WO2025006553A1

WO2025006553A1 - Metabotropic glutamate receptor positive allosteric modulators and uses thereof

Info

Publication number: WO2025006553A1
Application number: PCT/US2024/035544
Authority: WO
Inventors: Nicholas David Peter Cosford; Douglas J. Sheffler; Dhanya RAVEENDRA-PANICKAR; John Howard Hutchinson
Original assignee: Sanford Burnham Prebys Medical Discovery Institute
Priority date: 2023-06-27
Filing date: 2024-06-26
Publication date: 2025-01-02

Abstract

Provided herein are metabotropic glutamate subtype-2 and -3 receptor positive allosteric modulators (PAMS), compositions comprising said modulators, and methods of using said modulators and pharmaceutical compositions comprising said modulators.

Description

METABOTROPIC GLUTAMATE RECEPTOR POSITIVE ALLOSTERIC

MODULATORS AND USES THEREOF

CROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No. 63/510,547, filed on June 27, 2023, which is incorporated herein by reference in its entirety.

STATEMENT OF GOVERNMENT SUPPORT

[0002] This invention was made with government support under R01 DA023926, U01 DA041731, and U01 DA051077 awarded by the National Institutes of Health. The government has certain rights in the invention.

FIELD OF THE INVENTION

[0003] Described herein are metabotropic glutamate subtype -2 and -3 (mGlu2/3) (collectively Group II mGlus) receptor positive allosteric modulators, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders in which metabotropic glutamate receptors are involved.

SUMMARY

[0004] Described herein are compounds and compositions, and methods of using these compounds and compositions, as positive allosteric modulators of the metabotropic glutamate receptor subtype 2 receptor (mGlu2), and of the metabotropic glutamate receptor subtype 3 receptor (mGlu3) (collectively Group II mGlus), and for treating CNS disorders associated with Group II mGlus.

[0005] One embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,

wherein

X is -0-, -S-, or -NR⁴-;

A is selected from Ci-6 haloalkyl, substituted or unsubstituted Cs-i2 carbocyclyl, or Y¹-/¹; wherein Y^Z¹ is selected from:

Y¹ is a substituted or unsubstituted -CH2-; and Z¹ is selected from substituted cyclopropyl, substituted or unsubstituted C4-C5 cycloalkyl, substituted cyclohexyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted phenyl, provided that when Z¹ is substituted phenyl, the phenyl of Z¹ is not substituted with trifluoromethyl or trifluoromethoxyl; or

Y¹ is an unsubstituted or substituted C2-3 alkylene; and Z¹ is selected from substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted phenyl;

L is absent or Ci-Ce alkylene;

Q is -C(=O)OR⁵, -C(=O)NHOR⁶, -C(=O)NHCN, -C(=O)N(R⁷)₂, -C(=O)NHS(=O)₂R⁶, -

R¹ is a halogen; each R² is independently halogen, nitro, -CN, -OH, -OR⁶, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; m is 0, 1, 2, 3, or 4; each R³ is independently halogen, nitro, -CN, -OH, -OR⁶, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C6 cycloalkyl; n is 0, 1, 2, or 3;

R⁴ is hydrogen or substituted or unsubstituted C1-C4 alkyl; each of R⁵ and R⁶ is independently selected from hydrogen, substituted or unsubstituted Ci- Ce alkyl, or substituted or unsubstituted C3-C6 cycloalkyl; each R⁷ is independently hydrogen, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C6 cycloalkyl; or two R⁷ taken together with the nitrogen to which they are attached to form a substituted or unsubstituted C2-C8 heterocycloalkyl; Y is hydrogen, -OH, -OR⁸, halogen, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C6 cycloalkyl;

Z is hydrogen, -OH, -OR⁸, halogen, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C6 cycloalkyl; and each R⁸ is independently substituted or unsubstituted Ci-

C4 alkyl.

[0006] One embodiment provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof,

Formula (II), wherein

X' is -O- or -S-; ring B is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted heterocycloalkyl; ring C is a substituted or unsubstituted heteroarylene;

L is absent or Ci-Ce alkylene;

Q is -C(=O)OH, -C(=O)OR⁵, -C(=O)NHOR⁶, -C(=O)NHCN, -C(=O)N(R⁷)₂, - C(=O)NHS(=O)₂R⁶, -C(=O)R⁶, -S(=O)₂N(R⁷)₂, -S(=O)₂NHC(=O)R⁶, -

R¹ is a hydrogen or halogen; each R² is independently halogen, nitro, -CN, -OH, -OR⁶, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted cycloalkyl; m is 0, 1, 2, 3, or 4;

R⁵ is substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; R⁶ is hydrogen, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C6 cycloalkyl; each R⁷ is independently hydrogen, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted cycloalkyl; or two R⁷ taken together with the nitrogen to which they are attached to form a substituted or unsubstituted C2-C8 heterocycloalkyl;

Y is hydrogen, -OH, -OR⁸, halogen, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C6 cycloalkyl;

Z is hydrogen, -OH, -OR⁸, halogen, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C6 cycloalkyl; and

R⁸ is substituted or unsubstituted C1-C4 alkyl.

[0007] One embodiment provides a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof,

Formula (III), wherein ring D is selected from substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted aryl;

X' is -O- or -S-;

L is absent or Ci-Ce alkylene;

R¹ is a hydrogen or halogen; each R² is independently halogen, nitro, -CN, -OR⁵, substituted CH3, substituted or unsubstituted C2-C6 alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; m is 0, 1, 2, 3, or 4; each R³ is independently halogen, nitro, -CN, -OH, -OR⁶, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted cycloalkyl; n is 0, 1, 2, 3, or 4;

R⁵ is substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted heterocycloalkyl;

R⁶ is hydrogen, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C6 cycloalkyl; each R⁷ is independently hydrogen, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C6 cycloalkyl; or two R⁷ taken together with the nitrogen to which they are attached to form a substituted or unsubstituted C2-C8 heterocycloalkyl;

Y' is hydrogen, -OH, -OR⁸, -N(R⁹)2, halogen, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted aryl;

Z' is hydrogen, -OH, -OR⁸, -N(R⁹)2, halogen, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted aryl;

R⁸ is substituted or unsubstituted C1-C4 alkyl; each R⁹ is independently hydrogen, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted aryl; or two R⁹ taken together with the nitrogen to which they are attached to form a substituted or unsubstituted C2-C8 heterocycloalkyl; and wherein at least one of Y' and Z' is not hydrogen.

[0008] In one aspect, provided herein is a pharmaceutical composition comprising a compound of Formula (I), (II), (III), or Table 4, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0009] In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by intravenous administration, subcutaneous administration, oral administration, inhalation, nasal administration, dermal administration, or ophthalmic administration.

[0010] In some embodiments, the pharmaceutical composition is in the form of a tablet, a pill, a capsule, a liquid, a suspension, a gel, a dispersion, a solution, an emulsion, an ointment, or a lotion. [0011] In one aspect, described herein is a method of treating a central nervous disorder (CNS) disorder, the method comprising the step of administering to a subject in need thereof, an effective amount of the compound of Formula (I), (II), (III), or Table 4, or a pharmaceutically acceptable salt thereof. In some embodiments, the CNS disorder is an addictive disorder. In some embodiments, the addictive disorder is nicotine addiction, alcohol addiction, opiate addiction, amphetamine addiction, methamphetamine addiction, or cocaine addiction. In some embodiments, the addictive disorder is nicotine addiction. In some embodiments, the addictive disorder is cocaine addiction. In some embodiments, the CNS disorder is schizophrenia. In some embodiments, the CNS disorder is a neurodegenerative disease. In some embodiments, the neurodegenerative disease is Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, or Lou Gehrig's disease (Amyotrophic Lateral Sclerosis or ALS).

[0012] In one aspect, described herein is a method of treating substance abuse, the method comprising the step of administering to a subject in need thereof, an effective amount of the compound of Formula (I), (II), (III), or Table 4, or pharmaceutically acceptable salt thereof, wherein the effective amount is sufficient to diminish, inhibit or eliminate desire for and/or consumption of the substance in the subject. In some embodiments, the substance is nicotine, alcohol, opiates, amphetamines, methamphetamines, or cocaine.

[0013] In one aspect, described herein is a method for treating an addictive disorder, the method comprising the steps of: a) administering to a subject in need thereof, an effective amount of the compound of Formula (I), (II), (III), or Table 4, or pharmaceutically acceptable salt thereof, during a first time period, wherein the first time period is a time period wherein the subject expects to be in an environment wherein, or exposed to stimuli in the presence of which, the subject habitually uses an addictive substance; and b) administering an effective amount of the compound of Formula (I), (II), (III), or Table 4, or pharmaceutically acceptable salt thereof, during a second time period, wherein the second time period is a time period wherein the subject is suffering from withdrawal.

[0014] In one aspect, described herein is a method of treating a disease or condition by modulation of the mGlu2 receptor in a subject in need thereof, which method comprises administering to the subject a therapeutically effective amount of a compound of Formula (I), (II), (III), or Table 4, or a pharmaceutically acceptable salt thereof. In some embodiments, the disease or condition is a CNS disorder.

[0015] In another aspect, described herein is a method of treating a disease or condition by modulation of the mGlu3 receptor in a subject in need thereof, which method comprises administering to the subject a therapeutically effective amount of a compound of Formula (I), (II), (III), or Table 4, or a pharmaceutically acceptable salt thereof. In some embodiments, the disease or condition is a CNS disorder.

[0016] In one aspect, described herein is a method of treating a disease or condition by dual modulation of the mGlu2/3 receptors in a subject in need thereof, which method comprises administering to the subject a therapeutically effective amount of a compound of Formula (I), (II), (III), or Table 4, or a pharmaceutically acceptable salt thereof. In some embodiments, the disease or condition is a CNS disorder.

INCORPORATION BY REFERENCE

[0017] All publications and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

DETAILED DESCRIPTION

[0018] Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS), mediating fast synaptic transmission through ion channels, primarily the a- amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMP A) and kainate ionotropic glutamate receptor subtypes. The metabotropic glutamate (mGlu) receptors are a family of eight G protein-coupled receptors that are activated by glutamate and perform a modulatory function in the nervous system. The Group II mGlu receptors include the mGlu2 and mGlu3 receptor subtypes, which couple with Gi/₀ proteins to negatively regulate the activity of adenylyl cyclase. Localization studies suggest that mGlu2 receptors act predominantly as presynaptic autoreceptors to modulate the release of glutamate into the synaptic cleft (Cartmell, J. and Schoepp, D. D. J. Neurochem. 2000, 75, 889-907). On the other hand, mGlu3 receptors exhibit a broad distribution in the brain and have been shown to be present on astrocytes (Durand, D. et al. Neuropharmacology 2013, 66, 1-11). In addition, it has been shown that activation of mGlu3 receptors is required for the neuroprotective effects of mGlu2/3 agonists toward N-methyl-D-aspartate (NMD A) neurotoxicity in mixed cultures of astrocytes and neurons, whereas activation of mGlu2 receptors may be harmful (Corti, C. et al. J. Neurosci. 2007, 7, 8297-8308).

[0019] Various brain regions, including the cerebral cortex, hippocampus, striatum, amygdala, frontal cortex, and nucleus accumbens, display high levels of mGlu2 and mGlu3 receptor binding. This distribution pattern suggests a role for the mGlu2/3 receptor subtypes in the pathology of neuropsychiatric disorders such as anxiety, depression, schizophrenia, drug dependence, neuroprotection, Alzheimer’s disease, and sleep/wake architecture. Thus, there is significant potential for the development of selective Group II mGlu receptor activators, including agonists and positive allosteric modulators (PAMs), for the treatment of CNS diseases caused by aberrant glutamatergic signaling.

Metabotropic Glutamate Receptor Positive Allosteric Modulators

[0020] One embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,

Formula (I), wherein

X is -O-, -S-, or -NR⁴-;

L is absent or Ci-Ce alkylene; Q is -C(=O)OR⁵, -C(=O)NHOR⁶, -C(=O)NHCN, -C(=O)N(R⁷)₂, -C(=O)NHS(=O)₂R⁶, -

R⁴ is hydrogen or substituted or unsubstituted C1-C4 alkyl; each of R⁵ and R⁶ is independently selected from hydrogen, substituted or unsubstituted Ci- Ce alkyl, or substituted or unsubstituted C3-C6 cycloalkyl; each R⁷ is independently hydrogen, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C6 cycloalkyl; or two R⁷ taken together with the nitrogen to which they are attached to form a substituted or unsubstituted C₂-Cs heterocycloalkyl;

Z is hydrogen, -OH, -OR⁸, halogen, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C6 cycloalkyl; and each R⁸ is independently substituted or unsubstituted Ci- C4 alkyl.

[0021] Another embodiment provides a compound of Formula (I) having the structure of Formula (I- A):

Formula (I- A) or a pharmaceutically acceptable salt or solvate thereof.

[0022] Another embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt solvate thereof, wherein m is 0.

[0023] Another embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

[0024] Another embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is hydrogen.

[0025] Another embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is hydrogen.

[0026] Another embodiment provides a compound of Formula (I) having the structure of Formula (I-B):

Formula (I-B) or a pharmaceutically acceptable salt or solvate thereof.

[0027] Another embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L is absent.

[0028] Another embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Q is -C(=O)OR⁵, -C(=O)NHOR⁶, -C(=O)NHCN, - C(=O)N(R⁷)₂, -C(=O)NHS(=O)₂R⁶, -C(=O)R⁶, -S(=O)₂N(R⁷)₂, -S(=O)₂NHC(=O)R⁶, or - NHC(=O)NHS(=O)₂R⁶.

[0029] Another embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Q is -C(=O)OH.

[0030] Another embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R¹ is fluorine or chlorine.

[0031] Another embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R¹ is chlorine.

[0032] Another embodiment provides a compound of Formula (I) having the structure of Formula (I-C):

Formula (I-C) or a pharmaceutically acceptable salt or solvate thereof.

[0033] Another embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -O- or -NH-.

[0034] Another embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -O-.

[0035] Another embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein A is Ci-Ce haloalkyl, or substituted or unsubstituted Cs-Cn carbocyclyl.

[0036] Another embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein A is 2,2,2-trifluoroethyl, or A is indanyl.

[0037] Another embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein: A is selected from Y¹- Z¹.

[0038] Another embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y¹ is an unsubstituted -CH2-.

[0039] Another embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Z¹ is selected from phenyl, methoxyphenyl, fluorophenyl, or pyridyl.

[0040] Another embodiment provides a compound of Formula (I), or a pharmaceutically

[0041] In some embodiments, the compound is one of the compounds represented in Table 1, or a pharmaceutically acceptable salt or solvate thereof. Table 1

[0042] One embodiment provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof,

Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein

X' is -O- or -S-; ring B is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted heterocycloalkyl; ring C is a substituted or unsubstituted heteroarylene; L is absent or Ci-Ce alkylene;

R⁵ is substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl;

R⁶ is hydrogen, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C6 cycloalkyl; each R⁷ is independently hydrogen, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted cycloalkyl; or two R⁷ taken together with the nitrogen to which they are attached to form a substituted or unsubstituted C2-C8 heterocycloalkyl;

R⁸ is substituted or unsubstituted C1-C4 alkyl.

[0043] Another embodiment provides a compound of Formula (II) having the structure of Formula (II- A):

Formula (II- A), or a pharmaceutically acceptable salt or solvate thereof.

[0044] Another embodiment provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 0.

[0045] Another embodiment provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is hydrogen, -OH, -OR⁸, halogen, substituted or unsubstituted Ci-Ce alkyl, wherein the R⁸ of Y is substituted or unsubstituted Ci-Ce alkyl. [0046] Another embodiment provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is hydrogen.

[0047] Another embodiment provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is hydrogen, -OH, -OR⁸, halogen, or substituted or unsubstituted Ci-Ce alkyl, wherein the R⁸ of Z is substituted or unsubstituted Ci-Ce alkyl. [0048] Another embodiment provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is hydrogen.

[0049] Another embodiment provides a compound of Formula (II) having the structure of Formula (II-B):

Formula (II-B) or a pharmaceutically acceptable salt or solvate thereof.

[0050] Another embodiment provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L is absent.

[0051] Another embodiment provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Q is -C(=O)OH, -C(=O)OR⁵, -C(=O)NHOR⁶, - C(=O)N(R⁷)₂, -C(=O)NHS(=O)₂R⁶, -C(=O)R⁶, -S(=O)₂N(R⁷)₂, -S(=O)₂NHC(=O)R⁶,

wherein each R⁶ and R⁷ of Q is independently hydrogen, or substituted or unsubstituted Ci-Ce alkyl. [0052] Another embodiment provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R⁵ of Q is substituted or unsubstituted Ci-Ce alkyl. [0053] Another embodiment provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Q is -C(=O)OH.

[0054] Another embodiment provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R¹ is independently halogen or hydrogen.

[0055] Another embodiment provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R¹ is independently chloro or hydrogen.

[0056] Another embodiment provides a compound of Formula (II) having the structure of Formula (II-C):

Formula (II-C) or a pharmaceutically acceptable salt or solvate thereof.

[0057] Another embodiment provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein ring B is a substituted or unsubstituted cycloalkyl. [0058] Another embodiment provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein ring B is an unsubstituted Cs-Cecycloalkyl.

[0059] Another embodiment provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein ring B is cyclopentyl.

[0060] Another embodiment provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X' is -O-.

[0061] Another embodiment provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein ring C is a substituted or unsubstituted 5- to 6- membered heteroaryl.

[0062] Another embodiment provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein ring C is an unsubstituted 5- to 6-membered heteroaryl.

[0063] Another embodiment provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein ring C is selected from the group consisting of:

denotes the connection to the phenyl group of Formula (II).

[0064] In some embodiments, the compound is one of the compounds represented in Table 2, or a pharmaceutically acceptable salt or solvate thereof.

Table 2

[0065] One embodiment provides a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof,

or a pharmaceutically acceptable salt or solvate thereof, wherein ring D is selected from substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted aryl;

X' is -O- or -S-;

L is absent or Ci-Ce alkylene;

R¹ is a hydrogen or halogen; each R² is independently halogen, nitro, -CN, -OR⁵, substituted CH3, substituted or unsubstituted C₂-Ce alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; m is 0, 1, 2, 3, or 4; each R³ is independently halogen, nitro, -CN, -OH, -OR⁶, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted cycloalkyl; n is 0, 1, 2, 3, or 4;

R⁶ is hydrogen, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C6 cycloalkyl; each R⁷ is independently hydrogen, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C6 cycloalkyl; or two R⁷ taken together with the nitrogen to which they are attached to form a substituted or unsubstituted C₂-Cs heterocycloalkyl;

Y' is hydrogen, -OH, -OR⁸, -N(R⁹)₂, halogen, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted aryl;

Z' is hydrogen, -OH, -OR⁸, -N(R⁹)₂, halogen, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted aryl;

R⁸ is substituted or unsubstituted C1-C4 alkyl; each R⁹ is independently hydrogen, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted aryl; or two R⁹ taken together with the nitrogen to which they are attached to form a substituted or unsubstituted C₂-Cs heterocycloalkyl; and wherein at least one of Y' and Z' is not hydrogen.

[0066] Another embodiment provides a compound of Formula (III) having the structure of Formula (III- A):

Formula (III- A) or a pharmaceutically acceptable salt or solvate thereof.

[0067] Another embodiment provides a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 0.

[0068] Another embodiment provides a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

[0069] Another embodiment provides a compound of Formula (III) having the structure of Formula (III-B):

or a pharmaceutically acceptable salt or solvate thereof.

[0070] Another embodiment provides a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein L is absent.

[0071] Another embodiment provides a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Q is -C(=O)OH, -C(=O)OR⁵, -C(=O)NHOR⁶, - C(=O)N(R⁷)², -C(=O)NHS(=O)₂R⁶, -C(=O)R⁶, -S(=O)₂N(R⁷)₂, -S(=O)₂NHC(=O)R⁶,

wherein each R⁶ and R⁷ of Q is independently hydrogen or substituted or unsubstituted Ci-Cealkyl.

[0072] Another embodiment provides a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Q is -C(=O)OH.

[0073] Another embodiment provides a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R¹ is halogen.

[0074] Another embodiment provides a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R¹ is chloro.

[0075] Another embodiment provides a compound of Formula (III) having the structure of Formula (III-C):

Formula (III-C) or a pharmaceutically acceptable salt or solvate thereof.

[0076] Another embodiment provides a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Y' is hydrogen, and Z' is -OH, -OR⁸, -N(R⁹)2, halogen, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted aryl.

[0077] Another embodiment provides a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Y' is hydrogen and Z' is -N(R⁹)2, halogen, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted aryl; wherein each R⁹ of Y' is independently hydrogen or unsubstituted aryl.

[0078] Another embodiment provides a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Y' is hydrogen and Z' is -N(R⁹)2, halogen, unsubstituted Ci-Ce alkyl, or unsubstituted aryl; wherein each R⁹ of Y' is independently hydrogen or phenyl. [0079] Another embodiment provides a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Y' is hydrogen and Z' is selected from bromo,

„ H x T J methyl, phenyl, or

[0080] Another embodiment provides a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Z' is hydrogen and Y' is -OH, -OR⁸, -N(R⁹)2, halogen, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C3- cycloalkyl, or substituted or unsubstituted aryl.

[0081] Another embodiment provides a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Z' is hydrogen and Y' is -N(R⁹)2, halogen, unsubstituted Ci-Ce alkyl, or unsubstituted aryl; wherein each R⁹ of Y' is independently hydrogen or phenyl.

[0082] Another embodiment provides a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Z' is hydrogen and Y' is unsubstituted Ci-Ce alkyl. [0083] Another embodiment provides a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Z' is hydrogen and Y' is CH3.

[0084] Another embodiment provides a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein X' is -O-.

[0085] Another embodiment provides a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein ring D is a substituted or unsubstituted C3-C8 cycloalkyl.

[0086] Another embodiment provides a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein ring D is an unsubstituted C3-C6 cycloalkyl.

[0087] Another embodiment provides a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein ring D is cyclopentyl.

[0088] In some embodiments, the compound is one of the compounds represented in Table 3, or a pharmaceutically acceptable salt or solvate thereof.

Table 3

[0089] In some embodiments, the compound is one of the compounds represented in Table 4, or a pharmaceutically acceptable salt or solvate thereof.

Table 4

Further Forms of Compounds Disclosed Herein

Isomer s/Stereoisomers

[0090] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration, or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.

Labeled compounds

[0091] In some embodiments, the compounds described herein exist in their isotopically- labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chloride, such as ²H (D), ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷0, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶C1, respectively. Compounds described herein, and the pharmaceutically acceptable salts or solvates thereof which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds, for example those into which radioactive isotopes such as ³H and ¹⁴C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., ³H and carbon-14, i.e., ¹⁴C, isotopes are particularly preferred for their ease of preparation and detectability. Certain isotopically-labeled compounds, for example those into which radioactive isotopes such as ¹⁸F and ⁿC are incorporated, are useful in Positron Emission Tomography (PET), Positron Emission Tomography-Computed Tomography (PET/CT) scanning. The use of radiotracers allows for evaluation of drug distribution, receptor occupancy, diagnosis, treatment, and evaluation of various diseases.

[0092] In some embodiments, the abundance of deuterium in each of the substituents disclosed herein is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% of a total number of hydrogen and deuterium. In some embodiments, one or more of the substituents disclosed herein comprise deuterium at a percentage higher than the natural abundance of deuterium. In some embodiments, one or more hydrogens are replaced with one or more deuteriums in one or more of the substituents disclosed herein.

Pharmaceutically acceptable salts

[0093] In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0094] In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or a solvate thereof, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.

[0095] Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, acetic acid, trifluoroacetic acid, salicylic acid and the like.

[0096] In some embodiments, those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N⁺(CI-4 alkyl)4 hydroxide, and the like.

Tautomers

[0097] In addition, the compounds generically or specifically disclosed herein are intended to include all tautomeric forms. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated.

Synthesis of Compounds

[0098] The compounds described herein are made according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and/or from compounds described in the chemical literature.

[0099] In other embodiments, the starting materials and reagents used for the synthesis of the compounds described herein are synthesized or are obtained from commercial sources, such as, but not limited to, Sigma-Aldrich, Fisher Scientific (Fisher Chemicals), and Acros Organics. Synthetic routes to prepare the starting materials and compounds described herein can be developed using the Reaxys® Predictive Retrosynthesis tool.

[00100] Specific and analogous reactants are optionally identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society or Reaxys® of Elsevier, which are available in most public and university libraries, as well as through on-line databases. Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis houses, where many of the standard chemical supply houses (e.g., those listed above) provide custom synthesis services.

[00101] In one aspect, compounds are synthesized as described in the Examples section.

Definitions

[00102] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the invention may be practiced without these details. In other instances, well- known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments. Unless the context requires otherwise, throughout the specification and claims which follow, 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.” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[00103] As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. It should also be noted that the term “or” is generally employed in its sense including “and/or” unless the content clearly dictates otherwise.

[00104] The terms below, as used herein, have the following meanings, unless indicated otherwise:

[00105] “oxo” refers to =0.

[00106] “Carboxyl” refers to -COOH.

