WO2025024564A1 - Small molecules that prevent statin-induced accumulation of hmg coa reductase - Google Patents

Abstract

Compounds, compositions, and methods for making and using the compounds for treatment of cardiovascular or cholesterol related disorder diseases caused by mutations in UBIAD1 are provided herein. Mechanistically, these compounds were found to be allosteric activators of UBIAD1 gene and enhance its affinity for GGpp.

Description

SMALL MOLECULES THAT PREVENT STATIN-INDUCED ACCUMULATION OF HMG CoA REDUCTASE

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims the benefit of US Provisional Application No. 63/515,157 entitled “SMALL MOLECULES THAT PREVENT STATIN-INDUCED ACCUMULATION OF HMG CoA REDUCTASE”, filed on July 24, 2023, the entire contents of which are entirely incorporated by reference herein.

ACKNOWLEDGEMENT OF GOVERNMENT SUPPORT

[0001] Th is invention was made with government support undergrant no. GM141088 awarded by the National Institutes of Health (NIH). The government has certain rights in the invention.

BACKGROUND

1. Field

[0002] Provided herein are compositions and methods for treating or reducing the risk of acquiring a cardiovascular or cholesterol related disorder.

2. Discussion of Related Art

[0003] Cholesterol related disorders include any one or more of the following: hypercholesterolemia, hyperlipidemia, heart disease, metabolic syndrome, diabetes, coronary heart disease, stroke, cardiovascular diseases, Alzheimer's disease and generally dyslipidemias, which can be manifested, for example, by an elevated total serum cholesterol, elevated LDL, elevated triglycerides, elevated VLDL, and/or low HDL.

[0004] HMG CoA reductase (HMGCR) is the rate-limiting enzyme in the mevalonate pathwaythat produces cholesterol and nonsterol isoprenoids including geranylgeranyl pyrophosphate (GGpp). Feedback control of HMGCR involves its sterol -induced binding to ER membrane proteins called Insigs, which is obligatory for ubiquitination and ER-associated degradation (ERAD) of HMGCR. Sterols also cause HMGCR to bind UbiA prenyltransferase domain-containing protein-1 (UBIAD1 ), which uses GGpp to synthesize a subtype of vitamin K2.

[0005] UBIAD1 binding protects HMGCR from ERAD, allowing cells to continuously synthesize nonsterol isoprenoids when sterols are abundant. GGpp triggers release of UBIAD1 from HMGCR, enhancing ERAD and stimulating translocation of UBIAD1 from ER to Golgi.

[0006] More than 20 million American take statins daily to lower plasma low density lipoprotein (LDL)-cholesterol and reduce incidence of atherosclerotic cardiovascular disease (ACVD) and heart attacks. Statins competitively inhibit HMGCR and reduce cholesterol synthesis in liver, stimulating expression of hepatic LDL-receptors that remove LDL from circulation. Although statins reduce plasma LDL by up to 50%, further reduction is limited because the drugs block ERAD of HMGCR, causing its marked accumulation in livers of animals and humans. This accumulation partially overcomes inhibitory effects of statins, allowingcontinued synthesis of cholesterol th at limits LDL lowering. Because of this limitation, statins only reduce heart attacks by 30%. There is a need thereof for better treatments for cholesterol related disorders.

SUMMARY

[0007] In some embodiments, a compound of Formula (I) is provided

Formula (I) wherein Ri and R2 are independently of each other hydrogen, halogen, alkyl, alkyl amine, alkyl sulfonamide, aryl, substituted aryl, heterocyclic aryl amine, substituted heterocyclic aryl amine, cyclic aliphatic amine, heterocyclic aliphatic amine, substituted heterocyclic aliphatic amine, alkyne; or together with the carbon atom to form a cycloalkyl, a cycloalkenyl, or a heterocyclylalkyl ring;

R3 is an aryl or substituted aryl; and

Y is an oxygen, nitrogen, or sulfur; or a pharmaceutically acceptable salt thereof.

[0008] In some embodiments of the compound of Formula (I), the substituted aryl is a phenyl group with a substituted carbon atom on a para position as in Formula (II)

Formula (II).

[0009] In some embodiments, X in Formula (II) is a halogen or a cycloalkane carbonitrile with formula -CnH(2n-2)CN, wherein n is 3 or more.

[0010] In some embodiments, in Formula (II) the halogen is fluorine, chlorine, or iodine.

[0011] In some embodiments, the compound of Formula (I) comprises a biotin group.

[0012] In some embodiments of the compound, the biotin group is linked to the compound via the alkyne group.

[0013] In some embodiments of the present disclosure, the compound is photoactivatable.

[0014] In some embodiments of the present disclosure, in the compound of Formula (I) wherein Ri is hydrogen and R2 is selected from the group consisting of branched or unbranched alkyl, alkyl amine, alkyl sulfonamide, alkyne, aryl, substituted aryl, heterocyclic aryl amine, substituted heterocyclic aryl amine, heterocyclic aliphatic amine, and substituted heterocyclic aliphatic amine.

[0015] In some embodiments of the present disclosure, in the compound of Formula (I) R2 is selected from the group consisting of propane, isopentane, neopentane, toluene, 3-methylpyridine, 4-methylpyridine, 1-fluoro-4-methylbenzene, toluene, te/t- butyl 3-methylazetidine-1 -carboxylate, 1 -(methylsu If ony I )pi peri dine, ethanesulfonamide, and /V,/V-dimethylpropan-1 -amine.

[0016] In some embodiments of the present disclosure, in the compound of Formula (II) Ri and R2 combine to form a heterocycle with both amine and ether groups as in Formula (III)

Formula (III) wherein X is a halogen or a cycloalkane carbonitrile with formula -CnH(2n-2)CN, wherein n is 3 or more.

[0017] In some embodiments of the present disclosure, in the compound of Formula (I) Ri and R2are diethylenimide oxide.

[0018] In certain aspects, the compound is:

Compound 13;

Compound 17.

[0019] In some aspects, the compound of Formula (I) is an allosteric activator of a protein encoding gene.

[0020] In some aspects, the compound of Formula (I) is an allosteric activator of the protein encoding gene UBIAD1 . [0021] In some embodiments, the compound increases affinity of UBIAD1 for GGpp.

[0022] In some aspects, the present disclosure, a method of treating or reducing the risk of acquiring a cardiovascular or cholesterol related disorder to a subject in need thereof is provided. The method includes administering a therapeutically effective amount of a compound as described above orApatinib to the subject.

[0023] In some embodiments of the method, the subject has a high blood plasma cholesterol value relative to a predetermined blood plasma cholesterol value and/or has a genetic predisposition to high blood plasma cholesterol.

[0024] In some embodiments of the method, the subject has a high blood plasma cholesterol value relative to a predetermined blood plasma cholesterol value and the predetermined blood plasma cholesterol value is less than or equal to 200 mg/dL.

[0025] In some embodiments of the method, the subject has a genetic predisposition to high blood plasma cholesterol and the genetic predisposition is a mutation in UBIAD1 , LDLR, APOB, SREBP, SCAP, and/or PCSK9 genes.

[0026] In some embodiments of the method, the cholesterol is a low-density lipoprotein (LDL)-cholesterol.

[0027] In some embodiments of the method, the cardiovascular or cholesterol related disorder is Schnyder corneal dystrophy (SCD), corneal dystrophy, peripheral artery disease, hypercholesterolemia, hyperlipidemia/ dyslipidemia, sitosterolemia, atherosclerosis, arteriosclerosis, or xanthoma.

[0028] In some embodiments of the method, the compound reduces plasma cholesterol value by enabling ubiquitination and ER-associated degradation of HMG CoA reductase.

BRIEF DESCRIPTION OF THE FIGURES

[0029] The following drawings form part of the present specification and are included to further demonstrate certain embodiments of the present disclosure. Certain embodiments can be better understood by reference to one or more of these drawings in combination with the detailed description of specificembodiments presented herein. [0030] FIG. 1 represents an exemplary experiment illustrating a chemical reaction equation for the general synthesis of compounds in accordance with certain embodiments of the present disclosure.

[0031] FIG. 2 represents exemplary starting materials pyridine derivatives.

[0032] FIG. 3 represents an immunoblot of cells lacking endogenous UBIAD1 transfected with an expression plasmid encoding HMG CoA reductase in certain embodiments of the present disclosure.

[0033] FIG. 4 represents a SDS-PAGE and immunoblot analysisof proteins in certain embodiments of the present disclosure.

DEFINITIONS

[0034] To facilitate understanding of the disclosure set forth herein, a number of terms are defined below.

[0035] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. All patents, applications, published applications and other publications are incorporated by reference in their entirety. In the event that there are a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.

[0036] The singular forms “a,” “an,” and “the” include plural references, unless the context clearly dictates otherwise.

[0037] “About” is used to provide flexibility to a numerical range endpoint by providing that a given value may be “slightly above” or “slightly below” the endpoint without affecting the desired result. The term “about” in association with a numerical value means that the numerical value can vary plus orminus by 5% or less of the numerical value.

[0038] 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 itwere individually recited herein. For example, if a concentration range is stated as 1 % to 50%, it is intended that values such as 2% to 40%, 10% to 30%, or 1 % to 3%, etc., are expressly enumerated in this specification. These are only examples of what is specifically intended, and all possible combinations of numerical values between and including the lowest value and the highestvalue enumerated are to be considered to be expressly stated in this disclosure.

[0039] Th roughoutthis specification, unless the context requires otherwise, the word “comprise” and “include” and variations (e.g., “comprises,” “comprising,” “includes,” “including”) will be understood to imply the inclusion of a stated component, feature, element, or step or group of components, features, elements or steps but not the exclusion of any other integer or step or group of integers or steps.

[0040] As used herein, “and/or” refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations where interpreted in the alternative (“or”).

[0041] Moreover, the present disclosure also contemplates that in some embodiments, any feature or combination of features setforth herein can be excluded or omitted. To illustrate, if the specification states that a complex comprises components A, B and C, it is specifically intended that any of A, B or C, or a combination thereof, can be omitted and disclaimed singularly or in any combination.

[0042] “Pharmaceutical composition” means a mixture of substances suitable for administering to an individual that includes a pharmaceutical agent. As used herein a pharmaceutical composition comprises one or more of the compounds as disclosed herein compounded with suitable pharmaceutical excipients. The language “pharmaceutical composition” includes preparations suitable for administration to mammals, e.g., humans. When the compounds described herein are administered as pharmaceuticals to mammals, e.g., humans, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 % to 99.5% (preferably, 1 % to 90%) of active ingredient in combination with a pharmaceutically acceptable excipient.

