Oxopyrrolidine fpr2 agonists

Abstract

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

Description

[0001] Cross-reference to related applications

[0002] Pursuant to 35 USC §119(e), this application is entitled to priority of U.S. Provisional Patent Application No. 63 / 049,838, filed July 9, 2020, which is incorporated herein in its entirety. Background Technology

[0003] This invention relates to novel oxopyrrolidine 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 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 the small pro-remission mediator (SPM) class and have also been identified as agonists of FPR2 (Ye RD. 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+(FPR2) is a G-protein coupled receptor that is expressed on a variety of immune cells, including neutrophils, macrophages, T cells, and B cells. FPR2 modulates both the innate and adaptive immune systems. In neutrophils, FPR2 ligands modulate motility, cytotoxicity, and lifespan. In macrophages, agonism of FPR2 prevents apoptosis and enhances efferocytosis. (Chandrasekharan JA, Sharma-Walia N,. J. Inflamm. Res., 2015, 8, 181-92). Initiation of resolution of inflammation by FPR2 agonism is responsible for enhancing anti-fibrotic 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 pathway of many human 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. Non-productive wound healing associated with myocardial cell death and pathological remodeling caused by ischemia / reperfusion injury leads to scar formation, fibrosis, and progressive loss of heart function. It is 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). Furthermore, in the central nervous system, FPR2 pro-resolution agonists can be useful as therapeutic agents for treating various clinical I / R conditions including stroke in the brain (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 targeting the FPR2 receptor with novel pro-resolution agonists for the treatment of I / R-induced injury therapeutics, the utility of these ligands can also be applied to other diseases. It was found that in the cardiovascular system, the FPR2 receptor and its pro-resolution 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 been shown to be beneficial in preclinical models of chronic inflammatory human diseases including: infectious diseases, psoriasis, dermatitis, inflammatory bowel syndrome, Crohn's disease, ocular inflammation, sepsis, pain, metabolic diseases / diabetes, cancer, COPD, asthma and allergic diseases, cystic fibrosis, acute lung injury and fibrosis, rheumatoid arthritis and other joint diseases, Alzheimer's disease, kidney fibrosis, and organ transplantation (Romano M. et al., Eur. J. Pharmacol., 2015, 5, 49-63, Perrett, M. et al., Trends in Pharm. Sci., 2015, 36, 737-755). SUMMARY

[0008] The present application provides novel oxopyrrolidines and analogs thereof, including stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof, useful as FPR2 agonists.

[0009] The present application also provides processes and intermediates for making the compounds of the present application or stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof.

[0010] The present application also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and at least one compound of the present application or stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof.

[0011] The compounds of the present application are useful in therapy.

[0012] The compounds of the present application can be used for the treatment and / or prevention of a variety of diseases or disorders associated with FPR2, such as inflammatory diseases, heart diseases, chronic airway diseases, cancer, sepsis, allergic symptoms, HIV retroviral infection, circulatory disorders, neuroinflammation, neurological disorders, pain, prion diseases, amyloidosis and immune disorders. The heart diseases are selected from the group consisting of angina pectoris, unstable angina pectoris, myocardial infarction, acute coronary artery disease, cardiac iatrogenic damage and heart failure, including but not limited to acute heart failure, chronic heart failure of ischemic and non-ischemic origin, systolic heart failure, diastolic heart failure, heart failure with reduced ejection fraction (HF R EF) and heart failure with preserved ejection fraction (HF P EF).

[0013] The compounds of the present application can be used alone, in combination with other compounds of the present application or in combination with one or more other agents.

[0014] Further features and advantages of the present application will become clear from the following detailed description and claims. DETAILED DESCRIPTION

[0015] The present application encompasses compounds of formulae (I)-(VII) 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 the treatment of atherosclerosis, heart failure, chronic obstructive pulmonary disease (COPD) and related diseases.

[0016] One aspect of the present application is a compound of formula (I):

[0017]

[0018] or a pharmaceutically acceptable salt thereof, wherein:

[0019] * is an asymmetric carbon atom;

[0020] Ar 1 is aryl or pyridyl, each substituted with 1-3 R 1 ;

[0021] Ar 2 is C 3-6 cycloalkyl, aryl or 5- to 12-membered heterocyclyl comprising 1-4 heteroatoms selected from O, S(O) p , N and NR 2a , and each substituted with 0-3 R 2 ;

[0022] Ar 3is phenyl or pyridyl, each substituted with 1 R 5a , 1 R 5b , and 1 R 5c ;

[0023] R 1 is halo, C 1-4 haloalkyl, C 1-4 alkoxy, or C 1-4 haloalkoxy;

[0024] R 2 is oxo, cyano, halo, C e alkyl substituted with 0-5 R 1-6 , -OR b , -NR 3 R 4 , -NR 4 C(O)R b , -NR 4 (CR d R d ) 0-1 C(O)NR 3 R 4 , (C 1-4 alkyl)2(O)P-, C 3-6 cycloalkyl, aryl, 5- to 6-membered heterocyclyl comprising 1-4 heteroatoms selected from the group consisting of O, S(O) p , N, and NR a ;

[0025] R 2a is hydrogen, C e alkyl substituted with 0-5 R 1-4 , -(CR d R d ) 1-4 -NR 3 R 4 , -(CR d R d ) 1-4 -OR b , -(CR d R d ) 1-4 -C(O)NR 3 R 4 , -(CR e R d ) d -C r cycloalkyl, -(CR 3-6 R e ) d d r ​​-Aryl group, 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 - Heterocyclic group;

[0026] R 3 It is hydrogen, with 0-5 R e Replacement C 1-4 Alkyl groups, with 0-5 R groups e Replacement C 3-6 Cycloalkyl groups, or containing 1-4 alkyl groups selected from O, S(O). p , N and NR 8 heteroatoms and 0-5 R e Substituted heterocyclic groups;

[0027] R 4 Is it hydrogen or C? 1-4 alkyl;

[0028] 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 heterocyclic groups;

[0029] R 5a It is a hydrogen or halogroup;

[0030] R 5b It is a hydrogen or halogroup;

[0031] R 5c It is a halogenated group, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or deuterated alkoxy;

[0032] R 6 It is hydrogen, halogenated, oxo-substituted, hydroxyl, or surrounded by 0-5 R groups. e Replacement C 1-4 alkyl;

[0033] R 7 Is it hydrogen or C? 1-4 alkyl;

[0034] R 8 It is hydrogen, C 1-4 Alkyl or -S(O) p R c ;

[0035] 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 groups, or containing 1-4 groups selected from O, S(O). p NR d heteroatoms and 0-5 R e Substituted heterocyclic groups;

[0036] R b 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 groups, or containing 1-4 groups selected from O, S(O). p NR d heteroatoms and 0-5 R e Substituted heterocyclic groups;

[0037] R c It is 0-5 R e Replacement C 1-4 alkyl;

[0038] R d It is hydrogen or composed of 0-5 R atoms. e Replacement C 1-4 alkyl;

[0039] 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 group, or containing 1-4 ions selected from O, S(O) p , N and NR g heteroatoms and 0-5 R f Substituted -(CH2) r - Heterocyclic group;

[0040] R f is halo, cyano, hydroxy, oxo, C 1-5 alkyl, C 3-6 cycloalkyl, or phenyl;

[0041] R g is hydrogen, C 1-5 alkyl, C 3-6 cycloalkyl, aryl, or heterocyclyl; or R g and R g together with the nitrogen atom to which they are both attached form heterocyclyl;

[0042] n is 0 or 1 ;

[0043] p is 0, 1, or 2; and

[0044] r is 0, 1, 2, 3, or 4.

[0045] Another aspect of the application is a compound of Formula (II):

[0046]

[0047] or a pharmaceutically acceptable salt thereof, wherein:

[0048] Ar 2 is C 3-6 cycloalkyl, phenyl, 5- to 6-membered heterocyclyl comprising 1-2 N or NR 2a , each substituted with 0-2 R 2 ;

[0049] Ar 3 is phenyl substituted with 1 R 5a , 1 R 5b , and 1 R 5c ;

[0050] R 1 is halo, C 1-4 haloalkyl, or C 1-4 haloalkoxy;

[0051] R 2 is oxo, cyano, halo, C e alkyl substituted with 0-5 R 1-5 , -OR b , -NR 3 R 4 , -NR 4 C(O) b , (C 1-3 alkyl)2(O)P-, C 3-6 cycloalkyl, aryl, heterocyclyl comprising 1-4 members selected from O, S, N, and NRa 5- to 6-membered heterocyclyl containing 1-4 heteroatoms selected from O, S, N, and NR

[0052] R 2a is hydrogen, C e alkyl substituted with 0-4 R 1-4 alkyl, -(CHR d ) 1-3 -C(O)NR 3 R 4 , -(CHR e ) d r -C 3-6 ycloalkyl, -(CHR e ) d r -aryl, or -(CHR a ) containing 1-4 heteroatoms selected from O, S, N, and NR e ) d r -heterocyclyl;

[0053] R 3 is hydrogen, C e alkyl substituted with 0-4 R 1-4 alkyl, C 3-6 ycloalkyl, or heterocyclyl containing 1-4 heteroatoms selected from O, S, N, and NR 8 ) e

[0054] R 4 is hydrogen or C 1-3 alkyl;

[0055] alternatively, R 3 and R 4 , together with the nitrogen to which they are both attached, form a 4- to 8-membered heterocyclyl containing 1-4 heteroatoms selected from O, S, N, and NR 8 ) 6

[0056] R 5a is hydrogen or halo;

[0057] R 5b is hydrogen or halo;

[0058] R 5c is halo, C 1-4 alkyl, C 1-4 haloalkyl, or C 1-4 alkoxy;

[0059] R 6 ​​​​​is hydrogen, halo, oxo, hydroxy, or C e substituted C 1-4 alkyl;

[0060] R 7 is hydrogen or C 1-3 alkyl;

[0061] R 8 is hydrogen, C 1-3 alkyl or -S(O) p R c ;

[0062] R a is hydrogen or C e substituted C 1-6 alkyl;

[0063] R b is hydrogen, C e substituted C 1-6 alkyl, or heterocyclyl comprising 1 to 4 heteroatoms selected from the group consisting of O, S, N, NR d and substituted with 0 to 5 R e ;

[0064] R c is C e substituted C 1-3 alkyl;

[0065] R d is hydrogen or C 1-4 alkyl substituted with 0 to 1 -OC 1-4 alkyl;

[0066] R e is halo, cyano, oxo, -OR g , -NR g R g , -C(O)NR g R g , -S(O) p C 1-4 alkyl, C f substituted C 1-4 alkyl, -(CH2) f -C r cycloalkyl, -(CH2) 3-6 -aryl, or -(CH2) f heterocyclyl comprising 1 to 4 heteroatoms selected from the group consisting of O, S, N, and NR r and substituted with 0 to 5 R g ; f r heterocyclyl; ​

[0067] R f It is a halogenated group, cyano group, hydroxyl group, C 1-5 Alkyl or C 3-6 cycloalkyl;

[0068] R g It is hydrogen, C 1-5 Alkyl or heterocyclic groups;

[0069] n is 0; and

[0070] r can be 0, 1, 2, or 3.

