Compounds with antibacterial activity

Abstract

In one aspect, this document describes compounds and related pharmaceutical compositions for treating various bacterial infections and / or other diseases. For example, in some embodiments, compounds of formula (I) and / or salts thereof are described herein.

Description

[0001] Relevant application data

[0002] Pursuant to Article 8 of the Patent Cooperation Treaty, this application claims priority to U.S. Provisional Patent Application Serial No. 63 / 047,612, filed July 2, 2020, the entire contents of which are incorporated herein by reference.

[0003] Government Rights Statement

[0004] This invention was carried out with government support under approval number DP1AI124669 granted by the National Institutes of Health (NIH) in the United States. The government holds certain rights to this invention. Technical Field

[0005] This invention relates to antibacterial compounds and their modes of action. Background Technology

[0006] The discovery of penicillin in 1929 ushered in a "golden age" of antibiotic discovery, leading to the emergence of more than 20 unique antibiotics in the following 30 years. The discovery and development of these life-saving molecules has since declined dramatically. Since the end of the "golden age" in 1962, only two oral antibiotics with novel targets, linezolid and daptomycin, have been marketed. This decline in antibiotic discovery rates would not be alarming if not for the perpetual evolutionary assault—the continuous selection of antibiotic-resistant bacteria through horizontal gene transfer and spontaneous mutation. In the United States alone, this manifests as a record 2 million antibiotic-resistant infections, resulting in 23,000 deaths annually. Furthermore, it is estimated that such infections cost our health system up to $35 billion annually. Aside from better antibiotic management, which has proven effective in reducing hospital-acquired infection rates, the only way to combat bacterial infections is through the continuous development of antibiotics and other therapies with novel mechanisms of action (MOAs) that are not yet obsolete. Summary of the Invention

[0007] In one aspect, this document describes compounds and related pharmaceutical compositions for treating various bacterial infections and / or other diseases. In some embodiments, for example, compounds of formula (I) and / or salts thereof are provided:

[0008]

[0009] R1, R3, R4, and R5 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylene-aryl, alkylene-heteroaryl, amide, sulfonamide, acid, halogen, and urea, wherein the alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylene-aryl, alkylene-heteroaryl, amide, and sulfonamide are optionally substituted with one or more substituents selected from the group consisting of: (C1-C 10 )-alkyl, (C1-C 10 )-Alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, amide, sulfonamide, urea, halogen, hydroxyl, C(O)OR6 and C(O)R7, wherein R6 is selected from the group consisting of hydrogen, alkyl, and alkenyl, and R7 is selected from the group consisting of hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and NR8R9, wherein R8 and R9 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, and heteroaryl; and

[0010] R2 is selected from the group consisting of arylene-alkynyl, heteroarylene-alkynyl, arylene-alkenyl, heteroarylene-alkenyl, alkynyl-alkyl, alkynyl-cycloalkyl, alkynyl-heterocycloalkyl, alkynyl-aryl, alkynyl-heteroaryl, alkenyl-aryl, alkenyl-heteroaryl, alkynyl-amine, alkynyl-protected amine, and alkynyl-alkylsilane; and

[0011] X and Z are independently chosen from C, N, O, S, SO2, and NR. 10 R 11 The group consisting of R 10 and R 11 Independently selected from hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkenyl, aryl, heteroaryl, amide, sulfonamide, urea, and C(O)R 12 The group consisting of R 12 Selected from the group consisting of hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and R among them. 10 and R 11 Ring structures can be optionally formed; and

[0012] Y is selected from OH and NR. 12 R 13 The group consisting of R 13 and R 14 Independently selected from hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkenyl, aryl, heteroaryl, amide, sulfonamide, urea, and C(O)R 15 The group consisting of R 15 Selected from the group consisting of hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and R among them. 13and R 14 The ring structure can be optionally formed; and n is an integer between 0 and 5.

[0013] In another respect, compounds of formula (II) and / or their salts are provided:

[0014]

[0015] R1, R3, R4, and R5 are independently selected from hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, imine, cyanoimine, alkylene-aryl, alkylene-heteroaryl, amide, sulfonamide, acid, halogen, and urea, wherein the alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylene-aryl, alkylene-heteroaryl, amide, and sulfonamide are optionally substituted with one or more substituents selected from the group consisting of: (C1-C5) 10 )-alkyl, (C1-C 10 )-Alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, amide, sulfonamide, urea, halogen, cyano, hydroxyl, C(O)OR6 and C(O)R7, wherein R6 is selected from the group consisting of hydrogen, alkyl, and alkenyl, and R7 is selected from the group consisting of hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and NR8R9, wherein R8 and R9 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, and heteroaryl; and

[0016] R2 is selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, alkynyl, alkenyl, ynynyl-alkyl, ynynyl-cycloalkyl, ynynyl-heterocycloalkyl, ynynyl-aryl, ynynyl-heteroaryl, ynynyl-amine, ynynyl-protected amine, ynynyl-alkylsilane, fluoroalkyl, fluorinated, brominated, B(OH)2, nitro, cyano, and alkoxy groups; and

[0017] Group A consists of free aryl and heteroaryl groups; and

[0018] X and Z are independently chosen from C, N, O, S, SO2, and NR. 10 R 11 The group consisting of R 10 and R 11 Independently selected from hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkenyl, aryl, heteroaryl, amide, sulfonamide, urea, and C(O)R 12 The group consisting of R 12 Selected from the group consisting of hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and R among them. 10 and R 11 Ring structures can be optionally formed; and

[0019] Y is selected from OH, alkoxy, and NR. 13 R 14 The group consisting of R 13 and R 14 Independently selected from hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkenyl, aryl, heteroaryl, amide, sulfonamide, urea, alkylene-aryl, alkylene-heteroaryl, and C(O)R 15 The group consisting of R 15 Selected from the group consisting of hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and R among them. 13 and R 14 Optionally, a ring structure may be formed, wherein the aryl, heteroaryl, alkylene-aryl, and alkylene-heteroaryl groups are optionally substituted with one or more substituents selected from the group consisting of: alkyl, alkenyl, alkynyl, halogen, and alkynyl-alkylsilane; and

[0020] n is an integer between 0 and 5.

[0021] On the other hand, compounds of formula (III) and / or their salts are provided:

[0022]

[0023] R1–R6 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, amide, sulfonamide, halogen, urea, and -C(O)OR7, where R7 is selected from the group consisting of hydrogen and alkyl. X is independently selected from the group consisting of C, N, O, S, SO2, and NR8R9, where R8 and R9 are independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkenyl, aryl, heteroaryl, amide, sulfonamide, urea, and -C(O)OR7. 10 The group consisting of R 10 The group is selected from the group consisting of hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R8 and R9 may optionally form a ring structure; wherein Y is selected from OH and NR. 11 R 12 The group consisting of R 11 and R 12 Independently selected from hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkenyl, aryl, heteroaryl, amide, sulfonamide, urea and C(O)R 13 The group consisting of R 13 Selected from the group consisting of hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and R among them. 11 and R 12 The ring structure can be optionally formed; n is an integer from 0 to 5.

