KR-102961556-B1 - Prodrug Compounds, Methods for Manufacturing the Same, and Uses

Abstract

The present invention provides a prodrug compound, a method for manufacturing the same, and uses thereof. Specifically, the present invention provides a compound represented by formula (I), a method for manufacturing the same, and uses as a prodrug for manufacturing external formulations.

Inventors

• 야오, 유안샨
• 리, 아오
• 시, 준웨이
• 카오, 구오킹

Assignees

• 밍훼이 파마슈티컬 (항저우) 리미티드
• 밍훼이 파마슈티컬 (상하이) 리미티드

Dates

Publication Date

20260507

Application Date

20220209

Priority Date

20210209

Claims (20)

1. A compound having a structure represented by formula (I) or a pharmaceutically acceptable salt thereof, In the above formula, the G group is selected from the group consisting of, and ; Or the compound of formula (I) above has a structure represented by the following formula (IIB) or (IIC), In the above formula, T is N and; Y is N or CR 4 and; U and V are each independently CH; Z and W are each independently CR 4 ; Each R₄ independently contains H, halogen, -CN, -C(O) NH₂ , and Selected from a group consisting of; M is selected from the group consisting of chemical bonds, NR8 , and 5-7-membered heteroaryls; The B ring is selected from the group consisting of 4-10 heterocyclic and C4-C10 cycloalkyl; R6 is selected from the group consisting of C1-C4 alkyl, C2-C6 cyanoalkyl, -C(O) CH2CN , and -C(O) NHR7 ; R7 is selected from the group consisting of -OH, halogen, C1-C6 alkyl, and C1-C6 haloalkyl; R 8 is selected from the group consisting of H, C1-C4 alkyl and C2-C6 cyanoalkyl; s is selected from 0 or 1; R1 and R2 are each independently selected from the group consisting of H, D, and substituted or unsubstituted C1-C6 alkyls, or R1 and R2 form a C3-C8 carbon ring together with carbon atoms connected thereto; L is selected from the group consisting of chemically bonded and substituted or unsubstituted C1-C6 alkylenes; R3 is selected from the group consisting of substituted or unsubstituted C5-C20 alkyls; The above heteroaryl has 1 to 3 atoms selected from N, S and O; The above heterocyclil comprises 1 to 3 heteroatoms selected from the group consisting of N, O, and S(O) p ; p is selected from 0, 1, or 2; A compound or a pharmaceutically acceptable salt thereof, wherein, unless otherwise specified, the “substitution” means being substituted by one or more substituents selected from the group consisting of deuterium atoms, halogens, C1-C6 alkyls, C1-C6 alkyl halides, C1-C6 alkoxys, C1-C6 alkoxy halides, and C3-C8 cycloalkyls.
2. In paragraph 1, The above G group is a compound or a pharmaceutically acceptable salt thereof selected from the group consisting of: and
3. In paragraph 1, The compound of the above formula (I) has a structure represented by the following formula (IIB) or (IIC), In the above formula, each substituent is a compound or a pharmaceutically acceptable salt thereof as defined in claim 1.
4. In paragraph 1, is a compound or/or a pharmaceutically acceptable salt thereof selected from the following structures: and .
5. In paragraph 1, The compound of the above formula (I) has a structure represented by the following formula (IIA), In the above formula, Y is N or CC(O) NH2 ; R 4 is and Selected from a group consisting of; R 1 to R 3 and L are each a compound or a pharmaceutically acceptable salt thereof as defined in claim 1.
6. In any one of paragraphs 1 through 3, The compound of formula (I) above is a compound or a pharmaceutically acceptable salt thereof having a structure selected from the group consisting of the following formulas: and
7. In any one of paragraphs 1 through 3, The compound of formula (I) above is a compound or a pharmaceutically acceptable salt thereof having a structure selected from the group consisting of: and .
8. In any one of paragraphs 1 through 3, The compound of formula (I) above is a compound or a pharmaceutically acceptable salt thereof having a structure selected from the group consisting of:
9. As a method for manufacturing a compound according to paragraph 5, A method comprising the step of reacting the compound of Formula 2e with R3 -LC(O)X in an inert solvent to obtain the compound of Formula (IIA); wherein Y is N or CC(O) NH2 , X is OH, a halogen or OC(O) R3 , and R1 to R4 and L are each as defined in claim 5.
10. A pharmaceutical composition for the treatment or prevention of a disease related to the activity or expression amount of a JAK kinase, comprising a pharmaceutically acceptable carrier and a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, A pharmaceutical composition in which the above disease is selected from the group consisting of cancer, myeloproliferative disease, inflammation, immune disease, organ transplant, viral disease, cardiovascular disease or metabolic disease, human or animal autoimmune disease, rheumatoid arthritis, skin disease, multiple sclerosis, psoriatic arthritis, inflammatory bowel disease, myasthenia gravis, and psoriasis.
11. A compound according to any one of paragraphs 1 to 5; A skin penetration promoter selected from the group consisting of surfactants, dimethyl sulfoxide, azone, alcohol, ether, fatty acids and fatty acid esters, and combinations thereof; and As a topical administration formulation comprising a selective support layer, The above preparation is intended for the treatment or prevention of diseases related to the activity or expression level of JAK kinase, wherein the disease is a topical preparation selected from the group consisting of cancer, myeloproliferative diseases, inflammation, immune diseases, organ transplantation, viral diseases, cardiovascular diseases or metabolic diseases, human or animal autoimmune diseases, rheumatoid arthritis, skin diseases, multiple sclerosis, psoriatic arthritis, inflammatory bowel disease, myasthenia gravis, and psoriasis.
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Description

