A quinoline imidazole derivative, its preparation method and application

Abstract

This application provides a quinoline imidazole derivative, its preparation, and its application. The quinoline imidazole derivative has the structure shown in Formula I, exhibits excellent CDK9 inhibitory activity, and has high selectivity relative to CDK2, thus it can be used for the prevention and treatment of CDK9-mediated diseases.

Description

Technical Field

[0001] This invention relates to the field of pharmaceuticals, and more specifically, to a quinoline imidazole derivative, its preparation method, and its application. Background Technology

[0002] Cyclin-dependent kinases (CDKs) are a family of serine / threonine protein kinases that play a central role in various key cellular processes, including cell cycle progression, transcriptional regulation, and neuronal function. CDK9, as a key regulator of transcriptional elongation, forms a positive transcription elongation factor b complex with cyclin T, phosphorylating the C-terminal domain of RNA polymerase II. This drives the efficient transcriptional elongation of a series of genes, including short-lived survival-promoting genes such as Mcl-1, c-Myc, and XIAP. These genes play a decisive role in cell proliferation, differentiation, and apoptosis.

[0003] In recent years, research has revealed that abnormal CDK9 activation is closely related to the pathogenesis of various diseases, especially in the field of cancer. In many malignant tumors, dysregulation of CDK9 activity leads to the overexpression of its downstream pro-survival proteins, enabling cancer cells to evade apoptosis and develop resistance to traditional chemotherapy drugs. Therefore, selectively inhibiting CDK9 activity can rapidly downregulate these short-lived pro-survival proteins, efficiently inducing apoptosis in cancer cells, providing a highly attractive target for tumor therapy, particularly for refractory and relapsed hematologic malignancies and solid tumors.

[0004] Currently, several CDK small molecule inhibitors have entered clinical research stages. However, first-generation CDK inhibitors (such as Flavoiridol) are typically broad-spectrum inhibitors with poor selectivity for CDK9, and they also inhibit other family members such as CDK1 and CDK2, leading to severe dose-limiting toxicities, such as myelosuppression and gastrointestinal reactions, thus limiting their clinical application. Although second-generation selective CDK inhibitors (such as SNS-032 and AT-7519) have improved in selectivity, their pharmacokinetic properties, off-target effects, and the resulting adverse reactions such as cardiovascular toxicity and fatigue remain problems that urgently need to be addressed. Therefore, developing novel CDK9 inhibitors with entirely new chemical structures, high selectivity, high potency, and excellent pharmacokinetic properties has become an important direction in the field of anti-tumor drug development.

[0005] Quinoline and imidazole are both common and advantageous structures in medicinal chemistry, widely found in various bioactive small molecule drugs. Quinoline structures possess good planarity and rigidity, enabling effective π-π stacking interactions with the ATP-binding cavity of the kinase; while the imidazole ring can act as a hydrogen bond donor or acceptor, enhancing its binding affinity to key amino acid residues. By fusing or derivatizing these two pharmacophores through rational drug design, it is hoped that novel molecular frameworks capable of precisely targeting the CDK9 active pocket can be constructed.

[0006] Therefore, there is an urgent need in the field to provide a novel, highly selective, and highly effective CDK9 inhibitor to overcome the shortcomings of the prior art and provide new drug candidates for cancer treatment. Summary of the Invention

[0007] To address the problems existing in the prior art, this invention provides a quinoline imidazole derivative, and also provides its preparation method and application.

[0008] In a first aspect, the present invention provides a quinoline imidazole derivative of Formula I, a pharmaceutically acceptable salt thereof, and a stereoisomer thereof:

[0009]

[0010] Wherein, R1 is selected from R 11 -COR 12 ;

[0011] R 11 R 12 Each is independently selected from (C3-C10)cycloalkyl, (C6-C10)phenyl, 5-10 heteroaryl groups, which may be optionally substituted by one or more groups selected from halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-6 alkoxy or C1-6 alkylamino groups;

[0012] R2, R3, and R4 are each independently selected from hydrogen, halogen, hydroxyl, amino, (C1-C6)alkyl, and (C1-C6)alkoxy.

[0013] R5 is selected from CR 51 N;

[0014] R 51 Selected from hydrogen, (C1-C6)alkyl, halogen, hydroxyl, (C1-C6)alkoxy, (C3-C10)cycloalkyl, (C3-C10)cycloalkoxy, (C6-C10)phenyl, 5-10 heteroaryl;

[0015] R6 is selected from (C1-C6)alkyl, (C3-C10)cycloalkyl, and 4-10 membered heterocyclic groups having at least one N atom as a heteroatom, wherein the cycloalkyl or heterocyclic group is optionally substituted with one or more groups selected from halogen, hydroxyl, amino, C1-C6 alkyl, C1-6 alkoxy, hydroxy-substituted C1-C6 alkyl, C1-C6 alkylamino, and di(C1-C6 alkyl)amino groups.

[0016] In a preferred embodiment, the R 11 R 12 Each group is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, naphthyl, pyridyl, pyrimidinyl, furanyl, thiophene, and may be optionally substituted by one or more groups selected from halogen, hydroxyl, amino, cyano, C1-C4 alkyl, C1-4 alkoxy.

[0017] In a preferred embodiment, R1 is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, furanyl, thiophene, and -COR. 12 R 12 Selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0018] In a preferred embodiment, R2, R3, and R4 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, amino, (C1-C6)alkyl, and (C1-C6)alkoxy.

[0019] In a preferred embodiment, R2 and R4 are selected from hydrogen; R3 is selected from hydrogen, fluorine, chlorine, bromine, and iodine.

[0020] In a preferred embodiment, R 51 Selected from hydrogen, (C1-C6)alkyl, hydroxyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, and (C6-C10)phenyl.

[0021] In a preferred embodiment, R 51 It is selected from hydrogen, (C1-C6)alkyl, hydroxyl, (C1-C6)alkoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, and naphthyl.

[0022] In a preferred embodiment, R6 is selected from (C1-C6)alkyl, (C3-C8)cycloalkyl, 4-7 member monocyclic or bicyclic heterocyclic groups having only one N atom as a heteroatom, wherein the heterocyclic group is connected to the parent nucleus by a C atom, and the cyclic carbon atom of the cycloalkyl or heterocyclic group is optionally substituted with one or more groups selected from fluorine, chlorine, bromine, iodine, hydroxyl, amino, C1-C6 alkyl, C1-6 alkoxy, hydroxymethyl, hydroxyethyl, C1-C6 alkylamino, and di(C1-C6 alkyl)amino.

[0023] In a preferred embodiment, R6 is selected from (C1-C6) alkyl groups and one of the following structures:

[0024] .

[0025] In a preferred embodiment, R6 is selected from one of the following structures:

[0026] In a preferred embodiment, the quinoline imidazole derivative represented by Formula I is selected from:

[0027] .

[0028] The term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable organic or inorganic salt of the quinoline imidazole derivative. Exemplary salts include sulfates, acetates, oxalates, chlorides, bromides, iodides, nitrates, isonicotinate, lactates, salicylates, succinates, maleates, fumarates, formates, methanesulfonates, trifluoroacetates, etc.

[0029] Preferably, the pharmaceutically acceptable salt includes a trifluoroacetate. More preferably, in the trifluoroacetate, the molar ratio of the quinoline imidazole derivative to trifluoroacetic acid is 1:1.

[0030] The quinoline imidazole derivatives of the present invention may contain one or more chiral centers and thus exist as stereoisomers, such as enantiomers or diastereomers.

[0031] In a second aspect, the present invention also provides a pharmaceutical composition comprising the aforementioned quinoline imidazole derivative, a pharmaceutically acceptable salt thereof, and a stereoisomer.

[0032] In a preferred embodiment, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0033] In a third aspect, the present invention also provides the use of the quinoline imidazole derivative, its pharmaceutically acceptable salt, and stereoisomer in the preparation of CDK9 inhibitors.

[0034] The present invention also provides the use of the quinoline imidazole derivative, its pharmaceutically acceptable salt, and stereoisomers in the preparation of antiviral or antitumor drugs.

[0035] In a preferred embodiment, the virus is HIV, cytomegalovirus, EB virus, adenovirus, herpes simplex virus, or human T-cell lymphovirus.

[0036] In a preferred embodiment, the tumor is a glioma, various types of leukemia, lymphoma, liver cancer, stomach cancer, prostate cancer, ovarian cancer, breast cancer, or lung cancer.

[0037] In a fourth aspect, the present invention also provides a method for preparing the quinoline imidazole derivative, comprising:

[0038]

[0039] Among them, R1-R6 are as described in this article;

[0040] X1 is selected from chlorine or bromine, and X2 is selected from -B(OH)2 or... Alternatively, X2 may be selected from chlorine or bromine, and X1 may be selected from -B(OH)2 or... .

[0041] The preparation method further includes the steps of introducing a protecting group when necessary and removing the protecting group.

[0042] In this invention, the term halogen means fluorine, chlorine, bromine or iodine.

[0043] In this invention, the term alkyl means a straight-chain or branched alkyl group having 1-10 carbon atoms, or 1-6 carbon atoms, or 1-4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl.

[0044] In this invention, the term cycloalkyl means a straight-chain or branched alkyl group having 1-10 carbon atoms, or 1-6 carbon atoms, or 1-4 carbon atoms. Non-limiting examples of cycloalkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0045] In this invention, the term "cycloalkyl" refers to a saturated monocyclic cyclic hydrocarbon substituent comprising 3 to 10 carbon atoms, preferably 3 to 7 carbon atoms. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptyl, cyclooctyl, etc., with cyclopropyl being preferred.

[0046] In this invention, the term "aryl" refers to a 6- to 12-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6- to 12-membered, more preferably phenyl and naphthyl.

[0047] In this invention, the term "heteroaryl" refers to a 5- to 14-membered aryl group having 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen as ring atoms, with the remaining ring atoms being carbon. The heteroaryl group is preferably 5- to 10-membered, more preferably 5- or 6-membered, such as furanyl, thiophene, pyridyl, pyrroleyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc.

[0048] In this invention, the term "heterocyclic alkyl" refers to a saturated monocyclic, bicyclic, or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms, wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O)m (where m is an integer from 0 to 2), but excluding the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. Preferably, it comprises 3 to 12 ring atoms, or 3 to 7 ring atoms, wherein 1 to 4 are heteroatoms. Non-limiting examples of heterocyclic groups include azirrobutyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, 2-azirbicyclo[2.1.1]hexyl, etc.

[0049] The present invention provides a quinoline imidazole derivative that has excellent CDK9 inhibitory activity and high selectivity relative to CDK2, and therefore can be used for the prevention and treatment of CDK9-mediated diseases. Detailed Implementation

[0050] The invention is described in more detail below to aid in understanding it.

[0051] Those skilled in the art will recognize that the chemical reactions described in this invention can be suitably used to prepare many other compounds of this invention, and that other methods for preparing the compounds of this invention are considered to be within the scope of this invention. For example, the synthesis of those non-illustrative compounds according to this invention can be successfully accomplished by those skilled in the art through modification methods, such as by appropriately protecting interfering groups, by utilizing other known reagents besides those described in this invention, or by making some conventional modifications to the reaction conditions. Furthermore, the reactions disclosed in this invention or the known reaction conditions are also generally accepted to be applicable to the preparation of other compounds of this invention.

[0052] Synthesis example 1:

[0053]

[0054] 6-Bromo-4-chloro-3-nitroquinoline (36)

[0055] Phosphorus oxychloride (100 mL, 1.07 mol) and N,N-dimethylformamide (2 drops) were added to a flask containing 10 g (37.3 mmol) of 6-bromo-3-nitroquinoline-4-ol. The reaction mixture was stirred at 110 °C for 3 h. The reaction progress was monitored by thin-layer chromatography (petroleum ether / ethyl acetate = 8 / 1, v / v). After the reaction was complete, excess reagent was removed by vacuum distillation and the mixture was cooled to room temperature. The reaction mixture was slowly added to an ice-cold saturated sodium bicarbonate solution and extracted with dichloromethane (3 × 50 mL). The organic phases were combined, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1, v / v) to give a brown solid 36 (8.7 g, 82% yield). 1 H NMR (400 MHz, CDCl3) δ 9.22 (s, 1H), 8.53 (s, 1H), 8.04 (d, J =8.9 Hz, 1H), 7.97 (d, J = 8.9 Hz, 1H).

[0056] Synthesis example 2:

[0057]

[0058] (R)-3-((6-bromo-3-nitroquinoline-4-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester (37)

[0059] Compound 36 (5 g, 17.5 mmol) and (R)-3-aminopyrrolidine-1-carboxylic acid tert-butyl ester (6.5 g, 35.1 mmol) were dissolved in acetonitrile (110 mL), and N,N-diisopropylethylamine (DIPEA, 6.1 mL, 35.1 mmol) was added. The mixture was stirred at 25 °C for 3 hours, and the reaction progress was monitored by thin-layer chromatography (petroleum ether / ethyl acetate = 5 / 1, v / v). After the reaction was complete, the mixture was filtered, the residue was washed with acetonitrile, and dried to give compound 37 (6 g, 79% yield) as a yellow powder. 1 H NMR (400MHz, CDCl3) δ 9.72 – 9.45 (m, 1H), 9.38 (s, 1H), 8.33 (s, 1H), 7.96 – 7.80(m, 2H), 4.83 (s, 1H), 3.93 – 3.78 (m, 1H), 3.75 – 3.43 (m, 3H), 2.44 (s, 1H), 2.18 (s, 1H), 1.48 (s, 9H).

[0060] Synthesis example 3:

[0061]

[0062] (S)-3-((6-bromo-3-nitroquinoline-4-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester (38)

[0063] Following the synthetic method for compound 37, (R)-3-aminopyrrolidine-1-carboxylic acid tert-butyl ester was replaced with (S)-3-aminopyrrolidine-1-carboxylic acid tert-butyl ester to give compound 38, a yellow powder. Yield: 87%. ESI-MS m / z: 436.1 [M + H] + .

[0064] Synthesis example 4:

[0065]

[0066] (R)-3-((3-amino-6-bromoquinoline-4-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester (39)

[0067] Compound 37 (5.8 g, 13.3 mmol), iron powder (3.7 g, 66.5 mmol), and ammonium chloride (NH4Cl, 7.1 g, 134 mmol) were reacted in a mixed solvent of ethanol (120 mL) and water (30 mL) at 90 °C for 3 hours with stirring. After the reaction was complete, the reaction solution was cooled to room temperature, filtered through a diatomaceous earth mat, and water (100 mL) was added to the filtrate. The solution was extracted with dichloromethane (3 × 50 mL). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a yellow viscous compound 39 (4.6 g, 85% yield). 1 H NMR (400 MHz, CDCl3) δ 8.48 (s,1H), 7.88 (d, J = 2.1 Hz, 1H), 7.80 (d, J = 8.9 Hz, 1H), 7.49 (dd, J = 8.9,2.0 Hz, 1H), 4.19 – 4.13 (m, 1H), 4.03 (s, 2H), 3.72 – 3.21 (m, 5H), 2.15 –2.04 (m, 1H), 1.97 – 1.83 (m, 1H), 1.46 (d, J = 9.6 Hz, 9H).

[0068] Synthesis example 5:

[0069]

[0070] (S)-3-((3-amino-6-bromoquinoline-4-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester (40)

[0071] Following the synthetic method for compound 39, compound 37 was replaced with compound 38 to obtain a yellow, viscous compound 40. Yield: 89%. ESI-MS m / z: 406.1 [M + H] + .

[0072] Example 1:

[0073]

[0074] (R)-3-(8-bromo-1H-imidazo[4,5-c]quinolin-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (1a)

[0075] Acetic acid (0.2 mL) was added to a 2 mL ethanol solution of compound 39 (80 mg, 0.197 mmol) and triethyl orthoformate (88.8 mg, 0.600 mmol), and the mixture was stirred at 80 °C for 1 h. The reaction was monitored by TLC (ethyl acetate). Subsequently, the reaction solution was concentrated under reduced pressure and purified by column chromatography (gradient elution: petroleum ether / ethyl acetate = 1 / 2–1 / 5, v / v) to give a pale yellow oily compound 1a (65 mg, 79% yield). 1 H NMR (400 MHz, CDCl3) δ 9.30 (s, 1H), 8.24 (s, 1H), 8.13 (d, J = 8.9 Hz, 1H), 8.05 (s, 1H), 7.74 (d, J = 8.9 Hz, 1H), 5.47 (s, 1H), 4.28 – 3.92 (m, 2H), 3.80 – 3.61 (m, 1H), 3.60 – 3.39 (m, 1H), 2.66 (s, 1H), 2.52 – 2.37 (m, 1H), 1.48 (s, 9H).

[0076]

[0077] (R)-3-[8-(2-(cyclopropanecarbamoyl)pyridin-4-yl)-1H-imidazo[4,5-c]quinolin-1-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (1b)

[0078] Compound 1a (50 mg, 0.120 mmol), N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)pyridin-2-yl)cyclopropaneformamide (41.5 mg, 0.144 mmol), cesium carbonate (Cs₂CO₃, 117 mg, 0.360 mmol), and Pd(dppf)Cl₂ (4.4 mg, 0.006 mmol) were placed in a mixed solvent of 1,4-dioxane (2 mL) and water (0.5 mL). After degassing with nitrogen three times, the reaction mixture was heated at 95 °C for 12 hours. After the reaction was completed as monitored by TLC, water (6 mL) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (3 × 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was then purified by column chromatography (dichloromethane / methanol = 20 / 1, v / v) to give a pale yellow oily compound 1b (46 mg, yield 77%). 1H NMR (400 MHz, CDCl3) δ 9.35 (s, 1H), 9.16 (s, 1H), 8.68 (s, 1H), 8.48 (s, 1H), 8.35 (d, J = 9.1 Hz, 2H), 8.08 (s, 1H), 7.97 (d,J = 8.7 Hz, 1H), 7.35 (d, J = 5.1 Hz, 1H), 5.62 (brs, 1H), 4.36 – 3.99 (m,2H), 3.84 – 3.69 (m, 1H), 3.59 – 3.40 (m, 1H), 2.79 (s, 1H), 2.59 – 2.43 (m,1H), 1.75 – 1.59 (m, 1H), 1.49 (s, 9H), 1.13 (s, 2H), 0.97 – 0.86 (m, 2H).

[0079]

[0080] (R)-N-[4-(1-(pyrrolidone-3-yl)-1H-imidazo[4,5-c]quinolin-8-yl)pyridin-2-yl]cyclopropaneformamide 2,2,2-trifluoroacetate (1)

[0081] Compound 1b (30 mg, 0.060 mmol) was dissolved in hexafluoroisopropanol (HFIP, 2 mL), and trifluoroacetic acid (TFA, 0.4 mL) was added. The mixture was stirred at 30 °C for 6 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure and purified by preparative reversed-phase high-performance liquid chromatography (elution conditions: aqueous solution containing 0.1% TFA / acetonitrile = 82 / 18) to give compound 1 (26 mg, 85% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 9.77 (brs,1H), 9.58 (brs, 1H), 9.49 (s, 1H), 8.84 (s, 1H), 8.66 (s, 1H), 8.59 (s, 1H),8.47 (d, J = 5.2 Hz, 1H), 8.39 (d, J = 8.8 Hz, 1H), 8.14 (dd, J = 8.8, 1.8Hz, 1H), 7.66 (dd, J = 5.2, 1.7 Hz, 1H), 6.29 – 6.01 (m, 1H), 4.00 (s, 2H),3.58 (s, 2H), 2.89 – 2.76 (m, 1H), 2.76 – 2.65 (m, 1H), 2.14 – 2.02 (m, 1H), 0.99 – 0.76 (m, 4H); 13 C NMR (100 MHz, DMSO-d6) δ 173.1, 158.7 (q, J = 33.7Hz), 152.9, 148.5, 148.4, 144.2, 143.5, 141.6, 137.6, 136.7, 134.3, 128.9,126.9, 121.0, 119.7, 118.0, 117.7, 117.6, 115.1, 112.1, 111.7, 56.5, 49.7,44.1, 30.7, 14.3, 7.8 (2C); 19 F NMR (377 MHz, DMSO) δ -74.13.

