Oxopyrrolidine FPR2 agonist

Abstract

The present disclosure relates to compounds of formula (I), which are formylpeptide 2 (FPR2) receptor agonists and / or formylpeptide 1 (FPR1) receptor agonists. The disclosure also provides compositions and methods using the compounds to treat, for example, atherosclerosis, heart failure, chronic obstructive pulmonary disease (COPD), and related diseases. TIFF2023533037000263.tif35138

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No. 63 / 049,838, filed July 9, 2020, the contents of which are incorporated herein by reference in their entirety. [Background technology]

[0002] The present invention relates to novel oxopyrrolidine compounds that are formylpeptide 2 (FPR2) receptor agonists and / or formylpeptide 1 (FPR1) receptor agonists, and to compositions containing and methods of using such compounds for treating, for example, 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 (Journal of Autoimmunity 85, 2017, 64-77). Collectively, these receptors bind many structurally distinct agonists, including N-formyl and non-formyl peptides, which act as chemoattractants and activate phagocytes. The 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 identified as agonists of FPR2 (Ye RD. et al., Pharmacol. Rev., 2009, 61, 119-61).

[0004] Endogenous FPR2 inflammation-resolving ligands, such as lipoxin A4 and annexin A1, mediate Gi coupling, Ca 2+ FPR2 has been reported to trigger diverse cytoplasmic cascades, including the recruitment and β-arrestin recruitment of FPR2-dependent proteins (Int J Mol Sci. 2013 April;14(4):7193-7230). FPR2 regulates both the innate and adaptive immune system, including neutrophils, macrophages, T cells, and B cells. In neutrophils, FPR2 ligands regulate activity, cytotoxicity, and lifespan. In macrophages, FPR2 agonism prevents apoptosis and enhances efferocytosis (Chandrasekharan JA, Sharma-Walia N,. J. Inflamm. Res., 2015, 8, 181-92). The initiation of inflammation resolution through FPR2 agonism is associated with enhanced antifibrotic wound healing and the return of injured tissue to homeostasis (Romano M. et al., Eur. J. Pharmacol., 2015, 5, 49-63).

[0005] Chronic inflammation is part of the pathogenesis of many human diseases, and stimulating inflammation-resolving pathways with FPR2 agonists may have both protective and restorative 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. Nonproductive wound healing, accompanied by cardiomyocyte death and pathological remodeling as a result of I / R injury, leads to scar formation, fibrosis, and progressive loss of cardiac function. FPR2 modulation has been proposed to enhance myocardial wound healing and reduce adverse myocardial remodeling after injury (Kain V. et al., J. Mol. Cell. Cardiol., 2015, 84, 24-35). In addition, FPR2 inflammation-resolving agonists in the central nervous system may be useful therapeutic agents for treating various clinical I / R conditions, 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).

[0006] In addition to the beneficial effects of targeting the FPR2 receptor with novel inflammation-resolving agonists to treat I / R-induced injury, the utility of these ligands may also be applied to other diseases. In the cardiovascular system, both the FPR2 receptor and its inflammation-resolving agonists have been found to be involved in the stabilization and healing of atherogenic 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 / diabetic diseases, 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). Summary of the Invention

[0007] The present invention provides novel oxopyrrolidines and analogs thereof (including stereoisomers, tautomers, pharmaceutically acceptable salts or solvates thereof) that are useful as FPR2 agonists. The present invention also provides processes and intermediates for making the compounds of the present invention, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

[0008] The present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and at least one compound of the present invention, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof. The compounds of the invention may be used in therapy.

[0009] The compounds of the present invention can be used in the treatment and / or prevention of multiple diseases or disorders associated with FPR2, such as inflammatory diseases, heart disease, chronic airway disease, cancer, sepsis, allergic conditions, HIV retroviral infection, circulatory disorders, neuroinflammation, neurological disorders, pain, prion diseases, amyloidosis, and immune disorders. Heart disease includes angina pectoris, unstable angina pectoris, myocardial infarction, acute coronary artery disease, iatrogenic cardiac injury, and heart failure (acute heart failure, chronic heart failure of ischemic and non-ischemic origin, systolic heart failure, diastolic heart failure, heart failure with reduced left ventricular contractility (HF)). R EF), and heart failure with preserved left ventricular systolic function (HF) P EF)).

[0010] The compounds of the present invention may be used alone, in combination with other compounds of the present invention, or in combination with one or more other drugs. Other features and advantages of the invention will be apparent from the following detailed description and claims. DETAILED DESCRIPTION OF THE INVENTION

[0011] The present invention encompasses compounds of Formulas (I) to (VII), which are formylpeptide 2 (FPR2) receptor agonists and / or formylpeptide 1 (FPR1) receptor agonists, compositions containing the compounds, and methods of using them, for example, in the treatment of atherosclerosis, heart failure, chronic obstructive pulmonary disease (COPD), and related diseases.

[0012] One aspect of the present invention is a compound of formula (I): [ka] [In formula: * is an asymmetric carbon atom; Ar 1 are aryl or pyridyl, each of which is 1 to 3 R 1 is replaced by; Ar 2 is C 3-6Cycloalkyl, aryl, or 5-12 membered heterocyclyl (O, S(O) p , N, and NR 2a each containing 0 to 3 R 2 is replaced by; Ar 3 are phenyl or pyridyl, each of which is one R 5a , 1 R 5b , and one R 5c is replaced by; R 1 is halo, C 1-4 Haloalkyl, C 1-4 Alkoxy, or C 1-4 haloalkoxy; R 2 are oxo, cyano, halo, C 1-6 Alkyl (0 to 5 R e (replaced with), -OR b , -NR 3 R 4 , -NR 4 C(O)R b , -NR 4 (CR d R d ) 0-1 C(O)NR 3 R 4 , (C 1-4 alkyl)2(O)P-, C 3-6 Cycloalkyl, aryl, 5-6 membered heterocyclyl (O, S(O) p , N, and NR a containing 1 to 4 heteroatoms selected from: R 2a is hydrogen, C 1-4 Alkyl (0 to 5 R e ), -(CR d R d ) 1-4 -NR 3 R 4 , -(CR d R d ) 1-4 -OR b , -(CR d R d ) 1-4 -C(O)NR3 R 4 , -(CR d R d ) r -C 3-6 Cycloalkyl (0 to 5 R e ), -(CR d R d ) r -aryl (0 to 5 R e ), or -(CR d R d ) r -heterocyclyl(O,S(O) p , N, and NR a (0 to 5 R e ) and R 3 is hydrogen, C 1-4 Alkyl (0 to 5 R e (substituted with), C 3-6 Cycloalkyl (0 to 5 R e substituted with), or heterocyclyl (O, S(O) p , N, and NR 8 (0 to 5 R e ) and R 4 is hydrogen or C 1-4 Is it alkyl; Alternatively, R 3 and R 4 means, together with the nitrogen to which they are attached, a 4- to 9-membered heterocyclyl (O, S(O) p , N, and NR 8 (1 to 3 R 6 (substituted with); R 5a is hydrogen or halo; R 5b is hydrogen or halo; R 5c is halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 alkoxy, or deuterated alkoxy; R 6 is hydrogen, halo, oxo, hydroxy, or C 1-4 Alkyl (0 to 5 R e ) and R 7 is hydrogen or C 1-4 is alkyl; R 8 is hydrogen, C 1-4 Alkyl, or -S(O) p R c and; R a is hydrogen or C 1-6 Alkyl (0 to 5 R e (substituted with), C 3-6 Cycloalkyl (0 to 5 R e substituted with aryl (0 to 5 R e substituted with), or heterocyclyl (O, S(O) p , N.R. d (0 to 5 R e ) and R b is hydrogen, C 1-6 Alkyl (0 to 5 R e (substituted with), C 3-6 Cycloalkyl (0 to 5 R e substituted with aryl (0 to 5 R e substituted with), or heterocyclyl (O, S(O) p , N.R. d (0 to 5 R e ) and R c is C 1-4 Alkyl (0 to 5 R e ) and R d is hydrogen or C 1-4 Alkyl (0 to 5 R e ) and R e is halo, cyano, oxo, -OR g , -NR g R g, -C(O)NR g R g , -S(O) p C 1-4 Alkyl, C 1-6 Alkyl (0 to 5 R f substituted with), -(CH2) r -C 3-6 Cycloalkyl (0 to 5 R f substituted with), -(CH2) r -aryl (0 to 5 R f substituted with -(CH2) r -heterocyclyl(O,S(O) p , N, and NR g (0 to 5 R f ) and R f are halo, cyano, hydroxy, oxo, C 1-5 Alkyl, C 3-6 cycloalkyl, or phenyl; R g is hydrogen, C 1-5 Alkyl, C 3-6 cycloalkyl, aryl, or heterocyclyl; or R g and R g together with the nitrogen atom to which they are attached form a heterocyclyl; n is 0 or 1; p is 0, 1, or 2; and r is 0, 1, 2, 3, or 4] or a pharmaceutically acceptable salt thereof.

[0013] Another aspect of the present invention is a compound of formula (II): [ka] [In formula: Ar 2 is C 3-6 Cycloalkyl, phenyl, 5- or 6-membered heterocyclyl (1-2 N or NR 2a each of which contains 0 to 2 R 2is replaced by; Ar 3 is one R 5a , 1 R 5b , and one R 5c is phenyl substituted with; R 1 is halo, C 1-4 Haloalkyl, or C 1-4 haloalkoxy; R 2 are oxo, cyano, halo, C 1-5 Alkyl (0 to 5 R e (replaced with), -OR b , -NR 3 R 4 , -NR 4 C(O)R b , (C 1-3 alkyl)2(O)P-, C 3-6 Cycloalkyl, aryl, 5- to 6-membered heterocyclyl (O, S, N, and NR a containing 1 to 4 heteroatoms selected from: R 2a is hydrogen, C 1-4 Alkyl (0 to 4 R e substituted with), -(CHR d ) 1-3 -C(O)NR 3 R 4 , -(CHR d ) r -C 3-6 Cycloalkyl (0 to 4 R e substituted with), -(CHR d ) r -aryl (0 to 4 R e substituted with -(CHR d ) r -heterocyclyl (O, S, N, and NR a (0 to 4 R e ) and R 3 is hydrogen, C 1-4 Alkyl (0 to 4 R e (substituted with), C 3-6Cycloalkyl, or heterocyclyl (O, S, N, and NR 8 (0 to 4 R e ) and R 4 is hydrogen or C 1-3 Is it alkyl; Alternatively, R 3 and R 4 together with the nitrogen to which they are attached, form a 4- to 8-membered heterocyclyl (O, S, N, and NR 8 (1 to 3 R 6 (substituted with); R 5a is hydrogen or halo; R 5b is hydrogen or halo; R 5c is halo, C 1-4 Alkyl, C 1-4 Haloalkyl, or C 1-4 is alkoxy; R 6 is hydrogen, halo, oxo, hydroxy, or C 1-4 Alkyl (0 to 4 R e ) and R 7 is hydrogen or C 1-3 is alkyl; R 8 is hydrogen, C 1-3 Alkyl, or -S(O) p R c and; R a is hydrogen or C 1-6 Alkyl (0 to 5 R e ) and R b is hydrogen, C 1-6 Alkyl (0 to 5 R e substituted with), or heterocyclyl (O, S, N, NR d (0 to 5 R e ) and R c is C1-3 Alkyl (0 to 5 R e ) and R d is hydrogen or C 1-4 Alkyl (0 to 1 -OC) 1-4 alkyl-substituted); R e is halo, cyano, oxo, -OR g , -NR g R g , -C(O)NR g R g , -S(O) p C 1-4 Alkyl, C 1-4 Alkyl (0 to 5 R f substituted with), -(CH2) r -C 3-6 Cycloalkyl (0 to 5 R f substituted with), -(CH2) r -aryl (0 to 5 R f substituted with -(CH2) r -heterocyclyl (O, S, N, and NR g (0 to 5 R f ) and R f are halo, cyano, hydroxy, C 1-5 Alkyl, or C 3-6 is cycloalkyl; R g is hydrogen, C 1-5 alkyl, or heterocyclyl; n is 0; r is 0, 1, 2, or 3] or a pharmaceutically acceptable salt thereof.

[0014] Another aspect of the present invention is a compound of formula (III): [ka] [In formula: Ar 2 teeth [ka] and; R 1 is halo, C 1-3 Haloalkyl, or C 1-3 haloalkoxy; R 2 Cyano, halo, C 1-4 Alkyl (0 to 5 R e (replaced with), -OR b , -NR 3 R 4 , -NR 4 C(O)R b , (C 1-4 alkyl)2(O)P-, C 3-6 Cycloalkyl, aryl, or 5- or 6-membered heterocyclyl (O, S, N, and NR a containing 1 to 4 heteroatoms selected from: R 2a is hydrogen, C 1-4 Alkyl (0 to 3 R e substituted with), -(CHR d ) 1-2 -C(O)NR 3 R 4 , -(CH2) r -C 3-6 Cycloalkyl (0 to 3 R e substituted with), -(CH2) r -aryl (0 to 3 R e substituted with -(CH2) r -heterocyclyl (O, S, N, and NR a (0 to 3 R e ) and R 3 is hydrogen, C 1-4 Alkyl (0 to 3 R e (substituted with), C 3-6 Cycloalkyl, or heterocyclyl (O, S, N, and NR 8 (0 to 3 R e ) and R 4 is hydrogen or C1-2 is alkyl; Alternatively, R 3 and R 4 together with the nitrogen to which they are attached, form a 4- to 8-membered heterocyclyl (O, S, N, and NR 8 (1 to 3 R 6 (substituted with); R 5a is hydrogen or halo; R 5b is hydrogen or halo; R 5c is halo or C 1-2 is alkoxy; R 6 is hydrogen, halo, oxo, hydroxy, or C 1-4 Alkyl (0 to 3 R e ) and R 7 is hydrogen or CH3; R 8 is hydrogen, C 1-2 Alkyl, or S(O)2C 1-4 is alkyl; R a is hydrogen or C 1-5 Alkyl (0 to 4 R e ) and R b is hydrogen, C 1-5 Alkyl (0 to 4 R e substituted with), heterocyclyl (O, S, N, NR d (0 to 4 R e ) and R d is hydrogen or C 1-2 Alkyl (0 to 1 -OC) 1-4 alkyl-substituted); R e is halo, cyano, oxo, -OR g , -NR g R g , C(O)NR g R g , -S(O) p C1-4 Alkyl, C 1-4 Alkyl (0 to 4 R f substituted with), -(CH2) r -C 3-6 Cycloalkyl (0 to 4 R f substituted with), -(CH2) r -aryl (0 to 4 R f substituted with -(CH2) r -heterocyclyl (O, S, N, and NR g (0 to 4 R f ) and R f is halo, cyano, hydroxy, or C 1-5 is alkyl; R g is hydrogen or C 1-4 is alkyl; n is 0; and r is 0, 1, or 2] or a pharmaceutically acceptable salt thereof.