[0071] Another aspect of the present invention is a compound of formula (III):

[0072]

[0073] Or its pharmaceutically acceptable salt, wherein:

[0074] Ar 2 yes

[0075]

[0076] R 1 It is a halogenated group, C 1-3 Halogenated alkyl or C 1-3 Halogenated alkoxy groups;

[0077] 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 heterocyclic groups with heteroatoms;

[0078] 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 , by 0-3 R e Substituted -(CH2) r -C 3-6 cycloalkyl, with 0-3 R e Substituted -(CH2) raryl, or -(CH2)1-2- heterocyclyl comprising 1-4 heteroatoms selected from O, S, N, and NR a e r heterocyclyl;

[0079] R 3 is hydrogen, C e alkyl substituted with 0-3 R 1-4 3-6 cycloalkyl, or heterocyclyl comprising 1-4 heteroatoms selected from O, S, N, and NR 8 substituted with 0-3 R e

[0080] R 4 is hydrogen or C 1-2 alkyl;

[0081] alternatively, R 3 and R 4 together with the nitrogen to which they are both attached form a 4 to 8 membered heterocyclyl comprising 1-3 heteroatoms selected from O, S, N, and NR 8 substituted with 1-3 R 6

[0082] R 5a is hydrogen or halo;

[0083] R 5b is hydrogen or halo;

[0084] R 5c is halo or C 1-2 alkoxy;

[0085] R 6 is hydrogen, halo, oxo, hydroxyl, or C e alkyl substituted with 0-3 R 1-4

[0086] R 7 is hydrogen or CH3;

[0087] R 8 is hydrogen, C 1-2 alkyl or S(O)2C 1-4 alkyl;

[0088] R a is hydrogen or C e alkyl substituted with 0-4 R 1-5

[0089] R b is hydrogen, C e alkyl substituted with 0-4 R 1-5 , NR​​​​​​​d heterocycle comprising 1-4 heteroatoms selected from O, S, N, and NR e substituted heterocycle;

[0090] R d is hydrogen or C 1-4 alkyl substituted with 0-1 -OC 1-2 alkyl;

[0091] R e is halo, cyano, oxo, -OR g , -NR g R g , C(O)NR g R g , -S(O) p C 1-4 alkyl substituted with 0-4 R f substituted C 1-4 alkyl substituted with 0-4 R f -(CH2) r -C 3-6 cycloalkyl substituted with 0-4 R f -(CH2) r -aryl, or -(CH2) g substituted with 0-4 R f substituted -(CH2) r heterocycle;

[0092] R f is halo, cyano, hydroxy, or C 1-5 alkyl;

[0093] R g is hydrogen or C 1-4 alkyl;

[0094] n is 0; and

[0095] r is 0, 1, or 2.

[0096] Another aspect of the application is a compound of Formula (IVa):

[0097]

[0098] or a pharmaceutically acceptable salt thereof, wherein:

[0099] Ar 2 is

[0100]

[0101] R 1 is Cl, -CF3, -OCHF2, or -OCF3;

[0102] R 2 is cyano, halo, C e alkyl substituted with 0-4 R 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, or heterocyclyl comprising 1-4 heteroatoms selected from the group consisting of O, S, N and NR a ;

[0103] R 2a is hydrogen, C e alkyl substituted with 0-4 R 1-4 alkyl, -(CHR d ) 1-2 -C(O)NR 3 R 4 , -(CH2) e substituted with 0-2 R r -C 3-6 cycloalkyl, -(CH2) e substituted with 0-2 R r -aryl, or -(CH2) a heterocyclyl comprising 1-4 heteroatoms selected from the group consisting of O, S, N and NR e substituted with 0-2 R r ;

[0104] R 3 is hydrogen, C e alkyl substituted with 0-3 R 1-4 heterocyclyl comprising 1-4 heteroatoms selected from the group consisting of O, S, N and NR 8 substituted with 0-3 R e ;

[0105] R 4 is hydrogen or C 1-2 alkyl;

[0106] alternatively, R 3 and R 4 together with the nitrogen to which they are both attached form a 4 to 8 membered heterocyclyl comprising 1-3 heteroatoms selected from the group consisting of O, S, N and NR 8 substituted with 1-3 R 6 ;

[0107] R 5a is hydrogen, F or Cl;

[0108] R 5bIt is hydrogen, F, or Cl;

[0109] R 5c It is Cl or -OCH3;

[0110] R 6 It is hydrogen, halogenated, oxo-substituted, hydroxyl, or surrounded by 0-3 R groups. e Replacement C 1-3 alkyl;

[0111] R 7 Is it hydrogen or C? 1-2 alkyl;

[0112] R 8 It is hydrogen, C 1-2 Alkyl or -S(O)2C 1-3 alkyl;

[0113] R a It is hydrogen, with 0-3 Rs e Replacement C 1-4 alkyl;

[0114] 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 R e Substituted heterocyclic groups;

[0115] R d Is it hydrogen or 0-1 -OC? 1-4 Alkyl-substituted C 1-2 alkyl;

[0116] 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 Substituted -(CH2) r -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 -(CH2) r - Heterocyclic group;

[0117] R f It is a halogenated group, cyano group, hydroxyl group or C1-4 alkyl;

[0118] R g is hydrogen or C 1-3 alkyl; and

[0119] r is 0 or 1.

[0120] Another aspect of the application is a compound of Formula (IVa) or a pharmaceutically acceptable salt thereof, wherein:

[0121] Ar 2 is

[0122] R 2 is F, Cl, -CH2OH, -CH3, -CF3, or -CHF2; and

[0123] 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;

[0124] the other variables are as defined in Formula (IVa).

[0125] Another aspect of the application is a compound of Formula (IVb):

[0126]

[0127] or a pharmaceutically acceptable salt thereof, wherein:

[0128] R 1 is Cl, -CF3, -OCHF2, or -OCF3;

[0129] R 2 is cyano, F, Cl, CH3, CF3, CHF2, or -NHC(O)CH3;

[0130] 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, -CH2CH2S(O)2C 1-4 alkyl, -CHR d C(O)NR 3 R 4 , -(CH2) 0-1 -C 3-6 cycloalkyl, -(CH2) selected from the group consisting of 0-3 heterocyclyl;

[0131] R 3 and R 4 together with the nitrogen to which they are both attached form a heterocyclyl selected from the group consisting of

[0132] R 5a is hydrogen or F;

[0133] R 5b is hydrogen or F;

[0134] R 5c is Cl or -OCH3;

[0135] R 6 is hydrogen, oxo, halo, or -CH3, -CHF3, -CF3, or -CH2OH;

[0136] R 7 is hydrogen or C 1-2 alkyl;

[0137] R 8 is hydrogen, C 1-2 alkyl, or -S(O)2C 1-3 alkyl; and

[0138] R d is -CH2OCH3.

[0139] Another aspect of the application is a compound of Formula (IVc):

[0140] ​

[0141] or a pharmaceutically acceptable salt thereof, wherein:

[0142] R 1 is Cl, -CF3, -OCHF2, or -OCF3;

[0143] R 2 is cyano, F, Cl, CH2OH, CH3, CHF2, CF3, -OCH3, -OCH(CH3)2, -NR 3 R 4 , (CH3)2(O)P-, C 3-6 cycloalkyl,

[0144] R 3 is hydrogen or C e alkyl, 1-4

[0145] R 4 is hydrogen;

[0146] Alternatively, R 3 and R 4 together with the nitrogen to which they are both attached form a heterocyclyl selected from

[0147] R 5a is hydrogen or F;

[0148] R 5b is hydrogen or F;

[0149] R 5c is Cl or OCH3;

[0150] R 6 is hydrogen, halo, oxo, CH3, -CH2CH3, or -CH2OH;

[0151] R 7 is hydrogen or C 1-4 alkyl; and

[0152] R 8 is hydrogen, C 1-4 alkyl, or -S(O)2C 1-3 alkyl.

[0153] Another aspect of the application is a compound of Formula (IVd):

[0154]

[0155] or a pharmaceutically acceptable salt thereof, wherein: ​​

[0156] R 1 is Cl, -CF3, -OCHF2, or -OCF3;

[0157] R 2 is -OR b or (C 1-2 alkyl)2(O)P-;

[0158] R 5a is hydrogen or F;

[0159] R 5b is hydrogen or F;

[0160] R 5c is Cl or -OCH3;

[0161] R 7 is hydrogen or -CH3;

[0162] R b is hydrogen, C e alkyl substituted with 0-3 R 1-4 or

[0163] R e is F, Cl, or -OR g ; and

[0164] R g is hydrogen or C 1-3 alkyl.

[0165] Another aspect of the application is a compound of Formula (IVe):

[0166]

[0167] or a pharmaceutically acceptable salt thereof, wherein:

[0168] R 1 is Cl, -CF3, -OCHF2, or -OCF3;

[0169] R 2 is cyano, F, Cl, -CH2OH, -CH3, -CHF2, -CF3, -OCH3, -OCH(CH3)2, or -NR 3 R 4 ;

[0170] R 3 is hydrogen or C 1-4 alkyl;

[0171] R 4 is hydrogen or C 1-2 alkyl;

[0172] Alternatively, R3 and R 4 together with the nitrogen to which they are both attached form a heterocyclyl selected from

[0173] R 5a is hydrogen or F;

[0174] R 5b is hydrogen or F;

[0175] R 5c is Cl or -OCH3;

[0176] R 6 is hydrogen, halo, oxo, CH3, -CH2CH3, or -CH2OH;

[0177] R 7 is hydrogen or C 1-4 alkyl; and

[0178] R 8 is hydrogen or C 1-2 alkyl.

[0179] Another aspect of the application is a compound of Formula (IVf):

[0180]

[0181] or a pharmaceutically acceptable salt thereof, wherein:

[0182] R 1 is Cl, -CF3, -OCH3, -OCHF2, or -OCF3;

[0183] R 2 is cyano, F, Cl, -CH2OH, -CH3, -CHF2, or -CF3;

[0184] R 2a is -CH3, -CH2CH3, -CH2CHF2, -CH2CH2OCH3, -CH2CH(OH)CF3, -CH2CH(OH)CH3, -CH2CH2OH, -CH2CH(CH3)OH, or -CH2CH2CF3;

[0185] R 5a is hydrogen, F, or Cl;

[0186] R 5b is hydrogen, F, or Cl;

[0187] R 5c is Cl or -OCH3; and

[0188] R 7 ​is hydrogen or -CH3.

[0189] Another aspect of the application is a compound of Formula (V):

[0190]

[0191] or a pharmaceutically acceptable salt thereof, wherein:

[0192] Ar 2 is C 3-5 cycloalkyl;

[0193] R 1 is Cl, -CF3, -OCHF2, or -OCF3;

[0194] R 5a is F or Cl;

[0195] R 5b is F or Cl; and

[0196] R 5c is -OCH3.

[0197] Another aspect of the application is a compound of Formula (Va):

[0198]

[0199] or a pharmaceutically acceptable salt thereof, wherein:

[0200] R 1 is CF3, OCHF2, or OCF3;

[0201] R 5a is F or Cl;

[0202] R 5b is F or Cl; and

[0203] R 5c is OCH3.

[0204] Another aspect of the application is a compound of Formula (VI):

[0205]

[0206] or a pharmaceutically acceptable salt thereof, wherein:

[0207] R 1 is -CF3, -OCHF2, or -OCF3;

[0208] R 2 is F, Cl, -CH2OH, -CF3, -CHF2, -OCH3, -OCH(CH3)2, or (CH3)2(O)P-;

[0209] R 5a is F or Cl;

[0210] R 5b is F or Cl; and

[0211] R 5c is -OCH3.

[0212] Another aspect of the application is a compound of Formula (VII):

[0213]

[0214] or a pharmaceutically acceptable salt thereof, wherein:

[0215] R 1 is -CF3, -OCHF2, or -OCF3;

[0216] R 2 is F, Cl, or (CH3)2(O)P-;

[0217] R 5a is F;

[0218] R 5b is F; and

[0219] R 5c is -OCH3.

[0220] For compounds of Formula (I), (II), (III), (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), (V), (Va), (VI), or (VII), i.e., Formula (I-VII), any example of a variable substituent, including Ar 1 , Ar 2 , Ar 3 , R 1 , R 2 , R 2a , R 3 , R 4 , R 5a , R 5b , R 5c , R 6 , R 7 , R 8 , R a , R b , R c , R d , R e , R f , and R g may be used independently of the range of any other example of a variable substituent. Thus, the application includes combinations of different aspects.

[0221] In one non-limiting embodiment, for a compound of Formula (I), (II), or (III), Ar 1 is phenyl substituted with 1 R 1 ; R 1 is CF3, OCHF2, or OCF3; n is 0 or 1 ; Ar 2 is phenyl, pyridyl, or C 3-6 cycloalkyl, each substituted with 0-2 R 2 ; R 2 is F, CI, CH2OH, CF3, OCH3, OCH(CH3)2, CHF2, CF3, or (CH3)2(O)P; Ar 3 is phenyl substituted with R 5a , R 5b , and R 5c ; R 5a , R 5b , and R 5c are halo and alkoxy, respectively.

[0222] In one non-limiting embodiment, for a compound of Formula (I), (II), or (III), Ar 1 is phenyl substituted with 1 R 1 ; R 1 is CF3; n is 0; Ar 2 is phenyl, pyridyl, or C 3-6 cycloalkyl, each substituted with 0-2 R 2 ; R 2 is F, CI, CH2OH, CF3, OCH3, OCH(CH3)2, CHF2, CF3, or (CH3)2(O)P; Ar 3 is phenyl substituted with R 5a , R 5b , and R 5c ; R 5a , R 5b , and R 5c are halo and alkoxy, respectively.

