NZ794019A - Compounds for treating huntington's disease - Google Patents

Abstract

The present description relates to compounds, forms, and pharmaceutical compositions thereof and methods of using such compounds, forms, or compositions thereof for treating or ameliorating Huntington's disease. In particular, the present description relates to substituted monocyclic heteroaryl compounds of Formula (I), forms and pharmaceutical compositions thereof and methods of using such compounds, forms, or compositions thereof for treating or ameliorating Huntington's disease. ounds of Formula (I), forms and pharmaceutical compositions thereof and methods of using such compounds, forms, or compositions thereof for treating or ameliorating Huntington's disease.

Description

The present description relates to compounds, forms, and pharmaceutical itions thereof and methods of using such compounds, forms, or compositions thereof for treating or ameliorating Huntington's disease. In particular, the present description relates to substituted monocyclic heteroaryl nds of Formula (I), forms and pharmaceutical compositions thereof and methods of using such compounds, forms, or compositions f for treating or ameliorating Huntington's disease.

NZ 794019 COMPOUNDS FOR TREATING HUNTINGTON’S DISEASE This ation is a divisional of New Zealand patent ation , which is the national phase entry in New d of PCT international application (published as incorporated herein by reference.

An aspect of the present description relates to compounds, forms, and pharmaceutical compositions thereof and methods of using such compounds, forms, or compositions thereof useful for treating or ameliorating Huntington’s disease. In particular, another aspect of the present description relates to substituted monocyclic heteroaryl compounds, forms and pharmaceutical compositions f and methods of using such compounds, forms, or compositions thereof for treating or ameliorating gton’s disease.

BACKGROUND Huntington’s disease (HD) is a progressive, autosomal dominant neurodegenerative er of the brain, having symptoms characterized by involuntary movements, cognitive impairment, and mental deterioration. Death, lly caused by pneumonia or coronary artery disease, usually occurs 13 to 15 years after the onset of symptoms. The prevalence of HD is between three and seven individuals per 100,000 in populations of western European descent. In North America, an estimated 30,000 people have HD, while an additional 200,000 people are at risk of inheriting the disease from an affected parent. The disease is caused by an expansion of uninterrupted trinucleotide CAG repeats in the "mutant" huntingtin (Htt) gene, leading to production of HTT (Htt protein) with an expanded poly-glutamine ) stretch, also known as a "CAG repeat" sequence. There are no t small molecule therapies targeting the underlying cause of the disease, leaving a high unmet need for medications that can be used for treating or ameliorating HD. Consequently, there remains a need to identify and provide small le compounds for treating or ameliorating HD.

All other documents ed to herein are incorporated by reference into the present ation as though fully set forth herein.

SUMMARY An aspect of the present description includes compounds comprising, a compound of a (I): (I) or a form thereof, wherein X, B, R3, and n are as defined herein.

An aspect of the present description includes a method for treating or ameliorating HD in a subject in need thereof sing, administering to the subject an effective amount of a compound of Formula (I) or a form thereof.

An aspect of the present description includes a method for use of a nd of Formula (I) or a form or composition thereof for treating or ameliorating HD in a subject in need thereof comprising, stering to the t an effective amount of the compound of Formula (I) or a form or composition thereof.

An aspect of the present description includes a use for a compound of Formula (I) or a form f for treating or rating HD in a subject in need thereof comprising, administering to the subject an effective amount of the compound of Formula (I) or a form thereof.

An aspect of the present description includes a use for a compound of Formula (I) or a form thereof in the manufacture of a medicament for treating or ameliorating HD in a t in need thereof sing, administering to the subject an effective amount of the medicament.

An aspect of the present description includes a use for a compound of a (I) or a form thereof in a combination product with one or more therapeutic agents for treating or ameliorating HD in a subject in need thereof comprising, administering to the subject an effective amount of the compound of Formula (I) or a form thereof in combination with an effective amount of the one or more agents.

DETAILED DESCRIPTION An aspect of the present description relates to compounds comprising, a compound of Formula (I): (I) or a form thereof, wherein: X is CHR1a, C=O, O, NR1b, or a bond; R1a is independently ed from hydrogen, halogen, hydroxyl, cyano, C1-4alkyl, deutero- C1-4alkyl, halo-C1-4alkyl, amino, and hydroxyl-C1-4alkyl; R1b is independently selected from hydrogen, C1-4alkyl, deutero-C1-4alkyl, and halo-C1-4alkyl; B is heterocyclyl, wherein heterocyclyl is a saturated or partially unsaturated 3-7 membered monocyclic, 6-10 membered bicyclic or 13-16 ed polycyclic ring system having 1, 2, or 3 heteroatom ring members independently selected from N, O, or S, each optionally substituted with 1, 2, 3, 4, or 5 substituents each selected from R2; R2 is independently selected from halogen, C1-4alkyl, deutero-C1-4alkyl, amino, C1-4alkyl-amino, and (C1-4alkyl)2-amino; R3 is ndently selected from halogen, hydroxyl, cyano, C1-4alkyl, deutero-C1-4alkyl, halo- kyl, amino, C1-4alkyl-amino, lkyl)2-amino, C1-4alkoxy, halo-C1-4alkoxy, heteroaryl, cyclyl, and , wherein heteroaryl is a 3-7 membered monocyclic or 6-10 membered bicyclic ring system having 1, 2, 3, or 4 heteroatom ring s independently selected from N, O, or S, wherein heterocyclyl is a saturated or partially unsaturated 3-7 membered monocyclic, 6-10 membered bicyclic or 13-16 ed polycyclic ring system having 1, 2, or 3 heteroatom ring members independently selected from N, O, or S, and wherein each instance of phenyl, heteroaryl or heterocyclyl is optionally substituted with 1 or 2 substituents each selected from R4; n is 1, 2 or 3; and R4 is independently selected from halogen, yl, cyano, C1-4alkyl, deutero-C1-4alkyl, halo- C1-4alkyl, amino, C1-4alkyl-amino, (C1-4alkyl)2-amino, C1-4alkoxy, and halo-C1-4alkoxy; n a form of the compound is selected from the group consisting of a salt, e, solvate, racemate, enantiomer, diastereomer, stereoisomer, and tautomer form f.

ASPECTS OF THE PTION r aspect of the present description includes a compound of Formula (I): or a form f, wherein: X is CHR1a, C=O, O, NR1b, or a bond; R1a is independently selected from hydrogen, halogen, hydroxyl, cyano, C1-4alkyl, deutero- C1-4alkyl, halo-C1-4alkyl, amino, and hydroxyl-C1-4alkyl; R1b is independently selected from hydrogen, C1-4alkyl, deutero-C1-4alkyl, and halo-C1-4alkyl; B is heterocyclyl, wherein heterocyclyl is a saturated or partially unsaturated 3-7 membered clic, 6-10 membered bicyclic or 13-16 membered polycyclic ring system having 1, 2, or 3 heteroatom ring members independently selected from N, O, or S, each optionally substituted with 1, 2, 3, 4, or 5 substituents each selected from R2; R2 is independently selected from halogen, C1-4alkyl, deutero-C1-4alkyl, amino, C1-4alkyl-amino, and (C1-4alkyl)2-amino; R3 is independently selected from halogen, hydroxyl, cyano, C1-4alkyl, deutero-C1-4alkyl, halo- C1-4alkyl, amino, C1-4alkyl-amino, (C1-4alkyl)2-amino, C1-4alkoxy, halo-C1-4alkoxy, heteroaryl, heterocyclyl, and phenyl, wherein heteroaryl is a 3-7 ed monocyclic or 6-10 membered ic ring system having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, or S, wherein heterocyclyl is a saturated or partially unsaturated 3-7 membered monocyclic, 6-10 membered bicyclic or 13-16 membered polycyclic ring system having 1, 2, or 3 heteroatom ring members independently selected from N, O, or S, and wherein each instance of phenyl, heteroaryl or heterocyclyl is optionally substituted with 1 or 2 substituents each selected from R4; n is 1, 2 or 3; and R4 is independently selected from halogen, hydroxyl, cyano, C1-4alkyl, deutero-C1-4alkyl, halo- C1-4alkyl, amino, C1-4alkyl-amino, (C1-4alkyl)2-amino, C1-4alkoxy, and halo-C1-4alkoxy.

One aspect includes a nd of Formula (I), wherein X is selected from CHR1a, C=O, O, NR1b, and a bond.

Another aspect includes a compound of Formula (I) n X is CHR1a.

Another aspect includes a compound of Formula (I) n X is C=O.

Another aspect includes a compound of Formula (I) wherein X is O.

Another aspect includes a compound of Formula (I) wherein X is NR1b.

Another aspect includes a compound of Formula (I) wherein X is a bond.

One aspect includes a compound of Formula (I), wherein R1a is selected from hydrogen, n, hydroxyl, cyano, C1-4alkyl, deutero-C1-4alkyl, halo-C1-4alkyl, amino, and hydroxyl- C1-4alkyl.

Another aspect includes a compound of Formula (I), wherein R1a is selected from cyano and amino.

Another aspect includes a compound of Formula (I), wherein R1a is cyano. r aspect includes a compound of Formula (I), n R1a is amino.

One aspect includes a compound of Formula (I), wherein R1b is selected from hydrogen, C1-4alkyl, deutero-C1-4alkyl, and halo-C1-4alkyl.

Another aspect includes a compound of Formula (I), wherein R1b is selected from en and C1-4alkyl.

Another aspect es a compound of a (I), wherein R1b is hydrogen.

Another aspect includes a compound of Formula (I), wherein R1b is C1-4alkyl ed from methyl, ethyl, propyl, pyl, butyl, and tert-butyl.

Another aspect includes a compound of Formula (I), wherein R1b is methyl.

One aspect includes a compound of Formula (I), wherein B is heterocyclyl, wherein heterocyclyl is a saturated or partially unsaturated 3-7 membered monocyclic, 6-10 membered bicyclic or 13-16 ed polycyclic ring system having 1, 2, or 3 heteroatom ring members independently selected from N, O, or S, each optionally substituted with 1, 2, 3, 4, or 5 substituents each selected from R2.

Another aspect includes a nd of Formula (I), wherein B is heterocyclyl selected from azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, 1,4-diazepanyl, 1,2-dihydropyridinyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl, hexahydrocyclopentapyrrol-(1H)-yl, hexahydropyrrolo[3,2-b]pyrrol-(2H)-yl, hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl, hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, aS)-hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, octahydro-2H-pyrrolo[3,4-c]pyridinyl, octahydro-5H-pyrrolo[3,2-c]pyridinyl, octahydro-6H-pyrrolo[3,4-b]pyridinyl, (4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridinyl, (4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridinyl, hexahydropyrrolo[1,2-a]pyrazin-(2H)-one, dropyrrolo[1,2-a]pyrazin-(1H)-yl, (7R,8aS)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aS)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aR)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, hexahydro-1H-cyclobuta[1.2-c:1,4- c']dipyrrol-(3H)-yl, (8aS)-octahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aR)-octahydropyrrolo[1,2-a]pyrazin-(1H)-yl, octahydro-2H-pyrido[1,2-a]pyrazinyl, hexahydropyrrolo[3,4-b][1,4]oxazin-(2H)-yl, piro[2.4]heptanyl, 2-oxa ro[3.4]octanyl, 3-azabicyclo[3.1.0]hexanyl, 8-azabicyclo[3.2.1]octanyl, (1R,5S)azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]octen-yl, )azabicyclo[3.2.1]octen-yl, 9-azabicyclo[3.3.1]nonanyl, (1R,5S)azabicyclo[3.3.1]nonanyl, 2,5-diazabicyclo[2.2.1]heptanyl, (1S,4S)-2,5-diazabicyclo[2.2.1]heptanyl, 1,4-diazabicyclo[3.1.1]heptanyl, 3,6-diazabicyclo[3.2.0]heptanyl, 2,5-diazabicyclo[2.2.2]octanyl, 1,4-diazabicyclo[3.2.1]octanyl, 3,8-diazabicyclo[3.2.1]octanyl, (1R,5S)-3,8-diazabicyclo[3.2.1]octanyl, azabicyclo[3.2.2]nonanyl, azaspiro[3.3]heptanyl, 4,7-diazaspiro[2.5]octanyl, 2,6-diazaspiro[3.3]heptanyl, 2,6-diazaspiro[3.4]octanyl, 1,7,-diazaspiro[4.4]nonanyl, 1,7-diazaspiro[3.5]nonanyl, 2,6-diazaspiro[3.5]nonanyl, 2,7-diazaspiro[3.5]nonanyl, 5,8-diazaspiro[3.5]nonanyl, 2,7-diazaspiro[4.4]nonanyl, 2,7-diazaspiro[4.5]decanyl, 2,8-diazaspiro[4.5]decanyl, 6,9-diazaspiro[4.5]decyl, 6-oxa-2,9-diazaspiro[4.5]decanyl, azaspiro[5.5]undecanyl, and 7-azadispiro[5.1.58.36]hexadecanyl, optionally substituted with 1, 2, 3, 4, or 5 substituents each selected from R2.

Another aspect includes a compound of Formula (I), n B is heterocyclyl selected from pyrrolidinyl, piperidinyl, hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, 8-azabicyclo[3.2.1]octanyl, 2,6-diazaspiro[3.4]octanyl, and 7-azadispiro[5.1.58.36]hexadecanyl, optionally substituted with 1, 2, 3, 4, or 5 substituents each selected from R2.

Another aspect includes a compound of Formula (I), wherein B is heterocyclyl selected from pyrrolidinyl, piperidinyl, hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, 8-azabicyclo[3.2.1]octanyl, 2,6-diazaspiro[3.4]octanyl, and 7- azadispiro[5.1.58.36]hexadecanyl, ally substituted with 1, 2, 3, 4, or 5 substituents each ed from R2.

Another aspect includes a compound of Formula (I), wherein B is heterocyclyl selected from pyrrolidinyl and piperidinyl, optionally substituted with 1, 2, 3, 4, or 5 tuents each selected from R2.