[0024] On the other hand, compounds of formula (IV) and / or their salts are provided:

[0025]

[0026] R1-R6 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, amide, sulfonamide, halogen, urea, and -C(O)OR7, where R7 is selected from the group consisting of hydrogen and alkyl. X are each independently selected from the group consisting of C, N, O, S, SO2, and NR8R9, where R8 and R9 are independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkenyl, aryl, heteroaryl, amide, sulfonamide, urea, and -C(O)OR7. 10 The group consisting of R 10 The group is selected from the group consisting of hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R8 and R9 may optionally form a ring structure; wherein Y is selected from OH and NR. 11 R 12 The group consisting of R 11 and R 12 Independently selected from hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkenyl, aryl, heteroaryl, amide, sulfonamide, urea and C(O)R 13 The group consisting of R 13 Selected from the group consisting of hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and R among them. 11 and R 12 It may optionally form a ring structure; wherein AA is selected from the group consisting of arylene, heteroarylene, cycloalkylene, and heteroalkylene, and n is an integer from 0 to 5.

[0027] On the other hand, compounds of formula (V) and / or their salts are provided:

[0028]

[0029] R1–R6 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, amide, sulfonamide, halogen, urea, and -C(O)OR7, where R7 is selected from the group consisting of hydrogen and alkyl. X is independently selected from the group consisting of C, N, O, S, SO2, and NR8R9, where R8 and R9 are independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkenyl, aryl, heteroaryl, amide, sulfonamide, urea, and -C(O)OR7. 10 The group consisting of R 10 The group is selected from the group consisting of hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R8 and R9 may optionally form a ring structure; wherein Y is selected from OH and NR. 11 R12 The group consisting of R 11 and R 12 Independently selected from hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkenyl, aryl, heteroaryl, amide, sulfonamide, urea and C(O)R 13 The group consisting of R 13 Selected from the group consisting of hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and R among them. 11 and R 12 The ring structure can be optionally formed; n is an integer from 0 to 5.

[0030] On the other hand, compounds of formula (VI) and / or their salts are provided:

[0031]

[0032] R1-R6 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, amide, sulfonamide, halogen, urea, and -C(O)OR7, where R7 is selected from the group consisting of hydrogen and alkyl. X are each independently selected from the group consisting of C, N, O, S, SO2, and NR8R9, where R8 and R9 are independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkenyl, aryl, heteroaryl, amide, sulfonamide, urea, and -C(O)OR7. 10 The group consisting of R 10 The group is selected from the group consisting of hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R8 and R9 may optionally form a ring structure; wherein Y is selected from OH and NR. 11 R 12 The group consisting of R 11 and R 12 Independently selected from hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkenyl, aryl, heteroaryl, amide, sulfonamide, urea and C(O)R 13 The group consisting of R 13 Selected from the group consisting of hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and R among them. 11 and R 12 It may optionally form a ring structure; wherein AA is selected from the group consisting of arylene, heteroarylene, cycloalkylene, and heteroalkylene, and n is an integer from 0 to 5.

[0033] In a further aspect, compounds of formula (VII) and / or their salts are provided:

[0034]

[0035] R1-R4 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyl-aryl, alkyl-heteroaryl, amide, sulfonamide, and urea, wherein the alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyl-aryl, alkyl-heteroaryl, amide, and sulfonamide are optionally substituted with one or more substituents selected from the group consisting of: (C1-C4) 10 )-alkyl, (C1-C 10 )-Alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, amide, sulfonamide, urea, halogen, hydroxyl, C(O)OR5 and C(O)R6, wherein R5 is selected from the group consisting of hydrogen, alkyl, and alkenyl, and R6 is selected from the group consisting of hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and NR7R8, wherein R7 and R8 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, and heteroaryl; and

[0036] X and Z are independently selected from the groups composed of C, N, and O; and

[0037] Y is selected from OH and NR9R. 10 The group consists of R9 and R 10 Independently selected from hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkenyl, aryl, heteroaryl, amide, sulfonamide, urea, and C(O)R 11 The group consisting of R 11 Selected from the group consisting of hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and R9 and R... 10 A ring structure can be optionally formed;

[0038] n is an integer between 0 and 5.

[0039] On the other hand, this document describes pharmaceutical compositions. The pharmaceutical compositions comprise compounds selected from the group consisting of formulas I-VII, wherein said compounds are present in the pharmaceutical composition at a minimum inhibitory concentration (MIC) for treating bacterial infections. In some embodiments, for example, the compounds are present in the pharmaceutical composition in an amount from 0.0005 μm / ml to 200 μg / ml.

[0040] In another aspect, this document describes a method for treating bacterial infections. In some embodiments, the method includes administering a therapeutically effective amount of one or more compounds of formulas I-VII to a patient with a bacterial infection.

[0041] These and other embodiments are further described in the following detailed description. Detailed Implementation

[0042] The embodiments described herein can be more readily understood by referring to the following detailed description and examples, as well as their preceding and following descriptions. However, the elements, apparatus, and methods described herein are not limited to the specific embodiments presented in the detailed description and examples. It should be understood that these embodiments are merely illustrative of the principles of the invention. Many modifications and adjustments will be apparent to those skilled in the art without departing from the spirit and scope of the invention.

[0043] definition

[0044] As used herein, the term "alkyl," alone or in combination, refers to a straight-chain or branched saturated hydrocarbon group optionally substituted with one or more substituents. For example, an alkyl group can be C1–C 30 or C1–C 18 .

[0045] As used herein, the term "alkenyl," alone or in combination, refers to a straight-chain or branched hydrocarbon group having at least one carbon-carbon double bond and optionally substituted with one or more substituents.

[0046] As used herein, the term "alkynyl" alone or in combination refers to a straight-chain or branched hydrocarbon group having at least one carbon-carbon triple bond and optionally substituted with one or more substituents, including but not limited to alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, amine and / or alkylsilane.

[0047] As used herein, the term "aryl" alone or in combination refers to an aromatic monocyclic or polycyclic system that is optionally substituted with one or more cyclic substituents.

[0048] As used in this article, the term "heteroaryl" refers, alone or in combination, to an aromatic monocyclic or polycyclic ring system in which one or more ring atoms are elements other than carbon, such as nitrogen, oxygen, and / or sulfur.

[0049] As used herein, the term "cycloalkyl" alone or in combination refers to a non-aromatic, monocyclic or polycyclic system optionally substituted with one or more cyclic substituents.

[0050] As used herein, the term "heterocyclic alkyl" refers, alone or in combination, to a non-aromatic, monocyclic or polycyclic cyclic system in which one or more atoms in the cyclic system are elements other than carbon, such as nitrogen, oxygen or sulfur, alone or in combination, and in which the cyclic system is optionally substituted with one or more cyclic substituents.

[0051] As used herein, the term "heteroalkyl" alone or in combination refers to an alkyl moiety as defined above, in which one or more carbon atoms (e.g., one, two, or three carbon atoms) in the chain are replaced by one or more heteroatoms, which may be the same or different, wherein the connection point with the rest of the molecule is a carbon atom via a heteroalkyl radical.

[0052] As used herein, the term "alkoxy" alone or in combination refers to the RO- moiety, where R is an alkyl or alkenyl group as defined above.

[0053] As used in this article, the term "halogen," alone or in combination, refers to elements in Group VIIA of the periodic table. Halogens can be in a neutral or anionic state, depending on their chemical environment. For example, halogens include fluorine, chlorine, bromine, and iodine.

[0054] I. Compounds and pharmaceutical compositions for treating bacterial infections

[0055] This document describes various compounds. As discussed above and further illustrated in the examples below, the compounds may exhibit antibacterial properties in some examples. These compounds may belong to any of the formulas I-VII above.

