THR agonists for use in methods to lower plasma level of lipoprotein(a)

Abstract

Disclosed herein are methods to (i) decrease plasma concentration of lipoprotein(a) in a subject, (ii) lower risk of myocardial infarction, aortic valve stenosis, ischemic stroke, and / or peripheral vascular disease in a subject, (iii) prevent myocardial infarction, aortic valve stenosis, ischemic stroke, and / or peripheral vascular disease, or (iv) treat myocardial infarction, aortic valve stenosis, ischemic stroke, and / or peripheral vascular disease in a subject in need thereof, wherein the methods comprise administering to the subject a compound of Formula (I): or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

Description

Atty. Dkt. No.: 122400-0470METHODS TO LOWER PLASMA LEVEL OF LIPOPROTEIN(A)CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application Serial No. 63 / 791,023, filed on April 18, 2025, and to U.S. Provisional Patent Application Serial No. 63 / 932,105 filed on December 5, 2025, the entire disclosure of each of which is hereby incorporated by reference herein.FIELD OF THE DISCLOSURE

[0002] The present disclosure is in the field of THR-P modulators and their use.BACKGROUND OF THE DISCLOSURE

[0003] Thyroid hormone (TH) is essential for normal development, growth and metabolism of all vertebrates. Its effects are mediated principally through triiodothyronine (T3), which acts as a ligand for the TH receptors (TRs, or THRs) pi, P2 and al [1], In the absence of ligand, TR first binds as a heterodimer or homodimer on TH response elements (TRE) located in the promoter regions of target genes, where it interacts with corepressors. Upon ligand binding, the TR homodimers are dissociated in favor of heterodimer formation with the retinoid-X receptor (RXR), resulting in release of the corepressors and recruitment of coactivators. This new complex attracts a large number of proteins which engage the RNA polymerase II in the transcription of the targeted genes.

[0004] Two different genetic loci, denoted THRA and THRB, are responsible for encoding multiple interrelated TR isoforms that have distinct tissue distributions and biological functions. The two major isoforms with the broadest level of tissue expression are TRal and TRpi [2], While TRal is expressed first during fetal development and is widely expressed in adult tissues, TRpi appears later in development and displays highest expression in the adult liver, kidney, and lung [3], TRal is a key regulator of cardiac output, whereas TRpi helps in the control of metabolism in the liver. Importantly, the natural thyroid hormone T3 activates both TRal and TRpi without any significant selectivity.Atty. Dkt. No.: 122400-0470

[0005] Design of thyromimetic small molecule agents led to the identification of TR (or THR) agonists with varying levels of TRP selectivity despite high structural similarity between the ligand-binding domains for TRp and TRa. TRp selectivity achieved by some of these compounds resulted in an improved therapeutic index for lipid lowering relative to cardiac effects such as heart rate, cardiac hypertrophy, and contractility [4-6],

[0006] Lipoprotein(a) is an apolipoprotein BlOO-containing lipoprotein bound to a hydrophilic, highly glycosylated protein called apolipoprotein(a). Most individuals have two detectable circulating lipoprotein(a) isoforms, each arising from differently sized apo(a); the smaller isoform is usually present at higher levels in plasma.

[0007] Lipoprotein(a) is associated with poor cardiovascular prognosis due to pro-atherogenic, pro-thrombotic, pro-inflammatory, and pro-oxidative properties. Plasma levels of lipoprotein(a) vary widely in the global population, ranging from <1 mg / dL (2.5 nmol / L) to >250 mg / dL (625 nmol / L). High levels of lipoprotein(a), defined as >50 mg / dL (125 nmol / L), are common and increase the likelihood of cardiovascular conditions such as myocardial infarction, aortic valve stenosis, ischemic stroke, and / or peripheral vascular disease. However, many people with high levels of lipoprotein(a) exhibit no symptoms.

[0008] Lipoprotein(a) levels cannot be controlled by diet and exercise. Traditional lipid-lowering therapy (e.g., statins) does not provide sufficient lipoprotein(a) reduction. The only therapy currently approved by the Food and Drug Administration for treating high levels of lipoprotein(a) is lipoprotein apheresis.

[0009] Accordingly, other therapies are needed to control the plasma level of lipoprotein(a), thereby treating or mitigating the risk of myocardial infarction, aortic valve stenosis, ischemic stroke, and / or peripheral vascular disease. The compounds described herein address this unmet need.SUMMARY

[0010] Provided herein, in one aspect, is a method to decrease plasma concentration of lipoprotein(a) in a subject, the method comprising administering to the subject a compound of Formula (I):Atty. Dkt. No.: 122400-0470Formula (I)or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein:R1is Ci-Ce alkyl; C2-C10 alkenyl; C3-C12 cycloalkyl; a Ce-Cio aryl group; 3- to 6-membered heterocycloalkyl; 5- to 10-membered heteroaryl; (C3-C12 cycloalkyl)Ci-C3 alkyl; (Ce- C10 aryl)Ci-C3 alkyl; (5- to 10-membered heteroaryl)Ci-C3 alkyl; or (3- to 6-membered heterocycloalkyl)Ci-C3 alkyl; and R1is optionally substituted with 1 to 5 Rgindependently selected from the group consisting of oxo, hydroxy, halogen, -CN, Ci- Ce alkyl, Ce-Cio aryl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, and (Ce-Cio aryl)Ci-C3 alkoxy, or two Rgtogether with the atoms to which they are attached form an aromatic or nonaromatic 3- to 6-membered ring, optionally containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; wherein the 3- to 6- membered heterocycloalkyl and the 5- to 10-membered heteroaryl contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen;R2is hydrogen or an optionally substituted Ci-Ce alkyl;R3is -(C(Ra)2)z-, oxygen, sulfur, or -NRa-;each Rais independently a hydrogen or Ci-Ce alkyl;z is 0, 1, 2, 3, 4 or 5;each of R4and R5is independently selected from halogen, -CN, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkoxy, optionally substituted C2-C6 alkenyl, or cyclopropyl;R6is selected from hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkoxy, -CN, or halogen;optionally R5and R6taken together, along with the carbon atoms to which they are attached, form a C4-C6 cycloalkyl ring; a 4- to 6-membered heterocycloalkyl ring; a Ce-Cio aryl; or a 5- to 10-membered heteroaryl ring; wherein the 4- to 6-membered heterocycloalkylAtty. Dkt. No.: 122400-0470ring and the 5- to 10-membered heteroaryl ring contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen;Q is nitrogen or -CRC-, wherein Rcis hydrogen, halogen, or Ci-Ce alkyl;R7is -(C(Rd)2)n-N(Rd)2;each Rdis independently hydrogen or optionally substituted Ci-Ce alkyl; andeach n is independently selected from 0 or 1.In some embodiments, the subject is at risk for myocardial infarction, aortic valve stenosis, ischemic stroke, or peripheral vascular disease. In some embodiments, the subject is diagnosed with myocardial infarction, aortic valve stenosis, ischemic stroke, or peripheral vascular disease.

[0011] Provided herein, in another aspect, is a method to lower risk of myocardial infarction, aortic valve stenosis, ischemic stroke, or peripheral vascular disease in a subject, the method comprising administering to the subject a compound of Formula (I):Formula (I)or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein:R1is Ci-Ce alkyl; C2-Cio alkenyl; Cs-Ci2cycloalkyl; a Ce-Cio aryl group; 3- to 6-membered heterocycloalkyl; 5- to 10-membered heteroaryl; (Cs-Ci2cycloalkyl)Ci-C3 alkyl; (Ce- Cio aryl)Ci-C3 alkyl; (5- to 10-membered heteroaryl)Ci-C3 alkyl; or (3- to 6-membered heterocycloalkyl)Ci-C3 alkyl; and R1is optionally substituted with 1 to 5 Rgindependently selected from the group consisting of oxo, hydroxy, halogen, -CN, Ci- Ce alkyl, Ce-Cio aryl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, and (Ce-Cio aryl)Ci-C3 alkoxy, or two Rgtogether with the atoms to which they are attached form an aromatic or nonaromatic 3- to 6-membered ring, optionally containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; wherein the 3- to 6-Atty. Dkt. No.: 122400-0470membered heterocycloalkyl and the 5- to 10-membered heteroaryl contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen;R2is hydrogen or an optionally substituted Ci-Ce alkyl;R3is -(C(Ra)2)z-, oxygen, sulfur, or -NRa-;each Rais independently a hydrogen or Ci-Ce alkyl;z is 0, 1, 2, 3, 4 or 5;each of R4and R5is independently selected from halogen, -CN, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkoxy, optionally substituted C2-C6 alkenyl, or cyclopropyl;R6is selected from hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkoxy, -CN, or halogen;optionally R5and R6taken together, along with the carbon atoms to which they are attached, form a C4-C6 cycloalkyl ring; a 4- to 6-membered heterocycloalkyl ring; a Ce-Cio aryl; or a 5- to 10-membered heteroaryl ring; wherein the 4- to 6-membered heterocycloalkyl ring and the 5- to 10-membered heteroaryl ring contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen;Q is nitrogen or -CRC-, wherein Rcis hydrogen, halogen, or Ci-Ce alkyl;R7is -(C(Rd)2)n-N(Rd)2;each Rdis independently hydrogen or optionally substituted Ci-Ce alkyl; andeach n is independently selected from 0 or 1.In some embodiments, the subject is at risk for myocardial infarction, aortic valve stenosis, ischemic stroke, or peripheral vascular disease. In some embodiments, the subject is diagnosed with myocardial infarction, aortic valve stenosis, ischemic stroke, or peripheral vascular disease.

[0012] Provided herein, in another aspect, is a method to prevent myocardial infarction, aortic valve stenosis, ischemic stroke, or peripheral vascular disease in a subject, the method comprising administering to the subject a compound of Formula (I):Atty. Dkt. No.: 122400-0470Formula (I)or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein:R1is Ci-Ce alkyl; C2-C10 alkenyl; C3-C12 cycloalkyl; a Ce-Cio aryl group; 3- to 6-membered heterocycloalkyl; 5- to 10-membered heteroaryl; (C3-C12 cycloalkyl)Ci-C3 alkyl; (Ce- C10 aryl)Ci-C3 alkyl; (5- to 10-membered heteroaryl)Ci-C3 alkyl; or (3- to 6-membered heterocycloalkyl)Ci-C3 alkyl; and R1is optionally substituted with 1 to 5 Rgindependently selected from the group consisting of oxo, hydroxy, halogen, -CN, Ci- Ce alkyl, Ce-Cio aryl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, and (Ce-Cio aryl)Ci-C3 alkoxy, or two Rgtogether with the atoms to which they are attached form an aromatic or nonaromatic 3- to 6-membered ring, optionally containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; wherein the 3- to 6- membered heterocycloalkyl and the 5- to 10-membered heteroaryl contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen;R2is hydrogen or an optionally substituted Ci-Ce alkyl;R3is -(C(Ra)2)z-, oxygen, sulfur, or -NRa-;each Rais independently a hydrogen or Ci-Ce alkyl;z is 0, 1, 2, 3, 4 or 5;each of R4and R5is independently selected from halogen, -CN, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkoxy, optionally substituted C2-C6 alkenyl, or cyclopropyl;R6is selected from hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkoxy, -CN, or halogen;optionally R5and R6taken together, along with the carbon atoms to which they are attached, form a C4-C6 cycloalkyl ring; a 4- to 6-membered heterocycloalkyl ring; a Ce-Cio aryl; or a 5- to 10-membered heteroaryl ring; wherein the 4- to 6-membered heterocycloalkylAtty. Dkt. No.: 122400-0470ring and the 5- to 10-membered heteroaryl ring contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen;Q is nitrogen or -CRC-, wherein Rcis hydrogen, halogen, or Ci-Ce alkyl;R7is -(C(Rd)2)n-N(Rd)2;each Rdis independently hydrogen or optionally substituted Ci-Ce alkyl; andeach n is independently selected from 0 or 1.In some embodiments, the subject is at risk for myocardial infarction, aortic valve stenosis, ischemic stroke, or peripheral vascular disease. In some embodiments, the subject is diagnosed with myocardial infarction, aortic valve stenosis, ischemic stroke, or peripheral vascular disease.

[0013] Provided herein, in another aspect, is a method to treat myocardial infarction, aortic valve stenosis, ischemic stroke, or peripheral vascular disease in a subject in need thereof, the method comprising administering to the subject a compound of Formula (I):Formula (I)or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein:R1is Ci-Ce alkyl; C2-Cio alkenyl; Cs-Ci2cycloalkyl; a Ce-Cio aryl group; 3- to 6-membered heterocycloalkyl; 5- to 10-membered heteroaryl; (Cs-Ci2cycloalkyl)Ci-C3 alkyl; (Ce- Cio aryl)Ci-C3 alkyl; (5- to 10-membered heteroaryl)Ci-C3 alkyl; or (3- to 6-membered heterocycloalkyl)Ci-C3 alkyl; and R1is optionally substituted with 1 to 5 Rgindependently selected from the group consisting of oxo, hydroxy, halogen, -CN, Ci- Ce alkyl, Ce-Cio aryl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, and (Ce-Cio aryl)Ci-C3 alkoxy, or two Rgtogether with the atoms to which they are attached form an aromatic or nonaromatic 3- to 6-membered ring, optionally containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; wherein the 3- to 6-Atty. Dkt. No.: 122400-0470membered heterocycloalkyl and the 5- to 10-membered heteroaryl contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen;R2is hydrogen or an optionally substituted Ci-Ce alkyl;R3is -(C(Ra)2)z-, oxygen, sulfur, or -NRa-;each Rais independently a hydrogen or Ci-Ce alkyl;z is 0, 1, 2, 3, 4 or 5;each of R4and R5is independently selected from halogen, -CN, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkoxy, optionally substituted C2-C6 alkenyl, or cyclopropyl;R6is selected from hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkoxy, -CN, or halogen;optionally R5and R6taken together, along with the carbon atoms to which they are attached, form a C4-C6 cycloalkyl ring; a 4- to 6-membered heterocycloalkyl ring; a Ce-Cio aryl; or a 5- to 10-membered heteroaryl ring; wherein the 4- to 6-membered heterocycloalkyl ring and the 5- to 10-membered heteroaryl ring contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen;Q is nitrogen or -CRC-, wherein Rcis hydrogen, halogen, or Ci-Ce alkyl;R7is -(C(Rd)2)n-N(Rd)2;each Rdis independently hydrogen or optionally substituted Ci-Ce alkyl; andeach n is independently selected from 0 or 1.

[0014] Provided herein, in another aspect, is a method to decrease plasma concentration of low density lipoprotein cholesterol (LDL-C) in a subject, the method comprising administering to the subject a compound of Formula (I):^ / R3N'NR5Y N NH1R2R6Formula (I)Atty. Dkt. No.: 122400-0470or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, and an additional compound selected from the group consisting of GLP-1 receptor agonists and statins; wherein:R1is Ci-Ce alkyl; C2-C10 alkenyl; C3-C12 cycloalkyl; a Ce-Cio aryl group; 3- to 6-membered heterocycloalkyl; 5- to 10-membered heteroaryl; (C3-C12 cycloalkyl)Ci-C3 alkyl; (Ce- C10 aryl)Ci-C3 alkyl; (5- to 10-membered heteroaryl)Ci-C3 alkyl; or (3- to 6-membered heterocycloalkyl)Ci-C3 alkyl; and R1is optionally substituted with 1 to 5 Rgindependently selected from the group consisting of oxo, hydroxy, halogen, -CN, Ci- Ce alkyl, Ce-Cio aryl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, and (Ce-Cio aryl)Ci-C3 alkoxy, or two Rgtogether with the atoms to which they are attached form an aromatic or nonaromatic 3- to 6-membered ring, optionally containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; wherein the 3- to 6- membered heterocycloalkyl and the 5- to 10-membered heteroaryl contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen;R2is hydrogen or an optionally substituted Ci-Ce alkyl;R3is -(C(Ra)2)z-, oxygen, sulfur, or -NRa-;each Rais independently a hydrogen or Ci-Ce alkyl;z is 0, 1, 2, 3, 4 or 5;each of R4and R5is independently selected from halogen, -CN, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkoxy, optionally substituted C2-C6 alkenyl, or cyclopropyl;R6is selected from hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkoxy, -CN, or halogen;optionally R5and R6taken together, along with the carbon atoms to which they are attached, form a C4-C6 cycloalkyl ring; a 4- to 6-membered heterocycloalkyl ring; a Ce-Cio aryl; or a 5- to 10-membered heteroaryl ring; wherein the 4- to 6-membered heterocycloalkyl ring and the 5- to 10-membered heteroaryl ring contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen;Q is nitrogen or -CRC-, wherein Rcis hydrogen, halogen, or Ci-Ce alkyl;R7is -(C(Rd)2)n-N(Rd)2;each Rdis independently hydrogen or optionally substituted Ci-Ce alkyl; andAtty. Dkt. No.: 122400-0470each n is independently selected from 0 or 1.

[0015] In some embodiments, the method further comprises administering to the subject a GLP-1 receptor agonist, a statin, or a combination thereof. In some embodiments, the GLP-1 receptor agonist is danuglipron, albiglutide, retatrutide, dulaglutide, exenatide, liraglutide, lixisenatide, semaglutide, orforglipron, HS-10535, tirzepatide, beinaglutide, PEG-1 oxenati de, efpeglenatide, amy cretin, efocipegtrutide, CT-388, maridebart cafraglutide, VK2735, efinopegdutide, survodutide, cotadutide, pemvidutide, mazdutide, G49, or a combination of two or more thereof. In some embodiments, the GLP-1 receptor agonist is danuglipron, albiglutide, retatrutide, dulaglutide, exenatide, liraglutide, lixisenatide, semaglutide, orforglipron, HS-10535, tirzepatide, or a combination of two or more thereof. In some embodiments, the statin is atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, or a combination of two or more thereof.