Another aspect includes a compound of Formula (I), wherein B is heterocyclyl selected from ed from azetidinyl, tetrahydrofuranyl, pyrrolidinyl, idinyl, piperidinyl, dinyl, piperidinyl, piperazinyl, 1,4-diazepanyl, 1,2-dihydropyridinyl, 1,2-dihydropyridinyl, 1,2-dihydropyridinyl, hydropyridinyl, 1,2-dihydropyridinyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl, hexahydrocyclopentapyrrol-2(1H)-yl, hexahydropyrrolo[3,2-b]pyrrol-1(2H)-yl, hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl, hexahydropyrrolo[3,4-b]pyrrol-5(1H)- yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl, hexahydropyrrolo[3,4-c]pyrrol-1(1H)-yl, hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl, hexahydropyrrolo[3,4-c]pyrrol-5(1H)-yl, (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl, octahydro-2H-pyrrolo[3,4-c]pyridin- 2-yl, octahydro-5H-pyrrolo[3,2-c]pyridinyl, octahydro-6H-pyrrolo[3,4-b]pyridinyl, (4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridinyl, (4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridinyl, hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one, hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, (7R,8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, (8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, (8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, hexahydro-1H-cyclobuta[1.2-c:1,4- c']dipyrrol-2(3H)-yl, (8aS)-octahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, (8aR)-octahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, octahydro-2H-pyrido[1,2-a]pyrazinyl, dropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl, 5-azaspiro[2.4]heptanyl, 2-oxa azaspiro[3.4]octanyl, 3-azabicyclo[3.1.0]hexanyl, 8-azabicyclo[3.2.1]octanyl, (1R,5S)azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]octenyl, (1R,5S)azabicyclo[3.2.1]octenyl, 9-azabicyclo[3.3.1]nonanyl, (1R,5S)azabicyclo[3.3.1]nonanyl, 2,5-diazabicyclo[2.2.1]heptanyl, (1S,4S)-2,5-diazabicyclo[2.2.1]heptanyl, 1,4-diazabicyclo[3.1.1]heptanyl, 3,6-diazabicyclo[3.2.0]heptanyl, 3,6-diazabicyclo[3.2.0]heptanyl, 2,5-diazabicyclo[2.2.2]octanyl, 1,4-diazabicyclo[3.2.1]octanyl, 3,8-diazabicyclo[3.2.1]octanyl, (1R,5S)-3,8-diazabicyclo[3.2.1]octanyl, 1,4-diazabicyclo[3.2.2]nonanyl, azaspiro[3.3]heptanyl, azaspiro[2.5]octan yl, 4,7-diazaspiro[2.5]octanyl, 2,6-diazaspiro[3.3]heptanyl, 2,6-diazaspiro[3.4]octan- 2-yl, 2,6-diazaspiro[3.4]octanyl, 1,7,-diazaspiro[4.4]nonanyl, 1,7-diazaspiro[4.4]nonanyl, 1,7-diazaspiro[3.5]nonanyl, 2,6-diazaspiro[3.5]nonan- 2-yl, 2,6-diazaspiro[3.5]nonanyl, 2,7-diazaspiro[3.5]nonanyl, 2,7-diazaspiro[3.5]nonanyl, azaspiro[3.5]nonanyl, 2,7-diazaspiro[4.4]nonan yl, 2,7-diazaspiro[4.5]decanyl, 2,7-diazaspiro[4.5]decanyl, and 2,8-diazaspiro[4.5]decanyl. 6,9-diazaspiro[4.5]decyl, and ispiro[5.1.58.36]hexadecanyl, optionally substituted with 1, 2, 3, 4, or 5 substituents each ed from R2.

Another aspect includes a compound of Formula (I), n B is heterocyclyl selected from pyrrolidinyl, dinyl, hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl, 8-azabicyclo[3.2.1]octanyl, 2,6-diazaspiro[3.4]octanyl, and 7-azadispiro[5.1.58.36]hexadecanyl, ally substituted with 1, 2, 3, 4, or 5 substituents each selected from R2.

Another aspect includes a compound of Formula (I), wherein B is heterocyclyl ed from pyrrolidinyl and piperidinyl, optionally substituted with 1, 2, 3, 4, or 5 substituents each selected from R2.

One aspect includes a nd of Formula (I), wherein R2 is selected from halogen, C1-4alkyl, deutero-C1-4alkyl, amino, kyl-amino, and (C1-4alkyl)2-amino.

Another aspect includes a compound of Formula (I), wherein R2 is selected from C1-4alkyl and C1-4alkyl-amino.

Another aspect includes a compound of Formula (I), n R2 is C1-4alkyl selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl.

Another aspect includes a compound of Formula (I), wherein R2 is methyl.

Another aspect includes a compound of Formula (I), n R2 is C1-4alkyl-amino, wherein C1-4alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tyl, and tert-butyl.

Another aspect includes a compound of Formula (I), wherein R2 is C1-4alkyl-amino, wherein C1-4alkyl is tert-butyl.

Another aspect includes a nd of Formula (I), wherein R2 is kyl-amino, wherein C1-4alkyl is tert-butylamino.

One aspect includes a compound of Formula (I), wherein R3 is selected from halogen, hydroxyl, cyano, kyl, deutero-C1-4alkyl, halo-C1-4alkyl, amino, C1-4alkyl-amino, lkyl)2-amino, C1-4alkoxy, halo-C1-4alkoxy, heteroaryl, heterocyclyl, and phenyl, wherein heteroaryl is a 3-7 membered monocyclic or 6-10 membered bicyclic ring system having 1, 2, 3, or 4 heteroatom ring s ndently selected from N, O, or S, wherein heterocyclyl is a saturated or partially unsaturated 3-7 membered monocyclic, 6-10 membered bicyclic or 13-16 membered polycyclic ring system having 1, 2, or 3 heteroatom ring members independently selected from N, O, or S, and wherein each instance of phenyl, heteroaryl or heterocyclyl is optionally substituted with 1 or 2 substituents each selected from R4.

Another aspect includes a compound of Formula (I), wherein R3 is selected from halogen, hydroxyl, cyano, kyl, and heteroaryl, wherein aryl is a 3-7 membered monocyclic or 6-10 membered bicyclic ring system having 1, 2, 3, or 4 atom ring s independently selected from N, O, or S, n each instance of heteroaryl is optionally substituted with 1 or 2 substituents each selected from R4.

Another aspect includes a compound of Formula (I), wherein R3 is n selected from bromo, chloro, fluoro, and iodo.

Another aspect includes a compound of Formula (I), wherein R3 is halogen selected from chloro and fluoro.

Another aspect includes a compound of Formula (I), wherein R3 is chloro.

Another aspect includes a compound of Formula (I), wherein R3 is fluoro.

Another aspect includes a compound of Formula (I), wherein R3 is hydroxyl.

Another aspect includes a compound of Formula (I), wherein R3 is cyano.

Another aspect includes a compound of a (I), wherein R3 is C1-4alkyl selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl.

Another aspect includes a compound of Formula (I), wherein R3 is methyl.

Another aspect includes a compound of Formula (I), wherein R3 is heteroaryl selected from thienyl, 1H-pyrazolyl, 1H-imidazolyl, 1,3-thiazolyl, oxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1H-1,2,3-triazolyl, ,3-triazolyl, 1H-1,2,4- triazolyl, 1H-tetrazolyl, 2H-tetrazolyl, pyridinyl, pyridin-2(1H)-on-yl, pyrimidinyl, pyrimidin-4(3H)-on-yl, pyridazinyl, pyridazin-3(2H)-on-yl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1H-indolyl, 1H-indazolyl, 2H-indazolyl, indolizinyl, benzofuranyl, benzothienyl, 1H-benzimidazolyl, 1,3-benzoxazolyl, nzothiazolyl, 1,3-benzodioxolyl, 1,2,3-benzotriazolyl, 9H-purinyl, furo[3,2-b]pyridinyl, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, azolo[5,4-b]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl, pyrrolo[1,2-a]pyrimidinyl, pyrrolo[1,2-a]pyrazinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridin-yl, pyrazolo[1,5-a]pyridinyl, 1H-pyrazolo[3,4-b]pyrazinyl, 1H-pyrazolo[3,4-b]pyridinyl, 1H-pyrazolo[3,4-b]pyridinyl, azolo[3,4-c]pyridinyl, azolo[3,4-c]pyridinyl, 1H-pyrazolo[4,3-b]pyridinyl, 1H-pyrazolo[4,3-b]pyridinyl, 1H-pyrazolo[4,3-d]pyrimidinyl, 2H-pyrazolo[4,3-b]pyridinyl, 2H-pyrazolo[4,3-c]pyridinyl , 5H-pyrrolo[2,3-b]pyrazinyl, pyrazolo[1,5-a]pyrazinyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-c]pyrimidinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, o[1,2-a]pyrazinyl, 1H-imidazo[4,5-b]pyridinyl, 3H-imidazo[4,5-b]pyridinyl, imidazo[2,1-b][1,3]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, [1,3]oxazolo[4,5-b]pyridinyl, [1,2,3]triazolo[1,5- a]pyridinyl, [1,2,3]triazolo[1,5-a]pyridinyl, 1H-[1,2,3]triazolo[4,5-b]pyridinyl, 3H-[1,2,3]triazolo[4,5-b]pyridinyl, tetrazolo[1,5-a]pyridinyl, tetrazolo[1,5-b]pyridazinyl, quinolinyl, isoquinolinyl, and quinoxalinyl, optionally substituted with 1 or 2 substituents each selected from R4.

Another aspect includes a compound of Formula (I), wherein R3 is aryl selected from 1H-pyrazolyl, 1H-imidazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, pyridinyl, pyridin- 2(1H)-on-yl, pyrimidinyl, 1,3,5-triazinyl, imidazo[1,2-b]pyridazinyl, and imidazo[1,2-a]pyrazinyl, optionally substituted with 1 or 2 substituents each selected from Another aspect includes a compound of Formula (I), wherein R3 is heteroaryl selected from 2-yl, thienyl, 1H-pyrazolyl, 1H-pyrazolyl, 1H-pyrazolyl, 1H-pyrazolyl, dazolyl, dazolyl, iazolyl, iazolyl, oxazolyl, oxazolyl, oxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1H-1,2,3-triazolyl, 1H-1,2,3-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, ,3-triazolyl, 1H-1,2,4-triazolyl, 1H-1,2,4-triazolyl, 1H-1,2,4-triazolyl, 1H-tetrazolyl, 1H-tetrazolyl, 2H-tetrazolyl, 2H-tetrazol yl, pyridinyl, nyl, nyl, pyridin-2(1H)-onyl, pyridin-2(1H)-onyl, pyridin-2(1H)-onyl, pyrimidinyl, pyrimidinyl, pyrimidinyl, pyrimidin-4(3H)- onyl, pyridazinyl, pyridazinyl, pyridazin-3(2H)-onyl, 1,2,4-triazinyl, 1,3,5- triazinyl, 1H-indolyl, 1H-indolyl, 1H-indolyl, 1H-indolyl, 1H-indazolyl, 2H-indazolyl, indolizinyl, benzofuranyl, benzofuranyl, hienyl, benzothienyl, 1H-benzimidazolyl, 1H-benzimidazolyl, 1H-benzimidazolyl, 1,3-benzoxazolyl, 1,3-benzoxazolyl, 1,3-benzoxazolyl, 1,3-benzothiazolyl, 1,3-benzothiazolyl, 1,3-benzothiazolyl, 1,3-benzodioxolyl, 1,2,3-benzotriazol- -yl, 9H-purinyl, furo[3,2-b]pyridinyl, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, 1,3-oxazolo[5,4-b]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridin yl, pyrrolo[1,2-a]pyrimidinyl, pyrrolo[1,2-a]pyrazinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, 1H-pyrazolo[3,4-b]pyrazinyl, azolo[3,4-b]pyridinyl, 1H-pyrazolo[3,4-b]pyridinyl, 1H-pyrazolo[3,4- c]pyridinyl, 1H-pyrazolo[3,4-c]pyridinyl, 1H-pyrazolo[4,3-b]pyridinyl, 1H-pyrazolo[4,3-b]pyridinyl, 1H-pyrazolo[4,3-d]pyrimidinyl, 2H-pyrazolo[4,3-b]pyridinyl, 2H-pyrazolo[4,3-c]pyridinyl, 5H-pyrrolo[2,3- b]pyrazinyl, lo[1,5-a]pyrazinyl, imidazo[1,2-a]pyridinyl, o[1,2-a]pyridinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-c]pyrimidinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, imidazo[1,2-a]pyrazinyl, 1H-imidazo[4,5-b]pyridinyl, 3H-imidazo[4,5-b]pyridinyl, imidazo[2,1-b][1,3]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, [1,3]oxazolo[4,5-b]pyridinyl, [1,2,3]triazolo[1,5-a]pyridinyl, [1,2,3]triazolo[1,5- a]pyridinyl, 1H-[1,2,3]triazolo[4,5-b]pyridinyl, 2,3]triazolo[4,5-b]pyridin- -yl, tetrazolo[1,5-a]pyridinyl, tetrazolo[1,5-b]pyridazinyl, quinolinyl, isoquinolinyl, and quinoxalinyl, optionally substituted with 1 or 2 substituents each selected from R4.

Another aspect includes a compound of Formula (I), n R3 is heteroaryl ed from 1H-pyrazolyl, 1H-pyrazolyl, 1H-pyrazolyl, 1H-imidazolyl, 2H-1,2,3-triazol yl, 1H-1,2,4-triazolyl, pyridinyl, pyridinyl, pyridinyl, pyridin-2(1H)-onyl, pyrimidinyl, pyrimidinyl, 1,3,5-triazinyl, imidazo[1,2-b]pyridazinyl, and imidazo[1,2-a]pyrazinyl, optionally substituted with 1 or 2 substituents each selected from R4.

One aspect includes a compound of Formula (I), wherein R4 is selected from n, hydroxyl, cyano, C1-4alkyl, deutero-C1-4alkyl, halo-C1-4alkyl, amino, C1-4alkyl-amino, lkyl)2-amino, C1-4alkoxy, and halo-C1-4alkoxy.

Another aspect es a compound of Formula (I), wherein R4 is selected from n, hydroxyl, cyano, C1-4alkyl, deutero-C1-4alkyl, halo-C1-4alkyl, amino, and C1-4alkoxy.

Another aspect includes a compound of Formula (I), wherein R4 is halogen selected from bromo, chloro, fluoro, and iodo.

Another aspect includes a compound of Formula (I), wherein R4 is halogen selected from chloro and fluoro.

Another aspect includes a compound of Formula (I), n R4 is chloro.

Another aspect includes a compound of Formula (I), wherein R4 is fluoro.

Another aspect includes a compound of Formula (I), wherein R4 is hydroxyl.

Another aspect includes a compound of Formula (I), wherein R4 is cyano.

Another aspect includes a compound of Formula (I), wherein R4 is C1-4alkyl ed from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl.

Another aspect includes a compound of Formula (I), wherein R4 is methyl.

Another aspect includes a nd of a (I), wherein R4 is deutero-C1-4alkyl n C1-4alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl partially or completely substituted with one or more deuterium atoms where d by available valences.

