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EP-4737451-A1 - NOVEL CARBOXAMIDE DERIVATIVE COMPOUND AND PHARMACEUTICAL COMPOSITION COMPRISING SAME

EP4737451A1EP 4737451 A1EP4737451 A1EP 4737451A1EP-4737451-A1

Abstract

The present invention relates to: a carboxamide derivative compound represented by chemical formula I; a stereoisomer thereof; a pharmaceutically acceptable salt thereof or a hydrate or solvate thereof; a composition comprising same; a method using same in the prevention or treatment of IRAK-4- or IRAK-1-related diseases; and uses thereof.

Inventors

  • HWANG, YUN HA
  • CHO, SUNG JIN
  • HAN, SI YEON
  • HAN, GUN HEE
  • PARK, WHUI JUNG
  • JIN, YOUNG GU
  • CHOI, JUNG UK
  • JEONG, SEO HEE
  • OH, SEONG JUN
  • LEE, SANG HO
  • YOUM, Ji Hyun
  • SEO, JI WON

Assignees

  • Dong Wha Pharm. Co., Ltd.
  • Cimplrx Co., Ltd.

Dates

Publication Date
20260506
Application Date
20240628

Claims (10)

  1. A compound represented by chemical formula I, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof: wherein in above chemical formula I, X is phenyl or pyridinyl; at least one H of X is substituted with halogen, C1-C6 alkyl, C(=O)Ra, NH 2 , NO 2 , S(=O) 2 Rb, 5- to 12-membered heteroaryl including one to three heteroatoms independently selected from the group consisting of N, O and S in a ring; Ra and Rb are each independently C1-C6 alkyl, NH 2 , or 3- to 12-membered heterocycloalkyl including one to three heteroatoms independently selected from the group consisting of N, O and S in a ring; Y is a single bond, 6- to 14-membered arylene, 3- to 12-membered heterocycloalkylene including one to three heteroatoms independently selected from the group consisting of N, O and S in a ring, or 5- to 12-membered heteroarylene including one to three heteroatoms independently selected from the group consisting of N, O and S in a ring; L 1 is a single bond, C1-C6 alkylene, C(=O), C(=O)NH, C(=O)NH-(C1-C6 alkylene), C(=O)NH-(C1-C6 alkylene)-C(=O)O, or C(=O)NH-(C1-C6 alkylene)-C(=O)NH; R 1 is H, halogen, C1-C6 alkyl, C1-C6 alkoxy, OH, CF 3 , NRcRd, 3- to 12-membered heterocycloalkyl including one to three heteroatoms independently selected from the group consisting of N, O and S in a ring, or 5- to 12-membered heteroaryl including one to three heteroatoms independently selected from the group consisting of N, O and S in a ring; Rc and Rd are each independently H or C1-C6 alkyl; Q 1 and Q 2 are each independently N or N-L 2 -R 2 , in which Q 1 and Q 2 are not simultaneously N; when Q 2 is N, is and when Q 1 is N, is L 2 is C1-C6 alkylene or (C1-C6 alkylene)-O-(C1-C6 alkylene); R 2 is 3- to 12-membered heterocycloalkyl including one to three heteroatoms independently selected from the group consisting of N, O and S in a ring, C1-C6 alkoxy, CONH 2 , NReRf, SO 2 Rg or OH; Re, Rf and Rg are each independently H or C1-C6 alkyl.
  2. The compound represented by chemical formula I, the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the hydrate or solvate thereof of claim 1, wherein in above chemical formula I, X is phenyl or pyridinyl; at least one H of X is substituted with halogen, C(=O)Ra, NH 2 , NO 2 , S(=O) 2 Rb, 5-to 12-membered heteroaryl including one to three heteroatoms independently selected from the group consisting of N, O and S in a ring; Ra and Rb are each independently NH 2 , or 3- to 12-membered heterocycloalkyl including one to three heteroatoms independently selected from the group consisting of N, O and S in a ring; Y is a single bond, 6- to 14-membered arylene, 3- to 12-membered heterocycloalkylene including one to three heteroatoms independently selected from the group consisting of N, O and S in a ring, or 5- to 12-membered heteroarylene including one to three heteroatoms independently selected from the group consisting of N, O and S in a ring; L 1 is a single bond, C1-C6 alkylene, C(=O), C(=O)NH, C(=O)NH-(C1-C6 alkylene), C(=O)NH-(C1-C6 alkylene)-C(=O)O, or C(=O)NH-(C1-C6 