[0043] The phrase “pharmaceutically acceptable” refers to molecular entities and compositions that are physiologically tolerable and do not typically produce a toxic, allergic, or similar untoward reaction, such as gastric upset, dizziness and the like, when administered to a human. Preferably, as used herein, the term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. or European Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0044] The language “effective amount” of the compound as used herein is defined as the amountof the molecules of the present disclosure that are necessary to result in the desired physiological change in the cell or tissue to which it is administered. The term "therapeutically effective amount" as used herein is defined as the amount of the molecu les or compositions of the present disclosu re that ach ieves a desired effect with respect to treating or preventing a cardiovascular or cholesterol related disorder that is linked to UBIAD1 . Thus, in some aspects, an amount of molecules that provides a physiological change is considered an "effective amount" ora "therapeutically effective amount." In an example, a therapeutically effective amount of the compound described herein is the amount sufficient to treat Schnyder corneal dystrophy. In an example, an effective amount of the compound described herein is the amount sufficient to lower the blood plasma cholesterol. The effective amount can vary depending on such factors as the size and weight of the subject, the type of illness, or the particular compound described herein. For example, the choice of the compound described herein can affectwhat constitutes a “therapeutically effective amount.” One of ordinary skill in the art would be able to study the factors contained herein and make the determination regarding the therapeutically effective amount of the compounds described herein without undue experimentation.

[0045] As used herein, the term “patient”, “subject”, including “test subject” refers to any organism to which the compound or compounds described herein are administered in accordance with the present disclosure e.g., for experimental, diagnostic, prophylactic, and/or therapeutic purposes. Typical subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, humans, insects, worms, etc.). In an aspect, the subject is a human. Both pediatric and adult subjects are included. For example, in any of the methods described herein, the subject can be at least 6 months old (e.g., 6 months or older, 12 months or older, 18 months or older, 2 years or older, 4 years or older, 6 years or older, 10 years or older, 13 years or older, 16 years or older, 18 years or older, 21 years or older, 25 years or older, 30 years or older, 35 years or older, 40 years or older, 45 years or older, 50 years or older, 60 years or older, 65 years or older, 70 years or older, 75 years or older, 80 years or older, 85 years or older, 90 years or older, or 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14, 15, 16 ,18, 20, 21 , 24, 25, 27, 28, 30, 33, 35, 37, 39, 40, 42, 44, 45, 48, 50, 52, 55, 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98, 99, 100, 101 , 102, 103, 104, or more years old). In some aspects, a subject may have a cardiovascular or cholesterol related disorder. In some aspects, the cholesterol related disorder is Schnydercorneal dystrophy (SCD).

[0046] The term “treating,” as used herein refers to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or ameliorating one or more symptoms of such condition or disorder. The term “treatment,” “treatment” or “therapy” of a subject refers to any type of intervention, or the administration of a compound as disclosed herein, to a subject with the objective of reversing, alleviating, ameliorating, inhibiting, slowingdown orpreventingtheonset, progression, development, severity or recurrence of a symptom, complication, condition or biochemical indicia associated with a disease. In some aspects, the disease is a cardiovascular or cholesterol related disorder as provided herein.

[0047] The term “alkyl” as used herein means a straight or branched hydrocarbon radical having from 1 to 10 carbon atoms and includes, for example, methyl, ethyl, n- propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, iso-pentyl, n-hexyl, neopentyl, and the like.

[0048] The term “alkenyl” as used means straight and branched hydrocarbon radicals having from 2 to 8 carbon atoms and at least one double bond and includes, but is not limited to, ethenyl, 3-buten-1 -yl, 2-ethenylbutyl, 3-hexen-1 -yl, and the like. The term “alkenyl” includes cycloalkenyl, and heteroalkenyl in which 1 to 3 heteroatoms selected from O, S, N, or substituted nitrogen may replace carbon atoms.

[0049] The term “alkynyl” as used means straightand branched hydrocarbon radicals having from 2 to 8 carbon atoms and at least one triple bond and includes, but is not limited to, ethynyl, 3-butyn-1 -yl, propynyl, 2-butyn-1 -yl, 3-pentyn-1 -yl, and the like.

[0050] The term “cycloalkyl” as used means a monocyclic or polycyclic hydrocarbyl group having from 3 to 8 carbon atoms, for instance, cyclopropyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclobutyl, adamantyl, norpinanyl, decalinyl, norbornyl, cyclohexyl, and cyclopentyl. Such groups can be substituted with groups such as hydroxy, keto, amino, alkyl, and dialkylamino, and the like. Also included are rings in which 1 to 3 heteroatoms replace carbons. Such groups are termed “het-erocyclyl,” which means a cycloalkyl group also bearing at least one heteroatom selected from 0, S, N, or substituted nitrogen. Examples of such groups include, butare not limited to, oxiranyl, pyrrolidinyl, piperidyl, tetrahydropyran, and morpholine.

[0051] The term “alkoxy” as used herein means a straight or branched chain alkyl groups having 1 -10 carbon atoms and linked through oxygen. Examples of such groups include, butare not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyloxy, isopentoxy, n eopen toxy, hexoxy, 2- hexoxy, 3-hexoxy, and 3-methylpentoxy. In addition, alkoxy refers to polyethers such as — 0— (CH2)2— 0— CH3, and the like.

[0052] The alkyl, alkenyl, alkoxy, and alkynyl groups described herein are optionally substituted, prefer-ably by 1 to 3 groups selected from NR4R5, phenyl, substituted phenyl, th io C 1 -C6 alkyl, C1 -C6alkoxy, hydroxy, carboxy, C1 -C6 alkoxycarbonyl, halo, nitrile, cycloalkyl, and a 5- or 6-membered carbocyclic ring or heterocyclic ring having 1 or 2 heteroatoms selected from nitrogen, substituted nitrogen, oxygen, and sulfur. “Substituted nitrogen” means nitrogen bearing C1 -C6 alkyl or (CH2)pPh where p is 1 , 2, or 3. Perhalo and polyhalo substitution is also included.

[0053] Examples of substituted alkyl groups include, but are not limited to, 2- aminoethyl, 2-hydroxyethyl, pentachloroethyl, trifluoromethyl, 2-diethylaminoethyl, 2- dimethylaminopropyl, ethoxycarbonyl methyl, 3-phenylbutyl, methanylsulfanylmethyl, methoxymethyl, 3-hydroxypentyl, 2-carboxybutyl, 4-chlorobutyl, 3-cyclopropyl propyl, pentafluoroethyl, 3-morpholinopropyl, piper-azinylmethyl, and 2-(4- methylpiperazinyl)ethyl.

[0054] Examples of substituted alkynyl groups include, but are not limited to, 2- methoxyethynyl, 2-ethylsulfanylethynyl, 4-(1 -piperazinyl)-3-(butynyl), 3-phenyl-5- hexynyl, 3-diethylamino-3-butynyl, 4-chloro-3-butynyl, 4-cyclobutyl-4-hexenyl, andthe like.

[0055] Typical substituted alkoxy groups include aminomethoxy, trifluoromethoxy, 2- diethylaminoethoxy, 2-eth oxycarbonylethoxy, 3-hydroxypropoxy, 6-carboxhexyloxy, and the like.

[0056] Further, examples of substituted alkyl, alkenyl, and alkynyl groups include, but are not limited to, dimethylaminomethyl, carboxymethyl, 4-dimethylamino-3-buten-1- yl, 5-ethylmethylamino-3-pentyn-1 -yl, 4-morpholinobutyl, 4-tetrahydropyrinidylbutyl, 3- imidazolidin-1 -ylpropyl, 4-tetrahydrothiazol-3-yl-butyl, phenylmethyl, 3- chlorophenylmethyl, and the like.

[0057] The term “anion” as used herein means a negatively charged counterion such as chloride, bromide, trifluoroacetate, and triethylammonium.

[0058] The term “acyl” as used herein means an alkyl or aryl (Ar) group having from 1 -10 carbon atoms bonded through a carbonyl group, i.e., R — C(O) — . For example, acyl includes, but is not limited to, a C1 -C6 alkanoyl, including substituted alkanoyl, wherein the alkyl portion can be substituted by an amine, amide, carboxylic, or heterocyclic group. Typical acyl groups include acetyl, benzoyl, and the like.

[0059] The term “aryl” as used herein refers to an aromatic monocyclic hydrocarbon ring system or a polycyclic ring system where at least one of the rings in the ring system is an aromatic hydro-carbon ring and any other aromatic rings in the ring system include only hydrocarbons. In some embodiments, a monocyclic aryl group can have from 6 to 14 carbon atoms and a polycyclic aryl group can have from 8 to 14 carbon atoms. The aryl group can be covalently attached to the defined chemical structure at any carbon atom(s) that result in a stable structure. In some embodiments, an aryl group can have only aromatic carbocyclic rings, e.g., phenyl, 1 -naphthyl, 2- naphthyl, anthracenyl, phenanthrenyl groups, and the like. In other embodiments, an aryl group can be a polycyclic ring system in which at least one aromatic carbocyclic ring is fused (i.e., having a bond in common with) to one or more cycloalkyl or cycloheteroalkyl rings. Examples of such aryl groups include, among others, benzo derivatives of cyclopentane (i.e., an indanyl group, which is a 5,6-bicyclic cycloal kyl/aromatic ring system), cyclohexane (i.e., a tetrahydronaphthyl group, which is a 6,6-bicyclic cycloalkyl/aromatic ring system), imidazoline (i.e., a benzimidazolinyl group, which is a 5,6-bicyclic cycloheteroalkyl/aromatic ring system), and pyran (i.e., a chromenyl group, which is a 6,6-bicyclic cycloheteroal kyl/aromatic ring system). Other examples of aryl groups include benzodioxanyl, benzodioxolyl, chromanyl, indolinyl groups, and the like.

[0060] The terms “halogen” or “halo” as used herein means fluorine, bromine, chlorine, and iodine.

[0061] The term “haloalkyl” refers to an alkyl group having one or more halogen substituents. In some embodiments, a haloalkyl group can have 1 to 10 carbon atoms (e.g., from 1 to 8 carbon at-oms). Examples of haloalkyl groups include CFs, C2F5, CHF2, CH2F, CCI3, CHCI2, CH2CI, C2CI5, and the like. Perhaloalkyl groups, i.e., alkyl groups wherein all of the hydrogen atoms are replaced with halogen atoms (e.g., CFsand C2F5), are included within the definition of “haloalkyl.” For example, a Ci- 10 haloalkyl group can have the formula — CiH2i+1 -jXj, wherein X is F, Cl, Br, or I, i is an integer in the range of 1 to 10, and j is an integer in the range of 0 to 21 , provided thatj is less than or equal to 2i+1 .