Another aspect includes a compound of Formula (I), wherein R4 is (2H3)methyl.

Another aspect includes a compound of Formula (I), wherein R4 is halo-C1-4alkyl wherein C1-4alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl partially or tely substituted with one or more halogen atoms where allowed by available es.

Another aspect includes a compound of Formula (I), wherein R4 is trifluoromethyl.

Another aspect includes a compound of Formula (I), wherein R4 is amino.

Another aspect includes a compound of Formula (I), wherein R4 is koxy selected from methoxy, , propoxy, isopropoxy, butoxy, and tert-butoxy.

Another aspect includes a compound of Formula (I), wherein R4 y.

One aspect es a compound of Formula (I), n n is 1, 2 or 3.

Another aspect includes a compound of Formula (I), wherein n is 2.

Another aspect includes a compound of Formula (I), wherein n is 3.

An aspect of the compound of Formula (I) or a form thereof includes a compound ed from the group consisting of: 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64, and 65 wherein a form of the compound is selected from the group consisting of a salt, hydrate, solvate, racemate, enantiomer, diastereomer, stereoisomer, and tautomer form thereof.

An aspect the compound of Formula (I) or a form thereof (wherein compound number (#1) indicates that the salt form was isolated) includes a compound selected from the group consisting of: Cpd Name 4-(3-hydroxy{5-[methyl(2,2,6,6-tetramethylpiperidinyl)amino]pyrazin 1 nyl)pyridinol 21 5-(1H-pyrazolyl){5-[(2,2,6,6-tetramethylpiperidinyl)oxy]pyrazinyl}phenol 2-{5-[(7-azadispiro[5.1.58.36]hexadecanyl)(methyl)amino]pyrazinyl}(1H- 3 pyrazolyl)phenol Cpd Name -dichloro(1H-pyrazolyl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin- 4 4-yl)pyrazinamine -(1H-imidazolyl){5-[methyl(2,2,6,6-tetramethylpiperidinyl)amino]pyrazin yl}phenol 2-[5-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrazinyl](1H-pyrazol 61 yl)phenol 71 2-{5-[(piperidinyl)oxy]pyrazinyl}(1H-pyrazolyl)phenol 81 2-{5-[(piperidinyl)amino]pyrazinyl}(1H-pyrazolyl)phenol 2-{5-[methyl(2,2,6,6-tetramethylpiperidinyl)amino]pyrazinyl}[5- 9 (trifluoromethyl)-1H-pyrazolyl]phenol 2-[2,3-difluoro(1H-pyrazolyl)phenyl][(2,2,6,6-tetramethylpiperidin 101 yl)oxy]pyrazine -[2-fluoromethyl(1H-pyrazolyl)phenyl]-N-methyl-N-(2,2,6,6- 11 tetramethylpiperidinyl)pyrazinamine -(5-methyl-1H-pyrazolyl){5-[methyl(2,2,6,6-tetramethylpiperidin 12 yl)amino]pyrazinyl}phenol -[2,3-difluoro(1H-pyrazolyl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin- 131 4-yl)pyrazinamine -(3-amino-1H-pyrazolyl){5-[methyl(2,2,6,6-tetramethylpiperidin 14 yl)amino]pyrazinyl}phenol -[2,5-difluoro(1H-pyrazolyl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin- 4-yl)pyrazinamine -[3-fluoro(1H-pyrazolyl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin 16 yl)pyrazinamine -[3,5-difluoro(1H-pyrazolyl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin- 17 4-yl)pyrazinamine 4-(3-hydroxy{5-[methyl(2,2,6,6-tetramethylpiperidinyl)amino]pyrazin 18 yl}phenyl)methylpyridin-2(1H)-one 2-{5-[methyl(2,2,6,6-tetramethylpiperidinyl)amino]pyrazinyl}(1H-pyrazol 19 yl)phenol 2-{5-[methyl(piperidinyl)amino]pyrazinyl}(1H-pyrazolyl)phenol 21 2-[5-(2,6-diazaspiro[3.4]octanyl)pyrazinyl](1H-pyrazolyl)phenol ro{5-[methyl(2,2,6,6-tetramethylpiperidinyl)amino]pyrazinyl}(1H- 22 pyrazolyl)phenol -[5-chlorofluoro(1H-pyrazolyl)phenyl]-N-methyl-N-(2,2,6,6- 23 tetramethylpiperidinyl)pyrazinamine 4-fluoro{5-[methyl(2,2,6,6-tetramethylpiperidinyl)amino]pyrazinyl}(1H- 24 pyrazolyl)benzonitrile 251 2-[5-(8-azabicyclo[3.2.1]octyloxy)pyrazinyl](1H-pyrazolyl)phenol Cpd Name 2-{5-[methyl(2,2,6,6-tetramethylpiperidinyl)amino]pyrazinyl}(1H-pyrazol 261 yl)phenol -(1-methyl-1H-pyrazolyl){5-[methyl(2,2,6,6-tetramethylpiperidin 27 no]pyrazinyl}phenol -[1-(2H3)methyl-1H-pyrazolyl]{5-[methyl(2,2,6,6-tetramethylpiperidin 281 yl)amino]pyrazinyl}phenol (5-(2-hydroxy(1H-pyrazolyl)phenyl)pyrazinyl)(2,2,6,6-tetramethylpiperidin 29 yl)methanone 2-(5-(2-hydroxy(1H-pyrazolyl)phenyl)pyrazinyl)(2,2,6,6- tetramethylpiperidinyl)acetonitrile 2-(5-(amino(2,2,6,6-tetramethylpiperidinyl)methyl)pyrazinyl)(1H-pyrazol 31 yl)phenol 2-(5-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyrazinyl)(1,3,5-triazin 32 yl)phenol 4-(3-hydroxy(5-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyrazin 33 yl)phenyl)-1,3,5-triazinol -(4-amino-1,3,5-triazinyl)(5-(methyl(2,2,6,6-tetramethylpiperidin 34 yl)amino)pyrazinyl)phenol -(4-chloro-1,3,5-triazinyl)(5-(methyl(2,2,6,6-tetramethylpiperidin no)pyrazinyl)phenol -(5-chloro-1H-pyrazolyl)(5-(methyl(2,2,6,6-tetramethylpiperidin 36 no)pyrazinyl)phenol 4-(3-hydroxy(5-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyrazin 37 yl)phenyl)-1H-pyrazolecarbonitrile -(1,5-dimethyl-1H-pyrazolyl)(5-(methyl(2,2,6,6-tetramethylpiperidin 38 yl)amino)pyrazinyl)phenol hloromethyl-1H-pyrazolyl)(5-(methyl(2,2,6,6-tetramethylpiperidin 39 yl)amino)pyrazinyl)phenol 4-(3-hydroxy(5-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyrazin 40 yl)phenyl)methyl-1H-pyrazolecarbonitrile -[2,3-difluoro(4-methyl-1H-imidazolyl)phenyl]-N-methyl-N-(2,2,6,6- 41 tetramethylpiperidinyl)pyrazinamine -[2,5-difluoro(3-methyl-1H-1,2,4-triazolyl)phenyl]-N-methyl-N-(2,2,6,6- 42 tetramethylpiperidinyl)pyrazinamine -(3-fluoro-1H-pyrazolyl){5-[methyl(2,2,6,6-tetramethylpiperidin 431 yl)amino]pyrazinyl}phenol 441 5-(pyridinyl){5-[(2,2,6,6-tetramethylpiperidinyl)amino]pyrazinyl}phenol 451 5-(pyridinyl){5-[(2,2,6,6-tetramethylpiperidinyl)amino]pyrazinyl}phenol -(1H-pyrazolyl){5-[(2,2,6,6-tetramethylpiperidinyl)amino]pyrazin 461 yl}phenol 471 5-(pyrimidinyl){5-[(2,2,6,6-tetramethylpiperidinyl)amino]pyrazinyl}phenol Cpd Name 481 5-(pyridinyl){5-[(2,2,6,6-tetramethylpiperidinyl)amino]pyrazinyl}phenol ethoxypyrimidinyl){5-[(2,2,6,6-tetramethylpiperidinyl)amino]pyrazin- 491 2-yl}phenol -(1H-imidazolyl){5-[(2,2,6,6-tetramethylpiperidinyl)amino]pyrazin 501 yl}phenol 2-{5-[(2,2,6,6-tetramethylpiperidinyl)amino]pyrazinyl}(2H-1,2,3-triazol 511 yl)phenol 521 2-{5-[3-(tert-butylamino)pyrrolidinyl]pyrazinyl}(1H-pyrazolyl)phenol -(imidazo[1,2-a]pyrazinyl){5-[(2,2,6,6-tetramethylpiperidin 531 yl)amino]pyrazinyl}phenol -(1-methyl-1H-pyrazolyl){5-[(2,2,6,6-tetramethylpiperidinyl)amino]pyrazin- 541 2-yl}phenol -(1-methyl-1H-pyrazolyl){5-[(2,2,6,6-tetramethylpiperidinyl)amino]pyrazin- 55 2-yl}phenol -(imidazo[1,2-b]pyridazinyl){5-[(2,2,6,6-tetramethylpiperidin 561 yl)amino]pyrazinyl}phenol -(5-fluoro-1H-pyrazolyl){5-[(2,2,6,6-tetramethylpiperidinyl)amino]pyrazin- 571 2-yl}phenol -(1H-pyrazolyl){5-[(2,2,6,6-tetramethylpiperidinyl)amino]pyrazin 581 yl}phenol -(4-fluoro-1H-pyrazolyl){5-[(2,2,6,6-tetramethylpiperidinyl)amino]pyrazin- 591 2-yl}phenol 2-{5-[3-(tert-butylamino)pyrrolidinyl]pyrazinyl}[1-(2H3)methyl-1H-pyrazol- 601 4-yl]phenol 2-{5-[methyl(2,2,6,6-tetramethylpiperidinyl)amino]pyrazinyl}(2H-1,2,3- 611 triazolyl)phenol 2-{5-[3-(tert-butylamino)pyrrolidinyl]pyrazinyl}(1-methyl-1H-pyrazol 621 yl)phenol N-tert-butyl{5-[2,3-difluoro(1H-pyrazolyl)phenyl]pyrazinyl}pyrrolidin 631 amine N-tert-butyl{5-[2,5-difluoro(1H-pyrazolyl)phenyl]pyrazinyl}pyrrolidin 641 amine, and 3-(tert-butylamino)pyrrolidinyl]pyrazinyl}(3-fluoro-1H-pyrazol 651 nol; wherein a form of the compound is selected from the group ting of a salt, hydrate, solvate, racemate, enantiomer, diastereomer, stereoisomer, and tautomer form thereof.

Another aspect of the compound of Formula (I) or a form thereof is a compound salt selected from the group consisting of: Cpd Name pyrazolyl){5-[(2,2,6,6-tetramethylpiperidinyl)oxy]pyrazinyl}phenol 2 hydrochloride Cpd Name 2-[5-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrazinyl](1H-pyrazol 6 yl)phenol tetrahydrochloride 7 2-{5-[(piperidinyl)oxy]pyrazinyl}(1H-pyrazolyl)phenol trihydrochloride 2-{5-[(piperidinyl)amino]pyrazinyl}(1H-pyrazolyl)phenol 8 ydrochloride 2-[2,3-difluoro(1H-pyrazolyl)phenyl][(2,2,6,6-tetramethylpiperidin yl)oxy]pyrazine trihydrochloride -[2,3-difluoro(1H-pyrazolyl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin- 13 4-yl)pyrazinamine hydrochloride 2-[5-(8-azabicyclo[3.2.1]octyloxy)pyrazinyl](1H-pyrazolyl)phenol hydrochloride 2-{5-[methyl(2,2,6,6-tetramethylpiperidinyl)amino]pyrazinyl}(1H-pyrazol 26 yl)phenol hydrobromide -[1-(2H3)methyl-1H-pyrazolyl]{5-[methyl(2,2,6,6-tetramethylpiperidin 28 no]pyrazinyl}phenol dihydrochloride -(3-fluoro-1H-pyrazolyl){5-[methyl(2,2,6,6-tetramethylpiperidin 43 yl)amino]pyrazinyl}phenol dihydrochloride -(pyridinyl){5-[(2,2,6,6-tetramethylpiperidinyl)amino]pyrazinyl}phenol 44 formate -(pyridinyl){5-[(2,2,6,6-tetramethylpiperidinyl)amino]pyrazinyl}phenol 45 formate -(1H-pyrazolyl){5-[(2,2,6,6-tetramethylpiperidinyl)amino]pyrazin 46 yl}phenol formate -(pyrimidinyl){5-[(2,2,6,6-tetramethylpiperidinyl)amino]pyrazinyl}phenol 47 formate idinyl){5-[(2,2,6,6-tetramethylpiperidinyl)amino]pyrazinyl}phenol 48 formate -(6-methoxypyrimidinyl){5-[(2,2,6,6-tetramethylpiperidinyl)amino]pyrazin- 49 2-yl}phenol formate -(1H-imidazolyl){5-[(2,2,6,6-tetramethylpiperidinyl)amino]pyrazin 50 yl}phenol formate 2-{5-[(2,2,6,6-tetramethylpiperidinyl)amino]pyrazinyl}(2H-1,2,3-triazol 51 yl)phenol formate 2-{5-[3-(tert-butylamino)pyrrolidinyl]pyrazinyl}(1H-pyrazolyl)phenol 52 dihydrochloride -(imidazo[1,2-a]pyrazinyl){5-[(2,2,6,6-tetramethylpiperidin 53 yl)amino]pyrazinyl}phenol formate ethyl-1H-pyrazolyl){5-[(2,2,6,6-tetramethylpiperidinyl)amino]pyrazin- 54 2-yl}phenol formate -(imidazo[1,2-b]pyridazinyl){5-[(2,2,6,6-tetramethylpiperidin 56 no]pyrazinyl}phenol formate -(5-fluoro-1H-pyrazolyl){5-[(2,2,6,6-tetramethylpiperidinyl)amino]pyrazin- 57 2-yl}phenol formate Cpd Name -(1H-pyrazolyl){5-[(2,2,6,6-tetramethylpiperidinyl)amino]pyrazin 58 yl}phenol formate -(4-fluoro-1H-pyrazolyl){5-[(2,2,6,6-tetramethylpiperidinyl)amino]pyrazin- 59 2-yl}phenol formate 3-(tert-butylamino)pyrrolidinyl]pyrazinyl}[1-(2H3)methyl-1H-pyrazol- 60 4-yl]phenol dihydrochloride 2-{5-[methyl(2,2,6,6-tetramethylpiperidinyl)amino]pyrazinyl}(2H-1,2,3- 61 triazolyl)phenol dihydrochloride 2-{5-[3-(tert-butylamino)pyrrolidinyl]pyrazinyl}(1-methyl-1H-pyrazol 62 yl)phenol dihydrochloride N-tert-butyl{5-[2,3-difluoro(1H-pyrazolyl)phenyl]pyrazinyl}pyrrolidin 63 amine dihydrochloride N-tert-butyl{5-[2,5-difluoro(1H-pyrazolyl)phenyl]pyrazinyl}pyrrolidin 64 amine dihydrochloride, and 2-{5-[3-(tert-butylamino)pyrrolidinyl]pyrazinyl}(3-fluoro-1H-pyrazol 65 yl)phenol dihydrochloride; wherein a form of the compound is selected from the group consisting of a salt, hydrate, solvate, racemate, enantiomer, reomer, stereoisomer, and er form thereof.

