Thiazole GPR52 regulator compound

Abstract

The invention relates to a thiazole GPR52 regulator compound. The invention discloses a GPR52 regulator compound, the structure of the compound is as shown in formula (I), R1 and R2 are H, D, OH, halogen, CN, substituted or unsubstituted C1-5 alkyl, substituted or unsubstituted C1-5 alkoxy; wherein a substituent group is selected from one or more of H, D, OH, halogen and CN; ar is selected from a substituted or unsubstituted 5-to 10-membered aryl ring and a heteroaryl ring. The compounds, pharmaceutically acceptable salts and pharmaceutical compositions of the present invention are directed to methods useful for the treatment or prevention of nervous system diseases or disorders and conditions associated therewith. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of medical drugs, and specifically to a GPR52 modulator compound. Background of the Invention

[0003] Schizophrenia is a heterogeneous mental disorder with significant disability. As our understanding of the functions of GPCRs in the nervous system deepens, many GPCRs are considered promising drug targets for neurodegenerative and mental disorders. Among them, the orphan G protein-coupled receptor 52 (GPR52), which is mainly present in the brain, is considered an effective mental receptor. In 2014, Takeda Pharmaceutical Company in Japan conducted a distribution analysis of human, mouse, and rat tissues, and the results showed that GPR52 was highly expressed in the brain (especially in the striatum) and there were no significant differences among different species. Subsequently, in-situ hybridization studies on the adult rat brain found that GPR52 co-localized with the D 1 receptor in the medial prefrontal cortex and the D 2 receptor in the basal ganglia. This indicates that GPR52 may be involved in dopamine transmission in neurons expressing the D 1 receptor in the cortex and neurons expressing the D 2 receptor in the striatum. In the study of schizophrenia, it is considered that the reduced expression of the D 1 receptor in the prefrontal cortex affects negative symptoms and cognitive deficits, and excessive D 2 receptor signaling affects positive symptoms. Therefore, it is considered that GPR52 may be involved in the pathogenesis of schizophrenia. GPCRs play an indispensable role in the neurobiology of mental disorders. Approximately 35% of FDA-approved drugs act through GPCRs, and among them, drugs for central nervous system diseases account for 27%. However, currently, most drugs targeting GPCRs lack subtype selectivity, especially in the field of psychopharmaceutical research and development. Therefore, the development of therapeutic modulators with high specific subtype recognition ability is crucial for the development of effective drugs. Summary of the Invention

[0004] The present invention provides a compound having activity as a modulator of G protein-coupled receptor 52 (GPR52). The chemical formula is as shown in formula (I):

[0005]

[0006] Wherein:

[0007] R 1 and R 2 are H, D, OH, halogen, CN, substituted or unsubstituted C 1-5 alkyl, substituted or unsubstituted C 1-5Alkoxy; wherein the substituent is selected from one or more of H, D, OH, halogen, and CN;

[0008] Ar is selected from substituted or unsubstituted 5- to 10-membered aryl rings and heteroaryl rings; wherein the substituent is selected from H, OH, CN, F, Br, CF 3 、CF 2 H, OCF 2 H, OCH 3 , methyl, isopropyl, cyclopropyl, substituted or unsubstituted phenyl.

[0009] In formula (I), the pharmaceutically acceptable salt is a salt containing a pharmaceutically acceptable anion, and the anion salt is hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, oxalate, acetate, propionate, lactate, citrate, tartrate, maleate, fumarate, mesylate, esylate, propanesulfonate, gluconate, glucuronate, benzoate, p-toluate, benzenesulfonate or p-toluenesulfonate.

