include, for example, class I interferons (e.g., alpha-, beta-, delta-, and omega-interferons, tau-interferons, consensus interferons, and asialo-interferons), I I class interferons (e.g., gamma-interferons), and pegylated interferons.
Specific examples of immunomodulators include injectable or oral IL-29 (PEG-interferon lambda, ZymoGenetics), Belerofon (Nautilus Biotech), oral interferon alpha (Amarillo biosciences), BLX-883(Locteron, Biolex Therapeutics/Octoplus), omega interferon (Intacia Therapeutics), muleron (Viragen), Albuferon (Human Genome sciences), consensus interferon (Infergen, Three RiversPharmaceutics), jellyfish (Medusa) interferon (Flamel Technologies), NOV-205 (Noveos Therapeutics), ogluta sodium (polyitcon biosciences), SCV-07 (clone), and so on,(thymoa lfasin, ScClone/Sigma-Tau), AB68(XTL bio) and Civacir (N)ABI)。
The term "viral polymerase inhibitor" as used herein refers to an agent effective to inhibit the function of mammalian viral polymerases, including HCV polymerase. HCV polymerase inhibitors include non-nucleosides, such as those described in the following references: WO 03/010140(Boehringer Ingelheim), WO 03/026587(Bristol Myers Squibb); WO 02/100846A1, WO 02/100851A2, WO 01/85172AI (GSK), (GSK), WO 02/098424A1(GSK), WO 00/06529(Merck), WO 02/06246A1(Merck), WO 01/47883(Japan Tobacco), WO 03/000254(Japan Tobacco) and EP 1256628A2 (Agouron).
In addition, other HCV polymerase inhibitors also include nucleoside analogs, such as those described in the following references: WO 01/90121A2(Idenix), WO 02/069903A2(Biocryst Pharmaceuticals Inc.) and WO 02/057287A2(Merck/Isis) and WO 02/057425A2 (Merck/Isis).
Specific examples of nucleoside inhibitors of HCV polymerase include R1626/R1479(Roche), R7128(Roche), MK-0608(Merck), R1656 (Roche-pharmacy set), and Valopicitabine (Idenix). Specific examples of HCV polymerase inhibitors include JTK-002/003 and JTK-109(Japan Tobacco), HCV-796(Viropharma), GS-9190(Gilead), and PF-868,554 (Pfizer).
The term "viral helicase inhibitor" as used herein refers to an agent effective to inhibit the function of mammalian viral helicases, including those of the flaviviridae family.
The term "immunomodulator" as used herein refers to an agent which is effective in increasing or enhancing the immune system response of a mammal. Immunomodulators include, for example, class I interferons (e.g., alpha-, beta-, delta-, and omega-interferons, x-interferons, consensus interferons, and desialyl-interferons), I I-type interferons (e.g., gamma-interferons), and pegylated interferons.
Typical immunomodulators include, but are not limited to: thalidomide, IL-2, erythropoietin, IMPDH inhibitors such as Merimepoxib (Vertex Pharmaceuticals Inc.), interferons including natural interferons (e.g., OMNIFERON, Viragen, and SUMIFERON, Sumitomo, natural interferon blends), natural interferon alpha (ALFERON, Hemi sphere Biopharma, Inc.), interferon alpha n1(WELLFERON, GlaxoWellcome) from lymphoblastoid cells, oral alpha interferon, Peg-interferon alpha 2a (PEGASYS, Roche), recombinant interferon alpha 2a (FEFERON, Roche), inhaled interferon alpha 2b (AERX, Arigim), Peg-interferon alpha 2b (ALBUFERON, Hugomersen/Novagen, PEGING N, ImpH inhibitors such as Merimepoxib (Vertex Pharmaceuticals Inc.), interferon alpha (interferon alpha), interferon alpha 2b (interferon alpha, PEG, interferon alpha 2b, interferon alpha (interferon beta, interferon alpha, PEG, interferon beta, interferon alpha, va, lean pharmaceutical), interferon gamma-1 b (ACTIMMUNE, Intermune, Inc.), non-pegylated interferon alpha, alpha interferon and analogs thereof, and synthetic thymosin alpha 1(ZADAXIN, SciClone pharmaceutical Inc.).
The term "class I interferon" as used herein refers to interferons selected from the group consisting of interferons that both bind to type 1 receptors. It includes both naturally and synthetically produced class I interferons. Examples of class I interferons include alpha-, beta-, delta-and omega-interferons, tau-interferons, consensus interferons and desialyl-interferons. The term "class II interferon" as used herein refers to interferons selected from the group consisting of all type II receptor binding interferons. Examples of class II interferons include gamma interferon.
Antisense drugs include, for example, ISIS-14803.
Specific examples of HCV NS3 protease inhibitors include BILN-2061 (Boehringer Ingelheim) SCH-6 and SCH-503034/Boceprevir (Schering-Plough), VX-950/tiraprevir (Vertex) and ITMN-B (InterMune), GS9132(Gilead), TMC-435350(Tibotec/Medivir), ITMN-191(InterMune), MK-7009 (Merck).
Inhibitors of the Internal Ribosome Entry Site (IRES) include ISIS-14803 (ISISISISISPHrmaceuticals) and those compounds described in WO 2006019831(PTC therapeutics).
In one embodiment, the additional active agent is interferon alpha, ribavirin, silybum marianum, interleukin-12, amantadine, a ribozyme, thymosin, N-acetyl cysteine or cyclosporin.
In one embodiment, the additional active agent is interferon alpha, ribavirin, silybum marianum, interleukin-12, amantadine, a ribozyme, thymosin, N-acetyl cysteine or cyclosporin.
In one embodiment, the additional active agent is interferon alpha 1A, interferon alpha 1B, interferon alpha 2A, or interferon alpha 2B.
Interferons are obtained in pegylated and non-pegylated forms. The pegylated interferon comprises PEGASYStmAnd Peg-introntm。
The recommended dose of PEGASYSTM monotherapy for chronic hepatitis c is 180mg (1.0mL vial or 0.5mL prefilled syringe) once a week for 48 weeks by subcutaneous administration in the abdomen or thigh.
The recommended dose of PEGASYSTM for chronic hepatitis C when used in combination with ribavirin is 180mg (1.0mL vial or 0.5mL prefilled syringe) once a week.
The recommended dose for the PEG-Int ron (TM) regimen is 1.0 mg/kg/week subcutaneously for 1 year. The dose should be given on the same day of the week.
The recommended dose of PEG-Intron when administered in combination with ribavirin is 1.5 micrograms/kg/week.
Ribavirin is typically administered orally, and tablet forms of ribavirin are currently commercially available. Typical standard daily dosages of ribavirin tablets (e.g., about 200mg tablets) are from about 800mg to about 1200 mg. For example, ribavirin tablets are administered at about 1000mg to subjects weighing less than 75kg, or at about 1200mg to subjects weighing greater than or equal to 75 kg. Nevertheless, the methods or combinations of the present invention are not limited herein to any particular dosage form or regimen. Ribavirin is typically administered according to a dosage regimen described on a commercial label.
In one embodiment, the additional active agent is interferon α 1A, interferon α 1B, interferon α 2a (roferon), PEG-interferon α 2a (pegasys), interferon α 2B (Intron a), or PEG-interferon α 2B (PEG-Intron).
In one embodiment, the additional active agent is a combination of standard or pegylated interferon alpha (Roferon, Pegasys, Intron A, Peg-Intron) and ribavirin.
In one embodiment, the present invention provides a pharmaceutical composition comprising at least one compound of the present invention described herein, one or more additional active agents selected from the group consisting of non-nucleoside HCV polymerase inhibitors (e.g., HCV-796), nucleoside HCV polymerase inhibitors (e.g., R7128, R1626/R1479), HCV NS3 protease inhibitors (e.g., VX-950/telaprevir and ITMN-191), interferon, and ribavirin, and at least one pharmaceutically acceptable carrier or excipient.
The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier are encompassed by another aspect of the present invention. The individual components used in the method or combination of the invention may be administered sequentially or simultaneously in separate or combined pharmaceutical formulations.
In a further embodiment, the composition or combination of the invention further comprises at least one compound of the invention as described herein; one or more additional active agents selected from the group consisting of non-nucleoside HCV polymerase inhibitors (e.g., HCV-796), nucleoside HCV polymerase inhibitors (e.g., R7128, R1626/R1479), and HCV NS3 protease inhibitors (e.g., VX-950/tiramer vir and ITMN-191); and interferon and/or ribavirin.
In one embodiment, the additional active agent is interferon alpha 1A, interferon alpha 1B, interferon alpha 2A or interferon alpha 2B and optionally ribavirin.
In one embodiment, the present invention provides a method for treating or preventing an HCV viral infection in a host, comprising administering to the host a jointly therapeutically effective amount of at least one compound of the present invention described herein and one or more additional active agents selected from the group consisting of non-nucleoside HCV polymerase inhibitors (e.g., HCV-796), nucleoside HCV polymerase inhibitors (e.g., R7128, R1626/R1479), HCV NS3 protease inhibitors (e.g., VX-950/telaprevir and ITMN-191), interferons, and ribavirin.
In another combined embodiment, the compound and the additional active agent are administered sequentially.
In another combined embodiment, the compound and the additional active agent are administered simultaneously.
In one embodiment, a method is provided for inhibiting or reducing HCV viral polymerase activity in a host, comprising administering to the host a jointly therapeutically effective amount of at least one compound of the present invention and one or more additional active agents selected from the group consisting of non-nucleoside HCV polymerase inhibitors (e.g., HCV-796) and nucleoside HCV polymerase inhibitors (e.g., R7128, R1626/R1479), interferon, and ribavirin.
In one embodiment, the present invention provides the use of at least one compound of the present invention in combination with one or more additional active agents selected from the group consisting of non-nucleoside HCV polymerase inhibitors (e.g., HCV-796), nucleoside HCV polymerase inhibitors (e.g., R7128, R1626/R1479), HCV NS3 protease inhibitors (e.g., VX-950/tiramer and ITMN-191), interferons, and ribavirin, in the manufacture of a medicament for treating or preventing HCV infection in a host.
When the compounds of the invention described herein are used in combination with at least one second therapeutically active agent for the same virus, the dosage of each compound may be the same or different from the dosage of the compound used alone. Suitable dosages are readily understood by those skilled in the art.
When the ratio of the amount of a compound of the invention described herein to the amount of an additional active agent (a non-nucleoside HCV polymerase inhibitor (e.g., HCV-796), a nucleoside HCV polymerase inhibitor (e.g., R7128, R1626/R1479), an HCV NS3 protease inhibitor (e.g., VX-950/telaprevir and ITMN-191), an interferon, and ribavirin) will vary depending on the choice of compound and additional active agent.
In one embodiment, the additional active agent is selected from a-831(AZD0530, AstraZeneca from Arrow therapeutics), a TLR9 agonist: IMO-2125(Idera Pharmaceuticals), PYN17(Phynova), Vavituximab (Tarvacin, Peregrine), DEBIO-025(DEBIO), NIM-811(Novartis), SCY635(Scynexis), PF-03491390(IDN-6556, Pfizer), Suvus (formerly BIVN-401, Virostat, Bioenvision), MX-3253(Celgosivir, Migenix), Viranine midin (Taribavirin, Valerant Pharmaceuticals), Hepaconda (Giaconda), TT033 (Benitec/Tarcere/izer), SIRNA-034(Merck formerly Sirnapeicits) and EHC-18 (Phazox Acemia 5 (Acryon/Tarcex), J-K (Biocide), J-1097 (Biocide), J-Migene), and J-Migene (Biocide).
In one embodiment, the additional active agent is selected from CSL123(Chiron/CSL), IC41(Intercell Novart i s), GI 5005(Globeimmune), TG4040(Transgene), Chrnvac C (Tripep/Inovio), GNI-103 (GENimmmune), HCV/MF59(Chiron/Novartis), Pevipro PROTM(Pevion biotect).
PEGASYS for chronic hepatitis CtmThe recommended dose for monotherapy is 180mg (1.0mL vial or 0.5mL prefilled syringe) once a week for 48 weeks by subcutaneous administration in the abdomen or thigh.
In one embodiment, the viral serine protease inhibitor is a flaviviridae serine protease inhibitor.
In one embodiment, the viral polymerase inhibitor is a flaviviridae polymerase inhibitor.
In one embodiment, the viral helicase inhibitor is a flaviviridae helicase inhibitor.
In further embodiments:
the viral serine protease inhibitor is an HCV serine protease inhibitor;
the viral polymerase inhibitor is an HCV polymerase inhibitor;
the viral helicase inhibitor is an HCV helicase inhibitor.
In one embodiment, the present invention provides a method of treating or preventing a flaviviridae viral infection in a host comprising administering to the host a therapeutically effective amount of at least one compound of formula (I), (II), (III) or (IV).
In one embodiment, the viral infection is selected from flavivirus infections.
In one embodiment, the flavivirus infection is Hepatitis C Virus (HCV), Bovine Viral Diarrhea Virus (BVDV), hog cholera virus, dengue virus, Japanese encephalitis virus, or yellow fever virus.
In one embodiment, the flaviviridae viral infection is a hepatitis c virus infection (HCV).
In one embodiment, the host is a human.
In one embodiment, the present invention provides a method for treating or preventing a flaviviridae viral infection in a host, comprising administering to the host a therapeutically effective amount of at least one compound of the invention described herein and further comprising administering at least one additional active agent.
In one embodiment, the present invention provides a method for treating or preventing a flaviviridae viral infection in a host, comprising administering to the host a therapeutically effective amount of at least one compound of the present invention as described herein and further comprising administering at least one additional active agent selected from the group consisting of viral serine protease inhibitors, viral polymerase inhibitors, viral helicase inhibitors, immunomodulators, antioxidants, antibacterial agents, therapeutic vaccines, hepatoprotective agents, antisense drugs, inhibitors of HCV NS2/3 protease, and inhibitors of the ribosome entry site (IRES).
The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier are encompassed by another aspect of the present invention.
The components for use in the methods of the invention or the combinations of the invention may be administered sequentially or simultaneously in the form of separate or combined pharmaceutical preparations.
In one embodiment, the invention provides the use of a compound of the invention as described herein for the treatment or prevention of a flaviviridae infection in a host.
In one embodiment, the invention provides a compound of the invention as described herein and further comprising the use of at least one additional active agent selected from the group consisting of viral serine protease inhibitors, viral polymerase inhibitors, viral helicase inhibitors, immunomodulators, antioxidants, antibacterial agents, therapeutic vaccines, hepatoprotectants, antisense drugs, inhibitors of HCV NS2/3 protease and inhibitors of the ribosome entry site (IRES) in the treatment or prevention of a flaviviridae viral infection in a host.
In one embodiment, the invention provides the use of a compound of the invention as described herein for the manufacture of a medicament.
In one embodiment, the present invention provides the use of a compound of the invention as described herein in the manufacture of a medicament for the treatment or prevention of a flaviviridae infection in a host.
In one embodiment, the present invention provides the use of a compound of the invention as described herein and further comprising at least one additional active agent selected from the group consisting of viral serine protease inhibitors, viral polymerase inhibitors, viral helicase inhibitors, immunomodulators, antioxidants, antibacterial agents, therapeutic vaccines, hepatoprotective agents, antisense agents, inhibitors of HCV NS2/3 protease and inhibitors of the ribosome entry site (IRES), in the manufacture of a medicament for treating or preventing a flaviviridae viral infection in a host.
In one embodiment, the present invention provides a method of treating or preventing an infection caused by an HCV virus comprising contacting a biological sample or administering to a patient in need thereof an amount of a compound disclosed herein effective to treat or prevent the infection.
In one embodiment of the method, the HCV has genotype 1. In another embodiment, the HCV has genotype 1a, genotype 1b, or a combination thereof.
Unless otherwise indicated, structures shown herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational) isomeric) forms of the structure; for example, the R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Thus, single stereochemical isomers and mixtures of enantiomers, diastereomers and geometric isomers (or conformers) of the compounds of the present invention are within the scope of the present invention. Single optical isomers or enantiomers can be obtained by methods well known in the art, such as chiral HPLC, enzymatic resolution, and chiral auxiliary.
Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
In one embodiment, the compounds of the present invention are provided as single stereoisomers, wherein at least 95%, at least 97% and at least 99% are free of the corresponding stereoisomer.
In another embodiment, the compounds of the present invention are in a single stereoisomeric form, at least 95% of which is free of the corresponding stereoisomer.
In another embodiment, the compounds of the present invention are in a single stereoisomeric form, at least 97% free of the corresponding stereoisomer.
In another embodiment, the compounds of the present invention are in a single stereoisomeric form, at least 99% of which is free of the corresponding stereoisomer.
Also provided are pharmaceutically acceptable salts of the compounds of the invention. By the term pharmaceutically acceptable salts of the compounds are meant those salts derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acids include hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, trifluoroacetic, citric, methanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic and benzenesulfonic acids. Other acids, such as oxalic, while not themselves pharmaceutically acceptable, may be useful as intermediates in obtaining the compounds of the present invention and their pharmaceutically acceptable acid addition salts.
Also included are salts derived from amino acids (e.g., L-arginine, L-lysine).
Salts derived from suitable bases include alkali metals (e.g., sodium, lithium, potassium) and alkaline earth metals (e.g., calcium, magnesium).
Reference hereinafter to a compound of the invention includes the compound and pharmaceutically acceptable salts thereof.
For pharmaceutically acceptable Salts, see also the list of FDA-approved commercially available Salts listed in Table I by Berge et al, Pharmaceutical Salts, J.of Phar.Sci., vol.66, No.1,1977, month 1, pp.1-19, the disclosure of which is incorporated herein by reference.
It will be appreciated by those skilled in the art that the compounds of the invention may exist in different polymorphic forms. As is known in the art, polymorphism is the ability of a compound to crystallize as one or more different crystalline or "polymorph" species. Polymorphs are solid crystalline phases of a compound having at least two different arrangements or polymorphs of the compound molecule in the solid state. Polymorphs of any given compound are defined as the same chemical formula or composition and differ in chemical structure from the crystal structure as two different chemical compounds.
It will also be appreciated by those skilled in the art that the compounds of the invention may exist in different solvated forms, for example hydrates. Solvates of the compounds of the invention may also be formed when solvent molecules are incorporated into the lattice structure of the compound molecules during crystallization.
In addition to the compounds of the present invention, pharmaceutically acceptable derivatives or prodrugs and esters of the compounds of the present invention may also be used in compositions for the treatment or prevention of the disorders identified herein. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All publications, patent applications, patents, and other references cited herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.
For the purposes of the present invention, elements are identified according to the CAS version of the periodic Table of the elements, Handbook of chemistry and Physics, 75 th edition. In addition, the general principles of Organic Chemistry are described in "Organic Chemistry", Thomas Sorrell, university scienceBooks, Sausaltio: 1999 and "March's Advanced Organic Chemistry", 5 th edition, Ed.: smith, m.b. and March, j., John wiley & Sons, New York: 2001, the entire contents of these documents are incorporated herein by reference.
In the formulae and figures, the rings are transected and the radicals, for example B, B', R in formula (I)1、R4Or R4' bonded wire
Meaning that the group may be bonded to any carbon or, if appropriate, to a heteroatom such as N which is a valence-allowed ring.
The term "alkyl" denotes a straight, branched or cyclic hydrocarbon moiety. The terms "alkenyl" and "alkynyl" refer to straight, branched, or cyclic hydrocarbon moieties having one or more double or triple bonds in the chain. Examples of alkyl, alkenyl, and alkynyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, neohexyl, allyl, vinyl, ethynyl, vinyl, propenyl, isopropononitro, butenyl, isobutenyl, hexenyl, butadienyl, pentenyl, pentadienyl, hexenyl, heptadienyl, heptatrienyl, octenyl, propynyl, butynyl, pentynyl, hexynyl, cyclopropyl, cyclobutyl, cyclohexenyl, cyclohexadienyl, and cyclohexyl. The terms alkyl, alkenyl and alkynyl also include combinations of straight and branched chain groups such as cyclopropylmethyl, cyclohexylethyl and the like. The term alkenyl also includes C1 alkenyl, where one carbon atom is attached to the rest of the molecule through a double bond. If appropriate, "alkyl", "alkenyl" and "alkynyl" may be optionally substituted, for example, in the case of haloalkyl, one or more hydrogen atoms are replaced by halogen, such as alkyl halide. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, dichloromethyl, chloromethyl, trifluoroethyl, difluoroethyl, fluoroethyl, trichloroethyl, dichloroethyl, chloroethyl, chlorofluoromethyl, chlorodifluoromethyl, dichlorofluoroethyl. In addition to halogen, alkyl, alkenyl OR alkynyl may, if appropriate, also be optionally substituted by, for example, halogen, -ORaOxo, -NRaRb、=NO-Rc、-C(=O)ORa、-C(O)NRaRb、-C(=O)OH、-C(=O)Ra、-C(=NORc)Ra、-C(=NRc)NRaRb、-NRdC(=O)NRaRb、-NRbC(=O)Ra、-NRdC(=NRc)NRaRb、-NRbC(=O)ORa、-OC(=O)NRaRb、-OC(=O)Ra、-OC(=O)ORaHydroxy, nitro, azido, cyano, -S (O)0-3Ra、-SO2NRaRb、-NRbSO2Ra、-NRbSO2NRaRbOR-P (= O) ORaORbWherein R isa-RdEach independently is H, C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C6-12Aryl radical, C7-16Aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl.
The terms "cycloalkyl" and "cycloalkenyl" denote cycloalkylalkyl or alkenyl groups, respectively, and are meant to include monocyclic (e.g., cyclopropyl, cyclobutyl, cyclohexyl), spiro (e.g., spiro [2.3] hexyl), fused rings (e.g., bicyclo [4.4.0] decyl), and bridged ring (e.g., bicyclo [2.2.1] heptyl) hydrocarbon moieties.
The terms "alkoxy", "alkenyloxy" and "alkynyloxy" denote alkyl, alkenyl or alkynyl moieties, respectively, covalently bonded to an adjacent atom through an oxygen atom. Examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, tert-pentyloxy, hexyloxy, isohexyloxy, trifluoromethoxy, and neohexyloxy. As with alkyl, alkenyl and alkynyl, alkoxy, alkenyloxy and alkynyloxy groups may, if appropriate, be optionally substituted by groups such as halogen, -ORaOxo, -NRaRb、=NO-Rc、-C(=O)ORa、-C(O)NRaRb、-C(=O)OH、-C(=O)Ra、-C(=NORc)Ra、-C(=NRc)NRaRb、-NRdC(=O)NRaRb、-NRbC(=O)Ra、-NRdC(=NRc)NRaRb、-NRbC(=O)ORa、-OC(=O)NRaRb、-OC(=O)Ra、-OC(=O)ORaHydroxy, nitro, azido, cyano, -S (O)0-3Ra、-SO2NRaRb、-NRbSO2Ra、-NRbSO2NRaRbOR-P (= O) ORaORbWherein R isa-RdEach independently is H, C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C6-12Aryl radical, C7-16Aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl.
