Broad-spectrum antiviral compositions and methods

Abstract

New thiazole and isoquinoline containing compounds for treating and / or preventing a broad spectrum of viral infections are provided. Methods for treating and / or preventing a broad spectrum of viral infections are also provided. These compounds have shown inhibition of HCMV, influenza virus, Zika virus, BK virus and RSV replication in cell-based assays.

Description

[0001] Statement on Federally Sponsored Research

[0002] The U.S. Government has a paid-up license in this invention and the right, under limited circumstances, to require the patent owner to license others on reasonable terms as provided by the terms of Contract No. 1R44AI122488-01 awarded by the National Institute of Allergy and Infectious Diseases. Technical Field

[0003] The present application relates to compounds for preventing, treating or ameliorating viral infections.

[0004] Citation of Related Applications

[0005] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 574,067, filed on October 18, 2017, which is incorporated herein by reference in its entirety. Background Art

[0006] According to the Viral Disease Branch of the Walter Reed Army Institute of Research, non-adenoviral respiratory infections "account for 25-30% of infectious hospitalizations among troops and are the second cause of DNBI [disease and noncombat injury] among deployed troops after trauma."

[0007] Influenza A is a case in point. It contributes greatly to the military disease burden and also infects a large number of U.S. civilians each year, causing respiratory illness with severe morbidity and mortality. Each year, 5-20% of the U.S. population is infected with seasonal influenza, resulting in >200,000 hospitalizations and ~24,000 deaths. In addition, the inevitable emergence of lethal influenza A viruses poses a huge threat, and recent reports of genetic manipulation have shown the potential of influenza A as a biowarfare agent. Currently, influenza vaccines are not a solution; their effectiveness has ranged from 10-60% over the past 12 years. Marketed direct-acting antiviral therapies for influenza include viral neuraminidase (NA) inhibitors and M2 channel blockers. Other anti-influenza drugs are being evaluated in clinical trials, including repurposed antiprotozoal agents that block maturation of viral hemagglutinins by altering their glycosylation via unknown mechanisms. Currently, drugs face rapid emergence of resistance due to their direct interaction with viral proteins (direct-acting antivirals, DAAs). Replication of the viral RNA genome is highly error-prone and accompanied by reassortment of the segmented viral genome (genetic drift), and this high mutation rate (genetic drift) leads to the rapid evolution of resistant isolates that can infect like their wild-type counterparts. Therefore, there is still a significant unmet medical need for new therapeutic strategies that overcome the limitations of existing drugs. Despite minimizing the emergence of drug-resistant viruses, antiviral agents targeting a wide range of influenza subtypes still represent a major unmet public health need.

[0008] However, the need for new therapeutic agents for treating respiratory pathogens has significantly expanded beyond influenza. There are still no drugs available for the treatment of coronaviruses, such as MERS and SARS, parainfluenza viruses, or adenoviruses; and RSV infection is treated with ribavirin, which is slightly effective (virus-specific antibodies are also available, but only for preventive use). In addition, a variety of respiratory pathogens have similar symptoms, which are called influenza-like illnesses, so a single broad-spectrum drug that is effective against a variety of different pathogens would be of great use. There is still a need to develop a single drug that is effective against a broad spectrum of viruses that can cause respiratory infections - not only influenza viruses, but also coronaviruses, RSV, parainfluenza viruses, human cytomegalovirus (HCMV) and adenoviruses.

[0009] Human cytomegalovirus (HCMV) is the main cause of opportunistic infections in congenital defects and immunosuppressed individuals, and is a possible auxiliary factor in certain cancers. Organ transplant patients under immunosuppressive therapy have a high risk of viral infection; activation of latent viruses and donor or community-acquired primary infection can lead to significant complications, including transplant rejection, morbidity and death. Herpes viruses (e.g., HCMV, HSV-1), polyoma viruses (e.g., BKV and JCV), hepatitis viruses (HBV and HCV) and respiratory viruses (e.g., influenza A virus, adenovirus) are the 4 main viral categories that infect these patients. Cytomegalovirus (HCMV) is the most common post-transplant pathogen; HCMV can infect most organs, and although HCMV antiviral agents, such as ganciclovir, are available, the increase in nephrotoxic side effects and resistance rates significantly reduces the survival of transplants and patients. In addition, HCMV-mediated immune modulation can reactivate different latent viruses carried by most adults. FORGE Life Science, LLC previously disclosed thiazole-containing compounds active against HCMV replication in published patent applications WO 2016 / 077232 and WO 2016 / 077240. Summary of the invention

[0010] The present invention provides a compound having a structure shown in Formula I:

[0011]

[0012] in:

[0013] One of X1 and X2 is N and the other is S;

[0014] X3 and X4 are independently selected from C and N; and when X3 is C, it is optionally substituted with methyl, ethyl, propyl, isopropyl or n-propyl;

[0015] One of R1 and R2 is H and the other is a 5- or 6-membered aryl or cycloalkyl group having 0 to 3 ring heteroatoms independently selected from N and O and substituted with 0 to 3 groups independently selected from:

[0016] =O, C optionally substituted by -OR12 or NR7R8 1-6 Straight or branched alkyl, C optionally substituted by NR7R8 or -OR12 1-6 A straight chain or branched alkoxy group and a C optionally substituted by -R12, -OR12 or -NR7R8 3-6 Cycloalkyl,

[0017] or R1 and R2 together form a 5- or 6-membered aryl or cycloalkyl group having 0 to 3 ring heteroatoms independently selected from N and O and substituted with 0 to 3 groups independently selected from:

[0018] =O, C optionally substituted by -OR12 or NR7R8 1-6 Straight or branched alkyl, C optionally substituted by NR7R8 or -OR12 1-6 A straight chain or branched alkoxy group and a C optionally substituted by -R12, -OR12 or -NR7R8 3-6 Cycloalkyl;

[0019] R3 is selected from H, halo, -C≡CH, -C≡N, -OH, -OCF 3 、-OCHF 2 , C 1-4 Straight chain or branched alkoxy, -SO 2 (C 1-6 alkyl), -N(CH 3 ) 2 、-C(O)NH 2 、-NHSO 2 R7, -C(O)NR7R8 and a cyclic structure comprising a 5- or 6-membered aryl or a 4-, 5- or 6-membered cycloalkyl having 0 to 3 ring heteroatoms independently selected from N, O and S and substituted with 0 to 2 groups independently selected from =O, halo, C(O) optionally substituted with -OR12 or -NR7R8 1-6 Straight or branched alkyl, C optionally substituted by -NR7R8 or -OR12 1-6 Straight chain or branched alkoxy, -C(O)-C 1-6 Alkyl and -C(O)OC 1-6 alkyl;

[0020] R4 is selected from H, halo, -C≡CH, -C≡N, -OH, -OCF 3 、-OCHF 2 , C 1-4 Straight chain or branched alkoxy, -SO 2 (C 1-6 alkyl), -N(CH 3 ) 2 、-C(O)NH 2 、-NHSO 2R7, -C(O)NR7R8 and a cyclic structure comprising a 5- or 6-membered aryl or a 4-, 5- or 6-membered cycloalkyl having 0 to 3 ring heteroatoms independently selected from N, O and S and substituted with 0 to 2 groups independently selected from =O, halo, C(O) optionally substituted with -OR12 or -NR7R8 1-6 Straight or branched alkyl, C optionally substituted by -NR7R8 or -OR12 1-6 Straight chain or branched alkoxy, -C(O)-C 1-6 Alkyl and -C(O)OC 1-6 alkyl,

[0021] or the R4 group is bonded to X4 to form a 5- or 6-membered aryl or cycloalkyl group having 0 to 3 ring heteroatoms selected from N, O and S and substituted by 0 to 2 groups selected from =O, halo, C optionally substituted by -OR12 or -NR7R8 1-6 Straight or branched alkyl, C optionally substituted by -NR7R8 or -OR12 1-6 Straight chain or branched alkoxy, -C(O)-C 1-6 Alkyl and -C(O)OC 1-6 alkyl;

[0022] The conditions are:

[0023] At least one of R3 and R4 is selected from: H, halo, -C≡CH, -C≡N, -OH, -OCF 3 、-OCHF 2 , C 1-4 Straight chain or branched alkoxy, -SO 2 (C 1-6 alkyl), -N(CH 3 ) 2 、-C(O)NH 2 、-NHSO 2 R7 and -C(O)NR7R8, and

[0024] R3 and R4 are not H at the same time;

[0025] R5 is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, CF 3 , CH 2 CF 3 and halogenated;

[0026] R6 is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, CF 3 , CH 2 CF 3 , halo, cyclopropylmethyl and C1-4 Alkoxy;

[0027] In each case, R7 and R8 are independently selected from H, C 1-6 Straight or branched alkyl, C 3-6 cycloalkyl, cyclopropylmethyl, and cyclobutylmethyl; and

[0028] At each occurrence, R12 is independently selected from H and C 1-4 Straight chain or branched chain alkyl.

[0029] or a pharmaceutically acceptable salt or solvate thereof.

[0030] The compounds of the present invention are useful for treating and / or preventing viral infections. Specifically, the compounds of the present invention are broad-spectrum antiviral agents. For example, the compounds of the present invention block the replication of two very different human pathogens with considerable efficacy: the rapidly replicating orthomyxovirus influenza A virus with an RNA genome and the slowly replicating herpesvirus HCMV with a DNA genome.

[0031] The present invention also provides a method for preventing, treating and / or ameliorating HCMV infection using the compound represented by formula I. The present invention also provides a method for preventing, treating and / or ameliorating influenza virus infection using the compound represented by formula I.

[0032] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the invention belongs. Methods and materials for use in the present invention are described herein; other suitable methods and materials known in the art may also be used. The materials, methods, and examples are illustrative only and are not intended to be limiting. All patent publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In the event of a conflict, the present specification, including definitions, will prevail.

[0033] Other features and advantages of the invention will be apparent from the following detailed description and drawings, and from the claims. DETAILED DESCRIPTION

[0034] Provided herein are compounds useful for treating and / or preventing a broad range of viral infections.

[0035] Provided herein are methods for treating or preventing viral infections in subjects. In some embodiments, the methods include administering a therapeutically effective amount of one or more compounds provided herein. In some embodiments, the compounds provided herein can inhibit the production of the virus in cells infected by the virus. In these embodiments, cells are contacted with one or more compounds provided herein that inhibit the production of the virus.

[0036] Provided herein are compounds having the structure shown in Formula I:

[0037]

[0038] in:

[0039] One of X1 and X2 is N and the other is S;

[0040] X3 and X4 are independently selected from C and N; and when X3 is C, it is optionally substituted with methyl, ethyl, propyl, isopropyl or n-propyl;

[0041] One of R1 and R2 is H and the other is a 5- or 6-membered aryl or cycloalkyl group having 0 to 3 ring heteroatoms independently selected from N and O and substituted with 0 to 3 groups independently selected from:

[0042] =O, C optionally substituted by -OR12 or NR7R8 1-6 Straight or branched alkyl, C optionally substituted by NR7R8 or -OR12 1-6 A straight chain or branched alkoxy group and a C optionally substituted by -R12, -OR12 or -NR7R8 3-6 Cycloalkyl,

[0043] or R1 and R2 together form a 5- or 6-membered aryl or cycloalkyl group having 0 to 3 ring heteroatoms independently selected from N and O and substituted with 0 to 3 groups independently selected from:

[0044] =O, C optionally substituted by -OR12 or NR7R8 1-6 Straight or branched alkyl, C optionally substituted by NR7R8 or -OR12 1-6 A straight chain or branched alkoxy group and a C optionally substituted by -R12, -OR12 or -NR7R8 3-6 Cycloalkyl;

[0045] R3 is selected from H, halo, -C≡CH, -C≡N, -OH, -OCF 3 、-OCHF 2 , C 1-4 Straight chain or branched alkoxy, -SO 2 (C 1-6 alkyl), -N(CH 3 ) 2 、-C(O)NH 2 、-NHSO 2R7, -C(O)NR7R8 and a cyclic structure comprising a 5- or 6-membered aryl or a 4-, 5- or 6-membered cycloalkyl having 0 to 3 ring heteroatoms independently selected from N, O and S and substituted with 0 to 2 groups independently selected from =O, halo, C(O) optionally substituted with -OR12 or -NR7R8 1-6 Straight or branched alkyl, C optionally substituted by -NR7R8 or -OR12 1-6 Straight chain or branched alkoxy, -C(O)-C 1-6 Alkyl and -C(O)OC 1-6 alkyl;

[0046] R4 is selected from H, halo, -C≡CH, -C≡N, -OH, -OCF 3 、-OCHF 2 , C 1-4 Straight chain or branched alkoxy, -SO 2 (C 1-6 alkyl), -N(CH 3 ) 2 、-C(O)NH 2 、-NHSO 2 R7, -C(O)NR7R8 and a cyclic structure comprising a 5- or 6-membered aryl or a 4-, 5- or 6-membered cycloalkyl having 0 to 3 ring heteroatoms independently selected from N, O and S and substituted with 0 to 2 groups independently selected from =O, halo, C(O) optionally substituted with -OR12 or -NR7R8 1-6 Straight or branched alkyl, C optionally substituted by -NR7R8 or -OR12 1-6 Straight chain or branched alkoxy, -C(O)-C 1-6 Alkyl and -C(O)OC 1-6 alkyl,

[0047] or the R4 group is bonded to X4 to form a 5- or 6-membered aryl or cycloalkyl group having 0 to 3 ring heteroatoms selected from N, O and S and substituted by 0 to 2 groups selected from =O, halo, C optionally substituted by -OR12 or -NR7R8 1-6 Straight or branched alkyl, C optionally substituted by -NR7R8 or -OR12 1-6 Straight chain or branched alkoxy, -C(O)-C 1-6 Alkyl and -C(O)OC 1-6 alkyl;

[0048] The conditions are:

[0049] At least one of R3 and R4 is selected from: H, halo, -C≡CH, -C≡N, -OH, -OCF 3 、-OCHF 2 , C 1-4 Straight chain or branched alkoxy, -SO 2 (C 1-6 alkyl), -N(CH 3 ) 2 、-C(O)NH 2 、-NHSO 2 R7 and -C(O)NR7R8, and

[0050] R3 and R4 are not H at the same time;

[0051] R5 is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, CF 3 , CH 2 CF 3 and halogenated;

[0052] R6 is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, CF 3 , CH 2 CF 3 , halo, cyclopropylmethyl and C 1-4 Alkoxy;

[0053] In each case, R7 and R8 are independently selected from H, C 1-6 Straight or branched alkyl, C 3-6 cycloalkyl, cyclopropylmethyl, and cyclobutylmethyl; and

[0054] At each occurrence, R12 is independently selected from H and C 1-4 Straight chain or branched chain alkyl.

[0055] and pharmaceutically acceptable salts and solvates thereof.

[0056] The compounds represented by Formula I are useful for preventing, treating and / or ameliorating viral infections. Specifically, these compounds are broad-spectrum antiviral agents capable of treating a variety of infections caused by viruses, such as influenza virus, coronavirus, respiratory syncytial virus (RSV), parainfluenza virus, human cytomegalovirus (HCMV) and adenovirus. Specifically, the inventors have demonstrated the broad-spectrum antiviral use of the compounds represented by Formula I by demonstrating that these compounds block the replication of two very different human pathogens with considerable efficacy: the rapidly replicating orthomyxovirus influenza A virus with an RNA genome and the slowly replicating herpes virus HCMV with a DNA genome.

[0057] In some embodiments of the antiviral compound represented by Formula I,

[0058] One of R1 and R2 is H and the other is a 5- or 6-membered aryl or cycloalkyl group having 1 to 3 ring heteroatoms independently selected from N and O and substituted with 0 to 2 groups independently selected from:

[0059] =O, C optionally substituted by -OR12 or -NR7R8 1-6 Straight or branched alkyl, C optionally substituted by -NR7R8 or -OR12 1-6 straight-chain or branched alkoxy, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl and cyclohexyl,

[0060] or R1 and R2 together form a 5- or 6-membered aryl, cycloalkyl or cycloalkenyl group having 1 to 3 ring heteroatoms independently selected from N and O and substituted by 0 to 2 groups independently selected from:

[0061] =O, C optionally substituted by -OR12 or -NR7R8 1-6 Straight or branched alkyl, C optionally substituted by -NR7R8 or -OR12 1-6 Straight-chain or branched alkoxy, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0062] In some embodiments of the antiviral compound represented by Formula I, R3 is selected from:

[0063]

[0064] and-SO 2 (C 1-6 alkyl);

[0065] in:

[0066] R9 is selected from: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, C optionally substituted with -OR12 or -NR7R8 1-6 A straight chain or branched alkyl group and a C optionally substituted by -NR7R8 1-6 Straight or branched alkoxy; and

[0067] R10 and R11 are independently selected from: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, C optionally substituted with -OR12 or -NR7R8 1-4 Straight or branched alkyl, optionally substituted by NR7R8 1-4 Straight-chain or branched-chain alkoxy.

[0068] In some embodiments of the antiviral compound represented by Formula I, R4 is selected from:

[0069]

[0070] and-SO 2 (C 1-6 alkyl);

[0071] in:

[0072] R9 is selected from: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, C optionally substituted with -OR12 or -NR7R8 1-6 A straight chain or branched alkyl group and a C optionally substituted by -NR7R8 1-6 Straight or branched alkoxy; and

[0073] R10 and R11 are independently selected from: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, C optionally substituted with -OR12 or -NR7R8 1-4 Straight or branched alkyl, optionally substituted by NR7R8 1-4 Straight-chain or branched-chain alkoxy.

[0074] In some embodiments of the antiviral compound represented by Formula I,

[0075] One of R1 and R2 is H and the other is a 5- or 6-membered aryl or cycloalkyl group having at least one N ring heteroatom and 0 to 2 further ring heteroatoms independently selected from N and O and substituted with 0 to 2 groups independently selected from:

[0076] =O, C optionally substituted by -OR12 or NR7R8 1-6 Straight or branched alkyl, C optionally substituted by NR7R8 or -OR12 1-6 A straight chain or branched alkoxy group and a C optionally substituted by -R12, -OR12 or -NR7R8 3-6 Cycloalkyl.

[0077] Compounds of this embodiment include (but are not limited to):

[0078]

[0079] In some embodiments of the compounds represented by Formula I, one of R1 and R2 is H and the other is selected from:

[0080]

[0081] in:

[0082] R9 is selected from: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, C optionally substituted with -OR12 or -NR7R8 1-6 A straight chain or branched alkyl group and a C optionally substituted by -NR7R8 1-6 Straight or branched alkoxy; and

[0083] R10 and R11 are independently selected from: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, C optionally substituted with -OR12 or -NR7R8 1-4 Straight or branched alkyl, optionally substituted by NR7R8 1-4 Straight-chain or branched-chain alkoxy.

[0084] Compounds of this embodiment include (but are not limited to):

[0085]

[0086]

[0087] Some embodiments of the compound represented by Formula I are compounds represented by Formula II:

[0088]

[0089] wherein X1, X2, X3, X4, R3, R4, R5 and R6 are defined as they are for Formula I. In some embodiments of the antiviral compound represented by Formula II, R3 is selected from:

[0090]

[0091] and-SO 2 (C 1-6 alkyl);

[0092] in:

[0093] R9 is selected from: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, C optionally substituted with -OR12 or -NR7R8 1-6 A straight chain or branched alkyl group and a C optionally substituted by -NR7R8 1-6 Straight or branched alkoxy; and

[0094] R10 and R11 are independently selected from: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, C optionally substituted with -OR12 or -NR7R8 1-4 Straight or branched alkyl, optionally substituted by NR7R8 1-4 Straight-chain or branched-chain alkoxy.

[0095] In some embodiments of the antiviral compound represented by Formula II, R4 is selected from:

[0096]

[0097] and-SO 2 (C 1-6 alkyl);

[0098] in:

[0099] R9 is selected from: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, C optionally substituted with -OR12 or -NR7R8 1-6 A straight chain or branched alkyl group and a C optionally substituted by -NR7R8 1-6 Straight or branched alkoxy; and

[0100] R10 and R11 are independently selected from: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, C optionally substituted with -OR12 or -NR7R8 1-4 Straight or branched alkyl, optionally substituted by NR7R8 1-4 Straight-chain or branched-chain alkoxy.

[0101] Some embodiments of the compound represented by Formula I are compounds represented by Formula III:

[0102]

[0103] in:

[0104] R9 is selected from: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, C optionally substituted with -OR12 or -NR7R8 1-6 A straight chain or branched alkyl group and a C optionally substituted by -NR7R8 1-6 a linear or branched alkoxy group, and

[0105] X1, X2, X3, X4, R3, R4, R5, R6, R7, R8 and R12 are defined as they are for Formula I. In some embodiments of the antiviral compounds represented by Formula III, R3 is selected from:

[0106]

[0107] and-SO 2 (C 1-6 alkyl);

[0108] Wherein: R10 and R11 are independently selected from: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, C optionally substituted by -OR12 or -NR7R8 1-4 Straight or branched alkyl, optionally substituted by NR7R8 1-4 Straight-chain or branched-chain alkoxy.

[0109] In some embodiments of the antiviral compound represented by Formula III, R4 is selected from:

[0110]

[0111] and-SO2 (C 1-6 alkyl);

[0112] Wherein: R10 and R11 are independently selected from: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, C optionally substituted by -OR12 or -NR7R8 1-4 Straight or branched alkyl, optionally substituted by NR7R8 1-4 Straight-chain or branched-chain alkoxy.

[0113] Some embodiments of the compound represented by Formula I are compounds represented by Formula IV:

[0114]

[0115] in:

[0116] R10 and R11 are independently selected from: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, C optionally substituted with -OR12 or -NR7R8 1-4 Straight or branched alkyl, optionally substituted by NR7R8 1-4 a linear or branched alkoxy group, and

[0117] X1, X2, X3, X4, R3, R4, R5, R6, R7, R8 and R12 are defined as they are for Formula I. In some embodiments of the antiviral compounds represented by Formula IV, R3 is selected from:

[0118]

[0119] and-SO 2 (C 1-6 alkyl);

[0120] Wherein: R9 is selected from: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, C optionally substituted by -OR12 or -NR7R8 1-6 A straight chain or branched alkyl group and a C optionally substituted by -NR7R8 1-6 In some embodiments of the antiviral compound represented by Formula IV, R4 is selected from:

[0121]

[0122] and-SO 2 (C 1-6 alkyl);

[0123] Wherein: R9 is selected from: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, C optionally substituted by -OR12 or -NR7R8 1-6 A straight chain or branched alkyl group and a C optionally substituted by -NR7R81-6 Straight-chain or branched-chain alkoxy.

[0124] Some embodiments of the compound represented by Formula I are compounds represented by Formula V:

[0125]

[0126]

[0127] wherein X1, X2, X3, X4, R3, R4, R5 and R6 are defined as they are for Formula I. In some embodiments of the antiviral compound represented by Formula V, R3 is selected from:

[0128]

[0129] and-SO 2 (C 1-6 alkyl);

[0130] in:

[0131] R9 is selected from: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, C optionally substituted with -OR12 or -NR7R8 1-6 A straight chain or branched alkyl group and a C optionally substituted by -NR7R8 1-6 Straight or branched alkoxy; and

[0132] R10 and R11 are independently selected from: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, C optionally substituted with -OR12 or -NR7R8 1-4 Straight or branched alkyl, optionally substituted by NR7R8 1-4 Straight-chain or branched-chain alkoxy.

[0133] In some embodiments of the antiviral compound represented by Formula V, R4 is selected from:

[0134]

[0135] and-SO 2 (C 1-6 alkyl);

[0136] in:

[0137] R9 is selected from: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, C optionally substituted with -OR12 or -NR7R8 1-6 A straight chain or branched alkyl group and a C optionally substituted by -NR7R8 1-6 Straight or branched alkoxy; and

[0138] R10 and R11 are independently selected from: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, C optionally substituted with -OR12 or -NR7R8 1-4 Straight or branched alkyl, optionally substituted by NR7R8 1-4 Straight-chain or branched-chain alkoxy.

[0139] Some embodiments of the compound represented by Formula I are compounds represented by Formula VI:

[0140]

[0141] wherein X1, X2, X3, X4, R3, R4, R5 and R6 are defined as they are for Formula I. In some embodiments of the antiviral compound represented by Formula VI, R3 is selected from:

[0142]

[0143] and-SO 2 (C 1-6 alkyl);

[0144] in:

[0145] R9 is selected from: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, C optionally substituted with -OR12 or -NR7R8 1-6 A straight chain or branched alkyl group and a C optionally substituted by -NR7R8 1-6 Straight or branched alkoxy; and

[0146] R10 and R11 are independently selected from: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, C optionally substituted with -OR12 or -NR7R8 1-4 Straight or branched alkyl, optionally substituted by NR7R8 1-4 Straight-chain or branched-chain alkoxy.

[0147] In some embodiments of the antiviral compound represented by Formula VI, R4 is selected from:

[0148]

[0149] and-SO 2 (C 1-6 alkyl);

[0150] in:

[0151] R9 is selected from: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, C optionally substituted with -OR12 or -NR7R8 1-6 A straight chain or branched alkyl group and a C optionally substituted by -NR7R8 1-6Straight or branched alkoxy; and

[0152] R10 and R11 are independently selected from: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, C optionally substituted with -OR12 or -NR7R8 1-4 Straight or branched alkyl, optionally substituted by NR7R8 1-4 Straight-chain or branched-chain alkoxy.

[0153] Some embodiments of the compound represented by Formula I are compounds represented by Formula VII:

[0154]

[0155] in:

[0156] R9 is selected from: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, C optionally substituted with -OR12 or -NR7R8 1-6 A straight chain or branched alkyl group and a C optionally substituted by -NR7R8 1-6 a linear or branched alkoxy group, and

[0157] X1, X2, X3, X4, R3, R4, R5, R6, R7, R8 and R12 are defined as they are for Formula I. In some embodiments of the antiviral compounds represented by Formula VII, R3 is selected from:

[0158]

[0159] and-SO 2 (C 1-6 alkyl);

[0160] Wherein: R10 and R11 are independently selected from: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, C optionally substituted by -OR12 or -NR7R8 1-4 Straight or branched alkyl, optionally substituted by NR7R8 1-4 Straight-chain or branched-chain alkoxy.

[0161] In some embodiments of the antiviral compound represented by Formula VII, R4 is selected from:

[0162]

[0163] and-SO 2 (C 1-6 alkyl);

[0164] Wherein: R10 and R11 are independently selected from: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, C optionally substituted by -OR12 or -NR7R8 1-4Straight or branched alkyl, optionally substituted by NR7R8 1-4 Straight-chain or branched-chain alkoxy.

[0165] Some embodiments of the compound represented by Formula I are compounds represented by Formula VIII:

[0166]

[0167] in:

[0168] R10 and R11 are independently selected from: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, C optionally substituted with -OR12 or -NR7R8 1-4 Straight or branched alkyl, optionally substituted by NR7R8 1-4 a linear or branched alkoxy group, and

[0169] X1, X2, X3, X4, R3, R4, R5, R6, R7, R8 and R12 are defined as they are for Formula I. In some embodiments of the antiviral compounds represented by Formula VIII, R3 is selected from:

[0170]

[0171] and-SO 2 (C 1-6 alkyl);

[0172] Wherein: R9 is selected from: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, C optionally substituted by -OR12 or -NR7R8 1-6 A straight chain or branched alkyl group and a C optionally substituted by -NR7R8 1-6 Straight-chain or branched-chain alkoxy.

[0173] In some embodiments of the antiviral compound represented by Formula VIII, R4 is selected from:

[0174]

[0175] and-SO 2 (C 1-6 alkyl);

[0176] Wherein: R9 is selected from: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, C optionally substituted by -OR12 or -NR7R8 1-6 A straight chain or branched alkyl group and a C optionally substituted by -NR7R8 1-6 Straight-chain or branched-chain alkoxy.

