Cyclic tetrameric compounds as proprotein convertase subtilisin / kexin type 9 (PCSK9) inhibitors for the treatment of metabolic disorders

Abstract

The present disclosure relates to PCSK9 inhibitors useful for treating cholesterol lipid metabolism and other diseases in which PCSK9 plays a role, wherein the PCSK9 inhibitor has formula (I): #imgabs0# or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, N-oxide or tautomer thereof, wherein R1, R1, R1, R1, R1, R1, R1, R1, R1, X1, X2, and X3 are described herein.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of and priority to U.S. Provisional Application No. 62 / 772,030, filed November 27, 2018, and U.S. Provisional Application No. 62 / 924,828, filed October 23, 2019, the entire contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] The present disclosure relates to modulators of proprotein convertase subtilisin / kexin type 9 (PCSK9) for use in treating diseases or disorders associated with the PCSK9 protease. Specifically, the present disclosure relates to compounds and compositions that inhibit PCSK9, methods for treating diseases or disorders associated with PCSK9, and methods for synthesizing these compounds. Background Art

[0004] Proprotein convertase subtilisin / kexin type 9 (PCSK9) is a member of the secreted subtilase family of serine proteases that is expressed in many tissues and cell types. The PCSK9 protein comprises a signal sequence, a prodomain, a catalytic domain containing a triad of conserved residues (D186, H226, and S386), and a C-terminal domain. It is synthesized as a soluble 74 kDa precursor that undergoes autocatalytic cleavage in the endoplasmic reticulum. Autocatalytic activity has been shown to be required for secretion.

[0005] PCSK9 has a significant impact on plasma low-density lipoprotein cholesterol (LDL-C) levels by regulating the hepatic low-density lipoprotein receptor (LDLR), which is the main pathway for removing cholesterol from the circulation. PCSK9 binds to the LDLR and directs it to lysosomal degradation, thereby increasing plasma LDL-C levels and, in turn, increasing the risk of coronary heart disease (CHD). (Maxwell KN, Proc. Natl. Acad. Sci., 101, 2004, 7100-7105; Park, SW, J. Biol. Chem., 279, 2004, 50630-50638; Lagace TA, et al. J. Clin. Invest., 2006, 116(11):2995-3005). Overexpression of mouse or human PCSK9 in mice has been shown to increase total LDL-C levels and significantly reduce hepatic LDLR protein, without observed effects on mRNA, SREBP, or the nuclear-cytoplasmic ratio of SREBP protein (Maxwell K.N., Proc. Natl. Acad. Sci. [Proceedings of the National Academy of Sciences of the United States of America] 101, 2004, 7100-7105). In addition, PCSK9 mutations that cause loss of PCSK9 function in mouse models have also been shown to reduce total and LDL-C levels (Cohen, J.C., et al., N. Engl. J. Med. [New England Journal of Medicine], 354, 2006, 1264-1272). Therefore, the results indicate that modulation of PCSK9 leads to reduced LDLR protein levels.

[0006] Genetic deletion of PCSK9 has also been performed in mice. PCSK9 knockout mice show a reduction of approximately 50% in plasma cholesterol levels and an increased sensitivity to statins for lowering plasma cholesterol (Rashid, S., et al., Proc. Natl. Acad. Sci. [Proceedings of the National Academy of Sciences of the United States of America], 2005, 102: 5374-5379). Human genetic data strongly support the role of PCSK9 in LDL homeostasis. The link between PCSK9 and plasma LDL-C levels was first established by the discovery of PCSK9 missense mutations in patients with autosomal dominant familial hypercholesterolemia (Abifadel, M., et al., Nature [Nature], 2003, 34: 154-6). Patients carrying PCSK9 gain-of-function alleles have increased plasma LDL-C levels and premature CHD, while patients with PCSK9 loss-of-function alleles have significantly reduced plasma LDL-C and are protected from CHD.

[0007] PCSK9 also plays a role in lipoprotein (a) (Lp(a)) metabolism. Lp(a) is a pro-atherogenic lipoprotein composed of LDL particles covalently linked to apoLp(a). Human genetic studies have shown that Lp(a) is causally related to CHD risk. PCSK9 therapeutic antibodies have been shown to significantly reduce Lp(a) levels in patients with hypercholesterolemia. (Desai, NR, et al., Circulation. 2013, 128(9):962-969; Lambert, G., et al., Clin. Sci. 2017, 131, 261-268). Patients receiving statin therapy treated with monoclonal antibodies against PCSK9 showed a reduction of up to 32% in Lp(a) levels compared to placebo. (Desai NR, et al., Circulation. 2013, 128(9):962-969).

[0008] In addition to its cardiovascular effects, PCSK9 also plays an important role in sepsis, a life-threatening disease caused by the body's response to infection. Overexpression of PSCK9 in septic mice has been shown to aggravate sepsis by increasing inflammation, while inhibition of PCSK9 has been shown to reduce mortality. (Dwivedi, DJ, et al., Shock, 2016, 46(6), 672-680). In addition, flow cytometry studies in human HepG2 cells have shown that PCSK9 negatively regulates hepatocyte uptake of Gram-negative lipopolysaccharide (LPS) through an LDL-dependent mechanism by regulating LDLR-mediated bacterial lipid uptake of lipoteichoic acid (LTA) and LPS. (Grin, PM, et al., Nature, 2018, 8(1): 10496) Therefore, inhibition of PCSK9 has the potential to treat sepsis by reducing the body's immune response to infection.

[0009] Currently, there are no known small molecule inhibitors of PCSK9. The only known PCSK9 inhibitors on the market are anti-PCSK9 antibodies. Therefore, the use of small molecule inhibitors to inhibit PCSK9 has the potential to treat a range of diseases, including hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, peripheral arterial disease, vascular inflammation, elevated Lp(a), elevated LDL, triglyceride-rich lipoproteins (TRL), elevated triglycerides, sepsis, xanthomas, and other diseases. For these reasons, there remains a need for novel and effective small molecule PCSK9 inhibitors. Summary of the Invention

[0010] A first aspect of the present disclosure relates to compounds having formula (I):

[0011]

[0012] and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof,

[0013] in:

[0014] X1 and X2 are each independently H or (C1-C6)alkyl, or X1 and X2 together with the carbon atom to which they are attached form =(O);

[0015] X3 is -CH2- (when X1 and X2 are each independently H or (C1-C6)alkyl, or X1 and X2 together with the carbon atom to which they are attached form =(O)) or X3 is -O-, -NH- or -N(C1-C6)alkyl- (when X1 and X2 together with the carbon atom to which they are attached form =(O));

[0016] R1 is (C6-C 10 ) aryl or a 5-membered or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl are replaced by -OR 10 or -NR 21 R 10 substituted and optionally with one or more R 11 replace;

[0017] R2 is H, (C1-C6) alkyl, (C2-C6) alkenyl, (C1-C6) haloalkyl, -NR 12 R 13 , (C3-C7) carbocyclyl, (C3-C7) cycloalkenyl, a 5- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, (C6-C 10 ) aryl, or a 5-membered or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, wherein the alkyl group is optionally replaced by one or more R 18 and the carbocyclyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl groups are optionally substituted by one or more R 19 replace;

[0018] R3 is H, D, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, or (C1-C6)hydroxyalkyl, wherein the alkyl group is optionally replaced by one or more R 14 replace;

[0019] R4 is H or (C1-C6)alkyl; or

[0020] R3 and R4 together with the atoms to which they are attached form a 5- to 7-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O and S;

[0021] R5 and R7 are each independently H, D, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, or (C1-C6)hydroxyalkyl, wherein the (C1-C6)alkyl is optionally substituted with one or more D;

[0022] R6 is (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, or (C1-C6)hydroxyalkyl, wherein the alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of (C1-C6)alkoxy, (C1-C6)haloalkoxy, -C(O)(C1-C6)alkyl, -C(O)OH, and -C(O)O(C1-C6)alkyl;

[0023] R8 is H, (C1-C6) alkyl, or (C1-C6) haloalkyl, wherein the alkyl is optionally substituted by one or more substituents each independently selected from the group consisting of (C3-C7) carbocyclyl, a 4- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S, -NR 16 R 17 and -C(O)NR 16 R 17 ;

[0024] R9 is halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, -OH, or CN;

[0025] R 10 Yes (C6-C 10 ) aryl or a 5-membered or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl are optionally substituted by one or more R 22 replace;

[0026] Each R 11 is independently at each occurrence halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, -OH, or CN;

[0027] R 12 and R 13 are each independently H or (C1-C6)alkyl;

[0028] Each R 14 D, NR independently at each occurrence15 R 15' , (C3-C7)carbocyclyl, or a 3- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, and (C1-C6)haloalkoxy;

[0029] R 15 and R 15' are each independently H or (C1-C6)alkyl;

[0030] R 16 and R 17 are each independently H or (C1-C6) alkyl, or

[0031] R 16 and R 17 Together with the nitrogen atom to which they are attached, they form a 4- to 7-membered heterocyclyl ring optionally containing 1-2 additional heteroatoms selected from N, O and S;

[0032] Each R 18 is independently at each occurrence (C3-C7)carbocyclyl, 5- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, (C6-C 10 ) aryl, or a 5-membered or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, wherein the carbocyclyl, heterocyclyl, aryl and heteroaryl are optionally substituted by one or more R 20 replace;

[0033] Each R 19 is independently at each occurrence halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, -OH, or CN; or

[0034] Two R's 19 When on adjacent atoms together form (C6-C 10 )aryl or a 5- or 6-membered heteroaryl ring containing 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl groups are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, -OH and CN;

[0035] Each R 20is independently at each occurrence halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, oxo, -OH, or CN; or

[0036] When R 18 When it is a carbocyclic or heterocyclic group, the two R 20 When attached to the same carbon atom together form =(O);

[0037] R 21 is H or (C1-C6)alkyl;

[0038] Each R 22 is independently at each occurrence halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, -OH, CN, (C6-C 10 ) aryl, or a 5-membered or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl are optionally substituted by one or more R 23 replace;

[0039] Each R 23 is independently at each occurrence halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, -CH2(OCH2CH2) 1-3 OCH2CH3, -OH, CN, or a 4- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from N, O and S, wherein the heterocyclic group is optionally substituted by one or more substituents each independently selected from the following: halogen, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, -OH, -C(O)R 24 R 25 、-NR 24 C(O)R 25 , -NH2, -NH(C1-C6)alkyl, and -N((C1-C6)alkyl)2, and the alkyl group is optionally replaced by -NR 24 R 25 substituted, or a 4- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S (which is optionally substituted by one or more substituents each independently selected from the group consisting of halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, -OH, -NH2, -NH(C1-C6)alkyl, and -N((C1-C6)alkyl)2); and

[0040] R 24 and R 25are each independently H, (C1-C6)alkyl, or (C3-C7)carbocyclyl optionally substituted with one to two (C1-C6)alkyl groups;

[0041] or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, N-oxide or tautomer thereof.

[0042] In another aspect, the disclosure relates to compounds having formula (I), wherein:

[0043] X1 and X2 are each independently H or (C1-C6)alkyl, or X1 and X2 together with the carbon atom to which they are attached form =(O);

[0044] X3 is -CH2- (when X1 and X2 are each independently H or (C1-C6)alkyl, or X1 and X2 together with the carbon atom to which they are attached form =(O)) or X3 is -O-, -NH- or -N(C1-C6)alkyl- (when X1 and X2 together with the carbon atom to which they are attached form =(O));

[0045] R1 is (C6-C 10 ) aryl or a 5-membered or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl are replaced by -OR 10 or -NR 21 R 10 substituted and optionally with one or more R 11 replace;

[0046] R2 is H, (C1-C6) alkyl, (C2-C6) alkenyl, (C1-C6) haloalkyl, -NR 12 R 13 , (C3-C7) carbocyclyl, (C3-C7) cycloalkenyl, a 5- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, (C6-C 10 ) aryl, or a 5-membered or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, wherein the alkyl group is optionally replaced by one or more R 18 and the carbocyclyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl groups are optionally substituted by one or more R 19 replace;

[0047] R3 is H, D, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, or (C1-C6)hydroxyalkyl, wherein the alkyl group is optionally replaced by one or more R 14 replace;

[0048] R4 is H or (C1-C6)alkyl; or

[0049] R3 and R4 together with the atoms to which they are attached form a 5- to 7-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O and S;

[0050] R5 and R7 are each independently H, D, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, or (C1-C6)hydroxyalkyl, wherein the (C1-C6)alkyl is optionally substituted with one or more D;

[0051] R6 is (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, or (C1-C6)hydroxyalkyl, wherein the alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of (C1-C6)alkoxy, (C1-C6)haloalkoxy, -C(O)(C1-C6)alkyl, -C(O)OH, and -C(O)O(C1-C6)alkyl;

[0052] R8 is H, (C1-C6) alkyl, or (C1-C6) haloalkyl, wherein the alkyl is optionally substituted by one or more substituents each independently selected from the group consisting of (C3-C7) carbocyclyl, a 4- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S, -NR 16 R 17 and -C(O)NR 16 R 17 ;

[0053] R9 is halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, -OH, or CN;

[0054] R 10 Yes (C6-C 10 ) aryl or a 5-membered or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl are optionally substituted by one or more R 22 replace;

[0055] Each R 11 is independently at each occurrence halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, -OH, or CN;

[0056] R 12 and R 13 are each independently H or (C1-C6)alkyl;

[0057] Each R 14D, NR independently at each occurrence 15 R 15' , (C3-C7)carbocyclyl, or a 3- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, and (C1-C6)haloalkoxy;

[0058] R 15 and R 15' are each independently H or (C1-C6)alkyl;

[0059] R 16 and R 17 are each independently H or (C1-C6) alkyl, or

[0060] R 16 and R 17 Together with the nitrogen atom to which they are attached, they form a 4- to 7-membered heterocyclyl ring containing 1-2 additional heteroatoms selected from N, O and S;

[0061] Each R 18 is independently at each occurrence (C3-C7)carbocyclyl, 5- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, (C6-C 10 ) aryl, or a 5-membered or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, wherein the carbocyclyl, heterocyclyl, aryl and heteroaryl are optionally substituted by one or more R 20 replace;

[0062] Each R 19 is independently at each occurrence halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, -OH, or CN; or

[0063] Two R's 19 When on adjacent atoms together form (C6-C 10 )aryl or a 5- or 6-membered heteroaryl ring containing 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl groups are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, -OH and CN;

[0064] Each R 20is independently at each occurrence halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, oxo, -OH, or CN; or

[0065] When R 18 When it is a carbocyclic or heterocyclic group, the two R 20 When attached to the same carbon atom together form =(O);

[0066] R 21 is H or (C1-C6)alkyl;

[0067] Each R 22 is independently at each occurrence halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, -OH, CN, (C6-C 10 ) aryl, or a 5-membered or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl are optionally substituted by one or more R 23 replace;

[0068] Each R 23 is independently at each occurrence halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, -CH2(OCH2CH2) 1-3 OCH2CH3, -OH, CN, or a 4- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from N, O and S, wherein the heterocyclic group is optionally substituted by one or more substituents each independently selected from the following: halogen, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, -OH, -C(O)R 24 R 25 、-NR 24 C(O)R 25 , -NH2, -NH(C1-C6)alkyl, and -N((C1-C6)alkyl)2, and the alkyl group is optionally replaced by -NR 24 R 25 substituted, or a 4- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S (which is optionally substituted by one or more substituents each independently selected from the group consisting of halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, -OH, -NH2, -NH(C1-C6)alkyl, and -N((C1-C6)alkyl)2); and

[0069] R 24 and R 25are each independently H, (C1-C6)alkyl, or (C3-C7)carbocyclyl;

[0070] or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, N-oxide or tautomer thereof.

[0071] Another aspect of the present disclosure relates to a compound having formula (I) or a pharmaceutically acceptable salt thereof for use in treating, preventing, ameliorating or delaying the progression of a disease or disorder mediated by PCSK9 or for treating, preventing, ameliorating or delaying the progression of a disease or disorder requiring inhibition of PCSK9 or PCSK9 activity.

[0072] In another aspect, the present disclosure relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating, preventing, ameliorating or delaying the progression of a disease or disorder mediated by PCSK9 or for treating, preventing, ameliorating or delaying the progression of a disease or disorder that requires inhibition of PCSK9 or PCSK9 activity.

[0073] Another aspect of the present disclosure relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating, preventing, ameliorating or delaying the progression of a disease or disorder mediated by PCSK9 or for treating, preventing, ameliorating or delaying the progression of a disease or disorder that requires inhibition of PCSK9 or PCSK9 activity.

[0074] In another aspect, the present disclosure relates to a method for treating, preventing, ameliorating or delaying the progression of a PCSK9-mediated disease or disorder, comprising the steps of administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to the present disclosure, or a pharmaceutically acceptable salt thereof.

[0075] Another aspect of the present disclosure relates to a method for treating, preventing, ameliorating or delaying the progression of a disease or disorder mediated by PCSK9 or a disease or disorder requiring inhibition of PCSK9 or PCSK9 activity, the method comprising the steps of administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to the present disclosure, or a pharmaceutically acceptable salt thereof.

[0076] In another aspect, the present disclosure relates to a method for treating, preventing, inhibiting or eliminating hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, vascular inflammation, xanthomas, peripheral arterial disease, sepsis, elevated Lp(a), elevated LDL, elevated TRL or elevated triglycerides, comprising the steps of administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0077] Another aspect of the present disclosure relates to a method of (i) lowering Lp(a), (ii) lowering Lp(a) plasma levels, (iii) lowering Lp(a) serum levels, (iv) lowering serum TRL or LDL levels, (v) lowering serum triglyceride levels, (vi) lowering LDL-C, (vii) lowering total plasma apoB concentration, (viii) lowering LDL apoB, (ix) lowering TRL apoB, or (x) lowering non-HDL-C, comprising the steps of administering to a patient in need thereof a therapeutically effective amount of a compound having formula (I) or a pharmaceutically acceptable salt thereof.

[0078] In another aspect, the present disclosure also relates to a method of (i) lowering LDL-C, (ii) lowering total apolipoprotein B (apoB) concentration, (iii) lowering LDL apoB, (iv) lowering TRL apoB or (v) lowering non-HDL-C, and combinations thereof, in a patient in need thereof, wherein the method comprises administering to the patient a therapeutically effective amount of a compound having formula (I) or a pharmaceutically acceptable salt thereof.

[0079] Another aspect of the present disclosure relates to a method of reducing the total plasma concentration of a marker selected from the group consisting of: (i) LDL-C, (ii) apoB, (iii) LDL apoB, (iv) TRL apoB, and (v) non-HDL-C, and combinations thereof, in a patient in need thereof, wherein the method comprises administering to the patient a therapeutically effective amount of a compound having formula (I) or a pharmaceutically acceptable salt thereof.

[0080] In another aspect, the disclosure relates to a pharmaceutical composition comprising (eg, a therapeutically effective amount of) a compound of formula (I) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0081] Another aspect of the present disclosure relates to pharmaceutical compositions comprising (e.g., a therapeutically effective amount of) a compound having formula (I) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients for treating a PCSK9-mediated disease or disorder.

[0082] In another aspect, the disclosure relates to a method of modulating PCSK9 comprising administering to a patient in need thereof a compound having formula (I) or a pharmaceutically acceptable salt thereof.

[0083] Another aspect of the present disclosure relates to a method of inhibiting PCSK9, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient in need thereof. In another aspect, the present disclosure relates to a method of inhibiting PCSK9 activity, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0084] In another aspect, the present disclosure relates to a method of treating a PCSK9-mediated disease or disorder, comprising the step of administering to a patient in need thereof a therapeutically effective amount of a compound having formula (I) or a pharmaceutically acceptable salt thereof.

[0085] Another aspect of the present disclosure relates to a method of lowering LDL-C in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound having formula (I) or a pharmaceutically acceptable salt thereof, thereby lowering LDL-C in the patient.

[0086] In another aspect, the disclosure relates to a compound having formula (I) or a pharmaceutically acceptable salt thereof for use in treating a PCSK9-mediated disease or disorder.

[0087] Another aspect of the present disclosure relates to a compound having formula (I) or a pharmaceutically acceptable salt thereof for use in treating a PCSK9-mediated disease or disorder selected from hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, peripheral arterial disease, vascular inflammation, elevated Lp(a), elevated LDL, elevated TRL, elevated triglycerides, sepsis, and xanthomas.

[0088] In another aspect, the disclosure relates to the use of a compound having formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a PCSK9-mediated disease or disorder.

[0089] Another aspect of the present disclosure relates to a compound having formula (I) or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for treating a disease associated with inhibition of PCSK9 activity.

[0090] In another aspect, the present disclosure relates to the use of a compound having formula (I) or a pharmaceutically acceptable salt thereof for treating a disease associated with inhibition of PCSK9 activity.

[0091] In certain aspects, the PCSK9 modulating or inhibiting compounds of the present disclosure may be administered alone or in combination with other compounds (including other PCSK9 modulating or inhibitory agents) or other therapeutic agents.

[0092] Thus, in another aspect, the disclosure relates to a combination comprising (eg, a therapeutically effective amount of) a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more therapeutically active agents.

[0093] Another aspect of the present disclosure relates to a process for preparing a compound of formula (II) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, N-oxide or tautomer thereof,

[0094]

[0095] where R a1 and R5 are each independently (C1-C6 alkyl) and R9 is as defined above for formula (I), the method comprising:

[0096] (a) alkylating a compound of formula (IIa) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, N-oxide or tautomer thereof,

[0097]

[0098] wherein R5 is H and R9 is as defined above for formula (I),

[0099] The alkylation is carried out using an alkyl halide (eg, methyl iodide, ethyl iodide, etc.) and a base (eg, NaH) in a solvent (eg, DMF, acetonitrile, etc.) at low temperature to provide a compound having formula (IIb),

[0100]

[0101] wherein R5 is (C1-C6 alkyl) and R9 is as defined above for formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, N-oxide or tautomer thereof,

[0102] (b) reacting a compound of formula (IIb) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, N-oxide or tautomer thereof with an acid (e.g., trifluoroacetic acid) in a solvent (e.g., dichloromethane), followed by reaction with BocO and a base (e.g., N,N-diisopropylethylamine (DIPEA)) to form a compound of formula (IIc),

[0103]

[0104] wherein R5 is (C1-C6 alkyl) and R9 is as defined above for formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, N-oxide or tautomer thereof;

[0105] (c) alkylating a compound of formula (IIc) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, N-oxide or tautomer thereof with an alkylating agent (e.g., methyl iodide, ethyl iodide, etc.) in a solvent (e.g., DMF, acetonitrile, etc.) and optionally a metal oxide (e.g., silver (I) oxide (AgO), etc.) to provide a compound of formula (IId),

[0106]

[0107] where R a1 and R5 are each independently (C1-C6 alkyl) and R9 is as defined above for formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, N-oxide or tautomer thereof; and

[0108] (d) dealkylating a compound of formula (IId) with a palladium catalyst (e.g., tetrakis(triphenylphosphine)palladium(0) (Pd(PPh 3 ) 4 ) and N,N-dimethyltrimethylsilylamine in a solvent (e.g., DCM, etc.) to provide a compound of formula (II). In one embodiment, the palladium catalyst is tetrakis(triphenylphosphine)palladium(0) (Pd(PPh 3 ) 4 ).

[0109] In another aspect, the present disclosure relates to a method of making a compound of formula (II) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, N-oxide or tautomer thereof,

[0110]

[0111] where R a1 is H, R5 is (C1-C6 alkyl), and R9 is as defined above for formula (I), the method comprising reacting a compound of formula (IIb):

[0112]

[0113] wherein R5 is (C1-C6 alkyl) and R9 is as defined above for formula (I), reacted with a palladium catalyst (e.g., tetrakis(triphenylphosphine)palladium(0)(Pd(PPh3)4) or the like) N,N-dimethyltrimethylsilylamine in a solvent (e.g., DCM or the like) to provide a compound of formula (II). In one embodiment, the palladium catalyst is tetrakis(triphenylphosphine)palladium(0)(Pd(PPh3)4).

[0114] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which this disclosure belongs. In this specification, the singular also includes the plural, unless the context clearly indicates otherwise. Although methods and materials similar or equivalent to those described herein can be used for the practice and testing of this disclosure, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference. The references cited herein are not considered to be prior art of the disclosure claimed. In the event of a conflict, the present specification including the definitions shall prevail. In addition, materials, methods and examples are illustrative only and are not intended to be limiting.

[0115] Other features and advantages of the disclosure will be apparent from the following detailed description and claims. DETAILED DESCRIPTION

[0116] The present disclosure relates to compounds and compositions that can modulate PCSK9 activity. The present disclosure is characterized by administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof to treat, prevent or improve a disease or disorder in which PCSK9 plays a role. The methods of the present disclosure can be used to treat a variety of PCSK9-dependent diseases and disorders by regulating or inhibiting PCSK9. Inhibiting or modulating PCSK9 provides a novel method for treating, preventing or improving diseases, including but not limited to hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease (including aortic disease and cerebrovascular disease), peripheral arterial disease, vascular inflammation, elevated Lp(a), elevated LDL, elevated TRL, elevated triglycerides, sepsis and xanthomas.

[0117] The compounds disclosed herein have utility in treating hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, peripheral arterial disease, vascular inflammation, elevated Lp(a), elevated LDL, elevated TRL (e.g., elevated VLDL and / or chylomicrons), elevated triglycerides, sepsis, and xanthomas by inhibiting PCSK9.

[0118] For example, the compounds of formula (I) disclosed herein bind to PCSK9 and thereby inhibit PCSK9 and / or PCSK9 activity because PCSK9 is no longer able to bind to the low-density lipoprotein receptor (LDLR) or any other target receptor. For example, if PCSK9 is blocked, more LDLR is circulated and present on the cell surface to remove LDL particles from the extracellular fluid. Therefore, blocking PCSK9 can reduce the concentration of LDL particles in the blood.

[0119] Thus, the compounds of the present disclosure are potentially useful for treating, preventing, ameliorating, or delaying the progression of PCSK9-mediated diseases or disorders, or diseases or disorders in which PCSK9 plays a role, as well as conditions, diseases, and disorders that benefit from modulation of PCSK9 or PCSK9 activity.

[0120] Furthermore, the compounds of the present disclosure are therefore potentially useful for treating, preventing, ameliorating or delaying the progression of diseases or disorders requiring inhibition of PCSK9 or PCSK9 activity.

[0121] Such diseases and disorders include those selected from the group consisting of hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, peripheral arterial disease, vascular inflammation, elevated Lp(a), elevated LDL, elevated TRL (e.g., elevated VLDL and / or chylomicrons), elevated triglycerides, sepsis, and xanthomas.

[0122] Various embodiments of the present disclosure are described herein. It will be appreciated that features specified in each embodiment may be combined with other specified features of other embodiments to provide further embodiments.

[0123] In a first aspect of the present disclosure, compounds having formula (I) are described:

[0124]

[0125] and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, N-oxides and tautomers thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, X1, X2, and X3 are as described above.

[0126] The details of the present disclosure are set forth in the specification sheets attached below. Although methods and materials similar or equivalent to those described herein can be used for the practice or testing of the present disclosure, illustrative methods and materials are now described. According to the specification sheets and according to the claims, other features, objects and advantages of the present disclosure will be clear. In this specification sheet and the appended claims, the singular form also includes the plural form, unless the context clearly indicates otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those of ordinary skill in the art to which the present disclosure belongs. All patents and public documents cited in this specification sheet are incorporated herein by reference in their entirety.

[0127] Definitions of terms and conventions used

[0128] Terms that are not explicitly defined herein should be understood to have the meanings that would be derived by those skilled in the art based on this disclosure and the context. However, unless otherwise indicated, the following terms as used in this specification and the appended claims have the indicated meanings and adhere to the following conventions.

[0129] Chemical Nomenclature, Terminology, and Conventions

[0130] In the groups, radicals or moieties defined below, the number of carbon atoms is usually indicated before the radical, and for example (C1-C 10 ) alkyl means an alkyl group with 1 to 10 carbon atoms. Generally speaking, for a group comprising two or more subgroups, the last group mentioned is a group connection point, for example, "alkylaryl" means a monovalent group of the formula alkyl-aryl-, and "arylalkyl" means a monovalent group of the formula aryl-alkyl-. In addition, the term representing a monovalent group is used and wherein a divalent group is suitable, it is understood to represent a corresponding divalent group, and vice versa. Unless otherwise stated, the conventional definition of the term contrast and the atomic valence of conventional stable atoms are assumed and embodied in all formulas and groups. The article "a / an" as used in this disclosure refers to one / kind or more than one / kind (e.g., at least one / kind) of the grammatical object of the article. By way of example, "an element" means an element or more than one element.

[0131] Unless stated otherwise, the term "and / or" as used in this disclosure means "and" or "or".

[0132] The term "optionally substituted" means that a given chemical moiety (e.g., an alkyl group) can (but is not required to) be bonded to other substituents (e.g., heteroatoms). For example, an optionally substituted alkyl group can be a fully saturated alkyl chain (e.g., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group can have substituents other than hydrogen. For example, it can be bonded to a halogen atom, a hydroxyl group, or any other substituent described herein at any position along the chain. Thus, the term "optionally substituted" means that a given chemical moiety has the potential to contain other functional groups, but does not necessarily have any other functional groups. Suitable substituents for optional substitution of the groups include, but are not limited to, halogen, oxo, -OH, -CN, -COOH, -CH2CN, -O-(C1-C6)alkyl, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, -O-(C2-C6)alkenyl, -O-(C2-C6)alkynyl, (C2-C6)alkenyl, (C2-C6)alkynyl, -OH, -OP(O)(OH )2, -OC(O)(C1-C6)alkyl, -C(O)(C1-C6)alkyl, -OC(O)O(C1-C6)alkyl, -NH2, -NH((C1-C6)alkyl), -N((C1-C6)alkyl)2, -NHC(O)(C1-C6)alkyl, -C(O)NH(C1-C6)alkyl, -S(O)2(C1-C6)alkyl, -S(O)NH(C1-C6)alkyl, and S(O)N((C1-C6)alkyl)2. The substituents themselves may be optionally substituted. As used herein, "optionally substituted" also refers to substituted or unsubstituted, the meaning of which is described below.

[0133] The term "substituted" means that the specified group or moiety bears one or more suitable substituents, wherein the substituents may be attached to the specified group or moiety at one or more positions. For example, an aryl group substituted with a cycloalkyl group may indicate that the cycloalkyl group is attached to an atom of the aryl group by a bond or by being fused to the aryl group and sharing two or more common atoms.

[0134] The term "unsubstituted" means that the specified group has no substituents.

[0135] Unless otherwise specifically defined, "aryl" means a cyclic aromatic hydrocarbon group having 1 to 3 aromatic rings (including monocyclic or bicyclic groups), such as phenyl, biphenyl, or naphthyl. When containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group are optionally connected at a single point (e.g., biphenyl) or fused (e.g., naphthyl). The aryl group is optionally substituted with one or more substituents at any point of attachment, for example, 1 to 5 substituents. Exemplary substituents include, but are not limited to, -H, -halogen, -CN, -O-(C-C)alkyl, (C-C)alkyl, -O-(C-C)alkenyl, -O-(C-C)alkynyl, (C-C)alkenyl, (C-C)alkynyl, -OH, -OP(O)(OH)2, -OC(O)(C-C)alkyl, -C(O)(C-C)alkyl, -OC(O)O(C-C)alkyl, NH2, NH((C-C)alkyl), N((C-C)alkyl)2, -S(O)2-(C-C)alkyl, -S(O)NH(C-C)alkyl, and S(O)N((C-C)alkyl)2. The substituents themselves are optionally substituted. In addition, when containing two fused rings, the aryl group optionally has an unsaturated or partially saturated ring fused to the fully saturated ring. Exemplary ring systems of these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthyl, tetrahydrobenzoannulyl, etc.

[0136] Unless otherwise specifically defined, "heteroaryl" means a monovalent monocyclic aromatic group or polycyclic aromatic group of 5 to 24 ring atoms, which contains one or more ring heteroatoms selected from N, O, or S, the remaining ring atoms being C. Heteroaryl as defined herein also means a bicyclic heteroaromatic group, wherein the heteroatoms are selected from N, O, or S. Aromatic groups are optionally substituted independently with one or more substituents as described herein. Examples include, but are not limited to, furyl, thienyl, pyrrolyl, pyridyl, pyridyl N-oxide, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, imidazo[1,2-b]pyrazolyl, fluoro[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl, di Hydroindole, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, dihydrobenzooxanyl, quinolinyl, isoquinolinyl, 1,6-naphthyridinyl, benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl , tetrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoindolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl, pyrrolo[1,2-a]pyrimidinyl, tetrahydropyrrolo[1,2-a]pyrimidinyl, 3,4-dihydro-2H-1Δ 2-pyrrolo[2,1-b]pyrimidine, dibenzo[b,d]thiophene, pyridin-2-one, fluoro[3,2-c]pyridinyl, fluoro[2,3-c]pyridinyl, 1H-pyrido[3,4-b][1,4]thiazinyl, benzoxazolyl, benzisoxazolyl, fluoro[2,3-b]pyridinyl, benzophenylthio, 1,5-naphthyridinyl, fluoro[3,2-b]pyridine, [1,2,4]triazolo[l,5-a]pyridinyl, benzo[1,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl, [1,2,4] Triazolo[4,3-b]pyridazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one, 3,4-dihydro-2H-pyrazolo[1,5-b][1,2]oxazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thiazolo[5,4d]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, 3H-indolyl, and derivatives thereof. In addition, when containing two fused rings, the aryl groups defined herein may have an unsaturated or partially saturated ring fused to a fully saturated ring. Exemplary ring systems of these heteroaryl groups include indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuran, indolinyl, indolyl, and dihydrobenzooxanyl.

