Oxypyrrolidone FPR2 agonists

Abstract

This disclosure relates to compounds of formula (I) as formylpeptide 2 (FPR2) receptor agonists and / or formylpeptide 1 (FPR1) receptor agonists. This disclosure also provides compositions and methods of using said compounds, for example, for treating atherosclerosis, heart failure, chronic obstructive pulmonary disease (COPD), and related diseases. (I)

Description

[0001] Cross-reference to related applications

[0002] This application has priority under 35 U.S. SC §119(e) to U.S. Provisional Patent Application No. 63 / 064,640, filed August 12, 2020, which is incorporated herein by reference in its entirety. Background Technology

[0003] This invention relates to novel oxopyrrolidone urea compounds as formyl peptide 2 (FPR2) receptor agonists and / or formyl peptide 1 (FPR1) receptor agonists, compositions containing these compounds, and methods of using these compounds, for example, for treating atherosclerosis, heart failure, chronic obstructive pulmonary disease (COPD), and related diseases.

[0004] Formyl peptide receptor 2 (FPR2) belongs to the group of seven-transmembrane domain G protein-coupled receptors, which are expressed in a variety of human tissues, including immune cells, and are known to be important in host defense and inflammation. FPR2 shares significant sequence homology with FPR1 and FPR3 (Journal of Autoimmunity 85, 2017, 64-77). These receptors collectively bind to a number of structurally diverse agonists, including N-formyl peptides and nonformyl peptides that act as chemoretica and activate phagocytes. Endogenous peptide annexin A1 and its N-terminal fragment are examples of ligands that bind to human FPR1 and FPR2. Fatty acids (such as arachidic acid, lipoxygenin A4) belong to a small class of pro-remission mediators and have also been identified as agonists of FPR2 (YeRD. et al., Pharmacol. Rev., 2009, 61, 119-61).

[0005] It has been reported that endogenous FPR2 decay ligands (such as lipoxygen A4 and annexin A1) trigger a wide range of cytoplasmic cascade reactions (such as Gi coupling, Ca...). 2+(mobilization and recruitment of β-repressor proteins). (Int J Mol Sci. 2013 April; 14(4):7193–7230). FPR2 regulates both the innate and adaptive immune systems, including neutrophils, macrophages, T cells, and B cells. In neutrophils, FPR2 ligands regulate motility, cytotoxicity, and lifespan. In macrophages, FPR2 agonism prevents apoptosis and enhances cytotoxicity. (Chandrasekharan JA, Sharma-Walia N, J. Inflamm. Res., 2015, 8, 181-92). The initiation of inflammation remission through FPR2 agonism is responsible for enhancing antifibrotic wound healing and restoring damaged tissue to homeostasis (Romano M. et al., Eur. J. Pharmacol., 2015, 5, 49-63).

[0006] Chronic inflammation is part of the pathogenesis of many diseases, and stimulation of the resolution pathway with FPR2 agonists can have protective and reparative effects. Ischemia-reperfusion (I / R) injury is a common feature of several diseases associated with high morbidity and mortality, such as myocardial infarction and stroke. Healing of non-productive wounds associated with cardiomyocyte death and pathological remodeling induced by I / R injury leads to scarring, fibrosis, and progressive loss of cardiac function. It has been proposed that FPR2 modulation can enhance myocardial wound healing after injury and reduce adverse myocardial remodeling (Kain V. et al., J. Mol. Cell. Cardiol., 2015, 84, 24-35). In addition, in the central nervous system, FPR2 extinction agonists can be used as therapeutic agents for 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).

[0007] In addition to the beneficial effects of novel remission agonists targeting the FPR2 receptor to treat I / R-induced damage, the efficacy of these ligands can also be applied to other diseases. It has been found that in the cardiovascular system, the FPR2 receptor and its remission agonists are responsible for the stabilization and healing of atherosclerotic plaques (Petri MH. et al., Cardiovasc. Res., 2015, 105, 65-74; and Fredman G. et al., Sci. Trans. Med., 2015, 7(275); 275ra20). FPR2 agonists have also shown benefits in preclinical models of chronic inflammatory human diseases, including: infectious diseases, psoriasis, dermatitis, inflammatory bowel syndrome, Crohn's disease, ocular inflammation, sepsis, pain, metabolic diseases / diabetes, cancer, COPD, asthma and allergic diseases, cystic fibrosis, acute lung injury and fibrosis, rheumatoid arthritis and other joint diseases, Alzheimer's disease, renal fibrosis, and organ transplantation (Romano M. et al., Eur. J. Pharmacol., 2015, 5, 49-63; Perrett, M. et al., Trends in Pharm. Sci., 2015, 36, 737-755). Summary of the Invention

[0008] This invention provides novel oxopyrrolidone urea compounds and analogues thereof that can be used as FPR2 agonists, including their stereoisomers, tautomers, pharmaceutically acceptable salts or solvates.

[0009] The present invention also provides methods and intermediates for manufacturing the compounds of the present invention or their stereoisomers, tautomers, pharmaceutically acceptable salts or solvates.

[0010] The present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and at least one of the compounds of the present invention or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof.

[0011] The compounds of this invention can be used to treat and / or prevent a variety of diseases or disorders associated with FPR2, such as inflammatory diseases, heart disease, chronic airway disease, cancer, sepsis, allergic symptoms, HIV retroviral infection, circulatory disorders, neuroinflammation, neurological disorders, pain, prion diseases, amyloidosis, and immune disorders. The heart disease is selected from angina pectoris, unstable angina pectoris, myocardial infarction, acute coronary artery disease, iatrogenic cardiac damage, and heart failure. The heart failure includes, but is not limited to, acute heart failure, ischemic and non-ischemic chronic heart failure, systolic heart failure, diastolic heart failure, and heart failure with reduced ejection fraction (HF). REF) and heart failure with preserved ejection fraction (HF) P EF).

[0012] The compounds of the present invention can be used alone, in combination with other compounds of the present invention, or in combination with one or more other pharmaceutical agents.

[0013] Other features and advantages of the present invention will become clear from the following detailed description and claims. Detailed Implementation

[0014] The present invention covers compounds of formula (I) as formyl peptide 2 (FPR2) receptor agonists and / or formyl peptide 1 (FPR1) receptor agonists, compositions containing these compounds, and methods of using these compounds, for example, in the treatment of atherosclerosis, heart failure, chronic obstructive pulmonary disease (COPD) and related diseases.

[0015] One aspect of the present invention is a compound of formula (I):

[0016]

[0017] Or its pharmaceutically acceptable salt, wherein:

[0018] Ar 1 It is a cycloalkyl, cycloalkylalkyl, aryl, or heterocycloalkyl group, each marked with 0-3 R groups. 1 replace;

[0019] Ar 2 It is C 3-6 Cycloalkyl, aryl, or containing 1-4 groups selected from O, S(O) p , N and NR 2a The heteroatoms are 5 to 12-membered heteroaryl or heterocyclic alkyl groups, each surrounded by 0 to 3 R groups. 2 replace;

[0020] Ar 3 It is either phenyl or pyridyl, each surrounded by one R group. 5a 1 R 5b And 1 R 5c replace;

[0021] R 1 It is a halogenated group, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups or surrounded by 0-2 halogenated groups, C1-4 halogenated alkyl groups, or C1-4 halogenated alkyl groups. 1-4 Alkoxy-substituted aryl groups;

[0022] R 2It is an oxo group, cyano group, halogen group, with 0-5 R groups. e Replacement C 1-6 Alkyl, -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 containing 1-4 groups selected from O, S(O) p , N and NR a 5 to 6-membered heteroaryl or heterocyclic alkyl groups;

[0023] R 2a It is hydrogen, with 0-5 R e Replacement C 1-4 Alkyl, -(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 0-5 R e Replacement -(CR) d R d ) r -C 3-6 cycloalkyl, with 0-5 R e Replacement -(CR) d R d ) r -Aryl, or containing 1-4 ions selected from O, S(O)p, N, and NR a heteroatoms and 0-5 R e Replacement -(CR) d R d ) r - Heteroaryl or heterocyclic alkyl;

[0024] R 3 It is hydrogen, with 0-5 R e Replacement C 1-4 Alkyl groups, with 0-5 R groupse Replacement C 3-6 Cycloalkyl groups, comprising 1-4 ions selected from O, S(O)p, N, and NR 8 heteroatoms and 0-5 R e Substituted heteroaryl or heterocyclic alkyl groups;

[0025] R 4 Is it hydrogen or C? 1-4 alkyl;

[0026] Alternatively, R 3 and R 4 Together with the nitrogen atoms attached to them, they form a group consisting of 1-4 atoms selected from O, S(O)p, N, and NR. 8 heteroatoms and are surrounded by 1-3 R atoms 6 Substituted 4- to 9-membered heteroaryl or heterocyclic alkyl groups;

[0027] R 5a It is a hydrogen or halogroup;

[0028] R 5b It is a hydrogen or halogroup;

[0029] R 5c It is a halogenated group, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or deuterated alkoxy;

[0030] R 6 It is hydrogen, halogroup, oxogroup, hydroxyl group, or surrounded by 0-5 R groups. e Replacement C 1-4 alkyl;

[0031] R 7 Is it hydrogen or C? 1-4 alkyl;

[0032] R 8 It is hydrogen, C 1-4 Alkyl or -S(O) p R c ;

[0033] R a It is hydrogen or composed of 0-5 R atoms. e Replacement C 1-6 Alkyl groups, with 0-5 R groups e Replacement C 3-6 cycloalkyl, with 0-5 R e Substituted aryl group, or containing 1-4 aryl groups selected from O, S(O)p, N, NR d heteroatoms and 0-5 R e Substituted heteroaryl or heterocyclic alkyl groups;

[0034] Rb It is hydrogen, with 0-5 R e Replacement C 1-6 Alkyl groups, with 0-5 R groups e Replacement C 3-6 cycloalkyl, with 0-5 R e Substituted aryl group, or containing 1-4 aryl groups selected from O, S(O)p, N, NR d heteroatoms and 0-5 R e Substituted heteroaryl or heterocyclic alkyl groups;

[0035] R c It is 0-5 R e Replacement C 1-4 alkyl;

[0036] R d It is hydrogen or composed of 0-5 R atoms. e Replacement C 1-4 alkyl;

[0037] R e It is a halogenated group, cyano group, oxo group, -OR g -NR g R g -C(O)NR g R g -S(O) p C 1-4 Alkyl groups, with 0-5 R groups f Replacement C 1-6 Alkyl groups, with 0-5 R groups f Substituted -(CH2) r -C 3-6 cycloalkyl, with 0-5 R f Substituted -(CH2) r -Aryl, or containing 1-4 ions selected from O, S(O)p, N, and NR g heteroatoms and 0-5 R f Substituted -(CH2) r - Heteroaryl or heterocyclic alkyl;

[0038] R f It is a halogenated group, cyano group, hydroxyl group, C 1-5 Alkyl, C 3-6 cycloalkyl or phenyl;

[0039] R g It 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 atoms to which they are attached, they form heteroaryl or heterocyclic alkyl groups;

[0040] p is 0, 1, or 2; and

[0041] r can be 0, 1, 2, 3, or 4.

[0042] Another aspect of the present invention is a compound of formula (II):

[0043]

[0044] Or its pharmaceutically acceptable salt, wherein:

[0045] Ar 1 yes

[0046] Ar 2 It is C 3-6 Cycloalkyl, phenyl, or containing 1-2 N or NR atoms 2a 5 to 6-membered heteroaryl or heterocyclic alkyl groups, each surrounded by 0 to 2 R groups 2 replace;

[0047] Ar 3 It is by 1 R 5a 1 R 5b And 1 R 5c Substituted phenyl;

[0048] R 1 It is a halogenated group, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy group, or with 0-2 halogenated groups or C 1-4 Alkoxy-substituted phenyl;

[0049] R 2 It is an oxo group, cyano group, halogen group, with 0-5 R groups. e Replacement C 1-5 Alkyl, -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 containing 1-4 radicals selected from O, S, N, and NR a 5 to 6-membered heteroaryl or heterocyclic alkyl groups;

[0050] R 2a It is hydrogen, with 0-4 R e Replacement C 1-4 Alkyl, -(CHR) d )1-3 -C(O)NR 3 R 4 , by 0-4 R e Replacement -(CHR) d ) r -C 3-6 cycloalkyl, with 0-4 R e Replacement -(CHR) d ) r -Aryl, or containing 1-4 ions selected from O, S, N and NR a heteroatoms and 0-4 R e Replacement -(CHR) d ) r - Heteroaryl or heterocyclic alkyl;

[0051] R 3 It is hydrogen, with 0-4 R e Replacement C 1-4 Alkyl, C 3-6 Cycloalkyl, or containing 1-4 alkyl groups selected from O, S, N, and NR 8 heteroatoms and 0-4 R e Substituted heteroaryl or heterocyclic alkyl groups;

[0052] R 4 Is it hydrogen or C? 1-3 alkyl;

[0053] Alternatively, R 3 and R 4 Together with the nitrogen atoms attached to them, they form a mixture containing 1-4 atoms selected from O, S, N, and NR. 8 heteroatoms and are surrounded by 1-3 R atoms 6 Substituted 4- to 8-membered heteroaryl or heterocyclic alkyl groups;

[0054] R 5a It is a hydrogen or halogroup;

[0055] R 5b It is a hydrogen or halogroup;

[0056] R 5c It is a halogenated group, C 1-4 Alkyl, C 1-4 Halogenated alkyl or C 1-4 Alkoxy;

[0057] R 6 It is hydrogen, halogroup, oxogroup, hydroxyl group, or surrounded by 0-4 R groups. e Replacement C 1-4 alkyl;

[0058] R 7 Is it hydrogen or C? 1-3 alkyl;

[0059] R 8 It is hydrogen, C 1-3 Alkyl or -S(O) p R c ;

[0060] R a It is hydrogen or composed of 0-5 R atoms. e Replacement C 1-6 alkyl;

[0061] R b It is hydrogen, with 0-5 R e Replacement C 1-6 Alkyl groups, comprising 1-4 ions selected from O, S, N, and NR d heteroatoms and 0-5 R e Substituted heteroaryl or heterocyclic alkyl groups;

[0062] R c It is 0-5 R e Replacement C 1-3 alkyl;

[0063] R d Is it hydrogen or 0-1 -OC? 1-4 Alkyl-substituted C 1-4 alkyl;

[0064] R e It is a halogenated group, cyano group, oxo group, -OR g -NR g R g -C(O)NR g R g -S(O) p C 1-4 Alkyl groups, with 0-5 R groups f Replacement C 1-4 Alkyl groups, with 0-5 R groups f Substituted -(CH2) r -C 3-6 cycloalkyl, with 0-5 R f Substituted -(CH2) r -Aryl, or containing 1-4 ions selected from O, S, N and NR g heteroatoms and 0-5 R f Substituted -(CH2) r - Heteroaryl or heterocyclic alkyl;

[0065] R f It is a halogenated group, cyano group, hydroxyl group, C 1-5 Alkyl or C 3-6 cycloalkyl;

[0066] Rg It is hydrogen, C 1-5 Alkyl, heteroaryl, or heterocyclic alkyl;

[0067] n is 0; and

[0068] r can be 0, 1, 2, or 3.

