Broad-spectrum antiviral compositions and methods

Abstract

To provide a single drug that is effective against a wide range of viruses that can cause respiratory infection.SOLUTION: A thiazole and isoquinoline containing compound having the structure of formula I is provided. Said compound shows inhibition of HCMV, influenza virus, Zika virus, BK virus, and RSV replication in cell assay.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Federally Funded Research Statement

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

[0003] This document relates to compounds useful in the prevention, treatment, or amelioration of viral infections.

[0004] CROSS-REFERENCE TO RELATED APPLICATIONS

[0005] 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 technology]

[0006] According to the Viral Diseases Branch of the Walter Reed Army Institute of Research, non-adenoviral respiratory infections "cause 25-30% of infectious disease hospitalizations in the military and are second only to injuries as a cause of DNBI [diseases and non-combat injuries] among deployed troops."

[0007] Influenza A is a prime example. It significantly impacts the military disease burden and infects a significant portion of the US civilian population each year, causing a respiratory illness with significant morbidity and mortality. Each year, 5–20% of the US population is infected with seasonal influenza, resulting in over 200,000 hospitalizations and 24,000 deaths. Furthermore, the inevitable emergence of a deadly pandemic influenza A virus poses a serious threat, and recent reports of genetic manipulation have raised the possibility of influenza A as a potential tool for biological warfare. Current influenza vaccines are not a solution; their efficacy has ranged from 10–60% over the past 12 years. Commercially available antiviral treatments for influenza include viral neuraminidase (NA) inhibitors and M2 channel blockers. Additional anti-influenza drugs are being evaluated in clinical trials, including repurposed antiprotozoal agents that block the maturation of viral hemagglutinin by altering glycosylation through an unknown mechanism. Current drugs (direct-acting antivirals, or DAAs) directly interact with viral proteins and therefore suffer from the rapid emergence of resistance. Replication of the viral RNA genome is highly error-prone, and this high mutation rate (genetic drift), coupled with reassortment (gene shift) of the segmented viral genome, leads to the rapid evolution of drug-resistant isolates that are as infectious as wild-type ones. Consequently, there is a significant unmet medical need for new therapeutic strategies that overcome the limitations of existing drugs. Antiviral drugs that target a broad range of influenza subtypes while minimizing the emergence of drug-resistant viruses represent a major unmet public health need.

[0008] However, the need for new therapies to treat respiratory pathogens extends beyond influenza, particularly. There are no drugs available to treat coronaviruses such as MERS and SARS, parainfluenza viruses, or adenoviruses, and RSV infections are treated with ribavirin, but with limited efficacy (virus-specific antibodies are available, but only for prophylactic use). Furthermore, because there are multiple respiratory pathogens that exhibit similar symptoms, known as influenza-like illness, a single broad-spectrum drug with efficacy across a variety of different pathogens would be extremely useful. There is a need to develop a single drug that is effective against a wide range of viruses that can cause respiratory infections, including not only influenza but also coronaviruses, RSV, parainfluenza viruses, human cytomegalovirus (HCMV), and adenoviruses.

[0009] Human cytomegalovirus (HCMV) is a major cause of birth defects and opportunistic infections in immunosuppressed individuals and may be a cofactor in certain cancers. Organ transplant patients receiving immunosuppressive therapy are at high risk for viral infections, and activation of latent viruses, as well as donor- or community-acquired primary infections, can lead to significant complications, including graft rejection, morbidity, and mortality. Herpesviruses (e.g., HCMV, HSV-1), polyomaviruses (e.g., BKV and JCV), hepatitis viruses (HBV and HCV), and respiratory viruses (e.g., influenza A, adenovirus) are the four major viral classes that infect such patients. Cytomegalovirus (HCMV) is the most common post-transplant pathogen. HCMV can infect most organs, and despite the availability of HCMV antivirals such as ganciclovir, nephrotoxic side effects and increasing rates of drug resistance significantly reduce graft and patient survival. Furthermore, HCMV-mediated immunomodulation can reactivate the latent virus, which is present in most adults. FORGE Life Science, LLC has previously disclosed thiazole-containing compounds that are active against HCMV replication in published patent applications WO2016 / 077232 and WO2016 / 077240. Summary of the Invention

[0010] The present invention provides compounds having the structure of Formula I, or a pharmaceutically acceptable salt or solvate thereof: [ka] where: 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, i-propyl, or n-propyl; One of R1 and R2 is H and the other has 0 to 3 ring heteroatoms independently selected from N and O, and is selected from the following: C optionally substituted with =O, -OR12 or NR7R8 1-6 C optionally substituted with linear or branched alkyl, NR7R8 or -OR12 1-6 C optionally substituted with straight or branched alkoxy, -R, -OR, or -NR, 3-6 cycloalkyl is a 5- or 6-membered aryl or cycloalkyl substituted with 0 to 3 groups independently selected from Or, R1 and R2 together have 0 to 3 ring heteroatoms independently selected from N and O, and C optionally substituted with =O, -OR12 or NR7R8 1-6 C optionally substituted with linear or branched alkyl, NR7R8 or -OR12 1-6 C optionally substituted with straight or branched alkoxy, -R, -OR, or -NR, 3-6 cycloalkyl forming a 5- or 6-membered aryl or cycloalkyl substituted with 0 to 3 groups independently selected from: R3 is H, halo, -C≡CH, -C≡N, -OH, -OCF3, -OCHF2, C 1-4Linear or branched alkoxy, -SO2(C 1-6 alkyl), -N(CH3)2, -C(O)NH2, -NHSO2R7, -C(O)NR7R8, and C(O) having 0 to 3 ring heteroatoms independently selected from N, O, and S, optionally substituted with ═O, halo, -OR12, or -NR7R8; 1-6 C optionally substituted with linear or branched alkyl, -NR7R8 or -OR12 1-6 Linear or branched alkoxy, -C(O)-C 1-6 Alkyl and -C(O)OC 1-6 a ring structure comprising a 5- or 6-membered aryl or a 4-, 5-, or 6-membered cycloalkyl substituted with 0-2 groups independently selected from alkyl; R4 is H, halo, -C≡CH, -C≡N, -OH, -OCF3, -OCHF2, C 1-4 Linear or branched alkoxy, -SO2(C 1-6 alkyl), -N(CH3)2, -C(O)NH2, -NHSO2R7, -C(O)NR7R8, and 0 to 3 ring heteroatoms independently selected from N, O, and S, and optionally substituted with ═O, halo, -OR12, or -NR7R8; 1-6 C optionally substituted with linear or branched alkyl, -NR7R8 or -OR12 1-6 Linear or branched alkoxy, -C(O)-C 1-6 Alkyl and -C(O)OC 1-6 a ring system comprising a 5- or 6-membered aryl or a 4-, 5-, or 6-membered cycloalkyl substituted with 0-2 groups independently selected from alkyl; Or, the R group attached to X is a C group having 0 to 3 ring heteroatoms selected from N, O, S, and optionally substituted with ═O, halo, —OR or —NR 1-6 C optionally substituted with linear or branched alkyl, -NR7R8 or -OR12 1-6 Linear or branched alkoxy, -C(O)-C 1-6 Alkyl and -C(O)OC 1-6 forming a 5- or 6-membered aryl or cycloalkyl substituted with 0 to 2 groups selected from alkyl; however, At least one of R3 and R4 is H, halo, -C≡CH, -C≡N, -OH, -OCF3, -OCHF2, C 1-4 Linear 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 both H; R5 is selected from the group consisting of H, methyl, ethyl, n-propyl, isopropyl, n-butyl, CF3, CH2CF3, and halo; R6 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, CF3, CH2CF3, halo, cyclopropylmethyl and C 1-4 selected from the group consisting of alkoxy; R7 and R8 are, in each case, H, C 1-6 Straight or branched alkyl, C 3-6 independently selected from cycloalkyl, cyclopropylmethyl, and cyclobutylmethyl; and R12, in each case, is H and C 1-4 and the alkyl groups are independently selected from the group consisting of straight or branched chain alkyl groups. [Effects of the Invention]

[0011] The compounds of the present invention are useful for treating and / or preventing viral infections. In particular, the compounds of the present invention are broad-spectrum antiviral agents. For example, the compounds of the present invention inhibit the replication of two very different human pathogens with comparable efficacy: influenza A, a rapidly replicating orthomyxovirus with an RNA genome, and HCMV, a slowly replicating herpesvirus with a DNA genome.

[0012] The present invention also provides methods for preventing, treating, and / or ameliorating HCMV infection with compounds of formula I. The present invention also provides methods for preventing, treating, and / or ameliorating influenza infection with compounds of formula I. DETAILED DESCRIPTION OF THE INVENTION

[0013] Unless otherwise defined, 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 publications, patent applications, patents, sequence information, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

[0014] Other features and advantages of the invention will become apparent from the following detailed description and figures, and from the claims.

[0015] Detailed Description

[0016] Provided herein are compounds useful for the treatment and / or prevention of a wide range of viral infections.

[0017] Provided herein are methods for treating or preventing a viral infection in a subject. In some embodiments, the method comprises administering a therapeutically effective amount of one or more compounds provided herein. In some embodiments, the compounds provided herein can inhibit viral production in cells infected with a virus. In such embodiments, the cells are contacted with a viral production-inhibiting amount of one or more compounds provided herein.

[0018] Provided herein are compounds having the structure of Formula I, and pharmaceutically acceptable salts or solvates thereof: [ka] where: 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, i-propyl, or n-propyl; One of R1 and R2 is H and the other has 0-3 ring heteroatoms independently selected from N and O, and is selected from the following: =O, C optionally substituted with -OR12 or NR7R8 1-6 C optionally substituted with linear or branched alkyl, NR7R8 or -OR12 1-6 C optionally substituted with straight or branched alkoxy, -R, -OR, or -NR, 3-6 cycloalkyl is a 5- or 6-membered aryl or cycloalkyl substituted with 0-3 groups independently selected from Or, R1 and R2 together form a 5- or 6-membered aryl or cycloalkyl containing 0-3 heteroatoms; N and O are independently selected from the following: =O, C optionally substituted with -OR12 or NR7R8 1-6 C optionally substituted with linear or branched alkyl, NR7R8 or -OR12 1-6 C optionally substituted with straight or branched alkoxy, -R, -OR, or -NR, 3-6 cycloalkyl substituted with 0-3 groups independently selected from R3 is H, halo, -C≡CH, -C≡N, -OH, -OCF3, -OCHF2, C1-4 straight or branched alkoxy, -SO2(C 1-6alkyl), -N(CH3)2, -C(O)NH2, -NHSO2R7, -C(O)NR7R8, and 5- or 6-membered aryl, or C independently selected from N, O, S and optionally substituted with =O, halo, -OR12 or -NR7R8. 1-6 Straight or branched alkyl, -NR7R8 or -OR12, -C(O)-C 1-6 Alkyl and -C(O)OC 1-6 C optionally substituted with alkyl 1-6 a ring system containing 4-, 5-, or 6-membered cycloalkyl having 0-3 ring heteroatoms substituted with 0 to 2 groups independently selected from straight-chain or branched alkoxy; R4 is H, halo, -C≡CH, -C≡N, -OH, -OCF3, -OCHF2, C 1-4 Linear or branched alkoxy, -SO2(C 1-6 alkyl), -N(CH3)2, -C(O)NH2, -NHSO2R7, -C(O)NR7R8, N, O and S, and optionally substituted with =O, halo, -OR12 or -NR7R8 1-6 C optionally substituted with linear or branched alkyl, -NR7R8 1-6 a ring structure containing a 5- or 6-membered aryl or a 4-, 5-, or 6-membered cycloalkyl having 0-3 ring heteroatoms substituted with 0 to 2 groups independently selected from straight-chain or branched alkoxy; or -OR, -C(O)-C 1-6 Alkyl and -C(O)OC 1-6 alkyl, Or, the R group is attached to X and contains 0-3 ring heteroatoms selected from N, O, S, and is optionally substituted with ═O, halo, —OR or —NR 1-6 C optionally substituted with linear or branched alkyl, -NR7R8 1-6 Linear or branched alkoxy or -OR12, -C(O)-C 1-6 Alkyl and -C(O)OC 1-6 forming a 5- or 6-membered aryl or cycloalkyl substituted with 0-2 groups selected from alkyl; however, At least one of R3 and R4 is H, halo, -C≡CH, -C≡N, -OH, -OCF3, -OCHF2, C 1-4 Linear or branched alkoxy, -SO2(C 1-6 alkyl), —N(CH3)2, —C(O)NH2, —NHSO2R7, and —C(O)NR7R8, and R3 and R4 are both not H; R5 is selected from the group consisting of H, methyl, ethyl, n-propyl, isopropyl, n-butyl, CF3, CH2CF3, and halo; R6 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, CF3, CH2CF3, halo, cyclopropylmethyl and C 1-4 selected from the group consisting of alkoxy; R7 and R8 are each independently H, C 1-6 Straight or branched alkyl, C 3-6 independently selected from cycloalkyl, cyclopropylmethyl, and cyclobutylmethyl; and R12, in each case, is H and C 1-4 and the alkyl groups are independently selected from the group consisting of straight or branched chain alkyl groups.

[0019] The compounds of Formula I are useful for the prevention, treatment, and / or amelioration of viral infections. In particular, these compounds are broad-spectrum antiviral agents capable of treating a variety of infections caused by viruses, such as influenza, coronavirus, respiratory syncytial virus (RSV), parainfluenza virus, human cytomegalovirus (HCMV), and adenovirus. In particular, Applicants have demonstrated the broad-spectrum antiviral utility of the compounds of Formula I by showing the ability of these compounds to block the replication of two very different human pathogens with comparable efficacy: influenza A, a rapidly replicating orthomyxovirus with an RNA genome, and HCMV, a slowly replicating herpesvirus with a DNA genome.

[0020] In some embodiments of the antiviral compounds of Formula I, One of R1 and R2 is H and the other has 1-3 ring heteroatoms independently selected from N and O, and is: C optionally substituted with =O, -OR12 or -NR7R8 1-6 C optionally substituted with linear or branched alkyl, -NR7R8 or -OR12 1-6 Straight-chain or branched alkoxy, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, and cyclohexyl is a 5- or 6-membered aryl or cycloalkyl substituted with 0-2 groups independently selected from or R1 and R2 together contain 1-3 ring heteroatoms independently selected from N and O, and are: C optionally substituted with =O, -OR12 or -NR7R8 1-6 C optionally substituted with linear or branched alkyl, -NR7R8 or -OR12 1-6 Straight-chain or branched alkoxy, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, and cyclohexyl and forming a 5- or 6-membered aryl, cycloalkyl, or cycloalkenyl substituted with 0-2 groups independently selected from:

[0021] In some embodiments of the antiviral compounds of Formula I, R3 is: [ka] and -SO2(C 1-6 alkyl); is selected from the group consisting of where: R9 is H, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, C optionally substituted with -OR12 or -NR7R8. 1-6 C optionally substituted with linear or branched alkyl and -NR7R8 1-6 is selected from the group consisting of straight chain or branched alkoxy; and R10 and R11 are C optionally substituted with H, cyclopropyl, cyclopropylmethyl, cyclobutyl, -OR12 or -NR7R8.1-4 C optionally substituted with linear or branched alkyl, NR7R8 1-4 Independently selected from the group consisting of straight chain or branched alkoxy.

[0022] In some embodiments of the antiviral compounds of Formula I, R4 is: [ka] , and -SO2(C 1-6 alkyl); is selected from the group consisting of where: R9 is H, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, C optionally substituted with -OR12 or -NR7R8. 1-6 C optionally substituted with linear or branched alkyl and -NR7R8 1-6 is selected from the group consisting of straight chain or branched alkoxy; and R10 and R11 are C optionally substituted with H, cyclopropyl, cyclopropylmethyl, cyclobutyl, -OR12 or -NR7R8. 1-4 C optionally substituted with linear or branched alkyl, NR7R8 1-4 Independently selected from the group consisting of straight chain or branched alkoxy.

[0023] In some embodiments of the antiviral compounds of Formula I, One of R1 and R2 is H and the other is a 5- or 6-membered aryl or cycloalkyl having at least one N ring heteroatom and 0 to 2 additional ring heteroatoms independently selected from N and O, and C optionally substituted with =O, -OR12 or NR7R8 1-6 C optionally substituted with linear or branched alkyl, NR7R8 or -OR12 1-6 C optionally substituted with straight chain or branched alkoxy, -R, -OR, or -NR, 3-6 cycloalkyl and is substituted with 0 to 2 of the group independently selected from the group consisting of:

[0024] Compounds of this embodiment include: [ka] These include, but are not limited to:

[0025] In some embodiments of the compound of Formula I, one of R1 and R2 is H and the other is: [ka] is selected from the group consisting of where: R9 is H, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, C optionally substituted with -OR12 or -NR7R8. 1-6 C optionally substituted with linear or branched alkyl and -NR7R8 1-6 is selected from the group consisting of straight chain or branched alkoxy; and R10 and R11 are C optionally substituted with H, cyclopropyl, cyclopropylmethyl, cyclobutyl, -OR12 or -NR7R8. 1-4 C optionally substituted with linear or branched alkyl, -NR7R8 1-4 Independently selected from the group consisting of straight chain or branched alkoxy.

[0026] Compounds of this embodiment include: [ka] These include, but are not limited to:

[0027] Some embodiments of the compound of Formula I are compounds of Formula II: [ka] wherein X1, X2, X3, X4, R3, R4, R5, and R6 are defined as in Formula I. In some embodiments of the antiviral compound of Formula II, R3 is one of the following: [ka] and -SO2(C 1-6 alkyl); is selected from the group consisting of where: R9 is H, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, C optionally substituted with -OR12 or -NR7R8. 1-6 C optionally substituted with linear or branched alkyl and -NR7R8 1-6 is selected from the group consisting of straight chain or branched alkoxy; and R10 and R11 are C optionally substituted with H, cyclopropyl, cyclopropylmethyl, cyclobutyl, -OR12 or -NR7R8. 1-4 C optionally substituted with linear or branched alkyl, NR7R8 1-4 Independently selected from the group consisting of straight chain or branched alkoxy.

[0028] In some embodiments of the antiviral compound of Formula II, R4 is: [ka] and -SO2(C 1-6 alkyl); is selected from the group consisting of where: R9 is H, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, C optionally substituted with -OR12 or -NR7R8. 1-6 C optionally substituted with linear or branched alkyl and -NR7R8 1-6 is selected from the group consisting of straight chain or branched alkoxy; and R10 and R11 are C optionally substituted with H, cyclopropyl, cyclopropylmethyl, cyclobutyl, -OR12 or -NR7R8. 1-4 C optionally substituted with linear or branched alkyl, NR7R8 1-4 Independently selected from the group consisting of straight chain or branched alkoxy.

[0029] Some embodiments of the compound of formula I are compounds of formula III: [ka] where: R9 is H, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, C optionally substituted with -OR12 or -NR7R8. 1-6 C optionally substituted with linear or branched alkyl and -NR7R8 1-6 and X1, X2, X3, X4, R3, R4, R5, R6, R7, R8, and R12 are defined as in Formula I. In some embodiments of the antiviral compound of Formula III, R3 is selected from the group consisting of: [ka] and -SO2(C 1-6 alkyl); is selected from the group consisting of where: R10 and R11 are C optionally substituted with H, cyclopropyl, cyclopropylmethyl, cyclobutyl, -OR12 or -NR7R8. 1-4 C optionally substituted with linear or branched alkyl, NR7R8 1-4 Independently selected from the group consisting of straight chain or branched alkoxy. In some embodiments of the antiviral compound of Formula III, R4 is [ka] and -SO2(C 1-6 alkyl); is selected from the group consisting of where: R10 and R11 are C optionally substituted with H, cyclopropyl, cyclopropylmethyl, cyclobutyl, -OR12 or -NR7R8. 1-4 C optionally substituted with linear or branched alkyl, NR7R8 1-4Independently selected from the group consisting of straight chain or branched alkoxy.

[0030] Some embodiments of the compound of formula I are compounds of formula IV: [ka] where: R10 and R11 are C optionally substituted with H, cyclopropyl, cyclopropylmethyl, cyclobutyl, -OR12 or -NR7R8. 1-4 C optionally substituted with linear or branched alkyl, NR7R8 1-4 and X1, X2, X3, X4, R3, R4, R5, R6, R7, R8, and R12 are defined as in Formula I. In some embodiments of the antiviral compound of Formula IV, R3 is selected from the group consisting of: [ka] and -SO2(C 1-6 alkyl); is selected from the group consisting of where: R9 is H, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, C optionally substituted with -OR12 or -NR7R8. 1-6 C optionally substituted with linear or branched alkyl and -NR7R8 1-6 In some embodiments of the antiviral compound of Formula IV, R4 is selected from the group consisting of: straight chain or branched alkoxy. [ka] and -SO2(C 1-6 alkyl); is selected from the group consisting of where: R9 is H, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, C optionally substituted with -OR12 or -NR7R8. 1-6C optionally substituted with linear or branched alkyl and -NR7R8 1-6 It is selected from the group consisting of straight chain or branched alkoxy.

[0031] Some embodiments of the compound of formula I are compounds of formula V: [ka] wherein X1, X2, X3, X4, R3, R4, R5, and R6 are defined as in Formula I. In some embodiments of the antiviral compound of Formula V, R3 is one of the following: [ka] and -SO2(C 1-6 alkyl); is selected from the group consisting of where: R9 is H, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, C optionally substituted with -OR12 or -NR7R8. 1-6 C optionally substituted with linear or branched alkyl and -NR7R8 1-6 straight-chain or branched alkoxy; and R and R are selected from the group consisting of H, cyclopropyl, cyclopropylmethyl, cyclobutyl, C optionally substituted with -OR or -NR. 1-4 C optionally substituted with linear or branched alkyl, NR7R8 1-4 In some embodiments of the antiviral compound of Formula V, R4 is independently selected from the group consisting of: straight chain or branched alkoxy. [ka] and -SO2(C 1-6 alkyl); is selected from the group consisting of where: R9 is H, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, C optionally substituted with -OR12 or -NR7R8. 1-6C optionally substituted with linear or branched alkyl and -NR7R8 1-6 straight-chain or branched alkoxy; and R and R are selected from the group consisting of H, cyclopropyl, cyclopropylmethyl, cyclobutyl, C optionally substituted with -OR or -NR. 1-4 C optionally substituted with linear or branched alkyl, NR7R8 1-4 Independently selected from the group consisting of straight chain or branched alkoxy.

