COMPOUNDS INCLUDING PIMELIC ACID DERIVATIVES AS

HDAC INHIBITORS

CROSS REFERENCE TO RELATED APPLICATIONS This application claims the benefit of United States Provisional Application No.

61/093,919, filed on September 3, 2008, which is incorporated herein by reference in its entirety.

TECHNICAL FIELD

This invention relates to methods of identifying compounds useful for treatment of neurological conditions and new compounds for the treatment of neurological conditions.

BACKGROUND

Friedreich's ataxia (FRDA) is the most prevalent inherited ataxia in Caucasians (see Pandolfo (1999) Semin. Neurol., 19:311). Individuals with FRDA have a deficiency of the mRNA encoding frataxin, a highly conserved 210 amino acid nuclear-encoded, mitochondrial protein that is thought to be involved in iron homeostasis, storage, and transfer of iron-sulfur clusters to partner proteins such as aconitase (see Bulteau et al. (2004) Science, 305:242; Seznec et al. (2005) Hum. MoI. Genet., 14:463; Calabrese et al. (2005) J. Neurol. Sci., 233: 145).

Frataxin insufficiency leads to progressive spinocerebellar neurodegeneration resulting in gait and hand in-coordination, slurred speech, muscle weakness and sensory loss with extraneural scoliosis, cardiomyopathy, and diabetes. Generally within 15 to 20 years after the first appearance of symptoms, an affected individual is confined to a wheelchair and in later stages, become completely incapacitated. Most affected individuals die in early adulthood of heart disease. Although antioxidant- and iron-chelator-based strategies have been used to treat FRDA, these strategies treat only the symptoms of the disease and not the cause, i.e., frataxin deficiency. Therefore, there is a need to develop molecules that could restore frataxin protein expression for the treatment of a neurological condition such as FRDA.

The DNA abnormality found in 98% of FRDA patients is an unstable hyper-expansion of a GAA triplet repeat in the first intron of the frataxin gene (see Campuzano et al., Science 271 : 1423 (1996)). Triplet repeat expansion in genomic DNA is associated with many other neurological conditions (e.g., neurodegenerative and neuromuscular diseases) including myotonic dystrophy, spinal muscular atrophy, fragile X syndrome, Huntingdon's disease, spinocerebellar ataxias, amyotrophic lateral sclerosis, Kennedy's disease, spinal and bulbar muscular atrophy, and Alzheimer's disease. Triplet repeat expansion may cause disease by altering gene expression. For example, in Huntington's disease, spinocerebellar ataxias, fragile X syndrome, and myotonic dystrophy, expanded repeats lead to gene silencing. Therefore, there is a need to identify and develop molecules that can restore the normal function of genes in neurological conditions.

SUMMARY

The inventions described herein are based, inter alia, on the discovery of histone deacetylase (HDAC) inhibitors. Many of these inhibitors are most active on histone deacetylase 3 (HDAC3). HDAC3 inhibitors can be used for the treatment or prevention of certain neurological disorders. In one aspect, the invention features pentane bisamide compounds of Formula (I):

or pharmaceutically acceptable salt thereof; wherein:

R ¹ is selected from H, C ₁ . ₄ alkyl, CM haloalkyl, Ci _-4 alkoxycarbonyl, carbamyl, di-Ci_ ₄ -alkyl-carbamyl, and CM alkylcarbamyl; Ar ¹ is selected from phenyl, 6-membered heteroaryl, and 5-membered heteroaryl; each of which is substituted by n independently selected R ^y groups; wherein said phenyl, 6- membered heteroaryl, and 5-membered heteroaryl are each further optionally fused to a phenyl ring, which is optionally substituted by 1 or 2 groups independently selected from halogen, hydroxyl, cyano, nitro, Ci _-4 alkyl, C ₁ . ₄ haloalkyl, Ci _-4 alkoxy, CM haloalkoxy, amino, CM alkylamino, and di-Ci. ₄ -alkylamino;

Ar ² is selected from phenyl and 6-membered heteroaryl; wherein said phenyl and 6- membered heteroaryl are each substituted at one ortho position by one J group and are each substituted by m independently selected R ^z groups;

J is selected from hydroxyl and amino; L ¹ is selected from a bond or CM alkylene, when Ar ¹ is an optionally substituted 6- membered heteroaryl or 5-membered heteroaryl; or L ¹ is a bond, when Ar ¹ is optionally substituted phenyl;

L ² is straight chain C ₅ - CO alkylene, wherein (i) the straight chain C ₅ - Ce alkylene is optionally substituted by 1, 2, 3, or 4 independently selected R* groups or (ii) one of the carbon atoms of the straight chain C ₅ - Ce alkylene is replaced with -O-, provided that the carbon atom replaced with-O- is not the carbon atom that is directedly attached to C(O)NHAr ² or the carbon atom that is directedly attached to C(O)NR ¹ -L ^l -Ar ^l ; or

L ² is C ₄ -C ₆ alkenylene, which is optionally substituted by 1 , 2, 3, or 4 independently selected R ^x groups; each R" is independently selected from halogen, hydroxyl, oxo, cyano, nitro, CM alkyl, C) _-4 alkoxy, Ci _-4 haloalkyl, Ci _-4 haloalkoxy, amino, Ci _-4 alkylamino, and di-Ci _-4 - alkylamino; each R ^y is independently selected from halogen, cyano, nitro, C ₁ . ₆ alkyl, C ₂ - ₆ alkenyl, C ₂ - ₆ alkynyl, Cι_ ₆ haloalkyl, Cue alkoxy, C1.6 haloalkoxy, Ci.6 alkoxycarbonyl, Ci-6 alkylcarbonyl, carbamyl, C _\ .β alkylcarbamyl, di-Ci. ₆ alkylcarbamyl, C ₁ . ₆ alkylcarbonylamino, Ci- ₆ alkylcarbonyl-CCi^-alkyOamino, C ₁ . ₆ alkoxycarbonylamino, di-Ci. ₆ alkylamino, C3-7 cycloalkyl, C ₂ - ₆ heterocycloalkyl, phenyl, Cue heteroaryl, Ci-i cycloalkyl-Ci-4-alkyl, C2-6 heterocycloalkyl-Ci^-alkyl, phenyl-Ci. ₄ -alkyl, and Cue heteroaryl-Ci. ₄ -alkyl; wherein said Ci. ₆ alkyl, C ₂ - ₆ alkenyl, C ₂ - ₆ alkynyl, Ci- ₆ haloalkyl, C ₁ . ₆ alkoxy, Ci _-S haloalkoxy, C|.6 alkoxycarbonyl, Ci _-6 alkylcarbonyl, carbamyl, C ₁ . ₆ alkylcarbamyl, di-Ci. ₆ alkylcarbamyl, Ci-6 alkylcarbonylamino, Ci _-6 alkylcarbonyl-(Ci- ₄ -alkyl)amino, Ci- ₆ alkoxycarbonylamino, and di- Cι- ₆ alkylamino are each optionally substituted by 1 , 2, or 3 independently selected R ^y groups; and wherein said C _3-7 cycloalkyl, C ₂ - ₆ heterocycloalkyl, phenyl, C|. ₆ heteroaryl, C3.7 cycloaIkyl-Ci- ₄ -alkyl, C ₂ - ₆ heterocydoalkyl-Ci^-alkyl, phenyl-Ci _-4 -alkyl, and Ci. ₆ heteroaryl- Ci. ₄ -alkyl are each optionally substituted by 1 , 2, or 3 independently selected R ^y groups; provided that only one of R ^y is selected from optionally substituted C ₃ - ₇ cycloalkyl,

C ₂ - ₆ heterocycloalkyl, phenyl, C|. ₆ heteroaryl, C _3-7 cycloalkyl-C _M -alkyl, C _2-6 heterocycloalkyl-Ci^-alkyl, phenyl-Ci _-4 -alkyl, and Ci- ₆ heteroaryl-Ci _-4 -alkyl; each R ^z is independently selected from halogen, cyano, nitro, hydroxyl, Ci-6 alkyl, C2- ₆ alkenyl, C ₂ - ₆ alkynyl, Ci_ ₆ haloalkyl, C ₁ . ₆ alkoxy, C ₁ . ₆ haloalkoxy, Ci. ₆ alkoxycarbonyl, C1.6 alkylcarbonyl, carbamyl, C ₁ . ₆ alkylcarbamyl, di-Ci. ₆ alkylcarbamyl, Ci. ₆ alkylcarbonylamino, Ci- ₆ alkylcarbonyl-(Ci _-4 -alkyl)amino, C). ₆ alkoxycarbonylamino, amino, Ci- ₆ alkylamino, di- Ci _-O alkylamino, C ₃ . ₇ cycloalkyl, C ₂ - ₆ heterocycloalkyl, phenyl, and C|. ₆ heteroaryl; wherein said Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1.6 haloalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, Ci_6 alkoxycarbonyl, C ₁ . ₆ alkylcarbonyl, carbamyl, C _\ .β alkylcarbamyl, di-Ci. ₆ alkylcarbamyl, Ci-6 alkylcarbonylamino, Ci- ₆ alkyIcarbonyl-(Ci. ₄ -alkyl)amino, Ci- ₆ alkoxycarbonylamino, C\.β alkylamino, and di-Ci.6 alkylamino are each optionally substituted by 1 , 2, or 3 independently selected R ^z groups; and wherein said C ₃ . ₇ cycloalkyl,C ₂ -6 heterocycloalkyl, phenyl, and Ci_6 heteroaryl are each optionally substituted by 1 , 2, or 3 independently selected R ^z groups; provided that only one of R ^z is selected from optionally substituted C ₃ - ₇ cycloalkyl, optionally substituted C ₂ - ₆ heterocycloalkyl, optionally substituted phenyl, and optionally substituted Ci_ ₆ heteroaryl; each R ^y and R ^z is independently selected from hydroxyl, cyano, nitro, C ₁ - ₄ alkoxy, C ₁ . ₄ haloalkoxy, amino, C ₁ . ₄ alkylamino, and di-C|. ₄ -alkylamino; each R ^y and R ^z is independently selected from halogen, hydroxyl, cyano, nitro, C ₁ .4 alkyl, C ₁ .4 haloalkyl, CM alkoxy, Cμ haloalkoxy, amino, Ci _-4 alkylamino, and di-Ci-4- alkylamino; n is an integer selected from 0, 1, 2, 3, and 4; and m is an integer selected from 0, 1 , 2, and 3. In some embodiments, it is provided that when L ² is straight chain C ₆ alkylene, then m is 1 , 2, and 3, and one occurrence of R ^z is optionally substituted phenyl or optionally substituted Cι_ ₆ heteroaryl; and provided that the compound is not N'-(2-aminophenyl)-N ⁷ -phenyl-l ,7-heptanedioic acid diamide, N'-(2-aminophenyl)-N ⁷ -p-tolyl-l ,7-heptanedioic acid diamide, N'-(2- aminopheny I)-N ⁷ -o-toly 1-1 ,7-heptanedioic acid diamide, N'-(2-aminophenyl)-N ⁷ -(2- methoxyphenyl)-l,7-heptanedioic acid diamide, N'-(2-aminophenyl)-N ⁷ -(pyridin-2-yl)-l ,7- heptanedioic acid diamide, N'-(2-amino-3-methylphenyl)-N ⁷ -p-tolyl-l ,7-heptanedioic acid diamide, N'-(2-amino-4-methylphenyl)-N ⁷ -p-tolyl-l ,7-heptanedioic acid diamide, N'-(2- amino-4-(trifluoromethyl)phenyl)-N ⁷ -(pyridin-2-yl)-l ,7-heptanedioic acid diamide, N ^] -(2- amino-5-(thiophen-2-yl)phenyl)-N -phenyloctanediamide, or N -(biphenyl-3-yl)-N -(4- hydroxybiphenyl-3-yl)octanediamide.

In some embodiments, it is further provided that the compound is other than Nl -(4- aminobiphenyl-3-y])-N7-phenylheptanediamide.

In one aspect, the invention features pentane bisamide compounds of Formula (I):

and pharmaceutically acceptable salts, hydrates, and solvates thereof; wherein: R ¹ is selected from H, C _M alkyl, C _M haloalkyl, C _M alkoxycarbonyl, carbamyl, di-C|. ₄ -alkyl-carbamyl, and C ₁ . ₄ alkylcarbamyl;

Ar ¹ is selected from phenyl, 6-membered heteroaryl, and 5-membered heteroaryl; each of which is substituted by n independently selected R ^y groups; and wherein said phenyl, 6-membered heteroaryl, and 5-membered heteroaryl may each be optionally fused to a phenyl ring, which is optionally substituted by 1 or 2 groups independently selected from halogen, hydroxyl, cyano, nitro, C _M alkyl, C _M haloalkyl, Ci _-4 alkoxy, C _M haloalkoxy, amino, C1.4 alkylamino, and di-Ci-4-alkylamino;

Ar is selected from phenyl and 6-membered heteroaryl; wherein said phenyl and 6- membered heteroaryl are each substituted at one ortho position by one J group and are each substituted by m independently selected R ^z groups; J is selected from hydroxyl and amino;

L ¹ is selected from a bond or Ci _-4 alkylene, when Ar ¹ is an optionally substituted 6- membered heteroaryl or 5-membered heteroaryl; or L ¹ is a bond, when Ar ¹ is optionally substituted phenyl;

L ² is a straight chain C5 alkylene, which is optionally substituted by 1 , 2, 3, or 4 independently selected R" groups; each R ^x is independently selected from halogen, hydroxyl, cyano, nitro, Ci _-4 alkyl, Ci. ₄ alkoxy, C _M haloalkyl, Ci _-4 haloalkoxy, amino, Ci _-4 alkylamino, and di-Ci. ₄ -alkylamino; each R ^y is independently selected from halogen, cyano, nitro, Ci-6 alkyl, C ₂ -6 alkenyl,

C ₂ -6 alkynyl, Q.6 haloalkyl, Ci_6 alkoxy, Cι_6 haloalkoxy, Ci-6 alkoxycarbonyl, Ci-6 alkylcarbonyl, carbamyl, C _\ .(, alkylcarbamyl, di-Ci.6 alkylcarbamyl, C|.6 alkylcarbonylamino, C|. ₆ alkylcarbonyl-(Ci. ₄ -alkyl)amino, Cj. ₆ alkoxycarbonylamino, di-Ci-6 alkylamino, C3 _-7 cycloalkyl, C ₂ -6 heterocycloalkyl, phenyl, Ci_6 heteroaryl, C^.η cycloalkyl-Ci-4-alkyl, C2-6 heterocycloalkyl-Ci^-alkyl, phenyl-Ci. ₄ -alkyl, and C ₁ . ₆ heteroaryl-Ci- ₄ -alkyl; wherein said C ₁ .6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C ₁ . ₆ haloalkyl, Ci _-6 alkoxy, C). ₆ haloalkoxy, Ci_6 alkoxycarbonyl, C ₁ .6 alkylcarbonyl, carbamyl, Q.6 alkylcarbamyl, di-Cj.6 alkylcarbamyl, C1.6 alkylcarbonylamino, Ci_6 alkylcarbonyl-(Ci. ₄ -alkyl)amino, Ci_6 alkoxycarbonylamino, and di- C ₁ .6 alkylamino are each optionally substituted by 1 , 2, or 3 independently selected R ^y groups; and wherein said C ₃ / ₇ cycloalkyl, C ₂ -6 heterocycloalkyl, phenyl, C|.6 heteroaryl, C3. ₇ cycloalkyl-C _M -alkyl, C ₂ - ₆ heterocycloalkyl-C _M -alkyl, phenyl-Ci. ₄ -alkyl, and Ci. ₆ heteroaryl- Ci. ₄ -alkyl are each optionally substituted by 1 , 2, or 3 independently selected R ^y groups; provided that only one of R ^y is selected from optionally substituted C3.7 cycloalkyl, C ₂ - ₆ heterocycloalkyl, phenyl, C ₁ . ₆ heteroaryl, C3-7 cycloalkyl-CM-alkyl, C _2-6 heterocycloalkyl-Ci^-alkyl, phenyl-C|. ₄ -alkyl, and Ci _-6 heteroaryl-C|. ₄ -alkyl; each R ^z is independently selected from halogen, cyano, nitro, hydroxyl, Cι_6 alkyl, C ₂ . 6 alkenyl, C ₂ . ₆ alkynyl, Ci _-6 haloalkyl, C|.6 alkoxy, Cι-6 haloalkoxy, Cι-6 alkoxycarbonyl, Cι-6 alkylcarbonyl, carbamyl, Ci _-6 alkylcarbamyl, di-Ci-6 alkylcarbamyl, C\.β alkylcarbonylamino, Ci- ₆ alkylcarbonyl-(Ci. ₄ -alkyl)amino, Ci _-6 alkoxycarbonylamino, amino, C|.6 alkylamino, di- Ci- ₆ alkylamino, C ₃ .7 cycloalkyl, and C ₂ .6 heterocycloalkyl; wherein said Ci _-6 alkyl, C2-6 alkenyl, C ₂ _ ₆ alkynyl, Ci _-6 haloalkyl, Ci _-6 alkoxy, Ci _-6 haloalkoxy, C\^ alkoxycarbonyl, Ci _-6 alkylcarbonyl, carbamyl, Ci _-6 alkylcarbamyl, di-Ci.6 alkylcarbamyl, C\s alkylcarbonylamino, C|.6 alkylcarbonyl-(Ci-4-alkyl)amino, Ci _-6 alkoxycarbonylamino, Cue alkylamino, and di-Ci-β alkylamino are each optionally substituted by 1 , 2, or 3 independently selected R ^z groups; and wherein said C3.7 cycloalkyl and C ₂ -6 heterocycloalkyl are each optionally substituted by 1 , 2, or 3 independently selected R ^z groups; provided that only one of R ^z is selected from optionally substituted C3-7 cycloalkyl and C2-6 heterocycloalkyl; each R ^y and R ^z is independently selected from hydroxyl, cyano, nitro, C _M alkoxy, C ₁ . ₄ haloalkoxy, amino, Ci _-4 alkylamino, and di-Ci- ₄ -alkylamino; each R ^y and R ^z is independently selected from halogen, hydroxyl, cyano, nitro, Ci _-4 alkyl, C _M haloalkyl, C _M alkoxy, C _M haloalkoxy, amino, Ci _-4 alkylamino, and di-Ci _-4 - alkylamino; n is an integer selected from 0, 1, 2, 3, and 4; and m is an integer selected from 0, 1, 2, and 3.

In another aspect, the invention features phenylethylene bisamide compounds of Formula (II):

and pharmaceutically acceptable salts, hydrates, and solvates thereof; wherein: Ar ¹ is selected from Cβ-io aryl and C ₁ -9 heteroaryl; each of which is substituted with n independently selected R ^y groups; X is selected from -NHAr ² , -C(=O)N(R ^a ) ₂ , and -C(=O)R ^b ; R ¹ is selected from H, C _M alkyl, C _M haloalkyl, C _M alkoxycarbonyl, carbamyl, di-Ci. ₄ -alkyl-carbamyl, and Ci _-4 alkylcarbamyl;

L ¹ is selected from a bond and C _M alkylene;

Ar ² is selected from phenyl, 5-membered heteroaryl, and 6-membered heteroaryl; wherein said phenyl, 5-membered heteroaryl, and 6-membered heteroaryl are each substituted at one ortho position by one J group and by m independently selected R ^z groups; and wherein, in addition, said phenyl, 5-membered heteroaryl, and 6-membered heteroaryl may be further optionally fused to a phenyl or Cι_ ₆ heteroaryl ring, each of which is optionally substituted by 1 or 2 groups independently selected from halogen, hydroxy!, cyano, nitro, C _M alkyl, Ci _-4 haloalkyl, Ci _-4 alkoxy, C _M haloalkoxy, amino, Ci _-4 alkylamino, and di-Ci_ ₄ - alkylamino; each R ^a is independently selected from H, Ci-6 alkyl and Ci-6 haloalkyl;

R ^b is selected from Ci_6 alkyl and Ci.6 haloalkyl;

J is selected from amino and hydroxyl; each R ^x is independently selected from halogen, hydroxyl, cyano, nitro, Ci _-4 alkyl, C|.

4 alkoxy, C _M haloalkyl, Ci _-4 haloalkoxy, amino, Ci _-4 alkylamino, and di-Ci. ₄ -alkylamino; p is an integer selected from 0, 1 , 2, and 3; each R ^y is independently selected from halogen, cyano, nitro, hydroxyl, C|_6 alkyl, C ₂ . 6 alkenyl, C _2- 6 alkynyl, Cue haloalkyl, Ci.6 alkoxy, C|.6 haloalkoxy, Ci_6 alkoxycarbonyl, Ci.6 alkylcarbonyl, carbamyl, Ci.6 alkylcarbamyl, di-Ci-6 alkylcarbamyl, Ci.6 alkylcarbonylamino, Ci-6 alkylcarbonyl-(Ci_ ₄ -alkyl)amino, Ci-6 alkoxycarbonylamino, amino, C|.6 alkylamino, di- Ci-6 alkylamino, C3.7 cycloalkyl, C ₂ -6 heterocycloalkyl, phenyl, C ₁ .6 heteroaryl, C3.7 cycloalkyl-Ci. ₄ -alkyl, C ₂ . ₆ heterocycloalkyl-Ci^-alkyl, phenyl-Ci. ₄ -alkyl, and C ₁ .6 heteroaryl- Ci-4-alkyl; wherein said C ₁ .6 alkyl, C ₂ -6 alkenyl, C ₂ -6 alkynyl, C|.6 haloalkyl, C1.6 alkoxy, C1.6 haloalkoxy, C ₁ .6 alkoxycarbonyl, Cι_6 alkylcarbonyl, C|.6 alkylcarbamyl, di-Ci-6 alkylcarbamyl, C ₁ .6 alkylcarbonylamino, C ₁ .6 alkylcarbonyl-(Ci. ₄ -alkyl)amino, Ci-6 alkoxycarbonylamino, C ₁ . ₆ alkylamino, di-Ci.6 alkylamino are each optionally substituted by

1 , 2, or 3 independently selected R ^y groups; and wherein said C ₃ .7 cycloalkyl, C ₂ -6 heterocycloalkyl, phenyl, Cι_ ₆ heteroaryl, C3-7 cycloalkyl-Ci _-4 -alkyl, C ₂ -6 heterocycloalkyl-Ci. ₄ -alkyl, phenyl-Ci. ₄ -alkyl, and C ₁ . ₆ heteroaryl-C _M -alkyl are each optionally substituted by 1 ,

2, or 3 independently selected R ^y groups; provided that only one of R ^y is selected from optionally substituted C3.7 cycloalkyl, C ₂ -6 heterocycloalkyl, phenyl, C ₁ .6 heteroaryl, C3-7 cycloalkyl-Ci _-4 -alkyl, C2-6 heterocycloalkyl-C _M -alkyl, phenyl-CM-alkyl, and C _\ .(, heteroaryl-CM-alkyl; each R ^z is independently selected from halogen, cyano, nitro, hydroxyl, Cj.6 alkyl, C ₂ . 6 alkenyl, C ₂ -6 alkynyl, Ci-6 haloalkyl, Ci-6 alkoxy, Cι-6 haloalkoxy, Ci-6 alkoxycarbonyl, Ci-6 alkylcarbonyl, carbamyl, Q.6 alkylcarbamyl, di-Ci-6 alkylcarbamyl, Ci_6 alkylcarbonylamino, Ci-6 alkylcarbonyl-(C).4-alkyl)amino, Cι_6 alkoxycarbonylamino, C1.6 alkylamino, di-Ci.6 alkylamino, C ₃ . ₇ cycloalkyl, C ₂ - ₆ heterocycloalkyl, phenyl, C|. ₆ heteroaryl, C3-7 cycloalkyl-C|. ₄ -alkyl, C ₂ . ₆ heterocycloalkyl-Ci^-alkyl, phenyl-Ci- ₄ -alkyl, and Ci_6 heteroaryl-Ci.4-alkyl; wherein said Cue alkyl, C2-6 alkenyl, C ₂ -6 alkynyl, Ci-6 haloalkyl, Ci_6 alkoxy, Ci-6 haloalkoxy, Ci-6 alkoxycarbonyl, C\.β alkylcarbonyl, Ci_6 alkylcarbamyl, di-Ci-6 alkylcarbamyl, C).6 alkylcarbonylamino, Q.6 alkylcarbonyl-(C|. ₄ -alkyl)amino, Cue alkoxycarbonylamino, amino, C|_ ₆ alkylamino, di-Ci_ ₆ alkylamino are each optionally substituted by 1 , 2, or 3 independently selected R ^z groups; and wherein said C3.7 cycloalkyl, C ₂ -6 heterocycloalkyl, phenyl, C ₁ .6 heteroaryl, C3.7 cycloalkyl-Cι-4-alkyl, C2-6 heterocycloalkyl-Ci^-alkyl, phenyl-C|. ₄ -alkyl, and C ₁ . ₆ heteroaryl-Ci- ₄ -alkyl are each optionally substituted by 1 , 2, or 3 independently selected R ^z groups; provided that only one of R ^z is selected from optionally substituted C ₃ .7 cycloalkyl and C2-6 heterocycloalkyl; each R ^y and R ^z is independently selected from hydroxyl, cyano, nitro, C _M alkoxy, Cι- ₄ haloalkoxy, amino, Ci _-4 alkylamino, and di-Cj. ₄ -alkylamino; each R ^y and R ^z is independently selected from halogen, hydroxyl, cyano, nitro, C _M alkyl, C _M haloalkyl, C _M alkoxy, C _M haloalkoxy, amino, C _M alkylamino, and di-Cι- ₄ - alkylamino; n is an integer selected from 0, 1, 2, 3, and 4; and m is an integer selected from 0, 1, 2, and 3.

In a further aspect, the invention features bisamide or hydroxamide compounds of Formula (III): and pharmaceutically acceptable salts, hydrates, and solvates thereof; wherein: R ¹ is selected from H, C _M alkyl, C _M haloalkyl, C _M alkoxycarbonyl, carbamyl, di-C|. ₄ -alkyl-carbamyl, and C _M alkylcarbamyl; R ³ is selected from -R ^a and -N(R^ ₂ ;

R ^a is selected from C\.β alkyl, C\.β haloalkyl, C ₂ - ₆ alkenyl, and C2-6 alkynyl; each R ^b is independently selected from H, Ci_6 alkyl, Ci_6 haloalkyl, C ₂ -6 alkenyl, and C ₂ -6 alkynyl;

Ar ¹ is phenyl, 6-membered heteroaryl, and 5-membered heteroaryl; each of which is substituted by a R ^y group and by n additional independently selected R ^y groups; L ² is straight chain C ₅ alkylene, which is optionally substituted by 1, 2, 3, or 4 independently selected R ^x groups; each R ^x is independently selected from halogen, hydroxy!, cyano, nitro, Ci _-4 alkyl, Ci. ₄ alkoxy, Ci _-4 haloalkyl, C) _-4 haloalkoxy, amino, Ci _-4 alkylamino, and di-Ci _-4 -alkylamino; each R ^y is independently selected from halogen, cyano, nitro, Ci-β alkyl, C ₂ . ₆ alkenyl, C ₂ - ₆ alkynyl, C ₁ . ₆ haloalkyl, alkoxy, Ci_ ₆ haloalkoxy, Ci _-6 alkoxycarbonyl, Ci _-6 alkylcarbonyl, carbamyl, Ci- ₆ alkylcarbamyl, di-Ci- ₆ alkylcarbamyl, Ci_6 alkylcarbonylamino, Ci- ₆ alkylcarbonyl-(Ci_ ₄ -alkyl)amino, Ci- ₆ alkoxycarbonylamino, amino, Ci_ ₆ alkylamino, and di-Cι-6 alkylamino; wherein said C|.6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci.6 haloalkyl, Ci.6 alkoxy, Ci. ₆ haloalkoxy, C ₁ . ₆ alkoxycarbonyl, Ci. ₆ alkylcarbonyl, C|_ ₆ alkylcarbamyl, di-Ci.6 alkylcarbamyl, Ci- ₆ alkylcarbonylamino, Cι_ ₆ alkylcarbonyl-(Ci _-4 -alkyl)amino, Ci_ ₆ alkoxycarbonylamino, amino, Ci _-6 alkylamino, and di-Ci. ₆ alkylamino are each optionally substituted by 1 , 2, or 3 independently selected R ^y groups; each R ^y is independently selected from hydroxyl, cyano, nitro, Ci _-4 alkoxy, Ci _-4 haloalkoxy, amino, Ci _-4 alkylamino, and di-Ci _-4 -alkylamino; and n is an integer selected from 0, 1, 2, and 3.

In one aspect, compositions (e.g., a pharmaceutical composition) are featured, which includes a compound of formula (I) (or II or III) or a salt (e.g., a pharmaceutically acceptable salt) thereof as defined anywhere herein and a pharmaceutically acceptable carrier. In some embodiments, the composition can include an effective amount of the compound or salt. In some embodiments, the composition can further include an additional therapeutic agent.

The invention relates generally to inhibiting HDAC (e.g., HDACl, HDAC2, and/or HDAC3) with a compound of formula (I) (or II or III) or a salt (e.g., a pharmaceutically acceptable salt) thereof as defined anywhere herein. In some embodiments, the methods can include, e.g., contacting an HDAC (e.g., HDACl, HDAC2, or HDAC3) in a sample (e.g., a cell or tissue) with a compound of formula (I) (or II) or a salt (e.g., a pharmaceutically acceptable salt) thereof as defined anywhere herein. In other embodiments, the methods can include administering a compound of formula (I) (or II) or a salt (e.g., a pharmaceutically acceptable salt) thereof as defined anywhere herein to a subject (e.g., a mammal, such as a human). Accordingly, in yet another aspect, this invention includes methods of screening for compounds that inhibit (e.g., selectively inhibit) one or more HDACs.

In one aspect, methods of selectively inhibiting HDAC3 are featured, which includes contacting an HDAC3 in a sample (e.g., a cell or tissue) with a compound of formula (I) or a salt (e.g., a pharmaceutically acceptable salt) thereof as defined anywhere herein; or administering a compound of formula (I) (or II or HI) or a salt (e.g., a pharmaceutically acceptable salt) thereof as defined anywhere herein to a subject (e.g., a mammal, such as a human).

In one aspect, methods of selectively inhibiting HDACl or HDAC2 (e.g., HDACl ) are featured, which include contacting HDACl or HDAC2 (e.g., HDACl) in a sample (e.g., a cell or tissue) with a compound of formula (I) (or II or III)or a salt (e.g., a pharmaceutically acceptable salt) thereof as defined anywhere herein; or administering a compound of formula (I) (or II or HI) or a salt (e.g., a pharmaceutically acceptable salt) thereof as defined anywhere herein to a subject (e.g., a mammal, such as a human). In a further aspect, this application features methods of treating a neurological condition (e.g., Friedreich's ataxia, myotonic dystrophy, spinal muscular atrophy, fragile X syndrome, Huntington's disease, a spinocerebellar ataxia, Kennedy's disease, amyotrophic lateral sclerosis, spinal and bulbar muscular atrophy, or Alzheimer's disease) that include administering an HDAC inhibitor described herein to a patient having a neurological condition.

In another aspect, this application features the use of an HDAC inhibitor described herein in the preparation of, or for use as, a medicament for the treatment or prevention of a neurological condition (e.g., Friedreich's ataxia, myotonic dystrophy, spinal muscular atrophy, fragile X syndrome, Huntington's disease, a spinocerebellar ataxia, Kennedy's disease, amyotrophic lateral sclerosis, spinal and bulbar muscular atrophy, or Alzheimer's disease).

In a further aspect, this application features methods of treating a cancer (e.g., cutaneous T cell lymphoma, B cell lymphomas, and colorectal cancer), an inflammatory disorder (e.g., psoriasis, rheumatoid arthritis, and osteoarthritis), a neurological condition (e.g., Friedreich's ataxia, myotonic dystrophy, Parkinson's disease, spinal muscular atrophy, fragile X syndrome, Huntington's disease, a spinocerebellar ataxia, Kennedy's disease, amyotrophic lateral sclerosis, spinal and bulbar muscular atrophy, or Alzheimer's disease), or a Plasmodium falciparum infection (e.g., malaria) that includes administering an HDAC inhibitor described herein to a patient, e.g., a patient having a neurological condition In another aspect, this application features the use of an HDAC inhibitor described herein in the preparation of a medicament for the treatment or prevention of a cancer, an inflammatory disorder, a Plasmodium falciparum infection, or a neurological condition (e.g., as listed herein). In another aspect, this application features the use of an HDAC inhibitor described herein as a medicament, e.g., for the treatment or prevention of a cancer, an inflammatory disorder, a Plasmodium falciparum infection, or a neurological condition (e.g., as listed herein).

Some of the formula (I) compounds described herein (e.g., compounds in which L contains one or more double bonds) have enhanced (e.g., increased, e.g., increased by a factor of about 2 or more) stabilities in acid. In some embodiments, the formula (I) compounds have enhanced resistances to degradation, e.g., less than about 25% degradation (e.g., less than about 20% degradation, less than about 15% degradation, or less than about 10% degradation) when exposed to acidic pH, e.g., acidic conditions intended to mimic those in the stomach, e.g., incubation (e.g., as al O μM solution) at 50 ⁰ C and at a pH of about 2.0 for about four hours. The resistance of compounds to degradation or metabolism at acidic pH can be a useful feature for a pharmaceutical agent (e.g., a drug). Increased stability at low pH can allow, for example, process preparation steps, such as salt formation, to occur without significant degradation of the desired salt. In addition, it is preferable that orally administered pharmaceuticals are stable to the acidic pH of the stomach. Embodiments can include one or more of the following features.

Ar ¹ is not substituted at the ortho position.

Ar ¹ is substituted at the para position by C _h alky], then Ar ² is substituted by at least one R ^z group.

J is amino. L ² is straight chain Cs alkylene, which is optionally substituted by 1 , 2, 3, or 4 independently selected R" groups (e.g., -CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ -). m is 0.

Each R ^z is independently selected from halogen, cyano, nitro, Ci^ alkyl, Ci-6 haloalkyl, C|.6 alkoxy, Ci-β haloalkoxy, cycloalkyl, C _2-6 heterocycloalkyl, phenyl, and Ci- ₆ heteroaryl; wherein said C^alkyl, C|. ₆ haloalkyl, C|. ₆ alkoxy, and Ci^ haloalkoxy are each optionally substituted by 1 or 2 independently selected R ^z groups; and wherein said C ₃ - ₇ cycloalkyl, C ₂ .6 heterocycloalkyl, phenyl, and Cue heteroaryl are each optionally substituted by 1, 2, or 3 independently selected R ^z groups. Each R ^z is independently selected from halogen, cyano, nitro, Ci-βalkyl, C|.6 haloalkyl, Ci.6 alkoxy, Ci^ haloalkoxy, C ₃ . ₇ cycloalkyl, C2-6 heterocycloalkyl, phenyl, and C|. ₆ heteroaryl.

Each R ^z is independently selected from halogen, cyano, nitro, Ci^ alkyl, C|.6 haloalkyl, Ci_ ₆ alkoxy, Ci^ haloalkoxy; wherein said Ci-β alkyl, C 1.6 haloalkyl, Ci-β alkoxy, and Ci- _ό haloalkoxy are each optionally substituted by 1 or 2 independently selected R ^z groups.

Each R ^z is independently selected from halogen, cyano, nitro, Ci-βalkyl, Ci-6 haloalkyl, Ci_ ₆ alkoxy, Ci-ό haloalkoxy. m is 1. R ^z can be selected from halogen, C|_ ₆ alkyl, C ₁ .6 haloalkyl, C ₁ .6 alkoxy, and

C|. ₆ haloalkoxy. R ^z is halogen (e.g., fluoro). R ^z can be selected from phenyl and Cι-6 heteroaryl, each of which is optionally substituted by 1 , 2, or 3 independently selected R ^z groups.

R ¹ is hydrogen. The compound is a compound of Formula (Ic):

or pharmaceutically acceptable salt thereof.

Ar ¹ is 5-membered heteroaryl; which is substituted by n independently selected R ^y groups; and Ar ² is phenyl; which is substituted by m independently selected R ^z groups; or Ar ¹ is 6-membered heteroaryl; which is substituted with n independently selected R ^y groups; and Ar ² is phenyl; wherein said phenyl is substituted at one ortho position by one J group and by m independently selected R ^z groups.

Embodiments can include or further include any one or more of the features set forth in detailed description.

The following definitions are used, unless otherwise described. Specific and general values listed below for radicals, substituents, and ranges, are for illustration only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents. Alkyl, alkoxy, alkenyl, and the like denote both straight and branched groups. As used herein, the term "alkyl," employed alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight-chain or branched. In some embodiments, the alkyl group contains 1 to 12, 1 to 8, or 1 to 6 carbon atoms. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n- propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; higher homologs such as 2-methyl- 1 -butyl, n-pentyl, 3-pentyl, n-hexyl, 1 ,2,2-trimethylpropyl, n-heptyl, n-octyl, and the like. In some embodiments, the alkyl moiety is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, or 2,4,4-trimethylpentyl.

As used herein, the term "C _n - _m alkylene," employed alone or in combination with other terms, refers to a divalent alkyl linking group having n to m carbon atoms. Examples of alkylene groups include, but are not limited to, ethan-l,2-diyl, propan-l,3-diyl, propan-1,2- diyl, butan-l ,4-diyl, butan-l ,3-diyl, butan-l,2-diyl, 2-methyl-propan-l ,3-diyl, and the like.

As used herein, the term "straight chain C _n - _m alkylene," employed alone or in combination with other terms, refers to a non-branched alkylene group of n to m carbon atoms.