[0069] Another aspect of the present invention is a compound of formula (III):

[0070]

[0071] Or its pharmaceutically acceptable salt, wherein:

[0072] Ar 1 yes

[0073] Ar 2 yes

[0074]

[0075] R 1 It is a halogenated group, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl or C 1-3 Halogenated alkoxy groups;

[0076] R 2 It is a cyano group, a halo group, or has 0-5 R groups. e Replacement C 1-4 Alkyl, -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 containing 1-4 radicals selected from O, S, N, and NR a 5 to 6-membered heteroaryl or heterocyclic alkyl groups;

[0077] R 2a It is hydrogen, with 0-3 Rs e Replacement C 1-4 Alkyl, -(CHR) d ) 1-2 -C(O)NR 3 R 4 0-3 R e Substituted -(CH2) r -C 3-6 cycloalkyl, with 0-3 R eSubstituted -(CH2) r -Aryl, or containing 1-4 ions selected from O, S, N and NR a heteroatoms and 0-3 R e Substituted -(CH2) r - Heteroaryl or heterocyclic alkyl;

[0078] R 3 It is hydrogen, with 0-3 Rs e Replacement C 1-4 Alkyl, C 3-6 Cycloalkyl, or containing 1-4 alkyl groups selected from O, S, N, and NR 8 heteroatoms and 0-3 R e Substituted heteroaryl or heterocyclic alkyl groups;

[0079] R 4 Is it hydrogen or C? 1-2 alkyl;

[0080] Alternatively, R 3 and R 4 Together with the nitrogen atoms attached to them, they form a mixture containing 1-3 atoms selected from O, S, N, and NR. 8 heteroatoms and are surrounded by 1-3 R atoms 6 Substituted 4- to 8-membered heteroaryl or heterocyclic alkyl groups;

[0081] R 5a It is a hydrogen or halogroup;

[0082] R 5b It is a hydrogen or halogroup;

[0083] R 5c Is it a halogenated group or C 1-2 Alkoxy;

[0084] R 6 It is hydrogen, halogenated, oxo-substituted, hydroxyl, or surrounded by 0-3 R groups. e Replacement C 1-4 alkyl;

[0085] R 7 It is hydrogen or CH3;

[0086] R 8 It is hydrogen, C 1-2 Alkyl or -S(O)2C 1-4 alkyl;

[0087] R a It is hydrogen, with 0-4 R e Replacement C 1-5 alkyl;

[0088] R b It is hydrogen, with 0-4 Re Replacement C 1-5 Alkyl groups, comprising 1-4 ions selected from O, S, N, and NR d heteroatoms and 0-4 R e Substituted heteroaryl or heterocyclic alkyl groups;

[0089] R d Is it hydrogen or 0-1 -OC? 1-4 Alkyl-substituted C 1-3 alkyl;

[0090] R e It is a halogenated group, cyano group, oxo group, -OR g -NR g R g C(O)NR g R g -S(O) p C 1-4 Alkyl groups, with 0-4 R groups f Replacement C 1-4 Alkyl groups, with 0-4 R groups f Substituted -(CH2) r -C 3-6 cycloalkyl, with 0-4 R f Substituted -(CH2) r -Aryl, or containing 1-4 ions selected from O, S, N and NR g heteroatoms and 0-4 R f Substituted -(CH2) r - Heteroaryl or heterocyclic alkyl;

[0091] R f It is a halogenated group, cyano group, hydroxyl group or C 1-5 alkyl;

[0092] R g Is it hydrogen or C? 1-4 Alkyl; and

[0093] r is 0, 1, or 2.

[0094] Another aspect of the invention is a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein:

[0095] Ar 1 yes

[0096] Ar 2 yes

[0097] R 1 It is Cl, -CH3, -CF3, -OCH3, -OCHF2, or -OCF3;

[0098] R 2 It is a cyano group, a halo group, or has 0-4 R groups. e Replacement C 1-4 Alkyl, -OR b -NR 3 R 4 -NR 4 C(O)R b (C) 1-2 Alkyl)2(O)P-,C 3-6 Cycloalkyl groups, comprising 1-4 ions selected from O, S, N, and NR a heteroaryl or heterocyclic alkyl groups;

[0099] R 2a It is hydrogen, with 0-2 Rs e Replacement C 1-4 Alkyl, -(CHR) d ) 1-2 -C(O)NR 3 R 4 , by 0-2 R e Substituted -(CH2) r -C 3-6 cycloalkyl, with 0-2 R e Substituted -(CH2) r -Aryl, or containing 1-4 ions selected from O, S, N and NR a heteroatoms and 0-2 R e Substituted -(CH2) r - Heteroaryl or heterocyclic alkyl;

[0100] R 3 It is hydrogen, with 0-3 Rs e Replacement C 1-4 Alkyl groups, or those containing 1-4 alkyl groups selected from O, S, N, and NR. 8 heteroatoms and 0-3 R e Substituted heteroaryl or heterocyclic alkyl groups;

[0101] R 4 Is it hydrogen or C? 1-2 alkyl;

[0102] Alternatively, R 3 and R 4 Together with the nitrogen atoms attached to them, they form a mixture containing 1-3 atoms selected from O, S, N, and NR. 8 heteroatoms and are surrounded by 1-3 R atoms 6 Substituted 4- to 8-membered heteroaryl or heterocyclic alkyl groups;

[0103] R 5a It is hydrogen, F, or Cl;

[0104] R 5b It is hydrogen, F, or Cl;

[0105] R 5c It is Cl or -OCH3;

[0106] R 6 It is a C-shaped group that is hydrogen, halogroup, oxogroup, hydroxyl group, or substituted with 0-3 Re groups. 1-3 alkyl;

[0107] R 7 It is hydrogen or -CH3;

[0108] R 8 It is hydrogen, C 1-2 Alkyl or -S(O)2C 1-3 alkyl;

[0109] R a It is hydrogen, with 0-3 Rs e Replacement C 1-4 alkyl;

[0110] R b It is hydrogen, C replaced by 0-3 Re atoms. 1-4 Alkyl groups, comprising 1-4 ions selected from O, S, N, and NR d heteroatoms and 0-3 R e Substituted heteroaryl or heterocyclic alkyl groups;

[0111] R d Is it hydrogen or 0-1 -OC? 1-4 Alkyl-substituted C 1-2 alkyl;

[0112] R e It is a halogenated group, cyano group, oxo group, -OR g -NR g R g -C(O)NR g R g -S(O)2C 1-4 Alkyl groups, with 0-3 R groups f Replacement C 1-6 Alkyl groups, with 0-3 R groups f Replacement C 3-6 Cycloalkyl, or containing 1-4 alkyl groups selected from O, S, N, and NR g heteroatoms and 0-3 R f Substituted heteroaryl or heterocyclic alkyl groups;

[0113] R f It is a halogenated group, cyano group, hydroxyl group or C 1-4 Alkyl; and

[0114] Rg Is it hydrogen or C? 1-3 alkyl.

[0115] Another aspect of the invention is a compound of formula (I)-(III) or a pharmaceutically acceptable salt thereof, wherein:

[0116] Ar 2 yes

[0117] R 2 It is F, Cl, CH2OH, CH3, CF3, or CHF2; and

[0118] R 2a is -CH3, -CH2CH3, -CH2CHF2, -CH2CF3, -CH2CH2OCH3, -CH2CH(OH)CF3, -CH2CH(OH)CH3, -CH2CH2OH, -CH2CH(CH3)O H, -CH2CH(CF3)OH, -CH2CH2CF3, -CH(CH2OH)CH2OCH3, -CH(CH2NH2)OCH3, -CH2CH(CH3)OCH3 or -CH2CH(CF3)OCH3.

[0119] Another aspect of the present invention is a compound of formula (IV):

[0120]

[0121] Or its pharmaceutically acceptable salt, wherein:

[0122] Ar 1 yes

[0123] R 1 It is Cl, CH3, -CF3, -CHF2, -OCH3, -OCHF2, or -OCF3;

[0124] R 2 It is cyano, F, Cl, -CH3, -OCH3, -CF3, -CHF2, -CF3 or -NHC(O)CH3;

[0125] R 2ais -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, selected from -(CH2) 0-3 - Heterocyclic alkyl;

[0126] R 3 and R 4 Together with the nitrogen attached to them, they form a mixture selected from... Heterocyclic alkyl groups;

[0127] R 5a It is hydrogen or F;

[0128] R 5b It is hydrogen or F;

[0129] R 5c It is Cl or -OCH3;

[0130] R 6 It can be hydrogen, oxo group, halo group, -CH3, -CHF2, -CF3 or -CH2OH;

[0131] R 7 It is hydrogen or -CH3;

[0132] R 8 It is hydrogen, C 1-2 Alkyl or -S(O)2C 1-3 Alkyl; and

[0133] R d It is -CH2OCH3.

[0134] Another aspect of the present invention is a compound of formula (V):

[0135]

[0136] Or its pharmaceutically acceptable salt, wherein:

[0137] R 1 It is Cl or -OCH3;

[0138] R 2 It is cyano, F, Cl, -CH3, -OCH3, -CF3, -CHF2, or -CF3;

[0139] R 2a is -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, selected from -(CH2) 0-3 - Heterocyclic alkyl;

[0140] R 3 and R 4 Together with the nitrogen attached to them, they form a mixture selected from... Heterocyclic alkyl groups;

[0141] R 5a It is hydrogen or F;

[0142] R 5b It is hydrogen or F;

[0143] R 5c It is Cl or -OCH3;

[0144] R 6 It can be hydrogen, oxo group, halo group, -CH3, -CHF2, -CF3 or -CH2OH;

[0145] R 7 It is hydrogen or -CH3;

[0146] R 8 It is hydrogen, C 1-2 Alkyl or -S(O)2C 1-3 Alkyl; and

[0147] R d It is -CH2OCH3.

[0148] Another aspect of the present invention is a compound of formula (VI):

[0149]

[0150] Or its pharmaceutically acceptable salt, wherein:

[0151] Ar 1 yes

[0152] R 1 It is Cl, -CF3, CHF2, -OCHF2, -OCH3 or -OCF3;

[0153] R 2 It is cyano, F, Cl, -CH2OH, -CH3, -CHF2, -CF3, -OCH3, -OCH(CH3)2, -NR 3 R 4 (CH3)2(O)P-, C3-6 cycloalkyl

[0154] R 3 It is hydrogen or composed of 0-3 Rs. e Replacement C 1-4 alkyl,

[0155] R 4 It is hydrogen;

[0156] Alternatively, R 3 and R 4 Together with the nitrogen attached to them, they form a mixture selected from... Heterocyclic alkyl groups;

[0157] R 5a It is hydrogen or F;

[0158] R 5b It is hydrogen or F;

[0159] R 5c It is Cl or -OCH3

[0160] R 6 It can be hydrogen, halogroup, oxogroup, -CH3, -CH2CH3 or -CH2OH;

[0161] R7 It is hydrogen or -CH3;

[0162] R 8 It is hydrogen, C 1-4 Alkyl or -S(O)2C 1-3 Alkyl; and

[0163] R e It is a halogenated group, -OR g -C(O)NR g R g -S(O)2C 1-4 Alkyl groups, comprising 1-4 ions selected from O, S, N, and NR g heteroatoms and 0-3 R f Substituted heteroaryl or heterocyclic alkyl groups;

[0164] R f It is a halogenated group, cyano group, hydroxyl group or C 1-4 Alkyl; and

[0165] R g Is it hydrogen or C? 1-3 alkyl.

[0166] Another aspect of the present invention is a compound of formula (VII):

[0167]

[0168] Or its pharmaceutically acceptable salt, wherein:

[0169] Ar 1 yes

[0170] R 1 It is Cl, -CF3, CHF2, -OCHF2, -OCH3 or -OCF3;

[0171] R 2 It is F, Cl, -CH2OH, -CH3, -CHF2, -CF3, -OCH3, or -OCH(CH3)2;

[0172] R 5a It is hydrogen or F;

[0173] R 5b It is hydrogen or F;

[0174] R 5c It is Cl or -OCH3; and

[0175] R 7 It is hydrogen or -CH3.

