STATEMENT AS TO FEDERALLY SPONSORED RESEARCH

[0001] This invention was made with government support under Grant # 1U19 All 42784-01 awarded by the National Institutes of Health. The government has certain rights in the invention.

CROSS-REFERENCE

[0002] This application claims the benefit of US Provisional Application No. 63/275,881 filed on November 4, 2021, the entire contents of which are herein incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

[0003] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

[0004] FIG. 1 provides a graph demonstrating that compounds of the present disclosure induce autophagy comparable to ABT-737, a known autophagy inducer.

[0005] FIG. 2 provides a table of kD values demonstrating binding between compounds of the present disclosure to the BH3 pocket of a Bcl-2 protein fragment.

[0006] FIG. 3 provides gel electrophoresis demonstrating induction of autophagy in HeLa cells following treatment with compounds of the present disclosure.

[0007] FIG. 4 demonstrates induction of autophagy by compounds of the present disclosure at different concentrations.

[0008] FIG. 5 demonstrates induction of autophagy after 4-hour treatment with 40 pM of compounds of the present disclosure.

BACKGROUND OF THE INVENTION

[0009] Autophagy is a metabolic pathway where cells sequester unwanted or damaged cellular proteins or organelles by encasing those proteins in an autophagosome, a double membraned structure. Autophagy is significantly involved in various physiological roles, including cellular survival, stress adaptation, metabolism, development, immunity, protein and organellar homeostasis. Autophagy has also been implicated in protection against aging. Furthermore, emerging evidence has demonstrated a connection between impaired autophagy and the development of various diseases, including diabetes, infection, cancer, and neurodegenerative diseases. Whole-body or tissue-specific genetic disruption of autophagy in mice leads to multiple pathologies, including tissue abnormalities, aberrant inflammation, impaired immunity, neurodegeneration, and susceptibility to tumorigenesis. In humans, mutations or polymorphisms in autophagy genes have been associated with increased susceptibility to infection, as well as the development of many diseases, including cancer, inflammatory diseases, asthma, cerebral palsy, frontotemporal dementia, amyotrophic lateral sclerosis (ALS), Huntington's disease, and Parkinson's disease. Gain-of-function mutations or enforced expression of autophagy genes in mice have provided evidence that enhancement of the autophagy pathway may have beneficial effects including improved metabolism and tissue function, extended lifespan, neuroprotection, and decreased tumorigenesis. Thus, the development of autophagy-inducing agents may provide an important treatment modality for the prevention and/or treatment of disease.

[0010] One key mechanism of autophagy regulation is the binding of Bcl-2 to Beclin 1, a scaffold protein that is an essential determinant of the activity of the Beclin 1-VPS34 class III phosphatidylinisotol 3 kinase complex. Binding of Bcl-2 to Beclin 1 results in inhibition of autophagy. However, in some instances, it is desirable to selectively disrupt Beclin l/Bcl-2 binding but without affecting the function of other Bcl-2 (or other pro-apoptotic family members), thereby selectively inducing autophagy (a pro-survival pathway) without inducing apoptosis. Accordingly, there is a need for novel compounds that target the Beclin l/Bcl-2 interaction without perturbing the binding of Bcl-2 to pro-apoptotic BH3 domain-containing molecules.

SUMMARY OF THE INVENTION

[0011] In some aspects, the present disclosure provides a compound of Formula (I); wherein

A is a 5-to 8-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, Ci- ₄ alkyl, Ci- ₄ haloalkyl, -N(R ⁿ ) ₂ , -OR ¹¹ , -SR ¹¹ , -C(O)R ^U , -C(O)OR ^U , - OC(O)R ^U , -OC(O)N(R ^U )2, -C(O)N(R ¹¹ )2, -N(R ^U )C(O)R ¹¹ , -N(R ⁿ )C(O)OR ⁿ , - N(R ¹¹ )C(O)N(R ¹¹ ) ₂ , -N(R ¹¹ )C(S)N(R ¹¹ ) ₂ , -N(R ¹¹ )S(O) ₂ (R ¹¹ ), -S(O)R ^U , -S(O)2R ⁿ , - S(O)2N(R ^U )2, -NO ₂ , and -CN;

R ¹ is selected from halogen, Ci-6 alkyl, Ci-6 haloalkyl, -OR ¹² , -SR ¹² , -N(R ¹² ) ₂ , -C(O)R ¹² , - C(O)OR ¹² , -OC(O)R ¹² , -C(O)N(R ¹² ) ₂ , -N(R ¹² )C(O)R ¹² , -NO _2J and -CN; m is selected from 0, 1, 2, 3, and 4;

R ² is selected from halogen, Ci-6 alkyl, Ci-6 haloalkyl, -OR ¹³ , -SR ¹³ , -N(R ¹³ ) ₂ , -C(O)R ¹³ , - C(O)OR ¹³ , -OC(O)R ¹³ , -C(O)N(R ¹³ ) ₂ , -N(R ¹³ )C(O)R ¹³ , -NO _2J and -CN; p is selected from 0, 1, 2, 3, and 4;

L is selected from -C(O)-, -CO2-, and -C(O)N(R ³ )-;

R ³ is selected from hydrogen and Ci- ₄ alkyl;

R ^B is selected from halogen, -OR ¹⁸ , and Ci- ₄ alkyl, and when L is -C(O)N(R ³ )-, R ^B is further selected from hydrogen;

R ^A is selected from: halogen, -N(R ¹⁴ )(R ¹⁵ ), -OR ¹⁵ -SR ¹⁴ , -C(O)R ¹⁴ , -C(O)OR ¹⁴ , -OC(O)R ¹⁴ , -OC(O)N(R ¹⁴ ) ₂ , - C(O)N(R ¹⁴ ) ₂ , -N(R ¹⁴ )C(O)R ¹⁵ , -N(CH ₃ )C(O)OR ¹⁴ ; -N(R ¹⁴ )C(O)OR ¹⁶ , - N(R ¹⁴ )C(O)N(R ¹⁴ )(R ¹⁷ ), -N(R ¹⁴ )C(S)N(R ¹⁴ ) ₂ , -N(R ¹⁴ )S(O) ₂ (R ¹⁷ ), -S(O)R ¹⁴ , -S(O) ₂ R ¹⁴ , and -S(O) ₂ N(R ¹⁴ ) ₂ ;

CI alkyl substituted with one or more substituents independently selected from: halogen, -N(R ¹⁴ )(R ¹⁴ ), -OR ¹⁴ , -SR ¹⁴ , -C(O)R ¹⁴ , -C(O)OR ¹⁴ , -OC(O)R ¹⁴ , -OC(O)N(R ¹⁴ ) ₂ , - C(O)N(R ¹⁴ ) ₂ , -N(R ¹⁴ )C(O)R ¹⁴ , -N(R ¹⁴ )C(O)OR ¹⁴ , -N(R ¹⁴ )C(O)N(R ¹⁴ ) ₂ , - N(R ¹⁴ )C(S)N(R ¹⁴ ) ₂ , -N(R ¹⁴ )S(O) ₂ (R ¹⁴ ), -S(O)R ¹⁴ , -S(O) ₂ R ¹⁴ , -S(O) ₂ N(R ¹⁴ )2, and -CN;

C2-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -N(R ¹⁴ )(R ¹⁴ ), -OR ¹⁴ , -SR ¹⁴ , -C(O)R ¹⁴ , -C(O)OR ¹⁴ , -OC(O)R ¹⁴ , - OC(O)N(R ¹⁴ ) ₂ , -C(O)N(R ¹⁴ ) ₂ , -N(R ¹⁴ )C(O)R ¹⁴ , -N(R ¹⁴ )C(O)OR ¹⁴ , - N(R ¹⁴ )C(O)N(R ¹⁴ ) ₂ , -N(R ¹⁴ )C(S)N(R ¹⁴ ) ₂ , -N(R ¹⁴ )S(O) ₂ (R ¹⁴ ), -S(O)R ¹⁴ , -S(O) ₂ R ¹⁴ , - S(O) ₂ N(R ¹⁴ ) ₂ , and -CN; and

C3-5 carbocycle and 3- to 5-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, -N(R ¹⁴ )(R ¹⁴ ), - OR ¹⁴ , -SR ¹⁴ , -C(O)R ¹⁴ , -C(O)OR ¹⁴ , -OC(O)R ¹⁴ , -OC(O)N(R ¹⁴ ) ₂ , -C(O)N(R ¹⁴ ) ₂ , - N(R ¹⁴ )C(O)R ¹⁴ , -N(R ¹⁴ )C(O)OR ¹⁴ , -N(R ¹⁴ )C(O)N(R ¹⁴ ) ₂ , -N(R ¹⁴ )C(S)N(R ¹⁴ ) ₂ , - N(R ¹⁴ )S(O) ₂ (R ¹⁴ ), -S(O)R ¹⁴ , -S(O) ₂ R ¹⁴ , -S(O) ₂ N(R ¹⁴ )2, -NO2, and -CN; and when L is -C(O)N(R ³ )- or R ^B is Ci-4 alkyl or -OR ¹⁸ , R ^A is further selected from- N(R ¹⁴ )C(O)OR ¹⁴ ;

R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , and R ¹⁸ are each independently selected at each occurrence from: hydrogen;

Ci-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O-C1.4 alkyl, -O-C1.4 haloalkyl, =0, and -CN; and

C3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from halogen, C1.4 alkyl; C1.4 haloalkyl; -OH, -O-C1.4 alkyl, -O-C1.4 haloalkyl, =0, and -CN

R ¹⁵ is selected from:

Ci-2 alkyl substituted with one or more substituents independently selected from -OH, -O- C1.4 alkyl, -O-C1-4 haloalkyl, =0, and -CN;C3-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O-C1.4 alkyl, -O-Ci- 4 haloalkyl, =0, and -CN; and

C3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from halogen, C1.4 alkyl; C1.4 haloalkyl; -OH, -O-C1.4 alkyl, -O-C1.4 haloalkyl, =0, and -CN;

R ¹⁶ is selected from hydrogen;

Ci and C4 alkyl, any of which is substituted with one or more substituents independently selected from halogen, -OH, -O-C1.4 alkyl, -O-C1.4 haloalkyl, =0, and -CN;

C2-3 alkyl and C5-6 alkyl, any of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -O-C1.4 alkyl, -O-C1.4 haloalkyl, =0, and -CN; and

C3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from halogen, C1.4 alkyl; C1.4 haloalkyl; -OH, -O-C1.4 alkyl, -O-C1.4 haloalkyl, =0, and -CN; and

R ¹⁷ is selected from hydrogen;

Ci alkyl substituted with one or more substituents independently selected from -OH, -O- C1.4 alkyl, -O-C1-4 haloalkyl, =0, and -CN;

C2-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O-C1.4 alkyl, -O-C1.4 haloalkyl, =0, and -CN; and C3-5 carbocycle and 3- to 5-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from halogen, C1.4 alkyl; C1.4 haloalkyl; -OH, -O-C1.4 alkyl, -O-C1.4 haloalkyl, =0, and -CN.

[0012] In some embodiments, the present disclosure provides a pharmaceutical composition comprising pharmaceutically acceptable excipient and a compound or salt of Formula (I).

[0013] In some embodiments, the present disclosure provides a method of inducing autophagy in a cell, comprising administering to the subject a compound or salt of Formula (I).

[0014] In some embodiments, the present disclosure provides a method of inhibiting binding of Beclin 1 to Bcl2 in a subject, comprising administering to the subject a compound or salt of Formula (I).

[0015] In some embodiments, the present disclosure provides a method of treating an infection, cancer, neurodegeneration and aging disease or condition comprising administering to a subject in need thereof a compound or salt of Formula (I).

INCORPORATION BY REFERENCE

[0016] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

DETAILED DESCRIPTION OF THE INVENTION

[0017] Autophagy plays a crucial role in cellular homeostasis, development, immunity, tumor suppression, metabolism, prevention of neurodegeneration, and lifespan extension. Thus, pharmacological stimulation of autophagy provides effective approach for preventing or treating certain human diseases and/or aging. Using split-luciferase and AlphaLISA assays and SAR development we developed small molecules that selectively inhibit the Beclin l/Bcl-2 protein-protein interaction (versus inhibiting other Bcl-2/BH3-domain containing protein-protein interactions that would induce apoptosis). These small molecule disruptors of Beclin- l/Bcl-2 protein-protein interactions induce autophagy and hence are useful for treating a variety of indications where stimulation (induction) of autophagy is therapeutically useful, including cancer, infection (including Zika) immunity, neurodegeneration, longevity.

Definitions [0018] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference.

[0019] As used in the specification and claims, the singular form “a”, “an” and “the” includes plural references unless the context clearly dictates otherwise.

[0020] "Alkyl" refers to a straight or branched hydrocarbon chain monovalent radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, and preferably having from one to twelve carbon atoms (i.e., C1-C12 alkyl). The alkyl is attached to the remainder of the molecule through a single bond. In certain embodiments, an alkyl comprises one to twelve carbon atoms (i.e., C1-C12 alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (i.e., Ci-Cs alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (i.e., C1-C5 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (i.e., C1-C4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (i.e., C1-C3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (i.e., C1-C2 alkyl). In other embodiments, an alkyl comprises one carbon atom (z.e., Ci alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (z.e., C5-C15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (z.e., Cs-Cs alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (z.e., C2-C5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (z.e., C3-C5 alkyl). For example, the alkyl group may be attached to the rest of the molecule by a single bind, such as, methyl, ethyl, 1 -propyl (zz-propyl), 1 -methylethyl (z.w-propyl), 1 -butyl (zz-butyl), 1 -methylpropyl (.scc-butyl), 2-methylpropyl (z.w-butyl), 1,1 -dimethylethyl (tert-butyl), 1 -pentyl (zz-pentyl), and the like.

[0021] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and preferably having from two to twelve carbon atoms (z.e., C2-C12 alkenyl). In certain embodiments, an alkenyl comprises two to eight carbon atoms (z.e., C2-C8 alkenyl). In certain embodiments, an alkenyl comprises two to six carbon atoms (z.e., C2-C6 alkenyl). In other embodiments, an alkenyl comprises two to four carbon atoms (z.e., C2-C4 alkenyl). The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-l-enyl (i.e., allyl), but-l-enyl, pent-l-enyl, penta- 1,4-dienyl, and the like.

[0022] "Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, and preferably having from two to twelve carbon atoms (i.e., C2-C12 alkynyl). In certain embodiments, an alkynyl comprises two to eight carbon atoms i.e., C2-C8 alkynyl). In other embodiments, an alkynyl comprises two to six carbon atoms (i.e., C2-C6 alkynyl). In other embodiments, an alkynyl comprises two to four carbon atoms (i.e., C2-C4 alkynyl). The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.

[0023] "Alkylene" refers to a straight divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation, and preferably having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through the terminal carbons respectively. Alkylene chain may be optionally substituted by one or more substituents such as those substituents described herein. In certain embodiments, an alkylene comprises one to ten carbon atoms (i.e., C1-C10 alkylene). In certain embodiments, an alkylene comprises one to eight carbon atoms (i.e., Ci-Cs alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (i.e., C1-C5 alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (i.e., C1-C4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (i.e., C1-C3 alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (i.e., C1-C2 alkylene). In other embodiments, an alkylene comprises one carbon atom (i.e., Ci alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (i.e., Cs-Cs alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (i.e., C2-C5 alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (i.e., C3- C5 alkylene).

[0024] "Alkenylene" refers to a straight divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and preferably having from two to twelve carbon atoms. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group are through the terminal carbons respectively. Alkenylene chain may be optionally substituted by one or more substituents such as those substituents described herein. In certain embodiments, an alkenylene comprises two to ten carbon atoms (i.e., C2-C10 alkenylene). In certain embodiments, an alkenylene comprises two to eight carbon atoms (i.e., C2- Cx alkenylene). In other embodiments, an alkenylene comprises two to five carbon atoms (i.e., C2- C5 alkenylene). In other embodiments, an alkenylene comprises two to four carbon atoms (i.e., C2-C4 alkenylene). In other embodiments, an alkenylene comprises two to three carbon atoms (i.e., C2-C3 alkenylene). In other embodiments, an alkenylene comprises two carbon atom (i.e., C2 alkenylene). In other embodiments, an alkenylene comprises five to eight carbon atoms (i.e., C5- Cs alkenylene). In other embodiments, an alkenylene comprises three to five carbon atoms i.e., C3-C5 alkenylene).

