A quinuclidine derivative, its preparation and use

Abstract

The present application relates to the technical field of compound medicine, and in particular to a quinuclidine derivative, a preparation method and application thereof.The quinuclidine derivative of the present application has a structure general formula as shown in formula I.The quinuclidine derivative of the present application has obvious inhibitory effect on PD-1 or PD-L1, and can be used for drug research and development to treat diseases related to the PD-1 or PD-L1 signal pathway, such as cancer, infectious diseases and autoimmune diseases.The present application provides a lead compound and a new active skeleton for drug research and development of diseases related to the PD-1 or PD-L1 signal pathway.

Description

Technical Field

[0001] This invention relates to the field of compound drug technology, and in particular to a quinine ring derivative, its preparation method, and its application. Background Technology

[0002] Programmed cell death 1 (PD-1), also known as CD279, is widely distributed across various immune cells. PD-1 has two ligands, PD-L1 (also known as CD274) and PD-L2 (also known as CD273). PD-L1 is typically expressed on the surface of antigen-presenting cells and various tumor cells. Upon binding to PD-L1, PD-1 releases an inhibitory signal to activated T cells, inducing T cell apoptosis, anergy, and functional exhaustion—that is, T cell impairment. Under normal circumstances, the PD-1 / PD-L1 signaling pathway serves as a negative feedback mechanism of the body's innate immune system, suppressing the pro-inflammatory activity of T cells, thereby promoting self-tolerance and preventing autoimmune responses. However, in various tumor tissues, tumor cells express excessive amounts of PD-L1. This PD-L1, through its interaction with the receptor PD-1, inhibits the response of antigen-specific T cells, thereby enabling tumor immune escape. Therefore, activation of the PD-1 / PD-L1 signaling pathway is an important mechanism for tumor immune escape, while inhibiting the PD-1 / PD-L1 signaling pathway is the key to restoring tumor-specific T cell function.

[0003] Currently, the FDA has approved six drugs targeting PD-1 / PD-L1 inhibitors, all of which are monoclonal antibodies. Monoclonal antibodies targeting PD-1 include Pembrolizumab, Nivolumab, and Cemiplimab. Monoclonal antibodies targeting PD-L1 include Atezolizumab, Durvalumab, and Avelumab. These monoclonal antibody drugs have achieved great success in clinical practice, significantly improving the survival rate of positive-response cancer patients. However, they also suffer from problems unavoidable with large molecule drugs: 1) large molecular weight, resulting in poor oral bioavailability; 2) poor tissue penetration, leading to low efficacy; 3) the potential to cause severe immune-related adverse events (irAEs), and their long half-life makes this situation even more uncontrollable; 4) high production costs and poor stability. Small molecule drugs have numerous advantages that can compensate for the disadvantages of monoclonal antibody drugs, such as inability to be administered orally, slow onset of action, strong immune-related side effects, and high price. Therefore, the development of small molecule inhibitors of PD-1 / PD-L1 has gradually become a research hotspot. CA-170, jointly developed by Aurigene and Curis, has entered Phase II clinical trials, but its structure has not yet been published. Other small molecule inhibitors in preclinical research are mainly microcyclic peptides and benzyloxy-biphenyl derivatives developed by BMS. These two types of small molecules have clearly defined targets, exhibiting nanomolar inhibitory activity at the protein level for PD-1 / PD-L1, and also demonstrating antitumor activity in animals. Although there are thousands of derivatives, none of these two structural types have entered clinical trials, indicating a low likelihood of them becoming drugs. They do not meet the requirements and standards for developing small molecule drugs targeting PD-1 / PD-L1. Therefore, the discovery of novel small molecule scaffolds with certain activity is urgently needed. Summary of the Invention

[0004] To address the aforementioned technical problems, this invention provides a quinine ring derivative, its preparation method, and its application, laying the foundation for future discovery of new PD-1 / PD-L1 lead compounds and new "hot spots" (residues).

[0005] This invention provides a quinine ring derivative with the following general structural formula:

[0006]

[0007] Wherein, R1 is selected from substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted quinolinyl, and the substituted substituent is selected from C1-C8 alkyl and C6-C12 aryl;

[0008] R2 is selected from hydrogen, substituted or unsubstituted C1-C14 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted C1-C14 alkanoyl; the substituted substituent is selected from C3-C8 cycloalkyl, C6-C12 aryl, C3-C12 heteroaryl, C6-C12 aryl substituted by one or more aryl substituents, and C3-C12 heteroaryl substituted by one or more aryl substituents; the aryl substituent is selected from halogen, C1-C6 alkyl, halogen-substituted C1-C8 alkyl, C1-C8 alkoxy, C6-C12 aryloxy, C6-C12 aryl, -O-CH2-CH2-O-;

[0009] R3 is selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, phenyl-substituted C1-C6 alkyl, and phenyl-substituted C2-C6 alkenyl.

[0010] Optionally, the quinine ring derivative may be selected from compounds represented by general formula IA1 or general formula IA2:

[0011]

[0012] R 11 Selected from C1-C8 alkyl and C6-C12 aryl groups; R 21 The substituent is selected from hydrogen, C1-C8 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, substituted C1-C4 alkyl, C1-C6 alkanoyl, and substituted C1-C4 alkanoyl; the substituent is selected from C3-C6 cycloalkyl, C6-C12 aryl, C3-C12 heteroaryl, and C6-C12 aryl substituted by at least one aryl substituent; the aryl substituent is selected from halogen, halogen-substituted C1-C8 alkyl, C1-C6 alkoxy, C6-C12 aryloxy, and substituted C6-C12 aryl.

[0013] Optionally, the quinine ring derivative may be selected from compounds represented by general formula IB:

[0014]

[0015] Among them, R 12 Selected from hydrogen, C1-C8 alkyl, C6-C12 aryl; R 32 Selected from hydrogen, C6-C12 aryl, L is absent or selected from C1-C6 alkylene or C2-C6 alkenylene.

[0016] Optionally, the quinine ring derivative may be selected from compounds represented by general formula IC:

[0017]

[0018] Among them, R 13 Selected from hydrogen, C1-C8 alkyl, C6-C12 aryl; R23 It is selected from hydrogen, C1-C8 alkyl, and C6-C12 aryl.

[0019] This invention also provides a method for preparing quinine ring derivatives, comprising at least the following four methods:

[0020] Method 1:

[0021] Method 2:

[0022] Method 3:

[0023] Method 4:

[0024] This invention also provides the use of the above-mentioned quinine ring derivative in the preparation of medicaments for the prevention or treatment of diseases related to the PD-1 or PD-L1 signaling pathway; diseases related to the PD-1 or PD-L1 signaling pathway include cancer, infectious diseases, and autoimmune diseases; cancers include skin cancer, lung cancer, urinary tract tumors, hematologic malignancies, breast cancer, glioma, digestive system tumors, reproductive system tumors, lymphoma, nervous system tumors, brain tumors, and head and neck cancer; infectious diseases include bacterial infections and viral infections; autoimmune diseases include organ-specific autoimmune diseases and systemic autoimmune diseases; Specific autoimmune diseases include chronic lymphocytic thyroiditis, hyperthyroidism, insulin-dependent diabetes mellitus, myasthenia gravis, ulcerative colitis, pernicious anemia with chronic atrophic gastritis, pulmonary hemorrhage and nephritis syndrome, pemphigus vulgaris, bullous pemphigoid, primary biliary cirrhosis, multiple cerebral sclerosis, and acute idiopathic polyneuritis; systemic autoimmune diseases include systemic lupus erythematosus, rheumatoid arthritis, systemic vasculitis, scleroderma, pemphigus, dermatomyositis, mixed connective tissue disease, autoimmune hemolytic anemia, thyroid autoimmune diseases, and ulcerative colitis.

[0025] The present invention also provides a PD-1 or PD-L1 inhibitor containing at least one of the above-mentioned quinine ring derivatives.

[0026] The technical solution provided by the embodiments of the present invention has the following advantages compared with the prior art:

[0027] The quinine ring derivatives of this invention exhibit significant inhibitory effects on PD-1 or PD-L1, and can be used in drug development to treat diseases related to the PD-1 or PD-L1 signaling pathway, such as cancer, infectious diseases, and autoimmune diseases. This invention provides lead compounds and novel active scaffolds for drug development related to PD-1 or PD-L1 signaling pathway diseases. Detailed Implementation

[0028] To better understand the above-mentioned objectives, features, and advantages of the present invention, the solutions of the present invention will be further described below. It should be noted that, unless otherwise specified, the embodiments of the present invention and the features thereof can be combined with each other. Many specific details are set forth in the following description to provide a thorough understanding of the present invention, but the present invention can also be implemented in other ways different from those described herein; obviously, the embodiments in the specification are only some embodiments of the present invention, and not all embodiments.

[0029] This invention proposes a quinine ring derivative that exhibits significant inhibitory effects on PD-1 or PD-L1, and its general structural formula is shown in Formula I:

[0030]

[0031] Wherein, R1 is selected from substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, or substituted or unsubstituted quinolinyl, and the substituted substituent is selected from C1-C8 alkyl or C6-C12 aryl.

[0032] R2 is selected from hydrogen, substituted or unsubstituted C1-C14 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, and substituted or unsubstituted C1-C14 alkanoyl.

[0033] The substituents are selected from C6-C12 aryl, C3-C12 heteroaryl, C6-C12 aryl substituted with one or more aryl substituents, and C3-C12 heteroaryl substituted with one or more aryl substituents; the aryl substituents are selected from halogens, C1-C6 alkyl, halogen-substituted C1-C8 alkyl, C1-C8 alkoxy, C6-C12 aryloxy, C6-C12 aryl, and -O-CH2-CH2-O-.

[0034] R3 is selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, phenyl-substituted C1-C6 alkyl, and phenyl-substituted C2-C6 alkenyl.

[0035] In general formula I, among the optional substituents of R1, pyridyl is a substituent formed by removing a hydrogen atom from any carbon atom on the pyridine ring, and quinolinyl is a substituent formed by removing a hydrogen atom from any carbon atom on the quinoline ring, preferably substituted on the carbon atom at position 4 of the quinoline ring.