As referred to herein, the term "alkoxy" refers to a group of formula -O(alkyl). Alkoxy can be, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec- butoxy, pentoxy, 2-pentoxy, 3-pentoxy, or hexyloxy. As used herein, the term "aryl," employed alone or in combination with other terms, refers to a monocyclic or polycyclic (e.g., having 2, 3 or 4 fused or covalently linked rings) aromatic hydrocarbon moiety, such as, but not limited to, phenyl, 1-naphthyl, 2-naphthyl, anthracenyl, phenanthrenyl, and the like. In some embodiments, aryl groups have from 6 to 20 carbon atoms, about 6 to 10 carbon atoms, or about 6 to 8 carbons atoms. As referred to herein, "heteroaryl" refers to a monocyclic, bicyclic, or tricyclic ring system containing one, two, or three aromatic rings and containing at least one (typically one to about three) nitrogen, oxygen, or sulfur atoms in an aromatic ring. Heteroaryl groups can possess optional substituents as described herein.

Examples of heteroaryl groups include, but are not limited to, 2H-pyrrolyl, 3H- indolyl, 4H-quinolizinyl, acridinyl, benzo[b]thienyl, benzothiazolyl, β-carbolinyl, carbazolyl, chromenyl, cinnolinyl, dibenzo[b,d]furanyl, furazanyl, furyl, imidazolyl, imidizolyl, indazolyl, indolisinyl, indolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxazolyl, perimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, thiadiazolyl, thianthrenyl, thiazolyl, thienyl, triazolyl, and xanthenyl.

Within the above definition, the term "heteroaryl" can include a monocyclic aromatic ring containing five or six ring atoms containing carbon and 1 , 2, 3, or 4 heteroatoms independently selected from non-peroxide oxygen, sulfur, and N(Z) wherein Z is absent or is H, O, alkyl, phenyl or benzyl. The term heteroaryl can also include an ortho-fused bicyclic heterocycle of about eight to ten ring atoms derived therefrom, particularly a benz-derivative or one derived by fusing a propylene, trimethylene, or tetramethylene diradical thereto. As referred to herein, "optionally" substituted group refers to the substitution of a group in which one or more hydrogen atoms are each independently replaced with a non- hydrogen substituent. Groups that are optionally substituted are typically substituted with one to five substituents. In other embodiments, optionally substituted groups are substituted with one to three substituents. Typical substituents include, but are not limited to, -X, -R, -CF , =O, -OR, -S ^" , -SR, -S(=O)R, -S(=O) ₂ R, -S(=O) ₂ O ^~ , -S(=O) ₂ OH, -OS(=O) ₂ OR, -S(=O) ₂ NR, -NR ₂ , -N ⁺ R ₃ , =NR, -NC(=O)R, -CX ₃ , -C(O)O ^" , -C(=O)R, -C(=O)OR, -C(=O)X, - C(=O)NRR, -C(S)R, -C(S)OR, -C(O)SR, -C(S)SR, -C(S)NRR, -C(NR)NRR, -CN, -OP(O)(OR) ₂ , -P(=O)(OR) ₂ , -P(=O)(O ^" ) ₂ , -P(=O)(OH) ₂ , where each X is independently a halogen (F, Cl, Br, or I); and each R is independently H, alkyl, aryl, a heterocycle, or a protecting group. When the substituent is attached to a group by two bonds (e.g., by a "double bond"), two hydrogen atoms are replaced by the substituent.

As used herein, the phrase "optionally substituted" means unsubstituted (e.g., substituted with a H) or substituted. As used herein, the term "substituted" means that a hydrogen atom is removed and replaced by a substitutent. It is understood that substitution at a given atom is limited by valency.

As used herein, when a first ring is "optionally fused" to a second ring, the first ring may be unfused, or may be fused to the second ring. For example, a phenyl ring optionally fused to a phenyl ring refers to either an unfused phenyl ring or a naphthalene ring. As used herein, a ring "substituted at one ortho position" refers to a ring substituted at the position of the ring directly adjacent to the point of attachment of the ring to the core moiety (e.g. the core moiety of Formula (I)).

At various places in the present specification, substituents of compounds described herein are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges. For example, the term "Ci- ₆ alkyl" is specifically intended to individually disclose methyl, ethyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl, and C ₆ alkyl.

It is further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.

The term "n-membered" where n is an integer typically describes the number of ring- forming atoms in a moiety where the number of ring-forming atoms is n. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring and 1 ,2,3,4-tetrahydro- naphthalene is an example of a 10-membered cycloalkyl group.

For compounds described herein in which a variable appears more than once, each variable can be a different moiety independently selected from the group defining the variable. For example, where a structure is described as having two R groups that are simultaneously present on the same compound, the two R groups can represent different moieties independently selected from the group defined for R. In another example, when an optionally multiple substituent is designated in the form:

then it is understood that substituent R can occur/? number of times on the ring, and R can be a different moiety at each occurrence. It is understood that each R group may replace any hydrogen atom attached to a ring atom, including one or both of the (CH ₂ )P hydrogen atoms. Further, in the above example, should the variable Q be defined to include hydrogens, such as when Q is said to be CH ₂ , NH, etc., any floating substituent such as R in the above example, can replace a hydrogen of the Q variable as well as a hydrogen in any other non- variable component of the ring.

Throughout the definitions, the term "C _n . _m " (e.g., Ci _-4 , C\.β, and the like) is used, wherein n and m are integers and indicate the number of carbons, wherein n-m indicates a range which includes the endpoints.

Unless indicated otherwise, the nomenclature of substituents that are not explicitly defined herein are arrived at by naming the terminal portion of the functionality followed by the adjacent functionality toward the point of attachment. In generally, the point of attachment for a substituent is indicated by the last term in the group. For example, Cι_6 heteroaryl-Ci. ₄ alkyl refers to a moiety of heteroaryl-alkylene-, wherein the heteroaryl group has 1 to 6 carbon atoms, the alkylene linker has 1 to 4 carbons, and the substituent is attached through the alkylene linker.

As used herein, "C _n . _m alkynyl," employed alone or in combination with other terms, refers to an alkyl group having one or more triple carbon-carbon bonds with n to m carbon atoms. Example alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn- 2-yl, and the like. In some embodiments, the alkynyl moiety contains 2 to 10 or 2 to 6 carbon atoms.

As used herein, the term "C _n - _m alkynylene," employed alone or in combination with other terms, refers to a divalent alkynyl group having n to m carbon atoms. In some embodiments, the alkynylene moiety contains 2 to 12 carbon atoms. In some embodiments, the alkynylene moiety contains 2 to 6 carbon atoms. Example alkynylene groups include, but are not limited to, ethyn-l ,2-diyl, propyn-l ,3,-diyl, l-butyn-l ,4-diyl, l-butyn-l ,3-diyl, 2- butyn-l ,4-diyl, and the like. As used herein, "C _n . _m alkenyl," employed alone or in combination with other terms, refers to an alkyl group having one or more double carbon-carbon bonds, with n to m carbon atoms. In some embodiments, the alkenyl moiety contains 2 to 10 or 2 to 6 carbon atoms. Example alkenyl groups include, but are not limited to, ethenyl, «-propenyl, isopropenyl, n- butenyl, jec-butenyl, and the like. As used herein, the term "alkenylene," employed alone or in combination with other terms, refers to a divalent alkenyl group. In some embodiments, the alkenylene moiety contains 2 to 12 carbon atoms. In some embodiments, the alkenylene moiety contains 2 to 6 carbon atoms. Example alkenylene groups include, but are not limited to, ethen-l ,2-diyl, propen-l ,3-diyl, propen-l ,2-diyl, buten-l,4-diyl, buten-l ,3-diyl, buten-l ,2-diyl, 2-methyl- propen-l ,3-diyl, and the like.

As used herein, the term "amino," employed alone or in combination with other terms, refers to a group of formula -NH ₂ .

As used herein, the term "C _n - _m alkylamino," employed alone or in combination with other terms, refers to a group of formula -NH(alkyl), wherein the alkyl group has n to m carbon atoms.

As used herein, the term "di-C _n - _m -alkylamino," employed alone or in combination with other terms, refers to a group of formula -N(alkyl)2, wherein the alkylene group and two alkyl groups each has, independently, n to m carbon atoms. As used herein, the term "carbamyl," employed alone or in combination with other terms, refers to a group of formula -C(O)NHi.

As used herein, the term "C- _m alkylcarbamyl," employed alone or in combination with other terms, refers to a group of formula -C(O)-NH(alkyl), wherein the alkyl group has n to m carbon atoms.

As used herein, the term "di-C _n - _m -alkylcarbamyl," employed alone or in combination with other terms, refers to a group of formula -C(O)N(alkyl) ₂ , wherein the alkyl group has n to m carbon atoms.

As used herein, the term "C _n - _m alkoxycarbonyl," employed alone or in combination with other terms, refers to a group of formula -C(O)O-alkyl, wherein the alkyl group has n to m carbon atoms.

As used herein, the term "C _n - _m alkylcarbonyl," employed alone or in combination with other terms, refers to a group of formula -C(O)-alkyl, wherein the alkyl group has n to m carbon atoms. As used herein, the term "C _n - _m alkylcarbonylamino," employed alone or in combination with other terms, refers to a group of formula -NHC(O)-alkyl, wherein the alkyl group has n to m carbon atoms.

As used herein, the term "C _n - _m alkylcarbonyl-(C _n - _m alkyl)amino," employed alone or in combination with other terms, refers to a group of formula -N(alkyl)C(O)-alkyl, wherein each alkyl group, independently, has n to m carbon atoms.

As used herein, the term "C _n - _m alkoxycarbonylamino," employed alone or in combination with other terms, refers to a group of formula -NHC(O)O-alkyl, wherein the alkyl group has n to m carbon atoms.

As used herein, the term "carbonyl," employed alone or in combination with other terms, refers to a -C(O)- group, which is a divalent one-carbon moiety further bonded to an oxygen atom with a double bond.

As used herein, the term "carboxy," employed alone or in combination with other terms, refers to a group of formula -C(O)OH.

As used herein, the term "cycloalkyl," employed alone or in combination with other terms, refers to a non-aromatic cyclic hydrocarbon moiety, which may optionally contain one or more alkenylene or alkynylene groups as part of the ring structure. Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused or covalently linked rings) ring systems. Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example,

I 7 benzo derivatives of pentane, pentene, hexane, and the like. The term "cycloalkyl" also includes bridgehead cycloalkyl groups and spirocycloalkyl groups. As used herein, "bridgehead cycloalkyl groups" refers to non-aromatic cyclic hydrocarbon moieties containing at least one bridgehead carbon, such as adamantazn-1-yl. As used herein, "spirocycloalkyl groups" refers to non-aromatic hydrocarbon moieties containing at least two rings fused at a single carbon atom, such as spiro[2.5]octane and the like. In some embodiments, the cycloalkyl group has 3 to 14 ring members, 3 to 10 ring members, or 3 to 8 ring members. One or more ring- forming carbon atoms of a cycloalkyl group can be oxidized to form carbonyl linkages. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbomyl, norpinyl, norcarnyl, adamantyl, and the like. In some embodiments, the cycloalkyl group is admanatan-1 -yl.

As used herein, the term "cyano," employed alone or in combination with other terms, refers to a group of formula -CN, wherein the carbon and nitrogen atoms are bound together by a triple bond.

As used herein, the term "haloalkyl," employed alone or in combination with other terms, refers to an alkyl group having from one halogen atom to 2n+l halogen atoms which may be the same or different, where "n" is the number of carbon atoms in the alkyl group. In some embodiments, the halogen atoms are fluoro atoms. As used herein, "haloalkoxy," employed alone or in combination with other terms, refers to a group of formula -O-haloalkyl. An example haloalkoxy group is OCF ₃ . In some embodiments, the halogen atoms are fluoro atoms.

As used herein, the terms "halo" and "halogen," employed alone or in combination with other terms, refer to fluoro, chloro, bromo, and iodo. As used herein, the term "C _o - _p heteroaryl-C- _m -alkyl," employed alone or in combination with other terms, refers to a group of formula -alky lene-heteroaryl, the alkylene linker has n to m carbon atoms and the heteroaryl group has 0 to p carbon atoms. In some embodiments, the alkylene portion has 1 to 4 carbon atoms.

As used herein, the term "C _o -pCycloalkyl-Cn-m-alkyl," employed alone or in combination with other terms, refers to a group of formula -alkylene-cycloalkyl, the alkylene linker has n to m carbon atoms and the cycloalkyl group has 0 to p carbon atoms. In some embodiments, the alkylene portion has 1 to 4 carbon atoms.

As used herein, the term "C _o -paryl-C-m-alkyl," employed alone or in combination with other terms, refers to a group of formula -alky lene-aryl, the alkylene linker has n to m carbon atoms and the aryl group has o to p carbon atoms. In some embodiments, the alkylene portion has 1 to 4 carbon atoms.

As used herein, the term "phenyl-C _n - _m -alkyl," employed alone or in combination with other terms, refers to a group of formula -alkylene-phenyl, the alkylene linker has n to m carbon atoms. In some embodiments, the alkylene portion has 1 to 4 carbon atoms.

As used herein, the term "C _o-p heterocycloalkyl-C _n - _m -alkyl," employed alone or in combination with other terms, refers to a group of formula -alkylene-heterocycloalkyl, the alkylene linker has n to m carbon atoms and the heterocycloalkyl group has o to p carbon atoms. In some embodiments, the alkylene portion has 1 to 4 carbon atoms. As used herein, the term "heterocycloalkyl," "heterocycloalkyl ring," or

"heterocycloalkyl group," employed alone or in combination with other terms, refers to a non-aromatic ring system, which may optionally contain one or more alkenylene or alkynylene groups as part of the ring structure, and which has at least one heteroatom ring member selected from nitrogen, sulfur, and oxygen. When the heterocycloalkyl groups contains more than one heteroatom, the heteroatoms may be the same or different.

Heterocycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3, or 4 fused or covalently bonded rings) ring systems. Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the non-aromatic ring, for example, 1 ,2,3,4-tetrahydro-quinoline and the like. Heterocycloalkyl groups can also include bridgehead heterocycloalkyl groups and spiroheterocycloalkyl groups. As used herein, "bridgehead heterocycloalkyl group" refers to a heterocycloalkyl moiety containing at least one bridgehead atom, such as azaadamantan- 1 - yl and the like. As used herein, "spiroheterocycloalkyl group" refers to a heterocycloalkyl moiety containing at least two rings fused at a single atom, such as [1 ,4-dioxa-8-aza- spiro[4.5]decan-N-yl] and the like. In some embodiments, the heterocycloalkyl group has 3 to 20 ring-forming atoms, 3 to 10 ring-forming atoms, or about 3 to 8 ring forming atoms. The carbon atoms or hetereoatoms in the ring(s) of the heterocycloalkyl group can be oxidized to form a carbonyl, or sulfonyl group (or other oxidized linkage) or a nitrogen atom can be quaternized. Where a particular heteraryl or heterocycloalkyl group appears in the embodiments, such as "a pyrazole ring," the term is intended to refer to a pyrazole ring attached at any atom of the ring, as permitted by valency rules, and is intended to include various tautomeric forms of the ring. Conversely, in some embodiments, the point of attachment is indicated by the name, e.g., pyrazol-1-yl refers to a pyrazole ring attached at the 1 -position of the ring. As used herein, the term "hydroxyl," employed alone or in combination with other terms, refers to a group of formula -OH.

As to any of the above groups that contain one or more substituents, it is understood, of course, that such groups do not contain any substitution or substitution patterns that are sterically impractical and/or synthetically un- feasible. In addition, the compounds of this invention include all stereochemical isomers arising from the substitution of these compounds.

As used herein, a "base" refers to any molecule, ion, or other entity that acts as a proton acceptor. A base can be an organic compound or ion with an unshared electron pair. Typical bases include mono-, di-, and tri-alkyl substituted amines. A base can also be an inorganic compound or ion, such as a metal oxide or metal hydroxide. Bases used in organic synthesis are well known to those of skill in the art. Many bases are disclosed in, for example, the Aldrich Handbook of Fine Chemicals, 2003-2004 (Milwaukee, WI).

As used herein, "solvent" refers to a substance, usually a liquid, capable of dissolving another substance, e.g., a solid substance, semi-solid substance, or a liquid. Typical solvents include water and organic solvents. It is appreciated by those of skill in the art that the solvent should not chemically react with any of the starting materials or reagents present in the reaction mixture, to any significant degree, under the reaction conditions employed. As used herein, "solvent system" refers to a medium that includes one or more solvents. A solvent system can be homogeneous (miscible solvents) or heterogeneous (e.g., an organic/aqueous system).

As used herein, "reflux" refers to the process of boiling a liquid solvent system in a vessel, for example, a vessel attached to a condenser, so that the vapors of the solvent system continuously condense for reboiling. As used herein, "purifying" refers to the process of ridding a substrate (e.g., crystals, an amorphous solid, a liquid, or an oil) of impurities. Suitable methods of purifying include, for example, filtering, washing, recrystallizing and drying, distilling, and chromatography. As used herein, the terms "isolated" and "purified" refer to substances that are at least about 90% of other agents, for example, at least about 95%, , at least about 98%, or at least about 99% pure by weight.

As used herein, "anhydrous" refers to a substance that contains less than 10 wt.% water, less than about 1 wt.% water, less than about 0.5 wt.% water, less than about 0.1 wt.% water, e.g., or less than about 0.01 wt.% water. "Anhydrous conditions" refer to reaction conditions that have less than 2 wt.% water, e.g. less than about 1 wt.% water, less than about 0.5 wt.% water, less than about 0.1 wt.% water, or less than about 0.01 wt.% water present.

As used herein, "contacting" refers to the act of touching, making contact, or of bringing into immediate proximity. Compounds are typically contacted by forming a solution in a suitable solvent system.

When describing the details of the compounds, compositions, and other limitations, the numerical ranges given herein are those amounts that provide functional results in the composition. Thus, ranges are generally introduced with the term "about" to indicate a certain flexibility in the range. For example, the term "about" can refer to +/- one integer from a given number or the upper or lower limit of range. In other embodiments, the term "about" can refer to +/- two integers from a given number or the upper or lower limit of range. The term "about" can also refer to +/- 20% of a given number or numerical range. In other embodiments, the term "about" can refer to +/- 10%, or +/- 5% of a given number or numerical range. In yet other embodiments, the term "about" refers to +/- 1%. In still other embodiments, the term "about" refers to exactly the given number or numerical range.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

Other features and advantages of the invention will be apparent from the following detailed description, and from the claims.

DESCRIPTION OF DRAWINGS

FIG 1 is a bar graph depicting fold-upregulation of frataxin mRNA expression in human cells after administration of the indicated concentrations of the HDAC3-specific histone deacetylase inhibitor RGFA8.

DETAILED DESCRIPTION

This application provides new HDAC inhibitor compounds, including compounds that specifically inhibit HDAC3 or HDCAl and/or HDAC2. Described herein are compounds of Formulas (I)-(III), methods of making the compounds, and methods of using the compounds to treat certain disorders, e.g., neurological disorders, cancers, inflammatory disorders, and malaria.

HDAC Inhibitor Compounds

In one aspect, the invention features pentane bisamide compounds of Formula (I):

or pharmaceutically acceptable salt thereof; wherein:

R ¹ is selected from H, C ₁ . ₄ alkyl, CM haloalkyl, C ₁ . ₄ alkoxycarbonyl, carbamyl, di-C|. ₄ -alkyl-carbamyl, and C ₁ - ₄ alkylcarbamyl;

Ar ¹ is selected from phenyl, 6-membered heteroaryl, and 5-membered heteroaryl; each of which is substituted by n independently selected R ^y groups; wherein said phenyl, 6- membered heteroaryl, and 5-membered heteroaryl are each further optionally fused to a phenyl ring, which is optionally substituted by 1 or 2 groups independently selected from halogen, hydroxyl, cyano, nitro, C ₁ . ₄ alkyl, CM haloalkyl, CM alkoxy, CM haloalkoxy, amino, Ci _-4 alkylamino, and di-C|. ₄ -alkylamino;

Ar ² is selected from phenyl and 6-membered heteroaryl; wherein said phenyl and 6- membered heteroaryl are each substituted at one ortho position by one J group and are each substituted by m independently selected R ^z groups; J is selected from hydroxyl and amino;

L ¹ is selected from a bond or CM alkylene, when Ar ¹ is an optionally substituted 6- membered heteroaryl or 5-membered heteroaryl; or

L ¹ is a bond, when Ar ¹ is optionally substituted phenyl;

L ² is straight chain C ₅ - Ce alkylene, wherein (i) the straight chain C ₅ - Ce alkylene is optionally substituted by 1 , 2, 3, or 4 independently selected R ^x groups or (ii) one of the carbon atoms of the straight chain C ₅ - Ce alkylene is replaced with -O-, provided that the carbon atom replaced with-O- is not the carbon atom that is directedly attached to C(O)NHAr ² or the carbon atom that is directedly attached to C(O)NR'-L'-Ar'; or

L ² is C4-C ₆ alkenylene, which is optionally substituted by 1, 2, 3, or 4 independently selected R ^x groups; each R ^x is independently selected from halogen, hydroxyl, oxo, cyano, nitro, C1.4 alkyl, C ₁ . ₄ alkoxy, CM haloalkyl, CM haloalkoxy, amino, C1.4 alkylamino, and di-Ct-4- alkylamino; each R ^y is independently selected from halogen, cyano, nitro, C _\ .β alkyl, C ₂ - ₆ alkenyl, C ₂ - ₆ alkynyl, C\.β haloalkyl, C _\ .β alkoxy, Cj.6 haloalkoxy, C1.6 alkoxycarbonyl, C1.6 alkylcarbonyl, carbamyl, C|.β alkylcarbamyl, di-Ci- ₆ alkylcarbamyl, Ci_6 alkylcarbonylamino, Ci- ₆ alkylcarbonyl-(Ci-4-alkyl)amino, Ci_6 alkoxycarbonylamino, di-Ci-6 alkylamino, C3.7 cycloalkyl, C ₂ - ₆ heterocycloalkyl, phenyl, Ci-6 heteroaryl, C ₃ .7 cycloalkyl-Ci-4-alkyl, C2-6 heterocycloalkyl-Ci^-alkyl, phenyl-C|. ₄ -alkyl, and C ₁ . ₆ heteroaryl-Ci- ₄ -alkyl; wherein said Ci- ₆ alkyl, C ₂ . ₆ alkenyl, C ₂ - ₆ alkynyl, Ci_ ₆ haloalkyl, C ₁ . ₆ alkoxy, C _\ .β haloalkoxy, Cj.6 alkoxycarbonyl, C _\ .β alkylcarbonyl, carbamyl, C|. ₆ alkylcarbamyl, di-Ci- ₆ alkylcarbamyl, C\.β alkylcarbonylamino, Cι- ₆ alkylcarbonyl-(Ci-4-alkyl)amino, Ci-6 alkoxycarbonylamino, and di- C|. ₆ alkylamino are each optionally substituted by 1 , 2, or 3 independently selected R ^y groups; and wherein said C ₃ . ₇ cycloalkyl, C ₂ - ₆ heterocycloalkyl, phenyl, Cι_ ₆ heteroaryl, C ₃ .7 cycloalkyl-Ci^-alkyl, C ₂ - ₆ heterocycloalkyl-Ci^-alkyl, phenyl-C|. ₄ -alkyl, and Cι-6 heteroaryl- Cι- ₄ -alkyl are each optionally substituted by 1 , 2, or 3 independently selected R ^y groups; provided that only one of R ^y is selected from optionally substituted C ₃ .7 cycloalkyl, C ₂ - ₆ heterocycloalkyl, phenyl, C|. ₆ heteroaryl, C ₃ . ₇ cycloalkyl-Ci^-alkyl, C ₂ - ₆ heterocycloalkyl-Cj^-alkyl, phenyl-C|. ₄ -alkyl, and Ci- ₆ heteroaryl-Ci.4-alkyl; each R ^z is independently selected from halogen, cyano, nitro, hydroxyl, Ci- ₆ alkyl, C2-

₆ alkenyl, C ₂ - ₆ alkynyl, C|. ₆ haloalkyl, Cι_ ₆ alkoxy, C ₁ . ₆ haloalkoxy, C1.6 alkoxycarbonyl, Cue alkylcarbonyl, carbamyl, C|. ₆ alkylcarbamyl, di-Ci-β alkylcarbamyl, Q. ₆ alkylcarbonylamino, C|. ₆ alkylcarbonyl-(Ci. ₄ -alkyl)amino, C|. ₆ alkoxycarbonylamino, amino, Ci_ ₆ alkylamino, di- Cι- ₆ alkylamino, C ₃ . ₇ cycloalkyl, C ₂ - ₆ heterocycloalkyl, phenyl, and Ci_6 heteroaryl; wherein said Ci- ₆ alkyl, C2- ₆ alkenyl, C _2-6 alkynyl, C\.β haloalkyl, Ci-6 alkoxy, Ci-β haloalkoxy, C|.6 alkoxycarbonyl, Ci_ ₆ alkylcarbonyl, carbamyl, C ₁ . ₆ alkylcarbamyl, di-C|. ₆ alkylcarbamyl, Ci_ ₆ alkylcarbonylamino, C|. ₆ alkylcarbonyl-(Ci.4-alkyl)amino, Ci _-6 alkoxycarbonylamino, Cι_6 alkylamino, and di-Ci- ₆ alkylamino are each optionally substituted by 1, 2, or 3 independently selected R ^z groups; and wherein said C ₃ .7 cycloalkyl,C ₂ - ₆ heterocycloalkyl, phenyl, and Ci-β heteroaryl are each optionally substituted by 1 , 2, or 3 independently selected R ^z groups; provided that only one of R ^z is selected from optionally substituted C ₃ .7 cycloalkyl, optionally substituted C ₂ - ₆ heterocycloalkyl, optionally substituted phenyl, and optionally substituted C 1. ₆ heteroaryl; each R ^y and R ^z is independently selected from hydroxyl, cyano, nitro, C _M alkoxy, C _M haloalkoxy, amino, C ₁ . ₄ alkylamino, and di-C|.4-alkylamino; each R ^y and R ^z is independently selected from halogen, hydroxyl, cyano, nitro, Ci _-4 alkyl, Ci _-4 haloalkyl, C ₁ . ₄ alkoxy, C _M haloalkoxy, amino, Ci _-4 alkylamino, and di-Cι. ₄ - alkylamino; n is an integer selected from 0, 1 , 2, 3, and 4; and m is an integer selected from 0, 1 , 2, and 3; provided that when L ² is straight chain C _O alkylene, then m 1 , 2, and 3, and one occurrence of R ^z is optionally substituted phenyl or optionally substituted Ci _-6 heteroaryl; and provided that the compound is not N'-(2-aminophenyl)-N ⁷ -phenyl-l ,7-heptanedioic acid diamide, N'-(2-aminophenyl)-N ⁷ -p-tolyl-l ,7-heptanedioic acid diamide, N'-(2- aminophenyl)-N ⁷ -o-tolyl-l ,7-heptanedioic acid diamide, N'-(2-aminophenyl)-N ⁷ -(2- methoxyphenyl)-l ,7-heptanedioic acid diamide, N ¹ -(2-aminophenyl)-N ⁷ -(pyridin-2-yl)-l ,7- heptanedioic acid diamide, N'-(2-amino-3-methylphenyl)-N ⁷ -p-tolyl-l ,7-heptanedioic acid diamide, N'-(2-amino-4-methylphenyl)-N ⁷ -p-tolyl-l ,7-heptanedioic acid diamide, N'-(2- amino-4-(trifluoromethyl)phenyl)-N ⁷ -(pyridin-2-yl)-l ,7-heptanedioic acid diamide, N'-(2- amino-5-(thiophen-2-yl)phenyl)-N ⁸ -phenyloctanediamide, or N'-(biphenyl-3-yl)-N ⁸ -(4- hydroxybiphenyl-3-yl)octanediamide.

In some embodiments, it is further provided that the compound is other than Nl -(4- aminobiphenyl-3-yl)-N7-phenylheptanediamide.

In one aspect, the invention features pentane bisamide compounds of Formula (I):

and pharmaceutically acceptable salts, hydrates, and solvates thereof; wherein: R ¹ is selected from H, C ₁ . ₄ alkyl, CM haloalkyl, CM alkoxycarbonyl, carbamyl, di-C|.

₄ -alkyl-carbamyl, and CM alkylcarbamyl;

Ar ¹ is selected from phenyl, 6-membered heteroaryl, and 5-membered heteroaryl; each of which is substituted by n independently selected R ^y groups; and wherein said phenyl, 6-membered heteroaryl, and 5-membered heteroaryl may each be optionally fused to a phenyl ring, which is optionally substituted by 1 or 2 groups independently selected from halogen, hydroxyl, cyano, nitro, CM alkyl, CM haloalkyl, CM alkoxy, Ci _-4 haloalkoxy, amino, CM alkylamino, and di-Cι- ₄ -alkylamino; Ar ² is selected from phenyl and 6-membered heteroaryl; wherein said phenyl and 6- membered heteroaryl are each substituted at one ortho position by one J group and are each substituted by m independently selected R ^z groups;

J is selected from hydroxyl and amino; L ¹ is selected from a bond or CM alkylene, when Ar ¹ is an optionally substituted 6- membered heteroaryl or 5-membered heteroaryl; or

L ¹ is a bond, when Ar ¹ is optionally substituted phenyl;

L ² is a straight chain Cs alkylene, which is optionally substituted by 1 , 2, 3, or 4 independently selected R ^x groups; each R ^x is independently selected from halogen, hydroxyl, cyano, nitro, CM alkyl, C|.

₄ alkoxy, CM haloalkyl, Ci _-4 haloalkoxy, amino, CM alkylamino, and di-Ci-4-alkylamino; each R ^y is independently selected from halogen, cyano, nitro, Ci- ₆ alkyl, C ₂ _6 alkenyl, C ₂ - ₆ alkynyl, Ci- ₆ haloalkyl, Cι_ ₆ alkoxy, Ci- ₆ haloalkoxy, C1.6 alkoxy carbony I, C|.6 alkylcarbonyl, carbamyl, C ₁ . ₆ alkylcarbamyl, di-Ci. ₆ alkylcarbamyl, C ₁ . ₆ alkylcarbonylamino, Ci- ₆ alkylcarbonyl-(Ci- ₄ -alkyl)amino, C _\ .β alkoxycarbonylamino, di-Ci-6 alkylamino, C3-7 cycloalkyl, C ₂ - ₆ heterocycloalkyl, phenyl, Ci_ ₆ heteroaryl, C ₃ . ₇ cycloalkyl-Ci- ₄ -alkyl, C ₂ -6 heterocycloalkyl-Ci- ₄ -alkyl, phenyl-Ci. ₄ -alkyl, and Ci. ₆ heteroaryl-Ci^-alkyl; wherein said Cι- ₆ alkyl, C ₂ - ₆ alkenyl, C ₂ - ₆ alkynyl, C|. ₆ haloalkyl, C ₁ . ₆ alkoxy, C1. ₆ haloalkoxy, Ci.6 alkoxycarbonyl, Ci _-6 alkylcarbonyl, carbamyl, C|. ₆ alkylcarbamyl, di-Ci. ₆ alkylcarbamyl, Cι_6 alkylcarbonylamino, C ₁ . ₆ alkylcarbonyl-(Ci_ ₄ -alkyl)amino, Ci. ₆ alkoxycarbonylamino, and di- Ci- ₆ alkylamino are each optionally substituted by 1 , 2, or 3 independently selected R ^y groups; and wherein said C ₃ . ₇ cycloalkyl, C ₂ - ₆ heterocycloalkyl, phenyl, C|. ₆ heteroaryl, C3.7 cycloalkyl-Ci^-alkyl, C ₂ - ₆ heterocycloalkyl-C _M -alkyl, phenyl-Ci^-alkyl, and C|.6 heteroaryl- Cι- ₄ -alkyl are each optionally substituted by 1 , 2, or 3 independently selected R ^y groups; provided that only one of R ^y is selected from optionally substituted Cj,.η cycloalkyl,

C ₂ - ₆ heterocycloalkyl, phenyl, C|. ₆ heteroaryl, C ₃ . ₇ cycloalkyl-Ci^-alkyl, C ₂ - ₆ heterocycloalkyl-Ci. ₄ -alkyl, phenyl-Cι- ₄ -alkyl, and Ci. ₆ heteroaryl-C| _-4 -alkyl; each R ^z is independently selected from halogen, cyano, nitro, hydroxyl, Ci_6 alkyl, C2. ₆ alkenyl, C ₂ - ₆ alkynyl, Ci. ₆ haloalkyl, Ci-6 alkoxy, C|. ₆ haloalkoxy, d. ₆ alkoxycarbonyl, C1.6 alkylcarbonyl, carbamyl, C _\ .(, alkylcarbamyl, di-Ci. ₆ alkylcarbamyl, Cue alkylcarbonylamino, C|_ ₆ alkylcarbonyl-(Ci. ₄ -alkyl)amino, Ci_ ₆ alkoxycarbonylamino, amino, C ₁ . ₆ alkylamino, di- Cι- ₆ alkylamino, C ₃ .7 cycloalkyl, and C2-6 heterocycloalkyl; wherein said Ci.6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci^ haloalkyl, Cue alkoxy, C ₁ . ₆ haloalkoxy, C1.6 alkoxycarbonyl, Ci-6 alkylcarbonyl, carbamyl, C ₁ . ₆ alkylcarbamyl, di-C|. ₆ alkylcarbamyl, C _\ .β alkylcarbonylamino, Ci-6 alkylcarbonyl-(Ci^-alkyl)amino, Ci-6 alkoxycarbonylamino, Q.6 alkylamino, and di-Ci-β alkylamino are each optionally substituted by 1, 2, or 3 independently selected R ^z groups; and wherein said C3.7 cycloalkyl and C _2-6 heterocycloalkyl are each optionally substituted by 1 , 2, or 3 independently selected R ^z groups; provided that only one of R ^z is selected from optionally substituted C ₃ -7 cycloalkyl and C ₂ .6 heterocycloalkyl; each R ^y and R ^z is independently selected from hydroxyl, cyano, nitro, Ci _-4 alkoxy, Ci-4 haloalkoxy, amino, Ci _-4 alkylamino, and di-C _M -alkylamino; each R ^y and R ^z is independently selected from halogen, hydroxyl, cyano, nitro, Ci _-4 alkyl, Ci _-4 haloalkyl, Ci _-4 alkoxy, Ci _-4 haloalkoxy, amino, Ci _-4 alkylamino, and di-Ci _-4 - alkylamino; n is an integer selected from 0, 1 , 2, 3, and 4; and m is an integer selected from 0, 1 , 2, and 3; provided the compound is not N'-(2-aminophenyl)-N ⁷ -phenyl-l ,7-heptanedioic acid diamide, N'-(2-aminophenyl)-N ⁷ -p-tolyl-l ,7-heptanedioic acid diamide, N'-(2-aminophenyl)- N ⁷ -o-tolyl-l ,7-heptanedioic acid diamide, N ¹ -(2-aminophenyl)-N ⁷ -(2-methoxyphenyl)-l,7- heptanedioic acid diamide, N'-(2-aminophenyl)-N ⁷ -(pyridin-2-yl)-l,7-heptanedioic acid diamide, N'-(2-amino-3-methylphenyl)-N ⁷ -p-tolyl-l ,7-heptanedioic acid diamide, N'-(2- amino-4-methylphenyl)-N ⁷ -p-tolyl-l ,7-heptanedioic acid diamide, or N'-(2-amino-4- (trifluoromethyl)phenyl)-N ⁷ -(pyridin-2-yl)-l ,7-heptanedioic acid diamide.

In some of these compounds, Ar' is not substituted at the ortho position. In some embodiments, when Ar ¹ is substituted at the para position by C ₁ . ₆ alkyl, then Ar ² is substituted by at least one R ^z group. In some embodiments, when Ar ¹ is substituted at the para position by Ci^ alkyl, then Ar ² is substituted by at least one R ^z group selected from halogen. In some embodiments, the following provisos apply: (a) Ar ¹ is not substituted at one ortho position, and (b) when Ar ¹ is substituted at the para position by C ₁ .6 alkyl, then Ar is substituted by at least one R ^z group.

In other of these compounds, each R ^y is independently selected from halogen, cyano, nitro, Ci-6 alkyl, C ₂ -6alkenyl, C ₂ -6alkynyl, Cι_6 haloalkyl, C|.6 alkoxy, Ci.6 haloalkoxy, C3.7 cycloalkyl, C ₂ - ₆ heterocycloalkyl, phenyl, C|.6 heteroaryl, C ₃ . ₇ cycloalkyl-Ci. ₄ -alkyl, C ₂ -6 heterocycloalkyl-C _M -alkyl, phenyl-C _M -alkyl, and Ci. ₆ heteroaryl-Ci. ₄ -alkyl; wherein said C]. 6 alkyl, C ₂ - ₆ alkenyl, C ₂ - ₆ alkynyl, Ci_6 haloalkyl, C ₁ .6 alkoxy, and C ₁ .6 haloalkoxy are each optionally substituted by 1 , 2, or 3 independently selected R ^y groups; and wherein said C3.7 cycloalkyl, C ₂ -6 heterocycloalkyl, phenyl, Ci_6 heteroaryl, C ₃ . ₇ cycloalkyl-C _M -alkyl, C ₂ -6 heterocycloalkyl-C _M -alkyl, phenyl-Ci. ₄ -aIkyl, and Ci-δ heteroaryl-Ci^-alkyl are each optionally substituted by 1, 2, or 3 independently selected R ^y groups; with the proviso that only one of R ^y is selected from optionally substituted C ₃ .7 cycloalkyl, C ₂ -6 heterocycloalkyl, phenyl, C|. ₆ heteroaryl, Cs^ cycloalkyl-C^-alkyl, C^- _ό heterocycloalkyl-Ci^-alkyl, phenyl-C|. ₄ -alkyl, and Ci- _ό heteroaryl-Ci^-alkyl. In some embodiments, each R ^y is independently selected from halogen, cyano, nitro, Ci-β alkyl, Ci.6 haloalkyl, Ci-βalkoxy, Ci.6 haloalkoxy, phenyl, Ci_ ₆ heteroaryl, C ₃ . ₇ cycloalkyl-C _M -alkyl, and C ₂ -6 heterocycloalkyl-Ci- ₄ -alkyl; wherein said Q- ₆ alkyl, C|.6 haloalkyl, Ci.6 alkoxy, and Ci .6 haloalkoxy are each optionally substituted by 1 or 2 independently selected R ^y groups; and wherein said phenyl, Cι_6 heteroaryl, C ₃ . ₇ cycloalkyl-Ci- ₄ -alkyl, and C _2-6 heterocycloalkyl-Ci- ₄ -alkyl are each optionally substituted by 1 or 2 independently selected R ^y groups; provided that only one of R ^y is selected from optionally substituted phenyl, C ₁ -6 heteroaryl, C3.7 Cycloalkyl-Ci.4-alkyl, and C2- 6 heterocycloalkyl-Ci^-alkyl.

