Oxopyrrolidine urea 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 (I) for treating, for example, atherosclerosis, heart failure, chronic obstructive pulmonary disease (COPD), and related diseases. TIFF2023537410000164.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 / 064,640, filed August 12, 2020, the contents of which are incorporated herein by reference in their entirety. [Background technology]

[0002] The present invention relates to novel oxopyrrolidine urea 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 play important roles in host defense and inflammatory responses. 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 oxopyrrolidine urea compounds 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.

[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 formula (I), 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 disorders.

[0012] One aspect of the present invention is a compound of formula (I): [ka] [In formula: Ar 1 are cycloalkyl, cycloalkylalkyl, aryl, or heterocycloalkyl, each of which is 0 to 3 R 1 is replaced by; Ar 2 is C 3-6Cycloalkyl, aryl, or 5- to 12-membered heteroaryl or heterocycloalkyl (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 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 haloalkoxy, or aryl (0-2 halo, C 1-4 Haloalkyl, or C 1-4 substituted with alkoxy); 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, or 5- to 6-membered heteroaryl or heterocycloalkyl (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 , -(CRd 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 ), -(CR d R d ) r -aryl (0 to 5 R e ), or -(CR d R d ) r -heteroaryl or heterocycloalkyl (O, S(O) p , N, and NR a and 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), heteroaryl or heterocycloalkyl (O, S(O) p , N, and NR 8 and 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 both attached, a 4-9 membered heteroaryl or heterocycloalkyl (O, S(O) p , N, and NR 8 and 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 heteroaryl or heterocycloalkyl (O, S(O) p , N, NR d and 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 heteroaryl or heterocycloalkyl (O, S(O) p , N, NR d and 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 -heteroaryl or heterocycloalkyl (O, S(O) p , N, and NR g and 0 to 5 R f ) and R f are halo, cyano, hydroxy, C 1-5 Alkyl, C 3-6 cycloalkyl, or phenyl; R g is hydrogen, C 1-5 Alkyl, C 3-6 cycloalkyl, aryl, or heteroaryl or heterocycloalkyl; or R g and R g together with the nitrogen atom to which they are attached form a heteroaryl or heterocycloalkyl; 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 1 teeth [ka] and; Ar 2 is C 3-6 cycloalkyl, phenyl, 5- to 6-membered heteroaryl or heterocycloalkyl (1-2 N or NR 2a each of which contains 0 to 2 R 2 is replaced by; Ar 3 is phenyl (one R 5a , 1 R 5b , and one R 5c ) and R 1 is halo, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 haloalkoxy, or phenyl (0-2 halo or C 1-4 substituted with alkoxy); 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, or 5- to 6-membered heteroaryl or heterocycloalkyl (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)NR3 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 heteroaryl or heterocycloalkyl (O, S, N, and NR a and 0 to 4 R e ) and R 3 is hydrogen, C 1-4 Alkyl (0 to 4 R e (substituted with), C 3-6 Cycloalkyl, or heteroaryl or heterocycloalkyl (O, S, N, and NR 8 and 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 both attached form a 4- to 8-membered heteroaryl or heterocycloalkyl (O, S, N, and NR 8 and 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 heteroaryl or heterocycloalkyl (O, S, N, NR d and 0 to 5 R e ) and R c is C 1-3 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 heteroaryl or heterocycloalkyl (O, S, N, and NR g and 0 to 5 Rf ) and R f are halo, cyano, hydroxy, C 1-5 Alkyl, or C 3-6 is cycloalkyl; R g is hydrogen, C 1-5 is alkyl, heteroaryl, or heterocycloalkyl; n is 0; and 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 1 teeth [ka] and; Ar 2 teeth [ka] and; R 1 is halo, C 1-3 Alkyl, C 1-3 Alkoxy, 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- to 6-membered heteroaryl or heterocycloalkyl (O, S, N, and NR acontaining 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 heteroaryl or heterocycloalkyl (O, S, N, and NR a and 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 heteroaryl or heterocycloalkyl (O, S, N, and NR 8 and 0 to 3 R e ) and R 4 is hydrogen or C 1-2 Is it alkyl? Alternatively, R 3 and R 4 together with the nitrogen to which they are both attached form a 4- to 8-membered heteroaryl or heterocycloalkyl (O, S, N, and NR 8 and 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 6is 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, 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), or heteroaryl or heterocycloalkyl (O, S, N, NR d and 0 to 4 R e ) and R d is hydrogen or C 1-3 Alkyl (0 to 1 -OC) 1-4 alkyl-substituted); R e 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), -(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 heteroaryl or heterocycloalkyl (O, S, N, and NR g and 0 to 4 R f ) and Rf is halo, cyano, hydroxy, or C 1-5 is alkyl; R g is hydrogen or C 1-4 is alkyl; 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 (III) or a pharmaceutically acceptable salt thereof, wherein: Ar 1 but [ka] and; Ar 2 but [ka] and; R 1 is Cl, -CH3, -CF3, -OCH3, -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 3-6 Cycloalkyl, or heteroaryl or heterocycloalkyl (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 , -(CH2) r -C 3-6Cycloalkyl (0 to 2 R e substituted with), -(CH2) r -aryl (0 to 2 R e substituted with -(CH2) r heteroaryl or heterocycloalkyl (O, S, N, and NR a and 0 to 2 R e ) and R 3 is hydrogen, C 1-4 Alkyl (0 to 3 R e substituted with), or heteroaryl or heterocycloalkyl (O, S, N, and NR 8 and 0 to 3 R e ) and R 4 is hydrogen or C 1-2 Is it alkyl? Alternatively, R 3 and R 4 together with the nitrogen to which they are both attached form a 4- to 8-membered heteroaryl or heterocycloalkyl (O, S, N, and NR 8 and 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 C 1-3 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 1-3 is alkyl; R a is hydrogen, C 1-4Alkyl (0 to 3 R e ) and R b is hydrogen, C 1-4 Alkyl (0 to 3 R e substituted with), or heteroaryl or heterocycloalkyl (O, S, N, and NR d and 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 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), C 3-6 Cycloalkyl (0 to 3 R f substituted with), or heteroaryl or heterocycloalkyl (O, S, N, and NR g and 0 to 3 R f ) and R f is halo, cyano, hydroxy, or C 1-4 is alkyl; and R g is hydrogen or C 1-3 is alkyl, The compound or a pharmaceutically acceptable salt thereof.

[0016] Another aspect of the present invention is a compound of Formula (I)-(III), or a pharmaceutically acceptable salt thereof, wherein: Ar 2 but [ka] and; R 2 is F, Cl, CH2OH, CH3, CF3, or CHF2; and 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 compound or a pharmaceutically acceptable salt thereof.

[0017] Another aspect of the present invention is a compound of formula (IV): [ka] [In formula: Ar 1 teeth [ka] and; R 1 is Cl, CH3, -CF3, -CHF2, -OCH3, -OCHF2, or -OCF3; R 2 is cyano, F, Cl, -CH3, -OCH3, -CF3, -CHF2, -CF3, or -NHC(O)CH3; R 2a -CH3, CHF2, -CH2CH3, -CH2CN, -CH2CHF2, -CH2CH2OCH3, -CH2CH(OH)CF3, -CH2CH(OH)CH3, -CH2CH2OH, -CF2CH2OH, -CH2CH(CH3)OH, -CH2CH2CF3, -CH(CH2OH)CH2OCH3, -CH(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)2C1-4 Alkyl, -CHR d C(O)NR 3 R 4 , -(CH2) 0-1 -C 3-6 cycloalkyl, [ka] Selected from -(CH2) 0-3 -heterocycloalkyl; R 3 and R 4 and together with the nitrogen to which they are both attached, [ka] forming a heterocycloalkyl 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, -CHF2, -CF3, or -CH2OH; R 7 is hydrogen or -CH3; R 8 is hydrogen, C 1-2 Alkyl, or -S(O)2C 1-3 is alkyl; and R d is -CH2OCH3] or a pharmaceutically acceptable salt thereof.