[0036] In general formula I, among the optional substituents of R2, the unsubstituted C1-C14 alkyl group is selected from C1-C14 straight-chain alkyl groups, preferably C1-C12 straight-chain or branched alkyl groups, and more preferably C1-C6 straight-chain or branched alkyl groups; the substituted C1-C14 alkyl group is C1-C6 straight-chain or branched alkylene group, preferably C1-C4 straight-chain alkylene group, and is not limited to methylene or propylene. The C2-C8 alkenyl group is preferably C2-C6 alkenyl group, and is not limited to vinyl or propenyl groups; the C2-C8 alkynyl group is preferably C2-C6 alkenyl group, and is not limited to ethynyl or propynyl groups. The C1-C14 alkylyl group is preferably C1-C8 alkylyl group, more preferably C1-C6 alkylyl group, and is not limited to formyl or acetyl groups. Among the substituted alkyl, alkenyl, alkynyl, and alkylyl groups, the substituents can be selected from C3-C8 cycloalkyl, C6-C12 aryl, C3-C12 heteroaryl, C6-C12 aryl substituted with one or more aryl substituents, and C3-C12 heteroaryl substituted with one or more aryl substituents. C3-C8 cycloalkyl is preferably C3-C6 cycloalkyl, and more preferably cyclopropyl or cyclohexyl. C6-C12 aryl is not limited to phenyl, tolyl, naphthyl, biphenyl, etc., and C3-C12 heteroaryl is an aryl group containing at least one heteroatom, which can be selected from an oxygen atom or a nitrogen atom. C3-C12 heteroaryl includes, but is not limited to, pyridyl, isoxazolyl, quinolinyl, quinoxalinyl, etc. The aryl substituents on C6-C12 aryl and C3-C12 heteroaryl groups can be 0, 1, 2, or 3. The aryl substituent can be selected from halogens, C1-C6 alkyl groups, halogen-substituted C1-C8 alkyl groups, C1-C8 alkoxy groups, C6-C12 aryloxy groups, C6-C12 aryl groups, and -O-CH2-CH2-O- groups. The halogen can be selected from fluorine, chlorine, or bromine, with fluorine or chlorine being preferred. C1-C6 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Halogen-substituted C1-C8 alkyl groups are preferably halogen-substituted C1-C4 alkyl groups, and more preferably fluorine-substituted C1-C4 alkyl groups. Halogen substitution can be partial substitution, such as replacing one hydrogen atom with a halogen, or complete substitution, i.e., replacing all hydrogen atoms on the alkyl group with a halogen. Fluorine-substituted C1-C4 alkyl groups include, but are not limited to, trifluoromethyl and pentafluoroethyl. C1-C8 alkoxy groups can be selected from C1-C6 alkoxy groups, including but not limited to methoxy, ethoxy, n-propoxy, and isopropoxy. The C6-C12 aryl groups can be selected from phenyl, tolyl, or naphthyl. The C6-C12 aryloxy groups can be selected from phenoxy, tolyloxy, or naphthoxy. When the aryl substituent is selected from -O-CH2-CH2-O-, the oxygen atom substitutes for the aryl group or the two adjacent carbon atoms of the aryl group.

[0037] In general formula I, among the optional substituents of R3, when R3 is selected from hydrogen, that is, only one substituent is attached to the quinine ring, R3 can also be selected from C1-C4 alkyl, C2-C4 alkenyl, phenyl-substituted C1-C4 alkyl, phenyl-substituted C2-C4 alkenyl. More preferably, R3 can also be selected from methyl, ethyl, propyl, vinyl, propenyl, butenyl, phenyl-substituted ethyl, phenyl-substituted vinyl.

[0038] As a preferred embodiment of the quinine ring derivative, when R3 is selected from vinyl and R1 is selected from a substituted quinolinyl group, its general structural formula is shown in general formula IA1; when R3 is selected from vinyl and R1 is selected from quinolinyl, its general structural formula is shown in general formula IA2.

[0039]

[0040] R 11 Selected from C1-C8 alkyl and C6-C12 aryl; preferably n-propyl, n-butyl, isobutyl, n-hexyl, and phenyl;

[0041] R 21 The group is selected from hydrogen, C1-C8 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, substituted C1-C4 alkyl, C2-C6 alkanoyl, and substituted C1-C4 alkanoyl; the substituent is selected from C3-C6 cycloalkyl, C6-C12 aryl, C3-C12 heteroaryl, and C6-C12 aryl substituted with at least one aryl substituent; the aryl substituent is selected from halogen, halogen-substituted C1-C8 alkyl, C1-C6 alkoxy, C6-C12 aryloxy, and substituted C6-C12 aryl. Preferably, R 12 The substituent is selected from hydrogen, C1-C10 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, substituted C1-C4 alkyl, C1-C6 alkanoyl, and substituted C1-C4 alkanoyl; the substituent is selected from C3-C6 cycloalkyl, C6-C12 aryl, C3-C12 heteroaryl, and C6-C12 aryl substituted by at least one aryl substituent; the aryl substituent is selected from halogen, halogen-substituted C1-C8 alkyl, C1-C6 alkoxy, C6-C12 aryloxy, and substituted C6-C12 aryl.

[0042] As a preferred embodiment of the quinine ring derivative, according to R 21 Different substitution forms, general formula IA1 can be selected from compounds represented by general formulas IA11, IA12, IA13 or IA14:

[0043]

[0044] In general formula IA11, n is an integer from 1 to 6, and m is an integer from 0 to 5; R' is selected from halogens, perhalogenated C1 to C3 alkyl groups, C1 to C6 alkoxy groups, C6 to C12 aryl groups, C6 to C12 aryl groups, -O-CH2-CH2-O- groups, or R' fused with a benzene ring to form naphthyl, quinolinyl, or quinoxalinyl groups;

[0045] In general formula IA12, R 211 Selected from C1-C8 straight-chain or branched alkyl groups, C3-C6 cycloalkyl-substituted C1-C6 straight-chain or branched alkylene groups, C2-C6 alkenyl groups, and C2-C6 alkynyl groups;

[0046] In general formula IA13, m is an integer from 0 to 4; R' is selected from halogens, perhalogenated C1 to C3 alkyl groups, C1 to C6 alkoxy groups, C6 to C12 aryl groups, C6 to C12 aryl groups, -O-CH2-CH2-O- groups, or benzene rings fused with six-membered heterocycles.

[0047] In general formula IA14, m is an integer from 0 to 2; Z1 and Z2 each independently represent a nitrogen atom or an oxygen atom; R' is selected from C1 to C6 alkoxy, C6 to C12 aryloxy, C6 to C12 aryl, -O-CH2-CH2-O-, or a benzene ring fused with a five-membered heterocycle.

[0048] As a preferred embodiment of the quinine ring derivative, according to R 12 Different substitution forms, the general formula IA2 can be selected from compounds such as those shown in general formula IA21, general formula IA22 or general formula IA23:

[0049]

[0050] R 112 Selected from C2-C6 alkyl and phenyl groups, preferably n-propyl, n-butyl, isobutyl, n-hexyl, and phenyl; R 212 It is selected from C1 to C8 alkyl groups, preferably C1 to C6 alkyl groups.

[0051] As a preferred embodiment of the quinine ring derivative, when R2 is selected from hydrogen and R1 is selected from a substituted quinolinyl group, its structural formula is shown in general formula IB:

[0052]

[0053] R 12 Selected from hydrogen, C1-C8 alkyl, C6-C12 aryl; L is absent or selected from alkylene or alkenylene; R 32 Selected from hydrogen and C6-C12 aryl groups. Preferably, R 12 Selected from hydrogen, C1-C6 alkyl, phenyl; more preferably hydrogen, n-propyl, n-butyl, isobutyl, n-hexyl, phenyl; L is absent or selected from alkylene or alkenyl groups; R32 Selected from hydrogen and phenyl.

[0054] As a preferred embodiment of the quinine ring derivative, the compound represented by general formula IB is based on R... 23 The different compounds can be selected from those shown in general formulas IB1 and IB2:

[0055]

[0056] Among them, R 12 Selected from hydrogen, C1-C8 alkyl, C6-C12 aryl; R 321 Selected from hydrogen, C1-C6 alkyl, C6-C12 aryl, p is an integer from 1 to 4; R 322 Selected from hydrogen and C6-C12 aryl groups. Preferably, R 12 Selected from hydrogen, C1-C6 alkyl, phenyl, more preferably hydrogen, n-propyl, n-butyl, isobutyl, n-hexyl, phenyl; R 321 Selected from hydrogen, C1-C3 alkyl, phenyl, p is an integer from 1 to 4; R 322 Selected from hydrogen and phenyl.

[0057] In a preferred embodiment of the quinine ring derivative, when R2 is selected from an alkyl acyl group, R1 is selected from a substituted or unsubstituted quinolinyl group, and its structural formula is shown in general formula IC:

[0058]

[0059] Among them, R 13 Selected from hydrogen, C1-C8 alkyl, C6-C12 aryl; R 23 Selected from hydrogen, C1-C8 alkyl, and C6-C12 aryl. Preferably, R 13 Selected from hydrogen, C1-C6 alkyl, phenyl; R 23 Selected from hydrogen, C1-C6 alkyl, and phenyl.

[0060] In embodiments of the present invention, C1-C6 alkyl groups are selected from methyl, ethyl, propyl, butyl, isopropyl, isobutyl, tert-butyl, sec-butyl, pentyl, or hexyl; C1-C6 alkoxy groups are selected from methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, or sec-butoxy; C1-C6 alkylyl groups are selected from formyl, acetyl, propionyl, isopropionyl, butyryl, or isobutyryl; and halogens are selected from chlorine, fluorine, bromine, or iodine.

[0061] As a specific embodiment of the quinine ring derivative, the quinine ring derivative is selected from any of the following compounds:

[0062]

[0063]

[0064]

[0065]

[0066] The second aspect of this invention also provides a method for preparing the above-mentioned quinine ring derivative, which includes at least the following steps:

[0067] Method 1: First, react the hydroxyl group in compound A1 with NaH, then react it with a haloalkane (R). 21 X) undergoes affinity substitution to yield compounds of general formula IA1; wherein X represents a halogen and the substituent R 21 The meanings expressed are the same as those in general formulas IA1 and IA2.

[0068]

[0069] Specifically, compound A1 is cincorine. The C-9 hydroxyl group is dehydrogenated using NaH to form a basic sodium alkoxide, with THF as the reaction solvent. Then it reacts with a haloalkane (R... 21 X) undergoes affinity substitution at room temperature or under heating conditions to yield compounds of general formula IA1.

[0070] Method 2: First, react the hydroxyl group of compound A2 with NaH, then perform affinity substitution with a haloalkane to obtain the compound represented by general formula IA2. Where X represents a halogen; the substituent R... 21 The meanings expressed are the same as those in general formulas IA1 and IA2.

[0071]

[0072] Specifically, compound A2 is a C2-substituted cincorine. First, the C-9 hydroxyl group of compound A2 is dehydrogenated using NaH to generate a basic sodium alkoxide, with THF as the reaction solvent. Then, it undergoes affinity substitution with a haloalkane at room temperature to obtain the compound represented by the general formula IA2.

[0073] Method 3: Compound A3 undergoes an affinity addition reaction with alkyllithium, followed by oxidation to yield the compound represented by general formula IB; wherein, the substituent R 12 R 32 The meanings of L and L are the same as in the general formula IB.

[0074]

[0075] Specifically, compound A3 is a substituted cincorine. Alkyl lithium undergoes an affinity addition reaction with the quinoline ring of compound A3. THF is used as the reaction solvent for the addition reaction. After oxidation, a series of C2′-alkyl-substituted derivatives are obtained. Manganese dioxide can be used as the oxidant and dichloromethane as the solvent for the oxidation.

[0076] Method 4: Compounds of formula A4 are obtained by acylation reaction of alkyl chlorides or aryl carboxyl chlorides, and are represented by general formula IC.

[0077]

[0078] This invention also relates to the use of the aforementioned quinine ring derivatives in the preparation of medicaments for the prevention or treatment of diseases related to the PD-1 or PD-L1 signaling pathway; and in the preparation of medicaments for the prevention or treatment of diseases related to the PD-1 / PD-L1 signaling pathway. Diseases related to the PD-1 or PD-L1 signaling pathway include cancer, infectious diseases, and autoimmune diseases; cancers include skin cancer, lung cancer, urinary tract tumors, hematological malignancies, breast cancer, glioma, digestive system tumors, reproductive system tumors, lymphoma, nervous system tumors, brain tumors, and head and neck cancer. Infectious diseases include bacterial infections and viral infections. Autoimmune diseases include organ-specific autoimmune diseases and systemic autoimmune diseases. Organ-specific autoimmune diseases include chronic lymphocytic thyroiditis, hyperthyroidism, insulin-dependent diabetes mellitus, myasthenia gravis, ulcerative colitis, pernicious anemia with chronic atrophic gastritis, pulmonary hemorrhage-nephritis syndrome, pemphigus vulgaris, bullous pemphigoid, primary biliary cirrhosis, multiple cerebral sclerosis, and acute idiopathic polyneuritis; systemic autoimmune diseases include systemic lupus erythematosus, rheumatoid arthritis, systemic vasculitis, scleroderma, pemphigus, dermatomyositis, mixed connective tissue disease, autoimmune hemolytic anemia, thyroid autoimmune diseases, and ulcerative colitis.