[0177] Some embodiments of the compound represented by Formula I are compounds represented by Formula IX:

[0178]

[0179] wherein X1, X2, X3, X4, R3, R4, R5 and R6 are defined as they are for Formula I. In some embodiments of the antiviral compound represented by Formula IX, R3 is selected from:

[0180]

[0181] and-SO 2 (C 1-6 alkyl);

[0182] in:

[0183] R9 is selected from: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, C optionally substituted with -OR12 or -NR7R8 1-6 A straight chain or branched alkyl group and a C optionally substituted by -NR7R8 1-6 Straight or branched alkoxy; and

[0184] R10 and R11 are independently selected from: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, C optionally substituted with -OR12 or -NR7R8 1-4 Straight or branched alkyl, optionally substituted by NR7R8 1-4 Straight-chain or branched-chain alkoxy.

[0185] In some embodiments of the antiviral compound represented by Formula IX, R4 is selected from:

[0186]

[0187] and-SO 2 (C 1-6 alkyl);

[0188] in:

[0189] R9 is selected from: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, C optionally substituted with -OR12 or -NR7R8 1-6 A straight chain or branched alkyl group and a C optionally substituted by -NR7R8 1-6 Straight or branched alkoxy; and

[0190] R10 and R11 are independently selected from: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, C optionally substituted with -OR12 or -NR7R8 1-4 Straight or branched alkyl, optionally substituted by NR7R8 1-4 Straight-chain or branched-chain alkoxy.

[0191] Also provided herein is a method for treating or preventing a viral infection in a subject, comprising administering a therapeutically effective amount of a compound represented by Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, or a pharmaceutically acceptable salt or solvate thereof.

[0192] Also provided herein is a method for inhibiting virus production, comprising contacting virus-infected cells with a virus production-inhibiting amount of a compound represented by Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, or a pharmaceutically acceptable salt or solvate thereof.

[0193] Also provided herein is a method for treating or preventing HCMV infection in a subject by administering a therapeutically effective amount of a compound represented by Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, or a pharmaceutically acceptable salt or solvate thereof.

[0194] Also provided herein is a method for inhibiting HCMV production, comprising contacting HCMV-infected cells with a virus production-inhibiting amount of a compound represented by Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, or a pharmaceutically acceptable salt or solvate thereof.

[0195] Also provided herein is a method for treating or preventing influenza virus infection in a subject by administering a therapeutically effective amount of a compound represented by Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, or a pharmaceutically acceptable salt or solvate thereof.

[0196] Also provided herein is a method for inhibiting influenza virus production, comprising contacting cells infected with influenza virus with a virus production inhibiting amount of a compound represented by Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, or a pharmaceutically acceptable salt or solvate thereof.

[0197] Antiviral agents can also be administered in conjunction with the compounds and methods described herein. The agent can be any therapeutic agent useful in the treatment of viral infection, HCMV infection or influenza virus infection. For example, antiviral agents can include acyclovir, docosanol, ribavirin, interferon, etc.; cellulose acetate, carbopol and carrageenan, pleconaril, amantadine, rimantadine, fomivirsen, zidovudine, lamivudine, zanamivir, oseltamivir, brivudine, abacavir, adefovir, amprenavir, arbidol, atazanavir, lipitor, cidofovir, compavir, edouridine, efavirenz, emtricitabine, enfuvirtide, entecavir, famciclovir, fosamprenavir, foscarnet, fosfoacetic acid, ganciclovir, gardasi, ibacitabine, imunovir, iodoxuridine, imiquimod, indinavir, inosine, integrase inhibitors, lamivudine, lopinavir, loviride, mk-0518, maraviroc, morphine Guanidine, nelfinavir, nevirapine, nesavir, nucleotide and / or nucleoside analogs, oseltamivir, penciclovir, peramivir, podophyllotoxin, rimantadine, ritonavir, saquinavir, stavudine, tenofovir, tenofovir disoproxil, tipranavir, trifluridine, triazevir, tromantine, truvada, valacyclovir, valganciclovir, vicriviroc, adenosine, viramidine, zalcitabine, morpholino oligonucleotides, ribozymes, protease inhibitors, assembly inhibitors (e.g., rifampicin), zidovudine, brincidofovir, favipiravir, nitoxanide, letermovir, maribavir, CMX157, or a combination of two or more antiviral agents.

[0198] In some embodiments, the compounds provided herein can be administered before, after, or simultaneously with administration of one or more antiviral agents.

[0199] The antiviral agents provided herein, including pharmaceutically acceptable salts or solvates thereof, can be purchased commercially or prepared using known organic synthesis techniques.

[0200] The methods provided herein include the production and use of pharmaceutical compositions comprising a compound provided herein and one or more pharmaceutically acceptable carriers. Also provided herein are the compositions themselves.

[0201] Pharmaceutical compositions typically include a pharmaceutically acceptable carrier. As used herein, the language "pharmaceutically acceptable carrier" includes saline, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are compatible with pharmaceutical administration.

[0202] Pharmaceutical compositions are typically formulated to be compatible with their intended route of administration.Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), transmucosal, and rectal administration.

[0203] Methods for formulating suitable pharmaceutical compositions are known in the art, see, e.g., Remington: Science and Practice of Pharmacy , 21st edition, 2005; and Drugs and the Pharmaceutical Sciences:a Series of Textbooks and Monographs (Dekker, NY) series of books. For example, solutions or suspensions for parenteral, intradermal or subcutaneous administration may include the following components: a sterile diluent, such as water for injection, saline solution, fixed oils, polyethylene glycol, glycerol, propylene glycol or other synthetic solvents; antibacterial agents, such as benzyl alcohol or methyl parabens; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; buffers, such as acetates, citrates or phosphates; and agents for adjusting tonicity, such as sodium chloride or glucose. The pH may be adjusted with an acid or base, such as hydrochloric acid or sodium hydroxide. The parenteral formulation may be enclosed in an ampoule, disposable syringe or multiple dose vial made of glass or plastic.

[0204] Pharmaceutical compositions suitable for injection may include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL TM (BASF, Parsippany, NJ) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that there is easy injectability. The composition should be stable under production and storage conditions and must be preserved against microbial contamination, such as bacterial and fungal contamination. The carrier can be a solvent or dispersion medium containing (for example) water, ethanol, polyols (for example, glycerol, propylene glycol, liquid polyethylene glycol, etc.), a suitable mixture thereof. Suitable fluidity can be maintained, for example, by using a coating, such as lecithin, by maintaining the desired particle size and by using a surfactant in terms of a dispersion system. Prevention of microbial action can be achieved by a variety of antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. In most cases, isotonic agents, for example, sugars, polyols, such as mannitol, sorbitol and sodium chloride, will preferably be included in the composition. Extended absorption of injectable compositions can be caused by including an agent that delays absorption in the composition, for example, aluminum monostearate and gelatin.

[0205] Can prepare sterile injectable solution by mixing the compound provided herein of required amount in suitable solvent with a kind of composition or the combination of composition listed above as required after filtration sterilization.Usually, prepare dispersion system by mixing the compound provided herein in sterile vehicle, the vehicle comprises basic dispersion medium and other required components from those listed above.In the case of sterile powder for the preparation of sterile injectable solution, preferred preparation method is vacuum drying and freeze drying, it obtains the compound provided herein plus the powder of any other required components from its previous sterile-filtered solution.

[0206] Oral compositions generally include an inert diluent or an edible carrier. For the purpose of oral therapeutic administration, excipients may be incorporated into the compounds provided herein and used in the form of tablets, lozenges or capsules, for example, gelatin capsules. Oral compositions may also be prepared using fluid carriers for use as mouthwashes. Pharmaceutically compatible binders and / or adjuvant materials may be included as part of the composition. Tablets, pills, capsules, lozenges, etc. may contain any of the following ingredients or compounds with similar properties: binders, such as microcrystalline cellulose, tragacanth or gelatin; excipients, such as starch or lactose, disintegrants, such as alginic acid, Primogel or corn starch; lubricants, such as magnesium stearate or Sterotes; glidants, such as colloidal silicon dioxide; sweeteners, such as sucrose or saccharin; or flavorings, such as mint, methyl salicylate or orange flavoring.

[0207] For administration by inhalation, the compound may be delivered in the form of an aerosol spray from a pressure container or dispenser containing a suitable propellant, for example, a gas such as carbon dioxide, or a nebulizer. Such methods include those described in US Pat. No. 6,468,798.

[0208] Systemic administration of therapeutic compounds as described herein can also be by transmucosal or transdermal means.For transmucosal or transdermal administration, a suitable penetrant for the obstacle to be penetrated is used in the preparation.These penetrants are generally known in the art and for transmucosal administration, include (for example) detergents, bile salts and carboxy-chain spore acid derivatives.Transmucosal administration can be completed by using nasal sprays or suppositories.For transdermal administration, the compound provided herein can be formulated into an ointment, salves, gel or cream as generally known in the art.

[0209] The pharmaceutical compositions may also be prepared in the form of suppositories (eg, with conventional suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery.

[0210] In addition, intranasal delivery is possible, as described, inter alia, in Hamajima et al., Clin. Immunol. Immunopathol., 88(2), 205-10 (1998). Liposomes (e.g., as described in U.S. Pat. No. 6,472,375) and microencapsulation may also be used. Biodegradable targetable microparticle delivery systems (e.g., as described in U.S. Pat. No. 6,471,996) may also be used.

[0211] In one embodiment, the therapeutic compound is prepared with a carrier that will protect the therapeutic compound from rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers such as ethylene-vinyl acetate copolymers, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Standard techniques can be used to prepare or (for example) commercially obtain these preparations from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to selected cells by monoclonal antibodies against cell antigens) can also be used as drug-available carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811.

[0212] The pharmaceutical composition can be administered once, or can be divided into multiple smaller doses and administered at certain time intervals. It should be understood that accurate dosage and treatment duration are related to the disease to be treated, and can be determined empirically using known test procedures or by extrapolation of in vivo or in vitro test data. It should be noted that concentration and dosage values ​​can also vary with the severity of the condition to be alleviated. It should also be understood that for any particular patient, specific dosage administration regimens should be adjusted over time according to individual needs and the professional judgment of the personnel administering the composition or supervising the administration of the composition, and the concentration ranges described herein are only exemplary and are not intended to limit the scope or practice of the claimed composition.

[0213] Dosage forms or compositions containing a compound as described herein in a range of 0.005% to 100% with the remainder being made up of a non-toxic carrier can be prepared. Methods for preparing these compositions are known to those skilled in the art. The contemplated compositions can contain 0.001%-100% of the compound provided herein, in one embodiment, 0.1-95%, in another embodiment, 75-85%.

[0214] The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0215] As described above, the preparations of one or more compounds provided herein can be administered orally, parenterally, topically or rectally. Of course, they are administered in a form suitable for various routes of administration. For example, in the form of tablets or capsules, administered by injection, inhalation, eye wash, ointment, suppository, infusion; topically administered by lotion or ointment; and administered rectally by suppository. In some embodiments, administration is oral administration.

[0216] The phrase "parenteral administration" as used herein refers to forms of administration other than enteral and topical administration, which are usually by injection and include, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal and intrastemal injection and infusion.

[0217] Actual dosage levels of the active ingredients in the pharmaceutical compositions provided herein may be varied to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and form of administration, but is not toxic to the patient.

[0218] Based on several factors, including the dosage of the compound to be administered, the pharmacokinetic characteristics of the compound used, and the route of administration, the concentration of the compound provided herein in the available mixture of the drug will be different. In some embodiments, the composition provided herein for parenteral administration can be provided in an aqueous solution containing about 0.1-10% w / v of the compound disclosed herein together with other substances. Typical dosage ranges can include about 0.01 to about 500 mg / kg body weight per day, which is administered in 1-4 divided doses. Each divided dose can contain the same or different compounds. Based on several factors, including the preparation and route of administration of the patient's overall health and the selected compound, the dosage will be a therapeutically effective amount.

[0219] Although the dosage will vary based on the patient's symptoms, age and weight, the nature and severity of the condition to be treated or prevented, the route of administration and the form of the drug, a daily dosage of 0.01 to 2000 mg of the compound is recommended for adult patients, and this can be administered in a single dose or in divided doses. The amount of active ingredient that can be mixed with a carrier material to produce a single dosage form will generally be the amount of the compound that produces a therapeutic effect.

[0220] The exact time and / or amount of administration of the composition that will achieve the most effective results in terms of therapeutic efficacy in a given patient will depend on the activity, pharmacokinetics and bioavailability of the specific compound, the patient's physiological conditions (including age, sex, disease type and stage, general physical condition, responsiveness to a given dose and type of drug therapy), route of administration, etc. However, the above guidance can be used as the basis for fine-tuning of treatment, e.g., determining the optimal time and / or amount of administration, which will require routine experimentation at best, including monitoring the patient and adjusting the dose and / or timing.

[0221] Also provided herein is a combination therapy in which one or more other therapeutic agents are administered with a compound or a pharmaceutical composition comprising a compound provided herein. Such combination therapy may be achieved by simultaneous, sequential or separate dosage administration of the individual components of the treatment.

[0222] definition

[0223] Unless expressly stated otherwise, the terms "for example" and "such as" and their grammatical equivalents should be understood to be followed by the phrase "without limitation". As used herein, the term "about" is meant to account for variations due to experimental error. Unless expressly stated otherwise, all measurements reported herein should be understood to be modified by the term "about", whether or not the term "about" is expressly used. As used herein, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates.

[0224] As used herein, "subject" includes humans and other animals, particularly mammals. Therefore, the methods are applicable to both human therapy and veterinary applications. In some embodiments, the patient is a mammal, e.g., a primate. In some embodiments, the patient is a human.

[0225] A "therapeutically effective" amount of a compound provided herein is generally an amount sufficient to prevent, eliminate, improve or reduce symptoms of viral infection, including, but not limited to, influenza virus, coronavirus, respiratory syncytial virus (RSV), parainfluenza virus, human cytomegalovirus (HCMV) and adenovirus infection. It will be understood that for prevention, different concentrations than those for active disease treatment may be used.

[0226] The "virus production inhibition" amount of the compound provided herein is generally an amount sufficient to achieve a measurable reduction in the amount of virus produced by the cells contacted with the compound. In some embodiments, the "virus production inhibition" amount is an amount that inhibits virus production in untreated cells by at least 30%. In some embodiments, the "virus production inhibition" amount is an amount that inhibits virus production in untreated cells by at least 50%. In some embodiments, the "virus production inhibition" amount is an amount that inhibits virus production in untreated cells by at least 70%. In some embodiments, the "virus production inhibition" amount is an amount that inhibits virus production in untreated cells by at least 90%.

[0227] The terms "treatment" and "prevention" are recognized in the art and include the use of one or more compounds or pharmaceutical compositions provided herein. If applied before the clinical manifestation of an undesirable condition (e.g., a disease or other undesirable state of a subject), the treatment is preventive (i.e., it protects the subject from the occurrence of an undesirable condition). As used in the context, the term "prevention" means slowing down or preventing the onset of at least one symptom of a condition as provided herein. For example, this prevention can be carried out by the possibility of exposure to an infectious agent (e.g., a virus) or when the subject shows other symptoms indicating that a disease (e.g., a metabolic disorder or a cardiovascular disorder) may develop. Alternatively, if applied after the manifestation of an undesirable condition, the treatment is therapeutic (i.e., it is intended to alleviate, improve or stabilize an existing undesirable condition or its side effects). As used in the context, "treatment" means improving at least one symptom of a disease as provided herein.

[0228] The term "compound" as used herein is meant to include all stereoisomers, geometric isomers, and tautomers of the shown structure. Unless otherwise stated, herein, a compound identified by name or structure as a specific tautomeric form is intended to include other tautomeric forms.

[0229] In some embodiments, the compound or its salt provided herein is substantially separated. "Substantially separated" means that the compound is at least partially or substantially separated from the environment in which it is formed or detected. Partial separation can include, for example, a composition rich in the compound provided herein. Substantially separating can include a composition containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97% or at least about 99% of the compound or its salt provided herein by weight. The method for separating compounds and their salts is conventional in the art.

[0230] The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0231] The term "pharmaceutically available salt" refers to the relatively nontoxic inorganic and organic acid addition salts of the compounds provided herein. These salts can be prepared in situ during the final separation and purification of the compounds provided herein, or by reacting the compounds in the form of their free alkali with suitable organic or inorganic acids and separating the salts thus formed. Representative salts include hydrobromate, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthoate, mesylate, gluconate, lactobionate, dodecylsulfonate and amino acid salts, etc. (see, for example, Berge et al. (1977) "Pharmaceutical Salts", J.Pharm.Sci.66:1-19).

[0232] In some embodiments, the compound provided herein may contain one or more acidic functional groups and thus be able to form a drug-available salt with a drug-available base. In these cases, the term "drug-available salt" refers to the relatively nontoxic inorganic and organic base addition salts of the compound provided herein. Similarly, these salts can be prepared in situ during the final separation and purification of the compound, or by reacting the purified compound in the form of its free acid with a suitable base, such as a hydroxide, carbonate or bicarbonate of a drug-available metal cation, with ammonia or with a drug-available organic primary amine, secondary amine or tertiary amine. Representative alkali metal or alkaline earth metal salts include lithium, sodium, potassium, calcium, magnesium and aluminum salts, etc. Representative organic amines for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, etc. (see, for example, Berge et al., as above).

[0233] The term "solvate" refers to a compound that also includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. When the solvent is water, the solvate is a hydrate. The term "pharmaceutically acceptable solvate" refers to a relatively non-toxic solvate of a compound provided herein that uses a solvent that is suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit / risk ratio, within the scope of reasonable medical judgment.

[0234] As used herein, the term "alkyl" refers to straight and branched aliphatic groups having 1 to 12 carbon atoms, preferably 1-8 carbon atoms, and more preferably 1-6 carbon atoms, which are optionally substituted with 1, 2 or 3 substituents. Preferred alkyl groups include, without limitation, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl. "C 0 "Alkyl (as in "C 0 -C 3 -alkyl") is a covalent bond (such as "C 0 "hydrocarbon group). The term "lower alkyl" refers to straight and branched aliphatic groups having 1 to 6 carbon atoms. Unless otherwise specified, the term "alkyl" includes alkenyl, alkynyl and cycloalkyl.

[0235] As used herein, the term "alkenyl" refers to an unsaturated straight or branched chain aliphatic group having 2 to 12 carbon atoms, preferably 2-8 carbon atoms, and more preferably 2-6 carbon atoms, with one or more carbon-carbon double bonds, which may be optionally substituted with 1, 2 or 3 substituents. Preferred alkenyl groups include, without limitation, ethenyl, propenyl, butenyl, pentenyl and hexenyl.

[0236] The term "alkynyl" as used herein refers to an unsaturated straight or branched chain aliphatic group having 2 to 12 carbon atoms, preferably 2-8 carbon atoms, and more preferably 2-6 carbon atoms, with one or more carbon-carbon triple bonds, which may be optionally substituted with 1, 2 or 3 substituents. Preferred alkynyl groups include, without limitation, ethynyl, propynyl, butynyl, pentynyl and hexynyl.

[0237] As defined herein above, the term "heteroalkyl" refers to an alkyl group wherein one or more carbon atoms in the chain are replaced by a heteroatom selected from O, S and N.

[0238] An "aryl" group is C 6 -C 14 An aromatic moiety comprising 1 to 3 aromatic rings, which are optionally substituted. Preferably, the aryl group is C 6 -C 10 Aryl Groups. Preferred aryl groups include, without limitation, phenyl, naphthyl, anthracenyl, and fluorenyl.

[0239] "Heterocyclic radical" or "heterocycle" group is a cyclic structure with about 3 to about 8 atoms, wherein one or more atoms are selected from N, O and S. Heterocyclic radicals are optionally substituted on carbon at one or more positions. Heterocyclic radicals are also optionally substituted on nitrogen with alkyl, aryl, aralkyl, alkylcarbonyl, alkylsulfonyl, arylcarbonyl, arylsulfonyl, alkoxycarbonyl, aralkyloxycarbonyl, or independently on sulfur with oxygen or lower alkyl. Preferred heterocyclic radicals include epoxy, aziridine radicals, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, thiazolidinyl, oxazolidinyl, oxazolidinone radicals and morpholino without limitation. In some preferred embodiments, heterocyclic radicals are fused to aryl, heteroaryl or cycloalkyl groups. Examples of such fused heterocycles include tetrahydroquinoline and dihydrobenzofuran without limitation. Specifically, the scope of the term does not include compounds with adjacent ring O and / or S atoms.

[0240] As used herein, the term "heteroaryl" refers to a group having 5 to 14 ring atoms, preferably 5, 6, 9 or 10 ring atoms; having 6, 10 or 14 π electrons shared in the ring array; and each ring having 1 to 3 heteroatoms selected from N, O and S in addition to carbon atoms. "Heteroaralkyl" or "heteroarylalkyl" groups include heteroaryl groups covalently linked to an alkyl group, either of which is independently optionally substituted or unsubstituted. Preferred heteroalkyl groups include C 1 -C 6 The term "heteroarylalkyl" refers to a group of alkyl radicals having 5, 6, 9 or 10 ring atoms. Specifically, the ...

[0241] Embodiments of heterocyclic and heteroaryl groups include, but are not limited to, acridinyl, azocanyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, benzopyranyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofurano[2,3b]tetrahydrofuran, furanyl, 1H-indolyl, 1H-indazolyl, 1H-indolyl ... oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrinyl, phenazinyl, phenothiazinyl, phenoxathiol, phenoxazinyl, 2,3-diazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4- H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolyl, tetrahydroquinolyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthyl, thiazolyl, thienyl, thiathiazolyl, thiazolyl, thiaxazolyl, thiaimidazolyl, phenylthio, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl.

[0242] As used herein, when a moiety (e.g., cycloalkyl, alkyl, aryl, heteroaryl, heterocycle, urea, etc.) is described as "optionally substituted," it means that the group optionally has 1 to 4, preferably 1 to 3, more preferably 1 or 2 non-hydrogen substituents. Suitable substituents include, without limitation, halo, hydroxy, oxo (e.g., a ring -CH- substituted with oxo is -C(O)-), nitro, haloalkyl, alkyl, aryl, aralkyl, alkoxy, aryloxy, amino, amido, alkylcarbamoyl, arylcarbamoyl, aminoalkyl, acyl, carboxyl, hydroxyalkyl, alkanesulfonyl, arylsulfonyl, alkanesulfonamido, arylsulfonamido, aralkylsulfonamido, alkylcarbonyl, acyloxy, cyano, and ureido groups.

[0243] As used herein, the term "halogen" or "halo" refers to chlorine, bromine, fluorine or iodine. As used herein, the term "acyl" refers to an alkylcarbonyl or arylcarbonyl substituent. The term "acylamino" refers to an amide group attached to a nitrogen atom (i.e., R-CO-NH-). The term "carbamoyl" refers to an amide group attached to a carbonyl carbon atom (i.e., NH 2 -CO-). The nitrogen atom of the amido or carbamoyl substituent is optionally substituted. The term "sulfonylamino" refers to a sulfonamide substituent attached through a sulfur or nitrogen atom. The term "amino" refers to a NH 2 , alkylamino, arylamino and cyclic amino. The term "urea group" as used herein refers to a substituted or unsubstituted urea moiety.

[0244] The substituted part is a part in which one or more hydrogens have been independently replaced by another chemical substituent. As a non-limiting example, the substituted phenyl includes 2-fluorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluoro-phenyl, 2-fluoro-3-propylphenyl. As another non-limiting example, the substituted n-octyl includes 2,4-dimethyl-5-ethyl-octyl and 3-cyclopentyl-octyl. The methylene (-CH) substituted by oxygen to form a carbonyl-CO- 2 -) are included within the scope of this definition.

[0245] As defined above, "unsubstituted" moieties (e.g., unsubstituted cycloalkyl, unsubstituted heteroaryl, etc.) refer to moieties as defined above that do not have any optional substituents for which the definition of the moiety is otherwise provided (above). Thus, for example, although "aryl" includes phenyl and phenyl substituted with halo, "unsubstituted aryl" does not include phenyl substituted with halo.

[0246] Synthesis of the compounds of the present invention

[0247] The compounds of the present invention (compounds represented by Formula I) can be prepared using the general reaction schemes shown in the following schemes. The following abbreviations are used:

[0248] NMP, N-methyl-2-pyrrolidone; RT, room temperature; DCM, dichloromethane; DMF, N,N-dimethylformamide; THF, tetrahydrofuran; DCE, 1,2-dichloroethane; TES or TES-H, triethylsilane; TES, triethoxysilane; TFA, trifluoroacetic acid; EtOAc or EA, ethyl acetate; M, molar; TBAF, tetrabutylammonium fluoride; t-BuOH, tert-butanol; MeI, iodomethane; DMSO, dimethyl sulfoxide; MeCN, acetonitrile; XPhos, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl; MeOH, methanol; h or hrs, hours; aq., aqueous solution; DME, 1,2-dimethoxyethane; sat., saturated; atm, atmospheric pressure; Ac 2 O, acetic anhydride; conc., concentrated; eq, equivalent; DIEA, N,N-diisopropylethylamine; HATU, N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanium hexafluorophosphate N-oxide; DMA, N,N-dimethylacetamide; Pd 2 (dba) 3 , tris(dibenzylideneacetone)dipalladium(0); S-phos, dicyclohexyl(2',6'-dimethoxy[1,1'-biphenyl]-2-yl)phosphine; PE, petroleum ether; AcOK, potassium acetate; Pd(dppf)Cl 2 , [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); DMI, 1,3-dimethyl-2-imidazolidinone; prep-TLC, preparative thin layer chromatography; t-BuONa, sodium tert-butoxide; t-BuOK, potassium tert-butoxide; HMDS, hexamethyldisilazane; Pd(OAc) 2 , palladium(II) acetate; EtOH, ethanol; DEA, diethylamine; AcOH, acetic acid; BOC 2 O, di-tert-butyl dicarbonate; Et 3 N, triethylamine; Prep-HPLC, preparative HPLC; TsOH, p-toluenesulfonic acid; TBAB, tetra-n-butylammonium bromide.

[0249] Solution 1

[0250]

[0251] A base, such as n-BuLi or sec-BuLi can be reacted with 2-chloro-1,3-thiazole (2) and a suitable aromatic or heteroaromatic aldehyde or ketone represented by Formula 1 to provide compounds of general structure 3. Compounds of general structure 3 can be treated with a suitable reducing agent, such as a silane, such as triethylsilane, and an acid, such as trifluoroacetic acid to provide compounds of general structure 4. Compounds of general structure 4 can be treated with a suitable amine, such as a substituted or unsubstituted 1,2,3,4-tetrahydroisoquinoline to provide compounds of general structure 5. It will be appreciated that compounds of general structure 5 are the same as compounds represented by Formula I.

[0252] Solution 2

[0253]

[0254] A base, for example, n-BuLi or sec-BuLi or a metal, for example, Mg or Li, can be reacted with a suitable halogenated aromatic or heteroaromatic compound represented by Formula 6 (wherein X is Cl) and a compound of general structure 7 to provide a compound of general structure 8. The compound of general structure 8 can be treated with a suitable reducing agent, for example, a silane, such as triethylsilane, and an acid, such as trifluoroacetic acid to provide a compound of general structure 9. The compound of general structure 9 can be treated with a suitable amine, for example, a substituted or unsubstituted 1,2,3,9-tetrahydroisoquinoline to provide a compound of general structure 10. It will be appreciated that the compound of general structure 10 is the same as the compound represented by Formula I.

[0255] Those skilled in the art will recognize that there may be alternative synthetic routes that provide compounds represented by Formula I. The following schemes describe examples of such alternative synthetic routes, but they should not be considered limiting.