[00107] “Alkyl” refers to a straight-chain, or branched-chain fully saturated hydrocarbon monoradical having from one to about ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, 2-methyl- 1 -propyl, 2-methyl-2-propyl, 2 -m ethyl- 1 -butyl, and the like. Whenever it appears herein, a numerical range such as “Ci-Ce alkyl” or “Ci-ealkyl”, means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, the alkyl is a Ci-ioalkyl. In some embodiments, the alkyl is a Ci-ealkyl. In some embodiments, the alkyl is a Ci-salkyl. In some embodiments, the alkyl is a C alkyl. In some embodiments, the alkyl is a Ci-3alkyl. When indicated an alkyl group may be substituted with one, two, three, four, five or six groups each independently selected from oxo, halogen, -NH2, -CN, -NO2, -OH, C1-6 haloalkyl, C1-6 alkoxy, carboxyl, aryl, C3-10 cycloalkyl, heterocycloalkyl, and heteroaryl. In some embodiments, the alkyl is substituted with one or more -NH2, or aryl groups. In some embodiments, the alkyl is substituted with oxo, halogen, -CN, -COOH, -COOCH3, -OH, - OCH3, -NH2, or -NO2. In some embodiments, the alkyl is optionally substituted with halogen, -CN, -OH, or - OCH3. In some embodiments, the alkyl is substituted with halogen.

[00108] “Alkylene” refers to a straight or branched divalent hydrocarbon chain. Whenever it appears herein, a numerical range such as “Ci-Ce alkylene” or “C1-6 alkylene”, means that the alkylene group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkylene” where no numerical range is designated. In some embodiments, the alkylene is a C1-15 alkylene. In some embodiments, the alkylene is a C1-6 alkylene. In some embodiments, the alkylene is a Ce-io alkylene. In some embodiments, the alkylene is a C10-15 alkylene. In some embodiments, the alkylene is a C3-10 alkylene. In some embodiments, the alkylene is a C3-8 alkylene. When indicated an alkylene group may be substituted with one, two, three, four, five or six groups each independently selected from oxo, halogen, -NH2, -CN, -NO2, -OH, C1-6 haloalkyl, C1-6 alkoxy, carboxyl, aryl, C3-10 cycloalkyl, heterocycloalkyl, and heteroaryl. In some embodiments, the alkylene is substituted with oxo, halogen, -CN, -COOH, COOCH3, -OH, -OCH3, -NH2, or -NO2. In some embodiments, the alkylene is substituted with halogen, -CN, -OH, or -OCH3. In some embodiments, the alkylene is substituted with halogen.

[00109] “Alkoxy” refers to a radical of the formula -ORa where Ra is an alkyl radical as defined. When indicated an alkoxy group may be substituted with one, two, three, four, five or six groups each independently selected from oxo, halogen, -NH2, -CN, -NO2, -OH, C1-6 haloalkyl, C1-6 alkoxy, carboxyl, aryl, C3-10 cycloalkyl, heterocycloalkyl, and heteroaryl. In some embodiments, the alkoxy is substituted with halogen, -CN, -COOH, COOCH3, -OH, - OCH3, -NH2, or -NO2. In some embodiments, the alkoxy is substituted with halogen, -CN, - OH, or -OCH3. In some embodiments, the alkoxy is substituted with halogen. In some embodiments, the substituted alkoxy is -OCF3.

[00110] “Aryl” refers to a radical derived from a hydrocarbon ring system comprising 6 to 20 carbon atoms and at least one aromatic ring. The aryl radical may be a monocyclic, bicyclic, or tricyclic ring system. In some embodiments, the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl (phenyl). Examples of aryl groups include phenyl, naphthyl, phenanthrene, and the like. When indicated an aryl may be substituted with one, two, three, four, five or six groups each independently selected from halogen, -NH2, - CN, -NO2, -OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, carboxyl, aryl, C3-10 cycloalkyl, heterocycloalkyl, and heteroaryl. In some embodiments, the aryl is optionally substituted with one or more -NH2 groups. In some embodiments, the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOCH3, -CF3, -OH, -OCH3, -NH2, or -NO2. In some embodiments, the aryl is substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OCH3. In some embodiments, the aryl is substituted with halogen.

[00111] “Carboxy” refers to -CO2H. In some embodiments, carboxy moieties may be replaced with

.

[00112] “Cycloalkyl” refers to a partially or fully saturated, monocyclic, or polycyclic carbocyclic ring, which may include fused, spiro, or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated. In other embodiments, the cycloalkyl has unsaturation and is referred to as a cycloalkenyl ring system. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (C3-C15 cycloalkyl or C3-C15 cycloalkenyl), from three to ten carbon atoms (C3-C10 cycloalkyl or C3- C10 cycloalkenyl), from three to eight carbon atoms (C3-C8 cycloalkyl or C3-C8 cycloalkenyl), from three to six carbon atoms (C3-C6 cycloalkyl or C3-C6 cycloalkenyl), from three to five carbon atoms (C3-C5 cycloalkyl or C3-C5 cycloalkenyl), or three to four carbon atoms (C3-C4 cycloalkyl or C3-C4 cycloalkenyl). In some embodiments, the cycloalkyl is a 3 - to 10- membered cycloalkyl or a 3- to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3- to 6-membered cycloalkyl or a 3 - to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5- to 6-membered cycloalkyl or a 5- to 6-membered cycloalkenyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cisdecalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Polycyclic cycloalkyls fused to an aromatic ring system include, for example, 1 -indanyl, 2- indanyl, or 3-indanyl. Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. When indicated a cycloalkyl is substituted with one, two, three, four, five or six groups each independently selected from oxo, halogen, - NH2, -CN, -NO2, -OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, carboxyl, aryl, C3-10 cycloalkyl, heterocycloalkyl, and heteroaryl. In some embodiments, a cycloalkyl is substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOCH3, -CF3, -OH, -OCH3, - NH2, or -NO2. In some embodiments, a cycloalkyl is substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OCH3. In some embodiments, the cycloalkyl is substituted with halogen. [00113] “Halo” or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[00114] “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, tri chloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2- dibromoethyl, and the like. In some embodiments, a haloalkyl is fluoroalkyl. In some embodiments, a haloalkyl is chloroalkyl. In some embodiments, a haloalkyl is bromoalkyl. In some embodiments, a haloalkyl is iodoalkyl. In some embodiments, a haloalkyl is -CF3. In some embodiments, a haloalkyl is -CCI3.

[00115] “Heterocycloalkyl” refers to a 3 - to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, silicon, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl comprises one to three nitrogens. In some embodiments, the heterocycloalkyl comprises one or two nitrogens. In some embodiments, the heterocycloalkyl comprises one nitrogen. In some embodiments, the heterocycloalkyl comprises one nitrogen and one oxygen. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom), spiro, or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized. Representative heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (C2-C15 heterocycloalkyl or C2-C15 heterocycloalkenyl), from two to ten carbon atoms (C2-C10 heterocycloalkyl or C2-C10 heterocycloalkenyl), from two to eight carbon atoms (C2-C8 heterocycloalkyl or C2-C8 heterocycloalkenyl), from two to seven carbon atoms (C2-C7 heterocycloalkyl or C2-C7 heterocycloalkenyl), from two to six carbon atoms (C2-C6 heterocycloalkyl or C2-C7 heterocycloalkenyl), from two to five carbon atoms (C2-C5 heterocycloalkyl or C2-C5 heterocycloalkenyl), or two to four carbon atoms (C2-C4 heterocycloalkyl or C2-C4 heterocycloalkenyl). Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, pyranyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, and thiamorpholinyl. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e., skeletal atoms of the heterocycloalkyl ring). In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkenyl. When indicated a heterocycloalkyl may be substituted with one, two, three, four, five or six groups each independently selected from oxo, halogen, -NH2, -CN, -NO2, -OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, carboxyl, aryl, C3-10 cycloalkyl, heterocycloalkyl, and heteroaryl. In some embodiments, the heterocycloalkyl is substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOCH3, -CF3, -OH, -OCH3, -NH2, or -NO2. In some embodiments, the heterocycloalkyl is substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OCH3. In some embodiments, the heterocycloalkyl is substituted with halogen.

[00116] “Heteroaryl” refers to a 5- to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring containing a heteroatom. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl comprises one to three nitrogens. In some embodiments, the heteroaryl comprises one or two nitrogens. In some embodiments, the heteroaryl comprises one nitrogen. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system. In some embodiments, the heteroaryl is a 5- to 10- membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl. In some embodiments, the heteroaryl is a 6-membered heteroaryl. In some embodiments, the heteroaryl is a 5-membered heteroaryl. Examples include, but are not limited to, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, benzofuranyl, benzothienyl, benzotri azolyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophene, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, isoquinolyl, indolizinyl, isoxazolyl, 1,8-naphthyridinyl, oxadiazolyl, oxazolyl, phenazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thienyl. When indicated a heteroaryl may be substituted with one, two, three, four, five or six groups each independently selected from halogen, -NH2, -CN, -NO2, -OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, carboxyl, aryl, C3-10 cycloalkyl, heterocycloalkyl, and heteroaryl. In some embodiments, the heteroaryl is substituted with halogen, methyl, ethyl, -CN, -COOH, COOCH3, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroaryl is substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OCH3. In some embodiments, the heteroaryl is substituted with halogen.

[00117] Whenever a group is described as being “unsubstituted or substituted” it means that the subsequently described group may be substituted with one, two, three, four, five or six of the indicated substituents. For example, “unsubstituted or substituted alkyl” means either “alkyl” without substitution or “substituted alkyl” with one, two, three, four, five or six of the indicated substituents as defined above. It will be understood by those skilled in the art with respect to any group containing one or more substituents that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical and/or synthetically non-feasible.

[00118] The terms “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate “effective” amount in any individual case may be determined using techniques, such as a dose escalation study.

[00119] The term “pharmaceutical combination” as used herein, means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term “fixed combination” means that the active ingredients, e.g., a compound of Formula (I), (II), or (III), or Table 4, or pharmaceutically acceptable salt thereof, and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage. The term “non-fixed combination” means that the active ingredients, e.g., a compound of Formula (I), (II), or (III), or Table 4, or pharmaceutically acceptable salt thereof, and a co-agent, are administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides effective levels of the two compounds in the body of the patient. The latter also applies to cocktail therapy, e.g., the administration of three or more active ingredients.

[00120] The term “subject” or “patient” encompasses mammals. Examples of mammals include, but are not limited to, humans. In one embodiment, the mammal is a human. [00121] The terms “treat,” “treating” or “treatment,” as used herein, include alleviating, abating or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically.

[00122] A "tautomer" refers to a proton shift from one atom of a molecule to another atom of the same molecule. The compounds presented herein may exist as tautomers. Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Some examples of tautomeric interconversions include:

Dosing

[00123] In certain embodiments, the compositions containing the compound(s) described herein are administered for prophylactic and/or therapeutic treatments. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient’s health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and/or dose ranging clinical trial.

[00124] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition. Such an amount is defined to be a “prophylactically effective amount or dose.” In this use, the precise amounts also depend on the patient’s state of health, weight, and the like. When used in patients, effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient’s health status and response to the drugs, and the judgment of the treating physician. In one aspect, prophylactic treatments include administering to a mammal, who previously experienced at least one symptom of or risk factor for the disease being treated and is currently in remission, a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, in order to prevent a return of the symptoms of the disease or condition.

[00125] In certain embodiments wherein a patient’s status does improve, the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (i.e., a “drug holiday”). In specific embodiments, the length of the drug holiday is between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, or more than 28 days. The dose reduction during a drug holiday is, by way of example only, by 10%-100%, including by way of example only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.

[00126] The amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but nevertheless is determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.

[00127] In general, however, doses employed for adult human treatment are typically in the range of 0.01 mg-5000 mg per day. In one aspect, doses employed for adult human treatment are from about 1 mg to about 1000 mg per day. In one embodiment, the desired dose is conveniently presented in a single dose or in divided doses administered simultaneously or at appropriate intervals, for example as two, three, four or more sub-doses per day.

[00128] In one embodiment, the daily dosages appropriate for the compound described herein, or a pharmaceutically acceptable salt thereof, are from about 0.01 to about 50 mg/kg per body weight. In some embodiments, the daily dosage or the amount of active in the dosage form are lower or higher than the ranges indicated herein, based on a number of variables in regard to an individual treatment regime. In various embodiments, the daily and unit dosages are altered depending on a number of variables including, but not limited to, the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.

[00129] In any of the aforementioned aspects are further embodiments in which the effective amount of the compound described herein, or a pharmaceutically acceptable salt thereof, is: (a) systemically administered to the mammal; and/or (b) administered orally to the mammal; and/or (c) intravenously administered to the mammal; and/or (d) administered by injection to the mammal; and/or (e) administered topically to the mammal; and/or (f) administered non- systemically or locally to the mammal.

[00130] In any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered once a day; or (ii) the compound is administered to the mammal multiple times over the span of one day. [00131] In any of the aforementioned aspects are further embodiments comprising multiple administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered continuously or intermittently: as in a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the compound is administered to the mammal every 8 hours; (iv) the compound is administered to the subject every 12 hours; (v) the compound is administered to the subject every 24 hours. In further or alternative embodiments, the method comprises a drug holiday, wherein the administration of the compound is temporarily suspended or the dose of the compound being administered is temporarily reduced; at the end of the drug holiday, dosing of the compound is resumed. In one embodiment, the length of the drug holiday varies from 2 days to 1 year.

Routes of Administration

[00132] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. In addition, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections. Pharmaceutical Compositions and Formulations

[00133] The compounds described herein are administered to a subject in need thereof, either alone or in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice. In one embodiment, the compounds of this invention may be administered to animals. The compounds can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.

[00134] One embodiment provides a pharmaceutical composition comprising a compound of any one of Formula (I), Formula (I-A), Formula (II), Formula (III), Table 4, or a pharmaceutically acceptable salt, or solvate thereof, and at least one pharmaceutically acceptable excipient.

[00135] Another embodiment provides a pharmaceutical composition comprising a compound of any one of Formula (I), Formula (II), Formula (III), Table 4, or a pharmaceutically acceptable salt or solvate thereof, wherein the pharmaceutical composition is formulated for administration to a mammal by intravenous administration, subcutaneous administration, oral administration, inhalation, nasal administration, dermal administration, or ophthalmic administration. [00136] One embodiment provides a pharmaceutical composition comprising a compound of any one of Formula (I), Formula (II), Formula (III), Table 4, or a pharmaceutically acceptable salt or solvate thereof, wherein the pharmaceutical composition is in the form of a tablet, a pill, a capsule, a liquid, a suspension, a gel, a dispersion, a solution, an emulsion, an ointment, or a lotion.

[00137] In another aspect, provided herein are pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein can be 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 & Wilkinsl999), herein incorporated by reference for such disclosure.

[00138] In some embodiments, the pharmaceutically acceptable excipient is selected from carriers, binders, filling agents, suspending agents, flavoring agents, sweetening agents, disintegrating agents, dispersing agents, surfactants, lubricants, colorants, diluents, solubilizers, moistening agents, plasticizers, stabilizers, penetration enhancers, wetting agents, anti-foaming agents, antioxidants, preservatives, and any combinations thereof. [00139] The pharmaceutical compositions described herein are administered to a subject by appropriate administration routes, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal administration routes.

[00140] Pharmaceutical compositions including compounds described herein, or a pharmaceutically acceptable salt or solvate thereof are manufactured in a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or compression processes.

[00141] "Pharmaceutically acceptable salt" includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[00142] "Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.

[00143] "Pharmaceutically acceptable base addition salt" refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, ethylenediamine, ethylenedianiline, A-methylglucamine, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like.

[00144] Pharmaceutical compositions for oral use are obtained by mixing one or more solid excipient with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If desired, disintegrating agents are added, such as the cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

Method of Treatment

[00145] Disclosed herein is a method of treating a central nervous system (CNS) disorder, the method comprising the step of administering to a subject in need thereof, an effective amount of the compound disclosed herein, thereby treating the disorder. In some embodiments, the disorder is an addictive disorder. In some embodiments, the addictive disorder is nicotine addiction, alcohol addiction, opiate addiction, amphetamine addiction, methamphetamine addiction, or cocaine addiction. In some embodiments, the addictive disorder is nicotine addiction. In some embodiments, the addictive disorder is cocaine addiction. In some embodiments, the CNS disorder is schizophrenia. In some embodiments, the CNS disorder is a neurodegenerative disease. In some embodiments, the neurodegenerative disease is Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, or Lou Gehrig's disease (Amyotrophic Lateral Sclerosis or ALS).

[00146] Also disclosed herein is a method of treating substance abuse, the method comprising the step of administering to a subject in need thereof, an effective amount of a compound of Formula (I), (II), or (III), or Table 4, or pharmaceutically acceptable salt thereof, wherein the effective amount is sufficient to diminish, inhibit or eliminate desire for and/or consumption of the substance in the subject. In some embodiments, the substance is nicotine, alcohol, opiates, amphetamines, methamphetamines, or cocaine. In some embodiments, the substance is nicotine. In some embodiments, the substance is alcohol. In some embodiments, the substance is opiates. In some embodiments, the substance is amphetamines. In some embodiments, the substance is methamphetamines. In some embodiments, the substance is cocaine.

[00147] Also disclosed herein is a method for treating an addictive disorder, the method comprising the steps of: a) administering to a subject in need thereof, an effective amount of a compound disclosed herein, during a first time period, wherein the first time period is a time period wherein the subject expects to be in an environment wherein, or exposed to stimuli in the presence of which, the subject habitually uses an addictive substance; and b) administering an effective amount of the compound during a second time period, wherein the second time period is a time period wherein the subject is suffering from withdrawal. Positive Allosteric Modulator (PAM)

[00148] Allosteric modulators are substances which indirectly influence (modulates) the effects of an agonist or inverse agonist at a receptor. Allosteric modulators bind to a site distinct from that of the orthosteric agonist binding site. Usually they induce a conformational change within the protein structure. A positive allosteric modulator (PAM), which is also called an allosteric enhancer, induces an amplification of the agonist’s effect. PAMs, through their interaction at allosteric sites on the mGlu receptor, positively modulate (i.e., potentiate) the effects of the endogenous orthosteric mGlu agonist glutamate. The advantages of PAMs compared with orthosteric agonists includes enhanced subtype-selectivity, the potential for spatial and temporal modulation of receptor activation, and ease of optimization and finetuning of drug-like properties. Studies showed that selectively activating mGlu2 receptors on cocaine or nicotine dependence, unlike mGlu2/3 orthosteric agonists, decreased cocaine selfadministration in rats at doses that did not affect responding for food. Data suggests that mGlu2 receptor PAMs have the potential for therapeutic utility in the treatment of drug dependence.

[00149] There have been many accounts in the literature describing selective mGlu2 receptor PAMs, whereas very little has been reported on compounds which potentiate the effects of glutamate at mGlu3 receptors. This is somewhat surprising given the significant sequence homology (approximately 75%) within the transmembrane regions of mGlu2 and mGlu3 receptors. Considering the dearth of information on mixed mGlu2/3 receptor PAMs, the development of such compounds would provide valuable pharmacological tools. For example, a CNS penetrant mGlu2/3 receptor PAM could facilitate investigations into whether effects on food responding in rats are due to general activation of mGlu3 receptors or an effect specific to direct activation of the mGlu receptor by agonists that act at the mGlu orthosteric binding site.

[00150] In some embodiments, the compounds described herein are mGlu2/3 receptor PAMs. In some embodiments, the compounds described herein are used to treat a CNS disorder. In some embodiments, the CNS disorder is anxiety. In some embodiments, the CNS disorder is depression. In some embodiments, the CNS disorder is schizophrenia. In another some embodiments, the CNS disorder is an addictive disorder. In some embodiments, the addictive disorder is nicotine addiction, alcohol addiction, opiate addiction, amphetamine addiction, methamphetamine addiction, or cocaine addiction. In some embodiments, the addictive disorder is nicotine addiction. In some embodiments, the addictive disorder is cocaine addiction. [00151] In one aspect, described herein is a method of treating a disease or condition by modulation of the mGlu2 receptor in a subject in need thereof, which method comprises administering to the subject a therapeutically effective amount of a compound of Formula (I), (II), (III), or Table 4, or a pharmaceutically acceptable salt thereof. In some embodiments, the disease or condition is a CNS disorder.

[00152] In another aspect, described herein is a method of treating a disease or condition by modulation of the mGlu3 receptor in a subject in need thereof, which method comprises administering to the subject a therapeutically effective amount of a compound of Formula (I), (II), (III), or Table 4, or a pharmaceutically acceptable salt thereof. In some embodiments, the disease or condition is a CNS disorder.

[00153] In one aspect, described herein is a method of treating a disease or condition by dual modulation of the mGlu2/3 receptors in a subject in need thereof, which method comprises administering to the subject a therapeutically effective amount of a compound of Formula (I), (II), (III), or Table 4, or a pharmaceutically acceptable salt thereof. In some embodiments, the disease or condition is a CNS disorder.

[00154] In another aspect the disclosure provides methods for treating substance abuse, by administering to a subject in need thereof, an effective amount of a compound having Formula (I), (II), or (III), or Table 4, or pharmaceutically acceptable salt thereof, wherein the effective amount is sufficient to diminish, inhibit or eliminate desire for and/or consumption of the substance in the subject.

[00155] In another aspect the disclosure provides methods for treating substance abuse, wherein the substance is nicotine, alcohol, opiates, amphetamines, methamphetamines, or cocaine.

[00156] In another aspect the disclosure provides a method for treating an addictive disorder, by a) administering to a subject in need thereof, an effective amount of a compound having Formula (I), (II), or (III), or Table 4, or pharmaceutically acceptable salt thereof, during a first time period, wherein the first time period is a time period wherein the subject expects to be in an environment wherein, or exposed to stimuli in the presence of which, the subject habitually uses an addictive substance; and b) administering an effective amount of a compound having Formula I during a second time period, wherein the second time period is a time period wherein the subject is suffering from withdrawal.

[00157] In some embodiments, the CNS disorder is a neurodegenerative disease. In some embodiments, the neurodegenerative disease is Alzheimer’s disease. In some embodiments, the neurodegenerative disease is Parkinson’s disease. In some embodiments, the neurodegenerative disease is Huntington’s disease. In some embodiments, the neurodegenerative disease is Lou Gehrig's disease (Amyotrophic Lateral Sclerosis or ALS). In some embodiments, the compounds described herein provide neuroprotection.

Anxiety

[00158] Anxiety is an unpleasant state of inner turmoil, often accompanied by nervous behavior, such as pacing back and forth, somatic complaints and rumination. It is the subjectively unpleasant feelings of dread over anticipated events, such as the feeling of imminent death. Anxiety is a feeling of fear, worry, and uneasiness, usually generalized and unfocused as an overreaction to a situation that is only subjectively seen as menacing. It is often accompanied by muscular tension, restlessness, fatigue and problems in concentration. Anxiety can be appropriate, but when experienced regularly the individual may suffer from an anxiety disorder.

[00159] In some embodiments, the compounds described herein are mGlu2/3 receptor PAM used for treating anxiety symptoms. The method includes administering to a subject in need thereof, an effective amount of at least one mGlu2/3 receptor PAM, thereby treating the anxiety symptoms.

Depression

[00160] Depression is a state of low mood and aversion to activity that can affect a person's thoughts, behavior, feelings and sense of well-being. People with depressed mood can feel sad, anxious, empty, hopeless, helpless, worthless, guilty, irritable or restless. They may lose interest in activities that were once pleasurable, experience loss of appetite or overeating, have problems concentrating, remembering details or making decisions, and may contemplate, attempt or commit suicide. Insomnia, excessive sleeping, fatigue, aches, pains, digestive problems or reduced energy may also be present. Depressed mood is a feature of some psychiatric syndromes such as major depressive disorder, but it may also be a normal reaction to life events such as bereavement, a symptom of some bodily ailments or a side effect of some drugs and medical treatments.

[00161] Blockade of mGlu2/3 receptors has antidepressant properties as reflected in reversal of the negative affective (depression-like) aspects of nicotine withdrawal. Thus, blockade of mGlu2 and mGlu3 reverses depression-like symptoms observed during drug withdrawal, and possibly depression observed during drug dependence (Ahmed, S. H., et al. Nature Neuroscience, 5: 625-626 (2002)). Therefore, administration of an effective amount of an antagonist of mGlu2 and mGlu3 is likely to be efficacious for treating non-drug-induced depressions, based on the known neurobiological similarities mediating drug- and non-drug- induced depressions (Markou et al. 1998; Barr et al., 2002; Cryan et al., 2002; Harrison et al., Neuropsychopharmacology, 25:55-71 (2001); Markou A and Kenny P J 2002, Neurotoxicity Research, 4(4), 297-313).

[00162] In some embodiments, the compounds described herein are mGlu2/3 receptor PAM used for treating depressive symptoms and anxiety symptoms of depression. The method includes administering to a subject in need thereof, an effective amount of at least one antagonist which modulates the mGlu2 and/or mGlu3 receptor, thereby treating the depressive symptoms and anxiety symptoms. In another aspect, the disclosure provides at least one mGlu2/3 receptor PAM that can be administered during a depressed time period, wherein the subject experiences symptoms of depression.

Nicotine Addiction

[00163] Nicotine dependence is an addiction to tobacco products caused by the drug nicotine. Nicotine dependence means a person can't stop using the substance, even though it's causing harm. Nicotine produces physical and mood-altering effects in your brain that are temporarily pleasing. These effects make you want to use tobacco and lead to dependence. At the same time, stopping tobacco use causes withdrawal symptoms, including irritability and anxiety.

[00164] In certain aspects, the effective amount of at least one mGlu2/3 receptor PAM is administered to decrease nicotine consumption. For example, in one aspect an effective amount of a PAM of mGlu2 and/or mGlu3, can be administered to decrease nicotine consumption. In certain aspects of the disclosure, a PAM of mGlu2 and/or mGlu3 is administered while a subject is experiencing withdrawal. In another aspect of the disclosure, a PAM of mGlu2 and/or mGlu3 is administered during a time period when a subject is actively using an addictive substance. In another aspect of the disclosure, a PAM of mGlu2 and/or mGlu3 is administered during a time period when a subject is actively experiencing depression associated with drug use or not associated with drug use.

