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CN-122010898-A - 4-Sulfamoyl benzene propionamide compounds, and preparation method and application thereof

CN122010898ACN 122010898 ACN122010898 ACN 122010898ACN-122010898-A

Abstract

The invention discloses a 4-sulfamoyl-benzene propionamide compound and application thereof. The invention provides a compound shown as a formula (I), an isotope label thereof, a solvate thereof, a pharmaceutically acceptable salt thereof, a solvate of the pharmaceutically acceptable salt or a prodrug thereof. The compound can promote the ALP expression of osteoblasts, has better promoting activity on the differentiation of the osteoblasts, and has potential treatment effects on promoting bone anabolism and treating bone related diseases.

Inventors

  • YAO WEI
  • XU ANCHAO
  • CAI YONGLONG
  • CHEN LIANG
  • CHEN JIWEI

Assignees

  • 中山莱博瑞辰生物医药有限公司

Dates

Publication Date
20260512
Application Date
20251110
Priority Date
20241111

Claims (10)

  1. 1. A compound of formula (I), an isotopic label thereof, a solvate thereof, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, or a prodrug thereof, characterized in that: ; Wherein, the N is 0, 1 or 2; Each R 0 is independently selected from halogen, hydroxy, cyano, carboxy, C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkyl, deuterated C1-C6 alkyl, halo C1-C6 alkoxy, deuterated C1-C6 alkoxy, C3-C6 cycloalkyl; x 1 is selected from N or CH; X 2 is selected from N or CR 2 ; R 1 、R 2 、R 3 、R 4 is each independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, carboxy, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, -NH 2 , -NH- (C1-C6 alkyl), -C (O) NH 2 , -C (O) NH- (C1-C6 alkyl); Or R 1 、R 2 and the C atom between them together form phenyl which is unsubstituted or substituted by one or more substituents of group A, group A substituents including halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl; Ring a is selected from phenyl unsubstituted or substituted with one or more substituents of group B, 5-6 membered heteroaryl unsubstituted or substituted with one or more substituents of group B; the substituent group B comprises deuterium, halogen, hydroxyl, cyano, carboxyl, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, -NH 2 , -NH- (C1-C6 alkyl), -C (O) NH 2 , -C (O) NH- (C1-C6 alkyl), wherein the 5-6 membered heteroaryl is a 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O, S.
  2. 2. A compound of formula (I), an isotopic label thereof, a solvate thereof, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, or a prodrug thereof as claimed in claim 1 wherein: X 2 is selected from N or CR 2 ; r 3 is hydrogen; r 4 is hydrogen; r 2 is hydrogen; R 1 is hydrogen or-NH 2 ; Or R 1 、R 2 and the C atom between them together form an unsubstituted or halogen-substituted phenyl group.
  3. 3. A compound of formula (I), an isotopic label thereof, a solvate thereof, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, or a prodrug thereof as claimed in claim 1 wherein: Ring A is selected from phenyl which is unsubstituted or substituted by one or more substituents from group B, 5-6 membered heteroaryl which is unsubstituted or substituted by one or more substituents from group B, group B substituents including halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkyl, halo C1-C6 alkoxy, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, -C (O) NH 2 , -C (O) NH- (C1-C6 alkyl) and said 5-6 membered heteroaryl is a 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O, S.
  4. 4. A compound of formula (I), an isotopic label thereof, a solvate thereof, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, or a prodrug thereof as claimed in claim 1 wherein: ring A is selected from phenyl which is unsubstituted or substituted by one or more substituents of group B, unsubstituted or substituted by one or more substituents of group B Unsubstituted or substituted by one or more substituents of group B Unsubstituted or substituted by one or more substituents of group B Unsubstituted or substituted by one or more substituents of group B Unsubstituted or substituted by one or more substituents of group B Unsubstituted or substituted by one or more substituents of group B ; Group B substituents include halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, -C (O) NH 2 、-C(O)NH-CH 3 ; Preferably, ring a is selected from: 、 more preferably, ring A is 、 。
  5. 5. A compound of formula (I), an isotopic label thereof, a solvate thereof, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, or a prodrug thereof as claimed in claim 1 wherein: 。
  6. 6. A compound of formula (I), an isotopic label thereof, a solvate thereof, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, or a prodrug thereof as claimed in claim 1 wherein the compound of formula (I) is selected from the group consisting of: ; ; ; Wherein, the N is 0, 1 or 2; Each R 0 is independently selected from halogen, cyano, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoroethyl, trifluoromethoxy, cyclopropyl, isopropyl, R 1 is selected from hydrogen, deuterium, halogen, hydroxy, cyano, carboxy, C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkyl, deuterated C1-C6 alkyl, -NH 2 , -NH- (C1-C6 alkyl), -C (O) NH 2 , -C (O) NH- (C1-C6 alkyl); R a is selected from halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl; r b is selected from hydrogen and methyl.
  7. 7. A compound of formula (I), an isotopic label thereof, a solvate thereof, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, or a prodrug thereof as claimed in claim 1 wherein the compound of formula (I) is selected from the group consisting of: ; 。
  8. 8. A pharmaceutical composition comprising a compound of formula (I), an isotopic label, an enantiomer, a diastereomer, a solvate or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 7, and a pharmaceutically acceptable adjuvant.
  9. 9. Use of a compound of formula (I), an isotopic label, an enantiomer, a diastereomer, a solvate or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 7, or a pharmaceutical composition according to claim 8, for the preparation of a medicament for the treatment and/or prophylaxis of bone and joint related disorders.
  10. 10. The use according to claim 9, wherein the bone and joint related disorder is osteoporosis, osteoarthritis, bone fracture, osteonecrosis, alveolar bone loss.