alkylene)-C(=O)NH; R 1 is H, halogen, C1-C6 alkyl, C1-C6 alkoxy, OH, CF 3 , NRcRd, 3- to 12-membered heterocycloalkyl including one to three heteroatoms independently selected from the group consisting of N, O and S in a ring, or 5- to 12-membered heteroaryl including one to three heteroatoms independently selected from the group consisting of N, O and S in a ring; Rc and Rd are each independently C1-C6 alkyl; Q 1 and Q 2 are each independently N or N-L 2 -R 2 , in which Q 1 and Q 2 are not simultaneously N; when Q 2 is N, is and when Q 1 is N, is L 2 is C1-C6 alkylene or (C1-C6 alkylene)-O-(C1-C6 alkylene); R 2 is 3-to 12-membered heterocycloalkyl including one to three heteroatoms independently selected from the group consisting of N, O and S in a ring, C1-C6 alkoxy, CONH 2 , NReRf, SO 2 Rg or OH; Re, Rf and Rg are each independently C1-C6 alkyl.
  3. The compound represented by chemical formula I, the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the hydrate or solvate thereof of claim 1, wherein in above chemical formula I, X is phenyl or pyridinyl; at least one H of X is substituted with F, Cl, C(=O)Ra, NH 2 , NO 2 , S(=O) 2 Rb, 5- or 6-membered heteroaryl including one to three heteroatoms independently selected from the group consisting of N and S in a ring; Ra and Rb are each independently NH 2 , or 5- to 7-membered heterocycloalkyl including one to three heteroatoms independently selected from the group consisting of N and O in a ring; Y is a single bond, 6- to 12-membered arylene, 5- to 7-membered heterocycloalkylene including one to three heteroatoms independently selected from the group consisting of N, O and S in a ring, or 5- or 6-membered heteroarylene including one or two heteroatoms independently selected from the group consisting of N, O and S in a ring; L 1 is a single bond, C1-C4 alkylene, C(=O), C(=O)NH, C(=O)NH-(C1-C2 alkylene), C(=O)NH-(C1-C5 alkylene)-C(=O)O, or C(=O)NH-(C1-C3 alkylene)-C(=O)NH; R 1 is H, F, Cl, C1-C3 alkyl, C1-C3 alkoxy, OH, CF 3 , NRcRd, 5- to 7-membered heterocycloalkyl including one to three heteroatoms independently selected from the group consisting of N and O in a ring, or 5- or 6-membered heteroaryl including one or two heteroatoms independently selected from the group consisting of N and O in a ring; Rc and Rd are each independently C1-C3 alkyl; Q 1 and Q 2 are each independently N or N-L 2 -R 2 , in which Q 1 and Q 2 are not simultaneously N; when Q 2 is N, is and when Q 1 is N, is L 2 is C1-C6 alkylene or (C1-C3 alkylene)-O-(C1-C3 alkylene); R 2 is 5- to 7-membered heterocycloalkyl including one to three heteroatoms independently selected from the group consisting of N and O in a ring, C1-C3 alkoxy, CONH 2 , NReRf, SO 2 Rg or OH; Re, Rf and Rg are each independently C1-C3 alkyl.
  4. A compound described in a following table, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof: No. Structure No. Structure 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53
  5. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient.
  6. The pharmaceutical composition of claim 5, wherein the pharmaceutical composition is for preventing or treating IRAK-4- or IRAK-1-related diseases.
  7. The pharmaceutical composition of claim 6, wherein the IRAK-4- or IRAK-1-related disease is an autoimmune disease, an inflammatory disease or a tumor.
  8. A method for preventing or treating IRAK-4- or IRAK-1-related diseases, the method comprising administering a compound according to any one of claims 1 to 4, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof into a subject.
  9. A use of a compound according to any one of claims 1 to 4, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof for preventing or treating IRAK-4- or IRAK-1-related diseases.
  10. A use of a compound according to any one of claims 1 to 4, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof for preparing a medicament for preventing or treating IRAK-4- or IRAK-1-related diseases.