[0056] Pharmaceutical compositions using such compounds exhibiting antibacterial activity are provided. The compounds and / or salts of formulas I-VII may be administered individually in any amount appropriate for treating bacterial infections. In some embodiments, one or more compounds are administered in amounts or concentrations from 0.0005 μg / ml to 1 mg / ml. Any compound of formulas I-VII may also be administered in amounts or concentrations selected from Table I.

[0057] Table I – Amounts (μg / ml) of compounds of formulas I-VII

[0058] 0.0005-5 0.001-1 0.01-0.5 0.01-0.3 0.1-0.5

[0059] Furthermore, the compounds and / or salts of formulas I-VII can be combined with any physiologically suitable carrier or excipient.

[0060] The amount or concentration of compounds of formulas I-VII used in the pharmaceutical compositions described herein may depend on the identity and / or nature of the bacteria being treated. In some embodiments, the bacteria causing the infection treated with the compounds described herein are Gram-positive. Alternatively, the bacteria causing the infection may be Gram-negative. Furthermore, in some embodiments, two or more different compounds selected from formulas I-VII may be combined for treating bacterial infections. In some embodiments, some compounds of formulas I-VII are effective in treating the bacterial species and strains listed in Table II.

[0061] Table II – Bacterial Strains

[0062]

[0063]

[0064] In some embodiments, for example, one or more compounds belonging to any of formulas I-VII may exhibit a MIC of less than 10 μg / ml or less than 1 μg / ml against bacterial species / strains. Other MICs for bacterial species / strains belonging to one or more of formulas I-VII are provided in Table III.

[0065] MIC (μg / ml) of compounds in Table III–Formulas I–VII against bacterial species

[0066] 0.0005-5 0.001-1 0.01-0.5 0.01-0.3 0.1-0.5

[0067] II. Methods of treating bacterial infections

[0068] In another aspect, this document describes a method for treating bacterial infections. In some embodiments, the method includes administering a therapeutically effective amount of one or more compounds of formulas I-VII to a patient with a bacterial infection. In some embodiments, any compound of formulas I-VII is administered in an amount selected from Table I or Table III described herein. In some embodiments, a combination of any two or more compounds of formulas I-VII can be used to treat bacterial infections. In some embodiments, the bacterial infection treated with the compounds described herein is selected from Table II.

[0069] These and other embodiments are further illustrated in the following non-limiting embodiments.

[0070] Example - Compounds exhibiting antibacterial activity

[0071] Compounds belonging to formulas I-VII are prepared according to the following general reaction scheme. Common solvents are purified before use. All reagents are reagent grade and purified if necessary. The reaction is monitored by thin-layer chromatography (TLC) using Whatman pre-coated silica gel plates. Rapid column chromatography is performed on ultrapure silica gel (200-400 mesh) from Merck. Recordings are performed on a Bruker AVANCE 300 (300MHz), 400MHz, or 500MHz spectrometer. 1 H NMR spectrum. 1 The multiplicity of H NMR is specified as s = singlet, d = doublet, t = triplet, q = quart, quint = quint, sext = sext, dd = doublet of doublet, dt = doublet of triplet, m = multiplicity, and br = width. Electrospray shock (ESI) mass spectra are recorded on an ISQEC mass spectrometer.

[0072]

[0073] NaH (1.2 mmol) was added to a stirred solution of 7H-pyrrolo[3,2-f]quinazoline-1,3-diamine (1.0 mmol) in dry DMF (20 mL). The resulting reaction mixture was stirred at 0 °C for 0.5 h. Then, the corresponding bromide (1.5 mmol) was added. The reaction mixture was stirred at 0 °C for 1 h. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel, eluting with 10:1 DCM: MeOH containing 1% Et3N, to give the desired compound as a solid. The following specific compounds were synthesized according to the above steps.

[0074] Compound 1

[0075]

[0076] 1 H NMR (500MHz, DMSO-d6) δ7.71(d,J=9.0Hz,1H),7.62(d,J=3.0Hz,1H),7.41(d,J=8.0Hz,2H),7.15(d,J=8.0 Hz,2H),7.12(d,J=3.0Hz,1H),7.03(d,J=9.0Hz,1H),6.78(s,2H),5.89(s,2H),5.53(s,2H),4.14(s,1H). MS(ESI):[M+H + ]314.12.

[0077] Compound 2

[0078]

[0079] 1 H NMR(400MHz, DMSO-d6)δ7.92(d,J=9.0Hz,1H),7.85(d,J=3.2Hz,1H),7.65–7.56(m,5H),7.47–7.40(m,2H ),7.37–7.31(m,1H),7.29–7.24(m,2H),7.22–7.11(m,2H),6.74(s,2H),5.60(s,2H),3.84–3.66(m,4H).

[0080] Compound 3

[0081]

[0082] 1H NMR(300MHz,DMSO-d6)δ7.88(d,J=9.0Hz,1H),7.58(d,J=3.3Hz,1H),7.46–7.33(m,5H),7.17–7.06(m,2H),6.70(s,2H),5.72(s,2H),5.43(s,2H)。

[0083] MS(ESI):[M+H+]314.12。

[0084] Compound 4

[0085]

[0086] 1 H NMR(300MHz,DMSO-d6)δ7.80(d,J=9.0Hz,1H),7.52(d,J=3.0Hz,1H),7.43–7.37(m,2H),7.34–7.26(m,2H),7.26–7.22(m,1H),7.08(d,J=3.0Hz,1H),7.05(d,J=9.0Hz,1H),6.67(s,2H),6.52–6.46(m,2H),5.67(s,2H),5.09–5.01(m,2H)。

[0087] MS(ESI):[M+H+]316.15。

[0088] Compound 5

[0089]

[0090] 1 H NMR(300MHz,DMSO-d6)δ7.71(d,J=9.0Hz,1H),7.60(d,J=3.0Hz,1H),7.39–7.25(m,3H),7.13(d,J=7.2Hz,1H),7.08(d,J=3.0Hz,1H),7.02(d,J=9.0Hz,1H),6.97–6.89(m,3H),6.87–6.80(m,2H),6.68(s,2H),5.69(s,2H),5.50(s,2H)。

[0091] MS(ESI):[M+H+]382.12。

[0092] Compound 6

[0093]

[0094] Compound 7

[0095]

[0096] Compound 8

[0097]

[0098] 1 H NMR(500MHz,DMSO-d6)δ7.73(d,J=9.0Hz,1H),7.59(d,J=3.0Hz,1H),7.15(d,J=8.0Hz,2H),7.11(d,J=8.0Hz,2H),7.06(d,J=3.0Hz,1H),7.01(d,J=8.9Hz,1H),6.65(s,2H),5.65(s,2H),5.43(s,2H),2.80(p,J=7.0Hz,1H),1.12(d,J=6.9Hz,6H)。

[0099] MS(ESI):[M+H+]332.42。

[0100] Compound 9

[0101]

[0102] 1 H NMR(300MHz,DMSO-d6)δ7.70(d,J=9.0Hz,1H),7.62(d,J=3.0Hz,1H),7.41(d,J=8.2Hz,2H),7.14(d,J=8.2Hz,2H),7.11(d,J=3.0Hz,1H),7.09(d,J=9.0Hz,1H),6.68(s,2H),6.47–6.30(m,1H),5.53(s,2H),4.16(s,1H),2.84–2.70(m,1H),0.68–0.57(m,2H),0.48–0.39(m,2H)。

