Broad spectrum antiviral compositions and methods

Abstract

The present invention relates to broad spectrum antiviral compositions and methods. In particular, the present invention provides novel thiazole and isoquinoline containing compounds for use in the treatment and / or prevention of broad spectrum viral infections. Methods of treating and / or preventing broad spectrum 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] This application is a divisional application of Chinese patent application No. 201880080152.3, entitled “Broad-spectrum antiviral compositions and methods,” filed on October 17, 2018.

[0002] Statement on Federally Sponsored Research

[0003] 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 under the terms of Contract No. 1R44AI122488-01 awarded by the National Institute of Allergy and Infectious Diseases. Technical Field

[0004] The present application relates to compounds for preventing, treating or ameliorating viral infections.

[0005] Citation of Related Applications

[0006] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 574,067, filed October 18, 2017, which is incorporated herein by reference in its entirety. Background Art

[0007] 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 [diseases and noncombat injuries] among deployed troops, second only to trauma."

[0008] Influenza A is a case in point. It contributes significantly to the military's disease burden and also infects a significant number of US civilians annually, causing respiratory illness with significant morbidity and mortality. Each year, 5-20% of the US population contracts seasonal influenza, resulting in >200,000 hospitalizations and ~24,000 deaths. Furthermore, the inevitable emergence of lethal influenza A viruses poses a significant threat, and recent reports of genetic manipulation have demonstrated 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 the maturation of the viral hemagglutinin by altering its glycosylation via unknown mechanisms. Currently, these drugs face the rapid development of resistance due to their direct interaction with viral proteins (direct-acting antivirals, DAAs). The replication of the viral RNA genome is highly error-prone and is accompanied by reassortment of the segmented viral genome (genetic drift), and this high mutation rate (genetic drift) has led to the rapid evolution of drug-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. Although the emergence of drug-resistant viruses has been minimized, antiviral agents targeting a wide range of influenza subtypes still represent a major unmet public health need.

[0009] However, the need for new therapeutic agents to treat 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 prophylactic use). In addition, multiple respiratory pathogens have similar symptoms, which are called influenza-like illnesses, so a single broad-spectrum drug that is effective against multiple different pathogens would be of great use. There is still a need to develop a single drug that is effective against a wide spectrum of viruses that can cause respiratory infections - not only influenza viruses, but also coronaviruses, RSV, parainfluenza viruses, human cytomegalovirus (HCMV), and adenoviruses.

[0010] Human cytomegalovirus (HCMV) is the leading cause of congenital defects and opportunistic infections in immunosuppressed individuals and is a possible cofactor in certain cancers. Organ transplant patients on immunosuppressive therapy are at 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 mortality. 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 four main viral classes that infect these patients. Cytomegalovirus (HCMV) is the most common post-transplant pathogen; HCMV can infect most organs, and although HCMV antivirals such as ganciclovir are available, the increase in nephrotoxic side effects and resistance rates significantly reduces transplant and patient survival. 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

[0011] The present invention provides a compound having a structure shown in Formula I:

[0012]

[0013] in:

[0014] One of X1 and X2 is N and the other is S;

[0015] 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;

[0016] 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:

[0017] =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 or branched alkoxy group and a C group optionally substituted by -R12, -OR12 or -NR7R8 3-6 Cycloalkyl,

[0018] 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:

[0019] =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 or branched alkoxy group and a C group optionally substituted by -R12, -OR12 or -NR7R8 3-6 Cycloalkyl;

[0020] R3 is selected from H, halo, -C≡CH, -C≡N, -OH, -OCF3, -OCHF2, C 1-4 Straight chain or branched alkoxy, -SO2(C 1-6 alkyl), -N(CH3)2, -C(O)NH2, -NHSO2R7, -C(O)NR7R8, and a ring 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] R4 is selected from H, halo, -C≡CH, -C≡N, -OH, -OCF3, -OCHF2, C 1-4 Straight chain or branched alkoxy, -SO2(C 1-6 alkyl), -N(CH3)2, -C(O)NH2, -NHSO2R7, -C(O)NR7R8, and a ring 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,

[0022] Alternatively, 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 with 0 to 2 groups selected from =0, halo, C 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;

[0023] The conditions are:

[0024] At least one of R3 and R4 is selected from the group consisting of: H, halo, -C≡CH, -C≡N, -OH, -OCF3, -OCHF2, C 1-4 Straight chain or branched alkoxy, -SO2(C 1-6 alkyl), -N(CH3)2, -C(O)NH2, -NHSO2R7 and -C(O)NR7R8, and

[0025] R3 and R4 are not H at the same time;

[0026] R5 is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, CF3, CH2CF3 and halo;

[0027] R6 is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, CF3, CH2CF3, halo, cyclopropylmethyl and C 1-4 alkoxy;

[0028] In each case, R7 and R8 are independently selected from H, C 1-6 Straight-chain or branched alkyl, C 3-6 cycloalkyl, cyclopropylmethyl, and cyclobutylmethyl; and

[0029] At each occurrence, R12 is independently selected from H and C 1-4 Straight-chain or branched-chain alkyl.

[0030] or a pharmaceutically acceptable salt or solvate thereof.

[0031] The compounds described herein are useful for treating and / or preventing viral infections. Specifically, the compounds described herein are broad-spectrum antiviral agents. For example, the compounds described herein block the replication of two very different human pathogens with considerable efficacy: influenza A virus, a rapidly replicating orthomyxovirus with an RNA genome, and HCMV, a slowly replicating herpesvirus with a DNA genome.

[0032] The present invention also provides methods for preventing, treating and / or ameliorating HCMV infection using the compounds represented by Formula I. The present invention also provides methods for preventing, treating and / or ameliorating influenza virus infection using the compounds represented by Formula I.

[0033] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. 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 conflict, the present specification, including definitions, will control.

[0034] Other features and advantages of the invention will be apparent from the following detailed description and drawings, and from the claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 Shown is the proton (1H) NMR spectrum of Example 6 at 500 MHz in CD3OD.

[0036] Figure 2 Shown is the proton (1H) NMR spectrum of Example 7 at 500 MHz in CD3OD.

[0037] Figure 3 Shown is the proton (1H) NMR spectrum of Example 8 at 500 MHz in CD3OD.

[0038] Figure 4 Shown is the proton (1H) NMR spectrum of Example 9 in CD3Cl3 at 500 MHz.

[0039] Figure 5 Shown is the proton (1H) NMR spectrum of Example 10 at 500 MHz in CD3OD.

[0040] Figure 6 Shown is the proton (1H) NMR spectrum of Example 16 in DMSO-d6 at 500 MHz. DETAILED DESCRIPTION

[0041] Provided herein are compounds useful for treating and / or preventing a wide range of viral infections.

[0042] 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 viruses in cells infected by viruses. In these embodiments, cells are contacted with one or more compounds provided herein that inhibit viral production.

[0043] Provided herein are compounds having the structure shown in Formula I:

[0044]

[0045] in:

[0046] One of X1 and X2 is N and the other is S;

[0047] 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;

[0048] 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:

[0049] =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 or branched alkoxy group and a C group optionally substituted by -R12, -OR12 or -NR7R8 3-6 Cycloalkyl,

[0050] 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:

[0051] =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 or branched alkoxy group and a C group optionally substituted by -R12, -OR12 or -NR7R8 3-6 Cycloalkyl;

[0052] R3 is selected from H, halo, -C≡CH, -C≡N, -OH, -OCF3, -OCHF2, C 1-4 Straight chain or branched alkoxy, -SO2(C 1-6alkyl), -N(CH3)2, -C(O)NH2, -NHSO2R7, -C(O)NR7R8, and a ring 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;

[0053] R4 is selected from H, halo, -C≡CH, -C≡N, -OH, -OCF3, -OCHF2, C 1-4 Straight chain or branched alkoxy, -SO2(C 1-6 alkyl), -N(CH3)2, -C(O)NH2, -NHSO2R7, -C(O)NR7R8, and a ring 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,

[0054] Alternatively, 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 with 0 to 2 groups selected from =0, halo, C 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;

[0055] The conditions are:

[0056] At least one of R3 and R4 is selected from the group consisting of: H, halo, -C≡CH, -C≡N, -OH, -OCF3, -OCHF2, C1-4 Straight chain or branched alkoxy, -SO2(C 1-6 alkyl), -N(CH3)2, -C(O)NH2, -NHSO2R7 and -C(O)NR7R8, and

[0057] R3 and R4 are not H at the same time;

[0058] R5 is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, CF3, CH2CF3 and halo;

[0059] R6 is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, CF3, CH2CF3, halo, cyclopropylmethyl and C 1-4 alkoxy;

[0060] In each case, R7 and R8 are independently selected from H, C 1-6 Straight-chain or branched alkyl, C 3-6 cycloalkyl, cyclopropylmethyl, and cyclobutylmethyl; and

[0061] At each occurrence, R12 is independently selected from H and C 1-4 Straight-chain or branched-chain alkyl.

[0062] and pharmaceutically acceptable salts and solvates thereof.

[0063] 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 utility of the compounds represented by Formula I by demonstrating that these compounds block the replication of two very different human pathogens with comparable efficacy: the rapidly replicating orthomyxovirus influenza A virus with an RNA genome and the slowly replicating herpesvirus HCMV with a DNA genome.

[0064] In some embodiments of the antiviral compound represented by Formula I,

[0065] 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:

[0066] =O, C optionally substituted by -OR12 or -NR7R8 1-6 Straight or branched alkyl, C optionally substituted by -NR7R8 or -OR12 1-6straight-chain or branched alkoxy, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl and cyclohexyl,

[0067] 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 with 0 to 2 groups independently selected from:

[0068] =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.

[0069] In some embodiments of the antiviral compound represented by Formula I, R3 is selected from:

[0070]

[0071] and -SO2(C 1-6 alkyl);

[0072] in:

[0073] R9 is selected from the group consisting of: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, C optionally substituted with -OR12 or -NR7R8 1-6 A straight or branched chain alkyl group and a C group optionally substituted by -NR7R8 1-6 linear or branched alkoxy groups; and

[0074] R10 and R11 are independently selected from the group consisting of: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, C optionally substituted with -OR12 or -NR7R8 1-4 Straight or branched alkyl, optionally substituted by NR7R8 C 1-4 Straight-chain or branched alkoxy.

[0075] In some embodiments of the antiviral compound represented by Formula I, R4 is selected from:

[0076]

[0077] and -SO2(C 1-6 alkyl);

[0078] in:

[0079] R9 is selected from the group consisting of: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, C optionally substituted with -OR12 or -NR7R8 1-6 A straight or branched chain alkyl group and a C group optionally substituted by -NR7R8 1-6 linear or branched alkoxy groups; and

[0080] R10 and R11 are independently selected from the group consisting of: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, C optionally substituted with -OR12 or -NR7R8 1-4 Straight or branched alkyl, optionally substituted by NR7R8 C 1-4 Straight-chain or branched alkoxy.

[0081] In some embodiments of the antiviral compound represented by Formula I,

[0082] 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 other ring heteroatoms independently selected from N and O and substituted with 0 to 2 groups independently selected from:

[0083] =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 or branched alkoxy group and a C group optionally substituted by -R12, -OR12 or -NR7R8 3-6 Cycloalkyl.

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

[0085]

[0086] In some embodiments of the compound represented by Formula I, one of R1 and R2 is H and the other is selected from:

[0087]

[0088] in:

[0089] R9 is selected from the group consisting of: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, C optionally substituted with -OR12 or -NR7R8 1-6 A straight or branched chain alkyl group and a C group optionally substituted by -NR7R8 1-6 linear or branched alkoxy groups; and

[0090] R10 and R11 are independently selected from the group consisting of: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, C optionally substituted with -OR12 or -NR7R8 1-4 Straight or branched alkyl, optionally substituted by NR7R8 C 1-4 Straight-chain or branched alkoxy.

[0091] Compounds of this embodiment include (but are not limited to):

[0092]

[0093]

[0094] Some embodiments of the compound represented by Formula I are compounds represented by Formula II:

[0095]

[0096] 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:

[0097]

[0098] and -SO2(C 1-6 alkyl);

[0099] in:

[0100] R9 is selected from the group consisting of: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, C optionally substituted with -OR12 or -NR7R8 1-6 A straight or branched chain alkyl group and a C group optionally substituted by -NR7R8 1-6 linear or branched alkoxy groups; and

[0101] R10 and R11 are independently selected from the group consisting of: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, C optionally substituted with -OR12 or -NR7R8 1-4 Straight or branched alkyl, optionally substituted by NR7R8 C 1-4 Straight-chain or branched alkoxy.

[0102] In some embodiments of the antiviral compound represented by Formula II, R4 is selected from:

[0103]

[0104] and -SO2(C 1-6 alkyl);

[0105] in:

[0106] R9 is selected from the group consisting of: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, C optionally substituted with -OR12 or -NR7R8 1-6 A straight or branched chain alkyl group and a C group optionally substituted by -NR7R8 1-6 linear or branched alkoxy groups; and

[0107] R10 and R11 are independently selected from the group consisting of: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, C optionally substituted with -OR12 or -NR7R8 1-4 Straight or branched alkyl, optionally substituted by NR7R8 C 1-4 Straight-chain or branched alkoxy.

[0108] Some embodiments of the compound represented by Formula I are compounds represented by Formula III:

[0109]

[0110] in:

[0111] R9 is selected from the group consisting of: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, C optionally substituted with -OR12 or -NR7R8 1-6 A straight or branched chain alkyl group and a C group optionally substituted by -NR7R8 1-6 a straight-chain or branched alkoxy group, and

[0112] 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 compound represented by Formula III, R3 is selected from:

[0113]

[0114] and -SO2(C 1-6 alkyl);

[0115] 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 C 1-4 Straight-chain or branched alkoxy.

[0116] In some embodiments of the antiviral compound represented by Formula III, R4 is selected from:

[0117]

[0118] and -SO2(C 1-6 alkyl);

[0119] 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 C 1-4 Straight-chain or branched alkoxy.

[0120] Some embodiments of the compound represented by Formula I are compounds represented by Formula IV:

[0121]

[0122] in:

[0123] R10 and R11 are independently selected from the group consisting of: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, C optionally substituted with -OR12 or -NR7R8 1-4 Straight or branched alkyl, optionally substituted by NR7R8 C 1-4 a straight-chain or branched alkoxy group, and

[0124] 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 compound represented by Formula IV, R3 is selected from:

[0125]

[0126] and -SO2(C 1-6 alkyl);

[0127] Wherein: R9 is selected from: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, C optionally substituted with -OR12 or -NR7R8 1-6 A straight or branched chain alkyl group and a C group optionally substituted by -NR7R8 1-6 In some embodiments of the antiviral compound represented by Formula IV, R4 is selected from:

[0128]

[0129] and -SO2(C 1-6 alkyl);

[0130] Wherein: R9 is selected from: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, C optionally substituted with -OR12 or -NR7R8 1-6 A straight or branched chain alkyl group and a C group optionally substituted by -NR7R8 1-6 Straight-chain or branched alkoxy.

[0131] Some embodiments of the compound represented by Formula I are compounds represented by Formula V:

[0132]

[0133]

[0134] 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:

[0135]

[0136] and -SO2(C 1-6 alkyl);

[0137] in:

[0138] R9 is selected from the group consisting of: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, C optionally substituted with -OR12 or -NR7R8 1-6 A straight or branched chain alkyl group and a C group optionally substituted by -NR7R8 1-6 linear or branched alkoxy groups; and

[0139] R10 and R11 are independently selected from the group consisting of: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, C optionally substituted with -OR12 or -NR7R8 1-4 Straight or branched alkyl, optionally substituted by NR7R8 C 1-4 Straight-chain or branched alkoxy.

