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CN-121974919-A - Aromatic heterocompounds, preparation method and application thereof

CN121974919ACN 121974919 ACN121974919 ACN 121974919ACN-121974919-A

Abstract

The invention discloses an aromatic heterocompound, a preparation method and application thereof. The invention provides a compound shown in a formula I, a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof. The novel aromatic heterogenies are selective dopamine D1/D5 ligands, have good affinity and selectivity to targets, and can be used for treating D1/D5 mediated (or D1/D5-related) disorders, including schizophrenia, cognitive impairment, age-related cognitive decline, dementia, parkinson's disease and the like.

Inventors

  • WANG GUAN
  • HU ZHIJING
  • JIA JIAN
  • YANG YINI
  • SHI FAN
  • LI LEI
  • XIE PENG
  • FENG ZIJIN

Assignees

  • 江苏恩华药业股份有限公司
  • 上海医药工业研究院有限公司

Dates

Publication Date
20260505
Application Date
20260331
Priority Date
20250730

Claims (18)

  1. 1. A compound of formula I, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof: Wherein: X 3 is O or S; When present, R 1 is each independently hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, or C 3-8 cycloalkyl; Each R 2 is independently hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl or C 3-8 cycloalkyl, and at least one R 2 is not hydrogen; r 3a 、R 3b and R 4 are each independently hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl or C 3-10 cycloalkyl; m is an integer of 0 to 3, and N is an integer of 1 to 3.
  2. 2. A compound of formula I, a stereoisomer thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof as claimed in claim 1 wherein one or more of the following conditions are met: (1) When present, R 1 is each independently hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, or cyclopropyl; (2) R 2 is each independently hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, methoxy, ethoxy, cyclopropyl, -CD 3 、-CF 3 、-CHF 2 , or-CH 2 F; (3) R 3a 、R 3b and R 4 are each independently hydrogen, methyl or ethyl; (4) m is 0,1 or 2; (5) n is 1 or 2.
  3. 3. The compound of formula I, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein formula I is further as shown in formula II: Wherein: X 3 is O or S; When present, R 1 is each independently hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, or C 3-8 cycloalkyl; R 2 is deuterium, halogen, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy or C 3-8 cycloalkyl; r 3a 、R 3b and R 4 are each independently hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl or C 3-10 cycloalkyl; m is an integer of 0 to 3.
  4. 4. A compound of formula I, a stereoisomer thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof as claimed in claim 3 wherein one or more of the following conditions are met: (1) When present, R 1 is each independently hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, or cyclopropyl; (2) R 2 is deuterium, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, trifluoromethyl, methoxy, ethoxy, cyclopropyl, -CD 3 、-CHF 2 , or-CH 2 F; (3) R 3a 、R 3b and R 4 are each independently hydrogen, methyl or ethyl; (4) m is 0,1 or 2.
  5. 5. A compound of formula I, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof as claimed in claim 3 wherein formula II is further as shown in formula II-a or II-B: Or (b) Wherein: X 3 、R 1 、R 2 、R 3a 、R 3b 、R 4 and m are as defined in claim 3.
  6. 6. The compound of formula I, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein formula I is further as shown in formula III: Wherein: X 3 is O or S; R 2 is deuterium, halogen, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy or C 3-6 cycloalkyl.
  7. 7. The compound of formula I, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof of claim 6, wherein formula III is further as shown in formula III-a or III-B: Or (b) Wherein: X 3 and R 2 are as defined in claim 6.
  8. 8. The compound of formula I, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein formula I is further as shown in formula IV: Wherein: R 2 is deuterium, halogen, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy or C 3-8 cycloalkyl.
  9. 9. The compound of formula I, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, as claimed in claim 8 wherein R 2 is deuterium, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, trifluoromethyl, methoxy, ethoxy, cyclopropyl, -CD 3 、-CHF 2 , or-CH 2 F.
  10. 10. The compound of formulA I, A stereoisomer thereof, A tautomer thereof, or A pharmaceutically acceptable salt thereof, as claimed in claim 8, wherein formulA IV is further as shown in formulA IV-A or IV-B: Or (b) Wherein: r 2 is as defined in claim 8.
  11. 11. A compound of formula I, a stereoisomer thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, selected from the group consisting of: 。
  12. 12. A process for the preparation of a compound of formula I, a stereoisomer thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof as defined in any one of claims 1to 11, comprising the steps of: Wherein: Lg is halogen; x 3 、R 1 、R 2 、R 3a 、R 3b 、R 4 , m and n are as defined in any one of claims 1 to 11.
  13. 13. A process for preparing a compound of formula II, a stereoisomer thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof as claimed in claim 3, comprising the steps of: Wherein: LG is halogen; X 3 、R 1 、R 2 、R 3a 、R 3b 、R 4 and m are as defined in claim 3.
  14. 14. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 11, and a pharmaceutically acceptable carrier.
  15. 15. Use of a compound of formula I, a stereoisomer thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 11, or a pharmaceutical composition according to claim 14 for the manufacture of a medicament for the prophylaxis and/or treatment of a dopamine D1-like receptor mediated related disorder.
  16. 16. Use of a compound of formula I, a stereoisomer thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 11, or a pharmaceutical composition according to claim 14 for the manufacture of a medicament for the prophylaxis and/or treatment of neurological-related disorders.
  17. 17. The use according to claim 15 or 16, wherein the related disorder is selected from the group consisting of schizophrenia, cognitive impairment, attention deficit hyperactivity disorder, impulsivity, compulsive gambling, hyperphagia, autism spectrum disorders, dementia, restless legs syndrome, parkinson's disease, mild cognitive impairment, age-related cognitive decline, major depressive disorder, refractory depression, post-partum depression, dementia with alzheimer's disease, huntington's disease, anxiety, depression, bipolar disorder, long-term apathy, lack of interest, chronic fatigue, post-traumatic stress disorder, seasonal affective disorder, social anxiety disorder, serotonin syndrome, substance abuse and drug dependence, drug abuse recurrence, tourette syndrome, tardive dyskinesia, somnolence, excessive daytime sleepiness, cachexia, attention deficit, sexual dysfunction, migraine, systemic lupus erythematosus, hyperglycemia, atherosclerosis, dyslipidemia, obesity, diabetes, sepsis, post-ischemic renal tube necrosis, renal failure, post-ocular hypertension, post-operative pain, one or more of sleep onset, chronic pain, sleep onset of sleep, and post-operative conditions.
  18. 18. The use according to claim 17, wherein the related disorder is selected from one or more of schizophrenia, cognitive impairment, dementia, parkinson's disease, mild cognitive impairment, age-related cognitive decline, major depressive disorder, refractory depression, post-natal depression and dementia with alzheimer's disease.

