Modulators of g protein-coupled receptor 55 (GPR55)

Abstract

The disclosure provides compounds and salts thereof for the treatment of diseases, disorders or conditions. In embodiments, the compounds are represented by the structure of Formula (I): Formula (I), wherein values for the variables (e.g., A, E, R1, R2, R4, R5, R9, n, m) are described herein.

Description

MODULATORS OF G PROTEIN-COUPLED RECEPTOR 55 (GPR55)CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority of US Provisional Application No. 63 / 563,253, filed March 8, 2024; US Provisional Application No. 63 / 687,714, filed August 27, 2024; and US Provisional Application No. 63 / 754,055, filed February 5, 2025, each of which is incorporated by reference in its entirety for any purpose.BACKGROUND OF THE INVENTION

[0002] G protein-coupled receptor 55 (GPR55 or GPCR55) is an orphan receptor that was identified in 1999. Despite its low homology with the well-known cannabinoid receptors CB1 and CB2, being 13% and 14%, respectively, it has been suggested as a non-canonical cannabinoid receptor. Some endogenous, plant-derived, and synthetic cannabinoid ligands are able to modulate GPR55 activity. More recently, it has been shown that lysophosphatidylinositol (LPI) elicits several biological responses by GPR55 that include ERK phosphorylation and Ca2+ release via GPR55. These observations suggest that LPI is an endogenous natural ligand for GPR55. GPR55 expression has been described in diverse tissues GPR55 is expressed in a variety of tissues, including the appendix, brain, colon, duodenum, gall bladder, lymph nodes small intestine, stomach, testis and bladder. In some tissues, it is part of a complex signaling pathway involving other GPRs and non-GPRs. GPR55 is implicated in different pathophysiological conditions such as cancer, pain, and epilepsy. There remains a need for new compounds and treatments for diseases, disorders, or conditions.SUMMARY OF THE INVENTION

[0003] In an aspect, the present disclosure provides a compound represented by the structure of Formula (I):Formula (I) or a salt thereof, wherein:A is selected from N and CR6;E is selected from N and CR6a; wherein at least one of A or E is N;R1is selected from C3-8carbocycle, and 4- to 8-membered heterocycle, wherein the C3-8carbocycle, and 4- to 8-membered heterocycle are each optionally substituted with one or more substituents independently selected from:(i) halogen, -OR20, -SR20, -N(R20)2, -C(O)R20, -C(O)N(R20)2, - N(R20)C(O)R20-C(O)OR20, -OC(O)R20, -S(O)R20, -S(O)2R20, -P(O)(OR20)2, -OP(O)(OR20)2, -NO2, =O, =S, =N(R20), and -CN; and(ii) C1-10alkyl, C2-10alkenyl, and C2-10alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR20, -SR20, - N(R20)2, -C(O)R20, -C(O)N(R20)2, -N(R20)C(O)R20-C(O)OR20, -OC(O)R20, -S(O)R20, - S(O)2R20, -S(O)2N(R20)2, -S(O)N(R20)2, -NR20S(O)2R20, -P(O)(OR20)2, -OP(O)(OR20)2, - NO2, =O, =S, =N(R20), and -CN; each R2is independently selected from: halogen, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, - NO2, -CN, C3-6cycloalkyl and C1-6alkyl;R4is selected from 4- to 5-membered heterocycle, 6-membered heteroaryl, 7- to 9-membered heterocycle, 3- to 6-membered cycloalkyl, hydrogen, and -CO2H, wherein the 4- to 5- membered heterocycle, 6-membered heteroaryl, 7- to 9-membered heterocycle, and 3- to 6- membered cycloalkyl, are each optionally substituted with one or more substituents independently selected from:(iii) halogen, -OR20, -SR20, -N(R20)2, -C(O)R20, -C(O)N(R20)2, - N(R20)C(O)R20-C(O)OR20, -OC(O)R20, -S(O)R20, - S(O)2R20, -P(O)(OR20)2, -OP(O)(OR20)2, -NO2, and -CN; and(iv) C1-6alkyl, C2-6alkenyl, and C2-6alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR20, -SR20, -N(R20)2, -C(O)R20, -C(O)N(R20)2, -N(R20)C(O)R20-C(O)OR20, -OC(O)R20, - S(O)R20, -S(O)2R20, -S(O)2N(R20)2, -S(O)N(R20)2, -NR20S(O)2R20, -P(O)(OR20)2, -OP(O)(OR20)2, -NO2, =O, =S, =N(R20), and -CN; and(v) C3-6carbocycle each of which is optionally substituted with one or more substituents independently selected from halogen and C1-6alkyl;R5is selected from hydrogen; C1-6alkyl, and cyclopropyl each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -NH( C1-6alkyl), -N( C1-6alkyl)2, C1-10alkyl, -C1-io haloalkyl, -O- C1-10alkyl, oxo, and =NH; or R4and R5together with the atoms to which they are attached for a 4 to 8 membered heterocycle; or R5and one of R5atogether with the atoms to which they are attached form a 4 to 8-membered heterocyclene, which is optionally substituted with 1 to 4 substituents independently selected from R10;R6is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl;R6ais selected from hydrogen, C1-6alkyl, and C1-6haloalkyl;R7is selected from halogen, -CN, -NO2, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, C1-6alkyl, and C1-6haloalkyl;R8is selected from halogen, -CN, -NO2, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, C1-6alkyl, and C1-6haloalkyl;R8ais selected from halogen, -CN, -NO2, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, C1-6alkyl, and C1-6haloalkyl;R8bis selected from halogen, -CN, -NO2, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, C1-6alkyl, and C1-6haloalkyl;selected from N, S and O;R10is selected from halogen, -CN, -NO2, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, C1-6alkyl, and C1-6haloalkyl;L is selected from a C1-8alkylene, wherein the C1-8alkylene is optionally substituted with one or more R5a, wherein each R5ais independently selected from halogen, C1-6alkyl, -OH, -OCH3, and -CN; and wherein optionally two optional substituents on the same carbon atom of L come together to form a carbocycle or heterocycle; each R20is independently selected from hydrogen; and C1-6alkyl, C3-12carbocycle, and 3- to 12- membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -NH(C 1-6alkyl), -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, =NH, and cyclopropyl; m is selected from 0 and 1;n is selected from 0, 1, 2, 3, and 4; q is selected from 0, 1, 2, and 4; y is selected from 0, 1, and 2; and z is selected from 0, 1, and 2.

[0004] In some embodiments, the disclosure provides a pharmaceutical composition comprising a compound or salt of Formula (I), Formula (II), Formula (Illa), Formula (Illb), Formula (IVa), or Formula (IVb); and a pharmaceutically acceptable excipient.

[0005] In some embodiments, the disclosure provides a method of of treating a disease, disorder, or condition expressing GPR55, comprising administering to a subject in need thereof, an effective amount of a compound or salt of Formula (I), Formula (II), Formula (Illa), Formula (Illb), Formula (IVa), or Formula (IVb); or a pharmaceutical composition of any one thereof. In some cases, the disease, disorder, or condition is selected from a cancer expressing GPR55. In some cases, the cancer is selected from pancreatic cancer, brain cancer, colon cancer and ER+ breast cancer. In some cases, the cancer is a metastatic cancer. In some embodiments, the disease, disorder, or condition is epilepsy. In some embodiments, the epilepsy is treatmentresistant epilepsy, generalized seizures, partial seizures, pediatric epilepsy including Dravet syndrome, or temporal lobe epilepsy. In some embodiments, the disease, disorder, or condition is pain. In some embodiments, the pain is neuropathic pain. In some embodiments, the pain is inflammatory pain. In some embodiments, the pain is visceral pain.INCORPORATION BY REFERENCE

[0006] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and / or take precedence over any such contradictory material.DETAILED DESCRIPTION OF THE INVENTION

[0007] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicingthe invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.Definitions

[0008] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference.

[0009] As used in the specification and claims, the singular form “a”, “an” and “the” includes plural references unless the context clearly dictates otherwise. Furthermore, use of the term “including” as well as other forms, such as “include”, “includes,” and “included,” is not limiting.

[0010] Unless the context requires otherwise, throughout the present specification and claims, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to.”

[0011] As used in the specification, the phrase “in some cases” refers to examples of the embodiment s) discussed therein and may be considered embodiments.

[0012] The term “Cx-y” when used in conjunction with a chemical moiety, such as alkyl, alkenyl, or alkynyl is meant to include groups that contain from x to y carbons in the chain. For example, the term “ C1-6alkyl” refers to saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from 1 to 6 carbons. The term -Cx-yalkylene- refers to a substituted or unsubstituted alkylene chain with from x to y carbons in the alkylene chain. For example -C1-6alkylene- may be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any one of which is optionally substituted.

[0013] "Alkyl" as used herein refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, and preferably having from one to fifteen carbon atoms (i.e., C1-C15alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (i.e., C1-C13alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (i.e., C1-C8alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (i.e., C1-C5alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (i.e., C1-C4alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (i.e., C1-C3alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (i.e., C1-C2alkyl). In other embodiments, an alkyl comprises one carbon atom (i.e., C1alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (i.e., C5- C15alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (i.e., C5-C8alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (i.e., C2-C5alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (i.e., C3-C5alkyl). In certain embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n- propyl), 1-methylethyl (iso-propyl), 1 -butyl ( n-butyl), 1 -methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1 -dimethylethyl (tert-butyl), and 1 -pentyl (n- pentyl). The alkyl is attached to the rest of the molecule by a single bond. An alkyl group may be optionally substituted by one or more substituents such as those substituents described herein.

[0014] "Alkenyl" as used herein refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and preferably having from two to twelve carbon atoms (i.e., C2-C12alkenyl). In certain embodiments, an alkenyl comprises two to eight carbon atoms (i.e., C2-C8alkenyl). In certain embodiments, an alkenyl comprises two to six carbon atoms (i.e., C2-6alkenyl). In other embodiments, an alkenyl comprises two to four carbon atoms (i.e., C2-C4alkenyl). The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta- 1,4-dienyl, and the like. An alkenyl group may be optionally substituted by one or more substituents such as those substituents described herein.

[0015] "Alkynyl" as used herein refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, and preferably having from two to twelve carbon atoms (i.e., C2-C12alkynyl). In certain embodiments, an alkynyl comprises two to eight carbon atoms (i.e., C2-C8alkynyl). In other embodiments, an alkynyl comprises two to six carbon atoms (i.e., C2-6alkynyl). In other embodiments, an alkynyl comprises two to four carbon atoms (i.e., C2-C4alkynyl). The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. An alkynyl group may be optionally substituted by one or more substituents such as those substituents described herein.

[0016] The terms “Cx-yalkenyl” and “Cx-yalkynyl” refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond, respectively. The term -Cx-yalkenylene- refers to a substituted or unsubstituted alkenylene chain with from x to y carbons in the alkenylene chain. For example, - C2-6alkenylene- may be selected from ethenylene, propenylene, butenylene, pentenylene, and hexenylene, any one of which is optionally substituted. An alkenylene chain may have one double bond or more than one double bond in the alkenylene chain. The term -Cx-yalkynylene-refers to a substituted or unsubstituted alkynylene chain with from x to y carbons in the alkynylene chain. For example, -C2-6alkynylene- may be selected from ethynylene, propynylene, butynylene, pentynylene, and hexynylene, any one of which is optionally substituted. An alkynylene chain may have one triple bond or more than one triple bond in the alkynylene chain.

[0017] "Alkylene" refers to a straight divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation, and preferably having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through the terminal carbons, respectively. An alkylene chain may be optionally substituted by one or more substituents such as those substituents described herein.

[0018] "Alkenylene" refers to a straight divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and preferably having from two to twelve carbon atoms. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group are through the terminal carbons, respectively. An alkenylene chain may be optionally substituted by one or more substituents such as those substituents described herein.

[0019] "Alkynylene" refers to a straight divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and preferably having from two to twelve carbon atoms. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkynylene chain to the rest of the molecule and to the radical group are through the terminal carbons, respectively. An alkynylene chain may be optionally substituted by one or more substituents such as those substituents described herein.

[0020] "Halo" or "halogen" as used herein refers to halogen substituents such as bromo, chloro, fluoro and iodo substituents.

[0021] "Haloalkyl" as used herein refers to an alkyl radical, as defined above, that is substituted by one or more halogen radicals, for example, trifluoromethyl, dichloromethyl, bromomethyl,2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. Examples of halogen substituted alkanes (“haloalkanes”) include halom ethane (e.g., chloromethane, bromomethane, fluoromethane, and iodomethane), di-and trihalomethane (e.g., trichloromethane, tribromomethane, trifluoromethane, and triiodomethane), 1-haloethane, 2-haloethane, 1,2- dihaloethane, and any other suitable combinations of alkanes (or substituted alkanes) and halogens. When an alkyl group is substituted with more than one halogen radicals, each halogen may be independently selected, for example 1-chloro,2-bromoethane.

[0022] "Aminoalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more amine radicals, for example, propan-2-amine, butane- 1,2-diamine, pentane- 1, 2, 4-triamine and the like.

[0023] "Hydroxy alkyl" refers to an alkyl radical, as defined above, that is substituted by one or more hydroxy radicals, for example, propan-1-ol, butane- 1,4-diol, pentane- 1, 2, 4-triol, and the like.

[0024] "Alkoxyalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more alkoxy radicals, for example, methoxymethane, 1,3 -dimethoxybutane, 1 -methoxypropane, 2-ethoxypentane, and the like.

[0025] "Cyanoalkyl" as used herein refers to an alkyl radical, as defined above, that is substituted by one or more cyano radicals, for example, acetonitrile, 2-ethyl-3- methylsuccinonitrile, butyronitrile, and the like.

[0026] The term “carbocycle” as used herein refers to a saturated, unsaturated or aromatic ring in which each atom of the ring is carbon. Carbocycle may include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridged rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. In some embodiments, the carbocycle is an aryl. In some embodiments, the carbocycle is a cycloalkyl. In some embodiments, the carbocycle is a cycloalkenyl. In an exemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, are included in the definition of carbocyclic.Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. Bicyclic carbocycles may be fused, bridged or spiro-ring systems. A carbocycle may be optionally substituted by one or more substituents such as those substituents described herein.

[0027] The term “unsaturated carbocycle” refers to carbocycles with at least one degree of unsaturation and excluding aromatic carbocycles. Examples of unsaturated carbocycles include cyclohexadiene, cyclohexene, and cyclopentene.

[0028] The term “cycloalkyl” as used herein refers to a saturated carbocycle. Exemplary cycloalkyl rings include cyclopropyl, cyclohexyl, and norbornane. Carbocycles may be optionally substituted by one or more substituents such as those substituents described herein.

[0029] The term “Cx-ycarbocycle” is meant to include groups that contain from x to y carbons in the ring. For example, the term “C3-6carbocycle” refers to a saturated, unsaturated, or aromatic ring comprising from 3 to 6 carbons. For example -C3-6carbocycle- may be selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl, any one of which is optionally substituted.

[0030] "Aryl" as used herein refers to a radical derived from an aromatic monocyclic or aromatic multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or aromatic multicyclic hydrocarbon ring system contains only hydrogen and carbon and from five to eighteen carbon atoms, where at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) π-electron system in accordance with the Huckel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene. An aryl group may be optionally substituted by one or more substituents such as those substituents described herein.

[0031] The term “heterocycle” as used herein refers to a saturated, unsaturated or aromatic ring comprising one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. The heterocycle may be attached to the rest of the molecule through any atom of the heterocycle, valence permitting, such as a carbon or nitrogen atom of the heterocycle. Heterocycles include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridged rings. A bicyclic heterocycle includes any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits. In an exemplary embodiment, an aromatic ring, e.g., pyridyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, morpholine, piperidine or cyclohexene. A bicyclic heterocycle includes any combination of ring sizes such as 4-5 fused ring systems, 5-5 fused ring systems, 5- 6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6-7 fused ring systems, 5-8 fused ring systems, and 6-8 fused ring systems. Bicyclic heterocycles may be fused, bridged, or spiro-ring systems. A spiro-ring system may be referred as a “spiro heterocycle” or“spiroheterocycle” or “spiro-ring heterocycle”. In some cases, spiro heterocycle, spiro-ring heterocycles or spiroheterocycles have at least two molecular rings with only one common atom. The spiro heterocycle, spiro-ring heterocycle or spiroheterocycle comprises one or more heteroatoms. A heterocycle may be optionally substituted by one or more substituents such as those substituents described herein.

[0032] “Heteroaryl" or “aromatic heterocycle” refers to a radical derived from a heteroaromatic ring radical that comprises one to eleven carbon atoms and at least one heteroatom wherein each heteroatom may be selected from N, O, and S. As used herein, the heteroaryl ring may be selected from monocyclic or bicyclic and fused or bridged ring systems rings wherein at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) %- electron system in accordance with the Hückel theory. The heteroatom(s) in the heteroaryl radical may be optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl may be attached to the rest of the molecule through any atom of the heteroaryl, valence permitting, such as a carbon or nitrogen atom of the heteroaryl. Examples of heteroaryls include, but are not limited to, pyridine, pyrimidine, oxazole, furan, thiophene, benzthiazole, and imdazopyridine. A heteroaryl or aromatic heterocycle may be optionally substituted by one or more substituents such as those substituents described herein.

[0033] An “X-membered heteroaryl” refers to the number of endocylic atoms, i.e., X, in the ring. For example, a 5-membered heteroaryl ring or 5-membered aromatic heterocycle has 5 endocyclic atoms, e.g., triazole, oxazole, thiophene, etc.

[0034] The term “unsaturated heterocycle” refers to heterocycles with at least one degree of unsaturation and excluding aromatic heterocycles. Examples of unsaturated heterocycles include dihydropyrrole, dihydrofuran, oxazoline, pyrazoline, and dihydropyridine. Heterocycles may be optionally substituted by one or more substituents such as those substituents described herein.

[0035] The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons or substitutable heteroatoms, e.g., an NH or NH2of a compound. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, i.e., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. In certain embodiments, substituted refers to moieties having substituents replacing two hydrogen atoms on the same carbon atom, such as substituting the two hydrogen atoms on a single carbon with an oxo, imino or thioxo group. As used herein, the term “substituted” is contemplated toinclude all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds.

[0036] In some embodiments, substituents may include any substituents described herein, for example: halogen, hydroxy, oxo (=0), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-0H), hydrazino (=N- NH2), -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb- N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2), and -Rb-S(O)tN(Ra)2(where t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl any of which may be optionally substituted by alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=0), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-OH), hydrazine (=N- NH2), -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb- N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2); wherein each Rais independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, wherein each Ra, valence permitting, may be optionally substituted with alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=0), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-0H), hydrazine (=N- NH2), -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb- N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2); and wherein each Rbis independently selected from a direct bond or a straight or branched alkylene, alkenylene, or alkynylene chain, and each Rcis a straight or branched alkylene, alkenylene or alkynylene chain. It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate.

[0037] Chemical entities having carbon-carbon double bonds or carbon-nitrogen double bonds may exist in Z- or E- form (or cis- or trans- form). Furthermore, some chemical entities mayexist in various tautomeric forms. Unless otherwise specified, compounds described herein are intended to include all Z-, E- and tautomeric forms as well.

[0038] “Isomers” are different compounds that have the same molecular formula. “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space. “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1 : 1 mixture of a pair of enantiomers is a “racemic” mixture. The term “(±)” is used to designate a racemic mixture where appropriate. “Diastereoisomers” or “diastereomers” are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified by either R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) in which they rotate plane polarized light at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, the asymmetric centers of which can be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The present chemical entities, pharmaceutical compositions and methods are meant to include all such possible stereoisomers, including racemic mixtures, optically pure forms, mixtures of diastereomers and intermediate mixtures. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. The optical activity of a compound can be analyzed via any suitable method, including but not limited to chiral chromatography and polarimetry, and the degree of predominance of one stereoisomer over the other isomer can be determined.

[0039] When stereochemistry is not specified, molecules with stereocenters described herein include isomers, such as enantiomers and diastereomers, mixtures of enantiomers, including racemates, mixtures of diastereomers, and other mixtures thereof. In certain embodiments, the single enantiomers or diastereomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution of the racemates or mixtures of diastereomers. Resolution of the racemates or mixtures of diastereomers, if possible, can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example, a chiral high-pressure liquid chromatography (HPLC) column. Furthermore, a mixture of two enantiomers enriched in one of the two can be purified toprovide further optically enriched form of the major enantiomer by recrystallization and / or trituration.