The term "aryl" denotes a carbocyclic moiety (i.e. may be monocyclic or polycyclic) comprising at least one ring of benzenoid type and may, if appropriate, be optionally substituted by one or more substituents. Examples include, but are not limited to, phenyl, tolyl, dimethylphenyl, aminophenyl, anilino, naphthyl, anthracenyl, phenanthryl, or biphenyl. Aryl groups may, if appropriate, be optionally substituted by, for example, halogen, -ORa、-NRaRb、-C(=O)ORa、-C(O)NRaRb、-C(=O)OH、-C(=O)Ra、-C(=NORc)Ra、--C(=NRc)NRaRb、-NRdC(=O)NRaRb、-NRbC(=O)Ra、-NRdC(=NRc)NRaRb、-NRbC(=O)ORa、-OC(=O)NRaRb、-OC(=O)Ra、-OC(=O)ORaHydroxy, nitro, azido, cyano, -S (O)0-3Ra、-SO2NRaRb、-NRbSO2Ra、-NRbSO2NRaRbOR-P (= O) ORaORb、C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C6-12Aryl radical, C7-16Aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl,3-12 membered heterocycle or 4-18 membered heterocycle-alkyl, wherein Ra-RdEach independently is H, C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C6-12Aryl radical, C7-16Aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl.
The term "aralkyl" denotes an aryl group attached to an adjacent atom through an alkyl, alkenyl or alkynyl group. Such as aryl, aralkyl may also be optionally substituted, if appropriate. Examples include, but are not limited to, benzyl, benzhydryl, trityl, phenethyl, 3-phenylpropyl, 2-phenylpropyl, 4-phenylbutyl and naphthylmethyl. The aralkyl radical may, if appropriate, be optionally substituted one OR more times by, for example, halogen, -ORa、-NRaRb、-C(=O)ORa、-C(O)NRaRb、-C(=O)OH、-C(=O)Ra、-C(=NORc)Ra、--C(=NRc)NRaRb、-NRdC(=O)NRaRb、-NRbC(=O)Ra,-NRdC(=NRc)NRaRb、-NRbC(=O)ORa、-OC(=O)NRaRb、-OC(=O)Ra、-OC(=O)ORaHydroxy, nitro, azido, cyano, -S (O)0-3Ra、-SO2NRaRb、-NRbSO2Ra、-NRbSO2NRaRbOR-P (= O) ORaORb、C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C6-12Aryl radical, C7-16Aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle or 4-18 membered heterocycle-alkyl, wherein R isa-RdEach independently is H, C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C6-12Aryl radical, C7-16Aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl.
The term "heterocycle" denotesA non-aromatic saturated or partially saturated cyclic moiety, wherein the cyclic moiety is interrupted by at least one heteroatom selected from oxygen (O), sulfur (S) or nitrogen (N). The heterocyclic ring may be monocyclic or polycyclic. Examples include, but are not limited to azetidinyl, dioxolanyl, morpholinyl, morpholino, oxetanyl, piperazinyl, piperidinyl, cyclopentylpyrazolyl, cyclopentoxazinyl, cyclopentofuranyl, tetrahydrofuranyl, thiazolinyl, oxazolinyl, pyranyl, aziridinyl, azepinyl, dioxazepinyl, diazepinyl, oxolanyl, oxazinyl, pyrrolidinyl and thiopyranyl, thiopentanoyl, pyrazolidinyl, dioxanyl and imidazolidinyl. If appropriate, the heterocycle may be optionally substituted one OR more times by, for example, halogen, -ORaOxo, -NRaRb、=NO-Rc、-C(=O)ORa、-C(O)NRaRb、-C(=O)OH、-C(=O)Ra、-C(=NORc)Ra、-C(=NRc)NRaRb、-NRdC(=O)NRaRb、-NRbC(=O)Ra、-NRdC(=NRc)NRaRb、-NRbC(=O)ORa、-OC(=O)NRaRb、-OC(=O)Ra、-OC(=O)ORaHydroxy, nitro, azido, cyano, -S (O)0-3Ra、-SO2NRaRb、-NRbSO2Ra、-NRbSO2NRaRbOR-P (= O) ORaORb、C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C6-12Aryl radical, C7-16Aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl, wherein R isa-RdEach independently is H, C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C6-12Aryl radical, C7-16Aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl.
The term "heterocycle-alkyl" represents a heterocyclic group attached to an adjacent atom via an alkyl, alkenyl, or alkynyl group. It goes without saying that, for example in a 4-18 membered heterocycle-alkyl moiety, 4-18 membered represents the total number of ring atoms present in the heterocycle moiety and carbon atoms present in the alkyl, alkenyl or alkynyl group. For example, the following groups are encompassed by 7-membered heterocycle-alkyl (. beta. -. represents the point of attachment):
if appropriate, the heterocycle-alkyl may optionally be substituted one OR more times by, for example, halogen, -ORaOxo, -NRaRb,=NO-Rc、-C(=O)ORa、-C(O)NRaRb、-C(=O)OH、-C(=O)Ra、-C(=NORc)Ra、-C(=NRc)NRaRb、-NRdC(=O)NRaRb、-NRbC(=O)Ra、-NRdC(=NRc)NRaRb、-NRbC(=O)ORa、-OC(=O)NRaRb、-OC(=O)Ra、-OC(=O)ORaHydroxy, nitro, azido, cyano, -S (O)0-3Ra、-SO2NRaRb、-NRbSO2Ra、-NRbSO2NRaRbOR-P (= O) ORaORb,C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C6-12Aryl radical, C7-16Aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl, wherein R isa-RdEach independently is H, C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C6-12Aryl radical, C7-16Aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl.
The term "heteroaryl" denotes an aromatic cyclic moiety,wherein the cyclic moiety is interrupted by at least one heteroatom selected from oxygen (O), sulfur (S) or nitrogen (N). Heteroaryl groups can be monocyclic or polycyclic, wherein at least one ring on the polycyclic ring system is aromatic and at least one ring (not necessarily the same ring) contains heteroatoms. Examples include, but are not limited to, dithiadiazinyl, furyl, isoxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyridyl, pyrazolyl, pyrrolyl, thiatriazolyl, tetrazolyl, thiadiazolyl, triazolyl, thiazolyl, thienyl, tetrazinyl, thiadiazinyl, triazinyl, thiazinyl, furoisoxazolyl, imidazothiazolyl, thienoisothiazolyl, thienothiazolyl, imidazopyrazolyl, pyrrolopyrrolyl, thienothienyl, thiadiazolopyrimidyl, thiazolothiazinyl, thiazolopyrimidyl, thiazolopyridyl, oxazolopyrimidyl, oxazolopyridyl, benzoxazolyl, benzisothiazolyl, benzothiazolyl, benzodioxolyl, dihydrobenzodioxinyl, benzothiadiazolyl, thienofuryl, imidazopyrazinyl, thiadiazolyl, and the like, Purinyl, pyrazolopyrimidinyl, imidazopyridinyl, benzimidazolyl, indazolyl, benzoxathiocyclopentenyl, benzodioxolyl, indolizinyl, indolinyl, isoindolinyl, furopyrimidinyl, furopyridinyl, benzofuranyl, isobenzofuranyl, thienopyrimidinyl, thienopyridinyl, benzothienyl, benzoxazinyl, benzothiazinyl, quinazolinyl, naphthyridinyl, quinolinyl, isoquinolinyl, benzopyranyl, pyridopyridazinyl, chromene, benzodiazinyl. Heteroaryl groups may, if appropriate, be optionally substituted one OR more times by, for example, halogen, -ORa、-NRaRb、-C(=O)ORa、-C(O)NRaRb、-C(=O)OH、-C(=O)Ra、-C(=NORc)Ra、--C(=NRc)NRaRb、-NRdC(=O)NRaRb、-NRbC(=O)Ra、-NRdC(=NRc)NRaRb、-NRbC(=O)ORa、-OC(=O)NRaRb、-OC(=O)Ra、-OC(=O)ORaHydroxy, nitro, azido, cyano, -S (O)0-3Ra、-SO2NRaRb、-NRbSO2Ra、-NRbSO2NRaRbOR-P (= O) ORaORb、C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C6-12Aryl radical, C7-16Aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl, wherein R isa-RdEach independently is H, C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C6-12Aryl radical, C7-16Aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl.
The term "heteroaralkyl" denotes an optionally substituted heteroaryl group linked to adjacent atoms through an alkyl, alkenyl or alkynyl group. If appropriate, heteroaralkyl may be optionally substituted one OR more times by, for example, halogen, -ORa、-NRaRb、-C(=O)ORa、-C(O)NRaRb、-C(=O)OH、-C(=O)Ra、-C(=NORc)Ra、-C(=NRc)NRaRb、-NRdC(=O)NRaRb、-NRbC(=O)Ra、-NRdC(=NRc)NRaRb、-NRbC(=O)ORa、-OC(=O)NRaRb、-OC(=O)Ra、-OC(=O)ORaHydroxy, nitro, azido, cyano, -S (O)0-3Ra、-SO2NRaRb、-NRbSO2Ra、-NRbSO2NRaRbOR-P (= O) ORaORb、C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C6-12Aryl radical, C7-16Aralkyl, 5-12 membered heteroaryl, 6-18 memberedHeteroaralkyl, 3-12 membered heterocycle or 4-18 membered heterocycle-alkyl, wherein Ra-RdEach independently is H, C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C6-12Aryl radical, C7-16Aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl. It is understood that, for example, the 6-18 members of a 6-18 member heteroaralkyl moiety represent the total number of ring atoms present on the heterocyclic moiety plus the carbon atoms present on the alkyl, alkenyl, or alkynyl group. For example, the following groups are encompassed by 7-membered heteroaralkyl (— denotes the point of attachment):
the "halogen atom or halo" is specifically a fluorine atom, chlorine atom, bromine atom or iodine atom.
The term "oxo" means = O.
A dash ("-") when not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -CONRdReThrough the amide carbon.
The dashed line ("- - -") is used to indicate the point of attachment of the group. For example, a is attached through carbons at the 1 and 4 positions in the following representation:
if present, the sulfur atoms may be at different oxidation levels, i.e., S, SO or SO2. All such oxidation levels are within the scope of the present invention.
The term "independently" means that the substituents may be the same or different definitions for each item.
In general, the term "substituted" whether or not in placeBefore the term "optional" all means that the hydrogen group on a carbon or nitrogen atom of the specified structure is replaced with a group of the specified substituent. Specific substituents are set forth in the above definitions and in the description of the following compounds and examples thereof. Stated otherwise, an optionally substituted group may have a substituent at each substitutable group position, and when more than one position on any given structure may be substituted with more than one substituent selected from the specified group, the substituents may be the same or different at each position. For example, the word "unsubstituted or substituted with R10Substituted one or more times "means when the group is substituted with more than one R10When substituted by radicals, R10The groups may be different from each other. A ring substituent, such as a heterocyclic ring, may be bonded to another ring, such as a cycloalkyl, to form a spiro-bicyclic ring system, e.g., the two rings share a common atom.
As recognized by those skilled in the art, combinations of substituents contemplated by the present invention are those that result in the formation of stable or chemically feasible compounds. The term "stable" as used herein refers to a compound that is not substantially altered upon contact with conditions capable of producing, detecting, and preferably recovering and using it for one or more of the purposes disclosed herein. In some embodiments, a stable compound or a chemically feasible compound is one that does not substantially change when maintained at a temperature of 40 ℃ or less for at least 1 week in the absence of humidity or other chemical reaction conditions. When two alkoxy groups are bonded to the same atom or adjacent atoms, the two alkoxy groups may form a ring together with the atom to which they are attached.
In some embodiments, is represented as:
also included are compounds in which the R group replaces H on the nitrogen atom.
In addition, unless otherwise indicated, structures shown herein are also meant to include the mere presence of one or more elements rich in the sameCompounds that differ in the atom of the site. For example, compounds of the invention in which one or more hydrogen atoms are replaced by deuterium or tritium or one or more carbon atoms are enriched13C-or14Carbon substitution of C-is within the scope of the invention. For example, such compounds are useful as analytical tools, probes in biological assays, or antiviral compounds with improved therapeutic properties.
The term "host" or "patient" refers to a human, male or female, such as a child, adolescent or adult.
It will be appreciated that the amount of a compound of the invention required for use in treatment will vary not only with the particular compound selected, but also with the route of administration, the nature of the condition to be treated and the age and general condition of the patient and will ultimately be at the discretion of the attendant physician or veterinarian. In general, however, a suitable dosage is from about 0.1 to about 750mg/kg body weight per day, such as from 0.5 to 60 mg/kg/day, or such as from 1 to 20 mg/kg/day.
The required dose may conveniently be administered in a single dose or as divided doses administered at appropriate intervals, for example two, three, four or more doses per day.
The compounds are conveniently administered in unit dosage form, for example each unit dosage form contains from 10 to 1500mg, conveniently from 20 to 1000mg, most conveniently from 50 to 700mg, of the active ingredient.
Ideally, the active ingredient should achieve peak plasma concentrations of the active compound of about 1 to about 75 μ M, about 2 to 50 μ M, about 3 to about 30 μ M upon administration. This can be achieved, for example, by intravenous injection of a 0.1-5% solution of the active ingredient (optionally in saline solution) or oral administration of a bolus containing about 1 to about 500mg of the active ingredient. Desirable blood levels may be maintained by continuous infusion to provide from about 0.01 to about 5.0 mg/kg/hour or intermittent infusion containing from about 0.4 to about 15mg/kg of active ingredient.
Where a compound of the invention or a pharmaceutically acceptable salt thereof is used in combination with a second therapeutic agent having activity against the same virus, the dosage of each compound may be the same or different than when the compound is used alone. Suitable dosages are readily apparent to those skilled in the art.
For use in therapy, it is preferred that the active ingredient is administered as a pharmaceutical composition, although it is possible for the compounds of the invention to be administered as raw chemicals. Accordingly, the present invention further provides a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable derivative thereof together with one or more pharmaceutically acceptable carriers therefor, and optionally other therapeutic and/or prophylactic ingredients. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
Pharmaceutical compositions include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal or parenteral (including intramuscular, subcutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation. The formulations may conveniently be presented in discrete dosage units where appropriate, and may be prepared by any of the methods well known in the art of pharmacy. All methods comprise the following steps: the active compound is combined with a liquid carrier or a finely divided solid carrier, or both, and the product is then shaped into the desired formulation, as desired.
Pharmaceutical compositions suitable for oral administration may be presented as discrete dosage units each containing a predetermined amount of active ingredient, e.g., as capsules, cachets, or tablets; as a powder or granules; or as a solution, suspension or emulsion. The active ingredient may also be presented as a bolus, electuary or paste. Tablets and capsules for oral administration may contain conventional excipients such as binding agents, fillers, lubricants, disintegrants, or wetting agents. The tablets may be coated according to methods well known in the art. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), or preservatives.
The compounds of the present invention may also be formulated for parenteral administration (e.g., by injection, such as bolus injection or continuous infusion) and may be presented in unit dosage form in ampoules, pre-filled syringes, small volume infusion, or as multi-dose containers with an added preservative. The compositions may be in the form of suspensions, solutions or emulsions in oily or aqueous media, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in the form of a powder obtained by freeze-drying a sterile isolated solid or from solution for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.
For topical administration to the epidermis, the compounds of the invention may be formulated as ointments, creams or lotions, or as a transdermal patch. Such transdermal patches may contain penetration enhancers such as linalool, carvacrol, thymol, citral, menthol and t-anethole. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. 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.
Compositions suitable for topical administration in the mouth include: lozenges comprising the active ingredient in a flavoured base, usually sucrose and acacia or tragacanth; 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.
Pharmaceutical compositions suitable for rectal administration in which the carrier is a solid are provided, for example, as unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art, and the suppositories may be conveniently formed by mixing the active compound with the softened or molten carrier, followed by cooling and shaping in a mould.
Compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be suitable.
For intranasal administration, the compounds of the invention may be used as a liquid spray or dispersible powder, or in the form of drops. Drops may be formulated using an aqueous or non-aqueous base and may also include one or more dispersing, solubilising or suspending agents. Liquid sprays are conveniently presented from pressurized packs.
For administration by inhalation, the compounds of the invention are conveniently presented from an insufflator, nebulizer or other convenient device in pressurized packaging or delivering an aerosol spray. The pressurized package may include a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve for delivering a metered amount.
Alternatively, for administration by inhalation or insufflation, the compounds of the invention may be in the form of a dry powder composition, e.g., a powder mix of the compound with a suitable powder base (e.g., lactose or starch). The powder compositions may be presented in unit dosage form in capsules or cartridges or, for example, gelatin or blister packs, for example, the powder may be administered with the aid of an inhaler or insufflator.
The above formulations, which are suitable for producing sustained release of the active ingredient, may be employed, if desired.
Detailed Description
The following general schemes and examples are provided to illustrate various embodiments of the present invention and should not be construed as limiting the scope thereof. It will be appreciated by those skilled in the art that other compounds of the invention may be obtained by substituting the reactants and/or operating conditions described generally or specifically for the following examples.
In the following and in the following examples, all temperatures are given in uncalibrated degrees celsius; all parts and percentages are by weight, as otherwise indicated.
The following abbreviations may be used as follows:
aq water
Conc concentration
DCM dichloromethane
DIPEA diisopropylethylamine
DMF dimethyl formamide
DMSO dimethyl sulfoxide
EtOAc ethyl acetate
HATU O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethylurea
Hexafluorophosphates
M mol
MeOH methanol
MTBE methyl tert-butyl ether
n-BuLi n-butyl lithium
PdCl2dppf (1,1' -bis- (diphenylphosphino) -ferrocene) palladium (I I) dichloride
Pd(PPh3)2Cl2Trans-dichlorobis (triphenylphosphine) palladium (I I)
RT Room temperature
TEA Triethylamine
THF tetrahydrofuran
The compounds of the invention may be prepared according to the present description using procedures generally known to those skilled in the art. Those compounds can be analyzed by well known methods including, but not limited to, LCMS (liquid chromatography mass spectrometry), HPLC (high performance liquid chromatography), and NMR (nuclear magnetic resonance). It is to be understood that the specific conditions shown below are merely exemplary and are not meant to limit the scope of conditions that may be used to prepare the compounds of the present invention. The invention also includes conditions which will be apparent to those skilled in the art in light of the present specification for preparing the compounds of the invention. Otherwise, all variables in the following schemes are as defined herein. General scheme:
mass spectrum samples were analyzed on a MicroMass Quattro Micro of MicroMass LCZ mass spectrometer operating in single MS mode with electrospray ionization. The sample is introduced into the mass spectrometer using chromatography. The mobile phase used for all mass spectrometry analyses was made of 10mM pH 7 ammonium acetate and 1: 1 acetonitrile-methanol mixture. The method A comprises the following steps: column gradient conditions were 5% -100% acetonitrile-methanol, gradient time of 3.5mins and run time of 4.8mins on an ACE5C83.0x75mm column. The flow rate was 1.2 ml/min. The method B comprises the following steps: the column gradient was 5% -100% acetonitrile-methanol with a gradient time of 10mins and run time of 12mins on an ACE5C84.6X 150mm column. The flow rate was 1.5 mL/min. The term "rt (min)" as used herein refers to the retention time of LCMS in minutes associated with a compound. Otherwise stated, the LCMS method used to obtain the reported retention times is as described above. If Rt (min) <5min, method A is used; if Rt (min) >5min, method B is used.
1H-NMR spectra were recorded at 400MHz using a Bruker DPX 400 or Varian instrument.
Under standard conditions, a Phenomenex Gemini C18 column, 21.2mm ID x 250mm,5 μm,purification was performed by reverse phase HPLC. Using a linear gradient of 20-90% (CH)3CN in aqueous solution or CH containing 0.02% HCl3Aqueous CN) was eluted at a flow rate of 5.0 mL/min.
Examples
Under standard conditions, using a Phenomenex Gemini C18 column, 21.2mm ID x 250mm,5 μm,purification was performed by reverse phase HPLC. Using a linear gradient of 20-90% (CH)3CN in aqueous solution or CH containing 0.02% HCl3Aqueous CN) was eluted at a rate of 5.0 mL/min.
Example 1:
((S) -1- { (2S,4S) -2- [5- (4' - {2- [ (2S,4S) -1- ((S) -2-methoxycarbonylamino-3-methyl-butyryl) -4-methyl-pyrrolidin-2-yl ] -1H-imidazol-4-yl } -biphenyl-4-yl) -1H-benzimidazol-2-yl ] -4-methyl-pyrrolidine-1-carbonyl } -2-methyl-propyl) -methyl-carbamic acid methyl ester (Compound 7)
Step I:
2-bromo-1- [4- (4-bromophenyl) phenyl ] ethanone
To 1- [4- (4-bromophenyl) phenyl]Ethanone (5g,18.17 mmol) in CH2Cl2To a solution in (40mL) was added bromine (983. mu.L, 19 mmol). Placing the obtained mixture in a chamberStir for 48 hours with warming. The mixture was diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate, water, brine, dried over anhydrous sodium sulfate, and concentrated. Triturating the crude solid with diethyl ether to give 2-bromo-1- [4- (4-bromophenyl) phenyl]Ethanone (5.7g,88.6%) as a white solid.
Step I I:
4-Methylpyrrolidine-1, 2-dicarboxylic acid (2S,4S) -2- (2- (4' -bromobiphenyl-4-yl) -2-oxoethyl) 1-tert-butyl ester
To a solution of (2S,4S) -1-tert-butoxycarbonyl-4-methyl-pyrrolidine-2-carboxylic acid (437mg,1.905mmol) in acetonitrile (6mL) was added 2-bromo-1- [4- (4-bromophenyl) phenyl ] ethanone (693mg,1.732mmol) and DIPEA (0.332mL,1.905 mmol). The reaction mixture was stirred at rt for 4 h, diluted with EtOAc, and washed with brine (3 × 2 mL). The organic layer was concentrated to dryness, azeotroped with toluene (5mL), and purified by flash column chromatography on silica gel (6-50% EtOAc in hexanes) to give 4-methylpyrrolidine-1, 2-dicarboxylic acid (2S,4S) -2- (2- (4' -bromobiphenyl-4-yl) -2-oxoethyl) 1-tert-butyl ester (870mg,1.732 mmols).