[0079] This invention also relates to a PD-1 or PD-L1 inhibitor, which contains at least one of the aforementioned quinine ring derivatives. This inhibitor can be used as a drug for diseases related to the PD-1 or PD-L1 signaling pathway. Specific Implementation

[0081] The invention will be further described below with reference to embodiments, but these do not limit the scope of the invention. All reagents used are commercially available. Instruments used: A Broker DRX 500 NMR spectrometer for nuclear magnetic resonance spectroscopy, and an Aglilent LC / MS-6210 mass spectrometer for mass spectrometry.

[0082] Example 1: (1S,2R,4S,5R)-2-((S)-((2-fluorobenzyl)oxy)(quinoline-4-yl)methyl)-5-vinylquinine

[0083]

[0084] Cinconazole (294 mg, 1.0 mmol, 1.0 eq) was added to a reaction tube under N2 protection. 4 mL of DMF was added, followed by the rapid addition of NaH (100 mg, 2.5 mmol, 2.5 eq, T>15 min), which was 60% dispersed in mineral oil. After stirring at room temperature for 2 h, 1-(bromomethyl)-2-fluorobenzene (189 mg, 1.0 mmol, 1.0 eq) was added, and the mixture was stirred overnight at room temperature. The reaction was quenched with brine, and the mixture was extracted three times with ethyl acetate (EtOAc). The combined organic layers were washed three times with salt, dried over Na2SO4, and evaporated by a rotary evaporator (CH2Cl2:MeOH = 12:1). 326 mg of a pale yellow oil was obtained, with a yield of 81%. 1 H NMR(300MHz, CDCl3)δ8.91(d,J=4.5Hz,1H),8.20–8.11(m,2H),7.78–7.67(m,1H),7.64–7.56(m,1H),7 .56–7.51(m,1H),7.42(td,J=7.4,1.4Hz,1H),7.35–7.28(m,1H),7.14(td,J=7.5,0.8Hz,1H),7.04(t, J=9.4Hz,1H),5.93(ddd,J=17.6,10.4,7.5Hz,1H),5.39(s,1H),5.13–4.86(m,2H),4.60–4.40(m,2H), 3.32–3.18(m,1H),3.14–3.00(m,1H),2.94–2.64(m,3H),2.28–2.17(m,1H),2.11–2.03(m,1H),1.74(br s,1H),1.60–1.35(m,2H),1.33–1.20(m,1H).ESI-MS m / z calcd.for C 26 H 28 FN2O + [M+H]+:403.2,found:403.2.

[0085] Example 2: (1S,2R,4S,5R)-2-((S)-((4-fluorobenzyl)oxy)(quinoline-4-yl)methyl)-5-vinylquinine

[0086]

[0087] Replacing 1-(bromomethyl)-2-fluorobenzene with 1-(bromomethyl)-4-fluorobenzene, the procedure was the same as in Example 1, yielding 301 mg of a pale yellow oil, with a yield of 75.2%. 1 H NMR (500MHz, CDCl3) δ8.92(d,J=4.4Hz,1H),8.19-8.12(m,2H),7.74(ddd,J=8.3,6.9,1.3Hz,1H),7.62–7.56(m,1H),7.51(d,J=4 .3Hz,1H),7.33–7.26(m,2H),7.09–7.00(m,2H),6.02–5.88(m,1H),5.37(bs,1H),5.06–4.94(m,2H),4.45–4.33(m,2H),3.24(br s,1H),3.15–3.06(m,1H),2.93–2.70(m,3H),2.28–2.19(m,1H),2.12–2.03(m,1H),1.77(br s,1H),1.55–1.44(m,2H),1.36–1.28(m,1H).ESI-MS m / z calcd.forC 26 H 28 FN2O + [M+H]+:403.2,found:403.3.

[0088] Example 3: (1S,2R,4S,5R)-2-((S)-((3-fluorobenzyl)oxy)(quinolin-4-yl)methyl)-5-vinylquinine

[0089]

[0090] Replacing 1-(bromomethyl)-3-fluorobenzene with 1-(bromomethyl)-2-fluorobenzene, the procedure was the same as in Example 1, yielding 337 mg of a pale yellow oily substance, with a yield of 83%. 1H NMR(500MHz, CDCl3)δ8.92(d,J=4.4Hz,1H),8.17(dd,J=8.5,0.9Hz,1H),7.77–7.72(m,1H),7.63–7.58(m,1H),7. 51(d,J=4.3Hz,1H),7.35–7.27(m,1H),7.14–7.04(m,1H),7.00(td,J=8.5,2.6Hz,1H),6.04–5.91(m,1H),5.46(br s,1H),5.07-4.99(m,1H),4.51–4.37(m,1H),3.29(s,1H),3.19–3.08(m,1H),3.0 4–2.83(m,1H),2.82–2.71(m,1H),2.32–2.24(m,1H),2.18–2.09(m,1H),1.81(br s,1H),1.60–1.47(m,1H),1.39–

[0091] 1.30(m,1H).ESI-MS m / z calcd.for C 26 H 28 FN2O + [M+H]+:403.2,found:403.3.

[0092] Example 4: (1S,2R,4S,5R)-2-((S)-((2-iodobenzyl)oxy)(quinolin-4-yl)methyl)-5-vinylquinine

[0093]

[0094] Replacing 1-(bromomethyl)-2-iodobenzene with 1-(bromomethyl)-2-fluorobenzene, the procedure was the same as in Example 1, yielding 382 mg of a pale yellow oily substance, with a yield of 75%. 1H NMR(500MHz, CDCl3)δ8.91(d,J=4.4Hz,1H),8.22–8.14(m,2H),7.81(dd,J=7.9,0.8Hz,1H),7.77–7.72(m,1H),7. 63–7.58(m,1H),7.57–7.50(m,2H),7.37(t,J=7.5Hz,1H),7.00(td,J=7.7,1.6Hz,1H),6.05–5.94(m,1H),5.46(br s,1H),5.05-4.98(m,2H),4.49-4.38(m,2H),3.35–3.22(m,1H),3.17–3.09(m,1H), 3.00–2.82(m,2H),2.80–2.70(m,1H),2.30–2.21(m,1H),2.20–2.11(m,1H),1.80(br s,1H),1.59–1.44(m,2H),1.40–1.30(s,1H).ESI-MS m / z calcd.for C 26 H 28 IN2O + [M+H]+:511.1,found:511.2.

[0095] Example 5: (1s,2r,4s,5r)-2-((s)-((2-bromobenzyl)oxy)(quinolin-4-yl)methyl)-5-vinylquinine

[0096]

[0097] Replacing 1-(bromomethyl)-2-bromobenzene with 1-(bromomethyl)-2-fluorobenzene, the procedure was the same as in Example 1, yielding 376 mg of a pale yellow oily substance, with a yield of 81%. 1 H NMR (300MHz, CDCl3) δ8.91(d,J=4.4Hz,1H),8.18(dd,J=8.1,5.0Hz,2H),7.75(t,J=7.1Hz,1H),7.64– 7.51(m,4H),7.34(t,J=7.5Hz,1H),7.18(t,J=7.7Hz,1H),5.99(ddd,J=17.5,9.5,7.2Hz,1H),5.47(br s,1H),5.10–4.93(m,2H),4.58–4.45(m,2H),3.37–3.25(m,1H),3.19-3.08(m,1H),2.97–2.70(m,3H),2.32–2.21(m,1H),2.20–

[0098] 2.09(m,1H),1.80(br s,1H),1.57–1.46(m,2H),1.40–1.29(m,1H).ESI-MS m / zcalcd.for C 26 H 28 BrN2O + [M+H]+:463.1,found:463.1.

[0099] Example 6: (1S2R4S5R)-2-((S)-((3-methoxybenzyl)oxy)(quinoline-4-yl)methyl)-5-vinylquinine

[0100]

[0101] Replacing 1-(bromomethyl)-3-methoxybenzene with 1-(bromomethyl)-2-fluorobenzene, the procedure was the same as in Example 1, yielding 327 mg of a pale yellow oily substance, with a yield of 79%. 1 H NMR (500MHz, CDCl3) δ8.91(d,J=4.4Hz,1H),8.16(dd,J=8.5,0.9Hz,2H),7.74(ddd,J=8.3,6.9,1.2Hz,1H),7.62–7.56(m,1H),7.52(d,J=4.3Hz,1H),7 .28-7.24(m,1H),6.91-6.88(m,2H),6.87–6.83(m,1H),6.04–5.93(m,1H), 5.42(brs,1H),5.05–4.99(m,2H),4.47–4.36(m,2H),3.80(s,3H),3.29(br s,1H),3.16–3.08(m,1H),2.97–2.82(m,2H),2.80–2.70(m,1H),2.30–2.22(m, 1H),2.17–2.08(m,1H),1.78(brs,1H),1.57–1.45(m,2H),1.33(s,1H).ESI-MS m / z calcd.for C 27 H 31 N2O2 + [M+H]+:415.2,found:415.2.

[0102] Example 7: (1S,2R,4S,5R)-2-((S)-((2-methoxybenzyl)oxy)(quinoline-4-yl)methyl)-5-vinylquinine

[0103]

[0104] Replacing 1-(bromomethyl)-2-methoxybenzene with 1-(bromomethyl)-2-fluorobenzene, the procedure was the same as in Example 1, yielding 353 mg of a pale yellow oily substance, with a yield of 85%. 1 H NMR(500MHz, CDCl3)δ8.89(d,J=4.4Hz,1H),8.19–8.13(m,2H),7.73(ddd,J=8.3,6.8,1.3Hz,1H),7.62–7.53(m,2H),7.42(dd,J=7.4, 1.8Hz,1H),7.29(dd,J=7.7,1.8Hz,1H),6.97(td,J=7.5,1.0Hz,1H),6.83(d,J=8.2,1H),5.99(ddd,J=17.6,10.3,7.6Hz,1H),5.44(br s,1H),5.06–4.96(m,2H),4.48(s,2H),3.70(s,3H),3.37(br s,1H),3.11–3.02(m,1H),2.95–2.82(m,2H),2.79–2.71(m,1H),2.27–2.20(m,1H),2.18–2.12(m,1H),1.75(br s,1H),1.57–1.42(m,2H),1.27–1.21(m,1H).ESI-MS m / zcalcd.for C 27 H 31 N2O2 + [M+H]+:415.2,found:415.2.

[0105] Example 8: (1S,2R,4S,5R)-2-((S)-((2-phenoxybenzyl)oxy)(quinoline-4-yl)methyl)-5-vinylquinine

[0106]

[0107] Replacing 1-(bromomethyl)-2-phenoxybenzene with 1-(bromomethyl)-2-fluorobenzene, the procedure was the same as in Example 1, yielding 385 mg of a pale yellow oily substance, with a yield of 81%. 1H NMR(500MHz, CDCl3)δ8.79(d,J=4.4Hz,1H),8.13(dd,J=8.6,1.4Hz,2H),7.74–7.69(m,1H),7.59–7.53(m,2H),7.45(d,J=4.5Hz,1H) ,7.30–7.25(m,3H),7.16(td,J=7.5,1.1Hz,1H),7.10–7.03(m,1H),6.94–6.79(m,3H),5.97(ddd,J=17.5,10.3,7.5Hz,1H),5.43(br s,1H),5.07–4.94(m,2H),4.56–4.46(m,2H),3.36(br s,1H),3.10–3.02(m,1H),2.97–2.81(m,2H),2.80–2.70(m,1H),2.32–2.19(m,1H),2.14–2.06(m,1H),1.74(br s,1H),1.57–1.41(m,2H),1.26–1.16(m,1H).ESI-MS m / z calcd.forC 32 H 33 N2O2 + [M+H]+:477.2,found:477.4.