[0082] Example 2:

[0083]

[0084] (S)-3-(8-bromo-1H-imidazo[4,5-c]quinolin-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (2a)

[0085] Following the synthetic method for compound 1a, compound 39 was replaced with compound 40 to obtain a yellow oily compound 2a. Yield: 77%. 1H NMR (400 MHz, CDCl3) δ 9.34 (s, 1H), 8.29 (s, 1H), 8.17 (d, J = 9.0Hz, 1H), 8.07 (s, 1H), 7.78 (d, J = 9.5 Hz, 1H), 5.51 (brs, 1H), 4.21 (s,1H), 4.03 (s, 1H), 3.71 (s, 1H), 3.52 (s, 1H), 2.68 (s, 1H), 2.53 – 2.39 (m,1H), 1.51 (s, 9H).

[0086]

[0087] (S)-3-[8-(2-(cyclopropanecarbamoyl)pyridin-4-yl)-1H-imidazo[4,5-c]quinoline-1-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (2b)

[0088] Following the same synthetic method as compound 1b, compound 1a was replaced with compound 2a to obtain a yellow oily compound 2b. The yield was 69%. 1 H NMR (400 MHz, CDCl3) δ 9.35 (s, 1H), 9.21 (s, 1H), 8.68 (s, 1H), 8.48 (s, 1H), 8.40 – 8.31 (m, 2H), 8.09 (s, 1H), 7.97 (d, J = 8.7 Hz, 1H),7.35 (d, J = 5.1 Hz, 1H), 5.62 (brs, 1H), 4.39 – 4.19 (m, 1H), 4.18 – 4.00(m, 1H), 3.83 – 3.64 (m, 1H), 3.61 – 3.41 (m, 1H), 2.88 – 2.70 (m, 1H), 2.55– 2.47 (m, 1H), 1.73 – 1.62 (m, 1H), 1.49 (s, 9H), 1.16 – 1.10 (m, 2H), 0.94– 0.88 (m, 2H).

[0089]

[0090] (S)-N-[4-(1-(pyrrolidone-3-yl)-1H-imidazo[4,5-c]quinolin-8-yl)pyridin-2-yl]cyclopropaneformamide 2,2,2-trifluoroacetate (2)

[0091] Following the same synthetic method as compound 1, 1b was replaced with 2b to obtain compound 2. It is a white solid with a yield of 85%. 1 HNMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.71 (brs, 1H), 9.60 (s, 1H), 9.53(brs, 1H), 8.90 (s, 1H), 8.50 (d, J = 5.2 Hz, 1H), 8.44 (d, J = 8.8 Hz, 1H), 8.20 (dd, J = 8.8, 1.8 Hz, 1H), 7.68 (dd, J = 5.3, 1.7 Hz, 1H), 6.27 – 6.16 (m, 1H), 4.01 (s, 2H), 3.59 (s, 2H), 2.89 – 2.78 (m, 1H), 2.78 – 2.67 (m,1H), 2.13 – 2.05 (m, 1H), 0.95 – 0.79 (m, 4H); 13 C NMR (100 MHz, DMSO-d6) δ173.6, 159.02 (q, J = 33.5 Hz), 153.3, 149.0, 148.8, 144.6, 144.0, 141.0,137.9, 137.5, 135.6, 128.4, 128.0, 121.1, 120.3, 118.2, 118.1, 118.0, 115.2,112.2, 57.0, 50.2, 44.6, 31.2, 14.8, 8.3 (2C); 19 F NMR (377 MHz, DMSO) δ -74.39.

[0092] Example 3:

[0093]

[0094] (R)-3-(8-bromo-1H-[1,2,3]triazolo[4,5-c]quinoline-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (3a)

[0095] Compound 39 (80 mg, 0.197 mmol) was dissolved in acetic acid (2 mL), and an aqueous solution of sodium nitrite (20.7 mg, 0.300 mmol) (0.4 mL) was added. The reaction mixture was stirred at room temperature for 12 hours, then a saturated aqueous solution of sodium bicarbonate was added, and the mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1, v / v) to give compound 3a (56 mg, 67% yield), a pale yellow oil. 1 H NMR (400 MHz, CDCl3) δ 9.52 (s, 1H), 8.32 (d, J = 15.4 Hz, 1H), 8.18 (d, J = 8.4 Hz, 1H), 7.89 (s, 1H), 5.70 (brs, 1H), 4.27 – 3.99 (m, 2H), 3.92– 3.64 (m, 2H), 3.16 – 2.61 (m, 2H), 1.44 (s, 9H).

[0096]

[0097] (R)-3-[8-(2-(cyclopropanecarbamoyl)pyridin-4-yl)-1H-[1,2,3]triazolo[4,5-c]quinoline-1-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (3b)

[0098] Following the synthetic method for compound 1b, compound 1a was replaced with compound 3a to obtain a yellow oily compound 3b. The yield was 77%. 1 H NMR (400 MHz, CDCl3) δ 9.60 (s, 1H), 8.76 (s, 1H), 8.55 (s, 1H), 8.48 – 8.36 (m, 2H), 8.14 (d, J = 8.5 Hz, 1H), 7.55 (d, J = 7.0 Hz, 1H), 7.41(s, 1H), 5.88 (s, 1H), 4.38 – 4.18 (m, 2H), 3.91 – 3.75 (m, 2H), 3.15 – 2.73(m, 2H), 1.72 (s, 1H), 1.47 (s, 9H), 1.19 – 1.13 (m, 2H), 1.01 – 0.93 (m,2H).

[0099]

[0100] (R)-N-[4-(1-(pyrrolidone-3-yl)-1H-[1,2,3]triazolo[4,5-c]quinolin-8-yl)pyridin-2-yl]cyclopropaneformamide 2,2,2-trifluoroacetate (3)

[0101] Following the same synthetic method as compound 1, 1b was replaced with 3b to obtain compound 3. It is a white solid with a yield of 77%. 1 HNMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 9.67 (brs, 2H), 9.49 (brs, 1H), 8.73 (d, J = 2.0 Hz, 1H), 8.60 (d, J = 1.6 Hz, 1H), 8.50 (d, J = 5.2 Hz, 1H), 8.42(d, J = 8.7 Hz, 1H), 8.22 (dd, J = 8.7, 2.0 Hz, 1H), 7.69 (dd, J = 5.2, 1.7Hz, 1H), 6.50 (brs, 1H), 4.27 – 4.16 (m, 1H), 4.02 – 3.89 (m, 1H), 3.62 (brs,1H), 3.46 (brs, 1H), 2.86 – 2.68 (m, 2H), 2.13 – 1.99 (m, 1H), 0.94 – 0.79(m, 4H); 13 C NMR (101 MHz, DMSO-d6) δ 173.5, 158.8 (q, J = 33.9 Hz), 153.3,149.0, 148.7, 146.0, 145.6, 141.3, 137.7, 133.3, 131.7, 129.0, 121.5, 118.2,116.0, 115.3, 112.2, 60.2, 50.2, 44.8, 31.7, 14.8, 8.3 (2C); 19 F NMR (377 MHz, DMSO) δ -74.32.

[0102] Example 4:

[0103]

[0104] (S)-3-(8-bromo-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (4a)

[0105] Following the synthetic method of compound 3a, compound 39 was replaced with compound 40 to obtain yellow oily compound 3a in 54% yield. 1 H NMR (400 MHz, CDCl3) δ 9.56 (s, 1H), 8.34 (s, 1H), 8.23 ​​(d, J = 8.9Hz, 1H), 7.94 (d, J = 8.9 Hz, 1H), 5.71 (s, 1H), 4.27 – 4.04 (m, 2H), 4.00 –3.63 (m, 2H), 3.16 – 2.78 (m, 1H), 2.78 – 2.61 (m, 1H), 1.47 (s, 9H).

[0106]

[0107] (S)-3-[8-(2-(cyclopropanecarbamoyl)pyridin-4-yl)-1H-[1,2,3]triazolo[4,5-c]quinoline-1-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (4b)

[0108] Following the synthetic method of compound 1b, compound 1a was replaced with compound 4a to obtain yellow oily compound 4b in 72% yield. 1 H NMR (400 MHz, CDCl3) δ 9.60 (s, 1H), 8.72 (s, 1H), 8.53 (s, 1H), 8.49 – 8.39 (m, 2H), 8.14 (d, J = 8.5 Hz, 1H), 7.56 (s, 1H), 7.39 (s, 1H),5.86 (s, 1H), 4.39 – 4.16 (m, 2H), 3.95 – 3.74 (m, 2H), 3.17 – 2.69 (m, 2H),1.70 (s, 1H), 1.47 (s, 9H), 1.16 (s, 2H), 0.96 (d, J = 6.7 Hz, 2H).

[0109]

[0110] (S)-N-[4-(1-(pyrrolidone-3-yl)-1H-[1,2,3]triazolo[4,5-c]quinolin-8-yl)pyridin-2-yl]cyclopropaneformamide 2,2,2-trifluoroacetate (4)

[0111] Following the same synthetic method as compound 1, compound 1b was replaced with compound 4b to obtain compound 4. It is a white solid with a yield of 73%.1 H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 9.68 (s, 1H), 9.50 (s, 1H), 9.42 (s, 1H), 8.74 (d, J = 2.0 Hz, 1H), 8.60 (s, 1H), 8.51 (d, J = 5.2 Hz,1H), 8.44 (d, J = 8.7 Hz, 1H), 8.24 (dd, J = 8.8, 1.9 Hz, 1H), 7.69 (dd, J =5.2, 1.7 Hz, 1H), 6.49 (s, 1H), 4.26 – 4.19 (m, 1H), 3.99 – 3.90 (m, 1H),3.61 (brs, 1H), 3.45 (brs, 1H), 2.81 – 2.70 (m, 2H), 2.13 – 2.04 (m, 1H), 0.93 – 0.80 (m, 4H); 13 C NMR (101 MHz, DMSO-d6) δ 173.5, 158.4, 153.4, 149.1,148.7, 146.0, 145.7, 141.3, 137.8, 133.3, 131.7, 129.0, 121.5, 118.3, 116.0,115.4, 112.2, 60.2, 50.3, 44.9, 31.6, 14.8, 8.3 (2C); 19 F NMR (377 MHz, DMSO) δ-74.17.

[0112] Example 5:

[0113]

[0114] (R)-3-(8-bromo-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (5a)

[0115] Compound 39 (65 mg, 0.160 mmol), triethyl orthoacetate (82 mg, 0.506 mmol), and acetic acid (0.5 mL) were dissolved in anhydrous ethanol (2 mL), and the mixture was stirred at 25 °C for 3 h. The reaction progress was monitored by TLC (dichloromethane / methanol = 15 / 1). After the reaction was complete, saturated sodium bicarbonate solution (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 × 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by rapid column chromatography (dichloromethane / methanol = 20 / 1, v / v) to give a pale yellow oily compound 5a (55 mg, 80% yield). 1 H NMR (400 MHz, CDCl3) δ 9.22 (s, 1H), 8.23 ​​(s, 1H), 8.12 (d, J = 8.9 Hz, 1H), 7.71 (d, J =8.8 Hz, 1H), 5.55 – 5.42 (m, 1H), 4.20 – 4.08 (m, 1H), 4.03 – 3.96 (m, 1H), 3.96 – 3.88 (m, 1H), 3.65 – 3.54 (m, 1H), 2.77 (s, 3H), 2.75 – 2.65 (m, 1H), 2.54 – 2.42 (m, 1H), 1.58 – 1.43 (m, 9H).

[0116]

[0117] (R)-3-[8-(2-(cyclopropanecarbamoyl)pyridin-4-yl)-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (5b)

[0118] Following the synthetic method for compound 1b, compound 1a was replaced with compound 5a to obtain compound 5b. It is a brown oil with a yield of 57%. 1H NMR (400 MHz, CDCl3) δ 9.31 (s, 1H), 9.26 (s, 1H), 8.64 (s, 1H), 8.44 – 8.35 (m, 3H), 8.10 – 7.88 (m, 1H), 7.30 (s, 1H), 5.55 (quint, J = 9.2Hz, 1H), 4.29 – 4.15 (m, 1H), 4.07 – 3.95 (m, 2H), 3.67 – 3.56 (m, 1H), 3.06– 2.88 (m, 1H), 2.82 (s, 3H), 2.56 (s, 1H), 1.71 (s, 1H), 1.48 – 1.29 (m, 9H), 1.15 (s, 2H), 1.00 – 0.90 (m, 2H).

[0119]

[0120] (R)-N-[4-(2-methyl-1-(pyrrolidone-3-yl)-1H-imidazo[4,5-c]quinolin-8-yl)pyridin-2-yl]cyclopropaneformamide 2,2,2-trifluoroacetate (5)

[0121] Following the same synthetic method as compound 1, compound 1b was replaced with compound 5b to obtain compound 5. It is a white solid with a yield of 76%. 1 H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 9.54 (s, 1H), 9.49 (brs,2H), 8.62 (s, 1H), 8.50 (d, J = 5.3 Hz, 1H), 8.44 (d, J = 8.8 Hz, 1H), 8.23(d, J = 8.6 Hz, 1H), 7.71 (dd, J = 5.2, 1.7 Hz, 1H), 6.33 – 6.16 (m, 1H), 3.99 (brs, 1H), 3.83 (brs, 1H), 3.73 (brs, 1H), 3.58 (brs, 1H), 2.90 (s, 3H),2.87 – 2.77 (m, 1H), 2.75 – 2.59 (m, 1H), 2.14 – 2.02 (m, 1H), 0.97 – 0.76 (m, 4H); 13C NMR (101 MHz, DMSO-d6) δ 173.7, 158.9 (q, J = 34.5 Hz), 155.7,153.3, 149.1, 148.7, 142.2, 138.1, 137.4, 136.0, 128.1, 127.6, 120.6, 118.3,118.1, 117.5, 115.1, 112.3, 55.4, 46.7, 44.7, 29.0, 17.5, 14.8, 8.4 (2C); 19 FNMR (377 MHz, DMSO) δ -74.44.

[0122] Example 6:

[0123]

[0124] (S)-3-(8-bromo-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (6a)

[0125] Following the synthetic method for compound 5a, compound 39 was replaced with compound 40 to obtain compound 6a. It is a yellow oil with a yield of 75%. 1 H NMR (400 MHz, CDCl3) δ 9.25 (s, 1H), 8.26 (s, 1H), 8.15 (d, J =8.9 Hz, 1H), 7.74 (d, J = 8.9 Hz, 1H), 5.51 (t, J = 9.4 Hz, 1H), 4.22 – 4.11(m, 1H), 4.06 – 3.99 (m, 1H), 3.99 – 3.90 (m, 1H), 3.68 – 3.56 (m, 1H), 2.80(s, 3H), 2.77 – 2.67 (m, 1H), 2.58 – 2.44 (m, 1H), 1.63 – 1.44 (m, 9H).

[0126]

[0127] (S)-3-[8-(2-(cyclopropanecarbamoyl)pyridin-4-yl)-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (6b)

[0128] Following the synthetic method for compound 1b, compound 1a was replaced with compound 6a to obtain compound 6b. It is a brown oil with a yield of 84%. 1H NMR (400 MHz, CDCl3) δ 9.76 – 9.54 (m, 1H), 9.27 (s, 1H), 8.65 (s, 1H), 8.44 – 8.29 (m, 3H), 8.08 – 7.86 (m, 1H), 7.29 (d, J = 6.3 Hz, 1H), 5.54 (quint, J = 9.4 Hz, 1H), 4.28 – 4.07 (m, 1H), 4.07 – 3.93 (m, 2H), 3.65 – 3.52 (m, 1H), 3.04 – 2.83 (m, 1H), 2.80 (s, 3H), 2.63 – 2.44 (m, 1H), 1.78– 1.66 (m, 1H), 1.46 – 1.24 (m, 9H), 1.13 (s, 2H), 0.91 (d, J = 7.9 Hz, 2H).

[0129]

[0130] (S)-N-[4-(2-methyl-1-(pyrrolidone-3-yl)-1H-imidazo[4,5-c]quinolin-8-yl)pyridin-2-yl]cyclopropaneformamide 2,2,2-trifluoroacetate (6)

[0131] Following the same synthetic method as compound 1, compound 1b was replaced with compound 6b to obtain compound 6. It is a white solid with a yield of 93%. 1 H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.61 (s, 1H), 9.53 (brs,2H), 8.74 (s, 1H), 8.61 (s, 1H), 8.51 (d, J = 5.2 Hz, 1H), 8.46 (d, J = 8.8Hz, 1H), 8.26 (d, J = 8.8 Hz, 1H), 7.71 (d, J = 5.2 Hz, 1H), 6.32 – 6.19 (m,1H), 4.00 (brs, 1H), 3.84 (brs, 1H), 3.73 (brs, 1H), 3.58 (brs, 1H), 2.92 (s, 3H), 2.88 – 2.76 (m, 1H), 2.76 – 2.61 (m, 1H), 2.15 – 2.04 (m, 1H), 0.94 –0.83 (m, 4H); 13C NMR (101 MHz, DMSO-d6) δ 173.7, 159.0 (q, J = 35.5 Hz), 156.2, 153.3, 149.0, 148.6, 141.5, 138.7, 137.7, 135.8, 128.5, 126.8, 120.8,118.3, 117.9, 117.4, 115.0, 112.3, 55.5, 46.7, 44.7, 29.0, 17.5, 14.8, 8.4(2C); 19 F NMR (377 MHz, DMSO) δ -74.58.

[0132] Example 7:

[0133]

[0134] (R)-3-(8-bromo-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (7a)

[0135] Following the synthetic method of compound 1a, triethyl orthoformate was replaced with triethyl orthopropionate to obtain compound 7a. It is a yellow oil with a yield of 81%. 1 H NMR (400 MHz, CDCl3) δ 9.27 (s, 1H), 8.24 (s, 1H), 8.14 (d, J = 9.0 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 5.59 – 5.37 (m, 1H), 4.24 –4.10 (m, 1H), 4.04 – 3.95 (m, 1H), 3.96 – 3.88 (m, 1H), 3.67 – 3.52 (m, 1H), 3.07 (q, J = 7.5 Hz, 2H), 2.83 – 2.67 (m, 1H), 2.52 – 2.38 (m, 1H), 1.55 –1.44 (m, 9H), 1.22 (t, J = 6.0 Hz, 3H).

[0136]

[0137] (R)-3-[8-(2-(cyclopropanecarbamoyl)pyridin-4-yl)-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (7b)

[0138] Following the synthetic method for compound 1b, compound 1a was replaced with compound 7a to obtain compound 7b. It is a brown oil with a yield of 85%. 1 H NMR (400 MHz, CDCl3) δ 9.40 (s, 1H), 9.31 (s, 1H), 8.60 (s, 1H), 8.36 (d, J = 9.6 Hz, 3H), 8.05 – 7.84 (m, 1H), 7.27 (d, J = 6.0 Hz, 1H), 5.51(s, 1H), 4.29 – 4.13 (m, 1H), 4.04 – 3.89 (m, 2H), 3.63 – 3.50 (m, 1H), 3.08(q, J = 7.4 Hz, 2H), 3.03 – 2.83 (m, 1H), 2.49 (s, 1H), 1.74 – 1.65 (m, 1H),1.52 (t, J = 7.4 Hz, 3H), 1.40 – 1.24 (m, 9H), 1.14 – 1.08 (m, 2H), 0.94 –0.87 (m, 2H).