[0016] Provided herein, in another aspect, is a method to treat a disorder or disease in a subject in need thereof, the method comprising administering to the subject a compound of Formula (I):Formula (I)or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, and an additional compound selected from the group consisting of GLP-1 receptor agonists and statins; wherein:R1is Ci-Ce alkyl; C2-C10 alkenyl; C3-C12 cycloalkyl; a Ce-Cio aryl group; 3- to 6-membered heterocycloalkyl; 5- to 10-membered heteroaryl; (C3-C12 cycloalkyl)Ci-C3 alkyl; (Ce- C10 aryl)Ci-C3 alkyl; (5- to 10-membered heteroaryl)Ci-C3 alkyl; or (3- to 6-membered heterocycloalkyl)Ci-C3 alkyl; and R1is optionally substituted with 1 to 5 Rgindependently selected from the group consisting of oxo, hydroxy, halogen, -CN, Ci- Ce alkyl, Ce-Cio aryl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, and (Ce-Cio aryl)Ci-C3 alkoxy, or two Rgtogether with the atoms to which they are attached form an aromatic or nonAtty. Dkt. No.: 122400-0470aromatic 3- to 6-membered ring, optionally containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; wherein the 3- to 6- membered heterocycloalkyl and the 5- to 10-membered heteroaryl contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen;R2is hydrogen or an optionally substituted Ci-Ce alkyl;R3is -(C(Ra)2)z-, oxygen, sulfur, or -NRa-;each Rais independently a hydrogen or Ci-Ce alkyl;z is 0, 1, 2, 3, 4 or 5;each of R4and R5is independently selected from halogen, -CN, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkoxy, optionally substituted C2-C6 alkenyl, or cyclopropyl;R6is selected from hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkoxy, -CN, or halogen;optionally R5and R6taken together, along with the carbon atoms to which they are attached, form a C4-C6 cycloalkyl ring; a 4- to 6-membered heterocycloalkyl ring; a Ce-Cio aryl; or a 5- to 10-membered heteroaryl ring; wherein the 4- to 6-membered heterocycloalkyl ring and the 5- to 10-membered heteroaryl ring contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen;Q is nitrogen or -CRC-, wherein Rcis hydrogen, halogen, or Ci-Ce alkyl;R7is -(C(Rd)2)n-N(Rd)2;each Rdis independently hydrogen or optionally substituted Ci-Ce alkyl;each n is independently selected from 0 or 1; andthe disease or disorder is selected from metabolic dysfunction-associated steatohepatitis (MASH), obesity, hyperlipidemia, hypercholesterolemia, diabetes, liver steatosis, atherosclerosis, cardiovascular diseases, hypothyroidism, and thyroid cancer.In some embodiments, the GLP-1 receptor agonists are danuglipron, albiglutide, retatrutide, dulaglutide, exenatide, liraglutide, lixisenatide, semaglutide, orforglipron, HS-10535, tirzepatide, beinaglutide, PEG-1 oxenati de, efpeglenatide, amy cretin, efocipegtrutide, CT-388, maridebart cafraglutide, VK2735, efinopegdutide, survodutide, cotadutide, pemvidutide, mazdutide, and G49. In some embodiments, the GLP-1 receptor agonists are dulaglutide, exenatide, liraglutide, lixisenatide, semaglutide, orforglipron, HS-10535, and tirzepatide. InAtty. Dkt. No.: 122400-0470some embodiments, the statins are atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin.

[0017] Provided herein, in another aspect, is a method to decrease plasma concentration of total cholesterol in a subject, the method comprising administering to the subject a compound of Formula (I):Formula (I)or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, and an additional compound selected from the group consisting of GLP-1 receptor agonists; wherein: R1is Ci-Ce alkyl; C2-C10 alkenyl; C3-C12 cycloalkyl; a Ce-Cio aryl group; 3- to 6-membered heterocycloalkyl; 5- to 10-membered heteroaryl; (C3-C12 cycloalkyl)Ci-C3 alkyl; (Ce- C10 aryl)Ci-C3 alkyl; (5- to 10-membered heteroaryl)Ci-C3 alkyl; or (3- to 6-membered heterocycloalkyl)Ci-C3 alkyl; and R1is optionally substituted with 1 to 5 Rgindependently selected from the group consisting of oxo, hydroxy, halogen, -CN, Ci- Ce alkyl, Ce-Cio aryl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, and (Ce-Cio aryl)Ci-C3 alkoxy, or two Rgtogether with the atoms to which they are attached form an aromatic or nonaromatic 3- to 6-membered ring, optionally containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; wherein the 3- to 6- membered heterocycloalkyl and the 5- to 10-membered heteroaryl contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen;R2is hydrogen or an optionally substituted Ci-Ce alkyl;R3is -(C(Ra)2)z-, oxygen, sulfur, or -NRa-;each Rais independently a hydrogen or Ci-Ce alkyl;z is 0, 1, 2, 3, 4 or 5;each of R4and R5is independently selected from halogen, -CN, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkoxy, optionally substituted C2-C6 alkenyl, or cyclopropyl;Atty. Dkt. No.: 122400-0470R6is selected from hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkoxy, -CN, or halogen;optionally R5and R6taken together, along with the carbon atoms to which they are attached, form a C4-C6 cycloalkyl ring; a 4- to 6-membered heterocycloalkyl ring; a Ce-Cio aryl; or a 5- to 10-membered heteroaryl ring; wherein the 4- to 6-membered heterocycloalkyl ring and the 5- to 10-membered heteroaryl ring contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen;Q is nitrogen or -CRC-, wherein Rcis hydrogen, halogen, or Ci-Ce alkyl;R7is -(C(Rd)2)n-N(Rd)2;each Rdis independently hydrogen or optionally substituted Ci-Ce alkyl; andeach n is independently selected from 0 or 1.In some embodiments, the GLP-1 receptor agonists are danuglipron, albiglutide, retatrutide, dulaglutide, exenatide, liraglutide, lixisenatide, semaglutide, orforglipron, HS-10535, tirzepatide, beinaglutide, PEG-1 oxenati de, efpeglenatide, amy cretin, efocipegtrutide, CT-388, maridebart cafraglutide, VK2735, efinopegdutide, survodutide, cotadutide, pemvidutide, mazdutide, and G49. In some embodiments, the GLP-1 receptor agonists are dulaglutide, exenatide, liraglutide, lixisenatide, semaglutide, orforglipron, HS-10535, and tirzepatide.

[0018] Provided herein, in another aspect, is a method to decrease plasma concentration of total cholesterol in a subject, the method comprising administering to the subject a compound of Formula (I):Formula (I)or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R1is Ci-Ce alkyl; C2-Cio alkenyl; Cs-Ci2cycloalkyl; a Ce-Cio aryl group; 3- to 6-membered heterocycloalkyl; 5- to 10-membered heteroaryl; (Cs-Ci2cycloalkyl)Ci-C3 alkyl; (Ce- C10 aryl)Ci-C3 alkyl; (5- to 10-membered heteroaryl)Ci-C3 alkyl; or (3- to 6-membered heterocycloalkyl)Ci-C3 alkyl; and R1is optionally substituted with 1 to 5 RgAtty. Dkt. No.: 122400-0470independently selected from the group consisting of oxo, hydroxy, halogen, -CN, Ci- Ce alkyl, Ce-Cio aryl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, and (Ce-Cio aryl)Ci-C3 alkoxy, or two Rgtogether with the atoms to which they are attached form an aromatic or nonaromatic 3- to 6-membered ring, optionally containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; wherein the 3- to 6- membered heterocycloalkyl and the 5- to 10-membered heteroaryl contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen;R2is hydrogen or an optionally substituted Ci-Ce alkyl;R3is -(C(Ra)2)z-, oxygen, sulfur, or -NRa-;each Rais independently a hydrogen or Ci-Ce alkyl;z is 0, 1, 2, 3, 4 or 5;each of R4and R5is independently selected from halogen, -CN, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkoxy, optionally substituted C2-C6 alkenyl, or cyclopropyl;R6is selected from hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkoxy, -CN, or halogen;optionally R5and R6taken together, along with the carbon atoms to which they are attached, form a C4-C6 cycloalkyl ring; a 4- to 6-membered heterocycloalkyl ring; a Ce-Cio aryl; or a 5- to 10-membered heteroaryl ring; wherein the 4- to 6-membered heterocycloalkyl ring and the 5- to 10-membered heteroaryl ring contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen;Q is nitrogen or -CRC-, wherein Rcis hydrogen, halogen, or Ci-Ce alkyl;R7is -(C(Rd)2)n-N(Rd)2;each Rdis independently hydrogen or optionally substituted Ci-Ce alkyl;each n is independently selected from 0 or 1; andthe compound of Formula (I), or the stereoisomer or the tautomer thereof, or the pharmaceutically acceptable salt thereof, is the sole active agent administered to the subject

[0019] In some embodiments, R1is Ci-Ce alkyl, C2-Cio alkenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyridazin-3(2H)-one, phenyl, naphthyl, pyridinyl, cinnolinyl, isoquinolinyl, quinolinyl, pyrazolo[l,5-Atty. Dkt. No.: 122400-0470a]pyridinyl, imidazo[l,5-a]pyridinyl, benzo[b]thiophenyl, (cyclobutyl)Ci-C3 alkyl, (cyclopentyl)Ci-C3 alkyl, benzyl, (tetrahydrofuranyl)Ci-C3 alkyl, or (tetrahydropyranyl)Ci-C3 alkyl group; and R1is optionally substituted with 1 to 5 Rgindependently selected from the group consisting of hydroxy, halogen, -CN, Ci-Ce alkyl, Ce-Cio aryl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, and (Ce-Cio aryl)Ci-C3 alkoxy, or two Rgtogether with the atoms to which they are attached form an aromatic or non-aromatic 3- to 6-membered ring, optionally containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen. In some embodiments, R1is Ce-Cio aryl or 5- to 10-membered heteroaryl containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; and R1is optionally substituted with 1 to 5 Rgindependently selected from the group consisting of hydroxy, halogen, -CN, Ci-Ce alkyl, Ce-Cio aryl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, and (Ce-Cio aryl)Ci-C3 alkoxy, or two Rgtogether with the atoms to which they are attached form a non-aromatic 3- to 6-membered ring, optionally containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen. In some embodiments, R1is benzene optionally substituted with 1 to 5 Rgindependently selected from the group consisting of hydroxy, halogen, -CN, Ci-Ce alkyl, Ci-Ce alkoxy, and Ci-Ce haloalkoxy, or two Rgtogether with the atoms to which they are attached form a non-aromatic 3- to 6-membered ring, optionally containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen. In some embodiments, R1is Ci-Ce alkyl or C3-C12 cycloalkyl; and R1is optionally substituted with 1 to 5 Rgindependently selected from the group consisting of oxo, hydroxy, halogen, -CN, Ci-Ce alkyl, Ce-Cio aryl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, and (Ce-Cio aryl)Ci-C3 alkoxy. In some embodiments, R1is Ci-Ce alkyl optionally substituted with 1 to 5 Rgindependently selected from the group consisting of hydroxy, halogen, -CN, Ci-Ce alkyl, Ce-Cio aryl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, and (Ce-Cio aryl)Ci-C3 alkoxy. In some embodiments, R1is C3-C12 cycloalkyl optionally substituted with 1 to 5 Rgindependently selected from the group consisting of oxo, hydroxy, halogen, -CN, Ci-Ce alkyl, Ce-Cio aryl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, and (Ce-Cio aryl)Ci-C3 alkoxy. In some embodiments, R3is oxygen or -CH2-. In some embodiments, Q is -CH-. In some embodiments, each of R4and R5is independently halogen or C1-C5 alkyl optionally substituted with 1 to 5 substituents independently selected from hydroxy, halogen, and Ci-Ce alkoxy; and R6is hydrogen; or R4is halogen or C1-C5 alkyl optionally substituted with 1 to 5 substituents independently selected from hydroxy, halogen,Atty. Dkt. No.: 122400-0470and Ci-Ce alkoxy; and R5and R6taken together, along with the carbon atoms to which they are attached, form a cyclobutyl, cyclopentyl, or cyclohexyl ring.

[0020] In some embodiments, the compound is selected fromAtty. Dkt. No.: 122400-0470Atty. Dkt. No.: 122400-0470Atty. Dkt. No.: 122400-0470Atty. Dkt. No.: 122400-0470stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is selected from the group consisting of:Atty. Dkt. No.: 122400-0470\ or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I), isNH2 , or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof.Atty. Dkt. No.: 122400-0470

[0021] In some embodiments, the compound of Formula (I), or the stereoisomer or the tautomer thereof, or the pharmaceutically acceptable salt thereof, is administered at a daily dose of about 0.3 mg to about 1.2 mg. In some embodiments, the compound of Formula (I), or the stereoisomer or the tautomer thereof, or the pharmaceutically acceptable salt thereof, is administered at a daily dose of about 0.5 mg to about 0.9 mg. In some embodiments, the compound of Formula (I), or the stereoisomer or the tautomer thereof, or the pharmaceutically acceptable salt thereof, is administered for at least 12 weeks.BRIEF DESCRIPTION OF THE DRAWINGS

[0022] FIG. 1 depicts percent change from baseline to 28 days of plasma levels of lipoprotein(a) in healthy subjects treated with placebo or varying doses of compound A.

[0023] FIG. 2 depicts median percent change from baseline at Week 12 of plasma levels of lipoprotein(a) in all subjects treated with compound A. n = number of subjects with available data at week 12; N = number of subjects in Magnetic Resonance Imaging-Proton Density Fat Fraction (MRI-PDFF) analysis set; **p<0.01. Only patients weighing >85 kg were enrolled in the 0.9 mg dose group; no body weight restrictions were implemented in other dose groups.

[0024] FIG. 3 depicts mean percent change from baseline to Week 12 of plasma levels of lipoprotein(a) in all subjects treated with compound A. Only patients weighing >85 kg were enrolled in the 0.9 mg dose group; no body weight restrictions were implemented in other dose groups.

[0025] FIG. 4A and FIG. 4B depict median percent change from baseline at Week 12 of plasma levels of lipoprotein(a) in subjects with (FIG. 4A) or without (FIG. 4B) stable GLP-1 receptor agonist (GLP-1 RA) use who are treated with compound A. n = number of subjects with available data at week 12; N = number of subjects in full analysis set; n > 3 per dose group shown.

[0026] FIG. 5 depicts median percent change from baseline at Week 12 of plasma levels of low density lipoprotein cholesterol (LDL-C) in all subjects treated with compound A. n = number of subjects with available data at week 12; N = number of subjects in Magnetic Resonance Imaging-Proton Density Fat Fraction (MRI-PDFF) analysis set; **p<0.01. OnlyAtty. Dkt. No.: 122400-0470patients weighing >85 kg were enrolled in the 0.9 mg dose group; no body weight restrictions were implemented in other dose groups.

[0027] FIG. 6 depicts median percent change from baseline at Week 12 of plasma levels of low density lipoprotein cholesterol (LDL-C) in subjects without any GLP-1 RA use who are treated with compound A. n = number of subjects with available data at week 12; N = number of subjects in full analysis set; n > 3 per dose group shown.

[0028] FIG. 7 depicts median relative percent change in liver fat at Week 12 in subjects with or without stable GLP-1 RA use who are treated with compound A. Subjects using GLP-1 RA (semaglutide (n = 4), liraglutide (n = 4) or dulaglutide (n = 2)) at baseline were required to have stable use for >12 weeks prior to randomization. For derivation of duration of use, if a month and / or day for the start of GLP-1 RA use was unknown, it was imputed as January and / or the 1stof the month, respectively. Bolded dashed line indicates 30% relative reduction in liver fat.

[0029] FIGS. 8A-8E depict individual relative percent change in liver fat at Week 12 for placebo (FIG. 8A), 0.3 mg dosage (FIG. 8B), 0.5 mg dosage (FIG. 8C), 0.7 mg dosage (FIG.8D), and 0.9 mg dosage (FIG.8E) of compound A. Darkened bars represent subjects with both stable GLP-1 RA use and statin use. Subjects using GLP-1 RA (semaglutide (n = 4), liraglutide (n = 4) or dulaglutide (n = 2)) at baseline were required to have stable use for >12 weeks prior to randomization. For derivation of duration of use, if a month and / or day for the start of GLP-1 RA use was unknown, it was imputed as January and / or the 1stof the month, respectively.

[0030] FIGS. 9A-9E depict individual relative percent change in plasma levels of lipoprotein(a) at Week 12 for placebo (FIG. 9A), 0.3 mg dosage (FIG. 9B), 0.5 mg dosage (FIG. 9C), 0.7 mg dosage (FIG.9D), and 0.9 mg dosage (FIG.9E) of compound A. Darkened bars represent subjects with both stable GLP-1 RA use and statin use. Subjects using GLP-1 RA (semaglutide (n = 4), liraglutide (n = 4) or dulaglutide (n = 2)) at baseline were required to have stable use for >12 weeks prior to randomization. For derivation of duration of use, if a month and / or day for the start of GLP-1 RA use was unknown, it was imputed as January and / or the 1stof the month, respectively.Atty. Dkt. No.: 122400-0470

[0031] FIGS. 10A and 10B depict median percent change from baseline in LDL-C in patients treated with compound A, but not on GLP-1 RA and not on statins (FIG. 10A) and in patients treated with compound A and not on GLP-1 RA, but also on statins (FIG.10B).

[0032] FIG. 11 depicts mean change in plasma total cholesterol from baseline over the duration of the study described in Example 3 for diet-induced obese mice receiving vehicles (Veh 1 + Veh 2), 1 mg / kg compound A, 10 nmol / kg semaglutide (SEMA), a combination of 1 mg / kg compound A and 10 nmol / kg SEMA, 3 nmol / kg tirzepatide (TIRZEP lo), a combination of 1 mg / kg compound A and TIRZEP lo, 10 nmol / kg tirzepatide (TIRZEP hi), or a combination of 1 mg / kg compound A and TIRZEP hi. A one-way ANOVA with Tukey's multiple comparisons test was performed; ** =p-value <0.01; **** =p-value <0.0001.DETAILED DESCRIPTIONDEFINITIONS

[0033] Various embodiments are described hereinafter. It should be noted that the specific embodiments are not intended as an exhaustive description or as a limitation to the broader aspects discussed herein. One aspect described in conjunction with a particular embodiment is not necessarily limited to that embodiment and can be practiced with any other embodiment s).

[0034] As used herein, “about” will be understood by persons of ordinary skill in the art and will vary to some extent depending upon the context in which it is used. If there are uses of the term which are not clear to persons of ordinary skill in the art, given the context in which it is used, “about” will mean up to plus or minus 10% of the particular term.

[0035] The use of the terms “a” and “an” and “the” and similar referents in the context of describing the elements (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, isAtty. Dkt. No.: 122400-0470intended merely to better illuminate the embodiments and does not pose a limitation on the scope of the claims unless otherwise stated. No language in the specification should be construed as indicating any non-claimed element as essential.

[0036] In the definition of chemical substituents, each of Rxand Ryis independently hydrogen, alkyl, carbocyclic ring, heterocyclic ring, aryl, or heteroaryl, all of which, except hydrogen, are optionally substituted.

[0037] Unless otherwise indicated, the abbreviations “TR” and “THR” refer to thyroid hormone receptors.

[0038] As used herein, “pharmaceutically acceptable salt” refers to a salt of a compound that does not cause significant irritation to a patient to which it is administered and does not abrogate the biological activity and properties of the compound. Pharmaceutical salts can be obtained by reaction of a compound disclosed herein with an acid or base. Base-formed salts include, without limitation, ammonium salt (NHU); alkali metal, such as, without limitation, sodium or potassium, salts; alkaline earth, such as, without limitation, calcium or magnesium, salts; salts of organic bases such as, without limitation, dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine; and salts with the amino group of amino acids such as, without limitation, arginine and lysine. Useful acid-based salts include, without limitation, hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, methane-sulfonates, ethanesulfonates, p-toluenesulfonates and salicylates.

[0039] Where the compounds disclosed herein have at least one chiral center, they may exist as a racemate or as individual enantiomers. It should be noted that all such isomers and mixtures thereof are included in the scope of the present disclosure. Thus, the illustration of a chiral center without a designation of R or S signifies that the scope of the disclosure includes the R isomer, the S isomer, the racemic mixture of the isomers, or mixtures where one isomer is present in greater abundance than the other.