[0256] Solution 3

[0257]

[0258] In some cases, a suitable amine, for example, substituted or unsubstituted 1,2,3,4-tetrahydroisoquinoline can be reacted with 2-chloro-1,3-thiazole (2) to provide compounds of general structure 11. Compounds of general structure 11 can be reacted with a base, for example, n-BuLi or sec-BuLi and compounds of general structure 1 to provide compounds of general structure 12. Compounds of general structure 12 can be treated with a suitable reducing agent, for example, a silane, such as triethylsilane, and an acid, such as trifluoroacetic acid to provide compounds of general structure 5.

[0259] Solution 4

[0260]

[0261] In some cases, compounds of general structure 3 can be treated with a suitable amine, for example, substituted or unsubstituted 1,2,3,4-tetrahydroisoquinoline to provide compounds of general structure 12. Compounds represented by general formula 12 can be treated as described above to provide compounds represented by general formula 5.

[0262] Solution 5

[0263]

[0264] In some cases, a suitable amine, for example, a substituted or unsubstituted 1,2,3,4-tetrahydroisoquinoline can be reacted with a compound of general structure 7 to provide a compound of general structure 13. A base, for example, n-BuLi or sec-BuLi or a metal, for example, Mg or Li can be reacted with a suitable halogenated aromatic or heteroaromatic compound represented by general formula 6 (wherein X is Cl, Br or I) and a compound represented by general formula 13 to provide a compound represented by general formula 14. A compound represented by general formula 12 can be treated as described above to provide a compound represented by general formula 10.

[0265] Solution 6

[0266]

[0267] In some cases, compounds represented by Formula 8 can be reacted with suitable amines, for example, substituted or unsubstituted 1,2,3,4-tetrahydroisoquinoline to provide compounds represented by Formula 14. Compounds represented by Formula 14 can be treated as described above to provide compounds represented by Formula 10.

[0268] Methods for carrying out the above reactions and processes will be apparent to those skilled in the art based on the present disclosure or can be deduced analogously from the examples. Starting materials are commercially available or can be prepared by methods analogous to those described in the following examples.

[0269] Preparation of intermediates

[0270] Preparation of intermediate 1

[0271]

[0272] 1. A mixture of 1 (Key Organics, 15 g, 48.08 mmol), 2,4-dimethyl-1H-imidazole (13.8 g, 144.23 mmol), (S,S)-N,N'-dimethyl-1,2-diaminocyclohexane (1.37 g, 9.62 mmol), t-BuOK (16.15 g, 144.23 mmol) and CuI (4.58 g, 24.04 mmol) in NMP (150 mL) was heated at 160°C under N 2 The mixture was cooled to RT and NaHCO was added. 3 A saturated aqueous solution (50 mL) and Boc 2 O (26.2 g, 120 mmol), and the resulting mixture was stirred at RT overnight. The mixture was concentrated, and the residue was purified by chromatography on silica gel to provide material, which was purified by preparative-HPLC to provide 2 (6 g, yield 38%) as a light yellow oil. MS (ESI): C 19 H 25 N 3 O 2 Theoretical molecular weight: 327.43, m / z experimental molecular weight: 327.9 [M+H] + .

[0273] 2. To a solution of 2 (6 g, 18.35 mmol) in DCM (50 mL) was added TFA (50 mL). The resulting mixture was stirred at RT overnight, concentrated and the residue was diluted with water and washed with K. 2 CO 3 Alkalize to pH = 10, extract with DCM, wash the combined organic phase with brine, 2 SO 4 Drying, filtration and concentration of the filtrate afforded Intermediate 1 as a light yellow oil (3.4 g, yield 81.5%). MS (ESI): C 14 H 17 N 3 Theoretical molecular weight: 227.31, m / z experimental molecular weight: 227.9 [M+H] + .

[0274] Preparation of intermediate 2

[0275]

[0276] 1. To a solution of 1 (30 g, 163 mmol) in anhydrous DMF (250 mL) were added pyrazole (11.1 g, 163 mmol), Cs 2 CO 3(79.2 g, 243 mmol) and CuI (3 g, 15.8 mmol). The resulting mixture was stirred at 120 °C overnight. After cooling to RT, the residue was treated with water and extracted with EtOAc. The organic extract was washed with water, brine, and washed with anhydrous Na 2 SO 4 Drying, filtration and concentration afforded a crude oil. The crude product was purified by silica gel chromatography to afford 2 (12 g, 43%) as a yellow oil.

[0277] 2. At -78°C, N 2 To a solution of 2-chlorothiazole (8.3 g, 70 mmol) in anhydrous THF (100 mL) was added n-BuLi (28 mL, 70 mmol) dropwise. After 1 h, a solution of 2 (12 g, 70 mmol) in THF (30 mL) was added dropwise. The resulting solution was slowly heated to RT. The mixture was heated with NH 4 The reaction was diluted with Cl solution and extracted with EtOAc. The organic extracts were concentrated to afford a crude oil which was purified by silica gel chromatography to afford 3 (12.8 g, 63%) as a brown semisolid.

[0278] 3. To a solution of 3 (12.8 g, 44 mmol) in DCE (150 mL) was added TES-H (15.3 g, 132 mmol), the mixture was cooled to 0°C and TFA (50 g, 0.44 mol) was added dropwise. The resulting solution was stirred at 60°C for 4 h. The residue was concentrated and purified by silica gel chromatography to provide intermediate 2 (9.2 g, 76%) as a yellow oil.

[0279] Alternative preparation of intermediate 2

[0280] 1. 1 (18.5 g, 100 mmol), 1H-pyrazole (6.8 g, 100 mmol), Cs 2 CO 3 A mixture of 1,4-dihydro-2-nitropropene (35.9 g, 110 mmol), 18-crown-6 (1.9 g, 7.2 mmol), CuI (1.9 g, 10 mmol) in DMF (200 mL) was stirred at 80 ° C for 16 hours. The resulting mixture was cooled, filtered and concentrated, diluted with EA, washed with water, brine, and washed with Na 2 SO 4 Dry, concentrate and purify by Combi-Flash to obtain 2 as a yellow oil (9 g, yield 52%). MS (ESI): C 10 H 8 N 2 Theoretical molecular weight of O: 172, m / z experimental molecular weight: 173 [M+H] + .

[0281] 2. At -78 ° C, to a solution of 2-chlorothiazole (6.5 g, 55 mmol) in THF (250 mL), n-BuLi (25 mL, 60 mmol, 2.4 M solution in hexane) was slowly added, and the resulting mixture was stirred at -78 ° C for 1 h. At -78 ° C, a solution of 2 (8.5 g, 50 mmol) in THF (40 mL) was slowly added, and after stirring for 1 h, the reaction mixture was slowly heated to RT and stirred for 20 min. Then, saturated NH 4 The mixture was extracted with EA, and the combined extracts were washed with brine and washed with Na 2 SO 4 Dry, filter, concentrate and purify the residue by Combi-Flash to obtain 3 as a yellow solid (4.2 g, yield 29%). MS (ESI): C 13 H 10 C1N 3 Theoretical molecular weight of OS: 291, m / z experimental molecular weight: 292 [M+H] + .

[0282] 3. To a mixture of 3 (4.2 g, 14.4 mmol) and TFA (16.4 g, 144 mmol) in DCE (200 mL) was added TES (7.1 g, 43.3 mmol) at 0°C and the mixture was heated to 100°C for 16 hours. The resulting mixture was cooled to RT, washed with water, brine, and washed with Na 2 SO 4 Dry, filter, concentrate and purify by Combi-Flash to obtain the product intermediate 2 as yellow oil (2.2 g, yield 55%). MS (ESI): C 13 H 10 C1N 3 Theoretical molecular weight of S: 275.0, m / z experimental molecular weight: 276 [M+H] + .

[0283] Preparation of intermediate 3

[0284]

[0285] 1. To a solution of 1 (10 g, 80.6 mmol) in anhydrous DMF (100 mL) were added pyrazole (5.5 g, 80.6 mmol) and K 2 CO 3 (12.2 g, 88.7 mmol). The resulting mixture was stirred at 100 °C overnight. After cooling to RT, the mixture was treated with water and extracted with EA. The organic extract was washed with water, brine, and washed with anhydrous Na 2 SO 4Dry, filter and concentrate the filtrate to afford a crude oil. The crude product was purified by recrystallization to afford 2 (4 g, 29%). 1 HNMR (CDCl 3 ,300MHz)δ:6.5-6.6(s,1H),7.7-7.8(s,1H),7.9-8.0(d,2H),8.0-8.1(d,2H),8.1-8.2(s,1H),10.0-10.1(s,1H).

[0286] 2. At -78°C, N 2 To a solution of 2-chlorothiazole (1.45 g, 12.1 mmol) in anhydrous THF (10 mL) was added n-BuLi (5 mL, 12.1 mmol) dropwise. After 1 h, a solution of 2 (1.6 g, 9.3 mmol) was added dropwise at -78 °C. The resulting solution was slowly heated to RT. The mixture was heated with NH 4 The reaction was diluted with Cl solution and extracted with EA. The organic extract was concentrated to afford a crude oil. The crude product was purified by silica gel chromatography to afford 3 (1.2 g, 50%). 1 HNMR (CDCl 3 ,300MHz)δ:6.1-6.2(s,1H),6.5-6.6(s,1H),7.2-7.3(s,1H),7.4-7.5(d,2H),7.6-7.7(d,2H),7.7-7.8(s,1H),7.9-8.0(s,1H).

[0287] 3. To a solution of 3 (1.2 g, 4.1 mmol) in DCE (20 mL) was added TES-H (1.4 g, 12.8 mmol), the mixture was cooled to 0°C and TFA (4.7 g, 41 mmol) was added dropwise. The resulting solution was stirred at 60°C for 4 h. The residue was concentrated and purified by silica gel chromatography to provide intermediate 3 (1 g, 91%). 1 HNMR (CDCl 3 ,300MHz)δ:4.1-4.2(s,2H),6.4-6.5(s,1H),7.2-7.4(m,3H),7.6-7.8(m,3H),7.9-8.0(s,1H).

[0288] Alternative preparation of intermediate 3

[0289] 1. At -78°C, N 2To a solution of 2-chlorothiazole (3.85 g, 32.3 mmol) in anhydrous THF (80 mL) was added n-BuLi (14.3 mL, 35.5 mmol) dropwise at -78 °C. After 1 h, a solution of 2 (5.0 g, 29.1 mmol) in THF (40 mL) was added dropwise at -78 °C. The resulting solution was slowly heated to RT. The mixture was heated with NH 4 The reaction was diluted with Cl solution and extracted with EtOAc. The organic extract was concentrated to afford a crude oil. The crude product was purified by silica gel chromatography to afford 3 (5.9 g, 69.7%) as a light brown oil.

[0290] 2. To a solution of 3 (5.9 g, 20.3 mmol) in DCE (20 mL) was added TES-H (7.06 g, 60.9 mmol), the mixture was cooled to 0°C and TFA (22.8 g, 0.2 mol) was added dropwise. The resulting solution was stirred at 60°C for 4 h. The residue was concentrated and purified by silica gel chromatography to provide intermediate 3 (4.84 g, 86.9%) as a white solid.

[0291] Alternative preparation of intermediate 3

[0292] 1. 4-bromobenzaldehyde (100.0 g, 540 mmol), 1H-pyrazole (37 g, 540 mmol), Cs 2 CO 3 A mixture of 1,4-dihydro-1-(2-(2-hydroxy-1-methyl-2-oxo-1-yl)-4-nitropropene (194 g, 594 mmol), CuI (10.3 g, 54 mmol), 18-crown-6 (11 g, 41 mmol) in DMF (500 mL) was stirred at 80° C. for 24 hours under e. After cooling to room temperature, ice-water was added to the mixture, which was then extracted with EA. The organic extract was washed with water, brine and Na 2 SO 4 Dry, filter and concentrate. The resulting residue was purified by column chromatography on silica gel to provide 2 as a white solid (76 g, yield 81.7%). MS (ESI): C 10 H 8 N 2 Theoretical molecular weight of O: 172.18, m / z experimental molecular weight: 173.0 [M+H] + .

[0293] 2. To a solution of 2-chlorothiazole (54.2 g, 0.45 mol) in anhydrous (550 mL) was added n-BuLi (187.5 mL, 2.4 M, 0.45 mol) dropwise at -78°C. The mixture was stirred at -78°C for 1 hour and a solution of 2 (65 g, 0.38 mol) in THF (700 mL) was added dropwise at -78°C. The resulting solution was slowly heated to room temperature. The mixture was heated with NH 4The reaction mixture was quenched with a saturated aqueous solution of Cl and extracted with EA. The organic extract was washed with brine and washed with Na 2 SO 4 Dry, filter and concentrate. The resulting residue was purified by column chromatography on silica gel to provide 3 as a yellow solid (90 g, yield 82.6%). MS (ESI): C 13 H 10 C1N 3 Theoretical molecular weight of OS: 291.76, m / z experimental molecular weight: 291.7 [M+H] + .

[0294] 3. To a solution of 3 (66 g, 0.23 mol) in TFA (330 mL) was added TES (148 g, 0.9 mol) at room temperature. The reaction mixture was stirred at reflux for 1 h. The mixture was evaporated and diluted with EA. The mixture was washed with saturated NaHCO 3 , brine and Na 2 SO 4 Dry, filter and concentrate. The resulting residue was purified by column chromatography on silica gel to provide intermediate 3 as a yellow solid (55 g, yield 88.7%). MS (ESI): C 13 H 10 C1N 3 Theoretical molecular weight of S: 275.76, m / z experimental molecular weight: 275.8 [M+H] + .

[0295] Preparation of intermediate 4

[0296]

[0297] 1. 7-Bromo-1,2,3,4-tetrahydroisoquinoline hydrochloride (Key Organics, 250 mg, 1 mmol), intermediate 2 (276 mg, 1 mmol) and K 2 CO 3 A mixture of (414 mg, 3 mmol) in DMSO (5 mL) was stirred at 140 °C for 2 hours. Then, it was cooled to RT, poured into water, neutralized with 3N HCl, and extracted with EtOAc. The combined organic phases were washed with brine and washed with Na 2 SO 4 Dry, filter, concentrate and purify the resulting residue by chromatography on silica gel to provide intermediate 4 as an off-white solid (200 mg, yield 44%). MS (ESI): C 22 H 19 Bn 4Theoretical molecular weight of S: 451.39, m / z experimental molecular weight: 450.7452.7 [M+H] + .

[0298] Preparation of intermediate 5

[0299]

[0300] 1. Intermediate 3 (1.0 g, 3.6 mmol), Cs 2 CO 3 A mixture of 7-bromo-1,2,3,4-tetrahydroisoquinoline (Key Organics, 848 mg, 4.0 mmol) in DMSO (25 mL) was stirred at 140 °C for 2 h under nitrogen atmosphere. After cooling to RT, ice-water was added to the mixture, which was then extracted with EtOAc. The organic extract was washed with water, brine and Na 2 SO 4 Dry, filter and concentrate. The resulting residue was purified by column chromatography on silica gel to provide intermediate 5 (1.0 g, yield 61.3%) as a yellow solid. MS (ESI): C 22 H 19 Bn 4 Theoretical molecular weight of S: 451.38, m / z experimental molecular weight: 450.7 [M+H] + .

[0301] Preparation of intermediate 6

[0302]

[0303] 1. At -78°C, N 2 To a solution of 2-chlorothiazole (5.76 g, 48 mmol) in anhydrous THF (40 mL) was added n-BuLi (2.4 M, 20.0 mL, 48 mmol) dropwise. After 1 h, a solution of 4-bromobenzaldehyde (7.40 g, 40 mmol) in THF (40 mL) was added dropwise. The mixture was slowly heated to RT and stirred overnight. NH 4 The mixture was quenched with a saturated aqueous solution of Cl and extracted with EtOAc. The combined extracts were washed with brine and washed with Na 2 SO 4 Dry, filter, concentrate and purify the resulting residue by chromatography on silica gel to afford 1 (8.00 g, 66% yield) as a yellow oil. MS (ESI): C 10 H 7 Theoretical molecular weight of BrClNOS: 304.59, m / z experimental molecular weight: 305.7 [M+H] + .

[0304] 2. A mixture of 1 (8.00 g, 26.4 mmol) and TES (18 mL) in TFA (50 mL) was stirred at RT for 2 h, concentrated and washed with NaHCO 3 The residue was diluted with saturated aqueous solution of . The mixture was extracted with DCM and the combined organic extracts were washed with brine and washed with Na 2 SO 4 Dry, filter, concentrate and purify the residue by chromatography on silica gel to afford intermediate 6 as a brown oil (7.20 g, yield 94.7%). MS (ESI): C 10 H 7 Theoretical molecular weight of BrClNS: 288.59, m / z experimental molecular weight: 289.6 [M+H] + .

[0305] Preparation of intermediate 7

[0306]

[0307] 1. At -78°C, N 2 To a solution of 1 (20 g, 71.9 mmol) in anhydrous THF (100 mL) was added n-BuLi (31.7 mL, 79.1 mmol) dropwise. After 1 h, DMF (1.66 g, 79.1 mmol) was added dropwise at -78 °C. The resulting solution was slowly heated to RT. NH 4 The reaction was quenched with Cl solution and extracted with EA. The combined extracts were concentrated to afford a crude oil. The crude product was purified by silica gel chromatography to afford 2 (12 g, 73.5%).

[0308] 2. To a solution of 2 (12 g, 52.9 mmol) in anhydrous DMF (200 mL) were added 1H-pyrazole (4.0 g, 58.1 mmol), Cs 2 CO 3 (19 g, 58.1 mmol), CuI (1.2 g), 18-crown-6 (1.2 g) and the resulting mixture was stirred at 80 ° C for 24 h. The mixture was cooled to RT, diluted with water and extracted with EA. The combined organic layers were washed with water, brine, and washed with anhydrous Na 2 SO 4 Drying, filtration and concentration afforded a crude oil. The crude product was purified by recrystallization to afford 3 (7.3 g, 64.5%).

[0309] 3. At -78°C, N 2To a solution of 2-chlorothiazole (4.47 g, 37.5 mmol) in anhydrous THF (100 mL) was added n-BuLi (15 mL, 37.5 mmol) dropwise. After 1 h, a solution of 3 (7.3 g, 34.1 mmol) was added dropwise at -78 °C. The resulting mixture was slowly heated to RT. NH 4 The reaction was quenched with Cl solution and extracted with EA. The organic layer was concentrated to afford a crude oil. The crude product was purified by silica gel chromatography to afford 4 (4.6 g, 40.3%).

[0310] 4. To a solution of 4 (4.6 g, 13.8 mmol) in DCE (40 mL) was slowly added TFA (10.4 mL, 138 mmol), TES (6.6 mL, 41.3 mmol) at 0°C. The resulting solution was stirred at RT for 3 h. 2 The reaction was quenched with 0 and extracted with DCM. The combined extracts were concentrated to afford a crude oil which was purified by silica gel chromatography to afford intermediate 7 (1.8 g, 41.1%). 1 HNMR (CDCl 3 ,300MHz)δ:1.2-1.3(d,6H),2.9-3.0(m,1H),4.1-4.2(s,2H),6.4-6.5(s,1H), 7.0(s,1H),7.3-7.4(d,2H),7.4-7.5(s,1H),7.7-7.8(s,1H),7.9-8.0(s,1H).

[0311] Preparation of intermediate 9

[0312]

[0313] 1. 1 (Key Organics, 500 mg, 1.60 mmol), (trimethylsilyl)acetylene (236 mg, 2.40 mmol), Pd(PPh 3 ) 2 Cl 2 (140 mg, 0.20 mmol), CuI (60.8 mg, 0.32 mmol) and Et 3 A mixture of N (485 mg, 4.80 mmol) in anhydrous DMF (5.00 mL) was stirred at 60 °C for 1 h. The reaction was quenched with water and extracted with EtOAc. The combined organic layers were washed with water and brine, and washed with Na 2 SO 4 Drying and concentration gave a crude product which was purified by silica gel chromatography to afford 2 (494 mg, 94% yield) as a yellow oil.

[0314] 2. To a solution of 2 (494 mg, 1.50 mmol) in THF was added TBAF (1 M solution in THF, 10 mL) and stirred at RT for 6 h. The mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with water and brine and washed with Na 2 SO 4 Dried and concentrated.The residue was purified by silica gel column chromatography (petroleum ether / EtOAc=20 / 1) to afford 3 (280 mg, 73%) as a yellow solid.

[0315] 3. 3 (280 mg, 1.09 mmol), iodomethane (155 mg, 1.09 mmol), NaN 3 (84.5mg, 1.30mmol), CuI (207mg, 1.09mmol), t-BuOH (658mg, 8.89mmol) and H 2 A mixture of 1,2-dihydro-1,4-dihydro-2-nitropropene (2,4-dihydro-1,4-dihydro-2-nitropropene) (1.96 g, 109 mmol) was stirred at 100 °C overnight in a sealed tube. The mixture was cooled, quenched with water and extracted with EtOAc. The combined organic layers were washed with water and brine and washed with Na 2 SO 4 Drying and concentration gave a crude product, which was purified by silica gel column chromatography to afford 4 (171 mg, yield 50%) as a colorless solid.

[0316] 4. A mixture of 4 (171 mg, 0.54 mmol), HCl-dioxane (4M, 3.00 mL, 12.0 mmol) and DCM (3.00 mL) was stirred at RT for 2 h. The mixture was concentrated to afford intermediate 9 (100 mg, yield 74%) as an off-white solid.

[0317] Alternative preparation of intermediate 9

[0318]

[0319] 1. To a solution of intermediate 10 (2.5 g, 8.3 mmol) in DMF (20 mL) was added K 2 CO 3 (2.3 g, 16.6 mmol). The resulting mixture was stirred at 0 °C for 2 h, and MeI (2.6 mL) was added, and the mixture was stirred at RT for 4 h. The mixture was treated with water and extracted with EA. The combined extracts were washed with water, brine, and washed with anhydrous Na 2 SO 4 Drying, filtration and concentration afforded a crude oil. The crude product was purified by silica gel to afford 2 (1.4 g, 54%).

[0320] 2. To a solution of 2 (1.4 g) in anhydrous DMF (20 mL) was added HCl / ether (5 mL, 3 M) at 0°C. The resulting solution was slowly heated to RT and stirred overnight. The reaction was concentrated to afford intermediate 9 (1 g, 78%).

[0321] Preparation of intermediate 10

[0322]

[0323] 1. To a solution of compound 3 (4.6 g, 17.9 mmol) from the preparation of intermediate 9 in DMSO (40 mL) was added NaN 3 (1.4 g, 21.5 mmol) and NH 4 Cl (1.44 g, 26.8 mmol). The resulting solution was stirred at 70 °C overnight. The mixture was treated with water and extracted with EA. The combined extracts were washed with water, brine, and washed with anhydrous Na 2 SO 4 Drying, filtration and concentration afforded a crude oil. The crude product was purified by silica gel to afford 2 (3.4 g, 62.2%).

[0324] 2. To a solution of 2 (3.4 g) in anhydrous DMF (20 mL) was added HCl / ether (10 mL, 3 M) at 0°C. The resulting solution was slowly heated to RT and stirred overnight. The reaction was concentrated to provide intermediate 10 (1.76 g, 57.1%).

[0325] Preparation of intermediate 11

[0326]

[0327] 1. In 3 min, add 1 (1 g, 15 mmol) and K 2 CO 3 To a slurry of (3.1 g, 22.5 mmol) in MeCN (10 mL) was added a solution of 1-bromo-2-methoxyethane (2.5 g, 18 mmol) in MeCN (10 mL). The reaction mixture was stirred at RT for 2 h. The mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel chromatography to provide 2 (0.66 g, 35%) as a yellow oil.

[0328] 2. To a solution of 3 (Key Organics, 312 mg, 1 mmol) in DMF (6 mL) was added 2 (127 mg, 1 mmol), Pd(OAc) 2 (11 mg, 0.05 mmol), XPhos (48 mg, 0.1 mmol) and K 2 CO 3(276 mg, 2 mmol). The mixture was stirred at N 2 The mixture was heated to 100°C and stirred for 20 h. The reaction was quenched with water and extracted with EtOAc. The combined extracts were concentrated and the residue was purified by silica gel chromatography to provide 4 (0.108 g, 30%) as a yellow oil.

[0329] 3. To a solution of 4 (108 mg, 0.3 mmol) in MeOH (10 mL) was added HCl / dioxane (4 mL, 16 mmol). The mixture was stirred at RT for 3 h. The mixture was concentrated to afford intermediate 11 (100 mg, 100%).

[0330] Preparation of intermediate 12

[0331]

[0332] 1. To a solution of 1 (Key Organics, 160 mg, 0.5 mmol) in DMF (3 mL) was added Cs 2 CO 3 (165 mg, 0.5 mmol), imidazole (68 mg, 1 mmol), CuI (10 mg, 0.05 mmol). The mixture was heated to 100 °C and heated under N 2 The mixture was poured into water and extracted with EtOAc. The extract was washed with water and brine and then with Na 2 SO 4 Drying, filtration and concentration afforded 2 (168 mg, 90%).

[0333] 2. A mixture of 2 (160 mg, 0.53 mmol) and HCl / dioxane (3 mL, 12 mmol) was stirred at RT for 2 h. The mixture was concentrated to afford intermediate 12 (106 mg, 90%).

[0334] Preparation of intermediate 13

[0335]

[0336] 1. Intermediate 13 was prepared according to the procedure described for intermediate 12, except that 2-N-BOC-6-bromo-1,2,3,4-tetrahydroisoquinoline 1 (Bioorg. & Med. Chem. Lett. 2018, 28, 3050) was used instead of 2-N-BOC-7-bromo-1,2,3,4-tetrahydroisoquinoline.

[0337] Preparation of intermediate 14

[0338]

[0339] 1. Compound 3 (650 mg, 2.53 mmol) from the preparation of intermediate 9, 1-iodo-2-methoxyethane (471 mg, 2.53 mmol), NaN 3 (164 mg, 2.53 mmol), CuI (482 mg, 2.53 mmol), t-BuOH (748 mg, 10.1 mmol) and H 2 A mixture of 1,2-dihydro-1,4-dihydro-2-nitropropene (2,4-dihydro-1,4-dihydro- ... 2 SO 4 Drying and concentration gave a crude product which was purified by silica gel chromatography to afford 2 (350 mg, 39%) as an off-white solid.

[0340] 2. 2 (350 mg, 0.98 mmol), HCl-dioxane (4 M, 5 mL, 20.0 mmol) and CH 2 Cl 2 The mixture of 1H-Butyl pyrrolidone (10 mL) was stirred at RT for 2 h. The mixture was concentrated to afford Intermediate 14 (260 mg, 90%) as a white solid.

[0341] Preparation of intermediate 15

[0342]

[0343] 1. A mixture of 1 (Key Organics, 1.00 g, 3.20 mmol), (S,S)-N,N'-dimethyl-1,2-diaminocyclohexane (91.0 mg, 0.64 mmol), 4-methyl-1H-imidazole (525 mg, 6.39 mmol), CuI (304 mg, 1.60 mmol) and t-BuOK (1.07 g, 9.60 mmol) in DMF (5 mL) was stirred at 120° C. for 4 h. After cooling to RT, the mixture was directly purified by prep-HPLC to afford 2 (320 mg, 31% yield) as an off-white solid.

[0344] 2. 2 (220 mg, 0.70 mmol), HCl-dioxane (4 M, 3.00 mL, 12.0 mmol) and CH 2 Cl 2 The mixture of 1H-Butyl pyrrolidone (3 mL) was stirred at RT for 2 h. The mixture was concentrated to afford Intermediate 15 (150 mg, yield 86%) as an off-white solid.

[0345] Preparation of intermediate 16

[0346]

[0347] 1. 1 (J. Med. Chem. 42, 1, 118-134, 750 mg), intermediate 2 (908 mg, 3.29 mmol), Pd 2 (dba) 3 A mixture of 4-nitropropene (290 mg, 0.33 mmol), SPhos (132 mg, 0.33 mmol), t-BuOK (750 mg, 6.70 mmol) and dioxane (10 mL) was stirred at 100 °C for 4 h. The mixture was quenched with water and extracted with EtOAc. The combined organic extracts were washed with water and brine and washed with Na 2 SO 4 Dried and concentrated. The residue was purified by column chromatography to afford 2 (550 mg, 37% yield for 2 steps) as a yellow solid.