Cocaine Addiction

[00165] Cocaine addiction remains a major public health problem in the United States. There are several sources of motivation that contribute to the continuance of cocaine abuse, including: the positive reinforcing effects of cocaine; and the alleviation of the negative affective aspects of cocaine withdrawal. Conditioned stimuli previously associated with cocaine administration may also elicit conditioned "cravings" leading to the reinstatement of cocaine-seeking behavior even after a prolonged period of abstinence. Recent studies indicate that the neuronal mechanisms underlying various aspects of drug abuse may differ necessitating the use of different treatments for specific aspects of drug dependence. To date, a safe and effective pharmacological treatment for cocaine dependence has yet to be identified. Thus, there remains a need for the design of new chemical entities that can be used as novel medications for cocaine addiction.

[00166] It has been found that repeated cocaine exposure may alter the function of Group II metabotropic glutamate receptors (mGluII receptors), pointing to a possible role of these mGlu subtypes in the development of cocaine dependence. The mGluII receptor positive modulators may decrease the reinforcing effects of self-administered cocaine in rats that had extended access to cocaine, a putative model of cocaine dependence while having no effect in rats with limited access to cocaine. Positive mGluII receptor modulators may attenuate discriminatory cue-induced reinstatement of cocaine self-administration. In contrast, mGluII receptor negative modulators may reverse the reward deficits associated with early cocaine abstinence.

[00167] Cocaine addiction is a chronic relapsing disorder and remains a major public health problem in the United States. The number of cases of cocaine abuse has steadily risen in the past decade. To date, a safe and effective pharmacological treatment for cocaine dependence has yet to be identified, which highlights the need to design new chemical entities that may become future novel medications for cocaine addiction. Recent evidence suggests that mGlus play a significant role in the abuse-related effects of cocaine. For example, repeated administration of cocaine has been shown to alter the function of mGlus, as well as their regulation by cysteine/glutamate exchange in the nucleus accumbens. These findings suggest that mGlu2 may be involved in the development of cocaine dependence and may represent a possible target for drug discovery against different aspects of cocaine abuse and dependence. There are several sources of motivation that contribute to the maintenance of cocaine abuse. These include the positive reinforcing effects of cocaine and alleviation of the negative affective aspects of cocaine withdrawal. Further, conditioned stimuli previously associated with cocaine administration may elicit conditioned "cravings" leading to the reinstatement of cocaine-seeking behavior even after a prolonged period of abstinence. Recent studies suggest that the neuronal mechanisms underlying drug self-administration are different from those mediating relapse vulnerability during abstinence, and different from those mediating the negative effects of early drug withdrawal. Therefore, it is important to explore concurrently the neurochemical mechanisms that contribute to the different aspects of cocaine dependence using animal models assessing the positive reinforcing effects of cocaine, the negative affective symptoms of early withdrawal, and cue-induced reinstatement of cocaine-seeking behavior after prolonged abstinence from drug intake. The discovery and preclinical testing of highly selective mGluII receptor modulators with good brain penetration may significantly contribute to the discovery of novel therapeutic treatments for different aspects cocaine dependence.

[00168] The intravenous drug self-admini strati on procedure provides a reliable and robust model of human drug consumption. This procedure in animals provides a valid model of human drug abuse as studied in a controlled laboratory situation. Self-administration of drugs of abuse is thought to provide an operational measure of the rewarding effects of the drug. Increases in excitatory glutamatergic transmission are likely to contribute to the positive reinforcing properties of addictive drugs. Neurochemical studies indicate that systemic cocaine administration increase glutamate levels in the ventral tegmental area (VTA) and the nucleus accumbens, brain structures that are integral components of the extended amygdala, a brain circuit mediating the reward effects of all major drugs of abuse. The administration of a positive modulator of mGluII receptors may decrease cocaine self-administration in rats with extended access to cocaine by decreasing glutamate neurotransmission in limbic structures similar to the effects of mGlu2/3 agonists. In contrast, a negative modulator of mGluII receptors will most likely have no effect on cocaine self-administration, or possibly will shift the dose-response curve to the left, potentiating the reinforcing effects of cocaine.

[00169] Another challenge for the treatment of drug addiction is chronic vulnerability to relapse. One of the factors that precipitates drug craving and relapse to drug taking behavior in humans is environmental stimuli previously associated with drug-taking. These drug- associated stimuli can be divided into two categories: discrete drug cues (e.g., drug paraphernalia) that are associated with the rewarding effects of the drug, and discriminatory and contextual drug cues (e.g., specific environmental stimuli or specific environments) that predicts drug availability. In animals, discrete, discriminative and contextual conditioned cues can reinstate drug-seeking behavior, measured by variables derived from the reinstatement procedure. Recent data showed that reinstatement of cocaine-seeking was attenuated by systemic injections of N-acetylcysteine that leads to a tonic increase in nucleus accumbens glutamate levels in rats. Preliminary results in humans suggest that N- acetyl cysteine attenuated cocaine craving in addicted humans. Further, exposure to environmental cues previously paired with cocaine injections increased glutamate in the nucleus accumbens. A potential use for mGlu2/3 agonists as pharmacotherapeutic agents to inhibit relapse was recently shown using different rodent models of reinstatement. In some embodiments, mGlu2/3 agonists attenuate cocaine-seeking behavior induced by discriminative cocaine-associated cues or by cocaine priming. In addition, mGlu2/3 agonists have been shown to inhibit cue-induced reinstatement of heroin-seeking, alcohol-seeking, nicotine-seeking, and also inhibited food-seeking behavior. The decreases in cue-induced food responding suggest that the administration of mGlu2/3 agonist decreased motivation for a natural reinforcer also. Further, it has been hypothesized that susceptibility to relapse due to cue reactivity increases gradually over periods of weeks or months. Thus, the administration of a positive modulator of mGluII receptors during prolonged abstinence from cocaine selfadministration will decrease, while a negative modulator of mGluII receptors will have no effect on cocaine-seeking behavior induced by discriminative stimuli associated with cocaine availability.

[00170] Avoidance and alleviation of the negative affective state of early drug withdrawal with further drug abuse is hypothesized to be an important source of motivation that contributes significantly to the development of compulsive drug use and relapse during early abstinence. It has been hypothesized that susceptibility to relapse due to affective withdrawal symptoms peaks within days of cessation reflecting early rise in withdrawal symptoms. Thus, pharmacological treatments that reverse the depression-like aspects of early cocaine withdrawal would remove an important source of motivation that contributes to relapse to drug abuse shortly after the initial cessation of drug administration. Abrupt abstinence following chronic exposure to drugs of abuse, including cocaine results in a negative affective state reflected in significant elevations in intracranial self-stimulation (ICSS) thresholds. ICSS thresholds are thought to provide an operational measure of brain reward function; thus, elevations in ICSS thresholds reflect deficits in brain reward function. This threshold elevation is opposite to the lowering of ICSS thresholds observed after cocaine administration that reflects an increase in brain reward function that most likely underlies, or at least relates to, cocaine's euphorigenic effects. This increase in brain reward function associated with cocaine consumption is considered essential for the establishment and maintenance of cocaine self-administration behavior. The mechanisms that contribute to withdrawal-induced reward deficits or reward facilitation remain unclear. Group II mGlus have been implicated in the synaptic adaptations that occur in response to chronic drug exposure and contribute to the aversive behavioral withdrawal syndrome. The role of glutamate transmission in the early phase of cocaine withdrawal has not been studied extensively. However, based on the nicotine dependence findings and the hypothesis of overlapping mechanisms of withdrawal from different drugs of abuse, one may hypothesize that decreased glutamatergic neurotransmission will also partly mediate cocaine withdrawal in cocaine-dependent subjects. [00171] In some embodiments, the compounds described herein are mGlu2/3 receptor PAM used for treating cocaine addiction.

Schizophrenia

[00172] Schizophrenia is a devastating psychiatric illness that afflicts approximately 1% of the worldwide population. The core symptoms observed in schizophrenic patients include positive symptoms (thought disorder, delusions, hallucinations, paranoia), negative symptoms (social withdrawal, anhedonia, apathy, paucity of speech) and cognitive impairments such as deficits in perception, attention, learning, short- and long-term memory and executive function. The cognitive deficits in schizophrenia are one of the major disabilities associated with the illness and are considered a reliable predictor of long-term disability and treatment outcome. Currently available antipsychotics effectively treat the positive symptoms, but provide modest effects on the negative symptoms and cognitive impairments. Furthermore, some patients are unresponsive to current antipsychotic treatments and several of these agents are associated with adverse side effects, including disturbances in motor function, weight gain, and sexual dysfunction. Thus, there is a need for new treatment strategies for schizophrenia that provide major improvements in efficacy across multiple symptom clusters and have fewer adverse effects.

[00173] Although the underlying pathophysiology of schizophrenia remains unknown, accumulating evidence points to disruptions in multiple neurotransmitter systems that modulate neural circuits important for normal affect, sensory processing, and cognition. In particular, early clinical findings demonstrated that changes in glutamatergic transmission produced by antagonists of the N-methyl-D-aspartate (NMD A) subtype of ionotropic glutamate receptors, including phencyclidine (PCP), result in a state of psychosis in humans that is similar to that observed in schizophrenic patients. These studies suggest that agents that increase NMDA receptor function have potential as therapeutics for the treatment of all major symptom clusters (positive, negative, cognitive) of the disease. More recently, studies indicate that reduced NMDA receptor function induces complex changes in transmission through cortical and subcortical circuits that involve both glutamatergic and GABAergic synapses and include downstream increases in transmission at glutamatergic synapses in the prefrontal cortex. Importantly, these circuit changes might share common features with changes in brain circuit activities that occur in schizophrenia patients. One hypothesis is that NMDA receptors involved in these symptoms might reside at glutamatergic synapses on GABAergic projection neurons in midbrain regions as well as GABAergic interneurons and glutamatergic projection neurons in key cortical and limbic regions For example, under normal conditions the activation of NMD A receptors localized on GABAergic projection neurons in subcortical regions, such as the nucleus accumbens, provides inhibitory control on excitatory glutamatergic thalamocortical neurons that project to pyramidal neurons in the prefrontal cortex (PFC). Hypofunction or blockade of these NMD A receptors on midbrain inhibitory GABAergic neurons could result in a disinhibition of glutamatergic thalamocortical inputs to pyramidal neurons in the PFC. This disinhibition would lead to a subsequent increased activity of glutamatergic thalamic neurons and increased activity mediated by the DL-a-amino-3-hydroxy-5-methylisoxasole-4-propionate (AMP A) subtype of glutamate receptors at thalamocortical synapses in the PFC. Based on this model, manipulations that enhance NMDA receptor function, such as activation of metabotropic glutamate receptor subtype 5 (mGlu5) located on GABAergic neurons, have potential as a novel approach to the treatment of schizophrenia. An alternative approach might be to reduce excitatory glutamatergic transmission at key synapses, such as thalamocortical synapses in the PFC, by activation of metabotropic glutamate receptor subtypes 2 and 3 (mGlu2 and mGlu3) presynaptically located in these synapses. Although other viable models of circuit changes associated with schizophrenia exist, this hypothesis provides one possible framework within which to consider effects of ligands at mGlu receptors that might be relevant to schizophrenia.

[00174] A large number of preclinical and clinical studies provide strong evidence that agonists of mGlu2 and mGlu3 (group II mGlu receptors) also have potential as a novel approach to the treatment of schizophrenia. Consistent with the animal studies, clinical studies reveal that a highly selective agonist of group II mGlu receptors has robust efficacy in improving ratings for positive and negative symptoms in patients with schizophrenia. Unlike currently marketed antipsychotic agents, there were no major adverse events reported for the mGlu2/3 agonist in the clinical studies to date. However, further clinical studies will be required to fully establish safety of these compounds after long-term dosing in schizophrenic patients, as well as assess possible efficacy on the cognitive impairments in these patients. Taken together, these findings represent an important breakthrough and could ultimately lead to introduction of group II mGlu receptor activators as a fundamentally novel approach to the treatment of schizophrenia. As mentioned above, animal studies reveal that the psychotomimetic agents increase activity of glutamatergic synapses in the PFC, and hyperactivity of glutamate neurotransmission in the PFC and limbic structures has been postulated to play a critical role in the pathophysiology of schizophrenia. Interestingly, effects of psychotomimetic agents on glutamatergic transmission in the PFC are blocked by group II mGlu receptor agonists. Although it is not yet clear whether this action of group II mGlu receptor agonists is mechanistically related to the antipsychotic actions of these compounds, these actions fit well with current models of disruptions in subcortical and cortical circuits that might be involved in the psychotomimetic effects of NMD A receptor antagonists and the range of symptoms observed in schizophrenia patients. Despite advances in development of group II mGlu receptor agonists, it is not yet clear whether orthosteric agonists of these receptors will reach the market for broad clinical use. Long-term administration of group II mGlu receptor agonists induces robust tolerance in at least one rodent model that has been used to predict antipsychotic efficacy. These orthosteric agonists also activate both mGlu2 and mGlu3 and do not provide insights into which of these group II mGlu receptor subtypes is most important for clinical efficacy. Although, recent findings demonstrate that the antipsychotic-like effects of mGlu2/3 receptor agonists are absent in mGlu2-knockout, but not mGlu3 -knockout, mice. Thus, it is possible that positive allosteric modulators of mGlu2 might be an alternative approach that could provide greater selectivity and other potential advantages to orthosteric agonists.

[00175] In some embodiments, group II mGlu receptor agonists are useful in the treatment of schizophrenia. In some embodiments, selective mGlu2 PAMs represent a novel approach to the treatment of these disorders that is devoid of the adverse effects associated with currently available drugs.

[00176] In some embodiments, the compounds described herein are mGlu2/3 receptor PAM used for treating schizophrenia. The method includes administering to a subject in need thereof, an effective amount of at least one mGlu2/3 receptor PAM, thereby treating schizophrenia.

Alzheimer’s Disease

[00177] Alzheimer's disease (AD), also known as Alzheimer disease, or just Alzheimer's, accounts for 60% to 70% of cases of dementia. It is a chronic neurodegenerative disease that usually starts slowly and gets worse over time. The most common early symptom is difficulty in remembering recent events (short term memory loss). As the disease advances, symptoms can include: problems with language, disorientation (including easily getting lost), mood swings, loss of motivation, not managing self-care, and behavioral issues. As a person's condition declines, she or he often withdraws from family and society. Gradually, bodily functions are lost, ultimately leading to death. Although the speed of progression can vary, the average life expectancy following diagnosis is three to nine years. [00178] Various brain regions, including the cerebral cortex, hippocampus, striatum, amygdala, frontal cortex and nucleus accumbens, display high levels of mGlu2 and mGlu3 receptor binding. This distribution pattern suggests a role for the mGlu2/3 receptor subtypes in the pathology of neuropsychiatric disorders such as Alzheimer’s disease.

[00179] In some embodiments, the compounds described herein are mGlu2/3 receptor PAM used for treating Alzheimer’s disease. The method includes administering to a subject in need thereof, an effective amount of at least one mGlu2/3 receptor PAM, thereby treating Alzheimer’s disease.

Huntington’s Disease

[00180] Huntington's disease (HD) is a neurodegenerative genetic disorder that affects muscle coordination and leads to mental decline and behavioral symptoms. Symptoms of the disease can vary between individuals and affected members of the same family, but usually progress predictably. The earliest symptoms are often subtle problems with mood or cognition. A general lack of coordination and an unsteady gait often follows. As the disease advances, uncoordinated, jerky body movements become more apparent, along with a decline in mental abilities and behavioral symptoms. Physical abilities gradually worsen until coordinated movement becomes difficult. Mental abilities generally decline into dementia. Complications such as pneumonia, heart disease, and physical injury from falls reduce life expectancy to around twenty years from the point at which symptoms begin. Physical symptoms can begin at any age from infancy to old age, but usually begin between 35 and 44 years of age.

[00181] Excitotoxic injury to striatum by dysfunctional cortical input or aberrant glutamate uptake may contribute to Huntington's disease (HD) pathogenesis. Daily subcutaneous injection with a maximum tolerated dose (MTD) of the mGlu2/3 agonist LY379268 (20mg/kg) beginning at 4 weeks has been found to dramatically improves the phenotype in R6/2 mice (the most commonly used animal model of Huntington’s disease) (Reiner et al. Brain Research 1473 (2012) 161-172). For example, normalization of motor function in distance traveled, speed, the infrequency of pauses, and the ability to locomote in a straight line, and a rescue of a 15-20% striatal neuron loss at 10 weeks were observed.

[00182] In some embodiments, the compounds described herein are mGlu2/3 receptor PAM used for treating Huntington’s disease. The method includes administering to a subject in need thereof, an effective amount of at least one mGlu2/3 receptor PAM, thereby treating Huntington’s disease. Lou Gehrig’s Disease (ALS)

[00183] Amyotrophic lateral sclerosis (ALS) is a debilitating disorder characterized by rapidly progressive motor neuron degeneration, which results into weakness, muscle atrophy and spasticity. Riluzole is the only drug that improves survival of ALS patients, only to a modest extent. Thus, there is an urgent need for treatments that slow the progression of ALS. Familial ALS (FALS) is caused by mutations of several genes including SOD1 (type-1 superoxide dismutase). Although SOD1 mutations account for only 20% of FALS and about 2% of sporadic ALS, SOD1 mutant mice recapitulate several features of human ALS, and are widely employed as model for ALS. The validity of this model is strengthened by the evidence that SOD1 aggregates are detected in the spinal cord of people with sporadic ALS or with ALS caused by mutations of genes other than SOD1. The mechanisms by which SOD1 misfolding damages motor neurons are only partially elucidated and involve glutamate excitotoxicity, mitochondrial dysfunction, disruption of axonal transport, and abnormalities in astrocytes and microglia. One of the potential mechanisms of excitotoxicity in ALS is a reduced expression of the glutamate transporter, GLT-1, which clears glutamate from the synapses.

[00184] Enhancement of glial-derived neurotrophic factor (GDNF) is an established therapeutic target for amyotrophic lateral sclerosis (ALS). Activation of group II metabotropic glutamate (mGlu) receptors with the orthosteric agonist, LY379268, enhanced GDNF levels in cultured spinal cord astrocytes from wild-type mice and mGlu2 knockout mice, but not in astrocytes from mGlu3 knockout mice. LY379268 protected Stemberger monoclonal incorporated antibody-32 (SMI-32)⁺ motor neurons against excitotoxic death in mixed cultures of spinal cord cells, and its action was abrogated by anti -GDNF antibodies. Acute systemic injection of LY379268 (0.5, 1 or 5 mg/kg, i.p.) enhanced spinal cord GDNF levels in wild-type and mGlu2 knockout mice, but not in mGlu3 knockout mice. No tolerance developed to the GDNF-enhancing effect of LY379268 when the drug was continuously delivered for 28 days by means of s.c. osmotic minipumps (0.5-5 mg/day). Continuous infusion of LY379268 also enhanced the expression of the glutamate transporter GLT-1, in the spinal cord. Continuous treatment with 1 or 5 mg/kg/day with LY379268 had a beneficial effect on neurological disability in SOD1G93A mice. At day 40 of treatment, LY379268 enhanced spinal cord levels of GDNF and GLT-1, and rescued spinal cordmotor neurons, as assessed by stereologic counting of SMI-32⁺ cells.

[00185] In some embodiments, the compounds described herein are mGlu2/3 receptor PAM used for treating ALS. The method includes administering to a subject in need thereof, an effective amount of at least one mGlu2/3 receptor PAM, thereby treating ALS.

Parkinson’s Disease

[00186] Parkinson’s disease (PD) is a chronic movement disorder resulting from a disturbance in the normal functioning of the basal ganglia, a collection of subcortical nuclei that are essential for the initiation and control of motor activity. The underlying pathology of the disease is a progressive degeneration of the dopaminergic nigrostriatal tract that manifests as a range of motor deficits including akinesia or bradykinesia, tremor, rigidity and postural instability. Current therapies for PD are essentially based on dopamine replacement and include levodapa (L-DOPA), a precursor of dopamine, and dopamine receptor agonists. These agents are effective in treating the symptoms of the disease in the early stages, but are less effective as the disease progresses when debilitating side-effects such as “on-off ’ fluctuations in efficacy and uncontrollable dyskinesias (involuntary muscle movements) ensue. More importantly, dopaminergic treatments do not halt the disease progression. For these reasons, several investigators have started to focus on nondopaminergic interventions as symptomatic and neuroprotecive strategies in PD.

[00187] Studies have shown that Group II mGlu receptors play some role in alleviating akinesia in the rat. In functional studies (Murray et al. Pharmacology, Biochemistry and Behavior 73 (2002) 455-466), intracerebroventricular administration of LY379268 (1, 5, 10, 20 nmol/2 > 1) produced a dose-dependent increase in locomotor activity in the reserpine (5 mg/kg ip)-treated rat. In contrast, systemic administration of LY379268 (0.1, 1, 10 mg/kg ip) did not reverse reserpine-induced akinesia and failed to effect rotational behaviour 1 month after unilateral lesioning of the nigrostriatal tract by 6-hydroxydopamine (6-OHDA; 4 mg infused into the substantia nigra (SN)). These results suggest that mGlus may offer a nondopaminergic approach to the treatment of PD.

[00188] In some embodiments, the compounds described herein are mGlu2/3 receptor PAM used for treating Parkinson’s disease. The method includes administering to a subject in need thereof, an effective amount of at least one mGlu2/3 receptor PAM, thereby treating Parkinson’s disease.

Neuroprotection

[00189] In neuroprotective studies (Murray et al. Pharmacology, Biochemistry and Behavior 73 (2002) 455-466), animals were treated with LY379268 (10 mg/kg/day ip) either for 7 days following 6-OHDA injection into the SN (4 mg) or for 21 days following 6-OHDA injection into the striatum (10 mg) before measurement of tyrosine hydroxylase immunoreactivity in the striatum and/or SN as an index of neuroprotection. LY379268 provided some protection against nigral infusion of 6-OHDA and also some functional improvement and correction of dopamine turnover was observed. The compound also provided significant protection in the striatum and some protection in the SN against striatal infusion of 6-OHDA.

[00190] Low doses of the mGlu2/3 metabotropic glutamate receptor agonist, LY379268 (0.25-3 mg/kg, i.p.) increased glial cell line-derived neurotrophic factor (GDNF) mRNA and protein levels in the mouse brain, as assessed by in situ hybridization, real-time PCR, immunoblotting, and immunohistochemistry. This increase was prominent in the striatum, but was also observed in the cerebral cortex. GDNF mRNA levels peaked at 3 h and declined afterwards, whereas GDNF protein levels progressively increased from 24 to 72 h following LY379268 injection. The action of LY379268 was lost in mGlu3 receptor knockout mice, but not in mGlu2 receptor knockout mice. In pure cultures of striatal neurons, the increase in GDNF induced by LY379268 required the activation of the mitogen-activated protein kinase and phosphatidylinositol-3-kinase pathways, as shown by the use of specific inhibitors of the two pathways. Both in vivo and in vitro studies led to the conclusion that neurons were the only source of GDNF in response to mGlu3 receptor activation. Remarkably, acute or repeated injections of LY379268 at doses that enhanced striatal GDNF levels (0.25 or 3 mg/kg, i.p.) were highly protective against nigro-striatal damage induced by 1- methyl-4- phenyl-l,2,3,6-tetrahydropyridine in mice, as assessed by stereological counting of tyrosine hydroxylase-positive neurons in the pars compacta of the substantia nigra. It is speculated that selective mGlu3 receptor agonists or enhancers are potential candidates as neuroprotective agents in Parkinson’s disease, and their use might circumvent the limitations associated with the administration of exogenous GDNF. Hence, selective mGlu3 receptor agonists or positive allosteric modulators (PAMs) would potentially be helpful in the treatment of chronic neurodegenerative disorder by providing neuroprotection.

Combination Treatments

[00191] In certain instances, it is appropriate to administer at least one compound of Formula (I), (II), or (III), or Table 4, or pharmaceutically acceptable salt thereof, in combination with another therapeutic agent.

[00192] In one specific embodiment, a compound of Formula (I), (II), or (III), or Table 4, or pharmaceutically acceptable salt thereof, is co-administered with a second therapeutic agent, wherein the compound of Formula (I), (II), or (III), or Table 4, or pharmaceutically acceptable salt thereof, and the second therapeutic agent modulate different aspects of the disease, disorder or condition being treated, thereby providing a greater overall benefit than administration of either therapeutic agent alone. [00193] For combination therapies described herein, dosages of the co-administered compounds vary depending on the type of co-drug(s) employed, on the specific drug(s) employed, on the disease or condition being treated and so forth. In additional embodiments, when co-administered with one or more other therapeutic agents, the compound provided herein is administered either simultaneously with the one or more other therapeutic agents, or sequentially.

[00194] If administration is simultaneous, the multiple therapeutic agents are, by way of example only, provided in a single, unified form, or in multiple forms.

[00195] In some embodiments, compounds of Formula (I), (II), or (III), or Table 4, or pharmaceutically acceptable salt thereof, are administered to a mammal in combination with one or more additional neurodegenerative disease or disorder therapeutic agent. In some embodiments, the neurodegenerative disease or disorder is Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, or Lou Gehrig's Disease (Amyotrophic Lateral Sclerosis or ALS). In some embodiments, compounds of Formula (I), (II), or (III), or Table 4, or pharmaceutically acceptable salt thereof, are administered to a mammal in combination with one or more additional therapeutic agent that alleviate the symptoms or side effects of a neurodegenerative disease or disorder. In some embodiments the symptoms or side effects a neurodegenerative disease or disorder are dementia, memory loss, dyskinesias, cognitive impairment, tremors, rigidity, slowness of movement, postural instability, involuntary jerking or writhing movements (chorea), slow or abnormal eye movements, difficulty with the physical production of speech or swallowing, psychiatric disorders, muscle cramps and spasms, spasticity, constipation, fatigue, excessive salivation, excessive phlegm, pain, depression, sleep problems, uncontrolled outbursts of laughing or crying.