[0010] As a preferred technical solution of the present invention, the substituted C 1-5 alkyl is selected from H, D, OH, CN, substituted C 1-5 alkyl;

[0011] Unsubstituted C 1-5 alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, n-pentyl or isopentyl;

[0012] As a preferred technical solution of the present invention, the unsubstituted 5- to 10-membered aryl rings and heteroaryl rings are selected from furan, thiophene, pyrrole, pyrazole, triazole, tetrazole, phenyl, pyridine, pyrimidine, indole, benzothiophene, benzofuran, quinoline, naphthalene;

[0013] The substituted 5- to 10-membered aryl rings and heteroaryl rings are optionally substituted by one or more of the following substituents: H, OH, CN, F, Cl, CF 3 , CF 2 H, OCH 3 , OCF 2 H, methyl, isopropyl, cyclopropyl, substituted or unsubstituted phenyl.

[0014] The beneficial effects of the present invention are: The compounds, pharmaceutical salts and pharmaceutical compositions of the present invention are directed to methods useful for treating or preventing neurological diseases or disorders and related conditions. Detailed implementation mode

[0015] The preferred embodiments of the present invention will be described in detail below, so that the advantages and features of the present invention can be more easily understood by those skilled in the art, thereby making a clearer and more definite definition of the protection scope of the present invention.

[0016] Room temperature (r.t.) refers to about 20 °C - 27 °C. 1 1H NMR spectra were generally recorded at 500 MHz at ambient temperature, 13 13C NMR spectra were generally recorded at 125 MHz at ambient temperature unless otherwise specified. The solvents used for the determination were deuterated dimethyl sulfoxide (DMSO-d 6 6), deuterated chloroform (CDCl 3 3). Chemical shift values were expressed in parts per million (ppm), i.e., (δ) values. Standard abbreviations or their combinations were used for the multiplicity of NMR signals, e.g., s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, dt = doublet of triplets, m = multiplet. Coupling constants were listed as J values measured in Hz.

[0017] The compounds of the present invention can be prepared according to the following scheme:

[0018]

[0019] Reagents and conditions: (a) HCl-EtOAc, r.t.; (b) EtOH, 80 °C; (c) (1) HOBT, EDCI, r.t.,; (2) aminoethanol derivatives, r.t.

[0020] Synthesis of intermediates:

[0021] Typical procedure 1: Illustrated by the preparation of intermediate 1, 2-(4-fluorophenyl)thioacetamide

[0022]

[0023] To a 250 mL eggplant-shaped flask were successively added 5.4 g (40 mmol) of 4-fluorobenzyl cyanide, 40 mL of ethyl acetate, 10 mL of a hydrochloric acid gas solution in ethyl acetate, 10 mL of purified water, and 7.44 g (40 mmol) of O,O-diethyl-S-hydrogen thiophosphate. The reaction was stirred at room temperature. After the reaction was completed, the excess solvent was concentrated under reduced pressure, the organic phase was washed with saturated sodium bicarbonate, extracted with ethyl acetate, and after the extraction was completed, the organic phase was dried with anhydrous sodium sulfate and rotary evaporated. The product was coarsely treated by trituration with petroleum ether to obtain a pale yellow solid, which was 2-(4-fluorophenyl)thioacetamide (6.4 g, yield 94%). It was used directly in the next step.

[0024] Typical Procedure 2: Preparation of 4-(2-(4-fluorobenzyl)thiazol-4-yl)benzoic acid via Intermediate 2 is illustrated

[0025]

[0026] To a 250 mL eggplant-shaped flask, 3.7 g (22 mmol) of 2-(4-fluorophenyl)thioacetamide, 4.8 g (29 mmol) of 4-(bromoacetyl)benzoic acid, and 50 mL of ethanol were added successively. The mixture was heated under reflux at 110 °C for 0.5 h. After the reaction was completed, it was allowed to cool to room temperature, concentrated under reduced pressure, and triturated with dichloromethane. The white solid obtained was 4-(2-(4-fluorobenzyl)thiazol-4-yl)benzoic acid (5 g, yield 80%). 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.17 (s, 1H), 8.09 - 8.05 (m, 2H), 8.02 - 7.99 (m, 2H), 7.48 - 7.42 (m, 2H), 7.23 - 7.16 (m, 2H), 4.42 (s, 2H).