[0040] Where the processes for the preparation of the compounds disclosed herein give rise to mixtures of stereoisomers, such isomers may be separated by conventional techniques such as preparative chiral chromatography. The compounds may be prepared in racemic form or individual enantiomers may be prepared by stereoselective synthesis or by resolution. The compounds may be resolved into their component enantiomers by standard techniques, such asAtty. Dkt. No.: 122400-0470the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-d-tartaric acid and / or (+)-di-p-toluoyl-l-tartaric acid, followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides followed by chromatographic separation and removal of the chiral auxiliary.

[0041] Unless otherwise indicated, when a substituent is deemed to be “optionally substituted” it is meant that the substituent is a group that may be substituted with one or more (e.g., 1 or 2, or 1 to 3, or 1 to 4 or 1 to 5, or 1 to 6) group(s) individually and independently selected, without limitation, from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, O-cyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, and amino (e.g., -NRxRy), including mono- and di -substituted amino groups, and the protected derivatives thereof. The protecting groups that may form the protective derivatives of the above substituents are known to those of skill in the art and may be found in references such as Wuts, P.G.M., Greene’s Protective Groups in Organic Synthesis, 5th Ed., John Wiley & Sons, New York, N.Y., 2014.

[0042] As used herein, a “carbocyclic ring” or “carbocyclyl” is an aromatic or nonaromatic ring structure in which all the atoms in the ring are carbon atoms. As such, the ring structure may be fully saturated, fully unsaturated, or partially saturated. If any of the atoms in the ring is anything other than a carbon atom, then the ring is a “heterocyclic ring.” Examples of atoms that are within a ring include sulfur, oxygen, and nitrogen. A carbocyclic ring or a heterocyclic ring may be polycyclic, e.g., a fused ring system, a spirocyclic ring system, or a bridged ring system. These polycyclic rings include, for example, adamantyl, norbomyl ( / .< ., bicyclo[2.2.1 ]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Additional non-limiting examples include bicyclic rings such as but not limited to:Atty. Dkt. No.: 122400-0470

[0043] As used herein, “aryl” refers to a carbocyclic (all carbon) ring that has a fully delocalized pi-electron system. The “aryl” group can be made up of two or more fused rings (rings that share two adjacent carbon atoms). When the aryl is a fused ring system, then the ring that is connected to the rest of the molecule has a fully delocalized pi-electron system. The other ring(s) in the fused ring system may or may not have a fully delocalized pi-electron system. Further, the other ring(s) may or may not contain one or more ring heteroatoms (e.g., O, N, or S). Examples of aryl groups include, without limitation, the radicals of benzene, naphthalene and azulene. Additional non-limiting examples include:

[0044] As used herein, “heteroaryl” refers to a ring that has a fully delocalized pi-electron system and contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur in the ring. The “heteroaryl” group can be made up of two or more fused rings (rings that share two adjacent carbon atoms). When the heteroaryl is a fused ring system, then the ring that is connected to the rest of the molecule has a fully delocalized pi-electron system. The other ring(s) in the fused ring system may or may not have a fully delocalized pi-electron system. Examples of heteroaryl rings include, without limitation, furan, thiophene, phthalazinone, pyrrole, oxazole, thiazole, imidazole, pyrazole, isoxazole, isothiazole, triazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine and triazine.

[0045] Wherever “hetero” is used it is intended to mean a group as specified, such as an alkyl or an aryl group, where at least one carbon atom has been replaced with a heteroatom selected from nitrogen, oxygen and sulfur.

[0046] As used herein, “alkyl” refers to a straight or branched chain fully saturated (no double or triple bonds) hydrocarbon group. An alkyl group of the presently disclosed compounds may comprise from 1 to 20 carbon atoms. An alkyl group herein may also be of medium size having 1 to 10 carbon atoms. An alkyl group herein may also be a lower alkyl having 1 to 3 carbon atoms, 1 to 4 carbon atoms, 1 to 5 carbon atoms, or 1 to 6 carbon atoms. Examples of alkyl groups include, without limitation, methyl, ethyl, w-propyl, isopropyl, n-Atty. Dkt. No.: 122400-0470butyl, z-butyl, sec-butyl, / -butyl, amyl, / -amyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl.

[0047] An alkyl group of the presently disclosed compounds may be substituted or unsubstituted. When substituted, the substituent group(s) can be one or more group(s) independently selected from cycloalkyl, aryl, heteroaryl, heterocycloalkyl, hydroxy, protected hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, amino (e.g., -NRxRy) and protected amino.

[0048] As used herein, “alkenyl” refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more double bonds. An alkenyl group of the presently disclosed compounds may be unsubstituted or substituted. When substituted, the substituent(s) may be selected from the same groups disclosed above regarding alkyl group substitution, or with regard to optional substitution.

[0049] As used herein, “alkynyl” refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more triple bonds. An alkynyl group of the presently disclosed compounds may be unsubstituted or substituted. When substituted, the substituent(s) may be selected from the same groups disclosed above regarding alkyl group substitution, or with regard to optional substitution.

[0050] As used herein, “acyl” refers to an “RXC(=O)-” group.

[0051] As used herein, “cycloalkyl” refers to a hydrocarbon ring containing no double bonds or one or more double bonds provided that they do not form a fully delocalized pi-electron system in the ring. Cycloalkyl groups of the presently disclosed compounds may range from C3 to Cs. A cycloalkyl group may be unsubstituted or substituted. If substituted, the substituent(s) may be selected from those indicated above regarding substitution of an alkyl group. The “cycloalkyl” group can be made up of two or more fused rings (rings that share two adjacent carbon atoms). When the cycloalkyl group is a fused ring system, then the ring that is connected to the rest of the molecule is a cycloalkyl group as defined above. The other ring(s) in the fused ring system may be a cycloalkyl, an aryl, a heteroaryl, or a heterocycloalkyl group.Atty. Dkt. No.: 122400-0470

[0052] As used herein, “cycloalkenyl” refers to a cycloalkyl group that contains one or more double bonds in the ring although, if there is more than one, they cannot form a fully delocalized pi-electron system in the ring (otherwise the group would be “aryl,” as defined herein). A cycloalkenyl group of the presently disclosed compounds may be unsubstituted or substituted. When substituted, the substituent(s) may be selected from the same groups disclosed above regarding alkyl group substitution. The “cycloalkenyl” group can be made up of two or more fused rings (rings that share two adjacent carbon atoms). When the cycloalkenyl group is a fused ring system, then the ring that is connected to the rest of the molecule is a cycloalkenyl group as defined above. The other ring(s) in the fused ring system may be a cycloalkyl, a cycloalkenyl, an aryl, a heteroaryl, or a heterocycloalkyl group.

[0053] The term “alkylene” refers to an alkyl group, as defined herein, which is a biradical and is connected to two other moieties. Thus, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), isopropylene (IUPAC: (methyl)ethylene) (-CH2-CH(CH3)-), and isobutylene (IUPAC: 2-(methyl)propylene) (-CH2-CH(CH3)-CH2-) are examples, without limitation, of an alkylene group.

[0054] As used herein, “heterocycloalkyl” refers to a ring having in the ring system one or more heteroatoms independently selected from nitrogen, oxygen and sulfur. The ring may also contain one or more double bonds provided that they do not form a fully delocalized pi-electron system in the rings. The ring defined herein can be a stable 3- to 18-membered ring that consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Heterocycloalkyl groups of the presently disclosed compounds may be unsubstituted or substituted. When substituted, the substituent(s) may be one or more groups independently selected from the group consisting of halogen, hydroxy, protected hydroxy, cyano, nitro, alkyl, alkoxy, acyl, acyloxy, carboxy, protected carboxy, amino, protected amino, carboxamide, protected carboxamide, alkyl sulfonamido and trifluoromethane-sulfonamido. The “heterocycloalkyl” group can be made up of two or more fused rings (rings that share two adjacent carbon atoms). When the heterocycloalkyl group is a fused ring system, then the ring that is connected to the rest of the molecule is a heterocycloalkyl group as defined above. The other ring(s) in the fused ring system may be a cycloalkyl, a cycloalkenyl, an aryl, a heteroaryl, or a heterocycloalkyl group.Atty. Dkt. No.: 122400-0470

[0055] As used herein, “aralkyl” refers to an alkylene substituted with an aryl group.

[0056] As used herein, “(carbocyclic)alkyl” refers to an alkylene substituted with a carbocyclic group.

[0057] As used herein, “(heterocycloalkyl)alkyl” refers to an alkylene substituted with a heterocycloalkyl group.

[0058] An “O-carboxy” group refers to a “RXC(=O)O-” group.

[0059] A “C-carboxy” group refers to a “-C(=O)ORX” group.

[0060] An “acetyl” group refers to a CH3C(=O)- group.

[0061] A “C-amido” group refers to a “-C(=0)NRxRy” group.

[0062] An “N-amido” group refers to a “RyC(=O)NRx-” group.

[0063] Any unsubstituted or monosubstituted amine group on a compound herein can be converted to an amide, any hydroxy group can be converted to an ester and any carboxyl group can be converted to either an amide or ester using techniques well-known to those skilled in the art (see, for example Wuts, above).

[0064] It is understood that, in any compound of the presently disclosed compounds having one or more chiral centers, if an absolute stereochemistry is not expressly indicated, then each center may independently be R or S or a mixture thereof. In addition, it is understood that, in any compound of the presently disclosed compounds having one or more double bond(s) generating geometrical isomers that can be defined as E or Z each double bond may independently be E or Z, or a mixture thereof.

[0065] It is understood that the disclosure of a compound herein inherently includes the disclosure of a tautomer thereof, if applicable. For instance, the disclosure of:(wherein Rxis H)also includes the disclosure of:Atty. Dkt. No.: 122400-0470and vice versa, even if only one of the two structures is disclosed.

[0066] Throughout the present disclosure, when a compound is illustrated or named, it is understood that the isotopically enriched analogs of the compound are also contemplated. For example, a compound may have a deuterium incorporated instead of a hydrogen, or a carbon-13 instead of carbon with natural isotopic distribution. The isotopic enrichment may be in one location on the compound, i.e., only one hydrogen is replaced by a deuterium, or in more than one location. The present disclosure also encompasses compounds where all the similar atoms are replaced by their less common isotope, for example, a perdeutero compound where all the hydrogen atoms are replaced by a deuterium. The isotopically enriched compounds are useful when obtaining NMR spectra or when making use of an isotope effect in managing the kinetics of the reaction the compound undergoing.

[0067] The term “pharmaceutical composition” refers to a mixture of one or more compounds disclosed herein with one or more pharmaceutically acceptable excipients, such as, but not limited to, one or more surfactants, co-solvents, or a combination thereof. The pharmaceutical composition facilitates administration of the compound to an organism. The pharmaceutical compositions described herein are orally administered.

[0068] The term “pharmaceutically acceptable” defines an excipient or a salt that does not abrogate the biological activity and properties of the compound.

[0069] Unless otherwise specified, the term “effective amount” as used herein refers to an amount of a compound as described herein that is sufficient to achieve an intended pharmacological effect, such as (i) decreasing plasma concentration of lipoprotein(a), (ii) lowering risk of myocardial infarction, aortic valve stenosis, ischemic stroke, or peripheral vascular disease, (iii) preventing myocardial infarction, aortic valve stenosis, ischemic stroke, or peripheral vascular disease, or (iv) treating a disease or disorder afflicting a subject (e.g., myocardial infarction, aortic valve stenosis, ischemic stroke, or peripheral vascular disease). It is emphasized that a therapeutically effective amount may not always be effective in a given subject even though such amount is deemed to be a therapeutically effective amount by those of skill in the art. The therapeutically effective amount may vary based on the route of administration and dosage form, the age and weight of the subject, and / or the subject’s condition, The term “therapeutically effective amount” refers to an amount of compoundAtty. Dkt. No.: 122400-0470effective to prevent, alleviate, or ameliorate symptoms of disease or prolong the survival of the subject being treated. In some embodiments, a therapeutically effective amount means an amount of compound effective to alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated.

[0070] “Administration” or “administering” refers to any suitable route of administration, including parenteral (e.g., intravenous, subcutaneous, or intramuscular injection) and oral, and includes administration to the subject (patient), such as by a healthcare professional, and selfadministration by the subject (patient).

[0071] The terms “subject” and “patient” are used interchangeably herein, and refer to any individual mammalian subject, e.g., bovine, canine, feline, equine, or human. In specific embodiments, the subject or patient is a human. In further specific embodiments, the subject is a human patient suffering from, diagnosed with, or at risk of myocardial infarction, aortic valve stenosis, ischemic stroke, or peripheral vascular disease. In some embodiments, the subject is a human patient suffering from, diagnosed with, or at risk of a high level of lipoprotein(a). METHODS AND USES

[0072] In one aspect, provided herein is a method to decrease plasma concentration of lipoprotein(a) in a subject, the method comprising, consisting essentially of, or consisting of administering to the subject a compound of Formula (I):Formula (I)or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein:R1is Ci-Ce alkyl; C2-C10 alkenyl; C3-C12 cycloalkyl; a Ce-Cio aryl group; 3- to 6-membered heterocycloalkyl; 5- to 10-membered heteroaryl; (C3-C12 cycloalkyl)Ci-C3 alkyl; (Ce- C10 aryl)Ci-C3 alkyl; (5- to 10-membered heteroaryl)Ci-C3 alkyl; or (3- to 6-membered heterocycloalkyl)Ci-C3 alkyl; and R1is optionally substituted with 1 to 5 RgAtty. Dkt. No.: 122400-0470independently selected from the group consisting of oxo, hydroxy, halogen, -CN, Ci- Ce alkyl, Ce-Cio aryl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, and (Ce-Cio aryl)Ci-C3 alkoxy, or two Rgtogether with the atoms to which they are attached form an aromatic or nonaromatic 3- to 6-membered ring, optionally containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; wherein the 3- to 6- membered heterocycloalkyl and the 5- to 10-membered heteroaryl contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen;R2is hydrogen or an optionally substituted Ci-Ce alkyl;R3is -(C(Ra)2)z-, oxygen, sulfur, or -NRa-;each Rais independently a hydrogen or Ci-Ce alkyl;z is 0, 1, 2, 3, 4 or 5;each of R4and R5is independently selected from halogen, -CN, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkoxy, optionally substituted C2-C6 alkenyl, or cyclopropyl;R6is selected from hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkoxy, -CN, or halogen;optionally R5and R6taken together, along with the carbon atoms to which they are attached, form a C4-C6 cycloalkyl ring; a 4- to 6-membered heterocycloalkyl ring; a Ce-Cio aryl; or a 5- to 10-membered heteroaryl ring; wherein the 4- to 6-membered heterocycloalkyl ring and the 5- to 10-membered heteroaryl ring contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen;Q is nitrogen or -CRC-, wherein Rcis hydrogen, halogen, or Ci-Ce alkyl;R7is -(C(Rd)2)n-N(Rd)2;each Rdis independently hydrogen or optionally substituted Ci-Ce alkyl; andeach n is independently selected from 0 or 1.

[0073] The phrase “decrease plasma concentration of lipoprotein(a) in a subject” refers to decreasing or lowering the plasma concentration of lipoprotein(a) in a subject relative to the plasma concentration without administration of the compound of Formula (I), or theAtty. Dkt. No.: 122400-0470stereoisomer or the tautomer thereof, or the pharmaceutically acceptable salt thereof. In some embodiments, the plasma concentration of lipoprotein(a) is lowered to less than 50 mg / dL. This includes less than 49, 48, 47, 46, 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, or 30 mg / dL. In some embodiments, plasma concentration of lipoprotein(a) is lowered to 1 mg / dL to 49 mg / dL, 5 mg / dL to 49 mg / dL, 10 mg / dL to 49 mg / dL, 1 mg / dL to 30 mg / dL, 5 mg / dL to 30 mg / dL, or 10 mg / dL to 30 mg / dL. In some embodiments, plasma concentration oflipoprotein(a) is lowered to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, or 49 mg / dL.

[0074] In some embodiments, the plasma concentration of lipoprotein(a) is lowered by 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more, including any value therebetween, relative to the plasma concentration without administration of the compound of Formula (I), or the stereoisomer or the tautomer thereof, or the pharmaceutically acceptable salt thereof. In some embodiments, the plasma concentration of lipoprotein(a) is lowered by 10% to 95%. 10% to 90%, 10% to 85%, 10% to 80%, 10% to 75%, 10% to 70%, 10% to 65%, 10% to 60%, 10% to 55%, 10% to 50%, 10% to 45%, 10% to 40%, 10% to 35%, 10% to 30%, 10% to 25%, 20% to 95%, 20% to 90%, 20% to 85%, 20% to 80%, 20% to 75%, 20% to 70%, 20% to 65%, 20% to 60%, 20% to 55%, 20% to 50%, 20% to 40%, 20% to 30%, 30% to 95%, 30% to 90%, 30% to 85%, 30% to 80%, 30% to 75%, 30% to 70%, 30% to 65%, 30% to 60%, 30% to 55%, 30% to 50%, 40% to 95%, 40% to 90%, 40% to 85%, 40% to 80%, 40% to 75%, or 40% to 70% relative to the plasma concentration without administration of the compound of Formula (I), or the stereoisomer or the tautomer thereof, or the pharmaceutically acceptable salt thereof. In some embodiments, the plasma concentration of lipoprotein(a) is lowered by at least 10%, 15%, 20%, 25%, 30%, or more, including any value therebetween, relative to the plasma concentration without administration of the compound of Formula (I), or the stereoisomer or the tautomer thereof, or the pharmaceutically acceptable salt thereof.Atty. Dkt. No.: 122400-0470

[0075] In another aspect, provided herein is a method to lower risk of myocardial infarction, aortic valve stenosis, ischemic stroke, or peripheral vascular disease in a subject, the method comprising administering to the subject a compound of Formula (I):Formula (I)or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein:R1is Ci-Ce alkyl; C2-C10 alkenyl; C3-C12 cycloalkyl; a Ce-Cio aryl group; 3- to 6-membered heterocycloalkyl; 5- to 10-membered heteroaryl; (C3-C12 cycloalkyl)Ci-C3 alkyl; (Ce- C10 aryl)Ci-C3 alkyl; (5- to 10-membered heteroaryl)Ci-C3 alkyl; or (3- to 6-membered heterocycloalkyl)Ci-C3 alkyl; and R1is optionally substituted with 1 to 5 Rgindependently selected from the group consisting of oxo, hydroxy, halogen, -CN, Ci- Ce alkyl, Ce-Cio aryl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, and (Ce-Cio aryl)Ci-C3 alkoxy, or two Rgtogether with the atoms to which they are attached form an aromatic or nonaromatic 3- to 6-membered ring, optionally containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; wherein the 3- to 6- membered heterocycloalkyl and the 5- to 10-membered heteroaryl contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen;R2is hydrogen or an optionally substituted Ci-Ce alkyl;R3is -(C(Ra)2)z-, oxygen, sulfur, or -NRa-;each Rais independently a hydrogen or Ci-Ce alkyl;z is 0, 1, 2, 3, 4 or 5;each of R4and R5is independently selected from halogen, -CN, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkoxy, optionally substituted C2-C6 alkenyl, or cyclopropyl;Atty. Dkt. No.: 122400-0470R6is selected from hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkoxy, -CN, or halogen;optionally R5and R6taken together, along with the carbon atoms to which they are attached, form a C4-C6 cycloalkyl ring; a 4- to 6-membered heterocycloalkyl ring; a Ce-Cio aryl; or a 5- to 10-membered heteroaryl ring; wherein the 4- to 6-membered heterocycloalkyl ring and the 5- to 10-membered heteroaryl ring contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen;Q is nitrogen or -CRC-, wherein Rcis hydrogen, halogen, or Ci-Ce alkyl;R7is -(C(Rd)2)n-N(Rd)2;each Rdis independently hydrogen or optionally substituted Ci-Ce alkyl; andeach n is independently selected from 0 or 1.