[0062] The term “heteroaryl” as used herein refers to an aromatic monocyclic ring system containing at least one ring heteroatom selected from 0, N, and S or a polycyclic ring system where at least one of the rings in the ring system is aromatic and contains at least one ring heteroatom. A heteroaryl group, as a whole, can have from 5 to 14 ring atoms and contain 1 -5 ring heteroatoms. In some embodiments, heteroaryl groups can include monocyclic heteroaryl rings fused to one or more aromatic carbocyclic rings, non-aromatic carbocyclic rings, or non-aromatic cycloheteroalkyl rings. The heteroaryl group can be covalently attached to the defined chemical structure at any heteroatom or carbon atom that results in a stable structure. Generally, heteroaryl rings do not contain 0 — 0, S — S, or S — 0 bonds. However, one or more N or S atoms in a heteroaryl group can be oxidized (e.g., pyridine N-oxide, thiophene S-oxide, thiophene S,S-dioxide). Examples of such heteroaryl rings include pyrrolyl, furyl, thienyl, pyridyl, pyrimidyl, pyri-dazinyl , pyrazinyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, isothiazolyl, thiazolyl, thiadiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, indolyl, isoindolyl, benzofuryl, benzothienyl, quinolyl, 2-methylquinolyl, isoquinolyl, quinoxalyl, quinazolyl, benzotriazolyl, benzimidazolyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl, benzoxadiazolyl, benzoxazolyl, cinnolinyl, 1 H- indazolyl, 2H-indazolyl, indolizinyl, isobenzofuyl, naphthyridinyl, phthalazinyl, pteridinyl, purinyl, oxazolopyridi-nyl, th iazolopyridinyl, imidazopyridinyl, furopyridinyl, th ienopyridinyl, pyridopyrimidinyl, pyri-dopyrazinyl, pyridopyrdazinyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl groups, and the like. Further examples of heteroaryl groups include 4,5,6,7-tetrahydroindolyl, tetrahydroqu in o-linyl, benzoth ienopyridinyl, benzofuropyridinyl groups, and the like.

[0063] The term “lower alkenyl” as used herein refers to alkenyl groups which contains 2 to 6 carbon atoms. An alkenyl group is a hydrocarbyl group containing at least one carbon-carbon double bond. As defined herein, it may be unsubstituted or substituted with the substituents described herein. The carbon-carbon double bonds may be between any two carbon atoms of the alkenyl group. It is preferred that it contains 1 or 2 carbon -carbon double bonds and more preferably one carbon -carbon double bond. The alkenyl group may be straight chained or branched. Examples include but are not limited to ethenyl, 1 -propenyl, 2-propenyl, 1 -butenyl, 2-butenyl, 2-methyl-1 - propenyl, 1 ,3-butadienyl, and the like.

[0064] The term “lower alkynyl” as used herein, refers to an alkynyl group containing 2-6 carbon atoms. An alkynyl group is a hydrocarbyl group containing at least one carbon-carbon triple bond. The carbon-carbon triple bond may be between any two carbon atom of the alkynyl group. In an embodiment, the alkynyl group contains 1 or

2 carbon-carbon triple bonds and more preferably one carbon -carbon triple bond. The alkynyl group may be straight chained or branched. Exam-pies include but are not limited to ethynyl, 1 -propynyl, 2-propynyl, 1 -butynyl, 2-butynyl and the like.

[0065] The term “carbalkoxy” as used herein refers to an alkoxycarbonyl group, where the attachment to the main chain is through the carbonyl group, e.g., — C(O) — . Examples include but are not limited to methoxy carbonyl, ethoxy carbonyl, and the like.

[0066] The term “oxo” as used herein refers to a double-bonded oxygen (i.e. , =0). It is also to be understood that the terminology C(O) refers to a — C=O group, whether it be ketone, aldehyde or acid or acid derivative. Similarly, S(O) refers to a — S=O group.

[0067] The term “cycloalkyl” as used herein refersto a non -aromatic carbocyclic group including cyclized alkyl, alkenyl, and alkynyl groups. A cycloalkyl group can be monocyclic(e.g., cyclohexyl)orpolycyclic(e.g., containingfused, bridged, and/orspiro ring systems), wherein the carbon atoms are located inside or outside of the ring system. A cycloalkyl group, as a whole, can have from 3 to 14 ring atoms (e.g., from

3 to 8 carbon atoms for a monocyclic cycloalkyl group and from 7 to 14 carbon atoms for a polycyclic cycloalkyl group). Any suitable ring position of the cycloalkyl group can be covalently linked to the defined chemical structure. Examples of cyclo-alkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcaryl, adamantyl, and spiro[4.5]decanyl groups, as well as theirhomologs, isomers, and the like.

[0068] The term “heteroatom” as used herein refers to an atom of any element other than carbon or hydrogen and includes, for example, nitrogen, oxygen, sulfur, phosphorus, and selenium.

[0069] The term “cycloheteroalkyl” as used herein refers to a non -aromatic cycloalkyl group that contains at least one (e.g., one, two, three, four, or five) ring heteroatom selected from 0, N, and S, and optionally contains one or more (e.g., one, two, or three) double or triple bonds. A cyclo-heteroalkyl group, as a whole, can have from 3 to 14 ring atoms and contains from 1 to 5 ring heteroatoms (e.g., from 3-6 ring atoms for a monocyclic cycloheteroalkyl group and from 7 to 14 ring atoms for a polycyclic cycloheteroalkyl group). The cycloheteroalkyl group can be covalently attached to the defined chemical structure at any heteroatom(s) or carbon atom(s) that results in a stable structure. One or more N or S atoms in a cycloheteroalkyl ring may be oxidized (e.g., morpholine N-oxide, thiomorpholine S-oxide, thiomorpholine S,S-dioxide). Cyclohet-eroalkyl groups can also contain one or more oxo groups, such as phthalimidyl, piperidonyl, oxazolidinonyl, 2,4(1 H,3H)-dioxo-pyrimidinyl, pyridin-2(1 H)- onyl, and the like. Examples of cyclo-heteroalkyl groups include, among others, morpholinyl, thiomorpholinyl, pyranyl, imidazolidinyl, imidazolinyl, oxazolidinyl, pyrazolidinyl, pyrazolinyl, pyrrol idinyl, pyrrolinyl , tetrahydrofuranyl, tet-rahydrothienyl, piperidinyl, piperazinyl, azetidine, and the like.

[0070] The compounds described herein may contain chiral centers and therefore may exist in different enantiomeric and diastereomeric forms. One aspect described herein encompasses all optical isomers or stereoisomers of the compounds described herein both as racemic mixtures and as individual enantiomers or diastereoisomers, or mixtures thereof, and to all pharmaceutical compositions or methods of treatment described herein that contain or employ them, respectively. Individual isomers can be obtained by known methods, such as optical resolution, optically selective reaction, or chiral chromatographic separation in the preparation of the final product or its intermediate.

[0071] The compounds described herein can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms, including hydrated forms, are equivalent to unsolvated forms and are intended to be encompassed within the scope described herein.

[0072] Compounds described herein also includes isotopically labelled compounds, which are identical to those described herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes that can be incorporated into compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹¹C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶CI, respectively. Compounds described herein, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope described herein. Certain isotopically labelled compounds described herein, for example those into which radioactive isotopes such as ³H and ¹⁴C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., ³H, and carbon-14 i.e., ¹⁴C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., ²H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labelled compounds described herein and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples and Preparations below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.

[0073] Compounds described herein also includes compounds conjugated with probes including but not restricted to photocrosslinkers, dyes, biotin etc.

[0074] The term “analog” as used herein refers to a small organic compound, a nucleotide, a protein, or a polypeptide that possesses similar or identical activity or function(s) as the compound, nucleotide, protein or polypeptide or compound having the desired activity and therapeutic effect (e.g., inhibition of tumor growth), but need not necessarily comprise a sequence or structure that is similar or identical to the sequence or structure of the preferred embodiment. [0075] The term “derivative” as used herein refers to eithera compound, a protein or polypeptide that comprises an amino acid sequence of a parent protein or polypeptide that has been altered by the introduction of amino acid residue substitutions, deletions or additions, or a nucleic acid or nucleotide that has been modified by either introduction of nucleotide substitutions or deletions, additions or mutations. The derivative nucleic acid, nucleotide, protein, or polypeptide possesses a similar or identical function as the parent polypeptide.

DETAILED DESCRIPTION

[0076] In the following sections, certain exemplary compositions and methods are described to detail certain embodiments of the disclosure. It will be obvious to one skilled in the art that practicing the certain embodiments does not require the employment of all or even some of the specific details outlined herein, but rather that concentrations, times, and other specific details can be modified through routine experimentation. In some cases, well known methods, or components have not been included in the description.

[0077] Results of the present disclosure is based in part on the surprising discovery that Apatinib, a tyrosine kinase inhibitor th at inhibits vascular endothelial growth factor receptor-2 (VEGFR2), restores the Golgi localization of SCD-associated N102S variant of UBIAD1. Apatinib also accelerates ERAD of HMGCR in the presence of wild type UBIAD1. Apatinib also enhances GGpp-induced ER-to-Golgi transport of the protein.

[0078] This unexpected discovery was made during a high throughput screen of more than 1400 FDA-approved drugs for molecules that restore the Golgi localization of SCD-associated N102S variant of UBIAD1. The inventors conducted said screen in view results from their studies that indicated that statins deplete GGpp from hepatic ER membranes, causing UBIAD1 to become sequestered in the ER to block HMGCR ERAD. Those results led to the postulation that molecules that mimic GGpp will relieve statin-mediated inhibition of ERAD and the drugs to inh ibitthe HMGCR more efficiently. Missense mutations in UBIAD1 cause Schnyder corneal dystrophy (SCD), an autosomal disorder characterized by corneal opacification th at results from the over accumulation of cholesterol. SCD-associated UBIAD1 resists GGpp-induced release from HMGCR and remains sequestered in the ER to inhibit ERAD. This inhibition leads to enhanced synthesis and accumulation of cholesterol in cultured cells and tissues of knock-in mice expressing SCD-associated UBIAD1 . Apatinib was the most potent and least toxic of the drugs identified by the more than 1400 FDA-approved drug screen.

[0079] The chemical structure of Apatinib is show below.

Apatinib

[0080] Novel lead compounds and analogs and derivatives thereof provided herein were synthesized and tested in in vitro assays and found to be effective in restoring the Golgi localization of SCD-associated N102S variant of UBIAD1 .

[0081]Apatinib-induced translocation of UBIAD1 (N102S) to the Golgi was unexpectedly blocked by the statin compactin. Golgi translocation of the SCD- associated variant was restored by treatment of cells with both Apatinib and GGpp. The Apatinib-induced translocation of UBIAD1 (N102S) to the Golgi resulted in the accelerated ERAD of HMGCR. Importantly, Apatinib also accelerated ERAD of HMGCR in the presence of wild type UBIAD1 , which led us to the discovery the drug also enhances GGpp-induced ER-to-Golgi transport of the protein.

[0082] In one or more embodiments, the active derivatives are modified on the pyridine ring that mediates the kinase inhibitory activity of Apatinib.