[0137] Halogen or "halo" means fluorine, chlorine, bromine, or iodine.

[0138] "Alkyl" means a straight or branched chain saturated hydrocarbon containing 1 to 12 carbon atoms. Examples of (C1-C6)alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl.

[0139] "Alkoxy" means a straight or branched chain saturated hydrocarbon containing 1 to 12 carbon atoms, which contains a terminal "O" in the chain, such as -O(alkyl). Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, tert-butoxy, or pentoxy groups.

[0140] "Alkenyl" means a straight or branched unsaturated hydrocarbon containing 2-12 carbon atoms. An "alkenyl" group contains at least one double bond in the chain. The double bond of an alkenyl group can be unconjugated or conjugated to another unsaturated group. Examples of alkenyl groups include ethenyl, propenyl, n-butenyl, isobutenyl, pentenyl, or hexenyl. An alkenyl group can be unsubstituted or substituted and can be straight or branched.

[0141] "Alkynyl" means a straight or branched unsaturated hydrocarbon containing 2-12 carbon atoms. An "alkynyl" group contains at least one triple bond in the chain. Examples of alkenyl groups include ethynyl, propargyl, n-butynyl, isobutynyl, pentynyl, or hexynyl. Alkynyl groups can be unsubstituted or substituted.

[0142] "Cycloalkyl" means a monocyclic or polycyclic saturated carbocyclic ring containing 3-18 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, norbornenyl, bicyclo[2.2.2]octyl, or bicyclo[2.2.2]octenyl and derivatives thereof. (C3-C8)cycloalkyl is a cycloalkyl group containing between 3 and 8 carbon atoms. Cycloalkyl groups can be fused (e.g., decalin) or bridged (e.g., norbornadiene).

[0143] "Carbocyclyl" refers to a saturated or partially unsaturated carbocycle (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl etc.) containing a monocycle or polycycle of 3-18 carbon atoms. Examples of carbocyclyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutene, cyclopentyl, cyclopentene, cyclohexyl, cyclohexene, cycloheptyl, cyclooctyl, norbornyl (norboranyl), norbornenyl (norborenyl), bicyclo [2.2.2] octyl or bicyclo [2.2.2] octenyl and derivatives thereof. (C3-C8) carbocyclyl is a carbocyclyl group containing 3 to 8 carbon atoms. Carbocyclyl groups can be fused (e.g., decalin) or bridged (e.g., norbornadiene (norbomane)).

[0144] The term "cycloalkenyl" refers to a partially unsaturated carbocyclic ring containing 3 to 18 carbon atoms, preferably 4 to 12 carbon atoms and 1 or 2 double bonds. Exemplary cycloalkenyl groups include cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclohexadienyl, and cycloheptadienyl. (C3-C8)cycloalkenyl is a cycloalkenyl group containing 3 to 8 carbon atoms and at least one double bond.

[0145] "Heterocycloalkyl" means a saturated monocyclic or polycyclic ring containing carbon and at least one heteroatom selected from oxygen, nitrogen or sulfur (O, N or S), and wherein there is no shared non-localized n electron (aromaticity) between the ring carbon or heteroatom. The heterocycloalkyl ring structure can be substituted by one or more substituents. The substituent itself can be optionally substituted. The example of heterocycloalkyl ring includes but is not limited to oxetane, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxolinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, aza Oxalic acid Base, diazepine alkyl, tropanyl, oxazolidinyl, 1,4-dioxanyl, dihydrofuranyl, 1,3-dioxolanyl, imidazolidinyl, imidazolinyl, dithiolanyl, and homotropanyl.

[0146] "Heterocyclyl" means a saturated (e.g., heterocycloalkyl ring) or partially saturated monocyclic or polycyclic ring containing carbon and at least one heteroatom selected from oxygen, nitrogen, or sulfur (O, N, or S), and wherein there is no shared non-localized n electron (aromaticity) between the ring carbon or heteroatom. The heterocyclyl ring structure can be substituted by one or more substituents. The substituent itself can be optionally substituted. The example of a heterocyclyl ring includes but is not limited to oxetane, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, dihydropyrrolidinyl, pyridine-2 (1H) -one, dihydropyridyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxolinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, aza Oxalic acid Base, diazepine alkyl, tropanyl, oxazolidinyl, 1,4-dioxanyl, dihydrofuranyl, 1,3-dioxolanyl, imidazolidinyl, imidazolinyl, dithiolanyl, and homotropanyl.

[0147] "Hydroxyalkyl" means an alkyl group substituted with one or more -OH groups. Examples of hydroxyalkyl groups include HO-CH2-, HO-CH2CH2-, and CH2-CH(OH)-.

[0148] "Haloalkyl" means an alkyl group substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, and the like.

[0149] "Haloalkoxy" means an alkoxy group substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, and the like.

[0150] "Cyano" refers to a substituent having a nitrogen atom and a carbon atom connected by a triple bond, for example, C≡N.

[0151] As used herein, the term "oxo" refers to "-O ” group.

[0152] The term "N-oxide" refers to an oxygen atom bonded to a nitrogen atom (e.g., NO) via a single bond (e.g., "oxo"). ).

[0153] "Amino" means a substituent containing at least one nitrogen atom (eg, NH2).

[0154] Salt, Prodrug, Derivative, and Solvate Terms and Conventions

[0155] "Prodrug" or "prodrug derivative" means a covalently bonded derivative or carrier of a parent compound or active drug substance that undergoes at least some biotransformation before exhibiting one or more of its pharmacological effects. Generally speaking, such prodrugs have metabolically cleavable groups and are rapidly converted in vivo to produce the parent compound, for example, by hydrolysis in the blood, and generally include ester and amide analogs of the parent compound. Prodrugs are formulated with the goal of improving chemical stability, improving patient acceptance and compliance, improving bioavailability, extending duration of action, improving organ selectivity, improving formulations (e.g., increased water solubility) and / or reducing side effects (e.g., toxicity). Generally speaking, the prodrug itself has weak biological activity or no biological activity and is stable under normal conditions.Prodrugs can be readily prepared from the parent compound using methods known in the art, such as those described in A Textbook of Drug Design and Development, Krogsgaard-Larsen and H. Bundgaard (eds.), Gordon & Breach, 1991, in particular Chapter 5: "Design and Applications of Prodrugs"; Design of Prodrugs, H. Bundgaard (ed.), Elsevier, 1985; Prodrugs: Topical and Ocular Drug Delivery, KB Sloan (ed.), Marcel Dekker, 1998; Methods in Enzymology, K. Widder et al. (eds.), Vol. 42, Academic Press, 1996. Burger's Medicinal Chemistry and Drug Discovery, 5th ed., M. Wolff (ed.), John Wiley & Sons, 1995, in particular, volume 1 and pages 172-178 and 949-982; Pro-Drugs as Novel Delivery Systems, T. Higuchi and V. Stella (eds.), Am. Chem. Soc., 1975; Bioreversible Carriers in Drug Design, E. B. Roche (ed.), Elsevier, 1987, each of which is incorporated herein by reference in its entirety.

[0156] As used herein, "pharmaceutically acceptable prodrug" means a prodrug of the compounds of the present disclosure that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio, and, where possible, effective for its intended use as well as in zwitterionic form.

[0157] "Salt" means an ionic form of a parent compound or the product of the reaction between a parent compound and a suitable acid or base to prepare an acid salt or basic salt of the parent compound. Salts of the compounds of the present disclosure can be synthesized from parent compounds containing a basic or acidic moiety by conventional chemical methods. Generally, salts are prepared by reacting a free basic or acidic parent compound with a stoichiometric amount or with an excess of the desired salt-forming inorganic or organic acid or base in a suitable solvent or various combinations of solvents.

[0158] "Pharmaceutically acceptable salts" means salts of the compounds of the present disclosure that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, etc., commensurate with a reasonable benefit / risk ratio, are generally water-soluble or oil-soluble or dispersible, and are effective for their intended use. The term includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. Since the compounds of the present disclosure are useful in both free base form and salt form, in practice, using the salt form is equivalent to using the base form. A list of suitable salts is found, for example, in SM Birge et al., J. Pharm. Sci., 1977, 66, pp. 1-19, which is hereby incorporated by reference in its entirety.

[0159] "Pharmaceutically acceptable acid addition salts" means those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable and which are prepared by reacting with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, nitric acid, phosphoric acid, etc.) and organic acids (e.g., acetic acid, trichloroacetic acid, trifluoroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 2-acetoxybenzoic acid, butyric acid, camphoric acid, camphorsulfonic acid, cinnamic acid, citric acid, digluconic acid, ethanesulfonic acid, glutamic ... The present invention also includes but is not limited to amino acid, glycolic acid, glycerophosphate, hemisulfuric acid, heptanoic acid, hexanoic acid, formic acid, fumaric acid, 2-hydroxyethanesulfonic acid (hydroxyethylsulfonic acid), lactic acid, maleic acid, hydroxymaleic acid, malic acid, malonic acid, mandelic acid, mesitylenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, nicotinic acid, 2-naphthalenesulfonic acid, oxalic acid, pamoic acid, pectic acid, phenylacetic acid, 3-phenylpropionic acid, picric acid, pivalic acid, propionic acid, pyruvic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, p-aminobenzenesulfonic acid, tartaric acid, p-toluenesulfonic acid, undecanoic acid, etc.

[0160] "Pharmaceutically acceptable base addition salts" means salts that retain the biological effectiveness and properties of the free acids and are not biologically or otherwise undesirable, and are formed with inorganic bases (e.g., ammonia or hydroxides, carbonates, or ammonium bicarbonate) or metal cations (e.g., sodium, potassium, lithium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, etc.). Particularly preferred are ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amine compounds, substituted amines (including naturally occurring substituted amines), cyclic amines, and basic ion exchange resins, such as methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, isopropylamine, tripropylamine, tributylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, thiazolinone ... Preferred organic non-toxic bases include phenanthene, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, tetramethylammonium compounds, tetraethylammonium compounds, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, dibenzylamine, N,N-dibenzylphenethylamine, 1-diphenylhydroxymethylamine, N,N'-dibenzylethylenediamine, polyamine resins, etc. Particularly preferred organic non-toxic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0161] "Solvate" means a complex of variable stoichiometry formed by a solute (e.g., a compound of formula (I)) and a solvent (e.g., water, ethanol, or acetic acid). This physical association may involve varying degrees of ionic and covalent bonds, including hydrogen bonds. In some cases, the solvate is capable of separation (e.g., when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid). Generally, such solvents selected for the purposes of this disclosure do not interfere with the biological activity of the solute. Solvates encompass both solution-phase and separable solvates. Representative solvates include hydrates, ethanolates, methanolates, and the like.

[0162] "Hydrate" means a solvate wherein one or more of the solvent molecules is water.

[0163] The compounds of the present disclosure, as discussed below, include their free bases or acids, their salts, solvates, and prodrugs, and may include oxidized sulfur atoms or quaternized nitrogen atoms in their structures (even if not explicitly stated or shown), particularly their pharmaceutically acceptable forms. Such forms (particularly pharmaceutically acceptable forms) are intended to be included in the appended claims.

[0164] Isomer terminology and conventions

[0165] "Isomers" means compounds that have the same number and kind of atoms, and therefore the same molecular weight, but differ with respect to the arrangement or configuration of the atoms in space. The term includes stereoisomers and geometric isomers.

[0166] "Stereoisomer" or "optical isomer" means a stable isomer having at least one chiral atom or restricted rotation resulting in a vertical asymmetric plane (e.g., some biphenyls, allenes, and spiro compounds) and that can rotate plane-polarized light. Because asymmetric centers and other chemical structures are present in the compounds of the present disclosure that can cause stereoisomerism, the present disclosure contemplates stereoisomers and mixtures thereof. The compounds of the present disclosure and their salts include asymmetric carbon atoms and therefore can exist as single stereoisomers, racemates, and mixtures of enantiomers and diastereomers. Typically, such compounds will be prepared as racemic mixtures. However, if desired, such compounds can be prepared or separated into stereoisomers, i.e., as individual enantiomers or diastereomers, or as mixtures enriched in stereoisomers. As discussed in more detail below, individual stereoisomers of a compound are prepared by synthesis from optically active starting materials containing the desired chiral centre, or by preparing a mixture of enantiomeric products followed by separation or resolution (e.g., conversion to a mixture of diastereomers followed by separation or recrystallisation, chromatographic techniques, use of a chiral resolving agent, or direct separation of the enantiomers on a chiral chromatographic column). Starting compounds of specific stereochemistry are either commercially available or prepared by the methods described below and resolved by techniques well known in the art.

[0167] "Enantiomers" means a pair of stereoisomers that are non-superimposable mirror images of one another.

[0168] "Diastereomers" or "diastereomers" means optical isomers that are not mirror images of one another.

[0169] "Racemic mixture" or "racemate" means a mixture containing equal parts of individual enantiomers.

[0170] "Non-racemic mixture" means a mixture containing unequal parts of individual enantiomers.

[0171] "Geometric isomers" means stable isomers resulting from rotational freedom restrictions in double bonds (e.g., cis-2-butene and trans-2-butene) or ring structures (e.g., cis-1,3-dichlorocyclobutane and trans-1,3-dichlorocyclobutane). Because carbon-carbon double (olefinic) bonds, C=N double bonds, ring structures, etc. can be present in the compounds of the present disclosure, the present disclosure contemplates each of the different stable geometric isomers and mixtures thereof resulting from the arrangement of substituents around these double bonds and in these ring structures. Substituents and isomers are represented using the cis / trans convention or using the E or Z system, where the term "E" means that higher-order substituents are on opposite sides of the double bond and the term "Z" means that higher-order substituents are on the same side of the double bond. A detailed discussion of E and Z isomerism is provided in J. March, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 4th ed., John Wiley & Sons, 1992, which is hereby incorporated by reference in its entirety. Several of the following examples represent single E isomers, single Z isomers, and mixtures of E / Z isomers. Determination of E and Z isomers can be performed by analytical methods, such as X-ray crystallography, 1 H NMR, and 13 C NMR.

[0172] Some compounds of the present disclosure can exist in more than one tautomeric form. As mentioned above, the compounds of the present disclosure include all such tautomers.

[0173] It is well known in the art that the biological and pharmacological activities of compounds are sensitive to the stereochemistry of the compound. Thus, for example, enantiomers typically exhibit significantly different biological activities, including differences in pharmacokinetic properties (including metabolism, protein binding, etc.) and pharmacological properties (including the type of activity displayed, degree of activity, toxicity, etc.). Therefore, it will be understood by those skilled in the art that one enantiomer can be more active or can exhibit a beneficial effect when enriched relative to the other enantiomer or when separated from the other enantiomers. Additionally, those skilled in the art will know how to separate, enrich, or selectively prepare the enantiomers of the compounds of the present disclosure from the knowledge of the present disclosure and the prior art.

[0174] Thus, although the racemic form of a drug can be used, it is generally not as effective as administering an equal amount of the enantiomerically pure drug; in fact, in some cases, one enantiomer may be pharmacologically inactive and act merely as a simple diluent. For example, although ibuprofen has previously been administered as a racemate, only the S-isomer of ibuprofen has been found to be effective as an anti-inflammatory agent (however, in the case of ibuprofen, although the R-isomer is inactive, it is converted to the S-isomer in the body, so the racemic form of the drug is slower to act than the pure S-isomer). Furthermore, the pharmacological activity of enantiomers can have significantly different biological activities. For example, S-penicillamine is a therapeutic agent for chronic arthritis, while R-penicillamine is toxic. In fact, some purified enantiomers have advantages over the racemate, as it has been reported that purified individual isomers have faster transdermal penetration rates than the racemic mixture. See U.S. Patent Nos. 5,114,946 and 4,818,541.

[0175] Therefore, if one enantiomer is pharmacologically more active, less toxic, or has a more favorable body distribution than the other enantiomer, it would be therapeutically more beneficial to administer that enantiomer preferentially. In this way, the treated patient would be exposed to a lower total dose of the drug and a lower dose of the potentially toxic enantiomer or other enantiomer inhibitors.

[0176] The preparation of pure enantiomers or mixtures having the desired enantiomeric excess (ee) or enantiomeric purity can be accomplished by one or more of a number of methods known to those skilled in the art for (a) separation or resolution of enantiomers, or (b) enantioselective synthesis, or a combination of these methods. These resolution methods generally rely on chiral recognition and include, for example, chromatography using chiral stationary phases, enantioselective host-guest complexation, resolution or synthesis using chiral auxiliaries, enantioselective synthesis, enzymatic and non-enzymatic kinetic resolution, or spontaneous enantioselective crystallization. Such methods are generally disclosed in: Chiral Separation Techniques: A Practical Approach (2nd ed.), G. Subramanian (ed.), Wiley-VCH, 2000; TE Beesley and RPW Scott, Chiral Chromatography, John Wiley & Sons, 1999; and Satinder Ahuja, Chiral Separations by Chromatography, Am. Chem. Soc., 2000. In addition, there are equally well-known methods for quantifying enantiomeric excess or purity (e.g., GC, HPLC, CE, or NMR) and for identifying absolute configuration and conformation (e.g., CDORD, X-ray crystallography, or NMR).

[0177] In general, all tautomeric and isomeric forms and mixtures of a chemical structure or compound, whether individual geometric isomers or stereoisomers or racemic or non-racemic mixtures, are contemplated unless a specific stereochemistry or isomeric form is explicitly indicated in the compound name or structure.

[0178] Drug administration and treatment terminology and conventions

[0179] A "patient" or "subject" is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon, or rhesus monkey. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.

[0180] The term "pharmaceutically effective amount" or "therapeutically effective amount" or "effective amount" means an amount of a compound according to the present disclosure that, when administered to a patient in need thereof, is sufficient to achieve treatment of the disease state, condition or disorder in which the compound has utility. Such an amount is sufficient to elicit the biological or medical response of a tissue, system or patient that is being sought by the researcher or clinician. The amount of a compound according to the present disclosure that constitutes a therapeutically effective amount will vary according to factors such as the compound and its biological activity, the composition for administration, the time of administration, the route of administration, the rate of excretion of the compound, the duration of treatment, the type of disease state or disorder being treated and its severity, the drugs used in combination or together with the compounds of the present disclosure, and the age, weight, general health, sex and diet of the patient. Such a therapeutically effective amount can be routinely determined by those of ordinary skill in the art based on their own knowledge, the prior art and the present disclosure.

[0181] As used herein, the term "pharmaceutical composition" refers to a compound of the present disclosure or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, in a form suitable for oral or parenteral administration, and at least one pharmaceutically acceptable carrier.

[0182] "Carrier" encompasses vehicles, excipients, and diluents, and means a material, composition, or vehicle involved in carrying or transporting a pharmaceutical agent from one organ or part of a subject's body to another, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material.

[0183] "Combination" refers to a fixed combination in the form of one dosage unit, or combined administration (wherein a compound of the present disclosure and at least one combination partner (e.g., another drug, also referred to as "therapeutic agent" or "co-agent"), as explained below, may be administered independently at the same time or separately within time intervals, particularly where these time intervals allow the combination partners to exhibit a beneficial effect of the therapeutic agents acting together). Beneficial effects of the combination include, but are not limited to, synergistic effects resulting from the combination of therapeutic agents, such as synergistic effects and / or pharmacokinetic or pharmacodynamic co-action, or any combination thereof. In one embodiment, the combined administration of the therapeutic agents is performed over a defined period of time (e.g., minutes, hours, days or weeks, depending on the combination selected). "

[0184] The individual components can be packaged in a kit or packaged separately. One or both components (e.g., powder or liquid) can be reconstituted or diluted to the desired dose prior to administration. As used herein, the terms "co-administration" or "administered in combination" and the like are intended to encompass administration of the selected combination partners to a single subject (e.g., patient) in need thereof, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or are administered simultaneously.

[0185] As used herein, the term "drug combination" means a product produced by a mixture or combination of more than one therapeutic agent, and includes both fixed and non-fixed combinations of therapeutic agents. The term "fixed combination" means that therapeutic agents (e.g., compounds of the present disclosure and combination partners) are administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that therapeutic agents (e.g., compounds of the present disclosure and combination partners) are administered to a patient simultaneously, in parallel or sequentially as separate entities (without specific time limits), wherein such administration provides two compounds at therapeutically effective levels in the patient's body. The latter is also applicable to cocktail therapies, such as the administration of three or more therapeutic agents.

[0186] A subject (preferably a human) is "in need of" a treatment if the subject would benefit biologically, medically, or in quality of life from such treatment.

[0187] The terms "PCSK9" or "proprotein convertase subtilisin / kexin type 9" interchangeably refer to a native human proprotein convertase that belongs to the proteinase K subfamily of the secreted subtilisin family. PCSK9 is synthesized as a soluble zymogen that undergoes autocatalytic intramolecular processing in the endoplasmic reticulum and is thought to function as a proprotein convertase. PCSK9 plays a role in cholesterol homeostasis and may play a role in the differentiation of cortical neurons. Mutations in the PCSK9 gene are the cause of autosomal dominant familial hypercholesterolemia. (Burnett and Hooper, Clin. Biochem. Rev. (2008) 29(1):11-26)

[0188] As used herein, the terms "inhibit," "inhibition," or "inhibiting" refer to the reduction or suppression of a given condition, symptom or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

[0189] As used herein, the terms "treat," "treating," or "treatment" of any disease or disorder refers to alleviating or relieving the disease or disorder (i.e., slowing or arresting the progression of the disease or at least one clinical symptom thereof); or alleviating or improving at least one physical parameter or biomarker associated with the disease or disorder, including those that may not be discernible by the patient.

[0190] As used herein, the terms "prevent," "preventing," or "prevention" of any disease or disorder refers to prophylactic treatment of the disease or disorder; or delaying the onset or progression of the disease or disorder.

[0191] "Pharmaceutically acceptable" means that the substance or composition must be compatible chemically and / or toxicologically with the other ingredients comprising the formulation and / or the mammal being treated therewith.

[0192] Unless otherwise indicated, "disorder" is intended to refer to the term disease, condition, or ailment and is used interchangeably with these terms.

[0193] "Administer," "administering," or "administration" means administering a disclosed compound, or a pharmaceutically acceptable salt or composition of a disclosed compound, directly to a subject, or administering a prodrug derivative or analog of a compound, or a pharmaceutically acceptable salt or composition of a compound to a subject, which can form an equivalent amount of the active compound in the subject.

[0194] "Prodrug" means a compound that is convertible in vivo by metabolic means (eg, by hydrolysis) to a disclosed compound.

[0195] "Compounds of the present disclosure," "compounds of formula (I)," "compounds of the disclosure," and equivalent expressions (unless otherwise specifically indicated) refer to compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), and (Io) as described herein, including tautomers, prodrugs, salts (particularly pharmaceutically acceptable salts), and solvates and hydrates thereof, as well as all stereoisomers (including diastereomers and enantiomers), rotamers, tautomers, and isotopically labeled compounds (including deuterium ("D") substitution), as well as inherently formed moieties (e.g., polymorphs, solvates, and / or hydrates). For the purposes of the present disclosure, solvates and hydrates are generally considered to be compositions. Generally speaking and preferably, the compounds of the present disclosure and the formula representing the compounds of the present disclosure should be understood to include only stable compounds thereof and exclude unstable compounds, even if unstable compounds can be considered to be actually included in the compound formula. Similarly, where the context permits, reference to intermediates (whether or not they themselves are claimed) is intended to include their salts and solvates. For the sake of clarity, specific cases where the context permits are sometimes pointed out in the text, but these cases are purely illustrative and are not intended to exclude other cases where the context permits.

[0196] "Intermediates of the present disclosure," "disclosed intermediates," and equivalent expressions (unless otherwise specifically indicated) refer to compounds of formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), (IIIh), (IIIi), and (IIIj) as described herein, including tautomers, prodrugs, salts (particularly pharmaceutically acceptable salts), and solvates and hydrates thereof, (where the context permits) as well as all stereoisomers (including diastereomers and enantiomers), rotamers, tautomers, and isotopically labeled compounds (including deuterium ("D") substitution), as well as inherently formed moieties (e.g., polymorphs, solvates, and / or hydrates). For the purposes of the present disclosure, solvates and hydrates are generally considered to be compositions. Generally and preferably, intermediates of the present disclosure and formulas representing intermediates of the present disclosure should be understood to include only stable compounds thereof and exclude unstable compounds, even if unstable compounds may be considered to be actually included within the compound formula. Similarly, references to intermediates (whether or not they themselves are claimed) are intended to include their salts and solvates, where the context permits. For clarity, specific instances where the context permits are sometimes indicated in the text, but these are purely illustrative and are not intended to exclude other instances where the context permits.

[0197] By "stable compound" or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic or diagnostic agent. For example, compounds with "dangling valencies" or carbanions are not contemplated by the present disclosure.

[0198] In particular embodiments, the term "about" or "approximately" means within 20%, preferably within 10%, and more preferably within 5% of a given value or range.

[0199] As used herein, "modulator of PCSK9" refers to a compound or molecule that is capable of modulating the biological activity or function of PCSK9 and / or one or more downstream pathways mediated by PCSK9 activity.

[0200] As used herein, "PCSK9 inhibitor" refers to a compound or molecule that is capable of inhibiting PCSK9 biological activity or function and / or one or more downstream pathways mediated by PCSK9 signaling. Inhibitors of PCSK9 activity include compounds that block, antagonize, inhibit, or reduce (to any extent, including significantly) PCSK9 biological activity (including downstream pathways mediated by PCSK9 activity).

[0201] As used herein, "disorders or diseases responsive to inhibition of PCSK9," "disorders and conditions responsive to inhibition of PCSK9," "disorders and conditions responsive to inhibition of PCSK9 activity," "disorders responsive to inhibition of PCSK9," "disorders responsive to inhibition of PCSK9 activity," "disorders in which PCSK9 plays a role" and like terms include hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease (including aortic disease and cerebrovascular disease), peripheral arterial disease, vascular inflammation, elevated Lp(a), elevated LDL, elevated TRL, elevated triglycerides, sepsis, and xanthomas.

[0202] As used herein, "inhibiting PCSK9 activity" or "inhibiting PCSK9" refers to a decrease in PCSK9 activity, for example, by administering a compound of the invention.

[0203] The term "hypercholesterolemia" or "dyslipidemia" includes, for example, familial and non-familial hypercholesterolemia. Familial hypercholesterolemia (FH) is an autosomal dominant genetic disease characterized by elevated serum cholesterol bound to low-density lipoprotein (LDL). Familial hypercholesterolemia includes heterozygous FH and homozygous FH. Hypercholesterolemia (or dyslipidemia) is the presence of high levels of cholesterol in the blood. It is a form of hyperlipidemia (elevated lipid levels in the blood) and hyperlipoproteinemia (elevated lipoprotein levels in the blood).

[0204] Hyperlipidemia is an increase in lipids in the blood. These lipids include cholesterol, cholesterol esters, phospholipids, and triglycerides. Hyperlipidemia includes, for example, type I, type IIa, type IIb, type III, type IV, and type V.

[0205] Hypertriglyceridemia means high levels of triglycerides in the blood. Elevated triglyceride levels are associated with atherosclerosis (even in the absence of hypercholesterolemia) and a predisposition to cardiovascular disease.

[0206] "Sitosterolemia" or "phytosterolemia" is a rare autosomal recessive lipid metabolism disorder characterized by excessive absorption of sitosterol from the gastrointestinal tract and decreased biliary excretion of dietary sterols (i.e., leading to hypercholesterolemia, tendon and tuberous xanthomas, premature development of atherosclerosis), and altered cholesterol synthesis.

[0207] The term "atherosclerosis" encompasses hardening of the arteries involving the buildup of fatty substances, cholesterol, cellular waste products, calcium, and fibrin in the lining of the arteries. The resulting buildup is called plaque.

[0208] "Atherosclerosis" or "atherosclerotic vascular disease (ASVD)" is a specific form of arteriosclerosis that involves thickening, hardening, and loss of elasticity in the artery walls due to the invasion and accumulation of white blood cells (including live, active white blood cells (which produce inflammation)) and remnants of dead cells (including cholesterol and triglycerides). Thus, atherosclerosis is a syndrome that affects arterial blood vessels due to a chronic inflammatory response of white blood cells in the arterial wall.

[0209] Coronary heart disease, also known as atherosclerotic heart disease, atherosclerotic cardiovascular disease, coronary artery disease, or ischemic heart disease, is the most common type of heart disease and cause of heart attacks. The disease is caused by a buildup of plaque along the inner walls of the heart's arteries, which narrows the arteries and reduces blood flow to the heart.

[0210] Xanthomas are cutaneous manifestations of lipidosis, in which lipids accumulate in large foam cells within the skin. Xanthomas are associated with hyperlipidemia.

[0211] As used herein, the term "elevated Lp(a) concentration" refers to a serum Lp(a) concentration greater than 30 mg / dl (75 nmol / L). "Elevated serum Lp(a)" refers to a serum Lp(a) level greater than about 14 mg / dL. In certain embodiments, if the serum Lp(a) level measured in the patient is greater than about 15 mg / dL, about 20 mg / dL, about 25 mg / dL, about 30 mg / dL, about 35 mg / dL, about 40 mg / dL, about 45 mg / dL, about 50 mg / dL, about 60 mg / dL, about 70 mg / dL, about 80 mg / dL, about 90 mg / dL, about 100 mg / dL, about 20 mg / dL, about 140 mg / dL, about 150 mg dL, about 180 mg / dL, or about 200 mg / dL, the patient's serum Lp(a) level is considered elevated and the patient's serum Lp(a) level can be checked after a meal. In some embodiments, the Lp(a) level is measured after a period of fasting (e.g., after fasting for 8 hours, 8 hours, 10 hours, 12 hours, or more). Exemplary methods for measuring patient serum Lp(a) include, but are not limited to, rate immunoturbidimetry, ELISA, turbidimetry, immunoturbidimetry, and dissociation-enhanced lanthanide fluorescence immunoassay, although any clinically accepted diagnostic method may be used in the context of the present disclosure.

[0212] "Elevated triglyceride levels" or "ETL" refers to any level of triglyceride levels determined to be undesirable or targeted for regulation.

[0213] "Sepsis" is a systemic reaction characterized by arterial hypotension, metabolic acidosis, decreased systemic vascular resistance, tachypnea, and organ dysfunction. Sepsis can result from septicemia (i.e., an organism, its metabolic end products or toxins in the blood) (including bacteremia (i.e., bacteria in the blood)) and toxemia (i.e., toxins in the blood) (including endotoxemia (i.e., endotoxins in the blood). The term "sepsis" also includes fungemia (i.e., fungi in the blood), viremia (i.e., viruses or viral particles in the blood), and parasitemia (i.e., helminthic or protozoan parasites in the blood). Thus, septicemia and septic shock (acute circulatory failure caused by septicemia, often associated with multiple organ failure and high mortality) can be caused by many organisms.

[0214] Specific examples of compounds of formula (I)

[0215] The present disclosure relates to compounds capable of modulating PCSK9, or pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, or tautomers thereof (useful for treating diseases and disorders associated with the modulation of PCSK9 proteins or enzymes). In another embodiment, the present disclosure relates to compounds capable of inhibiting PCSK9, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof (useful for treating diseases and disorders associated with the inhibition of PCSK9 proteins or enzymes). The present disclosure further relates to compounds or pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, or tautomers thereof (useful for inhibiting PCSK9).

[0216] In one embodiment, the compound of formula (I) has the following structure: Formula (Ia):

[0217]

[0218] and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, N-oxides, and tautomers thereof.

[0219] In another embodiment, the compound of formula (I) has the following structure: Formula (Ib):

[0220]

[0221] and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, N-oxides, and tautomers thereof.

[0222] In another embodiment, the compound of formula (I) has the following structure: Formula (Ic):

[0223]

[0224] and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, N-oxides, and tautomers thereof.

[0225] In another embodiment, the compound of formula (I) has the following structure: Formula (Id):

[0226]

[0227] and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, N-oxides, and tautomers thereof.

[0228] In another embodiment, the compound of formula (I) has the following structure: Formula (Ie):

[0229]

[0230] and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, N-oxides, and tautomers thereof.

[0231] In another embodiment, the compound of formula (I) has the following structure: Formula (If):

[0232]

[0233] and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, N-oxides, and tautomers thereof.

[0234] In another embodiment, the compound of formula (I) has the following structure: Formula (Ig):

[0235]

[0236] and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, N-oxides, and tautomers thereof.

[0237] In another embodiment, the compound of formula (I) has the following structure: Formula (Ih):

[0238]

[0239] and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, N-oxides, and tautomers thereof.

[0240] In another embodiment, the compound of formula (I) has the following structure: Formula (Ii):

[0241]

[0242] and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, N-oxides, and tautomers thereof.

[0243] In another embodiment, the compound of formula (I) has the following structure: Formula (Ij):

[0244]

[0245] wherein x is 0, 1, or 2; and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, N-oxides, and tautomers thereof.

[0246] In another embodiment, the compound of formula (I) has the following structure: Formula (Ik):

[0247]

[0248] wherein x is 0, 1, or 2; and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, N-oxides, and tautomers thereof.

[0249] In another embodiment, the compound of formula (I) has the following structure: Formula (Im):

[0250]

[0251] wherein x is 0, 1, or 2; and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, N-oxides, and tautomers thereof.

[0252] In another embodiment, the compound of formula (I) has the following structure: Formula (Io):

[0253]

[0254] wherein x is 0, 1, or 2; and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, N-oxides, and tautomers thereof.