[0076] In another aspect, provided herein is a method to prevent myocardial infarction, aortic valve stenosis, ischemic stroke, or peripheral vascular disease in a subject, the method comprising administering to the subject a compound of Formula (I):Formula (I)or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein:R1is Ci-Ce alkyl; C2-Cio alkenyl; Cs-Ci2cycloalkyl; a Ce-Cio aryl group; 3- to 6-membered heterocycloalkyl; 5- to 10-membered heteroaryl; (Cs-Ci2cycloalkyl)Ci-C3 alkyl; (Ce- C10 aryl)Ci-C3 alkyl; (5- to 10-membered heteroaryl)Ci-C3 alkyl; or (3- to 6-membered heterocycloalkyl)Ci-C3 alkyl; and R1is optionally substituted with 1 to 5 Rgindependently selected from the group consisting of oxo, hydroxy, halogen, -CN, Ci- Ce alkyl, Ce-Cio aryl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, and (Ce-Cio aryl)Ci-C3 alkoxy, or two Rgtogether with the atoms to which they are attached form an aromatic or nonaromatic 3- to 6-membered ring, optionally containing 1 or 2 ring heteroatomsAtty. Dkt. No.: 122400-0470independently selected from oxygen, sulfur, and nitrogen; wherein the 3- to 6- membered heterocycloalkyl and the 5- to 10-membered heteroaryl contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen;R2is hydrogen or an optionally substituted Ci-Ce alkyl;R3is -(C(Ra)2)z-, oxygen, sulfur, or -NRa-;each Rais independently a hydrogen or Ci-Ce alkyl;z is 0, 1, 2, 3, 4 or 5;each of R4and R5is independently selected from halogen, -CN, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkoxy, optionally substituted C2-C6 alkenyl, or cyclopropyl;R6is selected from hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkoxy, -CN, or halogen;optionally R5and R6taken together, along with the carbon atoms to which they are attached, form a C4-C6 cycloalkyl ring; a 4- to 6-membered heterocycloalkyl ring; a Ce-Cio aryl; or a 5- to 10-membered heteroaryl ring; wherein the 4- to 6-membered heterocycloalkyl ring and the 5- to 10-membered heteroaryl ring contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen;Q is nitrogen or -CRC-, wherein Rcis hydrogen, halogen, or Ci-Ce alkyl;R7is -(C(Rd)2)n-N(Rd)2;each Rdis independently hydrogen or optionally substituted Ci-Ce alkyl; andeach n is independently selected from 0 or 1.

[0077] In another aspect, provided herein is a method to treat myocardial infarction, aortic valve stenosis, ischemic stroke, or peripheral vascular disease in a subject in need thereof, the method comprising administering to the subject a compound of Formula (I):Atty. Dkt. No.: 122400-0470Formula (I)or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein:R1is Ci-Ce alkyl; C2-C10 alkenyl; C3-C12 cycloalkyl; a Ce-Cio aryl group; 3- to 6-membered heterocycloalkyl; 5- to 10-membered heteroaryl; (C3-C12 cycloalkyl)Ci-C3 alkyl; (Ce- C10 aryl)Ci-C3 alkyl; or (5- to 10-membered heteroaryl)Ci-C3 alkyl; (3- to 6-membered heterocycloalkyl)Ci-C3 alkyl; and R1is optionally substituted with 1 to 5 Rgindependently selected from the group consisting of oxo, hydroxy, halogen, -CN, Ci- Ce alkyl, Ce-Cio aryl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, and (Ce-Cio aryl)Ci-C3 alkoxy, or two Rgtogether with the atoms to which they are attached form an aromatic or nonaromatic 3- to 6-membered ring, optionally containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; wherein the 3- to 6- membered heterocycloalkyl and the 5- to 10-membered heteroaryl contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen;R2is hydrogen or an optionally substituted Ci-Ce alkyl;R3is -(C(Ra)2)z-, oxygen, sulfur, or -NRa-;each Rais independently a hydrogen or Ci-Ce alkyl;z is 0, 1, 2, 3, 4 or 5;each of R4and R5is independently selected from halogen, -CN, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkoxy, optionally substituted C2-C6 alkenyl, or cyclopropyl;R6is selected from hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkoxy, -CN, or halogen;optionally R5and R6taken together, along with the carbon atoms to which they are attached, form a C4-C6 cycloalkyl ring; a 4- to 6-membered heterocycloalkyl ring; a Ce-Cio aryl;Atty. Dkt. No.: 122400-0470or a 5- to 10-membered heteroaryl ring; wherein the 4- to 6-membered heterocycloalkyl ring and the 5- to 10-membered heteroaryl ring contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen;Q is nitrogen or -CRC-, wherein Rcis hydrogen, halogen, or Ci-Ce alkyl;R7is -(C(Rd)2)n-N(Rd)2;each Rdis independently hydrogen or optionally substituted Ci-Ce alkyl; andeach n is independently selected from 0 or 1.

[0078] In another aspect, provided herein is a method to decrease plasma concentration of low density lipoprotein cholesterol (LDL-C) in a subject, the method comprising administering to the subject a compound of Formula (I):Formula (I)or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein:R1is Ci-Ce alkyl; C2-Cio alkenyl; Cs-Ci2cycloalkyl; a Ce-Cio aryl group; 3- to 6-membered heterocycloalkyl; 5- to 10-membered heteroaryl; (Cs-Ci2cycloalkyl)Ci-C3 alkyl; (Ce- Cio aryl)Ci-C3 alkyl; or (5- to 10-membered heteroaryl)Ci-C3 alkyl; (3- to 6-membered heterocycloalkyl)Ci-C3 alkyl; and R1is optionally substituted with 1 to 5 Rgindependently selected from the group consisting of oxo, hydroxy, halogen, -CN, Ci- Ce alkyl, Ce-Cio aryl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, and (Ce-Cio aryl)Ci-C3 alkoxy, or two Rgtogether with the atoms to which they are attached form an aromatic or nonaromatic 3- to 6-membered ring, optionally containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; wherein the 3- to 6- membered heterocycloalkyl and the 5- to 10-membered heteroaryl contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen;R2is hydrogen or an optionally substituted Ci-Ce alkyl;Atty. Dkt. No.: 122400-0470R3is -(C(Ra)2)z-, oxygen, sulfur, or -NRa-;each Rais independently a hydrogen or Ci-Ce alkyl;z is 0, 1, 2, 3, 4 or 5;each of R4and R5is independently selected from halogen, -CN, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkoxy, optionally substituted C2-C6 alkenyl, or cyclopropyl;R6is selected from hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkoxy, -CN, or halogen;optionally R5and R6taken together, along with the carbon atoms to which they are attached, form a C4-C6 cycloalkyl ring; a 4- to 6-membered heterocycloalkyl ring; a Ce-Cio aryl; or a 5- to 10-membered heteroaryl ring; wherein the 4- to 6-membered heterocycloalkyl ring and the 5- to 10-membered heteroaryl ring contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen;Q is nitrogen or -CRC-, wherein Rcis hydrogen, halogen, or Ci-Ce alkyl;R7is -(C(Rd)2)n-N(Rd)2;each Rdis independently hydrogen or optionally substituted Ci-Ce alkyl; andeach n is independently selected from 0 or 1.

[0079] The phrase “decrease plasma concentration of low density lipoprotein cholesterol (LDL-C) in a subject” refers to decreasing or lowering the plasma concentration of low density lipoprotein cholesterol in a subject relative to the plasma concentration without administration of the compound of Formula (I), or the stereoisomer or the tautomer thereof, or the pharmaceutically acceptable salt thereof. In some embodiments, the plasma concentration of low density lipoprotein cholesterol is lowered to less than 100 mg / dL. This includes less than 99, 98, 97, 96, 95, 94, 93, 92, 91, 90, 89, 88, 87, 86, 85, 84, 83, 82, 81, 80, 79, 78, 77, 76, 75, 74, 73, 72, 71, 70, 69, 68, 67, 66, 65, 64, 63, 62, 61, 60, 59, 58, 57, 56, 55, 54, 53, 52, 51, or 50 mg / dL. In some embodiments, the plasma concentration of low density lipoprotein cholesterol is lowered to 50 mg / dL to 99 mg / dL, 50 mg / dL to 95 mg / dL, 50 mg / dL to 90 mg / dL, 50 mg / dL to 80 mg / dL, 60 mg / dL to 99 mg / dL, 60 mg / dL to 95 mg / dL, 70 mg / dL to 99 mg / dL,Atty. Dkt. No.: 122400-0470Q mg / dL to 95 mg / dL, or 70 mg / dL to 90 mg / dL. In some embodiments, the plasma concentration of low density lipoprotein cholesterol is lowered to 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99 mg / dL.

[0080] In some embodiments, the plasma concentration of low density lipoprotein cholesterol is lowered by 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more, including any value therebetween, relative to the plasma concentration without administration of the compound of Formula (I), or the stereoisomer or the tautomer thereof, or the pharmaceutically acceptable salt thereof. In some embodiments, the plasma concentration of low density lipoprotein cholesterol is lowered by 10% to 95%. 10% to 90%, 10% to 85%, 10% to 80%, 10% to 75%, 10% to 70%, 10% to 65%, 10% to 60%, 10% to 55%, 10% to 50%, 10% to 45%, 10% to 40%, 10% to 35%, 10% to 30%, 10% to 25%, 20% to 95%, 20% to 90%, 20% to 85%, 20% to 80%, 20% to 75%, 20% to 70%, 20% to 65%, 20% to 60%, 20% to 55%, 20% to 50%, 20% to 40%, 20% to 30%, 30% to 95%, 30% to 90%, 30% to 85%, 30% to 80%, 30% to 75%, 30% to 70%, 30% to 65%, 30% to 60%, 30% to 55%, 30% to 50%, 40% to 95%, 40% to 90%, 40% to 85%, 40% to 80%, 40% to 75%, or 40% to 70% relative to the plasma concentration without administration of the compound of Formula (I), or the stereoisomer or the tautomer thereof, or the pharmaceutically acceptable salt thereof. In some embodiments, the plasma concentration of low density lipoprotein cholesterol is lowered by at least 10%, 15%, 20%, 25%, 30%, or more, including any value therebetween, relative to the plasma concentration without administration of the compound of Formula (I), or the stereoisomer or the tautomer thereof, or the pharmaceutically acceptable salt thereof.

[0081] In another aspect, provided herein is a method to decrease plasma concentration of total cholesterol in a subject, the method comprising administering to the subject a compound of Formula (I):Atty. Dkt. No.: 122400-0470Formula (I)or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein:R1is Ci-Ce alkyl; C2-C10 alkenyl; C3-C12 cycloalkyl; a Ce-Cio aryl group; 3- to 6-membered heterocycloalkyl; 5- to 10-membered heteroaryl; (C3-C12 cycloalkyl)Ci-C3 alkyl; (Ce- C10 aryl)Ci-C3 alkyl; or (5- to 10-membered heteroaryl)Ci-C3 alkyl; (3- to 6-membered heterocycloalkyl)Ci-C3 alkyl; and R1is optionally substituted with 1 to 5 Rgindependently selected from the group consisting of oxo, hydroxy, halogen, -CN, Ci- Ce alkyl, Ce-Cio aryl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, and (Ce-Cio aryl)Ci-C3 alkoxy, or two Rgtogether with the atoms to which they are attached form an aromatic or nonaromatic 3- to 6-membered ring, optionally containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; wherein the 3- to 6- membered heterocycloalkyl and the 5- to 10-membered heteroaryl contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen;R2is hydrogen or an optionally substituted Ci-Ce alkyl;R3is -(C(Ra)2)z-, oxygen, sulfur, or -NRa-;each Rais independently a hydrogen or Ci-Ce alkyl;z is 0, 1, 2, 3, 4 or 5;each of R4and R5is independently selected from halogen, -CN, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkoxy, optionally substituted C2-C6 alkenyl, or cyclopropyl;R6is selected from hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkoxy, -CN, or halogen;optionally R5and R6taken together, along with the carbon atoms to which they are attached, form a C4-C6 cycloalkyl ring; a 4- to 6-membered heterocycloalkyl ring; a Ce-Cio aryl;Atty. Dkt. No.: 122400-0470or a 5- to 10-membered heteroaryl ring; wherein the 4- to 6-membered heterocycloalkyl ring and the 5- to 10-membered heteroaryl ring contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen;Q is nitrogen or -CRC-, wherein Rcis hydrogen, halogen, or Ci-Ce alkyl;R7is -(C(Rd)2)n-N(Rd)2;each Rdis independently hydrogen or optionally substituted Ci-Ce alkyl;each n is independently selected from 0 or 1; andthe compound of Formula (I), or the stereoisomer or the tautomer thereof, or the pharmaceutically acceptable salt thereof, is the sole active agent administered to the subject.

[0082] In another aspect, provided herein is a compound of Formula (I):Formula (I)or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, for use in (i) decreasing plasma concentration of lipoprotein(a) in a subject, (ii) lowering risk of myocardial infarction, aortic valve stenosis, ischemic stroke, or peripheral vascular disease in a subject, (iii) preventing myocardial infarction, aortic valve stenosis, ischemic stroke, or peripheral vascular disease, (iv) treating myocardial infarction, aortic valve stenosis, ischemic stroke, or peripheral vascular disease in a subject in need thereof, or (v) decreasing plasma concentration of low density lipoprotein cholesterol (LDL-C) in a subject, wherein:R1is Ci-Ce alkyl; C2-Cio alkenyl; Cs-Ci2cycloalkyl; a Ce-Cio aryl group; 3- to 6-membered heterocycloalkyl; 5- to 10-membered heteroaryl; (Cs-Ci2cycloalkyl)Ci-C3 alkyl; (Ce- Cio aryl)Ci-C3 alkyl; (5- to 10-membered heteroaryl)Ci-C3 alkyl; or (3- to 6-membered heterocycloalkyl)Ci-C3 alkyl; and R1is optionally substituted with 1 to 5 Rgindependently selected from the group consisting of oxo, hydroxy, halogen, -CN, Ci- Ce alkyl, Ce-Cio aryl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, and (Ce-Cio aryl)Ci-C3 alkoxy,Atty. Dkt. No.: 122400-0470or two Rgtogether with the atoms to which they are attached form an aromatic or nonaromatic 3- to 6-membered ring, optionally containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; wherein the 3- to 6- membered heterocycloalkyl and the 5- to 10-membered heteroaryl contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen;R2is hydrogen or an optionally substituted Ci-Ce alkyl;R3is -(C(Ra)2)z-, oxygen, sulfur, or -NRa-;each Rais independently a hydrogen or Ci-Ce alkyl;z is 0, 1, 2, 3, 4 or 5;each of R4and R5is independently selected from halogen, -CN, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkoxy, optionally substituted C2-C6 alkenyl, or cyclopropyl;R6is selected from hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkoxy, -CN, or halogen;optionally R5and R6taken together, along with the carbon atoms to which they are attached, form a C4-C6 cycloalkyl ring; a 4- to 6-membered heterocycloalkyl ring; a Ce-Cio aryl; or a 5- to 10-membered heteroaryl ring; wherein the 4- to 6-membered heterocycloalkyl ring and the 5- to 10-membered heteroaryl ring contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen;Q is nitrogen or -CRC-, wherein Rcis hydrogen, halogen, or Ci-Ce alkyl;R7is -(C(Rd)2)n-N(Rd)2;each Rdis independently hydrogen or optionally substituted Ci-Ce alkyl; andeach n is independently selected from 0 or 1.

[0083] In another aspect, provided herein is a compound of Formula (I):Atty. Dkt. No.: 122400-0470Formula (I)or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, for use to decrease plasma concentration of total cholesterol in a subject, wherein:R1is Ci-Ce alkyl; C2-C10 alkenyl; C3-C12 cycloalkyl; a Ce-Cio aryl group; 3- to 6-membered heterocycloalkyl; 5- to 10-membered heteroaryl; (C3-C12 cycloalkyl)Ci-C3 alkyl; (Ce- C10 aryl)Ci-C3 alkyl; (5- to 10-membered heteroaryl)Ci-C3 alkyl; or (3- to 6-membered heterocycloalkyl)Ci-C3 alkyl; and R1is optionally substituted with 1 to 5 Rgindependently selected from the group consisting of oxo, hydroxy, halogen, -CN, Ci- Ce alkyl, Ce-Cio aryl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, and (Ce-Cio aryl)Ci-C3 alkoxy, or two Rgtogether with the atoms to which they are attached form an aromatic or nonaromatic 3- to 6-membered ring, optionally containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; wherein the 3- to 6- membered heterocycloalkyl and the 5- to 10-membered heteroaryl contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen;R2is hydrogen or an optionally substituted Ci-Ce alkyl;R3is -(C(Ra)2)z-, oxygen, sulfur, or -NRa-;each Rais independently a hydrogen or Ci-Ce alkyl;z is 0, 1, 2, 3, 4 or 5;each of R4and R5is independently selected from halogen, -CN, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkoxy, optionally substituted C2-C6 alkenyl, or cyclopropyl;R6is selected from hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkoxy, -CN, or halogen;optionally R5and R6taken together, along with the carbon atoms to which they are attached, form a C4-C6 cycloalkyl ring; a 4- to 6-membered heterocycloalkyl ring; a Ce-Cio aryl;Atty. Dkt. No.: 122400-0470or a 5- to 10-membered heteroaryl ring; wherein the 4- to 6-membered heterocycloalkyl ring and the 5- to 10-membered heteroaryl ring contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen;Q is nitrogen or -CRC-, wherein Rcis hydrogen, halogen, or Ci-Ce alkyl;R7is -(C(Rd)2)n-N(Rd)2;each Rdis independently hydrogen or optionally substituted Ci-Ce alkyl; andeach n is independently selected from 0 or 1.