[0103] MS(ESI):[M+H+]354.15。

[0104] Compound 10

[0105]

[0106] 1H NMR(500MHz,DMSO-d6)δ8.08(d,J=9.0Hz,1H),7.91(d,J=3.0Hz,1H),7.60(s,2H),7.37(d,J=3.0Hz,1H),7.31–7.24(m,2H),7.21(d,J=9.0Hz,1H),7.18–7.11(m,2H),5.56(s,2H)。

[0107] MS(ESI):[M+H+]308.15。

[0108] Compound 11

[0109]

[0110] 1 H NMR(500MHz,DMSO-d6)δ7.78(d,J=9.0Hz,1H),7.47(d,J=3.0Hz,1H),7.05(d,J=9.0Hz,1H),7.00(d,J=3.0Hz,1H),6.68(s,2H),5.69(s,2H),4.13(d,J=7.5Hz,2H),2.42–2.29(m,1H),1.66–1.58(m,2H),1.58–1.52(m,2H),1.51–1.44(m,2H),1.28–1.20(m,2H)。

[0111] MS(ESI):[M+H+]282.24。

[0112] Compound 12

[0113]

[0114] 1 H NMR(400MHz,DMSO-d6)δ7.92–7.82(m,1H),7.80–7.72(m,1H),7.39–7.31(m,1H),7.25–7.18(m,1H),7.14–7.05(m,2H),7.04–6.96(m,2H),5.55(s,2H)。

[0115] MS(ESI):[M+H+]308.06。

[0116] Compound 13

[0117]

[0118] 1H NMR(400MHz,DMSO-d6)δ7.75(d,J=9.0Hz,1H),7.63(d,J=3.0Hz,1H),7.41–7.34(m,1H),7.34–7.26(m,1H),7.11(d,J=3.0Hz,1H),7.03(d,J=9.0Hz,1H),7.02–6.99(m,1H),6.72(s,2H),5.73(s,2H),5.49(s,2H)。

[0119] MS(ESI):[M+H+]326.10。

[0120] Compound 14

[0121]

[0122] 1 H NMR(400MHz,DMSO-d6)δ7.76(d,J=9.0Hz,1H),7.66(d,J=3.2Hz,1H),7.18–7.09(m,2H),7.05(d,J=9.0Hz,1H),6.90–6.84(m,2H),6.78(s,2H),5.81(s,2H),5.54(s,2H)。

[0123] MS(ESI):[M+H+]326.10。

[0124] Compound 15

[0125]

[0126] 1 H NMR(400MHz,DMSO-d6)δ7.69(d,J=9.0Hz,1H),7.60(d,J=3.2Hz,1H),7.27(d,J=8.0Hz,2H),7.09(d,J=8.0Hz,3H),7.01(d,J=9.0Hz,1H),6.77(s,2H),5.78(s,2H),5.48(s,2H),2.81–2.65(m,1H),1.15(d,J=6.8Hz,6H)。

[0127] MS(ESI):[M+H + ]356.20

[0128] Compound 16

[0129]

[0130] 1 H NMR(500MHz,DMSO-d6)δ7.70(d,J=9.0Hz,1H),7.61(d,J=3.1Hz,1H),7.34–7.29(m,2H),7.29(s,1H),7.18–7.05(m,3H),7.01(d,J=9.0Hz,1H),6.79(s,2H),5.79(s,2H),5.49(s,2H),3.91(d,J=6.0Hz,2H),1.35(s,9H)。

[0131] MS(ESI):[M+H + ]443.53

[0132] Compound 17

[0133]

[0134] 1 H NMR(400MHz,DMSO-d6)δ7.68(m,1H),7.64–7.59(m,1H),7.34–7.26(m,2H),7.15–7.06(m,4H),6.67(s,2H),6.37(s,1H),5.51(s,2H),2.83–2.74(m,1H),1.18(d,J=6.9Hz,6H),0.63(m,2H),0.51–0.37(m,2H)。

[0135] MS(ESI):[M+H + ]396.50

[0136] Compound 18

[0137]

[0138] 1 H NMR(400MHz,DMSO-d6)δ7.73(d,J=9.2Hz,1H),7.69–7.60(m,1H),7.32(d,J=6.4Hz,2H),7.15–7.07(m,4H),5.51(s,2H),2.88–2.72(m,1H),0.86(t,J=6.4Hz,2H),0.64(dd,J=6.4,2.4Hz,2H)。

[0139] MS(ESI):[M+H + ]368.45

[0140] Compound 19

[0141]

[0142] 1 H NMR(400MHz,DMSO-d6)δ7.74(d,J=8.8Hz,1H),7.66(d,J=3.2Hz,1H),7.55–7.49(m,4H),7.42(d,J=3.2Hz,3H),7.20(d,J=8.0Hz,2H),7.15–7.11(m,2H),6.75(s,2H),6.46(s,1H),5.57(s,2H),2.79(m,1H),0.64(m,2H),0.52–0.40(m,2H)。

[0143] MS(ESI):[M+H + ]430.49

[0144] Compound 20

[0145]

[0146] 1 H NMR(400MHz,DMSO-d6)δ7.71(d,J=9.2Hz,1H),7.61(d,J=3.2Hz,1H),7.33–7.26(m,2H),7.16–7.06(m,4H),6.69(s,2H),6.40(s,1H),5.50(s,2H),2.79(m,1H),1.51(m,1H),0.91–0.81(m,4H),0.73–0.59(m,4H)

[0147] MS(ESI):[M+H + ]394.19

[0148] Compound 21

[0149]

[0150] Compound 22

[0151]

[0152] 1H NMR(400MHz,DMSO-d6)δ7.70(d,J=8.8Hz,1H),7.61(d,J=3.2Hz,1H),7.29(d,J=8.0Hz,2H),7.17–7.08(m,3H),7.02(d,J=8.8Hz,1H),6.73(s,2H),5.76(s,2H),5.50(s,2H),1.50(m,1H),0.91–0.79(m,2H),0.72–0.64(m,2H)。

[0153] MS(ESI):[M+H + ]354.46

[0154] Compound 23

[0155]

[0156] 1 H NMR(400MHz,DMSO-d6)δ7.80(d,J=8.8Hz,1H),7.71(d,J=3.2Hz,1H),7.57–7.46(m,4H),7.42(q,J=2.8Hz,3H),7.25–7.16(m,3H),7.08(d,J=8.8Hz,1H),6.13(s,2H),5.58(s,2H)。

[0157] MS(ESI):[M+H + ]390.41

[0158] Compound 24

[0159]

[0160] 1 H NMR(400MHz,DMSO-d6)δ8.06(d,J=9.0Hz,1H),7.93(d,J=3.2Hz,1H),7.67(s,2H),7.47–7.37(m,3H),7.22(dd,J=9.0,2.4Hz,3H),5.64(s,2H),3.98(s,2H)。

[0161] MS(ESI):[M+H + ]343.38

[0162] Compound 25

[0163]

[0164] 1H NMR(400MHz,DMSO-d6)δ7.75(d,J=9.0Hz,1H),7.65(d,J=3.2Hz,1H),7.37–7.26(m,2H),7.17–7.10(m,3H),7.04(d,J=9.0Hz,1H),6.88(s,2H),5.93(s,2H),5.51(s,2H),2.00(s,3H)。