[0025] " Alkynylene" refers to a straight divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and preferably having from two to twelve carbon atoms. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkynylene chain to the rest of the molecule and to the radical group are through the terminal carbons respectively. Alkynylene chain may be optionally substituted by one or more substituents such as those substituents described herein. In certain embodiments, an alkynylene comprises two to ten carbon atoms (i.e., C2-C10 alkynylene). In certain embodiments, an alkynylene comprises two to eight carbon atoms (i.e., C2- Cs alkynylene). In other embodiments, an alkynylene comprises two to five carbon atoms (i.e., C2-C5 alkynylene). In other embodiments, an alkynylene comprises two to four carbon atoms (i.e., C2-C4 alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (i.e., C2-C3 alkynylene). In other embodiments, an alkynylene comprises two carbon atom (i.e., C2 alkynylene). In other embodiments, an alkynylene comprises five to eight carbon atoms (i.e., C5- Cs alkynylene). In other embodiments, an alkynylene comprises three to five carbon atoms (i.e., C3-C5 alkynylene).

[0026] The term “C _x -y” when used in conjunction with a chemical moiety, such as alkyl, alkenyl, or alkynyl is meant to include groups that contain from x to y carbons in the chain. For example, the term “Ci-6 alkyl” refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from 1 to 6 carbons. The term -C _x -y alkylene- refers to a substituted or unsubstituted alkylene chain with from x to y carbons in the alkylene chain. For example, -Ci-6 alkylene- may be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any one of which is optionally substituted.

[0027] The terms “C _x.y alkenyl” and “C _x.y alkynyl” refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond, respectively. The term -C _x.y alkenylene- refers to a substituted or unsubstituted alkenylene chain with from x to y carbons in the alkenylene chain. For example, - C2-6 alkenylene- may be selected from ethenylene, propenylene, butenylene, pentenylene, and hexenylene, any one of which is optionally substituted. An alkenylene chain may have one double bond or more than one double bond in the alkenylene chain. The term -C _x-y alkynylene- refers to a substituted or unsubstituted alkynylene chain with from x to y carbons in the alkynylene chain. For example, -C2-6 alkynylene- may be selected from ethynylene, propynylene, butynylene, pentynylene, and hexynylene, any one of which is optionally substituted. An alkynylene chain may have one triple bond or more than one triple bond in the alkynylene chain.

[0028] The term “carbocycle” as used herein refers to a saturated, unsaturated or aromatic ring in which each atom of the ring is carbon. Carbocycle include 3- to 10-membered monocyclic rings and 6- to 12-membered bicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. Bicyclic carbocycles may be fused, bridged or spiroring systems. In some embodiments, the carbocycle is an aryl. In some embodiments, the carbocycle is a cycloalkyl. In some embodiments, the carbocycle is a cycloalkenyl. In an exemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, are included in the definition of carbocyclic. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. Carbocycle may be optionally substituted by one or more substituents such as those substituents described herein.

[0029] "Cycloalkyl" refers to a stable fully saturated monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, and preferably having from three to twelve carbon atoms (i.e., C3-12 cycloalkyl). In certain embodiments, a cycloalkyl comprises three to ten carbon atoms (i.e., C3-10 cycloalkyl). In other embodiments, a cycloalkyl comprises five to seven carbon atoms (i.e., C5-7 cycloalkyl). The cycloalkyl may be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl radicals include, for example, adamantyl, norbomyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Cycloalkyl may be optionally substituted by one or more substituents such as those substituents described herein.

[0030] "Cycloalkenyl" refers to a stable unsaturated non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, preferably having from three to twelve carbon atoms and comprising at least one double bond (i.e., C3-12 cycloalkenyl). In certain embodiments, a cycloalkenyl comprises three to ten carbon atoms (i.e., C3-10 cycloalkenyl). In other embodiments, a cycloalkenyl comprises five to seven carbon atoms (i.e., C5-7 cycloalkenyl). The cycloalkenyl may be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Cycloalkenyl may be optionally substituted by one or more substituents such as those substituents described herein.

[0031] "Aryl" refers to a radical derived from an aromatic monocyclic or aromatic multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or aromatic multicyclic hydrocarbon ring system contains only hydrogen and carbon and from five to eighteen carbon atoms, where at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) ^-electron system in accordance with the Hiickel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene. Aryl may be optionally substituted by one or more substituents such as those substituents described herein. [0032] A “C _x -y carbocycle” is meant to include groups that contain from x to y carbons in a ring. For example, the term “C3-6 carbocycle” can be a saturated, unsaturated or aromatic ring system that contains from 3 to 6 carbon atoms — any of which is optionally substituted as provided herein. [0033] The term “heterocycle” as used herein refers to a saturated, unsaturated, non-aromatic or aromatic ring comprising one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycles include 3- to 10-membered monocyclic rings and 6- to 12- membered bicyclic rings. Each ring of a bicyclic heterocycle may be selected from saturated, unsaturated, and aromatic rings. In some embodiments, the heterocycle comprises at least one heteroatom selected from oxygen, nitrogen, sulfur, or any combination thereof. In some embodiments, the heterocycle comprises at least one heteroatom selected from oxygen, nitrogen, or any combination thereof. In some embodiments, the heterocycle comprises at least one heteroatom selected from oxygen, sulfur, or any combination thereof. In some embodiments, the heterocycle comprises at least one heteroatom selected from nitrogen, sulfur, or any combination thereof. The heterocycle may be attached to the rest of the molecule through any atom of the heterocycle, valence permitting, such as a carbon or nitrogen atom of the heterocycle. In some embodiments, the heterocycle is a heteroaryl. In some embodiments, the heterocycle is a heterocycloalkyl. Exemplary heterocycles include pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiophenyl, oxazolyl, thiazolyl, morpholinyl, indazolyl, indolyl, and quinolinyl. Heterocycle may be optionally substituted by one or more substituents such as those substituents described herein. Bicyclic heterocycles may be fused, bridged or spiro-ring systems. In an exemplary embodiment, a heterocycle, e.g., pyridyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Heterocycle may be optionally substituted by one or more substituents such as those substituents described herein.

[0034] "Heterocycloalkyl" refers to a stable 3- to 12-membered non-aromatic ring radical that comprises two to twelve carbon atoms and at least one heteroatom wherein each heteroatom may be selected from N, O, Si, P, B, and S atoms. In some embodiments, the heterocycloalkyl comprises at least one heteroatom selected from oxygen, nitrogen, sulfur, or any combination thereof. In some embodiments, the heterocycloalkyl comprises at least one heteroatom selected from oxygen, nitrogen, or any combination thereof. In some embodiments, the heterocycloalkyl comprises at least one heteroatom selected from oxygen, sulfur, or any combination thereof. In some embodiments, the heterocycloalkyl comprises at least one heteroatom selected from nitrogen, sulfur, or any combination thereof. The heterocycloalkyl may be selected from monocyclic or bicyclic, and fused or bridged ring systems. The heteroatoms in the heterocycloalkyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocycloalkyl radical is partially or fully saturated. The heterocycloalkyl is attached to the rest of the molecule through any atom of the heterocycloalkyl, valence permitting, such as any carbon or nitrogen atoms of the heterocycloalkyl. Examples of heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Heterocycloalkyl may be optionally substituted by one or more substituents such as those substituents described herein.

[0035] The term “heteroaryl” refers to a radical derived from a 3- to 12-membered aromatic ring radical that comprises one to eleven carbon atoms and at least one heteroatom wherein each heteroatom may be selected from N, O, and S. In some embodiments, the heteroaryl comprises at least one heteroatom selected from oxygen, nitrogen, sulfur, or any combination thereof. In some embodiments, the heteroaryl comprises at least one heteroatom selected from oxygen, nitrogen, or any combination thereof. In some embodiments, the heteroaryl comprises at least one heteroatom selected from oxygen, sulfur, or any combination thereof. In some embodiments, the heteroaryl comprises at least one heteroatom selected from nitrogen, sulfur, or any combination thereof. As used herein, the heteroaryl ring may be selected from monocyclic or bicyclic and fused or bridged ring systems rings wherein at least one of the rings in the ring system is aromatic, /.< ., it contains a cyclic, delocalized (4n+2) ^-electron system in accordance with the Hiickel theory. The heteroatom(s) in the heteroaryl radical may be optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl may be attached to the rest of the molecule through any atom of the heteroaryl, valence permitting, such as a carbon or nitrogen atom of the heteroaryl. Heteroaryl includes aromatic single ring structures, preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like. Heteroaryl may be optionally substituted by one or more substituents such as those substituents described herein. Heteroaryl also includes polycyclic ring systems having two or more rings in which two or more atoms are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other rings can be aromatic or non-aromatic carbocyclic, or heterocyclic. Heteroaryl may be optionally substituted by one or more substituents such as those substituents described herein.

[0036] An “X-membered heterocycle” refers to the number of endocylic atoms, i.e., X, in the ring. For example, a 5-membered heteroaryl ring or 5-membered aromatic heterocycle has 5 endocyclic atoms, e.g., triazole, oxazole, thiophene, etc.

[0037] "Alkoxy" refers to a radical bonded through an oxygen atom of the formula -O-alkyl, where alkyl is an alkyl chain as defined above.

[0038] "Halo" or "halogen" refers to halogen substituents such as bromo, chloro, fluoro and iodo substituents.

[0039] As used herein, the term "haloalkyl" or “haloalkane” refers to an alkyl radical, as defined above, that is substituted by one or more halogen radicals, for example, trifluoromethyl, di chloromethyl, bromomethyl, 2,2,2-trifluoroethyl, l-fluoromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl part of the fluoroalkyl radical is optionally further substituted. Examples of halogen substituted alkanes (“haloalkanes”) include halomethane (e.g., chloromethane, bromomethane, fluoromethane, iodomethane), di-and trihalomethane (e.g., tri chloromethane, tribromomethane, trifluoromethane, triiodomethane), 1-haloethane, 2- haloethane, 1,2-dihaloethane, 1-halopropane, 2-halopropane, 3-halopropane, 1,2-dihalopropane, 1,3-dihalopropane, 2,3-dihalopropane, 1,2,3-trihalopropane, and any other suitable combinations of alkanes (or substituted alkanes) and halogens (e.g., Cl, Br, F, and I). When an alkyl group is substituted with more than one halogen radicals, each halogen may be independently selected for example, 1 -chloro, 2-fluoroethane.

[0040] The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons or substitutable heteroatoms, e.g., an NH or NH2 of a compound. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, /.< ., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. In certain embodiments, substituted refers to moieties having substituents replacing two hydrogen atoms on the same carbon atom, such as substituting the two hydrogen atoms on a single carbon with an oxo, imino or thioxo group. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds.

[0041] In some embodiments, substituents may include any substituents described herein, for example: halogen, hydroxy, oxo (=0), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-0H), hydrazine (=N-NH ₂ ), -R ^b -OR ^a , -R ^b -OC(O)-R ^a , -R ^b -OC(O)-OR ^a , - R ^b -OC(O)-N(R ^a ) ₂ , -R ^b -N(R ^a ) ₂ , -R ^b -C(O)R ^a , -R ^b -C(O)OR ^a , -R ^b -C(O)N(R ^a ) ₂ , - R ^b -O-R ^c -C(O)N(R ^a ) ₂ , -R ^b -N(R ^a )C(O)OR ^a , -R ^b -N(R ^a )C(O)R ^a , -R ^b -N(R ^a )S(O) _t R ^a (where t is 1 or 2), -R ^b -S(O)tR ^a (where t is 1 or 2), -R ^b -S(O)tOR ^a (where t is 1 or 2), and -R ^b -S(O)tN(R ^a )2 (where t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl any of which may be optionally substituted by alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=0), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo(=N-OH), hydrazine(=NNH ₂ ), -R ^b -0R ^a , -R ^b -OC(O)-R ^a , -R ^b -OC(O)-OR ^a , -R ^b -OC(O)-N(R ^a ) ₂ , -R ^b -N(R ^a ) ₂ , - R ^b -C(O)R ^a , -R ^b -C(O)OR ^a , -R ^b -C(O)N(R ^a ) ₂ , -R ^b -0-R ^c -C(0)N(R ^a ) ₂ , -R ^b -N(R ^a )C(0)0R ^a , -R ^b -N(R ^a ) C(O)R ^a , -R ^b -N(R ^a )S(O) _t R ^a (where t is 1 or 2), -R ^b -S(O) _t R ^a (where t is 1 or 2), -R ^b -S(O) _t OR ^a (where t is 1 or 2) and -R ^b -S(O)tN(R ^a )2 (where t is 1 or 2); wherein each R ^a is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, wherein each R ^a , valence permitting, may be optionally substituted with alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=0), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-0H), hydrazine(=NNH ₂ ), -R ^b -0R ^a , -R ^b -OC(O)-R ^a , -R ^b -OC(O)-OR ^a , -R ^b -0C(0)-N(R ^a ) ₂ , -R ^b -N(R ^a ) ₂ , -R ^b -C(O)R ^a , -R ^b -C(O)OR ^a , -R ^b -C(0)N(R ^a ) ₂ , -R ^b -0-R ^c -C(0)N(R ^a ) ₂ , -R ^b -N(R ^a )C(0)0R ^a , -R ^b -N(R ^a )C (O)R ^a , -R ^b -N(R ^a )S(O)tR ^a (where t is 1 or 2), -R ^b -S(O)tR ^a (where t is 1 or 2), -R ^b -S(O)tOR ^a (where t is 1 or 2) and -R ^b -S(O)tN(R ^a )2 (where t is 1 or 2); and wherein each R ^b is independently selected from a direct bond or a straight or branched alkylene, alkenylene, or alkynylene chain, and each R ^c is a straight or branched alkylene, alkenylene or alkynylene chain. It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate.

[0042] The term “salt” or “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0043] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

[0044] The phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.

[0045] The term “zzz vivo" is used to describe an event that takes place in a subject’s body.

[0046] The term “ex vivo" is used to describe an event that takes place outside of a subject’s body. An ex vivo assay is not performed on a subject. Rather, it is performed upon a sample separate from a subject. An example of an ex vivo assay performed on a sample is an “zzz vitro" assay.

[0047] The term “zzz vitro" is used to describe an event that takes place in a container for holding laboratory reagent such that it is separated from the biological source from which the material is obtained. In vitro assays can encompass cell-based assays in which living or dead cells are employed. In vitro assays can also encompass a cell-free assay in which no intact cells are employed.

[0048] As used herein, the term “about” a number refers to that number plus or minus 10% of that number. The term “about” a range refers to that range minus 10% of its lowest value and plus 10% of its greatest value.

[0049] The terms "subject," "individual," and "patient" may be used interchangeably and refer to humans, the as well as non-human mammals (e.g., non-human primates, canines, equines, felines, porcines, bovines, ungulates, lagomorphs, and the like). In various embodiments, the subject can be a human (e.g., adult male, adult female, adolescent male, adolescent female, male child, female child) under the care of a physician or other health worker in a hospital, as an outpatient, or other clinical context. In certain embodiments, the subject may not be under the care or prescription of a physician or other health worker.

[0050] As used herein, the phrase "a subject in need thereof refers to a subject, as described infra, that suffers from, or is at risk for, a pathology to be prophylactically or therapeutically treated with a compound or salt described herein.

[0051] The terms “determining,” “measuring,” “evaluating,” “assessing,” “assaying,” and “analyzing” are often used interchangeably herein to refer to forms of measurement. The terms include determining if an element is present or not (for example, detection). These terms can include quantitative, qualitative or quantitative and qualitative determinations. Assessing can be relative or absolute. “Detecting the presence of’ can include determining the amount of something present in addition to determining whether it is present or absent depending on the context.

[0052] The terms “administer”, “administered”, “administers” and “administering” are defined as providing a composition to a subject via a route known in the art, including but not limited to intravenous, intraarterial, intracranial, intracerebral, intrathecal, intracerebroventricular, oral, parenteral, buccal, topical, transdermal, rectal, intramuscular, subcutaneous, intraosseous, transmucosal, or intraperitoneal routes of administration. In certain embodiments, oral routes of administering a composition can be used. The terms “administer”, “administered”, “administers” and “administering” a compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individual in need.