[0176] Another aspect of the present invention is a compound of formula (VIII):

[0177]

[0178] Or its pharmaceutically acceptable salt, wherein:

[0179] Ar 1 yes

[0180] R 1 It is F, Cl, -CF3, CHF2, -OCHF2, -OCH3 or -OCF3;

[0181] R 3 It is hydrogen or composed of 0-2 R atoms. e Replacement C 1-4 alkyl;

[0182] R 4 It is hydrogen;

[0183] Alternatively, R 3 and R 4 Together with the nitrogen attached to them, they form a mixture selected from... Heterocyclic alkyl groups;

[0184] R 5a It is hydrogen or F;

[0185] R 5b It is hydrogen or F;

[0186] R 5c It is Cl or -OCH3;

[0187] R 6 It can be hydrogen, halogroup, hydroxyl group, oxogroup, -CH3, -CH2CH3 or -CH2OH;

[0188] R 7 It is hydrogen or -CH3;

[0189] R 8 It is hydrogen, C 1-4 Alkyl or -S(O)2C 1-3 Alkyl; and

[0190] R e It is -OH, -OC 1-4 Alkyl group, -C(O)NHC 1-4 Alkyl group, -S(O)2C 1-4 alkyl,

[0191] Another aspect of the present invention is a compound of formula (IX):

[0192]

[0193] Or its pharmaceutically acceptable salt, wherein:

[0194] Ar 2 It is either a pyridinyl or pyridone group, each surrounded by 0-2 R groups. 2 replace.

[0195] Ar 3 It is by 3 Rs 5 Substituted phenyl;

[0196] R 1 It is a halogenated group, C 1-4 Halogenated alkyl or C 1-4 Halogenated alkoxy groups;

[0197] R 2 It is cyano, halogenated, C 1-4 Alkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy or NR 3 R 4 ;

[0198] R 3 and R 4 Together with the nitrogen atoms attached to them, they form 4-6 membered heterocycles; and

[0199] R 5 It is a halogenated group, C 1-4 Alkyl, C 1-4 Halogenated alkyl or C 1-4 Alkyl group.

[0200] Another aspect of the present invention is a compound of formula (X):

[0201]

[0202] Or its pharmaceutically acceptable salt, wherein:

[0203] Ar 2 It is either a pyridinyl or pyridone group, each surrounded by 0-2 R groups. 2 replace.

[0204] Ar 3 It is by 3 Rs 5 Substituted phenyl;

[0205] R 1 It is a halogenated group, C 1-4 Halogenated alkyl or C 1-4 Halogenated alkoxy groups;

[0206] R2 It is cyano, halogenated, C 1-4 Alkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy or NR 3 R 4 ;

[0207] R 3 and R 4 Together with the nitrogen atoms attached to them, they form 4-6 membered heterocycles;

[0208] R 5 It is a halogenated group, C 1-4 Alkyl, C 1-4 Halogenated alkyl or C 1-4 alkoxy groups; and

[0209] n is zero or 1.

[0210] Another aspect of the present invention is a compound of formula (XI):

[0211]

[0212] Or its pharmaceutically acceptable salt, wherein:

[0213] Ar 2 It is either a pyridinyl or pyridone group, each surrounded by 0-2 R groups. 2 replace.

[0214] Ar 3 It is by 3 Rs 5 Substituted phenyl;

[0215] R 1 It is a halogenated group, C 1-4 Halogenated alkyl or C 1-4 Halogenated alkoxy groups;

[0216] R 2 It is cyano, halogenated, C 1-4 Alkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy or NR 3 R 4 ;

[0217] R 3 and R 4 Together with the nitrogen atoms attached to them, they form 4-6 membered heterocycles; and

[0218] R 5 It is a halogenated group, C 1-4 Alkyl, C 1-4 Halogenated alkyl or C 1-4 Alkyl group.

[0219] Another aspect of the present invention is a compound of formula (XII):

[0220]

[0221] Or its pharmaceutically acceptable salt, wherein:

[0222] Ar 2 It is either a pyridinyl or pyridone group, each surrounded by 0-2 R groups. 2 replace.

[0223] Ar 3 It is by 3 Rs 5 Substituted phenyl;

[0224] X is CH2 or O;

[0225] R 1 It is a halogenated group, C 1-4 Halogenated alkyl or C 1-4 Halogenated alkoxy groups;

[0226] R 1a It is methyl;

[0227] R 2 It is cyano, halogenated, C 1-4 Alkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy or NR 3 R 4 ;

[0228] R 3 and R 4 Together with the nitrogen atoms attached to them, they form 4-6 membered heterocycles; and

[0229] R 5 It is a halogenated group, C 1-4 Alkyl, C 1-4 Halogenated alkyl or C 1-4 Alkyl group.

[0230] Another aspect of the present invention is a compound of formula (XIII):

[0231]

[0232] Or its pharmaceutically acceptable salt, wherein: Ar 2 yes

[0233]

[0234] X is CH2 or O;

[0235] R 1 It is a halogenated group, C 1-4 Halogenated alkyl or C 1-4 Halogenated alkoxy

[0236] R 1a It is methyl;

[0237] R 2 It is cyano, halogenated, C 1-4 Alkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, NR 3 R 4 ;

[0238] R 3 and R 4 Together with the nitrogen atoms attached to them, they form 4-6 membered heterocycles;

[0239] R 5a It is a halogenated group;

[0240] R 5b It is a halogenated group; and

[0241] R 5c It is C 1-2 Alkyl group.

[0242] Another aspect of the present invention is a compound of formula (XIV):

[0243]

[0244] Or its pharmaceutically acceptable salt, wherein:

[0245] Ar 2 yes

[0246]

[0247] X is CH2 or O;

[0248] R 1 It is a halogenated group, C 1-4 Halogenated alkyl or C 1-4 Halogenated alkoxy groups;

[0249] R1a It is methyl;

[0250] R 2 It is cyano, halogenated, C 1-4 Alkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy or NR 3 R 4 ;

[0251] R 3 and R 4 Together with the nitrogen atoms attached to them, they form 4-6 membered heterocycles;

[0252] R 5a It is a halogenated group;

[0253] R 5b It is a halogenated group;

[0254] R 5c It is C 1-2 alkoxy groups; and

[0255] R 7 It is either hydrogen or methyl.

[0256] Another aspect of the present invention is a compound of formula (IIa):

[0257]

[0258] Or its pharmaceutically acceptable salt, wherein:

[0259] Ar 1 yes

[0260]

[0261] Ar 2 It is C 3-6 Cycloalkyl, phenyl, or containing 1-2 N or NR atoms 2a 5 to 6-membered heteroaryl or heterocyclic alkyl groups, each surrounded by 0 to 2 R groups 2 replace;

[0262] Ar 3 It is by 1 R 5a 1 R 5b And 1 R 5c Substituted phenyl;

[0263] R 1 It is a halogenated group, C 1-4 Alkyl, C 1-4 Alkoxy, C1-4 Haloalkyl, C 1-4 Halogenated alkoxy group, or with 0-2 halogenated groups or C 1-4 Alkoxy-substituted phenyl;

[0264] R 2 It is an oxo group, cyano group, halogen group, with 0-5 R groups. e Replacement C 1-5 Alkyl, -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 containing 1-4 radicals selected from O, S, N, and NR a 5 to 6-membered heteroaryl or heterocyclic alkyl groups;

[0265] R 2a It is hydrogen, with 0-4 R e Replacement C 1-4 Alkyl, -(CHR) d ) 1-3 -C(O)NR 3 R 4 , by 0-4 R e Replacement -(CHR) d ) r -C 3-6 cycloalkyl, with 0-4 R e Replacement -(CHR) d ) r -Aryl, or containing 1-4 ions selected from O, S, N and NR a heteroatoms and 0-4 R e Replacement -(CHR) d ) r - Heteroaryl or heterocyclic alkyl;

[0266] R 3 It is hydrogen, with 0-4 R e Replacement C 1-4 Alkyl, C 3-6 Cycloalkyl, or containing 1-4 alkyl groups selected from O, S, N, and NR 8 heteroatoms and 0-4 R e Substituted heteroaryl or heterocyclic alkyl groups;

[0267] R 4 Is it hydrogen or C? 1-3 alkyl;

[0268] Alternatively, R 3 and R4 Together with the nitrogen atoms attached to them, they form a mixture containing 1-4 atoms selected from O, S, N, and NR. 8 heteroatoms and are surrounded by 1-3 R atoms 6 Substituted 4- to 8-membered heteroaryl or heterocyclic alkyl groups;

[0269] R 5a It is a hydrogen or halogroup;

[0270] R 5b It is a hydrogen or halogroup;

[0271] R 5c It is a halogenated group, C 1-4 Alkyl, C 1-4 Halogenated alkyl or C 1-4 Alkoxy;

[0272] R 6 It is hydrogen, halogroup, oxogroup, hydroxyl group, or surrounded by 0-4 R groups. e Replacement C 1-4 alkyl;

[0273] R 7 Is it hydrogen or C? 1-3 alkyl;

[0274] R 8 It is hydrogen, C 1-3 Alkyl or -S(O) p R c ;

[0275] R a It is hydrogen or composed of 0-5 R atoms. e Replacement C 1-6 alkyl;

[0276] R b It is hydrogen, with 0-5 R e Replacement C 1-6 Alkyl groups, or containing 1-4 alkyl groups selected from O, S, N, NR d heteroatoms and 0-5 R e Substituted heteroaryl or heterocyclic alkyl groups;

[0277] R c It is 0-5 R e Replacement C 1-3 alkyl;

[0278] R d Is it hydrogen or 0-1 -OC? 1-4 Alkyl-substituted C 1-4 alkyl;

[0279] R e It is a halogenated group, cyano group, oxo group, -OR g-NR g R g -C(O)NR g R g -S(O) p C 1-4 Alkyl groups, with 0-5 R groups f Replacement C 1-4 Alkyl groups, with 0-5 R groups f Substituted -(CH2) r -C 3-6 cycloalkyl, with 0-5 R f Substituted -(CH2) r -Aryl, or containing 1-4 ions selected from O, S, N and NR g heteroatoms and 0-5 R f Substituted -(CH2) r - Heteroaryl or heterocyclic alkyl;

[0280] R f It is a halogenated group, cyano group, hydroxyl group, C 1-5 Alkyl or C 3-6 cycloalkyl;

[0281] R g It is hydrogen, C 1-5 Alkyl, heteroaryl, or heterocyclic alkyl;

[0282] n is 0; and

[0283] r can be 0, 1, 2, or 3.

[0284] Another aspect of the present invention is a compound of formula (IIIa):

[0285]

[0286] Or its pharmaceutically acceptable salt, wherein:

[0287] Ar 1 yes

[0288]

[0289] Ar 2 yes

[0290]

[0291] R 1 It is a halogenated group, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl or C 1-3 Halogenated alkoxy groups;

[0292] R 2 It is a cyano group, a halo group, or has 0-5 R groups. e Replacement C 1-4 Alkyl, -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 containing 1-4 radicals selected from O, S, N, and NR a 5 to 6-membered heteroaryl or heterocyclic alkyl groups;

[0293] R 2a It is hydrogen, with 0-3 Rs e Replacement C 1-4 Alkyl, -(CHR) d ) 1-2 -C(O)NR 3 R 4 0-3 R e Substituted -(CH2) r -C 3-6 cycloalkyl, with 0-3 R e Substituted -(CH2) r -Aryl, or containing 1-4 ions selected from O, S, N and NR a heteroatoms and 0-3 R e Substituted -(CH2) r - Heteroaryl or heterocyclic alkyl;

[0294] R 3 It is hydrogen, with 0-3 Rs e Replacement C 1-4 Alkyl, C 3-6 Cycloalkyl, or containing 1-4 alkyl groups selected from O, S, N, and NR 8 heteroatoms and 0-3 R e Substituted heteroaryl or heterocyclic alkyl groups;

[0295] R 4 Is it hydrogen or C? 1-2 alkyl;

[0296] Alternatively, R 3 and R 4 Together with the nitrogen atoms attached to them, they form a mixture containing 1-3 atoms selected from O, S, N, and NR. 8 heteroatoms and are surrounded by 1-3 R atoms 6 Substituted 4- to 8-membered heteroaryl or heterocyclic alkyl groups;

[0297] R 5a It is a hydrogen or halogroup;

[0298] R 5b It is a hydrogen or halogroup;

[0299] R 5c Is it a halogenated group or C 1-2 Alkoxy;

[0300] R 6 It is hydrogen, halogenated, oxo-substituted, hydroxyl, or surrounded by 0-3 R groups. e Replacement C 1-4 alkyl;

[0301] R 7 It is hydrogen or CH3;

[0302] R 8 It is hydrogen, C 1-2 Alkyl or -S(O)2C 1-4 alkyl;

[0303] R a It is hydrogen, with 0-4 R e Replacement C 1-5 alkyl;

[0304] R b It is hydrogen, with 0-4 R e Replacement C 1-5 Alkyl groups, comprising 1-4 ions selected from O, S, N, and NR d heteroatoms and 0-4 R e Substituted heteroaryl or heterocyclic alkyl groups;

[0305] R d Is it hydrogen or 0-1 -OC? 1-4 Alkyl-substituted C 1-3 alkyl;

[0306] R e It is a halogenated group, cyano group, oxo group, -OR g -NR g R g C(O)NR g R g -S(O) p C 1-4 Alkyl groups, with 0-4 R groups f Replacement C 1-4 Alkyl groups, with 0-4 R groups f Substituted -(CH2) r -C 3-6 cycloalkyl, with 0-4 R f Substituted -(CH2) r -Aryl, or containing 1-4 ions selected from O, S, N and NR gheteroatoms and 0-4 R f Substituted -(CH2) r - Heteroaryl or heterocyclic alkyl;

[0307] R f It is a halogenated group, cyano group, hydroxyl group or C 1-5 alkyl;

[0308] R g Is it hydrogen or C? 1-4 Alkyl; and

[0309] r is 0, 1, or 2.