[0040] In certain embodiments, compositions of the disclosure may comprise two or more enantiomers or diastereomers of a compound wherein a single enantiomer or diastereomer accounts for at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 98% by weight, or at least about 99% by weight or more of the total weight of all stereoisomers. Methods of producing substantially pure enantiomers are well known to those of skill in the art. For example, a single stereoisomer, e.g., an enantiomer, substantially free of its stereoisomer may be obtained by resolution of the racemic mixture using a method such as formation of diastereomers using optically active resolving agents (Stereochemistry of Carbon Compounds, (1962) by E. L. Eliel, McGraw Hill; Lochmuller (1975) J. Chromatogr., 113(3): 283-302). Racemic mixtures of chiral compounds can be separated and isolated by any suitable method, including, but not limited to: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions. Another approach for separation of the enantiomers is to use a Diacel chiral column and elution using an organic mobile phase such as done by Chiral Technologies (www.chiraltech.com) on a fee for service basis.

[0041] A "tautomer" refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. The compounds presented herein, in certain embodiments, exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:

[0042] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of2H,3H,nC,13C and / or14C. In one particular embodiment, the compound is deuterated in at least one position.

[0043] Unless otherwise stated, compounds described herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by13C- or14C-enriched carbon are within the scope of the present disclosure.

[0044] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as for example, deuterium (2H), tritium (3H), iodine-125 (125I) or carbon-14 (14C). Isotopic substitution with2H,nC,13C,14C,15C,12N,13N,15N,16N,16O,17O,14F,15F,16F,17F,18F,33S,34S,35S,36S,35C1,37C1,79Br,81Br, and125I are all contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention. In certain embodiments, the compounds disclosed herein have some or all of the1H atoms replaced with2H atoms. The methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.

[0045] Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000;6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0046] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds.Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.

[0047] Compounds of the present invention also include crystalline and amorphous forms of those compounds, salts, and pharmaceutically acceptable salts, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.

[0048] Included in the present disclosure are salts, particularly pharmaceutically acceptable salts, of the compounds described herein. The compounds of the present disclosure that possess a sufficiently acidic, a sufficiently basic, or both functional groups, can react with any of a number of inorganic bases, and inorganic and organic acids, to form a salt. Alternatively, compounds that are inherently charged, such as those with a quaternary nitrogen, can form a salt with an appropriate counterion, e.g., a halide such as bromide, chloride, or fluoride, particularly bromide.

[0049] The methods and compositions described herein include the use of amorphous forms as well as crystalline forms (also known as polymorphs). The compounds described herein may be in the form of pharmaceutically acceptable salts. In addition, the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein.

[0050] The phrases “parenteral administration” and “administered parenterally” as used herein refer to modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrastemal injection and infusion.

[0051] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of soundmedical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0052] The phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen- free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

[0053] The terms "subject," "individual," and "patient" may be used interchangeably and refer to humans, the as well as non-human mammals (e.g., non-human primates, canines, equines, felines, porcines, bovines, ungulates, lagomorphs, and the like). In various embodiments, the subject can be a human (e.g., adult male, adult female, adolescent male, adolescent female, male child, female child) under the care of a physician or other health worker in a hospital, as an outpatient, or other clinical context. In certain embodiments, the subject may not be under the care or prescription of a physician or other health worker.

[0054] As used herein, the phrase "a subject in need thereof' refers to a subject, as described infra, that suffers from, or is at risk for, a pathology to be prophylactically or therapeutically treated with a compound or salt described herein.

[0055] The terms “administer”, “administered”, “administers” and “administering” are defined as providing a composition to a subject via a route known in the art, including but not limited to intravenous, intraarterial, oral, parenteral, buccal, topical, transdermal, rectal, intramuscular, subcutaneous, intraosseous, transmucosal, or intraperitoneal routes of administration. In certainembodiments, oral routes of administering a composition can be used. The terms ““administer”, “administered”, “administers” and “administering” a compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individual in need.

[0056] The term “effective amount” or “therapeutically effective amount” refers to that amount of a compound or salt described herein that is sufficient to effect the intended application including but not limited to disease treatment, as defined below. The therapeutically effective amount may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. The term can also apply to a dose that can induce a particular response in target cells, e.g., reduction of proliferation or down regulation of activity of a target protein. The specific dose can vary depending on the particular compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.

[0057] As used herein, “treatment” or “treating” refers to an approach for obtaining beneficial or desired results with respect to a disease, disorder, or medical condition including, but not limited to, a therapeutic benefit. In certain embodiments, treatment or treating involves administering a compound or composition disclosed herein to a subject. A therapeutic benefit may include the eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit may be achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder, such as observing an improvement in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder. Treating can include, for example, reducing, delaying or alleviating the severity of one or more symptoms of the disease or condition, or it can include reducing the frequency with which symptoms of a disease, defect, disorder, or adverse condition, and the like, are experienced by a patient. Treating can be used herein to refer to a method that results in some level of treatment or amelioration of the disease or condition, and can contemplate a range of results directed to that end, including but not restricted to prevention of reoccurrence of the condition.

[0058] In certain embodiments, the terms “prevent” or “preventing” as related to a disease or disorder refers to the administration of a compound or compositions thereof that, in a statisticalsample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample. In certain embodiments, the term “prophylactic benefit as related to a disease or disorder refers to the administration of compounds or compositions thereof to a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.

[0059] A “therapeutic effect,” as that term is used herein, encompasses a therapeutic benefit as described above, including slowing, halting, or reversing the progression of a disease or condition. A “prophylactic effect” refers todelaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition.

[0060] The term “selective inhibition” or “selectively inhibit” as referred to a biologically active agent refers to the agent’s ability to preferentially reduce the target signaling activity as compared to off-target signaling activity, via direct or interact interaction with the target.

[0061] It is intended that every maximum numerical limitation given throughout this specification includes every lower numerical limitation, as if such lower numerical limitations were expressly written herein. Every minimum numerical limitation given throughout this specification will include every higher numerical limitation, as if such higher numerical limitations were expressly written herein. Every numerical range given throughout this specification will include every narrower numerical range that falls within such broader numerical range, as if such narrower numerical ranges were all expressly written herein.

[0062] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.Compounds

[0063] In an aspect, the present disclosure provides a compound represented by the structure of Formula (I):Formula (I)or a salt thereof, wherein:A is selected from N and CR6;E is selected from N and CR6a; wherein at least one of A or E is N;R1is selected from C3-8carbocycle, and 4- to 8-membered heterocycle, wherein the C3-8carbocycle, and 4- to 8-membered heterocycle are each optionally substituted with one or more substituents independently selected from:(i) halogen, -OR20, -SR20, -N(R20)2, -C(O)R20, -C(O)N(R20)2, - N(R20)C(O)R20-C(O)OR20, -OC(O)R20, -S(O)R20, -S(O)2R20, -P(O)(OR20)2, -OP(O)(OR20)2, -NO2, =O, =S, =N(R20), and -CN; and(ii) C1-10alkyl, C2-10 alkenyl, and C2-10 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR20, -SR20, - N(R20)2, -C(O)R20, -C(O)N(R20)2, -N(R20)C(O)R20-C(O)OR20, -OC(O)R20, -S(O)R20, - S(O)2R20, -S(O)2N(R20)2, -S(O)N(R20)2, -NR20S(O)2R20, -P(O)(OR20)2, -OP(O)(OR20)2, - N02, =O, =S, =N(R20), and -CN; each R2is independently selected from: halogen, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, - N02, -CN, C3-6cycloalkyl and C1-6alkyl;R4is selected from 4- to 5-membered heterocycle, 6-membered heteroaryl, 7- to 9-membered heterocycle, 3- to 6-membered cycloalkyl, hydrogen, and -C02H, wherein the 4- to 5- membered heterocycle, 6-membered heteroaryl, 7- to 9-membered heterocycle, and 3- to 6- membered cycloalkyl, are each optionally substituted with one or more substituents independently selected from:(iii) halogen, -OR20, -SR20, -N(R20)2, -C(O)R20, -C(O)N(R20)2, - N(R20)C(O)R20-C(O)OR20, -OC(O)R20, -S(O)R20, - S(O)2R20, -P(O)(OR20)2, -OP(O)(OR20)2, -N02, and -CN; and(iv) C1-6alkyl, C2-6alkenyl, and C2-6alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR20, -SR20, -N(R20)2, -C(O)R20, -C(O)N(R20)2, -N(R20)C(O)R20-C(O)OR20, -OC(O)R20, - S(O)R20, -S(O)2R20, -S(O)2N(R20)2, -S(O)N(R20)2, -NR20S(O)2R20, -P(O)(OR20)2, -OP(O)(OR20)2, -N02, =O, =S, =N(R20), and -CN; and(v) C3-6carbocycle each of which is optionally substituted with one or more substituents independently selected from halogen and C1-6alkyl;R5is selected from hydrogen; C1-6alkyl, and cyclopropyl each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -NH(C 1-6alkyl), -N(C1-6alkyl)2, C1-10alkyl, -C1-io haloalkyl, -O-C1-10alkyl, oxo, and =NH; or R4and R5together with the atoms to which they are attached for a 4 to 8 membered heterocycle; or R5and one of R5atogether with the atoms to which they are attached form a 4 to 8-membered heterocyclene, which is optionally substituted with 1 to 4 substituents independently selected from R10;R6is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl;R6ais selected from hydrogen, C1-6alkyl, and C1-6haloalkyl;R7is selected from halogen, -CN, -NO2, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, C1-6alkyl, and C1-6haloalkyl;R8is selected from halogen, -CN, -NO2, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, C1-6alkyl, and C1-6haloalkyl;R8ais selected from halogen, -CN, -NO2, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, C1-6alkyl, and C1-6haloalkyl;R8bis selected from halogen, -CN, -NO2, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, C1-6alkyl, and C1-6haloalkyl;selected from S and O;R10is selected from halogen, -CN, -NO2, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, C1-6alkyl, and C1-6haloalkyl;L is selected from a C1-8alkylene, wherein the C1-8alkylene is optionally substituted with one or more R5a, wherein each R5ais independently selected from halogen, C1-6alkyl, -OH, -OCH3, and -CN; and wherein optionally two optional substituents on the same carbon atom of L come together to form a carbocycle or heterocycle; each R20is independently selected from hydrogen; and C1-6alkyl, C3-12carbocycle, and 3- to 12- membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -NH(C 1-6alkyl), -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, =NH, and cyclopropyl; m is selected from 0 and 1;n is selected from 0, 1, 2, 3, and 4; q is selected from 0, 1, 2, and 4; y is selected from 0, 1, and 2; and z is selected from 0, 1, and 2.

[0064] In some embodiments, the compound or salt of Formula (I) is represented by the structure of Formula (II):Formula (II), or a pharmaceutically acceptable salt thereof.

[0065] In some embodiments, the compound or salt of Formula (I) is represented by the structure of Formula (Illa):Formula (Illa), or a pharmaceutically acceptable salt thereof.

[0066] In some embodiments, the compound or salt of Formula (I) is represented by the structure of Formula (Illb):Formula (Illb), or a pharmaceutically acceptable salt thereof.

[0067] In some embodiments, the compound or salt of Formula (I) is represented by the structure of Formula (IVa):Formula (IVa), or a pharmaceutically acceptable salt thereof.

[0068] In some embodiments, the compound or salt of Formula (I) is represented by the structure of Formula (IVb):Formula (IVb), or a pharmaceutically acceptable salt thereof.

[0069] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula(Illa), Formula (Illb), Formula (IVa), or Formula (IVb), A is selected from N and CR6. In some cases, A is selected from N and CH. In some cases, A is N. In some cases, A is selected fromCR6. In some cases, A is selected from CH, CCH3, and CCF3. In some cases, A is CH. In some cases, A is CCH3. In some cases, A is CCF3.

[0070] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (Illa), Formula (Illb), Formula (IVa), or Formula (IVb), E is selected from N and CR6a. In some cases, E is selected from N and CH. In some cases, E is N. In some cases, E is selected from CR6a. In some cases, E is selected from CH, CCH3, and CCF3. In some cases, E is CH. In some cases, E is CCH3. In some cases, E is CCF3.

[0071] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (Illa), Formula (Illb), Formula (IVa), or Formula (IVb), A is selected from N and CR6; and E is selected from N and CR6a; wherein at least one of A or E is N. In some cases, A is N; and E is selected from N and CR6a. In some cases, A is selected from CR6; and E is N. In some cases, A is N; and E is N. rln some cases, A is N; and E is selected from N and CH. In some cases, A is N; and E is selected from CR6a. In some cases, A is N; and E is selected from CH, CCH3, and CCF3. In some cases, A is N; E is CH. In some cases, A is N; and E is CCH3. In some cases, A is N; and E is CCF3. In some cases, A is selected from N and CR6; and E is N. In some cases, A is selected from N and CH; and E is N. In some cases, A is selected from CR6; and E is N. In some cases, A is selected from CH, CCH3, and CCF3; and E is N. In some cases, A is CH; and E is N. In some cases, A is CCH3; and E is N. In some cases, A is CCF3; and E is N.

[0072] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (Illa), Formula (Illb), Formula (IVa), or Formula (IVb), R1is selected from C6-8aryl and 5- to 8- membered heterocycle, wherein the C6-8aryl and 5- to 8-membered heterocycle are each optionally substituted. In some cases, R1is selected from C6-8aryl and 5- to 6-membered heterocycle, wherein the C6-8aryl and 5- to 6-membered heterocycle are each optionally substituted. In some cases, R1is selected from, , each of which is optionally substituted. In some cases, the heterocycle contains one oxygen atom. In some cases, the heterocycle contains at least one nitrogen atom. In some cases, the heterocycle contains one nitrogen atom. In some cases, the hetereocycle contains two nitrogen atoms. In some cases, R1is selected from C6-8aryl and 5- to 6-membered heteroaryl, wherein the C6-8aryl and 5- to 6-membered heteroaryl are each optionally substituted. In some cases, R1is selectedfrom, each of which is optionally substituted. In some cases, the heteroaryl contains one oxygen atom. In some cases, the heteroaryl contains at least one nitrogen atom. In some cases, the heteroaryl contains one nitrogen atom. In some cases, the hetereoaryl contains two nitrogen atoms.

[0073] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (Illa), Formula (Illb), Formula (IVa), or Formula (IVb), R1is selected from C6-8aryl and 5- to 6- membered heteroaryl, wherein the C6-8aryl and 5- to 6-membered heteroaryl are each optionally substituted. In some cases, R1is selected from C6-8aryl and 6-membered heteroaryl, wherein the C6-8aryl and 6-membered heteroaryl are each optionally substituted. In some cases, R1is selected from phenyl and 6-membered heteroaryl, wherein the phenyl and 6-membered heteroaryl are each optionally substituted. In some cases, R1is selected from, each of which is optionally substituted. In some cases, R1is selected from, each of which is optionally substituted. In some cases, R1is selected fromoptionally substituted. In some cases, the one or more optional substituents of R1is independently selected from: halogen, -OR20, -N(R20)2, -C(O)R20, -C(O)N(R20)2, -C(O)OR20, - OC(O)R20, -S(O)2R20, and -CN; and C1 -10alkyl, which is optionally substituted with one or more substituents independently selected from halogen, -OR20, -N(R20)2, =O, and -CN. In some cases, the one or more optional substituents of R1is independently selected from: halogen, -CN, C1-4alkyl, C1-4haloalkyl, -O-C1-4alkyl, and -O-C1-4haloalkyl. In some cases, R1is substituted with one or more substituents independently selected from: halogen, -CN, C1-4alkyl, C1-4haloalkyl, -O-C1-4alkyl, and -O-C1-4haloalkyl. In some cases, R1is selected fromis R1is substituted with one or more substituents independently selected from: halogen, -CN, C1-4alkyl, C1-4haloalkyl, -O-C1-4alkyl, and -O-C1-4haloalkyl. In some cases, R1is selected fromwherein, is R1is substituted with one or more substituents independently selected from:-O-C1-4alkyl. In some cases, R1is selected from ,

[0074] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (Illa), Formula (Illb), Formula (IVa), or Formula (IVb), R1is selected from an optionally substituted 6-membered heteroaryl. In some cases, the heteroaryl contains at least one nitrogen atom. In some cases, the heteroaryl contains one nitrogen atom. In some cases, the heteroaryl contains two nitrogen atoms. In some cases, R1is selected fromeach of which is optionally substituted.

[0075] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula(Illa), Formula (Illb), Formula (IVa), or Formula (IVb), R1is, which is optionally substituted.

[0076] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (Illa), Formula (Illb), Formula (IVa), or Formula (IVb), the one or more optional substituents of R1is independently selected from: (i) halogen, -OR20, -N(R20)2, -C(O)R20, -C(O)N(R20)2, -C(O)OR20, -OC(O)R20, -S(O)2R20, and -CN; and (ii) C1-io alkyl, which is optionally substituted with one or more substituents independently selected from halogen, - OR20, -N(R20)2, =O, and -CN. In some cases, the one or more optional substituents of R1is independently selected from: halogen, C1-6alkyl, -OR20, -N(R20)2, -C(O)R20, -C(O)N(R20)2, -C(O)OR20, -OC(O)R20, -S(O)2R20, and -CN. In some cases, the one or more optional substituents of R1is independently selected from: halogen and -OR20; and C1-4alkyl, which is optionally substituted with one or more substituents independently selected from halogen, -OR20, -N(R20)2, =O, and -CN. In some cases, the one or more optional substituents of R1is independently selected from: halogen and -OR20; and C1-4alkyl, which is optionallysubstituted with one or more substituents independently selected from halogen, -OH, and - OCH3; wherein each R20is independently selected from hydrogen; and C1-6alkyl, which is optionally substituted with one or more substituents independently selected from halogen. In some cases, the one or more optional substituents of R1is independently selected from: halogen, C1-4alkyl, C1-4haloalkyl, -O-C1-4alkyl, and -O-C1-4haloalkyl. In some cases, the one or more optional substituents of R1is halogen, C1-4alkyl, C1-4haloalkyl, and -O-C1-4alkyl. In some cases, the one or more optional substituents of R1is independently selected from: Cl, -CH3, - CF2H, and -OCH3. In some cases, R1is substituted. In some cases, R1is substituted with one or two substiutents.

[0077] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula(Illa), Formula (Illb), Formula (IVa), or Formula (IVb), R1is selected from

[0078] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula(Illa), Formula (Illb), Formula (IVa), or Formula (IVb), R1is selected from

[0079] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula(Illa), Formula (Illb), Formula (IVa), or Formula (IVb), R1is, which is optionally substituted. In some cases, the one or more optional substituents of R1is independently selected from: halogen, -CN, C1-4alkyl, C1-4haloalkyl, -O-C1-4alkyl, and -O-C1-4haloalkyl. In some cases, the one or more optional substituents of R1is independently selected from: F, -CN, Cl, - CH3, - CF2H, and -OCH3. In some cases, the one or more optional substituents of R1is independently selected from halogen. In some cases, R1is substituted. In some cases, R1is substituted with one or two substiutents. In some cases, R1is substituted with only one substiutent. In some cases, R1is substituted with only two substiutents. In some cases, R1is

[0080] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (Illa), Formula (Illb), Formula (IVa), or Formula (IVb), R1is selected from C6-8aryl and 5- to 8- membered heterocycle, wherein the C6-8aryl and 5- to 8-membered heterocycle are each optionally substituted. In some cases, R1is selected from C6-8aryl and 5- to 6-membered heterocycle, wherein the C6-8aryl and 5- to 6-membered heterocycle are each optionally substituted. In some cases, the heterocycle contains at least one oxygen atom. In some cases, the heterocycle contains one oxygen atom. In some cases, the heterocycle contains at least one nitrogen atom. In some cases, the heterocycle contains one nitrogen atom. In some cases, the heterocycle contains at least one sulfur atom. In some cases, the heterocycle contains one sulfur atom. In some cases, R1is selected from C6-8aryl, 5- to 6-membered heteroaryl, and 5- to 6- membered saturated heterocycle, wherein the C6-8aryl, 5- to 6-membered heteroaryl, and 5- to 6- membered saturated heterocycle are each optionally substituted. In some cases, the heteroarylcontains at least one oxygen atom. In some cases, the heteroaryl contains one oxygen atom. In some cases, the heteroaryl contains at least one nitrogen atom. In some cases, the heteroaryl contains one nitrogen atom. In some cases, the heteroaryl contains at least one sulfur atom. In some cases, the heteroaryl contains one sulfur atom. In some cases, the saturated heterocycle contains at least one oxygen atom. In some cases, the saturated heterocycle contains one oxygen atom. In some cases, the saturated heterocycle contains at least one nitrogen atom. In some cases, the saturated heterocycle contains one nitrogen atom. In some cases, the saturated heterocycle contains at least one sulfur atom. In some cases, the saturated heterocycle contains one sulfur atom. In some cases, R1is selected fromeach of which is optionally substituted.

