GPR4 modulators, compositions, and methods of use thereof

Abstract

The present disclosure relates to compounds that modulate GPR4, compositions, and the use of the compounds or compositions in the treatment and prevention of diseases and disorders associated with dysregulation of GPR4.

Description

GPR4 MODULATORS, COMPOSITIONS, AND METHODS OF USE THEREOF CROSS REFERENCE

[0001] This application claims priority to and benefit from Italian Patent Application No.102024000019879, filed on September 6, 2024, and Italian Patent Application No. 102024000020254, filed on September 11, 2024, each of which is incorporated herein by reference in its entirety. TECHNICAL FIELD

[0002] The present disclosure, in part, relates to compounds that modulate GPR4, compositions, and the use of said compounds or compositions in the treatment and prevention of diseases and disorders associated with dysregulation of GPR4. BACKGROUND

[0003] G protein coupled receptor 4 (GPR4) belongs to a family of pH-sensing G protein-coupled receptors (GPCRs). GPR4 is expressed in a variety of tissues, including but not limited to the brain, kidney, heart, skeletal muscles, and lung. Certain diseases and disorders are affected by dysregulation of GPR4 signaling and its downstream effectors such as Hippo pathway / YAP1, DAT, Parkin, and SQSTM1 / p62. There is a need for novel therapeutic compounds, compositions, and methods that regulate GPR4 and its downstream effectors. In some embodiments, the compounds, compositions, and methods of use disclosed herein, which modulate GPR4 and its downstream effectors, are directed toward this need. SUMMARY

[0004] The present disclosure, in some embodiments, is directed to compounds that modulate GPR4, compositions, and the use of said compounds or compositions in the treatment and prevention of diseases and conditions associated with dysregulation of GPR4.

[0005] In some embodiments, the present disclosure provides for pharmaceutical compositions comprising: a) a compound of Formula (II):or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein; and b) a pharmaceutically acceptable carrier.

[0006] In some embodiments, the present disclosure provides for compounds of Formula (II): or a pharmaceutically acceptable salt thereof, for use in therapy, such as in the treatment or prevention of diseases and conditions associated with dysregulation of GPR4.

[0007] In some embodiments, the present disclosure provides for compounds of Formula (II): (II), or a pharmaceutically acceptable salt thereof, for use in modulating GPR4 in a subject in need thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0008] FIGs.1A-1F show the relative expression levels of the genes YAP1 (FIG. 1A), CTGF (FIG.1B), VCL (FIG.1C), BDNF (FIG.1D), CCND3 (FIG.1E) and EXOC3L2 (FIG.1F) in homozygous E4 / E4 neurons treated with vehicle (VC) or Example L and homozygous E3 / E3 neurons treated with vehicle (VC).

[0009] FIGs.2A-2B show long-term potentiation (LTP) in Shaffer collaterals of hippocampal slices for vehicle (VC) and Example L (FIG.2A) and Example 91 (FIG.2B).

[0010] FIGs.3A-3C show the relative expression levels of the genes DAT (FIG.3A), LRRK2 (FIG.3B) and PDZRN4 (FIG.3C) in SNCA A53T dopaminergic neurons treated with vehicle (VC) or Example L and SNCA WT dopaminergic neurons treated with vehicle (VC).

[0011] FIGs.4A-4B show the relative expression levels of the genes DAT (FIG.4A) and COMT (FIG.4B) in LRRK2 G2019S dopaminergic neurons treated with vehicle (VC) or Example L and LRRK2 WT dopaminergic neurons treated with vehicle (VC).

[0012] FIG.5 shows the expression levels of the SQSTM1 / p62 protein in SNCA A53T dopaminergic neurons treated with vehicle (VC) or Example L and SNCA WT dopaminergic neurons treated with vehicle (VC).

[0013] FIG.6 shows the expression levels of the Parkin protein in SNCA A53T dopaminergic neurons treated with vehicle (VC) or Example L. DETAILED DESCRIPTION

[0014] The present disclosure provides, in some embodiments, compounds that modulate GPR4, compositions, and the use of said compounds or compositions in the treatment and prevention of diseases and conditions associated with dysregulation of GPR4 and its downstream effectors. Definitions

[0015] The following are definitions of terms used in the present specification. The initial definition provided for a group or term herein applies to that group or term throughout the present specification individually or as part of another group, unless otherwise indicated. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0016] As used herein the specification, “a” or “an” in some embodiments means one or more. As used herein, when used in conjunction with the word “comprising” the words “a” or “an” in some embodiments means one or more than one. As used herein, “another” in some embodiments means at least a second or more. Still further, the terms “having”, “including”, “containing” and “comprising” are interchangeable and one of skill in the art is cognizant that these terms are open ended terms. Some embodiments of the disclosure consist of or consist essentially of one or more elements, method steps, and / or methods of thedisclosure. It is contemplated that any method, compound, or composition described herein can be implemented with respect to any other method, compound, or composition described herein.

[0017] “About” and “approximately” shall generally mean an acceptable degree of error for the quantity measured given the nature or precision of the measurements. Exemplary degrees of error are within 20 percent (%), typically, within 10%, and more typically, within 5% of a given value or range of values.

[0018] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March’s Advanced Organic Chemistry, 5thEdition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987.

[0019] The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present disclosure. When describing the disclosure, which includes compounds and pharmaceutically acceptable salts thereof, pharmaceutical compositions containing such compounds, and methods of using such compounds and compositions, the following terms, if present, have the following meanings unless otherwise indicated. It should also be understood that when described herein any of the moieties defined forth below, in some embodiments, is substituted with a variety of substituents, and that the respective definitions are intended to include such substituted moieties within their scope as set out below. Unless otherwise stated, the term “substituted” is to be defined as set out below. It should be further understood that the terms “groups” and “radicals” can be considered interchangeable when used herein.

[0020] When a range of values is listed, it is intended to encompass each value and sub–range within the range. For example “C1–6alkyl” is intended to encompass, C1, C2, C3, C4, C5, C6, C1–6, C1–5, C1–4, C1–3, C1–2, C2–6, C2–5, C2–4, C2–3, C3–6, C3–5, C3–4, C4–6, C4–5, and C5–6alkyl.

[0021] As used herein, “alkyl” refers to a radical of a straight–chain or branched saturated hydrocarbon group, e.g., having 1 to 20 carbon atoms (“C1–20alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C1–10alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1–9alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1–8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1–7alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1–6alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1–5alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1–4alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1–3alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C1alkyl”). Examples of C1–6alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, and the like. In some embodiments, “alkyl” is unsubstituted or substituted with one or more substituents as described herein.

[0022] As used herein, “alkenyl” refers to a radical of a straight–chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon–carbon double bonds (e.g., 1, 2, 3, or 4 carbon–carbon double bonds), and optionally one or more carbon– carbon triple bonds (e.g., 1, 2, 3, or 4 carbon–carbon triple bonds) (“C2–20alkenyl”). In some embodiments, alkenyl does not contain any triple bonds. In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C2–10alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2–9alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2–8alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2–7alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2–6alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2–5alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2–4alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2–3alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“ C2alkenyl”). The one or more carbon– carbon double bonds can be internal (such as in 2–butenyl) or terminal (such as in 1–butenyl). Examples of C2–4alkenyl groups include ethenyl (C2), 1–propenyl (C3), 2–propenyl (C3), 1– butenyl (C4), 2–butenyl (C4), butadienyl (C4), and the like. Examples of C2–6alkenyl groups include the aforementioned C2–4alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. In some embodiments, “alkenyl” is unsubstituted or substituted with one or more substituents as described herein.

[0023] As used herein, “alkynyl” refers to a radical of a straight–chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon–carbon triple bonds (e.g., 1, 2, 3, or 4 carbon–carbon triple bonds), and optionally one or more carbon– carbon double bonds (e.g., 1, 2, 3, or 4 carbon–carbon double bonds) (“C2–20alkynyl”). In some embodiments, alkynyl does not contain any double bonds. In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C2–10alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2–9alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2–8alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2–7alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2–6alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2–5alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2–4alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2–3alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C2alkynyl”). The one or more carbon–carbon triple bonds can be internal (such as in 2–butynyl) or terminal (such as in 1– butynyl). Examples of C2–4alkynyl groups include, without limitation, ethynyl (C2), 1– propynyl (C3), 2–propynyl (C3), 1–butynyl (C4), 2–butynyl (C4), and the like. Examples of C2–6alkynyl groups include the aforementioned C2–4alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. In some embodiments, “alkynyl” is unsubstituted or substituted with one or more substituents as described herein.

[0024] As used herein, “alkylene,” “alkenylene,” and “alkynylene,” refer to a divalent radical of an alkyl, alkenyl, and alkynyl group respectively. When a range or number of carbons is provided for a particular “alkylene,” “alkenylene,” or “alkynylene,” group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain. “Alkylene,” “alkenylene,” and “alkynylene,” groups are unsubstituted or substituted with one or more substituents as described herein.

[0025] As used herein, the term “heteroalkyl” refers to an alkyl moiety as hereinbefore defined which contain one or more heteroatoms such as oxygen, sulfur, nitrogen, phosphorus, or silicon atoms in place of carbon atoms. An exemplary heteroalkyl is an alkoxy (O-alkyl).

[0026] As used herein, “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic, tricyclic, or tetracyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatomsprovided in the aromatic ring system (“C6–14aryl”). In some embodiments, an aryl group has six ring carbon atoms (“C6aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“C10aryl”; e.g., naphthyl such as 1–naphthyl and 2–naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C14aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Particularly aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. In some embodiments, “aryl” is unsubstituted or substituted with one or more substituents as described herein.

[0027] As used herein, “heteroaryl” refers to a radical of an aromatic ring system (e.g., having 6 or 10 electrons shared in a cyclic array) having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur. In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl can be monocyclic or polycyclic (e.g., bicyclic, tricyclic, tetracyclic). Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. Heteroaryl tricyclic ring systems can include one or more heteroatoms in one or two or all three rings. Heteroaryl tetracyclic ring systems can include one or more heteroatoms in one or two or three or all four rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl / heteroaryl) ring system. Bicyclic heteroaryl groups whereinone ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2– indolyl) or the ring that does not contain a heteroatom (e.g., 5–indolyl). In some embodiments, “heteroaryl” is unsubstituted or substituted with one or more substituents as described herein.

[0028] In some embodiments, a heteroaryl group is a 5–12 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–12 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5–10 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5–8 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5–6 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–6 membered heteroaryl”). In some embodiments, the 5–6 membered heteroaryl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heteroaryl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0029] Exemplary 5–membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5–membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5–membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5–membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6–membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6–membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6–membered heteroaryl groups containing three or four heteroatomsinclude, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7–membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6–bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6– bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0030] Examples of representative heteroaryls include the following: wherein each Z is selected from carbonyl, N, NR , O, and S; and RNNis independently hydrogen, C1-8alkyl, C3-10carbocyclyl, 4-10 membered heterocyclyl, C6-10aryl, and 5-10 membered heteroaryl.

[0031] As used herein, “carbocyclyl” or “carbocyclic” refers to a radical of a non– aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C3–14carbocyclyl”) and zero heteroatoms in the non–aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 12 ring carbon atoms (“C3–12carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“ C3-10carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3–8carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C3-7carbocycyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3–6carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5–10carbocyclyl”). Exemplary C3–6carbocyclyl groups include, without limitation, cyclopropyl (C3),cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3–8carbocyclyl groups include, withoutlimitation, the aforementioned C3–6carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C3–10carbocyclyl groups include, without limitation, the aforementioned C3–8carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro–1H–indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. As the foregoing examples illustrate, in some embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) and can be saturated or can be partially unsaturated. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. In some embodiments, “carbocyclyl” is unsubstituted or substituted with one or more substituents as described herein.

[0032] The term “cycloalkyl” refers to a monovalent saturated cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) hydrocarbon group of 3-12, 3-10, 3-8, 4-8, or 4-6 carbons, referred to herein, e.g., as “C3–12cycloalkyl,” “C3-10cycloalkyl,” “C3-8cycloalkyl,” “C4-8cycloalkyl,” or “C4-6cycloalkyl,” respectively, derived from a cycloalkane. Exemplary cycloalkyl groups include, but are not limited to, cyclohexanes, cyclopentanes, cyclobutanes and cyclopropanes. In some embodiments, “cycloalkyl” is unsubstituted or substituted with one or more substituents as described herein.

[0033] As used herein, “heterocyclyl” or “heterocyclic” refers to a radical of a 3– to 12–membered non–aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3–12 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on thecarbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” “heterocyclic radical,” and “heterocycloalkyl” are used interchangeably. In some embodiments, “heterocyclyl” is unsubstituted or substituted with one or more substituents as described herein.

[0034] In some embodiments, a heterocyclyl group is a 4-12 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“4-12 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 4-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“4-10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 4-7 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“4-7 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5–10 membered non–aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5–10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5–8 membered non–aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5–6 membered non–aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–6 membered heterocyclyl”). In some embodiments, the 5–6 membered heterocyclyl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heterocyclyl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0035] Exemplary 3–membered heterocyclyl groups containing one heteroatom include, without limitation, aziridinyl, oxiranyl, and thiiranyl. Exemplary 4–membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl,oxetanyl and thietanyl. Exemplary 5–membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl–2,5– dione. Exemplary 5–membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5–membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6–membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6–membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6–membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7–membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8– membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0036] Examples of saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, terahydropyranyl, pyrrolidinyl, pyridinonyl, pyrrolidonyl, piperidinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, morpholinyl, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, oxetanyl, azetidinyl and tetrahydropyrimidinyl. Where specified as being optionally substituted or substituted, substituents on a heterocyclyl (e.g., in the case of an optionally substituted heterocyclyl) in some embodiments is present on any substitutable position and, include, e.g., the position at which the heterocyclyl group is attached.

[0037] “Hetero” when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero in some embodiments is applied to any of the hydrocarbyl groups described above such as alkyl, e.g., heteroalkyl; carbocyclyl,e.g., heterocyclyl; aryl, e.g., heteroaryl; and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms.

[0038] The terms “halo” and “halogen” as used herein refer to an atom selected from fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), and iodine (iodo, -I). In some embodiments, the halo group is either fluoro or chloro.

[0039] The term “haloalkyl” includes mono, poly, and perhaloalkyl groups substituted with one or more halogen atoms where the halogens are independently selected from fluorine, chlorine, bromine, and iodine. For the group C1-4haloalkyl-O- C1-4alkyl, the point of attachment occurs on the alkyl moiety which is halogenated.

[0040] The term “alkoxy,” as used herein, refers to an alkyl group which is attached to another moiety via an oxygen atom (–O(alkyl)). Non-limiting examples include e.g., methoxy, ethoxy, propoxy, and butoxy.

[0041] “Haloalkoxy” is a haloalkyl group which is attached to another moiety via an oxygen atom such as, e.g., but are not limited to –OCHCF2or –OCF3.

[0042] As used herein, “cyano” refers to -CN.

[0043] As used herein, “nitro” refers to -NO2.

[0044] As used herein, “oxo” refers to refers to an oxygen atom doubly bonded to a carbon atom (=O).

[0045] As used herein, the term “hydroxy” or “hydroxyl” refers to -OH group.

[0046] As used herein, the terms "amine" and "amino" refer to both unsubstituted and substituted amines and salts thereof, e.g., a moiety that can be represented by -N(Rb)2or - N(Rb)3+wherein Rb each independently represents a hydrogen or optionally substituted hydrocarbyl group, or Rb groups are taken together with the N atom to which they are attached form a heterocyclic ring having from 4 to 8 atoms in the ring structure which in some embodiments is optionally substituted.

[0047] It will be appreciated that the compounds, as described herein, in some embodiments are substituted with any number of substituents or functional moieties. In general, the term “substituted” whether preceded by the term “optionally” or not, and substituents contained in formulas of this disclosure, refer to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. When more than one position in any given structure is substituted with more than one substituent selected from a specified group, the substituent is either the same or different at every position.

[0048] Exemplary carbon atom substituents include, but are not limited to, halogen, – CN, –NO2, –N3, –SO2H, –SO3H, –OH, –ORaa, –ON(Rbb)2, –N(Rbb)2, –N(Rbb)3+X–, – N(ORcc)Rbb, –SH, –SRaa, –SSRcc, –C(=O)Raa, –CO2H, –CHO, –C(ORcc)2, –CO2Raa, – OC(=O)Raa, –OCO2Raa, –C(=O)N(Rbb)2, –OC(=O)N(Rbb)2, –NRbbC(=O)Raa, –NRbbCO2Raa, – NRbbC(=O)N(Rbb)2, –C(=NRbb)Raa, –C(=NRbb)ORaa, –OC(=NRbb)Raa, –OC(=NRbb)ORaa, – C(=NRbb)N(Rbb)2, –OC(=NRbb)N(Rbb)2, –NRbbC(=NRbb)N(Rbb)2, –C(=O)NRbbSO2Raa, – NRbbSO2Raa, –SO2N(Rbb)2, –SO2Raa, –SO2ORaa, –OSO2Raa, –S(=O)Raa, –OS(=O)Raa, – Si(Raa)3, –OSi(Raa)3–C(=S)N(Rbb)2, –C(=O)SRaa, –C(=S)SRaa, –SC(=S)SRaa, –SC(=O)SRaa, – OC(=O)SRaa, –SC(=O)ORaa, –SC(=O)Raa, –P(=O)2Raa, –OP(=O)2Raa, –P(=O)(Raa)2, – OP(=O)(Raa)2, –OP(=O)(ORcc)2, –P(=O)2N(Rbb)2, –OP(=O)2N(Rbb)2, –P(=O)(NRbb)2, – OP(=O)(NRbb)2, –NRbbP(=O)(ORcc)2, –NRbbP(=O)(NRbb)2, –P(Rcc)2, –P(Rcc)3, –OP(Rcc)2, – OP(Rcc)3, –B(Raa)2, –B(ORcc)2, –BRaa(ORcc), C1–10alkyl, C1–10haloalkyl, C2–10alkenyl, C2–10alkynyl, C3-10carbocyclyl, 3–14 membered heterocyclyl, C6–14aryl, and 5–14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; or two geminal hydrogens on a carbon atom are replaced with the group =O, =S, =NN(Rbb)2, =NNRbbC(=O)Raa, =NNRbbC(=O)ORaa, =NNRbbS(=O)2Raa, =NRbb, or =NORcc; each instance of Raais, independently, selected from C1–10alkyl, C1–10haloalkyl, C2–10alkenyl, C2–10alkynyl, C3–10carbocyclyl, 3–14 membered heterocyclyl, C6–14aryl, and 5–14 membered heteroaryl, or two Raagroups are joined to form a 3–14 membered heterocyclyl or 5–14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rbbis, independently, selected from hydrogen, –OH, –ORaa, –N(Rcc)2, –CN, –C(=O)Raa, –C(=O)N(Rcc)2, –CO2Raa, –SO2Raa, –C(=NRcc)ORaa, –C(=NRcc)N(Rcc)2, – SO2N(Rcc)2, –SO2Rcc, –SO2ORcc, –SORaa, –C(=S)N(Rcc)2, –C(=O)SRcc, –C(=S)SRcc, – P(=O)2Raa, –P(=O)(Raa)2, –P(=O)2N(Rcc)2, –P(=O)(NRcc)2, C1–10alkyl, C1–10haloalkyl, C2–10alkenyl, C2–10alkynyl, C3–10carbocyclyl, 3–14 membered heterocyclyl, C6–14aryl, and 5–14 membered heteroaryl, or two Rbbgroups are joined to form a 3–14 membered heterocyclyl or 5–14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rccis, independently, selected from hydrogen, C1–10alkyl, C1–10haloalkyl, C2–10alkenyl, C2–10alkynyl, C3-10carbocyclyl, 3–14 membered heterocyclyl, C6–14aryl, and 5–14 membered heteroaryl, or two Rccgroups are joined to form a 3–14 memberedheterocyclyl or 5–14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rddis, independently, selected from halogen, –CN, –NO2, –N3, –SO2H, –SO3H, –OH, –ORee, –ON(Rff)2, –N(Rff)2, –N(Rff)3+X–, –N(ORee)Rff, –SH, –SRee, –SSRee, – C(=O)Ree, –CO2H, –CO2Ree, –OC(=O)Ree, –OCO2Ree, –C(=O)N(Rff)2, –OC(=O)N(Rff)2, – NRffC(=O)Ree, –NRffCO2Ree, –NRffC(=O)N(Rff)2, –C(=NRff)ORee, –OC(=NRff)Ree, – OC(=NRff)ORee, –C(=NRff)N(Rff)2, –OC(=NRff)N(Rff)2, –NRffC(=NRff)N(Rff)2,–NRffSO2Ree, –SO2N(Rff)2, –SO2Ree, –SO2ORee, –OSO2Ree, –S(=O)Ree, –Si(Ree)3, –OSi(Ree)3, – C(=S)N(Rff)2, –C(=O)SRee, –C(=S)SRee, –SC(=S)SRee, –P(=O)2Ree, –P(=O)(Ree)2, – OP(=O)(Ree)2, –OP(=O)(ORee)2, C1–6alkyl, C1–6haloalkyl, C2–6alkenyl, C2–6alkynyl, C3-10carbocyclyl, 3–10 membered heterocyclyl, C6–10aryl, 5–10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups, or two geminal Rddsubstituents can be joined to form =O or =S; each instance of Reeis, independently, selected from C1–6alkyl, C1–6haloalkyl, C2–6alkenyl, C2–6alkynyl, C3-10carbocyclyl, C6–10 aryl, 3–10 membered heterocyclyl, and 3–10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups; each instance of Rffis, independently, selected from hydrogen, C1–6alkyl, C1–6haloalkyl, C2–6alkenyl, C2–6alkynyl, C3–10carbocyclyl, 3–10 membered heterocyclyl, C6–10aryl and 5–10 membered heteroaryl, or two Rffgroups are joined to form a 3–14 membered heterocyclyl or 5–14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups; and each instance of Rggis, independently, halogen, –CN, –NO2, –N3, –SO2H, –SO3H, – OH, –OC1–6alkyl, –ON(C1–6alkyl)2, –N(C1–6alkyl)2, –N(C1–6alkyl)3+X–, –NH(C1–6alkyl)2+X–, –NH2(C1–6alkyl)+X–, –NH3+X–, –N(OC1–6alkyl)(C1–6alkyl), –N(OH)(C1–6alkyl), –NH(OH), –SH, –SC1–6alkyl, –SS(C1–6alkyl), –C(=O)(C1–6alkyl), –CO2H, –CO2(C1–6alkyl), –OC(=O)(C1–6alkyl), –OCO2(C1–6alkyl), –C(=O)NH2, –C(=O)N(C1–6alkyl)2, – OC(=O)NH(C1–6alkyl), –NHC(=O)( C1–6alkyl), –N(C1–6alkyl)C(=O)( C1–6alkyl), – NHCO2(C1–6alkyl), –NHC(=O)N(C1–6alkyl)2, –NHC(=O)NH(C1–6alkyl), –NHC(=O)NH2, – C(=NH)O(C1–6alkyl),–OC(=NH)(C1–6alkyl), –OC(=NH)OC1–6alkyl, –C(=NH)N(C1–6alkyl)2,–C(=NH)NH(C1–6alkyl), –C(=NH)NH2, –OC(=NH)N(C1–6alkyl)2, –OC(NH)NH(C1–6alkyl), –OC(NH)NH2, –NHC(NH)N(C1–6alkyl)2, –NHC(=NH)NH2, –NHSO2(C1–6alkyl), – SO2N(C1–6alkyl)2, –SO2NH(C1–6alkyl), –SO2NH2,–SO2C1–6alkyl, –SO2OC1–6alkyl, – OSO2C1–6alkyl, –SOC1–6alkyl, –Si(C1–6alkyl)3, –OSi(C1–6alkyl)3–C(=S)N(C1–6alkyl)2, C(=S)NH(C1–6alkyl), C(=S)NH2, –C(=O)S(C1–6alkyl), –C(=S)SC1–6alkyl, –SC(=S)SC1–6alkyl, –P(=O)2(C1–6alkyl), –P(=O)(C1–6alkyl)2, –OP(=O)(C1–6alkyl)2, –OP(=O)(OC1–6alkyl)2, C1–6alkyl, C1–6haloalkyl, C2–6alkenyl, C2–6alkynyl, C3-10carbocyclyl, C6–10 aryl, 3– 10 membered heterocyclyl, 5–10 membered heteroaryl; or two geminal Rggsubstituents can be joined to form =O or =S; wherein X–is a counterion.

[0049] Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quarternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, –OH, –ORaa, –N(Rcc)2, –CN, –C(=O)Raa, –C(=O)N(Rcc)2, –CO2Raa, –SO2Raa, –C(=NRbb)Raa, –C(=NRcc)ORaa, –C(=NRcc)N(Rcc)2, – SO2N(Rcc)2, –SO2Rcc, –SO2ORcc, –SORaa, –C(=S)N(Rcc)2, –C(=O)SRcc, –C(=S)SRcc, – P(=O)2Raa, –P(=O)(Raa)2, –P(=O)2N(Rcc)2, –P(=O)(NRcc)2, C1–10alkyl, C1–10haloalkyl, C2–10alkenyl, C2–10alkynyl, C3-10carbocyclyl, 3–14 membered heterocyclyl, C6–14aryl, and 5–14 membered heteroaryl, or two Rccgroups attached to a nitrogen atom are joined to form a 3–14 membered heterocyclyl or 5–14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups, and wherein Raa, Rbb, Rccand Rddare as defined above.

[0050] Unless otherwise indicated, any heteroatom with unsatisfied valences is assumed to have hydrogen atoms sufficient to satisfy the valences.

[0051] Certain compounds of the present disclosure in some embodiments exist in particular geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (d)- isomers, (l)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the disclosure. Additional asymmetric carbon atoms in some embodiments are present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this disclosure.

[0052] All stereoisomers of the present compounds (for example, those which in some embodiments exist due to asymmetric carbons on various substituents), including enantiomeric forms and diastereomeric forms, are contemplated within the scope of this disclosure. Individual stereoisomers of the compounds of the disclosure, for example, aresubstantially free of other isomers (e.g., as a pure or substantially pure optical isomer having a specified activity), or admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present disclosure in some embodiments have the S or R configuration as defined by the International Union of Pure and Applied Chemistry (IUPAC) 1974 Recommendations.

[0053] All configurational isomers of the compounds of the present disclosure are contemplated, either in admixture or in pure or substantially pure form. The definition of compounds of the present disclosure embraces both cis (Z) and trans (E) alkene isomers, as well as cis and trans isomers of cyclic hydrocarbon or heterocyclic rings.

[0054] Isomeric mixtures containing any of a variety of isomer ratios in some embodiments are utilized in accordance with the present disclosure. For example, where only two isomers are combined, mixtures containing 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0 isomer ratios are all contemplated by the present disclosure.

[0055] The present disclosure also includes isotopically-labeled compounds, which are identical to the compounds disclosed herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chlorine, such as2H,3H,13C,11C,14C,15N,18O,17O,31P,32P,35S,18F, and36Cl, respectively. Compounds of the present disclosure, or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this disclosure.

[0056] As used herein, “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1–19. Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acidssuch as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy– ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3–phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p–toluenesulfonate, undecanoate, valerate salts, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1–4alkyl)4salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0057] As used herein, “pharmaceutically acceptable carrier” refers to any substance in a pharmaceutical formulation other than the active pharmaceutical ingredient(s). Exemplary pharmaceutical carriers include those that aid the manufacturing process; protect, support or enhance stability; increase bioavailability; or increase patient acceptability. In some embodiments, they also assist in product identification or enhance the overall safety or function of the product during storage or use.

[0058] As used herein, a “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle–aged adult or senior adult)) and / or a non-human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non- human animal. The terms “human,” “patient,” “subject,” and “individual” are used interchangeably herein. None of these terms require the active supervision of medical personnel.

[0059] Disease, disorder, and condition are used interchangeably herein.

[0060] As used herein, and unless otherwise specified, the terms “treat,” “treating” and “treatment” contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or reverses or slows the progression of the disease, disorder or condition (also “therapeutic treatment”).

[0061] In general, the “effective amount” of a compound refers to an amount sufficient to elicit the desired biological response. As will be appreciated by those of ordinary skill in this art, the effective amount of a compound of the disclosure in some embodiments varies depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health, and condition of the subject. A “therapeutically effective amount” of a compound is an amount sufficient to provide a therapeutic benefit (e.g., treating, preventing, and / or ameliorating a disease or disorder disclosed herein, for example, neurodegenerative disease or disorder, in a subject, or modulating GPR4 receptor in a subject, at a reasonable benefit / risk ratio applicable to any medical treatment) in the treatment of a disease, disorder or condition, or to delay or minimize one or more symptoms associated with the disease, disorder or condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the disease, disorder or condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent. A “prophylactically effective amount” of a compound is an amount sufficient to prevent a disease, disorder or condition, or one or more symptoms associated with the disease, disorder or condition, or prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the disease, disorder or condition. The term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent. A “prophylactic treatment” contemplates an action that occurs before a subject begins to suffer from the specified disease, disorder or condition.

[0062] The term “associated” or “associated with”, “involving” or “mediated by” in the context of a GPR4 associated disease or disorder refers to that the disease or disorder is caused by in whole or in part, or a symptom of the disease is caused by in whole or in part bydysregulation of GPR4 receptors, or receptor activity, or function. For example, a symptom of a disease or condition associated with GPR4 activity in some embodiments is a symptom that results entirely or partially from dysregulation of GPR4 (e.g., in the level of activity of GPR4 receptors and or expression of GPR4 receptors). GPR4 Modulation

[0063] Certain diseases and disorders are affected by dysregulation of GPR4 signaling and its downstream effectors such as Hippo pathway / YAP1, DAT, Parkin, and SQSTM1 / p62.

[0064] For example, GPR4 activation leads to the stimulation of two G protein / effector systems, Gs alpha and G12 / 13alpha subunits, thereby enabling the formation of actin stress fibers, cell adhesion, “inside-out” activation of integrins, and recruitment of adaptor proteins and kinases forming focal adhesions. Maturation of focal adhesions inhibits Hippo signaling which affects the activity of transcription co-factor Yes Associated Protein 1 (YAP1) by affecting its subcellular localization and protein stability through phosphorylation.

[0065] The GPR4-YAP1 signaling pathway plays an important role in neurodegenerative diseases and disorders such as Alzheimer's Disease (AD). In the brain, YAP1 promotes and maintains peripheral axon myelination and regulates both neuronal differentiation and mature neurons as well as dendrite growth and arborization. YAP1 expression is decreased very early in AD patients before the onset of amyloid beta deposits or tau tangles. Focal adhesion maturation also allows for PI3K / Akt activation which controls phosphorylation and inactivation of GSK3β, thereby hindering Tau (MAPT) hyperphosphorylation. Over-activity of GSK3β causes Tau hyperphosphorylation and microtubule destabilization. Tau can be phosphorylated at several positions in Alzheimer's disease including at positions 181, 231 and 217. Alleles of the Hippo pathway regulator KIBRA (WWC1) are also associated with AD, memory performance, and cognition function. Certain muscular diseases such as myotonic dystrophy also present neuropsychiatric symptoms and cognitive impairments similar to AD. The YAP1 / Hippo pathway also controls organ size and cell shape, tissue homeostasis, wound healing and regeneration and is associated with metabolism, innate immunity, mitochondrial dynamics and autophagy.

[0066] The APOE4 allele, a genetic determining factor for AD, causes transcriptional effects in neurons, thereby reducing the expression of GPR4. Modulating GPR4 activity thus regulates the expression of YAP1 in human iPSC-derived neurons and other genes that are differentially expressed in neurons carrying the homozygous APOE4 genotype compared toneurons carrying the homozygous APOE3 genotype. In addition to YAP1, other differentially expressed genes including VCL, CCND3, CTGF, BDNF, ITGB3 and EXOC3L2 are regulated by GPR4 activity. APOE4 is also a significant risk factor for other diseases such as cardiovascular diseases, including cerebral amyloid angiopathy. The APOE4 allele creates a de novo binding site for the transcription factor NRF1, which affects vascular cell dysfunction.

[0067] Key pathways dysregulated in neurodegenerative conditions such as Parkinson’s disease include mitophagy, mitochondrial dynamics, autophagy, lysosomal protein degradation, and dopamine homeostasis. Accumulation of Lewy bodies aggregates whose major constituent is alpha-synuclein is the histological hallmark of the disease. Parkin, a YAP1 target gene, is specifically recruited to damaged mitochondria and promotes their autophagic degradation. Lower expression and / or activity of Parkin plays a pathogenic role in both inherited and sporadic Parkinson’s disease. The compounds and compositions described herein, which modulate GPR4 activity, regulate protein expression levels of Parkin.

[0068] Multifunctional autophagy receptor SQSTM1 / p62 (Sequestosome) also plays a role in various diseases and disorders. For example, in Parkinson’s disease, SQSTM1 / p62 plays a role in clearing protein aggregates, such as alpha-synuclein inclusions. In addition, SQSTM1 / p62 dysregulation underlies various metabolic diseases. For example, SQSTM1 / p62 limits inflammation in adipose tissue and SQSTM1 / p62 deficiency impairs brown adipose tissue thermogenesis. SQSTM1 / p62 knock-out mice develop mature-onset obesity, leptin resistance, as well as impaired glucose and insulin tolerance. Perturbation of SQSTM1 / p62 activity is also associated with the pathogenesis of certain liver diseases. In addition, SQSTM1 / p62-mediated clearance of inflammasomes contributes to lowering the atherosclerotic plaque burden. Furthermore, SQSTM1 / p62 is recruited to and facilitates clearance of damaged lysosomes by lysophagy. SQSTM1 / p62 deficiency also accelerates osteoclastogenesis and leads to Paget's disease-like bone phenotypes while SQSTM1 / p62 overexpression rescues pathologies associated with osteoporosis through a combination of bone-sparing and osteosynthetic effects. The compounds and compositions described herein, which modulate GPR4 activity, regulate protein expression levels of autophagy receptor SQSTM1 / p62.

[0069] Dopamine transporter dysregulation plays an important role in the development of certain neuropsychiatric disorders. For example, DAT / SLC6A3 overexpression (alternatively COMT under-expression) causes dopamine-induced toxicityand cell death. DAT and YAP1 target gene FOSB are also involved in depression and addiction. Moreover, dopamine dysfunction contributes to post-traumatic brain injury deficits. Modulating GPR4 activity affects the expression of the DAT and COMT genes that are differentially regulated in dopaminergic neurons carrying the LRRK2 G2019S genotype compared to LRRK2 WT neurons. In addition, modulating GPR4 activity affects the expression of DAT and the Notch pathway regulator PDZRN4 and LRRK2 in dopaminergic neurons heterozygous for the SNCA A53T genotype compared to neurons carrying the SNCA WT genotype. LRRK2 G2019S and SNCA A53T are alleles associated with Parkinson’s disease.

[0070] GPR4 also controls angiogenesis and is required for normal vessel formation under physiological conditions. GPR4 reduces migration and metastasis of certain cancer cells, such as melanoma and prostate cells. GPR4 deficiency is also associated with reduced renal acid excretion and causes metabolic acidosis in the kidney.

[0071] The present disclosure provides, in some embodiments, compounds and compositions which modulate GPR4, thereby restoring biological processes mediated by dysregulated activity of GPR4 and its downstream effectors. Compounds

[0072] In some embodiments, provided herein are compounds of Formula (I):, or a pharmaceutically acceptable salt thereof, wherein X is -C(=O)NR3- or -NR3C(=O)-; L is a bond or C1-4alkylene optionally substituted by one or more fluorine or deuterium; Y1, Y2, Y3, and Y4are each independently CR4or N; R1and R2are each independently selected from the group consisting of H, deuterium, C1-4alkyl, C3-6cycloalkyl, and halogen, or R1and R2together with the carbon to which the R1and R2are attached form C3-6cycloalkyl;R3is selected from the group consisting of H, C1-6alkyl, and C3-6cycloalkyl, wherein the C1-6alkyl or C3-6cycloalkyl is optionally substituted by one or more fluorine; Group A is selected from the group consisting of i) bicyclic heteroaryl having the structure:wherein X1, X2, X3, and X4are each independently CR5or N, provided that no more than two of X1, X2, X3, and X4are N, ii) naphthyl optionally substituted with one, two, or three R5substituents, and iii) -N(C1-4alkyl)phenyl or -N(C1-4alkyl)heteroaryl, each optionally substituted with one, two, or three R5substituents; Group C is aryl or heteroaryl; R4is each independently selected from the group consisting of H, halogen, - CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -OR7, -S(O)xR7, -NR7R8, -C(O)R7, -OC(O)R7, -C(O)OR7, -NR7C(O)R8, - C(O)NR7R8, -NR7C(O)OR8, -OC(O)NR7R8, -NR7SO2R8, and -SO2NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted by one or more R9; R5and R6are each independently selected from the group consisting of H, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -OR7, -S(O)xR7, -NR7R8, -C(O)R7, -OC(O)R7, -C(O)OR7, - NR7C(O)R8, -C(O)NR7R8, -NR7C(O)OR8, -OC(O)NR7R8, -NR7SO2R8, and - SO2NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted by one or more R9; R7and R8are each independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl, wherein the C1-6alkyl and C1-6haloalkyl are optionally substituted by one or more R10; R9and R10are each independently selected from the group consisting of halo, -CN, -OR11, -S(O)xR11, -NR11R12, C(O)R11, -OC(O)R11, -C(O)OR11, -NR11C(O)R12, and -C(O)NR11R12;R11and R12are each independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl; x is 0, 1, or 2; and p is 0, 1, 2, or 3; provided that: i) when X is -C(=O)NR3-, R3is H or CH3, L is bond, Y1, Y2, Y3, and Y4are CH, Group C is phenyl, R1and R2are H, and p is 0, then Group A is not - N(CH3)phenyl optionally substituted with CH3; ii) when X is -NR3C(=O)-, R3is H or CH3, L is bond, Y1, Y3, and Y4are CH, Y2is CH or C-NH2, Group C is phenyl, R1and R2are H, p is 1, and Group A is , then R6is not -NHC(O)CH3; and iii) when X is -C(=O)NR3-, R3is H, L is -CH2-, Y1and Y2are CH, Y4is N, Y3is C-CF3, Group C is phenyl, R1is H, R2is CH3, p is 1, and Group A is , then R6is not CH3.

[0073] In some embodiments, provided herein are compounds of Formula (I’): (I’), or a pharmaceutically acceptable salt thereof, wherein X is -C(=O)NR3- or -NR3C(=O)-; L is a bond or C1-4alkylene optionally substituted by one or more fluorine or deuterium; Y1, Y2, Y3, and Y4are each independently CR4or N;R1and R2are each independently selected from the group consisting of H, deuterium, C1-4alkyl, C3-6cycloalkyl, and halogen, or R1and R2together with the carbon to which the R1and R2are attached form C3-6cycloalkyl; R3is selected from the group consisting of H, C1-6alkyl, and C3-6cycloalkyl, wherein the C1-6alkyl or C3-6cycloalkyl is optionally substituted by one or more fluorine; Group A is i) bicyclic heteroaryl having the structure:wherein X1, X2, X3, and X4are each independently CR5or N, provided that no more than two of X1, X2, X3, and X4are N, or ii) -N(C1-4alkyl)phenyl or -N(C1-4alkyl)heteroaryl, each optionally substituted with one, two, or three R5substituents; Group C is aryl or heteroaryl; R4is each independently selected from the group consisting of H, halogen, - CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -OR7, -S(O)xR7, -NR7R8, -C(O)R7, -OC(O)R7, -C(O)OR7, -NR7C(O)R8, - C(O)NR7R8, -NR7C(O)OR8, -OC(O)NR7R8, -NR7SO2R8, and -SO2NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted by one or more R9; R5and R6are each independently selected from the group consisting of H, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -OR7, -S(O)xR7, -NR7R8, -C(O)R7, -OC(O)R7, -C(O)OR7, - NR7C(O)R8, -C(O)NR7R8, -NR7C(O)OR8, -OC(O)NR7R8, -NR7SO2R8, and - SO2NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted by one or more R9; R7and R8are each independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl, wherein the C1-6alkyl and C1-6haloalkyl are optionally substituted by one or more R10;R9and R10are each independently selected from the group consisting of halo, -CN, -OR11, -S(O)xR11, -NR11R12, C(O)R11, -OC(O)R11, -C(O)OR11, -NR11C(O)R12, and -C(O)NR11R12; R11and R12are each independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl; x is 0, 1, or 2; and p is 0, 1, 2, or 3; provided that: i) when X is -C(=O)NR3-, R3is H or CH3, L is bond, Y1, Y2, Y3, and Y4are CH, Group C is phenyl, R1and R2are H, and p is 0, then Group A is not - N(CH3)phenyl optionally substituted with CH3; ii) when X is -NR3C(=O)-, R3is H or CH3, L is bond, Y1, Y3, and Y4are CH, Y2is CH or C-NH2, Group C is phenyl, R1and R2are H, p is 1, and Group A is , then R6is not -NHC(O)CH3; and iii) when X is -C(=O)NR3-, R3is H, L is -CH2-, Y1and Y2are CH, Y4is N, Y3is C-CF3, Group C is phenyl, R1is H, R2is CH3, p is 1, and Group A is , then R6is not CH3.

[0074] In some embodiments, provided herein are compounds of Formula (II):, or a pharmaceutically acceptable salt thereof, wherein X is -C(=O)NR3- or -NR3C(=O)-; L is a bond or C1-4alkylene optionally substituted by one or more fluorine or deuterium;Y1, Y2, Y3, and Y4are each independently CR4or N; R1and R2are each independently selected from the group consisting of H, deuterium, C1-4alkyl, C3-6cycloalkyl, and halogen, or R1and R2together with the carbon to which the R1and R2are attached form C3-6cycloalkyl; R3is selected from the group consisting of H, C1-6alkyl, and C3-6cycloalkyl, wherein the C1-6alkyl or C3-6cycloalkyl is optionally substituted by one or more fluorine; Group A is i) bicyclic heteroaryl having the structure:wherein X1, X2, X3, and X4are each independently CR5or N, provided that no more than two of X1, X2, X3, and X4are N, or ii) -N(C1-4alkyl)phenyl or -N(C1-4alkyl)heteroaryl, each optionally substituted with one, two, or three R5substituents; Group C is aryl or heteroaryl; R4is each independently selected from the group consisting of H, halogen, - CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -OR7, -S(O)xR7, -NR7R8, -C(O)R7, -OC(O)R7, -C(O)OR7, -NR7C(O)R8, - C(O)NR7R8, -NR7C(O)OR8, -OC(O)NR7R8, -NR7SO2R8, and -SO2NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted by one or more R9; R5and R6are each independently selected from the group consisting of H, deuterium, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -OR7, -S(O)xR7, -NR7R8, -C(O)R7, -OC(O)R7, - C(O)OR7, -NR7C(O)R8, -C(O)NR7R8, -NR7C(O)OR8, -OC(O)NR7R8, -NR7SO2R8, and -SO2NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted by one or more R9; R7and R8are each independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl, wherein the C1-6alkyl and C1-6haloalkyl are optionally substituted by one or more R10;R9and R10are each independently selected from the group consisting of halo, deuterium, -CN, -OR11, -S(O)xR11, -NR11R12, C(O)R11, -OC(O)R11, -C(O)OR11, - NR11C(O)R12, and -C(O)NR11R12; R11and R12are each independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl; x is 0, 1, or 2; and p is 0, 1, 2, or 3; provided that: i) when X is -C(=O)NR3-, R3is H or CH3, L is bond, Y1, Y2, Y3, and Y4are CH, Group C is phenyl, R1and R2are H, and p is 0, then Group A is not - N(CH3)phenyl optionally substituted with CH3; ii) when X is -NR3C(=O)-, R3is H or CH3, L is bond, Y1, Y3, and Y4are CH, Y2is CH or C-NH2, Group C is phenyl, R1and R2are H, p is 1, and Group A is , then R6is not -NHC(O)CH3; and iii) when X is -C(=O)NR3-, R3is H, L is -CH2-, Y1and Y2are CH, Y4is N, Y3is C-CF3, Group C is phenyl, R1is H, R2is CH3, p is 1, and Group A is , then R6is not CH3.