[0310] Another aspect of the invention is a compound of formula (IIIa) or a pharmaceutically acceptable salt thereof, wherein:

[0311] Ar 1 yes

[0312] Ar 2 yes

[0313] R 1 It is Cl, -CH3, -CF3, -OCH3, -OCHF2, or -OCF3;

[0314] R 2 It is a cyano group, a halo group, or has 0-4 R groups. e Replacement C 1-4 Alkyl, -OR b -NR 3 R 4 -NR 4 C(O)R b (C) 1-2 Alkyl)2(O)P-,C 3-6 Cycloalkyl groups, comprising 1-4 ions selected from O, S, N, and NR a heteroaryl or heterocyclic alkyl groups;

[0315] R 2a It is hydrogen, with 0-2 Rs e Replacement C 1-4 Alkyl, -(CHR) d ) 1-2 -C(O)NR 3 R 4 , by 0-2 R e Substituted -(CH2) r -C 3-6 cycloalkyl, with 0-2 R e Substituted -(CH2) r -Aryl, or containing 1-4 ions selected from O, S, N and NRa heteroatoms and 0-2 R e Substituted -(CH2) r - Heteroaryl or heterocyclic alkyl;

[0316] R 3 It is hydrogen, with 0-3 Rs e Replacement C 1-4 Alkyl groups, or those containing 1-4 alkyl groups selected from O, S, N, and NR. 8 heteroatoms and 0-3 R e Substituted heteroaryl or heterocyclic alkyl groups;

[0317] R 4 Is it hydrogen or C? 1-2 alkyl;

[0318] Alternatively, R 3 and R 4 Together with the nitrogen atoms attached to them, they form a mixture containing 1-3 atoms selected from O, S, N, and NR. 8 heteroatoms and are surrounded by 1-3 R atoms 6 Substituted 4- to 8-membered heteroaryl or heterocyclic alkyl groups;

[0319] R 5a It is hydrogen, F, or Cl;

[0320] R 5b It is hydrogen, F, or Cl;

[0321] R 5c It is Cl or -OCH3;

[0322] R 6 It is hydrogen, halogenated, oxo-substituted, hydroxyl, or surrounded by 0-3 R groups. e Replacement C 1-3 alkyl;

[0323] R 7 It is hydrogen or -CH3;

[0324] R 8 It is hydrogen, C 1-2 Alkyl or -S(O)2C 1-3 alkyl;

[0325] R a It is hydrogen, with 0-3 Rs e Replacement C 1-4 alkyl;

[0326] R b It is hydrogen, with 0-3 Rs e Replacement C 1-4 Alkyl groups, comprising 1-4 ions selected from O, S, N, and NR d heteroatoms and 0-3 Re Substituted heteroaryl or heterocyclic alkyl groups;

[0327] R d Is it hydrogen or 0-1 -OC? 1-4 Alkyl-substituted C 1-2 alkyl;

[0328] R e It is a halogenated group, cyano group, oxo group, -OR g -NR g R g -C(O)NR g R g -S(O)2C 1-4 Alkyl groups, with 0-3 R groups f Replacement C 1-6 Alkyl groups, with 0-3 R groups f Replacement C 3-6 Cycloalkyl, or containing 1-4 alkyl groups selected from O, S, N, and NR g heteroatoms and 0-3 R f Substituted heteroaryl or heterocyclic alkyl groups;

[0329] R f It is a halogenated group, cyano group, hydroxyl group or C 1-4 Alkyl; and

[0330] R g Is it hydrogen or C? 1-3 alkyl.

[0331] Another aspect of the invention is a compound of formula (IIa)-(IIIa) or a pharmaceutically acceptable salt thereof, wherein:

[0332]

[0333] R 2 It is F, Cl, CH2OH, CH3, CF3, or CHF2; and

[0334] R 2a is -CH3, -CH2CH3, -CH2CHF2, -CH2CF3, -CH2CH2OCH3, -CH2CH(OH)CF3, -CH2CH(OH)CH3, -CH2CH2OH, -CH2CH(CH3)O H, -CH2CH(CF3)OH, -CH2CH2CF3, -CH(CH2OH)CH2OCH3, -CH(CH2NH2)OCH3, -CH2CH(CH3)OCH3 or -CH2CH(CF3)OCH3.

[0335] Another aspect of the present invention is a compound of formula (IVa):

[0336]

[0337] Or its pharmaceutically acceptable salt, wherein:

[0338] Ar 1 yes

[0339] R 1 It is Cl, CH3, -CF3, -CHF2, -OCH3, -OCHF2, or -OCF3;

[0340] R 2 It is cyano, F, Cl, -CH3, -OCH3, -CF3, -CHF2, -CF3 or -NHC(O)CH3;

[0341] R 2a is -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, selected from -(CH2) 0-3 - Heterocyclic alkyl;

[0342] R 3 and R 4 Together with the nitrogen attached to them, they form a mixture selected from... Heterocyclic alkyl groups;

[0343] R 5a It is hydrogen or F;

[0344] R 5b It is hydrogen or F;

[0345] R 5c It is Cl or -OCH3;

[0346] R 6 It can be hydrogen, oxo group, halo group, -CH3, -CHF2, -CF3 or -CH2OH;

[0347] R 7 It is hydrogen or -CH3;

[0348] R 8 It is hydrogen, C 1-2 Alkyl or -S(O)2C 1-3 Alkyl; and

[0349] R d It is -CH2OCH3.

[0350] Another aspect of the present invention is a compound of formula (Va):

[0351]

[0352] Or its pharmaceutically acceptable salt, wherein:

[0353] R 1 It is Cl or -OCH3;

[0354] R 2 It is cyano, F, Cl, -CH3, -OCH3, -CF3, -CHF2, or -CF3;

[0355] R 2a is -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, selected from -(CH2) 0-3 - Heterocyclic alkyl;

[0356] R 3 and R 4Together with the nitrogen attached to them, they form a mixture selected from... Heterocyclic alkyl groups;

[0357] R 5a It is hydrogen or F;

[0358] R 5b It is hydrogen or F;

[0359] R 5c It is Cl or -OCH3;

[0360] R 6 It can be hydrogen, oxo group, halo group, -CH3, -CHF2, -CF3 or -CH2OH;

[0361] R 7 It is hydrogen or -CH3;

[0362] R 8 It is hydrogen, C 1-2 Alkyl or -S(O)2C 1-3 Alkyl; and

[0363] R d It is -CH2OCH3.

[0364] Another aspect of the present invention is a compound of formula (VIa):

[0365]

[0366] Or its pharmaceutically acceptable salt, wherein:

[0367] Ar 1 yes

[0368] R 1 It is Cl, -CF3, CHF2, -OCHF2, -OCH3 or -OCF3;

[0369] R 2 It is cyano, F, Cl, -CH2OH, -CH3, -CHF2, -CF3, -OCH3, -OCH(CH3)2, -NR 3 R 4 (CH3)2(O)P-, C 3-6 cycloalkyl,

[0370] R 3 It is hydrogen or composed of 0-3 Rs. e Replacement C 1-4 alkyl,

[0371] R 4 It is hydrogen;

[0372] Alternatively, R 3 and R 4 Together with the nitrogen attached to them, they form a mixture selected from... Heterocyclic alkyl groups;

[0373] R 5a It is hydrogen or F;

[0374] R 5b It is hydrogen or F;

[0375] R 5c It is Cl or -OCH3

[0376] R 6 It can be hydrogen, halogroup, oxogroup, -CH3, -CH2CH3 or -CH2OH;

[0377] R 7 It is hydrogen or -CH3;

[0378] R 8 It is hydrogen, C 1-4 Alkyl or -S(O)2C 1-3 Alkyl; and

[0379] R e It is a halogenated group, -OR g -C(O)NR g R g -S(O)2C 1-4 Alkyl groups, comprising 1-4 ions selected from O, S, N, and NR g heteroatoms and 0-3 R f Substituted heteroaryl or heterocyclic alkyl groups;

[0380] R f It is a halogenated group, cyano group, hydroxyl group or C 1-4 Alkyl; and

[0381] R g Is it hydrogen or C? 1-3 alkyl.

[0382] Another aspect of the present invention is a compound of formula (VIIa):

[0383]

[0384] Or its pharmaceutically acceptable salt, wherein:

[0385] Ar 1 yes

[0386] R 1It is Cl, -CF3, CHF2, -OCHF2, -OCH3 or -OCF3;

[0387] R 2 It is F, Cl, -CH2OH, -CH3, -CHF2, -CF3, -OCH3, or -OCH(CH3)2;

[0388] R 5a It is hydrogen or F;

[0389] R 5b It is hydrogen or F;

[0390] R 5c It is Cl or -OCH3; and

[0391] R 7 It is hydrogen or -CH3.

[0392] Another aspect of the present invention is a compound of formula (VIIIa):

[0393]

[0394] Or its pharmaceutically acceptable salt, wherein:

[0395] Ar 1 yes

[0396] R 1 It is F, Cl, -CF3, CHF2, -OCHF2, -OCH3 or -OCF3;

[0397] R 3 It is hydrogen or composed of 0-2 R atoms. e Replacement C 1-4 alkyl;

[0398] R 4 It is hydrogen;

[0399] Alternatively, R 3 and R 4 Together with the nitrogen attached to them, they form a mixture selected from... Heterocyclic alkyl groups;

[0400] R 5a It is hydrogen or F;

[0401] R 5b It is hydrogen or F;

[0402] R 5c It is Cl or -OCH3;

[0403] R 6It can be hydrogen, halogroup, hydroxyl group, oxogroup, -CH3, -CH2CH3 or -CH2OH;

[0404] R 7 It is hydrogen or -CH3;

[0405] R 8 It is hydrogen, C 1-4 Alkyl or -S(O)2C 1-3 Alkyl; and

[0406] R e It is -OH, -OC 1-4 Alkyl group, -C(O)NHC 1-4 Alkyl group, -S(O)2C 1-4 alkyl,

[0407] Another aspect of the present invention is a compound of formula (XIIIa):

[0408]

[0409] Or its pharmaceutically acceptable salt, wherein:

[0410] Ar 2 yes

[0411]

[0412] X is CH2 or O;

[0413] R 1 It is a halogenated group, C 1-4 Halogenated alkyl or C 1-4 Halogenated alkoxy

[0414] R 1a It is methyl;

[0415] R 2 It is cyano, halogenated, C 1-4 Alkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, NR 3 R 4 ;

[0416] R 3 and R 4 Together with the nitrogen atoms attached to them, they form 4-6 membered heterocycles;

[0417] R 5a It is a halogenated group;

[0418] R5b It is a halogenated group; and

[0419] R 5c It is C 1-2 Alkyl group.

[0420] Another aspect of the present invention is a compound of formula (XIVa):

[0421]

[0422] Or its pharmaceutically acceptable salt, wherein:

[0423] Ar 2 yes

[0424]

[0425] X is CH2 or O;

[0426] R 1 It is a halogenated group, C 1-4 Halogenated alkyl or C 1-4 Halogenated alkoxy groups;

[0427] R 1a It is methyl;

[0428] R 2 It is cyano, halogenated, C 1-4 Alkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy or NR 3 R 4 ;

[0429] R 3 and R 4 Together with the nitrogen atoms attached to them, they form 4-6 membered heterocycles;

[0430] R 5a It is a halogenated group;

[0431] R 5b It is a halogenated group;

[0432] R 5c It is C 1-2 alkoxy groups; and

[0433] R 7 It is either hydrogen or methyl.

[0434] 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), including 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 The scope of any example of a variable substituent can be used independently of the scope of any other example of a variable substituent. Therefore, the invention includes combinations of different aspects.

[0435] Unless otherwise stated, these terms have the following meanings: "alkyl" means a straight-chain or branched alkyl group consisting of 1 to 6 carbon atoms. "alkenyl" means a straight-chain or branched alkyl group consisting of 2 to 6 carbon atoms having at least one double bond. "alkynyl" means a straight-chain or branched alkyl group consisting of 2 to 6 carbon atoms having at least one triple bond. "cycloalkyl" means a monocyclic ring system consisting of 3 to 7 carbon atoms. Terms with a hydrocarbon moiety (e.g., alkoxy) include straight-chain and branched isomers of the hydrocarbon moiety. "Halogenated" includes fluorine, chlorine, bromine, and iodine. "Halogenated alkyl" and "halogenated alkoxy" include all halogenated isomers from monohalogenated to perhalogenated. "Aryl" means a monocyclic or bicyclic aromatic hydrocarbon group having 6 to 12 carbon atoms, or a bicyclic fused ring system in which one or both rings are aromatic. Bicyclic fused ring systems consist of phenyl groups fused to four to seven-membered aromatic or non-aromatic carbon rings. Representative examples of aryl groups include, but are not limited to, phenyl, indenyl, indene, naphthyl, and tetrahydronaphthyl. "Heteroaryl" means a 5- to 7-membered monocyclic aromatic ring system or an 8- to 11-membered bicyclic aromatic ring system having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. If the bonding attachment site is not specified, the bond can be attached at any suitable location as understood by those skilled in the art. Combinations of substituents and bonding patterns are only those combinations that produce stable compounds as understood by those skilled in the art. Terms enclosed in parentheses and multiple parentheses are intended to clarify bonding relationships to those skilled in the art. For example, the term ((R)alkyl) means that the alkyl substituent is further substituted by the R substituent.