[0348] 2. 2 (550 mg, 1.28 mmol), LiOH (61.0 mg, 2.56 mmol), MeOH (3 mL) and H 2 The mixture of 4-nitropropene (2-nitropropene) and 4-nitropropene (2-nitropropene) (3 mL) was stirred at RT for 3 h. The mixture was acidified to pH 4-5 with 2N HCl, which resulted in a precipitate. The precipitate was filtered, washed with water and dried to provide 3 (170 mg, 32% yield) as an off-white solid.

[0349] 3. 3 (170 mg, 0.41 mmol), HATU (250 mg, 0.62 mmol), DIEA (280 mg, 2.17 mmol), NH 4 A mixture of Cl (134 mg, 2.5 mmol) and DMF (2 mL) was stirred at RT for 4 h. The mixture was quenched with water and extracted with EtOAc. The combined organic extracts were washed with water and brine and washed with Na 2 SO 4 Dried and concentrated. The residue was purified by prep-TLC to afford intermediate 16 (130 mg, yield 76%) as a yellow solid.

[0350] Preparation of intermediate 17

[0351]

[0352] 1. To a solution of 1 (J. Med. Chem. 42, 1, 118-134, 227 mg, 1 mmol) in dioxane (20 mL) were added intermediate 3 (300 mg, 1.1 mmol), Pd 2 (dba) 3(72 mg, 0.08 mmol), SPhos (65 mg, 0.16 mmol) and t-KOBu (340 mg, 3 mmol). The mixture was heated to 100 °C and heated under N 2 The mixture was stirred at 40 ℃ for 20 hours. The mixture was cooled to RT and LiOH (0.4 g, 10 mmol) and water (4 mL) were added. The resulting mixture was stirred at 60 ℃ for 2 hours, cooled, and acidified to pH ≈ 5 with 1N HCl. The resulting mixture was extracted with EtOAc and the organic extract was concentrated to provide a crude oil. The crude product was purified by silica gel chromatography to provide 2 (0.31 g, 74%) as a light yellow solid.

[0353] 2. To a solution of 2 (50 mg, 0.12 mmol) in DMF (2 mL) were added DIEA (25 mg, 0.18 mmol), HATU (0.69 g, 0.18 mmol) and NH 4 Cl (7.1 mg, 0.13 mmol). The mixture was stirred at RT for 1 h. The mixture was treated with water and extracted with EtOAc. The organic extract was washed with water, brine, and washed with anhydrous Na 2 SO 4 Drying, filtration and concentration afforded a crude oil. The crude product was purified by silica gel chromatography to afford Intermediate 17 (11.2 mg, 22.4%) as a white solid.

[0354] Preparation of intermediate 18

[0355]

[0356] 1. To a solution of 1 (20 g, 108.1 mmol) in anhydrous DMF (200 mL) were added 1H-imidazole (8.1 g, 118.9 mmol), Cs 2 CO 3 (38.7 g, 118.9 mmol), CuI (2 g), 18-crown-6 (2 g). The resulting solution was stirred at 80 °C for 24 h. The mixture was cooled to RT, treated with water and extracted with EA. The combined extracts were washed with water and brine and washed with anhydrous Na 2 SO 4 Drying, filtration and concentration afforded a crude oil. The crude product was purified by recrystallization to afford 2 (11 g, 59.2%).

[0357] 2. At -78°C, N 2 To a solution of 2-chlorothiazole (3.8 g, 32 mmol) in anhydrous THF (50 mL) was added n-BuLi (14 mL, 34.9 mmol) dropwise. After 1 h, a solution of 2 (5 g, 29.1 mmol) was added dropwise at -78 °C. The resulting solution was slowly heated to RT. NH4 The reaction was quenched with Cl solution and extracted with EA. The combined extracts were concentrated to afford a crude oil. The crude product was purified by silica gel chromatography to afford 3 (3.5 g, 41.4%).

[0358] 3. To a solution of 3 (3.5 g, 12.0 mmol) in DCE (60 mL) was slowly added TFA (9 mL, 120 mmol) and TES (5.8 mL, 36 mmol) at 0°C. The resulting solution was stirred at RT for 3 h. 2 The reaction was quenched with 0 and extracted with DCM. The organic layer was concentrated to afford a crude oil, which was purified by silica gel chromatography to afford intermediate 18 (1.8 g, 54.4%).

[0359] Preparation of intermediate 19

[0360]

[0361] 1. To a solution of 1 (6.20 g, 50 mmol) and 2,4-dimethyl-1H-imidazole (7.20 g, 75 mmol) in DMF (100 mL) was added Cs 2 CO 3 (48.70 g, 150 mmol). The resulting mixture was stirred at 120 °C for 2 h. It was cooled to RT, filtered and the filtrate was poured into water and washed with CH 2 Cl 2 Extraction, washing the combined organic phase with brine, 2 SO 4 Dry, filter and concentrate. The residue was purified by chromatography on silica gel to provide 2 (1.80 g, yield 18%) as a brown oil. MS (ESI): C 12 H 12 N 2 Theoretical molecular weight of O: 200.24, m / z experimental molecular weight: 200.9 [M+H] + .

[0362] 2. At -78°C, N 2 To a solution of 2-chlorothiazole (1.20 g, 10 mmol) in THF (20 mL) was added n-BuLi (2.4 M, 5.5 mL) dropwise. After 1 h, a solution of 2 (1.80 g, 9 mmol) in THF (20 mL) was added dropwise. The reaction was slowly heated to RT and stirred overnight. 4 The mixture was quenched with saturated aqueous Cl and extracted with EtOAc, and the combined organic phases were washed with brine and washed with Na 2 SO 4Dry, filter and concentrate. The residue was purified by chromatography on silica gel to afford 3 (1.83 g, 64% yield) as a yellow oil. MS (ESI): C 15 H 14 C1N 3 Theoretical molecular weight of OS: 319.81, m / z experimental molecular weight: 319.8 [M+H] + .

[0363] 3. A mixture of 3 (1.83 g, 5.7 mmol), TES (9 mL) in TFA (18 mL) was stirred at 60 °C for 3 h. Then, it was concentrated and washed with NaHCO 3 The residue was diluted with saturated aqueous solution of CH 2 Cl 2 Extraction, washing the combined organic phase with brine, 2 SO 4 Dry, filter, concentrate and purify the residue by chromatography on silica gel to afford intermediate 19 as a brown oil (1.20 g, yield 69.0%). MS (ESI): C 15 H 14 C1N 3 Theoretical molecular weight of S: 303.81, m / z experimental molecular weight: 303.8 [M+H] + .

[0364] Preparation of intermediate 20

[0365]

[0366] 1. 1 (Key Organics, 5.68 g, 0.018 mol), oxazolidin-2-one (4.7 g, 0.054 mol), Pd 2 (dba) 3 A mixture of 4-(4-(2-nitro-1-yl)-2-nitropropene (8.23 g, 0.009 mol), S-phos (3.69 g, 0.009 mol) and t-BuOK (6.0 g, 0.054 mol) in anhydrous 1,4-dioxane (150 mL) was stirred at 100 ° C overnight. The reaction mixture was cooled to RT, filtered and concentrated to provide a crude product. The residue was purified by silica gel chromatography to provide 2 (5.02 g, yield 88%) as a yellow solid. MS (ESI): C 17 H 22 N 2 O 4 Theoretical molecular weight: 318.37, m / z experimental molecular weight: 340.8 [M+H] + .

[0367] 2. To a solution of 2 (5.02 g, 16 mmol) in DCM (100 mL) was added TFA (25 mL). The reaction was stirred at RT for 6 h. Then, the reaction was concentrated to provide a crude product. It was dissolved in DCM and diluted with petroleum ether. The resulting suspension was filtered and the filter cake was washed with petroleum ether and dried to provide intermediate 20 (3.50 g, 70%), MS (ESI): C 14 H 15 F 3 N 2 O 3 Theoretical molecular weight: 316.28, m / z experimental molecular weight: 218.9 [M+H] + .

[0368] Preparation of intermediate 21

[0369]

[0370] 1. At -78°C, N 2 To a solution of 2-chlorothiazole (5.76 g, 48 mmol) in anhydrous THF (200 mL) was added n-BuLi (2.4 M, 25.0 mL, 60 mmol) dropwise. After 0.5 h, a solution of 1 (8.00 g, 43 mmol) in THF (50 mL) was added dropwise. The reaction was slowly heated to RT. NH 4 The mixture was quenched with saturated aqueous Cl and extracted with EtOAc and the combined organic phases were washed with brine and washed with Na 2 SO 4 Drying, filtration and concentration afforded the crude product, which was purified by chromatography on silica gel to afford 2 as a yellow oil (8.50 g, yield 64%). MS (ESI): C 10 H 7 Theoretical molecular weight of BrClNOS: 304.59, m / z experimental molecular weight: 305.7 [M+H] + .

[0371] 2. A mixture of 2 (8.50 g, 27.9 mmol) in TES (20 mL) and TFA (60 mL) was stirred at 60 °C for 2 h. The mixture was concentrated and washed with NaHCO 3 The residue was diluted with saturated aqueous solution and extracted with DCM and the combined organic phases were washed with brine and washed with Na 2 SO 4 Drying, filtration and concentration afforded a crude product which was purified by chromatography on silica gel to afford 3 as a brown oil (7.00 g, yield 86.9%). MS (ESI): C 10 H 7Theoretical molecular weight of BrClNS: 288.59, m / z experimental molecular weight: 289.6 [M+H] + .

[0372] 3. To a solution of 3 (3.00 g, 10.4 mmol) in DMSO (30 mL) were added intermediate 20 (3.45 g, 10.4 mmol) and K 2 CO 3 (4.31 g, 31.2 mmol). The reaction mixture was stirred at 140 °C for 3 h. The reaction mixture was cooled to RT, poured into ice-water, and washed with CH 2 Cl 2 Extraction, washing the combined organic phase with brine, 2 SO 4 Drying, filtration, concentration and purification by chromatography on silica gel afforded intermediate 21 as a yellow solid (2.10 g, yield 42.9%). MS (ESI): C 22 H 20 Bn 3 O 2 Theoretical molecular weight of S: 470.39, m / z experimental molecular weight: 470.5 [M+H] + .

[0373] Preparation of intermediate 22

[0374]

[0375] 1. At -78°C, N 2 To a solution of 2-chlorothiazole (5.76 g, 48 mmol) in anhydrous THF (40 mL) was added n-BuLi (2.4 M, 20.0 mL, 48 mmol) dropwise. After 1 h, a solution of 1 (7.40 g, 40 mmol) in THF (40 mL) was added dropwise. The reaction mixture was slowly heated to RT and stirred overnight. Then, NH 4 It was quenched with saturated aqueous Cl and extracted with EtOAc and the combined organic phases were washed with brine and washed with Na 2 SO 4 Dry, filter, concentrate and purify by chromatography on silica gel to afford 2 as a yellow oil (8.00 g, 66% yield). MS (ESI): C 10 H 7 Theoretical molecular weight of BrClNOS: 304.59, m / z experimental molecular weight: 305.7 [M+H] + .

[0376] 2. A mixture of (4-bromophenyl)(2-chlorothiazol-5-yl)methanol (8.00 g, 26.4 mmol) and TES (18 mL) in TFA (50 mL) was stirred at RT for 2 hours. Then, it was concentrated and washed with NaHCO 3 The residue was diluted with saturated aqueous solution of , extracted with DCM and the combined organic phases were washed with brine and washed with Na 2 SO 4 Drying, filtration, concentration and purification by chromatography on silica gel afforded 3 as a brown oil (7.20 g, yield 94.7%). MS (ESI): theoretical molecular weight of C10H7BrClNS: 288.59, m / z experimental molecular weight: 289.6 [M+H] + .

[0377] 3. To a solution of 3 (3.10 g, 11 mmol) in DMSO (30 mL) were added intermediate 20 (3.5 g, 11 mmol) and K 2 CO 3 (4.56 g, 33 mmol). The reaction was stirred at 140 °C for 3 h. The reaction was cooled to RT and then poured into ice-water and washed with CH 2 Cl 2 Extraction with Na 2 SO 4 The combined organic layers were concentrated to provide a crude product, which was purified by silica gel chromatography to provide intermediate 22 as a yellow solid (4.78 g, yield 92%). MS (ESI): C 22 H 20 Bn 3 O 2 Theoretical molecular weight of S: 470.39, m / z experimental molecular weight: 470.7 [M+H] + .

[0378] Preparation of intermediate 23

[0379]

[0380] 1. 1 (Key Organics, 15 g, 48 mmol), TEA (9.7 g, 96 mmol) and Pd(dppf)Cl were reacted with CO. 2A mixture of (2.8 g, 3.84 mmol) in MeOH (200 mL) and MeCN (50 mL) was purged 3× in a bomb and then heated at 100° C. under 120 atmospheres of CO for 24 h. The mixture was cooled, filtered through celite, the filter cake was washed with EA and the filtrate was concentrated to afford the crude product, which was purified by silica gel chromatography to afford 2 (11.5 g, 82.1% yield) as an oil. MS (ESI): C 16 H 21 NO 4 Theoretical molecular weight: 291.15, m / z experimental molecular weight: 313.9 [M+Na] + . 1 H NMR (400 MHz, CDCl 3 )δppm 7.84(d,J=8.2Hz,1H),7.82(s,1H),7.22(d,J=7.9Hz,1H),4.63(s,2H),3.93(s,3H),3.68(t,J=5.4Hz,2H),2.90(t,J=5.5Hz,2H),1.51(s,9H).

[0381] 2. To a solution of 2 (10.8 g, 37 mmol) in MeOH (20 mL) was added NH 3 Saturated MeOH (250 mL). The reaction was stirred in a bomb at 120 °C for 60 h, cooled to RT and concentrated to provide the crude product, which was purified by silica gel chromatography to provide 3 as a yellow solid (8.4 g, 81.9% yield). MS (ESI): C 15 H 20 N 2 O 3 Theoretical molecular weight: 276.34, m / z experimental molecular weight: 298.9 [M+Na] + . 1 H NMR(400MHz,DMSO)δppm 7.89(s,1H),7.69–7.67(m,2H),7.30(s,1H),7.23(d,J=8.0Hz,1H),4.54(s,2H),3.56(t,J=5.8Hz,2H),2.81(t,J=5.8Hz,2H),1.44(s,9H).

[0382] 3. To a solution of 3 (8.4 g, 30.3 mmol) in DCM (20 mL) was added TFA (12 mL). The reaction was stirred at RT for 6 h and concentrated to afford the crude product. It was dissolved with DCM and diluted with PE, which resulted in a precipitate that was collected by filtration. The filter cake was washed with EA and dried in vacuo to afford intermediate 23 (6.3 g, 71.4%), MS (ESI): C 12 H 13 F 3 N 2 O 3 Theoretical molecular weight: 290.24, m / z experimental molecular weight: 177.0 [M+H] + .

[0383] Preparation of intermediate 24

[0384]

[0385] 1. At -78°C, N 2 To a solution of 2-chlorothiazole (1.24 g, 10.35 mmol) in anhydrous THF (50 mL) was added n-BuLi (2.4 M, 4.8 mL) dropwise. After 0.5 h, a solution of 1 (Sigma-Aldrich, 1.80 g, 9.41 mmol) in anhydrous THF (10 mL) was added dropwise. The reaction was slowly heated to RT. NH 4 The mixture was quenched with aqueous Cl and extracted with DCM and quenched with Na 2 SO 4 The combined organic layers were concentrated to provide a crude product, which was purified by silica gel chromatography to provide 2 (2.00 g, yield 68.36%) as a white solid. MS (ESI): C 14 H 15 C1N 2 O 2 Theoretical molecular weight of S: 310.80, m / z experimental molecular weight: 311.4 [M+H] + .

[0386] 2. A mixture of 2 (2.0 g, 6.44 mmol), TES (10 mL) and TFA (30 mL) was stirred at 80 °C for 2 h. The mixture was concentrated and washed with NaHCO 3 The residue was washed with aqueous solution and extracted with DCM (30 mL x 3) and then with Na 2 SO 4 The combined extracts were concentrated to provide a crude product, which was purified by silica gel chromatography to provide intermediate 24 as a white solid (1.1 g, yield 57.94%). MS (ESI): C 14 H15 C1N 2 Theoretical molecular weight of OS: 294.8, m / z experimental molecular weight: 295.4 [M+H] + .

[0387] Preparation of intermediate 25

[0388]

[0389] 1. 1 (Key Organics, 5.0 g, 16.01 mmol), pyrrolidin-2-one (4.09 g, 48.03 mmol), Pd 2 (dba) 3 A mixture of 1,4-dioxane (200 mL) and t-BuOK (1.17 g, 1.6 mmol) was stirred overnight at 100 °C. The mixture was poured into water and extracted with DCM. 2 SO 4 Dry, filter and concentrate. The resulting residue was purified by silica gel chromatography to provide 2 (3.2 g, 63.17%) as a white solid. 18 H 24 N 2 O 3 Theoretical molecular weight: 316.40, m / z experimental molecular weight: 316.8 [M+H] + .

[0390] 2. A mixture of 2 (3.2 g, 10.11 mmol), DCM (40 mL) and TFA (20 mL) was stirred at room temperature for 5 h. The mixture was concentrated and washed with NaHCO 3 The residue was washed with aqueous solution and extracted with DCM. 2 SO 4 The combined extracts were concentrated to provide a crude product, which was purified by silica gel chromatography to provide intermediate 25 as a white solid (1.05 g, yield 48.02%). MS (ESI): C 13 H 16 N 2 Theoretical molecular weight of O: 216.28, m / z experimental molecular weight: 216.8 [M+H] + .

[0391] Preparation of intermediate 26

[0392]

[0393] 1. 1 (Sigma-Aldrich, 4 g, 26.7 mmol), 2-bromopyrimidine (3.51 g, 22.1 mmol), NaHCO 3 (6.73 g, 80.1 mmol), Pd(PPh 3 ) 4 (766 mg, 0.663 mmol) in DME / H 2 O (100 mL / 50 mL) was heated at 90 °C under N 2 Stir for 18 hours under atmosphere. Filter the mixture through celite and wash the filter cake with EA and concentrate the filtrate. Extract the mixture with EA, wash the combined extracts with brine, water and wash with Na 2 SO 4 The mixture was filtered and the filtrate was concentrated to provide a residue, which was purified by silica gel chromatography to provide 2 as a white solid (3.84 g, yield 78.1%). MS (ESI): C 11 H 8 N 2 Theoretical molecular weight of O: 184.20, m / z experimental molecular weight: 185.0 [M+H] + .

[0394] 2. At -78°C, N 2 To a solution of 2-chlorothiazole (2.69 g, 22.7 mmol) in anhydrous THF (80 mL) was added n-BuLi (2.4 M, 9.9 mL, 23.75 mmol) dropwise. After 1 h, a solution of 2 (3.8 g, 20.6 mmol, 106 mL THF) was added dropwise to the mixture. The reaction was slowly heated to RT and stirred for 18 h. 4 The resulting mixture was quenched with aqueous Cl and extracted with EtOAc and washed with Na 2 SO 4 The combined extracts were dried. The organic solution was concentrated to provide the crude product, which was purified by silica gel chromatography to provide 3 as a white solid (4.65 g, yield 74.2%). MS (ESI): C 14 H 10 C1N 3 Theoretical molecular weight of OS: 303.76, m / z experimental molecular weight: 303.8 [M+H] + .

[0395] 3. To a solution of 3 (3 g, 9.87 mmol) and TFA (11.3 g, 98.7 mmol) in anhydrous DCE at 0°C was added TES (3.42 g, 29.6 mmol) dropwise and the reaction was stirred at 60°C for 8 hours. The mixture was cooled and concentrated.3 The resulting residue was worked up, extracted with EA and the combined extracts were washed with brine, water and concentrated with Na 2 SO 4 Drying. Removal of the solvent gave a crude product, which was purified by flash chromatography to afford intermediate 26 as a white solid (1.2 g, yield 42.2%). MS (ESI): C 14 H 10 C1N 3 Theoretical molecular weight of S: 287.77, m / z experimental molecular weight: 287.8 [M+H] + .

[0396] Preparation of intermediate 27

[0397]

[0398] 1. 1 (2.00 g, 6.4 mmol), morpholine (1.80 g, 20.6 mmol), Pd 2 (dba) 3 (2.0 g, 2.2 mmol), S-Phos (1.20 g, 3.0 mmol) and K 2 CO 3 A mixture of (2.80 g, 20 mmol) in anhydrous 1,4-dioxane (80 mL) was stirred at 100 °C overnight. The reaction mixture was cooled to RT, filtered and the filtrate was concentrated. The resulting residue was purified by silica gel chromatography to provide 2 (1.30 g, 64%) as a yellow oil. 18 H 26 N 2 O 3 Theoretical molecular weight: 318.19, m / z experimental molecular weight: 319.0 [M+H] + .

[0399] 2. A mixture of 2 (1.30 g, 5 mmol) and TES (5 mL) in TFA (10 mL) was stirred at 50 °C for 2 h. The mixture was cooled, concentrated and washed with NaHCO 3 The residue was treated with a saturated aqueous solution of CH 2 Cl 2 The combined organic phases were extracted and washed with brine and then with Na 2 SO 4 Drying, filtration and concentration of the filtrate afforded intermediate 27 (1.4 g, crude product) as a brown oil. MS (ESI): C 13 H 18 N 2 Theoretical molecular weight of O: 218.14, m / z experimental molecular weight: 219.0 [M+H] + .

[0400] Preparation of intermediate 28

[0401]

[0402] 1. To a solution of 1 (4.46 g, 36 mmol) in DMF (100 mL) was added oxazolidin-2-one (2.61 g, 30 mmol) and Cs 2 CO 3 (11.74 g, 36 mmol). The resulting mixture was stirred at 120 °C overnight. The mixture was cooled to RT, filtered, the filtrate was poured into water and the mixture was extracted with EA. The combined extracts were washed with brine and washed with Na 2 SO 4 Drying, concentration and purification by chromatography on silica gel afforded 2 as a white solid (4.17 g, yield 70%). MS (ESI): C 10 H 9 NO 3 Theoretical molecular weight: 191.19, m / z experimental molecular weight: 192.0 [M+H] + .

[0403] 2. To a solution of 2-chlorothiazole (0.86 g, 7.2 mmol) in THF (25 mL) was added n-BuLi (3 mL, 7.2 mmol) dropwise at -78°C. After 1 h, a solution of 2 (1.06 g, 5.5 mmol) in THF (15 mL) was added dropwise. The reaction mixture was stirred for 2 h and NH 4 The reaction mixture was quenched with a saturated aqueous solution of Cl and extracted with EtOAc. The combined extracts were washed with brine and washed with Na 2 SO 4 Drying, filtration and concentration afforded 3 as a yellow oil (crude, 1.8 g). MS (ESI): C 14 H 12 C1N 3 O 2 Theoretical molecular weight of S: 310.75, m / z experimental molecular weight: 311.21 [M+H] + .

[0404] 3. A mixture of 3 (0.1 g, 0.32 mmol) and TES (0.5 mL) in TFA (1 mL) was stirred at RT for 2 h. The mixture was concentrated and the residue was purified by chromatography on silica gel to afford intermediate 28 as a white solid (78 mg, 82% yield). MS (ESI): C 13 H 11 C1N 2 O 2Theoretical molecular weight of S: 294.75, m / z experimental molecular weight: 295.19 [M+H] + .

[0405] Preparation of intermediate 29

[0406]

[0407] 1. A mixture of compound 1 (Key Organics, 5.40 g, 17.4 mmol), imidazolidin-2-one (4.50 g, 52.3 mmol), t-BuOK (5.75 g, 51.3 mmol), CuI (2.52 g, 13.2 mmol) and (S,S)-N,N'-dimethyl-1,2-diaminocyclohexane (0.83 g, 6.5 mmol) in DMF (200 mL) was stirred at 120°C overnight. The reaction mixture was cooled to RT, filtered and concentrated to provide 2 (5.1 g, 92%) as a yellow oil. 17 H 23 N 3 O 3 Theoretical molecular weight: 317.39, m / z experimental molecular weight: 317.9 [M+H] + .

[0408] 2. At 0°C, NaH (200 mg, 13.8 mmol) was added to a solution of 2 (1.50 g, 4.7 mmol) in THF (40 mL). After 0.5 h, a solution of iodomethane (1.41 g, 9.9 mmol) in THF (10 mL) was added dropwise. The reaction mixture was slowly heated to RT and stirred at 60°C for 4 h. The reaction was quenched with water and extracted with EA, the combined extracts were washed with brine, and the residue was washed with anhydrous Na 2 SO 4 Drying and concentration afforded 3 (1 g, 64%). 18 H 25 N 3 O 3 Theoretical molecular weight: 331.42.m / z Experimental molecular weight: 332.0[M+H] + .

[0409] 3. A mixture of 3 (2 g, 6 mmol) and TFA (9 mL) in DCM (40 mL) was stirred at RT for 2 h. Then, it was concentrated and washed with NaHCO 3 The residue was diluted with saturated aqueous solution of CH 2 Cl 2 The combined organic phases were extracted and washed with brine and then with Na 2 SO 4Drying, filtration and concentration afforded intermediate 29 (1.1 g) as a brown oil. MS (ESI): C 13 H 17 N 3 Theoretical molecular weight of O: 231.3, m / z experimental molecular weight: 231.9 [M+H] + .

[0410] Preparation of intermediate 30

[0411]

[0412] 1. Use N 2 The purged solution contained methyl 4-bromobenzoate (1.1 g, 5.12 mmol), 1 (Sigma-Aldrich, 1.1 g, 5.24 mmol), Pd(dppf)Cl 2 (299 mg, 0.41 mmol) and K 2 CO 3 (1.412 g, 10 mmol) in 1,4-dioxane (15 mL) and H 2 O (1 mL) three times and the resulting mixture was heated to 100° C. for 16 h. It was cooled to RT, concentrated and the residue was purified by chromatography on silica gel to provide 2 (940 mg, 93% yield) as a white solid. MS (ESI): C 13 H 14 O 3 Theoretical molecular weight: 218.25, m / z experimental molecular weight: 219.0 [M+H] + .

[0413] 2. A mixture of 2 (940 mg, 4.31 mmol) and Pd / C (250 mg) in EtOAc (40 mL) was stirred at RT under H 2 The mixture was filtered and concentrated to provide 3 (948 mg, 100% yield) as a colorless oil. MS (ESI): C 13 H 16 O 3 Theoretical molecular weight: 220.27, m / z experimental molecular weight: 221.0 [M+H] + .

[0414] 3. At 0°C, LiAlH 4 (160 mg, 4.09 mmol) was added to a solution of 3 (900 mg, 4.09 mmol) in anhydrous THF (15 mL). The mixture was heated to RT and stirred for 2 h, cooled to 0 °C and washed with NH 4The reaction mixture was quenched with a saturated aqueous solution of Cl and extracted with EtOAc. The combined extracts were washed with brine and washed with Na 2 SO 4 Drying, filtration and concentration afforded 4 (765 mg, 97% yield) as a yellow oil. MS (ESI): C 12 H 16 O 2 Theoretical molecular weight: 192.26, m / z experimental molecular weight: 175.0 [M-OH] + .

[0415] 4. To a solution of 4 in DCM (8 mL) was added Dess-Martin reagent (70 mg, 0.12 mmol). The resulting mixture was stirred at RT for 1 h, concentrated and the residue was purified by chromatography on silica gel to provide 5 (15.5 mg, 78% yield) as a yellow oil. MS (ESI): C 12 H 14 O 2 Theoretical molecular weight: 190.24, m / z experimental molecular weight: 191.0 [M+H] + .