[0015] Another aspect of the present invention is a compound of formula (IVa): [ka] [In formula: Ar 2 teeth [ka] and; R 1 is Cl, -CF3, -OCHF2, or -OCF3; R 2 Cyano, halo, C 1-4 Alkyl (0 to 4 R e (replaced with), -OR b , -NR 3 R 4 , -NR 4 C(O)R b , (C 1-2 alkyl)2(O)P, -C 3-6Cycloalkyl, or heterocyclyl (O, S, N, and NR a containing 1 to 4 heteroatoms selected from: R 2a is hydrogen, C 1-4 Alkyl (0 to 4 R e substituted with), -(CHR d ) 1-2 -C(O)NR 3 R 4 , -(CH2) r -C 3-6 Cycloalkyl (0 to 2 R e substituted with), -(CH2) r -aryl (0 to 2 R e substituted with -(CH2) r -heterocyclyl (O, S, N, and NR a (0 to 2 R e ) and R 3 is hydrogen, C 1-4 Alkyl (0 to 3 R e substituted with), or heterocyclyl (substituted with O, S, N, and NR 8 (0 to 3 R e ) and R 4 is hydrogen or C 1-2 is alkyl; Alternatively, R 3 and R 4 together with the nitrogen to which they are attached, form a 4- to 8-membered heterocyclyl (O, S, N, and NR 8 (1 to 3 R 6 (substituted with); R 5a is hydrogen, F, or Cl; R 5b is hydrogen, F, or Cl; R 5c is Cl or -OCH3; R 6 is hydrogen, halo, oxo, hydroxy, or C1-3 Alkyl (0 to 3 R e ) and R 7 is hydrogen or C 1-2 is alkyl; R 8 is hydrogen, C 1-2 Alkyl, or S(O)2C 1-3 is alkyl; R a is hydrogen, C 1-4 Alkyl (0 to 3 R e ) and R b is hydrogen, C 1-4 Alkyl (0 to 3 R e substituted with), heterocyclyl (O, S, N, and NR d (0 to 3 R e ) and R d is hydrogen or C 1-2 Alkyl (0 to 1 -OC) 1-4 alkyl-substituted); R e is halo, cyano, oxo, -OR g , -NR g R g , -C(O)NR g R g , -S(O)C 1-4 Alkyl, C 1-6 Alkyl (0 to 3 R f substituted with), -(CH2) r -C 3-6 Cycloalkyl (0 to 3 R f substituted with -(CH2) r -heterocyclyl (O, S, N, and NR g (0 to 3 R f ) and R f is halo, cyano, hydroxy, or C 1-4 is alkyl; R g is hydrogen or C 1-3 is alkyl; r is 0 or 1] or a pharmaceutically acceptable salt thereof.

[0016] Another aspect of the present invention is a compound of formula (IVa), or a pharmaceutically acceptable salt thereof, wherein: Ar 2 but [ka] and; R 2 is F, Cl, -CH2OH, -CH3, -CF3, or -CHF2; R 2a is -CH3, -CH2CH3, -CH2CHF2, -CH2CF3, -CH2CH2OCH3, -CH2CH(OH)CF3, -CH2CH(OH)CH3, -CH2CH2OH, -CH2CH(CH3)OH, -CH2CH(CF3)OH, -CH2CH2CF3, -CH(CH2OH)CH2OCH3, -CH(CH2NH2)OCH3, -CH2CH(CH3)OCH3, or -CH2CH(CF3)OCH3; The other variables are as defined in formula (IVa). The compound is, or a pharmaceutically acceptable salt thereof.

[0017] Another aspect of the present invention is a compound of formula (IVb): [ka] [In formula: R 1 is Cl, -CF3, -OCHF2, or -OCF3; R 2 is cyano, F, Cl, CH3, CF3, CHF2, or -NHC(O)CH3; R 2ais -CH3, -CH2CH3, -CH2CN, -CH2CHF2, -CH2CH2OCH3, -CH2CH(OH)CF3, -CH2CH(OH)CH3, -CH2CH2OH, -CF2CH2OH, -CH2CH(CH3)OH, -CH2CH2CF3, -CH(CH2OH)CH2OCH3, -C H(CH2NH2)OCH3, -CH2CH(CH3)OCH3, -CH2CH(CF3)OCH3, -CH(CH2NH2)CH2OCH3, -CH(C(O)N(CH3)2)CH2OCH3, -CH2C(CH3)(CH2OH)2, -CH2CH2N(CH3)2, -CH2CH2S(O)2C 1-4 Alkyl, -CHR d C(O)NR 3 R 4 , -(CH2) 0-1 -C 3-6 Cycloalkyl, -(CH2) 0-3 -heterocyclyl (where heterocyclyl is [ka] (selected from); R 3 and R 4 and together with the nitrogen to which they are both attached, [ka] forming a heterocyclyl selected from: R 5a is hydrogen or F; R 5b is hydrogen or F; R 5c is Cl or -OCH3; R 6 is hydrogen, oxo, halo, -CH3, -CHF3, -CF3, or -CH2OH; R 7 is hydrogen or C 1-2 is alkyl; R 8 is hydrogen, C 1-2 Alkyl, or -S(O)2C 1-3 is alkyl; R dis -CH2OCH3] or a pharmaceutically acceptable salt thereof.

[0018] Another aspect of the present invention is a compound of formula (IVc): [ka] [In formula: R 1 is Cl, -CF3, -OCHF2, or -OCF3; R 2 are cyano, F, Cl, CH2OH, CH3, CHF2, CF3, -OCH3, -OCH(CH3)2, -NR 3 R 4 , (CH3)2(O)P-, C 3-6 cycloalkyl, [ka] and; R 3 is hydrogen, C 1-4 Alkyl (0 to 2 R e ), [ka] and; R 4 is hydrogen; Alternatively, R 3 and R 4 and together with the nitrogen to which they are both attached, [ka] forming a heterocyclyl selected from: R 5a is hydrogen or F; R 5b is hydrogen or F; R 5c is Cl or OCH3; R 6 is hydrogen, halo, oxo, CH3, -CH2CH3, or -CH2OH; R 7is hydrogen or C 1-4 is alkyl; R 8 is hydrogen, C 1-4 Alkyl, or -S(O)2C 1-3 alkyl] or a pharmaceutically acceptable salt thereof.

[0019] Another aspect of the present invention is a compound of formula (IVd): [ka] [In formula: R 1 is Cl, -CF3, -OCHF2, or -OCF3; R 2 HA-OR b or (C 1-2 alkyl)2(O)P-; R 5a is hydrogen or F; R 5b is hydrogen or F; R 5c is Cl or -OCH3; R 7 is hydrogen or -CH3; R b is hydrogen, C 1-4 Alkyl (0 to 3 R e ), or [ka] and; R e is F, Cl, or -OR g and; R g is hydrogen or C 1-3 alkyl] or a pharmaceutically acceptable salt thereof.

[0020] Another aspect of the present invention is a compound of formula (IVe): [ka] [In formula: R 1 is Cl, -CF3, -OCHF2, or -OCF3; R 2 is cyano, F, Cl, -CH2OH, -CH3, -CHF2, -CF3, -OCH3, -OCH(CH3)2, or -NR 3 R 4 and; R 3 is hydrogen or C 1-4 is alkyl; R 4 is hydrogen or C 1-2 Is it alkyl; Alternatively, R 3 and R 4 and together with the nitrogen to which they are both attached, [ka] forming a heterocyclyl selected from: R 5a is hydrogen or F; R 5b is hydrogen or F; R 5c is Cl or -OCH3; R 6 is hydrogen, halo, oxo, CH3, -CH2CH3, or -CH2OH; R 7 is hydrogen or C 1-4 is alkyl; R 8 is hydrogen or C 1-2 alkyl] or a pharmaceutically acceptable salt thereof.

[0021] Another aspect of the present invention is a compound of formula (IVf): [ka] [In formula: R 1 is Cl, -CF3, -OCH3, -OCHF2, or -OCF3; R2 is cyano, F, Cl, -CH2OH, -CH3, -CHF2, or -CF3; R 2a is -CH3, -CH2CH3, -CH2CHF2, -CH2CH2OCH3, -CH2CH(OH)CF3, -CH2CH(OH)CH3, -CH2CH2OH, -CH2CH(CH3)OH, or -CH2CH2CF3; R 5a is hydrogen, F, or Cl; R 5b is hydrogen, F, or Cl; R 5c is Cl or -OCH3; R 7 is hydrogen or -CH3] or a pharmaceutically acceptable salt thereof.

[0022] Another aspect of the present invention is a compound of formula (V): [ka] [In formula: Ar 2 is C 3-5 is cycloalkyl; R 1 is Cl, -CF3, -OCHF2, or -OCF3; R 5a is F or Cl; R 5b is F or Cl; R 5c is -OCH3] or a pharmaceutically acceptable salt thereof.

[0023] Another aspect of the present invention is a compound of formula (Va): [ka] [In formula: R 1 is CF3, OCHF2, or OCF3; R 5ais F or Cl; R 5b is F or Cl; R 5c is OCH3] or a pharmaceutically acceptable salt thereof.

[0024] Another aspect of the present invention is a compound of formula (VI): [ka] [In formula: R 1 is -CF3, -OCHF2, or -OCF3; R 2 is F, Cl, -CH2OH, -CF3, -CHF2, -OCH3, -OCH(CH3)2, or (CH3)2(O)P-; R 5a is F or Cl; R 5b is F or Cl; R 5c is -OCH3] or a pharmaceutically acceptable salt thereof.

[0025] Another aspect of the present invention is a compound of formula (VII): [ka] [In formula: R 1 is -CF3, -OCHF2, or -OCF3; R 2 is F, Cl, or (CH3)2(O)P-; R 5a is F; R 5b is F; R 5c is -OCH3] or a pharmaceutically acceptable salt thereof.

[0026] In the compounds of formula (I), (II), (III), (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), (V), (Va), (VI), or (VII), i.e., formula (I-VII), Ar 1 , Ar 2 , Ar 3 , R 1 , R 2 , R 2a , R 3 , R 4 , R 5a , R 5b , R 5c , R 6 , R 7 , R 8 , R a , R b , R c , R d , R e , R f , and R g Any example range of a variable substituent, including: may be used independently of any other example range of a variable substituent. Thus, the invention encompasses combinations of different embodiments. In one non-limiting embodiment, in compounds of Formula (I), (II), or (III), Ar 1 There is one R 1 is phenyl substituted with R 1 is CF3, OCHF2, or OCF3; n is 0 or 1; Ar 2 is phenyl, pyridinyl, or C 3-6 cycloalkyl, each of which is 0 to 2 R 2 Replaced by ;R 2 is F, Cl, CH2OH, CF3, OCH3, OCH(CH3)2, CHF2, CF3, or (CH3)2(O)P; Ar 3 R 5a , R 5b , and R 5c is phenyl substituted with; R 5a , R 5b , and R 5c are halo and alkoxy, respectively.

[0027] In one non-limiting embodiment, in compounds of Formula (I), (II), or (III), Ar 1 There is one R 1 is phenyl substituted with R 1 is CF3; n is 0; Ar 2 is phenyl, pyridinyl, or C 3-6 cycloalkyl, each of which is 0 to 2 R 2 Replaced by ;R 2 is F, Cl, CH2OH, CF3, OCH3, OCH(CH3)2, CHF2, CF3, or (CH3)2(O)P; Ar 3 R 5a , R 5b , and R 5c is phenyl substituted with; R 5a , R 5b , and R 5c are halo and alkoxy, respectively. In one non-limiting embodiment, in compounds of Formula (I), (II), or (III), Ar 1 There is one R 1 is phenyl substituted with R 1 is OCHF2; n is 0; Ar 2 is phenyl, pyridinyl, or C 3-6 cycloalkyl, each of which is 0 to 2 R 2 Replaced by ;R 2 is F, Cl, CH2OH, CF3, OCH3, OCH(CH3)2, CHF2, CF3, or (CH3)2(O)P; Ar 3 R 5a , R 5b , and R 5c is phenyl substituted with; R 5a , R 5b , and R 5c are halo and alkoxy, respectively.

[0028] In one non-limiting embodiment, in compounds of Formula (I), (II), or (III), Ar 1 There is one R 1 is phenyl substituted with R 1is OCF3; n is 0; Ar 2 is phenyl, pyridinyl, or C 3-6 cycloalkyl, each of which is 0 to 2 R 2 Replaced by ;R 2 is F, Cl, CH2OH, CF3, OCH3, OCH(CH3)2, CHF2, CF3, or (CH3)2(O)P; Ar 3 R 5a , R 5b , and R 5c is phenyl substituted with; R 5a , R 5b , and R 5c are halo and alkoxy, respectively. In one non-limiting embodiment, in compounds of Formula (I), (II), or (III), Ar 1 There is one R 1 phenyl substituted with R 1 is CF3, OCHF2, or OCF3; n is 1; Ar 2 is phenyl (0 to 2 R 2 substituted with R 2 is halo or alkoxy; Ar 3 R 5a , R 5b , and R 5c is phenyl substituted with; R 5a , R 5b , and R 5c are halo and alkoxy, respectively.

[0029] In one non-limiting embodiment, in compounds of Formula (I), (II), or (III), Ar 1 There is one R 1 phenyl substituted with R 1 is CF3, OCHF2, or OCF3; n is 1; Ar 2 is cyclopropyl; Ar 3 R 5a , R 5b , and R 5c is phenyl substituted with; R 5a , R 5b , and R5c are halo and alkoxy, respectively. In one non-limiting embodiment, in compounds of Formula (I), (II), (III), or (IVa), Ar 1 There is one R 1 is phenyl substituted with R 1 is Cl, CF3, OCHF2, or OCF3; n is 0; Ar 2 but [ka] and R 2a is -CH3, -CH2CH3, -CH2CHF2, -CH2CF3, -CH2CH2OCH3, -CH2CH(OH)CF3, -CH2CH(OH)CH3, -CH2CH2OH, -CH2CH(CH3)OH, -CH2CH(CF3)OH, or -CH2CH2CF3; Ar 3 R 5a , R 5b , and R 5c is phenyl substituted with; R 5a , R 5b , and R 5c are halo and alkoxy, respectively.