[0027] Synthesis of the final product:

[0028] Example 1: Preparation of 4-(2-(4-fluorobenzyl)thiazol-4-yl)-N-(2-hydroxyethyl)benzamide

[0029]

[0030] To a 100 mL eggplant-shaped flask, 313 mg (1.0 mmol) of 4-(2-(4-fluorobenzyl)thiazol-4-yl)benzoic acid, 162 mg (1.2 mmol) of 1-hydroxybenzotriazole monohydrate, 229 mg (1.2 mmol) of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, and 15 mL of dichloromethane were added successively. After reacting at room temperature for 1 h, 73 mg (1.2 mmol) of ethanolamine was added, and the reaction continued at room temperature for 2 h. After the reaction was completed, it was washed with brine and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (dichloromethane - absolute ethanol, V / V = 15:1) to obtain a white powder, which was 4-(2-(4-fluorobenzyl)thiazol-4-yl)N-(2-hydroxyethyl)benzamide (284 mg, yield 80%). 1 H NMR (500 MHz, DMSO-d 6) δ 8.48 (t, J = 5.7 Hz, 1H), 8.10 (s, 1H), 8.02 (d, J = 8.4 Hz, 2H), 7.92 (d, J = 8.3 Hz, 2H), 7.44 (dd, J = 8.5, 5.7 Hz, 2H), 7.19 (t, J = 8.8 Hz, 2H), 4.77 (t, J = 5.6 Hz, 1H), 4.40 (s, 2H), 3.53 (q, J = 6.0 Hz, 2H), 3.35 (q, J = 6.0 Hz, 2H). 13 C NMR (126 MHz, DMSO-d 6 ) δ 170.3, 166.0, 161.3 (d, J = 242.8 HZ), 153.3, 136.5, 134.3 (d, J = 3.0 HZ), 133.7, 131.03 (d, J = 8.1 HZ), 127.8, 125.7, 115.8, 115.5 (d, J = 21.3 HZ), 59.5, 43.5, 37.8.

[0031] Example 2: Preparation of 4-(2-(4-fluorobenzyl)thiazol-4-yl)-N,N-bis(2-hydroxyethyl)benzamide

[0032]

[0033] Using the synthetic method of Example 1, the reaction conditions, equivalent ratios, and experimental operations were all carried out according to the synthetic method of Example 1. The title compound (300 mg, yield 75%) was prepared from Intermediate 2 and diethanolamine. 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.05 (s, 1H), 7.99 (d, J = 8.1 Hz, 2H), 7.49 - 7.41 (m, 4H), 7.19 (t, J = 8.8 Hz, 2H), 4.81 (dt, J = 24.8, 5.5 Hz, 2H), 4.41 (s, 2H), 3.63 (t, J = 6.0 Hz, 2H), 3.54 (t, J = 6.0 Hz, 2H), 3.47 (q, J = 6.0 Hz, 2H), 3.35 (d, J = 5.0 Hz, 2H). 13 C NMR (126 MHz, DMSO-d 6 ) δ 170.8, 169.4, 161.3 (d, J = 242.9 HZ), 154.0, 137.2, 134.5, 134.3 (d, J = 3.1 HZ), 131.0 (d, J = 8.2 HZ), 127.4, 125.7, 115.4, 115.5 (d, J = 21.3 HZ), 115.1, 59.3, 37.7.