[0223] In one non-limiting embodiment, for a compound of Formula (I), (II), or (III), Ar 1 is phenyl substituted with 1 R 1 ; R 1 is OCHF2; n is 0; Ar 2 is phenyl, pyridyl, or C 3-6 cycloalkyl, each substituted with 0-2 R 2 ; R 2F, Cl, CH2OH, CF3, OCH3, OCH(CH3)2, CHF2, CF3, or (CH3)2(O)P; Ar 3 is phenyl substituted with R 5a , R 5b , and R 5c ; R 5a , R 5b , and R 5c are halo and alkoxy, respectively.

[0224] In one non-limiting embodiment, for a compound of Formula (I), (II), or (III), Ar 1 is phenyl substituted with 1 R 1 ; R 1 is OCF3; n is 0; Ar 2 is phenyl, pyridyl, or C 3-6 cycloalkyl, each substituted with 0-2 R 2 ; R 2 is F, Cl, CH2OH, CF3, OCH3, OCH(CH3)2, CHF2, CF3, or (CH3)2(O)P; Ar 3 is phenyl substituted with R 5a , R 5b , and R 5c ; R 5a , R 5b , and R 5c are halo and alkoxy, respectively.

[0225] In one non-limiting embodiment, for a compound of Formula (I), (II), or (III), Ar 1 is phenyl substituted with 1 R 1 ; R 1 is CF3, OCHF2, or OCF3; n is 1; Ar 2 is phenyl substituted with 0-2 R 2 ; R 2 is halo or alkoxy; Ar 3 is phenyl substituted with R 5a , R 5b , and R 5c ; R 5a , R 5b , and R 5c are halo and alkoxy, respectively.

[0226] In one non-limiting embodiment, for a compound of Formula (I), (II), or (III), Ar 1 is phenyl substituted with 1 R 1 ; R 1CF3, OCHF2, or OCF3; n is 1 ; Ar 2 is cyclopropyl; Ar 3 is phenyl substituted with R 5a , R 5b , and R 5c ; R 5a , R 5b , and R 5c are halo and alkoxy, respectively.

[0227] In one non-limiting embodiment, for a compound of Formula (I), (II), (III), or (IVa), Ar 1 is phenyl substituted with 1 R 1 ; R 1 is CI, CF3, OCHF2, or OCF3; n is 0; Ar 2 is 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; Ar 3 is phenyl substituted with R 5a , R 5b , and R 5c ; R 5a , R 5b , and R 5c are halo and alkoxy, respectively.

[0228] In one non-limiting embodiment, for a compound of Formula (I), (II), (III), or (IVa), Ar 1 is phenyl substituted with 1 R 1 ; R 1 is CI, CF3, OCHF2, or OCF3; n is 0; Ar 2 is 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; Ar 3 is phenyl substituted with R 5a , R5b and R 5c Substituted phenyl; R 5a R 5b and R 5c They are halogenated and alkoxy groups, respectively.

[0229] In one non-limiting embodiment, for compounds of formula (I), (II), (III) or (IVa), Ar 1 It is by 1 R 1 Substituted phenyl; R 1 It is Cl, CF3, OCHF2, or OCF3; n is 0; Ar 2 yes R 2 It is cyano, F, Cl, CH3 or -NHC(O)CH3; R 2a is -CH3, -CH2CH3, -CH2CN, -CH2CHF2, -CH2CH2OCH3, -CH2CH(OH)CF3, -CH2CH(OH)CH3, -CH2CH2OH, -CF2CH2OH, -CH2CH(CH3)OH, -CH2CH2CF3, -CH(CH2OH)CH2OCH3, -C H(CH2NH2)OCH3, -CH2CH(CH3)OCH3, -CH2CH(CF3)OCH3, -CH(CH2NH2)CH2OCH3, -CH(C(O)N(CH3)2)CH2OCH3, -CH2C(CH3)(CH2OH)2, -CH2CH2N(CH3)2, -CH2CH2S(O)2C 1-4 Alkyl group, -(CH2) 0-1 -C 3-6 cycloalkyl, selected from -(CH2) 0-3 - Heterocyclic group; Ar 3 It was R 5a R 5b and R 5c Substituted phenyl; R 5a R 5b and R 5c They are halogenated and alkoxy groups, respectively.

[0230] In one non-limiting embodiment, for compounds of formula (I), (II), (III) or (IVa), Ar 1 It is by 1 R 1 Substituted phenyl; R 1 It is Cl, CF3, OCHF2, or OCF3; n is 0; Ar 2 yes R 2is cyano, F, Cl, CH3, or -NHC(O)CH3; R 2a is -CH3, -CH2CH3, -CH2CN, -CH2CHF2, -CH2CH2OCH3, -CH2CH(OH)CF3, -CH2CH(OH)CH3, -CH2CH2OH, -CF2CH2OH, -CH2CH(CH3)OH, -CH2CH2CF3, -CH(CH2OH)CH2OCH3, -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, -(CH2) 0-1 -C 3-6 cycloalkyl, -(CH2) heterocyclyl; Ar 0-3 - heterocyclyl; Ar 3 is phenyl substituted with R 5a , R 5b , and R 5c ; R 5a , R 5b , and R 5c are halo and alkoxy, respectively.

[0231] In one non-limiting embodiment, for a compound of Formula (I), (II), (III), or (IVa), Ar 1 is phenyl substituted with 1 R 1 ; R 1 is Cl, CF3, OCHF2, or OCF3; n is 0; Ar 2 is R 2 is cyano, F, Cl, CH2OH, CH3, CF3, CHF2, CF3, -OCH3, -OCH(CH3)2, -NR 3 R 4 , (CH3)2(O)P-, C 3-6 cycloalkyl, R 2a is -CH3, -CH2CH3, -CH2CN, -CH2CHF2, -CH2CH2OCH3, -CH2CH(OH)CF3, -CH2CH(OH)CH3, or -CH2CH2OH; R 3 is hydrogen or C e substituted with 0-2 R 1-4 alkyl, R4 Is it hydrogen or C? 1-2 Alkyl; alternatively, R 3 and R 4 Together with the nitrogen attached to them, they form a mixture selected from... heterocyclic groups; Ar 3 It was R 5a R 5b and R 5c Substituted phenyl; R 5a R 5b and R 5c They are halogenated and alkoxy groups, respectively.

[0232] In a non-limiting embodiment, for compounds of formula (I), Ar 1 It is by 1 R 1 Substituted phenyl; R 1 It is Cl, CF3, OCHF2, or OCF3; n is 0; Ar 2 yes R 2 It is an alkyl, haloalkyl, hydroxyalkyl, or cycloalkyl; Ar 3 It was R 5a R 5b and R 5c Substituted phenyl; R 5a R 5b and R 5c They are halogenated and alkoxy groups, respectively.

[0233] In one non-limiting embodiment, for compounds of formula (I), (II), (III) or (IVa), Ar 1 It is by 1 R 1 Substituted phenyl; R 1 It is Cl, CF3, OCHF2, or OCF3; n is 0; Ar 2 yes R 2 It is cyano, F, Cl, CH2OH, CF3, CHF2, CF3, -OCH3, -OCH(CH3)2, -NR 3 R 4 (CH3)2(O)P-, C 3-6 cycloalkyl, ;R 3 It is hydrogen or composed of 0-2 R atoms. e Replacement C 1-4 alkyl, R 4 Is it hydrogen or C? 1-2 Alkyl; alternatively, R 3 and R4 together with the nitrogen to which they are both attached form a heterocyclyl selected from heterocyclyl; Ar 3 is phenyl substituted with R 5a , R 5b , and R 5c ; R 5a , R 5b , and R 5c are halo and alkoxy, respectively.

[0234] In one non-limiting embodiment, for a compound of Formula (I), (II), (III), or (IVa), Ar 1 is phenyl substituted with 1 R 1 ; R 1 is CI, CF3, OCHF2, or OCF3; n is 0; Ar 2 is R 2 is alkoxy; R 2a is alkyl or haloalkyl; Ar 3 is phenyl substituted with R 5a , R 5b , and R 5c ; R 5a , R 5b , and R 5c are halo and alkoxy, respectively.

[0235] In one non-limiting embodiment, for a compound of Formula (I), Ar 1 is phenyl substituted with 1 R 1 ; R 1 is CI, CF3, OCHF2, or OCF3; n is 0; Ar 2 is R 2 is cyano, F, CI, CH3, or -NHC(O)CH3; R 2ais -CH3, -CH2CH3, -CH2CN, -CH2CHF2, -CH2CH2OCH3, -CH2CH(OH)CF3, -CH2CH(OH)CH3, -CH2CH2OH, -CF2CH2OH, -CH2CH(CH3)OH, -CH2CH2CF3, -CH(CH2OH)CH2OCH3, -C H(CH2NH2)OCH3, -CH2CH(CH3)OCH3, -CH2CH(CF3)OCH3, -CH(CH2NH2)CH2OCH3, -CH(C(O)N(CH3)2)CH2OCH3, -CH2C(CH3)(CH2OH)2, -CH2CH2N(CH3)2, -CH2CH2S(O)2C 1-4 Alkyl group, -(CH2) 0-1 -C 3-6 cycloalkyl, selected from -(CH2) 0-3 - Heterocyclic group; Ar 3 It was R 5a R 5b and R 5c Substituted phenyl; R 5a R 5b and R 5c They are halogenated and alkoxy groups, respectively.

[0236] In another embodiment, the compound of the present invention has ≤1 μM FPR2 EC 50 value.

[0237] In another embodiment, the compound of the present invention has ≤0.5 μM FPR2 EC 50 value.

[0238] In another embodiment, the compound of the present invention has ≤0.1 μM FPR2 EC 50 value.

[0239] In another embodiment, the compound of the present invention has ≤0.05 μM FPR2 EC 50 value.

[0240] In another embodiment, the compound of the present invention has ≤0.01 μM FPR2 EC 50 value.

[0241] In another embodiment, the compound of the present invention has ≤0.001 μM FPR2 EC 50 value.

[0242] Unless otherwise stated, these terms have the following meanings.

[0243] A dash “-” that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -CONH2is attached through the carbon atom.

[0244] A bond directed to a wavy line as used in structural formulae herein depicts the bond as a point of attachment of a moiety or substituent to the core or backbone structure.

[0245] “Cyano” means -CN.

[0246] “Hydroxy” means -OH.

[0247] “Alkyl” means a straight or branched chain hydrocarbon group consisting of 1 to 6 carbons. “Alkenyl” means a straight or branched chain alkyl group consisting of 2 to 6 carbons having at least one double bond. “Alkynyl” means a straight or branched chain alkyl group consisting of 2 to 6 carbons having at least one triple bond. The term having a hydrocarbon moiety (e.g., alkoxy) includes both straight chain and branched chain isomers of the hydrocarbon moiety.

[0248] “Halo” includes fluorine, chlorine, bromine, and iodine. “Haloalkyl” and “haloalkoxy” include all halo isomers from mono-halo to per-halo.

[0249] “Haloalkoxy” and derivatives (e.g., “C 1-6 Haloalkoxy”) are used interchangeably and mean an alkyl group substituted with a halo group attached through an oxygen atom. Haloalkoxy includes mono-substituted as well as multiple halo-substituted alkoxy groups, as well as per-halo-substituted alkoxy groups. For example, trifluoromethoxy and difluoromethoxy are included.

[0250] “Alkoxy” means an alkyl group attached to the rest of the molecule through an oxygen. Representative examples of such groups are -OCH3and -OC2H5. Unless otherwise stated or required by context or recitation, all alkoxy groups described or claimed herein can be straight chain or branched.

[0251] “Alkoxyalkyl” means an alkoxy group as defined above directly bonded to an alkyl group as defined above, e.g., -CH2-O-CH3, -CH2CH2-O-CH3, and the like.