[0030] In one non-limiting embodiment, in compounds of Formula (I), (II), (III), or (IVa), Ar 1 There is one R 1 is phenyl substituted with R 1 is Cl, CF3, OCHF2, or OCF3; n is 0; Ar 2 but [ka] and R 2ais -CH3, -CH2CH3, -CH2CHF2, -CH2CF3, -CH2CH2OCH3, -CH2CH(OH)CF3, -CH2CH(OH)CH3, -CH2CH2OH, -CH2CH(CH3)OH, -CH2CH(CF3)OH, -CH2CH2CF3, -CH(CH2OH)CH2OCH3, -CH(CH2NH2)OCH3, -CH2CH(CH3)OCH3, or -CH2CH(CF3)OCH3; Ar 3 R 5a , R 5b , and R 5c is phenyl substituted with; R 5a , R 5b , and R 5c are halo and alkoxy, respectively.

[0031] In one non-limiting embodiment, in compounds of Formula (I), (II), (III), or (IVa), Ar 1 There is one R 1 is phenyl substituted with R 1 is Cl, CF3, OCHF2, or OCF3; n is 0; Ar 2 but [ka] and;R 2 is cyano, F, Cl, CH3 or -NHC(O)CH3; R 2a is -CH3, -CH2CH3, -CH2CN, -CH2CHF2, -CH2CH2OCH3, -CH2CH(OH)CF3, -CH2CH(OH)CH3, -CH2CH2OH, -CF2CH2OH, -CH2CH(CH3)OH, -CH2CH2CF3, -CH(CH2OH)CH2OCH3, -C H(CH2NH2)OCH3, -CH2CH(CH3)OCH3, -CH2CH(CF3)OCH3, -CH(CH2NH2)CH2OCH3, -CH(C(O)N(CH3)2)CH2OCH3, -CH2C(CH3)(CH2OH)2, -CH2CH2N(CH3)2, -CH2CH2S(O)2C 1-4 Alkyl, -(CH2) 0-1 -C 3-6 Cycloalkyl, -(CH2)0-3 -heterocyclyl (where heterocyclyl is [ka] Ar 3 R 5a , R 5b , and R 5c is phenyl substituted with; R 5a , R 5b , and R 5c are halo and alkoxy, respectively.

[0032] In one non-limiting embodiment, in compounds of Formula (I), (II), (III), or (IVa), Ar 1 There is one R 1 is phenyl substituted with R 1 is Cl, CF3, OCHF2, or OCF3; n is 0; Ar 2 but [ka] and;R 2 is cyano, F, Cl, CH3 or -NHC(O)CH3; R 2a is -CH3, -CH2CH3, -CH2CN, -CH2CHF2, -CH2CH2OCH3, -CH2CH(OH)CF3, -CH2CH(OH)CH3, -CH2CH2OH, -CF2CH2OH, -CH2CH(CH3)OH, -CH2CH2CF3, -CH(CH2OH)CH2OCH3, -C H(CH2NH2)OCH3, -CH2CH(CH3)OCH3, -CH2CH(CF3)OCH3, -CH(CH2NH2)CH2OCH3, -CH(C(O)N(CH3)2)CH2OCH3, -CH2C(CH3)(CH2OH)2, -CH2CH2N(CH3)2, -CH2CH2S(O)2C 1-4 Alkyl, -(CH2) 0-1 -C 3-6 Cycloalkyl, -(CH2) 0-3 -heterocyclyl (where heterocyclyl is [ka] Ar 3 R 5a , R 5b , and R 5c is phenyl substituted with; R 5a , R 5b , and R 5c are halo and alkoxy, respectively.

[0033] In one non-limiting embodiment, in compounds of Formula (I), (II), (III), or (IVa), Ar 1 There is one R 1 phenyl substituted with R 1 is Cl, CF3, OCHF2, or OCF3; n is 0; Ar 2 but [ka] and;R 2 Cyano, F, Cl, CH2OH, CH3, CF3, CHF2, CF3, -OCH3, -OCH(CH3)2, -NR 3 R 4 , (CH3)2(O)P-, C 3-6 cycloalkyl, [ka] and;R 2a is -CH3, -CH2CH3, -CH2CN, -CH2CHF2, -CH2CH2OCH3, -CH2CH(OH)CF3, -CH2CH(OH)CH3, or -CH2CH2OH; R 3 is hydrogen or C 1-4 Alkyl (0 to 2 R e ), [ka] and;R 4 is hydrogen or C 1-2 alkyl; or alternatively, R 3 and R 4 and together with the nitrogen to which they are both bonded, [ka] to form a heterocyclyl selected from: Ar 3 R 5a , R 5b , and R 5c is phenyl substituted with; R 5a , R 5b , and R 5c are halo and alkoxy, respectively.

[0034] In one non-limiting embodiment, in the compound of Formula (I), Ar 1 There is one R 1 is phenyl substituted with R 1 is Cl, CF3, OCHF2, or OCF3; n is 0; Ar 2 but [ka] and;R 2 is alkyl, haloalkyl, hydroxyalkyl, or cycloalkyl; Ar 3 R 5a , R 5b , and R 5c is phenyl substituted with; R 5a , R 5b , and R 5c are halo and alkoxy, respectively.

[0035] In one non-limiting embodiment, in compounds of Formula (I), (II), (III), or (IVa), Ar 1 There is one R 1 is phenyl substituted with R 1 is Cl, CF3, OCHF2, or OCF3; n is 0; Ar 2 but [ka] and;R 2 Cyano, F, Cl, CH2OH, CF3, CHF2, CF3, -OCH3, -OCH(CH3)2, -NR 3R 4 , (CH3)2(O)P-, C 3-6 cycloalkyl, [ka] and;R 3 is hydrogen or C 1-4 Alkyl (0 to 2 R e ), [ka] and;R 4 is hydrogen or C 1-2 alkyl; or alternatively, R 3 and R 4 and together with the nitrogen to which they are both bonded, [ka] forming a heterocyclyl selected from: Ar 3 R 5a , R 5b , and R 5c is phenyl substituted with; R 5a , R 5b , and R 5c are halo and alkoxy, respectively.

[0036] In one non-limiting embodiment, in compounds of Formula (I), (II), (III), or (IVa), Ar 1 There is one R 1 is phenyl substituted with R 1 is Cl, CF3, OCHF2, or OCF3; n is 0; Ar 2 but [ka] and;R 2 is alkoxy; R 2a is alkyl or haloalkyl; Ar 3 R 5a , R 5b , and R 5cis phenyl substituted with; R 5a , R 5b , and R 5c are halo and alkoxy, respectively.

[0037] In one non-limiting embodiment, in the compound of Formula (I), Ar 1 There is one R 1 is phenyl substituted with R 1 is Cl, CF3, OCHF2, or OCF3; n is 0; Ar 2 but [ka] and;R 2 is cyano, F, Cl, CH3 or -NHC(O)CH3; R 2a is -CH3, -CH2CH3, -CH2CN, -CH2CHF2, -CH2CH2OCH3, -CH2CH(OH)CF3, -CH2CH(OH)CH3, -CH2CH2OH, -CF2CH2OH, -CH2CH(CH3)OH, -CH2CH2CF3, -CH(CH2OH)CH2OCH3, -C H(CH2NH2)OCH3, -CH2CH(CH3)OCH3, -CH2CH(CF3)OCH3, -CH(CH2NH2)CH2OCH3, -CH(C(O)N(CH3)2)CH2OCH3, -CH2C(CH3)(CH2OH)2, -CH2CH2N(CH3)2, -CH2CH2S(O)2C 1-4 Alkyl, -(CH2) 0-1 -C 3-6 Cycloalkyl, -(CH2) 0-3 -heterocyclyl (where heterocyclyl is [ka] Ar 3 R 5a , R 5b , and R 5c is phenyl substituted with; R 5a , R 5b , and R 5c are halo and alkoxy, respectively.

[0038] In another embodiment, the FPR2 EC 50 The value is < It is 1 μM. In another embodiment, the FPR2 EC 50 The value is < It is 0.5 μM. In another embodiment, the FPR2 EC 50 The value is < It is 0.1 μM.

[0039] In another embodiment, the FPR2 EC 50 The value is < It is 0.05 μM. In another embodiment, the FPR2 EC 50 The value is < It is 0.01 μM. In another embodiment, the FPR2 EC 50 The value is < It is 0.001 μM.

[0040] Unless otherwise specified, these terms have the following meanings: A dash "-" that is not between two letters or symbols is used to indicate a point of attachment for a substituent, for example, -CONH2 is attached through a carbon atom.

[0041] As used in the structural formulas herein, [ka] A bond to a wavy line, such as represents a bond at the point of attachment of the moiety or substituent to the core or backbone structure. "Cyano" means -CN. "Hydroxy" means --OH.

[0042] "Alkyl" means a straight or branched chain alkyl group of 1 to 6 carbons. "Alkenyl" means a straight or branched chain alkyl group of 2 to 6 carbons and at least one double bond. "Alkynyl" means a straight or branched chain alkyl group of 2 to 6 carbons and at least one triple bond. Certain terms with hydrocarbon moieties (e.g., alkoxy) include straight or branched chain isomers of the hydrocarbon moiety. "Halo" includes fluoro, chloro, bromo, and iodo. "Haloalkyl" and "haloalkoxy" include all halogenated isomers from monohalo to perhalo.

[0043] "Haloalkoxy" and "C 1-6 Derivatives such as "haloalkoxy" are used interchangeably and refer to a halo-substituted alkyl group linked through an oxygen atom. Haloalkoxy includes singly and multiply halo-substituted alkoxy groups up to perhalo-substituted alkoxy. Examples include trifluoromethoxy and difluoromethoxy. "Alkoxy" refers to an alkyl group attached to the remainder of the molecule via an oxygen linkage. Representative examples of such groups are -OCH3 and -OC2H5. Unless stated or indicated otherwise, all alkoxy groups described or claimed herein can be either straight or branched chain.

[0044] "Alkoxyalkyl" means an alkoxy group as defined above directly bonded to an alkyl group as defined above, for example, -CH2-O-CH3, -CH2CH2-O-CH3, and the like. "Cycloalkyl" means a non-aromatic mono- or multicyclic ring system of 3 to 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0045] "Aryl" means a monocyclic or bicyclic aromatic hydrocarbon group having 6 to 12 carbon atoms or a bicyclic fused ring system in which one or both rings are aromatic. A bicyclic fused ring system consists of a phenyl group fused to a 4- to 7-membered aromatic or non-aromatic carbocyclic ring. Representative examples of aryl groups include, but are not limited to, phenyl, indanyl, indenyl, naphthyl, and tetrahydronaphthyl.

[0046] "Heterocycle," "heterocyclyl," or "heterocyclic ring" is intended to mean a stable 3-, 4-, 5-, 6-, or 7-membered monocyclic or bicyclic, or 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-membered polycyclic heterocyclic ring that is saturated, partially unsaturated, or fully unsaturated and contains carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S, and includes any polycyclic group in which any of the above heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N→O and S(O)). p where p is 0, 1, or 2). The nitrogen atom can be substituted or unsubstituted (i.e., N or NR, where R, as defined, is H or other substituent). A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. The heterocyclic rings described herein can be substituted on a carbon atom or on a nitrogen atom if the resulting compound is stable. The nitrogen of a heterocyclyl can optionally be quaternized. When the total number of S and O atoms in a heterocyclyl exceeds 1, it is preferred that these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in a heterocyclyl is 1 or less. When the term "heterocyclyl" is used, it is intended to include heteroaryl.

[0047] Bridged rings are also included in the definition of heterocyclyl. A bridged ring occurs when one or more atoms (i.e., C, O, N, or S) connect two non-adjacent carbon or nitrogen atoms. Examples of bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and a carbon-nitrogen group. It should be noted that a bridge always converts a monocyclic ring into a tricyclic ring. When a ring is bridged, the substituents recited for the ring may also be present on the bridge.

[0048] "Heteroaryl" means a 5- to 7-membered monocyclic or 8- to 11-membered bicyclic aromatic ring system having from 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0049] When the bonding position is not specified, the bond may be made at any suitable position, as understood by those skilled in the art. Combinations of substituents and bonding patterns are only those that result in stable compounds, as understood by those skilled in the art. The term parentheses and multiple parentheses are intended to clarify the bonding relationship to those skilled in the art. For example, the term ((R) alkyl) means an alkyl substituent further substituted with a substituent R.

[0050] The present invention encompasses all pharmaceutically acceptable salt forms of the compound. Pharmaceutically acceptable salts are those whose counterions do not significantly contribute to the physiological activity or toxicity of the compound and function as pharmacological equivalents themselves. These salts can be prepared using commercially available reagents according to common organic techniques. Some anionic salt forms include acetate, acetonitrile, besylate, bromide, chloride, citrate, fumarate, glucuronate, hydrobromide, hydrochloride, hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate, phosphate, succinate, sulfate, tartrate, tosylate, and quinofoate. Some cationic salt forms include ammonium, aluminum, benzathine, bismuth, calcium, choline, diethylamine, diethanolamine, lithium, magnesium, meglumine, 4-phenylcyclohexylamine, piperazine, potassium, sodium, tromethamine, and zinc.

[0051] Some compounds of the present invention exist in stereoisomeric forms, including those below the carbon designated in the structure. The present invention encompasses all stereoisomeric forms of the compounds, including enantiomers and diastereomers. Methods for preparing and separating stereoisomers are known in the art. The present invention encompasses all tautomeric forms of the compounds. The present invention encompasses atropisomers and rotamers.

[0052] The present invention is intended to include all isotopes of atoms present in the compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include 13 C and 14Isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art, or by methods similar to those described herein, substituting an appropriately isotopically labeled reagent for an otherwise unlabeled reagent. Such compounds have a variety of potential uses, including as standards and reagents for measuring biological activity. Where the isotope is stable, such compounds may preferably modify biological, pharmacological, or pharmacokinetic properties.