[0255] In some embodiments of the above formulae (e.g., Formula (I), Formula (la), Formula (lb), Formula (Ic), Formula (Id), Formula (Ie), Formula (If), Formula (Ig), Formula (Ih), Formula (Ii), Formula (Ij), Formula (Ik), Formula (Im), and / or Formula (Io)),

[0256] X1 and X2 are each independently H or (C1-C6)alkyl, or X1 and X2 together with the carbon atom to which they are attached form =(O);

[0257] X3 is -CH2- (when X1 and X2 are each independently H or (C1-C6)alkyl, or X1 and X2 together with the carbon atom to which they are attached form =(O)) or X3 is -O-, -NH- or -N(C1-C6)alkyl- (when X1 and X2 together with the carbon atom to which they are attached form =(O));

[0258] R1 is (C6-C 10 ) aryl or a 5-membered or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl are replaced by -OR 10 or -NR 21 R 10 and optionally substituted by one to four R 11 replace;

[0259] R2 is H, (C1-C6) alkyl, (C2-C6) alkenyl, (C1-C6) haloalkyl, -NR 12 R 13 , (C3-C7) carbocyclyl, (C3-C7) cycloalkenyl, a 5- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, (C6-C 10 ) aryl, or a 5-membered or 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, wherein the alkyl group is optionally substituted by one to four R 18 substituted, and the carbocyclyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl are optionally substituted by one to four R 19 replace;

[0260] R3 is H, D, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, or (C1-C6)hydroxyalkyl, wherein the alkyl group is optionally substituted by one to four R 14 replace;

[0261] R4 is H or (C1-C6)alkyl; or

[0262] R3 and R4 together with the atoms to which they are attached form a 5- to 7-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O and S;

[0263] R5 and R7 are each independently H, D, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, or (C1-C6)hydroxyalkyl, wherein the (C1-C6)alkyl is optionally substituted with one to four D;

[0264] R6 is (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, or (C1-C6)hydroxyalkyl, wherein the alkyl is optionally substituted with one to four substituents each independently selected from the group consisting of (C1-C6)alkoxy, (C1-C6)haloalkoxy, -C(O)(C1-C6)alkyl, -C(O)OH, and -C(O)O(C1-C6)alkyl;

[0265] R8 is H, (C1-C6) alkyl, or (C1-C6) haloalkyl, wherein the alkyl is optionally substituted by one to four substituents each independently selected from the group consisting of (C3-C7) carbocyclyl, a 4- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S, -NR 16 R 17 and -C(O)NR 16 R 17 ;

[0266] R9 is halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, -OH, or CN;

[0267] R 10 Yes (C6-C 10 ) aryl or a 5-membered or 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl are optionally substituted by one to four R 22 replace;

[0268] Each R 11 is independently at each occurrence halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, -OH, or CN;

[0269] R 12 and R 13 are each independently H or (C1-C6)alkyl;

[0270] Each R 14 D, NR independently at each occurrence 15 R 15' , (C3-C7)carbocyclyl, or a 3- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one to four substituents each independently selected from halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, and (C1-C6)haloalkoxy;

[0271] R 15 and R 15’are each independently H or (C1-C6)alkyl;

[0272] R 16 and R 17 are each independently H or (C1-C6) alkyl, or

[0273] R 16 and R 17 Together with the nitrogen atom to which they are attached, they form a 4- to 7-membered heterocyclyl ring optionally containing 1-2 additional heteroatoms selected from N, O and S;

[0274] Each R 18 is independently at each occurrence (C3-C7)carbocyclyl, 5- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, (C6-C 10 ) aryl, or a 5-membered or 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, wherein the carbocyclyl, heterocyclyl, aryl and heteroaryl are optionally substituted by one to four R 20 replace;

[0275] Each R 19 is independently at each occurrence halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, -OH, or CN; or

[0276] Two R's 19 When on adjacent atoms together form (C6-C 10 )aryl or a 5- or 6-membered heteroaryl ring containing 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl groups are optionally substituted with one to four substituents each independently selected from halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, -OH and CN;

[0277] Each R 20 is independently at each occurrence halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, oxo, -OH, or CN; or

[0278] When R 18 When it is a carbocyclic or heterocyclic group, the two R 20 When attached to the same carbon atom together form =(O);

[0279] R 21 is H or (C1-C6)alkyl;

[0280] Each R 22is independently at each occurrence halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, -OH, CN, (C6-C 10 ) aryl, or a 5-membered or 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl are optionally substituted by one to four R 23 replace;

[0281] Each R 23 is independently at each occurrence halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, -CH2(OCH2CH2) 1-3 OCH2CH3, -OH, CN, or a 4- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from N, O and S (wherein the heterocyclic group is optionally substituted by one to four substituents each independently selected from the following: halogen, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, -OH, -C(O)R 24 R 25 、-NR 24 C(O)R 25 , -NH2, -NH(C1-C6)alkyl, and -N((C1-C6)alkyl)2, and the alkyl group is optionally replaced by -NR 24 R 25 substituted) or a 4- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S (which is optionally substituted by one to four substituents each independently selected from the following: halogen, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, -OH, -NH2, -NH(C1-C6) alkyl, and -N((C1-C6) alkyl)2); and

[0282] R 24 and R 25 are each independently H, (C1-C6)alkyl, or (C3-C7)carbocyclyl;

[0283] or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, N-oxide or tautomer thereof.

[0284] In some embodiments of the above formula, X1 and X2 are each independently H or (C1-C6)alkyl, or X1 and X2 together with the carbon atom to which they are attached form =(O);

[0285] X3 is -CH2- (when X1 and X2 are each independently H or (C1-C6)alkyl, or X1 and X2 together with the carbon atom to which they are attached form =(O)) or X3 is -O-, -NH- or -N(C1-C6)alkyl- (when X1 and X2 together with the carbon atom to which they are attached form =(O));

[0286] R1 is (C6-C 10 ) aryl or a 5-membered or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl are replaced by -OR 10 or -NR 21 R 10 and optionally substituted by one to four R 11 replace;

[0287] R2 is H, (C1-C6) alkyl, (C2-C6) alkenyl, (C1-C6) haloalkyl, -NR 12 R 13 , (C3-C7) carbocyclyl, (C3-C7) cycloalkenyl, a 5- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, (C6-C 10 ) aryl, or a 5-membered or 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, wherein the alkyl group is optionally substituted by one to four R 18 substituted, and the carbocyclyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl are optionally substituted by one to four R 19 replace;

[0288] R3 is H, D, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, or (C1-C6)hydroxyalkyl, wherein the alkyl group is optionally substituted by one to four R 14 replace;

[0289] R4 is H or (C1-C6)alkyl; or

[0290] R3 and R4 together with the atoms to which they are attached form a 5- to 7-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O and S;

[0291] R5 and R7 are each independently H, D, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, or (C1-C6)hydroxyalkyl, wherein the (C1-C6)alkyl is optionally substituted with one to four D;

[0292] R6 is (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, or (C1-C6)hydroxyalkyl, wherein the alkyl is optionally substituted with one to four substituents each independently selected from the group consisting of (C1-C6)alkoxy, (C1-C6)haloalkoxy, -C(O)(C1-C6)alkyl, -C(O)OH, and -C(O)O(C1-C6)alkyl;

[0293] R8 is H, (C1-C6) alkyl, or (C1-C6) haloalkyl, wherein the alkyl is optionally substituted by one to four substituents each independently selected from the group consisting of (C3-C7) carbocyclyl, a 4- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S, -NR 16 R 17 and -C(O)NR 16 R 17 ;

[0294] R9 is halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, -OH, or CN;

[0295] R 10 Yes (C6-C 10 ) aryl or a 5-membered or 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl are optionally substituted by one to four R 22 replace;

[0296] Each R 11 is independently at each occurrence halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, -OH, or CN;

[0297] R 12 and R 13 are each independently H or (C1-C6)alkyl;

[0298] Each R 14 D, NR independently at each occurrence 15 R 15' , (C3-C7)carbocyclyl, or a 3- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one to four substituents each independently selected from halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, and (C1-C6)haloalkoxy;

[0299] R 15 and R 15’are each independently H or (C1-C6)alkyl;

[0300] R 16 and R 17 are each independently H or (C1-C6) alkyl, or

[0301] R 16 and R 17 Together with the nitrogen atom to which they are attached, they form a 4- to 7-membered heterocyclyl ring containing 1-2 additional heteroatoms selected from N, O and S;

[0302] Each R 18 is independently at each occurrence (C3-C7)carbocyclyl, 5- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, (C6-C 10 ) aryl, or a 5-membered or 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, wherein the carbocyclyl, heterocyclyl, aryl and heteroaryl are optionally substituted by one to four R 20 replace;

[0303] Each R 19 is independently at each occurrence halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, -OH, or CN; or

[0304] Two R's 19 When on adjacent atoms together form (C6-C 10 )aryl or a 5- or 6-membered heteroaryl ring containing 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl groups are optionally substituted with one to four substituents each independently selected from halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, -OH and CN;

[0305] Each R 20 is independently at each occurrence halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, oxo, -OH, or CN; or

[0306] When R 18 When it is a carbocyclic or heterocyclic group, the two R 20 When attached to the same carbon atom together form =(O);

[0307] R 21 is H or (C1-C6)alkyl;

[0308] Each R 22is independently at each occurrence halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, -OH, CN, (C6-C 10 ) aryl, or a 5-membered or 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl are optionally substituted by one to four R 23 replace;

[0309] Each R 23 is independently at each occurrence halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, -CH2(OCH2CH2) 1-3 OCH2CH3, -OH, CN, or a 4- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from N, O and S (wherein the heterocyclic group is optionally substituted by one to four substituents each independently selected from the following: halogen, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, -OH, -C(O)R 24 R 25 、-NR 24 C(O)R 25 , -NH2, -NH(C1-C6)alkyl, and -N((C1-C6)alkyl)2, and the alkyl group is optionally replaced by -NR 24 R 25 substituted) or a 4- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S (which is optionally substituted by one to four substituents each independently selected from the following: halogen, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, -OH, -NH2, -NH(C1-C6) alkyl, and -N((C1-C6) alkyl)2); and

[0310] R 24 and R 25 are each independently H, (C1-C6)alkyl, or (C3-C7)carbocyclyl;

[0311] or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, N-oxide or tautomer thereof.

[0312] In some embodiments of the above formula, X 1 is H or (C 1 -C 6 ) alkyl. In another embodiment, X 1 is H. In yet another embodiment, X 1 is (C 1 -C 6 ) alkyl.

[0313] In some embodiments of the above formula, X2 is H or (C1-C6)alkyl. In another embodiment, X2 is H. In yet another embodiment, X2 is (C1-C6)alkyl.

[0314] In some embodiments of the above formula, X1 and X2, together with the carbon atom to which they are attached, form =(O).

[0315] In some embodiments of the above formula, X1 is H and X2 is H. In another embodiment, X1 is H and X2 is (C1-C6)alkyl. In yet another embodiment, X1 is (C1-C6)alkyl and X2 is (C1-C6)alkyl.

[0316] In some embodiments of the above formula, when X1 and X2, together with the carbon atom to which they are attached, form =(O), X3 is -O-, -NH-, or -N(C1-C6)alkyl-. In another embodiment, when X1 and X2, together with the carbon atom to which they are attached, form =(O), X3 is -N(C1-C6)alkyl-. In yet another embodiment, when X1 and X2, together with the carbon atom to which they are attached, form =(O), X3 is -O-. In another embodiment, when X1 and X2, together with the carbon atom to which they are attached, form =(O), X3 is -NH-. In yet another embodiment, when X1 and X2, each independently, is H or (C1-C6)alkyl, or when X1 and X2, together with the carbon atom to which they are attached, form =(O), X3 is -CH2-. In another embodiment, when X1 and X2 are each independently H or (C1-C6) alkyl, X3 is -CH2-. In yet another embodiment, when X1 and X2 together with the carbon atom to which they are attached form =(O), X3 is -CH2-.

[0317] In some embodiments of the above formula, R1 is (C6-C 10 ) aryl or a 5-membered or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl are replaced by -OR 10 or -NR 21 R 10 and optionally substituted by one to three R 11 In another embodiment, R1 is phenyl or a 5-membered or 6-membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S, wherein the phenyl or heteroaryl group is replaced by -OR 10 or -NR 21 R 10 and optionally substituted by one to three R 11 In yet another embodiment, R1 is (C6-C 10) aryl, or a 5-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl are replaced by -OR 10 or -NR 21 R 10 and optionally substituted by one to three R 11 In another embodiment, R1 is phenyl or a 5-membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S, wherein the phenyl or heteroaryl group is replaced by -OR 10 or -NR 21 R 10 and optionally substituted by one to three R 11 replace.

[0318] In yet another embodiment, R1 is (C6-C 10 ) aryl, or a 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl are replaced by -OR 10 or -NR 21 R 10 and optionally substituted by one to three R 11 In another embodiment, R1 is phenyl, or a 6-membered heteroaryl group containing 1-3 heteroatoms selected from N, O, and S, wherein the phenyl or heteroaryl group is replaced by -OR 10 or -NR 21 R 10 and optionally substituted by one to three R 11 In another embodiment, R1 is (C6-C 10 ) aryl, which is -OR 10 or -NR 21 R 10 and optionally substituted by one to three R 11 In yet another embodiment, R1 is phenyl, which is replaced by -OR 10 or -NR 21 R 10 and optionally substituted by one to three R 11 In another embodiment, R1 is (C6-C 10 ) aryl, which is -OR 10 or -NR 21 R 10 Replaced by one to three R 11 In yet another embodiment, R1 is phenyl, which is replaced by -OR 10 or -NR 21 R 10 Replaced by one to three R 11 replace.

[0319] In another embodiment, R1 is (C6-C10 ) aryl, which is -NR 21 R 10 and optionally substituted by one to three R 11 In yet another embodiment, R1 is phenyl, which is replaced by -NR 21 R 10 and optionally substituted by one to three R 11 In another embodiment, R1 is (C6-C 10 ) aryl, which is -NR 21 R 10 Replaced by one to three R 11 In yet another embodiment, R1 is phenyl, which is replaced by -NR 21 R 10 Replaced by one to three R 11 In another embodiment, R1 is (C6-C 10 ) aryl, which is -OR 10 and optionally substituted by one to three R 11 In another embodiment, R1 is phenyl, which is replaced by -OR 10 and optionally substituted by one to three R 11 In yet another embodiment, R1 is (C6-C 10 ) aryl, which is -OR 10 Replaced by one to three R 11 In another embodiment, R1 is phenyl, which is replaced by -OR 10 Replaced by one to three R 11 replace.

[0320] In some embodiments of the above formula, R2 is H, (C1-C6)alkyl, (C2-C6)alkenyl, (C1-C6)haloalkyl, -NR 12 R 13 , (C3-C7) carbocyclyl, (C3-C7) cycloalkenyl, a 5- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, (C6-C 10 ) aryl, or a 5-membered or 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, wherein the alkyl group is optionally substituted by one to three R 18 and the carbocyclyl, heterocyclyl, aryl and heteroaryl groups are optionally substituted by one to four R 19 In another embodiment, R2 is H, (C1-C3)alkyl, (C2-C4)alkenyl, (C1-C6)haloalkyl, -NR 12 R 13, (C3-C7) carbocyclyl, (C3-C7) cycloalkenyl, a 5- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, (C6-C 10 ) aryl, or a 5-membered or 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, wherein the alkyl group is optionally substituted by one to three R 18 substituted, and the carbocyclyl, heterocyclyl, aryl and heteroaryl are optionally substituted by one to four R 19 In yet another embodiment, R2 is H, (C1-C3)alkyl, (C1-C6)haloalkyl, -NR 12 R 13 , (C3-C7) carbocyclyl, 5- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, (C6-C 10 ) aryl, or a 5-membered or 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, wherein the alkyl group is optionally substituted by one to three R 18 substituted, and the carbocyclyl, heterocyclyl, aryl and heteroaryl are optionally substituted by one to four R 19 replace.

[0321] In another embodiment, R2 is H, (C1-C3)alkyl, (C1-C6)haloalkyl, -NR 12 R 13 , (C3-C7) carbocyclyl, or a 5- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein the alkyl group is optionally substituted by one to three R 18 and the carbocyclic and heterocyclic groups are optionally substituted by one to four R 19 In another embodiment, R2 is H, (C1-C6) alkyl, or -NR 12 R 13 wherein the alkyl group is optionally substituted by one to three R 18 In another embodiment, R2 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, or -NR 12 R 13 In yet another embodiment, R2 is H, (C1-C3) alkyl, (C1-C6) haloalkyl, (C3-C7) carbocyclyl, a 5- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S, wherein the alkyl is optionally substituted by one to three R 18 and the carbocyclic and heterocyclic groups are optionally substituted by one to four R 19 In another embodiment, R2 is (C1-C3)alkyl, which is optionally substituted with one to three R 18 In yet another embodiment, R2 is (C1-C3)alkyl substituted with one to three R 18In another embodiment, R2 is (C3-C7) carbocyclyl, or a 5- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted by one to four R 19 replace.

[0322] In another embodiment, R2 is (C1-C3) alkyl, (C1-C6) haloalkyl, (C3-C7) carbocyclyl, or a 5- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S, wherein the alkyl group is optionally substituted by one to three R 18 and the carbocyclic and heterocyclic groups are optionally substituted by one to four R 19 In another embodiment, R2 is (C1-C3) alkyl, (C1-C6) haloalkyl, (C3-C7) carbocyclyl, 5- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S, wherein the alkyl is replaced by one to three R 18 and the carbocyclic and heterocyclic groups are optionally substituted by one to four R 19 replace.

[0323] In some embodiments of the above formula, R3 is H, D, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, or (C1-C4)hydroxyalkyl, wherein the alkyl group is optionally replaced by one to three R 14 In another embodiment, R3 is H, D, (C1-C4)alkyl, (C1-C4)haloalkyl, or (C1-C4)hydroxyalkyl, wherein the alkyl group is optionally substituted by one to three R 14 In yet another embodiment, R3 is H, D, (C1-C4)alkyl, or (C1-C4)haloalkyl, wherein the alkyl is optionally substituted by one to three R 14 In another embodiment, R3 is H, D, or optionally substituted by one to three R 14 In yet another embodiment, R3 is H, D or optionally substituted by one or two R 14 In another embodiment, R3 is H or optionally substituted by one or two R 14 In yet another embodiment, R3 is H. In another embodiment, R3 is optionally substituted by one or two R 14 In yet another embodiment, R3 is H or (C1-C4)alkyl. In another embodiment, R3 is (C1-C4)alkyl.

[0324] In some embodiments of the above formula, R4 is H or (C1-C3)alkyl. In another embodiment, R4 is (C1-C3)alkyl. In yet another embodiment, R4 is H, methyl, ethyl, n-propyl, or i-propyl. In another embodiment, R4 is H, methyl, or ethyl. In yet another embodiment, R4 is H or methyl. In another embodiment, R4 is H.

[0325] In some embodiments of the above formula, R3 and R4, together with the atoms to which they are attached, form a 5- or 6-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O, and S. In another embodiment, R3 and R4, together with the atoms to which they are attached, form a 6- or 7-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O, and S. In yet another embodiment, R3 and R4, together with the atoms to which they are attached, form a 5-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O, and S. In another embodiment, R3 and R4, together with the atoms to which they are attached, form a 7-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O, and S. In yet another embodiment, R3 and R4, together with the atoms to which they are attached, form a 6-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O, and S.

[0326] In some embodiments of the above formula, R5 is H, D, (C1-C3)alkyl, (C1-C3)alkoxy, (C1-C3)haloalkyl, (C1-C3)haloalkoxy, or (C1-C3)hydroxyalkyl, wherein the (C1-C3)alkyl is optionally substituted with one or more (i.e., one to seven) D. In another embodiment, R5 is H, D, (C1-C3)alkyl, (C1-C3)haloalkyl, or (C1-C3)hydroxyalkyl, wherein the (C1-C6)alkyl is optionally substituted with one or more D. In yet another embodiment, R5 is H, D, (C1-C3)alkyl, (C1-C3)alkoxy, (C1-C3)haloalkoxy, or (C1-C3)hydroxyalkyl, wherein the (C1-C6)alkyl is optionally substituted with one or more D. In another embodiment, R5 is H, D, (C1-C3)alkyl, or (C1-C3)haloalkyl, wherein said (C1-C6)alkyl is optionally substituted with one or more D. In yet another embodiment, R5 is H, D, or (C1-C3)alkyl. In another embodiment, R5 is H or (C1-C3)alkyl. In yet another embodiment, R5 is H or (C1-C2)alkyl. In another embodiment, R5 is H, methyl, or ethyl. In yet another embodiment, R5 is H or methyl. In another embodiment, R5 is H. In yet another embodiment, R5 is methyl.

[0327] In some embodiments of the above formula, R6 is (C1-C3)alkyl, (C1-C3)alkoxy, (C1-C3)haloalkyl, (C1-C3)haloalkoxy, or (C1-C3)hydroxyalkyl, wherein the alkyl is optionally substituted with one to three substituents each independently selected from the group consisting of (C1-C6)alkoxy, (C1-C6)haloalkoxy, -C(O)(C1-C6)alkyl, -C(O)OH, and -C(O)O(C1-C6)alkyl. In another embodiment, R6 is (C1-C3)alkyl, (C1-C3)alkoxy, (C1-C3)haloalkyl, (C1-C3)haloalkoxy, or (C1-C3)hydroxyalkyl, wherein the alkyl is optionally substituted with one to three substituents each independently selected from the group consisting of (C1-C3)alkoxy, (C1-C3)haloalkoxy, -C(O)(C1-C3)alkyl, -C(O)OH, and -C(O)O(C1-C3)alkyl. In yet another embodiment, R6 is (C1-C3)alkyl, (C1-C3)haloalkyl, or (C1-C3)hydroxyalkyl, wherein the alkyl is optionally substituted with one to three substituents each independently selected from the group consisting of (C1-C3)alkoxy, (C1-C3)haloalkoxy, -C(O)(C1-C3)alkyl, -C(O)OH, and -C(O)O(C1-C3)alkyl. In another embodiment, R6 is (C1-C3)alkyl, (C1-C3)alkoxy, (C1-C3)haloalkoxy, or (C1-C3)hydroxyalkyl, wherein the alkyl is optionally substituted with one to three substituents each independently selected from the group consisting of (C1-C3)alkoxy, (C1-C3)haloalkoxy, -C(O)(C1-C3)alkyl, -C(O)OH, and -C(O)O(C1-C3)alkyl.

[0328] In another embodiment, R6 is (C1-C3)alkyl, or (C1-C3)haloalkyl, wherein the alkyl is optionally substituted with one to three substituents each independently selected from the group consisting of (C1-C3)alkoxy, (C1-C3)haloalkoxy, -C(O)(C1-C3)alkyl, -C(O)OH, and -C(O)O(C1-C3)alkyl. In yet another embodiment, R6 is (C1-C3)alkyl, optionally substituted with one to three substituents each independently selected from the group consisting of (C1-C3)alkoxy, (C1-C3)haloalkoxy, -C(O)(C1-C3)alkyl, -C(O)OH, and -C(O)O(C1-C3)alkyl. In another embodiment, R6 is (C1-C3)alkyl substituted by one to three substituents each independently selected from the group consisting of (C1-C3)alkoxy, (C1-C3)haloalkoxy, -C(O)(C1-C3)alkyl, -C(O)OH, and -C(O)O(C1-C3)alkyl. In yet another embodiment, R6 is (C1-C3)alkyl optionally substituted by one to three substituents each independently selected from the group consisting of (C1-C3)alkoxy, (C1-C3)haloalkoxy, -C(O)(C1-C3)alkyl, and -C(O)OH. In another embodiment, R6 is (C1-C3)alkyl substituted by one to three substituents each independently selected from the group consisting of (C1-C3)alkoxy, (C1-C3)haloalkoxy, -C(O)(C1-C3)alkyl, and -C(O)OH.

[0329] In some embodiments of the above formula, R is H, D, (C1-C3)alkyl, (C1-C3)alkoxy, (C1-C3)haloalkyl, (C1-C3)haloalkoxy, or (C1-C3)hydroxyalkyl, wherein said (C1-C6)alkyl is optionally substituted with one or more D. In another embodiment, R is H, D, (C1-C3)alkyl, (C1-C3)haloalkyl, or (C1-C3)hydroxyalkyl, wherein said (C1-C6)alkyl is optionally substituted with one or more D. In yet another embodiment, R is H, D, (C1-C3)alkyl, (C1-C3)alkoxy, (C1-C3)haloalkoxy, or (C1-C3)hydroxyalkyl, wherein said (C1-C6)alkyl is optionally substituted with one or more D. In another embodiment, R7 is H, D, (C1-C3) alkyl, or (C1-C3) haloalkyl, wherein said (C1-C6) alkyl is optionally substituted with one or more D. In yet another embodiment, R7 is H, D, or (C1-C3) alkyl. In another embodiment, R7 is H or (C1-C3) alkyl. In yet another embodiment, R7 is H or (C1-C2) alkyl. In another embodiment, R7 is H, methyl, or ethyl. In yet another embodiment, R7 is H or methyl. In another embodiment, R7 is H. In yet another embodiment, R7 is methyl.

[0330] In some embodiments of the above formula, R8 is H, (C1-C5)alkyl, or (C1-C5)haloalkyl, wherein the alkyl is optionally substituted with one to three substituents each independently selected from the group consisting of (C3-C7)carbocyclyl, a 4- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S, -NR 16 R 17 , and -C(O)NR 16 R 17 In another embodiment, R8 is H, (C1-C5) alkyl, or (C1-C5) haloalkyl, wherein the alkyl is optionally substituted with one to three substituents each independently selected from the following: a 4- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S, -NR 16 R 17 and -C(O)NR 16 R 17 In another embodiment, R8 is H, (C1-C5)alkyl, or (C1-C5)haloalkyl, wherein the alkyl is optionally substituted with one to three substituents each independently selected from the group consisting of (C3-C7)carbocyclyl, a 5- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S, -NR 16 R 17 and -C(O)NR 16R 17 In another embodiment, R8 is H, (C1-C5) alkyl, or (C1-C5) haloalkyl, wherein the alkyl is optionally substituted with one to three substituents each independently selected from the following: a 5- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S, -NR 16 R 17 and -C(O)NR 16 R 17 .

[0331] In some embodiments of the above formula, R9 is halogen, (C1-C3)alkyl, (C1-C3)alkoxy, (C1-C3)haloalkyl, (C1-C3)haloalkoxy, -OH, or CN. In another embodiment, R9 is halogen, (C1-C3)alkyl, (C1-C3)haloalkyl, -OH, or CN. In yet another embodiment, R9 is halogen, (C1-C3)alkoxy, (C1-C3)haloalkoxy, -OH, or CN. In another embodiment, R9 is halogen, (C1-C3)alkyl, (C1-C3)haloalkyl, or (C1-C3)haloalkoxy. In yet another embodiment, R9 is halogen, (C1-C3)alkyl, or (C1-C3)haloalkyl. In another embodiment, R9 is halogen, or (C1-C3)alkyl. In yet another embodiment, R9 is halogen or (C1-C3)haloalkyl. In another embodiment, R9 is halogen. In yet another embodiment, R9 is F, Cl or Br. In another embodiment, R9 is F or Cl. In yet another embodiment, R9 is F. In yet another embodiment, R9 is Cl.

[0332] In some embodiments having the above formula, R 10 Yes (C6-C 10 ) aryl or a 5-membered or 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl are optionally substituted by one to three R 22 In another embodiment, R 10 is phenyl or a 5-membered or 6-membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S, wherein the phenyl and heteroaryl groups are optionally substituted by one to three R 22 In yet another embodiment, R 10 Yes (C6-C 10 ) aryl or a 5-membered or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl are separated by one to three R 22 In another embodiment, R 10 is phenyl or a 5-membered or 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S, wherein the phenyl or heteroaryl group is surrounded by one to three R22 replace.

[0333] In another embodiment, R 10 Yes (C6-C 10 ) aryl or a 5-membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl are optionally substituted by one to three R 22 In another embodiment, R 10 Yes (C6-C 10 ) aryl or a 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl are optionally substituted by one to three R 22 In yet another embodiment, R 10 Yes (C6-C 10 ) aryl or a 5-membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl are separated by one to three R 22 In another embodiment, R 10 Yes (C6-C 10 ) aryl or 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl are separated by one to three R 22 replace.

[0334] In another embodiment, R 10 is phenyl or a 5-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S, wherein the phenyl and heteroaryl groups are optionally substituted by one to three R 22 In yet another embodiment, R 10 is phenyl or a 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S, wherein the phenyl and heteroaryl groups are optionally substituted by one to three R 22 In another embodiment, R 10 is phenyl or a 5-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S, wherein the phenyl or heteroaryl group is surrounded by one to three R 22 In yet another embodiment, R 10 is phenyl or a 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S, wherein the phenyl or heteroaryl group is surrounded by one to three R 22 replace.

[0335] In another embodiment, R 10 Yes (C6-C 10 ) aryl, which is optionally substituted by one to three R 22 In another embodiment, R 10 Yes (C6-C 10 ) aryl, which is substituted by one to three R 22 In another embodiment, R10 is a 5- or 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S, which is optionally substituted by one to three R 22 In yet another embodiment, R 10 is a 5-membered or 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S, which is surrounded by one to three R 22 In another embodiment, R 10 is a 5-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S, which is optionally substituted by one to three R 22 In yet another embodiment, R 10 A 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S, which is optionally substituted by one to three R 22 In another embodiment, R 10 is a 5-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S, which is surrounded by one to three R 22 In yet another embodiment, R 10 A 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S, which is surrounded by one to three R 22 In another embodiment, R 10 is phenyl or pyridinyl, wherein the phenyl or pyridinyl is optionally substituted by one to three R 22 In yet another embodiment, R 10 is phenyl or pyridinyl, wherein the phenyl or pyridinyl is separated by one to three R 22 replace.

[0336] In some embodiments having the above formula, each R 11 is independently halogen, (C1-C3)alkyl, (C1-C3)alkoxy, (C1-C3)haloalkyl, (C1-C3)haloalkoxy, -OH, or CN at each occurrence. In another embodiment, each R 11 is independently halogen, (C1-C3)alkyl, (C1-C3)alkoxy, (C1-C3)haloalkyl, or (C1-C3)haloalkoxy at each occurrence. In yet another embodiment, each R 11 is independently halogen, -OH, or CN at each occurrence. In another embodiment, each R 11 is independently halogen, (C1-C3)alkyl, or (C1-C3)haloalkyl at each occurrence. In another embodiment, each R 11 is independently halogen, (C1-C3)alkyl, (C1-C3)alkoxy, or (C1-C3)haloalkoxy at each occurrence. In yet another embodiment, each R 11is independently halogen, (C1-C3)alkyl, (C1-C3)haloalkyl, or (C1-C3)haloalkoxy at each occurrence. 11 is independently halogen, (C1-C3)haloalkyl, or (C1-C3)haloalkoxy at each occurrence. In yet another embodiment, each R 11 is independently halogen at each occurrence.

[0337] In some embodiments having the above formula, R 12 is H or (C1-C6) alkyl. In another embodiment, R 12 is H or (C1-C3) alkyl. In yet another embodiment, R 12 is H. In another embodiment, R 12 In yet another embodiment, R 12 is methyl, ethyl, n-propyl or i-propyl. In another embodiment, R 12 In yet another embodiment, R 12 It's methyl.

[0338] In some embodiments having the above formula, R 13 is H or (C1-C6) alkyl. In another embodiment, R 13 is H or (C1-C3) alkyl. In yet another embodiment, R 13 is H. In another embodiment, R 13 In yet another embodiment, R 13 is methyl, ethyl, n-propyl or i-propyl. In another embodiment, R 13 In yet another embodiment, R 13 It's methyl.

[0339] In some embodiments having the above formula, R 12 is H and R 13 is H. In another embodiment, R 12 is H and R 13 In yet another embodiment, R 12 is (C1-C3)alkyl and R 13 is H. In another embodiment, R 12 is (C1-C3)alkyl and R 13 In yet another embodiment, R 12 is methyl and R 13 It's methyl.

[0340] In some embodiments having the above formula, each R 14 D, -NR independently at each occurrence 15 R 15' , (C3-C7) carbocyclyl, or a 3- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one to three substituents each independently selected from halogen, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, and (C1-C6) haloalkoxy. In another embodiment, each R 14 D, -NR independently at each occurrence 15 R 15' , (C3-C7) carbocyclyl, or a 3- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one to three substituents each independently selected from halogen, (C1-C3) alkyl, (C1-C3) alkoxy, (C1-C3) haloalkyl, and (C1-C3) haloalkoxy. In yet another embodiment, each R 14 -NR independently at each occurrence 15 R 15' , (C3-C7)carbocyclyl, or a 3- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein the carbocyclyl and heterocyclyl are optionally substituted by one to three substituents each independently selected from halogen, (C1-C3)alkyl, (C1-C3)alkoxy, (C1-C3)haloalkyl, and (C1-C3)haloalkoxy.

[0341] In another embodiment, each R 14 -NR independently at each occurrence 15 R 15' or (C3-C7)carbocyclyl (which is optionally substituted by one to three substituents each independently selected from halogen, (C1-C3)alkyl, (C1-C3)alkoxy, (C1-C3)haloalkyl, and (C1-C3)haloalkoxy). In yet another embodiment, each R 14 -NR independently at each occurrence 15 R 15' or (C3-C7)carbocyclyl (which is optionally substituted by one to three substituents each independently selected from halogen, (C1-C3)alkyl, and (C1-C3)haloalkyl). In another embodiment, each R 14 -NR independently at each occurrence 15 R 15' or a (C3-C7)carbocyclyl group (which is optionally substituted with one to three (C1-C3)alkyl groups).

