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Msg  10309 of 10539  at  9/22/2022 9:38:35 AM  by

JBWIN


Building IP: BMY Patent APpl. re "BIARYL DIALKYL PHOSPHINE OXIDE FPR2 AGONISTS"

 
United States Patent Application20220298186
Kind CodeA1
Shirude; Pravin Sudhakar ; et al.September 22, 2022

BIARYL DIALKYL PHOSPHINE OXIDE FPR2 AGONISTS

Abstract

The disclosure relates to compounds of Formula (I), which are formyl peptide 2 (FPR2) receptor agonists and/or formyl peptide 1 (FPR1) receptor agonists. The disclosure also provides compositions and methods of using the compounds, for example, for the treatment of atherosclerosis, heart failure, chronic obstructive pulmonary disease (COPD), and related diseases. ##STR00001##


Inventors:Shirude; Pravin Sudhakar; (Bangalore, IN) ; Chattopadhyay; Amit Kumar; (Bangalore, IN) ; Kick; Ellen K.; (Pennington, NJ) ; Wurtz; Nicholas R.; (Pennington, NJ)
Applicant:
NameCityStateCountryType

BRISTOL-MYERS SQUIBB COMPANY

Princeton

NJ

US
Family ID:1000006445804
Appl. No.:17/616748
Filed:June 16, 2020
PCT Filed:June 16, 2020
PCT NO:PCT/US2020/037881
371 Date:December 6, 2021

Related U.S. Patent Documents

Application NumberFiling DatePatent Number
62862897Jun 18, 2019

Current U.S. Class:1/1
Current CPC Class:C07F 9/65583 20130101; C07F 9/59 20130101
International Class:C07F 9/6558 20060101 C07F009/6558; C07F 9/59 20060101 C07F009/59

Claims



1. A compound of Formula (I): ##STR00051## or a pharmaceutically acceptable salt thereof, wherein: Ar.sup.1 is phenyl substituted with 1-2 R.sup.1a and 1-2 R.sup.1b or 6-membered heteroaryl with 1-3 nitrogen atoms and substituted with 1-2 R.sup.1a and 1-2 R.sup.1b; Ar.sup.2 is phenyl substituted with 1-4 R.sup.2 or 6-membered heteroaryl with 1-3 nitrogen atoms and substituted with 1-4 R.sup.2; Ar.sup.3 is phenyl substituted with 0-4 R.sup.3 or pyridinyl substituted with 0-4 R.sup.3; R.sup.1a is hydrogen or halo; R.sup.1b is halo, haloalkyl, alkoxy, or haloalkoxy; R.sup.2 is hydrogen, cyano, halo, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, alkoxy, or haloalkoxy; R.sup.3 is cyano, halo, alkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, or haloalkyl; and R.sup.4 is alkyl or alkoxy.

2. The compound of claim 1, having Formula (II): ##STR00052## or a pharmaceutically acceptable salt thereof, wherein: Ar.sup.1 is phenyl substituted with 1 R.sup.1a and 1-2 R.sup.1b or 6-membered heteroaryl with 1-2 nitrogen atoms and substituted with 1R.sup.1a and 1-2 R.sup.1b; Ar.sup.2 is phenyl substituted with 1-3 R.sup.2 or pyridinyl substituted with 1-3 R.sup.2; R.sup.1a is hydrogen or halo; R.sup.1b is halo, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, or C.sub.1-4 haloalkoxy; R.sup.2 is hydrogen, halo, C.sub.1-4 alkyl, C.sub.1-4 hydroxyalkyl, C.sub.1-4 haloalkyl, C.sub.3-6 cycloalkyl, C.sub.1-4 alkoxy, or C.sub.1-4 haloalkoxy; and R.sup.4 is C.sub.1-3 alkyl.

3. The compound of claim 1, having Formula (III): ##STR00053## or a pharmaceutically acceptable salt thereof, wherein: Ar.sup.1 is phenyl substituted with 1R.sup.1a and 1-2 R.sup.1b, pyridinyl substituted with 1 R.sup.1a and 1-2 R.sup.1b, or pyrazinyl substituted with 1R.sup.1a and 1-2 R.sup.1b; R.sup.1a is hydrogen or halo; R.sup.1b is halo, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, or C.sub.1-4 haloalkoxy; R.sup.2 is hydrogen, halo, C.sub.1-4 alkyl, C.sub.1-4 hydroxyalkyl, C.sub.1-4 haloalkyl, C.sub.3-6 cycloalkyl, C.sub.1-4 alkoxy, or C.sub.1-4 haloalkoxy; and R.sup.4 is C.sub.1-2 alkyl.