[0053] biological methods N-formyl peptide receptors (FPRs) are a series of chemoattractant receptors that promote leukocyte responses during inflammation. FPRs belong to the seven-transmembrane G protein-coupled receptor superfamily and couple to inhibitory G proteins (Gi). Three family members (FPR1, FPR2, and FPR3) have been identified in humans and are found with diverse distributions primarily in myeloid cells, but also reported in multiple organs and tissues. After binding to an agonist, FPRs mediate intracellular signaling, Ca transduction, and IL-1 signaling. 2+ FPR2 and FPR1 activate multiple physiological pathways, including recruitment, recruitment, and transcription. This family interacts with a diverse set of ligands, including proteins, polypeptides, and fatty acid metabolites, which activate downstream responses, both pro-inflammatory and anti-inflammatory. The activity of the compounds of the present invention was measured using a cyclic adenosine monophosphate (cAMP) assay of FPR2 and FPR1.

[0054] FPR2 and FPR1 cyclic adenosine monophosphate (cAMP) assay A mixture of forskolin (5 μM final for FPR2 or 10 μM final for FPR1) and IBMX (200 μM final) was added to 384-well Proxiplates (Perkin-Elmer) pre-dotted with test compound / DMSO (1% final) at final concentrations ranging from 0.020 nM to 100 μM. Chinese hamster ovary (CHO) cells overexpressing human FPR1 or human FPR2 receptors were cultured in F-12 (Ham's) medium supplemented with 10% modified FBS, 250 μg / ml Zeocin, and 300 μg / ml hygromycin (Life Technologies). The reaction was initiated by adding 2,000 human FPR2 cells / well or 4,000 human FPR1 cells / well to Dulbecco's PBS (with calcium and magnesium) (Life Technologies) supplemented with 0.1% BSA (Perkin-Elmer). The reaction mixture was incubated at room temperature for 30 minutes. Intracellular cAMP levels were measured using the HTRF HiRange cAMP Assay Reagent Kit (Cisbio) according to the manufacturer's instructions. Solutions of cryptate-conjugated anti-cAMP and d2 fluorophore-labeled cAMP were prepared separately in the supplied lysis buffer. Upon reaction completion, cells were lysed with equal volumes of d2 cAMP and anti-cAMP solutions. After 1 hour of incubation at room temperature, time-resolved fluorescence intensity was measured using an Envision (Perkin-Elmer) with excitation at 400 nm and dual emission at 590 and 665 nm. A calibration curve was constructed by plotting the ratio of the fluorescence intensity at 665 nm to the fluorescence intensity at 590 nm versus the cAMP concentration using external cAMP standards at concentrations ranging from 1 μM to 0.1 pM. The potency and activity of compounds to inhibit cAMP production were then determined by fitting a four-parameter logistic equation to the cAMP levels plotted against the compound concentration.

[0055] The Examples disclosed below were tested in the above FPR2 and FPR1 cAMP assays and found to have FPR2 and / or FPR1 agonist activity. Table 1 below shows the EC agonist activity in the FPR2 and FPR1 cAMP assays measured for the Examples below. 50 Enumerate values.

[0056] Table 1 [Table 1] [Table 2] [Table 3] [Table 4] [Table 5]

[0057] [Table 6] [Table 7] [Table 8] [Table 9] [Table 10]

[0058] [Table 11] [Table 12] [Table 13] [Table 14] [Table 15]

[0059] [Table 16] [Table 17] [Table 18] [Table 19] [Table 20]

[0060] [Table 21] [Table 22] [Table 23]

[0061] Pharmaceutical Compositions and Methods of Use The compounds of the present invention may be administered to mammals, preferably humans, for the treatment of a variety of conditions and disorders, including pulmonary diseases, including atherosclerosis, heart failure, asthma, COPD, and cystic fibrosis; neuroinflammatory diseases, including multiple sclerosis, Alzheimer's disease, and stroke; and chronic inflammatory diseases, such as inflammatory bowel disease, rheumatoid arthritis, psoriasis, sepsis, and renal fibrosis.

[0062] Unless otherwise specified, the following terms have their ascribed meanings. The term "subject" refers to any human or other mammalian species that may benefit from treatment with an FPR2 and / or FPR1 agonist, as understood by those skilled in the art. A subject includes a human of any age with risk factors for cardiovascular disease. Common risk factors include age, sex, weight, family history, sleep apnea, alcohol or tobacco use, physical inactivity, arrhythmia, or signs of insulin resistance, such as acanthosis nigricans, hypertension, dyslipidemia, or polycystic ovary syndrome (PCOS). The term "patient" refers to a human suitable for treatment, as defined by those skilled in the art. "Treating" or "treatment" refers to the treatment of a patient or subject, as understood by those skilled in the art. "Preventing" or "prevention" refers to prophylactic treatment (i.e., prevention and / or risk reduction) of a subclinical condition in a patient or subject, with the aim of reducing the likelihood of the occurrence of a clinical condition, as understood by those skilled in the art. Patients are selected for prophylactic treatment based on factors known to increase their risk of suffering from a clinical condition compared to the general population. A "therapeutically effective amount" refers to an amount of a compound that is effective, as understood by those skilled in the art.

[0063] Another aspect of the present invention is a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formulas (I)-(VII) in combination with a pharmaceutical carrier. Another aspect of the present invention is a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formulas (I)-(VII) in combination with at least one other therapeutic agent and a pharmaceutical carrier.

[0064] "Pharmaceutical composition" refers to a composition comprising the compound of the present invention in combination with at least one additional pharmaceutically acceptable carrier. "Pharmaceutical acceptable carrier" refers to a medium generally accepted in the art for delivering biologically active agents to animals, particularly mammals, that is, adjuvants, excipients or vehicles, including diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants and dispersants, depending on the characteristics of the administration method and the dosage form.

[0065] Pharmaceutically acceptable carriers are formulated according to many factors well known to those skilled in the art. These include, but are not limited to, the type and characteristics of the active agent to be formulated; the subject to which the composition containing the agent is administered; the intended route of administration of the composition; and the therapeutic indication to be targeted. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as various solid and semi-solid dosage forms. Such carriers can contain many different components and additives in addition to the active agent, and are incorporated into the composition for various reasons, such as to stabilize the active agent. Such additional components are binders and the like, which are well known to those skilled in the art. Descriptions of suitable pharmaceutically acceptable carriers and the factors involved in their selection can be found in various readily available sources, such as Allen, LV, Jr. et al., Remington: The Science and Practice of Pharmacy (Vol. 2), 22nd Edition, Pharmaceutical Press (2012).

[0066] There is a possibility of chemical interactions between the combined active ingredients, especially when provided as a single dosage unit. For this reason, when a compound of the present invention and a second therapeutic agent are combined in a single dosage unit, the active ingredients are combined in a single dosage unit but formulated so that physical contact between the active ingredients is minimized (i.e., reduced). For example, one of the active ingredients may be enteric-coated. Enteric-coating one of the active ingredients not only minimizes contact between the combined active ingredients, but also tailors the release of one of these ingredients in the gastrointestinal tract so that it is not released in the stomach, but rather in the intestine. One of the active ingredients may be coated with a material that affects sustained release throughout the gastrointestinal tract and serves to minimize physical contact between the combined active ingredients. Furthermore, the sustained-release component may additionally be enteric-coated so that release of this component occurs exclusively in the intestine. Yet another approach involves formulating a combination product in which one component is coated with a sustained and / or enteric release polymer to further separate the active ingredients, and the other component is coated with a polymer such as low viscosity grade hydroxypropylmethylcellulose (HPMC) or other suitable material known in the art, which polymer coating serves to provide an additional barrier to interaction with the other component.

[0067] Another aspect of the present invention is a method for treating heart disease, comprising administering to a patient a therapeutically effective amount of a compound of Formulae (I)-(VII). Another aspect of the present invention is a method for treating cardiac disease, wherein the cardiac disease is selected from the group consisting of angina, unstable angina, myocardial infarction, heart failure, acute coronary artery disease, acute heart failure, chronic heart failure, and iatrogenic cardiac injury.

[0068] It will be understood that the treatment or prevention of heart failure may also include the treatment or prevention of cardiovascular events. The treatment or prevention referred to herein refers to the treatment or prevention of specific negative signs or symptoms associated with or resulting from cardiovascular events. For example, treatment or prevention includes reducing or preventing negative changes associated with or resulting from cardiovascular events in left ventricular fractional shortening, heart weight, lung weight, myocyte cross-sectional area, pressure overload-induced cardiac fibrosis, stress-induced cellular senescence, and / or cardiac hypertrophy characteristics, or any combination thereof. Treatment may be administered in preparation for or in response to a cardiovascular event to alleviate negative effects. Prevention includes proactive or prophylactic treatment, which can prevent cardiovascular events or reduce the occurrence of negative effects of cardiovascular events.

[0069] In one embodiment, the present invention provides the use of a compound of Formula (I)-(VII) or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for treating or preventing heart failure, e.g., heart failure resulting from hypertension, ischemic heart disease, non-ischemic heart disease, exposure to cardiotoxic compounds, myocarditis, Kawasaki disease, type I and type II diabetes, thyroid disease, viral infection, periodontitis, drug addiction, alcoholism, pericarditis, atherosclerosis, vascular disease, hypertrophic cardiomyopathy, dilated cardiomyopathy, myocardial infarction, atrial fibrosis, left ventricular systolic dysfunction, left ventricular diastolic dysfunction, coronary artery bypass surgery, pacemaker implantation, starvation, eating disorders, muscular dystrophy, and genetic defects. Preferably, the heart failure to be treated is diastolic heart failure, heart failure with reduced left ventricular contractility (HF). R EF), heart failure with preserved left ventricular systolic function (HF) P EF), acute heart failure, and chronic heart failure of ischemic and non-ischemic origin.

[0070] In one embodiment, the present invention provides the use of a compound of Formula (I)-(VII) for treating systolic and / or diastolic dysfunction, wherein the compound is administered in an amount therapeutically effective to increase the ability of cardiomyocytes to contract and relax, thereby increasing the filling and emptying ability of both the right and left ventricles, preferably the left ventricle. In another embodiment, the present invention provides the use of a compound of Formula (I)-(VII) for treating heart failure, wherein the compound is administered in an amount therapeutically effective to increase contractility in the left ventricle.

[0071] In yet another embodiment, the present invention provides the use of a compound of Formula (I)-(VII) for treating heart failure, wherein the compound is administered in an amount therapeutically effective to reduce fibrogenesis in cardiac tissue. Another aspect of the present invention is a method for treating cardiac disease, wherein the treatment of cardiac disease is after myocardial infarction. Another aspect of the invention is a method for treating cardiac disease, comprising administering to a patient a therapeutically effective amount of a compound of Formulas (I)-(VII) in combination with other therapeutic agents.

[0072] The compounds of the present invention can be administered by any suitable means, for example, orally, such as tablets, capsules (each of which contains sustained-release or extended-release formulations), pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions), syrups, and emulsions; sublingually; buccal; parenterally, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion (e.g., as a sterile injectable aqueous or non-aqueous solution or suspension); nasally, such as by inhalation spray, including administration to the nasal mucosa; topically, such as in the form of a cream or ointment; or rectally, such as in the form of a suppository. The compounds can be administered alone, but will generally be administered with a pharmaceutical carrier selected based on the chosen route of administration and standard pharmaceutical practice.

[0073] Dosage regimens for the compounds of the present invention will, of course, vary depending on known factors such as the pharmacokinetic properties of the particular agent and its method and route of administration; the species, age, sex, health, condition, and weight of the recipient; the nature and severity of the condition; the type of treatment currently being administered; the frequency of treatment; the route of administration, the patient's renal and hepatic function, and the desired effect.

[0074] As a general guide, the daily oral dosage of each active ingredient, when used for the indicated effects, will range from about 0.01 to about 5000 mg per day, preferably from about 0.1 to about 1000 mg, and most preferably from about 0.1 to about 250 mg. For intravenous administration, the most preferred dose will be in the range of about 0.001 to about 10 mg / kg / minute during a continuous metered infusion. The compounds of the present invention may be administered in a single dose per day, or the total daily dosage may be administered in divided doses, 2, 3, or 4 times per day.

[0075] Dosage forms (pharmaceutical compositions) suitable for administration may contain about 1 milligram to about 2000 milligrams of active ingredient per dosage unit. In these pharmaceutical compositions, the active ingredient will usually be present in an amount of about 0.1-95% by weight, based on the total weight of the composition. A typical capsule for oral administration contains at least one compound of the present invention (250 mg), lactose (75 mg), and magnesium stearate (15 mg). The mixture is passed through a 60-mesh sieve and packed into a No. 1 gelatin capsule. A typical injectable formulation is produced by aseptically placing at least one compound of the present invention (250 mg) into a vial, which is then aseptically lyophilized and sealed. At the time of use, the contents of the vial are mixed with 2 mL of saline to produce the injectable formulation.

[0076] The compounds of the present invention may be utilized in combination with other suitable therapeutic agents useful in the treatment of the above-mentioned diseases or disorders, such as anti-atherosclerotic agents, anti-dyslipidemic agents, anti-diabetic agents, anti-hyperglycemic agents, anti-hyperinsulinemia agents, anti-thrombotic agents, anti-retinopathic agents, anti-neuropathic agents, anti-nephropathic agents, anti-ischemic agents, anti-hypertensive agents, anti-obesity agents, anti-hyperlipidemic agents, anti-hypertriglyceridemic agents, anti-hypercholesterolemic agents, anti-restenosis agents, anti-pancreatic agents, lipid-lowering agents, appetite reducing agents, memory enhancing agents, anti-dementia agents, cognition enhancing agents, appetite suppressants, therapeutic agents for heart failure, therapeutic agents for peripheral arterial disease, therapeutic agents for malignant tumors, and anti-inflammatory agents.

[0077] The compounds of the present invention may be used together with at least one heart failure agent selected from the following: loop diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), angiotensin receptor-neprilysin inhibitors (ARNIs), beta-blockers, mineralocorticoid receptor antagonists, nitroxyl donors, RXFP1 agonists, APJ agonists, and cardiac inotropes, including, but not limited to, furosemide, bumetanide, torsemide, sacubitorial-valsartan, thiazide diuretics, captopril, enalapril, lisinopril, carvedilol, metopolol, bisoprolol, serelaxin, spironolactone, eplerenone, ivabradine, candesartan, eprosartan, irvestalain, losartan, olmesartan, telmisartan, and valsartan.