[0342] In some embodiments having the above formula, R 15 is H or (C1-C6) alkyl. In another embodiment, R 15 is H or (C1-C3) alkyl. In yet another embodiment, R 15 is H. In another embodiment, R 15 In yet another embodiment, R 15 is methyl, ethyl, n-propyl or i-propyl. In another embodiment, R 15 In yet another embodiment, R 15 It's methyl.

[0343] In some embodiments having the above formula, R 15' is H or (C1-C6) alkyl. In another embodiment, R 15' is H or (C1-C3) alkyl. In yet another embodiment, R 15' is H. In another embodiment, R 15' In yet another embodiment, R 15' is methyl, ethyl, n-propyl or i-propyl. In another embodiment, R 15' In yet another embodiment, R 15' It's methyl.

[0344] In some embodiments having the above formula, R 15 is H and R 15' is H. In another embodiment, R 15 is H and R 15' In yet another embodiment, R 15 is (C1-C3)alkyl and R 15' is H. In another embodiment, R 15 is (C1-C3)alkyl and R 15' In yet another embodiment, R 15 is methyl and R 15' It's methyl.

[0345] In some embodiments having the above formula, R 16 is H or (C1-C3) alkyl. In another embodiment, R 16 is H. In another embodiment, R 16 In yet another embodiment, R 16 is H, methyl, ethyl, n-propyl or i-propyl. In another embodiment, R 16In yet another embodiment, R 16 Is H, methyl or ethyl. In another embodiment, R 16 In yet another embodiment, R 16 Is H or methyl. In another embodiment, R 16 In yet another embodiment, R 16 is H or (C1-C3)alkyl; or R 16 and R 17 Together with the nitrogen atom to which they are attached, they form a 4- to 7-membered heterocyclyl ring containing 1-2 additional heteroatoms selected from N, O, and S. In yet another embodiment, R 16 is H or (C1-C3)alkyl; or R 16 and R 17 Together with the nitrogen atom to which they are attached they form a 4- to 7-membered heterocyclyl ring optionally containing 1-2 further heteroatoms selected from N, O and S.

[0346] In some embodiments having the above formula, R 17 is H or (C1-C3) alkyl. In another embodiment, R 17 is H. In another embodiment, R 17 In yet another embodiment, R 17 is H, methyl, ethyl, n-propyl or i-propyl. In another embodiment, R 17 In yet another embodiment, R 17 Is H, methyl or ethyl. In another embodiment, R 17 In yet another embodiment, R 17 Is H or methyl. In another embodiment, R 17 It's methyl.

[0347] In some embodiments having the above formula, R 16 and R 17 Together with the nitrogen atom to which they are attached, they form a 4- to 7-membered heterocyclyl ring containing 1-2 additional heteroatoms selected from N, O and S. In another embodiment, R 16 and R 17 Together with the nitrogen atom to which they are attached, they form a 4- to 6-membered heterocyclyl ring containing 1-2 additional heteroatoms selected from N, O, and S. In yet another embodiment, R 16 and R 17 Together with the nitrogen atom to which they are attached they form a 4- or 5-membered heterocyclyl ring containing 1-2 further heteroatoms selected from N, O and S.

[0348] In some embodiments having the above formula, R 16 and R 17 Together with the nitrogen atom to which they are attached, they form a 4- to 7-membered heterocyclyl ring optionally containing 1-2 additional heteroatoms selected from N, O and S. In another embodiment, R 16 and R 17 Together with the nitrogen atom to which they are attached, they form a 4- to 6-membered heterocyclyl ring optionally containing 1-2 additional heteroatoms selected from N, O and S. In yet another embodiment, R 16 and R 17 Together with the nitrogen atom to which they are attached they form a 4- or 5-membered heterocyclyl ring optionally comprising 1-2 further heteroatoms selected from N, O and S.

[0349] In some embodiments having the above formula, each R 18 is independently at each occurrence (C3-C7)carbocyclyl, 5- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, (C6-C 10 ) aryl, or a 5-membered or 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, wherein the carbocyclyl, heterocyclyl, aryl and heteroaryl are optionally substituted by one to four R 20 In another embodiment, each R 18 Each occurrence is independently (C3-C7)carbocyclyl, or 5- to 7-membered heterocyclyl, wherein the carbocyclyl and heterocyclyl are optionally substituted by one to four R 20 In yet another embodiment, each R 18 Each occurrence is independently (C3-C7)carbocyclyl, or (C6-C 10 ) aryl, wherein the carbocyclyl and aryl groups are optionally substituted by one to four R 20 In another embodiment, each R 18 is independently at each occurrence a 5- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S or a 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, wherein the heterocyclyl and heteroaryl are optionally substituted by one to four R 20 replace.

[0350] In another embodiment, each R 18 In each occurrence, independently (C6-C 10 ) aryl or a 5-membered or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl are separated by one to three R 20 In yet another embodiment, each R 18is independently phenyl at each occurrence or a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S, wherein the phenyl or heteroaryl group is surrounded by one to three R 20 In another embodiment, each R 18 In each occurrence, independently (C6-C 10 ) aryl or a 5-membered or 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl are optionally substituted by one to three R 20 In yet another embodiment, each R 18 is independently at each occurrence phenyl or a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S, wherein the phenyl and heteroaryl groups are optionally substituted by one to three R 20 replace.

[0351] In some embodiments having the above formula, R 19 is halogen, (C1-C3)alkyl, (C1-C3)alkoxy, (C1-C3)haloalkyl, (C1-C3)haloalkoxy, -OH, or CN. In another embodiment, R 19 is halogen, (C1-C3)alkyl, (C1-C3)alkoxy, (C1-C3)haloalkyl, or (C1-C3)haloalkoxy. 19 is halogen, (C1-C3)alkyl, (C1-C3)haloalkyl, -OH, or CN. In another embodiment, R 19 is halogen, (C1-C3)alkyl, (C1-C3)alkoxy, (C1-C3)haloalkyl, (C1-C3)haloalkoxy, or -OH. In another embodiment, R 19 is halogen, (C1-C3)alkyl, (C1-C3)alkoxy, (C1-C3)haloalkyl, (C1-C3)haloalkoxy, or CN. In another embodiment, R 19 is halogen, (C1-C3)alkyl, (C1-C3)alkoxy, (C1-C3)haloalkyl, -OH, or CN. In another embodiment, R 19 is halogen, (C1-C3)alkyl, (C1-C3)alkoxy, (C1-C3)haloalkoxy, -OH, or CN. In another embodiment, R 19 is halogen, (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C3)haloalkoxy, -OH, or CN. In another embodiment, R 19 is halogen, (C1-C3)alkyl, or (C1-C3)haloalkyl. In another embodiment, R 19 is halogen or (C1-C3)alkyl.

[0352] In some embodiments having the above formula, the two R 19 When on adjacent atoms together form (C6-C 10 )aryl or a 5-membered or 6-membered heteroaryl ring containing 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, -OH and CN. In another embodiment, two R 19 When on adjacent atoms together form (C6-C 10 )aryl, which is optionally substituted by one or more substituents each independently selected from the group consisting of halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, -OH, and CN. In yet another embodiment, both R 19 When on adjacent atoms, together they form a 5- or 6-membered heteroaryl ring containing 1-3 heteroatoms selected from N, O, and S, optionally substituted with one or more substituents each independently selected from halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, -OH, and CN. In another embodiment, the two R 19 When on adjacent atoms, together they form a phenyl group or a 5- or 6-membered heteroaryl ring containing 1-3 heteroatoms selected from N, O and S, wherein the phenyl and heteroaryl groups are optionally substituted with one or more substituents each independently selected from halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, -OH and CN.

[0353] In another embodiment, two R 19 When on adjacent atoms, together they form a phenyl group, which is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, -OH, and CN. In yet another embodiment, two R 19 When on adjacent atoms, together they form a 5-membered heteroaryl ring containing 1-3 heteroatoms selected from N, O, and S, which are optionally substituted with one or more substituents each independently selected from halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, -OH, and CN. In another embodiment, the two R 19When on adjacent atoms, taken together, they form a 6-membered heteroaryl ring comprising 1-3 heteroatoms selected from N, O and S, which are optionally substituted with one or more substituents each independently selected from halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, -OH and CN.

[0354] In some embodiments having the above formula, each R 20 is independently halogen, (C1-C3)alkyl, (C1-C3)alkoxy, (C1-C3)haloalkyl, (C1-C3)haloalkoxy, oxo, -OH, or CN at each occurrence. In another embodiment, each R 20 is independently halogen, (C1-C3)alkyl, (C1-C3)haloalkyl, oxo-OH, or CN at each occurrence. In yet another embodiment, each R 20 is independently halogen, (C1-C3)alkyl, (C1-C3)alkoxy, (C1-C3)haloalkyl, or (C1-C3)haloalkoxy at each occurrence. 20 is independently halogen, (C1-C3)alkyl, oxo, -OH, or CN at each occurrence. In yet another embodiment, each R 20 is independently halogen, (C1-C3)alkyl, (C1-C3)alkoxy, -OH, or CN at each occurrence. In another embodiment, each R 20 is independently halogen, (C1-C3)alkyl, (C1-C3)alkoxy, (C1-C3)haloalkoxy, -OH, or CN at each occurrence. In yet another embodiment, each R 20 and (C1-C3)alkyl, (C1-C3)alkoxy, (C1-C3)haloalkyl, or (C1-C3)haloalkoxy.

[0355] In another embodiment, each R 20 is independently halogen, (C1-C3)alkyl, or (C1-C3)haloalkyl at each occurrence. In yet another embodiment, each R 20 is independently halogen, (C1-C3)alkyl, (C1-C3)alkoxy at each occurrence. In another embodiment, each R 20 is independently halogen, (C1-C3)alkyl, (C1-C3)alkoxy, or (C1-C3)haloalkoxy at each occurrence. In yet another embodiment, each R 20 is independently halogen, (C1-C3)alkyl, or oxo at each occurrence. In another embodiment, each R 20is independently halogen or (C1-C3)alkyl at each occurrence. In yet another embodiment, each R 20 is independently (C1-C3)alkyl, (C1-C3)alkoxy, (C1-C3)haloalkyl, or (C1-C3)haloalkoxy at each occurrence. 20 is independently at each occurrence (C1-C3)alkyl or (C1-C3)haloalkyl.

[0356] In some embodiments having the above formula, each R 20 is independently halogen, (C1-C3)alkyl, or oxo at each occurrence; or when R 18 When it is a carbocyclic or heterocyclic group, the two R 20 When attached to the same carbon atom together form =(O). In another embodiment, each R 20 is independently halogen or (C1-C3)alkyl at each occurrence; or when R 18 When it is a carbocyclic or heterocyclic group, the two R 20 Together they form =(O) when attached to the same carbon atom.

[0357] In some embodiments having the above formula, when R 18 When it is a carbocyclic or heterocyclic group, the two R 20 When attached to the same carbon atom together form =(O). In another embodiment, when R 18 When it is a carbocyclic group, the two R 20 When attached to the same carbon atom together form =(O). In another embodiment, when R 18 When the heterocyclic group, the two R 20 When attached to the same carbon atom together form =(O). In another embodiment, R 18 Is one to three R 20 substituted carbocyclic or heterocyclic groups, and both R 20 When attached to the same carbon atom together form =(O). In another embodiment, R 18 Is one to three R 20 substituted carbocyclic group, and both R 20 When attached to the same carbon atom together form =(O). In another embodiment, R 18 Is one to three R 20 substituted heterocyclic group, and both R 20 Together they form =(O) when attached to the same carbon atom.

[0358] In some embodiments having the above formula, R 21 is H or (C1-C3) alkyl. In another embodiment, R 21is H. In another embodiment, R 21 In yet another embodiment, R 21 is H, methyl, ethyl, n-propyl or i-propyl. In another embodiment, R 21 In yet another embodiment, R 21 Is H, methyl or ethyl. In another embodiment, R 21 In yet another embodiment, R 21 Is H or methyl. In another embodiment, R 21 It's methyl.

[0359] In some embodiments having the above formula, each R 22 is independently at each occurrence halogen, (C1-C3)alkyl, (C1-C3)alkoxy, (C1-C3)haloalkyl, (C1-C3)haloalkoxy, -OH, CN, (C6-C 10 ) aryl, or a 5-membered or 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl are optionally substituted by one to three R 23 In another embodiment, each R 22 is independently at each occurrence halogen, (C1-C3)alkyl, (C1-C3)alkoxy, (C1-C3)haloalkyl, (C1-C3)haloalkoxy, (C6-C 10 ) aryl, or a 5-membered or 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl are optionally substituted by one to three R 23 In yet another embodiment, each R 22 is independently at each occurrence halogen, (C1-C3)alkyl, (C1-C3)haloalkyl, -OH, CN, (C6-C 10 ) aryl, or a 5-membered or 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl are optionally substituted by one to three R 23 In another embodiment, each R 22 is independently at each occurrence halogen, (C1-C3)alkyl, (C1-C3)alkoxy, (C1-C3)haloalkoxy, -OH, CN, (C6-C 10 ) aryl, or a 5-membered or 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl are optionally substituted by one to three R 23 replace.

[0360] In another embodiment, each R 22is independently at each occurrence halogen, (C1-C3)alkyl, (C1-C3)haloalkyl, (C6-C 10 ) aryl, or a 5-membered or 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl are optionally substituted by one to three R 23 In yet another embodiment, each R 22 is independently at each occurrence halogen, (C1-C3)alkyl, (C1-C3)alkoxy, (C1-C3)haloalkoxy, (C6-C 10 ) aryl, or a 5-membered or 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl are optionally substituted by one to three R 23 In another embodiment, each R 22 is independently at each occurrence halogen, (C1-C3)alkyl, (C6-C 10 ) aryl, or a 5-membered or 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl are optionally substituted by one to three R 23 In yet another embodiment, each R 22 is independently at each occurrence halogen, (C1-C3)alkyl, or optionally substituted by one to three R 23 Substituted (C6-C 10 In yet another embodiment, each R 22 is independently at each occurrence halogen, (C1-C3)alkyl, or a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from N, O, and S (which is optionally replaced by one to three R 23 In another embodiment, each R 22 is independently at each occurrence halogen, (C1-C3)alkyl, or a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from N, O, and S (which is optionally replaced by one to three R 23 replace).

[0361] In another embodiment, each R 22 is independently at each occurrence halogen, (C1-C3)alkyl, or a 5-membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S (which is optionally replaced by one to three R 23 In yet another embodiment, each R 22 is independently at each occurrence halogen, (C1-C3)alkyl, or a 6-membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S (which is optionally replaced by one to three R 23 In another embodiment, each R 22is independently halogen, (C1-C3)alkyl, or a 5-membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S (which is separated by one to three R 23 In yet another embodiment, each R 22 is independently at each occurrence halogen, (C1-C3)alkyl, or a 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S (which is separated by one to three R 23 In another embodiment, each R 22 is independently at each occurrence halogen, (C1-C3)alkyl, or optionally substituted by one to three R 23 In yet another embodiment, each R 22 Each occurrence is independently halogen, (C1-C3)alkyl, or substituted by one to three R 23 Substituted imidazolyl.

[0362] In some embodiments having the above formula, each R 23 is independently at each occurrence halogen, (C1-C3)alkyl, (C1-C3)alkoxy, (C1-C3)haloalkyl, (C1-C3)haloalkoxy, -CH2(OCH2CH2) 1-3 OCH2CH3, -OH, CN, or a 4- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from N, O and S (wherein the heterocyclic group is optionally substituted by one to three substituents each independently selected from the following: halogen, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, -OH, -C(O)R 24 R 25 、-NR 24 C(O)R 25 , -NH2, -NH(C1-C6)alkyl, and -N((C1-C6)alkyl)2, and the alkyl group is optionally replaced by -NR 24 R 25 substituted) or a 4- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S (which is optionally substituted by one to three substituents each independently selected from the following: halogen, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, -OH, -NH2, -NH(C1-C6) alkyl, and -N((C1-C6) alkyl)2).

[0363] In another embodiment, each R 23is independently at each occurrence halogen, (C1-C3)alkyl, (C1-C3)alkoxy, (C1-C3)haloalkyl, (C1-C3)haloalkoxy, -OH, CN, or a 4- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S, wherein the heterocyclyl is substituted with one to three substituents each independently selected from halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, -OH, -C(O)R 24 R 25 、-NR 24 C(O)R 25 , -NH2, -NH(C1-C6)alkyl, and -N((C1-C6)alkyl)2, and the alkyl group is optionally replaced by -NR 24 R 25 substituted) or a 4- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S (which is optionally substituted by one to three substituents each independently selected from the following: halogen, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, -OH, -NH2, -NH(C1-C6) alkyl, and -N((C1-C6) alkyl)2).

[0364] In another embodiment, each R 23 is independently at each occurrence halogen, (C1-C3)alkyl, (C1-C3)haloalkyl, -CH2(OCH2CH2) 1-3 OCH2CH3, -OH, CN, or a 4- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from N, O and S (wherein the heterocyclic group is optionally substituted by one to three substituents each independently selected from the following: halogen, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, -OH, -C(O)R 24 R 25 、-NR 24 C(O)R 25 , -NH2, -NH(C1-C6)alkyl, and -N((C1-C6)alkyl)2, and the alkyl group is optionally replaced by -NR 24 R 25 substituted) or a 4- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S (which is optionally substituted by one to three substituents each independently selected from the following: halogen, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, -OH, -NH2, -NH(C1-C6) alkyl, and -N((C1-C6) alkyl)2).

[0365] In another embodiment, each R 23 is independently at each occurrence halogen, (C1-C3)alkyl, (C1-C3)haloalkyl, -OH, CN, or a 4- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S (wherein the heterocyclyl is optionally substituted with one to three substituents each independently selected from halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, -OH, -C(O)R 24 R 25 、-NR 24 C(O)R 25 , -NH2, -NH(C1-C6)alkyl, and -N((C1-C6)alkyl)2, and the alkyl group is optionally replaced by -NR 24 R 25 substituted) or a 4- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S (which is optionally substituted by one to three substituents each independently selected from the following: halogen, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, -OH, -NH2, -NH(C1-C6) alkyl, and -N((C1-C6) alkyl)2).

[0366] In another embodiment, each R 23 is independently at each occurrence halogen, (C1-C3)alkyl, (C1-C3)alkoxy, (C1-C3)haloalkyl, (C1-C3)haloalkoxy, or a 4- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S, wherein the heterocyclyl is optionally substituted with one to three substituents each independently selected from halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, -OH, -C(O)R 24 R 25 、-NR 24 C(O)R 25 , -NH2, -NH(C1-C6)alkyl, and -N((C1-C6)alkyl)2, and the alkyl group is optionally replaced by -NR 24 R 25 substituted) or a 4- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S (which is optionally substituted by one to three substituents each independently selected from the following: halogen, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, -OH, -NH2, -NH(C1-C6) alkyl, and -N((C1-C6) alkyl)2).

[0367] In another embodiment, each R 23 is independently at each occurrence halogen, (C1-C3)alkyl, or a 4- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S (wherein the heterocyclyl is optionally substituted with one to three substituents each independently selected from halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, -OH, -C(O)R 24 R 25 、-NR 24 C(O)R 25 , -NH2, -NH(C1-C6)alkyl, and -N((C1-C6)alkyl)2, and the alkyl group is optionally replaced by -NR 24 R 25 substituted) or a 4- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S (which is optionally substituted by one to three substituents each independently selected from the following: halogen, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, -OH, -NH2, -NH(C1-C6) alkyl, and -N((C1-C6) alkyl)2). In yet another embodiment, each R 23 is independently (C1-C3)alkyl at each occurrence or a 4- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein the heterocyclyl is optionally substituted with one to three substituents each independently selected from halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, -OH, -C(O)R 24 R 25 、-NR 24 C(O)R 25 , -NH2, -NH(C1-C6)alkyl, and -N((C1-C6)alkyl)2, and the alkyl group is optionally replaced by -NR 24 R 25 substituted) or a 4- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S (which is optionally substituted by one to three substituents each independently selected from the following: halogen, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, -OH, -NH2, -NH(C1-C6) alkyl, and -N((C1-C6) alkyl)2).

[0368] In another embodiment, each R 23is independently (C1-C3)alkyl at each occurrence or a 4- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein the heterocyclyl is substituted with one to three substituents each independently selected from halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, -OH, -C(O)R 24 R 25 、-NR 24 C(O)R 25 , -NH2, -NH(C1-C6)alkyl, and -N((C1-C6)alkyl)2, and the alkyl group is optionally replaced by -NR 24 R 25 substituted) or a 4- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S (which is optionally substituted by one to three substituents each independently selected from the following: halogen, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, -OH, -NH2, -NH(C1-C6) alkyl, and -N((C1-C6) alkyl)2). In yet another embodiment, each R 23 is independently (C1-C3)alkyl at each occurrence or a 4- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S, wherein the heterocyclyl is optionally substituted with one to three substituents each independently selected from the group consisting of (C1-C6)alkyl, (C1-C6)haloalkyl, -OH, -C(O)R 24 R 25 、-NR 24 C(O)R 25 , -NH2, -NH(C1-C6)alkyl, and -N((C1-C6)alkyl)2, and the alkyl group is optionally replaced by -NR 24 R 25 substituted) or a 4- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S (which is optionally substituted by one to three substituents each independently selected from the following: halogen, (C1-C6) alkyl, (C1-C6) haloalkyl, -OH, -NH2, -NH(C1-C6) alkyl, and -N((C1-C6) alkyl)2).

[0369] In another embodiment, each R 23is independently (C1-C3)alkyl at each occurrence or a 4- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S, wherein the heterocyclyl is optionally substituted with one to three substituents, each independently selected from the group consisting of (C1-C6)alkyl, (C1-C6)haloalkyl, -OH, -NH2, -NH(C1-C6)alkyl, and -N((C1-C6)alkyl), and the alkyl is optionally substituted with -NR 24 R 25 substituted) or a 4- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S (which is optionally substituted by one to three substituents each independently selected from the following: (C1-C6) alkyl, (C1-C6) haloalkyl, -OH, -NH2, -NH(C1-C6) alkyl, and -N((C1-C6) alkyl)2). In yet another embodiment, each R 23 is independently (C1-C3)alkyl at each occurrence or a 4- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S (wherein said heterocyclyl is optionally substituted with one to three substituents each independently selected from the group consisting of (C1-C6)alkyl, -OH, -NH2, -NH(C1-C6)alkyl, and -N((C1-C6)alkyl)2, and said alkyl is optionally substituted with -NR 24 R 25 substituted) or a 4- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S (which is optionally substituted by one to three substituents each independently selected from the following: (C1-C6) alkyl, -OH, -NH2, -NH(C1-C6) alkyl, and -N((C1-C6) alkyl)2).

[0370] In another embodiment, each R 23 is independently at each occurrence (C1-C3)alkyl or a 4- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S (wherein said heterocyclyl is optionally substituted with one to three (C1-C6)alkyl, and said alkyl is optionally substituted with -NR 24 R 25 substituted) or a 4- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S (which is optionally substituted by one to three substituents each independently selected from the following: -OH, -NH2, -NH(C1-C6)alkyl, and -N((C1-C6)alkyl)2). In yet another embodiment, each R 23 is independently at each occurrence (C1-C3)alkyl or a 4- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S (wherein said heterocyclyl is optionally substituted with one to three (C1-C6)alkyl, and said alkyl is optionally substituted with -NR 24 R 25substituted) or a 4- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from N, O and S (which is optionally substituted by one to three substituents each independently selected from the following: -OH, and -N((C1-C6)alkyl)2).

[0371] In some embodiments having the above formula, R 24 is H, (C1-C3)alkyl, or (C3-C7)carbocyclyl optionally substituted with one to two (C1-C6)alkyl. 24 is H, (C1-C3)alkyl, or (C3-C7)carbocyclyl optionally substituted with one to two (C1-C3)alkyl groups. 24 is H, (C1-C3) alkyl, or (C3-C7) carbocyclyl. In another embodiment, R 24 is H, (C1-C3) alkyl, or (C3-C5) carbocyclyl. In yet another embodiment, R 24 is H or (C1-C3) alkyl. In another embodiment, R 24 is H. In another embodiment, R 24 In yet another embodiment, R 24 is a (C3-C5)carbocyclyl group, which is optionally substituted with one to two (C1-C6)alkyl groups. In yet another embodiment, R 24 is (C3-C5) carbocyclyl. In another embodiment, R 24 In yet another embodiment, R 24 is methyl, ethyl, n-propyl or i-propyl. In another embodiment, R 24 is H, methyl, ethyl, cyclopropyl, cyclobutyl or cyclopentyl, wherein the cyclopropyl, cyclobutyl and cyclopentyl are optionally substituted with one to two (C1-C3)alkyl groups. In yet another embodiment, R 24 is H, methyl, ethyl, cyclopropyl or cyclobutyl, wherein the cyclopropyl and cyclobutyl are optionally substituted with one to two (C1-C3)alkyl groups. 24 is H, methyl, ethyl, cyclopropyl, cyclobutyl or cyclopentyl. In yet another embodiment, R 24 is H, methyl, ethyl, cyclopropyl or cyclobutyl. In another embodiment, R 24 Is H, methyl or ethyl. In another embodiment, R 24 In yet another embodiment, R 24 Is H or methyl. In another embodiment, R 24 It's methyl.

[0372] In some embodiments having the above formula, R 25 is H, (C1-C3)alkyl, or (C3-C7)carbocyclyl optionally substituted with one to two (C1-C6)alkyl. 25 is H, (C1-C3)alkyl, or (C3-C7)carbocyclyl optionally substituted with one to two (C1-C3)alkyl groups. 25 is H, (C1-C3) alkyl, or (C3-C7) carbocyclyl. In another embodiment, R 25 is H, (C1-C3) alkyl, or (C3-C5) carbocyclyl. In yet another embodiment, R 25 is H or (C1-C3) alkyl. In another embodiment, R 25 is H. In another embodiment, R 25 In yet another embodiment, R 25 is a (C3-C5)carbocyclyl group, which is optionally substituted with one to two (C1-C6)alkyl groups. In yet another embodiment, R 25 is (C3-C5) carbocyclyl. In another embodiment, R 25 In yet another embodiment, R 25 is methyl, ethyl, n-propyl or i-propyl. In another embodiment, R 25 is H, methyl, ethyl, cyclopropyl, cyclobutyl or cyclopentyl, wherein the cyclopropyl, cyclobutyl and cyclopentyl are optionally substituted with one to two (C1-C3)alkyl groups. In yet another embodiment, R 25 is H, methyl, ethyl, cyclopropyl or cyclobutyl, wherein the cyclopropyl and cyclobutyl are optionally substituted with one to two (C1-C3)alkyl groups. 25 is H, methyl, ethyl, cyclopropyl, cyclobutyl or cyclopentyl. In yet another embodiment, R 25 is H, methyl, ethyl, cyclopropyl or cyclobutyl. In another embodiment, R 25 Is H, methyl or ethyl. In another embodiment, R 25 In yet another embodiment, R 25 Is H or methyl. In another embodiment, R 25 It's methyl.

[0373] In some embodiments of the above formula, R4 is H or (C1-C6) alkyl. In another embodiment, R4 is H or (C1-C6) alkyl and R5 is H or (C1-C6) alkyl. In another embodiment, R4 is H or (C1-C6) alkyl, R5 is H or (C1-C6) alkyl, and R7 is H or (C1-C6) alkyl. In another embodiment, R4 is H or (C1-C6) alkyl, R5 is H or (C1-C6) alkyl, R7 is H or (C1-C6) alkyl, and R9 is halogen. In another embodiment, R4 is H or (C1-C6) alkyl, R5 is H or (C1-C6) alkyl, R7 is H or (C1-C6) alkyl, and R9 is chlorine. In another embodiment, R4 is H and R5 is H or (C1-C6) alkyl. In another embodiment, R4 is H, R5 is H or (C1-C6) alkyl, and R7 is H or (C1-C6) alkyl. In another embodiment, R4 is H, R5 is H or (C1-C6) alkyl, R7 is H or (C1-C6) alkyl, and R9 is halogen. In another embodiment, R4 is H, R5 is H or (C1-C6) alkyl, R7 is H or (C1-C6) alkyl, and R9 is chlorine.

[0374] In some embodiments of the above formula, R4 is H or (C1-C6)alkyl and R5 is (C1-C6)alkyl. In another embodiment, R4 is H or (C1-C6)alkyl, R5 is (C1-C6)alkyl, and R7 is H or (C1-C6)alkyl. In another embodiment, R4 is H or (C1-C6)alkyl, R5 is (C1-C6)alkyl, R7 is H or (C1-C6)alkyl, and R9 is halogen. In another embodiment, R4 is H or (C1-C6)alkyl, R5 is (C1-C6)alkyl, R7 is H or (C1-C6)alkyl, and R9 is chlorine. In another embodiment, R4 is H and R5 is (C1-C6)alkyl. In another embodiment, R4 is H, R5 is (C1-C6)alkyl, and R7 is H or (C1-C6)alkyl. In another embodiment, R4 is H, R5 is (C1-C6) alkyl, R7 is H or (C1-C6) alkyl, and R9 is halogen. In another embodiment, R4 is H, R5 is (C1-C6) alkyl, R7 is H or (C1-C6) alkyl, and R9 is chlorine.

[0375] In some embodiments of the above formula, R4 is H or (C1-C6) alkyl, R5 is H or (C1-C6) alkyl, and R7 is (C1-C6) alkyl. In another embodiment, R4 is H or (C1-C6) alkyl, R5 is H or (C1-C6) alkyl, R7 is (C1-C6) alkyl, and R9 is halogen. In another embodiment, R4 is H or (C1-C6) alkyl, R5 is H or (C1-C6) alkyl, R7 is (C1-C6) alkyl, and R9 is chlorine. In another embodiment, R4 is H, R5 is H or (C1-C6) alkyl, and R7 is (C1-C6) alkyl. In another embodiment, R4 is H, R5 is H or (C1-C6) alkyl, R7 is (C1-C6) alkyl, and R9 is halogen. In another embodiment, R4 is H, R5 is H or (C1-C6)alkyl, R7 is (C1-C6)alkyl, and R9 is chloro.

[0376] In some embodiments of the above formula, R4 is H or (C1-C6) alkyl, R5 is (C1-C6) alkyl, and R7 is (C1-C6) alkyl. In another embodiment, R4 is H or (C1-C6) alkyl, R5 is (C1-C6) alkyl, R7 is (C1-C6) alkyl, and R9 is halogen. In another embodiment, R4 is H or (C1-C6) alkyl, R5 is (C1-C6) alkyl, R7 is (C1-C6) alkyl, and R9 is chlorine. In another embodiment, R4 is H, R5 is (C1-C6) alkyl, and R7 is (C1-C6) alkyl. In another embodiment, R4 is H, R5 is (C1-C6) alkyl, R7 is (C1-C6) alkyl, and R9 is halogen. In another embodiment, R4 is H, R5 is (C1-C6)alkyl, R7 is (C1-C6)alkyl, and R9 is chloro.

[0377] In some embodiments of the above formula, R5 is H or (C1-C6) alkyl. In another embodiment, R5 is H or (C1-C6) alkyl and R7 is H or (C1-C6) alkyl. In another embodiment, R5 is H or (C1-C6) alkyl, R7 is H or (C1-C6) alkyl, and R9 is halogen. In another embodiment, R4 is H or (C1-C6) alkyl, R5 is H or (C1-C6) alkyl, R7 is H or (C1-C6) alkyl, and R9 is chlorine.

[0378] In some embodiments of the above formula, R5 is (C1-C6)alkyl. In another embodiment, R5 is (C1-C6)alkyl and R7 is H or (C1-C6)alkyl. In another embodiment, R5 is (C1-C6)alkyl, R7 is H or (C1-C6)alkyl, and R9 is halogen. In another embodiment, R5 is (C1-C6)alkyl, R7 is H or (C1-C6)alkyl, and R9 is chlorine. In another embodiment, R5 is H or (C1-C6)alkyl and R7 is (C1-C6)alkyl. In another embodiment, R5 is H or (C1-C6)alkyl, R7 is (C1-C6)alkyl, and R9 is halogen.

[0379] In another embodiment, R5 is H or (C1-C6) alkyl, R7 is (C1-C6) alkyl, and R9 is chlorine. In another embodiment, R5 is (C1-C6) alkyl and R7 is (C1-C6) alkyl. In another embodiment, R5 is (C1-C6) alkyl, R7 is (C1-C6) alkyl, and R9 is halogen. In another embodiment, R5 is (C1-C6) alkyl, R7 is (C1-C6) alkyl, and R9 is chlorine.

[0380] In some embodiments of the above formula, R4 is H or (C1-C6)alkyl and R7 is H or (C1-C6)alkyl. In another embodiment, R4 is H or (C1-C6)alkyl, R7 is H or (C1-C6)alkyl, and R9 is halogen. In another embodiment, R4 is H or (C1-C6)alkyl, R7 is H or (C1-C6)alkyl, and R9 is chlorine. In another embodiment, R4 is H and R7 is H or (C1-C6)alkyl. In another embodiment, R4 is H, R7 is H or (C1-C6)alkyl, and R9 is halogen. In another embodiment, R4 is H, R7 is H or (C1-C6)alkyl, and R9 is chlorine. In some embodiments of the above formula, R4 is H or (C1-C6)alkyl and R7 is (C1-C6)alkyl. In another embodiment, R4 is H or (C1-C6) alkyl, R7 is (C1-C6) alkyl, and R9 is halogen. In another embodiment, R4 is H or (C1-C6) alkyl, R7 is (C1-C6) alkyl, and R9 is chlorine. In another embodiment, R4 is H and R7 is (C1-C6) alkyl. In another embodiment, R4 is H, R7 is (C1-C6) alkyl, and R9 is halogen. In another embodiment, R4 is H, R7 is (C1-C6) alkyl, and R9 is chlorine.