[0081] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (Illa), Formula (Illb), Formula (IVa), or Formula (IVb), R1is optionally substituted 4- to 8- membered heterocycle. In some cases, R1is optionally substituted 5- to 6-membered heterocycle. In some cases, R1is optionally substituted 5- to 6-membered heteroaryl. In some cases, the heteroaryl of R1contains at least one heteroatom selected from oxygen, nitrogen, and sulfur. In some cases, the heteroaryl of R1contains at least one heteroatom selected from oxygen and nitrogen. In some cases, the heteroaryl of R1contains at least one heteroatom selected from oxygen. In some cases, the heteroaryl of R1contains at least one heteroatom selected from nitrogen. In some cases, the heteroaryl of R1contains at least one heteroatom selected from sulfur. In some cases, the heteroaryl of R1contains one oxygen atom. In some cases, the heteroaryl of R1contains one nitrogen atom. In some cases, the heteroaryl of R1contains one sulfur atom. In some cases, the heteroaryl of R1contains at one nitrogen atom and one oxygen atom. In some cases, R1is selected fromcases, R1is selected fromsome cases,R1is. In some cases, R1is. In some cases, R1is

[0082] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (Illa), Formula (Illb), Formula (IVa), or Formula (IVb), R1is optionally substituted 4- to 8- membered heterocycle. In some cases, R1is optionally substituted 5- to 6-membered heterocycle. In some cases, R1is optionally substituted 5- to 6-membered saturated heterocycle. In some cases, the saturated heterocycle of R1contains at least one heteroatom selected from oxygen, nitrogen, and sulfur. In some cases, the saturated heterocycle of R1contains at least one heteroatom selected from oxygen and nitrogen. In some cases, the saturated heterocycle of R1contains at least one heteroatom selected from oxygen. In some cases, the saturated heterocycle of R1contains at least one heteroatom selected from nitrogen. In some cases, the saturated heterocycle of R1contains at least one heteroatom selected from sulfur. In some cases, the saturated heterocycle of R1contains one oxygen atom. In some cases, the saturated heterocycle of R1contains one nitrogen atom. In some cases, the saturated heterocycle of R1contains one sulfur atom. In some cases, the saturated heterocycle of R1contains at least one nitrogen atom and one oxygen atom. In some cases, the R1is selected fromIn some cases, the R1is selected from. In some cases, the R1is selected from. In some cases, the R1is. In some cases, the R1is selected from. In some cases, the R1is. In some cases, the R1isIn some cases, the R1is selected from . In somecases, the R1is selected fromIn some cases, the R1is selected from

[0083] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula(Illa), Formula (Illb), Formula (IVa), or Formula (IVb), R1is optionally substituted 4- to 8- membered heterocycle. In some cases, R1is optionally substituted 5- to 6-membered heterocycle. In some cases, the heterocycle of R1contains at least one heteroatom selected from oxygen, nitrogen, and sulfur. In some cases, the heterocycle of R1contains at least one heteroatom selected from oxygen and nitrogen. In some cases, the heterocycle of R1contains at least one heteroatom selected from oxygen. In some cases, the heterocycle of R1contains at least one heteroatom selected from nitrogen. In some cases, the heterocycle of R1contains at least one heteroatom selected from sulfur. In some cases, the heterocycle of R1contains one oxygen atom. In some cases, the heterocycle of R1contains one nitrogen atom. In some cases, the heterocycle of R1contains one sulfur atom. In some cases, the heterocycle of R1contains at least one nitrogen atom and one oxygen atom. In some cases, the R1is selected fromIn some cases, the R1is selected fromcases, the R1is selected fromR1is selected fromIn some cases, the R1issome cases, the R1is selected fromIn some cases, the R1In some cases, the R1is

[0084] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (Illa), Formula (Illb), Formula (IVa), or Formula (IVb), R1is selected from an optionally substituted 5- to 6-membered heterocycle, wherein the heterocycle contains one heteroatom selected from oxygen and nitrogen. In some cases, R1is selected from an optionally substituted 5- to 6-membered heterocycle, wherein the heterocycle contains one oxygen atom. In some cases, R1is selected from an unsubstituted 5- to 6-membered heterocycle, wherein the heterocycle contains one oxygen atom. In some cases, R1is selected from an optionally substituted 5- to 6-membered saturated heterocycle, wherein the heterocycle contains one oxygen atom. In some cases, R1is selected from an unsubstituted 5- to 6-membered saturated heterocycle, wherein the heterocycle contains one oxygen atom. In some cases, R1is selected

[0085] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (Illa), Formula (Illb), Formula (IVa), or Formula (IVb), the one or more optional substituents of R1is independently selected from halogen, -OR20, -N(R20)2, -C(O)R20, -C(O)N(R20)2, -C(O)OR20, -OC(O)R20, -S(O)2R20, and -CN; and C1-io alkyl, which is optionally substituted with one or more substituents independently selected from halogen, -OR20, -N(R20)2, =O, and -CN. In some cases, the one or more optional substituents of R1is independently selected from halogen, -OR20, -N(R20)2, -C(O)R20, -C(O)N(R20)2, -C(O)OR20, and -CN; and C1-6alkyl, which is optionally substituted with one or more substituents independently selected from halogen, -OR20, -N(R20)2, =O, and -CN. In some cases, the one or more optional substituents of R1is independently selected from halogen, -OR20, -N(R20)2, -C(O)OR20, and -CN; and C1-6alkyl, which is optionally substituted with one or more substituents independently selected from halogen, -OR20, -N(R20)2, =O, and -CN. In some cases, the one or more optional substituents of R1is independently selected from halogen, -OR20, and -CN; and C1-6alkyl, which is optionally substituted with one or more substituents independently selected from halogen, -OR20, -N(R20)2, =O, and -CN. In some cases, the one or more optional substituents of R1is independently selected from halogen, -OR20, and -CN; and C1-6alkyl, which is optionally substituted with one or more substituents independently selected from halogen, -OR20, and -CN. In some cases, the one or more optional substituents of R1is independently selected from halogen, -OR20, and -CN; and C1-6alkyl, which is optionally substituted with one or more substituents independently selected from halogen. In some cases, the one or more optional substituents of R1is independently selected from halogen, -OR20, -CN, and C1-6alkyl. In some cases, the one or more optional substituents of R1is independently selected from F, Cl, -OH, -OCH3, -OCH2F, -OCF2H, -OCF3, -CN, and -CH3. In some cases, the one or more optional substituents of R1is independently selected from F, Cl, -OCH3, -OCF2H, -CN, and -CH3. In some cases, the one or more optional substituents of R1is independently selected from: Cl, -CH3, -CF2H, -CN, and - OCH3. In some cases, the one or more optional substituents of R1is independently selected from: Cl, -CH3, and -OCH3. In some cases, the one or more optional substituents of R1is independently selected from halogen. In some cases, the one or more optional substituents of R1is independently selected from F and Cl. In some cases, the one or more optional substituents of R1is Cl. In some cases, the one or more optional substituents of R1is -CH3. In some cases, the one or more optional substituents of R1is OCH3. In some cases, R1is substituted. In some cases, R1is substituted with one or two substiutents. In some cases, R1is substituted with OCH3. Insome cases, R1is substituted with -CH3. In some cases, R1is substituted with one or more substituents independently selected from: Cl, -CH3, and -OCH3.

[0086] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula(Illa), Formula (Illb), Formula (IVa), or Formula (IVb), R1is selected fromsome cases, R1is selected from. In some cases, R1is selected fromIn some cases, R1is selected

[0087] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula(Illa), Formula (Illb), Formula (IVa), or Formula (IVb), R1is selected from, each of which is optionally substituted. In some cases,R1is, which is optionally substituted.

[0088] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula(Illa), Formula (Illb), Formula (IVa), or Formula (IVb), R1is selected from

[0089] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (Illa), Formula (Illb), Formula (IVa), or Formula (IVb), R1is selected from an optionally substituted unsaturated 6-membered heterocycle, wherein the heterocycle contains one oxygen.In some cases, R1is selected from an unsubstituted unsaturated 6-membered heterocycle, wherein the heterocycle contains one oxygen. In some cases, R1is selected from

[0090] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (Illa), Formula (Illb), Formula (IVa), or Formula (IVb), each R2is independently selected from: halogen, cyclopropyl, -OH, -OCH3, -CN, and C1-6alkyl.

[0091] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (Illa), Formula (Illb), Formula (IVa), or Formula (IVb), each R2is independently selected from: halogen, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, -NO2, -CN, and C1-6alkyl.

[0092] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (Illa), Formula (Illb), Formula (IVa), or Formula (IVb), each R2is independently selected from: halogen, -OR20, -N(R20)2, -C(O)R20, -C(O)N(R20)2, -C(O)OR20, -S(O)2R20, and -CN; and C1-6alkyl which is optionally substituted with one or more substituents independently selected from halogen, -OR20, -N(R20)2, =O, and -CN. In some cases, each R2is independently selected from: halogen, -OR20, -N(R20)2, and -CN; and C1-6alkyl which is optionally substituted with one or more substituents independently selected from halogen, -OR20, -N(R20)2, =O, and -CN. In some cases, each R2is independently selected from: halogen, -OR20, and -N(R20)2; and C1-6alkyl which is optionally substituted with one or more substituents independently selected fromhalogen, -OR20, -N(R20)2, =O, and -CN. In some cases, each R2is independently selected from: halogen, -OR20, and -N(R20)2; and C1-6alkyl which is optionally substituted with one or more substituents independently selected from halogen and -OR20. In some cases, each R2is independently selected from: halogen; and C1-6alkyl which is optionally substituted with one or more substituents independently selected from halogen and -OR20. In some cases, each R2is independently selected from: halogen; and C1-6alkyl. In some cases, each R2is independently selected from: halogen; and -CH3, -CH2CH3, -CH(CH3)2, and -CH(CH3)3. In some cases, each R2is independently selected from: F, Cl, and -CH3. In some cases, each R2is independently selected from: -CH3.

[0093] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (Illa), Formula (Illb), Formula (IVa), or Formula (IVb), each R2is independently selected from: C1-6alkyl. In some cases, each R2is independently selected from: -CH3, -CH2CH3, -CH(CH3)2, and -CH(CH3)3. In somes cases, each R2is independently selected from: -CH3.

[0094] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (Illa), Formula (Illb), Formula (IVa), or Formula (IVb), n is selected from 0, 1, and 2. In some cases, n is selected from 1 and 2. In some cases, n is selected from 0 and 1. In some cases, n is selected from 0 and 2. In some cases, n is 0. In some cases, n is 1. In some cases, n is 2. In some cases, N is 2 and each R2is -CH3.

[0095] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (Illa), Formula (Illb), Formula (IVa), or Formula (IVb):R4is selected from 4- to 5-membered heterocycle, 6-membered heteroaryl, and 7- to 9- membered heterocycle, wherein the 4- to 5-membered heterocycle, 6-membered heteroaryl, and 7- to 9-membered heterocycle are each optionally substituted with one or more substituents independently selected from:(i) halogen, -OR20, -SR20, -N(R20)2, -C(O)R20, -C(O)N(R20)2, - N(R20)C(O)R20-C(O)OR20, -OC(O)R20, -S(O)R20, - S(O)2R20, -P(O)(OR20)2, -OP(O)(OR20)2, -NO2, and -CN; and(ii) C1-6alkyl, C2-6alkenyl, and C2-6alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR20, -SR20, -N(R20)2, -C(O)R20, -C(O)N(R20)2, -N(R20)C(O)R20-C(O)OR20, -OC(O)R20, - S(O)R20, -S(O)2R20, -S(O)2N(R20)2, -S(O)N(R20)2, -NR20S(O)2R20, -P(O)(OR20)2, -OP(O)(OR20)2, -NO2, =O, =S, =N(R20), and -CN; and(iii) C3-6carbocycle each of which is optionally substituted with one or more substituents independently selected from halogen and C1-6alkyl; andR5is selected from hydrogen; C1-6alkyl, and cyclopropyl each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -NH(C1-6alkyl), -N( C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10 alkyl, oxo, and =NH.

[0096] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (Illa), Formula (Illb), Formula (IVa), or Formula (IVb), R4is selected from an optionally substituted 5- to 8-membered heteroaryl and an optionally substituted 8- to 9-membered unsaturated heterocycle. In some cases, R4is selected from an optionally substituted 5- membered heteroaryl and an optionally substituted 8- to 9-membered unsaturated heterocycle. In some cases, R4is selected from an optionally substituted 5- to 8-membered heteroaryl. In some cases, R4is selected from an optionally substituted 5- to 6-membered heteroaryl. In some cases, R4is selected from an optionally substituted 5-membered heteroaryl. In some cases, the heteroaryl has at least one nitrogen atom. In some cases, the heteroaryl has one nitrogen atom. In some cases, the heteroaryl has two nitrogen atoms. In some cases, the heteroaryl has one oxygen atom. In some cases, the heteroaryl has one oxygen atom and one nitrogen atom. In some cases, the heteroaryl has one sulfur atom. In some cases, the heteroaryl has one sulfur atom and one nitrogen atom. In some cases, R4is selected fromoptionally substituted. In some cases, R4is selected from, each of which is optionally substituted. In some cases, R4is selected fromsubstituted. In some cases, the one or more optional substituents of R4is independently selected from: halogen, -OR20, -N(R20)2, -C(O)R20, -C(O)N(R20)2, -C(O)OR20, -OC(O)R20, -S(O)2R20, and -CN; and C1-6alkyl and C3-6carbocycle, wherein the C1-6alkyl and C3-6carbocycle are each optionally substituted with one or more substituents independently selected from halogen, - OR20, -N(R20)2, =O, and -CN. In some cases, the one or more optional substituents of R4is independently selected from: C1-6alkyl and C3-6carbocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR20, -N(R20)2, =O, and -CN. In some cases, the one or more optional substituents of R4is independently selected from: C1-5alkyl and C3-6saturated carbocycle. In some cases, the one or more optional substituents of R4is independently selected from: C1-3alkyl and C3-5saturated carbocycle. In some cases, the one or more optional substituents of R4is independently selected from: C1-3alkyl. In some cases, the one or more optional substituents of R4is independently selected from:

[0097] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (Illa), Formula (Illb), Formula (IVa), or Formula (IVb), R4is selected from an optionally substituted 8- to 9-membered unsaturated heterocycle. In some cases, R4is selected from an optionally substituted 8- to 9-membered unsaturated heterocycle. In some cases, R4is selected from an optionally substituted 8-membered unsaturated heterocycle. In some cases, R4is selected from an optionally substituted 9-membered unsaturated heterocycle. In some cases, the heterocycle is bicyclic. In some cases, the heterocycle contains one oxygen atom. In some cases, the heterocycle contains at least one nitrogen atom. In some cases, the hetereocycle contains one nitrogen atom. In some cases, the heterocycle contains one oxygen atom and one nitrogen atom. In some cases, the heterocycle contains at least two nitrogen atoms. In some cases, the heterocycle is unsubstituted. In some cases, R4is selected fromand

[0098] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (Illa), Formula (Illb), Formula (IVa), or Formula (IVb), R4is selected from an optionally substituted 5-membered heteroaryl. In some cases, the heteroaryl of R5has a heteroatom selected from oxygen, sulfur, and nitrogen. In some cases, the heteroaryl of R5has a heteroatom selected from oxygen and nitrogen. In some cases, the heteroaryl of R5has a heteroatom selected from sulfur and nitrogen. In some cases, the heteroaryl of R5has two heteroatoms. In some cases, the heteroaryl of R5has at least two heteroatoms. In some cases, the heteroaryl of R5has at most 2 heteroatoms. In some cases, R4is selected from, and, each of which is optionally substituted. In some case, the one or more optional substituents of R4is independently selected from: C1-3alkyl and C3-6saturated carbocycle. In some case, the one or more optional substituents of R4is independently selectedfrom: C1-3alkyl. In some cases, the one or more optional substituents of R4is independently selected from: methyl, ethyl, isopropyl, and cyclopropyl. In some cases, the one or more optional substituents of R4is independently selected from: methyl, ethyl, and isopropyl. In some

[0099] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula(Illa), Formula (Illb), Formula (IVa), or Formula (IVb), R4is selected from, each of which is optionally substituted. In some cases, R4is, which is optionally substituted. In some cases, R4is substituted. In some cases, the one or more optional substituents of R4is independently selected from: C1-3alkyl and C3-6saturated carbocycle. In some cases, the one or more optional substituents of R4is independently selected from: methyl, ethyl, isopropyl, and cyclopropyl. In some cases, R4is selected fromsome cases, R4is selected from

[0100] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (Illa), Formula (Illb), Formula (IVa), or Formula (IVb), R5is selected from hydrogen; and C1-6alkyl, C3-6saturated carbocycle, and phenyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NH(C1-6alkyl), -N(C1-6alkyl)2, C1-4alkyl, -C1-4haloalkyl, and -O-C1-4alkyl; or one of R5and one of R5atogether with the atoms to which they are attached form a 4 to 8-membered heterocyclene, which is optionally substituted with 1 to 4 substituents independently selected from R7. In some cases, R5is selected from hydrogen; and C1-6alkyl, C3-6saturated carbocycle, and phenyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, - NH(C1-6alkyl), -N(C1-6alkyl)2, C1-4alkyl, -C1-4haloalkyl, and -O-C1-4alkyl; or one of R5and one of R5atogether with the atoms to which they are attached form a 4- to 8-membered heterocyclene. In some cases, R5is selected from hydrogen; and C1-6alkyl, C3-6saturated carbocycle, and phenyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, C1-4alkyl, -C1-4haloalkyl, and -O-C1-4alkyl; or one of R5and one of R5atogether with the atoms to which they are attached form a 4 to 8-membered heterocyclene. In some cases, R5is selected from hydrogen; and C1-6alkyl, C3-6saturated carbocycle, and phenyl; or one of R5and one of R5atogether with the atoms to which they are attached form a 4 to 8-membered heterocyclene. In some cases, R5is selected from hydrogen and C1-6alkyl; or one of R5and one of R5atogether with the atoms to which they are attached form a 4 to 8-membered heterocyclene. In some cases, R5is selected from hydrogen; and C1-6alkyl, C3-6saturated carbocycle, and phenyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NH(C1-6alkyl), -N(C1-6alkyl)2, C1-4alkyl, -C1-4haloalkyl, and -O-C1-4alkyl. In some cases, R5is selected from hydrogen; and C1-6alkyl, C3-6saturated carbocycle, and phenyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, C1-4alkyl, - C1-4haloalkyl, and -O-C1-4alkyl. In some cases, R5is selected from hydrogen; and C1-6alkyl, C3- 6 saturated carbocycle, and phenyl, each of which is optionally substituted with one or more substituents independently selected from F, Cl, -OH, -CH3, -CH2CH3, -CH(CH3)2, -CH2F, -CF2H, -CF3, and -OMe. In some cases, R5is selected from hydrogen; and C1-6alkyl, C3-6saturated carbocycle, and phenyl. In some cases, R5is selected from hydrogen; and C1-6alkyl and C3-6saturated carbocycle. In some cases, R5is selected from hydrogen; and C1-6alkyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In some cases, R5is selected from hydrogen and C1-6alkyl. In some cases, R5is hydrogen. In some cases, R5is -CH3, -CH2CH3, - CH(CH3)2, and -CH(CH3)3In some cases, R5is -CH3.

[0101] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (Illa), Formula (Illb), Formula (IVa), or Formula (IVb), R6is selected from hydrogen, -CH3, and -CF3. In some cases, R6is hydrogen.

[0102] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (Illa), Formula (Illb), Formula (IVa), or Formula (IVb), R6ais selected from hydrogen, -CH3, and -CF3. In some cases, R6ais hydrogen.

[0103] In some embodiments, for a compound or salt of Formula (I) or Formula (II), R7is selected from halogen, -CN, -NO2, -OR20, -SR20, -N(R20)2, C1-6alkyl, and C1-io haloalkyl. In some cases, R7is selected from halogen, -CN, -OH, -NH(C1-6alkyl), -N(C1-6alkyl)2, C1-4alkyl, C1-4haloalkyl, and -O-C1-4alkyl. In some cases, R7is selected from F, Cl, -CN, -OH, -N(C1-6alkyl)2, C1-4alkyl, C1-4haloalkyl, and -O-C1-4alkyl. In some cases, R7is selected from F, Cl, C1-4alkyl, C1-4haloalkyl, and -O-C1-4alkyl. In some cases, R7is selected from F, Cl, C1-4alkyl, and C1-4haloalkyl. In some cases, R7is selected from F. In some cases, q is 0. In some cases, q is 1.

[0104] In some embodiments, for a compound or salt of Formula (I), Formula (Illa), or Formula (Illb), R8is selected from halogen, -CN, -NO2, -OH, -OCH3, -NH2, -NHCH3, - N(CHS)2, C1-6alkyl, and C1-6haloalkyl. In some cases, R8is selected from halogen, -CN, -OH, - OCH3, C1-6alkyl, and C 1-6haloalkyl. In some cases, R8is selected from F, Cl, Br, -CN, -OH, - OCH3, C1-4alkyl, and C1-4haloalkyl. In some cases, R8is selected from F, Cl, -CN, -OH, -OCH3, -CH3, -CH2CH3, -CH(CH3)2, -CH2F, -CF2H, and -CF3. In some cases, R8is selected from F, Cl, - CN, -OH, -OCH3, -CH3, -CH2F, -CF2H, and -CF3. In some cases, R8is selected from F. In some cases, y is 0. In some cases, y is 1.