[0018] Another aspect of the present invention is a compound of formula (V): [ka] [In formula: R 1 is Cl or -OCH3; R 2is cyano, F, Cl, -CH3, -OCH3, -CF3, -CHF2, or -CF3; R 2a -CH3, CHF2, -CH2CH3, -CH2CN, -CH2CHF2, -CH2CH2OCH3, -CH2CH(OH)CF3, -CH2CH(OH)CH3, -CH2CH2OH, -CF2CH2OH, -CH2CH(CH3)OH, -CH2CH2CF3, -CH(CH2OH)CH2OCH3, -CH(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, [ka] Selected from -(CH2) 0-3 -heterocycloalkyl; R 3 and R 4 and together with the nitrogen to which they are both attached, [ka] forming a heterocycloalkyl 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, -CHF2, -CF3, or -CH2OH; R 7 is hydrogen or -CH3; R 8 is hydrogen, C 1-2Alkyl, or -S(O)2C 1-3 is alkyl; and R d is -CH2OCH3] or a pharmaceutically acceptable salt thereof.

[0019] Another aspect of the present invention is a compound of formula (VI): [ka] [In formula: Ar 1 teeth [ka] and; R 1 is Cl, -CF3, CHF2, -OCHF2, -OCH3, 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 or C 1-4 Alkyl (0 to 3 R e is replaced by ), or [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 heterocycloalkyl selected from: R5a 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 -CH3; R 8 is hydrogen, C 1-4 Alkyl, or -S(O)2C 1-3 is alkyl; and R e is halo, -OR g , -C(O)NR g R g , -S(O)C 1-4 alkyl, or heteroaryl or heterocycloalkyl (O, S, N, and NR g and 0 to 3 R f ) and R f is halo, cyano, hydroxy, or C 1-4 is alkyl; 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 (VII): [ka] [In formula: Ar 1 teeth [ka] and; R 1 is Cl, -CF3, CHF2, -OCHF2, -OCH3, or -OCF3; R 2is F, Cl, -CH2OH, -CH3, -CHF2, -CF3, -OCH3, or -OCH(CH3)2; R 5a is hydrogen or F; R 5b is hydrogen or F; R 5c is Cl or -OCH3; and R 7 is hydrogen or -CH3] or a pharmaceutically acceptable salt thereof.

[0021] Another aspect of the present invention is a compound of formula (VIII): [ka] [In formula: Ar 1 teeth [ka] and; R 1 is F, Cl, -CF3, CHF2, -OCHF2, -OCH3, or -OCF3; R 3 is hydrogen or C 1-4 Alkyl (0 to 2 R e ) 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 heterocycloalkyl selected from: R 5a is hydrogen or F; R 5b is hydrogen or F; R 5c is Cl or -OCH3; R 6is hydrogen, halo, hydroxy, oxo, -CH3, -CH2CH3, or -CH2OH; R 7 is hydrogen or -CH3; R 8 is hydrogen, C 1-4 Alkyl, or -S(O)2C 1-3 is alkyl; and R e -OH, -OC 1-4 Alkyl, -C(O)NHC 1-4 Alkyl, -S(O)2C 1-4 Alkyl, [ka] is] or a pharmaceutically acceptable salt thereof.

[0022] Another aspect of the present invention is a compound of formula (IX): [ka] [In formula: Ar 2 is pyridinyl or pyridinonyl, each of which is 0 to 2 R 2 is replaced by; Ar 3 is phenyl (three R 5 ) and R 1 is halo, C 1-4 Haloalkyl, or C 1-4 haloalkoxy; R 2 Cyano, halo, C 1-4 Alkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy or NR 3 R 4 Is it; R 3 and R 4which together with the nitrogen to which they are both attached form a 4- to 6-membered heterocyclic ring; and R 5 is halo, C 1-4 Alkyl, C 1-4 Haloalkyl, or C 1-4 Alkoxy] or a pharmaceutically acceptable salt thereof.

[0023] Another aspect of the present invention is a compound of formula (X): [ka] [In formula: Ar 2 are pyridinyl or pyridinonyl, each of which contains 0 to 2 R 2 is replaced by; Ar 3 is phenyl (three R 5 ) and R 1 is halo, C 1-4 Haloalkyl, or C 1-4 haloalkoxy; R 2 Cyano, halo, C 1-4 Alkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy or NR 3 R 4 Is it; R 3 and R 4 which, together with the nitrogen to which they are attached, form a 4- to 6-membered heterocyclic ring; R 5 is halo, C 1-4 Alkyl, C 1-4 Haloalkyl, or C 1-4 is alkoxy; and n is 0 or 1] or a pharmaceutically acceptable salt thereof.

[0024] Another aspect of the present invention is a compound of formula (XI): [ka] [In formula: Ar 2 are pyridinyl or pyridinonyl, each of which contains 0 to 2 R 2 is replaced by; Ar 3 is phenyl (three R 5 ) and R 1 is halo, C 1-4 Haloalkyl, or C 1-4 haloalkoxy; R 2 Cyano, halo, C 1-4 Alkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy or NR 3 R 4 and; R 3 and R 4 which together with the nitrogen to which they are both attached form a 4- to 6-membered heterocyclic ring; and R 5 is halo, C 1-4 Alkyl, C 1-4 Haloalkyl, or C 1-4 Alkoxy] or a pharmaceutically acceptable salt thereof.

[0025] Another aspect of the present invention is a compound of formula (XII): [ka] [In formula: Ar 2 are pyridinyl or pyridinonyl, each of which contains 0 to 2 R 2 is replaced by; Ar 3 is phenyl (three R 5) and X is CH2 or O; R 1 is halo, C 1-4 Haloalkyl, or C 1-4 haloalkoxy; R 1a is methyl; R 2 Cyano, halo, C 1-4 Alkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, or NR 3 R 4 and; R 3 and R 4 which together with the nitrogen to which they are both attached form a 4- to 6-membered heterocyclic ring; and R 5 is halo, C 1-4 Alkyl, C 1-4 Haloalkyl, or C 1-4 Alkoxy] or a pharmaceutically acceptable salt thereof.

[0026] Another aspect of the present invention is a compound of formula (XIII): [ka] [In formula: Ar 2 teeth [ka] and; X is CH2 or O; R 1 is halo, C 1-4 Haloalkyl, or C 1-4 haloalkoxy; R 1a is methyl; R 2 Cyano, halo, C 1-4 Alkyl, C1-4 Hydroxyalkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, NR 3 R 4 and; R 3 and R 4 which, together with the nitrogen to which they are attached, form a 4- to 6-membered heterocyclic ring; R 5a is a halo; R 5b is a halo; and R 5c is C 1-2 Alkoxy] or a pharmaceutically acceptable salt thereof.

[0027] Another aspect of the present invention is a compound of formula (XIV): [ka] [In formula: Ar 2 teeth [ka] and; X is CH2 or O; R 1 is halo, C 1-4 Haloalkyl, or C 1-4 haloalkoxy; R 1a is methyl; R 2 Cyano, halo, C 1-4 Alkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, or NR 3 R 4 and; R 3 and R 4which, together with the nitrogen to which they are attached, form a 4- to 6-membered heterocyclic ring; R 5a is a halo; R 5b is a halo; R 5c is C 1-2 is alkoxy; and R 7 is hydrogen or methyl] or a pharmaceutically acceptable salt thereof.