An aspect of the present description includes a method for preventing, treating or ameliorating HD in a subject in need thereof comprising, administering to the t an effective amount of a compound of Formula (I) or a form thereof.

An aspect of the present description includes a method for treating or ameliorating HD in a subject in need thereof comprising, administering to the subject an effective amount of a compound of Formula (I) or a form thereof.

Another aspect of the present description includes a method for treating or ameliorating HD in a subject in need thereof sing, administering to the t an effective amount of a compound salt of Formula (I) or a form thereof.

An aspect of the present description includes a method for use of a nd of Formula (I) or a form or composition thereof for treating or ameliorating HD in a subject in need thereof comprising, administering to the subject an effective amount of the compound of Formula (I) or a form or composition thereof.

Another aspect of the present description includes a method for use of a compound salt of Formula (I) or a form or composition thereof for treating or ameliorating HD in a t in need thereof sing, administering to the subject an effective amount of the nd salt of Formula (I) or a form thereof.

An aspect of the present description includes a use for a compound of Formula (I) or a form thereof for treating or ameliorating HD in a t in need thereof comprising, administering to the subject an effective amount of the compound of Formula (I) or a form thereof.

Another aspect of the present description includes a use for a compound salt of Formula (I) or a form thereof for treating or ameliorating HD in a subject in need thereof sing, administering to the subject an effective amount of the compound salt of Formula (I) or a form thereof.

An aspect of the present description includes a use for a compound of Formula (I) or a form thereof in the manufacture of a medicament for treating or ameliorating HD in a subject in need thereof comprising, administering to the subject an effective amount of the medicament.

Another aspect of the present description includes a use for a compound salt of Formula (I) or a form f in the manufacture of a medicament for treating or ameliorating HD in a subject in need thereof comprising, administering to the subject an effective amount of the medicament.

An aspect of the present description includes a use for a nd of a (I) or a form thereof in a combination product with one or more therapeutic agents for treating or ameliorating HD in a subject in need thereof sing, administering to the subject an ive amount of the compound of Formula (I) or a form thereof in combination with an effective amount of the one or more agents.

Another aspect of the present description includes a use for a nd salt of Formula (I) or a form thereof in a ation product with one or more therapeutic agents for ng or ameliorating HD in a t in need thereof comprising, administering to the subject an ive amount of the compound salt of Formula (I) or a form thereof in combination with an effective amount of the one or more agents.

CHEMICAL DEFINITIONS The chemical terms used above and throughout the description herein, unless specifically defined otherwise, shall be understood by one of ordinary skill in the art to have the ing indicated meanings.

As used herein, the term "C1-4alkyl" generally refers to saturated hydrocarbon radicals having from one to four carbon atoms in a straight or branched chain configuration, including, but not limited to, methyl, ethyl, yl (also referred to as propyl or propanyl), pyl, n-butyl (also referred to as butyl or butanyl), isobutyl, sec-butyl, tert-butyl and the like. A kyl radical is optionally substituted with substituent species as described herein where allowed by available valences.

As used herein, the term "C2-4alkenyl" generally refers to lly unsaturated hydrocarbon radicals having from two to four carbon atoms in a straight or ed chain configuration and one or more carbon-carbon double bonds therein, including, but not limited to, ethenyl (also referred to as vinyl), allyl, propenyl and the like. A C2-4alkenyl radical is optionally substituted with substituent species as bed herein where allowed by available valences.

As used herein, the term "C2-8alkynyl" generally refers to partially unsaturated hydrocarbon radicals having from two to eight carbon atoms in a ht or branched chain configuration and one or more carbon-carbon triple bonds therein, including, but not limited to, ethynyl, propynyl, butynyl and the like. In certain aspects, C2-8alkynyl es, but is not limited to, C2-6alkynyl, C2-4alkynyl and the like. A C2-8alkynyl radical is optionally substituted with substituent species as described herein where allowed by available valences.

As used herein, the term "C1-4alkoxy" generally refers to saturated hydrocarbon radicals having from one to four carbon atoms in a straight or branched chain uration of the formula: 4alkyl, including, but not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like. A C1-44alkoxy radical is ally substituted with substituent species as described herein where allowed by available es.

As used herein, the term "C3-7cycloalkyl" lly refers to a ted or partially unsaturated monocyclic, bicyclic or polycyclic arbon radical, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, and the like. A C3-7cycloalkyl radical is optionally substituted with substituent species as described herein where allowed by available valences.

As used herein, the term "aryl" generally refers to a monocyclic, bicyclic or polycyclic aromatic carbon atom ring structure radical, including, but not limited to, phenyl, naphthyl, anthracenyl, nyl, azulenyl, phenanthrenyl and the like. An aryl l is optionally substituted with substituent species as described herein where allowed by available valences.

As used herein, the term "heteroaryl" generally refers to a monocyclic, bicyclic or polycyclic aromatic carbon atom ring ure radical in which one or more carbon atom ring members have been replaced, where allowed by structural stability, with one or more heteroatoms, such as an O, S or N atom, including, but not d to, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, 1,3-thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, dinyl, nyl, pyridazinyl, triazinyl, indolyl, indazolyl, zinyl, isoindolyl, benzofuranyl, benzothienyl, benzoimidazolyl, 1,3-benzothiazolyl, 1,3-benzoxazolyl, purinyl, quinolinyl, nolinyl, quinazolinyl, quinoxalinyl, 1,3-diazinyl, 1,2-diazinyl, 1,2-diazolyl, 1,4-diazanaphthalenyl, acridinyl, furo[3,2-b]pyridinyl, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, 6H-thieno[2,3-b]pyrrolyl, thieno[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, pyrrolo[1,2-a]pyrazinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrazinyl, imidazo[1,2-a]pyridinyl, dazo[4,5-b]pyridinyl, imidazo[1,2-a]pyrimidinyl, o[1,2-c]pyrimidinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, imidazo[2,1-b][1,3]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, [1,2,4]triazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl and the like. A aryl radical is optionally substituted on a carbon or nitrogen atom ring member with substituent species as described herein where allowed by available valences.

In certain aspects, the nomenclature for a aryl radical may differ, such as in non- limiting examples where furanyl may also be referred to as furyl, thienyl may also be referred to as thiophenyl, pyridinyl may also be referred to as pyridyl, benzothienyl may also be referred to as benzothiophenyl and 1,3-benzoxazolyl may also be ed to as 1,3-benzooxazolyl.

In n other aspects, the term for a heteroaryl radical may also include other regioisomers, such as in non-limiting examples where the term pyrrolyl may also include 2H-pyrrolyl, 3H-pyrrolyl and the like, the term pyrazolyl may also include 1H-pyrazolyl and the like, the term imidazolyl may also include 1H-imidazolyl and the like, the term triazolyl may also include 1H-1,2,3-triazolyl and the like, the term oxadiazolyl may also include 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl and the like, the term tetrazolyl may also include 1H-tetrazolyl, 2H-tetrazolyl and the like, the term indolyl may also include 1H-indolyl and the like, the term lyl may also include 1H-indazolyl, 2H-indazolyl and the like, the term benzoimidazolyl may also e 1H-benzoimidazolyl and the term purinyl may also include 9H-purinyl and the like.

As used herein, the term "heterocyclyl" lly refers to a saturated or lly unsaturated monocyclic, ic or polycyclic carbon atom ring structure radical in which one or more carbon atom ring members have been replaced, where allowed by structural stability, with a heteroatom, such as an O, S or N atom, including, but not limited to, oxiranyl, oxetanyl, azetidinyl, tetrahydrofuranyl, inyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, olinyl, isoxazolidinyl, isothiazolinyl, isothiazolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, triazolinyl, triazolidinyl, oxadiazolinyl, oxadiazolidinyl, thiadiazolinyl, thiadiazolidinyl, olinyl, tetrazolidinyl, pyranyl, dihydro-2H-pyranyl, thiopyranyl, 1,3-dioxanyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,4-diazepanyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl, 2,3-dihydro-1,4-benzodioxinyl, hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl, hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, octahydro-5H-pyrrolo[3,2-c]pyridinyl, octahydro-6H-pyrrolo[3,4-b]pyridinyl, (4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridinyl, aS)-octahydro-6H-pyrrolo[3,4-b]pyridinyl, hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (7R,8aS)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aS)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aR)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aS)-octahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aR)-octahydropyrrolo[1,2-a]pyrazin-(1H)-yl, hexahydropyrrolo[1,2-a]pyrazin-(2H)-one, octahydro-2H-pyrido[1,2-a]pyrazinyl, 3-azabicyclo[3.1.0]hexyl, (1R,5S)azabicyclo[3.1.0]hexyl, 8-azabicyclo[3.2.1]octyl, (1R,5S)azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]octenyl, (1R,5S)azabicyclo[3.2.1]octenyl, 9-azabicyclo[3.3.1]nonyl, (1R,5S)azabicyclo[3.3.1]nonyl, 2,5-diazabicyclo[2.2.1]heptyl, (1S,4S)-2,5-diazabicyclo[2.2.1]heptyl, azabicyclo[2.2.2]octyl, 3,8-diazabicyclo[3.2.1]octyl, )-3,8-diazabicyclo[3.2.1]octyl, 1,4-diazabicyclo[3.2.2]nonyl, azaspiro[3.3]heptyl, 2,6-diazaspiro[3.3]heptyl, azaspiro[3.4]octyl, 2,7-diazaspiro[3.5]nonyl, ,8-diazaspiro[3.5]nonyl, 2,7-diazaspiro[4.4]nonyl, 6,9-diazaspiro[4.5]decyl, 7-azadispiro[5.1.58.36]hexadecanyl and the like. A heterocyclyl radical is optionally substituted on a carbon or nitrogen atom ring member with substituent species as described herein where allowed by ble valences.

In certain aspects, the nomenclature for a heterocyclyl radical may differ, such as in non- limiting examples where 1,3-benzodioxolyl may also be referred to as d][1,3]dioxolyl and 2,3-dihydro-1,4-benzodioxinyl may also be referred to as 2,3-dihydrobenzo[b][1,4]dioxinyl.

As used herein, the term "C1-4alkoxy-C1-4alkyl" refers to a radical of the formula: -C1-4alkyl-O-C1-4alkyl.

As used herein, the term "C1-4alkoxy-C1-4alkyl-amino" refers to a l of the formula: -NH-C1-4alkyl-O-C1-4alkyl.

As used , the term "(C1-4alkoxy-C1-4alkyl)2-amino" refers to a l of the formula: -N(C1-4alkyl-O-C1-4alkyl)2.

As used herein, the term lkoxy-C1-4alkyl-amino-C1-4alkoxy" refers to a radical of the formula: -O-C1-4alkyl-NH-C1-4alkyl-O-C1-4alkyl.

As used herein, the term alkoxy-C1-4alkyl)2-amino-C1-4alkoxy" refers to a radical of the formula: -O-C1-4alkyl-N(C1-4alkyl-O-C1-4alkyl)2.

As used herein, the term "(C1-4alkoxy-C1-4alkyl)(C1-4alkyl)amino-C1-4alkoxy" refers to a radical of the formula: -O-C1-4alkyl-N(C1-4alkyl)(C1-4alkyl-O-C1-4alkyl).

As used herein, the term "C1-4alkoxy-C1-4alkyl-amino-C1-4alkyl" refers to a radical of the formula: -C1-4alkyl-NH-C1-4alkyl-O-C1-4alkyl.

As used , the term "(C1-4alkoxy-C1-4alkyl)2-amino-C1-4alkyl" refers to a radical of the formula: -C1-4alkyl-N(C1-4alkyl-O-C1-4alkyl)2.

As used herein, the term "(C1-4alkoxy-C1-4alkyl)(C1-4alkyl)amino-C1-4alkyl" refers to a radical of the formula: -C1-4alkyl-N(C1-4alkyl)(C1-4alkyl-O-C1-4alkyl).

As used herein, the term "C1-4alkoxy-carbonyl" refers to a radical of the formula: -C(O)-O-C1-4alkyl.

As used herein, the term "C1-4alkoxy-carbonyl-C2-8alkenyl" refers to a radical of the formula: -C2-8alkenyl-C(O)-O-C1-4alkyl.

As used herein, the term "C1-4alkoxy-carbonyl-amino" refers to a radical of the formula: -NH-C(O)-O-C1-4alkyl.

As used herein, the term "C1-4alkyl-amino" refers to a radical of the formula: -NH-C1-4alkyl.

As used herein, the term "(C1-4alkyl)2-amino" refers to a radical of the formula: -N(C1-4alkyl)2.

As used herein, the term "C1-4alkyl-amino-C2-8alkenyl" refers to a radical of the formula: lkenyl-NH-C1-4alkyl.

As used herein, the term alkyl)2-amino-C2-8alkenyl" refers to a radical of the formula: -C2-8alkenyl-N(C1-4alkyl)2.

As used herein, the term "C1-4alkyl-amino-C1-4alkoxy" refers to a radical of the a: -O-C1-4alkyl-NH-C1-4alkyl.

As used herein, the term "(C1-4alkyl)2-amino-C1-4alkoxy" refers to a radical of the formula: -O-C1-4alkyl-N(C1-4alkyl)2.

As used herein, the term lkyl-amino-C1-4alkyl" refers to a radical of the formula: -C1-4alkyl-NH-C1-4alkyl.

As used herein, the term "(C1-4alkyl)2-amino-C1-4alkyl" refers to a radical of the formula: -C1-4alkyl-N(C1-4alkyl)2.

As used herein, the term "C1-4alkyl-amino-C1-4alkyl-amino" refers to a radical of the a: -NH-C1-4alkyl-NH-C1-4alkyl.

As used herein, the term "(C1-4alkyl)2-amino-C1-4alkyl-amino" refers to a radical of the formula: -NH-C1-4alkyl-N(C1-4alkyl)2.

