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US-12617759-B2 - Modifier of four-membered ring derivative, preparation method and application thereof

US12617759B2US 12617759 B2US12617759 B2US 12617759B2US-12617759-B2

Abstract

Provided is a modifier of a four-membered ring derivative, a preparation method and application thereof. In particular, provided is a compound represented by the general formula (IX-A), a preparation method thereof, a pharmaceutical composition containing the compound, and a use thereof as a G protein-coupled receptor modulator in the treatment or prevention of central nervous system diseases and/or mental diseases. The definition of each substituents in the general formula (IX-A) is same as the definition in the specification.

Inventors

  • Yidong Su
  • Xiaofeng MAO
  • Kailong LI
  • Jun Wang
  • Jiaqiang Cai
  • Rudi Bao

Assignees

  • SHANGHAI HANSOH BIOMEDICAL CO., LTD.
  • JIANGSU HANSOH PHARMACEUTICAL GROUP CO., LTD.

Dates

Publication Date
20260505
Application Date
20201029
Priority Date
20191029

Claims (20)

  1. 1 . A compound of formula (IX-A), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein: R 4 is selected from the group consisting of 5 to 6 membered N-containing heterocyclyl, R a is selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3 to 8 membered heterocyclyl, C 6-12 aryl and 5 to 12 membered heteroaryl; R b is selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3 to 8 membered heterocyclyl, C 6-12 aryl and 5 to 12 membered heteroaryl, wherein the amino, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3 to 8 membered heterocyclyl, C 6-12 aryl and 5 to 12 membered heteroaryl are each optionally further substituted by one or more substituents selected from the group consisting of deuterium, halogen, amino, nitro, hydroxy, cyano, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3 to 8 membered heterocyclyl, C 6-12 aryl and 5 to 12 membered heteroaryl; R 5 is selected from the group consisting of hydrogen, deuterium, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, halogen, amino, nitro, hydroxy, cyano, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3 to 8 membered heterocyclyl, C 6-12 aryl and 5 to 12 membered heteroaryl; or, any adjacent two R 5 are bonded to form a 5 to 6 membered heterocyclyl or 5 to 6 membered heteroaryl; r is 0, 1 or 2; m is 0 or 1; and t is 0, 1, 2 or 3; when and m is 1, then R 4 is not —NHC(O)C 2 H 5 , —NHC(O)N(CH 3 ) 2 , —NHC(O)NHCH 3 , —NHC(O)N(C 2 H 5 )CH 3 , —NHC(O)NHC 2 H 5 , when m is 2, then R 4 is not —NHC(O)N(CH 3 ) 2 .
  2. 2 . The compound, the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 1 , wherein the compound is further as shown in formula (X) or formula (X-A):
  3. 3 . The compound, the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 1 , wherein R 4 is selected from the group consisting of 5 to 6 membered N-containing heterocyclyl, R a is selected from the group consisting of hydrogen, cyano, halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy and C 3-6 cycloalkyl; R b is selected from the group consisting of amino, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3 to 6 membered heterocyclyl, C 6-10 aryl and 5 to 10 membered heteroaryl, optionally further substituted by one or more substituents selected from the group consisting of halogen, hydroxy, cyano, C 1-3 alkyl and C 1-3 alkoxy; and r is 0, 1 or 2.
  4. 4 . The compound, the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 1 , wherein the compound is further as shown in formula (XI): wherein: R 6 is selected from the group consisting of hydrogen, deuterium, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-5 alkoxy, C 1-6 haloalkoxy, halogen, amino, nitro, hydroxy, cyano, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3 to 8 membered heterocyclyl, C 6-12 aryl and 5 to 12 membered heteroaryl; R 7 is selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3 to 8 membered heterocyclyl, C 6-12 aryl, 5 to 12 membered heteroaryl, R ee , —C(O)(CH 2 ) n2 R ee , —(CH 2 ) n2 C(O)NR ee R ff , —C(O)NR ee R ff , —(CH 2 ) n2 C(O)NR ee C(O)R ff , —(CH 2 ) n2 S(O) n2 R ee , —(CH 2 ) n2 NR ee S(O) n2 R ff ; —(CH 2 ) n2 S(O) m2 NR ee R ff , —(CH 2 ) n1 S(O) m2 NR ee R ff , —(CH 2 ) n2 OR ee , —C(O)NR ee (CH 2 ) n2 R ff , —C(O)(CH 2 ) n2 OR ee , —(CH 2 ) n2 SR ee , —(CH 2 ) n2 C(O)OR ee , —P(O)R ee R ff ; —(CH 2 ) n2 NR ee C(O)R ff and —(CH 2 ) n2 NR ee S(O) m2 R ff , wherein the C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3 to 8 membered heterocyclyl, C 6-12 aryl and 5 to 12 membered heteroaryl are each optionally further substituted by one or more substituents selected from the group consisting of deuterium, halogen, amino, nitro, hydroxy, cyano, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3 to 8 membered heterocyclyl, C 6-12 aryl and 5 to 12 membered heteroaryl; R ee and R ff are each independently selected from the group consisting of hydrogen, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3 to 8 membered heterocyclyl, C 6-14 aryl and 5 to 14 membered heteroaryl, wherein the amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3 to 8 membered heterocyclyl, C 6-14 aryl and 5 to 14 membered heteroaryl are each optionally further substituted by one or more substituents selected from the group consisting of halogen, hydroxy, cyano, oxo, C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 alkoxy; n2 is selected from the group consisting of 0, 1 and 2; m2 is selected from the group consisting of 0, 1 and 2; and m is selected from the group consisting of 0, 1 and 2.
  5. 5 . The compound, the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 4 , wherein R ee and R ff are each independently selected from the group consisting of hydrogen and the following substituents:
  6. 6 . The compound, the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 4 , wherein, R 6 is selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 2-3 alkenyl and C 2-3 alkynyl; R 7 is selected from the group consisting of R ee , —C(O)(CH 2 ) n2 R ee , —C(O)NR ee R ff , —C(O)NR ff (CH 2 ) n2 R ee , —S(O) m2 R ee and —S(O) m2 NR ee R ff ; R ee is selected from the group consisting of hydrogen, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3 to 8 membered heterocyclyl, C 6-14 aryl and 5 to 14 membered heteroaryl, wherein the amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3 to 8 membered heterocyclyl, C 6-14 aryl and 5 to 14 membered heteroaryl are each optionally further substituted by one or more substituents selected from the group consisting of halogen, hydroxy, cyano, oxo, C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 alkoxy; R ff is selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3 to 8 membered heterocyclyl, C 6-12 aryl and 5 to 12 membered heteroaryl; n2 is selected from the group consisting of 0, 1 and 2; and m2 is selected from the group consisting of 0, 1 and 2.
  7. 7 . The compound, the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 4 , wherein the compound is further as shown in formula (XI-A) or formula (XI-B):
  8. 8 . The compound, the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 4 , wherein is selected from the group consisting
  9. 9 . The compound, the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 4 , wherein is selected from the group consisting
  10. 10 . The compound, the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 4 , wherein the compound is as shown in formula (XII): wherein: R 8 is selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3 to 8 membered heterocyclyl, C 6-12 aryl and 5 to 12 membered heteroaryl, wherein the amino, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3 to 8 membered heterocyclyl, C 6-12 aryl and 5 to 12 membered heteroaryl are each optionally further substituted by one or more substituents selected from the group consisting of deuterium, halogen, amino, nitro, hydroxy, cyano, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3 to 8 membered heterocyclyl, C 6-12 aryl and 5 to 12 membered heteroaryl; and v is 0 or 1; when v is 0, then R 8 is not —C 2 H 5 , —N(CH 3 ) 2 , —NHCH 3 , —NC 2 H 5 CH 3 , —NHC 2 H 5 when v is 1, then R 8 is not phenyl.