[0075] In some embodiments of Formula (I), (I’), and (II), Group A is a bicyclic heteroaryl having the structure: or , wherein X1, X2, X3, and X4are each independently CR5or N, provided that no more than two of X1, X2, X3, and X4are N. In someembodiments, Group A is or . In some embodiments, Group A is . In some embodiments, Group A is . In some embodiments, Group A is selected from the group consisting of: , wherein R5ais each independently selected from the group consisting of halogen, -CN, - NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, - OR7, -S(O)xR7, -NR7R8, -C(O)R7, -OC(O)R7, -C(O)OR7, -NR7C(O)R8, -C(O)NR7R8, - NR7C(O)OR8, -OC(O)NR7R8, -NR7SO2R8, and -SO2NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted by one or more R9. In some embodiments, Group A is selected from the group consisting of:, wherein R is each independently selected from the group consisting of halogen, -CN, - NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, - OR7, -S(O)xR7, -NR7R8, -C(O)R7, -OC(O)R7, -C(O)OR7, -NR7C(O)R8, -C(O)NR7R8, - NR7C(O)OR8, -OC(O)NR7R8, -NR7SO2R8, and -SO2NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted by one or more R9. In some embodiments, Group A is or . In some embodiments, Group A is . In some embodiments, Group A is .

[0076] In some embodiments of Formula (I), (I’), and (II), Group A is -N(C1-4alkyl)phenyl optionally substituted with one, two, or three R5substituents. In someembodiments, Group A is -N(C1-4alkyl)phenyl optionally substituted with one or two R5substituents. In some embodiments, Group A is -N(C1-4alkyl)phenyl optionally substituted with one R5substituent.

[0077] In some embodiments of Formula (I), (I’), and (II), Group A is -N(C1-2alkyl)phenyl optionally substituted with one, two, or three R5substituents. In some embodiments, Group A is -N(C1-2alkyl)phenyl optionally substituted with one or two R5substituents. In some embodiments, Group A is -N(C1-2alkyl)phenyl optionally substituted with one R5substituent.

[0078] In some embodiments of Formula (I), (I’), and (II), Group A is -N(C1-4alkyl)heteroaryl optionally substituted with one, two, or three R5substituents. In some embodiments, Group A is -N(C1-4alkyl)heteroaryl optionally substituted with one or two R5substituents. In some embodiments, Group A is -N(C1-4alkyl)heteroaryl optionally substituted with one R5substituent.

[0079] In some embodiments of Formula (I), (I’), and (II), Group A is -N(C1-4alkyl)(5-6 membered heteroaryl) optionally substituted with one, two, or three R5substituents. In some embodiments, Group A is -N(C1-4alkyl)(5-6 membered heteroaryl) optionally substituted with one or two R5substituents. In some embodiments, Group A is - N(C1-4alkyl)(5-6 membered heteroaryl) optionally substituted with one R5substituent.

[0080] In some embodiments of Formula (I), (I’), and (II), Group A is -N(C1-2alkyl)(5-6 membered heteroaryl) optionally substituted with one, two, or three R5substituents. In some embodiments, Group A is -N(C1-2alkyl)(5-6 membered heteroaryl) optionally substituted with one or two R5substituents. In some embodiments, Group A is - N(C1-2alkyl)(5-6 membered heteroaryl) optionally substituted with one R5substituent.

[0081] In some embodiments of Formula (I), Group A is naphthyl optionally substituted with one, two, or three R5substituents. In some embodiments, Group A is naphthyl optionally substituted with one or two R5substituents. In some embodiments, Group A is naphthyl optionally substituted with one R5substituent.

[0082] In some embodiments of Formula (I), (I’), and (II), X is -C(=O)NR3-. In other embodiments, X is -NR3C(=O)-.

[0083] In some embodiments of Formula (I), (I’), and (II), L is bond. In other embodiments, L is C1-4alkylene optionally substituted by one or more fluorine or deuterium. In some embodiments, L is C1-2alkylene optionally substituted by one or more fluorine or deuterium. In some embodiments, L is methylene optionally substituted by one or twofluorine or deuterium. In some embodiments, L is C1-2alkylene optionally substituted by one or more deuterium. In some embodiments, L is methylene optionally substituted by one or two deuterium.

[0084] In some embodiments, provided herein are compounds of Formula (I-A):(I-A), or a pharmaceutically acceptable salt thereof, wherein L is a bond or C1-4alkylene optionally substituted by one or more fluorine or deuterium; Y1, Y2, Y3, and Y4are each independently CR4or N; R1and R2are each independently selected from the group consisting of H, deuterium, C1-4alkyl, C3-6cycloalkyl, and halogen, or R1and R2together with the carbon to which the R1and R2are attached form C3-6cycloalkyl; R3is selected from the group consisting of H, C1-6alkyl, and C3-6cycloalkyl, wherein the C1-6alkyl or C3-6cycloalkyl is optionally substituted by one or more fluorine; X1, X2, X3, and X4are each independently CR5or N, provided that no more than two of X1, X2, X3, and X4are N; Group C is aryl or heteroaryl; R4is each independently selected from the group consisting of H, halogen, - CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -OR7, -S(O)xR7, -NR7R8, -C(O)R7, -OC(O)R7, -C(O)OR7, -NR7C(O)R8, - C(O)NR7R8, -NR7C(O)OR8, -OC(O)NR7R8, -NR7SO2R8, and -SO2NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted by one or more R9; R5and R6are each independently selected from the group consisting of H, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -OR7, -S(O)xR7, -NR7R8, -C(O)R7, -OC(O)R7, -C(O)OR7, - NR7C(O)R8, -C(O)NR7R8, -NR7C(O)OR8, -OC(O)NR7R8, -NR7SO2R8, and -SO2NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted by one or more R9; R7and R8are each independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl, wherein the C1-6alkyl and C1-6haloalkyl are optionally substituted by one or more R10; R9and R10are each independently selected from the group consisting of halo, -CN, -OR11, -S(O)xR11, -NR11R12, C(O)R11, -OC(O)R11, -C(O)OR11, -NR11C(O)R12, and -C(O)NR11R12; R11and R12are each independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl; x is 0, 1, or 2; and p is 0, 1, 2, or 3.

[0085] In some embodiments, provided herein are compounds of Formula (II-A): or a pharmaceutically accepta e sa t t ereo , w ere n L is a bond or C1-4alkylene optionally substituted by one or more fluorine or deuterium; Y1, Y2, Y3, and Y4are each independently CR4or N; R1and R2are each independently selected from the group consisting of H, deuterium, C1-4alkyl, C3-6cycloalkyl, and halogen, or R1and R2together with the carbon to which the R1and R2are attached form C3-6cycloalkyl; R3is selected from the group consisting of H, C1-6alkyl, and C3-6cycloalkyl, wherein the C1-6alkyl or C3-6cycloalkyl is optionally substituted by one or more fluorine; X1, X2, X3, and X4are each independently CR5or N, provided that no more than two of X1, X2, X3, and X4are N; Group C is aryl or heteroaryl;R4is each independently selected from the group consisting of H, halogen, - CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -OR7, -S(O)xR7, -NR7R8, -C(O)R7, -OC(O)R7, -C(O)OR7, -NR7C(O)R8, - C(O)NR7R8, -NR7C(O)OR8, -OC(O)NR7R8, -NR7SO2R8, and -SO2NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted by one or more R9; R5and R6are each independently selected from the group consisting of H, deuterium, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -OR7, -S(O)xR7, -NR7R8, -C(O)R7, -OC(O)R7, - C(O)OR7, -NR7C(O)R8, -C(O)NR7R8, -NR7C(O)OR8, -OC(O)NR7R8, -NR7SO2R8, and -SO2NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted by one or more R9; R7and R8are each independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl, wherein the C1-6alkyl and C1-6haloalkyl are optionally substituted by one or more R10; R9and R10are each independently selected from the group consisting of halo, deuterium, -CN, -OR11, -S(O)xR11, -NR11R12, C(O)R11, -OC(O)R11, -C(O)OR11, - NR11C(O)R12, and -C(O)NR11R12; R11and R12are each independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl; x is 0, 1, or 2; and p is 0, 1, 2, or 3.

[0086] In some embodiments of Formula (I-A) and (II-A), L is bond. In other embodiments, L is C1-4alkylene optionally substituted by one or more fluorine or deuterium. In some embodiments, L is C1-2alkylene optionally substituted by one or more fluorine or deuterium. In some embodiments, L is methylene optionally substituted by one or two fluorine or deuterium. In some embodiments, L is C1-2alkylene optionally substituted by one or more deuterium. In some embodiments, L is methylene optionally substituted by one or two deuterium.

[0087] In some embodiments, provided herein are compounds of Formula (I-B):(I-B), or a pharmaceutically acceptable salt thereof, wherein R’ and R’’ are each independently selected from the group consisting of H, fluorine, and deuterium; Y1, Y2, Y3, and Y4are each independently CR4or N; R1and R2are each independently selected from the group consisting of H, deuterium, C1-4alkyl, C3-6cycloalkyl, and halogen, or R1and R2together with the carbon to which the R1and R2are attached form C3-6cycloalkyl; R3is selected from the group consisting of H, C1-6alkyl, and C3-6cycloalkyl, wherein the C1-6alkyl or C3-6cycloalkyl is optionally substituted by one or more fluorine; X1, X2, X3, and X4are each independently CR5or N, provided that no more than two of X1, X2, X3, and X4are N; Group C is aryl or heteroaryl; R4is each independently selected from the group consisting of H, halogen, - CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -OR7, -S(O)xR7, -NR7R8, -C(O)R7, -OC(O)R7, -C(O)OR7, -NR7C(O)R8, - C(O)NR7R8, -NR7C(O)OR8, -OC(O)NR7R8, -NR7SO2R8, and -SO2NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted by one or more R9; R5and R6are each independently selected from the group consisting of H, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -OR7, -S(O)xR7, -NR7R8, -C(O)R7, -OC(O)R7, -C(O)OR7, - NR7C(O)R8, -C(O)NR7R8, -NR7C(O)OR8, -OC(O)NR7R8, -NR7SO2R8, and - SO2NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted by one or more R9;R7and R8are each independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl, wherein the C1-6alkyl and C1-6haloalkyl are optionally substituted by one or more R10; R9and R10are each independently selected from the group consisting of halo, -CN, -OR11, -S(O)xR11, -NR11R12, C(O)R11, -OC(O)R11, -C(O)OR11, -NR11C(O)R12, and -C(O)NR11R12; R11and R12are each independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl; x is 0, 1, or 2; and p is 0, 1, 2, or 3.

[0088] In some embodiments, provided herein are compounds of Formula (II-B): or a pharmaceutically acceptable salt thereof, wherein R’ and R’’ are each independently selected from the group consisting of H, fluorine, and deuterium; Y1, Y2, Y3, and Y4are each independently CR4or N; R1and R2are each independently selected from the group consisting of H, deuterium, C1-4alkyl, C3-6cycloalkyl, and halogen, or R1and R2together with the carbon to which the R1and R2are attached form C3-6cycloalkyl; R3is selected from the group consisting of H, C1-6alkyl, and C3-6cycloalkyl, wherein the C1-6alkyl or C3-6cycloalkyl is optionally substituted by one or more fluorine; X1, X2, X3, and X4are each independently CR5or N, provided that no more than two of X1, X2, X3, and X4are N; Group C is aryl or heteroaryl; R4is each independently selected from the group consisting of H, halogen, - CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -S(O)xR7, -NR7R8, -C(O)R7, -OC(O)R7, -C(O)OR7, -C(O)NR7R8, -NR7C(O)OR8, -OC(O)NR7R8, -NR7SO2R8, and -SO2NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted by one or more R9; R5and R6are each independently selected from the group consisting of H, deuterium, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -S(O)xR7, -NR7R8, -C(O)R7, -OC(O)R7, - C(O)OR7, -C(O)NR7R8, -NR7C(O)OR8, -OC(O)NR7R8, -NR7SO2R8, and -SO2NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted by one or more R9; R7and R8are each independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl, wherein the C1-6alkyl and C1-6haloalkyl are optionally substituted by one or more R10; R9and R10are each independently selected from the group consisting of halo, deuterium, -CN, -OR11, -S(O)xR11, -NR11R12, C(O)R11, -OC(O)R11, -C(O)OR11, - NR11C(O)R12, and -C(O)NR11R12; R11and R12are each independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl; x is 0, 1, or 2; and p is 0, 1, 2, or 3.

[0089] In some embodiments of Formula (I-B) and (II-B), R’ and R’’ are each independently selected from the group consisting of H and deuterium. In some embodiments, R’ and R’’ are each H. In some embodiments, R’ and R’’ are each fluorine. In some embodiments, R’ and R’’ are each deuterium.

[0090] In some embodiments, provided herein are compounds of Formula (I-C): (I-C), or a pharmaceutically acceptable salt thereof, wherein X is -C(=O)NR3- or -NR3C(=O)-;R’ and R’’ are each independently selected from the group consisting of H, fluorine, and deuterium; Y1, Y2, Y3, and Y4are each independently CR4or N; R1and R2are each independently selected from the group consisting of H, deuterium, C1-4alkyl, C3-6cycloalkyl, and halogen, or R1and R2together with the carbon to which the R1and R2are attached form C3-6cycloalkyl; R3is selected from the group consisting of H, C1-6alkyl, and C3-6cycloalkyl, wherein the C1-6alkyl or C3-6cycloalkyl is optionally substituted by one or more fluorine; R’’’ is C1-4alkyl; Group D is phenyl or heteroaryl, each optionally substituted with one, two, or three R5substituents; Group C is aryl or heteroaryl; R4is each independently selected from the group consisting of H, halogen, - CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -OR7, -S(O)xR7, -NR7R8, -C(O)R7, -OC(O)R7, -C(O)OR7, -NR7C(O)R8, - C(O)NR7R8, -NR7C(O)OR8, -OC(O)NR7R8, -NR7SO2R8, and -SO2NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted by one or more R9; R5and R6are each independently selected from the group consisting of H, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -OR7, -S(O)xR7, -NR7R8, -C(O)R7, -OC(O)R7, -C(O)OR7, - NR7C(O)R8, -C(O)NR7R8, -NR7C(O)OR8, -OC(O)NR7R8, -NR7SO2R8, and - SO2NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted by one or more R9; R7and R8are each independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl, wherein the C1-6alkyl and C1-6haloalkyl are optionally substituted by one or more R10; R9and R10are each independently selected from the group consisting of halo, -CN, -OR11, -S(O)xR11, -NR11R12, C(O)R11, -OC(O)R11, -C(O)OR11, -NR11C(O)R12, and -C(O)NR11R12; R11and R12are each independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl;x is 0, 1, or 2; and p is 0, 1, 2, or 3.

[0091] In some embodiments, provided herein are compounds of Formula (II-C):or a pharmaceutically acceptable salt thereof, wherein X is -C(=O)NR3- or -NR3C(=O)-; R’ and R’’ are each independently selected from the group consisting of H, fluorine, and deuterium; Y1, Y2, Y3, and Y4are each independently CR4or N; R1and R2are each independently selected from the group consisting of H, deuterium, C1-4alkyl, C3-6cycloalkyl, and halogen, or R1and R2together with the carbon to which the R1and R2are attached form C3-6cycloalkyl; R3is selected from the group consisting of H, C1-6alkyl, and C3-6cycloalkyl, wherein the C1-6alkyl or C3-6cycloalkyl is optionally substituted by one or more fluorine; R’’’ is C1-4alkyl; Group D is phenyl or heteroaryl, each optionally substituted with one, two, or three R5substituents; Group C is aryl or heteroaryl; R4is each independently selected from the group consisting of H, halogen, - CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -OR7, -S(O)xR7, -NR7R8, -C(O)R7, -OC(O)R7, -C(O)OR7, -NR7C(O)R8, - C(O)NR7R8, -NR7C(O)OR8, -OC(O)NR7R8, -NR7SO2R8, and -SO2NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted by one or more R9; R5and R6are each independently selected from the group consisting of H, deuterium, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -OR7, -S(O)xR7, -NR7R8, -C(O)R7, -OC(O)R7, -C(O)OR7, -NR7C(O)R8, -C(O)NR7R8, -NR7C(O)OR8, -OC(O)NR7R8, -NR7SO2R8, and -SO2NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted by one or more R9; R7and R8are each independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl, wherein the C1-6alkyl and C1-6haloalkyl are optionally substituted by one or more R10; R9and R10are each independently selected from the group consisting of halo, deuterium, -CN, -OR11, -S(O)xR11, -NR11R12, C(O)R11, -OC(O)R11, -C(O)OR11, - NR11C(O)R12, and -C(O)NR11R12; R11and R12are each independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl; x is 0, 1, or 2; and p is 0, 1, 2, or 3.

[0092] In some embodiments of Formula (I-C) and (II-C), X is -C(=O)NR3-. In other embodiments, X is -NR3C(=O)-.

[0093] In some embodiments of Formula (I-C) and (II-C), R’ and R’’ are each independently selected from the group consisting of H and deuterium. In some embodiments, R’ and R’’ are each H. In some embodiments, R’ and R’’ are each fluorine. In some embodiments, R’ and R’’ are each deuterium.

[0094] In some embodiments, provided herein are compounds of Formula (I-D):- , or a pharmaceutically acceptable salt thereof, wherein X is -C(=O)NR3- or -NR3C(=O)-; L is a bond or C1-4alkylene optionally substituted by one or more fluorine or deuterium; Y1, Y2, Y3, and Y4are each independently CR4or N;R1and R2are each independently selected from the group consisting of H, deuterium, C1-4alkyl, C3-6cycloalkyl, and halogen, or R1and R2together with the carbon to which the R1and R2are attached form C3-6cycloalkyl; R3is selected from the group consisting of H, C1-6alkyl, and C3-6cycloalkyl, wherein the C1-6alkyl or C3-6cycloalkyl is optionally substituted by one or more fluorine; Group A is naphthyl optionally substituted with one, two, or three R5substituents; Group C is aryl or heteroaryl; R4is each independently selected from the group consisting of H, halogen, - CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -OR7, -S(O)xR7, -NR7R8, -C(O)R7, -OC(O)R7, -C(O)OR7, -NR7C(O)R8, - C(O)NR7R8, -NR7C(O)OR8, -OC(O)NR7R8, -NR7SO2R8, and -SO2NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted by one or more R9; R5and R6are each independently selected from the group consisting of H, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -OR7, -S(O)xR7, -NR7R8, -C(O)R7, -OC(O)R7, -C(O)OR7, - NR7C(O)R8, -C(O)NR7R8, -NR7C(O)OR8, -OC(O)NR7R8, -NR7SO2R8, and - SO2NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted by one or more R9; R7and R8are each independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl, wherein the C1-6alkyl and C1-6haloalkyl are optionally substituted by one or more R10; R9and R10are each independently selected from the group consisting of halo, -CN, -OR11, -S(O)xR11, -NR11R12, C(O)R11, -OC(O)R11, -C(O)OR11, -NR11C(O)R12, and -C(O)NR11R12; R11and R12are each independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl; x is 0, 1, or 2; and p is 0, 1, 2, or 3.

[0095] In some embodiments, provided herein are compounds of Formula (II-D):(II-D), or a pharmaceutically acceptable salt thereof, wherein X is -C(=O)NR3- or -NR3C(=O)-; L is a bond or C1-4alkylene optionally substituted by one or more fluorine or deuterium; Y1, Y2, Y3, and Y4are each independently CR4or N; R1and R2are each independently selected from the group consisting of H, deuterium, C1-4alkyl, C3-6cycloalkyl, and halogen, or R1and R2together with the carbon to which the R1and R2are attached form C3-6cycloalkyl; R3is selected from the group consisting of H, C1-6alkyl, and C3-6cycloalkyl, wherein the C1-6alkyl or C3-6cycloalkyl is optionally substituted by one or more fluorine; Group A is naphthyl optionally substituted with one, two, or three R5substituents; Group C is aryl or heteroaryl; R4is each independently selected from the group consisting of H, halogen, - CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -OR7, -S(O)xR7, -NR7R8, -C(O)R7, -OC(O)R7, -C(O)OR7, -NR7C(O)R8, - C(O)NR7R8, -NR7C(O)OR8, -OC(O)NR7R8, -NR7SO2R8, and -SO2NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted by one or more R9; R5and R6are each independently selected from the group consisting of H, deuterium, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -OR7, -S(O)xR7, -NR7R8, -C(O)R7, -OC(O)R7, - C(O)OR7, -NR7C(O)R8, -C(O)NR7R8, -NR7C(O)OR8, -OC(O)NR7R8, -NR7SO2R8, and -SO2NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted by one or more R9;R7and R8are each independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl, wherein the C1-6alkyl and C1-6haloalkyl are optionally substituted by one or more R10; R9and R10are each independently selected from the group consisting of halo, deuterium, -CN, -OR11, -S(O)xR11, -NR11R12, C(O)R11, -OC(O)R11, -C(O)OR11, - NR11C(O)R12, and -C(O)NR11R12; R11and R12are each independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl; x is 0, 1, or 2; and p is 0, 1, 2, or 3.

[0096] In some embodiments of Formula (I), (I’), (II), (I-A), (II-A), (I-B), (II-B), (I- C), (II-C), (I-D), and (II-D), Y1, Y2, Y3, and Y4are each CR4. In other embodiments, one or two of Y1, Y2, Y3, and Y4are N and the remaining Y1, Y2, Y3, and Y4are CR4. In some embodiments, one of Y1, Y2, Y3, and Y4are N and the remaining Y1, Y2, Y3, and Y4are CR4.

[0097] In some embodiments of Formula (I), (I’), (II), (I-A), (II-A), (I-B), (II-B), (I- C), (II-C), (I-D), and (II-D), Y1, Y2, Y3, and Y4are each CH. In other embodiments, one or two of Y1, Y2, Y3, and Y4are N and the remaining Y1, Y2, Y3, and Y4are CH. In some embodiments, one of Y1, Y2, Y3, and Y4are N and the remaining Y1, Y2, Y3, and Y4are CH.

[0098] In some embodiments of Formula (I), (I’), (II), (I-A), (II-A), (I-B), (II-B), (I- C), (II-C), (I-D), and (II-D), Y1is CR4. In other embodiments, Y1is N.

