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JP-7855580-B2 - Aminoimidazole FPR2 agonist

JP7855580B2JP 7855580 B2JP7855580 B2JP 7855580B2JP-7855580-B2

Inventors

  • ペレス，ハイディ エル
  • ジョンソン，ジェイムズ エイ
  • デブナニ，スニタ ブイ

Assignees

  • ブリストル－マイヤーズ スクイブ カンパニー

Dates

Publication Date
20260508
Application Date
20211008
Priority Date
20201009

Claims (15)

  1. Formula (II): [In the formula: R1 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, (alkoxycarbonyl)alkyl, alkoxycarbonyl, ( NR6 R7 )carbonyl, Ar1 , or ( Ar1 )alkyl; Ar1 is a cycloalkyl, aryl, heteroaryl (containing a carbon atom and 1 to 4 heteroatoms selected from N, NR 5a , O, and S), heterocyclyl (containing a carbon atom and 1 to 4 heteroatoms selected from N, NR 5a , O, and S), spiroheterocyclyl (containing a carbon atom and 1 to 4 heteroatoms selected from N, NR 5a , O, and S), each substituted with 1 to 4 R5 ; R 3a is an alkoxy; R 3b is hydrogen, halo, or haloalkyl; R 4a is a halo or haloalkoxy; R5 is hydrogen, hydroxyl, cyano, halo, alkyl, haloalkyl, amino, haloalkylamino, alkoxyalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxycarbonyl, or alkylsulfonylamino; R 5a is hydrogen, alkyl, haloalkyl, alkoxyalkyl, hydroxyalkyl, hydroalkylcarbonyl, carboxyamide, alkylaminocarbonyl, aminocarbonylalkylcarbonyl, alkylsulfonyl, or alkoxycarbonyl; R6 and R7 are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heteroaryl (containing a carbon atom and 1 to 4 heteroatoms selected from N, NR8a , O, and S), arylalkyl, or heteroarylalkyl (containing a carbon atom and 1 to 4 heteroatoms selected from N, NR8a , O, and S), where the cycloalkyl, heteroaryl, or heteroarylalkyl is substituted with 1 to 4 R8s ; Alternatively, R6 and R7 , together with the nitrogen to which they are bonded, form a heterocyclyl or heteroaryl containing 0 to 3 further heteroatoms selected from N, NR8a , O, and S, where the heterocyclyl or heteroaryl is substituted with 1 to 4 R8 atoms; R8 is hydrogen, halo, hydroxy, hydroxyalkyl, alkyl, alkoxy, or oxo; R 8a is hydrogen, hydroxyalkyl, or alkyl. The compound indicated by or a pharmaceutically acceptable salt thereof.
  2. R1 is Ar1 (which can be replaced by 1 to 3 R5s ); Ar1 is a cycloalkyl, aryl, heteroaryl (containing a carbon atom and 1 to 3 heteroatoms selected from N, NR 5a , O, and S), heterocyclyl (containing a carbon atom and 1 to 3 heteroatoms selected from N, NR 5a , O, and S), spiroheterocyclyl (containing a carbon atom and 1 to 3 heteroatoms selected from N, NR 5a , O, and S), each substituted with 1 to 3 R5 ; R 3a is an alkoxy; R 3b is hydrogen or a halo; R 4a is a haloalkoxy; R 5 is hydrogen, hydroxyl, cyano, halo, alkyl, haloalkyl, amino, haloalkylamino, alkoxyalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxycarbonyl, or alkylsulfonylamino; R 5a is hydrogen, alkyl, haloalkyl, alkoxyalkyl, hydroxyalkyl, hydroalkylcarbonyl, alkylaminocarbonyl, aminocarbonylalkylcarbonyl, alkylsulfonyl, or alkoxycarbonyl. The compound according to claim 1 or a pharmaceutically acceptable salt thereof.
