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CN-122010946-A - Heterocyclic compounds

CN122010946ACN 122010946 ACN122010946 ACN 122010946ACN-122010946-A

Abstract

The present invention provides heterocyclic compounds having orexin type 2 receptor agonist activity. A compound represented by formula (I): (I) Wherein each symbol is as described in the present specification, or a salt thereof, is useful as an agent for preventing or treating narcolepsy.

Inventors

  • HATTORI SEISHI
  • HOASHI YASUTAKA
  • Nitano Yuhei
  • KAJITA YUICHI
  • KOIKE TATSUKI
  • Marilyn pyla
  • ITO YOSHIKAZU
  • TAKEUCHI KOHEI
  • Kimura Yingshi
  • Tokunaga Reihito
  • IKEDA SHUHEI
  • Martin Alexander. Palicek
  • Tezuka Zeheng

Assignees

  • 武田药品工业株式会社

Dates

Publication Date
20260512
Application Date
20231030
Priority Date
20221031

Claims (10)

  1. 1. A compound represented by formula (I): (I) Wherein the method comprises the steps of X 1 is NR 8 or CR 9 ; x 2 is O, NR 10 or S; X 3 and X 4 are both C, or one of X 3 and X 4 is N and the other is C; x 5 is CR 11 or N; X 6 is CR 12 ; X 7 is CR 13 or N; X 8 is CR 14 or N; x 9 is CR 2 or N; x 10 is CR 15 or N; R 1 is optionally substituted C 1-6 alkyl, optionally substituted C 3-10 cycloalkyl or optionally substituted mono or di C 1-6 alkylamino; r 2 and R 3 are each independently a hydrogen atom or an optionally substituted C 1-6 alkyl group, or When R is 0, then R 2 and R 3 can be taken together to form a bond, or When X 10 is CR 15 then R 3 can be taken together with R 15 to form a bond; r 4 is a hydrogen atom, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 alkoxy or hydroxy; R 5 is an optionally substituted 4-, 5-, or 6-membered monocyclic group; R 6 and R 7 are each independently a hydrogen atom, a halogen atom or an optionally substituted C 1-6 alkyl group; m is 0 or 1; q is 1 or 2; r is 0 or 1; R 9 、R 11 、R 12 and R 13 are each independently a hydrogen atom, an optionally substituted C 1-6 alkyl group, a halogen atom, an optionally substituted C 3-6 cycloalkyl group, an optionally substituted 3-to 7-membered nitrogen-containing heterocyclyl group, an optionally substituted C 1-6 alkoxy group, or a hydroxyl group; R 8 and R 10 are each independently absent or selected from a hydrogen atom and an optionally substituted C 1-6 alkyl group, and R 14 is a hydrogen atom, a halogen atom, or an optionally substituted C 1-6 alkyl group; R 15 is a hydrogen atom, a halogen atom or an optionally substituted C 1-6 alkyl group, or R 15 can be taken together with R 3 to form a bond; Or a salt thereof.
  2. 2. The compound according to claim 1, wherein X 8 is N; X 9 is CR 2 , wherein R 2 is a hydrogen atom, or when R is 0, then R 2 can form a bond with R 3 , and X 10 is N; Or a salt thereof.
  3. 3. The compound according to claim 1, wherein R 1 is (1) C 1-6 alkyl optionally substituted with 1 to 3 substituents independently selected from: (i) A halogen atom is used as a halogen atom, (Ii) C 1-6 alkoxy, and (Iii) C 3-6 cycloalkyl group, which is a group, (2) C 3-10 cycloalkyl, or (3) Mono-or di-C 1-6 alkylamino; r 2 and R 3 are each independently a hydrogen atom or a C 1-6 alkyl group, or When R is 0, then R 2 and R 3 can be taken together to form a bond, or When X 10 is CR 15 , then R 3 and R 15 taken together form a bond; R 4 is a hydrogen atom, C 1-6 alkyl, C 1-6 alkoxy or hydroxy; R 5 is phenyl, pyrazolyl, furanyl, thienyl, thiazolyl, pyridinyl, piperidinyl, or cyclobutyl, any of which is optionally substituted with one or more substituents independently selected from C 1-6 alkyl, halogen atom, halo (C 1-6 ) alkyl, and C 1-6 alkoxy; R 6 and R 7 are each independently a hydrogen atom, a halogen atom or a C 1-6 alkyl group; X 1 、X 2 、X 3 、X 4 、X 5 、X 6 and X 7 are selected to form a ring system, which is one of: (i) X 1 is NR 8 and R 8 is absent, X 2 is O, X 