[0436] As used herein, “heterocyclic alkyl” means a non-aromatic monocyclic or polycyclic heterocycle having one or more cyclic heteroatoms selected from O, N, or S. Heterocyclic alkyl may also include spirocyclic and bridged rings, such as 5- to 8-membered bridged heterocyclic alkyl rings optionally substituted with 0 to 2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur. Examples of heterocyclic alkyl groups include pyrrolidine-2-one, 1,3-isooxazolidine-2-one, pyranyl, tetrahydropyran, oxacyclobutane, aziridine, morpholine, thiomorpholino, piperazine, tetrahydrofuranyl, tetrahydrothiophene, piperidinyl, pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, oxazolyl, thiazolyl, imidazolyl, aziridine, benzo[a]azazepium, aziridine[3.1.0]hexyl, diazabicyclo[3.1.0]hexyl, oxabicyclo[2.1.1]hexyl, aziridine[2.2.1]heptyl, diazabicyclo[2.2.1]heptyl, aziridine[3.1.1]heptyl, diazabicyclo[3.1.1]heptyl, aziridine[3.2.1]octyl, diazabicyclo[ 3.2.1] Octyl, oxabicyclo[2.2.2] Octyl, azibicyclo[2.2.2] Octyl, azidamaranyl, diazidamaranyl, oxadamane, azidspirol[3.3] Heptyl, diazidspirol[3.3] Heptyl, azidspirol[3.3] Heptyl, azidspirol[3.4] Octyl, diazidspirol[3.4] Octyl, azidspirol[3.4] Octyl, azidspirol[2.5] Octyl, diazidspirol[2.5] Octyl, azidspirol[4.4] Nonyl, diazidspirol[4.4] Nonyl, azidspirol[4.4] Nonyl, azidspirol[4.5] Decyl, diazidspirol[4.5] Decyl, diazidspirol[4.4] Nonyl, azidspirol[4.4] Nonyl, azidspirol[4.4] Nonyl, azidane, etc. The cyclic carbon atoms and heteroatoms of a heterocyclic alkyl group may optionally be substituted with oxo groups or sulfur bridges (e.g., C(O), S(O), C(S), or S(O)₂, etc.). The heterocyclic alkyl group may be attached via a cyclic carbon atom or a cyclic heteroatom. In some embodiments, the heterocyclic alkyl group contains 0 to 3 double bonds. In some embodiments, the heterocyclic alkyl group contains 0 to 2 double bonds. Heterocyclic alkyl groups containing fused aromatic rings may be attached via any cyclic atom (including the cyclic atom of the fused aromatic ring). In some embodiments, the heterocyclic alkyl group is a monocyclic or bicyclic 4-10 membered heterocyclic alkyl group having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur and having one or more oxide ring members.

[0437] As used herein, “cycloalkyl” refers to a non-aromatic cyclic hydrocarbon comprising cycloalkyl and / or alkenyl groups. Cycloalkyl groups may include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) groups, spirocyclic, and bridged rings. The cyclic carbon atom of a cycloalkyl group may optionally be substituted with an oxo group or a sulfur bridge (e.g., C(O) or C(S)). The definition of cycloalkyl also includes a portion having one or more aromatic rings fused to (i.e., sharing a common bond with) the cycloalkyl ring, such as benzo or thiophene derivatives of cyclopentane, cyclohexane, etc. Cycloalkyl groups containing fused aromatic rings can be attached by any cyclic atom (including the cyclic atom of the fused aromatic ring). Cycloalkyl groups may have 3, 4, 5, 6, 7, 8, 9, or 10 cyclic carbons (C 3-10 In some embodiments, the cycloalkyl group is C10. 3-10 Monocyclic or bicyclic cycloalkyl groups. In some embodiments, the cycloalkyl group is C10. 3-7 Monocyclic cycloalkyl group. In some embodiments, the cycloalkyl group is C10. 4-10 Spirocyclic or bridged cycloalkyl groups. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cyclohepttrienyl, norbornyl, norpinel, norcamphenyl, cubane, adamantane, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, spiro[3.3]heptyl, etc. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0438] “Cycloalkylalkyl” means an alkyl group in which at least one hydrogen atom is replaced by a cycloalkyl group as defined herein.

[0439] This invention includes all pharmaceutically acceptable salt forms of the compounds. Pharmaceutically acceptable salts are those in which the counterions do not significantly enhance the physiological activity or toxicity of the compounds and thus act as pharmacologically equivalents. These salts can be prepared using commercially available reagents according to commonly used organic techniques. Some anionic salt forms include acetates, stearates, benzenesulfonates, bromides, chlorides, citrates, fumarates, glucurons, hydrobroms, hydrochlorides, hydroiodates, iodides, lactates, maleates, methanesulfonates, nitrates, bis(hydroxynaphthyl) salts, phosphates, succinates, sulfates, tartrates, toluenesulfonates, and xinofoate. Some cationic salt forms include ammonium, aluminum, benzathine, bismuth, calcium, choline, diethylamine, diethanolamine, lithium, magnesium, meglumine, 4-phenylcyclohexylamine, piperazine, potassium, sodium, tromethamine, and zinc.

[0440] Some of the compounds of this invention exist in stereoisomeric forms, including those having the indicated carbon atoms. This invention includes all stereoisomers of the compounds, including enantiomers and diastereomers. Methods for preparing and isolating stereoisomers are known in the art. This invention includes all tautomers of the compounds. This invention includes both rotational and rotational isomers.

[0441] This invention aims to include all isotopes of atoms appearing in the said compounds. Isotopes include those atoms with the same number of atoms but different mass numbers. By way of general example and not limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include... 13 C and 14 C. The isotopically labeled compounds of the present invention can generally be prepared using conventional techniques known to those skilled in the art or by methods similar to those described herein, using a suitable isotopically labeled reagent instead of the originally employed unlabeled reagent. Such compounds can have many potential uses, such as as standards and reagents in the determination of biological activity. In the case of stable isotopes, such compounds can have the potential to advantageously alter biological, pharmacological, or pharmacokinetic properties.

[0442] Biological methods

[0443] N-formyl peptide receptors (FPRs) belong to the chemotactic receptor family and promote leukocyte responses in inflammatory processes. FPRs belong to the seven-transmembrane G protein-coupled receptor superfamily and are associated with inhibitory G proteins (Gi). Three family members (FPR1, FPR2, and FPR3) have been identified in humans, primarily distributed in bone marrow cells, and have also been reported in multiple organs and tissues. Upon agonist binding, FPRs activate various physiological pathways, such as intracellular signal transduction and calcium channel blockers. 2 + Mobilization and transcription. This family interacts with a diverse set of ligands, including proteins, peptides, and fatty acid metabolites that activate pro-inflammatory and pro-remission downstream responses. FPR2 and FPR1 cyclic adenosine monophosphate (cAMP) assays were used to measure the activity of the compounds in this patent.

[0444] FPR2 and FPR1 cyclic adenosine monophosphate (cAMP) assays were performed. A mixture of tuftin (final 5 μM for FPR2 or final 10 μM for FPR1) and IBMX (final 200 μM) was added to the test compound (final 1%) pre-treated in DMSO to spot at final concentrations ranging from 0.020 nM to 100 μM in 384-well Proxiplate (Perkin-Elmer). Chinese hamster ovary cells (CHO) overexpressing human FPR1 or human FPR2 receptors were cultured in F-12 (Ham's) medium supplemented with 10% qualified FBS, 250 μg / ml bleomycin, and 300 μg / ml hygromycin (Life Technologies). The reaction was initiated by adding 2,000 personal FPR2 cells / well or 4,000 personal 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 min. Intracellular cAMP levels were determined using the HTRF HiRange cAMP assay kit (Cisbio) according to the manufacturer's instructions. Solutions of anti-cAMP and d2-fluorophore-labeled cAMP conjugated to the crypts were prepared separately in the provided lysis buffer. After the reaction was complete, cells were lysed with equal volumes of d2-cAMP and anti-cAMP solutions. After incubation at room temperature for 1 h, time-resolved fluorescence intensity was measured using an Envision (Perkin-Elmer) at 400 nm excitation and dual emission at 590 nm and 665 nm. Calibration curves were constructed using external cAMP standards with concentrations ranging from 1 μM to 0.1 pM, by plotting the ratio of fluorescence intensity emitted from 665 nm to fluorescence intensity emitted from 590 nm against cAMP concentration. The potency and activity of the compounds in inhibiting cAMP production were then determined by fitting a 4-parameter logistic equation to the cAMP level versus compound concentration graph.

[0445] The examples disclosed below were tested in the above-described FPR2 and FPR1 cAMP assays and were found to have FPR2 and / or FPR1 agonist activity. Table 1 below lists the EC values ​​in the FPR2 and FPR1 cAMP assays measured for the following examples. 50 value.

[0446] Table 1

[0447]

[0448]

[0449]

[0450]

[0451] Pharmaceutical Compositions and Methods of Use

[0452] The compounds of the present invention can be applied to mammals, preferably humans, for the treatment of a variety of conditions and disorders, including: atherosclerosis, heart failure; lung diseases, including 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.

[0453] Unless otherwise stated, the following terms have the meanings described. The term "subject" means any person or other mammalian species who may potentially benefit from treatment with an FPR2 and / or FPR1 agonist as understood by those skilled in the art. Some subjects include humans of any age with cardiovascular disease risk factors. Common risk factors include age, sex, weight, family history, sleep apnea, alcohol or smoking, lack of exercise-induced arrhythmia, or signs of insulin resistance such as acanthosis nigricans, hypertension, dyslipidemia, or polycystic ovary syndrome (PCOS). The term "patient" means a person deemed suitable for therapy as determined by those skilled in the art. "Treating" includes treatment of a patient or subject as understood by those skilled in the art. "Preventing" includes preventative treatment (i.e., prevention and / or risk reduction) of a patient or subject for a subclinical disease-state, with the aim of reducing the likelihood of the occurrence of a clinical disease-state as understood by those skilled in the art. Patients are selected for preventative therapy based on factors known to increase the risk of developing a clinical disease-state compared to the general population. "Therapeutic effective amount" means the amount of compound that is effective as understood by those skilled in the art.

[0454] Another aspect of the present invention is a pharmaceutical composition comprising a combination of a therapeutically effective amount of a compound of formula (I) and a pharmaceutical carrier.

[0455] Another aspect of the present invention is a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) combined with at least one other therapeutic agent and a pharmaceutical carrier.

[0456] "Pharmaceutical composition" means a composition comprising a combination of the compounds of the present invention with at least one other pharmaceutically acceptable carrier. "Pharmaceutically acceptable carrier" refers to a medium generally accepted in the art for delivering bioactive agents to animals (particularly mammals), including adjuvants, excipients, or mediators such as diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, aromatizers, antibacterial agents, antifungal agents, lubricants, and dispersants, depending on the method of administration and the nature of the dosage form.

[0457] Pharmaceutically acceptable carriers are formulated based on a number of factors well understood by those skilled in the art. These include, but are not limited to, the type and nature of the active agent being formulated; the subject to whom the composition containing the pharmaceutical agent is to be administered; the intended route of administration of the composition; and the target therapeutic indication. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as various solid and semi-solid dosage forms. Such carriers may also include many different components and additives in addition to the active agent, such additional components being included in the formulation for a variety of reasons well known to those skilled in the art (e.g., stabilization of the active agent, binder, etc.). Descriptions of suitable pharmaceutically acceptable carriers and the factors involved in their selection can be found in a variety of readily available sources, such as Allen, LV, Jr. et al., Remington: The Science and Practice of Pharmacy (Vol. 2), 22nd ed., Pharmaceutical Press (2012).

[0458] In particular, when provided as a single dose unit, there is a possibility of chemical interactions between the combined active ingredients. For this reason, when the compounds of the present invention and the second therapeutic agent are combined in a single dose unit, they are formulated such that, although the active ingredients are combined in a single dose unit, the physical contact between the active ingredients is minimized (i.e., reduced). For example, one active ingredient may be enteric-coated. By enteric-coating one of the active ingredients, not only can the contact between the combined active ingredients be minimized, but the release of one of these components in the gastrointestinal tract can also be controlled, so that one of these components is released in the intestine rather than in the stomach. One of the active ingredients may also be coated with a material that affects sustained release throughout the gastrointestinal tract and also serves to minimize the physical contact between the combined active ingredients. Furthermore, a sustained-release component may be additionally enteric-coated so that the release of this component occurs only in the intestine. Another approach involves formulating a combination product in which one component is coated with a sustained-release and / or enteric-release polymer, and another component is also coated with a polymer (such as low-viscosity hydroxypropyl methylcellulose (HPMC)) or other suitable materials as known in the art, to further separate the active components. The polymer coating serves to form an additional barrier against interaction with the other component.

[0459] Another aspect of the present invention is a method for treating heart disease, the method comprising administering a therapeutically effective amount of a compound of formula (I) to a patient.

[0460] Another aspect of the present invention is a method for treating heart disease, wherein the heart disease is selected from angina pectoris, unstable angina pectoris, myocardial infarction, heart failure, acute coronary artery disease, acute heart failure, chronic heart failure, and iatrogenic cardiac damage.

[0461] It should be understood that the treatment or prevention of heart failure can also involve the treatment or prevention of cardiovascular events. As used herein, treatment or prevention can refer to the treatment or prevention of certain negative symptoms or conditions associated with or caused by a cardiovascular event. For example, treatment or prevention can involve reducing or preventing negative changes in short-axis shortening, heart weight, lung weight, myocyte cross-sectional area, stress overload-induced cardiac fibrosis, stress-induced cellular senescence and / or cardiac hypertrophic characteristics, or any combination thereof, associated with or caused by a cardiovascular event. Treatment can be administered to prepare for or respond to a cardiovascular event to mitigate its negative effects. Prevention can involve active or preventative treatments to prevent cardiovascular events or reduce their negative impacts.

[0462] In one embodiment, the present invention provides the use of compounds of formula (I)-(XIVa) or pharmaceutically acceptable salts thereof in the preparation of pharmaceutical compositions for the treatment or prevention of heart failure, for example, heart failure caused by: 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, gingivitis, drug abuse, alcohol abuse, pericarditis, atherosclerosis, vascular disease, hypertrophic cardiomyopathy, dilated cardiomyopathy, myocardial infarction, atrial fibrosis, left ventricular systolic dysfunction, left ventricular diastolic dysfunction, coronary artery bypass grafting, 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 ejection fraction (HF). R EF), heart failure with preserved ejection fraction (HF) P EF), acute heart failure, and chronic heart failure of ischemic and non-ischemic origin.