Step III:
(2S,4S) -2- [4- (4' -bromo-biphenyl-4-yl) -1H-imidazol-2-yl ] -4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester
To a solution of (2S,4S) -2- (2- (4' -bromobiphenyl-4-yl) -2-oxoethyl) 1-tert-butyl 4-methylpyrrolidine-1, 2-dicarboxylate (870mg,1.732mmol) in toluene (8.7mL) was added ammonium acetate (2.670g,34.64 mmol). The reaction mixture was stirred at 100 ℃ for 21 hours, then cooled to room temperature and diluted with water (8.7 mL). The layers were separated, the aqueous layer was extracted with EtOAc (10mL), and Na was added2SO4The combined organic layers were dried, filtered, and concentrated to dryness. The residue was purified by flash column chromatography on silica gel (6-50% EtOAc in hexanes) to give (2S,4S) -2- [4- (4' -bromo-biphenyl-4-yl) -1H-imidazol-2-yl]-4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (727mg, overall yield from step I I87%).
1H NMR(300MHz,CDCl3)δ10.72(s,1H),7.81(s,1H),7.50(dd,6H),7.26(s,1H),4.93(s,1H),3.77(s,1H),2.86(s,1H),2.60(d,2H),2.26(d,1H),1.48(s,9H),1.11(d,3H)。
LC/MS：m/z=481.97(M+H+)。
Step IV:
(2S,4S) -4-methyl-2- {4- [4' - (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -biphenyl-4-yl ] -1H-imidazol-2-yl } -pyrrolidine-1-carboxylic acid tert-butyl ester
Reacting (2S,4S) -2- [4- (4' -bromo-biphenyl-4-yl) -1H-imidazol-2-yl in a nitrogen atmosphere]-4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (725mg,1.503mmol), 4,5, 5-tetramethyl-2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,3, 2-dioxaborolan-1, 3,2 (1.145g,4.509mmo l), Pd (DPPF) (Cl)2.CH2Cl2A solution of (122.7mg,0.1503mmol) and KOAc (737.5mg,7.515mmol) in DMF (7.3mL) was heated at 80 ℃ for 16 h. Then cooled to room temperature and filtered through a celite bed. The filtrate was diluted with water (15mL) and the mixture was extracted with EtOAc (75 mL). By H2The organic layer was washed with O (3 × 15mL) and concentrated to dryness. The residue was diluted with xylene (10mL) and evaporated to dryness. Purification by flash column chromatography on silica gel (6-50% EtOAc in hexane) afforded (2S,4S) -4-methyl-2- {4- [4' - (4,4,5, 5-tetramethyl- [1,3, 2)]Biphenyl-4-yl-oxaborolan-2-yl]-1H-imidazol-2-yl } -pyrrolidine-1-carboxylic acid tert-butyl ester (530mg, 67%).
1H NMR(300MHz,CDCl3)δ10.75(br s,1H),8.00-7.49(m,8H),7.30(s,1H),4.98(t,1H),3.88-3.71(m,1H),2.90(t,1H),2.77-2.42(m,2H),2.29(d,1H),1.56(d,9H),1.38(s,12H),1.15(d,3H)。
Step V:
(2S,4S) -2- {4- [4' - (2- { (2S,4S) -1- [ (S) -2- (methoxycarbonyl-methyl-amino) -3-methyl-butyryl ] -4-methyl-pyrrolidin-2-yl } -1H-benzimidazol-5-yl) -biphenyl-4-yl ] -1H-imidazol-2-yl } -4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester
To (2S,4S) -4-methyl-2- {4- [4' - (4,4,5, 5-tetramethyl- [1,3, 2)]Biphenyl-4-yl-oxaborolan-2-yl]-1H-imidazol-2-yl } -pyrrolidine-1-carboxylic acid tert-butyl ester (211mg,0.3985mmol), N- [1- [ (2S,4S) -2- (5-iodo-1H-benzoimidazol-2-yl) -4-methyl-pyrrolidine-1-carbonyl]-2-methyl-propyl]-methyl N-methyl-carbamate (198.6mg,0.3985mmol), Pd (DPPF) (Cl)2.CH2Cl2(32.54mg,0.03985mmol) to a suspension in 2-propanol (2.1mL) was added 1M NaHCO3Aqueous solution (2mL,2 mmol). The reaction mixture was stirred at 80 ℃ for 18 h, cooled to room temperature, filtered through a celite bed, and concentrated to dryness. The residue was purified by flash column chromatography on silica gel (12-100% EtOAc in hexanes) to give 2S,4S) -2- {4- [4' - (2- { (2S,4S) -1- [ (S) -2- (methoxycarbonyl-methyl-amino) -3-methyl-butyryl]-4-methyl-pyrrolidin-2-yl } -1H-benzimidazol-5-yl) -biphenyl-4-yl]-1H-imidazol-2-yl } -4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (115mg, 37%).
LC/MS：m/z=774.55(M+H+)。
Step VI
Methyl- { (S) -2-methyl-1- [ (2S,4S) -4-methyl-2- (5- {4' - [2- ((2S,4S) -4-methyl-pyrrolidin-2-yl) -1H-imidazol-4-yl ] -biphenyl-4-yl } -1H-benzimidazol-2-yl) -pyrrolidine-1-carbonyl ] -propyl } -carbamic acid methyl ester hydrochloride
To a solution of (2S,4S) -2- {4- [4' - (2- { (2S,4S) -1- [ (S) -2- (methoxycarbonyl-methyl-amino) -3-methyl-butyryl ] -4-methyl-pyrrolidin-2-yl } -1H-benzimidazol-5-yl) -biphenyl-4-yl ] -1H-imidazol-2-yl } -4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (115mg,0.1486mmol) in methanol was added a 4M HCl in dioxane solution (0.632mL,2.526 mmol). The reaction mixture was stirred at room temperature for 1 hour and concentrated to dryness. The title product was used as such in the next step.
Step VII
((S) -1- { (2S,4S) -2- [5- (4' - {2- [ (2S,4S) -1- ((S) -2-methoxycarbonylamino-3-methyl-butyryl) -4-methyl-pyrrolidin-2-yl ] -1H-imidazol-4-yl } -biphenyl-4-yl) -1H-benzimidazol-2-yl ] -4-methyl-pyrrolidine-1-carbonyl } -2-methyl-propyl) -methyl-carbamic acid methyl ester
To methyl- { (S) -2-methyl-1- [ (2S,4S) -4-methyl-2- (5- {4' - [2- ((2S,4S) -4-methyl-pyrrolidin-2-yl) -1H-imidazol-4-yl cooled with an ice bath in a nitrogen atmosphere]-biphenyl-4-yl } -1H-benzimidazol-2-yl) -pyrrolidine-1-carbonyl]To a solution of-propyl } -carbamic acid methyl ester hydrochloride (50.2mg,0.707mmol) in DMF (2mL) was added HATU (28.3mg,0.0744mmol) and DIPEA (0.037mL,0.212mmol) in that order. The reaction mixture was stirred at room temperature for 17 hours with saturated NaHCO3Aqueous solution (2 mL). The mixture was extracted with EtOAc (5 × 3mL) and H2The combined organic layers were washed with O (3X3mL) and Na2SO4Drying, filtering and concentrating to dryness. The residue was purified by preparative HPLC to give ((S) -1- { (2S,4S) -2- [5- (4' - {2- [ (2S,4S) -1- ((S) -2-methoxycarbonylamino-3-methyl-butyryl) -4-methyl-pyrrolidin-2-yl)]-1H-imidazol-4-yl } -biphenyl-4-yl) -1H-benzimidazol-2-yl]-4-methyl-pyrrolidine-1-carbonyl } -2-methyl-propyl) -methyl-carbamic acid methyl ester (29.1mg, 47%).
1H NMR(400MHz,dmso-d6)δ8.13(s,1H),7.86(m,11H),7.25(d,1H、J=7.9Hz),5.14(m,1H),5.06(m,1H),4.38(m,1H),4.08(m,3H),3.66(m,3H),3.51(s,3H),3.35(m,2H),2.72(m,3H),2.45(m,4H),1.95(m,4H),1.11(m,6H),0.79(d,3H、J=6.7Hz),0.73(m,9H)。
LC/MS：m/z=831.67(M+H+)。
Example 2:
n- [ (1S) -1- [ (2S,4S) -2- [4- [4- [4- [2- [ (2S,4S) -1- [ (2S) -2- [ methoxycarbonyl (methyl) amino ] -3-methyl-butyryl ] -4-methyl-pyrrolidin-2-yl ] -1H-benzimidazol-5-yl ] phenyl ] -1H-imidazol-2-yl ] -4-methyl-pyrrolidine-1-carbonyl ] -2-methyl-propyl ] -N-methyl-carbamic acid methyl ester (compound 6):
to (2S) -2- [ methoxycarbonyl (methyl) amino group cooled in ice bath in nitrogen atmosphere]-3-methyl-butyric acid (12.8mg,0.06765mmol) and ((S) -3-methyl-1- ((2S,4S) -4-methyl-2- (6- (4'- (2- ((2S,4S) -4-methylpyrrolidin-2-yl) -1H-imidazol-5-yl) - [1,1' -biphenyl]-4-yl) -1H-benzo [ d]To a solution of methyl imidazol-2-yl) pyrrolidin-1-yl) -1-oxobutan-2-yl) carbamate hydrochloride (48.1mg,0.0677mmol) in DMF (2mL) was added HATU (28.3mg,0.0744mmol) and DIPEA (0.035mL,0.203mmol) in that order. The reaction mixture was stirred at room temperature for 19 hours with saturated NaHCO3Aqueous solution (2 mL). The mixture was extracted with EtOAc (5X3mL) and H2The combined organic layers were washed with O (3X3mL) and Na2SO4Drying, filtering and concentrating to dryness. The residue was purified by preparative HPLC on reversed phase to give N- [ (1S) -1- [ (2S,4S) -2- [4- [4- [4- [2- [ (2S,4S) -1- [ (2S) -2- [ methoxycarbonyl (methyl) amino group]-3-methyl-butyryl]-4-methyl-pyrrolidin-2-yl]-1H-benzimidazol-5-yl]Phenyl radical]Phenyl radical]-1H-imidazol-2-yl]-4-methyl-pyrrolidine-1-carbonyl]-2-methyl-propyl]-methyl N-methyl-carbamate (24.4mg, 41%).
1H NMR(400MHz,dmso-d6)δ7.84(m,12H),5.06(m,2H),4.45(t,2H),4.28(m,1H),4.14(m,1H),4.07(m,1H),3.64(s,6H),3.36(m,2H),2.73(m,6H),2.43(m,4H),1.96(m,2H),1.87(m,2H),1.11(m,6H),0.74(m,12H)。
LC/MS：m/z=845.57(M+H+)。
Example 3:
methyl ((S) -1- ((2S,4S) -2- (4- (4'- (2- ((2S,4S) -1- ((S) -2- ((methoxycarbonyl) amino) -3-methylbutyryl) -4-methylpyrrolidin-2-yl) -3H-benzo [ d ] imidazol-6-yl) - [1,1' -biphenyl ] -4-yl) -1H-imidazol-2-yl) -4-methylpyrrolidin-1-yl) -3-methyl-1-oxobutan-2-yl) (methyl) carbamate (compound 8):
step I:
(2S,4S) -2- [4- (4' - {2- [ (2S,4S) -1- ((S) -2-methoxycarbonylamino-3-methyl-butyryl) -4-methyl-pyrrolidin-2-yl ] -1H-benzimidazol-5-yl } -biphenyl-4-yl) -1H-imidazol-2-yl ] -4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester
To (2S,4S) -4-methyl-2- {4- [4' - (4,4,5, 5-tetramethyl- [1,3, 2)]Biphenyl-4-yl-oxaborolan-2-yl]-1H-imidazol-2-yl } -pyrrolidine-1-carboxylic acid tert-butyl ester (138mg,0.2606mmol), ((S) -1- ((2S,4S) -2- (5-iodo-1H-benzo [ d)]Imidazol-2-yl) -4-methylpyrrolidin-1-yl) -3-methyl-1-oxobut-2-yl) carbamic acid methyl ester (126.2mg,0.2606mmol), Pd (DPPF) (Cl)2.CH2Cl2(21.3mg,0.02606mmol) to a suspension in 2-propanol (1.4mL) was added 1M NaHCO3Aqueous solution (1.3mL,1.3 mmol). The reaction mixture was heated at 80 ℃ for 19 h, cooled to room temperature, and extracted with dichloromethane (2X10 mL). With Na2SO4The organic layer was dried, filtered and concentrated to dryness. The residue was purified by flash column chromatography on silica gel (50-100% EtOAc in hexanes) to give (2S,4S) -2- [4- (4' - {2- [ (2S,4S) -1- ((S) -2-methoxycarbonylamino-3-methyl-butyryl) -4-methyl-pyrrolidin-2-yl]-1H-benzimidazol-5-yl } -biphenyl-4-yl) -1H-imidazol-2-yl]-4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (75mg, 38%). HPLC: waters symmetry Shield RP183.5 μm 4.6mm X50 mm, solvent A: 0.01% TFA in acetonitrile, solvent B: aqueous 0.01% TFA, gradient: 15: 85A: b-90: 10A: b, RT =4.87min over 10 min.
Step II:
{ (S) -2-methyl-1- [ (2S,4S) -4-methyl-2- (5- {4' - [2- ((2S,4S) -4-methyl-pyrrolidin-2-yl) -1H-imidazol-4-yl ] -biphenyl-4-yl } -1H-benzimidazol-2-yl) -pyrrolidine-1-carbonyl ] -propyl } -carbamic acid methyl ester hydrochloride
Tert-butyl (2S,4S) -2- [4- (4' - {2- [ (2S,4S) -1- ((S) -2-methoxycarbonylamino-3-methyl-butyryl) -4-methyl-pyrrolidin-2-yl ] -1H-benzimidazol-5-yl } -biphenyl-4-yl) -1H-imidazol-2-yl ] -4-methyl-pyrrolidine-1-carboxylate (75mg,0.0987mmol) was stirred with a 4M HCl solution in dioxane (4mL,16 mmol). The reaction mixture was stirred at room temperature for 0.5 h and concentrated to dryness. The product { (S) -2-methyl-1- [ (2S,4S) -4-methyl-2- (5- {4' - [2- ((2S,4S) -4-methyl-pyrrolidin-2-yl) -1H-imidazol-4-yl ] -biphenyl-4-yl } -1H-benzimidazol-2-yl) -pyrrolidine-1-carbonyl ] -propyl } -carbamic acid methyl ester hydrochloride was used as such as the next step.
Step III:
methyl ((S) -1- ((2S,4S) -2- (4- (4'- (2- ((2S,4S) -1- ((S) -2- ((methoxycarbonyl) amino) -3-methylbutyryl) -4-methylpyrrolidin-2-yl) -3H-benzo [ d ] imidazol-6-yl) - [1,1' -biphenyl ] -4-yl) -1H-imidazol-2-yl) -4-methylpyrrolidin-1-yl) -3-methyl-1-oxobutan-2-yl) (methyl) carbamate
To { (S) -2-methyl-1- [ (2S,4S) -4-methyl-2- (5- {4' - [2- ((2S,4S) -4-methyl-pyrrolidin-2-yl) -1H-imidazol-4-yl ] cooled with an ice bath in a nitrogen atmosphere]-biphenyl-4-yl } -1H-benzimidazol-2-yl) -pyrrolidine-1-carbonyl]-propyl } -carbamic acid methyl ester hydrochloride (68.7mg,0.0987mmol) and (2S) -2- [ methoxycarbonyl (methyl) amino]To a solution of-3-methyl-butyric acid (18.67mg,0.09867mmol) in DMF (2mL) was added HATU (41.25mg,0.1085mmol) and DIPEA (38.26mg, 51.56. mu.L, 0.2960mmol) in that order. The reaction mixture was stirred at room temperature for 5 hours and diluted with water (6 mL). The mixture was extracted with EtOAc (5X 6mL) and H2The combined organic layers were washed with O (3X3mL) and Na2SO4Drying, filtering and concentrating to dryness. The residue was purified by flash column chromatography on silica gel (0-10% methanol in CH)2Cl2Solution) was further purified by reverse phase preparative HPLC to give ((S) -1- ((2S,4S) -2- (4- (4' - (2- ((2S,4S) -1- ((S) -2- ((methoxycarbonyl) amino) -3-methylbutanoyl) -4-methylpyrrolidin-2-yl) -3H-benzo [ d]Imidazol-6-yl) - [1,1' -biphenyl]-4-yl) -1H-imidazol-2-yl) -4-methylpyrrolidin-1-yl) -3-methyl-1-oxobutan-2-yl) (methyl) carbamic acid methyl ester (36mg, 41%).
1H NMR(400MHz,dmso-d6)δ8.13(s,1H),7.88(m,11H),7.25(d,1H、J=8.3Hz),5.14(m,1H),5.08(m,1H),4.37(m,1H),4.13(m,2H),3.64(s,3H),3.51(s,3H),3.40(m,3H),2.72(s,3H),2.48(m,4H),1.93(m,4H),1.11(m,6H),0.76(m,12H)。
LC/MS：m/z=831.61(M+H+)。
Example 4:
((S) -1- { (2S,4S) -2- [5- (4' - {2- [ (2S,4S) -1- ((S) -2-methoxycarbonylamino-3-methyl-butyryl) -4-methyl-pyrrolidin-2-yl ] -1H-imidazol-4-yl } -biphenyl-4-yl) -1H-benzimidazol-2-yl ] -4-methyl-pyrrolidine-1-carbonyl } -2-methyl-propyl) -carbamic acid methyl ester (Compound 5):
step I:
2- (6- (4'- (2- ((2S,4S) -1- (tert-butoxycarbonyl) -4-methylpyrrolidin-2-yl) -1H-imidazol-4-yl) - [1,1' -biphenyl ] -4-yl) -3H-benzo [ d ] imidazol-2-yl) -4-methylpyrrolidine-1-carboxylic acid (2S,4S) -tert-butyl ester
With isopropanol (31.2mL)/NaHCO3(23.4mL of 1M H2O solution, 23.40mmol) preparation of (2S,4S) -2- (5-iodo-1H-benzimidazol-2-yl) -4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (2.0g,4.681mmol), (2S,4S) -4-methyl-2- [4- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Phenyl radical]-1H-imidazol-2-yl]Pyrrolidine-1-carboxylic acid tert-butyl ester (2.478g,4.681mmol) and [3- (2-dicyclohexylphosphinyl) -2, 4-dimethoxy-phenyl]Solution of sodium sulfonyloxy (VPHOS) (183.7mg,0.3745mmol) in N2Degassing in gas stream for 15 min. After addition of diacetoxypalladium (21.02mg,0.09362mmol), the solution was heated to 100 ℃ for 8 hours in a reflux condenser. The reaction mixture was cooled to room temperature and then diluted with EtOAc (10 mL). The phases were separated and the aqueous layer was extracted with EtOAc (2 × 10 mL). With Na2SO4The combined organic phases were dried, filtered and concentrated. The crude residue was purified by silica gel column (50-100% EtOAc/hexanes) to give 2- (6- (4'- (2- ((2S,4S) -1- (tert-butoxycarbonyl) -4-methylpyrrolidin-2-yl) -1H-imidazol-4-yl) - [1,1' -biphenyl]-4-Radical) -3H-benzo [ d]Imidazol-2-yl) -4-methylpyrrolidine-1-carboxylic acid (2S,4S) -tert-butyl ester (2.55g), Rf=0.3(EtOAc)。
1H NMR (300MHz, acetone-d 6) Δ 11.40(s,1H),11.09(s,1H),8.00-7.41(m,12H),5.05(s,1H),4.90(s,1H),3.86(s,2H),2.99(d,2H),2.39(ddt,5H),1.90-1.75(m,1H),1.45(s,9H),1.29-1.16(m,9H),1.11(d, 6H).
LC/MS：m/z=703.62(M+H+)。
Step II:
2- ((2S,4S) -4-methylpyrrolidin-2-yl) -6- (4'- (2- ((2S,4S) -4-methylpyrrolidin-2-yl) -1H-imidazol-4-yl) - [1,1' -biphenyl ] -4-yl) -3H-benzo [ d ] imidazole
In a 100mL flask, 2- (6- (4'- (2- ((2S,4S) -1- (tert-butoxycarbonyl) -4-methylpyrrolidin-2-yl) -1H-imidazol-4-yl) - [1,1' -biphenyl]-4-yl) -3H-benzo [ d]Imidazol-2-yl) -4-methylpyrrolidine-1-carboxylic acid (2S,4S) -tert-butyl ester (2.55g,3.628mmol) dissolved in CH2Cl2(10 mL). The solution was cooled to 0 ℃ and HCl (18.14mL of 2.0M,36.28mmol) was added. The reaction mixture was then stirred vigorously at room temperature for 30 min. The solution was concentrated and then dried under high vacuum. The yellow salt (2.353g) was used in the next reaction without further purification.
Step III
((S) -1- { (2S,4S) -2- [5- (4' - {2- [ (2S,4S) -1- ((S) -2-methoxycarbonylamino-3-methyl-butyryl) -4-methyl-pyrrolidin-2-yl ] -1H-imidazol-4-yl } -biphenyl-4-yl) -1H-benzimidazol-2-yl ] -4-methyl-pyrrolidine-1-carbonyl } -2-methyl-propyl) -carbamic acid methyl ester
In a 100mL round bottom flask, combine 2- ((2S,4S) -4-methylpyrrolidin-2-yl) -6- (4'- (2- ((2S,4S) -4-methylpyrrolidin-2-yl) -1H-imidazol-4-yl) - [1,1' -biphenyl in DMF (25.95mL)]-4-yl) -3H-benzo [ d]Imidazole (2.353g,3.628mmol), (2S) -2- (methoxycarbonylamino) -3-methyl-butyric acid (1.589g,9.070mmol) and HATU (4.966g,13.06 mmol) then cooled to 0 ℃. DIPEA (4.689g,6.319mL,36.28mmol) was added and the mixture was stirredThe reaction was stirred at room temperature for 8 hours. The reaction mixture was concentrated and the resulting residue was diluted with EtOAc (50 mL). With saturated NaHCO3The organic layer was washed with aqueous solution (20mL) and water (20 mL). The aqueous layer was back-extracted with EtOAc (20mL), washed with water (10mL), and Na2SO4The combined organic layers were dried, filtered, and concentrated. The crude residue was purified by silica gel chromatography (0-5% MeOH/EtOAc, R)f＝0.5,10%MeOH/CH2Cl2) To give ((S) -1- { (2S,4S) -2- [5- (4' - {2- [ (2S,4S) -1- ((S) -2-methoxycarbonylamino-3-methyl-butyryl) -4-methyl-pyrrolidin-2-yl)]-1H-imidazol-4-yl } -biphenyl-4-yl) -1H-benzimidazol-2-yl]-4-methyl-pyrrolidine-1-carbonyl } -2-methyl-propyl) -carbamic acid methyl ester (905mg,30%) as a yellow solid.