[0105] In some embodiments, for a compound or salt of Formula (I) or Formula (IVa), R8ais selected from halogen, -CN, -NO2, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, C1-6alkyl, and C1-6haloalkyl. In some cases, R8ais selected from halogen, -CN, -OH, -OCH3, C1-6alkyl, and C1-6haloalkyl. In some cases, R8ais selected from F, Cl, Br, -CN, -OH, -OCH3, C1-4alkyl, and C1-4haloalkyl. In some cases, R8ais selected from F, Cl, -CN, -OH, -OCH3, -CH3, -CH2CH3, -CH(CH3)2, -CH2F, -CF2H, and -CF3. In some cases, R8ais selected from F, Cl, -CN, -OH, - OCH3, -CH3, -CH2F, -CF2H, and -CF3.

[0106] In some embodiments, for a compound or salt of Formula (I) or Formula (IVb), R8bis selected from halogen, -CN, -NO2, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, C1-6alkyl, and C1-6haloalkyl. In some cases, R8bis selected from halogen, -CN, -OH, -OCH3, C1-6alkyl, and C1-6haloalkyl. In some cases, R8bis selected from F, Cl, Br, -CN, -OH, -OCH3, C1-4alkyl, and C1-4haloalkyl. In some cases, R8bis selected from F, Cl, -CN, -OH, -OCH3, -CH3, -CH2CH3, - CH(CH3)2, -CH2F, -CF2H, and -CF3. In some cases, R8bis selected from F, Cl, -CN, -OH, - OCH3, -CH3, -CH2F, -CF2H, and -CF3.

[0107] In some embodiments, for a compound or salt of Formula (I), R9is selected from, wherein X is selected from S and O. In some cases, R9is selected from, wherein X is selected from S and O. In some cases, R9is selected from, wherein X is selected from S and O.

[0108] In some embodiments, for a compound or salt of Formula (I), Formula (IVa), or Formula (IVb), X is selected from S, N, and O. In some cases, X is selected from S and O. In some cases, X is O. In some cases, X is S. In some cases, X is N.

[0109] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (Illa), Formula (Illb), Formula (IVa), or Formula (IVb), m is 0. In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (Illa), Formula (Illb), Formula (IVa), or Formula (IVb), , m is 1. In some cases, L is selected from a C1-6alkylene, wherein the C1-6alkylene is optionally substituted with one or more R5a. In some cases, L is selected from a C1-4alkylene, wherein the C1-4alkylene is optionally substituted with one or more R5a. In some cases,L is selected from a C1-4alkylene, wherein the C1-4alkylene is optionally substituted with one or more R5a. In some cases, L is selected from C1-4alkylene. In some cases, L is selected from, , wherein each is optionally substituted with one or more R5a. In some cases, each R5ais independently selected from halogen, C1-6alkyl, - OH, -OCH3, and -CN. In some cases, each R5ais independently selected from halogen and C1-6alkyl. In some cases, each R5ais independently selected from C1-6alkyl. In some cases, L isfrom C1-4alkylene. In some cases, L is selected fromsome cases, L is selected fromIn some cases, L issome cases, L is. In some cases, L is selected from

[0110] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (Illa), Formula (Illb), Formula (IVa), or Formula (IVb), m is selected from 0 and 1, wherein L is selected from C1-4alkylene. In some cases, m is selected from 0 and 1, wherein L is selected from C1-4alkylene, wherein the C1-4alkylene is optionally substituted with one or more R5a,wherein each R5ais independently selected from halogen, C1-6alkyl, -OH, -OCH3, and -CN. In some cases, m is selected from 0 and 1, wherein L is selected from C1-4alkylene, wherein the C1-4 alkylene is optionally substituted with one or more R5a, wherein each R5ais independently selected from halogen and C1-6alkyl. In some cases, m is selected from 0 and 1, wherein L is selected from C1-4alkylene, wherein the C1-4alkylene is optionally substituted with one or more R5a, wherein each R5ais independently selected from C1-6alkyl. In some cases, m is selected from 0 and 1, wherein L is selected from C2-4 alkylene. In some cases, m is selected from 0 and1, wherein L is selected from. In some cases, mis selected from 0 and 1, wherein L is selected from. In some cases, m is selected from 0 and 1, wherein L is selected from. In some cases, m is selected from 0 and 1, whereinL is selected from. In some cases, m is selected from 0 and 1, wherein L is selected from. In some cases, m is 1, wherein L is selected from. In some cases, m is 1, wherein L issome cases, m is 1, wherein L is. In some cases, m is 1, wherein L is

[0111] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (Illa), Formula (Illb), Formula (IVa), or Formula (IVb), m is 0.

[0112] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (Illa), Formula (Illb), Formula (IVa), or Formula (IVb), m is selected from 0 and 1.

[0113] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (Illa), Formula (Illb), Formula (IVa), or Formula (IVb), m is selected from 1.

[0114] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (Illa), Formula (Illb), Formula (IVa), or Formula (IVb), n is selected from 0, 1, and 2. In some cases, n is selected from 1 and 2. In some cases, n is selected from 0 and 1. In some cases, n is selected from 0 and 2. In some cases, n is 0. In some cases, n is 1. In some cases, n is 2.

[0115] In some embodiments, for a compound or salt of Formula (I) or Formula (II), q is selected from 0, 1, 2, and 4. In some cases, q is selected from 0, 1, and 2. In some cases, q is selected from 1 and 2. In some cases, q is selected from 0 and 1. In some cases, q is selected from 1 and 2. In some cases, q is 0. In some cases, q is 1. In some cases, q is 2. In some cases q is 4.

[0116] In some embodiments, for a compound or salt of Formula (I), Formula (Illa), or Formula (Illb), y is selected from 0, 1, and 2. In some cases, y is selected from 0 and 1. In some cases, y is selected from 1 and 2. In some cases, y is selected from 0 and 2. In some cases, y is 0. In some cases, y is 1. In some cases, y is 2.

[0117] In some embodiments, for a compound or salt of Formula (I), Formula (IVa), or Formula (IVb), z is selected from 0, 1, and 2. In some cases, z is selected from 0 and 1. In some cases, z is selected from 1 and 2. In some cases, z is selected from 0 and 2. In some cases, z is 0. In some cases, z is 1. In some cases, z is 2.

[0118] In some embodiments, the compound or salt is selected from a compound in Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, Table 7, Table 8 or Table 9, or a pharmaceutically acceptable salt of any one thereof. In some cases, the compound is selected from a compound of Table 5. In some cases, the compound is selected from a compound of Table 6. In some cases, the compound is selected from a compound of Table 7. In some cases, the compound is selected from a compound of Table 8. In some cases, the compound is selected from a compound of Table 9.

[0119] In some embodiments, the compound or salt is selected from a compound in Table 5, Table 6, Table 7, Table 8, or Table 9, or a pharmaceutically acceptable salt of any one thereof, that has an IC50in a beta-arrestin assay of less than or equal to 30 micromolar and greater than 10 micromolar. In some embodiments, the compound or salt is selected from a compound in Table 5, Table 6, Table 7, Table 8 and Table 8, or a pharmaceutically acceptable salt of any one thereof, that has an IC50in a beta-arrestin assay of less than or equal to 10 micromolar. In some embodiments, the compound or salt is selected from a compound in Table 5, Table 6, Table 7,Table 8 and Table 9, or a pharmaceutically acceptable salt of any one thereof, that has an IC50in a beta-arrestin assay of less than or equal to 10 micromolar and greater than or equal to 1 micromolar. In some embodiments, the compound or salt is selected from a compound in Table 5, Table 6, Table 7, Table 8 and Table 9, or a pharmaceutically acceptable salt of any one thereof, that has an IC50in a beta-arrestin assay of less than 1 micromolar.

[0120] In some embodiments, the compound or salt is selected from Compound No. 1007, 1019, 1020, 1021, 1022, 1027, 1028, 1030, 1032, 1045, 1046, 1047, 1049, 1050, 1052, 1053,1054, 1055, 1058, 1059, 1063, 1064, 1065, 1066, 1068, 1070, 1080, 1087, 1089, 1098, 1105,1106, 1110, 1112, 1113, 1115, 1118, 1119, 1131, 1135, 1142, 1143, 1148, 1152, 1153, 1162,1163, 1164, 1167, 1169, 1176, 1181, 1183, 1184, 1185, 1186, 1187, 1189, 1191, 1193, 1194,1196, 1198, 1199, 1202, 1203, 1204, 1208, 1215, 1216, 3000, 3004 and 4011, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the compound or salt is selected from Compound No. 1007, 1019, 1020, 1021, 1022, 1027, 1028, 1030, 1032, 1045, 1046, 1047, 1049, 1050, 1052, 1053, 1054, 1055, 1058, 1059, 1063, 1064, 1065, 1066, 1068,1070, 1080, 1087, 1089, 1098, 1105, 1106, 1110, 1112, 1113, 1115, 1118, 1119, 1131, 1135,1142, 1143, 1148, 1152, 1153, 1162, 1163, 1164, 1167, 1169, 1176, 1181, 1183, 1184, 1185,1186, 1187, 1189, 1191, 1193, 1194, 1196, 1198, 1199, 1202, 1203, 1204, 1208, 1215, 1216,1221, 1222, 1225, 1228, 1231, 1232, 1236, 1237, 1238, 1239, 1241, 1243, 1244, 1247, 1248,1249, 1250, 1251, 1253, 1255, 1256, 1258, 1259, 1260, 1600, 3000, 3004 and 4011, or a pharmaceutically acceptable salt of any one thereof.

[0121] In some embodiments, the compound or salt is selected from Compound No. 1019, 1032, 1039, 1069, 1072, 1091, 1097, 1122, 1175, 1182, 1184, 1188, 1190, 1192, 1195, 1201, 1207, 1213, and 4011, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the compound or salt is selected from Compound No. 1019, 1032, 1039, 1069, 1072, 1091, 1097, 1122, 1175, 1182, 1184, 1188, 1190, 1192, 1195, 1201, 1207, 1213, 1217, 1219, 1223, 1224, 1227, 1229, 1242, and 4011, or a pharmaceutically acceptable salt of any one thereof.Pharmaceutical Formulations

[0122] Provided herein, in certain embodiments, are compositions comprising a therapeutically effective amount of any compound or salt of Formula (I), Formula (II), Formula (Illa), Formula (Illb), Formula (IVa), or Formula (IVb), (also referred to herein as a “pharmaceutical agent”).

[0123] Pharmaceutical compositions may be formulated using one or more physiologically acceptable carriers including excipients and auxiliaries which facilitate processing of thepharmaceutical agent into preparations which are used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions is found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa., Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins, 1999).

[0124] The compositions and methods of the present disclosure may be utilized to treat an individual in need thereof. In certain embodiments, the individual is a mammal such as a human, or a non-human mammal. When administered to an animal, such as a human, the composition or the pharmaceutical agent, is preferably administered as a pharmaceutical composition comprising, for example, a pharmaceutical agent and a pharmaceutically acceptable carrier or excipient. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters. In a preferred embodiment, when such pharmaceutical compositions are for human administration, particularly for invasive routes of administration, e.g., routes such as injection or implantation that circumvent transport or diffusion through an epithelial barrier, the aqueous solution is pyrogen-free, or substantially pyrogen-free. The excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs. The pharmaceutical composition can be in dosage unit form such as tablet, capsule, granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like. The composition can also be present in a transdermal delivery system, e.g., a skin patch. The composition can also be present in a solution suitable for topical administration, such as an eye drop.

[0125] A pharmaceutically acceptable excipient can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a pharmaceutical agent. Such physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients. The choice of a pharmaceutically acceptable excipient, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition can be a self emulsifying drug delivery system or a selfmicroemulsifying drug delivery system. The pharmaceutical composition (preparation) also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the invention. Liposomes, for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.

[0126] A pharmaceutical composition can be administered to a subject by any of a number of routes of administration including, for example, orally, for example, aqueous or non-aqueous solutions or suspensions, tablets, capsules, including sprinkle capsules and gelatin capsules, boluses, powders, granules, pastes for application to the tongue; absorption through the oral mucosa, e.g., sublingually; anally, rectally or vaginally, for example, as a pessary, cream or foam; parenterally, including intramuscularly, intravenously, subcutaneously or intrathecally as, for example, a sterile solution or suspension; nasally; intraperitoneally; subcutaneously; transdermally, for example, as a patch applied to the skin; and topically, for example, as a cream, ointment or spray applied to the skin, or as an eye drop. The compound may also be formulated for inhalation. In certain embodiments, a compound may be simply dissolved or suspended in sterile water.

[0127] A pharmaceutical composition may be a sterile aqueous or non-aqueous solution, suspension or emulsion, e.g., a microemulsion. The excipients described herein are examples and are in no way limiting. An effective amount or therapeutically effective amount refers to an amount of the one or more pharmaceutical agents administered to a subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.

[0128] Subjects may generally be monitored for therapeutic effectiveness using assays and methods suitable for the condition being treated, which assays will be familiar to those having ordinary skill in the art and are described herein. Pharmacokinetics of a pharmaceutical agent, or one or more metabolites thereof, that is administered to a subject may be monitored by determining the level of the pharmaceutical agent or metabolite in a biological fluid, for example, in the blood, blood fraction, e.g., serum, and / or in the urine, and / or other biological sample or biological tissue from the subject. Any method practiced in the art and described herein to detect the agent may be used to measure the level of the pharmaceutical agent or metabolite during a treatment course.

[0129] The dose of a pharmaceutical agent described herein for treating a disease or disorder may depend upon the subject’s condition, that is, stage of the disease, severity of symptoms caused by the disease, general health status, as well as age, gender, and weight, and other factorsapparent to a person skilled in the medical art. Pharmaceutical compositions may be administered in a manner appropriate to the disease to be treated as determined by persons skilled in the medical arts. In addition to the factors described herein and above related to use of pharmaceutical agent for treating a disease or disorder, suitable duration and frequency of administration of the pharmaceutical agent may also be determined or adjusted by such factors as the condition of the patient, the type and severity of the patient’s disease, the particular form of the active ingredient, and the method of administration. Optimal doses of an agent may generally be determined using experimental models and / or clinical trials. The optimal dose may depend upon the body mass, weight, or blood volume of the subject. The use of the minimum dose that is sufficient to provide effective therapy is usually preferred. Design and execution of pre-clinical and clinical studies for a pharmaceutical agent, including when administered for prophylactic benefit, described herein are well within the skill of a person skilled in the relevant art. When two or more pharmaceutical agents are administered to treat a disease or disorder, the optimal dose of each pharmaceutical agent may be different, such as less than when either agent is administered alone as a single agent therapy. In certain particular embodiments, two pharmaceutical agents in combination may act synergistically or additively, and either agent may be used in a lesser amount than if administered alone. The optimal dose, per day or per course of treatment, may be different for the disease or disorder to be treated and may also vary with the administrative route and therapeutic regimen.

[0130] Pharmaceutical compositions comprising a pharmaceutical agent can be formulated in a manner appropriate for the delivery method by using techniques routinely practiced in the art. The composition may be in the form of a solid, e.g, tablet, capsule, semi-solid, e.g, gel, liquid, or gas, e.g., aerosol. In other embodiments, the pharmaceutical composition is administered as a bolus infusion.

[0131] Pharmaceutical acceptable excipients are well known in the pharmaceutical art and described, for example, in Rowe et al., Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties, and Safety, 5thEd., 2006, and in Remington: The Science and Practice of Pharmacy (Gennaro, 21stEd. Mack Pub. Co., Easton, PA (2005)). Exemplary pharmaceutically acceptable excipients include sterile saline and phosphate buffered saline at physiological pH. Preservatives, stabilizers, dyes, buffers, and the like may be provided in the pharmaceutical composition. In addition, antioxidants and suspending agents may also be used. In general, the type of excipient is selected based on the mode of administration, as well as the chemical composition of the active ingredient(s). Alternatively, compositions describedherein may be formulated as a lyophilizate. A composition described herein may be lyophilized or otherwise formulated as a lyophilized product using one or more appropriate excipient solutions for solubilizing and / or diluting the pharmaceutical agent(s) of the composition upon administration. In other embodiments, the pharmaceutical agent may be encapsulated within liposomes using technology known and practiced in the art. In certain particular embodiments, a pharmaceutical agent is not formulated within liposomes for application to a stent that is used for treating highly, though not totally, occluded arteries. Pharmaceutical compositions may be formulated for any appropriate manner of administration described herein and in the art.

[0132] A pharmaceutical composition, e.g., for oral administration or for injection, infusion, subcutaneous delivery, intramuscular delivery, intraperitoneal delivery or other method, may be in the form of a liquid. A liquid pharmaceutical composition may include, for example, one or more of the following: a sterile diluent such as water, saline solution, preferably physiological saline, Ringer’s solution, isotonic sodium chloride, fixed oils that may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial agents; antioxidants; chelating agents; buffers and agents for the adjustment of tonicity such as sodium chloride or dextrose. A parenteral composition can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. The use of physiological saline is preferred, and an injectable pharmaceutical composition is preferably sterile. In another embodiment, for treatment of an ophthalmological condition or disease, a liquid pharmaceutical composition may be applied to the eye in the form of eye drops. A liquid pharmaceutical composition may be delivered orally.

[0133] For oral formulations, at least one of the pharmaceutical agents described herein can be used alone or in combination with appropriate additives to make tablets, powders, granules or capsules, and if desired, with diluents, buffering agents, moistening agents, preservatives, coloring agents, and flavoring agents. The pharmaceutical agents may be formulated with a buffering agent to provide for protection of the compound from low pH of the gastric environment and / or an enteric coating. A pharmaceutical agent included in a pharmaceutical composition may be formulated for oral delivery with a flavoring agent, e.g., in a liquid, solid or semi-solid formulation and / or with an enteric coating.

[0134] A pharmaceutical composition comprising any one of the pharmaceutical agents described herein may be formulated for sustained or slow release, also called timed release or controlled release. Such compositions may generally be prepared using well known technology and administered by, for example, oral, rectal, intradermal, or subcutaneous implantation, or byimplantation at the desired target site. Sustained-release formulations may contain the compound dispersed in a carrier matrix and / or contained within a reservoir surrounded by a rate controlling membrane. Excipients for use within such formulations are biocompatible, and may also be biodegradable; preferably the formulation provides a relatively constant level of active component release. The amount of pharmaceutical agent contained within a sustained release formulation depends upon the site of implantation, the rate and expected duration of release, and the nature of the condition, disease or disorder to be treated or prevented.

[0135] In certain embodiments, the pharmaceutical compositions comprising a pharmaceutical agent are formulated for transdermal, intradermal, or topical administration. The compositions can be administered using a syringe, bandage, transdermal patch, insert, or syringe-like applicator, as a powder / talc or other solid, liquid, spray, aerosol, ointment, foam, cream, gel, paste. This preferably is in the form of a controlled release formulation or sustained release formulation administered topically or injected directly into the skin adjacent to or within the area to be treated, e.g., intradermally or subcutaneously. The active compositions can also be delivered via iontophoresis. Preservatives can be used to prevent the growth of fungi and other microorganisms. Suitable preservatives include, but are not limited to, benzoic acid, butylparaben, ethyl paraben, methyl paraben, propylparaben, sodium benzoate, sodium propionate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetypyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, thimerosal, and combinations thereof.

[0136] Pharmaceutical compositions comprising a pharmaceutical agent can be formulated as emulsions for topical application. An emulsion contains one liquid distributed in the body of a second liquid. The emulsion may be an oil-in-water emulsion or a water-in-oil emulsion. Either or both of the oil phase and the aqueous phase may contain one or more surfactants, emulsifiers, emulsion stabilizers, buffers, and other excipients. The oil phase may contain other oily pharmaceutically approved excipients. Suitable surfactants include, but are not limited to, anionic surfactants, non-ionic surfactants, cationic surfactants, and amphoteric surfactants. Compositions for topical application may also include at least one suitable suspending agent, antioxidant, chelating agent, emollient, or humectant.

[0137] Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and / or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. Liquid sprays may be delivered from pressurized packs, for example, via a specially shapedclosure. Oil-in-water emulsions can also be used in the compositions, patches, bandages and articles. These systems are semisolid emulsions, micro-emulsions, or foam emulsion systems.

[0138] In some embodiments, the pharmaceutical agent described herein can be formulated as in inhalant. Inhaled methods can deliver medication directly to the airway. The pharmaceutical agent can be formulated as aerosols, microspheres, liposomes, or nanoparticles. The pharmaceutical agent can be formulated with solvents, gases, nitrates, or any combinations thereof. Compositions described herein are optionally formulated for delivery as a liquid aerosol or inhalable dry powder. Liquid aerosol formulations are optionally nebulized predominantly into particle sizes that can be delivered to the terminal and respiratory bronchioles. Liquid aerosol and inhalable dry powder formulations are preferably delivered throughout the endobronchial tree to the terminal bronchioles and eventually to the parenchymal tissue.