[0139]

[0140] (R)-N-[4-(2-ethyl-1-(pyrrolidone-3-yl)-1H-imidazo[4,5-c]quinolin-8-yl)pyridin-2-yl]cyclopropaneformamide 2,2,2-trifluoroacetate (7)

[0141] Following the same synthetic method as compound 1, compound 1b was replaced with compound 7b to obtain compound 7. It is a white solid with a yield of 93%. 1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 9.66 (brs, 3H), 8.71 (s,1H), 8.49 (d, J = 5.2 Hz, 1H), 8.45 (d, J = 8.8 Hz, 1H), 8.26 (dd, J = 8.8,1.6 Hz, 1H), 7.70 (dd, J = 5.2, 1.7 Hz, 1H), 6.62 – 5.63 (m, 1H), 3.98 (brs,1H), 3.76 (brs, 2H), 3.59 (brs, 1H), 3.20 (q, J = 7.2 Hz, 2H), 2.91 – 2.76(m, 1H), 2.75 – 2.58 (m, 1H), 2.15 – 2.01 (m, 1H), 1.49 (t, J = 7.2 Hz, 3H), 0.95 – 0.79 (m, 4H); 13 C NMR (101 MHz, DMSO) δ 173.8, 160.9, 159.1 (q, J = 34.9Hz), 153.2, 148.9, 148.6, 141.5, 138.8, 137.7, 135.9, 128.6, 126.6, 120.9,118.3, 118.1, 117.4, 115.1, 112.3, 55.2, 46.7, 44.6, 29.0, 23.3, 14.8, 12.0,8.4 (2C); 19 F NMR (377 MHz, DMSO) δ -74.50.

[0142] Example 8:

[0143]

[0144] (R)-3-(8-bromo-2-cyclopropyl-1H-imidazo[4,5-c]quinoline-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (8a)

[0145] Compound 39 (800 mg, 1.97 mmol) was dissolved in ethanol (8 mL), and cyclopropaneformaldehyde (1380 mg, 19.7 mmol) was added. The mixture was stirred at 25 °C for 40 hours. The reaction progress was monitored by TLC (ethyl acetate). After the reaction was complete, the solvent was removed by concentration under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 6, v / v) to give compound 8a (630 mg, 70% yield), a pale yellow oil. 1 H NMR (400 MHz, CDCl3) δ 9.18 (s, 1H), 8.24 (s, 1H), 8.09 (d, J = 8.9 Hz, 1H), 7.69 (d, J = 8.9 Hz, 1H), 5.95 – 5.79 (m,1H), 4.11 – 3.93 (m, 3H), 3.66 – 3.54 (m, 1H), 2.85 – 2.67 (m, 1H), 2.59 –2.42 (m, 1H), 2.13 – 2.03 (m, 1H), 1.55 – 1.44 (m, 9H), 1.32 – 1.25 (m, 2H),1.23 – 1.19 (m, 2H).

[0146]

[0147] (R)-3-[8-(2-(cyclopropanecarbamoyl)pyridin-4-yl)-2-cyclopropyl-1H-imidazo[4,5-c]quinoline-1-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (8b)

[0148] Following the same synthetic method as compound 1b, compound 1a was replaced with compound 8a to obtain compound 8b. It is a brown oil with a yield of 71%. 1H NMR (400 MHz, CDCl3) δ 9.52 (s, 1H), 9.23 (s, 1H), 8.64 (s, 1H), 8.40 (s, 1H), 8.37 – 8.27 (m, 2H), 8.05 – 7.83 (m, 1H), 7.29 (d, J = 5.3 Hz,1H), 6.06 – 5.84 (m, 1H), 4.26 – 4.12 (m, 1H), 4.06 – 3.89 (m, 2H), 3.64 –3.54 (m, 1H), 3.07 – 2.83 (m, 1H), 2.56 (s, 1H), 2.15 – 2.05 (m, 1H), 1.74 –1.64 (m, 1H), 1.41 – 1.27 (m, 9H), 1.25 – 1.22 (m, 2H), 1.20 – 1.17 (m, 2H), 1.15 – 1.04 (m, 2H), 0.94 – 0.86 (m, 2H).

[0149]

[0150] (R)-N-[4-(2-cyclopropyl-1-(pyrrolidine-3-yl)-1H-imidazo[4,5-c]quinolin-8-yl)pyridin-2-yl]cyclopropaneformamide 2,2,2-trifluoroacetate (8)

[0151] Following the same synthetic method as compound 1, compound 1b was replaced with compound 8b to obtain compound 8. It is a white solid with a yield of 90%. 1H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.64 (brs, 1H), 9.46 (s,2H), 8.78 (d, J = 1.9 Hz, 1H), 8.64 (d, J = 1.7 Hz, 1H), 8.50 (d, J = 5.2 Hz,1H), 8.39 (d, J = 8.8 Hz, 1H), 8.21 (dd, J = 8.7, 1.7 Hz, 1H), 7.72 (dd, J =5.3, 1.7 Hz, 1H), 6.52 – 6.25 (m, 1H), 4.09 – 3.97 (m, 2H), 3.75 (brs, 1H),3.59 (brs, 1H), 2.98 – 2.71 (m, 2H), 2.49 – 2.38 (m, 1H), 2.14 – 2.02 (m,1H), 1.41 – 1.22 (m, 4H), 0.96 – 0.79 (m, 4H); 13 C NMR (101 MHz, DMSO-d6) δ173.6, 158.9, 158.5, 153.4, 149.1, 148.8, 143.4, 136.9, 136.6, 135.9, 130.1,129.4, 126.9, 120.1, 118.2, 117.6, 115.6, 112.1, 55.3, 46.8, 45.0, 29.6,14.8, 11.3, 10.8, 10.7, 8.3 (2C); 19 F NMR (376 MHz, DMSO) δ -74.26.

[0152] Example 9:

[0153]

[0154] (R)-3-(8-bromo-2-isopropyl-1H-imidazo[4,5-c]quinolin-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (9a)

[0155] Following the synthetic method of compound 8a, cyclopropaneformaldehyde was replaced with isobutyraldehyde to obtain compound 9a. It was a yellow oil with a yield of 78%.

[0156] 1H NMR (400 MHz, CDCl3) δ 9.35 (s, 1H), 8.28 (s, 1H), 8.16 (d, J = 8.9Hz, 1H), 7.76 (d, J = 8.7 Hz, 1H), 5.67 – 5.48 (m, 1H), 4.30 – 4.15 (m, 1H),4.09 – 3.93 (m, 2H), 3.70 – 3.59 (m, 1H), 3.46 – 3.34 (m, 1H), 2.94 – 2.72(m, 1H), 2.56 – 2.39 (m, 1H), 1.60 – 1.53 (m, 9H), 1.52 (d, J = 8.8 Hz, 6H).

[0157]

[0158] (R)-3-[8-(2-(cyclopropanecarbamoyl)pyridin-4-yl)-2-isopropyl-1H-imidazo[4,5-c]quinoline-1-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (9b)

[0159] Following the synthetic method for compound 1b, compound 1a was replaced with compound 9a to obtain compound 9b. It is a brown oil with a yield of 51%. 1 H NMR (400 MHz, CDCl3) δ 9.39 (s, 1H), 9.07 – 8.83 (m, 1H), 8.71 –8.56 (m, 1H), 8.47 – 8.34 (m, 3H), 8.11 – 7.91 (m, 1H), 7.32 (d, J = 5.4 Hz,1H), 5.69 – 5.53 (m, 1H), 4.37 – 4.20 (m, 1H), 4.09 – 3.95 (m, 2H), 3.62 (d,J = 9.5 Hz, 1H), 3.43 (p, J = 6.8 Hz, 1H), 3.02 (t, J = 11.3 Hz, 1H), 2.53(s, 1H), 1.79 – 1.64 (m, 1H), 1.57 (t, J = 6.6 Hz, 6H), 1.47 – 1.27 (m, 9H), 1.21 – 1.11 (m, 2H), 1.01 – 0.91 (m, 2H).

[0160]

[0161] (R)-N-[4-[2-isopropyl-1-(pyrrolidone-3-yl)-1H-imidazo[4,5-c]quinolin-8-yl]pyridin-2-yl]cyclopropaneformamide 2,2,2-trifluoroacetate (9)

[0162] Following the same synthetic method as compound 1, compound 1b was replaced with compound 9b to obtain compound 9. It is a white solid with a yield of 87%. 1 H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 9.68 (brs, 1H), 9.53 (brs,2H), 8.61 (dd, J = 4.1, 1.7 Hz, 2H), 8.50 (d, J = 5.2 Hz, 1H), 8.41 (d, J =8.8 Hz, 1H), 8.20 (dd, J = 8.8, 1.7 Hz, 1H), 7.69 (dd, J = 5.2, 1.7 Hz, 1H), 6.30 – 6.04 (m, 1H), 4.00 (brs, 1H), 3.81 (brs, 1H), 3.60 (brs, 2H), 3.55 –3.33 (m, 1H), 3.01 – 2.81 (m, 1H), 2.76 – 2.56 (m, 1H), 2.15 – 1.99 (m, 1H), 1.45 (t, J = 6.4 Hz, 6H), 1.00 – 0.78 (m, 4H); 13 C NMR (101 MHz, DMSO-d6) δ173.7, 163.9, 158.8, 153.3, 149.1, 148.8, 143.1, 140.8, 137.2, 136.8, 136.6,128.5, 127.7, 120.9, 118.3, 117.7, 115.3, 112.2, 54.7, 47.2, 44.6, 29.4,28.2, 22.9, 22.8, 14.8, 8.4 (2C); 19 F NMR (377 MHz, DMSO) δ -74.32.

[0163] Example 10:

[0164]

[0165] (R)-3-(8-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (10a)

[0166] Compound 39 (80 mg, 0.197 mmol) was dissolved in anhydrous ethanol (2 mL), and triethyl orthobutyrate (187 mg, 0.985 mmol) and acetic acid (0.5 mL) were added. The reaction mixture was stirred at 80 °C for 1 h. The reaction progress was monitored by TLC (dichloromethane / methanol = 25 / 1). After the reaction was complete, saturated sodium bicarbonate solution (10 mL) was added, and the mixture was extracted with ethyl acetate (3 × 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by rapid column chromatography (dichloromethane / methanol = 28 / 1, v / v) to give compound 10a (68 mg, 76% yield), a pale yellow oil. 1 H NMR(400 MHz, CDCl3) δ 9.27 (s, 1H), 8.26 (s, 1H), 8.15 (d, J = 9.2 Hz, 1H), 7.75(d, J = 8.9 Hz, 1H), 5.57 – 5.42 (m, 1H), 4.27 – 3.92 (m, 3H), 3.69 – 3.57(m, 1H), 3.05 (t, J = 8.0 Hz, 2H), 2.89 – 2.70 (m, 1H), 2.55 – 2.38 (m, 1H),1.96 – 1.85 (m, 2H), 1.56 – 1.48 (m, 9H), 1.36 – 1.18 (m, 2H), 1.02 (t, J = 7.4 Hz, 3H).

[0167]

[0168] (R)-3-[8-(2-(cyclopropanecarbamoyl)pyridin-4-yl)-2-propyl-1H-imidazo[4,5-c]quinoline-1-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (10b)

[0169] Following the same synthetic method as compound 1b, compound 1a was replaced with compound 10a to obtain compound 10b. It is a brown oil with a yield of 61%.

[0170] ESI-MS m / z 540.28 [M + H]+.

[0171]

[0172] (R)-N-[4-(2-propyl-1-(pyrrolidone-3-yl)-1H-imidazo[4,5-c]quinolin-8-yl]pyridin-2-yl]cyclopropaneformamide 2,2,2-trifluoroacetate (10)

[0173] Following the same synthetic method as compound 1, compound 1b was replaced with compound 10b to obtain compound 10. It is a white solid with a yield of 75%. 1 H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.90 – 9.42 (m, 3H), 8.65 (s, 1H), 8.60 (s, 1H), 8.49 (d, J = 5.1 Hz, 1H), 8.42 (d, J = 8.8 Hz,1H), 8.21 (d, J = 8.8 Hz, 1H), 7.69 (dd, J = 5.3, 1.8 Hz, 1H), 6.27 – 6.10(m, 1H), 4.08 – 3.90 (m, 1H), 3.88 – 3.65 (m, 2H), 3.68 – 3.54 (m, 1H), 3.13(t, J = 7.4 Hz, 2H), 2.94 – 2.76 (m, 1H), 2.75 – 2.58 (m, 1H), 2.18 – 2.05(m, 1H), 2.05 – 1.94 (m, 2H), 1.09 (t, J = 7.3 Hz, 3H), 0.93 – 0.83 (m, 4H); 13 C NMR (101 MHz, DMSO-d6) δ 173.7, 159.1, 159.1 (q, J = 34.2 Hz), 153.3,149.1, 148.7, 142.5, 140.3, 137.6, 137.3, 136.3, 127.9 (2C), 120.8, 118.3,117.5,116.8 (q, J = 295.2 Hz), 112.2, 56.5, 46.7, 44.5, 31.3, 29.0, 21.0,19.0, 14.1, 8.4 (2C); 19 F NMR (376 MHz, DMSO) δ -74.32.

[0174] Example 11:

[0175]

[0176] (R)-3-(8-bromo-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (11a)

[0177] Following the synthetic method of compound 10a, triethyl orthobutyrate was replaced with triethyl orthovalerate to obtain compound 11a. It is a yellow oil with a yield of 49%. 1 H NMR (400 MHz, CDCl3) δ 9.25 (s, 1H), 8.22 (s, 1H), 8.11(d, J = 8.9 Hz, 1H), 7.70 (d, J = 9.0 Hz, 1H), 5.57 – 5.39 (m, 1H), 4.28 –4.09 (m, 1H), 4.04 – 3.84 (m, 2H), 3.66 – 3.52 (m, 1H), 3.02 (t, J = 8.0 Hz,2H), 2.84 – 2.66 (m, 1H), 2.53 – 2.35 (m, 1H), 1.93 – 1.79 (m, 2H), 1.55 –1.42 (m, 11H), 0.98 (t, J = 7.4 Hz, 3H).

[0178]

[0179] (R)-3-[2-butyl-8-(2-(cyclopropanecarbamoyl)pyridin-4-yl)-1H-imidazo[4,5-c]quinoline-1-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (11b)

[0180] Following the synthetic method for compound 1b, compound 1a was replaced with compound 11a to obtain compound 11b. It is a brown oil with a yield of 86%. ESI-MS m / z 554.3 [M + H]+.

[0181]

[0182] (R)-N-[4-(2-butyl-1-(pyrrolidone-3-yl)-1H-imidazo[4,5-c]quinolin-8-yl)pyridin-2-yl]cyclopropaneformamide 2,2,2-trifluoroacetate (11)

[0183] Following the same synthetic method as compound 1, compound 1b was replaced with compound 11b to obtain compound 11. It is a white solid with a yield of 80%. 1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 10.19 – 9.20 (m, 3H), 8.61 (s, 1H), 8.58 (s, 1H), 8.49 (d, J = 5.2 Hz, 1H), 8.38 (d, J = 8.8 Hz,1H), 8.15 (dd, J = 8.8, 1.7 Hz, 1H), 7.68 (dd, J = 5.2, 1.7 Hz, 1H), 6.21 –6.03 (m, 1H), 3.97 (brs, 1H), 3.87 – 3.69 (m, 2H), 3.62 (brs, 1H), 3.13 (t, J= 7.5 Hz, 2H), 2.91 – 2.75 (m, 1H), 2.75 – 2.59 (m, 1H), 2.18 – 2.03 (m, 1H), 1.94 (quint, J = 7.6 Hz, 2H), 1.60 – 1.44 (m, 2H), 0.99 (t, J = 7.3 Hz, 3H),0.95 – 0.81 (m, 4H); 13 C NMR (101 MHz, DMSO-d6) δ 173.7, 159.0 (q, J = 33.3Hz), 158.4, 153.3, 149.1, 148.9, 143.6, 141.9, 136.9, 136.6, 136.4, 129.4,127.2, 120.7, 118.2, 117.7, 117.1 (q, J = 296.3 Hz), 112.2, 54.9, 46.7, 44.5,29.8, 29.2, 28.8, 22.3, 14.8, 14.4, 8.4 (2C); 19 F NMR (376 MHz, DMSO) δ -74.05.

[0184] Example 12:

[0185]

[0186] (R)-3-(8-bromo-2-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (12a)

[0187] Following the synthetic method of compound 10a, triethyl butyrate was replaced with phenyltriethoxymethane to obtain compound 12a. It is a yellow oil with a yield of 69%.1 H NMR (400 MHz, CDCl3) δ 9.36 (s, 1H), 8.16 (d, J =9.0 Hz, 1H), 8.02 (dd, J = 8.4, 1.5 Hz, 1H), 7.83 – 7.70 (m, 1H), 7.66 (dd, J= 6.7, 2.9 Hz, 2H), 7.62 – 7.56 (m, 3H), 5.61 – 5.42 (m, 1H), 4.19 – 4.05 (m,1H), 4.05 – 3.99 (m, 1H), 3.99 – 3.88 (m, 1H), 3.52 – 3.41 (m, 1H), 2.89 –2.71 (m, 1H), 2.41 – 2.27 (m, 1H), 1.51 – 1.46 (m, 9H).

[0188]

[0189] (R)-3-[8-(2-(cyclopropanecarbamoyl)pyridin-4-yl)-2-phenyl-1H-imidazo[4,5-c]quinolin-1-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (12b)

[0190] Following the synthetic method for compound 1b, compound 1a was replaced with compound 12a to obtain compound 12b. It is a brown oil with a yield of 74%. 1 H NMR (400 MHz, CDCl3) δ 9.44 (s, 1H), 8.86 (d, J = 7.0 Hz, 1H), 8.60 (s, 1H), 8.50 – 8.35 (m, 3H), 8.13 – 7.95 (m, 1H), 7.71 (dd, J = 6.5,3.0 Hz, 2H), 7.67 – 7.58 (m, 3H), 7.33 (s, 1H), 5.67 – 5.48 (m, 1H), 4.29 –4.17 (m, 1H), 4.06 – 3.95 (m, 1H), 3.95 – 3.86 (m, 1H), 3.48 – 3.39 (m, 1H), 3.23 – 2.97 (m, 1H), 2.52 – 2.38 (m, 1H), 1.68 (s, 1H), 1.43 – 1.27 (m, 9H), 1.15 (s, 2H), 0.96 – 0.91 (m, 2H).