4. The compound of claim 3, having Formula (IV): ##STR00054## or a pharmaceutically acceptable salt thereof, wherein: R.sup.1a is hydrogen or F; R.sup.1b is halo, C.sub.1-2 haloalkyl, or C.sub.1-2 alkoxy; R.sup.2 is hydrogen, halo, C.sub.1-3 alkyl, C.sub.1-3 haloalkyl, or C.sub.3-6 cycloalkyl; and R.sup.4 is methyl or ethyl.

5. The compound of claim 4, having Formula (VI): ##STR00055## or a pharmaceutically acceptable salt thereof, wherein: R.sup.1a is hydrogen or F; R.sup.1b is halo, C.sub.1-2 haloalkyl, or C.sub.1-2 alkoxy; R.sup.2 is halo, C.sub.1-3 alkyl, C.sub.1-3 haloalkyl, or C.sub.3-6 cycloalkyl; and R.sup.4 is methyl or ethyl.

6. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein: R.sup.1a is hydrogen or F; R.sup.1b is F, Cl, or CF.sub.3; R.sup.2 is hydrogen, F, Cl, isopropyl, CF.sub.3, or cyclopropyl; and R.sup.4 is methyl.

7. The compound of claim 3, having Formula (V): ##STR00056## or a pharmaceutically acceptable salt thereof, wherein: R.sup.1a is hydrogen or F; R.sup.1b is halo, C.sub.1-2 haloalkyl, or C.sub.1-2 alkoxy; R.sup.2 is halo; and R.sup.4 is methyl or ethyl.

8. The compound of claim 3, having Formula (VII): ##STR00057## or a pharmaceutically acceptable salt thereof, wherein: R.sup.1a is hydrogen or halo; R.sup.1b is halo, C.sub.1-2 haloalkyl, or C.sub.1-2 alkoxy; R.sup.2 is hydrogen, halo, C.sub.1-3 alkyl, or C.sub.3-6 cycloalkyl; and R.sup.4 is C.sub.1-2 alkyl.

9. The compound of claim 3, having Formula (VIII): ##STR00058## or a pharmaceutically acceptable salt thereof, wherein: R.sup.1b is halo, C.sub.1-2 haloalkyl, or C.sub.1-2 alkoxy; R.sup.2 is hydrogen, halo, C.sub.1-3 alkyl, or C.sub.3-6 cycloalkyl; and R.sup.4 is C.sub.1-2 alkyl.

10. The compound of claim 1, having Formula (IX): ##STR00059## or a pharmaceutically acceptable salt thereof, wherein: Ar.sup.1 is phenyl substituted with 1 R.sup.1a and 1-2 R.sup.1b, pyridinyl substituted with 1 R.sup.1a and 1-2 R.sup.1b, or pyrazinyl substituted with 1R.sup.1a and 1-2 R.sup.1b. R.sup.1a is hydrogen or halo; R.sup.1b is halo, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, or C.sub.1-4 haloalkoxy; and R.sup.4 is C.sub.1-2 alkyl.

11. A compound of claim 1 selected from the group consisting of: ##STR00060## ##STR00061## ##STR00062## ##STR00063## ##STR00064## ##STR00065## or a pharmaceutically acceptable salt thereof.

12. A composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

13. (canceled)

14. A method for treating a heart disease comprising administering a therapeutically effective amount of a compound of claim 1 to a patient in need thereof.

15. The method of claim 14 wherein the heart disease is selected from the group consisting of angina pectoris, unstable angina, myocardial infarction, heart failure, acute coronary disease, and cardiac iatrogenic damage.

16. The method of claim 15 wherein the heart failure is selected from the group consisting of congestive heart failure, systolic heart failure, diastolic heart failure, heart failure with reduced ejection fraction (HF.sub.REF), heart failure with preserved ejection fraction (HF.sub.PEF), acute heart failure, chronic heart failure of ischemic and non-ischemic origin.
Description



CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application is entitled to priority pursuant to 35 U.S.C. .sctn. 119(e) to U.S. provisional patent application No. 62/862,897, filed Jun. 18, 2019, which is incorporated herein in its entirety.

BACKGROUND OF THE INVENTION

[0002] The present invention relates to novel biaryl dialkyl phosphine oxide compounds, which are formyl peptide 2 (FPR2) receptor agonists and/or formyl peptide 1 (FPR1) receptor agonists, compositions containing them, and methods of using them, for example, for the treatment of atherosclerosis, heart failure, chronic obstructive pulmonary disease (COPD), and related diseases.