Description

Technical Field The present invention relates to a novel carboxamide derivative compound, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, and a pharmaceutical composition including the same. Background An IL-1 receptor/toll-like receptor (IL-1R/TLR) signaling pathway plays an important role in immune and inflammatory reactions, and has been reported to be involved in the development of various inflammatory diseases and autoimmune diseases such as sepsis, asthma, arteriosclerosis, Alzheimer's disease, rheumatoid arthritis, atopy, hidradenitis suppurativa, psoriasis, rheumatoid arthritis, ulcerative colitis, lupus, etc. (Journal of Investigative Dermatology. 2019; 139(1): 146-156/ Annals of the New York Academy of Sciences. 2008; 1143: 21-34/ Journal of Immunology research. 2019; 1824624/International Immunopharmacology. 2007; 7(10): 1271-1285). In particular, it has recently been reported that blockade of the IL-1R/TLR signaling pathway by suppressing interleukin-1 receptorassociated kinase 4 (IRAK-4) is also effective in chronic inflammatory skin diseases such as psoriasis and atopy (Science Translational Medicine. 2023; 15: eabj3289). It has been reported that IL-1R/TLR expression is also involved in proliferation of various cancer cells (Oncogene. 2008; 27(2): 218-224). In particular, it has been reported that ABC DLBCL, which is a type of diffuse large B-cell lymphoma (DLBCL), and Waldenstrom macroglobulinemia (WM), which is a lymphoid malignant tumor, are over-activated in IL-1R/TLR signaling due to MyD88 mutation (Nature. 2011; 470(7332): 115-119/ New England journal of medicine. 2012; 367(9): 826-833). Recently, it has been reported that IRAK-4 and IRAK-1 are also involved in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) (Current Opinion in Hematology. 2022; 29(1): 8-19). When a pathogen-associated molecular pattern (PAMP) commonly expressed in various pathogens and a damage-associated molecular pattern (DAMP) isolated from stressinduced or dying cells bind to IL-1R/TLR, a downstream signaling mechanism is activated, and an inflammatory reaction occurs. If this inflammatory reaction continues to occur, it develops into cancer (Nature Immunology. 2011 Jul 19; 12(8): 715-723). Through the above reports, studies have been actively conducted to develop materials which block the TLR per se, which plays an important role in an IL-1R/TLR signaling path, or inhibit the IRAK, which deals with a downstream signal of the TLR. In particular, there are many studies targeting IRAK-4. The IRAK is a serine/threonine kinase and has four subtypes (IRAK-1, IRAK-2, IRAK-M, IRAK-4). Among them, studies on IRAK-4 and IRAK-1 with a kinase function are mainly being conducted. In particular, IRAK-4, which plays an important role in forming a myddosome in the IL-1R/TLR signaling pathway, is the most frequently studied, and recently, studies on IRAK-1 are also being actively conducted. There is no drug which has been released to target IRAK-4 or IRAK-1 yet, but phase 1 and 2 clinical trials for various diseases (autoimmune diseases, inflammatory diseases, and blood cancer) are in progress. Detailed Description of the Invention Technical Problem The present invention provide a novel carboxamide derivative compound, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. The present invention provide a pharmaceutical composition comprising a novel carboxamide derivative compound, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. The present invention provide a pharmaceutical composition for preventing or treating IRAK-4- or IRAK-1-related diseases, comprising a novel carboxamide derivative compound, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient. The present invention provide a method for preventing or treating IRAK-4- or IRAK-1-related diseases, comprising administering a novel carboxamide derivative compound, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof into a subject. The present invention provide a use of a novel carboxamide derivative compound, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof for preventing or treating IRAK-4- or IRAK-1-related diseases. The present invention provide a use of a novel carboxamide derivative compound, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof for preparing a medicament for preventing or treating IRAK-4- or IRAK-1-related diseases. Technical Solution Accordingly, the present applicant has developed a compound having a novel structure which strongly inhibits IRAK-4 or IRAK-1. An activity of IRAK-4 and IRAK-1 enzymes and a change in secretion of inflammatory cytokines were evaluated, thus confirm