CN-122029152-A - Antioxidant drug conjugate FPR1 modulators, compositions comprising the modulators, and methods of use thereof

Abstract

The present disclosure provides compounds of formula (I), compositions comprising the compounds, and methods of use thereof, including use in the treatment of diseases, disorders, or conditions mediated by formyl peptide receptor 1 (FPR 1) signaling. (I)。

Inventors

• FANG LICHAO
• LIU MIAO

Assignees

• 百放开曼有限公司

Dates

Publication Date

20260512

Application Date

20231205

Claims (20)

1. 1. A compound of formula I: (I), A tautomer thereof, said compound or deuterated derivative of said tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein: (i) X and Y are independently selected from O, S, N, NR 4 、C(R 4 ) 2 and CR 4 , and at least one of X and Y is O, S, N or NR 4 ; (ii) Further, wherein R 4 is selected from the group consisting of hydrogen, CH 3 、CHF 2 , and CF 3 ; (iii) Z is C or N; Y 1 is absent or selected from O, S and NR 5 ; further, wherein R 5 is selected from the group consisting of hydrogen, straight chain alkyl, branched alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; (iv) R a is selected from the group consisting of straight chain alkyl, branched alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or R a and Y together with the atoms to which they are attached form cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; (v) R b is selected from the group consisting of hydrogen, straight chain alkyl, branched alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; (vi) Each R c is independently selected from the group consisting of hydrogen, straight chain alkyl, branched alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; (vii) Each Y 2 and Y 3 is independently absent or selected from the group consisting of: , Further, wherein each R 6 and R 7 is independently selected from hydrogen, straight chain alkyl, branched alkyl, cycloalkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, or is absent; (viii) L 1 is absent or selected from the group consisting of linear alkyl, branched alkyl, cycloalkyl, and PEG groups; (ix) Further, wherein each R 6 、R 7 and L 1 is independently and optionally substituted with at least one group selected from the group consisting of straight chain alkyl, branched chain alkyl, cycloalkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl. (X) D is selected from the following antioxidant compounds: 。
2. 2. The compound of claim 1, wherein the compound is of formula II: (II), A tautomer thereof, said compound or deuterated derivative of said tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein: A tautomer thereof, said compound or deuterated derivative of said tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein: (i) X-Y-Z is selected from-N (CH 3 ) -N=C-and-C (CH 3 ) =N-N-; (ii) Ring A is selected from optionally substituted cycloalkyl, heterocycloalkyl, aryl and heteroaryl; (iii) R' is independently selected from hydrogen, halogen groups and alkoxy groups; (iv) R 1 is independently selected from the group consisting of hydrogen, halo, cyano, straight chain alkyl, branched alkyl, and cycloalkyl; (v) R 2 is independently selected from hydrogen, methyl and cyclopropyl, or two R 2 groups are mutually connected to form a heterocyclic group; (vi) D is selected from the following antioxidant compounds: 。
3. 3. The compound of claim 1, wherein the compound is of formula II-i: (II-i), A tautomer thereof, said compound or deuterated derivative of said tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein: A tautomer thereof, said compound or deuterated derivative of said tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein: (i) X-Y-Z is selected from-N (CH 3 ) -N=C-and-C (CH 3 ) =N-N-; (ii) Ring A is selected from optionally substituted cycloalkyl, heterocycloalkyl, aryl and heteroaryl; (iii) R' is independently selected from hydrogen, halogen groups and alkoxy groups; (iv) R 1 is independently selected from the group consisting of hydrogen, halo, cyano, straight chain alkyl, branched alkyl, and cycloalkyl; (v) D is selected from the following antioxidant compounds: 。
4. 4. the compound of claim 1, wherein the compound is of formula III: (III), A tautomer thereof, said compound or deuterated derivative of said tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein: A tautomer thereof, said compound or deuterated derivative of said tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein: (i) X-Y-Z is selected from-N (CH 3 ) -N=C-and-C (CH 3 ) =N-N-; (ii) Ring A is selected from optionally substituted cycloalkyl, heterocycloalkyl, aryl and heteroaryl; (iii) R' is independently selected from hydrogen, halogen groups and alkoxy groups; (iv) R 1 is independently selected from the group consisting of hydrogen, halo, cyano, straight chain alkyl, branched alkyl, and cycloalkyl; (v) R 2 is independently selected from hydrogen, methyl and cyclopropyl, or two R 2 groups are mutually connected to form a heterocyclic group; (vi) D is selected from the following antioxidant compounds: 。
5. 5. The compound of claim 1, wherein the compound is of formula III-i: (III-i), A tautomer thereof, said compound or deuterated derivative of said tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein: A tautomer thereof, said compound or deuterated derivative of said tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein: (i) X-Y-Z is selected from-N (CH 3 ) -N=C-and-C (CH 3 ) =N-N-; (ii) Ring A is selected from optionally substituted cycloalkyl, heterocycloalkyl, aryl and heteroaryl; (iii) R' is independently selected from hydrogen, halogen groups and alkoxy groups; (iv) R 1 is independently selected from the group consisting of hydrogen, halo, cyano, straight chain alkyl, branched alkyl, and cycloalkyl; (v) D is selected from the following antioxidant compounds: 。
6. 6. the compound of any one of claims 1-5, wherein Z is C.
7. 7. The compound of any one of claims 1-5, wherein Z is N.
8. 8. A compound according to any one of claims 1-7, wherein D is edaravone.
9. 9. The compound of any one of claims 1-7, wherein D is borneol.
10. 10. The compound of any one of claims 1-7, wherein D is T-0080.
11. 11. The compound of any one of claims 1-7, wherein D is NDGA.
12. 12. The compound of any one of claims 1-7, wherein D is vanillin.
13. 13. The compound of any one of claims 1-7, wherein D is quercetin.
14. 14. The compound of any one of claims 1-7, wherein D is vitamin a.
15. 15. The compound of any one of claims 1-7, wherein D is vitamin C.
16. 16. The compound of any one of claims 1-7, wherein D is vitamin E.
17. 17. The compound of claim 1, wherein R a is aryl.
18. 18. The compound of claim 1, wherein R a is phenyl.
19. 19. The compound of claim 1, wherein R b is aryl.
20. 20. The compound of claim 1, wherein R b is phenyl.