[0165] MS(ESI):[M+H + ]328.37

[0166] Compound 26

[0167]

[0168] 1 H NMR(300MHz,DMSO-d6)δ7.90–7.79(m,4H),7.77(d,J=3.2Hz,1H),7.72(s,1H),7.52–7.43(m,2H),7.33(dd,J=8.5,1.8Hz,1H),7.19(d,J=3.2Hz,1H),7.06(d,J=9.0Hz,1H),6.22(s,2H),5.68(s,2H)。

[0169] MS(ESI):[M+H + ]340.35

[0170] Compound 27

[0171]

[0172] 1 H NMR(500MHz,DMSO-d6)δ7.70(s,1H),7.65(d,J=3.5Hz,1H),7.41–7.34(m,6H),7.31(s,1H),7.23(d,J=3.0Hz,1H),7.14(d,J=8.0Hz,2H),5.86(s,2H),5.51(s,2H),4.83(d,J=6.0Hz,2H),0.95(m,18H),0.59(m,12H)。

[0173] MS(ESI):[M+H + ]657.03

[0174] Compound 28

[0175]

[0176] Compound 29

[0177]

[0178] Compound 30

[0179]

[0180] Compound 31

[0181]

[0182] 1 H NMR(400MHz,DMSO-d6)δ7.79(d,J=9.0Hz,1H),7.65(d,J=3.2Hz,1H),7.13(t,J=3.2Hz,5H),7.05(d,J=9.0Hz,1H),6.92(s,2H),5.98(s,2H),5.46(s,2H),2.55(m,2H),1.12(t,J=7.6Hz,3H)。

[0183] MS(ESI):[M+H + ]318.36

[0184] Compound 32

[0185]

[0186] Compound 33

[0187]

[0188] 1 H NMR(500MHz,DMSO-d6)δ7.71(d,J=9.0Hz,1H),7.60(d,J=3.0Hz,1H),7.41–7.34(m,2H),7.13(d,J=8.2Hz,2H),7.07(d,J=3.0Hz,1H),7.00(d,J=9.0Hz,1H),6.74(s,2H),6.65(dd,J=17.6,11.0Hz,1H),5.81–5.68(m,3H),5.46(s,2H),5.19(dd,J=10.9,1.0Hz,1H)。

[0189] MS(ESI):[M+H + ]316.40

[0190] Compound 34

[0191]

[0192] 1 H NMR(400MHz,DMSO-d6)δ8.22–8.17(m,2H),7.96(d,J=9.0Hz,1H),7.91(d,J=3.2Hz,1H),7.43–7.35(m,3H),7.19(d,J=9.0Hz,1H),7.12(s,2H),5.76(s,2H)。MS(ESI):[M+H+]335.08

[0193] Compound 35

[0194]

[0195] Compound 36

[0196]

[0197] 1 H NMR(400MHz,DMSO-d6)δ7.80(d,J=3.2Hz,1H),7.74(d,J=8.8Hz,1H),7.33–7.23(m,2H),7.19–7.07(m,3H),7.01(d,J=8.8Hz,1H),6.80(s,2H),5.95(q,J=6.8Hz,1H),5.81(s,2H),1.90(d,J=6.8Hz,3H)。

[0198] MS(ESI):[M+H + ]322.32

[0199] Compound 37

[0200]

[0201] Compound 38

[0202]

[0203] 11H NMR (400 MHz, DMSO-d6) δ 9.07 (dd, J = 4.0, 2.0 Hz, 1H), 8.43 (dd, J = 8.4, 2.0 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 8.8 Hz, 1H), 7.73 (d, J = 3.2 Hz, 1H), 7.65 (dd, J = 8.4, 4.4 Hz, 1H), 7.47 (t, J = 8.0 Hz, 1H), 7.16 (d, J = 3.2 Hz, 1H), 7.03 (dd, J = 8.4, 4.4 Hz, 2H), 6.92 (s, 2H), 6.15 (s, 2H), 5.95 (s, 2H).

[0204] MS (ESI): [M+H + 341.33

[0205] Compound 39

[0206]

[0207] 1 1H NMR (400 MHz, DMSO-d6) δ 7.78 (d, J = 8.8 Hz, 1H), 7.37 (d, J = 3.2 Hz, 1H), 7.25–7.14 (m, 2H), 7.12–6.94 (m, 4H), 6.73 (s, 2H), 5.79 (s, 2H), 4.47 (t, J = 7.2 Hz, 2H), 3.08 (t, J = 7.2 Hz, 2H).

[0208] MS (ESI): [M+H + 341.33

[0209] Compound 40

[0210]

[0211] 1 1H NMR (300 MHz, methanol-d4) δ 7.78 (dd, J = 9.1, 0.9 Hz, 1H), 7.66 (d, J = 3.3 Hz, 1H), 7.62–7.55 (m, 2H), 7.41–7.30 (m, 2H), 7.25–7.18 (m, 2H).

[0212] MS (ESI): [M+H + 294.30

[0213] Compound 41

[0214]

[0215] 1 1H NMR (400 MHz, DMSO-d6) δ 7.74 (s, 1H), 7.65 (d, J = 3.2 Hz, 1H), 7.55–7.46 (m, 2H), 7.30–7.20 (m, 2H), 7.20–7.09 (m, 3H), 7.01–6.94 (m, 2H), 6.83 (s, 2H), 5.71 (s, 2H), 5.54 (s, 2H), 3.80 (s, 3H).

[0216] MS (ESI): [M+H + 414.48

[0217] Compound 42

[0218]

[0219] 1 1H NMR (400 MHz, DMSO-d6) δ 8.22–8.13 (m, 1H), 8.12–8.03 (m, 1H), 7.72 (d, J = 9.2 Hz, 1H), 7.66–7.57 (m, 2H), 7.48 (d, J = 3.2 Hz, 1H), 7.24 (d, J = 7.2 Hz, 1H), 7.11 (d, J = 3.2 Hz, 1H), 7.02 (d, J = 9.2 Hz, 1H), 6.70 (s, 2H), 6.68 (s, 1H), 5.97 (s, 2H), 5.70 (s, 2H), 2.62 (s, 3H).

[0220] MS (ESI): [M+H + 354.44

[0221] Compound 43

[0222]

[0223] 1 1H NMR (400 MHz, methanol-d4) δ 8.70 (dd, J = 2.2, 0.8 Hz, 1H), 8.57 (dd, J = 4.8, 1.6 Hz, 1H), 8.04 (dt, J = 8.0, 2.0 Hz, 1H), 7.83 (d, J = 0.8 Hz, 1H), 7.66 (d, J = 3.2 Hz, 1H), 7.56 (m, 1H), 7.29–7.18 (m, 2H), 7.13 (dd, J = 3.2, 0.8 Hz, 1H), 7.10–7.00 (m, 2H), 5.56 (s, 2H).