[0140] In some embodiments of the antiviral compound represented by Formula V, R4 is selected from:

[0141]

[0142] and -SO2(C 1-6 alkyl);

[0143] in:

[0144] R9 is selected from the group consisting of: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, C optionally substituted with -OR12 or -NR7R8 1-6 A straight or branched chain alkyl group and a C group optionally substituted by -NR7R8 1-6 linear or branched alkoxy groups; and

[0145] R10 and R11 are independently selected from the group consisting of: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, C optionally substituted with -OR12 or -NR7R8 1-4 Straight or branched alkyl, optionally substituted by NR7R8 C 1-4 Straight-chain or branched alkoxy.

[0146] Some embodiments of the compound represented by Formula I are compounds represented by Formula VI:

[0147]

[0148] wherein X1, X2, X3, X4, R3, R4, R5 and R6 are as defined for Formula I. In some embodiments of the antiviral compound represented by Formula VI, R3 is selected from:

[0149]

[0150] and -SO2(C 1-6 alkyl);

[0151] in:

[0152] R9 is selected from the group consisting of: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, C optionally substituted with -OR12 or -NR7R8 1-6 A straight or branched chain alkyl group and a C group optionally substituted by -NR7R8 1-6 linear or branched alkoxy groups; and

[0153] R10 and R11 are independently selected from the group consisting of: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, C optionally substituted with -OR12 or -NR7R8 1-4 Straight or branched alkyl, optionally substituted by NR7R8 C 1-4 Straight-chain or branched alkoxy.

[0154] In some embodiments of the antiviral compound represented by Formula VI, R4 is selected from:

[0155]

[0156] and -SO2(C 1-6 alkyl);

[0157] in:

[0158] R9 is selected from the group consisting of: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, C optionally substituted with -OR12 or -NR7R8 1-6 A straight or branched chain alkyl group and a C group optionally substituted by -NR7R8 1-6 linear or branched alkoxy groups; and

[0159] R10 and R11 are independently selected from the group consisting of: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, C optionally substituted with -OR12 or -NR7R8 1-4 Straight or branched alkyl, optionally substituted by NR7R8 C 1-4 Straight-chain or branched alkoxy.

[0160] Some embodiments of the compound represented by Formula I are compounds represented by Formula VII:

[0161]

[0162] in:

[0163] R9 is selected from the group consisting of: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, C optionally substituted with -OR12 or -NR7R8 1-6 A straight or branched chain alkyl group and a C group optionally substituted by -NR7R8 1-6 a straight-chain or branched alkoxy group, and

[0164] 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 compound represented by Formula VII, R3 is selected from:

[0165]

[0166] and -SO2(C 1-6 alkyl);

[0167] 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 C 1-4 Straight-chain or branched alkoxy.

[0168] In some embodiments of the antiviral compound represented by Formula VII, R4 is selected from:

[0169]

[0170] and -SO2(C 1-6 alkyl);

[0171] 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 C 1-4 Straight-chain or branched alkoxy.

[0172] Some embodiments of the compound represented by Formula I are compounds represented by Formula VIII:

[0173]

[0174] in:

[0175] R10 and R11 are independently selected from the group consisting of: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, C optionally substituted with -OR12 or -NR7R8 1-4 Straight or branched alkyl, optionally substituted by NR7R8 C1-4 a straight-chain or branched alkoxy group, and

[0176] 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 compound represented by Formula VIII, R3 is selected from:

[0177]

[0178] and -SO2(C 1-6 alkyl);

[0179] Wherein: R9 is selected from: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, C optionally substituted with -OR12 or -NR7R8 1-6 A straight or branched chain alkyl group and a C group optionally substituted by -NR7R8 1-6 Straight-chain or branched alkoxy.

[0180] In some embodiments of the antiviral compound represented by Formula VIII, R4 is selected from:

[0181]

[0182] and -SO2(C 1-6 alkyl);

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

[0184] Some embodiments of the compound represented by Formula I are compounds represented by Formula IX:

[0185]

[0186] wherein X1, X2, X3, X4, R3, R4, R5 and R6 are as defined for Formula I. In some embodiments of the antiviral compound represented by Formula IX, R3 is selected from:

[0187]

[0188] and -SO2(C 1-6 alkyl);

[0189] in:

[0190] R9 is selected from the group consisting of: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, C optionally substituted with -OR12 or -NR7R8 1-6 A straight or branched chain alkyl group and a C group optionally substituted by -NR7R8 1-6 linear or branched alkoxy groups; and

[0191] R10 and R11 are independently selected from the group consisting of: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, C optionally substituted with -OR12 or -NR7R8 1-4 Straight or branched alkyl, optionally substituted by NR7R8 C 1-4 Straight-chain or branched alkoxy.

[0192] In some embodiments of the antiviral compound represented by Formula IX, R4 is selected from:

[0193]

[0194] and -SO2(C 1-6 alkyl);

[0195] in:

[0196] R9 is selected from the group consisting of: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, C optionally substituted with -OR12 or -NR7R8 1-6 A straight or branched chain alkyl group and a C group optionally substituted by -NR7R8 1-6 linear or branched alkoxy groups; and

[0197] R10 and R11 are independently selected from the group consisting of: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, C optionally substituted with -OR12 or -NR7R8 1-4 Straight or branched alkyl, optionally substituted by NR7R8 C 1-4 Straight-chain or branched alkoxy.

[0198] Also provided herein are methods for treating or preventing 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, or Formula IX, or a pharmaceutically acceptable salt or solvate thereof.

[0199] 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, or Formula IX, or a pharmaceutically acceptable salt or solvate thereof.

[0200] Also provided herein are methods 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.

[0201] 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, or Formula IX, or a pharmaceutically acceptable salt or solvate thereof.

[0202] Also provided herein are methods 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, or Formula IX, or a pharmaceutically acceptable salt or solvate thereof.

[0203] Also provided herein is a method for inhibiting influenza virus production, comprising contacting influenza 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, or Formula IX, or a pharmaceutically acceptable salt or solvate thereof.

[0204] 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, edoxuridine, efavirenz, emtricitabine, enfuvirtide, entecavir, famciclovir, fosamprenavir, foscarnet, fosfoacetic acid, ganciclovir, gardazi, ibacitabine, imunovir, idoxuridine, 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, triazepam, tromantanamide, Truvada, valacyclovir, valganciclovir, vicriviroc, vidarabine, 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.

[0205] In some embodiments, the compounds provided herein can be administered before, after, or simultaneously with the administration of one or more antiviral agents.

[0206] The antiviral agents provided herein, including pharmaceutically acceptable salts or solvates thereof, can be purchased commercially or prepared using known organic synthesis techniques.

[0207] 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.

[0208] 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.

[0209] 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.

[0210] Methods for formulating suitable pharmaceutical compositions are known in the art, see, e.g., Remington: The Science and Practice ofPharmacy , 21st edition, 2005; and Drugs andthePharmaceuticalSciences:aSeriesofTextbooksandMonographs (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; an antibacterial agent, such as benzyl alcohol or methyl paraben; an antioxidant, such as ascorbic acid or sodium bisulfite; a chelating agent, such as ethylenediaminetetraacetic acid; a buffer, such as acetate, citrate, or phosphate; and an agent for adjusting tonicity, such as sodium chloride or dextrose. The pH may be adjusted with an acid or base, such as hydrochloric acid or sodium hydroxide. Parenteral formulations may be enclosed in ampoules, disposable syringes, or multiple-dose vials made of glass or plastic.

[0211] 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 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, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol, etc.), or a suitable mixture thereof. Suitable fluidity can be maintained, for example, by using a coating such as lecithin, by maintaining the desired particle size in the case of a dispersion, and by using a surfactant. Prevention of microbial action can be achieved by various antibacterial and antifungal agents, for example, parahydroxybenzoic acid, 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. Prolonged absorption of the injectable composition can be achieved by including an agent that delays absorption, for example, aluminum monostearate and gelatin in the composition.

[0212] Can be after filtration sterilization, by as needed, in the suitable solvent with a kind of composition or the combination of composition listed above, mix the compound that this paper provided of the required amount and prepare sterile injectable solution.Usually, by mix the compound that this paper provided and prepare dispersion system in sterile vehicle, described vehicle comprises basic dispersion medium and other required components from those listed above.In the case of the sterile powder for the preparation of sterile injectable solution, preferred preparation method is vacuum drying and freeze drying, it obtains the compound that this paper provided plus the powder of any other required component from its previous sterile-filtered solution.

[0213] Oral compositions typically include an inert diluent or an edible carrier. For the purpose of oral therapeutic administration, excipients can be incorporated into the compounds provided herein and used in the form of tablets, lozenges, or capsules, for example, gelatin capsules. Oral compositions can also be prepared using fluid carriers for use as mouthwashes. Pharmaceutically compatible binders and / or adjuvant materials can be included as part of the composition. Tablets, pills, capsules, lozenges, etc. can 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.

[0214] For administration by inhalation, the compound can be delivered in the form of an aerosol spray from a pressured container or dispenser or a nebulizer that contains a suitable propellant, eg, a gas such as carbon dioxide. Such methods include those described in US Patent No. 6,468,798.

[0215] Systemic administration of therapeutic compounds as described herein can also be by transmucosal or transdermal means.For transmucosal or transdermal administration, in the preparation, a suitable penetrant for the obstacle to be infiltrated is used. These penetrants are generally known in the art and for transmucosal administration, including (for example) detergents, bile salts and carboxylic 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.

[0216] 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.

[0217] 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.

[0218] In one embodiment, the therapeutic compound is prepared together 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 available 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 pharmaceutically 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.

[0219] The pharmaceutical composition can be administered in a disposable manner, 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 relevant to the disease to be treated, and known test procedures can be used or empirically determined by extrapolation of in vivo or in vitro test data. It should be noted that concentration and dosage value can also change with the severity of the patient's 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.

[0220] Dosage forms or compositions can be prepared containing a compound as described herein in the range of 0.005% to 100%, with the remainder consisting of a non-toxic carrier. Methods for preparing these compositions are known to those skilled in the art. Contemplated compositions can contain 0.001%-100% of a compound as provided herein, in one embodiment, 0.1-95%, and in another embodiment, 75-85%.

[0221] The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0222] As described above, the formulations 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 a variety of administration routes. For example, they can be administered in the form of tablets or capsules, by injection, inhalation, eyewash, ointment, suppository, infusion; topically by lotion or ointment; and rectally by suppository. In some embodiments, administration is oral administration.

[0223] The phrase "parenteral administration" as used herein refers to forms of administration other than enteral and topical administration, usually by injection and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal, and intrastemal injection and infusion.

[0224] 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.

[0225] 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 pharmaceutically available mixture will be different. In some embodiments, the compositions 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 overall health of the patient and the formulation and route of administration of the selected compound, the dosage will be a therapeutically effective amount.

[0226] 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 that amount of the compound that produces a therapeutic effect.

[0227] 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), the route of administration, etc. However, the above guidance can be used as a basis for fine-tuning treatment, e.g., determining the optimal time and / or amount of administration, which will require, at most, routine experimentation, including monitoring the patient and adjusting the dose and / or timing.

[0228] Also provided herein are combination therapies in which one or more other therapeutic agents are administered with the compounds or pharmaceutical compositions comprising the compounds provided herein. Such combination therapies can be achieved by simultaneous, sequential or separate dosing of the individual components of the treatment.

[0229] definition

[0230] 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 intended 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.

[0231] As used herein, "subject" includes humans and other animals, particularly mammals. Thus, 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.

[0232] A "therapeutically effective" amount of a compound as provided herein is generally an amount sufficient to prevent, eliminate, ameliorate or reduce the symptoms of a 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 may be used than for active disease treatment.

[0233] A "virus production inhibiting" amount of a compound provided herein is generally an amount sufficient to achieve a measurable reduction in the amount of virus produced by cells contacted with the compound. In some embodiments, a "virus production inhibiting" amount is an amount that inhibits virus production in untreated cells by at least 30%. In some embodiments, a "virus production inhibiting" amount is an amount that inhibits virus production in untreated cells by at least 50%. In some embodiments, a "virus production inhibiting" amount is an amount that inhibits virus production in untreated cells by at least 70%. In some embodiments, a "virus production inhibiting" amount is an amount that inhibits virus production in untreated cells by at least 90%.

[0234] 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 manifestations of an undesirable patient's 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 patient's condition). As used in the context, the term "prevention" represents the onset of at least one symptom of the patient's condition as provided herein. For example, this prevention can be carried out by the possibility of being exposed 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 manifestations of an undesirable patient's condition, the treatment is therapeutic (i.e., it is intended to alleviate, improve, or stabilize an existing undesirable patient's condition or its side effect). As used in the context, "treatment" represents the improvement of at least one symptom of a disease as provided herein.

[0235] As used herein, the term "compound" is meant to include all stereoisomers, geometric isomers, and tautomers of the shown structure. Unless otherwise indicated, herein, a compound identified by name or structure as one specific tautomeric form is intended to include other tautomeric forms.

[0236] 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 containing by weight 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. The method for separating compounds and their salts is conventional in the art.

[0237] 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.

[0238] The term "pharmaceutical salt" refers to the relatively nontoxic inorganic and organic acid addition salts of the compound provided herein. These salts can be prepared in situ during the final separation and purification of the compound provided herein, or by reacting the compound in the form of its free alkali with an applicable organic or inorganic acid and separating the salt 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).

[0239] In some embodiments, the compound provided herein may contain one or more acidic functional groups and therefore be able to form a pharmaceutically acceptable salt with a pharmaceutically acceptable base. In these cases, the term "pharmaceutically acceptable 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 pharmaceutically acceptable hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia or with a pharmaceutically acceptable 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. 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).

[0240] The term "solvate" refers to a compound that further comprises 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 utilizes a solvent that is suitable for use in 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 sound medical judgment.

[0241] As used herein, term " alkyl " refers to a straight chain and branched aliphatic group with 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. " C0 " alkyl (as in " C0-C3-alkyl") is a covalent bond (as " C0 " alkyl). Term " low alkyl " refers to a straight chain and branched aliphatic group with 1 to 6 carbon atoms. Unless otherwise stated, term " alkyl " includes alkenyl, alkynyl and cycloalkyl.

[0242] 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 is optionally substituted with 1, 2 or 3 substituents. Preferred alkenyl groups include, without limitation, ethenyl, propenyl, butenyl, pentenyl and hexenyl.

[0243] As used herein, the term "alkynyl" refers to an unsaturated straight or branched chain aliphatic radical 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 is optionally substituted with 1, 2 or 3 substituents. Preferred alkynyl groups include, without limitation, ethynyl, propynyl, butynyl, pentynyl and hexynyl.

[0244] 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.

[0245] "Aryl" groups are C6-C 14 An aromatic moiety comprising 1 to 3 aromatic rings, which are optionally substituted. Preferably, the aryl group is C6-C 10 Aryl Groups. Preferred aryl groups include, without limitation, phenyl, naphthyl, anthracenyl, and fluorenyl.

[0246] "Heterocyclyl" or "heterocycle" groups are cyclic structures having about 3 to about 8 atoms, wherein one or more atoms are selected from N, O, and S. The heterocyclyl is optionally substituted on the carbon at one or more positions. The heterocyclyl is 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 heterocyclyls include, without limitation, epoxy, aziridinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, thiazolidinyl, oxazolidinyl, oxazolidinone, and morpholino. In certain preferred embodiments, the heterocyclyl is fused to an aryl, heteroaryl, or cycloalkyl group. Examples of such fused heterocycles include, without limitation, tetrahydroquinoline and dihydrobenzofuran. Specifically, the scope of this term does not include compounds having adjacent ring O and / or S atoms.