[0463] In one embodiment, the present invention provides the use of compounds of formula (I)-(XIVa) for treating systolic and / or diastolic dysfunction, wherein the compounds are administered in a therapeutically effective amount to increase the ability of myocardial cells to contract and relax, thereby increasing the filling and emptying of the right ventricle and left ventricle (preferably the left ventricle).

[0464] In another embodiment, the present invention provides the use of compounds of formula (I)-(XIVa) for the treatment of heart failure, wherein the compounds are administered in a therapeutically effective amount to increase the ejection fraction in the left ventricle.

[0465] In yet another embodiment, the present invention provides the use of compounds of formula (I)-(XIVa) for the treatment of heart failure, wherein the compounds are administered in a therapeutically effective amount to reduce fibrosis in cardiac tissue.

[0466] Another aspect of the present invention is a method for treating heart disease, wherein the treatment is performed after a myocardial infarction.

[0467] Another aspect of the present invention is a method for treating heart disease, the method comprising administering a therapeutically effective amount of a compound of formula (I)-(XIVa) in combination with other therapeutic agents to a patient.

[0468] The compounds of the invention may be administered by any of the following suitable methods: for example, orally, such as tablets, capsules (each of which includes sustained-release or timed-release formulations), pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions), syrups, and emulsions; sublingually; buccally; parenterally, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally, including application to a nasal membrane, such as by inhalation spray; externally, such as in the form of creams or ointments; or rectally, such as in the form of suppositories. They may be administered alone, but will generally be administered in conjunction with a drug carrier selected based on the chosen route of administration and standard pharmaceutical practice.

[0469] Of course, the dosing regimen of the compounds of the present invention will vary according to known factors such as the pharmacodynamic characteristics of the particular agent and its administration method and route; the species, age, sex, health, medical condition and weight of the recipient; the nature and severity of symptoms; the type of concurrent treatment; the frequency of treatment; the route of administration, the patient's renal and hepatic function and the desired effect.

[0470] As a general guideline, when used for the indicated effects, the daily oral dose of each active ingredient will range from about 0.01 to about 5000 mg / day, preferably from about 0.1 to about 1000 mg / day, and most preferably from about 0.1 to about 250 mg / day. Intravenously, during a constant rate infusion, the most preferred dose range will be from about 0.01 to about 10 mg / kg / min. The compounds of the invention can be administered in a single daily dose, or the total daily dose can be administered in divided doses twice, three, or four times daily.

[0471] Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 mg to about 2000 mg of active ingredient per dose unit. In these pharmaceutical compositions, the active ingredient will generally be present in an amount of about 0.1% to 95% by weight based on the total weight of the composition. Typical capsules for oral administration contain 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 filled into No. 1 gelatin capsules. Typical injectable formulations are produced by aseptically placing at least one compound of the present invention (250 mg) into a vial, aseptically freeze-drying it, and sealing it. When used, the contents of the vial are mixed with 2 mL of physiological saline to produce an injectable formulation.

[0472] The compounds of the present invention can be used in combination with other suitable therapeutic agents for treating the aforementioned diseases or disorders, including: anti-atherosclerotic agents, anti-dyslipidemia agents, anti-diabetic agents, anti-hyperglycemic agents, anti-hyperinsulinemia agents, antithrombotic agents, anti-retinopathy agents, anti-neuropathy agents, anti-nephropathy agents, anti-ischemic agents, antihypertensive agents, anti-obesity agents, anti-hyperlipidemia agents, anti-hypertriglyceridemia agents, anti-hypercholesterol agents, anti-restenosis agents, anti-pancreatic agents, lipid-lowering agents, anorexia agents, memory-enhancing agents, anti-dementia agents, cognitive-promoting agents, appetite suppressants, agents for treating heart failure, agents for treating peripheral artery disease, agents for treating malignant tumors, and anti-inflammatory agents.

[0473] The compounds of this invention can be used with at least one heart failure agent selected from loop diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), angiotensin receptor-neprilysin inhibitors (ARNIs), beta-blockers, mineralocorticoid receptor antagonists, nitroglycerin donors, RXFP1 agonists, APJ agonists, and cardiotonic agents. These agents include, but are not limited to, furosemide, bumetanide, torasemide, sacubitrial-valsartan, thiazide diuretics, captopril, enalapril, lisinopril, carvedilol, metoprolol, bisoprolol, serelaxin, spironolactone, eplerenone, ivabradine, candesartan, eprisartan, irbestarain, losartan, olmesartan, telmisartan, and valsartan.

[0474] The compounds of the present invention can be used in combination with at least one of the following therapeutic agents in the treatment of atherosclerosis: anti-hyperlipidemic agents, plasma HDL-raising agents, anti-hypercholesterol agents, cholesterol biosynthesis inhibitors (such as HMGCoA reductase inhibitors), LXR agonists, probucol, raloxifene, nicotinic acid, nicotinamide, cholesterol absorption inhibitors, bile acid chelators (such as anion exchange resins, or quaternary ammonium compounds (e.g., cholestyramine or colestipol)), low-density lipoprotein receptor inducers, clofibrate, fenofibrate, bezafibrate, ciprofibrate, gemfibrozil, vitamin B6, vitamin B12. 12 Antioxidant vitamins, beta-blockers, antidiabetic drugs, angiotensin II antagonists, angiotensin-converting enzyme inhibitors, platelet aggregation inhibitors, fibrinogen receptor antagonists, aspirin, and fibrinolytic derivatives.

[0475] The compounds of the present invention can be used in treatment in combination with at least one of the following therapeutic agents: 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.

[0476] The compounds of the present invention can be used in combination with at least one of the following antidiabetic agents, depending on the desired target therapy. Studies have shown that adding a second agent to a treatment regimen can further improve the regulation of diabetes and hyperlipidemia. Examples of antidiabetic agents include, but are not limited to, sulfonylureas (such as chlorpropamide, tolbutamide, acetobenzylidene sulfonylurea, mesylate, glyburide, gliclazide, glynase, glimepiride, and glipizide), biguanides (such as metformin), thiazolidinediones (such as cycloglitazone, pioglitazone, troglitazone, and rosiglitazone), and related insulin sensitizers (such as selective and non-selective activators of PPARα, PPARβ, and PPARγ); dehydroepiandrosterone (also... The following are prohibited: DHEA (or its conjugated sulfates, DHEA-SO4); anti-glucocorticoids; TNFα inhibitors; dipeptidyl peptidase IV (DPP4) inhibitors (such as sitagliptin and 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 pancreatic peptide), other insulin secretagogues (such as repaglinide, glibenclamide, and nateglinide), insulin, and the above-mentioned therapeutic agents used to treat atherosclerosis.

[0477] The compounds of the present invention can be used in combination with at least one anti-obesity agent selected from the following: phenylpropanolamine, phenbutazone, amphetamine, malindole, benfluramine, dexfenfluramine, phentiramine, β3-adrenergic receptor agonists; sibutramine, gastrointestinal lipase inhibitors (such as orlistat), and leptin. Other agents for treating obesity or obesity-related disorders include neuropeptide Y, enterostatin, cholecystokinin, bufotoxin, amylin, histamine H3 receptor, dopamine D2 receptor modulators, melanocyte-stimulating hormone, corticotropin-releasing factor, glycopropylthiouracil, and gamma-aminobutyric acid (GABA).

[0478] The compounds of the present invention can also be used as standard or reference compounds in tests or assays involving FPR2, for example, as quality standards or controls. Such compounds can be provided in commercial kits, for example, for use in pharmaceutical studies involving FPR2 activity. For example, the compounds of the present invention can be used as references in assays to compare their known activities with those of compounds having unknown activities. This ensures that the experimenter performs the assay correctly and provides a basis for comparison, especially if the test compound is a derivative of the reference compound. When developing new assays or protocols, the compounds according to the present invention can be used to test their effectiveness. The compounds of the present invention can also be used in diagnostic assays involving FPR2.

[0479] This invention also covers articles of manufacture. As used herein, articles of manufacture are intended to include, but are not limited to, kits and packaging. Articles of manufacture of the present invention comprise: (a) a first container; (b) a pharmaceutical composition located within the first container, wherein the composition comprises: a first therapeutic agent comprising a compound of the present invention or a pharmaceutically acceptable salt thereof; and (c) a package insert indicating that the pharmaceutical composition can be used to treat dyslipidemia and its sequelae. In another embodiment, the package insert indicates that the pharmaceutical composition can be used in combination with a second therapeutic agent for treating dyslipidemia and its sequelae (as previously defined). Articles of manufacture may further comprise: (d) a second container wherein components (a) and (b) are located within the second container, and component (c) is located within or outside the second container. Located within the first and second containers means that the respective containers hold the article within their boundaries. The first container is a receiving container for holding the pharmaceutical composition. This container can be used for manufacturing, storage, transportation, and / or individual / bulk sales. The first container is intended to cover bottles, jars, vials, flasks, syringes, tubes (e.g., for cream formulations) or any other container for manufacturing, holding, storing, or dispensing pharmaceutical products. The second container is used to hold the first container and, optionally, the drug information leaflet. Examples of the second container include, but are not limited to, boxes (e.g., cardboard or plastic), crates, cartons, bags (e.g., paper or plastic bags), pouches, and large bags. The drug information leaflet may be physically attached to the outside of the first container via tape, glue, staples, or another attachment method, or it may remain inside the second container without any physical attachment to the first container. Alternatively, the drug information leaflet may be located on the outside of the second container. When located on the outside of the second container, it is preferred that the drug information leaflet be physically attached via tape, glue, staples, or another attachment method. Alternatively, it may be adjacent to or in contact with the outside of the second container, rather than physically attached. Packaging inserts are labels, tags, markers, etc., that list information relating to the pharmaceutical composition located within the first container. The listed information will generally be determined by the regulatory agency in the region where the product to be sold is regulated (e.g., the U.S. Food and Drug Administration). Preferably, the drug information leaflet specifically states the approved indications for the pharmaceutical composition. The package insert can be made of any material in which or on which information is readable by a person. Preferably, the package insert is a printable material (e.g., paper, plastic, cardboard, foil, adhesive paper, or plastic, etc.) on which the desired information has been formed (e.g., printed or applied).

[0480] Chemical methods

[0481] The abbreviations used in this article are defined as follows: "1x" means once, "2x" means twice, "3x" means three times, "°C" means degrees Celsius, "aq" means aqueous, "Col" means column, "eq" means one or more equivalents, "g" means gram, "mg" means milligram, "L" means liter, "mL" means milliliter, "μL" means microliter, "N" means equivalent concentration, "M" means mole, "nM" means nanomolar, "mol" means mole, "mmol" means millimole, "min" means minute, "h" means hour, "rt" means room temperature, "RT" means retention time, "ON" means overnight, "atm" means atmospheric pressure, "psi" means pounds per square inch, "conc." means concentrated, "aq" means "aqueous", "sat" or "sat'd" means saturated, "MW" means molecular weight, "mw" or "μwave" means microwave, "mp" means melting point, "Wt" means weight, "MS" or "Mass" means... "Spec" indicates mass spectrometry, "ESI" indicates electrospray ionization mass spectrometry, "HR" indicates high resolution, "HRMS" indicates high resolution mass spectrometry, "LCMS" indicates liquid chromatography-mass spectrometry, "HPLC" indicates high performance liquid chromatography, "RP HPLC" indicates reversed-phase HPLC, "TLC" or "tlc" indicates thin-layer chromatography, "NMR" indicates nuclear magnetic resonance spectroscopy, and "nOe" indicates nuclear overhausen effect spectroscopy. 1 "H" represents proton, "δ" represents delta, "s" represents singlet, "d" represents doublet, "t" represents triplet, "q" represents quartet, "m" represents multiplet, "br" represents broad peak, "Hz" represents Hertz, and "α", "β", "R", "S", "E" and "Z" are stereochemical names familiar to those skilled in the art.

[0482]

[0483]

[0484] The disclosed compounds can be prepared by a variety of methods known in the art, including those described in the following sections on specific embodiments. The structure and variable designations shown in the synthetic embodiments differ from and should not be confused with those in the claims or the remainder of the specification. The variables in the embodiments are intended only to illustrate how some of the compounds of the invention can be prepared.

[0485] This disclosure is not limited to the foregoing illustrative embodiments, and the embodiments should be considered illustrative rather than restrictive in all respects, and are therefore intended to include all variations within the meaning and scope of the equivalents of the claims.

[0486] A consideration in planning any synthetic route in this field is the selection of protecting groups for protecting the reactive functional groups present in the compounds described in this invention. An authoritative report describing this to trained practitioners is Greene, TW et al., Protecting Groups in Organic Synthesis, 4th ed., Wiley (2007).

[0487] Where A, B, and C respectively correspond to Ar 2 Ar 3 and Ar 1 Compounds of general formula (I'), (II') or (III') can be prepared by one or more of the following synthetic methods.

[0488]

[0489] The 1-arylpyrrolidone compounds of the present invention, wherein ring A and ring B are substituted phenyl or heteroaryl rings, can be prepared via the general route shown in Scheme 1. Compound 1a is synthesized according to the procedure reported in patent document (WO 2015079692). Compound 1b, wherein PG is a protecting group (such as Boc or Cbz compounds), is synthesized via Curtius rearrangement (e.g., treating 1a with diphenyl azidophosphate (DPPA) and a tertiary amine such as triethylamine (TEA)). Subsequently, benzyl alcohol is added to give Cbz-protected compound 1b. In the presence of a base (such as potassium carbonate or cesium carbonate) and a suitable ligand (such as N,N'-dimethylethylenediamine or Xanthphos), in a suitable solvent (such as butanol, dioxane, or toluene), copper- or Pd-catalyzed coupling of 1b with a substituted heteroaryl compound yields the desired compound 1c. Suitable heteroaryl halides are commercially available or readily obtained from readily available starting materials by methods known to those skilled in the art. Other methods for this conversion include variations of methods known to those skilled in the art for these coupling types, depending on the nature of ring B, involving Ullmann, Goldberg, and Buchwald copper-catalyzed amidation or Buchwald Pd-catalyzed CN coupling (see, for example, 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). Removing the protecting group from 1c and then condensing the resulting free amine with a suitably substituted aryl isocyanate, cycloalkyl isocyanate, or cycloalkyl acid can provide urea 1d. Suitable isocyanates or cycloalkyl acids are commercially available or readily obtainable by methods known to those skilled in the art.