[0099] In some embodiments of Formula (I), (I’), (II), (I-A), (II-A), (I-B), (II-B), (I- C), (II-C), (I-D), and (II-D), Y2is CR4. In other embodiments, Y2is N. [000100] In some embodiments of Formula (I), (I’), (II), (I-A), (II-A), (I-B), (II-B), (I- C), (II-C), (I-D), and (II-D), Y3is CR4. In other embodiments, Y3is N. [000101] In some embodiments of Formula (I), (I’), (II), (I-A), (II-A), (I-B), (II-B), (I- C), (II-C), (I-D), and (II-D), Y4is CR4. In other embodiments, Y4is N. [000102] In some embodiments of Formula (I), (I’), (II), (I-A), (II-A), (I-B), (II-B), (I- C), (II-C), (I-D), and (II-D), R4is each independently selected from the group consisting of H, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -OR7, -S(O)xR7, and -NR7R8. In some embodiments, R4is each independently selected from the group consisting of H, halogen, -CN, -C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, and C3-6cycloalkyl. In some embodiments, R4is each independently selected from the group consisting of H, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C3-6cycloalkyl, and -NR7R8. In some embodiments, R4is each independently selected from the group consisting of H, halogen, -C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, and C3-6cycloalkyl. In some embodiments, R4is each independently selected from the group consisting of H, halogen, C1-6alkyl, C1-6haloalkyl, -O(C1-6alkyl), and C3-6cycloalkyl. In some embodiments, R4is each independently selected from the group consisting of H, halogen, -C1-4alkyl, C1-4haloalkyl, -O(C1-4alkyl), and C3-4cycloalkyl. In some embodiments, R4is each independently selected from the group consisting of H, halogen, and C1-6alkyl. In some embodiments, R4is each independently selected from the group consisting of H, halogen, and C1-4alkyl. In some embodiments, R4is each independently selected from the group consisting of H, F, methyl, ethyl, isopropyl, CF3, CF2H, -OCH3, and cyclopropyl. [000103] In some embodiments of Formula (I), (I’), (II), (I-A), (II-A), (I-B), (II-B), (I- C), (II-C), (I-D), and (II-D), R1and R2are each independently selected from the group consisting of H, deuterium, and C1-4alkyl, and halogen. In some embodiments, R1and R2are each independently selected from the group consisting of H, deuterium, and C1-2alkyl. In some embodiments, R1and R2are each independently selected from the group consisting of H, deuterium, and methyl. In some embodiments, R1and R2together with the carbon to which the R1and R2are attached form C3-6cycloalkyl. In some embodiments, R1and R2together with the carbon to which the R1and R2are attached form C3-4cycloalkyl. [000104] In some embodiments of Formula (I), (I’), (II), (I-A), (II-A), (I-B), (II-B), (I- C), (II-C), (I-D), and (II-D), R3is selected from the group consisting of H, C1-4alkyl, and C3-4cycloalkyl, wherein the C1-4alkyl or C3-4cycloalkyl is optionally substituted by one or more fluorine. In some embodiments, R3is H or C1-2alkyl. In some embodiments, R3is H or methyl. [000105] In some embodiments of Formula (I), (I’), (II), (I-A), (II-A), (I-B), (II-B), (I- C), (II-C), (I-D), and (II-D), Group C is phenyl or 5-6 membered heteroaryl. In some embodiments, Group C is selected from the group consisting of phenyl, pyrazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, triazolyl, and pyridyl. In some embodiments, Group C is selected from the group consisting of phenyl, pyrazolyl, furanyl, thiophenyl, thiazolyl, triazolyl, and pyridyl. In some embodiments, Group C is selected from the group consisting of phenyl, pyrazolyl, and pyridyl. [000106] In some embodiments of Formula (I), (I’), (II), (I-A), (II-A), (I-B), (II-B), (I- C), (II-C), (I-D), and (II-D), R5is each independently selected from the group consisting ofH, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, - OR7, -S(O)xR7, and -NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted by one or more R9. In some embodiments, R5is each independently selected from the group consisting of H, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -OR7, -and -NR7R8, wherein the C1-6alkyl and C1-6haloalkyl are optionally substituted by one or two R9. In some embodiments, R5is each independently selected from the group consisting of H, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C3-6cycloalkyl, and -NR7R8. In some embodiments, R5is each independently selected from the group consisting of H, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, OR7, and -NR7R8. In some embodiments, R5is each independently selected from the group consisting of halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, OR7, and -NR7R8. [000107] In some embodiments of Formula (I), (I’), (II), (I-A), (II-A), (I-B), (II-B), (I- C), (II-C), (I-D), and (II-D), R5is each independently selected from the group consisting of H, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C3-6cycloalkyl, and - NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, and C1-6heteroalkyl are optionally substituted by one or more R9. In some embodiments, R5is each independently selected from the group consisting of H, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C3-6cycloalkyl, and -NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, and C1-6heteroalkyl are optionally substituted by one, two, or three R9. In some embodiments, R5is each independently selected from the group consisting of H, F, Cl, Br, -CN, -NO2, C1-2alkyl, C1-2haloalkyl, C3-4cycloalkyl, O(C1-2alkyl), O(C1-2haloalkyl), and -NH2. In some embodiments, R5is each independently selected from the group consisting of F, Cl, Br, -CN, -NO2, C1-2alkyl, C1-2haloalkyl, C3-4cycloalkyl, O(C1-2alkyl), O(C1-2haloalkyl), and -NH2. In some embodiments, R5is each independently selected from the group consisting of H, F, Cl, Br, - CN, -NO2, methyl, CF3, cyclopropyl, OCH3, OCF3, and -NH2. In some embodiments, R5is each independently selected from the group consisting of F, Cl, Br, -CN, -NO2, methyl, CF3, cyclopropyl, OCH3, OCF3, and -NH2. [000108] In some embodiments of Formula (II), (II-A), (II-B), (II-C), and (II-D), R5is each independently selected from the group consisting of H, deuterium, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C3-6cycloalkyl, and -NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, and C1-6heteroalkyl are optionally substituted by one or more R9. In some embodiments, R5is each independently selected from the group consisting of H,deuterium, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C3-6cycloalkyl, - and -NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, and C1-6heteroalkyl are optionally substituted by one, two, or three R9. In some embodiments, R5is each independently selected from the group consisting of H, deuterium, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C3-6cycloalkyl, and -NR7R8. In some embodiments, R5is each independently selected from the group consisting of H, deuterium, F, Cl, Br, -CN, -NO2, C1-2alkyl, C1-2haloalkyl, C3-4cycloalkyl, O(C1-2alkyl), O(C1-2haloalkyl), and -NH2. In some embodiments, R5is each independently selected from the group consisting of H, deuterium, F, Cl, Br, -CN, - NO2, methyl, CF3, cyclopropyl, OCH3, OCF3, and -NH2. [000109] In some embodiments of Formula (I), (I’), (II), (I-A), (II-A), (I-B), (II-B), (I- C), (II-C), (I-D), and (II-D), p is 0, 1, or 2. In some embodiments, p is 0 or 1. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. [000110] In some embodiments of Formula (I), (I’), (II), (I-A), (II-A), (I-B), (II-B), (I- C), (II-C), (I-D), and (II-D), R6is each independently selected from the group consisting of H, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, - OR7, -S(O)xR7, and -NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted by one or more R9. In some embodiments, R6is each independently selected from the group consisting of H, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -OR7, -and -NR7R8, wherein the C1-6alkyl and C1-6haloalkyl are optionally substituted by one or two R9. In some embodiments, R6is each independently selected from the group consisting of H, halogen, C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl, wherein the C1-6alkyl and C1-6haloalkyl are optionally substituted by one or two R9. In some embodiments, R6is each independently selected from the group consisting of halogen, -C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl. In some embodiments, R6is each independently selected from the group consisting of F and methyl. [000111] In some embodiments of Formula (I), (I’), (II), (I-A), (II-A), (I-B), (II-B), (I- C), (II-C), (I-D), and (II-D), R7and R8are each independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl, wherein the C1-6alkyl and C1-6haloalkyl are optionally substituted by one R10. In some embodiments, R7and R8are each independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R7and R8are each independently selected from the group consisting of H and C1-6alkyl. Insome embodiments, R7and R8are each independently selected from the group consisting of H and methyl. [000112] In some embodiments of Formula (I), (I’), (II), (I-A), (II-A), (I-B), (II-B), (I- C), (II-C), (I-D), and (II-D), R9and R10are each independently selected from the group consisting of halo, -CN, -OR11, -S(O)xR11, and -NR11R12. [000113] In some embodiments of Formula (II), (II-A), (II-B), (II-C), and (II-D), R9and R10are each independently selected from the group consisting of halo, deuterium, -CN, - OR11, -S(O)xR11, and -NR11R12. In some embodiments, R9and R10are each independently selected from the group consisting of halo and deuterium. [000114] In some embodiments of Formula (I), (I’), (II), (I-A), (II-A), (I-B), (II-B), (I- C), (II-C), (I-D), and (II-D), R11and R12are each independently selected from the group consisting of H and C1-6alkyl. In some embodiments, R11and R12are each independently selected from the group consisting of H and methyl. [000115] In some embodiments, provided herein are compounds of Formula (III): or a pharmaceutically acceptablesa t t ereo , w ere n X is -C(=O)NR3- or -NR3C(=O)-; L is a bond or C1-2alkylene optionally substituted by one or more deuterium; Y1, Y2, Y3, and Y4are each independently CR4or N; R1and R2are each independently selected from the group consisting of H, deuterium, C1-4alkyl, and halogen; R3is selected from the group consisting of H and C1-6alkyl; Group A is bicyclic heteroaryl having the structure:wherein X1, X2, X3, and X4are each independently CR5or N, provided that no more than two of X1, X2, X3, and X4are N; Group C is phenyl or 5-6 membered heteroaryl; R4is each independently selected from the group consisting of H, halogen, - CN, -NO2, C1-6alkyl, C1-6haloalkyl, -O(C1-6alkyl), C3-6cycloalkyl, and -NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, and -O(C1-6alkyl) are optionally substituted by one or more R9; R5is each independently selected from the group consisting of H, deuterium, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, -O(C1-6alkyl), C3-6cycloalkyl, and - NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, and -O(C1-6alkyl) are optionally substituted by one or more R9; R6is each independently selected from the group consisting of H, deuterium, halogen, C1-6alkyl, C1-6haloalkyl, -O(C1-6alkyl), and C3-6cycloalkyl, wherein the C1-6alkyl, C1-6haloalkyl, and -O(C1-6alkyl) are optionally substituted by one or more R9; R7and R8are each independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl; R9is each independently selected from the group consisting of halo and deuterium; and p is 0, 1, 2, or 3. [000116] In some embodiments, provided herein are compounds of Formula (IV): (IV), or a pharmaceutically acceptable salt thereof, wherein X is -C(=O)NR3- or -NR3C(=O)-; L is C1-2alkylene optionally substituted by one or more deuterium; Y1, Y2, Y3, and Y4are each independently CR4or N; R1and R2are each independently selected from the group consisting of H, deuterium, C1-4alkyl, and halogen; R3is selected from the group consisting of H and C1-6alkyl;Group A is -N(C1-4alkyl)phenyl optionally substituted with one, two, or three R5substituents; Group C is phenyl or 5-6 membered heteroaryl; R4is each independently selected from the group consisting of H, halogen, - CN, -NO2, C1-6alkyl, C1-6haloalkyl, -O(C1-6alkyl), C3-6cycloalkyl, and -NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, and -O(C1-6alkyl) are optionally substituted by one or more R9; R5is each independently selected from the group consisting of H, deuterium, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, -O(C1-6alkyl), C3-6cycloalkyl, and - NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, and -O(C1-6alkyl) are optionally substituted by one or more R9; R6is each independently selected from the group consisting of H, deuterium, halogen, C1-6alkyl, C1-6haloalkyl, -O(C1-6alkyl), and C3-6cycloalkyl, wherein the C1- 6 alkyl, C1-6haloalkyl, and -O(C1-6alkyl) are optionally substituted by one or more R9; R7and R8are each independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl; R9is each independently selected from the group consisting of halo and deuterium; and p is 0, 1, 2, or 3. [000117] In some embodiments of Formula (III), Group A is or . In some embodiments, Group A is . In some embodiments, Group A is . In some embodiments, Group A is selected from the group consisting of:, wherein R5ais each independently selected from the group consisting of deuterium, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, -O(C1-6alkyl), C3-6cycloalkyl, and -NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, and -O(C1-6alkyl) are optionally substituted by one or more R9. In some embodiments, Group A is selected from the group consisting of:, wherein R5ais each independently selected from the group consisting of deuterium, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, -O(C1-6alkyl), C3-6cycloalkyl, and -NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, and -O(C1-6alkyl) are optionally substituted by one or more R9. Insome embodiments, Group A is or . In some embodiments, Group A is . In some embodiments, Group A is . [000118] In some embodiments of Formula (IV), Group A is -N(C1-4alkyl)phenyl optionally substituted with one or two R5substituents. In some embodiments, Group A is - N(C1-4alkyl)phenyl optionally substituted with one R5substituent. [000119] In some embodiments of Formula (IV), Group A is -N(C1-2alkyl)phenyl optionally substituted with one, two, or three R5substituents. In some embodiments, Group A is -N(C1-2alkyl)phenyl optionally substituted with one or two R5substituents. In some embodiments, Group A is -N(C1-2alkyl)phenyl optionally substituted with one R5substituent. [000120] In some embodiments of Formula (III) and (IV), X is -C(=O)NR3-. In other embodiments, X is -NR3C(=O)-. [000121] In some embodiments of Formula (III), L is bond. In other embodiments, L is C1-2alkylene optionally substituted by one or more deuterium. In some embodiments, L is methylene optionally substituted by one or two deuterium. [000122] In some embodiments of Formula (IV), L is C1-2alkylene optionally substituted by one or more deuterium. In some embodiments, L is methylene optionally substituted by one or two deuterium. [000123] In some embodiments of Formula (III) and (IV), Y1, Y2, Y3, and Y4are each CR4. In other embodiments, one or two of Y1, Y2, Y3, and Y4are N and the remaining Y1, Y2, Y3, and Y4are CR4. In some embodiments, one of Y1, Y2, Y3, and Y4are N and the remaining Y1, Y2, Y3, and Y4are CR4. [000124] In some embodiments of Formula (III) and (IV), Y1, Y2, Y3, and Y4are each CH. In other embodiments, one or two of Y1, Y2, Y3, and Y4are N and the remaining Y1, Y2, Y3, and Y4are CH. In some embodiments, one of Y1, Y2, Y3, and Y4are N and the remaining Y1, Y2, Y3, and Y4are CH. [000125] In some embodiments of Formula (III) and (IV), Y1is CR4. In other embodiments, Y1is N.[000126] In some embodiments of Formula (III) and (IV), Y2is CR4. In other embodiments, Y2is N. [000127] In some embodiments of Formula (III) and (IV), Y3is CR4. In other embodiments, Y3is N. [000128] In some embodiments of Formula (III) and (IV), Y4is CR4. In other embodiments, Y4is N. [000129] In some embodiments of Formula (III) and (IV), R4is each independently selected from the group consisting of H, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, - O(C1-6alkyl), C3-6cycloalkyl, and -NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, and -O(C1-6alkyl) are optionally substituted by one, two, or three R9. In some embodiments, R4is each independently selected from the group consisting of H, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, -O(C1-6alkyl), and C3-6cycloalkyl. In some embodiments, R4is each independently selected from the group consisting of H, F, methyl, ethyl, isopropyl, CF3, CF2H, -OCH3, and cyclopropyl. [000130] In some embodiments of Formula (III) and (IV), R1and R2are each independently selected from the group consisting of H, deuterium, and C1-2alkyl, and halogen. In some embodiments, R1and R2are each independently selected from the group consisting of H, deuterium, and C1-2alkyl. In some embodiments, R1and R2are each independently selected from the group consisting of H, deuterium, and methyl. [000131] In some embodiments of Formula (III) and (IV), R3is H or C1-2alkyl. In some embodiments, R3is H or methyl. [000132] In some embodiments of Formula (III) and (IV), Group C is phenyl or 5-6 membered heteroaryl. In some embodiments, Group C is selected from the group consisting of phenyl, pyrazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, triazolyl, and pyridyl. In some embodiments, Group C is selected from the group consisting of phenyl, pyrazolyl, furanyl, thiophenyl, thiazolyl, triazolyl, and pyridyl. In some embodiments, Group C is selected from the group consisting of phenyl, pyrazolyl, and pyridyl. In some embodiments, Group C is pyrazolyl. In some embodiments, Group C is phenyl. In some embodiments, Group C is pyridyl. [000133] In some embodiments of Formula (III) and (IV), R5is each independently selected from the group consisting of H, deuterium, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, -O(C1-6alkyl), C3-6cycloalkyl, and -NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, and -O(C1-6alkyl) are optionally substituted by one, two, or three R9. In some embodimentsof Formula (III) and (IV), R5is each independently selected from the group consisting of H, deuterium, halogen, -CN, -NO2, C1-4alkyl, C1-4haloalkyl, -O(C1-4alkyl), C3-4cycloalkyl, and -NR7R8, wherein the C1-4alkyl, C1-4haloalkyl, and -O(C1-4alkyl) are optionally substituted by one, two, or three R9. In some embodiments, R5is each independently selected from the group consisting of H, deuterium, F, Cl, Br, -CN, -NO2, C1-2alkyl, C1-2haloalkyl, C3-4cycloalkyl, O(C1-2alkyl), and -NH2, wherein the C1-2alkyl, C1-2haloalkyl, and -O(C1-2alkyl) are optionally substituted by one, two, or three R9. In some embodiments, R5is each independently selected from the group consisting of H, deuterium, F, Cl, Br, -CN, -NO2, methyl, CF3, cyclopropyl, OCH3, OCF3, and -NH2. [000134] In some embodiments of Formula (III) and (IV), p is 0, 1, or 2. In some embodiments, p is 0 or 1. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. [000135] In some embodiments of Formula (III) and (IV), R6is H, deuterium, halogen, C1-6alkyl, C1-6haloalkyl, -O(C1-6alkyl), and C3-6cycloalkyl, wherein the C1-6alkyl, C1-6haloalkyl, and -O(C1-6alkyl) are optionally substituted by one, two, or three R9. In some embodiments, R6is H, deuterium, halogen, C1-4alkyl, C1-4haloalkyl, and C3-6cycloalkyl. In some embodiments, R6is each independently selected from the group consisting of F and methyl. [000136] In some embodiments of Formula (III) and (IV), R7and R8are each independently H or C1-6alkyl. In some embodiments, R7and R8are each independently H or methyl. In some embodiments, R7and R8are H. [000137] In some embodiments of Formula (III) and (IV), R9is each independently F or deuterium. [000138] In some embodiments, the compound is selected from Table 1, or a pharmaceutically acceptable salt thereof. Pharmaceutical Compositions [000139] Compounds provided in accordance with the present disclosure, in some embodiments, are administered in the form of pharmaceutical compositions. This disclosure therefore provides pharmaceutical compositions that comprise, as the active ingredient, one or more of the compounds described herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers. In some embodiments, the pharmaceutical compositions are administered in combination with other therapeutic agents.[000140] In some embodiments, provided herein are pharmaceutical compositions, comprising: a) a compound of Formula (I):(I), or a pharmaceutically acceptable salt thereof, wherein X is -C(=O)NR3- or -NR3C(=O)-; L is a bond or C1-4alkylene optionally substituted by one or more fluorine or deuterium; Y1, Y2, Y3, and Y4are each independently CR4or N; R1and R2are each independently selected from the group consisting of H, deuterium, C1-4alkyl, C3-6cycloalkyl, and halogen, or R1and R2together with the carbon to which the R1and R2are attached form C3-6cycloalkyl; R3is selected from the group consisting of H, C1-6alkyl, and C3-6cycloalkyl, wherein the C1-6alkyl or C3-6cycloalkyl is optionally substituted by one or more fluorine; Group A is selected from the group consisting of i) bicyclic heteroaryl having the structure: or ; wherein X1, X2, X3, and X4are each independently CR5or N, provided that no more than two of X1, X2, X3, and X4are N, ii) naphthyl optionally substituted with one, two, or three R5substituents, and iii) -N(C1-4alkyl)phenyl or -N(C1-4alkyl)heteroaryl, each optionally substituted with one, two, or three R5substituents; Group C is aryl or heteroaryl;R4is each independently selected from the group consisting of H, halogen, - CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -OR7, -S(O)xR7, -NR7R8, -C(O)R7, -OC(O)R7, -C(O)OR7, -NR7C(O)R8, - C(O)NR7R8, -NR7C(O)OR8, -OC(O)NR7R8, -NR7SO2R8, and -SO2NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted by one or more R9; R5and R6are each independently selected from the group consisting of H, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -OR7, -S(O)xR7, -NR7R8, -C(O)R7, -OC(O)R7, -C(O)OR7, - NR7C(O)R8, -C(O)NR7R8, -NR7C(O)OR8, -OC(O)NR7R8, -NR7SO2R8, and - SO2NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted by one or more R9; R7and R8are each independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl, wherein the C1-6alkyl and C1-6haloalkyl are optionally substituted by one or more R10; R9and R10are each independently selected from the group consisting of halo, -CN, -OR11, -S(O)xR11, -NR11R12, C(O)R11, -OC(O)R11, -C(O)OR11, -NR11C(O)R12, and -C(O)NR11R12; R11and R12are each independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl; x is 0, 1, or 2; and p is 0, 1, 2, or 3; provided that: i) when X is -C(=O)NR3-, R3is H or CH3, L is bond, Y1, Y2, Y3, and Y4are CH, Group C is phenyl, R1and R2are H, and p is 0, then Group A is not - N(CH3)phenyl optionally substituted with CH3; ii) when X is -NR3C(=O)-, R3is H or CH3, L is bond, Y1, Y3, and Y4are CH, Y2is CH or C-NH2, Group C is phenyl, R1and R2are H, p is 1, and Group A is , then R6is not -NHC(O)CH3; andiii) when X is -C(=O)NR3-, R3is H, L is -CH2-, Y1and Y2are CH, Y4is N, Y3is C-CF3, Group C is phenyl, R1is H, R2is CH3, p is 1, and Group A is , then R6is not CH3; and b) a pharmaceutically acceptable carrier. [000141] In some embodiments, provided herein are pharmaceutical compositions, comprising: a) a compound of Formula (I’):(I’), or a pharmaceutically acceptable salt thereof, wherein X is -C(=O)NR3- or -NR3C(=O)-; L is a bond or C1-4alkylene optionally substituted by one or more fluorine or deuterium; Y1, Y2, Y3, and Y4are each independently CR4or N; R1and R2are each independently selected from the group consisting of H, deuterium, C1-4alkyl, C3-6cycloalkyl, and halogen, or R1and R2together with the carbon to which the R1and R2are attached form C3-6cycloalkyl; R3is selected from the group consisting of H, C1-6alkyl, and C3-6cycloalkyl, wherein the C1-6alkyl or C3-6cycloalkyl is optionally substituted by one or more fluorine; Group A is i) bicyclic heteroaryl having the structure: or ;wherein X1, X2, X3, and X4are each independently CR5or N, provided that no more than two of X1, X2, X3, and X4are N, or ii) -N(C1-4alkyl)phenyl or -N(C1-4alkyl)heteroaryl, each optionally substituted with one, two, or three R5substituents; Group C is aryl or heteroaryl; R4is each independently selected from the group consisting of H, halogen, - CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -OR7, -S(O)xR7, -NR7R8, -C(O)R7, -OC(O)R7, -C(O)OR7, -NR7C(O)R8, - C(O)NR7R8, -NR7C(O)OR8, -OC(O)NR7R8, -NR7SO2R8, and -SO2NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted by one or more R9; R5and R6are each independently selected from the group consisting of H, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -OR7, -S(O)xR7, -NR7R8, -C(O)R7, -OC(O)R7, -C(O)OR7, - NR7C(O)R8, -C(O)NR7R8, -NR7C(O)OR8, -OC(O)NR7R8, -NR7SO2R8, and - SO2NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted by one or more R9; R7and R8are each independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl, wherein the C1-6alkyl and C1-6haloalkyl are optionally substituted by one or more R10; R9and R10are each independently selected from the group consisting of halo, -CN, -OR11, -S(O)xR11, -NR11R12, C(O)R11, -OC(O)R11, -C(O)OR11, -NR11C(O)R12, and -C(O)NR11R12; R11and R12are each independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl; x is 0, 1, or 2; and p is 0, 1, 2, or 3; provided that: i) when X is -C(=O)NR3-, R3is H or CH3, L is bond, Y1, Y2, Y3, and Y4are CH, Group C is phenyl, R1and R2are H, and p is 0, then Group A is not - N(CH3)phenyl optionally substituted with CH3;ii) when X is -NR3C(=O)-, R3is H or CH3, L is bond, Y1, Y3, and Y4are CH, Y2is CH or C-NH2, Group C is phenyl, R1and R2are H, p is 1, and Group A is , then R6is not -NHC(O)CH3; and iii) when X is -C(=O)NR3-, R3is H, L is -CH2-, Y1and Y2are CH, Y4is N, Y3is C-CF3, Group C is phenyl, R1is H, R2is CH3, p is 1, and Group A is, then R6is not CH3; and b) a pharmaceutically acceptable carrier. [000142] In some embodiments, provided herein are pharmaceutical compositions, comprising: a) a compound of Formula (II): or a pharmaceutically acceptablesa e eo , w e e X is -C(=O)NR3- or -NR3C(=O)-; L is a bond or C1-4alkylene optionally substituted by one or more fluorine or deuterium; Y1, Y2, Y3, and Y4are each independently CR4or N; R1and R2are each independently selected from the group consisting of H, deuterium, C1-4alkyl, C3-6cycloalkyl, and halogen, or R1and R2together with the carbon to which the R1and R2are attached form C3-6cycloalkyl; R3is selected from the group consisting of H, C1-6alkyl, and C3-6cycloalkyl, wherein the C1-6alkyl or C3-6cycloalkyl is optionally substituted by one or more fluorine; Group A isi) bicyclic heteroaryl having the structure:wherein X1, X2, X3, and X4are each independently CR5or N, provided that no more than two of X1, X2, X3, and X4are N, or ii) -N(C1-4alkyl)phenyl or -N(C1-4alkyl)heteroaryl, each optionally substituted with one, two, or three R5substituents; Group C is aryl or heteroaryl; R4is each independently selected from the group consisting of H, halogen, - CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -OR7, -S(O)xR7, -NR7R8, -C(O)R7, -OC(O)R7, -C(O)OR7, -NR7C(O)R8, - C(O)NR7R8, -NR7C(O)OR8, -OC(O)NR7R8, -NR7SO2R8, and -SO2NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted by one or more R9; R5and R6are each independently selected from the group consisting of H, deuterium, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -OR7, -S(O)xR7, -NR7R8, -C(O)R7, -OC(O)R7, - C(O)OR7, -NR7C(O)R8, -C(O)NR7R8, -NR7C(O)OR8, -OC(O)NR7R8, -NR7SO2R8, and -SO2NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted by one or more R9; R7and R8are each independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl, wherein the C1-6alkyl and C1-6haloalkyl are optionally substituted by one or more R10; R9and R10are each independently selected from the group consisting of halo, deuterium, -CN, -OR11, -S(O)xR11, -NR11R12, C(O)R11, -OC(O)R11, -C(O)OR11, - NR11C(O)R12, and -C(O)NR11R12; R11and R12are each independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl; x is 0, 1, or 2; and p is 0, 1, 2, or 3; provided that:i) when X is -C(=O)NR3-, R3is H or CH3, L is bond, Y1, Y2, Y3, and Y4are CH, Group C is phenyl, R1and R2are H, and p is 0, then Group A is not - N(CH3)phenyl optionally substituted with CH3; ii) when X is -NR3C(=O)-, R3is H or CH3, L is bond, Y1, Y3, and Y4are CH, Y2is CH or C-NH2, Group C is phenyl, R1and R2are H, p is 1, and Group A is, then R6is not -NHC(O)CH3; and iii) when X is -C(=O)NR3-, R3is H, L is -CH2-, Y1and Y2are CH, Y4is N, Y3is C-CF3, Group C is phenyl, R1is H, R2is CH3, p is 1, and Group A is , then R6is not CH3; andb) a pharmaceutically acceptable carrier. [000143] In some embodiments of Formula (I), (I’), and (II), Group A is a bicyclic heteroaryl having the structure: or ,wherein X1, X2, X3, and X4are each independently CR5or N, provided that no more than two of X1, X2, X3, and X4are N. In some embodiments, Group A is or . In some embodiments, Group A is . In some embodiments, Group A is . In some embodiments, Group A is selected from the group consisting of:, wherein R5ais each independently selected from the group consisting of halogen, -CN, - NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, - OR7, -S(O)xR7, -NR7R8, -C(O)R7, -OC(O)R7, -C(O)OR7, -NR7C(O)R8, -C(O)NR7R8, - NR7C(O)OR8, -OC(O)NR7R8, -NR7SO2R8, and -SO2NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted by one or more R9. In some embodiments, Group A is selected from the group consisting of:, wherein R5ais each independently selected from the group consisting of halogen, -CN, - NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, - OR7, -S(O)xR7, -NR7R8, -C(O)R7, -OC(O)R7, -C(O)OR7, -NR7C(O)R8, -C(O)NR7R8, -NR7C(O)OR8, -OC(O)NR7R8, -NR7SO2R8, and -SO2NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted by one or more R9. In some embodiments, Group A is In someembodiments, Group A is . In some embodiments, Group A is. [000144] In some embodiments of Formula (I), (I’), and (II), Group A is -N(C1-4alkyl)phenyl optionally substituted with one, two, or three R5substituents. In some embodiments, Group A is -N(C1-4alkyl)phenyl optionally substituted with one or two R5substituents. In some embodiments, Group A is -N(C1-4alkyl)phenyl optionally substituted with one R5substituent. [000145] In some embodiments of Formula (I), (I’), and (II), Group A is -N(C1-2alkyl)phenyl optionally substituted with one, two, or three R5substituents. In some embodiments, Group A is -N(C1-2alkyl)phenyl optionally substituted with one or two R5substituents. In some embodiments, Group A is -N(C1-2alkyl)phenyl optionally substituted with one R5substituent. [000146] In some embodiments of Formula (I), (I’), and (II), Group A is -N(C1-4alkyl)heteroaryl optionally substituted with one, two, or three R5substituents. In some embodiments, Group A is -N(C1-4alkyl)heteroaryl optionally substituted with one or two R5substituents. In some embodiments, Group A is -N(C1-4alkyl)heteroaryl optionally substituted with one R5substituent. [000147] In some embodiments of Formula (I), (I’), and (II), Group A is -N(C1-4alkyl)(5-6 membered heteroaryl) optionally substituted with one, two, or three R5substituents. In some embodiments, Group A is -N(C1-4alkyl)(5-6 membered heteroaryl) optionally substituted with one or two R5substituents. In some embodiments, Group A is - N(C1-4alkyl)(5-6 membered heteroaryl) optionally substituted with one R5substituent. [000148] In some embodiments of Formula (I), (I’), and (II), Group A is -N(C1-2alkyl)(5-6 membered heteroaryl) optionally substituted with one, two, or three R5substituents. In some embodiments, Group A is -N(C1-2alkyl)(5-6 membered heteroaryl) optionally substituted with one or two R5substituents. In some embodiments, Group A is - N(C1-2alkyl)(5-6 membered heteroaryl) optionally substituted with one R5substituent. [000149] In some embodiments of Formula (I), Group A is naphthyl optionally substituted with one, two, or three R5substituents. In some embodiments, Group A is naphthyl optionally substituted with one or two R5substituents. In some embodiments, Group A is naphthyl optionally substituted with one R5substituent. [000150] In some embodiments of Formula (I), (I’), and (II), X is -C(=O)NR3-. In other embodiments, X is -NR3C(=O)-. [000151] In some embodiments of Formula (I), (I’), and (II), L is bond. In other embodiments, L is C1-4alkylene optionally substituted by one or more fluorine or deuterium. In some embodiments, L is C1-2alkylene optionally substituted by one or more fluorine or deuterium. In some embodiments, L is methylene optionally substituted by one or two fluorine or deuterium. In some embodiments, L is C1-2alkylene optionally substituted by one or more deuterium. In some embodiments, L is methylene optionally substituted by one or two deuterium. [000152] In some embodiments, provided herein are pharmaceutical compositions, comprising: a) a compound of Formula (I-A): (I-A), or a pharmaceutically acceptable salt thereof, wherein L is a bond or C1-4alkylene optionally substituted by one or more fluorine or deuterium; Y1, Y2, Y3, and Y4are each independently CR4or N; R1and R2are each independently selected from the group consisting of H, deuterium, C1-4alkyl, C3-6cycloalkyl, and halogen, or R1and R2together with the carbon to which the R1and R2are attached form C3-6cycloalkyl;R3is selected from the group consisting of H, C1-6alkyl, and C3-6cycloalkyl, wherein the C1-6alkyl or C3-6cycloalkyl is optionally substituted by one or more fluorine; X1, X2, X3, and X4are each independently CR5or N, provided that no more than two of X1, X2, X3, and X4are N; Group C is aryl or heteroaryl; R4is each independently selected from the group consisting of H, halogen, - CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -OR7, -S(O)xR7, -NR7R8, -C(O)R7, -OC(O)R7, -C(O)OR7, -NR7C(O)R8, - C(O)NR7R8, -NR7C(O)OR8, -OC(O)NR7R8, -NR7SO2R8, and -SO2NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted by one or more R9; R5and R6are each independently selected from the group consisting of H, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -OR7, -S(O)xR7, -NR7R8, -C(O)R7, -OC(O)R7, -C(O)OR7, - NR7C(O)R8, -C(O)NR7R8, -NR7C(O)OR8, -OC(O)NR7R8, -NR7SO2R8, and - SO2NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted by one or more R9; R7and R8are each independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl, wherein the C1-6alkyl and C1-6haloalkyl are optionally substituted by one or more R10; R9and R10are each independently selected from the group consisting of halo, -CN, -OR11, -S(O)xR11, -NR11R12, C(O)R11, -OC(O)R11, -C(O)OR11, -NR11C(O)R12, and -C(O)NR11R12; R11and R12are each independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl; x is 0, 1, or 2; and p is 0, 1, 2, or 3; and b) a pharmaceutically acceptable carrier. [000153] In some embodiments, provided herein are pharmaceutical compositions, comprising: a) a compound of Formula (II-A):or a pharmaceutically acceptable salt thereof, wherein L is a bond or C1-4alkylene optionally substituted by one or more fluorine or deuterium; Y1, Y2, Y3, and Y4are each independently CR4or N; R1and R2are each independently selected from the group consisting of H, deuterium, C1-4alkyl, C3-6cycloalkyl, and halogen, or R1and R2together with the carbon to which the R1and R2are attached form C3-6cycloalkyl; R3is selected from the group consisting of H, C1-6alkyl, and C3-6cycloalkyl, wherein the C1-6alkyl or C3-6cycloalkyl is optionally substituted by one or more fluorine; X1, X2, X3, and X4are each independently CR5or N, provided that no more than two of X1, X2, X3, and X4are N; Group C is aryl or heteroaryl; R4is each independently selected from the group consisting of H, halogen, - CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -OR7, -S(O)xR7, -NR7R8, -C(O)R7, -OC(O)R7, -C(O)OR7, -NR7C(O)R8, - C(O)NR7R8, -NR7C(O)OR8, -OC(O)NR7R8, -NR7SO2R8, and -SO2NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted by one or more R9; R5and R6are each independently selected from the group consisting of H, deuterium, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -OR7, -S(O)xR7, -NR7R8, -C(O)R7, -OC(O)R7, - C(O)OR7, -NR7C(O)R8, -C(O)NR7R8, -NR7C(O)OR8, -OC(O)NR7R8, -NR7SO2R8, and -SO2NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted by one or more R9;R7and R8are each independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl, wherein the C1-6alkyl and C1-6haloalkyl are optionally substituted by one or more R10; R9and R10are each independently selected from the group consisting of halo, deuterium, -CN, -OR11, -S(O)xR11, -NR11R12, C(O)R11, -OC(O)R11, -C(O)OR11, - NR11C(O)R12, and -C(O)NR11R12; R11and R12are each independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl; x is 0, 1, or 2; and p is 0, 1, 2, or 3; and b) a pharmaceutically acceptable carrier. [000154] In some embodiments of Formula (I-A) and (II-A), L is bond. In other embodiments, L is C1-4alkylene optionally substituted by one or more fluorine or deuterium. In some embodiments, L is C1-2alkylene optionally substituted by one or more fluorine or deuterium. In some embodiments, L is methylene optionally substituted by one or two fluorine or deuterium. In some embodiments, L is C1-2alkylene optionally substituted by one or more deuterium. In some embodiments, L is methylene optionally substituted by one or two deuterium. [000155] In some embodiments, provided herein are pharmaceutical compositions, comprising: a) a compound of Formula (I-B):, or a pharmaceutically acceptable salt thereof, wherein R’ and R’’ are each independently selected from the group consisting of H, fluorine, and deuterium; Y1, Y2, Y3, and Y4are each independently CR4or N;R1and R2are each independently selected from the group consisting of H, deuterium, C1-4alkyl, C3-6cycloalkyl, and halogen, or R1and R2together with the carbon to which the R1and R2are attached form C3-6cycloalkyl; R3is selected from the group consisting of H, C1-6alkyl, and C3-6cycloalkyl, wherein the C1-6alkyl or C3-6cycloalkyl is optionally substituted by one or more fluorine; X1, X2, X3, and X4are each independently CR5or N, provided that no more than two of X1, X2, X3, and X4are N; Group C is aryl or heteroaryl; R4is each independently selected from the group consisting of H, halogen, - CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -OR7, -S(O)xR7, -NR7R8, -C(O)R7, -OC(O)R7, -C(O)OR7, -NR7C(O)R8, - C(O)NR7R8, -NR7C(O)OR8, -OC(O)NR7R8, -NR7SO2R8, and -SO2NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted by one or more R9; R5and R6are each independently selected from the group consisting of H, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -OR7, -S(O)xR7, -NR7R8, -C(O)R7, -OC(O)R7, -C(O)OR7, - NR7C(O)R8, -C(O)NR7R8, -NR7C(O)OR8, -OC(O)NR7R8, -NR7SO2R8, and - SO2NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted by one or more R9; R7and R8are each independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl, wherein the C1-6alkyl and C1-6haloalkyl are optionally substituted by one or more R10; R9and R10are each independently selected from the group consisting of halo, -CN, -OR11, -S(O)xR11, -NR11R12, C(O)R11, -OC(O)R11, -C(O)OR11, -NR11C(O)R12, and -C(O)NR11R12; R11and R12are each independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl; x is 0, 1, or 2; and p is 0, 1, 2, or 3; and b) a pharmaceutically acceptable carrier.