[0247] 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 in common in a ring arrangement (cyclic array); and each ring having 1 to 3 heteroatoms selected from N, O and S, in addition to carbon atoms. A "heteroaralkyl" or "heteroarylalkyl" group includes a heteroaryl group covalently attached to an alkyl group, either of which is independently optionally substituted or unsubstituted. Preferred heteroalkyl groups include C1-C6 alkyls and heteroaryl groups with 5, 6, 9 or 10 ring atoms. Specifically, the scope of this term does not include compounds with adjacent ring O and / or S atoms. Examples of preferred heteroaralkyl groups include pyridylmethyl, pyridylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, thiazolylmethyl and thiazolylethyl. Specifically, the scope of this term does not include compounds with adjacent ring O and / or S atoms.

[0248] Examples 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, dihydrofuro[2,3b]tetrahydrofuran, furanyl, benzothiazolyl ... 1H-indolyl, 1H-indole ... 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, pyridoxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4-pyrrolidone ... 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, thienyl, thiazolyl, thienyl, thiathiazolyl, thiaoxazolyl, thiaimidazolyl, phenylthio, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl.

[0249] 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 from 1 to 4, preferably from 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, arylalkylsulfonamido, alkylcarbonyl, acyloxy, cyano, and ureido groups.

[0250] As used herein, term "halogen" or "halo" refers to chlorine, bromine, fluorine or iodine. As used herein, term "acyl" refers to an alkylcarbonyl or arylcarbonyl substituent. Term "acylamino" refers to an amide group (i.e., R-CO-NH-) attached to a nitrogen atom. Term "carbamoyl" refers to an amide group (i.e., NH2-CO-) attached to a carbonyl carbon atom. The nitrogen atom of an acylamino or carbamoyl substituent is optionally substituted in addition. Term "sulfonylamino" refers to a sulfonamide substituent connected by sulfur or a nitrogen atom. Term "amino" refers to an NH2, alkylamino, arylamino and cyclic amino. Term "urea" as used herein refers to a substituted or unsubstituted urea moiety.

[0251] The substituted part is a part in which one or more hydrogens are independently replaced by another chemical substituent. As non-limiting examples, the phenyl substituted includes 2-fluorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluoro-phenyl, 2-fluoro 3-propylphenyl. As another non-limiting examples, the n-octyl substituted includes 2,4-dimethyl-5-ethyl-octyl and 3-cyclopentyl-octyl. The methylene (-CH2-) formed by oxygen-substituted carbonyl-CO- is included in the scope of this definition.

[0252] 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 definitions of such moieties are otherwise provided (above). Thus, for example, while "aryl" includes phenyl and phenyl substituted with a halo, "unsubstituted aryl" does not include phenyl substituted with a halo.

[0253] Synthesis of the compounds of the present invention

[0254] 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:

[0255] 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, methyl iodide; DMSO, dimethyl sulfoxide; Me CN, 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; Ac2O, acetic anhydride; conc., concentrated; eq, equivalent; DIEA, N,N-diisopropylethylamine; HATU, N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridine- [1-(1-methylmethylene)-N-methylmethanium hexafluorophosphate N-oxide]; DMA, N,N-dimethylacetamide; Pd2(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)Cl2, [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; BOC2O, di-tert-butyl dicarbonate; Et3N, triethylamine; Prep-HPLC, preparative HPLC; TsOH, p-toluenesulfonic acid; TBAB, tetra-n-butylammonium bromide.

[0256] Solution 1

[0257]

[0258] A base, for example, 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 a compound of general structure 3. The compound of general structure 3 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 4. The compound of general structure 4 can be treated with a suitable amine, for example, a substituted or unsubstituted 1,2,3,4-tetrahydroisoquinoline to provide a compound of general structure 5. It will be recognized that the compound of general structure 5 is the same as the compound represented by Formula I.

[0259] Option 2

[0260]

[0261] 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.

[0262] Those skilled in the art will recognize that alternative synthetic routes may exist to provide compounds represented by Formula I. The following schemes describe examples of such alternative synthetic routes, but should not be considered limiting.

[0263] Option 3

[0264]

[0265] In some cases, a suitable amine, for example, a substituted or unsubstituted 1,2,3,4-tetrahydroisoquinoline can be reacted with 2-chloro-1,3-thiazole (2) to provide a compound of general structure 11. The compound of general structure 11 can be reacted with a base, for example, n-BuLi or sec-BuLi, and a compound of general structure 1 to provide a compound of general structure 12. The compound 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 a compound of general structure 5.

[0266] Option 4

[0267]

[0268] 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 of general formula 12 can be treated as described above to provide compounds of general formula 5.

[0269] Option 5

[0270]

[0271] 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 of general formula 6 (wherein X is Cl, Br or I) and a compound of general formula 13 to provide a compound of general formula 14. A compound of general formula 12 can be treated as described above to provide a compound of general formula 10.

[0272] Option 6

[0273]

[0274] In some cases, compounds represented by Formula 8 can be reacted with a suitable amine, 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.

[0275] 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.

[0276] Preparation of intermediates

[0277] Preparation of intermediate 1

[0278]

[0279] 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 stirred at 160°C under N2 overnight. The mixture was cooled to RT, a saturated aqueous solution of NaHCO3 (50 mL) and Boc2O (26.2 g, 120 mmol) were added, 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, 38% yield) as a light yellow oil. MS (ESI): C 19 H25 Theoretical molecular weight of N3O2: 327.43, m / z experimental molecular weight: 327.9 [M+H] + .

[0280] 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, basified with K2CO3 to pH = 10, extracted with DCM, the combined organic phases were washed with brine, dried over Na2SO4, filtered and the filtrate was concentrated to provide intermediate 1 (3.4 g, yield 81.5%) as a light yellow oil. MS (ESI): C 14 H 17 Theoretical molecular weight of N3: 227.31, m / z experimental molecular weight: 227.9 [M+H] + .

[0281] Preparation of intermediate 2

[0282]

[0283] 1. To a solution of 1 (30 g, 163 mmol) in anhydrous DMF (250 mL) was added pyrazole (11.1 g, 163 mmol), Cs CO (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 and brine, dried over anhydrous Na SO , filtered and concentrated to provide a crude oil. The crude product was purified by silica gel chromatography to provide 2 (12 g, 43%) as a yellow oil.

[0284] 2. At -78 ° C, under N2, n-BuLi (28 mL, 70 mmol) was added dropwise to a solution of 2-chlorothiazole (8.3 g, 70 mmol) in anhydrous THF (100 mL). 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 reaction was diluted with NH4Cl solution and extracted with EtOAc. The organic extract was concentrated to provide a crude oil, which was purified by silica gel chromatography to provide 3 (12.8 g, 63%) as a brown semi-solid.

[0285] 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.

[0286] Alternative preparation of intermediate 2

[0287] 1. A mixture of 1 (18.5 g, 100 mmol), 1H-pyrazole (6.8 g, 100 mmol), Cs2CO3 (35.9 g, 110 mmol), 18-crown-6 (1.9 g, 7.2 mmol), and CuI (1.9 g, 10 mmol) in DMF (200 mL) was stirred at 80°C for 16 hours. The resulting mixture was cooled, filtered, concentrated, diluted with EA, washed with water and brine, dried over Na2SO4, concentrated, and purified by Combi-Flash to afford 2 (9 g, 52% yield) as a yellow oil. MS (ESI): C 10 Theoretical molecular weight of H8N2O: 172, m / z experimental molecular weight: 173 [M+H] + .

[0288] 2. At -78 ° C, to a solution of 2-chlorothiazole (6.5 g, 55 mmol) in THF (250 mL) was slowly added n-BuLi (25 mL, 60 mmol, 2.4 M solution in hexane), 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. It was then quenched with saturated NH4Cl. The mixture was extracted with EA, and the combined extracts were washed with brine, dried over Na2SO4, filtered, concentrated and the residue was purified by Combi-Flash to obtain 3 (4.2 g, yield 29%) as a yellow solid. MS (ESI): C 13 H 10 Theoretical molecular weight of ClN3OS: 291, m / z experimental molecular weight: 292 [M+H] + .

[0289] 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 and brine, dried over Na2SO4, filtered, concentrated, and purified by Combi-Flash to afford the product intermediate 2 (2.2 g, 55% yield) as a yellow oil. MS (ESI): C 13 H 10 Theoretical molecular weight of ClN3S: 275.0, m / z experimental molecular weight: 276 [M+H] + .

[0290] Preparation of intermediate 3

[0291]

[0292] 1. To a solution of 1 (10 g, 80.6 mmol) in anhydrous DMF (100 mL) was added pyrazole (5.5 g, 80.6 mmol) and KCO (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, dried over anhydrous NaSO, filtered, and the filtrate was concentrated to provide a crude oil. The crude product was purified by recrystallization to provide 2 (4 g, 29%). 1 HNMR (CDCl3, 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).

[0293] 2. At -78 ° C, under N2, n-BuLi (5 mL, 12.1 mmol) was added dropwise to a solution of 2-chlorothiazole (1.45 g, 12.1 mmol) in anhydrous THF (10 mL). 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 reaction was diluted with NH4Cl solution and extracted with EA. The organic extract was concentrated to provide a crude oil. The crude product was purified by silica gel chromatography to provide 3 (1.2 g, 50%). 1 HNMR(CDCl3,300MHz)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).

[0294] 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 (CDCl3, 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).

[0295] Alternative preparation of intermediate 3

[0296] 1. At -78 ° C, under N2, n-BuLi (14.3 mL, 35.5 mmol) was added dropwise to a solution of 2-chlorothiazole (3.85 g, 32.3 mmol) in anhydrous THF (80 mL). 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 reaction was diluted with NH4Cl solution and extracted with EtOAc. The organic extract was concentrated to provide a crude oil. The crude product was purified by silica gel chromatography to provide 3 (5.9 g, 69.7%) as a light brown oil.

[0297] 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.

[0298] Alternative preparation of intermediate 3

[0299] 1. A mixture of 4-bromobenzaldehyde (100.0 g, 540 mmol), 1H-pyrazole (37 g, 540 mmol), Cs2CO3 (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 under e for 24 hours. 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, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by column chromatography on silica gel to provide 2 (76 g, 81.7% yield) as a white solid. MS (ESI): C 10Theoretical molecular weight of H8N2O: 172.18, m / z experimental molecular weight: 173.0 [M+H] + .

[0300] 2. At -78 ° C, n-BuLi (187.5 mL, 2.4 M, 0.45 mol) was added dropwise to a solution of 2-chlorothiazole (54.2 g, 0.45 mol) in anhydrous (550 mL) 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 reaction mixture was quenched with a saturated aqueous solution of NH4Cl and extracted with EA. The organic extract was washed with brine and dried over Na2SO4, filtered and concentrated. The resulting residue was purified on silica gel by column chromatography to provide 3 (90 g, yield 82.6%) as a yellow solid. MS (ESI): C 13 H 10 Theoretical molecular weight of ClN3OS: 291.76, m / z experimental molecular weight: 291.7 [M+H] + .

[0301] 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 refluxed with stirring for 1 h. The mixture was evaporated and diluted with EA. The resulting mixture was washed with saturated NaHCO 3 , brine, dried over Na 2 SO 4 , filtered, and concentrated. The resulting residue was purified by column chromatography on silica gel to provide intermediate 3 (55 g, 88.7% yield) as a yellow solid. MS (ESI): C 13 H 10 Theoretical molecular weight of ClN3S: 275.76, m / z experimental molecular weight: 275.8 [M+H] + .

[0302] Preparation of intermediate 4

[0303]

[0304] 1. A mixture of 7-bromo-1,2,3,4-tetrahydroisoquinoline hydrochloride (Key Organics, 250 mg, 1 mmol), intermediate 2 (276 mg, 1 mmol) and K2CO3 (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, dried over Na2SO4, filtered, concentrated, and the resulting residue was purified by chromatography on silica gel to provide intermediate 4 (200 mg, 44% yield) as an off-white solid. MS (ESI): C 22 H 19 Theoretical molecular weight of BrN4S: 451.39, m / z experimental molecular weight: 450.7452.7 [M+H] + .

[0305] Preparation of intermediate 5

[0306]

[0307] 1. A mixture of intermediate 3 (1.0 g, 3.6 mmol), Cs2CO3 (3.5 g, 10.8 mmol) and 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 a 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, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by column chromatography on silica gel to provide intermediate 5 (1.0 g, 61.3% yield) as a yellow solid. MS (ESI): C 22 H 19 Theoretical molecular weight of BrN4S: 451.38, m / z experimental molecular weight: 450.7 [M+H] + .

[0308] Preparation of intermediate 6

[0309]

[0310] 1. At -78 ° C, under N2, to a solution of 2-chlorothiazole (5.76 g, 48 mmol) in anhydrous THF (40 mL) was added dropwise n-BuLi (2.4 M, 20.0 mL, 48 mmol). 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. The mixture was quenched with a saturated aqueous solution of NH4Cl and extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4, filtered, concentrated and the resulting residue was purified by chromatography on silica gel to provide 1 (8.00 g, 66% yield) as a yellow oil. MS (ESI): C 10 Theoretical molecular weight of H7BrClNOS: 304.59, m / z experimental molecular weight: 305.7 [M+H] + .

[0311] 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 hours, concentrated, and the residue was diluted with a saturated aqueous solution of NaHCO 3 . The mixture was extracted with DCM and the combined organic extracts were washed with brine, dried over Na 2 SO 4 , filtered, concentrated, and the residue was purified by chromatography on silica gel to provide intermediate 6 (7.20 g, 94.7% yield) as a brown oil. MS (ESI): C 10 Theoretical molecular weight of H7BrClNS: 288.59, m / z experimental molecular weight: 289.6 [M+H] + .

[0312] Preparation of intermediate 7

[0313]

[0314] 1. At -78 ° C, under N2, to a solution of 1 (20 g, 71.9 mmol) in anhydrous THF (100 mL) was added dropwise n-BuLi (31.7 mL, 79.1 mmol). After 1 h, DMF (1.66 g, 79.1 mmol) was added dropwise at -78 ° C. The resulting solution was slowly heated to RT. The reaction was quenched with NH4Cl solution and extracted with EA. The combined extracts were concentrated to provide a crude oil. The crude product was purified by silica gel chromatography to provide 2 (12 g, 73.5%).

[0315] 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), Cs2CO3 (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, dried over anhydrous Na2SO4, filtered and concentrated to afford a crude oil. The crude product was purified by recrystallization to afford 3 (7.3 g, 64.5%).

[0316] 3. At -78 ° C, under N2, n-BuLi (15 mL, 37.5 mmol) was added dropwise to a solution of 2-chlorothiazole (4.47 g, 37.5 mmol) in anhydrous THF (100 mL). 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. The reaction was quenched with NH4Cl solution and extracted with EA. The organic layer was concentrated to provide a crude oil. The crude product was purified by silica gel chromatography to provide 4 (4.6 g, 40.3%).

[0317] 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) and TES (6.6 mL, 41.3 mmol) at 0°C. The resulting solution was stirred for 3 h at RT. The reaction was quenched with H2O and extracted with DCM. The combined extracts were concentrated to provide a crude oil which was purified by silica gel chromatography to provide intermediate 7 (1.8 g, 41.1%). 1 HNMR(CDCl3,300MHz)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).

[0318] Preparation of intermediate 9

[0319]

[0320] 1. A mixture of 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 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, dried over Na 2 SO 4 and concentrated to provide a crude product, which was purified by silica gel chromatography to provide 2 (494 mg, 94% yield) as a yellow oil.

[0321] 2. To a solution of 2 (494 mg, 1.50 mmol) in THF, TBAF (1 M solution in THF, 10 mL) was added 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, dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc=20 / 1) to provide 3 (280 mg, 73%) as a yellow solid.