In some embodiments, each R ^y is independently selected from halogen, cyano, C ₁ .6 alkyl, C ₁ . ₆ haloalkyl, Ci^alkoxy, C ₁ . ₆ haloalkoxy, Ci_6alkoxycarbonyl, C|_6alkylcarbonyl, carbamyl, Ci. ₆ alkylcarbamyl, di-Ci^ alkylcarbamyl, Ci-βalkylcarbonylamino, Ci_6 alkylcarbonyl-(Ci_ ₄ -alkyl)amino, Ci-β alkoxycarbonylamino, and di-Ci.6alkylamino; wherein said Ci- ₆ alkyl, Ci. ₆ haloalkyl, Ci^ alkoxy, Ci-β haloalkoxy, C]. ₆ alkoxycarbonyl, Q.6 alkylcarbonyl, carbamyl, Ci-βalkylcarbamyl, di-Ci^alkylcarbamyl, Ci^ alkylcarbonylamino, Ci.6 alkylcarbonyl-(C]. ₄ -alkyl)amino, Ci-ό alkoxycarbonylamino, and di-Ci_6alkylamino are each optionally substituted by 1 , 2, or 3 independently selected R ^y groups. In some embodiments, each R ^y is independently selected from halogen, cyano, C|.β alkyl, C ₂ -6 alkenyl, C ₂ - ₆ alkynyl, C|. ₆ haloalkyl, Ci. ₆ alkoxy, C ₁ . ₆ haloalkoxy, and di-C|. ₆ alkylamino; wherein said C ₁ .6 alkyl, C ₂ - ₆ alkenyl, C ₂ -6alkynyl, Cι_6 haloalkyl, Ci-β alkoxy, C ₁ .6 haloalkoxy, and di-Cι-6 alkylamino are each optionally substituted by 1 , 2, or 3 independently selected R ^y groups. In some embodiments, each R ^y is independently selected from halogen, C ₁ .6 alkyl, C ₁ .6 haloalkyl, Ci. ₆ alkoxy, C ₂ - ₆ heterocycloalkyl, phenyl, Ci_6 heteroaryl, and C ₂ -6 heterocycloalkyl-Ci- ₄ -alkyl; wherein said Ci^ alkyl, Ci-β haloalkyl, Ci-βalkoxy, and Ci-6 haloalkoxy are each optionally substituted by a R ^y group; and wherein said phenyl, C1.6 heteroaryl, C ₃ . ₇ cycloalkyl-Ci^-alkyl, and C ₂ .6 heterocycloalkyl-C _M -alkyl are each optionally substituted by a R ^y group; with the proviso that only one of R ^y is selected from optionally substituted phenyl, C ₁ . ₆ heteroaryl, and C ₂ -6 heterocycloalkyl-C|_ ₄ -alkyl.

In further embodiments, each R ^y is independently selected from halogen, cyano, nitro,

Cι-6 alkyl, Ci_6 haloalkyl, C ₁ . ₆ alkoxy, C ι_6 haloalkoxy, C3.7 cycloalkyl, C2-6 heterocycloalkyl, phenyl, and C].β heteroaryl. In some embodiments, each R ^y is independently selected from halogen, cyano, Ci_6 alkyl, Ci _-6 haloalkyl, Ci- ₆ alkoxy, and C|.6 haloalkoxy. In some embodiments, each R ^y is independently selected from halogen, C|. ₆ alkyl, Ci.6 haloalkyl, Cj.6 alkoxy, and Ci. ₆ haloalkoxy. In some embodiments, each R ^y is independently selected from halogen, Ci _-4 alkyl, C] _-4 haloalkyl, Ci _-4 alkoxy, and Ci _-4 haloalkoxy. In some embodiments, each R ^y is independently selected from halogen, C|.β alkyl, and C|.6 haloalkyl. In some embodiments, each R ^y is independently selected from Ci _-6 alkoxy. In some embodiments, each R ^y is independently selected from methoxy. In some embodiments, each R ^y is independently selected from fluoro, methyl, and trifluoromethoxy. In some embodiments, each R ^y is independently selected from fluoro, methyl, trifluoromethyl, methoxy, phenyl, pyridin-4-yl, pyridin-3-yl, piperidinylmethyl, and morpholin-4-yl-methyl; wherein said methyl is optionally substituted by a R ^y group; and wherein said phenyl is optionally substituted by a R ^y group. In some embodiments, each R ^y is phenyl; wherein said phenyl is optionally substituted by a R ^y group. In certain embodiments, each R ^y is independently selected from Ci_6 alkyl and C].6 alkoxy, wherein said C|.6 alkyl and Ci. ₆ alkoxy are each optionally substituted by 1 , 2, or 3 independently selected R ^y groups.

In some of these compounds, each R ^z is independently selected from halogen, cyano, nitro, Ci-6 alkyl, C ₂ -6alkenyl, C ₂ - ₆ alkynyl, Ci-6 haloalkyl, Ci-6 alkoxy, Ci .6 haloalkoxy, C3.7 cycloalkyl, and C ₂ -6heterocycloalkyl; wherein said C|.6 alkyl, C ₂ -6 alkenyl, C _2- 6 alkynyl, Cι_6 haloalkyl, Ci-6 alkoxy, and C ₁ .6 haloalkoxy are each optionally substituted by 1, 2, or 3 independently selected R ^z groups; and wherein said C ₃ . ₇ cycloalkyl and C ₂ - ₆ heterocycloalkyl are each optionally substituted by 1, 2, or 3 independently selected R ^z groups; with the proviso that only one of R ^z is selected from optionally substituted C3.7 cycloalkyl and C2-6 heterocycloalkyl. In some embodiments, each R ^z is independently selected from halogen, cyano, C _h alky!, Ci- 6 haloalkyl, C|.β alkoxy, Ci_6 haloalkoxy, Ci^ alkoxycarbonyl, C|.β alkylcarbonyl, carbamyl, Ci^ alkylcarbamyl, di-Ci^ alkylcarbamyl, Ci^ alkylcarbonylamino, C].6 alkylcarbonyl-(Ci. ₄ -alkyl)amino, Ci-βalkoxycarbonylamino, and di-Ci_6 alkylamino; wherein said C|.β alkyl, Ci^ haloalkyl, Ci^ alkoxy, C ₁ .6 haloalkoxy, Ci-β alkoxycarbonyl, C1.6 alkylcarbonyl, carbamyl, C\.& alky lcarbamyl, di-Cj. ₆ alky lcarbamy 1, Ci-6 alky lcarbony lamino, Ci.6 alkylcarbonyl-(C|. ₄ -alkyl)amino, Ci_ ₆ alkoxycarbonylamino, and di-Ci.6alkylamino are each optionally substituted by 1, 2, or 3 independently selected R ^y groups.

In some embodiments, each R ^z is independently selected from halogen, cyano, nitro,

Ci.6 alkyl, C i-β haloalkyl, Ci-6 alkoxy, Cue haloalkoxy, C ₃ . ₇ cycloalkyl, C _2- 6 heterocycloalkyl, phenyl, and Ci-6 heteroaryl; in which said Ci-β alkyl, Ci-6 haloalkyl, Ci_6 alkoxy, and Ci.6 haloalkoxy are each optionally substituted by 1 or 2 independently selected R ^z groups; and in which said C3.7 cycloalkyl, C ₂ - ₆ heterocycloalkyl, phenyl, and Cj. ₆ heteroaryl are each optionally substituted by 1 , 2, or 3 independently selected R ^z groups. In some embodiments, each R ^z is independently selected from halogen, cyano, nitro,

C|.6 alkyl, Ci.6 haloalkyl, Ci-6 alkoxy, Ci_6 haloalkoxy, phenyl, and Ci.6 heteroaryl; in which said Ci_ ₆ alkyl, Ci_ ₆ haloalkyl, Ci. ₆ alkoxy, and Ci. ₆ haloalkoxy are each optionally substituted by 1 or 2 independently selected R ^z groups; and in which said phenyl and C|.6 heteroaryl are each optionally substituted by 1 , 2, or 3 independently selected R ^z groups. In further embodiments, each R ^z is independently selected from halogen, cyano, nitro,

Q _-6 alkyl, C|-6 haloalkyl, Ci _-6 alkoxy, and C ι_6 haloalkoxy; wherein said C|.β alkyl, C|.β haloalkyl, Cι_6 alkoxy, and Ci_6 haloalkoxy are each optionally substituted by 1 or 2 independently selected R ^z groups. In some embodiments, each R ^z is independently selected from halogen, cyano, nitro, Ci.6 alkyl, Q.6 haloalkyl, Ci-6 alkoxy, C |.6 haloalkoxy, C3-7 cycloalkyl, C _2- 6 heterocycloalkyl, phenyl, and Ci_ ₆ heteroaryl. In some embodiments, each R ^z is independently selected from halogen, cyano, Ci- ₆ alkyl, Ci-6 haloalkyl, Ci_6 alkoxy, and C1.6 haloalkoxy. In some embodiments, each R ^z is independently selected from halogen, C 1.6 alkyl, C ₁ - ₆ haloalkyl, Ci_ ₆ alkoxy, and Q _-6 haloalkoxy. In some embodiments, each R ^z is independently selected from halogen and Ci_6 alkoxy. In some embodiments, each R ^z is independently selected from halogen, C ₁ . ₄ alkyl, C _M haloalkyl, Q. ₄ alkoxy, and C ₁ . ₄ haloalkoxy. In some embodiments, each R ^z is independently selected from halogen, C ₁ -4 alkyl and C ₁ . ₄ alkoxy. In some embodiments, each R ^z is independently selected from C ₁ . ₄ alkyl and C _M alkoxy. In some embodiments, each R ^z is halogen. In some embodiments, each R ^z is independently selected from fluoro, methyl, and methoxy. In some embodiments, each R ^z is fluoro. In some embodiments, each R ^z is selected from halogen and Ci_ ₆ haloalkyl. In some embodiments, each R ^z is selected from halogen and trifluoromethyl. In some embodiments, each R ^z is selected from phenyl and Q.6 heteroaryl, each of which is optionally substituted by 1, 2, or 3 independently selected R ^z groups. In some embodiments, each R ^z is selected from phenyl and C\.β heteroaryl. In certain embodiments, each R ^z is phenyl or phenyl, which is substituted by 1, 2, or 3 independently selected R ^z groups. In certain embodiments, each R ^z is C|.6 heteroaryl or Ci.6 heteroaryl, which is optionally substituted by 1 , 2, or 3 independently selected R ^z groups.

In certain embodiments, m is 1. In embodiments, R ^z is selected from halogen, C|. ₆ alkyl, C\.β haloalkyl, C ₁ .6 alkoxy, and Cue haloalkoxy. In embodiments, R ^z is halogen (e.g., fluoro).

In other embodiments, R ^z is selected from phenyl and Ci_ ₆ heteroaryl, each of which is optionally substituted by 1 , 2, or 3 independently selected R ^z groups. In some embodiments, R ^z is selected from phenyl and C|. ₆ heteroaryl. In certain embodiments, R ^z is phenyl or phenyl, which is substituted by 1 , 2, or 3 independently selected R ^z groups. In certain embodiments, R ^z is Ci_ ₆ heteroaryl or Q. ₆ heteroaryl, which is optionally substituted by 1 , 2, or 3 independently selected R ^z groups.

In some of these compounds, each R ^y and R ^z group is independently selected from hydroxyl, cyano, nitro, Ci _-4 alkoxy, Ci _-4 haloalkoxy, amino, Ci _-4 alkylamino, and di-C _M - alkylamino. In some embodiments, each R ^y and R ^z group is independently selected from hydroxyl, Ci _-4 alkoxy, and Ci _-4 haloalkoxy. In some embodiments, each R ^y and R ^z group is independently selected from hydroxyl, cyano, nitro, Ci _-4 alkoxy, Ci _-4 haloalkoxy, amino, Ci _-4 alkylamino, and di-C]. ₄ -alkylamino. In some embodiments, each R ^y and R ^z group is independently selected from hydroxyl, Ci. ₄ alkoxy, and Ci _-4 haloalkoxy. In some embodiments, each R ^y is hydroxyl; and each R ^y is selected from fluoro and methoxy.

In some embodiments, R ¹ is selected from H, Ci _-4 alkyl, and Ci _-4 haloalkyl. In some embodiments, R ¹ is selected from H and Ci _-4 alkyl. In some embodiments, R ¹ is selected from H and C ₁ - ₃ alkyl. In some embodiments, R ¹ is H. In further embodiments, L ¹ is selected from a bond and Cι_ ₃ alkylene. In some embodiments, L ¹ is selected from a bond and C ₁ . ₂ alkylene. In some embodiments, L ¹ is selected from a bond, methan-l ,l -diyl, and ethan-l ,2-diyl.

In some embodiments, L ² is straight chain C ₅ alkylene, in which (i) the straight chain

C ₅ alkylene is optionally substituted by 1 , 2, 3, or 4 independently selected R" groups or (ii) one of the carbon atoms of the straight chain C ₅ alkylene is replaced with -O-, provided that the carbon atom replaced with-O- is not the carbon atom that is directedly attached to

C(O)NHAr ² or the carbon atom that is directedly attached to C^NR'-L'-Ar ¹ .

In certain embodiments, one of the carbon atoms of the straight chain C ₅ alkylene is replaced with -O-, provided that the carbon atom replaced with-O- is not the carbon atom that is directedly attached to C(O)NHAr ² or the carbon atom that is directedly attached to

C^NR'-L'-Ar ¹ . For example, L ² can be -CH ₂ -CH ₂ -O-CH ₂ -CH ₂ .

In other of these compounds, L ² is straight chain C ₅ alkylene; wherein said straight chain C ₅ alkylene is optionally substituted by 1 , 2, or 3 independently selected R ^x groups. In some embodiments, L ² is straight chain Cs alkylene; wherein said straight chain C ₅ alkylene is optionally substituted by 1 or 2 independently selected R" groups. In some embodiments, L ² is straight chain Cs alkylene; wherein said straight chain Cs alkylene is optionally substituted by a R" group. In some embodiments, L ² is -CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ -.

In some embodiments, L ² is C ₄ -G ₆ alkenylene, which is optionally substituted by 1 , 2, 3, or 4 independently selected R" groups.

In certain embodiments, L ² is straight chain C4.6 alkenylene, which is optionally substituted by 1 , 2, or 3 independently selected R" groups, and which has one double bond.

In some embodiments, L ² is unsubstituted straight chain C4-6 alkenylene. In certain embodiments, L ² is unsubstituted straight chain C4.6 alkenylene having one double bond. For example, L ² is selected from:

||- (CH ₂ )U - CH ₂ - CH=CH -|| and ||- (CH ₂ )i- ₃ - CH=CH - CH ₂ -|| .

In certain embodiments, L ² is ||- (CH ₂ )io — CH ₂ — CH=CH -|| . A non-limiting example of such a compound is:

In other embodiments, L ² is C ₄ alkenylene. For example, L ² can be -CH=CH- CH=CH-. In some embodiments, each R ^x is independently selected from halogen, hydroxyl, C ₁ .4 alkyl, Ci. ₄ alkoxy, Ci _-4 haloalkyl, and Ci. ₄ haloalkoxy. In some embodiments, each R ^x is independently selected from hydroxyl, Ci _-4 alkyl, and C ₁ . ₄ alkoxy. In some embodiments, each R* is independently selected from hydroxyl and C ₁ . ₄ alkyl. In some embodiments, each R ^x is independently selected from CM alkyl. In some embodiments, each R" is independently selected from halogen, hydroxyl, oxo

(double bonded oxygen, i.e., =O), CM alkyl, CM alkoxy, Ci^ haloalkyl, and Ci. ₄ haloalkoxy. In some embodiments, each R ^x is independently selected from hydroxyl, Cu ₄ alkyl, and Ci _-4 alkoxy. In some embodiments, each R ^x is independently selected from hydroxyl and CM alkyl. In some embodiments, each R ^x is independently selected from Ci _-4 alkyl. In embodiments, it is provided that when one (or more) of R ^x is oxo, the oxo group is not attached to the carbon atom that is directedly attached to C(O)NHAr ² or to the carbon atom that is directedly attached to C^NR'-L'-AΓ ¹ .

In further embodiments, J is amino. In some embodiments, J is hydroxyl. In other embodiments, n is an integer selected from 0, 1 , 2, and 3. In some embodiments, n is an integer selected from 0, 1, and 2. In some embodiments, n is an integer selected from 0 and 1. In some embodiments, n is 0. In some embodiments, m is an integer selected from 0, 1 , and 2. In some embodiments, m is an integer selected from 0 and 1. In some embodiments, m is 0. In some embodiments, m is 1.

In some embodiments:

Ar ¹ is 6-membered heteroaryl; which is substituted by n independently selected R ^y groups; and Ar ² is phenyl; which is substituted by m independently selected R ^z groups.

In further embodiments: Ar ¹ is phenyl; which is substituted by n independently selected R ^y groups; Ar ² is 6- membered heteroaryl; which is substituted by m independently selected R ^z groups.

In some embodiments:

Ar ¹ is phenyl; which is substituted by n independently selected R ^y groups; Ar ² is a pyridine ring; which is substituted by m independently selected R ^z groups; and any two R ^y groups, together with the atoms to which they are attached, do not form an optionally substituted phenyl ring.

In other embodiments:

Ar ¹ is pyridine ring; which is substituted by n independently selected R ^y groups; Ar ² is phenyl; which is substituted by m independently selected R ^z groups; and any two R ^y groups, together with the atoms to which they are attached, do not form an optionally substituted phenyl ring.

In further embodiments:

Ar ¹ is selected from 5-membered heteroaryl; which is substituted with n independently selected R ^y groups; and Ar ² is selected from phenyl and 6-membered heteroaryl; wherein said phenyl and 6-membered heteroaryl are each substituted at one ortho position by one J group and by m independently selected R ^z groups.

In some embodiments:

Ar ¹ is 5-membered heteroaryl; which is substituted by n independently selected R ^y groups; and Ar ² is phenyl; which is substituted by m independently selected R ^z groups; or Ar ¹ is 6-membered heteroaryl; which is substituted with n independently selected R ^y groups; and Ar ² is phenyl; wherein said phenyl is substituted at one ortho position by one J group and by m independently selected R ^z groups. In some embodiments, Ar ¹ is 5-membered heteroaryl fused to an optionally substituted phenyl ring; which is substituted by n independently selected R ^y groups. In certain embodiments, Ar ¹ is indolyl or indazolyl, each of which is substituted with n independently selected R ^y groups. In certain embodiments, Ar ¹ is indazolyl, which is substituted with n independently selected R ^y groups.

In embodiments, n is 0.

In other embodiments, n is an integer selected from 1 and 2. In certian embodiments, each occurrence of R ^y is independently selected from Cue alkyl and C\.β alkoxy, wherein said Cι- ₆ alkyl and Cj.6 alkoxy are each optionally substituted by 1, 2, or 3 independently selected R ^y groups.

In some embodiments:

Ar ¹ is 5-membered heteroaryl fused to an optionally substituted phenyl ring; which is substituted by n independently selected R ^y groups; and Ar ² is phenyl; which is substituted by m independently selected R ^z groups.

In some embodiments:

Ar ¹ is selected from 5-membered heteroaryl; which is substituted with n independently selected R ^y groups; and Ar ² is 6-membered heteroaryl; wherein said 6- membered heteroaryl is substituted at one ortho position by one J group and by m independently selected R ^z groups.

In other embodiments:

Ar ¹ is thiazol-2-yl; which is substituted with n independently selected R ^y groups; and Ar ² is pyridin-2-yl; which is substituted at one ortho position by one J group and by m independently selected R ^z groups. In some embodiments:

Ar ¹ is 5-membered heteroaryl; which is substituted with n independently selected R ^y groups; and Ar ² is phenyl; wherein said phenyl is substituted at one ortho position by one J group and by m independently selected R ^z groups.

In further embodiments: Ar ¹ is a thiazole ring; which is substituted with n independently selected R ^y groups; and Ar ² is phenyl; wherein said phenyl is substituted at one ortho position by one J group and by m independently selected R ^z groups.

In some embodiments, the compound is a compound of Formula (If):

or pharmaceutically acceptable salt thereof.

In some embodiments, the compound has Formula (Ie):

or pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula (Ia): or pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula (Ia-I) or (Ia-2):

or pharmaceutically acceptable salt thereof. In further embodiments, the compound is a compound of Formula (Ia-2), or pharmaceutically acceptable salt thereof, wherein: J is hydroxyl; L ² is Cs alkylene; R ¹ is H; each R ^z is phenyl; n is 0; and m is 1. In some embodiments, the compound is a compound of Formula (Ib):

or pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula (Ic):

or pharmaceutically acceptable salt thereof. In further embodiments, the compound is a compound of Formula (Ic), or pharmaceutically acceptable salt thereof, wherein:

J is amino;

L ² is straight chain Cs alkylene;

R ¹ is H; each R ^y is halogen; each R ^z is independently selected from halogen and phenyl; n is 1 ; and m is an integer selected from 1 and 2.

In further embodiments, the compound is a compound of Formula (Ic), or pharmaceutically acceptable salt thereof, wherein:

J is selected from amino and hydroxy!;

L ² is selected from straight chain C ₅ alkylene, which is optionally substituted by 1 , 2, 3, or 4 independently selected R ^x groups; R ¹ is selected from H, C ₁ . ₄ alkyl, and C ₁ . ₄ haloalkyl; each R ^y is independently selected from halogen, cyano, nitro, C ₁ . ₆ alkyl, Ci_ ₆ haloalkyl, Ci_ ₆ alkoxy, Ci- _ό haloalkoxy, C ₃ . ₇ cycloalkyl, C ₂ - ₆ heterocycloalkyl, phenyl, and Ci. ₆ heteroaryl; each R ^z is independently selected from halogen, cyano, nitro, C ₁ . ₆ alkyl, Ci- ₆ haloalkyl, C ₂ - ₆ alkenyl, C ₂ - ₆ alkynyl, C1.6 alkoxy, Ci-6 haloalkoxy, C3-7 cycloalkyl, C ₂ - ₆ heterocycloalkyl, phenyl, and Ci_ ₆ heteroaryl; each R" is independently selected from halogen, hydroxy 1, cyano, nitro, Ci _-4 alkyl, Ci.4 alkoxy, Ci _-4 haloalkyl, Ci _-4 haloalkoxy, amino, Ci _-4 alkylamino, and di-C| _-4 - alkylamino; n is an integer selected from 0, 1 , 2, and 3; and m is an integer selected from 0, 1 , and 2.

In other embodiments, the compound is a compound of Formula (Ic), or pharmaceutically acceptable salt thereof, wherein: J is amino and hydroxyl;

L ² is selected from Cs alkylene, which is optionally substituted by 1, 2, or 3 independently selected R* groups;

R ¹ is selected from H and Ci _-4 alkyl; each R ^y is independently selected from halogen, cyano, Ci. ₆ alkyl, Ci_6 haloalkyl, Ci.β alkoxy, and Ci. ₆ haloalkoxy; each R ^z is independently selected from halogen, cyano, Ci _-O alkyl, Ci.6 haloalkyl, Ci_ ₆ alkoxy, and Ci_ ₆ haloalkoxy; each R ^x is independently selected from halogen, hydroxyl, Ci _-4 alkyl, Ci _-4 alkoxy, Ci _-4 haloalkyl, and Ci-4 haloalkoxy; n is an integer selected from 0, 1, and 2; and m is an integer selected from 0, 1, and 2. In some embodiments, the compound is a compound of Formula (Ic), or pharmaceutically acceptable salt thereof, wherein: J is amino;

L ² is selected from C ₅ alkylene, which is optionally substituted by 1 or 2 independently selected R ^x groups; R ¹ is selected from H and C ₁ - ₃ alkyl; each R ^y is independently selected from halogen, Ci _-4 alkyl, Ci _-4 haloalkyl, Ci _-4 alkoxy, and Ci _-4 haloalkoxy; each R ^z is independently selected from halogen, Ci _-4 alkyl, Ci _-4 haloalkyl, CM alkoxy, and Ci _-4 haloalkoxy; each R ^x is independently selected from hydroxyl, Ci _-4 alkyl, and Ci _-4 alkoxy; n is an integer selected from 0, 1 , and 2; and m is an integer selected from 0, 1 , and 2. In further embodiments, the compound is a compound of Formula (Ic), or pharmaceutically acceptable salt thereof, wherein: J is amino;

L ² is selected from C ₅ alkylene, which is optionally substituted by 1 or 2 independently selected R* groups;

R ¹ is selected from H; each R ^y is independently selected from halogen, Ci^alkyl, C|-4 haloalkyl, CM alkoxy, and Ci.4 haloalkoxy; each R ^z is independently selected from halogen, CM alkyl, Q _-4 haloalkyl, CM alkoxy, and Ci.4 haloalkoxy; each R ^x is independently selected from hydroxyl and Ci. ₄ alkyl; n is an integer selected from 0, 1, and 2; and m is an integer selected from 0, 1 , and 2.

In other embodiments, the compound is a compound of Formula (Ic), or pharmaceutically acceptable salt thereof, wherein:

J is amino; L ² is -CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ -.

R ¹ is selected from H; each R ^y is independently selected from halogen, C^ alkyl, and Ci _-4 haloalkoxy; each R ^z is independently selected from halogen, Q^ alkyl, and CM alkoxy; n is an integer selected from 0, 1 , and 2; and m is an integer selected from 0 and 1.

In some embodiments, the compound is a compound of Formula (Ic), or pharmaceutically acceptable salt thereof, wherein:

J is amino; L ² is -CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ -.

R ¹ is selected from H; each R ^y is independently selected from fluoro, methyl, and trifluoromethoxy; each R ^z is independently selected from fluoro, methyl, and methoxy; n is an integer selected from 0, 1 , and 2; and m is an integer selected from 0 and 1.

In further embodiments, the compound has Formula (Ic), provided that Ar ² is substituted at the para position by halogen; or Ar ² is substituted at the meta position by C|. ₆ alkyl or Ci- ₆ alkoxy; or Ar ¹ is substituted at the ortho position by haloalkoxy. In other embodiments, the compound has Formula (Ic), provided that Ar ² is substituted at the para position by fluoro; or Ar ² is substituted at the meta position by methyl or methoxy; or Ar ¹ is substituted at the ortho position by trifluoromethoxy.

In embodiments where the compound has Formula (Ic) as described above, the following definitions of R ^z can also apply.

Each R ^z is independently selected from halogen, cyano, nitro, Ci-6 alkyl, C\.β haloalkyl, Cι_ ₆ alkoxy, Ci-β haloalkoxy, C ₃ _ ₇ cycloalkyl, C ₂ - ₆ heterocycloalkyl, phenyl, and Ci. 6 heteroaryl; in which said Ci-β alkyl, Ci.6 haloalkyl, C).6 alkoxy, and Ci-ό haloalkoxy are each optionally substituted by 1 or 2 independently selected R ^z groups; and in which said C3-7 cycloalkyl, C ₂ - ₆ heterocycloalkyl, phenyl, and C|.6 heteroaryl are each optionally substituted by 1 , 2, or 3 independently selected R ^z groups.

Each R ^z is independently selected from halogen, cyano, nitro, C _h alky!, C|.6 haloalkyl, Ci_ ₆ alkoxy, Ci-ό haloalkoxy, phenyl, and Ci _-6 heteroaryl; in which said Ci-βalkyl, C|_ ₆ haloalkyl, C ₁ . ₆ alkoxy, and Ci. ₆ haloalkoxy are each optionally substituted by 1 or 2 independently selected R ^z groups; and in which said phenyl and C1.6 heteroaryl are each optionally substituted by 1 , 2, or 3 independently selected R ^z groups.

Each R ^z is selected from phenyl and C|.6 heteroaryl, each of which is optionally substituted by 1, 2, or 3 independently selected R ^z groups. Each R ^z is selected from phenyl and Ci-6 heteroaryl. Each R ^z is phenyl or phenyl, which is substituted by 1, 2, or 3 independently selected R ^z groups. Each R ^z is Ci_6 heteroaryl or Cj.6 heteroaryl, which is optionally substituted by 1 , 2, or 3 independently selected R ^z groups.

In some embodiments:

Ar ² is selected from phenyl; which is substituted at one ortho position by one J group and by m independently selected R ^z groups; L ² is:

(i) straight chain C5 alkylene; or

(ii) optionally substituted straight chain C^ alkenylene (e.g., L ² is unsubstituted straight chain G^ alkenylene having one double bond; e.g., L ² is \[ (CH ₂ ) _I o — CH ₂ — CH=CH -II);

J is amino;

R ^z or one R ^z is selected from phenyl and C|.β heteroaryl, each of which is optionally substituted by 1, 2, or 3 independently selected R ^z groups, and attached to the meta position

(i.e., para to J); and m is 1 and 2.

In certain embodiments:

Ar ² is selected from phenyl; which is substituted at one ortho position by one J group and by m independently selected R ^z groups;

L ² is straight chain C5 alkylene;

J is amino;

R ^z or one R ^z is selected from phenyl and Cι-β heteroaryl, each of which is optionally substituted by 1 , 2, or 3 independently selected R ^z groups, and attached to the meta position (i.e., para to J); and m is 1 and 2.

In embodiments, R ^z or one R ^z is selected from phenyl optionally substituted by 1 , 2, or 3 independently selected R ^z groups, and attached to the meta position (i.e., para to J).

In embodiments, R ^z or one R ^z is Q. ₆ heteroaryl, each of which is optionally substituted by 1, 2, or 3 independently selected R ^z groups, and attached to the meta position (i.e., para to J).

For example, the compound of formula (I) can be:

In certain embodiments: Ar ² is selected from phenyl; which is substituted at one ortho position by one J group and by m independently selected R ^z groups;

L ² is optionally substituted straight chain C ₄ . ₆ alkenylene (e.g., L is unsubstituted straight chain C ₄ . ₆ alkenylene having one double bond; e.g., L ² is ||- (CH ₂ )Io — CH ₂ — CH=CH | ); J is amino;

R ^z or one R ^z is selected from phenyl and Cι_ ₆ heteroaryl, each of which is optionally substituted by 1 , 2, or 3 independently selected R ^z groups, and attached to the meta position (i.e., para to J); and m is 1 and 2. In embodiments, R ^z or one R ^z is selected from phenyl optionally substituted by 1 , 2, or 3 independently selected R ^z groups, and attached to the meta position (i.e., para to J).

In embodiments, R ^z or one R ^z is Ci. ₆ heteroaryl, each of which is optionally substituted by 1 , 2, or 3 independently selected R ^z groups, and attached to the meta position (i.e., para to J).

For example, the compound of formula (I) can be:

In some embodiments, the compound is a compound of Formula (Id):

or pharmaceutically acceptable salt thereof, wherein: R ^2p is selected from H, halogen, and Cue alkyl; each R ² ° is independently selected from H, halogen, and C|. ₆ haloalkoxy; R ^{l m} is selected from H, C _\ .β alkyl and Ci_ ₆ alkoxy; R ^{l p} is selected from H and halogen; and

L ² is -CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ -.

In further embodiments, the compound is a compound of Formula (Id), or pharmaceutically acceptable salt thereof, wherein:

R ^2p is selected from H, fluoro, and methyl; each R ² ° is independently selected from H and trifluoromethoxy;

R ^lm is selected from H, methyl and methoxy; R ^lp is selected from H and fluoro; and L ² is -CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ -.

In further embodiments, the compound is a compound of Formula (Id), or pharmaceutically acceptable salt thereof, wherein: R ^2p is fluoro; each R ²⁰ is H;

R ^lm is H or R ^z as defined above in conjunction with formula (Ic); R ^lp is selected from H, phenyl, fluoro; and L ² is -CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ -.

In other embodiments, the compound is a compound of Formula (Ia-I), (Ia-2), or (Ib), or pharmaceutically acceptable salt thereof, wherein: J is selected from amino and hydroxyl;

L ² is selected from C ₅ alkylene, which is optionally substituted by 1 or 2 independently selected R ^x groups;

R ¹ is selected from H and C ₁ -4 alkyl; each R ^z is independently selected from halogen, cyano, Ci_ ₆ alkyl, Cι_6 haloalkyl, C|. ₆ alkoxy, and Ci.6 haloalkoxy; each R ^y is independently selected from halogen, cyano, Ci _-6 alkyl, Ci _-6 haloalkyl, C ₁ . ₆ alkoxy, and Cj.6 haloalkoxy; each R ^x is independently selected from halogen, hydroxyl, Ci _-4 alkyl, Ci _-4 alkoxy, Ci _-4 haloalkyl, and Ci _-4 haloalkoxy; n is an integer selected from 0, 1, 2, and 3; and m is an integer selected from 0, 1, and 2. In some embodiments, the compound is a compound of Formula (Ia-I), (Ia-2), or

(Ib), or pharmaceutically acceptable salt thereof, wherein: J is selected from amino; L ² is -CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ -; R ¹ is selected from H; each R ^z is independently selected from halogen, C ₁ . ₆ alkyl, C|. ₆ haloalkyl, Ci-6 alkoxy, and Ci _-6 haloalkoxy; each R ^y is independently selected from halogen, C ₁ . ₆ alkyl, Ci _-6 haloalkyl, Ci_ ₆ alkoxy, and Ci _-6 haloalkoxy; n is an integer selected from 0, 1 , and 2; and m is an integer selected from 0 and 1.

In further embodiments, the compound is a compound of Formula (Ia-I), (Ia-2), or (Ib), or or pharmaceutically acceptable salt thereof, wherein: J is selected from amino;

L ² is -CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ -; R ¹ is selected from H; each R ^z is independently selected from halogen; each R ^y is independently selected Ci-6 alkoxy; n is an integer selected from 0, 1, and 2; and m is an integer selected from 0 and 1.

In other embodiments, the compound has Formula (Ia-I), (Ia-2), or (Ib), provided that Ar ² is substituted at the para position by halogen; or Ar ¹ is substituted at one ortho position by Ci_ ₆ alkoxy; or Ar ¹ is substituted at one para position by Cι_6 alkoxy.

In further embodiments, the compound has Formula (Ia-I), (Ia-2), or (Ib), provided that Ar ² is substituted at the para position by halogen.