[0083] In one or more embodiments the compounds include a photoactivatable Apatinib derivative harboring an alkyne group for biotin conjugation. This molecule stimulates ER-to-Golgi trafficking of wild type and N102S UBIAD1. Moreover, the molecule photoaffinity labels UBIAD1 in a manner that is blocked by the Apatinib parent compound and SAR derivatives the stimulate Golgi transport of Apatinib.

1. Compounds

[0084] In an aspect, the disclosure provides compounds comprising Formula (I) or a pharmaceutically acceptable salt thereof:

Formula (I); wherein:

Ri and R2 are independently of each other hydrogen, halogen, alkyl, alkyl amine, alkyl sulfonamide, aryl, substituted aryl, heterocyclic aryl amine, substituted heterocyclic aryl amine, cyclic aliphatic amine, heterocyclic aliphatic amine, substituted heterocyclic aliphatic amine, alkyne; or together with the carbon atom to form a cycloalkyl, a cycloalkenyl, or a heterocyclylalkyl ring;

R3 is an aryl or substituted aryl; and

Y is an oxygen, nitrogen, or sulfur.

[0085] In an aspect, the disclosure provides compounds comprising Formula (II) wherein the substituted aryl is a phenyl group with a substituted carbon atom on a para position as in Formula (II) or a pharmaceutically acceptable salt thereof:

Formula (II); wherein:

Ri and R2 are independently of each other hydrogen, halogen, alkyl, alkyl amine, alkyl sulfonamide, aryl, substituted aryl, heterocyclic aryl amine, substituted heterocyclic aryl amine, cyclic aliphatic amine, heterocyclic aliphatic amine, substituted heterocyclic aliphatic amine, alkyne; or together with the carbon atom to form a cycloalkyl, a cycloalkenyl, or a heterocyclylalkyl ring;

R3 is an aryl or substituted aryl;

X is a halogen or a cycloalkane carbonitrile with formula -CnH(2n-2)CN, wherein n is 3 or more; and

Y is an oxygen, nitrogen, or sulfur.

[0086] In an aspect, the disclosure provides compounds comprising Formula (III) wherein R1 and R2 combine to form a heterocycle with both amine and ether groups and X is a halogen or a cycloalkane carbonitrile with formula -CnH(2n-2)CN, wherein n is 3 or more or a pharmaceutically acceptable salt thereof:

Formula (III). [0087] In certain embodiments, the disclosure provides compounds comprising Formula (II) or a pharmaceutically acceptable salt thereof wherein X is cycloalkane carbon itrile with formula -CsHsCN, R1 is hydrogen, and R2 is methylbenzyl as shown below:

(Compound 1 ).

[0088] In certain embodiments, the disclosure provides compounds comprising Formula (II) or a pharmaceutically acceptable salt thereof wherein X is cycloalkane carbon itrile with formula -CsHsCN, R1 is hydrogen, and R2 is neopentane as shown below:

(Compound 2).

[0089] In certain embodiments, the disclosure provides compounds comprising Formula (I) or a pharmaceutically acceptable salt thereof wherein Ri is hydrogen, R2 is methylpyridine, and R3 is cyclohexane as shown below:

(Compound 3).

[0090] In certain embodiments, the disclosure provides compounds comprising Formula (I) or a pharmaceutically acceptable salt thereof wherein R1 is hydrogen, R2 is 4-methylpyridine, and R3 is toluene as shown below:

(Compound 4).

[0091] In certain embodiments, the disclosure provides compounds comprising Formula (II) or a pharmaceutically acceptable salt thereof wherein X is cycloalkane carbon itrile with formula -CsHsCN, R1 is hydrogen, and R2 is 3-methylpyradine as shown below:

(Compound s).

[0092] In certain embodiments, the disclosure provides compounds comprising Formula (II) or a pharmaceutically acceptable salt thereof wherein X is cycloalkane carbon itrile with formu la -CsHsCN, Ri is hydrogen, and R2 is 1 -fluoro-4-methylbenzene as shown below:

(Compound s).

[0093] In certain embodiments, the disclosure provides compounds comprising Formula (II) or a pharmaceutically acceptable salt thereof wherein X is cycloalkane carbonitrile with formula -CsHsCN, R1 is hydrogen, and R2 is propane as shown below:

(Compound 7).

[0094] In certain embodiments, the disclosure provides compounds comprising Formula (II) or a pharmaceutically acceptable salt thereof wherein X is cycloalkane carbonitrile with formula -CsHsCN, Ri is methyl, and R2 is methyl benzyl as shown below:

(Compound 8).

[0095] In certain embodiments, the disclosure provides compounds comprising Formula (III) or a pharmaceutically acceptable salt thereof wherein X is cycloalkane carbon itrile with formula -CsHsCN and the heterocycle is morpholine as shown below:

(Compound 9).

[0096] In certain embodiments, the disclosure provides compounds comprising Formula (II) or a pharmaceutically acceptable salt thereof wherein X is cycloalkane carbon itrile with formula -CsHsCN, R1 is hydrogen, and R2 is 1 - (methylsulfonyl)piperidine as shown below:

(Compound 10).

[0097] In certain embodiments, the disclosure provides compounds comprising Formula (II) or a pharmaceutically acceptable salt thereof wherein X is cycloalkane carbon itrile with formula -CsHsCN, R1 is hydrogen, and R2 is isopentane as shown below:

(Compound 11 ).

[0098] In certain embodiments, the disclosure provides compounds comprising Formula (II) or a pharmaceutically acceptable salt thereof wherein X is cycloalkane carbonitrile with formula -CsHsCN, Ri is hydrogen, and R2 is ethanesulfonamide, wherein the heterocycle is morpholine as shown below:

(Compound 12).

[0099] In certain embodiments, the disclosure provides compounds comprising Formula (II) or a pharmaceutically acceptable salt thereof wherein X is cycloalkane carbon itrile with formula -CsHsCN, R1 is hydrogen, and R2 is neopentyl as shown below:

(Compound 13).

[00100] In certain embodiments, the disclosure provides compounds comprising Formula (II) or a pharmaceutically acceptable salt thereof wherein X is cycloalkane carbon itrile with formu la -CsHsCN, Ri is hydrogen, and R2 is tert-butyl 3-ethylazetidine- 1 -carboxylate as shown below:

(Compound 14).

[00101] In certain embodiments, the disclosure provides compounds comprising Formula (II) or a pharmaceutically acceptable salt thereof wherein X is cycloalkane carbon itrile with formula -CsHsCN, R1 is hydrogen, and R2 is N,N-dimethylpropan-1- amine as shown below:

(Compound 15).

[00102] In certain embodiments, the disclosure provides compounds comprising Formula (II) or a pharmaceutically acceptable salt thereof wherein X is cycloalkane carbon itrile with formula -CsHsCN, R1 and R2 are hydrogen as shown below:

[00103] In certain embodiments, the disclosure provides compounds comprising Formula (II) or a pharmaceutically acceptable salt thereof wherein X is fluorine, Ri is hydrogen, and R2 is 4-methyl pyridine as shown below:

(Compound 17)

[00104] In other embodiments, the disclosure provides the compound of Table 1 , listed as compounds 1-17:

Table 1.

2. Methods of T reatment

[00105] In some aspects, the compounds provided herein may be used for treatment or a wide range of a cardiovascular or cholesterol related disorders. As such, provided is a method of treating a cardiovascular or cholesterol related disorder by administering to a subject in need thereof, one or more of the compounds disclosed herein. In some aspects, a therapeutically effective amount of the one or more compounds disclosed herein is administered.

[00106] In some aspects, the cardiovascular or cholesterol related disorder may be Schnyder corneal dystrophy (SCD), corneal dystrophy, peripheral artery disease, hypercholesterolemia, hyperlipidemia/ dyslipidemia, sitosterolemia, atherosclerosis, arteriosclerosis, or xanthoma.

[00107] In some aspects, the subject has a high blood plasma cholesterol value relative to a predetermined blood plasma cholesterol value and/or has a genetic predisposition to high blood plasma cholesterol. In some aspects, the subject has a high blood plasma cholesterol value relative to a predetermined blood plasma cholesterol value and the predetermined blood plasma cholesterol value is less than or equal to 200 mg/dL.

[00108] In some aspects, the subject has a genetic predisposition to high blood plasma cholesterol and the genetic predisposition is a mutation in UBIAD1 , LDLR, APOB, SREBP, SCAP, and/or PCSK9 genes.

[00109] In some aspects, disclosed is a method of activating the allosteric activator of UBIAD1 that enhances its affinity for GGpp in a subject. As a result of this allosteric activation, the GGpp-induced trafficking of UBIAD1 to the Golgi is augmented, which leads to accelerated ERAD of HMGCR that prevents its statin- induced overaccumulation.

[00110] In some aspects, the compounds may be used to treat patients with the eye disease Schnyder Corneal Dystrophy, which is caused by mutations in UBIAD1 and results in the opacification of the cornea owing to the accumulation of cholesterol in the tissue.

[00111] In some aspects, the one or more compounds used in a method of treating a cardiovascular or cholesterol related disorder comprises Apatinib.

[00112] In some aspects, the one or more compounds used in a method of treating a cardiovascular or cholesterol related disorder comprises one or more of compounds 1 -17. In some aspects, the one or more compounds comprises one or more of compounds 5-17. In some aspects, the one or more compounds comprises compound 1. In some aspects, the one or more compounds comprises compound 2. In some aspects, the one or more compounds comprises compound 3. In some aspects, the one or more compounds comprises compound 4. In some aspects, the one or more compounds comprises compound s. In some aspects, the one or more compounds comprises compound 6. In some aspects, the one or more compounds comprises compound 7. In some aspects, the one or more compounds comprises compound s. In some aspects, the one or more compounds comprises compound 9. In some aspects, the one or more compounds comprises compound 10. In some aspects, the one or more compounds comprises compound 11. In some aspects, the one or more compounds comprises compound 12. In some aspects, the one or more compounds comprises compound 13. In some aspects, the one or more compounds comprises compound 14. In some aspects, the one or more compounds comprises compound 15. In some aspects, the one or more compounds comprises compound 16. In some aspects, the one or more compounds comprises compound 17.

[00113] The one or more compounds may be pharmaceutically active or are prodrugs. The one or more compounds maybe a pharmaceutically acceptable salt. The one or more compounds may be Apatinib. The one or more compounds may be one or more of the compounds listed in Table 1 as 1 -17. The one or more compounds may be administered to the subject in a therapeutically effective amount. The subject may be an animal or human. The one or more compounds may be administered as a pharmaceutical compositions.

[00114] The subject treated is typically a human subject, although it is to be understood the methods described herein are effective with respect to other animals, such as mammals and vertebrate species. [00115] As described above, in some particular aspects the term “subject” includes individuals that have been diagnosed with a cardiovascular or cholesterol related disorder because of missense mutations in UBIAD1 .

[00116] Thus, in some aspects the current disclosure also encompasses use of disclosed compounds of treatment of Schnyder corneal dystrophy (SCD). In some aspects, the current disclosure encompasses use of the disclosed compositions for restoration of Golgi localization of SCD-associated N102S variant of UBIAD1 , in a subject in need thereof.