  3. Ar 1 is And; R5 is hydrogen, cyano, halo, alkyl, haloalkyl, alkoxyalkyl, hydroxyalkyl, alkoxy, or haloalkoxy. The compound according to claim 2 or a pharmaceutically acceptable salt thereof.
  4. Ar 1 is And; R5 is hydrogen, halo, alkyl, haloalkyl, alkoxyalkyl, hydroxyalkyl, alkoxy, alkoxycarbonyl, or haloalkoxy. The compound according to claim 2 or a pharmaceutically acceptable salt thereof.
  5. Ar 1 is And; R 5 is hydrogen, alkyl, or hydroxyalkyl; R 5a is hydrogen, alkyl, hydroalkylcarbonyl, alkylaminocarbonyl, aminocarbonylalkylcarbonyl, alkylsulfonyl, or alkoxycarbonyl. The compound according to claim 2 or a pharmaceutically acceptable salt thereof.
  6. Ar 1 is And; R5 is hydrogen, hydroxyl, hydroxyalkyl, amino, haloalkylamino, or alkylsulfonylamino. The compound according to claim 2 or a pharmaceutically acceptable salt thereof.
  7. R1 is an ( Ar1 ) alkyl group; R 3a is an alkoxy; R 3b is hydrogen or a halo; R 4a is a haloalkoxy. The compound according to claim 1 or a pharmaceutically acceptable salt thereof.
  8. Ar 1 is And; R 5 is hydrogen, cyano, halo, alkyl, haloalkyl, alkoxyalkyl, hydroxyalkyl, alkoxy, or haloalkoxy; R 5a is hydrogen or alkyl. The compound according to claim 7 or a pharmaceutically acceptable salt thereof.
  9. R1 is alkyl or haloalkyl; R 3a is an alkoxy; R 3b is hydrogen or a halo; R 4a is a haloalkoxy. The compound according to claim 1 or a pharmaceutically acceptable salt thereof.
  10. R1 is an alkoxycarbonyl or (alkoxycarbonyl)alkyl; R 3a is an alkoxy; R 3b is hydrogen or a halo; R 4a is a haloalkoxy. The compound according to claim 1 or a pharmaceutically acceptable salt thereof.
  11. R1 is a ( NR6R7 ) carbonyl ; R6 and R7 are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heteroaryl (containing a carbon atom and 1 to 3 heteroatoms selected from N, NR8a , O, and S), heteroaryl (containing a carbon atom and 1 to 3 heteroatoms selected from N, NR8a , O, and S), or heteroarylalkyl (containing a carbon atom and 1 to 3 heteroatoms selected from N, NR8a , O, and S), wherein the cycloalkyl, heteroaryl, or heteroarylalkyl is substituted with 1 to 3 R8s ; Alternatively, R6 and R7 , together with the nitrogen they bind to, Forming; R8 is hydrogen, halo, hydroxy, hydroxyalkyl, alkyl, alkoxy, or oxo; R 8a is hydrogen, hydroxyalkyl, or alkyl. The compound according to claim 1 or a pharmaceutically acceptable salt thereof.
  12. R6 is hydrogen; R 7 And; R8 is hydrogen, halo, hydroxy, hydroxyalkyl, alkyl, or alkoxy. The compound according to claim 11 or a pharmaceutically acceptable salt thereof.
  13. A pharmaceutical composition comprising the compound described in claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.
  14. A pharmaceutical composition according to claim 13 for treating heart disease.
  15. The pharmaceutical composition according to claim 14 , wherein the heart disease is selected from the group consisting of angina pectoris, unstable angina pectoris, myocardial infarction, heart failure, acute coronary artery disease, acute heart failure, chronic heart failure, and iatrogenic cardiac injury.