[0191]

[0192] (R)-N-[4-[2-phenyl-1-(pyrrolidone-3-yl)-1H-imidazo[4,5-c]quinolin-8-yl]pyridin-2-yl]cyclopropaneformamide 2,2,2-trifluoroacetate (12)

[0193] Following the same synthetic method as compound 1, compound 1b was replaced with compound 12b to obtain compound 12. It is a white solid with a yield of 85%. 1 H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.48 (s, 1H), 9.24 (brs,1H), 8.91 (brs, 1H), 8.62 (d, J = 1.7 Hz, 1H), 8.49 (d, J = 5.3 Hz, 1H), 8.46– 8.39 (m, 2H), 8.19 (dd, J = 8.7, 1.7 Hz, 1H), 7.86 – 7.78 (m, 2H), 7.74 –7.59 (m, 4H), 5.84 – 5.70 (m, 1H), 3.81 (brs, 1H), 3.64 – 3.33 (m, 3H), 2.82– 2.59 (m, 2H), 2.09 (quint, J = 6.4 Hz, 1H), 0.95 – 0.81 (m, 4H); 13 C NMR (151MHz, DMSO-d6) δ 173.8, 158.6 (q, J = 32.8 Hz), 156.0, 153.4, 149.3, 149.2,146.0, 144.5, 137.7, 136.7, 135.2, 131.7, 131.3, 131.0, 130.4, 129.5, 126.6,120.9, 118.1, 118.1, 116.1, 112.1, 56.0, 47.3, 44.0, 28.3, 14.8, 8.4 (2C); 19 FNMR (377 MHz, DMSO) δ -74.03.

[0194] Example 13:

[0195]

[0196] (R)-3-(8-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (13a)

[0197] Compound 39 (40 mg, 0.0985 mmol) was dissolved in anhydrous THF (2 mL), and triphosgene (29 mg, 0.0985 mmol) and N,N-diisopropylethylamine (DIPEA, 38 mg, 0.296 mmol) were added. The reaction mixture was stirred at 25 °C for 23 hours. The reaction progress was monitored by TLC (dichloromethane / methanol = 20 / 1, v / v). After the reaction was complete, the solvent was removed by concentration under reduced pressure, and the crude product was purified by rapid column chromatography (dichloromethane / methanol = 20 / 1, v / v) to give compound 13a (24 mg, 57% yield), which was a pale yellow oil. 1 H NMR (400 MHz, CDCl3) δ 10.56 (s, 1H), 8.98 (s, 1H), 8.20 (s,1H), 8.08 (s, 1H), 7.66 (d, J = 8.4 Hz, 1H), 5.58 (s, 1H), 4.04 – 3.78 (m,3H), 3.60 – 3.48 (m, 1H), 2.90 – 2.65 (m, 1H), 2.43 – 2.30 (m, 1H), 1.53 (s,9H).

[0198]

[0199] (R)-3-[8-(2-(cyclopropanecarbamoyl)pyridin-4-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinoline-1-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (13b)

[0200] Following the synthetic method for compound 1b, compound 1a was replaced with compound 13a to obtain compound 13b. It is a brown oil with a yield of 44%. 1H NMR (400 MHz, CDCl3) δ 9.38 (s, 1H), 9.06 (s, 1H), 8.90 (s, 1H), 8.67 (s, 1H), 8.47 – 8.30 (m, 3H), 8.00 (d, J = 8.7 Hz, 1H), 7.34 (s, 1H),5.46 – 5.34 (m, 1H), 4.21 – 4.11 (m, 1H), 4.06 – 3.98 (m, 1H), 3.65 – 3.53(m, 1H), 2.54 (s, 2H), 2.06 – 1.97 (m, 1H), 1.73 (s, 1H), 1.37 (s, 9H), 1.16 (s, 2H), 0.98 – 0.95 (m, 2H).

[0201]

[0202] (R)-N-[4-(2-oxo-1-(pyrrolidone-3-yl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl)pyridin-2-yl]cyclopropaneformamide 2,2,2-trifluoroacetate (13)

[0203] Following the same synthetic method as compound 1, compound 1b was replaced with compound 13b to obtain compound 13. It is a white solid with a yield of 87%. 1 H NMR (400 MHz, DMSO-d6) δ 12.31 (s, 1H), 11.02 (s, 1H), 9.31 (brs, 1H), 8.93 (s, 1H), 8.77 (brs, 1H), 8.61 (s, 1H), 8.57 (s, 1H), 8.48 (d,J = 5.2 Hz, 1H), 8.27 (d, J = 8.9 Hz, 1H), 8.09 (dd, J = 9.0, 1.7 Hz, 1H), 7.66 (dd, J = 5.3, 1.8 Hz, 1H), 5.95 (brs, 1H), 4.10 (brs, 1H), 3.71 – 3.55(m, 2H), 3.44 (brs, 1H), 2.73 – 2.61 (m, 1H), 2.55 (brs, 1H), 2.12 – 2.02 (m,1H), 0.93 – 0.78 (m, 4H); 13C NMR (101 MHz, DMSO) δ 173.5, 167.4, 158.9, 158.5,154.3, 153.3, 149.1, 148.8, 141.8, 136.6, 132.5, 128.9, 127.4, 122.6, 120.1,118.1, 115.5, 115.3, 112.0, 55.1, 47.8, 46.0, 30.8, 14.8, 8.3 (2C); 19 F NMR (377 MHz, DMSO) δ -74.32.

[0204] Example 14:

[0205]

[0206] (R)-3-(8-bromo-2-methoxy-1H-imidazo[4,5-c]quinolin-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (14a)

[0207] To compound 39 (50 mg, 0.123 mmol), glacial acetic acid (0.5 mL) and tetramethoxymethane (50 mg, 0.369 mmol) were added. The reaction mixture was stirred at 80 °C for 1.5 h. The reaction progress was monitored by TLC (dichloromethane / methanol = 20 / 1, v / v). After the reaction was complete, the mixture was cooled to room temperature, and saturated sodium bicarbonate solution (10 mL) was added. The mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by rapid column chromatography (dichloromethane / methanol = 20 / 1, v / v) to give compound 14a (50 mg, 91% yield), a pale yellow oil. 1 H NMR (400MHz, CDCl3) δ 9.14 (s, 1H), 8.24 (d, J = 2.1 Hz, 1H), 8.11 (d, J = 9.0 Hz,1H), 7.70 (s, 1H), 5.64 – 5.50 (m, 1H), 4.27 (s, 3H), 4.03 – 3.86 (m, 3H), 3.63 – 3.55 (m, 1H), 2.75 – 2.59 (m, 1H), 2.51 – 2.37 (m, 1H), 1.56 – 1.48 (m, 9H).

[0208]

[0209] (R)-3-[8-(2-(cyclopropanecarbamoyl)pyridin-4-yl)-2-methoxy-1H-imidazo[4,5-c]quinoline-1-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (14b)

[0210] Following the synthetic method for compound 1b, compound 1a was replaced with compound 14a to obtain compound 14b. It is a brown oil with a yield of 85%.

[0211] 1 H NMR (400 MHz, CDCl3) δ 9.48 (s, 1H), 9.15 (s, 1H), 8.66 (d, J =15.7 Hz, 1H), 7.97 – 7.84 (m, 1H), 7.30 (s, 1H), 5.66 (s, 1H), 4.26 (s, 3H),4.04 – 3.75 (m, 3H), 3.64 – 3.50 (m, 1H), 2.83 – 2.67 (m, 1H), 2.52 (s, 1H),1.77 – 1.64 (m, 1H), 1.49 – 1.32 (m, 9H), 1.12 (s, 2H), 0.95 – 0.85 (m, 2H).

[0212]

[0213] (R)-N-[4-(2-methoxy-1-(pyrrolidone-3-yl)-1H-imidazo[4,5-c]quinolin-8-yl)pyridin-2-yl]cyclopropaneformamide 2,2,2-trifluoroacetate (14)

[0214] Following the same synthetic method as compound 1, compound 1b was replaced with compound 14b to obtain compound 14. It is a white solid with a yield of 93%.

[0215] 1H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 10.00 (brs, 1H), 9.60 (brs,1H), 9.48 (s, 1H), 8.72 (d, J = 1.8 Hz, 1H), 8.51 (s, 1H), 8.46 (d, J = 5.3Hz, 1H), 8.38 (d, J = 8.9 Hz, 1H), 8.18 (dd, J = 9.0, 1.6 Hz, 1H), 7.66 (dd,J = 5.3, 1.7 Hz, 1H), 6.33 – 6.20 (m, 1H), 4.32 (s, 3H), 4.10 – 3.92 (m, 1H),3.92 – 3.78 (m, 1H), 3.74 – 3.61 (m, 1H), 3.56 – 3.45 (m, 1H), 2.86 – 2.69(m, 1H), 2.66 – 2.52 (m, 1H), 2.14 – 2.02 (m, 1H), 0.94 – 0.79 (m, 4H); 13 C NMR(101 MHz, DMSO-d6) δ 173.5, 159.7, 159.5 (q, J = 33.9 Hz), 159.0, 153.2,148.8, 148.2, 138.3, 137.8, 137.6, 137.0, 133.1, 128.9, 124.9, 121.3, 120.0,118.4, 118.1, 116.4, 115.4, 112.5, 112.10, 59.4, 56.1, 47.9, 45.5, 30.7,14.8, 8.3 (2C); 19 F NMR (377 MHz, DMSO) δ -74.38.

[0216]

[0217] (R)-3-(8-bromo-2-ethoxy-1H-imidazo[4,5-c]quinolin-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (15a)

[0218] Compound 39 (80 mg, 0.197 mmol) was dissolved in anhydrous ethanol (2 mL), and tetraethoxymethane (189.1 mg, 0.985 mmol) and acetic acid (0.5 mL) were added. The reaction mixture was stirred at 80 °C for 1 h. The reaction progress was monitored by TLC (dichloromethane / methanol = 25 / 1, v / v). After the reaction was complete, saturated sodium bicarbonate solution (3 mL) was added, and the mixture was extracted with ethyl acetate (3 × 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by rapid column chromatography (dichloromethane / methanol = 25 / 1, v / v) to give a pale yellow oil, compound 15a (78.8 mg, 87% yield).

[0219] 1 H NMR (400 MHz, CDCl3) δ 9.13 (s, 1H), 8.24 (d, J = 2.0 Hz, 1H), 8.15 (d, J = 9.0 Hz, 1H), 7.69 (dd, J = 9.0, 1.9 Hz, 1H), 5.60 (s, 1H), 4.70 (q, J= 7.1 Hz, 2H), 4.11 (q, J = 7.2 Hz, 1H), 4.08 – 3.84 (m, 3H), 3.67 – 3.53 (m,1H), 2.73 – 2.58 (m, 1H), 1.55 – 1.50 (m, 9H), 1.25 (t, J = 7.1 Hz, 3H).

[0220] Example 15:

[0221]

[0222] (R)-3-[8-(2-(cyclopropanecarbamoyl)pyridin-4-yl)-2-ethoxy-1H-imidazo[4,5-c]quinoline-1-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (15b)

[0223] Following the synthetic method for compound 1b, compound 1a was replaced with compound 15a to obtain compound 15b. It is a brown oil with a yield of 83%. 1H NMR (400 MHz, CDCl3) δ 9.15 (s, 1H), 8.94 (s, 1H), 8.70 – 8.58 (m, 1H), 8.42 – 8.30 (m, 3H), 7.93 (s, 1H), 7.32 (s, 1H), 5.77 – 5.61 (m,1H), 4.69 (q, J = 7.1 Hz, 2H), 4.04 – 3.69 (m, 3H), 3.66 – 3.50 (m, 1H), 2.85– 2.65 (m, 1H), 2.54 (s, 1H), 1.67 – 1.62 (m, 1H), 1.48 – 1.38 (m, 9H), 1.23– 1.20 (m, 3H), 1.13 – 1.10 (m, 2H), 0.93 – 0.88 (m, 2H).

[0224]

[0225] (R)-N-[4-(2-ethoxy-1-(pyrrolidone-3-yl)-1H-imidazo[4,5-c]quinolin-8-yl)pyridin-2-yl]cyclopropaneformamide 2,2,2-trifluoroacetate (15)

[0226] Following the synthetic method for compound 1, compound 1b was replaced with compound 15b to obtain compound 15. It is a white solid with a yield of 90%. 1H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 9.50 (brs, 2H), 9.35 (brs, 1H), 8.75 (d, J = 1.8 Hz, 1H), 8.58 (d, J = 1.7 Hz, 1H), 8.50 (d, J =5.2 Hz, 1H), 8.41 (d, J = 8.8 Hz, 1H), 8.21 (dd, J = 8.9, 1.7 Hz, 1H), 7.70 (dd, J = 5.2, 1.7 Hz, 1H), 6.29 – 6.17 (m, 1H), 4.81 – 4.73 (m, 2H), 3.95 –3.81 (m, 2H), 3.66 – 3.47 (m, 2H), 2.82 – 2.65 (m, 1H), 2.65 – 2.52 (m, 1H), 2.08 (quint, J = 6.2 Hz, 1H), 1.53 (t, J = 7.0 Hz, 3H), 0.93 – 0.80 (m, 4H); 13 C NMR (151 MHz, DMSO-d6) δ 173.5, 158.8 (q, J = 32.8 Hz), 158.3, 153.4 (2C),149.1, 148.8, 140.2, 137.0,136.1, 133.5, 127.6, 120.1, 119.8, 118.3, 118.1,116.9, 116.1, 114.2, 112.2 (2C), 68.7, 55.6, 47.9, 45.6, 30.1, 14.8, 14.6,8.3 (2C); 19 F NMR (377 MHz, DMSO) δ -74.03.

[0227] Example 16:

[0228]

[0229] (2R,4R)-4-((6-bromo-3-nitroquinoline-4-yl)amino)-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester (16a)

[0230] Compound 36 (120 mg, 0.418 mmol) was dissolved in acetonitrile (3 mL) with (2R,4R)-4-amino-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester (100 mg, 0.500 mmol) and N,N-diisopropylethylamine (80 mg, 0.620 mmol) was added. The reaction mixture was stirred at 25 °C for 1 hour, and the reaction was monitored by thin-layer chromatography (petroleum ether / ethyl acetate = 4 / 1, v / v). After the reaction was complete, the mixture was concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1, v / v) to give compound 16a (148 mg, 79% yield) as a yellow powder. ESI-MS m / z 450.1 [M + H]+.

[0231]

[0232] (2R,4R)-4-((3-amino-6-bromoquinoline-4-yl)amino)-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester (16b)

[0233] Compound 16a (120 mg, 0.267 mmol), iron powder (74.7 mg, 1.33 mmol), and ammonium chloride (142 mg, 2.67 mmol) were placed in a mixed solvent of ethanol (4 mL) and water (1 mL). The reaction mixture was stirred at 90 °C for 1 hour. After the reaction was complete, the mixture was cooled to room temperature, filtered through a diatomaceous earth mat, and water (10 mL) was added to the filtrate. The mixture was extracted with dichloromethane (3 × 15 mL). The combined organic phases were washed with saturated sodium chloride solution (25 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a yellow viscous compound 16b (91 mg, 81% yield).

[0234]

[0235] (2R,4R)-4-(8-bromo-2-ethoxy-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester (16c)

[0236] Following the synthetic method for compound 15a, compound 39 was replaced with compound 16b to obtain compound 16c. It is a yellow oil with a yield of 79%. 1H NMR (400 MHz, CDCl3) δ 9.12 (s, 1H), 8.19 (s, 1H), 8.08 (d, J= 9.0 Hz, 1H), 7.67 (dd, J = 8.9, 2.1 Hz, 1H), 5.78 – 5.51 (m, 1H), 4.68 (q,J = 7.1 Hz, 2H), 4.41 (s, 1H), 4.06 – 3.87 (m, 2H), 2.96 – 2.79 (m, 1H), 2.18 – 2.05 (m, 1H), 1.57 – 1.44 (m, 12H), 1.38 (d, J = 6.4 Hz, 3H).

[0237]

[0238] (2R,4R)-4-[8-(2-(cyclopropanecarbamoyl)pyridin-4-yl)-2-ethoxy-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester (16d)

[0239] Following the synthetic method for compound 1b, compound 1a was replaced with compound 16c to obtain compound 16d. It is a brown oil, with a yield of 86%. ESI-MS m / z 556.3 [M + H] + .

[0240]

[0241] N-[4-(2-ethoxy-1-((3R,5R)-5-methylpyrrolidone-3-yl)-1H-imidazo[4,5-c]quinolin-8-yl)pyridin-2-yl]cyclopropaneformamide 2,2,2-trifluoroacetate (16)

[0242] Following the synthetic method for compound 1, compound 16d was replaced with compound 16 to obtain compound 16. It is a white solid with a yield of 85%.

[0243] 1H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 9.70 (brs, 1H), 9.47 (s,1H), 9.33 (brs, 1H), 8.70 (d, J = 1.9 Hz, 1H), 8.60 (d, J = 1.7 Hz, 1H), 8.49(d, J = 5.2 Hz, 1H), 8.40 (d, J = 8.9 Hz, 1H), 8.21 (dd, J = 8.9, 1.7 Hz,1H), 7.71 (dd, J = 5.3, 1.7 Hz, 1H), 6.32 – 6.23 (m, 1H), 4.76 (q, J = 7.0Hz, 2H), 4.10 – 3.89 (m, 3H), 2.80 – 2.70 (m, 1H), 2.49 – 2.39 (m, 1H), 2.15– 2.00 (m, 1H), 1.54 (t, J = 7.0 Hz, 3H), 1.45 (d, J = 6.4 Hz, 3H), 0.95 –0.81 (m, 4H). 13 C NMR (101 MHz, DMSO-d6) δ 173.5, 158.9 (q, J = 33.6 Hz), 158.4, 153.4, 149.1, 148.5, 139.4, 138.8, 137.2, 136.9, 133.3, 128.1, 126.7,119.9, 118.1, 117.0 (q, J = 295.5 Hz), 112.6, 112.1, 68.9, 56.0, 55.9, 47.9,37.9, 17.3, 14.7, 14.6, 8.3 (2C). 19 F NMR (376 MHz, DMSO) δ -74.15.

[0244] Example 17:

[0245]

[0246] (3R,4S)-3-((6-bromo-3-nitroquinoline-4-yl)amino)-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (17a)

[0247] Following the synthetic method for compound 16a, (2R,4R)-4-amino-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester was replaced with (3R,4S)-3-amino-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester to obtain compound 17a. It is a yellow powdery solid with a yield of 63%. 1 H NMR (400 MHz, CDCl3) δ 9.39 (s, 1H), 9.17 (d, J = 10.6 Hz, 1H), 8.22(s, 1H), 7.99 – 7.84 (m, 2H), 5.20 – 4.90 (m, 1H), 4.76 – 4.52 (m, 1H), 4.33– 4.15 (m, 1H), 3.96 – 3.76 (m, 1H), 3.76 – 3.51 (m, 2H), 1.50 (s, 9H).

[0248]

[0249] (3R,4S)-3-((3-amino-6-bromoquinoline-4-yl)amino)-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (17b)

[0250] Following the synthetic method for compound 16b, compound 16a was replaced with 17a to obtain a yellow, viscous compound 17b. Yield: 73%. ESI-MS m / z: 424.1 [M + H] + .

[0251]

[0252] (3R,4S)-3-(8-bromo-2-ethoxy-1H-imidazo[4,5-c]quinolin-1-yl)-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (17c)

[0253] Following the synthetic method of compound 15a, compound 39 was replaced with compound 17b to obtain compound 17c. It is a yellow oil with a yield of 66%. 1 H NMR (400 MHz, CDCl3) δ 9.13 (s, 1H), 8.15 (s, 1H), 8.09 (d, J= 9.0 Hz, 1H), 7.68 (d, J = 10.9 Hz, 1H), 5.62 – 5.30 (m, 2H), 4.69 (q, J =7.1 Hz, 2H), 4.60 – 4.36 (m, 1H), 4.07 – 3.80 (m, 3H), 1.53 (s, 12H).