[000156] In some embodiments, provided herein are pharmaceutical compositions, comprising: a) a compound of Formula (II-B):(II-B), or a pharmaceutically acceptable salt thereof, wherein R’ and R’’ are each independently selected from the group consisting of H, fluorine, and deuterium; Y1, Y2, Y3, and Y4are each independently CR4or N; R1and R2are each independently selected from the group consisting of H, deuterium, C1-4alkyl, C3-6cycloalkyl, and halogen, or R1and R2together with the carbon to which the R1and R2are attached form C3-6cycloalkyl; R3is selected from the group consisting of H, C1-6alkyl, and C3-6cycloalkyl, wherein the C1-6alkyl or C3-6cycloalkyl is optionally substituted by one or more fluorine; X1, X2, X3, and X4are each independently CR5or N, provided that no more than two of X1, X2, X3, and X4are N; Group C is aryl or heteroaryl; R4is each independently selected from the group consisting of H, halogen, - CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -S(O)xR7, -NR7R8, -C(O)R7, -OC(O)R7, -C(O)OR7, -C(O)NR7R8, - NR7C(O)OR8, -OC(O)NR7R8, -NR7SO2R8, and -SO2NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted by one or more R9; R5and R6are each independently selected from the group consisting of H, deuterium, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -S(O)xR7, -NR7R8, -C(O)R7, -OC(O)R7, - C(O)OR7, -C(O)NR7R8, -NR7C(O)OR8, -OC(O)NR7R8, -NR7SO2R8, and -SO2NR7R8,wherein the C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted by one or more R9; R7and R8are each independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl, wherein the C1-6alkyl and C1-6haloalkyl are optionally substituted by one or more R10; R9and R10are each independently selected from the group consisting of halo, deuterium, -CN, -OR11, -S(O)xR11, -NR11R12, C(O)R11, -OC(O)R11, -C(O)OR11, - NR11C(O)R12, and -C(O)NR11R12; R11and R12are each independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl; x is 0, 1, or 2; and p is 0, 1, 2, or 3; and b) a pharmaceutically acceptable carrier. [000157] In some embodiments of Formula (I-B) and (II-B), R’ and R’’ are each independently selected from the group consisting of H and deuterium. In some embodiments, R’ and R’’ are each H. In some embodiments, R’ and R’’ are each fluorine. In some embodiments, R’ and R’’ are each deuterium. [000158] In some embodiments, provided herein are pharmaceutical compositions, comprising: a) a compound of Formula (I-C):- , or a pharmaceutically acceptable salt thereof, wherein X is -C(=O)NR3- or -NR3C(=O)-; R’ and R’’ are each independently selected from the group consisting of H, fluorine, and deuterium; Y1, Y2, Y3, and Y4are each independently CR4or N;R1and R2are each independently selected from the group consisting of H, deuterium, C1-4alkyl, C3-6cycloalkyl, and halogen, or R1and R2together with the carbon to which the R1and R2are attached form C3-6cycloalkyl; R3is selected from the group consisting of H, C1-6alkyl, and C3-6cycloalkyl, wherein the C1-6alkyl or C3-6cycloalkyl is optionally substituted by one or more fluorine; R’’’ is C1-4alkyl; Group D is phenyl or heteroaryl, each optionally substituted with one, two, or three R5substituents; Group C is aryl or heteroaryl; R4is each independently selected from the group consisting of H, halogen, - CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -OR7, -S(O)xR7, -NR7R8, -C(O)R7, -OC(O)R7, -C(O)OR7, -NR7C(O)R8, - C(O)NR7R8, -NR7C(O)OR8, -OC(O)NR7R8, -NR7SO2R8, and -SO2NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted by one or more R9; R5and R6are each independently selected from the group consisting of H, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -OR7, -S(O)xR7, -NR7R8, -C(O)R7, -OC(O)R7, -C(O)OR7, - NR7C(O)R8, -C(O)NR7R8, -NR7C(O)OR8, -OC(O)NR7R8, -NR7SO2R8, and - SO2NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted by one or more R9; R7and R8are each independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl, wherein the C1-6alkyl and C1-6haloalkyl are optionally substituted by one or more R10; R9and R10are each independently selected from the group consisting of halo, -CN, -OR11, -S(O)xR11, -NR11R12, C(O)R11, -OC(O)R11, -C(O)OR11, -NR11C(O)R12, and -C(O)NR11R12; R11and R12are each independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl; x is 0, 1, or 2; and p is 0, 1, 2, or 3; and b) a pharmaceutically acceptable carrier.[000159] In some embodiments, provided herein are pharmaceutical compositions, comprising: a) a compound of Formula (II-C):(II-C), or a pharmaceutically acceptable salt thereof, wherein X is -C(=O)NR3- or -NR3C(=O)-; R’ and R’’ are each independently selected from the group consisting of H, fluorine, and deuterium; Y1, Y2, Y3, and Y4are each independently CR4or N; R1and R2are each independently selected from the group consisting of H, deuterium, C1-4alkyl, C3-6cycloalkyl, and halogen, or R1and R2together with the carbon to which the R1and R2are attached form C3-6cycloalkyl; R3is selected from the group consisting of H, C1-6alkyl, and C3-6cycloalkyl, wherein the C1-6alkyl or C3-6cycloalkyl is optionally substituted by one or more fluorine; R’’’ is C1-4alkyl; Group D is phenyl or heteroaryl, each optionally substituted with one, two, or three R5substituents; Group C is aryl or heteroaryl; R4is each independently selected from the group consisting of H, halogen, - CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -OR7, -S(O)xR7, -NR7R8, -C(O)R7, -OC(O)R7, -C(O)OR7, -NR7C(O)R8, - C(O)NR7R8, -NR7C(O)OR8, -OC(O)NR7R8, -NR7SO2R8, and -SO2NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted by one or more R9; R5and R6are each independently selected from the group consisting of H, deuterium, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -OR7, -S(O)xR7, -NR7R8, -C(O)R7, -OC(O)R7, -C(O)OR7, -NR7C(O)R8, -C(O)NR7R8, -NR7C(O)OR8, -OC(O)NR7R8, -NR7SO2R8, and -SO2NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted by one or more R9; R7and R8are each independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl, wherein the C1-6alkyl and C1-6haloalkyl are optionally substituted by one or more R10; R9and R10are each independently selected from the group consisting of halo, deuterium, -CN, -OR11, -S(O)xR11, -NR11R12, C(O)R11, -OC(O)R11, -C(O)OR11, - NR11C(O)R12, and -C(O)NR11R12; R11and R12are each independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl; x is 0, 1, or 2; and p is 0, 1, 2, or 3; and b) a pharmaceutically acceptable carrier. [000160] In some embodiments of Formula (I-C) and (II-C), X is -C(=O)NR3-. In other embodiments, X is -NR3C(=O)-. [000161] In some embodiments of Formula (I-C) and (II-C), R’ and R’’ are each independently selected from the group consisting of H and deuterium. In some embodiments, R’ and R’’ are each H. In some embodiments, R’ and R’’ are each fluorine. In some embodiments, R’ and R’’ are each deuterium. [000162] In some embodiments, provided herein are pharmaceutical compositions, comprising: a) a compound of Formula (I-D):, or a pharmaceutically acceptable salt thereof, wherein X is -C(=O)NR3- or -NR3C(=O)-; L is a bond or C1-4alkylene optionally substituted by one or more fluorine or deuterium;Y1, Y2, Y3, and Y4are each independently CR4or N; R1and R2are each independently selected from the group consisting of H, deuterium, C1-4alkyl, C3-6cycloalkyl, and halogen, or R1and R2together with the carbon to which the R1and R2are attached form C3-6cycloalkyl; R3is selected from the group consisting of H, C1-6alkyl, and C3-6cycloalkyl, wherein the C1-6alkyl or C3-6cycloalkyl is optionally substituted by one or more fluorine; Group A is naphthyl optionally substituted with one, two, or three R5substituents; Group C is aryl or heteroaryl; R4is each independently selected from the group consisting of H, halogen, - CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -OR7, -S(O)xR7, -NR7R8, -C(O)R7, -OC(O)R7, -C(O)OR7, -NR7C(O)R8, - C(O)NR7R8, -NR7C(O)OR8, -OC(O)NR7R8, -NR7SO2R8, and -SO2NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted by one or more R9; R5and R6are each independently selected from the group consisting of H, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -OR7, -S(O)xR7, -NR7R8, -C(O)R7, -OC(O)R7, -C(O)OR7, - NR7C(O)R8, -C(O)NR7R8, -NR7C(O)OR8, -OC(O)NR7R8, -NR7SO2R8, and - SO2NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted by one or more R9; R7and R8are each independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl, wherein the C1-6alkyl and C1-6haloalkyl are optionally substituted by one or more R10; R9and R10are each independently selected from the group consisting of halo, -CN, -OR11, -S(O)xR11, -NR11R12, C(O)R11, -OC(O)R11, -C(O)OR11, -NR11C(O)R12, and -C(O)NR11R12; R11and R12are each independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl; x is 0, 1, or 2; and p is 0, 1, 2, or 3; and b) a pharmaceutically acceptable carrier.[000163] In some embodiments, provided herein are pharmaceutical compositions, comprising: a) a compound of Formula (II-D):(II-D), or a pharmaceutically acceptable salt thereof, wherein X is -C(=O)NR3- or -NR3C(=O)-; L is a bond or C1-4alkylene optionally substituted by one or more fluorine or deuterium; Y1, Y2, Y3, and Y4are each independently CR4or N; R1and R2are each independently selected from the group consisting of H, deuterium, C1-4alkyl, C3-6cycloalkyl, and halogen, or R1and R2together with the carbon to which the R1and R2are attached form C3-6cycloalkyl; R3is selected from the group consisting of H, C1-6alkyl, and C3-6cycloalkyl, wherein the C1-6alkyl or C3-6cycloalkyl is optionally substituted by one or more fluorine; Group A is naphthyl optionally substituted with one, two, or three R5substituents; Group C is aryl or heteroaryl; R4is each independently selected from the group consisting of H, halogen, - CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -OR7, -S(O)xR7, -NR7R8, -C(O)R7, -OC(O)R7, -C(O)OR7, -NR7C(O)R8, - C(O)NR7R8, -NR7C(O)OR8, -OC(O)NR7R8, -NR7SO2R8, and -SO2NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted by one or more R9; R5and R6are each independently selected from the group consisting of H, deuterium, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -OR7, -S(O)xR7, -NR7R8, -C(O)R7, -OC(O)R7, - C(O)OR7, -NR7C(O)R8, -C(O)NR7R8, -NR7C(O)OR8, -OC(O)NR7R8, -NR7SO2R8,and -SO2NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted by one or more R9; R7and R8are each independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl, wherein the C1-6alkyl and C1-6haloalkyl are optionally substituted by one or more R10; R9and R10are each independently selected from the group consisting of halo, deuterium, -CN, -OR11, -S(O)xR11, -NR11R12, C(O)R11, -OC(O)R11, -C(O)OR11, - NR11C(O)R12, and -C(O)NR11R12; R11and R12are each independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl; x is 0, 1, or 2; and p is 0, 1, 2, or 3; and b) a pharmaceutically acceptable carrier. [000164] In some embodiments of Formula (I), (I’), (II), (I-A), (II-A), (I-B), (II-B), (I- C), (II-C), (I-D), and (II-D), Y1, Y2, Y3, and Y4are each CR4. In other embodiments, one or two of Y1, Y2, Y3, and Y4are N and the remaining Y1, Y2, Y3, and Y4are CR4. In some embodiments, one of Y1, Y2, Y3, and Y4are N and the remaining Y1, Y2, Y3, and Y4are CR4. [000165] In some embodiments of Formula (I), (I’), (II), (I-A), (II-A), (I-B), (II-B), (I- C), (II-C), (I-D), and (II-D), Y1, Y2, Y3, and Y4are each CH. In other embodiments, one or two of Y1, Y2, Y3, and Y4are N and the remaining Y1, Y2, Y3, and Y4are CH. In some embodiments, one of Y1, Y2, Y3, and Y4are N and the remaining Y1, Y2, Y3, and Y4are CH. [000166] In some embodiments of Formula (I), (I’), (II), (I-A), (II-A), (I-B), (II-B), (I- C), (II-C), (I-D), and (II-D), Y1is CR4. In other embodiments, Y1is N. [000167] In some embodiments of Formula (I), (I’), (II), (I-A), (II-A), (I-B), (II-B), (I- C), (II-C), (I-D), and (II-D), Y2is CR4. In other embodiments, Y2is N. [000168] In some embodiments of Formula (I), (I’), (II), (I-A), (II-A), (I-B), (II-B), (I- C), (II-C), (I-D), and (II-D), Y3is CR4. In other embodiments, Y3is N. [000169] In some embodiments of Formula (I), (I’), (II), (I-A), (II-A), (I-B), (II-B), (I- C), (II-C), (I-D), and (II-D), Y4is CR4. In other embodiments, Y4is N. [000170] In some embodiments of Formula (I), (I’), (II), (I-A), (II-A), (I-B), (II-B), (I- C), (II-C), (I-D), and (II-D), R4is each independently selected from the group consisting of H, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -OR7, -S(O)xR7, and -NR7R8. In some embodiments, R4is eachindependently selected from the group consisting of H, halogen, -CN, -C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, and C3-6cycloalkyl. In some embodiments, R4is each independently selected from the group consisting of H, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C3-6cycloalkyl, and -NR7R8. In some embodiments, R4is each independently selected from the group consisting of H, halogen, -C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, and C3-6cycloalkyl. In some embodiments, R4is each independently selected from the group consisting of H, halogen, C1-6alkyl, C1-6haloalkyl, -O(C1-6alkyl), and C3-6cycloalkyl. In some embodiments, R4is each independently selected from the group consisting of H, halogen, -C1-4alkyl, C1-4haloalkyl, -O(C1-4alkyl), and C3-4cycloalkyl. In some embodiments, R4is each independently selected from the group consisting of H, halogen, and C1-6alkyl. In some embodiments, R4is each independently selected from the group consisting of H, halogen, and C1-4alkyl. In some embodiments, R4is each independently selected from the group consisting of H, F, methyl, ethyl, isopropyl, CF3, CF2H, -OCH3, and cyclopropyl. [000171] In some embodiments of Formula (I), (I’), (II), (I-A), (II-A), (I-B), (II-B), (I- C), (II-C), (I-D), and (II-D),R1and R2are each independently selected from the group consisting of H, deuterium, and C1-4alkyl, and halogen. In some embodiments, R1and R2are each independently selected from the group consisting of H, deuterium, and C1-2alkyl. In some embodiments, R1and R2are each independently selected from the group consisting of H, deuterium, and methyl. In some embodiments, R1and R2together with the carbon to which the R1and R2are attached form C3-6cycloalkyl. In some embodiments, R1and R2together with the carbon to which the R1and R2are attached form C3-4cycloalkyl. [000172] In some embodiments of Formula (I), (I’), (II), (I-A), (II-A), (I-B), (II-B), (I- C), (II-C), (I-D), and (II-D), R3is selected from the group consisting of H, C1-4alkyl, and C3-4cycloalkyl, wherein the C1-4alkyl or C3-4cycloalkyl is optionally substituted by one or more fluorine. In some embodiments, R3is H or C1-2alkyl. In some embodiments, R3is H or methyl. [000173] In some embodiments of Formula (I), (I’), (II), (I-A), (II-A), (I-B), (II-B), (I- C), (II-C), (I-D), and (II-D), Group C is phenyl or 5-6 membered heteroaryl. In some embodiments, Group C is selected from the group consisting of phenyl, pyrazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, triazolyl, and pyridyl. In some embodiments, Group C is selected from the group consisting of phenyl, pyrazolyl, furanyl, thiophenyl, thiazolyl,triazolyl, and pyridyl. In some embodiments, Group C is selected from the group consisting of phenyl, pyrazolyl, and pyridyl. [000174] In some embodiments of Formula (I), (I’), (II), (I-A), (II-A), (I-B), (II-B), (I- C), (II-C), (I-D), and (II-D), R5is each independently selected from the group consisting of H, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, - OR7, -S(O)xR7, and -NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted by one or more R9. In some embodiments, R5is each independently selected from the group consisting of H, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -OR7, -and -NR7R8, wherein the C1-6alkyl and C1-6haloalkyl are optionally substituted by one or two R9. In some embodiments, R5is each independently selected from the group consisting of H, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C3-6cycloalkyl, and -NR7R8. In some embodiments, R5is each independently selected from the group consisting of H, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, OR7, and -NR7R8. In some embodiments, R5is each independently selected from the group consisting of halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, OR7, and -NR7R8. [000175] In some embodiments of Formula (I), (I’), (II), (I-A), (II-A), (I-B), (II-B), (I- C), (II-C), (I-D), and (II-D), R5is each independently selected from the group consisting of H, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C3-6cycloalkyl, and - NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, and C1-6heteroalkyl are optionally substituted by one or more R9. In some embodiments, R5is each independently selected from the group consisting of H, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C3-6cycloalkyl, and -NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, and C1-6heteroalkyl are optionally substituted by one, two, or three R9. In some embodiments, R5is each independently selected from the group consisting of H, F, Cl, Br, -CN, -NO2, C1-2alkyl, C1-2haloalkyl, C3-4cycloalkyl, O(C1-2alkyl), O(C1-2haloalkyl), and -NH2. In some embodiments, R5is each independently selected from the group consisting of F, Cl, Br, -CN, -NO2, C1-2alkyl, C1-2haloalkyl, C3-4cycloalkyl, O(C1-2alkyl), O(C1-2haloalkyl), and -NH2. In some embodiments, R5is each independently selected from the group consisting of H, F, Cl, Br, - CN, -NO2, methyl, CF3, cyclopropyl, OCH3, OCF3, and -NH2. In some embodiments, R5is each independently selected from the group consisting of F, Cl, Br, -CN, -NO2, methyl, CF3, cyclopropyl, OCH3, OCF3, and -NH2.[000176] In some embodiments of Formula (II), (II-A), (II-B), (II-C), and (II-D), R5is each independently selected from the group consisting of H, deuterium, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C3-6cycloalkyl, and -NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, and C1-6heteroalkyl are optionally substituted by one or more R9. In some embodiments, R5is each independently selected from the group consisting of H, deuterium, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C3-6cycloalkyl, - and -NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, and C1-6heteroalkyl are optionally substituted by one, two, or three R9. In some embodiments, R5is each independently selected from the group consisting of H, deuterium, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C3-6cycloalkyl, and -NR7R8. In some embodiments, R5is each independently selected from the group consisting of H, deuterium, F, Cl, Br, -CN, -NO2, C1-2alkyl, C1-2haloalkyl, C3-4cycloalkyl, O(C1-2alkyl), O(C1-2haloalkyl), and -NH2. In some embodiments, R5is each independently selected from the group consisting of H, deuterium, F, Cl, Br, -CN, - NO2, methyl, CF3, cyclopropyl, OCH3, OCF3, and -NH2. [000177] In some embodiments of Formula (I), (I’), (II), (I-A), (II-A), (I-B), (II-B), (I- C), (II-C), (I-D), and (II-D), p is 0, 1, or 2. In some embodiments, p is 0 or 1. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. [000178] In some embodiments of Formula (I), (I’), (II), (I-A), (II-A), (I-B), (II-B), (I- C), (II-C), (I-D), and (II-D), R6is each independently selected from the group consisting of H, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, - OR7, -S(O)xR7, and -NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted by one or more R9. In some embodiments, R6is each independently selected from the group consisting of H, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -OR7, -and -NR7R8, wherein the C1-6alkyl and C1-6haloalkyl are optionally substituted by one or two R9. In some embodiments, R6is each independently selected from the group consisting of H, halogen, C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl, wherein the C1-6alkyl and C1-6haloalkyl are optionally substituted by one or two R9. In some embodiments, R6is each independently selected from the group consisting of halogen, -C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl. In some embodiments, R6is each independently selected from the group consisting of F and methyl. [000179] In some embodiments of Formula (I), (I’), (II), (I-A), (II-A), (I-B), (II-B), (I- C), (II-C), (I-D), and (II-D), R7and R8are each independently selected from the groupconsisting of H, C1-6alkyl, and C1-6haloalkyl, wherein the C1-6alkyl and C1-6haloalkyl are optionally substituted by one R10. In some embodiments, R7and R8are each independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R7and R8are each independently selected from the group consisting of H and C1-6alkyl. In some embodiments, R7and R8are each independently selected from the group consisting of H and methyl. [000180] In some embodiments of Formula (I), (I’), (II), (I-A), (II-A), (I-B), (II-B), (I- C), (II-C), (I-D), and (II-D), R9and R10are each independently selected from the group consisting of halo, -CN, -OR11, -S(O)xR11, and -NR11R12. [000181] In some embodiments of Formula (II), (II-A), (II-B), (II-C), and (II-D), R9and R10are each independently selected from the group consisting of halo, deuterium, -CN, - OR11, -S(O)xR11, and -NR11R12. In some embodiments, R9and R10are each independently selected from the group consisting of halo and deuterium. [000182] In some embodiments of Formula (I), (I’), (II), (I-A), (II-A), (I-B), (II-B), (I- C), (II-C), (I-D), and (II-D), R11and R12are each independently selected from the group consisting of H and C1-6alkyl. In some embodiments, R11and R12are each independently selected from the group consisting of H and methyl. [000183] In some embodiments, provided herein are pharmaceutical compositions, comprising: a) a compound of Formula (III):, or a pharmaceutically acceptable salt thereof, wherein X is -C(=O)NR3- or -NR3C(=O)-; L is a bond or C1-2alkylene optionally substituted by one or more deuterium; Y1, Y2, Y3, and Y4are each independently CR4or N; R1and R2are each independently selected from the group consisting of H, deuterium, C1-4alkyl, and halogen; R3is selected from the group consisting of H and C1-6alkyl;Group A is bicyclic heteroaryl having the structure:wherein X1, X2, X3, and X4are each independently CR5or N, provided that no more than two of X1, X2, X3, and X4are N; Group C is phenyl or 5-6 membered heteroaryl; R4is each independently selected from the group consisting of H, halogen, - CN, -NO2, C1-6alkyl, C1-6haloalkyl, -O(C1-6alkyl), C3-6cycloalkyl, and -NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, and -O(C1-6alkyl) are optionally substituted by one or more R9; R5is each independently selected from the group consisting of H, deuterium, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, -O(C1-6alkyl), C3-6cycloalkyl, and - NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, and -O(C1-6alkyl) are optionally substituted by one or more R9; R6is each independently selected from the group consisting of H, deuterium, halogen, C1-6alkyl, C1-6haloalkyl, -O(C1-6alkyl), and C3-6cycloalkyl, wherein the C1- 6 alkyl, C1-6haloalkyl, and -O(C1-6alkyl) are optionally substituted by one or more R9; R7and R8are each independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl; R9is each independently selected from the group consisting of halo and deuterium; and p is 0, 1, 2, or 3; and b) a pharmaceutically acceptable carrier. [000184] In some embodiments, provided herein are pharmaceutical compositions, comprising: a) a compound of Formula (IV):(IV), or a pharmaceutically acceptable salt thereof, wherein X is -C(=O)NR3- or -NR3C(=O)-; L is C1-2alkylene optionally substituted by one or more deuterium; Y1, Y2, Y3, and Y4are each independently CR4or N; R1and R2are each independently selected from the group consisting of H, deuterium, C1-4alkyl, and halogen; R3is selected from the group consisting of H and C1-6alkyl; Group A is -N(C1-4alkyl)phenyl optionally substituted with one, two, or three R5substituents; Group C is phenyl or 5-6 membered heteroaryl; R4is each independently selected from the group consisting of H, halogen, - CN, -NO2, C1-6alkyl, C1-6haloalkyl, -O(C1-6alkyl), C3-6cycloalkyl, and -NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, and -O(C1-6alkyl) are optionally substituted by one or more R9; R5is each independently selected from the group consisting of H, deuterium, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, -O(C1-6alkyl), C3-6cycloalkyl, and - NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, and -O(C1-6alkyl) are optionally substituted by one or more R9; R6is each independently selected from the group consisting of H, deuterium, halogen, C1-6alkyl, C1-6haloalkyl, -O(C1-6alkyl), and C3-6cycloalkyl, wherein the C1-6 alkyl, C1-6haloalkyl, and -O(C1-6alkyl) are optionally substituted by one or more R9; R7and R8are each independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl; R9is each independently selected from the group consisting of halo and deuterium; and p is 0, 1, 2, or 3; and b) a pharmaceutically acceptable carrier.[000185] In some embodiments of Formula (III), Group A is or . In some embodiments, Group A is . In some embodiments, Group A is . In some embodiments, Group A is selected from the group consisting of: , wherein R5ais each independently selected from the group consisting of deuterium, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, -O(C1-6alkyl), C3-6cycloalkyl, and -NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, and -O(C1-6alkyl) are optionally substituted by one or more R9. In some embodiments, Group A is selected from the group consisting of:, wherein R5ais each independently selected from the group consisting of deuterium, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, -O(C1-6alkyl), C3-6cycloalkyl, and -NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, and -O(C1-6alkyl) are optionally substituted by one or more R9. In some embodiments, Group A is or . In some embodiments, Group A is . In some embodiments, Group A is . [000186] In some embodiments of Formula (IV), Group A is -N(C1-4alkyl)phenyl optionally substituted with one or two R5substituents. In some embodiments, Group A is - N(C1-4alkyl)phenyl optionally substituted with one R5substituent. [000187] In some embodiments of Formula (IV), Group A is -N(C1-2alkyl)phenyl optionally substituted with one, two, or three R5substituents. In some embodiments, Group Ais -N(C1-2alkyl)phenyl optionally substituted with one or two R5substituents. In some embodiments, Group A is -N(C1-2alkyl)phenyl optionally substituted with one R5substituent. [000188] In some embodiments of Formula (III) and (IV), X is -C(=O)NR3-. In other embodiments, X is -NR3C(=O)-. [000189] In some embodiments of Formula (III), L is bond. In other embodiments, L is C1-2alkylene optionally substituted by one or more deuterium. In some embodiments, L is methylene optionally substituted by one or two deuterium. [000190] In some embodiments of Formula (IV), L is C1-2alkylene optionally substituted by one or more deuterium. In some embodiments, L is methylene optionally substituted by one or two deuterium. [000191] In some embodiments of Formula (III) and (IV), Y1, Y2, Y3, and Y4are each CR4. In other embodiments, one or two of Y1, Y2, Y3, and Y4are N and the remaining Y1, Y2, Y3, and Y4are CR4. In some embodiments, one of Y1, Y2, Y3, and Y4are N and the remaining Y1, Y2, Y3, and Y4are CR4. [000192] In some embodiments of Formula (III) and (IV), Y1, Y2, Y3, and Y4are each CH. In other embodiments, one or two of Y1, Y2, Y3, and Y4are N and the remaining Y1, Y2, Y3, and Y4are CH. In some embodiments, one of Y1, Y2, Y3, and Y4are N and the remaining Y1, Y2, Y3, and Y4are CH. [000193] In some embodiments of Formula (III) and (IV), Y1is CR4. In other embodiments, Y1is N. [000194] In some embodiments of Formula (III) and (IV), Y2is CR4. In other embodiments, Y2is N. [000195] In some embodiments of Formula (III) and (IV), Y3is CR4. In other embodiments, Y3is N. [000196] In some embodiments of Formula (III) and (IV), Y4is CR4. In other embodiments, Y4is N. [000197] In some embodiments of Formula (III) and (IV), R4is each independently selected from the group consisting of H, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, - O(C1-6alkyl), C3-6cycloalkyl, and -NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, and -O(C1-6alkyl) are optionally substituted by one, two, or three R9. In some embodiments, R4is each independently selected from the group consisting of H, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, -O(C1-6alkyl), and C3-6cycloalkyl. In some embodiments, R4is eachindependently selected from the group consisting of H, F, methyl, ethyl, isopropyl, CF3, CF2H, -OCH3, and cyclopropyl. [000198] In some embodiments of Formula (III) and (IV), R1and R2are each independently selected from the group consisting of H, deuterium, and C1-2alkyl, and halogen. In some embodiments, R1and R2are each independently selected from the group consisting of H, deuterium, and C1-2alkyl. In some embodiments, R1and R2are each independently selected from the group consisting of H, deuterium, and methyl. [000199] In some embodiments of Formula (III) and (IV), R3is H or C1-2alkyl. In some embodiments, R3is H or methyl. [000200] In some embodiments of Formula (III) and (IV), Group C is phenyl or 5-6 membered heteroaryl. In some embodiments, Group C is selected from the group consisting of phenyl, pyrazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, triazolyl, and pyridyl. In some embodiments, Group C is selected from the group consisting of phenyl, pyrazolyl, furanyl, thiophenyl, thiazolyl, triazolyl, and pyridyl. In some embodiments, Group C is selected from the group consisting of phenyl, pyrazolyl, and pyridyl. In some embodiments, Group C is pyrazolyl. In some embodiments, Group C is phenyl. In some embodiments, Group C is pyridyl. [000201] In some embodiments of Formula (III) and (IV), R5is each independently selected from the group consisting of H, deuterium, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, -O(C1-6alkyl), C3-6cycloalkyl, and -NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, and -O(C1-6alkyl) are optionally substituted by one, two, or three R9. In some embodiments of Formula (III) and (IV), R5is each independently selected from the group consisting of H, deuterium, halogen, -CN, -NO2, C1-4alkyl, C1-4haloalkyl, -O(C1-4alkyl), C3-4cycloalkyl, and -NR7R8, wherein the C1-4alkyl, C1-4haloalkyl, and -O(C1-4alkyl) are optionally substituted by one, two, or three R9. In some embodiments, R5is each independently selected from the group consisting of H, deuterium, F, Cl, Br, -CN, -NO2, C1-2alkyl, C1-2haloalkyl, C3-4cycloalkyl, O(C1-2alkyl), and -NH2, wherein the C1-2alkyl, C1-2haloalkyl, and -O(C1-2alkyl) are optionally substituted by one, two, or three R9. In some embodiments, R5is each independently selected from the group consisting of H, deuterium, F, Cl, Br, -CN, -NO2, methyl, CF3, cyclopropyl, OCH3, OCF3, and -NH2. [000202] In some embodiments of Formula (III) and (IV), p is 0, 1, or 2. In some embodiments, p is 0 or 1. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.[000203] In some embodiments of Formula (III) and (IV), R6is H, deuterium, halogen, C1-6alkyl, C1-6haloalkyl, -O(C1-6alkyl), and C3-6cycloalkyl, wherein the C1-6alkyl, C1-6haloalkyl, and -O(C1-6alkyl) are optionally substituted by one, two, or three R9. In some embodiments, R6is H, deuterium, halogen, C1-4alkyl, C1-4haloalkyl, and C3-6cycloalkyl. In some embodiments, R6is each independently selected from the group consisting of F and methyl. [000204] In some embodiments of Formula (III) and (IV), R7and R8are each independently H or C1-6alkyl. In some embodiments, R7and R8are each independently H or methyl. In some embodiments, R7and R8are H. [000205] In some embodiments of Formula (III) and (IV), R9is each independently F or deuterium. [000206] In some embodiments, the compound is selected from Table 1 and Table 2, or a pharmaceutically acceptable salt thereof. [000207] In some embodiments, the compound is selected from Table 1, or a pharmaceutically acceptable salt thereof. [000208] In some embodiments, the compound is selected from Table 2, or a pharmaceutically acceptable salt thereof. [000209] In some embodiments, the pharmaceutical compositions are administered in a single dose by any of the accepted modes of administration of agents having similar utilities, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, as an inhalant, or via an impregnated or coated device such as a stent, for example, or an artery-inserted cylindrical polymer. In some embodiments, the pharmaceutical compositions are administered in multiple doses. Methods of Use [000210] Compounds and compositions described herein are utilized in methods for treating, preventing, or reducing the risk or severity of a disease or disorder mediated by GPR4 dysregulation or a disease or disorder that is otherwise treatable with a GPR4 modulator. [000211] In some embodiments, the compounds and compositions of the present disclosure is used alone to provide a therapeutic effect. In other embodiments, the compounds and compositions of the present disclosure is used in combination with one or moreadditional therapeutic agents. In some embodiments, the additional therapeutic agent is a CNS active agent. [000212] In some embodiments, provided herein is a compound of Formula (I), (I’), (II), (I-A), (II-A), (I-B), (II-B), (I-C), (II-C), (I-D), (II-D), (III), and (IV) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I), (I’), (II), (I-A), (II-A), (I-B), (II-B), (I-C), (II-C), (I-D), (II-D), (III), and (IV) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, for use in therapy. [000213] In some embodiments, provided herein is a compound of Formula (I), (I’), (II), (I-A), (II-A), (I-B), (II-B), (I-C), (II-C), (I-D), (II-D), (III), and (IV) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I), (I’), (II), (I-A), (II-A), (I-B), (II-B), (I-C), (II-C), (I-D), (II-D), (III), and (IV) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, for use in treating or preventing a disease or condition associated with dysregulation of GPR4 in a subject in need thereof. [000214] In some embodiments, disease or condition is selected from the group consisting of neurodegenerative diseases or disorders, neuropsychiatric diseases or disorders, cardiovascular diseases or disorders, metabolic diseases or disorders, autoimmune diseases or disorders, cancers, muscular diseases or disorders, and bone diseases or disorders. [000215] In some embodiments, disease or condition is a neurodegenerative disease or disorder. Neurodegenerative diseases or disorders are selected from the group consisting of Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, frontotemporal dementia, tauopathies, Charcot-Marie-Tooth disease, Huntington’s disease, polyglutamine diseases, neurocognitive disorders, retinal degeneration, and Sveinsson chorioretinal atrophy. [000216] In some embodiments, disease or condition is a neuropsychiatric disease or disorder. Neuropsychiatric diseases or disorders are selected from the group consisting of neuropsychiatric disorders, including but not limited to bipolar disorder, attention deficit hyperactivity disorder, anxiety, addiction, seizures, schizophrenia, obsessive compulsive disorder, social phobia, Tourette’s syndrome and binge eating disorder, depression and post- traumatic brain injury deficits, intellectual and developmental disability disorders including but not limited to Down syndrome, sleep disorders, and sleep apnea.[000217] In some embodiments, disease or condition is a cardiovascular disease or disorder. Cardiovascular diseases or disorders are selected from the group consisting of angiogenesis, coronary artery diseases, cardiomyopathy, cerebral microhemorrhages, cerebral amyloid angiopathy, respiratory disorders, and dysregulated control of cerebral blood flow. [000218] In some embodiments, disease or condition is a metabolic disease or disorder. Metabolic diseases or disorders are selected from the group consisting of obesity, diabetes, acidosis, kidney diseases and kidney failure, autophagy-related diseases, liver diseases including but not limited to alcohol-related-liver disease, liver fibrosis, non-alcoholic and alcoholic fatty liver disease, steatosis, atherosclerosis, and lysosomal storage diseases. [000219] In some embodiments, disease or condition is an autoimmune disease or disorder. Autoimmune diseases or disorders are selected from the group consisting of irritable bowel syndrome and Graves’s disease. [000220] In some embodiments, disease or condition is cancer. Cancers include growth and metastasis of malignant cells including but not limited to melanoma and prostate cancer. [000221] In some embodiments, disease or condition is a muscular disease or disorder. Muscular diseases or disorders are selected from the group consisting of spinal muscular atrophy, demyelinating diseases, myotonic dystrophy, and muscular dystrophies. [000222] In some embodiments, disease or condition is a bone disease or disorder. Bone diseases or disorders are selected from the group consisting of Paget’s disease and osteoporosis. [000223] In some embodiments, provided herein is a compound of Formula (I), (I’), (II), (I-A), (II-A), (I-B), (II-B), (I-C), (II-C), (I-D), (II-D), (III), and (IV)or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I), (I’), (II), (I-A), (II-A), (I-B), (II-B), (I-C), (II-C), (I-D), (II-D), (III), and (IV) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, for use in modulating GPR4 in a subject in need thereof. EXAMPLES [000224] In some embodiments, the compound according to the present disclosure is provided in Table 1. Table 1. Exemplary compoundsGeneral Synthetic Procedures [000225] The compounds described herein are prepared in a number of ways based on the disclosures contained herein and synthetic procedures known in the art. In the description of the synthetic methods described below it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be chosen to be the conditions standard for that reaction, unless otherwise indicated. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule should be compatible with the reagents and reactions proposed. Substituents not compatible with the reaction conditions will be apparent to one skilled in the art, and alternate methods are therefore indicated. The starting materials for the examples are either commercially available or are prepared by standard methods from known materials. [000226] In some embodiments, it is desirable to protect certain substituent groups to prevent their undesired reaction. Protecting groups may be removed by a suitable method described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with the minimum disturbance of groups elsewhere in the molecule. Accordingly, if reactants include, for example, groups including but not limited to amino, carboxy, and hydroxy, it may be desirable to protect the group in some of the reactions described herein. [000227] By way of example, a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl or trifluoroacetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protectinggroups vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed by, for example, hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively, an acyl group such as a tert-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example BF3.OEt2. A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine. [000228] A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium, or sodium hydroxide, or ammonia. Alternatively, an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon. [000229] A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon. [000230] Resins may also be used as a protecting group. General Synthetic Routes [000231] In some embodiments, compounds of formulae (I), (I’), (II), (I-A), (II-A), (I- B), (II-B), (I-C), (II-C), (I-D), (II-D), (III), or (IV) are prepared by reacting a compound of formula (Ia)wherein group A, R1, and R2are as defined above for formulae (I), (I’), (II), (I-A), (II-A), (I- B), (II-B), (I-C), (II-C), (I-D), (II-D), (III), or (IV), with a compound of formula (Ib) or with a compound of formula (Ic):wherein group C, R3, Y1, Y2, Y3, Y4, L, R6, and p are as defined above for formulae (I), (I’), (II), (I-A), (II-A), (I-B), (II-B), (I-C), (II-C), (I-D), (II-D), (III), or (IV), wherein if any functional group is protected, the preparation further comprises removing the protecting group. In some embodiments, the preparation further comprises carrying out one or more of the following procedures: converting a compound of formula (I), (I’), (II), (I-A), (II-A), (I-B), (II-B), (I-C), (II-C), (I-D), (II-D), (III), or (IV) into another compound of formula (I), (I’), (II), (I-A), (II-A), (I-B), (II-B), (I-C), (II-C), (I-D), (II-D), (III), or (IV), respectively; forming a pharmaceutically acceptable salt; and / or preparing stereochemically isomeric forms thereof. [000232] In some embodiments, compounds of formulae (I), (I’), (II), (I-A), (II-A), (I- B), (II-B), (I-C), (II-C), (I-D), (II-D), (III), or (IV)are prepared by reacting a compound of formula (Id): wherein group A, R1, and R2are as define a ove or any of formulae (I), (I’), (II), (I-A), (II- A), (I-B), (II-B), (I-C), (II-C), (I-D), (II-D), (III), or (IV) with a compound of formula (Ie)wherein group C, Y1, Y2, Y3, Y4, L, R6, and p are as defined above for any of formulae (I), (I’), (II), (I-A), (II-A), (I-B), (II-B), (I-C), (II-C), (I-D), (II-D), (III), or (IV) wherein if any functional group is protected, the preparation further comprises removing the protecting group. In some embodiments, the preparation further comprises carrying out one or more of the following procedures: converting a compound of formula (I), (I’), (II), (I-A), (II-A), (I-B), (II-B), (I-C), (II-C), (I-D), (II-D), (III), or (IV) into another compound of formula (I), (I’), (II), (I-A), (II-A), (I-B), (II-B), (I-C), (II-C), (I-D), (II-D), (III), or (IV), respectively; forming a pharmaceutically acceptable salt; and / or preparing stereochemically isomeric forms thereof. [000233] In some embodiments, the reaction of a compound of formula (Ia) with a compound of formula (Ib) or formula (Ic) or the reaction of a compound of formula (Id) with a compound of formula (Ie) is performed in a reaction-inert solvent such as DCM, THF, acetonitrile, pyridine, DMF, and DMA, and optionally in the presence of a suitable base such as, for example, sodium carbonate, potassium carbonate or triethylamine, DIPEA, pyridine. In some embodiments, the reaction occurs in the presence of one or more amide- coupling agents. Non-limiting examples of suitable amide coupling agents include N,N'- dicyclohexylcarbodiimide (DCC), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), 1-(cyclohexylmethyl)-3-(2-morpholinoethyl)carbodiimide (COMU), 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), and 1,3-Dicyclohexylcarbodiimide (DCC). In some embodiments, stirring enhances the rate of the reaction. In some embodiments, the reaction is carried out at a temperature ranging between water freezing temperature (0oC) and the reflux temperature of the reaction mixture. [000234] In some embodiments, compounds of formulae (I), (I’), (II), (I-A), (II-A), (I- B), (II-B), (I-C), (II-C), (I-D), (II-D), (III), or (IV) are prepared in a single step by reacting a compound of formula (Ia’)wherein group A, R1, R2, X, Y1, Y2, Y3, Y4, and L are as defined above for any of formulae (I), (I’), (II), (I-A), (II-A), (I-B), (II-B), (I-C), (II-C), (I-D), (II-D), (III), or (IV), and Z is an appropriate leaving group such as, for example, halo, e.g., fluoro, chloro, bromo and the like, with a compound of formula (Ib’) or with a compound of formula (Ic’): wherein Group C, R6, and p are defined above for any of formulae (I), (I’), (II), (I-A), (II-A), (I-B), (II-B), (I-C), (II-C), (I-D), (II-D), (III), or (IV), and E is an appropriate moiety for reaction with formula (Ia’) (e.g., Suzuki coupling), and is for example, without limitation, a boronic acid or boronate ester. In some embodiments, if any functional group is protected, the preparation further comprises removing the protecting group. In some embodiments, the preparation further comprises carrying out one or more of the following procedures: converting a compound of formula (I), (I’), (II), (I-A), (II-A), (I-B), (II-B), (I-C), (II-C), (I- D), (II-D), (III), or (IV) into another compound of formula (I), (I’), (II), (I-A), (II-A), (I-B), (II-B), (I-C), (II-C), (I-D), (II-D), (III), or (IV), respectively; forming a pharmaceutically acceptable salt; and / or preparing stereochemically isomeric forms thereof. [000235] In some embodiments, the reaction of a compound of formula (Ia’) with a compound of formula (Ib’) or formula (Ic’) comprises a palladium catalyzed transformation including but not limited to as Buchwald-Hartwig, Suzuki-Miyaura, Heck, and Stille. In some embodiments, the reaction is performed in a reaction-inert solvent such as, for example, acetonitrile, DMF, DMA, 1,4-dioxane, NMP, and toluene. The reaction is typically conducted in the presence of a Pd(0) or Pd(II) catalyst, such as palladium acetate, palladium chloride, a palladium-phosphine complex such as [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium or palladium tetrakistriphenylphosphine, or palladium precatalysts. In some embodiments, the reaction is performed in the presence of a base which include but are not limited to, potassium carbonate, sodium carbonate, cesiumcarbonate, and potassium tert-butoxide. In some embodiments, additives such as cesium fluoride or copper iodide are used. The reaction is typically stirred to promote efficient mixing and generally conducted at temperatures ranging from ambient to elevated temperatures, typically between 25 °C and 150 °C, although reactions conducted outside this range are possible. [000236] In some embodiments, the reaction of a compound of formula (Ia’) with a compound of formula (Ic’) is carried out in SNAr conditions using a reaction-inert solvent such as, for example, acetonitrile, DMF, DMA, 1,4-dioxane, NMP, and toluene and in the presence of a suitable base such as, for example, sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, DIPEA, and pyridine. In some embodiments, additives such as sodium iodide or potassium iodide are used. In some embodiments, stirring enhances the rate of the reaction. In some embodiments, the reaction is carried out at a temperature ranging between water freezing temperature (0oC) and 200 °C. [000237] In some embodiments, compounds of formula (Ia’) are prepared by reacting a compound of formula (Id’):wherein group A, R1, and R2are as defined above for any of formulae (I), (I’), (II), (I-A), (II- A), (I-B), (II-B), (I-C), (II-C), (I-D), (II-D), (III), or (IV), with a compound of formula (Ie’) wherein Y1, Y2, Y3, Y4, and L are as defned above or any of formulae (I), (I’), (II), (I-A), (II-A), (I-B), (II-B), (I-C), (II-C), (I-D), (II-D), (III), or (IV), and Z is an appropriate leaving group such as, for example, halo, e.g., fluoro, chloro, bromo and the like, wherein if any functional group is protected, the preparation further comprises removing the protecting group. In some embodiments, the preparation further comprises carrying out one or more of the following procedures:converting a compound of formula (Ia’) into another compound of formula (Ia’); forming a pharmaceutically acceptable salt; and / or preparing stereochemically isomeric forms thereof. [000238] In some embodiments, the reaction of a compound of formula (Id’) with a compound of formula (Ie’) is performed in a reaction-inert solvent such as, for example, DCM, THF, acetonitrile, pyridine, DMF, and DMA, and optionally in the presence of a suitable base such as, for example, sodium carbonate, potassium carbonate or triethylamine, DIPEA, and pyridine. In some embodiments, the reaction occurs in the presence of one or more amide-coupling agents. Non-limiting examples of suitable amide coupling agents include N,N'-dicyclohexylcarbodiimide (DCC), benzotriazol-1- yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), 1-(cyclohexylmethyl)-3- (2-morpholinoethyl)carbodiimide (COMU), 1-[Bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (EDCI), and 1,3- Dicyclohexylcarbodiimide (DCC). In some embodiments, stirring enhances the rate of the reaction. In some embodiments, the reaction is carried out at a temperature ranging between water freezing temperature (0oC) and the reflux temperature of the reaction mixture.[000239] In some embodiments, compounds of formula (II’) (i.e., when group A of formula (I) is -N(C1-4alkyl)phenyl or -N(C1-4alkyl)heteroaryl) are prepared by reacting a compound of formula (IIa)wherein Group C, R1, R2, R3, L, Y1, Y2, Y3, and Y4are as defined above for any of formulae (I), (I’), (II), (I-A), (II-A), (I-B), (II-B), (I-C), (II-C), (I-D), (II-D), (III), or (IV), with a compound of formula (IIb) or with a compound of formula (IIc):(IIb) (IIc) wherein Group A’ is phenyl or heteroaryl, wherein Group A’ is optionally substituted with one, two, or three R5substituents, and Rzis C1-4alkyl, wherein if any functional group is protected, the preparation further comprises removing the protecting group. In some embodiments, the preparation further comprises carrying out one or more of the following procedures: converting a compound of formula (II’) into another compound of formula (II’); forming a pharmaceutically acceptable salt; and / or preparing stereochemically isomeric forms thereof. [000240] In the compound of formula (IIa), LG is an appropriate leaving group such as, for example, halo, e.g., fluoro, chloro, bromo and the like. [000241] In some embodiments, the reaction of a compound of formula (IIa) with a compound of formula (IIb) or formula (IIc) is performed in a solvent that is inert to the reaction, such as dichloromethane (DCM), tetrahydrofuran (THF), acetonitrile, pyridine, dimethylformamide (DMF), and N,N-dimethylacetamide (DMA), or another suitable polar aprotic solvent. In some embodiments, the reaction occurs in the presence of one or more bases. Non-limiting examples of suitable bases include sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, pyridine, and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), or a functional derivative thereof. In some embodiments, the reaction is carried out at a temperature ranging between water freezing temperature (0oC) and the reflux temperature of the reaction mixture.[000242] In some embodiments, the haloacetate derivatives of formula (IIa) are prepared by reaction of the respective haloderivatives (IIa’) with amine derivatives (IIb') in an amide-forming reaction under an inert atmosphere and in the presence of a coupling reagent. Examples of such reactions involve the coupling of bromo, chloro, or iodo acetic acid derivatives. Non-limiting examples of suitable amide coupling agents include N,N'- dicyclohexylcarbodiimide (DCC), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), 1-(cyclohexylmethyl)-3-(2-morpholinoethyl)carbodiimide (COMU), 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), and 1,3-Dicyclohexylcarbodiimide (DCC). Additionally, reagents such as thionyl chloride (SOCl2) and propylphosphonic anhydride (T3P) can be utilized for amide bond formation. In some embodiments, the reaction is carried out in a suitable solvent, such as 1,4-dioxane, toluene, benzene, dimethylformamide (DMF), dimethoxyethane (DME), or N,N-dimethylacetamide (DMA) solution, for example at temperatures ranging from room temperature to 100 °C.[000243] In some embodiments, compounds of formula (III’) (i.e., when group A of formula (I) is nitrogen bound bicyclic heteroaryl) are prepared by reacting a compound of formula (IIIa)wherein Group C, R1, R2, R3, Y1, Y2, Y3, Y4, and L are as defined above for any of formulae (I), (I’), (II), (I-A), (II-A), (I-B), (II-B), (I-C), (II-C), (I-D), and (II-D), with a compound of formula (IIIb):wherein Group A’’ is nitrogen bound bicyclic heteroaryl, wherein if any functional group is protected, the preparation further comprises removing the protecting group. In some embodiments, the preparation further comprises carrying out one or more of the following procedures: converting a compound of formula (III’) into another compound of formula (III’); forming a pharmaceutically acceptable salt; and / or preparing stereochemically isomeric forms thereof. [000244] In the compound of formula (IIIa), LG is an appropriate leaving group such as, for example, halo, e.g., fluoro, chloro, bromo and the like. [000245] In some embodiments, the reaction of a compound of formula (IIIa) with a compound of formula (IIIb) is performed in a solvent that is inert to the reaction, such as dichloromethane (DCM), tetrahydrofuran (THF), acetonitrile, pyridine, dimethylformamide (DMF), and N,N-dimethylacetamide (DMA), or another suitable polar aprotic solvent. In some embodiments, the reaction is conducted in the presence of one or more bases. Non- limiting examples of suitable bases include sodium hydride, sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, pyridine, and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), or a functional derivative thereof. In some embodiments, the reaction is carried out at a temperature ranging between water freezing temperature (0oC) and the reflux temperature of the reaction mixture. In some embodiments, additives such as potassium iodide, sodium iodide, tetrabutylammonium iodide or similar compounds are used. Abbreviations COMU (1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethyl-amino- morpholino-carbenium hexafluorophosphate CV column volumesDCM dichloromethane DMA N,N-dimethylacetamide DMF N,N-dimethylformamide DIPEA N,N-diisopropylethylamine EDCI.HCl 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride equiv molar equivalent h hour HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium- hexafluorphosphate MeCN acetonitrile min minute MPLC medium pressure liquid chromatography NMR nuclear magnetic resonance LC-MS liquid chromatography-mass spectometry r.t. room temperature THF tetrahydrofuran Analytical Methods LC-MS Methods LCMS single quadrupole 2020 method [000246] Analytical HPLC and molecular weight determinations were performed on a HPLC-ESI-MS instrument equipped with a UV-VIS (Nexera-I LC-2040C Plus) and an MS detector (LCMS2020 single quadrupole Shimadzu) using a reverse phase column (C18, 2.7 µm, 75 x 4.6 mm). Solvent A was water (0.1 % formic acid) and Solvent B was acetonitrile. The total analysis time was fixed at 5 min at a flow rate of 1 mL / min. The injection volume was fixed at 10 µL. The temperature of the column was fixed at 40 °C. [000247] The gradient started by equilibrating the column for 0.5 min with 5% B. The amount of B was subsequently increased to 95% for 3.5 min before being held isocratically for 0.5 min at 95% of B. The column was then re-equilibrated in 5% B for 0.5 min. [000248] The separation was first analyzed using a UV-VIS detector at a wavelength of 220 nm and 254 nm throughout the acquisition time. Then the separation was analyzed using an ESI-Single QUAD type mass spectrometer LCMS2020.[000249] Ionization was then carried out in positive mode and in negative mode at the same time by switching between positive and negative mode every 0.3 sec using an electrospray source. Then, the compounds were analyzed by a single quadrupole analyzer in a mass range from 100 to 1500 m / z. The scan speed was 5000 u / second and the interface voltage was 4.5 kV. The interface and desolvation line (DL) temperatures were fixed at 300 and 250 °C, respectively. The temperature of the heat block was fixed at 400 °C. Nebulizing gas flow and drying gas were set at 3 L / min and 15 L / min respectively. The data were then processed manually using the LabSolutions software. LCMS triple quadrupole 8045 method [000250] Analytical UPLC and molecular weight determinations were performed on a UPLC-ESI-MS instrument equipped with a UV-VIS (Nexera UHPLC system LC40) and a MS detector (LCMS8045 triple quadrupole Shimadzu) using a reverse phase column (C18, 1.8 µm, 50 x 4.6 mm). Solvent A was water (0.1 % formic acid) and Solvent B was acetonitrile. The total analysis time was fixed at 5 min at a flow rate of 1.0 mL / min. The injection volume was fixed at 10 µL. The temperature of the column was fixed at 40 °C. [000251] The gradient started by equilibrating the column for 0.5 min with 5% B. The amount of B was subsequently increased to 95% for 2.5 min before being held isocratically for 0.2 min at 95% of B. The column was then re-equilibrated in 5% B for 0.45 min. [000252] The separation was first analyzed using a UV-VIS detector at a wavelength of 220 nm and 254 nm throughout the acquisition time. Then the separation was analyzed using an ESI-Triple QUAD type mass spectrometer LCMS8045. [000253] Ionization was then carried out in positive mode and in negative mode at the same time by switching between positive and negative mode every 0.3 sec using an electrospray source. Then, the compounds were analyzed by a single quadrupole analyzer in a mass range from 100 to 1500 m / z. The scan speed was 3000 u / second and the interface voltage was 4.5 kV. The interface and desolvation line (DL) temperatures were fixed at 50 and 250 °C, respectively. The temperature of the heat block was fixed at 400 °C. Nebulizing gas flow and drying gas were set at 2.9 L / min and 15 L / min respectively. The data were then processed manually using the LabSolutions software. TLC-MS[000254] Analytical Thin Layer Chromatography coupled with mass spectrometry (TLC-MS) were performed on a Advion-Interchim System equipped with a sample extraction system equipped with an isocratic pump (Plate Express) and with a single quadrupole mass spectrometer equipped with APCI source (CMS L Advion interchim). For each sample spot, the total analysis time was 30 seconds. [000255] The analysis started with the extraction of the sample spot with pure methanol (HPLC grade). The extraction was done under a physical pressure of 250 Nm for 30 seconds. During extractions, the sample was eluted with an isocratic pump with methanol towards a single quadrupole mass spectrometer equipped with an APCI source. [000256] Ionization was then carried out in positive mode and in negative mode at the same time by switching between positive and negative mode every 0.3 sec using an APCI source. Then, the compounds were analyzed by a single quadrupole analyzer in a mass range from 100 to 1500 m / z. The scan speed was 10000 units / second and the interface voltage was 3.5 kV. The desolvation temperature was fixed at 350 °C. The temperature of the heat block was fixed at 400 °C. Nebulizing gas flow and Drying gas were set at 3.5 L / min and 15 L / min respectively. NMR [000257] All NMR spectra were obtained using Bruker Avance 400 MHz spectrometers running Topspin 4.0 Software.1H NMR spectra were recorded in deuterated solvents. Data are reported as follows : s = singlet, d = doublet, t = triplet, q = quartet, p = quintet, m = multiplet, br = broad; signal coupling constants J in Hz. MPLC MPLC Biotage System [000258] Normal phase purification was carried out on a Biotage Isolera 4 system equipped with 1 binary pump going to a maximum pressure of 8 bar and equipped with a UV-VIS detection system.[000259] Purifications were done with different mobile phases (cyclohexane / ethyl acetate or dichloromethane / methanol typically). Separation was achieved in gradient mode on a Claricep Flash Silica column of particle size 50 µm (from 4 g to 330 g). MPLC Advion-Interchim System [000260] Reverse phase purification was carried out on an MPLC XS520 plus system (Advion-Interchim) equipped with 1 quaternary pump going to a maximum pressure of 20 bar and equipped with a Diode Array Detector (DAD) detection system. [000261] Purifications were carried out with water (0.1% formic acid) / acetonitrile or methanol unless otherwise stated. Separation was achieved in gradient mode on a Claricep C18 column of particle size 30 µm (from 4 g to 120 g). Preparative HPLC Method A [000262] Preparative HPLC was performed on a preparative HPLC instrument equipped with a UV-VIS (LC10 Shimadzu systems) using a reverse phase column (Uptisphere C18, 5 µm, 250 x 21.2 mm). Solvent A was water (0.1% formic acid) and Solvent B was acetonitrile. The total analysis time was fixed at 120 min at a flow rate of 15.0 mL / min. The injection volume was fixed at 1 mL in 100% DMSO. The column was kept at room temperature. The gradient started by equilibrating the column for 5 min with 5% B. The amount of B was subsequently increased to 95% for 100 min before being held isocratically for 5 min at 95% of B. The column was then reequilibrated in 5% B for 10 min. The separation was first analyzed using a UV-VIS detector at a wavelength of 220 nm and 254 nm throughout the acquisition time. Then the separation was then collected with a fraction collector (FRC-40). All fractions were collected during the separation. General procedure A – Amide coupling[000263] To a mixture of the carboxylic acid (1 equiv) and amine (1 equiv) in dichloromethane (0.1 molar) was added N,N-diisopropylethylamine (1 equiv), followed by O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-hexafluorphosphat (1 equiv). The reaction mixture was stirred at room temperature for 1-24 h. The reaction mixture was diluted with saturated aqueous ammonium chloride and dichloromethane. The phases were separated and the aqueous phase was washed with dichloromethane (2x). The combined organic layers were washed with brine and dried over anhydrous magnesium sulfate, filtered and the solvent was removed under reduced pressure. The product was purified by column chromatography to afford the desired product. General procedure B – Amide coupling[000264] To a mixture of the carboxylic acid (1 equiv) and amine (1 equiv) in DMF (0.1 molar) was added N,N-diisopropylethylamine (2 equiv), followed by 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (1.5 equiv). The reaction mixture was stirred at room temperature for 1-24 h. The reaction mixture was diluted with ethyl acetate and water. The phases were separated, and the aqueous phase was washed with ethyl acetate (3x). The combined organic phases were washed with brine (3x), dried over anhydrous magnesium sulfate, filtered and the solvent was removed under reduced pressure. The product was purified by column chromatography to afford the desired product. General procedure C[000265] To a solution of N-(2-(1H-pyrazol-1-yl)benzyl)-2-chloroacetamide (1 equiv) in acetonitrile (0.2 molar), sodium bicarbonate (2 equiv), sodium iodide (2 equiv) and the corresponding amine (2 equiv) were added. The reaction mixture was stirred overnight at 80 °C. The reaction was diluted with ethyl acetate, then washed with saturated aqueous sodium thiosulfate. The phases were separated, and the aqueous phase was extracted with ethyl acetate (2x). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The product was purified by normal phase MPLC to afford the desired product. General procedure D[000266] To a solution of the indole derivative (1 equiv) in N,N-dimethylformamide (0.25 molar) was added sodium hydride (60 wt% dispersion in mineral oil, 1 equiv) and the reaction mixture was stirred for 30 min at room temperature. Then, N-(2-(1H-pyrazol-1- yl)benzyl)-2-chloroacetamide (1 equiv) was added at room temperature and the reaction mixture was stirred overnight at room temperature. The reaction was diluted with ethyl acetate and washed brine (2x). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The product was purified by normal phase MPLC to afford the desired product. General procedure E[000267] To a solution of the fluoronitrile (1 equiv) in anhydrous DMA (0.3 molar) was sequentially added the pyrazole (1.2 equiv) and cesium carbonate (1 equiv). The reaction mixture was stirred at 80 °C for 18 h. The reaction mixture was diluted with ethyl acetate and water. The phases were separated, and the aqueous phase was extracted with ethyl acetate (3x). The combined organic layers were washed with brine (3x), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The product was purified by column chromatography to afford the desired product. General procedure F[000268] The substituted nitrile (1 equiv) was dissolved in methanol (0.25 molar) under a nitrogen atmosphere and nickel (Raney) (0.75 equiv) was added. The mixture was stirred at room temperature under a hydrogen atmosphere (balloon) for 18 h. The reaction mixture was filtered through celite, washing with methanol. The solvent was removed. The product was purified by column chromatography or was used directly without further purification. General procedure G [000269] The aryl halide (1 equiv), boronic acid or boronic ester (2 equiv), potassium carbonate (4 equiv) and palladiumtetrakis (0.10 equiv) were mixed in degassed 1,4- dioxane / water (5:1 v / v) (0.10 molar). The mixture was heated to 100 °C overnight. The reaction mixture was poured into a separatory funnel, diluted with ethyl acetate and water was added. The phases were separated, the aqueous phase was washed with ethyl acetate(2x), and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude mixture was purified by MPLC to yield the desired product. General procedure H[000270] To a sealed tube were added palladium diacetate (0.10 equiv) and tricyclohexylphosphine (0.20 equiv). The solvents were degassed. Solvent ratio: toluene:water (3:1), overall concentration 0.08 M, (e.g. on 0.12 mmol scale: toluene (1.50 mL): water (0.50 mL)). Toluene (0.50 mL) was added and the mixture was degassed for 5 min. The aryl bromide (1 equiv) and cyclopropaneboronic acid (4 equiv) were dissolved in toluene (1.0 mL) and the mixture was degassed. This was added to the mixture of catalyst and ligand. Potassium phosphate tribasic (6 equiv) and water (0.50 mL) were added. The tube was placed under an atmosphere of nitrogen, sealed, and heated to 110 °C for 24 h. The reaction mixture was poured into a separatory funnel, diluted with ethyl acetate and washed with water (2 x 15 mL). The organic layer was dried over anhydrous sodium sulfate. The crude mixture was purified by MPLC to yield the desired product. General procedure I [000271] To a stirred solution of indole derivative (1.00 equiv) in anhydrous acetone (0.10 molar) was carefully added potassium hydroxide (5.00 equiv) under inert atmosphere. The vial was sealed then purged in an inert atmosphere. The reaction mixture was vigorouslystirred at 25 °C for 30 min then methyl iodide (2.00 equiv) was added dropwise. The reaction mixture was vigorously stirred at 25 °C for 16 h. Synthetic Methods N-(2-(1H-Pyrazol-1-yl)benzyl)-2-chloroacetamide[000272] (2-(1H-Pyrazol-1-yl)phenyl)methanamine (5.00 g, 28.87 mmol, 1 equiv) was dissolved in dichloromethane (144 mL, 0.2 molar) and the resulting solution was cooled to 0 °C. Sodium bicarbonate (9.7 g, 115.5 mmol, 4 equiv) was added, followed by the dropwise addition of chloracetyl chloride (2.76 mL, 34.64 mmol, 1.2 equiv) with strong stirring. The mixture was stirred at 0 °C for 2 h. Brine was added to the mixture and the phases were separated. The aqueous phase was extracted with dichloromethane (3x). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude mixture was purified by normal phase MPLC (0-100% ethyl acetate in cyclohexane, 20 CV, 120 g silica column). N-(2-(1H-Pyrazol-1-yl)benzyl)-2- chloroacetamide was isolated as a solid (4.95 g, 19.82 mmol, 69%). 1H NMR (400 MHz, CDCl3) δ 8.21 (br, 1H), 7.77 (dd, J = 1.9, 0.7 Hz, 1H), 7.74 (dd, J = 2.4, 0.7 Hz, 1H), 7.64 – 7.55 (m, 1H), 7.44 – 7.35 (m, 2H), 7.34 – 7.29 (m, 1H), 6.50 (t, J = 2.1 Hz, 1H), 4.38 (d, J = 6.4 Hz, 2H), 4.02 (s, 2H). N-(2-Bromobenzyl)-2-(1H-indol-3-yl)acetamide [000273] Synthesized from 2-(1H-indol-3-yl)acetic acid (1.00 g, 1 equiv, 5.71 mmol) and (2-bromophenyl)methylamine (1.06 g, 1 equiv, 5.71 mmol) according to generalprocedure A. The crude mixture was purified by reverse phase chromatography using a 5- 70% gradient of acetonitrile in water (0.1% formic acid) over 30 CV. N-(2-Bromobenzyl)-2- (1H-indol-3-yl)acetamide was isolated as a solid (1.22 g; 3.55 mmol; 62%). 1H NMR (400 MHz, CDCl3) δ 8.28 (br s, 1H), 7.56 (d, J = 7.9 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.42 – 7.36 (m, 1H), 7.26 – 7.18 (m, 3H), 7.18 – 7.11 (m, 2H), 7.11 – 7.05 (m, 1H), 6.19 (br, 1H), 4.43 (d, J = 6.2 Hz, 2H), 3.79 (s, 2H). N-((2-Chloropyridin-3-yl)methyl)-2-(1H-indol-3-yl)acetamide[000274] Synthesized from 2-(1H-indol-3-yl)acetic acid (2.00 g, 1 equiv, 11.4 mmol) and (2-chloropyridin-3-yl)methanamine (1.63 g, 1 equiv, 11.4 mmol) according to general procedure A. The crude mixture was purified by reverse phase chromatography using a 5- 95% gradient of acetonitrile in water (0.1% formic acid) over 15 CV. N-((2-Chloropyridin-3- yl)methyl)-2-(1H-indol-3-yl)acetamide was isolated as a solid (1.53 g; 5.10 mmol; 45%). 1H NMR (400 MHz, DMSO) δ 10.90 (br, 1H), 8.46 (t, J = 5.9 Hz, 1H), 8.28 (dd, J = 4.8, 1.9 Hz, 1H), 7.64 (dd, J = 7.6, 1.9 Hz, 1H), 7.55 (d, J = 7.9 Hz, 1H), 7.35 (d, J = 7.7 Hz, 1H), 7.34 – 7.28 (m, 1H), 7.22 (d, J = 2.4 Hz, 1H), 7.08 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H), 6.98 (ddd, J = 7.9, 7.0, 1.1 Hz, 1H), 4.30 (d, J = 5.8 Hz, 2H), 3.63 (s, 2H). N-(2-Bromophenyl)-2-(1H-indol-3-yl)acetamide [000275] Synthesized from indoleacetic acid (200 mg, 1 equiv, 1.14 mmol) and 2- bromoaniline (393 mg, 2 equiv, 2.28 mmol) according to general procedure A, using N,N- dimethylformamide as the solvent. The crude mixture was purified by normal phase MPLC (5-25% ethyl acetate in cyclohexane, 25 CV, 20 g silica column). N-(2-Bromophenyl)-2-(1H- indol-3-yl)acetamide was isolated as a solid (142 mg, 0.40 mmol, 35%).1H NMR (400 MHz, CDCl3) δ 8.38 (dd, J = 8.3, 1.6 Hz, 1H), 8.28 (s, 1H), 8.02 (s, 1H), 7.64 (d, J = 7.9 Hz, 1H), 7.43 (d, J = 8.2 Hz, 1H), 7.37 (dd, J = 8.0, 1.5 Hz, 1H), 7.32 – 7.22 (m, 3H), 7.17 (td, J = 7.5, 1.0 Hz, 1H), 6.89 (td, J = 7.7, 1.6 Hz, 1H), 3.95 (s, 2H). N-(1-(2-(1H-pyrazol-1-yl)phenyl)ethyl)-2-(1H-indol-3-yl)acetamide – Example 1[000276] Synthesized from indoleacetic acid (100 mg, 1 equiv, 571 μmol) and 1-(2- (1H-pyrazol-1-yl)phenyl)ethanamine (107 mg, 1 equiv, 571 μmol) according to general procedure A using tetrahydrofuran (5.71 mL, 0.1 molar) as solvent and N,N- diisopropylethylamine (1.1 equiv). The crude mixture was purified by reverse phase chromatography using a 20-95% gradient of acetonitrile in water (0.1% formic acid) over 25 CV. which afforded N-(1-(2-(1H-pyrazol-1-yl)phenyl)ethyl)-2-(1H-indol-3-yl)acetamide (85 mg, 0.25 mmol, 43 %) as a solid after freeze-drying.1H NMR (400 MHz, CDCl3) δ 8.19 (br s, 1H), 7.63 (d, J = 2.2 Hz, 1H), 7.54 (d, J = 7.9 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.37-7.27 (m, 3H), 7.21–7.10 (m, 3H), 7.00 – 6.92 (br, 1H), 6.31 (s, 1H), 5.19 (br, 1H), 3.88 – 3.53 (m, 2H), 0.88 (d, J = 6.4 Hz, 3H). N-(2-(1H-pyrazol-1-yl)phenyl)-2-(1H-indol-3-yl)acetamide – Example 2 [000277] Synthesized from indoleacetic acid (100 mg, 1 equiv, 571 μmol) and 2- (pyrazol-1-yl)aniline (90.9 mg, 1 equiv, 571 μmol) according to the general procedure A using N,N-diisopropylethylamine (1.1 equiv), N-[1-(cyano-2-ethoxy-2- oxoethylideneaminooxy)dimethylamino(morpholino)uronium hexafluorophosphate (1 equiv) instead of HATU. The crude mixture was purified by reverse phase chromatography using a 20-95% gradient of acetonitrile in water (0.1% formic acid) over 23 CV. N-(2-(1H-pyrazol-1- yl)phenyl)-2-(1H-indol-3-yl)acetamide was isolated as a solid (117 mg, 370 μmol, 65%).1H NMR (400 MHz, CDCl3) δ 9.94 (s, 1H), 8.53 (d, J = 8.3 Hz, 1H), 8.35 (s, 1H), 7.57 – 7.43 (m, 2H), 7.40 (d, J = 8.2 Hz, 1H), 7.37 – 7.30 (m, 1H), 7.24 – 7.14 (m, 2H), 7.14 – 7.03 (m, 3H), 7.01 – 6.94 (br, 1H), 6.39 – 5.68 (br, 1H), 3.86 (s, 2H). N-((1H-indol-3-yl)methyl)-2-(2-(1H-pyrazol-1-yl)phenyl)acetamide – Example 3Methyl 2-(2-(1H-pyrazol-1-yl)phenyl)acetate[000278] A vial was charged with methyl 2-(2-bromophenyl)acetate (505 mg, 2.20 mmol, 1.5 equiv), 1H-pyrazole (100 mg, 1.47 mmol, 1.0 equiv), Cu(I)2O (21 mg, 0.0147 mmol, 0.1 equiv) and cesium carbonate (957 mg, 2.94 mmol, 2.0 equiv). The vial was capped, evacuated and backfilled with nitrogen 3 times. dimethylformamide (5 mL) was added and the mixture was stirred at 100 °C for 36 h. The reaction mixture was cooled down to room temperature. Saturated aqueous ammonium chloride and water were added. The mixture was extracted twice with ethyl acetate. The combined organics were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (silica, 0-25% ethyl acetate in cyclohexane). Methyl 2- (2-(1H-pyrazol-1-yl)phenyl)acetate was isolated (71 mg, 0.33 mmol, 22%).1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 1.6 Hz, 1H), 7.68 (d, J = 2.3 Hz, 1H), 7.42 – 7.30 (m, 4H), 6.44 (t, J = 2.1 Hz, 1H), 3.69 (s, 2H), 3.62 (s, 3H). 2-(2-(1H-Pyrazol-1-yl)phenyl)acetic acid[000279] Methyl 2-(2-(1H-pyrazol-1-yl)phenyl)acetate (70 mg, 0.32 mmol, 1.0 equiv) was dissolved in methanol and water (1:1, 0.03 M overall concentration). Aqueous lithium hydroxide (1 M, 0.65 mL, 0.65 mmol, 2.0 equiv) was added. The mixture was stirred at room temperature for 5 hours. The mixture was acidified by the addition of aqueous hydrochloric acid (2 M) and extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. The crude mixture (64 mg) was used without further purification.1H NMR (400 MHz, CDCl3) δ 7.84 (dd, J = 2.1, 0.7 Hz, 1H), 7.80 (dd, J = 2.5, 0.7 Hz, 1H), 7.64 – 7.57 (m, 1H), 7.46 – 7.37 (m, 2H), 7.37 – 7.30 (m, 1H), 6.61 – 6.57 (m, 1H), 3.64 (s, 2H). N-((1H-indol-3-yl)methyl)-2-(2-(1H-pyrazol-1-yl)phenyl)acetamide [000280] Synthesized from 2-(2-(1H-pyrazol-1-yl)phenyl)acetic acid (64 mg, 0.32 mmol, 1.0 equiv) and (1H-indol-3-yl)methanamine (56 mg, 0.38 mmol, 1.2 equiv) according to general procedure A using EDCI (1.2 equiv) and N,N-diisopropylethylamine (3.0 equiv). The reaction mixture was concentrated. The crude mixture was purified by reverse phase chromatography using a 5-95% gradient of methanol in water (0.1% formic acid) over 15 CV. N-((1H-Indol-3-yl)methyl)-2-(2-(1H-pyrazol-1-yl)phenyl)acetamide was isolated as solid (40 mg, 0.32 mmol, 38%).1H NMR (400 MHz, CDCl3) δ 8.10 (br s, 1H), 7.77 (d, J = 7.6 Hz, 1H), 7.66 (d, J = 2.4 Hz, 1H), 7.61 (d, J = 7.9 Hz, 1H), 7.55 (d, J = 1.9 Hz, 1H), 7.47 – 7.31 (m, 3H), 7.29 – 7.24 (m, 1H), 7.23 – 7.15 (m, 2H), 7.10 (ddd, J = 8.0, 7.0, 1.0 Hz, 1H), 6.44 (t, J = 2.2 Hz, 1H), 4.61 (s, 2H), 3.64 (br s, 2H). N-(2-(1H-Pyrazol-1-yl)benzyl)-2-(1H-indol-3-yl)propanamide – Example 4[000281] Synthesized from α-methyl-1H-indole-3-acetic acid (30 mg, 1 equiv, 0.16 mmol) and (2-pyrazol-1-ylphenyl)methanamine (27 mg, 1 equiv, 0.16 mmol) according to general procedure A. The crude mixture was purified by reverse phase chromatography using a 5-95% gradient of acetonitrile in water (0.1% formic acid) over 30 CV. A second purification was required using normal phase MPLC (0-60% ethyl acetate in cyclohexane, 25 CV, 4 g silica column). N-(2-(1H-Pyrazol-1-yl)benzyl)-2-(1H-indol-3-yl)propanamide was isolated as a solid (21 mg, 60 μmol, 38%).1H NMR (400 MHz, CDCl3) δ 8.17 (br, 1H), 7.55 – 7.47 (m, 2H), 7.45 – 7.41 (m, 1H), 7.40 – 7.35 (m, 1H), 7.35 – 7.28 (m, 2H), 7.25 – 7.16 (m, 2H), 7.15 – 7.11 (m, 1H), 7.11 – 7.02 (m, 2H), 7.00 – 6.87 (m, 1H), 6.34 – 6.17 (m, 1H), 4.28 (dd, J = 14.2, 6.3 Hz, 1H), 4.20 (dd, J = 14.2, 6.3 Hz, 1H), 3.85 (q, J = 7.1 Hz, 1H), 1.62 (d, J = 7.1 Hz, 3H). ESI-MS: m / z calc. for C21H20N4O [M+H]+: 345.1710 , found 345.1. N-(2-(1H-Pyrazol-1-yl)benzyl)-2-(1H-indol-3-yl)-N-methylacetamide – Example 5 [000282] Synthesized from indole. mg, 1 equiv, 285 μmol) and 1-(2- (1H-pyrazol-1-yl)phenyl)-N-methylmethanamine dihydrochloride (74.3 mg, 1 equiv, 285 μmol) according to general procedure A using N,N-diisopropylethylamine (3 equiv). The crude mixture was purified by reverse phase chromatography using a 5-90% gradient of acetonitrile in water (0.1% formic acid) over 30 CV. N-(2-(1H-Pyrazol-1-yl)benzyl)-2-(1H- indol-3-yl)-N-methylacetamide was isolated as a solid (70 mg, 200 μmol, 71%).1H NMR (400 MHz, CDCl3) δ 8.24 – 8.11 (br s, 1H), 7.77 – 7.69 (m, 1H), 7.67 – 7.59 (m, 1H), 7.59 –7.55 (m, 1H), 7.43 – 7.00 (m, 8H), 6.49 – 6.38 (m, 1H), 4.63 – 4.59 (m, 2H), 3.87 – 3.76 (m, 2H), 2.92 –2.85 (m, 3H).ESI-MS: m / z calc. for C21H20N4O [M+H]+: 345.1710, found 345.0. N-(2-(4-Fluoro-1H-pyrazol-1-yl)benzyl)-2-(1H-indol-3-yl)acetamide – Example 62-(4-Fluoro-1H-pyrazol-1-yl)benzonitrile[000283] 2-(4-Fluoro-1H-pyrazol-1-yl)benzonitrile was prepared from 1H-4-fluoro- pyrazole (213.2 mg, 1.2 equiv, 2.48 mmol) and 2-fluorobenzenecarbonitrile (250.0 mg, 1.0 equiv, 2.06 mmol) according to general procedure E. The crude mixture was purified by normal phase MPLC (0-75% ethyl acetate in cyclohexane, 20 CV). 2-(4-Fluoro-1H-pyrazol- 1-yl)benzonitrile was isolated as a powder (359 mg, 1.92 mmol, 93%).1H NMR (400 MHz, CDCl3) δ 8.03 (dd, J = 4.8, 0.7 Hz, 1H), 7.81 – 7.62 (m, 4H), 7.44 (ddd, J = 7.8, 6.8, 1.9 Hz, 1H).19F NMR (376 MHz, CDCl3) δ -173.44 (t, J = 4.4 Hz). (2-(4-Fluoro-1H-pyrazol-1-yl)phenyl)methanamine [000284] (2-(4-Fluoro-1H-pyrazol-1-yl)phenyl)methanamine was prepared by the reduction of 2-(4-fluoro-1H-pyrazol-1-yl)benzonitrile (329.1 mg, 1.0 equiv, 1.76 mmol) according to general procedure F. The crude mixture was purified by reverse phase chromatography using a 5-95% gradient of acetonitrile in water (0.1% formic acid) over 30 CV. (2-(4-Fluoro-1H-pyrazol-1-yl)phenyl)methanamine was isolated as a solid (136 mg, 710 µmol, 40%).1H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 4.6 Hz, 1H), 7.65 – 7.57 (m, 2H), 7.49 – 7.40 (m, 2H), 7.30 (dd, J = 7.4, 1.8 Hz, 1H), 3.94 (s, 2H).19F NMR (376 MHz, CDCl3) δ -175.11 (t, J = 4.3 Hz, 1F).ESI-MS: m / z calc. for C10H10FN3 [M+MeCN+H]+: 233.119703; found 233. N-(2-(4-Fluoro-1H-pyrazol-1-yl)benzyl)-2-(1H-indol-3-yl)acetamide[000285] Synthesized from 2-(1H-indol-3-yl)acetic acid (64.1 mg, 1.0 equiv, 366 μmol) and (2-(4-fluoro-1H-pyrazol-1-yl)phenyl)methanamine (70.0 mg, 1.0 equiv, 366 μmol) according to general procedure A. The crude mixture was purified by reverse phase chromatography using a 5-90% gradient of acetonitrile in water (0.1% formic acid) over 30 CV on a 12 g C18 column. N-(2-(4-Fluoro-1H-pyrazol-1-yl)benzyl)-2-(1H-indol-3- yl)acetamide was obtained as a solid (42.2 mg, 121 µmol, 33%).1H NMR (400 MHz, CDCl3) δ 8.22 (br, 1H), 7.53 – 7.44 (m, 2H), 7.42 (d, J = 8.2 Hz, 1H), 7.35 – 7.27 (m, 3H), 7.26 – 7.23 (ddd, J = 8.3, 1.1 Hz, 1H), 7.16 – 7.08 (m, 2H), 7.06 (d, J = 2.4 Hz, 1H), 6.86 (t, J = 5.5 Hz, 1H), 6.80 (dd, J = 4.1, 0.7 Hz, 1H)., 4.28 (d, J = 6.3 Hz, 2H), 3.72 (s, 2H).19F NMR (376 MHz, CDCl3) δ -176.19 (t, J = 4.5 Hz, 1F). ESI-MS: m / z calc. for [M+H]+: 349.145916; found 349. N-(2-(3-Fluoro-1H-pyrazol-1-yl)benzyl)-2-(1H-indol-3-yl)acetamide – Example 7 2-(3-Fluoro-1H-pyrazol-1-yl)benzonitrile [000286] Synthesized from 2-fluorobenzonitrile (0.30 g, 1 equiv, 2.5 mmol) and 3- fluoro-1H-pyrazole (0.23 g, 1.1 equiv, 2.7 mmol) according to general procedure E. The crude mixture was purified by reverse phase chromatography using a 10-95% gradient ofacetonitrile in water (0.1% formic acid) over 30 CV on a 40 g C18 column.2-(3-Fluoro-1H- pyrazol-1-yl)benzonitrile was isolated as a solid (240 mg, 128 mmol, 52%).1H NMR (400 MHz, CDCl3) δ 8.04 (t, J = 2.6 Hz, 1H), 7.79 – 7.74 (m, 2H), 7.70 (ddd, J = 8.5, 7.4, 1.4 Hz, 1H), 7.43 (td, J = 7.4, 1.4 Hz, 1H), 6.13 (dd, J = 5.7, 2.6 Hz, 1H).19F NMR (376 MHz, CDCl3) δ -127.28 (d, J = 5.5 Hz, 1F). (2-(3-Fuoro-1H-pyrazol-1-yl)phenyl)methanamine[000287] Synthesized from 2-(3-fluoro-1H-pyrazol-1-yl)benzonitrile (240 mg, 1 equiv, 1.28 mmol) according to general procedure F. The crude mixture was purified by reverse phase chromatography using a 5-50% gradient of acetonitrile in water (0.1% formic acid) over 25 CV on a 20 g C18 column. (2-(3-Fuoro-1H-pyrazol-1-yl)phenyl)methanamine was isolated as a solid (154 mg, 805 μmol, 63%).1H NMR (400 MHz, CDCl3) δ 7.67 – 7.56 (m, 2H), 7.50 – 7.38 (m, 2H), 7.36 – 7.28 (m, 1H), 6.07 (dd, J = 5.6, 2.6 Hz, 1H), 3.97 (s, 2H).19F NMR (376 MHz, CDCl3) δ -127.89 (d, J = 5.5 Hz, 1F). N-(2-(3-Fluoro-1H-pyrazol-1-yl)benzyl)-2-(1H-indol-3-yl)acetamide [000288] Synthesized from 2-(1H-indol-3-yl)acetic acid (143 mg, 1 equiv, 816 μmol) and (2-(3-fluoro-1H-pyrazol-1-yl)phenyl)methanamine (156 mg, 1 equiv, 816 μmol) according to general procedure A. The crude mixture was purified by reverse phase chromatography using a 5-95% gradient of acetonitrile in water (0.1% formic acid) over 30 CV. N-(2-(3-Fluoro-1H-pyrazol-1-yl)benzyl)-2-(1H-indol-3-yl)acetamide was isolated as a solid (63 mg, 180 μmol, 22%).1H NMR (400 MHz, CDCl3) δ 8.25 (br s, 1H), 7.54 – 7.49 (m, 1H), 7.49 – 7.47 (m, 1H), 7.37 (d, J = 8.1 Hz, 1H), 7.35 – 7.28 (m, 2H), 7.28 – 7.26 (m, 1H), 7.23 – 7.17 (m, 1H), 7.17– 7.14 (m, 1H), 7.13 (d, J = 2.4 Hz, 1H), 7.10 – 7.03 (m, 1H), 6.71 (br t, 1H), 5.84 (dd, J = 5.7, 2.5 Hz, 1H), 4.32 (d, J = 6.4 Hz, 2H), 3.71 (s, 2H).19F NMR (376 MHz, CDCl3) δ -129.40 (dd, J = 5.7, 2.4 Hz). ESI-MS: m / z calc. for C20H17FN4O [M+H]+: 349.1459, found 349. 2-(1H-Indol-3-yl)-N-(2-(3-methyl-1H-pyrazol-1-yl)benzyl)acetamide – Example 82-(3-Methyl-1H-pyrazol-1-yl)benzonitrile[000289] Synthesized from 2-fluorobenzonitrile (500 mg, 4.13 mmol, 1 equiv) and 5- methyl-1H-pyrazole (407 mg, 4.95 mmol, 1.20 equiv) according to general procedure E. The product was purified by normal phase MPLC (0-50% ethyl acetate in cyclohexane, 15 CV, 80 g silica column) to afford 2-(5-methyl-1H-pyrazol-1-yl)benzonitrile (253 mg, 1.38 mmol, 33%) as an oil.1H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 2.5 Hz, 1H), 7.80 (dd, J = 8.4, 1.2 Hz, 1H), 7.74 (dd, J = 7.8, 1.5 Hz, 1H), 7.68 (ddd, J = 8.4, 7.5, 1.6 Hz, 1H), 7.37 (td, J = 7.6, 1.2 Hz, 1H), 6.33 (d, J = 2.5 Hz, 1H), 2.39 (s, 3H). ESI-MS: m / z calc. for C11H9N3[M+H]+: 184.08 found 184. (2-(3-Methyl-1H-pyrazol-1-yl)phenyl)methanamine [000290] Synthesized from 2-(3-methyl-1H-pyrazol-1-yl)benzonitrile (232 mg, 1.27 mmol, 1 equiv) according to general procedure F. The crude mixture was purified by reverse phase chromatography using a 5-95% gradient of acetonitrile in water (0.1% formic acid) over 35 CV on a 40 g C18 column. (2-(3-Methyl-1H-pyrazol-1-yl)phenyl)methanamine was isolated as a solid (187 mg, 1.00 mmol, 79%).1H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 2.4 Hz, 1H), 7.59 (dd, J = 7.6, 1.7 Hz, 1H), 7.45 (td, J = 7.6, 1.7 Hz, 1H), 7.38 (td, J = 7.5, 1.5 Hz, 1H), 7.30 (dd, J = 7.8, 1.5 Hz, 1H), 6.28 (d, J = 2.4 Hz, 1H), 5.77 (s, 2H), 3.97 (s, 2H), 2.36 (s, 3H). ESI-MS: m / z calc. for C11H13N3[M+H]+: 188.11; found 188. 