[0322] 3. A mixture of 3 (280 mg, 1.09 mmol), iodomethane (155 mg, 1.09 mmol), NaN (84.5 mg, 1.30 mmol), CuI (207 mg, 1.09 mmol), t-BuOH (658 mg, 8.89 mmol) and H O (1.96 g, 109 mmol) was placed in a sealed tube and stirred at 100° C. overnight. The mixture was cooled, quenched with water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na SO and concentrated to provide a crude product, which was purified by silica gel column chromatography to provide 4 (171 mg, 50% yield) as a colorless solid.

[0323] 4. A mixture of 4 (171 mg, 0.54 mmol), HCl-dioxane (4 M, 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, 74% yield) as an off-white solid.

[0324] Alternative preparation of intermediate 9

[0325]

[0326] 1. To a solution of intermediate 10 (2.5 g, 8.3 mmol) in DMF (20 mL) was added KCO (2.3 g, 16.6 mmol) at 0°C. 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, dried over anhydrous NaSO, filtered, and concentrated to provide a crude oil. The crude product was purified by silica gel to provide 2 (1.4 g, 54%).

[0327] 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 allowed to slowly warm to RT and stirred overnight. The reaction was concentrated to provide intermediate 9 (1 g, 78%).

[0328] Preparation of intermediate 10

[0329]

[0330] 1. To a solution of compound 3 (4.6 g, 17.9 mmol) prepared from intermediate 9 in DMSO (40 mL) was added NaN (1.4 g, 21.5 mmol) and NH 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, dried over anhydrous Na SO, filtered and concentrated to provide a crude oil. The crude product was purified by silica gel to provide 2 (3.4 g, 62.2%).

[0331] 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%).

[0332] Preparation of intermediate 11

[0333]

[0334] 1. To a slurry of 1 (1 g, 15 mmol) and KCO (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) over 3 min. 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.

[0335] 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) (11 mg, 0.05 mmol), XPhos (48 mg, 0.1 mmol) and KCO (276 mg, 2 mmol). The mixture was heated to 100° C. under N 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.

[0336] 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%).

[0337] Preparation of intermediate 12

[0338]

[0339] 1. To a solution of 1 (Key Organics, 160 mg, 0.5 mmol) in DMF (3 mL) was added Cs2CO3 (165 mg, 0.5 mmol), imidazole (68 mg, 1 mmol), and CuI (10 mg, 0.05 mmol). The mixture was heated to 100°C and stirred under N2 for 20 h. The mixture was poured into water and extracted with EtOAc. The extract was washed with water, brine, and dried over Na2SO4, filtered, and concentrated to provide 2 (168 mg, 90%).

[0340] 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%).

[0341] Preparation of intermediate 13

[0342]

[0343] 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.

[0344] Preparation of intermediate 14

[0345]

[0346] 1. A mixture of compound 3 (650 mg, 2.53 mmol), 1-iodo-2-methoxyethane (471 mg, 2.53 mmol), NaN (164 mg, 2.53 mmol), CuI (482 mg, 2.53 mmol), t-BuOH (748 mg, 10.1 mmol) and H O (5.00 g, 278 mmol) prepared from intermediate 9 was stirred overnight at 100° C. in a sealed tube. The mixture was cooled to RT and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over Na SO and concentrated to provide a crude product which was purified by silica gel chromatography to provide 2 (350 mg, 39%) as a yellow-white solid.

[0347] 2. A mixture of 2 (350 mg, 0.98 mmol), HCl-dioxane (4 M, 5 mL, 20.0 mmol) and CH2Cl2 (10 mL) was stirred at RT for 2 h. The mixture was concentrated to afford intermediate 14 (260 mg, 90%) as a white solid.

[0348] Preparation of intermediate 15

[0349]

[0350] 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 preparative HPLC to provide 2 (320 mg, 31% yield) as an off-white solid.

[0351] 2. A mixture of 2 (220 mg, 0.70 mmol), HCl-dioxane (4 M, 3.00 mL, 12.0 mmol) and CH2Cl2 (3 mL) was stirred at RT for 2 h. The mixture was concentrated to afford intermediate 15 (150 mg, 86% yield) as an off-white solid.

[0352] Preparation of intermediate 16

[0353]

[0354] 1. A mixture of 1 (J. Med. Chem. 42, 1, 118-134, 750 mg), intermediate 2 (908 mg, 3.29 mmol), Pd2(dba)3 (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, dried over Na2SO4 and concentrated. The residue was purified by column chromatography to provide 2 (550 mg, 37% yield over 2 steps) as a yellow solid.

[0355] 2. A mixture of 2 (550 mg, 1.28 mmol), LiOH (61.0 mg, 2.56 mmol), MeOH (3 mL) and H O (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 afford 3 (170 mg, 32% yield) as an off-white solid.

[0356] 3. A mixture of 3 (170 mg, 0.41 mmol), HATU (250 mg, 0.62 mmol), DIEA (280 mg, 2.17 mmol), NHCl (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, dried over NaSO and concentrated. The residue was purified by prep-TLC to provide intermediate 16 (130 mg, 76% yield) as a yellow solid.

[0357] Preparation of intermediate 17

[0358]

[0359] 1. To a solution of 1 (J. Med. Chem. 42, 1, 118-134, 227 mg, 1 mmol) in dioxane (20 mL) was added intermediate 3 (300 mg, 1.1 mmol), Pd2(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 stirred under N2 for 20 h. 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 ° C for 2 h, 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.

[0360] 2. To a solution of 2 (50 mg, 0.12 mmol) in DMF (2 mL) was added DIEA (25 mg, 0.18 mmol), HATU (0.69 g, 0.18 mmol) and NHCl (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, dried over anhydrous NaSO, filtered and concentrated to provide a crude oil. The crude product was purified by silica gel chromatography to provide intermediate 17 (11.2 mg, 22.4%) as a white solid.

[0361] Preparation of intermediate 18

[0362]

[0363] 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), Cs2CO3 (38.7 g, 118.9 mmol), CuI (2 g), and 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, brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford a crude oil. The crude product was purified by recrystallization to afford 2 (11 g, 59.2%).

[0364] 2. At -78 ° C, under N2, n-BuLi (14 mL, 34.9 mmol) was added dropwise to a solution of 2-chlorothiazole (3.8 g, 32 mmol) in anhydrous THF (50 mL). 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. The reaction was quenched with NH4Cl solution and extracted with EA. The combined extracts were concentrated to provide a crude oil. The crude product was purified by silica gel chromatography to provide 3 (3.5 g, 41.4%).

[0365] 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 for 3 h at RT. The reaction was quenched with H2O and extracted with DCM. The organic layer was concentrated to provide a crude oil, which was purified by silica gel chromatography to provide intermediate 18 (1.8 g, 54.4%).

[0366] Preparation of intermediate 19

[0367]

[0368] 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 Cs2CO3 (48.70 g, 150 mmol). The resulting mixture was stirred at 120°C for 2 hours. It was cooled to RT, filtered and the filtrate was poured into water, extracted with CH2Cl2, and the combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated. 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 Theoretical molecular weight of N2O: 200.24, m / z experimental molecular weight: 200.9 [M+H] + .

[0369] 2. At -78 ° C, under N2, n-BuLi (2.4M, 5.5 mL) was added dropwise to a solution of 2-chlorothiazole (1.20 g, 10 mmol) in THF (20 mL). 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. The mixture was quenched with a saturated aqueous solution of NH4Cl and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography on silica gel to provide 3 (1.83 g, 64% yield) as a yellow oil. MS (ESI): C 15 H14 Theoretical molecular weight of ClN3OS: 319.81, m / z experimental molecular weight: 319.8 [M+H] + .

[0370] 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 hours. Then, it was concentrated and the residue was diluted with a saturated aqueous solution of NaHCO 3 and extracted with CH 2 Cl 2 . The combined organic phases were washed with brine, dried over Na 2 SO 4 , filtered, concentrated, and the residue was purified by chromatography on silica gel to provide intermediate 19 (1.20 g, 69.0% yield) as a brown oil. MS (ESI): C 15 H 14 Theoretical molecular weight of ClN3S: 303.81, m / z experimental molecular weight: 303.8 [M+H] + .

[0371] Preparation of intermediate 20

[0372]

[0373] 1. A mixture of 1 (Key Organics, 5.68 g, 0.018 mol), oxazolidin-2-one (4.7 g, 0.054 mol), Pd2(dba)3 (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 the 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 Theoretical molecular weight of N2O4: 318.37, m / z experimental molecular weight: 340.8 [M+H] + .

[0374] 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. The reaction was then concentrated to provide a crude product. This 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 Theoretical molecular weight of F3N2O3: 316.28, m / z experimental molecular weight: 218.9 [M+H] + .

[0375] Preparation of intermediate 21

[0376]

[0377] 1. 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 at -78°C under N2. 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. The mixture was quenched with a saturated aqueous solution of NH4Cl and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated to provide a crude product, which was purified by chromatography on silica gel to provide 2 (8.50 g, 64% yield) as a yellow oil. MS (ESI): C 10 Theoretical molecular weight of H7BrClNOS: 304.59, m / z experimental molecular weight: 305.7 [M+H] + .

[0378] 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 the residue was diluted with a saturated aqueous solution of NaHCO 3 and extracted with DCM. The combined organic phases were washed with brine, dried over Na 2 SO 4 , filtered, and concentrated to provide a crude product, which was purified by chromatography on silica gel to provide 3 (7.00 g, 86.9% yield) as a brown oil. MS (ESI): C 10 Theoretical molecular weight of H7BrClNS: 288.59, m / z experimental molecular weight: 289.6 [M+H] + .

[0379] 3. To a solution of 3 (3.00 g, 10.4 mmol) in DMSO (30 mL) was added intermediate 20 (3.45 g, 10.4 mmol) and K2CO3 (4.31 g, 31.2 mmol). The reaction mixture was stirred at 140°C for 3 hours. The reaction was cooled to RT, poured into ice-water, extracted with CH2Cl2, and the combined organic phases were washed with brine, dried over Na2SO4, filtered, concentrated, and purified by chromatography on silica gel to provide intermediate 21 as a yellow solid (2.10 g, 42.9% yield). MS (ESI): C 22 H 20 Theoretical molecular weight of BrN3O2S: 470.39, m / z experimental molecular weight: 470.5 [M+H] + .

[0380] Preparation of intermediate 22

[0381]

[0382] 1. At -78 ° C, under N2, to a solution of 2-chlorothiazole (5.76 g, 48 mmol) in anhydrous THF (40 mL) was added dropwise n-BuLi (2.4 M, 20.0 mL, 48 mmol). 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. It was then quenched with a saturated aqueous solution of NH4Cl and extracted with EtOAc and the combined organic phases were washed with brine, dried over Na2SO4, filtered, concentrated and purified by chromatography on silica gel to provide 2 (8.00 g, yield 66%) as a yellow oil. MS (ESI): C 10 Theoretical molecular weight of H7BrClNOS: 304.59, m / z experimental molecular weight: 305.7 [M+H] + .

[0383] 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 the residue was diluted with a saturated aqueous solution of NaHCO 3 , extracted with DCM and the combined organic phases were washed with brine, dried over Na 2 SO 4 , filtered, concentrated and purified by chromatography on silica gel to provide 3 as a brown oil (7.20 g, 94.7% yield). MS (ESI): theoretical molecular weight of C 10 H 7 BrClNS: 288.59, m / z observed molecular weight: 289.6 [M+H] + .

[0384] 3. To a solution of 3 (3.10 g, 11 mmol) in DMSO (30 mL) was added intermediate 20 (3.5 g, 11 mmol) and K2CO3 (4.56 g, 33 mmol). The reaction was stirred at 140°C for 3 hours. The reaction was cooled to RT, then poured into ice-water, extracted with CH2Cl2, and dried over Na2SO4. 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, 92% yield). MS (ESI): C 22 H 20 Theoretical molecular weight of BrN3O2S: 470.39, m / z experimental molecular weight: 470.7 [M+H] + .

[0385] Preparation of intermediate 23

[0386]

[0387] 1. A mixture of 1 (Key Organics, 15 g, 48 mmol), TEA (9.7 g, 96 mmol) and Pd(dppf)Cl2 (2.8 g, 3.84 mmol) in MeOH (200 mL) and MeCN (50 mL) was purged 3× with CO in a bomb, 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 provide the crude product, which was purified by silica gel chromatography to provide 2 as an oil (11.5 g, 82.1% yield). MS (ESI): C 16 H 21 Theoretical molecular weight of NO4: 291.15, m / z experimental molecular weight: 313.9 [M+Na] + . 1 H NMR (400MHz, CDCl3) 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).

[0388] 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 a 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 Theoretical molecular weight of N2O3: 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).

[0389] 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. This was dissolved in DCM and diluted with PE, which resulted in a precipitate that was collected by filtration. The filter cake was washed with EA and dried under vacuum to afford intermediate 23 (6.3 g, 71.4%), MS (ESI): C 12 H 13 Theoretical molecular weight of F3N2O3: 290.24, m / z experimental molecular weight: 177.0 [M+H] + .

[0390] Preparation of intermediate 24

[0391]

[0392] 1. 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 at -78°C under N2. 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. The mixture was quenched with an aqueous solution of NH4Cl and extracted with DCM and dried over Na2SO4. The combined organic layers were concentrated to provide a crude product, which was purified by silica gel chromatography to provide 2 (2.00 g, 68.36% yield) as a white solid. MS (ESI): C 14 H 15 Theoretical molecular weight of ClN2O2S: 310.80, m / z experimental molecular weight: 311.4 [M+H] + .

[0393] 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 the residue was washed with aqueous NaHCO 3 solution and extracted with DCM (30 mL×3) and dried over 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 (1.1 g, 57.94% yield) as a white solid. MS (ESI): C 14 H 15 Theoretical molecular weight of ClN2OS: 294.8, m / z experimental molecular weight: 295.4 [M+H] + .

[0394] Preparation of intermediate 25

[0395]

[0396] 1. A mixture of 1 (Key Organics, 5.0 g, 16.01 mmol), pyrrolidin-2-one (4.09 g, 48.03 mmol), Pd2(dba)3 (1.17 g, 1.6 mmol), S-Phos (1.31 g, 3.2 mmol) and t-BuOK (5.38 g, 48.03 mmol) in anhydrous 1,4-dioxane (200 mL) was stirred at 100°C overnight. The mixture was poured into water and extracted with DCM, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by silica gel chromatography to provide 2 (3.2 g, 63.17%) as a white solid. 18 H 24 Theoretical molecular weight of N2O3: 316.40, m / z experimental molecular weight: 316.8 [M+H] + .

[0397] 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 the residue was washed with aqueous NaHCO 3 solution and extracted with DCM and dried over Na 2 SO 4 . The combined extracts were concentrated to provide a crude product, which was purified by silica gel chromatography to provide intermediate 25 (1.05 g, 48.02% yield) as a white solid. MS (ESI): C 13 H 16 Theoretical molecular weight of N2O: 216.28, m / z experimental molecular weight: 216.8 [M+H] + .

[0398] Preparation of intermediate 26

[0399]

[0400] 1. A mixture of 1 (Sigma-Aldrich, 4 g, 26.7 mmol), 2-bromopyrimidine (3.51 g, 22.1 mmol), NaHCO3 (6.73 g, 80.1 mmol), Pd(PPh3)4 (766 mg, 0.663 mmol) in DME / H2O (100 mL / 50 mL) was stirred at 90°C under N2 atmosphere for 18 hours. The mixture was filtered through celite and the filter cake was washed with EA and the filtrate was concentrated. The resulting mixture was extracted with EA, and the combined extracts were washed with brine, water, and dried over Na2SO4. The mixture was filtered and the filtrate was concentrated to provide a residue, which was purified by silica gel chromatography to provide 2 (3.84 g, yield 78.1%) as a white solid. MS (ESI): C 11Theoretical molecular weight of H8N2O: 184.20, m / z experimental molecular weight: 185.0 [M+H] + .