[0224] MS(ESI):[M+H + ]385.41

[0225] Compound 44

[0226]

[0227] 1 H NMR(400MHz,DMSO-d6)δ8.25(m,2H),7.79–7.70(m,4H),7.55(d,J=3.1Hz,1H),7.17(d,J=3.1Hz,1H),7.03(d,J=8.9Hz,1H),6.76(s,2H),6.54(d,J=7.7Hz,1H),6.04(s,2H),5.76(s,2H)。

[0228] MS(ESI):[M+H + ]418.31

[0229] Compound 45

[0230]

[0231] 1 H NMR(400MHz,DMSO-d6)δ8.24(d,J=2.4Hz,1H),7.99(d,J=8.9Hz,1H),7.82(t,J=5.5Hz,2H),7.47(s,2H),7.25(d,J=3.2Hz,1H),7.15(dd,J=8.9,2.4Hz,2H),6.58(s,2H),5.59(s,2H)。

[0232] MS(ESI):[M+H + ]309.36

[0233] Compound 46

[0234]

[0235] 1 H NMR(400MHz,DMSO-d6)δ8.21(s,1H),7.66(d,J=3.2Hz,1H),7.29–7.20(m,2H),7.20–7.09(m,3H),6.85(s,2H),5.94(s,2H),5.51(s,2H)。

[0236] MS(ESI):[M+H + ]386.21

[0237] Compound 47

[0238]

[0239] 1 ¹H NMR (400 MHz, chloroform-d+MeOD) δ 7.82 (d, J = 1.2 Hz, 1H), 7.30 (d, J = 8.0 Hz, 2H), 7.25–7.23 (m, 1H), 6.90 (d, J = 8.0 Hz, 2H), 6.72 (d, J = 3.2 Hz, 1H), 5.29 (s, 2H), 3.03 (s, 1H).

[0240] MS(ESI):[M+H + 393.25

[0241] Compound 48

[0242]

[0243] 1 H NMR (400MHz, DMSO-d6) δ8.00–7.86(m,2H),7.77(d,J=3.0Hz,1H),7.65(s,1H),7.29(d,J=3.0Hz,1H),7. 15(d,J=8.8Hz,1H),7.09(dd,J=8.0,2.4Hz,1H),6.95(dd,J=8.0,2.4Hz,1H),6.76(s,2H),5.63(s,2H).

[0244] MS(ESI):[M+H + 309.33

[0245] Compound 49

[0246]

[0247] 1 ¹H NMR (400MHz, methanol-d⁴) δ 7.59 (d, J = 4.4 Hz, 2H), 7.27–7.15 (m, 2H), 7.13–6.98 (m, 3H), 5.53 (s, 2H), 2.20 (m, 1H), 1.15–1.03 (m, 2H), 0.76–0.65 (m, 2H).

[0248] MS(ESI):[M+H + 348.45

[0249] Compound 50

[0250]

[0251] 1 ¹H NMR (400MHz, chloroform-d+MeOD) δ 8.35 (d, J = 2.0 Hz, 1H), 7.45 (m 2H), 7.35 (dd, J = 8.4, 2.0 Hz, 1H), 7.28 (s, 1H), 7.03 (d, J = 8.4 Hz, 1H), 6.77 (d, J = 3.2 Hz, 1H), 5.42 (s, 2H).

[0252] MS(ESI):[M+H + 359.30

[0253] Compound 51

[0254]

[0255] 1 H NMR (400MHz, DMSO-d6) δ8.03(m,3H),7.92(d,J=3.2Hz,1H),7.71(d,J=7.6Hz,2H),7.45( s, 2H), 7.38 (d, J = 3.2Hz, 1H), 7.21 (d, J = 8.8Hz, 1H), 7.15 (d, J = 7.6Hz, 2H), 5.59 (s, 2H).

[0256] MS(ESI):[M+H + 334.17

[0257] Compound 52

[0258]

[0259] 1 ¹H NMR (400MHz, methanol-d⁴) δ 7.79 (d, J = 0.8 Hz, 1H), 7.69 (d, J = 3.2 Hz, 1H), 7.56–7.44 (m, 2H), 7.30–7.19 (m, 4H), 7.16 (dd, J = 3.2, 0.8 Hz, 1H), 7.10–7.01 (m, 2H), 5.55 (s, 2H).

[0260] MS(ESI):[M+H + 402.40

[0261] Compound 53

[0262]

[0263] 1 1H NMR (400 MHz, DMSO-d6) δ 8.94 (d, J = 2.0 Hz, 1H), 8.76 (d, J = 2.0 Hz, 1H), 8.18 (d, J = 2.0 Hz, 1H), 7.94 (d, J = 9.0 Hz, 1H), 7.78 (d, J = 3.2 Hz, 1H), 7.23 (d, J = 3.2 Hz, 1H), 7.11 (d, J = 9.0 Hz, 1H), 6.28 (s, 2H), 5.64 (s, 2H).

[0264] MS (ESI): [M+H + 316.31

[0265] Compound 54

[0266]

[0267] 1 1H NMR (400 MHz, methanol-d4) δ 8.11 (d, J = 1.2 Hz, 1H), 7.45 (d, J = 3.2 Hz, 1H), 6.96 (dd, J = 3.2, 0.8 Hz, 1H), 6.27 (d, J = 1.0 Hz, 1H), 5.31 (d, J = 1.0 Hz, 1H), 5.14 (t, J = 1.6 Hz, 2H), 3.79 (s, 3H).

[0268] MS (ESI): [M+H + 376.22

[0269] Compound 55

[0270]

[0271] 1 1H NMR (400 MHz, methanol-d4) δ 7.60 (d, J = 3.2 Hz, 1H), 7.41 (t, J = 3.2 Hz, 1H), 7.19–7.14 (m, 2H), 7.04 (dd, J = 8.8, 3.2 Hz, 2H), 6.95 (t, J = 3.2 Hz, 1H), 5.44 (d, J = 3.2 Hz, 2H), 2.52 (d, J = 3.2 Hz, 3H).

[0272] MS (ESI): [M+H + 322.34

[0273] Compound 56

[0274]

[0275] 1 H NMR(400MHz,DMSO-d6)δ8.16(d,J=5.2Hz,1H),7.71(d,J=9.0Hz,1H),7.66(d,J=3.2Hz,1H),7.18(d,J=3.2Hz,1H),7.05(d,J=9.0Hz,1H),7.00–6.98(m,1H),6.84(d,J=1.5Hz,1H),6.79(s,2H),5.80(s,2H),5.64(s,2H)。

[0276] MS(ESI):[M+H + ]309.36

[0277] Compound 57

[0278]

[0279] 1 H NMR(400MHz,DMSO-d6)δ7.91–7.79(m,3H),7.63(d,J=3.2Hz,1H),7.11(d,J=3.2Hz,1H),7.05(d,J=8.8Hz,1H),6.74(s,2H),5.77(s,2H),5.51(s,2H)。

[0280] MS(ESI):[M+H + ]321.38

[0281] Compound 58

[0282]

[0283] 1 H NMR(400MHz,DMSO-d6)δ8.85(d,J=2.4Hz,1H),8.01(dd,J=8.4,2.4Hz,1H),7.78(d,J=9.2Hz,1H),7.74–7.63(m,3H),7.48(t,J=7.2Hz,2H),7.41(t,J=7.2Hz,1H),7.15(d,J=3.2Hz,1H),7.05(d,J=8.4Hz,2H),6.82(s,2H),5.83(s,2H),5.65(s,2H)。

[0284] MS(ESI):[M+H + ]367.41

[0285] Compound 59

[0286]

[0287] 1 H NMR(400MHz,DMSO-d6)δ8.42(d,J=2.4Hz,1H),7.77(d,J=8.8Hz,1H),7.68–7.54(m,2H),7.13(d,J=3.2Hz,1H),7.04(d,J=8.8Hz,1H),6.92(d,J=8.0Hz,1H),6.87(s,2H),5.91(s,2H),5.55(s,2H),2.88(m,1H),1.17(d,J=6.8Hz,6H)。