[00196] In some embodiments, the additional therapeutic agent is an Alzheimer’s disease therapeutic agent. In some embodiments, the additional therapeutic agent is a cholinesterase inhibitor. In some embodiments, the cholinesterase inhibitor is donepezil, galantamine, or rivastigmine. In some embodiments, the additional therapeutic agent is memantine. In some embodiments, the additional therapeutic agent is latrepirdine, idalopridine, or cerlapirdine. [00197] In some embodiments, the additional therapeutic agent is a Parkinson’s disease therapeutic agent. In some embodiments, the additional therapeutic agent is levodopa. In some embodiments, the additional therapeutic agent is carbidopa-levodopa. In some embodiments, the additional therapeutic agent is a Dopamine agonist. In some embodiments, the dopamine agonist is ropinirole, pramipexole, or rotigotine. In some embodiments, the additional therapeutic agent is a MAO-B inhibitor. In some embodiments, the MAO-B inhibitor is selegiline or rasagiline. In some embodiments, the additional therapeutic agent is a catechol O-methyltransferase (COMT) inhibitor. In some embodiments, the COMT inhibitor is opicapone, entacapone or tolcapone. In some embodiments, the additional therapeutic agent is an Anticholinergic. In some embodiments, the anticholinergic is benztropine or trihexyphenidyl. In some embodiments, the additional therapeutic agent is amantadine.

[00198] In some embodiments, compounds of Formula (I), (II), or (III), or Table 4, or pharmaceutically acceptable salt thereof, are administered to a mammal in combination with deep brain stimulation.

[00199] In some embodiments, the additional therapeutic agent is a Huntington’s disease therapeutic agent. In some embodiments, the additional therapeutic agent is tetrabenazine. In some embodiments, the additional therapeutic agent is an antipsychotic drug. In some embodiments, the antipsychotic drug is haloperidol, chlorpromazine, risperidone, olanzapine or quetiapine. In some embodiments, the additional therapeutic agent is amantadine, levetiracetam, or clonazepam. In some embodiments, the additional therapeutic agent is an antidepressant. In some embodiments, the antidepressant is citalopram, fluoxetine, or sertraline. In some embodiments, the additional therapeutic agent is a mood-stabilizing drug. In some embodiments, the mood-stabilizing drug is valproate, carbamazepine, or lamotrigine. [00200] In some embodiments, compounds of Formula (I), (II), or (III), or Table 4, or pharmaceutically acceptable salt thereof, are administered to a mammal in combination with psychotherapy, speech therapy, physical therapy or occupational therapy.

[00201] In some embodiments, the additional therapeutic agent is a Lou Gehrig's Disease (Amyotrophic Lateral Sclerosis or ALS) therapeutic agent. In some embodiments, the additional therapeutic agent is riluzole. In some embodiments, the additional therapeutic agent is baclofen, diazepam, trihexyphenidyl or amitriptyline.

[00202] In some embodiments, compounds of Formula (I), (II), or (III), or Table 4, or pharmaceutically acceptable salt thereof, are administered to a mammal in combination with one or more additional neuropychiatric disease or disorder therapeutic agent. In some embodiments, the neuropychiatric disease or disorder is schizophrenia, anxiety, sleep disorder, eating disorder, psychosis, or addictions.

[00203] In some embodiments, compounds of Formula (I), (II), or (III), or Table 4, or pharmaceutically acceptable salt thereof, are administered in combination with one or more additional anti -addiction therapeutic agent. In some embodiments, compounds of Formula (I), (II), or (III), or Table 4, or pharmaceutically acceptable salt thereof, are administered in combination with one or more additional anti-addiction therapeutic agent for the treatment of a substance use and/or substance abuse disorder. In some embodiments, the substance use disorder is a nicotine use disorder, a stimulant use disorder, an alcohol use disorder, or an opioid use disorder. In some embodiments, the anti -addiction therapeutic agent is selected from the group consisting of buprenorphine, methadone, naltrexone, subozone, naloxone, acamprosate, disulfiram, bupropion, varenicline, and a nicotine replacement therapy (NRT). [00204] In some embodiments, the additional therapeutic agent is an antipsychotic. In some embodiments, the antipsychotic is aripiprazole, asenapine, clozapine, iloperidone, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, ziprasidone, chlorpromazine, fluphenazine, haloperidol, or perphenazine. In some embodiments, the additional therapeutic agent is an antidepressant. In some embodiments, the antidepressant is a selective serotonin reuptake inhibitor (SSRI) or a serotonin norepinephrine reuptake inhibitor (SNRI). In some embodiments, the antidepressant is escitalopram, duloxetine, venlafaxine, or paroxetine. In some embodiments, the additional therapeutic agent is an anti-anxiety medication. In some embodiments, the anti-anxiety medication is buspirone. In some embodiments, the additional therapeutic agent is a benzodiazepine. In some embodiments the benzodiazepine is alprazolam, chlordiazepoxide, diazepam, or lorazepam.

[00205] In some embodiments, the additional therapeutic agent is a medication used to treat dependence. In some embodiments, the medication used to treat dependence is buprenorphine, methadone, naltrexone, subozone, naloxone, acamprosate, disulfiram, bupropion, varenicline, or a nicotine replacement therapy (NRT).

EXAMPLES

[00206] The following examples are intended to illustrate but not limit the disclosed embodiments.

I. Chemical Synthesis

[00207] All reactions were performed in oven-dried glassware under an atmosphere of argon with magnetic stirring. All solvents and chemicals used were purchased from Sigma-Aldrich or Acros, and were used as received without further purification. Purity of compounds was established by liquid chromatography -mass spectroscopy (HPLC-MS) and was >95% for all tested compounds. Silica gel column chromatography was carried out using prepacked silica cartridges from RediSep (ISCO Ltd.) and eluted using an Isco Companion system. ¹H- and ¹³C-NMR spectra were obtained on a Jeol 400 spectrometer at 400 MHz and 100 MHz, respectively. Chemical shifts are reported in 3 (ppm) relative to residual solvent peaks or TMS as internal standards. Coupling constants are reported in Hz. High-resolution ESI-TOF mass spectra were acquired from the Mass Spectrometry Core at The Sanford-Burnham Medical Research Institute (Orlando, Florida). HPLC-MS analyses were performed on a Shimadzu 2010EV LCMS using the following conditions: Kromisil Cl 8 column (reverse phase, 4.6 mm x 50 mm); a linear gradient from 10% acetonitrile and 90% water to 95% acetonitrile and 5% water over 4.5 min; flow rate of 1 mL/min; UV photodiode array detection from 200 to 300 nm.

General methods for the synthesis of mGlu2/3 receptor PAMs.

[00208] General method A'. A solution of appropriate chloride 1 (80 mmol, 1 equiv) in CH2Q2 (DCM; 20 mL) was added dropwise a stirred solution of AICI3 (10.64 g, 80 mmol, 1 equiv) in CH2CI2 (500 mL) at 0 °C under nitrogen. Substituted resorcinol derivative 2 (80 mmol, 1 equiv) was added to the reaction mixture, and the reaction was gradually warmed to room temperature (rt) and stirred at room temperature for 12 h. The pre-cooled reaction mixture was quenched by the dropwise addition of HC1 (5% aq.) and diluted with water. The organic layer was separated, and the aqueous layer was extracted with CH2Q2 (3X100 mL), and the combined organic extracts were washed with water, brine and dried over anhyd. sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude product, which was filtered with hexane and dried under vacuum to yield the substituted acylated derivatives 3 as a white/tan solid.

[00209] General method B: A mixture of appropriate methyl hydroxybenzoate derivative 4 (2 mmol), dibromo compound (6 mmol), and potassium carbonate (4 mmol) in acetonitrile (ACN; 15 mL) was refluxed for 6 h under an atmosphere of nitrogen. After cooled to room temperature, volatiles were removed under reduced pressure. The crude reaction mixture was diluted with water and DCM. The organic layer collected, and the aqueous layer extracted twice with DCM. Combined organic extracts were washed with water, brine, dried over anhyd. sodium sulfate, filtered and concentrated to give the crude product, which was purified by flash column chromatography (hexanes to 30% EtOAc in hexanes) to give intermediate derivatives 6.

[00210] General method C: To a stirred solution of the product 6 from general method B (1 mmol) and the substituted acylated derivative 3 from general method A (1 mmol) in ACN was added potassium carbonate (2 mmol). The resulting mixture was heated at 80 °C for 2 h (reaction monitored by LC-MS) under inert atmosphere. The precipitated solids were filtered off and the solvent removed under reduced pressure. The crude product was partitioned between water and ethyl acetate. The organic layer was collected, and the aqueous layer extracted with ethyl acetate twice. Combined organic layers were washed with water, brine, and dried over anhyd. sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude product which was used for next step without further purification.

[00211] General method D : To a solution of the above ester (1 mmol) in dioxane (10 mL) was added 2M Li OH aq. solution (2.5 mL, 5 mmol), and the resulting mixture was heated at 50 °C until the starting material was consumed as determined by LC-MS (~1 h). After completion of the reaction, the reaction mixture was cooled to rt and diluted with water. The pH was adjusted to 1 by the addition of IN HC1 and ethyl acetate (50 mL) was added. The organic layer was separated and dried over Na2SO4. The solvents were removed by rotary evaporation and the products were isolated by reverse phase HPLC and lyophilized to provide the final compounds which were determined to be >95% pure by HPLC-UV, HPLC-MS, and ¹ H NMR.

[00212] General method E'. Potassium carbonate (1 mmol) was added to a solution of appropriate resorcinol derivative (0.5 mmol) and methyl 3'-(bromomethyl)-biphenyl-3- carboxylate (0.5 mmol in ACN (5 mL). After stirring for 2 h at 80 °C, the organic phase was evaporated under reduced pressure and the crude material was partitioned between water and CH2Q2. The aqueous layer was extracted with CH2Q2 (3 x 15 mL). The organic layer was dried using Na2SO4 and evaporated to give the ester derivatives in quantitative yield. The crude ester derivative was used in the next step without further purification. 2M LiOH (0.25 mL g, 0.5 mmol) was added to a solution of the crude product (0.5 mmol) in THF (5 mL). The reaction mixture was heated under reflux for 30 min. and then cooled to room temperature and acidified with dil. HC1. and ethyl acetate (50 mL) was added. The organic layer was separated and dried over Na2SO4. The solvents were removed by rotary evaporation and the products were isolated by reverse phase HPLC and lyophilized to provide the final compounds which were determined to be >95% pure by HPLC-UV, HPLC-MS, and ¹ H NMR.

[00213] General method F Potassium carbonate (2.76 g, 20 mmol) was added to a solution of l-(2,4-dihydroxy-3-methylphenyl)-3,3-dimethylbutan-l-one (2.23 g, 10 mmol) and 1-bromo- 3-(bromomethyl)benzene (2.5 g, 10 mmol) in ACN (100 mL). After stirring for 2 h at 80 °C, the organic phase was evaporated under reduced pressure and the crude material was partitioned between water and CH2Q2. The aqueous layer was extracted with CH2Q2 (3x 50 mL). The organic phase was dried using Na2SO4 and evaporated to give l-(4-(3- bromobenzyloxy)-2-hydroxy-3-methylphenyl)-3,3-dimethylbutan-l-one (3.87 g, 98%). The crude product was used for the next step without further purification. LC-MS m/z calcd for C2oH23Br03 [M + H]⁺: 391.08. Found: 391.00. A mixture of l-(4-(3-bromobenzyloxy)-2- hydroxy-3-methylphenyl)-3,3-dimethylbutan-l-one (0.100 g, 0.25 mmol), boronic acid (0.375 mmol) and Pd(PPh3)4 (0.028 mg, 0.025 mmol) were taken in DME (2 mL). To this solution was added 2M Na2CO3 (0.5 mL) and the resulting mixture was heated at reflux under an atmosphere of N2 for 1 h. The reaction mixture was cooled to room temperature, diluted with water and neutralized using IM HC1. A usual work up with EtOAc followed by preparative HPLC yielded the desired compounds.

General synthetic scheme for the preparation of isoindolinone derivatives: General Procedure A

Synthesis of 4-chloro-3'-methylbiphenyl-3-carboxylic acid

[00214] Pd(OAc)2 (0.786 g, 3.5 mmol) was added to a solution of 2-chloro-5-iodobenzoic acid (19.8 g, 70 mmol), m-tolylboronic acid (11.42 g, 84 mmol) and Na2COs (22.9 g, 210 mmol) in water (100 mL) under a nitrogen atmosphere. The resulting mixture was stirred at 50 °C for 2 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was acidified with IM HC1. The precipitated 4-chl oro-3 '-methylbiphenyl-3 -carboxylic acid was filtered, washed with water and dried to provide a tan solid that was used without further purification in the next step (quantitative yield). 'H NMR (300 MHz, DMSO-d6): 5 8.03 (s, 1H), 7.83 (d, J = 8.1 Hz, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.55-7.50 (m, 2H), 7.40 (t, J = 7.8 Hz, 1H), 7.25 (d, J = 6.6 Hz, 1H), 2.41 (s, 3H).

[00215] To a solution of 4-chloro-3 '-methylbiphenyl-3 -carboxylic acid (14 g, 57 mmol) in acetone was added K2CO3 (55 g, 398 mmol) and CH3I (25 mL, 56 mmol). The resulting solution was heated at 50 °C for 1 h. After cooling, the excess solvent was removed under reduced pressure. The crude material was dissolved in DCM and washed with water. The organic layer was dried over Na2SO4, and the solvent was evaporated to afford methyl 4- chl oro-3 '-methylbiphenyl-3 -carboxylate as a reddish yellow viscous liquid (14.6 g, 98%) which was used in the next step without further purification. ^JH NMR (300 MHz, DMSO-de): 5 8.04 (s, 1H), 7.85 (d, J = 7.8 Hz, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.52-7.47 (m, 2H), 7.38 (t, J = 7.8 Hz, 1H), 7.23 (d, J = 7.5 Hz, 1H), 3.90 (s, 3H), 2.39 (s, 3H).

Synthesis of methyl 3'-(bromomethyl)-4-chlorobiphenyl-3-carboxylate

[00216] A catalytic amount of AIBN was added to a solution of methyl 4-chloro-3'- methylbiphenyl-3 -carboxylate (14.6 g, 56 mmol) and NBS (11 g, 61.6 mmol) in CCh. The reaction mixture was heated under reflux for 12 h. After cooling, the precipitated succinimide was removed by filtration. The filtrate was concentrated to afford the crude product.

Trituration with hexanes yielded methyl 3'-(bromomethyl)-4-chlorobiphenyl-3-carboxylate (17.6 g, 91%) as a colorless solid. ^XH NMR (300 MHz, CDC13): 5 8.07(s, 1H) 7.68-7.45 (m, 6H), 4.58 (s, 2H), 4.00 (s, 3H).

Synthesis of 2-cyclopentyl-5-methoxyisoindolin-l-one

[00217] To a solution of commercially available methyl 2-(bromomethyl)-4- methoxybenzoate(15 g, 57.9 mmol) in ACN (120 mL) was added cyclopentylamine (7.39 g, 87 mmol) and K2CO3 (11.98 g, 87 mmol). The resulting mixture was heated at reflux. After complete consumption (by LC-MS) of the starting material (3-4 h), the reaction mixture was cooled to ambient temperature and filtered. The filtrate was then concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography [ 10%-20% EtOAc/Hexane] to afford 2-cyclopentyl-5-methoxyisoindolin-l-one. White solid (12 g, 90%). 'H NMR (400 MHz, CDCI3): 8 7.74 (d, J= 8.2 Hz, 1H), 6.97 (d, J= 8.2 Hz, 1H), 6.93 (s, 1H), 4.76-4.73 (m, 1H), 4.30 (s, 2H), 3.86 (s, 3H), 1.99- 1.78 (m, 2H), 1.78-1.61 (m, 6H). LC-MS m/z calcd. for Ci4Hi₇NO₂[M+H]⁺232.13, found: 232.0. Synthesis of 2-cyclopentyl-5-hydroxyisoindolin-l-one

[00218] 2-Cyclopentyl-5-methoxyisoindolin-l-one (12 g, 52 mmol) was dissolved in DCM (100 mL) and placed in a flame-dried flask equipped with nitrogen inlet and rubber septum. The solution was cooled to -76 °C (dry ice-acetone), and BBrs (26 g, 104 mmol) was introduced via syringe. The reaction mixture was gradually warmed to room temperature then stirred for 3 h at room temperature, after which time water (50 mL) was added carefully and stirred for another 30 min. The volatiles were removed in vacuo, and cold water added stirred vigorously for about 30 min. The precipitated product was collected by filtration and washed with cold methanol: water (1 : 1) and dried. White solid (9.36 g, 83%). 'H NMR (400 MHz, CDC1₃): 8 7.74 (d, J = 8.2 Hz, 1H), 6.88 (s, 1H), 6.82 (d, J = 8.2 Hz, 1H), 4.52-4.48 (m, 1H), 4.32 (s, 2H), 1.88-1.80 (m, 2H), 1.77-1.57 (m, 6H). LC-MS m/z calcd. for C13H15NO2[M+H]+ 218.11, found: 218.

Example 1 2-Chloro-5-(3-{[l-oxo-2-(2,2,2-trifluoroethyl)isoindolin-5-yloxy]methyl}phenyl)benzoic acid

[00219] To mixture of 5-hydroxy-2-(2,2,2-trifluoro-ethyl)-2,3-dihydro-isoindol-l-one (0.23 g, 0.995 mmol) and 3 '-brom omethyl-4-chloro-biphenyl-3 -carboxylic acid methyl ester (0.405 g, 1.194 mmol) in acetone (15 mL), K2CO3 (0.275 g, 1.990 g) was added. The mixture was stirred at 80 °C for 2 hrs. The solid was filtered off and the solvent was removed, and the residue was purified with silica column to afford the desired product as a pale yellow solid. To a solution of 4-chloro-3'-[l-oxo-2-(2,2,2-trifluoro-ethyl)-2,3-dihydro-lH-isoindol-5- yloxymethyl]-biphenyl-3-carboxylic acid methyl ester (0.210 g, 0.429 mmol) in THF/H2O (5: 1, 5 mL), 2M LiOH (1.1 mL) was added. The mixture was stirred at 60 °C for 4 h. The reaction mixture was cooled to rt, diluted with water and acidified with IN HC1 to pH 2 and extracted with ethyl acetate (3 x 25 mL). The solvent was removed the residue was purified with C18 reverse phase column to afford the desired product as a yellow solid. 'H NMR (500 MHz, CDC13): 5 8.22 (s, 1H), 7.82 (d, J = 8.5 Hz, 1H), 7.70-7.45 (m, 6H), 7.12 (d, J = 8.5 Hz, 1H), 7.04 (s, 1H), 5.21 (s, 2H), 4.51 (s, 2H), 4.19 (q, J = 10.0 Hz, 2H). LC-MS m/z calcd. for C24H17C1F3NO4 [M+H]+ 476.08; found 476.1.

Example 2

(R)-4-Chloro-3'-(((2-(2,3-dihydro-lH-inden-l-yl)-l-oxoisoindolin-5-yl)oxy)methyl)-[l,l'- biphenyl]-3-carboxylic acid

[00220] To a solution (R)-2-(2,3-dihydro-lH-inden-l-yl)-5-hydroxyisoindolin-l-one (0.265 g, 1 mmol) in ACN (15 mL) was added K2CO3 (0.276 g, 2 mmol) and methyl 3'- (bromomethyl)-4-chloro-[l,l'-biphenyl]-3-carboxylate (0.374 g, 1.1 mmol) and the mixture was heated at reflux for 1 h. The reaction mixture was filtered and the solvent was evaporated in vacuo to obtain methyl ester. Crude ester was dissolved in dioxane (20 mL), 2M Li OH (2.5 mL) was added and the mixture was heated at reflux for 3 h. The solvent was evaporated and the residue was dissolved in water and neutralized using 2M HC1. The aqueous layer was extracted with ethyl acetate and the organic layer was dried over anhydrous Na2SO4. The solid was removed and the filtrate solvent was evaporated under reduced pressure to obtain the crude acid as a yellow solid. The crude residue was purified using reverse phase HPLC to yield the desired compound. White solid (0.398 g, 78%). ¹ H NMR (400 MHz, DMSO-de): 8 8.01 (d, J = 2.3 Hz, 1H), 7.81-7.76 (m, 2H), 7.64-7.58 (m, 3H), 7.49-7.42 (m, 2H), 7.29-7.10 (m, 5H), 7.01 (d, J = 7.3 Hz, 1H), 5.79 (t, J = 7.8 Hz, 1H), 5.21 (s, 2H), 4.28 (d, J = 17.4 Hz, 1H), 3.87 (d, J = 17.4 Hz, 1H), 3.00-2.87 (m, 2H), 2.35 (q, J = 4.3 Hz, 1H), 2.08-2.05 (m, 1H). LC-MS m/z [M+H]+ found: 510.15.

Example 3 (S)-4-Chloro-3'-(((2-(2,3-dihydro-lH-inden-l-yl)-l-oxoisoindolin-5-yl)oxy)methyl)-[l,l'- biphenyl]-3-carboxylic acid

[00221] To a solution (s)-2-(2,3-dihydro-lH-inden-l-yl)-5-hydroxyisoindolin-l-one (0.265 g, 1 mmol) in ACN (15 mL) was added K2CO3 (0.276 g, 2 mmol) and methyl 3'- (bromomethyl)-4-chloro-[l,l'-biphenyl]-3-carboxylate (0.374 g, 1.1 mmol) and the mixture was heated at reflux for 1 h. The reaction mixture was filtered and the solvent was evaporated in vacuo to obtain methyl ester. Crude ester was dissolved in dioxane (20 mL), 2M Li OH (2.5 mL) was added and the mixture was heated at reflux for 3 h. The solvent was evaporated and the residue was dissolved in water and neutralized using 2M HC1. The aqueous layer was extracted with ethyl acetate and the organic layer was dried over anhydrous Na2SO4. The solid was removed and the filtrate solvent was evaporated under reduced pressure to obtain the crude acid as a yellow solid. The crude residue was purified using reverse phase HPLC to yield the desired compound. White solid (0.368 g, 72%). 'H-NMR (400 MHz, DMSO-D6) 5 8.01 (d, J = 2.3 Hz, 1H), 7.81-7.77 (m, 2H), 7.65-7.58 (m, 3H), 7.49-7.44 (m, 2H), 7.28 (d, J = 7.3 Hz, 1H), 7.21 (t, J = 7.3 Hz, 1H), 7.15-7.10 (m, 2H), 7.02 (d, J = 7.3 Hz, 1H), 5.79 (t, J = 7.6 Hz, 1H), 5.21 (s, 2H), 4.28 (d, J = 17.9 Hz, 1H), 3.87 (d, J = 17.9 Hz, 1H), 3.00-2.97 (m, 1H), 2.89-2.85 (m, 1H), 2.36-2.34 (m, 1H), 2.08-2.03 (m, 1H). LC-MS m/z [M+H]+ found: 510.15.

Example 4 (S)-4-Chloro-3'-(((2-(l-cyclopropylethyl)-l-oxoisoindolin-5-yl)oxy)methyl)-[l,l'- biphenyl]-3-carboxylic acid

[00222] A mixture of (S)2-(l-cyclopropyl-ethyl)-5-hydroxy-2,3-dihydro-isoindol-l-one (0.1 g, 0.46 mmol) and 3 '-brom omethyl-4-chloro-biphenyl-3 -carboxylic acid methyl ester (0.188 g, 0.552 mmol) in ACN (10 mL) was treated with K2CO3 (0.127 g, 0.921 mmol). The mixture was stirred at 80 °C for 2 h. The solid was filtered off and the solvent was removed and the residue was purified with silica column to afford the desired product as a pale yellow solid (0.070 g, 32%). To a solution of (S)4-chloro-3'-[2-(l-cyclopropyl-ethyl)-l-oxo-2,3-dihydro- lH-isoindol-5-yloxymethyl]-biphenyl-3-carboxylic acid methyl ester (0.070 g, 0.147 mmol) in THF/H2O (5:1, 5 mL), 2M LiOH (0.37 mL) was added. The mixture was stirred at 60 °C for 4 h. The reaction mixture was cooled down to rt, diluted with water and acidified with IN HC1 to pH 2 and extracted with ethyl acetate (3x10 mL). The solid was removed and the filtrate solvent was evaporated under reduced pressure. The remainder was purified with Cl 8 reverse phase column to afford the desired product as a white solid. ¹ H NMR (500 MHz, CD3OD): 5 7.97 (s, 1H), 8.60-7.37 (m, 7H), 7.07 (s, 1H), 7.02 (d, J = 8.5 Hz, 1H), 5.09 (s, 2H), 4.82 (s, 2H), 3.54-3.52 (m, 1H), 1.24 (m, 3H), 1.01-0.99 (m, 1H), 0.56-0.54 (m, 1H), 0.36-0.19 (m, 3H). LC-MS m/z calcd. for C27H24C1NO4 [M+H]+ 462.14; found 462.2. Example 5

4-Chloro-3'-(((2-(4-methoxybenzyl)-l-oxoisoindolin-5-yl)oxy)methyl)-[l,l'-biphenyl]-3- carboxylic acid

[00223] To a solution of 5-hydroxy-2-(4-methoxybenzyl)isoindolin-l-one (0.27 g, 1 mmol) and K2CO3 (0.276 g, 2 mmol) in ACN (25 mL), was added methyl 3'-(bromomethyl)-4- chlorobiphenyl-3 -carboxylate (0.407 g, 1.2 mmol). The resulting mixture was heated at reflux for 1 h. The reaction mixture was filtered and the solvent was evaporated under reduced pressure to obtain methyl 4-chloro-3'-(((2-(4-methoxybenzyl)-l-oxoisoindolin-5- yl)oxy)methyl)biphenyl-3-carboxylate as a light yellow solid (0.5 g).