[0108] Example 9: (1S,2R,4S,5R)-2-((S)-((2,3-dimethoxybenzyl)oxy)(quinoline-4-yl)methyl)-5-vinylquinine

[0109]

[0110] Replacing 1-(bromomethyl)-2,3-dimethoxybenzene with 1-(bromomethyl)-2-fluorobenzene, the procedure was the same as in Example 1, yielding 312 mg of a pale yellow oil, with a yield of 74%. 1H NMR(500MHz, CDCl3)δ8.91(d,J=4.4Hz,1H),8.26–8.13(m,2H),7.73(ddd,J=8.3,6.9,1.2Hz,1H),7.64–7 .56(m,2H),7.10–7.05(m,2H),6.89(dd,J=7.0,2.7Hz,1H),5.94(ddd,J=17.5,10.3,7.5Hz,1H),5.47(br s,1H),5.02–4.95(m,2H),4.49(s,2H),3.86(s,3H),3.72(s,3H),3.45–3.30(m,1H), 3.16–3.08(m,1H),2.94–2.73(m,3H),2.29–2.20(m,1H),2.17–2.05(m,1H),1.76(br s,1H),1.55–1.45(m,2H),1.29–1.22(m,1H).ESI-MS m / z calcd.for C 28 H 33 N2O32 + [M+H]+:445.3,found:445.3.

[0111] Example 10: (1S,2R,4S,5R)-2-((S)-((3,5-dimethoxybenzyl)oxy)(quinoline-4-yl)methyl)-5-vinylquinine

[0112]

[0113] Replacing 1-(bromomethyl)-3,5-dimethoxybenzene with 1-(bromomethyl)-2-fluorobenzene, the procedure was the same as in Example 1, yielding 337 mg of a pale yellow oily substance, with a yield of 76%. 1H NMR (500MHz, CDCl3) δ8.91 (d, J=4.5Hz, 1H), 8.19–8.10 (m, 1H), 7.73 (ddd, J=8.4, 6.9, 1.3Hz, 1H), 7.57 (ddd, J=8.2, 6.9, 1. 3Hz,1H),7.52(d,J=4.4Hz,1H),6.46(d,J=2.3Hz,2H),6.40(t,J=2.3Hz,1H),6.02(ddd,J=17.5,10.3,7.6Hz,1H),5.33(br s,1H),5.07–4.99(m,2H),4.45–4.30(m,2H),3.77(s,6H),3.30–3.20(m,1H),3.16– 3.06(m,1H),2.98–2.79(m,2H),2.78–2.67(m,1H),2.28–2.20(m,1H),2.16–2.07(m,

[0114] 1H),1.77(s,1H),1.57–1.44(m,2H),1.40–1.30(m,1H).ESI-MS m / z calcd.forC 28 H 33 N2O3 + [M+H]+:445.3,found:445.3.

[0115] Example 11: (1S,2R,4S,5R)-2-((S)-((2-fluoro-6-methoxybenzyl)oxy)(quinoline-4-yl)methyl)-5-vinylquinine

[0116]

[0117] Replacing 1-(bromomethyl)-2-fluorobenzene with 2-(bromomethyl)-1-fluoro-3-methoxybenzene, the procedure was the same as in Example 1, yielding 371 mg of a pale yellow oil, with a yield of 86%. 1H NMR (500MHz, CDCl3) δ8.89 (d, J=4.5Hz, 1H), 8.20–8.10 (m, 2H), 7.73 (ddd, J=8.3, 6.8, 1.4Hz, 1H), 7.59 (ddd, J=8.4, 6.8, 1.3Hz, 1H), 7.52 (d, J=4.4Hz,1H),7.29–7.24(m,1H),6.94(ddd,J=8.8,8.1,3.2Hz,1H),6.72(dd,J=9.0,4.3Hz,1H),6.02(ddd,J=17.4,10.5,7.3Hz,1H),5.43(br s,1H),5.09–5.0(m,2H),4.50–4.37(m,2H),3.66(s,3H),3.37–3.27(m,1H),3.13-3.05(m ,1H),2.97–284(m,2H),2.80–2.71(m,1H),2.31–2.22(m,1H),2.20–2.12(m,1H),1.79(br s,1H),1.59–1.43(m,2H),1.34–1.25(m,

[0118] 1H). ESI-MS m / z calcd. for C 27 H 30 FN2O2 + [M+H]+:433.2,found:433.2.

[0119] Example 12: (1S,2R,4S,5R)-2-((S)-((2-fluoro-3-methoxybenzyl)oxy)(quinoline-4-yl)methyl)-5-vinylquinine

[0120]

[0121] Replacing 1-(bromomethyl)-2-fluorobenzene with 2-(bromomethyl)-1-fluoro-6-methoxybenzene, the procedure was the same as in Example 1, yielding 345 mg of a pale yellow oily substance in 80% yield. 1H NMR (500MHz, CDCl3) δ8.91 (d, J = 4.4Hz, 1H), 8.19–8.14 (m, 2H), 7.76–7.70m 1H),7.62–7.53(m,1H),7.55(d,J=4.5Hz,1H),7.06(td,J=7.9,1.4Hz,1H),7.02–6. 96(m,1H),6.93(td,J=8.1,1.7Hz,1H),5.94(ddd,J=17.6,10.3,7.5Hz,1H),5.42(br s,1H),5.05–4.93(m,2H),4.56–4.45(m,2H),3.32–3.21(m,1H),3.13–3.04(m,1H), 2.96–2.81(m,2H),2.79-2.69(m,1H),2.26–2.19(m,1H),2.12–2.04(m,1H),1.75(br s,1H),1.57–1.42(m,2H),1.33–1.21(m,1H).ESI-MS m / z calcd.for C 27 H 30 FN2O2 +

[0122] [M+H]+:433.2,found:433.2.

[0123] Example 13: (1S,2R,4S,5R)-2-((S)-((4-fluoro-3-methoxybenzyl)oxy)(quinoline-4-yl)methyl)-5-vinylquinine

[0124]

[0125] Replacing 1-(bromomethyl)-2-fluorobenzene with 4-(bromomethyl)-1-fluoro-2-methoxybenzene, the procedure was the same as in Example 1, yielding 341 mg of a pale yellow oil, with a yield of 79.0%. 1H NMR (500MHz, CDCl3) δ8.92 (d, J = 4.4Hz, 1H), 8.20-8.12 (m, 2H), 7.74 (t, J = 7.6Hz, 1H), 7. 59(t,J=7.6Hz,1H),7.51(d,J=4.3Hz,1H),7.04(dd,J=11.2,8.2Hz,1H),6.92(dd,J=8.2 ,1.6Hz,1H),6.81(ddd,J=8.0,4.2,1.8Hz,1H),6.04–5.90(m,1H),5.41(s,1H),5.08–4. 97(m,2H),4.42(d,J=11.4Hz,1H),4.35(d,J=11.4Hz,1H),3.85(d,J=4.0Hz,3H),3.28(br s,1H),3.15–3.08(m,1H),2.98–2.83(m,2H),2.81–2.70(m,1H),2.31–2.21(m,1H),2.14–2.04(m,1H),1.78(br s,1H),1.59–1.45(m,2H),1.38–1.29(m,1H).ESI-MS m / z calcd.for C 27 H 30 FN2O2 + [M+H]+:433.2,found:433.2.

[0126] Example 14: (1S,2R,4S,5R)-2-((S)-(benzo[d][1,3]dioxy-5-ylmethoxy)(quinoline-4-yl)methyl)-5-vinylquinine

[0127]

[0128] Replacing 1-(bromomethyl)-2-fluorobenzene with 5-(bromomethyl)benzo[d][1,3]dioxo, the procedure was the same as in Example 1, yielding 364 mg of a pale yellow oil, with a yield of 85%. 1H NMR (500MHz, CDCl3) δ8.91(d,J=4.4Hz,1H),8.20-8.11(m,2H),7.73(ddt,J=8.2,6.7,1.4Hz,1H),7.58(ddt,J=8.3,6.8,1.4Hz,1H),7.50(d,J=4.4 Hz,1H),6.84(d,J=1.5Hz,1H),6.78–6.69(m,2H),6.03–5.92(m,3H),5.3 1(brs,1H),5.02(ddd,J=5.1,3.0,1.3Hz,2H),4.41–4.22(m,2H),3.22(br s,1H),3.13-3.04(m,1H),2.95-2.78(m,2H),2.76–2.68(m,1H),2.28-2.20(m,1H),2.10-2.04(m,1H),1.76(br s,1H),1.57–1.43(m,2H),1.32(d,J=9.7Hz,1H).ESI-MS m / z calcd.for C 27 H 29 N2O3 + [M+H]+:429.2,found:429.1.

[0129] Example 15: (1S,2R,4S,5R)-2-((S)-((2-fluorobenzyl)oxy)(quinoline-4-yl)methyl)-5-vinylquinine

[0130]

[0131] Replacing 1-(bromomethyl)-2-fluorobenzene with 4-(bromomethyl)benzo[d][1,3]dioxo, the procedure was the same as in Example 1, yielding 347 mg of a pale yellow oil, with a yield of 81%. 1 H NMR (500MHz, CDCl3) δ8.90 (d, J=4.4Hz, 1H), 8.21–8.08 (m, 2H), 7.72 (ddd, J=8.4, 6.9, 1. 3Hz,1H),7.62–7.49(m,2H),6.87–6.73(m,3H),6.03–5.92(m,1H),5.86(s,2H),5.37(br s,1H),5.05–4.96(m,2H),4.50–4.35(m,2H),3.33–

[0132] 3.21(m,1H),3.10–3.02(m,1H),2.94–2.79(m,2H),2.79–2.67(m,1H),2.25–2.19(m,1H),2.12–2.06(m,1H),1.73(br s,1H),1.56–1.40(m,2H),1.33–1.21(m,1H).ESI-MSm / z calcd.for C 27 H 29 N2O3 + [M+H]+:429.2,found:429.1.

[0133] Example 16: (1S,2R,4S,5R)-2-((S)-((2,3-dihydrobenzo[b][1,4]dioxa-5-yl)methoxy)(quinolin-4-yl)methyl)-5-vinylquinine

[0134]

[0135] Replacing 1-(bromomethyl)-2-fluorobenzene with 5-bromomethyl-2,3-dihydro-1,4-benzodioxene, the procedure was the same as in Example 1, yielding 345 mg of a pale yellow oil, with a yield of 78%. 1 H NMR (500MHz, CDCl3) δ8.89 (d, J=4.4Hz, 1H), 8.15 (dd, J=8.5, 1.0Hz, 1H), 7.72 (ddd, J=8.4, 6.8, 1.3H z,1H),7.61–7.52(m,2H),6.95(dd,J=5.2,3.9Hz,1H),6.86–6.80(m,2H),6.00(ddd,J=17.0,10.3,7. 7Hz,1H),5.43(s,1H),5.05–4.98(m,2H),4.49–4.38(m,2H),4.24–4.08(m,4H),3.41–3.31(m,1H),3. 13-3.03(m,1H),2.94–2.81(m,2H),2.80–2.68(m,1H),2.29–2.21(m,1H),2.18–2.10(m,1H),1.74(br s,1H),1.56–1.40(m,2H),1.29–1.22(m,1H).ESI-MS m / z calcd.for C 28 H 31 N2O3 + [M+H]+:443.2,found:443.4.