[0084] In another aspect, provided herein is use of a compound of Formula (I):Formula (I)or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for (i) decreasing plasma concentration of lipoprotein(a) in a subject, (ii) lowering risk of myocardial infarction, aortic valve stenosis, ischemic stroke, or peripheral vascular disease in a subject, (iii) preventing myocardial infarction, aortic valve stenosis, ischemic stroke, or peripheral vascular disease, (iv) treating myocardial infarction, aortic valve stenosis, ischemic stroke, or peripheral vascular disease in a subject in need thereof, or (v) decrease plasma concentration of low density lipoprotein cholesterol (LDL-C) in a subject, wherein:R1is Ci-Ce alkyl; C2-Cio alkenyl; Cs-Ci2cycloalkyl; a Ce-Cio aryl group; 3- to 6-membered heterocycloalkyl; 5- to 10-membered heteroaryl; (Cs-Ci2cycloalkyl)Ci-C3 alkyl; (Ce- Cio aryl)Ci-C3 alkyl; (5- to 10-membered heteroaryl)Ci-C3 alkyl; or (3- to 6-membered heterocycloalkyl)Ci-C3 alkyl; and R1is optionally substituted with 1 to 5 Rgindependently selected from the group consisting of oxo, hydroxy, halogen, -CN, Ci- Ce alkyl, Ce-Cio aryl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, and (Ce-Cio aryl)Ci-C3 alkoxy, or two Rgtogether with the atoms to which they are attached form an aromatic or nonaromatic 3- to 6-membered ring, optionally containing 1 or 2 ring heteroatomsAtty. Dkt. No.: 122400-0470independently selected from oxygen, sulfur, and nitrogen; wherein the 3- to 6- membered heterocycloalkyl and the 5- to 10-membered heteroaryl contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen;R2is hydrogen or an optionally substituted Ci-Ce alkyl;R3is -(C(Ra)2)z-, oxygen, sulfur, or -NRa-;each Rais independently a hydrogen or Ci-Ce alkyl;z is 0, 1, 2, 3, 4 or 5;each of R4and R5is independently selected from halogen, -CN, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkoxy, optionally substituted C2-C6 alkenyl, or cyclopropyl;R6is selected from hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkoxy, -CN, or halogen;optionally R5and R6taken together, along with the carbon atoms to which they are attached, form a C4-C6 cycloalkyl ring; a 4- to 6-membered heterocycloalkyl ring; a Ce-Cio aryl; or a 5- to 10-membered heteroaryl ring; wherein the 4- to 6-membered heterocycloalkyl ring and the 5- to 10-membered heteroaryl ring contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen;Q is nitrogen or -CRC-, wherein Rcis hydrogen, halogen, or Ci-Ce alkyl;R7is -(C(Rd)2)n-N(Rd)2;each Rdis independently hydrogen or optionally substituted Ci-Ce alkyl; andeach n is independently selected from 0 or 1.

[0085] In another aspect, provided herein is use of a compound of Formula (I):R4Rl AN R Y N NHR6Formula (I)Atty. Dkt. No.: 122400-0470or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for decreasing plasma concentration of total cholesterol in a subject, wherein:R1is Ci-Ce alkyl; C2-C10 alkenyl; C3-C12 cycloalkyl; a Ce-Cio aryl group; 3- to 6-membered heterocycloalkyl; 5- to 10-membered heteroaryl; (C3-C12 cycloalkyl)Ci-C3 alkyl; (Ce- C10 aryl)Ci-C3 alkyl; (5- to 10-membered heteroaryl)Ci-C3 alkyl; or (3- to 6-membered heterocycloalkyl)Ci-C3 alkyl; and R1is optionally substituted with 1 to 5 Rgindependently selected from the group consisting of oxo, hydroxy, halogen, -CN, Ci- Ce alkyl, Ce-Cio aryl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, and (Ce-Cio aryl)Ci-C3 alkoxy, or two Rgtogether with the atoms to which they are attached form an aromatic or nonaromatic 3- to 6-membered ring, optionally containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; wherein the 3- to 6- membered heterocycloalkyl and the 5- to 10-membered heteroaryl contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen;R2is hydrogen or an optionally substituted Ci-Ce alkyl;R3is -(C(Ra)2)z-, oxygen, sulfur, or -NRa-;each Rais independently a hydrogen or Ci-Ce alkyl;z is 0, 1, 2, 3, 4 or 5;each of R4and R5is independently selected from halogen, -CN, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkoxy, optionally substituted C2-C6 alkenyl, or cyclopropyl;R6is selected from hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkoxy, -CN, or halogen;optionally R5and R6taken together, along with the carbon atoms to which they are attached, form a C4-C6 cycloalkyl ring; a 4- to 6-membered heterocycloalkyl ring; a Ce-Cio aryl; or a 5- to 10-membered heteroaryl ring; wherein the 4- to 6-membered heterocycloalkyl ring and the 5- to 10-membered heteroaryl ring contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen;Q is nitrogen or -CRC-, wherein Rcis hydrogen, halogen, or Ci-Ce alkyl;Atty. Dkt. No.: 122400-0470R7is -(C(Rd)2)n-N(Rd)2;each Rdis independently hydrogen or optionally substituted Ci-Ce alkyl;each n is independently selected from 0 or 1; andthe compound of Formula (I), or the stereoisomer or the tautomer thereof, or the pharmaceutically acceptable salt thereof, is the sole active agent in the medicament.

[0086] In some embodiments, the subject is at risk for myocardial infarction, aortic valve stenosis, ischemic stroke, or peripheral vascular disease.

[0087] Subjects at risk for myocardial infarction may be characterized by one or more of high LDL cholesterol and low HDL cholesterol, habitual smoking, hypertension, diabetes mellitus, and family history of premature coronary artery disease (men <55 years, women <65 years). Myocardial infarction is typically diagnosed based on one or more of (i) clinical symptoms, (ii) ECG findings, and (iii) cardiac biomarkers (e.g., cardiac troponins). Clinical symptoms include chest pain, upper extremity pain, mandibular or epigastric discomfort, dyspnea, or fatigue. The pain may be intermittent or persistent, and is usually not affected by positional changes or active movement of the region. Serial testing of cardiac troponins provides information regarding severity and time course of myocardial injury.

[0088] Subjects at risk of ischemic stroke may be characterized by one or more of hypertension, arterial fibrillation, diabetes mellitus, and smoking and heavy alcohol use. Ischemic stroke is typically diagnosed by imaging, such as computed tomography, magnetic resonance imaging, digital subtraction angiography, or positron emission tomography.

[0089] Subjects at risk of aortic valve stenosis may be characterized by one or both of chronic kidney disease and bicuspid aortic valve. Aortic valve stenosis is characterized by a systolic murmur that is audible with its maximum intensity in the second right intercostal space. Aortic valve stenosis is typically diagnosed using echocardiography

[0090] Subjects at risk of peripheral vascular disease may be characterized by one or more of high LDL cholesterol and low HDL cholesterol, habitual smoking, hypertension, diabetes mellitus, physical inactivity, coronary heart disease, and overweight. Peripheral vascular disease is typically diagnosed by one or more of angiogram, ankle-brachial index, magneticAtty. Dkt. No.: 122400-0470resonance angiography, pulse volume recording waveform analysis, treadmill exercise test, reactive hyperemia test, and Doppler ultrasound flow studies.

[0091] In some embodiments, the subject is diagnosed with myocardial infarction, aortic valve stenosis, ischemic stroke, or peripheral vascular disease. In some embodiments, the subject is diagnosed with myocardial infarction. In some embodiments, the subject is diagnosed with ischemic stroke. In some embodiments, the subject is diagnosed with aortic valve stenosis. In some embodiments, the subject is diagnosed with peripheral vascular disease. In some embodiments, the subject is diagnosed with a high level of lipoprotein(a) (>50 mg / dL or >125 nmol / L).

[0092] In some embodiments, the subject is administered an effective amount of the compound of Formula (I) or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is administered a therapeutically effective amount of the compound of Formula (I) or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0093] In some embodiments, R1is Ci-Ce alkyl, C2-C10 alkenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyridazin-3(2H)-one, phenyl, naphthyl, pyridinyl, cinnolinyl, isoquinolinyl, quinolinyl, pyrazolo[l,5-a]pyridinyl, imidazo[l,5-a]pyridinyl, benzo[b]thiophenyl, a (cyclopropyl)Ci-C3 alkyl group, a (cyclobutyl)Ci-C3 alkyl group, a (cyclopentyl)Ci-C3 alkyl group, a benzyl group, a (tetrahydrofuranyl)Ci-C3 alkyl group, or a (tetrahydropyranyl)Ci-C3 alkyl group; and R1is optionally substituted with 1 to 5 Rgindependently selected from the group consisting of hydroxy, halogen, -CN, Ci-Ce alkyl, Ce-Cio aryl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, and (Ce-Cio aryl)Ci-C3 alkoxy, or two Rgtogether with the atoms to which they are attached form an aromatic or non-aromatic 3- to 6-membered ring, optionally containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen.

[0094] In some embodiments, R1is a Ce-Cio aryl or a 5- to 10-membered heteroaryl containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; and R1is optionally substituted with 1 to 5 Rgindependently selected from the group consisting of hydroxy, halogen, -CN, Ci-Ce alkyl, Ce-Cio aryl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, and (Ce-C10 aryl)Ci-C3 alkoxy, or two Rgtogether with the atoms to which they are attached form aAtty. Dkt. No.: 122400-0470non-aromatic 3- to 6-membered ring, optionally containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen.

[0095] In some embodiments, R1is a Ce-Cio aryl group; and R1is optionally substituted with 1 to 5 Rgindependently selected from the group consisting of hydroxy, halogen, -CN, Ci-Ce alkyl, Ce-Cio aryl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, and (Ce-Cio aryl)Ci-C3 alkoxy, or two Rgtogether with the atoms to which they are attached form a non-aromatic 3- to 6-membered ring, optionally containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen.

[0096] In some embodiments, R1is a 5- to 10-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; and R1is optionally substituted with 1 to 5 Rgindependently selected from the group consisting of hydroxy, halogen, -CN, Ci-Ce alkyl, Ce-Cio aryl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, and (Ce-Cio aryl)Ci-C3 alkoxy, or two Rgtogether with the atoms to which they are attached form a non-aromatic 3- to 6-membered ring, optionally containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen.

[0097] In some embodiments, R1is benzene optionally substituted with 1 to 5 Rgindependently selected from the group consisting of hydroxy, halogen, -CN, Ci-Ce alkyl, Ci-Ce alkoxy, and Ci-Ce haloalkoxy, or two Rgtogether with the atoms to which they are attached form a non-aromatic 3- to 6-membered ring, optionally containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen.

[0098] In some embodiments, R1is Ci-Ce alkyl or C3-C12 cycloalkyl; and R1is optionally substituted with 1 to 5 Rgindependently selected from the group consisting of oxo, hydroxy, halogen, -CN, Ci-Ce alkyl, Ce-Cio aryl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, and (Ce-Cio aryl)Ci-C3 alkoxy. In some embodiments, R1is Ci-Ce alkyl optionally substituted with 1 to 5 Rgindependently selected from the group consisting of hydroxy, halogen, -CN, Ci-Ce alkyl, Ce-C10 aryl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, and (Ce-Cio aryl)Ci-C3 alkoxy. In some embodiments, R1is C3-C12 cycloalkyl optionally substituted with 1 to 5 Rgindependently selected from the group consisting of oxo, hydroxy, halogen, -CN, Ci-Ce alkyl, Ce-Cio aryl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, and (Ce-Cio aryl)Ci-C3 alkoxy. In some embodiments, R1is isopropyl.Atty. Dkt. No.: 122400-0470

[0099] In some embodiments, R1is (C3-C12 cycloalkyl)Ci-C3 alkyl; and R1is optionally substituted with 1 to 5 Rgindependently selected from the group consisting of oxo, hydroxy, halogen, -CN, Ci-Ce alkyl, Ce-Cio aryl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, and (Ce-Cio aryl)Ci-C3 alkoxy, or two Rgtogether with the atoms to which they are attached form an aromatic 3- to 6-membered ring, optionally containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen. In some embodiments, R1is (C3-C12 cycloalkyl)Ci-C3 alkyl; and R1is optionally substituted with 1 to 5 Rgindependently selected from the group consisting of oxo, hydroxy, halogen, -CN, Ci-Ce alkyl, Ce-Cio aryl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, and (Ce-Cio aryl)Ci-C3 alkoxy. In some embodiments, R1is (cyclopropyl)Ci-C3 alkyl; and R1is optionally substituted with 1 to 5 Rgindependently selected from the group consisting of oxo, hydroxy, halogen, -CN, Ci-Ce alkyl, Ce-Cio aryl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, and (Ce-Cio aryl)Ci-C3 alkoxy. In some embodiments, R1is (cyclopropyl)Ci-C3 alkyl.

[0100] In some embodiments, R1is (Ce-Cio aryl)Ci-C3 alkyl; and R1is optionally substituted with 1 to 5 Rgindependently selected from the group consisting of hydroxy, halogen, -CN, Ci-Ce alkyl, Ce-Cio aryl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, and (Ce-Cio aryl)Ci-C3 alkoxy, or two Rgtogether with the atoms to which they are attached form a non-aromatic 3- to 6-membered ring, optionally containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen. In some embodiments, R1is (Ce-Cio aryl)Ci-C3 alkyl; and R1is optionally substituted with 1 to 5 Rgindependently selected from the group consisting of hydroxy, halogen, -CN, Ci-Ce alkyl, Ce-Cio aryl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, and (Ce-Cio aryl)Ci-C3 alkoxy.

[0101] In some embodiments, R1is (5- to 10-membered heteroaryl)Ci-C3 alkyl; and R1is optionally substituted with 1 to 5 Rgindependently selected from the group consisting of hydroxy, halogen, -CN, Ci-Ce alkyl, Ce-Cio aryl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, and (Ce-Cio aryl)Ci-C3 alkoxy; or two Rgtogether with the atoms to which they are attached form a non-aromatic 3- to 6-membered ring, optionally containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; and the 5- to 10-membered heteroaryl contains 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen.

[0102] In some embodiments, R1is (3- to 6-membered heterocycloalkyl)Ci-C3 alkyl; and R1is optionally substituted with 1 to 5 Rgindependently selected from the group consisting ofAtty. Dkt. No.: 122400-0470oxo, hydroxy, halogen, -CN, Ci-Ce alkyl, Ce-Cio aryl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, and (Ce-Cio aryl)Ci-C3 alkoxy, or two Rgtogether with the atoms to which they are attached form an aromatic 3- to 6-membered ring, optionally containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; and the 3- to 6-membered heterocycloalkyl contains 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen. In some embodiments, R1is (3- to 6-membered heterocycloalkyl)Ci-C3 alkyl; and R1is optionally substituted with 1 to 5 Rgindependently selected from the group consisting of oxo, hydroxy, halogen, -CN, Ci-Ce alkyl, Ce-Cio aryl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, and (Ce-Cio aryl)Ci-C3 alkoxy.

[0103] In some embodiments, R2is hydrogen or Ci-Ce alkyl.

[0104] In some embodiments, R3is oxygen or -CH2-.

[0105] In some embodiments, Q is -CH-.

[0106] In some embodiments, each of R4and R5is independently selected from halogen, -CN, Ci-Ce alkyl, Ci-Ce alkoxy, C2-C6 alkenyl, or cyclopropyl; wherein Ci-Ce alkyl, Ci-Ce alkoxy, and C2-C6 alkenyl are optionally substituted with 1 to 5 substituents independently selected from hydroxy, halogen, and Ci-Ce alkoxy.

[0107] In some embodiments, R6is selected from hydrogen, Ci-Ce alkyl, Ci-Ce alkoxy, -CN, or halogen; wherein Ci-Ce alkyl and Ci-Ce alkoxy are optionally substituted with 1 to 5 substituents independently selected from hydroxy, halogen, and Ci-Ce alkoxy. In some embodiments, R6is hydrogen. In some embodiments, R6is Ci-Ce alkyl.

[0108] In some embodiments, R5and R6taken together, along with the carbon atoms to which they are attached, form a C4-C6 cycloalkyl ring; a 4- to 6-membered heterocycloalkyl ring; a Ce-Cio aryl; or a 5- to 10-membered heteroaryl ring; wherein the 4- to 6-membered heterocycloalkyl ring and the 5- to 10-membered heteroaryl ring contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen. In some embodiments, R5and R6taken together, along with the carbon atoms to which they are attached, form a C4-Ce cycloalkyl ring.

[0109] In some embodiments, each of R4and R5is independently halogen or C1-C5 alkyl optionally substituted with 1 to 5 substituents independently selected from hydroxy, halogen,Atty. Dkt. No.: 122400-0470and Ci-Ce alkoxy; and R6is hydrogen; or R4is halogen or C1-C5 alkyl optionally substituted with 1 to 5 substituents independently selected from hydroxy, halogen, and Ci-Ce alkoxy; and R5and R6taken together, along with the carbon atoms to which they are attached, form a cyclobutyl, cyclopentyl, or cyclohexyl ring.

[0110] In some embodiments, R7is -NH2.

[0111] In some embodiments, the compound is selected from the group consisting of:Atty. Dkt. No.: 122400-0470Atty. Dkt. No.: 122400-0470Atty. Dkt. No.: 122400-0470Atty. Dkt. No.: 122400-0470stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0112] In some embodiments, R1is unsubstituted Ci-Ce alkyl or unsubstituted C3-C6 cycloalkyl; R2is hydrogen; R3is -CH2- or oxygen; Q is -CH-; R7is NH2 and (i) each of R4and R5is independently selected from halogen and Ci-Ce alkyl, and R6is hydrogen or Ci-Ce alkyl, or (ii) R4is halogen, and R5and R6taken together, along with the carbon atoms to which they are attached, form a cyclobutyl, cyclopentyl, or cyclohexyl ring. In some embodiments, the compound is selected from the group consisting of:Atty. Dkt. No.: 122400-0470; or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0113] In some embodiments, the compoundis or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, theAtty. Dkt. No.: 122400-0470compoundis or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound isor a stereoisomer or a tautomer thereof, or a pharmaceuticallyacceptable salt thereof. In some embodiments, the compound is NH2 ORa stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof. In someembodiments, the compoundisNHz or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound isNH2 or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is In some embodiments, thecompoundis or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound isAtty. Dkt. No.: 122400-0470or a stereoisomer or a tautomer thereof, or a pharmaceuticallyacceptable salt thereof. In some embodiments, the compound isNH? or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof. In some ciembodiments, the compoundisNH? or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0114] In some embodiments, the compound of Formula (I), or the stereoisomer or the tautomer thereof, or the pharmaceutically acceptable salt thereof, is administered at a daily dose of about 0.3 mg to about 1.2 mg. This includes about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 1.1 mg, and about 1.2 mg, including values therebetween. In some embodiments, the compound of Formula (I), or the stereoisomer or the tautomer thereof, or the pharmaceutically acceptable salt thereof, is administered at a daily dose of about 0.5 mg to about 0.9 mg. In some embodiments, the compound of Formula (I), or the stereoisomer or the tautomer thereof, or the pharmaceutically acceptable salt thereof, is administered at a daily dose of about 0.7 mg to about 0.9 mg.

[0115] In some embodiments, the compound of Formula (I), or the stereoisomer or the tautomer thereof, or the pharmaceutically acceptable salt thereof, is administered for at least 12 weeks. This includes 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or more, including values therebetween. In some embodiments, the compound of Formula (I), or the stereoisomer or the tautomer thereof, or the pharmaceutically acceptable salt thereof, is administered for at least 1 year. This includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 years, or more, including values therebetween.Atty. Dkt. No.: 122400-0470

[0116] In some embodiments, the methods disclosed herein further comprise administering to the subject a GLP-1 receptor agonist (GLP-1 RA), a statin, or a combination thereof.

[0117] In some embodiments, the GLP-1 receptor agonist includes, but is not limited to, danuglipron, albiglutide, retatrutide, dulaglutide, exenatide, liraglutide, lixisenatide, semaglutide, orforglipron, HS-10535, tirzepatide, beinaglutide, PEG-1 oxenati de, efpeglenatide, amy cretin, efocipegtrutide, CT-388, maridebart cafraglutide, VK2735, efinopegdutide, survodutide, cotadutide, pemvidutide, mazdutide, G49, or a combination of two or more thereof. In some embodiments, the GLP-1 receptor agonist includes, but is not limited to, danuglipron, albiglutide, retatrutide, dulaglutide, exenatide, liraglutide, lixisenatide, semaglutide, orforglipron, HS-10535, tirzepatide, or a combination of two or more thereof.