[0032] Some embodiments of the compound of Formula I are compounds of Formula VI: [ka] wherein X1, X2, X3, X4, R3, R4, R5, and R6 are defined as in Formula I. In some embodiments of the antiviral compound of Formula VI, R3 is selected from the following: [ka] and -SO2(C 1-6 alkyl); is selected from the group consisting of where: R9 is H, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, C optionally substituted with -OR12 or -NR7R8. 1-6 C optionally substituted with linear or branched alkyl and -NR7R8 1-6 straight-chain or branched alkoxy; and R and R are selected from the group consisting of H, cyclopropyl, cyclopropylmethyl, cyclobutyl, C optionally substituted with -OR or -NR. 1-4 C optionally substituted with linear or branched alkyl, NR7R8 1-4 In some embodiments of the antiviral compound of Formula VI, R4 is independently selected from the group consisting of: straight chain or branched alkoxy. [ka] and -SO2(C 1-6 alkyl); is selected from the group consisting of where: R9 is H, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, C optionally substituted with -OR12 or -NR7R8. 1-6 C optionally substituted with linear or branched alkyl and -NR7R8 1-6 straight-chain or branched alkoxy; and R and R are selected from the group consisting of H, cyclopropyl, cyclopropylmethyl, cyclobutyl, C optionally substituted with -OR or -NR. 1-4 C optionally substituted with linear or branched alkyl, NR7R8 1-4 Independently selected from the group consisting of straight chain or branched alkoxy.

[0033] Some embodiments of the compound of Formula I are compounds of Formula VII: [ka] where: R9 is H, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, C optionally substituted with -OR12 or -NR7R8. 1-6 C optionally substituted with linear or branched alkyl and -NR7R8 1-6 and X1, X2, X3, X4, R3, R4, R5, R6, R7, R8, and R12 are defined as in Formula I. In some embodiments of the antiviral compound of Formula VII, R3 is selected from the group consisting of: [ka] and -SO2(C 1-6 alkyl); is selected from the group consisting of wherein R and R are H, cyclopropyl, cyclopropylmethyl, cyclobutyl, C optionally substituted with -OR or -NR. 1-4 C optionally substituted with linear or branched alkyl, NR7R8 1-4In some embodiments of the antiviral compound of Formula VII, R4 is independently selected from the group consisting of: straight chain or branched alkoxy. [ka] and -SO2(C 1-6 alkyl); is selected from the group consisting of wherein R and R are H, cyclopropyl, cyclopropylmethyl, cyclobutyl, C optionally substituted with -OR or -NR. 1-4 C optionally substituted with linear or branched alkyl, NR7R8 1-4 Independently selected from the group consisting of straight chain or branched alkoxy.

[0034] Some embodiments of the compound of Formula I are compounds of Formula VIII: [ka] wherein R and R are H, cyclopropyl, cyclopropylmethyl, cyclobutyl, C optionally substituted with -OR or -NR. 1-4 C optionally substituted with linear or branched alkyl, NR7R8 1-4 and X1, X2, X3, X4, R3, R4, R5, R6, R7, R8, and R12 are defined as in Formula I. In some embodiments of the antiviral compound of Formula VIII, R3 is selected from the following: [ka] and -SO2(C 1-6 alkyl); is selected from the group consisting of where: R9 is H, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, C optionally substituted with -OR12 or -NR7R8. 1-6 C optionally substituted with linear or branched alkyl and -NR7R8 1-6 It is selected from the group consisting of straight chain or branched alkoxy. In some embodiments of the antiviral compound of Formula VIII, R4 is: [ka] and -SO2(C 1-6 alkyl); is selected from the group consisting of where: R9 is H, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, C optionally substituted with -OR12 or -NR7R8. 1-6 C optionally substituted with linear or branched alkyl and -NR7R8 1-6 It is selected from the group consisting of straight chain or branched alkoxy.

[0035] Some embodiments of the compound of formula I are compounds of formula IX: [ka] wherein X1, X2, X3, X4, R3, R4, R5, and R6 are defined as in Formula I. In some embodiments of the antiviral compound of Formula IX, R3 is one of the following: [ka] and -SO2(C 1-6 alkyl); is selected from the group consisting of where: R9 is H, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, C optionally substituted with -OR12 or -NR7R8. 1-6 C optionally substituted with linear or branched alkyl and -NR7R8 1-6 straight-chain or branched alkoxy; and R and R are selected from the group consisting of H, cyclopropyl, cyclopropylmethyl, cyclobutyl, C optionally substituted with -OR or -NR. 1-4 C optionally substituted with linear or branched alkyl, NR7R8 1-4 Independently selected from the group consisting of straight chain or branched alkoxy. In some embodiments of the antiviral compound of Formula IX, R4 is: [ka] and -SO2(C 1-6 alkyl); is selected from the group consisting of where: R9 is H, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, C optionally substituted with -OR12 or -NR7R8. 1-6 C optionally substituted with linear or branched alkyl and -NR7R8 1-6 straight-chain or branched alkoxy; and R and R are selected from the group consisting of H, cyclopropyl, cyclopropylmethyl, cyclobutyl, C optionally substituted with -OR or -NR. 1-4 C optionally substituted with linear or branched alkyl, NR7R8 1-4 Independently selected from the group consisting of straight chain or branched alkoxy.

[0036] Also provided herein are methods for treating or preventing a viral infection in a subject, comprising administering a therapeutically effective amount of a compound of 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.

[0037] Also provided herein are methods of inhibiting viral production, comprising contacting a virally infected cell with a viral production-inhibiting amount of a compound of 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.

[0038] Also provided herein are methods for treating or preventing HCMV infection in a subject by administering a therapeutically effective amount of a compound of 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.

[0039] Also provided herein are methods of inhibiting HCMV production, comprising contacting HCMV-infected cells with a viral production-inhibiting amount of a compound of 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.

[0040] Also provided herein are methods of treating or preventing influenza infection in a subject by administering a therapeutically effective amount of a compound of 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.

[0041] Also provided herein are methods of inhibiting influenza production, comprising contacting influenza-producing cells with a virus-production-inhibiting amount of a compound of 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.

[0042] Antiviral agents may also be administered in combination with the compounds and methods described herein. The agent may be any therapeutic agent useful in treating a viral infection, an HCMV infection, or an influenza infection. For example, antiviral agents include acyclovir, docosanol, ribarivin, and interferon; cellulose acetate, carbopol, and carrageenan, pleconaril, amantidine, rimantidine, fomivirsen, zidovudine, lamivudine, zanamivir, oseltamivir, brivudine, abacavir, adefovir, amprenavir, arbidol, atazanavir, atripla, cidofovitabien, comvisvin, envitabine, famciclovir, fosamprenavir, foscarnet, fosfonet, ganciclovir, gardasil, ibacitabine, immunovir, idoxuridine, imiquimod, indinavir, inosine, integrase inhibitors, lamivudine, lopinavir, lovirid, mk-0518, mavicidal, ramivudine ... The antiviral agents may include raviroc, moroxydine, nelfinavir, nevirapine, nexavir, nucleotide and / or nucleoside analogs, oseltamivir, penciclovir, peramivir, podophyllotoxin, rimantadine, ritonavir, saquinavir, stavudine, tenofovir, tenofovir disoproxil, bipravidin, tripravidine, tipranovitol, travavalganciclovir, vicriviroc, vidarabine, viramidine, zalcitabine, morpholino oligonucleotides, ribozymes, protease inhibitors, assembly inhibitors (e.g., rifampicin), zidovudine, brincidofovir, favipiravir, nitoxanide, letermovir, maribavir, CMX157, or combinations or two or more thereof.

[0043] In some embodiments, a compound provided herein can be administered either before, after, or simultaneously with one or more antiviral agents.

[0044] The antiviral agents provided herein (including pharmaceutically acceptable salts or solvates thereof) are commercially available or can be prepared using known organic synthesis techniques.

[0045] The methods provided herein include the preparation and use of pharmaceutical compositions comprising a compound provided herein and one or more pharmaceutically acceptable carriers. Also provided herein are compositions themselves.

[0046] Pharmaceutical compositions typically include a pharmaceutically acceptable carrier. As used herein, the term "pharmaceutically acceptable carrier" includes saline, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration.

[0047] A pharmaceutical composition is typically formulated to be compatible with its intended route of administration, which includes parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), transmucosal, and rectal administration.

[0048] Methods for formulating suitable pharmaceutical compositions are known in the art; see, for example, Remington: The Science and Practice of Pharmacy, 21st ed., 2005; and the books in the series Drugs and the Pharmaceutical Sciences: a Series of Textbooks and Monographs (Dekker, NY). For example, solutions or suspensions used for parenteral, intradermal, or subcutaneous administration may contain the following components: a sterile diluent such as water for injection, saline, fixed oils, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents; antibacterial agents such as benzyl alcohol or methylparabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid, buffers such as acetates, citrates, or phosphates, and agents for adjusting tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases such as hydrochloric acid or sodium hydroxide. Parenteral preparations can be enclosed in ampoules, disposable syringes, or multiple-dose vials made of glass or plastic.

[0049] 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 dispersion. 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 easy syringability exists. The composition must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. The prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it is preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, and sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

[0050] Sterile injectable solutions can be prepared by incorporating the compounds provided herein into a suitable solvent, if necessary, with one or a combination of the ingredients listed above, as needed, followed by filtered sterilization.Generally, dispersions are prepared by incorporating the compounds provided herein into a sterile vehicle containing a basic dispersion medium and the required other ingredients listed above.For sterile powders for the preparation of sterile injectable solutions, the preferred preparation method is vacuum drying and freeze-drying, which yields a powder of the compounds provided herein and any additional desired ingredients from the previously sterile-filtered solution.

[0051] Oral compositions generally contain an inert diluent or an edible carrier. For oral therapeutic administration, the compounds provided herein can be incorporated with excipients and used in the form of tablets, troches, or capsules, such as gelatin capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash. Pharmaceutically compatible binders and / or adjuvant materials can be included as part of the composition. Tablets, pills, capsules, troches, etc. can contain any of the following ingredients, or compounds of a similar nature: binders such as microcrystalline cellulose, tragacanth gum, 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 peppermint, methyl salicylate, or orange flavor.

[0052] For administration by inhalation, the compounds can be delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer, including those described in U.S. Patent No. 6,468,798.

[0053] Systemic administration of the therapeutic compounds described herein can also be via transmucosal or transdermal means. For transmucosal or transdermal administration, a penetrant appropriate to the barrier to be permeated is used in the formulation. Such penetrants are generally known in the art and include, for example, surfactants, bile salts, and fusidic acid derivatives for transmucosal administration. Transmucosal administration can be achieved using nasal sprays or suppositories. For transdermal administration, the compounds provided herein can be formulated into ointments, salves, gels, or creams, as is generally known in the art.

[0054] Pharmaceutical compositions can also be prepared in the form of suppositories (e.g., with conventional suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery.

[0055] Additionally, 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 can also be used. Biodegradable targetable microparticle delivery systems (e.g., as described in U.S. Pat. No. 6,471,996) can also be used.

[0056] In one embodiment, the therapeutic compound is prepared with a carrier that protects the therapeutic compound against rapid elimination from the body, such as a controlled-release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Such formulations can be prepared using standard techniques or are commercially available from, for example, Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to selected cells with monoclonal antibodies against cellular antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.

[0057] The pharmaceutical composition can be administered at once or divided into multiple smaller doses to be administered at time intervals. It is understood that the precise dosage and duration of treatment are a function of the disease being treated and can be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. It should be noted that concentration and dosage values ​​may also vary depending on the severity of the condition being alleviated. It should be further understood that for any particular patient, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the composition, and the concentration ranges set forth herein are merely exemplary and are not intended to limit the scope or practice of the claimed compositions.

[0058] Dosage forms or compositions can be prepared containing 0.005%-100% of the compounds described herein, with the remainder consisting of a non-toxic carrier. Methods for preparing these compositions are known to those skilled in the art. Contemplated compositions may contain 0.001%-100%, in one embodiment 0.1-95%, and in another embodiment 75-85% of the compounds provided herein.

[0059] The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0060] As described above, the preparation 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 each administration route. For example, they are administered in the form of tablets or capsules, injections, inhalations, eye drops, ointments, suppositories, infusions; topically as lotions or ointments; and rectal suppositories. In some embodiments, administration is oral.

[0061] As used herein, the phrases "parenteral administration" and "administered parenterally" refer to modes of administration other than enteral and topical administration, usually by injection, and include, but are not limited to, intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, intradermal, intra-articular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

[0062] Actual dosage levels of the active ingredients in the pharmaceutical compositions provided herein may be varied to obtain an amount of active ingredient that is effective in achieving the desired therapeutic response for a particular patient, composition, and method of administration without causing toxicity to the patient.

[0063] The concentration of the compounds provided herein in a pharmaceutically acceptable mixture will vary depending on several factors, including the dosage of the compound administered, the pharmacokinetic properties of the compound used, and the route of administration. In some embodiments, the compositions provided herein can be provided in an aqueous solution containing, among other substances, about 0.1-10% w / v of a compound disclosed herein for parenteral administration. A typical dose range can include about 0.01 to about 500 mg / kg body weight per day when given in 1-4 divided doses. Each divided dose can contain the same or different compounds. The dosage will be a therapeutically effective amount, depending on several factors, including the patient's overall health, as well as the formulation and route of administration of the compound selected.

[0064] The dosage varies depending on the condition, age, and weight of the patient, the nature and severity of the disease to be treated or prevented, the route of administration, and the drug form, but generally, a daily dosage of 0.01-2000 mg of the compound is recommended for adult patients, and can be administered in a single dose or in divided doses. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be the amount of the compound that produces a therapeutic effect.

[0065] The exact time of administration and / or amount of composition that will produce the most effective results in terms of therapeutic efficacy in a given patient will depend on the activity, pharmacokinetics of the particular compound, bioavailability, the physiological state of the patient (including age, sex, type and stage of disease, general health, responsiveness to a given dosage, and type of medication), route of administration, etc. The above guidelines can be used as a basis for fine-tuning treatment, e.g., determining the optimal time and / or amount of administration, which does not require anything more than routine considerations of patient monitoring and adjustment of dosage and timing.

[0066] Also provided herein are combination therapies in which one or more other therapeutic agents are administered together with a compound or pharmaceutical composition comprising a compound provided herein. Such conjoint treatment may be achieved by the simultaneous, sequential, or separate administration of the individual components of the treatment.

[0067] definition

[0068] The terms "for example," "such as," and grammatical equivalents are understood to be followed by the phrase "and without limitation," unless expressly stated otherwise. As used herein, the term "about" is meant to account for variation due to experimental error. All measurements reported herein are understood to be modified by the term "about," unless otherwise stated, whether or not the term is expressly used. As used herein, "a," "an," and "the" refer to the singular, and "the" includes plural referents unless the context clearly dictates otherwise.

[0069] As used herein, "subject" includes both 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, such as a primate. In some embodiments, the patient is human.

[0070] A "therapeutically effective" amount of a compound provided herein is generally an amount sufficient to prevent, eliminate, ameliorate, or reduce symptoms of a viral infection, including, but not limited to, influenza, coronavirus, respiratory syncytial virus (RSV), parainfluenza virus, human cytomegalovirus (HCMV), and adenovirus infection. It will be understood that different concentrations may be used for prophylaxis than for treatment of active disease.

[0071] A "virus production inhibiting" amount of a compound provided herein is typically an amount sufficient to achieve a measurable decrease 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 by at least 30% in untreated cells. In some embodiments, a "virus production inhibiting" amount is an amount that inhibits virus production by at least 50% in untreated cells. In some embodiments, a "virus production inhibiting" amount is an amount that inhibits virus production by at least 70% in untreated cells. In some embodiments, a "virus production inhibiting" amount is an amount that inhibits virus production by at least 90% in untreated cells.

[0072] The terms "treatment" and "prevention" are art-recognized and include the administration of one or more of the compounds or pharmaceutical compositions provided herein. If it is administered before the clinical manifestation of an undesired condition (e.g., a disease or other undesired condition in a subject), the treatment is prophylactic (i.e., it protects the subject from developing the undesired condition). As used in this context, the term "prevent" means delaying or preventing the onset of at least one symptom of a disorder provided herein. For example, such prevention may be prompted by potential exposure to an infectious agent (e.g., a virus) or when a subject is likely to exhibit other symptoms indicative of the onset of a disorder (e.g., a metabolic or cardiovascular disorder). Alternatively, if it is administered after the onset of an undesired condition, the treatment is therapeutic (i.e., it aims to reduce, ameliorate, or stabilize an existing undesired condition or its side effects). As used in this context, "treat" means ameliorating at least one symptom of a disorder provided herein.

[0073] As used herein, the term "compound" is meant to include all stereoisomers, geometric isomers, and tautomers of the structure shown. A compound identified by name or structure herein as a particular tautomer is intended to include other tautomers unless otherwise specified.

[0074] In some embodiments, the compounds provided herein or salts thereof are substantially isolated. "Substantially isolated" means that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, a composition enriched in the compounds provided herein. Substantial separation can include a composition containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compounds provided herein, or salts thereof. Methods for isolating compounds and their salts are routine in the art.

[0075] The phrase "pharmaceutically acceptable" is used herein to refer to compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0076] The term "pharmaceutically acceptable salt" refers to relatively non-toxic, inorganic and organic acid addition salts of the compounds provided herein. These salts can be prepared in situ during the final isolation and purification of the compounds provided herein, or by separately reacting the free base form of the compound with a suitable organic or inorganic acid and isolating the salt thus formed. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, laurylsulfonate, amino acid salts, and the like. (See, e.g., Berge et al. (1977) "Pharmaceutical Salts," J. Pharm. Sci. 66: 1-19.)

[0077] In some embodiments, the compounds provided herein may contain one or more acidic functional groups and, therefore, can form pharmaceutically acceptable salts with pharmaceutically acceptable bases. The term "pharmaceutically acceptable salts" in these examples refers to the relatively non-toxic, inorganic and organic base addition salts of the compounds provided herein. These salts can also be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid form with a suitable base, such as, for example, a hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation, ammonia, or a pharmaceutically acceptable organic primary, secondary, or tertiary amine. Representative alkali or alkaline earth salts include lithium, sodium, potassium, calcium, magnesium, and aluminum salts, and the like. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like (see, e.g., Berge et al., supra).

[0078] The term "solvate" means a compound that further includes a stoichiometric or non-stoichiometric amount of 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, using a solvent that is suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, within the scope of sound medical judgment, commensurate with a reasonable benefit / risk ratio.

[0079] The term "alkyl," as used herein, refers to straight- and branched-chain aliphatic groups having 1-12 carbon atoms, preferably 1-8 carbon atoms, and more preferably 1-6 carbon atoms, optionally substituted with one, two, or three substituents. Preferred alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl. A "C0" alkyl (such as a "C0-C3-alkyl") is a covalent bond (as in a "C0" hydrocarbyl). The term "lower alkyl" refers to straight- and branched-chain aliphatic groups having 1-6 carbon atoms. Unless otherwise specified, the term "alkyl" includes alkenyl, alkynyl, and cyclic alkyl groups.

[0080] As used herein, the term "alkenyl" refers to an unsaturated straight- or branched-chain aliphatic group having one or more carbon-carbon double bonds, having 2-12 carbon atoms, preferably 2-8 carbon atoms, and more preferably 2-6 carbon atoms, and optionally substituted with one, two, or three substituents. Preferred alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, and hexenyl.

[0081] The term "alkynyl," as used herein, refers to an unsaturated straight- or branched-chain aliphatic group having one or more carbon-carbon triple bonds, having 2-12 carbon atoms, preferably 2-8 carbon atoms, and more preferably 2-6 carbon atoms, and is optionally substituted with one, two, or three substituents. Preferred alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

[0082] The term "heteroalkyl" refers to an alkyl group, as defined hereinabove, wherein one or more carbon atoms within the chain is replaced with a heteroatom selected from the group consisting of O, S, and N.

[0083] An "aryl" group is a C-C alkyl group containing 1-3 aromatic rings, which are optionally substituted. 14 Preferably, the aryl group is C-C 10 Aryl groups. Preferred aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and fluorenyl.

[0084] A "heterocyclyl" or "heterocyclic" group is a ring structure having about 3 to about 8 atoms, one or more of which is selected from the group consisting of N, O, and S. Heterocyclic groups are optionally substituted at one or more carbon positions. Heterocyclic groups are optionally substituted independently on nitrogen with alkyl, aryl, aralkyl, alkylcarbonyl, alkylsulfonyl, arylcarbonyl, arylsulfonyl, alkoxycarbonyl, aralkoxycarbonyl, or on sulfur with oxo or lower alkyl. Preferred heterocyclic groups include, but are not limited to, epoxy, aziridinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, thiazolidinyl, oxazolidinyl, oxazolidinonyl, and morpholino. In certain preferred embodiments, the heterocyclic group is fused to an aryl, heteroaryl, or cycloalkyl group. Examples of such fused heterocycles include, but are not limited to, tetrahydroquinoline and dihydrobenzofuran. Specifically excluded from the scope of this term are compounds having adjacent ring O and / or S atoms.

[0085] As used herein, the term "heteroaryl" refers to a group having 5-14 ring atoms, preferably 5, 6, 9, or 10 ring atoms. It has 6, 10, or 14 pi-electrons shared in a cyclic arrangement. In addition to carbon atoms, it has 1-3 heteroatoms per ring selected from the group consisting of N, O, and S. A "heteroaralkyl" or "heteroarylalkyl" group comprises a heteroaryl group covalently linked to an alkyl group, either of which is independently optionally substituted or unsubstituted. Preferred heteroalkyl groups include C1-C6 alkyl groups and heteroaryl groups having 5, 6, 9, or 10 ring atoms. Specifically excluded from the scope of this term are compounds having adjacent ring O and / or S atoms. Examples of preferred heteroaralkyl groups include pyridylmethyl, pyridylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, thiazolylmethyl, and thiazolylethyl. Specifically excluded from the scope of this term are compounds having vicinal cyclic O and / or S atoms.

[0086] Heterocyclyl and heteroaryl embodiments include acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3b]tetrahydrofuran, furanyl , furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl Oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl , 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienoxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,These include, but are not limited to, 4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.

[0087] As used herein, when a moiety (e.g., cycloalkyl, hydrocarbyl, aryl, heteroaryl, heterocyclic, urea, etc.) is described as "optionally substituted," it means that the group optionally has 1 to 4, preferably 1 to 3, and more preferably 1 or 2 non-hydrogen substituents. Suitable substituents include, but are not limited to, halo, hydroxy, oxo (e.g., a cyclic -CH- substituted with oxo is -C(O)-), nitro, halohydrocarbyl, hydrocarbyl, aryl, aralkyl, alkoxy, aryloxy, amino, acylamino, alkylcarbamoyl, arylcarbamoyl, aminoalkyl, acyl, carboxy, hydroxyalkyl, alkanesulfonyl, arenesulfonyl, alkanesulfonamido, arenesulfonamido, aralkylsulfonamido, alkylcarbonyl, acyloxy, cyano, and ureido groups.