[0136] Example 17: (1S,2R,4S,5R)-2-((S)-((2,3-dihydrobenzo[b][1,4]dioxane-6-yl)methoxy)(quinoline-4-yl)methyl)-5-vinylquinine

[0137]

[0138] Replacing 1-(bromomethyl)-2-fluorobenzene with 6-bromomethyl-2,3-dihydro-1,4-benzodioxene, the procedure was the same as in Example 1, yielding 358 mg of a pale yellow oil, with a yield of 81%. 1 H NMR(500MHz, CDCl3)δ8.93(d,J=4.4Hz,1H),8.23–8.15(m,2H),7.75(ddd,J=8.3,6.9,1.2Hz,1H),7.61( t,J=7.2Hz,1H),7.53(d,J=4.2Hz,1H),6.90–6.83(m,2H),6.82–6.75(m,1H),6.04–5.93(m,1H),5.39(br s,1H),5.11–

[0139] 4.99(m,2H),4.41–4.23(m,6H),340–3.24(m,1H),3.19–3.07(m,1H),3.00–2 .84(m,2H),2.83–2.73(m,1H),2.32–2.24(m,1H),2.18–2.09(m,1H),1.79(br s,1H),1.60–1.47(m,2H),1.38–1.31(m,1H).ESI-MS m / z calcd.for C 28 H 31 N2O3 + [M+H]+:443.2,found:443.4.

[0140] Example 18: (1S,2R,4S,5R)-2-((S)-((2-methylbenzyl)oxy)(quinoline-4-yl)methyl)-5-vinylquinine

[0141]

[0142] Replacing 1-(bromomethyl)-2-methylbenzene with 1-(bromomethyl)-2-fluorobenzene, the procedure was the same as in Example 1, yielding 330 mg of a pale yellow oily substance, with a yield of 83%. 1H NMR (300MHz, CDCl3) δ8.91 (d, J = 4.4Hz, 1H), 8.23-8.15 (m, 2H), 7.75 (t, J = 7.7Hz, 1H), 7.6 0(t,J=7.1Hz,1H),7.54(d,J=4.4Hz,1H),7.40–7.34(m,1H),7.25-7.14(m,3H),5.95(ddd, J=16.7,10.8,7.4Hz,1H),5.40(s,1H),5.09–4.92(m,2H),4.53–4.36(m,2H),3.32-3.18(m ,1H),3.17-3.04(m,1H),2.95-2.70(m,3H),2.29-2.19(m,4H),2.12-2.04(m,1H),1.78(br s,1H),1.56-1.44(m,2H),1.40-1.30(m,1H).ESI-MS m / zcalcd.for C 27 H 31 N2O + [M+H]+:399.2,found:399.1.

[0143] Example 19: (1S,2R,4S,5R)-2-((S)-quinoline-4-yl((2,4,6-trimethylbenzyl)oxy)methyl)-5-vinylquinine

[0144]

[0145] Replacing 1-(bromomethyl)-2-fluorobenzene with 2-(bromomethyl)-1,3,5-trimethylbenzene, the procedure was the same as in Example 1, yielding 332 mg of a pale yellow oily substance, with a yield of 78%. 1 H NMR (500MHz, CDCl3) δ8.92(d,J=4.4Hz,1H),8.40–8.12(m,2H),7.72(ddd,J=8.4,6.8,1.4Hz,1H),7.62–7.40(m,2H),6.82(s,2H),5.91(ddd,J=

[0146] 17.4,10.4,7.3Hz,1H),4.05–4.91(m,2H),4.36(s,2H),3.25–2.90(m,2H),2.87 –2.78(m,1H),2.77–258(m,2H),2.30–2.10(m,10H),2.01–1.89(m,1H),1.75(br s,1H),1.51–1.45(m,2H). 13C NMR (126MHz, CDCl3) δ150.0,148.6,147.3,140.4,137.83,130.9,130.5,129.1,128.9,128.9,126.9,12 6.5,123.4,118.7,114.4,79.5,66.0,60.8,53.4,49.8,49.0,49.0,39.9,28.0,26.5,21.0,19.6.ESI-MS m / z calcd.for C 29 H 35 N2O + [M+H]+:427.3,found:427.3.

[0147] Example 20: (1S,2R,4S,5R)-2-((S)-quinoline-4-yl((3-(trifluoromethyl)benzyl)oxy)methyl)-5-vinylquinine

[0148]

[0149] Replacing 1-(bromomethyl)-3-(trifluoromethyl)benzene with 1-(bromomethyl)-2-fluorobenzene, the procedure was the same as in Example 1, yielding 344 mg of a pale yellow oily substance, with a yield of 76%. 1 H NMR (500MHz, CDCl3) δ8.92 (d, J=4.4Hz, 1H), 8.26–8.10 (m, 2H), 7.75 (ddd, J=8.2, 6.8, 1.3Hz, 1H), 7.64 (s, 1H ),7.62–7.54(m,2H),7.50(d,J=4.5Hz,1H),7.48–7.43(m,2H),5.97(ddd,J=16.9,10.7,7.4Hz,1H),5.38(br s,1H),5.10–4.96(m,2H),4.55–4.43(m,2H),3.28–3.19(m,7.9Hz,1H),3.17–3.08(m,1 H),2.98–2.82(m,2H),2.802.70(m,1H),2.29–2.21(m,1H),2.14–2.06(m,1H),1.79(br s,1H),1.59–1.45(m,2H),1.44–1.30(m,1H).ESI-MS m / z calcd.for C 27 H 28 F3N2O + [M+H]+:453.2,found:453.3.

[0150] Example 21: (1S,2R,4S,5R)-2-((S)-((2-methyl-3-(trifluoromethyl)benzyl)oxy)(quinoline-4-yl)methyl)-5-vinylquinine

[0151]

[0152] Replacing 1-(bromomethyl)-2-methyl-3-(trifluoromethyl)benzene with 1-(bromomethyl)-2-fluorobenzene, the procedure was the same as in Example 1, yielding 368 mg of a pale yellow oil, with a yield of 79%. 1 H NMR(500MHz, CDCl3)δ8.91(d,J=4.4Hz,1H),8.20–8.14(m,2H),7.77–7.72(m,1H),7.62–7.57(m,2H),7.54( d,J=7.5Hz,1H),7.49(d,J=4.2Hz,1H),7.29(d,J=7.8Hz,1H),5.92(ddd,J=17.4,10.4,7.2Hz,1H),5.35(br s,1H),5.07–4.94(m,2H),4.50–4.42(m,2H),3.21–3.08(m,2H),2.94–2.77(m,2H ),2.76–2.68(m,1H),2.36(s,3H),2.28–2.19(m,1H),2.08–2.00(m,1H),1.79(br s,1H),1.57–1.45(m,2H),1.43–1.33(s,1H).ESI-MS m / z calcd.for C 28 H 30 F3N2O + [M+H]+:467.2,found:467.3.

[0153] Example 22: (1S,2R,4S,5R)-2-((S)-([1,1'-biphenyl]-4-ylmethoxy)(quinoline-4-yl)methyl)-5-vinylquinine

[0154]

[0155] Replacing 1-(bromomethyl)-2-fluorobenzene with 4-(bromomethyl)-1,1'-biphenyl, the procedure was the same as in Example 1, yielding 350 mg of a pale yellow oily substance with a yield of 76%. 1H NMR (500MHz, CDCl3) δ8.93(d,J=4.4Hz,1H),8.17(dd,J=8.4,1.4Hz,2H),7.74(ddd,J=8.3,6.8,1.3Hz,1H ),7.63–7.53(m,6H),7.47–7.42(m,2H),7.41–7.33(m,3H),5.99(ddd,J=17.6,10.4,7.5Hz,1H),5.38(br s,1H),4.54–4.40(m,2H),4.47(dd,J=34.4,11.5Hz,2H),3.32–3.21(m,1H),3.17–3.07(m,1H),2.97–2 .88(m,1.3Hz,1H),2.87-2.80(m,1H),2.79–2.68(m,1H),2.29–2.20(m,1H),2.17–2.08(m,1H),1.77(br s,1H),1.57–1.44(m,2H),1.38–1.29(m,1H).ESI-MS m / z calcd.for C 32 H 33 N2O + [M+H]+:461.3,found:461.3.

[0156] Example 23: (1S,2R,4S,5R)-2-((S)-([1,1'-biphenyl]-3-ylmethoxy)(quinoline-4-yl)methyl)-5-vinylquinine

[0157]

[0158] Replacing 1-(bromomethyl)-2-fluorobenzene with 3-(bromomethyl)-1,1'-biphenyl, the procedure was the same as in Example 1, yielding 359 mg of a pale yellow oily substance, with a yield of 78%. 1H NMR (500MHz, CDCl3) δ8.91 (d, J=4.4Hz, 1H), 8.17 (dd, J=8.5, 1.3Hz, 2H), 7.7 4(ddd,J=8.3,6.8,1.3Hz,1H),7.62–7.52(m,6H),7.48–7.40(m,3H),7.38–7 .33(m,1H),7.29(d,J=7.6Hz,1H),5.98(ddd,J=17.5,10.2,7.5Hz,1H),5.44 (brs,1H),5.05–4.96(m,1H),4.95–4.90(m,1H),4.56-4.46(m,2H),3.31(br s,1H),3.18–3.08(m,1H),3.01–2.83(m,2H),2.80–2.70(m,1H),2.28–2.21(m,1H),2.19–2.10(m,1H),1.77(br s,1H),1.59–1.44(m,2H),1.39–1.29(m,1H).ESI-MS m / z calcd.for C 32 H 33 N2O + [M+H]+:461.3,found:461.3.

[0159] Example 24: (1S,2R,4S,5R)-2-((S)-((2,3-dihydrobenzo[b][1,4]dioxane-6-yl)methoxy)(quinoline-4-yl)methyl)-5-vinylquinine

[0160]

[0161] Replacing 1-(bromomethyl)-2-methyl-1,1'-biphenyl with 3-(bromomethyl)-2-fluorobenzene, the procedure was the same as in Example 1, yielding 388 mg of a pale yellow oily substance, with a yield of 82%. 1H NMR (500MHz, CDCl3) δ8.91(d,J=4.4Hz,1H),8.24–8.15(m,2H),7.74(ddd,J=8.4,6.8,1.3Hz,1H),7.59(ddd,J=8.4,6.8,1.4Hz,1H),7.55( d,J=4.5Hz,1H),7.43–7.37(m,3H),7.37–7.31(m,1H),7.28-7.23(m,3H),7.22-7.17(m,1H),5.97(ddd,J=17.0,10.6,7.3Hz,1H),5.39(br s,1H),5.06–4.97(m,2H),4.55-4.10(m,2H),3.23(br s,1H),3.17-3.09(m,1H),2.94-2.80(m,2H),2.77-2.68(m,1H),2.28-2.21(m,1H),2.16–

[0162] 2.06(m,4H),1.78(br s,1H),1.56–1.46(m,2H),1.44–1.34(m,1H).ESI-MS m / zcalcd.for C 33 H 35 N2O + [M+H]+:475.3,found:475.3.