[0252] “Cycloalkyl” means a non-aromatic monocyclic or polycyclic ring system having 3 to 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0253] “Aryl” means a monocyclic or bicyclic aromatic hydrocarbon radical of 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 a phenyl ring fused to a four- to seven-membered aromatic or non-aromatic carbocyclic ring. Representative examples of aryl groups include, but are not limited to, phenyl, indanyl, indenyl, naphthyl, and tetrahydronaphthyl. ​

[0254] "Heterocycle," "heterocyclyl," or "heterocyclic ring" means a stable 3-, 4-, 5-, 6-, or 7-membered monocyclic or 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-membered bicyclic heterocyclic ring which is saturated, partially unsaturated, or fully unsaturated, and contains carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S; and includes any polycyclyl group wherein any of the above-defined heterocyclic rings is fused with a benzene ring. The nitrogen and sulfur heteroatoms can optionally be oxidized (i.e., N→O and S(O) p wherein p is 0, 1, or 2). The nitrogen atom can be substituted or unsubstituted (i.e., N or NR, where R is H or another substituent, if defined). The heterocyclic ring can be attached laterally at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein can be substituted on carbon or on a nitrogen atom, if the resulting compound is stable. The nitrogen in a heterocyclyl group can optionally be quaternized. Preferably, when the total number of S and O atoms in a heterocyclyl group exceeds 1, then these heteroatoms are not adjacent to one another. Preferably, the total number of S and O atoms in a heterocyclyl group does not exceed 1. When the term "heterocyclyl" is used, it is intended to include heteroaryl groups.

[0255] Bridged rings are also included in the definition of heterocyclyl. A bridged ring occurs when one or more atoms (i.e., C, O, N, or S) connect two non-adjacent carbon or nitrogen atoms. Examples of bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and a carbon-nitrogen group. It should be noted that a bridge always converts a monocyclic ring into a tricyclic ring. Substituents recited for the ring can also be present on the bridge when the ring is bridged.

[0256] "Heteroaryl" means a 5- to 7-membered monocyclic aromatic ring system or an 8- to 11-membered bicyclic aromatic ring system having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0257] If the bonding attachment position is not specified, the bond can be attached at any appropriate position as understood by one of skill in the art. Combinations of substituents and bonding modes are permissible only if the stable compounds result. Terms in parentheses and in multiple parentheses are intended to clarify bonding relationships to one of skill in the art. For example, the term such as ((R)alkyl) means that the alkyl substituent is further substituted with an R substituent.

[0258] The present application includes all pharmaceutically acceptable salt forms of the compounds. Pharmaceutically acceptable salts are those in which the counter-ion does not contribute significantly to the physiological activity or toxicity of the compounds and thus act as pharmacological equivalents. These salts can be made according to common organic techniques employing commercially available reagents. Some anionic salt forms include acetate, acistrate, besylate, bromide, chloride, citrate, fumarate, glucuronate, hydrobromide, hydrochloride, hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate, phosphate, succinate, sulfate, tartrate, tosylate, 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.

[0259] Some of the compounds of the present application exist as stereoisomers, including the following structures with the indicated carbons. The present application includes all stereoisomeric forms of the compounds, including enantiomers and diastereomers. Methods for the production and separation of stereoisomers are known in the art. The present application includes all tautomeric forms of the compounds. The present application includes atropisomers and rotamers.

[0260] The present application is intended to include all isotopes of atoms occurring in the compounds. Isotopes include atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include 13 C and 14 C. Isotopically-labeled compounds of the present application can generally be prepared by conventional techniques known to those skilled in the art, or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed. Such compounds are deemed to be within the scope of the present application. Such compounds can have a number of potential uses, for example as standards and reagents in determining biological activity. In the case of stable isotopes, such compounds can have the potential to advantageously alter the biological, pharmacological, or pharmacokinetic properties of the compounds.

[0261] Biological methods

[0262] N-formyl peptide receptors (FPRs) are a family of chemoattractant receptors that facilitate leukocyte responses in inflammatory processes. FPRs belong to the seven-transmembrane G protein-coupled receptor superfamily and associate with inhibitory G proteins (Gi). Three family members (FPR1, FPR2, and FPR3) have been identified in humans and are found primarily in different distributions in myeloid cells and have also been reported in multiple organs and tissues. Upon agonist binding, FPRs activate a variety of physiological pathways such as intracellular signal transduction, Ca 2+Mobilization and transcription. The family interacts with a diverse set of ligands, including proteins, polypeptides, and fatty acid metabolites that activate proinflammatory and pro-resolving downstream responses. FPR2 and FPR1 cyclic adenosine monophosphate (cAMP) assays were used to measure the activity of the compounds in this patent.

[0263] FPR2 and FPR1 cyclic adenosine monophosphate (cAMP) assays. A mixture of forskolin (final 5 mM for FPR2 or final 10 mM for FPR1) and IBMX (final 200 mM) was added to a 384-well Proxiplate (Perkin-Elmer) previously spotted with test compounds in DMSO (final 1%) at final concentrations ranging from 0.020 nM to 100 mM. 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 mg / ml of bovine serum albumin, and 300 mg / ml of hygromycin (Life Technologies). Reactions were initiated by adding 2,000 human FPR2 cells / well or 4,000 human FPR1 cells / well in 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. The levels of intracellular cAMP were determined using the HTRF HiRange cAMP assay kit (Cisbio) according to the manufacturer's instructions. Solutions of cryptate-conjugated anti-cAMP and d2 fluorophore-labeled cAMP were prepared in the provided lysis buffer. After completion of the reaction, the cells were lysed with equal volumes of the d2-cAMP solution and the anti-cAMP solution. After 1 h of incubation at room temperature, the time-resolved fluorescence intensity was measured using Envision (Perkin-Elmer) at 400 nm excitation and dual emission at 590 nm and 665 nm. A calibration curve was constructed with external cAMP standards at concentrations ranging from 1 mM to 0.1 pM by plotting the ratio of fluorescence intensity emitted from 665 nm to that emitted from 590 nm versus cAMP concentration. The potency and activity of the compounds to inhibit cAMP production were then determined by fitting a 4-parameter logistic equation to the plot of cAMP levels versus compound concentration.

[0264] The following disclosed examples were tested in the above FPR2 and FPR1 cAMP assays and were found to have FPR2 and / or FPR1 agonist activity. Table 1 below lists the EC 50 values measured for the following examples in the FPR2 and FPR1 cAMP assays.

[0265] Table 1

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278]

[0279]

[0280]

[0281]

[0282]

[0283]

[0284] Pharmaceutical compositions and methods of use

[0285] The compounds of the present application can be administered to mammals, preferably humans, for the treatment of a variety of conditions and disorders, which include: atherosclerosis, heart failure; pulmonary 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.

[0286] The following terms have the meanings set forth unless otherwise specified. The term "subject" refers to any human or other mammalian species that can potentially benefit from treatment with an FPR2 and / or FPRl agonist as understood by practitioners in the art. Some subjects include humans of any age who have risk factors for cardiovascular disease. Common risk factors include age, sex, body weight, family history, sleep apnea, alcohol or tobacco use, lack of exercise, cardiac arrhythmias, or signs of insulin resistance such as acanthosis nigricans, hypertension, dyslipidemia, or polycystic ovary syndrome (PCOS). The term "patient" means a human suitable for therapy as determined by practitioners in the art. "Treating" or "treatment" includes therapy of a patient or subject as understood by practitioners in the art. "Preventing" or "prevention" includes prophylactic treatment (i.e., prevention and / or reduction of risk) of a subclinical disease-state in a patient or subject with the aim of reducing the likelihood of the occurrence of a clinical disease-state as understood by practitioners in the art. Patients are selected for prophylactic therapy based on factors known to increase the risk of suffering from a clinical disease-state compared to the general population. "Therapeutically effective amount" means an amount of a compound effective to achieve its intended purpose as understood by practitioners in the art.

[0287] Another aspect of the application is a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I)-(VII) in combination with a pharmaceutical carrier.

[0288] Another aspect of the application is a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I)-(VII) in combination with at least one other therapeutic agent and a pharmaceutical carrier.

[0289] "Pharmaceutical composition" means a composition comprising a compound of the application in combination with at least one additional pharmaceutically acceptable carrier. "Pharmaceutically acceptable carrier" refers to a medium generally accepted in the art for the delivery of biologically active agents to animals, in particular, mammals, including adjuvants, excipients or vehicles such as diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweetening agents, flavoring agents, perfuming agents, antibacterial agents, antifungal agents, lubricating agents, and dispersing agents, depending on the nature of the mode of administration and the dosage form.

[0290] Pharmaceutically acceptable carriers are formulated in accordance with a number of factors according to routine procedures in the art. These include, but are not limited to, the type and nature of the active agent being formulated; the subject to which the composition containing the 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 can also include a number of different ingredients and additives in addition to the active agent, such additional ingredients being included in the formulation for a variety of reasons (e.g., stabilization of the active agent, binder, etc.) well known to those of ordinary skill in the art. A description of suitable pharmaceutically acceptable carriers and the factors involved in their selection can be found in a variety of sources well known to those of ordinary skill in the art, such as, for example, Allen, L.V., Jr. et al., Remington: The Science and Practice of Pharmacy (2 Vols.), 22ndEdition, Pharmaceutical Press (2012).

[0291] In particular when provided as a single dosage unit, there is a potential for chemical interaction between the active ingredients of the combination. For this reason, when the compounds of the application and the second therapeutic agent are combined in a single dosage unit, they are formulated such that, although the active ingredients are combined in a single dosage unit, physical contact between the active ingredients is minimized (that is, reduced). For example, one of the active ingredients can be enteric coated. By enteric coating one of the active ingredients, not only can the contact between the active ingredients of the combination be minimized, but also the release of one of these components in the gastrointestinal tract can be controlled such that it is not released in the stomach but in the intestine. It is also possible to coat one of the active ingredients with a material which effects sustained release throughout the gastrointestinal tract and also serves to minimize physical contact between the active ingredients of the combination. Furthermore, the sustained release component can be additionally enteric coated such that release of this component only occurs in the intestine. Yet another approach involves formulating the combination product wherein one component is coated with a sustained release and / or enteric release polymer and the other component is also coated with a polymer such as low viscosity grade hydroxypropyl methylcellulose (HPMC) or other appropriate material 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.

[0292] Another aspect of the application is a method for treating heart disease comprising administering to a patient a therapeutically effective amount of a compound of formula (I)-(VII).

[0293] Another aspect of the application is a method for treating heart disease, wherein the heart disease is selected from the group consisting of angina, unstable angina, myocardial infarction, heart failure, acute coronary artery disease, acute heart failure, chronic heart failure, and cardiac iatrogenic damage.

[0294] It will be appreciated that the treatment or prevention of heart failure can also involve the treatment or prevention of cardiovascular events. Treatment or prevention as referred to herein can refer to the treatment or prevention of certain negative symptoms or conditions associated with or caused by cardiovascular events. For example, the treatment or prevention can involve reducing or preventing negative changes in short axis fractional shortening, heart weight, lung weight, myocyte cross-sectional area, pressure overload-induced cardiac fibrosis, stress-induced cellular senescence, and / or cardiac hypertrophic properties or any combination thereof associated with or caused by cardiovascular events. Treatment can be administered in preparation for or in response to a cardiovascular event to mitigate negative effects. Prevention can involve active or prophylactic types of treatment to prevent cardiovascular events or reduce the occurrence of negative effects of cardiovascular events.

[0295] In one embodiment, the application provides the use of a compound of formula (I)-(VII) or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical composition for the treatment or prevention of heart failure, e.g., 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 surgery, pacemaker implantation surgery, 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.

[0296] In one embodiment, the application provides the use of a compound of formula (I)-(VII) to treat systolic and / or diastolic dysfunction, wherein the compound is 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 and left ventricles, preferably the left ventricle.

[0297] In another embodiment, the application provides the use of a compound of formula (I)-(VII) to treat heart failure, wherein the compound is administered in a therapeutically effective amount to increase the ejection fraction in the left ventricle.

[0298] In yet another embodiment, the present application provides the use of a compound of Formulae (I)-(VII) to treat heart failure, wherein the compound is administered in a therapeutically effective amount to reduce fibrosis in cardiac tissue.

[0299] Another aspect of the present application is a method for treating heart disease, wherein the treatment is performed after myocardial infarction.

[0300] Another aspect of the present application is a method for treating heart disease, comprising administering to a patient a therapeutically effective amount of a compound of Formulae (I)-(VII) in combination with another therapeutic agent.

[0301] The compounds of the present application can be administered by any of the following suitable modes: 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; bucally; 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 administration to the nasal membranes, such as by inhalation spray; topically, such as in creams or ointments; or rectally, such as in suppositories. They can be administered alone, but will generally be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

[0302] The dosing regimen of the compounds of the present application will, of course, vary depending on known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment(s); the frequency with which treatment is to be effected; the route of administration, the renal and hepatic function of the patient, and the effect desired.