3. Pharmaceutical Compositions

[00117] In other embodiments, the present disclosure provides pharmaceutical compositions. The pharmaceutical compositions of the instant disclosure include at least one compound according to the instant disclosure for use to treat, prevent, or ameliorate a cardiovascular or cholesterol related disorder in a subject in need thereof. The compound can be, for example as described in Section 1. The pharmaceutical compositions can be administered to treat a disease or disorder, such as, but not limited to, those described in Section 2.

[00118] In some aspects, disclosed is a pharmaceutical composition that comprises one or more of the compounds disclosed herein and at least one pharmaceutically acceptable excipient. In some aspects, the pharmaceutical compositions disclosed herein are used in the methods of treating a cardiovascular or cholesterol related disorder as disclosed herein. The pharmaceutical compositions disclosed herein may comprise a therapeutically effective amount of one or more of the compounds disclosed herein. The compounds disclosed herein may be administered to a subject in need thereof in a therapeutically effective amount.

[00119] In some embodiments, pharmaceutical compositionscan includeatleast one compound disclosed herein and at least one pharmaceutically acceptable carrier. In certain embodiments, pharmaceutical compositions can include pharmaceutically acceptable carriers, excipients, and/or stabilizers are nontoxicto recipients at dosages and/or concentrations used to practice the methods disclosed herein.

[00120] In some embodiments, the pharmaceutically acceptable excipient can include, but is not limited to a diluent, a binder, a filler, a buffering agent, a pH modifying agent, a disi ntegrant, a dispersant, a preservative, a lubricant, or a coloring agent. The concentrations and types of excipients utilized to form pharmaceutical compositions disclosed herein and contemplated herein can be selected according to known principles of pharmaceutical science and knowledge in the art.

[00121] In some embodiments, the excipient can be a diluent. The diluentcan be compressible (i.e., plastically deformable) or abrasively brittle. Non-limiting examples of suitable compressible diluents can include, but are not limited to, microcrystalline cellulose (MCC), cellulose derivatives, cellulose powder, cellulose esters (i.e., acetate and butyrate mixed esters), ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, corn starch, phosphated corn starch, pregelatinized com starch, rice starch, potato starch, tapioca starch, starch -lactose, starch-calcium carbonate, sodium starch glycolate, glucose, fructose, lactose, lactose monohydrate, sucrose, xylose, lactitol, mannitol, malitol, sorbitol, xylitol, maltodextrin, dextran, and trehalose or the like. Non-limiting examples of suitable abrasively brittle diluents include dibasic calcium phosphate (anhydrous or dihydrate), calcium phosphate tribasic, calcium carbonate, and magnesium carbonate.

[00122] In anotherembodiment, the excipientcan be a binder. Suitable binders include, but are not limited to, starches, pregelatinized starches, gelatin, polyvinylpyrrolidone, cellulose, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, polyacrylamides, polyvinyloxoazolidone, polyvinylalcohols, C12-C18 fatty acid alcohol, polyethylene glycol, polyols, saccharides, oligosaccharides, polypeptides, oligopeptides, and combinations thereof.

[00123] In another embodiment, the excipient can be a filler. Suitable fillers include, but are not limited to, carbohydrates, inorganic compounds, and polyvinylpyrrolidone. By way of non-limiting example, the filler can be calcium sulfate, both di- and tri-basic, starch, calcium carbonate, magnesium carbonate, microcrystalline cellulose, dibasic calcium phosphate, magnesium carbonate, magnesium oxide, calcium silicate, talc, modified starches, lactose, sucrose, mannitol, or sorbitol.

[00124] In still another embodiment, the excipient can be a buffering agent. Representative examples of suitable buffering agents include, but are not limited to, phosphates, carbonates, citrates, tris buffers, polysaccharide buffers, and buffered saline salts (e.g., Tris buffered saline, or phosphate buffered saline).

[00125] In various embodiments, the excipient can be a pH modifier. By way of non-limiting example, the pH modifying agent can be sodium carbonate, sodium bicarbonate, sodium citrate, citric acid, or phosphoric acid.

[00126] In a further embodiment, the excipient can be a disintegrant. The disintegrant can be non -effervescent or effervescent. Suitable examples of non- effervescentdisintegrants include, but are not limited to, starches such as corn starch, potato starch, pregelatinized and modified starches thereof, sweeteners, clays, such as bentonite, micro-crystalline cellulose, alginates, sodium starch glycolate, gums such as agar, guar, locust bean, karaya, pecitin, and tragacanth. Non-limiting examples of suitable effervescent disintegrants include sodium bicarbonate in combination with citric acid and sodium bicarbonate in combination with tartaric acid.

[00127] In yet another embodiment, the excipient can be a dispersant or dispersing enhancing agent. Suitable dispersants can include, but are not limited to, starch, alginicacid, polyvinylpyrrolidones, guar gum, kaolin, bentonite, purified wood cellulose, sodium starch glycolate, amorphous silicate, and microcrystalline cellulose.

[00128] In anotherembodiment, the excipientcan be a preservative. Non-limiting examples of suitable preservatives include antioxidants, such as BHA, BHT, vitamin A, vitamin C, vitamin E, or retinyl palmitate, citric acid, sodium citrate; chelators such as EDTA or EGTA; and antimicrobials, such as parabens, chlorobutanol, or phenol.

[00129] In a further embodiment, the excipient can be a lubricant. Non-limiting examples of suitable lubricants include minerals such as talc or silica; and fats such as vegetable stearin, magnesium stearate, or stearic acid.

[00130] In still a further embodiment, the excipient can be a coloring agent. Suitable color additives include, but are not limited to, food, drug and cosmetic colors (FD&C), drug and cosmetic colors (D&C), or external drug and cosmetic colors (Ext. D&C).

[00131] Other pharmaceutically acceptable carriers, excipients, and/or stabilizers can include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3- pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrans; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g. Zn-protein complexes); and/or non-ionic surfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG).

[00132] The regimen of administration can affect what constitutes an effective amount. Further, several divided dosages as well as staggered dosages, can be administered daily or sequentially, or the dose can be continuously infused, orcan be a bolus injection. Further, the dosages of the compound(s) described herein can be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation.

[00133] Compounds described herein may be used in the treatment of states, disorders or diseases as described herein, or for the manufacture of pharmaceutical compositions for use in the treatment of these diseases for example a cardiovascular or cholesterol related disorder. Methods of use of the compounds described herein in the treatment of these diseases, or pharmaceutical preparations having the compounds described herein for the treatment of these diseases.

[00134] The phrase “pharmaceutically acceptable excipient” includes any pharmaceutically acceptable material, composition, or vehicle, suitable for administering the compounds described herein to mammals. The excipient includes liquid or solid filler, a diluent, a binder a buffering agent, a pH modifying agent, a disintegrant, a dispersant, a preservative, a lubricant or wetting agent, taste-masking agent, an antioxidant, carrier, adjuvant, stabilizing agent, emulsifying agent, solution promoter, salt, solubilizer, antifoaming agent, surfactant, a flavoring agent, a coloring agent, solvent or encapsulating material or any combination thereof. Each excipient must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. The amountand types of excipients utilized to form pharmaceutical compositions may be selected according to known principles of pharmaceutical science. In each of the aspects described herein, a composition of the disclosure may optionally comprise one or more additional drug or therapeutically active agent in addition to the at least one factor disclosed herein. Thus, in addition to the therapies described herein, one may also provide to the subject other therapies known to be efficacious for treatment of the disease, disorder, or condition.

[00135] In some aspects, the excipient may be a dispersant or dispersing enhancing agent. Suitable dispersants may include, but are not limited to, starch, alginic acid, polyvinylpyrrolidones, guar gum, kaolin, bentonite, purified wood cellulose, sodium starch glycolate, iso-amorphous silicate, and microcrystalline cellulose.

[00136] In some aspects, the excipient may be a preservative. Non-limiting examples of suitable preservatives include antioxidants, such as BHA, BHT, vitamin A, vitamin C, vitamin E, or retinyl palmitate, citric acid, sodium citrate; chelators such as EDTA or EGTA; and antimicrobials, such as parabens, chlorobutanol, or phenol.

[00137] In some aspects, theexcipientmay be a lubricant. Non limiting examples of suitable lubricants include minerals such astalc or silica; andfats such as vegetable stearin, magnesium stearate, or stearic acid.

[00138] Some additional examples of materials which can serve as pharmaceutically acceptable excipients include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, saffloweroil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations. [00139] Wetting agents, emulsifiers, or lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and per-fuming agents, preservatives and antioxidants can also be present in the compositions.

[00140] Examples of pharmaceutically acceptable antioxidants include: water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (B HA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, a-tocopherol, and the like; and metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[00141] The weight fraction of the excipient or combination of excipients in the composition may be about 99% or less, about 97% or less, about 95% or less, about 90% or less, about 85% or less, about 80% or less, about75% or less, about 70% or less, about 65% or less, about 60% or less, about 55% or less, about 50% or less, about 45% or less, about 40% or less, about 35% or less, about 30% or less, about 25% or less, about 20% or less, about 15% or less, about 10% or less, about 5% or less, about 2%, or about 1 % or less of the total weight of the composition.

[00142] The compositions described herein can be formulated by any conventional manner using one or more pharmaceutically acceptable carriers or excipients as described in, for example, Remington’s Pharmaceutical Sciences (A.R. Gennaro, Ed.), 21st edition, ISBN: 0781746736 (2005), incorporated herein by reference in its entirety. Such formulations will contain a therapeutically effective amountof a biologically active factor described herein, which can be in purifiedform, together with a suitable amount of carrier so as to provide the form for proper administration to the subject.

[00143] Formulations described herein includethosesuitableforparenteral, oral, intraadiposal, intraarterial, intraarticular, intracranial, intradermal, intralesional, intramuscular, intranasal, intraocular, intrapericardial, intraperitoneal, intrapleural, intraprostatical, intrarectal, intrathecal, intratracheal, intratumoral, intraumbilical, intravaginal, intravenous, intravascular, intravitreal , liposomal, local, mucosal, parenteral, rectal, subconjunctival, subcutaneous, sublingual, topical, trans buccal, and transdermal route. The formulations may conveniently be presented in unit dosage form and may be prepared by any methodswell known in the art of pharmacy. The amount of active ingredient that can be combined with an excipient material to produce a single dosage form will generally be that amount of the compound that produces a therapeutic effect. Generally, out of one hundred percent, this amountwill rangefrom aboutl percentto aboutninety-ninepercentof active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.

[00144] Methods of preparing these formulations or compositions include the step of bringing into association a compound as described herein with the excipient and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound described herein with liquid excipients, or finely divided solid excipients, or both, and then, if necessary, shaping the product.

[00145] Formulations described herein suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amountofa compound described herein as an active ingredient. A compound described herein may also be administered as a bolus, electuary, or paste.