[0416] 5. n-BuLi (1.45 mL, 3.47 mmol, 2.4 M) was added dropwise to a solution of 2-chlorothiazole (416 mg, 3.47 mmol) in THF (3 mL) at -78°C. After 30 min, a solution of 5 (600 mg, 3.16 mmol) in THF (6 mL) was added dropwise and the resulting mixture was heated to RT and stirred overnight. NH 4 The mixture was quenched with a saturated aqueous solution of Cl and extracted with EtOAc. The combined extracts were washed with brine and washed with Na 2 SO 4 Drying, filtration, concentration and purification by chromatography on silica gel afforded 6 (860 mg, 88% yield) as a white solid. MS (ESI): C 15 H 16 ClNO 2 Theoretical molecular weight of S: 309.81, m / z experimental molecular weight: 309.8 [M+H] + .

[0417] 6. A mixture of 6 (690 mg, 2.23 mmol), TES (2 mL) and TFA (2 mL) was stirred at RT under N 2 The mixture was concentrated and washed with NaHCO 3 The residue was diluted with a saturated aqueous solution of 5% HCl and extracted with DCM. The combined extracts were washed with brine and washed with Na 2 SO 4The resulting residue was dried, filtered, concentrated and purified by chromatography on silica gel to afford intermediate 30 as a yellow oil (566.6 mg, yield 87%). MS (ESI): C 15 H 16 Theoretical molecular weight of ClNOS: 293.81, m / z experimental molecular weight: 294.1 [M+H] + .

[0418] Preparation of intermediate 31

[0419]

[0420] 1. At -78°C, N 2 To a solution of 2-chlorothiazole (3.59 g, 29.9 mmol) in anhydrous THF (94 mL) was added n-BuLi (2.4 M in Hex, 13.0 mL, 31.2 mmol) dropwise. After 1 h, a solution of 1 (enamine, 5 g, 27.2 mmol) in anhydrous THF (200 mL) was added dropwise. The reaction was heated to RT and stirred for 18 h. The mixture was heated to 40 °C with saturated NH 4 The mixture was quenched with aqueous Cl and extracted with EtOAc. 2 SO 4 The combined extracts were dried and concentrated to provide the crude product, which was purified by silica gel chromatography to afford 2 (1.6 g, yield 19.4%) as a white solid. MS (ESI): C 11 H 10 ClNO 3 S 2 Theoretical molecular weight: 303.78, m / z experimental molecular weight: 303.7 [M+H] + .

[0421] 2. To a solution of 2 (1.6 g, 5.26 mmol) in TFA (12 mL) was added TES (3 g, 26.3 mmol) dropwise over 15 min. The reaction was stirred at 70 °C for 2 h and washed with saturated NaHCO 3 The mixture was quenched and extracted with EtOAc. The combined extracts were washed with water and washed with Na 2 SO 4 Drying and concentration gave a crude product, which was purified by silica gel chromatography to afford intermediate 31 as a white solid (1.3 g, yield 85.8%). MS (ESI): C 11 H 10 ClNO 2 S 2 Theoretical molecular weight: 287.78, m / z experimental molecular weight: 287.7 [M+H] + .

[0422] Preparation of intermediate 34

[0423]

[0424] 1. In N 2 To a solution of 1H-pyrazole (5.86 g, 86.2 mmol) in anhydrous DMF (50.0 mL) was added NaH (60%, 10.3 g, 258.6 mmol) and the reaction mixture was stirred at 60 °C for 1 h. Then, 1 (15.1 g, 86.2 mmol) was added and the resulting mixture was stirred at 120 °C for 3 h. The reaction was quenched with water and extracted with EtOAc. The combined organic layers were washed with water, brine, and washed with Na 2 SO 4 Drying and concentration gave a crude product which was purified by silica gel chromatography to afford 2 (4.0 g, yield 21%) as a colorless oil.

[0425] 2. At -78°C, N 2 To a solution of 2 (2.66 g, 18.0 mmol) in anhydrous THF (50 mL) was added n-BuLi (2.5 M in hexane, 7.2 mL, 18.0 mmol) dropwise. After 1 h, a solution of 2-chloro-4-formylthiazole (Sigma-Aldrich, 4.00 g, 18.02 mmol) in THF (10 mL) was added dropwise. The resulting mixture was heated to room temperature. The mixture was heated with saturated NH 4 The reaction was quenched with Cl and extracted with EtOAc. The combined organic extracts were concentrated to provide a crude oil, which was purified by silica gel chromatography to afford 3 (420 mg, 8% yield) as a yellow oil.

[0426] 3. To a solution of 3 (400 mg, 1.44 mmol) in TFA (10 mL) was added TES (3 mL) and the resulting mixture was stirred at 100° C. for 2 h. The reaction was concentrated and the residue was purified by silica gel chromatography to afford intermediate 34 (250 mg, 63% yield) as a yellow solid.

[0427] Preparation of intermediate 35

[0428]

[0429] 1. 1 (4 g, 22.5 mmol) was added to NaHCO 3 BOC was added to a mixture of saturated aqueous solution (50 mL) and THF (50 mL). 2 O (5.63 g, 25.8 mmol) and the resulting mixture was stirred at RT for 16 h. The mixture was concentrated and the residue was extracted with EtOAc, and the combined organic phases were washed with brine and washed with Na2 SO 4 Drying, filtration, concentration and purification by chromatography on silica gel afforded 2 as a brown solid (5.8 g, 93.5% yield). MS (ESI): C 14 H 18 N 2 O 4 Theoretical molecular weight: 278.31, m / z experimental molecular weight: 301.0 [M+Na] + .

[0430] 2. A mixture of 2 (5.8 g, 20.9 mmol) and Pd / C (1.2 g) in EtOAc (60 mL) was stirred at RT under H 2 The mixture was filtered and concentrated to afford 3 (5 g, 96.7% yield) as a brown oil. MS (ESI): C 14 H 20 N 2 O 2 Theoretical molecular weight: 248.33, m / z experimental molecular weight: 271.0 [M+Na] + .

[0431] 3. A mixture of 3 (2 g, 8.06 mmol) and 3-chloropropyl isocyanate (1.16 g, 9.68 mmol) in anhydrous DCM (20 mL) was stirred at RT for 16 h. Then, it was concentrated and the residue was washed with a mixture of EA / PE (1 / 50), filtered and the resulting solid was dried in vacuo to provide 4 (2.8 g, yield 95%) as a brown solid. MS (ESI): C 18 H 26 C1N 3 O 3 Theoretical molecular weight: 367.87, m / z experimental molecular weight: 368.0 [M+H] + .

[0432] 4. To a solution of 4 (2.7 g, 7.4 mmol) in THF (270 mL) was added NaH (888 mg, 22.2 mmol) in portions at 0°C. It was then heated to RT and stirred for 16 h. The volume was reduced to about 40 mL, allowed to cool to 0°C, MeI (1.58 g, 11.1 mmol) was added and the resulting mixture was heated to RT and stirred for 16 h. The mixture was quenched with water, extracted with EtOAc, the combined organic extracts were washed with brine, washed with Na 2 SO 4 Dry, filter and concentrate. The resulting residue was purified by chromatography on silica gel to provide 5 (2.4 g, 96% yield) as a yellow oil. MS (ESI): C 19 H27 N 3 O 3 Theoretical molecular weight: 345.44, m / z experimental molecular weight: 346.0 [M+H] + .

[0433] 5. To a solution of 5 (2.4 g, 6.96 mmol) in DCM (15 mL) was added TFA (15 mL). After stirring for 16 h, it was concentrated and the residue was washed with EtOAc, filtered and dried in vacuo to provide the desired product intermediate 35 as a white solid (2.2 g, yield 88%). MS (ESI): C 16 H 20 F 3 N 3 O 3 Theoretical molecular weight: 359.35, m / z experimental molecular weight: 246.0 [M-TFA+H] + .

[0434] Example

[0435] Example 1.

[0436] 1. To a solution of intermediate 7 (346 mg, 1.09 mmol) in DMSO (10 mL) was added intermediate 9 (329 mg, 1.31 mmol) and K 2 CO 3 (300 mg, 2.18 mmol). The mixture was stirred at 120 °C overnight and cooled to RT. The mixture was treated with water and extracted with EA. The combined organic extracts were washed with water, brine, and washed with anhydrous Na 2 SO 4 Drying, filtering and concentration afforded a crude oil. The crude product was purified by silica gel chromatography to afford 90.36 mg of Example 1. 1 HNMR (CDCl 3 ,300MHz)δ:δ:1.3-1.4(d,6H),3.0-3.1(m,2H),3.6-3.8(m,2H),4.1(s,2H),4.2-4.3(s,2H),4.8-4.9(s,2H),6.5(s,1H),7.0-7. 1(s,1H),7.1-7.2(s,1H),7.4-7.5(s,1H),7.5-7.6(s,1H),7.7.6-7.7(d,1H),7.7-7.8(s,1H),7.8-7.9(s,1H),7.9-8.0(s,1H). LC-MS: m / z=496.5(M+1) + .

[0437] Example 2.

[0438] 1. Intermediate 9 (100 mg, 0.40 mmol), intermediate 3 (121 mg, 0.44 mmol), Pd 2 (dba) 3 A mixture of 4-(36.6 mg, 0.04 mmol), SPhos (16.4 mg, 0.04 mmol) and t-BuOK (123 mg, 1.10 mmol) in dioxane (2.00 mL) was stirred at 95 °C for 2 h. The reaction was quenched with water and extracted with EtOAc. The combined organic extracts were washed with water and brine and washed with Na 2 SO 4 Dried and concentrated. The residue was purified by prep-HPLC to afford Example 2 (45.9 mg, yield 25%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ2.91(2H,t,J=5.6Hz),3.67(2H,t,J=5.6Hz),4.04(2H,s),4.08(3H,s),4.60(2H,s),6.53(1H,t,J=2.0Hz),7.03(1H,s),7.25(1H,d,J=8.0Hz),7.36(2H,d,J=8.4Hz),7.63-7.73(3H,m),7.77(2H,d,J=8.4Hz),8.46(2H,d,J=2.0Hz). MS theoretical value: 453.2; MS experimental value: 454.2[M+H] + .

[0439] Example 3.

[0440] 1. Following the procedure described for Example 1, Intermediate 9 and Intermediate 2 were reacted to provide 11.03 mg of Example 3. (9.58 mg) 1 HNMR (CDCl 3 ,300MHz)δ:3.0-3.1(m,2H),3.7-3.8(m,2H),4.1(s,2H),4.4.3(s,2H),4.6(s,2H),6.5(s,1H),7.0-7.1(s,1H ),7.1-7.3(m,2H),7.3(s,1H),7.4(m,1H),7.5-7.7(m,4H),7.7-7.8(s,1H),7.8-7.9(s,1H),7.9-8.0(s,1H). LC-MS: m / z=454.4(M+1) + .

[0441] Example 4.

[0442] 1. Following the procedure described for Example 1, Intermediate 10 and Intermediate 2 were reacted to provide 11.03 mg of Example 4. 1 HNMR (CDCl 3 ,300MHz)δ:3.0-3.1(m,2H),3.6-3.8(m,2H),4.1(s,2H),4.8(s,2H),6.5(s,1H),7.7.1-7.3 (m,5H),7.4-7.5(m,1H),7.6-7.7(m,3H),7.7-7.8(s,1H),7.8-7.9(s,1H),7.9-8.0(s,1H). LC-MS: m / z=440.4(M+1) + .

[0443] Example 5.

[0444] 1. Following the procedure described for Example 1, Intermediate 10 and Intermediate 3 were reacted to provide 30.02 mg of Example 5. 1 HNMR (CDCl 3 ,300MHz)δ:3.0-3.1(m,4H),3.6-3.8(m,2H),4.1(s,2H),4.8-4.9(s,2H),6.4-6.5(s,1H) ,7.1-7.3(m,5H),7.4(m,1H),7.5-7.6(m,3H),7.7(s,1H),7.7.8(s,1H),7.9-8.0(s,1H). LC-MS: m / z=440.4(M+1) + .

[0445] Example 6.

[0446]

[0447] 1. To a solution of 1 (Sigma-Aldrich, 158 mg, 1 mmol) in EtOH (20 mL) was added NH 2 OH (1.5 mL). The mixture was heated to reflux for 20 h. The mixture was cooled and concentrated to afford 2 (0.19 g, 100%) as a white solid.

[0448] 2. 2 (0.19 g, 1 mmol) was dissolved in Ac 2The mixture in 0 (10 mL) was heated to reflux for 2 h. The mixture was cooled and concentrated, the residue was dissolved in concentrated HCl (10 mL) and the mixture was heated to reflux overnight. The mixture was concentrated to afford 3 (0.4 g, 100%) as a white solid.

[0449] 3. To a solution of 3 (20 mg, 0.5 mmol) in dioxane (10 mL) were added intermediate 3 (250 mg, 0.9 mmol), Pd 2 (dba) 3 (32 mg, 0.04 mmol), SPhos (30 mg, 0.07 mmol) and t-BuOK (165 mg, 0.75 mmol). The resulting mixture was heated to 100 °C and heated under N 2 The mixture was quenched with water and extracted with EtOAc. The combined extracts were concentrated to provide a crude oil, which was purified by silica gel chromatography to provide Example 6 (40 mg, 20%) as a yellow solid. LC-MS: m / z=455.1 (M+1) + . 1 HNMR (CD 3 OD,500MHz):

[0450]

[0451] Example 7.

[0452] 1. To a solution of intermediate 11 (82 mg, 0.3 mmol, 1 eq.) in dioxane (20 mL) were added intermediate 3 (137 mg, 0.5 mmol, 1.6 eq.), Pd 2 (dba) 3 (18 mg, 0.027 mmol, 0.09 equiv), SPhos (18 mg, 0.04 mmol, 0.13 equiv) and t-BuOK (330 mg, 3 mmol, 10 equiv). The mixture was heated to 100 °C and heated under N 2 The mixture was stirred at 40 °C for 20 h. The mixture was quenched with water and extracted with EtOAc. The combined extracts were concentrated to provide a crude oil, which was purified by silica gel chromatography to provide Example 7 (40 mg, 27%) as a yellow solid. LC-MS: m / z=498.2 (M+1) + . 1 HNMR (CD 3 OD,500MHz):

[0453]

[0454] Example 8.

[0455] 1. The title compound was prepared according to the procedure described for Example 7 using Intermediate 2 instead of Intermediate 3 and 5 equivalents of t-BuOK to provide Example 8 as a yellow solid (90 mg, 27%) LC-MS: m / z = 498.2 (M+1) + . 1 HNMR (CD 3 OD,500MHz):

[0456]

[0457] Example 9.

[0458] 1. Use intermediate 12 instead of intermediate 11, 1 equivalent of intermediate 3, 0.06 equivalent of Pd 2 (dba) 3 , 0.07 eq. SPhos and 2.4 eq. t-BuOK, the title compound was prepared according to the procedure described for Example 7 to provide Example 9 (100 mg, 45.6%) as a white solid. LC-MS: m / z = 439.2 (M+1) + . 1 HNMR (CDCl 3 ,500MHz):

[0459]

[0460] Example 10.

[0461]

[0462] 1. A mixture of 1 (Sigma-Aldrich, 2.03 g, 8.86 mmol) in 45% HBr in HOAC (15 mL) was heated to 110° C. and stirred for 5 h. After cooling to RT, the precipitate was filtered to afford 2 (1.92 g, 88%) as a white solid.

[0463] 2. Add BOC in THF (20 mL) 2 O (1.88 g, 8.61 mmol) and TEA (2.8 mL, 16.45 mmol) were added dropwise to a suspension of 2 (1.92 g, 7.83 mmol) in water (6 mL). The mixture was stirred at RT overnight. After concentration, the residue was dissolved in EtOAc and washed with water. 2 SO 4 The organic mixture was dried and concentrated. The residue was purified by flash column chromatography to afford 3 (1.8 g, 86.9%).

[0464] 3. To a solution of 3 (0.4 g, 1.5 mmol) in dioxane (20 mL) was added 1,2-dibromoethane (0.31 g, 1.66 mmol), 2N aqueous NaOH (5 mL, 10 mmol) and TBAB (20 mg, 0.16 mmol). The mixture was heated to 90 °C and stirred overnight. The reaction was quenched with water and extracted with EtOAc. Na 2 SO 4 The organic extracts were dried, filtered and concentrated to provide 4 (210 mg, 47.8%).

[0465] 4. To a solution of 4 (210 mg, 0.72 mmol) in DCM (20 mL) was added 4M HCl / dioxane (3 mL, 12 mmol). The mixture was stirred at RT overnight and then concentrated to afford 5 (150 mg, 92%).

[0466] 5. To a solution of 5 (137 mg, 0.6 mmol) in dioxane (10 mL) were added intermediate 2 (170 mg, 0.62 mmol), Pd 2 (dba) 3 (55 mg, 0.06 mmol), SPhos (50 mg, 0.12 mmol) and t-KOBu (135 mg, 1.2 mmol). The mixture was heated to 100 °C and heated under N 2 The mixture was stirred at 40 °C for 20 h. The mixture was quenched with water and extracted with EtOAc. The combined organic extracts were concentrated. The resulting material was purified by silica gel chromatography to provide Example 10 (80 mg, 30%) as a white solid. m / z=431.1 (M+H) + . 1 HNMR (CD 3 OD,500MHz):

[0467]

[0468] Example 11.

[0469] 1. Use intermediate 14 instead of intermediate 11, 1 equivalent of intermediate 3, 0.09 equivalent of Pd 2 (dba) 3 The title compound was prepared according to the procedure described for Example 7 using 4-(4-(2-methyl-1-oxo-4-yl)-1-nitropropene 4 ... 1 HNMR (400 MHz, DMSO-d 6)δ2.92(2H,t,J=6.0Hz),3.26(3H,s),3.67(2H,t,J=6.0Hz),3.77(2H,t,J= 5.2Hz),4.04(2H,s),4.56(2H,t,J=5.6Hz),4.60(2H,s),6.52-6.53(1H,m), 7.03(1H,s),7.25(1H,d,J=8.0Hz),7.36(2H,d,J=8.8Hz),7.65-7.67(1H,m ),7.70-7.72(2H,m),7.76-7.78(2H,m),8.45(1H,d,J=2.4Hz),8.48(1H,s). MS theoretical value: 497.2; MS experimental value: 498.2 [M+H] + .

[0470] Example 12.

[0471] 1. Use intermediate 14 instead of intermediate 11, 1 equivalent of intermediate 2 instead of intermediate 3, 0.09 equivalent of Pd 2 (dba) 3 The title compound was prepared according to the procedure described for Example 7 using 4-(4-(2-amino-4-nitropropene)-2-nitropropene 4 ... 1 H NMR (400 MHz, DMSO-d 6 )δ2.91(2H, t, J=6.0Hz),3.26(3H, s),3.67(2H, t, J=6.0Hz),3.77(2H, t, J=5.2Hz),4.08(2H, s),4.56(2H, t, J=5.2Hz),4.59(2H, s),6.54(1H, t, J=2.0Hz),7.06(1H, s),7.19(1H, d, J=7.6Hz),7.25(1H, d, J=8.0Hz),7.43(1H, t, J=8.0Hz),7.65-7.77(5H, m),8.48-8.49(2H, m). MS theoretical value: 497.2; MS experimental value: 498.2[M+H] + .

[0472] Example 13.

[0473] 1. Use intermediate 15 instead of intermediate 11, 1 equivalent of intermediate 3, 0.09 equivalent of Pd 2 (dba) 3The title compound was prepared according to the procedure described for Example 7 using 4-(4-(2-nitropropene)-4-nitropropene ... 1 H NMR (400 MHz, DMSO-d 6 )δ2.15(3H,s),2.91(2H,t,J=5.6Hz),3.66(2H,t,J=6.0Hz),4.04(2H,s),4.60(2H,s),6.53(1H,t,J=2.0Hz),7.03(1H,s),7.29(1H,d,J=8.0Hz),7.35-7.43(4H,m),7.51(1H,d,J=2.0Hz),7.72(1H,d,J=1.6Hz),7.77(2H,d,J=8.8Hz),8.08(1H,d,J=1.2Hz),8.46(1H,d,J=2.4Hz). MS theoretical value: 452.2; MS experimental value: 453.2[M+H] + .

[0474] Example 14.

[0475] 1. Intermediate 1 (100 mg, 0.38 mmol), intermediate 3 (115 mg, 0.42 mmol), Pd 2 (dba) 3 A mixture of 4-nitropropene (36.6 mg, 0.04 mmol), SPhos (32.9 mg, 0.08 mmol) and t-BuOK (128 mg, 1.14 mmol) in anhydrous dioxane (4.00 mL) was stirred at 90 °C for 4 h. When the reaction was complete, it was quenched with water and extracted with EtOAc. The combined organic layers were washed with water, brine, and washed with Na 2 SO 4 Drying and concentration gave a crude product, which was purified by prep-HPLC to give Example 14 (33.5 mg, yield 19%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6)δ2.08(3H,s),2.22(3H,s),2.94(2H,t,J=5.6Hz),3.67(2H,d,J=5.6Hz),4.04(2H,s),4.59(2H,s),6.53(1H,t,J=2.0Hz),6.92(1H,s),7.03(1H,s),7.21(1H,d,J=8.0,2.0Hz),7.30-7.32(2H,m),7.36(2H,d,J=8.4Hz),7.72(1H,d,J=2.0Hz),7.77(2H,d,J=8.8Hz),8.46(1H,d,J=2.4Hz). MS theoretical value: 466.2; MS experimental value: 467.2[M+H] + .

[0476] Alternative Preparation of Example 14

[0477] 1. To a solution of intermediate 1 (25 g, 110 mmol) in DMSO (500 mL) was added intermediate 3 (40 g, 145 mmol) and K 2 CO 3 (45.54 g, 330 mmol). 2 The flask was purged three times and stirred at 140°C for 2 hours, cooled to RT, diluted with EA, filtered, concentrated and the residue was purified by chromatography on silica gel, eluted to provide material, which was recrystallized with EtOAc to provide Example 14 as an off-white solid (21.8 g, 42.5% yield). MS (ESI): C 27 H 26 N 6 Theoretical molecular weight of S: 466.61, m / z experimental molecular weight: 466.8 [M+H] + . 1 H NMR(400MHz,DMSO)δppm 8.46(d,J=2.3Hz,1H),7.78(d,J=8.4Hz,2H),7.73(s,1H),7.37(d,J=8.4Hz,2H),7.33–7.31(m,2H),7.22(d,J=8.1Hz,1H),7.03(s ,1H),6.94(s,1H),6.53(s,1H),4.60(s,2H),4.05(s,2H),3.68(t,J=5.9Hz,2H),2.95(t,J=5.8Hz,2H),2.23(s,3H),2.09(s,3H).

[0478] Example 15.

[0479] 1. A mixture of intermediate 16 (130 mg, 0.31 mmol) and DMF-DMA (10 mL) was stirred at 100° C. for 1 h. The mixture was concentrated and the residue was dissolved in EtOH (10 mL) and N 2 H 4 *H 2 O (2mL) was added to a mixture and the resulting mixture was stirred at RT for 0.5h. The mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with water and brine and washed with Na 2 SO 4 Dried and concentrated. The residue was purified by prep-HPLC to afford Example 15 (11.0 mg, yield 8%) as a white solid. 1 HNMR (400 MHz, DMSO-d 6 )δ2.92-2.94(2H,m),3.68(2H,t,J=6.0Hz),4.08(2H,s),4.61(2H,s),6.54( 1H,t,J=2.0Hz),7.06(1H,s),7.18(1H,d,J=8.0Hz),7.25-7.30(1H,m),7.43( 1H,t,J=7.6Hz),7.67-7.69(1H,m),7.73(1H,d,J=1.6Hz),7.77(1H,s),7.81 -7.84(2H,m),8.49(1H,d,J=2.8Hz),8.58-8.62(1H,m),14.09-14.40(1H,m). MS theoretical value: 439.2; MS experimental value: 440.1 [M+H] + .

[0480] Example 16.

[0481] 1. Following the procedure described for Example 15, Intermediate 17 (0.18 g, 0.43 mmol) was converted to Example 16 (60 mg, 31%) as a white solid. LC-MS: m / z = 440.2 (M+1) + . 1 HNMR (DMSO-d 6 ,500MHz):

[0482]

[0483] Example 17.

[0484] 1. Following the procedure described for Example 1, Intermediate 18 and Intermediate 12 were reacted to provide 19.6 mg of Example 17. 1 HNMR (CDCl3 ,300MHz)δ:3.0-3.1(m,2H),3.7-3.8(m,2H),4.1(m,2H),4.7-4.8(s,2H),7.0-7.1(s,1H),7.2-7.5(m,14H),7.8-7.9(s,2H). LC-MS: m / z=439.4(M+1) + .

[0485] Example 18.

[0486] 1. Following the procedure described for Example 1, 300 mg of Intermediate 3 and 350 mg of Intermediate 13 were converted to Example 18 (24.62 mg). 1 HNMR (CDCl 3 ,300MHz)δ:3.0-3.1(m,2H),3.7-3.8(m,2H),4.0-4.1(m,2H),4.6-4.7(s,2H),6.4-6.5(s,1H),6.9-7. 0(s,1H),7.2(s,1H),7.3-7.4(d,2H),7.6-7.7(d,1H),7.7-7.8(s,1H),7.8-7.9(s,1H)7.9-8.0(s,1H). LC-MS: m / z=439.3(M+1) + .

[0487] Example 19.

[0488] 1. Use intermediate 1 instead of intermediate 11, 1.2 equivalents of intermediate 2 instead of intermediate 3, 0.11 equivalents of Pd 2 (dba) 3 , 0.22 equivalents of SPhos and 3 equivalents of t-BuOK, following the procedure described for Example 7 provided Example 19 (33.5 mg, 20% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d 6)δ2.08(3H,s),2.21(3H,s),2.94(2H,t,J=5.6Hz),3.67(2H,t,J=2.0Hz),4. 09(2H,d,J=4.8Hz),4.59(2H,s),6.54(1H,t,J=2.4Hz),6.91(1H,s),7.06-7 .07(1H,m),7.20(2H,t,J=8.0Hz),7.29-7.35(2H,m),7.40-7.44(1H,m),7.6 9(1H,d,J=8.4Hz), 7.73(1H,d,J=1.2Hz), 7.76(1H,s), 8.48(1H,d,J=2.8Hz). MS theoretical value: 466.2; MS experimental value: 467.3 [M+H] + .

[0489]

[0490] Example 20.

[0491] 1. In N 2 To a mixture of 1 (PCT Int. Appl. (2008), WO 2008079277A, 4 g, 14 mmol), tert-butyl 2-bromo-1H-imidazole-1-carboxylate (FCH Group, 1.8 g, 7 mmol) and NaOH (3 mL, 1.5 M) in toluene (20 mL) and ethanol (2 mL) was added Pd(PPh 3 ) 4 (0.084 g, 0.14 mmol). The resulting mixture was stirred at 120 °C for 24 h. The mixture was cooled to RT, treated with water and extracted with EA. The combined organic extracts were washed with water, brine, and washed with anhydrous Na 2 SO 4 Drying, filtration and concentration afforded a crude oil. The crude product was purified by recrystallization to afford 2 (1.1 g, 38%).

[0492] 2. 2 (1.1 g, 2.76 mmol) was dissolved in HCl / Et 2 The mixture was stirred at RT overnight. The mixture was filtered and washed with Et 2 O to wash the filter cake to afford 3 (0.4 g, 80%).

[0493] 3. To a mixture of 3 (0.3 g, 1.6 mmol) in DMSO (5 mL) were added intermediate 3 (0.3 g, 1.1 mmol) and K 2 CO 3(0.3 g, 2.2 mmol). The mixture was stirred at 140 °C overnight. The mixture was cooled to RT, treated with water and extracted with EA. The combined organic extracts were washed with water, brine, and washed with anhydrous Na 2 SO 4 Drying, filtration and concentration gave a crude oil which was purified by silica gel chromatography to give Example 20 (15 mg). 1 HNMR (CDCl 3 ,300MHz)δ:2.9-3.1(m,2H),3.7-3.8(m,2H),4.0-4.1(m,2H),4.6-4.7(s,2H),6. 4-6.5(s,1H),6.9-7.0(s,1H),7.1-7.2(m,3H),7.6-7.8(m,4H),7.9-8.0(s,1H). LC-MS: m / z=439.4(M+23) +

[0494] Example 21.