[0028] Another aspect of the present invention is a compound of formula (IIa): [ka] [In formula: Ar 1 teeth [ka] and; Ar 2 is C 3-6 cycloalkyl, phenyl, 5- to 6-membered heteroaryl or heterocycloalkyl (1-2 N or NR 2a each of which contains 0 to 2 R 2 is replaced by; Ar 3 is phenyl (one R 5a , 1 R 5b , and one R 5c ) and R 1 is halo, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 haloalkoxy, or phenyl (0-2 halo or C 1-4 substituted with alkoxy); R 2 are oxo, cyano, halo, C 1-5 Alkyl (0 to 5 R e (replaced with), -OR b , -NR 3 R4 , -NR 4 C(O)R b , (C 1-3 alkyl)2(O)P-, C 3-6 Cycloalkyl, aryl, or 5- to 6-membered heteroaryl or heterocycloalkyl (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 heteroaryl or heterocycloalkyl (O, S, N, and NR a and 0 to 4 R e ) and R 3 is hydrogen, C 1-4 Alkyl (0 to 4 R e (substituted with), C 3-6 Cycloalkyl, or heteroaryl or heterocycloalkyl (O, S, N, and NR 8 and 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 both attached form a 4- to 8-membered heteroaryl or heterocycloalkyl (O, S, N, and NR 8and 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 heteroaryl or heterocycloalkyl (O, S, N, NR d and 0 to 5 R e ) and R c is C 1-3 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 Rg , -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 heteroaryl or heterocycloalkyl (O, S, N, and NR g and 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 heteroaryl or heterocycloalkyl; n is 0; and r is 0, 1, 2, or 3] or a pharmaceutically acceptable salt thereof.

[0029] Another aspect of the present invention is a compound of formula (IIIa): [ka] [In formula: Ar 1 teeth [ka] and; Ar 2 teeth [ka] and; R 1 is halo, C 1-3 Alkyl, C 1-3 Alkoxy, C1-3 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- to 6-membered heteroaryl or heterocycloalkyl (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 heteroaryl or heterocycloalkyl (O, S, N, and NR a and 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 heteroaryl or heterocycloalkyl (O, S, N, and NR 8 and 0 to 3 R e ) and R 4 is hydrogen or C 1-2 Is it alkyl? Alternatively, R 3 and R 4 together with the nitrogen to which they are both attached form a 4- to 8-membered heteroaryl or heterocycloalkyl (O, S, N, and NR 8 and 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, 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), or heteroaryl or heterocycloalkyl (O, S, N, NR d and 0 to 4 R e ) and R d is hydrogen or C 1-3 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 heteroaryl or heterocycloalkyl (O, S, N, and NR g and 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; and r is 0, 1, or 2] or a pharmaceutically acceptable salt thereof.

[0030] Another aspect of the present invention is a compound of formula (IIIa) or a pharmaceutically acceptable salt thereof, wherein: Ar 1 but [ka] and; Ar 2 but [ka] and; R 1 is Cl, -CH3, -CF3, -OCH3, -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)Rb , (C 1-2 alkyl)2(O)P-, C 3-6 Cycloalkyl, heteroaryl, or heterocycloalkyl (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 , -(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 heteroaryl or heterocycloalkyl (O, S, N, and NR a and 0 to 2 R e ) and R 3 is hydrogen, C 1-4 Alkyl (0 to 3 R e substituted with), or heteroaryl or heterocycloalkyl (O, S, N, and NR 8 and 0 to 3 R e ) and R 4 is hydrogen or C 1-2 Is it alkyl? Alternatively, R 3 and R 4 together with the nitrogen to which they are both attached form a 4- to 8-membered heteroaryl or heterocycloalkyl (O, S, N, and NR 8 and 1 to 3 R 6 (substituted with); R 5a is hydrogen, F, or Cl; R 5bis hydrogen, F, or Cl; R 5c is Cl or -OCH3; R 6 is hydrogen, halo, oxo, hydroxy, or C 1-3 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 1-3 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), or heteroaryl or heterocycloalkyl (O, S, N, and NR d and 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 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), C 3-6 Cycloalkyl (0 to 3 R f substituted with), or heteroaryl or heterocycloalkyl (O, S, N, and NR g and 0 to 3 R f ) and R fis halo, cyano, hydroxy, or C 1-4 is alkyl; R g is hydrogen or C 1-3 is alkyl, The compound or a pharmaceutically acceptable salt thereof.

[0031] Another aspect of the present invention is a compound of formula (IIa)-(IIIa) 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 compound or a pharmaceutically acceptable salt thereof.

[0032] Another aspect of the present invention is a compound of formula (IVa): [ka] [In formula: Ar 1 teeth [ka] and; R 1 is Cl, CH3, -CF3, -CHF2, -OCH3, -OCHF2, or -OCF3; R 2is cyano, F, Cl, -CH3, -OCH3, -CF3, -CHF2, -CF3, or -NHC(O)CH3; R 2a -CH3, CHF2, -CH2CH3, -CH2CN, -CH2CHF2, -CH2CH2OCH3, -CH2CH(OH)CF3, -CH2CH(OH)CH3, -CH2CH2OH, -CF2CH2OH, -CH2CH(CH3)OH, -CH2CH2CF3, -CH(CH2OH)CH2OCH3, -CH(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, [ka] Selected from -(CH2) 0-3 -heterocycloalkyl; R 3 and R 4 and together with the nitrogen to which they are both attached, [ka] forming a heterocycloalkyl 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, -CHF2, -CF3, or -CH2OH; R 7 is hydrogen or -CH3; R 8 is hydrogen, C 1-2Alkyl, or -S(O)2C 1-3 is alkyl; R d is -CH2OCH3] or a pharmaceutically acceptable salt thereof.

[0033] Another aspect of the present invention is a compound of formula (Va): [ka] [In formula: R 1 is Cl or -OCH3; R 2 is cyano, F, Cl, -CH3, -OCH3, -CF3, -CHF2, or -CF3; R 2a -CH3, CHF2, -CH2CH3, -CH2CN, -CH2CHF2, -CH2CH2OCH3, -CH2CH(OH)CF3, -CH2CH(OH)CH3, -CH2CH2OH, -CF2CH2OH, -CH2CH(CH3)OH, -CH2CH2CF3, -CH(CH2OH)CH2OCH3, -CH(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, [ka] Selected from -(CH2) 0-3 -heterocycloalkyl; R 3 and R 4 and together with the nitrogen to which they are both attached, [ka] forming a heterocycloalkyl 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, -CHF2, -CF3, or -CH2OH; R 7 is hydrogen or -CH3; R 8 is hydrogen, C 1-2 Alkyl, or -S(O)2C 1-3 is alkyl; R d is -CH2OCH3] or a pharmaceutically acceptable salt thereof.

[0034] Another aspect of the present invention is a compound of formula (VIa): [ka] [In formula: Ar 1 teeth [ka] and; R 1 is Cl, -CF3, CHF2, -OCHF2, -OCH3, 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 or C 1-4 Alkyl (0 to 3 Re ), [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 heterocycloalkyl 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 -CH3; R 8 is hydrogen, C 1-4 Alkyl, or -S(O)2C 1-3 is alkyl; R e is halo, -OR g , -C(O)NR g R g , -S(O)C 1-4 Alkyl, heteroaryl, or heterocycloalkyl (O, S, N, and NR g and 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 alkyl] or a pharmaceutically acceptable salt thereof.

[0035] Another aspect of the present invention is a compound of formula (VIIa): [ka] [In formula: Ar 1 teeth [ka] and; R 1 is Cl, -CF3, CHF2, -OCHF2, -OCH3, or -OCF3; R 2 is F, Cl, -CH2OH, -CH3, -CHF2, -CF3, -OCH3, or -OCH(CH3)2; R 5a is hydrogen or F; R 5b is hydrogen or F; R 5c is Cl or -OCH3; R 7 is hydrogen or -CH3] or a pharmaceutically acceptable salt thereof.

[0036] Another aspect of the present invention is a compound of formula (VIIIa): [ka] [In formula: Ar 1 teeth [ka] and; R 1 is F, Cl, -CF3, CHF2, -OCHF2, -OCH3, or -OCF3; R 3 is hydrogen or C 1-4 Alkyl (0 to 2 R e ) and R 4 is hydrogen; Alternatively, R 3 and R4 and together with the nitrogen to which they are both attached, [ka] forming a heterocycloalkyl 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, hydroxy, oxo, -CH3, -CH2CH3, or -CH2OH; R 7 is hydrogen or -CH3; R 8 is hydrogen, C 1-4 Alkyl, or -S(O)2C 1-3 is alkyl; R e -OH, -OC 1-4 Alkyl, -C(O)NHC 1-4 Alkyl, -S(O)2C 1-4 Alkyl, [ka] is] or a pharmaceutically acceptable salt thereof.