[0118] In some embodiments, the statin includes, but is not limited to, atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, or a combination of two or more thereof.

[0119] In some embodiments, the compound of Formula (I), or the stereoisomer or the tautomer thereof, or the pharmaceutically acceptable salt thereof and the GLP-1 receptor agonist are administered in a single composition. In some embodiments, the compound of Formula (I), or the stereoisomer or the tautomer thereof, or the pharmaceutically acceptable salt thereof, and the GLP-1 receptor agonist are each administered as separate compositions.

[0120] In some embodiments, the compound of Formula (I), or the stereoisomer or the tautomer thereof, or the pharmaceutically acceptable salt thereof, and the statin are administered in a single composition. In some embodiments, the compound of Formula (I), or the stereoisomer or the tautomer thereof, or the pharmaceutically acceptable salt thereof, and the statin are each administered as separate compositions.

[0121] In some embodiments, the compound of Formula (I), or the stereoisomer or the tautomer thereof, or the pharmaceutically acceptable salt thereof, the GLP-1 receptor agonist, and the statin are administered in a single composition. In some embodiments, the compound of Formula (I), or the stereoisomer or the tautomer thereof, or the pharmaceutically acceptable salt thereof, the GLP-1 receptor agonist, and the statin are each administered as separate compositions.Atty. Dkt. No.: 122400-0470

[0122] In some embodiments, the subject is a GLP-1 RA treatment-naive subject. In some embodiments, the subject is a statin treatment-naive subject. In some embodiments, the subject is a GLP-1 RA- and statin-treatment-naive subject. In some embodiments, the subject is on stable GLP-1 RA use (i.e., treated with GLP-1 RA for at least 12 weeks and up to 468 weeks prior to treatment with a compound of Formula (I)), stable statin use (i.e., treated with statin for at least 12 weeks and up to 468 weeks prior to treatment with a compound of Formula (I)), or both.

[0123] In another aspect, provided herein is a method to treat a disorder or disease in a subject in need thereof, the method comprising administering to the subject a compound of Formula (I):Formula (I)or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, and an additional compound selected from the group consisting of GLP-1 receptor agonists and statins; wherein:R1is Ci-Ce alkyl; C2-C10 alkenyl; C3-C12 cycloalkyl; a Ce-Cio aryl group; 3- to 6-membered heterocycloalkyl; 5- to 10-membered heteroaryl; (C3-C12 cycloalkyl)Ci-C3 alkyl; (Ce- C10 aryl)Ci-C3 alkyl; (5- to 10-membered heteroaryl)Ci-C3 alkyl; or (3- to 6-membered heterocycloalkyl)Ci-C3 alkyl; and R1is optionally substituted with 1 to 5 Rgindependently selected from the group consisting of oxo, hydroxy, halogen, -CN, Ci- Ce alkyl, Ce-Cio aryl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, and (Ce-Cio aryl)Ci-C3 alkoxy, or two Rgtogether with the atoms to which they are attached form an aromatic or nonaromatic 3- to 6-membered ring, optionally containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; wherein the 3- to 6- membered heterocycloalkyl and the 5- to 10-membered heteroaryl contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen;R2is hydrogen or an optionally substituted Ci-Ce alkyl;Atty. Dkt. No.: 122400-0470R3is -(C(Ra)2)z-, oxygen, sulfur, or -NRa-;each Rais independently a hydrogen or Ci-Ce alkyl; andz is 0, 1, 2, 3, 4 or 5;each of R4and R5is independently selected from halogen, -CN, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkoxy, optionally substituted C2-C6 alkenyl, or cyclopropyl;R6is selected from hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkoxy, -CN, or halogen;optionally R5and R6taken together, along with the carbon atoms to which they are attached, form a C4-C6 cycloalkyl ring; a 4- to 6-membered heterocycloalkyl ring; a Ce-Cio aryl; or a 5- to 10-membered heteroaryl ring; wherein the 4- to 6-membered heterocycloalkyl ring and the 5- to 10-membered heteroaryl ring contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen;Q is nitrogen or -CRC-, wherein Rcis hydrogen, halogen, or Ci-Ce alkyl;R7is -(C(Rd)2)n-N(Rd)2;each Rdis independently hydrogen or optionally substituted Ci-Ce alkyl;each n is independently selected from 0 or 1; andthe disease or disorder is selected from metabolic dysfunction-associated steatohepatitis (MASH), obesity, hyperlipidemia, hypercholesterolemia, diabetes, liver steatosis, atherosclerosis, cardiovascular diseases, hypothyroidism, and thyroid cancer.

[0124] In another aspect, provided herein is a method to treat a disorder or disease in a subject in need thereof, the method comprising administering to the subject a compound of Formula (I):Formula (I)Atty. Dkt. No.: 122400-0470or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, and an additional compound selected from the group consisting of GLP-1 receptor agonists and statins; wherein:R1is Ci-Ce alkyl; C2-C10 alkenyl; C3-C12 cycloalkyl; a Ce-Cio aryl group; 3- to 6-membered heterocycloalkyl; 5- to 10-membered heteroaryl; (C3-C12 cycloalkyl)Ci-C3 alkyl; (Ce- C10 aryl)Ci-C3 alkyl; (5- to 10-membered heteroaryl)Ci-C3 alkyl; or (3- to 6-membered heterocycloalkyl)Ci-C3 alkyl; and R1is optionally substituted with 1 to 5 Rgindependently selected from the group consisting of oxo, hydroxy, halogen, -CN, Ci- Ce alkyl, Ce-Cio aryl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, and (Ce-Cio aryl)Ci-C3 alkoxy, or two Rgtogether with the atoms to which they are attached form an aromatic or nonaromatic 3- to 6-membered ring, optionally containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; wherein the 3- to 6- membered heterocycloalkyl and the 5- to 10-membered heteroaryl contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen;R2is hydrogen or an optionally substituted Ci-Ce alkyl;R3is -(C(Ra)2)z-, oxygen, sulfur, or -NRa-;each Rais independently a hydrogen or Ci-Ce alkyl;z is 0, 1, 2, 3, 4 or 5;each of R4and R5is independently selected from halogen, -CN, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkoxy, optionally substituted C2-C6 alkenyl, or cyclopropyl;R6is selected from hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkoxy, -CN, or halogen;optionally R5and R6taken together, along with the carbon atoms to which they are attached, form a C4-C6 cycloalkyl ring; a 4- to 6-membered heterocycloalkyl ring; a Ce-Cio aryl; or a 5- to 10-membered heteroaryl ring; wherein the 4- to 6-membered heterocycloalkyl ring and the 5- to 10-membered heteroaryl ring contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen;Q is nitrogen or -CRC-, wherein Rcis hydrogen, halogen, or Ci-Ce alkyl;Atty. Dkt. No.: 122400-0470R7is -(C(Rd)2)n-N(Rd)2;each Rdis independently hydrogen or optionally substituted Ci-Ce alkyl;each n is independently selected from 0 or 1; andthe disease or disorder is selected from metabolic dysfunction-associated steatohepatitis (MASH), obesity, hyperlipidemia, hypercholesterolemia, diabetes, liver steatosis, atherosclerosis, hypothyroidism, and thyroid cancer.

[0125] In another aspect, provided herein is a method to decrease plasma concentration of total cholesterol in a subject, the method comprising administering to the subject a compound of Formula (I):Formula (I)or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, and an additional compound selected from the group consisting of GLP-1 receptor agonists; wherein: R1is Ci-Ce alkyl; C2-Cio alkenyl; Cs-Ci2cycloalkyl; a Ce-Cio aryl group; 3- to 6-membered heterocycloalkyl; 5- to 10-membered heteroaryl; (Cs-Ci2cycloalkyl)Ci-C3 alkyl; (Ce- Cio aryl)Ci-C3 alkyl; (5- to 10-membered heteroaryl)Ci-C3 alkyl; or (3- to 6-membered heterocycloalkyl)Ci-C3 alkyl; and R1is optionally substituted with 1 to 5 Rgindependently selected from the group consisting of oxo, hydroxy, halogen, -CN, Ci- Ce alkyl, Ce-Cio aryl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, and (Ce-Cio aryl)Ci-C3 alkoxy, or two Rgtogether with the atoms to which they are attached form an aromatic or nonaromatic 3- to 6-membered ring, optionally containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; wherein the 3- to 6- membered heterocycloalkyl and the 5- to 10-membered heteroaryl contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen;R2is hydrogen or an optionally substituted Ci-Ce alkyl;R3is -(C(Ra)2)z-, oxygen, sulfur, or -NRa-;Atty. Dkt. No.: 122400-0470each Rais independently a hydrogen or Ci-Ce alkyl;z is 0, 1, 2, 3, 4 or 5;each of R4and R5is independently selected from halogen, -CN, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkoxy, optionally substituted C2-C6 alkenyl, or cyclopropyl;R6is selected from hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkoxy, -CN, or halogen;optionally R5and R6taken together, along with the carbon atoms to which they are attached, form a C4-C6 cycloalkyl ring; a 4- to 6-membered heterocycloalkyl ring; a Ce-Cio aryl; or a 5- to 10-membered heteroaryl ring; wherein the 4- to 6-membered heterocycloalkyl ring and the 5- to 10-membered heteroaryl ring contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen;Q is nitrogen or -CRC-, wherein Rcis hydrogen, halogen, or Ci-Ce alkyl;R7is -(C(Rd)2)n-N(Rd)2;each Rdis independently hydrogen or optionally substituted Ci-Ce alkyl; andeach n is independently selected from 0 or 1.

[0126] In another aspect, provided herein is a combination of (i) a compound of Formula (I):Formula (I)or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, and (ii) an additional compound selected from the group consisting of GLP-1 receptor agonists for use to decrease plasma concentration of total cholesterol in a subject; wherein:R1is Ci-Ce alkyl; C2-Cio alkenyl; Cs-Cn cycloalkyl; a Ce-Cio aryl group; 3- to 6-membered heterocycloalkyl; 5- to 10-membered heteroaryl; (C3-C12 cycloalkyl)Ci-C3 alkyl; (Ce-Atty. Dkt. No.: 122400-0470Cio aryl)Ci-C3 alkyl; (5- to 10-membered heteroaryl)Ci-C3 alkyl; or (3- to 6-membered heterocycloalkyl)Ci-C3 alkyl; and R1is optionally substituted with 1 to 5 Rgindependently selected from the group consisting of oxo, hydroxy, halogen, -CN, Ci- Ce alkyl, Ce-Cio aryl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, and (Ce-Cio aryl)Ci-C3 alkoxy, or two Rgtogether with the atoms to which they are attached form an aromatic or nonaromatic 3- to 6-membered ring, optionally containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; wherein the 3- to 6- membered heterocycloalkyl and the 5- to 10-membered heteroaryl contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen;R2is hydrogen or an optionally substituted Ci-Ce alkyl;R3is -(C(Ra)2)z-, oxygen, sulfur, or -NRa-;each Rais independently a hydrogen or Ci-Ce alkyl;z is 0, 1, 2, 3, 4 or 5;each of R4and R5is independently selected from halogen, -CN, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkoxy, optionally substituted C2-C6 alkenyl, or cyclopropyl;R6is selected from hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkoxy, -CN, or halogen;optionally R5and R6taken together, along with the carbon atoms to which they are attached, form a C4-C6 cycloalkyl ring; a 4- to 6-membered heterocycloalkyl ring; a Ce-Cio aryl; or a 5- to 10-membered heteroaryl ring; wherein the 4- to 6-membered heterocycloalkyl ring and the 5- to 10-membered heteroaryl ring contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen;Q is nitrogen or -CRC-, wherein Rcis hydrogen, halogen, or Ci-Ce alkyl;R7is -(C(Rd)2)n-N(Rd)2;each Rdis independently hydrogen or optionally substituted Ci-Ce alkyl; andeach n is independently selected from 0 or 1.

[0127] In another aspect, provided herein is use of (i) a compound of Formula (I):Atty. Dkt. No.: 122400-0470Formula (I)or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, and (ii) an additional compound selected from the group consisting of GLP-1 receptor agonists, for use in the manufacture of a medicament for decreasing plasma concentration of total cholesterol in a subject; wherein:R1is Ci-Ce alkyl; C2-C10 alkenyl; C3-C12 cycloalkyl; a Ce-Cio aryl group; 3- to 6-membered heterocycloalkyl; 5- to 10-membered heteroaryl; (C3-C12 cycloalkyl)Ci-C3 alkyl; (Ce- C10 aryl)Ci-C3 alkyl; (5- to 10-membered heteroaryl)Ci-C3 alkyl; or (3- to 6-membered heterocycloalkyl)Ci-C3 alkyl; and R1is optionally substituted with 1 to 5 Rgindependently selected from the group consisting of oxo, hydroxy, halogen, -CN, Ci- Ce alkyl, Ce-Cio aryl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, and (Ce-Cio aryl)Ci-C3 alkoxy, or two Rgtogether with the atoms to which they are attached form an aromatic or nonaromatic 3- to 6-membered ring, optionally containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; wherein the 3- to 6- membered heterocycloalkyl and the 5- to 10-membered heteroaryl contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen;R2is hydrogen or an optionally substituted Ci-Ce alkyl;R3is -(C(Ra)2)z-, oxygen, sulfur, or -NRa-;each Rais independently a hydrogen or Ci-Ce alkyl;z is 0, 1, 2, 3, 4 or 5;each of R4and R5is independently selected from halogen, -CN, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkoxy, optionally substituted C2-C6 alkenyl, or cyclopropyl;R6is selected from hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkoxy, -CN, or halogen;Atty. Dkt. No.: 122400-0470optionally R5and R6taken together, along with the carbon atoms to which they are attached, form a C4-C6 cycloalkyl ring; a 4- to 6-membered heterocycloalkyl ring; a Ce-Cio aryl; or a 5- to 10-membered heteroaryl ring; wherein the 4- to 6-membered heterocycloalkyl ring and the 5- to 10-membered heteroaryl ring contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen;Q is nitrogen or -CRC-, wherein Rcis hydrogen, halogen, or Ci-Ce alkyl;R7is -(C(Rd)2)n-N(Rd)2;each Rdis independently hydrogen or optionally substituted Ci-Ce alkyl; andeach n is independently selected from 0 or 1.

[0128] The phrase “decrease plasma concentration of total cholesterol in a subject” refers to decreasing or lowering the plasma concentration of total cholesterol in a subject relative to the plasma concentration of total cholesterol without administration of (a) the compound of Formula (I), or the stereoisomer or the tautomer thereof, or the pharmaceutically acceptable salt thereof, and (b) an additional compound selected from the group consisting of GLP-1 receptor agonists. In some embodiments, the plasma concentration of total cholesterol is lowered by at least about 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, or more, including any value therebetween, relative to the plasma concentration of total cholesterol without administration of (a) the compound of Formula (I), or the stereoisomer or the tautomer thereof, or the pharmaceutically acceptable salt thereof, and (b) an additional compound selected from the group consisting of GLP-1 receptor agonists. In some embodiments, the plasma concentration of total cholesterol is lowered by about 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, or more, including any value therebetween, relative to the plasma concentration of total cholesterol without administration of (a) the compound of Formula (I), or the stereoisomer or the tautomer thereof, or theAtty. Dkt. No.: 122400-0470pharmaceutically acceptable salt thereof, and (b) an additional compound selected from the group consisting of GLP-1 receptor agonists. In some embodiments, the plasma concentration of total cholesterol is lowered by 10% to 70%, 10% to 65%, 10% to 60%, 10% to 55%, 10% to 50%, 10% to 45%, 10% to 40%, 10% to 35%, 10% to 30%, 10% to 25%, 20% to 75%, 20% to 70%, 20% to 65%, 20% to 60%, 20% to 55%, 20% to 50%, 20% to 40%, 20% to 30%, 30% to 70%, 30% to 65%, 30% to 60%, 30% to 55%, 30% to 50%, 40% to 70%, 50% to 70%, or 60% to 75% relative to the plasma concentration of total cholesterol without administration of (a) the compound of Formula (I), or the stereoisomer or the tautomer thereof, or the pharmaceutically acceptable salt thereof, and (b) an additional compound selected from the group consisting of GLP-1 receptor agonists. In some embodiments, the plasma concentration of total cholesterol is lowered by at least 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, or more, including any value therebetween, relative to the plasma concentration of total cholesterol without administration of (a) the compound of Formula (I), or the stereoisomer or the tautomer thereof, or the pharmaceutically acceptable salt thereof, and (b) an additional compound selected from the group consisting of GLP-1 receptor agonists. In humans, plasma concentration of total cholesterol is typically calculated as the sum of the amount of high-density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL) cholesterol plus 20% of the amount of triglycerides in the plasma. However, for non-human animal studies (e.g., mice), plasma concentration of total cholesterol may be measured as a single value via an enzymatic colorimetry kit, wherein cholesterol esterase breaks down cholesterol esters into free cholesterol, cholesterol oxidase oxidizes the free cholesterol into a substance that produces hydrogen peroxide, and peroxidase uses the resultant hydrogen peroxide to create a red quinone-imine dye through an oxidative coupling reaction with phenol and 4-aminophenazone.

[0129] In some embodiments, prior to administration of (a) the compound of Formula (I), or the stereoisomer or the tautomer thereof, or the pharmaceutically acceptable salt thereof, and (b) an additional compound selected from the group consisting of GLP-1 receptor agonists, the subject has a plasma concentration of total cholesterol of at least 150 mg / dL. In some embodiments, prior to administration of (a) the compound of Formula (I), or the stereoisomer or the tautomer thereof, or the pharmaceutically acceptable salt thereof, and (b) an additional compound selected from the group consisting of GLP-1 receptor agonists, the subject has a plasma concentration of total cholesterol of at least 200 mg / dL. In some embodiments, prior toAtty. Dkt. No.: 122400-0470administration of (a) the compound of Formula (I), or the stereoisomer or the tautomer thereof, or the pharmaceutically acceptable salt thereof, and (b) an additional compound selected from the group consisting of GLP-1 receptor agonists, the subject has a plasma concentration of total cholesterol of about 200 mg / dL to about 239 mg / dL. In some embodiments, prior to administration of (a) the compound of Formula (I), or the stereoisomer or the tautomer thereof, or the pharmaceutically acceptable salt thereof, and (b) an additional compound selected from the group consisting of GLP-1 receptor agonists, the subject has a plasma concentration of total cholesterol of at least 240 mg / dL. In some embodiments, prior to administration of (a) the compound of Formula (I), or the stereoisomer or the tautomer thereof, or the pharmaceutically acceptable salt thereof, and (b) an additional compound selected from the group consisting of GLP-1 receptor agonists, the subject has a plasma concentration of total cholesterol of about 240 mg / dL to about 1000 mg / dL, about 240 mg / dL to about 900 mg / dL, about 240 mg / dL to about 800 mg / dL, about 240 mg / dL to about 700 mg / dL, about 240 mg / dL to about 600 mg / dL, about 240 mg / dL to about 500 mg / dL, about 240 mg / dL to about 400 mg / dL, about 240 mg / dL to about 350 mg / dL, or about 240 mg / dL to about 300 mg / dL.SYNTHESIS OF THE COMPOUNDS

[0130] The presently disclosed compounds were synthesized using the general synthetic procedures set forth in US Patent Publication US 20200354345A1 (also US granted patent 11,091,467).EXAMPLES

[0131] Example 1. Lipoprotein(a) lowering in healthy human subjects

[0132] Compound A was administered to healthy human subjects (oral doses: 0.3, 0.5, 0.6, 0.75, or 1.0 mg; QD for 14 days). Blood samples were collected to evaluate change from baseline in level of lipoprotein(a). Results are shown in FIG. 1.cr N' ci N NHH i I

[0133] The chemical structure of compoundA is NH2

[0134] Example 2. Phase 2a Clinical TrialAtty. Dkt. No.: 122400-0470

[0135] In a randomized, double-blind, placebo-controlled Phase 2a study, 12 weeks of once daily compound A treatment in subjects with presumed MASH and F1-F3 fibrosis was well-tolerated and met the primary endpoint, demonstrating significant reductions in liver fat.