[0053] As used herein, the terms “treatment” or “treating” are used in reference to a pharmaceutical or other intervention regimen for obtaining beneficial or desired results in the recipient. Beneficial or desired results include but are not limited to a therapeutic benefit and/or a prophylactic benefit. A therapeutic benefit may refer to eradication or amelioration of symptoms or of an underlying disorder being treated. Also, a therapeutic benefit can be achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder. A prophylactic effect includes delaying, preventing, or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof. For prophylactic benefit, a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease may undergo treatment, even though a diagnosis of this disease may not have been made. [0054] In certain embodiments, the term “prevent” or “preventing” as related to a disease or disorder may refer to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample.

[0055] A “therapeutic effect,” as that term is used herein, encompasses a therapeutic benefit and/or a prophylactic benefit as described above. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0056] Unless defined otherwise herein, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0057] It is intended that every maximum numerical limitation given throughout this specification includes every lower numerical limitation, as if such lower numerical limitations were expressly written herein. Every minimum numerical limitation given throughout this specification will include every higher numerical limitation, as if such higher numerical limitations were expressly written herein. Every numerical range given throughout this specification will include every narrower numerical range that falls within such broader numerical range, as if such narrower numerical ranges were all expressly written herein.

[0058] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

Compounds

[0059] In some aspects, the present disclosure provides a compound of Formula (I); or a pharmaceutically acceptable salt thereof; wherein A is a 5-to 8-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -N(R ^U ) ₂ , -OR ¹¹ , -SR ¹¹ , -C(O)R ^U , -C(O)OR ⁿ , -OC(O)R ^U , -OC(O)N(R ^U )2, - C(O)N(R ⁿ ) ₂ , -N(R ¹¹ )C(O)R ¹¹ , -N(R ¹¹ )C(O)OR ¹¹ , -N(R ¹¹ )C(O)N(R ¹¹ ) ₂ , - N(R ¹¹ )C(S)N(R ¹¹ ) ₂ , -N(R ⁿ )S(O)2(R ⁿ ), -S(O)R ^U , -S(O)2R ^U , -S(O)2N(R ^U )2, -NO ₂ , and -CN;

R ¹ is selected from halogen, Ci-6 alkyl, Ci-6 haloalkyl, -OR ¹² , -SR ¹² , -N(R ¹² )2, -C(O)R ¹² , - C(O)OR ¹² , -OC(O)R ¹² , -C(O)N(R ¹² ) ₂ , -N(R ¹² )C(O)R ¹² , -NO _2J and -CN; m is selected from 0, 1, 2, 3, and 4;

R ² is selected from halogen, Ci-6 alkyl, Ci-6 haloalkyl, -OR ¹³ , -SR ¹³ , -N(R ¹³ )2, -C(O)R ¹³ , - C(O)OR ¹³ , -OC(O)R ¹³ , -C(O)N(R ¹³ ) ₂ , -N(R ¹³ )C(O)R ¹³ , -NO _2J and -CN; p is selected from 0, 1, 2, 3, and 4;

L is selected from -C(O)-, -CO2-, and -C(O)N(R ³ )-;

R ³ is selected from hydrogen and C1.4 alkyl,

R ^B is selected from halogen, -OR ¹⁸ , and C1.4 alkyl, and when L is -C(O)N(R ³ )-, R ^B is further selected from hydrogen;

R ^A is selected from: halogen, -N(R ¹⁴ )(R ¹⁵ ), -OR ¹⁵ -SR ¹⁴ , -C(O)R ¹⁴ , -C(O)OR ¹⁴ , -OC(O)R ¹⁴ , -OC(O)N(R ¹⁴ ) ₂ , - C(O)N(R ¹⁴ ) ₂ , -N(R ¹⁴ )C(O)R ¹⁵ , -N(CH ₃ )C(O)OR ¹⁴ ; -N(R ¹⁴ )C(O)OR ¹⁶ , - N(R ¹⁴ )C(O)N(R ¹⁴ )(R ¹⁷ ), -N(R ¹⁴ )C(S)N(R ¹⁴ ) ₂ , -N(R ¹⁴ )S(O) ₂ (R ¹⁷ ), -S(O)R ¹⁴ , -S(O) ₂ R ¹⁴ , and -S(O) ₂ N(R ¹⁴ ) ₂ ;

CI alkyl substituted with one or more substituents independently selected from: halogen, -N(R ¹⁴ )(R ¹⁴ ), -OR ¹⁴ , -SR ¹⁴ , -C(O)R ¹⁴ , -C(O)OR ¹⁴ , -OC(O)R ¹⁴ , -OC(O)N(R ¹⁴ ) ₂ , - C(O)N(R ¹⁴ ) ₂ , -N(R ¹⁴ )C(O)R ¹⁴ , -N(R ¹⁴ )C(O)OR ¹⁴ , -N(R ¹⁴ )C(O)N(R ¹⁴ ) ₂ , - N(R ¹⁴ )C(S)N(R ¹⁴ ) ₂ , -N(R ¹⁴ )S(O) ₂ (R ¹⁴ ), -S(O)R ¹⁴ , -S(O) ₂ R ¹⁴ , -S(O) ₂ N(R ¹⁴ )2, and -CN;

C2-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -N(R ¹⁴ )(R ¹⁴ ), -OR ¹⁴ , -SR ¹⁴ , -C(O)R ¹⁴ , -C(O)OR ¹⁴ , -OC(O)R ¹⁴ , - OC(O)N(R ¹⁴ ) ₂ , -C(O)N(R ¹⁴ ) ₂ , -N(R ¹⁴ )C(O)R ¹⁴ , -N(R ¹⁴ )C(O)OR ¹⁴ , - N(R ¹⁴ )C(O)N(R ¹⁴ ) ₂ , -N(R ¹⁴ )C(S)N(R ¹⁴ ) ₂ , -N(R ¹⁴ )S(O) ₂ (R ¹⁴ ), -S(O)R ¹⁴ , -S(O) ₂ R ¹⁴ , - S(O) ₂ N(R ¹⁴ ) ₂ , and -CN; and

C3-5 carbocycle and 3- to 5-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, -N(R ¹⁴ )(R ¹⁴ ), - OR ¹⁴ , -SR ¹⁴ , -C(O)R ¹⁴ , -C(O)OR ¹⁴ , -OC(O)R ¹⁴ , -OC(O)N(R ¹⁴ ) ₂ , -C(O)N(R ¹⁴ ) ₂ , - N(R ¹⁴ )C(O)R ¹⁴ , -N(R ¹⁴ )C(O)OR ¹⁴ , -N(R ¹⁴ )C(O)N(R ¹⁴ ) ₂ , -N(R ¹⁴ )C(S)N(R ¹⁴ ) ₂ , - N(R ¹⁴ )S(O) ₂ (R ¹⁴ ), -S(O)R ¹⁴ , -S(O) ₂ R ¹⁴ , -S(O) ₂ N(R ¹⁴ )2, -NO ₂ , and -CN; and when L is -C(O)N(R ³ )- or R ^B is -OR ¹⁸ or C1.4 alkyl, R ^A is further selected firom- N(R ¹⁴ )C(O)OR ¹⁴ ;

R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , and R ¹⁸ are each independently selected at each occurrence from: hydrogen;

Ci-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O-C1.4 alkyl, -O-C1.4 haloalkyl, =0, and -CN; and

C3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from halogen, C1.4 alkyl; C1.4 haloalkyl; -OH, -O-C1.4 alkyl, -O-C1.4 haloalkyl, =0, and -CN

R ¹⁵ is selected from:

Ci-2 alkyl substituted with one or more substituents independently selected from -OH, -O- C1.4 alkyl, -O-C1-4 haloalkyl, =0, and -CN;C3-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O-C1.4 alkyl, -O-Ci- 4 haloalkyl, =0, and -CN; and

C3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from halogen, C1.4 alkyl; C1.4 haloalkyl; -OH, -O-C1.4 alkyl, -O-C1.4 haloalkyl, =0, and -CN;

R ¹⁶ is selected from hydrogen;

Ci and C4 alkyl, any of which is substituted with one or more substituents independently selected from halogen, -OH, -O-C1.4 alkyl, -O-C1.4 haloalkyl, =0, and -CN;

C2-3 alkyl and C5-6 alkyl, any of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -O-C1.4 alkyl, -O-C1.4 haloalkyl, =0, and -CN; and

C3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from halogen, C1.4 alkyl; C1.4 haloalkyl; -OH, -O-C1.4 alkyl, -O-C1.4 haloalkyl, =0, and -CN; and

R ¹⁷ is selected from hydrogen;

Ci alkyl substituted with one or more substituents independently selected from -OH, -O- C1.4 alkyl, -O-C1-4 haloalkyl, =0, and -CN; C2-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O-C1.4 alkyl, -O-C1.4 haloalkyl, =0, and -CN; and

C3-5 carbocycle and 3- to 5-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from halogen, C1.4 alkyl; C1.4 haloalkyl; -OH, -O-C1.4 alkyl, -O-C1.4 haloalkyl, =0, and -CN.

[0060] In some embodiments, for the compound of Formula (I), A is a 5-to 8-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, Ci- ₄ alkyl, Ci- ₄ haloalkyl, -N(R ⁿ ) ₂ , -OR ¹¹ , -SR ¹¹ , -C(O)R ^U , -C(O)OR ^U , -OC(O)R ⁿ , - OC(O)N(R ⁿ ) ₂ , -C(O)N(R ^U )2, -N(R ¹¹ )C(O)R ¹¹ , -N(R ¹¹ )C(O)OR ¹¹ , -N(R ¹¹ )C(O)N(R ^U )2, - N(R ¹¹ )C(S)N(R ¹¹ ) ₂ , -N(R ¹¹ )S(O) ₂ (R ¹¹ ), -S(O)R ^U , -S(O)2R ^U , -S(O)2N(R ^U )2, -NO2, and -CN. In some embodiments, A is a 5-to 8-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, C1.4 alkyl, C1.4 haloalkyl, -N(R ⁿ )2, -OR ¹¹ , - SR ¹¹ , -NO2, and -CN. In some embodiments, A is a 5-to 8-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, C1.4 alkyl, C1.4 haloalkyl, and -CN. In some embodiments, A is a 5-to 8-membered heterocycle.

[0061] In some embodiments, for the compound of Formula (I), A is a 5-to 6-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, Ci- ₄ alkyl, Ci- ₄ haloalkyl, -N(R ⁿ ) ₂ , -OR ¹¹ , -SR ¹¹ , -C(O)R ^U , -C(O)OR ^U , -OC(O)R ⁿ , - OC(O)N(R ⁿ )2, -C(O)N(R ^U )2, -N(R ¹¹ )C(O)R ¹¹ , -N(R ¹¹ )C(O)OR ¹¹ , -N(R ¹¹ )C(O)N(R ^U )2, - N(R ¹¹ )C(S)N(R ¹¹ ) ₂ , -N(R ¹¹ )S(O) ₂ (R ¹¹ ), -S(O)R ^U , -S(O)2R ^U , -S(O)2N(R ^U )2, -NO2, and -CN. In some embodiments, A is a 5-to 6-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, C1.4 alkyl, C1.4 haloalkyl, -N(R ⁿ )2, -OR ¹¹ , - SR ¹¹ , -NO2, and -CN. In some embodiments, A is a 5-to 6-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, C1.4 alkyl, C1.4 haloalkyl, and -CN. In some embodiments, A is a 5-to 6-membered heterocycle.

[0062] In some embodiments, for the compound of Formula (I), A is a 6-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, C1.4 alkyl, C1.4 haloalkyl, -N(R ⁿ ) ₂ , -OR ¹¹ , -SR ¹¹ , -C(O)R ⁿ , -C(O)OR ⁿ , -OC(O)R ^U , -OC(O)N(R ^U )2, - C(O)N(R ⁿ ) ₂ , -N(R ¹¹ )C(O)R ¹¹ , -N(R ¹¹ )C(O)OR ¹¹ , -N(R ¹¹ )C(O)N(R ¹¹ ) ₂ , -N(R ¹¹ )C(S)N(R ¹¹ ) ₂ , - N(R ¹¹ )S(O) ₂ (R ¹¹ ), -S(O)R ⁿ , -S(O)2R ⁿ , -S(O)2N(R ^U )2, -NO2, and -CN. In some embodiments, A is a 6-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, C1.4 alkyl, C1.4 haloalkyl, -N(R ⁿ )2, -OR ¹¹ , -SR ¹¹ , -NO ₂ , and -CN. In some embodiments, A is a 6-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, Ci-4 alkyl, Ci-4 haloalkyl, and -CN. In some embodiments, A is a 6-membered heterocycle.

[0063] In some embodiments, for the compound of Formula (I), A is a 6-membered heteroaryl optionally substituted with one or more substituents independently selected from: halogen, Ci-4 alkyl, Ci-4 haloalkyl, -N(R ⁿ ) ₂ , -OR ¹¹ , -SR ¹¹ , -C(O)R ⁿ , -C(O)OR ⁿ , -OC(O)R ^U , -OC(O)N(R ^U )2, - C(O)N(R ⁿ ) ₂ , -N(R ¹¹ )C(O)R ¹¹ , -N(R ¹¹ )C(O)OR ¹¹ , -N(R ¹¹ )C(O)N(R ¹¹ ) ₂ , -N(R ¹¹ )C(S)N(R ¹¹ ) ₂ , - N(R ¹¹ )S(O) ₂ (R ¹¹ ), -S(O)R ⁿ , -S(O)2R ⁿ , -S(O)2N(R ^U )2, -NO ₂ , and -CN. In some embodiments, A is a 6-membered heteroaryl optionally substituted with one or more substituents independently selected from: halogen, Ci-4 alkyl, Ci-4 haloalkyl, -N(R ⁿ )2, -OR ¹¹ , -SR ¹¹ , -NO ₂ , and -CN. In some embodiments, A is a 6-membered heteroaryl optionally substituted with one or more substituents independently selected from: halogen, Ci-4 alkyl, Ci-4 haloalkyl, and -CN. In some embodiments, A is a 6-membered heteroaryl.

[0064] In some embodiments, for the compound of Formula (I), A is a pyridyl optionally substituted with one or more substituents independently selected from: halogen, Ci-4 alkyl, Ci-4 haloalkyl, -N(R ⁿ ) ₂ , -OR ¹¹ , -SR ¹¹ , -C(O)R ^U , -C(O)OR ⁿ , -OC(O)R ⁿ , -OC(O)N(R ⁿ )2, - C(O)N(R ⁿ ) ₂ , -N(R ¹¹ )C(O)R ¹¹ , -N(R ¹¹ )C(O)OR ¹¹ , -N(R ¹¹ )C(O)N(R ¹¹ ) ₂ , -N(R ¹¹ )C(S)N(R ¹¹ ) ₂ , - N(R ¹¹ )S(O) ₂ (R ¹¹ ), -S(O)R ⁿ , -S(O)2R ⁿ , -S(O)2N(R ^U )2, -NO ₂ , and -CN. In some embodiments, A is a pyridyl optionally substituted with one or more substituents independently selected from: halogen, Ci-4 alkyl, Ci-4 haloalkyl, -N(R ⁿ )2, -OR ¹¹ , -SR ¹¹ , -NO ₂ , and -CN. In some embodiments, A is a pyridyl optionally substituted with one or more substituents independently selected from: halogen, Ci-4 alkyl, Ci-4 haloalkyl, and -CN. In some embodiments, A is a pyridyl. In some embodiments,

[0065] In some embodiments, for the compound of Formula (I), R ¹ is selected from halogen, Ci-6 alkyl, C i-6 haloalkyl, -OR ¹² , -SR ¹² , -N(R ¹² ) ₂ , -C(O)R ¹² , -C(O)OR ¹² , -OC(O)R ¹² , -C(O)N(R ¹² ) ₂ , - N(R ¹² )C(O)R ¹² , -NO ₂ , and -CN. In some embodiments, R ¹ is selected from halogen, Ci-6 alkyl, Ci- 6 haloalkyl, -OR ¹² , -SR ¹² , -N(R ¹² ) ₂ , -NO ₂ , and -CN. In some embodiments, R ¹ is selected from halogen, Ci-6 alkyl, Ci-6 haloalkyl, and -CN. In some embodiments, R ¹ is selected from halogen, and -CN. In some embodiments, R ¹ is selected from halogen.