[0163] Example 25: (1S,2R,4S,5R)-2-((S)-(naphth-2-ylmethoxy)(quinoline-4-yl)methyl)-5-vinylquinine

[0164]

[0165] Replacing 1-(bromomethyl)-2-methyl-1,1'-biphenyl with 3-(bromomethyl)-2-fluorobenzene, the procedure was the same as in Example 1, yielding 348 mg of a pale yellow oily substance, with a yield of 80%. 1H NMR(300MHz, CDCl3)δ8.93(d,J=4.4Hz,1H),8.22–8.14(m,2H),7.88–7.74(m,5H),7.61–7.43(m,5H),5.98(ddd,J=17.5,10.3,7.5Hz,1H),5.45(br s,1H),5.08–4.89(m,2H),4.67–4.52(m,2H),3.38–3.24(m,1H),3.19–3.08(m,1H),2.97–2.71(m,3H),2.33–2.09(m,2H),1.78(br s,1H),1.56–1.45(m,2H),1.40–1.30(m,1H).ESI-MS m / z calcd.for C 30 H 31 N2O + [M+H]+:435.2,found:435.2.

[0166] Example 26: (1S,2R,4S,5R)-2-((S)-quinoline-4-yl(quinoline-8-ylmethoxy)methyl)-5-vinylquinine

[0167]

[0168] Replacing 1-(bromomethyl)-2-fluorobenzene with 8-(bromomethyl)quinoline, the procedure was the same as in Example 1, yielding 339 mg of a pale yellow oily substance with a yield of 78%. 1 H NMR (500MHz, CDCl3) δ8.85(d,J=4.4Hz,1H),8.79(dd,J=4.2,1.8Hz,1H),8.19(d,J=8.5Hz,1H),8.14(ddd, J=8.3,3.8,1.5Hz,2H),8.01(dd,J=7.2,1.4Hz,1H),7.76(dd,J=8.2,1.5Hz,1H),7.72(ddd,J=8.4,6.8,1. 3Hz,1H),7.62–7.53(m,3H),7.37(dd,J=8.2,4.2Hz,1H),6.06–5.92(m,1H),5.70–5.56(m,1H),5.27–5.08 (m,2H),5.03–4.90(m,2H),3.42–3.30(m,1H),3.20–3.05(td,J=9.2,4.0Hz,1H),3.00–2.82(m,2H),2.81–

[0169] 2.70(m,1H),2.31–2.14(m,2H),1.77(br s,1H),1.55–1.43(m,2H),1.37–1.26(m,1H).ESI-MS m / z calcd.for C 29 H 30 N3O + [M+H]+:436.2,found:436.2.

[0170] Example 27: (1S,2R,4S,5R)-2-((S)-quinoline-4-yl(quinoxaloline-5-ylmethoxy)methyl)-5-vinylquinine

[0171]

[0172] Replacing 1-(bromomethyl)-2-fluorobenzene with 5-(bromomethyl)quinoxaline, the procedure was the same as in Example 1, yielding 326 mg of a pale yellow oily substance with a yield of 75%. 1 H NMR (500MHz, CDCl3) δ8.86 (d, J=4.5Hz, 1H), 8.81 (dd, J=4.1, 1.8Hz, 1H), 8.2 4(d,J=8.2Hz,1H),8.17–8.11(m,2H),8.00(d,J=7.0Hz,1H),7.77(d,J=8.2H z,1H),7.73(ddd,J=8.4,6.8,1.4Hz,1H),7.62–7.60(m,1H),7.59–7.56(m,1 H),7.37(dd,J=8.3,4.2Hz,1H),5.97(ddd,J=17.4,9.9,7.3Hz,1H),5.69(br s,1H),5.26–5.14(m,2H),5.02–4.95(m,2H),3.46–3.31(m,1H),3.19–3.1 1(m,1H),3.00–2.87(m,2H),2.82–2.73(m,1H),2.29–2.17(m,2H),1.78(br s,1H),1.59–1.44(m,2H),1.33–1.27(m,1H).ESI-MS m / z calcd.for C 29 H 30 N3O + [M+H]+:436.2,found:436.2.

[0173] Example 28: (1S,2R,4S,5R)-2-((S)-(pyridin-2-ylmethoxy)(quinolin-4-yl)methyl)-5-vinylquinine

[0174]

[0175] Replacing 1-(bromomethyl)-2-fluorobenzene with 2-(bromomethyl)pyridine, the procedure was the same as in Example 1, yielding 313 mg of a pale yellow oily substance, with a yield of 81%. 1 H NMR (500MHz, CDCl3) δ8.89(d,J=4.4Hz,1H),8.52(d,J=4.7Hz,1H),8.22–8.13(m,2H),7.75–7. 69(m,2H),7.62–7.57(m,1H),7.56–7.52(m,2H),7.22–7.18(m,1H),6.04–5.95(m,1H),5.52(br s,1H),5.07–5.01(m,2H),4.62–4.54(m,2H),3.32(br s,1H),3.20–3.13(m,1H),3.01–2.85(m,2H),2.82–2.72(m,1H),2.32-2.24(m,1H),2.20–

[0176] 2.12(m,1H),1.80(br s,1H),1.61–1.46(m,2H),1.39–1.30(m,1H).ESI-MS m / zcalcd.for C 25 H 28 N3O + [M+H]+:386.2,found:386.3.

[0177] Example 29: (1S,2R,4S,5R)-2-((S)-(pyridin-3-ylmethoxy)(quinolin-4-yl)methyl)-5-vinylquinine

[0178]

[0179] Replacing 1-(bromomethyl)-2-fluorobenzene with 3-(bromomethyl)pyridine, the procedure was the same as in Example 1, yielding 319 mg of a pale yellow oily substance, with a yield of 83%. 1H NMR (500MHz, CDCl3) δ8.94(d,J=4.4Hz,1H),8.66–8.57(m,2H),8.25–8.14(m,2H),7.77(ddd,J=8.3,6.9,1.2Hz,1H),7.69(d,J=7 .8Hz,1H),7.63(ddd,J=8.2,7.0,1.1Hz,1H),7.53(d,J=4.3Hz,1H),7.32(ddd,J=7.8,4.8,0.6Hz,1H),6.02–5.90(m,1H),5.48(br s,1H),5.07–4.98(m,2H),4.50(s,2H),3.33–3.23(m,1H),3.21–3.10(m,1H),2.0 1–2.86(m,2H),2.83–2.72(m,1H),2.32–2.24(m,1H),2.16–2.06(m,1H),1.81(br s,1H),1.64–1.48(m,2H),1.39–1.30(s,1H).ESI-MS m / z calcd.for C 25 H 28 N3O + [M+H]+:386.2,found:386.3.

[0180] Example 30: (1S,2R,4S,5R)-2-((S)-(pyridin-4-ylmethoxy)(quinolin-4-yl)methyl)-5-vinylquinine

[0181]

[0182] Replacing 1-(bromomethyl)-2-fluorobenzene with 4-(bromomethyl)pyridine, the procedure was the same as in Example 1, yielding 305 mg of a pale yellow oily substance with a yield of 79%. 1 H NMR (500MHz, CDCl3) δ8.91(dd,J=4.4,1.4Hz,1H),8.59(dd,J=4.4,1.7Hz,2H),8.22–8.10(m,2H),7.74(ddd,J=8.4,6. 8,1.4Hz,1H),7.60(ddd,J=8.3,6.8,1.5Hz,1H),7.49(d,J=4.4Hz,1H),7.32–7.24(m,2H),6.11–5.93(m,1H),5.41(br s,1H),5.10–

[0183] 5.01(m,2H),4.45(s,2H),3.30–3.22(m,1H),3.19–3.10(m,1H),2.98–2.92(m,1H),2.91–2.83(m,1H),2.82–2 .70(m,1H),2.33–2.24(m,1H),2.19–2.08(m,1H),1.82(brs,1H),1.59–1.46(m,2H),1.43–1.32(m,1H).ESI-MS m / z calcd.for C 25 H 28 N3O + [M+H]+:386.2,found:386.3.

[0184] Example 31: 3-(((S)-quinoline-4-yl((1S,2R,4S,5R)-5-vinylquinin-2-yl)methoxy)methyl)benzo[d]isoxazole

[0185]

[0186] Replacing 1-(bromomethyl)benzo[d]isoxazole with 3-(bromomethyl)-2-fluorobenzene, the procedure was the same as in Example 1, yielding 332 mg of a pale yellow oily substance with a yield of 78%. 1 H NMR (500MHz, CDCl3) δ8.92(d,J=4.4Hz,1H),8.26–8.14(m,2H),7.80(d,J=7.9Hz,1H),7.75(ddd,J=8.3,6.9,1 .2Hz,1H),7.64–7.50(m,4H),7.34(ddd,J=7.9,6.0,1.9Hz,1H),5.78(ddd,J=17.4,10.3,7.4Hz,1H),5.47(br s,1H),4.93–4.75(m,4H),3.25-3.05(m,2H),2.91–2.78(m,2H),2.76–2.65(m,1H),2.25–2.15(m,1H),2.01–

[0187] 1.90(m,1H),1.74(s,1H),1.56–1.46(m,2H),1.44–1.34(m,1H).ESI-MS m / zcalcd.for C 27 H 28 N3O2 + [M+H]+:426.2,found:426.3.

[0188] Example 32: 3-Methyl-5-(((S)-quinoline-4-yl((1S,2R,4S,5R)-5-vinylquinin-2-yl)methoxy)methyl)isoxazole

[0189]

[0190] Replacing 1-(bromomethyl)-2-fluorobenzene with 5-(bromomethyl)-3-methylisoxazole, the procedure was the same as in Example 1, yielding 292 mg of a pale yellow oily substance, with a yield of 75%. 1 H NMR(500MHz, CDCl3)δ8.92(d,J=4.4Hz,1H),8.20–8.06(m,2H),7.74(ddd,J=8.3,6.9,1.3Hz,1H), 7.60(ddd,J=8.2,6.9,1.2Hz,1H),7.51(d,J=4.3Hz,1H),6.08(s,1H),6.04–5.95(m,1H),5.39(br s,1H),5.09–5.02(m,2H),4.56–4.43(m,2H),3.22(br s,1H),3.13–3.04(m,1H),2.98–2.81(m,2H),2.79–2.70(m,1H),2.32–2.21(m,4H),2.10–2.00(m,1H),1.77(br s,1H),1.58–1.44(m,2H),1.35–1.23(m,1H). 13 CNMR (126MHz, CDCl3) δ168.2,159.7,150.2,148.6,145.2,140.4,130.6,129.3,126.9,126. 3,123.0,118.7,114.7,104.0,81.2,62.1,60.3,50.1,49.4,39.9,28.1,26.4,21.9.ESI-MS m / z calcd.for C 24 H 28 N3O2 + [M+H]+:390.2,found:390.3.

[0191] Example 33: (1S,2R,4S,5R)-2-((S)-(4-cyclohexylbutoxy)(quinoline-4-yl)methyl)-5-vinylquinine

[0192]

[0193] Replacing 1-(bromomethyl)-2-fluorobenzene with (4-bromobutyl)cyclohexane, the procedure was the same as in Example 1, yielding 212 mg of a pale yellow oil, with a yield of 49%.1 H NMR(500MHz, CDCl3)δ8.92(d,J=4.4Hz,1H),8.21–8.12(m,2H),7.74(ddd,J=8.3,6.9,1.3H z,1H),7.60(ddd,J=8.2,6.9,1.2Hz,1H),7.51(d,J=4.4Hz,1H),6.20–6.09(m,1H),5.33(br s,1H),5.15–5.08(m,2H),3.49–3.33(m,3H),3.07–2.89(m,3H),2.87–2.76(m,1H),2.34–2.25(m,1H),2.23–2.13(m,1H),1.78(br s,1H),1.75–1.43(m,10H),1.37–1.09(m,8H),0.95–0.85(m,2H).ESI-MS m / z calcd.for C 29 H 41 N2O + [M+H]+:433.3,found:433.4.