[0495] 1. A mixture of intermediate 4 (190 mg, 0.42 mmol), 4-methyl-1H-imidazole (104 mg, 1.26 mmol), (S,S)-N,N'-dimethyl-1,2-diaminocyclohexane (12 mg, 0.08 mmol), t-BuOK (141 mg, 1.26 mmol) and CuI (40 mg, 0.21 mmol) in NMP (5 mL) was heated at 140°C under N 2 The mixture was cooled to RT, diluted with MeOH, filtered, and the filtrate was concentrated and purified by prep-HPLC to provide Example 21 as an off-white solid (20 mg, yield 10.5%). MS (ESI): C 26 H 24 N 6 Theoretical molecular weight of S: 452.58, m / z experimental molecular weight: 452.8 [M+H] + . 1H NMR(400MHz,DMSO)δppm 8.49(d,J=2.3Hz,1H),8.08(s,2H),7.77(s,1H),7.74(s,1H),7.69(d,J=8.3Hz,1H),7.51(s,1H),7.44–7.41(m,2H),7.29(d,J=8.2Hz,1 H), 7.20 (d, J = 7.6Hz, 1H), 7.07 (s, 1H), 6.55 (s, 1H), 4.60 (s, 2H), 4.09 (s, 2H), 3.66 (t, J = 5.9Hz, 2H), 2.92 (t, J = 5.8Hz, 2H), 2.16 (s, 2H).

[0496] Example 22.

[0497]

[0498] 1. To a solution of 1 (4.50 g, 20.93 mmol) in DMF (30 mL) were added (R,R)-N,N'-dimethyl-1,2-diaminocyclohexane (0.30 g, 2.09 mmol), 1H-pyrazole (1.42 g, 20.93 mmol), CuI (0.40 g, 2.09 mmol) and K 2 CO 3 (5.75 g, 41.7 mmol). The reaction mixture was stirred at 150 °C for 18 h. The reaction mixture was cooled to RT, poured into ice-water, and washed with CH 2 Cl 2 Extraction with Na 2 SO 4 The combined organic extracts were concentrated under reduced pressure and purified by chromatography on silica gel to afford 2 as a yellow solid (1.80 g, 42.6% yield). MS (ESI): C 20 H 18 Bn 3 Theoretical molecular weight of OS: 202.21, m / z experimental molecular weight: 202.7 [M+H] + .

[0499] 2. To a solution of 2-chlorothiazole (1.07 g, 8.9 mmol) in anhydrous THF (40 mL) was added n-BuLi (2.4 M, 4.0 mL, 9.6 mmol) dropwise at -78°C. After 1 h, a solution of 2 (1.80 g, 8.9 mmol) in THF (40 mL) was added dropwise. The reaction was slowly heated to RT. NH 4 The mixture was quenched with saturated aqueous Cl, extracted with EtOAc and the combined organic extracts were washed with brine and washed with Na 2 SO4 Dry, filter and concentrate. The resulting residue was purified by chromatography on silica gel to provide 3 (1.4 g, 48.9% yield) as a yellow oil. MS (ESI): C 10 H 7 Theoretical molecular weight of BrClNOS: 321.78, m / z experimental molecular weight: 322.4 [M+H] + .

[0500] 3. A mixture of 3 (1.40 g, 4.35 mmol) in TES (5 mL) and TFA (15 mL) was stirred at 60 °C for 2 h. The mixture was concentrated and eluted with NaHCO 3 The residue was washed with a saturated aqueous solution of CH 2 Cl 2 Extraction with Na 2 SO 4 The organic extract was concentrated to give the crude product, which was purified by chromatography on silica gel to give 4 as a yellow oil (1.2 g, 90.2% yield). MS (ESI): C 10 H 7 Theoretical molecular weight of BrClNS: 305.78, m / z experimental molecular weight: 306.2 [M+H] + .

[0501] 4. To a solution of 4 (0.2 g, 0.65 mmol) in 1,4-dioxane (30 mL) were added intermediate 1 (0.148 g, 0.65 mmol) and K 2 CO 3 (0.27 g, 1.95 mmol). The reaction was stirred at 120 °C for 5 h. The mixture was cooled to RT, poured into ice-water, and washed with CH 2 Cl 2 The combined organic extracts were extracted and washed with brine and washed with Na 2 SO 4 Dry, filter, and concentrate under reduced pressure. The resulting residue was purified by preparative-HPLC to provide Example 22 (18.5 mg, yield 5.7%) as a yellow solid. MS (ESI): C 28 H 28 N 6 Theoretical molecular weight of OS: 496.63, m / z experimental molecular weight: 496.7 [M+H] + . 1H NMR(400MHz,DMSO-d6)δppm 8.16(d,J=2.4Hz,1H),7.68(s,1H),7.53(d,J=1.6Hz,1H),7.32(d,J=8.4Hz,2H),7.28–7.15(m,3H),7.03(s,1H),6.93(s,1H),6.4 7(s,1H),4.59(s,2H),4.02(s,2H),3.67(t,J=5.8Hz,3H),2.67(t,J=5.8Hz,2H),2.95(t,J=5.8Hz,2H),2.23(s,3H),2.09(s,3H).

[0502] Example 23.

[0503] 1. Following the procedure described for Example 1, Intermediate 19 (225 mg) and Intermediate 1 (202 mg) were converted to Example 23 as a white solid. MS (ESI): C 29 H 30 N 6 Theoretical molecular weight of S: 494.66, m / z experimental molecular weight: 494.8 [M+H] + . 1 H NMR(400MHz,DMSO)δppm 7.44(s,4H),7.39(d,J=8.8Hz,2H),7.31(d,J=8.1Hz,1H),7.21(d,J=8.3Hz,2H),7.07(s,1H),4.63( s, 2H), 4.10 (s, 2H), 3.69 (t, J = 5.7Hz, 2H), 2.98 (t, J = 5.6Hz, 2H), 2.35 (d, J = 5.2Hz, 6H), 2.19 (s, 6H).

[0504] Example 24.

[0505] 1. The title compound was prepared according to the procedure described for Example 21 using Intermediate 5 (100 mg) instead of Intermediate 4, oxazolidin-2-one (1.15 eq) instead of 4-methyl-1H-imidazole, t-BuOK (3 eq), CuI (0.6 eq), (S,S)-N,N'-dimethyl-1,2-diaminocyclohexane (0.2 eq) to provide Example 24 (40 mg, 14.8% yield) as a yellow solid. MS (ESI): C 25 H 23 N 5 O 2 Theoretical molecular weight of S: 457.55, m / z experimental molecular weight: 457.7 [M+H]+ . 1 H NMR(400MHz,DMSO-d6)δppm 8.46(d,J=2.0Hz,1H),7.78(d,J=8.4Hz,2H),7.73(s,1H),7.45(d,J=8.4Hz,1H),7.39-7.36(m,3H),7.21(d,J=8.4Hz,1H),7 .08(s,1H),6.54(s,1H),4.57(s,2H),4.44(t,J=7.6Hz,2H),4.08–4.00(m,4H),3.67(t,J=5.6Hz,2H),2.89(t,J=6.0Hz,2H).

[0506] Example 25.

[0507] 1. The title compound was prepared according to the procedure described for Example 21 using Intermediate 5 (200 mg) instead of Intermediate 4, imidazolidin-2-one (1 eq) instead of 4-methyl-1H-imidazole, t-BuOK (3 eq), CuI (0.5 eq), (S,S)-N,N'-dimethyl-1,2-diaminocyclohexane (0.2 eq) to provide Example 25 (30 mg, 14.8% yield) as a yellow solid. MS (ESI): C 25 H 24 N 6 Theoretical molecular weight of OS: 456.56, m / z experimental molecular weight: 456.8 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δppm 8.45(d,J=2.4Hz,1H),7.76(d,J=8.4Hz,2H),7.72(s,1H),7.44(dd,J=8.4,1.6Hz,1H),7.38–7.31(m,3H),7.09(d,J=8.4Hz,1H),7.01(s,1H), 6.91(s,1H),6.52(s,1H),4.51(s,2H),4.03(s,2H),3.80(t,J=7.6Hz,2 H), 3.63 (t, J = 6.0 Hz, 2H), 3.38 (t, J = 8.4 Hz, 2H), 2.82 (t, J = 6.0 Hz, 2H).

[0508] Example 26.

[0509] 1. Intermediate 5 (100 mg, 0.22 mmol), 1-methylimidazolidin-2-one (66 mg, 0.66 mmol), (Pd 2(dba) 3 A mixture of ) (100 mg, 0.11 mmol), t-BuOK (74 mg, 0.66 mmol) and SPhos (44 mg, 0.11 mmol) in dioxane (10 mL) was stirred at 100 ° C. for 16 h under nitrogen atmosphere. The solvent was removed under reduced pressure and the residue was purified by prep-HPLC to provide Example 26 (50 mg, yield 48.1%) as a yellow solid. MS (ESI): C 26 H 26 N 6 Theoretical molecular weight of OS: 470.59, m / z experimental molecular weight: 470.8 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δppm 8.45(d,J=2.4Hz,1H),7.76(d,J=8.4Hz,2H),7.72(s,1H),7.47(dd,J=8.4,2.0Hz,1H),7.38–7.31(m,3H),7.10(d,J=8.4Hz,1H),7.01(s,1H), 6.52(s,1H),4.51(s,2H),4.03(s,2H),3.74(t,J=7.2Hz,2H),3.63(t,J =5.6Hz, 2H), 3.41 (t, J = 8.4Hz, 2H), 2.83 (t, J = 6.0Hz, 2H), 2.75 (s, 3H).

[0510] Example 27.

[0511]

[0512] 1. 4-Fluoro-3-methoxy-benzaldehyde (5.0 g, 32.4 mmol), 1H-pyrazole (3.3 g, 48.6 mmol), K 2 CO 3 A mixture of (6.8 g, 48.6 mmol) in DMF (30 mL) was stirred under N 2 The mixture was stirred at 120° C. for 20 h. After cooling to RT, ice-water was added to the mixture, which was then extracted with EA. The combined organic extracts were washed with water, brine and Na 2 SO 4 Dry, filter and concentrate. The resulting residue was purified by column chromatography on silica gel to provide 2 (3.0 g, 53.4% ​​yield) as a light yellow solid. MS (ESI): C 11 H 10 N 2 O 2 Theoretical molecular weight: 202.21, m / z experimental molecular weight: 202.9 [M+H]+ .

[0513] 2. At -78 ° C, n-BuLi (11.3 mL, 2.4 M, 27.2 mmol) was added dropwise to a solution of 2-chlorothiazole (3.0 g, 25.1 mmol) in anhydrous THF (100 mL) and stirred at this temperature for 1 h. At -78 ° C, a solution of 2 (4.2 g, 20.9 mmol) was added dropwise. The resulting solution was slowly heated to RT. NH 4 The reaction mixture was quenched with Cl solution and extracted with EA. The combined organic extracts were washed with brine and washed with Na 2 SO 4 Dry, filter and concentrate. The resulting residue was purified by column chromatography on silica gel to provide 3 (5.6 g, yield 83.8%) as a yellow solid. MS (ESI): C 14 H 12 C1N 3 O 2 Theoretical molecular weight of S: 321.78, m / z experimental molecular weight: 321.8 [M+H] + .

[0514] 3. To a solution of 3 (5.6 g, 17.4 mmol) in TFA (20 mL) was added TES (11.4 g, 69.6 mmol) at RT. The reaction mixture was stirred at reflux for 1 h. The mixture was evaporated, and ice-water was added to the mixture, which was then extracted with EA. The mixture was washed with saturated NaHCO 3 The combined organic extracts were washed with Na 2 SO 4 Dry, filter and concentrate. The resulting residue was purified by column chromatography on silica gel to provide 4 (4.8 g, yield 90.2%) as a clear liquid. MS (ESI): C 14 H 12 C1N 3 Theoretical molecular weight of OS: 305.78, m / z experimental molecular weight: 305.8 [M+H] + .

[0515] 4. Following the procedure described for Example 1, 4 (200 mg) and Intermediate 1 (148 mg) were converted to Example 27 (10 mg, 57.3% yield) as a white solid. MS (ESI): C 28 H 28 N 6 Theoretical molecular weight of OS: 496.63, m / z experimental molecular weight: 496.8 [M+H] + . 1H NMR(400MHz,DMSO-d6)δppm 8.11(d,J=2.4Hz,1H),7.66(s,1H),7.53(d,J=8.4Hz,1H),7.36(m,2H),7.28(d,J=8.0Hz,1H),7.16(s,1H),7.13(s,1H),7.05(s,1H),6.93( d,J=8.0Hz,1H),6.45(s,1H),4.61(s,2H),4.06(s,2H),3.83(s,3H),3.68(t,J=6.0Hz,2H),2.96(t,J=6.0Hz,2H),2.31(s,3H),2.15(s,3H).

[0516] Example 28.

[0517] 1. Following the procedure described for Example 1, Intermediate 20 and Intermediate 2 were reacted to provide Example 28 as a white solid (43.2 mg, 26.2% yield). MS (ESI): C 25 H 23 N 5 O 2 Theoretical molecular weight of S: 457.55, m / z experimental molecular weight: 457.8 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δppm 8.48(d,J=2.0Hz,1H),7.75(d,J=12.4Hz,2H),7.69(d,J=8.0Hz,1H),7.44(dd,J=15.8,7.8Hz,2H),7.36(s,1H),7.19(d,J=8.0Hz,2H),7.0 5(s,1H),6.54(s,1H),4.54(s,2H),4.43(t,J=7.8Hz,2H),4.08(s,2H),4.03(t,J=8.0Hz,2H),3.64(t,J=5.8Hz,2H),2.86(t,J=5.6Hz,2H).

[0518] Example 29.

[0519] 1. Intermediate 22 (329 mg, 0.48 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-di(1,3,2-dioxaborolane) (203 mg, 0.8 mmol), Pd(dppf)Cl 2A mixture of (102 mg, 0.14 mmol) and AcOK (206 mg, 2.1 mmol) in anhydrous 1,4-dioxane (20 mL) was stirred at 100° C. overnight. The mixture was cooled to RT, concentrated and the residue was purified by chromatography on silica gel to provide 1 (250 mg, 69.0%). 28 H 32 BN 3 Theoretical molecular weight of O4S: 517.45, m / z experimental molecular weight: 517.6 [M+H] + .

[0520] 2. 1 (100 mg, 0.19 mmol) and 2-chloropyrimidine (23 mg, 0.20 mmol) were dissolved in 1,4-dioxane (8 mL) and H 2 O (2 mL) was added to the mixture 2 CO 3 (80mg, 0.57mmol), Pd(dppf)Cl 2 (14 mg, 0.02 mmol). The resulting mixture was stirred at 100°C overnight. The mixture was cooled to room temperature, poured into ice-water, extracted with EA, and the combined organic phases were washed with brine and washed with Na 2 SO 4 Dry, filter and concentrate. The resulting residue was purified by prep-TLC to provide Example 29 (9 mg, 10%) as a white solid. 26 H 23 N 5 O 2 Theoretical molecular weight of S: 469.16, m / z experimental molecular weight: 469.7 [M+H] + , 1 H NMR(400MHz,DMSO)δppm 8.90(d,J=4.8Hz,2H),8.34(d,J=8.1Hz,2H),7.51–7.32(m,5H),7.20(d,J=8.4Hz,1H),7.05(s,1H),4.55(s, 2H), 4.43 (t, J = 7.9Hz, 2H), 4.09 (s, 2H), 4.03 (t, J = 8.0Hz, 2H), 3.65 (t, J = 5.8Hz, 2H), 2.87 (t, J = 5.7Hz, 2H).

[0521] Example 30.

[0522] 1. To a solution of intermediate 22 (180 mg, 0.38 mmol) in DMI (6 mL) was added CuCN (70 mg, 0.78 mmol) and CuI (90 mg, 0.46 mmol). The resulting mixture was heated to 190 °C in a microwave for 1 h. The reaction mixture was cooled to RT, poured into water and precipitated with CH 2 Cl 2 Extraction. Using Na 2 SO 4 The combined extracts were dried, filtered and the filtrate was concentrated. The resulting residue was purified by prep-TLC to afford Example 30 (11 mg, 7%) as a white solid. 23 H 20 N 4 O 2 Theoretical molecular weight of S: 416.5, m / z experimental molecular weight: 416.8 [M+H] + , 1 H NMR(400MHz,DMSO-d6)δppm 7.78(d,J=8.1Hz,2H),7.46(d,J=8.1Hz,2H),7.37(s,1H),7.20(d,J=8.5Hz,1H),7.04(s,1H),4.55(s ,2H),4.46–4.41(m,2H),4.11(s,2H),4.06–4.01(m,2H),3.65(t,J=5.9Hz,2H),2.86(t,J=5.8Hz,2H).

[0523] Example 31.

[0524] 1. Intermediate 22 (240 mg, 0.5 mmol), morpholine (131 mg, 1.5 mmol), Pd 2 (dba) 3 (229 mg, 0.25 mmol), SPhos (103 mg, 0.25 mmol) and K 2 CO 3 A mixture of (207 mg, 1.5 mmol) in 1,4-dioxane (15 mL) was stirred at 100 °C overnight. The mixture was cooled to RT, poured into water and washed with CH 2 Cl 2 Extraction. Using Na 2 SO 4 The combined extracts were dried, filtered and the filtrate was concentrated. The resulting residue was purified by prep-TLC to provide Example 31 (10 mg, 4.2%) as a white solid. 26 H 28 N 4 O3 Theoretical molecular weight of S: 476.6, m / z experimental molecular weight: 476.8 [M+H] + , 1 H NMR(400MHz,DMSO-d6)δppm 7.45(d,J=9.9Hz,1H),7.37(s,1H),7.19(d,J=8.4Hz,1H),7.09(d,J=8.4Hz,2H),6.95(s,1H),6.87(d,J=8.5Hz,2H),4.53(s,2H),4. 48–4.34(m,2H),4.12–3.95(m,2H),3.88(s,2H),3.75–3.67(m,4H),3.64(t,J=5.8Hz,2H),3.08–3.01(m,4H),2.87(d,J=5.9Hz,2H).

[0525] Example 32.

[0526] 1. Following the procedure described for Example 31, t-BuOK (170 mg) was used instead of K 2 CO 3 , Intermediate 22 (240 mg) and oxazolidin-2-one (170 mg) were converted to Example 32 (10 mg, 4%) as a white solid. 25 H 24 N 4 O 4 Theoretical molecular weight of S: 476.55, m / z experimental molecular weight: 476.7 [M+H] +,1 H NMR(400MHz,DMSO)δppm 7.50(d,J=8.4Hz,2H),7.45(d,J=8.2Hz,1H),7.37(s,1H),7.26(d,J=8.4Hz,2H),7.20(d,J=8.3Hz,1H),6.98(s,1H), 4.54 (s, 2H), 4.43 (t, J = 7.0Hz, 4H), 4.04 (t, J = 7.1Hz, 4H), 3.98 (s, 2H), 3.64 (t, J = 5.9Hz, 2H), 2.86 (t, J = 5.9Hz, 2H).

[0527] Example 33.

[0528] 1. Following the procedure described for Example 31, using Cs 2 CO 3 (488mg) instead of K 2 CO 3, Intermediate 21 (220 mg) and thiomorpholine 1,1-dioxide (270 mg) were converted to Example 33 (7.8 mg, 2.9%) as a white solid. 26 H 28 N 4 O 4 S 2 Theoretical molecular weight: 524.65, m / z experimental molecular weight: 524.7 [M+H] + , 1 H NMR (400 MHz, CDCl 3 )δppm 7.38(d,J=8.8Hz,2H),7.25(d,J=7.8Hz,1H),7.19(d,J=8.4Hz,1H),7.00(s,1H),6.87–6.77(m,3H),4.64(s,2H),4.51(dd,J=8.8,7.0 Hz, 2H), 4.16 (t, J = 8.0Hz, 2H), 3.98 (s, 2H), 3.85 (t, J = 5.2Hz, 4H), 3.76 (t, J = 5.8Hz, 2H), 3.11 (t, J = 5.0Hz, 4H), 2.96 (t, J = 5.8Hz, 2H).

[0529] Example 34.

[0530]

[0531] 1. At -78°C, N 2 To a solution of 2-chlorothiazole (0.72 g, 6.00 mmol) in anhydrous THF (50 mL) was added n-BuLi (2.4 M, 2.5 mL, 6 mmol) dropwise. After 0.5 h, a solution of 1 (1.00 g, 5.43 mmol) in anhydrous THF (5 mL) was added dropwise. The reaction was slowly heated to RT. Saturated NH 4 The reaction was quenched with Cl and extracted with EtOAc. The combined organic extracts were washed with brine and washed with Na 2 SO 4 Drying, filtering and concentrating the filtrate gave the crude product, which was purified by silica gel chromatography to give 2 as a yellow oil (0.60 g, yield 36%). MS (ESI): C 11 H 10 ClNO 3 S 2 Theoretical molecular weight: 303.78, m / z experimental molecular weight: 304.1 [M+H] + .

[0532] 2. A mixture of 2 (600 mg, 1.97 mmol) in TES (3 mL) and TFA (10 mL) was stirred at 60 °C for 2 h. The mixture was concentrated and washed with saturated NaHCO 3 The residue was diluted, extracted with DCM and the combined organic extracts were washed with brine and washed with Na 2 SO 4 Dry, filter and concentrate. The resulting residue was purified by silica gel chromatography to provide 3 (400 mg, yield 70.5%) as a brown oil. MS (ESI): C 11 H 10 ClNO 2 S 2 Theoretical molecular weight: 287.78, m / z experimental molecular weight: 288.0 [M+H] + .

[0533] 3. Following the procedure described for Example 1, intermediates 20 (229 mg) and 3 (200 mg) were converted to Example 34 (30 mg, 9.26% yield) as a yellow solid. MS (ESI): C 23 H 23 N 3 O 4 S 2 Theoretical molecular weight: 469.57, m / z experimental molecular weight: 469.7 [M+H] + . 1 HNMR(301MHz,DMSO-d6)δppm 7.80(d,J=7.5Hz,2H),7.61(s,2H),7.45(d,J=7.2Hz,1H),7.37(s,1H),7.19(d,J=8.1Hz,1H),7.05(s,1H),4.54(s,2H) ,4.42(t,J=7.8Hz,2H),4.14(s,2H),4..02(t,J=7.8Hz,2H),3.64(t,J=5.4Hz,2H),3.18(s,3H),2.86(t,J=5.1Hz,2H).

[0534] Example 35.

[0535] 1. Following the procedure described for Example 31, using Cs 2 CO 3 (488mg) instead of K 2 CO 3 , Intermediate 21 (235 mg) and morpholine (130 mg) were converted to Example 35 (10.6 mg, 4.4%) as a white solid. 26 H 28 N4 O 3 Theoretical molecular weight of S: 476.60, m / z experimental molecular weight: 476.8 [M+H] + , 1 H NMR(400MHz,DMSO-d6)δppm 7.45(d,J=6.0Hz,1H),7.37(s,1H),7.23–7.12(m,2H),6.98(s,1H),6.8 4(s,1H),6.79(d,J=7.6Hz,1H),6.68(d,J=7.6Hz,1H),4.54(s,2H),4.43 (t,J=7.8Hz,2H),4.03(t,J=7.8Hz,2H),3.92(s,2H),3.72(t,J=4.6Hz,4H),3.64(t,J=6.0Hz,2H),3.08(t,J=4.6Hz,4H),2.86(t,J=5.8Hz,2H).

[0536] Example 36.

[0537] 1. Following the procedure described for Example 31, using Cs 2 CO 3 (371mg) instead of K 2 CO 3 , Intermediate 22 (180 mg) and thiomorpholine 1,1-dioxide (154 mg) were converted to Example 36 (9 mg, 4%) as a white solid. 26 H 28 N 4 O 4 S 2 Theoretical molecular weight: 524.65, m / z experimental molecular weight: 524.7 [M+H] + , 1 H NMR(300MHz,DMSO-d6)δppm 7.40(d,J=8.7Hz,1H),7.32(s,1H),7.14(d,J=8.4Hz,1H),7.07(d,J=8.3Hz,2H),6.92(d,J=4.6Hz,3H),4.50(s,2H),4 .39(t,J=7.8Hz,2H),3.99(t,J=7.8Hz,2H),3.85(s,2H),3.69(s,4H),3.60(t,J=5.7Hz,2H),3.07(s,4H),2.83(s,2H).

[0538] Alternative Preparation of Example 36

[0539] 1. Intermediate 22 (50 g, 0.106 mol), thiomorpholine 1,1-dioxide (71.8 g, 0.531 mol), Pd(OAc) 2 (12g, 0.053mol), SPhos (23.4g, 0.053mol) and Cs 2 CO 3 A mixture of (43.3 g, 0.133 mol) in anhydrous 1,4-dioxane (2.8 L) was heated at 100 °C under N 2 The mixture was stirred for 6 hours at 40 °C. The mixture was diluted with DCM: MeOH 10: 1 (1 L) and the resulting suspension was filtered. The filter cake was washed twice with DCM: MeOH = 10: 1, and the combined filtrate was concentrated. The resulting residue was dissolved with DCM: MeOH 10: 1 (200 mL), the mixture was heated to reflux for 30 min, MeOH (300 mL) was added and the mixture was heated to reflux for 20 min, and the suspension was filtered through diatomaceous earth. The filtrate was concentrated and the residue was treated four times as described above. After the fourth filtration, the combined filtrate was concentrated to provide a crude product as an orange solid, which was slurried twice with MeCN (300 mL) to provide Example 36 (25.9 g, 46.4%) as a white solid. MS (ESI): C 26 H 28 N 4 O 4 S 2 Theoretical molecular weight: 524.65, experimental molecular weight of m / z: 524.8 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δppm 7.45(dd,J=8.4,2.4,1H),7.37(d,J=2.1,1H),7.19(d,J=8.4,1H),7.12(d,J=8.7,2H),6.99–6.94(m,3H),4.54(s,2H),4.43(dd,J= 8.9,7.1,2H),4.03(dd,J=8.9,7.2,2H),3.89(s,2H),3.76–3.70(m,4H),3.64(t,J=6.0,2H),3.16–3.07(m,4H),2.86(t,J=5.9,2H).

[0540] Example 37.

[0541] 1. Intermediate 5 (225 mg, 0.50 mmol), tetrahydropyrimidin-2(1H)-one (150 mg, 1.50 mmol), Pd 2 (dba) 3A mixture of 1,4-dioxane (20 mL) and t-BuOK (92 mg, 0.1 mmol), SPhos (82 mg, 0.2 mmol) was stirred at 100 °C overnight. The mixture was cooled, poured into water and extracted with DCM. 2 SO 4 Dry, filter and concentrate the filtrate. The resulting residue was purified by prep-TLC to provide Example 37 (3.4 mg, 1.4%) as a white solid. 26 H 26 N 6 Theoretical molecular weight of OS: 470.60, m / z experimental molecular weight: 470.8 [M+H] + , 1 H NMR (400MHz, CD 3 OD)δppm 8.20(d,J=2.8Hz,1H),7.72(d,J=1.6Hz,2H),7.70(s,1H),7.68(s,1H),7.40(d,J=8.8Hz,2H),7.20(d,J=9.2Hz,1H),7 .14(s,1H),4.58(s,2H),4.09(s,2H),3.70(m,1H),3.40(t,J=5.8Hz,4H),2.97(t,J=5.8Hz,2H),2.1(t,J=6.0Hz,2H).

[0542] The compounds listed in Table 2 below were prepared in a similar manner to that described in Example 37.