[0254]

[0255] (3R,4S)-3-[8-(2-(cyclopropanecarbamoyl)pyridin-4-yl)-2-ethoxy-1H-imidazo[4,5-c]quinolin-1-yl]-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (17d)

[0256] Following the synthetic method for compound 1b, compound 1a was replaced with compound 17c to obtain compound 17d. It is a brown oil with a yield of 64%. 1 H NMR (400 MHz, CDCl3) δ 9.18 (s, 1H), 8.66 (d, J = 13.2 Hz, 2H), 8.45 – 8.33 (m, 2H), 8.30 (d, J = 8.9 Hz, 1H), 7.93 (s, 1H), 7.37 (s, 1H),5.73 – 5.39 (m, 2H), 4.71 (t, J = 7.1 Hz, 2H), 4.60 – 3.86 (m, 4H), 1.62 (s,1H), 1.59 – 1.47 (m, 9H), 1.35 (s, 3H), 1.18 – 1.09 (m, 2H), 0.93 (d, J = 7.7Hz, 2H).

[0257]

[0258] N-[4-(2-ethoxy-1-((3R,4S)-4-fluoropyrrolidine-3-yl)-1H-imidazo[4,5-c]quinolin-8-yl]pyridin-2-yl]cyclopropaneformamide 2,2,2-trifluoroacetate (17)

[0259] Following the same synthetic method as compound 1, compound 1b was replaced with compound 17d to obtain compound 17. It is a white solid with a yield of 84%. 1H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 9.37 (brs, 2H), 8.62 (s,1H), 8.60 (d, J = 1.7 Hz, 1H), 8.47 (d, J = 5.2 Hz, 1H), 8.36 (d, J = 8.9 Hz,1H), 8.16 (d, J = 8.8 Hz, 1H), 7.70 (dd, J = 5.3, 1.6 Hz, 1H), 6.47 – 6.26(m, 1H), 6.02 – 5.79 (m, 1H), 4.71 (q, J = 7.0 Hz, 2H), 4.53 – 4.41 (m, 1H),4.04 – 3.78 (m, 3H), 2.07 (quint, J = 6.3 Hz, 1H), 1.48 (t, J = 7.0 Hz, 3H), 0.96 – 0.80 (m, 4H); 13 C NMR (101 MHz, DMSO-d6) δ 173.6, 159.1, 158.6, 153.3,149.0, 148.6, 141.2, 136.9, 135.3, 133.7, 128.7, 127.2, 119.6, 118.2, 117.0,115.5, 112.2, 90.7 (d, J = 186.5 Hz), 68.6, 57.4 (d, J = 17.3 Hz), 50.1 (d, J= 22.3 Hz), 44.1, 14.8, 14.6, 8.3 (2C); 19 F NMR (376 MHz, DMSO) δ -74.12, -190.99.

[0260] Example 18:

[0261]

[0262] (3R,4R)-3-((6-bromo-3-nitroquinoline-4-yl)amino)-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (18a)

[0263] Following the synthetic method for compound 16a, (2R,4R)-4-amino-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester was replaced with (3R,4R)-3-amino-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester to give compound 18a. It is a yellow powdery solid in 89% yield; ESI-MS m / z 454.1 [M + H]+ .

[0264]

[0265] (3R,4R)-3-((3-amino-6-bromoquinoline-4-yl)amino)-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (18b)

[0266] Following the synthetic method for compound 16b, compound 16a was replaced with 18a to obtain a yellow gelatinous compound 18b. Yield: 86%. ESI-MS m / z: 424.1 [M + H] + .

[0267]

[0268] (3R,4R)-3-(8-bromo-2-ethoxy-1H-imidazo[4,5-c]quinolin-1-yl)-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (18c)

[0269] Following the synthetic method for compound 15a, compound 39 was replaced with compound 18b to obtain compound 18c. It is a yellow oil with a yield of 51%. 1 H NMR (400 MHz, CDCl3) δ 9.08 (s, 1H), 8.17 (s, 1H), 8.07 (d, J= 9.0 Hz, 1H), 7.66 (d, J = 11.1 Hz, 1H), 5.70 – 5.46 (m, 2H), 4.67 (q, J =7.1 Hz, 2H), 4.23 – 4.12 (m, 1H), 4.04 – 3.77 (m, 3H), 1.53 – 1.47 (m, 12H).

[0270]

[0271] (3R,4R)-3-[8-(2-(cyclopropanecarbamoyl)pyridin-4-yl)-2-ethoxy-1H-imidazo[4,5-c]quinolin-1-yl]-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (18d)

[0272] Following the synthetic method for compound 1b, compound 1a was replaced with compound 18c to obtain compound 18d. It is a brown oil with a yield of 86%. 1H NMR (400 MHz, CDCl3) δ 9.18 (s, 1H), 8.65 (s, 1H), 8.44 – 8.28 (m, 4H), 7.97 (d, J = 9.4 Hz, 1H), 7.35 (s, 1H), 5.90 – 5.53 (m, 2H), 4.71(q, J = 7.1 Hz, 2H), 4.22 – 3.93 (m, 3H), 3.93 – 3.78 (m, 1H), 1.61 (t, J =4.4 Hz, 1H), 1.57 – 1.53 (m, 3H), 1.53 – 1.42 (m, 9H), 1.15 (s, 2H), 0.94(dd, J = 7.7, 3.2 Hz, 2H).

[0273]

[0274] N-[4-(2-ethoxy-1-((3R,4R)-4-fluoropyrrolidine-3-yl)-1H-imidazo[4,5-c]quinolin-8-yl)pyridin-2-yl]cyclopropaneformamide 2,2,2-trifluoroacetate (18)

[0275] Following the same synthetic method as compound 1, compound 1b was replaced with compound 18d to obtain compound 18. It is a white solid with a yield of 90%. 1 H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 10.17 (brs, 2H), 9.44(s, 1H), 8.67 (s, 1H), 8.54 (s, 1H), 8.49 (d, J = 5.2 Hz, 1H), 8.40 (d, J =8.9 Hz, 1H), 8.15 (d, J = 8.2 Hz, 1H), 7.62 (d, J = 4.6 Hz, 1H), 6.53 – 6.21(m, 1H), 6.17 – 5.84 (m, 1H), 4.74 (q, J = 7.0 Hz, 2H), 4.26 – 4.09 (m, 1H),4.04 – 3.93 (m, 1H), 3.93 – 3.72 (m, 2H), 2.07 (quint, J = 6.1 Hz, 1H), 1.52(t, J = 7.0 Hz, 3H), 0.91 – 0.81 (m, 4H); 13C NMR (101 MHz, DMSO-d6) δ 173.4,159.1 (q, J = 33.7 Hz), 158.0, 153.4, 149.1, 148.8, 140.3, 139.9, 137.3,136.0, 133.7, 127.9, 127.8, 121.3, 119.2, 118.4, 118.0, 116.8, 115.5, 112.5,112.2, 95.0 (d, J = 181.7 Hz), 69.0, 61.3 (d, J = 30.9 Hz), 50.9 (d, J = 25.2Hz), 46.9, 14.7, 14.5, 8.3 (2C); 19 F NMR (376 MHz, DMSO) δ -74.21, -174.81.

[0276] Example 19:

[0277]

[0278] (3S,4R)-3-((6-bromo-3-nitroquinoline-4-yl)amino)-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (19a)

[0279] Following the synthetic method for compound 16a, (2R,4R)-4-amino-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester was replaced with (3S,4R)-3-amino-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester to give compound 19a. It is a yellow powdery solid in 89% yield. ESI-MS m / z 454.1 [M + H] + .

[0280]

[0281] (3S,4R)-3-((3-amino-6-bromoquinoline-4-yl)amino)-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (19b)

[0282] Following the synthetic method for compound 16b, compound 16a was replaced with 19a to obtain a yellow gelatinous compound 19b. Yield: 86%. ESI-MS m / z: 424.1 [M + H] + .

[0283]

[0284] (3S,4R)-3-(8-bromo-2-ethoxy-1H-imidazo[4,5-c]quinolin-1-yl)-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (19c)

[0285] Following the synthetic method for compound 15a, compound 39 was replaced with compound 19b to obtain compound 19c. It is a yellow oil with a yield of 58%. ESI-MS m / z 478.1 [M + H] + .

[0286]

[0287] (3S,4R)-3-[8-(2-(cyclopropanecarbamoyl)pyridin-4-yl)-2-ethoxy-1H-imidazo[4,5-c]quinolin-1-yl]-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (19d)

[0288] Following the synthetic method of compound 1b, compound 1a was replaced with compound 19c to obtain compound 19d. It is a brown oil with a yield of 86%. 1 H NMR (400 MHz, CDCl3) δ 9.12 (s, 1H), 9.06 (s, 1H), 8.65 (s, 1H), 8.41 – 8.28 (m, 2H), 8.25 (d, J = 8.8 Hz, 1H), 7.88 (s, 1H), 7.31 (s, 1H),5.79 – 5.35 (m, 2H), 4.67 (q, J = 7.2 Hz, 2H), 4.04 – 3.79 (m, 4H), 1.66 (s,1H), 1.58 – 1.39 (m, 12H), 1.10 – 1.06 (m, 4H).

[0289]

[0290] N-[4-(2-ethoxy-1-((3S,4R)-4-fluoropyrrolidine-3-yl)-1H-imidazo[4,5-c]quinolin-8-yl]pyridin-2-yl]cyclopropaneformamide 2,2,2-trifluoroacetate (19)

[0291] Following the synthetic method for compound 1, compound 1b was replaced with compound 19d to obtain compound 19. It is a white solid with a yield of 93%. 1H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 9.97 (s, 2H), 9.47 (s,1H), 8.68 (d, J = 1.7 Hz, 1H), 8.60 (d, J = 1.6 Hz, 1H), 8.48 (d, J = 5.2 Hz,1H), 8.41 (d, J = 8.8 Hz, 1H), 8.22 (dd, J = 8.9, 1.6 Hz, 1H), 7.71 (dd, J =5.2, 1.6 Hz, 1H), 6.56 – 6.29 (m, 1H), 6.07 – 5.77 (m, 1H), 4.74 (q, J = 7.0Hz, 2H), 4.14 – 3.66 (m, 4H), 2.07 (p, J = 6.9 Hz, 1H), 1.50 (t, J = 7.0 Hz, 3H), 0.95 – 0.81 (m, 4H); 13 C NMR (101 MHz, DMSO-d6) δ 173.6, 159.6, 158.9,153.3, 149.0, 148.4, 139.7, 139.1, 137.4, 136.8, 133.5, 128.1, 126.9, 119.9,118.3, 116.8, 115.4, 112.3, 90.7 (d, J = 186.9 Hz), 68.9, 57.49 (d, J = 17.0Hz), 50.03 (d, J = 22.3 Hz), 44.1, 14.8, 14.5, 8.3 (2C); 19 F NMR (377 MHz, DMSO-d6) δ -74.30, -190.88.

[0292] Example 20:

[0293]

[0294] (3S,4S)-3-((6-bromo-3-nitroquinoline-4-yl)amino)-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (20a)

[0295] Following the synthetic method of compound 16a, (2R,4R)-4-amino-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester was replaced with (3S,4S)-3-amino-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester to obtain compound 20a. It is a yellow powdery solid with a yield of 95%. 1H NMR (400 MHz, CDCl3) δ 9.39 (s, 1H), 9.22 (d, J = 7.6 Hz, 1H), 8.37 (s,1H), 8.01 – 7.81 (m, 2H), 5.43 – 5.09 (m, 1H), 4.84 (s, 1H), 4.03 – 3.60 (m,4H), 1.51 (s, 9H).

[0296]

[0297] (3S,4S)-3-((3-amino-6-bromoquinoline-4-yl)amino)-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (20b)

[0298] Following the synthetic method for compound 16b, compound 16a was replaced with 20a to obtain a yellow gelatinous compound 20b. Yield: 86%. ESI-MS m / z: 424.1 [M + H]+.

[0299]

[0300] (3S,4S)-3-(8-bromo-2-ethoxy-1H-imidazo[4,5-c]quinolin-1-yl)-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (20c)

[0301] Following the synthetic method for compound 15a, compound 39 was replaced with compound 20b to obtain compound 20c. It is a yellow oil with a yield of 67%. 1 H NMR (400 MHz, CDCl3) δ 9.06 (d, J = 4.6 Hz, 1H), 8.16 (s, 1H), 8.03 (dd, J = 8.9, 3.5 Hz, 1H), 7.64 (d, J = 8.9 Hz, 1H), 5.68 – 5.44 (m,2H), 4.66 (q, J = 5.9 Hz, 2H), 4.20 – 3.75 (m, 4H), 1.49 (d, J = 6.1 Hz, 12H).

[0302]

[0303] (3S,4S)-3-[8-(2-(cyclopropanecarbamoyl)pyridin-4-yl)-2-ethoxy-1H-imidazo[4,5-c]quinolin-1-yl]-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (20d)

[0304] Following the synthetic method for compound 1b, compound 1a was replaced with compound 20c to obtain compound 20d. It is a brown oil, with a yield of 89%. ESI-MS m / z 460.2 [M + H] + .

[0305]

[0306] N-[4-(2-ethoxy-1-((3S,4S)-4-fluoropyrrolidine-3-yl)-1H-imidazo[4,5-c]quinolin-8-yl]pyridin-2-yl]cyclopropaneformamide 2,2,2-trifluoroacetate (20)

[0307] Following the same synthetic method as compound 1, compound 1b was replaced with compound 20d to obtain compound 20. It is a white solid with a yield of 88%. 1 H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 10.27 (brs, 2H), 9.51(s, 1H), 8.70 (d, J = 1.9 Hz, 1H), 8.52 (d, J = 1.7 Hz, 1H), 8.48 (d, J = 5.2Hz, 1H), 8.43 (d, J = 8.8 Hz, 1H), 8.20 (dd, J = 9.0, 1.7 Hz, 1H), 7.63 (dd,J = 5.3, 1.7 Hz, 1H), 6.40 – 6.28 (m, 1H), 6.16 – 5.92 (m, 1H), 4.75 (q, J =7.1 Hz, 2H), 4.30 – 4.06 (m, 1H), 4.04 – 3.93 (m, 1H), 3.92 – 3.72 (m, 2H), 2.19 – 1.92 (m, 1H), 1.52 (t, J = 7.0 Hz, 3H), 0.94 – 0.74 (m, 4H); 13C NMR(101 MHz, DMSO-d6) δ 173.5, 159.3 (q, J = 34.6 Hz), 158.4, 153.3, 148.9,148.7, 139.0, 138.3, 137.7, 137.3, 133.6, 128.7, 126.3, 119.5, 118.1, 116.7(q, J = 294.4 Hz), 116.6, 112.2, 94.9 (d, J = 181.9 Hz), 69.3, 61.4 (d, J =31.0 Hz), 50.9 (d, J = 25.4 Hz), 46.8, 14.7, 14.4, 8.3 (2C); 19 F NMR (376 MHz, DMSO) δ -74.39, -174.77.

[0308] Example 21:

[0309]

[0310] (2R,4R)-4-((6-bromo-3-nitroquinoline-4-yl)amino)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (21a)

[0311] Following the synthetic method of compound 16a, (2R,4R)-4-amino-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester was replaced with (2R,4R)-4-amino-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester to obtain compound 21a. It is a yellow powdery solid with a yield of 92%. 1 H NMR (400 MHz, CDCl3) δ 9.91 – 9.42 (m, 1H), 9.16 (s, 1H), 8.19 (s, 1H), 7.86 – 7.60 (m, 2H), 4.89 – 4.30 (m, 2H), 4.28 – 3.92 (m, 4H), 3.77– 3.45 (m, 2H), 2.81 – 2.58 (m, 1H), 1.44 (s, 9H).

[0312]

[0313] (2R,4R)-4-((3-amino-6-bromoquinoline-4-yl)amino)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (21b)

[0314] Following the synthetic method for compound 16b, compound 16a was replaced with 21a to obtain a yellow gelatinous compound 21b. Yield: 82%. ESI-MS m / z: 438.1 [M + H] + .

[0315]

[0316] (2R,4R)-4-(8-bromo-2-cyclopropyl-1H-imidazo[4,5-c]quinoline-1-yl)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (21c)

[0317] Following the synthetic method of compound 8a, compound 39 was replaced with compound 21b to obtain compound 21c. It is a yellow oil with a yield of 73%. 1 H NMR (400 MHz, CDCl3) δ 9.24 (s, 1H), 8.39 (d, J = 2.1 Hz, 1H), 8.15 (d, J = 8.9 Hz, 1H), 7.76 (dd, J = 8.7, 2.0 Hz, 1H), 5.81 (q, J = 9.7Hz, 1H), 5.20 (s, 1H), 4.26 – 4.15 (m, 3H), 4.06 – 3.84 (m, 2H), 2.61 (s,2H), 2.15 (d, J = 8.1 Hz, 1H), 1.53 (s, 9H), 1.31 (d, J = 10.2 Hz, 4H).

[0318]

[0319] (2R,4R)-4-[8-(2-(cyclopropanecarbamoyl)pyridin-4-yl)-2-cyclopropyl-1H-imidazo[4,5-c]quinoline-1-yl]-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (21d)

[0320] Following the synthetic method for compound 1b, compound 1a was replaced with compound 21c to obtain compound 21d. It is a brown oil, with a yield of 79%. ESI-MS m / z 568.3 [M + H] + .

[0321]

[0322] N-[4-(2-cyclopropyl-1-((3R,5R)-5-(hydroxymethyl)pyrrolidine-3-yl)-1H-imidazo[4,5-c]quinolin-8-yl]pyridin-2-yl]cyclopropaneformamide 2,2,2-trifluoroacetate (21)

[0323] Following the same synthetic method as compound 1, compound 1b was replaced with compound 21d to obtain compound 21. It is a white solid with a yield of 74%. 1 H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 9.79 (s, 1H), 9.36 (s,2H), 8.81 (s, 1H), 8.66 (s, 1H), 8.49 (d, J = 5.0 Hz, 1H), 8.35 (d, J = 8.7Hz, 1H), 8.17 (d, J = 8.8 Hz, 1H), 7.73 (d, J = 5.1 Hz, 1H), 6.57 – 6.38 (m,1H), 3.98 – 3.75 (m, 6H), 2.99 – 2.81 (m, 1H), 2.79 – 2.58 (m, 1H), 2.46 –2.34 (m, 1H), 2.15 – 2.00 (m, 1H), 1.42 – 1.21 (m, 4H), 0.98 – 0.78 (m, 4H); 13 C NMR (101 MHz, DMSO-d6) δ 173.7, 158.8 (2C), 153.4, 149.1, 148.6, 143.1,140.5, 136.5, 135.7, 132.2, 127.0, 120.1, 118.5, 118.1, 117.5, 115.6, 112.0,60.6, 59.6, 55.2, 46.5, 32.2, 14.8, 11.6, 11.1, 8.3 (2C); 19 F NMR (376 MHz, DMSO) δ -74.07.

[0324] Example 22:

[0325]

[0326] (2S,4R)-4-((6-bromo-3-nitroquinoline-4-yl)amino)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (22a)

[0327] Following the synthetic method of compound 16a, (2R,4R)-4-amino-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester was replaced with (2S,4R)-4-amino-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester to obtain compound 22a. It is a yellow powdery solid with a yield of 92%. 1 H NMR (400 MHz, CDCl3) δ 9.45 (d, J = 8.7 Hz, 1H), 9.26 (s, 1H), 8.31 (s, 1H), 7.86 – 7.63 (m, 2H), 5.03 – 4.74 (m, 1H), 4.29 – 3.90 (m, 2H), 3.89 – 3.54 (m, 4H), 2.29 (s, 2H), 1.43 (s, 9H).