[0490] Similarly, the 1-arylpyrrolidone compounds of the present invention (formula (I'), (II') or (III')) wherein ring A and ring B are substituted phenyl rings or heteroaryl rings can be prepared by the general route shown in Scheme 2.

[0491]

[0492] Other features of the invention will become clear in the following description of exemplary embodiments given for the purpose of illustrating the invention and not intended to limit it.

[0493] Unless otherwise specified, the following methods are used in the exemplary embodiments. Purification of intermediates and final products is performed by normal-phase or reversed-phase chromatography. Unless otherwise instructed, normal-phase chromatography is performed using a pre-packed SiO2 column with gradient elution of hexane and ethyl acetate or DCM and MeOH. Reversed-phase preparative HPLC was performed using a C18 column with UV 220 nm or preparative LCMS detection. Elution was performed using a gradient of solvent A (90% water, 10% MeOH, 0.1% TFA) and solvent B (10% water, 90% MeOH, 0.1% TFA), or a gradient of solvent A (95% water, 5% Acn, 0.1% TFA) and solvent B (5% water, 95% Acn, 0.1% TFA), or a gradient of solvent A (95% water, 2% Acn, 0.1% HCOOH) and solvent B (98% Acn, 2% water, 0.1% HCOOH), or a gradient of solvent A (95% water, 5% Acn, 10mM NH4OAc) and solvent B (98% Acn, 2% water, 10mM NH4OAc). Elution can be performed using a gradient of NH4OAc, or a gradient of solvent A (98% water, 2% Acn, 0.1% NH4OH) and solvent B (98% Acn, 2% water, 0.1% NH4OH).

[0494] The LC / MS method used to characterize the embodiments. In conjunction with Waters Reversed-phase analytical HPLC / MS was performed on a Waters Acquity system coupled to the ZQ mass spectrometer.

[0495] Method A: A linear gradient from 0 to 100% B over 3 minutes, with a hold time of 0.75 minutes at 100% B;

[0496] UV visualization at 220nm

[0497] Column: Waters BEH C18 2.1 x 50mm

[0498] Flow rate: 1.0 mL / min

[0499] Solvent A: 0.1% TFA, 95% water, 5% Acn

[0500] Solvent B: 0.1% TFA, 5% water, 95% Acn

[0501] Method B: A linear gradient from 0 to 100% B over 3 minutes, with a hold time of 0.75 minutes at 100% B;

[0502] UV visualization at 220nm

[0503] Column: Waters BEH C18 2.1 x 50mm

[0504] Flow rate: 1.0 mL / min

[0505] Solvent A: 10mM ammonium acetate, 95% water, 5% Acn

[0506] Solvent B: 10mM ammonium acetate, 5% water, 95% Acn

[0507] Analytical HPLC: A method for characterizing the examples

[0508] Product analysis was performed using reversed-phase analytical HPLC on a Shimadzu analytical HPLC system running Discovery VP software. RT = retention time.

[0509] 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: 0-100% B for 3 min, then hold at 100% B for 1 min; Flow rate: 1.1 mL / min.

[0510] Method D: Ascentis Express C18, 2.1 x 50 mm, 2.7 μm particles; Solvent A: 95% water, 5% acetonitrile (containing 10 mM ammonium acetate); Solvent B: 95% acetonitrile, 5% water (containing 10 mM ammonium acetate); Temperature: 50 °C; Gradient: 0-100% B for 3 minutes, then held at 100% B for 1 minute; Flow rate: 1.1 mL / min.

[0511] Method E: Kinetex biphenyl (4.6 x 100) 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: 0-100% B for 3 min, then hold at 100% B for 1 min; Flow rate: 1.1 mL / min.

[0512] Method F: Ascentis Express C18, 2.1 x 50 mm, 2.7 μm particles; Solvent A: 95% water, 5% acetonitrile (containing 10 mM ammonium formate); Solvent B: 95% acetonitrile, 5% water (containing 10 mM ammonium formate); Temperature: 50 °C; Gradient: 0-100% B for 3 minutes, then held at 100% B for 1 minute; Flow rate: 1.1 mL / min.

[0513] SFC and chiral purity methods

[0514] 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).

[0515] 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).

[0516] 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).

[0517] NMR was used to characterize the embodiments. A Bruker or [other] system operating at the following frequencies was used. Fourier transform spectrometer obtained 1 H NMR spectrum: 1 H NMR: 300MHz (Bruker or ) or 400MHz (Bruker or ) or 500MHz (Bruker or ). 13 C NMR: 100MHz (Bruker or Spectral data are reported in the following format: chemical shifts (multiplicity, coupling constant, and hydrogen number). Chemical shifts at the low field of the tetramethylsilane internal standard are specified in ppm (δ units, tetramethylsilane = 0 ppm) and / or reference solvent peaks, where the solvent peaks are located at... 1 In the 1H NMR spectrum, it appears at 2.49 ppm for CD2HSOCD3, 3.30 ppm for CD2HOD, 1.94 ppm for CD3CN, and 7.24 ppm for CHCl3, and... 13 The C NMR spectra show values ​​at 39.7 ppm for CD3SOCD3, 49.0 ppm for CD3OD, and 77.0 ppm for CDCl3. All 13 C NMR spectra are all proton-decoupled.

[0518] Intermediate 1: 4-(2-chloro-3-(trifluoromethyl)pyridin-4-yl)morpholine

[0519]

[0520] Morpholine (202 mg, 0.78 mmol) and Cs₂CO₃ (754 mg, 2.32 mmol) were added to a stirred solution of 2,4-dichloro-3-(trifluoromethyl)pyridine (500 mg, 2.3 mmol) in 1,2-dichloroethane (5 mL). The reaction mixture was heated at 80 °C for 16 hours. The reaction mixture was then cooled, filtered through a diatomaceous earth (Celite) pad, and the filtrate was concentrated under reduced pressure to give a 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. The purified fraction was 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 using 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).

[0521] Intermediate 2: ((3S,4R)-4-(2,6-difluoro-4-methoxyphenyl)-1-(4-morpholino-3-(trifluoromethyl)pyridin-2-yl)-2-oxopyrrolidine-3-yl) tert-butyl carbamate

[0522]

[0523] At room temperature, 4-(2-chloro-3-(trifluoromethyl)pyridin-4-yl)morpholine (171 mg, 0.643 mmol), Cs₂CO₃ (381 mg, 1.17 mmol), and Xantphos (67.6 mg, 0.117 mmol) were added to a stirred solution of ((3S,4R)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidone-3-yl)carbamate (200 mg, 0.584 mmol) in 1,4-dioxane (3 mL). The reaction mixture was purged with nitrogen for 5 min, and then Pd₂(dba)₃ (54 mg, 0.058 mmol) was added. The reaction mixture was again purged with nitrogen for 3 min and heated at 100 °C for 16 h. The brown reaction mixture was cooled, filtered through a diatomaceous earth pad, and the filtrate was concentrated under reduced pressure to give the crude compound. The crude compound 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. The purified fraction was 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-oxopyrrolidine-3-yl)carbamate (200 mg, 0.35 mmol, 60% yield) as a pale yellow solid. MS (ESI) m / z: 573.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ = 8.45 (d, J = 5.7Hz, 1H), 7.34 (br s,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).

[0524] Intermediate 3: (3S,4R)-3-amino-4-(2,6-difluoro-4-methoxyphenyl)-1-(4-morpholino-3-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2-one hydrochloride

[0525]

[0526] At 0 °C, 4 M HCl in 1,4-dioxane (0.87 mL, 3.5 mmol) was added to a stirred solution of ((3S,4R)-4-(2,6-difluoro-4-methoxyphenyl)-1-(4-morpholino-3-(trifluoromethyl)pyridin-2-yl)-2-oxopyrrolidine-3-yl)carbamate (0.20 g, 0.35 mmol) in 1,4-dioxane (2 mL). The reaction mixture was stirred at room temperature for another 3 hours and concentrated under reduced pressure to give a crude compound, which was then ground with diethyl ether to give (3S,4R)-3-amino-4-(2,6-difluoro-4-methoxyphenyl)-1-(4-morpholino-3-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2-one, HCl (160 mg, 0.31 mmol, 90% yield) as a pale yellow solid. MS(ESI) m / z: 473.3 [M+H] + Intermediate 4: Methyl 2-(3-bromo-2-oxopyridin-1(2H)-yl)-3-methoxypropionate

[0527]

[0528] K₂CO₃ (12 g, 86 mmol) and methyl 2-bromo-3-methoxypropionate (5.8 mL, 43 mmol) were added to a stirred solution of 3-bromopyridin-2(1H)-one (5.0 g, 29 mmol) in DMF (30 mL) at room temperature. The reaction mixture was then stirred at room temperature for an additional 16 hours. The reaction mixture was cooled, filtered through a diatomaceous earth pad, and the filtrate was concentrated under reduced pressure to give a 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-methoxypropionate (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).

[0529] Intermediate 5: 3-bromo-1-(1-hydroxy-3-methoxypropane-2-yl)pyridin-2(1H)-one

[0530]

[0531] Sodium borohydride (0.2 g, 5.2 mmol) was added to a stirred solution of methyl 2-(3-bromo-2-oxopyridin-1(2H)-yl)-3-methoxypropionate (1.0 g, 3.5 mmol) in MeOH (10 mL) at 0 °C. The reaction mixture was gradually warmed to room temperature over a period of 3 hours and then quenched with water. The reaction mixture was then extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous NH4Cl solution brine, dried over Na2SO4, and concentrated under reduced pressure to give crude 3-bromo-1-(1-hydroxy-3-methoxypropane-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 ¹H 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). Intermediate 6: ((3S,4R)-4-(2,6-difluoro-4-methoxyphenyl)-1-(1-(1-hydroxy-3-methoxypropane-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2-oxopyrrolidine-3-yl) tert-butyl carbamate

[0532]

[0533] At room temperature, 3-bromo-1-(1-hydroxy-3-methoxyphenyl)-2-oxopyrrolidone-3-yl)carbamate tert-butyl (250 mg, 0.73 mmol) was added to a stirred solution of ((3S4R)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidone-3-yl)carbamate (5 mL), cesium carbonate (476 mg, 1.46 mmol), and N,N'-dimethylethylenediamine (0.016 mL, 0.15 mmol). The reaction mixture was purged with nitrogen for 5 min, and then copper iodide (I) (14 mg, 0.073 mmol) was added. The reaction mixture was again purged with nitrogen for 3 min and heated at 100 °C for 16 h. The reaction mixture was cooled, filtered through a diatomaceous earth pad, and the filtrate was concentrated under reduced pressure to give the crude compound. The crude compound 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 give tert-butyl ((3S,4R)-4-(2,6-difluoro-4-methoxyphenyl)-1-(1-(1-hydroxy-3-methoxypropane-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2-oxopyrrolidine-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).

[0534] Intermediate 7: 3-((3S,4R)-3-amino-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidone-1-yl)-1-(1-hydroxy-3-methoxypropane-2-yl)pyridine-2(1H)-one hydrochloride

[0535]

[0536] A solution of 4M HCl in 1,4-dioxane (1.2 mL, 4.8 mmol) was added to a stirred solution of ((3S,4R)-4-(2,6-difluoro-4-methoxyphenyl)-1-(1-(1-hydroxy-3-methoxypropane-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2-oxopyrrolidine-3-yl)carbamate (250 mg, 0.48 mmol) in 1,4-dioxane (5 mL). The reaction mixture was gradually warmed to room temperature over a period of 2 hours. The reaction mixture was then concentrated under reduced pressure to obtain a gelatinous solid, which was further ground with diethyl ether and dried under high vacuum to give 3-((3S,4R)-3-amino-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidine-1-yl)-1-(1-hydroxy-3-methoxypropane-2-yl)pyridine-2(1H)-one hydrochloride (200 mg, 0.44 mmol, 91% yield) as a brown solid. MS (ESI) m / z: 424.2 [M+H] + .

[0537] Intermediate 8: 6-Methoxy-1,2,3,4-Tetrahydronaphthalene-2-carboxylic acid

[0538]

[0539] Compound 8 was chiralized using a chiral SFC. Enantiomers 8A and 8B were used in the reaction. SFC preparation conditions: column / size: Whelk(R,R) (250 x 30) mm, 5 μm; % CO2: 90%; % cosolvent: 10% 4M methylamine in 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 ¹H NMR (400MHz, DMSO-d⁶) δ=12.22(br s, 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: 1H NMR(400MHz,DMSO-d6)δ=12.22(br s,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).

[0540] Example 1: 1-((3S,4R)-4-(2,6-difluoro-4-methoxyphenyl)-1-(4-morpholino-3-(trifluoromethyl)pyridin-2-yl)-2-oxopyrrolidine-3-yl)-3-((1r,4S)-4-(difluoromethyl)cyclohexyl)urea

[0541]

[0542] TEA (0.043 mL, 0.309 mmol) and diphenyl azide phosphate (0.067 mL, 0.31 mmol) were added 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). The reaction mixture was stirred at room temperature for 3 hours, followed by stirring at 80 °C for 30 min. Then, the reaction mixture was cooled to room temperature, intermediate 3 (80 mg, 0.17 mmol) was added, and the mixture was stirred at room temperature for another 16 hours. The reaction mixture was filtered through a diatomaceous earth pad and evaporated under reduced pressure to give a crude product as a brown solid. The crude product was purified by reversed-phase HPLC to give a grayish-white solid of 1-((3S,4R)-4-(2,6-difluoro-4-methoxyphenyl)-1-(4-morpholino-3-(trifluoromethyl)pyridin-2-yl)-2-oxopyrrolidine-3-yl)-3-((1r,4S)-4-(difluoromethyl)cyclohexyl)urea (10 mg, 0.015 mmol, 5.3% yield). MS (ESI) m / z: 643.3 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ=8.49-8.35(m,1H),7.20(d,J=5.6Hz,1H),6.77(d,J=10.8H z,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).