[0303] As a general guide, the daily oral dosage of each active ingredient, when used for the indicated effects, will range between about 0.01 to about 5000 mg per day, preferably between about 0.1 to about 1000 mg per day, and most preferably between about 0.1 to about 250 mg per day. Intravenously, the most preferred dosage will range from about 0.01 to about 10 mg / kg / minute during a constant rate infusion. The compounds of the present application can be administered in a single daily dose, or the total daily dosage can be administered in divided doses of two, three, or four times daily.

[0304] Dosage forms (pharmaceutical compositions) suitable for administration can contain from about 1 milligram to about 2000 milligrams of active ingredient per dosage unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.1%-95% by weight based on the total weight of the composition. A typical capsule for oral administration contains at least one compound of the present application (250 mg), lactose (75 mg) and magnesium stearate (15 mg). The mixture is passed through a 60 mesh sieve and packed into a No. 1 gelatin capsule. A typical injectable formulation is produced by sterile processing of at least one compound of the present application (250 mg) into a vial, sterile lyophilized, and sealed. At the point of use, the contents of the vial are mixed with 2 mL of normal saline to create an injectable formulation.

[0305] The compounds of the present application can be used in combination with other suitable therapeutic agents useful in the treatment of the diseases or disorders described above, including: anti-atherosclerotic agents, anti-dyslipidemic agents, anti-diabetic agents, anti-hyperglycemic agents, anti-hyperinsulinemic agents, anti-thrombotic agents, anti-retinopathic agents, anti-neuropathic agents, anti- nephropathic agents, anti-ischemic agents, anti-hypertensive agents, anti-obesity agents, anti- hyperlipidemic agents, anti-hypertriglyceridemic agents, anti-hypercholesterolemic agents, anti- restenotic agents, anti-pancreatic agents, hypolipidemic agents, anorectic agents, memory enhancing agents, anti-dementia agents, cognition promoting agents, appetite suppressants, agents for the treatment of heart failure, agents for the treatment of peripheral arterial disease, agents for the treatment of malignant tumors, and anti-inflammatory agents.

[0306] The compounds of the present application 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 receptor blockers, mineralocorticoid receptor antagonists, nitroxyl donors, RXFP1 agonists, APJ agonists, and inotropes. These agents include, but are not limited to, furosemide, bumetanide, torsemide, sacubitrail-valsartan, thiazide diuretics, captopril, enalapril, lisinopril, carvedilol, metoprolol, bisoprolol, serelaxin, spironolactone, eplerenone, ivabradine, candesartan, eprosartan, irbestarain, losartan, olmesartan, telmisartan, and valsartan.

[0307] The compounds of the application can be used in combination with at least one of the following therapeutic agents in the treatment of atherosclerosis: an antihyperlipidemic agent, a plasma HDL-raising agent, an antihypercholesterolemic agent, a cholesterol biosynthesis inhibitor (such as an HMG CoA reductase inhibitor), an LXR agonist, probucol, raloxifene, niacin, nicotinamide, a cholesterol absorption inhibitor, a bile acid sequestrant (such as an anion exchange resin, or a quaternary amine (e.g., cholestyramine or colestipol)), a low density lipoprotein receptor inducer, clofibrate, fenofibrate, benzofibrate, cipofibrate, gemfibrizol, vitamin B6, vitamin B 12 , an antioxidant vitamin, a beta-blocker, an antidiabetic agent, an angiotensin II antagonist, an angiotensin converting enzyme inhibitor, a platelet aggregation inhibitor, a fibrinogen receptor antagonist, aspirin, and a fibric acid derivative.

[0308] The compounds of the application can be used in combination with at least one of the following therapeutic agents in the treatment of atherosclerosis: an antihyperlipidemic agent, a plasma HDL-raising agent, an antihypercholesterolemic agent, a cholesterol biosynthesis inhibitor (such as an HMG CoA reductase inhibitor), an LXR agonist, probucol, raloxifene, niacin, nicotinamide, a cholesterol absorption inhibitor, a bile acid sequestrant (such as an anion exchange resin, or a quaternary amine (e.g., cholestyramine or colestipol)), a low density lipoprotein receptor inducer, clofibrate, fenofibrate, benzofibrate, cipofibrate, gemfibrizol, vitamin B6, vitamin B

[0309] The compounds of the application can be used in combination with at least one of the following antidiabetic agents, depending on the desired target therapy. Research has shown that the modulation of diabetes and hyperlipidemia can be further improved by adding a second agent to the therapeutic regimen. Examples of antidiabetic agents include, but are not limited to, sulfonylureas (such as chlorpropamide, tolbutamide, acetohexamide, tolazamide, glyburide, glicazide, glynase, glimepiride, and glipizide), biguanides (such as metformin), thiazolidinediones (such as ciglitazone, pioglitazone, troglitazone, and rosiglitazone) and related insulin sensitizers (such as selective and nonselective activators of PPARa, PPARb, and PPARy); dehydroepiandrosterone (also known as DHEA or its conjugated sulfate ester, DHEA-SO4); antiglucocorticoids; TNFa inhibitors; dipeptidyl peptidase IV (DPP4) inhibitors (such as sitagliptin, saxagliptin), GLP-1 agonists or analogs (such as exenatide), a-glucosidase inhibitors (such as acarbose, miglitol, and voglibose), pramlintide (a synthetic analog of the human hormone amylin), other insulin secretagogues (such as repaglinide, gliclazide, and nateglinide), insulin, and the above therapeutic agents for the treatment of atherosclerosis.

[0310] The compounds of the application can be used in combination with at least one antiobesity agent selected from phenylpropanolamine, phentermine, diethylpropion, mazindol, fenfluramine, dexfenfluramine, phentiramine, beta 3-adrenergic receptor agonists; sibutramine, a gastrointestinal lipase inhibitor such as orlistat and leptin. Other agents useful in the treatment of obesity or obesity related disorders include neuropeptide Y, enterostatin, cholecystokinin, bombesin, amylin, histamine H3 receptor, dopamine D2 receptor modulators, melanocyte stimulating hormone, corticotropin releasing factor, galanin and gamma aminobutyric acid (GABA).

[0311] The compounds of the application can also be used as standards 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 research involving FPR2 activity. For example, a compound of the application can be used as a reference in an assay to compare its known activity with a compound of unknown activity. This will ensure that the experimenter is performing the assay correctly and provides a basis for comparison, particularly if the test compound is a derivative of the reference compound. When developing new assays or protocols, a compound according to the application can be used to test their effectiveness. The compounds of the application can also be used in diagnostic assays involving FPR2.

[0312] The present application also encompasses articles of manufacture. As used herein, an article of manufacture is intended to encompass, but not be limited to, kits and packages. An article of manufacture of the present application comprises: (a) a first container; (b) a pharmaceutical composition contained within the first container, wherein the composition comprises: a first therapeutic agent comprising a compound of the present application or a pharmaceutically acceptable salt form thereof; and (c) a package insert indicating that the pharmaceutical composition can be used for the treatment of 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 (as previously defined) for the treatment of dyslipidemia and its sequelae. The article of manufacture can further comprise: (d) a second container, wherein components (a) and (b) are contained within the second container, and component (c) is contained within or outside the second container. Contained within the first and second containers means that the respective container holds the item within its boundaries. The first container is a recipient container for holding the pharmaceutical composition. This container can be used for manufacturing, storing, shipping, and / or selling individually / bulk. The first container is intended to encompass a bottle, a jar, a vial, a flask, a syringe, a tube (e.g., for a cream formulation), or any other container used for manufacturing, holding, storing, or dispensing a pharmaceutical product. The second container is a container for holding the first container and, optionally, the package insert. Examples of the second container include, but are not limited to, a box (e.g., paper or plastic), a crate, a carton, a bag (e.g., paper or plastic bag), a pouch, and a sack. The package insert can be physically attached to the outside of the first container via tape, glue, staples, or another method of attachment, or it can rest on the inside of the second container without any physical means of attachment to the first container. Alternatively, the package insert is on the outside of the second container. When on the outside of the second container, preferably, the package insert is physically attached via tape, glue, staples, or another method of attachment. Alternatively, it can be adjacent to or in contact with the outside of the second container without being physically attached. The package insert is a label, tag, marker, or the like that lists information pertaining to the pharmaceutical composition contained within the first container. The information listed will typically be determined by the regulatory agency of the region where the article of manufacture is to be sold (e.g., the U.S. Food and Drug Administration). Preferably, the package insert specifically indicates the approved indication(s) for which the pharmaceutical composition has been approved. The package insert can be made of any material in which a person can read the information contained therein or thereon. Preferably, the package insert is a printable material (e.g., paper, plastic, cardboard, foil, adhesive-backed paper or plastic, or the like) on which the desired information has been formed (e.g., printed or applied).

[0313] Chemical methods

[0314] The abbreviations as used herein are defined as follows: "lx" means once, "2x" means twice, "3x" means three times, "°C" means degrees Celsius, "aq" means aqueous, "Col" means column, "eq" means equivalent or equivalents, "g" means gram, "mg" means milligram, "L" means liter, "mL" means milliliter, "μL" means microliter, "N" means normality, "M" means molar, "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 atmosphere, "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 Spec" means mass spectrometry, "ESI" means electrospray ionization mass spectrometry, "HR" means high resolution, "HRMS" means high resolution mass spectrometry, "LCMS" means liquid chromatography mass spectrometry, "HPLC" means high pressure liquid chromatography, "RP HPLC" means reverse phase HPLC, "TLC" or "tlc" means thin layer chromatography, "NMR" means nuclear magnetic resonance spectroscopy, "nOe" means nuclear Overhauser effect spectroscopy, "H" means proton, "δ" means delta, "s" stands for singlet, "d" means doublet, "t" means triplet, "q" means quartet, "m" means multiplet, "br" means broad, "Hz" means hertz, and "α", "β", "R", "S", "E", and "Z" are stereochemical designations familiar to one skilled in the art. 1 H" means proton, "δ" means delta, "s" stands for singlet, "d" means doublet, "t" means triplet, "q" means quartet, "m" means multiplet, "br" means broad, "Hz" means hertz, and "α", "β", "R", "S", "E", and "Z" are stereochemical designations familiar to one skilled in the art.

[0315] Ac of acetic acid

[0316] AcOH acetic acid

[0317] Acn (or MeCN) acetonitrile

[0318] Bn benzyl

[0319] Boc tert-butyl carbonyl

[0320] Boc2O di-tert-butyl dicarbonate

[0321] Bu butyl

[0322] dba of (Pd2(dba)3) dibenzylideneacetone

[0323] dba of

[0324] Cbz carboxybenzyl

[0325] DCM dichloromethane

[0326] DEA diethylamine

[0327] DIEA or DIPEA diisopropylethylamine

[0328] DMAP 4-dimethylaminopyridine

[0329] DMF dimethylformamide

[0330] DMSO dimethylsulfoxide

[0331] dppf 1,1'-bis(diphenylphosphino)ferrocene

[0332] Et ethyl

[0333] EtOH ethanol

[0334] EtOAc ethyl acetate

[0335] HATU 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate

[0336] HBTU 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate

[0337] i-Bu isobutyl

[0338] IPA isopropyl alcohol

[0339] i-Pr isopropyl

[0340] LAH lithium aluminum hydride

[0341] Me methyl

[0342] MeOH methanol

[0343] pet petroleum

[0344] Ph phenyl

[0345] Pr propyl

[0346] t-Bu tert-butyl

[0347] TEA triethylamine

[0348] TFA trifluoroacetic acid

[0349] THF tetrahydrofuran

[0350] Ts tosyl

[0351] The disclosed compounds can be made by a variety of methods known in the art, including those methods in the schemes and specific embodiments section. The structure numbering and variable numbering shown in the synthetic schemes are not to be confused with the structure or variable numbering in the claims or the rest of the specification. The variables in the schemes are intended only to illustrate how to make some compounds of the invention.

[0352] A consideration in the planning of any synthetic route in the art is the choice of protecting groups for protecting reactive functional groups present in the compounds described in the invention. An authoritative account of the art of protecting group use is found in Greene, T.W. et al., Protecting Groups in Organic Synthesis, 4th edition, Wiley (2007).

[0353] Compounds having the general formula (I) and formula (II): in general formula (I) A, B and C are each defined above as Ar 1 , Ar 2 and Ar 3 , in general formula (II) A, B and Y are each defined above as Ar 1 , Ar 2 and alkyl and / or cycloalkyl, and can be made from one or more of the following synthetic schemes.