[0136] 102 subjects (~20 / arm) were randomized to receive 0.3, 0.5, 0.7 or 0.9 mg compound A or placebo orally once daily for 12 weeks. Only subjects with body weight >85 kg were enrolled in the 0.9 mg arm, with no weight restrictions for other arms.

[0137] The primary endpoint was relative change from baseline in liver fat by MRI-PDFF at Week 12 and was analyzed across subgroups, defined according to baseline characteristics, e.g., gender, body weight, GLP-1 receptor agonist use, statin use and type 2 diabetes status. Subjects on glucagon-like peptide- 1 (GLP-1) receptor agonists at a stable dose for >12 weeks prior to compound A dosing were included.

[0138] Blood samples were collected to evaluate change from baseline in levels of low density lipoprotein cholesterol (LDL-C) and lipoprotein(a) (Lp(a)).

[0139] Baseline characteristics were generally similar across arms and representative of the MASH patient population: 62% female, mean age 50 yrs, mean BMI 39 kg / m2, 47% Hispanic, 18% GLP-1 RA use, 35% statin use, 46% Type 2 diabetes. The mean time of GLP-1 RA use before first dose of compound A was 130 weeks.

[0140] Compound A dose groups met the primary endpoint, with statistically significant placebo-adjusted median relative reductions in liver fat of up to 46.2% at Week 12 with a dose response between 0.3-0.7 mg. Up to 70% of subjects achieved >30% relative reduction in liver fat compared to baseline, a positive prognostic indicator of histological improvements in MASH resolution and fibrosis reduction.

[0141] Eighteen subjects who were on stable GLP-1 RA therapy qualified for enrollment in the study, with liver fat content meeting the inclusion criteria of >10% at baseline as measured by Magnetic Resonance Imaging-Proton Density Fat Fraction (MRI-PDFF). Notably, 11 / 14 subjects on stable GLP-1 RA treated with compound A had liver fat decreases, whereas 4 / 4 subjects on stable GLP-1 RA treated with placebo had increases in liver fat over the 12-week dosing period.Atty. Dkt. No.: 122400-0470

[0142] Significant reductions in LDL-C and lipoprotein(a) were observed. In particular, compound A demonstrated a dose-dependent reduction from baseline of up to 26.8% at Week 12 for lipoprotein(a) (FIG. 2) for all subjects. The lipoprotein(a) mean percent change increased progressively in an overall dose-dependent fashion until the end of dosing at week 12 (FIG. 3). Further, lipoprotein(a) was reduced in a dose-dependent manner in the subset of subjects with stable GLP-1 RA use (i.e., treated with GLP-1 receptor agonist for at least 12 weeks and up to 468 weeks prior to treatment with compound A) who were treated with compound A (FIG.4A). More particularly, subjects on placebo only saw minor median percent change from baseline levels of lipoprotein(a), but the median percent change increased as dose of compound A increased. Comparative results for the subset of subjects who were not taking GLP-1 RA are shown in FIG. 4B. Subjects not taking GLP-1 RA and not treated with compound A exhibited an increase in lipoprotein(a) levels; however, subjects not taking GLP-1 RA but treated with compound A demonstrated up to 29.2% median percent change in lipoprotein(a) levels. Accordingly, administration of compound A was effective in reducing lipoprotein(a) levels in GLP-1 RA treatment-naive subjects but also in subjects with stable GLP-1 RA usage.

[0143] In general, compound A demonstrated a reduction from baseline of up to 15.9% at Week 12 for LDL-C (FIG. 5) for all subjects. More particularly, in subjects without any GLP-1 RA use, compound A demonstrated a reduction from baseline of up to 16% at Week 12 for LDL-C (FIG.6). The exception observed at the 0.5 mg dose is likely attributable to the limited sample size and high variability, causing this data point to deviate from the expected decrease in LDL-C median percent change from baseline, relative to placebo, that is observed in all other dose groups.

[0144] Median placebo-adjusted liver fat reduction by selected subgroups were as follows: gender (male: up to 49%; female: up to 48%), body weight (up to 39% for >100 kg and up to 52% <100 kg), statin use (yes: up to 55%, no: up to 36%), GLP-1 RA use (yes: up to 52%; no: up to 36%), or type 2 diabetes status (yes: up to 46%; no: up to 39%). Notably, subgroup analysis also indicated that there were no clinically relevant differences in liver fat reduction among participants with or without GLP-1 RA use (FIG. 7).Atty. Dkt. No.: 122400-0470

[0145] Relative percent change in liver fat at Week 12 for each individual subject is shown in FIGS. 8A-8E. Subjects who were on stable GLP-1 RA and statin therapy are indicated by darkened bars. An increasing proportion of subjects experienced a reduction in liver fat with higher doses of Compound A. These findings suggest that, even among subjects maintained on both statin and GLP-1 RA therapy, treatment with Compound A provides an additional, dosedependent decrease in liver fat. Relative percent change in lipoprotein(a) at Week 12 for each individual subject is shown in FIGS.9A-9E. Although there were no subjects with both stable GLP-1 RA use and statin use in the 0.3 mg and 0.5 mg groups, FIGS. 9A, 9D, and 9E suggest that treatment with compound A results in reduction in lipoprotein(a) for subjects with both stable GLP-1 RA use and statin use.

[0146] Taking a closer look at subjects with neither GLP-1 RA or statin use, median percent change from baseline LDL-C in such patients treated with compound A is presented in FIG. 10A. This data suggest that GLP-1 RA and statin-treatment naive subjects demonstrate reduction in LDL-C levels of up to 16.7%. Comparative data for subjects with statin use (but no GLP-1 RA use) is shown in FIG. 10B. These subjects also exhibit reduction in LDL-C levels despite that patients on placebo appear to have increased LDL-C levels. The exception observed at the 0.5 mg dose is likely attributable to the limited sample size and high variability, causing this data point to deviate from the expected decrease in LDL-C median percent change from baseline, relative to placebo, that is observed in all other dose groups.

[0147] Treatment with compound A was well-tolerated. The majority of treatment emergent adverse events (TEAEs) were mild to moderate, with one discontinuation due to worsening insomnia in a subject with pre-existing insomnia. No clinically meaningful findings in laboratory tests, ECGs, vital signs, physical exams or clinical evidence of hypo / hyperthyroidism were observed. Incidence of gastrointestinal (Gl)-related TEAEs were similar in compound A dose groups compared to placebo, including a lower incidence of diarrhea for compound A vs. placebo.

[0148] Example 3. Assessment of compound A and GLP-1 receptor agonist in diet-induced obese (DIO) mice.

[0149] Wild-type, male C57BL / 6RJRj mice were fed a high fat diet for 25 weeks to induce obesity. Animals were randomized into groups based on body weight (BW) and fat tissue massAtty. Dkt. No.: 122400-0470as measured by EchoMRI and then treated once daily with vehicles, oral (PO) 1 mg / kg compound A, subcutaneous (SC) administration GLP-1 receptor agonists (RAs), 10.0 nmol / kg semaglutide (SEMA), 3.0 nmol / kg tirzepatide (TIRZEP lo), 10.0 nmol / kg tirzepatide (TIRZEP hi), or combinations of compound A with SEMA, TIRZEP lo, or TIRZEP hi for 28 days. At the end of the study, blood samples were collected in heparinized tubes and plasma was separated. Plasma total cholesterol was measured using commercial kits (Roche Diagnostics), on the cobas c 501 analyzer.

[0150] As shown in FIG. 11, DIO mice treated with compound A monotherapy showed 47.0 ±2.8% decrease in plasma total cholesterol as compared to baseline. The SEMA monotherapy group showed 26.1 ±3.1% decrease in plasma total cholesterol mass as compared to baseline, while the combination of SEMA and compound A had an additional 40.9% decrease (67.0 ±1.5%). The low and high doses of TIRZEP led to 35.2 ±2.9% and 44.4 ±2.1% decrease in plasma total cholesterol, respectively. Combination of TIRZEP lo or TIRZEP hi with compound A induced an additional 33.3% decrease (68.5 ±0.8%) and 19.6% decrease (64.0 ±2.4%), respectively. The difference in plasma total cholesterol reduction was statistically significant between the SEMA and SEMA in combination with compound A groups, the TIRZEP lo and TIRZEP lo in combination with compound A groups, and between the TIRZEP hi and TIRZEP hi in combination with compound A groups.

[0151] References:1. Harvey CB, Williams GR. Mechanism of thyroid hormone action. Thyroid, 2002 Jun;12(6):441-6.2. Bookout AL, Jeong Y, Downes M, Yu RT, Evans RM, Mangelsdorf DJ. Anatomical profiling of nuclear receptor expression reveals a hierarchical transcriptional network. Cell, 2006, 126:789-7993. Flamant F, Baxter JD, Forrest D, Refetoff S, Samuels HH, Scanlan TS, Vennstrom B, Samarut J. International union of pharmacology. LIX. The pharmacology and classification of the nuclear receptor superfamily: thyroid hormone receptors. Pharmacol. Rev., 2006, 58:705-711Atty. Dkt. No.: 122400-04704. Haning H, Woltering M, Mueller U, Schmidt G, Schmeck C, Voehringer V, Kretschmer A, Pernerstorfer J. Bioorg. Med Chem Lett., 2005 Apr 1, 15(7): 1835-40. Novel heterocyclic thyromimetics.5. Hirano T, Kagechika H. Thyromimetics: a review of recent reports and patents (2004 - 2009). Expert Opin Ther Pat., 2010 Feb; 20(2):213-28. doi: 10.1517 / 13543770903567069.6. Kowalik MA, Columbano A, Perra A. Thyroid Hormones, Thyromimetics and Their Metabolites in the Treatment of Liver Disease. Front Endocrinol (Lausanne), 2018 Jul 10; 9:382. doi: 10.3389 / fendo.2018.00382. eCollection 2018.

[0152] While certain embodiments have been illustrated and described, it should be understood that changes and modifications can be made therein in accordance with ordinary skill in the art without departing from the technology in its broader aspects as defined in the following claims.

[0153] The embodiments, illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms “comprising,” “including,” “containing,” etc. shall be read expansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the claimed technology. Additionally, the phrase “consisting essentially of’ will be understood to include those elements specifically recited and those additional elements that do not materially affect the basic and novel characteristics of the claimed technology. The phrase “consisting of’ excludes any element not specified.

[0154] The present disclosure is not to be limited in terms of the particular embodiments described in this application. Many modifications and variations can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. Functionally equivalent methods and compositions within the scope of the disclosure, in addition to those enumerated herein, will be apparent to those skilled in the art from the foregoing descriptions. Such modifications and variations are intended to fall within the scope of the appended claims. The present disclosure is to be limited only by the terms of the appended claims, along with the fullAtty. Dkt. No.: 122400-0470scope of equivalents to which such claims are entitled. It is to be understood that this disclosure is not limited to particular methods, reagents, compounds, or compositions, which can of course vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0155] In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group.

[0156] As will be understood by one skilled in the art, for any and all purposes, particularly in terms of providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of subranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as “up to,” “at least,” “greater than,” “less than,” and the like, include the number recited and refer to ranges which can be subsequently broken down into subranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member.

[0157] All publications, patent applications, issued patents, and other documents referred to in this specification are herein incorporated by reference as if each individual publication, patent application, issued patent, or other document was specifically and individually indicated to be incorporated by reference in its entirety. Definitions that are contained in text incorporated by reference are excluded to the extent that they contradict definitions in this disclosure.

Claims

Atty. Dkt. No.: 122400-0470WHAT IS CLAIMED IS:

1. A method to decrease plasma concentration of lipoprotein(a) in a subject, the method comprising administering to the subject a compound of Formula (I):Formula (I)or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein:R1is Ci-Ce alkyl; C2-C10 alkenyl; C3-C12 cycloalkyl; a Ce-Cio aryl group; 3- to 6-membered heterocycloalkyl; 5- to 10-membered heteroaryl; (C3-C12 cycloalkyl)Ci-C3 alkyl; (Ce- C10 aryl)Ci-C3 alkyl; (5- to 10-membered heteroaryl)Ci-C3 alkyl; or (3- to 6-membered heterocycloalkyl)Ci-C3 alkyl; and R1is optionally substituted with 1 to 5 Rgindependently selected from the group consisting of oxo, hydroxy, halogen, -CN, Ci- Ce alkyl, Ce-Cio aryl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, and (Ce-Cio aryl)Ci-C3 alkoxy, or two Rgtogether with the atoms to which they are attached form an aromatic or nonaromatic 3- to 6-membered ring, optionally containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; wherein the 3- to 6- membered heterocycloalkyl and the 5- to 10-membered heteroaryl contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen;R2is hydrogen or an optionally substituted Ci-Ce alkyl;R3is -(C(Ra)2)z-, oxygen, sulfur, or -NRa-;each Rais independently a hydrogen or Ci-Ce alkyl;z is 0, 1, 2, 3, 4 or 5;each of R4and R5is independently selected from halogen, -CN, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkoxy, optionally substituted C2-C6 alkenyl, or cyclopropyl;Atty. Dkt. No.: 122400-0470R6is selected from hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkoxy, -CN, or halogen;optionally R5and R6taken together, along with the carbon atoms to which they are attached, form a C4-C6 cycloalkyl ring; a 4- to 6-membered heterocycloalkyl ring; a Ce-Cio aryl; or a 5- to 10-membered heteroaryl ring; wherein the 4- to 6-membered heterocycloalkyl ring and the 5- to 10-membered heteroaryl ring contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen;Q is nitrogen or -CRC-, wherein Rcis hydrogen, halogen, or Ci-Ce alkyl;R7is -(C(Rd)2)n-N(Rd)2;each Rdis independently hydrogen or optionally substituted Ci-Ce alkyl; andeach n is independently selected from 0 or 1.

2. A method to lower risk of myocardial infarction, aortic valve stenosis, ischemic stroke, or peripheral vascular disease in a subject, the method comprising administering to the subject a compound of Formula (I):Formula (I)or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein:R1is Ci-Ce alkyl; C2-Cio alkenyl; Cs-Ci2cycloalkyl; a Ce-Cio aryl group; 3- to 6-membered heterocycloalkyl; 5- to 10-membered heteroaryl; (Cs-Ci2cycloalkyl)Ci-C3 alkyl; (Ce- C10 aryl)Ci-C3 alkyl; (5- to 10-membered heteroaryl)Ci-C3 alkyl; or (3- to 6-membered heterocycloalkyl)Ci-C3 alkyl; and R1is optionally substituted with 1 to 5 Rgindependently selected from the group consisting of oxo, hydroxy, halogen, -CN, Ci- Ce alkyl, Ce-Cio aryl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, and (Ce-Cio aryl)Ci-C3 alkoxy, or two Rgtogether with the atoms to which they are attached form an aromatic or nonAtty. Dkt. No.: 122400-0470aromatic 3- to 6-membered ring, optionally containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; wherein the 3- to 6- membered heterocycloalkyl and the 5- to 10-membered heteroaryl contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen;R2is hydrogen or an optionally substituted Ci-Ce alkyl;R3is -(C(Ra)2)z-, oxygen, sulfur, or -NRa-;each Rais independently a hydrogen or Ci-Ce alkyl;z is 0, 1, 2, 3, 4 or 5;each of R4and R5is independently selected from halogen, -CN, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkoxy, optionally substituted C2-C6 alkenyl, or cyclopropyl;R6is selected from hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkoxy, -CN, or halogen;optionally R5and R6taken together, along with the carbon atoms to which they are attached, form a C4-C6 cycloalkyl ring; a 4- to 6-membered heterocycloalkyl ring; a Ce-Cio aryl; or a 5- to 10-membered heteroaryl ring; wherein the 4- to 6-membered heterocycloalkyl ring and the 5- to 10-membered heteroaryl ring contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen;Q is nitrogen or -CRC-, wherein Rcis hydrogen, halogen, or Ci-Ce alkyl;R7is -(C(Rd)2)n-N(Rd)2;each Rdis independently hydrogen or optionally substituted Ci-Ce alkyl; andeach n is independently selected from 0 or 1.

3. A method to prevent myocardial infarction, aortic valve stenosis, ischemic stroke, or peripheral vascular disease in a subject, the method comprising administering to the subject a compound of Formula (I):Atty. Dkt. No.: 122400-0470Formula (I)or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein:R1is Ci-Ce alkyl; C2-C10 alkenyl; C3-C12 cycloalkyl; a Ce-Cio aryl group; 3- to 6-membered heterocycloalkyl; 5- to 10-membered heteroaryl; (C3-C12 cycloalkyl)Ci-C3 alkyl; (Ce- C10 aryl)Ci-C3 alkyl; (5- to 10-membered heteroaryl)Ci-C3 alkyl; or (3- to 6-membered heterocycloalkyl)Ci-C3 alkyl; and R1is optionally substituted with 1 to 5 Rgindependently selected from the group consisting of oxo, hydroxy, halogen, -CN, Ci- Ce alkyl, Ce-Cio aryl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, and (Ce-Cio aryl)Ci-C3 alkoxy, or two Rgtogether with the atoms to which they are attached form an aromatic or nonaromatic 3- to 6-membered ring, optionally containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; wherein the 3- to 6- membered heterocycloalkyl and the 5- to 10-membered heteroaryl contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen;R2is hydrogen or an optionally substituted Ci-Ce alkyl;R3is -(C(Ra)2)z-, oxygen, sulfur, or -NRa-;each Rais independently a hydrogen or Ci-Ce alkyl;z is 0, 1, 2, 3, 4 or 5;each of R4and R5is independently selected from halogen, -CN, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkoxy, optionally substituted C2-C6 alkenyl, or cyclopropyl;R6is selected from hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkoxy, -CN, or halogen;optionally R5and R6taken together, along with the carbon atoms to which they are attached, form a C4-C6 cycloalkyl ring; a 4- to 6-membered heterocycloalkyl ring; a Ce-Cio aryl;Atty. Dkt. No.: 122400-0470or a 5- to 10-membered heteroaryl ring; wherein the 4- to 6-membered heterocycloalkyl ring and the 5- to 10-membered heteroaryl ring contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen;Q is nitrogen or -CRC-, wherein Rcis hydrogen, halogen, or Ci-Ce alkyl;R7is -(C(Rd)2)n-N(Rd)2;each Rdis independently hydrogen or optionally substituted Ci-Ce alkyl; andeach n is independently selected from 0 or 1.