[0088] As used herein, the term "halogen" or "halo" refers to chlorine, bromine, fluorine, or iodine. As used herein, the term "acyl" refers to an alkylcarbonyl or arylcarbonyl substituent. The term "acylamino" refers to an amide group attached to the nitrogen atom (i.e., R-CO-NH-). The term "carbamoyl" refers to an amide group attached to the carbonyl carbon atom (i.e., NH-CO-). The nitrogen atom of an acylamino or carbamoyl substituent is optionally further substituted. The term "sulfonamido" refers to a sulfonamido substituent attached by either the sulfur or the nitrogen atom. The term "amino" is meant to include NH, alkylamino, arylamino, and cyclic amino groups. As used herein, the term "ureido" refers to a substituted or unsubstituted urea moiety.

[0089] A substituted moiety is one in which one or more hydrogens are independently replaced with another chemical substituent. As a non-limiting example, substituted phenyl includes 2-fluorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluoro-phenyl, and 2-fluoro-3-propylphenyl. As another non-limiting example, substituted n-octyl includes 2,4 dimethyl-5-ethyl-octyl and 3-cyclopentyl-octyl. Included in this definition is methylene (—CH—) substituted with oxygen to form carbonyl (—CO—).

[0090] An "unsubstituted" moiety as defined above (e.g., unsubstituted cycloalkyl, unsubstituted heteroaryl, etc.) means a moiety as defined above without any substituents that the definition of the moiety (above) otherwise provides. Thus, for example, "aryl" includes phenyl and phenyl substituted with halo, but "unsubstituted aryl" does not include phenyl substituted with halo.

[0091] Synthesis of Compounds of the Invention

[0092] The compounds of the present invention (compounds of formula I) can be prepared using the general reaction scheme shown in the scheme below. The following abbreviations are used: 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, mole; TBAF, tetrabutylammonium fluoride; t-BuOH, t-butanol; MeI, methyl iodide; DMSO, dimethyl sulfoxide; MeCN, acetonitrile tolyl; XPhos, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl; MeOH, methanol; h or hrs, hours; aq., aqueous; DME, 1,2-dimethoxyethane; sat., saturated; atm, atmosphere; Ac2O, acetic anhydride; conc., concentrated; eq., equivalent; DIEA, N,N-diisopropylethylamine; HATU, N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium 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; Pr ep-TLC, preparative thin-layer chromatography; t-BuONa, sodium t-butoxide; t-BuOK, potassium t-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.

[0093] Scheme 1 [ka]

[0094] A base, such as n-BuLi or sec-BuLi, can be reacted with 2-chloro-1,3-thiazole (2) and an appropriate aromatic or heteroaromatic aldehyde or ketone of general formula 1 to provide compounds of general structure 3. Compounds 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 compounds of general structure 4. Compounds of general structure 4 can be treated with a suitable amine, for example, substituted or unsubstituted 1,2,3,4-tetrahydroisoquinoline, to provide compounds of general structure 5. It will be recognized that compounds of general structure 5 are identical to compounds of formula I.

[0095] Scheme 2 [ka]

[0096] A base, such as n-BuLi or sec-BuLi, or a metal, such as Mg or Li, can be reacted with an appropriate aromatic or heteroaromatic halide of general formula 6, where X is Cl, Br, or I. Compounds of general structure 7 can then be reacted to give compounds of general structure 8. Compounds 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 compounds of general structure 9. Compounds of general structure 9 can be treated with a suitable amine, for example, substituted or unsubstituted 1,2,3,4-tetrahydroisoquinoline, to give compounds of general structure 10. It will be recognized that compounds of general structure 10 are identical to compounds of formula I.

[0097] Those skilled in the art will recognize that there may be alternative synthetic routes to provide compounds of Formula I. The following schemes illustrate examples of such alternative synthetic routes, but should not be construed as limiting.

[0098] Scheme 3 [ka]

[0099] In some examples, an appropriate amine, for example, substituted or unsubstituted 1,2,3,4-tetrahydroisoquinoline, can be reacted with 2-chloro-1,3-thiazole (2) to provide compounds of general structure 11. Compounds of general structure 11 can be reacted with a base, for example, n-BuLi or sec-BuLi, and compounds of general structure 1 to provide compounds of general structure 12. Compounds of general structure 12 can be treated with a suitable reducing agent, for example, a silane, such as triethylsilane, and an acid, such as trifluoroacetic acid, to provide compounds of general structure 5.

[0100] Scheme 4 [ka]

[0101] In some instances, compounds of general structure 3 can be treated with an appropriate amine, such as 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.

[0102] Scheme 5 [ka]

[0103] In some examples, an appropriate amine, such as 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, such as n-BuLi or sec-BuLi or a metal, such as Mg or Li, can be reacted with an appropriate halogenated aromatic or heteroaromatic compound of general formula 6, where 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.

[0104] Scheme 6 [ka]

[0105] Optionally, compounds of general formula 8 can be reacted with an appropriate amine, such as substituted or unsubstituted 1,2,3,4-tetrahydroisoquinoline, to provide compounds of general formula 14. Compounds of general formula 14 can be treated as described above to provide compounds of general formula 10.

[0106] 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 by analogy from the examples. Starting materials are commercially available or can be prepared by methods analogous to those described in the examples below.

[0107] Preparation of intermediates

[0108] Preparation of Intermediate 1 [ka]

[0109] 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 overnight under N. The mixture was cooled to room temperature and saturated. NaHCO (50 mL) and BocO (26.2 g, 120 mmol) were added, and the resulting mixture was stirred at room temperature overnight. The mixture was concentrated, and the residue was purified by silica gel chromatography to give the material, which was purified by preparative HPLC to give 2 (6 g, 38% yield) as a pale yellow oil. MS (ESI): mass calculation for C19 H 25 N3O2327.43, m / z found 327.9 [M+H] + .

[0110] 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 overnight at room temperature and concentrated. The residue was diluted with water, alkalized with K2CO3 to pH = 10, and extracted with DCM. The resulting organic phase was washed with brine, dried over Na2SO4, filtered, and the filtrate gave intermediate 1 (3.4 g, 81.5% yield) as a pale yellow oil. MS (ESI): mass calcd. for C 14 H 17 N3227.31, m / z found 227.9 [M+H] + .

[0111] Preparation of intermediate 2 [ka]

[0112] 1. To a solution of 1 (30 g, 163 mmol) in dry DMF (250 mL) was added pyrazole (11.1 g, 163 mmol), CsCO (79.2 g, 243 mmol), and CuI (3 g, 15.8 mmol). The resulting mixture was stirred at 120 °C overnight. After cooling to room temperature, the residue was treated with water and extracted with EtOAc. The organic extract was washed with water, brine, dried over anhydrous NaSO, filtered, and concentrated to give a crude oil. The crude product was purified by silica gel chromatography to give 2 as a yellow oil (12 g, 43%).

[0113] 2. To a solution of 2-chlorothiazole (8.3 g, 70 mmol) in dry THF (100 mL) was added n-BuLi (28 mL, 70 mmol) dropwise at −78° C. under N2. After 1 h, a solution of 2 (12 g, 70 mmol) in THF (30 mL) was added dropwise. The resulting solution was allowed to warm slowly to room temperature. The reaction was diluted with NH4Cl solution and extracted with EtOAc. The organic extract was concentrated to give a crude oil, which was purified by silica gel chromatography to give 3 as a brown semi-solid (12.8 g, 63%).

[0114] 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 give intermediate 2 as a yellow oil (9.2 g, 76%).

[0115] Alternative preparation of intermediate 2

[0116] 1. A mixture of 1 (18.5 g, 100 mmol), 1H-pyrazole (6.8 g, 100 mmol), CsCO (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 h. The resulting mixture was cooled, filtered, concentrated, diluted with EA, washed with water, brine, dried over NaSO, concentrated, and purified by Combi-Flash to give 2 (9 g, 52% yield) as a yellow oil. MS (ESI): mass calcd. for C 10 H8N 2O 172, m / z found 173 [M+H] + .

[0117] 2. To a solution of 2-chlorothiazole (6.5 g, 55 mmol) in THF (250 ml) at -78 °C, n-BuLi (25 mL, 60 mmol, 2.4 M in hexane) was slowly added, and the resulting mixture was stirred at -78 °C for 1 h. A solution of 2 (8.5 g, 50 mmol) in THF (40 ml) was slowly added at -78 °C, and after stirring for 1 h, the reaction mixture was slowly warmed to room temperature 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, and concentrated. The residue was purified by Combi-Flash to give 3 (4.2 g, 29% yield) as a yellow solid. MS (ESI): mass calcd. for C 13 H 10 ClN 3O S 291, m / z found 292 [M+H] + .

[0118] 3. To a mixture of 3 (4.2 g, 14.4 mmol), 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 h. The resulting mixture was cooled to room temperature, washed with water, brine, dried over NaSO, filtered, concentrated, and purified by Combi-Flash to give intermediate 2 (2.2 g, 55% yield) as a yellow oil. MS (ESI): mass calcd. for C 13 H 10 ClN3S 275.0, m / z found 276 [M+H] + .

[0119] Preparation of intermediate 3 [ka]

[0120] 1. To a solution of 1 (10 g, 80.6 mmol) in dry DMF (100 mL) was added pyrazole (5.5 g, 80.6 mmol) and K2CO3 (12.2 g, 88.7 mmol). The resulting mixture was stirred at 100 °C overnight. After cooling to room temperature, the mixture was treated with water and extracted with EA. The organic extract was washed with water, brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to give a crude oil. The crude product was purified by recrystallization to give 2 (4 g, 29%). 1 HNMR (CDCl3, 300 MHz) δ: 6.5-6.6 (s, 1 H), 7.7-7.8 (s, 1 H), 7.9-8.0 (d, 2 H), 8.0-8.1 (d, 2 H), 8.1-8.2 (s, 1 H), 10.0-10.1 (s, 1 H).

[0121] 2. To a solution of 2-chlorothiazole (1.45 g, 12.1 mmol) in dry THF (10 mL) was added n-BuLi (5 mL, 12.1 mmol) dropwise at −78° C. under N2. After 1 h, a solution of 2 (1.6 g, 9.3 mmol) was added dropwise at −78° C. The resulting solution was allowed to warm slowly to room temperature. The reaction was diluted with NH4Cl solution and extracted with EA. The organic extract was concentrated to give a crude oil. The crude product was purified by silica gel chromatography to give 3 (1.2 g, 50%). 1 HNMR (CDCl3, 300 MHz) δ: 6.1-6.2 (s, 1 H), 6.5-6.6 (s, 1 H), 7.2-7.3 (s, 1 H), 7.4-7.5 (d, 2 H), 7.6-7.7 (d, 2 H), 7.7-7.8 (s, 1 H), 7.9-8.0 (s, 1 H).

[0122] 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 give intermediate 3 (1 g, 91%). 1HNMR (CDCl3, 300 MHz) δ: 4.1-4.2 (s, 2 H), 6.4-6.5 (s, 1 H), 7.2-7.4 (m, 3 H), 7.6-7.8 (m, 3 H), 7.9-8.0 (s, 1 H).

[0123] Alternative preparation of intermediate 3

[0124] 1. To a solution of 2-chlorothiazole (3.85 g, 32.3 mmol) in dry THF (80 mL) was added n-BuLi (14.3 mL, 35.5 mmol) dropwise at −78° C. under N2. 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 allowed to warm slowly to room temperature. The reaction was diluted with NH4Cl solution and extracted with EtOAc. The organic extract was concentrated to give a crude oil. The crude product was purified by silica gel chromatography to give 3 as a light brown oil (5.9 g, 69.7%).

[0125] 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 give intermediate 3 as a white solid (4.84 g, 86.9%).

[0126] Alternative preparation of intermediate 3

[0127] 1. A solution of 4-bromobenzaldehyde (100.0 g, 540 mmol), 1H-pyrazole (37 g, 540 mmol), CsCO (194 g, 594 mmol), CuI (10.3 g, 54 mmol), and 18-crown-6 (11 g, 41 mmol) in DMF (500 mL) was stirred at 80 °C for 24 h under reduced pressure. 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 NaSO, filtered, and concentrated. The resulting residue was purified by column chromatography on silica gel to give 2 (76 g, 81.7% yield) as a white solid. MS (ESI): mass calcd. for C 10 H8N2O 172.18, m / z found 173.0 [M+H] + .

[0128] 2. To a solution of 2-chlorothiazole (54.2 g, 0.45 mol) in dry (550 mL) was added n-BuLi (187.5 mL, 2.4 M, 0.45 mol) dropwise at −78° C. The mixture was stirred at −78° C. for 1 h, 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 warmed to room temperature. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with EA. The organic extract was washed with brine, dried over sNa2SO4, filtered, and concentrated. The resulting residue was purified by column chromatography on silica gel to give 3 (90 g, 82.6% yield) as a yellow solid. MS (ESI): mass calcd. for C 13 H 10 ClN 3O S 291.76, m / z found 291.7 [M+H] + .

[0129] 3. To a solution of 3 (66 g, 0.23 mol) in TFA (330 mL) was added TES (148 g, 0.9 mol) at room temperature. The reaction mixture was stirred at reflux for 1 hour. The mixture was evaporated and diluted with EA. The resulting mixture was washed with saturated NaHCO3, brine, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by column chromatography on silica gel to give intermediate 3 (55 g, 88.7% yield) as a yellow solid. MS (ESI): mass calcd. for C 13 H 10 ClN3S 275.76, m / z found 275.8 [M+H] + .

[0130] Preparation of Intermediate 4 [ka]

[0131] 1. A mixture (5 mL) 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 was stirred at 140 °C for 2 hours. It was then cooled to room temperature, poured into water, neutralized with 3N HCl, and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated, and the resulting residue was purified by silica gel chromatography to give intermediate 4 (200 mg, 44% yield) as a pale yellow solid. MS (ESI): mass calcd. for C 22 H 19 BrN4S 451.39, m / z found 450.7 452.7 [M+H] + .

[0132] Preparation of Intermediate 5 [ka]

[0133] 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-tetrahydroisoquinoine (Key Organics, 848 mg, 4.0 mmol) in DMSO (25 mL) was stirred at 140 °C for 2 hours under a nitrogen atmosphere. After cooling to room temperature, 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 give intermediate 5 (1.0 g, 61.3% yield) as a yellow solid. MS (ESI): mass calcd. for C 22 H 19 BrN4S 451.38, m / z found 450.7 [M+H] + .

[0134] Preparation of Intermediate 6 [ka]

[0135] 1. To a solution of 2-chlorothiazole (5.76 g, 48 mmol) in dry THF (40 mL) was added n-BuLi (2.4 M, 20.0 mL, 48 mmol) dropwise at -78 °C under N2. After 1 h, a solution of 4-bromobenzaldehyde (7.40 g, 40 mmol) in THF (40 mL) was added dropwise. The mixture was slowly warmed to room temperature and stirred overnight. The mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated, and the resulting residue was purified by silica gel chromatography to give 1 (8.00 g, 66% yield) as a yellow oil. MS (ESI): mass calcd. for C 10 H7BrClNOS 304.59, m / z found 305.7 [M+H] + .

[0136] 2. A mixture of 1 (8.00 g, 26.4 mmol) and TES (18 mL) in TFA (50 mL) was stirred at room temperature for 2 hours, concentrated, and the residue was diluted with saturated aqueous NaHCO3. The mixture was extracted with DCM, and the combined organic extracts were washed with brine, dried over Na2SO4, filtered, concentrated, and the residue was purified by silica gel chromatography to give intermediate 6 (7.20 g, 94.7% yield) as a brown oil. MS (ESI): mass calcd. for C 10 H7BrClNS 288.59, m / z found 289.6 [M+H] + .

[0137] Preparation of intermediate 7 [ka]

[0138] 1. To a solution of 1 (20 g, 71.9 mmol) in dry THF (100 mL) was added n-BuLi (31.7 mL, 79.1 mmol) dropwise at −78° C. under N2. After 1 h, DMF (1.66 g, 79.1 mmol) was added dropwise at −78° C. The resulting solution was slowly warmed to room temperature. The reaction was quenched with NH4Cl solution and extracted with EA. The reaction extract was concentrated to give a crude oil. The crude product was purified by silica gel chromatography to give 2 (12 g, 73.5%).

[0139] 2. A solution of 2 (12 g, 52.9 mmol) in dry DMF (200 mL) was added with 1H-pyrazole (4.0 g, 58.1 mmol), CsCO (19 g, 58.1 mmol), CuI (1.2 g), and 18-crown-6 (1.2 g), and the resulting mixture was stirred at 80 °C for 24 h. The mixture was cooled to room temperature, diluted with water, and extracted with EA. The combined organic layers were washed with water, brine, dried over anhydrous NaSO, filtered, and concentrated to give a crude oil. The crude product was purified by recrystallization to give 3 (7.3 g, 64.5%).

[0140] 3. To a solution of 2-chlorothiazole (4.47 g, 37.5 mmol) in dry THF (100 mL) at −78°C under a N2 atmosphere was added n-BuLi (15 mL, 37.5 mmol) dropwise. After 1 h, a solution of 3 (7.3 g, 34.1 mmol) was added dropwise at −78°C. The resulting mixture was slowly warmed to room temperature. The reaction was quenched with NH4Cl solution and extracted with EA. The organic layer was concentrated to give a crude oil. The crude product was purified by silica gel chromatography to give 4 (4.6 g, 40.3%).

[0141] 4. To a solution of 4 (4.6 g, 13.8 mmol) in DCE (40 mL) at 0 °C, TFA (10.4 mL, 138 mmol) and TES (6.6 mL, 41.3 mmol) were slowly added. The resulting solution was stirred at room temperature for 3 h. The reaction was quenched with H2 and extracted with DCM. The combined extracts were concentrated to give a crude oil, which was purified by silica gel chromatography to give intermediate 7 (1.8 g, 41.1%). 1 HNMR (CDCl3, 300 MHz) δ: 1.2-1.3 (d, 6 H), 2.9-3.0 (m, 1 H), 4.1-4.2 (s, 2 H), 6.4-6.5 (s, 1 H), 7.0 (s, 1 H), 7.3-7.4 (d, 2 H), 7.4-7.5 (s, 1 H), 7.7-7.8 (s, 1 H), 7.9-8.0 (s, 1 H).

[0142] Preparation of Intermediate 9 [ka]

[0143] 1. 1 (Key Organics, 500 mg, 1.60 mmol), ethynyltrimethylsilane (236 mg, 2.40 mmol), Pd(PPh)Cl (140 mg, 0.20 mmol), CuI (60.8 mg, 0.32 mmol), and EtN (485 mg, 4.80 mmol in dry DMF (5.00 mL)) were 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 NaSO, and concentrated to give the crude product, which was purified by silica gel chromatography to give 2 (494 mg, 94% yield) as a yellow oil.

[0144] 2. To a solution of 2 (494 mg, 1.50 mmol) in THF was added TBAF (1 M in THF, 10 mL) and stirred at room temperature 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 give 3 (280 mg, 73%) as a yellow solid.

[0145] 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 HO (1.96 g, 109 mmol) was stirred in a sealed tube 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 NaSO, and concentrated to give the crude product, which was purified by silica gel column chromatography to give 4 (171 mg, 50% yield) as a colorless solid.

[0146] 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 room temperature for 2 hours. The mixture was concentrated to give intermediate 9 (100 mg, 74% yield) as an off-white solid.

[0147] Alternative preparation of intermediate 9 [ka]

[0148] 1. To a solution of intermediate 10 (2.5 g, 8.3 mmol) in DMF (20 mL) at 0 °C was added K2CO3 (2.3 g, 16.6 mmol). The resulting mixture was stirred at 0 °C for 2 h, 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 extract was washed with water, brine, dried over anhydrous Na2SO4, filtered, and concentrated to give a crude oil. The crude product was purified by silica gel to give 2 (1.4 g, 54%).

[0149] 2. To a solution of 2 (1.4 g) in dry DCM (20 mL) at 0 °C was added HCl / ether (5 mL, 3 M). The resulting solution was slowly warmed to room temperature and stirred overnight. The reaction was concentrated to give intermediate 9 (1 g, 78%).

[0150] Preparation of Intermediate 10 [ka]

[0151] 1. To a solution of compound 3 (4.6 g, 17.9 mmol) from the preparation of intermediate 9 in DMSO (40 mL) was added NaN (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 extract was washed with water, brine, dried over anhydrous Na SO , filtered, and concentrated to give a crude oil. The crude product was purified by silica gel to give 2 (3.4 g, 62.2%).

[0152] 2. To a solution of 2 (3.4 g) in dry DCM (20 mL) at 0° C. was added HCl / ether (10 mL, 3 M). The resulting solution was slowly warmed to room temperature and stirred overnight. The reaction was concentrated to give Intermediate 10 (1.76 g, 57.1%).

[0153] Preparation of intermediate 11 [ka]

[0154] 1. To a slurry of 1 (1 g, 15 mmol) and K2CO3 (3.1 g, 22.5 mmol) in MeCN (10 mL) was added a solution of 1-bromo-2-methoxyethane (2.5 g, 18 mmol) in MeCN (10 mL). The reaction mixture was stirred at room temperature for 2 h. The mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography to give 2 as a yellow oil (0.66 g, 35%).

[0155] 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 reaction extract was concentrated, and the residue was purified by silica gel chromatography to give 4 as a yellow oil (0.108 g, 30%).

[0156] 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 room temperature for 3 hours. The mixture was concentrated to give intermediate 11 (100 mg, 100%).

[0157] Preparation of Intermediate 12 [ka]

[0158] 1. To a solution of 1 (Key Organics, 160 mg, 0.5 mmol) in DMF (3 mL) was added CsCO (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 N for 20 h. The mixture was poured into water and extracted with EtOAc. The extract was washed with water, brine, dried over NaSO, filtered, and concentrated to give 2 (168 mg, 90%).

[0159] 2. A mixture of 2 (160 mg, 0.53 mmol) and HCl / dioxane (3 mL, 12 mmol) was stirred at room temperature for 2 hours. The mixture was concentrated to give intermediate 12 (106 mg, 90%).

[0160] Preparation of intermediate 13 [ka]

[0161] 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.

[0162] Preparation of intermediate 14 [ka]

[0163] 1. Compound 3 (650 mg, 2.53 mmol) from the preparation of intermediate 9, 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 HO (5.00 g, 278 mmol) were stirred at 100 °C in a sealed tube overnight. The mixture was cooled to room temperature and extracted with EtOAc. The extracted organic layer was washed with water, brine, dried over NaSO, and concentrated to give the crude product, which was purified by silica gel chromatography to give 2 (350 mg, 39%) as an off-white solid.

[0164] 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 room temperature for 2 hours. The mixture was concentrated to give intermediate 14 (260 mg, 90%) as a white solid.

[0165] Preparation of Intermediate 15 [ka]

[0166] 1. A solution of 1 (Key Organics, 1.00 g, 3.20 mmol), (S,S)-N,N'-dimethyl-1,2-diaminocyclohexane (91.0 mg, 0.64 mmol), a mixture of 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 room temperature, the mixture was directly purified by preparative HPLC to give 2 (320 mg, 31% yield) as an off-white solid.