[0037] Another aspect of the present invention is a compound of formula (XIIIa): [ka] [In formula: Ar 2 teeth [ka] and; X is CH2 or O; R 1 is halo, C 1-4 Haloalkyl, or C 1-4 haloalkoxy; R 1a is methyl; R 2 Cyano, halo, C 1-4 Alkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, NR 3 R 4 and; R 3 and R 4 which, together with the nitrogen to which they are attached, form a 4- to 6-membered heterocyclic ring; R 5a is a halo; R 5b is a halo; R 5c is C 1-2 Alkoxy] or a pharmaceutically acceptable salt thereof.

[0038] Another aspect of the present invention is a compound of formula (XIVa): [ka] [In formula: Ar 2 teeth [ka] and; X is CH2 or O; R 1 is halo, C 1-4 Haloalkyl, or C 1-4 haloalkoxy; R 1a is methyl; R 2 Cyano, halo, C 1-4 Alkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4Haloalkoxy, or NR 3 R 4 and; R 3 and R 4 which, together with the nitrogen to which they are attached, form a 4- to 6-membered heterocyclic ring; R 5a is a halo; R 5b is a halo; R 5c is C 1-2 Alkoxy; R 7 is hydrogen or methyl] or a pharmaceutically acceptable salt thereof.

[0039] For compounds of formula (I), (II), (III), (IIIa), (IV), (IV2), (V), (Va), (VI), (VIa), (VII), (VIIa), (VIII), (VIIIa), (IX), (X), (XI), (XII), (XIII), (XIIIa), (XIV), or (XIVa), Ar 1 , Ar 2 , Ar 3 , R 1 (R 1a ), R 2 , R 3 , R 4 , R 5 (R 5a , R 5b and R 5c ), R 6 , R 7 , 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.

[0040] Unless otherwise specified, these terms have the following meanings: "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. "Cycloalkyl" means a monocyclic ring system of 3 to 7 carbons. Terms with a hydrocarbon moiety (e.g., alkoxy) include both straight and 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. "Aryl" means a monocyclic or bicyclic aromatic hydrocarbon group of 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. "Heteroaryl" refers to a 5- to 7-membered monocyclic or 8- to 11-membered bicyclic aromatic ring system having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. If the position of attachment is not specified, the attachment may be made at any suitable position, as understood by those skilled in the art. Combinations of substituents and bonding patterns are limited to those that result in stable compounds, as understood by those skilled in the art. Parentheses and multiple parentheses are intended to clarify the bond relationship to those skilled in the art. For example, the term ((R)alkyl) refers to an alkyl substituent further substituted with the substituent R.

[0041] As used herein, "heterocycloalkyl" refers to a non-aromatic monocyclic or polycyclic heterocycle having one or more ring-forming heteroatoms selected from O, N, or S. Heterocycloalkyl groups also include spirocycles and bridged rings, e.g., bridged 5- to 8-membered heterocycloalkyl rings optionally substituted with 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur. Exemplary heterocycloalkyl groups include pyrrolidin-2-one, 1,3-isoxazolidin-2-one, pyranyl, tetrahydrofuran, oxetanyl, azetidinyl, morpholine, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, isopropyl, ... Midazolidinyl, azepanyl, benzazapene, azabicyclo[3.1.0]hexanyl, diazabicyclo[3.1.0]hexanyl, oxabicyclo[2.1.1]hexanyl, azabicyclo[2.2.1]heptanyl, diazabicyclo[2.2.1]heptanyl, azabicyclo[3.1.1]heptanyl, diazabicyclo[3.1.1]heptanyl, azabicyclo[3.2.1]octanyl, di Azabicyclo[3.2.1]octanyl, oxabicyclo[2.2.2]octanyl, azabicyclo[2.2.2]octanyl, azaadamantanyl, diazaadamantanyl, oxa-adamantanyl, azaspiro[3.3]heptanyl, diazaspiro[3.3]heptanyl, oxa-azaspiro[3.3]heptanyl, azaspiro[3.4]octanyl, diazaspiro[3.4]octanyl, ox Examples include sa-azaspiro[3.4]octanyl, azaspiro[2.5]octanyl, diazaspiro[2.5]octanyl, azaspiro[4.4]nonanyl, diazaspiro[4.4]nonanyl, oxa-azaspiro[4.4]nonanyl, azaspiro[4.5]decanyl, diazaspiro[4.5]decanyl, diazaspiro[4.4]nonanyl, oxa-diazaspiro[4.4]nonanyl, and chroman.The ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally substituted with oxo or sulfido (e.g., C(O), S(O), C(S), or S(O)2, etc.). A heterocycloalkyl group can be bonded through a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, a heterocycloalkyl group has 0 to 3 double bonds. In some embodiments, a heterocycloalkyl group contains 0 to 2 double bonds. A heterocycloalkyl group containing a fused aromatic ring can be bonded through any atom forming the ring, including the ring-forming atoms of the fused aromatic ring. In some embodiments, a heterocycloalkyl is a monocyclic or bicyclic 4-10-membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur and having one or more oxidized ring members.

[0042] As used herein, "cycloalkyl" refers to a non-aromatic cyclic hydrocarbon, including cyclized alkyl and / or alkenyl groups. Cycloalkyl groups can include monocyclic or polycyclic (e.g., 2, 3, or 4 fused rings), spirocycles, and bridged rings. The ring-forming carbon atoms of a cycloalkyl group can be optionally substituted with oxo or sulfido (e.g., C(O) or C(S)). Also included within the definition of cycloalkyl are moieties having one or more aromatic rings fused (i.e., covalently bonded) to the cycloalkyl ring, e.g., benzo or thienyl derivatives such as cyclopentane, cyclohexane, and the like. Cycloalkyl groups containing fused aromatic rings can be bonded through any ring-forming atom, including the ring-forming atoms of the fused aromatic ring. Cycloalkyl groups can include 3, 4, 5, 6, 7, 8, 9, or 10 ring-forming carbon atoms (C 3-10 In some embodiments, cycloalkyl can have C 3-10 In some embodiments, cycloalkyl is C 3-7 In some embodiments, the cycloalkyl is C4-10 It is a spirocycle or bridged cycloalkyl. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbomyl, norpinyl, norcamyl, cubane, adamantane, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, bicyclo[2.2.2]octanyl, spiro[3.3]heptanyl, and the like. In some embodiments, the cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0043] "Cycloalkylalkyl" refers to an alkyl group in which at least one hydrogen atom is replaced with a cycloalkyl group, as defined herein.

[0044] 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.

[0045] 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.

[0046] 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 14 Isotopically 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.

[0047] 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.

[0048] 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 a 384-well Proxiplate (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.

[0049] 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.

[0050] Table 1 [Table 1] [Table 2] [Table 3]

[0051] 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.

[0052] 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. Some subjects include humans of an age that is a risk factor 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 ovarian 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.

[0053] Another aspect of the present invention is a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) 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 formula (I) in combination with at least one other therapeutic agent and a pharmaceutical carrier.

[0054] "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, includes adjuvants, excipients or vehicles such as diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants and dispersing agents, depending on the characteristics of the administration method and the dosage form.

[0055] 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).

[0056] 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.

[0057] 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 formula (I). 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.

[0058] 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.

[0059] In one embodiment, the present invention provides the use of a compound of Formula (I)-(XIVa) 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.

[0060] In one embodiment, the present invention provides the use of a compound of Formula (I)-(XIVa) 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)-(XIVa) for treating heart failure, wherein the compound is administered in an amount therapeutically effective to increase contractility in the left ventricle.