[0288] MS(ESI):[M+H + ]333.40

[0289] Compound 60

[0290]

[0291] 1 H NMR(400MHz,DMSO-d6)δ7.92–7.82(m,2H),7.62(d,J=3.2Hz,1H),7.13(d,J=3.2Hz,1H),7.07(d,J=9.2Hz,1H),6.83(s,2H),5.87(s,2H),5.71(s,2H)。

[0292] MS(ESI):[M+H + ]365.33

[0293] Compound 61

[0294]

[0295] 1 H NMR(400MHz,DMSO-d6)δ8.63(dt,J=4.8,1.6Hz,1H),8.06–7.98(m,2H),7.94–7.81(m,2H),7.78(d,J=9.0Hz,1H),7.69(d,J=3.2Hz,1H),7.35–7.25(m,3H),7.15(d,J=3.2Hz,1H),7.05(d,J=9.0Hz,1H),6.85(s,2H),5.93–5.80(m,2H),5.58(s,2H)。MS(ESI):[M+H +]367.41

[0296] Compound 62

[0297]

[0298] 1 H NMR(400MHz,DMSO-d6)δ7.71(d,J=8.8Hz,1H),7.45(d,J=3.2Hz,1H),7.14–6.99(m,2H),6.66(s,2H),6.15(s,1H),5.67(s,2H),5.24(s,1H),5.14(s,2H),3.73(s,3H)。

[0299] MS(ESI):[M+H + ]298.11

[0300] Compound 63

[0301]

[0302] 1 HNMR(400MHz,DMSO-d6)δ8.47–8.25(m,1H),7.91–7.55(m,2H),7.01(m,5H),6.59(s,1H),6.04(s,2H),5.52(s,2H),3.73(s,3H)。

[0303] MS(ESI):[M+H+]321.20。

[0304] Compound 64

[0305]

[0306] 1 H NMR(400MHz,DMSO-d6)δ7.83(s,2H),7.51–7.38(m,2H),7.19–7.11(m,4H),7.08(s,1H),6.55(s,2H),6.29(t,J=6.4Hz,1H),4.29(d,J=6.0Hz,2H)。

[0307] MS(ESI):[M+H + ]284.30

[0308] Compound 65

[0309]

[0310] 1 H NMR(400MHz,DMSO-d6)δ7.70(d,J=9.2Hz,1H),7.51(d,J=3.2Hz,1H),7.11(dd,J=8.0,2.8Hz,2H),7.05(d,J=9.2Hz,1H),6.84(dd,J=8.4,2.4Hz,1H),6.76(s,2H),6.73(d,J=8.4Hz,1H),5.78(s,2H),5.50(s,2H),3.74(s,3H)。

[0311] MS(ESI):[M+H + ]354.79

[0312] Compound 66

[0313]

[0314] 1 H NMR(400MHz,DMSO-d6)δ7.74(dd,J=9.0,0.8Hz,1H),7.62(d,J=3.2Hz,1H),7.13–7.08(m,1H),7.04(d,J=9.0Hz,1H),6.75(s,2H),6.38(t,J=2.4Hz,1H),6.34(d,J=2.4Hz,2H),5.76(s,2H),5.41(s,2H),3.67(s,6H)。

[0315] MS(ESI):[M+H + ]350.34

[0316] Compound 67

[0317]

[0318] 1 H NMR(400MHz,DMSO-d6)δ7.79(dd,J=9.0,0.8Hz,1H),7.69–7.50(m,2H),7.18–7.09(m,1H),7.05(d,J=8.8Hz,1H),6.78(s,2H),6.69(dd,J=8.8,0.8Hz,1H),6.51(dd,J=7.2,0.8Hz,1H),5.80(s,2H),5.49(s,2H),3.82(s,3H)。

[0319] MS(ESI):[M+H + ]321.37

[0320] Compound 68

[0321]

[0322] 1 H NMR(400MHz,DMSO-d6)δ7.67(d,J=9.0Hz,1H),7.62–7.51(m,2H),7.33–7.13(m,2H),7.04(d,J=9.0Hz,1H),6.76(s,2H),6.39(dd,J=7.6,1.2Hz,1H),5.76(s,2H),5.65(s,2H)。

[0323] MS(ESI):[M+H + ]359.21

[0324] Compound 69

[0325]

[0326] 1 H NMR(400MHz,DMSO-d6)δ7.78(d,J=8.8Hz,1H),7.62(d,J=3.0Hz,1H),7.08(d,J=3.0Hz,1H),7.03(d,J=8.8Hz,1H),6.88–6.79(m,2H),6.76–6.73(m,1H),5.96(s,2H),5.76(s,2H),5.38(s,2H)。

[0327] MS(ESI):[M+H + ]334.36

[0328] Compound 70

[0329]

[0330] 1 H NMR(400MHz,DMSO-d6)δ7.71(d,J=8.8Hz,1H),7.55(d,J=3.2Hz,1H),7.43(dd,J=8.8,2.4Hz,1H),7.10(d,J=3.2Hz,1H),7.07–7.01(m,2H),6.79(d,J=2.4Hz,1H),6.73(s,2H),5.75(s,2H),5.42(s,2H),3.87(s,3H)。

[0331] MS(ESI):[M+H+]398.24。

[0332] Compound 71

[0333]

[0334] 1 H NMR (400MHz, DMSO-d6) δ7.83(d,J=9.2Hz,1H),7.64(d,J=3.2Hz,1H),7.09(d,J=3.2Hz,1H),7.04 (d,J=9.2Hz,1H),6.74(s,2H),6.61(s,2H),5.76(s,2H),5.38(s,2H),3.68(s,6H),3.59(s,3H).

[0335] MS(ESI): [M+H+] 398.24

[0336] Compounds 1-71 were then tested to determine their MICs relative to the following five bacterial species / strains: Staphylococcus aureus, NRS384; Enterococcus faecalis, ATCC 51575; Salmonella typhimurium, CMCC 50115; Escherichia coli, ATCCBAA-198; and Acinetobacter baumannii, ATCC 17978. The MIC tests for the compounds were performed according to the following protocol.

[0337] 1. Materials and Reagents

[0338] Laboratory equipment supplier Table of Contents # / Batch # Biosafety cabinet AIRTECH BSC-1604IIA2 Incubator Thermo 371 96-hole V-shaped base plate Axygen WIPP02280 96-hole round bottom plate Corning 3788 Mueller Hinton II Broth (Cation-Regulated) / CAMHB BD 212322 Mueller Hinton II agar (cation-regulated) / CAMHA BD 211438 Dimethyl sulfoxide (DMSO) SIGMA SIGMA-276855-1L NaCl Richjoint Chemical 20151007 Cell density meter Biochrom Ultrospec 10

[0339] 2. Bacterial strain group

[0340] Experimental organisms

[0341] No. strains Strain description NRS 384 Staphylococcus aureus ATCC ATCC 51575 Enterococcus faecalis ATCC CMCC 50115 Salmonella typhimurium CMCC ATCC BAA-198 E. coli ATCC ATCC 17978 Acinetobacter baumannii ATCC

[0342] 2.1. Strain preparation and regulation

[0343] For each test strain, fresh stripes were made on CAMHA from stock glycerol at -80°C.