[00146] In solid dosage forms described herein for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosph ate, and/oranyofthe following: fillers orextenders, such as starches, lactose, sucrose, glucose, mannitol, and/orsilicicacid; binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; humectants, such as glycerol; disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginicacid, certain silicates, and sodium carbonate; solution retarding agents, such as paraffin; absorption accelerators, such as quaternary ammonium compounds; wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; absorbents, such as kaolin and bentonite clay; lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof, and coloring agents. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[00147] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[00148] The tablets, and other solid dosage forms of the pharmaceutical compositions described here-in, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or micro-spheres. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dis-solved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.

[00149] Liquid dosage forms for oral administration of the compounds described herein include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, or elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluent commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butyleneglycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

[00150] Besides inertdiluents, the oral compositions can also include adjuvants such as wetting agents, emu Isifying agents, suspending agents, sweeten ing, flavoring, coloring, perfuming, preservative agents, or combinations thereof.

[00151] Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[00152] Pharmaceutical compositions described herein suitable for parenteral administration comprise one or more compounds described herein in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutionsordispersionsjust priorto use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonicwith the blood of the intended recipient or suspending or thickening agents.

[00153] Examples of suitable aqueous and nonaqueous excipients that may be employed in the pharmaceutical compositions described herein includewater, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Properfluidity can be maintained, forexample, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[00154] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, dispersing agents, or combinations thereof. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate andgelatin.

[00155] In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystal line or amorphous material having poorwater solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which inturn, may de-pend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

[00156] Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue.

[00157] The preparations described herein may be given orally, parenterally, topically, or rectally. They are of course given by forms suitableforeach administration route. For example, they are ad-ministered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc., administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories. Oral and/or IV administration is preferred.

[00158] The phrases “parenteral administration” and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternal injection or infusion.

[00159] The phrases “systemic administration,” “administered systemically,” “peripheral administration” and “administered peripherally” as used herein mean the administration of a compound, drug or other material otherthan directly in to the central nervous system, such that it enters the patient's system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.

[00160] As provided herein, these compounds may be administered to humans and other animals for therapy by any suitable route of administration, including parenteral, oral, intraadiposal, intraarterial, intraarticular, intracranial, intradermal, intralesional, intramuscular, intranasal, intraocular, intrapericardial, intraperitoneal, intrapleural, intraprostatical, intrarectal, intrathecal, intratracheal, intratumoral, intraumbilical, intravaginal, intravenous, intravascular, intravitreal , liposomal, local, mucosal, parenteral, rectal, subconjunctival, subcutaneous, sublingual, topical, trans buccal, and transdermal route.

[00161] Regardless of the route of administration selected, the compounds described herein, which may be used in a suitable hydrated form, and/or the pharmaceutical compositions described herein, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those of skill in the art.

[00162] Actual dosage levels of the active ingredients in the pharmaceutical compositions described herein may be varied to obtain an amount of the active ingredientthat is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[00163] The selected dosage level will depend upon a variety of factors including the activity of the particular compound described herein employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.

[00164] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds described herein employed in the pharmaceutical composition at levels lower than th at required in order to achieve the desired therapeuticeffectand gradually increase the dosage until the desired effect is achieved. [00165] In general, a suitable daily dose of a compound described herein will be that amountof the compoundthatis the lowest dose effective to producea therapeutic effect. Such an effective dose will generallydepend upon thefactors described herein.

[00166] In some aspects, the total daily dose of compound described herein may be from about 5 mg to about 850 mg. The dose may be about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about225 mg, about 230 mg, about235 mg, about240 mg, about245 mg, about250 mg, about255 mg, about265 mg, about 270 mg, about275 mg, about280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about345 mg, about350 mg, about 355 mg, about365 mg, about370 mg, about 375 mg, about 380 mg, about 385 mg, about 390 mg, about 395 mg, about 400 mg, about405 mg, about 410 mg, about 415 mg, about420 mg, about425 mg, about430 mg, about435 mg, about440 mg, about 445 mg, about450 mg, about455 mg, about 465 mg, about 470 mg, about 475 mg, about 480 mg, about 485 mg, about 490 mg, about495 mg, about 500 mg, about 505 mg, about510 mg, about515 mg, about520 mg, about525 mg, about530 mg, about 535 mg, about540 mg, about545 mg, about 550 mg, about 555 mg, about 565 mg, about 570 mg, about 575 mg, about 580 mg, about585 mg, about 590 mg, about 595 mg, about600 mg, about605 mg, about610 mg, about615 mg, about620 mg, about 625 mg, about630 mg, about635 mg, about 640 mg, about 645 mg, about 650 mg, about 655 mg, about 665 mg, about 670 mg, about675 mg, about 680 mg, about 685 mg, about690 mg, about695 mg, about 700 mg, about705 mg, about710 mg, about 715 mg, about720 mg, about725 mg, about 730 mg, about 735 mg, about 740 mg, about 745 mg, about 750 mg, about 755 mg, about765 mg, about 770 mg, about 775 mg, about780 mg, about785 mg, about790 mg, about795 mg, about800 mg, about 805 mg, about810 mg, about815 mg, about 820 mg, about 825 mg, about 830 mg, about 835 mg, about 840 mg, about 845 mg, or about 850 mg.

[00167] If desired, the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. [00168] While it is possible for a compound described herein to be administered alone, it may be administered in combination with other active composition.

[00169] By the term “combination” is meant either a fixed combination in one dosage unit form, or a kit of parts for the combined administration where a compound described herein anda combination partnermay be administered independentlyat the same time or separately within time intervals th at especially allow th at the combination partners show a cooperative, e.g., synergistic, effect, or any combination thereof. The compounds described herein may be administered, simultaneously or sequentially, with an anti-inflammatory, antiproliferative, antibiotics, NSAIDs, painkillers, chemotherapeutic agent, immunosuppressant, other drugs, or salt thereof.

4. Methods of Making the Compounds

[00170] In some aspects, the current disclosure encompasses methods of making (synthesizing) the compound or salt thereof comprising any one of the compounds disclosed herein. In some aspects, the compound or salt thereof comprising any one of the compounds 1 -17 provided in Table 1 .

[00171] The compounds described herein are prepared from commonly available compounds using procedures known to those skilled in the art and/or as provided in the examples herein. Some common methods are described for example in reference works, such as e.g., Science of Synthesis: Houben-Weyl Methods of Molecular Transformation. Georg Thieme Verlag, Stuttgart, Germany (2005); McOmie, “Protective Groups in Organic Chemistry,” Plenum Press, London and New York (1973).

[00172] Analytical techniques including but not limited to ¹H, ¹³C, ¹⁹F NMR, thin layer chromatography, and LC/MS may be used to monitor the reactions and to characterize the reaction intermediates and desired final products.

[00173] In one or more embodiments, methods of making the compounds include reacting a substituted pyridine carboxamide with an amine in the presence of a base in a solvent for a specific reaction time under an appropriate temperature. Examples of suitable bases include DIPEA, ammonia, or combinations thereof. Examples of suitable solvents include DMSO, dioxane, DMF, or combinationsthereof. [00174] The specific reaction time may be from about5 hrs to about48 hrs. The specific reaction time may be about 5 hrs, about 6 hrs, about? hrs, about 8 hrs, about 9 hrs, about 10, hrs, about 11 hrs, about 12 hrs, about 13 hrs, about 14 hrs, about 15 hrs, about 16 hrs, about 17, hrs, about 18 hrs, about 19 hrs, about 20 hrs, about 21 hrs, about 22 hrs, about 23 hrs, about 24 hrs, about 25 hrs, about 26 hrs, about 27, hrs, about 28 hrs, about 29 hrs, about 30 hrs, about 31 hrs, about 32 hrs, about 33 hrs, about 34 hrs, about 35 hrs, about 36 hrs, about 37, hrs, about 38 hrs, about 39 hrs, about 40 hrs, about 41 hrs, about 42 hrs, about 43 hrs, about 44 hrs, about 45 hrs, about 46 hrs, about 47 hrs, about 48 hrs, about 49 hrs, or about 50 hrs.

[00175] The appropriate temperature may be from about 25°C to about 150°C. The appropriate temperature may be 25°C, 26°C, 27°C, 28°C, 29°C, 30°C, 31 °C, 32°C, 33°C, 34°C, 35°C, 36°C, 37°C, 38°C, 39°C, 40°C, 41 °C, 42°C, 43°C, 44°C, 45°C, 46°C,

47°C, 48°C, 49°C, 50°C, 51 °C, 52°C, 53°C, 54°C, 55°C, 56°C, 57°C, 58°C, 59°C, 60°C,

61 °C, 62°C, 63°C, 64°C, 65°C, 66°C, 67°C, 68°C, 69°C, 70°C, 71 °C, 72°C, 73°C, 74°C,

75°C, 76°C, 77°C, 78°C, 79°C, 80°C, 81 °C, 82°C, 83°C, 84°C, 85°C, 86°C, 87°C, 88°C,

89°C, 90°C, 91 °C, 92°C, 93°C, 94°C, 95°C, 96°C, 97°C, 98°C, 99°C, 100°C, 101 °C, 102°C,

103°C, 104°C, 105°C, 106°C, 107°C, 108°C, 109°C, 110°C, 111 °C, 112°C, 113°C, 114°C,

115°C, 116°C, 117°C, 118°C, 119°C, 120°C, 121 °C, 122°C, 123°C, 124°C, 125°C, 126°C,

127°C, 128°C, 129°C, 130°C, 131 °C, 132°C, 133°C, 134°C, 135°C, 136°C, 137°C, 138°C,

139°C, 140°C, 141 °C, 142°C, 143°C, 144°C, 145°C, 146°C, 147°C, 148°C, 149°C, or 150°C.

[00176] Salts of the compounds described herein having at least one salt-forming group may be prepared in a manner known per se. For example, salts of the compounds described herein having acid groups may be formed, for example, by treating the compounds with metal compounds, such as alkali metal salts of suitable organic carboxylic acids, with organic alkali metal or alkaline earth metal compounds, such as the corresponding hydroxides, carbonates or hydrogen carbonates, such as sodium or potassium hydroxide, carbonate or hydrogen carbonate, with corresponding calcium compounds or with ammonia or a suitable organic amine, stoichiometric amounts or only a small excess of the salt-forming agent preferably being used. Acid addition salts of the compounds described herein are obtained in customary manner, e.g., by treating the compounds with an acid or a suitable anion exchange reagent. Internal salts of the compounds described herein containing acid and basic saltforming groups, e.g., a free carboxy group and a free amino group, may be formed, e.g., by the neutralization of salts, such as acid addition salts, to the isoelectric point, e.g., with weak bases, or by treatment with ion exchangers.

[00177] Salts can be converted in customary manner into the free compounds; metal and ammonium salts can be converted, for example, by treatment with suitable acids, and acid addition salts, for example, by treatment with a su itable basic agent.