1H NMR(400MHz,dmso-d6)δ12.29(m,1H),12.02(m,1H),7.73(m,12H),7.23(m,2H),5.02(m,1H),4.91(m,1H),4.10(m,4H),3.51(br.s,6H),3.28(m,2H),3.15(d,2H),2.38(m,4H),1.81(m,4H),1.09(m,6H),0.80(m,12H)。
LC/MS：m/z=816.99(M+H+)。
Example 4 (alternative route)
((S) -1- { (2S,4S) -2- [5- (4' - {2- [ (2S,4S) -1- ((S) -2-methoxycarbonylamino-3-methyl-butyryl) -4-methyl-pyrrolidin-2-yl ] -1H-imidazol-4-yl } -biphenyl-4-yl) -1H-benzimidazol-2-yl ] -4-methyl-pyrrolidine-1-carbonyl } -2-methyl-propyl) -carbamic acid methyl ester (Compound 5):
to N- [ (1S) -1- [ (2S,4S) -2- (5-iodo-1H-benzimidazol-2-yl) -4-methyl-pyrrolidine-1-carbonyl in a microwave vial]-2-methyl-propyl]Methyl carbamate (52.40mg,0.1082mmol), ((S) -methyl 1- ((2S,4S) -2- (4-iodo-1H-imidazol-2-yl) -4-methylpyrrolidin-1-yl) -3-methyl-1-oxobutan-2-yl) carbamate (47mg,0.1082mmol), [1,1' -biphenyl]-4,4' -Diylboronic acid (26.17mg, 0.1082)mmol)、Pd(DPPF)(Cl)2.CH2Cl2(4.418mg,0.005410mmol) and 1mL of 2-propanol were added to a suspension of 1M NaHCO3Aqueous solution (541.0. mu.L, 0.5410 mmol). The mixture was stirred at room temperature for 3 minutes and heated in a microwave to 150 ℃ for 10 minutes. The reaction mixture was concentrated to dryness. The residue was purified by flash column chromatography on silica gel (0-10% methanol in CH)2Cl2Solution) was further purified by reverse phase preparative HPLC to give ((S) -1- { (2S,4S) -2- [5- (4' - {2- [ (2S,4S) -1- ((S) -2-methoxycarbonylamino-3-methyl-butyryl) -4-methyl-pyrrolidin-2-yl)]-1H-imidazol-4-yl } -biphenyl-4-yl) -1H-benzimidazol-2-yl]-4-methyl-pyrrolidine-1-carbonyl } -2-methyl-propyl) -carbamic acid methyl ester (12mg, 25%).
LC/MS：m/z=817.62(M+H+)。
Example 5:
((S) -1- { (S) -2- [5- (4' - {2- [ (S) -1- ((S) -2-methoxycarbonylamino-3-methyl-butyryl) -pyrrolidin-2-yl ] -3H-benzimidazol-5-yl } -biphenyl-4-yl) -1H-imidazol-2-yl ] -pyrrolidine-1-carbonyl } -2-methyl-propyl) -carbamic acid methyl ester (Compound 4):
step I:
(S) -4- (4 '-bromo- [1,1' -biphenyl ] -4-yl) -2- (pyrrolidin-2-yl) -1H-imidazole
A suspension of (S) -tert-butyl 2- (4- (4 '-bromo- [1,1' -biphenyl ] -4-yl) -1H-imidazol-2-yl) pyrrolidine-1-carboxylate (505mg,1.078mmol) in HCl (4M in dioxane 5.4mL,21.6mmol) was stirred at room temperature for 2 hours and diluted with ether (2 mL). The suspension was cooled with an ice bath and the product was collected by filtration to give (S) -4- (4 '-bromo- [1,1' -biphenyl ] -4-yl) -2- (pyrrolidin-2-yl) -1H-imidazole hydrochloride (436mg, 99%).
Step II:
((S) -1- ((S) -2- (4- (4 '-bromo- [1,1' -biphenyl ] -4-yl) -1H-imidazol-2-yl) pyrrolidin-1-yl) -3-methyl-1-oxobutan-2-yl) carbamic acid methyl ester
To (S) -4- (4 '-bromo- [1,1' -biphenyl) in a nitrogen atmosphere]To a solution of (4-yl) -2- (pyrrolidin-2-yl) -1H-imidazole hydrochloride (423mg,1.045mmol) in DMF (5mL) was added sequentially (2S) -2- (methoxycarbonylamino) -3-methyl-butyric acid (201.5mg,1.150mmol), DIPEA (405.2mg, 546.1. mu.L, 3.135 mmol) and HATU (596.2mg,1.568 mmol). The reaction mixture was stirred at room temperature for 2 hours with saturated NaHCO3Aqueous solution (10 mL). The reaction mixture was extracted with EtOAc (5 × 10mL) and H2The combined organic layers were washed with O (3 × 10mL) and concentrated to dryness. The residue was purified by flash column chromatography on silica gel (2-20% methanol in CH)2Cl2Solution) to give ((S) -1- ((S) -2- (4- (4 '-bromo- [1,1' -biphenyl)]-4-yl) -1H-imidazol-2-yl) pyrrolidin-1-yl) -3-methyl-1-oxobutan-2-yl) carbamic acid methyl ester (462mg, 84%).
Step III:
((S) -1- { (S) -2- [5- (4' - {2- [ (S) -1- ((S) -2-methoxycarbonylamino-3-methyl-butyryl) -pyrrolidin-2-yl ] -3H-benzimidazol-5-yl } -biphenyl-4-yl) -1H-imidazol-2-yl ] -pyrrolidine-1-carbonyl } -2-methyl-propyl) -carbamic acid methyl ester
To ((S) -1- ((S) -2- (4- (4 '-bromo- [1,1' -biphenyl)]-4-yl) -1H-imidazol-2-yl) pyrrolidin-1-yl) -3-methyl-1-oxobutan-2-yl carbamic acid methyl ester (99.6mg,0.1896mmol), ((S) -3-methyl-1-oxo-1- ((S) -2- (6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3H-benzo [ d ] c]Imidazol-2-yl) pyrrolidin-1-yl) butan-2-yl) carbamic acid methyl ester and Pd (DPPF) (Cl)2.CH2Cl2(15.48mg,0.01896mmol) to a suspension in acetonitrile (2mL) was added 1M NaHCO3Aqueous solution (0.284mL,0.569 mmol). The reaction mixture was heated in a microwave oven at 130 ℃ for 10 minutes, cooled to room temperature, and diluted with water (10 mL). By CH2Cl2The reaction mixture was extracted (5X10mL) with Na2SO4The combined organic layers were dried, filtered, and concentrated to dryness. By passingThe residue was purified by flash column chromatography on silica gel (2-20% methanol in CH)2Cl2Solution) was further purified by reverse phase preparative HPLC to give ((S) -1- { (S) -2- [5- (4' - {2- [ (S) -1- ((S) -2-methoxycarbonylamino-3-methyl-butyryl) -pyrrolidin-2-yl)]-3H-benzimidazol-5-yl } -biphenyl-4-yl) -1H-imidazol-2-yl]-pyrrolidine-1-carbonyl } -2-methyl-propyl) -carbamic acid methyl ester (30mg, 19%).
1H NMR(400MHz,dmso-d6)δ8.13(s,1H),7.89(m,11H),7.32(m,2H),5.25(m,1H),5.15(m,1H),4.11(q,2H、J=8.2Hz),3.93(m,2H),3.85(m,2H),3.52(s,6H),2.42(m,2H),2.16(m,4H),2.04(m,4H),0.82(d,6H、J=6.8Hz),0.76(d,6H、J=6.8Hz)。
Example 6:
IN- [ (1S) -1- [ (2S,4S) -2- [5- [4- [4- [2- [ (2S,4S) -1- [ (2S) -2- (methoxycarbonylamino) -3-methyl-butyryl ] -4-methyl-pyrrolidin-2-yl ] -1H-benzimidazol-5-yl ] phenyl ] -4-methyl-1H-imidazol-2-yl ] -4-methyl-pyrrolidine-1-carbonyl ] -2-methyl-propyl ] carbamic acid methyl ester (compound 15):
the procedure is the same as described for example 4((S) -1- { (2S,4S) -2- [5- (4' - {2- [ (2S,4S) -1- ((S) -2-methoxycarbonylamino-3-methyl-butyryl) -4-methyl-pyrrolidin-2-yl ] -1H-imidazol-4-yl } -biphenyl-4-yl) -1H-benzimidazol-2-yl ] -4-methyl-pyrrolidine-1-carbonyl } -2-methyl-propyl) -carbamic acid methyl ester.
1H NMR(400MHz,CD3OD)δ7.97-7.70(m,11H),7.69-7.62(m,2H),5.35(m,1H),5.13(m,1H),4.35(m,2H),4.10(m,2H),3.64(s,6H),3.45(m,2H),2.67-2.40(m,4H),2.40(s,3H),2.05-1.80(m,4H),1.37(m,6H),0.95(m 6H),0.78(m,6H)。
LC/MS：m/z=831.46(M+H+)。
Intermediate:
2- (5- (4 '-bromo- [1,1' -biphenyl ] -4-yl) -4-methyl-1H-imidazol-2-yl) -4-methylpyrrolidine-1-carboxylic acid (2S,4S) -tert-butyl ester:
to a solution of (2S,4S) -2- (5-iodo-4-methyl-1H-imidazol-2-yl) -4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (289mg,0.7387mmol) in 6mL 5: 1, toluene: to the solution in methanol was added [4- (4-bromophenyl) phenyl group in this order]Boric acid (346.7mg,1.252mmol), K3PO4(199.3mg,0.9389mmol) and Pd (PPh)3)4(71.85mg,0.06218 mmol). The reaction mixture was heated at 75 ℃ for 3 hours. The reaction mixture was concentrated, diluted with ethyl acetate, washed with water and brine. The organic layer was concentrated to dryness. The residue was dissolved in dichloromethane and purified by flash column chromatography on silica gel (0-10% methanol/dichloromethane) to give 2- (5- (4 '-bromo- [1,1' -biphenyl)]-4-yl) -4-methyl-1H-imidazol-2-yl) -4-methylpyrrolidine-1-carboxylic acid (2S,4S) -tert-butyl ester (160mg,0.322 mmol).
LC-MS：m/z=497.91(M+H+)。
Example 7
Methyl N- [ (1S) -1- [ (2S) -2- [4- [4- [2- [ (2S) -1- [ (2S) -2- (methoxycarbonylamino) -3-methyl-butyryl ] pyrrolidin-2-yl ] -1H-benzimidazol-5-yl ] phenyl ] -1H-imidazol-2-yl ] pyrrolidine-1-carbonyl ] -2-methyl-propyl ] carbamate (compound 3):
step I:
(2S) -2- [4- [4- [2- [ (2S) -1- [ (2S) -2- (methoxycarbonylamino) -3-methyl-butyryl ] pyrrolidin-2-yl ] -1H-benzimidazol-5-yl ] phenyl ] -1H-imidazol-2-yl ] pyrrolidine-1-carboxylic acid tert-butyl ester
To a (2S) -2- [4- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl group in a sealed test tube (25mL) under a nitrogen atmosphere]-1H-imidazol-2-yl]Pyrrolidine-1-carboxylic acid tert-butyl ester (169mg,0.3847mmol) (see WO 2008/021923), ((S) -1- ((S) -2- (5-iodo-1H-benzo [ d ]]Imidazol-2-yl) pyrrolidin-1-yl) -3-methyl-1-oxobutan-2-yl) carbamic acid methyl ester (180.9mg,0.3847mmol) and Pd (dppf) Cl2-CH2Cl2(47.13mg,0.05771mmol) in acetonitrile (4mL) was added aqueous sodium bicarbonate (961.8. mu.L of 1M,0.9618 mmol). The resulting suspension was heated in an oil bath at 100 ℃ for 16 hours, concentrated, washed with water and CH2Cl2Diluting, separating the organic solution, extracting the aqueous solution with dichloromethane, washing the combined extracts with brine, and drying (Na)2SO4). The residue was purified on a 25+ M biotage silica gel column using MeOH-ethyl acetate (0: 100-15: 85) as eluent to give (2S) -2- [4- [4- [2- [ (2S) -1- [ (2S) -2- (methoxycarbonylamino) -3-methyl-butyryl]Pyrrolidin-2-yl radical]-1H-benzimidazol-5-yl]Phenyl radical]-1H-imidazol-2-yl]Pyrrolidine-1-carboxylic acid tert-butyl ester (101mg,0.1491mmol,38.75%) as a light brown solid.
LC/MS：m/z=656.55(M+H+)。
Step II:
4- (4- (2- ((S) -1- ((S) -2- ((methoxycarbonyl) amino) -3-methylbutyryl) pyrrolidin-2-yl) -1H-benzo [ d ] imidazol-5-yl) phenyl) -2- ((S) -pyrrolidin-1-ium-2-yl) -1H-imidazol-3-ium chloride
To a solution of tert-butyl (2S) -2- [4- [4- [2- [ (2S) -1- [ (2S) -2- (methoxycarbonylamino) -3-methyl-butyryl ] pyrrolidin-2-yl ] -1H-benzimidazol-5-yl ] phenyl ] -1H-imidazol-2-yl ] pyrrolidine-1-carboxylate (100mg,0.1525mmol) in MeOH (0.15mL) was added HC i dioxane solution (381.2 μ L of 4M,1.525 mmol), stirred overnight at room temperature, then concentrated to give 4- (4- (2- ((S) -1- ((S) -2- ((methoxycarbonyl) amino) -3-methylbutyryl) pyrrolidin-2-yl) -1H-benzo [ d ] imidazole -5-yl) phenyl) -2- ((S) -pyrrolidin-1-ium-2-yl) -1H-imidazol-3-ium chloride (100mg,0.1529mmol,100.3%) as a light brown solid. LC-MS showed the presence of the desired compound, which was used as such in the next step without further purification.
LC/MS：m/z=556.33(M+H+)。
Step III:
n- [ (1S) -1- [ (2S) -2- [4- [4- [2- [ (2S) -1- [ (2S) -2- (methoxycarbonylamino) -3-methyl-butyryl ] pyrrolidin-2-yl ] -1H-benzimidazol-5-yl ] phenyl ] -1H-imidazol-2-yl ] pyrrolidine-1-carbonyl ] -2-methyl-propyl ] carbamic acid methyl ester
To cold (0-4 ℃) stirred 4- (4- (2- ((S) -1- ((S) -2- ((methoxycarbonyl) amino) -3-methylbutyryl) pyrrolidin-2-yl) -1H-benzo [ d]Imidazol-5-yl) phenyl) -2- ((S) -pyrrolidin-1-ium-2-yl) -1H-imidazol-3-ium chloride (98.09mg,0.15mmol) and a bright suspension of (2S) -2- (methoxycarbonylamino) -3-methyl-butyric acid (28.91mg,0.1650mmol) in DMF (1.5mL) were added HATU (85.55mg,0.2250mmol) and DIPEA (116.3mg, 156.7. mu.L, 0.9000 mmol) in that order. The resulting mixture was slowly warmed to room temperature, stirred overnight, then diluted with water (5mL) and extracted with ethyl acetate (3 × 6 mL). The combined extracts were washed with saturated bicarbonate solution, brine and dried (Na)2SO4) And (4) concentrating. Using 25+ M biotage SiO2Column, purification of the residue using MeOH-EtOAc (0: 100, 15: 85) as eluent gave N- [ (1S) -1- [ (2S) -2- [4- [4- [2- [ (2S) -1- [ (2S) -2- (methoxycarbonylamino) -3-methyl-butyryl]Pyrrolidin-2-yl radical]-1H-benzimidazol-5-yl]Phenyl radical]-1H-imidazol-2-yl]Pyrrolidine-1-carbonyl]-2-methyl-propyl]Methyl carbamate (45.8mg,0.06007mmol,37.45%) as a white solid. The product was re-purified by reverse phase HPLC to give N- [ (1S) -1- [ (2S) -2- [4- [4- [2- [ (2S) -1- [ (2S) -2- (methoxycarbonylamino) -3-methyl-butyryl]Pyrrolidin-2-yl radical]-1H-benzimidazol-5-yl]Phenyl radical]-1H-imidazol-2-yl]Pyrrolidine-1-carbonyl]-2-methyl-propyl]Methyl carbamate (29.6mg) as a white solid.
1H NMR(400MHz,CD3OD)δ7.87-7.20(m,10H),5.27(dd,1H),5.17(dd,1H),4.3-4.2(m,2H),4.12-38(m,5H),3.65(s,6H),3.55-3.45(m,1H),2.51-1.92(m,10H),1.02-0.80 (doublet, 12H).
LC/MS：m/z=713.6(M+H+)。
Example 8
IN- [ (1S) -1- [ (2S,5S) -2- [4- [4- [4- [2- [ (2S,5S) -1- [2- (methoxycarbonylamino) -3-methyl-butyryl ] -5-methyl-pyrrolidin-2-yl ] -1H-benzimidazol-5-yl ] phenyl ] -1H-imidazol-2-yl ] -5-methyl-pyrrolidine-1-carbonyl ] -2-methyl-propyl ] carbamic acid methyl ester (compound 13):
step I:
(2S,5S) -2- [4- [4- [4- [2- [ (2S,5S) -1- [2- (methoxycarbonylamino) -3-methyl-butyryl ] -5-methyl-pyrrolidin-2-yl ] -1H-benzimidazol-5-yl ] phenyl ] -1H-imidazol-2-yl ] -5-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester
To (2S,5S) -2-methyl-5- [4- [4- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Phenyl radical]-1H-imidazol-2-yl]Pyrrolidine-1-carboxylic acid tert-butyl ester (180mg,0.34mmol), N- [ (1S) -1- [ (2S,5S) -2- (5-iodo-1H-benzimidazol-2-yl) -5-methyl-pyrrolidine-1-carbonyl]-2-methyl-propyl]Methyl carbamate (164.7mg,0.34mmol), Pd (dppf) (Cl)2.CH2Cl2(27.77mg,0.034mmol) in 2-propanol (2ml) was added NaHCO3Aqueous solution (1.7mL of 1M,1.7 mmol). With N2The reaction mixture was purified, heated at 80 ℃ overnight, diluted with EtOAc and washed with H2O and brine wash. With Na2SO4The organic phase was dried, filtered and concentrated. Flash column through silica gel (1-30% MeOH in CH)2Cl2Solution) chromatography of the residue to give (2S,5S) -2- [4- [4- [4- [2- [ (2S,5S) -1- [2- (methoxycarbonylamino) -3-methyl-butyryl]-5-methyl-pyrrolidin-2-yl]-1H-benzimidazol-5-yl]Phenyl radical]Phenyl radical]-1H-imidazol-2-yl]-5-ATert-butyl yl-pyrrolidine-1-carboxylate (97mg,37.5%) as a light brown solid.
LC/MS：m/z=760.5(M+H+)。
Step II:
n- [ 2-methyl-1- [ (2S,5S) -2-methyl-5- [4- [4- [4- [2- [ (2S,5S) -5-methylpyrrolidin-2-yl ] -1H-imidazol-5-yl ] phenyl ] -1H-benzimidazol-2-yl ] pyrrolidine-1-carbonyl ] propyl ] -carbamic acid methyl ester
To a solution of (2S,5S) -2- [4- [4- [4- [2- [ (2S,5S) -1- [2- (methoxycarbonylamino) -3-methyl-butyryl ] -5-methyl-pyrrolidin-2-yl ] -1H-benzimidazol-5-yl ] phenyl ] -1H-imidazol-2-yl ] -5-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (97mg,0.12mmol) in MeOH (1ml) was added HC i (638.0 μ L in 4M dioxane, 2.5 mmol). The reaction mixture was stirred at room temperature for 3 hours, concentrated, co-evaporated with toluene and dried to give N- [ 2-methyl-1- [ (2S,5S) -2-methyl-5- [4- [4- [4- [2- [ (2S,5S) -5-methylpyrrolidin-2-yl ] -1H-imidazol-5-yl ] phenyl ] -1H-benzimidazol-2-yl ] pyrrolidine-1-carbonyl ] propyl ] -carbamic acid methyl ester as a light yellow residue which was used in the next step without further purification.
Step III:
methyl N- [ (1S) -1- [ (2S,5S) -2- [4- [4- [4- [2- [ (2S,5S) -1- [2- (methoxycarbonylamino) -3-methyl-butyryl ] -5-methyl-pyrrolidin-2-yl ] -1H-benzimidazol-5-yl ] phenyl ] -1H-imidazol-2-yl ] -5-methyl-pyrrolidine-1-carbonyl ] -2-methyl-propyl ] carbamate
To N- [ 2-methyl-1- [ (2S,5S) -2-methyl-5- [4- [4- [2- [ (2S,5S) -5-methylpyrrolidin-2-yl group at 0 DEG C]-1H-imidazol-5-yl]Phenyl radical]Phenyl radical]-1H-benzimidazol-2-yl]Pyrrolidine-1-carbonyl]Propyl radical]To a mixture of methyl carbamate (88mg,0.126mmol), (2S) -2- (methoxycarbonylamino) -3-methyl-butyric acid (22mg,0.126mmol) and 2,4, 6-collidine (50.11. mu.l, 0.38 mmol) in DMF (3.5ml) was added HATU (52.8mg,0.14 mmol). The reaction mixture was stirred at rt for 5H, diluted with EtOAc, and concentrated with H2O and brine wash. With Na2SO4The organic phase was dried, filtered and concentrated. Flash column chromatography on silica gel (1-20% MeOH in CH)2Cl2Solution) purification of the residue by reverse phase HPLC using CH3CN/water gradient repurification to obtain N- [ (1S) -1- [ (2S,5S) -2- [4- [4- [4- [2- [ (2S,5S) -1- [2- (methoxycarbonylamino) -3-methyl-butyryl]-5-methyl-pyrrolidin-2-yl]-1H-benzimidazol-5-yl]Phenyl radical]Phenyl radical]-1H-imidazol-2-yl]-5-methyl-pyrrolidine-1-carbonyl]-2-methyl-propyl]Methyl carbamate (22mg,19.9%) as a white loose powder.