In embodiments where the compound has Formula (Ia-I), (Ia-2), or (Ib) as described above, R ^z can also be as defined in conjunction with formula (Ic). In some embodiments:

Ar ¹ is 5-membered heteroaryl; which is substituted with n independently selected R ^y groups; wherein said or 5-membered heteroaryl may be optionally fused to a phenyl ring; which is optionally substituted by 1 or 2 groups selected from halogen, hydroxyl, cyano, nitro, C _h alky], Ci _-4 haloalkyl, Ci _-4 alkoxy, C|. ₄ haloalkoxy, amino, C| _-4 alkylamino, and di-Cι- ₄ -alkylamino;

Ar ² is phenyl; wherein said phenyl is substituted at one ortho position by one J group and by m independently selected R ^z groups;

J is selected from amino and hydroxyl; R ¹ is selected from H, Ci _-4 alkyl, and Ci _-4 haloalkyl; L ¹ is selected from a bond and Ci _-4 alkylene;

L ² is straight chain C5 alkylene; wherein said straight chain C5 alkylene is optionally substituted by 1, 2, 3, or 4 independently selected R ^x groups; each R ^x is independently selected from halogen, hydroxyl, cyano, nitro, Ci _-4 alkyl, Ci _-4 alkoxy, Ci _-4 haloalkyl, Ci _-4 haloalkoxy, amino, Ci _-4 alkylamino, and di-Ci. ₄ - alkylamino; each R ^y is independently selected from halogen, cyano, nitro, C1.6 alkyl, C2-6 alkenyl, C ₂ - ₆ alkynyl, Ci . ₆ haloalkyl, Ci.6alkoxy, Ci^ haloalkoxy, C ₃ _ ₇ cycloalkyl, C ₂ -6 heterocycloalkyl, phenyl, Ci_ ₆ heteroaryl, C3-7cycloalkyl-Ci. ₄ -alkyl, C ₂ -6 heterocycloalkyl-Ci. 4-alkyl, phenyl-C^-alkyl, and Ci-ό heteroaryl-Ci^-alkyl; wherein said C ₁ .6 alkyl, C ₂ .6 alkenyl, C2-6alkynyl, C|. ₆ haloalkyl, C|.6 alkoxy, and Cuό haloalkoxy are each optionally substituted by 1 , 2, or 3 independently selected R ^y groups; and wherein said C3.7 cycloalkyl, C ₂ -6 heterocycloalkyl, phenyl, Ci- ₆ heteroaryl, C ₃ - ₇ cycloalkyl-C _M -alkyl, C ₂ - ₆ heterocycloalkyl-Ci. ₄ -alkyl, phenyl-C|_ ₄ -alkyl, and Ci-β heteroaryl-Ci^-alkyl are each optionally substituted by 1 , 2, or 3 independently selected R ^y groups; provided that only one of R ^y is selected from optionally substituted C ₃ . ₇ cycloalkyl, C _2-O heterocycloalkyl, phenyl, Ci. ₆ heteroaryl, C ₃ - ₇ cycloalkyl-Ci- ₄ -alkyl, C ₂ -6 heterocycloalkyl-Ci^-alkyl, phenyl-Ci. ₄ -alkyl, and C]. ₆ heteroaryl-C|.4-alkyl; each R ^z is independently selected from halogen, cyano, nitro, Ci^ alkyl, C2-6 alkenyl, C ₂ - ₆ alkynyl, C|. ₆ haloalkyl, C|. ₆ alkoxy, Ci- _ό haloalkoxy, 0 ₃ . ₇ cycloalkyl, and C2-6 heterocycloalkyl; wherein said Ci. ₆ alkyl, C ₂ - ₆ alkenyl, C ₂ - ₆ alkynyl, Ci-6 haloalkyl, C|.β alkoxy, and Ci-β haloalkoxy are each optionally substituted by 1 , 2, or 3 independently selected R ^z groups; and wherein said €3.7 cycloalkyl and C ₂ -6 heterocycloalkyl are each optionally substituted by 1, 2, or 3 independently selected R ^z groups; provided that only one of R ^z is selected from optionally substituted C3.7 cycloalkyl and C ₂ - ₆ heterocycloalkyl; each R ^y and R ^z group is independently selected from hydroxyl, cyano, nitro,

Ci- ₄ alkoxy, Ci. ₄ haloalkoxy, amino, CM alky lam ino, and di-Ci. ₄ -alkylamino; each R ^y and R ^z group is independently selected from halogen, hydroxyl, cyano, nitro, C _h alky I, Ci. ₄ haloalkyl, Ci _-4 alkoxy, Ci^ haloalkoxy, amino, Ci^ alkylamino, and di-Ci-4-alkylamino; n is an integer selected from 0, 1 , 2, 3, and 4; and m is an integer selected from 0, 1, 2, and 3. In other embodiments:

Ar ¹ is 5-membered heteroaryl; which is substituted with n independently selected R ^y groups; wherein said or 5-membered heteroaryl may be optionally fused to a phenyl ring;

Ar ² is phenyl; wherein said phenyl is substituted at one ortho position by one J group and by m independently selected R ^z groups;

J is selected from amino and hydroxyl; R ¹ is selected from H, CM alkyl, and CM haloalkyl; L ¹ is selected from a bond and C ₁ . ₃ alkylene;

L ² is straight chain C ₅ alkylene; wherein said straight chain C ₅ alkylene is optionally substituted by 1 , 2, or 3 independently selected R ^x groups; each R ^x is independently selected from halogen, hydroxyl, cyano, CM alkyl,

Cι- ₄ alkoxy, CM haloalkyl, and Ci.4 haloalkoxy; each R ^y is independently selected from halogen, cyano, nitro, C|.β alkyl, Cι-6 haloalkyl, Q. ₆ alkoxy, Ci . ₆ haloalkoxy, phenyl, Ci- ₆ heteroaryl, C ₃ . ₇ Cycloalkyl-C|. ₄ -alkyl, and C ₂ - ₆ heterocycloalkyl-Ci. ₄ -alkyl; wherein said C|. ₆ alkyl, Ci _-6 haloalkyl, Ci. ₆ alkoxy, and C|.6 haloalkoxy are each optionally substituted by 1 or 2 independently selected R ^y groups; and wherein said phenyl, Ci _-6 heteroaryl, Cs.ycycloalkyl-C _M -alkyl, and C ₂ - ₆ heterocycloalkyl-Ci_ ₄ -alkyl are each optionally substituted by 1 or 2 independently selected R ^y groups; provided that only one of R ^y is selected from optionally substituted phenyl, Ci. ₆ heteroaryl, C ₃ . ₇ cycloalkyl-Ci _-4 -alkyl, and C ₂ - ₆ heterocycloalkyl-Ci.4-alkyl; each R ^z is independently selected from halogen, cyano, nitro, C|. ₆ alkyl, Ci_6 haloalkyl, Ci_ ₆ alkoxy, and Ci_ ₆ haloalkoxy; wherein said Ci. ₆ alkyl, C).6 haloalkyl, C|.6 alkoxy, and C|. ₆ haloalkoxy are each optionally substituted by 1 or 2 independently selected R ^z groups; each R ^y and R ^z group is independently selected from hydroxyl, Ci _-4 alkoxy, and Ci _-4 haloalkoxy; each R ^y and R ^z group is independently selected from halogen, hydroxyl, C1.4 alkyl, Ci _-4 haloalkyl, Ci _-4 alkoxy, and Ci _-4 haloalkoxy; n is an integer selected from 0, 1, 2, and 3; and m is an integer selected from 0, 1 , and 2. In some embodiments: Ar ¹ is 5-membered heteroaryl; which is substituted with n independently selected R ^y groups; wherein said or 5-membered heteroaryl may be optionally fused to a phenyl ring;

Ar ² is phenyl; wherein said phenyl is substituted at one ortho position by one J group and by m independently selected R ^z groups; J is selected from amino;

R ¹ is H;

L ¹ is selected from a bond and Ci _-2 alkylene;

L ² is straight chain C ₅ alkylene; wherein said straight chain C ₅ alkylene is optionally substituted by 1 or 2 independently selected R ^x groups; each R ^x is independently selected from Ci _-4 alkyl and Ci _-4 alkoxy; each R ^y is independently selected from halogen, C|. ₆ alkyl, Ci_ ₆ haloalkyl, C|. ₆ alkoxy, C ₂ - ₆ heterocycloalkyl, phenyl, C ₁ . ₆ heteroaryl, and C ₂ - ₆ heterocycloalkyl-Ci _-4 -alkyl; wherein said Ci_6 alkyl, Ci- ₆ haloalkyl, Cι_6 alkoxy, and C i_ ₆ haloalkoxy are each optionally substituted by a R ^y group; and wherein said phenyl, Ci-β heteroaryl, C ₃ . ₇ cycloalkyl-C ₁ .4- alkyl, and C2-6 heterocycloalkyl-Ci- ₄ -alkyl are each optionally substituted by a R ^y group; provided that only one of R ^y is selected from optionally substituted phenyl, C|. β heteroaryl, and C ₂ - ₆ heterocycloalkyl-C|. ₄ -alkyl; R ^z is selected from halogen and C ₁ . ₆ haloalkyl;

R ^y is hydroxyl;

R ^y is selected from halogen and CM alkoxy; n is an integer selected from 0, 1, and 2; and m is an integer selected from 0, 1 , and 2. In further embodiments, L ¹ is a bond. In some embodiments, L ¹ is Ci. ₂ alkylene.

In other embodiments:

Ar ¹ is a thiazole ring; which is optionally substituted with 1 or 2 independently selected R ^y groups; and

L ¹ is a bond. In some embodiments:

Ar ¹ is selected from a thiazole ring, an imidazole ring, an oxazole ring, and a thiophene ring; each of which is substituted with n independently selected R ^y groups; wherein said thiazole ring, imidazole ring, oxazole ring, and thiophene ring are each optionally fused to a phenyl ring. Ar ² is phenyl; wherein said phenyl is substituted at one ortho position by one J group and by m independently selected R ^z groups; J is selected from amino; R ¹ is H;

L ¹ is selected from a bond, methan-l,l-diyl, and ethan-l ,2-diyl; L ² is -CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ -; each R ^y is independently selected from halogen, Ci^alkyl, C|.β haloalkyl, C|.6 alkoxy, C _2-6 heterocycloalkyl, phenyl, Ci^ heteroaryl, and C ₂ - ₆ heterocycloalkyl-Ci- ₄ -alkyl; wherein said Ci^ alkyl, Ci- ₆ haloalkyl, Ci_ ₆ alkoxy, and Ci-β haloalkoxy are each optionally substituted by a R ^y group; and wherein said phenyl, C|.6 heteroaryl, C ₃ .7 cycloalkyl-C1.4- alkyl, and C ₂ . ₆ heterocycloalkyl-C|. ₄ -alkyl are each optionally substituted by a R ^y group; with the proviso that only one of R ^y is selected from optionally substituted phenyl, C|. ₆ heteroaryl, and C ₂ - ₆ heterocycloalkyl-Ci_4-alkyl; R ^z is selected from halogen and Cue haloalkyl;

R ^y is hydroxyl; R ^y is selected from halogen and d^ alkoxy; n is an integer selected from 0, 1, and 2; and m is an integer selected from 0, 1 , and 2. In further embodiments: Ar ¹ is selected from thiazol-2-yl, imidazol-2-yl, imidazol-4-yl, oxazol-2-yl, and thiophen-2-yl; each of which is substituted with n independently selected R ^y groups; and wherein said -2-yl, imidazol-2-yl, imidazol-4-yl, oxazol-2-yl, and thiophen-2-yl may each be optionally fused to a phenyl ring;

Ar ² is phenyl; wherein said phenyl is substituted at one ortho position by one J group and by m independently selected R ^z groups; J is selected from amino; R ¹ is selected from H;

L ¹ is selected from a bond, methan-l ,l-diyl, and ethan-l,2-diyl; L ² is -CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ -; each R ^y is independently selected from fluoro, methyl, trifluoromethyl, methoxy, phenyl, pyridin-4-yl, pyridin-3-yl, piperidinylmethyl, and morpholin-4-yl-methyl; wherein said methyl is optionally substituted by a R ^y group; and wherein said phenyl is optionally substituted by a R ^y group; with the proviso that only one of R ^y is selected from optionally substituted phenyl, pyridin-4-yl, pyridin-3-yl, piperidinylmethyl, and morpholin-4-yl-methyl; R ^z is selected from halogen and trifluoromethyl; R ^y is hydroxy I;

R ^y is selected from fluoro and methoxy; n is an integer selected from 0, 1 , and 2; and m is an integer selected from 0, 1, and 2.

In other embodiments:

Ar ¹ is selected from 5-membered heteroaryl; which is substituted with n independently selected R ^y groups;

Ar ² is 6-membered heteroaryl; wherein said 6-membered heteroaryl is substituted at one ortho position by one J group and by m independently selected R ^z groups; J is selected from amino and hydroxyl; R ¹ is selected from H, C ₁ . ₄ alkyl, and CM haloalkyl; L ¹ is selected from a bond; L ² is straight chain Cs alkylene; wherein said straight chain Cs alkylene is optionally substituted by 1 , 2, or 3 independently selected R ^x groups; each R ^x is independently selected from halogen, hydroxyl, cyano, CM alky 1, C|. ₄ alkoxy, Ci. ₄ haloalkyl, and Ci_ ₄ haloalkoxy; each R ^y is independently selected from halogen, cyano, nitro, Q. ₆ alkyl, Ci_6 haloalkyl, Ci- ₆ alkoxy, Cι- ₆ haloalkoxy, phenyl, Ci. ₆ heteroaryl, C ₃ . ₇ cycloalkyl-C|. ₄ -alkyl, and C ₂ - ₆ heterocycloalkyl-C|. ₄ -alkyl; wherein said Q. ₆ alkyl, Cι- ₆ haloalkyl, Ci. ₆ alkoxy, and Ci-6 haloalkoxy are each optionally substituted by 1 or 2 independently selected R ^y groups; and wherein said phenyl, Ci. ₆ heteroaryl, C ₃ . ₇ cycloalkyl-Ci. ₄ -alkyl, and C ₂ - ₆ heterocycloalkyl-Ci_ ₄ -alkyl are each optionally substituted by 1 or 2 independently selected R ^y groups; with the proviso that only one of R ^y is selected from optionally substituted phenyl, Ci_ ₆ heteroaryl, C ₃ . ₇ cycloalkyl-Ci_ ₄ -alkyl, and C ₂ - ₆ heterocycloalkyl-Ci. ₄ -alkyl; each R ^z is independently selected from halogen, cyano, nitro, Ci. ₆ alkyl, Ci_6 haloalkyl, C|.β alkoxy, and C |. ₆ haloalkoxy; wherein said C _h alky], Ci _-6 haloalkyl, Ci. ₆ alkoxy, and Ci _-6 haloalkoxy are each optionally substituted by 1 or 2 independently selected R ^z groups; each R ^y and R ^z group is independently selected from hydroxyl, C ₁ . ₄ alkoxy, and Ci- ₄ haloalkoxy; each R ^y and R ^z group is independently selected from halogen, hydroxyl, C1.4 alkyl, CM haloalkyl, CM alkoxy, and CM haloalkoxy; n is an integer selected from 0, 1, and 2; and m is an integer selected from 0, 1, and 2. In some embodiments:

Ar ¹ is selected from 5-membered heteroaryl; which is substituted with n independently selected R ^y groups;

Ar ² is 6-membered heteroaryl; wherein said 6-membered heteroaryl is substituted at one ortho position by one J group and by m independently selected R ^z groups; J is selected from amino; R ¹ is H; L ¹ is a bond;

L ² is straight chain C ₅ alkylene; wherein said straight chain C ₅ alkylene is optionally substituted by 1 or 2 independently selected R ^x groups; each R ^x is independently selected from CM alkyl and Ci _-4 alkoxy; each R ^y is independently selected from halogen, C|-6 alkyl, Ci^ haloalkyl, C\.β alkoxy, C ₂ - ₆ heterocycloalkyl, phenyl, C i_ ₆ heteroaryl, and C2-6 heterocycloalkyl-Ci.4-alkyl; wherein said C _h alky!, Ci _-6 haloalkyl, C|. ₆ alkoxy, and Ci-β haloalkoxy are each optionally substituted by a R ^y group; and wherein said phenyl, Ci_ ₆ heteroaryl, C ₃ .7 cycloalkyl-Ci.4- alkyl, and C ₂ - ₆ heterocycloalkyl-C _M -alkyl are each optionally substituted by a R ^y group; with the proviso that only one of R ^y is selected from optionally substituted phenyl, C ₁ . ₆ heteroaryl, and C ₂ - ₆ heterocycloalkyl-Ci_ ₄ -alkyl; R ^z is selected from halogen and Ci_ ₆ haloalkyl; R ^y is hydroxyl; R ^y is selected from halogen and Ci- ₄ alkoxy; n is an integer selected from 0, 1, and 2; and m is an integer selected from 0, 1 , and 2. In further embodiments:

Ar ¹ is selected from a thiazol-2-yl ring; which is substituted with n independently selected R ^y group;

Ar ² is pyridin-2-yl; wherein said phenyl is substituted at one ortho position by one J group and by m independently selected R ^z groups; J is selected from amino; R ¹ is H; L ¹ is a bond;

L ² is -CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ -; each R ^y is phenyl; wherein said phenyl is optionally substituted by a R ^y group;

R ^y is selected from CM alkoxy; n is an integer selected from 0 and 1 ; and m is an integer selected from 0, 1 , and 2. In some embodiments, the compound is:

N'-(2-amino-4-fluorophenyl)-N ⁷ -p-tolyl-l ,7-heptanedioic acid diamide; N'-(2-amino-5-fluorophenyl)-N ⁷ -p-tolyl-l ,7-heptanedioic acid diamide; N'-(2-amino-5-methylphenyl)-N ⁷ -p-tolyl-l,7-heptanedioic acid diamide;

N ^l -(2-amino-5-methoxyphenyl)-N ⁷ -p-tolyl-l ,7-heptanedioic acid diamide; N'-(2-amino-4-fluorophenyl)-N ⁷ -(4-fluorophenyl)-l,7-heptanedioic acid diamide; N'-(2-amino-5-fluorophenyl)-N ⁷ -(4-fluorophenyl)-l ,7-rieptanedioic acid diamide;

N'-(2-aminophenyl)-N ⁷ -(4-fluorophenyl)-l,7-heptanedioic acid diamide; N'-(2-aminophenyl)-N ⁷ -(2-(trifluoromethoxy)phenyl)-l,7-heptanedioic acid diamide;

N ¹ -(2-amino-4-fluorophenyl)-N ⁷ -(4-methylthiazol-2-yl)-l,7-heptanedioic acid diamide;

N'-(2-aminophenyl)-N ⁷ -(5-methylthiazol-2-yl)-l ,7-heptanedioic acid diamide; N'-(2-amino-4-fluorophenyl)-N ⁷ -(benzo[d]thiazol-2-yl)-l,7-heptanedioic acid diamide;

N ^l -(2-amino-4-fluorophenyl)-N ⁷ -(2,6-dimethoxypyridin-3-yl)-l ,7-heptanedioic acid diamide;

N'-(2-aminophenyl)-N ⁷ -(2,6-dimethoxypyridin-3-yl)-l ,7-heptanedioic acid diamide; N ^l -(2-amino-4-fluorophenyl)-N ⁷ -(pyridin-2-yl)-l ,7-heptanedioic acid diamide;

N'-(2-aminophenyl)-N ⁷ -(thiophen-2-ylmethyl)-l ,7-heptanedioic acid diamide;

N'-(2-(l H-imidazol-4-yl)ethyl)-N ⁷ -(2-aminophenyl)-l ,7-heptanedioic acid diamide;

N ¹ -(2-aminophenyl)-N ⁷ -(4-(4-methoxyphenyl)thiazol-2-yl)-l ,7-heptanedioic acid diamide; N'-P-aminopyridin^-yO-N^p-tolyl-l J-heptanedioic acid diamide;

N'-(2-hydroxyphenyl)-N ⁷ -p-tolyl-l ,7-heptanedioic acid diamide;

N'-(2-amino-4-fluorophenyl)-N ⁷ -(4-(pyridin-4-yl)thiazol-2-yl)-l,7-heptanedioic acid diamide;

N'-(2-amino-4-fluorophenyl)-N ⁷ -(4-(trifluoromethyl)thiazol-2-yl)-l ,7-heptanedioic acid diamide;

N ^l -(2-amino-4-fluorophenyl)-N ⁷ -(4-(piperidin-l-ylmethyl)thiazol-2-yl)-l ,7- heptanedioic acid diamide;

N'-(2-aminophenyI)-N ⁷ -(4-(pyridin-4-yl)thiazol-2-yl)-l ,7-heptanedioic acid diamide;

N'-(2-amino-4-fluorophenyl)-N ⁷ -(4-(4-fluorophenyl)thiazol-2-yl)-l ,7-heptanedioic acid diamide;

N'-(2-amino-4-fluorophenyl)-N ⁷ -(4-(4-methoxyphenyl)oxazol-2-yl)-l,7-heptanedioic acid diamide;

N ^l -(2-amino-4-fluorophenyl)-N ⁷ -(4-(moφholin-4-ylmethyl)thiazol-2-yl)-l ,7- heptanedioic acid diamide; N'-(2-(l H-imidazol-2-yl)ethyl)-N ⁷ -(2-amino-4-fluorophenyl)-l ,7-heptanedioic acid diamide;

N'-(2-amino-5-fluorophenyl)-N ⁷ -(thiophen-2-ylmethyl)-l,7-heptanedioic acid diamide; N ^l -(2-amino-5-fluorophenyl)-N ⁷ -(4-(pyridin-3-yl)thiophen-2-yl)-l ,7-heptanedioic acid diamide;

N ^l -(2-amino-4-fluorophenyl)-N ⁷ -(4-(4-methoxyphenyI)thiazol-2-yl)-l ,7-heptanedioic acid diamide; N'-(2-amino-5-fluorophenyl)-N ⁷ -(4-(4-methoxyphenyl)thiazol-2-yl)-l,7-heptanedioic acid diamide

N'-(2-amino-4-fluorophenyl)-N ⁷ -(thiazol-2-yl)-l ,7-heptanedioic acid diamide;

N ¹ -(3-aminopyridin-2-yl)-N ⁷ -(thiazol-2-yl)-l ,7-heptanedioic acid diamide;

N ¹ -(2-amino-5-(trifluoromethyl)pheny I)-N ⁷ -(4-(4-methoxyphenyl)thiazol-2-yl)- 1 ,7- heptanedioic acid diamide;

N'-(2-amino-4,5-difluorophenyl)-N ⁷ -(4-(4-methoxyphenyl)thiazol-2-yl)-l ,7- heptanedioic acid diamide;

N'-(3-aminopyridin-2-yl)-N ⁷ -(4-(4-methoxyphenyl)thiazol-2-yl)-l,7-heptanedioic acid diamide; N'-(2-amino-4-fluorophenyl)-N ⁷ -(4-(hydroxymethyl)thiazol-2-yl)-l ,7-heptanedioic acid diamide;

N'-(2-amino-4-fluorophenyl)-N ⁷ -(5-methylthiazol-2-yl)-l,7-heptanedioic acid diamide;

N'-(2-amino-4-fluorophenyl)-N ⁷ -(5-trifluoromethylthiazol-2-yl)-l,7-heptanedioic acid diamide;

N'-(2-amino-5-fluorophenyl)-N ⁷ -(5-methylthiazol-2-yl)-l,7-heptanedioic acid diamide;

N'-(2-amino-5-fluorophenyl)-N ⁷ -(thiazol-2-yl)-l ,7-heptanedioic acid diamide;

N'-(2-amino-4-fluorophenyl)-N ⁷ -(pyridin-2-y I)- 1 ,7-heptanedioic acid diamide; N'-(2-amino-5-fluorophenyl)-N ⁷ -(4-methy lthiazol-2-yl)- 1 ,7-heptanedioic acid diamide;

N ^l -(2-amino-5-fluorophenyl)-N ⁷ -(2,6-dimethoxypyridin-3-yl)-l ,7-heptanedioic acid diamide;

N'-(4-fluorophenyl)-N ⁷ -(2-amino-5-(methoxycarbonyl)phenyl)-l ,7-heptanedioic acid diamide;

N'-(4-fluorophenyl)-N ⁷ -(2-amino-4-(methoxycarbonyl)phenyl)-l ,7-heptanedioic acid diamide;

N'-(2-amino-5-tert-butylphenyl)-N ⁷ -(4-fluorophenyl)-l ,7-heptanedioic acid diamide;

N'-(2-amino-4-tert-butylphenyl)-N ⁷ -(4-fluorophenyl)-l ,7-heptanedioic acid diamide; N'-(2-amino-5-chlorophenyl)-N ⁷ -/?-tolyl-l,7-heptanedioic acid diamide;

N'-(2-amino-4-(trifluoromethyl)phenyl)-N ⁷ -p-tolylheptanediamide;

N ¹ -(2-aminophenyl)-4-oxo-N ⁷ -p-tolylheptanediamide;

N ¹ -(2-amino-4-(trifluoromethyl)phenyl)-N ⁷ -(pyridin-2-yl)heptanediamide; N'-(2-amino-4-fluorophenyl)-N ⁷ -(pyridin-2-yl)heptanediamide;

N-(2-aminophenyl)-3-(3-oxo-3-(p-tolylamino)propoxy)propan amide;

N'-(2-amino-3-methylphenyl)-N ⁷ -p-tolylheptanediamide;

N ' -(2-am ino-4-methy lpheny l)-N ⁷ -p-toly lheptaned iamide;

N'-(2-aminophenyl)-N ⁷ -(benzo[d]thiazol-2-yl)heptanediamide; N'-(2-amino-4-fluorophenyl)-N ⁷ -(4-(4-moφholinophenyl)thiazol-2- yl)heptanediamide;

N'-(2-amino-4-methoxyphenyl)-N ⁷ -p-tolylheptanediamide;

N'-(2-amino-4,5-difluorophenyl)-N ⁷ -p-tolylheptanediamide;

N'-(2-amino-4-cyanophenyl)-N ⁷ -p-tolylheptanediamide; N'-(2-amino-5-cyanophenyl)-N ⁷ -p-tolylheptanediamide;

N'-(4-aminobiphenyl-3-yl)-N ⁷ -(4-fluorophenyl)heptanediamide;

N ^l -(2-amino-4-fluorophenyl)-N ⁷ -(4-fluorophenyl)-N ⁷ -methylheptanediamide;

N'-(3-aminobiphenyl-4-yl)-N ⁷ -(4-fluorophenyl)heptanediamide;

N ¹ ,N ⁷ -bis(2-amino-4-fluorophenyl)heptanediamide; N'-(4-fluoro-2-hydroxyphenyl)-N ⁷ -p-tolylheptanediamide;

N ¹ -(2-amino-4-(trifluoromethyl)phenyl)-N ⁷ -(4-fluorophenyl)heptanediamide;

N ¹ -(2-amino-4-fluorophenyl)-N ⁷ -(5-(trifluoromethyl)thiazol-2-yl)heptanediamide;

N'-(2-amino-4-fluorophenyl)-N ⁷ -(lH-pyrazol-5-yl)heptanediamide;

N ^l -(2-amino-4-fluorophenyl)-N ⁷ -(isoxazol-3-yl)heptanediamide; N'-(2-amino-4-fluorophenyl)-N ⁷ -(5-methyloxazol-2-yl)heptanediamide;

N ^l -(4-amino-6-fluorobiphenyl-3-yl)-N ⁷ -(4-fluorophenyl)heptanediamide;

N'-(4-hydroxybiphenyl-3-yl)-N ⁷ -(pyridin-3-yl)heptanediamide; and

N ^l -(2-amino-4-fluorophenyl)-N ⁷ -p-tolylheptanediamide; or a pharmaceutically acceptable salt, hydrate, or solvate thereof. In another aspect, the invention features phenylethylene bisamide compounds of

Formula (II): and pharmaceutically acceptable salts, hydrates, and solvates thereof; wherein: Ar ¹ is selected from Cβ-io aryl and C ₁ . ₉ heteroaryl; each of which is substituted with n independently selected R ^y groups;

X is selected from, -NHAr ² , -C(=O)N(R ^a ) ₂ , and -C(=O)R ^b ;

R ¹ is selected from H, Ci _-4 alkyl, CM haloalkyl, Ci _-4 alkoxycarbonyl, carbamyl, di-Cj. ₄ -alkyl-carbamyl, and C|. ₄ alkylcarbamyl; L ¹ is selected from a bond and Ci _-4 alkylene;

Ar ² is selected from phenyl, 5-membered heteroaryl, and 6-membered heteroaryl; wherein said phenyl, 5-membered heteroaryl, and 6-membered heteroaryl are each substituted at one ortho position by one J group and by m independently selected R ^z groups; and wherein, in addition, said phenyl, 5-membered heteroaryl, and 6-membered heteroaryl may be further optionally fused to a phenyl or Ci_ ₆ heteroaryl ring, each of which is optionally substituted by 1 or 2 groups independently selected from halogen, hydroxyl, cyano, nitro, Ci _-4 alkyl, Ci _-4 haloalkyl, Ci _-4 alkoxy, CM haloalkoxy, amino, Ci _-4 alkylamino, and di-C|. ₄ - alkylamino; each R ^a is independently selected from H, C ₁ . ₆ alkyl and Ci- ₆ haloalkyl; R ^b is selected from Cι_ ₆ alkyl and C ₁ . ₆ haloalkyl;

J is selected from hydroxyl and amino; each R ^x is independently selected from halogen, hydroxyl, cyano, nitro, Ci _-4 alkyl, Ci- ₄ alkoxy, Ci _-4 haloalkyl, Ci _-4 haloalkoxy, amino, Ci _-4 alkylamino, and di-C]. ₄ -alkylamino; p is an integer selected from 0, 1 , 2, and 3; each R ^y is independently selected from halogen, cyano, nitro, hydroxyl, C ₁ . ₆ alkyl, C ₂ .

₆ alkenyl, C ₂ - ₆ alkynyl, Ci- ₆ haloalkyl, Ci _-6 alkoxy, Cι_ ₆ haloalkoxy, C|. ₆ alkoxycarbonyl, Q.6 alkylcarbonyl, carbamyl, C^ alkylcarbamyl, di-Ci-β alkylcarbamyl, Ci_ ₆ alkylcarbonylamino, Ci- ₆ alkylcarbonyl-(C|. ₄ -alkyl)amino, C _\ .β alkoxycarbonylamino, amino, C ₁ . ₆ alkylamino, di- Ci- ₆ alkylamino, C ₃ .7 cycloalkyl, C _2-6 heterocycloalkyl, phenyl, C ₁ . ₆ heteroaryl, C ₃ . ₇ cycloalkyl-C _M -alkyl, C _2-6 heterocycloalkyl-C _M -alkyl, phenyl-C _M -alkyl, and Cue heteroaryl- Ci-4-alkyl; wherein said C1.6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci_6 haloalkyl, Ci_ ₆ alkoxy, Ci-6 haloalkoxy, C|. ₆ alkoxycarbonyl, C ₁ . ₆ alkylcarbonyl, C ₁ . ₆ alkylcarbamyl, di-C|. ₆ alkylcarbamyl, C ₁ . ₆ alkylcarbonylamino, C|.6 alkylcarbonyl-(Ci _-4 -alkyl)amino, Cι_ ₆ alkoxycarbonylamino, C|. ₆ alkylamino, di-Ci- ₆ alkylamino are each optionally substituted by 1, 2, or 3 independently selected R ^y groups; and wherein said C ₃ - ₇ cycloalkyl, C ₂ -6 heterocycloalkyl, phenyl, C|. ₆ heteroaryl, C _3-7 cycloalkyl-Ci^-alkyl, C ₂ -β heterocycloalkyl-Ci. ₄ -alkyl, phenyl-C^-alkyl, and C|. ₆ heteroaryl-C|. ₄ -alkyl are each optionally substituted by 1 , 2, or 3 independently selected R ^y groups; provided that only one of R ^y is selected from optionally substituted C ₃ . ₇ cycloalkyl, C ₂ - ₆ heterocycloalkyl, phenyl, C _\ .β heteroaryl, C ₃ . ₇ cycloalkyl-Cι- ₄ -alkyl, C2-6 heterocycloalkyl-Ci^-alkyl, phenyl-Ci-4-alkyl, and Ci-6 heteroaryl-CM-alkyl; each R ^z is independently selected from halogen, cyano, nitro, hydroxyl, Cue alkyl, C ₂ . ₆ alkenyl, C ₂ - ₆ alkynyl, Ci_ ₆ haloalkyl, C ₁ . ₆ alkoxy, Ci. ₆ haloalkoxy, C|. ₆ alkoxycarbonyl, C|.6 alkylcarbonyl, carbamyl, Cι- ₆ alkylcarbamyl, di-Ci.β alkylcarbamyl, Ci- ₆ alkylcarbonylamino, Ci- ₆ alky lcarbony U(C ι- ₄ -alkyl)amino, Ci_ ₆ alkoxycarbonylamino, Ci-6 alkylamino, di-C|_6 alkylamino, C ₃ . ₇ cycloalkyl, C ₂ - ₆ heterocycloalkyl, phenyl, C _\ .β heteroaryl, C ₃ . ₇ cycloalkyl-Ci- ₄ -alkyl, C ₂ - ₆ heterocycloalkyl-Ci^-alkyl, phenyl-C|_ ₄ -alkyl, and Ci_ ₆ heteroaryl-Ci. ₄ -alkyl; wherein said C|.6 alkyl, C ₂ - ₆ alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, Ci_6 alkoxy, Ci-6 haloalkoxy, C ₁ . ₆ alkoxycarbonyl, Ci_ ₆ alkylcarbonyl, Ci-6 alkylcarbamyl, di-Ci- ₆ alkylcarbamyl, Q. ₆ alkylcarbonylamino, C _\ .β alkylcarbonyl-(Ci-4-alkyl)amino, C1.6 alkoxycarbonylamino, amino, C ₁ . ₆ alkylamino, di-Ci. ₆ alkylamino are each optionally substituted by 1, 2, or 3 independently selected R ^z groups; and wherein said C ₃ . ₇ cycloalkyl, C ₂ -6 heterocycloalkyl, phenyl, Ci_ ₆ heteroaryl, C ₃ - ₇ cycloalkyl-Ci- ₄ -alkyl, C2-6 heterocycloalkyl-Ci^-alkyl, phenyl-Ci -4-alkyl, and Cι_ ₆ heteroaryl-Ci-4-alkyl are each optionally substituted by 1 , 2, or 3 independently selected R ^z groups; provided that only one of R ^z is selected from optionally substituted C ₃ . ₇ cycloalkyl and C2-6 heterocycloalkyl; each R ^y and R ^z is independently selected from hydroxyl, cyano, nitro, CM alkoxy,

CM haloalkoxy, amino, C ₁ . ₄ alkylamino, and di-Ci- ₄ -alkylamino; each R ^y and R ^z is independently selected from halogen, hydroxyl, cyano, nitro, C ₁ .4 alkyl, CM haloalkyl, Ci _-4 alkoxy, CM haloalkoxy, amino, CM alkylamino, and di-Cι.4- alkylamino; n is an integer selected from 0, 1 , 2, 3, and 4; and m is an integer selected from 0, 1 , 2, and 3.

In some of these compounds, each R ^y is independently selected from halogen, cyano, nitro, Ci-6 alkyl, C _2-O alkenyl, C ₂ - ₆ alkynyl, C\.β haloalkyl, C ₁ . ₆ alkoxy, C1.6 haloalkoxy, C3.7 cycloalkyl, C ₂ - ₆ heterocycloalkyl, phenyl, C _\ .β heteroaryl, C ₃ . ₇ cycloalkyl-Ci-4-alkyl, C ₂ . ₆ heterocycloalkyl-Ci- ₄ -alkyl, phenyl-Ci- ₄ -alkyl, and Ci-δ heteroaryl-Ci^-alkyl; wherein said Ci. ₆ alkyl, C ₂ - ₆ alkenyl, C ₂ - ₆ alkynyl, Ci_ ₆ haloalkyl, Ci- ₆ alkoxy, and Ci.6 haloalkoxy are each optionally substituted by 1 , 2, or 3 independently selected R ^y groups; and wherein said C3.7 cycloalkyl, C ₂ - _δ heterocycloalkyl, phenyl, C ₁ . ₆ heteroaryl, C ₃ .7 cycloalkyl-C|. ₄ -alkyl, C ₂ -6 heterocycloalkyl-Ci^-alkyl, phenyl-Ci. ₄ -alkyl, and Ci- _δ heteroaryl-Ci^-alkyl are each optionally substituted by 1 , 2, or 3 independently selected R ^y groups; with the proviso that only one of R ^y is selected from optionally substituted C3-7 cycloalkyl, C ₂ - ₆ heterocycloalkyl, phenyl, Ci.6 heteroaryl, C3.7 cycloalkyl-Ci. ₄ -alkyl, C2-6 heterocycloalkyl-Ci^-alkyl, phenyl-C|. ₄ -alkyl, and Ci^ heteroaryl-C _M -alkyl. In some embodiments, each R ^y is independently selected from halogen, cyano, nitro,

Ci- ₆ alkyl, Ci. ₆ haloalkyl, Ci. ₆ alkoxy, C|. ₆ haloalkoxy, phenyl, C i-β heteroaryl, C3-7 cycloalkyl- Ci- ₄ -alkyl, and C ₂ - ₆ heterocycloalkyl-Ci. ₄ -alkyl; wherein said Ci_ ₆ alkyl, C|. ₆ haloalkyl, Cι_6 alkoxy, and C|.6 haloalkoxy are each optionally substituted by 1 or 2 independently selected R ^y groups; and wherein said phenyl, Ci_ ₆ heteroaryl, C ₃ . ₇ cycloalkyl-C|. ₄ -alkyl, and C ₂ -6 heterocycloalkyl-Ci^-alkyl are each optionally substituted by 1 or 2 independently selected R ^y groups; provided that only one of R ^y is selected from optionally substituted phenyl, Cι_6 heteroaryl, C3.7 cycIoalkyl-Ci_ ₄ -alkyl, and C ₂ -6 heterocycloalkyl-Ci. ₄ -alkyl. In some embodiments, each R ^y is independently selected from halogen, cyano, C^alkyl, C|.6 haloalkyl, C|.6 alkoxy, C|.6 haloalkoxy, Ci_6alkoxycarbonyl, Ci-β alkylcarbonyl, carbamyl, Cj. 6 alkylcarbamyl, di-Ci-6 alkylcarbamyl, Ci_6 alky lcarbony lam ino, Ci_6 alkylcarbonyl-(Ci-4- alkyl)amino, Ci-β alkoxycarbonylamino, and di-Ci.6 alkylamino; wherein said Ci _-6 alkyl, Ci _-6 haloalkyl, C ₁ . ₆ alkoxy, C|. ₆ haloalkoxy, C _\ .(, alkoxy carbonyl, C|. ₆ alkylcarbonyl, carbamyl, Ci- ₆ alkylcarbamyl, di-Ci-β alkylcarbamyl, Ci-galkylcarbonylamino, Ci- _ό alkylcarbonyKCi^- alkyl)amino, Ci_6 alkoxycarbonylamino, and di-Ci- ₆ alkylamino are each optionally substituted by 1 , 2, or 3 independently selected R ^y groups.