Methyl 4-chloro-3'-((2-cyclopentyl-l,3-dioxoisoindolin-5-yloxy)methyl)biphenyl-3- carboxylate (0.5 g, 0.96 mmol) was dissolved in tetrahydrofuran (10 mL), 2M LiOH (2.5 mL) was added and the mixture was heated at reflux for 30 min. The solvent was evaporated and the residue was dissolved in water and neutralized using 2M HC1. The aqueous layer was extracted with ethyl acetate and the organic layer was dried over anhydrous ISfeSC The solid was removed and the filtrate solvent was evaporated under reduced pressure to obtain the crude acid as a yellow solid. The crude residue was purified by reverse phase column chromatography (ACN; H2O solvent system) compound as a white solid (0.38 g, 74%). 'H NMR (400 MHz, DMSO-d₆): 8 8.00 (d, J= 2.3 Hz, 1H), 7.81-7.77 (m, 2H), 7.66-7.58 (m, 2H), 7.49-7.46 (m, 2H), 7.18-7.09 (m, 5H), 6.88-6.85 (m, 2H), 5.21 (s, 2H), 4.56 (s, 2H), 4.22 (s, 2H), 3.67 (s, 3H). LC-MS m/z [M+H]⁺ found: 514.00.

Example 6

4-Chloro-3'-(((l-oxo-2-(pyridin-2-ylmethyl)isoindolin-5-yl)oxy)methyl)-[l,l'-biphenyl]-

3-carboxylic acid

[00224] To a solution 5-hydroxy-2-(pyridin-2-ylmethyl)isoindolin-l-one (0.120 g, 0.5 mmol) in ACN (15 mL) was added K2CO3 (0.138 g, 1 mmol) and methyl 3'-(bromomethyl)-4- chloro-[l,l'-biphenyl]-3-carboxylate (0.138 g, 0.550 mmol). The resulting mixture was heated at reflux for 1 h. The reaction mixture was filtered and the solvent was evaporated in vacuo to obtain methyl ester. Crude ester was dissolved in dioxane (20 mL), 2M LiOH (1.25 mL) was added and the mixture was heated at reflux for 1 h. The solvent was evaporated and the residue was dissolved in water and neutralized using 2M HC1. The aqueous layer was extracted with ethyl acetate and the organic layer was dried over anhydrous ISfeSC The solid was removed and the filtrate solvent was evaporated under reduced pressure to obtain the crude acid as a yellow solid. The crude residue was purified using reverse phase HPLC to yield the desired compound. White solid (0.178 g, 73.4%). 'H-NMR (400 MHz, DMSO-de) 5 8.47 (s, 1H), 8.02 (d, J= 13.3 Hz, 1H), 7.78-7.70 (m, 4H), 7.61 (t, J= 8.7 Hz, 3H), 7.50-7.43 (m, 3H), 7.28-7.19 (m, 2H), 7.12 (d, J= 8.2 Hz, 1H), 5.25 (s, 2H), 4.75 (s, 2H), 4.42 (s, 2H). LC-MS m/z [M+H]⁺ found: 485.15.

Example 7 4-Chloro-3'-(((l-oxo-2-(pyridin-4-ylmethyl)isoindolin-5-yl)oxy)methyl)-[l,l'-biphenyl]- 3-carboxylic acid

[00225] To a solution 5-hydroxy-2-(pyridin-4-ylmethyl)isoindolin-l-one (0.20 g, 0.834 mmol) in ACN (15 mL) was added K2CO3 (0.230 g, 1.665 mmol) and methyl 3'- (bromomethyl)-4-chloro-[l,l'-biphenyl]-3-carboxylate (0.311 g, 0.915 mmol) and the mixture was heated at reflux for 1 h. The reaction mixture was filtered and the solvent was evaporated in vacuo to obtain methyl ester. Crude ester was dissolved in dioxane (20 mL), 2M LiOH (2.08 mL) was added and the mixture was heated at reflux for 1 h. The solvent was evaporated and the residue was dissolved in water and neutralized using 2M HC1. The aqueous layer was extracted with ethyl acetate and the organic layer was dried over anhydrous Na2SO4. The solid was removed and the filtrate solvent was evaporated under reduced pressure to obtain the crude acid as a yellow solid. The crude residue was purified using reverse phase HPLC to yield the desired compound. White solid (0.298 g, 73.8%). LC- MS m/z [M+H]⁺ found: 485.00.

Example 8 4-Chloro-3'-(((l-oxo-2-(pyridin-3-ylmethyl)isoindolin-5-yl)oxy)methyl)-[l,l'-biphenyl]- 3-carboxylic acid

[00226] To a solution 5-hydroxy-2-(pyridin-3-ylmethyl)isoindolin-l-one (0.120 g, 0.5 mmol) in ACN (15 mL) was added K2CO3 (0.138 g, 1 mmol) and methyl 3'-(bromomethyl)-4- chloro-[l,l'-biphenyl]-3-carboxylate (0.179 g, 0.55 mmol) and the mixture was heated at reflux for 1 h. The reaction mixture was filtered, and the solvent was evaporated in vacuo to obtain methyl ester. Crude ester was dissolved in dioxane (20 mL), 2M LiOH (1.25 mL) was added and the mixture was heated at reflux for 3 h. The solvent was evaporated and the residue was dissolved in water and neutralized using 2M HC1. The aqueous layer was extracted with ethyl acetate and the organic layer was dried over anhydrous ISfeSC The solid was removed and the filtrate solvent was evaporated under reduced pressure to obtain the crude acid as a yellow solid. The crude residue was purified using reverse phase HPLC to yield the desired compound. White solid (0.123 g, 50.7%). %). 'H NMR (400 MHz, DMSO- d₆): 8 10.07 (s, 1H), 8.49-8.45 (m, 2H), 8.15-7.64 (m, 10 H), 7.20 (d, J= 1.8 Hz, 1H), 7.11 (dd, J= 8.7, 2.3 Hz, 1H), 5.22 (s, 2H), 4.68 (s, 2H), 4.31 (s, 2H). LC-MS m/z [M+H]⁺ found: 485.10.

Example 9 4-Chloro-3'-(((l-oxo-2-phenethylisoindolin-5-yl)oxy)methyl)-[l,l'-biphenyl]-3- carboxylic acid

[00227] To a solution 5-hydroxy-2-phenethylisoindolin-l-one (0.127 g, 0.5 mmol) in ACN (15 mL) was added K2CO3 (0.138 g, 1 mmol) and methyl 3'-(bromomethyl)-4-chloro-[l,l'- biphenyl]-3-carboxylate (0.179 g, 0.55 mmol). The resulting mixture was heated at reflux for 1 h. The reaction mixture was filtered, and the solvent was evaporated in vacuo to obtain methyl ester. Crude ester was dissolved in dioxane (20 mL), 2M LiOH (1.25 mL) was added and the mixture was heated at reflux for 3 h. The solvent was evaporated, and the residue was dissolved in water and neutralized using 2M HC1. The aqueous layer was extracted with ethyl acetate and the organic layer was dried over anhydrous Na2SO4. The solid was removed and the filtrate solvent was evaporated under reduced pressure to obtain the crude acid as a yellow solid. The crude residue was purified using reverse phase HPLC to yield the desired compound. White solid (0.161 g, 64.7%).¹H-NMR (400 MHz, DMSO-d₆) 8 8.02-8.00 (m, 1H), 7.80 (dt, J= 8.4, 2.2 Hz, 2H), 7.67-7.13 (m, 12H), 5.21 (s, 2H), 4.28 (s, 2H), 3.68 (t, J= 7.3 Hz, 2H), 2.86 (t, J= 7.3 Hz, 2H). LC-MS m/z [M+H]⁺ found: 498.20.

Example 10

2-Chloro-5-[3-({2-[(4-fluorophenyl)methyl]-l-oxoisoindolin-5- yloxy}methyl)phenyl]benzoic acid

[00228] To a solution of 2-(4-fluorobenzyl)-5-hydroxyisoindolin-l-one in (0.129 g, 0.5 mmol) ACN (15 mL) was added K2CO3 (0.138 g, 1 mmol), and methyl 3'-(bromomethyl)-4-chloro- [1, l'-biphenyl]-3 -carboxylate (0.204 g, 0.6 mmol) the mixture was heated at reflux for 1 h. The reaction mixture was filtered and the solvent was evaporated under reduced pressure to obtain methyl ester as a yellow solid. Crude ester was dissolved in dioxane (10 mL), 2M LiOH (1.25 mL) was added and the mixture was heated at reflux for 3 h. The solvent was evaporated and the residue was dissolved in water and neutralized using 2M HC1. The aqueous layer was extracted with ethyl acetate and the organic layer was dried over anhydrous ISfeSC The solid was removed and the filtrate solvent was evaporated under reduced pressure to obtain the crude acid as a yellow solid. The crude residue was purified by automated preparative HPLC to yield the desired compound. Pale yellow solid (0.16 g, 63.8%). ‘HNMR (400 MHz, DMSO-d6): 6 8.02 (d, J = 2.3 Hz, 1H), 7.83-7.79 (m, 2H), 7.62 (d, J = 8.7 Hz, 2H), 7.49-7.48 (m, 3H), 7.30-7.27 (m, 2H), 7.21-7.12 (m, 4H), 5.23 (s, 2H), 4.65 (s, 2H), 4.28 (s, 2H). LC-MS m/z calcd. for for C29H21C1FNO4 [M+H]+ 502.11; found 502.2.

Example 11 2-Chloro-5-(3-{[l-oxo-2-benzylisoindolin-5-yloxy]methyl}phenyl)benzoic acid

[00229] A mixture of 2-benzyl-5-hydroxy-2,3-dihydro-isoindol-l-one (0.24 g, 1 mmol) and 3 '-brom omethyl-4-chloro-biphenyl-3 -carboxylic acid methyl ester (0.409 g, 1.2 mmol) in acetone (15 mL) was treated with K2CO3 (0.276 g, 2 mmol). The mixture was stirred at 80 °C for 2 hrs. The solid was filtered off and the solvent was removed. The residue was purified with silica column to afford the desired product as a pale yellow solid. To a solution of 3'-(2- benzyl-1 -oxo-2, 3-dihydro-lH-isoindol-5-yloxymethyl)-4-chloro-biphenyl-3-carboxylic acid methyl ester (0.3 g, 0.6 mmol) in THF/H2O (5: 1, 5 mL), 2M LiOH (1.5 mL) was added. The mixture was stirred at 60 °C for 4 h. The reaction mixture was cooled to rt, diluted with water, acidified with IN HC1 to pH 2 and extracted with ethyl acetate (3x25 mL). The solvent was removed and the residue was purified with C18 reverse phase column to afford the desired product as a white solid. 'H NMR (500 MHz, CDCI3): d 8.50 (s, 1H), 8.16 (d, J= 8.5 Hz, 1H), 7.96-7.93 (m, 2H), 7.85-7.57 (m, 9H), 7.38 (d, J= 8.5 Hz, 1H), 7.26 (s, 1H), 5.47 (s, 2H), 5.09 (s, 2H), 4.53 (s, 2H). LC-MS m/z calcd. for C29H22CINO4 [M+H]⁺ 484.12; found 484.1.

Example 12 3-{5-[(2-Cyclopentyl-l-oxoisoindolin-5-yloxy)methyl]-l,2,4-oxadiazol-3-yl}benzoic acid

[00230] To a solution of 2-cyclopentyl-5-hydroxyisoindolin-l-one (0.109 g, 0.5 mmol) and methyl 3-(5-(chloromethyl)-l,2,4-oxadiazol-3-yl)benzoate (0.152 g, 0.6 mmol) in ACN (5 mL) was added K2CO3 (0.138 g, 1 mmol). The resulting mixture was heated at 80 °C for 2 h. The mixture was cooled to room temperature and solvent removed under reduced pressure, and pardoned between DCM and water. The organic phase collected, and the aqueous phase extracted three times with DCM. The combined organic phase was washed with water, and brine, and dried over anhyd. sodium sulfate. The solid was removed and the filtrate solvent was removed under reduced pressure affording the methyl ester. Crude ester was taken in dioxane (10 mL) and 2M LiOH solution (2.5 mL) was added and the resulting mixture was heated at 80 °C for 30 min. Crude reaction mixture was diluted with water, acidified using dil. HC1 and extracted with ethyl acetate. Removal of the solvent followed by reverse phase HPLC yielded the desired compound. White solid (0.148 g, 70.6%). ^JH NMR (400 MHz, DMSO-de): 6 8.54 (s, 1H), 8.24-8.22 (m, 1H), 8.15-8.12 (m, 1H), 7.70 (t, J= 7.8 Hz, 1H), 7.59 (d, J= 8.2 Hz, 1H), 7.28 (J = 2.3 Hz, 1H), 7.18 (dd, J= 2.3 Hz, 8.2 Hz, 1H), 5.71 (s, 2H), 4.53-4.51 (m, 1H), 4.40 (s, 2H), 1.83-1.56 (m, 8H). LC-MS m/z calcd. for C23H21N3O5 [M+H]⁺ 420.15; found 420.05. Example 24

5-{3-[(6-Bromo-2-cyclopentyl-l-oxoisoindolin-5-yloxy)methyl]phenyl}-2-chlorobenzoic acid

[00231] To a solution of 6-bromo-2-cyclopentyl-5-hydroxyisoindolin-l-one (0.444 g, 1.5 mmol) and methyl 3'-(bromomethyl)-4-chloro-[l,l'-biphenyl]-3-carboxylate (0.509 g, 1.5 mmol) in ACN (25 mL) was added K2CO3 (0.415 g, 3 mmol). The resulting mixture was heated at 80 °C for 2 h. The reaction mixture was cooled to rt, filtered and concentration of the filtrate under reduced pressure yielded the ester, which was purified by silica column (redi Sep isco, 20 g column: hexane to 20% DCM in hexane) to afford a white solid (0.593 g, 71.2%). The resultant (0.593 g, 1.069 mmol) was taken in dioxane and heated with 2M LiOH solution (5.4 mL) at 80 °C, after the completion of the reaction, the reaction mixture was diluted with water and acidified. The precipitated compound was collected by filtration and purified by column chromatography (DCM to 10% MeOH in DCM). White solid (0.578 g, 94%). 'H NMR (400 MHz, DMSO-d₆): 8 8.06 (s, 1H), 7.86-7.79 (m, 3H), 7.69-7.63 (m, 2H), 7.52-7.40 (m, 3H), 5.38 (s, 2H), 4.56-4.39 (m, 1H), 4.40 (s, 2H), 1.81-1.60 (m, 8H). LC-MS m/z calcd. for C₂7H23BrClNO₄ [M+H]⁺ 540.05; found 542.10.

Example 25 2-Chloro-5-{3-[(2-cyclopentyl-l-oxo-6-phenylisoindolin-5-yloxy)methyl]phenyl}benzoic acid

[00232] A mixture of 3'-(((6-bromo-2-cyclopentyl-l-oxoisoindolin-5-yl)oxy)methyl)-4- chloro-[l,l'-biphenyl]-3-carboxylic acid (0.108 g, 0.2 mmol), phenyl boronic acid (0.037 g, 0.3 mmol) and Pd(PPh3)₄ (23 mg, 0.02 mmol) were combined in DME (10 mL). To this, 2M Na₂CO3 solution was added and the resulting mixture was refluxed in an atmosphere of N2 for 6-12 h. The reaction mixture cooled to room temperature and diluted with water and then acidified using IN HC1. The aqueous mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous Na2SO₄. The solid was removed and the filtrate solvent was evaporated in vacuum to obtain the crude product. The crude product was purified using automated prep-HPLC to yield the desired compound as a white solid (0.078 g, 72%). 'HNMR (400 MHz, DMSO-d₆): 8 7.93 (d, J= 2.3 Hz, 1H), 7.70-7.67 (m, 4H), 7.60-7.56 (m, 2H), 7.55-7.33 (m, 7H), 5.28 (s, 2H), 4.53-4.51 (m, 1H), 4.44 (s, 2H), 1.85-1.83 (m, 2H), 1.72-1.58 (m, 6H). LC-MS m/z calcd. for C33H28CINO4 [M+H]⁺ 538.17; found 538.25.

Example 26 2-Chloro-5-{3-[(2-cyclopentyl-6-methyl-l-oxoisoindolin-5-yloxy)methyl]phenyl}benzoic

[00233] A mixture of 3'-(((6-Bromo-2-cyclopentyl-l-oxoisoindolin-5-yl)oxy)methyl)-4- chloro-[l,l'-biphenyl]-3-carboxylic acid (0.108 g, 0.2 mmol), methylboronic acid (0.018 g, 0.3 mmol) and Pd(PPh3)4 (2.3 mg, 0.002 mmol) were combined in DME (10 mL). To this, 2M Na2CC>3 solution was added and the resulting mixture was refluxed in an atmosphere of N2 for 6-12 h. The reaction mixture cooled to room temperature and diluted with water and then acidified using IN HC1. The aqueous mixture was extracted with ethyl acetate and washed with brine and the organic layer was dried over anhydrous Na2SO4. The solid was removed and the filtrate solvent was evaporated in vacuum to obtain the crude product. The crude product was purified using automated prep-HPLC to yield the desired compound as a white solid (0.075 g, 79%). ‘HNMR (400 MHz, DMSO-d₆): 6 8.10 (s, 1H), 7.83-7.76 (m, 2H), 7.64-7.59 (m, 2H), 5.59-7.41 (m, 3H), 7.20 (s, 1H), 5.33 (s, 2H), 4.48-4.45 (m, 1H), 4.36 (s, 2H), 2.23 (s, 3H), 1.78-1.55 (m, 8H). LC-MS m/z calcd. for C28H26CINO4 [M+H]⁺ 476.15; found 476.0.

Example 27

2-Chloro-5-(3-{[2-cyclopentyl-l-oxo-6-(phenylamino)isoindolin-5- yloxy]methyl}phenyl)benzoic acid

[00234] To a stirred solution of 3'-(((6-bromo-2-cyclopentyl-l-oxoisoindolin-5- yl)oxy)methyl)-4-chloro-[l,l'-biphenyl]-3-carboxylic acid (0.081 mg, 0.15 mmol) in 1,4- dioxane (10 mL) under inert atmosphere were added aniline (0.019 g, 0.2 mmol), xanthphos (4 mg, 0.007 mmol), and cesium carbonate (0.065 g, 0.2 mmol) at rt in a sealed tube purged with argon for 10 min. Then Pd2(dba)s (0.005 g, 0.006 mmol) was added to the mixture and again purged for 15 min; heated to 100 °C and stirred for 2 h. The reaction mixture was filtered through a celite pad. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse phase HPLC. White solid (0.028 g, 50.7%). 'H NMR (400 MHz, DMSO-d₆): 6 7.59 (d, J= 2.3 Hz, 1H), 7.77 (s, 1H), 7.71 (dd, J= 2.3 Hz, 8.7 Hz, 1H), 7.61-7.56 (m, 2H), 7.51 (s, 1H), 7.47-7.41 (m, 2H), 7.38- 7.21 (m, 2H), 7.20 (t, J= 8.2 Hz, 2H), 7.02 (d, J= 13 Hz, 2H), 6.80 (d, J= 13 Hz, 1H), 5.32 (s, 2H), 4.50-4.44 (m, 1H), 4.31 (s, 2H), 1.79-1.58 (m, 8H). LC-MS m/z calcd. for for C33H29CIN2O4 [M+H]⁺ 553.18; found 553.2.

Example 28 2-Chloro-5-{3-[(2-cyclopentyl-7-methyl-l-oxoisoindolin-5-yloxy)methyl]phenyl}benzoic acid

[00235] To a solution 2-cyclopentyl-5-hydroxy-7-methylisoindolin-l-one (0.231 g, 1 mmol) in ACN (15 mL) was added K2CO3 (0.276 g, 2 mmol) and methyl 3'-(bromomethyl)-4- chloro-[l,l'-biphenyl]-3-carboxylate (0.374 g, 1.1 mmol). The resulting mixture was heated at reflux for 1 h. The reaction mixture was allowed to cool to rt and filtered. The filtrate solvent was evaporated under reduced pressure to obtain methyl ester. Crude ester was dissolved in dioxane (20 mL), 2M LiOH (2.5 mL) was added and the mixture was heated at reflux for 3 h. The solvent was evaporated and the residue was dissolved in water and neutralized using 2M HC1. The aqueous layer was extracted with ethyl acetate and the organic layer was dried over anhydrous ISfeSC The solid was removed and the filtrate solvent was evaporated in vacuo to obtain the crude acid as a yellow solid. The crude residue was purified by reverse phase HPLC to yield the desired compound. White solid (0.376 g, 79%). ‘HNMR (400 MHz, DMSO-d₆): 8 7.99 (s, 1H), 7.79-7.79 (m, 2H), 7.63-7.56 (m, 2H), 7.46-7.44 (m, 2H), 6.96 (s, 1H), 6.83 (s, 1H), 5.17 (s, 2H), 4.48-4.46 (m, 1H), 4.24 (s, 2H), 2.49 (s, 3H), 1.87-1.48 (m, 8H). LC-MS m/z calcd. for C28H26CINO4 [M+H]⁺ 476.15; found 476.2. Example 29

2-Chloro-5-(3-{[(2-cyclopentyl-l-oxoisoindolin-5-yl)amino]methyl}phenyl)benzoic acid

[00236] To a solution of 5-amino-2-cyclopentylisoindolin-l-one (0.108 g, 0.5 mmol) in ACN (15 mL) was added K2CO3 (0.138 g, 1 mmol) and methyl 3'-(bromomethyl)-4-chloro-[l,l'- biphenyl]-3-carboxylate (0.340 g, 1 mmol). The resulting mixture was heated at reflux for 1 h. The reaction mixture was allowed to cool to rt and filtered. The filtrate solvent was evaporated under reduced pressure to obtain methyl ester. Crude ester was dissolved in dioxane (17 mL), 2M LiOH (2.5 mL) was added and the mixture was heated at reflux for 3 h. The solvent was evaporated and the residue was dissolved in water and neutralized using 2M HC1. The aqueous layer was extracted with ethyl acetate and the organic layer was dried over anhydrous ISfeSC The solid was removed and the filtrate solvent was evaporated to afford the crude acid as a yellow solid. The crude residue was purified using automated preparative HPLC to yield the desired compound. Pale yellow solid (0.089 g, 38.6%). ^JH NMR (400 MHz, DMSO-d6): 5 7.98 (d, J = 2.3 Hz, 1H), 7.79 (dd, J = 2.3 Hz, 8.2 Hz, 1H), 7.59 (d, J = 8.2 Hz, 2H), 7.51-7.45 (m, 3H), 7.35 (t, J = 7.8 Hz, 1H), 7.20 (d, J = 7.3 Hz, 1H), 4.60 (d, J = 2.8 Hz, 2H), 4.54 (s, 2H), 4.35-4.31 (m, 1H), 1.90-1.55 (m, 8H). LC-MS m/z calcd. for C27H25C1N2O3 [M+H]+ 461.15; found 461.0.

Example 30 2-Chloro-5-{3-[(2-methyl-l-oxoisoindolin-5-yloxy)methyl]phenyl} benzoic acid

[00237] To mixture of 5-hydroxy-2-methyl-2,3-dihydro-isoindol-l-one (0.160 g, 0.981 mmol) and 3 '-brom omethyl-4-chloro-biphenyl-3 -carboxylic acid methyl ester (0.04, 1.18 mmol) in acetone (15 mL), K2CO3 (0.291, 1.76 mmol) was added. The mixture was stirred at 80 °C for 2 h. The solid was filtered off, the solvent was removed and the residue was purified with silica column to afford the desired product as a pale yellow solid (0.200 g, 46%). To a solution of 4-Chl oro-3'-(2 -methyl- 1 -oxo-2, 3-dihy dro-lH-isoindol-5-yloxymethyl)-biphenyl- 3-carboxylic acid methyl ester (0.160 g, 0.38 mmol) in THF/H2O (5: 1, 5 mL), 2 M LiOH (1 mL) was added. The mixture was stirred at 60 °C for 4 h. The reaction mixture was cooled to rt, diluted with water and acidified with IN HC1 to pH 2 and extracted with ethyl acetate (3x20 mL). The solvent was removed the residue was purified with Cl 8 reverse phase column to afford the desired product as a yellow solid. ¹ H NMR (500 MHz, CDCh): 8 8.08 (s, 1H), 7.72 (m, 1H), 7.60-7.42 (m, 6H), 7.09 (d, J= 8.5 Hz,lH), 6.99 (s, 1H), 5.16 (s, 2H), 4.31 (s, 2H), 3.14 (s, 3H). LC-MS m/z calcd. for C₂3HI₈C1NO₄ [M+H]⁺ 408.09; found 408.1.

Example 31 2-Chloro-5-{3-[(2-ethyl-l-oxoisoindolin-5-yloxy)methyl]phenyl}benzoic acid

[00238] To a solution of 2-ethyl-5-hydroxyisoindolin-l-one (0.12 g, 0.677 mmol) in ACN (15 mL) was added K2CO3 (0.187g, 1.354 mmol) and methyl 3'-(bromomethyl)-4-chloro-[l,l'- biphenyl]-3-carboxylate (0.276 g, 0.813 mmol). The resulting mixture was heated at reflux for 1 h. The reaction mixture was allowed to cool to rt and filtered. The filtrate solvent was evaporated under reduced pressure to obtain methyl ester as a yellow solid. Crude ester was dissolved in dioxane (17 mL), 2M LiOH was added and the mixture was heated at reflux for 3 h. The solvent was evaporated and the residue was dissolved in water and neutralized using 2M HC1. The aqueous layer was extracted with ethyl acetate and the organic layer was dried over anhydrous Na2SO₄. The solid was removed and the filtrate solvent was evaporated in vacuo to obtain the crude acid as a yellow solid. The crude residue was purified using automated preparative HPLC to yield the desired compound as a white solid. ¹ H NMR (500 MHz, CD3OD): 3 8.05 (s, 1H), 7.74-7.48 (m, 6H), 7.19 (s, 1H), 7.13 (d, J= 8.5 Hz, 1H), 5.23 (s, 2H), 4.42 (s, 2H), 3.61(m, 2H), 1.25-1.21 (m, 3H). LC-MS m/z calcd. for C₂₄H2OC1N0₄ [M+H]⁺ 422. I l; found 422.2.