Description

Cross-reference of related applications: This application is granted priority to U.S. Provisional Patent Application No. 63/089,730, filed 9 October 2020, pursuant to 35 U.S.C. § 119(e), the entirety of which is incorporated herein by reference. This invention relates to a novel aminoimidazole compound represented by formula (I), which is a formylpeptide 2 (FPR2) receptor agonist, and to compositions containing the compound for the treatment of, for example, atherosclerosis, heart failure, chronic obstructive pulmonary disease (COPD) and related diseases, and to methods for using them for that purpose. Formyl peptide receptor 2 (FPR2) belongs to a small group of seven-transmembrane domain G protein-binding receptors that are expressed in multiple human tissues (including immune cells) and are known to be important in host defense and inflammation. FPR2 shares significant sequence homology with FPR1 and FPR3 (Chen K. et al., Journal of Autoimmunity 85, 2017, 64-77). Comprehensively, these receptors bind to many structurally different agonists that act as chemoattractants and activate phagocytic cells, including N-formyl and non-formyl peptides. Endogenous peptide annexin A1 and its N-terminal fragment are examples of ligands that bind to human FPR1 and FPR2. Fatty acids, such as eicosanoids and lipoxin A4, which belong to the group of small pro-resolution mediators (SPMs), have also been reported as FPR2 agonists (Ye RD. et al., Pharmacol. Rev., 2009, 61, 119-61). Endogenous FPR2 inflammation-converging ligands such as lipoxin A4 and annexin A1 have been reported to trigger diverse cytoplasmic cascades including Gi coupling, Ca2 + recruitment, and β-arrestin replacement (Cattaneo, F. et al., Int J Mol Sci. 2013 April;14(4):7193-7230). FPR2 regulates both innate and adaptive immune systems, including neutrophils, macrophages, T cells, and B cells. In neutrophils, FPR2 ligands regulate activity, cytotoxicity, and lifespan. In macrophages, FPR2 activating inhibits apoptosis and enhances efferocytosis (Chandrasekharan JA, Sharma-Walia N, J. Inflamm. Res., 2015, 8, 181-92). The initiation of inflammation resolution through FPR2 activation is associated with enhanced antifibrotic wound healing and the return of damaged tissue to homeostasis (Romano M. et al., Eur. J. Pharmacol., 2015, 5, 49-63). Chronic inflammation is part of the pathways that lead to the development of many human diseases, and stimulating the inflammatory response pathway with FPR2 agonists may have both protective and reparative effects. Ischemia-reperfusion (I/R) injury is a common feature of several diseases associated with high morbidity and mortality, such as myocardial infarction and stroke. Unproductive wound healing associated with cardiomyocyte death and pathological remodeling resulting from ischemia-reperfusion injury leads to scarring, fibrosis, and progressive loss of cardiac function. FPR2 modulation has been proposed to enhance post-injury myocardial wound healing and reduce harmful myocardial remodeling (Kain V. et al., J. Mol. Cell. Cardiol., 2015, 84, 24-35). In addition, FPR2 resolving agonists in the central nervous system may be useful therapeutic agents for treating various clinical I/R symptoms, including stroke (Gavins FN., Trends Pharmacol. Sci., 2010, 31, 266-76) and I/R-induced spinal cord injury (Liu ZQ. et al., Int. J. Clin. Exp. Med., 2015, 8, 12826-33). In addition to the beneficial effects of targeting the FPR2 receptor with novel anti-inflammatory agonists to treat I/R-induced injury, the usefulness of these ligands may be applicable to other diseases. In the cardiovascular system, both the FPR2 receptor and its anti-inflammatory agonist have been found to be involved in the stabilization and healing of atherosclerotic plaques (Petri MH. et al., Cardiovasc. Res., 2015, 105, 65-74; and Fredman G. et al., Sci. Trans. Med., 2015, 7(275); 275ra20). FPR2 agonists have also been shown to be beneficial in preclinical models of chronic inflammatory human diseases, including infectious diseases, psoriasis, dermatitis, inflammatory bowel syndrome, Crohn's disease, ocular inflammation, sepsis, pain, metabolic/diabetes, cancer, COPD, asthma and allergic diseases, cystic fibrosis, acute lung injury and fibrosis, rheumatoid arthritis and other joint diseases, Alzheimer's disease, renal fibrosis, and organ transplantation (Romano M. et al., Eur. J. Pharmacol., 2015, 5, 49-63; Perrett, M. et al., Trends in Pharm. Sci., 2015, 36, 737-755). The present invention encompasses a compound of formula (I) that is a formylpeptide 2 (FPR2) receptor agonist, a composition containing the compound, and methods of using them, for example, in the treatment of atherosclerosis, heart failure, chronic obstructive pulmonary disease (COPD), and related diseases. One aspect of the present invention is formula (I): [In the formula: R1 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, (alkoxycarbonyl)alkyl, alkoxycarbonyl, ( NR6 R7 )carbonyl, Ar1 , or