As used herein, the term "(C1-4alkyl-amino-C1-4alkyl)2-amino" refers to a radical of the formula: -N(C1-4alkyl-NH-C1-4alkyl)2.

As used herein, the term "[(C1-4alkyl)2-amino-C1-4alkyl]2-amino" refers to a radical of the formula: -N[C1-4alkyl-N(C1-4alkyl)2]2.

As used , the term "(C1-4alkyl-amino-C1-4alkyl)(C1-4alkyl)amino" refers to a radical of the formula: -N(C1-4alkyl)(C1-4alkyl-NH-C1-4alkyl).

As used herein, the term "[(C1-4alkyl)2-amino-C1-4alkyl](C1-4alkyl)amino" refers to a radical of the formula: -N(C1-4alkyl)[C1-4alkyl-N(C1-4alkyl)2].

As used herein, the term "C1-4alkyl-amino-C2-8alkynyl" refers to a radical of the a: -C2-8alkynyl-NH-C1-4alkyl.

As used herein, the term "(C1-4alkyl)2-amino-C2-8alkynyl" refers to a l of the formula: -C2-8alkynyl-N(C1-4alkyl)2.

As used herein, the term "C1-4alkyl-carbonyl" refers to a radical of the formula: -C(O)-C1-4alkyl.

As used herein, the term "C1-4alkyl-carbonyl-amino" refers to a radical of the a: -NH-C(O)-C1-4alkyl.

As used herein, the term lkyl-thio" refers to a radical of the formula: -S-C1-4alkyl.

As used herein, the term "amino-C2-8alkenyl" refers to a radical of the formula: -C2-8alkenyl-NH2.

As used herein, the term -C1-4alkoxy" refers to a radical of the formula: -O-C1-4alkyl-NH2.

As used herein, the term -C1-4alkyl" refers to a radical of the formula: -C1-4alkyl-NH2.

As used herein, the term "amino-C1-4alkyl-amino" refers to a radical of the formula: -NH-C1-4alkyl-NH2.

As used herein, the term "(amino-C1-4alkyl)2-amino" refers to a radical of the formula: -N(C1-4alkyl-NH2)2.

As used herein, the term "(amino-C1-4alkyl)(C1-4alkyl)amino" refers to a radical of the formula: -N(C1-4alkyl)(C1-4alkyl-NH2).

As used herein, the term "amino-C2-8alkynyl" refers to a radical of the a: lkynyl-NH2.

As used herein, the term "aryl-C1-4alkoxy-carbonyl" refers to a radical of the formula: -C(O)-O-C1-4alkyl-aryl.

As used herein, the term "aryl-C1-4alkyl" refers to a radical of the formula: -C1-4alkyl-aryl.

As used herein, the term "aryl-C1-4alkyl-amino" refers to a radical of the a: -NH-C1-4alkyl-aryl.

As used herein, the term "(aryl-C1-4alkyl)2-amino" refers to a radical of the formula: -N(C1-4alkyl-aryl)2.

As used herein, the term "(aryl-C1-4alkyl)(C1-4alkyl)amino" refers to a radical of the formula: -N(C1-4alkyl)(C1-4alkyl-aryl).

As used herein, the term "aryl-C1-4alkyl-amino-C1-4alkyl" refers to a radical of the formula: -C1-4alkyl-NH-C1-4alkyl-aryl.

As used herein, the term "(aryl-C1-4alkyl)2-amino-C1-4alkyl" refers to a l of the formula: -C1-4alkyl-N(C1-4alkyl-aryl)2.

As used herein, the term "(aryl-C1-4alkyl)(C1-4alkyl)amino-C1-4alkyl" refers to a radical of the formula: -C1-4alkyl-N(C1-4alkyl)(C1-4alkyl-aryl).

As used herein, the term amino" refers to a radical of the formula: -NH-aryl.

As used herein, the term "aryl-amino-carbonyl" refers to a radical of the a: -C(O)-NH-aryl.

As used herein, the term "aryl-sulfonyloxy-C1-4alkyl" refers to a l of the formula: -C1-4alkyl-O-SO2-aryl.

As used herein, the term "benzoxy-carbonyl" refers to a l of the formula: -C(O)-O-CH2-phenyl.

As used herein, the term "C3-14cycloalkyl-C1-4alkyl" refers to a radical of the formula: -C1-4alkyl-C3-14cycloalkyl.

As used herein, the term cycloalkyl-amino" refers to a l of the formula: -14cycloalkyl.

As used herein, the term "C3-14cycloalkyl-oxy" refers to a radical of the formula: -O-C3-14cycloalkyl.

As used herein, the term " deutero-C1-4alkyl," refers to a radical of the formula: -C1-4alkyl-deutero, wherein C1-4alkyl is partially or completely substituted with one or more deuterium atoms where allowed by available valences.

As used herein, the term "halo" or "halogen" generally refers to a halogen atom radical, including fluoro, chloro, bromo and iodo.

As used herein, the term C1-4alkoxy" refers to a radical of the formula: -O-C1-4alkyl-halo, wherein C1-4alkyl is partially or completely substituted with one or more halogen atoms where allowed by available valences.

As used herein, the term "halo-C1-4alkyl" refers to a radical of the formula: -C1-4alkyl-halo, wherein C1-4alkyl is partially or completely substituted with one or more halogen atoms where allowed by available valences.

As used herein, the term "halo-C1-4alkyl-amino" refers to a radical of the formula: -NH-C1-4alkyl-halo.

As used herein, the term "(halo-C1-4alkyl)(C1-4alkyl)amino" refers to a radical of the formula: -N(C1-4alkyl)(C1-4alkyl-halo).

As used herein, the term "(halo-C1-4alkyl)2-amino" refers to a radical of the formula: -N(C1-4alkyl-halo)2.

As used herein, the term "heteroaryl-C1-4alkoxy" refers to a l of the a: -O-C1-4alkyl-heteroaryl.

As used herein, the term "heteroaryl-C1-4alkyl" refers to a radical of the formula: -C1-4alkyl-heteroaryl.

As used herein, the term "heteroaryl-C1-4alkyl-amino" refers to a radical of the formula: -4alkyl-heteroaryl.

As used herein, the term "(heteroaryl-C1-4alkyl)2-amino" refers to a radical of the formula: -N(C1-4alkyl-heteroaryl)2.

As used herein, the term "(heteroaryl-C1-4alkyl)(C1-4alkyl)amino" refers to a radical of the formula: -N(C1-4alkyl)(C1-4alkyl-heteroaryl).

As used herein, the term "heteroaryl-C1-4alkyl-amino-C1-4alkyl" refers to a radical of the formula: lkyl-NH-C1-4alkyl-heteroaryl.

As used herein, the term "(heteroaryl-C1-4alkyl)2-amino-C1-4alkyl" refers to a l of the formula: -C1-4alkyl-N(C1-4alkyl-heteroaryl)2.

As used herein, the term "(heteroaryl-C1-4alkyl)(C1-4alkyl)amino-C1-4alkyl" refers to a radical of the formula: -C1-4alkyl-N(C1-4alkyl)(C1-4alkyl-heteroaryl).

As used herein, the term "heteroaryl-amino" refers to a radical of the formula: -NH-heteroaryl.

As used herein, the term ocyclyl-C1-4alkoxy" refers to a radical of the formula: 4alkyl-heterocyclyl.

As used herein, the term "heterocyclyl-C1-4alkyl" refers to a radical of the formula: -C1-4alkyl-heterocyclyl.

As used herein, the term "heterocyclyl-C1-4alkyl-amino" refers to a radical of the formula: -NH-C1-4alkyl-heterocyclyl.

As used herein, the term "(heterocyclyl-C1-4alkyl)2-amino" refers to a l of the formula: -N(C1-4alkyl-heterocyclyl)2.

As used herein, the term "(heterocyclyl-C1-4alkyl)(C1-4alkyl)amino" refers to a radical of the formula: 4alkyl)(C1-4alkyl-heterocyclyl).

As used herein, the term ocyclyl-C1-4alkyl-amino-C1-4alkyl" refers to a l of the formula: -C1-4alkyl-NH-C1-4alkyl-heterocyclyl.

As used herein, the term "(heterocyclyl-C1-4alkyl)2-amino-C1-4alkyl" refers to a radical of the formula: -C1-4alkyl-N(C1-4alkyl-heterocyclyl)2.

As used herein, the term "(heterocyclyl-C1-4alkyl)(C1-4alkyl)amino-C1-4alkyl" refers to a radical of the formula: -C1-4alkyl-N(C1-4alkyl)(C1-4alkyl-heterocyclyl).

As used herein, the term "heterocyclyl-amino" refers to a radical of the formula: terocyclyl.

As used herein, the term "(heterocyclyl)(C1-4alkyl)amino" refers to a radical of the formula: -N(C1-4alkyl)(heterocyclyl).

As used herein, the term "heterocyclyl-amino-C1-4alkyl" refers to a radical of the formula: lkyl-NH-heterocyclyl.

As used herein, the term "heterocyclyl-carbonyl" refers to a radical of the formula: -C(O)-heterocyclyl.

As used herein, the term "heterocyclyl-carbonyl-oxy" refers to a radical of the formula: -O-C(O)-heterocyclyl.

As used herein, the term "heterocyclyl-oxy" refers to a radical of the formula: erocyclyl.

As used herein, the term "hydroxy" refers to a radical of the formula: -OH.

As used herein, the term "hydroxy-C1-4alkoxy-C1-4alkyl" refers to a radical of the formula: -C1-4alkyl-O-C1-4alkyl-OH.

As used herein, the term "hydroxy-C1-4alkyl" refers to a radical of the formula: -C1-4alkyl-OH, wherein C1-4alkyl is partially or completely substituted with one or more hydroxy ls where allowed by available valences.

As used herein, the term "hydroxy-C1-4alkyl-amino" refers to a radical of the formula: -NH-C1-4alkyl-OH.

As used herein, the term "(hydroxy-C1-4alkyl)2-amino" refers to a radical of the formula: -N(C1-4alkyl-OH)2.

As used herein, the term "(hydroxy-C1-4alkyl)(C1-4alkyl)amino" refers to a radical of the formula: -N(C1-4alkyl)(C1-4alkyl-OH).

As used herein, the term "hydroxy-C1-4alkyl-amino-C1-4alkyl" refers to a radical of the a: -C1-4alkyl-NH-C1-4alkyl-OH.

As used herein, the term "(hydroxy-C1-4alkyl)2-amino-C1-4alkyl" refers to a radical of the formula: -C1-4alkyl-N(C1-4alkyl-OH)2.

As used herein, the term "(hydroxy-C1-4alkyl)(C1-4alkyl)amino-C1-4alkyl" refers to a radical of the formula: -C1-4alkyl-N(C1-4alkyl)(C1-4alkyl-OH).

As used herein, the term "hydroxy-C1-4alkyl-amino-C1-4alkoxy" refers to a radical of the formula: -O-C1-4alkyl-NH-C1-4alkyl-OH.

As used herein, the term "(hydroxy-C1-4alkyl)2-amino-C1-4alkoxy" refers to a radical of the formula: -O-C1-4alkyl-N(C1-4alkyl-OH)2.

As used herein, the term "(hydroxy-C1-4alkyl)(C1-4alkyl)amino-C1-4alkoxy" refers to a radical of the formula: -O-C1-4alkyl-N(C1-4alkyl)(C1-4alkyl-OH).

As used herein, the term "hydroxy-C1-4alkyl-amino-C1-4alkyl-amino" refers to a l of the formula: -NH-C1-4alkyl-NH-C1-4alkyl-OH.

As used , the term "(hydroxy-C1-4alkyl-amino-C1-4alkyl)2-amino" refers to a radical of the formula: -N(C1-4alkyl-NH-C1-4alkyl-OH)2.

As used herein, the term "(hydroxy-C1-4alkyl)2-amino-C1-4alkyl-amino" refers to a l of the formula: -NH-C1-4alkyl-N(C1-4alkyl-OH)2.

As used herein, the term "(hydroxy-C1-4alkyl-amino-C1-4alkyl)(C1-4alkyl)amino" refers to a radical of the formula: -N(C1-4alkyl)(C1-4alkyl-NH-C1-4alkyl-OH).

As used , the term "[(hydroxy-C1-4alkyl)2-amino-C1-4alkyl](C1-4alkyl)amino" refers to a radical of the formula: -N(C1-4alkyl)[C1-4alkyl-N(C1-4alkyl-OH)2].

As used herein, the term "(hydroxy-C1-4alkyl)(C1-4alkyl)amino-C1-4alkyl-amino" refers to a radical of the formula: -NH-C1-4alkyl-N(C1-4alkyl,C1-4alkyl-OH).

As used herein, the term "[(hydroxy-C1-4alkyl)(C1-4alkyl)amino- kyl](C1-4alkyl)amino" refers to a radical of the a: -N(C1-4alkyl)[C1-4alkyl- N(C1-4alkyl)(C1-4alkyl-OH)].

As used herein, the term "substituent" means positional variables on the atoms of a core molecule that are substituted at a designated atom position, replacing one or more hydrogens on the designated atom, provided that the designated atom’s normal y is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are sible only if such combinations result in stable compounds. A person of ordinary skill in the art should note that any carbon as well as heteroatom with valences that appear to be unsatisfied as described or shown herein is assumed to have a ient number of hydrogen atom(s) to satisfy the valences described or shown. In certain instances one or more substituents having a double bond (e.g., "oxo" or "=O") as the point of attachment may be described, shown or listed herein within a substituent group, wherein the structure may only show a single bond as the point of attachment to the core structure of Formula (I). A person of ordinary skill in the art would understand that, while only a single bond is shown, a double bond is intended for those substituents.

As used herein, the term "and the like," with reference to the definitions of chemical terms provided herein, means that variations in chemical structures that could be expected by one skilled in the art e, t limitation, isomers (including chain, branching or positional structural isomers), hydration of ring s (including saturation or partial unsaturation of monocyclic, bicyclic or polycyclic ring structures) and all other variations where allowed by available valences which result in a stable compound.

For the purposes of this description, where one or more substituent variables for a compound of Formula (I) or a form thereof encompass onalities incorporated into a compound of Formula (I), each functionality appearing at any location within the disclosed compound may be independently selected, and as appropriate, independently and/or optionally substituted.

As used herein, the terms "independently ed," or "each selected" refer to functional variables in a substituent list that may occur more than once on the structure of Formula (I), the pattern of substitution at each occurrence is independent of the pattern at any other occurrence.

Further, the use of a generic tuent variable on any a or structure for a compound bed herein is understood to include the replacement of the generic substituent with species substituents that are included within the ular genus, e.g., aryl may be replaced with phenyl or naphthalenyl and the like, and that the ing compound is to be included within the scope of the compounds described herein.