1H NMR(400MHz,CD3OD)：δ[ppm]7.95-7.71(m,11H),7.33-7.26(m,1H),5.21(m,1H),5.12(m,1H),4.13-4.07(m,2H),3.62(s,6H),2.5(m,2H),2.3-2.25(m,4H),2.01-1.96(m,4H),1.54(m,6H),1.24-1.2(m,2H),0.97(m,6H),0.85(m,6H)。
LC/MS：m/z=817.5(M+H+)。
Intermediate:
methyl N- [ (1S) -1- [ (2S,5S) -2- (5-iodo-1H-benzimidazol-2-yl) -5-methyl-pyrrolidine-1-carbonyl ] -2-methyl-propyl ] carbamate:
step I:
(2S,5S) -1- [ (2S) -2- (methoxycarbonylamino) -3-methyl-butyryl ] -5-methyl-pyrrolidine-2-carboxylic acid ethyl ester
To a cold (0-4 ℃) stirred solution of ethyl (2S,5S) -5-methylpyrrolidin-1-ium-2-carboxylate (7g,24.4mmol) (J.Med.chem.2006, 49, 3520-. The resulting mixture was slowly warmed to room temperature and stirred for 20 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed with sodium bicarbonate, brine and driedDry (Na)2SO4) And (4) concentrating. The residue was purified by flash column chromatography on silica gel using ethyl acetate-hexane (3: 7-4: 6) to give (2S,5S) -1- [ (2S) -2- (methoxycarbonylamino) -3-methyl-butyryl group]-ethyl 5-methyl-pyrrolidine-2-carboxylate (5.6g,73%) as a white solid.
LC/MS：m/z=314.9(M+H+)。
Step II:
(2S,5S) -1- [ (2S) -2- (methoxycarbonylamino) -3-methyl-butyryl ] -5-methyl-pyrrolidine-2-carboxylic acid
To the ice-cooled stirred (2S,5S) -1- [ (2S) -2- (methoxycarbonylamino) -3-methyl-butyryl]To a solution of ethyl-5-methyl-pyrrolidine-2-carboxylate (5.6g,17.8mmol) in ethanol (18mL) was added a solution of lithium hydroxide monohydrate (17.8mL of 1.7M,30.3 mmol). The mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated, diluted with water and washed with diethyl ether. Acidifying the aqueous solution with 1N HCl aqueous solution, and adding CH2Cl2And (4) extracting. The combined extracts were washed with brine and dried (Na)2SO4) Concentrating to obtain (2S,5S) -1- [ (2S) -2- (methoxycarbonylamino) -3-methyl-butyryl]-5-methyl-pyrrolidine-2-carboxylic acid (5g,94%) as a white solid.
LC/MS：m/z=286.8(M+H+)。
Step III:
n- [ (1S) -1- [ (2S,5S) -2- (5-iodo-1H-benzimidazol-2-yl) -5-methyl-pyrrolidine-1-carbonyl ] -2-methyl-propyl ] carbamic acid methyl ester
To cold (0-4 deg.C) stirred 4-iodobenzene-1, 2-diamine (1.3g,5.3mmol) and (2S,5S) -1- [ (2S) -2- (methoxycarbonylamino) -3-methyl-butyryl]To a solution of-5-methyl-pyrrolidine-2-carboxylic acid (1.52g,4.99mmol) in DMF (23.8ml) were added HATU (2.321g,6.103mmol) and 2,4, 6-collidine (1.052ml,7.964 mmol) in that order. The reaction mixture was stirred at room temperature overnight, diluted with water and extracted with ethyl acetate. The combined extracts were washed with water, saturated bicarbonate, brine and dried (N)a2SO4) Concentrated and dried under high vacuum to give the crude amide. The resulting residue, dissolved in acetic acid (28ml), was heated at 60 ℃ for 8 hours. Removing acetic acid with saturated NaHCO3The residue was neutralized with a solution, which was diluted with ethyl acetate (20 ml). The aqueous solution was extracted with ethyl acetate and NaHCO3The combined organic extracts were washed with aqueous solution, brine and dried (Na)2SO4) And (4) concentrating. Purifying the concentrate by flash column chromatography on silica gel using ethyl acetate-hexane (1: 1-7: 3) as eluent to obtain N- [ (1S) -1- [ (2S,5S) -2- (5-iodo-1H-benzimidazol-2-yl) -5-methyl-pyrrolidine-1-carbonyl]-2-methyl-propyl]Methyl carbamate (2.3g,2.28mmo l, 92%).
1H NMR(400MHz,CD3OD, 2: 1), major rotamers δ 8.0-7.2(m,3H),5.13(dd,1H),4.78-4.70(m,1H),4.2-4.1(m,1H),3.64(s,3H),2.8-1.8(m,5H),1.49(d,3H),0.93(d, J =6.7Hz,3H),0.80(d, J =6.8Hz, 3H). Peaks selected for the minor rotamer. 5.48(m,1H),3.58(s,3H),1.205(d,3H),0.99(t, 6H).
LC/MS：m/z=484.9(M+H+)。
Intermediate:
(2S,5S) -2-methyl-5- [4- [4- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] -1H-imidazol-2-yl ] pyrrolidine-1-carboxylic acid tert-butyl ester:
step I:
2- [2- [4- (4-bromophenyl) phenyl ] -2-oxo-ethyl ] -1-tert-butyl- (2S,5S) -5-methylpyrrolidine-1, 2-dicarboxylic acid tert-butyl ester
To 2-bromo-1- [4- (4-bromophenyl) phenyl]Ethanone (735.3mg,2mmol), (2S,5S) -1-tert-butoxycarbonyl-5-methyl-pyrrolidine-2-carboxylic acid (500mg,2.18mmol) in acetonitrile (10ml)DI PEA (380. mu.L, 2.18mmol) was added to the mixture (suspension). The reaction mixture was stirred at room temperature for 3 hours with EtOAc and H2And (4) diluting with oxygen. The organic phase was washed with brine and Na2SO4Drying, filtering and concentrating. The residue was purified by flash column chromatography on silica gel (0-30% EtOAc in hexane) to give 2- [2- [4- (4-bromophenyl) phenyl ] ethyl]-2-oxo-ethyl]-tert-butyl 1-tert-butyl- (2S,5S) -5-methylpyrrolidine-1, 2-carboxylate (0.8g,76.7%) as a white solid.
Step II:
(2S,5S) -2- [4- [4- (4-bromophenyl) phenyl ] -1H-imidazol-2-yl ] -5-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester
To a solution of (2S,5S) -5-methylpyrrolidine-1, 2-dicarboxylic acid 2- [2- [4- (4-bromophenyl) phenyl ] in toluene (5.8ml)]-2-oxo-ethyl]1-tert-butyl ester (620mg,1.23mmol) ammonium acetate (1.9g,24.7mmol) was added. The reaction mixture was heated at 100 ℃ overnight, then with EtOAc and H2And (4) diluting with oxygen. The organic phase was washed with brine and Na2SO4Drying, filtering and concentrating. The residue was purified by flash column chromatography on silica gel (5-50% EtOAc in hexane) to give (2S,5S) -2- [4- [4- (4-bromophenyl) phenyl ] -ethyl acetate]-1H-imidazol-2-yl]-5-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (430mg, 72.2%).
LC/MS：m/z=483.9(M+H+)。
Step III:
(2S,5S) -2-methyl-5- [4- [4- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] -1H-imidazol-2-yl ] pyrrolidine-1-carboxylic acid tert-butyl ester
To (2S,5S) -2- [4- [4- (4-bromophenyl) phenyl]-1H-imidazol-2-yl]-5-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (180mg,0.37mmo l), 4,5, 5-tetramethyl-2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,3, 2-dioxaborolan-ane (284mg,1.11mmol) and Pd (DPPF) (Cl)2.CH2Cl2(30.47mg,0.03731mmol) KOAc (183.1mg,1.866 mmol) was added to a mixture of DMF (1.800 ml). Will be reversedThe mixture was stirred at 85 ℃ overnight with Et OAc and H2Diluted with O and filtered through celite. The organic phase was washed with brine and Na2SO4Drying, filtering and concentrating. The residue was purified by flash column chromatography on silica gel (5-50% EtOAc in hexane) to give (2S,5S) -2-methyl-5- [4- [4- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Phenyl radical]-1H-imidazol-2-yl]Pyrrolidine-1-carboxylic acid tert-butyl ester (180mg,91%) as a yellow oil.
LC/MS：m/z=530.1(M+H+)。
Example 9
Methyl N- [ (1S) -1- [ (2S,4S) -2- [4- [4- [2- [2- [ (2S,4S) -1- [ (2S) -2- (methoxycarbonylamino) -3-methyl-butyryl ] -4-methyl-pyrrolidin-2-yl ] -1H-benzimidazol-5-yl ] ethynyl ] phenyl ] -1H-imidazol-2-yl ] -4-methyl-pyrrolidine-1-carbonyl ] -2-methyl-propyl ] carbamate (compound 9):
step I:
(2S,4S) -2- [4- [4- [2- [2- [ (2S,4S) -1-tert-butoxycarbonyl-4-methyl-pyrrolidin-2-yl ] -1H-benzimidazol-5-yl ] ethynyl ] phenyl ] -1H-imidazol-2-yl ] -4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester
To a mixture of (2S,4S) -2- (5-iodo-1H-benzimidazol-2-yl) -4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (68.5mg,0.16mmol) in DMF (3mL) was added (2S,4S) -2- [4- (4-ethynylphenyl) -1H-imidazol-2-yl]-4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (47mg,0.13mmol), Pd (DPPF) (Cl)2.CH2Cl2(5.4mg,0.0067mmol), the mixture was degassed thoroughly in vacuo, and TEA (37uL,0.27mmol) was added followed by CuI (1.2mg,0.0067 mmol). The reaction mixture was then stirred at room temperature overnight under a nitrogen atmosphere. After removal of the solvent, by using methanol/CH2Cl20-5% of the crude product is purified by flash column chromatography on silica gel to give (2S,4S) -2- [4- [4- [2- [2- [ (2S,4S) -1-tert-butoxycarbonyl-4-methyl-pyrrolidin-2-yl]-1H-benzimidazol-5-yl]Ethynyl group]Phenyl radical]-1H-imidazol-2-yl]-4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (56mg, 64%).
LC/MS：m/z=651.41(M+H+)。
Step II:
2- [ (2S,4S) -4-methylpyrrolidin-2-yl ] -5- [2- [4- [2- [ (2S,4S) -4-methylpyrrolidin-2-yl ] -1H-imidazol-4-yl ] phenyl ] ethynyl ] -1H-benzimidazole HCl salt
To a solution of (2S,4S) -2- [4- [4- [2- [2- [ (2S,4S) -1-tert-butoxycarbonyl-4-methyl-pyrrolidin-2-yl ] -1H-benzimidazol-5-yl ] ethynyl ] phenyl ] -1H-imidazol-2-yl ] -4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (56mg,0.086 mmol) in methanol (2mL) was added 4M HCl/dioxane (430uL,1.72 mmol). The mixture was stirred at room temperature for 3 hours. The solvent was removed in vacuo to give 2- [ (2S,4S) -4-methylpyrrolidin-2-yl ] -5- [2- [4- [2- [ (2S,4S) -4-methylpyrrolidin-2-yl ] -1H-imidazol-4-yl ] phenyl ] ethynyl ] -1H-benzimidazole HCl salt. The crude product was used directly in the next step.
Step III:
methyl N- [ (1S) -1- [ (2S,4S) -2- [4- [4- [2- [2- [ (2S,4S) -1- [ (2S) -2- (methoxycarbonylamino) -3-methyl-butyryl ] -4-methyl-pyrrolidin-2-yl ] -1H-benzimidazol-5-yl ] ethynyl ] phenyl ] -1H-imidazol-2-yl ] -4-methyl-pyrrolidine-1-carbonyl ] -2-methyl-propyl ] carbamate
To 2- [ (2S,4S) -4-methylpyrrolidin-2-yl]-5- [2- [4- [2- [ (2S,4S) -4-methylpyrrolidin-2-yl]-1H-imidazol-4-yl]Phenyl radical]Ethynyl group]To a solution of (1H-benzimidazole HCl salt (25mg,0.042mmol) in DMF (3mL) was added sequentially (2S) -2- (methoxycarbonylamino) -3-methyl-butyric acid (17.6mg,0.10mmol), HATU (39.8mg,0.10mmol) and DIPEA (73uL,0.42 mmol). The mixture was stirred at room temperature overnight. After removal of the solvent under reduced pressure, by using 0-7% MeOH/CH2Cl2Purifying the residue by flash column chromatography on silica gel, prepared by reverse phaseform-HPLC further purifying the main fraction to yield N- [ (1S) -1- [ (2S,4S) -2- [4- [4- [2- [2- [ (2S,4S) -1- [ (2S) -2- (methoxycarbonylamino) -3-methyl-butyryl]-4-methyl-pyrrolidin-2-yl]-1H-benzimidazol-5-yl]Ethynyl group]Phenyl radical]-1H-imidazol-2-yl]-4-methyl-pyrrolidine-1-carbonyl]-2-methyl-propyl]Methyl carbamate (19mg, 58.9%).
1H NMR(CD3OD,400MHz)：7.33-7.66(m,8H),5.03-5.11(m,2H),4.20(m,4H),3.62(s,6H),3.41(m,2H),2.46(m,4H),1.96(m,4H),1.20(m,6H),0.84(m,12H)。
LC/MS：m/z=651.41(M+H+)。
Intermediate:
(2S,4S) -2- [4- (4-ethynylphenyl) -1H-imidazol-2-yl ] -4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester:
step I:
tert-butyl (2S,4S) -4-methyl-2- [4- [4- (2-trimethylsilylethynyl) phenyl ] -1H-imidazol-2-yl ] pyrrolidine-1-carboxylic acid tert-butyl ester
To (2S,4S) -2- (4-iodo-1H-imidazol-2-yl) -4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (150mg,0.3976mmol) and ([4- (2-trimethylsilylethynyl) phenyl]To a solution of boric acid (130mg,0.6mmol) in isopropanol (3mL) was added Pd (DPPF) (Cl) in order2.CH2Cl2(16mg,0.02mmol) and 2M NaHCO3(600uL,1.2 mmol). The mixture was heated to 85 ℃ overnight in a sealed tube. After the reaction, the solvent was removed under reduced pressure by using methanol/CH2Cl2Purifying the residue by flash column chromatography on silica gel at 0-5% to obtain (2S,4S) -4-methyl-2- [4- [4- (2-trimethylsilylethynyl) phenyl]-1H-imidazol-2-yl]Pyrrolidine-1-carboxylic acid tert-butyl ester (168mg, 95%).
LC/MS：m/z=423.98(M+H+)。
Step II:
(2S,4S) -2- [4- (4-ethynylphenyl) -1H-imidazol-2-yl ] -4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester
To (2S,4S) -4-methyl-2- [4- [4- (2-trimethylsilylethynyl) phenyl]-1H-imidazol-2-yl]To a solution of pyrrolidine-1-carboxylic acid tert-butyl ester (57mg,0.1346mmo l) in MeOH (2mL) was added K2CO3(37.2mg,0.27 mmol). The mixture was stirred at room temperature for 2 hours. After removal of the solvent under reduced pressure, by using 0-5% MeOH/CH2Cl2Purifying the residue by flash column chromatography on silica gel to give (2S,4S) -2- [4- (4-ethynylphenyl) -1H-imidazol-2-yl]-4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (47mg, 99%).
1H NMR(CD3OD,400MHz)：7.33-7.66(m,5H),4.79(m,1H),3.79(m,1H),3.46(s,1H),3.14(m,1H),2.29-2.46(m,2H),1.70(m,1H),1.09-1.40(m,12H)。
Example 10:
n- [ (1S) -1- [ (2S,4S) -2- [4- [4- [2- [2- [ (2S,4S) -1- [ (2S) -2- [ methoxycarbonyl- (methyl) amino ] -3-methyl-butyryl ] -4-methyl-pyrrolidin-2-yl ] -1H-benzimidazol-5-yl ] ethynyl ] phenyl ] -1H-imidazol-2-yl ] -4-methyl-pyrrolidine-1-carbonyl ] -2-methyl-propyl ] -N-methyl-carbamic acid methyl ester (compound 10):
to 2- [ (2S,4S) -4-methylpyrrolidin-2-yl]-5- [2- [4- [2- [ (2S,4S) -4-methylpyrrolidin-2-yl]-1H-imidazol-4-yl]Phenyl radical]Ethynyl group](2S) -2- [ methoxycarbonyl (methyl) amino ] sequentially added to a solution of (1H) -benzimidazole HCl salt (32mg,0.053mmol) in DMF (3mL)]-3-methyl-butyric acid (24.3mg,0.13mmo l), HATU (51mg,0.13mmol) and DIPEA (93uL,0.53 mmol). The mixture was stirred at room temperature overnight. Removing the solvent under reduced pressure, and introducingBy using 0-7% MeOH/CH2Cl2Purifying the residue by flash column chromatography on silica gel and further purifying the main fraction by preparative HPLC on reversed phase to give N- [ (1S) -1- [ (2S,4S) -2- [4- [4- [2- [2- [ (2S,4S) -1- [ (2S) -2- [ methoxycarbonyl (methyl) amino group]-3-methyl-butyryl]-4-methyl-pyrrolidin-2-yl]-1H-benzimidazol-5-yl]Ethynyl group]Phenyl radical]-1H-imidazol-2-yl]-4-methyl-pyrrolidine-1-carbonyl]-2-methyl-propyl]-methyl N-methyl-carbamate (20mg, 45.4%).
1H NMR(CD3OD,400MHz)：7.33-7.66(m,8H),4.91-5.09(m,2H),4.20-4.57(m,4H),3.62(s,6H),3.41(m,2H),2.83(m,6H),1.84-2.60(m,8H),1.20(m,6H),0.84(m,12H)。
LC/MS：m/z=793.38(M+H+)。
Example 11:
methyl N- [ (1S) -1- [ (2S,4S) -2- [4- [2- [4- [2- [ (2S,4S) -1- [ (2S) -2- (methoxycarbonylamino) -3-methyl-butyryl ] -4-methyl-pyrrolidin-2-yl ] -1H-benzimidazol-5-yl ] phenyl ] ethynyl ] -1H-imidazol-2-yl ] -4-methyl-pyrrolidine-1-carbonyl ] -2-methyl-propyl ] carbamate (compound 12):
step I:
(2S,4S) -4-methyl-2- [5- [4- (2-trimethylsilylethynyl) phenyl ] -1H-benzimidazol-2-yl ] pyrrolidine-1-carboxylic acid tert-butyl ester
Ethynyl-trimethyl-silane (34.44mg,49.55 μ L,0.3506mmol), (2S,4S) -2- [5- (4-bromophenyl) -1H-benzimidazol-2-yl]-4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (80mg,0.1753mmol), Pd (DPPF) (Cl)2.CH2Cl2(14.32mg,0.01753 mmol), TEA (35.48mg, 48.87. mu.L, 0.3506mmol) and CuI (3.339mg,0.01753mmol) were dissolved in anhydrous DMF (2 mL). The mixture was heated at 70 ℃ to N2Stir under atmosphere overnight.After removal of the solvent under reduced pressure, by using methanol/CH2Cl2(0-5%) silica gel SP125M flash column chromatography purified the residue in 20cv to give (2S,4S) -4-methyl-2- [5- [4- (2-trimethylsilylethynyl) phenyl]-1H-benzimidazol-2-yl]Pyrrolidine-1-carboxylic acid tert-butyl ester (40 mg).
LC/MS：m/z=474.15(M+H+)。
Step II:
(2S,4S) -2- [4- [2- [4- [2- [ (2S,4S) -1-tert-butoxycarbonyl-4-methyl-pyrrolidin-2-yl ] -1H-benzimidazol-5-yl ] phenyl ] ethynyl ] -1H-imidazol-2-yl ] -4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester
To a well degassed (2S,4S) -2- (4-iodo-1H-imidazol-2-yl) -4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (38.21mg,0.1013mmol), (2S,4S) -4-methyl-2- [5- [4- (2-trimethylsilylethynyl) phenyl]-1H-benzimidazol-2-yl]Pyrrolidine-1-carboxylic acid tert-butyl ester (40mg,0.08444mmol), Pd (DPPF) (Cl)2.CH2Cl2Solutions of (6.896mg,0.008444mmol), CuI (3.217mg,0.01689mmol), DBU (128.5mg, 126.2. mu.L, 0.8444mmol) and water (4.563mg, 4.563. mu.L, 0.2533 mmol) in DMF (3mL) at 70 ℃ in N2Stir under atmosphere overnight. After removal of the solvent under reduced pressure, by using methanol/CH2Cl2(0-6%) of the residue was purified by flash column chromatography on silica gel to give the desired (2S,4S) -2- [4- [2- [4- [2- [ (2S,4S) -1-tert-butoxycarbonyl-4-methyl-pyrrolidin-2-yl]-1H-benzimidazol-5-yl]Phenyl radical]Ethynyl group]-1H-imidazol-2-yl]-4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (34mg,61.8% yield). LC/MS: m/z =651.42(M + H)+)。
Step III:
2- [ (2S,4S) -4-methylpyrrolidin-2-yl ] -5- [4- [2- [2- [ (2S,4S) -4-methylpyrrolidin-2-yl ] -1H-imidazol-4-yl ] ethynyl ] phenyl ] -1H-benzimidazole
Tert-butyl (2S,4S) -2- [4- [2- [4- [2- [ (2S,4S) -1-tert-butoxycarbonyl-4-methyl-pyrrolidin-2-yl ] -1H-benzimidazol-5-yl ] phenyl ] ethynyl ] -1H-imidazol-2-yl ] -4-methyl-pyrrolidine-1-carboxylate (28mg,0.04302mmol) was dissolved in methanol (2mL) and HCl (107.6 μ L, 4M,0.4302mmol) was added thereto. The mixture was stirred at room temperature overnight. After removal of the solvent under reduced pressure, 2- [ (2S,4S) -4-methylpyrrolidin-2-yl ] -5- [4- [2- [2- [ (2S,4S) -4-methylpyrrolidin-2-yl ] -1H-imidazol-4-yl ] ethynyl ] phenyl ] -1H-benzimidazole was used as such as the next step.
Step IV:
methyl N- [ (1S) -1- [ (2S,4S) -2- [4- [2- [4- [2- [ (2S,4S) -1- [ (2S) -2- (methoxycarbonylamino) -3-methyl-butyryl ] -4-methyl-pyrrolidin-2-yl ] -1H-benzimidazol-5-yl ] phenyl ] ethynyl ] -1H-imidazol-2-yl ] -4-methyl-pyrrolidine-1-carbonyl ] -2-methyl-propyl ] carbamate
Mixing (2S) -2- (methoxycarbonylamino) -3-methyl-butyric acid (19.09mg,0.1090mmol) and 2- [ (2S,4S) -4-methylpyrrolidin-2-yl]-5- [4- [2- [2- [ (2S,4S) -4-methylpyrrolidin-2-yl]-1H-imidazol-4-yl]Ethynyl group]Phenyl radical]A solution of-1H-benzimidazole (26mg,0.04359mmol), HATU (41.45mg,0.1090mmol) and DIPEA (56.34mg, 75.93. mu.L, 0.4359mmol) in DMF (2mL) was stirred at room temperature overnight. After removal of the solvent, by using methanol/CH2Cl2The crude product was purified by flash column chromatography on 0-6% silica gel. The main fraction was further purified by preparative HPLC on reversed phase to give N- [ (1S) -1- [ (2S,4S) -2- [4- [2- [4- [2- [ (2S,4S) -1- [ (2S) -2- (methoxycarbonylamino) -3-methyl-butyryl]-4-methyl-pyrrolidin-2-yl]-1H-benzimidazol-5-yl]Phenyl radical]Ethynyl group]-1H-imidazol-2-yl]-4-methyl-pyrrolidine-1-carbonyl]-2-methyl-propyl]Methyl carbamate (18mg,53% yield) as a white solid.