[0034] Example 3: Preparation of 4-(2-(4-fluorobenzyl)thiazol-4-yl)-N-(3-hydroxypropyl)benzamide

[0035]

[0036] Using the synthetic method of Example 1, the reaction conditions, equivalent ratios, and experimental operations were all carried out according to the synthetic method of Example 1. The title compound (303 mg, yield 82%) was prepared from intermediate 2 and propanolamine. 1 H NMR(500MHz,DMSO-d 6 )δ8.50(t,J=5.6Hz,1H),8.11(s,1H),8.06-8.01(m,2H),7.95-7.89(m,2H),7.45(dd,J=8.4,5.5Hz,2H),7.20(t,J=8.8Hz,2H),4.51(t,J=5.2Hz,1H),4.41(s,2H),3.49(q,J=5.8Hz,2H),3.37-3.31(m,2H).1.76-1.66,(m,2H). 13 C NMR(126MHz,DMSO-d 6 )δ170.2,165.8,161.3(d,J=243.0HZ),153.3,136.4,134.2(d,J=3.1HZ),133.8,131.0(d,J=8.1HZ),127.7,125.7,115.8,115.5(d,J=21.2HZ),58.6,37.7,36.6,32.5.

[0037] Example 4: Preparation of 4-(2-(4-fluorobenzyl)thiazol-4-yl)-N-(4-hydroxybutyl)benzamide

[0038]

[0039] Using the synthetic method of Example 1, the reaction conditions, equivalent ratios, and experimental operations were all carried out according to the synthetic method of Example 1. The title compound (296 mg, yield 77%) was prepared from intermediate 2 and 4-hydroxybutylamine. 1 H NMR(500MHz,DMSO-d 6)δ 8.51 (t, J = 5.7 Hz, 1H), 8.11 (s, 1H), 8.05 - 8.01 (m, 2H), 7.94 - 7.90 (m, 2H), 7.45 (dd, J = 8.4, 5.5 Hz, 2H), 7.20 (t, J = 8.8 Hz, 2H), 4.44 (t, J = 5.1 Hz, 1H), 4.42 (s, 2H), 3.44 (q, J = 6.0 Hz, 2H), 3.29 (q, J = 6.6 Hz, 2H), 1.61 - 1.54, (m, 2H), 1.52 - 1.45, (m, 2H). 13 C NMR (126 MHz, DMSO - d 6 )δ 170.2, 165.7, 161.3 (d, J = 242.9 HZ), 153.3, 136.4, 134.2 (d, J = 3.1 HZ), 133.9, 131.0 (d, J = 8.2 HZ), 127.7, 125.7, 115.7, 115.4 (d, J = 21.3 HZ), 60.5, 39.0, 37.7, 30.1, 25.9.

[0040] The above embodiments only illustrate several implementation manners of the present invention. The description is relatively specific and detailed, but it should not be construed as a limitation on the scope of the invention patent. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present invention, several modifications and improvements can still be made, and these all fall within the protection scope of the present invention.

Claims

1. A GPR52 modulator compound, characterized in that: The compound is represented by the following formula (I): in: R1 and R2 are H, D, OH, CN, substituted or unsubstituted C 1-5 Alkyl; wherein the substituent is selected from one or more of H, D, OH, and CN; Ar is selected from substituted or unsubstituted 5- to 10-membered aryl and heteroaryl rings; wherein the substituents are selected from H, OH, CN, F, Br, CF3, CF2H, OCF2H, OCH3, methyl, isopropyl, and cyclopropyl.

2. A GPR52 modulator compound according to claim 1, characterized in that: The substituted C 1-5 The alkyl group is selected from H, D, OH, CN, substituted C 1-5 alkyl; Unsubstituted C 1-5 The alkyl group is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, n-pentyl or isopentyl.

3. A GPR52 modulator compound according to claim 1, characterized in that: The unsubstituted 5- to 10-membered aryl ring and heteroaryl ring are selected from furan, thiophene, pyrrole, pyrazole, triazole, tetrazole, phenyl, pyridine, pyrimidine, indole, benzothiophene, benzofuran, quinoline, and naphthalene; The substituted 5- to 10-membered aryl and heteroaryl rings are optionally substituted with one or more of the following substituents: H, OH, CN, F, Br, CF3, CF2H, OCH3, OCF2H, methyl, isopropyl, cyclopropyl, substituted or unsubstituted phenyl.

Images