Example 32

5-(3- { [2-(tert-Butyl)- l-oxoisoindolin-5-yloxy] methyl} phenyl)-2-chlorobenzoic acid

[00239] To a solution of 2-tert-butyl-5-hydroxyisoindolin-l-one (0.55 g, 1.7 mmol) in ACN (15 mL) was added K2CO3 (0.47 g, 3.4 mmol) and methyl 3'-(bromomethyl)-4-chloro-[l,l'- biphenyl]-3-carboxylate (0.695 g, 2.046 mmol). The resulting mixture was heated at reflux for 1 h. The reaction mixture was allowed to cool to rt and filtered. The filtrate solvent was evaporated under reduced pressure to obtain methyl ester as a yellow solid. Crude ester was dissolved in dioxane (17 mL), 2M LiOH was added and the mixture was heated at reflux for 3 h. The solvent was evaporated and the residue was dissolved in water and neutralized using 2M HC1. The aqueous layer was extracted with ethyl acetate and the organic layer was dried over anhydrous Na2SO4. The solid was removed and the filtrate solvent was evaporated under reduced pressure to obtain the crude acid as a yellow solid. The crude residue was purified using automated preparative HPLC to yield the desired compound as a white solid. ¹ H NMR (500 MHz, CDCI3): d 8.21 (s, 1H), 7.78 (d, J= 8.5 Hz, 1H), 7.74-7.46 (m, 6H), 7.07 (d, J= 8.5 Hz, 1H), 6.98 (s, 1H), 5.19 (s, 2H), 4.41(s, 2H), 4.30 (s, 2H), 1.55(s, 9H). LC-MS m/z calcd. for C26H24CINO4 [M+H]+ 450.14; found: 450.1.

Example 33 5-(3-{[2-(2,2-Dimethylpropyl)-l-oxoisoindolin-5-yloxy]methyl}phenyl)-2-chlorobenzoic acid

[00240] To mixture of 2-(2,2-dimethyl-propyl)-5-hydroxy-2,3-dihydro-isoindol-l-one (0.23 g, 1.049 mmol), and 3-bromomethyl-4-chloro-biphenyl-3-carboxylic acid methyl ester (0.289, 1.259 mmol) in acetone (15 mL) was added K2CO3 (0.280 g, 2.1 mmol). The mixture was stirred at 80 °C for 2 h. The solid was removed by filtration and the solvent was removed under reduced pressure to afford a residue. The residue was purified with silica column to afford the desired product as a pale yellow solid. To a solution of above ester (0.35 g, 0.711 mmol) in THF/H2O (5:1, 5 mL) was added 2M LiOH (1.8 mL). The mixture was stirred at 60 °C for 4 hrs. The reaction mixture was cooled to rt, diluted with water, acidified with IN HC1 to pH 2 and extracted with ethyl acetate (3 x 20 mL). The solvent was removed under reduced pressure and the residue was purified by Cl 8 reverse phase column to afford the desired product as a white solid. 'H NMR (500 MHz, CDCI3): 5 8.21 (s, 1H), 7.78 (d, J= 8.5 Hz, 1H), 7.67-7.65 (m, 2H), 7.56-7.45 (m, 4H), 7.09 (d, J= 8.5 Hz, 1H ), 7.01 (s, 1H), 5.20 (s, 2H), 4.47 (s, 2H), 3.37 (s, 2H), 1.02 (s, 9H). LC-MS m/z calcd. for C27H26CINO4 [M+H]⁺ 464.16, found: 464.3.

Example 41

Methyl 4-chloro-3'-(((2-cyclopentyl-l-oxoisoindolin-5-yl)oxy)methyl)-[l,l'-biphenyl]-3- carboxylate

[00241] To a mixture of 2-cyclopentyl-5-hydroxyisoindolin-l-one (0.5 g, 2.3 mmol) and K2CO3 (1.8 g, 4.6 mmol) in ACN (25 mL), was added methyl 3'-(bromomethyl)-4- chlorobiphenyl-3 -carboxylate (0.92 g, 2.7 mmol). The resulting mixture was heated at reflux for 1 h. The reaction mixture was allowed to cool to rt and filtered. The filtrate solvent was evaporated under reduced pressure to obtain methyl 4-chl oro-3 '-((2-cy cl opentyl-1- oxoisoindolin-5-yloxy)methyl)biphenyl-3-carboxylate as a light yellow solid (1.09 g). ^JH NMR (400 MHz, CDCI3): 8 8.05 (s, 1H), 7.77 (d, J= 8.2 Hz, 1H), 7.65-7.63 (m, 2H), 7.56- 7.44 (m, 4H), 7.07 (d, J= 8.2 Hz, 1H), 7.02 (s, 1H), 5.19 (s, 2H), 4.76-4.72 (m, 1H), 4.30 (s, 2H), 3.96 (s, 3H), 1.99- 1.93 (s, 2H), 1.77-1.59 (m, 8H). LC-MS m/z calcd. for C₂8H26C1NO₄[M+H]⁺476.16, found: 476.20.

Example 51 2-Chloro-5-{3-[(2-cyclopentyl-3-oxoisoindolin-5-yloxy)methyl]phenyl}benzoic acid

[00242] To a solution 2-cyclopentyl-6-hydroxyisoindolin-l-one (0.217 g, 1 mmol) in ACN (15 mL) was added K2CO3 (0.276 g, 2 mmol) and methyl 3'-(bromomethyl)-4-chloro-[l,l'- biphenyl]-3-carboxylate (0.374 g, 1.1 mmol). The resulting mixture was heated at reflux for 1 h. The reaction mixture was allowed to cool to rt and filtered. The filtrate solvent was evaporated in vacuo to obtain methyl ester. Crude ester was dissolved in dioxane (20 mL), 2M LiOH (2.5 mL) was added and the mixture was heated at reflux for 3 h. The mixture was allowed to cool to rt and the solvent was removed under reduced pressure. The residue was dissolved in water and neutralized using 2M HC1. The aqueous layer was extracted with ethyl acetate and the organic layer was dried over anhydrous Na₂SO4. The solid was removed and the filtrate solvent was evaporated under reduced pressure to obtain the crude acid as a yellow solid. The crude residue was purified using automated preparative HPLC to yield the desired compound. White solid (0.295 g, 64%). ^XH NMR (400 MHz, DMSO-d₆): 6 8.03 (s, 1H), 7.85-7.80 (m, 2H), 7.70-7.44 (m, 5H), 7.25-7.22 (m, 2H), 5.27 (s, 2H), 4.55-4.52 (m, 1H), 4.36 (s, 2H), 1.82-1.59 (m, 8H). LC-MS m/z calcd. for C27H24CINO4 [M+H]⁺ 462.14; found 462.15. General synthetic scheme for the preparation of isoindolinone derivatives: General

Procedure B

Synthesis of 5-((3-Bromobenzyl)oxy)-2-cyclopentylisoindolin-l-one

[00243] Potassium carbonate (5.52 g, 40 mmol) was added to a solution of 2-cyclopentyl-5- hydroxyisoindolin-l-one (4.35 g, 20 mmol) and l-bromo-3-(bromomethyl)benzene (5 g, 20 mmol) in ACN (100 mL). After stirring for 1 h at 80 °C, the organic phase was evaporated under reduced pressure and the crude material was partitioned between water and DCM. The aqueous layer was extracted with DCM (3x 50 mL). The organic phase was dried over Na2SO4, filtered and evaporated under reduced pressure to afford 5-((3-bromobenzyl)oxy)-2- cyclopentylisoindolin-l-one as a pale yellow solid. The crude product was used for the next step without further purification. White solid (3.8 g, quantitative yield). ^JH NMR (400 MHz, CDC1₃): 8 7.73 (d, J= 8.2 Hz, 1H), 7.58 (s, 1H), 7.45 (d, J= 8.2 Hz, 1H), 7.32 (d, J= 7.8 Hz, 1H), 7.26-7.24 (m, 1H), 7.00 (dd, J= 2.3 Hz, 8.2 Hz, 1H), 6.96 (s, 1H), 5.07 (s, 2H), 4.74- 4.70 (m, 1H), 4.28 (s, 2H), 1.98-1.97 (m, 2H), 1.76-1.64 (m, 6H). LC-MS m/z calcd. for for C₂oH2oBrN0₂ [M+H]⁺ 386.07; found 386.0.

Example 13 2-Chloro-5-{6-[(2-cyclopentyl-l-oxoisoindolin-5-yloxy)methyl]pyrazin-2-yl}benzoic acid

[00244] The title compound was synthesized according to the general procedure B using 5-(6- bromo-pyrazin-2-ylmethoxy)-2-cyclopentyl-2,3-dihydro-isoindol-l-one (0.2 g, 0.515 mmol), 5-borono-2-chlorobenzoic acid (0.155 g, 0.773 mmol), Pd(PPh3)4 (0.059 g, 0.051 mmol) and 2M Na₂CO₃ solution (1 mL). White solid. 'HNMR (400 MHz, CDC1₃): 8 8.98 (s, 1H), 8.73 (s, 1H), 8.57 (s, 1H), 8.06 (d, J= 8.5 Hz, 1H), 7.77 (d, J= 8.0 Hz, 1H), 7.59 (d, J= 8. 0 Hz, 1H), 7.19 (d, J= 8.0 Hz, 1H), 7.04 (s, 1H), 5.36 (s, 2H), 4.71-4.66 (m, 1H), 4.31 (s, 2H), 2.02- 1.96 (m, 2H), 1.73-1.63 (m, 6H). LC-MS m/z calcd. for C25H22CIN3O4 [M+H]⁺ 464.13; found 464.2.

Example 14 2-Chloro-5-{5-[(2-cyclopentyl-l-oxoisoindolin-5-yloxy)methyl]pyrazin-2-yl}benzoic acid

[00245] The title compound was synthesized according to the general procedure B using 5-(5- bromo-pyrazin-2-ylmethoxy)-2-cyclopentyl-2,3-dihydro-isoindol-l-one (0.2 g, 0.515 mmol), 5-borono-2-chlorobenzoic acid (0.155 g, 0.773 mmol), Pd(PPh₃)4 ( 0.059 g, 0.051 mmol) and 2M Na₂CO₃ solution (1 mL). White solid. 'HNMR (400 MHz, CDCI3): 6 9.02 (s, 1H), 8.83 (s, 1H), 8.55 (s, 1H), 8.10 (d, J= 8.0 Hz, 1H), 7.76 (d, J= 8.0 Hz, 1H), 7.57 (d, J= 8.0 Hz, 1H), 7.10 (d, J= 8.0 Hz, 1H), 7.04 (s, 1H), 5.31 (s, 2H), 4.72-4.67 (m, 1H), 4.31 (s, 2H), 2.02-1.93 (m, 2H), 1.75-1.63 (m, 6H), (m, 8H). LC-MS m/z calcd. for C25H22CIN3O4 [M+H]⁺ 464.13; found 464.2.

Example 15 2-Chloro-5-{5-[(2-cyclopentyl-l-oxoisoindolin-5-yloxy)methyl](3-pyridyl)}benzoic acid

[00246] The title compound was synthesized according to the general procedure B using 5- ((5-bromopyridin-3-yl)methoxy)-2-cyclopentylisoindolin-l-one (0.2 g, 0.515 mmol), 5- borono-2-chlorobenzoic acid (0.155 g, 0.775 mmol), Pd(PPh₃)4 ( 0.059 g, 0.051 mmol) and 2M Na₂CO₃ solution (1 mL). White solid. 'HNMR (400 MHz, CDCI3): 6 8.81 (s, 1H), 8.69 (s, 1H), 8.11 (s, 1H), 8.07 (s, 1H), 7.78-7.55 (m, 3H), 7.28 (s, 1H), 7.10-7.03 (m, 2H), 5.28 (s, 2H), 4.71-4.68 (m, 1H), 4.33 (s, 2H), 1.98-1.65 (m, 8H). LC-MS m/z calcd. for C26H23CIN2O4 [M+H]+ 463.13; found 463.2. Example 16

2-Chloro-5-(2-(((2-cyclopentyl-l-oxoisoindolin-5-yl)oxy)methyl)pyridin-4-yl)benzoic acid

[00247] The title compound was synthesized according to the general procedure B using 5-(2- bromo-pyridin-4-ylmethoxy)-2-cyclopentyl-2,3-dihydro-isoindol-l-one (0.2 g, 0.515 mmol), 5-borono-2-chlorobenzoic acid (0.155 g, 0.775 mmol), Pd(PPh₃)4 (0.059 g, 0.051 mmol) and 2M Na₂CO₃ solution (1 mL). White solid. 'HNMR (400 MHz, CDC1₃): 8 8.60 (s, 1H), 8.10 (s, 1H), 7.70-7.62 (m, 3H), 7.54-7.47 (m, 2H), 7.09-7.03 (m, 2H), 5.27 (s, 2H), 4.65-4.60 (m, 1H), 4.28 (s, 2H), 1.93-1.59 (m, 8H). 5.27 (s, 2H), 4.65-4.59 (m, 1H), 4.28 (s, 2H), 1.95-1.59 (m, 8H). LC-MS m/z calcd.for C26H23CIN2O4 [M+H]⁺ 463.13; found 463.2.

Example 17

2-Chloro-5-{6-[(2-cyclopentyl-l-oxoisoindolin-5-yloxy)methyl]pyridazin-3-yl} benzoic acid

[00248] 5-((6-Bromopyridazin-3-yl)methoxy)-2-cyclopentylisoindolin-l-one (0.7 g, 0.18 mmol), 5-borono-2-chlorobenzoic acid (0.037 g, 0.18mmol) and Pd(PPh₃)4 (0.021 g, 0.002 mmol) were taken in DME (10 mL). To this, 2M Na₂CO3 (0.31 mL) solution was added and the resulting solution was mixture was processed according to the general procedure B to yield the title compound. White solid (0.05 g, 59.8%). ¹ H NMR (400 MHz, CDCI3): 6 8.66 (s, 1H), 8.26 (d, J = 8.7 Hz, 1H), 7.81-7.75 (m, 2H), 7.65 (d, J = 8.7 Hz, 2H), 7.09 (d, J= 8.7 Hz, 1H), 6.98 (s, 1H), 5.56 (s, 2H), 4.75-4.74 (m, 1H), 4.29 (s, 2H), 2.09-1.98 (m, 2H), 1.84-1.62 (m, 6H). LC-MS m/z calcd. for C₂5H22C1N3O₄[M+H]⁺ 464.13; found: 464.0.

Example 18

2-Chloro-5-{5-[(2-cyclopentyl-l-oxoisoindolin-5-yloxy)methyl](l,3,4-thiadiazol-2- yl)}benzoic acid

[00249] 5-((5-Bromo-l,3,4-thiadiazol-2-yl)methoxy)-2-cyclopentylisoindolin-l-one (0.15 g, 0.38 mmol), 5-borono-2-chlorobenzoic acid (0.08 g, 0.38 mmol) and Pd(PPh₃)4 (0.044 g, 0.038 mmol) were taken in DME (10 mL). To this, 2M Na₂CO₃ (0.76 mL) solution was added and the resulting mixture was processed according to the general procedure B to yield the title compound as a white solid (0.097 g, 54.3%). ^JH NMR (400 MHz, DMSO-de): 8 8.29 (d, J= 2.3 Hz, 1H), 8.07 (dd, J= 8.5, 2.1 Hz, 1H), 7.69 (d, J= 8.2 Hz, 1H), 7.57 (d, J= 8.2 Hz, 1H), 7.27 (s, 1H), 7.15 (dd, J= 8.2, 2.3 Hz, 1H), 5.71 (s, 2H), 4.49-4.47 (m, 1H), 4.38 (s, 2H), 1.81-1.55 (m, 8H). LC-MS m/z [M+H]⁺ 470.08; found: 470.10.

Example 19 2-Chloro-5-{2-[(2-cyclopentyl-l-oxoisoindolin-5-yloxy)methyl](l,3-thiazol-5-yl)}benzoic

[00250] The title compound was synthesized according to the general procedure using 5-(5- bromo-thiazol-2-ylmethoxy)-2-cyclopentyl-2,3-dihydro-isoindol-l-one (0.200 g, 0.509 mmol) 5-borono-2-chlorobenzoic acid (0.153 g, 0.763 mmol), Pd(PPh₃)4 (0.06 g, 0.051 mmol) and 2M Na₂CO₃ solution (1 mL). White solid. ^XH NMR (400 MHz, CDC1₃): 6 8.02 (s, 1H), 7.72-7.70 (m, 1H), 7.66-7.64 (m, 1H), 7.35 (s, 1H), 7.20 (s, 1H), 7.16 (s, 1H), 7.11-7.09 (m, 1H), 5.34 (s, 2H), 4.64-4.60 (m, 1H), 4.43 (s, 2H), 1.96-1.68 (m, 8H). LC-MS m/z calcd. for C24H21CIN2O4S [M+H]⁺ 469.09; found 469.1.

Example 20 2-Chloro-5-{5-[(2-cyclopentyl-l-oxoisoindolin-5-yloxy)methyl](2-furyl)}benzoic acid

[00251] The title compound was synthesized according to the general procedure B using 5- ((5-bromofuran-2-yl)methoxy)-2-cyclopentylisoindolin-l-one (0.200 g, 0.532 mmol), 5- borono-2-chlorobenzoic acid (0.160 g, 0.797 mmol), Pd(PPh₃)4 (0.06 g, 0.053 mmol) and 2M Na2CC>3 solution (1 mL). White solid. LC-MS m/z calcd. for C25H22CINO5 [M+H]⁺ 452.11; found 452.2.

Example 21 2-Chloro-5-{5-[(2-cyclopentyl-l-oxoisoindolin-5-yloxy)methyl](2-thienyl)}benzoic acid

[00252] The title compound was synthesized according to the general procedure B using 5-(5- bromo-thiophen-2-ylmethoxy)-2-cyclopentyl-2,3-dihydro-isoindol-l-one (0.200 g, 0.51 mmol), 5-borono-2-chlorobenzoic acid (0.150 g, 0.765 mmol), Pd(PPh₃)4 (0.06 g, 0.051 mmol) and 2M Na₂CO₃ solution (1 mL). White solid. 'HNMR (500 MHz, CDCI3): 8 8.02 (s, 1H), 7.93 (s, 1H), 7.71-7.43 (m, 3H), 7.25 (s, 1H), 7.07-7.03 (m, 2H), 5.39 (s, 2H), 4.66-4.63 (m, 1H), 4.28 (s, 2H), 1.97-1.56 (m, 8H). LC-MS m/z calcd. for C25H22CINO4S [M+H]⁺ 468.10; found 468.2.

Example 22 2-Chloro-5-{5-[(2-cyclopentyl-l-oxoisoindolin-5-yloxy)methyl](3-thienyl)}benzoic acid

[00253] The title compound was synthesized according to the general procedure B using 5- ((4-bromothiophen-2-yl)methoxy)-2-cyclopentylisoindolin-l-one (0.200 g, 0.51 mmol), 5- borono-2-chlorobenzoic acid (0.150 g, 0.765 mmol), Pd(PPh₃)4 (0.06 g, 0.051 mmol) and 2M Na₂CO₃ solution (1 mL). White solid. 'HNMR (400 MHz, CDCI3): 6 8.10 (s, 1H), 7.78-7.68 (m, 3H), 7.54-7.51 (m, 2H), 7.19 (s, 1H), 7.15-7.12 (m, 1H), 5.38 (s, 2H), 4.67-4.66 (m, 1H), 4.44 (s, 2H), 2.01-1.72 (m, 8H). LC-MS m/z calcd. for C25H22CINO4S [M+H]⁺ 468.10; found 468.2.

Example 23 2-Chloro-5-{4-[(2-cyclopentyl-l-oxoisoindolin-5-yloxy)methyl](2-pyridyl)}benzoic acid

[00254] 5-((2-Bromopyridin-4-yl)methoxy)-2-cyclopentylisoindolin-l-one (0.3 g, 0.775 mmol), 5-borono-2-chlorobenzoic acid (0.233 g, 1.16 mmol), Pd(PPh₃)4 (0.09 g, 0.077 mmol) and 2M Na2COs solution (1.5 mL) were processed according to the general procedure B. White solid. ^XH NMR (400 MHz, CDC1₃): 8 8.64-8.58 (m, 1H), 8.40-8.35 (m, 1H), 8.00-7.95 (m, 1H), 7.79-7.66 (m, 2H), 7.53-7.50 (m, 1H), 7.36-7.33 (m, 1H), 7.25 (s, 1H), 7.03-6.94 (m, 2H), 5.18 (s, 2H), 4.63-4.59 (m, 1H), 4.28 (s, 2H), 1.95-1.55 (m, 8H). LC-MS m/z calcd.for C26H23CIN2O4 [M+H]⁺ 463.13; found 463.2.

Example 37 3-{3-[(2-Cyclopentyl-l-oxoisoindolin-5-yloxy)methyl]phenyl}-4-fluorobenzoic acid

[00255] 5-((3-Bromobenzyl)oxy)-2-cyclopentylisoindolin-l-one (0.193 g, 0.5 mmol), 3- borono-4-fluorobenzoic acid (0.138 g, 0.75 mmol) and Pd(PPh3)4 (0.06 g, 0.05 mol) were taken in DME (10 mL). To this, 2M ISfeCCh (1 mL) solution was added and the resulting mixture was refluxed under an atmosphere of N2 for 2 h. The reaction mixture cooled to room temperature and diluted with water and then acidified using IN HC1. The product was extracted with ethyl acetate and washed with brine and the organic layer was dried over anhydrous Na2SO4. The solvent was evaporated in vacuum to obtain the crude product. The crude product was purified using automated prep-HPLC to afford the title compound. Yellow solid (0.12 g, 53.9%).¹HNMR (400 MHz, DMSO-d₆): 6 8.06 (dd, J= 1.8 Hz, 8.2 Hz, 1H), 7.99-7.98 (m, 1H), 7.67 (m, 1H), 7.56-7.52 (m, 4H), 7.45 (t, J= 8.7 Hz, 1H), 7.23 (d, J= 1.8 Hz, 1H), 7.12 (dd, J= 2.3 Hz, 10.3 Hz, 1H), 5.27 (s, 2H), 4.52-4.49 (m, 1H), 4.38 (s, 2H), 1.84-1.81 (m, 2H), 1.71-1.57 (m, 6H). LC-MS [M+H]⁺ found: 447.00.

Example 38 4-Chloro-3'-(2-((2-cyclopentyl-l-oxoisoindolin-5-yl)oxy)acetyl)-[l,l'-biphenyl]-3-

[00256] 5-(2-(3-bromophenyl)-2-oxoethoxy)-2-cyclopentylisoindolin-l-one (0.4 g, 0.965 mmol), 5-borono-2-chlorobenzoic acid (0.29 g,1.45 mmol) and Pd(dppf)2C12 (0.07 g, 0.097 mmol) were taken in DME (10 mL). To this, 2M Na2COs (1.93 mL) solution was added and the resulting mixture was refluxed in an atmosphere of N2 for 2 h. The reaction mixture cooled to room temperature and diluted with water and acidified using 2N HC1. The product was extracted with ethyl acetate and washed with brine and the organic layer was dried over anhydrous ISfeSC The solvent was evaporated in vacuum to obtain the crude product. The crude product was purified using automated prep-HPLC to yield the title compound as a white solid (0.315 g, 66.6%). 'HNMR (400 MHz, DMSO-d₆): 8 8.28 (s, 1H), 8.10 (d, J = 2.7 Hz, 1H), 8.00 (dt, J = 7.6, 1.9 Hz, 2H), 7.90 (dd, J = 8.2, 2.3 Hz, 1H), 7.52 (t, J = 4.1 Hz, 1H), 7.14 (d, J = 1.8 Hz, 1H), 7.06 (dd, J = 8.5, 2.1 Hz, 1H), 5.78 (s, 2H), 4.49 (t, J = 7.8 Hz, 1H), 4.33 (s, 2H), 1.83-1.53 (m, 8H). LC-MS m/z [M+H]⁺ found: 490.10.

Example 39 5-{3-[(2-Cyclopentyl-l-oxoisoindolin-5-yloxy)methyl]phenyl}-2-fluorobenzoic acid

[00257] 5-((3-Bromobenzyl)oxy)-2-cyclopentylisoindolin-l-one (0.193 g, 0.5 mmol), 5- borono-2-fluorobenzoic acid (0.138 g, 0.75 mmol) and Pd(PPhs)4 (0.06 g, 0.05 mol) were taken in DME (10 mL). To this, 2M ISfeCCh (1 mL) solution was added and the resulting mixture was refluxed in an atmosphere of N2 for 2 h. The reaction mixture cooled to room temperature and diluted with water and then acidified using IN HC1. The product was extracted with ethyl acetate and washed with brine and the organic layer was dried over anhydrous Na2SO4. The solvent was evaporated in vacuum to obtain the crude product. The crude product was purified using automated prep-HPLC to yield the title compound. White solid (0.15 g, 67.3%). 'HNMR (400 MHz, DMSO-d₆): 6 8.10 (dd, J= 2.3 Hz, 8.2 Hz, 1H), 7.98-7.91 (m, 1H), 7.78 (s, 1H), 7.66-7.64 (m, 1H), 7.56 (d, J= 8.7 Hz, 1H), 7.53-7.49 (m, 2H), 7.42 (t, J= 8.7 Hz, 1H), 7.23 (d, I = 2.3 Hz, 1H), 7.11 (dd, J= 2.3 Hz, 8.2 Hz, 1H), 5.27 (s, 2H), 4.58-4.52 (m, 1H), 4.38 (s, 2H), 1.82-1.72 (m, 2H), 1.64-1.58 (m, 6H). LC-MS [M+H]⁺ found: 446.00.