[0328]

[0329] (2S,4R)-4-((3-amino-6-bromoquinoline-4-yl)amino)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (22b)

[0330] Following the synthetic method for compound 16b, compound 16a was replaced with 22a to obtain a yellow gelatinous compound 22b. Yield: 84%. ESI-MS m / z: 438.1 [M + H] + .

[0331]

[0332] (2S,4R)-4-(8-bromo-2-cyclopropyl-1H-imidazo[4,5-c]quinoline-1-yl)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (22c)

[0333] Following the synthetic method for compound 8a, compound 39 was replaced with compound 22b to obtain compound 22c. It is a yellow oil with a yield of 73%. 1H NMR (400 MHz, CDCl3) δ 9.22 (s, 1H), 8.24 (s, 1H), 8.13 (d, J =8.8 Hz, 1H), 7.71 (d, J = 6.5 Hz, 1H), 6.36 – 6.15 (m, 1H), 4.68 – 4.41 (m,1H), 4.19 – 3.98 (m, 3H), 3.82 – 3.66 (m, 2H), 3.03 – 2.86 (m, 1H), 2.60 –2.40 (m, 1H), 2.16 – 2.06 (m, 1H), 1.48 (s, 9H), 1.31 – 1.26 (m, 2H), 1.22 –1.17 (m, 2H).

[0334]

[0335] (2S,4R)-4-[8-(2-(cyclopropanecarbamoyl)pyridin-4-yl)-2-cyclopropyl-1H-imidazo[4,5-c]quinoline-1-yl]-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (22d)

[0336] Following the synthetic method for compound 1b, compound 1a was replaced with compound 22c to obtain compound 22d. It is a brown oil, with a yield of 83%. ESI-MS m / z 568.3 [M + H] + .

[0337]

[0338] N-[4-(2-cyclopropyl-1-((3R,5S)-5-(hydroxymethyl)pyrrolidine-3-yl)-1H-imidazo[4,5-c]quinolin-8-yl]pyridin-2-yl]cyclopropaneformamide 2,2,2-trifluoroacetate (22)

[0339] Following the same synthetic method as compound 1, compound 1b was replaced with compound 22d to obtain compound 22. It is a white solid with a yield of 58%. 1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 10.24 (s, 1H), 9.46 (s,1H), 9.29 (s, 1H), 8.70 (s, 1H), 8.57 (s, 1H), 8.49 (d, J = 5.3 Hz, 1H), 8.40(d, J = 8.8 Hz, 1H), 8.18 (d, J = 8.8 Hz, 1H), 7.67 (dd, J = 5.3, 1.7 Hz,1H), 6.44 (quint, J = 9.4 Hz, 1H), 4.30 (s, 1H), 4.09 (s, 2H), 3.94 – 3.83(m, 1H), 3.83 – 3.71 (m, 1H), 3.08 – 2.85 (m, 1H), 2.84 – 2.67 (m, 1H), 2.50 – 2.39 (m, 2H), 2.15 – 2.03 (m, 1H), 1.47 – 1.22 (m, 4H), 0.95 – 0.79 (m,4H); 13 C NMR (101 MHz, DMSO-d6) δ 173.7, 159.9, 159.1 (q, J = 34.0 Hz), 153.3,149.1, 148.7, 142.0, 139.9, 138.2, 137.3, 135.6, 127.9, 127.7, 120.1, 118.2,117.4,116.9 (q, J = 295.0 Hz), 112.1, 61.3, 60.4, 55.3, 47.6, 31.9, 14.8,11.3, 10.8 (2C), 8.3 (2C); 19 F NMR (376 MHz, DMSO) δ -74.25.

[0340] Example 23:

[0341]

[0342] (1R,3R)-3-((6-bromo-3-nitroquinoline-4-yl)amino)cyclopentylcarbamate tert-butyl ester (23a)

[0343] Following the synthetic method of compound 16a, (2R,4R)-4-amino-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester was replaced with (1R,3R)-3-aminocyclopentylcarbamate tert-butyl ester to obtain compound 23a. It is a yellow powdery solid with a yield of 64%. 1 H NMR (400 MHz, CDCl3) δ 9.71 (d, J = 7.9 Hz, 1H), 9.34 (s, 1H), 8.40 (s,1H), 7.89 – 7.79 (m, 2H), 4.77 – 4.68 (m, 1H), 4.61 (s, 1H), 4.26 – 4.14 (m,1H), 2.53 – 2.39 (m, 1H), 2.37 – 2.13 (m, 3H), 1.89 – 1.74 (m, 1H), 1.68 –1.56 (m, 1H), 1.45 (s, 9H).

[0344]

[0345] (1R,3R)-3-((3-amino-6-bromoquinoline-4-yl)amino)cyclopentylcarbamate tert-butyl ester (23b)

[0346] Following the synthetic method for compound 16b, compound 16a was replaced with 23a to obtain a yellow gelatinous compound 23b. Yield: 89%. ESI-MS m / z: 420.1 [M + H] + .

[0347]

[0348] (1R,3R)-3-(8-bromo-2-cyclopropyl-1H-imidazo[4,5-c]quinoline-1-yl)cyclopentylcarbamate tert-butyl ester (23c)

[0349] Following the synthetic method for compound 8a, compound 39 was replaced with compound 23b to obtain compound 23c. It is a yellow oil with a yield of 89%. 1H NMR (400 MHz, CDCl3) δ 9.17 (s, 1H), 8.29 (s, 1H), 8.12 (d, J =8.9 Hz, 1H), 7.68 (d, J = 8.9 Hz, 1H), 5.86 – 5.71 (m, 1H), 4.95 (s, 1H),4.52 – 4.39 (m, 1H), 2.90 – 2.74 (m, 1H), 2.60 – 2.44 (m, 3H), 2.34 (s, 1H),2.13 – 2.04 (m, 1H), 1.96 – 1.81 (m, 1H), 1.46 (s, 9H), 1.37 – 1.31 (m, 2H), 1.22 – 1.18 (m, 2H).

[0350]

[0351] (1R,3R)-3-[8-(2-(cyclopropanecarbamoyl)pyridin-4-yl)-2-cyclopropyl-1H-imidazo[4,5-c]quinoline-1-yl]cyclopentylcarbamate tert-butyl ester (23d)

[0352] Following the synthetic method of compound 1b, compound 1a was replaced with compound 23c to obtain compound 23d. It is a brown oil with a yield of 86%. 1 H NMR (400 MHz, CDCl3) δ 9.35 (s, 1H), 9.21 (s, 1H), 8.80 (s, 1H), 8.70 (s, 1H), 8.37 (dd, J = 14.4, 7.0 Hz, 2H), 7.97 (d, J = 10.6 Hz, 1H),7.47 (d, J = 5.1 Hz, 1H), 6.21 (s, 1H), 5.98 – 5.84 (m, 1H), 4.45 (s, 1H),2.98 – 2.84 (m, 1H), 2.64 – 2.35 (m, 4H), 2.21 – 2.08 (m, 1H), 2.01 – 1.90 (m, 1H), 1.79 – 1.66 (m, 1H), 1.41 (s, 9H), 1.34 – 1.25 (m, 2H), 1.23 – 1.19(m, 2H), 1.19 – 1.07 (m, 2H), 0.99 – 0.91 (m, 2H).

[0353]

[0354] N-[4-(1-((1R,3R)-3-aminocyclopentyl)-2-cyclopropyl-1H-imidazo[4,5-c]quinoline-8-yl)pyridin-2-yl]cyclopropanecarboxamide 2,2,2-trifluoroacetate (23)

[0355] Following the same synthetic method as compound 1, compound 1b was replaced with compound 23d to obtain compound 23. It is a white solid with a yield of 91%. 1 H NMR (400 MHz, DMSO) δ 11.10 (s, 1H), 9.53 (s, 1H), 8.68 – 8.57 (m, 2H), 8.51 (d, J = 5.2 Hz, 1H), 8.42 (d, J = 8.8 Hz, 1H), 8.33 – 8.13 (m,4H), 7.66 (dd, J = 5.2, 1.7 Hz, 1H), 6.24 – 6.05 (m, 1H), 4.13 (brs, 1H), 2.99 – 2.82 (m, 1H), 2.75 – 2.58 (m, 1H), 2.59 – 2.51 (m, 3H), 2.50 – 2.39(m, 2H), 2.15 – 2.05 (m, 1H), 2.05 – 1.93 (m, 1H), 1.40 – 1.22 (m, 4H), 0.99 – 0.80 (m, 4H); 13 C NMR (101 MHz, DMSO) δ 173.8, 161.0, 158.9 (q, J = 33.9 Hz), 153.4, 149.3, 148.6, 141.6, 139.2, 138.2, 137.3, 135.9, 128.1, 127.0, 121.3,120.9, 118.3, 118.2, 117.3, 115.4, 112.5, 111.8, 56.3, 50.4, 35.4, 30.2,30.1, 14.8, 10.7, 10.5, 10.3, 8.4 (2C); 19 F NMR (376 MHz, DMSO) δ -74.27.

[0356] Example 24:

[0357]

[0358] (1S,3R)-3-((6-bromo-3-nitroquinoline-4-yl)amino)cyclopentylcarbamate tert-butyl ester (24a)

[0359] Following the synthetic method of compound 16a, (2R,4R)-4-amino-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester was replaced with (1S,3R)-3-aminocyclopentylcarbamate tert-butyl ester to obtain compound 24a. It is a yellow powdery solid with a yield of 88%. 1 H NMR (400 MHz, CDCl3) δ 9.71 (d, J = 8.1 Hz, 1H), 9.31 (s, 1H), 8.40 (s,1H), 7.88 – 7.79 (m, 2H), 4.69 (s, 1H), 4.64 – 4.52 (m, 1H), 4.15 – 3.99 (m,1H), 2.77 – 2.65 (m, 1H), 2.34 – 2.10 (m, 2H), 2.03 – 1.91 (m, 1H), 1.84 –1.73 (m, 2H), 1.45 (s, 9H).

[0360]

[0361] (1S,3R)-3-((3-amino-6-bromoquinoline-4-yl)amino)cyclopentylcarbamate tert-butyl ester (24b)

[0362] Following the synthetic method for compound 16b, compound 16a was replaced with 24a to obtain a yellow gelatinous compound 24b. Yield: 82%. ESI-MS m / z: 420.1 [M + H]+.

[0363]

[0364] (1S,3R)-3-(8-bromo-2-cyclopropyl-1H-imidazo[4,5-c]quinoline-1-yl)cyclopentylcarbamate tert-butyl ester (24c)

[0365] Following the synthetic method for compound 8a, compound 39 was replaced with compound 24b to obtain compound 24c. It is a yellow oil with a yield of 93%. 1H NMR (400 MHz, CDCl3) δ 9.19 (s, 1H), 8.34 (s, 1H), 8.10 (d, J =8.9 Hz, 1H), 7.69 (d, J = 11.1 Hz, 1H), 5.68 – 5.50 (m, 1H), 4.87 (d, J = 7.5Hz, 1H), 4.28 (s, 1H), 2.74 – 2.60 (m, 1H), 2.60 – 2.50 (m, 1H), 2.50 – 2.32(m, 3H), 2.19 – 2.04 (m, 2H), 1.45 (s, 9H), 1.35 – 1.27 (m, 2H), 1.21 – 1.14(m, 2H).

[0366]

[0367] (1S,3R)-3-[8-(2-(cyclopropanecarbamoyl)pyridin-4-yl)-2-cyclopropyl-1H-imidazo[4,5-c]quinoline-1-yl]cyclopentylcarbamate tert-butyl ester (24d)

[0368] Following the synthetic method of compound 1b, compound 1a was replaced with compound 24c to obtain compound 24d. It is a brown oil with a yield of 81%. 1 H NMR (400 MHz, CDCl3) δ 9.54 (s, 1H), 9.24 (s, 1H), 8.73 (s, 1H), 8.49 (s, 1H), 8.36 (dd, J = 16.4, 7.0 Hz, 2H), 7.87 (d, J = 8.7 Hz, 1H), 7.35(d, J = 5.4 Hz, 1H), 6.55 (s, 1H), 5.56 (d, J = 10.8 Hz, 1H), 4.24 (s, 1H),2.72 – 2.54 (m, 2H), 2.54 – 2.39 (m, 1H), 2.39 – 2.21 (m, 3H), 2.16 – 2.06(m, 1H), 1.79 – 1.65 (m, 1H), 1.44 (s, 9H), 1.33 – 1.23 (m, 4H), 1.20 – 1.11(m, 2H), 0.98 – 0.88 (m, 2H).

[0369]

[0370] N-[4-(1-((1R,3S)-3-aminocyclopentyl)-2-cyclopropyl-1H-imidazo[4,5-c]quinoline-8-yl)pyridin-2-yl]cyclopropanecarboxamide 2,2,2-trifluoroacetate (24)

[0371] Following the same synthetic method as compound 1, compound 1b was replaced with compound 24d to obtain compound 24. It is a white solid with a yield of 83%. 1 H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 9.53 (s, 1H), 8.80 (d, J= 1.8 Hz, 1H), 8.67 (d, J = 1.6 Hz, 1H), 8.50 (d, J = 5.2 Hz, 1H), 8.41 (d, J = 8.8 Hz, 1H), 8.36 (d, J = 5.4 Hz, 3H), 8.27 (dd, J = 8.8, 1.7 Hz, 1H), 7.68 (dd, J = 5.3, 1.7 Hz, 1H), 6.13 – 5.87 (m, 1H), 3.90 (brs, 1H), 2.87 – 2.74(m, 1H), 2.74 – 2.61 (m, 2H), 2.61 – 2.52 (m, 2H), 2.45 – 2.26 (m, 1H), 2.23 – 2.01 (m, 2H), 1.45 – 1.23 (m, 4H), 0.99 – 0.78 (m, 4H); 13 C NMR (101 MHz, DMSO-d6) δ 173.7, 161.0, 158.9 (q, J = 34.0 Hz), 153.4, 149.2, 148.3, 141.1,138.8, 137.1, 135.4, 128.1, 126.4, 121.3, 120.4, 118.4, 118.0, 117.3, 115.4,111.9, 56.9, 49.2, 36.1, 28.8, 28.7, 14.8, 11.3, 11.2, 8.4 (2C); 19 F NMR (376MHz, DMSO) δ -74.25.

[0372] Example 25:

[0373]

[0374] (1S,4S,5R)-5-((6-bromo-3-nitroquinoline-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (25a)

[0375] Following the synthetic method of compound 16a, (2R,4R)-4-amino-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester was replaced with (1S,4S,5R)-5-amino-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester to obtain compound 25a. It is a yellow powder solid with a yield of 97%. 1 H NMR (400 MHz, CDCl3) δ 9.50 (s, 1H), 9.38 (s, 1H), 8.39 (s, 1H), 8.02 – 7.78 (m, 2H), 4.55 (s, 1H), 4.16 – 4.11 (m, 1H), 3.50 (s,2H), 3.24 (s, 1H), 1.85 – 1.61 (m, 2H), 1.53 – 1.41 (m, 9H).

[0376]

[0377] (1S,4S,5R)-5-((3-amino-6-bromoquinoline-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (25b)

[0378] Following the synthetic method for compound 16b, compound 16a was replaced with 25a to obtain a yellow gelatinous compound 25b. Yield: 97%. ESI-MS m / z: 418.1 [M + H] + .

[0379]

[0380] (1S,4S,5R)-5-(8-bromo-2-cyclopropyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (25c)

[0381] Following the synthetic method for compound 8a, compound 39 was replaced with compound 25b to obtain compound 25c. It is a yellow oil with a yield of 54%. 1H NMR (400 MHz, CDCl3) δ 9.17 (s, 1H), 8.25 (s, 1H), 8.11 (s, 1H), 7.69 (dd, J = 8.9, 2.2 Hz, 1H), 5.27 – 5.12 (m, 1H), 4.79 (s, 1H), 3.76 – 3.67 (m, 1H), 3.67 – 3.55 (m, 1H), 3.32 (s, 1H), 3.16 (s, 1H), 2.43 – 2.25 (m, 1H), 2.10 (s, 1H), 1.57 – 1.40 (m, 9H), 1.35 – 1.30 (m, 2H), 1.21 – 1.11(m, 2H).

[0382]

[0383] (1S,4S,5R)-5-(8-(2-(cyclopropanecarbamoyl)pyridin-4-yl)-2-cyclopropyl-1H-imidazo[4,5-c]quinoline-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (25d)

[0384] Following the synthetic method for compound 1b, compound 1a was replaced with compound 25c to obtain compound 25d. It is a brown oil with a yield of 69%. ESI-MS m / z 550.3 [M + H]+.

[0385]

[0386] N-[4-(1-((1S,4S,5R)-2-azabicyclo[2.1.1]hex-5-yl)-2-cyclopropyl-1H-imidazo[4,5-c]quinolin-8-yl)pyridin-2-yl]cyclopropanecarboxamide 2,2,2-trifluoroacetate (25)

[0387] Following the same synthetic method as compound 1, compound 1b was replaced with compound 25d to obtain compound 25. It is a white solid with a yield of 97%. 1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 9.47 (brs, 2H), 8.71 (brs, 3H), 8.51 (d, J = 5.2 Hz, 1H), 8.39 (d, J = 8.8 Hz, 1H), 8.25 (d, J =8.9 Hz, 1H), 7.67 (dd, J = 5.3, 1.7 Hz, 1H), 5.76 (brs, 1H), 5.00 (brs, 1H), 4.11 (brs, 1H), 3.47 (brs, 1H), 2.41 (brs, 2H), 2.09 (quint, J = 6.3 Hz, 1H),1.78 – 1.67 (m, 1H), 1.44 (brs, 1H), 1.38 – 1.25 (m, 2H), 1.27 – 1.12 (m,2H), 0.94 – 0.81 (m, 4H); 13 C NMR (151 MHz, DMSO-d6) δ 173.6, 159.8, 158.7 (q,J = 33.6 Hz), 153.5, 149.3, 148.2, 141.8, 140.0, 137.8, 136.7, 136.6, 127.6(2C), 121.6, 119.8, 117.8, 117.8, 117.3, 115.9, 113.9, 111.9, 63.0, 56.8,44.9, 43.5, 31.7, 14.8, 11.1, 9.6, 9.0, 8.3 (2C); 19 F NMR (376 MHz, DMSO) δ -74.21.

[0388] Example 26:

[0389]

[0390] (1S,4S,5R)-5-(8-bromo-2-ethoxy-1H-imidazo[4,5-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (26c)

[0391] Following the synthetic method for compound 15a, compound 39 was replaced with compound 25b to obtain compound 26c. It is a yellow oil with a yield of 74%. ESI-MS m / z 474.1 [M + H]+.

[0392]

[0393] (1S,4S,5R)-5-[8-(2-(cyclopropanecarbamoyl)pyridin-4-yl)-2-ethoxy-1H-imidazo[4,5-c]quinolin-1-yl]-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (26d)

[0394] Following the synthetic method for compound 1b, compound 1a was replaced with compound 26c to obtain compound 26d. It is a brown oil with a yield of 83%. ESI-MS m / z 554.3 [M + H]+.