3 and X 4 are both C, X 5 is CR 11 ,X 6 is CR 12 , and X 7 is CR 13 ; (ii) X 1 is NR 8 and R 8 is absent, X 2 is O, X 3 and X 4 are both C, X 5 is N, X 6 is CR 12 , and X 7 is CR 13 ; (iii) X 1 is NR 8 and R 8 is absent, X 2 is O, X 3 and X 4 are both C, X 5 is CR 11 ,X 6 is CR 12 , and X 7 is N; (iv) X 1 is NR 8 and R 8 is absent, X 2 is S, X 3 and X 4 are both C, X 5 is N, X 6 is CR 12 , and X 7 is CR 13 ; (v) X 1 is NR 8 and R 8 is absent, X 2 is S, X 3 and X 4 are both C, X 5 is CR 11 ,X 6 is CR 12 , and X 7 is CR 13 ; (vi) X 1 is NR 8 and X 2 is NR 10 , and one of R 8 and R 10 is absent and the other of R 8 and R 10 is C 1-6 alkyl, X 3 and X 4 are both C, X 5 is CR 11 ,X 6 is CR 12 , and X 7 is CR 13 ; (vii) X 1 is CR 9 ,X 2 is NR 10 and R 10 is absent, X 3 is N, X 4 is C, X 5 is CR 11 ,X 6 is CR 12 and X 7 is CR 13 , and (Viii) X 1 is CR 9 ,X 2 is NR 10 and R 10 is absent, X 3 is C, X 4 is N, X 5 is CR 11 ,X 6 is CR 12 , and X 7 is CR 13 ; X 8 、X 9 、X 10 , m, q, and r are selected to form a ring system, which is one of: (i) X 8 is N, X 9 is CR 2 ,X 10 is N, m is 0, q is 1, and r is 0; (ii) X 8 is N, X 9 is CR 2 ,X 10 is N, m is 1, q is 1, and r is 0; (iii) X 8 is N, X 9 is CR 2 ,X 10 is N, m is 0, q is 1, and r is 1; (iv) X 8 is N, X 9 is N, X 10 is CR 15 , m is 0, q is 1, and r is 0; (v) X 8 is CR 14 ,X 9 is CR 2 ,X 10 is N, m is 0, q is 1, and r is 0, and (Vi) X 8 is N, X 9 is CR 2 ,X 10 is N, m is 0, q is 2, and r is 0; R 9 、R 11 、R 12 and R 13 are each independently selected from the group consisting of a hydrogen atom, a C 1-6 alkyl group, a halogen atom, a C 3-6 cycloalkyl group, a C 3-6 cycloalkyl (C 1-6 ) alkoxy group, a halo (C 1-6 ) alkyl group, a halo (C 1-6 ) alkoxy group, a C 1-6 alkoxy (C 1-6 ) alkyl group, an azetidinyl group, a C 1-6 alkoxy group, a hydroxyl group, and a hydroxyl (C 1-6 ) alkyl group, and R 14 is a hydrogen atom, a halogen atom or a C 1-6 alkyl group, and R 15 and R 3 together form a bond; Or a salt thereof.
  4. 4. The compound of claim 1, wherein the partial structure is represented by the formula: , Wherein each symbol is as defined in claim 1, Is one of partial structures represented by the following formula: 、 、 、 、 、 And , Wherein each symbol is as defined in claim 1.
  5. 5. The compound of claim 1, wherein the compound is represented by formula (Ia): (Ia) Wherein the method comprises the steps of R 1 is C 1-6 alkyl, C 3-10 cycloalkyl or mono C 1-6 alkylamino; r is 0 or 1; R 2 and R 3 are each independently a hydrogen atom, or When R is 0, then R 2 and R 3 can be taken together to form a bond; r 4 is a hydrogen atom; r 5 is phenyl optionally substituted with 1 to 3 halogen atoms; r 6 and R 7 are each independently a hydrogen atom or a halogen atom; X 5 is CH or N, and R 12 and R 13 are each independently a hydrogen atom, a C 1-6 alkyl group or a halogen atom; Or a salt thereof.
  6. 6. A medicament comprising a compound as defined in any one of claims 1 to 5 or a salt thereof.
  7. 7. Use of a compound as defined in any one of claims 1 to 5 or a salt thereof for the manufacture of a medicament for the treatment of a disease or condition associated with orexin type 2 receptors.
  8. 8. The use according to claim 7, wherein the disease or condition is selected from the group consisting of narcolepsy, idiopathic hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcolepsy-like symptoms, hypersomnia syndrome with daytime hypersomnia, alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases related to bone loss, sepsis, consciousness disturbance, and side effects and complications caused by anesthesia.
  9. 9. The use according to claim 7, wherein the disease or condition is selected from the group consisting of narcolepsy, idiopathic hypersomnia, and sleep apnea syndrome.
  10. 10. The use of claim 7, wherein the disease or disorder is narcolepsy.