[0381] In some embodiments of the above formula, R4 is H or (C1-C6) alkyl, R5 is H or (C1-C6) alkyl, and R9 is halogen. In another embodiment, R4 is H or (C1-C6) alkyl, R5 is H or (C1-C6) alkyl, and R9 is chlorine. In another embodiment, R4 is H, R5 is H or (C1-C6) alkyl, and R9 is halogen. In another embodiment, R4 is H, R5 is H or (C1-C6) alkyl, and R9 is chlorine. In another embodiment, R4 is H or (C1-C6) alkyl, R5 is (C1-C6) alkyl, and R9 is halogen. In another embodiment, R4 is H or (C1-C6) alkyl, R5 is (C1-C6) alkyl, and R9 is halogen. In another embodiment, R4 is H or (C1-C6) alkyl, R5 is (C1-C6) alkyl, and R9 is chlorine. In another embodiment, R4 is H, R5 is (C1-C6) alkyl, and R9 is halogen. In another embodiment, R4 is H, R5 is (C1-C6)alkyl, and R9 is chloro.

[0382] In some embodiments of the above formula, R4 is H or (C1-C6) alkyl and R9 is halogen. In another embodiment, R4 is H or (C1-C6) alkyl and R9 is chlorine. In another embodiment, R4 is H and R9 is halogen. In another embodiment, R4 is H and R9 is chlorine. In another embodiment, R5 is H or (C1-C6) alkyl and R9 is halogen. In another embodiment, R5 is H or (C1-C6) alkyl and R9 is chlorine. In another embodiment, R5 is (C1-C6) alkyl and R9 is halogen. In another embodiment, R5 is (C1-C6) alkyl and R9 is halogen. In another embodiment, R7 is H or (C1-C6) alkyl and R9 is halogen. In another embodiment, R7 is H or (C1-C6) alkyl and R9 is chlorine. In another embodiment, R7 is (C1-C6) alkyl and R9 is halogen. In another embodiment, R7 is (C1-C6)alkyl and R9 is chloro.

[0383] In some embodiments of the above formula, X1 and X2, together with the carbon atoms to which they are attached, form =(O), and X3 is -CH2-. In another embodiment, X1 and X2, together with the carbon atoms to which they are attached, form =(O), X3 is -CH2-, and R9 is Cl. In another embodiment, X1 and X2, together with the carbon atoms to which they are attached, form =(O), X3 is -CH2-, R9 is Cl, and R4 is H. In yet another embodiment, X1 and X2, together with the carbon atoms to which they are attached, form =(O), X3 is -CH2-, R9 is Cl, R4 is H, and R7 is H. In another embodiment, X1 and X2, together with the carbon atoms to which they are attached, form =(O), X3 is -CH2-, R9 is Cl, R4 is H, and R7 is H. In another embodiment, X1 and X2, together with the carbon atoms to which they are attached, form =(O), X3 is -CH2-, R9 is Cl, R4 is H, R7 is H, and R5 is H or (C1-C4)alkyl. In yet another embodiment, X1 and X2 together with the carbon atoms to which they are attached form =(O), R9 is Cl, R4 is H, R7 is H, R5 is H or (C1-C4)alkyl, and R1 is phenyl, or a 5-membered or 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S, wherein the phenyl or heteroaryl is replaced by -OR 10 and optionally substituted by one to three R 11 replace.

[0384] In another embodiment, X1 and X2 together with the carbon atoms to which they are attached form =(O), X3 is -CH2-, R9 is Cl, R4 is H, R7 is H, and R5 is H or (C1-C4)alkyl. In yet another embodiment, X1 and X2 together with the carbon atoms to which they are attached form =(O), R9 is Cl, R4 is H, R7 is H, R5 is H or (C1-C4)alkyl, and R1 is phenyl, or a 5-membered or 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S, wherein the phenyl or heteroaryl is replaced by -OR 10 and optionally substituted by one to three R 11 In another embodiment, X1 and X2 together with the carbon atoms to which they are attached form =(O), X3 is -CH2-, R9 is Cl, R4 is H, R7 is H, R5 is H or (C1-C4)alkyl, R1 is phenyl, or a 5-membered or 6-membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S, wherein the phenyl or heteroaryl group is replaced by -OR 10 and optionally substituted by one to three R 11 substituted, and R2 is H, (C1-C6) alkyl, -NR 12 R 13 , (C1-C6)haloalkyl, (C3-C7)carbocyclyl, or a 5- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein the alkyl group is optionally substituted by one to four R18 and the carbocyclic and heterocyclic groups are optionally substituted by one to four R 19 replace.

[0385] In another embodiment, X1 and X2 together with the carbon atoms to which they are attached form =(O), X3 is -CH2-, R9 is Cl, R4 is H, R7 is H, R5 is H or (C1-C4)alkyl, R1 is phenyl, or a 5-membered or 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, wherein the phenyl or heteroaryl is replaced by -OR 10 and optionally substituted by one to three R 11 Substituted, R2 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, -NR 12 R 13 , (C3-C7) carbocyclyl, or a 5- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein the alkyl group is optionally substituted by one to four R 18 and the carbocyclic and heterocyclic groups are optionally substituted by one to four R 19 substituted, and R3 is H, (C1-C6)haloalkyl, or optionally substituted by one to three R 14 In yet another embodiment, X1 and X2 together with the carbon atoms to which they are attached form =(O), X3 is -CH2-, R9 is Cl, R4 is H, R7 is H, R5 is H or (C1-C4)alkyl, R1 is phenyl, or a 5-membered or 6-membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S, wherein the phenyl or heteroaryl group is replaced by -OR 10 and optionally substituted by one to three R 11 Substituted, R2 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, -NR 12 R 13 , (C3-C7) carbocyclyl, or a 5- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein the alkyl group is optionally substituted by one to four R 18 and the carbocyclic and heterocyclic groups are optionally substituted by one to four R 19 substituted, R3 is H, (C1-C6) haloalkyl, or optionally substituted by one to three R 14 substituted (C1-C6)alkyl, and R6 is (C1-C6)hydroxyalkyl or (C1-C6)alkyl optionally substituted by one to three substituents each independently selected from the group consisting of (C1-C6)alkoxy, (C1-C6)haloalkoxy, -C(O)(C1-C6)alkyl, -C(O)OH and -C(O)O(C1-C6)alkyl.

[0386] In another embodiment, X1 and X2 together with the carbon atoms to which they are attached form =(O), X3 is -CH2-, R9 is Cl, R4 is H, R7 is H, R5 is H or (C1-C4)alkyl, R1 is phenyl, or a 5-membered or 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, wherein the phenyl or heteroaryl is replaced by -OR 10 and optionally substituted by one to three R 11 Substituted, R2 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, -NR 12 R 13 , (C3-C7) carbocyclyl, or a 5- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein the alkyl group is optionally substituted by one to four R 18 and the carbocyclic and heterocyclic groups are optionally substituted by one to four R 19 substituted, R3 is H, (C1-C6) haloalkyl, or optionally substituted by one to three R 14 substituted (C1-C6)alkyl, R6 is (C1-C6)hydroxyalkyl or (C1-C6)alkyl optionally substituted by one to three substituents each independently selected from the group consisting of (C1-C6)alkoxy, (C1-C6)haloalkoxy, -C(O)(C1-C6)alkyl, -C(O)OH and -C(O)O(C1-C6)alkyl, and R8 is H, (C1-C6)haloalkyl, or (C1-C6)alkyl optionally substituted by one to three substituents each independently selected from the group consisting of a 4- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O and S, and -C(O)NR 16 R 17 .

[0387] In yet another embodiment, X1 and X2 together with the carbon atom to which they are attached form =(O), X3 is -CH2-, R9 is Cl, R4 is H, R7 is H, R5 is H or (C1-C4)alkyl, R1 is phenyl, or a 5-membered or 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, wherein the phenyl or heteroaryl is replaced by -OR 10 and optionally substituted by one to three R 11 Substituted, R2 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, -NR 12 R 13 , (C3-C7) carbocyclyl, or a 5- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein the alkyl group is optionally substituted by one to four R 18 and the carbocyclic and heterocyclic groups are optionally substituted by one to four R 19 substituted, R3 is H, (C1-C6)haloalkyl, or optionally substituted by one to three more R14 substituted (C1-C6)alkyl, R6 is (C1-C6)hydroxyalkyl or (C1-C6)alkyl optionally substituted by one to three substituents each independently selected from the group consisting of (C1-C6)alkoxy, (C1-C6)haloalkoxy, -C(O)(C1-C6)alkyl, -C(O)OH and -C(O)O(C1-C6)alkyl, R8 is H, (C1-C6)haloalkyl, or (C1-C6)alkyl optionally substituted by one to three substituents each independently selected from the group consisting of a 4- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O and S, and -C(O)NR 16 R 17 , and R 10 is phenyl, or a 5-membered or 6-membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl groups are optionally substituted by one to three R 22 replace.

[0388] In another embodiment, X1 and X2 together with the carbon atoms to which they are attached form =(O), X3 is -CH2-, R9 is Cl, R4 is H, R7 is H, and R5 is H or methyl. In another embodiment, X1 and X2 together with the carbon atoms to which they are attached form =(O), R9 is Cl, R4 is H, R7 is H, R5 is H or methyl, and R1 is phenyl, or a 5-membered or 6-membered heteroaryl group containing 1-3 heteroatoms selected from N, O, and S, wherein the phenyl or heteroaryl group is replaced by -OR 10 and optionally substituted by one to three R 11 In yet another embodiment, X1 and X2 together with the carbon atoms to which they are attached form =(O), R9 is Cl, R4 is H, R7 is H, R5 is H or methyl, R1 is phenyl, or a 5-membered or 6-membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S, wherein the phenyl or heteroaryl group is replaced by -OR 10 and optionally substituted by one to three R 11 substituted, and R2 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, -NR 12 R 13 , (C3-C7) carbocyclyl, or a 5- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein the alkyl group is optionally substituted by one to four R 18 and the carbocyclic and heterocyclic groups are optionally substituted by one to four R 19 replace.

[0389] In another embodiment, X1 and X2 together with the carbon atoms to which they are attached form =(O), X3 is -CH2-, R9 is Cl, R4 is H, R7 is H, R5 is H or methyl, R1 is phenyl, or a 5-membered or 6-membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S, wherein the phenyl or heteroaryl group is replaced by -OR 10 and optionally substituted by one to three R 11 Substituted, R2 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, -NR 12 R 13 , (C3-C7) carbocyclyl, or a 5- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein the alkyl group is optionally substituted by one to four R 18 and the carbocyclic and heterocyclic groups are optionally substituted by one to four R 19 substituted, and R3 is H, (C1-C6)haloalkyl, or optionally substituted by one to three R 14 In yet another embodiment, X1 and X2 together with the carbon atoms to which they are attached form =(O), X3 is -CH2-, R9 is Cl, R4 is H, R7 is H, R5 is H or methyl, R1 is phenyl, or a 5-membered or 6-membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S, wherein the phenyl or heteroaryl group is replaced by -OR 10 and optionally substituted by one to three R 11 Substituted, R2 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, -NR 12 R 13 , (C3-C7) carbocyclyl, or a 5- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein the alkyl group is optionally substituted by one to four R 18 and the carbocyclic and heterocyclic groups are optionally substituted by one to four R 19 substituted, R3 is H, (C1-C6) haloalkyl, or optionally substituted by one to three R 14 substituted (C1-C6)alkyl, and R6 is (C1-C6)hydroxyalkyl or (C1-C6)alkyl optionally substituted by one to three substituents each independently selected from the group consisting of (C1-C6)alkoxy, (C1-C6)haloalkoxy, -C(O)(C1-C6)alkyl, -C(O)OH and -C(O)O(C1-C6)alkyl.

[0390] In another embodiment, X1 and X2 together with the carbon atoms to which they are attached form =(O), X3 is -CH2-, R9 is Cl, R4 is H, R7 is H, R5 is H or methyl, R1 is phenyl, or a 5-membered or 6-membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S, wherein the phenyl or heteroaryl group is replaced by -OR 10 and optionally substituted by one to three R 11 Substituted, R2 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, -NR 12 R 13 , (C3-C7) carbocyclyl, or a 5- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein the alkyl group is optionally substituted by one to four R 18 and the carbocyclic and heterocyclic groups are optionally substituted by one to four R 19 substituted, R3 is H, (C1-C6) haloalkyl, or optionally substituted by one to three R 14 substituted (C1-C6)alkyl, R6 is (C1-C6)hydroxyalkyl or (C1-C6)alkyl optionally substituted by one to three substituents each independently selected from the group consisting of (C1-C6)alkoxy, (C1-C6)haloalkoxy, -C(O)(C1-C6)alkyl, -C(O)OH and -C(O)O(C1-C6)alkyl, and R8 is H, (C1-C6)haloalkyl, or (C1-C6)alkyl optionally substituted by one to three substituents each independently selected from the group consisting of a 4- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O and S, and -C(O)NR 16 R 17 .

[0391] In yet another embodiment, X1 and X2 together with the carbon atom to which they are attached form =(O), X3 is -CH2-, R9 is Cl, R4 is H, R7 is H, R5 is H or methyl, R1 is phenyl, or a 5-membered or 6-membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S, wherein the phenyl or heteroaryl group is replaced by -OR 10 and optionally substituted by one to three R 11 Substituted, R2 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, -NR 12 R 13 , (C3-C7) carbocyclyl, or a 5- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein the alkyl group is optionally substituted by one to four R 18 and the carbocyclic and heterocyclic groups are optionally substituted by one to four R 19 substituted, R3 is H, (C1-C6) haloalkyl, or optionally substituted by one to three R 14substituted (C1-C6)alkyl, R6 is (C1-C6)hydroxyalkyl or (C1-C6)alkyl optionally substituted by one to three substituents each independently selected from the group consisting of (C1-C6)alkoxy, (C1-C6)haloalkoxy, -C(O)(C1-C6)alkyl, -C(O)OH and -C(O)O(C1-C6)alkyl, R8 is H, (C1-C6)haloalkyl, or (C1-C6)alkyl optionally substituted by one to three substituents each independently selected from the group consisting of a 4- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O and S, and -C(O)NR 16 R 17 , and R 10 is phenyl, or a 5-membered or 6-membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl groups are optionally substituted by one to three R 22 Replace, and R 10 is phenyl, or a 5-membered or 6-membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl groups are optionally substituted by one to three R 22 replace.

[0392] In some embodiments of the above formula, X1 is H and X2 is H and X3 is -CH2-. In another embodiment, X1 is H and X2 is H, X3 is -CH2-, and R9 is Cl. In another embodiment, X1 is H and X2 is H, R9 is Cl, and R4 is H. In yet another embodiment, X1 is H and X2 is H, X3 is -CH2-, R9 is Cl, R4 is H, and R7 is H. In another embodiment, X1 is H and X2 is H, X3 is -CH2-, R9 is Cl, R4 is H, R7 is H, and R5 is H or (C1-C4)alkyl. In yet another embodiment, X1 is H and X2 is H, X3 is -CH2-, R9 is Cl, R4 is H, R7 is H, R5 is H or (C1-C4)alkyl, and R1 is phenyl, or a 5-membered or 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S, wherein the aryl and heteroaryl are replaced by -OR 10 and optionally substituted by one to three R 11 In another embodiment, X1 is H and X2 is H, X3 is -CH2-, R9 is Cl, R4 is H, R7 is H, R5 is H or (C1-C4) alkyl, R1 is phenyl, or a 5-membered or 6-membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S, wherein the phenyl or heteroaryl group is replaced by -OR 10 and optionally substituted by one to three R 11 substituted, and R2 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, -NR 12 R13 , (C3-C7) carbocyclyl, or a 5- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein the alkyl group is optionally substituted by one to four R 18 and the carbocyclic and heterocyclic groups are optionally substituted by one to four R 19 replace.

[0393] In yet another embodiment, X1 is H and X2 is H, X3 is -CH2-, R9 is Cl, R4 is H, R7 is H, R5 is H or (C1-C4)alkyl, R1 is phenyl, or a 5-membered or 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, wherein the phenyl or heteroaryl is replaced by -OR 10 and optionally substituted by one to three R 11 Substituted, R2 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, -NR 12 R 13 , (C3-C7) carbocyclyl, or a 5- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein the alkyl group is optionally substituted by one to four R 18 and the carbocyclic and heterocyclic groups are optionally substituted by one to four R 19 substituted, and R3 is H, (C1-C6)haloalkyl, or optionally substituted by one to three R 14 In another embodiment, X1 is H and X2 is H, X3 is -CH2-, R9 is Cl, R4 is H, R7 is H, R5 is H or (C1-C4) alkyl, R1 is phenyl, or a 5-membered or 6-membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S, wherein the phenyl or heteroaryl group is replaced by -OR 10 and optionally substituted by one to three R 11 Substituted, R2 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, -NR 12 R 13 , (C3-C7) carbocyclyl, or a 5- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein the alkyl group is optionally substituted by one to four R 18 and the carbocyclic and heterocyclic groups are optionally substituted by one to four R 19 substituted, R3 is H, (C1-C6) haloalkyl, or optionally substituted by one to three R 14 substituted (C1-C6)alkyl, and R6 is (C1-C6)hydroxyalkyl or (C1-C6)alkyl optionally substituted by one to three substituents each independently selected from the group consisting of (C1-C6)alkoxy, (C1-C6)haloalkoxy, -C(O)(C1-C6)alkyl, -C(O)OH and -C(O)O(C1-C6)alkyl.

[0394] In yet another embodiment, X1 is H and X2 is H, X3 is -CH2-, R9 is Cl, R4 is H, R7 is H, R5 is H or (C1-C4)alkyl, R1 is phenyl, or a 5-membered or 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, wherein the phenyl or heteroaryl is replaced by -OR 10 and optionally substituted by one to three R 11 Substituted, R2 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, -NR 12 R 13 , (C3-C7) carbocyclyl, or a 5- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein the alkyl group is optionally substituted by one to four R 18 and the carbocyclic and heterocyclic groups are optionally substituted by one to four R 19 substituted, R3 is H, (C1-C6) haloalkyl, or optionally substituted by one to three R 14 substituted (C1-C6)alkyl, R6 is (C1-C6)hydroxyalkyl or (C1-C6)alkyl optionally substituted by one to three substituents each independently selected from the group consisting of (C1-C6)alkoxy, (C1-C6)haloalkoxy, -C(O)(C1-C6)alkyl, -C(O)OH and -C(O)O(C1-C6)alkyl, and R8 is H, (C1-C6)haloalkyl, or (C1-C6)alkyl optionally substituted by one to three substituents each independently selected from the group consisting of a 4- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O and S, and -C(O)NR 16 R 17 .

[0395] In another embodiment, X1 is H and X2 is H, X3 is -CH2-, R9 is Cl, R4 is H, R7 is H, R5 is H or (C1-C4) alkyl, R1 is phenyl, or a 5-membered or 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, wherein the phenyl or heteroaryl is replaced by -OR 10 and optionally substituted by one to three R 11 Substituted, R2 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, -NR 12 R 13 , (C3-C7) carbocyclyl, or a 5- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein the alkyl group is optionally substituted by one to four R 18 and the carbocyclic and heterocyclic groups are optionally substituted by one to four R 19 substituted, R3 is H, (C1-C6) haloalkyl, or optionally substituted by one to three R 14substituted (C1-C6)alkyl, R6 is (C1-C6)hydroxyalkyl or (C1-C6)alkyl optionally substituted by one to three substituents each independently selected from the group consisting of (C1-C6)alkoxy, (C1-C6)haloalkoxy, -C(O)(C1-C6)alkyl, -C(O)OH and -C(O)O(C1-C6)alkyl, R8 is H, (C1-C6)haloalkyl, or (C1-C6)alkyl optionally substituted by one to three substituents each independently selected from the group consisting of a 4- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O and S, and -C(O)NR 16 R 17 , R8 is H, (C1-C6)haloalkyl, or (C1-C6)alkyl optionally substituted by one to three substituents each independently selected from the following: a 4- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, and -C(O)NR 16 R 17 , and R 10 is phenyl, or a 5-membered or 6-membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl groups are optionally substituted by one to three R 22 Replace, and R 10 is phenyl, or a 5-membered or 6-membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl groups are optionally substituted by one to three R 22 replace.

[0396] In some embodiments of the above formula, X1 is H and X2 is H, X3 is -CH2-, R9 is Cl, R4 is H, R7 is H, and R5 is H or methyl. In another embodiment, X1 is H and X2 is H, R9 is Cl, R4 is H, R7 is H, R5 is H or methyl, and R1 is phenyl, or a 5-membered or 6-membered heteroaryl group containing 1-3 heteroatoms selected from N, O, and S, wherein the phenyl or heteroaryl group is replaced by -OR 10 and optionally substituted by one to three R 11 In yet another embodiment, X1 is H and X2 is H, R9 is Cl, R4 is H, R7 is H, R5 is H or methyl, R1 is phenyl, or a 5-membered or 6-membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S, wherein the phenyl or heteroaryl group is replaced by -OR 10 and optionally substituted by one to three R 11 substituted, and R2 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, -NR 12 R 13 , (C3-C7) carbocyclyl, or a 5- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein the alkyl group is optionally substituted by one to four R 18and the carbocyclic and heterocyclic groups are optionally substituted by one to four R 19 replace.

[0397] In another embodiment, X1 is H and X2 is H, X3 is -CH2-, R9 is Cl, R4 is H, R7 is H, R5 is H or methyl, R1 is phenyl, or a 5-membered or 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, wherein the phenyl or heteroaryl is replaced by -OR 10 and optionally substituted by one to three R 11 Substituted, R2 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, -NR 12 R 13 , (C3-C7) carbocyclyl, or a 5- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein the alkyl group is optionally substituted by one to four R 18 and the carbocyclic and heterocyclic groups are optionally substituted by one to four R 19 substituted, and R3 is H, (C1-C6)haloalkyl, or optionally substituted by one to three R 14 In yet another embodiment, X1 is H and X2 is H, X3 is -CH2-, R9 is Cl, R4 is H, R7 is H, R5 is H or methyl, R1 is phenyl, or a 5-membered or 6-membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S, wherein the phenyl or heteroaryl group is replaced by -OR 10 and optionally substituted by one to three R 11 Substituted, R2 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, -NR 12 R 13 , (C3-C7) carbocyclyl, or a 5- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein the alkyl group is optionally substituted by one to four R 18 and the carbocyclic and heterocyclic groups are optionally substituted by one to four R 19 substituted, R3 is H, (C1-C6)haloalkyl, or (C1-C6)alkyl optionally substituted by one to three R 14 substituted, and R6 is (C1-C6)hydroxyalkyl or (C1-C6)alkyl optionally substituted by one to three substituents each independently selected from the group consisting of (C1-C6)alkoxy, (C1-C6)haloalkoxy, -C(O)(C1-C6)alkyl, -C(O)OH and -C(O)O(C1-C6)alkyl.

[0398] In another embodiment, X1 is H and X2 is H, X3 is -CH2-, R9 is Cl, R4 is H, R7 is H, R5 is H or methyl, R1 is phenyl, or a 5-membered or 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, wherein the phenyl or heteroaryl is replaced by -OR 10 and optionally substituted by one to three R 11 Substituted, R2 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, -NR 12 R 13 , (C3-C7) carbocyclyl, or a 5- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein the alkyl group is optionally substituted by one to four R 18 and the carbocyclic and heterocyclic groups are optionally substituted by one to four R 19 substituted, R3 is H, (C1-C6) haloalkyl, or optionally substituted by one to three R 14 substituted (C1-C6)alkyl, R6 is (C1-C6)hydroxyalkyl or (C1-C6)alkyl optionally substituted by one to three substituents each independently selected from the group consisting of (C1-C6)alkoxy, (C1-C6)haloalkoxy, -C(O)(C1-C6)alkyl, -C(O)OH and -C(O)O(C1-C6)alkyl, and R8 is H, (C1-C6)haloalkyl, or (C1-C6)alkyl optionally substituted by one to three substituents each independently selected from the group consisting of a 4- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O and S, and -C(O)NR 16 R 17 .

[0399] In yet another embodiment, X1 is H and X2 is H, X3 is -CH2-, R9 is Cl, R4 is H, R7 is H, R5 is H or methyl, R1 is phenyl, or a 5-membered or 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, wherein the phenyl or heteroaryl is replaced by -OR 10 and optionally substituted by one to three R 11 Substituted, R2 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, -NR 12 R 13 , (C3-C7) carbocyclyl, or a 5- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein the alkyl group is optionally substituted by one to four R 18 and the carbocyclic and heterocyclic groups are optionally substituted by one to four R 19 substituted, R3 is H, (C1-C6) haloalkyl, or optionally substituted by one to three R 14substituted (C1-C6)alkyl, R6 is (C1-C6)hydroxyalkyl or (C1-C6)alkyl optionally substituted by one to three substituents each independently selected from the group consisting of (C1-C6)alkoxy, (C1-C6)haloalkoxy, -C(O)(C1-C6)alkyl, -C(O)OH and -C(O)O(C1-C6)alkyl, R8 is H, (C1-C6)haloalkyl, or (C1-C6)alkyl optionally substituted by one to three substituents each independently selected from the group consisting of a 4- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O and S, and -C(O)NR 16 R 17 , and R 10 is phenyl, or a 5-membered or 6-membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl groups are optionally substituted by one to three R 22 Replace, and R 10 is phenyl, or a 5-membered or 6-membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl groups are optionally substituted by one to three R 22 replace.

[0400] In some embodiments of the above formula, X1 and X2, together with the carbon atoms to which they are attached, form =(O), X3 is -CH2-, R9 is Cl, and R3 and R4, together with the atoms to which they are attached, form a 5- to 7-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O, and S. In another embodiment, X1 and X2, together with the carbon atoms to which they are attached, form =(O), X3 is -CH2-, R9 is Cl, R3 and R4, together with the atoms to which they are attached, form a 5- to 7-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O, and S, and R7 is H. In yet another embodiment, X1 and X2, together with the carbon atoms to which they are attached, form =(O), X3 is -CH2-, R9 is Cl, R3 and R4, together with the atoms to which they are attached, form a 5- to 7-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O, and S, R7 is H, and R5 is H or (C1-C4)alkyl. In another embodiment, X1 and X2, together with the carbon atoms to which they are attached, form =(O), X3 is -CH2-, R9 is Cl, R3 and R4, together with the atoms to which they are attached, form a 5- to 7-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O, and S, R7 is H, R5 is H or (C1-C4)alkyl, and R1 is phenyl, or a 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S, wherein the phenyl or heteroaryl is replaced by -OR 10 and optionally substituted by one to three R 11 replace.

[0401] In another embodiment, X1 and X2 together with the carbon atoms to which they are attached form =(O), X3 is -CH2-, R9 is Cl, R3 and R4 together with the atoms to which they are attached form a 5- to 7-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O, and S, R7 is H, R5 is H or (C1-C4)alkyl, R1 is phenyl, or a 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S, wherein the phenyl or heteroaryl is replaced by -OR 10 and optionally substituted by one to three R 11 substituted, and R2 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, -NR 12 R 13 , (C3-C7) carbocyclyl, or a 5- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein the alkyl group is optionally substituted by one to four R 18 and the carbocyclic and heterocyclic groups are optionally substituted by one to four R 19 In yet another embodiment, X1 and X2, together with the carbon atoms to which they are attached, form =(O), X3 is -CH2-, R9 is Cl, R3 and R4, together with the atoms to which they are attached, form a 5- to 7-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O, and S, R7 is H, R5 is H or (C1-C4)alkyl, R1 is phenyl, or a 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S, wherein the phenyl or heteroaryl is replaced by -OR 10 and optionally substituted by one to three R 11 Substituted, R2 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, -NR 12 R 13 , (C3-C7) carbocyclyl, or a 5- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein the alkyl group is optionally substituted by one to four R 18 and the carbocyclic and heterocyclic groups are optionally substituted by one to four R 19 substituted, and R6 is (C1-C6)hydroxyalkyl or (C1-C6)alkyl optionally substituted by one to three substituents each independently selected from the group consisting of (C1-C6)alkoxy, (C1-C6)haloalkoxy, -C(O)(C1-C6)alkyl, -C(O)OH and -C(O)O(C1-C6)alkyl.

[0402] In another embodiment, X1 and X2 together with the carbon atoms to which they are attached form =(O), X3 is -CH2-, R9 is Cl, R3 and R4 together with the atoms to which they are attached form a 5- to 7-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O, and S, R7 is H, R5 is H or (C1-C4)alkyl, R1 is phenyl, or a 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S, wherein the phenyl or heteroaryl is replaced by -OR 10 and optionally substituted by one to three R 11 Substituted, R2 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, -NR 12 R 13 , (C3-C7) carbocyclyl, or a 5- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein the alkyl group is optionally substituted by one to four R 18 and the carbocyclic and heterocyclic groups are optionally substituted by one to four R 19 R6 is (C1-C6)hydroxyalkyl or (C1-C6)alkyl optionally substituted by one to three substituents each independently selected from the group consisting of (C1-C6)alkoxy, (C1-C6)haloalkoxy, -C(O)(C1-C6)alkyl, -C(O)OH and -C(O)O(C1-C6)alkyl, and R8 is H, (C1-C6)haloalkyl, or (C1-C6)alkyl optionally substituted by one to three substituents each independently selected from the group consisting of a 4- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O and S, and -C(O)NR 16 R 17 .

[0403] In yet another embodiment, X1 and X2 together with the carbon atoms to which they are attached form =(O), X3 is -CH2-, R9 is Cl, R3 and R4 together with the atoms to which they are attached form a 5- to 7-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O, and S, R7 is H, R5 is H or (C1-C4)alkyl, R1 is phenyl, or a 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S, wherein the phenyl or heteroaryl is replaced by -OR 10 and optionally substituted by one to three R 11 Substituted, R2 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, -NR 12 R 13 , (C3-C7) carbocyclyl, or a 5- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein the alkyl group is optionally substituted by one to four R 18 and the carbocyclic and heterocyclic groups are optionally substituted by one to four R 19R6 is (C1-C6)hydroxyalkyl or (C1-C6)alkyl optionally substituted by one to three substituents each independently selected from the group consisting of: (C1-C6)alkoxy, (C1-C6)haloalkoxy, -C(O)(C1-C6)alkyl, -C(O)OH and -C(O)O(C1-C6)alkyl, R8 is H, (C1-C6)haloalkyl, or (C1-C6)alkyl optionally substituted by one to three substituents each independently selected from the group consisting of: a 4- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O and S, and -C(O)NR 16 R 17 , and R 10 is phenyl, or a 5-membered or 6-membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl groups are optionally substituted by one to three R 22 Replace, and R 10 is phenyl, or a 5-membered or 6-membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl groups are optionally substituted by one to three R 22 replace.

[0404] In some embodiments of the above formula, X1 and X2, together with the carbon atoms to which they are attached, form =(O), X3 is -CH2-, R9 is Cl, R3 and R4, together with the atoms to which they are attached, form a 5- to 7-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O, and S, R7 is H, and R5 is H or methyl. In another embodiment, X1 and X2, together with the carbon atoms to which they are attached, form =(O), X3 is -CH2-, R9 is Cl, R3 and R4, together with the atoms to which they are attached, form a 5- to 7-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O, and S, R7 is H, R5 is H or methyl, and R1 is phenyl, or a 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S, wherein the phenyl or heteroaryl is replaced by -OR 10 and optionally substituted by one to three R 11 replace.

[0405] In yet another embodiment, X1 and X2 together with the carbon atoms to which they are attached form =(O), X3 is -CH2-, R9 is Cl, R3 and R4 together with the atoms to which they are attached form a 5- to 7-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O, and S, R7 is H, R5 is H or methyl, R1 is phenyl, or a 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S, wherein the phenyl or heteroaryl is replaced by -OR 10 and optionally substituted by one to three R 11 substituted, and R2 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, -NR12 R 13 , (C3-C7) carbocyclyl, or a 5- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein the alkyl group is optionally substituted by one to four R 18 and the carbocyclic and heterocyclic groups are optionally substituted by one to four R 19 In another embodiment, X1 and X2 together with the carbon atoms to which they are attached form =(O), X3 is -CH2-, R9 is Cl, R3 and R4 together with the atoms to which they are attached form a 5- to 7-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O, and S, R7 is H, R5 is H or methyl, R1 is phenyl, or a 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S, wherein the phenyl or heteroaryl is replaced by -OR 10 and optionally substituted by one to three R 11 Substituted, R2 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, -NR 12 R 13 , (C3-C7) carbocyclyl, or a 5- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein the alkyl group is optionally substituted by one to four R 18 and the carbocyclic and heterocyclic groups are optionally substituted by one to four R 19 substituted, and R6 is (C1-C6)hydroxyalkyl or (C1-C6)alkyl optionally substituted by one to three substituents each independently selected from the group consisting of (C1-C6)alkoxy, (C1-C6)haloalkoxy, -C(O)(C1-C6)alkyl, -C(O)OH and -C(O)O(C1-C6)alkyl.