[0078] The compounds of the present invention may be utilized in combination with at least one of the following therapeutic agents in treating atherosclerosis: hyperlipidemic agents, agents that increase plasma HDL, antihypercholesterolemic agents, cholesterol biosynthesis inhibitors (such as HMG-CoA reductase inhibitors), LXR agonists, probucol, raloxifene, nicotinic acid, niacinamide, cholesterol absorption inhibitors, bile acid sequestrants (such as anion exchange resins, or quaternary amines such as cholestyramine or colestipol), low-density lipoprotein receptor inducers, clofibrate, fenofibrate, benzofibrates, sipofibrate, gemfibrizol, vitamin B6, vitamin B12, antioxidant vitamins, beta-blockers, antidiabetic agents, angiotensin II antagonists, angiotensin-converting enzyme inhibitors, platelet aggregation inhibitors, fibrinogen receptor antagonists, aspirin, and fibric acid derivatives.

[0079] The compounds of the present invention may be utilized in combination with at least one of the following therapeutic agents when treating with cholesterol biosynthesis inhibitors, particularly HMG CoA reductase inhibitors: Examples of suitable HMG CoA reductase inhibitors include, but are not limited to, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, and rosuvastatin.

[0080] The compounds of the present invention may be used in combination with at least one of the following antidiabetic agents, depending on the desired targeted therapy. Studies have shown that diabetes and hyperlipidemia control can be further improved by adding a second agent to the treatment regimen. Examples of antidiabetic agents include sulfonylureas (such as chlorpropamide, tolbutamide, acetohexamide, tolazamide, glyburide, gliclazide, glinase, glimepiride, and glipizide), biguanides (such as metformin), thiazolidinediones (such as ciglitazone, pioglitazone, troglitazone, and rosiglitazone), and related insulin sensitizers such as selective and non-selective activators of PPARα, PPARβ, and PPARγ; dehydroepiandrosterone (DHEA or its conjugated sulfate ester, also known as DHEA·SO4); antiglucocorticoids; TNFα inhibitors; dipeptidyl peptidase IV (DPP4) inhibitors (such as sitagliprine, saxagliptin), GLP-1 agonists or analogs (such as exenatide), α-glucosidase inhibitors (such as acarbose, miglitol, and voglibose), pramlintide (a synthetic analog of the human hormone amylin), other insulin secretagogues (such as repaglinide, gliquidone, and nateglinide), insulin, and the therapeutic agents listed above for treating atherosclerosis.

[0081] The compounds of the present invention may be used in combination with at least one anti-obesity agent selected from the following: phenylpropanolamine, phentermine, diethylpropion, mazindol, fenfluramine, dexfenfluramine, phentyramine, β3-adrenergic receptor agonists; sibutramine, gastrointestinal lipase inhibitors (such as orlistat), and leptin. Other agents used in the treatment of obesity or obesity-related disorders include neuropeptide Y, enterostatin, cholecystokinin, bombesin, amylin, histamine H3 receptor, dopamine D2 receptor modulator, melanocyte-stimulating hormone, corticotrophin-releasing factor, galanin, and gamma-aminobutyric acid (GABA).

[0082] The compounds of the present invention are also useful as standard or reference compounds, for example, as quality standards or controls, in tests or assays involving FPR2. Such compounds can be provided in commercially available kits, for example, for use in pharmaceutical research involving FPR2 activity. For example, the compounds of the present invention can be used as references in assays to compare their known activity to compounds with unknown activity. This ensures the experimenter that the assay is being performed properly and provides a basis for comparison, especially when the test compound is a derivative of the reference compound. When a new assay or protocol is developed, its effectiveness can be tested using the compounds of the present invention. The compounds of the present invention can also be used in diagnostic assays involving FPR2.

[0083] The present invention also encompasses an article of manufacture. As used herein, the term "article of manufacture" includes, but is not limited to, kits and packages. The article of manufacture of the present invention comprises: (a) a first container; (b) a pharmaceutical composition in the first container (wherein the composition comprises a first therapeutic agent, including a compound of the present invention or a pharmaceutically acceptable salt form thereof); and (c) a package insert stating that the pharmaceutical composition can be used to treat dyslipidemia and its sequelae. In another embodiment, the package insert states that the pharmaceutical composition can be used in combination with a second therapeutic agent (as defined above) to treat dyslipidemia and its sequelae. The article of manufacture may further comprise (d) a second container (wherein components (a) and (b) are placed in the second container, and component (c) is placed inside or outside the second container). "Placed in the first and second containers" means that each container holds the component within its area. The first container is a container used to hold the pharmaceutical composition. The container may be for manufacturing, storage, transportation, and / or individual / bulk sales. The first container is intended to include a bottle, jar, vial, flask, syringe, tube (e.g., for a cream formulation), or any other container used in the manufacturing, holding, storage, or distribution of a pharmaceutical formulation. The second container is used to hold the first container and, optionally, the package insert. Examples of the second container include, but are not limited to, a box (e.g., cardboard or plastic), a wooden box, a carton, a bag (e.g., a paper or plastic bag), a pouch, and a sack. The package insert can be physically attached to the outside of the first container by tape, adhesive, staples, or other attachment methods, or can be placed within the second container without any physical means of attachment to the first container. Alternatively, the package insert is located outside the second container. If located outside the second container, the package insert is preferably physically attached by tape, adhesive, staples, or other attachment methods. Alternatively, it can be in close proximity to or in contact with the outside of the second container without being physically attached.The package insert is a label, tag, marker, etc. that provides information related to the pharmaceutical composition contained in the first container. The information will typically be determined by a regulatory agency (e.g., the U.S. Food and Drug Administration) that governs the geographic area in which the product will be sold. Preferably, the package insert specifically describes the indications for which the pharmaceutical composition has been approved. The package insert may be made of any material from which a person can read the information contained therein or thereon. Preferably, the package insert is a printable material (e.g., paper, plastic, cardboard, wheel, or paper or plastic sticker, etc.) onto which the desired information can be formed (e.g., printed or affixed).

[0084] chemical method Abbreviations used herein are as follows: "1x" for 1 time, "2x" for 2 times, "3x" for 3 times, "°C" for degrees Celsius, "aq" for aqueous, "Col" for column, "eq" for equivalents, "g" for grams, "mg" for milligrams, "L" for liters, "mL" for milliliters, "μL" for microliters, "N" for normal, "M" for mole, "nM" for nanomole, "mol" for mole, and millimole. "mmol" for minute, "min" for hour, "h" for hour, "rt" for room temperature, "RT" for hold time, "ON" for overnight, "atm" for ambient, "psi" for pounds per square inch, "conc." for concentrate, "aq" for aqueous, "sat" or "sat'd" for saturated, "MW" for molecular weight, "mw" or "μwave" for micro, "mp" for melting point, "Wt" for weight, "MS" or "Mass" for mass spectrometry Spec”, “ESI” for electrospray ionization mass spectrometry, “HR” for high resolution, “HRMS” for high resolution mass spectrometry, “LCMS” for liquid chromatography mass spectrometry, “HPLC” for high pressure liquid chromatography, “RPHPLC” for reverse phase HPLC, “TLC” or “tlc” for thin layer chromatography, “NMR” for nuclear magnetic resonance spectroscopy, “nOe” for nuclear Overhauser effect spectroscopy, “1H” for proton, “δ” for delta, “s” for singlet, “d” for doublet, “t” for triplet, “q” for quartet, “m” for multiplet, “br” for broad, and “Hz” for Hertz, where “α”, “β”, “R”, “S”, “E”, and “Z” are stereochemical designators well known to those skilled in the art.

[0085] [Table 24] [Table 25]

[0086] The disclosed compounds can be made by a variety of methods known in the art, including those in the schemes below and those described in the specific embodiments section. The numbering of structures and variable groups shown in the synthetic schemes is different from, and should not be confused with, the numbering of structures or variables in the claims or the remainder of the specification. The variables in the schemes are only intended to illustrate how to make some compounds of the invention. A consideration in planning any synthetic route in the art is the choice of protecting groups used to protect functional groups present in the compounds described in this invention. A definitive account describing many alternative options for those skilled in the art is Greene, TW et al., Protecting Groups in Organic Synthesis, 4th Edition, Wiley (2007).

[0087] General formula (I) (wherein A, B and C are each Ar 1 , Ar 2 and Ar 3 and formula (II) (wherein A, B and Y are each selected from the group consisting of Ar 1 , Ar 2 and alkyl and / or cycloalkyl groups as defined above) can be prepared by one or more of the following synthetic schemes. [ka]

[0088] The 1-arylpyrrolidinone compounds of the present invention (Formula I), where A is a substituted phenyl or cycloalkyl ring, Ring B is a phenyl or heteroaryl ring, and Ring C is a substituted phenyl or heteroaryl ring, can be prepared by the general route shown in Scheme 1. Compound 1a was synthesized according to the procedure reported in the patent literature (WO2015079692). Compound 1a was treated with diphenylphosphoryl azide (DPPA) and a tertiary amine such as triethylamine (TEA). Subsequent addition of benzyl alcohol gave Cbz-protected compound 1b. The Cbz protecting group was removed from 1b using Pd / C in the presence of hydrogen, followed by amide coupling of the resulting free amine with an appropriately substituted phenyl acid to give amide 1c. Other deprotection conditions and protecting groups known to those skilled in the art could also be used in this reaction scheme. Copper or Pd-catalyzed coupling of 1c to a substituted iodobenzene or bromobenzene or other suitable haloaryl or heteroaryl compound in the presence of a base such as potassium carbonate or cesium carbonate and a suitable ligand such as N,N'-dimethylethylenediamine or Xantphos in a suitable solvent such as butanol, dioxane, or toluene can provide the desired compound 1d. The appropriate aryl or heteroaryl halides are either commercially available or can be easily obtained from the corresponding readily available starting materials by methods known to those skilled in the art. Additional methods for carrying out this transformation include Ullmann, Goldberg, and other variations of Buchwald copper-catalyzed amidations or Buchwald Pd-catalyzed C-N couplings, depending on the properties of ring B, using methods known to those skilled in the art for these types of couplings (see, e.g., Yin & Buchwald, Organic Lett. 2000, 2, 1101; Klapers et al., JACS, 2001, 123, 7727; Klapars et al., JACS, 2002, 124, 7421; Yin & Buchwald, JACS. 2002, 124, 6043; Kiyomor, Madoux & Buchwald, Tet. Lett., 1999, 40, 2657).Similarly, 1-arylpyrrolidinone compounds of the present invention (Formula I) (wherein rings A and C are substituted phenyl rings or heteroaryl or cycloalkyl, and ring B is phenyl or heteroaryl) can be prepared by the general route shown in Scheme 2.

[0089] Scheme 1 [ka]

[0090] Scheme 2 [ka]

[0091] The 1-arylpyrrolidinone compounds of the present invention (Formula II), where rings A and C are phenyl rings and Y is a substituted benzyl, heteroarylalkyl, alkyl and / or cycloalkyl group, can be prepared by the general synthetic route shown in Scheme 3, starting from intermediate 1c, prepared as shown in Scheme 1.

[0092] Scheme 3 [ka]

[0093] In Scheme 3, Y is C 1-6 The alkyl groups are benzyl and heteroaryl with alkyl spacers, and X is a leaving group such as chloride, bromide, iodide, methanesulfonyloxy, trifluoromethanesulfonyloxy, or other known groups. Compound 1e can be obtained by reacting compound 1c with an alkylating agent YX in a suitable solvent such as DMF or DMSO in the presence of a suitable base with heating, or by other methods known in the art.

[0094] Other features of the present invention will become apparent in the course of the following description of exemplary embodiments, which are given to illustrate the invention and are not intended to be limiting thereof. In the illustrative examples, the following methods were used unless otherwise noted. Purification of intermediates and final products was carried out via either normal-phase or reverse-phase chromatography. Normal-phase chromatography was carried out using pre-loaded SiO2 cartridges, eluting with a gradient of either hexanes and ethyl acetate or DCM and MeOH, unless otherwise noted. Reverse-phase preparative HPLC was performed using a C18 column with UV detection at 220 nm or preparative LCMS detection, with a gradient of solvent A (90% water, 10% MeOH, 0.1% TFA) and solvent B (10% water, 90% MeOH, 0.1% TFA), or with a gradient of solvent A (95% water, 5% Acn, 0.1% TFA) and solvent B (5% water, 95% Acn, 0.1% TFA), or with a gradient of solvent A (95% water, 2% Acn, 0.1% HCOOH) and solvent B (98% Acn, 2% water, 0.1% HCOOH), or with a gradient of solvent A (95% water, 5% Acn, 10 mM NHOAc) and solvent B (98% Acn, 2% water, 10 mM NHOAc), or with a gradient of solvent A (98% water, 2% Acn, 0.1% The column was eluted with a gradient of solvent B (98% Acn, 2% water, 0.1% NH4OH) and solvent B (98% Acn, 2% water, 0.1% NH4OH).

[0095] LC / MS methods used to characterize the example compounds Reverse-phase analytical HPLC / MS was performed on a Waters Acquity system coupled to a Waters MICROMASS® ZQ Mass Spectrometer.