[0139] Aerosolized formulations described herein are optionally delivered using an aerosol forming device, such as a jet, vibrating porous plate or ultrasonic nebulizer, preferably selected to allow the formation of aerosol particles having with a mass medium average diameter predominantly between 1 to 5 p. Further, the formulation preferably has balanced osmolarity ionic strength and chloride concentration, and the smallest aerosolizable volume able to deliver effective dose of the pharmaceutical agent. Additionally, the aerosolized formulation preferably does not impair negatively the functionality of the airways and does not cause undesirable side effects.

[0140] Aerosolization devices suitable for administration of aerosol formulations described herein include, for example, jet, vibrating porous plate, ultrasonic nebulizers and energized dry powder inhalers, that are able to nebulize the formulation into aerosol particle size predominantly in the size range from 1-5 p. Predominantly in this application means that at least 70% but preferably more than 90% of all generated aerosol particles are within 1-5 p range. A jet nebulizer works by air pressure to break a liquid solution into aerosol droplets. Vibrating porous plate nebulizers work by using a sonic vacuum produced by a rapidly vibrating porous plate to extrude a solvent droplet through a porous plate. An ultrasonic nebulizer works by a piezoelectric crystal that shears a liquid into small aerosol droplets. A variety of suitable devices are available, including, for example, AeroNebTM and AeroDoseTM vibrating porous plate nebulizers (AeroGen, Inc., Sunnyvale, California), Sidestream® nebulizers (Medic- Aid Ltd., West Sussex, England), Pari LC® and Pari LC Star® jet nebulizers (Pari Respiratory Equipment, Inc., Richmond, Virginia), and AerosonicTM (DeVilbiss Medizinische Produkte(Deutschland) GmbH, Heiden, Germany) and UltraAire® (Omron Healthcare, Inc., Vernon Hills, Illinois) ultrasonic nebulizers.

[0141] In some embodiments, the pharmaceutical agent(s) can be formulated with oleaginous bases or ointments to form a semisolid composition with a desired shape. In addition to the pharmaceutical agent, these semisolid compositions can contain dissolved and / or suspended bactericidal agents, preservatives and / or a buffer system. A petrolatum component that may be included may be any paraffin ranging in viscosity from mineral oil that incorporates isobutylene, colloidal silica, or stearate salts to paraffin waxes. Absorption bases can be used with an oleaginous system. Additives may include cholesterol, lanolin (lanolin derivatives, beeswax, fatty alcohols, wool wax alcohols, low HLB (hydrophobic lipophobice balance) emulsifiers, and assorted ionic and nonionic surfactants, singularly or in combination.

[0142] Controlled or sustained release transdermal or topical formulations can be achieved by the addition of time-release additives, such as polymeric structures, matrices, that are available in the art. For example, the compositions may be administered through use of hot-melt extrusion articles, such as bioadhesive hot-melt extruded film. The formulation can comprise a crosslinked polycarboxylic acid polymer formulation. A cross-linking agent may be present in an amount that provides adequate adhesion to allow the system to remain attached to target epithelial or endothelial cell surfaces for a sufficient time to allow the desired release of the compound.

[0143] An insert, transdermal patch, bandage or article can comprise a mixture or coating of polymers that provide release of the pharmaceutical agents at a constant rate over a prolonged period of time. In some embodiments, the article, transdermal patch or insert comprises water- soluble pore forming agents, such as polyethylene glycol (PEG) that can be mixed with water insoluble polymers to increase the durability of the insert and to prolong the release of the active ingredients.

[0144] Transdermal devices (inserts, patches, bandages) may also comprise a water insoluble polymer. Rate controlling polymers may be useful for administration to sites where pH change can be used to effect release. These rate controlling polymers can be applied using a continuous coating film during the process of spraying and drying with the active compound. In one embodiment, the coating formulation is used to coat pellets comprising the active ingredients that are compressed to form a solid, biodegradable insert.

[0145] A polymer formulation can also be utilized to provide controlled or sustained release. Bioadhesive polymers described in the art may be used. By way of example, a sustained-releasegel and the compound may be incorporated in a polymeric matrix, such as a hydrophobic polymer matrix. Examples of a polymeric matrix include a microparticle. The microparticles can be microspheres, and the core may be of a different material than the polymeric shell. Alternatively, the polymer may be cast as a thin slab or film, a powder produced by grinding or other standard techniques, or a gel such as a hydrogel. The polymer can also be in the form of a coating or part of a bandage, stent, catheter, vascular graft, or other device to facilitate delivery of the pharmaceutical agent. The matrices can be formed by solvent evaporation, spray drying, solvent extraction and other methods known to those skilled in the art.

[0146] Kits with unit doses of one or more of the agents described herein, usually in oral or injectable doses, are provided. Such kits may include a container containing the unit dose, an informational package insert describing the use and attendant benefits of the drugs in treating disease, and optionally an appliance or device for delivery of the composition.Therapeutic Applications

[0147] In some embodiments, the present disclosure provides a method of antagonizing a GPR55 receptor(s) in a subject comprising administering an effective amount of a compound or salt thereof of Formula (I), Formula (II), Formula (Illa), Formula (Illb), Formula (IVa), or Formula (IVb). In some cases, the activity of the GPR55 receptor is reduced. In some cases, the method comprises antagonizing a GPR55 receptor(s) by administering a pharmaceutical composition comprising a compound or salt thereof of Formula (I), Formula (II), Formula (Illa), Formula (Illb), Formula (IVa), or Formula (IVb); and a pharmaceutically acceptable excipient. In some cases, the activity of the GPR55 receptor is reduced. As used herein, “antagonizing a GRP55 receptor(s)” refers to completely or partially blocking the interaction of a GPR55 receptor(s) with a ligand and / or down-modulating signaling or other biological response by a GPR55 receptor in response to a ligand binding to the receptor.

[0148] In some embodiments, provided is a method of treating a GPR55+ disease, disorder or condition by administering to a subject having the GPR55+ disease, disorder or condition an effective amount of a compound or salt thereof of Formula (I), Formula (II), Formula (Illa), Formula (Illb), Formula (IVa), or Formula (IVb); or a pharmaceutical composition thereof. In some embodiments, described herein is a method of treating, preventing, delaying of progress, or ameliorating symptoms of a disease or a condition associated with GPR55 activity activity level in a subject in need thereof, comprising administering a therapeutically effective amount of a compound or salt thereof of Formula (I), Formula (II), Formula (Illa), Formula (Illb), Formula(IVa), or Formula (IVb); or a pharmaceutical composition thereof, wherein the GPR55 activity level is reduced. In some cases, the symptom of the disease disorder or condition is ameliorated.

[0149] In some cases, the disease, disorder, or condition is cancer. In some cases, the cancer is metastatic cancer. In some cases, the cancer is selected from pancreatic cancer, brain cancer, colon cancer and ER+ breast cancer. In some cases, the cancer is a metastatic cancer selected from pancreatic cancer, brain cancer, colon cancer and ER+ breast cancer. In some cases, the progression of the cancer is reduced.

[0150] In some embodiments, provided is a method of treating a disease, disorder, or condition associated with GPR55 receptor activity, comprising administering to a subject having the disease, disorder or condition, a compound or salt thereof of Formula (I), Formula (II), Formula (Illa), Formula (Illb), Formula (IVa), or Formula (IVb), or a pharmaceutical composition of any one thereof.

[0151] In some aspects, the disease, disorder, or condition is cancer. In some embodiments, the cancer is metastatic cancer. In some embodiments, the cancer is selected from pancreatic cancer, brain cancer, colon cancer and ER+ breast cancer. In some embodiments, the cancer is a metastatic cancer selected from pancreatic cancer, brain cancer, colon cancer and ER+ breast cancer. In some cases, the cancer is a metastatic cancer selected from pancreatic cancer, brain cancer, colon cancer and ER+ breast cancer. In some cases, the progression of the cancer is reduced.

[0152] In some aspects, the disease, disorder, or condition is epilepsy. In some aspects, the disease, disorder, or condition is a seizure or seizures. In some aspects, the disease, disorder, or condition is a seizure or seizures associated with epilepsy. In some embodiments, the seizure or seizures are selected from generalized or partial seizures. In some embodiments, the seizure or seizures are associated with a pediatric epilepsy. In some embodiments, the pediatric epilepsy is Dravet syndrome or Lennox-Gastaut syndrome. In some embodiments, the epilepsy is temporal lobe epilepsy.

[0153] In some aspects, the disease, disorder, or condition is pain. In some embodiments, the pain is selected from neuropathic pain, inflammatory pain, or visceral pain. In some embodiments, the pain is neuropathic pain. In some embodiments, the pain is inflammatory pain. In some embodiments, the pain is visceral pain.Preparation of Compounds

[0154] The compounds of the present disclosure can generally be prepared in a number of ways well known to those skilled in the art of organic synthesis. By way of example, compounds ofthe present disclosure can be synthesized using the methods described herein, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereof as appreciated by those skilled in the art.EXAMPLES

[0155] The following examples are offered to illustrate, but not to limit the claimed invention. It will be recognized that these preparation methods are illustrative and not limiting. Using the teaching provided herein, numerous other methods of producing the compounds described herein will be available to one of skill in the art.General Information

[0156] General information on 1H NMR, LC-MS and HPLC: 1H NMR of samples were recorded on a Avance Neo 400 system; LC-MS data were recorded on an ESI by using Column: AGILENT 010 XB RIDGE and Shimazu 3.5 pm, 3.0*50mm,C18 (Mobile phase: 0.1% Formic acid in Water(A) / ACN(B) Gradient / (time / %B): 0.0 / 10, 2 / 95, 4.0 / 95,4.1 / 10,4.5 / 10; Flow: 1 mL / min); and HPLC data were recorded on Column:- YMC-Trairts C18150x4.6mm, 5p; Mobile Phase:- A;-0.1% TFA in Aq , B:-ACN Gradient:- T / %B:- 0 / 30,1 / 70,6 / 100,8 / 100,10 / 30, 12 / 30; Flow Rate:- 1 mL / min; Colum temp: 40°C.

[0157] Unless indicated otherwise in the following Examples, the compounds are isolated as a racemic mixture.

[0158] Abbreviations: The following abbreviations may be relevant for the application.AcOH: acetic acidDIPEA: N,N-diisopropylethylamineDMF : dimethylformamideDMSO: dimethylsulfoxideEq or eq equivalentEtOAc: ethyl acetateEtOH: ethanol g: gramsH or h: hoursHATU : ( 1 - [bi s(dimethylamino)m ethylene] - 1 H- l,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphateHOBt: hydroxybenzotriazoleHPLC: high performance liquid chromatographyLC-MS: liquid chromatography-mass spectrometryPrep HPLC: preparative high performance liquid chromatographyPOCl3: phosphorus oxychloride rt or RT: room temperatureTFA: trifluoroacetic acidTHF: tetrahydrofuranTLC: thin layer chromatographyVol or vol volume(s)GENERAL PROCEDURESGeneral Procedure 1: Synthesis of substituted quinoline based compoundsGeneral Procedure 1A. Synthesis of Intermediates 1a-1hSynthesis of 6,8-Dimethyl-2-(pyridin-2-yl) quinoline-4-carboxylic acid (Intermediate 1a)

[0159] To a stirred solution of 5, 7-dimethylindoline-2, 3-dione (1 eq), 1-(pyridin-2-yl) ethan-1- one (1 eq) in water (10 vol) was added KOH (5 eq) and the mixture was heated for 4 h at 100°C. The reaction was monitored by TLC. After TLC indicated the reaction was complete, the reaction mixture was cooled to room temperature (rt) and acidified by using 2 N HC1. The precipitatedsolid was filtered, washed with water and dried to obtained Intermediate 1a as white solid. LC- MS: 279.0 [M+H]+.Synthesis of 6,8-Dimethyl-2-(pyridin-3-yl) quinoline-4-carboxylic acid (Intermediate 1b)

[0160] Intermediate 1b was synthesized by General Procedure 1 A using 5,7-dimethylindoline-2, 3-dione (1 eq), 1-(pyri din-3 -yl) ethan-1-one (1 eq), and KOH (5 eq) in water (10 vol). Intermediate lb was obtained as a white solid. LC-MS: 279.0 [M+H]+.Synthesis of 2-(2-Chlorophenyl)-6,8-dimethylquinoline-4-carboxylic acid (Intermediate 1c)

[0161] Intermediate 1c was synthesized by General Procedure 1A using 5,7-dimethylindoline-2, 3-dione (1 eq) and 1-(2-chlorophenyl) ethan-1-one (1 eq) and KOH (5 eq) in water (10 vol). Intermediate 1c was obtained as a white solid. LC-MS: 312.0 [M+H]+.Synthesis of 2-(2-(difluoromethyl)phenyl)-6,8-dimethylquinoline-4-carboxylic acid ) (Intermediate Id)

[0162] Intermediate 1d was synthesized by General Procedure 1A using 5,7-dimethylindoline-2, 3-dione (1 eq), 1-(2-(difluoromethyl)phenyl)ethan-1-one (1 eq) and KOH (5 eq) in water (10 Vol). Intermediate 1d was obtained as white solid. LC-MS: 328.2 [M+H]+.Synthesis of 6,8-dimethyl-2-(o-tolyl)quinoline-4-carboxylic acid (Intermediate 1e)

[0163] Intermediate 1e was synthesized by General Procedure 1A using 5,7-dimethylindoline-2, 3-dione (1 eq), 1-(o-tolyl)ethan-1-one (1 eq) and KOH (5 eq) in water (10 Vol). Intermediate le was obtained as a white solid. LC-MS: 292.1 [M+H]+.Synthesis of 2-(2-methoxyphenyl)-6,8-dimethylquinoline-4-carboxylic acid (Intermediate If)

[0164] Intermediate 1f was synthesized by General Procedure 1A using 5,7-dimethylindoline-2, 3-dione (1 eq), 1-(2-methoxyphenyl) ethan-1-one (1 eq) and KOH (5 eq) in water (10 vol). Intermediate 1f was obtained as a white solid. LC-MS: 307.95 [M+H]+Synthesis of 2-(furan-2-yl)-6,8-dimethylquinoline-4-carboxylic acid (Intermediate 1g)

[0165] Intermediate 1g was synthesized by General Procedure 1 A using 5,7-dimethylindoline-2, 3-dione (1 eq), 1-(furan-2-yl)ethan-1-one (1 eq) and KOH (5 eq) in water (10 Vol). Intermediate 1g was obtained as a white solid. LC-MS: 268.2 [M+H]+Synthesis of 6,8-dimethyl-2-(tetrahydrofuran-2-yl) quinoline-4-carboxylic acid (Intermediate 1h)

[0166] Intermediate 1h was synthesized following General Procedure 1A using 5,7- dimethylindoline-2,3-dione (1 eq), 1-(tetrahydrofuran-2-yl)ethan-1-one (1 eq) and KOH (10 eq) in water (10 vol). Intermediate Ih was obtained as a white solid. LC-MS: 272.2 [M+H]+.General Procedure IB. Synthesis of intermediates 2a-2hSynthesis of methyl 4-(6,8-dimethyl-2-(pyridin-2-yl) quinoline-4-carboxamido) benzoate (Intermediate 2a)

[0167] To a stirred solution 6,8-dimethyl-2-(pyridin-2-yl) quinoline-4-carboxylic acid (Intermediate la; 1 eq) in DMF (10 vol) were added HATU (1.5 eq), DIPEA (3 eq), and methyl 4-aminobenzoate (1 eq) at room temperature. The mixture was heated to 50°C. and then was stirred for 12 hours. After thin layer chromatograhy (TLC) indicated reaction completion, the mixture was diluted with water and EtOAc. The organic layer was separated and then washed with brine solution, dried over Na2SO4and filtered. The solvent was concentrated in vacuo. The crude material was purified by Comb-flash to afford Intermediate 2a as a brown solid. LC-MS: 412.5 [M+H]+.Synthesis of methyl 4-(6,8-dimethyl-2-(pyridin-3-yl) quinoline-4-carboxamido) benzoate (Intermediate 2b)

[0168] Intermediate 2b was synthesized by General Procedure 1B using 6,8-dimethyl-2-(pyridin- 3-yl) quinoline-4-carboxylic acid (Intermediate la; 1 eq) in DMF (10 vol), HATU (1.2 eq), DIPEA (3 eq), and methyl 4-aminobenzoate (1 eq). Intermediate 2b was obtained) as a white solid. LC- MS: 412.10 [M+H]+.Synthesis of methyl 4-(2-(2-chlorophenyl)-6,8-dimethylquinoline-4-carboxamido) benzoate (Intermediate 2c)

[0169] Intermediate 2c was synthesized using General Procedure 1B using 2-(2-chlorophenyl)- 6,8-dimethylquinoline-4-carboxylic acid (Intermediate 1c; 1 eq) in DMF (20 vol), HATU (1.2 eq), DIPEA (3 eq), and methyl 4-aminobenzoate (1 eq). Intermediate 2c was obtained as a white solid. LC-MS:445.10 [M+H]+.Synthesis of methyl 4-(2-(2-(difluoromethyl)phenyl)-6,8-dimethylquinoline-4- carboxamido)benzoate (Intermediate 2d)

[0170] Intermediate 2d was synthesized following General Procedure 1B using 2-(2- (difluoromethyl)phenyl)-6,8-dimethylquinoline-4-carboxylic acid (Intermediate 1d, 1 eq) in DMF (10 vol), HATU (1.5 eq), DIPEA (5 eq), and methyl 4-aminobenzoate (1 eq). Intermediate 2d was obtained as white solid. LC-MS: 461.10 [M+H]+.Synthesis of methyl 4-(2-(2-(di Methyl 4-(6,8-dimethyl-2-(o-tolyl)quinoline-4- carboxamido)benzoate (Intermediate 2e)

[0171] Intermediate 2e was synthesized by General Procedure 1B using 6,8-dimethyl-2-(o- tolyl)quinoline-4-carboxylic acid (Intermediate le; 1 eq) in DMF (10 vol), HATU (1.5 eq), DIPEA (5 eq) and methyl 4-aminobenzoate 4 (1 eq). Intermediate 2e was obtained as a white solid. LC- MS: 423.05 [M-H]-.Synthesis of methyl 4-(2-(2-methoxyphenyl)-6,8-dimethylquinoline-4-carboxamido) benzoate (Intermediate 2f)

[0172] Intermediate 2f was synthesized by General Procedure 1B using 2-(2-methoxyphenyl)- 6,8-dimethylquinoline-4-carboxylic acid (Intermediate 1f; 1 eq), HATU (1.5 eq), DIPEA (5 eq) and methyl 4-aminobenzoate (1 eq) in DMF (10 vol). Intermediate 2f was obtained as a white solid. LC-MS: 440.10 [M+H]+.Synthesis of methyl 4-(2-(furan-2-yl)-6,8-dimethylquinoline-4-carboxamido) benzoate (Intermediate 2g)

[0173] Intermediate 2g was synthesized by General Procedure 1B using 2-(furan-2-yl)-6,8- dimethylquinoline-4-carboxylic acid (Intermediate 1g; 1 eq), HATU (1.5 eq), DIPEA (5 eq) and methyl 4-aminobenzoate (1 eq) in DMF (10 vol). Intermediate 2g was obtained as a white solid. LC-MS: 399.00 [M+H]+.Synthesis of methyl 4-(6,8-dimethyl-2-(tetrahydrofuran-2-yl) quinoline-4-carboxamido) benzoate (Intermediate 2h)

[0174] Intermediate 2h was synthesized by General Procedure 1B using 6,8-dimethyl-2- (tetrahydrofuran-2-yl)quinoline-4-carboxylic acid (Intermediate 1h; 1 eq), HATU (1.5 eq), DIPEA (5 eq) and methyl 4-aminobenzoate (1 eq) in DMF (10 vol). Intermediate 2h was obtained as a white solid. LC-MS: 405.05 [M+H]+.Synthesis of methyl 5-(2-(2-chlorophenyl)-6,8-dimethylquinoline-4-carboxamido) picolinate (Intermediate 2i)

[0175] Intermediate 2i was synthesized by General Procedure 1B using 2-(2-chlorophenyl)-6,8- dimethylquinoline-4-carboxylic acid (Intermediate 1c; 1 eq), HATU (1.5 eq), DIPEA (5 eq) and methyl 5-aminopicolinate (1 eq) in DMF (10 vol). Intermediate 2i was obtained as a white solid. LC-MS: 446.2 [M+H]+.Synthesis of methyl 6-(2-(2-chlorophenyl)-6,8-dimethylquinoline-4-carboxamido)nicotinate (Intermediate 2j)