[0066] In some embodiments, for the compound of Formula (I), m is selected from 0, 1, 2, 3, and 4. In some embodiments, m is selected from 0, 1, and 2. In some embodiments, m is selected from 0 and 1. In some embodiments, m is 0. [0067] In some embodiments, for the compound of Formula (I), R ² is selected from halogen, Ci-6 alkyl, Ci. ₆ haloalkyl, -OR ¹³ , -SR ¹³ , -N(R ¹³ ) ₂ , -C(O)R ¹³ , -C(O)OR ¹³ , -OC(O)R ¹³ , -C(O)N(R ¹³ ) ₂ , - N(R ¹³ )C(O)R ¹³ , -NO ₂ , and -CN. In some embodiments, R ² is selected from halogen, Ci-6 alkyl, Ci- e haloalkyl, -OR ¹³ , -SR ¹³ , -N(R ¹³ ) ₂ , -NO ₂ , and -CN. In some embodiments, R ² is selected from halogen, Ci-6 alkyl, Ci-6 haloalkyl, and -CN. In some embodiments, R ² is selected from halogen and -CN. In some embodiments, R ² is halogen.

[0068] In some embodiments, for the compound of Formula (I), p is selected from 0, 1, 2, 3, and 4. In some embodiments, p is selected from 0, 1, and 2. In some embodiments, p is selected from 0 and 1. In some embodiments, p is 0.

[0069] In some embodiments, for the compound of Formula (I), L is selected from -C(O)-, -CO ₂ -, and -C(O)N(R ³ )-. In some embodiments, L is selected from -C(O)- and -C(O)N(R ³ )-. In some embodiments, L is selected from -C(O)-. In some embodiments, L is selected from -C(O)N(R ³ )-. [0070] In some embodiments, for the compound of Formula (I), R ³ is selected from hydrogen and Ci-4 alkyl. In some embodiments, R ³ is hydrogen.

[0071] In some embodiments, for the compound of Formula (I), R ^B is selected from bromine, - OR ¹⁸ , and Ci-4 alkyl, and when L is -C(O)N(R ³ )-, R ^B is further selected from hydrogen.

[0072] In some embodiments, for the compound of Formula (I), R ^B is selected from halogen, - OMe, and methyl, and when L is -C(O)N(R ³ )-, R ^B is further selected from hydrogen. In some embodiments, R ^B is selected from bromine, -OMe, and methyl; and when L is -C(O)N(R ³ )-, R ^B is further selected from hydrogen. In some embodiments, R ^B is selected from halogen, -OR ¹⁸ , and Ci-4 alkyl. In some embodiments, R ^B is selected from halogen. In some embodiments, R ^B is selected from bromine. In some embodiments, R ^B is selected from -OR ¹⁸ . In some embodiments, R ^B is -OMe. In some embodiments, R ^B is methyl. In some embodiments, when L is -C(O)N(R ³ )-, R ^B is hydrogen.

[0073] In some embodiments, for the compound of Formula (I), R ^A is selected from: halogen, - N(R ¹⁴ )(R ¹⁵ ), -OR ¹⁵ -SR ¹⁴ , -C(O)R ¹⁴ , -C(O)OR ¹⁴ , -OC(O)R ¹⁴ , -OC(O)N(R ¹⁴ ) ₂ , -C(O)N(R ¹⁴ ) ₂ , - N(R ¹⁴ )C(O)R ¹⁵ , -N(CH ₃ )C(O)OR ¹⁴ ; -N(R ¹⁴ )C(O)OR ¹⁶ , -N(R ¹⁴ )C(O)N(R ¹⁴ )(R ¹⁷ ), - N(R ¹⁴ )C(S)N(R ¹⁴ ) ₂ , -N(R ¹⁴ )S(O) ₂ (R ¹⁷ ), -S(O)R ¹⁴ , -S(O) ₂ R ¹⁴ , and -S(O) ₂ N(R ¹⁴ ) ₂ . In some embodiments, for the compound of Formula (I), R ^A is selected from: halogen, -N(R ¹⁴ )(R ¹⁵ ), -OR ¹⁵ -SR ¹⁴ , -C(O)R ¹⁴ , -C(O)OR ¹⁴ , -OC(O)R ¹⁴ , -OC(O)N(R ¹⁴ ) ₂ , -C(O)N(R ¹⁴ ) ₂ , -N(R ¹⁴ )C(O)R ¹⁵ , - N(CH ₃ )C(O)OR ¹⁴ ; -N(R ¹⁴ )C(O)OR ¹⁶ , -N(R ¹⁴ )C(O)N(CH ₃ )(R ¹⁷ ), -N(R ¹⁴ )C(S)N(R ¹⁴ ) ₂ , - N(R ¹⁴ )S(O) ₂ (R ¹⁷ ), -S(O)R ¹⁴ , -S(O) ₂ R ¹⁴ , and -S(O) ₂ N(R ¹⁴ ) ₂ .

[0074] In some embodiments, for the compound of Formula (I), R ^A is Ci alkyl substituted with one or more substituents independently selected from: halogen, -N(R ¹⁴ )(R ¹⁴ ), -OR ¹⁴ , -SR ¹⁴ , - C(O)R ¹⁴ , -C(O)OR ¹⁴ , -OC(O)R ¹⁴ , -OC(O)N(R ¹⁴ ) ₂ , -C(O)N(R ¹⁴ ) ₂ , -N(R ¹⁴ )C(O)R ¹⁴ , - N(R ¹⁴ )C(O)OR ¹⁴ , -N(R ¹⁴ )C(O)N(R ¹⁴ ) ₂ , -N(R ¹⁴ )C(S)N(R ¹⁴ ) ₂ , -N(R ¹⁴ )S(O) ₂ (R ¹⁴ ), -S(O)R ¹⁴ , - S(O) ₂ R ¹⁴ , -S(O) ₂ N(R ¹⁴ ) ₂ , and -CN.

[0075] In some embodiments, for the compound of Formula (I), R ^A is C ₂ -6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -N(R ¹⁴ )(R ¹⁴ ), - OR ¹⁴ , -SR ¹⁴ , -C(O)R ¹⁴ , -C(O)OR ¹⁴ , -OC(O)R ¹⁴ , -OC(O)N(R ¹⁴ ) ₂ , -C(O)N(R ¹⁴ ) ₂ , -N(R ¹⁴ )C(O)R ¹⁴ , - N(R ¹⁴ )C(O)OR ¹⁴ , -N(R ¹⁴ )C(O)N(R ¹⁴ ) ₂ , -N(R ¹⁴ )C(S)N(R ¹⁴ ) ₂ , -N(R ¹⁴ )S(O) ₂ (R ¹⁴ ), -S(O)R ¹⁴ , - S(O) ₂ R ¹⁴ , -S(O) ₂ N(R ¹⁴ ) ₂ , and -CN.

[0076] In some embodiments, for the compound of Formula (I), R ^A is C3-5 carbocycle and 3- to 5- membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, -N(R ¹⁴ )(R ¹⁴ ), -OR ¹⁴ , -SR ¹⁴ , -C(O)R ¹⁴ , -C(O)OR ¹⁴ , - OC(O)R ¹⁴ , -OC(O)N(R ¹⁴ ) ₂ , -C(O)N(R ¹⁴ ) ₂ , -N(R ¹⁴ )C(O)R ¹⁴ , -N(R ¹⁴ )C(O)OR ¹⁴ , - N(R ¹⁴ )C(O)N(R ¹⁴ ) ₂ , -N(R ¹⁴ )C(S)N(R ¹⁴ ) ₂ , -N(R ¹⁴ )S(O) ₂ (R ¹⁴ ), -S(O)R ¹⁴ , -S(O) ₂ R ¹⁴ , -S(O) ₂ N(R ¹⁴ ) ₂ , -NO ₂ , and -CN.

[0077] In some embodiments, for the compound of Formula (I), R ^A is selected from: halogen, - N(R ¹⁴ )(R ¹⁵ ), -OR ¹⁵ -SR ¹⁴ , -C(O)R ¹⁴ , -C(O)OR ¹⁴ , -OC(O)R ¹⁴ , -OC(O)N(R ¹⁴ ) ₂ , -C(O)N(R ¹⁴ ) ₂ , - N(R ¹⁴ )C(O)R ¹⁵ , -N(CH ₃ )C(O)OR ¹⁴ ; -N(R ¹⁴ )C(O)OR ¹⁶ , -N(R ¹⁴ )C(O)N(R ¹⁴ )(R ¹⁷ ), - N(R ¹⁴ )C(S)N(R ¹⁴ ) ₂ , -N(R ¹⁴ )S(O) ₂ (R ¹⁷ ), -S(O)R ¹⁴ , -S(O) ₂ R ¹⁴ , and -S(O) ₂ N(R ¹⁴ ) ₂ ; and when L is - C(O)N(R ³ )- or R ^B is -OR ¹⁸ or C1.4 alkyl, R ^A is further selected from-N(R ¹⁴ )C(O)OR ¹⁴ .

[0078] In some embodiments, for the compound of Formula (I), R ^A is selected from: - N(R ¹⁴ )(R ¹⁵ ), -OC(O)N(R ¹⁴ ) ₂ , -C(O)N(R ¹⁴ ) ₂ , -N(R ¹⁴ )C(O)R ¹⁵ , -N(CH ₃ )C(O)OR ¹⁴ ; - N(R ¹⁴ )C(O)OR ¹⁶ , -N(R ¹⁴ )C(O)N(R ¹⁴ )(R ¹⁷ ), -N(R ¹⁴ )C(S)N(R ¹⁴ ) ₂ , -N(R ¹⁴ )S(O) ₂ (R ¹⁷ ), -S(O)R ¹⁴ , - S(O) ₂ R ¹⁴ , and -S(O) ₂ N(R ¹⁴ ) ₂ ; and when L is -C(O)N(R ³ )- or R ^B is -OR ¹⁸ or Ci- ₄ alkyl, R ^A is further selected from-N(R ¹⁴ )C(O)OR ¹⁴ . In some embodiments, for the compound of Formula (I), R ^A is selected from: -N(R ¹⁴ )(R ¹⁵ ), -OC(O)N(R ¹⁴ ) ₂ , -C(O)N(R ¹⁴ ) ₂ , -N(R ¹⁴ )C(O)R ¹⁵ , - N(CH ₃ )C(O)OR ¹⁴ ; -N(R ¹⁴ )C(O)OR ¹⁶ , -N(R ¹⁴ )C(O)N(CH ₃ )(R ¹⁷ ), -N(R ¹⁴ )C(S)N(R ¹⁴ ) ₂ , - N(R ¹⁴ )S(O) ₂ (R ¹⁷ ), -S(O)R ¹⁴ , -S(O) ₂ R ¹⁴ , and -S(O) ₂ N(R ¹⁴ ) ₂ ; and when L is -C(O)N(R ³ )- or R ^B is - OR ¹⁸ or Ci-4 alkyl, R ^A is further selected from-N(R ¹⁴ )C(O)OR ¹⁴ .

[0079] In some embodiments, for the compound of Formula (I), R ^A is selected from: - N(R ¹⁴ )C(O)R ¹⁵ , -N(CH ₃ )C(O)OR ¹⁴ ; -N(R ¹⁴ )C(O)OR ¹⁶ , -N(R ¹⁴ )C(O)N(R ¹⁴ )(R ¹⁷ ), - N(R ¹⁴ )C(S)N(R ¹⁴ ) ₂ , -N(R ¹⁴ )S(O) ₂ (R ¹⁷ ), and -S(O) ₂ N(R ¹⁴ ) ₂ ; and when L is -C(O)N(R ³ )- or R ^B is - OR ¹⁸ or Ci-4 alkyl, R ^A is further selected from-N(R ¹⁴ )C(O)OR ¹⁴ . for the compound of Formula (I), R ^A is selected from: -N(R ¹⁴ )C(O)R ¹⁵ , -N(CH ₃ )C(O)OR ¹⁴ ; -N(R ¹⁴ )C(O)OR ¹⁶ , - N(R ¹⁴ )C(O)N(CH ₃ )(R ¹⁷ ), -N(R ¹⁴ )C(S)N(R ¹⁴ ) ₂ , -N(R ¹⁴ )S(O) ₂ (R ¹⁷ ), and -S(O) ₂ N(R ¹⁴ ) ₂ ; and when L is -C(O)N(R ³ )- or R ^B is -OR ¹⁸ or Ci-4 alkyl, R ^A is further selected from-N(R ¹⁴ )C(O)OR ¹⁴ .

[0080] In some embodiments, for the compound of Formula (I), R ^A is selected from: - N(CH ₃ )C(O)OR ¹⁴ and -N(R ¹⁴ )C(O)OR ¹⁶ , and when L is -C(O)N(R ³ )- or R ^B is -OR ¹⁸ or Ci- ₄ alkyl, R ^A is further selected from-N(R ¹⁴ )C(O)OR ¹⁴ . In some embodiments, for the compound of Formula (I), R ^A is selected from: -N(CH ₃ )C(O)OR ¹⁴ and -N(R ¹⁴ )C(O)OR ¹⁶ .

[0081] In some embodiments, for the compound of Formula (I), R ¹⁴ of -N(CH ₃ )C(O)OR ¹⁴ is independently selected at each occurrence from: hydrogen;

Ci-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O-Ci-4 alkyl, -O-Ci-4 haloalkyl, =0, and -CN;

C ₃ -6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from halogen, Ci-4 alkyl; Ci-4 haloalkyl; - OH, -O-Ci-4 alkyl, -O-Ci-4 haloalkyl, =0, and -CN.

[0082] In some embodiments, for the compound of Formula (I), R ¹⁴ of -N(CH ₃ )C(O)OR ¹⁴ is independently selected at each occurrence from Ci-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O-Ci-4 alkyl, -O-Ci-4 haloalkyl, =0, and -CN. In some embodiments, R ¹⁴ of -N(CH ₃ )C(O)OR ¹⁴ is independently selected at each occurrence from Ci-6 alkyl. In some embodiments, R ¹⁴ of -N(CH ₃ )C(O)OR ¹⁴ is tert-butyl.

[0083] In some embodiments, for the compound of Formula (I), R ¹⁴ of -N(R ¹⁴ )C(O)OR ¹⁶ is independently selected at each occurrence from: hydrogen;

Ci-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O-Ci-4 alkyl, -O-Ci-4 haloalkyl, =0, and -CN.

[0084] In some embodiments, for the compound of Formula (I), R ¹⁴ of -N(R ¹⁴ )C(O)OR ¹⁶ is independently selected at each occurrence from hydrogen and Ci-6 alkyl. In some embodiments, R ¹⁴ of -N(R ¹⁴ )C(O)OR ¹⁶ is hydrogen. In some embodiments, R ¹⁴ of -N(R ¹⁴ )C(O)OR ¹⁶ is independently selected at each occurrence from Ci- ₃ alkyl. In some embodiments, R ¹⁴ of - N(R ¹⁴ )C(O)OR ¹⁶ is methyl. In some embodiments, R ¹⁶ of -N(R ¹⁴ )C(O)OR ¹⁶ is selected from hydrogen; Ci and C4 alkyl, any of which is substituted with one or more substituents independently selected from halogen, -OH, -O-C1.4 alkyl, -O-C1.4 haloalkyl, =0, and -CN; C _2.3 alkyl and C5-6 alkyl, any of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -O-C1.4 alkyl, -O-C1.4 haloalkyl, =0, and -CN; and C ₃ . 6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from halogen, Ci-4 alkyl; Ci.4 haloalkyl; -OH, -O-C1.4 alkyl, -O-Ci-4 haloalkyl, =0, and -CN.