[0167] 2. A mixture of 2 (220 mg, 0.70 mmol), HCl-dioxane (4 M, 3.00 mL, 12.0 mmol), and CHCl (3 mL) was stirred at room temperature for 2 hours. The mixture was concentrated to give intermediate 15 (150 mg, 86% yield) as an off-white solid.

[0168] Preparation of Intermediate 16 [ka]

[0169] 1. 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) were stirred at 100 °C for 4 h. The mixture was quenched with water and extracted with EtOAc. The organic extract was washed with water and brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography to give 2 (550 mg, 37% yield for two steps) as a yellow solid.

[0170] 2. A mixture of 2 (550 mg, 1.28 mmol), LiOH (61.0 mg, 2.56 mmol), MeOH (3 mL), and HO (3 mL) was stirred at room temperature for 3 h. The mixture was acidified to pH 4-5 with 2 N HCl, resulting in the formation of a precipitate. The precipitate was filtered, washed with water, and dried to give 3 (170 mg, 32% yield) as an off-white solid.

[0171] 3. A mixture of 3 (170 mg, 0.41 mmol), HATU (250 mg, 0.62 mmol), DIEA (280 mg, 2.17 mmol), NH4Cl (134 mg, 2.5 mmol), and DMF (2 mL) was stirred at room temperature for 4 h. The mixture was quenched with water and extracted with EtOAc. The organic extract was washed with water and brine, dried over Na2SO4, and concentrated. The residue was purified by preparative TLC to give intermediate 16 (130 mg, 76% yield) as a yellow solid.

[0172] Preparation of intermediate 17 [ka]

[0173] 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 room temperature, 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 1 N HCl. The resulting mixture was extracted with EtOAc, and the organic extract was concentrated to give a crude oil. The crude product was purified by silica gel chromatography to give 2 as a pale yellow solid (0.31 g, 74%).

[0174] 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 NH4Cl (7.1 mg, 0.13 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was treated with water and extracted with EtOAc. The organic extract was washed with water, brine, dried over anhydrous Na2SO4, filtered, and concentrated to give a crude oil. The crude product was purified by silica gel chromatography to give Intermediate 17 as a white solid (11.2 mg, 22.4%).

[0175] Preparation of intermediate 18 [ka]

[0176] 1. To a solution of 1 (20 g, 108.1 mmol) in dry DMF (200 mL) was added 1H-imidazole (8.1 g, 118.9 mmol), CsCO (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 room temperature, treated with water, and extracted with EA. The extract was washed with water, brine, dried over anhydrous NaSO, filtered, and concentrated to give a crude oil. The crude product was purified by recrystallization to give 2 (11 g, 59.2%).

[0177] 2. To a solution of 2-chlorothiazole (3.8 g, 32 mmol) in dry THF (50 mL) was added N-BuLi (14 mL, 34.9 mmol) dropwise at −78° C. under N. After 1 h, a solution of 2 (5 g, 29.1 mmol) was added dropwise at −78° C. The resulting solution was slowly warmed to room temperature. The reaction was quenched with NH4Cl solution and extracted with EA. The extract was concentrated to give a crude oil. The crude product was purified by silica gel chromatography to give 3 (3.5 g, 41.4%).

[0178] 3. To a solution of 3 (3.5 g, 12.0 mmol) in DCE (60 mL) at 0 °C, TFA (9 mL, 120 mmol) and TES (5.8 mL, 36 mmol) were slowly added. The resulting solution was stirred at room temperature for 3 h. The reaction was quenched with HO and extracted with DCM. The organic layer was concentrated to give a crude oil, which was purified by silica gel chromatography to give Intermediate 18 (1.8 g, 54.4%).

[0179] Preparation of intermediate 19 [ka]

[0180] 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 CsCO (48.70 g, 150 mmol). The resulting mixture was stirred at 120 °C for 2 h. The mixture was cooled to room temperature, filtered, and the filtrate was poured into water and extracted with CHCl. ​​The organic phase was washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by chromatography on silica gel to give 2 (1.80 g, 18% yield) as a brown oil. MS (ESI): mass calcd. for C 12 H 12 N2O 200.24, m / z found 200.9 [M+H] + .

[0181] 2. To a solution of 2-chlorothiazole (1.20 g, 10 mmol) in THF (20 mL) at −78° C. under N2, N-BuLi (2.4 M, 5.5 mL) was added dropwise. After 1 h, a solution of 2 (1.80 g, 9 mmol) in THF (20 mL) was added dropwise. The reaction was slowly warmed to room temperature and stirred overnight. The mixture was quenched with saturated aqueous NH4Cl, extracted with EtOAc, 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 give 3 (1.83 g, 64% yield) as a yellow oil. MS (ESI): mass calcd. for C 15 H 14 ClN3OS 319.81, m / z found 319.8 [M+H] + .

[0182] 3. A mixture of 3 (1.83 g, 5.7 mmol), TES (9 mL) in TFA (18 mL) was stirred at 60 °C for 3 h. It was then concentrated, and the residue was diluted with saturated aqueous NaHCO and extracted with CHCl. ​​The combined organic phases were washed with brine, dried over NaSO, filtered, concentrated, and the residue was purified by silica gel chromatography to give intermediate 19 (1.20 g, 69.0% yield) as a brown oil. MS (ESI): mass calcd. for C15 H 14 ClN3S 303.81, m / z found 303.8 [M+H] + .

[0183] Preparation of Intermediate 20 [ka]

[0184] 1. A mixture of 1 (Key Organics, 5.68 g, 0.018 mol), oxazolidin-2-one (4.7 g, 0.054 mol), Pd(dba) (8.23 g, 0.009 mol), S-phos (3.69 g), and dry 1,4-dioxane (150 mcg) was stirred at 150 °C overnight. The reaction mixture was cooled to room temperature, filtered, and concentrated to give the crude product. The residue was purified by silica gel chromatography to give 2 (5.02 g, 88% yield) as a yellow solid. MS (ESI): mass calcd. for C 17 H 22 N2O4318.37, m / z found 340.8 [M+H] + .

[0185] 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 room temperature for 6 hours. The reaction was then concentrated to give the crude product, which was dissolved in DCM and diluted with petroleum ether. The resulting suspension was filtered, and the filtrate was washed with petroleum ether and dried to give intermediate 20 (3.50 g, 70%). MS (ESI): mass calcd. for C 14 H 15 F3N2O3316.28, m / z found 218.9 [M+H] + .

[0186] Preparation of intermediate 21 [ka]

[0187] 1. To a solution of 2-chlorothiazole (5.76 g, 48 mmol) in dry THF (200 mL) at −78 °C under N was added n-BuLi (2.4 M, 25.0 mL, 60 mmol) dropwise. After 0.5 h, a solution of 1 (8.00 g, 43 mmol) in THF (50 mL) was added dropwise. The reaction was allowed to warm slowly to room temperature. The mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The resulting organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated to give the crude product, which was purified by silica gel chromatography to give 2 (8.50 g, 64% yield) as a yellow oil. MS (ESI): mass calcd. for C 10 H7BrClNOS 304.59, m / z found 305.7 [M+H] + .

[0188] 2. A mixture of 2 (8.50 g, 27.9 mmol) and TFA (60 mL) in TES (20 mL) was stirred at 60 °C for 2 h. The mixture was concentrated, and the residue was diluted with saturated aqueous NaHCO and extracted with DCM. The resulting organic phase was washed with brine, dried over NaSO, filtered, and concentrated to give the crude product, which was purified by silica gel chromatography to give 3 (7.00 g, 86.9% yield) as a brown oil. MS (ESI): mass calcd. for C 10 H7BrClNS 288.59, m / z found 289.6 [M+H] + .

[0189] 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 h. The reaction was cooled to room temperature, poured into ice water, extracted with C2Cl2, and the combined organic phases were washed with brine, dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography to give intermediate 21 (2.10 g, 42.9% yield) as a yellow solid. MS (ESI): mass calcd. for C 22 H 20BrN3O2S 470.39, m / z found 470.5 [M+H] + .

[0190] Preparation of intermediate 22 [ka]

[0191] 1. To a solution of 2-chlorothiazole (5.76 g, 48) in dry THF (40 mL) was added N-BuLi (2.4 M, 20.0 mL, 48 mmol) dropwise at −78° C. under N. After 1 h, a solution of 1 (7.40 g, 40 mmol) in THF (40 mL) was added dropwise. The reaction mixture was slowly warmed to room temperature and stirred overnight. It was then quenched with saturated aqueous NH4Cl and extracted with EtOAc. The resulting organic phase was washed with brine, dried over Na2SO4, filtered, concentrated, and purified by chromatography on silica gel to give 2 (8.00 g, 66% yield) as a yellow oil. MS (ESI): mass calcd. for C 10 H7BrClNOS 304.59, m / z found 305.7 [M+H] + .

[0192] 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 room temperature for 2 hours. It was then concentrated, and the residue was diluted with saturated aqueous NaHCO3 and extracted with DCM. The resulting organic phase was washed with brine, dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography to give 3 (7.20 g, 94.7% yield) as a brown oil. MS (ESI): mass calcd. for C 10 H7BrClNS 288.59, m / z found 289.6 [M+H] + .

[0193] 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 h. The reaction was cooled to room temperature and then poured into ice water, extracted with C2Cl2, and dried over Na2SO4. The resulting organic layer was concentrated to give the crude product, which was purified by silica gel chromatography to give intermediate 22 (4.78 g, 92% yield) as a yellow solid. MS (ESI): mass calcd. for C 22 H 20 BrN3O2S 470.39, m / z found 470.7 [M+H] + .

[0194] Preparation of intermediate 23 [ka]

[0195] 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 with CO three times in a vessel and then heated under 120 atm of CO at 100 atm for 24 h. The mixture was cooled, filtered through Celite, the filter cake was washed with EA, and the filtrate was concentrated to give the crude product, which was purified by silica gel chromatography to give 2 (11.5 g, 82.1% yield) as an oil. MS (ESI): mass calcd. for C 16 H 21 NO4291.15, m / z found 313.9 [M+Na] + . 1H NMR (400 MHz, CDCl3) δ ppm 7.84 (d, J = 8.2 Hz, 1H), 7.82 (s, 1H), 7.22 (d, J = 7.9 Hz, 1H), 4.63 (s, 2H), 3.93 (s, 3H), 3.68 (t, J = 5.4 Hz, 2H), 2.90 (t, J = 5.5 Hz, 2H), 1.51 (s, 9H).

[0196] 2. To a solution of 2 (10.8 g, 37 mmol) in MeOH (20 mL) was added MeOH saturated with NH3 (250 mL). The reaction was stirred in a bomb at 120 °C for 60 h, cooled to room temperature, and concentrated to give the crude product, which was purified by silica gel chromatography to give 3 (8.4 g, 81.9% yield) as a yellow solid. MS (ESI): mass calcd. for C 15 H20N2O3276.34, m / z found 298.9 [M+Na]+. 1 H NMR (400 MHz, DMSO) δ ppm 7.89 (s, 1H), 7.69 - 7.67 (m, 2H), 7.30 (s, 1H), 7.23 (d, J = 8.0 Hz, 1H), 4.54 (s, 2H), 3.56 (t, J = 5.8 Hz, 2H), 2.81 (t, J = 5.8 Hz, 2H), 1.44 (s, 9H).

[0197] 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 room temperature for 6 hours and concentrated to give the crude product, which was dissolved in DCM and diluted with PE to give a precipitate, which was collected by filtration. The filter cake was washed with EA and dried in vacuo to give intermediate 23 (6.3 g, 71.4%). MS (ESI): mass calcd. for C 12 H 13 F3N2O3290.24, m / z found 177.0 [M+H] + .

[0198] Preparation of intermediate 24 [ka]

[0199] 1. To a solution of 2-chlorothiazole (1.24 g, 10.35 mmol) in dry THF (50 mL) was added n-BuLi (2.4 M, 4.8 mL) dropwise at −78° C. under N. After 0.5 h, a solution of 1 (Sigma-Aldrich, 1.80 g, 9.41 mmol) in dry THF (10 mL) was added dropwise. The reaction was allowed to warm slowly to room temperature. The mixture was quenched with water, extracted with NH4Cl and DCM, and dried over Na2SO4. The resulting organic layer was concentrated to give the crude product, which was purified by silica gel chromatography to give 2 (2.00 g, 68.36% yield) as a white solid. MS (ESI): mass calcd. for C 14 H 15 ClN2O2S 310.80, m / z found 311.4 [M+H] + .

[0200] 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 water. It was extracted with NaHCO3 and DCM (30 mL x 3) and dried over Na2SO4. The extract was concentrated to give the crude product, which was purified by silica gel chromatography to give intermediate 24 (1.1 g, 57.94% yield) as a white solid. MS (ESI): mass calcd. for C 14 H 15 ClN2OS 294.8, m / z found 295.4 [M+H] + .

[0201] Preparation of Intermediate 25 [ka]

[0202] 1. 1 (Key Organics, 5.0 g, 16.01 mmol), pyrrolidin-2-one (4.09 g, 48.03 mmol), Pd(dba) (1.17 g, 1.6 mmol), S-Phos (1.31 g, 3.2 mmol in dry 1,4-dioxane (200 mL)), and t-BuOK (5.38 g, 48.03 mmol) were stirred at 100 °C overnight. The mixture was poured into water, extracted with DCM, dried over NaSO, filtered, and concentrated. The resulting residue was purified by silica gel chromatography to give 2 (3.2 g, 63.17%) as a white solid. Mass calcd. for C 18 H 24 N2O3316.40, m / z found 316.8 [M+H] + .

[0203] 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 hours. The mixture was concentrated, and the residue was washed with aqueous NaHCO3, extracted with DCM, and dried over Na2SO4. The extract was concentrated to give the crude product, which was purified by silica gel chromatography to give Intermediate 25 (1.05 g, 48.02% yield) as a white solid. MS (ESI): mass calcd. for C 13 H 16 N2O 216.28, m / z found 216.8 [M+H] + .

[0204] Preparation of Intermediate 26 [ka]

[0205] 1. A mixture of 1 (Sigma-Aldrich, 4 g, 26.7 mmol), 2-bromopyrimidine (3.51 g, 22.1 mmol), NaHCO (6.73 g, 80.1 mmol), and Pd(PPh) (766 mg, 0.663 mmol) in DME / HO (100 mL / 50 mL) was stirred at 90 °C for 18 h under a N atmosphere. The mixture was filtered through Celite, 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 NaSO. The mixture was filtered, and the filtrate was concentrated to give a residue that was purified by silica gel chromatography to give 2 (3.84 g, 78.1% yield) as a white solid. MS (ESI): mass calcd. for C 11 H8N2O 184.20, m / z found 185.0 [M+H] + .

[0206] 2. To a solution of 2-chlorothiazole (2.69 g, 22.7 mmol) in dry THF (80 mL) was added n-BuLi (2.4 M, 9.9 mL, 23.75 mmol) dropwise at −78° C. under N2. 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 warmed to room temperature and stirred for 18 h. The resulting mixture was quenched with aqueous NH4Cl. It was extracted with EtOAc, and the combined extracts were dried over Na2SO4. The organic solution was concentrated to give the crude product, which was purified by silica gel chromatography to give 3 (4.65 g, 74.2% yield) as a white solid. MS (ESI): mass calcd. for C 14 H 10 ClN3OS 303.76, m / z found 303.8 [M+H] + .

[0207] 3. To a solution of 3 (3 g, 9.87 mmol) and TFA (11.3 g, 98.7 mmol) in dry DCE at 0 °C, TES (3.42 g, 29.6 mmol) was added dropwise, and the reaction was stirred at 60 °C for 8 h. The mixture was cooled and concentrated. The resulting residue was treated with saturated NaHCO and extracted with EA, and the combined extracts were washed with brine, water, and dried over NaSO. Removal of the solvent gave the crude product, which was purified by flash chromatography to give intermediate 26 (1.2 g, 42.2% yield) as a white solid. MS (ESI): mass calcd. for C 14 H 10 ClN3S 287.77, m / z found 287.8 [M+H] + .

[0208] Preparation of intermediate 27 [ka]

[0209] 1. A mixture of 1 (2.00 g, 6.4 mmol), morpholine (1.80 g, 20.6 mmol), Pd(dba) (2.0 g, 2.2 mmol), S-Phos (1.20 g, 3.0 mmol), and KCO (2.80 g, 20 mmol) in dry 1,4-dioxane (80 mL) was stirred at 100 °C overnight. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated. The resulting residue was purified by silica gel chromatography to give 2 (1.30 g, 64%) as a yellow oil. Mass calculation for C 18 H 26 N2O3318.19, m / z found 319.0[M+H] + .

[0210] 2. A mixture of 2 (1.30 g, 5 mmol) and TES (5 mL) in TFA (10 mL) was stirred at 50 °C for 2 h. The mixture was cooled and concentrated, the residue was treated with saturated aqueous NaHCO3, extracted with CHCl2, the organic phase was washed with brine, dried over NaSO4, filtered, and the filtrate was concentrated to give intermediate 27 (1.4 g, crude) as a brown oil. MS (ESI): mass calcd. for C 13 H 18 N2O 218.14, m / z found 219.0[M+H] + .

[0211] Preparation of intermediate 28 [ka]

[0212] 1. To a solution of 1 (4.46 g, 36 mmol) in DMF (100 mL) were 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 room temperature, filtered, the filtrate was poured into water, and the mixture was extracted with EA. The extract was washed with brine, dried over Na2SO4, concentrated, and purified by silica gel chromatography to give 2 (4.17 g, 70% yield) as a white solid. MS (ESI): mass calcd. for C 10 H9NO3191.19, m / z found 192.0 [M+H] + .

[0213] 2. To a solution of 2-chlorothiazole (0.86 g, 7.2 mmol) in THF (25 mL) was added n-BuLi (3 mL, 7.2 mmol) dropwise at −78° C. After 1 h, a solution of 2 (1.06 g, 5.5 mmol) in THF (15 mL) was added dropwise. The reaction mixture was stirred for 2 h, quenched with saturated NH4Cl, and extracted with EtOAc. The extract was washed with brine, dried over Na2SO4, filtered, and concentrated to give 3 (crude, 1.8 g) as a yellow oil. MS (ESI): mass calcd. for C14 H 12 ClN3O2S 310.75, m / z found 311.21[M+H] + .

[0214] 3. A mixture of 3 (0.1 g, 0.32 mmol) and TES (0.5 mL) in TFA (1 mL) was stirred at room temperature for 2 hours. The mixture was concentrated, and the residue was purified by chromatography on silica gel to give intermediate 28 (78 mg, 82% yield) as a white solid. MS (ESI): mass calcd. for C 13 H 11 ClN2O2S 294.75, m / z found 295.19[M+H] + .

[0215] Preparation of intermediate 29 [ka]

[0216] 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 room temperature, filtered, and concentrated to give 2 (5.1 g, 92%) as a yellow oil. Mass calcd. for C 17 H 23 N3O3317.39, m / z found 317.9[M+H] + .

[0217] 2. To a solution of 2 (1.50 g, 4.7 mmol) in THF was added NaH (200 mg, 13.8 mmol) at 0 °C (40 mL). After 0.5 h, a solution of iodomethane (1.41 g, 9.9 mmol) in THF (10 mL) was added dropwise. The reaction mixture was slowly warmed to room temperature and stirred at 60 °C for 4 h. The reaction was quenched with water and extracted with EA. The combined extracts were washed with brine, dried over anhydrous NaSO, and concentrated to give 3 (1 g, 64%). Mass calcd. for C 18 H 25 N3O3331.42. m / z found 332.0 [M+H] + .

[0218] 3. A mixture of 3 (2 g, 6 mmol) and TFA (9 mL) in DCM (40 mL) was stirred at room temperature for 2 hours. It was then concentrated, and the residue was diluted with saturated aqueous NaHCO3 and extracted with CHCl2. The resulting organic phase was washed with brine, dried over NaSO4, filtered, and concentrated to give intermediate 29 (1.1 g) as a brown oil. MS (ESI): mass calcd. for C 13 H 17 N3O 231.3, m / z found 231.9 [M+H] + .

[0219] Preparation of Intermediate 30 [ka]

[0220] 1. 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 HO (1 mL) were purged with N three times, and the resulting mixture was heated to 100 °C for 16 h. It was cooled to room temperature, concentrated, and the residue was purified by silica gel chromatography to give 2 (940 mg, 93% yield) as a white solid. MS (ESI): mass calcd. for C13 H 14 O3218.25, m / z found 219.0 [M+H] + .

[0221] 2. A mixture of 2 (940 mg, 4.31 mmol) and Pd / C (250 mg) in EtOAc (40 mL) was stirred under H at room temperature for 16 h. The mixture was filtered and concentrated to give 3 (948 mg, 100% yield) as a colorless oil. MS (ESI): mass calcd. for C 13 H 16 O3220.27, m / z found 221.0 [M+H] + .

[0222] 3. LiAlH4 (160 mg, 4.09 mmol) was added to a solution of 3 (900 mg, 4.09 mmol) in dry THF (15 mL) at 0 °C. The mixture was warmed to room temperature, stirred for 2 h, quenched at 0 °C with saturated NH4Cl, and then extracted with EtOAc. The extract was washed with brine, dried over Na2SO4, filtered, and concentrated to give 4 (765 mg, 97% yield) as a yellow oil. MS (ESI): mass calcd. for C 12 H 16 O2192.26, m / z found 175.0 [M-OH] + .

[0223] 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 room temperature for 1 h, concentrated, and the residue was purified by silica gel chromatography to give 5 (15.5 mg, 78% yield) as a yellow oil. MS (ESI): mass calcd. for C 12 H 14 O2190.24, m / z found 191.0 [M+H] + .

[0224] 5. n-BuLi (1.45 mL, 3.47 mmol, 2.4 M) was added dropwise to a solution of 2-chlorothiazole (416 mg, 3.47 mmol) in THF (3 mL) at −78° C. After 30 min, a solution of 5 (600 mg, 3.16 mmol) in THF (6 mL) was added dropwise, and the resulting mixture was warmed to room temperature and stirred overnight. The mixture was quenched with saturated NH4Cl and extracted with EtOAc. The extract was washed with brine, dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography to give 6 (860 mg, 88% yield) as a white solid. MS (ESI): mass calcd. for C 15 H 16 ClNO2S 309.81, m / z found 309.8 [M+H] + .

[0225] 6. A mixture of 6 (690 mg, 2.23 mmol), TES (2 mL), and TFA (2 mL) was stirred under N2 at room temperature for 2 h. The mixture was concentrated, and the residue was diluted with saturated NaHCO3 and extracted with DCM. The extract was washed with brine, dried over Na2SO4, filtered, and concentrated, and the residue was purified by silica gel chromatography to give intermediate 30 (566.6 mg, 87% yield) as a yellow oil. MS (ESI): mass calcd. for C 15 H 16 ClNOS 293.81, m / z found 294.1 [M+H] + .