[0401] 2. At -78 ° C, under N2, n-BuLi (2.4M, 9.9 mL, 23.75 mmol) was added dropwise to a solution of 2-chlorothiazole (2.69 g, 22.7 mmol) in anhydrous THF (80 mL). 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 hours. The resulting mixture was quenched with an aqueous solution of NH4Cl and extracted with EtOAc, and the combined extracts were dried over Na2SO4. The organic solution was concentrated to provide a crude product, which was purified by silica gel chromatography to provide 3 (4.65 g, 74.2% yield) as a white solid. MS (ESI): C 14 H 10 Theoretical molecular weight of ClN3OS: 303.76, m / z experimental molecular weight: 303.8 [M+H] + .

[0402] 3. To a solution of 3 (3 g, 9.87 mmol) and TFA (11.3 g, 98.7 mmol) in anhydrous DCE was added TES (3.42 g, 29.6 mmol) dropwise at 0°C and the reaction was stirred at 60°C for 8 hours. The mixture was cooled and concentrated. The resulting residue was treated with saturated NaHCO3, extracted with EA and the combined extracts were washed with brine, water and dried over Na2SO4. The solvent was removed to provide a crude product which was purified by flash chromatography to provide intermediate 26 (1.2 g, 42.2% yield) as a white solid. MS (ESI): C 14 H 10 Theoretical molecular weight of ClN3S: 287.77, m / z experimental molecular weight: 287.8 [M+H] + .

[0403] Preparation of intermediate 27

[0404]

[0405] 1. A mixture of 1 (2.00 g, 6.4 mmol), morpholine (1.80 g, 20.6 mmol), Pd2(dba)3 (2.0 g, 2.2 mmol), S-Phos (1.20 g, 3.0 mmol) and K2CO3 (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 Theoretical molecular weight of N2O3: 318.19, m / z experimental molecular weight: 319.0 [M+H] + .

[0406] 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 hours. The mixture was cooled, concentrated, and the residue was treated with a saturated aqueous solution of NaHCO 3 , extracted with CH 2 Cl 2 , and the combined organic phases were washed with brine, dried over Na 2 SO 4 , filtered, and the filtrate was concentrated to provide intermediate 27 (1.4 g, crude product) as a brown oil. MS (ESI): C 13 H 18 Theoretical molecular weight of N2O: 218.14, m / z experimental molecular weight: 219.0 [M+H] + .

[0407] Preparation of intermediate 28

[0408]

[0409] 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 Cs2CO3 (11.74 g, 36 mmol). The resulting mixture was stirred at 120°C overnight. The mixture was cooled to RT, filtered, the filtrate poured into water and the mixture was extracted with EA. The combined extracts were washed with brine, dried over Na2SO4, concentrated and purified by chromatography on silica gel to provide 2 (4.17 g, 70% yield) as a white solid. MS (ESI): C 10 Theoretical molecular weight of H9NO3: 191.19, m / z experimental molecular weight: 192.0 [M+H] + .

[0410] 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) 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, quenched with a saturated aqueous solution of NH4Cl and extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated to provide 3 (crude, 1.8 g) as a yellow oil. MS (ESI): C 14 H 12 Theoretical molecular weight of ClN3O2S: 310.75, m / z experimental molecular weight: 311.21 [M+H] + .

[0411] 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 provide intermediate 28 as a white solid (78 mg, 82% yield). MS (ESI): C 13 H 11 Theoretical molecular weight of ClN2O2S: 294.75, m / z experimental molecular weight: 295.19 [M+H] + .

[0412] Preparation of intermediate 29

[0413]

[0414] 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 Theoretical molecular weight of N3O3: 317.39, m / z experimental molecular weight: 317.9 [M+H] + .

[0415] 2. To a solution of 2 (1.50 g, 4.7 mmol) in THF (40 mL) was added NaH (200 mg, 13.8 mmol) at 0°C. 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, and the combined extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated to provide 3 (1 g, 64%). 18 H 25 Theoretical molecular weight of N3O3: 331.42.m / z Experiential molecular weight: 332.0 [M+H] + .

[0416] 3. A mixture of 3 (2 g, 6 mmol) and TFA (9 mL) in DCM (40 mL) was stirred at RT for 2 h. It was then concentrated and the residue was diluted with a saturated aqueous solution of NaHCO 3 , extracted with CH 2 Cl 2 and the combined organic phases were washed with brine, dried over Na 2 SO 4 , filtered, and concentrated to afford intermediate 29 (1.1 g) as a brown oil. MS (ESI): C 13 H 17 Theoretical molecular weight of N3O: 231.3, m / z experimental molecular weight: 231.9 [M+H] + .

[0417] Preparation of intermediate 30

[0418]

[0419] 1. A vessel containing a mixture of methyl 4-bromobenzoate (1.1 g, 5.12 mmol), 1 (Sigma-Aldrich, 1.1 g, 5.24 mmol), Pd(dppf)Cl (299 mg, 0.41 mmol) and KCO (1.412 g, 10 mmol) in 1,4-dioxane (15 mL) and H0 (1 mL) was purged with N3 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 Theoretical molecular weight of O3: 218.25, m / z experimental molecular weight: 219.0 [M+H] + .

[0420] 2. A mixture of 2 (940 mg, 4.31 mmol) and Pd / C (250 mg) in EtOAc (40 mL) was stirred at RT under H2 for 16 h. The mixture was filtered and concentrated to afford 3 (948 mg, 100% yield) as a colorless oil. MS (ESI): C 13 H 16 Theoretical molecular weight of O3: 220.27, m / z experimental molecular weight: 221.0 [M+H] + .

[0421] 3. LiAlH4 (160 mg, 4.09 mmol) was added to a solution of 3 (900 mg, 4.09 mmol) in anhydrous THF (15 mL) at 0°C. The mixture was heated to RT and stirred for 2 h, cooled to 0°C and quenched with a saturated aqueous solution of NH4Cl and extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated to provide 4 (765 mg, 97% yield) as a yellow oil. MS (ESI): C 12 H 16 Theoretical molecular weight of O2: 192.26, m / z experimental molecular weight: 175.0 [M-OH] + .

[0422] 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 as a yellow oil (15.5 mg, 78% yield). MS (ESI): C 12 H 14 Theoretical molecular weight of O2: 190.24, m / z experimental molecular weight: 191.0 [M+H] + .

[0423] 5. At -78 ° C, 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). 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. The mixture was quenched with a saturated aqueous solution of NH4Cl and extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4, filtered, concentrated and purified by chromatography on silica gel to provide 6 (860 mg, 88% yield) as a white solid. MS (ESI): C 15 H 16 Theoretical molecular weight of ClNO2S: 309.81, m / z experimental molecular weight: 309.8 [M+H]+ .

[0424] 6. A mixture of 6 (690 mg, 2.23 mmol), TES (2 mL) and TFA (2 mL) was stirred at RT under N2 for 2 h. The mixture was concentrated and the residue was diluted with a saturated aqueous solution of NaHCO3 and extracted with DCM. The combined extracts were washed with brine, dried over Na2SO4, filtered, concentrated and the resulting residue was purified by chromatography on silica gel to provide intermediate 30 (566.6 mg, 87% yield) as a yellow oil. MS (ESI): C 15 H 16 Theoretical molecular weight of ClNOS: 293.81, m / z experimental molecular weight: 294.1 [M+H] + .

[0425] Preparation of intermediate 31

[0426]

[0427] 1. At -78 ° C, under N2, n-BuLi (2.4M in Hex, 13.0 mL, 31.2 mmol) was added dropwise to a solution of 2-chlorothiazole (3.59 g, 29.9 mmol) in anhydrous THF (94 mL). 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 hours. The mixture was quenched with saturated NH4Cl aqueous solution and extracted with EtOAc. The combined extracts were dried over Na2SO4 and concentrated to provide a crude product, which was purified by silica gel chromatography to provide 2 (1.6 g, 19.4% yield) as a white solid. MS (ESI): C 11 H 10 Theoretical molecular weight of ClNO3S2: 303.78, m / z experimental molecular weight: 303.7 [M+H] + .

[0428] 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, quenched with saturated NaHCO 3 and extracted with EtOAc. The combined extracts were washed with water, dried over Na 2 SO 4 and concentrated to provide a crude product which was purified by silica gel chromatography to provide intermediate 31 (1.3 g, 85.8% yield) as a white solid. MS (ESI): C 11 H 10 Theoretical molecular weight of ClNO2S2: 287.78, m / z experimental molecular weight: 287.7 [M+H] + .

[0429] Preparation of intermediate 34

[0430]

[0431] 1. Under N2, 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, dried over Na2SO4 and concentrated to provide a crude product, which was purified by silica gel chromatography to provide 2 (4.0 g, 21% yield) as a colorless oil.

[0432] 2. To a solution of 2 (2.66 g, 18.0 mmol) in anhydrous THF (50 mL) was added dropwise n-BuLi (2.5 M in hexane, 7.2 mL, 18.0 mmol) at -78°C under N2. 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 warmed to room temperature. The reaction was quenched with saturated NH4Cl and extracted with EtOAc. The combined organic extracts were concentrated to provide a crude oil, which was purified by silica gel chromatography to provide 3 (420 mg, 8% yield) as a yellow oil.

[0433] 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 for 2 h at 100° C. 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.

[0434] Preparation of intermediate 35

[0435]

[0436] 1. To a mixture of 1 (4 g, 22.5 mmol) in a saturated aqueous solution of NaHCO 3 (50 mL) and THF (50 mL) was added BOC 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, dried over Na 2 SO 4 , filtered, concentrated, and purified by chromatography on silica gel to provide 2 (5.8 g, 93.5% yield) as a brown solid. MS (ESI): C 14H 18 Theoretical molecular weight of N2O4: 278.31, m / z experimental molecular weight: 301.0 [M+Na] + .

[0437] 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 H2 for 16 h. The mixture was filtered and concentrated to afford 3 (5 g, 96.7% yield) as a brown oil. MS (ESI): C 14 H 20 Theoretical molecular weight of N2O2: 248.33, m / z experimental molecular weight: 271.0 [M+Na] + .

[0438] 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, 95% yield) as a brown solid. MS (ESI): C 18 H 26 Theoretical molecular weight of ClN3O3: 367.87, m / z experimental molecular weight: 368.0 [M+H] + .

[0439] 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. The mixture was then heated to RT and stirred for 16 h. The volume was reduced to approximately 40 mL, cooled 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, and the combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by chromatography on silica gel, eluting to provide 5 (2.4 g, 96% yield) as a yellow oil. MS (ESI): C 19 H 27 Theoretical molecular weight of N3O3: 345.44, m / z experimental molecular weight: 346.0 [M+H] + .

[0440] 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, 88% yield). MS (ESI): C 16 H 20 Theoretical molecular weight of F3N3O3: 359.35, m / z experimental molecular weight: 246.0 [M-TFA+H] + .

[0441] Example

[0442] Example 1.

[0443] 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 KCO (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, dried over anhydrous NaSO, filtered and concentrated to provide a crude oil. The crude product was purified by silica gel chromatography to provide 90.36 mg of Example 1. 1 HNMR(CDCl3,300MHz)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) + .

[0444] Example 2.

[0445] 1. A mixture of Intermediate 9 (100 mg, 0.40 mmol), Intermediate 3 (121 mg, 0.44 mmol), Pd2(dba)3 (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, dried over Na2SO4 and concentrated. The residue was purified by preparative HPLC to provide Example 2 (45.9 mg, 25% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 2.91 (2H, t, J = 5.6 Hz), 3.67 (2H, t, J = 5.6 Hz), 4.04 (2H, s), 4.08 (3H, s), 4.60 (2H, s), 6.53 (1H, t, J = 2.0 Hz), 7.03 (1H, s), 7.25 (1H, d, J = 8.0 Hz), 7.36 (2H, d, J = 8.4 Hz), 7.63-7.73 (3H, m), 7.77 (2H, d, J = 8.4 Hz), 8.46 (2H, d, J = 2.0 Hz). MS calc: 453.2; MS found: 454.2 [M+H] + .

[0446] Example 3.

[0447] 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(CDCl3,300MHz)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) + .

[0448] Example 4.

[0449] 1. Following the procedure described for Example 1, Intermediate 10 and Intermediate 2 were reacted to provide 11.03 mg of Example 4. 1HNMR(CDCl3,300MHz)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) + .

[0450] Example 5.

[0451] 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(CDCl3,300MHz)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) + .

[0452] Example 6.

[0453]

[0454] 1. To a solution of 1 (Sigma-Aldrich, 158 mg, 1 mmol) in EtOH (20 mL) was added NH2OH (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.

[0455] 2. A mixture of 2 (0.19 g, 1 mmol) in AcO (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 provide 3 (0.4 g, 100%) as a white solid.

[0456] 3. To a solution of 3 (20 mg, 0.5 mmol) in dioxane (10 mL) was added intermediate 3 (250 mg, 0.9 mmol), Pd2(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 maintained under N2 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 6 (40 mg, 20%) as a yellow solid. LC-MS: m / z=455.1 (M+1) + The product of Example 6 1 The HNMR spectrum is shown in Figure 1 middle.

[0457] Example 7.

[0458] 1. To a solution of intermediate 11 (82 mg, 0.3 mmol, 1 eq) in dioxane (20 mL) was added intermediate 3 (137 mg, 0.5 mmol, 1.6 eq), Pd2(dba)3 (18 mg, 0.027 mmol, 0.09 eq), SPhos (18 mg, 0.04 mmol, 0.13 eq) and t-BuOK (330 mg, 3 mmol, 10 eq). The mixture was heated to 100° C. and stirred under N2 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) + The product of Example 7 1 The HNMR spectrum is shown in Figure 2 middle.

[0459] Example 8.

[0460] 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) + The product of Example 8 1 The HNMR spectrum is shown in Figure 3 middle.

[0461] Example 9.

[0462] 1. The title compound was prepared according to the procedure described for Example 7 using Intermediate 12 instead of Intermediate 11, 1 equivalent of Intermediate 3, 0.06 equivalent of Pd2(dba)3, 0.07 equivalent of SPhos and 2.4 equivalents of t-BuOK to provide Example 9 as a white solid (100 mg, 45.6%). LC-MS: m / z = 439.2 (M+1) + The product of Example 9 1 The HNMR spectrum is shown in Figure 4 middle.

[0463] Example 10.

[0464]

[0465] 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.

[0466] 2. BOC2O (1.88 g, 8.61 mmol) and TEA (2.8 mL, 16.45 mmol) in THF (20 mL) were added dropwise to a suspension of 2 (1.92 g, 7.83 mmol) in water (6 mL). The mixture was stirred overnight at RT. After concentration, the residue was dissolved in EtOAc and washed with water. The organic mixture was dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography to provide 3 (1.8 g, 86.9%).

[0467] 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 NaOH aqueous solution (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. The organic extract was dried over Na2SO4, filtered and concentrated to provide 4 (210 mg, 47.8%).

[0468] 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%).

[0469] 5. To a solution of 5 (137 mg, 0.6 mmol) in dioxane (10 mL) was added intermediate 2 (170 mg, 0.62 mmol), Pd2(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 stirred under N2 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) + The product of Example 10 1 The HNMR spectrum is shown in Figure 5 middle.

[0470] Example 11.