1H NMR(CD3OD,400MHz)：7.51-7.66(m,8H),4.92-5.15(m,2H),4.20(m,4H),3.62(s,6H),3.41(m,2H),2.46(m,4H),1.96(m,4H),1.20(m,6H),0.84(m,12H)。
LC/MS：m/z=765.53(M+H+)。
Example 12:
methyl N- [ (1S) -1- [ (2S,4S) -2- [4- [5- [2- [ (2S,4S) -1- [ (2S) -2- (methoxycarbonylamino) -3-methyl-butyryl ] -4-methyl-pyrrolidin-2-yl ] -1H-benzimidazol-5-yl ] thieno [3,2-b ] thiophen-2-yl ] -1H-imidazol-2-yl ] -4-methyl-pyrrolidine-1-carbonyl ] -2-methyl-propyl ] carbamate (compound 16):
to degassed (vacuum/nitrogen stream) N- [ (1S) -1- [ (2S,4S) -2- (4-iodo-1H-imidazol-2-yl) -4-methyl-pyrrolidine-1-carbonyl]-2-methyl-propyl]Methyl carbamate (153.5mg,0.3347mmo l), N- [ (1S) -1- [ (2S,4S) -2- (5-iodo-1H-benzimidazol-2-yl) -4-methyl-pyrrolidine-1-carbonyl]-2-methyl-propyl]Methyl carbamate (162.1mg,0.3347mmol), 4,5, 5-tetramethyl-2- [5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) thieno [3,2-b ] thieno [2, 2-b ] methyl ester]Thien-2-yl]-1,3, 2-dioxaborole (125mg,0.3188mmol) and K2CO3(220.3mg,1.594mmol) in degassed isopropanol (3.750mL) and H2To the mixture in O (1.250mL) was added [3- (2-dicyclohexylphosphinyl) -2, 4-dimethoxy-phenyl]Sodium sulfonyloxy (VPHOS) (13.07mg,0.02550mmol) and Pd (OAc)2(1.431mg,0.006376 mmol). After 2 degassing, the reaction mixture was heated at 90 ℃ for 16 hours and then diluted with ethyl acetate (30 mL). The aqueous solution was discarded, the organic solution was washed with water, brine and dried (Na)2SO4) And (4) concentrating. The residue was purified by silica gel chromatography using ethyl acetate-8% MeOH-EtOAc as eluent to give the product mixture (160mg) as a yellow solid. Isolation of the desired compound by preparative reverse phase HPLC to afford N- [ (1S) -1- [ (2S,4S) -2- [4- [5- [2- [ (2S,4S) -1- [ (2S) -2- (methoxycarbonylamino) -3-methyl-butyryl]-4-methyl-pyrrolidin-2-yl]-1H-benzimidazol-5-yl]Thieno [3,2-b]Thien-2-yl]-1H-imidazol-2-yl]-4-methyl-pyrrolidine-1-carbonyl]-2-methyl-propyl]Methyl carbamate (34.4mg) as a yellow solid.
1H NMR(400MHz,CD3OD)δ7.8-7.2(m,6H),5.14(dd,1H),5.02(dd，1H)，4.29(t，1H)，4.25-4.18(m，3H)，3.64(s，3H)，3.49-3.36(m，2H)，2.66-2.26(m，4H)，2.09-1.80(m，4H)，1.21(d，3H)，1.19(d，3H)，0.95-0.89(m，6H)，0.8 7(d，3H)，0.835(d，3H)。
LC/MS：m/z＝803.34(M+H+)。
Intermediate:
2- (4- (4 '-bromo- [1,1' -biphenyl ] -4-yl) -1H-imidazol-2-yl) pyrrolidine-1-carboxylic acid (2S) -silence-butyl ester:
step I:
(2S,4S) -2- (2- (4' -bromobiphenyl-4-yl) -2-oxoethyl) 1-tert-butyl-4-methylpyrrolidine-1, 2-dicarboxylate
To a solution of 2-bromo-1- [4- (4-bromophenyl) phenyl ] ethanone (759mg, 1.897mmol) and (2S) -1-silent-butoxycarbonylpyrrolidine-2-carboxylic acid (484.3mg, 2.25mmol) in acetonitrile (7.5mL) was added DIPEA (290.8mg, 392. mu.L, 2.25 mmol). The reaction mixture was stirred at room temperature for 2 hours, washed with brine (3 × 5 mL). The organic layer was concentrated to dryness. The residue was diluted with toluene (5mL), concentrated to dryness and purified by flash column chromatography on silica gel (2-20% EtOAc in hexanes) to give 4-methylpyrrolidine-1, 2-dicarboxylic acid (2S,4S) -2- (2- (4' -bromobiphenyl-4-yl) -2-oxoethyl) 1-tert-butyl ester (855mg, 93%), which was used as such in the next step.
Step II:
2- (4- (4 '-bromo- [1,1' -biphenyl ] -4-yl) -1H-imidazol-2-yl) pyrrolidine-1-carboxylic acid (2S) -tert-butyl ester
To a solution of (2S,4S) -2- (2- (4' -bromobiphenyl-4-yl) -2-oxoethyl) 1-tert-butyl 4-methylpyrrolidine-1, 2-dimethyl ester (855mg, 1.751mmol) in toluene (8mL) was added ammonium acetate (2.699g, 35.02 mmol). The reaction mixture was heated at 100 ℃ for 24 hours, cooled to room temperature,dilute with water (10 mL). The layers were separated, the aqueous layer was extracted with EtOAc (10mL), dried Na2SO4The organic layer was filtered and concentrated to dryness. The residue was purified by flash column chromatography on silica gel (6-80% EtOAc in hexane) to give 2- (4- (4 '-bromo- [1,1' -biphenyl)]-4-yl) -1H-imidazol-2-yl) pyrrolidine-1-carboxylic acid (2S) -tert-butyl ester (511mg, 62%).
Intermediates
4,4,5, 5-tetramethyl-2- [5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) thieno [3,2-b ] thiophen-2-yl ] -1,3, 2-dioxaborolan:
at-78 ℃ in N2To thieno [3,2-b ] in an atmosphere]A solution of thiophene (1.5g,10.70mmo l) in THF (25.5mL) was added dropwise to a solution of BuLi in hexane (8.988mL, 2.5M,22.47mmol), stirred for 20min, replaced the cooling bath with an ice bath, and stirred for 50 min. The resulting thick suspension was quenched with 2-isopropoxy-4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan (4.181g,4.584mL,22.47 mmol). The reaction mixture was kept overnight and then saturated NH was used4Aqueous Cl solution was quenched. By CH2Cl2After extraction (2 × 100mL), the combined extracts were washed with brine and dried (Na)2SO4). The organic solution was diluted with-20 mL ethyl acetate and slowly concentrated on a rotary evaporator until the CH was removed2Cl2Until now. The resulting white fine crystals were collected by filtration. The solid was washed with heptane and dried under high vacuum to give 4,4,5, 5-tetramethyl-2- [5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) thieno [3,2-b]Thien-2-yl]1,3, 2-Dioxyborocyclopentane (2.57g,6.554mmol,61.25%) as a half-white solid.1H NMR(400MHz,CDCl3)δ7.75(s,2H),1.343(s,12H)。
Intermediates
(2S) -2- (methoxycarbonylamino) -3-methyl-butyric acid:
l-valine (140g,1.195mol) was added to a stirred 1M sodium hydroxide solution (1.183L,1.183 mol). After complete dissolution, sodium carbonate (65.8g,621.4mmol) was added followed by methyl chloride hormone (122g,99.75mL,1.291mol) at 0 ℃ over 40 minutes. The reaction mixture was stirred at room temperature for 3.5 hours and then washed with diethyl ether (3 × 200 ml). The aqueous layer was cooled to 0 ℃ and acidified to pH 1-2. The white solid formed was filtered through Buchner, washed with cold water and dried to give the title compound (2S) -2- (methoxycarbonylamino) -3-methyl-butyric acid (140g, 67%).
Intermediates
(2S) -2- [ methoxycarbonyl (methyl) amino ] -3-methyl-butyric acid:
(2S) -3-methyl-2-methylamino-butyric acid (5g,38.12mmol) was added to a stirred sodium hydroxide solution (76.2mL of 1M,76.24 mmol). After complete dissolution, sodium carbonate (2.1g,19.82mmol) was added followed by methyl chloroformate (3.18mL,41.17mmol) over 40 minutes at 0 ℃. The reaction mixture was stirred at room temperature for 4 hours, then washed with diethyl ether (2 × 75 ml). Cooling the aqueous layer to 0 deg.C, acidifying to pH 1-2, adding CH2Cl2And (4) extracting. With MgSO4The organic phase was dried, filtered and concentrated to dryness to give the title compound (2S) -2- [ methoxycarbonyl (methyl) amino]3-methyl-butyric acid (5.12g,71%) as a clear oil.
Intermediates
Methyl N- [ (1S) -1- [ (2S,4S) -2- (4-iodo-1H-imidazol-2-yl) -4-methyl-pyrrolidine-1-carbonyl ] -2-methyl-propyl ] carbamate:
step I:
(2S) -1-tert-butoxycarbonyl-4-methyl-pyrrolidine-2-carboxylic acid
In N2A solution of (2S) -1-tert-butoxycarbonyl-4-methylene-pyrrolidine-2-carboxylic acid (25g,110mmo l) in methanol or ethanol (250mL) was purged 3 times under atmosphere and then PtO was added2(2.5g,11 mmol). Vacuum and H are again used2The solution was purified and the process was repeated 3 times. The reaction mixture was then stirred under a hydrogen atmosphere for 20 hours. The reaction mixture was filtered through celite to remove the catalyst and the filtrate was concentrated to dryness to give (2S) -1-tert-butoxycarbonyl-4-methyl-pyrrolidine-2-carboxylic acid (24.9g,98.7%) as a white solid (cis/trans mixture, ratio of about 80/20).
Step I I:
(2S) -2- (hydroxymethyl) -4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester
To a solution of (2S) -1-tert-butoxycarbonyl-4-methyl-pyrrolidine-2-carboxylic acid (26.6g,116.0 mmol) in THF (160mL) at 0 deg.C was added a 1M solution of borane in THF (243.6mL,243.6 mmol). The reaction mixture was stirred at room temperature overnight. Then saturated NH was carefully added at 4 deg.C4Aqueous Cl (50mL) (dropwise) followed by H2O (100 mL). The mixture was extracted with EtOAc and H2O washing the organic phase with Na2SO4Drying, filtering and concentrating to dryness. The residue was purified by flash column chromatography on silica gel (0-20% EtOAc in hexanes) to give (2S) -tert-butyl 2- (hydroxymethyl) -4-methyl-pyrrolidine-1-carboxylate (23.5g, 94%).
Step III:
(2S) -2-formyl-4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester.
Oxalyl chloride (319.4mL of 2M,638.8mmol) in CH over 30min2Cl2DMSO (90.69mL,1.28mol) was added to the solution in (460mL) maintaining the internal temperature at about-60 ℃. Then added to CH at-78 ℃ over 50 minutes2Cl2(2S) -2- (hydroxymethyl) -4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (55g,255.5 mmol) in (460 mL). The reaction mixture was stirred for 20 minutes, then DIPEA (445mL,2.55mol) was added dropwise. The reaction mixture was stirred at-78 ℃ for 2 hours, and warmed to room temperature over 2 hours. To this mixture was added slowly 1N HC l (800 mL). After stirring, the organic phase was separated and washed with Na2SO4Drying, filtering and concentrating to dryness. The residue was purified by flash column chromatography on silica gel (0-20% EtOAc in hexanes) to give (2S) -tert-butyl 2-formyl-4-methyl-pyrrolidine-1-carboxylate (48.5g,227.4mmol,85%) as a brown oil (cis/trans mixture 77/23).
Step IV:
(2S) -2- (1H-imidazol-2-yl) -4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester
To a stirred solution of (2S) -2-formyl-4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (45g,211mmol) in MeOH (90mL) was added NH4OH (90 mL). Oxalaldehyde (85.6g,67.7mL of 40% w/v,466.7mmol) was added in portions (exothermic reaction). The reaction mixture was stirred at room temperature overnight with H2Diluted with O (300ml) and CH2Cl2(2X 300ml) extraction. Extracting the aqueous phase with 2 nd extraction, using H2The combined organic layers were washed with Na2SO4Dried, filtered and evaporated to dryness. The residue was purified by recrystallization from EtOAc to give 24g of the title compound. The filtrate was evaporated to dryness and the residue was purified by flash column chromatography on silica gel (25-100% EtOAc in hexane) to give 9.67g of the title compound. The two isolated solids were combined to give (2S) -2- (1H-imidazol-2-yl) -4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (33.67g, 63.5%).
1H NMR (400MHz, dmso-d6, cis and trans isomers and mixtures of rotamers thereof) delta 11.71(s,1H),6.85(s,2H),4.86-4.58(m,2H),3.75-3.5(m,2H),3.03-2.82(m,2H),2.36-2.25(m,1H),2.25-2.11(m,1H),1.6-1.45(m,1H),1.39(s, minor rotamer of minor isomer), 1.37(s, minor rotamer of major isomer), 1.15(s, major rotamer of minor isomer), 1.09(s, major rotamer of major isomer) 1.005(d, minor isomer) 0.99(d, major isomer).
Step V:
(2S,4S) -2- (4, 5-diiodo-1H-imidazol-2-yl) -4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester
(2S) -2- (1H-imidazol-2-yl) -4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (36.6g,145.6mmol) stirred in CH at 5 ℃ over 15min2Cl2(366.0mL) was added 1-iodopyrrolidine-2, 5-dione (68.80g,305.8 mmol). After 1 hour, 10% sodium thiosulfate solution (800ml) was added. After stirring for 10 minutes, the organic phase is separated, washed with water and Na2SO4Dried, filtered and evaporated to dryness. The crude product was purified by flash column chromatography on silica gel (0-50% EtOAc in hexanes) to give (2S,4S) -2- (4, 5-diiodo-1H-imidazol-2-yl) -4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (52.3g, 65.7%).
1H NMR (400MHz, dmso-d6, 2.5: 1 rotamer mixture), peak δ 12.70(s,1H),4.57(dd,1H),3.62-3.52(m,1H),2.95(t,1H),2.35-2.0(m,2H),1.50(dd,1H),1.10(s,9H),1.01(d,3H) for the major rotamers.
Tert-butyl (2S,4R) -2- (4, 5-diiodo-1H-imidazol-2-yl) -4-methyl-pyrrolidine-1-carboxylate (10.5g,13%) was also isolated.
1H NMR (400MHz, dmso-d6, 1.2: 1 rotamer mixture), peak of major rotamers, δ 12.65(br s,1H),4.69(dd,1H),3.69-3.50(m,1H),2.82(t,1H),2.45-2.3(m,1H),1.91-1.68(m,2H),1.15(s,9H),0.97(d, J =6.6Hz, 3H). Peaks selected for minor rotamers: 4.77(d), 1.38(s).
Step VI:
(2S,4S) -2- (4-iodo-1H-imidazol-2-yl) -4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester
A THF solution of Li Cl (3.9mL of a 0.5M solution, 1.99mmol) was added to (2S,4S) -2- (4, 5-diiodo-1H-imidazol-2-yl) -4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1g,1.99 mmol). After stirring at room temperature for 5 minutes, the reaction mixture was cooled to-20 ℃ and a solution of methylmagnesium chloride in THF (946.7 μ L of 2.1M,1.99mmol) was added dropwise. After stirring at-20 ℃ for 20 minutes, a solution of isopropylmagnesium chloride in THF (3.2mL of 1.24M,3.97mmol) was added dropwise. The reaction mixture was slowly warmed to room temperature and stirred for 2 hours. The reaction mixture was cooled to 0 ℃ and saturated NH was slowly added4Aqueous Cl solution, then water was added. The mixture was then extracted with EtOAc (3 × 20mL), the combined organic layers were washed with brine, and Na2SO4Drying, filtering and concentrating to dryness. The residue was purified by flash column chromatography on silica gel (0-25% EtOAC/hexanes) to give (2S,4S) -2- (4-iodo-1H-imidazol-2-yl) -4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (636mg,83%) as a white solid.
1H NMR (400MHz, dmso-d6, 2: 1 rotamer mixture), peaks for the major rotamers,. delta.12.15 (s,1H),7.19(s,1H),4.65-4.57(m,1H),3.65-3.55(m,1H),2.95(t,1H),2.4-2.1(m,2H),1.52(dd,1H),1.10(s,9H),1.00(d, 3H). Peaks of the selected minor rotamers, 12.09(s),7.15(s), 1.36(s).
Step VII:
4-iodo-2- [ (2S,4S) -4-methylpyrrolidin-2-yl ] -1H-imidazole as HCl salt.
To a solution of (2S,4S) -2- (4-iodo-1H-imidazol-2-yl) -4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.6g,4.242mmol) in MeOH (16mL) at 0 ℃ was added 4M HCl in dioxane (16 mL). The reaction mixture was stirred at rt overnight and evaporated to dryness to give 4-iodo-2- [ (2S,4S) -4-methylpyrrolidin-2-yl ] -1H-imidazole (1.37g,92.5%) as a yellow solid.
1H NMR(400MHz,dms o-d6)δ9.98(br s,1H),9.17(br s,1H),7.46(s,1H),4.8-4.6(m,1H),3.45-3.35(m,1H),2.9-2.75(m,1H),2.5-2.3(m,2H),1.88-1.78(m,1H),1.09(d,3H)。
Step VIII:
methyl N- [ (1S) -1- [ (2S,4S) -2- (4-iodo-1H-imidazol-2-yl) -4-methyl-pyrrolidine-1-carbonyl ] -2-methyl-propyl ] carbamate.
To a solution of (2S) -2- (methoxycarbonylamino) -3-methyl-butyric acid (644.5mg,3.68mmol) in DMF (25mL) at 0 deg.C was added HATU (1.4g,3.68 mmol), DIPEA (2.5mL,14.57mmol) followed by 4-iodo-2- [ (2S,4S) -4-methylpyrrolidin-2-yl) as the HCl salt]-1H-imidazole (1.28g,3.64 mmol). The reaction mixture was stirred at room temperature for 20H, using EtOAc and H2And (4) diluting with oxygen. Separating the organic phase from H2O washing with Na2SO4Drying, filtering and concentrating to dryness. The residue was purified by flash column chromatography on silica gel (0-100% EtOAC/hexanes) to give N- [ (1S) -1- [ (2S,4S) -2- (4-iodo-1H-imidazol-2-yl) -4-methyl-pyrrolidine-1-carbonyl]-2-methyl-propyl]Methyl carbamate (1.3g,87.3%) as a white solid.
1H NMR(400MHz,dmso-d6)δ12.03(s,1H),7.19(d,1H),7.18(s,1H),4.83(dd,1H),4.16-3.91(m,2H),3.52(s,3H),3.16(t,1H),2.38-2.08(m,2H),1.9-1.72(m,1H),1.72-1.61(m,1H),1.06(d,3H),0.76(d,3H),0.755(m,3H)。
Intermediates
Methyl N- [ (1S) -1- [ (2S,4S) -2- (5-iodo-1H-imidazol-2-yl) -4-methyl-pyrrolidine-1-carbonyl ] -2-methyl-propyl ] carbamate:
step I
(2S) -4-methyl-2- (4-methyl-1H-imidazol-2-yl) pyrrolidine-1-carboxylic acid tert-butyl ester
Stirring of (2S) -2-formyl-4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (282mg,1.322 mm)ol) solution in MeOH (5,6mL) was cooled to-20 deg.C and the ammonia gas was bubbled for 10 minutes. 2-oxopropanal (35% w/w in water, 1.905g,9.254mmol) was added and the reaction mixture was allowed to warm to room temperature for more than 1 hour. The mixture was then heated to 65 ℃ for 1 hour, concentrated, and 5mL of water was added to the residue. By CH2Cl2The aqueous layer was extracted (3 × 10 mL). With Na2SO4The combined organic layers were dried, filtered and evaporated to dryness. The residue was purified by flash column chromatography on silica gel (0-20% MeOH in CH)2Cl2Solution) to give (2S) -4-methyl-2- (4-methyl-1H-imidazol-2-yl) pyrrolidine-1-carboxylic acid tert-butyl ester (307mg, 88%).
Step II
(2S,4S) -2- (5-iodo-4-methyl-1H-imidazol-2-yl) -4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester.
To a stirred solution of tert-butyl (2S) -4-methyl-2- (4-methyl-1H-imidazol-2-yl) pyrrolidine-1-carboxylate (307mg,1.013mmol) in CH at 5 deg.C2Cl2To the solution (15mL) was added N-iodosuccinimide (240mg,1.013 mmol). The reaction mixture was stirred for 1 hour and water (2mL) was added. Separating the organic layer with Na2SO4Drying and evaporating to dryness. The residue was purified by flash column chromatography on silica gel (12-100% EtOAc in hexanes) to give (2S,4S) -2- (5-iodo-4-methyl-1H-imidazol-2-yl) -4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (246mg, 62%).
Intermediates
(S) -2- (5-iodo-1H-benzoimidazol-2-yl) -pyrrolidine-1-carboxylic acid tert-butyl ester:
to a dry 1000mL round bottom flask was added 4-iodo-benzene-1, 2-diamine (45g), (S) -pyrrolidine-1, 2-dicarboxylic acid 1-tert-butyl ester (41.39g), and THF (450mL) under a nitrogen atmosphere. The reaction mixture was stirred until completely dissolved and then cooled to 0-2 ℃. DIPEA (50.17ml) was added dropwise to control the exotherm, followed by one addition of HATU (80.38 g). The reaction mixture was stirred in an ice bath for 3 hours and then subjected to HPLC to monitor completion of the reaction. To this solution was added 500ml of water and 500ml of ethyl acetate. The aqueous phase was extracted 2 times with ethyl acetate. The organic phases were combined and evaporated half way. 450ml of acetic acid are added to the organic phase and the mixture is evaporated to 300 ml. This procedure was repeated 3 times for-470 ml of residue, and the mixture was then heated at 50 ℃ overnight. Toluene (200ml) was added and evaporated to give a small residue (6 replicates). To the solution was added 450ml of ethyl acetate. The organic phase is washed with saturated sodium carbonate, dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified on a silica gel pad using a 25% ethyl acetate/hexane mixture to give (S) -tert-butyl 2- (5-iodo-1H-benzoimidazol-2-yl) -pyrrolidine-1-carboxylate (67g) as a light brown powder.