Description

Aromatic heterocompounds, preparation method and application thereof The application claims priority from China patent application 202511059684.7 with application date of 2025, 7, 30 and China patent application 202511282442.4 with application date of 2025, 9. The present application incorporates the entirety of the above-mentioned chinese patent application. Technical Field The invention belongs to the field of pharmaceutical chemistry, and in particular relates to an aromatic heterocompound, a preparation method and application thereof. Background G-protein coupled receptors (GPCRs) are a superfamily of receptors with seven transmembrane helical domains that are involved in a variety of physiological processes in humans. Dopamine receptors are important targets for GPCRs, with therapeutic potential for the treatment of motor deficits caused by Parkinson's Disease (PD) and cognitive disorders caused by neuropsychiatric diseases such as alzheimer's disease, PD, and schizophrenia. Dopamine receptors can be divided into two subfamilies, including D1-like receptors (D1R and D5R), which are coupled primarily to G s protein to stimulate adenylate cyclase (cAMP) production, and D2-like receptors (D2R, D3R and D4R), which are coupled to G i/o protein and inhibit cAMP production. D1-like receptors are highly expressed in multiple brain regions, and are associated with a variety of physiological effects, such as synaptic plasticity, cognitive and memory functions, targeted motor functions, and potentially rewarding processes. However, there is currently no drug marketed only to the central nervous system for D1-like receptors. Tavapadon (CVL-751) is a selective D1/D5 receptor partial agonist developed by the company Consumer, and has a K i value of 8.54 nM for the human D1 receptor, currently in clinical phase III trials for the treatment of early PD. Tavapadon has been reported to provide a balance of motor control, safety and tolerability to patients by selectively activating the D1/D5 receptor along the striatal pathway while avoiding overdose of the D2/D3 receptor, which is the source of side effects from current dopamine receptor agonists. Furthermore, international patent application WO2015162518A1 discloses a series of furo [2,3-d ] pyrimidine heteroaromatic compounds, of which example 9 is representative. There remains a need in the clinic to develop novel and more effective drugs (e.g., agonists or partial agonists) to obtain drugs with better D1-like receptor agonistic activity, D1 receptor affinity and/or in vivo potency to meet tremendous market demands. Disclosure of Invention The invention aims to solve the technical problem of providing an aromatic heterocompound, a preparation method and application thereof. The compounds can be used as dopamine D1-like receptor agonists and can be used for treating or/and preventing nervous system related diseases, in particular Parkinson's disease. Compared with the known compounds in the prior art, the compounds have novel structures, can be orally administered, have the advantages of good D1-like receptor agonistic activity, D1 receptor affinity, obviously enhanced in-vivo pharmacodynamic action and the like, and provide a new choice for treating or reducing the severity of the parkinsonism. The invention aims to provide a compound shown in a formula I, a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof: Wherein: X 3 is O or S; When present, R 1 is each independently hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl or C 3-8 cycloalkyl, a 3-8 membered heterocyclyl containing 1-4 heteroatoms independently selected from N, O and S, a 5-10 membered aryl, or a 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O and S; R 2 is each independently hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl or C 3-8 cycloalkyl; R 3a、R3b and R 4 are each independently hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl 、-(CRccRdd)yC(O)Raa、-(CRccRdd)yC(O)ORaa、-(CRccRdd)yC(O)NRaaRbb、-(CRccRdd)yORaa、-(CRccRdd)yOS(O)2Raa、-(CRccRdd)yNRaaRbb、-(CRccRdd)yOC(O)Raa, or- (CR ccRdd)yOP(O)(ORaa)2; When present, R aa、Rbb、Rcc and R dd are each independently hydrogen, deuterium, hydroxy, halogen, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl or C 3-10 cycloalkyl; m is an integer of 0 to 3; n is an integer of 1-4, and Y is an integer from 0 to 5. In a further preferred embodiment of the invention, at least one R 2 is not hydrogen. In a further preferred embodiment of the invention, R 1, when present,