Description

4-Sulfamoyl benzene propionamide compounds, and preparation method and application thereof The present application claims priority from chinese patent application 2024115952006, whose filing date is 2024, 11. The present application incorporates the entirety of the above-mentioned chinese patent application. Technical Field The invention belongs to the field of medicines, and particularly relates to a 4-sulfamoyl benzene propionamide compound, a preparation method and application thereof. Background Bone is a tissue with dynamic balance, including osteoblast-dominated bone formation and osteoclast-dominated bone resorption. This dynamic cyclic process is called bone remodeling. Osteoblasts are differentiated from bone marrow mesenchymal stem cells. The decrease in osteoblast activity will unbalance bone homeostasis, resulting in the development of various bone diseases such as osteoporosis, slow bone growth, slow fracture repair, etc. Most of the current treatments for bone repair are to reduce bone loss by inhibiting bone resorption, such as bisphosphonates, selective estrogen receptor modulators, etc., and although these anti-bone resorption drugs are effective in preventing bone loss further, the mere use of anti-bone resorption drugs cannot restore lost bone structure, and a treatment to increase the number or activity of osteoblasts may be a more attractive method to enhance bone formation and promote bone regeneration. The now osteogenic drugs include recombinant human parathyroid hormone drugs such as hPTH (1-34) (teriparatide) and PTHrp (abamectin), bone sclerostin mab Evenity (romosozumab), which are all FDA approved. However, as hormonal agents, clinical implications are that there is a risk of inducing osteosarcoma, such as long-term use of teriparatide and abaclotide, while it is not recommended to use teriparatide and abaclotide in patients with a history of radiation, primary or secondary hyperparathyroidism. Evenity is a fully humanized monoclonal antibody which acts by inhibiting the activity of osteopetron (Sclerostin) and in the ARCH test Evenity shows a stronger potency than the existing anti-bone resorption drug alendronate, the vertebral and non-vertebral fracture rates are reduced, but group Evenity shows a certain risk of cardiovascular side effects. All of these drugs must be administered by injection. There is therefore an urgent need to find new osteogenic anabolic drugs with oral potential for the relevant treatment of related diseases. The activity of alkaline phosphatase (alkalinephosphate, ALP), a marker protein, is significantly increased at the beginning of the osteoblast differentiation process, so that it can be determined whether or not the compound promotes osteoblast differentiation by detecting the level of ALP activity. At present, no report on the effect of 4-sulfonamide-type phenylpropionamide compounds on promoting osteoblast differentiation exists, and the compound provided by the invention has better effect of promoting osteoblast ALP expression, and is beneficial to osteoblast differentiation and mineralization. Disclosure of Invention The invention provides a 4-sulfamoyl benzene propionamide compound and application thereof, wherein the compound can promote the ALP expression of osteoblasts, has better promoting activity on the differentiation of the osteoblasts, and has potential treatment effect on the aspect of treating bone and joint related diseases. The invention provides a compound shown as a formula (I), an isotope label thereof, a solvate thereof, a pharmaceutically acceptable salt thereof, a solvate of the pharmaceutically acceptable salt or a prodrug thereof; ; Wherein, the Each R 0 is independently selected from halogen, hydroxy, cyano, carboxy, C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkyl, deuterated C1-C6 alkyl, halo C1-C6 alkoxy, deuterated C1-C6 alkoxy, C3-C6 cycloalkyl; x 1 is selected from N or CH; X 2 is selected from N or CR 2; R 1、R2、R3、R4 is each independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, carboxy, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, -NH 2, -NH- (C1-C6 alkyl), -C (O) NH 2, -C (O) NH- (C1-C6 alkyl); Or R 1、R2 and the C atom between them together form phenyl which is unsubstituted or substituted by one or more substituents of group A, group A substituents including halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl; Ring a is selected from phenyl unsubstituted or substituted with one or more substituents of group B, 5-6 membered heteroaryl unsubstituted or substituted with one or more substituents of group B; the substituent group B comprises deuterium, halogen, hydroxyl, cyano, carboxyl, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, -NH 2, -NH- (C1-C6 alkyl), -C (O) NH 2, -C (O) NH- (C1-C6 alkyl), wherein the 5-6 membered heteroaryl is a 5-6 membered heteroaryl containing 1-3