[0226] Preparation of intermediate 31 [ka]

[0227] 1. To a solution of 2-chlorothiazole (3.59 g, 29.9 mmol) in dry THF (94 mL) was added n-BuLi (2.4 M in Hex, 13.0 mL, 31.2 mmol) dropwise at -78 °C under N2. After 1 h, a solution of 1 (enamine, 5 g, 27.2 mmol) in dry THF (200 mL) was added dropwise. The reaction was allowed to warm to room temperature and stirred for 18 h. The mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The extract was dried over Na2SO4 and concentrated to give the crude product, which was purified by silica gel chromatography to give 2 (1.6 g, 19.4% yield) as a white solid. MS (ESI): mass calcd. for C 11 H 10 ClNO3S2303.78, m / z found 303.7 [M+H] + .

[0228] 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 NaHCO3, and extracted with EtOAc. The extract was washed with water, dried over Na2SO4, and concentrated to give the crude product, which was purified by silica gel chromatography to give intermediate 31 (1.3 g, 85.8% yield) as a white solid. MS (ESI): mass calcd. for C 11 H 10 ClNO2S2 287.78, m / z found 287.7 [M+H] + .

[0229] Preparation of intermediate 34 [ka]

[0230] 1. To a solution of 1H-pyrazole (5.86 g, 86.2 mmol) in anhydrous DMF (50.0 mL) under N was added NaH (60%, 10.3 g, 258.6 mmol), and the reaction mixture was stirred at 60 °C for 1 h. 1 (15.1 g, 86.2 mmol) was then added, and the resulting mixture was stirred at 120 °C for 3 h. The reaction was quenched with water and extracted with EtOAc. The organic layer was washed with water, brine, dried over NaSO, and concentrated to give the crude product, which was purified by silica gel chromatography to give 2 (4.0 g, 21% yield) as a colorless oil.

[0231] 2. To a solution of 2 (2.66 g, 18.0 mmol) in dry THF (50 mL) was added n-BuLi (2.5 M in hexane, 7.2 mL, 18.0 mmol) dropwise under N at −78 °C. After 1 h, a solution of 2-chloro-4-thiazolecarboxaldehyde (Sigma-Aldrich, 4.00 g, 18.02 mmol) in THF (10 mL) was added dropwise. The resulting mixture was allowed to warm to room temperature. The reaction was quenched with saturated NH Cl and extracted with EtOAc. The organic extract was concentrated to give a crude oil, which was purified by silica gel chromatography to give 3 (420 mg, 8% yield) as a yellow oil.

[0232] 3. To a solution of 3 (400 mg, 1.44 mmol) in TFA (10 mL) was added TES (3 mL), and the resulting mixture was stirred at 100° C. for 2 h. The reaction was concentrated, and the residue was purified by silica gel chromatography to give intermediate 34 (250 mg, 63% yield) as a yellow solid.

[0233] Preparation of Intermediate 35 [ka]

[0234] 1. To a mixture of 1 (4 g, 22.5 mmol) in saturated aqueous NaHCO (50 mL) and THF (50 mL) was added BOC O (5.63 g, 25.8 mmol), and the resulting mixture was stirred at room temperature for 16 h. The mixture was concentrated, the residue was extracted with EtOAc, and the combined organic phases were washed with brine, dried over Na SO , filtered, concentrated, and purified by chromatography on silica gel to give 2 (5.8 g, 93.5% yield) as a brown solid. MS (ESI): mass calcd. for C 14 H 18 N2O4 278.31, m / z found 301.0 [M+Na] + .

[0235] 2. A mixture of 2 (5.8 g, 20.9 mmol) and Pd / C (1.2 g) in EtOAc (60 mL) was stirred under H at room temperature for 16 h. The mixture was filtered and concentrated to give 3 (5 g, 96.7% yield) as a brown oil. MS (ESI): mass calcd. for C 14 H 20 N2O2248.33, m / z found 271.0 [M+Na] + .

[0236] 3. A mixture of 3 (2 g, 8.06 mmol) and 3-chloropropyl isocyanate (1.16 g, 9.68 mmol) in dry DCM (20 mL) was stirred at room temperature for 16 h. It was then concentrated, the residue was washed with a mixture of EA / PE (1 / 50), filtered, and the resulting solid was dried in vacuo to give 4 (2.8 g, 95% yield) as a brown solid. MS (ESI): mass calcd. for C 18 H 26 ClN3O3367.87, m / z found 368.0 [M+H] + .

[0237] 4. To a solution of 4 (2.7 g, 7.4 mmol) in THF (270 mL) was added NaH (888 mg, 22.2 mmol) portionwise at 0 °C. It was then warmed to room temperature and stirred for 16 h. The volume was reduced to approximately 40 mL, cooled to 0 °C, and MeI (1.58 g, 11.1 mmol) was added. The resulting mixture was warmed to room temperature and stirred for 16 h. The mixture was quenched with water and extracted with EtOAc. 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 give 5 (2.4 g, 96% yield) as a yellow oil. MS (ESI): mass calcd. for C 19 H 27 N3O3345.44, m / z found 346.0 [M+H] + .

[0238] 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 hours, it was concentrated, and the residue was washed with EtOAc, filtered, and dried in vacuo to give the desired product Intermediate 35 (2.2 g, 88% yield) as a white solid. MS (ESI): mass calcd. for C 16 H 20 F3N3O3359.35, m / z found 246.0 [M-TFA+H] + . [Example]

[0239] Example 1 [ka]

[0240] 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 K2CO3 (300 mg, 2.18 mmol). The mixture was stirred at 120 °C overnight and cooled to room temperature. The mixture was treated with water and extracted with EA. The organic extract was washed with water, brine, dried over anhydrous Na2SO4, filtered, and concentrated to give a crude oil. The crude product was purified by silica gel chromatography to give 90.36 mg of Example 1. 1 HNMR (CDCl3, 300 MHz) δ: δ: 1.3-1.4 (d, 6 H), 3.0-3.1 (m, 2 H), 3.6-3.8 (m, 2 H), 4.1 (s, 2 H), 4.2-4.3 (s, 2 H), 4.8-4.9 (s, 2 H), 6.5 (s, 1 H), 7.0-7.1 (s, 1 H), 7.1-7.2 (s, 1 H), 7.4-7.5 (s, 1 H), 7.5-7.6 (s, 1 H), 7.7.6-7.7 (d, 1 H), 7.7-7.8 (s, 1 H), 7.8-7.9 (s, 1 H), 7.9-8.0 (s, 1 H). LC-MS: m / z=496.5 (M+1) + .

[0241] Example 2 [ka]

[0242] 1. A solution 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 a mixture of t-BuOK (123 mg, 1.10 mmol) in dioxane (2.00 mL) was stirred at 95 °C for 2 hours. The reaction was quenched with water and extracted with EtOAc. The organic extract was washed with water and brine, dried over Na2SO4, and concentrated. The residue was purified by preparative HPLC to give Example 2 (45.9 mg, 25% yield) as a yellow solid. 1H 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 Calcd.: 453.2; MS Found: 454.2 [M+H] + .

[0243] Example 3 [ka]

[0244] 1. Intermediate 9 and Intermediate 2 were reacted according to the procedure described for Example 1 to give 11.03 mg of Example 3 (9.58 mg). 1 HNMR (CDCl3, 300 MHz) δ: 3.0-3.1 (m, 2 H), 3.7-3.8 (m, 2 H), 4.1 (s, 2 H), 4.4.3 (s, 2 H), 4.6 (s, 2 H), 6.5 (s, 1 H), 7.0-7.1 (s, 1 H), 7.1-7.3 (m, 2 H), 7.3 (s, 1 H), 7.4 (m, 1 H), 7.5-7.7 (m, 4 H), 7.7-7.8 (s, 1 H), 7.8-7.9 (s, 1 H), 7.9-8.0 (s, 1 H). LC-MS: m / z=454.4 (M+1) + .

[0245] Example 4 [ka]

[0246] 1. Intermediate 10 and Intermediate 2 were reacted according to the procedure described for Example 1 to give 11.03 mg of Example 4. 1 HNMR (CDCl3, 300 MHz) δ: 3.0-3.1 (m, 2 H), 3.6-3.8 (m, 2 H), 4.1 (s, 2 H), 4.8 (s, 2 H), 6.5 (s, 1 H), 7.7.1-7.3 (m, 5 H), 7.4-7.5 (m, 1 LC-MS: m / z=440.4 (M+1) + .

[0247] Example 5 [ka]

[0248] 1. Intermediate 10 and Intermediate 3 were reacted according to the procedure described for Example 1 to give 30.02 mg of Example 5. 1 HNMR (CDCl3, 300 MHz) δ: 3.0-3.1 (m, 4 H), 3.6-3.8 (m, 2 H), 4.1 (s, 2 H), 4.8-4.9 (s, 2 H), 6.4-6.5 (s, 1 H), 7.1-7.3 (m, 5 H), 7.4 (m, 1 H), 7.5-7.6 (m, 3 H), 7.7 (s, 1 H), 7.7.8 (s, 1 H), 7.9-8.0 (s, 1 H). LC-MS: m / z=440.4 (M+1) + .

[0249] Example 6 [ka]

[0250] 1. To a solution of 1 (Sigma-Aldrich, 158 mg, 1 mmol) in EtOH (20 mL) was added NHOH (1.5 mL). The mixture was heated to reflux for 20 h. The mixture was cooled and concentrated to give 2 as a white solid (0.19 g, 100%).

[0251] 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, and the residue was dissolved in concentrated sulfuric acid. HCl (10 mL) was added and the mixture was heated to reflux overnight. The mixture was concentrated to give 3 as a white solid (0.4 g, 100%).

[0252] 3. To a solution of 3 (20 mg, 0.5 mmol) in dioxane (10 mL) was added intermediate 3 (250 mg, 0.9 mmol), Pd(dba) (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 stirred under N for 20 h. The mixture was quenched with water and extracted with EtOAc. The extract was concentrated to give a crude oil, which was purified by silica gel chromatography to give Example 6 as a yellow solid (40 mg, 20%). LC-MS: m / z = 455.1 (M+1). + . 1 HNMR (CD3OD, 500 MHz): [ka]

[0253] Example 7 [ka]

[0254] 1. To a solution of intermediate 11 (82 mg, 0.3 mmol, 1 equiv.) in dioxane (20 mL), intermediate 3 (137 mg, 0.5 mmol, 1.6 equiv.), Pd2(dba)3 (18 mg, 0.027 mmol, 0.09 equiv.), SPhos (18 mg, 0.04 mmol, 0.13 equiv.), and t-BuOK (330 mg, 3 mmol, 10 equiv.) were added. 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 extract was concentrated to give a crude oil, which was purified by silica gel chromatography to give Example 7 as a yellow solid (40 mg, 27%). LC-MS: m / z = 498.2 (M+1). + . 1 HNMR (CD3OD, 500 MHz): [ka]

[0255] Example 8 [ka]

[0256] 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 give Example 8 as a yellow solid (90 mg, 27%). LC-MS: m / z = 498.2 (M+1). + . 1 HNMR (CD3OD, 500 MHz): [ka]

[0257] Example 9 [ka]

[0258] 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 equivalents of Pd2(dba)3, 0.07 equivalents of SPhos, and 2.4 equivalents of t-BuOK to give Example 9 as a white solid (100 mg, 45.6%). LC-MS: m / z = 439.2 (M+1). + . 1 HNMR (CDCl3, 500 MHz): [ka]

[0259] Example 10 [ka] 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 room temperature, the precipitate was filtered to give 2 as a white solid (1.92 g, 88%).

[0260] 2. BOC0 (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 at room temperature overnight. After concentration, the residue was dissolved in EtOAc and washed with water. The organic mixture was dried over NaSO and concentrated. The residue was purified by flash column chromatography to give 3 (1.8 g, 86.9%).

[0261] 3. A solution of 3 (0.4 g, 1.5 mmol) in dioxane (20 mL) was added with 1,2-dibromoethane (0.31 g, 1.66 mmol), 2 N aqueous NaOH (5 mL, 10 mmol) and TBAB (20 mg, 0.05 mL), quenched and extracted with EtOAc. The organic extract was dried over NaSO, filtered and concentrated to give 4 (210 mg, 47.8%).

[0262] 4. To a solution of 4 (210 mg, 0.72 mmol) in DCM (20 mL) was added 4 M HCl / dioxane (3 mL, 12 mmol). The mixture was stirred at room temperature overnight and then concentrated to give 5 (150 mg, 92%).

[0263] 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 organic extract was concentrated. The resulting material was purified by silica gel chromatography to give Example 10 as a white solid (80 mg, 30%). m / z = 431.1 (M+H). + . 1 HNMR (CD3OD, 500 MHz): [ka]

[0264] Example 11 [ka]

[0265] 1. The title compound was prepared according to the procedure described in Example 7, using Intermediate 14 instead of Intermediate 11, 1 equivalent of Intermediate 3, 0.09 equivalents of Pd(dba), 0.16 equivalents of SPhos, and 3 equivalents of t-BuOK to afford Example 11 (75.9 mg, 35%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 2.92 (2H, t, J = 6.0 Hz), 3.26 (3H, s), 3.67 (2H, t, J = 6.0 Hz), 3.77 (2H, t, J = 5.2 Hz), 4.04 (2H, s), 4.56 (2H, t, J = 5.6 Hz), 4.60 (2H, s), 6.52-6.53 (1H, m), 7.03 (1H, s), 7.25 (1H, d, J = 8.0 Hz), 7.36 (2H, d, J = 8.8 Hz), 7.65-7.67 (1H, m), 7.70-7.72 (2H, m), 7.76-7.78 (2H, m), 8.45 (1H, d, J = 2.4 Hz), 8.48 (1H, s). MS Calcd.: 497.2; MS Found: 498.2 [M + H] + .

[0266] Example 12 [ka]

[0267] 1. The title compound was prepared according to the procedure described in Example 7 using Intermediate 14 instead of Intermediate 11, 1 equivalent of Intermediate 2 instead of Intermediate 3, 0.09 equivalents of Pd(dba), 0.18 equivalents of SPhos, and 3 equivalents of t-BuOK to give Example 12 (51.5 mg, 23%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 2.91 (2H, t, J = 6.0 Hz), 3.26 (3H, s), 3.67 (2H, t, J = 6.0 Hz), 3.77 (2H, t, J = 5.2 Hz), 4.08 (2H, s), 4.56 (2H, t, J = 5.2 Hz), 4.59 (2H, s), 6.54 (1H, t, J = 2.0 Hz), 7.06 (1H, s), 7.19 (1H, d, J = 7.6 Hz), 7.25 (1H, d, J = 8.0 Hz), 7.43 (1H, t, J = 8.0 Hz), 7.65-7.77 (5H, m), 8.48-8.49 (2H, m). MS Calcd.: 497.2; MS Found: 498.2 [M + H] + .

[0268] Example 13 [ka]

[0269] 1. The title compound was prepared according to the procedure described in Example 7 using Intermediate 15 instead of Intermediate 11, 1 equivalent of Intermediate 3, 0.09 equivalents of Pd(dba), 0.2 equivalents of SPhos, and 2.8 equivalents of t-BuOK to give Example 13 (33.4 mg, 15% yield), a white solid. 1H NMR (400 MHz, DMSO-d6) δ 2.15 (3H, s), 2.91 (2H, t, J = 5.6 Hz), 3.66 (2H, t, J = 6.0 Hz), 4.04 (2H, s), 4.60 (2H, s), 6.53 (1H, t, J = 2.0 Hz), 7.03 (1H, s), 7.29 (1H, d, J = 8.0 Hz), 7.35-7.43 (4H, m), 7.51 (1H, d, J = 2.0 Hz), 7.72 (1H, d, J = 1.6 Hz), 7.77 (2H, d, J = 8.8 Hz), 8.08 (1H, d, J = 1.2 Hz), 8.46 (1H, d, J = 2.4 Hz). MS Calcd.:452.2; MS Found: 453.2 [M + H] + .

[0270] Example 14 [ka]

[0271] 1. A mixture of Intermediate 1 (100 mg, 0.38 mmol), Intermediate 3 (115 mg, 0.42 mmol), Pd(dba) (36.6 mg, 0.04 mmol), SPhos (32.9 mg, 0.08 mmol), and t-BuOK (128 mg, 1.14 mmol) in dry dioxane (4.00 mL) was stirred at 90 °C for 4 hours. Upon completion of the reaction, it was quenched with water and extracted with EtOAc. The organic layer was washed with water, brine, dried over NaSO, and concentrated to give the crude product, which was purified by preparative HPLC to give Example 14 (33.5 mg, 19% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 2.08 (3H, s), 2.22 (3H, s), 2.94 (2H, t, J = 5.6 Hz), 3.67 (2H, d, J = 5.6 Hz), 4.04 (2H, s), 4.59 (2H, s), 6.53 (1H, t, J = 2.0 Hz), 6.92 (1H, s), 7.03 (1H, s), 7.21 (1H, d, J = 8.0, 2.0 Hz), 7.30-7.32 (2H, m), 7.36 (2H, d, J = 8.4 Hz), 7.72 (1H, d, J = 2.0 Hz), 7.77 (2H, d, J = 8.8 Hz), 8.46 (1H, d, J = 2.4 Hz). MS Calcd.: 466.2; MS Found: 467.2 [M + H] + .

[0272] Alternative Preparation of Example 14

[0273] 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, stirred at 140 °C for 2 h, cooled to room temperature, diluted with EA, filtered, concentrated, and the residue was purified by silica gel chromatography. Elution and recrystallization with EtOAc gave Example 14 (21.8 g, 42.5% yield) as an off-white solid. MS (ESI): mass calcd. for C 27 H 26 N6S 466.61, m / z found 466.8 [M+H] + . 1H NMR (400 MHz, DMSO) δ ppm 8.46 (d, J = 2.3 Hz, 1H), 7.78 (d, J = 8.4 Hz, 2H), 7.73 (s, 1H), 7.37 (d, J = 8.4 Hz, 2H), 7.33 - 7.31 (m, 2H), 7.22 (d, J = 8.1 Hz, 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 = 5.9 Hz, 2H), 2.95 (t, J = 5.8 Hz, 2H), 2.23 (s, 3H), 2.09 (s, 3H).

[0274] Example 15 [ka]

[0275] 1. A mixture of Intermediate 16 (130 mg, 0.31 mmol) and DMF-DMA (10 mL) was stirred at 100°C for 1 hour. 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 room temperature for 0.5 hours. The mixture was quenched with water and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated. The residue was purified by preparative HPLC to give Example 15 (11.0 mg, 8% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 2.92-2.94 (2H, m), 3.68 (2H, t, J = 6.0 Hz), 4.08 (2H, s), 4.61 (2H, s), 6.54 (1H, t, J = 2.0 Hz), 7.06 (1H, s), 7.18 (1H, d, J = 8.0 Hz), 7.25-7.30 (1H, 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 Calcd.: 439.2; MS Found: 440.1 [M + H] + .

[0276] Example 16 [ka]

[0277] 1. Following the procedure described for Example 15, Intermediate 17 (0.18 g, 0.43 mmol) was converted to Example 16 as a white solid (60 mg, 31%). LC-MS: m / z = 440.2 (M+1) + . 1 HNMR (DMSO-d6, 500 MHz): [ka]

[0278] Example 17 [ka]

[0279] 1. Intermediate 18 and Intermediate 12 were reacted according to the procedure described for Example 1 to give 19.6 mg of Example 17.1 HNMR (CDCl3, 300 MHz) δ: 3.0-3.1 (m, 2 H), 3.7-3.8 (m, 2 H), 4.1 (m, 2 H), 4.7-4.8 (s, 2 H), 7.0-7.1 (s, 1 H), 7.2-7.5 (m, 14 H), 7.8-7.9 (s, 2 H). LC-MS: m / z=439.4 (M+1) + .

[0280] Example 18 [ka]

[0281] 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, 300 MHz) δ: 3.0-3.1 (m, 2 H), 3.7-3.8 (m, 2 H), 4.0-4.1 (m, 2 H), 4.6-4.7 (s, 2 H), 6.4-6.5 (s, 1 H), 6.9-7.0 (s, 1 H), 7.2 (s, 1 H), 7.3-7.4 (d, 2 H), 7.6-7.7 (d, 1 H), 7.7-7.8 (s, 1 H), 7.8-7.9 (s, 1 H)7.9-8.0 (s, 1 H). LC-MS: m / z=439.3 (M+1) + .

[0282] Example 19 [ka]

[0283] 1. Following the procedure described in Example 7, but using Intermediate 1 instead of Intermediate 11, and 1.2 equivalents of Intermediate 2 instead of Intermediate 3, 0.11 equivalents of Pd(dba), 0.22 equivalents of SPhos, and 3 equivalents of t-BuOK, Example 19 (33.5 mg, 20% yield) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 2.08 (3H, s), 2.21 (3H, s), 2.94 (2H, t, J = 5.6 Hz), 3.67 (2H, t, J = 2.0 Hz), 4.09 (2H, d, J = 4.8 Hz), 4.59 (2H, s), 6.54 (1H, t, J = 2.4 Hz), 6.91 (1H, s), 7.06-7.07 (1H, m), 7.20 (2H, t, J = 8.0 Hz), 7.29-7.35 (2H, m), 7.40-7.44 (1H, m), 7.69 (1H, d, J = 8.4 Hz), 7.73 (1H, d, J = 1.2 Hz), 7.76 (1H, s), 8.48 (1H, d, J = 2.8 Hz). MS Calcd.: 466.2; MS Found: 467.3 [M + H] + .

[0284] Example 20 [ka]

[0285] 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) under N was added Pd(PPh) (0.084 g, 0.14 mmol). The resulting mixture was stirred at 120 °C for 24 h. The mixture was cooled to room temperature, treated with water, and extracted with EA. The organic extract was washed with water, brine, dried over anhydrous NaSO, filtered, and concentrated to give a crude oil. The crude product was purified by recrystallization to give 2 (1.1 g, 38%).

[0286] 2. A mixture of 2 (1.1 g, 2.76 mmol) in HCl / EtO (3 M, 20 ml) was stirred at room temperature overnight. The mixture was filtered and the filter cake was washed with EtO to give 3 (0.4 g, 80%).