[0096] Method A: Linear gradient from 0 to 100% B over 3 minutes, hold at 100% B for 0.75 minutes; UV visualization (220nm) Column: Waters BEH C18 2.1 x 50mm Flow rate: 1.0mL / min Solvent A: 0.1% TFA, 95% water, 5% AcOEt Solvent B: 0.1% TFA, 5% water, 95% AcOEt

[0097] Method B: Linear gradient from 0 to 100% B over 3 min, hold at 100% B for 0.75 min; UV visualization (220nm) Column: Waters BEH C18 2.1 x 50mm Flow rate: 1.0mL / min Solvent A: 10 mM ammonium acetate, 95% water, 5% AcOEt Solvent B: 10 mM ammonium acetate, 5% water, 95% AcOEt

[0098] Analytical HPLC: Method used to characterize the example compounds The product was analyzed using reverse phase analytical HPLC (Shimadzu analytical HPLC, performed using a system running Discovery VP software, RT = retention time). Method C: Ascentis Express C18, 2.1 x 50 mm, 2.7 μm particles; Solvent A: 95% water, 5% acetonitrile, 0.05% TFA; Solvent B: 95% acetonitrile, 5% water, 0.1% TFA; Temperature: 50 °C; Gradient: 0 to 100% B over 3 min, then hold at 100% B for 1 min; Flow rate: 1.1 mL / min

[0099] Method D: Ascentis Express C18, 2.1 x 50 mm, 2.7 μm particles; Solvent A: 95% water, 5% acetonitrile + 10 mM ammonium acetate; Solvent B: 95% acetonitrile, 5% water + 10 mM ammonium acetate; Temperature: 50 °C; Gradient: 0 to 100% B over 3 min, then hold at 100% B for 1 min; Flow rate: 1.1 mL / min

[0100] The following typical conditions were used to screen the compounds for chiral purity: Other conditions were used as well. Columns: Chiralpak IA, 250 x 4.6 mm, 5.0 μm particles, Chiralpak IB, 250 x 4.6 mm, 5.0 μm particles, Chiralpak IC, 250 x 4.6 mm, 5.0 μm particles, Chiralpak ID, 250 x 4.6 mm, 5.0 μm particles, Chiralpak IE, 250 x 4.6 mm, 5.0 μm particles and Chiralpak IF, 250 x 4.6 mm, 5.0 μm particles; Mobile phase: 0.2% ammonia in Acn:MeOH (1:1)

[0101] NMR used to characterize the compounds of the examples 1 H NMR spectra were obtained using a Bruker or JEOL® Fourier transform spectrometer operating at the following frequencies: 1 H NMR: 300 MHz (Bruker or JEOL®) or 400 MHz (Bruker or JEOL®) or 500 MHz (Bruker or JEOL®); 13 C NMR: 100 MHz (Bruker or JEOL®). Spectral data are reported in the format: chemical shift (multiplicity, coupling constant, and number of hydrogens). Chemical shifts are specified in ppm downfield of the tetramethylsilane internal standard (d units, tetramethylsilane = 0 ppm) and / or relative to the solvent peak ( 1 In the H NMR spectrum, it appears at 2.49 ppm in CD2HSOCD3, 3.30 ppm in CD2HOD, 1.94 ppm in CD3CN, and 7.24 ppm in CHCl3. 13 In the C NMR spectrum, it is noted that HCl appears at 39.7 ppm in CD3SOCD3, 49.0 ppm in CD3OD, and 77.0 ppm in CDCl3. 13 All C NMR spectra were proton decoupled.

[0102] Intermediate 1: Benzyl ((3S,4R)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl)carbamate [ka]

[0103] To a stirred solution of (3S,4R)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidine-3-carboxylic acid (6.0 g, 22 mmol), TEA (3.7 mL, 27 mmol) in toluene (60 mL) and acetonitrile (12 mL) was added diphenylphosphoryl azide (5.7 mL, 27 mmol). The mixture was stirred at room temperature for 3 hours and then at 80° C. for 30 minutes. After cooling to room temperature, benzyl alcohol (12 mL, 110 mmol) was added and the mixture was stirred at 100° C. for 16 hours. The reaction mixture was cooled and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether-ethyl acetate) to give Intermediate 1 (4.0 g, 11 mmol, 50%) as a colorless liquid. MS (ESI) m / z: 377.3 [M+H] +

[0104] Intermediate 2: (3S,4R)-3-amino-4-(2,6-difluoro-4-methoxyphenyl)pyrrolidin-2-one [ka]

[0105] To a degassed solution of Intermediate 1 (4.0 g, 11 mmol) in EtOH (60 mL) was added Pd—C (0.11 g, 1.1 mmol). The reaction mixture was purged with H and stirred at room temperature under an H atmosphere for 16 hours. The mixture was filtered through a Celite pad and concentrated under reduced pressure to give (3S,4R)-3-amino-4-(2,6-difluoro-4-methoxyphenyl)pyrrolidin-2-one (2.5 g, 10.3 mmol, 97%) as a white solid. The crude material was used in the next synthetic step without further purification. MS (ESI) m / z: 243.2 [M+H] +

[0106] Intermediate 3: N-((3S,4R)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl)-4-(difluoromethoxy)benzamide [ka]

[0107] To a solution of intermediate 2 (1.2 g, 5.0 mmol) in DMF (10 mL) stirred at room temperature under an argon atmosphere was added DIEA (1.0 mL, 6.0 mmol), 4-(difluoromethoxy)benzoic acid (1.1 g, 6.0 mmol), and HATU (2.3 g, 6.0 mmol). After 16 hours, the reaction mixture was quenched with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with water and brine (20 mL each), dried over NaSO, and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (petroleum ether-ethyl acetate) to give intermediate 3 (1.2 g, 2.9 mmol, 59% yield) as a white solid. MS (ESI) m / z: 413.1 [M+H] + ; 1 H NMR (300MHz, DMSO-d6) δ 8.85(d,J=8.6Hz,1H), 8.19(s,1H), 7.86(d,J=8.6Hz,2H), 7.35(t,J=75.0Hz,1H), 7.26(d,J=8.6Hz,2H), 6.7 5(d,J=12.0Hz,2H), 4.90-4.80(m,1H), 4.06-3.79(m,1H), 3.75(s,3H), 3.60-3.45(m,1H), 3.42-3.32(m,1H)

[0108] Intermediate 4: N-((3S,4R)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl)-4-(trifluoromethoxy)benzamide [ka]

[0109] Intermediate 4 was synthesized following a similar protocol as described above for Intermediate 3. MS(ESI) m / z: 431.1 [M+H] + ; 1 H NMR (300MHz, CDCl3) δ =7.77(d,J=8.4Hz,2H), 7.19(d,J=7.9Hz,2H), 6.47(m,3H), 6.23(s,1 H), 5.14-4.97(m,1H), 4.07-3.95(m,1H), 3.82-3.75(m,4H), 3.68-3.63(m,1H)

[0110] Intermediates 5A and 5B: 3-bromo-4-methyl-1-(3,3,3-trifluoro-2-hydroxypropyl)pyridin-2(1H)-one: [ka]

[0111] To a stirred solution of 3-bromo-4-methylpyridin-2(1H)-one (1.5 g, 8.0 mmol) in DMF (15 mL) at room temperature, 3-bromo-1,1,1-trifluoropropan-2-ol (2.3 g, 12 mmol) and KCO (3.3 g, 24 mmol) were added. The reaction mixture was heated at 90 °C for 16 hours. The reaction mixture was cooled, filtered through a Celite pad, and concentrated under reduced pressure. The crude compound was purified by silica gel chromatography (petroleum ether-ethyl acetate), and the enantiomers were separated by chiral SFC separation to give intermediate 5A (0.80 g, 2.7 mmol, 33.4% yield) and intermediate 5B (0.80 g, 2.7 mmol, 33% yield). SFC preparative conditions: Column / dimensions: Whelk (R,R) (250x4.6) mm, 5μ; CO2: 85%, % co-solvent: 0.2% DEA in 15% IPA; total flow rate: 3.0 g / min, back pressure: 100 bar, temperature: 40°C, UV: 220 nm; retention times: Peak 1 = 3.2 min and Peak 2 = 4.4 min; Enantiomer 1: MS (ESI) m / z: 299.9 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ =7.60(d,J=7.0Hz,1H), 6.62(d,J=6.5Hz,1H), 6.29(d,J=7.0Hz,1H), 4.42-4.29(m,2H), 3.87-3.79(m,1H), 2.28(s,3H), Enantiomer 2:MS(ESI)m / z:299.9 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ =7.60(d,J=7.0Hz,1H), 6.62(d,J=6.5Hz,1H), 6.29(d,J=7.0Hz,1H), 4.42-4.29(m,2H), 3.87-3.79(m,1H), 2.28(s,3H)

[0112] Intermediate 6: 2-(2-methoxyethyl)-5-methylpyridazin-3(2H)-one [ka]

[0113] To a stirred solution of 5-methylpyridazin-3(2H)-one (1.0 g, 9.1 mmol) in DMF (10 mL) at room temperature, potassium carbonate (3.8 g, 27 mmol) and 1-bromo-2-methoxyethane (1.5 g, 11 mmol) were added. The reaction mixture was heated at 70° C. for 15 hours. The reaction mixture was then cooled, filtered through a Celite pad, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (petroleum ether-ethyl acetate) to give Intermediate 6 (1.0 g, 6.0 mmol, 66% yield) as a yellow liquid. MS (ESI) m / z: 169.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ =7.79(d,J=2.0Hz,1H), 6.73(m,1H), 4.18(t,J=5.8Hz,2H), 3.64(t,J=5.8Hz,2H), 3.23(s,3H), 2.16(d,J=2.0Hz,3H)

[0114] Intermediate 7: 4-Bromo-2-(2-methoxyethyl)-5-methylpyridazin-3(2H)-one [ka]

[0115] To a stirred solution of 2-(2-methoxyethyl)-5-methylpyridazin-3(2H)-one (500 mg, 3.0 mmol) in acetonitrile (5 mL) at room temperature was added NBS (1060 mg, 5.95 mmol). The reaction mixture was then heated at 80° C. for 16 hours. The reaction mixture was cooled and filtered through a Celite pad, and the filtrate was concentrated under reduced pressure. The crude compound was purified by silica gel chromatography (petroleum ether-ethyl acetate) to give Intermediate 7 (350 mg, 1.4 mmol, 48% yield) as an orange solid. MS (ESI) m / z: 249.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ =7.86(s,1H), 4.26(t,J=5.5Hz,2H), 3.67(t,J=5.5Hz,2H), 3.22(s,3H), 2.27(s,3H)

[0116] Example 1: N-((3S,4R)-1-(2-cyanopyridin-3-yl)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl)-4-(difluoromethoxy)benzamide [ka]

[0117] To a stirred solution of Intermediate 3 (80 mg, 0.19 mmol) in 1,4-dioxane (2 mL) were added 3-bromopicolinonitrile (43 mg, 0.23 mmol) and CsCO (130 mg, 0.39 mmol). The reaction mixture was purged with nitrogen for 5 minutes and charged with Xantphos (22 mg, 0.039 mmol) and Pd(dba) (18 mg, 0.019 mmol). The reaction mixture was again purged with nitrogen for 3 minutes and heated at 100° C. for 16 hours. The reaction mixture was cooled and filtered through a Celite pad. The filtrate was concentrated under reduced pressure, and the crude product was purified by reverse-phase HPLC to give Example 1 (26 mg, 0.051 mmol, 26% yield) as a white solid. MS(ESI)m / z:515.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ =9.14(d,J=8.3Hz,1H), 8.72(d,J=4.6Hz,1H), 8.24(d,J=8.3Hz,1H), 7.94-7.87(m,3H), 7.35(s,1H), 7.29(d,J=8.8Hz,2 H), 6.81(d,J=10.8Hz,2H), 5.16-5.02(m,1H), 4.34-4.22(m,2H), 4.18-4.09(m,1H), 3.78(s,3H); RT=1.725 minutes, 100% (Method D)

[0118] Example 2: N-((3S,4R)-4-(2,6-difluoro-4-methoxyphenyl)-1-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-oxopyrrolidin-3-yl)-4-(difluoromethoxy)benzamide [ka]

[0119] To a stirred solution of Intermediate 3 (60 mg, 0.15 mmol) in 1,4-dioxane (2 mL) at room temperature was added 5-bromo-1-methylpyridin-2(1H)-one (33 mg, 0.18 mmol), CsCO (95 mg, 0.29 mmol), and N,N'-dimethylethylenediamine (2.6 mg, 0.029 mmol). The reaction mixture was purged with nitrogen for 5 minutes, then charged with copper(I) iodide (5.5 mg, 0.029 mmol), purged with nitrogen for 3 minutes, and heated at 100 °C for 16 hours. The reaction mixture was cooled, filtered through a Celite pad, and concentrated under reduced pressure to give the crude product, which was purified by reverse-phase HPLC to give Example 2 (32 mg, 0.062 mmol, 42% yield) as a white solid. MS(ESI)m / z:520.1 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ =9.03(d,J=8.6Hz,1H), 8.01(d,J=2.7Hz,1H), 7.93-7.81(m,3H), 7.55-7.13(m,3H), 6.80(d,J=10.8Hz,2H), 6.46(d,J=10.0Hz, 1H), 4.98(m,1H), 4.18-4.07(m,1H), 4.00(t,J=8.8Hz,1H), 3.93-3.85(m,1H), 3.78(s,3H), 3.45(s,3H); RT=1.677 minutes, 100% (Method D)

[0120] Example 3: N-((3S,4R)-1-(cyclopropylmethyl)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl)-4-(difluoromethoxy)benzamide [ka]

[0121] To a solution of Intermediate 3 (60 mg, 0.15 mmol) in DMF (2 mL) stirred at 0° C. under an argon atmosphere, NaH (8.7 mg, 0.22 mmol) was added, and the resulting reaction mixture was stirred for 30 minutes. Bromomethylcyclopropane (24 mg, 0.18 mmol) was then added to the reaction mixture, and the mixture was allowed to warm gradually to room temperature over 2 hours. The reaction mixture was quenched with ice / water and extracted with EtOAc (20 mL x 2). The organic layers were combined, washed with water (10 mL) and brine (10 mL), dried over NaSO, and concentrated under reduced pressure. The crude product was purified by reverse-phase HPLC to give Example 3 (23 mg, 0.049 mmol, 33% yield) as a white solid. MS (ESI) m / z: 467.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ =8.91(d,J=8.8Hz,1H), 7.87(d,J=8.8Hz,2H), 7.34(s,1H), 7.26(d,J=8.6Hz,2 H), 6.76(d,J=10.8Hz,2H), 4.92(t,J=9.5Hz,1H), 3.97-3.88(m,1H), 3.77(s,3H) ), 3.75-3.70(m,1H), 3.65-3.55(m,1H), 3.31-3.24(m,1H), 3.07(m,1H), 1.01- 0.93(m,1H), 0.51(d,J=8.1Hz,2H), 0.32-0.20(m,2H); RT=1.810 minutes, 99.2% (Method D)

[0122] Examples 4 and 5: N-((3S,4R)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxo-1-(2-oxo-1-(3,3,3-trifluoro-2-hydroxypropyl)-1,2-dihydropyridin-3-yl)pyrrolidin-3-yl)-4-(difluoromethoxy)benzamide (Enantiomers 1 and 2) [ka]