[0406] In another embodiment, X1 and X2 together with the carbon atoms to which they are attached form =(O), X3 is -CH2-, R9 is Cl, R3 and R4 together with the atoms to which they are attached form a 5- to 7-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O, and S, R7 is H, R5 is H or methyl, R1 is phenyl, or a 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S, wherein the phenyl or heteroaryl is replaced by -OR 10 and optionally substituted by one to three R 11 Substituted, R2 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, -NR 12 R 13 , (C3-C7) carbocyclyl, or a 5- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein the alkyl group is optionally substituted by one to four R 18 and the carbocyclic and heterocyclic groups are optionally substituted by one to four R 19R6 is (C1-C6)hydroxyalkyl or (C1-C6)alkyl optionally substituted by one to three substituents each independently selected from the group consisting of (C1-C6)alkoxy, (C1-C6)haloalkoxy, -C(O)(C1-C6)alkyl, -C(O)OH and -C(O)O(C1-C6)alkyl, and R8 is H, (C1-C6)haloalkyl, or (C1-C6)alkyl optionally substituted by one to three substituents each independently selected from the group consisting of a 4- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O and S, and -C(O)NR 16 R 17 .

[0407] In yet another embodiment, X1 and X2 together with the carbon atoms to which they are attached form =(O), X3 is -CH2-, R9 is Cl, R3 and R4 together with the atoms to which they are attached form a 5- to 7-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O, and S, R7 is H, R5 is H or methyl, R1 is phenyl, or a 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S, wherein the phenyl or heteroaryl is replaced by -OR 10 and optionally substituted by one to three R 11 Substituted, R2 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, -NR 12 R 13 , (C3-C7) carbocyclyl, or a 5- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein the alkyl group is optionally substituted by one to four R 18 and the carbocyclic and heterocyclic groups are optionally substituted by one to four R 19 R6 is (C1-C6)hydroxyalkyl or (C1-C6)alkyl optionally substituted by one to three substituents each independently selected from the group consisting of: (C1-C6)alkoxy, (C1-C6)haloalkoxy, -C(O)(C1-C6)alkyl, -C(O)OH and -C(O)O(C1-C6)alkyl, R8 is H, (C1-C6)haloalkyl, or (C1-C6)alkyl optionally substituted by one to three substituents each independently selected from the group consisting of: a 4- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O and S, and -C(O)NR 16 R 17 , and R 10 is phenyl, or a 5-membered or 6-membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl groups are optionally substituted by one to three R 22 replace.

[0408] In some embodiments of the above formula, X1 is H and X2 is H, X3 is -CH2-, R9 is Cl, and R3 and R4, together with the atoms to which they are attached, form a 5- to 7-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O, and S. In another embodiment, X1 is H and X2 is H, X3 is -CH2-, R9 is Cl, R3 and R4, together with the atoms to which they are attached, form a 5- to 7-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O, and S, and R7 is H. In yet another embodiment, X1 is H and X2 is H, X3 is -CH2-, R9 is Cl, R3 and R4, together with the atoms to which they are attached, form a 5- to 7-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O, and S, R7 is H, and R5 is H or (C1-C4)alkyl. In another embodiment, X1 is H and X2 is H, X3 is -CH2-, R9 is Cl, R3 and R4 together with the atoms to which they are attached form a 5- to 7-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O, and S, R7 is H, R5 is H or (C1-C4)alkyl, and R1 is phenyl, or a 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S, wherein the phenyl or heteroaryl is replaced by -OR 10 and optionally substituted by one to three R 11 replace.

[0409] In another embodiment, X1 is H and X2 is H, X3 is -CH2-, R9 is Cl, R3 and R4 together with the atoms to which they are attached form a 5- to 7-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O, and S, R7 is H, R5 is H or (C1-C4)alkyl, R1 is phenyl, or a 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S, wherein the phenyl or heteroaryl is replaced by -OR 10 and optionally substituted by one to three R 11 substituted, and R2 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, -NR 12 R 13 , (C3-C7) carbocyclyl, or a 5- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein the alkyl group is optionally substituted by one to four R 18 and the carbocyclic and heterocyclic groups are optionally substituted by one to four R 19 replace.

[0410] In yet another embodiment, X1 is H and X2 is H, X3 is -CH2-, R9 is Cl, R3 and R4 together with the atoms to which they are attached form a 5- to 7-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O, and S, R7 is H, R5 is H or (C1-C4)alkyl, R1 is phenyl, or a 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S, wherein the phenyl or heteroaryl is replaced by -OR 10 and optionally substituted by one to three R 11 Substituted, R2 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, -NR 12 R 13 , (C3-C7) carbocyclyl, or a 5- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein the alkyl group is optionally substituted by one to four R 18 and the carbocyclic and heterocyclic groups are optionally substituted by one to four R 19 substituted, and R6 is (C1-C6)hydroxyalkyl or (C1-C6)alkyl optionally substituted by one to three substituents each independently selected from the group consisting of (C1-C6)alkoxy, (C1-C6)haloalkoxy, -C(O)(C1-C6)alkyl, -C(O)OH and -C(O)O(C1-C6)alkyl.

[0411] In another embodiment, X1 is H and X2 is H, X3 is -CH2-, R9 is Cl, R3 and R4 together with the atoms to which they are attached form a 5- to 7-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O, and S, R7 is H, R5 is H or (C1-C4)alkyl, R1 is phenyl, or a 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S, wherein the phenyl or heteroaryl is replaced by -OR 10 and optionally substituted by one to three R 11 Substituted, R2 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, -NR 12 R 13 , (C3-C7) carbocyclyl, or a 5- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein the alkyl group is optionally substituted by one to four R 18 and the carbocyclic and heterocyclic groups are optionally substituted by one to four R 19R6 is (C1-C6)hydroxyalkyl or (C1-C6)alkyl optionally substituted by one to three substituents each independently selected from the group consisting of (C1-C6)alkoxy, (C1-C6)haloalkoxy, -C(O)(C1-C6)alkyl, -C(O)OH and -C(O)O(C1-C6)alkyl, and R8 is H, (C1-C6)haloalkyl, or (C1-C6)alkyl optionally substituted by one to three substituents each independently selected from the group consisting of a 4- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O and S, and -C(O)NR 16 R 17 .

[0412] In yet another embodiment, X1 is H and X2 is H, X3 is -CH2-, R9 is Cl, R3 and R4 together with the atoms to which they are attached form a 5- to 7-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O, and S, R7 is H, R5 is H or (C1-C4)alkyl, R1 is phenyl, or a 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S, wherein the phenyl or heteroaryl is replaced by -OR 10 and optionally substituted by one to three R 11 Substituted, R2 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, -NR 12 R 13 , (C3-C7) carbocyclyl, or a 5- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein the alkyl group is optionally substituted by one to four R 18 and the carbocyclic and heterocyclic groups are optionally substituted by one to four R 19 R6 is (C1-C6)hydroxyalkyl or (C1-C6)alkyl optionally substituted by one to three substituents each independently selected from the group consisting of: (C1-C6)alkoxy, (C1-C6)haloalkoxy, -C(O)(C1-C6)alkyl, -C(O)OH and -C(O)O(C1-C6)alkyl, R8 is H, (C1-C6)haloalkyl, or (C1-C6)alkyl optionally substituted by one to three substituents each independently selected from the group consisting of: a 4- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O and S, and -C(O)NR 16 R 17 , and R 10 is phenyl, or a 5-membered or 6-membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl groups are optionally substituted by one to three R 22 replace.

[0413] In some embodiments of the above formula, X1 is H and X2 is H, X3 is -CH2-, R9 is Cl, R3 and R4 together with the atoms to which they are attached form a 5- to 7-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O, and S, R7 is H, R5 is H or methyl, and R1 is phenyl, or a 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S, wherein the aryl and heteroaryl are replaced by -OR 10 and optionally substituted by one to three R 11 In another embodiment, X1 is H and X2 is H, R9 is Cl, R3 and R4 together with the atoms to which they are attached form a 5- to 7-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O, and S, R7 is H, R5 is H or methyl, R1 is phenyl, or a 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S, wherein the aryl and heteroaryl are replaced by -OR 10 and optionally substituted by one to three R 11 substituted, and R2 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, -NR 12 R 13 , (C3-C7) carbocyclyl, or a 5- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein the alkyl group is optionally substituted by one to four R 18 and the carbocyclic and heterocyclic groups are optionally substituted by one to four R 19 replace.

[0414] In yet another embodiment, X1 is H and X2 is H, X3 is -CH2-, R9 is Cl, R3 and R4 together with the atoms to which they are attached form a 5- to 7-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O, and S, R7 is H, R5 is H or methyl, R1 is phenyl, or a 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S, wherein the aryl and heteroaryl are replaced by -OR 10 and optionally substituted by one to three R 11 Substituted, R2 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, -NR 12 R 13 , (C3-C7) carbocyclyl, or a 5- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein the alkyl group is optionally substituted by one to four R 18 and the carbocyclic and heterocyclic groups are optionally substituted by one to four R 19substituted, and R6 is (C1-C6)hydroxyalkyl or (C1-C6)alkyl optionally substituted by one to three substituents each independently selected from the group consisting of (C1-C6)alkoxy, (C1-C6)haloalkoxy, -C(O)(C1-C6)alkyl, -C(O)OH and -C(O)O(C1-C6)alkyl.

[0415] In another embodiment, X1 is H and X2 is H, X3 is -CH2-, R9 is Cl, R3 and R4 together with the atoms to which they are attached form a 5- to 7-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O, and S, R7 is H, R5 is H or methyl, R1 is phenyl, or a 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S, wherein the aryl and heteroaryl are replaced by -OR 10 and optionally substituted by one to three R 11 Substituted, R2 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, -NR 12 R 13 , (C3-C7) carbocyclyl, or a 5- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein the alkyl group is optionally substituted by one to four R 18 and the carbocyclic and heterocyclic groups are optionally substituted by one to four R 19 R6 is (C1-C6)hydroxyalkyl or (C1-C6)alkyl optionally substituted by one to three substituents each independently selected from the group consisting of (C1-C6)alkoxy, (C1-C6)haloalkoxy, -C(O)(C1-C6)alkyl, -C(O)OH and -C(O)O(C1-C6)alkyl, and R8 is H, (C1-C6)haloalkyl, or (C1-C6)alkyl optionally substituted by one to three substituents each independently selected from the group consisting of a 4- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O and S, and -C(O)NR 16 R 17 .

[0416] In another embodiment, X1 is H and X2 is H, X3 is -CH2-, R9 is Cl, R3 and R4 together with the atoms to which they are attached form a 5- to 7-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O, and S, R7 is H, R5 is H or methyl, R1 is phenyl, or a 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S, wherein the aryl and heteroaryl are replaced by -OR 10 and optionally substituted by one to three R 11 Substituted, R2 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, -NR 12 R 13, (C3-C7) carbocyclyl, or a 5- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein the alkyl group is optionally substituted by one to four R 18 and the carbocyclic and heterocyclic groups are optionally substituted by one to four R 19 R6 is (C1-C6)hydroxyalkyl or (C1-C6)alkyl optionally substituted by one to three substituents each independently selected from the group consisting of: (C1-C6)alkoxy, (C1-C6)haloalkoxy, -C(O)(C1-C6)alkyl, -C(O)OH and -C(O)O(C1-C6)alkyl, R8 is H, (C1-C6)haloalkyl, or (C1-C6)alkyl optionally substituted by one to three substituents each independently selected from the group consisting of: a 4- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O and S, and -C(O)NR 16 R 17 , and R 10 is phenyl, or a 5-membered or 6-membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl groups are optionally substituted by one to three R 22 replace.

[0417] In another embodiment, X1 and X2 together with the carbon atoms to which they are attached form =(O), X3 is -CH2-, R9 is Cl, R3 and R4 together with the atoms to which they are attached form a 5- to 7-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O, and S, R7 is H, R5 is H or methyl, R1 is phenyl (which is replaced by -OR 10 and optionally substituted by one to three R 11 substituted), R2 is (C1-C6) alkyl, or (C3-C7) carbocyclyl (wherein the alkyl is optionally substituted by one to four R 18 substituted, and the carbocyclyl is optionally substituted by one to four R 19 substituted), R6 is (C1-C6)hydroxyalkyl, R8 is (C1-C6)alkyl optionally substituted by one to three substituents each independently selected from the following substituents: a 4- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, and -C(O)NR 16 R 17 , and R 10 Is one to three R 22 Substituted phenyl.

[0418] Example 1. A compound according to formula (I).

[0419] Embodiment 2. The compound of embodiment 1, wherein R4 is H or (C1-C6)alkyl.

[0420] Embodiment 3. The compound of embodiment 1 or 2, wherein R4 is H.

[0421] Embodiment 4. The compound according to embodiment 1, wherein R3 and R4 together with the atoms to which they are attached form a 5- to 7-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O and S.

[0422] Embodiment 5. The compound according to embodiment 1 or 3, wherein R3 and R4 together with the atoms to which they are attached form a 6-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O and S.

[0423] Embodiment 6. A compound according to any one of embodiments 1-5, wherein R5 is H or (C1-C6)alkyl.

[0424] Embodiment 7. A compound according to any one of embodiments 1-6 wherein R5 is (C1-C6)alkyl.

[0425] Embodiment 8. A compound according to any one of embodiments 1-7, wherein R7 is H or (C1-C6)alkyl.

[0426] Embodiment 9. A compound according to any one of embodiments 1-8 wherein R7 is (C1-C6)alkyl.

[0427] Embodiment 10. The compound of any one of embodiments 1-9, wherein R9 is halogen.

[0428] Embodiment 11. A compound according to any one of embodiments 1-10, wherein R9 is chloro.

[0429] Embodiment 12. A compound according to any one of embodiments 1-11, wherein R8 is (C1-C6)alkyl optionally substituted by one to three substituents each independently selected from the group consisting of: (C3-C7)carbocyclyl, a 4- to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S, -NR 16 R 17 and -C(O)NR 16 R 17 .

[0430] Embodiment 13. A compound according to any one of embodiments 1-12 wherein R8 is (C1-C6)alkyl.

[0431] Embodiment 14. A compound according to Embodiment 1, which has Formula (Ia)-(Ib)-(Ic)-(Id)-(Ie)-(If)-(Ig)-(Ih) or Formula (Ii).

[0432] Embodiment 15. A compound according to any one of embodiments 1-14, wherein R1 is phenyl, which is replaced by -OR 10 and optionally substituted by one to three R 11 replace.

[0433] Embodiment 16. A compound according to any one of embodiments 1-14, wherein R1 is pyridinyl, which is replaced by -OR 10 and optionally substituted by one to three R 11 replace.

[0434] Embodiment 17. The compound of embodiment 1, having Formula (Ij), Formula (Ik), Formula (Im), or Formula (Io), wherein x is 0, 1, or 2.

[0435] Embodiment 18. A compound according to any one of embodiments 1-17, wherein R 10 is a phenyl group, which is separated by one to three R 22 replace.

[0436] Embodiment 19. A compound according to any one of embodiments 1-17, wherein R 10 is a pyridyl group, which is supported by one to three R 22 replace.

[0437] Example 20. The compound (Cmd) according to Example 1, which is selected from

[0438]

[0439]

[0440]

[0441]

[0442]

[0443]

[0444]

[0445]

[0446]

[0447]

[0448]

[0449]

[0450]

[0451]

[0452]

[0453]

[0454]

[0455]

[0456]

[0457]

[0458]

[0459]

[0460] Embodiment 21. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of Embodiments 1-20 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0461] Embodiment 22. A combination comprising a compound according to any one of embodiments 1-20, or a pharmaceutically acceptable salt thereof, and one or more additional therapeutically active agents.

[0462] Embodiment 23. The combination according to embodiment 22, wherein the additional therapeutically active agent is a statin.

[0463] Embodiment 24. The pharmaceutical composition according to embodiment 21 or the combination according to embodiment 22 or 23 for use in treating, preventing, ameliorating or delaying the progression of a disease or disorder mediated by PCSK9.

[0464] Example 25. A pharmaceutical composition or combination according to Example 24, wherein the PCSK9-mediated disease or disorder or the disease or disorder requiring inhibition of PCSK9 activity is selected from hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, peripheral arterial disease, vascular inflammation, elevated Lp(a), elevated LDL, elevated TRL, elevated triglycerides, sepsis and xanthomas.

[0465] Embodiment 26. A method of modulating PCSK9, comprising administering to a patient in need thereof a compound according to any one of embodiments 1-20 or a pharmaceutically acceptable salt thereof.

[0466] Example 27. A method of inhibiting PCSK9, comprising administering to a patient in need thereof a compound according to any one of Examples 1-20 or a pharmaceutically acceptable salt thereof.

[0467] Example 28. A method for treating, preventing, ameliorating or delaying the progression of a disease or disorder mediated by PCSK9, comprising the steps of administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of Examples 1-20 or a pharmaceutically acceptable salt thereof.

[0468] Example 29. The method of Example 28, wherein the PCSK9-mediated disease or disorder is selected from hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, peripheral arterial disease, vascular inflammation, elevated Lp(a), elevated LDL, elevated TRL, elevated triglycerides, sepsis, and xanthomas.

[0469] Example 30. A method of (i) lowering Lp(a), (ii) lowering Lp(a) plasma levels, (iii) lowering Lp(a) serum levels, (iv) lowering serum TRL or LDL levels, (v) lowering serum triglyceride levels, (vi) lowering LDL-C, (vii) lowering total plasma apoB concentration, (viii) lowering LDL apoB, (ix) lowering TRL apoB, or (x) lowering non-HDL-C levels, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of Examples 1-20, or a pharmaceutically acceptable salt thereof, thereby lowering the patient's LDL-C.

[0470] Embodiment 31. The method of any one of embodiments 26-30, wherein administration is performed orally, parenterally, subcutaneously, by injection, or by infusion.

[0471] Embodiment 32. A compound according to any one of embodiments 1-20, or a pharmaceutically acceptable salt thereof, for use in treating a PCSK9-mediated disease or disorder.

[0472] Embodiment 33. A compound according to any one of embodiments 1-20, or a pharmaceutically acceptable salt thereof, for use in treating, preventing, ameliorating or delaying progression of, or treating, preventing, ameliorating or delaying progression of, a disease or disorder requiring inhibition of PCSK9.

[0473] Embodiment 34. Use of a compound according to any one of embodiments 1-20 or a pharmaceutically acceptable salt thereof for treating, preventing, ameliorating or delaying the progression of a disease or disorder mediated by PCSK9 or for treating, preventing, ameliorating or delaying the progression of a disease or disorder requiring inhibition of PCSK9.

[0474] Example 35. Use of a compound according to any one of Examples 1-20 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating, preventing, ameliorating or delaying the progression of a disease or disorder mediated by PCSK9 or for treating, preventing, ameliorating or delaying the progression of a disease or disorder that requires inhibition of PCSK9.

[0475] Example 36. A method for treating, preventing, ameliorating or delaying the progression of a disease or disorder mediated by PCSK9 or a disease or disorder requiring inhibition of PCSK9 or PCSK9 activity, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of Examples 1-20 or a pharmaceutically acceptable salt thereof.

[0476] Embodiment 37. The compound for use according to embodiment 33, the use according to embodiment 34 or 35, or the method according to embodiment 36, wherein the PCSK9-mediated disease or disorder or the disease or disorder requiring inhibition of PCSK9 is selected from hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, peripheral arterial disease, vascular inflammation, elevated Lp(a), elevated LDL, elevated TRL, elevated triglycerides, sepsis, and xanthomas.

[0477] Embodiment 38. A compound according to embodiment 1 selected from the group consisting of:

[0478] (3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7,12-dimethyl-3-(pyridin-2-ylmethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone;

[0479] (3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7,12-dimethyl-3-(pyridin-2-ylmethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone;

[0480] (3R,7S,10S,13R)-3-Benzyl-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone;

[0481] (3S,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-3-((S)-2,3-dihydro-1H-inden-1-yl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone;

[0482] (3R,7S,10S,13R)-3-Benzyl-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7,12-dimethyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone;

[0483] (3R,7S,10S,13R)-3-Benzyl-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone;

[0484] (3R,7S,10S,13R)-3-Benzyl-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7,12-dimethyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone;

[0485] (3S,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7,12-dimethyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone;

[0486] (3S,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7,12-dimethyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone;

[0487] (3S,7S,10S,13R)-6-(4-chloro-2-fluoro-6-(4-(1-methyl-2-((methylamino)methyl)-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7,12-dimethyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; and

[0488] (3S,7S,10S,13R)-6-(4-chloro-2-fluoro-6-(4-(1-methyl-2-((methylamino)methyl)-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7,12-dimethyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone;

[0489] or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, N-oxide or tautomer thereof.

[0490] Embodiment 39. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of Embodiments 1-20 and Embodiment 38, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0491] Embodiment 40. The pharmaceutical composition of embodiment 39, further comprising at least one additional pharmaceutical agent.

[0492] Embodiment 41. The pharmaceutical composition of embodiment 39 or embodiment 40 for use in treating a disease or disorder mediated by PCSK9.

[0493] Example 42. A method of modulating PCSK9, comprising administering to a patient in need thereof a compound according to any one of Examples 1-20 and Example 38, or a pharmaceutically acceptable salt thereof.

[0494] Example 43. A method of inhibiting PCSK9, comprising administering to a patient in need thereof a compound according to any one of Examples 1-20 and Example 38, or a pharmaceutically acceptable salt thereof.

[0495] Example 44. A method of inhibiting PCSK9 activity, comprising administering to a patient in need thereof a compound according to any one of Examples 1-20 and Example 38, or a pharmaceutically acceptable salt thereof.

[0496] Example 45. A method of treating a disease or disorder mediated by PCSK9, comprising the steps of administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of Examples 1-20 and Example 38, or a pharmaceutically acceptable salt thereof.

[0497] Example 46. The method of Example 45, wherein the PCSK9-mediated disease or disorder is selected from hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, vascular inflammation, and xanthomas.

[0498] Example 47. A method of lowering LDL-C in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound according to any one of Examples 1-20 and Example 38, or a pharmaceutically acceptable salt thereof, thereby lowering the patient's LDL-C.

[0499] Embodiment 48. The method of any one of embodiments 42 to 47, wherein administration is performed orally, parenterally, subcutaneously, by injection, or by infusion.

[0500] Embodiment 49. A compound according to any one of Embodiments 1-20 and Embodiment 38, or a pharmaceutically acceptable salt thereof, for use in treating a PCSK9-mediated disease or disorder.

[0501] Example 50. A compound according to any one of Examples 1-20 and Example 38, or a pharmaceutically acceptable salt thereof, for use in treating a PCSK9-mediated disease or disorder selected from hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, vascular inflammation, and xanthomas.

[0502] Example 51. Use of a compound according to any one of Examples 1-20 and Example 38, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a PCSK9-mediated disease or disorder.

[0503] Example 52. The use according to claim 51, wherein the PCSK9-mediated disease or disorder is selected from hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, vascular inflammation, and xanthomas.

[0504] Example 53. A compound according to any one of Examples 1-20 and Example 38, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for treating a disease associated with inhibition of PCSK9 activity.

[0505] Example 54. Use of the compound according to any one of Examples 1-20 and Example 38 or a pharmaceutically acceptable salt thereof in treating a disease associated with inhibition of PCSK9 activity.

[0506] Example 55. The use according to Example 54, wherein the disease associated with inhibition of PCSK9 activity is selected from hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, vascular inflammation, and xanthomas.

[0507] Example 56. A method of making a compound of formula (II) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, N-oxide or tautomer thereof,

[0508]

[0509] where R a1 and R5 are each independently (C1-C6 alkyl) and R9 is as defined above for formula (I), the method comprising:

[0510] (d) alkylating a compound of formula (IIa) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, N-oxide or tautomer thereof,

[0511]

[0512] wherein R5 is H and R9 is as defined above for formula (I),

[0513] The alkylation is carried out using an alkyl halide and a base in a solvent at low temperature to provide a compound having formula (IIb),

[0514]

[0515] wherein R5 is (C1-C6 alkyl) and R9 is as defined above for formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, N-oxide or tautomer thereof,

[0516] (e) reacting a compound of formula (IIb) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, N-oxide or tautomer thereof with an acid in a solvent, followed by reaction with Boc2O and a base to form a compound of formula (IIc),

[0517]

[0518] wherein R5 is (C1-C6 alkyl) and R9 is as defined above for formula (I), a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, N-oxide or tautomer thereof;

[0519] (f) alkylating a compound of formula (IIc) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, N-oxide or tautomer thereof using an alkylating agent in a solvent and optionally a metal oxide to provide a compound of formula (IId),

[0520]

[0521] where R a1 and R5 are each independently (C1-C6 alkyl) and R9 is as defined above for formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, N-oxide or tautomer thereof; and

[0522] (d) Dealkylating the compound of formula (IId) using a palladium catalyst and N,N-dimethyltrimethylsilylamine in a solvent to provide a compound of formula (II).

[0523] Embodiment 57. The method of embodiment 56, wherein the solvent in step (a) is DMF.

[0524] Embodiment 58. The method of embodiment 56 or 57, wherein the temperature in step (a) is about 0°C.

[0525] Embodiment 59. The method of any one of embodiments 56 to 58, wherein the acid in step (b) is trifluoroacetic acid (TFA).

[0526] Embodiment 60. The method of any one of embodiments 56-59, wherein a metal oxide is used in step (c).

[0527] Embodiment 61. The method of embodiment 60, wherein the metal oxide is silver (I) oxide (Ag2O).

[0528] Embodiment 62. The method of any one of embodiments 56-61, wherein the palladium catalyst in step (d) is tetrakis(triphenylphosphine)palladium(0).

[0529] Example 63. A method of making a compound of formula (II) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, N-oxide or tautomer thereof,

[0530]

[0531] where R a1 is H, R5 is (C1-C6 alkyl), and R9 is as defined above for formula (I), the method comprising reacting a compound of formula (IIb):

[0532]

[0533] wherein R5 is (C1-C6 alkyl) and R9 is as defined above for formula (I), reacted with a palladium catalyst and N,N-dimethyltrimethylsilylamine in a solvent to provide a compound having formula (II).

[0534] Embodiment 64. The method of embodiment 63, wherein the solvent is in dichloromethane.

[0535] Embodiment 65. The method of embodiment 63 or 64, wherein the palladium catalyst is tetrakis(triphenylphosphine)palladium(0).

[0536] In another embodiment, the compound of formula (I) is selected from:

[0537] (3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7,12-dimethyl-3-(pyridin-2-ylmethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone;

[0538] (3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7,12-dimethyl-3-(pyridin-2-ylmethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone;

[0539] (3R,7S,10S,13R)-3-Benzyl-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone;

[0540] (3S,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-3-((S)-2,3-dihydro-1H-inden-1-yl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone;

[0541] (3R,7S,10S,13R)-3-Benzyl-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7,12-dimethyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone;

[0542] (3R,7S,10S,13R)-3-Benzyl-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; and

[0543] (3R,7S,10S,13R)-3-Benzyl-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7,12-dimethyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone.

[0544] Another aspect of the disclosure relates to intermediates having formula (IIIa):

[0545]

[0546] or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, N-oxide or tautomer thereof, wherein R c is -NH2, -NH(C1-C6)alkyl, -C(O)NH2 or Where * indicates chiral center, R d is H or a nitrogen protecting group (e.g., tert-butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), etc.) and R9 is as defined above for formula (I). In one embodiment, R d is a nitrogen protecting group. In another embodiment, R d is tert-butyloxycarbonyl (Boc). In another embodiment, R d It’s H.

[0547] Another aspect of the disclosure relates to intermediates having formula (IIIb):

[0548]

[0549] or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, N-oxide or tautomer thereof, wherein R d is H or a nitrogen protecting group (e.g., tert-butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), etc.), R e is H or -C(O)OCH2CH=CH2, R7 is H and R5, R6 and R9 are as defined above for formula (I). In one embodiment, R d is a nitrogen protecting group. In another embodiment, R d is tert-butyloxycarbonyl (Boc). In another embodiment, R d It’s H.

[0550] Another aspect of the disclosure relates to intermediates having formula (IIIc):

[0551]

[0552] or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, N-oxide or tautomer thereof, wherein R d and R fEach is independently H or a nitrogen protecting group (e.g., tert-butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), etc.), and R1, R5, R6, R7, R8, and R9 are as defined above for formula (I). In one embodiment, R d is a nitrogen protecting group. In another embodiment, R d is tert-butyloxycarbonyl (Boc). In another embodiment, R d is H. In one embodiment, R f is a nitrogen protecting group. In another embodiment, R f is tert-butyloxycarbonyl (Boc). In another embodiment, R f It’s H.

[0553] Another aspect of the disclosure relates to intermediates having formula (IIId):

[0554]

[0555] or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, N-oxide or tautomer thereof, wherein R f is H or a nitrogen protecting group (e.g., tert-butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), etc.), R g is -OH or -O(C1-C6)alkyl, X1 and X2 together with the carbon atom to which they are attached form =(O), X3 is -CH2-, and R1, R2, R5, R6, R7, R8 and R9 are as defined above for formula (I). In one embodiment, R f is a nitrogen protecting group. In another embodiment, R f is tert-butyloxycarbonyl (Boc). In another embodiment, R f It’s H.

[0556] Another aspect of the disclosure relates to intermediates having formula (IIIe) or (IIIf):

[0557]

[0558] or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, N-oxide or tautomer thereof, wherein R H is -OH, -O(C1-C6)alkyl, -O triflate, or halogen, and R 10 and R 11 is as defined above for formula (I).

[0559] Another aspect of the disclosure relates to intermediates having formula (IIIg) or (IIIh):

[0560]

[0561] or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, N-oxide or tautomer thereof, wherein R H is -OH, -O(C1-C6)alkyl, -O triflate, or halogen, and R 10 and R 11 is as defined above for formula (I).

[0562] Another aspect of the disclosure relates to intermediates having formula (IIIi) or (IIIj):

[0563]

[0564] or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, N-oxide or tautomer thereof, wherein R H is -OH, -O(C1-C6)alkyl, -O triflate, or halogen, and R 22 is as defined above for formula (I).

[0565] Another aspect of the disclosure relates to an intermediate selected from the group consisting of:

[0566]

[0567]

[0568] or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, N-oxide or tautomer thereof.

[0569] In another embodiment of the present disclosure, the compound of formula (I) is an enantiomer. In some embodiments, the compound is an (S)-enantiomer. In other embodiments, the compound is an (R)-enantiomer. In other embodiments, the compound of formula (I) can be a (+) or (-) enantiomer.

[0570] In another embodiment of the present disclosure, intermediates (IIIa), (IIIb), (IIIc), and (IIId) are enantiomers. In some embodiments, the intermediate is an (S)-enantiomer. In other embodiments, the intermediate is an (R)-enantiomer. In other embodiments, the intermediate can be a (+) or (-) enantiomer.

[0571] In another embodiment of the present disclosure, the compound of formula (I) is a diastereomer. In another embodiment of the present disclosure, the intermediates of formula (IIIa), (IIIb), (IIIc) and (IIId) are diastereomers.

[0572] It should be understood that all isomeric forms are included in the present disclosure, including mixtures thereof. If the compound contains a double bond, the substituents may be in the E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituents may have cis- or trans-configuration. All tautomeric forms are also intended to be included.

[0573] The compounds and intermediates of the present disclosure and their pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, and prodrugs can exist in their tautomeric forms (e.g., as amides or imino ethers). All such tautomeric forms are considered part of the present disclosure herein.

[0574] The compounds and intermediates disclosed herein may contain asymmetric centers or chiral centers and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds and intermediates disclosed herein and mixtures thereof (including racemic mixtures) all constitute a part of the disclosure. In addition, the disclosure includes all geometric isomers and positional isomers. For example, if the compounds or intermediates disclosed herein contain double bonds or fused rings, both cis-forms and trans-forms and mixtures are included within the scope of the disclosure. Each compound or intermediate disclosed herein includes all enantiomers that meet the general structure of the compound or intermediate. The compound or intermediate may be in racemic or enantiomer-pure form, or any other form with respect to stereochemistry. The assay result may reflect data collected for racemic form, enantiomer-pure form, or any other form with respect to stereochemistry.

[0575] Diastereomeric mixtures can be separated into their individual diastereomers based on their physicochemical differences by methods well known to those skilled in the art (such as by chromatography and / or fractional crystallization). Enantiomers can be separated as follows: by reacting the enantiomeric mixture with an appropriate optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acidchlorid), converting the enantiomeric mixture into a diastereomeric mixture, separating these diastereomers, and converting (e.g., hydrolyzing) the individual diastereomers into the corresponding pure enantiomers. In addition, some compounds of the present disclosure can be atropisomers (e.g., substituted biaryls) and are considered to be part of the present disclosure. Enantiomers can also be separated using chiral HPLC columns.

[0576] The compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. In addition, for example, all keto-enol and imine-enamine forms of the compounds are included in the present disclosure.

[0577] All stereoisomers (e.g., geometric isomers, optical isomers, etc.) of the compounds of the present disclosure (including salts, solvates, esters, and prodrugs of those compounds, and salts, solvates, and esters of the prodrugs), such as those that may exist due to asymmetric carbons on different substituents (including enantiomeric forms (even asymmetric carbons may exist), rotameric forms, atropisomers, and diastereomeric forms) are included within the scope of the present disclosure, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl). (For example, if a compound having formula (I) contains a double bond or a fused ring, both the cis-form and the trans-form, as well as mixtures, are included within the scope of the present disclosure. In addition, for example, all keto-enol and imine-enamine forms of the compounds are included in the present disclosure). Individual stereoisomers of the compounds of the present disclosure may, for example, be substantially free of other isomers, or may be mixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present disclosure may have the S or R configuration as defined by the IUPAC 1974 recommendations. The use of the terms "salt," "solvate," "ester," "prodrug," and the like is intended to apply equally to enantiomers, stereoisomers, rotational isomers, tautomers, positional isomers, racemates, or salts, solvates, esters, and prodrugs of the compounds of the invention.