As used herein, the terms "each instance of" or "in each instance, when present," when used ing a phrase such as "…C3-14cycloalkyl, ycloalkyl-C1-4alkyl, aryl, aryl-C1-4alkyl, heteroaryl, heteroaryl-C1-4alkyl, cyclyl and heterocyclyl-C1-4alkyl," are intended to refer to the C3-14cycloalkyl, aryl, heteroaryl and heterocyclyl ring systems when each are present either alone or as a substituent.

As used herein, the term "optionally substituted" means optional substitution with the specified substituent variables, , ls or moieties.

COMPOUND FORMS As used herein, the term "form" means a compound of a (I) having a form selected from the group consisting of a free acid, free base, prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.

In certain aspects described herein, the form of the compound of Formula (I) is a free acid, free base or salt thereof.

In certain aspects described herein, the form of the compound of Formula (I) is a salt thereof.

In certain aspects described herein, the form of the compound of Formula (I) is an isotopologue thereof.

In certain aspects bed herein, the form of the compound of Formula (I) is a stereoisomer, racemate, enantiomer or diastereomer thereof.

In certain aspects bed herein, the form of the compound of Formula (I) is a tautomer thereof.

In certain aspects described herein, the form of the compound of Formula (I) is a pharmaceutically acceptable form.

In n aspects described herein, the compound of Formula (I) or a form thereof is isolated for use.

As used herein, the term "isolated" means the physical state of a compound of Formula (I) or a form thereof after being isolated and/or purified from a synthetic process (e.g., from a reaction e) or natural source or combination thereof ing to an isolation or cation process or processes described herein or which are well known to the skilled artisan (e.g., chromatography, recrystallization and the like) in sufficient purity to be characterized by standard analytical techniques bed herein or well known to the skilled n.

As used herein, the term "protected" means that a functional group in a compound of Formula (I) or a form thereof is in a form modified to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by nce to standard textbooks such as, for example, T.W. Greene et al, Protective Groups in organic Synthesis (1991), Wiley, New York. Such functional groups include hydroxy, phenol, amino and carboxylic acid. le protecting groups for hydroxy or phenol include trialkylsilyl or diarylalkylsilyl (e.g., ldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, substituted benzyl, , methoxymethanol, and the like. Suitable protecting groups for amino, amidino and guanidino include t-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitable ting groups for carboxylic acid include alkyl, aryl or arylalkyl esters. In certain instances, the protecting group may also be a r resin, such as a Wang resin or a 2-chlorotrityl-chloride resin. Protecting groups may be added or removed in accordance with standard techniques, which are well-known to those skilled in the art and as described herein. It will also be appreciated by those skilled in the art, although such protected tives of compounds described herein may not s pharmacological activity as such, they may be administered to a subject and thereafter lized in the body to form compounds described herein which are pharmacologically active.

Such derivatives may therefore be described as "prodrugs". All prodrugs of compounds described herein are included within the scope of the use described .

As used herein, the term "prodrug" means a form of an instant compound (e.g., a drug precursor) that is transformed in vivo to yield an active compound of Formula (I) or a form thereof. The transformation may occur by various mechanisms (e.g., by metabolic and/or non-metabolic chemical processes), such as, for example, by ysis and/or metabolism in blood, liver and/or other organs and tissues. A discussion of the use of prodrugs is provided by T.

Higuchi and W. Stella, "Pro-drugs as Novel Delivery s," 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.

In one example, when a compound of Formula (I) or a form thereof ns a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a functional group such as alkyl and the like. In another e, when a compound of Formula (I) or a form thereof contains a hydroxyl functional group, a prodrug form can be prepared by replacing the hydrogen atom of the hydroxyl with another functional group such as alkyl, alkylcarbonyl or a phosphonate ester and the like. In another example, when a compound of Formula (I) or a form thereof contains an amine functional group, a prodrug form can be prepared by replacing one or more amine en atoms with a functional group such as alkyl or substituted carbonyl. Pharmaceutically acceptable gs of compounds of Formula (I) or a form thereof include those compounds substituted with one or more of the following groups: carboxylic acid esters, sulfonate esters, amino acid , phosphonate esters and mono-, di- or triphosphate esters or alkyl substituents, where appropriate.

As described herein, it is tood by a person of ordinary skill in the art that one or more of such substituents may be used to provide a compound of Formula (I) or a form thereof as a prodrug.

One or more compounds described herein may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and the description herein is intended to embrace both solvated and unsolvated forms.

As used herein, the term "solvate" means a al association of a compound described herein with one or more solvent les. This physical association involves varying degrees of ionic and covalent g, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. As used herein, te" encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include lates, methanolates, and the like.

As used herein, the term te" means a solvate wherein the solvent molecule is water.

The compounds of Formula (I) can form salts, which are intended to be included within the scope of this description. Reference to a compound of a (I) or a form thereof herein is understood to include nce to salt forms thereof, unless otherwise indicated. The term "salt(s)", as employed herein, s acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or c bases. In addition, when a compound of Formula (I) or a form thereof contains both a basic moiety, such as, without tion an amine moiety, and an acidic moiety, such as, but not limited to a ylic acid, zwitterions ("inner ) may be formed and are included within the term "salt(s)" as used herein.

The term "pharmaceutically acceptable salt(s)", as used herein, means those salts of compounds described herein that are safe and effective (i.e., non-toxic, physiologically acceptable) for use in mammals and that possess biological activity, although other salts are also useful. Salts of the compounds of the Formula (I) may be formed, for e, by reacting a compound of Formula (I) or a form f with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.

Pharmaceutically acceptable salts e one or more salts of acidic or basic groups present in compounds bed herein. Particular aspects of acid addition salts include, and are not limited to, acetate, ascorbate, benzoate, benzenesulfonate, ate, rate, borate, bromide, butyrate, chloride, citrate, camphorate, camphorsulfonate, ethanesulfonate, formate, fumarate, gentisinate, gluconate, glucaronate, glutamate, iodide, isonicotinate, lactate, maleate, methanesulfonate, naphthalenesulfonate, nitrate, oxalate, pamoate, pantothenate, phosphate, propionate, saccharate, late, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate (also known as tosylate), trifluoroacetate salts and the like. Certain particular aspects of acid addition salts include chloride or dichloride.

Additionally, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook of ceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33, 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D.C. on their e). These disclosures are orated herein by nce thereto.

Suitable basic salts include, but are not limited to, aluminum, ammonium, m, lithium, magnesium, potassium, sodium and zinc salts.

All such acid salts and base salts are intended to be included within the scope of pharmaceutically acceptable salts as described herein. In addition, all such acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of this description.

Compounds of Formula (I) and forms thereof, may further exist in a tautomeric form. All such tautomeric forms are contemplated and intended to be included within the scope of the compounds of Formula (I) or a form thereof as described herein.

The compounds of Formula (I) or a form thereof may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. The present description is intended to e all stereoisomeric forms of the compounds of Formula (I) as well as mixtures thereof, including racemic mixtures.

The compounds described herein may include one or more chiral centers, and as such may exist as c mixtures (R/S) or as substantially pure omers and diastereomers. The compounds may also exist as substantially pure (R) or (S) omers (when one chiral center is present). In one particular aspect, the compounds described herein are (S) isomers and may exist as enantiomerically pure compositions substantially comprising only the (S) isomer. In another particular aspect, the compounds described herein are (R) s and may exist as enantiomerically pure compositions substantially comprising only the (R) isomer. As one of skill in the art will ize, when more than one chiral center is present, the compounds bed herein may also exist as a (R,R), (R,S), (S,R) or (S,S) isomer, as defined by IUPAC Nomenclature Recommendations.

As used herein, the term "substantially pure" refers to compounds consisting substantially of a single isomer in an amount greater than or equal to 90%, in an amount greater than or equal to 92%, in an amount r than or equal to 95%, in an amount greater than or equal to 98%, in an amount greater than or equal to 99%, or in an amount equal to 100% of the single isomer.

In one aspect of the description, a nd of Formula (I) or a form thereof is a substantially pure (S) enantiomer form present in an amount greater than or equal to 90%, in an amount greater than or equal to 92%, in an amount greater than or equal to 95%, in an amount greater than or equal to 98%, in an amount greater than or equal to 99%, or in an amount equal to 100%.

In one aspect of the description, a compound of Formula (I) or a form thereof is a substantially pure (R) enantiomer form present in an amount greater than or equal to 90%, in an amount greater than or equal to 92%, in an amount greater than or equal to 95%, in an amount greater than or equal to 98%, in an amount greater than or equal to 99%, or in an amount equal to 100%.

As used herein, a "racemate" is any mixture of isometric forms that are not "enantiomerically pure", including mixtures such as, without limitation, in a ratio of about 50/50, about 60/40, about 70/30, or about 80/20.

In addition, the present description embraces all geometric and positional isomers. For example, if a compound of Formula (I) or a form thereof incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are ed within the scope of the description. Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those d in the art, such as, for example, by chromatography and/or fractional llization. Enantiomers can be ted by use of chiral HPLC column or other chromatographic methods known to those skilled in the art. Enantiomers can also be separated by converting the omeric mixture into a diastereomeric mixture by on with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid de), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Also, some of the compounds of Formula (I) may be atropisomers (e.g., substituted biaryls) and are considered as part of this description.

All stereoisomers (for example, geometric isomers, optical s and the like) of the present compounds (including those of the salts, solvates, esters and prodrugs of the nds as well as the salts, es and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of tric carbons), rotameric forms, atropisomers, and reomeric forms, are contemplated within the scope of this description, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl). Individual stereoisomers of the compounds described herein may, for example, be substantially free of other isomers, or may be present in a racemic mixture, as bed supra.

The use of the terms "salt", "solvate", "ester", "prodrug" and the like, is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or isotopologues of the instant compounds.

The term "isotopologue" refers to isotopically-enriched compounds bed herein which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds described herein include isotopes of hydrogen, carbon, nitrogen, , phosphorus, ne and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, 35Cl and 36Cl, tively, each of which are also within the scope of this description.

Certain isotopically-enriched compounds described herein (e.g., those labeled with 3H and 14C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3H) and carbon-14 (i.e., 14C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2H) may afford certain therapeutic ages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.

Polymorphic crystalline and amorphous forms of the compounds of Formula (I) and of the salts, solvates, hydrates, esters and prodrugs of the nds of Formula (I) are further intended to be included in the present description.

COMPOUND USES In accordance with the intended scope of the present description, aspects of the t description e compounds that have been identified and have been demonstrated to be useful in selectively preventing, treating or ameliorating HD and have been provided for use for preventing, treating or ameliorating HD.

An aspect of the present description includes a method for preventing, ng or ameliorating HD in a subject in need thereof comprising, administering to the subject an effective amount of a compound of Formula (I) or a form thereof.

An aspect of the present description includes a method for treating or ameliorating HD in a subject in need thereof comprising, stering to the subject an effective amount of a compound of a (I) or a form thereof.

An aspect of the present description es a method for preventing HD in a subject in need thereof comprising, administering to the subject an effective amount of a compound of Formula (I) or a form thereof.

An aspect of the present ption es a method for treating HD in a subject in need thereof comprising, administering to the subject an effective amount of a compound of Formula (I) or a form thereof.

An aspect of the present description includes a method for ameliorating HD in a subject in need thereof comprising, administering to the t an effective amount of a compound of Formula (I) or a form thereof.

Another aspect of the present ption es a method for treating or rating HD in a subject in need thereof comprising, administering to the subject an effective amount of a compound salt of Formula (I) or a form thereof.

An aspect of the present description includes a method for use of a compound of Formula (I) or a form or composition thereof for ng or ameliorating HD in a subject in need thereof comprising, administering to the subject an effective amount of the compound of Formula (I) or a form or composition thereof.

Another aspect of the present description includes a method for use of a compound salt of Formula (I) or a form or composition thereof for treating or rating HD in a subject in need thereof comprising, administering to the subject an effective amount of the compound salt of Formula (I) or a form thereof.

An aspect of the present ption includes a use for a compound of a (I) or a form thereof for treating or ameliorating HD in a t in need thereof comprising, administering to the subject an effective amount of the compound of Formula (I) or a form thereof.

Another aspect of the present description includes a use for a compound salt of Formula (I) or a form thereof for ng or ameliorating HD in a subject in need thereof comprising, administering to the subject an effective amount of the compound salt of Formula (I) or a form thereof.

An aspect of the present description includes a use for a compound of a (I) or a form thereof in the manufacture of a medicament for treating or ameliorating HD in a subject in need thereof comprising, administering to the subject an effective amount of the medicament.

Another aspect of the present description includes a use for a compound salt of Formula (I) or a form thereof in the manufacture of a medicament for treating or ameliorating HD in a t in need thereof comprising, administering to the t an effective amount of the medicament.

An aspect of the present description includes in vitro or in vivo use of the compound of Formula (I) or a form f having activity toward HD.

An aspect of the present description includes a use of the nd of Formula (I) or a form thereof in a combination therapy to provide additive or synergistic activity, thus enabling the development of a combination product for treating or ameliorating HD.

Another aspect of the present description includes a combination therapy comprising compounds described herein in combination with one or more known drugs or one or more known therapies may be used to treat HD regardless of whether HD is responsive to the known drug.

An aspect of the present description includes a use for a compound of Formula (I) or a form thereof in a combination product with one or more therapeutic agents for treating or ameliorating HD in a subject in need thereof comprising, administering to the subject an effective amount of the compound of Formula (I) or a form thereof in combination with an ive amount of the one or more .

Another aspect of the t description es a use for a compound salt of Formula (I) or a form f in a ation product with one or more therapeutic agents for treating or ameliorating HD in a subject in need f comprising, administering to the subject an effective amount of the compound salt of Formula (I) or a form thereof in combination with an effective amount of the one or more agents.

In an aspect of a use or method provided herein, compounds of Formula (I) or a form thereof used in combination with one or more additional agents can be administered to a subject or contacted with a subject or patient cell(s) prior to, concurrently with, or subsequent to administering to the subject or patient or contacting the cell with an additional agent(s). A compound(s) of Formula (I) or a form thereof and an additional agent(s) can be administered to a subject or contacted with a cell in single composition or ent compositions. In a specific aspect, a compound(s) of Formula (I) or a form thereof is used in combination with gene therapy to t HTT expression (using, e.g., viral delivery vectors) or the administration of another small molecule HTT inhibitor. In another specific aspect, a compound(s) of Formula (I) or a form f are used in combination with cell replacement using entiated non-mutant HTT stem cells. In another specific aspect, a compound(s) of Formula (I) or a form thereof are used in combination with cell replacement using differentiated HTT stem cells.