In some embodiments, each R ^y is independently selected from halogen, cyano, Cj.6 alkyl, C ₂ - ₆ alkenyl, C ₂ - ₆ alkynyl, Ci_ ₆ haloalkyl, C ₁ . ₆ alkoxy, Cj. ₆ haloalkoxy, and di-Cj. ₆ alkylamino; wherein said Cj.6 alkyl, C ₂ -6alkenyl, C ₂ -βalkynyl, Cue haloalkyl, Cj.6 alkoxy, Q.6 haloalkoxy, and di-Q- ₆ alkylamino are each optionally substituted by 1 , 2, or 3 independently selected R ^y groups. In some embodiments, each R ^y is independently selected from halogen, Ci-6 alkyl, Ci_6 haloalkyl, Ci_ ₆ alkoxy, C ₂ -6 heterocycloalkyl, phenyl, Ci.6 heteroaryl, and C ₂ -6 heterocycloalkyl-Ci^-alkyl; wherein said Ci_6 alkyl, C _\ .β haloalkyl, C1.6 alkoxy, and C|.6 haloalkoxy are each optionally substituted by a R ^y group; and wherein said phenyl, C ₁ .6 heteroaryl, C ₃ -7 cycloalkyl-Ci_ ₄ -alkyl, and C2-6 heterocycloalkyl-Ci-4-alkyl are each optionally substituted by a R ^y group; with the proviso that only one of R ^y is selected from optionally substituted phenyl, Ci-όheteroaryl, and C ₂ - ₆ heterocycIoalkyl-Ci. ₄ -alkyl. In some embodiments, each R ^y is independently C _h alky). In some embodiments, each R ^y is methyl. In some embodiments, each R ^z is independently selected from halogen, cyano, nitro, Ci-6 alkyl, C ₂ -6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, Ci_6 alkoxy, C1.6 haloalkoxy, C3.7 cycloalkyl, and C ₂ - ₆ heterocycloalkyl; wherein said Ci_6 alkyl, C ₂ -6 alkenyl, C2.6 alkynyl, Cι_6 haloalkyl, C ₁ . ₆ alkoxy, and C|.6 haloalkoxy are each optionally substituted by 1 , 2, or 3 independently selected R ^z groups; and wherein said C3.7 cycloalkyl and C ₂ -6 heterocycloalkyl are each optionally substituted by 1 , 2, or 3 independently selected R ^z groups; with the proviso that only one of R ^z is selected from optionally substituted C3.7 cycloalkyl and C2-6 heterocycloalkyl. In some embodiments, each R ^z is independently selected from halogen, cyano, C ₁ .6 alkyl, Ci_6 haloalkyl, Ci-6 alkoxy, C 1-6 haloalkoxy, Ci.6 alkoxycarbonyl, Ci.6 alkylcarbonyl, carbamyl, Ci_6alkylcarbamyl, di-Ci-β alkylcarbamyl, Ci_6 alkylcarbonylamino, Ci.6alkylcarbonyl-(Ci. ₄ -alkyl)amino, Ci_6 alkoxycarbonylamino, and di-C|.6 alkylamino; wherein said C ₁ .6 alkyl, C ₁ .6 haloalkyl, Ci_6 alkoxy, C1.6 haloalkoxy, Ci-βalkoxycarbonyl, C|.6 alkylcarbonyl, carbamyl, Ci.6alkylcarbamyl, di-Ci.6alkylcarbamyl, Ci-6 alkylcarbonylamino, Ci.6alkylcarbonyl-(Ci- ₄ -alkyl)amino, Ci^alkoxycarbonylamino, and di-Ci.6 alkylamino are each optionally substituted by 1, 2, or 3 independently selected R ^y groups. In some embodiments, each R ^z is independently selected from halogen, cyano, nitro, C|.6 alkyl, Cι_6 haloalkyl, C ₁ .6 alkoxy, and Ci_6 haloalkoxy; wherein said C).6 alkyl, Ci-6 haloalkyl, Ci_6 alkoxy, and C ₁ . ₆ haloalkoxy are each optionally substituted by 1 or 2 independently selected R ^z groups. In some embodiments, each R ^z is independently halogen. In some embodiments, each R ^z is fluoro.

In some embodiments, each R ^y and R ^z group is independently selected from hydroxyl, cyano, nitro, C ₁ .4 alkoxy, C1-4 haloalkoxy, amino, C1.4 alkylamino, and di-CM- alkylamino. In some embodiments, each R ^y and R ^z group is independently selected from hydroxyl, C _M alkoxy, and C _M haloalkoxy. In some embodiments, each R ^y and R ^z group is independently selected from hydroxyl, cyano, nitro, C _M alkoxy, C _M haloalkoxy, amino, C _M alkylamino, and di-Ci- ₄ -alkylamino. In some embodiments, each R ^y and R ^z group is independently selected from hydroxyl, C _M alkoxy, and C _M haloalkoxy.

In further embodiments, R ¹ is selected from H, C _M alkyl, and C _M haloalkyl. In some embodiments, R ¹ is selected from H and C _M alkyl. In some embodiments, R ¹ is H. In other embodiments, L ¹ is selected from a bond and Ci^ alkylene. In some embodiments, L ¹ is selected from a bond and Ci.2 alkylene. In some embodiments, each R* is independently selected from halogen, hydroxyl, Ci _-4 alkyl, Ci^ alkoxy, Ci. ₄ haloalkyl, and C _M haloalkoxy. In some embodiments, each R ^x is independently selected from hydroxyl, C) _-4 alkyl, and Ci _-4 alkoxy. In some embodiments, each R ^x is independently selected from Ci _-4 alkyl. In further embodiments, J is selected from amino and hydroxyl. In some embodiments, J is amino.

In other embodiments, p is an integer selected from 0, 1 , and 2. In some embodiments, p is an integer selected from 0 and 1. In some embodiments, p is 0. In some embodiments, n is an integer selected from 0, 1 , 2, and 3. In some embodiments, n is an integer selected from 0, 1 , and 2. In some embodiments, n is an integer selected from 0 and 1. In some embodiments, n is 0. In some embodiments, m is an integer selected from 0, 1 , and 2. In some embodiments, m is an integer selected from 0 and 1. In some embodiments, m is 0.

In some embodiments, X is -NHAr ² . In some embodiments, X is -C(=O)N(R ^a ) ₂ . In some embodiments, X is -C(=O)R ^b ;

In further embodiments, each R ^a is independently selected from H and C|. ₆ alkyl. In some embodiments, one R ^a is H and the other R ^a is Ci_ ₆ alkyl. In some embodiments, one R ^a is H and the other R ^a is methyl. In some embodiments, R ^b is selected Cue alkyl. In some embodiments, R ^b is methyl. In other embodiments, Ar ¹ is selected from phenyl and Ci. ₆ heteroaryl; each of which is substituted with n independently selected R ^y groups. In some embodiments:

Ar ¹ is phenyl; which is substituted with n independently selected R ^y groups; Ar ² is phenyl; which is substituted at one ortho position by one J group and by m independently selected R ^z groups. In further embodiments:

Ar ¹ is phenyl; which is substituted with n independently selected R ^y groups; Ar ² is 5-membered heteroaryl; which is substituted at one ortho position by one J group and by m independently selected R ^z groups. In other embodiments:

Ar ¹ is phenyl; which is substituted with n independently selected R ^y groups; Ar ² is 6-membered heteroaryl; which is substituted at one ortho position by one J group and by m independently selected R ^z groups.

In some embodiments: Ar ¹ is Ci- ₆ heteroaryl; which is substituted with n independently selected R ^y groups;

Ar ² is phenyl; which is substituted at one ortho position by one J group and by m independently selected R ^z groups. In some embodiments:

Ar ¹ is Ci_ ₆ heteroaryl; which is substituted with n independently selected R ^y groups;

Ar ² is 5-membered heteroaryl; which is substituted at one ortho position by one J group and by m independently selected R ^z groups. In further embodiments:

Ar ¹ is Ci. ₆ heteroaryl; which is substituted with n independently selected R ^y groups;

Ar ² is 6-membered heteroaryl; which is substituted at one ortho position by one J group and by m independently selected R ^z groups. In other embodiments:

Ar ¹ is selected from phenyl and Cι_ ₆ heteroaryl; each of which is substituted with n independently selected R ^y groups;

X is selected from -NHAr ² , -C(=O)N(R ^a ) ₂ , and -C(=O)R ^b ;

R ¹ is selected from H, C ₁ . ₄ alkyl, and Ci _-4 haloalkyl; L ¹ is selected from a bond and Ci _-4 alkylene;

Ar ² is selected from phenyl, 5-membered heteroaryl, and 6-membered heteroaryl; wherein said phenyl, 5-membered heteroaryl, and 6-membered heteroaryl are each substituted at one ortho position by one J group and by m independently selected R ^z groups; each R ^a is independently selected from H, Ci. ₆ alkyl and Ci. ₆ haloalkyl; R ^b is selected from Ci_ ₆ alkyl and Ci- ₆ haloalkyl;

J is selected from amino and hydroxyl; each R ^x is independently selected from halogen, hydroxyl, cyano, nitro, Ci _-4 alkyl, Ci _-4 alkoxy, Ci _-4 haloalkyl, and Ci _-4 haloalkoxy; p is an integer selected from 0, 1, or 2; each R ^y is independently selected from halogen, cyano, nitro, C|.β alkyl, C|. ₆ haloalkyl, Ci. ₆ alkoxy, Ci^ haloalkoxy, C ₃ _ ₇ cycloalkyl, C _2- β heterocycloalkyl, phenyl, C|. ₆ heteroaryl, Cs^ cycloalkyl-Ci^-alkyl, C2- ₆ heterocycloalkyl-Ci. ₄ -alkyl, phenyl-C| _-4 -alkyl, and Ci-β heteroaryl-Ci^-alkyl; wherein said Cι_6 alkyl, Ci^ haloalkyl, C|- ₆ alkoxy, and C|_6 haloalkoxy are each optionally substituted by 1, 2, or 3 independently selected R ^y groups; and wherein said C ₃ -7cycloalkyl, C ₂ - ₆ heterocycloalkyl, phenyl, Ci- ₆ heteroaryl, C3-7 cycloalkyl-Ci- ₄ -alkyl, C2-6 heterocycloalkyl-C|. ₄ -alkyl, phenyl-C|_ ₄ -aIkyl, and Ci- ₆ heteroaryl- C|. ₄ -alkyl are each optionally substituted by 1 or 2 independently selected R ^y groups; with the proviso that only one of R ^y is selected from optionally substituted C3.7 cycloalkyl, C ₂ - ₆ heterocycloalkyl, phenyl, Cι_ ₆ heteroaryl, C ₃ -7cycloalkyl-Ci_4-alkyl, C2-6 heterocycloalkyl-Ci- ₄ -alkyl, phenyl-Ci. ₄ -alkyl, and Ci- ₆ heteroaryl-Ci. ₄ -alkyl; each R ^z is independently selected from halogen, cyano, nitro, Ci-6 alkyl, C1.6 haloalkyl, Ci. ₆ alkoxy, and Ci_ ₆ haloalkoxy; wherein said C ₁ . ₆ alkyl, Ci. ₆ haloalkyl, C1.6 alkoxy, and C i_ ₆ haloalkoxy are each optionally substituted by 1 , 2, or 3 independently selected R ^z groups; or any two R ^z groups, together with the atoms to which they are attached, form a phenyl or C ₁ . ₆ heteroaryl ring; each of which is optionally substituted by 1 or 2 groups selected from halogen, hydroxy!, cyano, nitro, Ci- ₄ alkyl, C ₁ . ₄ haloalkyl, C ₁ . ₄ alkoxy, and C1-4 haloalkoxy; each R ^y and R ^z is independently selected from hydroxyl, cyano, nitro, CM alkoxy, and Ci _-4 haloalkoxy; each R ^y is independently selected from halogen, hydroxyl, cyano, nitro, Ci _-4 alkyl, C ₁ . ₄ haloalkyl, C ₁ . ₄ alkoxy, and CM haloalkoxy; n is an integer selected from 0, 1, 2, and 3; and m is an integer selected from 0, 1 , and 2.

In further embodiments:

Ar ¹ is selected from phenyl and C i_ ₆ heteroaryl; each of which is substituted with n independently selected R ^y groups;

X is -NHAr ² ; R ¹ is selected from H and C]. ₄ alkyl;

L ¹ is selected from a bond and C|. ₄ alkylene;

Ar ² is selected from phenyl, 5-membered heteroaryl, and 6-membered heteroaryl; wherein said phenyl, 5-membered heteroaryl, and 6-membered heteroaryl are each substituted at one ortho position by one J group and by m independently selected R ^z groups; J is selected from amino and hydroxyl; each R ^x is independently selected from halogen, hydroxyl, cyano, nitro, CM alkyl, CM alkoxy, CM haloalkyl, and CM haloalkoxy; p is an integer selected from 0 or 1 ; each R ^y is independently selected from halogen, cyano, Ci^alkyl, Ci-6 haloalkyl, Ci- ₆ alkoxy, and Ci-β haloalkoxy; wherein said Ci-β alkyl, Ci-6 haloalkyl, Ci-6 alkoxy, and Ci^ haloalkoxy are each optionally substituted by 1 , 2, or 3 independently selected R ^y groups; each R ^z is independently selected from halogen, cyano, nitro, Ci^alkyl, C|.6 haloalkyl, Cι- ₆ alkoxy, and Ci- _ό haloalkoxy; wherein said Ci- ₆ alkyl, Cue haloalkyl, Ci-6 alkoxy, and C|. _ό haloalkoxy are each optionally substituted by 1 or 2 independently selected R ^z groups; each R ^y and R ^z group is independently selected from hydroxyl, Ci _-4 alkoxy, and Ci. ₄ haloalkoxy; n is an integer selected from 0, 1, and 2; and m is an integer selected from 0, 1 , and 2. In some embodiments, X is -NHC(=O)Ar ² . In other embodiments: Ar ¹ is selected from phenyl and 5-membered heteroaryl; each of which is substituted with n independently selected R ^y groups; X is -NHAr ² ; R ¹ is H;

L ¹ is selected from a bond, methan-l ,l-diyl, and ethan-l ,2-diyl; Ar ² is selected from phenyl; wherein said phenyl is substituted at one ortho position by one J group and by m independently selected R ^z groups; J is amino; p is O;

R ^y is C|. ₆ alkyl; R ^z is halogen; n is an integer selected from 0 and 1 ; and m is an integer selected from 0 arid 1. In some embodiments:

Ar ¹ is selected from phenyl, thiophen-2-yl, and pyrazol-2-yl; each of which is substituted with n independently selected R ^y group; X is -NHAr ² ; R ¹ is H; L ¹ is selected from a bond, methan-l ,l -diyl, and ethan-l ,2-diyl; Ar ² is selected from phenyl; wherein said phenyl is substituted at one ortho position by one J group and by m independently selected R ^z group; J is amino; p is O; R ^y is methyl; and

R ^z is fluoro.

In some embodiments, the compound is selected from:

(E)-N-(3-(3-(2-aminophenylamino)-3-oxoprop-l -enyl)phenyl)-4-methylbenzamide; (E)-N-(2-amino-4-fluorophenyl)-3-(3-(2-(thiophen-2- yl)acetamido)phenyl)acrylamide; or

(E)-3-(3-(3-(l H-imidazol-2-yl)propanamido)phenyl)-N-(2-aminophenyl)acrylam ide, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

In a further aspect, the invention features bisamide or hydroxamide compounds of Formula (III): and pharmaceutically acceptable salts, hydrates, and solvates thereof; wherein: R ¹ is selected from H, Ci _-4 alkyl, Ci _-4 haloalkyl, Ci _-4 alkoxycarbonyl, carbamyl, di-Ci. ₄ -alkyl-carbamyl, and Ci _-4 alkylcarbamyl; R ³ is selected from -R ^a and -N(R ^b ) ₂ ;

R ^a is selected from Ci.6 alkyl, Cι_ ₆ haloalkyl, C2-6 alkenyl, and C2-6 alkynyl; each R ^b is independently selected from H, Ci- ₆ alkyl, Ci_ ₆ haloalkyl, C ₂ - ₆ alkenyl, and C ₂ -6 alkynyl;

Ar ¹ is phenyl, 6-membered heteroaryl, and 5-membered heteroaryl; each of which is substituted by a R ^y group and by n additional independently selected R ^y groups;

L ² is straight chain C ₅ alkylene, which is optionally substituted by 1 , 2, 3, or 4 independently selected R ^x groups; each R ^x is independently selected from halogen, hydroxyl, cyano, nitro, Ci _-4 alkyl, Ci- ₄ alkoxy, CM haloalkyl, Ci _-4 haloalkoxy, amino, Ci _-4 alkylamino, and di-C|. ₄ -alkylamino; each R ^y is independently selected from halogen, cyano, nitro, Ci _-6 alkyl, C ₂ - ₆ alkenyl,

C ₂ - ₆ alkynyl, C ₁ . ₆ haloalkyl, C1.6 alkoxy, Ci_6 haloalkoxy, Ci-6 alkoxycarbonyl, Ci _-6 alkylcarbonyl, carbamyl, C ₁ . ₆ alkylcarbamyl, di-Ci- ₆ alkylcarbamyl, Ci _-6 alkylcarbonylamino, Ci-6 alkylcarbonyl-(Ci-4-alkyl)amino, Ci_ ₆ alkoxycarbonylamino, amino, C\.β alkylamino, and di-Cι-6 alkylamino; wherein said Ci_ ₆ alkyl, C ₂ -6 alkenyl, C2-6 alkynyl, C1.6 haloalkyl, Ci _-6 alkoxy, C ₁ . ₆ haloalkoxy, Ci_ ₆ alkoxycarbonyl, C ₁ .6 alkylcarbonyl, C ₁ .6 alkylcarbamyl, di-Ci.6 alkylcarbamyl, Cι_6 alkylcarbonylamino, C ₁ .6 alkylcarbonyl-(Ci.4-alkyl)amino, C ₁ .6 alkoxycarbonylamino, amino, C ₁ . ₆ alkylamino, and di-Ci-6 alkylamino are each optionally substituted by 1 , 2, or 3 independently selected R ^y groups; each R ^y is independently selected from hydroxyl, cyano, nitro, C1-4 alkoxy, C1.4 haloalkoxy, amino, C ₁ . ₄ alkylamino, and di-C|. ₄ -alkylamino; and n is an integer selected from 0, 1 , 2, and 3; In some embodiments, each R ^y is independently selected from halogen, cyano, C|.6 alkyl, Cι_ ₆ haloalkyl, Ci _-6 alkoxy, C |. ₆ haloalkoxy, Ci.6 alkoxycarbonyl, C ι-6 alkylcarbonyl, carbamyl, Ci_ ₆ alkylcarbamyl, di-Ci.6 alkylcarbamyl, Ci_6 alkylcarbonylamino, Ci^ alkylcarbonyl-(Ci- ₄ -alkyl)amino, C ₁ . ₆ alkoxycarbonylamino, and di-Ci_6 alkylamino; wherein said C|.6 alkyl, Ci_ ₆ haloalkyl, Ci _-6 alkoxy, C ₁ .6 haloalkoxy, C ₁ .6 alkoxycarbonyl, Ci _-6 alkylcarbonyl, carbamyl, Ci _-6 alkylcarbamyl, di-Ci.6 alkylcarbamyl, Ci _-6 alkylcarbonylamino, C].6alkylcarbonyl-(Ci. ₄ -alkyl)amino, C|.6 alkoxycarbonylamino, and di-Q-6 alkylamino are each optionally substituted by 1 , 2, or 3 independently selected R ^y groups. In some embodiments, each R ^y is independently selected from halogen, C ₁ .6 alkyl, C ₁ .6 haloalkyl, Cι_6 alkoxy, and Cι_6 haloalkoxy; wherein said Q.6 alkyl, Ci_6 haloalkyl, Q.6 alkoxy, and C1.6 haloalkoxy are each optionally substituted by 1 or 2 independently selected R ^y groups. In some embodiments, each R ^y is independently selected from halogen, Ci_6 alkyl, Cι_6 haloalkyl, C ₁ . ₆ alkoxy, and C ₁ .6 haloalkoxy; wherein said C ₁ .6 alkyl, C ₁ .6 haloalkyl, C|.6 alkoxy, and Ci_ ₆ haloalkoxy are each optionally substituted by a R ^y group.

In further embodiments, R ¹ is selected from H, C ₁ . ₄ alkyl, and C _M haloalkyl. In some embodiments, R ¹ is selected from H and C _M alkyl. In some embodiments, R ¹ is H.

In other embodiments, L ² is straight chain C5 alkylene; wherein said straight chain C5 alkylene is optionally substituted by 1 , 2, or 3 independently selected R ^x groups. In some embodiments, L ² is straight chain C ₅ alkylene; wherein said straight chain C ₅ alkylene is optionally substituted by 1 or 2 independently selected R ^x groups. In some embodiments, L ² is straight chain C ₅ alkylene; wherein said straight chain C ₅ alkylene is optionally substituted by a R ^x group. In some embodiments, L ² is -CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ -. In some embodiments, each R ^x is independently selected from halogen, cyano, nitro, C _M alkyl, C _M haloalkyl; In some embodiments, each R ^x is independently selected from halogen, C _M alkyl and Ci- ₄ haloalkyl. In some embodiments, each R ^x is independently selected from Ci _-4 alkyl and C]. ₄ haloalkyl. In some embodiments, each R ^x is independently selected from C|. ₄ alkyl.

In further embodiments, R ^a is selected from C|.6 alkyl. In some embodiments, each R ^b is independently selected from H and C|.6 alkyl. In some embodiments, n is an integer selected from O, 1 , and 2. In some embodiments, n is an integer selected from 0 and 1. In some embodiments, n is 0.

In further embodiments, Ar ¹ is phenyl; which is substituted by a R ^y group and by n additional independently selected R ^y groups. In some embodiments, Ar ¹ is 5-membered heteroaryl; which is substituted by a R ^y group and by n additional independently selected R ^y groups. In some embodiments, Ar ¹ is 6-membered heteroaryl; which is substituted by a R ^y group and by n additional independently selected R ^y groups.

In other embodiments, the compound is a compound of Formula (IHa): or pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula (HIb):

or pharmaceutically acceptable salt thereof. In other embodiments, the compound is a compound of Formula (IHa) or (HIb), or pharmaceutically acceptable salt thereof, wherein:

R ¹ is selected from H, C ₁ . ₄ alkyl, and Ci _-4 haloalkyl; R ^a is selected from C|.6 alkyl; each R ^b is independently selected from H and Ci. ₆ alkyl; Ar ¹ is phenyl, 6-membered heteroaryl, and 5-membered heteroaryl; each of which is substituted by a R ^y group and by n additional independently selected R ^y groups;

L ² is straight chain C ₅ alkylene, which is optionally substituted by 1 , 2, or 3 independently selected R ^x groups; each R ^x is independently selected from halogen, hydroxyl, Ci _-4 alkyl, Ci _-4 alkoxy, Ci _-4 haloalkyl, and C ₁ . ₄ haloalkoxy; each R ^y is independently selected from halogen, cyano, Ci_ ₆ alkyl, C ₁ . ₆ haloalkyl, Cι_ ₆ alkoxy, C|. ₆ haloalkoxy, Ci.6alkoxycarbonyl, Ci-β alkylcarbonyl, carbamyl, C|. _ό alkylcarbamyl, di-Ci-6 alkylcarbamyl, Ci- _ό alkylcarbonylamino, C|. ₆ alkylcarbonyl-(C|.4- alkyl)amino, C|.6alkoxycarbonylamino, and di-Ci. ₆ alkylamino; wherein said Ci^alkyl, Cι_6 haloalkyl, C|. ₆ alkoxy, Ci. ₆ haloalkoxy, Ci. ₆ alkoxycarbonyl, C|. ₆ alkylcarbonyl, carbamyl, C|. βalkylcarbamyl, di-Ci- _ό alkylcarbamyl, Ci^alkylcarbonylamino, C|_ ₆ alkylcarbonyl-(C|.4- alkyl)amino, Ci- _δ alkoxycarbonylamino, and di-Ci- _δ alkylamino are each optionally substituted by 1, 2, or 3 independently selected R ^y groups. each R ^y is independently selected from hydroxyl, cyano, nitro, C|.4 alkoxy, and CM haloalkoxy; and n is an integer selected from 0, 1, and 2. In some embodiments, the compound is a compound of Formula (Ilia) or (HIb), or pharmaceutically acceptable salt thereof, wherein: R ¹ is selected from H; R ^a is selected from Ci. ₆ alkyl; each R ^b is independently selected from H and Ci. ₆ alkyl; Ar ¹ is phenyl, 6-membered heteroaryl, and 5-membered heteroaryl; each of which is substituted by a R ^y group and by n additional independently selected R ^y groups;

L ² is straight chain Cs alkylene, which is optionally substituted by 1 or 2 independently selected R" groups; each R ^x is independently selected from halogen, C|- ₄ alkyl, and CM haloalkyl; each R ^y is independently selected from halogen, Ci. ₆ alkyl, Ci.β haloalkyl, Ci_6 alkoxy, and Ci_ ₆ haloalkoxy; wherein said Ci^ alkyl, Q- ₆ haloalkyl, C|-6 alkoxy, and Ci-6 haloalkoxy are each optionally substituted by 1 or 2 independently selected R ^y groups; each R ^y is independently selected from hydroxyl, C ₁ . ₄ alkoxy, and Ci_4 haloalkoxy; and n is an integer selected from 0 and 1.

In further embodiments, the compound is a compound of Formula (HIa) or (HIb), or pharmaceutically acceptable salt thereof, wherein: R ¹ is selected from H; R ^a is selected from Ci-βalkyl; each R ^b is independently selected from H and C|- ₆ alkyl;

Ar ¹ is phenyl, 6-membered heteroaryl, and 5-membered heteroaryl; each of which is substituted by a R ^y group and by n additional independently selected R ^y groups; L ² is -CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ - each R ^y is independently selected from halogen, C|.6 alkyl, Ci-6 haloalkyl, Ci-6 alkoxy, and Ci. ₆ haloalkoxy; wherein said Cι_ ₆ alkyl, Ci-β haloalkyl, Ci. ₆ alkoxy, and Ci _-6 haloalkoxy are each optionally substituted by a R ^y group; each R ^y is independently selected from hydroxyl, Ci _-4 alkoxy, and CM haloalkoxy; and n is an integer selected from 0 and 1.

In other embodiments, the compound is a compound of Formula (HIa) or (HIb), or pharmaceutically acceptable salt thereof, wherein:

R ¹ is selected from H; R ^a is selected from C _\ .β alkyl; each R ^b is independently selected from H and Ci- ₆ alkyl; Ar ¹ is phenyl;

L ² is -CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ - each R ^y is independently selected from halogen, Ci_ ₆ alkyl, Ci^ haloalkyl, Ci.6 alkoxy, and Ci. ₆ haloalkoxy; wherein said Ci- ₆ alkyl, Ci. ₆ haloalkyl, Ci_ ₆ alkoxy, and Ci.6 haloalkoxy are each optionally substituted by a R ^y group; each R ^y is independently selected from hydroxyl, CM alkoxy, and Ci _-4 haloalkoxy; and n is an integer selected from 0 and 1. In some embodiments, the compound is: 7,8-dioxo-N-p-tolylnonanamide or Nl- methyl-2-oxo-N8-p-tolyloctanediamide; or pharmaceutically acceptable salt thereof.

The compounds described herein may contain one or more asymmetric centers, which can thus give rise to optical isomers (enantiomers) and diastereomers. While shown without respect to the stereochemistry in Formulas I-III, the present invention includes such optical isomers (enantiomers) and diastereomers (geometric isomers); as well as the racemic and resolved, enantiomerically pure R and S stereoisomers; as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof. The use of these compounds is intended to cover the racemic mixture or either of the chiral enantiomers.

Optical isomers can be obtained in pure form by standard procedures known to those skilled in the art, and include, but are not limited to, diastereomeric salt formation, kinetic resolution, and asymmetric synthesis. See, for example, Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S. H., et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw- Hill, NY, 1962); Wilen, S.H. Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972), each of which is incorporated herein by reference in their entireties. It is also understood that this invention encompasses all possible regioisomers, and mixtures thereof, which can be obtained in pure form by standard separation procedures known to those skilled in the art, and include, but are not limited to, column chromatography, thin-layer chromatography, and high-performance liquid chromatography.

One skilled in the art will also recognize that it is possible for tautomers to exist for the compounds described herein. The present invention includes all such tautomers even though not shown in the formulas herein. The present invention also includes various hydrate and solvate forms of the compounds.

Compounds described herein can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

The compounds described herein also include pharmaceutically acceptable salts of the compounds disclosed herein. As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed by the addition of a pharmaceutically acceptable acid or base to a compound disclosed herein. As used herein, the phrase "pharmaceutically acceptable" refers to a substance that is acceptable for use in pharmaceutical applications from a toxicological perspective and does not adversely interact with the active ingredient. Pharmaceutically acceptable salts, including mono- and bi- salts, include, but are not limited to, those derived from organic and inorganic acids such as, but not limited to, acetic, lactic, (+)-L-tartaric, (+)- L-lactic, (+/-)-DL-lactic, glutaric, citric, cinnamic, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, oxalic, propionic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, glycolic, pyruvic, methanesulfonic, ethanesulfonic, toluenesulfonic, salicylic, benzoic, and similarly known acceptable acids. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418; Journal of Pharmaceutical Science, 66, 2 (1977); and "Pharmaceutical Salts: Properties, Selection, and Use A Handbook; Wermuth, C. G. and Stahl, P. H. (eds.) Verlag Helvetica Chimica Acta, Zurich, 2002 [ISBN 3-906390-26-8] each of which is incorporated herein by reference in their entireties.

In some embodiments, the compounds are prodrugs. As used herein, "prodrug" refers to a moiety that releases a compound described herein when administered to a patient. Prodrugs can be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds. Examples of prodrugs include compounds described herein as described herein that contain one or more molecular moieties appended to a hydroxyl, amino, sulfhydryl, or carboxyl group of the compound, and that when administered to a patient, cleave in vivo to form the free hydroxyl, amino, sulfhydryl, or carboxyl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds described herein. Preparation and use of prodrugs is discussed in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A. C. S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference in their entireties.

Methods of Making HDAC Inhibitor Compounds The compounds described herein can be prepared in a variety of ways known to one skilled in the art of organic synthesis. The compounds described herein can be synthesized using the methods as hereinafter described below, together with synthetic methods known in the art of synthetic organic chemistry or variations thereon as appreciated by those skilled in the art. The compounds described herein can be conveniently prepared in accordance with the procedures outlined in the schemes below, from commercially available starting materials, compounds known in the literature, or readily prepared intermediates, by employing standard synthetic methods and procedures known to those skilled in the art. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be readily obtained from the relevant scientific literature or from standard textbooks in the field. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures. T hose skilled in the art of organic synthesis will recognize that the nature and order of the synthetic steps presented may be varied for the purpose of optimizing the formation of the compounds described herein.

The processes described herein can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., ¹ H or ¹³ C NMR) infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry, or by chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography.

Preparation of compounds can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in Greene, et al., Protective Groups in Organic Synthesis, 4d. Ed., Wiley & Sons, 2007, which is incorporated herein by reference in its entirety. Adjustments to the protecting groups and formation and cleavage methods described herein may be adjusted as necessary in light of the various substituents.

The reactions of the processes described herein can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially nonreactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, i.e., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected.

One method of preparing the compounds of Formula (I) is shown in General Scheme I (wherein one of the amines (b) and (c) is Ar'-L'N(R')H and the other amine is Ar ² NH ₂ ). Pimelic anhydride, or appropriate derivative thereof, is first prepared from an appropriate alkanedioic acid such as pimelic acid, followed by reaction with an appropriate amine (b) to produce an amide. The amide can then be reacted with a second amine (c) in the presence of coupling agent such l-(3-methylaminopropyl)-3-ethylcarbodiimide hydrochloride or O- benzotriazole-N,N,N',N'-tetramethyl-uronium-hexafluoro-phosp hate (HBTU) in the presence of a tertiary amine such as triethylamino, 4-(N,N-dimethylamino)pyridine, or diisopropylethylamine (DIPEA) to produce the diamide compound (d). If desired, the J group on Ar ² can be protected using an appropriate protecting group such as Fmoc (9H- fluoren-9-ylmethoxycarbonyl) before reaction in one of the steps of General Scheme I. The protecting group can removed at the end of the synthesis by methods known in the art. For example, Fmoc can be removed by the used of piperidine. General Scheme I

Alternatively, the compounds of Formula (I) can be made by procedures such as those shown in General Scheme II. A l -nitro-2-aminoaryl compound (a) (wherein J is an amino group) is first reacted to protect the amino group. For example, compound (a) can be treated with benzyl chloroformate to produce the carboxybenzyl (Cbz) protected amine (b). When J is hydroxyl group, other well-known protecting groups can be used in the alternative. The nitro group of compound (b) can then be reduced to an amino compound (c). Compound (c) can then be reacted with the carboxylic acid (d) in the presence of a coupling reagent to give compound (e). The protecting group on compound (e) can then be removed under appropriate conditions. For example, a Cbz protecting group can be removed by the hydrogenation using palladium on carbon in methanol solvent. The carboxylic acid (d) can be produced by the methods summarized above in General Scheme I (e.g., by reacting Ar ¹ - L'N(R')H with a cyclic anhydride).

General Scheme II

Compounds of Formula (II), wherein X is -NHAr can be produced by the method shown in General Scheme III. Accordingly, 3-iodobenzoic acid (a) is coupled with methyl acrylate (b) in the presence of a base and a palladium catalyst such as Pd(dppf) ₂ at a temperature such as 90 ⁰ C for several hours to produce intermediate (c). Intermediate (c) is then reacted with an amine (d) in the presence of a coupling agent such as l-ethyl-3-(3'- dimethylaminopropyl)carbodiimide (EDCI) and 1 -hydroxybenzotriazole (HOBt) to produce intermediate (e). Intermediate (e) can be hydrolyzed to give the carboxylic acid (f). The carboxylic acid can then be reacted mmol) with a second amine (g) in the presence of a coupling agent and a non-protic base to give the desired compound (h).

General Scheme III

Compounds of Formula (III), wherein x is 1 and R ³ is -R ^a or -N(R ^k ) ₂ , can be produced by the methods shown in General Scheme IV. The carboxylic acid (a) can first be reacted to produced the alkoxyamide (b) by reaction with a base, such as N-methylmophline, isobutylchloroformate, and Ν,O-dimethylhydroxylamine hydrochloride. The alkoxyamide (b) can then be reacted to give compound (c) by adding terf-butyllithium to ethyl vinyl ether, followed by treatment with magnesium bromide etherate, followed by treatment with the alkoxyamide (b). The ketone compound (d) can then be produced by treating compound (c) with concentrated hydrochloric acid. To produce the amide compound (f), compound (c) is instead treated with ozone at -78 ⁰ C in the presence of pyridine to give the ester compound (e) which is then reacted with an amine to give the amide compound.

Compounds of Formula (II), wherein X is selected from -C(=O)N(R ^a ) ₂ or -C(=O)R ^b can be made by methods analogous to those shown in General Scheme IV, except substituting compound (f) of General Scheme III for compound (a) of General Scheme IV. Accordingly, compounds analogous to those of compounds (d) and (f) of General Scheme IV can be produced.

General Scheme IV

Methods of Using HDAC3 Inhibitors

HDAC3 inhibitors described herein can be used prophylactically or as a treatment for various neurological conditions (e.g., neurological conditions associated with frataxin deficiency). More specifically, the HDAC3 inhibitors can be used to delay or prevent the onset of a neurodegenerative or neuromuscular condition, as well as to treat a mammal, such as a human subject, suffering from a neurological condition (e.g., a neurodegenerative or neuromuscular condition). Non- limiting examples of neurodegenerative conditions include, without limitation, fragile X syndrome, Friedreich's ataxia, Huntington's disease, spinocerebellar ataxias, amyotrophic lateral sclerosis, Kennedy's disease, spinal and bulbar muscular atrophy and Alzheimer's disease. Non-limiting examples of neuromuscular conditions include spinal muscular atrophy and myotonic dystrophy.

Mammals, e.g. humans, to which HDAC3 inhibitors can be administered include those suffering from, or diagnosed as having, the conditions discussed herein as well as those who are at risk for developing the above conditions. A mammal at risk for developing a neurodegenerative condition can be identified in numerous ways, including, for example, first determining (1) the length, extent, and/or number of repeats of particular nucleic acid sequences (e.g., a frataxin gene sequence, a huntingtin gene sequence, an ataxin gene sequence, a fragile X mental retardation (FMR]) gene sequence, a dystrophia myotonica protein kinase (DMPK) gene sequence, or an androgen receptor gene sequence) in the individual's genome; the degree of acetylation of core histones; or the expression level of a particular mRNA or protein (e.g., frataxin, huntingtin, brain derived neurotrophic factor (BDNF), peroxisome proliferator-activated receptor-gamma, coactivator 1 , alpha (PGClA), ataxin, fragile X mental retardation (FMRl), dystrophia myotonica protein kinase (DMPK), or androgen receptor), and then (2) comparing it with that of a normal individual (see Riley et al., 2006, Genes Dev., 20:2183-92; Tan et al., 2005, Expert Rev. MoI. Diagn., 5: 101-109; Everett et al., 2004, Brain, 127:2385-2405; Monckton et al., 1995, Circulation, 91 :513-520; and Caskey et al., 1992, Science, 256:784-789). An individual at risk for developing a neurodegenerative or neuromuscular condition is one who has an aberrant number of repeats of a particular nucleic aid sequence, degree of acetylation of core histones or expression of a particular gene. For example, an animal or person at risk for developing Friedreich's ataxia can be identified by determining the length, extent, or number of repeats of a GAA triplet in the first intron of the frataxin gene. A person would be at risk for Friedreich's ataxia if the above analysis indicates that there are more than 34 repeats of the GAA triplet, for example, if the person has more than 66 repeats of the GAA triplet. A person at risk for Friedreich's ataxia could also be identified by determining the levels of frataxin mRNA or protein expressed in the person. A person would be at risk for Friedreich's ataxia if the levels of frataxin mRNA or protein is lower than the level normally observed in a healthy individual such as for example, an unaffected sibling.

The DNA abnormality found in 98% of FRDA patients is an unstable hyper-expansion of a GAA triplet repeat in the first intron of the frataxin gene that results in a defect in transcription of the frataxin gene (see Campuzano et al., 1996, Science, 271 : 1423-27). FRDA patients have a marked deficiency of frataxin mRNA, and the longer the GAA triplet repeats, the more profound the frataxin deficiency. FRDA is typical of triplet repeat diseases: normal alleles have 6-34 repeats while FRDA patient alleles have 66-1700 repeats. Longer GAA triplet repeats are associated with earlier onset and increased severity of the disease. The invention provides for methods of identifying specific HDAC3 inhibitors that can restore gene function in a neurological disease that is associated with expansion of a triplet repeat, such as FRDA or Huntington's disease. For example, HDAC3 inhibitors can increase frataxin mRNA and protein in lymphocytes from FRDA patients. A "histone deacetylase 3 (HDAC3) inhibitor" is a small molecule that binds to HDAC3 to modulate the levels of acetylation of histones, non-histone chromosomal proteins, and other cellular proteins. An HDAC3 inhibitor identified by the methods described herein may interact with a HDAC3 to modulate the level of acetylation of cellular targets.