[0287] 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 K2CO3 (0.3 g, 2.2 mmol). The mixture was stirred at 140 °C overnight. The mixture was cooled to room temperature, treated with water, and extracted with EA. The organic extract was washed with water, brine, dried over anhydrous Na2SO4, filtered, and concentrated to give a crude oil, which was purified by silica gel chromatography to give Example 20 (15 mg). 1 HNMR (CDCl3, 300 MHz) δ: 2.9-3.1 (m, 2 H), 3.7-3.8 (m, 2 H), 4.0-4.1 (m, 2 H), 4.6-4.7 (s, 2 H), 6.4-6.5 (s, 1 H), 6.9-7.0 (s, 1 H), 7.1-7.2 (m, 3 H), 7.6-7.8 (m, 4 H), 7.9-8.0 (s, 1 H). LC-MS: m / z=439.4 (M+23) +

[0288] Example 21 [ka]

[0289] 1. 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) were stirred overnight at 140 °C under a N atmosphere. The mixture was cooled to room temperature, diluted with MeOH, filtered, and the filtrate was concentrated and purified by preparative HPLC to give Example 21 (20 mg, 10.5% yield) as a pale yellow solid. MS (ESI): mass calcd. for C26 H 24 N6S 452.58, m / z found 452.8 [M+H] + . 1 H NMR (400 MHz, DMSO) δ ppm 8.49 (d, J = 2.3 Hz, 1H), 8.08 (s, 2H), 7.77 (s, 1H), 7.74 (s, 1H), 7.69 (d, J = 8.3 Hz, 1H), 7.51 (s, 1H), 7.44 - 7.41 (m, 2H), 7.29 (d, J = 8.2 Hz, 1H), 7.20 (d, J = 7.6 Hz, 1H), 7.07 (s, 1H), 6.55 (s, 1H), 4.60 (s, 2H), 4.09 (s, 2H), 3.66 (t, J = 5.9 Hz, 2H), 2.92 (t, J = 5.8 Hz, 2H), 2.16 (s, 2H).

[0290] Example 22 [ka]

[0291] 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 mixture was cooled to room temperature, poured into ice water, extracted with C2Cl2, and dried over Na2SO4. The organic extract was concentrated under reduced pressure and purified by silica gel chromatography to give 2 (1.80 g, 42.6% yield) as a yellow solid. MS (ESI): mass calcd. for C 20 H 18 BrN3OS 202.21, m / z found 202.7 [M+H] + .

[0292] 2. To a solution of 2-chlorothiazole (1.07 g, 8.9 mmol) in dry THF (40 mL) at -78 °C was added n-BuLi (2.4 M, 4.0 mL, 9.6 mmol) dropwise. After 1 h, a solution of 2 (1.80 g, 8.9 mmol) in THF (40 mL) was added dropwise. The reaction was allowed to warm slowly to room temperature. The mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic extract was washed with brine, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by chromatography on silica gel to give 3 (1.4 g, 48.9% yield) as a yellow oil. MS (ESI): mass calcd. for C 10 H7BrClNOS 321.78, m / z found 322.4 [M+H] + .

[0293] 3. A mixture of 3 (1.40 g, 4.35 mmol) and TFA (15 mL) in TES (5 mL) was stirred at 60 °C for 2 h. The mixture was concentrated, and the residue was washed with saturated aqueous NaHCO, extracted with CHCl, and dried over NaSO. The organic extract was concentrated to give the crude product, which was purified by chromatography on silica gel to give 4 (1.2 g, 90.2% yield) as a yellow oil. MS (ESI): mass calcd. for C 10 H7BrClNS 305.78, m / z found 306.2 [M+H] + .

[0294] 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 room temperature, poured into ice water, extracted with C2Cl2, 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 give Example 22 (18.5 mg, 5.7% yield) as a yellow solid. MS (ESI): mass calcd. for C 28 H 28N6OS 496.63, m / z found 496.7 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.16 (d, J = 2.4 Hz, 1H), 7.68 (s, 1H), 7.53 (d, J = 1.6 Hz, 1H), 7.32 (d, J = 8.4 Hz, 2H), 7.28 - 7.15 (m, 3H), 7.03 (s, 1H), 6.93 (s, 1H), 6.47 (s, 1H), 4.59 (s, 2H), 4.02 (s, 2H), 3.67 (t, J = 5.8 Hz, 3H), 2.67 (t, J = 5.8 Hz, 2H), 2.95 (t, J = 5.8 Hz, 2H), 2.23 (s, 3H), 2.09 (s, 3H).

[0295] Example 23 [ka]

[0296] 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): mass calcd. for C 29 H 30 N6S 494.66, m / z found 494.8 [M+H] + . 1 H NMR (400 MHz, DMSO) δ ppm 7.44 (s, 4H), 7.39 (d, J = 8.8 Hz, 2H), 7.31 (d, J = 8.1 Hz, 1H), 7.21 (d, J = 8.3 Hz, 2H), 7.07 (s, 1H), 4.63 (s, 2H), 4.10 (s, 2H), 3.69 (t, J = 5.7 Hz, 2H), 2.98 (t, J = 5.6 Hz, 2H), 2.35 (d, J = 5.2 Hz, 6H), 2.19 (s, 6H).

[0297] Example 24 [ka]

[0298] 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 give Example 24 (40 mg, 14.8% yield) as a yellow solid. MS (ESI): mass calcd. for C 25 H 23 N5O2S 457.55, m / z found 457.7 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.46 (d, J = 2.0 Hz, 1H), 7.78 (d, J = 8.4 Hz, 2H), 7.73 (s, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.39-7.36 (m, 3H), 7.21 (d, J = 8.4 Hz, 1H), 7.08 (s, 1H), 6.54 (s, 1H), 4.57 (s, 2H), 4.44 (t, J = 7.6 Hz, 2H), 4.08 - 4.00 (m, 4H), 3.67 (t, J = 5.6 Hz, 2H), 2.89 (t, J = 6.0 Hz, 2H).

[0299] Example 25 [ka]

[0300] 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 give Example 25 (30 mg, 14.8% yield) as a yellow solid. MS (ESI): mass calcd. for C 25 H 24 N6OS 456.56, m / z found 456.8 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.45 (d, J = 2.4 Hz, 1H), 7.76 (d, J = 8.4 Hz, 2H), 7.72 (s, 1H), 7.44 (dd, J = 8.4, 1.6 Hz, 1H), 7.38 - 7.31 (m, 3H), 7.09 (d, J = 8.4 Hz, 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 = 7.6 Hz, 2H), 3.63 (t, J = 6.0 Hz, 2H), 3.38 (t, J = 8.4 Hz, 2H), 2.82 (t, J = 6.0 Hz, 2H).

[0301] Example 26 [ka]

[0302] 1. Intermediate 5 (100 mg, 0.22 mmol), 1-methylimidazolidin-2-one (66 mg, 0.66 mmol), (Pd(dba)) (100 mg, 0.11 mmol), t-BuOK (74 mg, 0.66 mmol), and SPhos (44 mg, 0.11 mmol) in dioxane (10 mL) were stirred at 100° C. for 16 hours under a nitrogen atmosphere. The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC to give Example 26 (50 mg, 48.1% yield) as a yellow solid. MS (ESI): mass calcd. for C 26 H 26 N6OS 470.59, m / z found 470.8 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.45 (d, J = 2.4 Hz, 1H), 7.76 (d, J = 8.4 Hz, 2H), 7.72 (s, 1H), 7.47 (dd, J = 8.4, 2.0 Hz, 1H), 7.38 - 7.31 (m, 3H), 7.10 (d, J = 8.4 Hz, 1H), 7.01 (s, 1H), 6.52 (s, 1H), 4.51 (s, 2H), 4.03 (s, 2H), 3.74 (t, J = 7.2 Hz, 2H), 3.63 (t, J = 5.6 Hz, 2H), 3.41 (t, J = 8.4 Hz, 2H), 2.83 (t, J = 6.0 Hz, 2H), 2.75 (s, 3H).

[0303] Example 27 [ka]

[0304] 1. A mixture of 4-fluoro-3-methoxy-benzaldehyde (5.0 g, 32.4 mmol), 1H-pyrazole (3.3 g, 48.6 mmol), and K2CO3 (6.8 g, 48.6 mmol) in DMF (30 mL) was stirred at 120 °C under N2 for 20 h. 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 give 2 (3.0 g, 53.4% ​​yield) as a pale yellow solid. MS (ESI): mass calcd. for C 11 H 10 N2O2202.21, m / z found 202.9 [M+H] + .

[0305] 2. To a solution of 2-chlorothiazole (3.0 g, 25.1 mmol) in dry THF (100 mL) at −78° C. was added n-BuLi (11.3 mL, 2.4 M, 27.2 mmol) dropwise and stirred at this temperature for 1 h. A solution of 2 (4.2 g, 20.9 mmol) was added dropwise at −78° C. The resulting solution was slowly warmed to room temperature. The reaction mixture was quenched with NH4Cl solution and extracted with EA. The organic extract was washed with brine, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by column chromatography on silica gel to give 3 (5.6 g, 83.8% yield) as a yellow solid. MS (ESI): mass calcd. for C 14 H 12 ClN3O2S 321.78, m / z found 321.8 [M+H] + .

[0306] 3. To a room temperature solution of 3 (5.6 g, 17.4 mmol) in TFA (20 mL) was added TES (11.4 g, 69.6 mmol). 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 organic extract was washed with saturated NaHCO3 solution, brine, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by column chromatography on silica gel 4 (4.8 g, 90.2% yield) as a clear liquid. MS (ESI): mass calcd. for C 14 H 12 ClN3OS 305.78, m / z found 305.8 [M+H] + .

[0307] 4. Following the procedure described in 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): mass calcd. for C 28 H 28 N6OS 496.63, m / z found 496.8 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.11 (d, J = 2.4 Hz, 1H), 7.66 (s, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.36 (m, 2H), 7.28 (d, J = 8.0 Hz, 1H), 7.16 (s, 1H), 7.13 (s, 1H), 7.05 (s, 1H), 6.93 (d, J = 8.0 Hz, 1H), 6.45 (s, 1H), 4.61 (s, 2H), 4.06 (s, 2H), 3.83 (s, 3H), 3.68 (t, J = 6.0 Hz, 2H), 2.96 (t, J = 6.0 Hz, 2H), 2.31 (s, 3H), 2.15 (s, 3H).

[0308] Example 28 [ka]

[0309] 1. Following the procedure described for Example 1, Intermediate 20 and Intermediate 2 were reacted to give Example 28 (43.2 mg, 26.2% yield) as a white solid. MS (ESI): mass calcd. for C 25 H 23 N5O2S 457.55, m / z found 457.8 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.48 (d, J = 2.0 Hz, 1H), 7.75 (d, J = 12.4 Hz, 2H), 7.69 (d, J = 8.0 Hz, 1H), 7.44 (dd, J = 15.8, 7.8 Hz, 2H), 7.36 (s, 1H), 7.19 (d, J = 8.0 Hz, 2H), 7.05 (s, 1H), 6.54 (s, 1H), 4.54 (s, 2H), 4.43 (t, J = 7.8 Hz, 2H), 4.08 (s, 2H), 4.03 (t, J = 8.0 Hz, 2H), 3.64 (t, J = 5.8 Hz, 2H), 2.86 (t, J = 5.6 Hz, 2H).

[0310] Example 29 [ka]

[0311] 1. A solution of intermediate 22 (329 mg, 0.48 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(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 dry 1,4-dioxane (20 mL) was stirred at 100 °C overnight. The mixture was cooled to room temperature and concentrated, and the residue was purified by silica gel chromatography to give 1 (250 mg, 69.0%). Mass calculation for C 28 H 32BN3O4S 517.45, m / z found 517.6 [M+H] + .

[0312] 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 HO (2 mL) was added KCO (80 mg, 0.57 mmol) and Pd(dppf)Cl (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 phase was washed with brine, dried over NaSO, filtered, and concentrated. The resulting residue was purified by preparative TLC to give Example 29 (9 mg, 10%) as a white solid. Mass calcd. For C 26 H 23 N5O2S 469.16. m / z found 469.7 [M+H] + , 1 H NMR (400 MHz, DMSO) δ ppm 8.90 (d, J = 4.8 Hz, 2H), 8.34 (d, J = 8.1 Hz, 2H), 7.51 - 7.32 (m, 5H), 7.20 (d, J = 8.4 Hz, 1H), 7.05 (s, 1H), 4.55 (s, 2H), 4.43 (t, J = 7.9 Hz, 2H), 4.09 (s, 2H), 4.03 (t, J = 8.0 Hz, 2H), 3.65 (t, J = 5.8 Hz, 2H), 2.87 (t, J = 5.7 Hz, 2H).

[0313] Example 30 [ka]

[0314] 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 hour. The reaction mixture was cooled to room temperature, poured into water, and extracted with CHCl. ​​The extract was dried over NaSO, filtered, and the filtrate was concentrated. The resulting residue was purified by preparative TLC to give Example 30 (11 mg, 7%) as a white solid. Mass calcd. for C 23 H 20 N4O2S 416.5, m / z found 416.8 [M+H] + , 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.78 (d, J = 8.1 Hz, 2H), 7.46 (d, J = 8.1 Hz, 2H), 7.37 (s, 1H), 7.20 (d, J = 8.5 Hz, 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 = 5.9 Hz, 2H), 2.86 (t, J = 5.8 Hz, 2H).

[0315] Example 31 [ka]

[0316] 1. Intermediate 22 (240 mg, 0.5 mmol), morpholine (131 mg, 1.5 mmol), Pd(dba) (229 mg, 0.25 mmol), SPhos (103 mg, 0.25 mmol), and KCO (207 mg, 1.5 mmol) in 1,4-dioxane (15 mL) were stirred at 100 °C overnight. The mixture was cooled to room temperature, poured into water, and extracted with CHCl. ​​The extract was dried over NaSO, filtered, and the filtrate was concentrated. The resulting residue was purified by preparative TLC to give Example 31 (10 mg, 4.2%) as a white solid. Mass calcd. for C26 H 28 N4O3S 476.6, m / z found 476.8 [M+H] + , 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.45 (d, J = 9.9 Hz, 1H), 7.37 (s, 1H), 7.19 (d, J = 8.4 Hz, 1H), 7.09 (d, J = 8.4 Hz, 2H), 6.95 (s, 1H), 6.87 (d, J = 8.5 Hz, 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 = 5.8 Hz, 2H), 3.08 - 3.01 (m, 4H), 2.87 (d, J = 5.9 Hz, 2H).

[0317] Example 32 [ka]

[0318] 1. Following the procedure described in 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. Mass calculation for C 25 H 24 N4O4S 476.55, m / z found 476.7 [M+H] + , 1H NMR (400 MHz, DMSO) δ ppm 7.50 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.2 Hz, 1H), 7.37 (s, 1H), 7.26 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 8.3 Hz, 1H), 6.98 (s, 1H), 4.54 (s, 2H), 4.43 (t, J = 7.0 Hz, 4H), 4.04 (t, J = 7.1 Hz, 4H), 3.98 (s, 2H), 3.64 (t, J = 5.9 Hz, 2H), 2.86 (t, J = 5.9 Hz, 2H).

[0319] Example 33 [ka]

[0320] 1. Following the procedure described in Example 31 using CsCO (488 mg) instead of KCO, 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. Mass calcd. For C 26 H 28 N4O4S2524.65, m / z found 524.7 [M+H] + , 1 H NMR (400 MHz, CDCl3) δ ppm 7.38 (d, J = 8.8 Hz, 2 H), 7.25 (d, J = 7.8 Hz, 1H), 7.19 (d, J= 8.4 Hz, 1H), 7.00 (s, 1H), 6.87 - 6.77 (m, 3H), 4.64 (s, 2 H), 4.51 (dd, J = 8.8, 7.0 Hz, 2 H), 4.16 (t, J = 8.0 Hz, 2H), 3.98 (s, 2 H), 3.85 (t, J = 5.2 Hz, 4 H), 3.76 (t, J = 5.8 Hz, 2H), 3.11 (t, J = 5.0 Hz, 4H), 2.96 (t, J = 5.8 Hz, 2H).

[0321] Example 34 [ka]

[0322] 1. To a solution of 2-chlorothiazole (0.72 g, 6.00 mmol) in dry THF (50 mL) was added n-BuLi (2.4 M, 2.5 mL, 6 mmol) dropwise at -78 °C under N2. After 0.5 h, a solution of 1 (1.00 g, 5.43 mmol) in dry THF (5 mL) was added dropwise. The reaction was allowed to warm slowly to room temperature. The reaction was quenched with saturated NH4Cl and extracted with EtOAc. The organic extract was washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product, which was purified by silica gel chromatography to give 2 (0.60 g, 36% yield) as a yellow oil. MS (ESI): mass calcd. for C 11 H 10 ClNO3S2303.78, m / z found 304.1 [M+H] + .

[0323] 2. A mixture of 2 (600 mg, 1.97 mmol) and TFA (10 mL) in 3 mL of TES was stirred at 60 °C for 2 h. The mixture was concentrated, and the residue was diluted with saturated NaHCO and extracted with DCM. The combined organic extracts were washed with brine, dried over NaSO, filtered, and concentrated. The resulting residue was purified by silica gel chromatography to give 3 (400 mg, 70.5% yield) as a brown oil. MS (ESI): mass calcd. for C 11 H 10 ClNO2S2287.78, m / z found 288.0 [M+H] + .

[0324] 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): mass calcd. for C23 H 23 N3O4S2469.57, m / z found 469.7 [M+H] + . 1 H NMR (301 MHz, DMSO-d6) δ ppm 7.80 (d, J = 7.5 Hz, 2H), 7.61 (s, 2H), 7.45 (d, J = 7.2 Hz, 1H), 7.37 (s, 1H), 7.19 (d, J = 8.1 Hz, 1H), 7.05 (s, 1H), 4.54 (s, 2H), 4.42 (t, J = 7.8 Hz, 2H), 4.14 (s, 2H), 4..02 (t, J = 7.8 Hz, 2H), 3.64 (t, J = 5.4 Hz, 2H), 3.18 (s, 3H), 2.86 (t, J = 5.1 Hz, 2H).

[0325] Example 35 [ka]

[0326] 1. Following the procedure described in Example 31 using CsCO (488 mg) instead of KCO, intermediate 21 (235 mg) and morpholine (130 mg) were converted to Example 35 (10.6 mg, 4.4%) as a white solid. Mass calcd. for C 26 H 28 N4O3S 476.60, m / z found 476.8 [M+H] + , 1H NMR (400 MHz, DMSO-d6) δ ppm 7.45 (d, J = 6.0 Hz, 1H), 7.37 (s, 1H), 7.23 - 7.12 (m, 2H), 6.98 (s, 1H), 6.84 (s, 1H), 6.79 (d, J = 7.6 Hz, 1H), 6.68 (d, J = 7.6 Hz, 1H), 4.54 (s, 2H), 4.43 (t, J = 7.8 Hz, 2H), 4.03 (t, J = 7.8 Hz, 2H), 3.92 (s, 2H), 3.72 (t, J = 4.6 Hz, 4H), 3.64 (t, J = 6.0 Hz, 2H), 3.08 (t, J = 4.6 Hz, 4H), 2.86 (t, J = 5.8 Hz, 2H).

[0327] Example 36 [ka]

[0328] 1. Following the procedure described for Example 31, using CsCO (371 mg) instead of KCO, intermediate 22 (180 mg) and thiomorpholine 1,1-dioxide (154 mg) were converted to the white solid of Example 36 (9 mg, 4%). Mass calculation for C 26 H 28 N4O4S2524.65, m / z found 524.7 [M+H] + , 1H NMR (300 MHz, DMSO-d6) δ ppm 7.40 (d, J = 8.7 Hz, 1H), 7.32 (s, 1H), 7.14 (d, J = 8.4 Hz, 1H), 7.07 (d, J = 8.3 Hz, 2H), 6.92 (d, J = 4.6 Hz, 3H), 4.50 (s, 2H), 4.39 (t, J = 7.8 Hz, 2H), 3.99 (t, J = 7.8 Hz, 2H), 3.85 (s, 2H), 3.69 (s, 4H), 3.60 (t, J = 5.7 Hz, 2H), 3.07 (s, 4H), 2.83 (s, 2H).

[0329] Alternative Preparation of Example 36

[0330] 1. A mixture of Intermediate 22 (50 g, 0.106 mol), thiomorpholine 1,1-dioxide (71.8 g, 0.531 mol), Pd(OAc) (12 g, 0.053 mol), and SPhos (23.4 g, 0.053 mol) in dry 1,4-dioxane (2.8 L) was stirred with CsCO (43.3 g, 0.133 mol) under N at 100 °C for 6 h. The mixture was diluted with 10:1 DCM:MeOH (1 L), and the resulting suspension was filtered. The filter cake was washed twice with 10:1 DCM:MeOH, and the combined filtrates were concentrated. The resulting residue was dissolved in 200 mL of 10:1 DCM:MeOH, and the mixture was heated to reflux for 30 min. Then, 300 mL of MeOH was added, and the mixture was heated to reflux for 20 min. The suspension was then filtered through Celite. The filtrate was concentrated, and the residue was treated four times as above. After the fourth filtration, the combined filtrates were concentrated to give the crude product as an orange solid, which was slurried twice with MeCN (300 mL) to give Example 36 (25.9 g, 46.4%) as a white solid. MS (ESI): mass calcd. for C 26 H 28 N4O4S2524.65 m / z found 524.8 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ ppm 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).

[0331] Example 37 [ka]

[0332] A mixture of intermediate 5 (225 mg, 0.50 mmol), tetrahydropyrimidin-2(1H)-one (150 mg, 1.50 mmol), Pd(dba) (92 mg, 0.1 mmol), SPhos (82 mg, 0.2 mmol), and t-BuOK (168 mg, 1.5 mmol) in 1,1,4-dioxane (20 mL) was stirred at 100° C. overnight. The mixture was cooled, poured into water, extracted with DCM, dried over NaSO, filtered, and the filtrate was concentrated. The resulting residue was purified by preparative TLC to give Example 37 (3.4 mg, 1.4%) as a white solid. Mass calcd. for C 26 H 26 N6OS 470.60, m / z found 470.8 [M+H] + , 1H NMR (400 MHz, CD3OD) δ ppm 8.20 (d, J=2.8 Hz, 1H), 7.72 (d, J=1.6 Hz, 2H), 7.70 (s, 1H), 7.68 (s, 1H), 7.40 (d, J=8.8 Hz, 2H), 7.20 (d, J=9.2 Hz, 1H), 7.14 (s, 1H), 4.58 (s, 2H), 4.09 (s, 2H), 3.70 (m, 1H), 3.40 (t, J=5.8 Hz, 4H), 2.97 (t, J=5.8 Hz, 2H), 2.1 (t, J=6.0 Hz, 2H).