In one aspect, provided herein is the use of compounds of Formula (I) or a form thereof in combination with supportive standard of care ies, ing palliative care.

An aspect of the present ption includes a use for a compound of Formula (I) or a form thereof in the preparation of a kit for treating or ameliorating HD in a subject in need thereof comprising, the compound of Formula (I) or a form thereof and instructions for administering an effective amount of the compound of Formula (I) or a form thereof.

An aspect of the present description includes a use for a nd of Formula (I) or a form thereof in the ation of a kit for treating or ameliorating HD in a subject in need thereof comprising, the nd of Formula (I) or a form thereof and instructions for administering an effective amount of the compound of a (I) or a form thereof; and optionally, for administering to the subject an ive amount of the compound of Formula (I) or a form thereof in a combination product with an effective amount of one or more eutic agents.

An aspect of the present description includes a use for a compound of Formula (I) or a form thereof in the preparation of a kit for treating or ameliorating HD in a subject in need thereof comprising, the compound of Formula (I) or a form f and ctions for administering an effective amount of the compound of Formula (I) or a form thereof; and optionally, for administering to the subject an effective amount of the compound of Formula (I) or a form thereof in a combination product with an effective amount of the one or more therapeutic agents; and optionally, for administering to the subject an effective amount of the compound of Formula (I) or a form thereof in a combination product with an effective amount of the one or more therapeutic agents in a combination therapy with a rd of care supportive y, wherein the standard of care supportive therapy is tive care.

In one respect, for each of such aspects, the subject is treatment naive. In another respect, for each of such aspects, the subject is not treatment naive.

As used herein, the term "preventing" refers to keeping a disease, disorder or condition from occurring in a subject that may be predisposed to the disease, disorder and/or condition but has not yet been diagnosed as having the disease, disorder and/or condition.

As used , the term "treating" refers to inhibiting the progression of a disease, disorder or condition in a subject already ting the symptoms of the disease, disorder and/or condition, i.e., arresting the development of a disease, er and/or ion that has y affected the subject.

As used herein, the term orating" refers to ing the symptoms of a disease, disorder or condition in a subject already exhibiting the symptoms of the e, disorder and/or ion, i.e., causing regression of the disease, disorder and/or condition that has y affected the t.

As used herein, the term "subject" refers to an animal or any living organism having sensation and the power of voluntary movement, and which requires oxygen and organic food.

Nonlimiting examples include members of the human, primate, equine, porcine, bovine, murine, rattus, canine and feline specie. In certain aspects, the subject is a mammal or a warm-blooded vertebrate animal. In other aspects, the subject is a human. As used herein, the term "patient" may be used interchangeably with "subject" and ".

As used herein, the terms "effective amount" or peutically effective amount" mean an amount of compound of Formula (I) or a form, composition or medicament thereof that achieves a target plasma concentration that is effective in ng or ameliorating HD as described herein and thus producing the desired eutic, ameliorative, inhibitory or preventative effect in a subject in need thereof. In one aspect, the effective amount may be the amount required to treat HD in a subject or patient, more specifically, in a human.

In another aspect, the concentration-biological effect relationships observed with regard to a compound of Formula (I) or a form thereof indicate a target plasma concentration ranging from approximately 0.001 μg/mL to approximately 50 µg/mL, from approximately 0.01 µg/mL to approximately 20 µg/mL, from approximately 0.05 µg/mL to approximately 10 µg/mL, or from approximately 0.1 µg/mL to approximately 5 µg/mL. To achieve such plasma concentrations, the compounds described herein may be administered at doses that vary, such as, for example, without limitation, from 1.0 ng to 10,000 mg.

In one aspect, the dose administered to achieve an ive target plasma concentration may be administered based upon subject or patient specific factors, wherein the doses administered on a weight basis may be in the range of from about 0.001 mg/kg/day to about 3500 mg/kg/day, or about 0.001 mg/kg/day to about 3000 mg/kg/day, or about 0.001 mg/kg/day to about 2500 mg/kg/day, or about 0.001 mg/kg/day to about 2000 mg/kg/day, or about 0.001 mg/kg/day to about 1500 mg/kg/day, or about 0.001 mg/kg/day to about 1000 mg/kg/day, or about 0.001 mg/kg/day to about 500 mg/kg/day, or about 0.001 mg/kg/day to about 250 mg/kg/day, or about 0.001 mg/kg/day to about 200 mg/kg/day, or about 0.001 day to about 150 mg/kg/day, or about 0.001 mg/kg/day to about 100 mg/kg/day, or about 0.001 mg/kg/day to about 75 mg/kg/day, or about 0.001 mg/kg/day to about 50 mg/kg/day, or about 0.001 mg/kg/day to about 25 day, or about 0.001 mg/kg/day to about 10 mg/kg/day, or about 0.001 mg/kg/day to about 5 mg/kg/day, or about 0.001 mg/kg/day to about 1 mg/kg/day, or about 0.001 mg/kg/day to about 0.5 mg/kg/day, or about 0.001 mg/kg/day to about 0.1 mg/kg/day, or from about 0.01 mg/kg/day to about 3500 mg/kg/day, or about 0.01 day to about 3000 mg/kg/day, or about 0.01 mg/kg/day to about 2500 mg/kg/day, or about 0.01 mg/kg/day to about 2000 day, or about 0.01 mg/kg/day to about 1500 mg/kg/day, or about 0.01 mg/kg/day to about 1000 mg/kg/day, or about 0.01 mg/kg/day to about 500 mg/kg/day, or about 0.01 mg/kg/day to about 250 mg/kg/day, or about 0.01 mg/kg/day to about 200 mg/kg/day, or about 0.01 mg/kg/day to about 150 mg/kg/day, or about 0.01 mg/kg/day to about 100 mg/kg/day, or about 0.01 mg/kg/day to about 75 mg/kg/day, or about 0.01 day to about 50 mg/kg/day, or about 0.01 mg/kg/day to about 25 mg/kg/day, or about 0.01 mg/kg/day to about 10 mg/kg/day, or about 0.01 mg/kg/day to about 5 day, or about 0.01 mg/kg/day to about 1 mg/kg/day, or about 0.01 mg/kg/day to about 0.5 mg/kg/day, or about 0.01 mg/kg/day to about 0.1 mg/kg/day, or from about 0.1 mg/kg/day to about 3500 mg/kg/day, or about 0.1 day to about 3000 mg/kg/day, or about 0.1 day to about 2500 mg/kg/day, or about 0.1 mg/kg/day to about 2000 mg/kg/day, or about 0.1 mg/kg/day to about 1500 mg/kg/day, or about 0.1 mg/kg/day to about 1000 mg/kg/day, or about 0.1 mg/kg/day to about 500 mg/kg/day, or about 0.1 mg/kg/day to about 250 mg/kg/day, or about 0.1 mg/kg/day to about 200 mg/kg/day, or about 0.1 mg/kg/day to about 150 mg/kg/day, or about 0.1 mg/kg/day to about 100 mg/kg/day, or about 0.1 mg/kg/day to about 75 mg/kg/day, or about 0.1 mg/kg/day to about 50 mg/kg/day, or about 0.1 mg/kg/day to about 25 mg/kg/day, or about 0.1 mg/kg/day to about 10 mg/kg/day, or about 0.1 mg/kg/day to about 5 day, or about 0.1 mg/kg/day to about 1 mg/kg/day, or about 0.1 mg/kg/day to about 0.5 mg/kg/day. ive amounts for a given t may be determined by routine experimentation that is within the skill and judgment of a clinician or a practitioner skilled in the art in light of s related to the subject. Dosage and administration may be adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors which may be taken into account include genetic screening, severity of the disease state, status of disease progression, general health of the subject, ethnicity, age, , gender, diet, time of day and frequency of administration, drug combination(s), reaction sensitivities, experience with other therapies, and tolerance/response to therapy.

The dose stered to e an effective target plasma concentration may be orally administered once (once in approximately a 24 hour period; i.e., "q.d."), twice (once in approximately a 12 hour period; i.e., ." or "q.12h"), thrice (once in approximately an 8 hour period; i.e., ." or "q.8h"), or four times (once in approximately a 6 hour period; i.e., "q.d.s.", "q.i.d." or "q.6h") daily.

In certain aspects, the dose administered to e an ive target plasma concentration may also be administered in a single, divided, or continuous dose for a patient or subject having a weight in a range of between about 40 to about 200 kg (which dose may be ed for patients or subjects above or below this range, ularly children under 40 kg).

The typical adult t is expected to have a median weight in a range of about 70 kg. Long- acting pharmaceutical compositions may be administered every 2, 3 or 4 days, once every week, or once every two weeks depending on half-life and clearance rate of the particular formulation.

The compounds and compositions described herein may be administered to the subject via any drug delivery route known in the art. Nonlimiting examples include oral, ocular, rectal, buccal, topical, nasal, sublingual, transdermal, subcutaneous, intramuscular, intraveneous (bolus and infusion), intracerebral, and pulmonary routes of administration.

In another aspect, the dose administered may be adjusted based upon a dosage form described herein formulated for ry at about 0.02, 0.025, 0.03, 0.05, 0.06, 0.075, 0.08, 0.09, 0.10, 0.20, 0.25, 0.30, 0.50, 0.60, 0.75, 0.80, 0.90, 1.0, 1.10, 1.20, 1.25, 1.50, 1.75, 2.0, 3.0, 5.0, , 20, 30, 40, 50, 100, 150, 200, 250, 300, 400, 500, 1000, 1500, 2000, 2500, 3000 or 4000 mg/day.

For any compound, the effective amount can be estimated initially either in cell culture assays or in relevant animal models, such as a mouse, guinea pig, chimpanzee, et or tamarin animal model. Relevant animal models may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans. Therapeutic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED50 (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% of the population). The dose ratio between therapeutic and toxic effects is therapeutic index, and can be expressed as the ratio, LD50/ED50. In certain aspects, the effective amount is such that a large therapeutic index is achieved. In further particular aspects, the dosage is within a range of circulating concentrations that include an ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of stration.

In one aspect, provided herein are methods for modulating the amount of HTT (huntingtin protein), comprising contacting a human cell with a compound of Formula (I) or a form thereof.

In a specific aspect, provided herein are methods for modulating the amount of HTT, comprising contacting a human cell with a compound of Formula (I) or a form thereof that modulates the expression of HTT. The human cell can be contacted with a nd of Formula (I) or a form thereof in vitro, or in vivo, e.g., in a non-human animal or in a human. In a specific aspect, the human cell is from or in a human. In another ic aspect, the human cell is from or in a human with HD. In r specific aspect, the human cell is from or in a human with HD, caused by a CAG repeat in the Htt gene, resulting in a loss of HTT expression and/or function. In another aspect, the human cell is from a human with HD. In another aspect, the human cell is in a human with HD. In one aspect, the compound is a form of the compound of Formula (I).

In a specific aspect, provided herein is a method for ing the inhibition of mutant HTT transcribed from the Htt gene, comprising contacting a human cell with a compound of Formula (I) or a form f. The human cell can be ted with a nd of Formula (I) or a form thereof in vitro, or in vivo, e.g., in a non-human animal or in a human. In a ic aspect, the human cell is from or in a human. In another specific aspect, the human cell is from or in a human with HD. In another specific aspect, the human cell is from or in a human with HD, caused by a CAG repeat in the Htt gene, resulting in a loss of wild-type "normal" HTT expression and/or function. In another aspect, the human cell is from a human with HD. In another aspect, the human cell is in a human with HD. In one aspect, the compound is a form of the compound of Formula (I).

In another aspect, provided herein is a method for modulating the inhibition of mutant HTT transcribed from the Htt gene, comprising administering to a non-human animal model for HD a compound of Formula (I) or a form f. In a ic aspect, provided herein is a method for modulating the inhibition of mutant HTT transcribed from the Htt gene, comprising administering to a non-human animal model for HD a compound of Formula (I) or a form thereof.

In a specific aspect, the compound is a form of the compound of Formula (I).

In another aspect, ed herein is a method for decreasing the amount of mutant HTT, comprising contacting a human cell with a nd of Formula (I) or a form thereof. In a specific aspect, provided herein is a method for decreasing the amount of mutant HTT, comprising contacting a human cell with a compound of Formula (I) that inhibits the transcription of mutant HTT (huntingtin mRNA) from the Htt gene. In another specific , provided herein is a method for decreasing the amount of HTT, sing contacting a human cell with a compound of Formula (I) that inhibits the expression of mutant HTT transcribed from the Htt gene. The human cell can be contacted with a compound of Formula (I) or a form thereof in vitro, or in vivo, e.g., in a non-human animal or in a human. In a specific , the human cell is from or in a human. In another specific aspect, the human cell is from or in a human with HD. In another specific aspect, the human cell is from or in a human with HD, caused by a CAG repeat in the Htt gene, resulting in a loss of HTT expression and/or function. In r aspect, the human cell is from a human with HD. In another aspect, the human cell is in a human with HD. In one aspect, the compound is a form of the compound of Formula (I).

In certain aspects, treating or ameliorating HD with a compound of Formula (I) or a form thereof (alone or in combination with an additional agent) has a therapeutic effect and/or cial effect. In a specific , treating HD with a compound of Formula (I) or a form thereof (alone or in combination with an additional agent) s in one, two or more of the following effects: (i) reduces or ameliorates the severity of HD; (ii) delays onset of HD; (iii) inhibits the progression of HD; (iv) s hospitalization of a subject; (v) reduces hospitalization length for a subject; (vi) increases the survival of a subject; (vii) improves the y of life for a subject; (viii) reduces the number of symptoms associated with HD; (ix) reduces or ameliorates the severity of a m(s) associated with HD; (x) reduces the duration of a symptom associated with HD; (xi) prevents the recurrence of a symptom associated with HD; (xii) inhibits the development or onset of a symptom of HD; and/or (xiii) inhibits of the progression of a symptom associated with HD.

METABOLITES Another aspect included within the scope of the present description are the use of in vivo metabolic products of the nds described herein. Such products may result, for example, from the oxidation, reduction, hydrolysis, ion, esterification and the like of the administered compound, primarily due to enzymatic ses. Accordingly, the description es the use of compounds produced by a process sing contacting a compound described herein with a mammalian tissue or a mammal for a period of time sufficient to yield a metabolic product thereof.