[0085] In some embodiments, for the compound of Formula (I), R ¹⁴ of -N(R ¹⁴ )C(O)OR ¹⁴ is independently selected at each occurrence from: hydrogen;

Ci-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O-Ci-4 alkyl, -O-Ci-4 haloalkyl, =0, and -CN;

C3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from halogen, C1.4 alkyl; C1.4 haloalkyl; - OH, -O-C1-4 alkyl, -O-C1.4 haloalkyl, =0, and -CN.

[0086] In some embodiments, R ¹⁴ of -N(R ¹⁴ )C(O)OR ¹⁴ is independently selected at each occurrence from hydrogen and Ci-6 alkyl. In some embodiments, R ¹⁴ of -N(R ¹⁴ )C(O)OR ¹⁴ is hydrogen and tert-butyl.

[0087] In some embodiments, for the compound of Formula (I), R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , and R ¹⁸ are each independently selected at each occurrence from: hydrogen;

Ci-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O-C1.4 alkyl, -O-C1.4 haloalkyl, =0, and -CN; and

C3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from halogen, C1.4 alkyl; C1.4 haloalkyl; - OH, -O-C1-4 alkyl, -O-C1.4 haloalkyl, =0, and -CN.

[0088] In some embodiments, for the compound of Formula (I), R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , and R ¹⁸ are each independently selected at each occurrence from: hydrogen and Ci-6 alkyl. In some embodiments, R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , and R ¹⁸ are each independently selected at each occurrence from: hydrogen, isopropyl, cyclopropyl, oxetanyl, and azetidinyl, wherein oxetanyl, and azetidinyl are each optionally substituted with C1.4 alkyl.

[0089] In some embodiments, for the compound of Formula (I), R ¹⁶ is selected from: hydrogen;

Ci and C4 alkyl, any of which is substituted with one or more substituents independently selected from halogen, -OH, -O-C1.4 alkyl, -O-C1.4 haloalkyl, =0, and -CN;

C2-3 alkyl and C5-6 alkyl, any of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -O-C1.4 alkyl, -O-C1.4 haloalkyl, =0, and -CN; and C3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from halogen, C1.4 alkyl; C1.4 haloalkyl; - OH, -O-C1-4 alkyl, -O-C1.4 haloalkyl, =0, and -CN.

[0090] In some embodiments, for the compound of Formula (I), R ¹⁶ is selected from C2-3 alkyl;

C5-6 alkyl; C3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from halogen and C1.4 alkyl. In some embodiments, R ¹⁶ is selected from isopropyl, cyclopropyl, oxetanyl, and azetidinyl, wherein oxetanyl, and azetidinyl are each optionally substituted with C1.4 alkyl.

[0091] In some embodiments, for the compound of Formula (I), R ¹⁶ of -N(R ¹⁴ )C(O)OR ¹⁶ is selected from:

C4 alkyl substituted with one or more substituents independently selected from halogen, - OH, -O-C1-4 alkyl, -O-C1.4 haloalkyl, =0, and -CN;

C2-3 alkyl and C5-6 alkyl, any of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -O-C1.4 alkyl, -O-C1.4 haloalkyl, =0, and -CN; and

C3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from halogen, C1.4 alkyl; C1.4 haloalkyl; - OH, -O-C1-4 alkyl, -O-C1.4 haloalkyl, =0, and -CN.

[0092] In some embodiments, R ¹⁶ of -N(R ¹⁴ )C(O)OR ¹⁶ is selected from:

C2-3 alkyl and C5-6 alkyl, any of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -O-C1.4 alkyl, -O-C1.4 haloalkyl, =0, and -CN; and

C3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from halogen, C1.4 alkyl; C1.4 haloalkyl; - OH, -O-C1-4 alkyl, -O-C1.4 haloalkyl, =0, and -CN.

[0093] In some embodiments, for the compound of Formula (I), R ¹⁶ of -N(R ¹⁴ )C(O)OR ¹⁶ is selected from C2-3 alkyl; C3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from halogen and C1.4 alkyl. In some embodiments, R ¹⁶ of -N(R ¹⁴ )C(O)OR ¹⁶ is selected from C2-3 alkyl; C3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with C1.4 alkyl. In some embodiments, R ¹⁶ of -N(R ¹⁴ )C(O)OR ¹⁶ is selected from C2-3 alkyl; C3-6 carbocycle and 3- to 6- membered heterocycle, any of which is optionally substituted with halogen. In some embodiments, R ¹⁶ of -N(R ¹⁴ )C(O)OR ¹⁶ is selected from C2-3 alkyl; C3 carbocycle and 4-membered heterocycle, any of which is optionally substituted with C1.4 alkyl. In some embodiments, R ¹⁶ of - N(R ¹⁴ )C(O)OR ¹⁶ is selected from isopropyl, cyclopropyl, oxetanyl, and azetidinyl, wherein oxetanyl and azetidinyl are each optionally substituted with Ci-4 alkyl.

In some embodiments, for the compound of Formula (I), R ^A is selected from . In some embodiments, R ^A is selected embodiments, R ^A is selected from

[0094] In some embodiments, the compound of Formula (I) is selected from: Table A.

Table A

[0095] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

[0096] Chemical entities having carbon-carbon double bonds or carbon-nitrogen double bonds may exist in Z- or E- form (or cis- or trans- form). Furthermore, some chemical entities may exist in various tautomeric forms. Unless otherwise specified, compounds or salt of Formula (I) and (I- a), are intended to include all Z-, E- and tautomeric forms as well.

[0097] “ Isomers” are different compounds that have the same molecular formula. “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space. “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1 : 1 mixture of a pair of enantiomers is a “racemic” mixture. The term “(±)” is used to designate a racemic mixture where appropriate. “Diastereoisomers” or “diastereomers” are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified by either R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) in which they rotate plane polarized light at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, the asymmetric centers of which can be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The present chemical entities, pharmaceutical compositions and methods are meant to include all such possible stereoisomers, including racemic mixtures, optically pure forms, mixtures of diastereomers and intermediate mixtures. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. The optical activity of a compound can be analyzed via any suitable method, including but not limited to chiral chromatography and polarimetry, and the degree of predominance of one stereoisomer over the other isomer can be determined.

[0098] The compounds or salts of Formula (I) herein may in some cases exist as diastereomers, enantiomers, or other stereoisomeric forms. The compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the racemates, mixtures of diastereomers, and other mixtures thereof, to the extent they can be made by one of ordinary skill in the art by routine experimentation. Separation of stereoisomers may be performed by chromatography or by forming diastereomers and separating by recrystallization, or chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981, herein incorporated by reference for this disclosure). Stereoisomers may also be obtained by stereoselective synthesis. Furthermore, a mixture of two enantiomers enriched in one of the two can be purified to provide further optically enriched form of the major enantiomer by recrystallization and/or trituration.

[0099] In certain embodiments, compounds or salts of Formula (I), may comprise two or more enantiomers or diastereomers of a compound wherein a single enantiomer or diastereomer accounts for at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 98% by weight, or at least about 99% by weight or more of the total weight of all stereoisomers. Methods of producing substantially pure enantiomers are well known to those of skill in the art. For example, a single stereoisomer, e.g, an enantiomer, substantially free of its stereoisomer may be obtained by resolution of the racemic mixture using a method such as formation of diastereomers using optically active resolving agents (Stereochemistry of Carbon Compounds, (1962) by E. L. Eliel, McGraw Hill; Lochmuller (1975) J. Chromatogr., 113(3): 283-302). Racemic mixtures of chiral compounds can be separated and isolated by any suitable method, including, but not limited to: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions. Another approach for separation of the enantiomers is to use a Diacel chiral column and elution using an organic mobile phase such as done by Chiral Technologies (www.chiraltech.com) on a fee for service basis.

[0100] A "tautomer" refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. In certain embodiments, the compounds or salts of Formula (I), exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers may exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some non-limiting examples of tautomeric equilibrium include:

[0101] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of ² H, ³ H, ⁿ C, ¹³ C and/or ¹⁴ C. In one particular embodiment, the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.

[0102] In certain embodiments, the compounds disclosed herein have some or all of the ⁴ H atoms replaced with ² H atoms. The methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.

[0103] Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0104] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.

[0105] Unless otherwise stated, compounds described herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by ¹³ C- or ¹⁴ C-enriched carbon are within the scope of the present disclosure.

[0106] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as for example, deuterium ( ² H), tritium ( ³ H), iodine-125 ( ¹²⁵ I) or carbon-14 ( ¹⁴ C). Isotopic substitution with ² H, ⁿ C, ¹³ C, ¹⁴ C, ¹⁵ C, ¹² N, ¹³ N, 15 _N , 16 _N , 16Q 17Q 14p, 15p, 16p, 17 _p? 18p, 33 g, 34g, 35g, 36g, 35Q, 37Q, 79 _Br , 81g _r , _and 125j _{are a} p contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0107] Included in the present disclosure are salts, particularly pharmaceutically acceptable salts, of the compounds of Formula (I). The compounds of the present disclosure may possess a sufficiently acidic, a sufficiently basic, or both functional groups, can react with any of a number of inorganic bases, and inorganic and organic acids, to form a salt. Alternatively, compounds that are inherently charged, such as those with a quaternary nitrogen, can form a salt with an appropriate counterion, e.g., a halide such as bromide, chloride, or fluoride, particularly bromide. [0108] The methods and compositions of Formula (I), include the use of amorphous forms as well as crystalline forms (also known as polymorphs). The compounds described herein may be in the form of pharmaceutically acceptable salts. As well, in some embodiments, active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure. In addition, the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein. [0109] Compounds of Formula (I), also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.

[0110] Included in the present disclosure are salts, particularly pharmaceutically acceptable salts, of compounds represented by Formula (I). The compounds of the present invention that possess a sufficiently acidic, a sufficiently basic, or both functional groups, can react with any of a number of inorganic bases, and inorganic and organic acids, to form a salt. Alternatively, compounds that are inherently charged, such as those with a quaternary nitrogen, can form a salt with an appropriate counterion, e.g., a halide such as bromide, chloride, or fluoride, particularly bromide, [oni] In certain embodiments, compounds or salts of Formula (I), may be prodrugs, e.g., wherein a hydroxyl in the parent compound is presented as an ester or a carbonate, or carboxylic acid present in the parent compound is presented as an ester. The term “prodrug” is intended to encompass compounds which, under physiologic conditions, are converted into pharmaceutical agents of the present disclosure. One method for making a prodrug is to include one or more selected moieties which are hydrolyzed under physiologic conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal such as specific target cells in the host animal. For example, esters or carbonates (e.g., esters or carbonates of alcohols or carboxylic acids and esters of phosphonic acids) are preferred prodrugs of the present disclosure.

[0112] Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. Prodrugs may help enhance the cell permeability of a compound relative to the parent drug. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. Prodrugs may be designed as reversible drug derivatives, for use as modifiers to enhance drug transport to site-specific tissues or to increase drug residence inside of a cell.

[0113] In certain embodiments, the prodrug may be converted, e.g., enzymatically or chemically, to the parent compound under the conditions within a cell. In certain embodiments, the parent compound comprises an acidic moiety, e.g., resulting from the hydrolysis of the prodrug, which may be charged under the conditions within the cell. In particular embodiments, the prodrug is converted to the parent compound once it has passed through the cell membrane into a cell. In certain embodiments, the parent compound has diminished cell membrane permeability properties relative to the prodrug, such as decreased lipophilicity and increased hydrophilicity.

[0114] In some embodiments, the design of a prodrug increases the lipophilicity of the pharmaceutical agent. In some embodiments, the design of a prodrug increases the effective water solubility. See, e.g., Fedorak et al., Am. J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol, 106:405-413 (1994); Hochhaus et al., Biomed. Chrom., 6:283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988); Sinkula et al., J. Pharm. Sci., 64: 181-210 (1975); T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series; and Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, all incorporated herein for such disclosure). According to another embodiment, the present disclosure provides methods of producing the above-defined compounds. The compounds may be synthesized using conventional techniques. Advantageously, these compounds are conveniently synthesized from readily available starting materials.

[0115] Synthetic chemistry transformations and methodologies useful in synthesizing the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations (1989); T. W. Greene and P. G. M.

Wuts, Protective Groups in Organic Synthesis, 2d. Ed. (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995).

Pharmaceutical Formulations

[0116] In certain aspects, the disclosure provides a pharmaceutical composition comprising a compound or salt of Formula (I) and a pharmaceutically acceptable excipient.

[0117] Pharmaceutical compositions can be formulated using one or more physiologically- acceptable carriers comprising excipients and auxiliaries. Formulation can be modified depending upon the route of administration chosen. Pharmaceutical compositions comprising a compound, salt or conjugate can be manufactured, for example, by lyophilizing the compound, salt or conjugate, mixing, dissolving, emulsifying, encapsulating or entrapping the conjugate. The pharmaceutical compositions can also include the compounds, salts or conjugates in a free-base form or pharmaceutically-acceptable salt form.

[0118] Methods for formulation of the conjugates can include formulating any of the compounds, salts or conjugates with one or more inert, pharmaceutically-acceptable excipients or carriers to form a solid, semi-solid, or liquid composition. Solid compositions can include, for example, powders, tablets, dispersible granules and capsules, and in some aspects, the solid compositions further contain nontoxic, auxiliary substances, for example wetting or emulsifying agents, pH buffering agents, and other pharmaceutically-acceptable additives. Alternatively, the compounds, salts or conjugates can be lyophilized or in powder form for re-constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0119] Pharmaceutical compositions can comprise at least one active ingredient (e.g., a compound, salt or conjugate). The active ingredients can be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization (e.g., hydroxymethylcellulose or gelatin microcapsules and poly-(methylmethacylate) microcapsules, respectively), in colloidal drug-delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions.

[0120] A compound or salt of any one of Formula (I) may be formulated in any suitable pharmaceutical formulation. A pharmaceutical formulation of the present disclosure typically contains an active ingredient (e.g., compound or salt of Formula (I)), and one or more pharmaceutically acceptable excipients or carriers, including but not limited to: inert solid diluents and fillers, diluents, sterile aqueous solution and various organic solvents, permeation enhancers, antioxidents, solubilizers, and adjuvants.

[0121] Pharmaceutical compositions may also be prepared from a compound or salt of Formula (I) , and one or more pharmaceutically acceptable excipients suitable for transdermal, inhalative, sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intraspinal administration. Preparations for such pharmaceutical composition are well-known in the art. See, e.g., Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, Ninth Edition, McGraw Hill, 2003; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001; Remingtons Pharmaceutical Sciences, 20th Ed., Lippincott Williams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, 1999).

Methods of Treatment

[0122] The compounds described herein can be used in the preparation of medicaments for the prevention or treatment of diseases or conditions. In addition, a method for treating any of the diseases or conditions described herein in a subject in need of such treatment, involves administration of pharmaceutical compositions containing at least one compound described herein (e.g., a compound of Formula (I)), or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said subject.

[0123] The compositions containing the compound(s) described herein can be administered for prophylactic and/or therapeutic treatments. In therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest the symptoms of the disease or condition. Amounts effective for this use will depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician.

[0124] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition. Such an amount is defined to be a "prophylactically effective amount or dose." In this use, the precise amounts also depend on the patient's state of health, weight, and the like. When used in a patient, effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician.

[0125] Without being bound to any particular mechanism, provided herein by the disclosure are compositions and methods for the modulation of protein structures and protein complexes (such as Beclin 1 and Bcl-2) into alternate conformational states. In some embodiments, the compounds and salts disclosed herein (e.g., compound or salts of Formula (I)) modulate the binding of Beclin 1 and Bcl-2. In some embodiments, the compounds and salts disclosed herein (e.g., compound or salts of Formula (I)) inhibit the binding of Beclin 1 and Bcl-2. The Beclin 1 protein is a central regulator of autophagy in mammalian cells. Autophagy is an essential process used to maintain cellular homeostasis by degrading and recycling cellular components such as damaged or worn- out organelles and macromolecules. Inhibition of Beclin-l/Bcl-2 protein-protein interactions induce autophagy and hence are useful for treating a variety of indications where stimulation of autophagy is therapeutically useful. Thus, in some embodiments, the compounds and salts disclosed herein (e.g., compound or salts of Formula (I)) induce autophagy.