[0333] The compounds listed in Table 2 below were prepared in a manner similar to that described in Example 37. [ka] [ka]

[0334] Example 38 [ka]

[0335] 1. A solution of Example 37 (30 mg, 0.064 mmol) in dry DMF (3 mL) was cooled to 0° C., NaH (24 mg, 1 mmol) was added, and after 0.5 h, CHCl was added. The reaction was allowed to warm to room temperature and stirred overnight. The mixture was poured into water and extracted with DCM. The extract was dried over NaSO, filtered, and the filtrate was concentrated. The resulting residue was purified by preparative TLC to give Example 38 (10.06 mg, 34.22%) as a white solid. Mass calcd. for C 27 H 28 N6OS 484.62, m / z found 484.8 [M+H] + . 1H NMR (400 MHz, CDCl3) δ = 7.92 (d, J=2.1 Hz, 1H), 7.74 (d, J=1.5 Hz, 1H), 7.66 (d, J=8.5 Hz, 2H), 7.34 (d, J=8.5 Hz, 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=5.8 Hz, 2H), 3.71 - 3.64 (m, 2H), 3.40 (t, J=6.1 Hz, 2H), 2.95 (t, J=5.8 Hz, 2H), 2.13 (dt, J=11.9 Hz, 6.0 Hz, 2H).

[0336] Example 39 [ka]

[0337] 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, the solid was washed with DCM / MeOH (10:1) and water, and the aqueous layer was extracted with DCM / MeOH (10:1). The organic extract was washed with water, brine, dried over NaSO, filtered, and the filtrate was concentrated. The resulting residue was purified by preparative TLC to give Example 39 (8.5 mg, 5.7% yield) as a white solid. MS (ESI): mass calcd. for C 23 H 20 N4O2S 416.50, m / z found 416.8 [M+H] + . 1H NMR (400 MHz, CDCl3) δ ppm 7.59 - 7.53 (m, 2H), 7.50 (d, J=7.9 Hz, 1H), 7.45 (d, J=7.8 Hz, 1H), 7.42 - 7.37 (m, 2H), 7.20 (d, J=9.0 Hz, 1H), 7.00 (s, 1H), 4.64 (s, 2H), 4.51 (dd, J=8.8 Hz, 7.0 Hz, 2H), 4.06 (t, J=8.0 Hz, 4H), 3.75 (t, J=5.9 Hz, 2H), 2.97 (t, J=5.8 Hz, 2H).

[0338] Example 40 [ka]

[0339] 1. Following the procedure described in Example 31 using CsCO (488 mg) instead of KCO, intermediate 21 (235 mg) and oxazolidin-2-one (200 mg) were converted to Example 40 (5 mg, 2%) as a white solid. Mass calculation for C 25 H 24 N4O4S 476.55, m / z found 476.8 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ ppm 7.47 - 7.39 (m, 3H), 7.38 - 7.32 (m, 2H), 7.19 (d, J = 8.4 Hz, 1H), 7.05 (d, J = 7.6 Hz, 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 = 5.6 Hz, 2H), 2.96 (t, J = 5.8 Hz, 2H).

[0340] Example 41 [ka]

[0341] 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 room temperature and then poured into ice water, extracted with C2Cl2, and the extract was dried over Na2SO4. The organic extract was concentrated to give a residue that was purified by silica gel chromatography to give 2 (1.00 g, 53.7% yield) as a yellow solid. MS (ESI): mass calcd. for C9H7N3O 173.18, m / z found 173.8 [M+H] + .

[0342] 2. To a solution of 2-chlorothiazole (762 mg, 6.35 mmol) in dry THF (50 mL) was added n-BuLi (2.4 M, 2.89 mL) dropwise at −78° C. under N2. After 0.5 h, a solution of 2 (1.00 g, 5.77 mmol) in dry THF (10 mL) was added dropwise. The reaction was allowed to warm slowly to room temperature. The mixture was quenched with aqueous NH4Cl and extracted with EtOAc, and the extract was dried over Na2SO4. The organic extract was concentrated to give a residue that was purified by silica gel chromatography to give 3 (800 mg, 47.36% yield) as a white solid. MS (ESI): mass calcd. for C 12 H9ClN4OS 292.74, m / z found 292.8 [M+H] + .

[0343] 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 aqueous NaHCO and extracted with DCM. The extract was dried over NaSO. The extract was concentrated to give the crude product, which was purified by silica gel chromatography to give 4 (400 mg, 52.9% yield) as a white solid. MS (ESI): mass calcd. for C 12H9ClN4S 276.74, m / z found 276.8 [M+H] + .

[0344] 4. To a solution of 4 (400 mg, 1.46 mmol) in DMSO (10 mL) was added 7-bromo-1,2,3,4-tetrahydroisoquinoline (Key Organics, 335 mg, 1.58 mmol) and CsCO (1.54 g, 4.74 mmol). The reaction was stirred at 140 °C for 5 h, cooled to room temperature, poured into ice water, and extracted with DCM. The extract was dried over NaSO and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography to give 5 (300 mg, 45.42% yield) as a white solid. MS (ESI): mass calcd. for C 21 H 18 BrN5S 452.37, m / z found 452.8 [M+H] + .

[0345] 5. A mixture of 5 (300 mg, 0.45 mmol), oxazolidin-2-one (136 mg, 1.36 mmol), Pd(dba) (66 mg, 0.09 mmol), SPhos (92 mg, 0.225 mmol), and t-BuOK (162 mg, 1.35 mmol) in dry 1,4-dioxane was stirred at 100 °C overnight. The mixture was cooled, poured into water, extracted with CHCl, dried over NaSO, filtered, and the filtrate was concentrated to give a residue. The residue was purified by prep-HPLC to give Example 41 (39.6 mg, 19.19%) as a white solid. Mass calcd. for C 24 H 22 N6O2S 458.54, m / z found 458.8 [M+H] + , 1H NMR (400 MHz, DMSO-d6) δ ppm 8.59 (dd, J=2.8, 0.6 Hz ,1H), 8.39 (d, J=1.6 Hz, 1H), 7.90- 7.84(m, 2H), 7.82 - 7.79 (m, 1H), 7.45 (dd, J=8.4 Hz, 2.4, 1H), 7.37 (d, J=2.2 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H), 7.04 (s, 1H), 6.57 (dd, J=2.5 Hz, 1.7 Hz, 1H), 4.56 (s, 2H), 4.43 (dd, J=9.6 Hz, 6.4 Hz, 2H), 4.09 (s, 2H), 4.03 (dd, J=8.4 Hz, 7.0 Hz, 2H), 3.65 (t, J=6.0 Hz, 2H), 2.87 (t, J=6.0 Hz, 2H).

[0346] Example 42 [ka]

[0347] 1. To a solution of Intermediate 5 (225 mg, 0.50 mmol) and morpholin-3-one (171 mg, 1.50 mmol) in dry 1,4-dioxane (15 mL), 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) were added. The resulting solution was stirred in a microwave at 150 °C for 1.5 hours. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated. The resulting residue was purified by preparative TLC to give Example 42 (20.8 mg, 5.6%) as a white solid. Mass calcd. for C 26 H 25 N5O2S 471.58, m / z found 471.8 [M+H] + , 1H NMR (400 MHz, DMSO-d6) δ ppm 8.45 (d, J=2.4 Hz, 1H), 7.77 (d, J=8.8 Hz, 2H), 7.73 (d, J=1.6 Hz, 1H), 7.36 (d, J=8.4 Hz, 2H), 7.25 (s, 1H), 7.21 (s, 2H), 7.02 (s, 1H), 6.53 (t, J = 2.2 Hz, 1H), 4.55 (s, 2H), 4.19 (s, 2H), 4.04 (s, 2H), 3.96 (t, J = 5.0 Hz, 2H), 3.70 (t, J = 5.0 Hz, 2H), 3.66 (t, J=6.0 Hz, 2H), 2.90 (t, J=6.0 Hz, 2H).

[0348] Example 43

change

[0349] 1. In Example 1, it is recorded that the intermediate 20 (357 mg) and the intermediate 31 are recorded in the manual. (270mg), the white solid was replaced by the same as Example 43 (55mg, 13% yield). MS (ESI): mass calcd. for C 23 H 23 N3O4S2469.11, m / z found 69.7 [M+H] + , 1 H NMR (400 MHz, DMSO) δ ppm 7.87 (d, J = 8.3 Hz, 2H), 7.52 (d, J = 8.3 Hz, 2H), 7.45 (dd, J = 8.4, 2.3 Hz, 1H), 7.38 (d, J = 2.0 Hz, 1H), 7.20 (d, J = 8.4 Hz, 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 = 5.9 Hz, 2H), 3.19 (s, 3H), 2.87 (t, J = 5.9 Hz, 2H).

[0350] Example 44 [ka]

[0351] 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 give Example 44 (12 mg, 4% yield) as a white solid. MS (ESI): mass calcd. for C 27 H 27 N5O2S 485.19. m / z found 486.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.46 (d, J = 8.7 Hz, 1H), 7.36 (dd, J = 14.2, 7.2 Hz, 5H), 7.20 (d, J = 8.4 Hz, 1H), 7.05 (s, 1H), 6.97 (s, 1H), 4.56 (s, 2H), 4.44 (t, J = 7.9 Hz, 2H), 4.06 (d, J = 5.5 Hz, 2H), 4.03 (d, J = 7.7 Hz, 2H), 3.66 (t, J = 5.9 Hz, 2H), 2.88 (t, J = 5.6 Hz, 2H), 2.23 (s, 3H), 2.09 (s, 3H).

[0352] Example 45 [ka]

[0353] 1. 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 room temperature for 16 hours. The mixture was concentrated, and the residue was purified by chromatography on silica gel to give 1 (630 mg, 30% yield) as a white solid. MS (ESI): mass calcd. for CH 14 N2O2S 158.20, m / z found 159.0 [M+H] + .

[0354] 2. 1 (245 mg, 1.55 mmol), Intermediate 5 (140 mg, 0.31 mmol), t-BuONa (104 mg, 1.1 mmol), Pd(OAc) (43 mg, 0.19 mmol), and SPhos (78 mg, 0.19 mmol) in 1,4-dioxane (8 mL) were purged with N three times. 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 was concentrated. The resulting residue was purified by chromatography on silica gel to give Example 45 (13 mg, 8% yield) as a white solid. MS (ESI): mass calcd. for C 29 H 32 N6O2S 528.68, m / z found 528.8 [M+H] + . 1 H NMR (400 MHz, DMSO) δ ppm 8.46 (s, 1H), 7.77 (d, J = 8.3 Hz, 2H), 7.72 (s, 1H), 7.36 (d, J = 8.3 Hz, 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 = 5.8 Hz, 1H), 2.01 - 1.96 (m, 2H).

[0355] Example 46

[0356] Example 47 [ka]

[0357] 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 purged with N2 three times and stirred at 130 °C for 3 h. The mixture was cooled to room temperature, diluted with a mixture of DCM / MeOH 20 / 1 (20 mL), filtered, and the filtrate was concentrated and purified by chromatography on silica gel to give the crude product. The crude product was purified by SFC (Chiralpak-1B, CO2-EtOH(DEA)) to give Example 46 (56.38 mg, 17.6% yield) as a white solid. MS (ESI): mass calcd. for C 28 H 31 N5OS 485.65, m / z found 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). Example 47 (15 mg) was also obtained as a yellow / white solid. MS (ESI): mass calculation for C 28 H 31 N5OS 485.65, m / z found 485.9 [M+H] + .1 H NMR (400 MHz, DMSO) δ ppm 7.35 (d, J = 8.2 Hz, 1H), 7.25 (s, 1H), 7.15 (d, J = 7.9 Hz, 1H), 7.10 (d, J = 8.4 Hz, 2H), 6.96 (s, 1H), 6.88 (d, J = 8.5 Hz, 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 = 5.4 Hz, 2H), 2.09 (s, 3H), 1.95 (s, 3H).

[0358] Example 48 [ka]

[0359] 1. Following the procedure described in Example 1, except that the mixture was heated at 100° C. for 2 hours, intermediate 1 (280 mg) and intermediate 6 (403 mg) were converted to a crude product, which was purified by CombiFlash to give 1 (380 mg, 66% yield) as a white solid. MS (ESI): mass calcd. for C 24 H 23 BrN4S 479.4, m / z found 479 [M+H] + .

[0360] 2. A mixture of 1 (240 mg, 0.5 mmol), thiomorpholine 1,1-dioxide (135 mg, 1 mmol), Pd(dba) (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, diluted with EA, washed with water, brine, dried over NaSO, filtered, and concentrated. The resulting residue was purified by prep-HPLC to give Example 48 (50 mg, 22% yield) as a white solid. MS (ESI): mass calcd. for C 28 H31 N5O2S2533.7, m / z found 534 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H), 7.31 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.3 Hz, 1H), 7.12 (d, J = 8.4 Hz, 2H), 6.97 (d, J = 7.4 Hz, 3H), 6.92 (s, 1H), 4.59 (s, 2H), 3.90 (s, 2H), 3.73 (s, 5H), 3.67 (t, J = 5.7 Hz, 2H), 3.11 (s, 4H), 2.94 (t, J = 5.5 Hz, 2H), 2.23 (s, 3H), 2.08 (s, 3H).

[0361] Example 49 [ka]

[0362] 1. Following the procedure described in Example 1, except that the mixture was heated at 100° C. for 5 hours, Intermediate 25 (200 mg) and Intermediate 26 (266 mg) were converted to crude products, which were purified by preparative HPLC to give Example 49 (82.6 mg, 19.20%) as a white solid. Mass calculation for C 27 H 25 N5OS 467.59, m / z found 467.8 [M+H] + , 1H NMR (400 MHz, DMSO-d6) δ ppm 8.90 (d, J=4.8 Hz, 2H), 8.34 (d, J=8.0 Hz, 2H), 7.52 (d, J=8.4 Hz, 1H), 7.42 (m, 4H), 7.17 (d, J=8.4 Hz, 1H), 7.04 (s, 1H), 4.54 (s, 2H), 4.09 (s, 2H), 3.80 (t, J=7.0 Hz, 2H), 3.65 (t, J=5.8 Hz, 2H), 2.86 (t, J=5.4 Hz, 2H), 2.47 (d, J=7.8 Hz, 2H), 2.05 (dt, J=14.7 Hz, 7.3 Hz, 1H).

[0363] Example 50 [ka]

[0364] 1. The mixture was heated at 100° C. for 5 hours and converted to the crude product according to the procedure described in Example 1, except that CsCO (663 mg) was used instead of KCO, Intermediate 25 (235 mg), and Intermediate 24 (200 mg), which was purified by prep-HPLC to give Example 50 (66.2 mg, 20.51%) as a white solid. Mass calcd. for C 27 H 30 N4O2S 474.62, m / z found 474.8 [M+H] + , 1H NMR (400 MHz, DMSO-d6) δ ppm 7.52 (d, J=8.4 Hz, 1H), 7.45 (s, 1H), 7.17 (d, J=8.4 Hz, 1H), 7.09 (d, J=8.4 Hz, 2H), 6.95 (s, 1H), 6.88 (d, J=8.4 Hz, 2H), 4.52 (s, 2H), 3.88 (s, 2H), 3.80 (t, J=7.0 Hz, 2H), 3.73(t, J=7.0 Hz, 4H), 3.63 (t, J=5.8 Hz, 2H), 3.01(t, J=4.6 Hz, 4H), 2.86 (t, J=5.8 Hz, 2H), 2.47 (t, J=4.0 Hz, 2H), 2.09 - 1.99 (m, 2H).

[0365] Example 51 [ka]

[0366] 1. Following the procedure described in Example 1, except that the mixture was heated at 100° C. for 2 hours, intermediate 25 (380 mg) and intermediate 6 (366 mg) were converted to a crude product, which was purified by Combiflash to give 1 (280 mg, 52% yield) as a white solid. MS (ESI): mass calcd. for C 23 H 22 BrN3OS 468.4, m / z found 468 [M+H] + .

[0367] 2. A mixture of 1 (235 mg, 0.5 mmol), thiomorpholine 1,1-dioxide (135 mg, 1 mmol), Pd(dba) (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, diluted with EA, washed with water, brine, dried over NaSO, filtered, and concentrated. The resulting residue was purified by prep-HPLC to give Example 51 (110 mg, 42% yield) as a white solid. MS (ESI): mass calcd. for C 27 H 30 N4O3S2 522.7, m / z found 523 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ ppm 7.51 (d, J = 8.2 Hz, 1H), 7.45 (s, 1H), 7.16 (d, J = 8.3 Hz, 1H), 7.11 (d, J = 8.2 Hz, 2H), 6.99 - 6.93 (m, J = 4.9 Hz, 3H), 4.52 (s, 2H), 3.89 (s, 2H), 3.80 (t, J = 6.9 Hz, 2H), 3.72 (s, 4H), 3.66 - 3.59 (m, 2H), 3.10 (s, 4H), 2.85 (t, J = 5.6 Hz, 2H), 2.47 (d, J = 8.0 Hz, 2H), 2.07 - 1.99 (m, 2H).

[0368] Example 52 [ka]

[0369] 1. Following the procedure described in Example 1, except that the mixture was heated at 100° C. for 4 hours, 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 give 1 (380 mg, 78.7% yield) as a white solid. MS (ESI): mass calcd. for C 23 H 19 BrN4S 463.40, m / z found 462.8 [M+H] + .

[0370] 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 dry 1,4-dioxane (21 mL) was stirred at 100 °C for 6 h. The mixture was diluted with 10:1 DCM:MeOH, filtered, and the filter cake was washed twice with 10:1 DCM:MeOH. The combined filtrate was concentrated, and the residue was purified by flash chromatography to give the product. This was purified by prep-HPLC to give Example 52 (69 mg, 44.2%, 99.1% purity at 214 nm) as a white solid. MS (ESI): mass calcd. for C 27 H 26 N6OS 482.61 m / z found 482.8 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ ppm 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).

[0371] Example 53 [ka]

[0372] 1. A mixture of the product of Example 52, Step 1 (150 mg, 0.324 mmol) and imidazolidin-2-one (139 mg, 1.62 mmol) was treated as described in Example 52, Step 2 to give the crude product, which was purified by flash chromatography. The resulting material was slurried in 1:1 PE:hexane to give Example 53 (54.3 mg, 35.8%, 99.8% purity at 214 nm) as a white solid. MS (ESI): mass calcd. for C 26 H 24 N6OS 468.58 m / z found 468.8 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ ppm 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).

[0373] Example 54 [ka]

[0374] 1. Intermediate 26 (170 mg) and Intermediate 27 (224 mg) were converted to crude products according to the procedure described in Example 1, except that the mixture was heated at 100° C. for 5 hours. The crude products were purified by preparative HPLC to give Example 54 (64.7 mg, 23.35%) as a white solid. Mass calculation for C 27 H 27 N5OS 469.61, m / z found 469.8 [M+H] + , 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.90 (d, J=4.8 Hz, 2H), 8.34 (d, J=7.6 Hz, 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=4.4 Hz, 2H), 3.61 (t, J=5.6 Hz, 2H), 3.05(t, J=4.8 Hz, 4H), 2.79(t, J=5.8 Hz, 2H).

[0375] Example 55 [ka]

[0376] 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 N three times, and the mixture was heated to 120 °C for 16 h. The mixture was cooled to room temperature, diluted with EtOAc, filtered, and the filtrate was concentrated. The resulting residue was purified by chromatography on silica gel to give a mixture of 1 and 2 (1 g, impure) as a brown solid. MS (ESI): mass calcd. for C9H7N3O 173.18, m / z found 174.0 [M+H] + .

[0377] 2. To a mixture of 1 and 2 (1 g, 5.78 mmol) in methanol (10 mL) was added NaBH (330 mg, 8.67 mmol) at 0 °C, and the mixture was warmed to room temperature and stirred for 2 h. The mixture was concentrated, and the residue was purified by silica gel chromatography to give 2 (470 mg, 25% yield) as a white solid. MS (ESI): mass calcd. for C H N O 175.19, m / z found 176.1 [M+H] + .

[0378] 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 room temperature for 30 min, concentrated, and the residue was purified by chromatography on silica gel to give 1 (420 mg, 90% yield) as a white solid. MS (ESI): mass calcd. for C9H7N3O 173.18, m / z found 174.0 [M+H] + .

[0379] 4. n-BuLi (1.32 mL, 3.16 mmol, 2.4 M) was added dropwise to a solution of 2-chlorothiazole (378 mg, 3.16 mmol) in THF (2 mL) at −70° C. under N. 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 warmed to room temperature and stirred overnight. The mixture was quenched with saturated aqueous NH4Cl (20 mL), extracted with EtOAc, the organic extract was washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated. The resulting residue was purified by chromatography on silica gel to give 3 (490 mg, 69% yield) as a pale yellow solid. MS (ESI): mass calcd. for C 12 H9ClN4OS 292.74, m / z found 292.8 [M+H] + .

[0380] 5. To a solution of 3 (490 mg, 1.68 mmol) in DCM (8 mL) was added SOCl (240 mg, 2.01 mmol) dropwise. After stirring for 2 h, the mixture was concentrated to give a pale yellow solid. The solid was dissolved in AcOH (10 mL), Zn powder (546 mg, 8.4 mmol) was added, and the resulting mixture was stirred at room temperature for 1 h, neutralized with saturated aqueous NaHCO and extracted with EtOAc. The organic phase was washed with brine, dried over NaSO, filtered, and the filtrate was concentrated. The resulting residue was purified by chromatography on silica gel to give 4 (350 mg, 75% yield) as a white oil. MS (ESI): mass calcd. for C 12 H9ClN4S 276.74, m / z found 277.0 [M+H] + .

[0381] 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 for 2 h under a nitrogen atmosphere, cooled to room temperature, and 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 the filtrate was concentrated. The resulting residue was purified by preparative TLC to give Example 55 (75 mg, 45.5% yield) as a yellow solid. MS (ESI): mass calcd. for C 24 H 22 N6O2S 458.54, m / z found 458.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.97 (d, J = 2.0 Hz, 1H), 8.60 (d, J = 2.0 Hz, 1H), 8.44 (s, 1H), 8.12 (s, 1H), 7.80 (s, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.36 (s, 1H), 7.18 (d, J = 8.4 Hz, 1H), 7.07 (s, 1H), 6.60 (s, 1H), 4.54 (s, 2H), 4.42 (t, J = 8.0 Hz, 2H), 4.14 (s, 2H), 4.02 (t, J = 8.0 Hz, 2H), 3.64 (t, J = 5.6 Hz, 2H), 2.86 (t, J = 5.6 Hz, 2H).

[0382] Example 56 [ka]

[0383] 1. Following the procedure described in Example 1, except that the mixture was heated at 120° C. for 3 hours, Intermediate 1 (100 mg) and Intermediate 28 (156 mg) were converted to a crude product, which was purified by preparative HPLC to give Example 56 (60 mg, 0.124 mmol, 28% yield) as a white solid. MS (ESI): mass calcd. for C9H9BrO2 485.19, m / z found 485.9 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 7.51 ppm (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 8.7 Hz, 3H), 7.22 (d, J = 8.1 Hz, 1H), 6.96 (s, 1H), 6.93 (s, 1H), 4.63 (s, 2H), 4.47 (t, J = 8.2 Hz, 2H), 4.09 (t, J = 8.0 Hz, 2H), 4.00 (s, 2H), 3.72 (t, J = 5.9 Hz, 2H), 3.03 (t, J = 5.8 Hz, 2H), 2.33 (s, 3H), 2.22 (s, 3H).

