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CN-122010922-A - Benzoxazole compounds, pharmaceutical compositions containing same and uses thereof

CN122010922ACN 122010922 ACN122010922 ACN 122010922ACN-122010922-A

Abstract

The present disclosure provides a benzoxazole compound represented by formula I, a tautomer or stereoisomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a deuterated compound thereof, a hydrate thereof, or a solvate thereof, a pharmaceutical composition comprising the same, and their use as orexin receptor antagonists or for treating orexin signaling pathway-related diseases, disorders, or conditions. I。

Inventors

  • JIAN SHUN
  • FU YUANTAO
  • LIU RENXIANG
  • SHI SHAOCHUN
  • ZHOU JIE
  • HE YICHAO
  • LIU RUIHUAN
  • GONG YUN

Assignees

  • 株洲千金药业股份有限公司

Dates

Publication Date
20260512
Application Date
20260205
Priority Date
20250630

Claims (10)

  1. 1. A benzoxazole compound represented by formula I, a tautomer or stereoisomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a deuteride thereof, a hydrate thereof, or a solvate thereof, I Wherein n is 0,1, 2, 3 or 4; R 1 is independently at each occurrence deuterium, tritium, halogen, C1-C10 alkyl, C1-C10 haloalkyl, C3-C10 cycloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, cyano, amino, amido, or hydroxy; Y is O or S; R 2 is C1-C10 alkyl, C1-C10 haloalkyl, C2-C10 alkenyl, or C2-C10 alkynyl; m is 0,1, 2 or 3; R 3 is, independently at each occurrence, deuterium, tritium, halogen, C1-C10 alkyl, C1-C10 haloalkyl, C3-C10 cycloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, cyano, amino, or hydroxy; z is C or S, and Is that 、 Or (b) ; Ring A is a C6-C10 aryl, a 5-10 membered heteroaryl containing 1-3 heteroatoms, a C5-C10 cycloalkenyl, or a 5-10 membered heterocycloalkenyl containing 1-3 heteroatoms; p is 0,1, 2, 3, 4 or 5; r 4 is independently at each occurrence C1-C10 alkoxy, C1-C10 haloalkoxy, halogen, C1-C10 alkyl, C1-C10 haloalkyl, C3-C10 cycloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, 5-10 membered heteroaryl containing 1-3 heteroatoms, C6-C10 aryl, C5-C10 cycloalkenyl, or 5-10 membered heterocycloalkenyl containing 1-3 heteroatoms; The R 4 is optionally substituted with one or more groups selected from halogen, C1-C10 alkyl, C1-C10 haloalkyl, hydroxy, amino.
  2. 2. The compound of claim 1, a tautomer or stereoisomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a deuterate thereof, a hydrate thereof, or a solvate thereof, wherein n is 1, 2, or 3, and/or R 1 is independently at each occurrence deuterium, tritium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cyano, amino, amido, or hydroxy; preferably, R 1 is, independently at each occurrence, deuterium, tritium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, cyano, amino, or hydroxy; Preferably, R 1 is independently at each occurrence fluorine, chlorine, bromine, iodine, methyl, ethyl, or propyl; More preferably, n is 2 and each R 1 is independently at each occurrence fluorine, chlorine, bromine, iodine, methyl, ethyl, or propyl.
  3. 3. The compound of claim 1 or 2, a tautomer or stereoisomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a deuterate thereof, a hydrate thereof, or a solvate thereof, wherein Y is O; and/or R 2 is C1-C6 alkyl, or C1-C6 haloalkyl; Preferably, R 2 is C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl or C1-C3 alkyl; More preferably, R 2 is methyl, ethyl, or propyl.