[0471] 1. The title compound was prepared according to the procedure described for Example 7 using Intermediate 14 in place of Intermediate 11, 1 equivalent of Intermediate 3, 0.09 equivalent of Pd2(dba)3, 0.16 equivalent of SPhos and 3 equivalents of t-BuOK to provide Example 11 (75.9 mg, 35%) as a white solid. 1 H NMR(400MHz,DMSO-d6)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 calc: 497.2; MS exp: 498.2 [M+H] + .

[0472] Example 12.

[0473] 1. The title compound was prepared according to the procedure described for Example 7 using Intermediate 14 instead of Intermediate 11, 1 equivalent of Intermediate 2 instead of Intermediate 3, 0.09 equivalent of Pd2(dba)3, 0.18 equivalent of SPhos and 3 equivalents of t-BuOK to provide Example 12 as a white solid (51.5 mg, 23%).1 H NMR (400MHz, DMSO-d6) 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(2 H,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 calc: 497.2; MS exp: 498.2 [M+H] + .

[0474] Example 13.

[0475] 1. The title compound was prepared according to the procedure described for Example 7 using Intermediate 15 in place of Intermediate 11, 1 equivalent of Intermediate 3, 0.09 equivalent of Pd2(dba)3, 0.2 equivalent of SPhos and 2.8 equivalents of t-BuOK to provide Example 13 as a white solid (33.4 mg, 15% yield). 1 H NMR(400MHz, DMSO-d6)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] + .

[0476] Example 14.

[0477] 1. A mixture of Intermediate 1 (100 mg, 0.38 mmol), Intermediate 3 (115 mg, 0.42 mmol), Pd2(dba)3 (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, dried over Na2SO4 and concentrated to provide the crude product, which was purified by preparative HPLC to provide Example 14 (33.5 mg, 19% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ2.08(3H,s),2.22(3H,s),2.94(2H,t,J=5.6Hz),3.6 7(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] + .

[0478] Alternative Preparation of Example 14

[0479] 1. To a solution of intermediate 1 (25 g, 110 mmol) in DMSO (500 mL) was added intermediate 3 (40 g, 145 mmol) and K2CO3 (45.54 g, 330 mmol). The flask was purged with N2 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, eluting 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 Theoretical molecular weight of N6S: 466.61, m / z experimental molecular weight: 466.8 [M+H] + . 1H 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).

[0480] Example 15.

[0481] 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 a mixture of EtOH (10 mL) and N2H4*H2O (2 mL), and the resulting mixture was stirred at RT for 0.5 h. The mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated. The residue was purified by preparative-HPLC to provide Example 15 (11.0 mg, 8% yield) as a white solid. 1 HNMR(400MHz,DMSO-d6)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(1 H, m), 7.43 (1H, t, J = 7.6 Hz), 7.67-7.69 (1H, m), 7.73 (1H, d, J = 1.6 Hz), 7.77 (1H, s), 7.81-7.84 (2H, m), 8.49 (1H, d, J = 2.8 Hz), 8.58-8.62 (1H, m), 14.09-14.40 (1H, m). MS calc: 439.2; MS exp: 440.1 [M+H] + .

[0482] Example 16.

[0483] 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)+ .

[0484] The product of Example 16 1 The HNMR spectrum is shown in Figure 6 middle.

[0485] Example 17.

[0486] 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) + .

[0487] Example 18.

[0488] 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(CDCl3,300MHz)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) + .

[0489] Example 19.

[0490] 1. Following the procedure described for Example 7 using Intermediate 1 instead of Intermediate 11, 1.2 equivalents of Intermediate 2 instead of Intermediate 3, 0.11 equivalents of Pd2(dba)3, 0.22 equivalents of SPhos and 3 equivalents of t-BuOK, provided Example 19 (33.5 mg, 20% yield) as a white solid. 1H NMR (400MHz, DMSO-d6) 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) ,7.69(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] + .

[0491]

[0492] Example 20.

[0493] 1. To a mixture of 1 (PCT Int. Appl. (2008), WO 2008079277 A, 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) under N 2 . 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, dried over anhydrous Na 2 SO 4 , filtered and concentrated to provide a crude oil. The crude product was purified by recrystallization to provide 2 (1.1 g, 38%).

[0494] 2. A mixture of 2 (1.1 g, 2.76 mmol) in HCl / Et2O (3 M, 20 mL) was stirred overnight at RT. The mixture was filtered and the filter cake was washed with Et2O to provide 3 (0.4 g, 80%).

[0495] 3. To a mixture of 3 (0.3 g, 1.6 mmol) in DMSO (5 mL) was added intermediate 3 (0.3 g, 1.1 mmol) and K CO (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, dried over anhydrous Na SO , filtered and concentrated to provide a crude oil which was purified by silica gel chromatography to provide Example 20 (15 mg).1 HNMR(CDCl3,300MHz)δ:2.9-3.1(m,2H),3.7-3.8(m,2H),4.0-4.1(m,2H),4.6-4.7(s,2 H),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) +

[0496] Example 21.

[0497] 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 stirred at 140°C under N2 overnight. The mixture was cooled to RT, diluted with MeOH, filtered, and the filtrate was concentrated and purified by preparative HPLC to provide Example 21 as an off-white solid (20 mg, 10.5% yield). MS (ESI): C 26 H 24 Theoretical molecular weight of N6S: 452.58, m / z experimental molecular weight: 452.8 [M+H] + . 1 H 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).

[0498] Example 22.

[0499]

[0500] 1. To a solution of 1 (4.50 g, 20.93 mmol) in DMF (30 mL) was 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 K2CO3 (5.75 g, 41.7 mmol). The reaction mixture was stirred at 150°C for 18 h. The reaction was cooled to RT, poured into ice-water, extracted with CH2Cl2, and dried over Na2SO4. The combined organic extracts were concentrated under reduced pressure and purified by chromatography on silica gel to provide 2 (1.80 g, 42.6% yield) as a yellow solid. MS (ESI): C 20 H 18 Theoretical molecular weight of BrN3OS: 202.21, m / z experimental molecular weight: 202.7 [M+H] + .

[0501] 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. The mixture was quenched with a saturated aqueous solution of NH4Cl, extracted with EtOAc, and the combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. 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 Theoretical molecular weight of H7BrClNOS: 321.78, m / z experimental molecular weight: 322.4 [M+H] + .

[0502] 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 hours. The mixture was concentrated and the residue was washed with a saturated aqueous solution of NaHCO 3 , extracted with CH 2 Cl 2 , and dried over Na 2 SO 4 . The organic extracts were concentrated to provide a crude product, which was purified by chromatography on silica gel to provide 4 (1.2 g, 90.2% yield) as a yellow oil. MS (ESI): C 10 Theoretical molecular weight of H7BrClNS: 305.78, m / z experimental molecular weight: 306.2 [M+H] + .

[0503] 4. To a solution of 4 (0.2 g, 0.65 mmol) in 1,4-dioxane (30 mL) was added intermediate 1 (0.148 g, 0.65 mmol) and K2CO3 (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, extracted with CH2Cl2 and the combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative-HPLC to provide Example 22 (18.5 mg, 5.7% yield) as a yellow solid. MS (ESI): C 28 H 28 Theoretical molecular weight of N6OS: 496.63, m / z experimental molecular weight: 496.7 [M+H] + . 1 H 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).

[0504] Example 23.

[0505] 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 Theoretical molecular weight of N6S: 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).

[0506] Example 24.

[0507] 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 Theoretical molecular weight of N5O2S: 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).

[0508] Example 25.

[0509] 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 equivalent) instead of 4-methyl-1H-imidazole, t-BuOK (3 equivalents), CuI (0.5 equivalents), (S,S)-N,N'-dimethyl-1,2-diaminocyclohexane (0.2 equivalents) to provide Example 25 as a yellow solid (30 mg, 14.8% yield). MS (ESI): C 25 H 24 Theoretical molecular weight of N6OS: 456.56, m / z experimental molecular weight: 456.8 [M+H] + . 1H 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).

[0510] Example 26.

[0511] 1. A mixture of intermediate 5 (100 mg, 0.22 mmol), 1-methylimidazolidin-2-one (66 mg, 0.66 mmol), (Pd2(dba)3) (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 a nitrogen atmosphere. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC to provide Example 26 (50 mg, 48.1% yield) as a yellow solid. MS (ESI): C 26 H 26 Theoretical molecular weight of N6OS: 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).

[0512] Example 27.

[0513]

[0514] 1. A mixture of 4-fluoro-3-methoxy-benzaldehyde (5.0 g, 32.4 mmol), 1H-pyrazole (3.3 g, 48.6 mmol), K2CO3 (6.8 g, 48.6 mmol) in DMF (30 mL) was stirred at 120°C for 20 h under N2. 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, dried over Na2SO4, filtered, and concentrated. 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 Theoretical molecular weight of N2O2: 202.21, m / z experimental molecular weight: 202.9 [M+H] + .

[0515] 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. The reaction mixture was quenched with NH4Cl solution and extracted with EA. The combined organic extracts were washed with brine and dried with Na2SO4, filtered and concentrated. The resulting residue was purified on silica gel by column chromatography to provide 3 (5.6 g, 83.8% yield) as a yellow solid. MS (ESI): C 14 H 12 Theoretical molecular weight of ClN3O2S: 321.78, m / z experimental molecular weight: 321.8 [M+H] + .

[0516] 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 combined organic extracts were washed with saturated NaHCO3 solution, brine, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by column chromatography on silica gel to provide 4 (4.8 g, 90.2% yield) as a clear liquid. MS (ESI): C 14 H 12 Theoretical molecular weight of ClN3OS: 305.78, m / z experimental molecular weight: 305.8 [M+H] + .

[0517] 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 Theoretical molecular weight of N6OS: 496.63, m / z experimental molecular weight: 496.8 [M+H] + . 1 H 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).

[0518] Example 28.

[0519] 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 Theoretical molecular weight of N5O2S: 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).

[0520] Example 29.

[0521] 1. A mixture of intermediate 22 (329 mg, 0.48 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (203 mg, 0.8 mmol), Pd(dppf)Cl2 (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 Theoretical molecular weight of BN3O4S: 517.45, m / z experimental molecular weight: 517.6 [M+H] + .

[0522] 2. To a mixture of 1 (100 mg, 0.19 mmol) and 2-chloropyrimidine (23 mg, 0.20 mmol) in 1,4-dioxane (8 mL) and H2O (2 mL) was added K2CO3 (80 mg, 0.57 mmol) and Pd(dppf)Cl2 (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, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by prep-TLC to provide Example 29 (9 mg, 10%) as a white solid. 26 H 23 Theoretical molecular weight of N5O2S: 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).

[0523] Example 30.

[0524] 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 extracted with CH2Cl2. The combined extracts were dried over Na2SO4, filtered and the filtrate concentrated. The resulting residue was purified by prep-TLC to provide Example 30 (11 mg, 7%) as a white solid. 23 H 20 Theoretical molecular weight of N4O2S: 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).

[0525] Example 31.

[0526] 1. A mixture of intermediate 22 (240 mg, 0.5 mmol), morpholine (131 mg, 1.5 mmol), Pd2(dba)3 (229 mg, 0.25 mmol), SPhos (103 mg, 0.25 mmol) and K2CO3 (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 extracted with CH2Cl2. The combined extracts were dried over Na2SO4, 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 Theoretical molecular weight of N4O3S: 476.6, m / z experimental molecular weight: 476.8 [M+H] + , 1H 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).

[0527] Example 32.

[0528] 1. Following the procedure described for Example 31, using t-BuOK (170 mg) instead of K2CO3, 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 Theoretical molecular weight of N4O4S: 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).

[0529] Example 33.

[0530] 1. Following the procedure described for Example 31, using Cs2CO3 (488 mg) instead of K2CO3, 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 Theoretical molecular weight of N4O4S2: 524.65, m / z experimental molecular weight: 524.7 [M+H] + , 1H NMR (400MHz, CDCl3) 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).

[0531] Example 34.

[0532]

[0533] 1. At -78 ° C, 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 under N2. 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. The reaction was quenched with saturated NH4Cl and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and the filtrate was concentrated to provide a crude product, which was purified by silica gel chromatography to provide 2 (0.60 g, 36% yield) as a yellow oil. MS (ESI): C 11 H 10 Theoretical molecular weight of ClNO3S2: 303.78, m / z experimental molecular weight: 304.1 [M+H] + .

[0534] 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, the residue diluted with saturated NaHCO 3 , extracted with DCM and the combined organic extracts washed with brine, dried over Na 2 SO 4 , filtered and concentrated. The resulting residue was purified by silica gel chromatography to provide 3 (400 mg, 70.5% yield) as a brown oil. MS (ESI): C 11 H 10 Theoretical molecular weight of ClNO2S2: 287.78, m / z experimental molecular weight: 288.0 [M+H] + .

[0535] 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 Theoretical molecular weight of N3O4S2: 469.57, m / z experimental molecular weight: 469.7 [M+H] + . 1 H NMR(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).

[0536] Example 35.

[0537] 1. Following the procedure described for Example 31, using Cs2CO3 (488 mg) instead of K2CO3, 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 Theoretical molecular weight of N4O3S: 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).

[0538] Example 36.

[0539] 1. Following the procedure described for Example 31, using Cs2CO3 (371 mg) instead of K2CO3, 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 Theoretical molecular weight of N4O4S2: 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).

[0540] Alternative Preparation of Example 36

[0541] 1. A mixture of intermediate 22 (50 g, 0.106 mol), thiomorpholine 1,1-dioxide (71.8 g, 0.531 mol), Pd(OAc)2 (12 g, 0.053 mol), SPhos (23.4 g, 0.053 mol), and Cs2CO3 (43.3 g, 0.133 mol) in anhydrous 1,4-dioxane (2.8 L) was stirred at 100°C under N2 for 6 hours. 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 filtrates were concentrated. The resulting residue was dissolved in DCM:MeOH 10:1 (200 mL), and the mixture was heated to reflux for 30 minutes. MeOH (300 mL) was added and the mixture was heated to reflux for 20 minutes. The suspension was filtered through celite. The filtrate was concentrated and the residue was treated four times as described above. After the fourth filtration, the combined filtrates were concentrated to provide the crude product as an orange solid, which was slurried twice with MeCN (300 mL) to provide Example 36 as a white solid (25.9 g, 46.4%). MS (ESI): C 26 H 28 Theoretical molecular weight of N4O4S2: 524.65, experimental molecular weight of m / z: 524.8 [M+H] + . 1H 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).

[0542] Example 37.

[0543] 1. A mixture of Intermediate 5 (225 mg, 0.50 mmol), tetrahydropyrimidin-2(1H)-one (150 mg, 1.50 mmol), Pd2(dba)3 (92 mg, 0.1 mmol), SPhos (82 mg, 0.2 mmol) and t-BuOK (168 mg, 1.5 mmol) in 1,4-dioxane (20 mL) was stirred at 100°C overnight. The mixture was cooled, poured into water and extracted with DCM, dried over Na2SO4, filtered and the filtrate concentrated. The resulting residue was purified by prep-TLC to provide Example 37 (3.4 mg, 1.4%) as a white solid. 26 H 26 Theoretical molecular weight of N6OS: 470.60, m / z experimental molecular weight: 470.8 [M+H] + , 1 H NMR(400MHz,CD3OD)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).

[0544] The compounds listed in Table 2 below were prepared in a similar manner to that described in Example 37.

[0545] Table 2

[0546]

[0547]

[0548]

[0549] Example 38.

[0550] 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, CH3I was added. The reaction was heated to RT and stirred overnight. The mixture was poured into water and extracted with DCM. The combined extracts were dried over Na2SO4, 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 28 Theoretical molecular weight of N6OS: 484.62, m / z experimental molecular weight: 484.8 [M+H] + . 1 H NMR (400MHz, CDCl3) 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,1H),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).