[0578] Compounds of formula (I) may form salts, which are also within the scope of the present disclosure. Unless otherwise indicated, reference to a compound of the formulae herein is understood to include reference to salts thereof.

[0579] The present disclosure relates to compounds that are modulators of PCSK9. In one embodiment, the compounds of the present disclosure are PCSK9 inhibitors.

[0580] The present disclosure relates to compounds as described herein and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, as well as pharmaceutical compositions comprising one or more compounds as described herein, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof.

[0581] Activity of the compound

[0582] The activity of the compounds according to the present disclosure as PCSK9 inhibitors can be assessed using a time-resolved fluorescence resonance energy transfer (TR-FRET) assay. The time-resolved fluorescence resonance energy transfer (TR-FRET) assay measures the ability of the compounds of the present disclosure to interfere with the binding of human PCSK9 to human LDLR, providing measurements of potency (IC50) and efficacy (Amax).

[0583] Solutions of varying concentrations were prepared by diluting the compounds of the present disclosure in dimethyl sulfoxide (DMSO) and pipetting the resulting solutions onto the plates. DMSO was used as a negative control. An intermediate plate was prepared by transferring a known amount of each compound solution and control from the compound plate to the corresponding wells containing assay buffer and mixing thoroughly. A third plate was then prepared for the assay by adding human PCSK9 Alexa Fluor 647 followed by a known amount of each solution from the intermediate plate. Unlabeled human PCSK9 in assay buffer containing DMSO was used as a positive control for the assay. After incubation, human LDLR extracellular domain-Europium Kryptate was added to each well of the assay plate and the resulting mixture was incubated for an additional period of time. The TR-FRET signal was measured and the IC of the compound was calculated using the FRET ratio (FRET / Europium) 50 and Amax.

[0584] Synthesis methods of compounds

[0585] The compounds of the present disclosure can be prepared by a variety of methods, including standard chemistry. Suitable synthetic routes are described in the schemes given below.

[0586] Compounds with formula (I) can be prepared by methods known in the art of organic synthesis, as partially illustrated by the following synthesis scheme. In the scheme described below, it is well understood that, according to general principles or chemistry, protective groups for sensitive groups or reactive groups are used when necessary. Protective groups are operated according to standard methods for organic synthesis (TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis," 3rd edition, Wiley, New York 1999). These groups are removed at a convenient stage of compound synthesis using methods apparent to those skilled in the art. The selection process and reaction conditions and their order of implementation should be consistent with the preparation of compounds with formula (I).

[0587] Those skilled in the art will recognize whether there is a stereocenter in the compound with formula (I). Therefore, the present disclosure includes two possible stereoisomers (unless indicated in the synthesis) and not only includes racemic compounds, but also includes independent enantiomers and / or diastereomers. When needing compound as single enantiomer or diastereomer, can be obtained by stereospecific synthesis or by splitting final product or any convenient intermediate. The splitting of final product, intermediate or starting material can be subject to the influence of any suitable method known in the art. Referring to, for example, " Stereochemistry of Organic Compounds [stereochemistry of organic compounds] " author E.L. Elliel, S.H. Wilen, and L.N. Mander (Wiley-Interscience [Wiley Science Press], 1994).

[0588] The compounds described herein can be prepared from commercially available starting materials or synthesized using known organic, inorganic and / or enzymatic methods.

[0589] Preparation of compounds

[0590] The compounds of the present disclosure can be prepared in a variety of ways well known to those skilled in the art of organic synthesis. For example, the compounds of the present disclosure can be synthesized using the methods described below, as well as synthetic methods known in the field of synthetic organic chemistry, or variations thereof understood by those skilled in the art. Preferred methods include, but are not limited to, those described below. The compounds of the present disclosure can be synthesized by following the steps outlined in General Schemes 1 and 2, which include the order of different assembly intermediates 1-a, 1-b, 1-c, 1-d, 1-e, 1-f, 1-g, 1-h, 1-i, 2-a, 2-b, 2-c, 2-d, and 2-e. The starting material is commercially available or prepared by known procedures reported in the literature or as described.

[0591] General Solution 1

[0592]

[0593] wherein R1, R2, R3, R4, R5, R6, R7, R8 and R9 are defined in formula (I), X3 is CH2, X1 and X2 together with the carbon atom to which they are attached form =(O), and P is an amine protecting group (e.g., tert-butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), etc.).

[0594] A general method for preparing compounds of formula (I) by using intermediates 1-a, 1-b, 1-c, 1-d, 1-e, 1-f, 1-g, 1-h, and 1-i is outlined in General Scheme 1. Treatment of 1-a with PS-2-chlorotrityl chloride resin in the presence of a base (e.g., triethylamine (TEA), N,N-diisopropylethylamine (DIPEA), etc.) and in a solvent (e.g., dichloromethane (DCM), dimethylformamide (DMF), etc.) provides 1-b. The synthesis of intermediate 1-d can be accomplished by reacting an amide coupling agent (e.g., 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), O-(1H-6-chlorobenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HCTU), or O-(7-azobenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), etc.) and an optional base (e.g., TEA, DIPEA, etc.) in a solvent (e.g., N-methylpyrrolidine (NMP) or DMF) on a resin (e.g., TentaGel) under standard coupling conditions. TM 1-b is coupled with 1-c on a 4-methylpiperidine / DMA resin, followed by removal of the amine protecting group P (e.g., treatment with 4-methylpiperidine / DMA to remove the Fmoc group). 1-d and the acid 1-e are coupled using an amide coupling agent (e.g., TBTU, HCTU, HATU, etc.) and an optional base (e.g., TEA, DIPEA, etc.), followed by deprotection (e.g., treatment with 4-methylpiperidine / DMA to remove the Fmoc group or treatment with TFA to remove the Boc group) to provide 1-f.

[0595] 1-f is cleaved from the resin by repeated treatment with 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP) in a solvent such as DCM to provide 1-g. Reductive amination of amine 1-g and aldehyde 1-h in a reducing agent (e.g., sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, etc.), optionally in the presence of an acid (e.g., acetic acid (AcOH)) in a solvent such as methanol (MeOH) and / or DCM, provides 1-i. Cyclization of 1-i using standard coupling conditions (e.g., an amide coupling agent (e.g., HATU, HOAt, TBTU, and / or HCTU) with an optional base (e.g., 2,6-lutidine, TEA, DIPEA, etc.) in a solvent such as DCM, NMP, DMF, etc.) provides the desired compound of formula (I).

[0596] General Solution 2

[0597]

[0598] wherein R1, R2, R3, R4, R5, R6, R7, R8 and R9 are defined in formula (I), X3 is CH2, X1 and X2 together with the carbon atom to which they are attached form =(O), R' is an alkyl group, and P is an amine protecting group (e.g., tert-butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), etc.).

[0599] Alternatively, compounds of formula (I) can be prepared by using intermediates 1-c, 1-e, 1-h, 1-i, 2-a, 2-b, 2-c, 2-d, and 2-e as outlined in General Scheme 2. The synthesis of intermediate 2-c can be accomplished by coupling 2-a with 2-b under standard coupling conditions using an amide coupling agent (e.g., TBTU, HCTU, or HATU, etc.) and an optional base (e.g., TEA, DIPEA, etc.) in a solvent (e.g., NMP or DMF, etc.), followed by removal of the amine protecting group P (e.g., 4-methylpiperidine / DMA treatment to remove the Fmoc group). Amine 2-c and acid 1-c are coupled using an amide coupling agent (e.g., TBTU, HCTU, HATU, etc.) and an optional base (e.g., TEA, DIPEA, etc.), followed by deprotection (e.g., treatment with 4-methylpiperidine / DMA to remove the Fmoc group or treatment with TFA to remove the Boc group) to provide 2-d. The coupling and deprotection steps are repeated in step 3 using the standard coupling conditions described above to provide intermediate 2-e. Reductive amination of amine 2-e and aldehyde 1-h in the presence of a reducing agent (e.g., sodium triacetoxyborohydride, sodium cyanoborohydride, or sodium borohydride) and, optionally, an acid (e.g., AcOH) in a solvent (e.g., MeOH and / or DCM) followed by ester hydrolysis using an acid (e.g., TFA) in a solvent (e.g., DCM) provides 1-i. Cyclization of 1-i using standard coupling conditions (e.g., an amide coupling agent (e.g., HATU, HOAt, TBTU, and / or HCTU) with an optional base (e.g., 2,6-lutidine, TEA, or DIPEA) in a solvent (e.g., DCM, NMP, or DMF) provides the desired compound of formula (I).

[0600] It should be understood that in the descriptions and formulae shown above, each group X1, X2, X3, R1, R2, R3, R4, R5, R6, R7, R8, and R9, as well as other variables, are as defined above, unless otherwise indicated. In addition, for synthetic purposes, the compounds of General Schemes 1 and 2 are merely representatives of selected groups to illustrate the general synthetic methods of compounds of Formula (I) as defined herein.

[0601] Methods of using the disclosed compounds

[0602] Another aspect of the present disclosure is directed to a method of modulating PCSK9, comprising administering to a patient in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.

[0603] In another aspect, the present disclosure is directed to methods for inhibiting PCSK9. The methods involve administering to a patient in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.

[0604] Another aspect of the present disclosure relates to a method for treating, preventing, inhibiting or eliminating a disease or disorder in which PCSK9 plays a role. The method comprises administering to a patient in need of treatment for a disease or disorder in which PCSK9 plays a role an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, and a pharmaceutically acceptable carrier.

[0605] Another aspect of the present disclosure relates to a method for treating, preventing, inhibiting or eliminating a disease or disorder associated with the inhibition of PCSK9 in a patient, the method comprising administering to a patient in need thereof an effective amount of a compound having formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, or a pharmaceutical composition comprising a compound having formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, and a pharmaceutically acceptable carrier.

[0606] In another aspect, the present disclosure relates to methods for treating, preventing, inhibiting, or eliminating a disease or disorder mediated by PCSK9. The methods comprise administering to a patient in need of treatment for a disease or disorder mediated by PCSK9 an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.

[0607] Another aspect of the present disclosure relates to a method for treating, preventing, inhibiting or eliminating hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, vascular inflammation, xanthomas, peripheral arterial disease, sepsis, elevated Lp(a), elevated LDL, elevated TRL or elevated triglycerides. The method comprises administering to a patient in need of treatment an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, and a pharmaceutically acceptable carrier.

[0608] In another aspect, the disclosure relates to a method of reducing Lp(a), reducing Lp(a) plasma levels, reducing Lp(a) serum levels, reducing serum TRL or LDL levels, reducing serum triglyceride levels, reducing LDL-C, reducing total plasma apoB concentration, reducing LDL apoB, reducing TRL apoB, or reducing non-HDL-C. The method comprises administering to a patient in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.

[0609] In another aspect, the present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, and a pharmaceutically acceptable carrier, for use in treating, preventing, inhibiting or eliminating a disease or disorder in which PCSK9 plays a role.

[0610] Another aspect of the present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, or a pharmaceutical composition (which comprises a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, and a pharmaceutically acceptable carrier) for treating, preventing, inhibiting or eliminating diseases associated with the inhibition of PCSK9.

[0611] Another aspect of the present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, and a pharmaceutically acceptable carrier, for treating, preventing, inhibiting or eliminating hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, vascular inflammation, xanthomas, peripheral arterial disease, sepsis, elevated Lp(a), elevated LDL, elevated TRL or elevated triglycerides.

[0612] In another aspect, the present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, and a pharmaceutically acceptable carrier, for lowering Lp(a), lowering Lp(a) plasma levels, lowering Lp(a) serum levels, lowering serum TRL or LDL levels, lowering serum triglyceride levels, lowering LDL apoB, lowering TRL apoB, or lowering non-HDL-C.

[0613] Another aspect of the present disclosure relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, and a pharmaceutically acceptable carrier for treating, preventing, inhibiting or eliminating a disease or disorder in which PCSK9 plays a role.

[0614] In another aspect, the present disclosure relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, and a pharmaceutically acceptable carrier in the manufacture of a medicament for inhibiting PCSK9.

[0615] In another aspect, the present disclosure relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, and a pharmaceutically acceptable carrier in the manufacture of a medicament for treating, preventing, inhibiting or eliminating hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, vascular inflammation, xanthomas, peripheral arterial disease, sepsis, elevated Lp(a), elevated LDL, elevated TRL or elevated triglycerides.

[0616] Another aspect of the present disclosure relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, and a pharmaceutically acceptable carrier, in the manufacture of a medicament for lowering Lp(a), lowering Lp(a) plasma levels, lowering Lp(a) serum levels, lowering serum TRL or LDL levels, lowering serum triglyceride levels, lowering LDL apoB, lowering TRL apoB or lowering non-HDL-C.

[0617] In another aspect, the present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, and a pharmaceutically acceptable carrier, for use in the manufacture of a medicament for treating a disease associated with the inhibition of PCSK9.

[0618] Another aspect of the present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, and a pharmaceutically acceptable carrier, for use in the manufacture of a medicament for treating a disease in which PCSK9 plays a role.

[0619] In another aspect, the present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, and a pharmaceutically acceptable carrier, for use in the manufacture of a medicament for treating, preventing, inhibiting or eliminating hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, vascular inflammation, xanthomas, peripheral arterial disease, sepsis, elevated Lp(a), elevated LDL, elevated TRL or elevated triglycerides.

[0620] Another aspect of the present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, and a pharmaceutically acceptable carrier, for use in the manufacture of a medicament for lowering Lp(a), lowering Lp(a) plasma levels, lowering Lp(a) serum levels, lowering serum TRL or LDL levels, lowering serum triglyceride levels, lowering LDL apoB, lowering TRL apoB or lowering non-HDL-C.

[0621] In another aspect, the present disclosure relates to the use of an inhibitor of PCSK9 in the preparation of a medicament for treating, preventing, inhibiting or eliminating hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, peripheral arterial disease, vascular inflammation, elevated Lp(a), elevated LDL, elevated TRL, elevated triglycerides, sepsis or xanthomas.

[0622] Another aspect of the present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, and a pharmaceutically acceptable carrier, for use in treating a PCSK9-mediated disease or disorder.

[0623] Another aspect of the present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, and a pharmaceutically acceptable carrier for use in treating a PCSK9-mediated disease or disorder selected from hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, peripheral arterial disease, vascular inflammation, elevated Lp(a), elevated LDL, elevated TRL, elevated triglycerides, sepsis and xanthomas.

[0624] In another aspect, the present disclosure relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, and a pharmaceutically acceptable carrier, in the manufacture of a medicament for treating a PCSK9-mediated disease or disorder.

[0625] Another aspect of the present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, and a pharmaceutically acceptable carrier, for use in the manufacture of a medicament for treating a PCSK9-mediated disease or disorder.

[0626] In another aspect, the present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, and a pharmaceutically acceptable carrier, for use as a medicament.

[0627] The present disclosure also relates to the use of an inhibitor of PCSK9 in the preparation of a medicament for treating, preventing, inhibiting or eliminating a disease or condition in which PCSK9 plays a role, wherein the medicament comprises a compound having formula (I).

[0628] In another aspect, the present disclosure relates to a method for manufacturing a medicament for treating, preventing, inhibiting or eliminating a disease or condition mediated by PCSK9, wherein the medicament comprises a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, and a pharmaceutically acceptable carrier.

[0629] In some embodiments of the above methods, the PCSK9-mediated disease or disorder, the disease or disorder in which PCSK9 plays a role, the disease or disorder associated with inhibition of PCSK9 in the patient, and the disease associated with inhibition of PCSK9 are selected from hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, peripheral arterial disease, vascular inflammation, elevated Lp(a), elevated LDL, elevated TRL, elevated triglycerides, sepsis, and xanthomas.

[0630] The compound of the present disclosure can be used to reduce or reduce the low-density lipoprotein cholesterol (LDL-C) of an individual in need. An individual may have a continuously elevated LDL-C level. In certain embodiments, the LDL-C plasma level of an individual is always higher than 70 mg / dL, for example, higher than 80 mg / dL, 90 mg / dL, 100 mg / dL, 110 mg / dL, 120 mg / dL, 130 mg / dL, 140 mg / dL, 150 mg / dL, 160 mg / dL, 170 mg / dL, 180 mg / dL or 190 mg / dL, or higher. The compound of the present disclosure can also be used to reduce or reduce non-high-density lipoprotein cholesterol (non-HDL-C) or total cholesterol in an individual in need.

[0631] The present disclosure also relates to methods for improving blood cholesterol markers associated with increased risk of heart disease. These markers include high total cholesterol, high LDL, a high total cholesterol to HDL ratio, and a high LDL to HDL ratio. A total cholesterol level below 200 mg / dL is considered ideal, a cholesterol level between 200 mg / dL and 239 mg / dL is considered borderline high, and a cholesterol level of 240 mg / dL and higher is considered high.

[0632] In another aspect, the present disclosure provides a method of lowering LDL-C, non-HDL-C and / or total cholesterol in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound or pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable carrier as described herein.

[0633] In another embodiment, the present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, or a pharmaceutical composition comprising a compound of formula (I) disclosed herein or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof and a pharmaceutically acceptable carrier, for use in treating diseases including but not limited to hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, peripheral arterial disease, vascular inflammation, elevated Lp(a), elevated LDL, elevated TRL, elevated triglycerides, sepsis and xanthomas.

[0634] In one embodiment, a method for treating a disease or disorder in which PCSK9 plays a role is provided, wherein the disease or disorder includes hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, peripheral arterial disease, vascular inflammation, elevated Lp(a), elevated LDL, elevated TRL, elevated triglycerides, sepsis, and xanthomas, the method comprising administering to a patient suffering from at least one of the diseases or disorders a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.

[0635] The disclosed compounds of the present disclosure can be administered in an effective amount to treat or prevent a disorder and / or prevent its progression in a subject.

[0636] The disclosed compounds of the present disclosure can be administered in an effective amount to treat or prevent a disorder and / or prevent its progression in a subject.

[0637] Administration, pharmaceutical compositions and dosages of disclosed compounds

[0638] Administration of the disclosed compounds can be accomplished via any mode of administration of a therapeutic agent, including systemic or local administration, such as oral, nasal, parenteral, transdermal, subcutaneous, vaginal, buccal, rectal, or topical administration.

[0639] Depending on the intended mode of administration, the disclosed compositions can be in solid, semisolid or liquid dosage forms, such as, for example, injections, tablets, suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, etc., sometimes in unit doses, and consistent with conventional pharmaceutical practice. They can also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous or intramuscular form, and all of the methods used are well known to those skilled in the art of pharmacy.

[0640] Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, and a pharmaceutically acceptable carrier. A pharmaceutically acceptable carrier may further include an excipient, a diluent, or a surfactant. In another embodiment, the composition comprises at least two pharmaceutically acceptable carriers (such as those described herein). The pharmaceutical composition can be formulated for a specific route of administration, such as oral administration, parenteral administration (such as by injection, infusion, transdermal or topical administration) and rectal administration. Topical application may also involve inhalation or intranasal application. The pharmaceutical composition of the present disclosure can be in solid form (including but not limited to capsules, tablets, pills, granules, powders or suppositories) or in liquid form (including but not limited to solutions, suspensions or emulsions). Tablets can be added with a film coating or enteric coating according to methods known in the art. Typically, a pharmaceutical composition is a tablet or gelatin capsule comprising an active ingredient and one or more of the following:

[0641] a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine;

[0642] b) lubricants, for example, silicon dioxide, talc, stearic acid, its magnesium or calcium salts and / or polyethylene glycol; in the case of tablets, also

[0643] c) binders, for example, magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; if desired

[0644] d) disintegrants, for example, starch, agar, alginic acid or its sodium salt or effervescent mixtures; and

[0645] e) Adsorbents, colorants, flavorings and sweeteners.

[0646] Liquid (particularly injectable) compositions can be prepared, for example, by dissolution, dispersion, etc. For example, the disclosed compounds are dissolved in or mixed with a pharmaceutically acceptable solvent (such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, etc.) to form an injectable isotonic solution or suspension. Proteins (such as albumin, chylomicron particles, or serum proteins) can be used to dissolve the disclosed compounds.

[0647] The disclosed compounds may also be formulated as suppositories, which may be prepared in fatty emulsions or suspensions; using polyalkylene glycols (eg, propylene glycol) as carriers.

[0648] Parenteral injectable administration is generally for subcutaneous, intramuscular or intravenous injection and infusion. Injections can be prepared in conventional forms (as liquid solutions or suspensions, or solid forms suitable for dissolution in liquid prior to injection).

[0649] The compositions can be prepared according to conventional mixing, granulating or coating methods, respectively, and the pharmaceutical compositions of the present invention can contain from about 0.1% to about 99%, from about 5% to about 90%, or from about 1% to about 20% of the disclosed compounds by weight or volume of the disclosed compounds.

[0650] The dosage regimen for the disclosed compounds is selected based on a variety of factors, including the type, species, age, weight, sex, and medical condition of the patient; the severity of the condition to be treated; the route of administration; the patient's renal or hepatic function; and the specific disclosed compound used. A physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition.

[0651] When used for the indicated effects, the effective dose range of the disclosed compound, disclosed pharmaceutical composition or disclosed combination is from about 0.5 mg to about 5000 mg of the disclosed compound required for treating the disease. The composition for in vivo or in vitro use can contain about 0.5, 5, 20, 50, 75, 100, 150, 250, 500, 750, 1000, 1250, 2500, 3500 or 5000 mg of the disclosed compound, or a range from one amount to another in the dosage list. In one embodiment, the composition is in the form of a tablet that can be scored. The therapeutically effective dose of a compound, pharmaceutical composition or its combination depends on the species, body weight, age and individual condition, disease or disease or its severity in the treatment of the subject. A physician, clinician or veterinarian with ordinary skills can easily determine the effective amount of each active ingredient necessary for preventing, treating or suppressing a disease or disease progression.

[0652] The above dosage characteristics are demonstrated in vitro and in vivo tests using favorable mammals (e.g., mice, rats, dogs, monkeys) or their separated organs, tissues, and products. The compounds disclosed herein can be administered in vitro in the form of a solution (e.g., an aqueous solution), and enterally, parenterally, advantageously intravenously, for example, as a suspension or in an aqueous solution. The in vitro dose can be between about 10-3 molar and 10-9 molar concentrations. Depending on the route of administration, the therapeutically effective amount in vivo can be between about 0.1-500 mg / kg, or in the range of about 1-100 mg / kg.

[0653] Combination therapy

[0654] The compounds of the present disclosure can be administered in a therapeutically effective amount in combination therapy with one or more therapeutic agents (drug combinations) or modalities (e.g., non-drug therapies). For example, synergy may occur with other cardiovascular agents, antihypertensive agents, coronary vasodilators, and diuretics. When the compounds of the present application are administered in combination with other therapies, the dosage of the co-administered compound will of course vary depending on the type of combined drug used, the specific drug used, the condition being treated, etc.

[0655] The compounds of the present disclosure can be administered simultaneously with one or more other therapeutic agents or before or after the therapeutic agent. The compounds of the present disclosure can be administered separately by the same or different routes of administration, or administered together in the same pharmaceutical composition as other agents. The therapeutic agent is, for example, a chemical compound, peptide, antibody, antibody fragment, or nucleic acid, which, when administered to a patient in combination with the compounds of the present disclosure, has therapeutic activity or enhances therapeutic activity.

[0656] In one embodiment, the present invention provides a product comprising a compound of the present disclosure and at least one other therapeutic agent as a combination preparation for simultaneous, separate or sequential use in therapy. In one embodiment, the therapy is for treating a disease or condition mediated by PCSK9. The product provided as a combination preparation includes a composition comprising a compound of the present disclosure and one or more other therapeutic agents together in the same pharmaceutical composition, or a compound of the present disclosure and one or more other therapeutic agents in separate form (e.g., in the form of a kit).

[0657] In another aspect, the disclosure includes compounds of Formula (I)-(la ... A compound, composition, medicament and compound for use having Formula (I)-(Ia)-(Ib)-(Ic)-(Id)-(Ie)-(If)-(Ig)-(Ih)-(Ii)-(Ij)-(Ik)-(Im)-(Io), a compound according to any one of Examples 1 to 20 or 38, or any embodiment of Formula (I)-(Ia)-(Ib)-(Ic)-(Id)-(Ie)-(If)-(Ig)-(Ih)-(Ii)-(Ij)-(Ik)-(Im)-(Io) or a pharmaceutically acceptable salt thereof as described herein, can be advantageously used in combination with one or more other therapeutic agents.

[0658] Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, a pharmaceutically acceptable carrier and one or more therapeutic agents. The pharmaceutically acceptable carrier may further include an excipient, a diluent, or a surfactant.

[0659] Combination therapy includes further combining with other biologically active ingredients (such as, but not limited to, a second agent, such as, but not limited to, a cardiovascular agent, an adrenergic blocker, an antihypertensive agent, an angiotensin system inhibitor, angiotensin converting enzyme (ACE) inhibitor, a coronary vasodilator, a diuretic or an adrenergic stimulant or a second agent targeting PCSK9) and non-drug therapy (such as, but not limited to, surgery or radiotherapy) to administer the compound to the subject. For example, the compound of the present application can be used in combination with other pharmaceutically active compounds (preferably, compounds that can enhance the effect of the compound of the present application). The compound of the present application can be administered to other drug therapies or treatment modalities simultaneously (as a single preparation or a separate preparation) or sequentially. In general, combination therapy envisions administering two or more drugs during a single cycle or course of treatment.

[0660] In some embodiments, the compounds of the present application can be used in combination with agents known to be beneficial for lowering cholesterol (including LDL-C, non-HDL-C, triglyceride-lowering agents, and total cholesterol) and / or raising HDL-C.

[0661] Exemplary therapeutic agents that can be used in combination with the compounds of the present disclosure include, but are not limited to, hypolipidemic agents, niacin and its analogs, bile acid sequestrants, thyroid hormone mimetics, thyroid hormone receptor (THR) β-selective agonists, microsomal triglyceride transfer protein (MTP) inhibitors, acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) inhibitors, Niemann Pick C1-like 1 (NPC1-L1) inhibitors, agonists of ATP-binding cassette (ABC) proteins G5 or G8, inhibitory nucleic acids targeting PCSK9, inhibitory nucleic acids targeting apoB100, apoA-I upregulators / inducers, ABCA1 stabilizers or inducers, phospholipid transfer protein (PLTP) inhibitors, fish oils, anti-diabetic agents, anti-obesity agents, peroxisome proliferator-activated receptor agonists, ATP citrate lyase (ACL) inhibitors, and anti-hypertensive agents.

[0662] Examples of lipid-lowering agents that can be used in combination with the compounds of the present disclosure include, but are not limited to, HMG-CoA reductase inhibitors, squalene synthase inhibitors, LXR agonists, FXR agonists, fibrates, cholesterol absorption inhibitors, nicotinic acid bile acid binding resins, niacin and other GPR109 agonists, and aspirin.

[0663] HMG-CoA reductase inhibitors (i.e., statins) are a class of drugs used to reduce cholesterol levels by inhibiting HMG-CoA reductase, which plays an important role in the production of cholesterol in the liver. Elevated cholesterol levels are associated with cardiovascular diseases, and therefore statins can be used to prevent these diseases. Exemplary statins include, but are not limited to, atorvastatin, cerivastatin, mevastatin, dalvastatin, dihydromevastatin, fluvastatin, fluvastatin, lovastatin, pitavastatin, mevastatin, pravastatin, rivastatin, simvastatin, and its pharmaceutically acceptable salt.

[0664] Fibrates or fibric acid derivatives reduce triglycerides and increase HDL cholesterol. They may have little effect on LDL cholesterol. For example, gemfibrozil or fenofibrate can be used for people whose triglyceride levels are very high or whose HDL levels are low and whose triglyceride levels are high. Gemfibrozil can be used to reduce the risk of heart attack in patients with coronary artery disease (CAD) with low HDL and high triglycerides. Examples of fibrates include but are not limited to clofibrate, gemfibrozil, fenofibrate, ciprofibrate and bezafibrate.

[0665] Cholesterol absorption inhibitors are a class of compounds that prevent cholesterol from being absorbed from the small intestine into the circulation and thereby lower the concentration of plasma LDL-C. Elevated cholesterol levels are associated with an increased risk of CVD; therefore, cholesterol absorption inhibitors are used with the goal of reducing CVD risk. A non-limiting example of a cholesterol absorption inhibitor is ezetimibe, previously known as "Sch-58235." Another example is Sch-48461. Both compounds were developed by Schering-Plough.

[0666] Examples of bile acid sequestrants that can be used in combination with the compounds of the present disclosure include, but are not limited to, cholestyramine, colestipol, and colesvelam.

[0667] A non-limiting example of a thyroid hormone mimetic that can be used in combination with the compounds of the present disclosure is compound KB2115.

[0668] A non-limiting example of a thyroid hormone receptor (THR) beta-selective agonist that can be used in combination with the compounds of the present disclosure is MGL-3196.

[0669] DGAT is an enzyme that catalyzes the final step in triacylglycerol biosynthesis. DGAT catalyzes the coupling of 1,2-diacylglycerol with fatty acyl-CoA, producing coenzyme A and triacylglycerol. Two enzymes that exhibit DGAT activity have been identified: DGAT1 (acyl-CoA-diacylglycerol acyltransferase 1, see Cases et al., Proc. Natl. Acad. Sci. [Proceedings of the National Academy of Sciences of the United States of America]. 95: 13018-13023, 1998) and DGAT2 (acyl-CoA-diacylglycerol acyltransferase 2, see Cases et al., J. Biol. Chem. [Journal of Biological Chemistry] 276: 38870-38876, 2001). DGAT1 and DGAT2 have no significant protein sequence homology. Importantly, DGAT1 knockout mice are protected from high-fat diet-induced weight gain and insulin resistance (Smith et al., Nature Genetics 25:87-90, 2000). The phenotype of DGAT1 knockout mice suggests that DGAT1 inhibitors may be useful for treating obesity and obesity-related complications. DGAT1 inhibitors useful in the described combinations are generally and specifically the compounds and analogs disclosed in, for example, WO 2007 / 126957 and WO 2009 / 040410, particularly in the compound claims, as well as the final products of the working examples, the subject matter of the final products, the pharmaceutical formulations, and the claims.

[0670] Examples of DGAT1 inhibitors suitable for use in combination with the compounds of the present disclosure include, but are not limited to, {4-[4-(3-methoxy-5-phenylamino-pyridin-2-yl)-phenyl]-cyclohexyl}-acetic acid, (4-{4-[5-(1-methyl-1H-pyrazol-3-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-acetic acid, (4-{4-[5-(5-fluoro-6-methoxy-pyridin-3-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-acetic acid, (4-{5-[5-(6-trifluoromethyl-pyridin-3-ylamino)-pyridin-2-yl]-spirocyclohexylidene-1,1′-indanyl}-acetic acid, (4-{4-[5-(1-methyl-1H-pyrazol-3-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-acetic acid, -2-yl]-phenyl}-cyclohexyl)-acetic acid, 4-(4-{4-[2-(3-chlorophenylamino)-oxazol-5-yl]-phenyl}-cyclohexyl)-butyric acid, (4-{4-[5-(6-trifluoromethyl-pyridin-3-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-acetic acid, (6-{4-[4-(2H-tetrazol-5-ylmethyl)-cyclohexyl]-phenyl}-pyridazin-3-yl)-(6-trifluoromethyl-pyridin-3-yl)-amine, 3-(4-{4-[6-(6-trifluoromethyl-pyridin-3-ylamino)-pyridazin-3-yl]-phenyl}-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one, (1-{4-[6-(3-trifluoromethyl-phenylamino)-oxazol-5-yl]-phenyl}-cyclohexyl)-acetic acid, (6-{4-[4-(2H-tetrazol-5-ylmethyl)-cyclohexyl]-phenyl}-pyridazin-3-yl)-(6-trifluoromethyl-pyridin-3-yl)-amine, phenyl}-piperidin-4-yl)-acetic acid, (4-{4-[4-methyl-6-(6-trifluoromethyl-pyridin-3-ylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-acetic acid, (4-{4-[5-(6-trifluoromethyl-pyridin-3-ylamino)-pyrazin-2-yl]-phenyl}-cyclohexyl)-acetic acid, 6-[5-(4-chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-2-(2,6-dichloro-phenyl)-1H-benzimidazole, 6-(5-cyclohexyl-[1,3,4]oxadiazol-2-yl)-2-(2,6-dichloro-phenyl)-1H-benzimidazole, 6-(5-butyl-[1,3,4]oxadiazol-2-yl)- 2-(2,6-dichloro-phenyl)-1H-benzimidazole, 2-(2,6-dichloro-phenyl)-6-[5-(5-methyl-pyridin-3-yl)-[1,3,4]oxadiazol-2-yl]-1H-benzimidazole, 6-[5-(4-chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-2-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-1H-benzimidazole, 6-[5-(4-chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-2-(3,5-dichloro-pyridin-4-yl)-1H-benzimidazole, 3-(4-{5-[5-(4-methoxy-phenyl)-[1,3,4]oxadiazol-2-yl]-1H-benzimidazole-3,5-dimethyl-phenyl)-2,2-dimethyl-propionic acid, 3-(4-{6-[5-(4-methoxy-phenyl)-[1,3,4]oxadiazol-2-yl]-1H-benzimidazol-2-yl}-3,5-dimethyl-phenyl)-propionic acid, 3-(4-{6-[5-(4-methoxyphenylamino)-[1,3,4]oxadiazol-2-yl]-1H-benzimidazol-2-yl}-3,5-dimethylphenyl)-propionic acid, [3-(4-{6-[5-(4-chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-1H-benzimidazol-2-yl}-3,5-dimethyl-phenyl)-propyl]-phosphine Acid, 2-(2,6-dichloro-phenyl)-6-(4,5-diphenyl-oxazol-2-yl)-1H-benzimidazole, (4-{6-[5-(4-chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-1H-benzimidazole-2-yl}-3,5-dimethyl-phenoxy)-acetic acid, 2-(2,6-dichloro-phenyl)-6-(5-pyrrolidin-1-yl-[1,3,4]oxadiazol-2-yl)-1H-benzimidazole, and 3,5-dimethyl-4-{6-[5-(4-trifluoromethyl-phenylamino)-[1,3,4]oxadiazol-2-yl]-1H-benzimidazole-2-yl}-phenol.