  4. 4. A compound as claimed in any one of claims 1 to 3, a tautomer or stereoisomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a deuterate thereof, a hydrate thereof or a solvate thereof, wherein m is 0,1 or 2, preferably m is 0, and/or R 3 is independently at each occurrence deuterium, tritium, halogen, C1-C6 alkyl, or C1-C6 haloalkyl; preferably, R 3 is, independently at each occurrence, deuterium, tritium, fluorine, chlorine, bromine, iodine, methyl, ethyl, or propyl.
  5. 5. The compound of any one of claims 1-4, a tautomer or stereoisomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a deuterate thereof, a hydrate thereof, or a solvate thereof, wherein Z is C, an Is that Or (b) And/or Ring A is a C6-C10 aryl, a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N or O or S, a C5-C10 cycloalkenyl group, or a 5-10 membered heterocycloalkenyl group containing 1-3 heteroatoms selected from N or O or S; Preferably, ring A is a C6-C10 aryl group, or a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N or O or S; Preferably, ring A is phenyl, or a 5-6 membered heteroaryl containing 1-2 heteroatoms selected from N or O or S; preferably, ring a is one or more selected from phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thienyl, pyrrolyl and furanyl; preferably, ring a is one or more selected from phenyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl and isoxazolyl; more preferably, ring a is phenyl, or pyridinyl.
  6. 6. The compound of any one of claims 1-5, a tautomer or stereoisomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a deuterate thereof, a hydrate thereof, or a solvate thereof, wherein p is 1, 2, or 3, and/or R 4 is independently at each occurrence C1-C10 alkoxy, C1-C10 haloalkoxy, halogen, C1-C10 alkyl, C1-C10 haloalkyl, C3-C10 cycloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N or O or S, C6-C10 aryl, C5-C10 cycloalkenyl, or 5-10 membered heterocycloalkenyl containing 1-3 heteroatoms selected from N or O or S; Preferably, R 4 at each occurrence is independently C1-C6 alkoxy, C1-C6 haloalkoxy, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, 5-8 membered heteroaryl containing 1-3 heteroatoms selected from N or O or S, C6-C10 aryl, C5-C8 cycloalkenyl, or 5-8 membered heterocycloalkenyl containing 1-3 heteroatoms selected from N or O or S; Preferably, R 4 is, independently at each occurrence, C1-C6 alkoxy, C1-C6 haloalkoxy, halogen, C1-C6 alkyl, C1-C6 haloalkyl, 5-8 membered heteroaryl containing 1 to 3N atoms, phenyl, C5-C8 cycloalkenyl, or 5-8 membered heterocycloalkenyl containing 1 to 3N atoms; Preferably, R 4 is independently at each occurrence C1-C6 alkoxy, fluoro, chloro, bromo, iodo, C1-C6 alkyl, 5-8 membered heteroaryl containing 1-3N atoms, or phenyl; preferably, R 4 is independently at each occurrence C1-C3 alkoxy, fluoro, chloro, bromo, iodo, C1-C3 alkyl, 5-6 membered heteroaryl containing 1-3N atoms, or phenyl; preferably, R 4 is, independently at each occurrence, methoxy, ethoxy, propoxy, fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, triazolyl, pyrazolyl, imidazolyl, pyrrolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, or phenyl; preferably, R 4 is, independently at each occurrence, methoxy, ethoxy, propoxy, fluoro, chloro, bromo, methyl, ethyl, propyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, or phenyl; More preferably, R 4 is, independently at each occurrence, methyl, ethyl, propyl, pyridinyl, pyrazinyl, pyrimidinyl, or phenyl, and/or The R 4 is optionally substituted with one or more groups selected from halogen, C1-C10 alkyl, C1-C10 haloalkyl; preferably, the R 4 is optionally substituted with fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, halomethyl, haloethyl, or halopropyl; More preferably, the R 4 is optionally substituted with fluorine, chlorine, bromine or iodine.
