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WO-2026090857-A1 - POLYSUBSTITUTED AMINOQUINOLINE COMPOUND AND USE THEREOF

WO2026090857A1WO 2026090857 A1WO2026090857 A1WO 2026090857A1WO-2026090857-A1

Abstract

Disclosed in the present invention are a polysubstituted aminoquinoline compound and the use thereof. Specifically disclosed in the present invention is a compound as represented by formula (I), or a stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof. The compound of the present invention is a CD38 inhibitor, and can be used in the preparation of a drug for treating and/or preventing diseases related to abnormal expression or activity of CD38.

Inventors

  • HUANG, JINWEN
  • LIU, Yunli
  • JIN, Huize
  • LI, Zhongyuan
  • SHEN, Xiaokun

Assignees

  • 甫康（上海）健康科技有限责任公司

Dates

Publication Date
20260507
Application Date
20241029

Claims (10)

  1. A compound of formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs, in, X is N or CR a ; Ra is selected from the following group: H, D, halogen, C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy; Ring A is a 5-9 membered heteroaryl or a 4-9 membered heterocyclic group; Ring B is selected from the following group: C 6-10 aryl, 5-9 membered heteroaryl, C 3-10 cycloalkyl, 4-9 membered heterocyclic; n is 1, 2, 3, 4 or 5; R1 is selected from the group consisting of : deuterium, halogen, cyano, carboxyl, C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C2-4 ester, -CONH2, -CONH- C1-6 alkyl ; the above groups are optionally substituted by 1, 2 or 3 Rb ; Rb is selected from the following group: -S(O) 2 - C1-6 alkyl, C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkoxy, C1-6 alkylamino, -C(O) OC1-6 alkyl, -C(O)NH- C1-6 alkyl, -C(O)N( C1-6 alkyl) 2 ; R2 , R3 and R4 are each independently selected from the following group: H, D, halogen, C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, 3-8 membered cycloalkyl, 4-7 membered heterocyclic group.
  2. The compound, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs as claimed in claim 1, characterized in that X is N or CR a ; Ra is selected from the group consisting of: H, D, halogens, C1-4 alkyl, C1-4 deuterated alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy. Preferably, X is N or CRa ; Ra is selected from the group consisting of: H, halogen, methyl, ethyl, n-propyl, isopropyl, C1-3 fluoroalkyl; More preferably, X is selected from the group consisting of: N, CH, CCH3 , CCF3 .
  3. The compound, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs as claimed in claim 1, characterized in that ring A is a 5-9 member sulfur-containing heteroaryl group; Preferably, ring A is selected from the group consisting of 5-7 nucleotide sulfur-containing heteroaryl groups and 5-7 nucleotide oxygen-containing heteroaryl groups; More preferably, the ring A is selected from the group consisting of 5-7 nucleotides containing sulfur and nitrogen, and 5-7 nucleotides containing oxygen and nitrogen. More preferably, the ring A is selected from the group consisting of:
  4. The compound, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs as claimed in claim 1, characterized in that ring B is selected from the group consisting of: phenyl, naphthyl, 5-7-membered heteroaryl, C3-8 cycloalkyl, and 4-7-membered heterocyclic groups; Preferably, the ring B is selected from the group consisting of: phenyl, naphthyl, 5-7 member nitrogen-containing heteroaryl, C3-6 cycloalkyl, 4-6 member heteroaryl. Cyclic groups; More preferably, the ring B is selected from the group consisting of: cyclopentane, cyclohexane, benzene ring, naphthalene, furan, pyran, dihydropyran, tetrahydropyran, thiophene, pyrrole, thiazole, thiadiazole, diazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetraazole, pyrazole, pyridine, pyrimidine, pyrazine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine.