[0061] In yet another embodiment, the present invention provides use of a compound of Formula (I)-(XIVa) 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 Formula (I)-(XIVa) in combination with other therapeutic agents.

[0062] 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.

[0063] 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.

[0064] 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.

[0065] 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.

[0066] 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.

[0067] 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.

[0068] The compounds of the present invention may be used 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 (e.g., cholestyramine or colestipol)), low-density lipoprotein receptor inducers, clofibrate, fenofibrate, benzofibrate, sipofibrate, gemfibrizol, vitamin B6, vitamin B 12 , antioxidant vitamins, beta-blockers, antidiabetic agents, angiotensin II antagonists, angiotensin converting enzyme inhibitors, platelet aggregation inhibitors, fibrinogen receptor antagonists, aspirin and fibric acid derivatives.

[0069] 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.

[0070] 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.

[0071] 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).

[0072] 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.

[0073] 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).

[0074] 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.

[0075] [Table 4]

[0076] 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.

[0077] The present disclosure is not limited to the illustrative embodiments described above, which are to be considered in all respects as illustrative and not restrictive, and all modifications that come within the meaning and range of equivalency of the claims are therefore intended to be embraced. 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).

[0078] A compound represented by the general formula (I'), (II') or (III') (wherein A, B and C are each Ar 2 , Ar 3 and Ar 1 ) can be prepared by one or more of the following synthetic schemes: [ka]

[0079] The 1-arylpyrrolidinone compounds of the present invention (wherein rings A and B are substituted phenyl or heteroaryl rings) can be prepared by the general route shown in Scheme 1. Compound 1a was synthesized by the procedure reported in the patent literature (WO2015079692). Compound 1b (PG is a protecting group such as Boc or a Cbz compound) was synthesized by the Curtius rearrangement, for example, by treating 1a with a tertiary amine such as diphenylphosphoryl azide (DPPA) and triethylamine (TEA). Subsequent addition of benzyl alcohol afforded the Cbz-protected compound 1b. Copper- or Pd-catalyzed coupling of 1b to a substituted 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, affords the desired compound 1c. Suitable heteroaryl halides are either commercially available or can be readily obtained from the corresponding readily available starting materials by methods known to those skilled in the art. Additional methods for this transformation include Ullmann, Goldberg, and Buchwald copper-catalyzed amidation or other variations of Buchwald's Pd-catalyzed C-N coupling, depending on the nature of ring B, and these types of couplings are accomplished using methods known to those skilled in the art (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). Removal of the protecting group from 1c followed by condensation of the resulting free amine with an appropriately substituted aryl or cycloalkyl isocyanate, or cycloalkyl isocyanate, or cycloalkyl acid can give urea 1d.Suitable isocyanates or cycloalkyl acids are either commercially available or readily obtainable by methods known to those skilled in the art.

[0080] Similarly, 1-arylpyrrolidinone compounds of the present invention (formula (I'), (II'), or (III')) where rings A and B are substituted phenyl or heteroaryl rings can be prepared by the general route shown in Scheme 2.

[0081] Scheme 1 [ka]

[0082] Scheme 2 [ka]

[0083] 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).

[0084] 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.

[0085] 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

[0086] 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

[0087] 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

[0088] 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

[0089] Method E: Kinetex biphenyl (4.6x100) mm, 2.6 μm particles; Solvent A: 95% buffer (0.05% TFA in water), 5% acetonitrile; Solvent B: 95% acetonitrile, 5% buffer (0.05% TFA in water); 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

[0090] Method F: Ascentis Express C18, 2.1 x 50 mm, 2.7 μm particles; Solvent A: 95% water, 5% acetonitrile + 10 mM ammonium formate; Solvent B: 95% acetonitrile, 5% water + 10 mM ammonium formate; 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

[0091] SFC and Chiral Purification Methods Method A: DAD-1: Chiralpak IA (250*4.6) mm, 5 μm; DAD-2: Chiralpak IB (250*4.6) mm, 5 μm. Co-solvent: 0.2% ammonia in acetonitrile:methanol (1:1). Method B: DAD-1: Chiralpak IC (250*4.6) mm, 5 μm; DAD-2: Chiralpak ID (250*4.6) mm, 5 μm. Co-solvent: 0.2% ammonia in acetonitrile:methanol (1:1). Method C: DAD-1: Chiralpak IE (250*4.6) mm, 5 μm; DAD-2: Chiralpak IF (250*4.6) mm, 5 μm. Co-solvent: 0.2% ammonia in acetonitrile:methanol (1:1).

[0092] 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.

[0093] Intermediate 1: 4-(2-chloro-3-(trifluoromethyl)pyridin-4-yl)morpholine [ka]

[0094] To a stirred solution of 2,4-dichloro-3-(trifluoromethyl)pyridine (500 mg, 2.3 mmol) in 1,2-dichloroethane (5 mL) were added morpholine (202 mg, 2.32 mmol) and CsCO (754 mg, 2.32 mmol). The reaction mixture was heated at 80 °C for 16 h. The reaction mixture was then cooled and filtered through a Celite pad. The filtrate was concentrated under reduced pressure to give the crude compound, which was purified by Combiflash chromatography (24 g silica gel column; petroleum ether-ethyl acetate as eluent). The desired product was eluted with 80-90% ethyl acetate in petroleum ether. Pure fractions were evaporated under reduced pressure to give 4-(2-chloro-3-(trifluoromethyl)pyridin-4-yl)morpholine (200 mg, 0.75 mmol, 32% yield) as a pale yellow solid. Two regioisomers were formed in a 7:3 ratio. The structure of the major isomer was confirmed by NOE experiments. MS(ESI) m / z: 267.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ =8.23(d,J=5.8Hz,1H), 6.85(d,J=5.8Hz,1H), 3.87-3.82(m,4H), 3.20-3.14(m,4H)

[0095] Intermediate 2: tert-butyl ((3S,4R)-4-(2,6-difluoro-4-methoxyphenyl)-1-(4-morpholino-3-(trifluoromethyl)pyridin-2-yl)-2-oxopyrrolidin-3-yl)carbamate [ka]

[0096] To a stirred solution of tert-butyl ((3S,4R)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl)carbamate (200 mg, 0.584 mmol) in 1,4-dioxane (3 mL) at room temperature, 4-(2-chloro-3-(trifluoromethyl)pyridin-4-yl)morpholine (171 mg, 0.643 mmol), CsCO (381 mg, 1.17 mmol), and Xantphos (67.6 mg, 0.117 mmol) were added. The reaction mixture was purged with nitrogen for 5 minutes and then charged with Pd(dba) (54 mg, 0.058 mmol). The reaction mixture was purged with nitrogen again for 3 minutes and heated at 100° C. for 16 hours. The brown reaction mixture was cooled and filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure to give the crude compound, which was purified by silica gel chromatography (12 g silica gel column; petroleum ether-ethyl acetate as eluent). The desired product was eluted with 80% ethyl acetate in petroleum ether. Pure fractions were evaporated under reduced pressure to give tert-butyl ((3S,4R)-4-(2,6-difluoro-4-methoxyphenyl)-1-(4-morpholino-3-(trifluoromethyl)pyridin-2-yl)-2-oxopyrrolidin-3-yl)carbamate (200 mg, 0.35 mmol, 60% yield) as a pale yellow solid. MS (ESI) m / z: 573.2 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ =8.45(d,J=5.7Hz,1H), 7.34(brs,1H), 7.21(d,J=6.0Hz,1H), 6.87-6.77(m,2H), 4.57-4.43(m,1H), 4.35-4.16(m,1H), 4.13-3.95(m,2H), 3.79(s,3H), 3.86-3.62(m,4H), 3.32-3.01(m,4H), 1.33(s,9H)

[0097] Intermediate 3: (3S,4R)-3-amino-4-(2,6-difluoro-4-methoxyphenyl)-1-(4-morpholino-3-(trifluoromethyl)pyridin-2-yl)pyrrolidin-2-one hydrochloride [ka]