[00178] Mixtures of isomers obtainable as described herein can be separated in a manner known per se into the individual isomers; diastereoisomers can be separated, for example, by partitioning be-tween polyphasic solvent mixtures, recrystallisation and/or chromatographic separation, for example over silica gel or by, e.g., medium pressure liquid chromatography over a reversed phase column, and racemates can be separated, for example, by theformation of salts with optically pure salt-forming reagents and separation of the mixture of diastereoisomers so obtainable, for example by means of fractional crystallization, or by chromatography over optically active column materials. Intermediates and final products can be worked up and/or purified according to standard methods, e.g., using chromatographic methods, distribution methods, (re-) crystallization, and the like.

EXAMPLES

[00179] All patents and publications mentioned in the specification are indicative of the levels of those skilled in the art to which the present disclosure pertains. All patents and publications are herein incorporated by reference to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference.

[00180] The publications discussed throughout are provided solely for their disclosure before the filing date of the present application. Nothing herein is to be construed as an admission th at the invention isnotentitled to antedate such disclosure by virtue of prior invention.

[00181] The following examples are included to demonstrate the disclosure. It should be appreciated by those of skill in the art that the techniques disclosed in the following examples represent techniques discovered by the inventors to function well in the practice of the disclosure. Those of skill in the art should, however, in light of the present disclosure, appreciate that many changes could be made in the disclosure and still obtain a like or similar result without departing from the spirit and scope of the disclosure, therefore all matter set forth is to be interpreted as illustrative and not in a limiting sense.

Detailed methods of synthesis

[00182] Details of the protocols for synthesis are provided herein.

General Procedure:

[00183] To a 5 mL disposable culture tube, 2-chloro-/V-substituted-3- pyridinecarboxamide (1 .0 equiv., 0.1 mmol), amine (2.0 equiv., 0.2 mmol), DIPEA (34 mL, 0.2 mmol, 2.0 equiv.), and DMSO (1.0 mL) were added. The tube was capped and heated at 130°C for 12-48 h. TLC analysis indicated formation of products. Water (4 mL) and ethyl acetate (4 mL) were added, and the organic phase was separated. The aqueous layer was extracted with ethyl acetate (4 mL) for two times, and the organic solutions were combined. The resulting solution was dried with Na2SO4, filtered, concentrated, and purified by chromatography (using silica gel and a mixture of ethyl acetate and hexanes) to yield the products. Figure 1 illustrates the general chemical reaction for the formation of the disclosed compounds. Figure 2 illustrates examples of sample chloro-/V-substituted-3-pyridinecarboxamide in one or more embodiments of the present disclosure.

[00184] All NMR experiments were recorded on Broker Ascend-600 spectrometer, Varian In ova-400 spectrometer, and Broker Ascend-400 spectrometer. Data for ¹H and ¹³C NMR spectra are reported as follows: chemical shift (5, ppm), integration, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, ddd = doublet of doublets of doublets, dt = doublet of triplets and m = multiplet) and coupling constant (Hz). The 7.26, 3.31 and 2.50 resonance residuals of CDCh, MeOD and DMSO for proton spectra and the 77.23, 49.00 and 39.52 resonance of CDCI3, MeOD and DMSO respectively for carbon spectra were used as internal references. Silica gel flash chromatography purifications were performed using 40-63 micron flash silica gel purchased from Sorbtech Technologies. Thin layer chromatography (TLC) was performed on silica gel 60 F254 pre-coated glass plates (0.25 mm) purchased from E. Merck. Visualization of TLC plateswas performed using ultraviolet light (254 nm), ceric ammonium molybdate (CAM) or KMnO4 stain and heat as developing agents. Mass spectra were acquired on an Agilenttechnologies 1200 series LC/MS using indicated ionization methods. Example 1. Synthesis of 2-(benzylamino)-N-(4-(1- cyanocyclopentyl) phenyl) nicotinamide (TQYY-1)

(Compound 1 )

[00185] 0.1 mmol of 2-chloro-N-[4-(1 -cyanocyclopentyl)phenyl] -3- pyridinecarboxamide and 0.2 mmol of benzyl amine were reacted according to the general procedure. The reaction mixture was purified using preparative TLC (pTLC) in a 3:1 hexanes to acetone solvent mixture. The reaction and purification formed 20.8 mg of compound TQYY-1 with a 53% yield.

Example 2. Synthesis of 2-(tert-butylamino)-N-(4-(1- cyanocyclopentyl)phenyl)nicotinamide (TQYY-2)

(Compound 2)

[00186] 0.1 mmol of 2-chloro-/V-[4-(1 -cyanocyclopentyl)phenyl] -3- pyridinecarboxamide and O.2 mmol of tert-butyl amine were reacted according to the general procedure. The reaction mixture was purified using preparative TLC (pTLC) in a 2:1 hexanes to acetone solvent mixture. The reaction and purification formed 1.7 mg of compound TQYY-2 with a 5% yield.

Example 3. Synthesis of N-cyclohexyl-2-((pyridin-4- ylmethyl)amino)nicotinamide (TQYY-3)

(Compound s) [00187] 0.1 mmol of 2-chloro-/V-[4-(1 -cyanocyclopentyl)phenyl] -3- pyridinecarboxamide and 0.2 mmol of 4-picolylaminewere reacted according to the general procedure. The reaction mixture was purified using preparative TLC (pTLC) in a 2:1 hexanes to acetone solvent mixture. The reaction and purification formed 10.4 mg of compound TQYY-3 with a 34% yield.

Example 4. Synthesis of N-benzyl-2-((pyridin-4- ylmethyl)amino)nicotinamide (TQYY-4)

(Compound 4)

[00188] 0.1 mmol of A/-benzyl-2 -chloronicotinamide and 0.2 mmol of 4- picolylaminewere reacted according to the general procedure. The reaction mixture was purified using preparative TLC (pTLC) in a 1 :1 hexanes to acetone solvent mixture. The reaction and purification formed 7.4 mg of compound TQYY-4 with a 23% yield.

Example 5. Synthesis of N-(4-(1 -cyanocyclopentyl) phenyl)-2-((pyridin-3- ylmethyl)amino)nicotinamide (TQYY-5)

(Compound s)

[00189] 0.1 mmol of 2-chloro-/V-[4-(1 -cyanocyclopentyl)phenyl] -3- pyridinecarboxamide and 0.2 mmol of 3-picolylaminewere reacted according to the general procedure. The reaction mixture was purified using preparative TLC (pTLC) in a 4:1 hexanes to acetone solvent mixture. The reaction and purification formed 15.0 mg of compound TQYY-5 with a 38% yield. Example 6. Synthesis of N-(4-(1 -cyanocyclopentyl) phenyl)-2-((4- fluorobenzyl)amino)nicotinamide (TQYY-6)

(Compound 6)

[00190] 0.1 mmol of 2-chloro-/V-[4-(1 -cyanocyclopentyl)phenyl] -3- pyridinecarboxamide and 0.2 mmol of 4-fluorobenzylaminewere reacted according to the general procedure. The reaction mixture was purified using preparative TLC (pTLC) in a 4:1 hexanes to acetone solvent mixture. The reaction and purification formed 16.2 mg of compound TQYY-6 with a 39% yield.

Example 7. Synthesis of N-(4-(1-cyanocyclopentyl)phenyl)-2-

(propylamino) nicotinamide (TQYY-7)

(Compound 7)

[00191] 0.1 mmol of 2-chloro-/V-[4-(1 -cyanocyclopentyl)phenyl] -3- pyridin ecarboxamide and 0.2 mmol of propylamine were reacted according to the general procedure. The reaction mixture was purified using preparative TLC (pTLC) in a 5:1 hexanes to acetone solvent mixture. The reaction and purification resulted in formation 27.1 mg of TQYY-7 with a 39% yield. Example 8. Synthesis of 2-(benzyl(methyl)amino)-N-(4-(1- cyanocyclopentyl) phenyl) nicotinamide (TQYY-8)

(Compound 8)

[00192] 0.1 mmol of 2-chloro-/V-[4-(1 -cyanocyclopentyl)phenyl] -3- pyridinecarboxamide and 0.2 mmol of N-benzylmethylamine were reacted according to the general procedure. The reaction mixture was purified using preparative TLC (pTLC) in a 5:1 hexanes to acetone solvent mixture. The reaction and purification yield 37.6 mg of the compound TQYY-8. The reaction and purification formed 37.6 mg of compound TQYY-8 with a 92% yield.

Example 9. Synthesis of 2-(benzylamino)-N-(4-(1- cyanocyclopentyl)phenyl)nicotinamide (TQYY-9)

(Compound 9)

[00193] 0.1 mmol of 2-chloro-/V-[4-(1 -cyanocyclopentyl)phenyl] -3- pyridin ecarboxamide and 0.2 mmol of morpholine were reacted according to the general procedure. The reaction mixture was purified using preparative TLC (pTLC) in a 5:1 hexanes to acetone solvent mixture. The reaction and purification formed 11 .4 mg of compound TQYY-9 with a 30% yield. Example 10. Synthesis of N-(4-(1 -cyanocyclopentyl) phenyl)-2-((1- (methylsulfonyl)piperidin-4-yl)amino)nicotinamide (TQYY-10)

(Compound 10)

[00194] 0.1 mmol of 2-chloro-/V-[4-(1 -cyanocyclopentyl)phenyl] -3- pyridin ecarboxamide and 0.2 mmol of 1 -(methylsulfonyl) piperidin-4-amine were reacted according to the general procedure. The reaction mixture was purified using preparative TLC (pTLC) in a 3:1 hexanes to acetone solvent mixture. The reaction and purification resulted in 12.7 mg of the compound TQYY-9 at a 27% yield.

Example 11. Synthesis of N-(4-(1-cyanocyclopentyl)phenyl)-2- (isopentylamino) nicotinamide (TQYY-11)

(Compound 1 1 )

[00195] 0.1 mmol of 2-chloro-/V-[4-(1 -cyanocyclopentyl)phenyl] -3- pyridinecarboxamide and 0.2 mmol of isopentylamine were reacted according to the general procedure. The reaction mixture was purified using preparative TLC (pTLC) in a 3:1 hexanes to acetone solvent mixture. The reaction and purification resulted in 37.4 mg of the compound TQYY-11 at a 99% yield. Example 12. Synthesis of N-(4-(1 -cyanocyclopentyl) phenyl)-2-((2- sulfamoylethyl)amino)nicotinamide (TQYY-12)

(Compound 12)

[00196] 0.1 mmol of 2-chloro-/V-[4-(1 -cyanocyclopentyl)phenyl] -3- pyri din ecarboxamide and 0.2 mmol of 2-aminoethanesulfonamide hydrochloride were reacted according to the general procedure. The reaction mixture was purified using preparative TLC (pTLC) in a 1 :1 methylenechloride:ethyl acetatesolventmixture. The reaction and purification resulted in 7.0 mg of the compound TQYY-12 at a 17% yield.