  5. The compound of claim 1, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs, characterized in that R1 is selected from the group consisting of: deuterium, halogen, cyano, carboxyl, C1-4 alkyl, C1-4 deuterated alkyl, C1-4 haloalkyl , C1-4 alkoxy, C1-4 haloalkoxy, C2-4 ester , -CONH2, -CONH- C1-4 alkyl; wherein the above groups are optionally substituted by 1, 2 , or 3 Rb ; Rb is selected from the following group: -S(O) 2 - C1-4 alkyl, C1-4 alkyl, C1-4 deuterated alkyl, C1-4 haloalkyl, C1-4 haloalkoxy, C1-4 alkoxy, C1-4 alkylamino, -C(O) OC1-4 alkyl, -C(O)NH- C1-4 alkyl, -C(O)N( C1-4 alkyl) 2 ; Preferably, R1 is selected from the group consisting of: deuterium, halogen, cyano, carboxyl, C1-3 alkyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C2-4 ester, -CONH2 , -CONH- C1-3 alkyl; the above groups are optionally substituted by 1, 2 or 3 Rb ; Rb is selected from the following group: -S(O) 2 - C1-3 alkyl, C1-3 alkyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 haloalkoxy, C1-3 alkoxy, C1-3 alkylamino, -C(O) OC1-3 alkyl, -C(O)NH- C1-3 alkyl, -C(O)N( C1-3 alkyl) 2 ; More preferably, R1 is selected from the group consisting of: F, Cl, Br, -OC1-3 -alkylene- Rb ; Rb is selected from the following group: -S(O) 2 - C1-3 alkyl, C1-3 alkyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 haloalkoxy, C1-3 alkoxy, C1-3 alkylamino, -C(O) OC1-3 alkyl, -C(O)NH- C1-3 alkyl, -C(O)N( C1-3 alkyl) 2 ; More preferably, R1 is selected from the group consisting of: F, Cl,
  6. The compound, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs as claimed in claim 1, characterized in that... Selected from the following group:
  7. The compound, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs as claimed in claim 1, is characterized in that the compound is selected from the group consisting of:
  8. A pharmaceutical composition, characterized in that the composition comprises: (i) the compound, stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate, or prodrug as described in any one of claims 1-7; and (ii) Pharmaceutically acceptable carriers, excipients or excipients.
  9. The use of the compound, stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug as claimed in any one of claims 1-7, or the pharmaceutical composition as claimed in claim 8, is characterized in that it is used to prepare a medicament for treating and/or preventing diseases related to abnormal expression or activity of CD38. Preferably, the disease associated with abnormal expression or activity of CD38 is cancer or an immune disease; More preferably, the cancer is selected from the group consisting of: leukemia, B-cell lymphoma, T-cell lymphoma, NK-cell lymphoma, plasma cell malignancy, myeloma, tumors of exhausted T cells, tumors defined as hot, variant, or cold immune tumors based on immune scores, breast cancer, central nervous system cancer, endometrial cancer, kidney cancer, colorectal cancer, lung cancer, esophageal cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, head and neck (upper respiratory and digestive tract) cancer, urinary tract cancer, colon cancer, Hodgkin's lymphoma, and non-Hodgkin's lymphoma. Lymphoma (non-Hodgkin’s lymphoma), multiple myeloma, B-cell lymphoma (e.g., diffuse large B-cell lymphoma (DLBCL)), chronic lymphocytic lymphoma (CLL), T-cell lymphoma, pilocellular lymphoma, Burkitt's lymphoma, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), melanoma, colon cancer; The immune diseases mentioned are selected from the following group: rheumatoid arthritis, systemic lupus erythematosus, asthma, inflammatory bowel disease, multiple sclerosis, Crohn's disease, gastritis, Hashimoto's thyroiditis, ankylosing spondylitis, graft-versus-host disease, and immune-mediated thrombocytopenic symptoms.
  10. An intermediate compound, characterized in that the compound is selected from the group consisting of:

Description

A multi-substituted aminoquinoline compound and its uses Technical Field This invention relates to the field of pharmaceutical technology, specifically to a multi-substituted aminoquinoline compound and its uses. Background Technology CD38 is a member of the ADP-ribosyl cyclase family, primarily responsible for degrading NAD+ (nicotinamide adenine dinucleotide), and is widely expressed on the surface of various cell types. It was initially thought to be a surface antigen on immune cells and plays a crucial role in cell signaling, intracellular Ca2 + regulation, and cell metabolism. CD38 can convert NAD+ into ADPR (ADP-ribose) or cADPR (cyclic ADPR) and nicotinamide, participating in intracellular and extracellular metabolic regulation and signaling pathways. NAD+ is an important intracellular redox carrier involved in cellular metabolism, energy balance, and cell signaling. Regulation of NAD+ levels is crucial for maintaining normal cellular function. CD38, as a consumer of NAD+, can increase NAD+ levels through inhibition, potentially offering therapeutic benefits for certain diseases associated with decreased NAD+ levels. CD38 is a surface protein widely expressed in various cell types, including immune cells such as B cells, T cells, and natural killer (NK) cells. It plays a crucial role in cell signaling, cell proliferation, differentiation, and senescence. CD38 activity is associated with a variety of biological processes, including calcium regulation, cell cycle control, and age-related diseases. Studies have shown that CD38 knockout (KO) mice exhibit significantly reduced levels of endogenous cADPR in multiple tissues/organs, affecting the function of various cell types, including pancreatic islets, acinar cells, and neutrophils. Furthermore, CD38 expression is closely related to the immunosuppressive function of regulatory T cells (Tregs), tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs). In the tumor microenvironment, CD38 expression is associated with tumor progression and may promote tumor escape from immune checkpoint inhibition by influencing T cell function. The role of CD38 in tumorigenesis and immunosuppression is an active area of research. Studies have reported that aberrant expression or activity of CD38 is associated with the development of various cancers, including non-small cell lung cancer, melanoma, cervical cancer, glioma, colorectal cancer, and esophageal cancer. Furthermore, CD38 is also associated with various diseases such as HIV/AIDS, adoptive T-cell therapy, and pancreatic cancer. In summary, CD38 plays a crucial role not only in cellular physiological functions but is also closely related to the development and progression of various diseases. Inhibiting abnormal expression or activity of CD38 may provide new strategies for treating related diseases. However, the efficacy and selectivity of existing CD38 inhibitors do not meet clinical needs. Therefore, there is an urgent need in the field for a CD38 inhibitor with excellent efficacy and high selectivity for the treatment of other diseases or conditions characterized by abnormal expression or activity of CD38. Summary of the Invention To address the above problems, this invention provides a CD38 inhibitor with excellent efficacy and high selectivity. In a first aspect of the invention, a compound of formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs are provided. in, X is N or CR a ; Ra is selected from the following group: H, D, halogen, C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy; Ring A is a 5-9 membered heteroaryl or a 4-9 membered heterocyclic group; Ring B is selected from the following group: C 6-10 aryl, 5-9 membered heteroaryl, C 3-10 cycloalkyl, 4-9 membered heterocyclic; n is 1, 2, 3, 4 or 5; R1 is selected from the group consisting of : deuterium, halogen, cyano, carboxyl, C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C2-4 ester, -CONH2, -CONH- C1-6 alkyl ; the above groups are optionally substituted by 1, 2 or 3 Rb ; Rb is selected from the following group: -S(O) 2 - C1-6 alkyl, C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkoxy, C1-6 alkylamino, -C(O) OC1-6 alkyl, -C(O)NH- C1-6 alkyl, -C(O)N( C1-6 alkyl) 2 ; R2 , R3 and R4 are each independently selected from the following group: H, D, halogen, C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, 3-8 membered cycloalkyl, 4-7 membered heterocyclic group. In another preferred embodiment, R2 , R3 and R4 are each independently selected from the group consisting of: H, D, F, Cl, Br, I, C1-4 alkyl, C1-4 deuterated alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, 3-6 membered cycloalkyl, and 5-6 membered heterocyclic groups. In a preferred embodiment, X is N or CR a ; Ra is selected from the group consisting of: H, D, halogen, C1-4 a