2-(1H-Indol-3-yl)-N-(2-(3-methyl-1H-pyrazol-1-yl)benzyl)acetamide[000291] Synthesized from 2-(1H-indol-3-yl)acetic acid (150 mg, 854 μmol, 1 equiv) and (2-(5-methyl-1H-pyrazol-1-yl)phenyl)methanamine (160 mg, 854 μmol, 1 equiv) according to general procedure A. The crude mixture was purified by reverse phase chromatography using a 5-95% gradient of acetonitrile in water (0.1% formic acid) over 35 CV on a 40 g C18 column.2-(1H-Indol-3-yl)-N-(2-(3-methyl-1H-pyrazol-1- yl)benzyl)acetamide was isolated as a solid (38 mg, 110 μmol, 13%).1H NMR (400 MHz, CDCl3): δ 8.41 (s, 1H), 7.52 – 7.47 (m, 1H), 7.47 – 7.43 (m, 1H), 7.33 (d, J = 2.3 Hz, 1H), 7.29 – 7.22 (m, 3H), 7.16 – 7.09 (m, 2H), 7.06 – 6.93 (m, 3H), 6.01 (d, J = 2.3 Hz, 1H), 4.25 (d, J = 6.4 Hz, 2H), 3.66 (s, 2H), 1.86 (s, 3H). ESI-MS: m / z calc. for C21H20N4O [M+H]+; 345.1710; found 345. N-(2-(1H-Pyrazol-1-yl)benzyl)-2-(methyl(phenyl)amino)acetamide – Example 9 [000292] Synthesized from N-phenyl-N-methylglycine hydrochloride (200 mg, 1 equiv, 992 μmol) and (2-(1H-pyrazol-1-yl)phenyl)methanamine (172 mg, 1 equiv, 992 μmol) according to general procedure A. The crude mixture was purified by reverse phase chromatography using a 5-95% gradient of acetonitrile in water (0.1% formic acid) over 30 CV on a 20 g C18 column. N-(2-(1H-Pyrazol-1-yl)benzyl)-2- (methyl(phenyl)amino)acetamide was isolated as an oil (167 mg, 521 μmol, 53%).1H NMR (400 MHz, CDCl3) δ 7.87 (br t, J = 5.4 Hz, 1H), 7.36 (dd, J = 5.8, 3.4 Hz, 2H), 7.39 – 7.32 (m, 2H), 7.28 – 7.20 (m, 3H), 6.80 (t, J = 7.3 Hz, 1H), 6.68 (d, J = 7.8 Hz, 2H), 6.33 (t, J = 2.1 Hz, 1H), 4.34 (d, J = 6.4 Hz, 2H), 3.86 (s, 2H), 2.97 (s, 3H). ESI-MS: m / z calc. for C19H20N4O [M+H]+: 321.1710, found 321.1. N-(2-(1H-Pyrazol-1-yl)benzyl)-2-((4-chlorophenyl)(methyl)amino)acetamide – Example 10[000293] Synthesized from 4-chloro-N-methylaniline (57 mg, 0.40 mmol, 2 equiv) and N-(2-(1H-pyrazol-1-yl)benzyl)-2-chloroacetamide (50 mg, 200 μmol, 1 equiv) according to general procedure C. The crude mixture was purified by normal phase MPLC (10-70% ethyl acetate in cyclohexane, 15 CV, 4 g silica column) to afford N-(2-(1H-Pyrazol-1-yl)benzyl)-2- ((4-chlorophenyl)(methyl)amino)acetamide as a solid (38.7 mg, 109 μmol, 54%).1H NMR (400 MHz, CDCl3) δ 7.87 (br, 1H), 7.53 (d, J = 2.4 Hz, 1H), 7.50-7.47 (m, 1H), 7.35 – 7.27 (m, 2H), 7.24 (d, J = 1.8 Hz, 1H), 7.19 – 7.15 (m, 1H), 7.12 – 7.03 (m, 2H), 6.57 – 6.48 (m, 2H), 6.30 (t, J = 2.1 Hz, 1H), 4.25 (d, J = 6.2 Hz, 2H), 3.78 (s, 2H), 2.91 (s, 3H). ESI-MS: m / z calc. for C19H19ClN4O [M+H]+: 355.12; found 355. N-(2-(1H-Pyrazol-1-yl)benzyl)-2-((4-cyanophenyl)(methyl)amino)acetamide – Example 11 [000294] Synthesized from 4-(methylamino)-benzonitrile (53 mg, 2 equiv, 0.40 mmol) and N-(2-(1H-pyrazol-1-yl)benzyl)-2-chloroacetamide (50 mg, 200 μmol, 1 equiv) according to general procedure C. The crude mixture was purified by normal phase MPLC (30-70%ethyl acetate in cyclohexane, 25 CV, 4 g silica column). N-(2-(1H-Pyrazol-1-yl)benzyl)-2- ((4-cyanophenyl)(methyl)amino)acetamide was isolated as a solid (27 mg, 78 μmol, 39%).1H NMR (400 MHz, CDCl3) δ 8.05 (br t, 1H), 7.64 – 7.59 (m, 1H), 7.58 – 7.52 (m, 1H), 7.47 – 7.42 (m, 2H), 7.42 – 7.33 (m, 2H), 7.24 – 7.21 (m, 1H), 7.18 (dd, J = 1.9, 0.7 Hz, 1H), 6.66 – 6.58 (m, 2H), 6.37 (t, J = 2.2 Hz, 1H), 4.27 (d, J = 6.3 Hz, 2H), 3.97 (s, 2H), 3.09 (s, 3H). ESI-MS: m / z calc. for C20H19N5O [M+H]+: 346.1662, found 346.1. N-(2-(1H-Pyrazol-1-yl)benzyl)-2-((4-fluorophenyl)(methyl)amino)acetamide – Example 12[000295] N-(2-(1H-Pyrazol-1-yl)benzyl)-2-((4-fluorophenyl)(methyl)amino)acetamide was synthesized from 4-fluoro-N-methylaniline (50 mg, 0.40 mmol, 2 equiv) and N-(2-(1H- pyrazol-1-yl)benzyl)-2-chloroacetamide (50 mg, 200 μmol, 1 equiv) according to general procedure C. The crude mixture was purified by normal phase MPLC (10-70% ethyl acetate in cyclohexane, 15 CV, 4 g column) to afford N-(2-(1H-pyrazol-1-yl)benzyl)-2-((4- fluorophenyl)(methyl)amino)acetamide as a solid (36.9 mg, 109 μmol, 54%).1H NMR (400 MHz, CDCl3) δ 7.94 (br, 1H), 7.59 (d, J = 2.4 Hz, 1H), 7.57 – 7.43 (m, 1H), 7.40 – 7.35 (m, 2H), 7.34 (d, J = 1.8 Hz, 1H), 7.26 – 7.22 (m, 1H), 6.99 – 6.82 (m, 2H), 6.67 – 6.54 (m, 2H), 6.36 (t, J = 2.1 Hz, 1H), 4.34 (d, J = 6.4 Hz, 2H), 3.81 (s, 2H), 2.95 (s, 3H).19F NMR (376 MHz, CDCl3) δ -127.73 (1F). ESI-MS: m / z calc. for C19H19FN4O [M+H]+: 339.15; found 339. N-(2-(1H-Pyrazol-1-yl)benzyl)-2-(5,6-difluoro-1H-indol-3-yl)acetamide – Example 13[000296] Synthesized from 2-(5,6-difluoro-1H-indol-3-yl)acetic acid (50 mg, 0.24 mmol, 1 equiv) and (2-(1H-pyrazol-1-yl)phenyl)methanamine (45 mg, 0.26 mmol, 1.1 equiv) according to general procedure A. The crude mixture was purified by reverse phase chromatography using a 5-95% gradient of acetonitrile in water (0.1% formic acid) over 35 CV on a 4 g C18 column. N-(2-(1H-Pyrazol-1-yl)benzyl)-2-(5,6-difluoro-1H-indol-3- yl)acetamide was isolated as a solid (34.2 mg, 93.3 μmol, 39%).1H NMR (400 MHz, CDCl3) δ 8.09 (br, 1H), 7.55 – 7.44 (m, 2H), 7.28 (dd, J = 5.8, 3.4 Hz, 2H), 7.18 – 7.01 (m, 6H), 6.27 (t, J = 2.2 Hz, 1H), 4.19 (d, J = 6.0 Hz, 2H), 3.56 (s, 2H).19F NMR (376 MHz, CDCl3) δ -143.35 (ddd, J = 20.8, 10.3, 7.6 Hz, 1F), -146.75 (ddd, J = 20.8, 10.8, 6.7 Hz, 1F). ESI-MS: m / z calc. for C20H16F2N4O [M+H]+: 367.1365; found 367. N-(2-(1H-Pyrazol-1-yl)benzyl)-2-(7-fluoro-1H-indol-3-yl)acetamide – Example 14 [000297] Synthesized from 2-(7-fluoro-1H-indol-3-yl)acetic acid (100 mg, 518 μmol, 1 equiv) and (2-(1H-pyrazol-1-yl)phenyl)methanamine (98.6 mg, 569 μmol, 1.1 equiv) according to general procedure A. The crude mixture was purified by reverse phase chromatography using a 5-95% gradient acetonitrile in water (0.1% formic acid) over 35 CV on a 4 g C18 column. N-(2-(1H-Pyrazol-1-yl)benzyl)-2-(7-fluoro-1H-indol-3-yl)acetamide was isolated as a solid (71.1 mg, 204 μmol, 39%).1H NMR (400 MHz, CDCl3) δ 8.38 (br, 1H), 7.54 (dd, J = 5.7, 3.5 Hz, 1H), 7.51 (d, J = 2.4 Hz, 1H), 7.33 (dd, J = 5.8, 3.4 Hz, 2H), 7.28 (d, J = 7.9 Hz, 1H), 7.19 (dd, J = 5.7, 3.5 Hz, 1H), 7.15 – 7.07 (m, 3H), 7.01 (td, J = 7.9, 4.8 Hz, 1H), 6.94 (dd, J = 11.1, 7.8 Hz, 1H), 6.28 (t, J = 2.2 Hz, 1H), 4.26 (d, J = 6.3 Hz, 2H), 3.70 (s, 2H).19F NMR (376 MHz, CDCl3) δ -135.46 (dd, J = 11.0, 4.8 Hz, 1F). ESI-MS: m / z calc. for C20H17FN4O [M+H]+: 349.1459; found 349. N-(2-(1H-Pyrazol-1-yl)benzyl)-2-(4-fluoro-1H-indol-3-yl)acetamide – Example 15[000298] Synthesized from 2-(4-fluoro-1H-indol-3-yl)acetic acid (100 mg, 518 μmol, 1.00 equiv) and (2-(1H-pyrazol-1-yl)phenyl)methanamine (98.6 mg, 569 μmol, 1.1 equiv) according to general procedure A. The crude mixture was purified by reverse phase chromatography using a 5-95% gradient of acetonitrile in water (0.1% formic acid) over 30 CV on a 4 g C18 column. N-(2-(1H-Pyrazol-1-yl)benzyl)-2-(4-fluoro-1H-indol-3- yl)acetamide was isolated as a solid (82.9 mg, 238 μmol, 46%).1H NMR (400 MHz, CDCl3) δ 8.46 (br, 1H), 7.57 - 7.50 (m, 2H), 7.36 – 7.28 (m, 2H), 7.23 – 7.17 (m, 1H), 7.17 – 7.02 (m, 4H), 6.97 (d, J = 2.4 Hz, 1H), 6.74 (ddd, J = 11.0, 6.6, 1.9 Hz, 1H), 6.30 (t, J = 2.2 Hz, 1H), 4.28 (d, J = 6.3 Hz, 2H), 3.78 (s, 2H).19F NMR (376 MHz, CDCl3) δ --124.17 (dd, J = 10.8, 4.0 Hz, 1F). ESI-MS: m / z calc. For C20H17FN4O [M+H]+: 349.1459 found 349. N-(2-(1H-Pyrazol-1-yl)benzyl)-2-(1H-pyrrolo[2,3-c]pyridin-3-yl)acetamide – Example 16 [000299] Synthesized from 2-(1-pyrrolo[2,3-c]pyridin-3-yl)acetic acid (40 mg, 230 μmol, 1 equiv) and (2-(1H-pyrazol-1-yl)phenyl)methanamine (39 mg, 230 μmol, 1 equiv) according to general procedure B. The crude mixture was purified by reverse phase chromatography using a 5-95% gradient of methanol in water (0.1% formic acid) over 30 CV on a 4 g C18 column. N-(2-(1H-Pyrazol-1-yl)benzyl)-2-(1H-pyrrolo[2,3-c]pyridin-3- yl)acetamide was isolated as a solid (4.7 mg, 14 μmol, 6%).1H NMR (400 MHz, CDCl3) δ 9.13 (br, 1H), 8.04 (br, 1H), 7.68 – 7.52 (m, 4H), 7.43 – 7.27 (m, 4H), 7.23 – 7.17 (m, 1H), 6.35 (t, J = 2.2 Hz, 1H), 4.27 (d, J = 6.3 Hz, 2H), 3.72 (s, 2H). ESI-MS: m / z calc. for C19H17N5O [M+H]+: 332.1506; found 332.N-(2-(1H-Pyrazol-1-yl)benzyl)-2-(5-fluoro-1H-indol-1-yl)acetamide – Example 17[000300] Synthesized from 5-fluoro-1H-indole (27 mg, 1 equiv, 0.20 mmol) and N-(2- (1H-pyrazol-1-yl)benzyl)-2-chloroacetamide (50 mg, 0.20 mmol, 1 equiv) according to general procedure D. The crude mixture was purified by MPLC (5-60% ethyl acetate in cyclohexane, 20 CV, 4 g silica column). N-(2-(1H-Pyrazol-1-yl)benzyl)-2-(5-fluoro-1H- indol-1-yl)acetamide was isolated as a solid (42 mg, 120 μmol, 60%).1H NMR (400 MHz, CDCl3) δ 7.57 – 7.49 (m, 2H), 7.45 (br t, J = 6.3 Hz, 1H), 7.37 – 7.29 (m, 3H), 7.20 – 7.15 (m, 1H), 7.13 (dd, J = 8.9, 4.3 Hz, 1H), 7.08 (d, J = 3.2 Hz, 1H), 6.93 (td, J = 9.1, 2.5 Hz, 1H), 6.89 (d, J = 2.6 Hz, 1H), 6.55 (dd, J = 3.2, 0.8 Hz, 1H), 6.25 (t, J = 2.1 Hz, 1H), 4.76 (s, 2H), 4.21 (d, J = 6.3 Hz, 2H).19F NMR (376 MHz, CDCl3) δ -124.93 (1F). ESI-MS: m / z calc. for C20H17FN4O [M+H]+: 349.1459, found 349. N-(2-(1H-Pyrazol-1-yl)benzyl)-2-(6-fluoro-1H-indol-1-yl)acetamide – Example 18 [000301] Synthesized from 6-fluoro-1H-indole (27 mg, 0.20 mmol, 1 equiv) and N-(2- (1H-pyrazol-1-yl)benzyl)-2-chloroacetamide (50 mg, 0.20 mmol, 1 equiv) according to general procedure D. The product was purified by normal phase MPLC (10-70% ethyl acetate in cyclohexane, 15 CV, 4 g silica column) to afford N-(2-(1H-pyrazol-1-yl)benzyl)-2-(6- fluoro-1H-indol-1-yl)acetamide (42.6 mg, 122 μmol, 61%) as a solid.1H NMR (400 MHz, CDCl3) δ 7.61 – 7.50 (m, 3H), 7.46 (br, 1H), 7.38 – 7.30 (m, 2H), 7.21 – 7.13 (m, 1H), 7.02 (d, J = 3.2 Hz, 1H), 6.97 – 6.84 (m, 3H), 6.56 (dd, J = 3.2, 0.9 Hz, 1H), 6.25 (t, J = 2.2 Hz, 1H), 4.72 (s, 2H), 4.23 (d, J = 6.4 Hz, 2H).19F NMR (376 MHz, CDCl3) δ -119.88 (td, J = 9.7, 5.2 Hz, 1F).ESI-MS: m / z calc. for C20H17FN4O [M+H]+: 349.1459 found 349. N-(2-(1H-Pyrazol-1-yl)benzyl)-2-(7-fluoro-1H-indol-1-yl)acetamide – Example 19[000302] Synthesized from 7-fluoro-1H-indole (27 mg, 0.20 mmol, 1 equiv) and N-(2- (1H-pyrazol-1-yl)benzyl)-2-chloroacetamide (50 mg, 0.20 mmol, 1 equiv) according to general procedure D. The product was purified by normal phase MPLC (10-70% ethyl acetate in cyclohexane, 15 CV, 4 g silica column). N-(2-(1H-Pyrazol-1-yl)benzyl)-2-(7-fluoro-1H- indol-1-yl)acetamide was isolated as a solid (37.6 mg, 108 μmol, 54%).1H NMR (400 MHz, CDCl3) δ 7.61 – 7.49 (m, 2H), 7.42 (d, J = 7.9 Hz, 2H), 7.34 (dd, J = 5.8, 3.4 Hz, 2H), 7.17 (dd, J = 5.7, 3.5 Hz, 1H), 7.03 (td, J = 7.9, 4.5 Hz, 1H), 7.00 (d, J = 3.1 Hz, 1H), 6.91 – 6.79 (m, 2H), 6.58 (t, J = 2.8 Hz, 1H), 6.24 (t, J = 2.2 Hz, 1H), 4.94 (s, 2H), 4.25 (d, J = 6.4 Hz, 2H).19F NMR (376 MHz, CDCl3) δ -136.39 (dt, J = 12.4, 4.1 Hz, 1F). ESI-MS: m / z calc. for C20H17FN4O [M+H]+: 349.1459; found 349. N-(2-(1H-Pyrazol-1-yl)benzyl)-2-(5-methoxy-1H-indol-1-yl)acetamide – Example 20 [000303] Synthesized from 5-methoxy-1H-indole (88 mg, 601 μmol, 1 equiv) and N- (2-(1H-pyrazol-1-yl)benzyl)-2-chloroacetamide (150 mg, 601 μmol, 1 equiv) according to general procedure D. The crude mixture was purified by reverse phase chromatography using a 5-90% gradient of methanol in water (0.1% formic acid) over 25 CV on a 20 g C18 column. N-(2-(1H-Pyrazol-1-yl)benzyl)-2-(5-methoxy-1H-indol-1-yl)acetamide was isolated as a solid (121 mg, 336 µmol, 56%).1H NMR (400 MHz, CDCl3) δ 7.55 – 7.45 (m, 2H), 7.38 – 7.27 (m, 3H), 7.20 – 7.08 (m, 3H), 7.01 (d, J = 3.1 Hz, 1H), 6.95 – 6.91 (m, 1H), 6.86 (dd, J = 8.8, 2.5 Hz, 1H), 6.51 (dd, J = 3.2, 0.9 Hz, 1H), 6.24 (t, J = 2.1 Hz, 1H), 4.74 (s, 2H), 4.22 (d, J = 6.4 Hz, 2H), 3.87 (s, 3H). ESI-MS: m / z calc. for [M-H]-: 359.151354; found 359.2. N-(2-(1H-Pyrazol-1-yl)benzyl)-2-(4-chloro-1H-indol-3-yl)acetamide – Example 21[000304] Synthesized from 2-(4-chloro-1H-indol-3-yl)acetic acid (100 mg, 477 μmol, 1.00 equiv) and (2-(1H-pyrazol-1-yl)phenyl)methanamine (90.9 mg, 525 μmol, 1.1 equiv) according to general procedure A. The crude mixture was purified by reverse phase chromatography using a 5-95% gradient of acetonitrile in water (0.1% formic acid) over 30 CV on a 20 g C18 column. N-(2-(1H-Pyrazol-1-yl)benzyl)-2-(4-chloro-1H-indol-3- yl)acetamide was isolated as a solid (41.8 mg, 115 μmol, 24%).1H NMR (400 MHz, CDCl3) δ 8.66 (br, 1H), 7.60 – 7.53 (m, 1H), 7.51 (d, J = 2.4 Hz, 1H), 7.36 – 7.28 (m, 2H), 7.22 (dd, J = 7.7, 1.3 Hz, 1H), 7.19 – 7.15 (m, 1H), 7.12 – 7.02 (m, 3H), 6.99 (dd, J = 11.9, 2.2 Hz, 2H), 6.26 (t, J = 2.1 Hz, 1H), 4.29 (d, J = 6.3 Hz, 2H), 3.89 (s, 2H). ESI-MS: m / z calc. C20H17ClN4O for [M+H]+: 365.1164; found 365. N-(2-(1H-Pyrazol-1-yl)benzyl)-2-(6-chloro-1H-indol-1-yl)acetamide – Example 22 [000305] Synthesized from 6-chloro-1H-indole (30 mg, 0.20 mmol, 1 equiv) and N-(2- (1H-pyrazol-1-yl)benzyl)-2-chloroacetamide (50 mg, 0.20 mmol, 1 equiv). The product was purified by normal phase MPLC (0-70% ethyl acetate in cyclohexane, 15 CV, 4 g silicacolumn). N-(2-(1H-Pyrazol-1-yl)benzyl)-2-(6-chloro-1H-indol-1-yl)acetamide was isolated as a solid (44.2 mg, 121 μmol, 61%).1H NMR (400 MHz, CDCl3) δ 7.61 – 7.49 (m, 3H), 7.44 (br t, J = 6.3 Hz, 1H), 7.39 – 7.31 (m, 2H), 7.23 (t, J = 1.2 Hz, 1H), 7.20 – 7.16 (m, 1H), 7.13 (dd, J = 8.4, 1.8 Hz, 1H), 7.03 (d, J = 3.2 Hz, 1H), 6.90 (d, J = 1.9 Hz, 1H), 6.56 (d, J = 3.2 Hz, 1H), 6.25 (t, J = 2.2 Hz, 1H), 4.73 (s, 2H), 4.23 (d, J = 6.3 Hz, 2H) ESI-MS: m / z calc. for C20H17ClN4O [M+H]+: 365.1164; found 365. N-(2-(1H-Pyrazol-1-yl)benzyl)-2-(5,6-difluoro-1H-indol-1-yl)acetamide – Example 23[000306] Synthesized from 5,6-difluoro-indole (31 mg, 0.20 mmol, 1 equiv) and N-(2- (1H-pyrazol-1-yl)benzyl)-2-chloroacetamide (50 mg, 0.20 mmol, 1 equiv) according to general procedure D. The crude mixture was purified by MPLC (5-80% ethyl acetate in cyclohexane, 25 CV, 4 g silica column). N-(2-(1H-Pyrazol-1-yl)benzyl)-2-(5,6-difluoro-1H- indol-1-yl)acetamide was isolated as a solid (61 mg, 0.17 mmol, 83%).1H NMR (400 MHz, CDCl3) δ 7.65 – 7.50 (m, 2H), 7.49 (br t, J = 6.3 Hz, 1H), 7.43 – 7.29 (m, 3H), 7.22 – 7.13 (m, 1H), 7.07 (d, J = 3.2 Hz, 1H), 7.01 – 6.88 (m, 2H), 6.53 (d, J = 3.2 Hz, 1H), 6.29 (t, J = 2.2 Hz, 1H), 4.71 (s, 2H), 4.22 (d, J = 6.3 Hz, 2H).19F NMR (377 MHz, CDCl3) δ -142.46 (ddd, J = 20.6, 10.8, 8.0 Hz, 1F), -147.29 (ddd, J = 20.8, 10.6, 6.5 Hz, 1F). ESI-MS: m / z calc. for C20H16F2N4O [M+H]+: 367.1365, found 367.1. N-(2-(1H-Pyrazol-1-yl)benzyl)-2-(5-chloro-1H-indol-1-yl)acetamide – Example 24[000307] Synthesized from 5-Chloroindole (30 mg, 0.20 mmol, 1 equiv) and N-(2-(1H- pyrazol-1-yl)benzyl)-2-chloroacetamide (50 mg, 0.20 mmol, 1 equiv) according to general procedure D. The crude mixture was purified by reverse phase chromatography using a 5- 95% gradient of methanol in water (0.1% formic acid) over 30 CV on a 12 g C18 column. N- (2-(1H-Pyrazol-1-yl)benzyl)-2-(5-chloro-1H-indol-1-yl)acetamide was isolated as a solid (6.4 mg, 18 μmol, 9%).1H NMR (400 MHz, CDCl3) δ 7.64 (br, 1H), 7.59 – 7.49 (m, 2H), 7.49 – 7.40 (br t, J = 6.4 Hz, 1H), 7.40 – 7.30 (m, 2H), 7.22 – 7.16 (m, 1H), 7.16 – 7.11 (m, 2H), 7.07 (d, J = 3.2 Hz, 1H), 6.89 (d, J = 1.9 Hz, 1H), 6.53 (d, J = 3.2 Hz, 1H), 6.26 (t, J = 2.2 Hz, 1H), 4.76 (s, 2H), 4.21 (d, J = 6.4 Hz, 2H). ESI-MS: m / z calc. for C20H17ClN4O [M+H]+: 365.1164, found 365.0. N-(2-Fluoro-6-(1H-pyrazol-1-yl)benzyl)-2-(1H-indol-3-yl)acetamide – Example 25 2-Fluoro-6-(1H-pyrazol-1-yl)benzonitrile [000308] 2-Fluoro-6-(1H-pyrazol-1-y ) enzon trile was prepared from 2,6- difluorobenzonitrile (50.0 mg, 1 equiv, 359 μmol) and pyrazole (29.4 mg, 1.2 equiv, 431 μmol) according to general procedure E. The crude mixture was purified by normal phase MPLC (5-80% ethyl acetate in cyclohexane, 17 CV, 12 g silica column).2-Fluoro-6-(1H- pyrazol-1-yl)benzonitrile was obtained as an oil (43.1 mg, 230 μmol, 64%).1H NMR (400 MHz, CDCl3) δ 8.18 (d, J = 2.6 Hz, 1H), 7.82 (d, J = 1.8 Hz, 1H), 7.74 – 7.51 (m, 2H), 7.23 – 7.13 (m, 1H), 6.56 (t, J = 2.2 Hz, 1H).19F NMR (377 MHz, CDCl3) δ -103.49 (dd, J = 8.3, 5.7 Hz, 1F). (2-Fluoro-6-(1H-pyrazol-1-yl)phenyl)methanamine[000309] (2-Fluoro-6-(1H-pyrazol-1-yl)phenyl)methanamine was prepared by the reduction of 2-fluoro-6-(1H-pyrazol-1-yl)benzonitrile (43.1 mg, 1 equiv, 230 μmol) according to general procedure F. The solvent was removed yielding a the crude (2-fluoro-6- (1H-pyrazol-1-yl)phenyl)methanamine as a solid (75 mg) which was used directly without further purification.1H NMR (400 MHz, DMSO) δ 8.25 (d, J = 2.4 Hz, 1H), 7.79 (d, J = 1.8 Hz, 1H), 7.52 – 7.40 (m, 1H), 7.35 – 7.24 (m, 2H), 6.56 (t, J = 2.1 Hz, 1H), 3.59 (d, J = 2.0 Hz, 2H).19F NMR (377 MHz, DMSO) δ -116.54 (1F). N-(2-Fluoro-6-(1H-pyrazol-1-yl)benzyl)-2-(1H-indol-3-yl)acetamide - Example 25[000310] Indole-3-acetic acid (39 mg, 1 equiv, 0.22 mmol) and the crude (2-fluoro-6- (1H-pyrazol-1-yl)phenyl)methanamine (42 mg, 1 equiv, 0.22 mmol) coupled according to general procedure A and the mixture was stirred at room temperature for 18 h. The crude mixture was purified by reverse phase chromatography using a 5-70% gradient of methanol in water (0.1% formic acid) over 30 CV on a 20 g C18 column and then by preparative HPLC (see preparative HPLC Method A). N-(2-Fluoro-6-(1H-pyrazol-1-yl)benzyl)-2-(1H-indol-3- yl)acetamide was isolated as a solid (3.0 mg, 9 μmol, 4% over 2 steps).1H NMR (400 MHz, CDCl3) δ 8.16 (br s, 1H), 7.59 – 7.46 (m, 2H), 7.41 (d, J = 8.1 Hz, 1H), 7.33 – 7.27 (m, 1H), 7.28 – 7.20 (m, 1H), 7.18 – 7.01 (m, 3H), 6.99 (d, J = 7.9 Hz, 1H), 6.90 (d, J = 1.9 Hz, 1H), 6.24 (t, J = 2.1 Hz, 1H), 4.35 (d, J = 1.9 Hz, 2H), 3.72 (s, 2H).19F NMR (377 MHz, CDCl3) δ -112.23 (t, J = 7.5 Hz, 1F). ESI-MS: m / z calc. for C20H17FN4O [M+H]+: 349.1459, found 349. N-((2-(1H-Pyrazol-1-yl)phenyl)methyl-d2)-2-(1H-indol-3-yl)acetamide – Example 26[000311] Lithium aluminium deuteride (54.6 mg, 1.1 equiv, 1.30 mmol) was diluted with dry tetrahydrofuran (1.36 mL) (overall reaction concentration: 0.50 molar) and was cooled to 0 °C.2-Pyrazol-1-ylbenzonitrile (200 mg, 1 equiv, 1.18 mmol) was added dropwise as a solution in dry tetrahydrofuran (1.00 mL). The solution was warmed to room temperature and heated to reflux overnight. Diethyl ether (20 mL), water (2 mL) and aqueous sodium hydroxide (1molar) (3 mL) were added. The mixture was stirred at room temperature for 5 min. The mixture was filtered through celite, washed with diethyl ether. Water was added, the phases were separated, and the aqueous phase was washed with diethyl ether (2x). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and the solvent was removed in vacuo. The crude product (2-(1H-pyrazol-1-yl)phenyl)methan-d2- amine was obtained as a oil (162 mg) which was coupled with with indoleacetic acid (162 mg, 1 equiv, 924 μmol) according to general procedure A. The crude mixture was purified by MPLC (20-90% ethyl acetate in cyclohexane, 20 CV, 20 g silica column), followed by a second purification by reverse phase chromatography using a 5-70% gradient of methanol in water (0.1% formic acid) over 30 CV on a 20 g C18 column. N-((2-(1H-Pyrazol-1- yl)phenyl)methyl-d2)-2-(1H-indol-3-yl)acetamide was isolated as a solid (140 mg, 421 μmol, 36% over two steps).1H NMR (400 MHz, CDCl3) δ 8.20 (brz, 1H), 7.57 – 7.49 (m, 2H), 7.47 (d, J = 2.4 Hz, 1H), 7.39 (d, J = 8.1 Hz, 1H), 7.36 – 7.29 (m, 2H), 7.25 – 7.21 (m, 1H), 7.20 – 7.15 (m, 1H), 7.13 (d, J = 7.5 Hz, 1H), 7.11 – 7.04 (m, 2H), 7.01 (d, J = 1.9 Hz, 1H), 6.25 (t, J = 2.2 Hz, 1H), 3.72 (s, 2H). ESI-MS: m / z calc. for C20H16D2N4O [M+H]+: 333.1679, found 333.0. N-(2-(1H-1,2,4-Triazol-1-yl)benzyl)-2-(1H-indol-3-yl)acetamide – Example 27[000312] Synthesized from indoleacetic acid (101 mg, 1 equiv, 574 μmol) and (2-(1H- 1,2,4-triazol-1-yl)phenyl)methanamine (100 mg, 1 equiv, 574 μmol) according to general procedure A. The crude mixture was purified by reverse phase chromatography using a 5- 70% gradient of methanol in water (0.1% formic acid) over 30 CV on a 20 g C18 column. N- (2-(1H-1,2,4-Triazol-1-yl)benzyl)-2-(1H-indol-3-yl)acetamide was isolated as a solid (68 mg, 0.21 mmol, 36%).1H NMR (400 MHz, CDCl3) δ 8.30 (br, 1H), 8.06 (s, 1H), 7.60 – 7.53 (m, 1H), 7.51 (s, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.45 – 7.39 (m, 2H), 7.36 (td, J = 7.6, 1.7 Hz, 1H), 7.24 (d, J = 8.3 Hz, 1H), 7.19 – 7.15 (m, 1H), 7.14 – 7.06 (m, 2H), 6.73 (br t, J = 6.6 Hz, 1H), 4.25 (d, J = 6.4 Hz, 2H), 3.72 (s, 2H). ESI-MS: m / z calc. for C19H17N5O [M+H]+: 332.1506, found 332.0. N-((2-(1H-1,2,4-Triazol-1-yl)pyridin-3-yl)methyl)-2-(1H-indol-3-yl)acetamide – Example 28 [000313] Synthesized from indole-3-acetic acid (50 mg, 1 equiv, 0.29 mmol) and (2- (1H-1,2,4-triazol-1-yl)pyridin-3-yl)methanamine (50 mg, 1 equiv, 0.29 mmol) according to general procedure A. The crude mixture was purified by reverse phase chromatography using a 5-70% gradient of methanol in water (0.1% formic acid) over 30 CV on a 12 g C18 column. N-((2-(1H-1,2,4-Triazol-1-yl)pyridin-3-yl)methyl)-2-(1H-indol-3-yl)acetamide was isolated as a solid (51.4 mg, 155 µmol, 54%).1H NMR (400 MHz, CDCl3) δ 8.87 (s, 1H), 8.36 (dd, J = 4.7, 1.7 Hz, 1H), 8.24 (br s, 1H), 7.99 (dd, J = 7.6, 1.8 Hz, 1H), 7.46 – 7.34 (m, 3H), 7.30 (dd, J = 7.6, 4.7 Hz, 1H), 7.24 – 7.13 (m, 2H), 7.10 – 6.95 (m, 2H), 4.52 (d, J = 6.7 Hz, 2H), 3.70 (s, 2H).ESI-MS: m / z calc. for C18H16N6O [M+H]+: 333.1458, found 333.1. N-((2-(1H-1,2,4-Triazol-1-yl)pyridin-3-yl)methyl)-2-(7-methyl-1H-indol-3-yl)acetamide – Example 29[000314] Synthesized from 2-(7-methyl-1H-indol-3-yl)acetic acid (54 mg, 1 equiv, 0.29 mmol) and (2-(1H-1,2,4-triazol-1-yl)pyridin-3-yl)methanamine (50 mg, 1 equiv, 0.29 mmol) according to general procedure A. The crude mixture was purified by reverse phase chromatography using a 5-70% gradient of methanol in water (0.1% formic acid) over 30 CV on a 12 g C18 column. N-((2-(1H-1,2,4-Triazol-1-yl)pyridin-3-yl)methyl)-2-(7-methyl-1H- indol-3-yl)acetamide was isolated as a solid (56.8 mg, 164 µmol, 57%).1H NMR (400 MHz, CDCl3) δ 8.88 (s, 1H), 8.36 (dd, J = 4.7, 1.8 Hz, 1H), 8.12 (br s, 1H), 7.99 (dd, J = 7.6, 1.8 Hz, 1H), 7.39 (s, 1H), 7.29 (dd, J = 7.6, 4.7 Hz, 1H), 7.22 (d, J = 7.8 Hz, 1H), 7.20 – 7.10 (m, 1H), 7.06 – 6.99 (m, 2H), 6.96 (t, J = 7.5 Hz, 1H), 4.52 (d, J = 6.7 Hz, 2H), 3.69 (s, 2H), 2.51 (s, 3H). ESI-MS: m / z calc. for C19H18N6O [M+H]+: 347.1615, found 347.1. N-(2-(1H-Pyrazol-1-yl)benzyl)-2-((3-fluorophenyl)(methyl)amino)acetamide – Example 30 [000315] Synthesized from 3-fluoro-N-methyl-aniline (50 mg, 2 equiv, 0.40 mmol) and N-(2-(1H-pyrazol-1-yl)benzyl)-2-chloroacetamide (50 mg, 200 μmol, 1 equiv) according to general procedure C. The crude mixture was purified by MPLC (5-60% ethyl acetate incyclohexane, 22 CV, 4 g silica column). N-(2-(1H-Pyrazol-1-yl)benzyl)-2-((3- fluorophenyl)(methyl)amino)acetamide was isolated as an oil (56.8 mg, 168 µmol, 84%).1H NMR (400 MHz, CDCl3) δ 7.91 (br t, J = 6.2 Hz, 1H), 7.59 (d, J = 2.4 Hz, 1H), 7.57 – 7.49 (m, 1H), 7.42 – 7.32 (m, 2H), 7.28 (d, J = 1.9 Hz, 1H), 7.26 – 7.22 (m, 1H), 7.14 (td, J = 8.1, 6.8 Hz, 1H), 6.47 (td, J = 8.3, 2.3 Hz, 1H), 6.44 – 6.31 (m, 3H), 4.33 (d, J = 6.2 Hz, 2H), 3.87 (s, 2H), 2.98 (s, 3H).19F NMR (377 MHz, CDCl3) δ -112.18 (dt, J = 12.2, 7.7 Hz, 1F). ESI-MS: m / z calc. for C19H19FN4O [M+H]+: 339.1616, found 339.3. N-(2-(1H-Pyrazol-1-yl)benzyl)-2-((3,4-difluorophenyl)(methyl)amino)acetamide – Example 31[000316] Synthesized from N-(2-(1H-pyrazol-1-yl)benzyl)-2-chloroacetamide (50 mg, 1 equiv, 200 μmol) and 3,4-difluoro-N-methylaniline (57 mg, 2 equiv, 400 μmol) according to general procedure C. The crude mixture was purified by MPLC (0-100% ethyl acetate in cyclohexane, 17 CV, 4 g silica column). N-(2-(1H-Pyrazol-1-yl)benzyl)-2-((3,4- difluorophenyl)(methyl)amino)acetamide was isolated as an oil (46.0 mg, 163 µmol, 81%).1H NMR (400 MHz, CDCl3) δ 7.94 (br t, J = 6.4 Hz, 1H), 7.62 (d, J = 2.5 Hz, 1H), 7.58 – 7.51 (m, 1H), 7.41 – 7.31 (m, 3H), 7.26 – 7.22 (m, 1H), 6.97 (dt, J = 10.1, 9.1 Hz, 1H), 6.44 (ddd, J = 13.4, 6.6, 3.1 Hz, 1H), 6.38 (t, J = 2.2 Hz, 1H), 6.28 (dtd, J = 9.0, 3.1, 1.5 Hz, 1H), 4.32 (d, J = 6.4 Hz, 2H), 3.82 (s, 2H), 2.96 (s, 3H).19F NMR (377 MHz, CDCl3) δ -136.45 – -136.66 (m, 1F), -152.69 (dddd, J = 22.5, 10.1, 6.5, 3.1 Hz, 1F). ESI-MS: m / z calc. for C19H18F2N4O [M+H]+: 357.152146; found 357. N-(2-(1H-Pyrazol-1-yl)benzyl)-2-(ethyl(4-fluorophenyl)amino)acetamide – Example 32[000317] Synthesized from N-ethyl-4-fluoroaniline hydrochloride (49 mg, 2 equiv, 0.28 mmol) and N-(2-(1H-pyrazol-1-yl)benzyl)-2-chloroacetamide (35 mg, 1 equiv, 0.14 mmol) according to general procedure C using 4 equivalents of sodium bicarbonate. The reaction crude was purified by normal phase MPLC (10-50% ethyl acetate in cyclohexane, 20 CV, 4 g silica column) and subsequently by reverse phase chromatography using a gradient of 5-95% methanol in water (0.1% formic acid) over 20 CV on a 4 g C18 column. N-(2-(1H-Pyrazol-1- yl)benzyl)-2-(ethyl(4-fluorophenyl)amino)acetamide was isolated as a solid (42 mg, 0.12 mmol, 85%).1H NMR (400 MHz, CD3OD) δ 7.83 (d, J = 2.4 Hz, 1H), 7.55 (d, J = 2.1 Hz, 1H), 7.45 – 7.36 (m, 3H), 7.35 – 7.22 (m, 1H), 6.95 – 6.86 (m, 2H), 6.70 – 6.60 (m, 2H), 6.47 (t, J = 2.2 Hz, 1H), 4.27 (s, 2H), 3.82 (s, 2H), 3.42 (q, J = 7.0 Hz, 2H), 1.11 (t, J = 7.0 Hz, 3H).19F NMR (377 MHz, CD3OD) δ -126.02 (dt, J = 8.5, 4.2 Hz, 1F). N-(2-(1H-Pyrazol-1-yl)benzyl)-2-((3,4-difluorophenyl)(ethyl)amino)acetamide – Example 33 [000318] Synthesized from N-(3,4-difluorophenyl)-N-ethylamine (50 mg, 2 Eq, 0.32 mmol) and N-(2-(1H-pyrazol-1-yl)benzyl)-2-chloroacetamide (40 mg, 1 equiv, 0.16 mmol) according to general procedure C. The crude mixture was purified by normal phase chromatography (10-50% ethyl acetate in cyclohexane, 20 CV, 4 g silica column) and subsequently by reverse phase chromatography using a 5-95% gradient of methanol in water (0.1% formic acid) over 20 CV on a 4 g C18 column. N-(2-(1H-Pyrazol-1-yl)benzyl)-2-((3,4- difluorophenyl)(ethyl)amino)acetamide was obtained as a solid (44 mg, 0.12 mmol, 74 %).1H NMR (400 MHz, CD3OD) δ 7.88 – 7.83 (m, 1H), 7.58 (d, J = 1.9 Hz, 1H), 7.45 – 7.37 (m, 3H), 7.37 – 7.27 (m, 1H), 7.07 – 6.96 (m, 1H), 6.57 – 6.46 (m, 2H), 6.40 – 6.29 (m, 1H), 4.28 (s, 2H), 3.86 (s, 2H), 3.43 (q, J = 7.1 Hz, 2H), 1.13 (t, J = 7.1 Hz, 3H).19F NMR (377 MHz, CD3OD) δ -135.54 (ddd, J = 22.2, 13.9, 9.2 Hz, 1F), -148.16 – -157.03 (m, 1F). N-(2-(1H-Pyrazol-1-yl)benzyl)-2-((4-bromophenyl)(methyl)amino)acetamide – Example 34[000319] Synthesized from N-(2-(1H-pyrazol-1-yl)benzyl)-2-chloroacetamide (250 mg, 1 equiv, 1.00 mmol) and (4-bromophenyl)methylamine (373 mg, 2 equiv, 2.00 mmol) according to general procedure C. The crude mixture was purified by MPLC (0-100% ethyl acetate in cyclohexane, 17 CV, 12 g silica column). N-(2-(1H-Pyrazol-1-yl)benzyl)-2-((4- bromophenyl)(methyl)amino)acetamide was isolated as an oil (383 mg, 960 µmol, 95%).1H NMR (400 MHz, CDCl3) δ 7.92 (br, 1H), 7.59 (d, J = 2.3 Hz, 1H), 7.57 – 7.51 (m, 1H), 7.40 – 7.33 (m, 2H), 7.30 – 7.22 (m, 5H), 6.56 – 6.47 (m, 2H), 6.36 (t, J = 2.1 Hz, 1H), 4.32 (d, J = 6.4 Hz, 2H), 3.84 (s, 2H), 2.97 (s, 3H). ESI-MS: m / z calc. for C19H19BrN4O [M-H]-: 397.066944; found 397.2. N-(2-(1H-Pyrazol-1-yl)benzyl)-2-(5-cyclopropyl-1H-indol-3-yl)acetamide – Example 35 [000320] Synthesized from 2-(5-cyclopropyl-1H-indol-3-yl)acetic acid (50 mg, 1 equiv, 0.23 mmol) and (2-(1H-pyrazol-1-yl)phenyl)methanamine (40 mg, 1 equiv, 0.23 mmol) according to general procedure A. The crude mixture was purified by reverse phasechromatography using a 5-70% gradient of methanol in water (0.1% formic acid) over 30 CV on a 12 g C18 column. N-(2-(1H-Pyrazol-1-yl)benzyl)-2-(5-cyclopropyl-1H-indol-3- yl)acetamide was isolated as a solid (45 mg, 0.12 mmol, 52%).1H NMR (400 MHz, CDCl3) δ 8.25 (s, 1H), 7.57 – 7.50 (m, 1H), 7.45 (d, J = 2.4 Hz, 1H), 7.38 – 7.30 (m, 2H), 7.29 – 7.25 (m, 1H), 7.25 – 7.21 (m, 1H), 7.21 – 7.15 (m, 1H), 7.10 (d, J = 1.8 Hz, 1H), 7.07 – 6.94 (m, 3H), 6.26 (t, J = 2.1 Hz, 1H), 4.28 (d, J = 6.3 Hz, 2H), 3.69 (s, 2H), 2.13 – 1.89 (m, 1H), 1.08 – 0.83 (m, 2H), 0.75 – 0.37 (m, 2H). ESI-MS: m / z calc. for C23H22N4O [M+H]+: 371.1866, found 371. N-(2-(1H-Pyrazol-1-yl)benzyl)-2-(4-bromo-1H-indol-3-yl)acetamide – Example 36[000321] Synthesized from 4-bromo-3-indoleacetic acid (250 mg, 1 equiv, 984 μmol) and (2-(1H-pyrazol-1-yl)phenyl)methanamine (170 mg, 1 equiv, 984 μmol) according to general procedure A. The crude mixture was purified by reverse phase chromatography using a 5-70% gradient of methanol in water (0.1% formic acid) over 30 CV on a 20 g C18 column. N-(2-(1H-Pyrazol-1-yl)benzyl)-2-(4-bromo-1H-indol-3-yl)acetamide was isolated as a solid (272 mg, 665 µmol, 68%).1H NMR (400 MHz, CDCl3) δ 8.53 (br s, 1H), 7.63 – 7.53 (m, 1H), 7.51 (d, J = 2.3 Hz, 1H), 7.38 – 7.27 (m, 3H), 7.25 (d, J = 0.8 Hz, 1H), 7.21 – 7.14 (m, 1H), 7.12 – 7.00 (m, 3H), 6.95 (d, J = 1.9 Hz, 1H), 6.24 (t, J = 2.2 Hz, 1H), 4.29 (d, J = 6.3 Hz, 2H), 3.91 (s, 2H). ESI-MS: m / z calc. for C20H17BrN4O [M+H]+: 409.0658, found 409. N-(2-(1H-Pyrazol-1-yl)benzyl)-2-(4-cyclopropyl-1H-indol-3-yl)acetamide – Example 37[000322] Synthesized from N-(2-(1H-pyrazol-1-yl)benzyl)-2-(4-bromo-1H-indol-3- yl)acetamide (50 mg, 1 equiv, 0.12 mmol) according to general procedure H. The crude mixture was purified by reverse phase chromatography using a 5-70% gradient of acetonitrile in water (0.1% formic acid) over 30 CV on a 12 g C18 column. N-(2-(1H-Pyrazol-1- yl)benzyl)-2-(4-cyclopropyl-1H-indol-3-yl)acetamide was isolated as a solid (18.4 mg, 50 µmol, 41%).1H NMR (400 MHz, CDCl3) δ 8.17 (br s, 1H), 7.60 – 7.47 (m, 1H), 7.39 (dd, J = 2.4, 0.7 Hz, 1H), 7.37 – 7.28 (m, 2H), 7.24 (d, J = 7.0 Hz, 1H), 7.20 – 7.08 (m, 3H), 7.04 (d, J = 2.5 Hz, 1H), 6.86 – 6.66 (m, 2H), 6.18 (t, J = 2.1 Hz, 1H), 4.26 (d, J = 6.3 Hz, 2H), 3.96 (s, 2H), 2.42 – 2.06 (m, 1H), 0.97 – 0.76 (m, 2H), 0.74 – 0.54 (m, 2H). ESI-MS: m / z calc. for C23H22N4O [M+H]+: 371.1866, found 371. N-((2-(1H-1,2,4-Triazol-1-yl)pyridin-3-yl)methyl)-2-(4-bromo-1H-indol-3-yl)acetamide – Example 38 [000323] Synthesized from 2-(4-bromo-1H-indol-3-yl)acetic acid (250 mg, 1 equiv, 984 μmol) and (2-(1H-1,2,4-triazol-1-yl)pyridin-3-yl)methanamine (172 mg, 1 equiv, 984 μmol) according to general procedure A. The crude mixture was purified by reverse phase chromatography using a 5-70% gradient of acetonitrile in water (0.1% formic acid) over 30 CV on a 20 g C18 column. N-((2-(1H-1,2,4-Triazol-1-yl)pyridin-3-yl)methyl)-2-(4-bromo- 1H-indol-3-yl)acetamide was isolated as a solid (103 mg, 250 µmol, 26%).1H NMR (400 MHz, DMSO) δ 11.30 (br s, 1H), 9.13 (s, 1H), 8.46 (dd, J = 4.7, 1.7 Hz, 1H), 8.13 (s, 1H), 8.04 – 7.86 (m, 2H), 7.65 – 7.48 (m, 1H), 7.43 – 7.36 (m, 1H), 7.31 (d, J = 2.5 Hz, 1H), 7.13 (dd, J = 7.6, 0.9 Hz, 1H), 6.96 (t, J = 7.8 Hz, 1H), 4.44 (d, J = 6.0 Hz, 2H), 3.82 (s, 2H). ESI-MS: m / z calc. for C18H15BrN6O [M+H]+: 411.0563, found 411. N-((2-(1H-1,2,4-Triazol-1-yl)pyridin-3-yl)methyl)-2-(4-cyclopropyl-1H-indol-3- yl)acetamide – Example 39[000324] Synthesized according to the above procedure from N-((2-(1H-1,2,4-triazol-1- yl)pyridin-3-yl)methyl)-2-(4-bromo-1H-indol-3-yl)acetamide (49 mg, 1 equiv, 0.12 mmol) according to general procedure H with full conversion observed by LC-MS after 24 h. The crude mixture was purified by reverse phase chromatography using a 5-70% gradient of acetonitrile in water (0.1% formic acid) over 30 CV on a 12 g C18 column. N-((2-(1H-1,2,4- Triazol-1-yl)pyridin-3-yl)methyl)-2-(4-cyclopropyl-1H-indol-3-yl)acetamide was isolated as a solid (17.2 mg, 46 µmol, 39%).1H NMR (400 MHz, CDCl3) δ 8.87 (s, 1H), 8.37 (dd, J = 4.7, 1.8 Hz, 1H), 8.12 (br, 1H), 7.99 (dd, J = 7.6, 1.8 Hz, 1H), 7.33 – 7.20 (m, 4H), 7.11 (t, J = 7.7 Hz, 1H), 6.99 (d, J = 2.5 Hz, 1H), 6.67 (d, J = 7.3 Hz, 1H), 4.53 (d, J = 6.7 Hz, 2H), 3.93 (s, 2H), 2.10 – 1.91 (m, 1H), 0.94 – 0.70 (m, 2H), 0.69 – 0.45 (m, 2H). ESI-MS: m / z calc. for C21H20N6O [M+H]+: 373.1771, found 373. N-(2-(2H-1,2,3-Triazol-2-yl)benzyl)-2-(1H-indol-3-yl)acetamide – Example 40 2-(2H-1,2,3-Triazol-2-yl)benzonitrile and 2-(1H-1,2,3-triazol-2-yl)benzonitrile [000325] Cesium carbonate (21 g, 2.2 equiv, 64 mmol) was added to a solution of triazacyclopentadiene (1.7 mL, 1 equiv, 29 mmol) and 2-fluorobenzenecarbonitrile (3.1 mL, 1 equiv, 29 mmol) in dimethylformamide (0.14 L, 0.2 molar, 29 mmol). The biphasic mixture was stirred at room temperature over 5 days. Water was added. The aqueous solution was extracted three times with ethyl acetate. The combined organics were washed three timeswith brine, dried over anhydrous sodium sulfate, filtered and concentrated to a light solid. Purification was performed by normal phase MPLC (5-50% ethyl acetate in cyclohexane 25 CV, 80 g silica column). Upon concentration 2-(2H-1,2,3-triazol-2-yl)benzonitrile (562 mg, 3.30 mmol, 11%) and 2-(1H-1,2,3-triazol-1-yl)benzonitrile (795 mg, 4.67 mmol, 16%) were obtained as solids. 2-(2H-1,2,3-Triazol-2-yl)benzonitrile, N2-connected triazole:1H NMR (400 MHz, CDCl3) δ 8.09 (dd, J = 8.4, 1.2 Hz, 1H), 7.93 (s, 2H), 7.83 (dd, J = 7.8, 1.5 Hz, 1H), 7.73 (ddd, J = 8.3, 7.6, 1.5 Hz, 1H), 7.53 – 7.40 (m, 1H). 2-(1H-1,2,3-Triazol-1-yl)benzonitrile, N1-connected triazole1H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 7.95 – 7.77 (m, 4H), 7.60 (br td, J = 7.7, 1.3 Hz, 1H). (2-(2H-1,2,3-Triazol-2-yl)phenyl)methanamine[000326] Synthesized from 2-(2H-1,2,3-triazol-2-yl)benzonitrile (100 mg, 1 equiv, 588 μmol) according to general procedure F over 72 h. The crude mixture was purified by reverse phase chromatography using a 5-95% gradient of acetonitrile in water (0.1% formic acid) over 20 CV on a 12 g C18 column. (2-(2H-1,2,3-triazol-2-yl)phenyl)methanamine was obtained a colorless oil (71 mg, 0.41 mmol, 69 %).1H NMR (400 MHz, MeOD) δ 8.07 (s, 2H), 7.97 (dd, J = 8.1, 1.3 Hz, 1H), 7.68 (br dd, J = 7.6, 1.6 Hz, 1H), 7.63 (td, J = 7.8, 1.6 Hz, 1H), 7.54 (br td, J = 7.5, 1.3 Hz, 1H), 4.26 (s, 2H). N-(2-(2H-1,2,3-Triazol-2-yl)benzyl)-2-(1H-indol-3-yl)acetamide - Example 40 [000327] Synthesized from indoleacetic acid (71 mg, 1 equiv, 0.41 mmol) and (2-(2H- 1,2,3-triazol-2-yl)phenyl)methanamine (71 mg, 1 equiv, 0.41 mmol) according to general procedure A for 20 hours. The crude mixture was purified by reverse phase chromatography using a 5-95% gradient of acetonitrile in water (0.1% formic acid) over 20 CV on a 12 g C18column. N-(2-(2H-1,2,3-Triazol-2-yl)benzyl)-2-(1H-indol-3-yl)acetamide was obtained as a solid (77 mg, 0.23 mmol, 57 %).1H NMR (400 MHz, CDCl3) δ 8.12 (br s, 1H), 7.67 – 7.61 (m, 1H), 7.60 – 7.55 (m, 1H), 7.52 (d, J = 7.9 Hz, 1H), 7.44 – 7.31 (m, 5H), 7.26 – 7.20 (m, 1H), 7.16 – 7.01 (m, 3H), 4.38 (d, J = 6.5 Hz, 2H), 3.74 (s, 2H). N-(2-(Furan-2-yl)benzyl)-2-(1H-indol-3-yl)acetamide – Example 41[000328] Synthesized from indoleacetic acid (40 mg, 1 equiv, 228 μmol) and 1-[2- (furan-2-yl)phenyl]methanamine hydrochloride (47.9 mg, 1 equiv, 228 μmol) according to general procedure A using N,N-diisopropylethylamine (3 equiv). The crude mixture was purified by reverse phase chromatography using a 5-70% gradient of methanol (0.1% formic acid) over 30 CV on a 12 g C18 column. N-(2-(Furan-2-yl)benzyl)-2-(1H-indol-3- yl)acetamide was isolated as a solid (45.0 mg, 136 µmol, 60%).1H NMR (400 MHz, CDCl3) δ 8.29 (br s, 1H), 7.55 (d, J = 7.9 Hz, 1H), 7.46 (dd, J = 7.4, 1.7 Hz, 1H), 7.38 (d, J = 8.2 Hz, 1H), 7.32 (dd, J = 7.2, 1.8 Hz, 1H), 7.29 – 7.18 (m, 3H), 7.18 – 7.09 (m, 1H), 7.05 (d, J = 2.4 Hz, 1H), 6.95 (d, J = 1.8 Hz, 1H), 6.36 (d, J = 3.3 Hz, 1H), 6.31 (dd, J = 3.4, 1.8 Hz, 1H), 6.25 (br t, J = 6.1 Hz, 1H), 4.51 (d, J = 6.1 Hz, 2H), 3.76 (s, 2H). ESI-MS: m / z calc. for C21H18N2O2[M+H]+: 331.1441, found 331. N-(2-(1H-1,2,4-Triazol-1-yl)pyridin-3-yl)-2-(4-methyl-1H-indol-3-yl)acetamide – Example 42[000329] Synthesized from 4-methyl-indole-3-acetic acid (50.0 mg, 1 equiv, 264 μmol) and 2-(1H-1,2,4-triazol-1-yl)pyridin-3-amine (42.6 mg, 1 equiv, 264 μmol) according to general procedure A. The crude mixture was purified by reverse phase chromatography using a 5-70% gradient of methanol in water (0.1% formic acid) over 30 CV on a 20 g C18 column. N-(2-(1H-1,2,4-Triazol-1-yl)pyridin-3-yl)-2-(4-methyl-1H-indol-3-yl)acetamide was isolated as a solid (15 mg, 45 µmol, 17%).1H NMR (400 MHz, DMSO) δ 11.11 (s, 1H), 10.52 (s, 1H), 9.16 (s, 1H), 8.94 (dd, J = 8.4, 1.6 Hz, 1H), 8.22 (dd, J = 4.5, 1.6 Hz, 1H), 7.58 (s, 1H), 7.51 (dd, J = 8.4, 4.6 Hz, 1H), 7.38 (d, J = 2.5 Hz, 1H), 7.28 (d, J = 8.1 Hz, 1H), 6.99 – 6.89 (m, 1H), 6.66 (d, J = 7.1 Hz, 1H), 3.98 (s, 2H), 3.29 (s, 2H), 2.47 (s, 3H). ESI-MS: m / z calc. for C18H16N6O [M+H]+: 333.1458, found 333. N-(2-(1H-Pyrazol-1-yl)benzyl)-2-(7-methyl-1H-indol-1-yl)acetamide – Example 43 [000330] Synthesized from 7-methyl indole (26 mg, 0.20 mmol, 1 equiv) and N-(2-(1H- pyrazol-1-yl)benzyl)-2-chloroacetamide (50 mg, 0.20 mmol, 1 equiv) according to general procedure D, requiring the addition of extra sodium hydride (4.0 mg, 60% Wt, 0.5 equiv, 0.10 mmol), with a total reaction time of 24 h. The crude mixture was purified by MPLC (15-50% ethyl acetate in cyclohexane, 25 CV, 4 g silica column). N-(2-(1H-Pyrazol-1-yl)benzyl)-2-(7- methyl-1H-indol-1-yl)acetamide was isolated as a solid (20.0 mg, 58 µmol, 29%).1H NMR (400 MHz, CDCl3) δ 7.57 – 7.48 (m, 2H), 7.45 (d, J = 2.4 Hz, 1H), 7.43 – 7.37 (m, 1H), 7.38 – 7.29 (m, 2H), 7.19 – 7.12 (m, 1H), 7.07 – 6.99 (m, 1H), 6.95 – 6.86 (m, 2H), 6.76 (d, J = 1.9 Hz, 1H), 6.55 (d, J = 3.2 Hz, 1H), 6.20 (t, J = 2.2 Hz, 1H), 4.97 (s, 2H), 4.24 (d, J = 6.4 Hz, 2H), 2.51 (s, 3H). ESI-MS: m / z calc. for C21H20N4O [M+H]+: 345.1710, found 345. N-(2-(1H-Pyrazol-1-yl)benzyl)-2-(4,5-difluoro-1H-indol-1-yl)acetamide – Example 44Synthesized from 4,5-difluoro-1H-indole (31 mg, 0.20 mmol, 1 equiv) and N-(2-(1H-pyrazol- 1-yl)benzyl)-2-chloroacetamide (50 mg, 0.20 mmol, 1 equiv) according to general procedure D, requiring the addition of extra sodium hydride (4.0 mg, 60% Wt, 0.5 equiv, 0.10 mmol), with a total reaction time of 24 h. The crude mixture was purified by MPLC (15-50% ethyl acetate in cyclohexane, 25 CV, 4 g silica column). N-(2-(1H-Pyrazol-1-yl)benzyl)-2-(4,5- difluoro-1H-indol-1-yl)acetamide was isolated as a solid (45.7 mg, 125 µmol, 62%).1H NMR (400 MHz, CDCl3) δ 7.59 – 7.51 (m, 2H), 7.47 (br, 1H), 7.40 – 7.29 (m, 2H), 7.22 – 7.13 (m, 1H), 7.07 (d, J = 3.3 Hz, 1H), 7.04 – 6.92 (m, 2H), 6.86 (dd, J = 8.9, 3.2 Hz, 1H), 6.69 (d, J = 3.2 Hz, 1H), 6.29 (t, J = 2.2 Hz, 1H), 4.75 (s, 2H), 4.22 (d, J = 6.4 Hz, 2H).19F NMR (377 MHz, CDCl3) δ -147.83 (dd, J = 20.8, 7.4 Hz, 1F), -151.81 (ddd, J = 20.9, 10.9, 3.3 Hz, 1F). N-(2-(1H-Pyrazol-1-yl)benzyl)-2-(5-bromo-1H-indol-3-yl)acetamide – Example 45 [000331] Synthesized from 2-(5-bromo-1H-indol-3-yl)acetic acid (250 mg, 1 equiv, 984 μmol) and (2-(1H-pyrazol-1-yl)phenyl)methanamine (170 mg, 1 equiv, 984 μmol) according to general procedure A. The crude mixture was purified by reverse phase chromatography using a 5-95% gradient of methanol in water (0.1% formic acid) over 30 CV on a 20 g C18 column. N-(2-(1H-Pyrazol-1-yl)benzyl)-2-(5-bromo-1H-indol-3-yl)acetamide was isolated as a solid (310 mg, 757 µmol, 77%).1H NMR (400 MHz, CDCl3) δ 8.26 (br s, 1H), 7.65 (d, J = 1.8 Hz, 1H), 7.60 – 7.51 (m, 2H), 7.40 – 7.28 (m, 3H), 7.25 – 7.18 (m, 3H), 7.17 (d, J = 1.9 Hz, 1H), 7.08 (d, J = 2.4 Hz, 1H), 6.32 (t, J = 2.2 Hz, 1H), 4.27 (s, 2H), 3.66 (s, 2H). ESI-MS: m / z calc. for C20H17BrN4O [M+H]+: 409.0658, found 409.N-(2-(1H-Pyrazol-1-yl)benzyl)-2-(6-bromo-1H-indol-3-yl)acetamide – Example 46[000332] Synthesized from 2-(6-bromo-1H-indol -3-yl)acetic acid (500 mg, 1 equiv, 1.97 mmol) and (2-(1H-pyrazol-1-yl)phenyl)methanamine (682 mg, 2 equiv, 3.94 mmol) according to general procedure A. The crude mixture was purified by reverse phase chromatography using a 5-80% gradient of acetonitrile in water (0.1% formic acid) over 30 CV on a 40 g C18 column. N-(2-(1H-Pyrazol-1-yl)benzyl)-2-(6-bromo-1H-indol-3- yl)acetamide was isolated as a solid (555 mg, 1.36 mol, 69%).1H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 7.62 – 7.46 (m, 3H), 7.43 – 7.30 (m, 3H), 7.24 – 7.16 (m, 2H), 7.16 – 7.08 (m, 2H), 7.04 – 6.97 (m, 1H), 6.31 (t, J = 2.1 Hz, 1H), 4.25 (d, J = 6.3 Hz, 2H), 3.67 (s, 2H). ESI-MS: m / z calc. for C20H17BrN4O [M+H]+: 409.0658, found 409. N-(2-(1H-1,2,4-Triazol-1-yl)benzyl)-2-(6-fluoro-1H-indol-3-yl)acetamide – Example 47 [000333] Synthesized from (6-fluoro-1H-indol-3-yl)acetic acid (50 mg, 1 equiv, 0.26 mmol) and (2-(1H-1,2,4-Triazol-1-yl)phenyl)methanamine (45 mg, 1 equiv, 0.26 mmol) according to general procedure A. The crude mixture was purified by reverse phase chromatography using a 5-80% gradient of acetonitrile in water (0.1% formic acid) over 30 CV on a 12 g C18 column. N-(2-(1H-1,2,4-Triazol-1-yl)benzyl)-2-(6-fluoro-1H-indol-3- yl)acetamide was isolated as a solid (29.0 mg, 83 µmol, 32%).1H NMR (400 MHz, CDCl3) δ 8.26 (br s, 1H), 8.14 (s, 1H), 7.63 (s, 1H), 7.56 (dd, J = 7.4, 1.8 Hz, 1H), 7.48 – 7.31 (m, 3H), 7.20 (dd, J = 7.6, 1.5 Hz, 1H), 7.08 (dd, J = 9.2, 2.3 Hz, 2H), 6.95 – 6.81 (m, 1H), 6.75 (br t, 1H), 4.26 (d, J = 6.4 Hz, 2H), 3.69 (s, 2H).19F NMR (377 MHz, CDCl3) δ -120.36 (td, J = 9.4, 5.2 