Description

Antioxidant drug conjugate FPR1 modulators, compositions comprising the modulators, and methods of use thereof Technical Field The present disclosure provides compounds of formula I, their tautomers, said compounds or deuterated derivatives of said tautomers, as well as pharmaceutically acceptable salts of the foregoing, pharmaceutical compositions comprising compounds of formula I, their tautomers, deuterated derivatives of said compounds or tautomers, and/or pharmaceutically acceptable salts of the foregoing, and methods of using the same for treating a disease, disorder, or condition mediated, for example, by formyl peptide receptor 1 (FPR 1) protein modulation. Background Antioxidants refer to drugs that are capable of neutralizing free radicals by accepting or donating electrons to eliminate the unpaired state of the free radicals. Antioxidant drugs can react directly with and scavenge certain active free radicals, which can become new free radicals that are less active, longer-lived, and less hazardous than the original active free radicals. In general, antioxidants exert these effects through a variety of mechanisms including scavenging peroxidation-initiating species, quenching singlet oxygen molecules, sequestering metal ions, breaking free radical chain reactions, or reducing superoxide. Some antioxidants may also regulate Reactive Oxygen Species (ROS) -related enzymes and provide important defenses against free radicals by inhibiting the activity and expression of free radical generating enzymes such as NAD (P) H oxidase and Xanthine Oxidase (XO), or by enhancing the activity and expression of antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT) and Glutathione Peroxidase (GPX) to reduce the levels of intracellular free radicals. Antioxidant enzyme imbalance has been reported to be associated with many other specific pathologies such as chronic granulomatosis, down's syndrome, diabetic complications, hepatitis, rheumatoid arthritis, influenza virus, ulcers, pneumonia, HIV infection, cataracts and glaucoma. Thus, the main property of antioxidants is to prevent oxidation in cells, a chemical reaction that generates free radicals and reactive oxygen species, thereby protecting healthy cells in living beings from oxidative damage. Representative antioxidants include vitamin a, vitamin C, vitamin E, uric acid, glutathione, phenolics (e.g., phenol and polyphenol), flavonoids, carotenoids, steroids, thiol compounds, edaravone (edaravone), borneol, T-0080, nordihydroguaiaretic acid (NDGA), vanillin, and quercetin. In recent years, formyl peptide receptors (FPR 1, FPR2, FPR 3) have become increasingly important as therapeutic targets due to their beneficial biological properties. FPR is a G protein-coupled receptor that is activated by recognition of formyl peptides, then transmits chemotactic signals in phagocytes, and mediates host defenses as well as inflammatory responses, including cell adhesion, targeted migration, particle release, and superoxide production. Recovery of body homeostasis following injury or pathogen infection is critical to ensure survival of the organism. Physiological wound healing and the innate immune response are triggered by soluble mediators released by invasive pathogens or damaged lesions. The time-regulated interactive repair process involves, for example, a number of chemokines, cytokines, acute phase proteins, infiltrating cells, and resident cells, fibroblasts, nerve cells, and vasculature. If the injury persists or is severe in extent, physiological wound repair or anti-infective reactions may become pathological, leading to excessive inflammation, edema, unnecessary fibrotic repair, organ dysfunction, acute Respiratory Distress Syndrome (ARDS), sepsis, ultimately leading to organ failure and/or death. Thus, effective modulation of the intensity and duration of the inflammatory and regressive response is critical for repair of the injury. Following tissue injury or infection by a pathogen (bacterial, viral, fungal and/or microbial infection), invading pathogens, damaged cells and diseased tissue release a series of formyl peptides, injury-related molecular pattern molecules (DMAPs), inflammatory lipid mediators (such as leukotrienes and lipoxins) and acute phase proteins (such as annexin). Three FPR receptors serve as key sensors for these chemotactic and activating molecules in humans and they are highly expressed on neutrophils, macrophages, T lymphocytes, dendritic cells, epithelial cells, fibroblasts, microglia and astrocytes. These chemically active molecules and acute proteins bind to the FPR receptor and recruit leukocytes, stimulate production of superoxide and cytokines, activate microglia, astrocytes, and other inflammatory and regression responses to repair injury and host defense. On the other hand, the pathological inflammatory response caused by imbalance in FPR receptor-mediated signal transduction is the cause of a variety of disease s