Prodrug Compounds, Methods for Manufacturing the Same, and Uses The present invention relates to the field of small molecule drugs. Specifically, the present invention provides a prodrug compound as a kinase inhibitor, a pharmaceutically acceptable salt, hydrate, or solvate thereof, and a pharmaceutical composition (preferably, a topical formulation) comprising said component. The JAK-STAT signaling pathway is a recently discovered cytokine-stimulated signaling pathway in which JAK plays a crucial role in cytokine signaling, and downstream substrates of the JAK kinase family include the signaling and activating agents (STAT) of transcription proteins. JAK proteins are important components of the pathway, and abnormal enhancement of their activity often leads to the development of diseases. Many diseases are associated with abnormal cellular responses in the JAK-STAT signaling pathway, and these diseases include autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, and Alzheimer's disease. Rheumatoid arthritis (RA) is a common chronic autoimmune disease in clinical practice. Its main symptoms include joint swelling, pain, stiffness, deformity, and severe functional impairment, with an incidence rate of 0.5%–1.0% in the population. Because the pathogenesis of RA is unclear, it is difficult to control the pathological process, resulting in a high disability rate, severe damage to the patient's physical and mental health, and a decline in their quality of life. Currently, drugs used to treat RA primarily include non-steroidal anti-inflammatory drugs (NSAIDs), disease-modifying antirheumatic drugs (DMARDs), and antibody drugs. For a long time, DMARDs were the primary drugs for RA treatment; in 1988, methotrexate (MTX), the first DMARD drug, was approved by the FDA for RA treatment, marking a significant milestone in the history of RA treatment. While these drugs are widely used due to their advantages in efficacy, tolerability, and safety, they have side effects such as nausea, vomiting, gastric discomfort, and hepatotoxicity. In contrast, newly developed antibody drugs have excellent therapeutic efficacy and safety indicators for moderate RA, but because they target specific cytokines, the beneficiary group is significantly limited, and at the same time, treatment costs and injectable administration also limit the distribution of these drugs. Over the past 20 years of development, RA treatment has made significant progress, and patients' disease states can be effectively controlled by existing treatment methods. Nevertheless, RA patients still suffer from issues such as disease recurrence, unsatisfactory treatment efficacy, long-term resistance, and certain side effects. More importantly, since the quality of life of RA patients—including organ function such as joints—has not been substantially improved by existing treatments, there remains a significant unmet clinical demand in this field focused on restoring normal patient function. According to research, the key role of RA treatment is for monocytes/macrophages, lymphocytes, etc. infiltrating RA synovial tissue and cells to generate large amounts of cytokines through autosecretion, and these cytokines interact to activate the JAK/STAT signaling pathway (Janus kinase/Signal transducer and activators of transcription signaling pathway) through different pathways. Since the JAK/STAT signaling pathway can be specifically inhibited to block the cascade amplification of the cytokines, thereby improving symptoms of damaged joints in RA patients, the JAK/STAT signaling pathway has become a potential target for RA treatment. Because JAK kinases are involved in various important physiological processes within the body, broad inhibition of different subtypes can cause adverse effects. Tofacitinib is used in patients with moderate RA who lack an MTX response or resistance, and clinical trials have observed specific side effects, including infection, tuberculosis, tumors, anemia, liver damage, and elevated cholesterol. Tofacitinib possesses significant inhibitory activity against JAK1, JAK2, and JAK3 subtypes; JAK2 activity is associated with erythrocyte differentiation and lipid metabolism, and some of the aforementioned side effects have been considered to be related to the drug's non-selective inhibitory characteristics. Therefore, finding selective JAK1 and/or JAK3 inhibitors will be a new direction in RA drug research. Currently, JAK inhibitors have been proven to be effective therapeutic agents for hematological diseases, tumors, rheumatoid arthritis, and psoriasis. However, JAK compositions available for topical administration in this field remain very limited. The inventors have developed a compound represented by Formula (I) through long-term and in-depth research. Since the compound consists of a hydrophilic drug molecule terminal and a h