[0384] Example 57 [ka]

[0385] 1. Intermediate 29 (135 mg) and Intermediate 28 (100 mg) were converted to a crude product following the procedure described in Example 1, except that the mixture was heated at 120° C. for 2 hours. This was purified by preparative TLC to give Example 57 (35 mg, 35.3% yield) as a white solid. MS (ESI): mass calcd. for C 26 H 27 N5O3S 489.59, m / z found 489.9 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ ppm 7.50-7.45 (m, 3H), 7.32 (s, 1H), 7.25 (d, J = 8.0 Hz, 2H), 7.10 (d, J = 8.4 Hz, 1H), 6.97 (s, 1H), 4.51-4.48 (m, 2H), 4.42 (t, J = 8.0 Hz, 2H), 4.03 (t, J = 8.4 Hz, 2H), 3.96 (s, 2H), 3.74 (t, J = 8.0 Hz, 2H), 3.62 (t, J = 5.6 Hz, 2H), 3.42 (t, J = 8.4 Hz, 2H), 2.82 (t, J = 5.6 Hz, 2H), 2.75 (s, 3H).

[0386] Example 58 [ka]

[0387] 1. Following the procedure described in Example 1, except that the mixture was heated at 120° C. for 3 hours, Intermediate 27 (300 mg) and Intermediate 28 (307 mg) were converted to crude products, which were purified by preparative TLC to give Example 58 (38 mg, 8% yield) as a white solid. MS (ESI): mass calcd. for C 26 H 28 N4O3S, 476.19. m / z found 476.9 [M+H] + , 1H NMR (400 MHz, DMSO-d6) δ ppm 7.49 (d, J = 8.3 Hz, 2H), 7.26 (d, J = 8.4 Hz, 2H), 7.03 (d, J = 8.1 Hz, 1H), 6.97 (s, 1H), 6.80 (d, J = 10.1 Hz, 2H), 4.44 (dd, J = 17.0, 9.1 Hz, 4H), 4.04 (t, J = 7.9 Hz, 2H), 3.97 (s, 2H), 3.78 - 3.64 (m, 4H), 3.60 (t, J = 5.7 Hz, 2H), 3.06 (d, J = 5.1 Hz, 4H), 2.78 (t, J = 5.7 Hz, 2H).

[0388] Example 59 [ka]

[0389] 1. Following the procedure described in Example 1, Intermediate 35 (351 mg) and Intermediate 30 (250 mg) were heated at 130 °C for 2 hours. The mixture was cooled to room temperature, diluted with a mixture of DCM / MeOH 20 / 1 (20 mL), filtered, and the filtrate was concentrated. The resulting residue was purified by chromatography on silica gel to give Example 59 (37.5 mg, 9% yield) as a pale yellow solid. MS (ESI): mass calcd. for C 29 H 34 N4O2S 502.68, m / z found 502.9 [M+H] + . 1H NMR (400 MHz, DMSO) δ ppm 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).

[0390] Example 60 [ka]

[0391] 1. Intermediate 35 (100 mg) and Intermediate 24 (106 mg) were converted to the crude product following the procedure described in Example 1, using Cs2CO3 (313 mg) instead of K2CO3 and heating the mixture at 130 °C for 4 h. It was purified by Prep-TLC to give Example 60 (20 mg, 13% yield) as a white solid. MS (ESI): mass calcd. C 28 H 33 N5O2S 503.24. 1 H NMR (400 MHz, DMSO) δ ppm 7.21 (s, 1H), 7.13 (dd, J = 9.4, 5.6 Hz, 5H), 6.92 (d, J = 8.5 Hz, 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 = 6.0 Hz, 2H), 3.17 - 3.00 (m, 4H), 2.91 (t, J = 5.7 Hz, 2H), 2.85 (s, 3H), 2.18 - 1.93 (m, 2H).

[0392] Example 61 [ka]

[0393] 1. Following the procedure described in Example 1, except that the mixture was heated at 100° C. for 3 hours, Intermediate 35 (170 mg) and Intermediate 31 (200 mg) were converted to a crude product, which was purified by preparative TLC to give Example 61 (27 mg, 8% yield) as a white solid. MS (ESI): mass calcd. for C 25 H 28 N4O3S2, 496.16. m / z found 497.0 [M+H] + , 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.87 (d, J = 8.0 Hz, 2H), 7.52 (d, J = 8.2 Hz, 2H), 7.08 (dd, J = 15.4, 7.2 Hz, 4H), 4.51 (s, 2H), 4.14 (s, 2H), 3.62 (dt, J = 15.4, 5.6 Hz, 4H), 3.32 (d, J = 9.1 Hz, 2H), 3.19 (s, 3H), 2.92 - 2.77 (m, 5H), 2.08 - 1.95 (m, 2H).

[0394] Example 62 [ka]

[0395] 1. Following the procedure described in Example 59, except that the mixture was heated at 130° C. for 4.5 hours, Intermediate 20 (204 mg) and Intermediate 30 (150 mg) were converted to Example 62 (56 mg, 23% yield) as an off-white solid. MS (ESI): mass calcd. for C 27 H 29 N3O3S 475.61, m / z found 475.8 [M+H] + . 1H 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 Example 61 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).

[0396] Example 63 [ka]

[0397] 1. Following the procedure described in Example 31, using CsCO (833 mg) instead of KCO, and purging the vessel with N three times, Intermediate 22 (200 mg) and 3-methoxyazetidine hydrochloride (159 mg) were heated at 100 °C for 5 hours. The mixture was cooled to room temperature, diluted with a mixture (DCM / MeOH, 10 / 1, 20 mL), filtered, and the filtrate was concentrated. The resulting residue was purified by chromatography on silica gel to give Example 63 (35.7 mg, 17.7% yield) as a pale yellow solid. MS (ESI): mass calcd. for C 26 H 28 N4O3S 476.60, m / z found 476.8 [M+H] + . 1H NMR (400 MHz, DMSO) δ ppm 7.45 (d, J = 8.3 Hz, 1H), 7.37 (s, 1H), 7.19 (d, J = 8.7 Hz, 1H), 7.04 (d, J = 8.1 Hz, 2H), 6.93 (s, 1H), 6.38 (d, J = 8.2 Hz, 2H), 4.53 (s, 2H), 4.43 (t, J = 7.8 Hz, 2H), 4.32 - 4.27 (m, 1H), 4.05 - 3.99 (m, 4H), 3.85 (s, 2H), 3.64 (t, J = 5.8 Hz, 2H), 3.55 - 3.52 (m, 2H), 3.23 (s, 3H), 2.86 (t, J = 5.8 Hz, 2H).

[0398] Example 64 [ka]

[0399] 1. Following the procedure described in Example 1, except that the mixture was heated at 130° C. for 3 hours, intermediate 27 (900 mg) and intermediate 6 (1.1 g) were converted to 1 (400 mg, 23% yield) as a yellow solid. MS (ESI): mass calcd. for C 23 H 24 BrN3OS 469.08, m / z found 469.7 [M+H] + .

[0400] 2. A mixture of 1 (150 mg, 0.32 mmol), thiomorpholine 1,1-dioxide (180 mg, 1.3 mmol), Pd(dba) (90 mg, 0.1 mmol), SPhos (80 mg, 0.2 mmol), and t-BuONa (170 mg, 1.8 mmol) in dry 1,4-dioxane (25 mL) was stirred at 100 °C overnight. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated to give a residue that was purified by prep-TLC to give Example 64 (35 mg, 21%) as a white solid. Mass calculation for C 27 H32 N4O3S2524.19, m / z found 524.8 [M+H] + , 1 H NMR (400 MHz, DMSO) δ ppm 7.08 (d, J = 8.4 Hz, 2H), 7.00 (d, J = 8.2 Hz, 1H), 6.94 (d, J = 5.5 Hz, 3H), 6.77 (d, J = 9.1 Hz, 2H), 4.45 (s, 2H), 3.87 (s, 2H), 3.69 (m, 8H), 3.58 (t, J = 5.7 Hz, 2H), 3.04 (m, 8H), 2.76 (t, J = 5.6 Hz, 1H).

[0401] Example 65 [ka]

[0402] 1. A mixture of intermediate 5 (200 mg, 0.44 mol), TEA (134 mg, 1.33 mmol), and Pd(dppf)Cl (32.4 mg, 0.044 mmol) in MeOH (2 mL) and MeCN (1 mL) in a bomb under a CO atmosphere was heated at 100 °C for 24 h. The mixture was filtered through Celite, the filter cake was washed with EA, and the combined filtrate was concentrated to give the crude product, which was purified by silica gel chromatography to give 1 (140 mg, 73.4% yield) as a white solid. MS (ESI): mass calcd. for C 24 H 22 N4O2S 430.53, m / z found 430.8 [M+H] + .

[0403] 2. A mixture of 1 (140 mg, 0.33 mmol), N2H4·H2O (130 mg, 2.60 mmol), EtOH (1 mL), and THF (1 mL) was placed in a bomb and heated at 80 °C for 5 days. The mixture was concentrated to give the crude product, which was purified by silica gel chromatography to give 2 (125 mg, 89.3% yield) as a white solid. MS (ESI): mass calcd. for C 23 H 22 N6OS 430.53, m / z found 430.8 [M+H] + .

[0404] 3. A mixture of 2 (120 mg, 0.28 mmol), trimethyl orthoacetate (132 mg, 0.70 mmol), and NHCl (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 h. The mixture was cooled, and trimethyl orthoacetate (132 mg, 0.70 mmol) and NHCl (4.5 mg, 0.08 mmol) were added, and the mixture was heated at 80 °C for 18 h. The mixture was cooled, and trimethyl orthoacetate (132 mg, 0.70 mmol) and NHCl (4.5 mg, 0.08 mmol) were added, and the mixture was heated at 80 °C for 18 h. The mixture was cooled and concentrated. The resulting residue was purified by preparative HPLC to give Example 65 (30 mg, 23.7% yield, 96.2% purity at 214 nm) as a white solid. MS (ESI): mass calculation for C 25 H 22 N6OS 454.55 m / z found 454.8 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ ppm 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).

[0405] Example 66 [ka]

[0406] 1. A mixture of the hydrochloride salt of Intermediate 1 (55 mg, 0.21 mmol), Intermediate 34 (57.7 mg, 0.21 mmol), Pd(dba) (27.5 mg, 0.03 mmol), SPhos (24.7 mg, 0.06 mmol), and t-BuOK (84 mg, 0.75 mmol) in dry dioxane (4 mL) was stirred at 90 °C under N for 4 hours. The mixture was cooled to room temperature, poured into water, and extracted with EtOAc. The organic layer was washed with water, brine, dried over NaSO, and concentrated to give the crude product, which was purified by prep-HPLC to give Example 66 (1.9 mg, 2% yield) as a white solid. MS Calcd: 467.2; MS Found: 468.3 [M + H] + . 1H NMR (400 MHz, DMSO-d6) δ 2.08 (3H, s), 2.23 (3H, s), 2.96 (2H, t, J = 6.4 Hz),, 3.68 (2H, t, J = 6.0 Hz), 3.95 (2H, s), 4.61 (2H, s), 6.29 (1H, d, J = 1.6 Hz), 6.38 (1H, s), 6.93 (1H, s), 7.22 (1H, d, J = 7.6 Hz), 7.31-7.34 (2H, m), 7.42-7.44 (2H, m), 7.50-7.60 (5H, m).

[0407] Example 67 [ka]

[0408] 1. A mixture of 1 (2.00 g, 16.0 mmol), ethanediol (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 EtO, and the solution was washed with 10% NaHCO. The organic mixture was dried over NaSO, filtered, and the filtrate was evaporated to give 2 (1.45 g, 54%) as a colorless oil.

[0409] 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. Next, 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 room temperature, poured into water, and extracted with EtOAc. The combined organic extracts were washed with water, brine, dried over Na2SO4, and concentrated to give the crude product, which was purified by silica gel chromatography to give 3 (862 mg, 58% yield) as a colorless oil.

[0410] 3. A mixture of 3 (862 mg, 3.97 mmol), CuSO (64.0 mg, 0.40 mmol), HO (5.00 mL), and HCOH (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 KCO. The mixture was extracted with EtOAc. The organic extract was washed with water, brine, dried over NaSO, and concentrated to give the crude product, which was purified by silica gel chromatography to give 4 (320 mg, 46% yield) as a colorless oil.

[0411] 4. To a solution of 2-chlorothiazole (221 mg, 1.85 mmol) in dry 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 dry THF (3 mL) was added dropwise. The resulting solution was allowed to warm slowly to room temperature. The mixture was diluted with NH4Cl solution and extracted with EtOAc. The organic extract was concentrated to give a residue that was purified by silica gel chromatography to give 5 (173 mg, 32% yield) as a yellow oil.

[0412] 5. A mixture of 5 (388 mg, 1.33 mmol), Intermediate 1 hydrochloride (350 mg, 1.33 mmol), Pd(dba) (91.5 mg, 0.1 mmol), SPhos (82.3 mg, 0.2 mmol), and t-BuOK (446 mg, 3.99 mmol) in dry dioxane (6 mL) was stirred at 90 °C for 4 h under N. The mixture was cooled to room temperature, poured into water, and extracted with EtOAc. The organic extract was washed with water, brine, dried over NaSO, and concentrated to give the crude product, which was purified by preparative HPLC to give 6 (170 mg, 26% yield) as a white solid.

[0413] 6. To a solution of 6 (170 mg, 0.35 mmol) in TFA (10 mL) was added TES (3 mL), and the resulting mixture was stirred at 100° C. for 1 h. The mixture was concentrated, and the residue was purified by preparative HPLC to give Example 67 (5.20 mg, 3% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 2.08 (3H, s), 2.22 (3H, s), 2.94 (2H, t, J = 5.6 Hz),, 3.67 (2H, t, J = 5.6 Hz), 4.15 (2H, s), 4.60 (2H, s), 6.60 (1H, t, J = 2.0 Hz), 6.91 (1H, s), 7.08 (1H, s), 7.22 (1H, s), 7.30 (2H, d, J = 8.0 Hz), 7.81 (1H, d, J = 1.2 Hz), 8.13 (1H, s), 8.45 (1H, d, J = 1.6 Hz), 8.60 (1H, d, J = 2.0 Hz), 8.97 (1H, d, J = 2.4 Hz).

[0414] Example 68 [ka]

[0415] 1. Following the procedure described in Example 1, except that CsCO (1.37 mg) was used instead of KCO, the mixture was heated at 110° C. for 2 hours to convert intermediate 6 (400 mg) and intermediate 35 (580 mg) to 1 (600 mg, 85%) as a brown oil. MS (ESI): mass calcd. for C 24 H 25 BrN4OS 496.09. m / z found 496.8 [M+H] + .

[0416] 2. A mixture of 1 (500 mg, 1 mmol), thiomorpholine 1,1-dioxide (405 mg, 3 mmol), Pd(dba)2 (288 mg, 0.5 mmol), SPhos (205 mg, 0.5 mmol), and t-BuONa (290 mg, 3.0 mmol) in dry 1,4-dioxane (30 mL) was stirred at 100 °C overnight. The mixture was cooled to room temperature, filtered, and concentrated. The resulting residue was purified by silica gel chromatography. The resulting material was purified by preparative TLC to give Example 68 (50 mg, 9%) as a white solid. Mass calcd. for C 28 H 33 N5O3S2551.2, m / z found 551.72 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 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, 4H), 3.62 (m, 4H), 3.19 - 3.03 (m, 4H), 2.86 (m, 5H), 2.07 - 1.94 (m, 2H), 1.24 (s, 2H).

[0417] Evaluation of antiviral activity against human cytomegalovirus (HCMV)

[0418] To assess their antiviral activity, several compounds were tested in vitro against human cytomegalovirus (HCMV). Human MRC5 cells were grown to confluency (approximately 1.0 x 10^4 cells / well) in a 96-well plate format in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum (FBS), 2 mM L-glutamine, 0.1 mM non-essential amino acids, 10 mM HEPES, and 100 U / ml each of penicillin and streptomycin. They were infected with an HCMV variant expressing mCherry-tagged pUL99 (the product of the late viral UL99 gene) at a multiplicity of 0.01 infectious units (IU) per cell. Assays were performed in triplicate. After 1 hour, the cell culture medium was replaced with fresh medium containing 25, 12.5, 6.25, 3.13, 1.56, 0.78, or 0.39 μM of the indicated compound or the vehicle (DMSO) in which the compound was dissolved. The final concentration of DMSO was 0.5% for each treatment. Viral yield in the culture was determined 7 days post-infection by quantification of fluorescent (mCherry-positive) cells in each well using a fluorescent microscope. To calculate IC50 values, the results were plotted using CDD Vault (CDD Vault was developed by Collaborative Drug Discovery, Inc., 1633 Bayshore Hwy, Suite 342, Burlingame, CA 94010). Results for compounds tested in this assay are shown in Table 1.

[0419] Evaluation of antiviral activity against influenza

[0420] To evaluate their antiviral activity, several compounds were tested in vitro against mouse-adapted human influenza virus (PR8). Canine MDCK cells were grown in 96-well plate format to confluence (approximately 1.0 x 10^4 cells / well) in Eagle's minimum essential medium (EMEM) supplemented with 10% fetal bovine serum (FBS) and 100 U / ml penicillin and streptomycin. Wells were washed with 1x PBS and infected with a PR8 variant expressing mCherry downstream, cleaved from the NS-1 protein at the 2A autocleavage site, at a multiplicity of 0.01 infectious units (IU) per cell in serum-free EMEM. Tests were performed in triplicate. After 1 hour, the virus-containing medium in the cells was replaced with fresh complete medium containing 25, 12.5, 6.25, 3.13, 1.56, 0.78, or 0.39 μM of compound or vehicle, dissolved in DMSO, and supplemented with 2.5 μg / ml TPCK trypsin. The final DMSO concentration was 0.5% for each treatment. Viral yield in the culture was determined on day 3 postinfection by quantifying fluorescent (mCherry-positive) cells in each well using a fluorescent microscope. To calculate IC50 values, the results were plotted using CDD Vault (CDD Vault was developed by Collaborative Drug Discovery, Inc., 1633 Bayshore Hwy, Suite 342, Burlingame, CA 94010). The results for the compounds tested in this evaluation are shown in Table 1.

[0421] [Table 1-1]

[0422] [Table 1-2]

[0423] [Table 1-3]

[0424] [Table 1-4]

[0425] [Table 1-5]

[0426] [Table 1-6]

[0427] [Table 1-7]

[0428] [Table 1-8]

[0429] [Table 1-9]

[0430] [Table 1-10]

[0431] [Table 1-11] ND = not implemented

[0432] Several 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.

[0433] Other embodiments

[0434] While the present invention has been described in conjunction with its detailed description, it should be understood that the foregoing description is intended to be illustrative and not limiting of the scope of the invention, which is defined by the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

1. below: 【Chemistry 1】 or a pharmaceutically acceptable salt or solvate of said compound.

2. The compound 【Chemistry 2】 2. The compound of claim 1, wherein:

3. The compound 【Transformation 3】 2. The compound of claim 1, wherein:

4. The compound 【Chemistry 4】 2. The compound of claim 1, wherein:

5. The compound 【Transformation 5】 2. The compound of claim 1, wherein:

6. The compound 【Transformation 6】 2. The compound of claim 1, wherein:

7. The compound 【Transformation 7】 2. The compound of claim 1, wherein:

8. 8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lauryl sulfonate, amino acid salts, hydroxide salts, carbonate salts, and bicarbonate salts.

9. 9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt of said compound, or a solvate of said compound, wherein the solvate is a hydrate.

10. A solvate of a compound according to any one of claims 1 to 8.

11. The solvate of claim 10, wherein the solvate is a hydrate.

12. 12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 and / or a solvate according to claim 10 or 11, further comprising a pharmaceutically acceptable carrier.

13. 13. The pharmaceutical composition of claim 12, wherein the pharmaceutically acceptable carrier is selected from the group consisting of saline, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents compatible with pharmaceutical administration.

14. 14. The pharmaceutical composition of claim 12 or 13, formulated to be compatible with its intended route of administration, the route of administration being selected from the group consisting of parenteral, intradermal, subcutaneous, oral, transdermal, transmucosal, and rectal administration.

15. 15. The pharmaceutical composition of claim 14, wherein the route of administration is selected from the group consisting of intravenous administration, inhalation, and topical administration.

16. 16. A pharmaceutical composition according to any one of claims 12 to 15 for use in a method for treating or preventing a viral infection in a subject, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition according to any one of claims 12 to 15.

17. 17. The pharmaceutical composition of claim 16, wherein the viral infection is caused by one or more viruses selected from the group consisting of influenza virus, coronavirus, respiratory syncytial virus (RSV), parainfluenza virus, human cytomegalovirus (HCMV), and adenovirus.

18. 18. The pharmaceutical composition of claim 17, wherein the viral infection is caused by influenza virus and / or human cytomegalovirus (HCMV).

19. 19. The pharmaceutical composition of claim 18, wherein the viral infection is caused by an influenza virus.

20. 19. The pharmaceutical composition of claim 18, wherein the viral infection is caused by human cytomegalovirus (HCMV).

21. 21. The pharmaceutical composition of any one of claims 16 to 20, wherein the subject is a mammal.

22. 22. The pharmaceutical composition of any one of claims 16 to 21, wherein the subject is a primate.

23. 23. The pharmaceutical composition of any one of claims 16 to 22, wherein the subject is a human.

24. 24. The pharmaceutical composition of any one of claims 16 to 23, wherein the route of administration is selected from the group consisting of parenteral administration, intradermal administration, subcutaneous administration, oral administration, transdermal administration, transmucosal administration, and rectal administration.

25. 25. The pharmaceutical composition of claim 24, wherein the route of administration is selected from the group consisting of intravenous administration, inhalation, and topical administration.

26. 26. The pharmaceutical composition of any one of claims 16 to 25, wherein the method further comprises administering a therapeutically effective amount of an antiviral agent.

27. Antiviral agents include acyclovir, docosanol, ribavirin, interferon, cellulose acetate, carbopol, carrageenan, pleconaril, amantadine, fomivirsen, zanamivir, oseltamivir, brivudine, abacavir, adefovir, amprenavir, umifenovir, atazanavir, cidofovir, edoxudine, efavirenz, emtricitabine, enfuvirtide, entecavir, famciclovir, fosamprenavir, foscarnet, fosfonet, ganciclovir, ibacitabine, immunovir, idoxuridine, imiquimod, indinavir, inosine, lamivudine, lopinavir, lovirid, and raltegravir.

27. The pharmaceutical composition of claim 26, wherein the benzodiazepine is selected from the group consisting of benzodiazepine, benzodiazepine, benzocaine ...

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