  11. 11 . The compound, the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 10 , wherein the compound of formula (XII) is as shown in formula (XII-A) or formula (XII-B):
  12. 12 . The compound, the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 1 , wherein, R 4 is R b is selected from the group consisting of C 3-6 cycloalkyl and 5 to 10 membered heteroaryl containing 1 to 2 nitrogen, oxygen, sulfur atoms, optionally further substituted by one or more substituents selected from the group consisting of deuterium, halogen, amino, hydroxy, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy and C 1-3 haloalkoxy; R 5 is selected from the group consisting of hydrogen, halogen and C 1-3 alkyl; m is 1; t is 1, 2 or 3; and when r is 0 and R b is then R b is substituted by at least one substituent; or when r is 0 and R b is then R b is substituted by at least one substituent.
  13. 13 . The compound, the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 12 , wherein R b is selected from the group consisting of C 3-6 cycloalkyl, 5 to 6 membered heteroaryl containing nitrogen or oxygen and 9 to 10 membered fused heteroaryl containing nitrogen, optionally further substituted by one or more substituents selected from the group consisting of deuterium, halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy and C 1-3 haloalkoxy.
  14. 14 . The compound, the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 1 , wherein the specific structure of the compound is as follows:
  15. 15 . A method for preparing the compound of formula (XII), the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 10 , comprising the following step of, reacting a compound of formula (XII-1) with an acyl chloride or carboxylic acid of formula (XII-2) to obtain the compound of formula (XII), the stereoisomer thereof or the pharmaceutically acceptable salt thereof.
  16. 16 . A compound of formula (XII-1), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,
  17. 17 . A method for preparing the compound of formula (XII-1), the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 16 , comprising the following step of, deprotecting a compound of formula (XII-3) to obtain the compound of formula (XII-1), the stereoisomer thereof or the pharmaceutically acceptable salt thereof; wherein: Pg 1 is an amino protecting group, selected from the group consisting of allyloxycarbonyl, trifluoroacetyl 2,4-dimethoxybenzyl, nitrobenzenesulfonyl, trityl, fluorenemethoxycarbonyl, p-toluenesulfonyl, formate, acetyl, benzyloxycarbonyl, tert-butoxycarbonyl, benzyl and p-methoxyphenyl; optionally, reacting a compound of formula (XII-4) with a compound of formula (XII-5) to obtain the compound of formula (XII-3), the stereoisomer thereof or the pharmaceutically acceptable salt thereof; Pg 2 is a hydroxy protecting group, selected from the group consisting of methyl, tert-butyl, triphenyl, methylthiomethyl ether, 2-methoxyethoxymethyl ether, methoxymethyl ether, p-methoxybenzyl ether, pivaloyl, benzyl ether group, methoxymethyl, trimethylsilyl, tetrahydrofuranyl, tert-butyldisilyl, acetyl, benzoyl and p-toluenesulfonyl.
  18. 18 . A pharmaceutical composition, comprising a therapeutically effective dose of the compound, the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 1 , and one or more pharmaceutically acceptable carriers, diluents or excipients.
  19. 19 . A method of treating a disease or disorder mediated by a G protein-coupled receptor modulator, comprising administering to a subject in need thereof a therapeutically effective amount of the compound, the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 1 .
  20. 20 . A method of treating a central nervous system disease or psychiatric disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of the compound, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof according to claim 1 .