[0003] Formyl peptide receptor 2 (FPR2) belongs to a small group of seven-transmembrane domain, G protein-coupled 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). Collectively, these receptors bind a number of structurally diverse agonists, including N-formyl and nonformyl peptides which act as chemo attractants and activate phagocytes. The endogenous peptide Annexin A1 and its N-terminal fragments are examples of ligands that bind human FPR1 and FPR2. Fatty acids such as eicosanoid, lipoxin A4, which belongs to a class of small pro-resolution mediators (SPMs), has also been identified as an agonist for FPR2 (Ye R D., et al., Pharmacol. Rev., 2009, 61, 119-61).

[0004] Endogenous FPR2 pro-resolution ligands, such as lipoxin A.sub.4 and Annexin A1, have been reported to trigger a wide array of cytoplasmatic cascades such as Gi coupling, Ca.sup.2+ mobilization and .beta.-arrestin recruitment. (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-, and B-cells. In neutrophils, FPR2 ligands modulate movement, cytotoxicity and life span. In macrophages, agonism of FPR2 prevents apoptosis and enhances efferocytosis. (Chandrasekharan J A, Sharma-Walia N. J. Inflamm. Res., 2015, 8, 181-92). The initiation of resolution of inflammation by FPR2 agonism is responsible for enhancing anti-fibrotic wound healing and returning of the injured tissue to homeostasis (Romano M., et al., Eur. J. Pharmacol., 2015, 5, 49-63).

[0005] Chronic inflammation is part of the pathway of pathogenesis of many human diseases and stimulation of resolution pathways with FPR2 agonists may have both protective and reparative effects. Ischaemia-reperfusion (I/R) injury is a common feature of several diseases associated with high morbidity and mortality, such as myocardial infarction and stroke. Non-productive wound healing associated with cardiomyocyte death and pathological remodeling resulting from ischemia-reperfusion injury leads to scar formation, fibrosis, and progressive loss of heart function. FPR2 modulation is proposed to enhance myocardial wound healing post injury and diminish adverse myocardial remodeling (Kain V., et al., J. Mol. Cell. Cardiol., 2015, 84, 24-35). In addition, FPR2 pro-resolution agonists, in the central nervous system, may be useful therapeutics for the treatment of a variety of clinical I/R conditions, including stroke in brain (Gavins F N., Trends Pharmacol. Sci., 2010, 31, 266-76) and I/R induced spinal cord injury (Liu Z Q., et al., Int. J. Clin. Exp. Med., 2015, 8, 12826-33).

[0006] In addition to beneficial effects of targeting the FPR2 receptor with novel pro-resolution agonists for treatment of I/R induced injury therapeutic, utility of these ligands can also be applied to other diseases. In the cardiovascular system both the FPR2 receptor and its pro-resolution agonists were found to be responsible for atherogenic-plaque stabilization and healing (Petri M H., et al., Cardiovasc. Res., 2015, 105, 65-74; and Fredman G., et al., Sci. Trans. Med., 2015, 7(275); 275ra20). FPR2 agonists also have 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 diseases, cancer, COPD, asthma and allergic diseases, cystic fibrosis, acute lung injury and fibrosis, rheumatoid arthritis and other joint diseases, Alzheimer's disease, kidney 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).

SUMMARY OF THE INVENTION

[0007] The present invention provides novel biaryl dialkyl phosphine oxide compounds, and their analogues thereof, which are useful as FPR2 agonists, including stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof.

[0008] The present invention also provides processes and intermediates for making the compounds of the present invention or stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof.

[0009] The present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and at least one of the compounds of the present invention or stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof.

[0010] The compounds of the invention may be used in therapy.

[0011] The compounds of the invention may be used in the treatment and/or prophylaxis of multiple diseases or disorders associated with FPR2, such as inflammatory diseases, heart diseases, chronic airway diseases, cancers, septicemia, allergic symptoms, HIV retrovirus infection, circulatory disorders, neuroinflammation, nervous disorders, pains, prion diseases, amyloidosis, and immune disorders. The heart diseases are selected from the group consisting of angina pectoris, unstable angina, myocardial infarction, acute coronary disease, cardiac iatrogenic damage, and heart failure including, but not limited to, acute heart failure, chronic heart failure of ischemic and non-ischemic origin, systolic heart failure, diastolic heart failure, heart failure with reduced ejection fraction (HF.sub.REF), and heart failure with preserved ejection fraction (HF.sub.PEF).

[0012] The compounds of the invention can be used alone, in combination with other compounds of the present invention, or in combination with one or more other agent(s).

[0013] Other features and advantages of the invention will be apparent from the following detailed description and claims.


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