[0671] A non-limiting example of a Niemann-Pick C1-like 1 (NPC1-L1) inhibitor that can be used in combination with the compounds of the present disclosure is ezetimibe.

[0672] Apolipoprotein AI is a protein encoded by the APOA1 gene in humans. It plays a specific role in lipid metabolism. Apolipoprotein AI is the major protein component of high-density lipoprotein (HDL) in plasma. Chylomicrons secreted by enterocytes also contain ApoA-I, but are rapidly transferred to HDL in the blood. The protein promotes the efflux of cholesterol from tissues to the liver for secretion. It is a cofactor for lecithin cholesterol acyltransferase (LCAT), which is responsible for the formation of most plasma cholesterol esters. As assessed by intravascular ultrasound, infusion of apoA-I variants in humans has been shown to regress atherosclerotic plaques; thus, apoA-I reduces CVD risk and has the ability to slow the progression and induce regression of atherosclerosis. A non-limiting example of an apoA-I upregulator / inducer is RVX208.

[0673] ATP-binding cassette transporter ABCA1 (member 1 of the human transporter subfamily ABCA), also known as cholesterol efflux regulatory protein (CERP), is a protein encoded by the ABCA1 gene in humans. This transporter is a major regulator of cellular cholesterol and phospholipid homeostasis. A non-limiting example of an ABCA1 modulator is probucol. Probucol lowers blood cholesterol levels by increasing the rate of LDL catabolism. In addition, probucol can inhibit cholesterol synthesis and delay cholesterol absorption. Probucol is a powerful antioxidant that inhibits the oxidation of cholesterol in LDL; this slows the formation of foam cells that contribute to atherosclerotic plaques.

[0674] Liver X receptors (LXRs) are members of the nuclear receptor family of transcription factors and are closely related to nuclear receptors such as PPARs, FXRs, and RXRs. Liver X receptors (LXRs) are important regulators of cholesterol, fatty acid, and glucose homeostasis. LXR agonists are effective in treating atherosclerosis, diabetes, inflammation, and Alzheimer's disease in mouse models. Treatment with LXR agonists (including but not limited to hypocholamide, T0901317, GW3965, or N,N-dimethyl-3-β-hydroxycholesteramide (DMHCA)) reduces serum and liver cholesterol levels and inhibits the progression of atherosclerosis in mouse disease models. Examples of LXR agonists include but are not limited to GW3965 (a synthetic nonsteroidal liver X receptor (LXR) agonist / activator) and T0901317 (a dual LXR and FXR agonist).

[0675] The farnesoid X receptor (FXR), also known as NR1H4 (nuclear receptor subfamily 1, group H, member 4), is a nuclear hormone receptor that has activity similar to other steroid receptors (such as estrogen or progesterone), but is more similar in form to PPARs, LXRs, and RXRs. Activation of the nuclear receptor FXR is known to improve hyperglycemia and hyperlipidemia. A non-limiting example of an FXR agonist is GW4064 (3-(2,6-dichlorophenyl)-4-(3'-carboxy-2-chlorostilbene-4-yl)oxymethyl-5-isopropylisoxazole).

[0676] Phospholipid transfer protein (PLTP) is a protein encoded by the PLTP gene in humans. The protein encoded by this gene is one of at least two lipid transfer proteins found in human plasma, the other being CETP. The encoded protein transfers phospholipids from triglyceride-rich lipoproteins to HDL. In addition to regulating HDL particle size, this protein may also participate in cholesterol metabolism. At least two transcript variants encoding different isoforms of this gene have been identified. Because PLTP affects both triglyceride-rich lipoprotein and HDL metabolism, modulating this transfer protein has the potential to alter cardiovascular disease risk.

[0677] Fish oil is derived from the tissues of oily fish. Fish oil contains the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are precursors to eicosanoids known to have many health benefits. The use of fish oil and other omega-3 sources is strongly recommended in the following situations: hypertriglyceridemia, secondary cardiovascular disease, and prevention of hypertension. For example, Used with a low-fat and low-cholesterol diet, it can reduce very high triglycerides (fats) in the blood. Examples of omega-3 fatty acids that can be used in combination with the compounds of the present disclosure include, but are not limited to and (icosapent ethyl).

[0678] Examples of antidiabetic agents that can be used in combination with the compounds of the present disclosure include, but are not limited to, insulin, insulin derivatives and mimetics; and insulin secretagogues, such as sulfonylureas; insulinotropic sulfonylurea receptor ligands, such as meglitinides, such as nateglinide and repaglinide; protein tyrosine phosphatase-1B (PTP-1B) inhibitors, including but not limited to PTP-112; GSK3 (glycogen synthase kinase-3) inhibitors, including but not limited to SB-517955, SB-4195052, SB-216763, NN-57-05441 and NN-57-05445; RXR ligands, including but not limited to GW-0791 and AGN-194204; sodium-dependent glucose co-transporter inhibitors, including but not limited to T-1095; glycogen phosphorylase A inhibitors, including but not limited to BAY R3401; biguanides, including but not limited to metformin; α-glucosidase inhibitors, including but not limited to acarbose; GLP-1 (glucagon-like peptide-1), GLP-1 analogs (including but not limited to exendin-4) and GLP-1 mimetics; and DPPIV (dipeptidyl peptidase IV) inhibitors, including but not limited to vildagliptin.

[0679] Examples of sulfonylureas include, but are not limited to, tolbutamide, chlorpropamide, tolsulfonylamine, acetophenonesulfonylcyclohexamide, 4-chloro-N-[(1-pyrrolidinylamino)carbonyl]-benzenesulfonamide (glyburide), glyburide (glyburide), gliclazide, 1-butyl-3-aminobenzenesulfonyl urea, amoxicillin, glibenclamide, glipizide, gliquidone, glipizide, glitazole, glibuzole, glyhexamide, glipizide, gliperamide, tolbutamide, amaryl and tolylcyclamide, or pharmaceutically acceptable salts thereof.

[0680] DPP-IV (Dipeptidyl peptidase IV) is responsible for inactivating GLP-1. More specifically, DPP-IV produces a GLP-1 receptor antagonist and thereby shortens the physiological response to GLP-1. GLP-1 is the primary stimulator of pancreatic insulin secretion and has a direct beneficial effect on glucose disposal.

[0681] DPP-IV inhibitors can be peptides or preferably non-peptides. Examples of DPP-IV inhibitors also include, but are not limited to, those disclosed generally and specifically in WO 98 / 19998, DE 196 16 486A1, WO 00 / 34241 and WO 95 / 15309 (in each case, particularly in the compound claims), and the end products of the working examples, the subject matter of the end products, the pharmaceutical preparations and the claims are hereby incorporated into the present ...

Claims

1. A compound selected from: (3R,7S,10S,13R)-6-(4-chloro-2-(4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-3-(pyridin-2-ylmethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3S,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7-methyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; 2-(((3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7,12-dimethyl-2,5,8,11-tetraoxo-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-3-yl)methyl)pyridine 1-oxide; (3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7-methyl-3-((6-methylpyridin-2-yl)methyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3S,7S,10S,13R)-6-(4-chloro-2-(4-(2-((cyclobutylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3S,7S,10S,13R)-6-(2-(4-(2-((tert-butylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-4-chlorobenzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7-methyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3S,7S,10S,13R)-6-(4-chloro-2-(4-(4-((dimethylamino)methyl)-5-methyl-1H-imidazol-1-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-3-((S)-2,3-dihydro-1H-inden-1-yl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3S,7S,10S,13R)-6-(4-chloro-2-((6-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)pyridin-3-yl)oxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7-methyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3S,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7,12-dimethyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3R,7S,10S,13R)-6-(4-chloro-2-fluoro-6-(4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-3-(cyclopropylmethyl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3R,7S,10S,13R)-3-benzyl-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3S,7S,10S,13R)-6-(4-chloro-2-((6-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)pyridin-3-yl)oxy)benzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7,12-dimethyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7,12-dimethyl-3-((6-methylpyridin-2-yl)methyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3R,7S,10S,13R)-6-(4-chloro-2-fluoro-6-(4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7,12-dimethyl-3-((6-methylpyridin-2-yl)methyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3S,7S,10S,13R)-6-(4-chloro-2-fluoro-6-(4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3S,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-3-((R)-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3R,7S,10S,13R)-3-benzyl-6-((5-chloro-3-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)pyridin-2-yl)methyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7,12-dimethyl-3-(pyridin-2-ylmethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-3-(pyridin-3-ylmethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3S,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7,12-dimethyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7-methyl-3-(pyridin-2-ylmethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3S,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7,12-dimethyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7-methyl-3-(pyridin-3-ylmethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3R,7S,10S,13R)-6-(4-chloro-2-((6-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)pyridin-3-yl)oxy)benzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7,12-dimethyl-3-((6-methylpyridin-2-yl)methyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3R,7S,10S,13R)-3-benzyl-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-3-fluorobenzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3R,7S,10S,13R)-6-(4-chloro-2-(4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-3-ethyl-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3R,7S,10S,13R)-3-benzyl-6-(4-chloro-2-((6-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)pyridin-3-yl)oxy)benzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7,12-dimethyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3S,7S,10S,13R)-6-(2-(4-(2-(azetidin-1-ylmethyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-4-chloro-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3S,7S,10S,13R)-6-((5-chloro-3-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)pyridin-2-yl)methyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7-methyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3R,7S,10S,13R)-6-(4-chloro-2-(4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-((difluoromethoxy)methyl)-7-methyl-3-(pyridin-2-ylmethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3S,7S,10S,13R)-6-(4-chloro-2-((5-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)pyridin-2-yl)oxy)benzyl)-13-(4-chlorobenzyl)-3-((R)-2,3-dihydro-1H-inden-1-yl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3S,7S,10S,13R)-6-(4-chloro-2-((5-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)pyridin-2-yl)oxy)benzyl)-13-(4-chlorobenzyl)-3-((S)-2,3-dihydro-1H-inden-1-yl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7,12-dimethyl-3-(pyridin-2-ylmethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3S,7S,10S,13R)-6-(2-(4-(2-(azetidin-1-ylmethyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-4-chlorobenzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7-methyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-3-(2,6-difluorobenzyl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7-methyl-3-(oxazol-2-ylmethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-(2,2,2-trifluoroethoxy)benzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7,12-dimethyl-3-(2,4,6-trifluorobenzyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7,12-dimethyl-3-((6-methylpyridin-2-yl)methyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3R,7S,10S,13R)-3-benzyl-6-(4-chloro-2-fluoro-6-(4-(5-methyl-4-(pyrrolidin-1-ylmethyl)-1H-imidazol-1-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3R,7S,10S,13R)-3-((E)-but-2-en-1-yl)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-3-((6-methylpyridin-2-yl)methyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-3-(cyclopropylmethyl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3R,7S,10S,13R)-3-benzyl-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)-3-fluorophenoxy)benzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7-methyl-3-((1-methyl-6-oxo-1,6-dihydropyridin-2-yl)methyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3S,7S,10S,13R)-6-(4-chloro-2-(4-(2-((cyclobutylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7-methyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-3-(2,4,6-trifluorobenzyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3R,7S,10S,13R)-6-(4-chloro-2-(4-(1-methyl-2-(morpholinomethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-3-(pyridin-3-ylmethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-3-(2,3,4-trifluorobenzyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3S,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-3-((S)-2,3-dihydro-1H-inden-1-yl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3R,7S,10S,13R)-3-benzyl-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-3-propyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3R,7S,10S,13R)-3-benzyl-6-(4-chloro-2-((6-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)pyridin-3-yl)oxy)benzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3R,7S,10S,13R)-3-benzyl-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7,12-dimethyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3R,7S,10S,13R)-3-benzyl-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-5-fluorobenzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3S,7S,10S,13R)-13-(4-chlorobenzyl)-3-((S)-2,3-dihydro-1H-inden-1-yl)-6-(2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3R,7S,10S,13R)-3-benzyl-6-(4-chloro-2-(4-(5-((dimethylamino)methyl)-4-methyl-4H-1,2,4-triazol-3-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7,12-dimethyl-3-(pyridin-2-ylmethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3S,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-3-(2,2-difluoroethyl)-10-(hydroxymethyl)-7-methyl-1,4,6,9,12-pentazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3R,7S,10S,13R)-3-benzyl-6-(4-chloro-2-(4-(2-(((S)-3-hydroxypyrrolidin-1-yl)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3S,7S,10S,13R)-3-benzyl-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-1,4,6,9,12-pentazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3R,7S,10S,13R)-3-benzyl-6-(4-chloro-2-(4-(2-((4-hydroxypiperidin-1-yl)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-3-(4-(trifluoromethyl)benzyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-3-ethyl-10-(methoxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3S,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-((S)-1-hydroxyethyl)-7-methyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3R,7S,10S,13R)-3-benzyl-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7,12-dimethyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; 2-(((3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-2,5,8,11-tetraoxo-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-3-yl)methyl)pyridine 1-oxide; (3S,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-3-isopropyl-7-methyl-1,4,6,9,12-pentazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3S,7S,10S,13R)-6-(4-chloro-2-(4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-3-((R)-2,3-dihydro-1H-inden-1-yl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3S,7S,10S,13R)-6-(4-chloro-2-(4-(1-methyl-2-(1-methylazetidin-3-yl)-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-3-((S)-2,3-dihydro-1H-inden-1-yl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3S,7S,10S,13R)-6-(4-chloro-2-(4-(2-((R)-1-(dimethylamino)ethyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-3-((S)-2,3-dihydro-1H-inden-1-yl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3R,7S,10S,13R)-3-benzyl-6-(4-chloro-2-((6-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)pyridin-3-yl)oxy)benzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7,12-dimethyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3R,7S,10S,13R)-3-benzyl-6-(4-chloro-2-(4-(2-(((S)-3-(dimethylamino)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3S,7S,10S,13R)-13-(4-chlorobenzyl)-3-((S)-2,3-dihydro-1H-inden-1-yl)-6-(2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-4-fluorobenzyl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3S,7S,10S,13R)-13-(4-chlorobenzyl)-3-((S)-2,3-dihydro-1H-inden-1-yl)-6-(2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-5-fluorobenzyl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3S,7S,10S,13R)-6-(4-chloro-2-(4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-3-((S)-2,3-dihydro-1H-inden-1-yl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3R,7S,10S,13R)-3-benzyl-13-(4-chlorobenzyl)-6-(2,4-difluoro-6-(4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3R,7S,10S,13R)-3-benzyl-6-(4-chloro-2-(4-(1-methyl-2-((4-methylpiperazin-1-yl)methyl)-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3S,7S,10S,13R)-6-(4-chloro-2-(4-(1-methyl-2-(1-methyl-2,5-dihydro-1H-pyrrol-3-yl)-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-3-((S)-2,3-dihydro-1H-inden-1-yl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3S,7S,10S,13R)-3-benzyl-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-4-oxa-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3R,7S,10S,13R)-3-benzyl-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7,12-dimethyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-3-(3-(trifluoromethyl)benzyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (2S,5S,8R,12S)-1-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-8-(4-chlorobenzyl)-5-(hydroxymethyl)-2,7,10-trimethyl-12-((1R,3S)-3-methyl-2,3-dihydro-1H-inden-1-yl)-1,4,7,10-tetraazacyclotetradecane-3,6,11,14-tetraone; (3S,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7,12-dimethyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3S,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3S,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-3-((S)-2,3-dihydro-1H-inden-1-yl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3R,7S,10S,13R)-3-benzyl-6-((5-chloro-3-((6-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)pyridin-3-yl)oxy)pyridin-2-yl)methyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7,12-dimethyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (2S,5S,8R,12S)-1-(4-chloro-2-(4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-8-(4-chlorobenzyl)-12-((R)-2,3-dihydro-1H-inden-1-yl)-5-(hydroxymethyl)-2,7,10-trimethyl-1,4,7,10-tetraazacyclotetradecane-3,6,11,14-tetraone; (3R,7S,10S,13R)-3-benzyl-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)-2-fluorophenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3S,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-ethyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (2S,5S,8R,12R)-12-benzyl-1-(4-chloro-2-(4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-8-(4-chlorobenzyl)-5-(hydroxymethyl)-2,7-dimethyl-1,4,7,10-tetraazacyclotetradecane-3,6,11,14-tetraone; (3S,7S,10S,13R)-13-(4-chlorobenzyl)-3-((S)-2,3-dihydro-1H-inden-1-yl)-6-(2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-4-(trifluoromethyl)benzyl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (2S,5S,8R,12S)-1-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-8-(4-chlorobenzyl)-12-((R)-2,3-dihydro-1H-inden-1-yl)-5-(hydroxymethyl)-2,7,10-trimethyl-1,4,7,10-tetraazacyclotetradecane-3,6,11,14-tetraone; (2S,5S,8R,12R)-12-benzyl-1-(4-chloro-2-(4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-8-(4-chlorobenzyl)-5-(methoxymethyl)-2,7-dimethyl-1,4,7,10-tetraazacyclotetradecane-3,6,11,14-tetraone; (2S,5S,8R,12S)-1-(4-chloro-2-(4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-8-(4-chlorobenzyl)-5-(hydroxymethyl)-2,7,10-trimethyl-12-((1R,3S)-3-methyl-2,3-dihydro-1H-inden-1-yl)-1,4,7,10-tetraazacyclotetradecane-3,6,11,14-tetraone; (3R,7S,10S,13R)-6-(4-chloro-2-((6-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)pyridin-3-yl)oxy)benzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7,12-dimethyl-3-(pyridin-2-ylmethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3S,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-3-((S)-2,3-dihydro-1H-inden-1-yl)-10-(methoxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3S,7S,10S,13R)-6-(4-chloro-2-(4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-3-((R)-2,3-dihydro-1H-inden-1-yl)-10-(methoxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3S,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-((R)-1-hydroxyethyl)-7-methyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3R,7S,10S,13R)-3-benzyl-13-(4-chlorobenzyl)-6-(2,4-dichloro-6-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-3,7,12-trimethyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3S,10S,13R)-6-(5-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-3-((S)-2,3-dihydro-1H-inden-1-yl)-10-(hydroxymethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-3-((S)-2,3-dihydro-1H-inden-1-yl)-10-(hydroxymethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (2S,5S,8R,12S)-1-(4-chloro-2-(4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-8-(4-chlorobenzyl)-12-((R)-2,3-dihydro-1H-inden-1-yl)-5-(methoxymethyl)-2,7,10-trimethyl-1,4,7,10-tetraazacyclotetradecane-3,6,11,14-tetraone; (2S,5S,8R,12S)-1-(4-chloro-2-(4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-8-(4-chlorobenzyl)-12-((R)-2,3-dihydrobenzofuran-3-yl)-5-(hydroxymethyl)-2,7,10-trimethyl-1,4,7,10-tetraazacyclotetradecane-3,6,11,14-tetraone; (2S,5S,8R,12S)-1-(4-chloro-2-(4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-8-(4-chlorobenzyl)-5-(hydroxymethyl)-12-((R)-7-methoxy-2,3-dihydrobenzofuran-3-yl)-2,7,10-trimethyl-1,4,7,10-tetraazacyclotetradecane-3,6,11,14-tetraone; (3S,7S,10S,13R)-3-benzyl-6-(4-chloro-2-(4-(2-((2-(2-ethoxyethoxy)ethoxy)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-1,4,6,9,12-pentazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3R,7S,10S,13R)-3-benzyl-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-7-(2-fluoroethyl)-10-(methoxymethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (2S,5S,8R,12R)-12-benzyl-1-(4-chloro-2-(3,5-difluoro-4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-8-(4-chlorobenzyl)-5-(hydroxymethyl)-2,7,10-trimethyl-1,4,7,10-tetraazacyclotetradecane-3,6,11,14-tetraone; (2S,5S,8R,12S)-1-(4-chloro-2-(4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-8-(4-chlorobenzyl)-5-(hydroxymethyl)-2,7,10-trimethyl-12-((R)-1-phenylethyl)-1,4,7,10-tetraazacyclotetradecane-3,6,11,14-tetraone; (2S,5S,8R,12R)-12-benzyl-1-(4-chloro-2-(4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-8-(4-chlorobenzyl)-5-(hydroxymethyl)-2,7,10-trimethyl-1,4,7,10-tetraazacyclotetradecane-3,6,11,14-tetraone; (3R,7S,10S,13R)-3-benzyl-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-((S)-1-hydroxyethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (2S,5S,8R,12S)-1-(4-chloro-2-(4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-8-(4-chlorobenzyl)-12-((R)-7-methoxy-2,3-dihydrobenzofuran-3-yl)-5-(methoxymethyl)-2,7,10-trimethyl-1,4,7,10-tetraazacyclotetradecane-3,6,11,14-tetraone; (2S,5S,8R,12S)-1-(4-chloro-2-(4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-8-(4-chlorobenzyl)-12-((R)-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl)-5-(methoxymethyl)-2,7,10-trimethyl-1,4,7,10-tetraazacyclotetradecane-3,6,11,14-tetraone; (2S,5S,8R,12R)-1-(4-chloro-2-(4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)-6-(2,2,2-trifluoroethoxy)benzyl)-8-(4-chlorobenzyl)-12-ethyl-5-(hydroxymethyl)-2,7-dimethyl-1,4,7,10-tetraazacyclotetradecane-3,6,11,14-tetraone; (2S,5S,8R,12S)-1-(4-chloro-2-(4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-8-(4-chlorobenzyl)-10-(3,3-difluoropropyl)-12-((R)-2,3-dihydro-1H-inden-1-yl)-5-(methoxymethyl)-2,7-dimethyl-1,4,7,10-tetraazacyclotetradecane-3,6,11,14-tetraone; (2S,5S,8R,12R)-12-benzyl-1-(4-chloro-2-(4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-8-(4-chlorobenzyl)-5-(methoxymethyl)-2,7,10-trimethyl-1,4,7,10-tetraazacyclotetradecane-3,6,11,14-tetraone; (2S,5S,8R,12S)-1-(4-chloro-2-(4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-8-(4-chlorobenzyl)-12-((R)-2,3-dihydro-1H-inden-1-yl)-5-(methoxymethyl)-2,7-dimethyl-10-((1-methylcyclopropyl)methyl)-1,4,7,10-tetraazacyclotetradecane-3,6,11,14-tetraone; (2S,5S,8R,12R)-12-benzyl-1-(4-chloro-2-(4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-8-(4-chlorobenzyl)-10-(3-(dimethylamino)propyl)-5-(methoxymethyl)-2,7-dimethyl-1,4,7,10-tetraazacyclotetradecane-3,6,11,14-tetraone; (2S,5S,8R,12R)-12-benzyl-1-(4-chloro-2-(3,5-difluoro-4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-8-(4-chlorobenzyl)-5-(methoxymethyl)-2,7,10-trimethyl-1,4,7,10-tetraazacyclotetradecane-3,6,11,14-tetraone; (2S,5S,8S,12S)-8-(4-chlorobenzyl)-12-((S)-2,3-dihydro-1H-inden-1-yl)-1-(2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-4-ethylbenzyl)-5-(hydroxymethyl)-2,7,10-trimethyl-1,4,7,10-tetraazacyclotetradecane-3,6,11,14-tetraone; (2S,5S,8R,12S)-8-(4-chlorobenzyl)-12-((S)-2,3-dihydro-1H-inden-1-yl)-1-(2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-4-ethylbenzyl)-5-(hydroxymethyl)-2,7,10-trimethyl-1,4,7,10-tetraazacyclotetradecane-3,6,11,14-tetraone; (3R,7S,10S,13R)-3-benzyl-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,8,11-trione; (2S,5R,8R,12S)-8-(4-chlorobenzyl)-12-((S)-2,3-dihydro-1H-inden-1-yl)-1-(2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-4-ethylbenzyl)-5-(hydroxymethyl)-2,7,10-trimethyl-1,4,7,10-tetraazacyclotetradecane-3,6,11,14-tetraone; (3R,7S,10R,13R)-3-benzyl-6-(4-chloro-2-((6-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)pyridin-3-yl)oxy)benzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3S,10S,13R)-13-(4-chlorobenzyl)-3-((S)-2,3-dihydro-1H-inden-1-yl)-6-(4-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-2-fluorobenzyl)-10-(hydroxymethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3S,7S,10S,13R)-13-(4-chlorobenzyl)-3-((S)-2,3-dihydro-1H-inden-1-yl)-6-(4-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-2-fluorobenzyl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (2S,5S,8R,12R)-1-(4-chloro-2-(4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-8-(4-chlorobenzyl)-12-ethyl-5-(hydroxymethyl)-2,7-dimethyl-1,4,7,10-tetraazacyclotetradecane-3,6,11,14-tetraone; (2S,5S,8R,12S)-1-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-8-(4-chlorobenzyl)-12-((R)-2,3-dihydro-1H-inden-1-yl)-5-(methoxymethyl)-7,10-dimethyl-2-(2-morpholinoethyl)-1,4,7,10-tetraazacyclotetradecane-3,6,11,14-tetraone; (2S)-N-((3R,8S,11R)-3-benzyl-11-(4-chlorobenzyl)-10-methyl-2,5,9-trioxa-6-oxa-1,10-diazabicyclo[9.3.1]pentadecan-8-yl)-2-((4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)amino)propanamide; (2S,5S,8R,12S)-1-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-8-(4-chlorobenzyl)-12-((R)-2,3-dihydro-1H-inden-1-yl)-5-(methoxymethyl)-7,10-dimethyl-2-(3-morpholinopropyl)-1,4,7,10-tetraazacyclotetradecane-3,6,11,14-tetraone; (2S,5S,8R,12R)-1-(4-chloro-2-(4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-8-(4-chlorobenzyl)-12-ethyl-5-(hydroxymethyl)-2,7,10-trimethyl-1,4,7,10-tetraazacyclotetradecane-3,6,11,14-tetraone; (2S,5S,8R,12R)-12-benzyl-1-(4-chloro-2-(4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-8-(4-chlorobenzyl)-2,7,10-trimethyl-5-(2-oxapropyl)-1,4,7,10-tetraazacyclotetradecane-3,6,11,14-tetraone; (2S)-N-((3S,8R,11R)-8-Benzyl-11-(4-chlorobenzyl)-10-methyl-2,6,9-trioxa-5-oxa-1,10-diazabicyclo[9.3.1]pentadecan-3-yl)-2-((4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)amino)propanamide; (2S,5S,8R,12S)-1-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-8-(4-chlorobenzyl)-12-((R)-2,3-dihydro-1H-inden-1-yl)-5-(methoxymethyl)-7,10-dimethyl-2-(4-morpholinobutyl)-1,4,7,10-tetraazacyclotetradecane-3,6,11,14-tetraone; (2S,5S,8R,12S)-2-(3-(azetidin-1-yl)-3-oxapropyl)-1-(4-chloro-2-(4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-8-(4-chlorobenzyl)-12-((R)-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl)-5-(methoxymethyl)-7,10-dimethyl-1,4,7,10-tetraazacyclotetradecane-3,6,11,14-tetraone; (3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-3-isopropyl-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (2S,5S,8R,12R)-1-(4-chloro-2-(4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-8-(4-chlorobenzyl)-12-(dimethylamino)-5-(methoxymethyl)-2,7,10-trimethyl-1,4,7,10-tetraazacyclotetradecane-3,6,11,14-tetraone; 2-((2S,5S,8R,12R)-12-benzyl-1-(4-chloro-2-(4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-8-(4-chlorobenzyl)-2,7,10-trimethyl-3,6,11,14-tetraoxo-1,4,7,10-tetraazacyclotetradec-5-yl)acetic acid; (3S,7S,10S,13R)-6-(2-(4-(2-((tert-butylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-4-chloro-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7,12-dimethyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3S,7S,10S,13R)-6-(2-(4-(2-((tert-butyl(methyl)amino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-4-chloro-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7-methyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3S,7S,10S,13R)-6-(2-(4-(2-((tert-butylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-4-chloro-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7-methyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3S,7S,10S,13R)-6-(4-chloro-2-(4-(2-((cyclobutyl(methyl)amino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3S,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-3-cyclobutyl-10-(methoxymethyl)-7,12-dimethyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3S,7S,10S,13R)-6-(2-(4-(2-((tert-butyl(methyl)amino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-4-chloro-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7,12-dimethyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3R,7S,10S,13R)-6-(2-(4-(2-((tert-butylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-4-chloro-6-fluorobenzyl)-13-(4-chlorobenzyl)-3-(cyclopropylmethyl)-10-(methoxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3S,7S,10S,13R)-6-(2-(4-(2-((tert-butyl(methyl)amino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-4-chlorobenzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-3-((1-methylcyclopropyl)methyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-3-(cyclopropylmethyl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3S,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-3-(2,2-difluoropropyl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3S,7S,10S,13R)-6-(2-(4-(2-((tert-butylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-4-chlorobenzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3R,7S,10S,13R)-6-(2-(4-(2-((tert-butylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-4-chlorobenzyl)-13-(4-chlorobenzyl)-3-(cyclopropylmethyl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3R,7S,10S,13R)-3-benzyl-6-(2-(4-(2-((tert-butylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-4-chlorobenzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3R,7S,10S,13R)-3-benzyl-6-(4-chloro-2-(4-(1-methyl-2-((methylamino)methyl)-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7,12-dimethyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3S,7S,10S,13R)-6-(4-chloro-2-(4-(2-((ethyl(1-methylcyclopropyl)amino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((cyclobutylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-3-(cyclopropylmethyl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3R,7S,10S,13R)-6-(2-(4-(2-((tert-butylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-4-chloro-6-fluorobenzyl)-13-(4-chlorobenzyl)-3-(cyclopropylmethyl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-3-(cyclobutylmethyl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3S,7S,10S,13R)-3-benzyl-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7-methyl-4-oxa-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3S,7S,10S,13R)-6-(2-(4-(2-(azetidin-1-ylmethyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-4-chloro-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7,12-dimethyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3S,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-3-(2,2-difluoropropyl)-10-(methoxymethyl)-7,12-dimethyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3R,7S,10S,13R)-3-benzyl-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7,12-dimethyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3S,7S,10S,13R)-6-(4-chloro-2-(4-(2-((cyclobutyl(methyl)amino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7-methyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3S,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-3-(3,3-difluorocyclobutyl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3R,7S,10S,13R)-6-(2-(4-(2-((tert-butyl(methyl)amino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-4-chlorobenzyl)-13-(4-chlorobenzyl)-3-(cyclopropylmethyl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3R,7S,10S,13R)-6-(2-(4-(2-((tert-butyl(methyl)amino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-4-chloro-6-fluorobenzyl)-13-(4-chlorobenzyl)-3-(cyclopropylmethyl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3S,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-3-(3,3-difluorocyclobutyl)-10-(hydroxymethyl)-7,12-dimethyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3S,7S,10S,13R)-6-(2-(4-(2-((tert-butylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-4-chloro-6-fluorobenzyl)-13-(4-chlorobenzyl)-3-(3,3-difluorocyclobutyl)-10-(methoxymethyl)-7,12-dimethyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3S,7S,10S,13R)-6-(2-(4-(2-(aminomethyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-4-chloro-6-fluorobenzyl)-13-(4-chlorobenzyl)-3-(3,3-difluorocyclobutyl)-10-(methoxymethyl)-7,12-dimethyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3R,7S,10S,13R)-6-(4-chloro-2-fluoro-6-(4-(1-methyl-2-((methylamino)methyl)-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7,12-dimethyl-3-((6-methylpyridin-2-yl)methyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; 2-(((3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7,12-dimethyl-2,5,8,11-tetraoxo-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-3-yl)methyl)-6-methylpyridine 1-oxide; (3S,7S,10S,13R)-6-(2-(4-(2-((tert-butyl(methyl)amino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-4-chloro-6-fluorobenzyl)-13-(4-chlorobenzyl)-3-(3,3-difluorocyclobutyl)-10-(methoxymethyl)-7,12-dimethyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7,12-dimethyl-3-((6-methylpyridin-2-yl)methyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3S,7S,10S,13R)-6-(4-chloro-2-((6-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)pyridin-3-yl)oxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-3-(3,3-difluorocyclobutyl)-10-(methoxymethyl)-7,12-dimethyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3S,7S,10S,13R)-6-(4-chloro-2-fluoro-6-(4-(1-methyl-2-((methylamino)methyl)-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7,12-dimethyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3S,7S,10S,13R)-6-(4-chloro-2-((6-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)pyridin-3-yl)oxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7,12-dimethyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3S,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7,12-dimethyl-3-(tetrahydro-2H-pyran-4-yl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3S,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-((difluoromethoxy)methyl)-7,12-dimethyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3S,7R,10S,13R)-6-(4-chloro-2-((6-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)pyridin-3-yl)oxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7,12-dimethyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; (3S,7S,10S,13R)-6-(4-chloro-2-fluoro-6-(4-(1-methyl-2-((methylamino)methyl)-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7,12-dimethyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; and (3R,7S,10S,13R)-7-(2-aminoethyl)-3-benzyl-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8,11-tetraone; or a pharmaceutically acceptable salt, stereoisomer, N-oxide or tautomer thereof.

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