Description

PRIORITY CLAIM TO RELATED APPLICATIONS This application is a U.S. national stage filing under 35 U.S.C. § 371 from International Application No. PCT/CN2020/124609, filed on 29 Oct. 2020, which claims priority to Chinese Application No. 201911039123.5, filed on 29 Oct. 2019, and to Chinese Application No. 202010028151.3, filed on 10 Jan. 2020, and to Chinese Application No. 202010725922.4, filed on 24 Jul. 2020. This application incorporates by reference the entirety of International Application No. PCT/CN2020/124609 and its published version WO2021/083246 (published 6 May 2021). FIELD OF THE INVENTION The present invention belongs to the field of drug synthesis, and specifically relates to a four-membered ring derivative inhibitor, a method for preparing the same, and a use thereof. BACKGROUND OF THE INVENTION Dopamine D3 receptor is a member of the G protein-coupled receptor family, and is a subtype of the dopamine receptor. It belongs to D2-like inhibitory receptor along with dopamine D2 and D4 receptors. Upon binding to DA, it reduces cAMP level by inhibiting G-protein. D3 receptors are mainly distributed in the mesolimbic system, especially the nucleus accumbens, olfactory tubercle and calleja's islets which are not related to motor function. Highly active D3 receptor modulators may have good anti-schizophrenia activity. D3 receptor is closely related to mood, cognition, spirit, addiction, etc., and can improve the negative symptoms of schizophrenia patients. D3 receptor may play a regulatory role in cognition by regulating the release of acetylcholine and regulating glutamate receptor. Partial agonism of the D3 receptor can improve cognition. 5-Hydroxytryptamine 2A (5-HT2A) receptor is a member of the G protein-coupled receptor family, and is a major excitatory receptor subtype of the 5-HT receptor. They are distributed in the center and periphery, and are closely related to spirit, emotion, learning, memory, etc. Highly active 5-HT2A receptor inhibitors have significant anti-schizophrenia effects, and can reduce the side effects of extrapyramidal symptoms. Schizophrenia is a mental illness with the highest prevalence, with a slow course of disease, is prone to repeated attacks, aggravation or exacerbation, resulting in serious burden and adverse consequences for patients and their families. Psychopaths may experience positive symptoms such as delusion, hallucination and disturbance in thought, language and behavior, negative symptoms such as lack of emotion and expression, poor speech and lack of pleasure, and other symptoms such as cognitive disorder. Although the research, development and clinical application of anti-schizophrenia drugs have developed greatly in the past few decades, both traditional antipsychotics (first-generation) (haloperidol, droperidol, thioridazine, etc.) and atypical antipsychotics (second-generation) (clozapine, risperidone, olanzapine, aripiprazole, etc.) are effective in treating positive symptoms, while poor in improving negative symptoms and cognitive disorder. Therefore, there is an urgent need to develop anti-schizophrenia drugs that can improve not only positive symptoms but also negative symptoms and cognitive disorder. Highly active dopamine D3 receptor modulators can improve negative symptoms, positive symptoms and cognitive disorder in patients with schizophrenia, without the side effects of the first- and second-generation antipsychotics such as extrapyramidal symptoms and weight gain. Antagonists or partial agonists of D3 receptor have a good efficacy on improving the positive symptoms, negative symptoms and cognitive disorder of schizophrenia. International patent applications WO2007093540, WO2009013212A2, WO2010031735A1 and WO2012117001A1 report D3 receptor and 5HT2A dual modulator compounds, but most of the binding activities Ki of the compounds to D3 receptor and 5HT2A are above 10 nM. Patent application WO2014086098A1 filed by Jiangsu Hengyi Pharmaceutical Co., LTD reports D3 selective inhibitors, but no study on the binding activity to 5HT2A is reported. Cariprazine, a D3 antagonist developed by Gedeon Richter Plc., was available in 2015 and applied for the international patent application WO2005012266A1. Cariprazine has a potent D3 receptor agonist activity, and its use in the treatment of schizophrenia for negative symptoms has significant advantages over existing drugs. However, Cariprazine has weak inhibitory activity on 5-HT2A receptor, resulting in severe side effects of extrapyramidal symptoms (ESP). Therefore, there is an urgent need to develop highly active D3 receptor modulators with optimized 5HT2A binding activity to reduce the side effects of extrapyramidal symptoms and improve the effects on negative symptoms and cognitive improvement in schizophrenia. SUMMARY OF THE INVENTION All content involved in patent application PCT/CN2020/073153 is incorporated into the present invention by way of reference. The objective of the present invention is