[0126] Without being bound to any particular mechanism, the present disclosure provides that a compound or salt of Formula (I), or a pharmaceutical composition comprising a compound or salt of Formula (I), causes inhibition of Beclin 1 binding to Bcl-2. In some embodiments, a compound or salt of Formula (I), or a pharmaceutical composition comprising a compound or salt of Formula (I), causes inhibition of Beclin 1 binding to Bcl-2 and induces autophagy. In some embodiments, a compound or salt of Formula (I), or a pharmaceutical composition comprising a compound or salt of Formula (I), causes inhibition of Beclin 1 binding to Bcl-2 and induces autophagy effective for the treatment of a disease or condition in a subject in need thereof.

[0127] In some aspects, the present disclosure provides a method for treating a disease or condition in a subject in need thereof, comprising administering to the subject an effective amount of a compound or salt of Formula (I). In some embodiments, the disease or condition is selected from microbial infection, cancer, and neurodegeneration. In some embodiments, the disease or condition is selected from microbial infection. In some embodiments, the disease or condition is selected from bacterial infection. In some embodiments, the disease or condition is selected from cancer. In some embodiments, the disease or condition is selected from a neurodegenerative disease.

[0128] In some aspects, the present disclosure provides a method of inhibiting Beclin 1 binding to Bcl-2 to induce autophagy, comprising administering to a subject in need thereof an effective amount of a compound or salt of Formula (I), or a pharmaceutical composition comprising a compound or salt of Formula (I). In some aspects, the present disclosure provides a method of selectively inhibiting Beclin 1 binding to Bcl-2 to induce autophagy, comprising administering to a subject in need thereof an effective amount of a compound or salt of Formula (I), or a pharmaceutical composition comprising a compound or salt of Formula (I).

[0129] In some aspects, the present disclosure provides a method of selectively inhibiting Beclin 1 binding to Bcl-2 to induce autophagy comprising administering to a subject in need thereof an effective amount of a compound or salt of Formula (I), or a pharmaceutical composition comprising a compound or salt of Formula (I). In some aspects, the administration of a compound or salt of Formula (I) selectively inhibits Beclin 1 binding to Bcl-2, but does not significantly affect other Bcl-2 function or the interaction between Bcl-2 with other proteins. [0130] In certain aspects, the disclosure provides a method of inducing autophagy in a cell, comprising administering a compound or salt of Formula (I) or a pharmaceutical composition comprising a compound or salt of Formula (I) and a pharmaceutically acceptable excipient. [0131] In certain aspects, the disclosure provides a method of inhibiting binding of Beclin 1 to Bcl2 in a subject, comprising administering to the subject a compound or salt of Formula (I) or a pharmaceutical composition comprising a compound or salt of Formula (I) and a pharmaceutically acceptable excipient.

[0132] In certain aspects, the disclosure provides a method of treating an infection, cancer, neurodegeneration and aging disease or condition comprising administering to a subject in need thereof a compound or salt of Formula (I) or a pharmaceutical composition comprising a compound or salt of Formula (I) and a pharmaceutically acceptable excipient.

EXAMPLES

[0133] The invention now being generally described, it will be more readily understood by reference to the following examples which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and are not intended to limit the invention in any way.

[0134] The following synthetic schemes are provided for purposes of illustration, not limitation. The following examples illustrate the various methods of making compounds described herein. It is understood that one skilled in the art may be able to make these compounds by similar methods or by combining other methods known to one skilled in the art. It is also understood that one skilled in the art would be able to make, in a similar manner as described below by using the appropriate starting materials and modifying the synthetic route as needed. In general, starting materials and reagents can be obtained from commercial vendors or synthesized according to sources known to those skilled in the art or prepared as described herein.

Example 1:-Synthesis of tert-butyl N-14-[l-(4-methylbenzoyl)-5-(pyridin-2-yl)-4.,5- dihydropyrazol-S-yllphenyBcarbamate (Compound 1)

[0135] To a stirring solution of tert-butyl (4-acetylphenyl)carbamate (50 mg, 0.21 mmol) in Acetonitrile (2 ml) was added 10M aqueous sodium hydroxide (0.2 ml, 2.1 mmol) followed immediately by pyridine-2-carbaldehyde (25mg, 0.23mmol). The reaction was left to stir overnight at room temperature until the synthesis of the intermediate chaicone was complete. The reaction was then immediately telescoped to the next step without workup or purification.

[0136] To the reaction mixture from the previous step aqueous hydrazine hydrate (55 wt%, 0.275 ml, 1.1 mmol) was added. The reaction was then left to stir for 3 hours at room temperature until the pyrazoline intermediate was formed. The reaction was then immediately telescoped to the next step without workup or purification.

[0137] To the reaction mixture from the previous step was added Triethylamine (0.04 ml, 0.255 mmol) followed by excess 4-methylbenzoyl chloride (492.8 mg, 3.2 mmol) was added portionwise and left to stir overnight until completion. The reaction mixture was then filtered to remove salts formed and then concentrated in vacuo. The resulting crude was purified via silica chromatography (eluent: hexanes/ethyl acetate) to afford tert-butyl N-{4-[l-(4-methylbenzoyl)-5- (pyridin-2-yl)-4,5-dihydropyrazol-3-yl]phenyl}carbamate (16.8 mg). LCMS: m/z [M+H] ⁺ 457.24. Example 2: Synthesis of tert-butyl N-methyl-N-14-[l-(4-methylbenzoyl)-5-(pyridin-2-yl)-4.,5- dihvdropyrazol-3-yl]phenvncarbamate (Compound 2)

[0138] To a stirring solution of tert-butyl (4-(l-(4-methylbenzoyl)-5-(pyridin-2-yl)-4,5-dihydro- lH-pyrazol-3-yl)phenyl)carbamate (5 mg, 0.011 mmol) in THF (1ml) was added methyl iodide (3.1 mg, 0.022 mmol) at room temperature. Then potassium tert-butoxide in IM THF (1.2 mg, 0.011 ml) was added and the reaction was left to stir overnight. The resulting crude was purified via silica chromatography (eluent: hexanes/ethyl acetate) to afford tert-butyl N-methyl-N-{4-[l- (4-methylbenzoyl)-5-(pyridin-2-yl)-4,5-dihydropyrazol-3-yl]p henyl}carbamate (4.6 mg). LCMS: m/z [M+H] ⁺ 471.29.

Example 3: Synthesis of tert-butyl (4-(l-(phenylcarbamoyl)-5-(pyridin-2-yl)-4.,5-dihvdro- lH-pyrazol-3-yl)phenyl)carbamate (Compound 3)

[0139] To a stirring solution of tert-butyl (4-acetylphenyl)carbamate (30mg, 0.13 mmol) in Acetonitrile (2ml) was added 10M aqueous sodium hydroxide (0.064 ml, 0.64 mmol) followed immediately by pyridine-2-carbaldehyde (15mg, 0.14 mmol). The reaction was left to stir overnight at room temperature until the synthesis of the intermediate chaicone was complete. The reaction was then immediately telescoped to the next step without workup or purification. [0140] To the reaction mixture from the previous step IM anhydrous hydrazine in acetonitrile (0.25 ml, 0.25mmol) was added. The reaction was then left to stir for 3 hours at room temperature until the pyrazoline intermediate was formed. The reaction was then immediately telescoped to the next step without workup or purification.

[0141] To the reaction mixture from the previous step was added Triethylamine (0.04 ml, 0.255 mmol) followed by excess N-phenylcarbamoyl chloride (139 mg, 0.89 mmol) was added portionwise and left to stir overnight until completion. The reaction mixture was then filtered to remove salts formed and then concentrated in vacuo. The resulting crude was purified via silica chromatography (eluent: hexanes/ethyl acetate) to afford tert-butyl N-{4-[l-(phenylcarbamoyl)-5- (pyridin-2-yl)-4,5-dihydropyrazol-3-yl]phenyl}carbamate (24 mg). LCMS: m/z [M+H] ⁺ 457.30

Example 4: Synthesis of tert-butyl N- [5-(2-methyl-l.,3-oxazol-4-yl)-l-(4-methylbenzoyl)-

4,5-dihvdroDyrazol-3-yl]phenvncarbamate (Compound 4)

[0142] To a stirring solution of tert-butyl (4-acetylphenyl)carbamate (96mg, 0.41 mmol) in Acetonitrile (2ml) was added 10M aqueous sodium hydroxide (0.12 ml, 1.2 mmol) followed immediately by 2-methyl-l,3-oxazole-4-carbaldehyde (50mg, 0.45 mmol). The reaction was left to stir overnight at room temperature until the synthesis of the intermediate chaicone was complete. The reaction was then immediately telescoped to the next step without workup or purification.

[0143] To the reaction mixture from the previous step IM anhydrous hydrazine in acetonitrile (1.2 ml, 1.2 mmol) was added. The reaction was then left to stir for 3 hours at room temperature until the pyrazoline intermediate was formed. The reaction was then immediately telescoped to the next step without workup or purification.

[0144] To the reaction mixture from the previous step was added triethylamine (0.115 ml, 0.82 mmol) followed by excess 4-methylbenzoyl chloride (441 mg, 2.85 mmol) was added portionwise and left to stir overnight until completion. The reaction mixture was then filtered to remove salts formed and then concentrated in vacuo. The resulting crude was purified via silica chromatography (eluent: hexanes/ethyl acetate) then concentrated in vacuo, redissolved in DMSO and purified again via reverse phase preparatory HPLC (eluent: water/acetonitrile with 0.1% Formic acid) to afford tert-butyl N-{4-[5-(2-methyl-l,3-oxazol-4-yl)-l-(4-methylbenzoyl)-4,5- dihydropyrazol-3-yl]phenyl} carbamate (14.8 mg). LCMS: m/z [M+H] ⁺ 461.35.

Example 5: Synthesis of tert-butyl N-[4-(5-[imidazo[l.,2-a]Dyridin-5-vn-l-(4- methylbenzoyl)-4.,5-dihydroDyrazol-3-yl)Dhenyl] carbamate (Compound 5)

[0145] To a stirring solution of tert-butyl (4-acetylphenyl)carbamate (63mg, 0.27 mmol) in Acetonitrile (2ml) was added 10M aqueous sodium hydroxide (0.081 ml, 0.81 mmol) followed immediately by imidazo[l,2-a]pyridine-5-carbaldehyde (43.6mg, 0.3 mmol). The reaction was left to stir overnight at room temperature until the synthesis of the intermediate chaicone was complete. The reaction was then immediately telescoped to the next step without workup or purification.

[0146] To the reaction mixture from the previous step IM anhydrous hydrazine in acetonitrile (0.81 ml, 0.81 mmol) was added. The reaction was then left to stir for 3 hours at room temperature until the pyrazoline intermediate was formed. The reaction was then immediately telescoped to the next step without workup or purification.

[0147] To the reaction mixture from the previous step was added triethylamine (0.076 ml, 0.54 mmol) followed by excess 4-methylbenzoyl chloride (294 mg, 1.9 mmol) was added portionwise and left to stir overnight until completion. The reaction mixture was then filtered to remove salts formed and then concentrated in vacuo. The resulting crude was purified via silica chromatography (eluent: hexanes/ethyl acetate to afford tert-butyl N-[4-(5-{imidazo[l,2- a]pyridin-5-yl}-l-(4-methylbenzoyl)-4,5-dihydropyrazol-3-yl) phenyl]carbamate (90.8 mg). LCMS: m/z [M+H] ⁺ 496.27.

Example 6: Synthesis of tert-butyl N-14-[l-(4-methoxybenzoyl)-5-(pyridin-2-yl)-4.,5- dihydropyrazol-S-ylIphenyBcarbamate (Compound 6)

[0148] To a stirring solution of tert-butyl (4-acetylphenyl)carbamate (30mg, 0.27 mmol) in Acetonitrile (2ml) was added 10M aqueous sodium hydroxide (0.064 ml, 0.64 mmol) followed immediately by pyridine-2-carbaldehyde (15 mg, 0.14 mmol). The reaction was left to stir overnight at room temperature until the synthesis of the intermediate chaicone was complete. The reaction was then immediately telescoped to the next step without workup or purification.

[0149] To the reaction mixture from the previous step aqueous hydrazine hydrate (55 wt%, 0.1 ml, .38 mmol) was added. The reaction was then left to stir for 3 hours at room temperature until the pyrazoline intermediate was formed. The reaction was then immediately telescoped to the next step without workup or purification.

[0150] To the reaction mixture from the previous step was added triethylamine (0.036 ml, 0.25 mmol) followed by excess 4-methylbenzoyl chloride (152.2 mg, 0.89 mmol) was added portionwise and left to stir overnight until completion. The reaction mixture was then filtered to remove salts formed and then concentrated in vacuo. The resulting crude was purified via silica chromatography (eluent: hexanes/ethyl acetate to afford tert-butyl N-{4-[l-(4-methoxybenzoyl)- 5-(pyridin-2-yl)-4,5-dihydropyrazol-3-yl]phenyl}carbamate (7.6 mg). LCMS: m/z [M+H] ⁺ 473.26. Example 7: Synthesis of tert-butyl N-^4-[^-methyl-2-(4-methylbenzoy^)-3■,4-dihydro-[3■,3 ^, - biDyrazol]-5-yl]Dhenyncarbamate (Compound 7)

[0151] To a stirring solution of tert-butyl (4-acetylphenyl)carbamate (lOOmg, 0.42 mmol) in Acetonitrile (2ml) was added 10M aqueous sodium hydroxide (0.13 ml, 1.3 mmol) followed immediately by l-methylpyrazole-3-carbaldehyde (51 mg, 0.47 mmol). The reaction was left to stir overnight at room temperature until the synthesis of the intermediate chaicone was complete. The reaction was then immediately telescoped to the next step without workup or purification. [0152] To the reaction mixture from the previous step IM anhydrous hydrazine in acetonitrile (1.3 ml, 1.3 mmol) was added. The reaction was then left to stir for 3 hours at room temperature until the pyrazoline intermediate was formed. The reaction was then immediately telescoped to the next step without workup or purification.

[0153] To the reaction mixture from the previous step was added triethylamine (0.12 ml, 0.85 mmol) followed by excess 4-methylbenzoyl chloride (460 mg, 2.98 mmol) was added portion wise and left to stir overnight until completion. The reaction mixture was then filtered to remove salts formed and then concentrated in vacuo. The resulting crude was purified via silica chromatography (eluent: hexanes/ethyl acetate) then concentrated in vacuo, redissolved in DMSO and purified again via reverse phase preparatory HPLC (eluent: water/acetonitrile with 0.1% Formic acid) to afford tert-butyl N-{4-[l'-methyl-2-(4-methylbenzoyl)-3,4-dihydro-[3,3'- bipyrazol]-5-yl]phenyl}carbamate (23 mg). LCMS: m/z [M+H] ⁺ 460.28 Example 8: Synthesis of Intermediate - tert-Butyl 3-(((4-(l-(4-bromobenzoyl)-5-(pyridin-2- yl)-4.,5-dihydro-lH-Dyrazol-3-yl)Dhenyl)carbamoyl)oxy)azetid ine-l-carboxylate

Step 2

[0154] Step 1 : Synthesis of tert-butyl (4-acetylphenyl)carbamate. To a stirred solution of l-(4- aminophenyl)ethan-l-one (50 g, 369.9 mmol) in dioxane (400 mL) were added BOC2O (95.8 mL, 443.8 mmol) at rt. The resulting reaction mixture was stirred at 100 °C for 16 h. The reaction progress was monitored by TLC. The reaction mixture was concentrated in vacuo and added IN HC1 (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layer was washed with brine (100 mL), dried over Na2SO4 and concentrated in vacuo. The crude compound was triturated with 20% ethyla acetate in pet-ether to get tert-butyl (4-acetylphenyl)carbamate (60 g) {TLC system; (20% Ethyl acetate in pet-ether, Rf: 0.48). LC-MS (ES-API+) m/z = 236.1 [M+H] ⁺ .