Description

Heterocyclic compounds The application relates to a Chinese patent application (application day: 2023, 10 month and 30 days, application name: heterocyclic compound) with the application number 202380083827.0. Technical Field The present invention relates to heterocyclic compounds, in particular heterocyclic compounds having orexin type 2 receptor agonist activity. Background Orexin is a neuropeptide specifically produced by specific neurons sparsely distributed in the lateral hypothalamus and surrounding areas, and consists of two subtypes, orexin a and orexin B. Both orexin a and orexin B are endogenous ligands for orexin receptors, which are G protein-coupled receptors mainly present in the brain, and both types 1 and 2 of orexin receptors are known (non-patent document 1). Since orexin-producing neurons (orexin neurons) are located near the feeding center, and intraventricular administration of orexin peptides leads to an increase in food intake, orexin is initially attracting attention as a neuropeptide with regulation of feeding behavior. However, thereafter, the cause of narcolepsy in dogs has been reported to be genetic variation of orexin type 2 receptors (non-patent document 2), and the role of orexin in controlling sleep and wakefulness has also been studied. From studies using transgenic mice with denatured orexin neurons and double transgenic mice obtained by crossing such mice with transgenic mice overexpressing orexin, disappearance of narcolepsy-like symptoms arising from orexin neuron degeneration due to sustained expression of orexin was observed. Similarly, when an orexin peptide was administered intraventricularly to a transgenic mouse having denatured orexin neurons, improvement of narcolepsy-like symptoms was observed (non-patent document 3). Studies on orexin type 2 receptor knockout mice have shown that orexin type 2 receptors are important for maintaining arousal (non-patent document 4, non-patent document 5). This background indicates that orexin type 2 receptor agonists are therapeutic agents for narcolepsy or other sleep disorders that exhibit excessive sleepiness (non-patent document 6). In addition, it was shown that peptide agonists that selectively act on orexin type 2 receptors improve obesity in mice due to high-fat dietary load (non-patent document 7). In addition, it was shown that intraventricular administration of orexin peptide shortens the general anesthesia time of rats (non-patent document 8). In addition, it was shown that patients suffering from sleep apnea syndrome showed lower levels of orexin a concentration in plasma (non-patent document 9). In addition, it was shown that intraventricular administration of orexin peptide improves memory retention in aging acceleration model mice (SAMP 8) with cognitive dysfunction (non-patent document 10). In addition, orexin type 2 receptor agonists are shown to be therapeutic agents for heart failure (patent document 1 and non-patent document 11). In addition, it has been shown that daytime sleepiness in patients with Parkinson's disease is caused by orexin neurasthenia (non-patent document 12). In addition, it is shown that orexin regulates bone formation and bone loss, and orexin type 2 receptor agonists will become therapeutic agents for diseases associated with bone loss, such as osteoporosis, rheumatoid arthritis, and the like (patent document 2). In addition, it has been shown that an orexin receptor agonist can be used for the prevention or treatment of sepsis, severe sepsis and septic shock, because mortality can be significantly improved by merely continuously administering orexin from the periphery of a septic shock model mouse (patent document 3). Accordingly, compounds having orexin type 2 receptor agonist activity are expected to be useful as therapeutic agents for the treatment of narcolepsy, idiopathic hypersomnia, sleep apnea syndrome, consciousness disturbance (such as coma, etc.), narcolepsy syndrome accompanied by narcolepsy-like symptoms, hypersomnia syndrome accompanied by daytime hypersomnia (e.g., parkinson's disease, guillain-Barre syndrome and Crohn Levin syndrome (KLEINE LEVIN syndrome)), alzheimer's disease (Alzheimer), obesity, insulin resistance syndrome, heart failure, diseases associated with bone loss, sepsis, etc. In addition, orexin type 2 receptor agonists are useful as antagonists of anesthesia or as prophylactic or therapeutic agents for side effects and complications resulting from anesthesia. As sulfonamide derivatives, compounds represented by the following formula have been reported , Wherein each symbol is as described in the document (patent document 4). In addition, as compounds having orexin type 2 receptor agonist activity, the following compounds have been reported. A compound represented by the formula , Wherein each symbol is as described in the document (patent document 5). A compound represented by the formula , Wherein each symbol is as described in the document (patent doc