[0354]

[0355] The 1-arylpyrrolidinone compounds of the present invention (Formula I) wherein ring A is a substituted phenyl or cycloalkyl ring, ring B is a phenyl or heteroaryl ring, and ring C is a substituted phenyl or heteroaryl ring, can be prepared by the general route shown in Scheme 1. Compound la is synthesized following the procedure reported in the patent literature (WO 2015079692). Compound la is treated with diazophosphoric acid diphenyl ester (DPPA) and a tertiary amine (TEA) such as triethylamine. Subsequent addition of benzyl alcohol gives the Cbz-protected compound lb. The Cbz protecting group is removed from lb in the presence of hydrogen gas using Pd / C, and the resulting free amine is subjected to amide coupling with an appropriately substituted phenyl acid to give amide lc. Other deprotection conditions and protecting groups known to those skilled in the art can also be used in this order. Copper or Pd catalyzed coupling of lc with substituted iodobenzene or bromobenzene or other suitable haloaryl or heteroaryl compounds 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 or dioxane or toluene) can give the desired compound Id. Suitable aryl or heteroaryl halides are either commercially available or can be readily obtained from the corresponding readily available starting materials by methods known to those skilled in the art. Additional methods for this transformation include other variants of Ullmann, Goldberg and Buchwald copper catalyzed amidation or Buchwald Pd catalyzed C-N coupling depending on the nature of ring B according to methods known to those skilled in the art for these types of couplings (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). Similarly, the 1-arylpyrrolidinone compounds of the present invention (Formula I) wherein ring A and ring C are substituted phenyl rings or heteroaryl or cycloalkyl, and ring B is phenyl or heteroaryl, can be prepared by the general route shown in Scheme 2.

[0356] Scheme 1

[0357]

[0358] Scheme 2

[0359]

[0360] The 1-arylpyrrolidine ketone compounds of the present application (Formula II) wherein ring A and ring C are phenyl rings and Y is substituted benzyl, heteroarylalkyl, alkyl and / or cycloalkyl can be prepared by the general route shown in Scheme 3, starting from intermediate 1c prepared as shown in Scheme 1.

[0361] Scheme 3

[0362]

[0363] In Scheme 3, Y is C 1-6 alkyl, benzyl and heteroaryl, X is a leaving group such as chloride, bromide, iodide, methanesulfonyloxy, trifluoromethanesulfonyloxy or other known groups. Compound 1e can be obtained by reacting compound 1c with an alkylating agent YX in the presence of a suitable base in an appropriate solvent such as DMF or DMSO by heating in the solvent or by other methods known to those skilled in the art.

[0364] Other features of the application will become apparent in the course of the following descriptions of exemplary embodiments given for illustration of the application and are not intended to be limiting thereof.

[0365] The following methods were used in the exemplary examples except where otherwise noted. Purification of intermediates and final products was carried out by normal phase or reverse phase chromatography. Normal phase chromatography was carried out using pre-packed Si02columns eluted with gradients of hexanes and ethyl acetate or DCM and MeOH, unless otherwise indicated. Reverse phase preparative HPLC was carried out using C18 columns with UV 220 nm or preparative LCMS detection, with elution 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, 10 mM NH4OAc) and solvent B (98% Acn, 2% water, 10 mM NH4OAc), or a gradient of solvent A (98% water, 2% Acn, 0.1% NH4OH) and solvent B (98% Acn, 2% water, 0.1% NH4OH).

[0366] LC / MS method used for characterization of examples. Reverse phase analytical HPLC / MS was carried out on a Waters Acquity system coupled to a Waters ZQ mass spectrometer. Reverse phase analytical HPLC / MS was carried out on a Waters Acquity system coupled to a Waters ZQ mass spectrometer.

[0367] Method A: Linear gradient of 0 to 100% B over 3 min with a hold time at 100% B of 0.75 min;

[0368] UV visualization at 220 nm

[0369] Column: Waters BEH C18 2.1 x 50 mm

[0370] Flow rate: 1.0 mL / min

[0371] Solvent A: 0.1% TFA, 95% water, 5% Acn

[0372] Solvent B: 0.1% TFA, 5% water, 95% Acn

[0373] Method B: Linear gradient of 0 to 100% B over 3 min with a hold time at 100% B of 0.75 min;

[0374] UV visualization at 220 nm

[0375] Column: Waters BEH C18 2.1 x 50 mm

[0376] Flow rate: 1.0 mL / min

[0377] Solvent A: 10 mM ammonium acetate, 95% water, 5% Acn

[0378] Solvent B: 10 mM ammonium acetate, 5% water, 95% Acn

[0379] Analytical HPLC: Method used to characterize examples

[0380] Products were analyzed by reverse phase analytical HPLC on a Shimadzu analytical HPLC: system run Discovery VP software. RT = retention time.

[0381] 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 over 3 minutes, then a 1 -minute hold at 100% B; Flow: 1.1 mL / min.

[0382] Method D: Ascentis Express C18, 2.1 x 50 mm, 2.7-μm particles; Solvent A: 95% water, 5% acetonitrile with 10 mM ammonium acetate; Solvent B: 95% acetonitrile, 5% water with 10 mM ammonium acetate; Temperature: 50 °C; Gradient: 0-100% B over 3 minutes, then a 1 -minute hold at 100% B; Flow: 1.1 mL / min.

[0383] The following representative conditions were used to screen compounds for chiral purity. Other conditions were also used.

[0384] Column: Chiralpak IA, 250 x 4.6 mm, 5.0-μm particles, Chiralpak IB, 250 x 4.6 mm, 5.0-μm particles, Chiralpak IC, 250 x 4.6 mm, 5.0-μm particles, Chiralpak ID, 250 x 4.6 mm, 5.0-μm particles, Chiralpak IE, 250 x 4.6 mm, 5.0-μm particles, and Chiralpak IF, 250 x 4.6 mm, 5.0-μm particles;

[0385] Mobile phase: 0.2% ammonia in Acn:MeOH (1 :1 ).

[0386] NMRs for characterization of examples. Bruker or Fourier transform spectrometers were used 1 H NMR spectra: 1 H NMR: 300 MHz (Bruker or ) or 400 MHz (Bruker or ) or 500 MHz (Bruker or ). 13 C NMR: 100 MHz (Bruker or ). Spectral data are reported in the following format: chemical shift (multiplicity, coupling constants, and number of hydrogens). Chemical shifts are assigned in ppm (delta units, tetramethylsilane = 0 ppm) and / or referenced to solvent peaks, which appear at 2.49 ppm for CD2HSOCD3, 3.30 ppm for CD2HOD, 1.94 for CD3CN, and 7.24 ppm for CHCI3in H NMR spectra, and at 39.7 ppm for CD3SOCD3, 49.0 ppm for CD3OD, and 77.0 ppm for CDCl3in C NMR spectra. All 1 H NMR spectra appear at 2.49 ppm for CD2HSOCD3, 3.30 ppm for CD2HOD, 1.94 for CD3CN, and 7.24 ppm for CHCI3, and at 39.7 ppm for CD3SOCD3, 49.0 ppm for CD3OD, and 77.0 ppm for CDCl3. All 13 C NMR spectra appear at 2.49 ppm for CD2HSOCD3, 3.30 ppm for CD2HOD, 1.94 for CD3CN, and 7.24 ppm for CHCI3, and at 39.7 ppm for CD3SOCD3, 49.0 ppm for CD3OD, and 77.0 ppm for CDCl3. All 13The C NMR spectra were all proton decoupled.

[0387] Intermediate 1 : (3S,4R)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl)benzylcarbamate

[0388]

[0389] To a stirred solution of (3S,4R)-4-(2,6-difluoro-4-methoxyphenyl)-2- oxopyrrolidine-3-carboxylic acid (6.0 g, 22 mmol), TEA (3.7 mL, 27 mmol) in toluene (60 mL) and acetonitrile (12 mL) was added diphenyl phosphorazide (5.7 mL, 27 mmol). The mixture was stirred at room temperature for 3 h, then at 80 °C for 30 min. After the mixture was cooled to room temperature, benzyl alcohol (12 mL, 110 mmol) was added and the mixture was stirred at 100 °C for 16 h. The reaction mixture was cooled and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether-ethyl acetate) to give Intermediate 1 (4.0 g, 11 mmol, 50%) as a colorless liquid. MS (ESI) m / z: 377.3 [M+H] +

[0390] Intermediate 2: (3S,4R)-3-amino-4-(2,6-difluoro-4-methoxyphenyl)pyrrolidin-2-one

[0391]

[0392] To a degassed solution of Intermediate 1 (4.0 g, 11 mmol) in EtOH (60 mL) was added Pd-C (0.11 g, 1.1 mmol). The reaction mixture was purged with H2and stirred at room temperature under H2atmosphere for 16 h. The mixture was filtered through a pad of celite and concentrated under reduced pressure to give (3S,4R)-3-amino-4-(2,6-difluoro-4-methoxyphenyl)pyrrolidin-2-one (2.5 g, 10.3 mmol, 97%) as a white solid. The crude material was used in the next synthetic step without further purification. MS (ESI) m / z: 243.2 [M+H] +

[0393] Intermediate 3: N-((3S,4R)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl)-4- (difluoromethoxy)benzamide

[0394]

[0395] To a stirred solution of intermediate 2 (1.2 g, 5.0 mmol) in DMF (10 mL) was added DIEA (1.0 mL, 6.0 mmol), 4-(difluoromethoxy)benzoic acid (1.1 g, 6.0 mmol) and HATU (2.3 g, 6.0 mmol) at room temperature under argon atmosphere. After 16 h, the reaction mixture was quenched with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with water and brine (20 mL each), dried over Na2S04and concentrated under reduced pressure to get the crude product which was purified by column chromatography (petroleum ether- ethyl acetate) to get intermediate 3 (1.2 g, 2.9 mmol, 59% yield) as a white solid. MS (ESI) m / z: 413.1 [M+H] + . 1 H NMR (300 MHz, DMSO-d6) d 8.85 (d, J = 8.6 Hz, 1H), 8.19 (s, 1H), 7.86 (d, J = 8.6 Hz, 2H), 7.35 (t, J = 75.0 Hz, 1H), 7.26 (d, J = 8.6 Hz, 2H), 6.75 (d, J = 12.0 Hz, 2H), 4.90 - 4.80 (m, 1H), 4.06 - 3.79 (m, 1H), 3.75 (s, 3H), 3.60 - 3.45 (m, 1H), 3.42 - 3.32 (m, 1H).

[0396] Intermediate 4: N-((3S,4R)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl)-4- (trifluoromethoxy)benzamide

[0397]

[0398] Intermediate 4 was synthesized following a similar procedure as described above for intermediate 3. MS (ESI) m / z: 431.1 [M+H] + . 1 H NMR (300 MHz, CDCl3) d = 7.77 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 7.9 Hz, 2H), 6.47 (m, 3H), 6.23 (s, 1H), 5.14 - 4.97 (m, 1H), 4.07 - 3.95 (m, 1H), 3.82 - 3.75 (m, 4H), 3.68 - 3.63 (m, 1H).

[0399] Intermediate 5A and 5B: 3-bromo-4-methyl-l-(3,3,3-trifluoro-2-hydroxypropyl)pyridin- 2(lH)-one:

[0400]

[0401] To a stirred solution of 3-bromo-4-methylpyridin-2(lH)-one (1.5 g, 8.0 mmol) in DMF (15 mL) was added 3-bromo-l,l,l-trifluoropropan-2-ol (2.3 g, 12 mmol) and K2CO3(3.3 g, 24 mmol) at room temperature. The reaction mixture was heated at 90 °C for 16 h. The reaction mixture was cooled, filtered through a pad of celite and concentrated under reduced pressure. The crude compound was purified by silica gel chromatography (petroleum ether-ethyl acetate) and enantiomers were separated by chiral SFC to give intermediate 5A (0.80 g, 2.7 mmol, 33.4% yield) and intermediate 5B (0.80 g, 2.7 mmol, 33% yield). SFC prep conditions: Column / Size: Whelk (R,R) (250 X 4.6) mm, 5 μ; CO2: 85%, % co-solvent: 15% of 0.2% DEA in IPA. Total flow: 3.0 g / min, back pressure: 100 bar, temperature: 40 °C, UV: 220 nm. Retention time: Peak 1 = 3.2 min and Peak 2 = 4.4 min. Enantiomer 1: MS (ESI) m / z: 299.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d = 7.60 (d, J = 7.0 Hz, 1H), 6.62 (d, J = 6.5 Hz, 1H), 6.29 (d, J = 7.0 Hz, 1H), 4.42-4.29 (m, 2H), 3.87-3.79 (m, 1H), 2.28 (s, 3H). Enantiomer 2: MS (ESI) m / z: 299.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d = 7.60 (d, J = 7.0 Hz, 1H), 6.62 (d, J = 6.5 Hz, 1H), 6.29 (d, J = 7.0 Hz, 1H), 4.42-4.29 (m, 2H), 3.87-3.79 (m, 1H), 2.28 (s, 3H).