Hz, 1F). ESI-MS: m / z calc. for C19H16FN5O [M+H]+: 350.1412, found 350. N-((2-(1H-1,2,4-Triazol-1-yl)pyridin-3-yl)methyl)-2-(5,6-difluoro-1H-indol-3- yl)acetamide – Example 48[000334] Synthesized from 5,6-difluoro-1H-indole-3-acetic acid (50 mg, 1 equiv, 0.24 mmol) and (2-(1H-1,2,4-triazol-1-yl)pyridin-3-yl)methanamine (41 mg, 1 equiv, 0.24 mmol) according to general procedure A. The crude mixture was purified by reverse phase chromatography using a 5-70% gradient of acetonitrile in water (0.1% formic acid) over 30 CV on a 12 g C18 column. N-((2-(1H-1,2,4-Triazol-1-yl)pyridin-3-yl)methyl)-2-(5,6- difluoro-1H-indol-3-yl)acetamide was isolated as a solid (48.8 mg, 132 µmol, 56%).1H NMR (400 MHz, CDCl3) δ 8.96 (s, 1H), 8.39 (dd, J = 4.8, 1.8 Hz, 1H), 8.16 (br s, 1H), 8.01 (dd, J = 7.6, 1.8 Hz, 1H), 7.62 (s, 1H), 7.32 (dd, J = 7.6, 4.7 Hz, 1H), 7.18 – 7.10 (m, 2H), 7.09 – 7.00 (m, 2H), 4.54 (d, J = 6.7 Hz, 2H), 3.61 (s, 2H).19F NMR (377 MHz, CDCl3) δ -142.64 (ddd, J = 20.7, 10.4, 7.6 Hz, 1F), -146.15 (ddd, J = 20.6, 10.6, 6.7 Hz, 1F). ESI-MS: m / z calc. for C18H14F2N6O [M+H]+: 369.1270, found 369. N-(3-Fluoro-2-(1H-pyrazol-1-yl)benzyl)-2-(1H-indol-3-yl)acetamide – Example 49 3-Fluoro-2-(1H-pyrazol-1-yl)benzonitrile[000335] Synthesized from 2,3-difluoro-benzonitrile (736 mg, 1.2 equiv, 5.29 mmol) according to General procedure E at 100 °C for 5 hours. The reaction mixture was cooled down to room temperature and water was added. The precipitate was collected by filtration and washed with water. No further purification was performed to 3-fluoro-2-(1H-pyrazol-1- yl)benzonitrile (550 mg, 2.94 mmol, 67 %).1H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 1.8 Hz, 1H), 7.76 (t, J = 2.7 Hz, 1H), 7.60 – 7.50 (m, 1H), 7.47 – 7.31 (m, 2H), 6.50 (t, J = 2.2 Hz, 1H).19F NMR (377 MHz, CDCl3) δ -120.35 (ddd, J = 8.2, 6.0, 2.8 Hz, 1F). (3-Fluoro-2-(1H-pyrazol-1-yl)phenyl)methanamine [000336] Synthesized from 3-fluoro-2-(1H-pyrazol-1-yl)benzonitrile (100 mg, 1 equiv, 534 μmol) according to General procedure F over 72 h. The crude mixture was purified by reverse phase chromatography using a 5-95% gradient of acetonitrile in water (0.1% formic acid) over 20 CV. (3-Fluoro-2-(1H-pyrazol-1-yl)phenyl)methanamine was obtained as a powder (35 mg, 0.18 mmol, 34%).1H NMR (400 MHz, MeOD) δ 8.01 (br t, J = 3.0 Hz, 1H), 7.87 (d, J = 1.9 Hz, 1H), 7.61 – 7.54 (m, 1H), 7.53 – 7.40 (m, 2H), 6.63 (br t, J = 2.2 Hz, 1H), 3.90 (s, 2H).19F NMR (377 MHz, MeOD) δ -124.70 (dt, J = 9.4, 4.1 Hz, 1F). N-(3-Fluoro-2-(1H-pyrazol-1-yl)benzyl)-2-(1H-indol-3-yl)acetamide Example 49 [000337] Synthesized from indoleacetic acid (32 mg, 1 equiv, 0.18 mmol) and (3- fluoro-2-(1H-pyrazol-1-yl)phenyl)methanamine (35 mg, 1 equiv, 0.18 mmol) according to General procedure A. The crude mixture was purified by reverse phase chromatographyusing a 5-95% gradient of acetonitrile in water (0.1% formic acid) over 15 CV. N-(3-Fluoro- 2-(1H-pyrazol-1-yl)benzyl)-2-(1H-indol-3-yl)acetamide was obtained as a solid (23 mg, 66 μmol, 36%).1H NMR (400 MHz, DMSO) δ 10.88 (br s, 1H), 8.22 (t, J = 6.0 Hz, 1H), 7.97 (br t, J = 1.9 Hz, 1H), 7.71 (d, J = 1.8 Hz, 1H), 7.52 (d, J = 7.9 Hz, 1H), 7.48 – 7.39 (m, 1H), 7.38 – 7.26 (m, 2H), 7.23 – 7.14 (m, 2H), 7.07 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 7.02 – 6.90 (m, 1H), 6.50 (t, J = 2.1 Hz, 1H), 4.01 (d, J = 5.9 Hz, 2H), 3.56 (s, 2H).19F NMR (377 MHz, DMSO) δ -124.43 (dd, J = 9.8, 5.5 Hz, 1F). N-(5-Fluoro-2-(1H-pyrazol-1-yl)benzyl)-2-(1H-indol-3-yl)acetamide – Example 505-Fluoro-2-(1H-pyrazol-1-yl)benzonitrile [000338] Pyrazole (300 mg, 1 equiv, 4.41 mmol), potassium carbonate (913 mg, 1.5 equiv, 6.61 mmol) and 2.5-difluoro benzonitrile (736 mg, 1.2 equiv, 5.29 mmol) were mixed in dimethylformamide (4.09 mL, 12 equiv) was stirred at 100 °C for 5 hours. The reaction was cooled down to room temperature and water was added. The precipitate was collected by filtration and washed with water. No further purification was performed on 5-fluoro-2-(1H- pyrazol-1-yl)benzonitrile (767 mg, 4.10 mmol, 93 %).1H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 2.6 Hz, 1H), 7.93 – 7.65 (m, 2H), 7.54 – 7.34 (m, 2H), 6.67 – 6.27 (m, 1H).19F NMR (377 MHz, CDCl3) δ -112.24 (td, J = 7.6, 4.8 Hz, 1F). (5-Fluoro-2-(1H-pyrazol-1-yl)phenyl)methanamine[000339] Synthesized from 5-fluoro-2-(1H-pyrazol-1-yl)benzonitrile (100 mg, 1 equiv, 534 μmol) according to General procedure F for 72 hours. The crude mixture was purified by reverse phase chromatography using a 5-95% gradient of acetonitrile in water (0.1% formic acid) over 20 CV on a 12 g C18 column. (5-fluoro-2-(1H-pyrazol-1-yl)phenyl)methanamine was obtained as a powder (30 mg, 0.16 mmol, 29 %).1H NMR (400 MHz, DMSO) δ 8.07 (s, 1H), 7.83 (s, 1H), 7.68 – 7.51 (m, 1H), 7.50 – 7.41 (m, 1H), 7.35 (s, 1H), 6.60 (s, 1H), 4.01 (s, 2H).19F NMR (377 MHz, DMSO-) δ -110.76 (q, J = 7.2 Hz, 1F). N-(5-Fluoro-2-(1H-pyrazol-1-yl)benzyl)-2-(1H-indol-3-yl)acetamide -Example 50[000340] Synthesized from indoleacetic acid (27 mg, 1 equiv, 0.16 mmol) and (5- fluoro-2-(1H-pyrazol-1-yl)phenyl)methanamine (30 mg, 1 equiv, 0.16 mmol) according to General procedure A. The crude mixture was purified by reverse phase chromatography using a 5-95% gradient of acetonitrile in water (0.1% formic acid) over 20 CV on a 4 g C18 column. N-(5-Fluoro-2-(1H-pyrazol-1-yl)benzyl)-2-(1H-indol-3-yl)acetamide was obtained as a solid (18 mg, 52 μmol, 33%).1H NMR (400 MHz, DMSO) δ 10.90 (br, 1H), 8.29 (t, J = 6.0 Hz, 1H), 8.03 (d, J = 2.4 Hz, 1H), 7.67 (d, J = 1.8 Hz, 1H), 7.54 (d, J = 7.9 Hz, 1H), 7.40 (dd, J = 8.7, 5.3 Hz, 1H), 7.35 (d, J = 8.1 Hz, 1H), 7.26 – 7.15 (m, 2H), 7.15 – 7.04 (m, 2H), 7.02 – 6.94 (m, 1H), 6.47 (t, J = 2.1 Hz, 1H), 4.15 (d, J = 6.0 Hz, 2H), 3.59 (s, 2H).19F NMR (377 MHz, DMSO) δ -113.55 (td, J = 9.0, 5.2 Hz, 1F). N-((2-(1H-Pyrazol-1-yl)-4-(trifluoromethyl)pyridin-3-yl)methyl)-2-(1H-indol-3- yl)acetamide – Example 512-(1H-Pyrazol-1-yl)-4-(trifluoromethyl)nicotinonitrile [000341] Pyrazole (49.4 mg, 1.5 equiv, 726 μmol) and potassium carbonate (134 mg, 2 equiv, 968 μmol) were placed in N,N-dimethylformamide (2.42 mL, 0.20 molar).2-Chloro- 3-cyano-4-(trifluoromethyl)pyridine (100 mg, 1 equiv, 484 μmol) was added and the mixture was stirred at 60 °C for 18 h. The mixture was cooled down to room temperature. Water was added and a precipitate formed. The mixture was stirred for 15 min at room temperature then the solid was collected by filtration using a sinter funnel, washing with water.2-(1H-Pyrazol- 1-yl)-4-(trifluoromethyl)nicotinonitrile was isolated as a solid (101 mg, 424 μmol, 88%).1H NMR (400 MHz, DMSO) δ 9.02 (d, J = 5.0 Hz, 1H), 8.66 (d, J = 2.7 Hz, 1H), 8.02 (d, J = 1.6 Hz, 1H), 8.00 (d, J = 5.1 Hz, 1H), 6.72 (dd, J = 2.7, 1.7 Hz, 1H).19F NMR (377 MHz, DMSO) δ -62.86 (3F). (2-(1H-Pyrazol-1-yl)-4-(trifluoromethyl)pyridin-3-yl)methanamine [000342] 2-(1H-Pyrazol-1-yl)-4-(trifluoromethyl)nicotinonitrile (99.0 mg, 1 equiv, 416 μmol) was dissolved in methanol (4.16 mL, 0.10 molar) and palladium dihydroxide (146 mg, 20% Wt, 0.5 equiv, 208 μmol) was added. Ammonia (7 molar in MeOH, 594 μL, 10 equiv, 4.16 mmol) was added. The mixture was stirred at room temperature for 2.5 h under a hydrogen atmosphere (6 bar; autoclave). The reaction mixture was filtered (PTFE syringe filter), washing with methanol. The crude (2-(1H-pyrazol-1-yl)-4-(trifluoromethyl)pyridin-3- yl)methanamine was isolated as an oil (79 mg) which was used without further purification. N-((2-(1H-Pyrazol-1-yl)-4-(trifluoromethyl)pyridin-3-yl)methyl)-2-(1H-indol-3- yl)acetamide -Example 51 [000343] Synthesized from 2-(1H-indol-3-yl)acetic acid (55.7 mg, 1 equiv, 318 μmol) and (2-(1H-pyrazol-1-yl)-4-(trifluoromethyl)pyridin-3-yl)methanamine (77.0 mg, 1 equiv, 318 μmol) according to general procedure A. The crude purified by normal phase MPLC (0- 30% methanol (10% in dichloromethane) in dichloromethane, 18 CV, 12 g silica column).The isolated product was further purified by reverse phase chromatography using a 5-70% gradient of acetonitrile in water (0.1% formic acid) over 25 CV on a 4 g C18 column. N-((2- (1H-Pyrazol-1-yl)-4-(trifluoromethyl)pyridin-3-yl)methyl)-2-(1H-indol-3-yl)acetamide was isolated as a solid (13.3 mg, 33 μmol, 11%). 1H NMR (400 MHz, DMSO) δ 10.86 (br, 1H), 8.72 (d, J = 5.1 Hz, 1H), 8.26 (dd, J = 2.6, 0.7 Hz, 1H), 7.85 (d, J = 5.1 Hz, 1H), 7.84 – 7.79 (m, 1H), 7.45 (dd, J = 1.8, 0.7 Hz, 1H), 7.41 (d, J = 7.9 Hz, 1H), 7.34 (dt, J = 8.2, 0.9 Hz, 1H), 7.12 (d, J = 2.4 Hz, 1H), 7.07 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 6.96 (ddd, J = 8.0, 6.9, 1.0 Hz, 1H), 6.49 (dd, J = 2.6, 1.7 Hz, 1H), 4.51 (d, J = 4.9 Hz, 2H), 3.45 (s, 2H). 19F NMR (377 MHz, DMSO) δ -59.67 (s, 3F). N-((4-Cyclopropyl-2-(1H-pyrazol-1-yl)pyridin-3-yl)methyl)-2-(1H-indol-3-yl)acetamide – Example 52 2-Chloro-4-cyclopropylnicotinonitrile [000344] Cyclopropaneboronic acid (395 mg, 1.00 equiv, 4.60 mmol) was added to a degassed stirred mixture of 4-bromo-2-chloronicotinonitrile (1.00 g, 1 equiv, 4.60 mmol), sodium carbonate (1.46 g, 3.00 equiv, 13.8 mmol), 1,1'-bis(diphenylphosphino)ferrocene- palladium(II) dichloride (336 mg, 0.10 equiv, 460 μmol) and water (7.66 mL, 0.6 molar) in 1,4-dioxane (27.1 mL, 0.17 molar). The reaction vessel was sealed, heated to 110 °C for 17 h and cooled down to room temperature. Water was added. The precipitate was filtered andwashed with water (2-chloro-4-cyclopropylnicotinonitrile (425 mg, 2.1 mmol, 47%). The filtrate was extracted with ethyl acetate. The combined organics were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to yield a solid which was purified by normal phase chromatography on a 20 g Agilent silica column using a 10-50% ethyl acetate in cyclohexane. The product containing fractions were combined to deliver 2- chloro-4-cyclopropylnicotinonitrile (125 mg, 700 μmol, 15%) as a solid.1H NMR (400 MHz, CDCl3) δ 8.36 (d, J = 5.4 Hz, 1H), 6.69 (d, J = 5.5 Hz, 1H), 2.33 (tt, J = 8.2, 4.9 Hz, 1H), 1.36 (ddd, J = 8.2, 7.0, 4.9 Hz, 2H), 0.96 (dt, J = 7.2, 4.9 Hz, 2H). 4-Cyclopropyl-2-(1H-pyrazol-1-yl)nicotinonitrile[000345] Dimethylsulfoxide (2.5 mL, 0.2 molar) was added to a reactor containing 2- chloro-4-cyclopropylnicotinonitrile (90 mg, 1 equiv, 0.50 mmol), potassium carbonate (0.10 g, 1.5 equiv, 0.76 mmol) and pyrazole (51 mg, 1.5 equiv, 0.76 mmol). The mixture was stirred at 130 °C for 18 h. LCMS showed full conversion. The reactor was cooled down to room temperature. Water was added. The precipitate was filtered off and dried in air.4- Cyclopropyl-2-(1H-pyrazol-1-yl)nicotinonitrile (105 mg, 499 μmol, 99%) was isolated as a solid.1H NMR (400 MHz, CDCl3) δ 8.47 (d, J = 2.7 Hz, 1H), 8.39 (d, J = 5.3 Hz, 1H), 7.88 (d, J = 1.8 Hz, 1H), 6.68 (d, J = 5.3 Hz, 1H), 6.51 (dd, J = 2.7, 1.6 Hz, 1H), 2.54 (tt, J = 8.4, 4.9 Hz, 1H), 1.44 – 1.24 (m, 2H), 0.96 (dt, J = 7.0, 4.9 Hz, 2H). tert-Butyl ((4-cyclopropyl-2-(1H-pyrazol-1-yl)pyridin-3-yl)methyl)carbamate[000346] Sodium borohydride (68 mg, 6.0 equiv, 1.8 mmol) was added to a mixture of 4-cyclopropyl-2-(1H-pyrazol-1-yl)nicotinonitrile (63 mg, 1 equiv, 0.30 mmol), di-tert-butyl dicarbonate (0.13 g, 2.0 equiv, 0.60 mmol) and nickel (II) dichloride hexahydrate (18 mg, 0.25 equiv, 75 μmol) in methanol (3.0 mL, 0.1 molar). The mixture was stirred for 16 h at room temperature. The crude mixture was diluted with methanol. Silica was added and themixture was concentrated to yield a powder which was purified by normal phase chromatography using a 10-50% ethyl acetate gradient in cyclohexane over 10 CV (12 g column). The product containing fractions were combined and concentrated to provide tert- butyl-((4-cyclopropyl-2-(1H-pyrazol-1-yl)pyridin-3-yl)methyl)carbamate (20 mg, 64 μmol, 21%) as an oil.1H NMR (400 MHz, CDCl3) δ 8.51 – 7.93 (m, 2H), 7.70 (d, J = 1.7 Hz, 1H), 6.71 (d, J = 5.2 Hz, 1H), 6.41 (dd, J = 2.6, 1.8 Hz, 1H), 6.22 (s, 1H), 4.47 (d, J = 6.6 Hz, 2H), 2.53 (td, J = 8.2, 4.3 Hz, 1H), 1.39 (s, 9H), 1.18 – 1.01 (m, 2H), 0.81 – 0.58 (m, 2H). (4-Cyclopropyl-2-(1H-pyrazol-1-yl)pyridin-3-yl)methanamine[000347] tert-Butyl-((4-cyclopropyl-2-(1H-pyrazol-1-yl)pyridin-3-yl)methyl)carbamate (10 mg, 1 equiv, 32 μmol) was dissolved in hydrochloric acid (4 M in dioxane, 0.5 mL). After 1 hour, LCMS showed full conversion of starting material. The reaction mixture was concentrated to dryness. No further purification was carried out. N-((4-Cyclopropyl-2-(1H-pyrazol-1-yl)pyridin-3-yl)methyl)-2-(1H-indol-3-yl)acetamide Example 52 [000348] N-((4-Cyclopropyl-2-(1H-pyrazol-1-yl)pyridin-3-yl)methyl)-2-(1H-indol-3- yl)acetamide was prepared following general procedure A on 0.03 mmol scale starting from 2-(1H-indol-3-yl)acetic acid (5.6 mg, 1 equiv, 32 μmol) and (4-cyclopropyl-2-(1H-pyrazol-1- yl)pyridin-3-yl)methanamine (6.8 mg, 1 equiv, 32 μmol). The crude mixture was purified by reverse phase chromatography using a 5-95% gradient of acetonitrile in water (0.1% formic acid) over 15 CV on a 12 g C18 column. Upon freeze-drying N-((4-cyclopropyl-2-(1H- pyrazol-1-yl)pyridin-3-yl)methyl)-2-(1H-indol-3-yl)acetamide (6 mg, 15 μmol, 50%) was obtained as a solid.1H NMR (400 MHz, DMSO) δ 10.89 (br, 1H), 8.26 (d, J = 5.2 Hz, 1H), 8.22 (dd, J = 2.5, 0.7 Hz, 1H), 7.88 (t, J = 5.5 Hz, 1H), 7.54 – 7.44 (m, 1H), 7.37 – 7.36 (m, 1H), 7.35 (dt, J = 6.1, 0.7 Hz, 1H), 7.20 (d, J = 2.4 Hz, 1H), 7.08 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H), 6.97 (dd, J = 7.1, 1.0 Hz, 1H), 6.98 – 6.92 (m, 1H), 6.45 (dd, J = 2.5, 1.8 Hz, 1H), 4.44 (d, J = 5.5 Hz, 2H), 3.56 (s, 2H), 2.25 (td, J = 8.5, 4.2 Hz, 1H), 1.06 – 0.89 (m, 2H), 0.86 – 0.72 (m, 2H). 2-(1H-Indol-3-yl)-N-(2-(5-methylfuran-2-yl)benzyl)acetamide - Example 53[000349] Synthesized from (5-methyl-2-furyl)boronic acid (31 μL, 2 equiv, 0.29 mmol) and N-(2-bromobenzyl)-2-(1H-indol-3-yl)acetamide (50 mg, 1 equiv, 0.15 mmol) according to general procedure G, heating at 100 °C for 48 h. The crude mixture was purified by reverse phase chromatography using a 5-70% gradient of acetonitrile in water (0.1% formic acid) over 30 CV on a 12 g C18 column.2-(1H-Indol-3-yl)-N-(2-(5-methylfuran-2- yl)benzyl)acetamide was isolated as a solid (4 mg, 0.01 mmol, 7%).1H NMR (400 MHz, CDCl3) δ 8.12 (br, 1H), 7.53 (dd, J = 8.0, 1.1 Hz, 1H), 7.47 (dd, J = 7.6, 1.6 Hz, 1H), 7.36 (dt, J = 8.2, 1.0 Hz, 1H), 7.31 (dd, J = 7.5, 1.6 Hz, 1H), 7.25 – 7.15 (m, 3H), 7.15 – 7.03 (m, 2H), 6.27 (d, J = 3.2 Hz, 1H), 6.16 (br, 1H), 6.00 – 5.85 (m, 1H), 4.54 (d, J = 6.0 Hz, 2H), 3.76 (s, 2H), 2.00 (s, 3H). ESI-MS: m / z calc. for C22H20N2O2[M+H]+: 345.1598, found 345. N-(2-(Furan-3-yl)benzyl)-2-(1H-indol-3-yl)acetamide – Example 54 [000350] Synthesized from furan-3-boronic acid (33 mg, 2 equiv, 0.29 mmol) and N-(2- bromobenzyl)-2-(1H-indol-3-yl)acetamide (50 mg, 1 equiv, 0.15 mmol) according to general procedure G , stirring at 100 °C for 72 h. The crude mixture was purified by reverse phasechromatography using a 5-70% gradient of acetonitrile in water (0.1% formic acid) over 30 CV on a 12 g C18 column. N-(2-(Furan-3-yl)benzyl)-2-(1H-indol-3-yl)acetamide was isolated as a solid (22.8 mg, 69 µmol, 47%).1H NMR (400 MHz, CDCl3) δ 8.29 (br s, 1H), 7.55 (d, J = 7.9 Hz, 1H), 7.43 (d, J = 8.2 Hz, 1H), 7.37 (t, J = 1.7 Hz, 1H), 7.32 – 7.21 (m, 6H), 7.17 (td, J = 7.5, 1.0 Hz, 1H), 7.11 (d, J = 2.4 Hz, 1H), 6.40 – 6.27 (m, 1H), 5.89 (br t, 1H), 4.48 (d, J = 5.7 Hz, 2H), 3.80 (s, 2H). ESI-MS: m / z calc. for C21H18N2O2[M+H]+: 331.1441, found 331. 2-(1H-Indol-3-yl)-N-(2-(thiophen-2-yl)benzyl)acetamide – Example 55[000351] Synthesized from thiophene-2-boronic acid (37 mg, 2 equiv, 0.29 mmol) and N-(2-bromobenzyl)-2-(1H-indol-3-yl)acetamide (50 mg, 1 equiv, 0.15 mmol) according to general procedure G, using bis-(triphenylphosphino)-palladous chloride (10 mg, 0.10 equiv, 15 μmol) as the catalyst. The mixture was heated at 100 °C for 18 h. The crude mixture was purified by reverse phase chromatography using a 5-70% gradient of acetonitrile in water (0.1% formic acid) over 30 CV on a 12 g C18 column.2-(1H-Indol-3-yl)-N-(2-(thiophen-2- yl)benzyl)acetamide was isolated as a solid (32.0 mg, 92 µmol, 63%).1H NMR (400 MHz, CDCl3) δ 8.24 (br s, 1H), 7.51 (d, J = 7.9 Hz, 1H), 7.38 (d, J = 8.2 Hz, 1H), 7.31 – 7.26 (m, 2H), 7.26 – 7.18 (m, 4H), 7.17 – 7.09 (m, 1H), 7.06 (d, J = 2.4 Hz, 1H), 6.95 – 6.84 (m, 1H), 6.74 (dd, J = 3.5, 1.2 Hz, 1H), 6.05 – 5.58 (m, 1H), 4.46 (d, J = 5.8 Hz, 2H), 3.74 (s, 2H). ESI-MS: m / z calc. for C21H18N2OS [M+H]+: 347.1213, found 347. 2-(1H-Indol-3-yl)-N-(2-(pyridin-2-yl)benzyl)acetamide – Example 56(2-((2-(1H-Indol-3-yl)acetamido)methyl)phenyl)boronic acid [000352] Indoleacetic acid (250 mg, 1 equiv, 1.43 mmol) and (2- (aminomethyl)phenyl)boronic acid (215 mg, 1 equiv, 1.43 mmol) were added to N,N- dimethylformamide (14.3 mL, 0.10 molar). N,N-diisopropylethylamine (994 μL, 4 equiv, 5.71 mmol) was added, followed by O-(7-azabenzotriazol-1-yl)-N,N,N′,N′- tetramethyluronium-hexafluorphosphat (543 mg, 1 equiv, 1.43 mmol). The mixture was stirred at room temperature overnight. Saturated aqueous ammonium chloride and dichloromethane were added. The phases were separated, and the aqueous layer was washed with dichloromethane (2x). The combined organic layers were washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed. The crude mixture was purified by reverse phase chromatography using a gradient of water (0.1% formic acid) / acetonitrile 95 / 5 to 30 / 70 over 30 CV on a 12 g C18 column. (2-((2-(1H-Indol-3- yl)acetamido)methyl)phenyl)boronic acid was isolated as a solid (307 mg, 996 µmol, 70%).1H NMR (400 MHz, DMSO) δ 10.88 (br, 1H), 8.57 (t, J = 6.1 Hz, 1H), 8.42 (d, J = 4.1 Hz, 2H), 7.51 (d, J = 7.9 Hz, 1H), 7.47 (d, J = 7.4 Hz, 1H), 7.34 (d, J = 8.1 Hz, 1H), 7.29 (td, J = 7.4, 1.5 Hz, 1H), 7.24 (d, J = 7.5 Hz, 1H), 7.22 – 7.14 (m, 2H), 7.06 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 7.00 – 6.91 (m, 1H), 4.34 (d, J = 5.9 Hz, 2H), 3.57 (s, 2H). 2-(1H-Indol-3-yl)-N-(2-(pyridin-2-yl)benzyl)acetamide [000353] (2-((2-(1H-Indol-3-yl)acetamido)methyl)phenyl)boronic acid (50 mg, 1 equiv, 0.16 mmol), alpha-bromopyridine (31 μL, 2 equiv, 0.32 mmol), K2CO3(90 mg, 4 equiv, 0.65 mmol) and tetrakis(triphenylphosphin)palladium(0) (19 mg, 0.10 equiv, 16 μmol) were stirred in degassed 1,4-dioxane / water (5:1 v / v) (1.6 mL, 0.10 molar). The mixture was heated to 100 °C for 18 h. Water and ethyl acetate were added. The phases were separated, and the aqueous phase was washed with ethyl acetate (2x). The combined organic layers were dried over anhydrous magnesium sulfate and the solvent was removed. The crude mixture was purified by reverse phase chromatography using a 5-70% gradient of acetonitrile in water(0.1% formic acid) over 30 CV on a 12 g C18 column.2-(1H-Indol-3-yl)-N-(2-(pyridin-2- yl)benzyl)acetamide was isolated as a solid (18 mg, 53 µmol, 32%).1H NMR (400 MHz, DMSO) δ 10.88 (br, 1H), 8.36 (dt, J = 5.3, 1.3 Hz, 1H), 8.16 (t, J = 5.9 Hz, 1H), 7.83 (td, J = 7.7, 1.9 Hz, 1H), 7.56 – 7.48 (m, 2H), 7.44 – 7.28 (m, 6H), 7.18 (d, J = 2.3 Hz, 1H), 7.08 (ddd, J = 8.1, 6.9, 1.3 Hz, 1H), 7.01 – 6.93 (m, 1H), 4.30 (d, J = 5.9 Hz, 2H), 3.55 (s, 2H). N-([1,1'-Biphenyl]-2-ylmethyl)-2-(1H-indol-3-yl)acetamide– Example 57[000354] Synthesized from benzeneboronic acid (36 mg, 2 equiv, 0.29 mmol) and N-(2- bromobenzyl)-2-(1H-indol-3-yl)acetamide (50 mg, 1 equiv, 0.15 mmol) according to general procedure G, heating at 100 °C for 18 h. The crude mixture was purified by reverse phase chromatography using a 5-70% gradient of acetonitrile in water (0.1% formic acid) over 30 CV on a 12 g C18 column. N-([1,1'-Biphenyl]-2-ylmethyl)-2-(1H-indol-3-yl)acetamide was isolated as a solid (31.4 mg, 92 µmol, 63%).1H NMR (400 MHz, CDCl3) δ 8.21 (br, 1H), 7.49 (d, J = 7.9 Hz, 1H), 7.43 – 7.33 (m, 1H), 7.31 – 7.19 (m, 7H), 7.18 – 7.08 (m, 2H), 7.08 – 6.96 (m, 3H), 5.87 – 5.62 (m, 1H), 4.34 (d, J = 5.9 Hz, 2H), 3.70 (s, 2H). ESI-MS: m / z calc. for C23H20N2O [M+H]+: 341.1648, found 341. N-((2-(Furan-3-yl)pyridin-3-yl)methyl)-2-(1H-indol-3-yl)acetamide – Example 58 [000355] Synthesized from furan-3-boronic acid (56 mg, 3 equiv, 0.50 mmol) and N- ((2-chloropyridin-3-yl)methyl)-2-(1H-indol-3-yl)acetamide (50 mg, 1 equiv, 0.17 mmol) according to general procedure G, using potassium carbonate (0.14 g, 1.0 mmol, 6 equiv) andheating at 100 °C for 72 h. The crude mixture was purified by reverse phase chromatography using a 5-70% gradient of acetonitrile in water (0.1% formic acid) over 30 CV on a 12 g C18 column. N-((2-(Furan-3-yl)pyridin-3-yl)methyl)-2-(1H-indol-3-yl)acetamide was isolated as a solid (36 mg, 0.11 mmol, 65%).1H NMR (400 MHz, CDCl3) δ 8.58 – 8.41 (m, 1H), 8.24 (br s, 1H), 7.63 – 7.45 (m, 3H), 7.44 – 7.35 (m, 2H), 7.23 (br dd, J = 8.2, 1.2 Hz, 1H), 7.18 – 7.12 (m, 1H), 7.13 – 7.06 (m, 2H), 6.88 – 6.35 (m, 1H), 5.94 (br t, 1H), 4.50 (d, J = 5.9 Hz, 2H), 3.80 (s, 2H). ESI-MS: m / z calc. for C20H17N3O2[M+H]+: 331.1321, found 331. 2-(1H-Indol-3-yl)-N-(5-methyl-2-(1H-pyrazol-1-yl)benzyl)acetamide – Example 595-Methyl-2-(1H-pyrazol-1-yl)benzonitrile [000356] 2-Fluoro-5-methyl-benzonitrile (200 mg, 1 equiv, 1.48 mmol), potassium carbonate (307 mg, 1.5 equiv, 2.22 mmol) and pyrazole (111 mg, 1.1 equiv, 1.63 mmol) were mixed in dimethylformamide (1.38 mL, 1.07 molar). The mixture was stirred at 70 °C for 96 hours. Full starting material consumption was observed. A solid precipitated. Water was added to the mixture which dissolved the salt. The mixture was filtered. The solid was triturated in water and dried in vacuo to provide 5-methyl-2-(1H-pyrazol-1-yl)benzonitrile (155 mg, 846 μmol, 57%) as a solid.1H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 2.5 Hz, 1H), 7.79 (d, J = 1.8 Hz, 1H), 7.66 (d, J = 8.3 Hz, 1H), 7.57 (d, J = 2.1 Hz, 1H), 7.50 (dd, J = 8.3, 2.1 Hz, 1H), 6.62 – 6.02 (m, 1H), 2.43 (s, 3H). (5-Methyl-2-(1H-pyrazol-1-yl)phenyl)methanamine[000357] Synthesized from 5-methyl-2-(1H-pyrazol-1-yl)benzonitrile (120 mg, 1 equiv, 655 μmol) according to general procedure F for 72 h. The crude mixture was purified by reverse phase chromatography using a 5-95% gradient of acetonitrile in water (0.1% formic acid) over 20 CV on a 12 g C18 column. (5-Methyl-2-(1H-pyrazol-1-yl)phenyl)methanamine was obtained as a powder (62 mg, 0.33 mmol, 51%).1H NMR (400 MHz, DMSO) δ 8.74 – 6.84 (br m, 5H), 6.52 (br s, 1H), 3.70 (s, 2H), 2.38 (s, 3H). 2-(1H-Indol-3-yl)-N-(5-methyl-2-(1H-pyrazol-1-yl)benzyl)acetamide -Example 59[000358] Synthesized from 2-(1H-indol-3-yl)acetic acid (29 mg, 1 equiv, 0.17 mmol) and (5-methyl-2-(1H-pyrazol-1-yl)phenyl)methanamine (31 mg, 1 Eq, 0.17 mmol) according to general procedure A. The crude mixture was purified by reverse phase chromatography using a 5-95% gradient of acetonitrile in water (0.1% formic acid) over 15 CV on a 12 g C18 column.2-(1H-Indol-3-yl)-N-(5-methyl-2-(1H-pyrazol-1-yl)benzyl)acetamide was obtained as a solid (6 mg, 0.02 mmol, 10%).1H NMR (400 MHz, DMSO) δ 11.04 – 10.56 (m, 1H), 8.19 (t, J = 6.0 Hz, 1H), 7.97 (d, J = 2.4 Hz, 1H), 7.61 (d, J = 1.8 Hz, 1H), 7.57 (d, J = 7.9 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.21 (dd, J = 5.2, 2.8 Hz, 2H), 7.13 (dd, J = 8.1, 1.9 Hz, 1H), 7.11 – 7.06 (m, 1H), 7.04 (d, J = 1.9 Hz, 1H), 7.02 – 6.92 (m, 1H), 6.44 (t, J = 2.3 Hz, 1H), 4.13 (d, J = 5.9 Hz, 2H), 3.57 (s, 2H), 2.18 (s, 3H). N-(2-(1H-Pyrazol-1-yl)pyridin-3-yl)-2-(6-fluoro-1H-indol-3-yl)acetamide – Example 60[000359] Synthesized from (6-fluoro-1H-indol-3-yl)acetic acid (50.0 mg, 1 equiv, 259 μmol) and 2-pyrazol-1-ylpyridin-3-amine (41.5 mg, 1 equiv, 259 μmol) according to general procedure A heating at 40 °C for 18 h. The crude mixture was purified by reverse phase chromatography using a 5-70% gradient of acetonitrile in water (0.1% formic acid) over 30 CV on a 12 g C18 column. N-(2-(1H-Pyrazol-1-yl)pyridin-3-yl)-2-(6-fluoro-1H-indol-3- yl)acetamide was isolated as a solid (35.1 mg, 105 μmol, 40%).1H NMR (400 MHz, DMSO) δ 11.38 (br, 1H), 11.21 (br, 1H), 8.98 (dd, J = 8.3, 1.6 Hz, 1H), 8.50 (dd, J = 2.6, 0.7 Hz, 1H), 8.14 (dd, J = 4.6, 1.6 Hz, 1H), 7.47 (dd, J = 8.7, 5.4 Hz, 1H), 7.45 – 7.41 (m, 1H), 7.37 (dd, J = 8.3, 4.6 Hz, 1H), 7.31 – 7.24 (m, 1H), 7.21 (dd, J = 10.1, 2.4 Hz, 1H), 6.82 (ddd, J = 9.8, 8.6, 2.4 Hz, 1H), 6.47 (dd, J = 2.6, 1.8 Hz, 1H), 3.87 (s, 2H).19F NMR (377 MHz, DMSO) δ -122.01 (td, J = 8.9, 4.0 Hz, 1F). ESI-MS: m / z calc. for C18H14FN5O [M+H]+: 336.1255, found 336. N-(2-(1H-Pyrazol-1-yl)pyridin-3-yl)-2-(5-fluoro-1H-indol-3-yl)acetamide – Example 61[000360] Synthesized from 5-fluoroindole-3-aceticacid (50.0 mg, 1 equiv, 259 μmol) and 2-pyrazol-1-ylpyridin-3-amine (41.5 mg, 1 equiv, 259 μmol) according to general procedure A heating at 40 °C for 18 h. The crude mixture was purified by reverse phase chromatography using a 5-70% gradient of acetonitrile in water (0.1% formic acid) over 30 CV on a 12 g C18 column. N-(2-(1H-Pyrazol-1-yl)pyridin-3-yl)-2-(5-fluoro-1H-indol-3- yl)acetamide was isolated as a solid (35.4 mg, 106 μmol, 41%).1H NMR (400 MHz, DMSO) δ 11.37 (br, 1H), 11.25 (br, 1H), 8.99 (dd, J = 8.3, 1.6 Hz, 1H), 8.51 (d, J = 2.6 Hz, 1H), 8.15 (dd, J = 4.6, 1.6 Hz, 1H), 7.51 (d, J = 2.4 Hz, 1H), 7.44 (dd, J = 8.8, 4.6 Hz, 1H), 7.37 (dd, J = 8.3, 4.6 Hz, 1H), 7.27 (dd, J = 10.0, 2.6 Hz, 1H), 7.19 (d, J = 1.8 Hz, 1H), 6.94 (td, J = 9.2, 2.6 Hz, 1H), 6.46 (dd, J = 2.6, 1.8 Hz, 1H), 3.86 (s, 2H).19F NMR (377 MHz, DMSO) δ -125.05 (td, J = 9.7, 4.6 Hz, 1F). ESI-MS: m / z calc. for C18H14FN5O [M+H]+: 336.1255, found 336.N-(2-(1H-Pyrazol-1-yl)pyridin-3-yl)-2-(5,6-difluoro-1H-indol-3-yl)acetamide – Example 62[000361] Synthesized from 5,6-difluoro-1h-indole-3acetic acid (50 mg, 1 equiv, 0.24 mmol) and 2-pyrazol-1-ylpyridin-3-amine (38 mg, 1 equiv, 0.24 mmol) according to general procedure A heating at 40 °C for 18 h. The crude mixture was purified by reverse phase chromatography using a 5-70 % gradient of acetonitrile in water (0.1% formic acid) over 30 CV on a 12 g C18 column. N-(2-(1H-Pyrazol-1-yl)pyridin-3-yl)-2-(5,6-difluoro-1H-indol-3- yl)acetamide was isolated as a solid (43.0 mg, 122 μmol, 51%).1H NMR (400 MHz, DMSO) δ 11.31 (br, 2H), 8.98 (dd, J = 8.3, 1.6 Hz, 1H), 8.51 (d, J = 2.6 Hz, 1H), 8.15 (dd, J = 4.6, 1.6 Hz, 1H), 7.58 – 7.42 (m, 3H), 7.38 (dd, J = 8.3, 4.6 Hz, 1H), 7.24 (d, J = 1.9 Hz, 1H), 6.63 – 6.31 (m, 1H), 3.87 (s, 2H).19F NMR (377 MHz, DMSO) δ-145.53 (ddd, J = 22.2, 11.4, 8.2 Hz, 1F), -148.80 (ddd, J = 22.2, 11.3, 7.0 Hz, 1F). ESI-MS: m / z calc. for C18H13F2N5O [M+H]+: 354.1161, found 354. N-(2-(1H-1,2,4-Triazol-1-yl)pyridin-3-yl)-2-(6-fluoro-1H-indol-3-yl)acetamide – Example 63 [000362] Synthesized from (6-fluoro-1H-indol-3-yl)acetic acid (47.9 mg, 1 equiv, 248 μmol) and 2-(1H-1,2,4-triazol-1-yl)pyridin-3-amine (40.0 mg, 1 equiv, 248 μmol) according to general procedure A heating at 40 °C for 18 h. The crude mixture was purified by reverse phase chromatography using a 5-70% gradient of acetonitrile in water (0.1% formic acid) over 30 CV on a 12 g C18 column. N-(2-(1H-1,2,4-Triazol-1-yl)pyridin-3-yl)-2-(6-fluoro- 1H-indol-3-yl)acetamide was isolated as a solid (26.2 mg, 78 μmol, 31%).1H NMR (400 MHz, DMSO) δ 11.17 (br, 1H), 10.43 (br, 1H), 8.93 – 8.69 (m, 1H), 8.23 (dd, J = 4.6, 1.6 Hz, 1H), 7.83 (s, 1H), 7.62 – 7.42 (m, 2H), 7.40 (d, J = 2.3 Hz, 1H), 7.21 (dd, J = 10.1, 2.4 Hz, 1H), 6.87 – 6.77 (m, 1H), 3.85 (s, 2H).19F NMR (377 MHz, DMSO) δ -121.92 (td, J = 9.9, 5.4 Hz, 1F). ESI-MS: m / z calc. for C17H13FN6O [M+H]+: 337.1208 , found 337. N-(2-(Furan-2-yl)phenyl)-2-(1H-indol-3-yl)acetamide – Example 64[000363] Synthesized from furan-2-boronic acid (51 mg, 3 equiv, 0.46 mmol) and N-(2- bromobenzyl)-2-(1H-indol-3-yl)acetamide (50 mg, 1 equiv, 0.15 mmol) according to general procedure G, heating at 100 °C for 72 h. The crude mixture was purified by reverse phase chromatography using a 5-70% gradient of water (0.1% formic acid) over 30 CV on a 12 g C18 column. N-(2-(Furan-2-yl)phenyl)-2-(1H-indol-3-yl)acetamide was isolated as a solid (15.7 mg, 50 μmol, 33%).1H NMR (400 MHz, DMSO) δ 11.04 (br, 1H), 9.28 (br, 1H), 7.83 (d, J = 8.1 Hz, 1H), 7.63 – 7.55 (m, 2H), 7.41 (d, J = 7.6 Hz, 2H), 7.35 (d, J = 2.4 Hz, 1H), 7.32 – 7.25 (m, 1H), 7.24 – 7.14 (m, 1H), 7.14 – 7.06 (m, 1H), 7.00 (t, J = 7.4 Hz, 1H), 6.57 – 6.15 (m, 2H), 3.82 (s, 2H). ESI-MS: m / z calc. for C20H16N2O2[M+H]+: 317.128456, found 317. N-((2-(1H-Pyrazol-1-yl)pyridin-3-yl)methyl)-2-(1H-pyrrolo[2,3-c]pyridin-3-yl)acetamide formate – Example 65 [000364] Synthesized from 2-{1H-pyrrolo[2,3-c]pyridin-3-yl}acetic acid hydrochloride (40.0 mg, 1 equiv, 188 μmol) and [2-(1H-pyrazol-1-yl)pyridin-3-yl]methanamine hydrochloride (39.6 mg, 1 equiv, 188 μmol) according to general procedure B using N,N-diisopropylethylamine (164 μL, 5 equiv, 941 μmol) and 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (54.1 mg, 1.5 equiv, 282 μmol). The crude mixture was purified by reverse phase chromatography using a 5-50% gradient of water (0.1% formic acid) over 30 CV on a 12 g C18 column. N-((2-(1H-Pyrazol-1-yl)pyridin-3-yl)methyl)-2- (1H-pyrrolo[2,3-c]pyridin-3-yl)acetamide formate was isolated as a solid (15.2 mg, 40 μmol, 21%).1H NMR (400 MHz, DMSO) δ 11.44 (br, 1H), 8.71 (d, J = 1.1 Hz, 1H), 8.40 (d, J = 2.5 Hz, 1H), 8.38 (dd, J = 4.7, 1.7 Hz, 1H), 8.30 (t, J = 6.1 Hz, 1H), 8.16 (s, 1H), 8.07 (d, J = 5.5 Hz, 1H), 7.80 (dd, J = 7.7, 1.8 Hz, 1H), 7.70 (d, J = 1.7 Hz, 1H), 7.53 – 7.45 (m, 2H), 7.35 (dd, J = 7.7, 4.7 Hz, 1H), 6.53 (dd, J = 2.6, 1.7 Hz, 1H), 4.53 (d, J = 6.0 Hz, 2H), 3.63 (s, 2H). ESI-MS: m / z calc. for C18H16N6O [M+H]+: 333.1459, found 333. N-((2-(1H-Pyrazol-1-yl)pyridin-3-yl)methyl)-2-(1H-pyrrolo[3,2-c]pyridin-3-yl)acetamide formate – Example 66 [000365] Synthesized from 2-(1H-pyrrolo[3,2-c]pyridin-3-yl)acetic acid hydrochloride (40.0 mg, 1 equiv, 188 μmol) and [2-(1H-pyrazol-1-yl)pyridin-3-yl]methanamine hydrochloride (39.6 mg, 1 equiv, 188 μmol) according to general procedure B using N,N- diisopropylethylamine (164 μL, 5 equiv, 941 μmol) and 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (54.1 mg, 1.5 equiv, 282 μmol). The crude mixture was purified by reverse phase chromatography using a 5-50% gradient of water (0.1% formic acid) over 30 CV on a 12 g C18 column. N-((2-(1H-Pyrazol-1-yl)pyridin-3-yl)methyl)-2- (1H-pyrrolo[3,2-c]pyridin-3-yl)acetamide formate was isolated as a solid (15.9 mg, 42 μmol, 22%).1H NMR (400 MHz, DMSO) δ 11.46 (br, 1H), 8.72 (d, J = 1.1 Hz, 1H), 8.45 – 8.36 (m, 2H), 8.31 (t, J = 6.1 Hz, 1H), 8.16 (s, 1H), 8.07 (d, J = 5.5 Hz, 1H), 7.81 (dd, J = 7.8, 1.7 Hz, 1H),7.70 (d, J = 1.6 Hz, 1H), 7.54 – 7.45 (m, 2H), 7.35 (dd, J = 7.7, 4.7 Hz, 1H), 6.53 (dd, J = 2.6, 1.7 Hz, 1H), 4.53 (d, J = 6.0 Hz, 2H), 3.63 (s, 2H). ESI-MS: m / z calc. for C18H16N6O [M+H]+: 333.1459, found 333. N-(2-(1H-Pyrazol-1-yl)benzyl)-2-(5-fluoro-1H-indol-3-yl)acetamide – Example 67[000366] Synthesized from (2-pyrazol-1-ylphenyl)methanamine (50 mg, 1 equiv, 0.29 mmol) and 5-fluoroindole-3-acetic acid (56 mg, 1 equiv, 0.29 mmol) according to general procedure A. The crude mixture was purified by reverse phase chromatography using a 5- 70% gradient of acetonitrile in water (0.1% formic acid) over 30 CV on a 12 g C18 column. N-(2-(1H-Pyrazol-1-yl)benzyl)-2-(5-fluoro-1H-indol-3-yl)acetamide isolated as a solid (36.5 mg, 105 μmol, 36%).1H NMR (400 MHz, CDCl3) δ 8.35 (br, 1H), 7.59 – 7.50 (m, 2H), 7.41 – 7.31 (m, 2H), 7.30 – 7.24 (m, 1H), 7.24 – 7.13 (m, 3H), 7.11 (s, 1H), 6.96 (td, J = 9.0, 2.5 Hz, 1H), 6.33 z(t, J = 2.2 Hz, 1H), 4.26 (s, 2H), 3.69 (s, 2H).19F NMR (377 MHz, CDCl3) δ -124.00 (td, J = 9.5, 4.3 Hz, 1F). ESI-MS: m / z calc. for C20H17FN4O [M+H]+: 349.1459, found 349. N-(2-(1H-Pyrazol-1-yl)benzyl)-2-(6-fluoro-1H-indol-3-yl)acetamide – Example 68 [000367] Synthesized from (2-pyrazol-1-ylphenyl)methanamine (50 mg, 1 equiv, 0.29 mmol) and (6-fluoro-1H-indol-3-yl)acetic acid (56 mg, 1 equiv, 0.29 mmol) according to general procedure A. The crude mixture was purified by reverse phase chromatography using a 5-70% gradient of acetonitrile in water (0.1% formic acid) over 30 CV on a 12 g C18column. N-(2-(1H-Pyrazol-1-yl)benzyl)-2-(6-fluoro-1H-indol-3-yl)acetamide was isolated as a solid (46.2 mg, 133 μmol, 46%).1H NMR (400 MHz, DMSO) δ 10.95 (br, 1H), 8.25 (t, J = 5.9 Hz, 1H), 8.04 (d, J = 2.4 Hz, 1H), 7.66 (d, J = 1.8 Hz, 1H), 7.51 (dd, J = 8.7, 5.5 Hz, 1H), 7.41 – 7.32 (m, 4H), 7.20 (d, J = 2.3 Hz, 1H), 7.12 (dd, J = 10.1, 2.4 Hz, 1H), 6.93 – 6.71 (m, 1H), 6.48 (t, J = 2.1 Hz, 1H), 4.19 (d, J = 5.9 Hz, 2H), 3.56 (s, 2H).19F NMR (377 MHz, DMSO) δ -122.36 (td, J = 10.1, 5.5 Hz, 1F). ESI-MS: m / z calc. for C20H17FN4O [M+H]+: 349.1459, found 349. N-(2-(1H-Pyrazol-1-yl)benzyl)-2-(5-methoxy-1H-indol-3-yl)acetamide – Example 69[000368] Synthesized from (2-pyrazol-1-ylphenyl)methanamine (50 mg, 1 equiv, 0.29 mmol) and 5-methoxy-1H-indole-3-acetic acid (59 mg, 1 equiv, 0.29 mmol) according to general procedure A. The crude mixture was purified by reverse phase chromatography using a 5-70% gradient of acetonitrile in water (0.1% formic acid) over 30 CV on a 12 g C18 column. N-(2-(1H-Pyrazol-1-yl)benzyl)-2-(5-methoxy-1H-indol-3-yl)acetamide was isolated as a solid (31.0 mg, 86 μmol, 30%).1H NMR (400 MHz, DMSO) δ 10.72 (br, 1H), 8.20 (t, J = 5.9 Hz, 1H), 8.03 (d, J = 2.4 Hz, 1H), 7.64 (d, J = 1.8 Hz, 1H), 7.45 – 7.27 (m, 4H), 7.23 (d, J = 8.7 Hz, 1H), 7.15 (d, J = 2.4 Hz, 1H), 7.03 (d, J = 2.5 Hz, 1H), 6.72 (dd, J = 8.8, 2.5 Hz, 1H), 6.46 (t, J = 2.1 Hz, 1H), 4.19 (d, J = 6.0 Hz, 2H), 3.71 (s, 3H), 3.53 (s, 2H). ESI-MS: m / z calc. for C21H20N4O2[M+H]+: 361.1659, found 361. N-(2-(1H-Pyrazol-1-yl)benzyl)-2-(6-methoxy-1H-indol-3-yl)acetamide – Example 70[000369] Synthesized from (2-pyrazol-1-ylphenyl)methanamine (50 mg, 1 equiv, 0.29 mmol) and 6-methoxy-1H-indole-3-acetic acid (59 mg, 1 equiv, 0.29 mmol) according to general procedure A. The crude mixture was purified by reverse phase chromatography using a 5-70% gradient of acetonitrile in water (0.1% formic acid) over 30 CV on a 12 g C18 column. N-(2-(1H-Pyrazol-1-yl)benzyl)-2-(6-methoxy-1H-indol-3-yl)acetamide was isolated as a solid (53.7 mg, 149 μmol, 52%).1H NMR (400 MHz, DMSO) δ 10.66 (br, 1H), 8.18 (t, J = 5.9 Hz, 1H), 8.03 (dd, J = 2.4, 0.6 Hz, 1H), 7.64 (dd, J = 1.8, 0.6 Hz, 1H), 7.42 – 7.31 (m, 5H), 7.03 (d, J = 2.2 Hz, 1H), 6.84 (d, J = 2.2 Hz, 1H), 6.63 (dd, J = 8.6, 2.3 Hz, 1H), 6.47 – 6.45 (m, 1H), 4.17 (d, J = 5.9 Hz, 2H), 3.74 (s, 3H), 3.53 – 3.46 (m, 2H). ESI-MS: m / z calc. for C21H20N4O2[M+H]+: 361.1659, found 361. N-((2-(1H-Pyrazol-1-yl)pyridin-3-yl)methyl)-2-(5-methoxy-1H-indol-3-yl)acetamide – Example 71 [000370] Synthesized from [2-(1H-pyrazol-1-yl)pyridin-3-yl]methanamine hydrochloride (50 mg, 1 equiv, 0.24 mmol) and 5-methoxy-1H-indole-3-acetic acid (49 mg, 1 equiv, 0.24 mmol) according to general procedure A using N,N-diisopropylethylamine (83 μL, 2 equiv, 0.47 mmol). The crude mixture was purified by reverse phase chromatography using a 5-70% gradient of acetonitrile in water (0.1% formic acid) over 30 CV on a 12 g C18 column. N-((2-(1H-Pyrazol-1-yl)pyridin-3-yl)methyl)-2-(5-methoxy-1H-indol-3- yl)acetamide was isolated as a solid (28.6 mg, 79 μmol, 33%).1H NMR (400 MHz, DMSO) δ 10.74 (br, 1H), 8.39 (d, J = 2.5 Hz, 1H), 8.38 (dd, J = 4.8, 1.8 Hz, 1H), 8.20 (t, J = 6.1 Hz, 1H), 7.80 (dd, J = 7.7, 1.8 Hz, 1H), 7.68 (d, J = 1.7 Hz, 1H),7.31 (dd, J = 7.7, 4.7 Hz, 1H), 7.24 (d, J = 8.7 Hz, 1H), 7.16 (d, J = 2.4 Hz, 1H), 7.01 (d, J = 2.4 Hz, 1H), 6.72 (dd, J = 8.7, 2.5 Hz, 1H), 6.52 (dd, J = 2.6, 1.7 Hz, 1H), 4.52 (d, J = 6.0 Hz, 2H), 3.70 (s, 3H), 3.56 (s, 2H). ESI-MS: m / z calc. for C20H19N5O2[M+H]+: 362.1611, found 362. N-((2-(1H-Pyrazol-1-yl)pyridin-3-yl)methyl)-2-(5-fluoro-1H-indol-3-yl)acetamide – Example 72[000371] Synthesized from [2-(1H-pyrazol-1-yl)pyridin-3-yl]methanamine hydrochloride (50 mg, 1 equiv, 0.24 mmol) and 5-fluoroindole-3-acetic acid (46 mg, 1 equiv, 0.24 mmol) according to general procedure A using N,N-diisopropylethylamine (83 μL, 2 equiv, 0.47 mmol). The crude mixture was purified by reverse phase chromatography using a 5-70% gradient of acetonitrile in water (0.1% formic acid) over 30 CV on a 12 g C18 column. N-((2-(1H-Pyrazol-1-yl)pyridin-3-yl)methyl)-2-(5-fluoro-1H-indol-3-yl)acetamide was isolated as a solid (42.4 mg, 121 μmol, 51%).1H NMR (400 MHz, DMSO) δ 11.01 (br, 1H), 8.41 (dd, J = 2.6, 0.7 Hz, 1H), 8.39 (dd, J = 4.7, 1.7 Hz, 1H), 8.27 (t, J = 6.1 Hz, 1H), 7.80 (dd, J = 7.7, 1.7 Hz, 1H), 7.70 (dd, J = 1.7, 0.7 Hz, 1H), 7.35 (dd, J = 5.7, 4.7 Hz, 1H), 7.33 (t, J = 4.6 Hz, 1H), 7.29 – 7.23 (m, 2H), 6.92 (td, J = 9.2, 2.6 Hz, 1H), 6.53 (dd, J = 2.6, 1.7 Hz, 1H), 4.53 (d, J = 6.0 Hz, 2H), 3.58 (s, 2H).19F NMR (377 MHz, DMSO) δ -125.51 (td, J = 9.8, 4.6 Hz, 1F). ESI-MS: m / z calc. for C19H16FN5O [M+H]+: 350.1412, found 350. N-((2-(1H-Pyrazol-1-yl)pyridin-3-yl)methyl)-2-(6-fluoro-1H-indol-3-yl)acetamide – Example 73[000372] Synthesized from [2-(1H-pyrazol-1-yl)pyridin-3-yl]methanamine hydrochloride (50 mg, 1 equiv, 0.24 mmol) and 6-fluoroindole-3-acetic acid (46 mg, 1 equiv, 0.24 mmol) according to general procedure A using N,N-diisopropylethylamine (83 μL, 2 equiv, 0.47 mmol). The crude mixture was purified by reverse phase chromatography using a 5-70% gradient of acetonitrile in water (0.1% formic acid) over 30 CV on a 12 g C18 column. N-((2-(1H-Pyrazol-1-yl)pyridin-3-yl)methyl)-2-(6-fluoro-1H-indol-3-yl)acetamide was isolated as a solid (42.2 mg, 121 μmol, 51%).1H NMR (400 MHz, DMSO) δ 10.97 (s, 1H), 8.41 (dd, J = 2.5, 0.7 Hz, 1H), 8.38 (dd, J = 4.7, 1.8 Hz, 1H), 8.25 (t, J = 6.1 Hz, 1H), 7.79 (dd, J = 7.7, 1.7 Hz, 1H), 7.70 (dd, J = 1.8, 0.7 Hz, 1H), 7.49 (dd, J = 8.7, 5.5 Hz, 1H), 7.34 (dd, J = 7.7, 4.7 Hz, 1H), 7.20 (d, J = 2.3 Hz, 1H), 7.13 (dd, J = 10.1, 2.3 Hz, 1H), 6.83 (ddd, J = 9.8, 8.7, 2.4 Hz, 1H), 6.53 (dd, J = 2.6, 1.7 Hz, 1H), 4.52 (d, J = 6.0 Hz, 2H), 3.59 (s, 2H).19F NMR (377 MHz, DMSO) δ -122.30 (td, J = 10.2, 5.6 Hz, 1F). ESI-MS: m / z calc. for C19H16FN5O [M+H]+: 350.1412, found 350. N-((2-(1H-Pyrazol-1-yl)pyridin-3-yl)methyl)-2-(6-methoxy-1H-indol-3-yl)acetamide – Example 74 [000373] Synthesized from [2-(1H-pyrazol-1-yl)pyridin-3-yl]methanamine hydrochloride (50 mg, 1 equiv, 0.24 mmol) and 6-methoxyindole-3-acetic acid (49 mg, 1 equiv, 0.24 mmol) according to general procedure A using N,N-diisopropylethylamine (83 μL, 2 equiv, 0.47 mmol). The crude mixture was purified by reverse phase chromatography using a 5-70% gradient of acetonitrile in water (0.1% formic acid) over 30 CV on a 12 g C18 column. N-((2-(1H-Pyrazol-1-yl)pyridin-3-yl)methyl)-2-(6-methoxy-1H-indol-3- yl)acetamide was isolated as a solid (25.7 mg, 71 μmol, 30%).1H NMR (400 MHz, DMSO) δ 1H NMR (400 MHz, DMSO) δ 10.69 (br, 1H), 8.41 (dd, J = 2.6, 0.7 Hz, 1H), 8.38 (dd, J = 4.7, 1.7 Hz, 1H), 8.20 (t, J = 6.1 Hz, 1H), 7.79 (dd, J = 7.7, 1.7 Hz, 1H), 7.70 (dd, J = 1.7, 0.7 Hz, 1H), 7.37 (d, J = 8.6 Hz, 1H), 7.34 (dd, J = 7.7, 4.7 Hz,1H), 7.06 (d, J = 2.2 Hz, 1H), 6.86 (d, J = 2.2 Hz, 1H), 6.64 (dd, J = 8.6, 2.3 Hz, 1H), 6.53 (dd, J = 2.6, 1.7 Hz, 1H), 4.52 (d, J = 6.1 Hz, 2H), 3.76 (s, 3H), 3.55 (s, 2H). ESI-MS: m / z calc. for C20H19N5O2[M+H]+: 362.1611, found 362. N-((2-(1H-1,2,4-Triazol-1-yl)pyridin-3-yl)methyl)-2-(5-methoxy-1H-indol-3- yl)acetamide – Example 75[000374] Synthesized from (2-(1H-1,2,4-triazol-1-yl)pyridin-3-yl)methanamine (50 mg, 1 equiv, 0.29 mmol) and 5-methoxy-1H-indole-3-acetic acid (59 mg, 1 equiv, 0.29 mmol) according to general procedure A. The crude mixture was purified by reverse phase chromatography using a 5-70% gradient of acetonitrile in water (0.1% formic acid) over 30 CV on a 12 g C18 column. N-((2-(1H-1,2,4-Triazol-1-yl)pyridin-3-yl)methyl)-2-(5-methoxy- 1H-indol-3-yl)acetamide was isolated as a solid (30.6 mg, 84 μmol, 30%).1H NMR (400 MHz, DMSO) δ 10.74 (br, 1H), 9.14 (s, 1H), 8.45 (dd, J = 4.7, 1.7 Hz, 1H), 8.27 (t, J = 6.0 Hz, 1H), 8.22 (s, 1H), 7.87 (dd, J = 7.8, 1.7 Hz, 1H), 7.46 (dd, J = 7.8, 4.7 Hz, 1H), 7.24 (d, J = 8.7 Hz, 1H), 7.16 (d, J = 2.4 Hz, 1H), 7.01 (d, J = 2.4 Hz, 1H), 6.73 (dd, J = 8.8, 2.5 Hz, 1H), 4.45 (d, J = 5.9 Hz, 2H), 3.71 (s, 3H), 3.56 (s, 2H). ESI-MS: m / z calc. for C19H18N6O2[M+H]+: 363.1564, found 363. N-((2-(1H-1,2,4-Triazol-1-yl)pyridin-3-yl)methyl)-2-(6-methoxy-1H-indol-3- yl)acetamide – Example 76 [000375] Synthesized from (2-(1H-1,2,4-triazol-1-yl)pyridin-3-yl)methanamine (50 mg, 1 equiv, 0.29 mmol) and 6-methoxy-1H-indole-3-acetic acid (59 mg, 1 equiv, 0.29 mmol) according to general procedure A. The crude mixture was purified by reverse phase chromatography using a 5-70% gradient of acetonitrile in water (0.1% formic acid) over 30CV on a 12 g C18 column. N-((2-(1H-1,2,4-Triazol-1-yl)pyridin-3-yl)methyl)-2-(6-methoxy- 1H-indol-3-yl)acetamide was isolated as a solid (47.5 mg, 131 μmol, 46%).1H NMR (400 MHz, DMSO) δ 10.68 (br, 1H), 9.14 (s, 1H), 8.45 (dd, J = 4.7, 1.7 Hz, 1H), 8.25 (t, J = 6.1 Hz, 1H), 8.23 (s, 1H), 7.86 (dd, J = 7.8, 1.7 Hz, 1H), 7.48 (dd, J = 7.8, 4.7 Hz, 1H), 7.36 (d, J = 8.6 Hz, 1H), 7.05 (d, J = 2.3 Hz, 1H), 6.85 (d, J = 2.2 Hz, 1H), 6.63 (dd, J = 8.6, 2.3 Hz, 1H), 4.44 (d, J = 5.9 Hz, 2H...