[0551] Example 39.

[0552] 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 dried over Na2SO4, filtered and the filtrate was concentrated. 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 H20 Theoretical molecular weight of N4O2S: 416.50, m / z experimental molecular weight: 416.8 [M+H] + . 1 H NMR (400MHz, CDCl3) 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).

[0553] Example 40.

[0554] 1. Following the procedure described for Example 31, using Cs2CO3 (488 mg) instead of K2CO3, 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 Theoretical molecular weight of N4O4S: 476.55, m / z experimental molecular weight: 476.8 [M+H] + . 1 H NMR (400MHz, CDCl3) 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).

[0555] Example 41.

[0556]

[0557] 1. To a solution of 1 (2.00 g, 10.75 mmol) in DMF (30 mL) was added 1H-pyrazole (1.10 g, 16.13 mmol) and K2CO3 (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, extracted with CHCl2, and the extract dried over Na2SO4. 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): theoretical molecular weight for C9H7N3O: 173.18, m / z observed molecular weight: 173.8 [M+H] + .

[0558] 2. At -78 ° C, under N2, n-BuLi (2.4M, 2.89 mL) was added dropwise to a solution of 2-chlorothiazole (762 mg, 6.35 mmol) in anhydrous THF (50 mL). 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. The mixture was quenched with an aqueous solution of NH4Cl and extracted with EtOAc and the extract was dried with Na2SO4. The organic extract was concentrated to provide a residue, which was purified by silica gel chromatography to provide 3 (800 mg, 47.36% yield) as a white solid. MS (ESI): C 12 Theoretical molecular weight of H9ClN4OS: 292.74, m / z experimental molecular weight: 292.8 [M+H] + .

[0559] 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 the residue was diluted with an aqueous solution of NaHCO 3 , extracted with DCM, and the extract was dried over Na 2 SO 4 . The extract was concentrated to provide a crude product, which was purified by silica gel chromatography to provide 4 (400 mg, 52.9% yield) as a white solid. MS (ESI): C 12 Theoretical molecular weight of H9ClN4S: 276.74, m / z experimental molecular weight: 276.8 [M+H] + .

[0560] 4. To a solution of 4 (400 mg, 1.46 mmol) in DMSO (10 mL) were added 7-bromo-1,2,3,4-tetrahydroisoquinoline (Key Organics, 335 mg, 1.58 mmol) and Cs2CO3 (1.54 g,

[0561] The reaction was stirred at 140°C for 5 h, cooled to RT and poured into ice-water, extracted with DCM. The combined extracts were dried over Na2SO4 and concentrated under reduced pressure to provide the crude product. The crude product was purified by silica gel chromatography to provide 5 (300 mg, 45.42% yield) as a white solid. MS (ESI): C 21 H 18 Theoretical molecular weight of BrN5S: 452.37, m / z experimental molecular weight: 452.8 [M+H] + .

[0562] 5. A mixture of 5 (300 mg, 0.45 mmol), oxazolidin-2-one (136 mg, 1.36 mmol), Pd2(dba)3 (66 mg, 0.09 mmol), SPhos (92 mg, 0.225 mmol) and t-BuOK (162 mg, 1.35 mmol) in anhydrous 1,4-dioxane was stirred at 100°C overnight. The mixture was cooled, poured into water and extracted with CH2Cl2, dried over Na2SO4, filtered and the filtrate concentrated to provide a residue. The residue was purified by preparative HPLC to provide Example 41 (39.6 mg, 19.19%) as a white solid. 24 H 22 Theoretical molecular weight of N6O2S: 458.54, m / z experimental molecular weight: 458.8 [M+H] + , 1 H NMR(400MHz,DMSO-d6)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).

[0563] Example 42.

[0564] 1. To a solution of intermediate 5 (225 mg, 0.50 mmol), morpholin-3-one (171 mg, 1.50 mmol) in anhydrous 1,4-dioxane (15 mL) was added K2CO3 (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 Theoretical molecular weight of N5O2S: 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).

[0565] Example 43.

[0566] 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 Theoretical molecular weight of N3O4S2: 469.11, m / z experimental molecular weight: 69.7 [M+H] +,1H NMR(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).

[0567] Example 44.

[0568] 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 as a white solid (12 mg, 4% yield). MS (ESI): C 27 H 27 Theoretical molecular weight of N5O2S: 485.19, m / z experimental molecular weight: 486.9 [M+H] + . 1 H 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).

[0569] Example 45.

[0570] 1.

[0571] To a mixture of 2-methoxyethan-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 provide 1 (630 mg, 30% yield) as a white solid. MS (ESI): C7H 14 Theoretical molecular weight of N2O2S: 158.20, m / z experimental molecular weight: 159.0 [M+H] + .

[0572] 2. A mixture of 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) was purged with N2 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 Theoretical molecular weight of N6O2S: 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).

[0573] Example 46.

[0574]

[0575] Example 47.

[0576] 1. A mixture of intermediate 1 (150 mg, 0.66 mmol), intermediate 24 (233 mg, 0.79 mmol) and K2CO3 (273 mg, 1.98 mmol) in DMSO (6 mL) was evacuated and refilled with N2 three times and stirred at 130°C for 3 h. The mixture was cooled to RT, diluted with a mixture of DCM / MeOH 20 / 1 (20 mL), filtered and the filtrate 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 Theoretical molecular weight of N5OS: 485.65, m / z experimental molecular weight: 485.9 [M+H] + . 1 H 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 Theoretical molecular weight of N5OS: 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).

[0577] Example 48.

[0578]

[0579] 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 a 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 Theoretical molecular weight of BrN4S: 479.4, m / z experimental molecular weight: 479 [M+H] + .

[0580] 2. A mixture of 1 (240 mg, 0.5 mmol), thiomorpholine 1,1-dioxide (135 mg, 1 mmol), Pd2(dba)3 (41 mg, 0.05 mmol), SPhos (20 mg, 0.05 mmol), and 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, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by preparative HPLC to provide Example 48 (50 mg, 22% yield) as a white solid. MS (ESI): C 28 H 31 Theoretical molecular weight of N5O2S2: 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).

[0581] Example 49.

[0582] 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 25Theoretical molecular weight of N5OS: 467.59, m / z experimental molecular weight: 467.8 [M+H] + , 1 H 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).

[0583] Example 50.

[0584] 1. Following the procedure described for Example 1, except that the mixture was heated at 100° C. for 5 h and Cs 2 CO 3 (663 mg) was used instead of K 2 CO 3 , 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 Theoretical molecular weight of N4O2S: 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).

[0585] Example 51.

[0586]

[0587] 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 a crude product, which was purified by Combi-Flash to provide 1 (280 mg, 52% yield) as a white solid. MS (ESI): C 23 H 22 Theoretical molecular weight of BrN3OS: 468.4, m / z experimental molecular weight: 468 [M+H] + .

[0588] 2. A mixture of 1 (235 mg, 0.5 mmol), thiomorpholine 1,1-dioxide (135 mg, 1 mmol), Pd2(dba)3 (41 mg, 0.05 mmol), SPhos (20 mg, 0.05 mmol), and 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, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by preparative HPLC to provide Example 51 (110 mg, 42% yield) as a white solid. MS (ESI): C 27 H 30 Theoretical molecular weight of N4O3S2: 522.7, m / z experimental molecular weight: 523 [M+H] + . 1 H NMR (400MHz, CDCl3) 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),3.1 0(s,4H),2.85(t,J=5.6Hz,2H),2.47(d,J=8.0Hz,2H),2.07-1.99(m,2H).

[0589] Example 52.

[0590]

[0591] 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 provide 1 (380 mg, 78.7% yield) as a white solid. MS (ESI): C 23 H 19 Theoretical molecular weight of BrN4S: 463.40, m / z experimental molecular weight: 462.8 [M+H] + .

[0592] 2. A mixture of 1 (150 mg, 0.324 mmol), 1-methylimidazolidin-2-one (162 mg, 1.62 mmol), Pd2(dba)3 (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 filtrates were 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 Theoretical molecular weight of N6OS: 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).

[0593] Example 53.

[0594] 1. A mixture of the product from step 1 of Example 52 (150 mg, 0.324 mmol) and imidazolidin-2-one (139 mg, 1.62 mmol) was treated as described in step 2 of Example 52 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 Theoretical molecular weight of N6OS: 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).

[0595] Example 54.

[0596] 1. Intermediate 26 (170 mg) and Intermediate 27 (224 mg) were converted to crude products according to 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 provide Example 54 (64.7 mg, 23.35%) as a white solid. 27 H 27 Theoretical molecular weight of N5OS: 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).

[0597] Example 55.

[0598]

[0599] 1. A mixture of 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 CsCO (10.6 g, 32.4 mmol) in DMF (40 mL) was purged with N2 three times and heated to 120°C for 16 h. The mixture was cooled to RT, diluted with EtOAc, filtered and the filtrate 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): theoretical molecular weight for C9H7N3O: 173.18, m / z observed molecular weight: 174.0 [M+H] + .

[0600] 2. To a mixture of 1 and 2 (1 g, 5.78 mmol) in MeOH (10 mL) at 0°C was added NaBH4 (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, 25% yield). MS (ESI): theoretical molecular weight for C9H9N3O: 175.19, m / z experimental molecular weight: 176.1 [M+H] + .

[0601] 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): theoretical molecular weight for C9H7N3O: 173.18, m / z experimental molecular weight: 174.0 [M+H] + .

[0602] 4. At -70 ° C, under 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). 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. The mixture was quenched with a saturated aqueous solution of NH4Cl (20 mL), extracted with EtOAc and the combined organic extracts were washed with brine, dried with Na2SO4, filtered and the filtrate was concentrated. The resulting residue was purified by chromatography on silica gel to provide 3 (490 mg, 69% yield) as a yellow-white solid. MS (ESI): C 12 Theoretical molecular weight of H9ClN4OS: 292.74, m / z experimental molecular weight: 292.8 [M+H] + .

[0603] 5. SOCl2 (240 mg, 2.01 mmol) was added dropwise to a solution of 3 (490 mg, 1.68 mmol) in DCM (8 mL). 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 for 1 h at RT, neutralized with a saturated aqueous solution of NaHCO3 and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated. 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 Theoretical molecular weight of H9ClN4S: 276.74, m / z experimental molecular weight: 277.0 [M+H] + .

[0604] 6. A mixture of 4 (100 mg, 0.36 mmol), intermediate 20 (140 mg, 0.44 mmol) and K2CO3 (150 mg, 1.08 mmol) in DMSO (10 mL) was stirred at 120°C under nitrogen for 2 h, cooled to RT and ice-water was added to the mixture, which was then extracted with EA. The combined organic extracts were washed with water, brine and dried over Na2SO4, filtered and the filtrate concentrated. 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 Theoretical molecular weight of N6O2S: 458.54, m / z experimental molecular weight: 458.9 [M+H] + . 1H 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).

[0605] Example 56.

[0606] 1. Following the procedure described for Example 1, except that the mixture was heated at 120° C. for 3 h, Intermediate 1 (100 mg) and Intermediate 28 (156 mg) were converted to a crude product, which was purified by preparative HPLC to afford Example 56 as a white solid (60 mg, 0.124 mmol, 28% yield). MS (ESI): MW theoretical for C9H9BrO2: 485.19, m / z observed MW: 485.9 [M+H] + . 1 H NMR (400MHz, CD3OD) 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).

[0607] Example 57.

[0608] 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 27Theoretical molecular weight of N5O3S: 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).

[0609] Example 58.

[0610] 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 28 Theoretical molecular weight of N4O3S: 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).

[0611] Example 59.

[0612] 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 20 / 1 mixture of DCM / MeOH (20 mL), filtered, and the filtrate concentrated. The resulting residue was purified by chromatography on silica gel to provide Example 59 (37.5 mg, 9% yield) as an off-white solid. MS (ESI): C 29 H 34 Theoretical molecular weight of N4O2S: 502.68, m / z experimental molecular weight: 502.9 [M+H] + . 1 H NMR(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).

[0613] Example 60.

[0614] 1. Following the procedure described for Example 1, using Cs2CO3 (313 mg) instead of K2CO3 and heating the mixture at 130°C for 4 h, Intermediate 35 (100 mg) and Intermediate 24 (106 mg) were converted to a crude product, which was purified by prep-TLC to afford Example 60 (20 mg, 13% yield) as a white solid. MS (ESI): C 28 H 33 The theoretical molecular weight of N5O2S is 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).

[0615] Example 61.

[0616] 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 a 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 Theoretical molecular weight of N4O3S2: 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).

[0617] Example 62.

[0618] 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 Theoretical molecular weight of N3O3S: 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).

[0619] Example 63.

[0620] 1. Following the procedure described for Example 31, using Cs2CO3 (833 mg) instead of K2CO3 and purging the vessel 3× with N2, 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 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 Theoretical molecular weight of N4O3S: 476.60, m / z experimental molecular weight: 476.8 [M+H] + . 1 H NMR(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).

[0621] Example 64.

[0622]

[0623] 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 Theoretical molecular weight of BrN3OS: 469.08, m / z experimental molecular weight: 469.7 [M+H] + .

[0624] 2. A mixture of 1 (150 mg, 0.32 mmol), thiomorpholine 1,1-dioxide (180 mg, 1.3 mmol), Pd2(dba)3 (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 that was purified by prep-TLC to provide Example 64 (35 mg, 21%) as a white solid. 27 H 32 Theoretical molecular weight of N4O3S2: 524.19, m / z experimental molecular weight: 524.8 [M+H] + , 1 H 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).

[0625] Example 65.

[0626]

[0627] 1. A mixture of intermediate 5 (200 mg, 0.44 mmol), TEA (134 mg, 1.33 mmol) and Pd(dppf)Cl2 (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 flask under a CO atmosphere. The mixture was filtered through celite, the filter cake was washed with EA and the combined filtrates were concentrated to provide the crude product, which was purified by silica gel chromatography to provide 1 (140 mg, 73.4% yield) as a white solid. MS (ESI): C 24 H 22 Theoretical molecular weight of N4O2S: 430.53, m / z experimental molecular weight: 430.8 [M+H] + .

[0628] 2. A mixture of 1 (140 mg, 0.33 mmol), N2H4·H2O (130 mg, 2.60 mmol) in EtOH (1 mL) and THF (1 mL) was placed in a bomb flask 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 Theoretical molecular weight of N6OS: 430.53, m / z experimental molecular weight: 430.8 [M+H] + .

[0629] 3. A mixture of 2 (120 mg, 0.28 mmol), trimethyl orthoacetate (132 mg, 0.70 mmol), NH4Cl (4.5 mg, 0.08 mmol) in EtOH (1 mL) and THF (1 mL) was placed in a sealed tube and heated at 80°C for 18 hours. The mixture was cooled and trimethyl orthoacetate (132 mg, 0.70 mmol) and NH4Cl (4.5 mg, 0.08 mmol) were added, and the mixture was heated at 80°C for 18 hours. The mixture was cooled and trimethyl orthoacetate (132 mg, 0.70 mmol) and NH4Cl (4.5 mg, 0.08 mmol) were added, and the mixture was heated at 80°C for 18 hours. The mixture was allowed to cool and concentrated. The resulting residue was purified by preparative-HPLC to provide Example 65 (30 mg, 23.7% yield, 96.2% purity at 214 nm) as a white solid. MS (ESI): C 25 H 22 Theoretical molecular weight of N6OS: 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).

[0630] Example 66.