[0176] Intermediate 2j was synthesized by General Procedure 1B using 2-(2-chlorophenyl)-6,8- dimethylquinoline-4-carboxylic acid (Intermediate 1c; 1 eq), HOBt (1.2 eq), DIC (1.2 eq) and methyl 6-aminonicotinate (1.5 eq) in DMF (10 vol). Intermediate 2j was obtained as a white solid. LC-MS: 446.10 [M+H]+.Synthesis of methyl 4-(2-(2-chlorophenyl)-6,8-dimethylquinoline-4-carboxamido)-2- fluorobenzoate (Intermediate 2k)

[0177] Intermediate 2k was synthesized by General Procedure 1B using 2-(2-chlorophenyl)-6,8- dimethylquinoline-4-carboxylic acid (Intermediate 1c; 1 eq), HATU (1.5 eq), DIPEA (5 eq) and methyl 4-amino-2-fluorobenzoate (1 eq) in DMF (10 vol). Intermediate 2k was obtained as a white solid. LC-MS: 461.10 [M+H]+.General Procedure 1C. Synthesis of Intermediates 3a-3kSynthesis of 4-(6,8-dimethyl-2-(pyridin-2-yl) quinoline-4-carboxamido) benzoic acid (Intermediate 3a)

[0178] To a stirred solution of methyl 4-(6,8-dimethyl-2-(pyridin-2-yl) quinoline-4- carboxamido) benzoate (Intermediate 2a; 1 eq) in THF: MeOH: H2O (3: 1 : 1) (10 vol) was added LiOH H2O (2 eq) and the mixture was stirred at room temperature for 2.5 h. The reaction was monitored by TLC. After completion, the reaction mixture was concentrated, acidified with 2N HC1 solution (pH=6.5), filtered, washed with water and dried under vacuum to afford Intermediate 3a as a white solid. LC-MS: 398.0 [M+H]+.Synthesis of 4-(6,8-dimethyl-2-(pyridin-3-yl) quinoline-4-carboxamido) benzoic acid (Intermediate 3b)

[0179] Intermediate 3b was synthesized by General Procedure 1C using methyl 4-(6,8-dimethyl- 2-(pyridin-3-yl) quinoline-4-carboxamido) benzoate (Intermediate 2b; 1 eq) in THF: MeOH: H2O (3: 1 : 1) (10 vol) and LiOH H2O (2 eq). Intermediate 3b was obtained as a white solid. LC-MS: 398.0 [M+H]+.Synthesis of 4-(2-(2-chlorophenyl)-6,8-dimethylquinoline-4-carboxamido) benzoic acid (Intermediate 3c)

[0180] Intermediate 3c was synthesized by General Procedure 1C using methyl 4-(2-(2- chlorophenyl)-6,8-dimethylquinoline-4-carboxamido) benzoate (Intermediate 2c; 1 eq) in THF: MeOH: H2O (3: 1 : 1) (10 vol) and LiOH H2O (2 eq). Intermediate 3c was obtained as a white solid. LC-MS: 431.5 [M+H]+.4-(2-(2-Chlorophenyl)-6,8-dimethylquinoline-4-carboxamido) benzoic acid (Intermediate 3d)

[0181] Intermediate 3d was synthesized by General Procedure 1C using methyl (4-2-(2- (difluoromethyl)phenyl)-6,8-dimethylquinoline-4-carboxamido)benzoate (Intermediate 2d; 1 eq) in THF: MeOH: H2O (3: 1 : 1) (10 vol), LiOH H2O (6 eq). Intermediate 3d was obtained as a white solid. LC-MS: 447.50 [M+H]+.4-(6,8-dimethyl-2-(o-tolyl)quinoline-4-carboxamido)benzoic acid (Intermediate 3e)

[0182] Intermediate 3e was synthesized by General Procedure 1C using methyl 4-(6,8-dimethyl- 2-(o-tolyl)quinoline-4-carboxamido)benzoate (Intermdiate 2e; 1 eq) in THF: MeOH: H2O (3: 1 : 1) (10 vol) and LiOH H2O (5 eq). Intermediate 3e was obtained as a white solid. LC-MS: 411.10 [M+H]+.4-(2-(2-methoxyphenyl)-6,8-dimethylquinoline-4-carboxamido) benzoic acid (Intermediate 3f):

[0183] Intermediate 3f was synthesized by General Procedure 1C using methyl 4-(2-(2- methoxyphenyl)-6,8-dimethylquinoline-4-carboxamido)benzoate (Intermediate 2f; 1 eq) and LiOH H2O (5 eq) in THF: MeOH: H2O (3: 1 : 1, 10 vol). Intermediate 3f was obtained as a white solid. LC-MS: 427.00 [M+H]+.4-(2-(furan-2-yl)-6,8-dimethylquinoline-4-carboxamido) benzoic acid (Intermediate 3g)

[0184] Intermediate 3g was synthesized by General Procedure 1C using methyl 4-(2-(furan-2- yl)-6,8-dimethylquinoline-4-carboxamido)benzoate and (Intermediate 2g; 1 eq), and LiOH H2O (5 eq) in THF: MeOH: H2O (3: 1 : 1, 10 vol). Intermediate 3g was obtained as a white solid. LC- MS: 447.50 [M+H]+.4-(6,8-dimethyl-2-(tetrahydrofuran-2-yl) quinoline-4-carboxamido) benzoic acid (Intermediate 3h)

[0185] Intermediate 3h was synthesized by General Procedure 1C using methyl 4-(6,8-dimethyl- 2-(tetrahydrofuran-2-yl)quinoline-4-carboxamido)benzoate (Intermediate 1 eq) and LiOH H2O (6 eq) in THF : MeOH: H2O (3: 1 : 1, 10 vol). Intermediate 3h was obtained as a white solid. LC-MS: 391.15[M+H]+.5-(2-(2-chlorophenyl)-6,8-dimethylquinoline-4-carboxamido) picolinic acid (Intermediate

[0186] Intermediate 3i was synthesized by General Procedure 1C using methyl 5-(2-(2- chlorophenyl)-6,8-dimethylquinoline-4-carboxamido) picolinate (Intermediate 2i; 1 eq) and LiOH H2O (1 eq) in THF: MeOH: H2O (3: 1 : 1, 10 vol). Intermediate 3i was obtained as a white solid. LC-MS: 432.05 [M+H]+.6-(2-(2-chlorophenyl)-6,8-dimethylquinoline-4-carboxamido) nicotinic acid (Intermediate 3j)

[0187] Intermediate 3j was synthesized by General Procedure 1C using methyl 6-(2-(2- chlorophenyl)-6,8-dimethylquinoline-4-carboxamido)nicotinate (Intermediate 2j; 1 eq) and LiOH H2O (5 eq) in THF: MeOH: H2O (3: 1 : 1, 10 vol). Intermediate 3j was obtained as a white solid. LC-MS: 432.05 [M+H]+.4-(2-(2-chlorophenyl)-6,8-dimethylquinoline-4-carboxamido)-2-fluorobenzoic acid (Intermediate 3k)

[0188] Intermediate 3k was synthesized by General Procedure 1C using methyl 4-(2-(2- chlorophenyl)-6,8-dimethylquinoline-4-carboxamido)-2-fluorobenzoate (Intermediate 2k; 1 eq) and LiOH H2O (6 eq) in THF: MeOH: H2O (3: 1: 1, 10 vol). Intermediate 3k was obtained as a white solid. LC-MS: 447.50 [M+H]+.General Procedure ID for the Synthesis of the Final Compounds

[0189] To a stirred solution of Intermediate 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j or 3k (1 eq.) in DMF (10 Vol) at 0°C were added HATU (1.2 eq) and DIPEA (2 eq.), the appropriate amine (1 eq.) and the reaction mixture was stirred for 3 h at 50°C. The reaction was monitored by TLC and after completion the reaction mixture was diluted with water (10 Vol) and EtOAc (20 Vol). The organic layer was separated and washed with brine solution (10 Vol) and dried with Na2SO4, filtered, and concentrated in vacuo. The crude compounds were purified by prep HPLC to afford the final compounds.General Procedure IE for the Synthesis of the Final Compounds

[0190] To a stirred solution of Intermediate 3a, 3b or 3c or 3e (1 eq) in pyridine (10 vol) and the appropriate amine (1 eq.) was added POCI3 (3 eq) dropwise at 0 °C. The reaction mixture was brought to room temperature and stirred for 15 min. The reaction was monitored by TLC and after completion the reaction mixture was diluted with water (10 Vol) and EtOAc (20 Vol). The organic layer was separated and washed with brine solution (10 Vol) and then dried with Na2SO4, filtered, and concentrated in vacuo. The crude compounds were purified by prep HPLC to afford the final compounds.IllGeneral Procedure 2: Synthesis of substituted quinazoline based compounds.Scheme 2General Procedure 2A. Sodium 2-(2-aminophenyl)-2-oxoacetate (Intermediate 4a)

[0191] Indoline-2, 3-dione (1 eq) was added to a solution of NaOH solution (1.2 eq) in water (10 vol) and the mixture was stirred for 2 h at RT. When TLC indicated a complete reaction, the mass was neutralized with 2N HC1 until reaching pH 7. The solvents were removed on a rotary evaporator at 45°C. Then, the precipitate was crystallized from a DMF-ethyl acetate mixture and dried in vacuo to afford compound Intermediate 4a as a brown solid. LC-MS: 187.00 [M+H]+.Sodium 2-(2-amino-5-methylphenyl)-2-oxoacetate (Intermediate 4b)

[0192] Intermediate 4b was synthesized by General Procedure 2A using 5 -methylindoline-2, 3- dione (1 eq) in aq. NaOH solution (2 eq). The solution was stirred for 2 h at RT. Intermediate 4b was obtained as a brown solid.Sodium 2-(2-amino-4-methylphenyl)-2-oxoacetate (Intermediate 4c)

[0193] Intermediate 4c was synthesized by General Procedure 2A using 6-methylindoline-2,3- dione (1 eq) in aq. NaOH solution (2 eq). The solution was stirred for 2 h at RT. Intermediate 4c was obtained as a brown solid.Sodium 2-(2-amino-3-methylphenyl)-2-oxoacetate (Intermediate 4d)

[0194] Intermediate 4d was synthesized by General Procedure 2A using 7-methylindoline-2,3- dione (1 eq) in aq. KOH solution (1.2 eq). The solution was stirred for 2 h at RT. Intermediate 4d was obtained as a brown solid. LC-MS: 231.29 [M+H]+.General Procedure 2B. Synthesis of Sodium 2-(2-amino-4-methylphenyl)-2-oxoacetate (Intermediate 5a)

[0195] To a stirred solution of sodium 2-(2-aminophenyl)-2-oxoacetate (Intermediate 4a; 1 eq) and 2-methylbenzaldehyde (1 eq) in ethanol (10 vol) was added ammonium acetate (9 eq) and the mixture was stirred for 24 h at 85°C. After TLC indicated the reaction was complete, the reaction mixture was concentrated, then was neutralized with 2N HC1 till reaching pH 7. The solid wasfiltered, washed with ether and dried in vacuo was obtained Intermediate 5a as a white solid. LC- MS: 265.00[M+H]+.2-(2,4-Dimethylphenyl) quinazoline-4-carboxylic acid (Intermediate 5b)

[0196] Intermediate 5b was synthesized by General Procedure 2B using sodium 2-(2- aminophenyl)-2-oxoacetate (Intermediate 4a; 1 eq) and 2, 4-dimethylbenzaldehyde (1 eq) in ethanol (10 vol) with ammonium acetate (10 eq). Intermediate 5b was obtained as a white solid. LC-MS: 279.1 [M+H]+.2-(2-Chlorophenyl) quinazoline-4-carboxylic acid (Intermediate 5c)

[0197] Intermediate 5c was synthesized by General Procedure 2B using sodium 2-(2- aminophenyl)-2-oxoacetate (Intermediate 4a; 1 eq), 2-chlorobenzaldehyde (1 eq) and ammonium acetate (10 eq) in ethanol (10 vol). The solution was stirred for 24 h at 85°C. Intermediate 5c was obtained as a white solid. LC-MS: 285.04 [M+H]+.6-Methyl-2-(o-tolyl)quinazoline-4-carboxylic acid (Intermediate 5d)

[0198] Intermediate 5d was synthesized by General Procedure 2B using sodium 2-(2-amino-5- methylphenyl)-2-oxoacetate (Intermediate 4b; 1 eq), 2-methylbenzaldehyde (1 eq) and ammonium acetate (10 eq) in ethanol (10 vol). The solution was stirred for 24 h at 85°C. Intermediate 5d was obtained as a white solid, LC-MS: 279.1 [M+H]+.7-Methyl-2-(o-tolyl)quinazoline-4-carboxylic acid (Intermediate 5e)

[0199] Intermediate 5e was synthesized by General Procedure 2B using sodium 2-(2-amino-4- methylphenyl)-2-oxoacetate (Intermediate 4b 1 eq), 2-methylbenzaldehyde (1 eq) and ammonium acetate (9 eq) in ethanol (10 vol). Intermediate 5e was obtained as a white solid. LC-MS: 279.1 [M+H]+.8-Methyl-2-(o-tolyl)quinazoline-4-carboxylic acid (Intermediate 51)

[0200] Intermediate 5e was synthesized by General Procedure 2B using sodium 2-(2-amino-3- methylphenyl)-2-oxoacetate (Intermediate 4c, 1 eq), 2-methylbenzaldehyde (1 eq) and ammonium acetate (10 eq) in ethanol (10 vol). Intermediate 5f was obtained as a white solid. LC-MS: 279.1 [M+H]+.General Procedure 2C. Synthesis of methyl 4-(2-(o-tolyl)quinazoline-4- carboxamido)benzoate (Intermediate 6a)

[0201] To a solution of 2-(o-tolyl)quinazoline-4-carboxylic acid (Intermediate 5a; 1 eq) in stirred at room temperature in DMF (10 Vol) were added HATU (1.5 eq), DIPEA (5 eq) and methyl 4- aminobenzoate 4 (1 eq). The mixture was heated to 50°C and stirred for 12 h at until TLC indicated reaction completion then the mixture was diluted with water and EtOAc. The organic layer was separated, washed with brine solution and dried with Na2SO4, and concentrated in vacuo. The crude material was purified by Combiflash to afford Intermediate 6a as a brown solid. LC-MS: 398.05 [M+H]+Methyl 4-(2-(2,4-dimethylphenyl)quinazoline-4-carboxamido)benzoate (Intermediate 6b)

[0202] Intermediate 6b was synthesized by General Procedure 2C using 2-(2,4- dimethylphenyl)quinazoline-4-carboxylic acid (Intermediate 5b; 1 eq) in DMF (10 vol.), HATU (1.5 eq), DIPEA (5 eq) and methyl 4-aminobenzoate (1 eq). Intermediate 6b was obtained as a white solid.Methyl 4-(2-(2-chlorophenyl)quinazoline-4-carboxamido)benzoate (Intermediate 6c)

[0203] Intermediate 6c was synthesized by General Procedure 2C using 2-(2- chlorophenyl)quinazoline-4-carboxylic acid (Intermediate 5c; 1 eq) in DMF (10 vol), HATU (1.2 eq), DIPEA (3 eq) and methyl 4-aminobenzoate 4 (1 eq). Intermediate 6c was obtained as a white solid. LC-MS: 418.05 [M+H]+.Methyl 4-(2-(2-methylphenyl)quinazoline-4-carboxamido)benzoate (Intermediate 6d)

[0204] Intermediate 6d was synthesized by General Procedure 2C using 6-methyl-2-(o- tolyl)quinazoline-4-carboxylic acid (Intermediate 5d; 1 eq) in DMF (10 vol) with HATU (1.2 eq), DIPEA (3 eq) and methyl 4-aminobenzoate 4 (1 eq). Intermediate 6c was obtained as a white solid. LC-MS: 412.0 [M+H]+.Methyl 4-(7-methyl-2-(o-tolyl) quinazoline-4-carboxamido) benzoate (Intermediate 6e)

[0205] Intermediate 6e was synthesized by General Procedure 2C using 7-methyl-2-(o- tolyl)quinazoline-4-carboxylic acid (Intermediate 5e; 1 eq) in DMF (10 vol), HATU (1.5 eq), DIPEA (5 eq) and methyl 4-aminobenzoate 4 (1 eq). Intermediate 6e was obtained as a white solid. LC-MS: 412.4 [M+H]+.Methyl 4-(8-methyl-2-(o-tolyl) quinazoline-4-carboxamido) benzoate (Intermediate 6f)

[0206] Intermediate 6f was synthesized by General Procedure 2C using 8-methyl-2-(o- tolyl)quinazoline-4-carboxylic acid (Intermediate 5f; 1 eq), methyl 4-aminobenzoate(l eq) in DMF (10 vol), HATU (1.5 eq) and DIPEA (5 eq). Intermediate 6f was obtained as a white solid. LC-MS: 412.20[M+H]+.General Procedure 2D. Synthesis of 4-(2-(o-Tolyl)quinazoline-4-carboxamido)benzoic acid (Intermediate 7a)

[0207] To a stirred solution of methyl 4-(2-(o-tolyl)quinazoline-4-carboxamido)benzoate (Intermediate 6a; 1 eq) in THF: MeOH: H2O (3: 1 : 1, 10 vol) was added LiOH.H2O (5 eq) and the mixture was stirred at room temperature for 2.5 h. After TLC indicated reaction completion, the mixture was concentrated in vacuo and acidified with 2N HC1 solution to pH 6.5. The product was filtered, washed with water and dried under vacuum to afford Intermediate 7a as a white solid.LC-MS: 383.95 [M+H]+.4-(2-(2,4-Dimethylphenyl)quinazoline-4-carboxamido)benzoic acid (Intermediate 7b)

[0208] Intermediate 7b was synthesized by General Procedure 2D using methyl 4-(2-(2,4- dimethylphenyl)quinazoline-4-carboxamido)benzoate (Intermediate 6b; 1 eq) inTHF:MeOH:H2O (5:2:2, 10 vol) and LiOH.H2O (5 eq). Intermediate 7b was obtained as a white solid.4-(2-(2-Chlorophenyl)quinazoline-4-carboxamido)benzoic acid (Intermediate 7c)

[0209] Intermediate 7c was synthesized by General Procedure 2D using methyl 4-(2-(2- chlorophenyl)quinazoline-4-carboxamido)benzoate (Intermediate 6c; 1 eq) in THF : MeOH: H2O(3: 1 : 1, 10 vol) and LiOH.H2O (5 eq). Intermediate 7c was obtained as a white solid. LC-MS: 402.05 [M-H]-.4-(6-Methyl-2-(o-tolyl)quinazoline-4-carboxamido)benzoic acid (Intermediate 7d)

[0210] Intermediate 7d was synthesized by General Procedure 2D using methyl 4-(6-methyl-2- (o-tolyl)quinazoline-4-carboxamido)benzoate (1 eq) in THF: MeOH: H2O (3: 1 : 1) (10 vol) was added LiOH.H2O (5 eq). Intermediate 7d was obtained as a white solid. LC-MS: 398.0 [M+H]+.4-(7-Methyl-2-(o-tolyl)quinazoline-4-carboxamido)benzoic acid (Intermediate 7e)

[0211] Intermediate 7e was synthesized by General Procedure 2D using methyl 4-(7-methyl-2- (o-tolyl)quinazoline-4-carboxamido) benzoate (Intermediate 6e; 1 eq) in THF: MeOH: H2O (3: 1 : 1, 10 vol) and LiOH.H2O (10 eq). Intermediate 7e was obtained as a white solid. LC-MS: 398.0 [M+H]+.4-(8-Methyl-2-(o-tolyl)quinazoline-4-carboxamido)benzoic acid (Intermediate 7f)

[0212] Intermediate 7f was synthesized by General Procedure 2D using methyl 4-(8-methyl-2- (o-tolyl)quinazoline-4-carboxamido) benzoate (Intermediate 6f; 1 eq) in THF: MeOH: H2O (3: 1 : 1) (10 vol) was added LiOH.H2O (10 eq). Intermediate 7f was obtained as a white solid, LC-MS: 398.0 [M+H]+.General synthetic procedure 2E:

[0213] To the stirred solution of Intermediate 7a-7f (1 eq.) in DMF (10 Vol) at 0°C were added HATU (1.2 eq) and DIPEA (2 eq.), and the appropriate amine (1 eq.) and then the reaction mixture was stirred for 3 h at 50°C. The reaction was monitored by TLC and after completion the reaction mixture was diluted with water (10 Vol) and EtOAc (20 Vol). The organic layer was separated and washed with brine solution (10 Vol) and dried with Na2SO4, filtered, and concentrated in vacuo. The crude compounds were purified by prep HPLC to afford the final compounds.General synthetic procedure 2F:

[0214] To a stirred solution of Intermediate 7a-7f (1 eq) in pyridine (10 vol), the appropriate amine (1 eq.) was added POCI3 (3 eq) dropwise at 0°C. The reaction mixture was brought to room temperature and stirred for 15 min. The reaction was monitored by TLC and after completion the reaction mixture was diluted with water (10 Vol) and EtOAc (20 Vol). The organic layer was separated and washed with brine solution (10 Vol) and dried with Na2SO4, filtered, and concentrated in vacuo. The crude compounds were purified by prep HPLC to afford the final compounds.Scheme-3: General Procedure for synthesis of substituted quinazoline based compounds.Synthetic procedure 3A. Synthesis of potassium 2-(2-amino-4,6-dimethylphenyl)-2- oxoacetate (Intermediate 8)

[0215] To a stirred suspension of 5, 7-dimethylindoline-2, 3-dione (1 eq) in water (10 vol) was added KOH (1.2 eq) and the mixture was stirred for 2 h at RT. After TLC indicated reaction completion, the solution was neutralized with 2N HC1 until reaching pH 7. The solvents were removed on a rotary evaporator at 45°C. Then, the residual solid was crystallized from DMF-ethylacetate mixture and dried in vacuo. Intermediate 8 was obtained as a brown solid. LC-MS: 231.29 [M+H]+.General synthetic procedure 3B. Synthesis of 6,8-Dimethyl-2-(pyridin-2-yl) quinazoline-4- carboxylic acid (Intermediate 9a)

[0216] To a stirred solution of potassium 2-(2-amino-4,6-dimethylphenyl)-2-oxoacetate (Intermediate 8; 1 eq) and picolinaldehyde (1 eq) stirred in ethanol was added ammonium acetate (2 eq). Then the mixture was heated to 85°C and stirred for 24 h. After TLC indicated reaction completion, the mixture was concentrated, and then neutralized with 2N HC1 to pH 7. The resulting solid was filtered, washed with ether and dried in vacuo affording Intermediate 9a as a white solid. LC-MS: 279.1 [M+H]+.2-(2-Chlorophenyl)-6,8-dimethylquinazoline-4-carboxylic acid (Intermediate 9b)

[0217] Intermediate 9b was synthesized by General Procedure 3B using potassium 2-(2-amino- 4,5-dimethylphenyl)-2-oxoacetate (Intermediate 8; 1 eq), 2- chlorobenzaldehyde (1 eq), and ammonium acetate (2 eq) in EtOH (10 vol). Intermediate 9b was obtained as a brown solid. LC- MS: 313.1 [M+H]+.2-(3,4-Dichlorophenyl)-6,8-dimethylquinazoline-4-carboxylic acid (Intermediate 9c)

[0218] Intermediate 9c was synthesized by General Procedure 3B using potassium 2-(2-amino- 4,5-dimethylphenyl)-2-oxoacetate (Intermediate 8; 1 eq), 3,4- dichlorobenzaldehyde (1 eq) and ammonium acetate (2 eq) in EtOH (10 vol.). Intermediate 9c was obtained as a brown solid. LC- MS: 346.0 [M-H]-.General synthetic procedure 3C. Synthesis of final compounds.