[0123] To a stirred solution of N-((3S,4R)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl)-4-(difluoromethoxy)benzamide (500 mg, 1.2 mmol) in 1,4-dioxane (10 mL) at room temperature, cesium carbonate (790 mg, 2.4 mmol) and 3-bromo-1-(3,3,3-trifluoro-2-hydroxypropyl)pyridin-2(1H)-one (382 mg, 1.34 mmol) were added. The reaction mixture was purged with nitrogen for 5 minutes and then charged with N,N-dimethylethane-1,2-diamine (21 mg, 0.24 mmol) and copper(I) iodide (23 mg, 0.12 mmol). The reaction mixture was again purged with nitrogen for 3 minutes and heated at 100° C. for 16 hours. The reaction mixture was cooled, filtered through a Celite pad, and concentrated under reduced pressure. The crude compound was purified by reverse-phase HPLC followed by chiral SFC to give Example 4 (68 mg, 0.11 mmol, 9.1% yield) and Example 5 (65 mg, 0.10 mmol, 8.7% yield). SFC preparative conditions: Column / dimensions: Luxcellulose (250x30) mm, 5μ; % CO2: 60%, % co-solvent: 40% 4M methanolic ammonia in MeOH; total flow rate: 120.0 g / min, back pressure: 100 bar, temperature: 30°C, UV: 220 nm; retention times: Peak 1 = 4.6 min and 2 = 9.7 min, Enantiomer 1: MS (ESI) m / z: 618.2 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ =9.01(brd,J=8.6Hz,1H), 7.93-7.81(m,2H), 7.70(dd,J=6.8, 2.0Hz,1H), 7.65(dd,J=7.3 , 2.0Hz,1H), 7.34(t,J=73.6Hz,1H), 7.27(m,2H), 6.76(d,J=10.8Hz,2H), 6.37(t,J=7.1H) z,1H), 5.16-5.04(m,1H), 4.45(dd,J=13.1, 2.8Hz,1H), 4.39-4.27(m,1H), 4.17-4.06(m, 1H), 4.06-3.98(m,1H), 3.97-3.88(m,1H), 3.88-3.80(m,1H), 3.76(s,3H), 3.35(brs,1H). Enantiomer 2:MS(ESI)m / z:618.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ =9.02(d,J=8.8Hz,1H), 7.93-7.83(m,2H), 7.69(dd,J=6.7, 2.1Hz,1H), 7.64(dd,J=7.3, 2.1 Hz,1H), 7.34(t,J=73.6Hz,1H), 7.28(d,J=8.8Hz,2H), 6.77(d,J=10.8Hz,2H), 6.37(t,J=7. 0Hz,1H), 5.08(dd,J=10.9, 8.9Hz,1H), 4.44(dd,J=13.1, 3.1Hz,1H), 4.39-4.26(m,1H), 4.1 5-3.99(m,2H), 3.97-3.90(m,1H), 3.84(dd,J=13.3, 9.4Hz,1H), 3.76(s,3H), 3.36(brs,1H)

[0124] The following examples listed in Table 2 were prepared using procedures similar to those set forth in Examples 1-5, and / or modifications thereof known to those skilled in the art.

[0125] Table 2 [Table 26] [Table 27] Table 28 Table 29 Table 30

[0126] Table 31 Table 32 Table 33 Table 34 Table 35

[0127] Table 36 Table 37 Table 38 Table 39 Table 40

[0128] Table 41 Table 42 Table 43 Table 44 Table 45

[0129] Table 46 Table 47 Table 48 Table 49 Table 50

[0130] Table 51 Table 52 Table 53 Table 54 Table 55

[0131] Table 56 Table 57 Table 58 Table 59 Table 60

[0132] Table 61 Table 62 Table 63 Table 64 Table 65

[0133] Table 66 Table 67 Table 68 Table 69 Table 70

[0134] Table 71 Table 72 Table 73 Table 74 Table 75

[0135] Table 76 Table 77 Table 78 Table 79 Table 80

[0136] Table 81 Table 82 Table 83 Table 84 Table 85

[0137] Table 86 Table 87 Table 88 Table 89 Table 90

[0138] Table 91 Table 92 Table 93 Table 94 Table 95

[0139] Table 96 Table 97 Table 98 Table 99

[0140] Table 100 Table 101 Table 102 Table 103 Table 104 Table 105

[0141] Table 106 Table 107 Table 108 Table 109 Table 110

[0142] Table 111 Table 112 Table 113 Table 114 Table 115

[0143] Table 116 Table 117 Table 118 Table 119 Table 120

[0144] Table 121 Table 122

Table 123

[0145] Table 126 Table 127 Table 128 Table 129 Table 130

[0146] Table 131 Table 132 Table 133 Table 134 Table 135

[0147] Table 136 Table 137 Table 138 Table 139 Table 140

[0148] Table 141 Table 142 Table 143 Table 144 Table 145

[0149] Table 146 Table 147 Table 148 Table 149 Table 150

[0150] Table 151 Table 152 Table 153 Table 154 Table 155

[0151] Table 156 Table 157 Table 158 Table 159 Table 160

[0152] Table 161 Table 162 Table 163 Table 164 Table 165

[0153] Table 166 Table 167 Table 168 Table 169 Table 170

[0154] Table 171 Table 172 Table 173 Table 174 Table 175

[0155] Table 176 Table 177 Table 178 Table 179 Table 180

[0156] [Table 181] [Table 182]

[0157] It will be apparent to those skilled in the art that the present disclosure is not limited to the illustrative examples set forth above, and that it may be embodied in other specific forms without departing from its essential characteristics. The examples, therefore, are to be considered in all respects as illustrative and not restrictive, and reference should be made to the appended claims rather than to the examples set forth above, and all changes that come within the meaning and range of equivalence of the claims are intended to be embraced therein.

Claims

1. Formula (I): 【Chemistry 1】 [In the formula: * is an asymmetric carbon atom; Ar １ are aryl or pyridyl, each of which is 1 to 3 R １ is replaced by; Ar ２ is C ３－６ Cycloalkyl, aryl, or 5-12 membered heterocyclyl (O, S(O) ｐ , N, and NR ２ａ each containing 0 to 3 R ２ is replaced by; Ar ３ are phenyl or pyridyl, each of which is one R ５ａ , one R ５ｂ , and one R ５ｃ is replaced by; R １ Halo, C １－４ Haloalkyl, C １－４ Alkoxy, or C １－４ haloalkoxy; R ２ is oxo, cyano, halo, C １－６ Alkyl (0 to 5 R ｅ substituted with), -OR ｂ , -NR ３ R ４ , -NR ４ C(O)R ｂ , -NR ４ (CR ｄ R ｄ ) ０－１ C(O)NR ３ R ４ , (C １－４ alkyl) ２ (O) P-, C ３－６ Cycloalkyl, aryl, or 5-6 membered heterocyclyl (O, S(O) ｐ , N, and NR ａ containing 1 to 4 heteroatoms selected from: R ２ａ is hydrogen, C １－４ Alkyl (0 to 5 R ｅ substituted with), -(CR ｄ R ｄ ) １－４ -NR ３ R ４ , -(CR ｄ R ｄ ) １－４ -OR ｂ , -(CR ｄ R ｄ ) １－４ -C(O)NR ３ R ４ , -(CR ｄ R ｄ ) ｒ -C ３－６ Cycloalkyl (0 to 5 R ｅ substituted with), -(CR ｄ R ｄ ) ｒ -aryl (0 to 5 R ｅ substituted with -(CR ｄ R ｄ ) ｒ -heterocyclyl(O,S(O) ｐ , N, and NR ａ (0 to 5 R ｅ substituted with R ３ is hydrogen, C １－４ Alkyl (0 to 5 R ｅ substituted with), C ３－６ Cycloalkyl (0 to 5 R ｅ substituted with), or heterocyclyl (O, S(O) ｐ , N, and NR ８ (0 to 5 R ｅ substituted with R ４ is hydrogen or C １－４ Is alkyl; Alternatively, R ３ and R ４ means, together with the nitrogen to which they are both attached, a 4- to 9-membered heterocyclyl (O, S(O) ｐ , N, and NR ８ (1 to 3 R ６ substituted with; R ５ａ is hydrogen or halo; R ５ｂ is hydrogen or halo; R ５ｃ Halo, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ alkoxy, or deuterated alkoxy; R ６ is hydrogen, halo, oxo, hydroxy, or C １－４ Alkyl (0 to 5 R ｅ substituted with R ７ is hydrogen or C １－４ is alkyl; R ８ is hydrogen, C １－４ Alkyl, or —S(O) ｐ R ｃ and R ａ is hydrogen or C １－６ Alkyl (0 to 5 R ｅ substituted with), C ３－６ Cycloalkyl (0 to 5 R ｅ aryl (substituted with 0 to 5 R ｅ substituted with), or heterocyclyl (O, S(O) ｐ , N.R. ｄ (0 to 5 R ｅ substituted with R ｂ is hydrogen, C １－６ Alkyl (0 to 5 R ｅ substituted with), C ３－６ Cycloalkyl (0 to 5 R ｅ aryl (substituted with 0 to 5 R ｅ substituted with), or heterocyclyl (O, S(O) ｐ , N.R. ｄ (0 to 5 R ｅ substituted with R ｃ is C １－４ Alkyl (0 to 5 R ｅ substituted with R ｄ is hydrogen or C １－４ Alkyl (0 to 5 R ｅ substituted with R ｅ is halo, cyano, oxo, -OR ｇ , -NR ｇ R ｇ , —C(O)NR ｇ R ｇ , -S(O) ｐ C １－４ Alkyl, C １－６ Alkyl (0 to 5 R ｆ substituted with), -(CH ２ ) ｒ -C ３－６ Cycloalkyl (0 to 5 R ｆ substituted with), -(CH ２ ) ｒ -aryl (0 to 5 R ｆ substituted with -(CH ２ ) ｒ -heterocyclyl(O,S(O) ｐ , N, and NR ｇ (0 to 5 R ｆ substituted with R ｆ is halo, cyano, hydroxy, oxo, C １－５ Alkyl, C ３－６ cycloalkyl, or phenyl; R ｇ is hydrogen, C １－５ Alkyl, C ３－６ cycloalkyl, aryl, or heterocyclyl; or R ｇ and R ｇ together with the nitrogen atom to which they are both attached form a heterocyclyl; n is 0 or 1; p is 0, 1, or 2; r is 0, 1, 2, 3, or 4. or a pharmaceutically acceptable salt thereof.

2. Formula (II): 【Chemistry 2】 [In the formula: Ar ２ is C ３－６ cycloalkyl, phenyl, 5- or 6-membered heterocyclyl (1-2 N or NR ２ａ each containing 0 to 2 R ２ is replaced by; Ar ３ is one R ５ａ , one R ５ｂ , and one R ５ｃ is phenyl substituted with; R １ Halo, C １－４ haloalkyl, or C １－４ haloalkoxy; R ２ is oxo, cyano, halo, C １－５ Alkyl (0 to 5 R ｅ substituted with), -OR ｂ , -NR ３ R ４ , -NR ４ C(O)R ｂ , (C １－３ alkyl) ２ (O) P-, C ３－６ Cycloalkyl, aryl, or 5- to 6-membered heterocyclyl (O, S, N, and NR ａ containing 1 to 4 heteroatoms selected from: R ２ａ is hydrogen, C １－４ Alkyl (0 to 4 R ｅ substituted with), -(CHR ｄ ) １－３ -C(O)NR ３ R ４ , -(CHR ｄ ) ｒ -C ３－６ Cycloalkyl (0 to 4 R ｅ substituted with), -(CHR ｄ ) ｒ -aryl (0 to 4 R ｅ substituted with -(CHR ｄ ) ｒ heterocyclyl (O, S, N, and NR ａ (0 to 4 R ｅ substituted with R ３ is hydrogen, C １－４ Alkyl (0 to 4 R ｅ substituted with), C ３－６ cycloalkyl, or heterocyclyl (O, S, N, and NR ８ (0 to 4 R ｅ substituted with R ４ is hydrogen or C １－３ Is alkyl; Alternatively, R ３ and R ４ together with the nitrogen to which they are attached, form a 4- to 8-membered heterocyclyl (O, S, N, and NR ８ (1 to 3 R ６ substituted with; R ５ａ is hydrogen or halo; R ５ｂ is hydrogen or halo; R ５ｃ Halo, C １－４ Alkyl, C １－４ haloalkyl, or C １－４ is alkoxy; R ６ is hydrogen, halo, oxo, hydroxy, or C １－４ Alkyl (0 to 4 R ｅ substituted with R ７ is hydrogen or C １－３ is alkyl; R ８ is hydrogen, C １－３ Alkyl, or —S(O) ｐ R ｃ and R ａ is hydrogen or C １－６ Alkyl (0 to 5 R ｅ substituted with R ｂ is hydrogen, C １－６ Alkyl (0 to 5 R ｅ substituted with), or heterocyclyl (substituted with O, S, N, NR ｄ (0 to 5 R ｅ substituted with R ｃ is C １－３ Alkyl (0 to 5 R ｅ substituted with R ｄ is hydrogen or C １－４ Alkyl (0 to 1 -OC １－４ substituted with alkyl; R ｅ is halo, cyano, oxo, -OR ｇ , -NR ｇ R ｇ , —C(O)NR ｇ R ｇ , -S(O) ｐ C １－４ Alkyl, C １－４ Alkyl (0 to 5 R ｆ substituted with), -(CH ２ ) ｒ -C ３－６ Cycloalkyl (0 to 5 R ｆ substituted with), -(CH ２ ) ｒ -aryl (0 to 5 R ｆ substituted with -(CH ２ ) ｒ heterocyclyl (O, S, N, and NR ｇ (0 to 5 R ｆ substituted with R ｆ are halo, cyano, hydroxy, C １－５ Alkyl, or C ３－６ is cycloalkyl; R ｇ is hydrogen, C １－５ alkyl, or heterocyclyl; n is 0; r is 0, 1, 2, or 3.