Example 40 3-{3-[(2-cyclopentyl-l-oxoisoindolin-5-yloxy)methyl]phenyl}benzoic acid

[00258] 5-((3-Bromobenzyl)oxy)-2-cyclopentylisoindolin-l-one (0.2 g, 0.518 mmol) 3- boronobenzoic acid (0.129 g, 0.777 mmol), Pd(PPhs)4 (0.06 g, 0.052 mmol) and 2M Na2COs (1 mL) were refluxed in DME and heated at reflux for 4 h under an atmosphere of nitrogen. The reaction mixture cooled to room temperature and the solvent was removed under vacuum and the residue was dissolved in water and neutralized using IM HC1. The aqueous layer was extracted with ethyl acetate and the organic layer was dried over anhydrous ISfeSC The solvent was evaporated in vacuum to obtain the crude acid as a yellow solid. The crude residue was purified using automated prep-HPLC to yield the title compound as a white solid. 'H NMR (500 MHz, CDCI3): 8 8.36-8.35 (m, 1H), 8.12 (d, J= 8.5 Hz, 1H), 7.84-7.46 (m, 7H), 7.11-7.07 (m, 1H), 7.03 (d, J= 8.5 Hz, 1H), 5.19 (s, 2H), 4.78-4.73 (m, 1H), 4.32 (s, 2H), 2.01-1.95 (m, 2H), 1.77-1.60 (m, 6H). LC-MS m/z calcd. for C27H25NO4 [M+H]⁺ 428.18; found 428.2.

Example 42 2-Chloro-4-{3-[(2-cyclopentyl-l-oxoisoindolin-5-yloxy)methyl]phenyl}benzoic acid

[00259] The title compound was synthesized according to the general procedure B using 5-(3- bromo-benzyloxy)-2-cyclopentyl-2,3-dihydro-isoindol-l-one (1.2 g, 3.11 mmol), 4-borono-2- chlorobenzoic acid (0.934 g, 4.66 mmol), Pd(PPhs)4 (0.359 g, 0.311 mmol) and 2M Na2COs (6.2 mL) in DME. White solid (1.1 g). 'HNMR (400 MHz, CDCI3): 6 8.11-8.09 (m, 1H), 7.82-7.80 (m, 1H), 7.72-7.50 (m, 6H), 7.10 (d, J= 8.5 Hz, 1H), 7.04 (s, 1H), 5.20 (s, 2H), 4.79-4.73 (m, 1H), 4.34 (s, 2H), 2.01-1.62 (m, 8H). LC-MS m/z calcd. for C27H24CINO4 [M+H]⁺ 462.14; found 462.2.

Example 43 2-Chloro-5-{4-[(2-cyclopentyl-l-oxoisoindolin-5-yloxy)methyl]phenyl}benzoic acid

[00260] The title compound was synthesized according to the general procedure B using 5-(4- bromo-benzyloxy)-2-cyclopentyl-2,3-dihydro-isoindol-l-one (0.3 g, 1.035 mmol), 5-borono- 2-chlorobenzoic acid (0.400 g, 2 mmol), Pd(PPh3)4 (0.115 g, 0.1 mmol and 2M ISfeCCh (2 mL) were taken in DME. White solid. 'H NMR (500 MHz, CDCI3): 6 8.11 (s, 1H), 7.73-7.71 (m, 1H), 7.63-7.48 (m, 6H), 7.07-7.00 (m, 2H), 5.16 (s, 2H), 4.70-4.65(m, 1H), 4.31 (s, 2H), 1.99-1.96 (m, 2H), 1.76-1.63 (m, 6H). LC-MS m/z calcd. for C27H24CINO4 [M+H]⁺ 462.14; found 462.2.

Example 44

5-{3-[(2-Cyclopentyl-l-oxoisoindolin-5-yloxy)methyl]phenyl}-2-fluorobenzaldehyde

[00261] 5-((3-bromobenzyl)oxy)-2-cyclopentylisoindolin-l-one (0.193 g, 0.5 mmol), (4- fluoro-3-formylphenyl)boronic acid (0.126 g, 0.75 mmol) and Pd(PPhs)4 (0.05g, 0.05 mmol) were taken in DME (10 mL). To this, 2M Na2COs solution was added and the resulting solution was refluxed in an atmosphere of N2 for 6-12 h. The reaction mixture cooled to room temperature and diluted with water. The product was extracted with ethyl acetate and washed with brine and the organic layer was dried over anhydrous Na2SO4. The solvent was evaporated in vacuum to obtain the crude product. The crude product was purified using automated prep-HPLC to yield the title compound as a white solid (0.167 g, 78%). ^JH NMR (400 MHz, DMSO-d₆): 8 10.26 (s, 1H), 8.10-8.05 (m, 1H), 7.82 (s, 1H), 7.69-7.67 (m, 1H), 7.52-7.50 (m, 4H), 7.23 (s, 1H), 7.11 (d, J= 8.7 Hz, 1H), 5.26 (s, 2H), 4.51-4.52 (m, 1H), 4.38 (s, 2H), 1.81-1.59 (m, 8H). LC-MS [M+H]⁺ found: 430.00.

Example 45 2-Cyclopentyl-5-({3-[4-fluoro-3-(hydroxymethyl)phenyl]phenyl}methoxy)isoindolin-l-

[00262] To a solution of 3'-(((2-cyclopentyl-l-oxoisoindolin-5-yl)oxy)methyl)-4-fluoro-[l,T- biphenyl]-3-carbaldehyde (0.075 g, 0.175 mmol) in methanol (5 mL) at 0 °C was added sodium borohydride (0.010 g, 0.265 mmol). The resulting mixture was gradually warmed to rt and stirred for another 30 min. The reaction mixture was carefully quenched by the addition of water and extracted with ethyl acetate. The combined organic extracts were washed with water, brine, dried over anhyd. Na2SO4 and filtered to remove solid. Removal of the solvent followed by reverse phase column chromatography yielded title compound as a white solid (0.056 g, 74.3%). *HNMR (400 MHz, DMSO-d₆): 6 7.73-7.71 (m, 2H), 7.82 (s, 1H), 7.60-7.43 (m, 6H), 7.25-7.21 (m, 42), 7.10 (dd, J= 2.3 Hz, 8.2 Hz, 1H), 5.32 (t, J= 5.9 Hz, 1H), 5.23 (s, 2H), 4.58 (d, J= 5.5 Hz, 2H), 4.51-4.48 (m, 1H), 4.37 (s, 2H), 1.89-1.58 (m, 8H). LC-MS [M+H]⁺ found: 432.00.

General synthetic scheme for the preparation of isoindolinone derivatives: General

Procedure C

Synthesis of (3-(((2-cyclopentyl-l-oxoisoindolin-5-yl)oxy)methyl)phenyl)boronic acid

[00263] To a solution of 2-cyclopentyl-5-hydroxyisoindolin-l-one (5 g, 23 mmol) in acetone (200 mL), K2CO3 (12 g, 87 mmol) and 3-(bromomethyl)phenylboronic acid (6.5 g, 30 mmol) were added and refluxed for 3 h. The reaction mixture was filtered and solvent was evaporated in vacuo to obtain 3-((2-cyclopentyl-l-oxoisoindolin-5- yloxy)methyl)phenylboronic acid as a white solid (5.83 g, 72%). The crude product was used for the next step without further purification. ¹ H NMR (400 MHz, DMSO - de): 8 7.86 (s, 1H), 7.75 - 7.69 (m, 2H), 7.55 - 7.32 (m, 4H), 7.19 (s, 1H), 7.09 - 7.07 (m, 1H), 5.15 (s, 2H), 4.55 - 4.49 (m, 1H), 4.37 (s, 2H), 1.84 - 1.56 (m, 8H). LRMS calcd. for C20H22BNO4 [M+H]⁺ 352.16; found: 352.

Example 34 2,6-Dichloro-4-{3-[(2-cyclopentyl-l-oxoisoindolin-5-yloxy)methyl]phenyl}benzoic acid

[00264] A mixture of (3-(((2-cyclopentyl-l-oxoisoindolin-5-yl)oxy)methyl)phenyl)boronic acid (0.176 g, 0.5 mmol), 4-bromo-2,6-dichlorobenzoic acid (0.202 g, 0.75 mmol) and Pd(PPhs)4 (5.78 mg, 0.005 mmol) were taken in DME (10 mL). To this, a 2M Na2COs solution was added and the resulting solution was refluxed under an atmosphere of N2 for 6- 12 h. The reaction mixture cooled to room temperature and diluted with water and then acidified using IN HC1. The product was extracted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous Na2SO4 and filtered to remove solid. The solvent was evaporated in vacuum to obtain the crude product. The crude product was purified using automated prep-HPLC to yield the desired compound as a white solid (0.168 g, 67.7%). ^JH NMR (400 MHz, DMSO-d₆): 8 7.88 (d, J = 12.8 Hz, 3H), 7.67-7.79 (1H), 7.54 (d, J = 7.8 Hz, 3H), 7.24 (s, 1H), 7.05-7.18 (1H), 5.25 (s, 2H), 4.45-4.61 (1H), 4.39 (s, 2H), 1.69-1.5 (s, 8H). LC-MS [M+H]⁺ found: 496.10.

Example 35 4-{3-[(2-Cyclopentyl-l-oxoisoindolin-5-yloxy)methyl]phenyl}-2,6-dimethylbenzoic acid

[00265] (3-(((2-cyclopentyl-l-oxoisoindolin-5-yl)oxy)methyl)phenyl)boronic acid (0.176g, 0.5 mmol), 4-bromo-2,6-dimethylbenzoic acid (0.115 g, 0.75 mmol) and Pd(PPhs)4 (0.05 g, 0.05 mmol) were taken in DME (10 mL). To this, 2M Na2COs solution was added and the resulting solution was refluxed under an atmosphere of N2 for 6-12 h. The reaction mixture cooled to room temperature and diluted with water and then acidified using IN HC1. The product was extracted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous Na2SO4 and filtered to remove solid. The solvent was evaporated under vacuum to obtain the crude product. The crude product was purified using automated prep- HPLC to afford the title compound as a white solid (0.13 g, 57.1 %).'H NMR (400 MHz, CDCI3): 6 7.76 (d, J= 8.7 Hz, 1H), 7.63 (s, 1H), 7.55 (d, J= 7.8 Hz, 1H), 7.48-7.40 (m, 2H), 7.26 (s, 2H), 7.07 (dd, J= 2.3 Hz, 8.2 Hz, 1H), 7.02 (d, J= 1.8 Hz, 1H), 5.18 (s, 2H), 4.79- 4.71 (m, 1H), 4.32 (s, 2H), 2.49 (s, 3H), 2.48 (s, 3H), 2.00-1.98 (m, 2H), 1.77-1.63 (m, 6H). LC-MS [M+H]⁺ found: 456.25.

Example 36 3-{3-[(2-Cyclopentyl-l-oxoisoindolin-5-yloxy)methyl]phenyl}-2-methylbenzoic acid

[00266] (3-(((2-Cyclopentyl-l-oxoisoindolin-5-yl)oxy)methyl)phenyl)boronic acid (0.1 g, 0.285 mmol),3-bromo-2-methylbenzoic acid(0.092 g, 0.427 mmol) and Pd(PPh3)4 (0.033 g, 0.03 mmol) were taken in DME (10 mL). To this, 2M Na2COs (0.06 mL) solution was added and the resulting mixture was refluxed under an atmosphere of N2 for 6-12 h. The reaction mixture was cooled to room temperature, diluted with water and then acidified using IN HC1. The product was extracted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous Na2SO4 and filtered to remove solid. The solvent was evaporated in vacuum to obtain the crude product. The crude product was purified using automated prep- HPLC to afford the title compound as a white solid (0.09 g, 71.6%). ^JH NMR (400 MHz, DMSO-de): 8 7.69 (t, J= 2.7 Hz, 1H), 7.53-7.19 (m, 8H), 7.07 (d, J= 8.2 Hz, 1H), 5.21 (s, 2H), 4.50-4.47 (m, 1H), 4.34 (s, 2H), 2.27 (s, 3H), 1.78-1.56 (m, 8H). LC-MS [M+H]⁺ found: 442.20.

Example 46 3-Chloro-5-{3-[(2-cyclopentyl-l-oxoisoindolin-5-yloxy)methyl]phenyl}pyridine-2- carboxylic acid

[00267] (3-(((2-Cyclopentyl-l-oxoisoindolin-5-yl)oxy)methyl)phenyl)boronic acid (0.176g, 0.5 mmol), 5-bromo-3-chloropicolinic acid (0.177 g, 0.75 mmol) and Pd(PPhs)4 (5.78 g, 0.005 mmol) were taken in DME (10 mL). To this, 2M Na2COs solution was added and the resulting mixture was refluxed under an atmosphere of N2 for 6-12 h. The reaction mixture was cooled to room temperature, diluted with water and then acidified using IN HC1. The product was extracted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous Na2SO4 and filtered to remove solid. The solvent was evaporated under vacuum to obtain the crude product. The crude product was purified using automated prep- HPLC to afford the title compound as a white solid (0.1 g, 43.2%).¹ H NMR (400 MHz, DMSO - d₆): 6 8.89 (d, J= 1.8 Hz, 1H), 8.37 (d, J= 1.8 Hz, 1H), 7.74 (s, 1H), 7.81-7.79 (m, 1H), 7.58-7.50 (m, 3H), 7.32 (d, J= 1.8 Hz, 1H), 7.11 (dd, J= 2.3 Hz, 8.7 Hz, 1H), 5.28 (s, 2H), 4.66-4.43 (m, 1H), 4.38 (s, 2H), 1.80-1.57 (m, 8H). LC-MS [M+H]⁺ found: 463.00.

Example 47 2-(2-Chloro-5-{3-[(2-cyclopentyl-l-oxoisoindolin-5-yloxy)methyl]phenyl}phenyl)acetic acid

[00268] (3-(((2-Cyclopentyl-l-oxoisoindolin-5-yl)oxy)methyl)phenyl)boronic acid (1 g, 2.85 mmol), 2-(5-bromo-2-chlorophenyl)acetic acid (0.710 g, 2.85 mmol) and Pd(PPhs)4 (0.329 g, 0.285 mmol) were taken in DME (10 mL). To this, 2M ISfeCCh (5.6 mL) solution was added and the resulting mixture was refluxed under an atmosphere of N2 for 6-12 h. The reaction mixture was cooled to room temperature, diluted with water and then acidified using IN HC1. The product was extracted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous Na2SO4 and filtered to remove solid. The solvent was evaporated under vacuum to obtain the crude product. The crude product was purified using automated prep- HPLC to afford the title compound as a white solid. (0.75 g, 55.3%). ^JH NMR (400 MHz, DMSO - d₆): 8 7.68-7.40 (m, 8H), 7.01 (brs, 2H), 5.27 (s, 2H), 4.66-4.58 (m, 1H), 4.28 (s, 2H), 3.77 (s, 2H), 1.98-1.61 (m, 8H). LC-MS [M+H]⁺ found: 476.25.

Example 48 2-(2-Chloro-4-{3-[(2-cyclopentyl-l-oxoisoindolin-5-yloxy)methyl]phenyl}phenyl)acetic

[00269] (3-(((2-Cyclopentyl-l-oxoisoindolin-5-yl)oxy)methyl)phenyl)boronic acid (0.176 g, 0.5 mmol), 2-(4-bromo-2-chlorophenyl)acetic acid (0.187 g, 0.75 mmol) and Pd(PPhs)4 (0.05 g, 0.05 mmol) were taken in DME (10 mL). To this, 2M Na2COs solution was added and the resulting mixture was refluxed in an atmosphere of N2 for 6-12 h. The reaction mixture was cooled to room temperature, diluted with water and then acidified using IN HC1. The product was extracted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous Na2SO4 and filtered to remove solid. The solvent was evaporated under vacuum to obtain the crude product. The crude product was purified using automated prep-HPLC to afford the title compound as a white solid (0.14 g, 58.8%). 'H NMR (400 MHz, CDCI3): 6 7.76 (d, J= 8.7 Hz, 1H), 7.63-7.61 (m, 2H), 7.53-7.36 (m, 5H), 7.07 (dd, J= 2.3 Hz, 8.7 Hz, 1H), 7.01 (s, 1H), 5.17 (s, 2H), 4.78-4.71 (m, 1H), 4.30 (s, 2H), 3.86 (s, 2H), 2.09-1.58 (m, 8H). LC-MS [M+H]⁺ found: 476.25. Example 49

2-(3-{3-[(2-Cyclopentyl-l-oxoisoindolin-5-yloxy)methyl]phenyl}phenyl)acetic acid

[00270] (3-(((2-Cyclopentyl-l-oxoisoindolin-5-yl)oxy)methyl)phenyl)boronic acid (0.088 g, 0.25 mmol), 2-(3-iodophenyl)acetic acid (0.098 g, 0.325 mmol) and Pd(PPh3)4 (0.03g, 0.025 mmol) were taken in DME (10 mL). To this, 2M ISfeCCh (0.5 mL) solution was added and the resulting mixture was refluxed in an atmosphere of N2 for 6-12 h. The reaction mixture was cooled to room temperature, diluted with water and then acidified using IN HC1. The product was extracted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous Na2SO4 and filtered to remove solid. The solvent was evaporated under vacuum to obtain the crude product. The crude product was purified using automated prep- HPLC to afford the title compound as a white solid (0.067 g, 60.7%). ^JH NMR (400 MHz, DMSO-de): 6 7.71 (s, 1H), 7.57-7.43 (m, 8H), 7.25-7.19 (m, 1H), 7.09 (d, J= 1.8 Hz, 1H), 5.23 (s, 2H), 4.43-4.57 (m, 1H), 4.35 (s, 2H), 3.29 (s, 2H), 1.78-1.56 (m, 8H). LC-MS [M+H]⁺ found: 442.10.

Example 50 2-Cyclopentyl-5-({3-[4-(fluorosulfonyl)phenyl]phenyl}methoxy)isoindolin-l-one

[00271] (3-(((2-Cyclopentyl-l-oxoisoindolin-5-yl)oxy)methyl)phenyl)boronic acid (0.176 g, 0.5 mmol), 4-bromobenzenesulfonyl fluoride (0.179 g, 0.75 mmol) and Pd(PPhs)4 (0.05 g, 0.05 mmol) were taken in DME (10 mL). To this, 2M Na2COs solution (1 mL) was added and the resulting mixture was refluxed in an atmosphere of N2 for 6-12 h. The reaction mixture was cooled to room temperature and diluted with water. The product was extracted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous Na2SO4 and filtered to remove solid. The solvent was evaporated under vacuum to obtain the crude product. The crude product was purified using automated prep-HPLC to afford the title compound as an off- white solid (0.098 g, 42%). 'H NMR (400 MHz, DMSO-de): 5 8.18 (d, J = 13 Hz, 2H), 8.05 (d, J= 7.8 Hz, 2H), 7.87 (s, 1H), 7.74 (d, J= 4.6 Hz, 1H), 7.55-7.52 (m, 3H), 7.20 (s, 1H), 7.09 (d, J= 8.2 Hz, 1H), 5.25 (s, 2H), 4.48 (t, J= 7.6 Hz, 1H), 4.35 (s, 2H), 1.78-1.57 (m, 8H).

Synthesis of 2-(4-Chloro-3'-(((2-cyclopentyl-l-oxoisoindolin-5-yl)oxy)methyl)-[l,l'- biphenyl]-3-yl)propanoic acid and 2-(4-Chloro-3'-(((2-cyclopentyl-l-oxoisoindolin-5- yl)oxy)methyl)-[l,l'-biphenyl]-3-yl)-2-methylpropanoic acid

[00272] 2-(4-Chloro-3'-(((2-cyclopentyl-l-oxoisoindolin-5-yl)oxy)methyl)-[l,l'-biphenyl]-3- yl)acetic acid (0.25 g, 0.525 mmol) was dissolved in dry DMF (0.2 M) and cooled to -78 °C under nitrogen. The cooled mixture was treated with NaH (0.076 g, 2.63 mmol) and the resulting mixture was stirred at -78 °C for 30 minutes. The mixture was warmed to room temperature and heated at 80 °C for 30 min. The reaction mixture was carefully quenched by the addition of water and extracted with ethyl acetate. The organic layer was washed with water, and brine. The organic layer was dried over anhydrous Na2SO4 and filtered to remove solid. The solvent was removed under reduced pressure to afford crude mixture (a mixture of mono and dialkylated ester as indicated by LC-MS). The crude mixture was dissolved in dioxane and 2M LiOH solution (2.6 mL) was added to it. The resulting mixture was heated at reflux for 30 min. and then allowed to cool to rt. The mixture was diluted with water and acidified. The product was extracted with ethyl acetate. The organic layer washed with water, and brine. The organic layer was then dried over anhydrous Na2SO4 and filtered to remove solid. The solvent was evaporated under vacuum to obtain the crude product. The crude product was purified by reverse phase HPLC to afford mono and dimethylated acids characterized below in Example 52 and 53, respectively.

Example 52 2-(4-Chloro-3'-(((2-cyclopentyl-l-oxoisoindolin-5-yl)oxy)methyl)-[l,l'-biphenyl]-3- yl)propanoic acid

[00273] White solid (0.053 g, 21%). 'H-NMR (400 MHz, CDC13) 5 7.73 (d, J = 8.2 Hz, 1H), 7.54-7.39 (m, 7H), 7.02-6.98 (m, 2H), 5.15 (s, 2H), 4.73-4.72 (m, 1H), 4.32-4.28 (m, 3H), 1.99-1.97 (m, 2H), 1.76-1.60 (m, 6H), 1.55 (d, J = 6.8 Hz, 3H).

Example 53

2-(4-Chloro-3'-(((2-cyclopentyl-l-oxoisoindolin-5-yl)oxy)methyl)-[l,l'-biphenyl]-3-yl)-2- methylpropanoic acid

[00275] A solution of 4-chloro-3'-(2-cyclopentyl-l-oxo-2,3-dihydro-lH-isoindol-5- yloxymethyl)-biphenyl-3-carboxylic acid (0.300 g, 0.649 mmol) in ACN (10 mL) was treated with DIEA (0.168 g, 1.3 mmol) followed by HATU (0.271 g, 0.714 mmol). The resulting mixture was stirred at rt for 15 min, after which time the dark clear mixture was treated with ammonium hydrate (1 mL). The resulting mixture was stirred at rt for 1 h. The mixture was diluted with EtOAc (20 mL) and washed with IN HC1 (2 x 10 mL), and brine. The organic layer was then dried over anhydrous Na2SO4, filtered to remove solid and concentrated under reduced pressure. The resulting crude residue was purified with Cl 8 reverse phase column to afford the title compound as a yellow solid.

Example 54 2-Chloro-5-{3-[(2-cyclopentyl-l-oxoisoindolin-5-yloxy)methyl]phenyl}benzamide

[00276] A solution of 4-chloro-3'-(2-cyclopentyl-l-oxo-2,3-dihydro-lH-isoindol-5- yloxymethyl)-biphenyl-3-carboxylic acid (0.300 g, 0.649 mmol) in ACN (10 mL), was treated with DIEA (0.168 g, 1.3 mmol) followed by HATU (0.271 g, 0.714 mmol). The resulting mixture was stirred at rt for 15 min, after which time the dark clear mixture was treated with ammonium hydrate (1 mL). The resulting mixture was stirred at rt for 1 h. The mixture was diluted with EtOAc (20 mL) and washed with IN HC1 (2 x 10 mL), and brine. The organic layer was then dried over anhydrous Na2SO4, filtered to remove solid and concentrated under reduced pressure. The resulting crude residue was purified with C18 reverse phase column to afford the title compound as a yellow solid. ^JH NMR (500 MHz, CDC1₃): 8 8.06 (s, 1H), 7.76-7.75 (m, 1H), 7.55-7.00 (m, 6H), 7.06-7.00 (m, 2H), 6.48 (s, 1H), 5.96 (s, 1H), 5.17 (s, 2H), 4.74 - 4.71 (m, 1H), 4.30 (s, 2H), 1.98 - 1.60 (m, 8H). LC-MS m/z calcd. for C27H25CIN2O3 [M+H]⁺ 461.16 found: 461.0.

Example 55 (2-Chloro-5-{3-[(2-cyclopentyl-l-oxoisoindolin-5-yloxy)methyl]phenyl}phenyl)-N-

[00277] A solution acid of 4-Chloro-3'-(2-cyclopentyl-l-oxo-2,3-dihydro-lH-isoindol-5- yloxymethyl)-biphenyl-3-carboxylic acid (0.300 g, 0.649 mmol) in ACN (10 mL), was treated with DIEA (0.168 g, 1.3 mmol) followed by HATU (0.271 g, 0.714 mmol). The resulting mixture was stirred at rt for 15 min, after which time the dark clear mixture was treated methyl amine in methanol (1 mL). The resulting mixture was stirred at rt for 1 h. The mixture was diluted with EtOAc (20 mL) and washed with IN HC1 (2 x 10 mL), and brine. The organic layer was then dried over anhydrous Na2SO4, filtered to remove solid and concentrated under reduced pressure. The resulting crude residue was purified reverse phase column to afford the title compound as a yellow solid. ¹ H NMR (400 MHz, CDCI3): 6 7.93 (s, 1H), 7.75-7.73 (m, 1H), 7.63-7.44 (m, 6H), 7.07-7.01(m, 2H), 6.34 (s, 1H), 5.17 (s, 2H), 4.76 - 4.70 (m, 1H), 4.30 (s, 2H), 3.06 (d, J= 2.3 Hz, 3H), 2.01-1.06 (m, 8H). LC-MS calcd. for C28H27CIN2O3 [M+H]⁺ 475.17 found: 475.1.