  7. 7. The compound of any one of claims 1-6, a tautomer or stereoisomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a deuterate thereof, a hydrate thereof, or a solvate thereof, wherein p is 1 and R 4 is a 5-6 membered heteroaryl containing 1-3N atoms, or phenyl, or P is 2, one R 4 is C1-C3 alkoxy, fluoro, chloro, bromo, iodo, or C1-C3 alkyl, and the other R 4 is a 5-6 membered heteroaryl group containing 1-3N atoms, or phenyl.
  8. 8. The compound of any one of claims 1-7, a tautomer or stereoisomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a deuterate thereof, a hydrate thereof, or a solvate thereof, wherein the compound is: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 Or (b) 。
  9. 9. A pharmaceutical composition, wherein the pharmaceutical composition comprises a benzoxazole compound represented by formula I, a tautomer or stereoisomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a deuteride thereof, a hydrate thereof, or a solvate thereof according to any one of claims 1 to 8; preferably, the pharmaceutical composition further comprises pharmaceutically acceptable excipients.
  10. 10. Use of a benzoxazole compound of formula I, a tautomer or stereoisomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a deuteride thereof, a hydrate thereof, or a solvate thereof as defined in any one of claims 1 to 8, or a pharmaceutical composition thereof, for the manufacture of an orexin receptor antagonist, or for the manufacture of a medicament for the treatment of a disease, disorder or condition associated with aberrant orexin signaling pathway; Preferably, the disease, disorder or condition associated with an abnormality in the orexin signaling pathway is selected from the group consisting of: depression, anxiety, bipolar disorder, mood disorder, drug addiction, alcohol dependence, gambling addiction, obsessive-compulsive disorder, schizophrenia, confusion, dementia, severe mental retardation, movement disorders, parkinson's disease, epilepsy, anorexia nervosa, bulimia nervosa, binge eating disorders, cachexia, obesity, pathological eating behaviors, sexual dysfunction, psychosexual disorder, sex anxiety disorder, obesity genitalia, kalman syndrome, functional amenorrhea, cushing's syndrome, pituitary adenoma, hyperprolactinemia, hypopituitarism, hypothalamic hypothyroidism, hypothalamic-adrenal dysfunction, sudden hyperprolactinemia, hypothalamic-related growth hormone deficiency, diabetes mellitus, impaired glucose tolerance narcolepsy, insomnia, various forms of sleep disorders, jet lag syndrome, hyperalgesia, allodynia, acute pain, chronic pain, arthritic pain, motor impairment pain, migraine, atypical facial pain, back pain, visceral pain, pain associated with infection or therapy, taste/appetite disorders, nausea, vomiting, hypertension, hypotension, angina, acute myocardial infarction, acute and chronic congestive heart failure, cardiac arrhythmias, asthma, urinary retention, overactive bladder, urge urinary incontinence, inflammatory bowel disease, gastric dysfunction, gastric ulcers, benign prostatic hyperplasia, chronic kidney disease/renal failure, osteoporosis, allergic reactions, tolerance to narcotics/opioids and withdrawal symptoms, inhibition of the cata-dementia-parkinsonism-amyotrophic syndrome.