4. The method of any one of claims 1-3, wherein the subject is at risk for myocardial infarction, aortic valve stenosis, ischemic stroke, or peripheral vascular disease.

5. The method of claim 1, wherein the subject is diagnosed with myocardial infarction, aortic valve stenosis, ischemic stroke, or peripheral vascular disease.

6. A method to treat myocardial infarction, aortic valve stenosis, ischemic stroke, or peripheral vascular disease in a subject in need thereof, the method comprising administering to the subject a compound of Formula (I):Formula (I)or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein:R1is Ci-Ce alkyl; C2-Cio alkenyl; Cs-Ci2cycloalkyl; a Ce-Cio aryl group; 3- to 6-membered heterocycloalkyl; 5- to 10-membered heteroaryl; (Cs-Ci2cycloalkyl)Ci-C3 alkyl; (Ce- Cio aryl)Ci-C3 alkyl; (5- to 10-membered heteroaryl)Ci-C3 alkyl; or (3- to 6-membered heterocycloalkyl)Ci-C3 alkyl; and R1is optionally substituted with 1 to 5 Rgindependently selected from the group consisting of oxo, hydroxy, halogen, -CN, Ci- Ce alkyl, Ce-Cio aryl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, and (Ce-Cio aryl)Ci-C3 alkoxy,Atty. Dkt. No.: 122400-0470or two Rgtogether with the atoms to which they are attached form an aromatic or nonaromatic 3- to 6-membered ring, optionally containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; wherein the 3- to 6- membered heterocycloalkyl and the 5- to 10-membered heteroaryl contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen;R2is hydrogen or an optionally substituted Ci-Ce alkyl;R3is -(C(Ra)2)z-, oxygen, sulfur, or -NRa-;each Rais independently a hydrogen or Ci-Ce alkyl;z is 0, 1, 2, 3, 4 or 5;each of R4and R5is independently selected from halogen, -CN, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkoxy, optionally substituted C2-C6 alkenyl, or cyclopropyl;R6is selected from hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkoxy, -CN, or halogen;optionally R5and R6taken together, along with the carbon atoms to which they are attached, form a C4-C6 cycloalkyl ring; a 4- to 6-membered heterocycloalkyl ring; a Ce-Cio aryl; or a 5- to 10-membered heteroaryl ring; wherein the 4- to 6-membered heterocycloalkyl ring and the 5- to 10-membered heteroaryl ring contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen;Q is nitrogen or -CRC-, wherein Rcis hydrogen, halogen, or Ci-Ce alkyl;R7is -(C(Rd)2)n-N(Rd)2;each Rdis independently hydrogen or optionally substituted Ci-Ce alkyl; andeach n is independently selected from 0 or 1.

7. A method to decrease plasma concentration of low density lipoprotein cholesterol (LDL-C) in a subject, the method comprising administering to the subject a compound of Formula (I):Atty. Dkt. No.: 122400-0470Formula (I)or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof; wherein: R1is Ci-Ce alkyl; C2-C10 alkenyl; C3-C12 cycloalkyl; a Ce-Cio aryl group; 3- to 6-membered heterocycloalkyl; 5- to 10-membered heteroaryl; (C3-C12 cycloalkyl)Ci-C3 alkyl; (Ce- C10 aryl)Ci-C3 alkyl; (5- to 10-membered heteroaryl)Ci-C3 alkyl; or (3- to 6-membered heterocycloalkyl)Ci-C3 alkyl; and R1is optionally substituted with 1 to 5 Rgindependently selected from the group consisting of oxo, hydroxy, halogen, -CN, Ci- Ce alkyl, Ce-Cio aryl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, and (Ce-Cio aryl)Ci-C3 alkoxy, or two Rgtogether with the atoms to which they are attached form an aromatic or nonaromatic 3- to 6-membered ring, optionally containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; wherein the 3- to 6- membered heterocycloalkyl and the 5- to 10-membered heteroaryl contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen;R2is hydrogen or an optionally substituted Ci-Ce alkyl;R3is -(C(Ra)2)z-, oxygen, sulfur, or -NRa-;each Rais independently a hydrogen or Ci-Ce alkyl;z is 0, 1, 2, 3, 4 or 5;each of R4and R5is independently selected from halogen, -CN, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkoxy, optionally substituted C2-C6 alkenyl, or cyclopropyl;R6is selected from hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkoxy, -CN, or halogen;optionally R5and R6taken together, along with the carbon atoms to which they are attached, form a C4-C6 cycloalkyl ring; a 4- to 6-membered heterocycloalkyl ring; a Ce-Cio aryl;Atty. Dkt. No.: 122400-0470or a 5- to 10-membered heteroaryl ring; wherein the 4- to 6-membered heterocycloalkyl ring and the 5- to 10-membered heteroaryl ring contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen;Q is nitrogen or -CRC-, wherein Rcis hydrogen, halogen, or Ci-Ce alkyl;R7is -(C(Rd)2)n-N(Rd)2;each Rdis independently hydrogen or optionally substituted Ci-Ce alkyl; andeach n is independently selected from 0 or 1.

8. The method of any one of claims 1-7, wherein the method further comprises administering to the subject a GLP-1 receptor agonist, a statin, or a combination thereof.

9. The method of claim 8, wherein the GLP-1 receptor agonist is danuglipron, albiglutide, retatrutide, dulaglutide, exenatide, liraglutide, lixisenatide, semaglutide, orforglipron, HS-10535, tirzepatide, beinaglutide, PEG-1 oxenati de, efpeglenatide, amy cretin, efocipegtrutide, CT-388, maridebart cafraglutide, VK2735, efinopegdutide, survodutide, cotadutide, pemvidutide, mazdutide, G49, or a combination of two or more thereof.

10. The method of claim 8 or claim 9, wherein the statin is atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, or a combination of two or more thereof.

11. A method to treat a disorder or disease in a subject in need thereof, the method comprising administering to the subject a compound of Formula (I):Formula (I)or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, and an additional compound selected from the group consisting of GLP-1 receptor agonists and statins; wherein:Atty. Dkt. No.: 122400-0470R1is Ci-Ce alkyl; C2-C10 alkenyl; C3-C12 cycloalkyl; a Ce-Cio aryl group; 3- to 6-membered heterocycloalkyl; 5- to 10-membered heteroaryl; (C3-C12 cycloalkyl)Ci-C3 alkyl; (Ce- C10 aryl)Ci-C3 alkyl; (5- to 10-membered heteroaryl)Ci-C3 alkyl; or (3- to 6-membered heterocycloalkyl)Ci-C3 alkyl; and R1is optionally substituted with 1 to 5 Rgindependently selected from the group consisting of oxo, hydroxy, halogen, -CN, Ci- Ce alkyl, Ce-Cio aryl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, and (Ce-Cio aryl)Ci-C3 alkoxy, or two Rgtogether with the atoms to which they are attached form an aromatic or nonaromatic 3- to 6-membered ring, optionally containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; wherein the 3- to 6- membered heterocycloalkyl and the 5- to 10-membered heteroaryl contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen;R2is hydrogen or an optionally substituted Ci-Ce alkyl;R3is -(C(Ra)2)z-, oxygen, sulfur, or -NRa-;each Rais independently a hydrogen or Ci-Ce alkyl;z is 0, 1, 2, 3, 4 or 5;each of R4and R5is independently selected from halogen, -CN, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkoxy, optionally substituted C2-C6 alkenyl, or cyclopropyl;R6is selected from hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkoxy, -CN, or halogen;optionally R5and R6taken together, along with the carbon atoms to which they are attached, form a C4-C6 cycloalkyl ring; a 4- to 6-membered heterocycloalkyl ring; a Ce-Cio aryl; or a 5- to 10-membered heteroaryl ring; wherein the 4- to 6-membered heterocycloalkyl ring and the 5- to 10-membered heteroaryl ring contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen;Q is nitrogen or -CRC-, wherein Rcis hydrogen, halogen, or Ci-Ce alkyl;R7is -(C(Rd)2)n-N(Rd)2;each Rdis independently hydrogen or optionally substituted Ci-Ce alkyl;Atty. Dkt. No.: 122400-0470each n is independently selected from 0 or 1; andthe disease or disorder is selected from metabolic dysfunction-associated steatohepatitis (MASH), obesity, hyperlipidemia, hypercholesterolemia, diabetes, liver steatosis, atherosclerosis, cardiovascular diseases, hypothyroidism, and thyroid cancer.

12. The method of claim 11, wherein the GLP-1 receptor agonists are danuglipron, albiglutide, retatrutide, dulaglutide, exenatide, liraglutide, lixisenatide, semaglutide, orforglipron, HS-10535, tirzepatide, beinaglutide, PEG-1 oxenati de, efpeglenatide, amy cretin, efocipegtrutide, CT-388, maridebart cafraglutide, VK2735, efinopegdutide, survodutide, cotadutide, pemvidutide, mazdutide, and G49.

13. The method of claim 11 or claim 12, wherein the statins are atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin.

14. A method to decrease plasma concentration of total cholesterol in a subject, the method comprising administering to the subject a compound of Formula (I):Formula (I)or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, and an additional compound selected from the group consisting of GLP-1 receptor agonists; wherein: R1is Ci-Ce alkyl; C2-C10 alkenyl; C3-C12 cycloalkyl; a Ce-Cio aryl group; 3- to 6-membered heterocycloalkyl; 5- to 10-membered heteroaryl; (C3-C12 cycloalkyl)Ci-C3 alkyl; (Ce- C10 aryl)Ci-C3 alkyl; (5- to 10-membered heteroaryl)Ci-C3 alkyl; or (3- to 6-membered heterocycloalkyl)Ci-C3 alkyl; and R1is optionally substituted with 1 to 5 Rgindependently selected from the group consisting of oxo, hydroxy, halogen, -CN, Ci- Ce alkyl, Ce-Cio aryl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, and (Ce-Cio aryl)Ci-C3 alkoxy, or two Rgtogether with the atoms to which they are attached form an aromatic or nonaromatic 3- to 6-membered ring, optionally containing 1 or 2 ring heteroatomsAtty. Dkt. No.: 122400-0470independently selected from oxygen, sulfur, and nitrogen; wherein the 3- to 6- membered heterocycloalkyl and the 5- to 10-membered heteroaryl contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen;R2is hydrogen or an optionally substituted Ci-Ce alkyl;R3is -(C(Ra)2)z-, oxygen, sulfur, or -NRa-;each Rais independently a hydrogen or Ci-Ce alkyl;z is 0, 1, 2, 3, 4 or 5;each of R4and R5is independently selected from halogen, -CN, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkoxy, optionally substituted C2-C6 alkenyl, or cyclopropyl;R6is selected from hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkoxy, -CN, or halogen;optionally R5and R6taken together, along with the carbon atoms to which they are attached, form a C4-C6 cycloalkyl ring; a 4- to 6-membered heterocycloalkyl ring; a Ce-Cio aryl; or a 5- to 10-membered heteroaryl ring; wherein the 4- to 6-membered heterocycloalkyl ring and the 5- to 10-membered heteroaryl ring contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen;Q is nitrogen or -CRC-, wherein Rcis hydrogen, halogen, or Ci-Ce alkyl;R7is -(C(Rd)2)n-N(Rd)2;each Rdis independently hydrogen or optionally substituted Ci-Ce alkyl; andeach n is independently selected from 0 or 1.

15. The method of claim 14, wherein the GLP-1 receptor agonists are danuglipron, albiglutide, retatrutide, dulaglutide, exenatide, liraglutide, lixisenatide, semaglutide, orforglipron, HS-10535, tirzepatide, beinaglutide, PEG-1 oxenati de, efpeglenatide, amy cretin, efocipegtrutide, CT-388, maridebart cafraglutide, VK2735, efinopegdutide, survodutide, cotadutide, pemvidutide, mazdutide, and G49.Atty. Dkt. No.: 122400-047016. A method to decrease plasma concentration of total cholesterol in a subject, the method comprising administering to the subject a compound of Formula (I):N'NR5N NHI i iR2R6Formula (I)or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R1is Ci-Ce alkyl; C2-C10 alkenyl; C3-C12 cycloalkyl; a Ce-Cio aryl group; 3- to 6-membered heterocycloalkyl; 5- to 10-membered heteroaryl; (C3-C12 cycloalkyl)Ci-C3 alkyl; (Ce- C10 aryl)Ci-C3 alkyl; (5- to 10-membered heteroaryl)Ci-C3 alkyl; or (3- to 6-membered heterocycloalkyl)Ci-C3 alkyl; and R1is optionally substituted with 1 to 5 Rgindependently selected from the group consisting of oxo, hydroxy, halogen, -CN, Ci- Ce alkyl, Ce-Cio aryl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, and (Ce-Cio aryl)Ci-C3 alkoxy, or two Rgtogether with the atoms to which they are attached form an aromatic or nonaromatic 3- to 6-membered ring, optionally containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; wherein the 3- to 6- membered heterocycloalkyl and the 5- to 10-membered heteroaryl contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen;R2is hydrogen or an optionally substituted Ci-Ce alkyl;R3is -(C(Ra)2)z-, oxygen, sulfur, or -NRa-;each Rais independently a hydrogen or Ci-Ce alkyl;z is 0, 1, 2, 3, 4 or 5;each of R4and R5is independently selected from halogen, -CN, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkoxy, optionally substituted C2-C6 alkenyl, or cyclopropyl;R6is selected from hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkoxy, -CN, or halogen;Atty. Dkt. No.: 122400-0470optionally R5and R6taken together, along with the carbon atoms to which they are attached, form a C4-C6 cycloalkyl ring; a 4- to 6-membered heterocycloalkyl ring; a Ce-Cio aryl; or a 5- to 10-membered heteroaryl ring; wherein the 4- to 6-membered heterocycloalkyl ring and the 5- to 10-membered heteroaryl ring contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen;Q is nitrogen or -CRC-, wherein Rcis hydrogen, halogen, or Ci-Ce alkyl;R7is -(C(Rd)2)n-N(Rd)2;each Rdis independently hydrogen or optionally substituted Ci-Ce alkyl;each n is independently selected from 0 or 1; andthe compound of Formula (I), or the stereoisomer or the tautomer thereof, or the pharmaceutically acceptable salt thereof, is the sole active agent administered to the subject.

17. The method of any one of claims 1-16, wherein R1is Ci-Ce alkyl, C2-Cio alkenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyridazin-3(2H)-one, phenyl, naphthyl, pyridinyl, cinnolinyl, isoquinolinyl, quinolinyl, pyrazolo[l,5-a]pyridinyl, imidazo[l,5-a]pyridinyl, benzo[b]thiophenyl, (cyclobutyl)Ci-C3 alkyl, (cyclopentyl)Ci-C3 alkyl, benzyl, (tetrahydrofuranyl)Ci-C3 alkyl, or (tetrahydropyranyl)Ci-C3 alkyl group; and R1is optionally substituted with 1 to 5 Rgindependently selected from the group consisting of hydroxy, halogen, -CN, Ci-Ce alkyl, Ce-C10 aryl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, and (Ce-Cio aryl)Ci-C3 alkoxy, or two Rgtogether with the atoms to which they are attached form an aromatic or non-aromatic 3- to 6-membered ring, optionally containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen.

18. The method of any one of claims 1-16, wherein R1is Ce-Cio aryl or 5- to 10-membered heteroaryl containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; and R1is optionally substituted with 1 to 5 Rgindependently selected from the group consisting of hydroxy, halogen, -CN, Ci-Ce alkyl, Ce-Cio aryl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, and (Ce-Cio aryl)Ci-C3 alkoxy, or two Rgtogether with the atoms to which they are attachedAtty. Dkt. No.: 122400-0470form a non-aromatic 3- to 6-membered ring, optionally containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen.

19. The method of any one of claims 1-16, wherein R1is benzene optionally substituted with 1 to 5 Rgindependently selected from the group consisting of hydroxy, halogen, -CN, Ci-Ce alkyl, Ci-Ce alkoxy, and Ci-Ce haloalkoxy, or two Rgtogether with the atoms to which they are attached form a non-aromatic 3- to 6-membered ring, optionally containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen.

20. The method of any one of claims 1-16, wherein R1is Ci-Ce alkyl or C3-C12 cycloalkyl; and R1is optionally substituted with 1 to 5 Rgindependently selected from the group consisting of oxo, hydroxy, halogen, -CN, Ci-Ce alkyl, Ce-Cio aryl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, and (Ce-Cio aryl)Ci-C3 alkoxy.

21. The method of any one of claims 1-16, wherein R1is Ci-Ce alkyl optionally substituted with 1 to 5 Rgindependently selected from the group consisting of hydroxy, halogen, -CN, Ci-Ce alkyl, Ce-Cio aryl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, and (Ce-Cio aryl)Ci-C3 alkoxy.

22. The method of any one of claims 1-16, wherein R1is C3-C12 cycloalkyl optionally substituted with 1 to 5 Rgindependently selected from the group consisting of oxo, hydroxy, halogen, -CN, Ci-Ce alkyl, Ce-Cio aryl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, and (Ce-Cio aryl)Ci-C3 alkoxy.

23. The method of any one of claims 1-22, wherein R3is oxygen or -CH2-.

24. The method of any one of claims 1-23, wherein Q is -CH-.

25. The method of any one of claims 1-24, wherein:each of R4and R5is independently halogen or C1-C5 alkyl optionally substituted with 1 to 5 substituents independently selected from hydroxy, halogen, and Ci-Ce alkoxy; and R6is hydrogen; orR4is halogen or C1-C5 alkyl optionally substituted with 1 to 5 substituents independently selected from hydroxy, halogen, and Ci-Ce alkoxy; and R5and R6taken together, alongAtty. Dkt. No.: 122400-0470with the carbon atoms to which they are attached, form a cyclobutyl, cyclopentyl, or cyclohexyl ring.

26. The method of any one of claims 1-16, wherein the compound is selected from the group consisting of:Atty. Dkt. No.: 122400-0470Atty. Dkt. No.: 122400-0470Atty. Dkt. No.: 122400-0470Atty. Dkt. No.: 122400-0470Atty. Dkt. No.: 122400-0470stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

27. The method of any one of claims 1-16, wherein the compound is selected from the group consisting of:Atty. Dkt. No.: 122400-0470Cl; or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

28. The method of any one of claims 1-16, wherein the compound of Formula (I), is, or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

29. The method of any one of claims 1-28, wherein the compound of Formula (I), or the stereoisomer or the tautomer thereof, or the pharmaceutically acceptable salt thereof, is administered at a daily dose of about 0.3 mg to about 1.2 mg.

30. The method of any one of claims 1-29, wherein the compound of Formula (I), or the stereoisomer or the tautomer thereof, or the pharmaceutically acceptable salt thereof, is administered at a daily dose of about 0.5 mg to about 0.9 mg.

31. The method of any one of claims 1-30, wherein the compound of Formula (I), or the stereoisomer or the tautomer thereof, or the pharmaceutically acceptable salt thereof, is administered for at least 12 weeks.

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