1H NMR(400MHz,CD3OD)：δ[ppm]8.0-7.7(bs,1H),7.5(m,1H),7.4-7.1(bs,1H),5.1-4.9(m,1H),3.8-3.6(m,1H),3.6-3.4(m,1H),2.6-2.2(m,1H),2.2-1.8(m,3H),1.4(s,3H),1.1(s,6H)
LC/MS：m/z=413.95(M+H+)。
Intermediates
2- (5-iodo-1H-benzo [ d ] imidazol-2-yl) -4-methylpyrrolidine-1-carboxylic acid tert-butyl ester (1) and (2S,4S) -tert-butyl (2S,4S) -2- (5-iodo-1H-benzo [ d ] imidazol-2-yl) -4-methylpyrrolidine-1-carboxylic acid (2):
(2S) -1-tert-butoxycarbonyl-4-methyl-pyrrolidine-2-carboxylic acid (880mg,3.83mmol), 4-iodobenzene-1, 2-diamine (1.07,4.60mmol), HATU (1.75g,4.6mmol) and 2,4, 6-collidine (1.52mL,11.5mmol) were added to 14mL DMF. The mixture was stirred at room temperature overnight, the solvent was removed in vacuo, and the residue was dissolved in 10mL of AcOH and heated to 50 ℃ overnight. After the AcOH was removed in vacuo,the residue was purified by silica gel chromatography 0-50% ethyl acetate/hexanes to give the trans compound 2(2S,4R) -2- (5-iodo-1H-benzoimidazol-2-yl) -4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (260mg, 15%).1H NMR(400MHz,CD3OD) δ 7.85(d,1H),7.49(dt,1H),7.31(d,1H),4.98(m,1H),3.90(m,1H),3.04(dt,1H),2.48(dd,1H),2.25-1.94(m,2H),1.47(d,3H),1.08(s, 9H). Further elution gave the cis-compound tert-butyl 1(2S,4S) -2- (5-iodo-1H-benzimidazol-2-yl) -4-methyl-pyrrolidine-1-carboxylate (1.38g,84%)1H NMR(400MHz,CD3OD)δ7.82(d,1H),7.49(m,1H),7.31(d,1H),4.90(m,1H),3.82(m,1H),3.15(t,1H),2.55(m,1H),2.36(m,1H),1.40(d,3H),1.08(s,9H)。
5-iodo-2- ((2S,4S) -4-methylpyrrolidin-2-yl) -1H-benzo [ d ] imidazole:
to a stirred solution of tert-butyl (2S,4S) -2- (5-iodo-1H-benzimidazol-2-yl) -4-methyl-pyrrolidine-1-carboxylate (3.70g,8.659mmol) in dichloromethane (34mL) was added TFA (17.22mL,223.5mmol) and stirred at room temperature for 1H. The reaction mixture was concentrated, azeotroped with toluene 2X and dried in vacuo. The residue was diluted with dichloromethane (200mL), washed 2X with saturated sodium bicarbonate and brine, then dried over sodium sulfate. Evaporation of the organic layer gave 5-iodo-2- [ (2S,4S) -4-methylpyrrolidin-2-yl ] -1H-benzimidazole (2.32g, 82%).
(S) -methyl 1- ((2S,4S) -2- (5-iodo-1H-benzo [ d ] imidazol-2-yl) -4-methylpyrrolidin-1-yl) -3-methyl-1-oxobutan-2-ylcarbamate:
to 5-iodo-2- [ (2S,4S) -4-methylpyrrolidin-2-yl ] -1H-benzimidazole (2.29g,7.00mmol) and (2S) -2- (methoxycarbonylamino) -3-methyl-butyric acid (1.49g,7.70mmol) in DMF was added HATU (3.46g,9.1mmol) and DIPEA (2.4mL,14.0mmol) at room temperature. The reaction mixture was stirred at room temperature overnight. To the reaction mixture was added water (350mL) with rapid stirring, at which time a solid precipitated out. The solid was filtered off with suction and dried in vacuo to give methyl N- [ (1S) -1- [ (2S,4S) -2- (5-iodo-1H-benzimidazol-2-yl) -4-methyl-pyrrolidine-1-carbonyl ] -2-methyl-propyl ] carbamate (2.73g, 81%).
1H NMR(400MHz,CD3OD)δ7.83(d,1H),7.49(dd,1H),7.29(d,1H),5.09(dd,1H),4.31-4.15(m,2H),3.59(s,6H),2.54(m,1H),2.43(m,1H),2.00-1.90(m,2H),1.18(d,3H),0.95(d,3H),0.82(d,3H)。
LC/MS：m/z=485.0(M+H+)。
(S) -methyl 1- ((2S,4R) -2- (5-iodo-1H-benzo [ d ] imidazol-2-yl) -4-methylpyrrolidin-1-yl) -3-methyl-1-oxobutan-2-ylcarbamate:
1H NMR(400MHz,CD3OD)δ7.84(d,1H),7.48(dd,1H),7.30(d,1H),5.29(dd,1H),4.24-4.15(m,1H),4.01(dt,1H),3.66(s,3H),3.57-3.46(m,1H),2.80-2.69(m,1H),2.25(m,1H),2.01(m,2H),1.17(d,3H),0.91(d,3H),0.88(d,3H)。
LC/MS：m/z=485.0(M+H+)。
intermediates
{ (S) -1- [ (S) -2- (5-iodo-1H-benzoimidazol-2-yl) -pyrrolidine-1-carbonyl ] -2-methyl-propyl } -carbamic acid methyl ester:
step I:
(S) -5-iodo-2- (pyrrolidin-2-yl) -1H-benzo [ d ] imidazole-TFA salt.
To a stirred solution of (S) -2- (5-iodo-1H-benzimidazol-2-yl) -pyrrolidine-1-carboxylic acid tert-butyl ester (20g,48mmol) in CH at 0 deg.C2Cl2To the mixture (200mL) was added TFA (200 mL). The reaction mixture was stirred at room temperature for 2 hours and concentrated in vacuo. The residue was dissolved in CH2Cl2And saturated NaHCO3Aqueous solution of saturated NaHCO3The organic layer was washed with aqueous solution, dried over sodium sulfate and concentrated in vacuo to give (S) -5-iodo-2- (pyrrolidin-2-yl) -1H-benzo [ d ]]imidazole-TFA salt (12 g).
1H NMR(400MHz,CDCl3)：δ[ppm]8.40(br s,2H),7.82(s,1H),7.45(d,1H),7.26(d,1H),4.66(t,1H),3.10(m,2H),2.30(m,1H),2.18(m,1H),1.90(m,2H)。
Step II:
((S) -1- ((S) -2- (5-iodo-1H-benzo [ d ] imidazol-2-yl) pyrrolidin-1-yl) -3-methyl-1-oxobutan-2-yl) carbamic acid methyl ester
To a mixture of (S) -2-methoxycarbonylamino-3-methyl-butyric acid (68mg,0.39mmol) and (S) -5-iodo-2- (pyrrolidin-2-yl) -1H-benzo [ d ] imidazole-TFA salt (100mg,0.32 mmol) in anhydrous DMF (2mL) was added DIPEA (0.25mL,1.43mmol) followed by HATU (142mg,0.37 mmol). The mixture was stirred at room temperature for 4 hours. Ice was added and the product was extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (EtOAc/MeOH 0% -10%) to give methyl ((S) -1- ((S) -2- (5-iodo-1H-benzo [ d ] imidazol-2-yl) pyrrolidin-1-yl) -3-methyl-1-oxobutan-2-yl) carbamate (150 mg).
1H NMR(400MHz,dms o-d6)12.25(d,1H),7.8(d,1H),7.45-7.33(m,1H),7.33-7.15(m,2),5.1-5.2(m,1H),3.9-3.7(m,2H),3.5(s,3H),2.25-2.05(m,2H),2.05-1.8(m,3H),0.8(m,7H)
LC/MS：m/z=470.90(M+H+)。
HPLC (method C): t is tR=7.78mi n.
Intermediates
((S) -3-methyl-1-oxo-1- ((S) -2- (5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-benzo [ d ] imidazol-2-yl) pyrrolidin-1-yl) but-2-yl) carbamic acid methyl ester:
reacting ((S) -1- ((S) -2- (5-iodo-1H-benzo [ d)]Imidazol-2-yl) pyrrolidin-1-yl) -3-methyl-1-oxobutan-2-yl) carbamic acid methyl ester (2.23g,4.74mmol), 4,4, 4', 4', 5,5,5 ', 5 ' -octamethyl-2, 2 '; bis (1,3, 2-dioxaborole cyclopentane (3.61g,14.22mmol), PdCl2dppf (193mg) and potassium acetate (1.53g,15.64mmol) were added to dry DMF (40 mL). The mixture was purged with nitrogen and stirred at 85 ℃ overnight. After removal of the solvent under reduced pressure, the residue was purified by flash chromatography on silica gel (methanol/CH)2Cl20-5%) to give ((S) -3-methyl-1-oxo-1- ((S) -2- (5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-benzo [ d ] a]Imidazol-2-yl) pyrrolidin-1-yl) butan-2-yl) carbamic acid methyl ester (1.5 g).
1H NMR(400MHz,CDCl3)：δ[ppm]7.60-7.95(m,3H),5.82(m,1H),5.42(m,1H),4.29(m,1H),3.63-3.75(m,6H),3.04(m,1H),1.91-2.40(m,5H),1.26-1.34(m,12H),0.79-1.03(m,6H)。
LC/MS：m/z 471.19(M+H+)。
Compounds 1-3, 11, 14, 15 and 17-57
Compounds 1-3, 11, 14, 15 and 17-57 as disclosed in tables 1A and 1B were prepared according to the procedures outlined in examples 1-12 using the appropriate intermediate starting materials.
Example 13
Activity assays Using ELISA and subgenomic replicon 1a cell lines
Cell line W11.8 containing the subgenomic HCV replicon of genotype 1a was used to determine drug efficacy. At 4 days of drug treatment, RNA replication in this cell line in the presence of different drug concentrations was determined indirectly from NS5A protein levels. The results show that NS5A protein levels are closely related to HCV RNA levels in replicon cell lines. Cells divide 2 times a week to maintain confluency below 85% of the surface area of the culture flask. The medium used for cell passaging consisted of DMEM-10% fetal bovine serum with 100UI/mL penicillin, 100. mu.g/mL streptomycin, 2mM glutamine, 1mM sodium pyruvate, non-essential amino acids (1X) and 600. mu.g/mL G418 final concentration. Monolayers of W11.8 cells were trypsinized and the cells counted. Cells were diluted with complete DMEM without G418 at 50,000 cells/mL, and approximately 5,000 viable cells (100 μ L) were plated on white opaque 96-well microtiter plates. At 37 ℃ and 5% CO2After an incubation period of 2-4 hours in the incubator, compounds were added at various concentrations. The drug was resuspended in DMSO at a stock solution concentration of 10 mM. The drug was then serially diluted to 2-fold final concentration in the same medium. Then 1 volume (100 μ L) of each drug dilution was added to each well containing cells. Control compounds were used as internal standards for each plate assay. 16 wells were used as drug-free controls (0% inhibition). 8 wells were used as background controls (100% inhibition) containing 2 μm (final concentration) of a control drug that demonstrated near 100% inhibition of NS5A expression and no toxicity to cells. The wells from 100% inhibition were averaged and used as background. At 37 ℃ and 5% CO2The cells were incubated in the incubator for an additional 4 days. After 4 days incubation time, the medium was removed and the wells were washed 1 time, 5 minutes at room temperature with 150 μ LPBS. Cells were then fixed for 5 minutes using 150 μ L of cold (-20 ℃) fixing solution (50% methanol/50% acetone mixture) per well. The cells were then washed 2 times with 150 μ LPBS (phosphate buffered saline)/well and after addition of 150 μ L of blocking solution, the cells were incubated at 37 ℃ for 1 hour to block non-specific sites. Remove the blocking solution and use 150. mu. LPBS/wellCells were washed 2 times and 1 time with 150 μ L PBS solution (PBS/0.1% Triton X-100/0.02% SDS)/well. Then 50. mu.L of mouse monoclonal anti-NS 5A antibody (Santa Cruz, Cat. No. sc-52417) was added to each well, diluted with blocking solution according to 1/1,000, and incubated overnight at 4 ℃. The following day, the medium was removed and the plates were washed 5 times with a 150. mu. LPBS/well 5min incubation at room temperature. Then 50. mu.L/well of peroxidase-conjugated donkey anti-mouse antibody (Jackson Immunoresearch, Ca t. No. 715-036-. The plates were washed 4 times with 150. mu.L PBS solution/well and 1 time with 150. mu.L PBS. Substrate solution (100. mu.l, SuperSignal ELISA Pico Chemicals center Substrate, Fisher Cat. No.37069) was then added to each well, the plates were incubated for 60 minutes at room temperature, and luminescence (relative light units) was read in an Analyst HT plate reader. Percent inhibition (in duplicate) was calculated for each test drug concentration. The concentration required to reduce viral replication by 50% (IC) was then determined from the dose-response curve using non-linear regression analysis with GraphPad Prism Software version 2.0 (GraphPad Software inc., San Diego, CA, USA)50)。
Example 14
Cell culture based on determination of the RNA replication of the luciferase reporter Gene HCV (Ib)
Such as Krieger, N; lohmann, V; the replicon cell line Huh-5.2 derived from the Huh-7 hepatoma cell line was maintained in culture as generally described by Bartenschlager, R.enhancement of hepatitis Cvirus RNA replication by cell culture tubes-adaptation. The Huh-5.2 cells contain highly adapted cell culture replicon I389The luc-ubi-neo/NS 3-3'/5.1 construct, which carries, in addition to the neomycin gene, a copy integrated into the firefly luciferase gene (Krieger, N; Lohmann, V; Bartenschlager, R.Enhancement of hepatitis C virus RNA replication by cell tissue-adaptive immunity. J.Virol.2001,75, 4614-Linear 4624). This cell line allows measurement byLuciferase activity was measured for replication and translation of HCV RNA. It has previously been shown that luciferase activity closely follows replicon RNA levels in these cells (Krieger, N; Lohmann, V; Bartenschlager, R.enhancement of hepatitis C virus RNA replication by cell tube-adaptation of J.Virol.2001,75, 4614-d.4624). The Huh-ET cell line has the same characteristics as mentioned for the Huh-5.2 cell line, except that the ET cells are more robust and comprise an adaptive mutation of the HCV NS4B gene instead of NS 5A. Both cell lines were maintained in culture at below fusion levels (< 85%) because replicon RNA levels were highest in actively proliferating cells. The medium used for the passage of the cells consisted of DMEM (Gibco BRL Laboratories, Mississ auga, ON, Canada) supplemented with 10% fetal bovine serum, containing 1% penicillin/streptomycin, 1% glutamine, 1% sodium pyruvate, 1% nonessential amino acids, and 350ug/ml G418 at the final concentration. Cells were incubated at 5% CO2Was cultured at 37 ℃ and passaged twice a week to remain below confluency.
Approximately 3000 viable Huh-ET cells (100 μ Ι) were plated in each well in a white opaque 96-well microtiter plate. The cell culture medium used for the assay was the same as described above except that it did not contain G418 and did not contain phenol red. 5% CO at 37 ℃2After an incubation period of 3-4 hours in the incubator of (1), compounds (100. mu.l) were added at different concentrations. The cells were then further incubated at 37 ℃ with 5% CO2Culturing in an incubator for 4 days. Thereafter, the medium was removed and the cells were lysed by adding 95 μ l of luciferase buffer (luciferin substrate in buffered detergent). The cell lysate was incubated at room temperature and direct light was avoided for at least 10 minutes. Use a photometer (Wallac MicroBeta Trilux, Perkin ElmerTMMA, USA) reading plates.
HCV 1a and 1b are the two most common HCV genotypes and are the most difficult to treat. It has proven problematic in the past to find compounds with good activity for both genotypes. However, the compounds of the present invention, particularly those having 4-methylpyrrolidinyl groups, are active against both HCV 1a and 1b genotypes. The above examples may be repeated in a similarly successful manner by substituting those reactants and/or operating conditions of the invention generally or specifically described for the above examples.
From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.
In duplicate, 50% Inhibitory Concentration (IC) for inhibition was determined from a dose response curve using 11 concentrations of each compound50s). Curves were fitted to the data points using non-linear regression analysis and IC was interpolated from the resulting curves using GraphPad Pr i sm software version 2.0 (GraphPad Sof tware inc., San Di ego, CA, USA)50s。
Table 2 shows representative compounds of the invention.
TABLE 2
uM：+++<=0.005<++<=5.0<+
Table 3 shows comparative data for typical compounds of formula (I). As shown in the table, some of the compounds have a substituent at the 4-position of the pyrrolidine ring (i.e., the compounds of the present invention, wherein R is4And R4’Is methyl). Data show IC for subgenomic replicon 1a and 1b cell lines50The value is obtained.
TABLE 3
Claims (76)
1. A compound of formula (IIIA):
or a pharmaceutically acceptable salt thereof, wherein
A is each independently C6-14Aryl, 4-12 membered heterocycle, C3-10Cycloalkyl or 5-12 membered heteroaryl;
b and B' are each independently absent, C1-6Alkyl radical, C2-6Alkenyl or C2-6An alkynyl group;
R1is halogen, -ORa、-NRaRb、-C(=O)ORa、-C(O)NRaRb、-C(=O)OH、-C(=O)Ra、-C(=NORc)Ra、-C(=NRc)NRaRb、-NRdC(=O)NRaRb、-NRbC(=O)Ra、-NRdC(=NRc)NRaRb、-NRbC(=O)ORa、-OC(=O)NRaRb、-OC(=O)Ra、-OC(=O)ORaHydroxy, nitro, azido, cyano, -S (O)0-3Ra、-SO2NRaRb、-NRbSO2Ra、-NRbSO2NRaRb、-P(=O)ORaORbUnsubstituted or substituted by R10Substituted one or more times by C1-6Alkyl, unsubstituted or substituted by R10Substituted one or more times by C2-6Alkenyl, unsubstituted or substituted by R10Substituted one or more times by C2-6Alkynyl, or any two occurrences of R1May form together with the atom to which they are attached an unsubstituted or substituted R115-7 cycloalkyl substituted once or more times, or unsubstituted or substituted by R12A 5-7 membered heterocyclic ring substituted one or more times;
Ra-Rdeach independently is H, C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C6-12Aryl radical, C7-16Aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl;
R2' is halogen, C1-10Alkyl radical, C1-6Haloalkyl, - (CH)2)1-6OH、-NRbC(=O)Ra、C6-12Aryl or 5-12 membered heteroaryl;
R2each independently is halogen, C1-10Alkyl radical, C1-6Haloalkyl, - (CH)2)1-6OH、-ORa、-C(=O)ORa,-NRaRb、-NRbC(=O)Ra,-C(O)NRaRb、-S(O)0-3Ra、C6-12Aryl, 5-12 membered heterocycle or 5-12 membered heteroaryl;
R3and R3' independently of each other is H, C1-6Alkyl, - (CH)2)1-6OH、C2-6Alkenyl or C2-6An alkynyl group;
R4and R4' each independently is C1-6An alkyl group;
x and Y are each independently
Or a bond;
wherein the asterisk (—) indicates the point of attachment to the pyrrolidine ring nitrogen;
R5and R5' independently of one another are H, unsubstituted or substituted by R10Substituted one or more times by C1-18Alkyl, unsubstituted or substituted by R10Substituted one or more times by C2-12Alkenyl, unsubstituted or substituted by R10Substituted one or more times by C2-12Alkynyl, unsubstituted or substituted by R11Substituted one or more times by C6-14Aryl, unsubstituted or substituted by R11Substituted one or more times by C7-16Aralkyl, unsubstituted or substituted by R115-12 membered heteroaryl, unsubstituted or substituted once or many times by R116-18 membered heteroaralkyl, unsubstituted or substituted once or many times by R123-12 membered heterocyclic ring substituted once or more times, or unsubstituted or substituted by R124-18 membered heterocyclyl-alkyl substituted one or more times;
R6is H, C1-6Alkyl or halo C1-6An alkyl group;
m and n are each independently 0,1, 2,3 or 4 and the sum of m and n is 1,2, 3 or 4;
p is 0,1, 2,3 or 4;
q is 0,1 or 2;
u is 0 or 1;
s is 0,1, 2,3 or 4;
R10is halogen, -ORaOxo, -NRaRb、=NO-Rc、-C(=O)ORa、-C(O)NRaRb、-C(=O)OH、-C(=O)Ra、-C(=NORc)Ra、-C(=NRc)NRaRb、-NRdC(=O)NRaRb、-NRbC(=O)Ra、-NRdC(=NRc)NRaRb、-NRbC(=O)ORa、-OC(=O)NRaRb、-OC(=O)Ra、-OC(=O)ORaHydroxy, nitro, azido, cyano, -S (O)0-3Ra、-SO2NRaRb、-NRbSO2Ra、-NRbSO2NRaRbOR-P (= O) ORaORb；
R11Is halogen, -ORa、-NRaRb、-C(=O)ORa、-C(O)NRaRb、-C(=O)OH、-C(=O)Ra、-C(=NORc)Ra、-C(=NRc)NRaRb、-NRdC(=O)NRaRb、-NRbC(=O)Ra、-NRdC(=NRc)NRaRb、-NRbC(=O)ORa、-OC(=O)NRaRb、-OC(=O)Ra、-OC(=O)ORaHydroxy, nitro, azido, cyano, -S (O)0-3Ra、-SO2NRaRb、-NRbSO2Ra、-NRbSO2NRaRbOR-P (= O) ORaORb、C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C6-12Aryl radical, C7-16Aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl; and is
R12Is halogen, -ORaOxo, -NRaRb,=NO-Rc、-C(=O)ORa、-C(O)NRaRb、-C(=O)OH、-C(=O)Ra、-C(=NORc)Ra、-C(=NRc)NRaRb、-NRdC(=O)NRaRb、-NRbC(=O)Ra、-NRdC(=NRc)NRaRb、-NRbC(=O)ORa、-OC(=O)NRaRb、-OC(=O)Ra、-OC(=O)ORaHydroxy, nitro, azido, cyano, -S (O)0-3Ra、-SO2NRaRb、-NRbSO2Ra、-NRbSO2NRaRbOR-P (= O) ORaORb、C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C6-12Aryl radical, C7-16Aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl.