2. The compound of claim 1, wherein: or a pharmaceutically acceptable salt thereof.

3. Formula (III): 【Transformation 3】 [In the formula: Ar ２ teeth 【Chemistry 4】 and R １ Halo, C １－３ haloalkyl, or C １－３ haloalkoxy; R ２ Cyano, halo, C １－４ Alkyl (0 to 5 R ｅ substituted with), -OR ｂ , -NR ３ R ４ , -NR ４ C(O)R ｂ , (C １－４ alkyl) ２ (O) P-, C ３－６ Cycloalkyl, aryl, or 5- to 6-membered heterocyclyl (O, S, N, and NR ａ containing 1 to 4 heteroatoms selected from: R ２ａ is hydrogen, C １－４ Alkyl (0 to 3 R ｅ substituted with), -(CHR ｄ ) １－２ -C(O)NR ３ R ４ , -(CH ２ ) ｒ -C ３－６ Cycloalkyl (0 to 3 R ｅ substituted with), -(CH ２ ) ｒ -aryl (0 to 3 R ｅ substituted with -(CH ２ ) ｒ heterocyclyl (O, S, N, and NR ａ (0 to 3 R ｅ substituted with R ３ is hydrogen, C １－４ Alkyl (0 to 3 R ｅ substituted with), C ３－６ cycloalkyl, or heterocyclyl (O, S, N, and NR ８ (0 to 3 R ｅ substituted with R ４ is hydrogen or C １－２ Is alkyl; Alternatively, R ３ and R ４ together with the nitrogen to which they are attached, form a 4- to 8-membered heterocyclyl (O, S, N, and NR ８ (1 to 3 R ６ substituted with; R ５ａ is hydrogen or halo; R ５ｂ is hydrogen or halo; R ５ｃ is halo or C １－２ is alkoxy; R ６ is hydrogen, halo, oxo, hydroxy, or C １－４ Alkyl (0 to 3 R ｅ substituted with R ７ is hydrogen or CH ３ and R ８ is hydrogen, C １－２ Alkyl, or —S(O) ２ C １－４ is alkyl; R ａ is hydrogen, C １－５ Alkyl (0 to 4 R ｅ substituted with R ｂ is hydrogen, C １－５ Alkyl (0 to 4 R ｅ heterocyclyl (substituted with O, S, N, NR ｄ (0 to 4 R ｅ substituted with R ｄ is hydrogen or C １－３ Alkyl (0 to 1 -OC １－４ substituted with alkyl; R ｅ is halo, cyano, oxo, -OR ｇ , -NR ｇ R ｇ , C(O)NR ｇ R ｇ , -S(O) ｐ C １－４ Alkyl, C １－４ Alkyl (0 to 4 R ｆ substituted with), -(CH ２ ) ｒ -C ３－６ Cycloalkyl (0 to 4 R ｆ substituted with), -(CH ２ ) ｒ -aryl (0 to 4 R ｆ substituted with -(CH ２ ) ｒ heterocyclyl (O, S, N, and NR ｇ (0 to 4 R ｆ substituted with R ｆ is halo, cyano, hydroxy, or C １－５ is alkyl; R ｇ is hydrogen or C １－４ alkyl; r is 0, 1, or 2.

2. The compound of claim 1, wherein: or a pharmaceutically acceptable salt thereof.

4. Formula (IVa): 【Transformation 5】 [In the formula: Ar ２ teeth 【Transformation 6】 and R １ is Cl, -CF ３ , -OCHF ２ , or -OCF ３ and R ２ Cyano, halo, C １－４ Alkyl (0 to 4 R ｅ substituted with), -OR ｂ , -NR ３ R ４ , -NR ４ C(O)R ｂ , (C １－２ alkyl) ２ (O) P-, C ３－６ cycloalkyl, or heterocyclyl (O, S, N, and NR ａ containing 1 to 4 heteroatoms selected from: R ２ａ is hydrogen, C １－４ Alkyl (0 to 2 R ｅ substituted with), -(CHR ｄ ) １－２ -C(O)NR ３ R ４ , -(CH ２ ) ｒ -C ３－６ Cycloalkyl (0 to 2 R ｅ substituted with), -(CH ２ ) ｒ -aryl (0 to 2 R ｅ substituted with -(CH ２ ) ｒ heterocyclyl (O, S, N, and NR ａ (0-2 R ｅ substituted with R ３ is hydrogen, C １－４ Alkyl (0 to 3 R ｅ substituted with O, S, N, and NR ８ (0 to 3 R ｅ substituted with R ４ is hydrogen or C １－２ Is alkyl; Alternatively, R ３ and R ４ together with the nitrogen to which they are attached, form a 4- to 8-membered heterocyclyl (O, S, N, and NR ８ (1 to 3 R ６ substituted with; R ５ａ is hydrogen, F, or Cl; R ５ｂ is hydrogen, F, or Cl; R ５ｃ is Cl or -OCH ３ and R ６ is hydrogen, halo, oxo, hydroxy, or C １－３ Alkyl (0 to 3 R ｅ substituted with R ８ is hydrogen, C １－２ Alkyl, or S(O) ２ C １－３ is alkyl; R ａ is hydrogen, C １－４ Alkyl (0 to 3 R ｅ substituted with R ｂ is hydrogen, C １－４ Alkyl (0 to 3 R ｅ heterocyclyl (substituted with O, S, N, and NR ｄ (0 to 3 R ｅ substituted with R ｄ is hydrogen or C １－２ Alkyl (0 to 1 -OC １－４ substituted with alkyl; R ｅ is halo, cyano, oxo, -OR ｇ , -NR ｇ R ｇ , —C(O)NR ｇ R ｇ , -S(O) ２ C １－４ Alkyl, C １－６ Alkyl (0 to 3 R ｆ substituted with), -(CH ２ ) ｒ -C ３－６ Cycloalkyl (0 to 3 R ｆ substituted with -(CH ２ ) ｒ heterocyclyl (O, S, N, and NR ｇ (0 to 3 R ｆ substituted with R ｆ is halo, cyano, hydroxy, or C １－４ is alkyl; R ｇ is hydrogen or C １－３ alkyl; r is 0 or 1.

4. The compound of claim 3, wherein: or a pharmaceutically acceptable salt thereof.

5. Ar ２ but 【Transformation 7】 and R ２ is F, Cl, CH ２ OH, CH ３ , C.F. ３ , or CHF ２ and R ２ａ Ga-CH ３ , -CH ２ CH ３ , -CH ２ CHF ２ , -CH ２ CF ３ , -CH ２ CH ２ OCH ３ , -CH ２ CH(OH)CF ３ , -CH ２ CH(OH)CH ３ , -CH ２ CH ２ OH, -CH ２ CH (CH ３ ) OH, —CH ２ CH (CF ３ ) OH, —CH ２ CH ２ CF ３ , -CH(CH ２ OH)CH ２ OCH ３ , -CH(CH ２ NH ２ ) OCH ３ , -CH ２ CH (CH ３ ) OCH ３ , or -CH ２ CH (CF ３ ) OCH ３ 5. The compound of claim 4, wherein:

6. Formula (IVb): 【Transformation 8】 [In the formula: R １ is Cl, -CF ３ , -OCHF ２ , or -OCF ３ and R ２ is cyano, F, Cl, -CH ３ , -CF ３ , -CHF ２ , -CF ３ or —NHC(O)CH ３ and R ２ａ は-CH ３ 、\HF ２ 、-CH ２ CH ３ 、-CH ２ CN、-H ２ CHF ２ 、-CH ２ CH ２ OCH ３ 、-CH ２ CH(OH)CF ３ 、-CH ２ CH(OH)CH ３ 、-CH ２ CH ２ OH、-CF ２ CH ２ OH、-H ２ HH(H) ３ )OH、-H ２ CH ２ CF ３ ,-EH(EH ２ OH)CH ２ OCH ３ ,-EH(EH ２ NH ２ )OCH ３ 、-CH ２ HH(H) ３ )OCH ３ 、-CH ２ CH(CF) ３ )OCH ３ ,-EH(EH ２ NH ２ )CH ２ OCH ３ 、-CH(C(O)N(CH ３ ) ２ )CH ２ OCH ３ 、-CH ２ C(CH) ３ )(CH ２ (O) ２ 、-CH ２ CH ２ N(CH) ３ ) ２ 、-CH ２ CH ２ S (O) ２ C １－４ alkyl、-CHRR ｄ C(O)NR ３ R ４ , -(CH ２ ) ０－１ -C ３－６ Cycloalkyl, -(CH ２ ) ０－３ -heterocyclyl (wherein heterocyclyl is 【Chemistry 9】 ) selected from: R ３ and R ４ and together with the nitrogen to which they are both attached, 【Chemistry 10】 forming a heterocyclyl selected from: R ５ａ is hydrogen or F; R ５ｂ is hydrogen or F; R ５ｃ is Cl or -OCH ３ and R ６ is hydrogen, oxo, halo, -CH ３ , -CHF ２ , -CF ３ , or -CH ２ OH; R ８ is hydrogen, C １－２ Alkyl, or —S(O) ２ C １－３ alkyl; R ｄ Ha-CH ２ OCH ３ is] 5. The compound of claim 4, wherein: or a pharmaceutically acceptable salt thereof.

7. Formula (IVc): 【Chemistry 11】 [In the formula: R １ is Cl, -CF ３ , -OCHF ２ , or -OCF ３ and R ２ is cyano, F, Cl, -CH ２ OH, -CH ３ , -CHF ２ , -CF ３ , -OCH ３ , -OCH(CH ３ ) ２ , -NR ３ R ４ , (CH ３ ) ２ (O) P-, C ３－６ cycloalkyl, 【Chemistry 12】 and R ３ is hydrogen or C １－４ Alkyl (0-1 S(O) ２ C １－３ substituted with alkyl), 【Chemistry 13】 and R ４ is hydrogen; Alternatively, R ３ and R ４ and together with the nitrogen to which they are both attached, 【Chemistry 14】 forming a heterocyclyl selected from: R ５ａ is hydrogen or F; R ５ｂ is hydrogen or F; R ５ｃ is Cl or -OCH ３ and R ６ is hydrogen, halo, oxo, -CH ３ , -CH ２ CH ３ , or -CH ２ OH; R ８ is hydrogen, C １－４ Alkyl, or —S(O) ２ C １－３ alkyl] 5. The compound of claim 4, wherein: or a pharmaceutically acceptable salt thereof.

8. Formula (IVd): 【Chemistry 15】 [In the formula: R １ is Cl, -CF ３ , -OCHF ２ , or -OCF ３ and R ２ Ha-OR ｂ or (C １－２ alkyl) ２ (O) P-; R ５ａ is hydrogen or F; R ５ｂ is hydrogen or F; R ５ｃ is Cl or -OCH ３ and R ｂ is hydrogen, C １－４ Alkyl (0 to 3 R ｅ ), or 【Chemistry 16】 and R ｅ is F, Cl, or -OR ｇ and R ｇ is hydrogen or C １－３ alkyl] 5. The compound of claim 4, wherein: or a pharmaceutically acceptable salt thereof.

9. Formula (IVe): 【Chemistry 17】 [In the formula: R １ is Cl, -CF ３ , -OCHF ２ , or -OCF ３ and R ２ is cyano, F, Cl, -CH ２ OH, -CH ３ , -CHF ２ , -CF ３ , -OCH ３ , -OCH(CH ３ ) ２ , or -NR ３ R ４ and R ３ is hydrogen or C １－４ is alkyl; R ４ is hydrogen or C １－２ Is alkyl; Alternatively, R ３ and R ４ and together with the nitrogen to which they are both attached, [Chemistry 18] forming a heterocyclyl selected from: R ５ａ is hydrogen or F; R ５ｂ is hydrogen or F; R ５ｃ is Cl or -OCH ３ is] 5. The compound of claim 4, wherein: or a pharmaceutically acceptable salt thereof.

10. Formula (IVf): 【Chemistry 19】 [In the formula: R １ is Cl, -CF ３ , -OCH ３ , -OCHF ２ , or -OCF ３ and R ２ is cyano, F, Cl, -CH ２ OH, -CH ３ , -CHF ２ , or -CF ３ and R ２ａ Ha-CH ３ , -CH ２ CH ３ , -CH ２ CHF ２ , -CH ２ CH ２ OCH ３ , -CH ２ CH(OH)CF ３ , -CH ２ CH(OH)CH ３ , -CH ２ CH ２ OH, -CH ２ CH (CH ３ ) OH, or —CH ２ CH ２ CF ３ and R ５ａ is hydrogen, F, or Cl; R ５ｂ is hydrogen, F, or Cl; R ５ｃ is Cl or -OCH ３ is] 2. The compound of claim 1, wherein: or a pharmaceutically acceptable salt thereof.

11. Formula (V): 【Chemistry 20】 [In the formula: Ar ２ is C ３－５ is cycloalkyl; R １ is Cl, -CF ３ , -OCHF ２ , or -OCF ３ and R ５ａ is F or Cl; R ５ｂ is F or Cl; R ５ｃ Ha-OCH ３ is] 2. The compound of claim 1, wherein: or a pharmaceutically acceptable salt thereof.

12. Formula (VI): 【Chemistry 21】 [In the formula: R １ Ha-CF ３ , -OCHF ２ , or -OCF ３ and R ２ is cyano, F, Cl, -CH ２ OH, -CHF ２ , -CF ３ , -OCH ３ , -OCH(CH ３ ) ２ , or (CH ３ ) ２ (O) P-; R ５ａ is F or Cl; R ５ｂ is F or Cl; R ５ｃ Ha-OCH ３ is] 4. The compound of claim 3, wherein: or a pharmaceutically acceptable salt thereof.

13. Formula (VII): 【Chemistry 22】 [In the formula: R １ Ha-CF ３ , -OCHF ２ , or -OCF ３ and R ２ is F, Cl, or (CH ３ ) ２ (O) P-; R ５ａ is F; R ５ｂ is F; R ５ｃ Ha-OCH ３ is] 4. The compound of claim 3, wherein: or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 13 and a pharmaceutically acceptable carrier or diluent.

15. A pharmaceutical composition comprising the compound of any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof for the treatment and / or prevention of inflammatory diseases, heart diseases, chronic airway diseases, cancer, sepsis, allergic conditions, HIV retroviral infection, circulatory disorders, neuroinflammation, neurological disorders, pain, prion diseases, amyloidosis, and immune disorders.

16. 16. The pharmaceutical composition of claim 15, wherein the cardiac disease is selected from the group consisting of angina, unstable angina, myocardial infarction, heart failure, acute coronary artery disease, acute heart failure, chronic heart failure, and cardiac iatrogenic damage.

17. 17. The pharmaceutical composition of claim 16, wherein the heart failure is caused by hypertension, ischemic heart disease, non-ischemic heart disease, exposure to cardiodamaging compounds, myocarditis, Kawasaki disease, type I and type II diabetes, thyroid disease, viral infection, periodontitis, drug intoxication, alcoholism, pericarditis, atherosclerosis, vascular disease, hypertrophic cardiomyopathy, dilated cardiomyopathy, myocardial infarction, atrial fibrosis, left ventricular systolic dysfunction, left ventricular diastolic dysfunction, coronary artery bypass surgery, pacemaker implantation, starvation, eating disorders, muscular dystrophy, and genetic defects.

Images