[0395]

[0396] N-[4-(1-((1S,4S,5R)-2-azabicyclo[2.1.1]hexane-5-yl)-2-ethoxy-1H-imidazo[4,5-c]quinolin-8-yl]pyridin-2-yl]cyclopropaneformamide 2,2,2-trifluoroacetate (26)

[0397] Following the same synthetic method as compound 1, compound 1b was replaced with compound 26d to obtain compound 26. It is a white solid with a yield of 88%. 1 H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 9.86 (brs, 1H), 9.45 (s,1H), 8.90 (brs, 1H), 8.70 (d, J = 1.6 Hz, 1H), 8.66 (d, J = 1.9 Hz, 1H), 8.51(d, J = 5.2 Hz, 1H), 8.39 (d, J = 8.9 Hz, 1H), 8.27 (dd, J = 8.9, 1.8 Hz,1H), 7.67 (dd, J = 5.3, 1.7 Hz, 1H), 5.42 (s, 1H), 5.01 (d, J = 6.0 Hz, 1H),4.70 (q, J = 6.5 Hz, 2H), 3.80 – 3.71 (m, 1H), 3.44 (brs, 1H), 3.19 (brs,1H), 2.34 (d, J = 8.9 Hz, 1H), 2.15 – 2.03 (m, 1H), 1.68 (d, J = 9.3 Hz, 1H),1.51 (t, J = 7.0 Hz, 3H), 0.87 (d, J = 6.1 Hz, 4H); 13C NMR (101 MHz, DMSO-d6)δ 173.6, 159.0, 157.9, 154.0, 153.5, 149.3, 148.1, 140.4, 136.3, 136.0,134.2, 127.6, 127.2, 121.6, 120.8, 118.7, 117.7, 116.8, 115.9, 112.8, 111.7,68.5, 62.7, 55.5, 44.9, 43.7, 31.9, 14.7, 14.6, 8.3 (2C); 19 F NMR (377 MHz, DMSO) δ -74.32.

[0398] Example 27:

[0399]

[0400] (R)-3-((6-bromo-3-nitroquinoline-4-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (27a)

[0401] Following the synthetic method for compound 16a, (2R,4R)-4-amino-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester was replaced with (R)-3-aminopiperidine-1-carboxylic acid tert-butyl ester to give compound 27a. It is a yellow powdery solid in 84% yield. ESI-MS m / z 452.1 [M + H]+.

[0402]

[0403] (R)-3-((3-amino-6-bromoquinoline-4-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (27b)

[0404] Following the synthetic method for compound 16b, compound 16a was replaced with 27a to obtain a yellow gelatinous compound 27b. Yield: 93%. ESI-MS m / z: 422.1 [M + H]+.

[0405]

[0406] (R)-3-(8-bromo-2-ethoxy-1H-imidazo[4,5-c]quinolin-1-yl)piperidine-1-carboxylic acid tert-butyl ester (27c)

[0407] Following the synthetic method for compound 15a, compound 39 was replaced with compound 27b to obtain compound 27c. It is a yellow oil with a yield of 42%. 1H NMR (400 MHz, CDCl3) δ 9.08 (s, 1H), 8.28 (s, 1H), 8.07 (d, J= 8.9 Hz, 1H), 7.66 (dd, J = 8.9, 2.1 Hz, 1H), 4.84 – 4.71 (m, 1H), 4.66 (q,J = 7.1 Hz, 2H), 4.56 – 4.12 (m, 2H), 3.56 – 3.39 (m, 1H), 2.78 (s, 1H), 2.51(d, J = 12.0 Hz, 1H), 2.15 (d, J = 13.0 Hz, 1H), 1.92 (d, J = 13.9 Hz, 1H),1.75 (t, J = 13.3 Hz, 1H), 1.53 (t, J = 7.1 Hz, 3H), 1.48 (s, 9H).

[0408]

[0409] (R)-3-(8-(2-(cyclopropanecarbamoyl)pyridin-4-yl)-2-ethoxy-1H-imidazo[4,5-c]quinoline-1-yl)piperidine-1-carboxylic acid tert-butyl ester (27d)

[0410] Following the synthetic method for compound 1b, compound 1a was replaced with compound 27c to obtain compound 27d. It is a brown oil with a yield of 85%. 1H NMR (400 MHz, CDCl3) δ 9.28 (s, 1H), 9.13 (s, 1H), 8.71 (s, 1H), 8.46 (s, 1H), 8.34 (d, J = 5.2 Hz, 1H), 8.28 (d, J = 8.7 Hz, 1H), 7.90 (dd, J= 8.8, 1.8 Hz, 1H), 7.37 (s, 1H), 5.06 – 4.89 (m, 1H), 4.68 (q, J = 7.1 Hz,2H), 4.61 – 4.13 (m, 2H), 3.61 – 3.43 (m, 1H), 2.79 (s, 1H), 2.52 (d, J =12.7 Hz, 1H), 2.25 (s, 1H), 1.99 – 1.69 (m, 2H), 1.69 – 1.59 (m, 1H), 1.54(t, J = 7.1 Hz, 3H), 1.52 – 1.23 (m, 9H), 1.15 – 1.05 (m, 2H), 0.95 – 0.84(m, 2H).

[0411]

[0412] (R)-N-[4-(2-ethoxy-1-(piperidin-3-yl)-1H-imidazo[4,5-c]quinolin-8-yl)pyridin-2-yl]cyclopropaneformamide 2,2,2-trifluoroacetate (27)

[0413] Following the same synthetic method as compound 1, compound 1b was replaced with compound 27d to obtain compound 27. It is a white solid with a yield of 90%. 1H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.66 (brs, 1H), 9.42 (s,1H), 9.01 (brs, 1H), 8.62 (d, J = 12.1 Hz, 2H), 8.49 (d, J = 5.2 Hz, 1H), 8.39 (d, J = 8.8 Hz, 1H), 8.19 (d, J = 8.8 Hz, 1H), 7.68 (dd, J = 5.3, 1.6Hz, 1H), 5.56 (brs, 1H), 4.70 (q, J = 7.0 Hz, 1H), 3.90 – 3.70 (m, 2H), 3.50– 3.36 (m, 1H), 3.04 (brs, 1H), 2.43 – 2.23 (m, 2H), 2.14 – 2.02 (m, 1H), 1.52 (t, J = 7.0 Hz, 3H), 0.95 – 0.78 (m, 4H); 13 C NMR (101 MHz, DMSO-d6) δ173.5, 159.0 (q, J = 32.9 Hz), 158.9, 153.4, 149.1, 148.6, 139.7, 139.3,137.2, 136.1, 133.7, 128.0, 127.1, 121.5, 119.5, 118.5, 118.1, 116.7, 115.6,112.6, 112.1, 68.6, 52.5, 45.2, 43.4, 27.7, 22.0, 14.8, 14.7, 8.4 (2C); 19 F NMR (376 MHz, DMSO) δ -74.14.

[0414] Example 28:

[0415]

[0416] 3-((6-bromo-3-nitroquinoline-4-yl)amino)azacyclobutane-1-carboxylic acid tert-butyl ester (28a)

[0417] Following the synthetic method of compound 16a, (2R,4R)-4-amino-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester was replaced with 3-aminoazacyclobutane-1-carboxylic acid tert-butyl ester to obtain compound 28a. It is a yellow powdery solid with a yield of 95%. 1H NMR(400 MHz, CDCl3) δ 9.84 (d, J = 6.4 Hz, 1H), 9.36 (s, 1H), 7.95 – 7.82 (m,3H), 4.94 – 4.80 (m, 1H), 4.57 – 4.45 (m, 2H), 4.10 – 4.01 (m, 2H), 1.47 (s, 9H).

[0418]

[0419] 3-((3-amino-6-bromoquinoline-4-yl)amino)azacyclobutane-1-carboxylic acid tert-butyl ester (28b)

[0420] Following the synthetic method for compound 16b, compound 16a was replaced with 28a to obtain a yellow gelatinous compound 28b. Yield: 83%. ESI-MS m / z: 392.1 [M + H] + .

[0421]

[0422] 3-(8-bromo-2-ethoxy-1H-imidazo[4,5-c]quinolin-1-yl)azacyclobutane-1-carboxylic acid tert-butyl ester (28c)

[0423] Following the synthetic method for compound 15a, compound 39 was replaced with compound 28b to obtain compound 28c. It is a yellow oil with a yield of 81%. 1 H NMR (400 MHz, CDCl3) δ 9.09 (s, 1H), 8.32 (d, J = 2.1 Hz, 1H), 8.04 (d, J = 9.0 Hz, 1H), 7.66 (dd, J = 9.0, 2.0 Hz, 1H), 5.78 – 5.67 (m,1H), 4.70 (q, J = 7.1 Hz, 2H), 4.63 – 4.55 (m, 2H), 4.55 – 4.46 (m, 2H), 1.55 (t, J = 7.1 Hz, 3H), 1.49 (s, 9H).

[0424]

[0425] 3-(8-(2-(cyclopropanecarbamoyl)pyridin-4-yl)-2-ethoxy-1H-imidazo[4,5-c]quinoline-1-yl)azacyclobutane-1-carboxylic acid tert-butyl ester (28d)

[0426] Following the synthetic method for compound 1b, compound 1a was replaced with compound 28c to obtain compound 28d. It is a brown oil with a yield of 78%. ESI-MS m / z 528.2 [M + H]+.

[0427]

[0428] N-[4-(2-ethoxy-1-(azacyclobut-3-yl)-1H-imidazo[4,5-c]quinolin-8-yl)pyridin-2-yl]cyclopropaneformamide 2,2,2-trifluoroacetate (28)

[0429] Following the same synthetic method as compound 1, compound 1b was replaced with compound 28d to obtain compound 28. It is a white solid with a yield of 83%. 1 H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 9.43 (s, 1H), 9.36 (brs,1H), 9.28 (brs, 1H), 8.67 (d, J = 1.9 Hz, 1H), 8.55 (d, J = 1.7 Hz, 1H), 8.51(d, J = 5.2 Hz, 1H), 8.37 (d, J = 8.9 Hz, 1H), 8.13 (dd, J = 8.9, 1.7 Hz,1H), 7.73 (dd, J = 5.2, 1.7 Hz, 1H), 6.42 (quint, J = 8.0 Hz, 1H), 4.83 (q, J= 7.0 Hz, 2H), 4.82 – 4.72 (m, 2H), 4.63 – 4.51 (m, 2H), 2.14 – 2.02 (m, 1H), 1.59 (t, J = 7.0 Hz, 3H), 0.94 – 0.79 (m, 4H); 13 C NMR (101 MHz, DMSO) δ 173.5,159.1, 158.6, 153.3, 149.0, 148.9, 140.1, 137.1, 136.2, 133.5, 128.0, 127.3,123.2, 120.2, 118.4, 116.7, 115.5, 112.3, 68.8, 51.6 (2C), 47.7, 14.8, 14.7,8.3 (2C); 19 F NMR (376 MHz, DMSO) δ -74.15.

[0430] Example 29:

[0431]

[0432] 6-Bromo-N-isopropyl-3-nitroquinoline-4-amine (29a)

[0433] Following the synthetic method for compound 16a, (2R,4R)-4-amino-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester was replaced with propan-2-amine to give compound 29a. It is a yellow powdery solid with a yield of 77%. ESI-MS m / z 309.0 [M + H]+.

[0434]

[0435] 6-Bromo-N 4 -Isopropylquinoline-3,4-diamine (29b)

[0436] Following the synthetic method for compound 16b, compound 16a was replaced with 29a to obtain a yellow gelatinous compound 29b. Yield: 87%. ESI-MS m / z: 279 [M + H] + .

[0437]

[0438] 8-Bromo-2-ethoxy-1-isopropyl-1H-imidazo[4,5-c]quinoline (29c)

[0439] Following the synthetic method of compound 15a, compound 39 was replaced with compound 29b to obtain compound 29c. It is a yellow oil with a yield of 45%. 1 H NMR (400 MHz, CDCl3) δ 9.06 (s, 1H), 8.27 (d, J = 2.1 Hz, 1H), 8.03 (d, J = 9.0 Hz, 1H), 7.61 (dd, J = 9.0, 2.1 Hz, 1H), 5.24 – 5.16 (m,1H), 4.64 (q, J = 7.1 Hz, 2H), 1.68 (d, J = 6.9 Hz, 6H), 1.50 (t, J = 7.1 Hz, 3H).

[0440]

[0441] N-[4-(2-ethoxy-1-isopropyl-1H-imidazo[4,5-c]quinolin-8-yl)pyridin-2-yl]cyclopropaneformamide (29)

[0442] Following the synthetic method of compound 1b, compound 1a was replaced with compound 29c to obtain compound 29. It is a brown oil with a yield of 69%. 1 H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 9.03 (s, 1H), 8.69 –8.47 (m, 2H), 8.43 (d, J = 5.2 Hz, 1H), 8.20 (d, J = 8.8 Hz, 1H), 7.90 (dd,1H), 7.57 (dd, J = 5.3, 1.8 Hz, 1H), 5.77 – 5.26 (m, 1H), 4.61 (q, J = 7.0Hz, 2H), 2.17 – 2.00 (m, 1H), 1.67 (d, J = 6.7 Hz, 6H), 1.46 (t, J = 7.0 Hz,3H), 1.02 – 0.67 (m, 4H); 13 C NMR (101 MHz, DMSO-d6) δ 173.4, 163.9, 158.0,153.4, 149.4, 149.1, 144.3, 143.8, 135.5, 134.0, 131.9, 124.9, 119.2, 117.9,117.5, 111.7, 67.1, 49.4, 21.4 (2C), 14.9, 14.8, 8.2 (2C).

[0443] Example 30:

[0444]

[0445] 6-Bromo-N-cyclopentyl-3-nitroquinoline-4-amine (30a)

[0446] Following the synthetic method for compound 16a, (2R,4R)-4-amino-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester was replaced with cyclopentylamine to give compound 30a. It is a yellow powdery solid in 80% yield. ESI-MS m / z 335.0 [M + H] + .

[0447]

[0448] 6-Bromo-N 4 -Cyclopentylquinoline-3,4-diamine (30b)

[0449] Following the synthetic method for compound 16b, compound 16a was replaced with 30a to obtain a yellow gelatinous compound 30b. Yield: 84%. ESI-MS m / z: 305.1 [M + H] + .

[0450]

[0451] 8-Bromo-1-cyclopentyl-2-ethoxy-1H-imidazo[4,5-c]quinoline (30c)

[0452] Following the synthetic method for compound 15a, compound 39 was replaced with compound 30b to obtain compound 30c. It is a yellow oil with a yield of 76%. ESI-MS m / z 359.1 [M + H] + .

[0453]

[0454] N-[4-(1-cyclopentyl-2-ethoxy-1H-imidazo[4,5-c]quinolin-8-yl)pyridin-2-yl]cyclopropaneformamide (30)

[0455] Following the synthetic method for compound 1b, compound 1a was replaced with compound 30c to obtain compound 30. It is a brown oil with a yield of 84%. 1 H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.03 (s, 1H), 8.59 (d, J= 16.0 Hz, 2H), 8.44 (d, J = 5.2 Hz, 1H), 8.20 (d, J = 8.7 Hz, 1H), 7.93 (d,J = 8.7 Hz, 1H), 7.56 (d, J = 5.2 Hz, 1H), 5.54 (quint, J = 8.5 Hz, 1H), 4.61(q, J = 7.0 Hz, 2H), 2.39 – 2.12 (m, 4H), 2.12 – 2.02 (m, 1H), 2.02 – 1.87(m, 2H), 1.87 – 1.69 (m, 2H), 1.45 (t, J = 7.0 Hz, 3H), 1.04 – 0.69 (m, 4H); 13C NMR (101 MHz, DMSO-d6) δ 173.4, 157.6, 153.5, 149.3, 149.2, 144.4, 143.8,135.3, 134.0, 132.4, 131.9, 124.8, 119.3, 117.7, 117.6, 111.6, 67.2, 57.7,31.1 (2C), 25.0 (2C), 14.8, 14.7, 8.2 (2C).

[0456] Synthesis example 6:

[0457]

[0458] (R)-3-(2-cyclopropyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-imidazo[4,5-c]quinoline-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (42)

[0459] A mixture of compound 8a (500 mg, 1.10 mmol), pinacol diboronate (333 mg, 1.32 mmol), potassium acetate (321 mg, 3.30 mmol), and Pd(dppf)Cl2 (40 mg, 0.055 mmol) in 1,4-dioxane (20 mL) was degassed three times by nitrogen purging and then heated at 90 °C for 12 h. After the reaction was completed as monitored by TLC, water (15 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (3 × 30 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by rapid column chromatography (ethyl acetate) to give a brown oily compound 42 (330 mg, 60% yield). 1H NMR (400 MHz, CDCl3) δ 9.28 (s, 1H), 8.64 (s, 1H), 8.26 (d, J = 8.3Hz, 1H), 8.04 (d, J = 8.3 Hz, 1H), 6.12 – 5.82 (m, 1H), 4.31 – 4.16 (m, 1H),4.10 – 3.98 (m, 2H), 3.87 – 3.71 (m, 1H), 3.08 – 2.92 (m, 1H), 2.72 – 2.50(m, 1H), 2.24 – 2.07 (m, 1H), 1.48 (s, 9H), 1.41 (d, J = 2.2 Hz, 12H), 1.35 –1.29 (m, 2H), 1.26 – 1.20 (m, 2H).

[0460] Example 31:

[0461]

[0462] N-(4-chloro-5-methylpyridin-2-yl)cyclopropionamide (43)

[0463]

[0464] Compound 1a (100 mg, 0.79 mmol) and triethylamine (242 mg, 2.4 mmol, 3.0 equiv) were dissolved in dry acetone (3 mL), and cyclopropylformyl chloride (181 mg, 1.73 mmol, 2.2 equiv) was added to the solution at room temperature. The reaction mixture was stirred overnight at room temperature. After confirming the completion of the reaction by TLC or LC-MS analysis, the reaction solution was diluted with ethyl acetate and washed successively with water and saturated brine. The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The intermediate 1b was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:0 → 75:25). Rf = 0.5 (petroleum ether:ethyl acetate = 3:1), colorless oil, 90% yield (186 mg). Compound 1b (150 mg, 0.57 mmol) and sodium bicarbonate (72 mg, 0.85 mmol, 1.5 equiv) were dissolved in methanol (3 mL) and stirred overnight at 40 °C. After confirming the completion of the reaction by TLC or LC-MS, the pH was adjusted to 7–8 by adding 1 M hydrochloric acid. The reaction solution was diluted with ethyl acetate and washed successively with water and saturated brine. Purification by silica gel column chromatography (petroleum ether:ethyl acetate = 100:0 → 75:25) gave intermediate 43. Rf = 0.4 (petroleum ether:ethyl acetate = 3:1), white solid, yield 83% (92 mg).

[0465] (R)-3-[8-(2-(cyclopropanecarbamoyl)-5-methylpyridin-4-yl)-2-cyclopropyl-1H-imidazo[4,5-c]quinoline-1-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (31a)

[0466] Compound 42 (50 mg, 0.0992 mmol), N-(4-chloro-5-methylpyridin-2-yl)cyclopropaneformamide 43 (25 mg, 0.119 mmol), potassium phosphate (63 mg, 0.298 mmol), and Sphos Pd G2 (3.6 mg, 0.00496 mmol) were placed in a mixed solvent of 1,4-dioxane (2 mL) and water (0.5 mL). The mixture was purged three times with nitrogen and then heated at 95 °C for 16 hours. After the reaction was complete, 6 mL of water was added to the system, and the mixture was extracted three times with ethyl acetate (10 mL each time). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane / methanol = 25 / 1, v / v) to give a brown oily compound 31a (46 mg, 84% yield). 1H NMR (400 MHz, CDCl3) δ 9.27 (s, 1H), 8.61(s, 1H), 8.41 – 8.23 ​​(m, 2H), 8.19 (s, 1H), 8.10 (s, 1H), 7.65 (s, 1H), 5.91(s, 1H), 4.21 (q, J = 5.8 Hz, 1H), 4.10 (d, J = 6.6 Hz, 2H), 3.51 (d, J =10.0 Hz, 1H), 2.90 (s, 1H), 2.51 (d, J = 11.1 Hz, 1H), 2.28 (s, 3H), 2.11 (s,1H), 1.51 – 1.44 (m, 1H), 1.42 – 1.30 (m, 9H), 1.07 (s, 4H), 0.97 – 0.88 (m, 4H).