Claims

1. CLAIMS 1. A pharmaceutical composition, comprising: a) a compound of Formula (II): or a pharmaceutically acceptable salt thereof, wherein X is -C(=O)NR3- or -NR3C(=O)-; L is a bond or C1-4alkylene optionally substituted by one or more fluorine or deuterium; Y1, Y2, Y3, and Y4are each independently CR4or N; R1and R2are each independently selected from the group consisting of H, deuterium, C1-4alkyl, C3-6cycloalkyl, and halogen, or R1and R2together with the carbon to which the R1and R2are attached form C3-6cycloalkyl; R3is selected from the group consisting of H, C1-6alkyl, and C3-6cycloalkyl, wherein the C1-6alkyl or C3-6cycloalkyl is optionally substituted by one or more fluorine; Group A is i) bicyclic heteroaryl having the structure: or ; wherein X1, X2, X3, and X4are each independently CR5or N, provided that no more than two of X1, X2, X3, and X4are N, or ii) -N(C1-4alkyl)phenyl or -N(C1-4alkyl)heteroaryl, each optionally substituted with one, two, or three R5substituents; Group C is aryl or heteroaryl; R4is each independently selected from the group consisting of H, halogen, - CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -OR7, -S(O)xR7, -NR7R8, -C(O)R7, -OC(O)R7, -C(O)OR7, -NR7C(O)R8, - C(O)NR7R8, -NR7C(O)OR8, -OC(O)NR7R8, -NR7SO2R8, and -SO2NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted by one or more R9; R5and R6are each independently selected from the group consisting of H, deuterium, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -OR7, -S(O)xR7, -NR7R8, -C(O)R7, -OC(O)R7, - C(O)OR7, -NR7C(O)R8, -C(O)NR7R8, -NR7C(O)OR8, -OC(O)NR7R8, -NR7SO2R8, and -SO2NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted by one or more R9; R7and R8are each independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl, wherein the C1-6alkyl and C1-6haloalkyl are optionally substituted by one or more R10; R9and R10are each independently selected from the group consisting of halo, deuterium, -CN, -OR11, -S(O)xR11, -NR11R12, C(O)R11, -OC(O)R11, -C(O)OR11, - NR11C(O)R12, and -C(O)NR11R12; R11and R12are each independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl; x is 0, 1, or 2; and p is 0, 1, 2, or 3; provided that: i) when X is -C(=O)NR3-, R3is H or CH3, L is bond, Y1, Y2, Y3, and Y4are CH, Group C is phenyl, R1and R2are H, and p is 0, then Group A is not - N(CH3)phenyl optionally substituted with CH3; ii) when X is -NR3C(=O)-, R3is H or CH3, L is bond, Y1, Y3, and Y4are CH, Y2is CH or C-NH2, Group C is phenyl, R1and R2are H, p is 1, and Group A is , then R6is not -NHC(O)CH3; and iii) when X is -C(=O)NR3-, R3is H, L is -CH2-, Y1and Y2are CH, Y4is N, Y3is C-CF3, Group C is phenyl, R1is H, R2is CH3, p is 1, and Group A is , then R6is not CH3; and b) a pharmaceutically acceptable carrier.

2. The pharmaceutical composition of claim 1, wherein Group A is 3. The pharmaceutical composition of claim 1, wherein Group A is -N(C1-4alkyl)phenyl optionally substituted with one, two, or three R5substituents.

4. The pharmaceutical composition of claim 1, wherein Group A is -N(C1-4alkyl)heteroaryl optionally substituted with one, two, or three R5substituents.

5. The pharmaceutical composition of any one of claims 1-4, wherein X is -C(=O)NR3-.

6. The pharmaceutical composition of any one of claims 1-4, wherein X is -NR3C(=O)-.

7. A pharmaceutical composition, comprising: a) a compound of Formula (II-A): (II-A), or a pharmaceutically acceptable salt thereof, wherein L is a bond or C1-4alkylene optionally substituted by one or more fluorine or deuterium; Y1, Y2, Y3, and Y4are each independently CR4or N; R1and R2are each independently selected from the group consisting of H, deuterium, C1-4alkyl, C3-6cycloalkyl, and halogen, or R1and R2together with the carbon to which the R1and R2are attached form C3-6cycloalkyl; R3is selected from the group consisting of H, C1-6alkyl, and C3-6cycloalkyl, wherein the C1-6alkyl or C3-6cycloalkyl is optionally substituted by one or more fluorine; X1, X2, X3, and X4are each independently CR5or N, provided that no more than two of X1, X2, X3, and X4are N; Group C is aryl or heteroaryl; R4is each independently selected from the group consisting of H, halogen, - CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -OR7, -S(O)xR7, -NR7R8, -C(O)R7, -OC(O)R7, -C(O)OR7, -NR7C(O)R8, - C(O)NR7R8, -NR7C(O)OR8, -OC(O)NR7R8, -NR7SO2R8, and -SO2NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted by one or more R9; R5and R6are each independently selected from the group consisting of H, deuterium, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -OR7, -S(O)xR7, -NR7R8, -C(O)R7, -OC(O)R7, - C(O)OR7, -NR7C(O)R8, -C(O)NR7R8, -NR7C(O)OR8, -OC(O)NR7R8, -NR7SO2R8, and -SO2NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted by one or more R9; R7and R8are each independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl, wherein the C1-6alkyl and C1-6haloalkyl are optionally substituted by one or more R10; R9and R10are each independently selected from the group consisting of halo, deuterium, -CN, -OR11, -S(O)xR11, -NR11R12, C(O)R11, -OC(O)R11, -C(O)OR11, - NR11C(O)R12, and -C(O)NR11R12; R11and R12are each independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl; x is 0, 1, or 2; and p is 0, 1, 2, or 3; and b) a pharmaceutically acceptable carrier.

8. The pharmaceutical composition of any one of claims 1-7, wherein L is a bond.

9. The pharmaceutical composition of any one of claims 1-7, wherein L is C1-2alkylene optionally substituted by one or more deuterium.

10. A pharmaceutical composition, comprising: a) a compound of Formula (II-B):or a pharmaceutically acceptable salt thereof, wherein R’ and R’’ are each independently selected from the group consisting of H, fluorine, and deuterium; Y1, Y2, Y3, and Y4are each independently CR4or N; R1and R2are each independently selected from the group consisting of H, deuterium, C1-4alkyl, C3-6cycloalkyl, and halogen, or R1and R2together with the carbon to which the R1and R2are attached form C3-6cycloalkyl; R3is selected from the group consisting of H, C1-6alkyl, and C3-6cycloalkyl, wherein the C1-6alkyl or C3-6cycloalkyl is optionally substituted by one or more fluorine; X1, X2, X3, and X4are each independently CR5or N, provided that no more than two of X1, X2, X3, and X4are N; Group C is aryl or heteroaryl; R4is each independently selected from the group consisting of H, halogen, - CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -S(O)xR7, -NR7R8, -C(O)R7, -OC(O)R7, -C(O)OR7, -C(O)NR7R8, - NR7C(O)OR8, -OC(O)NR7R8, -NR7SO2R8, and -SO2NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted by one or more R9; R5and R6are each independently selected from the group consisting of H, deuterium, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -S(O)xR7, -NR7R8, -C(O)R7, -OC(O)R7, - C(O)OR7, -C(O)NR7R8, -NR7C(O)OR8, -OC(O)NR7R8, -NR7SO2R8, and -SO2NR7R8,wherein the C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted by one or more R9; R7and R8are each independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl, wherein the C1-6alkyl and C1-6haloalkyl are optionally substituted by one or more R10; R9and R10are each independently selected from the group consisting of halo, deuterium, -CN, -OR11, -S(O)xR11, -NR11R12, C(O)R11, -OC(O)R11, -C(O)OR11, - NR11C(O)R12, and -C(O)NR11R12; R11and R12are each independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl; x is 0, 1, or 2; and p is 0, 1, 2, or 3; and b) a pharmaceutically acceptable carrier.

11. A pharmaceutical composition, comprising: a) a compound of Formula (II-C):(II-C), or a pharmaceutically acceptable salt thereo , wherein X is -C(=O)NR3- or -NR3C(=O)-; R’ and R’’ are each independently selected from the group consisting of H, fluorine, and deuterium; Y1, Y2, Y3, and Y4are each independently CR4or N; R1and R2are each independently selected from the group consisting of H, deuterium, C1-4alkyl, C3-6cycloalkyl, and halogen, or R1and R2together with the carbon to which the R1and R2are attached form C3-6cycloalkyl; R3is selected from the group consisting of H, C1-6alkyl, and C3-6cycloalkyl, wherein the C1-6alkyl or C3-6cycloalkyl is optionally substituted by one or more fluorine; R’’’ is C1-4alkyl;Group D is phenyl or heteroaryl, each optionally substituted with one, two, or three R5substituents; Group C is aryl or heteroaryl; R4is each independently selected from the group consisting of H, halogen, - CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -OR7, -S(O)xR7, -NR7R8, -C(O)R7, -OC(O)R7, -C(O)OR7, -NR7C(O)R8, - C(O)NR7R8, -NR7C(O)OR8, -OC(O)NR7R8, -NR7SO2R8, and -SO2NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted by one or more R9; R5and R6are each independently selected from the group consisting of H, deuterium, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -OR7, -S(O)xR7, -NR7R8, -C(O)R7, -OC(O)R7, - C(O)OR7, -NR7C(O)R8, -C(O)NR7R8, -NR7C(O)OR8, -OC(O)NR7R8, -NR7SO2R8, and -SO2NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted by one or more R9; R7and R8are each independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl, wherein the C1-6alkyl and C1-6haloalkyl are optionally substituted by one or more R10; R9and R10are each independently selected from the group consisting of halo, deuterium, -CN, -OR11, -S(O)xR11, -NR11R12, C(O)R11, -OC(O)R11, -C(O)OR11, - NR11C(O)R12, and -C(O)NR11R12; R11and R12are each independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl; x is 0, 1, or 2; and p is 0, 1, 2, or 3; and b) a pharmaceutically acceptable carrier.

12. The pharmaceutical composition of any one of claims 1-11, wherein Y1, Y2, Y3, and Y4are CR4.

13. The pharmaceutical composition of any one of claims 1-11, wherein one or two of Y1, Y2, Y3, and Y4are N and the remaining Y1, Y2, Y3, and Y4are CR4.

14. The pharmaceutical composition of any one of claims 1-13, wherein R4is each independently selected from the group consisting of H, halogen, C1-6alkyl, C1-6haloalkyl, -O(C1-6alkyl), and C3-6cycloalkyl.

15. The pharmaceutical composition of any one of claims 1-14, wherein R4is each independently selected from the group consisting of H, halogen, and C1-6alkyl.

16. The pharmaceutical composition of any one of claims 1-15, wherein R1and R2are each independently selected from the group consisting of H, deuterium, and C1-2alkyl.

17. The pharmaceutical composition of any one of claims 1-16, wherein R3is H or C1-2alkyl.

18. The pharmaceutical composition of any one of claims 1-17, wherein Group C is phenyl or 5-6 membered heteroaryl.

19. The pharmaceutical composition of any one of claims 1-18, wherein Group C is selected from the group consisting of phenyl, pyrazolyl, furanyl, oxazolyl, thiophenyl, thiazolyl, triazolyl, and pyridiyl.

20. The pharmaceutical composition of any one of claims 1-19, wherein R5is each independently selected from the group consisting of H, deuterium, halogen, -CN, - NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C3-6cycloalkyl, and -NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, and C1-6heteroalkyl are optionally substituted by one, two, or three R9.

21. The pharmaceutical composition of any one of claims 1-20, wherein R5is each independently selected from the group consisting of H, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C3-6cycloalkyl, and -NR7R8.

22. The pharmaceutical composition of any one of claims 1-21, wherein R7and R8are each independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl.

23. The pharmaceutical composition of any one of claims 1-22, wherein R9is each independently halo or deuterium.

24. The pharmaceutical composition of any one of claims 1-23, wherein p is 0 or 1.

25. The pharmaceutical composition of any one of claims 1-24, wherein R6is each independently selected from the group consisting of halogen, C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl.

26. A pharmaceutical composition comprising: a) a compound selected from Table 1 or Table 2, or a pharmaceutically acceptable salt thereof; and b) a pharmaceutically acceptable carrier.

27. A compound selected from Table 1, or a pharmaceutically acceptable salt thereof.

28. A compound of Formula (II):(II), or a pharmaceutically acceptable salt thereof, wherein X is -C(=O)NR3- or -NR3C(=O)-; L is a bond or C1-4alkylene optionally substituted by one or more fluorine or deuterium; Y1, Y2, Y3, and Y4are each independently CR4or N; R1and R2are each independently selected from the group consisting of H, deuterium, C1-4alkyl, C3-6cycloalkyl, and halogen, or R1and R2together with the carbon to which the R1and R2are attached form C3-6cycloalkyl; R3is selected from the group consisting of H, C1-6alkyl, and C3-6cycloalkyl, wherein the C1-6alkyl or C3-6cycloalkyl is optionally substituted by one or more fluorine; Group A is i) bicyclic heteroaryl having the structure: or ; wherein X1, X2, X3, and X4are each independently CR5or N, provided that no more than two of X1, X2, X3, and X4are N, or ii) -N(C1-4alkyl)phenyl or -N(C1-4alkyl)heteroaryl, each optionally substituted with one, two, or three R5substituents; Group C is aryl or heteroaryl; R4is each independently selected from the group consisting of H, halogen, - CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -OR7, -S(O)xR7, -NR7R8, -C(O)R7, -OC(O)R7, -C(O)OR7, -NR7C(O)R8, -C(O)NR7R8, -NR7C(O)OR8, -OC(O)NR7R8, -NR7SO2R8, and -SO2NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted by one or more R9; R5and R6are each independently selected from the group consisting of H, deuterium, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -OR7, -S(O)xR7, -NR7R8, -C(O)R7, -OC(O)R7, - C(O)OR7, -NR7C(O)R8, -C(O)NR7R8, -NR7C(O)OR8, -OC(O)NR7R8, -NR7SO2R8, and -SO2NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted by one or more R9; R7and R8are each independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl, wherein the C1-6alkyl and C1-6haloalkyl are optionally substituted by one or more R10; R9and R10are each independently selected from the group consisting of halo, deuterium, -CN, -OR11, -S(O)xR11, -NR11R12, C(O)R11, -OC(O)R11, -C(O)OR11, - NR11C(O)R12, and -C(O)NR11R12; R11and R12are each independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl; x is 0, 1, or 2; and p is 0, 1, 2, or 3; provided that: i) when X is -C(=O)NR3-, R3is H or CH3, L is bond, Y1, Y2, Y3, and Y4are CH, Group C is phenyl, R1and R2are H, and p is 0, then Group A is not - N(CH3)phenyl optionally substituted with CH3; ii) when X is -NR3C(=O)-, R3is H or CH3, L is bond, Y1, Y3, and Y4are CH, Y2is CH or C-NH2, Group C is phenyl, R1and R2are H, p is 1, and Group A is , then R6is not -NHC(O)CH3; andiii) when X is -C(=O)NR3-, R3is H, L is -CH2-, Y1and Y2are CH, Y4is N, Y3is C-CF3, Group C is phenyl, R1is H, R2is CH3, p is 1, and Group A is , then R6is not CH3, for use in therapy.

29. A compound of Formula (II): or a pharmaceutically acceptable salt thereof, wherein X is -C(=O)NR3- or -NR3C(=O)-; L is a bond or C1-4alkylene optionally substituted by one or more fluorine or deuterium; Y1, Y2, Y3, and Y4are each independently CR4or N; R1and R2are each independently selected from the group consisting of H, deuterium, C1-4alkyl, C3-6cycloalkyl, and halogen, or R1and R2together with the carbon to which the R1and R2are attached form C3-6cycloalkyl; R3is selected from the group consisting of H, C1-6alkyl, and C3-6cycloalkyl, wherein the C1-6alkyl or C3-6cycloalkyl is optionally substituted by one or more fluorine; Group A is i) bicyclic heteroaryl having the structure: or ;wherein X1, X2, X3, and X4are each independently CR5or N, provided that no more than two of X1, X2, X3, and X4are N, or ii) -N(C1-4alkyl)phenyl or -N(C1-4alkyl)heteroaryl, each optionally substituted with one, two, or three R5substituents; Group C is aryl or heteroaryl; R4is each independently selected from the group consisting of H, halogen, - CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -OR7, -S(O)xR7, -NR7R8, -C(O)R7, -OC(O)R7, -C(O)OR7, -NR7C(O)R8, - C(O)NR7R8, -NR7C(O)OR8, -OC(O)NR7R8, -NR7SO2R8, and -SO2NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted by one or more R9; R5and R6are each independently selected from the group consisting of H, deuterium, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -OR7, -S(O)xR7, -NR7R8, -C(O)R7, -OC(O)R7, - C(O)OR7, -NR7C(O)R8, -C(O)NR7R8, -NR7C(O)OR8, -OC(O)NR7R8, -NR7SO2R8, and -SO2NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted by one or more R9; R7and R8are each independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl, wherein the C1-6alkyl and C1-6haloalkyl are optionally substituted by one or more R10; R9and R10are each independently selected from the group consisting of halo, deuterium, -CN, -OR11, -S(O)xR11, -NR11R12, C(O)R11, -OC(O)R11, -C(O)OR11, - NR11C(O)R12, and -C(O)NR11R12; R11and R12are each independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl; x is 0, 1, or 2; and p is 0, 1, 2, or 3; provided that: i) when X is -C(=O)NR3-, R3is H or CH3, L is bond, Y1, Y2, Y3, and Y4are CH, Group C is phenyl, R1and R2are H, and p is 0, then Group A is not - N(CH3)phenyl optionally substituted with CH3;ii) when X is -NR3C(=O)-, R3is H or CH3, L is bond, Y1, Y3, and Y4are CH, Y2is CH or C-NH2, Group C is phenyl, R1and R2are H, p is 1, and Group A is, then R6is not -NHC(O)CH3; and iii) when X is -C(=O)NR3-, R3is H, L is -CH2-, Y1and Y2are CH, Y4is N, Y3is C-CF3, Group C is phenyl, R1is H, R2is CH3, p is 1, and Group A is, then R6is not CH3, for use in treating or preventing a disease or condition associated with dysregulation of GPR4 in a subject in need thereof.

30. The compound for use of claim 29, wherein the disease or condition is selected from the group consisting of neurodegenerative diseases or disorders, neuropsychiatric diseases or disorders, cardiovascular diseases or disorders, metabolic diseases or disorders, autoimmune diseases or disorders, cancers, muscular diseases or disorders, and bone diseases or disorders.

31. The compound for use of claim 30, wherein the neurodegenerative diseases or disorders are selected from the group consisting of Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, frontotemporal dementia, tauopathies, Charcot-Marie-Tooth disease, Huntington’s disease, polyglutamine diseases, neurocognitive disorders, retinal degeneration, and Sveinsson chorioretinal atrophy.

32. The compound for use of claim 30, wherein the neuropsychiatric diseases or disorders are selected from the group consisting of neuropsychiatric disorders, including but not limited to bipolar disorder, attention deficit hyperactivity disorder, anxiety, addiction, seizures, schizophrenia, obsessive compulsive disorder, social phobia, Tourette’s syndrome and binge eating disorder, depression and post-traumatic brain injury deficits, intellectual and developmental disability disorders including but not limited to Down syndrome, sleep disorders, and sleep apnea.

33. The compound for use of claim 30, wherein the cardiovascular diseases or disorders are selected from the group consisting of angiogenesis, coronary artery diseases, cardiomyopathy, cerebral microhemorrhages, cerebral amyloid angiopathy, respiratory disorders, and dysregulated control of cerebral blood flow.

34. The compound for use of claim 30, wherein the metabolic diseases or disorders are selected from the group consisting of obesity, diabetes, acidosis, kidney diseases and kidney failure, autophagy-related diseases, liver diseases including but not limited to alcohol-related-liver disease, liver fibrosis, non-alcoholic and alcoholic fatty liver disease, steatosis, atherosclerosis, and lysosomal storage diseases.

35. The compound for use of claim 30, wherein the autoimmune diseases or disorders are selected from the group consisting of irritable bowel syndrome and Graves’s disease 36. The compound for use of claim 30, wherein the cancer is selected from the group consisting of melanoma and prostate cancer.

37. The compound for use of claim 30, wherein the muscular diseases or disorders are selected from the group consisting of spinal muscular atrophy, demyelinating diseases, myotonic dystrophy, and muscular dystrophies.

38. The compound for use of claim 30, wherein the bone diseases or disorders are selected from the group consisting of Paget’s disease and osteoporosis.

39. A compound of Formula (II):, or a pharmaceutically acceptable salt thereof, wherein X is -C(=O)NR3- or -NR3C(=O)-; L is a bond or C1-4alkylene optionally substituted by one or more fluorine or deuterium; Y1, Y2, Y3, and Y4are each independently CR4or N; R1and R2are each independently selected from the group consisting of H, deuterium, C1-4alkyl, C3-6cycloalkyl, and halogen, or R1and R2together with the carbon to which the R1and R2are attached form C3-6cycloalkyl;R3is selected from the group consisting of H, C1-6alkyl, and C3-6cycloalkyl, wherein the C1-6alkyl or C3-6cycloalkyl is optionally substituted by one or more fluorine; Group A is i) bicyclic heteroaryl having the structure:wherein X1, X2, X3, and X4are each independently CR5or N, provided that no more than two of X1, X2, X3, and X4are N, or ii) -N(C1-4alkyl)phenyl or -N(C1-4alkyl)heteroaryl, each optionally substituted with one, two, or three R5substituents; Group C is aryl or heteroaryl; R4is each independently selected from the group consisting of H, halogen, - CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -OR7, -S(O)xR7, -NR7R8, -C(O)R7, -OC(O)R7, -C(O)OR7, -NR7C(O)R8, - C(O)NR7R8, -NR7C(O)OR8, -OC(O)NR7R8, -NR7SO2R8, and -SO2NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted by one or more R9; R5and R6are each independently selected from the group consisting of H, deuterium, halogen, -CN, -NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -OR7, -S(O)xR7, -NR7R8, -C(O)R7, -OC(O)R7, - C(O)OR7, -NR7C(O)R8, -C(O)NR7R8, -NR7C(O)OR8, -OC(O)NR7R8, -NR7SO2R8, and -SO2NR7R8, wherein the C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted by one or more R9; R7and R8are each independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl, wherein the C1-6alkyl and C1-6haloalkyl are optionally substituted by one or more R10; R9and R10are each independently selected from the group consisting of halo, deuterium, -CN, -OR11, -S(O)xR11, -NR11R12, C(O)R11, -OC(O)R11, -C(O)OR11, - NR11C(O)R12, and -C(O)NR11R12;R11and R12are each independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl; x is 0, 1, or 2; and p is 0, 1, 2, or 3; provided that: i) when X is -C(=O)NR3-, R3is H or CH3, L is bond, Y1, Y2, Y3, and Y4are CH, Group C is phenyl, R1and R2are H, and p is 0, then Group A is not - N(CH3)phenyl optionally substituted with CH3; ii) when X is -NR3C(=O)-, R3is H or CH3, L is bond, Y1, Y3, and Y4are CH, Y2is CH or C-NH2, Group C is phenyl, R1and R2are H, p is 1, and Group A is , then R6is not -NHC(O)CH3; andiii) when X is -C(=O)NR3-, R3is H, L is -CH2-, Y1and Y2are CH, Y4is N, Y3is C-CF3, Group C is phenyl, R1is H, R2is CH3, p is 1, and Group A is , then R6is not CH3,for use in modulating GPR4 in a subject in need thereof.

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