Description

Benzoxazole compounds, pharmaceutical compositions containing same and uses thereof Technical Field The disclosure belongs to the field of pharmaceutical chemistry, and in particular relates to a benzoxazole compound shown in a formula I, a tautomer or stereoisomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a deuteride thereof, a hydrate thereof or a solvate thereof, a pharmaceutical composition containing the benzoxazole compound and the tautomer or stereoisomer thereof, and medical application of the benzoxazole compound and the tautomer or stereoisomer thereof. Background Orexin (Orexin, also known as Hypocretin) is a family of neuropeptides produced by proteolytic cleavage of the precursor protein prepro-orexin, whose synthesis is limited primarily to specific neurons in the lateral hypothalamic region (Lateral Hypothalamus, LH). Two active forms have been identified, orexin A (Orexin-A, OX-A) and orexin B (Orexin-B, OX-B). OX-A and OX-B are expressed by a common precursor gene (HCRT), but after cleavage form functionally distinct active peptides by different post-translational modifications. Orexin acts through two G protein-coupled receptors of seven transmembrane structure, OX1R (HCRTR 1) and OX2R (HCRTR), OX1R specifically couples to Gq protein, activates phospholipase C (PLC) -IP 3-Ca2+ signaling pathway, mediating neuronal excitability enhancement. OX2R can be coupled with Gq and Gi/o proteins simultaneously, can trigger Ca 2+ to release and inhibit cAMP from generating, and has more diversity in signal regulation. OX-A can activate both OX1R and OX2R, while OX-B preferentially activates OX2R. The distribution of OX1R and OX2R in the brain showed partially overlapping and different expression patterns. OX1Rs are selectively expressed in the locus coeruleus nuclear region (LC) and cingulate gyrus cortex, while OX2Rs are selectively expressed in tubercular papillary nuclei (TMN), hypothalamic paraventricular nuclei (PVN) and nucleus accumbens (NAc). Both receptors are expressed in the hypothalamic outer zone (LH), the medial frontal cortex (mPFC), the hippocampus (Hip), the central nucleus of the amygdala (cela), the striatal Bed Nucleus (BNST), the dorsal central suture nucleus (DR), the ventral midbrain covered region (VTA), the dorsal lateral covered region (LDT) and the solitary Nucleus (NTS), OX1Rs are specifically expressed in the locus blue (LC) and cingulate cortex, and OX2Rs are specifically expressed in the tuberculous papillary nucleus (TMN), the hypothalamic paraventricular nucleus (PVN) and the nucleus accumbens (NAc). Orexin systems and their receptors play an important role in regulating a variety of fundamental physiological processes, including sleep-wake cycle, energy metabolism, facility behavior, reward pathways, and stress responses. The dysfunction of this pathway is closely associated with a variety of diseases, disorders and conditions, such as depression, anxiety, bipolar disorder (manic depression), mood disorders, drug addiction, alcohol dependence, gambling addiction, obsessive-compulsive disorders, schizophrenia, confusion, dementia (such as Alzheimer's disease), severe mental retardation, movement disorders (such as Huntington's chorea, tourette's syndrome/Tourette's syndrome), parkinson's disease, epilepsy, anorexia nervosa, bulimia nervosa, binge eating disorders, cachexia, obesity, pathological feeding behavior (such as addictive feeding, binge-scavenging behavior), sexual dysfunction, sexual psychological disorders, sex anxiety, obesity genitalia, kalman syndrome (hypothalamic hypogonadism with loss of smell/hypofunction), functional amenorrhea, cushing's syndrome (adrenocortical dysfunction), pituitary adenoma (prolactinoma, growth hormone tumor, etc. leading to acromegaly/giant person), hypergalactiae, hypopituitarism (complete or partial hypopituitarism, such as dwarfism caused by growth hormone deficiency), hypothalamic hypothyroidism, hypothalamic-adrenal dysfunction, sudden hyperprolactinemia, hypothalamic related growth hormone deficiency, diabetes, impaired glucose tolerance, narcolepsy (somnolence), insomnia, various forms of sleep disorders (such as parasomnia, sleep apnea, sleep problems associated with neurological diseases or pain), jet lag, hyperalgesia, allodynia (such as causalgia), tactile pain), acute pain, chronic pain (neuropathic pain such as causalgia, postherpetic neuralgia, post-stroke pain, post-operative pain, phantom limb pain, complex regional pain syndrome I/II), arthritic pain, motor impairment pain, migraine, atypical facial pain, back pain, visceral pain (such as irritable bowel syndrome, angina-related pain), and pain associated with infections (such as HIV) or treatments (such as chemotherapy), taste/appetite disorders, nausea, vomiting, hypertension, hypotension, angina, acute myocardial infarction, acute and chronic congestive heart failure, cardiac arrhythmias, asthma, urinary retention, overactive bl