[0194] Example 34: ((1S,2R,4S,5R)-2-((S)-(4-phenylbutoxy)(quinoline-4-yl)methyl)-5-vinylquinine

[0195]

[0196] Replacing 1-(bromomethyl)-2-fluorobenzene with (4-bromobutyl)cyclohexane, the procedure was the same as in Example 1, yielding 191 mg of a pale yellow oil, with a yield of 45%. 1 H NMR(500MHz, CDCl3)δ8.89(d,J=4.4Hz,1H),8.17–8.09(m,2H),7.72(t,J=7.6Hz,1H),7.60–7.55(m,J=8 .2,7.1Hz,1H),7.47(d,J=4.4Hz,1H),7.30–7.27(m,2H),7.21–7.13(m,3H),6.18–5.99(m,1H),5.30(br s,1H),5.12–5.04(m,2H),3.49–3.32(m,3H),3.09–2.86(m,3H),2.85–2.74(m,1H),2.62(t,J=7.5Hz, 2H),2.31-2.22(m,1H),2.18–2.08(m,1H),1.78–1.66(m,5H),1.60–1.42(m,2H),1.16(m,1H).ESI-MS m / zcalcd.for C29 H 35 N2O + [M+H]+:427.3,found:427.2.

[0197] Example 35: (1S,2R,4S,5R)-2-((S)-propoxy(quinolin-4-yl)methyl)-5-vinylquinine

[0198]

[0199] Replacing 1-(bromomethyl)-2-fluorobenzene with 1-iodopropane, the procedure was the same as in Example 1, yielding 189 mg of a pale yellow oily substance, with a yield of 54%. 1 H NMR (500MHz, CDCl3) δ8.90(d,J=4.4Hz,1H),8.20(d,J=8.6Hz,1H),8.15(dd,J=8.4,0.8Hz,1 H),7.76–7.71(m,1H),7.64–7.58(m,1H),7.49(d,J=4.4Hz,1H),6.15–6.04(m,1H),5.53(br s,1H),5.16–5.10(m,2H),3.62–3.43(m,2H),3.42–3.33(m,1H),3.14–2.97(m,3H),2.90-2.81(m,1H),2.39–2.30(m,1H), 2.25–2.16(m,1H),1.81(brs,1H),1.69–1.59(m,3H),1.54–1.38(m,3H),1.21–1.10(m,1H),0.92(t,J=7.4Hz,3H).ESI-MS m / z calcd.for C 23 H 21 N2O + [M+H]+:351.2,found:351.3.

[0200] Example 36: (1S,2R,4S,5R)-2-((S)-pentoxy(quinolin-4-yl)methyl)-5-vinylquinine

[0201]

[0202] Replacing 1-(bromomethyl)-2-fluorobenzene with 1-iodopentane, the procedure was the same as in Example 1, yielding 185 mg of a pale yellow oily substance, with a yield of 51%. 1H NMR (500MHz, CDCl3) δ8.91 (d, J = 4.4Hz, 1H), 8.26 (br s,1H),8.15(d,J=8.4Hz,1H),7.74(t,J=7.6Hz,1H),7.63(t,J=7.5Hz,1H),7.50(d,J=4.4Hz,1H),6.17–

[0203] 6.01(m,1H),5.69(br s,1H),5.15(d,J=15.3Hz,2H),3.64(br s,1H),3.55–3.47(m,1H),3.43–3.35(m,1H),3.16–3.05(m,2H),2.96-2.85(m,1H),2.43–2.34(m,1H),2.31–2.21(m,1H),1.85(br s,1H),1.72–1.61(m,4H),1.58–1.51(m,1H),1.44–1.30(m,4H),1.21–1.13(m,1H),0.91(t,J=7.1Hz,3H). 13 C NMR (126MHz, CDCl3) δ150.0,148.5,145.5,139.3,130.4,129.3,127.2,126.2,123.3,118 .2,115.6,69.9,60.1,49.8,49.2,39.3,29.7,28.4,28.0,25.4,22.5,20.3,14.0.ESI-MS m / z calcd.for C 24 H 33 N2O + [M+H]+:365.2,found:365.2.

[0204] Example 37: (1S,2R,4S,5R)-2-((S)-heptaoxy(quinolin-4-yl)methyl)-5-vinylquinine

[0205]

[0206] Replacing 1-(bromomethyl)-2-fluorobenzene with 1-iodoheptane, the procedure was the same as in Example 1, yielding 196 mg of a pale yellow oil, with a yield of 50%. 1H NMR(500MHz, CDCl3)δ8.90(d,J=4.4Hz,1H),8.25–8.13(m,2H),7.73(t,J=7.7Hz,1H), 7.64–7.57(m,1H),7.49(d,J=4.4Hz,1H),6.10(ddd,J=17.3,10.5,7.7Hz,1H),5.46(br s,1H),5.17–5.07(m,2H),3.57-3.34(m,3H),3.14–2.92(m,3H),2.90–2.78(m,1H),2.41–2.26(m,2H),2.24–2.13(m,1H),1.80(br s,1H),1.70–1.55(m,3H),1.54–1.47(m,1H),1.44–1.35(m,2H),1.33–1.24(m,6H),1.19–1.12(m,1H),0.92–0.86(m,3H). 13 CNMR (126MHz, CDCl3) δ149.4,147.8,145.6,139.5,129.8,128.5,126.2,125.7,122.6,117.6,114. 3,79.5,69.2,59.5,49.3,48.8,39.2,31.2,29.4,28.5,27.5,25.6,25.3,22.0,20.1,13.5.ESI-MS m / z calcd.for C 26 H 37 N2O + [M+H]+:393.3,found:393.3.

[0207] Example 38: (1S,2R,4S,5R)-2-((S)-isobutoxy(quinoline-4-yl)methyl)-5-vinylquinine

[0208]

[0209] Cinconazole (1.0 g, 3.4 mmol, 1.0 eq) was added to a reaction tube under N2 protection. 15 mL of DMF was added, followed by the rapid addition of NaH (680 mg, 2.5 mmol, 2.5 eq), a 60% concentration dispersed in mineral oil. The mixture was stirred at room temperature for 2 h, then 1-iodo-2-methylpropane (625 mg, 3.4 mmol, 1.0 eq) was added, and the mixture was heated to 120 °C and stirred for 12 h. The reaction mixture was cooled to room temperature, diluted with brine, and extracted three times with ethyl acetate. The combined organic layers were washed three times with salt, dried over Na2SO4, and then evaporated to dryness before column chromatography (CH2Cl2:MeOH = 12:1). 226 mg of a pale yellow oil was obtained, with a yield of 19%.1 H NMR (500MHz, CDCl3) δ8.90 (d, J=4.4Hz, 1H), 8.18-8.08 (m, 2H), 7.72 (ddd, J=8.4, 6.8, 1.3Hz, 1H), 7. 57(ddd,J=8.3,6.8,1.3Hz,1H),7.48(d,J=4.4Hz,1H),6.11(ddd,J=16.8,10.6,7.7Hz,1H),5.29(br s,1H),5.17–5.04(m,2H),3.45–3.34(m,1H),3.23–3.17(m,1H),3.13–3.08(m,1H),3.04–2.8 6(m,3H),2.82–2.73(m,1H),2.30–2.21(m,1H),2.18–2.10(m,1H),2.00–1.88(m,1H),1.76(br s,1H),1.57–1.41(m,2H),1.23–1.15(m,1H),0.97(d,J=6.7Hz,1H),0.94(d,J=6.8Hz,1H).ESI-MS m / zcalcd.for C 23 H 31 N2O + [M+H]+:351.2,found:351.2.

[0210] Example 39: (1S,2R,4S,5R)-2-((S)-(4-cyclohexylmethoxy)(quinoline-4-yl)methyl)-5-vinylquinine

[0211]

[0212] Replacing 1-iodo-2-methylpropane with (bromomethyl)cyclohexane, the procedure was the same as in Example 38, yielding 225 mg of a pale yellow oil, with a yield of 17%. 1H NMR (500MHz, CDCl3) δ8.90 (d, J = 4.4Hz, 1H), 8.17-8.08 (m, 2H), 7.72 (t, J = 8.1Hz, 1H), 7. 57(t,J=7.7Hz,1H),7.47(d,J=4.4Hz,1H),6.12(ddd,J=16.9,10.5,7.7Hz,1H),5.25(br s,1H),5.12-5.04(m,2H),3.45–3.32(m,1H),3.25–3.19(m,1H),3.18– 3.12(m,1H),3.08–2.84(m,3H),2.82–2.72(m,1H),2.31–2.21(m,1H), 2.20–2.09(m,1H),1.88–1.82(m,1H),1.80–1.60(m,6H),1.57–1.39(m ,2H),1.31–1.21(m,2H),1.20–1.10(m,2H),1.05–0.94(m,2H).ESI-MS m / z calcd.for C 26 H 35 N2O + [M+H]+:391.2,found:391.3.

[0213] Example 40: (S)-(2-propylquinoline-4-yl)((1S,2R,4S,5R)-5-vinylquinin-2-yl)methanol

[0214]

[0215] CN (900 mg, 3.0 mmol, 1.0 eq) was added to a reaction tube under N2 protection. 18 mL of tBuOMe was added, and the reaction mixture was cooled to -10 °C. A cyclohexane solution of n-propyllithium (30.0 mmol, 3.0 eq) was added, and the mixture was stirred for 20 min. The mixture was then heated to room temperature and stirred for 1 h. After the reaction was monitored by TLC until complete, it was quenched with 0.9 mL of AcOH, followed by the addition of 15 mL of water and extraction with EtOAc (3 × 20 mL). The organic layers were combined, dried over Na2SO4, and then evaporated to dryness. The obtained intermediate 1',2'-dihydroadduct was dissolved in CH2Cl2, and 600 mg of activated MnO2 was added. The reaction mixture was heated to 40 °C and stirred until the intermediate disappeared. The mixture was filtered and evaporated to dryness to obtain the crude product. A small amount of the crude product was purified by scraping (CH2Cl2:MeOH = 10:1) to obtain the target compound as an amorphous solid. 1H NMR (500MHz, CDCl3) δ7.87(d,J=8.3Hz,1H),7.77(d,J=8.4Hz,1H),7.61(s,1H),7.38–7.30(m,1H),6.98(t,J=7 .2Hz,1H),6.56(s,1H),6.08(ddd,J=17.5,10.0,7.4Hz,1H),5.31–5.23(m,2H),4.48–4.39(m,1H),3.48–3.41( m,1H),3.39–3.33(m,1H),3.33–3.27(m,1H),3.15–3.05(m,1H),2.98–2.89(m,2H),2.61–2.53(m,1H),2.46–2. 37(m,1H),1.97(s,1H),1.89–1.83(m,2H),1.70–1.63(m,1H),1.05(t,J=7.3Hz,3H),1.01–0.92(m,2H).ESI-MS m / z calcd.forC 22 H 29 N2O + [M+H]+:337.2,found:337.2.