[0098] To a stirred solution of tert-butyl ((3S,4R)-4-(2,6-difluoro-4-methoxyphenyl)-1-(4-morpholino-3-(trifluoromethyl)pyridin-2-yl)-2-oxopyrrolidin-3-yl)carbamate (0.20 g, 0.35 mmol) in 1,4-dioxane (2 mL) at 0° C. was added 4 M HCl in 1,4-dioxane (0.87 mL, 3.5 mmol). The reaction mixture was stirred at room temperature for an additional 3 hours and concentrated under reduced pressure to give the crude compound, which was triturated with diethyl ether to give (3S,4R)-3-amino-4-(2,6-difluoro-4-methoxyphenyl)-1-(4-morpholino-3-(trifluoromethyl)pyridin-2-yl)pyrrolidin-2-one·HCl (160 mg, 0.31 mmol, 90% yield) as a pale yellow solid. MS (ESI) m / z: 473.3 [M+H] +

[0099] Intermediate 4: Methyl 2-(3-bromo-2-oxopyridin-1(2H)-yl)-3-methoxypropanoate [ka]

[0100] To a stirred solution of 3-bromopyridin-2(1H)-one (5.0 g, 29 mmol) in DMF (30 mL) at room temperature, K2CO3 (12 g, 86 mmol) and methyl 2-bromo-3-methoxypropanoate (5.8 mL, 43 mmol) were added. The reaction mixture was then stirred at room temperature for an additional 16 hours. The reaction mixture was cooled, filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to give the crude compound, which was purified by silica gel chromatography (24 g silica gel column; petroleum ether-ethyl acetate as eluent). The desired product was eluted with 60% ethyl acetate in petroleum ether to give methyl 2-(3-bromo-2-oxopyridin-1(2H)-yl)-3-methoxypropanoate (4.5 g, 16 mmol, 54% yield) as a white solid. MS (ESI) m / z: 290.0 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ =7.97(d,J=7.0Hz,1H), 7.76(d,J=7.0Hz,1H), 6.33-6.17(m,1H), 5.51-5.38(m,1H) , 4.10-3.97(m,1H), 3.94-3.84(m,1H), 3.67(s,3H), 3.35-3.27(m,1H), 3.25(s,3H)

[0101] Intermediate 5: 3-Bromo-1-(1-hydroxy-3-methoxypropan-2-yl)pyridin-2(1H)-one [ka]

[0102] To a stirred solution of methyl 2-(3-bromo-2-oxopyridin-1(2H)-yl)-3-methoxypropanoate (1.0 g, 3.5 mmol) in MeOH (10 mL) at 0 °C was added sodium borohydride (0.2 g, 5.2 mmol). The reaction mixture was allowed to warm gradually to room temperature over 3 hours and quenched with water. The reaction mixture was then extracted with ethyl acetate. The organic layers were combined, washed with saturated aqueous NH4Cl, brine, dried over Na2SO4, and concentrated under reduced pressure to give crude 3-bromo-1-(1-hydroxy-3-methoxypropan-2-yl)pyridin-2(1H)-one (0.85 g, 3.2 mmol, 94% yield) as a white solid. MS (ESI) m / z: 262.0 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ =7.90-7.87(m,1H), 7.74-7.71(m,1H), 6.21-6.16(m,1H), 5.05-4.99(m,2H), 3.78-3.55(m,4H), 3.22(s,3H)

[0103] Intermediate 6: tert-butyl ((3S,4R)-4-(2,6-difluoro-4-methoxyphenyl)-1-(1-(1-hydroxy-3-methoxypropan-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2-oxopyrrolidin-3-yl)carbamate [ka]

[0104] To a solution of tert-butyl ((3S,4R)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl)carbamate (250 mg, 0.73 mmol) in 1,4-dioxane (5 mL) stirred at room temperature, 3-bromo-1-(1-hydroxy-3-methoxypropan-2-yl)pyridin-2(1H)-one (191 mg, 0.730 mmol), cesium carbonate (476 mg, 1.46 mmol), and N,N'-dimethylethylenediamine (0.016 mL, 0.15 mmol) were added. The reaction mixture was purged with nitrogen for 5 minutes and then charged with copper(I) iodide (14 mg, 0.073 mmol). The reaction mixture was purged with nitrogen again for 3 minutes and heated at 100 ° C. for 16 hours. The reaction mixture was cooled and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to obtain the crude compound, which was purified by silica gel chromatography (24 g silica gel column; petroleum ether-ethyl acetate as eluent). The desired product was eluted with 75% ethyl acetate in petroleum ether to obtain tert-butyl ((3S,4R)-4-(2,6-difluoro-4-methoxyphenyl)-1-(1-(1-hydroxy-3-methoxypropan-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2-oxopyrrolidin-3-yl)carbamate (250 mg, 0.48 mmol, 65% yield) as a brown liquid. MS (ESI) m / z: 524.0 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ =7.70-7.66(m,1H), 7.56-7.49(m,1H), 7.33-7.27(m,1H), 6.84-6.75(m,2H), 6.35-6.29(m,1H), 5.08-5.01( m,2H), 4.52-4.45(m,1H), 3.79(s,3H), 3.76-3.59(m,4H), 3.58-3.55(m,3H), 3.23(s,3H), 1.37-1.21(m,9H)

[0105] Intermediate 7: 3-((3S,4R)-3-amino-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-1-yl)-1(1-hydroxy-3-methoxypropan-2-yl)pyridin-2(1H)-one hydrochloride [ka]

[0106] To a solution of tert-butyl ((3S,4R)-4-(2,6-difluoro-4-methoxyphenyl)-1-(1-(1-hydroxy-3-methoxypropan-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2-oxopyrrolidin-3-yl)carbamate (250 mg, 0.48 mmol) in 1,4-dioxane (5 mL) stirred at 0 ° C., 4 M HCl solution in 1,4-dioxane (1.2 mL, 4.8 mmol) was added. The reaction mixture was allowed to warm gradually to room temperature over 2 hours. The reaction mixture was then concentrated under reduced pressure to give a gummy solid, which was further triturated with diethyl ether and dried under high vacuum to give 3-((3S,4R)-3-amino-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-1-yl)-1-(1-hydroxy-3-methoxypropan-2-yl)pyridin-2(1H)-one hydrochloride (200 mg, 0.44 mmol, 91% yield) as a brown solid. MS (ESI) m / z: 424.2 [M+H] +

[0107] Intermediate 8: 6-Methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid [ka]

[0108] Compound 8 was chirally separated using chiral SFC. Enantiomers 8A and 8B were used in the reaction. SFC preparative conditions: Column / dimensions: Whelk (R,R) (250x30) mm, 5μ; % CO2: 90%, % cosolvent: 4M methanolic ammonia in 10% MeOH; total flow rate: 14.0 g / min; back pressure: 100 bar, temperature: 30°C, UV: 220 nm; retention times: Peak 1 = 3.8 min, and Peak 2 = 4.9 min. Enantiomer 8A: 1 H NMR (400MHz, DMSO-d6) δ =12.22(brs,1H), 7.00(d,J=8.3Hz,1H), 6.73-6.56(m,2H), 3.7(s,3H), 2.91-2.83( m,1H), 2.80-2.71(m,3H), 2.65-2.57(m,1H), 2.11-2.02(m,1H), 1.76-1.63(m,1H); Enantiomer 8B: 1 H NMR (400MHz, DMSO-d6) δ =12.22(brs,1H), 7.00(d,J=8.3Hz,1H), 6.70-6.61(m,2H), 3.7(s,3H), 2.91-2.82 (m,1H), 2.80-2.71(m,3H), 2.66-2.56(m,1H), 2.12-2.01(m,1H), 1.75-1.63(m,1H)