[0543] Table 2

[0544]

[0545]

[0546] Example 38.

[0547] 1. A solution of Example 37 (30 mg, 0.064 mmol) in anhydrous DMF (3 mL) was cooled to 0°C, NaH (24 mg, 1 mmol) was added and after 0.5 h, CH 3 I. The reaction was heated to RT and stirred overnight. The mixture was poured into water and extracted with DCM. 2 SO 4 The combined extracts were dried, filtered and the filtrate was concentrated. The resulting residue was purified by prep-TLC to provide Example 38 (10.06 mg, 34.22%) as a white solid. 27 H 28N 6 Theoretical molecular weight of OS: 484.62, m / z experimental molecular weight: 484.8 [M+H] + . 1 H NMR (400 MHz, CDCl 3 )δ=7.92(d,J=2.1Hz,1H),7.74(d,J=1.5Hz,1H),7.66(d,J=8.5Hz,2H),7. 34(d,J=8.5Hz,2H),7.13(s,2H),7.08(s,1H),7.01(s,1H),6.54–6.45(m,1 H),4.61(s,2H),4.05(s,2H),3.75(d,J=5.8Hz,2H),3.71–3.64(m,2H),3. 40(t,J=6.1Hz,2H), 2.95(t,J=5.8Hz,2H), 2.13(dt,J=11.9Hz,6.0Hz,2H).

[0548] Example 39.

[0549] 1. A mixture of intermediate 21 (170 mg, 0.36 mmol), CuCN (39 mg, 0.72 mmol) and CuI (168 mg, 1.44 mmol) in DMI (2 mL) was heated to 190 ° C in a microwave for 50 minutes. The mixture was cooled, filtered and the solid was washed with DCM / MeOH (10:1) and water, and the aqueous layer was extracted with DCM / MeOH (10:1). The combined organic extracts were washed with water, brine and Na 2 SO 4 Dry, filter and concentrate the filtrate. The resulting residue was purified by prep-TLC to provide Example 39 (8.5 mg, 5.7% yield) as a white solid. MS (ESI): C 23 H 20 N 4 O 2 Theoretical molecular weight of S: 416.50, m / z experimental molecular weight: 416.8 [M+H] + . 1 H NMR (400 MHz, CDCl 3)δppm 7.59–7.53(m,2H),7.50(d,J=7.9Hz,1H),7.45(d,J=7.8Hz,1H),7.42–7.37(m,2H),7.20(d,J=9.0Hz,1H),7.00(s,1 H), 4.64 (s, 2H), 4.51 (dd, J = 8.8Hz, 7.0Hz, 2H), 4.06 (t, J = 8.0Hz, 4H), 3.75 (t, J = 5.9Hz, 2H), 2.97 (t, J = 5.8Hz, 2H).

[0550] Example 40.

[0551] 1. Following the procedure described for Example 31, using Cs 2 CO 3 (488mg) instead of K 2 CO 3 , Intermediate 21 (235 mg) and oxazolidin-2-one (200 mg) were converted to Example 40 (5 mg, 2%) as a white solid. 25 H 24 N 4 O 4 Theoretical molecular weight of S: 476.55, m / z experimental molecular weight: 476.8 [M+H] + . 1 H NMR (400 MHz, CDCl 3 )δppm 7.47–7.39(m,3H),7.38–7.32(m,2H),7.19(d,J=8.4Hz,1H),7.05(d,J=7.6Hz,1H),7.00(s,1H), 4.64(s,2H),4.53–4.48(m,4H),4.10–4.03(m,6H),3.75(t,J=5.6Hz,2H),2.96(t,J=5.8Hz,2H).

[0552] Example 41.

[0553]

[0554] 1. To a solution of 1 (2.00 g, 10.75 mmol) in DMF (30 mL) were added 1H-pyrazole (1.10 g, 16.13 mmol) and K 2 CO 3 (4.46 g, 32.25 mmol). The reaction was stirred at 100 °C for 18 h. The reaction was cooled to RT and then poured into ice-water and washed with CH 2 Cl 2 Extraction with Na2 SO 4 The extract was dried. The organic extract was concentrated to provide a residue, which was purified by silica gel chromatography to provide 2 (1.00 g, 53.7% yield) as a yellow solid. MS (ESI): C 9 H 7 N 3 Theoretical molecular weight of O: 173.18, m / z experimental molecular weight: 173.8 [M+H] + .

[0555] 2. At -78°C, N 2 To a solution of 2-chlorothiazole (762 mg, 6.35 mmol) in anhydrous THF (50 mL) was added n-BuLi (2.4 M, 2.89 mL) dropwise. After 0.5 h, a solution of 2 (1.00 g, 5.77 mmol) in anhydrous THF (10 mL) was added dropwise. The reaction was slowly heated to RT. NH 4 The mixture was quenched with aqueous Cl and extracted with EtOAc and Na 2 SO 4 The extract was dried. The organic extract was concentrated to provide a residue, which was purified by silica gel chromatography to provide 3 as a white solid (800 mg, yield 47.36%). MS (ESI): C 12 H 9 C1N 4 Theoretical molecular weight of OS: 292.74, m / z experimental molecular weight: 292.8 [M+H] + .

[0556] 3. A mixture of 3 (800 mg, 2.73 mmol), TES (5 mL) and TFA (15 mL) was stirred at 70 °C for 2 h. The mixture was concentrated and eluted with NaHCO 3 The residue was diluted with aqueous solution, extracted with DCM, and washed with Na 2 SO 4 The extract was dried. The extract was concentrated to provide a crude product, which was purified by silica gel chromatography to provide 4 (400 mg, yield 52.9%) as a white solid. MS (ESI): C 12 H 9 C1N 4 Theoretical molecular weight of S: 276.74, m / z experimental molecular weight: 276.8 [M+H] + .

[0557] 4. To a solution of 4 (400 mg, 1.46 mmol) in DMSO (10 mL) was added 7-bromo-1,2,3,4-tetrahydroisoquinoline (Key Organics, 335 mg, 1.58 mmol) and Cs2 CO 3 (1.54 g, 4.74 mmol). The reaction was stirred at 140 °C for 5 h, cooled to RT and poured into ice-water and extracted with DCM. 2 SO 4 The combined extracts were dried and concentrated under reduced pressure to provide a crude product. The crude product was purified by silica gel chromatography to provide 5 (300 mg, yield 45.42%) as a white solid. MS (ESI): C 21 H 18 Bn 5 Theoretical molecular weight of S: 452.37, m / z experimental molecular weight: 452.8 [M+H] + .

[0558] 5. 5 (300 mg, 0.45 mmol), oxazolidin-2-one (136 mg, 1.36 mmol), Pd 2 (dba) 3 A mixture of 1,4-dioxane (66 mg, 0.09 mmol), SPhos (92 mg, 0.225 mmol) and t-BuOK (162 mg, 1.35 mmol) was stirred at 100 °C overnight. The mixture was cooled, poured into water and washed with CH 2 Cl 2 Extraction with Na 2 SO 4 Dry, filter and concentrate the filtrate to provide a residue. The residue was purified by prep-HPLC to provide Example 41 (39.6 mg, 19.19%) as a white solid. 24 H 22 N 6 O 2 Theoretical molecular weight of S: 458.54, m / z experimental molecular weight: 458.8 [M+H] + , 1 H NMR (400 MHz, DMSO-d 6)δppm 8.59(dd,J=2.8,0.6Hz,1H),8.39(d,J=1.6Hz,1H),7.90-7.84(m,2H),7.82–7.79(m, 1H),7.45(dd,J=8.4Hz,2.4,1H),7.37(d,J=2.2Hz,1H),7.20(d,J=8.4Hz,1H),7.04(s ,1H),6.57(dd,J=2.5Hz,1.7Hz,1H),4.56(s,2H),4.43(dd,J=9.6Hz,6.4Hz,2H),4.0 9 (s, 2H), 4.03 (dd, J = 8.4Hz, 7.0Hz, 2H), 3.65 (t, J = 6.0Hz, 2H), 2.87 (t, J = 6.0Hz, 2H).

[0559] Example 42.

[0560] 1. To a solution of intermediate 5 (225 mg, 0.50 mmol) and morpholin-3-one (171 mg, 1.50 mmol) in anhydrous 1,4-dioxane (15 mL) was added K 2 CO 3 (209 mg, 1.51 mmol), CuI (10 mg, 0.05 mmol) and (S,S)-N,N'-dimethyl-1,2-diaminocyclohexane (8 mg, 0.05 mmol). The resulting solution was stirred at 150 °C for 1.5 h in a microwave. The mixture was cooled to RT, filtered and the filtrate was concentrated. The resulting residue was purified by prep-TLC to provide Example 42 (20.8 mg, 5.6%) as a white solid. 26 H 25 N 5 O 2 Theoretical molecular weight of S: 471.58, m / z experimental molecular weight: 471.8 [M+H] + , 1 H NMR(400MHz,DMSO-d6)δppm 8.45(d,J=2.4Hz,1H),7.77(d,J=8.8Hz,2H),7.73(d,J=1.6Hz,1H),7.36(d,J=8.4Hz,2H),7.25(s,1H),7.21(s,2H),7.02(s,1H),6.53(t,J= 2.2Hz, 1H), 4.55 (s, 2H), 4.19 (s, 2H), 4.04 (s, 2H), 3.96 (t, J = 5.0Hz, 2H), 3.70 (t, J = 5.0Hz, 2H), 3.66 (t, J = 6.0Hz, 2H), 2.90 (t, J = 6.0Hz, 2H).

[0561] Example 43.

[0562] 1. Following the procedure described for Example 1, Intermediate 20 (357 mg) and Intermediate 31 (270 mg) were converted to Example 43 (55 mg, 13% yield) as a white solid. MS (ESI): C 23 H 23 N 3 O 4 S 2 Theoretical molecular weight: 469.11, m / z experimental molecular weight: 69.7 [M+H] + ,1HNMR(400MHz,DMSO)δppm 7.87(d,J=8.3Hz,2H),7.52(d,J=8.3Hz,2H),7.45(dd,J=8.4,2.3Hz,1H),7.38(d,J=2.0Hz,1H),7.20(d,J=8.4Hz,1H),7.06(s, 1H), 4.55 (s, 2H), 4.48–4.35 (m, 2H), 4.13 (s, 2H), 4.09–3.98 (m, 2H), 3.65 (t, J = 5.9Hz, 2H), 3.19 (s, 3H), 2.87 (t, J = 5.9Hz, 2H).

[0563] Example 44.

[0564] 1. Following the procedure described for Example 1, Intermediate 20 (227 mg) and Intermediate 19 (200 mg) were converted to a crude product, which was purified by prep-TLC to provide Example 44 (12 mg, 4% yield) as a white solid. MS (ESI): C 27 H 27 N 5 O 2 Theoretical molecular weight of S: 485.19, m / z experimental molecular weight: 486.9 [M+H] + . 1H NMR(400MHz,DMSO-d6)δppm 7.46(d,J=8.7Hz,1H),7.36(dd,J=14.2,7.2Hz,5H),7.20(d,J=8.4Hz,1H),7.05(s,1H),6.97(s,1H),4.56(s,2H),4.44(t,J=7 .9Hz, 2H), 4.06 (d, J = 5.5Hz, 2H), 4.03 (d, J = 7.7Hz, 2H), 3.66 (t, J = 5.9Hz, 2H), 2.88 (t, J = 5.6Hz, 2H), 2.23 (s, 3H), 2.09 (s, 3H).

[0565] Example 45.

[0566] 1.

[0567] To a mixture of 2-methoxyethyl-1-amine (1 g, 13.3 mmol) in DMF (100 mL) was added 3-chloropropyl isocyanate (1.9 g, 16 mmol) followed by t-BuOK (2.23 g, 20 mmol) and the resulting mixture was stirred at RT for 16 h. The mixture was concentrated and the residue was purified by chromatography on silica gel to afford 1 (630 mg, 30% yield) as a white solid. MS (ESI): C 7 H 14 N 2 O 2 Theoretical molecular weight of S: 158.20, m / z experimental molecular weight: 159.0 [M+H] + .

[0568] 2. Use N 2 Purged 1 (245 mg, 1.55 mmol), intermediate 5 (140 mg, 0.31 mmol), t-BuONa (104 mg, 1.1 mmol), Pd(OAc) 2 (43 mg, 0.19 mmol) and SPhos (78 mg, 0.19 mmol) in 1,4-dioxane (8 mL) 3×. The resulting mixture was stirred at 100 °C for 15 h, cooled to RT, diluted with a mixture (DCM / MeOH, 10 / 1, 20 mL), filtered and the filtrate concentrated. The resulting residue was purified by chromatography on silica gel to provide Example 45 (13 mg, 8% yield) as a white solid. MS (ESI): C 29 H 32 N 6 O 2 Theoretical molecular weight of S: 528.68, m / z experimental molecular weight: 528.8 [M+H] + .1 HNMR(400MHz,DMSO)δppm 8.46(s,1H),7.77(d,J=8.3Hz,2H),7.72(s,1H),7.36(d,J=8.3Hz,2H),7.00–7.06(m,3H),7.02(s,1H),6.53(s,1H),4 .50(s,2H),4.04(s,2H),3.66–3.58(m,4H),3.45–3.40(m,6H),3.26(s,3H),2.85(t,J=5.8Hz,1H),2.01–1.96(m,2H).

[0569] Example 46.

[0570]

[0571] Example 47.

[0572] 1. Intermediate 1 (150 mg, 0.66 mmol), intermediate 24 (233 mg, 0.79 mmol) and K 2 CO 3 A mixture of (273 mg, 1.98 mmol) in DMSO (6 mL) was degassed and heated with N 2 Refill 3 times and stir at 130°C for 3h. The mixture was cooled to RT, diluted with a mixture of DCM / MeOH 20 / 1 (20 mL), filtered and the filtrate was concentrated, and purified by chromatography on silica gel to provide a crude product. The crude product was purified by SFC (chiralpak-IB, CO2-EtOH (DEA)) to provide Example 46 (56.38 mg, yield 17.6%) as a white solid, MS (ESI): C 28 H 31 N 5 Theoretical molecular weight of OS: 485.65, m / z experimental molecular weight: 485.9 [M+H] + . 1H NMR (400 MHz, DMSO) δ ppm 7.32-7.30 (m, 2H), 7.21 (d, J = 7.7 Hz, 1H), 7.10 (d, J = 8.2 Hz, 2H), 6.96 (s, 1H), 6.92 (s, 1H), 6.88 (d, J = 8.4 Hz, 2H), 4.58 (s, 2H), 3.89 (s, 2H), 3.74-3.71 (m, 4H), 3.66 (t, J = 5.7 Hz, 2H), 3.09-3.01 (m, 4H), 2.94 (t, J = 5.7 Hz, 2H), 2.23 (s, 3H), 2.08 (s, 3H) and Example 47 (15 mg) as a yellow / white solid, MS (ESI): C 28 H 31 N 5 Theoretical molecular weight of OS: 485.65, m / z experimental molecular weight: 485.9 [M+H] + . 1 H NMR (400MHz, DMSO) δppm7.35(d,J=8.2Hz,1H),7.25(s,1H),7.15(d,J=7.9Hz,1H),7.10(d,J=8.4Hz,2H),6.96(s,1H),6.88(d,J=8.5H z,2H),6.62(s,1H),4.60(s,2H),3.89(s,2H),3.74–3.67(m,6H),3.07–3.05(m,4H),2.98(t,J=5.4Hz,2H),2.09(s,3H),1.95(s,3H).

[0573] Example 48.

[0574]

[0575] 1. Following the procedure described for Example 1, except that the mixture was heated at 100°C for 2 h, intermediate 1 (280 mg) and intermediate 6 (403 mg) were converted to crude product, which was purified by Combi-Flash to provide 1 (380 mg, 66% yield) as a white solid. MS (ESI): C 24 H 23 Bn 4 Theoretical molecular weight of S: 479.4, m / z experimental molecular weight: 479 [M+H] + .

[0576] 2. 1 (240 mg, 0.5 mmol), thiomorpholine 1,1-dioxide (135 mg, 1 mmol), Pd 2 (dba) 3A mixture of 4-(41 mg, 0.05 mmol), SPhos (20 mg, 0.05 mmol), t-BuOK (122 mg, 1 mmol) in toluene (10 mL) was stirred at 100 °C for 2 h. The mixture was cooled and diluted with EA, washed with water, brine and washed with Na 2 SO 4 Dry, filter and concentrate. The resulting residue was purified by prep-HPLC to provide Example 48 (50 mg, yield 22%) as a white solid. MS (ESI): C 28 H 31 N 5 O 2 S 2 Theoretical molecular weight: 533.7, m / z experimental molecular weight: 534 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.16(s,1H),7.31(d,J=8.4Hz,2H),7.22(d,J=8.3Hz,1H),7.12(d,J=8.4Hz,2H),6.97(d,J=7.4Hz,3H),6.92 (s,1H),4.59(s,2H),3.90(s,2H),3.73(s,5H),3.67(t,J=5.7Hz,2H),3.11(s,4H),2.94(t,J=5.5Hz,2H),2.23(s,3H),2.08(s,3H).

[0577] Example 49.

[0578] 1. Following the procedure described for Example 1, except that the mixture was heated at 100°C for 5 h, Intermediate 25 (200 mg) and Intermediate 26 (266 mg) were converted to a crude product which was purified by prep-HPLC to afford Example 49 (82.6 mg, 19.20%) as a white solid. 27 H 25 N 5 Theoretical molecular weight of OS: 467.59, m / z experimental molecular weight: 467.8 [M+H] + , 1H NMR(400MHz,DMSO-d6)δppm 8.90(d,J=4.8Hz,2H),8.34(d,J=8.0Hz,2H),7.52(d,J=8.4Hz,1H),7.42(m,4H),7.17(d,J=8.4Hz,1H),7.04(s,1H),4.54(s,2H),4. 09 (s, 2H), 3.80 (t, J = 7.0Hz, 2H), 3.65 (t, J = 5.8Hz, 2H), 2.86 (t, J = 5.4Hz, 2H), 2.47 (d, J = 7.8Hz, 2H), 2.05 (dt, J = 14.7Hz, 7.3Hz, 1H).

[0579] Example 50.

[0580] 1. Except that the mixture was heated at 100°C for 5 h and Cs 2 CO 3 (663mg) instead of K 2 CO 3 In addition, following the procedure described for Example 1, Intermediate 25 (235 mg) and Intermediate 24 (200 mg) were converted to a crude product, which was purified by prep-HPLC to afford Example 50 (66.2 mg, 20.51%) as a white solid. 27 H 30 N 4 O 2 Theoretical molecular weight of S: 474.62, m / z experimental molecular weight: 474.8 [M+H] + , 1 H NMR(400MHz,DMSO-d6)δppm 7.52(d,J=8.4Hz,1H),7.45(s,1H),7.17(d,J=8.4Hz,1H),7.09(d,J=8.4H z,2H),6.95(s,1H),6.88(d,J=8.4Hz,2H),4.52(s,2H),3.88(s,2H),3.80( t,J=7.0Hz,2H),3.73(t,J=7.0Hz,4H),3.63(t,J=5.8Hz,2H),3.01(t,J=4 .6Hz, 4H), 2.86 (t, J = 5.8Hz, 2H), 2.47 (t, J = 4.0Hz, 2H), 2.09–1.99 (m, 2H).

[0581] Example 51.

[0582]

[0583] 1. Following the procedure described for Example 1, except that the mixture was heated at 100°C for 2 h, intermediate 25 (380 mg) and intermediate 6 (366 mg) were converted to crude products, which were purified by Combi-Flash to provide 1 (280 mg, 52% yield) as a white solid. MS (ESI): C 23 H 22 Bn 3 Theoretical molecular weight of OS: 468.4, m / z experimental molecular weight: 468 [M+H] + .

[0584] 2. 1 (235 mg, 0.5 mmol), thiomorpholine 1,1-dioxide (135 mg, 1 mmol), Pd 2 (dba) 3 A mixture of 4-(41 mg, 0.05 mmol), SPhos (20 mg, 0.05 mmol), t-BuOK (122 mg, 1 mmol) in toluene (10 mL) was stirred at 100 °C for 2 h. The mixture was cooled and diluted with EA, washed with water, brine and washed with Na 2 SO 4 Dry, filter and concentrate. The resulting residue was purified by prep-HPLC to provide Example 51 (110 mg, yield 42%) as a white solid. MS (ESI): C 27 H 30 N 4 O 3 S 2 Theoretical molecular weight: 522.7, m / z experimental molecular weight: 523 [M+H] + . 1 H NMR (400 MHz, CDCl 3 )δppm7.51(d,J=8.2Hz,1H),7.45(s,1H),7.16(d,J=8.3Hz,1H),7.11(d,J=8.2Hz,2H),6.99–6.93(m,J=4.9Hz,3H),4.52(s,2H),3.89(s, 2H),3.80(t,J=6.9Hz,2H),3.72(s,4H),3.66–3.59(m,2H),3.10(s,4H),2.85(t,J=5.6Hz,2H),2.47(d,J=8.0Hz,2H),2.07–1.99(m,2H).

[0585] Example 52.

[0586]

[0587] 1. Following the procedure described for Example 1, except that the mixture was heated at 100° C. for 4 h, intermediate 26 (300 mg) and 7-bromo-1,2,3,4-tetrahydroisoquinoline hydrochloride (Key Organics, 270 mg) were converted to a crude product which was purified by flash chromatography to afford 1 (380 mg, 78.7% yield) as a white solid. MS (ESI): C 23 H 19 Bn 4 Theoretical molecular weight of S: 463.40, m / z experimental molecular weight: 462.8 [M+H] + .

[0588] 2. 1 (150 mg, 0.324 mmol), 1-methylimidazolidin-2-one (162 mg, 1.62 mmol), Pd 2 (dba) 3 A mixture of 4-nitropropene (148 mg, 0.162 mmol), SPhos (67 mg, 0.162 mmol) and t-BuOK (109 mg, 0.972 mol) in anhydrous 1,4-dioxane (21 mL) was stirred at 100° C. for 6 hours. The mixture was diluted with DCM:MeOH 10:1 and filtered, and the filter cake was washed twice with DCM:MeOH 10:1. The combined filtrate was concentrated and the residue was purified by flash chromatography to provide the product, which was purified by preparative-HPLC to provide Example 52 (69 mg, 44.2%, 99.1% purity at 214 nm) as a white solid. MS (ESI): C 27 H 26 N 6 Theoretical molecular weight of OS: 482.61, m / z experimental molecular weight: 482.8 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δppm 8.90(d,J=4.6,2H),8.34(d,J=7.6,2H),7.48(d,J=8.2,1H),7.42(dd,J=14.3,6.4,3H),7.33(s,1H),7.11(d,J=8.4,1H),7.04( s,1H),4.52(s,2H),4.09(s,2H),3.74(t,J=7.9,2H),3.64(t,J=5.8,2H),3.42(t,J=7.7,2H),2.83(t,J=5.5,2H),2.75(s,3H).

[0589] Example 53.

[0590] 1. A mixture of the product of Example 52 Step 1 (150 mg, 0.324 mmol) and imidazolidin-2-one (139 mg, 1.62 mmol) was treated as described in Example 52 Step 2 to provide a crude product that was purified by flash chromatography. The resulting material was slurried with PE:hexanes 1:1 to provide Example 53 (54.3 mg, 35.8%, 99.8% purity at 214 nm) as a white solid. MS (ESI): C 26 H 24 N 6 Theoretical molecular weight of OS: 468.58, m / z experimental molecular weight: 468.8 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δppm 8.90(d,J=4.8,2H),8.34(d,J=8.0,2H),7.43(dd,J=16.4,8.5,4H),7.34(s,1H),7.10(d,J=8.4,1H),7.05(s,1H),6. 92(s,1H),4.52(s,2H),4.09(s,2H),3.82(t,J=5.8,2H),3.64(t,J=5.8,2H),3.43–3.36(m,4H),2.84(t,J=5.7,2H).

[0591] Example 54.

[0592] 1. Intermediate 26 (170 mg) and Intermediate 27 (224 mg) were converted to crude products following the procedure described for Example 1, except that the mixture was heated at 100°C for 5 h. The crude product was purified by prep-HPLC to afford Example 54 (64.7 mg, 23.35%) as a white solid. 27 H 27 N 5 Theoretical molecular weight of OS: 469.61, m / z experimental molecular weight: 469.8 [M+H] + , 1 H NMR(400MHz,DMSO-d6)δppm 8.90(d,J=4.8Hz,2H),8.34(d,J=7.6Hz,2H),7.51–7.36(m,3H),7.10–6.98(m,2H),6.86–6.75(m,2H),4.49(s ,2H),4.08(s,2H),3.72(t,J=4.4Hz,2H),3.61(t,J=5.6Hz,2H),3.05(t,J=4.8Hz,4H),2.79(t,J=5.8Hz,2H).

[0593] Example 55.

[0594]

[0595] 1. Use N 2 Purge 5-bromonicotinaldehyde (2 g, 10.8 mmol), 1H-pyrazole (1.46 g, 21.5 mmol), CuI (1.03 g, 5.4 mmol), (S,S)-N,N'-dimethyl-1,2-diaminocyclohexane (307 mg, 2.16 mmol) and Cs 2 CO 3 (10.6 g, 32.4 mmol) in DMF (40 mL) was added 3 times and the mixture was heated to 120 ° C for 16 h. The mixture was cooled to RT, diluted with EtOAc, filtered and the filtrate was concentrated. The resulting residue was purified by chromatography on silica gel to provide a mixture of 1 and 2 as a brown solid (1 g, impure). MS (ESI): C 9 H 7 N 3 Theoretical molecular weight of O: 173.18, m / z experimental molecular weight: 174.0 [M+H] + .

[0596] 2. To a mixture of 1 and 2 (1 g, 5.78 mmol) in MeOH (10 mL) was added NaBH at 0 °C. 4 (330 mg, 8.67 mmol), and the mixture was heated to RT and stirred for 2 h. The mixture was concentrated and the residue was purified by chromatography on silica gel to provide 2 as a white solid (470 mg, yield 25%). MS (ESI): C 9 H 9 N 3 Theoretical molecular weight of O: 175.19, m / z experimental molecular weight: 176.1 [M+H] + .

[0597] 3. To 2 (470 mg, 2.69 mmol) in DCM (15 mL) was added Dess-Martin reagent (1.48 g, 3.49 mmol). The resulting mixture was stirred at RT for 30 min, concentrated and the residue was purified by chromatography on silica gel to provide 1 (420 mg, 90% yield) as a white solid. MS (ESI): C 9 H 7 N 3 Theoretical molecular weight of O: 173.18, m / z experimental molecular weight: 174.0 [M+H] + .

[0598] 4. At -70°C, N2 n-BuLi (1.32 mL, 3.16 mmol, 2.4 M) was added dropwise to a solution of 2-chlorothiazole (378 mg, 3.16 mmol) in THF (2 mL) at 4 °C. After stirring for 30 min, a solution of 1 (420 mg, 2.43 mmol) in THF (15 mL) was added dropwise and the resulting mixture was heated to RT and stirred overnight. NH 4 The mixture was quenched with saturated aqueous Cl (20 mL), extracted with EtOAc and the combined organic extracts were washed with brine and washed with Na 2 SO 4 Dry, filter and concentrate the filtrate. The resulting residue was purified by chromatography on silica gel to provide 3 (490 mg, 69% yield) as an off-white solid. MS (ESI): C 12 H 9 C1N 4 Theoretical molecular weight of OS: 292.74, m / z experimental molecular weight: 292.8 [M+H] + .