[0155] Step 2: Synthesis of tert-Butyl (E)-(4-(3-(pyridin-2-yl)acryloyl)phenyl)carbamate. To a stirred solution of tert-butyl (4-acetylphenyl)carbamate (20 g, 85.11 mmol) and KOH (14.29 g, 255.3 mmol) in a mixture of MeOH and water (3: 1, 120 mL) at rt, was added 2-pyridine carboxaldehyde (9.57 g, 89.36 mmol) at rt. The reaction mixture was allowed to attain rt and stirred for 16 h. The reaction progress was monitored by TLC. The reaction mixture was poured into cold water (300 mL) and the precipitated solid was filtered and dried to get tert-butyl (E)-(4- (3-(pyridin-2-yl)acryloyl)phenyl) (17 g) {TLC system; (50% Ethyl acetate in pet-ether, Rf: 0.5)}. LC-MS (ES-API+) m/z = 325.33 [M+H] ⁺

[0156] Step 3: Synthesis of tert-Butyl (4-(5-(pyridin-2-yl)-4,5-dihydro-lH-pyrazol-3- yl)phenyl)carbamate. A solution of tert-butyl (E)-(4-(3-(pyri din-2 -yl)acryloyl)phenyl)carbamate (2 g , 6.17 mmol) in EtOH (15 mL) at rt was degassed with argon for 15 minutes. Then hydrazine hydrate (0.46 mL, 9.25 mmol) was added and stirred for 15 min at 120 °C in microwave. Rection progress was monitored by TLC. Solvent was evaporated and triturated with diethyl ether (3 x 15mL) and dried.

[0157] Similarly another 9 x 2 g of tert-butyl (E)-(4-(3-(pyridin-2-yl)acryloyl)phenyl)carbamate was treated with hydrazine hydrate and all the batches were combined to get tert-Butyl (4-(5- (pyridin-2-yl)-4,5-dihydro-lH-pyrazol-3-yl)phenyl)carbamate (12 g). TLC System (10% MeOH in DCM, rf = 0.3), LC-MS (ES-API+) m/z = 339 [M+H] ⁺ , ^X H NMR (400 MHz, CDCh): 8 (ppm) = 8.57-8.55 (m, 1H), 7.71-7.66 (m, 1H), 7.61-7.58 (m, 2H), 7.43 (d, 1H, J=8.0 Hz), 7.37-7.35 (m, 2H), 7.21-7.18 (m, 1H), 6.55 (s, 1H), 5.08-5.03 (m, 1H), 3.59-3.52 (m, 1H), 3.23-3.17 (m, 1H), 1.53 (s, 9H).

[0158] Step 4: Synthesis of tert-Butyl 3-(((4-(l-(4-bromobenzoyl)-5-(pyridin-2-yl)-4,5-dihydro- lH-pyrazol-3-yl)phenyl)carbamoyl)oxy)azetidine-l-carboxylate . 4-Bromobenzoyl chloride (96 mg, 0.44 mmol) was added to a solution of tert-butyl (4-(5-(pyridin-2-yl)-4,5-dihydro-lH- pyrazol-3-yl)phenyl)carbamate (100 mg, 0.29 mmol) in pyridine (2.50 mL) at 0 °C. The resulting reaction mixture was allowed to attain RT and stirred for 16 h. Reaction was monitored by LC- MS & TLC. The reaction mixture was quenched into cold water (10 mL) and the precipitated solid was filtered and dried. The crude compound was purified by prep HPLC to afford tert-butyl (4-(l-(4-bromobenzoyl)-5-(pyridin-2-yl)-4,5-dihydro-lH-pyraz ol-3-yl)phenyl)carbamate (110 mg). TLC system: 10% MeOH in dichloromethane; Rf : 0.50. TLC system: Ethyl acetate; Rf: 0.40. 'H-NMR (400 MHz, DMSO-d ₆ ): 6 9.61 (s, 1H), 8.52 (s, 1H), 7.84-776 (m, 3H), 7.69 (d, 2H), 7.63 (d, 2H), 7.53 (d, 2H), 7.43 (d, 1H), 7.31-7.28 (m, 1H), 5.80-5.76 (m, 1H), 3.86-3.79 (m, 1H), 3.28-3.26 (m, 1H), 1.48 (s, 9H); LC-MS (ES-API ⁺ ): m/z = 521.36 [M+H] ⁺ ion present

[0159] Step 5: Synthesis of (3-(4-Aminophenyl)-5-(pyridin-2-yl)-4,5-dihydro-lH-pyrazol-l - yl)(4-bromophenyl)methanone. TFA (2 mL) was added to a solution of tert-butyl (4-(l-(4- bromobenzoyl)-5-(pyridin-2-yl)-4,5-dihydro-lH-pyrazol-3-yl)p henyl)carbamate (250 mg, 0.48 mmol) in DCM (5 mL) at 0 °C. The resulting reaction mixture was allowed to attain RT and stirred for 16 h. Reaction was monitored by LC-MS & TLC. The reaction mixture was concentrated in vacuo; the residue was quenched with saturated sodium bicarbonate solution (50 mL) and extracted with Ethyl acetate (2 x 30 mL). The combined organic layer was washed with water (10 mL), brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to get (3-(4-aminophenyl)-5-(pyridin-2-yl)-4,5-dihydro-lH-pyrazol-l -yl)(4- bromophenyl)methanone (150 mg, crude). TLC system: 10% MeOH in dichloromethane; Rf : 0.20. LC-MS (ES-API+) m/z = 421.16 [M+H] ⁺ Example 9: Synthesis of cyclopropyl (4-(l-(4-bromobenzoyl)-5-(pyridin-2-yl)-4.,5-dihvdro- lH-pyrazol-3-yl)phenyl)carbamate (Compound 8)

[0160] : To a stirred solution of (3-(4-aminophenyl)-5-(pyridin-2-yl)-4,5-dihydro-lH-pyrazol-l - yl)(4-bromophenyl)methanone (50 mg, 0.11 mmol) and DIPEA (0.01 mL, 1.13 mmol) in dichloromethane (2 mL) was added cyclopropylcarbonochloridate (14 mg, 0.14 mmol) at 0 °C under nitrogen atmosphere. The resulting reaction mixture was stirred at RT for 16 h. The reaction was monitored by TLC & LC-MS. The reaction mixture was quenched with saturated sodium bicarbonate solution (50 mL) and extracted with Ethyl acetate (2 x 30 mL). The combined organic layer was washed with water (10 mL), brine (10 mL), dried over anhydrous ISfeSCU and concentrated under reduced pressure. Similarly another 100 mg of (3-(4-aminophenyl)-5-(pyridin- 2-yl)-4,5-dihydro-lH-pyrazol-l-yl)(4-bromophenyl)methanone was treated with cyclopropylcarbonochloridate and both the batches were mixed and purified by preparative HPLC to afford cyclopropyl (4-(l-(4-bromobenzoyl)-5-(pyridin-2-yl)-4,5-dihydro-lH-pyraz ol-3- yl)phenyl)carbamate (45 mg) . TLC system: Ethyl acetate; Rr 0.50. 'H-NMR (400 MHz, DMSO- d ₆ ): 8 9.92 (s, 1H), 8.51 (d, 1H), 7.84-7.78 (m, 3H), 7.70-7.65 (m, 4H), 7.54 (d, 2H), 7.43 (d, 1H), 7.31-7.28 (m, 1H), 5.81-5.75 (m, 1H), 4.10-4.05 (m, 1H), 3.86-3.79 (m, 1H), 3.30-3.28 (m, 1H), 0.71-0.67 (m, 4H); LC-MS (ES-API ⁺ ): m/z = 505.35 [M+H] ⁺ ion present.

Example 10: Synthesis of Isopropyl (4-(l-(4-bromobenzoyl)-5-(pyridin-2-yl)-4.,5-dihvdro- lH-pyrazol-3-yl)phenyl)carbamate (Compound 9) [0161] To a stirred solution of (3-(4-aminophenyl)-5-(pyridin-2-yl)-4,5-dihydro-lH-pyrazol-l - yl)(4-bromophenyl)methanone (50 mg, 0.119 mmol) and DIPEA (0.064 mL, 0.357 mmol) in dichloromethane (10 mL) was added isopropyl carb onochlori date (84 mg, 1.00 mmol) at 0 °C under nitrogen atmosphere. The resulting reaction mixture was stirred at RT for 16 h. The reaction was monitored by TLC & LC-MS. The reaction mixture was quenched with saturated sodium bicarbonate solution (50 mL) and extracted with Ethyl acetate (2 x 30 mL). The combined organic layer was washed with water (10 mL), brine (10 mL), dried over anhydrous ISfeSCU and concentrated under reduced pressure. Similarly another 150 mg of (3-(4-aminophenyl)-5-(pyridin- 2-yl)-4,5-dihydro-lH-pyrazol-l-yl)(4-bromophenyl)methanone was treated with isopropyl carb onochlori date and both the batches of crude compounds were mixed and purified by preparative HPLC to afford isopropyl (4-(l-(4-bromobenzoyl)-5-(pyridin-2-yl)-4,5-dihydro-lH- pyrazol-3-yl)phenyl)carbamate (38 mg). TLC system: Ethyl acetate; Rr 0.50. 'H-NMR (400 MHz, DMSO-de): 8 9.83 (s, IH), 8.52 (d, IH), 7.85-7.77 (m, 3H), 7.70-7.64 (m, 4H), 7.55 (d, 2H), 7.43 (d, IH), 7.28 (d, IH), 5.780-5.76 (m, IH), 4.93-4.87 (m, IH), 3.86-3.79 (m, IH), 3.31- 3.27 (m, IH), 1.25 (d, 6H); LC-MS (ES-API ⁺ ): m/z = 507.39 [M+H] ⁺ ion present.

Example 11: Synthesis of 3-(4-(l-(4-bromobenzoyl)-5-(pyridin-2-yl)-4.,5-dihvdro-lH-

Pyrazol-3-yl)phenyl)-l-isopropyl-l-methylurea (Compound 10)

[0162] To a stirred solution of N-methylpropan-2-amine (72 mg, 0.95 mmol) and DIPEA (0.50 mL, 2.85 mmol) in dichloromethane (10 mL) was added triphosgene (140 mg, 0.47 mmol) at 0 °C under nitrogen atmosphere. The resulting reaction mixture was allowed to attain RT and stirred for Ih. The reaction was monitored by TLC. The reaction mixture was cooled to 0 °C and a solution of (3-(4-aminophenyl)-5-(pyridin-2-yl)-4,5-dihydro-lH-pyrazol-l -yl)(4- bromophenyl)methanone (400 mg, 0.95 mmol) in DCM (2 mL) followed by DIPEA (0.17 mL, 0.95 mmol) were added. The resulting reaction mixture was allowed to attain RT and stirred for 16 h. The reaction was monitored by TLC & LC-MS. The reaction mixture quenched with saturated sodium bicarbonate solution (50 mL) and extracted with Ethyl acetate (2 x 30 mL). The combined organic layer was washed with water (10 mL), brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified by preparative HPLC to afford (3-(4-(l-(4-bromobenzoyl)-5-(pyridin-2-yl)-4,5-dihydro-lH-py razol- 3-yl)phenyl)-l-isopropyl-l-methylurea (180 mg). TLC system: Ethyl acetate; Rr 0.40. 'H-NMR (400 MHz, DMSO-de): 8 8.51 (d, IH), 8.44 (s, IH), 7.84-7.76 (m, 3H), 7.70 (d, 2H), 7.62-7.57 (m, 4H), 7.43 (d, IH), 7.31-7.28 (m, IH), 5.80-5.75 (m, IH), 4.57-4.54 (m, IH), 3.87-3.79 (m, IH), 3.31-3.29 (m, IH), 2.79 (s, 3H), 1.07 (d, 6H); LC-MS (ES-API ⁺ ): m/z = 520.10 [M+H] ⁺ ion present.

Example 12: Synthesis of Oxetan-3-yl (4-(l-(4-bromobenzoyl)-5-(pyridin-2-yl)-4.,5-dihvdro- lH-pyrazol-3-yl)phenyl)carbamate (Compound 11)

[0163] To a stirred solution of oxetan-3-ol (70.31 mg, 0.95 mmol) and DIPEA (0.50 mL, 2.85 mmol) in dichloromethane (10 mL) was added triphosgene (140 mg, 0.47 mmol) at 0 °C under nitrogen atmosphere. The resulting reaction mixture was allowed to attain RT and stirred for Ih. The reaction was monitored by TLC. The reaction mixture was cooled to 0 °C and a solution of (3-(4-aminophenyl)-5-(pyri din-2 -yl)-4,5-dihydro-lH-pyrazol-l-yl)(4-bromophenyl)methanone (400 mg, 0.95 mmol) in DCM (2 mL) followed by DIPEA (0.17 mL, 0.95 mmol) were added. The resulting reaction mixture was allowed to attain RT and stirred for 16 h. The reaction was monitored by TLC & LC-MS. The reaction mixture quenched with saturated sodium bicarbonate solution (50 mL) and extracted with Ethyl acetate (2 x 30 mL). The combined organic layer was washed with water (10 mL), brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified by preparative HPLC to afford oxetan-3- yl(4-(l-(4-bromobenzoyl)-5-(pyridin-2-yl)-4,5-dihydro-lH-pyr azol-3yl)phenyl)carbamate (170 mg). TLC system: Ethyl acetate; R _f : 0.30. 'H-NMR (400 MHz, DMSO-d ₆ ): 8 10.17 (s, IH), 8.51 (d, IH), 7.84-7.76 (m, 3H), 7.70-7.67 (m, 4H), 7.54 (d, 2H), 7.44 (d, IH), 7.31-7.28 (m, IH), 5.81-5.75 (m, IH), 5.45-5.40 (m, IH), 4.84-4.80 (m, 2H), 4.57-4.54 (m, 2H), 3.87-3.79 (m, IH), 3.31-3.29 (m, IH); LC-MS (ES-API ⁺ ): m/z = 521.30 [M+H] ⁺ ion present.

Example 13: l-methylazetidin-3-yl (4-(l-(4-bromobenzoyl)-5-(pyridin-2-yl)-4.,5-dihydro-lH- pyrazol-3-yl)phenyl)carbamate (Compound 12)

[0164] Step 1 : Synthesis of tert-Butyl 3-(((4-(l-(4-bromobenzoyl)-5-(pyridin-2-yl)-4,5-dihydro- lH-pyrazol-3-yl)phenyl)carbamoyl)oxy)azetidine-l-carboxylate . To a stirred solution of tert-butyl 3 -hydroxyazetidine-1 -carboxylate (409 mg, 2.38 mmol) and DIPEA (1.30 mL, 7.12 mmol) in di chloromethane (10 mL) was added triphosgene (352 mg, 1.18 mmol) at 0 °C under nitrogen atmosphere. The resulting reaction mixture was allowed to attain RT and stirred for Ih. The reaction was monitored by TLC. The reaction mixture was cooled to 0 °C and a solution of (3-(4- aminophenyl)-5-(pyridin-2-yl)-4,5-dihydro-lH-pyrazol-l-yl)(4 -bromophenyl)methanone (1.0 g, 2.38 mmol) in DCM (2 mL) followed by DIPEA (0.43 mL, 2.38 mmol) were added. The resulting reaction mixture was allowed to attain RT and stirred for 16 h. The reaction was monitored by TLC & LC-MS. The reaction mixture quenched with saturated sodium bicarbonate solution (50 mL) and extracted with Ethyl acetate (2 x 30 mL). The combined organic layer was washed with water (10 mL), brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified by preparative HPLC to afford tert-butyl 3-(((4-(l-(4- bromobenzoyl)-5-(pyridin-2-yl)-4,5-dihydro-lH-pyrazol-3-yl)p henyl)carbamoyl)oxy)azetidine-l- carboxylate (150 mg). TLC system: Ethyl acetate; Rr 0.30. LC-MS (ES-API ⁺ ): m/z = 620.13 [M+H] ⁺ ion present.

[0165] Step 2: Synthesis of azetidin-3-yl (4-(l-(4-bromobenzoyl)-5-(pyridin-2-yl)-4,5-dihydro- lH-pyrazol-3-yl)phenyl)carbamate. TFA (0.50 mL) was added to a solution of tert-butyl 3-(((4- (l-(4-bromobenzoyl)-5-(pyridin-2-yl)-4,5-dihydro-lH-pyrazol- 3- yl)phenyl)carbamoyl)oxy)azetidine-l -carboxylate (100 mg, 0.38 mmol) in DCM (1.50 mL) at 0 °C. The resulting reaction mixture was allowed to attain RT and stirred for 16 h. Reaction was monitored by LC-MS & TLC. The reaction mixture was concentrated in vacuo.