Example 57

2-Chloro-4-{3-[(2-cyclopentyl-l-oxoisoindolin-5-yloxy)methyl]phenyl}benzamide

[00278] A solution of 3-chloro-3'-(2-cyclopentyl-l-oxo-2,3-dihydro-lH-isoindol-5- yloxymethyl)-biphenyl-4-carboxylic acid (0.300 g, 0.649 mmol) in ACN (10 mL), was treated with DIEA (0.168 g, 1.3 mmol) followed by HATU (0.271 g, 0.714 mmol). The resulting mixture was stirred at rt for 15 min, after which time the dark clear mixture was treated with ammonium hydrate (1 mL). The resulting mixture was stirred at rt for 1 h. The mixture was diluted with EtOAc (20 mL) and washed with IN HC1 (2 x 10 mL), and brine. The organic layer was then dried over anhydrous Na2SO4, filtered to remove solid and concentrated under reduced pressure. The resulting crude residue was purified by reverse phase column chromatography to afford the title compound. ¹ H NMR (400 MHz, CDCI3): 8 7.95-7.92 (m, 1H), 7.79-7.77 (m, 1H), 7.67 (m, 2H), 7.60-7.50 (m, 4H), 7.11-7.04 (m, 2H), 6.61 (s, 1H), 6.21 (s, 1H), 5.22 (s, 2H), 4.76-4.74 (m, 1H), 4.30 (s, 2H), 2.02 - 1.60 (m, 8H). LC-MS m/z calcd. for C27H25CIN2O3 [M+H]⁺ 461.16; found: 461.2.

Example 58 (2-Chloro-4-{3-[(2-cyclopentyl-l-oxoisoindolin-5-yloxy)methyl]phenyl}phenyl)-N-

[00279] A solution of 3-chloro-3'-(2-cyclopentyl-l-oxo-2,3-dihydro-lH-isoindol-5- yloxymethyl)-biphenyl-4-carboxylic acid (0.300 g, 0.649 mmol) in DCM (10 mL), was treated with DIEA (0.168 g, 1.3 mmol) followed by HATU (0.271 g, 0.714 mmol). The resulting mixture was stirred at rt for 15 min, after which time the dark clear mixture was treated with methylamine in ethanol (1 mL). The resulting mixture was stirred at rt for 1 h. The mixture was diluted with EtOAc (20 mL) and washed with IN HC1 (2 x 10 mL), and brine. The organic layer was then dried over anhydrous Na2SO4, filtered to remove solid and concentrated under reduced pressure. The resulting crude residue was purified by reverse phase column chromatography to afford the title compound. ¹ H NMR (400 MHz, CDCI3): 8 7.81-7.75 (m, 2H), 7.64-7.63 (m, 2H), 7.57-7.48 (m, 4H), 7.10-7.03 (m,2H), 6.44 (s, 1H), 5.20 (s, 2H), 4.80 - 4.70 (m, 1H), 4.32 (s, 2H), 3.07 (d, J= 2.3 Hz, 3H), 2.02-1.60 (m, 8H).

LC-MS m/z calcd. for C28H27CIN2O3 [M+H]⁺ 475.17; found: 475.2.

Example 59

(2-chloro-4-{3-[(2-cyclopentyl-l-oxoisoindolin-5-yloxy)methyl]phenyl}phenyl)-N,N- dimethylcarboxamide

[00280] A solution of 3-chloro-3'-(2-cyclopentyl-l-oxo-2,3-dihydro-lH-isoindol-5- yloxymethyl)-biphenyl-4-carboxylic acid (0.300 g, 0.649 mmol) in DCM (10 mL) was treated with DIEA (0.168 g, 1.3 mmol) followed by HATU (0.271 g, 0.714 mmol). The resulting mixture was stirred at rt for 15 min, after which time the dark clear mixture was treated with dimethylamine in ethanol (1 mL). The resulting mixture was stirred at rt for 1 h. The mixture was diluted with EtOAc (20 mL) and washed with IN HC1 (2 x 10 mL), and brine. The organic layer was then dried over anhydrous Na2SO4, filtered to remove solid and concentrated under reduced pressure. The resulting crude residue was purified by reverse phase column chromatography to afford the title compound. ^JH NMR (400 MHz, CDCh): 8 7.79-7.76 (m, 1H), 7.63-7.62 (m, 2H), 7.55-7.44 (m, 4H), 7.38-7.36 (m, 1H), 7.09-7.02 (m, 2H), 5.19 (s, 2H), 4.77-4.71 (m, 1H), 4.31 (s, 2H), 3.16 (s, 3H), 2.92 (s, 3H), 2.00- 1.58 (m, 8H). LC-MS calcd. for C29H29CIN2O3 [M+H]⁺ 489.19; found: 489.2.

General synthetic scheme for the preparation of isoindolinone derivatives: General Procedure F

Example 56

2-[(2-Chloro-5-{3-[(2-cyclopentyl-l-oxoisoindolin-5- yloxy)methyl]phenyl}phenyl)carbonylamino]ethanesulfonic acid

[00281] 4-Chloro-3'-(((2-cyclopentyl-l-oxoisoindolin-5-yl)oxy)methyl)-[l,l'-biphenyl]-3- carboxylic acid (0.115 g, 0.25 mmol) was dissolved in DMF (4 mL) at room temperature. The resulting mixture was treated with HOBt (0.037 g, 0.275 mmol) in one portion followed by EDC (0.053 g, 0.275 mmol). The resulting mixture was stirred at room temperature for 30 min and then treated with taurine (0.035 g, 0.3 mmol) and triethylamine (0.031 g, 0.3 mmol) and stirred for 2h. The organic phase was evaporated under reduced pressure and the crude material was partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate (3 x 5 mL). The organic phase was dried over Na2SO4, filtered to remove solid and concentrated under reduced pressure to afford crude product. The crude product was purified by HPLC using ACN: water to afford the title compound (0.083 g, 58.3%). ¹H- NMR 'H NMR (400 MHz, DMSO-d₆): 8 8.37 (t, J= 5.6 Hz, 1H), 7.79-7.64 (m, 4H), 7.55- 7.46 (m, 4H), 7.22-7.15 (m, 1H), 7.10 (s, 1H), 5.25 (s, 2H), 4.48 (t, J= 7.6 Hz, 1H), 4.36 (s, 2H), 3.49-3.44 (m, 2H), 2.67-2.60 (m, 2H), 1.78-1.54 (m, 8H), 1.23-1.22 (m, 1H). LC-MS m/z [M+H]⁺ found: 569.15.

II. Biological Evaluation

Example 1: mGlu receptor in vitro assays.

[00282] Immortalized cell lines co-expressing rat mGlu receptors 2, 3, 4, 6, 7 or 8 and G protein-coupled inwardly-rectifying potassium (GIRK) channels were grown in Growth Media containing 45% DMEM, 45% F-12, 10% FBS, 20 mM HEPES, 2 mM L-glutamine, antibiotic/antimycotic, non-essential amino acids, 700 pg/mL G418, and 0.6 pg/mL puromycin at 37 °C in the presence of 5% CO2. Cells expressing rat mGlul and mGlu5 receptor were cultured as described in Hemstapat et al (Mol. Pharmacol. 2006, 70, 616-626). All cell culture reagents were purchased from Invitrogen Corp. (Carlsbad, CA) unless otherwise noted. Calcium assays were used to assess activity of compounds at mGlul and mGlu5, as previously described in Engers et al (J. Med. Chem. 2009, 52, 4115-4118). Calcium assays at mGlu3 were performed as described for mGlu5 with the exception that TREx293 mGlu3 Gal 5 cells were treated with tetracycline at 20 ng/mL for 20 h prior to assay. [00283] Compound activity at the group II (mGlu2 and mGlu3) and group III (mGlu4, mGlu6, mGlu7, and mGlu8) was assessed using thallium flux through GIRK channels, a method that has been described in detail. Briefly, cells were plated into 384-well, blackwalled, clear-bottomed poly-D-lysine-coated plates at a density of 15,000 cells/20 pL/well in DMEM containing 10% dialyzed FBS, 20 mM HEPES, and 100 units/mL penicillin/ streptomycin (assay media). Plated cells were incubated overnight at 37 °C in the presence of 5% CO2. The following day, the medium was exchanged from the cells to assay buffer [Hanks’ balanced salt solution (Invitrogen) containing 20 mM HEPES, pH 7.3] using an ELX405 microplate washer (BioTek), leaving 20 pL/well, followed by the addition of 20 pL/well FluoZin2-AM (330 nM final concentration) indicator dye (Invitrogen; prepared as a stock in DMSO and mixed in a 1 :1 ratio with Pluronic acid F-127) in assay buffer. Cells were incubated for 1 h at room temperature, and the dye exchanged to assay buffer using an ELX405, leaving 20 pL/well. Test compounds were diluted to 2 times their final desired concentration in assay buffer (0.3% DMSO final concentration). Agonists were diluted in thallium buffer [125 mM sodium bicarbonate (added fresh the morning of the experiment), 1 mM magnesium sulfate, 1.8 mM calcium sulfate, 5 mM glucose, 12 mM thallium sulfate, and 10 mM HEPES, pH 7.3] at 5 times the final concentration to be assayed. Cell plates and compound plates were loaded onto a kinetic imaging plate reader (FDSS 6000 or 7000; Hamamatsu Corporation, Bridgewater, NJ). Appropriate baseline readings were taken (10 images at 1 Hz; excitation, 470 ± 20 nm; emission, 540 ± 30 nm) and test compounds were added in a 20 pL volume and incubated for approximately 2.5 min before the addition of 10 pL of thallium buffer with or without agonist. After the addition of agonist, data were collected for approximately an additional 2.5 min. Data were analyzed using Excel (Microsoft Corp, Redmond, WA). The slope of the fluorescence increase beginning 5 s after thallium/agonist addition and ending 15 s after thallium/agoni st addition was calculated, corrected to vehicle and maximal agonist control slope values, and plotted in using either XLfit (ID Business Solutions Ltd) or Prism software (GraphPad Software, San Diego, CA) to generate concentration-response curves. Potencies were calculated from fits using a four- point parameter logistic equation. For concentration-response curve experiments, compounds are serially diluted 1 :3 into 10-point concentration response curves and were transferred to daughter plates using an Echo acoustic plate reformatter (Labcyte, Sunnyvale, CA). Test compounds were applied and followed by EC20 concentrations of glutamate. For selectivity experiments, full concentration-response curves of glutamate or L-AP4 (for mGlu7) were performed in the presence of a 10 pM concentration of compound and compounds that affected the concentration-response by less than 2-fold in terms of potency or efficacy were designated as inactive.

[00284] Representative in vitro biochemical data for mGlu2 and mGlu3 is presented in Table 5.

Table 5

NT = not tested

III. Pharmaceutical Compositions

Example 1: Parenteral Composition

[00285] To prepare a parenteral pharmaceutical composition suitable for administration by injection, 100 mg of a water-soluble salt of a compound of Formula (I), (II), or (III), or Table 4, or a pharmaceutically acceptable salt or solvate thereof, is dissolved in 2% HPMC, 1% Tween 80 in DI water, pH 2.2 with MSA, q.s. to at least 20 mg/mL. The mixture is incorporated into a dosage unit form suitable for administration by injection.

Example 2: Oral Composition

[00286] To prepare a pharmaceutical composition for oral delivery, 100 mg of a compound of Formula (I), (II), or (III), or Table 4, or a pharmaceutically acceptable salt or solvate thereof, is mixed with 750 mg of starch. The mixture is incorporated into an oral dosage unit for, such as a hard gelatin capsule, which is suitable for oral administration.

[00287] While preferred embodiments of the present disclosure have been shown and described herein, it will be obvious to and understood by those skilled in the art that such embodiments are provided by way of example only. It is not intended that the embodiments be limited by the specific examples provided within the specification. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the instant disclosure and embodiments. It should be understood that various alternatives to the embodiments described herein may be employed in practicing the invention. It is therefore contemplated that the invention shall also cover any such alternatives, modifications, variations, or equivalents. It is intended that the following claims define the scope of the embodiments disclosed herein, and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

1. A compound of Formula (I):

or a pharmaceutically acceptable salt or solvate thereof, wherein

X is -O-, -S-, or -NR⁴-;

A is selected from C1-6 haloalkyl, substituted or unsubstituted Cs-i2 carbocyclyl, or Y^Z¹; wherein Y^Z¹ is selected from: i) Y¹ is a substituted or unsubstituted -CH2-; and Z¹ is selected from substituted cyclopropyl, substituted or unsubstituted C4-C5 cycloalkyl, substituted cyclohexyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted phenyl, provided that when Z¹ is substituted phenyl, the phenyl of Z¹ is not substituted with trifluoromethyl or trifluoromethoxyl; or ii) Y¹ is an unsubstituted or substituted C2-3 alkylene; and Z¹ is selected from substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted phenyl;

L is absent or Ci-Ce alkylene;

R⁴ is hydrogen or substituted or unsubstituted C1-C4 alkyl; each of R⁵ and R⁶ is independently selected from hydrogen, substituted or unsubstituted Ci- Ce alkyl, or substituted or unsubstituted C3-C6 cycloalkyl; each R⁷ is independently hydrogen, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C6 cycloalkyl; or two R⁷ taken together with the nitrogen to which they are attached to form a substituted or unsubstituted C2-C8 heterocycloalkyl;

2. The compound of claim 1 having the structure of Formula (I-A):

Formula (I-A) or a pharmaceutically acceptable salt or solvate thereof.

3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt solvate thereof, wherein m is 0.

4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt or solvate thereof, wherein Y is hydrogen.

6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt or solvate thereof, wherein Z is hydrogen.

7. The compound of claim 1 having the structure of Formula (I-B):

Formula (I-B); or a pharmaceutically acceptable salt or solvate thereof.

8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt or solvate thereof, wherein L is absent.

9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt or solvate thereof, wherein Q is -C(=O)OR⁵, -C(=O)NHOR⁶, -C(=O)NHCN, -C(=O)N(R⁷)₂, - C(=O)NHS(=O)₂R⁶, -C(=O)R⁶, -S(=O)₂N(R⁷)₂, -S(=O)₂NHC(=O)R⁶, or - NHC(=O)NHS(=O)₂R⁶.

10. The compound of claim 9, or a pharmaceutically acceptable salt or solvate thereof, wherein Q is -C(=O)OH.

11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt or solvate thereof, wherein R¹ is fluorine or chlorine.

12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt or solvate thereof, wherein R¹ is chlorine.

13. The compound claim 1 having the structure of Formula (I-C):

Formula (I-C) or a pharmaceutically acceptable salt or solvate thereof.

14. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt or solvate thereof, wherein X is -O- or -NH-.

15. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt or solvate thereof, wherein X is -O-.

16. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt or solvate thereof, wherein A is Ci-Ce haloalkyl, or substituted or unsubstituted Cs-Ci₂ carbocyclyl.

17. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt or solvate thereof, wherein A is 2,2,2-trifluoroethyl, or A is indanyl.

18. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt or solvate thereof, wherein: A is selected from Y¹- Z¹.

19. The compound of any one of claims 1 to 15, or 18, or a pharmaceutically acceptable salt or solvate thereof, wherein Y¹ is an unsubstituted -CH2-.

20. The compound of any one of claims 1 to 15, 18 or 19, or a pharmaceutically acceptable salt or solvate thereof, wherein Z¹ is selected from phenyl, methoxyphenyl, fluorophenyl, or pyridyl.

21. The compound of any one of claims 1 to 15 or 18 to 20, or a pharmaceutically

22. A compound, or pharmaceutically acceptable salt or solvate thereof, selected from the group consisting of:

Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein

X' is -0- or -S-; ring B is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted Cs-Cs cycloalkyl, or substituted or unsubstituted heterocycloalkyl; ring C is a substituted or unsubstituted heteroarylene;

L is absent or Ci-Ce alkylene;

R⁸ is substituted or unsubstituted C1-C4 alkyl.

24. The compound of claim 23, having the structure of Formula (II-A):

Formula (II-A), or a pharmaceutically acceptable salt or solvate thereof.

25. The compound of claim 23 or 24, or a pharmaceutically acceptable salt or solvate thereof, wherein m is 0.

26. The compound of any one of claims 23 to 25, or a pharmaceutically acceptable salt or solvate thereof, wherein Y is hydrogen, -OH, -OR⁸, halogen, substituted or unsubstituted Ci- Ce alkyl, wherein the R⁸ of Y is substituted or unsubstituted Ci-Ce alkyl.

27. The compound of any one of claims 23 to 26, or a pharmaceutically acceptable salt or solvate thereof, wherein Y is hydrogen.

28. The compound of any one of claims 23 to 27, or a pharmaceutically acceptable salt or solvate thereof, wherein Z is hydrogen, -OH, -OR⁸, halogen, or substituted or unsubstituted Ci-Ce alkyl, wherein the R⁸ of Z is substituted or unsubstituted Ci-Ce alkyl.

29. The compound of any one of claims 23 to 28, or a pharmaceutically acceptable salt or solvate thereof, wherein Z is hydrogen.

30. The compound of claim 23, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (II-B):

Formula (II-B), or a pharmaceutically acceptable salt or solvate thereof.

31. The compound of any one of claims 23 to 30, or a pharmaceutically acceptable salt or solvate thereof, wherein L is absent.

32. The compound of any one of claims 23 to 31, or a pharmaceutically acceptable salt or solvate thereof, wherein Q is -C(=O)OH, -C(=O)OR⁵, -C(=O)NHOR⁶, -C(=O)N(R⁷)2, -

and R⁷ of Q is independently hydrogen, or substituted or unsubstituted Ci-Ce alkyl.

33. The compound of any one of claims 23 to 32, or a pharmaceutically acceptable salt or solvate thereof, wherein R⁵ of Q is substituted or unsubstituted Ci-Ce alkyl.

34. The compound of any one of claims 23 to 33, or a pharmaceutically acceptable salt or solvate thereof, wherein Q is -C(=O)OH.

35. The compound of any one of claims 23 to 34, or a pharmaceutically acceptable salt or solvate thereof, wherein R¹ is independently halogen or hydrogen.

36. The compound of any one of claims 23 to 35, or a pharmaceutically acceptable salt or solvate thereof, wherein R¹ is independently chloro or hydrogen.

37. The compound of claim 23, having the structure of Formula (II-C):

or a pharmaceutically acceptable salt or solvate thereof.

38. The compound of any one of claims 23 to 37, or a pharmaceutically acceptable salt or solvate thereof, wherein ring B is a substituted or unsubstituted cycloalkyl.

39. The compound of any one of claims 23 to 38, or a pharmaceutically acceptable salt or solvate thereof, wherein ring B is an unsubstituted Cs-Cecycloalkyl.

40. The compound of any one of claims 23 to 39, or a pharmaceutically acceptable salt or solvate thereof, wherein ring B is cyclopentyl.

41. The compound of any one of claims 23 to 40, or a pharmaceutically acceptable salt or solvate thereof, wherein X' is -O-.

42. The compound of any one of claims 23 to 41, or a pharmaceutically acceptable salt or solvate thereof, wherein ring C is a substituted or unsubstituted 5- to 6-membered heteroaryl.

43. The compound of any one of claims 23 to 42, or a pharmaceutically acceptable salt or solvate thereof, wherein ring C is an unsubstituted 5- to 6-membered heteroaryl.

44. The compound of any one of claims 23 to 43, or a pharmaceutically acceptable salt or solvate thereof, wherein ring C is selected from the group consisting of:

denotes the connection to the phenyl group of Formula (II).

45. A compound selected from the group consisting of:

no

or a pharmaceutically acceptable salt or solvate thereof.

46. A compound of Formula (III):

X' is -O- or -S-;

L is absent or Ci-Ce alkylene;

47. The compound of claim 46 having the structure of Formula (III- A):

Formula (III- A), or a pharmaceutically acceptable salt or solvate thereof.

48. The compound of claim 46 or claim 47, or a pharmaceutically acceptable salt or solvate thereof, wherein m is 0.

49. The compound of any one of claims 46 to 48, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

50. The compound of claim 46 having the structure of Formula (III-B):

or a pharmaceutically acceptable salt or solvate thereof.

51. The compound of any one of claims 46 to 50, or a pharmaceutically acceptable salt or solvate thereof, wherein L is absent.

52. The compound of any one of claims 46 to 51, or a pharmaceutically acceptable salt or solvate thereof, wherein Q is -C(=O)OH, -C(=O)OR⁵, -C(=O)NHOR⁶, -C(=O)N(R⁷)², -

and R⁷ of Q is independently hydrogen or substituted or unsubstituted Ci-Cealkyl.

53. The compound of any one of claims 46 to 52, or a pharmaceutically acceptable salt or solvate thereof, wherein Q is -C(=O)OH.

54. The compound of any one of claims 46 to 53, or a pharmaceutically acceptable salt or solvate thereof, wherein R¹ is halogen.

55. The compound of any one of claims 46 to 54, or a pharmaceutically acceptable salt or solvate thereof, wherein R¹ is chloro.

56. The compound of claim 46 having the structure of Formula (III-C):

Formula (III-C) or a pharmaceutically acceptable salt or solvate thereof.

57. The compound of any one of claims 46 to 56, or a pharmaceutically acceptable salt or solvate thereof, wherein Y' is hydrogen, and Z' is -OH, -OR⁸, -N(R⁹)2, halogen, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted aryl.

58. The compound of any one of claims 46 to 56, or a pharmaceutically acceptable salt or solvate thereof, wherein Y' is hydrogen and Z' is -N(R⁹)2, halogen, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted aryl; wherein each R⁹ of Y' is independently hydrogen or unsubstituted aryl.

59. The compound of any one of claims 46 to 58, or a pharmaceutically acceptable salt or solvate thereof, wherein Y' is hydrogen and Z' is -N(R⁹)2, halogen, unsubstituted Ci-Ce alkyl, or unsubstituted aryl; wherein each R⁹ of Y' is independently hydrogen or phenyl.

60. The compound of any one of claims 46 to 59, or a pharmaceutically acceptable salt or solvate thereof, wherein Y' is hydrogen and Z' is selected from bromo, methyl, phenyl, or

61. The compound of any one of claims 46 to 56, or a pharmaceutically acceptable salt or solvate thereof, wherein Z' is hydrogen and Y' is -OH, -OR⁸, -N(R⁹)2, halogen, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted aryl.

62. The compound of any one of claims 46 to 56, or 61, or a pharmaceutically acceptable salt or solvate thereof, wherein Z' is hydrogen and Y' is -N(R⁹)2, halogen, unsubstituted Ci- Ce alkyl, or unsubstituted aryl; wherein each R⁹ of Y' is independently hydrogen or phenyl.

63. The compound of any one of claims 46 to 56, 61, or 62, or a pharmaceutically acceptable salt or solvate thereof, wherein Z' is hydrogen and Y' is unsubstituted Ci-Ce alkyl.

64. The compound of any one of claims 46 to 56 or 61 to 63, or a pharmaceutically acceptable salt or solvate thereof, wherein Z' is hydrogen and Y' is CH3.

65. The compound of any one of claims 46 to 64, or a pharmaceutically acceptable salt or solvate thereof, wherein X' is -O-.

66. The compound of any one of claims 46 to 65, or a pharmaceutically acceptable salt or solvate thereof, wherein ring D is a substituted or unsubstituted C3-C8 cycloalkyl.

67. The compound of any one of claims 46 to 66, or a pharmaceutically acceptable salt or solvate thereof, wherein ring D is an unsubstituted C3-C6 cycloalkyl.

68. The compound of any one of claims 46 to 67, or a pharmaceutically acceptable salt or solvate thereof, wherein ring D is cyclopentyl.

69. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt or solvate thereof.

70. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt or solvate thereof.

71. A pharmaceutical composition comprising a compound of any one of claims 1-70, or a pharmaceutically acceptable salt, or solvate thereof, and at least one pharmaceutically acceptable excipient.

72. The pharmaceutical composition of claim 71, or a pharmaceutically acceptable salt or solvate thereof, wherein the pharmaceutical composition is formulated for administration to a mammal by intravenous administration, subcutaneous administration, oral administration, inhalation, nasal administration, dermal administration, or ophthalmic administration.

73. The pharmaceutical composition of claim 72, or a pharmaceutically acceptable salt or solvate thereof, wherein the pharmaceutical composition is in the form of a tablet, a pill, a capsule, a liquid, a suspension, a gel, a dispersion, a solution, an emulsion, an ointment, or a lotion.

74. A method of treating a central nervous disorder (CNS) disorder, the method comprising the step of administering to a subject in need thereof, an effective amount of the compound of any one of claims 1-70, or a pharmaceutically acceptable salt or solvate thereof.

75. The method of claim 74, wherein the CNS disorder is an addictive disorder.

76. The method of claim 75, wherein the addictive disorder is nicotine addiction, alcohol addiction, opiate addiction, amphetamine addiction, methamphetamine addiction, or cocaine addiction.

77. The method of claim 75, wherein the addictive disorder is nicotine addiction.

78. The method of claim 75, wherein the addictive disorder is cocaine addiction.

79. The method of claim 74, wherein the CNS disorder is schizophrenia.

80. The method of claim 74, wherein the CNS disorder is a neurodegenerative disease.

81. The method of claim 80, wherein the neurodegenerative disease is Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, or Lou Gehrig's disease (Amyotrophic Lateral Sclerosis or ALS).

82. A method of treating substance abuse, the method comprising the step of administering to a subject in need thereof, an effective amount of the compound of any one of claims 1-71, or a pharmaceutically acceptable salt or solvate thereof, wherein the effective amount is sufficient to diminish, inhibit or eliminate desire for and/or consumption of the substance in the subject.

83. The method of claim 82, wherein the substance is nicotine, alcohol, opiates, amphetamines, methamphetamines, or cocaine.

84. A method for treating an addictive disorder, the method comprising the steps of: a) administering to a subject in need thereof, an effective amount of the compound of any one of claims 1-70, or a pharmaceutically acceptable salt or solvate thereof, during a first time period, wherein the first time period is a time period wherein the subject expects to be in an environment wherein, or exposed to stimuli in the presence of which, the subject habitually uses an addictive substance; and b) administering an effective amount of the compound of any one of claims 1-70, or a pharmaceutically acceptable salt or solvate thereof, during a second time period, wherein the second time period is a time period wherein the subject is suffering from withdrawl.