[0599] 5. To a solution of 3 (490 mg, 1.68 mmol) in DCM (8 mL) was added SOCl dropwise 2 (240 mg, 2.01 mmol). After stirring for 2 h, the mixture was concentrated to provide a yellow-white solid. The solid was dissolved in AcOH (10 mL) and Zn powder (546 mg, 8.4 mmol) was added. The resulting mixture was stirred at RT for 1 h and washed with NaHCO 3 The combined organic phases were washed with brine and washed with Na 2 SO 4 Dry, filter and concentrate the filtrate. The resulting residue was purified by chromatography on silica gel to provide 4 (350 mg, 75% yield) as a white oil. MS (ESI): C 12 H 9 C1N 4 Theoretical molecular weight of S: 276.74, m / z experimental molecular weight: 277.0 [M+H] + .

[0600] 6. 4 (100 mg, 0.36 mmol), intermediate 20 (140 mg, 0.44 mmol) and K 2 CO 3 A mixture of (150 mg, 1.08 mmol) in DMSO (10 mL) was stirred at 120° C. under nitrogen atmosphere for 2 h, cooled to RT and ice-water was added to the mixture, followed by extraction with EA. The combined organic extracts were washed with water, brine and Na 2 SO4 Dry, filter and concentrate the filtrate. The resulting residue was purified by prep-TLC to provide Example 55 (75 mg, 45.5% yield) as a yellow solid. MS (ESI): C 24 H 22 N 6 O 2 Theoretical molecular weight of S: 458.54, m / z experimental molecular weight: 458.9 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δppm 8.97(d,J=2.0Hz,1H),8.60(d,J=2.0Hz,1H),8.44(s,1H),8.12(s,1H), 7.80(s,1H),7.45(d,J=8.4Hz,1H),7.36(s,1H),7.18(d,J=8.4Hz,1H), 7.07(s,1H),6.60(s,1H),4.54(s,2H),4.42(t,J=8.0Hz,2H),4.14(s,2 H), 4.02 (t, J = 8.0Hz, 2H), 3.64 (t, J = 5.6Hz, 2H), 2.86 (t, J = 5.6Hz, 2H).

[0601] Example 56.

[0602] 1. Intermediate 1 (100 mg) and intermediate 28 (156 mg) were converted to crude product according to the procedure described for Example 1, except that the mixture was heated at 120°C for 3 h. The crude product was purified by preparative-HPLC to afford Example 56 (60 mg, 0.124 mmol, 28% yield) as a white solid. MS (ESI): C 9 H 9 B O 2 Theoretical molecular weight: 485.19, m / z experimental molecular weight: 485.9 [M+H] + . 1 H NMR (400MHz, CD 3OD)δ7.51ppm(d,J=8.4Hz,2H),7.36(d,J=8.0Hz,1H),7.27(d,J=8.7Hz,3H),7.22(d,J=8.1Hz,1H),6.96(s,1H),6.93(s,1H),4.63(s, 2H), 4.47 (t, J = 8.2Hz, 2H), 4.09 (t, J = 8.0Hz, 2H), 4.00 (s, 2H), 3.72 (t, J = 5.9Hz, 2H), 3.03 (t, J = 5.8Hz, 2H), 2.33 (s, 3H), 2.22 (s, 3H).

[0603] Example 57.

[0604] 1. Following the procedure described for Example 1, except that the mixture was heated at 120°C for 2 h, Intermediate 29 (135 mg) and Intermediate 28 (100 mg) were converted to a crude product, which was purified by prep-TLC to provide Example 57 (35 mg, 35.3% yield) as a white solid. MS (ESI): C 26 H 27 N 5 O 3 Theoretical molecular weight of S: 489.59, m / z experimental molecular weight: 489.9 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δppm 7.50-7.45(m,3H),7.32(s,1H),7.25(d,J=8.0Hz,2H),7.10(d,J=8.4Hz,1H),6.97(s,1H),4.51-4.48(m,2H),4.42(t,J=8.0Hz,2H),4.0 3(t,J=8.4Hz,2H), 3.96(s,2H), 3.74(t,J=8.0Hz,2H), 3.62(t,J=5.6Hz,2H), 3.42(t,J=8.4Hz,2H), 2.82(t,J=5.6Hz,2H), 2.75(s,3H).

[0605] Example 58.

[0606] 1. Following the procedure described for Example 1, except that the mixture was heated at 120°C for 3 h, Intermediate 27 (300 mg) and Intermediate 28 (307 mg) were converted to crude products, which were purified by prep-TLC to provide Example 58 (38 mg, 8% yield) as a white solid. MS (ESI): C 26 H 28N 4 O 3 Theoretical molecular weight of S: 476.19, m / z experimental molecular weight: 476.9 [M+H] + , 1 H NMR(400MHz,DMSO-d6)δppm 7.49(d,J=8.3Hz,2H),7.26(d,J=8.4Hz,2H),7.03(d,J=8.1Hz,1H),6.97(s,1H),6.80(d,J=10.1Hz,2H),4.44(dd,J=17.0,9.1Hz ,4H),4.04(t,J=7.9Hz,2H),3.97(s,2H),3.78–3.64(m,4H),3.60(t,J=5.7Hz,2H),3.06(d,J=5.1Hz,4H),2.78(t,J=5.7Hz,2H).

[0607] Example 59.

[0608] 1. Following the procedure described for Example 1, Intermediate 35 (351 mg) and Intermediate 30 (250 mg) were heated at 130° C. for 2 h. The mixture was cooled to RT, diluted with a mixture of DCM / MeOH 20 / 1 (20 mL), filtered and the filtrate concentrated. The resulting residue was purified by chromatography on silica gel to afford Example 59 (37.5 mg, 9% yield) as an off-white solid. MS (ESI): C 29 H 34 N 4 O 2 Theoretical molecular weight of S: 502.68, m / z experimental molecular weight: 502.9 [M+H] + . 1 HNMR(400MHz,DMSO)δppm 7.20–7.16(m,4H),7.10–7.04(m,3H),6.98(s,1H),4.49(s,2H),3.95–3.92(m,4H),3.64–3.59(m,4H),3. 44–3.38(m,2H),3.32–3.31(m,2H),2.84(s,5H),2.76–2.68(m,1H),2.04–1.98(m,2H),1.67–1.61(m,4H).

[0609] Example 60.

[0610] 1. Following the procedure described for Example 1, using Cs 2 CO 3 (313mg) instead of K2 CO 3 And the mixture was heated at 130°C for 4h, and Intermediate 35 (100mg) and Intermediate 24 (106mg) were converted into crude products, which were purified by prep-TLC to provide Example 60 (20mg, yield 13%) as a white solid. MS (ESI): C 28 H 33 N 5 O 2 Theoretical molecular weight of S: 503.24. 1 H NMR(400MHz,DMSO)δppm 7.21(s,1H),7.13(dd,J=9.4,5.6Hz,5H),6.92(d,J=8.5Hz,2H),4.56(s,2H),3.93(s,2H),3.79–3.70(m,4H),3.68(t,J=5.9 Hz,2H),3.64–3.54(m,2H),3.33(t,J=6.0Hz,2H),3.17–3.00(m,4H),2.91(t,J=5.7Hz,2H),2.85(s,3H),2.18–1.93(m,2H).

[0611] Example 61.

[0612] 1. Following the procedure described for Example 1, except that the mixture was heated at 100°C for 3 h, Intermediate 35 (170 mg) and Intermediate 31 (200 mg) were converted to crude product, which was purified by prep-TLC to provide Example 61 (27 mg, 8% yield) as a white solid. MS (ESI): C 25 H 28 N 4 O 3 S 2 Theoretical molecular weight: 496.16, m / z experimental molecular weight: 497.0 [M+H] +,1 H NMR(400MHz,DMSO-d6)δppm 7.87(d,J=8.0Hz,2H),7.52(d,J=8.2Hz,2H),7.08(dd,J=15.4,7.2Hz,4H),4.51(s,2H),4.14(s,2H),3 .62(dt,J=15.4,5.6Hz,4H),3.32(d,J=9.1Hz,2H),3.19(s,3H),2.92–2.77(m,5H),2.08–1.95(m,2H).

[0613] Example 62.

[0614] 1. Intermediate 20 (204 mg) and intermediate 30 (150 mg) were converted to Example 62 (56 mg, 23% yield) as an off-white solid according to the procedure described for Example 59, except that the mixture was heated at 130°C for 4.5 h. MS (ESI): C 27 H 29 N 3 O 3 Theoretical molecular weight of S: 475.61, m / z experimental molecular weight: 475.8 [M+H] + . 1 H NMR (400 MHz, DMSO) δ ppm 7.45 (d, J = 8.1 Hz, 1H), 7.37 (s, 1H), 7.20–7.17 (m, 5H), 6.99 (s, 1H), 4.54 (s, 2H), 4.45–4.41 (m, 2H), 4.05–4.01 (m, 2H), 3.95–3.92 (m, 4H), 3.64 (t, J = 5.7 Hz, 2H), 3.45–3.39 (m, 2H), 2.86 (t, J = 5.7 Hz, 2H), 2.75–2.71 (m, 1H), 1.67–1.61 (m, 4H).

[0615] Example 63.

[0616] 1. Following the procedure described for Example 31, using Cs 2 CO 3 (833mg) instead of K 2 CO 3 And use N 2 The vessel was purged 3×, Intermediate 22 (200 mg) and 3-methoxyazetidine hydrochloride (159 mg) were heated at 100° C. for 5 h, and the mixture was cooled to RT, diluted with a mixture (DCM / MeOH, 10 / 1, 20 mL), filtered and the filtrate was concentrated. The resulting residue was purified by chromatography on silica gel to provide Example 63 (35.7 mg, 17.7% yield) as an off-white solid. MS (ESI): C 26 H 28 N 4 O 3 Theoretical molecular weight of S: 476.60, m / z experimental molecular weight: 476.8 [M+H] + . 1HNMR(400MHz,DMSO)δppm 7.45(d,J=8.3Hz,1H),7.37(s,1H),7.19(d,J=8.7Hz,1H),7.04(d,J=8.1Hz,2H),6.93(s,1H),6.38(d,J=8.2Hz,2H),4.53(s,2H),4.43(t,J= 7.8Hz,2H),4.32–4.27(m,1H),4.05–3.99(m,4H),3.85(s,2H),3.64(t,J=5.8Hz,2H),3.55–3.52(m,2H),3.23(s,3H),2.86(t,J=5.8Hz,2H).

[0617] Example 64.

[0618]

[0619] 1. Intermediate 27 (900 mg) and intermediate 6 (1.1 g) were converted to 1 (400 mg, 23% yield) as a yellow solid according to the procedure described for Example 1, except that the mixture was heated at 130°C for 3 h. MS (ESI): C 23 H 24 Bn 3 Theoretical molecular weight of OS: 469.08, m / z experimental molecular weight: 469.7 [M+H] + .

[0620] 2. 1 (150 mg, 0.32 mmol), thiomorpholine 1,1-dioxide (180 mg, 1.3 mmol), Pd 2 (dba) 3 A mixture of 4-nitropropene (90 mg, 0.1 mmol), SPhos (80 mg, 0.2 mmol) and t-BuONa (170 mg, 1.8 mmol) in anhydrous 1,4-dioxane (25 mL) was stirred at 100° C. overnight. The reaction mixture was cooled to RT, filtered and the filtrate was concentrated to provide a residue, which was purified by prep-TLC to provide Example 64 (35 mg, 21%) as a white solid. 27 H 32 N 4 O 3 S 2 Theoretical molecular weight: 524.19, m / z experimental molecular weight: 524.8 [M+H] + , 1H NMR(400MHz,DMSO)δppm 7.08(d,J=8.4Hz,2H),7.00(d,J=8.2Hz,1H),6.94(d,J=5.5Hz,3H),6.77(d,J=9.1Hz,2H),4.4 5(s,2H),3.87(s,2H),3.69(m,8H),3.58(t,J=5.7Hz,2H),3.04(m,8H),2.76(t,J=5.6Hz,1H).

[0621] Example 65.

[0622]

[0623] 1. Intermediate 5 (200 mg, 0.44 mmol), TEA (134 mg, 1.33 mmol) and Pd(dppf)Cl 2 A mixture of (32.4 mg, 0.044 mmol) in MeOH (2 mL) and MeCN (1 mL) was heated at 100 °C for 24 h in a bomb under CO atmosphere. The mixture was filtered through celite, the filter cake was washed with EA and the combined filtrates were concentrated to give the crude product, which was purified by silica gel chromatography to give 1 (140 mg, 73.4% yield) as a white solid. MS (ESI): C 24 H 22 N 4 O 2 Theoretical molecular weight of S: 430.53, m / z experimental molecular weight: 430.8 [M+H] + .

[0624] 2. 1 (140 mg, 0.33 mmol), N 2 H 4 ·H 2 A mixture of O (130 mg, 2.60 mmol) in EtOH (1 mL) and THF (1 mL) was placed in a bomb and heated at 80° C. for 5 days. The mixture was concentrated to provide a crude product, which was purified by silica gel chromatography to provide 2 (125 mg, 89.3% yield) as a white solid. MS (ESI): C 23 H 22 N 6 Theoretical molecular weight of OS: 430.53, m / z experimental molecular weight: 430.8 [M+H] + .

[0625] 3. 2 (120 mg, 0.28 mmol), trimethyl orthoacetate (132 mg, 0.70 mmol), NH 4A mixture of Cl (4.5 mg, 0.08 mmol) in EtOH (1 mL) and THF (1 mL) was placed in a sealed tube, which was then heated at 80 °C for 18 hours. The mixture was cooled and trimethyl orthoacetate (132 mg, 0.70 mmol) and NH 4 Cl (4.5 mg, 0.08 mmol) was added and the mixture was heated at 80 °C for 18 h. The mixture was cooled and trimethyl orthoacetate (132 mg, 0.70 mmol) and NH 4 Cl (4.5 mg, 0.08 mmol) was added and the mixture was heated at 80 °C for 18 hours. The mixture was cooled and concentrated. The residue was purified by prep-HPLC to provide Example 65 as a white solid (30 mg, 23.7% yield, 96.2% purity at 214 nm). MS (ESI): C 25 H 22 N 6 Theoretical molecular weight of OS: 454.55, m / z experimental molecular weight: 454.8 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δppm 8.46(d,J=2.2,1H),7.85(s,1H),7.80–7.76(m,3H),7.73(d,J=1.5,1H),7.40(d,J=8.0,1H),7.36(d,J=8.6,2H),7. 04(s,1H),6.53(dd,J=2.4,1.8,1H),4.65(s,2H),4.05(s,2H),3.70(t,J=5.9,2H),2.98(t,J=5.8,2H),2.58(s,3H).

[0626] Example 66.

[0627] 1. The hydrochloride salt of intermediate 1 (55 mg, 0.21 mmol), intermediate 34 (57.7 mg, 0.21 mmol), Pd 2 (dba) 3 A mixture of 1,2-dioxane (4 mL) and 1,2-dioxane (27.5 mg, 0.03 mmol), SPhos (24.7 mg, 0.06 mmol) and t-BuOK (84 mg, 0.75 mmol) was heated at 90 °C under N 2 The mixture was cooled to RT, poured into water and extracted with EtOAc. The combined organic layers were washed with water and brine, and then washed with Na 2 SO 4Drying and concentration gave a crude product, which was purified by prep-HPLC to give Example 66 as a white solid (1.9 mg, yield 2%). MS calc: 467.2; MS found: 468.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ2.08(3H,s),2.23(3H,s),2.96(2H,t,J=6.4Hz),,3.68(2H,t,J=6.0Hz),3.95(2H,s),4.61(2H,s),6.29(1H,d,J =1.6Hz),6.38(1H,s),6.93(1H,s),7.22(1H,d,J=7.6Hz),7.31-7.34(2H,m),7.42-7.44(2H,m),7.50-7.60(5H,m).

[0628] Example 67.

[0629]

[0630] 1. A mixture of 1 (2.00 g, 16.0 mmol), ethylene glycol (1.12 g, 18.0 mmol) and TsOH (100 mg, 0.53 mmol) in benzene (10 mL) was refluxed for 18 h and concentrated. The residue was dissolved in Et 2 O and 10% NaHCO 3 Wash the solution with Na 2 SO 4 The organic mixture was dried and filtered, and the filtrate was evaporated to afford 2 (1.45 g, 54%) as a colorless oil.

[0631] 2. In N 2 To a solution of 1H-pyrazole (1.16 g, 17.0 mmol) in anhydrous DMF (10.0 mL) was added NaH (60% dispersion in mineral oil, 3.50 g, 87.0 mmol) and the resulting mixture was stirred at 60 ° C for 2 h. Then, a solution of 2 (1.45 g, 8.57 mmol) in DMF (3.0 mL) was added dropwise and the resulting mixture was stirred at 80 ° C for 3 h. The mixture was cooled to RT, poured into water and extracted with EtOAc. The combined organic extracts were washed with water, brine, and Na 2 SO 4 Drying and concentration gave a crude product which was purified by silica gel chromatography to afford 3 (862 mg, 58% yield) as a colorless oil.

[0632] 3. 3 (862 mg, 3.97 mmol), CuSO4 (64.0 mg, 0.40 mmol), H 2 O (5.00 mL) and HCO 2 The mixture was stirred at 80 °C for 4 h. The mixture was cooled, poured into water and treated with K 2 CO 3 The aqueous solution was basified to pH 8. The mixture was extracted with EtOAc. The combined organic extracts were washed with water, brine, and Na 2 SO 4 Drying and concentration gave a crude product which was purified by silica gel chromatography to afford 4 (320 mg, 46% yield) as a colorless oil.

[0633] 4. At -78°C, N 2 To a solution of 2-chlorothiazole (221 mg, 1.85 mmol) in anhydrous THF (10 mL) was added n-BuLi (2.5 M, 0.8 mL, 2.00 mmol) dropwise. After 1 h, a solution of 4 (320 mg, 1.85 mmol) in anhydrous THF (3 mL) was added dropwise. The resulting solution was slowly heated to RT. The mixture was heated with NH 4 The mixture was diluted with Cl solution and extracted with EtOAc. The organic extract was concentrated to provide a residue, which was purified by silica gel chromatography to provide 5 (173 mg, 32% yield) as a yellow oil.

[0634] 5. 5 (388 mg, 1.33 mmol), hydrochloride of intermediate 1 (350 mg, 1.33 mmol), Pd 2 (dba) 3 A mixture of 1,2-dioxane (6 mL) and 1,2-dioxane (91.5 mg, 0.1 mmol), SPhos (82.3 mg, 0.2 mmol) and t-BuOK (446 mg, 3.99 mmol) was heated at 90 °C under N 2 The mixture was cooled to RT, poured into water and extracted with EtOAc. The combined organic extracts were washed with water and brine, and then washed with Na 2 SO 4 Drying and concentration gave a crude product, which was purified by prep-HPLC to afford 6 (170 mg, yield 26%) as a white solid.

[0635] 6. To a solution of 6 (170 mg, 0.35 mmol) in TFA (10 mL) was added TES (3 mL) and the resulting mixture was stirred at 100° C. for 1 h. The mixture was concentrated and the residue was purified by prep-HPLC to afford Example 67 (5.20 mg, yield 3%) as a white solid. 1H NMR (400 MHz, DMSO-d 6 )δ2.08(3H,s),2.22(3H,s),2.94(2H,t,J=5.6Hz),,3.67(2H,t,J=5.6H z),4.15(2H,s),4.60(2H,s),6.60(1H,t,J=2.0Hz),6.91(1H,s),7.08(1 H,s),7.22(1H,s),7.30(2H,d,J=8.0Hz),7.81(1H,d,J=1.2Hz),8.13(1H , s), 8.45 (1H, d, J = 1.6Hz), 8.60 (1H, d, J = 2.0Hz), 8.97 (1H, d, J = 2.4Hz).

[0636] Example 68.

[0637]

[0638] 1. In addition to using Cs 2 CO 3 (1.37mg) instead of K 2 CO 3 Intermediate 6 (400 mg) and intermediate 35 (580 mg) were converted to 1 (600 mg, 85%) as a brown oil according to the procedure described for Example 1, except that the mixture was heated at 110°C for 2 h. MS (ESI): C 24 H 25 Bn 4 Theoretical molecular weight of OS: 496.09, m / z experimental molecular weight: 496.8 [M+H] + .

[0639] 2. 1 (500 mg, 1 mmol), thiomorpholine 1,1-dioxide (405 mg, 3 mmol), Pd 2 (dba) 3 A mixture of 4-nitropropene (288 mg, 0.5 mmol), SPhos (205 mg, 0.5 mmol) and t-BuONa (290 mg, 3.0 mmol) in anhydrous 1,4-dioxane (30 mL) was stirred at 100 °C overnight. The mixture was cooled to RT, filtered and concentrated. The resulting residue was purified by silica gel chromatography. The resulting material was purified by prep-TLC to provide Example 68 (50 mg, 9%) as a white solid. 28 H 33 N 5 O 3 S 2 Theoretical molecular weight: 551.2, m / z experimental molecular weight: 551.72 [M+H]+ . 1 HNMR(400MHz,DMSO-d6)δppm 7.17–7.03(m,5H),7.00–6.92(m,3H),4.49(s,2H),3.90(s,2H),3.77–3.69(m,4 H),3.62(m,4H),3.19–3.03(m,4H),2.86(m,5H),2.07–1.94(m,2H),1.24(s,2H).

[0640] Evaluation of antiviral activity against human cytomegalovirus (HCMV)

[0641] To evaluate their antiviral activity, some compounds were tested in vitro against human cytomegalovirus (HCMV). Human MRC5 cells were grown to confluence (~1.0×10^4 cells / well) in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum (FBS), 2mM L-glutamine, 0.1mM non-essential amino acids, 10mM HEPES, and 100U / ml of penicillin and streptomycin, respectively, in a 96-well plate format and infected with an HCMV variant expressing mCherry-tagged pUL99 (the product of the late viral UL99 gene) at a multiplicity of infection of 0.01 infectious units (IU) per cell. The assay was repeated three times. After 1 hour, the cell culture medium was replaced with fresh culture medium containing 25, 12.5, 6.25, 3.13, 1.56, 0.78, 0.39 μM of the specified compound or a vehicle (DMSO) in which the compound was dissolved. In each treatment, the final concentration of DMSO was 0.5%. At 7 days post-infection, the virus yield in the culture was determined by quantification of fluorescent (mCherry positive) cells in each well by fluorescence microscopy. The results were plotted using CDD Vault (CDD Vault is developed by Collaborative Drug Discovery, Inc., 1633 Bayshore Hwy, Suite 342, Burlingame, CA 94010) to calculate IC50. The results of the compounds tested by this assay are provided in Table 1.

[0642] Evaluation of antiviral activity against influenza virus

[0643] To evaluate their antiviral activity, some compounds were tested in vitro against murine adapted human influenza virus (PR8). Dog MDCK cells were grown to confluence (~1.0×10^4 cells / well) in Eagle's Minimum Essential Medium (EMEM) supplemented with 10% fetal bovine serum (FBS) and 100 U / ml of penicillin and streptomycin, respectively, in a 96-well plate format. The wells were washed with 1×PBS and infected with a PR8 variant expressing mCherry downstream of the NS-1 protein and separated by a 2A self-cleavage site in serum-free EMEM at a multiplicity of infection of 0.01 infectious units (IU) per cell. The assay was repeated three times. After 1 hour, the virus-containing medium in the cells was replaced with fresh complete medium containing 25, 12.5, 6.25, 3.13, 1.56, 0.78, 0.39 μM of the specified compound or a vehicle (DMSO) in which the compound was dissolved and supplemented with 2.5 μg / ml TPCK trypsin. In each treatment, the final concentration of DMSO was 0.5%. At 3 days post-infection, the fluorescent (mCherry positive) cells in each well were quantified by fluorescence microscopy to determine the virus yield in culture. CDD Vault (CDD Vault is developed by Collaborative Drug Discovery, Inc., 1633 Bayshore Hwy, Suite 342, Burlingame, CA 94010) was used to plot the results to calculate IC50. The results of the compounds tested by this assay are provided in Table 1.

[0644] Table 1

[0645]

[0646]

[0647]

[0648]

[0649]

[0650]

[0651]

[0652]

[0653]

[0654]

[0655]

[0656]

[0657] ND = Not Conducted

[0658] Some of the compounds in Table 1 were also tested and found to inhibit the replication of RSV, Zika virus strain MR776, and BK virus in cell culture.

[0659] Other Implementations

[0660] It is to be understood that although the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages and modifications are within the scope of the following claims.

Claims

1. A composition comprising a compound selected from the group consisting of:

2. The composition according to claim 1, wherein The compound is selected from the group consisting of:

3. The composition according to claim 1, wherein The compound is selected from the group consisting of:

4. The composition according to claim 1, wherein The compound is:

5. The composition according to claim 1, wherein The compound is:

6. The composition according to claim 1, wherein the compound is:

7. The composition of claim 1, wherein the compound is:

8. A pharmaceutical composition comprising the composition according to any one of claims 1 to 7.

9. Use of a therapeutically effective amount of a composition according to any one of claims 1 to 7 or a pharmaceutical composition according to claim 8 in the preparation of a medicament for treating or preventing a viral infection in a subject, wherein: The viral infection is influenza virus infection and / or human cytomegalovirus (HCMV) infection.

10. The use according to claim 9, wherein the treatment or prevention further comprises administering a therapeutically effective amount of an additional antiviral agent.

11. The use according to claim 10, wherein the additional antiviral agent is selected from the group consisting of acyclovir, docosanol, ribavirin, interferon; cellulose acetate, carbopol and carrageenan, pleconaril, amantadine, rimantadine, fomivirsen, zidovudine, lamivudine, zanamivir, oseltamivir, brivudine, abacavir, adefovir, amprenavir, arbidol, atazanavir, lipitor, cidofovir, compavir, edouridine, efavirenz, emtricitabine, enfuvirtide, entecavir, famciclovir, fosamprenavir, foscarnet, fosfoacetic acid, ganciclovir, gardasil, ibacitabine, imunovir, idoxuridine, imiquimod, indinavir, Inosine, lopinavir, loviramide, mk-0518, maraviroc, morpholinoguanidine, nelfinavir, nevirapine, nesavir, penciclovir, peramivir, podophyllotoxin, rimantadine, ritonavir, saquinavir, stavudine, tenofovir, tenofovir disoproxil, tipranavir, trifluridine, trizevir, tromantanamide, truvada, valacyclovir, valganciclovir, vicriviroc, adenosine, viramidine, zalcitabine, morpholino oligonucleotides, brincidofovir, favipiravir, nitoxanide, letermovir, maribavir, CMX157, or a combination thereof.

12. Use of a virus production inhibiting amount of the composition according to any one of claims 1 to 7 in the preparation of a medicament for inhibiting virus production, wherein: The inhibition comprises contacting a virus-infected cell with the agent, wherein the virus is influenza virus and / or human cytomegalovirus (HCMV).

13. The use according to claim 12, wherein the inhibition further comprises administering a therapeutically effective amount of an additional antiviral agent.

14. The use according to claim 13, wherein the additional antiviral agent is selected from the group consisting of acyclovir, docosanol, ribavirin, interferon; cellulose acetate, carbopol and carrageenan, pleconaril, amantadine, rimantadine, fomivirsen, zidovudine, lamivudine, zanamivir, oseltamivir, brivudine, abacavir, adefovir, amprenavir, arbidol, atazanavir, lipitor, cidofovir, compavir, edouridine, efavirenz, emtricitabine, enfuvirtide, entecavir, famciclovir, fosamprenavir, foscarnet, fosfoacetic acid, ganciclovir, gardasil, ibacitabine, imunovir, idoxuridine, imiquimod, indinavir, Inosine, lopinavir, loviramide, mk-0518, maraviroc, morpholinoguanidine, nelfinavir, nevirapine, nesavir, penciclovir, peramivir, podophyllotoxin, rimantadine, ritonavir, saquinavir, stavudine, tenofovir, tenofovir disoproxil, tipranavir, trifluridine, trizevir, tromantanamide, truvada, valacyclovir, valganciclovir, vicriviroc, adenosine, viramidine, zalcitabine, morpholino oligonucleotides, brincidofovir, favipiravir, nitoxanide, letermovir, maribavir, CMX157, or a combination thereof.

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