[0543] Examples 2 and 3: 1-((3S,4R)-4-(2,6-difluoro-4-methoxyphenyl)-1-(1-(1-hydroxy-3-methoxypropane-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2-oxopyrrolidine-3-yl)-3-(6-methoxy-1,2,3,4-tetrahydronaphthyl-2-yl)urea

[0544]

[0545] TEA (0.043 mL, 0.31 mmol) and diphenyl azide phosphate (0.067 mL, 0.31 mmol) were added 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). The reaction mixture was stirred at room temperature for 3 hours, followed by stirring at 80 °C for 30 min. Then, the reaction mixture was 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 diatomaceous earth pad and evaporated under reduced pressure to give a crude product as a brown solid. The crude product was purified by reversed-phase HPLC, followed by chiral SFC, to give 1-((3S,4R)-4-(2,6-difluoro-4-methoxyphenyl)-1-(1-(1-hydroxy-3-methoxypropane-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2-oxopyrrolidine-3-yl)-3-(6-methoxy-1,2,3,4-tetrahydronaphthyl-2-yl)urea (Example). 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-methoxypropane-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2-oxopyrrolidine-3-yl)-3-(6-methoxy-1,2,3,4-tetrahydronaphthyl-2-yl)urea (Example 3, diastereomer B, 25 mg, 0.040 mmol, 13% yield). SFC preparation conditions: column / size: Chiralpak IC (250 x 21) mm, 5 μm; % CO2: 65%; % cosolvent: 35% 4M methanolamine in MeOH. Total flow rate: 90.0 g / min, back pressure: 100 bar, temperature: 35℃, UV: 222 nm; retention time: peak 1 = 7.6 min and peak 2 = 10.1 min. Example 2, diastereomer A: MS (ESI) m / z: 627.4 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ = 7.67 (dd, J = 7.0, 1.9 Hz, 1H), 7.52 ( dd, J = 7.1, 1.9 Hz, 1H), 6.93 ( d, J = 8.3 Hz,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=7.6H z,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).

[0546] The following embodiments in Table 2 are manufactured using a similar procedure to that shown in Examples 1-3.

[0547] Table 2

[0548]

[0549]

[0550]

[0551]

[0552]

[0553]

[0554]

[0555]

[0556]

[0557]

[0558]

[0559]

[0560]

[0561]

[0562]

[0563]

[0564]

[0565]

[0566]

[0567]

[0568]

[0569]

[0570]

[0571]

[0572]

[0573]

[0574]

[0575]

[0576]

[0577] It will be clear to those skilled in the art that this disclosure is not limited to the foregoing illustrative embodiments, and that it may be embodied in other specific forms without departing from the essential nature of this disclosure. Therefore, it is intended that the embodiments be considered illustrative rather than restrictive in all respects, with reference to the appended claims rather than the foregoing embodiments, and all variations falling within the meaning and scope of the equivalents of the claims are intended to be included therein.

Claims

1. A compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein: p is 0, 1, or 2.

2. The compound according to claim 1, having Formula (II): or a pharmaceutically acceptable salt thereof, wherein: p is 2. Ar 1 is Ar 2 is Ar is phenyl substituted with 1 R 3 , 1 R 5a , 1 R 5b , and 1 R 5c . R 1 is halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 1-4 haloalkoxy; R 2 is halo, C e 1-4 alkyl substituted by 0-5 R 1-6 , -OR b , -NR 3 R 4 or 5 to 6 membered heteroaryl or heterocycloalkyl comprising 1-4 heteroatoms selected from O, S(O) p , N and NR a ; R 2a is hydrogen or C e alkyl substituted by 0-5 R 1-4 alkyl; R 3 is hydrogen, C e substituted C 1-4 alkyl, oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl; R 4 is hydrogen or C 1-4 alkyl; Alternatively, R 3 and R 4 together with the nitrogen to which they are both attached form a 4- to 9-membered heteroaryl or heterocycloalkyl group comprising 1-4 heteroatoms selected from O, S(O)p, N and NR 8 substituted with 1-3 R 6 substituted with 1-3 R 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 C 1-4 deuteroalkoxy; R 6 is hydrogen, halo, oxo, hydroxy, or C e alkyl substituted with 0-5 R 1-4 alkyl; R 7 is hydrogen or C 1-4 alkyl; R 8 is hydrogen, C 1-4 alkyl or -S(O) p R c ; R a is hydrogen or C e alkyl substituted by 0-5 R 1-6 alkyl; R b is hydrogen or C e alkyl substituted by 0-5 R 1-6 alkyl; R c is C e alkyl substituted by 0-5 R 1-4 alkyl; R d is hydrogen or C e alkyl substituted by 0-5 R 1-4 alkyl; R e is halo, -OR g , -NR g R g , -C(O)NR g R g , -S(O) p C 1-4 alkyl, R g is hydrogen or C 1-5 alkyl; and 3. The compound according to claim 2, having Formula (III): or a pharmaceutically acceptable salt thereof, wherein: p is 2.

4. The compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein: 5 5. The compound according to claim 4, or a pharmaceutically acceptable salt thereof, wherein: 6 Ar 1 is Ar 2 is Ar is phenyl substituted with 1 R 3 , 1 R 5a , 1 R 5b , and 1 R 5c . R 1 is halo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl or C 1-4 haloalkoxy; R 2 is halo, C e alkyl substituted with 0-5 R 1-5 , -OR b , -NR 3 R 4 , or 5- to 6-membered heteroaryl or heterocycloalkyl comprising 1-4 heteroatoms selected from O, S, N and NR a ; R 2a is hydrogen or C e alkyl substituted by 0-4 R 1-4 alkyl; R 3 is hydrogen, C1-4alkyl, oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl; n is 0, 1, 2, 3, or 4; e R 1-4 is hydrogen, C1-4alkyl, oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl; n is 0, 1, 2, 3, or 4; R 4 is hydrogen or C 1-3 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 group comprising 1-4 heteroatoms selected from O, S, N and NR 8 substituted with 1-3 R 6 substituted with 1-3 R 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 alkoxy; R 6 is hydrogen, halo, oxo, hydroxy, or C e alkyl substituted with 0-4 R 1-4 alkyl; R 7 is hydrogen or C 1-3 alkyl; R 8 is hydrogen, C 1-3 alkyl or -S(O) p R c ; R a is hydrogen or C e alkyl substituted by 0-5 R 1-6 alkyl; R b is hydrogen or C e alkyl substituted by 0-5 R 1-6 alkyl; R c is C e alkyl substituted by 0-5 R 1-3 alkyl; R e is halo, -OR g , -NR g R g , -C(O)NR g R g , -S(O) p C 1-4 alkyl, R g is hydrogen or C 1-5 alkyl; and 6. The compound according to claim 4, having Formula (IV): or a pharmaceutically acceptable salt thereof, wherein: 7 7. The compound according to claim 4, having Formula (V): or a pharmaceutically acceptable salt thereof, wherein: 8 8. The compound according to claim 4, having Formula (VI): or a pharmaceutically acceptable salt thereof, wherein: 9 Ar 1 is Ar 2 is R 1 is halo, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl or C 1-3 haloalkoxy; R 2 halo, C e 1-6 alkyl substituted with 0-5 R 1-4 , -OR b , -NR 3 R 4 , or 5-6 membered heteroaryl or heterocycloalkyl comprising 1-4 heteroatoms selected from O, S, N and NR a ; R 2a Is it hydrogen or composed of 0-3 Rs? e Replacement C 1-4 alkyl; R 3 is hydrogen, C e substituted with 0-3 R 1-4 alkyl, oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl; R 4 is hydrogen or C 1-2 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 group comprising 1-3 heteroatoms selected from O, S, N and NR 8 substituted with 1-3 R 6 substituted with 1-3 R R 5a is hydrogen or halo; R 5b is hydrogen or halo; R 5c is halo or C 1-2 alkoxy; R 6 is hydrogen, halo, oxo, hydroxy, or C e alkyl substituted with 0-3 R 1-4 alkyl; R 7 is hydrogen or CH3; R 8 is hydrogen, C 1-2 alkyl or -S(O)2C 1-4 alkyl; R a is hydrogen, C1-4alkyl substituted with 0-4 R e substituted C 1-5 alkyl; R b is hydrogen or C e alkyl substituted by 0-4 R 1-5 alkyl; R e is halo, -OR g , -NR g R g , C(O)NR g R g , -S(O) p C 1-4 alkyl, R g is hydrogen or C 1-4 alkyl; and 9. The compound according to claim 8, having Formula (VII): or a pharmaceutically acceptable salt thereof, wherein: 10 10. The compound according to claim 8, having Formula (VIII): or a pharmaceutically acceptable salt thereof, wherein: 11 Ar 1 is Ar 2 is R 1 is CI, -CH3, -CF3, -OCH3, -OCHF2, or -OCF3; R 2 is halo, C e 1-4 alkyl substituted by 0-4 R 1-4 1-4 alkyl, -OR b , -NR 3 R 4 or a 5 to 6 membered heteroaryl or heterocycloalkyl group containing 1-4 heteroatoms selected from O, S, N and NR a ; R 2a is hydrogen or C e substituted with 0-2 R 1-4 alkyl; R 3 is hydrogen, C e substituted with 0-3 R 1-4 alkyl, oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl; R 4 is hydrogen or C 1-2 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 group comprising 1-3 heteroatoms selected from O, S, N and NR 8 substituted with 1-3 R 6 groups; R 5a is hydrogen, F or CI; R 5b is hydrogen, F or CI; R 5c is Cl or -OCH3; R 6 is hydrogen, halo, oxo, hydroxy, or C e alkyl substituted with 0-3 R 1-3 alkyl; R 7 is hydrogen or -CH3; R 8 is hydrogen, C 1-2 alkyl or -S(O)2C 1-3 alkyl; R a is hydrogen, C1-6alkyl substituted with 0-3 R e substituted C 1-4 alkyl; R b is hydrogen or C e alkyl substituted by 0-3 R 1-4 alkyl; R e halo, -OR g , -NR g R g , -C(O)NR g R g , -S(O)2C 1-4 alkyl, and R g is hydrogen or C 1-3 alkyl.

11. A compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof. Ar 2 is 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.

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

13. Use of a compound according to any one of claims 1-11, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 12, in the manufacture of a medicament for the treatment or prevention of an inflammatory disease, a cardiac disease, a chronic airway disease, a cancer, sepsis, an allergic symptom, an HIV retrovirus infection, a circulatory disorder, a neurological disorder, pain, a prion disease, an amyloidosis, and an immune disorder. Ar 1 is R 1 is CI, CH3, -CF3, -CHF2, -OCH3, -OCHF2, or -OCF3; R 2 is F, Cl, -CH3, -OCH3, -CF3, -CHF2, -CF3, or -NHC(O)CH3; R 2a -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, or -CH2CH2S(O)2C 1-4 alkyl; R 5a is hydrogen or F; R 5b is hydrogen or F; R 5c is CI or -OCH3; and R 7 is hydrogen or -CH3.

14. The use according to claim 13, wherein the inflammatory disease is neuroinflammation.

15. The use according to claim 13, wherein the cardiac disease is selected from the group consisting of angina pectoris, myocardial infarction, heart failure, acute coronary artery disease, and cardiac iatrogenic damage. R 1 is Cl or -OCH3; R 2 is 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, or -CH2CH2S(O)2C 1-4 alkyl; R 5a is hydrogen or F; R 5b is hydrogen or F; R 5c is CI or -OCH3; and R 7 is hydrogen or -CH3.

16. The use according to claim 15, wherein the heart failure is acute heart failure or chronic heart failure.

17. The use according to claim 15 or 16, wherein the heart failure is caused by 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, gingivitis, drug abuse, alcohol abuse, 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 surgery, starvation, eating disorders, muscular dystrophy, and genetic defects. Ar 1 is R 1 is CI, -CF3, CHF2, -OCHF2, -OCH3, or -OCF3; R 2 is F, Cl, -CH2OH, -CH3, -CHF2, -CF3, -OCH3, -OCH(CH3)2, -NR 3 R 4 , R 3 is hydrogen or C e substituted with 0-3 R 1-4 alkyl, R 4 is hydrogen; Alternatively, R 3 and R 4 together with the nitrogen to which they are both attached form a heterocycloalkyl selected from heterocycloalkyl; 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 alkyl; R e is halo, -OR g , -C(O)NR g R g , -S(O)2C 1-4 alkyl, and R g is hydrogen or C 1-3 alkyl.

18. The use according to claim 15, wherein the angina pectoris is unstable angina pectoris. ​ Ar 1 is R 1 is CI, -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 CI or -OCH3; and R 7 is hydrogen or -CH3. ​ ​ Ar 1 is R 1 is F, Cl, -CF3, CHF2, -OCHF2, -OCH3, or -OCF3; R 3 is hydrogen or C e alkyl substituted with 0-2 R 1-4 alkyl; R 4 is hydrogen; Alternatively, R 3 and R 4 together with the nitrogen to which they are both attached form a heterocycloalkyl selected from heterocycloalkyl; R 5a is hydrogen or F; R 5b is hydrogen or F; R 5c is Cl or -OCH3 R 6 is hydrogen, halo, hydroxyl, 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 alkyl; and R e is -OH, -OC 1-4 alkyl, -C(O)NHC 1-4 alkyl, -S(O)2C 1-4 alkyl, ​ ​ ​ ​ ​ ​ ​ ​ ​

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