[0216] Example 41: (S)-(2-isobutylquinoline-4-yl)((1S,2R,4S,5R)-5-vinylquinin-2-yl)methanol

[0217]

[0218] Isobutyllithium was used instead of n-propyllithium, and the procedure was the same as in Example 40. A small amount of the crude product was purified by scraping (CH2Cl2:MeOH = 10:1) to obtain the target compound as an amorphous solid. δ 1H NMR (500MHz, CDCl3) δ7.86-7.80(m,1H),7.72(d,J=8.4Hz,1H),7.58(s,1H),7.23(t,J=7.6Hz, 1H),6.88-6.81(m,1H),6.57-6.49(m,1H),6.08(ddd,J=17.5,9.8,7.7Hz,1H),5.26-5.20(m,2 H),4.48-4.33(m,1H),3.43–3.31(m,2H),3.28–3.22(m,1H),3.11-3.03(d,J=10.1Hz,1H),2.8 6-2.79(m,2H),2.60-2.51(m,1H),2.46–2.37(m,1H),2.24-2.14(m,1H),1.95(s,1H),1.86(br s,1H),1.67-1.60(m,1H),0.99-0.96(m,6H).ESI-MS m / z calcd.for C 23 H 31 N2O + [M+H]+:351.2,found:351.2.

[0219] Example 42: (S)-(2-hexylquinoline-4-yl)((1S,2R,4S,5R)-5-vinylquinin-2-yl)methanol

[0220]

[0221] Using hexyllithium instead of propyllithium, the procedure was the same as in Example 40. A small amount of crude product was taken and purified by scraping (CH2Cl2:MeOH = 10:1) to obtain the target compound as an amorphous solid. 1H NMR(500MHz, CDCl3)δ7.94–7.84(m,1H),7.82–7.71(m,1H),7.61(s,1H),7.35–7.2 7(m,1H),7.01–6.92(m,1H),6.60–6.50(m,1H),6.08(ddd,J=17.5,10.1,7.4Hz,1H) ,5.31–5.15(m,2H),4.50-4.40(m,1H),3.50–3.35(m,2H),3.34–3.26(m,1H),3.15 –3.06(m,1H),2.95(t,J=7.9Hz,2H),2.63–2.54(m,1H),2.47–2.37(m,1H),1.97(br s,1H),1.93–1.84(m,1H),1.84–1.77(m,2H),1.71–1.62(m,1H),1.48–1.40 (m,2H),1.38–1.30(m,4H),0.99–0.93(m,1H),0.90(t,J=7.0Hz,3H).ESI-MS m / zcalcd.for C 25 H 35 N2O + [M+H]+:379.3,found:379.2.

[0222] Example 43: (1S,2R,4S,5R)-2-((S)-(2-butylquinoline-4-yl)(ethoxy)methyl)-5-vinylquinine

[0223]

[0224] C2'-butyl-substituted cinchonine (175 mg, 0.5 mmol, 1.0 eq) was added to a reaction tube under N2 protection. 4 mL of DMF was added, followed by rapid addition of NaH (50 mg, 2.5 mmol, 2.5 eq, T>15 min) dispersed in mineral oil at a 60% concentration. After stirring at room temperature for 2 h, bromoethane (0.5 mmol, 1.0 eq) was added, and the mixture was stirred overnight at room temperature. The reaction was quenched with brine, extracted three times with EtOAc, and the organic layers were combined, washed three times with salt, dried over Na2SO4, and then evaporated by a rotary evaporator (CH2Cl2:MeOH = 12:1). 151 mg of a pale yellow oil was obtained, with a yield of 80%. 1H NMR (500MHz, CDCl3) δ8.12–8.02(m,2H),7.71–7.64(m,1H),7.56–7.45(m,1H),7.39(s,1H),6.22–6.08(m,1H),5.36(br s,1H),5.18–5.06(m,2H),3.56–3.40(m,3H),3.01–2.93(m,4H),2.88–2.76(m,1H),2.32–2.25(m,1H),2.21–2.11(m,1H),1.8 6–1.74(m,3H),1.60–1.52(m,1H),1.51–1.40(m,3H),1.27(t,J=7.0Hz,3H),1.19–1.09(m,1H),0.97(t,J=7.4Hz,3H).ESI-MS m / z calcd.for C 25 H 35 N2O + [M+H]+:379.3,found:379.2.

[0225] Example 44: (1S,2R,4S,5R)-2-((S)-(2-butylquinoline-4-yl)(propoxy)methyl)-5-vinylquinine

[0226]

[0227] Using bromopropane instead of bromoethane, the procedure was the same as in Example 43, yielding 158 mg of a pale yellow oily substance, with a yield of 81%. 1 HNMR (500MHz, CDCl3) δ8.11–8.04(m,2H),7.71–7.65(m,1H),7.55–7.48(m,1H),7.39(s,1H),6.13(ddd,J=16.9,10.5,7.8Hz,1H),5.37(br s,1H),5.20–5.06(m,2H),3.54–3.38(m,2H),3.37–3.29(m,1H),3.06–2.90(m,5H),2.88–2.77(m,1H),2.34–2.27(m,1H),2.23–

[0228] 2.15(m,1H),1.83–1.75(m,3H),1.74–1.63(m,2H),1.601.53(m,1H),1.51–1.40(m,3H),1.18–1.10(m,1H),1.10–0.94(m,6H).ESI-MS m / z calcd.for C 26 H 37N2O + [M+H]+:393.3,found:393.2.

[0229] Example 45: (1S,2R,4S,5R)-2-((S)-(2-butylquinoline-4-yl)(butoxy)methyl)-5-vinylquinine

[0230]

[0231] Using bromobutane instead of bromoethane, the procedure was the same as in Example 43, yielding 169 mg of a pale yellow oily substance, with a yield of 83%. 1 HNMR(500MHz, CDCl3)δ8.11-8.03(m,2H),7.71–7.65(m,1H),7.55–7.48(m,1H),7.38(s,1H),6.13(ddd,J=17.0,10.5,7.8Hz,1H),5.34(br s,1H),5.19–5.05(m,2H),3.53–3.30(m,3H),3.09–2.88(m,5H),2.85–2.75(m,1H),2.32–2.24(m,1H),2.21–2.12(m,1H),1.86–

[0232] 1.74(m,3H),1.70–1.52(m,3H),1.51–1.37(m,5H),1.18–1.10(m,1H),1.01–0.86(m,6H).ESI-MS m / z calcd.for C 27 H 39 N2O + [M+H]+:407.3,found:407.2.

[0233] Example 46: (1S,2R,4S,5R)-2-((S)-(benzo[d][1,3]dioxo-4-ylmethoxy)(2-butylquinoline-4-yl)methyl)-5-vinylquinine

[0234]

[0235] Using 4-(bromomethyl)benzo[d][1,3]dioxo instead of bromoethane, the procedure was the same as in Example 43, yielding 188 mg of a pale yellow oil, with a yield of 78%. 1H NMR (500MHz, CDCl3) δ813–8.02(m,2H),7.68(ddd,J=8.3,6.8,1.3Hz,1H),7.51(ddd,J=8.2,6.8,1.3Hz,1H),7.45(br s,1H),6.90–6.72(m,3H),5.99(ddd,J=17.1,10.3,7.8Hz,1H),5.87(dd,J=2.9,1.5Hz,2H),5.45(br s,1H),5.08–4.92(m,2H),4.52-4.36(m,2H),3.37(br s,1H),3.12–3.01(m,1H),2.98–2.83(m,3H),2.81–2.70(m,1H),2.29–2.22(m,1H),2.17–2.10(m,1H),1 .84–1.71(m,3H),1.58–1.50(m,1H),1.49–1.40(m,3H),1.35–1.15(m,3H),0.96(t,J=7.4Hz,3H).ESI-MS m / z calcd.forC 31 H 37 N2O3 +

[0236] [M+H]+:485.3,found:485.2.

[0237] Experimental Example: PD-1 / PD-L1 Inhibitory Activity Assay

[0238] The determination method is as follows:

[0239] (1) Preparation of standard solutions

[0240] Accurately dissolve 2–3 mg of the standard in a 0.5 mL EP tube, and dilute with an appropriate volume of DMSO to prepare an initial concentration of 20 mM. Then dilute with DMSO to the required stock solution concentration. Take 3 μL of the sample DMSO stock solution into a 0.5 mL EP tube and dilute 20 times with the diluent provided with the HTRF kit (purchased from Cisbio, Cat#64ICP01PEG) for later use.

[0241] (2) Preparation of protein solution

[0242] Dilute the two proteins in the kit, Tag1-PD-L1 protein (T1) and Tag2-PD1 protein (T2), to concentrations of 25 nM and 250 nM respectively using diluent. Prepare the other two proteins in the kit, anti-Tag1-Eu. 3+(A1) and anti-Tag2-XL665 (A2) were diluted 100 times and 25 times respectively with diluent for later use.

[0243] (3) Sample addition and determination

[0244] Sample loading: For each concentration of all samples, double-duplicate loading was set up. 2 μL of sample diluent, 4 μL of T1 solution, and 4 μL of T2 solution were added sequentially to the 96-well shallow plate. After incubation at room temperature for 15 min, 10 μL of equal volume of premixed solution A1 and A2 was added.

[0245] Sample addition for control groups: There are four control groups (double duplicate wells) in this experiment.

[0246] Control group (10 μL diluent, 10 μL test solution); Cryptorate control group (10 μL diluent, 5 μL test solution, 5 μL anti-Tag1-Eu); Negative control group (6 μL diluent, 4 μL Tag2-PD1); Positive control group (2 μL diluent, 4 μL Tag1-PD-L1, 4 μL Tag2-PD1, 10 μL premixed anti-Tag reagent). The order of sample addition was the same as that of the sample groups.

[0247] After adding the sample as described above, seal the plate with sealing film, incubate at room temperature overnight, and then use the HTRF module of a multi-functional microplate reader to measure the fluorescence signals at 620 nM and 665 nM, respectively.

[0248] (4) Data processing

[0249] Calculation of inhibition rate: First, calculate the ratio of fluorescence signals at 665nm and 620nm and then calculate the mean of each group. Ratio = Signal 665nm / Signal 620nm × 10 4 Inhibition rate (%) = (mean positive control group ratio - mean compound group ratio) / (mean positive control group ratio - mean negative control group ratio) × 100%. The experimental results are as follows:

[0250] Table 1: Inhibitory activity of some compounds against PD-1 / PD-L1

[0251]

[0252]

[0253] The above description is merely a specific embodiment of the present invention, enabling those skilled in the art to understand or implement the invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the invention. Therefore, the present invention is not to be limited to the embodiments described herein, but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. An application of a quinine ring derivative, characterized in that, The quinine ring derivative is used to prepare drugs for the prevention or treatment of diseases related to the PD-1 or PD-L1 signaling pathway; The diseases associated with the PD-1 or PD-L1 signaling pathway are cancers; The cancers mentioned are selected from skin cancer, urinary tract tumors, hematological malignancies, breast cancer, digestive system tumors, reproductive system tumors, nervous system tumors, and head and neck cancer. The general structural formula of the quinine ring derivative is: (IA11) In general formula IA11, n is an integer from 1 to 6, and m is an integer from 0 to 5; R' is selected from halogens, perhalogenated C1 to C3 alkyl groups, C1 to C6 alkoxy groups, C6 to C12 aryl groups, C6 to C12 aryl groups, -O-CH2-CH2-O- groups, or R' fused with a benzene ring to form naphthyl, quinolinyl, or quinoxalinyl groups.

2. The application as described in claim 1, characterized in that, The hematologic malignancy is lymphoma, and the nervous system tumor is brain tumor.

3. The application as described in claim 2, characterized in that, The brain tumor in question is a glioma.

4. The application as described in any one of claims 1-3, characterized in that, The quinine ring derivative is selected from any of the following compounds: ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； 。 5. A PD-1 or PD-L1 inhibitor, characterized in that, The PD-1 or PD-L1 inhibitor contains at least one of a quinine ring derivative, which is selected from any of the following compounds; ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； 。

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