[0402] Intermediate 6: 2-(2-methoxyethyl)-5-methylpyridazin-3(2H)-one

[0403]

[0404] To a stirred solution of 5-methylpyridazin-3(2H)-one (1.0 g, 9.1 mmol) in DMF (10 mL) was added potassium carbonate (3.8 g, 27 mmol) and 1-bromo-2-methoxyethane (1.5 g, 11 mmol) at room temperature. The reaction mixture was heated at 70 °C for 15 h. Then, the reaction mixture was cooled, filtered through a pad of celite and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (petroleum ether-ethyl acetate) to give intermediate 6 (1.0 g, 6.0 mmol, 66% yield) as a yellow liquid. MS (ESI) m / z: 169.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d = 7.79 (d, J = 2.0 Hz, 1H), 6.73 (m, 1H), 4.18 (t, J = 5.8 Hz, 2H), 3.64 (t, J = 5.8 Hz, 2H), 3.23 (s, 3H), 2.16 (d, J = 2.0 Hz, 3H).

[0405] Intermediate 7: 4-bromo-2-(2-methoxyethyl)-5-methylpyridazin-3(2H)-one

[0406]

[0407] To a stirred solution of 2-(2-methoxyethyl)-5-methylpyridazin-3(2H)-one (500 mg, 3.0 mmol) in acetonitrile (5 mL) was added NBS (1060 mg, 5.95 mmol) at room temperature. Then, the reaction mixture was heated at 80 °C for 16 h. The reaction mixture was cooled, filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The crude compound was purified by silica gel chromatography (petroleum ether-ethyl acetate) to give intermediate 7 (350 mg, 1.4 mmol, 48% yield) as an orange solid. MS (ESI) m / z: 249.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d = 7.86 (s, 1H), 4.26 (t, J = 5.5 Hz, 2H), 3.67 (t, J = 5.5 Hz, 2H), 3.22 (s, 3H), 2.27 (s, 3H).

[0408] Example 1: N-((3S,4R)-1-(2-cyanopyridin-3-yl)-4-(2,6-difluoro-4-methoxyphenyl)-2- oxopyrrolidin-3-yl)-4-(difluoromethoxy)benzamide

[0409]

[0410] To a stirred solution of intermediate 3 (80 mg, 0.19 mmol) in 1,4-dioxane (2 mL) was added 3-bromopicolinonitrile (43 mg, 0.23 mmol) and Cs2CO3(130 mg, 0.39 mmol). The reaction mixture was purged with nitrogen for 5 min and charged with xanthphos (22 mg, 0.039 mmol) and Pd2(dba)3(18 mg, 0.019 mmol). The reaction mixture was purged with nitrogen again for 3 min and heated at 100 °C for 16 h. The reaction mixture was cooled and filtered through a pad of celite. The filtrate was concentrated under reduced pressure and the crude product was purified by reverse phase HPLC to give example 1 (26 mg, 0.051 mmol, 26% yield) as a white solid.

[0411] MS (ESI) m / z: 515.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d = 9.14 (d, J = 8.3 Hz, 1H), 8.72 (d, J = 4.6 Hz, 1H), 8.24 (d, J = 8.3 Hz, 1H), 7.94 - 7.87 (m, 3H), 7.35 (s, 1H), 7.29 (d, J = 8.8 Hz, 2H), 6.81 (d, J = 10.8 Hz, 2H), 5.16 - 5.02 (m, 1H), 4.34 - 4.22 (m, 2H), 4.18 - 4.09 (m, 1H), 3.78 (s, 3H). RT = 1.725 min, 100% (Method D).

[0412] Example 2: N-((3S,4R)-4-(2,6-difluoro-4-methoxyphenyl)-1-(1-methyl-6-oxo-1,6- dihydropyridin-3-yl)-2-oxopyrrolidin-3-yl)-4-(difluoromethoxy)benzamide

[0413]

[0414] To a stirred solution of intermediate 3 (60 mg, 0.15 mmol) in 1,4-dioxane (2 mL) was added 5-bromo-1-methylpyridin-2(1H)-one (33 mg, 0.18 mmol), Cs2CO3(95 mg, 0.29 mmol) and N,N'-dimethylethylenediamine (2.6 mg, 0.029 mmol) at room temperature. The reaction mixture was purged with nitrogen for 5 min and then charged with copper(I) iodide (5.5 mg, 0.029 mmol), purged with nitrogen for 3 min and heated at 100 °C for 16 h. The reaction mixture was cooled, filtered through a pad of celite and concentrated under reduced pressure to give a crude product which was purified by reverse phase HPLC to give example 2 (32 mg, 0.062 mmol, 42% yield) as a white solid. MS (ESI) m / z: 520.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d = 9.03 (d, J = 8.6 Hz, 1H), 8.01 (d, J = 2.7 Hz, 1H), 7.93 - 7.81 (m, 3H), 7.55 - 7.13 (m, 3H), 6.80 (d, J = 10.8 Hz, 2H), 6.46 (d, J = 10.0 Hz, 1H), 4.98 (m, 1H), 4.18 - 4.07 (m, 1H), 4.00 (t, J = 8.8 Hz, 1H), 3.93 - 3.85 (m, 1H), 3.78 (s, 3H), 3.45 (s, 3H). RT = 1.677 min, 100% (Method D).

[0415] Example 3: N-((3S,4R)-1-(cyclopropylmethyl)-4-(2,6-difluoro-4-methoxyphenyl)-2- oxopyrrolidin-3-yl)-4-(difluoromethoxy)benzamide

[0416]

[0417] To a stirred solution of intermediate 3 (60 mg, 0.15 mmol) in DMF (2 mL) was added NaH (8.7 mg, 0.22 mmol) at 0 °C under an atmosphere of argon and the resulting reaction mixture was stirred for 30 min. To the reaction mixture was then added bromomethylcyclopropane (24 mg, 0.18 mmol) and the mixture was allowed to gradually warm to rt over a period of 2 h. The reaction mixture was quenched with ice / water and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over Na2S04and concentrated under reduced pressure. The crude product was purified by reverse phase HPLC to give example 3 (23 mg, 0.049 mmol, 33% yield) as a white solid. MS (ESI) m / z: 467.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d = 8.91 (d, J = 8.8 Hz, 1H), 7.87 (d, J = 8.8 Hz, 2H), 7.34 (s, 1H), 7.26 (d, J = 8.6 Hz, 2H), 6.76 (d, J = 10.8 Hz, 2H), 4.92 (t, J = 9.5 Hz, 1H), 3.97-3.88 (m, 1H), 3.77 (s, 3H), 3.75-3.70 (m, 1H), 3.65-3.55 (m, 1H), 3.31-3.24 (m, 1H), 3.07 (m, 1H), 1.01-0.93 (m, 1H), 0.51 (d, J = 8.1 Hz, 2H), 0.32-0.20 (m, 2H). RT = 1.810 min, 99.2% (Method D).

[0418] Example 4 and 5: N-((3S,4R)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxo-l-(2-oxo-l-(3,3,3- trifluoro-2-hydroxypropyl)-l,2-dihydropyridin-3-yl)pyrrolidin-3-yl)-4- (difluoromethoxy)benzamide (enantiomers 1 and 2)

[0419]

[0420] To a stirred solution of N-((3S,4R)-4-(2,6-difluoro-4-methoxyphenyl)-2- oxopyrrolidin-3-yl)-4-(difluoromethoxy)benzamide (500 mg, 1.2 mmol) in 1,4- dioxane (10 mL) was added cesium carbonate (790 mg, 2.4 mmol) and 3-bromo-1- (3,3,3-trifluoro-2-hydroxypropyl)pyridin-2(1H)-one (382 mg, 1.34 mmol) at room temperature. The reaction mixture was purged with nitrogen for 5 min and then charged with N,N-dimethylethane-1,2-diamine (21 mg, 0.24 mmol) and copper(I) iodide (23 mg, 0.12 mmol). The reaction mixture was purged with nitrogen again for 3 min and heated at 100 °C for 16 h. The reaction mixture was cooled, filtered through a pad of celite, concentrated under reduced pressure. The crude compound was purified by reverse phase HPLC followed by chiral SFC to give Example 4 (68 mg, 0.11 mmol, 9.1% yield) and Example 5 (65 mg, 0.10 mmol, 8.7% yield). SFC prep conditions: Column / size: Luxcellulose (250 X 30) mm, 5 μ; % CO2: 60%, % co-solvent: 40% of 4M methanolic amine in MeOH. Total flow: 120.0 g / min, back pressure: 100 bar, temperature: 30 °C, UV: 220 nm; Retention time: Peak 1 = 4.6 min and Peak 2 = 9.7 min. Enantiomer 1: MS (ESI) m / z: 618.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d = 9.01 (br d, J = 8.6 Hz, 1H), 7.93 - 7.81 (m, 2H), 7.70 (dd, J = 6.8, 2.0 Hz, 1H), 7.65 (dd, J = 7.3, 2.0 Hz, 1H), 7.34 (t, J = 73.6 Hz, 1H), 7.27 (m, 2H), 6.76 (d, J = 10.8 Hz, 2H), 6.37 (t, J = 7.1 Hz, 1H), 5.16 - 5.04 (m, 1H), 4.45 (dd, J = 13.1, 2.8 Hz, 1H), 4.39 - 4.27 (m, 1H), 4.17 - 4.06 (m, 1H), 4.06 - 3.98 (m, 1H), 3.97 - 3.88 (m, 1H), 3.88 - 3.80 (m, 1H), 3.76 (s, 3H), 3.35 (br s, 1H). Enantiomer 2: MS (ESI) m / z: 618.2 [M+H] + . 1HNMR (400 MHz, DMSO-d6) δ = 9.02 (d, J = 8.8 Hz, 1H), 7.93 - 7.83 (m, 2H), 7.69 (dd, J = 6.7, 2.1 Hz, 1H), 7.64 (dd, J = 7.3, 2.1 Hz, 1H), 7.34 (t, J = 73.6 Hz, 1H), 7.28 (d, J = 8.8 Hz, 2H), 6.77 (d, J = 10.8 Hz, 2H), 6.37 (t, J = 7.0 Hz, 1H), 5.08 (dd, J = 10.9, 8.9 Hz, 1H), 4.44 (dd, J = 13.1, 3.1 Hz, 1H), 4.39 - 4.26 (m, 1H), 4.15 - 3.99 (m, 2H), 3.97 - 3.90 (m, 1H), 3.84 (dd, J = 13.3, 9.4 Hz, 1H), 3.76 (s, 3H), 3.36 (br s, 1H).

[0421] The following examples in Table 2 were prepared by using similar procedures as shown in Examples 1-5 and / or modifications known to those skilled in the art.

[0422] Table 2

[0423]

[0424]

[0425]

[0426]

[0427]

[0428]

[0429]

[0430]

[0431]

[0432]

[0433]

[0434]

[0435]

[0436]

[0437]

[0438]

[0439]

[0440]

[0441]

[0442]

[0443]

[0444]

[0445]

[0446]

[0447]

[0448]

[0449]

[0450]

[0451]

[0452]

[0453]

[0454]

[0455]

[0456]

[0457]

[0458]

[0459]

[0460]

[0461]

[0462]

[0463]

[0464]

[0465]

[0466]

[0467]

[0468]

[0469]

[0470]

[0471]

[0472]

[0473]

[0474]

[0475]

[0476]

[0477]

[0478]

[0479]

[0480]

[0481]

[0482]

[0483]

[0484]

[0485]

[0486]

[0487]

[0488]

[0489]

[0490]

[0491]

[0492]

[0493]

[0494]

[0495]

[0496]

[0497]

[0498]

[0499]

[0500]

[0501]

[0502]

[0503]

[0504]

[0505]

[0506]

[0507]

[0508]

[0509]

[0510]

[0511]

[0512]

[0513]

[0514]

[0515]

[0516]

[0517]

[0518]

[0519]

[0520]

[0521]

[0522]

[0523]

[0524]

[0525]

[0526]

[0527]

[0528]

[0529]

[0530]

[0531]

[0532]

[0533]

[0534]

[0535]

[0536]

[0537]

[0538]

[0539]

[0540]

[0541]

[0542]

[0543]

[0544]

[0545]

[0546]

[0547]

[0548]

[0549]

[0550]

[0551]

[0552]

[0553]

[0554]

[0555]

[0556]

[0557]

[0558]

[0559]

[0560]

[0561]

[0562]

[0563]

[0564]

[0565]

[0566] It will be apparent to those skilled in the art that the present disclosure is not limited to the foregoing illustrative embodiments and that it can be embodied in other specific forms without departing from the essential attributes thereof. It is therefore desired that the embodiments be considered in all respects as illustrative and not restrictive, reference being made to the appended claims rather than to the foregoing embodiments, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.