[0344] 2.2. Culture medium preparation

[0345] CAMHB: Dissolve 22g of powder in 1L of purified water. Mix thoroughly. Autoclave at 121°C for 10 minutes. Store at room temperature (RT) for no more than 1 week.

[0346] Brine: Dissolve 9g of powder in 1L of purified water. Mix thoroughly. Autoclave at 121℃ for 30 minutes. Store at room temperature (RT) for no more than 1 week.

[0347] 2.3. Preparation of Composite Boards

[0348] 2.3.1. Preparation of the stock solution

[0349] Prepare the stock solution of the test compound.

[0350] 2.3.2. Preparation of the mother plate (96-V base plate)

[0351] For compounds:

[0352] a) Dispense 20 μL of the compound into the wells in column 1, and dispense 20 μL of DMSO into the wells in columns 2 through 12;

[0353] b) Dilute the compound by transferring 10 μL of the compound in column 1 to 20 μL of DMSO in column 2; mix with a pipette.

[0354] c) Repeat until column 11 to obtain 3× serial dilutions. Column 12 is the DMSO control.

[0355] 2.4. Preparation of Sub-plate (96-U Base Plate)

[0356] Use a multichannel pipette to deliver 1 μl of diluted compound into each well of the corresponding subplate.

[0357] 2.5. Preparation of inoculum

[0358] Scrape 4-8 single colonies from an agar plate into 5 ml of saline in a 14 ml Falcon conical tube. Vortex the tube to suspend the bacteria. Adjust the turbidity to ~0.2 (corresponding to 0.5 McFarland) using an Ultrospec 10 cell density meter.

[0359] 2.6. Add bacteria

[0360] The bacterial suspension was diluted 200-fold in CAMHB medium and dispensed into sterile containers. Then, using a multichannel pipette, 99 μl of the diluted inoculum was delivered to each well of the corresponding subplate.

[0361] 2.7. Incubation

[0362] Incubate the seed plate at 37°C and 85% humidity for 18-20 hours.

[0363] 2.8. MIC Score

[0364] Read the MIC and record it as the lowest concentration of each reagent that completely inhibits visible microbial growth after incubation. Use a magnifying glass apparatus to score the presence of growth in the wells. Photograph the 96-well microplate.

[0365] The results of the MIC test are provided in Table IV.

[0366] Table IV – Compound MIC (μg / ml)

[0367]

[0368]

[0369] The MICs of compounds 10, 14, 32, 40, 45, and 48 against Pseudomonas aeruginosa PA14 were also determined according to the above scheme. The results are presented in Table V.

[0370] Table V - MIC (μg / ml) against Pseudomonas aeruginosa PA14

[0371] compound Pseudomonas aeruginosa PA14 10 25 14 25 32 8.8 40 45 45 6.3 48 12.5

[0372] Various embodiments of the invention have been described to achieve its various objectives. It should be understood that these embodiments are merely illustrative of the principles of the invention. Many modifications and adaptations thereto will be apparent to those skilled in the art without departing from the spirit and scope of the invention.

Claims

1. Compounds of formula (I) and / or their salts: Wherein R1 is selected from the group consisting of hydrogen and cycloalkyl, R3 is selected from the group consisting of hydrogen and alkyl, R4 is hydrogen, and R5 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and halogen, wherein the aryl group is substituted with one or more substituents selected from the group consisting of: halogen and C(O)R7, wherein R7 is alkyl; and R2 is selected from the group consisting of arylene-alkynyl, heteroarylene-alkynyl, alkynyl-cycloalkyl, alkynyl-aryl, alkynyl-amine, alkynyl-protected amine, and alkynyl-alkylsilane; and Where X and Z are independently C; and Where Y is NR 12 R 13 , where R 12 and R 13 Independently, it is hydrogen; and n is an integer between 0 and 5.

2. The compound and / or its salt according to claim 1, wherein R2 is selected from the group consisting of arylene-alkynyl, heteroarylene-alkynyl, alkynyl-cycloalkyl, and alkynyl-aryl.

3. The compound and / or its salt according to claim 2, wherein R1 and R4 are independently hydrogen.

4. The compound and / or its salt according to claim 2, having the formula: Group A consists of free aryl and heteroaryl groups.

5. The compound and / or its salt according to claim 4, wherein X and Z are each C, and wherein R1, R3 and R4 are independently hydrogen.

6. A pharmaceutical composition comprising a compound of formula (I) and / or its salt: Wherein R1 is selected from the group consisting of hydrogen and cycloalkyl, R3 is selected from the group consisting of hydrogen and alkyl, R4 is hydrogen, and R5 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and halogen, wherein the aryl group is substituted with one or more substituents selected from the group consisting of: halogen and C(O)R7, wherein R7 is alkyl; and R2 is selected from the group consisting of arylene-alkynyl, heteroarylene-alkynyl, alkynyl-cycloalkyl, alkynyl-aryl, alkynyl-amine, alkynyl-protected amine, and alkynyl-alkylsilane; and Where X and Z are independently C; and Where Y is NR 12 R 13 , where R 12 and R 13 Independently, it is hydrogen; and n is an integer between 0 and 5. The compound of formula (I) is present in the pharmaceutical composition in an amount sufficient to exhibit antibacterial properties.

7. The pharmaceutical composition according to claim 6, wherein the compound of formula (I) is present at a minimum inhibitory concentration for bacterial growth of 0.0005 μg / ml to 1 mg / ml.

8. The pharmaceutical composition according to claim 6, wherein the compound of formula (I) is present at a minimum inhibitory concentration for bacterial growth of 0.001 μg / ml to 100 μg / ml.

9. The pharmaceutical composition according to claim 6, wherein the compound of formula (I) is present at a minimum inhibitory concentration for bacterial growth of 0.001 μg / ml to 10 μg / ml.

10. The pharmaceutical composition according to claim 6, wherein R2 is selected from the group consisting of arylene-alkynyl, heteroarylene-alkynyl, alkynyl-cycloalkyl, and alkynyl-heteroarylene.

11. The pharmaceutical composition according to claim 10, wherein R1 and R4 are independently hydrogen.

12. The pharmaceutical composition according to claim 6, wherein the compound has the formula: Group A consists of free aryl and heteroaryl groups.

13. The pharmaceutical composition according to claim 12, wherein X and Z are each C, and wherein R1, R3 and R4 are independently hydrogen.

14. The pharmaceutical composition according to claim 6, which exhibits antibacterial properties against Gram-negative bacteria.

15. The pharmaceutical composition according to claim 8, wherein the bacterial growth is Pseudomonas aeruginosa bacterial growth.

16. A compound having the following formula and / or its salt:

17. A pharmaceutical composition comprising the compound of claim 16 and / or a salt thereof, wherein the compound is present in the pharmaceutical composition in an amount sufficient to exhibit antibacterial properties.

18. The pharmaceutical composition of claim 17, wherein the compound is present at a minimum inhibitory concentration for bacterial growth of 0.0005 μg / ml to 1 mg / ml.

19. The pharmaceutical composition of claim 17, wherein the compound is present at a minimum inhibitory concentration for bacterial growth of 0.001 μg / ml to 100 μg / ml.

20. The pharmaceutical composition of claim 17, wherein the compound is present at a minimum inhibitory concentration for bacterial growth of 0.001 μg / ml to 10 μg / ml.

21. The pharmaceutical composition according to claim 17, which exhibits antibacterial properties against Gram-negative bacteria.

Images