A histone deacetylase (HDAC), as described herein, can be any polypeptide having features characteristic of polypeptides that catalyze the removal of the acetyl group (deacetylation) from acetylated target proteins. Features characteristic of HDACs are known in the art, see, for example, Finnin et al., 1999, Nature, 401 : 188. Thus, an HDAC can be a polypeptide that represses gene transcription by deacetylating the ε-amino groups of conserved lysine residues located at the N-termini of histones, e.g., H3, H4, H2A, and H2B, that form the nucleosome. HDACs also deacetylate other proteins such as p53, E2F, α- tubulin, and MyoD. See Annemieke et al., 2003, Biochem. J., 370:737. HDACs can also be localized to the nucleus and certain HDACs can be found in both the nucleus and also the cytoplasm.

HDAC3-specific inhibitors described herein may interact with any HDAC. However, the HDAC3 inhibitors will have at least about 2-fold (e.g., at least about 5-fold, 10-fold, 15- fold, or 20- fold) greater activity to inhibit HDAC3 as compared to one or more other HDACs (e.g., one or more HDACs of class I or class II). Class I HDACs are those that most closely resemble the yeast transcriptional regulator RPD3. Examples of class I HDACs include HDACs 1, 2, 3 and 8, as well as any HDAC that has a deacetylase domain exhibiting from 45 % to 93 % identity in amino acid sequence to HDACs 1, 2, 3 and 8. Class II HDACs are those that most closely resemble the yeast HDACl enzyme. Examples of class II HDACs include HDACs 4, 5, 6, 7, 9 and 10.

The invention relates, inter alia, to the discovery that specific histone deacetylase 3 (HDAC3) inhibitors also increase expression of frataxin, and could therefore be useful in the treatment of neurological conditions (e.g., neurological conditions associated with reduced frataxin expression). Accordingly, the invention provides HDAC3 inhibitors, methods of treating various chronic and/or acute neurological conditions such as, for example, Friedreich's ataxia, and methods of identifying compounds that could be used as therapeutics for various chronic and/or acute neurological conditions such as, for example, Friedreich's ataxia. This application features methods of treating a neurological condition (e.g.,

Friedreich's ataxia, myotonic dystrophy, spinal muscular atrophy, fragile X syndrome, Huntington's disease, a spinocerebellar ataxia, Kennedy's disease, amyotrophic lateral sclerosis, spinal and bulbar muscular atrophy, or Alzheimer's disease) that include administering an HDAC inhibitor described herein to a patient having a neurological condition.

This application also features the use of an HDAC inhibitor described herein in the preparation of, or for use as, a medicament for the treatment or prevention of a neurological condition (e.g., Friedreich's ataxia, myotonic dystrophy, spinal muscular atrophy, fragile X syndrome, Huntington's disease, a spinocerebellar ataxia, Kennedy's disease, amyotrophic lateral sclerosis, spinal and bulbar muscular atrophy, or Alzheimer's disease).

The present invention also provides a method of treating a cancer in patient in need thereof, comprising administering a therapeutically effective amount of an HDAC inhibitor as described herein, or pharmaceutically, acceptable salt thereof. In some embodiments, the cancer is a solid tumor, neoplasm, carcinoma, sarcoma, leukemia, or lymphoma. In some embodiments, leukemias include acute leukemias and chronicleukemias such as acute lymphocytic leukemia (ALL), acute myeloid leukemia chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML) and Hairy Cell Leukemia; lymphomas such as cutaneous T-cell lymphomas (CTCL), noncutaneous peripheral T-cell lymphomas, lymphomas associated with human T-celllymphotrophic virus (fITLV) such as adult T-cell leukemia/lymphoma (ATLL), Hodgkin's disease and non-Hodgkin's lymphomas, large-cell lymphomas, diffuse large B-celllymphoma (DLBCL); Burkitt's lymphoma; primary central nervous system (CNS) lymphoma; multiple myeloma; childhood solid tumors such as brain tumors, neuroblastoma, retinoblastoma, Wilm's tumor, bone tumors, and soft-tissue sarcomas, common solid tumors of adults such as head and neck cancers (e.g., oral, laryngeal and esophageal), genito urinary cancers (e.g., prostate, bladder, renal, uterine, ovarian, testicular, rectal and colon), lung cancer, breast cancer.

In some embodiments, the cancer is (a) Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; (b) Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma], lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma [pinealoma], glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, .non-Hodgkin's lymphoma [malignant lymphoma]; Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands: neuroblastoma conditions.

The present invention further provides methods of treating an inflammatory disorder in a patient in need thereof, comprising administering a therapeutically effective amount of an HDAC inhibitor as described herein, or pharmaceutically, acceptable salt thereof. In some embodiments, the inflammatory disorder is an acute and chronic inflammatory disease, autoimmune disease, allergic disease, disease associated with oxidative stress, and diseases characterized by cellular hyperproliferation. Non-limiting examples are inflammatory conditions of a joint including rheumatoid arthritis (RA) and psoriatic arthritis; inflammatory bowel diseases such as Crohn's disease and ulcerative colitis; spondyloarthropathies; scleroderma; psoriasis (including T-cell mediated psoriasis) and inflammatory dermatoses such an dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria; vasculitis (e.g., necrotizing, cutaneous, and hypersensitivity vasculitis); eosinphilic myositis, eosinophilic fasciitis; cancers with leukocyte infiltration of the skin or organs, ischemic injury, including cerebral ischemia (e.g., brain injury as a result of trauma, epilepsy, hemorrhage or stroke, each of which may lead to neurodegeneration); HIV, heart failure, chronic, acute or malignant liver disease, autoimmune thyroiditis; systemic lUpus erythematosus, Sjorgren's syndrome, lung diseases (e.g., ARDS); acute pancreatitis; amyotrophic lateral sclerosis (ALS); Alzheimer's disease; cachexia/anorexia; asthma; atherosclerosis; chronic fatigue syndrome, fever; diabetes (e.g., insulin diabetes or juvenile onset diabetes); glomerulonephritis; graft versus host rejection (e.g., in transplantation); hemohorragic shock; hyperalgesia: inflammatory bowel disease; multiple sclerosis; myopathies (e.g., muscle protein metabolism, esp. in sepsis); osteoporosis; Parkinson's disease; pain; pre-term labor; psoriasis; reperfusion injury; cytokine-induced toxicity (e.g., septic shock, endotoxic shock); side effects from radiation therapy, temporal mandibular joint disease, tumor metastasis; or an inflammatory condition resulting from strain, sprain, cartilage damage, trauma such as burn, orthopedic surgery, infection or other disease processes. Allergic diseases and conditions, include but are not limited to respiratory allergic diseases such as asthma, allergic rhinitis, hypersensitivity lung diseases, hypersensitivity pneumonitis, eosinophilic pneumonias (e.g., Loeffler's syndrome, chronic eosinophilic pneumonia), delayed-type hypersensitivity, interstitial lung diseases (ILD) (e.g., idiopathic pulmonary fibrosis, or ILD associated with rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, systemic sclerosis, Sjogren's syndrome, polymyositis or dermatomyositis); systemic anaphylaxis or hypersensitivity responses, drug allergies (e.g., to penicillin, cephalosporins), insect sting allergies, and the like.

HDAC inhibitors have been shown to have antimalarial activity (Andrews et al., 2000, Int. J. Parasitol., 30:761 -768; Andrews et al., Antimicrob. Agents Chemother., 52: 1454-61). The present invention provides methods of treating a Plasmodium falciparum infection (e.g., malaria) in a patient in need thereof.

In another aspect, this application features use of an HDAC inhibitor described herein in the preparation of, or for use as, a medicament for the treatment or prevention of a cancer, an inflammatory disorder, or malaria. For test purposes, an HDAC3 inhibitor can be administered to an animal or cellular model of a neurological condition. In some embodiments, an HDAC3 inhibitor is administered to an animal model with a naturally occurring or genetically engineered triplet repeat expansion. Exemplary animal models are described in Al-Mahdawi et al., 2006, Genomics, 88:580-590; Rai et al., 2008, PLoS ONE 3:el958 doi: 10.1371/journal.pone.0001958; Wang et al., 2006, Acta Pharmacol. Sin. 27: 1287-1302; Butler et al., 2006, Nat. Rev. Neurosci., 7:784-796; Bates and Gonitel, 2006, MoI. Biotechnol., 32: 147-158; Puccio, 2007, Handb. Exp. Pharmacol., 178:365-375; Bates and Hay, 2004, Methods MoI. Biol., 277:3-15; Wansink and Wieringa, 2003, Cytogenet. Genome Res., 100:230-421; Merry et al., 2005, NeuroRx, 2:471-479; Gu and Nelson, 2003, Cytogenet. Genome Res., 100: 129-139; Hoogeveen et al., 2002, Microsc. Res. Tech., 57: 148-155; Gardian, 2006, Ideggyogy Sz., 59:396-399; Li et al., 2005, NeuroRx, 2:447-464; Levine et al., 2004, Trends Neurosci., 27:691-697; Everett and Wood, 2004, Brain, 127:2385-2405; Outeiro and Muchowski, 2004, J. MoI. Neurosci., 23:49-60; Beal and Ferrante, Nat. Rev. Neurosci., 5:373-384; Link, 2001 , Mech. Ageing Dev., 122: 1639-49; Heintz and Zoghbi, 2000, Annu. Rev. Physiol., 62:779-802; Martin, 2007, Rev. Neurosci., 18: 1 15-136; Cauchi and van den Heuvel, 2006, Neurodegener. Dis., 3:338-356; Grieb, 2004, Folia Neuropathol., 42:239-248; Robertson et al., 2002, Biochimie, 84: 1 151-60; Newman et al., 2007, Biochim. Biophys. Acta, 1772:285-297; Van Dam and De Deyn, 2006, Nat. Rev. Drug Discov., 5:956- 970; and Shaughnessy et al., J. MoI. Neurosci., 24:23-32.

For therapy or prophylaxis, the amount of HDAC3 inhibitor to be administered to the individual can be any amount appropriate to restore the level of histone acetylation, or the level of mRNA or protein expression, in the afflicted individual to that typical of a healthy individual such as an unaffected sibling. The amount of the HDAC3 inhibitor to be administered can be an effective dose or an appropriate fraction thereof, if administration is performed serially. Such amounts will depend on individual patient parameters including age, physical condition, size, weight, the condition being treated, the severity of the condition, and any concurrent treatment. For example, the effective dose range that is necessary to prevent or delay the onset of the neurodegenerative condition, can be lower than the effective dose range for inhibiting the progression of the condition being treated. Factors that determine appropriate dosages are well known to those of ordinary skill in the art and can be addressed with routine experimentation. For example, determination of the physicochemical, toxicological and pharmacokinetic properties can be made using standard chemical and biological assays and through the use of mathematical modeling techniques known in the chemical, pharmacological and toxicological arts. The therapeutic utility and dosing regimen can be extrapolated from the results of such techniques and through the use of appropriate pharmacokinetic and/or pharmacodynamic models. The precise amount of HDAC3 inhibitor administered to a patient will be the responsibility of the attendant physician.

In particular, HDAC3 inhibitors can be administered orally or by injection at a dose of from 0.1 to 30 mg per kg weight of the mammal, typically 2 to 15 mg/kg weight of the mammal. The dose range for adult humans is generally from 8 to 2,400 mg/day, e.g., from 35 to 1,050 mg/day. If the salt of the compound is administered, then the amount of salt administered is calculated in terms of the base.

HDAC3 inhibitors can be administered in numerous ways. For example, the HDAC3 inhibitors can be administered orally, rectally, topically, or by intramuscular, intraperitoneal subcutaneous or intravenous injection. Preferably, the inhibitors are administered orally or by injection. Other routes include intrathecal administration directly into spinal fluid and direct introduction onto, in the vicinity of, or within the target cells. The route of administration will depend on the condition being treated and its severity.

Toxicity and therapeutic efficacy of HDAC3 inhibitors can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50/ED50. Compounds that exhibit high therapeutic indices are preferred. In another embodiment, the therapeutic index can be estimated by assaying the HDAC3 specific inhibitory activity of a HDAC3 inhibitor (the HDAC3 ICs ₀ ) as compared to the growth inhibitory activity of the HDAC3 inhibitor on a cell in vitro, e.g., a HepG2 cell or other cell line (the growth ICs ₀ ). The ratio between the growth inhibitory (e.g., cytotoxic or cytostatic) effect and the HDAC3 specific inhibitory effect provides an estimate of the therapeutic index.

Methods of Assaying Test Compounds In one aspect, the invention features methods of identifying a candidate compound for treatment of a neurological condition by obtaining a test compound; assaying a first activity of the test compound to inhibit histone deacetylase activity of a histone deacetylase 3 (HDAC3); assaying a second activity of the test compound to inhibit histone deacetylase activity of a class I histone deacetylase other than the HDAC3 (e.g., HDACl, HDAC2, or HDAC8); and identifying the test compound as a candidate compound for treatment of a neurological condition associated with a frataxin deficiency if the first activity of the test compound is greater than the second activity of the test compound.

In another aspect, the invention features methods of identifying a candidate compound for treatment of a neurological condition by obtaining a test compound; assaying a first activity of the test compound to inhibit histone deacetylase activity of a HDAC3; assaying a second activity of the test compound to inhibit histone deacetylase activity of a HDACl ; assaying a third activity of the test compound to inhibit histone deacetylase activity of a HDAC2; assaying a fourth activity of the test compound to inhibit histone deacetylase activity of a HDAC8; and identifying the test compound as a candidate compound for treatment of a neurological condition if the first activity of the test compound is greater than each of the second, third, and fourth activities of the test compound.

In a further aspect, the invention features methods of identifying a candidate compound for treatment of a neurological condition by obtaining a test compound; assaying a first activity of the test compound to inhibit histone deacetylase activity of a HDAC3; assaying a second activity of the test compound to inhibit histone deacetylase activity of a class I or class II histone deacetylase other than the HDAC3 (e.g., HDACl, HDAC2, HDAC4, HDAC5, HDAC6, HDAC7, HDAC8, HDAC9, or HDAClO); and identifying the test compound as a candidate compound for treatment of a neurological condition associated with a frataxin deficiency if the first activity of the test compound is greater than the second activity of the test compound.

In another aspect, this application features methods of identifying a candidate compound for treatment of a neurological condition by obtaining a test compound; assaying a first activity of the test compound to inhibit histone deacetylase activity of a HDAC3; assaying a set of activities of the test compound to inhibit histone deacetylase activity of each of histone deacetylases 1 , 2, 4, 5, 6, 7, 8, 9, and 10; and identifying the test compound as a candidate compound for treatment of a neurological condition if the first activity of the test compound is greater than each activity of the set of activities of the test compound.

In some embodiments of the methods described herein, one or more of the HDACs (e.g., HDAC3) is a human HDAC (e.g., a human HDAC3).

In some embodiments of the methods described herein, the test compound is identified as a candidate compound for treatment of a neurological condition if the first activity is at least about 1.5-fold greater (e.g., at least about 2-fold, 3-fold, 4-fold, 5-fold, 10- fold, 15-fold, or 20-fold greater) than another activity (e.g., the second, third, or fourth activity, or each activity of the set of activities).

In some embodiments of the methods described herein, the neurological condition is Friedreich's ataxia, myotonic dystrophy, spinal muscular atrophy, fragile X syndrome, Huntington's disease, a spinocerebellar ataxia, Kennedy's disease, amyotrophic lateral sclerosis, spinal and bulbar muscular atrophy, or Alzheimer's disease. In some embodiments of the methods described herein, the neurological condition is associated with expansion of a triplet repeat (e.g., Friedreich's ataxia, myotonic dystrophy, spinal muscular atrophy, fragile X syndrome, Huntington's disease, spinocerebellar ataxias, or Kennedy's disease). In some embodiments of the methods described herein, the methods further include assaying the activity of the candidate compound to increase expression of one or more genes whose expression is decreased in the neurological condition (e.g., frataxin, huntingtin, brain derived neurotrophic factor (BDNF), peroxisome proliferator-activated receptor-gamma, coactivator 1 , alpha (PGCl A), ataxin, fragile X mental retardation (FMRl), dystrophia myotonica protein kinase (DMPK), or androgen receptor). In some embodiments, the activity of the candidate compound to increase expression of one or more genes whose expression is decreased in the neurological condition is measured in an animal, e.g., an animal model of the neurological condition.

In some embodiments of the methods described herein, the method is repeated for a plurality of test compounds (e.g., at least 10, 20, 50, 100, 200, 500, or 1000 test compounds).

In another aspect, this application features methods of treating a neurological condition (e.g., Friedreich's ataxia, myotonic dystrophy, spinal muscular atrophy, fragile X syndrome, Huntington's disease, spinocerebellar ataxias, Kennedy's disease, amyotrophic lateral sclerosis, spinal and bulbar muscular atrophy, or Alzheimer's disease) that include performing any of the methods described herein, formulating the candidate compound in a pharmaceutical composition, and administering the pharmaceutical composition to a patient having a neurological condition.

Specific inhibitors of HDAC3 provide advantages for treatment of neurological conditions over the use of broad-spectrum HDAC inhibitors by reducing toxicities associated with inhibition of other HDACs. Such specific HDAC3 inhibitors provide a higher therapeutic index, resulting in better tolerance by patients during chronic or long-term treatment.

In certain aspects, HDAC3 inhibitors are found by identifying test compounds (e.g., from a group of test compounds) that inhibit the activity of HDAC3 more, e.g., 2, 3, 4, 5, 10, or more times, than they inhibit the activity of one or more other HDACs. HDAC inhibitory activity of test compounds can be assayed by standard means. Briefly, an assay typically involves incubating an acetylated HDAC substrate with a HDAC enzyme in the presence or absence of a test compound and detecting the removal of acetyl groups from the substrate. HDAC inhibition assays can be performed, e.g., in a cell, in a cell extract, or in a cell-free mixture. Exemplary HDAC inhibition assays are described in Perez-Balado et al., 2007, J. Med. Chem., 50:2497-2505; Herman et al., 2006, Nat. Chem. Biol., 2:551-558; and Beckers et al., 2007, Int. J. Cancer, 121 :1 138-48. HDAC assay kits are commercially available from BIOMOL (Plymouth Meeting, PA) and Upstate (Charlottesville, VA). A small molecule microarray method for screening for HDAC inhibitors is described in Vegas et al., 2007, Angew. Chem. Int. Ed. Engl., 46:7960-64.

HDAC3 and other HDAC enzymes can be provided, e.g., as purified proteins, partially purified proteins, purified recombinant proteins, in cells, or cell extracts. Purification or partial purification of HDAC3 and other HDAC enzymes can be performed by standard means, including affinity chromatography and immunoprecipitation.

The HDAC substrate can be a commercially available substrate (e.g., Fluor de Lys™, BIOMOL) or an acetylated cellular HDAC substrate, e.g., histone H2A, histone H2B, histone H3, histone H4, α-tubulin, NFκB-3, or p53. Exemplary substrates further include acetylated peptides of the preceding proteins, e.g., residues 2-24 or 1-18 of Histone H4. The deacetylation of the HDAC substrate can be detected by standard means.

Commercially available substrates are provided with fluorimetric or colorimetric reagents that detect deacetylated lysines. In other aspects, the substrate can be ³ H-acetylated, and deacetylation is detected by measuring the release of ³ H from the substrate. In further aspects, antibodies can be used to distinguish acetylated substrates from deacetylated substrates. For example, antibodies specific for acetylated α-tubulin are available from Sigma, and antibodies specific for acetylated histone H3 are available from Upstate.

Compounds identified as HDAC3 inhibitors can be further tested for induction of expression of one or more genes that are underexpressed in a neurological disorder, e.g., frataxin (GenBank Accession No. NM OOO 144.3), huntingtin (GenBank Accession No. NM 0021 1 1.6), brain derived neurotrophic factor (BDNF; GenBank Accession No.

NM l 70735.4), peroxisome proliferator-activated receptor-gamma, coactivator 1 , alpha (PGCl A; GenBank Accession No. NM 013261.3), ataxins (e.g., ataxin 1 (GenBank Accession No. NM 000332.2), fragile X mental retardation (FMRl ; GenBank Accession No.

NM 002024.3), dystrophia myotonica protein kinase (DMPK; GenBank Accession No. NM_004409.3), or androgen receptor (GenBank Accession No. NM_000044.2). Listed GenBank accession numbers indicate exemplary human cDNA sequences and are not meant to be limiting. Sequences of other alleles or alternatively spliced versions can also be used. Typically, the inhibitor is administered to a cell or cell-free extract that expresses a nucleic acid or protein product of the gene, and the expression of the gene product is compared to its expression in the absence of the inhibitor. Any cells can be used, including primary cells obtained from a subject (e.g., a subject having a neurological disorder) or cells of a cell line. Exemplary cells include neural cells, neuronal cells, and lymphocytes. The cells can be isolated and stored frozen in aliquots to provide ease in scaling the assay to allow multiple samples or multiple assays to be done with the same cell source. In one embodiment, the cells are lymphocytes (e.g., derived from Friedreich's ataxia patients), which are primary cells or cells of a lymphoblastoid cell line.

Determination of the expression of nucleic acid and protein gene products can be accomplished by any of several standard methods. Nucleic acid expression can be determined, e.g., by hybridization (e.g., Northern blotting), nucleic acid microarrays, PCR

(e.g., reverse transcription-PCR (RT-PCR) or quantitative RT-PCR), primer extension, serial analysis of gene expression, nuclease protection assays, or reporter gene constructs. Protein expression can be determined, e.g., by immunoblotting (e.g., Western blotting), immunoprecipitation, immunosorbent assay (e.g., ELISA or RIA), peptide microarrays, or fusion proteins (e.g., GFP fusions).

Useful compounds for chronic treatment include those that inhibit HDAC3 at concentrations that do not show significant cytotoxic activity. Cytotoxic activity can be measured by incubating compounds with an indicator cell line (e.g., the human transformed liver cell HepG2). Viable cell number is determined after an incubation period, typically between 24-72 hours following administration of the compound. Viable cells can be determined by many methods including but not limited to cell counting or using a substrate converted to a colored product by live cells such as MTS. The ratio of HDAC3 activity to cytotoxicity can identify molecules that increase expression of gene products reduced by disease and are tolerable to administration over long periods of time.

Pharmaceutical Compositions and Kits

HDAC3 inhibitors can be administered neat or formulated as pharmaceutical compositions. Pharmaceutical compositions include an appropriate amount of the HDAC inhibitor in combination with an appropriate carrier and optionally as other useful ingredients.

Acceptable salts of HDAC inhibitors include, but are not limited to, those prepared from the following acids: alkyl, alkenyl, aryl, alkylaryl and alkenylaryl mono-, di- and tricarboxylic acids of 1 to 20 carbon atoms, optionally substituted by 1 to 4 hydroxyls; alkyl, alkenyl, aryl, alkylaryl and alkenylaryl mono-, di- and trisulfonic acids of 1 to 20 carbon atoms, optionally substituted by 1 to 4 hydroxyls; dibasic acids (e.g., fumaric; glutaric; maleic; salicyclic; tartaric (including (+)-L-tartaric); malonic; and succinic acids); and mineral acids. Examples include hydrochloric; hydrobromic; sulfuric; nitric; phosphoric; lactic (including (+)-L-lactic, (+/-)-DL-lactic); acetic; p- toluenesulfoniccitric; methanesulfonic; formic; malonic; succinic; naphthalene-2-sulfonic; and benzenesulfonic acid.

Pharmaceutical compositions of HDAC3 inhibitors suitable for oral administration can be in the form of (1) discrete units such as capsules, sachets, tablets, or lozenges each containing a predetermined amount of the HDAC3 inhibitor; (2) a powder or granules; (3) a bolus, electuary, or paste; (4) a solution or a suspension in an aqueous liquid or a nonaqueous liquid; or (5) an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. Compositions suitable for topical administration in the mouth, for example buccally or sublingually, include lozenges. Compositions suitable for parenteral administration include aqueous and non-aqueous sterile suspensions or injection solutions. Compositions suitable for rectal administration can be presented as a suppository.

Pharmaceutical compositions of HDAC3 inhibitors can be formulated using a solid or liquid carrier. The solid or liquid carrier should be compatible with the other ingredients of the formulation and not deleterious to the recipient. If the pharmaceutical composition is in tablet form, then the HDAC3 inhibitor is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. If the composition is in powder form, the carrier is a finely divided solid in admixture with the finely divided active ingredient. The powders and tablets can contain up to 99% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins. A solid carrier can include one or more substances that can act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents. A suitable carrier can also be an encapsulating material. If the composition is a solution, suspension, emulsion, syrup, elixir, or pressurized composition, then liquid carriers can be used. In this case, the HDAC3 inhibitor is dissolved or suspended in a pharmaceutically acceptable liquid carrier. Suitable examples of liquid carriers for oral and parenteral administration include (1) water; (2) alcohols, e.g. monohydric alcohols and polyhydric alcohols such as glycols, and their derivatives; and (3) oils, e.g. fractionated coconut oil and arachis oil. For parenteral administration, the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Liquid carriers for pressurized compositions include halogenated hydrocarbon or other pharmaceutically acceptable propellant. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers; emulsifiers; buffers; preservatives; sweeteners; flavoring agents; suspending agents; thickening agents; colors; viscosity regulators; stabilizers; osmo-regulators; cellulose derivatives such as sodium carboxymethyl cellulose; antioxidants; and bacteriostatics. Other carriers include those used for formulating lozenges such as sucrose, acacia, tragacanth, gelatin and glycerin as well as those used in formulating suppositories such as cocoa butter or polyethylene glycol.

If the composition is to be administered intravenously or intraperitoneal Iy by infusion or injection, solutions of the HDAC3 inhibitor can be prepared in water, optionally mixed with a nontoxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. The composition suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient, which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. In all cases, the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or liquid dispersion medium as described above. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin. Sterile injectable solutions are prepared by incorporating the HDAC3 inhibitor in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze-drying techniques, which yield a powder of the HDAC3 inhibitor, plus any additional desired ingredient present in the previously sterile- filtered solutions.

Pharmaceutical compositions can be in unit-dose or multi-dose form or in a form that allows for slow or controlled release of the HDAC3 inhibitor. Each unit-dose can be in the form of a tablet, capsule or packaged composition such as, for example, a packeted powder, vial, ampoule, prefilled syringe or sachet containing liquids. The unit-dose form also can be the appropriate number of any such compositions in package form. Pharmaceutical compositions in multi-dose form can be in packaged in containers such as sealed ampoules and vials. In this case, the HDAC3 inhibitor can be stored in a freeze- dried (lyophilized) condition requiring only the addition of a sterile liquid carrier immediately prior to use. In addition, extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules and tablets of the kind previously described.

The application also provides a kit for the treatment or prevention of a disorder selected from Friedreich's ataxia, myotonic dystrophy, spinal muscular atrophy, fragile X syndrome, Huntingdon's disease, a spinocerebellar ataxia, Kennedy's disease, amyotrophic lateral sclerosis, spinal and bulbar muscular atrophy, and Alzheimer's disease in a patient in need thereof, comprising (i) a compound described herein, or a pharmaceutically acceptable salt thereof; and (ii) instructions comprising a direction to administer said compound to said patient.

EXAMPLES Example 1. RGFA8 Increases Expression of Frataxin

To determine whether RGFA8 (N ^l -(2-aminophenyl)-N ⁷ -/?-tolyl-l,7-heptanedioic acid diamide; WO 2007/058927) or other compounds could increase expression of frataxin, human lymphocytes isolated from peripheral blood from normal donors were incubated with 1-30 μM RGFA8. Frataxin mRΝA levels were measured with quantitative RT-PCR and normalized to expression levels of the housekeeping gene GADPH (Herman et al., Nat. Chem. Biol., 2:551-558, 2006).

RGFA8 increased expression of frataxin in normal lymphocytes or patient lymphocytes at all concentrations tested, with a maximum observed increase of about 16-fold compared to vehicle control (FIG. 1, normal lymphocytes). This example indicates that RGFA8 could be used to treat patients with Friedreich's ataxia by increasing frataxin expression.

Example 2. RGF A8 is a Specific Inhibitor of HDAC3

To determine whether RGFA8 was specific for any particular HDAC or subset of HDACs, the activities of RGFA8 and known HDAC inhibitor trichostatin A (TSA) were tested on a panel of individual purified HDAC enzymes and a nuclear extract, which contained a mixture of HDACs. HDAC enzyme inhibition assays were performed using purified HDACs 1-10 essentially as described in Beckers et al., 2007, Int. J. Cancer.,

121 : 1 138-48 and Perez-Balado et al., 2007, J. Med. Chem., 50:2497-2505. Inhibition assays using nuclear extract were performed essentially as described in Herman et al., 2006, Nat. Chem. Biol., 2:551-558. Briefly, the purified HDACs or nuclear extract were incubated with an acetylated substrate in the absence of the compound to be assayed and with increasing concentrations of the compound. The rate of substrate deacetylation was measured under each condition, and half-maximal inhibitory concentration with regard to each HDAC was determined by standard means.

RGFA8 was most active on HDAC3, with a half-maximal inhibitory concentration (IC ₅₀ ) of 0.20 ± 0.23 μM (Table 1). At least 10-fold lesser activity was observed by RGFA8 on other HDACs or on nuclear extract. Although TSA was found to be a more potent inhibitor of HDAC3 than RGF8, TSA had greater inhibitory activity on HDAC6 (IC ₅₀ of 0.0014 ± 0.0006) and HDACl (IC ₅₀ of 0.0067 ± 0.001 1) as compared to HDAC3 (IC ₅₀ of 0.0096 ± 0.0071). Sub-micromolar inhibition by TSA was observed for all HDACs tested.

Table 1. Inhibition of HDAC Activity by RGFA8 and TSA

This example demonstrates that RGFA8 specifically inhibits HDAC3 as compared to other human HDACs. HDAC inhibitors that are specific for HDAC3 can be used to treat neurological conditions (e.g., Friedreich's ataxia).

Example 3. Screen for HDAC3 Inhibitors

A chemical library was screened to identify compounds that specifically inhibited HDAC3, relative to other HDACs. Briefly, a chemical library of test compounds was created by standard organic chemistry methods, and the inhibitory activity of the compounds on purified HDACs 1 -10 was determined (see Example 2). Fourteen compounds were identified that had stronger inhibitory activity for HDAC3 as compared to one or more other HDACs. These compounds, their structures, and inhibitory activities for HDACl , HDAC2, HDAC3, HDAC5, are presented in Table 2, along with growth inhibitory activity on HepG2 cells. HDAC inhibitory activities were measured essentially as described in Example 2. Growth inhibition of HepG2 cells was measured by adding serial dilutions of the compounds to HepG2 cells at a density of 5* 10 ⁴ cells/ml, and incubating the mixture for 72 hours at 37 ⁰ C, 5% CO ₂ . The viable cells were then measured using a CellTiter 96™ AQueous One Solution cell proliferation assay (Promega, Madison, WI). The activities of RGFA 8 and the known HDAC inhibitor MS 275 are also presented.

Table 2. Activity of Identified HDAC3 Inhibitors

Example 4. Additional HDAC3 Inhibitors

Additional HDAC3 inhibitors were identified as above. The activities of the compounds to inhibit HDACl and HDAC3 are listed in Table 3.

Table 3. Activity of Additional HDAC3 Inhibitors

The additional compounds were also tested for growth inhibitory activity as described above using both HepG2 cells and HCTl 16 cells. The results of growth inhibition and relative inhibitory activity on HDACl as compared to HDAC3 is presented in Table 4.

Table 4. Relative Inhibition and Proliferation Inhibition of HDAC3 Inhibitors

N. D.: Not determined.

Relative inhibitory activities for selected compounds were determined by dividing the IC ₅₀ for HDACs 1 , 2, and 5 by the IC ₅₀ for HDAC3 (Table 5). The estimated therapeutic index for each compound was determined by dividing the HepG2 growth IC ₅₀ by the IC50 for HDAC3 activity (Table 5).

Example 4. HDAC Inhibitors Increase Frataxin Expression

Selected compounds were assayed by quantitative RT-PCR for their activity to increase expression of frataxin (FXN]) mRNA in human lymphocytes isolated from peripheral blood of normal donors (see Example 1). Briefly, the identified compounds were added to lymphocytes at a concentration of 10 μM, and increase in expression of FXNl mRNA was determined compared to vehicle control. The majority of the identified compounds increased frataxin mRNA expression at a concentration of 10 μM (Table 5), indicating that these compounds can be useful in treatment of Friedrich's ataxia and other neurological disorders described herein.

Table 5. Relative HDAC Inhibition Activities and Effect on FXNl Expression

N. D.: Not determined. 5

Example 5. HDAC Inhibitors Increase Frataxin Expression In Vivo

Compound B04 is administered to knock-in mice homozygous for a (GAA) ₂₃₀ repeat in the first intron of the endogenous frataxin gene (Miranda et al., 2002, FEBS Lett., 512:291-297). The mice are treated by subcutaneous daily injections with 150 mg/kg of

10. compound or its equivalent of vehicle, for 3 consecutive days. Brain, heart, and skeletal muscle are recovered 24 hours after the last injection. Total RNA from brain stem, heart, and/or cerebellum is extracted. Frataxin mRNA expression is determined by one step quantitative real-time PCR using the primers 5 '-CCTGGCCGAGTTCTTTGAAGO ' (SEQ ID NO: 1) and 5 '-GCCAGATTTGCTTGTTTGGO ' (SEQ ID NO:2). Frataxin mRNA is

15 significantly lower in the brain, cerebellum and heart of vehicle-treated knock-in mice than in similarly treated wild-type animals. Treatment with compound B04 increases knock-in frataxin mRNA to levels that do not significantly differ from wild-type, thus demonstrating correction of fxn defciciency in these animals. Western blotting confirms that increased fxn mRNA levels result in higher frataxin protein level. Treatment with compound B04 does not result in increased frataxin mRNA levels in wild-type animals, indicating that its effect is due to removal of the inhibition caused by the GAA expansion.

Example 6. Synthesis of BOl

Λ^-^-amino-^fluorophenylJ-Λ^-p-tolyl-l^-heptanedioic acid diamide (BOl)

The title compound was made by the use of scheme 1, by adding the arylamine with the ortho-amino group in the second step, described below in 23% yield. ¹ H NMR (300 MHz, CD ₃ OD) δ 7.43 (d, 2H, J=8.4 Hz), 7.11 (d, 2H, J=8.4 Hz), 7.02 (m, 1 H), 6.53 (m, 1 H), 6.34 (m, 1 H), 2.43 (m, 4H), 2.30 (s, 3H), 1.77 (m, 4H), 1.50 (m, 2H).

Scheme 1

Example 7

Synthesis of Intermediate (a): Pimelic Anhydride

A solution of pimelic acid (4.8 g, 30 mmol) in acetic anhydride (100 mL) is refluxed for 3 hours. After cooling to ambient temperature, the solvent is removed and xylene (30 mL) added. The mixture is evaporated to dryness to give the title compound as a pale yellow solid (4.8 g, quantitative). The product cam be used directly in next reaction without further purification. GC-MS (M ⁺ ) 142, HPLC > 95% purity (214 nm, UV). Example 8

Synthesis of General Intermediate (c)

To a solution of pimelic anhydride (30 mmol) in anhydrous THF (40 mL) is added amine (b) (45 mmol). The solution is stirred at ambient temperature for 1 hour. The solvent was removed and the residue is treated with 3 N aqueous solution of sodium hydroxide (20 mL), washed with ethyl acetate (2 X 30 mL). The aqueous phase is acidified with concentrated HCl to pH = 3, the resulting precipitate is filtered and dried to give general intermediate (c)

Synthesis of General Compound (e) l -(3-Dimethylamino-propyl)-3-ethylcarbodiimine hydrochloride (230 mg, 1.2 mmol) is added in portions to a solution of general intermediate (c) (1 mmol), Et 3N (121 mg, 1.2 mmol), 4-N,N-dimethylaminopyridine (61 mg, 0.5 mmol) and amine (d) (1 mmol) in dichloromethane (5 mL). The mixture is stirred at ambient temperature for 18 hours, and then diluted with dichloromethane (30 mL) and washed with water (2 x 20 mL), then dried and concentrated. The residue can be purified by preparative TLC to give general compound (e).

Example 9. Synthesis of B02

(E)-Ν-(3-(3-(2-aminophenylamino)-3-oxoprop-l-enyl)phenyl )-4- methylbenzamide (B02) was made according to scheme 2(A).

Scheme 2(A)

3-(2-Methoxycarbonylvinyl)benzoic acid

A mixture of 3-iodobenzoic acid (12.5 g, 50 mmol), acrylic acid methyl ester (13 g, 150 mmol), triethylamine (35 ml, 250 mmol), Pd(dppf>2 (2 g, 2.5 mmol) and DMF (150 mL) was stirred at 90 ⁰ C for 14 hours. After cooling, the mixture was poured into water. The solid was collected by filtration and washed with water, dried to give the title compound (8 g, 78%). The product was used in the next step without further purification. ¹ H NMR (300MHz, DMSO-ύk) δ 13.06 (s, I H), 8.17 (s, I H), 7.95-7.97 (m, 2H), 7.62 (d, J= 7.8 Hz, I H), 7.51-7.53 (m, I H), 6.67 (d, J= 16.00 Hz, I H), 3.72 (s,3H).