[0219] To a stirred solution of Intermediate 9a, 9b or 9c (1 eq.) in DMF (10 Vol) at 0°C were added HATU (1.2 eq) and DIPEA (2 eq.) and the appropriate amine (1 eq.) and then reaction mixture was stirred for 3 h at 50°C. The reaction was monitored by TLC and after completion the reaction mixture was diluted with water (10 Vol) and EtOAc (20 Vol). The organic layer was separated and washed with brine solution (10 Vol) and dried over Na2SO4, filtered, and concentrated in vacuo. The crude compounds were purified by prep HPLC to afford the final compounds.Scheme-4: General Procedure for synthesis of substituted quinoline based compoundsSynthetic procedure 4A._Substituted l,2-dihydroquinoline-4-carboxylic acid:

[0220] To the stirred solution of a substituted indoline-2, 3-dione (1 eq) in acetic acid (10 vol) was added malonic acid (3.5 eq) and sodium acetate (0.2 eq) and the mixture was stirred at 110°C for 12 h. After TLC indicated reaction completion, the reaction mixture was quenched with cold water. The precpitated solid was filtered and dried under vacuum to afford the substituted 2-oxo- l,2-dihydroquinoline-4-carboxylic acid as a white solid.Synthetic procedure 4B. Substituted 2-oxo-1,2-dihydroquinoline-4-carboxylate:

[0221] To the stirred solution of substituted 2-oxo-1,2-dihydroquinoline-4-carboxylic acid (1 eq) in methanol (10 vol) was added sulfuric acid (4 eq) and the solution was stirred at 90°C for 12 h.After TLC indicated reaction completion the reaction mixture was diluted with water (10 Vol) and EtOAc (20 Vol). The organic layer was separated and washed with brine solution (10 Vol) and dried over Na2SO4, filtered, and concentrated in vacuo. The crude compound was purified by Combi flash chromatography using 5% MeOH in DCM as mobile phase to afford substituted methyl 2-oxo-1,2-dihydroquinoline-4-carboxylate as a white solid.Synthetic procedure 4C. Substituted 2-bromo-quinoline-4-carboxylate:

[0222] To the stirred solution of substituted methyl 2-oxo-1,2-dihydroquinoline-4-carboxylate (1 eq) in toluene (10 vol) was added POBr3(3 eq) and the mixture was stirred at 120°C for 2 h. After TLC indicated reaction completion, the reaction mixture was diluted with water (10 Vol) and EtOAc (20 Vol). The organic layer was separated and washed with brine solution (10 Vol), dried over Na2SO4, filtered, and concentrated in vacuo. The crude compound was purified by Combi flash chromatography using 50% ethyl acetate in hexane as mobile phase to afford substituted methyl 2-bromoquinoline-4-carboxylate as a white solid.Synthetic procedure 4D. Substituted methyl 2-(3,4-dihydro-2H-pyran-6-yl)-quinoline-4- carboxylate:

[0223] To the stirred solution of substituted methyl 2-bromoquinoline-4-carboxylate (1 eq) in dioxane (10 vol) was added 2-(3,4-dihydro-2H-pyran-6-yl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (1.5 eq), Cs2CO33.O eq), and X-Phos Pd-G4 (0.29 g, 0.1 eq) then the reaction vessel was purged with argon for 10 min and was stirred at 100°C for 12 h. After TLC indicated reaction completion, the reaction mixture was diluted with water (10 Vol) and EtOAc (20 Vol). The organic layer was separated and washed with brine solution (10 Vol), dried over Na2SO4, filtered, and concentrated in vacuo. The crude compound was purified by Combi flash chromatography using 50% ethyl acetate in hexane as mobile phase to afford substituted methyl 2-(3,4-dihydro-2H- pyran-6-yl)quinoline-4-carboxylate as a white solid.Synthetic procedure 4E. Substituted 2-(3,4-dihydro-2H-pyran-6-yl)-quinoline-4-carboxylicacid:

[0224] To the stirred solution of substituted methyl 2-(3,4-dihydro-2H-pyran-6-yl)quinoline-4- carboxylate (1 eq) in THF: MeOH: H2O (3: 1 : 1) (10 vol) was added LiOH.H2O (2 eq) and was stirred at room temperature for 2.5 h. The reaction was monitored by TLC. After completion, reaction mixture was concentrated, acidified with 2N HC1 solution (pH=6.5), filtered, washed with water and dried under vacuo to afford substituted 2-(3,4-dihydro-2H-pyran-6-yl)quinoline-4- carboxylic acid as a white solid.Synthetic procedure 4F: Substituted methyl 4-(2-(3,4-dihydro-2H-pyran-6-yl) quinoline-4- carboxamido) benzoate:

[0225] To the stirred solution substituted 2-(3,4-dihydro-2H-pyran-6-yl)quinoline-4-carboxylic acid (1 eq.) in DMF (10 Vol) at 0°C, were added HATU (1.2 eq) and DIPEA (2 eq.), and methyl 4-aminobenzoate (1 eq.) then reaction mixture was stirred for 3 h at 50 °C. After TLC indicated reaction completion, the reaction mixture was diluted with water (10 Vol) and EtOAc (20 Vol). The organic layer was separated, washed with brine solution (10 Vol), dried overNa2SO4, filtered and concentrated in vacuo. The crude compound was purified by prep HPLC to afford substituted methyl 4-(2-(3,4-dihydro-2H-pyran-6-yl)quinoline-4-carboxamido)benzoate.Synthetic procedure 4G. Substituted 4-(2-(3,4-dihydro-2H-pyran-6-yl) quinoline-4- carboxamido) benzoic acid:

[0226] To the stirred solution of substituted methyl 4-(2-(3,4-dihydro-2H-pyran-6-yl)quinoline- 4-carboxamido)benzoate (5 g, 1 eq) in THF: MeOH: H2O (3: 1 : 1) (10 vol) was added LiOH.H2O (2 eq) and the mixture was stirred at room temperature for 2.5 h. After TLC indicated reaction completion, the reaction mixture was concentrated, acidified with 2N HC1 solution (pH=6.5), filtered, washed with water and dried in vacuo to afford substituted 4-(2-(3,4-dihydro-2H-pyran- 6-yl)quinoline-4-carboxamido)benzoic acid.Synthetic procedure 4F. Substituted 2-(3,4-dihydro-2H-pyran-6-yl)-N-(4-((2-(2- methyloxazol-5-yl) ethyl) carbamoyl) phenyl) quinoline-4-carboxamide:

[0227] To a stirred solution of substituted 4-(2-(3,4-dihydro-2H-pyran-6-yl)quinoline-4- carb oxami do)benzoic acid (1 eq) in DMF (10 Vol) and amine (1 eq.) was added EDC.HC1 (2 eq), HOAt (2 eq), and 2,6-Lutidene (5 eq.). The reaction mixture was stirred at 85°C for 12 hr. The reaction was monitored by TLC and after completion the reaction mixture was diluted with water (10 Vol) and EtOAc (20 Vol). The organic layer was separated and washed with brine solution (10 Vol), dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by prep HPLC to afford the final compounds.Synthetic procedure 41. Substituted N-(4-((2-(2-methyloxazol-5-yl) ethyl) carbamoyl) phenyl)-2-(tetrahydro-2H-pyran-2-yl) quinoline-4-carboxamide:

[0228] To a stirred solution of the dihydropyran compound (1 eq) in ethanol (10 vol) was added Pd-C (1 eq), the reaction mixture was stirred at rt for 3 hr under a H2 atmosphere. After TLC indicated reaction completion the reaction mixture was filter through a Celite bed. The organic layer was concentrated in vacuo, the crude compounds were purified by prep HPLC to afford the final compounds.Example Bl: Beta- Arrestin AssayThe activity of certain compounds was determined using an enzyme fragment completion betaarrestin recruitment assay for GPR55 (see generally Zhao et al., J. Biomol. Screen 13(8):737-747 (2008)). Briefly, Prolink-human GPR55 and enzyme acceptor-tagged beta-arrestin codingsequences were inserted into Chinese hamster ovary cells (“transfected CHO cells”). Activation of GPR55 in the absence of an antagonist resulted in beta-arrestin recruitment to the receptor and the Prolink and enzyme acceptor domains associating to form a complete beta-galactosidase enzyme. The resulting enzyme hydrolyzed substrate present in the detection reagents to generate a chemiluminescent signal that was used to quantify the ability of compounds to antagonize GPR55. Transfected CHO cells were plated in 384-format at 20,000 cells / well. The cells were pre-treated with selected compounds for one hour at 37 °C prior to adding 6 μM of GPR55 activator, L-a-Lysophosphatidylinositol sodium salt (Millipore Sigma). The cells were activated for 90 minutes at room temperature, then chemilumincent substrate was added and the cells were incubated for an additional 90 minutes. Luminescence was then read and used to determine half maximal inhibitory concentration (IC50). The results are shown in Tables 5-9. Compounds having an IC50 value of < 1.0 μM are indicated as +++; > 1.0 μM to 10.0 μM as ++; and >10.0 uM to 30 μM as +. NA means > 30 μM. NT means not tested.Example B2: Anti-proliferative Activity of the Compounds

[0229] Certain test compounds were tested for anti-proliferative effects on cancer cells in vitro. Select test compounds were tested in the presence of an effective concentration of a GPR55 ligand, L-a-lysophosphatidylinositol (LPI). The cancer cells used were MCF-7 breast cancer cells, an estrogen positive, GPR55 sensitive cell line. The cells were cultured as recommended by the supplier.

[0230] Briefly, test compounds in cell culture medium were evaluated in triplicate wells of a 96-well microtiter plate. Cell proliferation was measured by Promega CellTiter-Glo® assay. IC50values were calculated as compared to the relative light units of the untreated cell controls following three days incubation. When the cells reached a density of about 70% confluence, the cells were treated with an effective concentration of a GPR55 ligand alone (L-a- lysophosphatidylinositol or LPI, 50 μM).

[0231] MCF7 cells were plated at 5 x 103cells per well in flat bottom 96-well microtiter plates and incubated at 37 °C / 5% CO2overnight for adherence. Staurosporine, a cell-permeable, reversible, ATP-competitive and broad spectrum inhibitor of protein kinases, was tested in a similar manner as a positive control. Six wells in the test plates received medium alone as an untreated control and six wells received LPI only. Following three days of culture in the presence of test compound, cell viability was measured using Promega CellTiterGlo. Chemiluminescence data were collected and imported into a customized Excel workbook for determination of the TC50values. The results are shown in Table 10, where “+++” indicates inhibition of proliferation with a TC50value below 1 μM under the test conditions; “++” indicates inhibition of proliferation with TC50between 1 and 10 μM under the test conditions ; “+” indicates inhibition of proliferation with TC50greater than 10 up to 30 μM under the test conditions, indicates inhibition of proliferation with TC50above 30 μM .Table 10. Cytoxicity AssayExample B3: Cytotoxic Activity of the Compounds by LDH Assay

[0232] This study was designed to obtain a preliminary assessment of nonspecific cytotoxicity. Compounds were tested at high concentrations to determine if any cytotoxic effects were observed on hepatocyte (HepG2), rat cortical neurons, and mouse microglia cell cultures by measuring the release of lactate dehydrogenase (LDH) into the culture media as a measurement of lysed / dead cells.

[0233] HepG2 cells were plated in 96-well cell culture plates and allowed to attach at least overnight at 37°C, 5% CO2in growth media conditions (e.g., EMEM media + 10% FBS). Treatments were made in complete media (e.g., EMEM + 10% FBS) and included test compounds at a concentration of 100 μM. A known cytotoxin, cerivastatin, was used as a positive assay control and prepared at a final concentration of 0.5 μM.

[0234] Growth media was replaced with treatment media (e.g., EMEM + 10% FBS containing test compound dissolved in DMSO) and the cells were incubated with test compounds for 48 hours. At the end of the incubation period, supernatant media from each well was transferred to a new plate and LDH assay working solution was added. The LDH assay solution undergoes a colorimetric reaction in proportion to the amount of lactate dehydrogenase (an intracellular protein that is only found in the media in the presence of lysed cells) in the media. Color reaction was quantified by measurement of absorbance at a wavelength of 490 nm.

[0235] The signal range of the assay was determined by no manipulation in a negative control treatment and full lysis of all cells in a lysis control sample. Compounds that increase the level of cytotoxicity more than 20% above negative control samples were considered cytotoxic in this assay. Results are shown in Table 11, where “+” indicates toxicity of 20% or greater compared to vehicle-treated samples; indicates toxicity of less than 20% compared to vehicle-treated samples; and “NT” means the compound was not tested.Table 11. Compound Cytotoxicity by LDH AssayExample B4: Cell Migration Assay

[0236] Nine compounds were evaluated at 30 μM) for anti -migratory effects on the cancer cell line SR for cell migration using an Abeam Cell Migration Assay kit (96 well, 5 pm; ab235693). ML193, a selective GPR55 antagonist, was used as a positive control. Prior to the assay, SR cells were incubated in serum-free RPMI medium for 18-24 hours. Cells (5xl04cells / 50 pL) in RPMI medium without FBS (fetal bovine serum) and each test article (100 pL / well) were then placed in the top chamber of a transwell and 150 pL of RPMI medium with 10% FBS was placed in the bottom chamber. A standard curve was evaluated in a 96-well, white plate with clear bottom. Cell Dye was added for a 1-hour incubation at 37 °C and fluorescence read at 530 (Ex) / 590 (Em) nm. Following incubation at 37 °C / 5% CO2for 24 hours of the cells with test article, the medium and cells were removed from the top chamber. The bottom chamber was centrifuged at 1000 x g for 5 minutes and the medium removed. Cells were washed buffer and centrifuged again at 1000 x g for 5 minutes to remove the wash buffer. Cell Dye diluted in Cell Dissociation solution was added to the bottom chamber and incubated for 1 hour at 37 °C, then fluorescence was read at 530 / 590 nm. The number of cells that migrated was calculated compared to a standard curve of cell dilutions. Statistical analysis consisted of Student’s t-test of test compound-treated wells versus cell cultures treated with vehicle alone, with a p-value of 0.05 being considered significant. The results are shown in Table 12, where “ +” indicates statistically significant inhibition of cell migration; andindicates no statistically significant inhibition of cell migration.Table 12. Cell Migration Assay

[0237] Compounds 1019, 1152, 1083, 1135, and 1072 inhibited cell migration in this assay.Example B5: Mult-Electrode Array Studies

[0238] GPR55 activity is thought to contribute to seizure-like neuron firing activity in epilepsy. To evaluate the anti-seizure potential of test compounds, seizure-like firing in hippocampal neurons was evaluated by stimulation of neuron cultures with pyridine-4-amine (4-AP) and recording of neuron firing activity in multi-electrode array (MEA) culture plates. MEA systems use a grid of tightly spaced microscopic electrodes embedded in the bottom of each well in a multi-well MEA plate. Neurons, which are electrically active, can be cultured over the electrodes creating a cohesive network. The functional behavior or electrical activity of this network can be recorded as extracellular field potentials.

[0239] To study the activity of selected compounds on epileptiform activity, hippocampus tissue was harvested from embryonic day 18 chr:NMRI mouse embryos (Charles River Laboratories). Pregnant mice were sacrificed by cervical dislocation according to the German Animal Protection Act §4 and Animal Welfare Laboratory Animal Ordinance §2 Section 2, Appendix 2. The tissue was dissociated by enzymatic digestion and mechanical trituration. The resulting suspension was cell-counted, vitality controlled, set to 7.5 million cells / ml, and plated in a 20 pl drop of DMEM containing laminin (10 μg / ml), 10% fetal bovine serum, and 10% horse serum on 48-well MEA plates. Cultures in the MEA apparatus were incubated at 37°C in a 10% CO2atmosphere for 27-29 days in vitro prior to study. Culture media were replenished two times a week with DMEM containing 10% horse serum. The developing cultures were treated with the mitosis inhibitor 5-fluoro-2'-deoxyuridine and uridine between day 3 and 5 after seeding to prevent further glial cell proliferation.

[0240] For the recording, a multichannel recording system, MAESTRO™ from Axion Biosystems Inc. (USA), was used. For extracellular recording, 48-well MEA plates were placed into the recording station and maintained at 37°C. Recordings were made in the original medium. The pH was maintained at 7.4 with a continuous stream of filtered, humidified airflow with appropriate CO2levels. The action potentials, or "spikes", were recorded.

[0241] After recording the native baseline activity, 4-aminopyridin (4-AP) was added at 100 μM to induce epileptiform activity. This activity was followed for 60 minutes. After 60 minutes, selected compounds were added. The neuronal activity was recorded for 1 hour, and the last 30 minutes of activity was analyzed. 24 hours after compound application MEAs were recorded again for 60 minutes.

[0242] Analysis: Epileptiform activity in neuron cultures was characterized by the spike rate, with greater spikes per second indicating greater seizure-like firing activity. Within the 4-AP treated group, the effects of the test compounds were compared to their vehicle (DMSO) controls. The data of the 4-AP episodes of all experiments were pooled to characterize its effects on the spike rate of the treated neurons.

[0243] For the compound effects, data were normalized to the 4-AP activity. Compound effects were compared to the vehicle effects and the 4-AP control “water / DMSO”. Spikes were quantitatively described via direct spike train analysis using the program NPWaveX™ (NeuroProof GmbH, Rostock, Germany).

[0244] Statistical significance was determined by paired Student’ s t-test versus 4-AP effect, with a p-value of 0.05 being considered significant. The results are shown in Table 13.Table 13: Results of exemplary compounds characterizing reduction of 4-AP-stimulated epileptiform activity

[0245] The results of hippocampal neuron epileptiform spiking behavior characterization indicate that certain tested compounds were able to modulate spiking behavior. Compounds 1019, 1227, and 1262 reduced spike rates at the 24-hour time point, and compound 1227 reduced spike rate at the 1-hour time point.