[0109] Example 1: 1-((3S,4R)-4-(2,6-difluoro-4-methoxyphenyl)-1-(4-morpholino-3-(trifluoromethyl)pyridin-2-yl)-2-oxopyrrolidin-3-yl)-3-((1r,4S)-4-(difluoromethyl)cyclohexyl)urea [ka]

[0110] To a stirred solution of (1R,4R)-4-(difluoromethyl)cyclohexane-1-carboxylic acid (50 mg, 0.28 mmol) in toluene (5 mL) and acetonitrile (1 mL), TEA (0.043 mL, 0.309 mmol) and diphenylphosphoryl azide (0.067 mL, 0.31 mmol) were added. The reaction mixture was stirred at room temperature for 3 hours, followed by stirring at 80° C. for 30 minutes. The reaction mixture was then cooled to room temperature, and Intermediate 3 (80 mg, 0.17 mmol) was added, and the mixture was stirred at room temperature for an additional 16 hours. The reaction mixture was filtered through a pad of Celite and evaporated under reduced pressure to give the crude product as a brown solid, which was purified by reverse phase HPLC to give 1-((3S,4R)-4-(2,6-difluoro-4-methoxyphenyl)-1-(4-morpholino-3-(trifluoromethyl)pyridin-2-yl)-2-oxopyrrolidin-3-yl)-3-((1r,4S)-4-(difluoromethyl)cyclohexyl)urea (10 mg, 0.015 mmol, 5.3% yield) as an off-white solid. MS(ESI) m / z: 643.3 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ =8.49-8.35(m,1H), 7.20(d,J=5.6Hz,1H), 6.77(d,J=10.8Hz,2H), 6.36-6.20 (m,1H), 6.04-5.92(m,1H), 5.84(dt,J=60.8, 4.0Hz,1H), 4.75(dd,J=11.0, 8. 8Hz,1H), 4.33-4.08(m,1H), 4.07-3.91(m,1H), 3.78(s,3H), 3.76-3.57(m,5H ), 3.27-3.06(m,5H), 1.91-1.79(m,1H), 1.77-1.58(m,4H), 1.19-0.94(m,4H)

[0111] Examples 2 and 3: 1-((3S,4R)-4-(2,6-difluoro-4-methoxyphenyl)-1-(1-(1-hydroxy-3-methoxypropan-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2-oxopyrrolidin-3-yl)-3-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)urea [ka]

[0112] To a stirred solution of 6-methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (70 mg, 0.34 mmol) (Intermediate 8A or 8B) in toluene (4 mL) and acetonitrile (1 mL) was added TEA (0.043 mL, 0.31 mmol) and diphenylphosphoryl azide (0.067 mL, 0.31 mmol). The reaction mixture was stirred at room temperature for 3 hours and then at 80° C. for 30 minutes. The reaction mixture was then cooled to room temperature, Intermediate 7 (156 mg, 0.339 mmol) was added, and the mixture was stirred at 60° C. for 6 hours. The reaction mixture was filtered through a pad of Celite and evaporated under reduced pressure to give the crude product as a brown solid, which was purified by reverse phase HPLC followed by chiral SFC to give 1-((3S,4R)-4-(2,6-difluoro-4-methoxyphenyl)-1-(1-(1-hydroxy-3-methoxypropan-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2-oxopyrrolidin-3-yl)-3-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)urea (pure HCl). Example 2, diastereomer A, 26 mg, 0.040 mmol, 13% yield) and 1-((3S,4R)-4-(2,6-difluoro-4-methoxyphenyl)-1-(1-(1-hydroxy-3-methoxypropan-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2-oxopyrrolidin-3-yl)-3-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)urea (Example 3, diastereomer B, 25 mg, 0.040 mmol, 13% yield) were obtained. SFC preparative conditions: Column / dimensions: Chiralpak IC (250x21) mm, 5μ; % CO2: 65%, % co-solvent: 35% 4M methanolic ammonia in MeOH; total flow rate: 90.0 g / min, back pressure: 100 bar, temperature: 35°C, UV: 222 nm; retention times: Peak 1 = 7.6 min, and Peak 2 = 10.1 min; Example 2, Diastereomer A: MS (ESI) m / z: 627.4 [M+H] + ;1 H NMR (400MHz, DMSO-d6) δ =7.67(dd,J=7.0, 1.9Hz,1H), 7.52(dd,J=7.1, 1.9Hz,1H), 6.93(d,J=8.3Hz,1H), 6.78(d,J=10.9Hz, 2H), 6.70-6.56(m,2H), 6.37-6.21(m,2H), 6.09(d,J=7.9Hz,1H), 5.05(m,2H), 4.73(m,1H), 3.95-3. 88(m,1H), 3.86-3.77(m,5H), 3.77-3.70(m,3H), 3.69(s,3H), 3.68-3.59(m,2H), 3.23(s,3H), 2.85- 2.71(m,3H), 2.44(m,1H), 1.93-1.81(m,1H), 1.62-1.51(m,1H); Example 3, Diastereomer B: MS(ESI) m / z:627.4 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ =7.67(dd,J=6.9, 1.9Hz,1H), 7.53(dd,J=7.2, 1.9Hz,1H), 6.93(d,J=8.4Hz,1H), 6.78(d,J=10.6Hz ,2H), 6.67(dd,J=8.0, 3.1Hz,1H), 6.65-6.57(m,1H), 6.38-6.26(m,2H), 6.10(d,J=7.6Hz,1H), 5.05 (m,2H), 4.79-4.68(m,1H), 3.93-3.78(m,3H), 3.79(s,3H), 3.77-3.70(m,3H),3.69(s,3H), 3.68-3 .59(m,2H), 3.23(s,3H), 2.84-2.72(m,3H), 2.46-2.39(m,1H), 1.92-1.82(m,1H), 1.64-1.51(m,1H)

[0113] The following examples listed in Table 2 were prepared using procedures similar to those set forth in Examples 1-3. Table 2 [Table 5] [Table 6] Table 7 Table 8 Table 9 Table 10 Table 11 Table 12 Table 13 Table 14 Table 15 Table 16 Table 17 Table 18 Table 19 Table 20 Table 21 Table 22 Table 23 Table 24 Table 25 Table 26 Table 27 Table 28 Table 29 Table 30 Table 31 Table 32 Table 33 Table 34 Table 35 Table 36 Table 37 Table 38 Table 39 Table 40 Table 41 Table 42 Table 43 Table 44 Table 45 Table 46 Table 47 Table 48 Table 49 Table 50 Table 51 Table 52 Table 53 Table 54 Table 55 Table 56 Table 57