Methyl 3-(3-(/Molylaminocarbonyl)phenyl)acrylate

A mixture of 3-(2-methoxycarbonylvinyl)benzoic acid (1.3 g, 5 mmol), /?-toluidine (540 mg, 5 mmol), EDCI (960 mg, 5 mmol), HOBt (1.35 g, 10 mmol) and triethylamine (1.01 g, 10 mmol) in dichloromethane (50 mL) was stirred at room temperature under nitrogen overnight. The reaction mixture was washed with water, 1 N hydrochloric acid, 2 N sodium hydroxide solution and brine, dried (Na ₂ SO,)) and evaporated to give the title compound (0.92 g, 62%) as a solid, which was used in the next step without further purification. ¹ H NMR (300MHz, DMSO-^ ₆ ) δ 10.21 (s, 1 H), 8.28 (s, 1 H), 7.94-7.98 (m, 2H), 7.69 (d, J = 16.2 Hz, I H), 7.55-7.64 (m, 3H), 7.17 (d, J= 8.1 Hz, I H), 6.67 (d, J= 16.2 Hz, I H), 3.75 (s,3H), 2.23 (s,3H).

3-(3-p-Tolylaminocarbonyl-phenyl)acrylic acid

To a slution of methyl 3-(3-(/?-tolylaminocarbonyl)phenyl)acrylate (0.89 g, 3 mmol) in methanol (50 mL) was added lithium hydroxide (0.36 g, 15 mmol) and water (5 mL). The reaction mixture was stirred at ambient temperature for 16 hours, evaporated to remove methanol, and water (20 mL) was added. The aqueous solution was washed with ethyl acetate and then acidified with 1 N hydrochloric acid. The product was extracted with ethyl acetate, washed with water, brine, dried (Na ₂ SC> ₄ ) and evaporated to give the title compound (0.76 g, 89%) as a solid, which was used in the next step without further purification. ¹ H NMR (300MHz, DMSO-^ ₆ ) δ 12.51 (s, IH), 10.22 (s, IH), 8.25 (s, I H), 7.88-7.96 (m, 2H), 7.54- 7.70 (m, 4H), 7.17 (d, J= 8.1 Hz, 2H), 6.67 (d, J= 16.2 Hz, IH), 2.23 (s,3H).

3-|(£)-2-(2-(amino)phenylaminocarbonyl)vinyl]-Λ ^r -/7-tolylbenzamide (B02).

A mixture of 3-(3-/?-tolylaminocarbonylphenyl)acrylic acid (658 mg, 2.34 mmol), benzene- 1 ,2- diamine (253 mg, 2.34 mmol), EDCI (449 mg, 2.34 mmol), HOBt (632 mg, 4.68 mmol) and triethylamine (473 mg, 4.68 mmol) in dichloromethane (20 mL) was stirred at room temperature under nitrogen overnight. The precipitate was filtered and washed with water and dichloromethane, and then dried to give the title compound (387 mg, 43%) as a white solid. ¹ H NMR (DMSO): δ 10.30 (s, IH,), 9.46 (s, IH), 8.20 (s, IH,), 7.97 (d, J= 7.5 Hz, 1 H), 7.83 (d, J = 7.5 Hz, 1 H),7.59-7.64 (m, 4H), 7.39 (d, J = 7.5 Hz, 1 H), 7.17-7.20 (m, 2H), 7.06 (d, J= 15.6 Hz, IH), 6.91-6.96 (m, I H), 6.77 (d, J= 7.8 Hz, IH), 6.58-6.62 (m, I H), 5.00 (s, 2H), 2.29 (s, 3H). LC-MS: 372( MH _} , purity > 95%. Example 10. Synthesis of B03 Λ^-(2-amino-4-fluorophenyl)-Λ' ⁷ -(pyridin-2-yl)-l,7-heptanedioic acid diamide (B03)

The title compound was made using procedures analogous to those used to make as Example 6 in 27% yield.

Example 11. Synthesis of B04 Λ ^fI -(2-aminophenyl)-Λ ^r7 -(4-fluorophenyl)-l,7-heptanedioic acid diamide (B04)

The title compound was made using procedures analogous to those used to make Example 6 in 32% yield. ¹ H NMR (300 MHz, DMSO-J6) δ 7.59 (m, 2H), 7.12 (m, 3H), 6.86 (m, I H), 6.69 (m, IH), 6.52 (m, I H), 2.30 (m, 4H), 1.61 (m, 4H), 1.35 (m, 2H).

Example 12. Synthesis of B05 yv'-(2-aminophenyl)-Λ' ⁷ -(thiophen-2-ylmethyl)-l,7-heptanedioic acid diamide (BOS)

The title compound was made using procedures analogous to those used to make Example 6 in 28% yield. Example 13. Synthesis of B06 7V ¹ -(2-(lH-imidazoI-4-yl)ethyl)-7V ⁷ -(2-aminophenyl)-l,7-heptanedioic acid diamide (B06)

The title compound was made using procedures analogous to those used to make Example 6 in 19% yield. ¹ H NMR (DMSO): 69.14 (s, IH), 7.88 (s, IH), 7.79 (s, IH), 7.16 (m, I H), 6.86-6.91 (m, 2H), 6.70-6.72 (m, IH), 6.50-6.55 (m, lH),3.24-3.37 (m, 2H), 2.62- 2 _; 70(m, 3H),2.28-2.33(2H, m), 2.04-2.08 (m, 2H) ,1.47-1.58 (m, 4H), 1.24-1.29 (m, 4H). LC- MS: 344 (MH ) ⁺ purity >93%.

Example 14. Synthesis of B07 yV'-(2-aminophenyl)-/V ⁷ -(2-(trifluoromethoxy)phenyl)-l,7-heptanedioic acid diamide (B07)

The title compound was made using procedures analogous to those used to make Example 6 in 43% yield. ¹ H NMR (300 MHz, CDCl ₃ ) 58.35 (s, 1 H), 57.56-7.24 (m, 2H),

57.1 1 -7.06 (m, 2H), 57.04-6.89 (m, 2H), 56.85-6.82 (m, 2H), 52.48-2.42 (m, 4H), 51.83-1.78 (m, 4H), 51.55- 1.51 (m, 2H); LC-MS>95% (Purity), 410 (MH) ⁺ ; HPLC 99% (Purity).

Example 15. Synthesis of B08 yv'-(2-aminophenyl)-yV ⁷ -(2,6-dimethoxypyridin-3-yl)-l,7-heptanedioic acid diamide (B08) was made according to scheme 3(A), using 2-amino-N-(9- florenylmethoxycarbonyl)aniline in the third step. Scheme 3(A)

(9H-fluoren-9-yl)methyl 2-aminophenylcarbamate

To a solution of benzene- 1 ,2-diamine (21.69 g, 0.195 mol) and NaHCO ₃ (32.76 g, 0.390 mol) in 1 ,4-dioxane (250 mL) and water (500 mL) was added a solution of Fmoc-CI (30.3 g 0.1 17 mol) in 1 ,4-dioxane (250 mL) dropwise. The resulting mixture was stirred at room temperature overnight. 1,4-Dioxane was removed under reduced pressure. The product was extracted with EtOAc. The organic layer was dried over Na ₂ SO ₄ . The solvent was evaporated to give the title compound (31.6 g, 48%) as a white solid. LC-MS 331 (M+l) ⁺ .

N-|2-(9H-fluoren-9-yl)methoxy)carbonylamino)phenyl]-l,7-h eptanedioic acid amide

A solution of (9H-fluoren-9-yl)methyl-2-aminophenylcarbamate (5 g, 0.015 mol) and oxepane-2,7-dione (1.8 g, 0.012 mol) in THF (50 mL) was stirred at room temperature overnight. The solvent was evaporated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and 2N NaOH (30 mL) was added slowly on cooling. The aqueous layer was washed with EtOAc three times. Then IN HCl (60 mL) were added to acidify the aqueous layer. The precipitate was filtered to give the title compound (3.6 g, 50%) as a white solid. LC-MS 473 (M+l).

W'-^o-dimethoxypyridin-a-yO-WMZ-^H-fluoren-^ yl)methoxycarbonylamino)phenyl]-l,7-heptanedioic acid diamide

A mixture of N-[2-(9H-fluoren-9-yl)methoxy)carbonylamino)phenyl]-l ,7- heptanedioic acid amide (640 mg, 1.36 mmol), 2,6-dimethoxypyridin-3-amine (258 mg, 1.36 mmol), HBTU (516 mg, 1.36 mmol), and DIPEA (351 mg, 2.72 mmol) in THF (50 mL) was stirred at room temperature overnight. The solvent was removed and the residue was purified by column chromatograph on silica gel (petroleum ether / ethyl acetate = 3: 1 to 1 : 1 ) to give the title compound (494 mg, 60%).

7V ¹ -(2-aminophenyl)-iV ⁷ -(2,6-dimethoxypyridin-3-yl)-l,7-heptanedioic acid diamide (B08)

A solution of N'-(2,6-dimethoxypyridin-3-yl)-N ⁷ -[2-((9H-fluoren-9- yl)methoxycarbonylamino)phenyl]-l ,7-heptanedioic acid diamide (494 mg, 0.8 mmol) in piperidine (10% in THF, 50 mL) was stirred at room temperature for 30min. The solvent was evaporated under reduced pressure and the residue was washed with EtOAc three times to give the title compound (200 mg, 65%) as a white solid. ¹ H-NMR (DMSO): 9.1 1 (s, 1 H), 9.06(s, I H), 7.98-6.31(m, 6H), 4.79(s, 2H), 3.89(s, 3H), 3.82(s, 3H), 2.49-1.33(m, 10H). LC- MS: 387 (M+l), HPLC 99.2% (Purity). Example 16. Synthesis of B09

Λ^-(2-aminophenyl)-yV ⁷ -(4-(4-methoxyphenyl)thiazol-2-yl)-l,7-heptanedioic acid diamide (B09)

The title compound was made using procedures analogous to those used to make

Example 6 in 44% yield. ¹ H NMR (300 MHz, DMSO-ck) 512.16 (s, I H), 59.26 (s, I H), 58.70 (d, 2H), 57.45 (s, I H), 57.80 (d, I H), 59.00 (d, 2H), 57.05 (t, IH), 56.90 (d, I H), 57.50 (t, I H), 54.79 (s, 2H), 53.77 (s, 3H), 52.33-2.26 (m, 4H), 51.63-1.61 (m, 4H), 51.36-1.33 (m, 2H); LC-MS>95% (Purity), 439 (MH) ⁺ ; HPLC 97% (Purity).

2-Amino-4-(4-methoxyphenyl)thiazole

A solution of 2-bromo-l-(4-methoxyphenyl)ethanone (500 mg, 4.37 mmol) and thiourea (664 mg, 8.73 mmol) in absolute ethanol was refluxed for 1 hour. The solvent was evaporated. To the residue were added crushed ice and 3% NaOH. The precipitate was filtered, washed with water and recrystallized from ethanol to give the title compound (300 mg, 66.7%) as a white solid. ¹ H NMR (300 MHz, DMSO-rf ₆ ) δ 9.00 (d, 2H), δ 7.53 (s, 2H), δ 6.90 (d, 2H), δ 6.82 (s, I H), δ 2.53 (s, 3H); LC-MS>95% (Purity), 207 (MH) ⁺ ; HPLC 98% (Purity).

Example 17 A. Synthesis of BlO

Λ ^fl -(3-aminopyridin-2-yl)-/V ⁷ -p-tolyl-l,7-heptanedioic acid diamide (BlO) was made according to the scheme 4(A).

Scheme 4(A)

3-(Benzyloxycarbonylamino)-2-nitropyridine

To a solution of 2-nitropyridin-3-amine (30 g, 0.215 mol) in anhydrous CH ₂ Cl ₂ (500 mL) TEA (50 mL) was added under argon followed by benzyl chloroformate (55.2 g, 0.323 mol). The mixture was stirred for 5 hours at ambient temperature. The reaction mixture was washed with water (2 * 500 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel (petroleum ether/ethyl acetate = 3: 1 ) to give the title product (31.8 g, 54%) as a pale yellow solid. ¹ H NMR (300 MHz, CDCI ₃ ) δ 9.65 (s,l H), 9.07 (t, J=5.4 Hz, IH), 8.28 (d, J=4.2 Hz, I H), 7.65 (m, I H), 7.30 (m, 5H), 5.26 (d, J=5.4 Hz, 2H); ESI-MS 274 (M ⁺ +l).

3-(Benzyloxycarbonylamino)-2-aminopyridine

Raney Ni (2 g, 0.034 mol) was suspended in a solution of 3-

(benzyloxycarbonylamino)-2-nitropyridine (10.0 g, 0.036 mol) in methanol (300 mL). The mixture was stirred at room temperature under hydrogen at a pressure of 0.1 MPa for one hour. The catalyst was filtered. The solvent was evaporated and the residue was purified by chromatography on silica gel (petroleum ether/ethyl acetate = 2:1) to give the title compound (7.2 g, 82.1 %) as a pale yellow solid. ¹ H NMR (300 MHz, CD ₃ OD) δ 7.76 (d, J=5.1 Hz, I H), 7.63 (s, I H), 7.30 (m, 5H), 6.70 (m, I H), 5.19 (s, 2H). ESI-MS 244 (M ⁺ +l).

Λ^-(3-(benzyloxycarbonylamino)pyridin-2-yl)-7V ⁷ -p-tolyl-l,7-heptanedioic acid diamide

To a solution of 7-(p-toluidino)-7-oxoheptanoic acid (5.0 g, 20 mmol) in DMF (100 mL), N,N-4-dimethylpyridine (0.61 g, 5 mmol), EDCI (4.7 g, 25 mmol), and 3- (benzyloxycarbonylamino)-2-aminopyridine (4.88 g, 20 mmol) were added. The resulting cloudy reaction mixture was stirred for 16 hours at ambient temperature. The reaction mixture was diluted with EtOAc (300 mL), washed with IN HCI (500 mL) and water (3x40 mL), dried over Na ₂ SO ₄ , filtered, and evaporated in vacuo. The residue was purified by chromatography on silica gel eluting with 1 : 1 petroleum ether /ethyl acetate to give the title compound (5.8 g, 61%) as a yellow solid. ¹ H NMR (300 MHz, CDCl ₃ ) δ 10.65 (s,l H), 8.45 (s,l H), 8.20 (d, J=1.2 Hz, I H), 8.07 (d, J=3.9 Hz, IH), 7.83 (s, I H), 7.37 (m, 6H), 7.21 (m,l H), 7.02 (m,l H), 5.18 (d, J=4.5 Hz, 2H), 2.45 (t, J=7.2 Hz, 2H), 2.17 (s, 3H), 2.1 1 (t, J=7.5 Hz, 2H), 1.63 (m, 3H), 1.30 (m, 3H). ESI-MS 475 (M ⁺ +l ).

Λ^-(3-aminopyridin-2-yl)-./V ⁷ -/7-tolyl-l,7-heptanedioic acid diamide (BlO)

Pd/C (10%, 0.3 g) was suspended in a solution of N'-(3-(benzyloxycarbonylamino) pyridin- 2-yl)-N ⁷ -/?-tolyl-l ,7-heptanedioic acid diamide (2.24 g, 4.7 mmol) in methanol (200 mL). The mixture was stirred at ambient temperature under hydrogen gas at a pressure of 0.1 MPa for one hour. The catalyst was filtered. The solvent was evaporated, and the residue was purified by chromatography on silica gel to give the title compound (1.05 g, 66%) as a pale yellow solid. ¹ H NMR (300 MHz, DMSO-^6) 57.38 (m, 2H), 7.26 (m, IH), 7.1 1 (m, 4 H), 2.42 (m, 4H), 2.29 (s, 3H), 1.70 (m, 4 H), 1.51 (m, 2 H). ESI-MS 341 (M ⁺ +!).

Example 17 B. Synthesis of B 1 1 and B 12

7,8-Dioxo-Mp-tolylnonanamide (BIl) and ./v'-methyl-Z-oxo-Λ^-p-tolyl-l^-octanedioic acid diamide (B12)

The compounds were made according to the scheme 5, using N,O- dimethylhydroxylamine hydrochloride in the first step.

Scheme 5

V-methoxy-yv'-methyl-jV ⁷ -/7-tolyl-l,7-heptanedioic acid diamide

To a solution of 7-(p-toluidino)-7-oxoheptanoic acid (5 g, 20 mmol) in DCM (50 mL) were added lN-methylmophline (4.05 g, 40 mmol), isobutylchloroformate (3.0 g, 22 mmol), and Ν,O-dimethy!hydroxylamine hydrochloride (2.34 g, 24 mmol). The mixture was stirred at room temperature until the reaction was completed. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel to give the title compound (3.4 g, 58.6%) as a white solid. ¹ H NMR (300MHz, DMSO) δ 9.723 (s, IH); δ 7.445 (d, J = 8.1 Hz, 2H); δ 7.062 (d, J= 8.1 Hz, 2H); δ 3.628 (s, 3H); δ 2.494 (s, 3H); δ 2.325-2.374 (m, 2H); δ 2.221-2.578 (m, 5H); δ 1.483-1.593 (m, 4H); δ 1.301 (d, J= 8.1 Hz, 2H) ESI-MS 293( MH ) ⁺ _, Purity>95%.

8-Ethoxy-7-ox<WV-p-tolylnon-8-enamide

To a solution of ethyl vinyl ether (1 ml, 10.8 mmol) in tetrahydrofuran (4 mL) was added tert-butyllithium (7 mL, 10.4 mmol) at -78 ⁰ C. The mixture was warmed to 0 ⁰ C over a 1 hour period, stirred for 45 minutes, and cooled to -30 ⁰ C. Magnesium bromide etherate (2.58 g, 10 mmol) was added to the solution. The mixture was warmed to 0 ⁰ C over a 15 minute period, followed by the addition of N'-methoxy-N'-methyl-N'-p-tolyl-lJ- heptanedioic acid diamide (584 mg, 2 mmol) in THF (5 mL). The mixture was allowed to warm to room temperature and stirred for 2 hours. The mixture was poured into aqueous

NH ₄ CI and extracted with diethyl ether (3 ^χ 100 mL). The combined extracts were dried over Na ₂ SO ₄ and evaporated. The residue was purified by chromatography on silica gel to give the title compound (330 mg, 54.4%) as a yellow solid.

7,8-Dioxo-W-p-tolylnonanamide (BIl)

To a solution of 8-ethoxy-7-oxo-N-p-tolylnon-8-enamide (330 mg, 1.09 mmol) indioxane and H ₂ O (1 1 mL, v/v = 5: 1) was added concentrated HCl (0.1 1 mL). The mixture was stirred for 24 hours at room temperature and then poured into aqeuous ΝaHCθ ₃ . The product was extracted with ethyl acetate (3 ^χ 5O mL). The combined extracts were dried over Na ₂ SO ₄ and evaporated. The residue was purified by flash chromatography (30% EtOAc/hexane) to give the title compound (96 mg, 16.7%) as a yellow solid. ¹ H NMR (300MHz, DMSO) δ 9.754 (s, IH); δ 7.462 (d, J= 8.1 Hz, 2H); δ 7.073 (d, J= 8.1 Hz, 2H); δ 2.676-2.724 (m, 2H); δ 2.231-2.295 (m, 8H); δ 1.480-1.604 (m, 4H); δ 1.269-1.320 (m, 2H). ESI-MS 274 ( MH ) ⁺ _, Purity>95%.

Ethyl 8-(/Moluidino)-2,8-dioxooctanoate

A solution of 8-ethoxy-7-oxo-N-p-tolylnon-8-enamide (302 mg, 1 mmol) in DCM (50 mL) and pyridine (1 mL) was cooled to -78 °C and treated with ozone until the appearance of a blue color. Oxygen was bubbled through the reaction mixture to remove excess ozone followed by the addition of dimethylsulfide (1 mL). The mixture was stirred for 3 minutes and poured into H ₂ O. The product was extracted with DCM, dried over Na ₂ SO ₄ , and evaporated. The residue was purified by chromatography on silica gel to give the title compound (245 mg 80.6%) as a white solid. ¹ H NMR (DMSO): δ 9.74 (s, IH), 7.44-7.46 (m, 2H), 7.06-7.08 (m, 2H), 4.18-4.25 (m, 2H), 2.79-2.84 (m, 2H), 2.23-2.29 (m, 4H), 1.50-1.59 (m, 4H), 1.23-1.31 (m, 2H) . LC-MS: 306 (MH ) ⁺ . purity>95%.

iV ¹ -methyl-2-oxo-./V ⁸ -/?-tolyl-l,8-octanedioic acid diamide (B12)

To a solution of methanamine (2N in THF, 10 mL) in THF (20 mL) was added ethyl 8-(p-toluidino)-2,8-dioxooctanoate (150 mg, 0.50 mmol). The mixture was stirred overnight and THF was evaporated to give the title compound (102 mg, 70%). ¹ H NMR (CDC13): δ 7.38-7.41 (m, 2H), 7.1 1 -4-7.14 (m, 3H), 7.1 1 (s, I H), 2.88-2.97 (m, 5H), 2.32-2.38 (m, 5H), 1.65-1.79 (m, 4H), 1.44 (m, 2H). LC-MS: 291 (MH ) ⁺ Purity>95%.

Example 18. Synthesis of B13 V-(2-hydroxyphenyl)-7V ⁷ -p-tolyl-l,7-heptanedioic acid diamide (B13)

The title compound was made using procedures analogous to those used to make

Example 6 in 10% yield. ¹ HNMR (300M, OMSO-d ₆ ) δ 7.63 (d, J=7.8Hz,l H), 7.44 (d, J=8.1 Hz,2H), 7.1 (d, J= 8.1 Hz, 2H), 6.98(t,J=7.5Hz,lH), 6.88-6.72 ( m,2H), 1.61(t, J=7.5Hz,4H), 1.35 (m,2H); LC-MS m/z =341 , [M+H]; HPLC>95%.

Example 19. Synthesis of B14

V-(2-amino-5-chlorophenyl)-./V ⁷ -/?-tolyl-l,7-heptanedioic acid diamide (B14)

The title compound was made using procedures analogous to those used to make Example 6 in 18% yield. ¹ HNMR (300M, DMSO-^ ₅ ) δ 9.71(s, IH), 9.09(s, IH), 7.44(d, J=7.5Hz, 2H), 7.33(s, IH), 7.05(d, J=7.5Hz, 2H), 6.91(d, J=8.4Hz, I H), 6.72(d, J=8.4Hz, I H), 2.34(m, 4H), 2.22(s, 3H), 1.58(m, 4H), 1.36(m, 2H).,

Example 20. Synthesis of B 15 Λ^-(2-amino-5-methylphenyl)-iV ⁷ -/?-tolyl-l,7-heptanedioic acid diamide (B15)

The title compound was made using procedures analogous to those used to make Example 6 in 59% yield. ¹ HNMR (300M, DMSO-c/ ₆ ) δ 9.74(s, I H), 9.54(s, I H), 7.44(d, J=8.1 Hz, 2H), 7.04(d, J=8.1 Hz, 2H), 7.03(s, I H), 6.9(s, 2H), 2.33(m, 4H), 2.2 l(s, 3H), 2.19(s, 3H), 1.60(m, 4H), 1.34(m, 2H).

Example 21. Synthesis of B 16

V-(2-amino-5-fluorophenyl)-7V ⁷ -p-tolyl-l,7-heptanedioic acid diamide (B16)

The title compound was made using procedures analogous to those used to make Example 6 in 58% yield. ¹ HNMR (300M, DMSO-^ ₅ ) δ 9.74 (s, 1 H), 9.08 (s, 1 H), 7.46 (d, J = 8.1 Hz, 2H), 7.22 (d, J= 10.5 Hz, I H), 7.07 (d, J= 8.1 Hz, 2H), 6.72-6.69 (m, 2H), 4.76 (s, 2H), 2.50-2.26 (m, 4H), 2.23 (s, 3H), 1.61 (t, J= 7.2 Hz, 4H), 1.36-1.34 (m, 2H). LC-MS: 358(M+H) ⁺ ; Purity >97% (214 nm, UV).

Example 22. Synthesis of B 17 Λ^-^-amino-S-methoxyphenyty-Λ^-p-tolyl-l^-heptanedioic acid diamide (B17)

The title compound was made using procedures analogous to those used to make Example 6 in 56% yield. ¹ HNMR (300M, DMSO-^ ₆ ) 57.66 (s, I H), 7.39-7.36 (m, 3H), 7.16-7.08 (m, 3H), 6.81-6.78 (m, I H), 6.66-6.63 (m, I H), 3.75 (s, 3H), 2.47-2.39 (m, 4H), 2.32 (s, 3H), 1.79 (br, 4H), 1.52-1.50 (m, 2H); LC-MS: 370 (M+H) ⁺ ; Purity >97% (214 nm, UV).

Example 23. Synthesis of Bl 8 N'-(2-aminophenyl)-N ⁷ -(5-methylthiazol-2-yl)-l,7-heptanedioic acid diamide (B18)

This compound was made by the process shown below.

Example 24. Synthesis of B19

N ¹ -(2-(lH-imidazol-2-yl)ethyI)-N ⁷ -(2-amino-4-fluorophenyl)-l,7-heptanedioic acid diamide

This compound was made by the process shown below.

Example 25. Synthesis of B20 N ¹ -(2-amino-5-fluorophenyl)-N ⁷ -(thiophen-2-ylmethyl)-1,7-heptanedioic acid diamide

This compound was made by the process shown below.

Example 26. Synthesis of B21

N'-(2-amino-5-fluorophenyl)-N ⁷ -(4-(pyridin-3-yl)thiophen-2-yl)-l,7-heptanedioic acid diamide

This compound was made by the process shown below.

Example 27. Synthesis of B22, B23, B24, B25, and B26.

N ¹ -(2-amino-4-fluorophenyl)-N ⁷ -(4-(4-methoxyphenyl)thiazol-2-yl)-l,7-heptanedioic acid diamide N ¹ -(2-amino-5-fluorophenyl)-N ⁷ -(4-(4-methoxyphenyl)thiazol-2-yl)-l,7-heptanedioic acid diamide

N ¹ -(2-amino-5-(trifluoromethyl)phenyl)-N ⁷ -(4-(4-methoxypheny l)thiazol-2-y I)- 1 ,7- heptanedioic acid diamide

N'-(2-amino-4,5-difluorophenyl)-N ⁷ -(4-(4-methoxyphenyl)thiazol-2-yl)-l,7-heptanedioic acid diamide

N'-(3-aminopyridin-2-yl)-N ⁷ -(4-(4-methoxyphenyl)thiazol-2-yl)-l,7-heptanedioic acid diamide These compounds where made by the process shown below.

Example 28. Synthesis of B27 and B28

N'-(2-amino-4-fluorophenyl)-N ⁷ -(thiazol-2-yl)-l,7-heptanedioic acid diamide N'-(3-aminopyridin-2-yI)-N ⁷ -(thiazol-2-yl)-l,7-heptanedioic acid diamide

These compounds were made by the process of Scheme below.

Example 29. Synthesis of B29. N ^I -(2-amino-4-fluorophenyl)-N ⁷ -(4-(hydroxymethyl)thiazol-2-yl)-l,7-heptanedioic acid diamide

This compound was made by the process shown below.

Example 30. Synthesis of B30 N'-(2-amino-4-fluorophenyl)-N ⁷ -(5-methylthiazol-2-yl)-l,7-heptanedioic acid diamide

This compound was made by the process of Scheme below.

Example 31. Synthesis of B32 and BOl

N'-(2-amino-4-fluorophenyl)-N ⁷ -p-tolyl-l,7-heptanedioic acid diamide N ^l -(2-amino-5-fluorophenyl)-N ⁷ -p-tolyl-l,7-heptanedioic acid diamide

These compounds were made by the process of shown below.

Example 32. Synthesis of B33 and B34

N'-(2-amino-4-fluorophenyl)-N ⁷ -(4-fluorophenyl)-l,7-heptanedioic acid diamide N ¹ -(2-amino-5-fluorophenyl)-N ⁷ -(4-fluorophenyl)-l,7-heptanedioic acid diamide

These compounds were made by the process shown below.

Example 33 A. Synthesis of B35. N ¹ -(2-amino-4-fluorophenyI)-N ⁷ -(pyridin-2-yl)-l,7-heptanedioic acid diamide

This compound was made by the process shown below.

Example 33 B. Synthesis of B36

N'-(2-amino-4-fluorophenyl)-N ⁷ -(4-(pyridin-4-yl)thiazol-2-yl)-l,7-heptanedioic acid diamide

This compound was made by the process below:

Example 34. Synthesis of B37 (E)-N-(2-amino-4-fluorophenyl)-3-(3-(2-(thiophen-2-yl)acetam ido)phenyl)acrylamide

This compound was made by the process below.

Example 35. Synthesis of B38

N'-(2-amino-4-fluorophenyl)-N ⁷ -(4-(trifluoromethyl)thiazol-2-yl)-l,7-heptanedioic acid diamide

This compound was made by the process below.

Example 36. Synthesis of B39

N'-(2-amino-4-fluorophenyl)-N ⁷ -(4-(piperidin-l-ylmethyl)thiazol-2-yl)-l,7-heptanedio ic acid diamide

This compound was made by the process below.

Example 37. Synthesis of B40 N'-(2-amino-4-fluorophenyl)-N ⁷ -(4-methylthiazol-2-yl)-l,7-heptanedioic acid diamide

This compound was made by the process below.

Example 38. Synthesis of B41 N ¹ -(2-aminophenyl)-N ⁷ -(4-(pyridin-4-yl)thiazol-2-yl)-l,7-heptanedioic acid diamide This compound was made by the process below, starting from an intermediate from the synthesis of B36.

I2l Example 39. Synthesis of B42

N ¹ -(2-amino-4-fluorophenyl)-N ⁷ -(4-(4-fluorophenyl)thiazol-2-yl)-l,7-heptanedioic acid diamide

This compound was made by the process below.

Example 40. Synthesis of B43 N ^I -(2-amino-4-fluorophenyl)-N ⁷ -(benzo[d]thiazol-2-yl)-l,7-heptanedioic acid diamide

This compound was made by the process below.

Example 41. Synthesis of B44 N'-(2-amino-4-fluorophenyl)-N ⁷ -(2,6-dimethoxypyridin-3-yl)-l,7-heptanedioic acid diamide This compound was made by the process below.

Example 42. Synthesis of B45

N ¹ -(2-amino-4-fluorophenyl)-N ⁷ -(4-(4-methoxyphenyl)oxazol-2-yl)-l,7-heptanedioic acid diamide

This compound was made by the process below.

Example 43. Synthesis of B46 N'-(2-amino-5-fluorophenyl)-N ⁷ -(4-methylthiazol-2-yl)-l,7-heptanedioic acid diamide

This compound was synthesized by the process below.

Example 44. Synthesis of B47

N'-(2-amino-5-fluorophenyl)-N ⁷ -(2,6-dimethoxypyridin-3-yI)-l,7-heptanedioic acid diamide

This compound was synthesized by the process below.

Example 45. Synthesis of B48 and B49

N ¹ -(4-fluorophenyl)-N ⁷ -(2-amino-5-(methoxycarbonyl)phenyl)-l,7-heptanedioic acid diamide (B48)

N'-(4-fluorophenyl)-N ⁷ -(2-amino-4-(methoxycarbonyl)phenyl)-l,7-heptanedioic acid diamide (B49) These compounds were synthesized by the procedures below.

Example 46. Synthesis of B50 and B51

N'-fZ-amino- 5-tert-butylphenyl)-N ⁷ -(4-fluorophenyl)-l,7-heptanedioic acid diamide

(B50)

N ¹ -(2-amino-4-tert-butylphenyl)-N ⁷ -(4-fluorophenyl)-l,7-heptanedioic acid diamide

(B51)

These compounds were synthesized by the procedures below.

Example 47. Synthesis of B52

Nl-(2-amino-4-fluorophenyl)-N7-(4-(morpholin-4-γlmethyl) thiazol-2-yl)-l,7- heptanedioic acid diamide

This compound was made by the procedure below.

Example 48. Synthesis of B53

N ¹ -(2-amino-4-fluorophenyl)-N ⁷ -(5-trifluoromethyIthiazol-2-yl)-l,7-heptanedioic acid diamide

This compound was made by the procedure below.

Example 49. Synthesis of B54

N ^I -(2-amino-5-fluorophenyl)-N ⁷ -(5-methyIthiazol-2-yl)-l,7-heptanedioic acid diamide

This compound was made by the procedure below.

Example 50. Synthesis of B55 N ¹ -(2-amino-5-fluorophenyl)-N ⁷ -(thiazol-2-yl)-l,7-heptanedioic acid diamide

This compound was made by the procedure below.

Example 51. Synthesis of B56

Λ^-(2-Amino-4-fluorophenyl)-./V ⁷ -(4-(pyridin-4-yl)thiazol-2-yl)heptanediamide was made according to the general scheme IA.

General Scheme IA

Pimelic Anhydride

A solution of pimelic acid (4.8 g, 30 mmol) in acetic anhydride (100 mL) was refluxed for 3 hours. After cooling to ambient temperature, the solvent was removed and xylene (30 mL) added, this procedure repeated three times. The mixture was evaporated to dryness to give the title compound as a pale yellow solid (4.8 g, quantitative). The product was used directly in next reaction without further purification. GC-MS 142 (M ⁺ ), HPLC > 95% purity.

7-Oxo-7-(4-(pyridin-4-yl)thiazol-2-ylamino)heptanoic acid To a solution of pimelic anhydride (1.42 g, 10 mmol) in anhydrous DMF (20 mL) was added 4-(pyridin-4-yl)thiazol-2-amine(1.77 g, 10 mol). The mixture was stirred at 140 ⁰ C overnight. The mixture was cooled to ambient temperature and poured into water (100 mL). The solid precipitate formed was filtered and washed with ethyl acetate to give the title compound as a white solid (2.2 g, 70%). ¹ H NMR (300 MHz, CD ₃ OD) δ 12.33 (s, IH), 11.99 (s, I H), 8.61 (d, J= 4.5 Hz 2H), 7.97 (s, I H), 7.82 (d, J = 4.5 Hz, 2H), 2.18-2.24 (m, 4H), 1.47-1.67 (m, 4H), 1.30-1.34 (m, 2H). LC-MS 320 (MH) ⁺ .

V-(2-Amino-4-fluorophenyl)-N ⁷ -(4-(pyridin-4-yl)thiazol-2-yl)heptanediamide (B56)

A mixture of 7-oxo-7-(4-(pyridin-4-yl)thiazol-2-ylamino)heptanoic acid (3.19 g, 0.01 mol), 4-fluorobenzene-l ,2-diamine (1.26 g, 0.01 mol), HBTU (3.79 g, 0.01 mol) and DIPEA (2.58 g, 0.02 mol) in DMF (20 mL) was stirred at 140 ⁰ C for overnight. The mixture was poured into water (100 mL). The precipitate formed was filtered to give the crude product which was purified by column chromatography on silica gel (4 x 16 cm, THF/petroleum ether = 1 : 1 elution) to give the title compound as a white solid (1.5O g, 35%). ¹ H NMR (300 MHz, OMSO-d ₆ ) δ 12.35 (s, I H), 9.02 (s, I H), 8.62 (d, J= 5.7Hz 2H), 7.98 (s, I H), 7.83 (d, J= 5.7 Hz, 2H), 7.05-7.10 (m, I H), 6.45-6.50 (m, I H), 6.25-6.31 (m, I H), 5.13 (s, 2H), 2.28-2.50 (m, 4H), 1.56-1.68 (m, 4H), 1.34-1.37 (m, 2H); LC-MS 428.1 (MH) ⁺ ; Purity > 95%.

Example 52. Λ ^fl -(2-amino-4-(trifluoromethyl)phenyl)-Λ' ⁷ -/7-tolylheptanediainide(B57)

The title compound was made by using the same procedure as in Example 51 following general Scheme I A in 21% yield. ¹ H NMR (300 MHz, CD ₃ OD) δ7.45 (m, 3H), 7.24 (d, I H, , J=8.4 Hz), 7.10 (d, 2H, J=8.1 Hz), 6.88 (d, 1 H, J=8.4 Hz), 2.48 (m, 4H), 2.39 (s, 3H), 1.78 (m, 4H), 1.52 (m, 2H).

Example 53. Λ^-(2-amino-4-(trifluoromethyl)phenyI)-N ⁷ -(pyridin-2-yl)heptanediamide (B58)

The title compound was made by using the same procedure as in Example 51 following general Scheme I A in 37% yield. ¹ H NMR (300 MHz, CD ₃ OD) δ 8.35 (m, IH), 8.15 (d, J=8.4 Hz, I H), 7.82 (m, I H), 7.51 (s, I H), 7.32 (d, J=8.1 Hz, I H), 7.17 (m, I H), 6.95 (d, J=8.4 Hz, I H), 2.55 (m, 4H), 1.83 (m, 4H), 1.58 (m, 2H)

Example 54. V-(2-amino-4-fIuorophenyl)-./V ⁷ -(pyridin-2-yl)heptanediamide (B59)

The title compound was made by using the same procedure as in Example 51 following general Scheme I A in 27% yield.

Example 55. Λ ^fl -(2-aminophenyl)-Λ' ⁷ -(2-morpholinoethyl)heptanediamide (B60)

The title compound was made by using the same procedure as in Example 51 following general Scheme I A in 15% yield. ¹ H NMR (CDC13): δ 7.48 (s, I H), 7.21 (s, I H), 7.02-7.07 (m, 1 H), 6.79 (d, J = 3.0 Hz, 2H), 6.31 (s, IH), 3.75 (m, 4H), 3.37 (d, J= 3.0Hz, 2H),2.53 (m, 4H), 2.43-2.47 (m, 2H), 2.22-2.27 (m, 2H) , 1.70-1.81(m, 4H) ,1.43-1.48 (m, 4H) . LC-MS: 363(MH ) ⁺ . purity >93%.

Example 56. Λ ^fI -(2-amino-6-methylphenyl)-Λ ^?7 -p-tolylheptanediamide (B61)

The title compound was made by using the same procedure as in Example 51 following general Scheme IA in 60% yield. ¹ HNMR (300M, DMSO-Cf ₆ ) δ 9.76(s,lH), 9.04(s, lH),7.47(d, 2H, J=8.1 Hz), 7.04(d, 2H, J=8.4Hz), 7.00(d, IH, J=7.5Hz), 6.8 l(d, I H, J=7.2Hz), 6.46(t, IH, 7.5Hz), 4.53(s, 2H), 2.51~2.24(m, 7H), 2.09(s, 3H), 1.67~1.57(m, 4H),1.33~1.41(m, 2H); LC-MS: m/z = 354 [M+H].