Claims

CLAIMSWHAT IS CLAIMED IS:

1. A compound represented by the structure of Formula (I):Formula (I) or a salt thereof, wherein:A is selected from N and CR6;E is selected from N and CR6a; wherein at least one of A or E is N;R1is selected from C3-8carbocycle, and 4- to 8-membered heterocycle, wherein the C3-8carbocycle, and 4- to 8-membered heterocycle are each optionally substituted with one or more substituents independently selected from:(i) halogen, -OR20, -SR20, -N(R20)2, -C(O)R20, -C(O)N(R20)2, - N(R20)C(O)R20-C(O)OR20, -OC(O)R20, -S(O)R20, -S(O)2R20, -P(O)(OR20)2, -OP(O)(OR20)2, -NO2, =O, =S, =N(R20), and -CN; and(ii) C1-10alkyl, C2-10 alkenyl, and C2-10 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR20, -SR20, -N(R20)2, -C(O)R20, -C(O)N(R20)2, -N(R20)C(O)R20-C(O)OR20, -OC(O)R20, -S(O)R20, -S(O)2R20, -S(O)2N(R20)2, -S(O)N(R20)2, -NR20S(O)2R20, -P(O)(OR20)2, -OP(O)(OR20)2, -N02, =O, =S, =N(R20), and -CN; each R2is independently selected from: halogen, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, -N02, -CN, C3-6cycloalkyl and C1-6alkyl;R4is selected from 4- to 5-membered heterocycle, 6-membered heteroaryl, 7- to 9-membered heterocycle, 3- to 6-membered cycloalkyl, hydrogen, and -C02H, wherein the 4- to 5- membered heterocycle, 6-membered heteroaryl, 7- to 9-membered heterocycle, and 3- to 6-membered cycloalkyl, are each optionally substituted with one or more substituents independently selected from:(i) halogen, -OR20, -SR20, -N(R20)2, -C(O)R20, -C(O)N(R20)2, -N(R20)C(O)R20-C(O)OR20, -OC(O)R20, -S(O)R20, -S(O)2R20, -P(O)(OR20)2, -OP(O)(OR20)2, -NO2, and -CN; and(ii) C1-6alkyl, C2-6alkenyl, and C2-6alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR20, -SR20, -N(R20)2, -C(O)R20, -C(O)N(R20)2, -N(R20)C(O)R20-C(O)OR20, -OC(O)R20, -S(O)R20, -S(O)2R20, -S(O)2N(R20)2, -S(O)N(R20)2, -NR20S(O)2R20, -P(O)(OR20)2, -OP(O)(OR20)2, -NO2, =O, =S, =N(R20), and -CN; and(iii) C3-6carbocycle each of which is optionally substituted with one or more substituents independently selected from halogen and C1-6alkyl;R5is selected from hydrogen; C1-6alkyl, and cyclopropyl each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, and =NH; or R4and R5together with the atoms to which they are attached for a 4 to 8 membered heterocycle; or R5and one of R5atogether with the atoms to which they are attached form a 4 to 8- membered heterocyclene, which is optionally substituted with 1 to 4 substituents independently selected from R10;R6is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl;R6ais selected from hydrogen, C1-6alkyl, and C1-6haloalkyl;R7is selected from halogen, -CN, -NO2, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, C1-6alkyl, and C1-6haloalkyl;R8is selected from halogen, -CN, -NO2, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, C1-6alkyl, and C1-6haloalkyl;R8ais selected from halogen, -CN, -NO2, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, C1-6alkyl, and C1-6haloalkyl;R8bis selected from halogen, -CN, -NO2, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, C1-6alkyl, and C1-6haloalkyl;X is selected from N, S and O;R10is selected from halogen, -CN, -NO2, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, C1-6alkyl, and C1-6haloalkyl;L is selected from a C1-8alkylene, wherein the C1-8alkylene is optionally substituted with one or more R5a, wherein each R5ais independently selected from halogen, C1-6alkyl, -OH, -OCH3, and -CN; and wherein optionally two optional substituents on the same carbon atom of L come together to form a carbocycle or heterocycle; each R20is independently selected from hydrogen; and C1-6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2,-NH(C1-6alkyl), -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, =NH, and cyclopropyl; m is selected from 0 and 1; n is selected from 0, 1, 2, 3, and 4; q is selected from 0, 1, 2, and 4; y is selected from 0, 1, and 2; and z is selected from 0, 1, and 2.

2. The compound or salt of claim 1, wherein:R4is selected from 4- to 5-membered heterocycle, 6-membered heteroaryl, and 7- to 9-membered heterocycle, wherein the 4- to 5-membered heterocycle, 6-membered heteroaryl, and 7- to 9-membered heterocycle are each optionally substituted with one or more substituents independently selected from:(i) halogen, -OR20, -SR20, -N(R20)2, -C(O)R20, -C(O)N(R20)2, -N(R20)C(O)R20-C(O)OR20, -OC(O)R20, -S(O)R20, -S(O)2R20, -P(O)(OR20)2, -OP(O)(OR20)2, -NO2, and -CN; and(ii) C1-6alkyl, C2-6alkenyl, and C2-6alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR20, -SR20, -N(R20)2, -C(O)R20, -C(O)N(R20)2, -N(R20)C(O)R20-C(O)OR20, -OC(O)R20, -S(O)R20, -S(O)2R20, -S(O)2N(R20)2, -S(O)N(R20)2, -NR20S(O)2R20, -P(O)(OR20)2, -OP(O)(OR20)2, -NO2, =O, =S, =N(R20), and -CN; and(iii) C3-6carbocycle each of which is optionally substituted with one or more substituents independently selected from halogen and C1-6alkyl; andR5is selected from hydrogen; C1-6alkyl, and cyclopropyl each of which is optionally substituted with one or more substituents independently selected from halogen,-OH, -CN, -NO2, -NH2, -NH(C 1-6alkyl), -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, and =NH.

3. The compound or salt of claim 1 or 2, wherein R4is selected from an optionally substituted 5- to 9-membered heteroaryl and optionally substituted 8- to 9-membered unsaturated heterocycle.

4. The compound or salt of any one of claims 1 to 3, wherein R4is selected from an optionally substituted 5- to 6-membered heteroaryl and optionally substituted 8- to 9- membered unsaturated heterocycle.

5. The compound or salt of any one of claims 1 to 4, wherein R4is selected from an optionally substituted 5-membered heteroaryl and optionally substituted 8- to 9-membered unsaturated heterocycle.optionally substituted.

7. The compound or salt of any one of claims 1 to 6, wherein R4is selected fromof which is optionally substituted.

8. The compound or salt of any one of claims 1 to 7, wherein the one or more optional substituents of R4is independently selected from: halogen, -OR20, -N(R20)2, -C(O)R20, -C(O)N(R20)2, -C(O)OR20, -OC(O)R20, -S(O)2R20, and -CN; and C1-6alkyl and C3-6carbocycle, wherein the C1-6alkyl is each optionally substituted with one or more substituents independently selected from halogen, -OR20, -N(R20)2, =O, and -CN; and the C3-6carbocycle is optionally substituted with one or more substituents independently selected from halogen and C1-6alkyl.

9. The compound or salt of any one of claims 1 to 8, wherein the one or more optional substituents of R4is independently selected from: C1-6alkyl is optionally substituted with oneor more substituents independently selected from halogen, -OR20, -N(R20)2, =O, and -CN, and the C3-6carbocycle is optionally substituted with one or more substituents independently selected from halogen and C1-6alkyl.

10. The compound or salt of any one of claims 1 to 9, wherein the one or more optional substituents of R4is independently selected from: C1-5alkyl and C3-6saturated carbocycle.

11. The compound or salt of any one of claims 1 to 10, wherein the one or more optional substituents of R4is independently selected from: methyl, ethyl, isopropyl, and cyclopropyl.

12. The compound or salt of any one of claims 1 to 11, wherein R4is selected from13. The compound or salt of any one of claims 1 to 5, wherein R4is selected from an optionally substituted 5-membered heteroaryl.

14. The compound or salt of claim 13, wherein R4is selected fromeach of which is optionally substituted.

15. The compound or salt of claim 13 or 14, wherein the one or more optional substituents of R4is independently selected from: C1-3alkyl and C3-6saturated carbocycle.

16. The compound or salt of any one of claims 13 to 15, wherein R4is selected fromThe compound or salt of claims 1 or 13, wherein R4is selected from, each of which is optionally substituted.

18. The compound or salt of claims 1 or 17, wherein R4is , which is optionally substituted.

19. The compound or salt of claims 1, 2, 17 to 18, wherein the one or more optional substituents of R4is independently selected from: C1-3alkyl and C3-6saturated carbocycle.

20. The compound or salt of claims 1, 2, or 12, wherein R4is selected from21. The compound or salt of any one of claims 1, 2, 12, or 20, wherein R4is selected from23. The compound or salt of any one of claims 1 to 5, wherein R4is selected from an optionally substituted 8- to 9-membered unsaturated heterocycle.

24. The compound or salt of claim 23, wherein R4is selected from an optionally substituted 8- to 9-membered unsaturated heterocycle, wherein the heterocycle has at least one oxygen atom.

25. The compound or salt of claims 23 or 24, wherein R4is selected from26. The compound or salt of any one of claims 1 to 25, wherein m is 1.

27. The compound or salt of any one of claims 1 to 26, wherein L is selected from C1-4alkylene, which is optionally substituted.

28. The compound or salt of any one of claims 1 to 27, wherein L is selected from29. The compound or salt of any one of claims 1 to 28, wherein L is30. The compound or salt of any one of claims 1 to 25, wherein m is 0.

31. The compound or salt of any one of claims 1 to 25, wherein m is selected from 0 and1, and wherein L is selected from32. The compound or salt of any one of claims 1 to 31, wherein R1is selected from C6-8aryl and 5- to 8-membered heterocycle, wherein the C6-8aryl and 5- to 8-membered heterocycle are each optionally substituted.

33. The compound or salt of any one of claims 1 to 31, wherein R1is selected fromeach of which is optionally substituted.

34. The compound or salt of any one of claims 1, 2, 32, or 33, wherein the one or more optional substituents of R1is independently selected from:(i) halogen, -OR20, -N(R20)2, -C(O)R20, -C(O)N(R20)2, -C(O)OR20, -OC(O)R20,-S(O)2R20, and -CN; and(ii) C1-10alkyl, which is optionally substituted with one or more substituents independently selected from halogen, -OR20, -N(R20)2, =O, and -CN.

35. The compound or salt of any one of claims 1 to 34, wherein R1is selected from36. The compound or salt of any one of claims 1 to 33, or 35, wherein R1iswhich is optionally substituted.

37. The compound or salt of any one of claims 1, 2, or 32 to 36, wherein the one or more optional substituents of R1is independently selected from: halogen and -OR20; and C1-4alkyl, which is optionally substituted with one or more substituents independently selected from halogen, -OR20, -N(R20)2, =O, and -CN.

38. The compound or salt of any one of claims 1, 2, or 32 to 37, wherein the one or more optional substituents of R1is independently selected from: halogen and -OR20; and C1-4alkyl, which is optionally substituted with one or more substituents independently selected from halogen, -OH, and -OCH3; wherein each R20is independently selected from hydrogen; and C1-6alkyl, which is optionally substituted with one or more substituents independently selected from halogen.

39. The compound or salt of any one of claims 1, 2, or 32 to 36, wherein the one or more optional substituents of R1is independently selected from: halogen, -CN, C1-4alkyl, C1-4haloalkyl, -O-C1-4alkyl, and -O-C1-4haloalkyl.

40. The compound or salt of any one of claims 1, 2, 32 to 36, or 39, wherein the one or more optional substituents of R1is independently selected from: F, -CN, Cl, -CH3, -CF2H, and -OCH3.

41. The compound or salt of any one of claims 1, 2, or 32 to 40, wherein R1is selected42. The compound or salt of any one of claims 1, 2, or 32 to 41, wherein R1is43. The compound or salt of any one of claims 1, 2, 32 to 34, or 36 to 40, wherein the one or more optional substituents of R1is independently selected from halogen.

44. The compound or salt of any one of claims 1, 2, 32 to 34, or 36 to 41, or 43, whereinR1is selected from45. The compound or salt of any one of claims 1, 2, 32 to 34, or 36 to 41, or 43 to 44, wherein R1is selected from46. The compound or salt of any one of claims 1, 2, or 6 to 31, wherein R1is optionally substituted 4- to 8-membered heterocycle.

47. The compound or salt of any one of claims 1, 2, 6 to 32, or 46, wherein R1is optionally substituted 5- to 6-membered heterocycle.

48. The compound or salt of any one of claims 1, 2, 6 to 32, 46, or 47, wherein the heterocycle is an aromatic heterocycle.

49. The compound or salt of any one of claims 1, 2, 6 to 32, or 46 to 48, wherein R1is50. The compound or salt of claim 1, 2, or 49, wherein R1is,51. The compound or salt of any one of claims 1, 2, 6 to 32, or 46 to 50, wherein R1is selected from52. The compound or salt of any one of claims 1, 2, 6 to 32, or 51, wherein R1is53. The compound or salt of any one of claims 1, 2, 6 to 32, or 51, wherein R1is54. The compound or salt of any one of claims 1, 2, 6 to 32, or 46 to 49, wherein R1is55. The compound or salt of any one of claims 1, 2, 6 to 32, or 46, wherein R1is selected56. The compound or salt of any one of claims 1, 2, 6 to 32, 46, or 47, wherein R1is optionally substituted 5- to 6-membered saturated heterocycle.

57. The compound or salt of any one of claims 1, 2, 6 to 32, 46, 47, or 56, wherein the heterocycle of R1contains at least one heteroatom selected from oxygen and nitrogen.

58. The compound or salt of any one of claims 1, 2, 6 to 32, 46, 47, 56, or 57, wherein R159. The compound or salt of any one of claims 1, 2, 6 to 32, 46, 47, or 56 to 58, whereinR1is selected from60. The compound or salt of any one of claims 1, 2, 6 to 32, 46, 47, or 56 to 58, whereinR1is selected from61. The compound or salt of any one of claims 1, 2, 6 to 32, 46, 47, or 56 to 58, whereinZ OR1is selected from — ' .

62. The compound or salt of any one of claims 1, 2, 6 to 32, 46, 47, or 56 to 58, whereinR1is selected from.

63. The compound or salt of any one of claims 1 to 62, wherein each R2is independently selected from: halogen, cyclopropyl, -OH, -OCH3, -CN, and C1-6alkyl.

64. The compound or salt of any one of claims 1 to 63, wherein each R2is independently selected from: halogen; and C1-6alkyl.

65. The compound or salt of any one of claims 1 to 64, wherein each R2is independently selected from: halogen; and C1-3alkyl.

66. The compound or salt of any one of claims 1 to 65, wherein each R2is independently selected from: F, Cl, and -CH3.

67. The compound or salt of any one of claims 1 to 65, wherein each R2is independently selected from: C1-3alkyl.

68. The compound or salt of any one of claims 1 to 64 or 67, wherein each R2is -CH3.

69. The compound or salt of any one of claims 1 to 68, wherein n is selected from 0, 1, and 2.

70. The compound or salt of any one of claims 1 to 69, wherein n is 0.

71. The compound or salt of any one of claims 1 to 69, wherein n is 1.

72. The compound or salt of any one of claims 1 to 69, wherein n is 2.

73. The compound or salt of any one of claims 1 to 72, wherein R5is selected from hydrogen; and C1-6alkyl, and cyclopropyl, each of which is optionally substituted with one or more substituents independently selected from halogen.

74. The compound or salt of any one of claims 1 to 73, wherein R5is selected from hydrogen; and C1-6alkyl which is optionally substituted with one or more substituents independently selected from halogen.

75. The compound or salt of any one of claims 1 to 74, wherein R5is selected from hydrogen and C1-6alkyl.

76. The compound or salt of any one of claims 1 to 75, wherein R5is hydrogen.

77. The compound or salt of any one of claims 1 to 75, wherein R5is -CH3.

78. The compound or salt of any one of claims 1 to 77, wherein A is N.

79. The compound or salt of any one of claims 1 to 77, wherein A is CR6.

80. The compound or salt of any one of claims 1 to 77 or 79, wherein R6is selected from hydrogen, -CH3, and -CF3.

81. The compound or salt of any one of claims 1 to 77 or 79-80, wherein R6is hydrogen.

82. The compound or salt of any one of claims 1 to 77 or 80-81, wherein A is selected from N and CH.

83. The compound or salt of any one of claims 1 to 82, wherein E is N.

84. The compound or salt of any one of claims 1 to 82, wherein E is CR6a.

85. The compound or salt of any one of claims 1 to 82 or 84, wherein R6ais selected from hydrogen, -CH3, and -CF3.

86. The compound or salt of any one of claims 1 to 82 or 84-85, wherein R6ais hydrogen.

87. The compound or salt of any one of claims 1 to 86, wherein A is selected from N orCH.

88. The compound or salt of any one of claims 1 to 87, wherein R9is selected from89. The compound or salt of any one of claims 1 to 88, wherein R9is selected from90. The compound or salt of any one of claims 1 to 87, wherein R9is selected from91. The compound or salt of any one of claims 1 to 87 or 90, wherein R9is selected from92. The compound or salt of any one of claims 1 to 87, wherein R9is selected from93. The compound or salt of any one of claims 1 to 87 or 92, wherein R9is selected from94. The compound or salt of any one of claims 1 to 87 or 92, wherein R9is selected from95. The compound or salt of any one of claims 1 to 95, wherein the salt is a pharmaceutically acceptable salt.

96. A compound selected from a compound in Table 1, Table 2, Table 3, Table 4, Table5, Table 6, Table 7, Table 8 and Table 9, or a pharmaceutically acceptable salt of any one thereof.

97. The compound or salt of claim 96 selected from Compound No. 1007, 1019, 1020,1021, 1022, 1027, 1028, 1030, 1032, 1045, 1046, 1047, 1049, 1050, 1052, 1053, 1054, 1055,1058, 1059, 1063, 1064, 1065, 1066, 1068, 1070, 1080, 1087, 1089, 1098, 1105, 1106, 1110,1112, 1113, 1115, 1118, 1119, 1131, 1135, 1142, 1143, 1148, 1152, 1153, 1162, 1163, 1164,1167, 1169, 1176, 1181, 1183, 1184, 1185, 1186, 1187, 1189, 1191, 1193, 1194, 1196, 1198,1199, 1202, 1203, 1204, 1208, 1215, 1216, 1221, 1222, 1225, 1228, 1231, 1232, 1236, 1237,1238, 1239, 1241, 1243, 1244, 1247, 1248, 1249, 1250, 1251, 1253, 1255, 1256, 1258, 1259,1260, 1600, 3000, 3004, and 4011, or a pharmaceutically acceptable salt of any one thereof.

98. The compound or salt of claim 96 selected from Compound No. 1019, 1032, 1039,1069, 1072, 1091, 1097, 1122, 1175, 1182, 1184, 1188, 1190, 1192, 1195, 1201, 1207, 1213,1217, 1219, 1223, 1224, 1227, 1229, 1242, and 4011, or a pharmaceutically acceptable salt of any one thereof.

99. A pharmaceutical composition comprising a compound or salt of any one of claims 1 to 98 and a pharmaceutically acceptable excipient.

100. A method of antagonizing a GPR55 receptor of a subject, comprising administering to the subject with a disease, disorder, or condition, an effective amount of compound or salt of any one of claims 1 to 98 or a pharmaceutical composition of claim 99.

101. A method of treating a disease, disorder, or condition associated with GPR55 receptor activity, comprising administering to a subject in need thereof an effective amount of a compound or salt of any one of claims 1 to 98 or a pharmaceutical composition of claim 99.

102. A method of treating a disease, disorder, or condition expressing GPR55 receptor, comprising administering to a subject in need thereof an effective amount of a compound or salt of any one of claims 1 to 98 or a pharmaceutical composition of claim 99.

103. The method of any one of claims 100-102, wherein the disease, disorder, or condition is selected from a cancer expressing GPR55 receptor.

104. The method of claim 103, wherein the cancer is selected from pancreatic cancer, brain cancer, colon cancer and ER+ breast cancer.

105. The method of claim 103 or 104, wherein the cancer is a metastatic cancer.

106. The method of any one of claims 100-102, wherein the disease, disorder, or condition is epilepsy, seizure or seizures, or seizure or seizures associated with epilepsy.

107. The method of claim 106, wherein the disease, disorder, or condition is epilepsy.

108. The method of claim 107, wherein the epilepsy is pediatric epilepsy or temporal lobe epilepsy.

109. The method of claim 106, wherein the disease, disorder or condition is seizure or seizures.

110. The method of claim 109, wherein seizure or seizures are generalized seizures or partial seizures.

111. The method of any one of claims 100-102, wherein the disease, disorder, or condition is pain.

112. The method of claim 111, wherein the pain is neuropathic pain, inflammatory pain, or visceral pain.

113. A compound or salt of any one of claims 1 to 98, or a pharmaceutical composition of claim 99, for use in a method of treating a GPR55+ disease, disorder, or condition of a subject,.

114. The compound, salt, or composition for use according to claim 113, wherein the disease, disorder, or condition is a GPR55+ cancer.

115. The use of claims 113 or 114, wherein the disease, disorder, or condition is associated with GPR55 activity.

116. Use of a compound or salt of any one of claims 1-98 in the manufacture of a medicament for the treatment of a condition or disease associated with GPR55 activity level.

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