[0166] Similarly another 50 mg of tert-butyl 3-(((4-(l-(4-bromobenzoyl)-5-(pyridin-2-yl)-4,5- dihydro-lH-pyrazol-3-yl)phenyl)carbamoyl)oxy)azetidine-l-car boxylate was treated with TFA and both the batches were mixed and co-distilled with CHCL to get (110 mg, crude) azetidin-3-yl (4-(l-(4-bromobenzoyl)-5-(pyridin-2-yl)-4,5-dihydro-lH-pyraz ol-3-yl)phenyl)carbamate as a pale yellow gummy mass. TLC system: 10% MeOH in dichloromethane; Rf : 0.10. LC-MS (ES-API+) m/z = 522.15 [M+H] ⁺

[0167] Step 3: Synthesis of 1-Methylazeti din-3 -yl (4-(l-(4-bromobenzoyl)-5-(pyridin-2-yl)-4,5- dihydro-lH-pyrazol-3-yl)phenyl)carbamate. Sodium cyanoborohydride (17 mg, 0.28 mmol) was added to a stirred solution of azetidin-3-yl (4-(l-(4-bromobenzoyl)-5-(pyridin-2-yl)-4,5-dihydro- lH-pyrazol-3-yl)phenyl)carbamate (100 mg, 0.19 mmol), 37% formaldehyde (0.02mL, 0.38 mmol) and acetic acid (0.05 mL) in MeOH (5 mL) at 0 °C. The resulting reaction mixture was allowed to attain RT and stirred for 16 h. Reaction was monitored by LC-MS & TLC. The reaction mixture was concentrated in vacuo; the residue was quenched with saturated sodium bicarbonate solution (50 mL) and extracted with Ethyl acetate (2 x 30 mL). The combined organic layer was washed with water (10 mL), brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to get (40 mg) 1-methylazeti din-3 -yl (4-(l-(4- bromobenzoyl)-5-(pyridin-2-yl)-4,5-dihydro-lH-pyrazol-3-yl)p henyl)carbamate. TLC system: Ethyl acetate; R _f : 0.40. 'H-NMR (400 MHz, DMSO-d ₆ ): 6 10.25 (s, IH), 10.14 (s, IH), 8.51 (d, IH), 7.84-7.78 (m, 3H), 7.69 (d, 4H), 7.55 (d, 2H), 7.45 (d, IH), 7.32-7.29 (m, IH), 5.82-5.78 (m, IH), 5.30-5.12 (m, IH), 4.61-4.58 (m, IH), 4.32-4.29 (m, 2H), 4.08-4.01 (m, IH), 3.34-3.28 (m, IH), 2.91-2.88 (m, 3H); LC-MS (ES-API ⁺ ): m/z = 534.10 [M+H] ⁺ ion present

Example 14: Synthesis of U-Dioxidothietan-3-yl (4-(l-(4-bromobenzoyl)-5-(pyridin-2-yl)-

4,5-dihvdro-lH-pyrazol-3-yl)phenyl)carbamate (Compound 13)

[0168] To a stirred solution of (3-(4-aminophenyl)-5-(pyridin-2-yl)-4,5-dihydro-lH-pyrazol-l - yl)(4-bromophenyl)methanone (225 mg, 0.52 mmol) and triethylamine (0.20 mL, 1.46 mmol) in dichloromethane (10 mL) was added triphosgene (155 mg, 0.523 mmol) at 0 °C under nitrogen atmosphere. The resulting reaction mixture was stirred at RT for Ih. The reaction was monitored by TLC. The reaction mixture was cooled to 0 °C and a solution of 3-hydroxythietane 1,1-dioxide (65 mg, 0.52 mmol) in DCM (2 mL) was added. The resulting reaction mixture was allowed to attain RT and stirred for 16 h. The reaction was monitored by TLC & LC-MS. The reaction mixture quenched with saturated sodium bicarbonate solution (50 mL) and extracted with Ethyl acetate (2 x 30 mL). The combined organic layer was washed with water (10 mL), brine (10 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure and purified by preparative HPLC to afford l,l-dioxidothietan-3-yl-(4-(l-(4-bromobenzoyl)-5-(pyridin-2- yl)-4,5-dihydro-lH- pyrazol-3-yl)-phenyl)-carbamate (52 mg). TLC system: Ethyl acetate; Rr 0.30. 'H-NMR (400 MHz, DMSO-de): 8 10.28 (s, IH), 8.52 (s, IH), 7.84-7.76 (m, 3H), 7.70-7.67 (m, 4H), 7.56 (d, 2H), 7.44 (d, IH), 7.31-7.28 (m, IH), 5.81-5.77 (m, IH), 5.35-5.30 (m, IH), 4.76-4.70 (m, 2H), 4.28-4.23 (m, 2H), 3.87-3.80 (m, IH), 3.29-3.28 (m, IH); LC-MS (ES-API ⁺ ): m/z = 569.32 [M+H] ⁺ ion present. Example 15: Synthesis of (4-(l-(4-bromo-2-fluorobenzoyl)-5-(pyridin-2-yl)-4.,5-dihvdr o-lH- pyrazol-3-yl)phenyl)carbamate (Compound 14) and Analogs Thereof

[0169] Step 1 : tert-butyl (4-(l-(4-bromo-2-fluorobenzoyl)-5-(pyridin-2-yl)-4,5-dihydro -lH- pyrazol-3-yl)phenyl)carbamate: 4-bromo-2-fluorobenzoyl chloride (210 mg, 0.89 mmol) was added to a solution of tert-butyl (4-(5-(pyridin-2-yl)-4,5-dihydro-lH-pyrazol-3- yl)phenyl)carbamate (300 mg, 0.89 mmol) in DCM (3mL) and triethylamine (179mg, 1.77 mmol) at 0 °C. The resulting reaction mixture was allowed to attain RT and stirred for 16 h. Reaction was monitored by LC-MS & TLC. The reaction was concentrated under reduced pressure after completion. The reaction was dissolved in ethyl acetate (5ml) and washed with water(lOml) then the organic phase was filtered dried and concentrated. The residue was then purified via column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=4/6) to afford tert-butyl (4-(l-(4- bromobenzoyl)-5-(pyridin-2-yl)-4,5-dihydro-lH-pyrazol-3-yl)p henyl)carbamate (300 mg,

[0170] Step 2: (3-(4-aminophenyl)-5-(pyridin-2-yl)-4,5-dihydro-lH-pyrazol-l -yl)(4-bromo-2- fluorophenyl)m ethanone: To a solution of tert-butyl (4-(l-(4-bromobenzoyl)-5-(pyridin-2-yl)-4,5- dihydro-lH-pyrazol-3-yl)phenyl)carbamate (300 mg, 0.56mol) in DCM (0.5 mL) was added dropwise TFA (770 mg, 6.75 mmol) The resulting mixture was stirred at 25°C for 1 h. The resulting mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether/Ethyl acetate=3/7 to afford the title compound (200 mg, 0.46 mmol) as a white solid. MS (ES-API ⁺ ): m/z = 439.1 [M+H] ⁺ ion present.

[0171] Step 3: isopropyl (4-(l-(4-bromo-2-fluorobenzoyl)-5-(pyridin-2-yl)-4,5-dihydro -lH- pyrazol-3-yl)phenyl)carbamate: To a solution of (3-(4-aminophenyl)-5-(pyridin-2-yl)-4,5- dihydro-lH-pyrazol-l-yl)(4-bromo-2-fluorophenyl)methanone (200 mg, 0.46 mmol) in DCM (3 mL) was added TEA 138 mg, 1.4 mmol), DMAP (83 mg, 0.68 mmol) and Isopropyl chloroformate (111 mg, 0.91 mmol). The resulting reaction mixture was stirred at 40°C for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (neutral condition) to afford the title compound (16 mg, 0.030 mmol) was obtained as a yellow solid. 1H NMR: (400 MHz, DMSO-d4) 8 ppm: 9.82 (s, 1H), 8.55 (d, J = 3.6 Hz, 1H), 7.82 (dt, J = 1.6, 7.6 Hz, 1H), 7.68 (dd, J = 1.6, 9.2 Hz, 1H), 7.56 - 7.49 (m, 4H), 7.45 (dd, J = 7.6, 16.4 Hz, 2H), 7.32 (dd, J = 5.2, 7.2 Hz, 1H), 5.77 (dd, J = 4.8, 11.6 Hz, 1H), 4.94 - 4.82 (m, 1H), 3.88 (dd, J = 11.6, 18.0 Hz, 1H), 3.42 - 3.34 (m, 1H), 1.25 (d, J = 6.2 Hz, 6H). MS (ES-API ⁺ ): m/z = 525.1 [M+H] ⁺ .

[0172] Compounds 15-19 were synthesized using an analogous route and are presented in Table 1.

[0173] Table 1: Spectroscopic Data for Compounds 15-19

Example 16: Binding to the BH3 Pocket of Bcl-2 Protein

[0174] Binding to the BH3 pocket of Bcl-2 was quantified for compounds of the present disclosure, as well as known ligands (BAX BH3 domain, ABT-737, amino acids 104-450 of Beclin 1, and Beclin 1 BH3 domain). FIG. 2 provides a table of KD values, demonstrating that some compounds of the present disclosure bind to the BH3 pocket of Bcl-2.

Example 17: Profiling Autophagy Induction and Apoptosis in Hela Cells

[0175] HeLa cells were treated with ABT-737, Compound G, or Compound 12 (identified as Compound E in the figure) at 10 pM, 10, pM, and 5 pM for 4 hours, 8 hours, or 24 hours. The cells were lysed and gel electrophoresis was performed to identify cleaved PARP (a marker of apoptosis) and LC3-I/LC-II (marker of autophagy induction). As shown in FIG. 3, ABT-737 treatment induces apoptosis, as shown by the presence of cleaved PARP. In contrast, compounds of the present disclosure did not induce apoptosis. Further, FIG. 3 demonstrates that compounds of the present disclosure induce autophagy, as indicated by the increased presence of LC3-II at higher concentrations of compound.

Example 18: High Throughput Screen to Identify Autophagy Inducers that Function by Disrupting Beclin l/Bcl-2 Binding

[0176] Autophagy, a lysosomal degradation pathway, plays a crucial role in cellular homeostasis, development, immunity, tumor suppression, metabolism, prevention of neurodegeneration and lifespan extension. Thus, pharmacological stimulation of autophagy may be an effective approach for preventing or treating certain human diseases and/or aging. A method was developed to identify new chemical compounds that specifically induce autophagy. An AlphaLISA assay was used to identify compounds that target a key regulatory node of autophagy induction — specifically, the binding of Bcl-2 (a negative regulator of autophagy) to Beclin 1 (an allosteric modulator of the Beclin 1/VPS34 lipid kinase complex that functions in autophagy initiation). New compounds were identified that directly inhibit Beclin l/Bcl-2 interaction with an IC50 in the micromolar range and increase autophagic flux. These compounds do not demonstrate significant cytotoxicity and they exert selectivity for disruption of Bcl-2 binding to the BH3 domain of Beclin 1 compared to the BH3 domain of the pro-apoptotic Bcl-2 family members, Bax and Bim. [0177] Beclin l/Bcl-2 AlphaLISA Assay Protocol: AlphaLISA is a bead-based luminescent amplification assay, offering greater sensitivity, a wider dynamic range and small sample sizes over traditional ELISA. The purpose of the study is to determine potency (IC50) of compounds for their ability to disrupt Bcl-2/Beclin 1 BH3 complex formation.

[0178] The reactions were conducted in duplicate at room temperature for 30 minutes in a 10 pl mixture containing assay buffer, BCL2-1, biotinylated substrate, and the test compound. These 10 pl reactions were carried out in wells of 384-well Optiplate (PerkinElmer). Dilutions of the test compounds were prepared in assay buffer (5% DMSO concentration) and 2 pl of the dilution was added to a 5 pl of BCL2-1 for preincubation (30 minutes at room temperature with slow shaking). Complex formation was initiated by addition of 3 pl of the substrate (BH3 peptide) mix. Final concentration of DMSO was 1% in all of reactions. After complex formation, 10 pl of Nickel Acceptor beads (PerkinElmer, diluted 1 :250 with lx detection buffer) were added to the reaction mix. After brief shaking, plate was incubated for 30 minutes. Finally, 10 pl of AlphaScreen Streptavidin-conjugated donor beads (PerkinElmer, diluted 1 : 125 with lx detection buffer) were added. In 15 minutes, the samples were measured in AlphaScreen microplate reader (EnSpire Alpha 2390 Multilabel Reader, PerkinElmer).

[0179] Binding activity assays were performed in duplicate at each concentration. The data were analyzed using the computer software, Graphpad Prism. In the absence of the compound, the A- screen intensity (At) in each data set was defined as 100 % activity. In the absence of the Bcl-2 protein, the A-screen signal (Ab) in each data set was defined as 0% activity. The percent activity in the presence of each compound was calculated according to the following equation: % activity = [(A -Ab)/(At-Ab)]x 100, where A = the A-screen signal in the presence of the compound.

[0180] The percent inhibition was calculated according to the following equation: % inhibition = 100 -% activity. The values of % activity versus a series of compound concentrations were then plotted using non-linear regression analysis of Sigmoidal dose-response curve generated with the equation Y=B+(T-B)/l+10((LogEC50-X)xHill Slope), where Y=percent activity, B=minimum percent activity, T=maximum percent activity, X= logarithm of compound and Hill Slope=slope factor or Hill coefficient.

[0181] Table 2 includes percent inhibition for Beclin l/Bcl-2 inhibition at 40 uM for selected compounds, with compounds having and A > 75%; B 40% - 70%; and C < 40%.

[0182] Table 2. Beclin l/Bcl-2 Percent inhibition for selected compounds

Example 19: GFP Puncta Assay

[0183] The underlying processes of autophagy are conserved across eukaryotes and involve the formation of double-membraned structures known as autophagosomes. Autophagosome numbers are widely assessed by quantifying LC3-II pun eta numbers in cells using immunocytochemistry/immunohistochemistry for endogenous LC3, or immunofluorescence for fluorescent-tagged LC3. Such assays have been used for chemical and genetic screens and for assessing autophagy status both in cells and in vivo in different conditions. To assess LC3-II puncta numbers, the follow assay was performed.

[0184] First, cells were grown and plated in 96-well plates. Hela/GFP-LC3 cells were grown in T175 culture flasks until -75% to 85% confluency, at which time, growth media was removed, and washed with PBS. The cells were then harvested by addition of 5 mL TrypLE, subsequent dilution with media, and transferred to a falcon tube. Cells were centrifuged at 1 lOxG, and the supernatant was aspirated. Cells were resuspended in growth media, counted, diluted to 60,000 cells/mL, and transferred to a 96-well plate (100 pL/well).

[0185] Second, cells were treated and analyzed. Serial dilutions of compounds were prepared and administered to the 96-well plates containing the Hela/GFP-LC3 cells. Cells were then incubated for different times (e.g., 4 hours, 8 hours, 24 hours). After treatment, puthe supernatant was aspirated and 100 pL of 4% PFA in PBS solution was added to each well. The cells were then fixed at room temperature in the dark for 10 minutes. Cells were then washed 3 times with PBS, and 50uL of Fluromount G with DAPI mounting medium was added to each well. After storage at 4 degrees Celsius, the plates were imaged and analyzed using ImageXpress.

[0186] FIG. 4 provides a graph of total puncta area over cell area (normalized to DMSO) for cells treated with compounds of the present disclosure, as well as ABT-737, a Bcl-2 inhibitor known to bind to the BH3 domain and induce autophagy. As can be seen in FIG. 4, compounds of the present disclosure induce autophagy at concentrations comparable to ABT- 737.

[0187] FIG. 5 provides a bar graph depicting the total puncta area over cell area (normalized to DMSO) for cells treated with 40 pM of compounds of the present disclosure and ABT- 737. FIG. 5 shows that Compound 11 (identified as Compound D in the figure), induces autophagy to a comparable degree as ABT-737.