2. The compound of claim 1, wherein
Each A is independently cyclopropyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperazinyl, piperidinyl, phenyl, naphthyl, thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, indazolyl, benzimidazolyl, benzoxazolyl, benzodioxolyl, benzothiazolyl, benzothiadiazolyl, dihydrobenzodioxine, thienofuranyl, thienothienyl, thienopyrrolyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, or triazolyl; and wherein A is each independently (R)1)pAnd (4) substitution.
3. The compound of claim 2, wherein each A is independently cyclopropyl, cyclohexyl, phenyl, or naphthalene, wherein each A is independently (R)1)pAnd (4) substitution.
4. The compound of claim 3, wherein each A is independently selected from:
and is
t1+t2=p。
5. The compound of claim 4, wherein A is:
6. the compound of claim 2, wherein each a is independently piperazinyl, piperidinyl, thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, thiadiazolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzoxazolyl, benzodioxolyl, benzothiazolyl, benzothiadiazolyl, dihydrobenzodioxinyl, thienofuryl, thienothienyl, quinolinyl, or triazolyl.
7. The compound of claim 6, wherein each A is independently selected from:
and is
t1+t2=p。
8. The compound of claim 1, wherein each a is independently a 5-12 membered heteroaryl, wherein the heteroatoms are selected from the group consisting of oxygen and sulfur; wherein A is each independentlyFloor quilt (R)1)pAnd (4) substitution.
9. The compound of any one of claims 1-8, wherein B and B' are independently absent, C1-6Alkyl or C2-6Alkynyl.
10. The compound of claim 9, wherein B and B' are independently absent, - (CH)2)2-or- (C.ident.C) -.
11. The compound of claim 10, wherein B and B' are independently absent or- (C ≡ C) -.
12. The compound of any one of claims 1 or 8-11, whereinSelected from:
and is
t1+t2=p。
13. The compound of claim 12, whereinSelected from:
and is
t1+t2=p。
14. The compound of claim 13, whereinSelected from:and is
t1+t2=p。
15. The compound of claim 14, whereinThe method comprises the following steps:
and is
t1+t2=p。
16. The compound of claim 15, whereinThe method comprises the following steps:
and is
t1+t2=p。
17. The compound of claim 14, whereinThe method comprises the following steps:
and is
t1+t2=p。
18. The compound of claim 15, whereinThe method comprises the following steps:
and is
t1+t2=p。
19. The compound of any one of claims 1-13, wherein R1Is halogen, unsubstituted or substituted by R10Substituted one or more times by C1-4Alkyl, -C (= O) ORa、-C(O)NRaRbHydroxy, cyano or C1-3An alkoxy group.
20. The compound of claim 19, wherein R1Is chlorine, fluorine, bromine, methyl, ethyl, propyl, butyl, -CH2OH, difluoromethyl, trifluoromethyl, -C (= O) ORaHydroxy, cyano or methoxy.
21. The compound of any one of claims 1-20, wherein R2' is methyl, trifluoromethyl, iodine, CH2OH or NHC (O) CH3。
22. The compound of claim 21, wherein u is 0.
23. The compound of any one of claims 1-22, wherein R2Each independently being fluoro or methyl.
24. The compound of claim 23, wherein s is 0.
25. The compound of any one of claims 1-24, wherein R3And R3' is H or methyl.
26. The compound of claim 25, wherein R4And R4' is methyl.
27. The compound of any one of claims 1-26, wherein one of m and n is 1 and the other is 0.
28. The compound of claim 27, wherein m and n are 1.
29. The compound of any one of claims 1-28, wherein X and Y are
30. The compound of any one of claims 1-29, wherein R5And R5' are each independently unsubstituted or substituted with R10Substituted one or more times by C1-8Alkyl, unsubstituted or substituted by R10Substituted one or more times by C2-8Alkenyl, unsubstituted or substituted by R10Substituted one or more times by C2-8Alkynyl, unsubstituted or substituted by R11Phenyl substituted once or many times, unsubstituted or by R11Substituted one or more times by C7-8Aralkyl, unsubstituted or substituted by R115-6 membered heteroaryl, unsubstituted or substituted once or many times by R116-8 membered heteroaralkyl, unsubstituted or substituted once or many times by R123-6 membered heterocyclic ring substituted once or more than once, or unsubstituted or substituted by R124-8 membered heterocyclyl-alkyl substituted one or more times.
31. The compound of claim 30, wherein R5And R5' are each independently unsubstituted or substituted with R10Substituted one or more times by C1-6Alkyl, unsubstituted or substituted by R10Substituted one or more times by C2-6Alkenyl, unsubstituted or substituted by R10Substituted one or more times by C2-6Alkynyl, unsubstituted or substituted by R11Phenyl substituted once or many times, unsubstituted or by R11Benzyl substituted once or many times, unsubstituted or by R115-6 membered heteroaryl, unsubstituted or substituted once or many times by R116-7 membered heteroaralkyl, unsubstituted or substituted once or many times by R125-6 membered heterocycle substituted once or more than once, or unsubstituted or substituted by R126-7 membered heterocycle-alkyl substituted one or more times.
32. The compound of claim 31, wherein R5And R5' are each independently unsubstituted or substituted with R10Substituted one or more times by C1-6Alkyl, unsubstituted or substituted by R10Substituted one or more times by C2-6Alkenyl, unsubstituted or substituted by R10Substituted one or more times by C2-6Alkynyl.
33. The compound of claim 32, wherein R5And R5' are each independently methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, 2-methylbutane, 3-methylbutane, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or Cyclohexyl (CH)2) -, whichUnsubstituted or substituted by R10One or more substitutions.
34. The compound of claim 31, wherein R5And R5' are each independently unsubstituted or substituted with R11Phenyl substituted one or more times.
35. The compound of claim 31, wherein R5And R5' are each independently unsubstituted or substituted with R11Benzyl substituted one or more times.
36. The compound of any one of claims 1-35, wherein R10Is halogen, -ORaOxo, -NRaRb,=NO-Rc、-C(=O)ORa、-C(O)NRaRb、-C(=O)OH、-C(=O)Ra、-C(=NORc)Ra、-C(=NRc)NRaRb、-NRdC(=O)NRaRb、-NRbC(=O)Ra,-NRdC(=NRc)NRaRb、-NRbC(=O)ORa、-OC(=O)NRaRb、-OC(=O)Ra、-OC(=O)ORaHydroxy, nitro, azido, cyano, -S (O)0-3Ra、-SO2NRaRb、-NRbSO2Raor-NRbSO2NRaRbWherein R isa-RdEach independently is H, C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C6-12Aryl radical, C7-16Aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl.
37. The compound of claim 36, wherein R10is-NRaRb、-NRdC(=O)NRaRb、-NRbC(=O)Ra、-NRdC(=NRc)NRaRb、-NRbC(=O)ORa、-NRbSO2Raor-NRbSO2NRaRb。
38. The compound of claim 36, wherein R10is-NRaRb,-NRdC(=O)NRaRb、-NRbC(=O)Ra、-NRbC(=O)ORaor-NRbSO2Ra。
39. The compound of any one of claims 1-38, wherein Ra-RdEach independently is H, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, phenyl, C7-8Aralkyl, 5-6 membered heteroaryl, 6-8 membered heteroaralkyl, 5-6 membered heterocycle, or 6-8 membered heterocycle-alkyl.
40. The compound of claim 39, wherein RaAnd RcEach independently is H, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, phenyl, C7-8Aralkyl, 5-6 membered heteroaryl, 6-8 membered heteroaralkyl, 5-6 membered heterocycle, or 6-8 membered heterocycle-alkyl, and RbAnd RdEach independently is H or C1-3An alkyl group.
41. The compound of claim 39, wherein Ra-RdEach independently isH or C1-3An alkyl group.
42. The compound of any one of claims 1-41, wherein the compound has formula (IV):
or a pharmaceutically acceptable salt thereof, wherein
R7And R7' are each independently unsubstituted or substituted with R10Substituted one or more times by C1-8Alkyl, unsubstituted or substituted by R10Substituted one or more times by C2-8Alkenyl, unsubstituted or substituted by R10Substituted one or more times by C2-8Alkynyl, unsubstituted or substituted by R11Phenyl substituted once or many times, unsubstituted or by R11Benzyl substituted once or many times, unsubstituted or by R115-6 membered heteroaryl, unsubstituted or substituted once or many times by R116-7 membered heteroaralkyl, unsubstituted or substituted once or many times by R123-6 membered heterocyclic ring substituted once or more than once, or unsubstituted or substituted by R124-7 membered heterocyclyl-alkyl substituted one or more times;
R8and R8' each independently is-NRaRb、-NRdC(=O)NRaRb、-NRbC(=O)Ra、-NRdC(=NRc)NRaRb、-NRbC(=O)ORa、-NRbSO2Raor-NRbSO2NRaRbWherein R isa-RdEach independently is H, C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C6-12Aryl radical, C7-16Aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl.
43. The compound of claim 42, whereinThe method comprises the following steps:
44. the compound of claim 42, wherein R8And R8' each independently is-NRaRb、-NRbC(=O)Ra、-NRbC(=O)ORaWherein R isa-RbEach independently is H, C1-6Alkyl, phenyl, benzyl, 5-6 membered heteroaryl, 6-8 membered heteroaralkyl, 5-6 membered heterocycle, or 6-8 membered heterocycle-alkyl.
45. The compound of claim 42, wherein R in formula (IV)8And R8' each independently is-NRbC(=O)ORaWherein R isa-RbEach independently is H, C1-6Alkyl, phenyl, tetrahydrofuran or benzyl.
46. The compound of any one of claims 42-45, wherein R7And R7' are each independently unsubstituted or substituted with R11Phenyl substituted one or more times.
47. The compound of any one of claims 42-45, wherein R7And R7' are each independently unsubstituted or substituted with R10Substituted one or more times by C1-6An alkyl group.
48. The compound of any one of claims 42-45, wherein R7And R7' are each independently methyl, ethyl, propyl, isopropyl, methoxyisopropyl, butyl, sec-butyl, tert-butyl, pentyl, 2-methylbutane, 3-methylbutane, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
49. The compound of any one of claims 42-47, wherein R7And R8Or R7' and R8' together with the carbon to which they are attached are each independently:
50. the compound of any one of claims 1-49, wherein the compound has formula (V):
or a pharmaceutically acceptable salt thereof.
51. A compound of formula (VI):
or a pharmaceutically acceptable salt thereof, wherein
Ra-RdEach independently is H, C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C6-12Aryl radical, C7-16Aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl;
R1is halogen, -ORa、-NRaRb、-C(=O)ORa、-C(O)NRaRb、-C(=O)OH、-C(=O)Ra、-C(=NORc)Ra、-C(=NRc)NRaRb、-NRdC(=O)NRaRb、-NRbC(=O)Ra、-NRdC(=NRc)NRaRb、-NRbC(=O)ORa、-OC(=O)NRaRb、-OC(=O)Ra、-OC(=O)ORaHydroxy, nitro, azido, cyano, -S (O)0-3Ra、-SO2NRaRb、-NRbSO2Ra、-NRbSO2NRaRb、-P(=O)ORaORbUnsubstituted or substituted by R10Substituted one or more times by C1-6Alkyl, unsubstituted or substituted by R10Substituted one or more times by C2-6Alkenyl, unsubstituted or substituted by R10Substituted one or more times by C2-6Alkynyl, or R in any two occurrences1May form together with the atom to which they are attached an unsubstituted or substituted R115-7 cycloalkyl substituted once or more times, or unsubstituted or substituted by R12A 5-7 membered heterocyclic ring substituted one or more times;
R2' is halogen, C1-10Alkyl radical, C1-6Haloalkyl, - (CH)2)1-6OH、-NRbC(=O)Ra、C6-12Aryl or 5-12 membered heteroaryl;
R2each independently is halogen, C1-10Alkyl radical, C1-6Haloalkyl, - (CH)2)1-6OH、-ORa、-C(=O)ORa、-NRaRb、-NRbC(=O)Ra、-C(O)NRaRb、-S(O)0-3Ra、C6-12Aryl, 5-12 membered heterocycle or 5-12 membered heteroaryl;
R4and R4' each independently is C1-6An alkyl group;
x and Y are each independently
Or a bond;
wherein the asterisk (—) indicates the point of attachment to the pyrrolidine ring nitrogen;
R5and R5' independently of one another are H, unsubstituted or substituted by R10Substituted one or more times by C1-18Alkyl, unsubstituted or substituted by R10Substituted one or more times by C2-12Alkenyl, unsubstituted or substituted by R10Substituted one or more times by C2-12Alkynyl, unsubstituted or substituted by R11Substituted one or more times by C6-14Aryl, unsubstituted or substituted by R11Substituted one or more times by C7-16Aralkyl, unsubstituted or substituted by R115-12 membered heteroaryl, unsubstituted or substituted once or many times by R116-18 membered heteroaralkyl, unsubstituted or substituted once or many times by R123-12 membered heterocyclic ring substituted once or more times, or unsubstituted or substituted by R124-18 membered heterocyclyl-alkyl substituted one or more times;
R6is H, C1-6Alkyl or halo C1-6An alkyl group;
m and n are each independently 0,1 or 2, provided that at least one of m and n is 1;
p is 0,1, 2,3 or 4;
q is 1 or 2;
u is 0 or 1;
s is 0,1, 2,3 or 4;
R10is halogen, -ORaOxo, -NRaRb,=NO-Rc、-C(=O)ORa、-C(O)NRaRb、-C(=O)OH、-C(=O)Ra、-C(=NORc)Ra、-C(=NRc)NRaRb、-NRdC(=O)NRaRb、-NRbC(=O)Ra、-NRdC(=NRc)NRaRb、-NRbC(=O)ORa、-OC(=O)NRaRb、-OC(=O)Ra、-OC(=O)ORaHydroxy, nitro, azido, cyano, -S (O)0-3Ra、-SO2NRaRb、-NRbSO2Ra、-NRbSO2NRaRbOR-P (= O) ORaORb；
R11Is halogen, -ORa、-NRaRb、-C(=O)ORa、-C(O)NRaRb、-C(=O)OH、-C(=O)Ra、-C(=NORc)Ra、-C(=NRc)NRaRb、-NRdC(=O)NRaRb、-NRbC(=O)Ra、-NRdC(=NRc)NRaRb、-NRbC(=O)ORa、-OC(=O)NRaRb、-OC(=O)Ra、-OC(=O)ORaHydroxy, nitro, azido, cyano, -S (O)0-3Ra、-SO2NRaRb、-NRbSO2Ra、-NRbSO2NRaRbOR-P (= O) ORaORb、C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C6-12Aryl radical, C7-16Aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl; and is
R12Is halogen, -ORaOxo, -NRaRb、=NO-Rc、-C(=O)ORa、-C(O)NRaRb、-C(=O)OH、-C(=O)Ra、-C(=NORc)Ra、-C(=NRc)NRaRb、-NRdC(=O)NRaRb、-NRbC(=O)Ra、-NRdC(=NRc)NRaRb、-NRbC(=O)ORa、-OC(=O)NRaRb、-OC(=O)Ra、-OC(=O)ORaHydroxy, nitro, azido, cyano, -S (O)0-3Ra、-SO2NRaRb、-NRbSO2Ra、-NRbSO2NRaRbOR-P (= O) ORaORb、C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C6-12Aryl radical, C7-16Aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl.
52. The compound of claim 51, wherein R1Is halogen, unsubstituted or substituted by R10Substituted one or more times by C1-4Alkyl, -C (= O) ORa、-C(O)NRaRbHydroxy, cyano or C1-3An alkoxy group.
53. The compound of claim 51 or 52, wherein p is 0.
54. The compound of claim 52, wherein R4And R4At least one of them is methyl.
55. The compound of claim 52, wherein R4And R4' is methyl.
56. The compound of any one of claims 51-55, wherein one of m and n is 1 and the other is 0.
57. The compound of any one of claims 51-55, wherein m and n are 1.
58. The compound of any one of claims 51-55, wherein X and Y are
59. The compound of any one of claims 51-55, wherein q is 2.
60. The compound of any one of claims 51-59, wherein the compound has formula (VIA):
or a pharmaceutically acceptable salt thereof, wherein
p' is each independently 0,1 or 2;
R7and R7' are each independently unsubstituted or substituted with R10Substituted one or more times by C1-8Alkyl, unsubstituted or substituted by R10Substituted one or more times by C2-8Alkenyl, unsubstituted or substituted by R10Substituted one or more times by C2-8Alkynyl, unsubstituted or substituted by R11Phenyl substituted once or many times, unsubstituted or by R11Benzyl substituted once or many times, unsubstituted or by R115-6 membered heteroaryl, unsubstituted or substituted once or many times by R116-7 membered heteroaralkyl, unsubstituted or substituted once or many times by R123-6 membered heterocyclic ring substituted once or more than once, or unsubstituted or substituted by R124-7 membered heterocyclyl-alkyl substituted one or more times; and is
R8And R8' each independently is-NRaRb、-NRdC(=O)NRaRb、-NRbC(=O)Ra、-NRdC(=NRc)NRaRb、-NRbC(=O)ORa、-NRbSO2Raor-NRbSO2NRaRbWherein R isa-RdEach independently is H, C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C6-12Aryl radical, C7-16Aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl.
61. The compound of any of claims 51-60, wherein the compound has the formula (VIB):
or a pharmaceutically acceptable salt thereof, wherein
R7And R7' are each independently unsubstituted or substituted with R10Substituted one or more times by C1-8Alkyl, unsubstituted or substituted by R10Substituted one or more times by C2-8Alkenyl, unsubstituted or substituted by R10Substituted one or more times by C2-8Alkynyl, unsubstituted or substituted by R11Phenyl substituted once or many times, unsubstituted or by R11Benzyl substituted once or many times, unsubstituted or by R115-6 membered heteroaryl, unsubstituted or substituted once or many times by R116-7 membered heteroaralkyl, unsubstituted or substituted once or many times by R123-6 membered heterocyclic ring substituted once or more than once, or unsubstituted or substituted by R124-7 membered heterocyclyl-alkyl substituted one or more times; and is
R8And R8' each independently is-NRaRb、-NRdC(=O)NRaRb、-NRbC(=O)Ra、-NRdC(=NRc)NRaRb、-NRbC(=O)ORa、-NRbSO2Raor-NRbSO2NRaRbWherein R isa-RdEach independently is H, C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C6-12Aryl radical, C7-16Aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl.
62. The compound of any one of claims 51-60, wherein the compound has formula (VIIA):
or a pharmaceutically acceptable salt thereof, wherein
p' is each independently 0,1 or 2;
R7and R7' are each independently unsubstituted or substituted with R10Substituted one or more times by C1-8Alkyl, unsubstituted or substituted by R10Substituted one or more times by C2-8Alkenyl, unsubstituted or substituted by R10Substituted one or more times by C2-8Alkynyl, unsubstituted or substituted by R11Phenyl substituted once or many times, unsubstituted or by R11Benzyl substituted once or many times, unsubstituted or by R115-6 membered heteroaryl, unsubstituted or substituted once or many times by R116-7 membered heteroaralkyl, unsubstituted or substituted once or many times by R123-6 membered heterocyclic ring substituted once or more than once, or unsubstituted or substituted by R124-7 membered heterocyclyl-alkyl substituted one or more times; and is
R8And R8' each independently is-NRaRb、-NRdC(=O)NRaRb、-NRbC(=O)Ra、-NRdC(=NRc)NRaRb、-NRbC(=O)ORa、-NRbSO2Raor-NRbSO2NRaRbWherein R isa-RdEach independently is H, C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C6-12Aryl radical, C7-16Aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl.
63. The compound of any one of claims 51-62, wherein the compound has formula (VIIB):
or a pharmaceutically acceptable salt thereof, wherein
R7And R7' are each independently unsubstituted or substituted with R10Substituted one or more times by C1-8Alkyl, unsubstituted or substituted by R10Substituted one or more times by C2-8Alkenyl, unsubstituted or substituted by R10Substituted one or more times by C2-8Alkynyl, unsubstituted or substituted by R11Phenyl substituted once or many times, unsubstituted or by R11Benzyl substituted once or many times, unsubstituted or by R115-6 membered heteroaryl, unsubstituted or substituted once or many times by R116-7 membered heteroaralkyl, unsubstituted or substituted once or many times by R123-6 membered heterocyclic ring substituted once or more than once, or unsubstituted or substituted by R124-7 membered heterocyclyl-alkyl substituted one or more times; and is
R8And R8' each independently is-NRaRb、-NRdC(=O)NRaRb、-NRbC(=O)Ra、-NRdC(=NRc)NRaRb、-NRbC(=O)ORa、-NRbSO2Raor-NRbSO2NRaRbWherein R isa-RdEach independently is H, C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C6-12Aryl radical, C7-16Aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl.
64. The compound of any one of claims 60-63, wherein R8And R8' each independently is-NRaRb、-NRbC(=O)Ra、-NRbC(=O)ORaWherein R isa-RbEach independently is H, C1-6Alkyl, phenyl, benzyl, 5-6 membered heteroaryl, 6-8 membered heteroaralkyl, 5-6 membered heterocycle, or 6-8 membered heterocycle-alkyl.
65. The compound of any one of claims 60-63, wherein R in formula (IV)8And R8' each independently is-NRbC(=O)ORaWherein R isa-RbEach independently is H, C1-6Alkyl, phenyl, tetrahydrofuran or benzyl.
66. The compound of any one of claims 60-65, wherein R7And R7' are each independently unsubstituted or substituted with R11Phenyl substituted one or more times.
67. The compound of any one of claims 60-65, wherein R7And R7' are each independently unsubstituted or substituted with R10Substituted one or more times by C1-6An alkyl group.
68. The compound of any one of claims 60-65, wherein R7And R7' are each independently methyl, ethyl, propyl, isopropyl, methoxyisopropyl, butyl, sec-butyl, tert-butyl, pentyl, 2-methylbutane, 3-methylbutane, cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl.
69. The compound of any one of claims 60-65, wherein R7And R8Or R7' and R8' together with the carbon to which they are attached are each independently:
70. the compound of any one of claims 60-69, wherein s and u are 0.
71. A compound selected from table 1B or a pharmaceutically acceptable salt thereof.
72. The compound of any one of claims 1-71 for use in the treatment or prevention of hepatitis c virus infection in a human.
73. A pharmaceutical composition comprising at least one compound of any one of claims 1-72 and at least one pharmaceutically acceptable carrier or excipient.
74. A method for treating or preventing HCV viral infection comprising contacting a biological sample or administering to a patient in need thereof an amount of a compound of any of claims 1-72 effective to treat or prevent such infection.
75. The method of claim 74, wherein HCV has genotype 1.
76. The method of claim 74, wherein HCV has genotype 1a, genotype 1b, or a combination thereof.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US61/316,988 | 2010-03-24 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HK1179266A true HK1179266A (en) | 2013-09-27 |
Family
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