[0467]

[0468] (R)-N-[4-(2-cyclopropyl-1-(pyrrolidone-3-yl)-1H-imidazo[4,5-c]quinolin-8-yl)-5-methylpyridin-2-yl]cyclopropaneformamide 2,2,2-trifluoroacetate (31)

[0469] Following the same synthetic method as compound 1, compound 1b was replaced with compound 31a to obtain compound 31. It is a white solid with a yield of 78%. 1 H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 9.68 (brs, 1H), 9.62 (s,1H), 9.39 (brs, 1H), 8.68 (d, J = 1.8 Hz, 1H), 8.43 (d, J = 8.7 Hz, 1H), 8.36(s, 1H), 8.16 (s, 1H), 7.98 (dd, J = 8.8, 1.5 Hz, 1H), 6.33 (quint, J = 9.2Hz, 1H), 3.97 (s, 2H), 3.70 (s, 1H), 3.49 (s, 1H), 2.87 – 2.65 (m, 2H), 2.46– 2.36 (m, 1H), 2.28 (s, 3H), 2.08 – 1.98 (m, 1H), 1.41 – 1.24 (m, 4H), 0.88 – 0.73 (m, 4H); 13C NMR (101 MHz, DMSO-d6) δ 173.1, 159.8, 159.1, 151.0, 149.8,149.4, 141.8, 139.2, 138.8, 138.2, 135.6, 130.1, 129.8, 127.0, 126.5, 121.3,117.1, 114.4, 55.2, 47.0, 45.0, 29.6, 17.0, 14.7, 11.4, 11.1, 10.9, 8.1 (2C); 19 F NMR (376 MHz, DMSO) δ -74.46

[0470] Example 32:

[0471]

[0472] N-(4-bromo-5-chloro-pyridin-2-yl)cyclopropionamide (44)

[0473]

[0474] Compound 2a (3 g, 14.46 mmol) and pyridine (1.72 g, 21.69 mmol) were dissolved in 30 mL of THF, and a THF solution (30 mL) of cyclopropylformyl chloride (1.81 g, 17.35 mmol) was slowly added dropwise. The reaction was carried out at room temperature for 6 hours. After the reaction was complete, the reaction solution was evaporated to dryness, 200 mL of water was added to the system, and the mixture was filtered to obtain intermediate 44 (3.7 g, 94%), which could be directly reacted in the next step without purification.

[0475] (R)-3-(8-(5-chloro-2-(cyclopropanecarbamoyl)pyridin-4-yl)-2-cyclopropyl-1H-imidazo[4,5-c]quinoline-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (32a)

[0476] Compound 42 (50 mg, 0.0992 mmol), N-(4-bromo-5-chloro-pyridin-2-yl)cyclopropaneformamide (32.6 mg, 0.119 mmol, synthesized according to the method in European Journal of Medicinal Chemistry 222 (2021) 113554), cesium carbonate (96.7 mg, 0.298 mmol), and Pd(dppf)Cl2 (3.6 mg, 0.00496 mmol) were placed in a mixed solvent of 1,4-dioxane (2 mL) and water (0.5 mL). The mixture was purged three times with nitrogen and then heated at 95 °C for 12 hours. After the reaction was complete, 6 mL of water was added to the system, and the mixture was extracted three times with ethyl acetate (10 mL each time). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane / methanol = 25 / 1, v / v) to give a brown oily compound 32a (50 mg, yield 89%). 1 H NMR (400 MHz, CDCl3) δ 9.27 (s, 1H), 8.77 (s,1H), 8.44 (s, 1H), 8.39 – 8.23 ​​(m, 3H), 7.87 – 7.72 (m, 1H), 6.10 – 5.79 (m,1H), 4.20 – 4.01 (m, 3H), 3.57 – 3.43 (m, 1H), 3.04 – 2.80 (m, 1H), 2.51 (s,1H), 2.10 (s, 1H), 1.47 (s, 1H), 1.43 – 1.26 (m, 9H), 1.23 – 1.15 (m, 4H), 1.08 (s, 2H), 0.90 (d, J = 8.0 Hz, 2H).

[0477]

[0478] (R)-N-[5-chloro-4-(2-cyclopropyl-1-(pyrrolidine-3-yl)-1H-imidazo[4,5-c]quinolin-8-yl)pyridin-2-yl]cyclopropaneformamide 2,2,2-trifluoroacetate (32)

[0479] Following the same synthetic method as compound 1, compound 1b was replaced with compound 32a to obtain compound 32. It is a white solid with a yield of 88%. 1H NMR (400 MHz, DMSO-d6) δ 11.17 (s, 1H), 9.75 (brs, 1H), 9.49 (s,2H), 8.76 (d, J = 1.8 Hz, 1H), 8.58 (s, 1H), 8.40 (d, J = 8.7 Hz, 1H), 8.36(s, 1H), 7.97 (dd, J = 8.7, 1.6 Hz, 1H), 6.31 (quint, J = 9.2 Hz, 1H), 3.98(s, 2H), 3.71 (s, 1H), 3.49 (s, 1H), 2.96 – 2.65 (m, 2H), 2.47 – 2.32 (m,1H), 2.15 – 2.00 (m, 1H), 1.41 – 1.21 (m, 4H), 0.92 – 0.77 (m, 4H); 13 C NMR (101 MHz, DMSO-d6). 13 C NMR (101 MHz, DMSO) δ 173.5, 159.1, δ 159.0 (q, J =33.1 Hz), 151.6, 148.2 (2C), 143.3, 141.1, 137.1, 135.9, 135.7, 128.9, 128.4,123.9, 122.1, 121.5, 118.6, 117.0, 115.9, 115.6, 112.7, 55.2, 46.9, 45.0,29.6, 14.8, 11.1, 10.8, 10.8, 8.4 (2C); 19 F NMR (376 MHz, DMSO) δ -74.20.

[0480] Synthesis example 7:

[0481]

[0482] (R)-3-[8-(2-chloro-5-fluoropyridin-4-yl)-2-cyclopropyl-1H-imidazo[4,5-c]quinolin-1-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (45)

[0483] Compound 42 (174 mg, 0.345 mmol), 2-chloro-5-fluoro-4-iodopyridine (177 mg, 0.690 mmol), potassium carbonate (143 mg, 1.04 mmol), and Pd(dppf)Cl2 (12.6 mg, 0.0172 mmol) were dissolved in a mixed solvent of 1,4-dioxane (4 mL) and water (1 mL). The system was degassed three times by nitrogen purging and then heated at 95 °C for 12 h. After the reaction was complete (TLC monitoring, dichloromethane / methanol = 20 / 1, v / v), water (6 mL) was added to the system, and the mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by rapid column chromatography (dichloromethane / methanol = 25 / 1, v / v) to give a brown oily compound 45 (146 mg, 83% yield). 1 H NMR (400MHz, CDCl3) δ 9.21 (s, 1H), 8.42 – 8.24 (m, 3H), 7.72 (d, J = 8.7 Hz, 1H), 7.47 (d, J = 5.5 Hz, 1H), 6.01 – 5.80 (m, 1H), 3.99 – 3.87 (m, 3H), 3.65 –3.43 (m, 1H), 2.98 – 2.71 (m, 1H), 2.58 – 2.41 (m, 1H), 2.15 – 2.01 (m, 1H), 1.53 – 1.34 (m, 9H), 1.27 – 1.22 (m, 4H).

[0484] Example 33:

[0485]

[0486] (R)-3-[8-(2-(cyclopropanecarbamoyl)-5-fluoropyridin-4-yl)-2-cyclopropyl-1H-imidazo[4,5-c]quinoline-1-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (33a)

[0487] A mixture of compound 45 (55 mg, 0.108 mmol), cyclopropaneformamide (18 mg, 0.216 mmol), cesium carbonate (105 mg, 0.324 mmol), Xantphos Pd G3 (10.2 mg, 0.0108 mmol), and Xantphos (12 mg, 0.216 mmol) in 1,4-dioxane (2 mL) was degassed three times by nitrogen purging and then reacted at 110 °C for 16 h. After the reaction was complete (TLC monitoring, dichloromethane / methanol = 20 / 1, v / v), water (6 mL) was added to the system, and the mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by rapid column chromatography (dichloromethane / methanol = 25 / 1, v / v) to give a brown oily compound 33a (51 mg, 85% yield). 1 H NMR (400MHz, CDCl3) δ 9.31 (s, 1H), 8.74 (s, 1H), 8.59 (s, 1H), 8.47 (s, 1H), 8.39(d, J = 8.7 Hz, 1H), 8.23 ​​(s, 1H), 7.94 (d, J = 8.7 Hz, 1H), 6.06 – 5.82 (m,1H), 4.97 – 4.77 (m, 1H), 4.08 – 3.90 (m, 2H), 3.56 (d, J = 9.2 Hz, 1H), 3.11– 2.80 (m, 1H), 2.55 (s, 1H), 2.14 (s, 1H), 1.72 – 1.58 (m, 1H), 1.48 – 1.27 (m, 9H), 1.24 (d, J = 6.8 Hz, 4H), 1.13 (s, 2H), 1.03 – 0.92 (m, 2H).

[0488]

[0489] (R)-N-[4-(2-cyclopropyl-1-(pyrrolidone-3-yl)-1H-imidazo[4,5-c]quinolin-8-yl)-5-fluoropyridin-2-yl]cyclopropaneformamide 2,2,2-trifluoroacetate (33)

[0490] Following the same synthetic method as compound 1, compound 1b was replaced with compound 33a to obtain compound 33. It is a white solid with a yield of 78%. 1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.58 (brs, 1H), 9.33 (s,2H), 8.73 (s, 1H), 8.52 (d, J = 2.0 Hz, 1H), 8.48 (d, J = 6.1 Hz, 1H), 8.35(d, J = 8.7 Hz, 1H), 8.00 (d, J = 8.7 Hz, 1H), 6.44 – 6.13 (m, 1H), 3.72(brs, 2H), 3.51 (brs, 1H), 2.84 – 2.71 (m, 2H), 2.45 – 2.35 (m, 1H), 2.10 –2.00 (m, 1H), 1.42 – 1.31 (m, 1H), 1.31 – 1.18 (m, 4H), 0.86 (d, J = 6.1 Hz,4H); 13 C NMR (101 MHz, DMSO) δ 173.2, 158.2, 154.6, 152.1, 149.5 (d, J = 2.7Hz), 144.7, 137.1, 137.0, 136.7, 136.2, 135.8, 131.5, 130.5, 130.1, 127.7,122.0, 117.5, 114.9, 55.1, 46.8, 44.9, 29.5, 14.7, 10.9, 10.7, 10.5, 8.3(2C); 19 F NMR (376 MHz, DMSO) δ -73.99, -139.75.

[0491] Example 34:

[0492]

[0493] (R)-3-(2-cyclopropyl-8-(5-fluoro-2-(pyridin-2-ylamino)pyridin-4-yl)-1H-imidazo[4,5-c]quinoline-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (34a)

[0494] Following the synthetic method for compound 33a, cyclopropaneformamide was replaced with 2-aminopyridine to obtain compound 34a. It was a white solid with a yield of 78%. 1H NMR (400 MHz, CDCl3) δ 9.30 (s, 1H), 8.46 (s, 1H), 8.39 (d,J = 8.7 Hz, 1H), 8.26 (s, 2H), 8.20 – 8.02 (m, 1H), 8.01 – 7.83 (m, 2H), 7.65– 7.55 (m, 1H), 7.53 – 7.30 (m, 1H), 6.94 – 6.76 (m, 1H), 6.14 – 5.80 (m,1H), 4.24 – 4.13 (m, 1H), 4.10 – 3.94 (m, 2H), 3.67 – 3.50 (m, 1H), 3.11 –2.85 (m, 1H), 2.65 – 2.49 (m, 1H), 2.19 – 2.07 (m, 1H), 1.43 – 1.27 (m, 11H), 1.24 – 1.19 (m, 2H).

[0495]

[0496] (R)-4-(2-cyclopropyl-1-(pyrrolidone-3-yl)-1H-imidazo[4,5-c]quinolin-8-yl)-5-fluoro-N-(pyridin-2-yl)pyridin-2-amine 2,2,2-trifluoroacetate (34)

[0497] Following the same synthetic method as compound 1, compound 1b was replaced with compound 34a to obtain compound 34. It is a white solid with a yield of 85%. 1H NMR (400 MHz, DMSO-d6) δ 11.68 (s, 1H), 9.92 (s, 1H), 9.73 (s,1H), 9.48 (s, 1H), 8.84 (d, J = 1.7 Hz, 1H), 8.51 (d, J = 2.0 Hz, 1H), 8.43(d, J = 8.8 Hz, 1H), 8.35 (dd, J = 5.9, 1.8 Hz, 1H), 8.15 – 8.01 (m, 2H), 7.94 (d, J = 5.6 Hz, 1H), 7.62 (d, J = 8.7 Hz, 1H), 7.28 – 7.10 (m, 1H), 6.40(quint, J = 9.2 Hz, 1H), 4.13 – 3.93 (m, 2H), 3.84 – 3.68 (m, 1H), 3.63 –3.40 (m, 1H), 2.93 – 2.76 (m, 2H), 2.49 – 2.38 (m, 1H), 1.43 – 1.26 (m, 4H); 13 C NMR (101 MHz, DMSO-d6) δ 159.8, 159.3 (q, J = 34.1 Hz), 154.2, 151.6 (d, J= 10.0 Hz), 150.8, 150.7, 142.7, 141.2, 140.2, 138.4 (d, J (d, J = 6.2 Hz), 112.5, 55.3, 46.8, 44.9, 29.6, 11.3, 11.0, 10.8; 19 F NMR (377 MHz, DMSO) δ -74.24.

[0498] Pharmacodynamic Examples: Evaluation of CDK9 and CDK2 Inhibitory Activity

[0499] Kinase Glo assay was performed using a yellow 96-well plate in assay buffer. 1 μL (10 μM) of the test compound (dissolved in DMSO and then diluted to the desired concentration with kinase buffer) and 2 μL (5 ng) of enzyme were added to each well, followed by 2 μL of a mixture containing 0.2 μg of substrate and 25 μM ATP. After incubation at room temperature for 60 minutes, the enzymatic reaction was stopped with 5 μL of kinase Glo reagent, and the remaining ATP was removed. After incubation at room temperature for another 40 minutes, the ADP generated in the reaction was converted to ATP using a kinase assay reagent. The luminescence value was recorded using a multi-mode microplate reader after 30 minutes. Conclusion: Experiments demonstrate that most of the compounds prepared in this invention can effectively inhibit CDK9 activity, with an IC50 value of [missing value]. 50 The value is less than 10 nM and it has higher selectivity compared to CDK2.

[0500] Table 1. CDK9 / CDK2 inhibitory activities of compounds 1-34

[0501]

[0502]

[0503] The value is calculated from data points obtained by averaging the values ​​of repeated holes. Undetermined.

[0504] . ; .

[0505] The preferred embodiments of the present invention have been described above, but are not intended to limit the invention. Those skilled in the art can make modifications and variations to the embodiments disclosed herein without departing from the scope and spirit of the invention.

Claims

1. A quinoline imidazole derivative of formula I, pharmaceutically acceptable salts, stereoisomers thereof: ###0001### Formula I wherein, R1 is selected from the group consisting of hydrogen, halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, (C1-C6)alkylsulfinyl, (C1-C6)alkylamino, di(C1-C6)alkylamino, (C1-C6)alkoxycarbonyl, (C1-C6)alkylcarbonyl, (C1-C6)alkylcarbonyloxy, (C1-C6)alkylcarbonylamino, (C1-C6)alkylcarbonyl(C1-C6)alkyl, (C1-C6)alkylcarbonyl(C1-C6)alkoxy, (C1-C6)alkylcarbonyl(C1-C6)alkylamino, (C1-C6)alkylcarbonyl(C1-C6)alkylsulfonyl, (C1-C6)alkylcarbonyl(C1-C6)alkylsulfinyl, (C1-C6)alkylcarbonyl(C1-C6)alkyl, (C1-C6)alkylcarbonyl(C1-C6)alkyl, (C1-C6)alkylcarbonyl(C1-C6)alkyl, (C1-C6)alkylcarbonyl(C1-C6)alkyl, (C1-C6)alkylcarbonyl(C1-C6)alkyl, (C1-C6)alkylcarbonyl(C1-C6)alkyl, (C1-C6)alkylcarbonyl(C1-C6)alkyl, (C1-C6)alkylcarbonyl(C1-C6)alkyl, (C1-C6)alkylcarbonyl(C1-C6)alkyl, (C1-C6)alkylcarbonyl(C1-C6)alkyl, (C1-C6)alkylcarbonyl(C1-C6)alkyl, (C1-C6)alkylcarbonyl(C1-C6)alkyl, (C1-C6)alkylcarbonyl(C1-C6)alkyl, (C1-C6)alkylcarbonyl(C1-C6)alkyl, (C1-C6)alkylcarbonyl(C1-C6)alkyl, (C1-C6)alkylcarbonyl(C1-C6)alkyl, (C1-C6)alkylcarbonyl(C1-C6)alkyl, (C1-C6)alkylcarbonyl(C1-C6)alkyl, (C1-C6)alkylcarbonyl(C1-C6)alkyl, (C1-C6)alkylcarbonyl(C1-C6)alkyl, (C1-C6)alkylcarbonyl(C1-C6)alkyl, (C1-C6)alkylcarbonyl(C1-C6)alkyl, (C1-C6)alkylcarbonyl(C1-C6)alkyl, (C1-C6)alkylcarbonyl(C1-C6)alkyl, (C1-C6)alkylcarbonyl(C1-C6)alkyl, (C1-C6)alkylcarbonyl(C1-C6)alkyl, (C1-C6)alkylcarbonyl(C1-C6)alkyl, (C1-C6)alkylcarbonyl(C1-C6)alkyl, (C1-C6)alkylcarbonyl(C1-C6)alkyl, (C1-C6)alkylcarbonyl wherein R1is selected from pyridyl, -COR 12 , R 12 is selected from cyclopropyl; ​ R5is selected from CR 51 , N; R 51 selected from the group consisting of hydrogen, (Ci-C6)alkyl, hydroxy, (Ci-C6)alkoxy, (C3-C8)cycloalkyl, phenyl; ​ 。 2. The quinoline and imidazole derivative according to claim 1, a pharmaceutically acceptable salt thereof, a stereoisomer, characterized by, ​ 3. The quinoline and imidazole derivative according to claim 1, pharmaceutically acceptable salt thereof, stereoisomer, characterized by, R 51 selected from hydrogen, (Ci-C6)alkyl, (Ci-C6)alkoxy, (C3-C8)cycloalkyl, phenyl.

4. The quinoline and imidazole derivative according to claim 1, pharmaceutically acceptable salt thereof, stereoisomer, characterized by, ​ 。 5. The quinoline and imidazole derivative according to claim 1, pharmaceutically acceptable salt thereof, stereoisomer, characterized by, ​ 。 6. The quinoline and imidazole derivative according to claim 1, pharmaceutically acceptable salt thereof, stereoisomer, characterized by, ​ ​ ​ ​ ​ X1is selected from chlorine or bromine and X2is selected from -B(OH)2or ; or X2is selected from chlorine or bromine and X1is selected from -B(OH)2or .

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