Example 57. Λf'-^-amino-^methylphenyO-Λ^-p-tolylheptanediamide (B62)

The title compound was made by using the same procedure as in Example 51 following general Scheme I A in 78% yield. ¹ H NMR (300 MHz, CD ₃ OD) 57.41 (d, 2H, J=8.1 Hz), 7.10 (d, 2H, J=8.1 Hz), 6.92 (d, 1 H, J=8.1 Hz), 6.68 (s, 1 H), 6.52 (d, 1 H, J=8.1 Hz), 2.40 (m, 4H), 2.30 (s, 3H), 2.23 (s, 3H), 1.77 (m, 4H), 1.50 (m, 2H).

Example 58. yVl-(2-aminophenyl)-N7-(benzo(d]thiazol-2-yl)heptanediamide (B63)

The title compound was made following general Scheme 2. General Scheme 2

Dimethyl heptanedioate Intermediate 1

To a solution of heptanedioic acid (2.4g, 15 mmol) in methanol (30 ml) was added slowly SOCb (4.5 ml) under cooling with icy water. After addition, the solution was stirred for 0.5 h at ambient temperature, then refluxed for 3 h. The solution was evaporated under reduced pressure to remove most of methanol. Then sat.NaHCU3(aq) was added and the mixture was extracted with EA. The combined organic phase was washed with water, then brine, dried over Na ₂ SO ₄ . After concentration, the residue was washed with n-hexane to give the yellow liquid intermediate 1. (2.7 g, 95%). ¹ H NMR (300 MHz^ DMSO) δl .29-1.31 (m, 2H), 1.55-1.61 (m, 4H), 2.23-2.28 (m, 4H), 3.60 (s, 6H).

7-Methoxy-7-oxoheptanoic acid Intermediate 2

A mixture of potassium hydroxide (0.69 g, 0.9 mmol) in MeOH (20 ml) was added to dimethyl heptanedioate (2.7 g, 13.8 mmol) and stirred for 2 h at ambient temperature. Then the mixture was concentrated. The residue was adjusted pH to 6 with HCI (3 N), the mixture was extracted with EA. The combined organic phase was washed with water, then brine, dried over Na ₂ SO ₄ . After concentration, the residue was washed with n-hexane to obtain intermediate 2. (1.7 g, yield: 68%). ¹ H NMR (300 MHz, DMSO) δl .37-1.40 (m, 2H), 1.65- 1.67 (m, 4H), 2.29-2.38 (m, 4H), 3.66 (s, 3H) LC-MS 175 (M+l) ⁺

Methyl 7-(benzo[d]thiazol-2-ylamino)-7-oxoheptanoate Intermediate 3 A mixture of 7-methoxy-7-oxoheptanoic acid (1.7 g, 10 mmol), benzo[d]thiazol-2- amine (1.65 g, 1 1 mmol), EDCI (2.5 g, 13 mmol) and HOBT (680 mg, 5 mmol) in DMF (1 OmL) was stirred at ambiemt temperature overnight. TLC monitoring indicated 7- methoxy-7-oxoheptanoic acid was consumed. Then water was added and the solid formed was filtered. The filter cake was washed with methanol and ethyl ether (1 : 10) to give intermediate 3 as a white solid (1 g, 33%). ¹ H NMR (300 MHz, DMSO) δl .28-1.40 (m, 2H), 1.61 -1.66 (m, 2H), 1.73-1.79 (m, 2H), 2.28-2.33 (m, 2H), 2.48-2.53 (m, 2H), 3.64 (s, 3H), 7.32-7.36 (t, I H), 7.45-7.48 (t, I H), 7.74-7.77 (d, IH), 7.81-7.84 (d, IH).

7-(Benzo[d]thiazol-2-ylamino)-7-oxoheptanoic acid Intermediate 4 A mixture of sodium hydroxide (78 mg, 1.96 mmol) in CH3OH/H2O (5 ml/1 ml) and methyl 7-(benzo[d]thiazol-2-ylamino)-7-oxoheptanoate (200 mg, 0.65 mmol) was stirred for 4 h at ambient temperature. Then the mixture was concentrated. The residue was adjusted PH to 3 with HCl (3N), the precipitate formed was filtered. The filter cake was washed with methanol and ethyl ether (1 : 10) to give intermediate 4. (134 mg, 70 %).

M-(2-Aminophenyl)-N7-(benzo[d]thiazol-2-yl)heptanediamide (B63)

A mixture of 7-(benzo[d]thiazol-2-ylamino)-7-oxoheptanoic acid (934 mg, 3.2 mmol), benzene- 1 ,2-diamine (453 mg, 4.2 mmol), EDCI (794 mg, 4.2mmol) and HOBT (216 mg, 1.6 mmol) in DMF (20 ml) was stirred at ambient temperature overnight. TLC monitoring indicated 7-(benzo[d]thiazol-2-ylamino)-7-oxoheptanoic acid was consumed. Then water was added and the precipitate formed was filtered. The filter cake was washed with ethyl ether, then recrystallized from methanol to give B63 (1 g, 83 %). ¹ H NMR (300 MHz, DMSO) δl .24-1.27 (m, 2H), 1.34-1.40 (m, 2H), 1.60-1.69 (m, 4H), 2.30-2.35 (m, 2H), 4.80 (s, 2H), 6.49-6.54 (t, IH), 6.69-6.72 (d, I H), 6.86-6.88 (t, IH), 7.13-7.16 (d, I H), 7.27- 7.32 (t, IH), 7.40-7.46 (t, I H), 7.72-7.74 (d, IH), 7.95-7.98 (d, IH), 9.08 (s, I H), 12.3 (s, IH) ; LC-MS 383 (M+l) ⁺ ; purity>96%.

Example 59. /V ^l -(2-Amino-4-fIuorophenyl)-W ⁷ -(4-(4-morpholinophenyl)thiazol-2- yl)heptanediamide (B64)

The title compound was made by using the same procedure in Example 51 following general Scheme IA. ¹ H NMR (300 MHz, DMSCW ₆ ) 512.16 (s, 1 H), 9.O1 (s, IH), 7.75 (d, J= 8.4 Hz, 2H), 7.37 (s, I H), 7.05-7.10 (m, IH), 6.98 (d, J= 8.4 Hz, IH), 6.45-6.50 (m, I H), 6.26- 6.31 (m, IH), 5.13 (s, 2H), 3.74 (t, J= 4.5 Hz, 4H), 3.15 (t, J= 4.5 Hz, 4H), 2.43-2.50 (m, 2H), 2.28-2.33 (m, 2H), 1.61-1.64 (m, 4H), 1.34-1.36 (m, 2H); LC-MS > 95% (Purity) 512.2 (MH) ⁺ , 534.1 (M+Na) ⁺ .

4-(4-Morpholinophenyl)thiazol-2-amine was made according to Scheme 3

Scheme 3

l-(4-Morpholinophenyl)ethanone

A mixture of l-(4-fluorophenyl)ethanone (5 g, 36.20 mmol), morpholine (6.31 g, 72.39 mmol) and K ₂ CO ₃ (1 O g, 72.39 mmol) in DMF was stirred at 100 ⁰ C for overnight. The reaction mixture was cooled to ambient temperature and evapoerated to remove the solvent. The residue was purified by column chromatography on silica gel (4 x 16 cm, 10% ethyl acetate/petroleum ether elution) to give the ttitle compound as a yellow solid (2.63 g, 35.4%). ¹ H NMR (300 MHz, CDCl ₃ ) 68.40 (d, J = 8.4 Hz, 2H), 8.70 (d, J = 8.4 Hz, 2H), 3.88-3.85 (m, 4H), 3.33-3.29 (m, 4H), 2.53 (s, 3H); LC-MS > 95% (Purity), 206 (MH) ⁺

2,2-Dibromo-l-(4-morphoIinophenyl)ethanone and 2,2,2-tribromo-l-(4-morpholino- phenyl)ethanone

A solution of l-(4-morpholinophenyl)ethanone (5 g, 24.36 mmol) in cone, sulfuric acid (30 mL) was cooled to O ⁰ C. To the solution was slowly added bromine (1.28 mL, 25.09 mmol). The resulting mixture was gradually warmed to ambient temperature and stirred for additional 6 hours. The reaction mixture was poured into ice water. The precipitate formed was filtered, washed with water and air-dried to give the products as green solid. LC-MS 363.9 (MH) ⁺ (78%) and 442.8 (MH) ⁺ (22%).

2-Bromo-l-(4-morpholinophenyl)ethanone

A mixture of 2,2-dibromo-l-(4-morpholinophenyl)ethanone and 2,2,2-tribromo-l-(4- rηorpholinophenyl)ethanone (200 mg, 0.44 mmol) in THF was cooled to 0 ⁰ C. To the solution was added dropwise a solution of dimethylphosphite (50.8 mg, 0.46 mmol) and triethylamine (46.5 mg, 0.46 mmol) in THF. The resulting mixture was gradually warmed to ambient temperature and stirred for additional 6 hours. The reaction mixture was concentrated in vacuo and poured into ice/water. The precipitate formed was filtered, washed with water and air-dried to give the title product as a yellow solid (57.8 mg, 46%). ¹ H NMR (300 MHz, DMSO-^ ₅ ) 59.00 (d, J = 8.4 Hz, 2H), 9.00 (d, J = 8.4 Hz, 2H), 4.75 (s, 2H), 3.75- 3.71 (m, 4H), 3.34-3.31 (m, 4H); LC-MS > 95% (Purity), 286 (MH) ⁺ .

4-(4-Morpholinophenyl)thiazol-2-amine

A solution of 2-bromo-l-(4-moφholinophenyl)ethanone (70 mg, 2.46 mmol) and thiourea (38 mg, 4.93 mmol) in absolute ethanol (10 mL) was refluxed for 2 hours. The precipitate formed was filtered, washed with methanol. The solid was dissolved in boiling water and slowly added IN NaOH. The resulting precipitate was filtered and dried to give the title compound as a brown solid (59 mg, 91.6%). ¹ H NMR (300 MHz, DMSO-^ ₆ ) 57.67-7.64 (m, 2H), 6.97-6.91 (m, 3H), 6.77 (s, 2H), 3.74-3.72 (m, 4H), 3.14-3.12 (m, 4H); LC-MS > 95% (Purity), 262 (MH) ⁺ .

Example 60. Λl-(2-amino-4-methoxyphenyl)-N7-p-tolylheptanediamide (B65)

The title compound was made by using the same procedure as in Example 51 following general Scheme I A. ¹ H NMR (dmso-d6): δ 9.77 (s, I H), 8.94 (s, I H), 7.47 (d, 2H), 7.07 (d, 2H), 6.94 (d, I H), 6.28 (d, I H), 6.1 1 (m, I H), 4.82 (s, 2H), 3.65 (s, 3H), 2.50-2.24 (m, 4H), 2.24 (s, 3H), 1.63-1.59 (m, 4H), 1.36-1.24 (m, 2H). LC-MS: calc'd 370.5 (MH+); obs'd 370.1(MH ) ⁺ . purity >98%.

Example 61. Nl-(2-amino-4,5-difluorophenyl)-N7-p-tolylheptanedianiide (B66)

The title compound was made by using the same procedure as in Example 51 following general Scheme I A. ¹ H NMR (dmso-d6): δ 9.76 (s, IH), 9.07 (s, I H), 7.48-7.45 (m, 2H), 7.32-7.28 (m, I H), 7.09-7.06 (m, 2H), 6.70-6.63 (m, IH), 5.03 (s, 2H), 2.34-2.24 (m, 4H), 2.24 (s, 3H), 1.66-1.56 (m, 4H), 1.39-1.24 (m, 2H). LC-MS: calc'd 376.4 (MH+); obs'd 376.1(MH ) ⁺ . purity >98%.

Example 62. M-(2-amino-4-cyanophenyl)-N7-p-tolylheptanediamide (B67)

The title compound was made by using the same procedure as in Example 51 following general Scheme IA. ¹ H NMR (dmso-d6): δ 9.76 (s, IH), 9.09 (s, I H), 7.62 (s, I H), 7.48-7.45 (m, 2H), 7.29-7.27 (m, I H), 7.09-7.07 (m, 2H), 6.78-6.75 (m, I H), 5.92 (s, 2H), 2.51-2.24 (m, 4H), 2.24 (s, 3H), 1.67-1.57 (m, 4H), 1.40-1.24 (m, 2H). LC-MS: calc'd 365.4 (MH+); obs'd 365.1 (MH ) ⁺ . purity >98%.

Example 63. M-(2-amino-5-cyanophenyl)-N7-p-tolylheptanediamide (B68)

The title compound was made by using the same procedure as in Example 51 following general Scheme I A. 'H NMR (dmso-d6): δ 9.76 (s, IH), 9.21 (s, I H), 7.59-7.57 (m, I H), 7.48-7.45 (m, 2H), 7.10-7.05 (m, 3H), 6.96-6.93 (m, IH), 5.40 (s, 2H), 2.40-2.24 (m, 4H), 2.24 (s, 3H), 1.67-1.57 (m, 4H), 1.40-1.24 (m, 2H). LC-MS: calc'd 365.4 (MH+); obs'd 365.1(MH ) ⁺ . purity >98%.

Example 64. Nl-(2-amino-4-fluorophenyl)-N7-(4-fluorophenyl)-N7- methylheptanediamide (B69)

The title compound was made by using the same procedure as in Example 51 following general Scheme IA. ¹ H NMR (CDC13): δ 7.47 (s, IH), 7.13-7.09 (m, 5H), 6.54- 6.49 (m, 2H), 3.20 (s, 3H), 2.41 -2.36 (m, 2H), 2.06-2.04 (m, 2H), 1.70-1.59 (m, 3H), 1.34- 1.25 (m, 3H). LC-MS: calc'd 376.4 (MH+); obs'd 376.2 (MH ) ⁺ . purity >96%.

Example 65. jYl,Λ7-bis(2-amino-4-fluorophenyl)heptanediamide (B70)

The title compound was made by using the same procedure as in Example 51 following general Scheme IA. ¹ H NMR (dmso-d6): δ 9.03 (s, 2H), 7.12-7.07 (m, 2H), 6.50- 6.27 (m, 4H), 5.14 (s, 4H), 2.34-2.29 (m, 4H), 1.64-1.59 (m, 4H), 1.38-1.36 (m, 2H). LC- MS: calc'd 377.4 (MH+); obs'd 377.1 (MH ) ⁺ . purity >96%.

Example 66. 7Vl-(4-fluoro-2-hydroxyphenyl)-N7-p-tolylheptanediamide (B71)

The title compound was made by using the same procedure as in Example 51 following general Scheme I A. ¹ H NMR (dmso-dό): δ 10.29 (s, I H), 9.81 (s, I H), 9.27 (s, 1 H), 7.71 -7.50 (m, 3H), 7.14-7.1 1 (m, 2H), 6.71 -6.60 (m, 2H), 2.44-2.29 (m, 4H), 2.28 (s, 3H), 1.67-1.63 (m, 4H), 1.40-1.37 (m, 2H). LC-MS: calc'd 359.4 (MH+); obs'd 359.1 (MH ) ⁺ . purity >97%.

Example 67. M-(2-amino-4-(trifluoromethyl)phenyl)-Λ7-(4-fluorophenyl)- heptanediamide (B72)

The title compound was made by using the same procedure as in Example 51 following general Scheme I A. ¹ H NMR (dmso-dό): δ 9.92 (s, IH), 9.1 1 (s, I H), 7.61-7.58 (m, 3H), 7.15-7.09 (m, 3H), 6.83-6.80 (m, I H), 5.59 (s, 2H), 2.38-2.29 (m, 4H), 1.66-1.61 (m, 4H), 1.36-1.24 (m, 2H). LC-MS: calc'd 412.4 (MH+); obs'd 412.1 (MH ) ⁺ . purity >98%.

Example 68. Λ7-(2-amino-4-fluorophenyl)-N7-(5-(trifluoromethyl)thiazol- 2- yl)heptanediamide (B73)

The title compound was made by using the same procedure as in Example 51 following general Scheme 1 A. ¹ H NMR (dmso-d6): δ 12.67 (s, 1 H), 8.98 (s, 1 H), 8.07 (s, I H), 7.07-7.02 (m, IH), 6.46-6.43 (m, I H), 6.25 (m, I H), 5.10 (s, 2H), 2.30-2.25 (m, 4H), 1.62-1.55 (m, 4H), 1.33-1.31 (m, 2H). LC-MS: calc'd 419.4 (MH+); obs'd 419.1 (MH ) ⁺ . purity >97%.

Example 69. M-(2-amino-4-fluorophenyl)-N7-(lH-pyrazol-5-yl)heptanediamid e (B74)

The title compound was made by using the same procedure as in Example 51 following general Scheme IA. ¹ H NMR (dmso-d6): δ 12.25 (s, IH), 10.29 (s, I H), 9.01 (s, I H), 7.56 (s, I H), 7.08-7.06 (m, IH), 6.49-6.29 (m, 3H), 5.12 (s, 2H), 2.30-2.27 (m, 4H), 1.62-1.57 (m, 4H), 1.38-1.32 (m, 2H). LC-MS: calc'd 334.4 (MH+); obs'd 334.1 (MH ) ⁺ . purity >98%.

Example 70. M-(2-amino-4-fluorophenyI)-N7-(isoxazol-3-yl)heptanediamide (B75)

The title compound was made by using the same procedure as in Example 51 following general Scheme IA. ¹ H NMR (dmso-d6): δ 10.97 (s, I H), 9.00 (s, IH), 8.76 (s, IH), 7.09-6.91 (m, 2H), 6.49-6.45 (m, IH), 6.31-6.25 (m, I H), 5.12 (s, 2H), 2.36-2.27 (m, 4H), 1.60-1.55 (m, 4H), 1.31-1.23 (m, 2H). LC-MS: calc'd 335.4 (MH+); obs'd 335.1 (MH ) ⁺ . purity >97%.

Example 71. Λf/-(2-amino-4-fluorophenyI)-N7-(5-methyloxazol-2-yl)heptan ediamide (B76)

The title compound was made by using the same procedure as in Example 51 following general Scheme I A. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 1 1.89 (s, I H), 9.01 (s, I H), 7.09-7.06 (m, 1 H), 6.68 (s, 1 H), 6.50-6.46 (m, 1 H), 6.28-6.27 (m, 1 H), 5.13 (s, 1 H), 2.33- 2.23 (m, 7H), 1.60-1.50 (m, 4H), 1.37-1.25 (m, 2H); LC-MS: m/z = 349 [M+H] ⁺ .

Example 72. 7V ¹ -(2-aminophenyl)-4-oxo-./V ⁷ -/?-tolylheptanediamide (B77) was made according to the general Scheme 3.

General Scheme 3

Oxocane-2,5,8-trione

A solution of 4-oxoheptanedioic acid (1.74 g, 10 mmol) in acetic anhydride (100 mL) was refluxed for 3 h. After cooling to ambient temperature, the solvent was removed and xylene (30 mL) added. The mixture was evaporated to dryness to give the title compound (1.55 g, quantitative) as a pale yellow solid. The product was used directly in next reaction without further purification. 6-(p-Tolylcarbamoyl)-4-oxohexanoic acid

To a solution of oxocane-2,5,8-trione(1.55 g, 9.94 mmol) in anhydrous THF (50 mL) was added p-toluidine (1.6O g, 15 mmol). The solution was refluxed overnight. The solvent was removed and the residue was treated with 2N aqueous solution of sodium hydroxide (10 mL), washed with ethyl acetate (2><50 mL). The aqueous phase was acidified with concentrated HCl to pH < 5, the resulting precipitate was filtered and dried to give the title compound (1.19 g, 45%) as a yellow solid.

N -(2-aminophenyl)-4-oxo-./V -p-tolylheptanediamide (B77)

A mixture of 6-(p-tolylcarbamoyl)-4-oxohexanoic acid (1 190 mg, 4.53 mmol), o- phenylene- diamine (489 mg, 4.53 mmol), EDCI (870 mg, 4.53 mmol), HOBt (1223 mg, 9.06 mmol) and triethylamine (915mg, 9.06 mmol) in dichloromethane (50 mL) was stirred at room temperature overnight. The mixture was washed with water and brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by chromatography on silica gel (dichloromethane /methanol = 9: 1) to give the title compound (423 mg, 30%) as a white solid. ¹ H NMR (DMSO): δ 9.82 (s, IH,), 9.10 (s, IH,), 7.41-7.44 (m, 2H), 7.05-7.12 (m, 3H), 6.84-6.89 (m, 1 H),6.67 (d, J = 3.0 Hz, I H), 6.47-6.52 (m, I H), 4.80 (s, I H) 2.73-2.76 (m, 4H), 2.49-2.56 (m, 4H) ,2.22 (s, 3H). LC-MS: 354(MH) ⁺ . HPLC: >95%(purity, 214nm). Example 73. N-(2-aminophenyl)-3-(3-oxo-3-(p-tolylamino)propoxy)propanami de (B78) was made according to the Scheme 4.

Scheme 4

Methyl 3-methoxypropanoate

Methyl acrylate (30 g, 0.349 mole) was adde to a solution Of CH ₃ ONa (6O g, 1.1 1 mole) in methanol (300 mL). The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure. The residue was purified by chromatography on silica gel (petroleum ether / ethyl acetate = 5: 1 to 1 : 1 ) to give the title compound (36.4 g, 70%).

3-Methoxypropanoic acid

To a solution of LiOH H ₂ O (20 g, 0.477 mol) in THF and water (50OmL, v/v = 1) was added methyl 3-methoxypropanoate (36.4 g, 0.308 mol). The mixture was stirred at room temperature overnight. THF was removed and cone. HCl was added to acidify the solution. The precipitate was filtered to give the title compound (32.1 g, 100%).

3-Methoxy-yV-/j-tolyIpropanamide

A mixture of 3-methoxypropanoic acid (32.1 g, 0.308 mol) and /?-toluidine (33.0g, 0.308 mol), HBTU (117.0 g, 0.308 mol) and DIPEA (79.6 g, 0.617 mmol) in THF (500 mL) was stirred at room temperature overnight. The solvent was removed and the residue was purified by chromatography on silica gel (petroleum ether / ethyl acetate = 3: 1 to 1 : 1 ) to give the title compound (33.4 g, 54%), LC-MS 194 (M+l).

S-Hydroxy-Λ'-p-tolylpropanamide

A solution of 3-methoxy-N-p-tolylpropanamide (33.4g, 0.173 mol) in CH ₂ Ch (300 mL) was cooled to -40~30°C. BBr ₃ (86 g, 0.343 mol) in CH ₂ Cl ₂ (200 mL) was then added dropwise and the temperature was maintained below -30°C. The reaction was monitored by TLC. After the reaction was completed the solvent was removed under reduced pressure. The residue was purified by chromatography on silica gel (petroleum ether / ethyl acetate = 5 : 1 to 1 : 1 ) to give the title compound (22 g, 71%) as a white solid. ¹ H ΝMR (300 MHz, CDCI ₃ ) δ 7.61 (s,

I H), 6 7.4-7.1 (m, 4H), δ 4.01-3.98 (t, J=5.1 Hz, 2H), δ 2.65-2.61 (t, J=5. I Hz, 2H), 2.53(s, 1 H), 2.32(s, 3H), LC-MS 180 (M+H).

Methyl 3-(2-(/7-tolyIcarbamoyl)ethoxy)propanoate

3-Hydroxy-N-/?-tolylpropanamide (22 g, 0.123 mol) was dissolved in a solution Of CH ₃ ONa (16.7 g, 0.309 mol) in THF (300 mL). Methyl aery late (12.3 g, 0.14 mol) in THF (50 mL) was added dropwise. The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure. The residue was purified by chromatography on silica gel (petroleum ether / ethyl acetate = 5: 1 to 1 : 1) to give the title compound (15.4 g, 47%). LC- MS 266 (M+H).

3-(2-(p-Tolylcarbamoyl)ethoxy)propanoic acid

To a solution Of LiOH H ₂ O (1 O g, 238 mol) in THF and water (200 mL, v/v=l) was added methyl 3-(2-(p-tolylcarbamoyl)ethoxy)propanoate (15.4 g, 58.1 mmol). The mixture was stirred at room temperature overnight. THF was removed and cone. HCl was added to acidify the solution, the precipitate was filtered to give the title compound (14.6 g, 100%) as a white solid. LC-MS 252 (M+H).

N-(2-aminophenyl)-3-(3-oxo-3-(p-tolylamino)propoxy)propan amide (B78)

A mixture of 3-(2-(p-tolylcarbamoyl)ethoxy)propanoic acid (500 mg, 2.0 mmol), benzene- 1,2-diamine (216 mg, 2.0 mmol), HBTU (760 mg, 2.0 mmol) and DIPEA (516 mg, 4 mmol) in THF (50 mL) was stirred at room temperature overnight. The solvent was removed and the residue was purified by chromatography on silica gel to give the title compound (280 mg, 42%), ¹ H NMR (300 MHz, DMSO) 59.82 (s, 1 H), 9.18 (s, 1 H), 7.49-7.07 (m, 7H), 4.82 (s, 2H), 3.73-3.69 (m, 4H), 2.56-2.51 (m, 4H), 2.25 (s, 3H), LC-MS 342 (M+ 1).

Example 74. vVl-(4-aminobiphenyl-3-yl)-N7-(4-fluorophenyl)heptanediamide (B79)

Λ^-(4-aminobiphenyl-3-yl)-Λ ^r7 -(4-fluorophenyl)heptanediamide (B79) was made according to the Scheme 5.

Scheme 5

(4-Bromo-2-nitro-phenyl)-carbamic acid tert-butyl ester To a solution of 4-bromo-2-nitro-phenylamine (5 g, 15.8mmol ) in DMF(30mL) was added NaH (0.76 g, 19 mmol ) and the reaction was stirred at O ⁰ C. 10 minutes later, d\-t- butyl dicarbonate (3.8 g, 17.4 mmol) in DMF (30 mL) was dropwised to the solution at this temperature, and stirred for 16 hours. Then the reaction mixture was poured into ice- water (50 mL), and extracted with ethyl acetate (10OmL x 3). The organic layer was washed with water (200mLx3) and brine (100mLx2), dried over anhydrous sodium sulfate. Then the solvent was distilled and the residue was purified by column chromatography with ethyl acetate in hexane (20%) to give the product (2.6g, 50% yield). ¹ H NMR (300MHz, CDCI ₃ ) δ: 9.62 (s, IH), 8.53 (d,J= 9.3 Hz, I H), 8.34 (s, I H), 7.70 (d, J= 2.1 Hz, I H), 1.42(s, 9H); MS(ESI): mass calcd. for CnHi ₃ BrN ₂ O ₄ , 317.14; m/z found 318.0 [M+H] ⁺ .

(3-Nitro-biphenyl-4-yl)-carbamic acid tert-butyl ester

A mixture of N-Boc 4-bromo-2-nitroaniline (2.5 g, 7.89 mmol), phenylboronic acid (1.06 g, 8.68 mmol) and K ₂ CO ₃ (2.18 g, 15.78 mmol) in 22 mL of dioxane and 9.5mL of water was degassed by bubbling nitrogen through the mixture for 30 minutes, and then

Pd(PPh ₃ ) ₄ (0.28 g, 0.24 mmol) was added. The organic mixture was heated to 80 ⁰ C for 16 hours, cooled to ambient temperature, the solution was evaporated and the residue was added water (25 mL), extracted with ethyl acetate (50mLx3). The organic layer was washed with water (20mLx3) and brine (50mLx2), dried over anhydrous sodium sulfate. Then the solvent was evaporated under reduced pressure and the residue was washed with ether to afford the title product as a white solid (1.74 g, 70% yield). ¹ H NMR (300MHz, CDCl ₃ ) δ: 9.68 (s, 1 H), 8.63 (d, J = 8.7Hz, I H), 8.42 (s, I H), 7.85 (d, J= 2.4 Hz, I H), 7.59 (d,J= 7.2 Hz,2H), 7.49-7.39 (m, 3H), 1.57 (s, 9H);MS(ESI): mass calcd. for C ₇ H ₁₈ N ₂ O ₄ , 314.34; m/z found 315.1 [M+H] ⁺ .

(2-Amino-octa-2,6-dienyl)-carbamic acid tert-butyl ester

To a solution of (3-nitro-biphenyl-4-yl)-carbamic acid tert-butyl ester (1.74 g, 5.54 mmol) in ethyl acetate (2OmL) was added 10 percent Palladium on carbon catalyst (180mg), the solution was stirred for 16 hours at ambient temperature under H ₂ pressure. The solution was filtrated and concentrated under reduced pressure to give the product (1.48 g, 94.6% yield ). ¹ H NMR (300MHz, CDCl ₃ ) δ: 8.37 (s, I H), 7.53 (d, J= 7.2 Hz, 2H), 7.30 (t, J= 6.9 Hz, 2H), 6.99 (d, J= 2.1 Hz, I H), 6.83 (dd, J = 2. I Hz, IH), 4.97 (s, 2H), 1.48 (s, 9H); MS(ESI): mass calcd. for C ₇ H ₂₀ N ₂ O ₂ , 284.35; m/z found 285.1 [M+H] ⁺

t-Butyl 3-(7-(4-fluorophenylamino)-7-oxoheptanamido)biphenyI-4-yl carbamate

A mixture of 6-(4-fluoro-phenylcarbamoyl)-hexanoic acid (507 mg, 2 mmol), (2- amino-octa-2, 6-dienyl)-carbamic acid tert-butyl ester (568 mg, 2 mmol), EDCI (422 mg, 2.2 mmol) and HOBT (135 mg, 1 mmol) in DMF (10 mL) was stirred at ambient temperature for 16 hours. Then the reaction solution was poured into ice-water (30 mL), extracted with ethyl acetate (20mLx3). The combined organic layer was dried over Na ₂ SO ₄ , evaporated under reduced pressure. The residue was washed with ether and methanol (15/1 , v/v) to give the white product (670mg, 64.5% yield). ¹ H NMR (300MHz, DMSO-^ ₅ ) δ: 9.95 (s, IH), 9.58 (s, I H), 8.46 (s, IH), 7.75 (s, I H), 7.67-7.58 (m, 5H), 7.48-7.43 (m, 3H), 7.37-7.35 (m, I H), 7.11 (t, J = 8.7Hz, 2H), 2.42-2.29 (m, 4H), 1.69- 1.61 (m, 4H), 1.49- 1.32 (m, 1 H); MS(ESI): mass calcd. for C ₃₀ H ₃₄ FN ₃ O ₄ , 519.61 ; m/z found 520.0 [M+H] ⁺

Λ^4-aminobiphenyl-3-yl)-N ⁷ -(4-fluorophenyl)heptanediamide (B79)

/-Butyl 3-(7-(4-fIuorophenylamino)-7-oxoheptanamido)biphenyl-4-ylcar bamate (650 mg, 1.25 mmol) was dissolved in CH ₂ Cl ₂ (6 mL) and CF ₃ COOH (3 mL) at 0 ⁰ C. The solution was stirred at this temperature for 50 minutes, and diluted with CHjCl ₂ (30 mL), then washed with saturated NaHCO ₃ (10 mL), dried over Na ₂ SO4, evaporated under reduced pressure, The residue was washed with ether and methanol (15/1 , v/v), to give the white product (510 mg, 97% yield). I H-NMR (300MHz, DMSO-d ₆ ) δ: 9.97 (s, IH), 9.21 (s, I H), 7.62-7.49 (m,7H), 7.23 (d, J= 7.5 Hz, 2H), 7.13-7.07(m, 2H), 6.79 (d, J= 8.4 Hz, I H), 5.04 (s, 2H), 2.50-2.29 (m, 4H),1.63 (m, 4H), 1.37(d, J= 6.6 Hz, 2H); MS(ESI): mass calcd. for C ₂₅ H ₂₆ FN ₃ O ₂ , 419.49; m/z found 420.0 [M+H] ⁺ ; HPLC: 97% (214nm), 97%(254nm), t _R =5.08 min.

Example 75. M-(3-aminobiphenyl-4-yl)-N7-(4-fluorophenyl)heptanediamide (B80)

The title compound was made by using the same procedure as in Example 74 following general Scheme 5. ¹ H NMR (dmso-d6): δ 9.93 (s, IH), 9.14 (s, IH), 7.63-6.81 (m, 12H), 4.96 (broad s, 2H), 2.37-2.29 (m, 4H), 1.66-1.62 (m, 4H), 1.40-1.37 (m, 2H). LC-MS: calc'd 420.5 (MH+); obs'd 420.4(MH ) ⁺ . purity >98%.

Example 76. yVl-(4-amino-6-fluorobiphenyl-3-yl)-7V7-(4-fluorophenyl)-hep tanediainide (B81)

The title compound was made by using the same procedure as in Example 74 following general Scheme 5. 'H NMR (dmso-d6): δ 9.94 (s, IH), 9.1 1 (s, IH), 7.59-7.1 1 (m, 10H), 6.61-6.56 (m, IH), 5.31 (broad s, 2H), 2.31-2.29 (m, 4H), 1.66-1.60 (m, 4H), 1.35-1.24 (m, 2H). LC-MS: calc'd 438.5 (MH+); obs'd 438.0(MH ) ⁺ . purity >98%.

Example 77. Nl-(3-aminobiphenyl-4-yl)-N8-(pyridin-3-yl)octanediamide (B82)

The title compound was made in a similar fashion as described for Example 74 in scheme 5. ¹ H NMR (dmso-d6): δ 10.09 (s, 1 H), 9.16 (s, IH), 8.73 (S, I H), 8.05-8.02 (m, I H), 7.53-7.23 (m, 8H), 6.81-6.79 (m, I H) 5.03 (broad s, 2H), 2.37-2.29 (m, 4H), 1.66-1.62 (m, 4H), 1.40-1.37 (m, 4H). LC-MS: calc'd 417.5 (MH+); obs'd 417.2 (MH ) ⁺ . purity >98%.

Example 78. Λ ^f l-(4-hydroxybiphenyl-3-yl)-N7-(pyridin-3-yl)heptanedia mide (B83)

The title compound was made by using the same procedure as in Example 74 following general Scheme 5. ¹ H NMR (dmso-d6): δ 10.09 (s, IH), 9.94 (s, I H), 9.30 (s, I H),

8.72 (s, IH), 8.23-8.22 (m, IH), 8.06-8.01 (m, 2H), 7.54-7.23 (m, 8H), 6.95-6.92 (m, I H), 2.37-2.33 (m, 4H), 1.66-1.61 (m, 4H), 1.38-1.24 (m, 2H). LC-MS: calc'd 404.5 (MH+); obs'd 404.1 (MH ) ⁺ . purity >98%.

Example 79. (2E,4E)-M-(2-aminophenyl)-./V6-(pyridin-3-yl)hexa-2,4-diened iamide (B84)

B84 was prepared as described in Scheme 6.

Scheme 6

(2E,4E)-6-oxo-6-(pyrϊdin-3-ylamino)hexa-2,4-dienoic acid (1). To the solution of (2E,4E)-hexa-2,4-dienedioic acid (142 mg, 1 mmol) in dichloromethane, was added pyridin- 3-amine (94 mg, 1 mmol), HATU (381 mg, 1 mmol) and DIEA (1 mmol) and stirred overnight. The reaction mixture was washed with aqueous NaHCCb and organic layer was collected and concentrated. The residue was purified by column chromatography to afford the title compound(l 58 mg, 72%) as light yellow solid. (2E,4E)-N'-(2-aminophenyl)-N ⁶ -(pyridin-3-yl)hexa-2,4-dienedi -amide (B84). To the solution of (2E,4E)-6-oxo-6-(pyridin-3-ylamino)hexa-2,4-dienoic acid (158 mg, 0.72 mmol) in dichloromethane, was added benzene- 1 ,2-diamine (68 mg, 0.72 mmol), HATU (274 mg, 0.72 mmol) and DIEA (0.72 mmol) and stirred overnight. The reaction mixture was washed with aqueous NaHCCb and organic layer was collected and concentrated. The residue was purified by column chromatography to afford the title compound(166 mg, 75%) as light yellow solid. ¹ H NMR (300 MHz, DMSO-d6) δ 10.53 (s, IH), 9.53 (s, I H), 8.84 (s, I H), 8.31-8.13 (m, 2H), 7.38-7.31 (m, 4H), 6.96-6.58 (m, 5H), 4.96 (s, 2H). LC-MS: calc'd 309.3 (MH+); obs'd 309.2 (MH ) ⁺ . purity >97%.

10

Example 80. Additional HDAC3 Inhibitors

Additional HDAC3 inhibitors were identified using the methods outlined in Example 3. The activities of the compounds to inhibit HDACl and HDAC3 are listed in Table 6.

Example 81. Acid Stability Method

From a DMSO stock solution (1 OmM), 1 mL of lOOuM solution of each compound was prepared in 0.01N HCl (pH=2). Immediately after mixing, about 100 uL of each sample was transferred to a HPLC sample vial and run using the standard purity check HPLC/UV method (t=0 data). Then the samples were incubate at 50 ⁰ C and tested after 2, 4, and 24 hrs. The percent remaining was calculated using the ratio of area under the peak after incubation time over the initial time (t=0) times 100. The results are shown below.

Acid Stability, pH=2, 5OC

A:

B:

C:

D:

E:

This example demonstrates that the inclusion of an α,β double bond in L ² should increase the acid stability of the formula (I) compounds described herein.

Compounds A and B are described in Attorney Docket No.: 00231 -0127WO 1 filed on even date herewith; compounds C and D are described in Attorney Docket No.: 00231- 013 I POl filed on even date herewith. Compound E is described herein.

OTHER EMBODIMENTS

A number of embodiments of the invention have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are within the scope of the following claims.