Claims

1. A compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein: the halo group is selected from fluoro, chloro, bromo, and iodo; * is an asymmetric carbon atom; Ar 1 It is phenyl or pyridyl, each surrounded by 1-3 R groups. 1 replace; Ar 2 It is C 3-6 Cycloalkyl, phenyl, containing 1-2 N or NR atoms 2a The 5- to 6-membered heterocyclic groups are each surrounded by 0-2 R groups. 2 replace; 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 haloalkyl or C 1-4 haloalkoxy; R 2 is oxo, cyano, halo, C e alkyl substituted with 0-5 R 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, or a 5- to 6-membered heterocyclyl comprising 1-4 heteroatoms selected from O, S, N and NR a ; R 2a is hydrogen, C e alkyl substituted with 0-4 R 1-4 ; d -(CHR 1-3 ) 3 -C(O)NR 4 R e , -(CHR d ) r -C 3-6 ycloalkyl, or -(CHR a ) e substituted with 0-4 R d ; r -3 to 14 membered heterocyclyl; R 3 is hydrogen, C e alkyl substituted with 0-4 R 1-4 , C 3-6 cycloalkyl, or a 3- to 14-membered heterocyclyl comprising 1-4 heteroatoms selected from O, S, N and NR 8 substituted with 0-4 R e ; R 4 is hydrogen or C 1-3 alkyl; or R 3 and R 4 together with the nitrogen to which they are both attached form a 4 to 8 membered heterocyclyl comprising 1-4 heteroatoms selected from O, S, N and NR 8 substituted with 1-3 R 6 ; 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, C e alkyl substituted with 0-5 R 1-6 or a 3- to 14-membered heterocyclyl comprising 1-4 heteroatoms selected from O, S, N, NR d and substituted with 0-5 R e alkyl; R c is C e alkyl substituted by 0-5 R 1-3 alkyl; R d is hydrogen or substituted with 0-1 -OC 1-4 alkyl; and 1-4 alkyl; and 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, or containing 1-4 alkyl groups selected from O, S, N, and NR g heteroatoms and 0-5 R f Substituted -(CH2) r -3 to 14-membered heterocyclic groups; R f is halo, cyano, hydroxy, C 1-5 alkyl or C 3-6 cycloalkyl; R g is hydrogen or C 1-5 alkyl; n is 0; p is 0, 1, or 2; and r is 0, 1, 2, or 3.

2. The compound of claim 1, having Formula (III): or a pharmaceutically acceptable salt thereof, wherein: r is 0, 1, or 2.

3. The compound of claim 2, having Formula (IVa): or a pharmaceutically acceptable salt thereof, wherein: Ar 2 is R 1 is halo, C 1-3 haloalkyl or C 1-3 haloalkoxy; R 2 is cyano, halo, C e alkyl substituted with 0-5 R 1-4 alkyl, -OR b , -NR 3 R 4 , -NR 4 C(O)R b , (C 1-3 alkyl)2(O)P-, C 3-6 cycloalkyl, or a 5- to 6-membered heterocyclyl comprising 1-4 heteroatoms selected from O, S, N and NR a ; R 2a is hydrogen, C e 1-6 alkyl substituted with 0-3 R 1-4 a d -(CHR 1-2 ) 3 R 4 , -(CH2) e substituted with 0-3 R r -C 3-6 cycloalkyl, or -(CH2) a containing 1-4 heteroatoms selected from the group consisting of O, S, N and NR e substituted with 0-3 R r -3 to 14 membered heterocyclyl; R 3 is hydrogen, C e alkyl substituted with 0-3 R 1-4 alkyl, C 3-6 cycloalkyl, or a 3- to 14-membered heterocyclyl comprising 1-4 heteroatoms selected from O, S, N and NR 8 and substituted with 0-3 R e substituents; R 4 is hydrogen or C 1-2 alkyl; or R 3 and R 4 together with the nitrogen to which they are both attached form a 4- to 8-membered heterocyclyl comprising 1-3 heteroatoms selected from O, S, N and NR 8 substituted with 1-3 R 6 ; 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, C e alkyl substituted with 0-4 R 1-5 alkyl, 3- to 14-membered heterocyclyl comprising 1-4 heteroatoms selected from O, S, N, NR d substituted with 0-4 R e substituted with 0-4 R R d is hydrogen or C1-6alkyl substituted by 0-1 -OC 1-4 alkyl; and 1-3 alkyl; and R e halo, cyano, oxo, -OR g , -NR g R g , C(O)NR g R g , -S(O) p C 1-4 alkyl, C f alkyl substituted with 0-4 R 1-4 , -(CH2) f -3 to 14 membered heterocyclyl; and r -C 3-6 cycloalkyl, or -(CH2) g containing 1-4 heteroatoms selected from the group consisting of O, S, N and NR f substituted with 0-4 R r ; R f is halo, cyano, hydroxy or C 1-5 alkyl; R g is hydrogen or C 1-4 alkyl; and r is 0 or 1.

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

5. The compound of claim 3, having Formula (IVb): or a pharmaceutically acceptable salt thereof, wherein: Ar 2 is R 1 is CI, -CF3, -OCHF2, or -OCF3; R 2 is cyano, halo, C e alkyl substituted with 0-4 R 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, or a 5- to 6-membered heterocyclyl comprising 1-4 heteroatoms selected from O, S, N and NR a ; R 2a is hydrogen, C e 1-6 alkyl substituted with 0-2 R 1-4 substituted C d 1-6 alkyl, -(CHR 1-2 ) 3 -C(O)NR 4 R e substituted -(CH2) r -C 3-6 cycloalkyl, or -(CH2) a containing 1-4 heteroatoms selected from the group consisting of O, S, N and NR e substituted -(CH2) r -3 to 14 membered heterocyclyl; R 3 is hydrogen, C e alkyl substituted with 0-3 R 1-4 alkyl, or a 3- to 14-membered heterocyclyl comprising 1-4 heteroatoms selected from O, S, N and NR 8 substituted with 0-3 R e substituted with 0-3 R R 4 is hydrogen or C 1-2 alkyl; or R 3 and R 4 together with the nitrogen to which they are both attached form a 4- to 8-membered heterocyclyl comprising 1-3 heteroatoms selected from O, S, N and NR 8 substituted with 1-3 R 6 ; 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 8 is hydrogen, C 1-2 alkyl or -S(O)2C 1-3 alkyl; R a is hydrogen, C e substituted with 0-3 R 1-4 alkyl; R b is hydrogen, C e 1-4 heteroatoms selected from O, S, N and NR 1-4 substituted with 0-3 R d substituted with 0-3 R e substituted with 0-3 R R d is hydrogen or C1-6alkyl substituted by 0-1 -OC 1-4 alkyl; and R is hydrogen or C1-6alkyl substituted by 0-1 -OC 1-2 alkyl; and R is hydrogen or C1-6alkyl substituted by 0-1 -OC R e is halo, cyano, oxo, -OR g , -NR g R g , -C(O)NR g R g , -S(O)2C 1-4 alkyl, C f 3 alkyl substituted with 0-3 R 1-4 , -(CH2) f 0-3 R r , -C 3-6 3 cycloalkyl, or -(CH2) g 1-4 heteroatoms selected from the group consisting of O, S, N, and NR f 0-3 R r substituted; R f is halo, cyano, hydroxy or C 1-4 alkyl; R g is hydrogen or C 1-3 alkyl; and 6. The compound of claim 3, having Formula (IVc): or a pharmaceutically acceptable salt thereof, wherein:

7. The compound of claim 3, having Formula (IVd): or a pharmaceutically acceptable salt thereof, wherein: Ar 2 is R 2 is F, CI, 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.

8. The compound of claim 3, having Formula (IVe): or a pharmaceutically acceptable salt thereof, wherein:

9. The compound of claim 1, having Formula (IVf): or a pharmaceutically acceptable salt thereof, wherein: R 1 is CI, -CF3, -OCHF2, or -OCF3; R 2 is cyano, F, Cl, -CH3, -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, -CH2CH2S(O)2C 1-4 alkyl, -CHR d C(O)NR 3 R 4 , -(CH2) 0-1 -C 3-6 cycloalkyl, -(CH2) 0-1 -heterocyclyl, wherein the heterocyclyl is selected from R 3 and R 4 together with the nitrogen to which they are both attached form a heterocyclyl selected from heterocyclyl; R 5a is hydrogen or F; R 5b is hydrogen or F; R 5c is Cl or -OCH3; R 6 is hydrogen, oxo, halo, -CH3, -CHF2, -CF3, or -CH2OH; R 8 is hydrogen, C 1-2 alkyl or -S(O)2C 1-3 alkyl; and R d is -CH2OCH3.

10. The compound of claim 2, having Formula (V): or a pharmaceutically acceptable salt thereof, wherein:

11. The compound of claim 2, having Formula (VI): or a pharmaceutically acceptable salt thereof, wherein: R 1 is CI, -CF3, -OCHF2, or -OCF3; R 2 is cyano, F, Cl, -CH2OH, -CH3, -CHF2, -CF3, -OCH3, -OCH(CH3)2, -NR 3 R 4 , (CH3)2(O)P-, C 3-6 cycloalkyl, R 3 is hydrogen or substituted with 0-1 S(O)2C 1-3 alkyl substituted C 1-4 alkyl, R 4 is hydrogen; or R 3 and R 4 together with the nitrogen to which they are both attached form a heterocyclyl selected from heterocyclyl; 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; and R 8 is hydrogen, C 1-4 alkyl or -S(O)2C 1-3 alkyl.

12. A compound selected from or a pharmaceutically acceptable salt thereof. R 1 is CI, -CF3, -OCHF2, or -OCF3; R 2 is -OR b or (C 1-2 alkyl)2(O)P-; R 5a is hydrogen or F; R 5b is hydrogen or F; R 5c is Cl or -OCH3; R b is hydrogen, C e alkyl substituted with 0-3 R 1-4 alkyl or R e is F, CI or -OR g ; and R g is hydrogen or C 1-3 alkyl.

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

14. Use of a compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 13, in the manufacture of a medicament for the treatment or prevention of a cardiac disorder associated with Formyl Peptide Receptor 2 (FPR2). R 1 is CI, -CF3, -OCHF2, or -OCF3; R 2 is cyano, F, Cl, -CH2OH, -CH3, -CHF2, -CF3, -OCH3, -OCH(CH3)2, or -NR 3 R 4 ; R 3 is hydrogen or C 1-4 alkyl; R 4 is hydrogen or C 1-2 alkyl; or R 3 and R 4 together with the nitrogen to which they are both attached form a heterocyclyl selected from heterocyclyl; R 5a is hydrogen or F; R 5b is hydrogen or F; and R 5c is Cl or -OCH3.

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

16. The use of claim 15, 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, 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. R 1 is CI, -CF3, -OCHF2, or -OCF3; R 2 is cyano, F, Cl, -CH2OH, -CH3, -CHF2, or -CF3; R 2a is -CH3, -CH2CH3, -CH2CHF2, -CH2CH2OCH3, -CH2CH(OH)CF3, -CH2CH(OH)CH3, -CH2CH2OH, -CH2CH(CH3)OH, or -CH2CH2CF3; R 5a is hydrogen, F or CI; R 5b is hydrogen, F or CI; and R 5c is Cl or -OCH3. ​ ​ Ar 2 is C 3-5 cycloalkyl; R 1 is CI, -CF3, -OCHF2, or -OCF3; R 5a is F or CI; R 5b is F or CI; and R 5c is -OCH3. ​ ​ R 1 is -CF3, -OCHF2, or -OCF3; R 2 is cyano, F, Cl, -CH2OH, -CHF2, -CF3, -OCH3, -OCH(CH3)2, or (CH3)2(O)P-; R 5a is F or CI; R 5b is F or CI; and R 5c is -OCH3. ​ ​ ​ ​ ​ ​

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