Example 13. Synthesis of N-(4-(1-cyanocyclopentyl)phenyl)-2- (neopentylamino) nicotinamide (TQYY-13)

(Compound 13)

[00197] 0.1 mmol of 2-chloro-/V-[4-(1 -cyanocyclopentyl)phenyl] -3- pyridinecarboxamide and 0.2 mmol of amylamine were reacted according to the general procedure. The reaction mixture was purified using preparative TLC (pTLC) in a 3:1 hexanes:acetone solvent mixture. The reaction and purification resulted in 19.1 mg of the compound TQYY-13 at a 51 % yield. Example 14. Synthesis of tert-butyl 3-(((3-((4-(1- cyanocyclopentyl)phenyl)carbamoyl)pyridin-2-yl)amino)methyl) azetidine-1- carboxylate (TQYY-14)

(Compound 14)

[00198] 0.1 mmol of 2-chloro-/V-[4-(1-cyanocyclopentyl)phenyl] -3- pyri din ecarboxamide and 0.2 mmol of 1-Boc-3-(aminomethyl)azetidinewere reacted according to the general procedure. The reaction mixture was purified using preparative TLC (pTLC) in a 4:1 hexanes:acetone solvent mixture. The reaction and purification resulted in 23.6 mg of the compound TQYY-14 at a 50% yield.

Example 15. Synthesis of N-(4-(1 -cyanocyclopentyl) phenyl)-2-((3- (dimethylamino)propyl)amino)nicotinamide (TQYY-15)

(Compound 15)

[00199] 0.1 mmol of 2-chloro-/V-[4-(1 -cyanocyclopentyl)phenyl] -3- pyridinecarboxamide and 0.2 mmol of 3-(dimethylamino)-1 -propylamine were reacted according to the general procedure. The reaction mixture was purified using preparative TLC (pTLC) in a 10:1 methylene chloride: methanol solvent mixture. The reaction and purification resulted in 3.6 mg of the compound TQYY-15 at a 9% yield. Example 16. Synthesis of 2-amino-N-(4-(1- cyanocyclopentyl) phenyl) nicotinamide (TQYY-16)

(Compound 16)

[00200] To a 5 mL disposable culture tube, 2-chloro-/V-[4-(1 - cyanocyclopentyl)phenyl] -3-pyridinecarboxamide (1.0 equiv., 0.1 mmol), ammonia (25% in water, 4.0 mL), and dioxane (1 .0 mL) were added. The tube was capped and heated at 140°C overnight. TLC analysis indicated complete consumption of 2- chloropyridine. Water (4 mL) and ethyl acetate (4 mL) were added, and the organic phasewas separated. The aqueous layerwas extracted with ethyl acetate (4 mL), and the organic solutions were combined. The resulting solution was dried with Na2SO4, filtered, concentrated, and purified by pTLC (hexanes: acetone, 1 :1 ). The reaction and purification resulted in 3.6 mg of compound TQYY-16 with a 67% yield.

Example 17. Synthesis of N-(4-fluorophenyl)-2-((pyridin-4- ylmethyl)amino)nicotinamide (TQYY-17)

(Compound 17)

[00201] To a 5 mL disposableculturetube, 2-((pyridin-4-ylmethyl)amino)nicotinic acid (1 .0 equiv., 0.1 mmol, 22.9 mg), 4-picolylamine (1 .5 equiv., 0.15 mmol, 16.2 mg), BOP reagent (1.8 equiv., 0.18 mmol, 78 mg) and DMF (1.0 mL) were added. Then DIPEA (0.05 mL, 0.3 mmol, 3.0 equiv.) was added to the mixture andthe reaction tube was stirred at room temperature overnight. TLC analysis indicated complete consumption of carboxylic acid. Water (4 mL) and ethyl acetate (4 mL) were added, and the organic phase was separated. The aqueous layer was extracted with ethyl acetate (4 mL), and the organic solutionswere combined and washed with water and brine. The resultingsolution wasdriedwith Na2SO4, filtered, concentrated, and purified by pTLC (hexanes: acetone, 2:1 ). The reaction and purification resulted in 7.2 mg of compound TQYY-17 with a 22% yield.

[00202] Table 2 provides the ¹H, ¹³C, ¹⁹F NMR and LC-MS characterization of the synthesized compounds. Appendix A, incorporated by reference herein in its entirety, provides the NMR spectra of compounds 1-17 is Table 2.

Table 2.

[00203] Table 3 provides the physical state, melting point, and Rf value in an appropriate solvent of the compound of Table 1 , listed as compounds 1-17:

Table 3

Example 18.

[00204] Cells lacking endogenous UBIAD1 were transfected with an expression plasmid encoding HMG CoA reductase (HMGCR) in the absence or presence of wild type (WT) or SCD-associated N102S UBIAD1. After transfection, cells were treated in the absence or presence of Apatinib for 5 hr, after which the cells were harvested for isolation of membranes and analysis by immunoblot. FIG. 3 shows that HMGCR exhibited low expression when transfected alone (lane 1 ) and Apatinib had no effect on the level of the protein (lane 2). Co-transfection of UBIAD1 (WT) stabilized HMGCR (lane 3); however, its expression was reduced in the presence of Apatinib (lane 4) as a result of accelerated degradation. HMGCR was further stabilized by UBIAD1 (N102S) (lane 5) and degradation was enhanced in the presence of Apatinib. These results are consistentwith the conclusion that Apatinib accelerates the degradation of both WT and SCD-associated variants of UBIAD1 .

Example 19.

[00205] Chow-fed mice were subjected to daily treatments by oral gavage with vehicle (corn oil) or Apatinib (200 pg/g of body weight)for fourconsecutive days. As shown in FIG. 4, the results show that treatment with Apatinib led to a significant decrease in the amount of hepatic HMGCR as determined by immunoblot analysis. The level of UBIAD1 was also reduced by Apatinib treatment, which is consistent with enhanced translocation of UBIAD1 to the Golgi from which it is subjected to basal autophagic degradation. These results indicatethat Apatinib modulates the ERAD of HMGCR and ER-to-Golgi trafficking of UBIAD1 in livers of mice through mechanisms similar to those we observed in cultured cells.

[00206] Apatinib causes reduction in levels of HMGCR and UBIADI in livers of mice. Male C57BL/6 mice (10 weeks of age) fed chow diet ad libitum were subjected to daily oral gavage with vehicle (corn oil) or Apatinib (200 pg/g of body weight) for four consecutive days. The mice were sacrificed and livers were harvested for subcellular fractionation. Aliquots of resulting membranefractionswere subjected to SDS-PAGE, followed by immunoblot analysis with antibodies against the indicated proteins (FIG. 4).

Claims

CLAIMS What is claimed is:

1. A compound of Formula (I):

Formula (I) wherein Ri and R2 are independently of each other hydrogen, halogen, alkyl, alkyl amine, alkyl sulfonamide, aryl, substituted aryl, heterocyclic aryl amine, substituted heterocyclic aryl amine, cyclic aliphatic amine, heterocyclic aliphatic amine, substituted heterocyclic aliphatic amine, alkyne; or together with the carbon atom to form a cycloalkyl, a cycloalkenyl, or a heterocyclylalkyl ring;

R3 is an aryl or substituted aryl;

Y is an oxygen, nitrogen, or sulfur; or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein the substituted aryl is a phenyl group with a substituted carbon atom on a para position as in Formula (II)

Formula (II).

3. The compound of claim 2, wherein X is a halogen or a cycloalkane carbonitrile with formula -CnH(2n-2)CN, wherein n is 3 or more.

4. The compound of claim 3, wherein the halogen is fluorine, chlorine, or iodine.

5. The compound of claim 1 , wherein the compound comprises a biotin group.

6. The compound of claim 5, wherein the biotin group is linked to the compound via the alkyne group.

7. The compound of claim 1 , wherein the compound is photoactivatable.

8. The compound of claim 1 , wherein Ri is hydrogen and R2 is selected from the group consistingof branch edorunbranchedalkyl, alkyl amine, alkyl sulfonamide, alkyne, aryl, substituted aryl, heterocyclic aryl amine, substituted heterocyclic aryl amine, heterocyclicaliphaticamine, and substituted heterocyclicaliphaticamine.

9. The compound of claim 8, wherein R2 is selected from the group consisting of propane, isopentane, neopentane, toluene, 3-methylpyridine, 4-methylpyridine, 1 -fl uoro-4-methy I benzene, toluene, te/t-bu ty 1 3-methylazetidine-1 -carboxylate, 1 - (methylsulfonyl)piperidine, ethanesulfonamide, and A/,/\/-dimethylpropan-1- amine.

10. The compound of claim 2, wherein R1 and R2 combine to form a heterocycle with both amine and ether groups as in Formula (III)

Formula (III) wherein X is a halogen or a cycloalkane carbon itrile with formula -CnH(2n-2)CN, wherein n is 3 or more.

11 . The compound of claim 1 , wherein Ri and R2 are diethylenimide oxide.

12. The compound of claim 1 , wherein the compound is selected from the group consisting of:

ompoun ;

Compound 11 ;

Compound 15; and

Compound 17.

13. The compound of claim 1 , wherein the compound is an allosteric activator of a protein encoding gene.

14. The compound of claim 13, wherein the protein encoding gene is UBIAD1 .

15. The compound of claim 14, wherein the compound increases affinity of UBIAD1 for GGpp.

16. A method of treating or reducing the risk of acquiring a cardiovascular or cholesterol related disorder to a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound according to any one of claims 1 -15, compound

Apatinib to the su bject.

17. The method of claim 16, wherein the subject has a high blood plasma cholesterol value relative to a predetermined blood plasma cholesterol value and/or has a genetic predisposition to high blood plasma cholesterol.

18. The method of claim 17, wherein the subject has a high blood plasma cholesterol value relative to a predetermined blood plasma cholesterol value and the predetermined blood plasma cholesterol value is less than or equal to 200 mg/dL.

19. The method of claim 17, wherein the subject has a genetic predisposition to high blood plasma cholesterol andthe genetic predisposition is a mutation in UBIAD1, LDLR, APOB, SREBP, SCAP, and/or PCSK9 genes.

20. The method of any one of claims 17 to 19, wherein thecholesterol isa low-density lipoprotein (LDL)-cholesterol.

21. The method of any one of claims 16 to 20, wherein the cardiovascular or cholesterol related disorder is Schnyder corneal dystrophy (SCD), corneal dystrophy, peripheral artery disease, hypercholesterolemia, hyperlipidemia/ dyslipidemia, sitosterolemia, atherosclerosis, arteriosclerosis, or xanthoma.

22. The method of any one of claims 16 to 21 , wherein the compound reduces plasma cholesterol value by enabling ubiquitination and ER-associated degradation of HMG CoA reductase.