[0114] 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: Ar １ are cycloalkyl, cycloalkylalkyl, aryl, or heterocycloalkyl, each of which is 0 to 3 R １ is replaced by; Ar ２ is a 6-membered heteroaryl or heterocycloalkyl (containing 1-2 N or NR 2a), each containing 0-3 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 Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, C １－４ haloalkoxy, or aryl (0-2 halo, C １－４ haloalkyl, or C １－４ substituted with alkoxy; 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- to 6-membered heteroaryl or heterocycloalkyl (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 -heteroaryl or -(CR ｄ R ｄ ) ｒ -heterocycloalkyl(O,S(O) ｐ , N, and NR ａ and 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 heteroaryl or heterocycloalkyl (O, S(O) ｐ , N, and NR ８ and 0 to 5 R ｅ substituted with R ４ is hydrogen or C １－４ Is alkyl; Alternatively, R ３ and R ４ together with the nitrogen to which they are both attached form a 4-9 membered heteroaryl or heterocycloalkyl (O, S(O) ｐ , N, and NR ８ and 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, 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 heteroaryl or heterocycloalkyl (O, S(O) ｐ , N, N.R. ｄ and 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 heteroaryl or heterocycloalkyl (O, S(O) ｐ , N, N.R. ｄ and 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 -heteroaryl or heterocycloalkyl (O, S(O) ｐ , N, and NR ｇ and 0 to 5 R ｆ substituted with R ｆ are halo, cyano, hydroxy, C １－５ Alkyl, C ３－６ cycloalkyl, or phenyl; R ｇ is hydrogen, C １－５ Alkyl, C ３－６ cycloalkyl, aryl, or heteroaryl or heterocycloalkyl; or R ｇ and R ｇ together with the nitrogen atom to which they are both attached form a heteroaryl or heterocycloalkyl; 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 １ teeth 【Transformation 3】 and Ar ２ is a 6-membered heteroaryl or heterocycloalkyl (1-2 N or NR ２ａ each containing 0 to 2 R ２ is replaced by; Ar ３ is phenyl (one R ５ａ , one R ５ｂ , and one R ５ｃ substituted with R １ Halo, C １－４ Alkyl, C １－４ Alkoxy, C １－４ Haloalkyl, C １－４ haloalkoxy, or phenyl (0-2 halo or C １－４ substituted with alkoxy; 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 heteroaryl or heterocycloalkyl (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 heteroaryl or heterocycloalkyl (O, S, N, and NR ａ and 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 heteroaryl or heterocycloalkyl (O, S, N, and NR ８ and 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 both attached form a 4- to 8-membered heteroaryl or heterocycloalkyl (O, S, N, and NR ８ and 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 heteroaryl or heterocycloalkyl (substituted with O, S, N, NR ｄ and 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 heteroaryl or heterocycloalkyl (O, S, N, and NR ｇ and 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 heteroaryl or heterocycloalkyl; 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): 【Chemistry 4】 [In the formula: Ar １ teeth 【Transformation 5】 and Ar ２ teeth 【Transformation 6】 and R １ Halo, C １－３ Alkyl, C １－３ Alkoxy, 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 heteroaryl or heterocycloalkyl (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 heteroaryl or heterocycloalkyl (O, S, N, and NR ａ and 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 heteroaryl or heterocycloalkyl (O, S, N, and NR ８ and 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 both attached form a 4- to 8-membered heteroaryl or heterocycloalkyl (O, S, N, and NR ８ and 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 substituted with), or heteroaryl or heterocycloalkyl (substituted with O, S, N, NR ｄ and 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 heteroaryl or heterocycloalkyl (O, S, N, and NR ｇ and 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.

3. The compound according to claim 2, which is represented by the formula: or a pharmaceutically acceptable salt thereof.

4. Ar １ but 【Transformation 7】 and Ar ２ but 【Transformation 8】 and R １ is Cl, -CH ３ , -CF ３ , -OCH 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 heteroaryl or heterocycloalkyl (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 heteroaryl or heterocycloalkyl (O, S, N, and NR ａ and 0 to 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 and 0 to 3 R ｅ substituted with 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 form a 4- to 8-membered heteroaryl or heterocycloalkyl (O, S, N, and NR ８ and 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 ７ is hydrogen or -CH ３ and 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 substituted with O, S, N, and NR ｄ and 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), C ３－６ Cycloalkyl (0 to 3 R ｆ substituted with O, S, N, and NR ｇ and 0 to 3 R ｆ substituted with R ｆ is halo, cyano, hydroxy, or C １－４ alkyl; R ｇ is hydrogen or C １－３ alkyl] 4. The compound according to claim 3, which is represented by the formula: or a pharmaceutically acceptable salt thereof.

5. Ar ２ but 【Chemistry 9】 and R ２ is F, Cl, CH ２ OH, CH ３ , C.F. ３ , or CHF ２ and R ２ａ is -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 is, 5. The compound of claim 4 or a pharmaceutically acceptable salt thereof.

6. Formula (IV): 【Chemistry 10】 [In the formula: Ar １ teeth 【Chemistry 11】 and R １ is Cl, CH ３ , -CF ３ , -CHF ２ , -OCH ３ , -OCHF ２ , or -OCF ３ and R ２ is cyano, F, Cl, -CH ３ , -OCH 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, 【Chemistry 12】 -(CH ２ ) ０－３ -heterocycloalkyl; R ３ and R ４ and together with the nitrogen to which they are both attached, 【Chemistry 13】 forming a heterocycloalkyl 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 ７ is hydrogen or -CH ３ and 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 according to claim 4, which is represented by the formula: or a pharmaceutically acceptable salt thereof.

7. Formula (V): 【Chemistry 14】 [In the formula: R １ is Cl or -OCH ３ and R ２ is cyano, F, Cl, -CH ３ , -OCH ３ , -CF ３ , -CHF ２ , or -CF 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, 【Chemistry 15】 -(CH ２ ) ０－３ -heterocycloalkyl; R ３ and R ４ and together with the nitrogen to which they are both attached, 【Chemistry 16】 forming a heterocycloalkyl 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 ７ is hydrogen or -CH ３ and 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 according to claim 4, which is represented by the formula: or a pharmaceutically acceptable salt thereof.

8. Formula (VI): 【Chemistry 17】 [In the formula: Ar １ teeth [Chemistry 18] and R １ is Cl, -CF ３ , CHF ２ , -OCHF ２ , -OCH ３ , 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 19】 and R ３ is hydrogen, C １－４ Alkyl (0 to 3 R ｅ (replaced by 【Chemistry 20】 and R ４ is hydrogen; Alternatively, R ３ and R ４ and together with the nitrogen to which they are both attached, 【Chemistry 21】 forming a heterocycloalkyl 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 ７ is hydrogen or -CH ３ and R ８ is hydrogen, C １－４ Alkyl, or —S(O) ２ C １－３ is alkyl; R ｅ is halo, -OR ｇ , —C(O)NR ｇ R ｇ , -S(O) ２ C １－４ alkyl, or heteroaryl or heterocycloalkyl (O, S, N, and NR ｇ and 0 to 3 R ｆ substituted with R ｆ is halo, cyano, hydroxy, or C １－４ alkyl; R ｇ is hydrogen or C １－３ alkyl] 5. The compound according to claim 4, which is represented by the formula: or a pharmaceutically acceptable salt thereof.

9. Formula (VII): 【Chemistry 22】 [In the formula: Ar １ teeth 【Chemistry 23】 and R １ is Cl, -CF ３ , CHF ２ , -OCHF ２ , -OCH ３ , or -OCF ３ and R ２ is F, Cl, -CH ２ OH, -CH ３ , -CHF ２ , -CF ３ , -OCH ３ , or -OCH(CH ３ ) ２ and R ５ａ is hydrogen or F; R ５ｂ is hydrogen or F; R ５ｃ is Cl or -OCH ３ and R ７ is hydrogen or -CH ３ is] 9. The compound according to claim 8, which is represented by the formula: or a pharmaceutically acceptable salt thereof.

10. Formula (VIII): 【Chemistry 24】 [In the formula: Ar １ teeth 【Chemistry 25】 and R １ is F, Cl, -CF ３ , CHF ２ , -OCHF ２ , -OCH ３ , or -OCF ３ and R ３ is hydrogen or C １－４ Alkyl (0 to 2 R ｅ substituted with R ４ is hydrogen; Alternatively, R ３ and R ４ and together with the nitrogen to which they are both attached, 【Chemistry 26】 forming a heterocycloalkyl 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, hydroxy, oxo, -CH ３ , -CH ２ CH ３ , or -CH ２ OH; R ７ is hydrogen or -CH ３ and R ８ is hydrogen, C １－４ Alkyl, or —S(O) ２ C １－３ alkyl; R ｅ -OH, -OC １－４ Alkyl, —C(O)NHC １－４ Alkyl, —S(O) ２ C １－４ Alkyl, 【Chemistry 27】 is] 9. The compound according to claim 8, which is represented by the formula: or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 10, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier or diluent.

12. A pharmaceutical composition comprising the compound of any one of claims 1 to 10 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 infections, circulatory disorders, neuroinflammation, neurological disorders, pain, prion diseases, amyloidosis, or immune disorders.

13. 13. The pharmaceutical composition of claim 12, 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.

14. 14. The pharmaceutical composition of claim 13, wherein the heart failure is caused by high blood pressure, 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, or genetic defects.

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