[0631] 1. A mixture of the hydrochloride salt of Intermediate 1 (55 mg, 0.21 mmol), Intermediate 34 (57.7 mg, 0.21 mmol), Pd2(dba)3 (27.5 mg, 0.03 mmol), SPhos (24.7 mg, 0.06 mmol) and t-BuOK (84 mg, 0.75 mmol) in anhydrous dioxane (4 mL) was stirred at 90° C. under N2 for 4 h. The mixture was cooled to RT, poured into water and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated to afford the crude product, which was purified by preparative HPLC to afford Example 66 (1.9 mg, 2% yield) as a white solid. MS Required: 467.2; MS Found: 468.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) 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).

[0632] Example 67.

[0633]

[0634] 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 Et2O and the solution was washed with 10% NaHCO3. The organic mixture was dried over Na2SO4 and filtered, and the filtrate was evaporated to provide 2 (1.45 g, 54%) as a colorless oil.

[0635] 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) under N2, 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, dried over Na2SO4, and concentrated to provide the crude product, which was purified by silica gel chromatography to provide 3 (862 mg, 58% yield) as a colorless oil.

[0636] 3. A mixture of 3 (862 mg, 3.97 mmol), CuSO4 (64.0 mg, 0.40 mmol), H2O (5.00 mL) and HCO2H (20.0 mL) was stirred at 80°C for 4 h. The mixture was cooled, poured into water and basified to pH 8 with aqueous K2CO3. The mixture was extracted with EtOAc. The combined organic extracts were washed with water, brine, dried over Na2SO4 and concentrated to provide the crude product, which was purified by silica gel chromatography to provide 4 (320 mg, 46% yield) as a colorless oil.

[0637] 4. 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 at -78°C under N2. 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 diluted with NH4Cl 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.

[0638] 5. A mixture of 5 (388 mg, 1.33 mmol), the hydrochloride salt of intermediate 1 (350 mg, 1.33 mmol), Pd2(dba)3 (91.5 mg, 0.1 mmol), SPhos (82.3 mg, 0.2 mmol) and t-BuOK (446 mg, 3.99 mmol) in anhydrous dioxane (6 mL) was stirred at 90° C. under N2 for 4 h. The mixture was cooled to RT, poured into water and extracted with EtOAc. The combined organic extracts were washed with water, brine, dried over Na2SO4 and concentrated to provide the crude product, which was purified by preparative HPLC to provide 6 (170 mg, 26% yield) as a white solid.

[0639] 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 for 1 h at 100° C. The mixture was concentrated and the residue was purified by prep-HPLC to afford Example 67 (5.20 mg, 3% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ2.08(3H,s),2.22(3H,s),2.94(2H,t,J=5.6Hz),,3.6 7(2H,t,J=5.6Hz),4.15(2H,s),4.60(2H,s),6.60(1H,t,J=2.0Hz),6.91(1H, s),7.08(1H,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).

[0640] Example 68.

[0641]

[0642] 1. Following the procedure described for Example 1, intermediate 6 (400 mg) and intermediate 35 (580 mg) were converted to 1 (600 mg, 85%) as a brown oil, except that Cs2CO3 (1.37 mg) was used instead of K2CO3 and the mixture was heated at 110°C for 2 h. MS (ESI): C 24 H 25 Theoretical molecular weight of BrN4OS: 496.09, m / z experimental molecular weight: 496.8 [M+H] + .

[0643] 2. A mixture of 1 (500 mg, 1 mmol), thiomorpholine 1,1-dioxide (405 mg, 3 mmol), Pd2(dba)3 (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 Theoretical molecular weight of N5O3S2: 551.2, m / z experimental molecular weight: 551.72 [M+H] + .1 H NMR(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).

[0644] Evaluation of antiviral activity against human cytomegalovirus (HCMV)

[0645] 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, or 0.39 μM of the indicated compound or with vehicle (DMSO) in which the compound was dissolved. The final concentration of DMSO in each treatment was 0.5%. At 7 days post-infection, the virus yield in the culture was determined by quantifying the fluorescent (mCherry-positive) cells in each well by fluorescence microscopy. The results were plotted using CDD Vault (developed by Collaborative Drug Discovery, Inc., 1633 Bayshore Hwy, Suite 342, Burlingame, CA 94010) to calculate the IC50. The results for the compounds tested by this assay are provided in Table 1.

[0646] Evaluation of antiviral activity against influenza virus

[0647] To evaluate their antiviral activity, some compounds were tested in vitro against a murine-adapted human influenza virus (PR8). Canine 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 autocleavage site in serum-free EMEM at a multiplicity of infection (MOI) of 0.01 per cell. The assay was repeated three times. After one 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, or 0.39 μM of the indicated compound, or 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%. Three days after infection, the fluorescent (mCherry positive) cells in each well were quantified by fluorescence microscopy to determine the virus yield in culture. The results were plotted using CDD Vault (developed by Collaborative Drug Discovery, Inc., 1633 Bayshore Hwy, Suite 342, Burlingame, CA 94010) to calculate IC50. The results for the compounds tested by this assay are provided in Table 1.

[0648] Table 1

[0649]

[0650]

[0651]

[0652]

[0653]

[0654]

[0655]

[0656]

[0657]

[0658]

[0659]

[0660] ND = Not Conducted

[0661] 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.

[0662] Other implementations

[0663] It is to be understood that while 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 represented by formula I or a pharmaceutically acceptable salt or solvate thereof: in: One of X1 and X2 is N and the other is S; 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; 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: =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 or branched alkoxy group and a C group optionally substituted by -R12, -OR12 or -NR7R8 3-6 Cycloalkyl, 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: =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 or branched alkoxy group and a C group optionally substituted by -R12, -OR12 or -NR7R8 3-6 Cycloalkyl; R3 is selected from H, halo, -C≡CH, -C≡N, -OH, -OCF3, -OCHF2, C 1-4 Straight chain or branched alkoxy, -SO2(C 1-6 alkyl), -N(CH3)2, -C(O)NH2, -NHSO2R7, -C(O)NR7R8, and a ring 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; R4 is selected from H, halo, -C≡CH, -C≡N, -OH, -OCF3, -OCHF2, C 1-4 Straight chain or branched alkoxy, -SO2(C 1-6 alkyl), -N(CH3)2, -C(O)NH2, -NHSO2R7, -C(O)NR7R8, and a ring 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, Alternatively, the R4 group is bonded to X4 to form a 5- or 6-membered aryl or cycloalkyl group having 0 to 3 ring heteroatoms independently selected from N, O and S and substituted with 0 to 2 groups independently selected from =0, halo, C 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; The conditions are: At least one of R3 and R4 is selected from the group consisting of: H, halo, -C≡CH, -C≡N, -OH, -OCF3, -OCHF2, C 1-4 Straight chain or branched alkoxy, -SO2(C 1-6 alkyl), -N(CH3)2, -C(O)NH2, -NHSO2R7 and -C(O)NR7R8, and R3 and R4 are not H at the same time; R5 is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, CF3, CH2CF3 and halo; R6 is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, CF3, CH2CF3, halo, cyclopropylmethyl and C 1-4 alkoxy; In each case, R7 and R8 are independently selected from H, C 1-6 Straight-chain or branched alkyl, C 3-6 cycloalkyl, cyclopropylmethyl, and cyclobutylmethyl; and At each occurrence, R12 is independently selected from H and C 1-4 Straight-chain or branched-chain alkyl.

2. The composition according to claim 1, wherein: R3 is selected from: and -SO2(C 1-6 alkyl); in: R9 is selected from the group consisting of: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, C optionally substituted with -OR12 or -NR7R8 1-6 A straight or branched chain alkyl group and a C group optionally substituted by -NR7R8 1-6 linear or branched alkoxy groups; and R10 and R11 are independently selected from the group consisting of: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, C optionally substituted with -OR12 or -NR7R8 1-4 Straight or branched alkyl, optionally substituted by NR7R8 C 1-4 Straight-chain or branched alkoxy.

3. The composition according to claim 1, wherein: R4 is selected from: and -SO2(C 1-6 alkyl); in: R9 is selected from the group consisting of: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, C optionally substituted with -OR12 or -NR7R8 1-6 A straight or branched chain alkyl group and a C group optionally substituted by -NR7R8 1-6 linear or branched alkoxy groups; and R10 and R11 are independently selected from the group consisting of: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, C optionally substituted with -OR12 or -NR7R8 1-4 Straight or branched alkyl, optionally substituted by NR7R8 C 1-4 Straight-chain or branched alkoxy.

4. The composition according to claim 1, wherein: 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: =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, 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 with 0 to 2 groups independently selected from: =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.

5. The composition according to claim 4, wherein: R3 is selected from: and -SO2(C 1-6 alkyl); in: R9 is selected from the group consisting of: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, C optionally substituted with -OR12 or -NR7R8 1-6 A straight or branched chain alkyl group and a C group optionally substituted by -NR7R8 1-6 linear or branched alkoxy groups; and R10 and R11 are independently selected from the group consisting of: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, C optionally substituted with -OR12 or -NR7R8 1-4 Straight or branched alkyl, optionally substituted by NR7R8 C 1-4 Straight-chain or branched alkoxy.

6. The composition according to claim 4, wherein: R4 is selected from: and -SO2(C 1-6 alkyl); in: R9 is selected from the group consisting of: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, C optionally substituted with -OR12 or -NR7R8 1-6 A straight or branched chain alkyl group and a C group optionally substituted by -NR7R8 1-6 linear or branched alkoxy groups; and R10 and R11 are independently selected from the group consisting of: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, C optionally substituted with -OR12 or -NR7R8 1-4 Straight or branched alkyl, optionally substituted by NR7R8 C 1-4 Straight-chain or branched alkoxy.

7. The composition according to claim 4, wherein: 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 other ring heteroatoms independently selected from N and O and substituted with 0 to 2 groups independently selected from: =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 or branched alkoxy group and a C group optionally substituted by -R12, -OR12 or -NR7R8 3-6 Cycloalkyl.

8. The composition according to claim 7, wherein the compound represented by formula I is:

9. The composition according to claim 7, wherein: R3 is selected from: and -SO2(C 1-6 alkyl); in: R9 is selected from the group consisting of: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, C optionally substituted with -OR12 or -NR7R8 1-6 A straight or branched chain alkyl group and a C group optionally substituted by -NR7R8 1-6 linear or branched alkoxy groups; and R10 and R11 are independently selected from the group consisting of: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, C optionally substituted with -OR12 or -NR7R8 1-4 Straight or branched alkyl, optionally substituted by NR7R8 C 1-4 Straight-chain or branched alkoxy.

10. The composition according to claim 9, wherein the compound represented by formula I is selected from:

11. The composition according to claim 7, wherein: R4 is selected from: and -SO2(C 1-6 alkyl); in: R9 is selected from the group consisting of: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, C optionally substituted with -OR12 or -NR7R8 1-6 A straight or branched chain alkyl group and a C group optionally substituted by -NR7R8 1-6 linear or branched alkoxy groups; and R10 and R11 are independently selected from the group consisting of: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, C optionally substituted with -OR12 or -NR7R8 1-4 Straight or branched alkyl, optionally substituted by NR7R8 C 1-4 Straight-chain or branched alkoxy.

12. The composition according to claim 7, wherein: One of R1 and R2 is H and the other is selected from: in: R9 is selected from the group consisting of: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, C optionally substituted with -OR12 or -NR7R8 1-6 A straight or branched chain alkyl group and a C group optionally substituted by -NR7R8 1-6 straight-chain or branched alkoxy; R10 and R11 are independently selected from the group consisting of: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, C optionally substituted with -OR12 or -NR7R8 1-4 Straight or branched alkyl, optionally substituted by NR7R8 C 1-4 Straight-chain or branched alkoxy.

13. The composition according to claim 12, wherein the compound represented by formula I is:

14. The composition according to claim 12, wherein: R3 is selected from: and -SO2(C 1-6 alkyl); in: R9 is selected from the group consisting of: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, C optionally substituted with -OR12 or -NR7R8 1-6 A straight or branched chain alkyl group and a C group optionally substituted by -NR7R8 1-6 linear or branched alkoxy groups; and R10 and R11 are independently selected from the group consisting of: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, C optionally substituted with -OR12 or -NR7R8 1-4 Straight or branched alkyl, optionally substituted by NR7R8 C 1-4 Straight-chain or branched alkoxy.

15. The composition according to claim 14, wherein the compound represented by formula I is selected from:

16. The composition of claim 12, wherein: R4 is selected from: and -SO2(C 1-6 alkyl); in: R9 is selected from the group consisting of: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, C optionally substituted with -OR12 or -NR7R8 1-6 A straight or branched chain alkyl group and a C group optionally substituted by -NR7R8 1-6 linear or branched alkoxy groups; and R10 and R11 are independently selected from the group consisting of: H, cyclopropyl, cyclopropylmethyl, cyclobutyl, C optionally substituted with -OR12 or -NR7R8 1-4 Straight or branched alkyl, optionally substituted by NR7R8 C 1-4 Straight-chain or branched alkoxy.

17. The composition according to claim 16, wherein the compound represented by formula I is:

18. A pharmaceutical composition comprising the composition according to any one of claims 1 to 17.

19. A method for treating or preventing a viral infection in a subject, the method comprising administering to the subject a therapeutically effective amount of the composition according to any one of claims 1 to 17.

20. The method of claim 19, wherein the method further comprises administering a therapeutically effective amount of an antiviral agent.

21. The method of claim 20, wherein the antiviral agent is selected from the group consisting of 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, edoxuridine, efavirenz, emtricitabine, enfuvirtide, entecavir, famciclovir, fosamprenavir, foscarnet, fosfoacetic acid, ganciclovir, Gardasil, ibacitabine, imunovir, idoxuridine, imiquimod, indinavir, inosine, integrase inhibitors, lamivudine, lopinavir, loviride, mk- 0518, maraviroc, morpholinoguanidine, nelfinavir, nevirapine, nesavir, nucleotide and / or nucleoside analogs, oseltamivir, penciclovir, peramivir, podophyllotoxin, rimantadine, ritonavir, saquinavir, stavudine, tenofovir, tenofovir disoproxil fumarate, tipranavir, trifluridine, triazepam, tromantanamide, Truvada, valacyclovir, valganciclovir, vicriviroc, vidarabine, viramidine, zalcitabine, morpholino oligonucleotides, ribozymes, protease inhibitors, assembly inhibitors, zidovudine, brincidofovir, favipiravir, nitoxanide, letermovir, maribavir, CMX157, or a combination thereof.

22. A method for inhibiting virus production, comprising contacting virus-infected cells with a virus production-inhibiting amount of a compound according to any one of claims 1 to 17.

23. The method of claim 22, wherein the method further comprises administering a therapeutically effective amount of an antiviral agent.

24. The method of claim 23, wherein the antiviral agent is selected from the group consisting of 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, edoxuridine, efavirenz, emtricitabine, enfuvirtide, entecavir, famciclovir, fosamprenavir, foscarnet, fosfoacetic acid, ganciclovir, Gardasil, ibacitabine, imunovir, idoxuridine, imiquimod, indinavir, inosine, integrase inhibitors, lamivudine, lopinavir, loviride, mk- 0518, maraviroc, morpholinoguanidine, nelfinavir, nevirapine, nesavir, nucleotide and / or nucleoside analogs, oseltamivir, penciclovir, peramivir, podophyllotoxin, rimantadine, ritonavir, saquinavir, stavudine, tenofovir, tenofovir disoproxil fumarate, tipranavir, trifluridine, triazepam, tromantanamide, Truvada, valacyclovir, valganciclovir, vicriviroc, vidarabine, viramidine, zalcitabine, morpholino oligonucleotides, ribozymes, protease inhibitors, assembly inhibitors, zidovudine, brincidofovir, favipiravir, nitoxanide, letermovir, maribavir, CMX157, or a combination thereof.

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