Such products typically are identified by preparing a radio-labeled isotopologue (e.g., 14C or 3H) of a compound described herein, administering the radio-labeled compound in a detectable dose (e.g., greater than about 0.5 mg/kg) to a mammal such as a rat, mouse, guinea pig, dog, monkey or human, ng sufficient time for metabolism to occur (typically about 30 s to about 30 hours), and fying the metabolic conversion ts from urine, bile, blood or other biological samples. The conversion products are easily isolated since they are "radiolabeled" by virtue of being isotopically-enriched s are isolated by the use of antibodies capable of binding epitopes surviving in the metabolite). The metabolite ures are determined in conventional n, e.g., by MS or NMR analysis. In general, analysis of metabolites may be done in the same way as conventional drug metabolism studies well-known to those skilled in the art. The conversion products, so long as they are not otherwise found in vivo, are useful in stic assays for therapeutic dosing of the compounds described herein even if they possess no biological activity of their own.

PHARMACEUTICAL COMPOSITIONS In accordance with the intended scope of the present description, aspects of the present description include compounds that have been identified and have been demonstrated to be useful in selectively preventing, treating or ameliorating HD and have been provided for use as one or more pharmaceutical compositions for preventing, treating or ameliorating HD.

An aspect of the present description includes a use for a compound of Formula (I) or a form thereof in the preparation of a pharmaceutical composition for treating or ameliorating HD in a subject in need thereof comprising, administering to the subject an effective amount of the compound of Formula (I) or a form thereof in admixture with one or more pharmaceutically acceptable excipients.

An aspect of the t description includes a use for a pharmaceutical composition of the compound of Formula (I) or a form thereof in the preparation of a kit for treating or ameliorating HD in a t in need thereof comprising, the pharmaceutical composition of the compound of Formula (I) or a form thereof and ctions for administering the pharmaceutical composition.

As used , the term "composition" means a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

The pharmaceutical composition may be ated to e a physiologically ible pH, ranging from about pH 3 to about pH 11. In certain aspects, the pharmaceutical composition is formulated to achieve a pH of from about pH 3 to about pH 7. In other aspects, the pharmaceutical ition is formulated to achieve a pH of from about pH 5 to about pH 8.

The term "pharmaceutically acceptable excipient" refers to an excipient for administration of a pharmaceutical agent, such as the nds described herein. The term refers to any pharmaceutical excipient that may be administered without undue toxicity. Pharmaceutically acceptable excipients may be ined in part by the particular composition being administered, as well as by the particular mode of administration and/or dosage form.

Nonlimiting examples of pharmaceutically acceptable excipients include carriers, solvents, stabilizers, adjuvants, diluents, etc. Accordingly, there exists a wide y of suitable formulations of pharmaceutical compositions for the instant compounds described herein (see, e.g., Remington’s ceutical Sciences).

Suitable excipients may be carrier molecules that include large, slowly metabolized macromolecules such as proteins, polysaccharides, polylactic acids, polyglycolic acids, polymeric amino acids, amino acid copolymers, and inactive antibodies. Other exemplary excipients include antioxidants such as ascorbic acid; chelating agents such as EDTA; carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose (e.g., hydroxypropylmethylcellulose, also known as HPMC), stearic acid; liquids such as oils, water, saline, glycerol and l; wetting or emulsifying agents; pH buffering substances; and the like. Liposomes are also ed within the definition of pharmaceutically acceptable excipients.

The pharmaceutical compositions described herein may be formulated in any form suitable for the intended use described herein. Suitable ations for oral stration e solids, liquid solutions, emulsions and suspensions, while suitable inhalable formulations for pulmonary administration include s and powders. Alternative formulations include syrups, creams, ointments, tablets, and lyophilized solids which can be reconstituted with a physiologically compatible solvent prior to administration.

When intended for oral use for example, tablets, troches, lozenges, aqueous or oil suspensions, non-aqueous solutions, sible powders or granules (including micronized particles or nanoparticles), emulsions, hard or soft capsules, syrups or elixirs may be prepared.

Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents including sweetening agents, flavoring agents, ng agents, and preserving agents, in order to provide a palatable preparation.

Pharmaceutically acceptable excipients suitable for use in conjunction with tablets e, for example, inert diluents, such as celluloses, calcium or sodium carbonate, lactose, calcium or sodium phosphate; disintegrating agents, such as croscarmellose sodium, cross-linked povidone, maize starch, or alginic acid; g agents, such as ne, starch, gelatin or acacia; and lubricating agents, such as ium stearate, stearic acid, or talc. Tablets may be ed or may be coated by known techniques including ncapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or yl distearate alone or with a wax may be employed.

Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example oses, lactose, calcium phosphate, or kaolin, or as soft gelatin capsules n the active ingredient is mixed with non-aqueous or oil medium, such as glycerin, propylene glycol, polyethylene glycol, peanut oil, liquid paraffin, or olive oil.

In other aspects, pharmaceutical compositions described herein may be formulated as suspensions sing a compound of Formula (I) or a form thereof in admixture with one or more pharmaceutically acceptable excipients suitable for the manufacture of a suspension. In yet other aspects, pharmaceutical compositions described herein may be formulated as dispersible s and granules suitable for preparation of a suspension by the addition of one or more excipients.

Excipients le for use in connection with sions include suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gum anth, gum acacia, dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycethanol), a condensation product of ne oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate); and thickening agents, such as carbomer, beeswax, hard paraffin, or cetyl alcohol. The suspensions may also contain one or more preservatives such as acetic acid, methyl and/or n-propyl oxy-benzoate; one or more coloring agents; one or more flavoring agents; and one or more sweetening agents such as sucrose or saccharin.

The pharmaceutical compositions described herein may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, such as olive oil or s oil, a mineral oil, such as liquid paraffin, or a mixture of these. Suitable emulsifying agents include naturallyoccurring gums, such as gum acacia and gum tragacanth; naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids; hexitol anhydrides, such as sorbitan eate; and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such ations may also contain a demulcent, a preservative, a flavoring or a coloring agent.

Additionally, the pharmaceutical compositions described herein may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous emulsion or oleaginous suspension. Such emulsion or suspension may be formulated according to the known art using those le sing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable on or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,2-propanediol. The sterile injectable ation may also be prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be employed are water, ’s solution and isotonic sodium chloride solution. In addition, sterile fixed oils may be employed as a solvent or suspending medium. For this e any bland fixed oil may be employed including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of injectables.

The compounds described herein may be substantially ble in water and gly soluble in most pharmaceutically acceptable protic solvents and vegetable oils, but generally soluble in medium-chain fatty acids (e.g., caprylic and capric acids) or triglycerides and in propylene glycol esters of medium-chain fatty acids. Thus, contemplated in the ption are compounds which have been modified by substitutions or additions of chemical or biochemical moieties which make them more suitable for delivery (e.g., increase solubility, bioactivity, palatability, decrease adverse reactions, etc.), for example by esterification, glycosylation, PEGylation, etc.

In certain s, the compound described herein is formulated for oral administration in a lipid-based ition suitable for low solubility compounds. based formulations can generally enhance the oral bioavailability of such compounds. As such, ceutical compositions described herein may comprise a effective amount of a compound of a (I) or a form thereof, together with at least one pharmaceutically acceptable excipient selected from medium chain fatty acids or ene glycol esters thereof (e.g., propylene glycol esters of edible fatty acids such as caprylic and capric fatty acids) and pharmaceutically acceptable surfactants, such as polysorbate 20 or 80 (also referred to as Tween® 20 or Tween® 80, respectively) or polyoxyl 40 hydrogenated castor oil.

In other aspects, the bioavailability of low solubility compounds may be enhanced using particle size optimization techniques including the preparation of nanoparticles or nanosuspensions using techniques known to those skilled in the art. The compound forms present in such preparations include amorphous, partially amorphous, partially crystalline or crystalline forms.

In alternative aspects, the pharmaceutical composition may r comprise one or more aqueous solubility enhancer(s), such as a cyclodextrin. Nonlimiting examples of cyclodextrin include hydroxypropyl, hydroxyethyl, yl, maltosyl and maltotriosyl derivatives of α-, β-, and γ-cyclodextrin, and hydroxypropyl-β-cyclodextrin (HPBC). In certain s, the pharmaceutical ition further comprises HPBC in a range of from about 0.1% to about %, from about 1% to about 15%, or from about 2.5% to about 10%. The amount of solubility enhancer employed may depend on the amount of the compound in the composition.

ATION OF COMPOUNDS GENERAL SYNTHETIC METHODS As disclosed herein, general methods for preparing the compounds of Formula (I) or a form thereof as described herein are ble via standard, well-known synthetic methodology.

Many of the starting materials are commercially available or, when not available, can be prepared using the routes described below using ques known to those skilled in the art. The synthetic schemes provided herein comprise multiple on steps, each of which is intended to stand on its own and can be carried out with or without any preceding or ding step(s). In other words, each of the individual reaction steps of the synthetic schemes provided herein in isolation is contemplated.

Scheme A Compounds of Formula (I), wherein B is cyclyl, X is O, NH, or NR1b, and R1b is C1-4alkyl, may be prepared as described in Scheme A below.

Compound A1 (where W1 and W2 are independently bromine, chlorine and the like) is converted to Compound A2 by a nucleophilic tution with a primary or secondary amine or an alcohol (BXH) in the presence of a suitable base (such as Et3N and the like) in a suitable solvent (such as DMF and the like). Alternatively, Compound A1 is converted to Compound A2 via cross coupling with a primary or a secondary amine or an alcohol in the ce of a suitable st (such as RuPhos Pd G2 and the like) and base (such as sodium tert-butoxide and the like) in an appropriate solvent such as 1,4-dioxane and the like). Compound A2 is ted to Compound A3 by a Suzuki coupling with an aryl- or heteroaryl-boronic acid (or pinacol boronic ester) in the presence of a catalyst (such as Pd(dppf)Cl2 and the like) and base (such as aqueous K2CO3 and the like) in a suitable solvent (such as 1,4-dioxane and the like). Alternatively, Compound A2 is converted to Compound A3 by a Stille coupling with an aryl- or heteroaryl-stannane in the presence of a catalyst (such as Pd2(dba)3 and the like), a ligand (such as X-Phos and the like) and a base (such as CsF and the like) in a suitable solvent (such as 1,4-dioxane and the like). Any protecting groups may be removed upon ent with a suitable reagent (such as HCl in dioxane for a Boc protecting group and the like) in a suitable solvent (such as dioxane and the like).

Scheme B Compounds of Formula (I), wherein (R3)n is hydrogen, halogen, hydroxy, or C1-4alkoxy, n is 0 or 1, R3 is cyclyl, heteroaryl, or phenyl, B is heterocyclyl; X is O, NH or NR1b, and R1b is C1-4alkyl, may be prepared as described in Scheme B below.

Compound B1 (where W1 and W2 are independently bromine, chlorine and the like) is converted to Compound B3 by a Suzuki ng with an aryl-boronic acid (or pinacol boronic ester) B2 (where W3 is e, chlorine and the like; (R3)n is hydrogen, n, hydroxy, or koxy, and n is 0 or 1; and PG is a protecting group such as MOM and the like) in the presence of a catalyst (such as Pd(dppf)Cl2 and the like) and base (such as aqueous K2CO3 and the like) in a suitable solvent (such as 1,4-dioxane and the like). Compound B3 is converted to Compound B4 by a nucleophilic substitution with a primary or a secondary amine or an alcohol (BXH, where X is O, NH, or NR1b, and where R1b is C1-4alkyl) in the presence of a suitable base (such as Et3N and the like) in a suitable solvent (such as DMF and the like). Alternatively, Compound B3 is converted to Compound B4 via cross coupling with a primary or a secondary amine or an alcohol in the presence of a suitable catalyst (such as RuPhos Pd G2 and the like) and base (such as sodium tert-butoxide and the like) in an appropriate solvent such as oxane and the like).

Compound B4 is converted to Compound B5 by a Suzuki coupling with an aryl- or heteroarylboronic acid (or pinacol boronic ester) in the presence of a catalyst (such as Pd(dppf)Cl2 and the like) and a base (such as aqueous K2CO3 and the like) in a le solvent (such as 1,4-dioxane and the like). Alternatively, Compound B4 is converted to Compound B5 by a Stille coupling with an aryl- or heteroaryl-stannane in the presence of a catalyst (such as Pd2(dba)3 and the like), a ligand (such as X-Phos and the like) and a base (such as CsF and the like) in a suitable solvent (such as 1,4-dioxane and the like). Alternatively, Compound B4 is converted to Compound B5 by treatment with pinacolatodiboron and a base (such as KOAc and the like) in the presence of a catalyst (such as Pd(dppf)Cl2 and the like) in an riate solvent (such as 1,4-dioxane and the like), followed by on of an aryl- or heteroaryl-halide. Alternatively, Compound B4 is converted to Compound B5 by a Buchwald-Hartwig coupling with a heteroaryl or amine in the presence of a catalyst (such as Pd2(dba)3 and the like), a ligand (such as tBuX-Phos and the like) and a base (such as K3PO4 and the like) in a suitable t (such as 1,4-dioxane and the like).

Compound B5 is converted to Compound B6 upon treatment with conditions appropriate to the removal of the protecting groups (such as HCl in dioxane for a MOM ting group) in a suitable solvent (such as dioxane and the like).

Scheme C Following the l conditions described in General Scheme B, but reversing the order of steps 1 and 2, compound C1 can be converted to compound C6.

IC SYNTHETIC EXAMPLES To describe in more detail and assist in understanding, the following non-limiting examples are offered to more fully illustrate the scope of compounds described herein and are not to be construed as specifically limiting the scope f. Such variations of the compounds bed herein that may be now known or later developed, which would be within the purview of one skilled in the art to ascertain, are considered to fall within the scope of the compounds as described herein and hereinafter claimed. These examples illustrate the preparation of certain nds. Those of skill in the art will understand that the techniques described in these examples represent techniques, as described by those of ry skill in the art, that function well in synthetic practice, and as such constitute preferred modes for the practice thereof. However, it should be appreciated that those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific methods that are disclosed and still obtain a like or similar result without departing from the spirit and scope of the present description.

Other than in the following examples of the embodied compounds, unless indicated to the contrary, all numbers expressing quantities of ingredients, reaction conditions, experimental data, and so forth used in the specification and claims are to be understood as being modified by the term "about". Accordingly, all such numbers represent approximations that may vary depending upon the desired properties sought to be obtained by a reaction or as a result of variable mental conditions. Therefore, within an expected range of experimental reproducibility, the term "about" in the context of the ing data, refers to a range for data provided that may vary according to a standard deviation from the mean. As well, for experimental results provided, the resulting data may be rounded up or down to t data consistently, without loss of significant figures. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should be construed in light of the number of significant digits and rounding techniques used by those of skill in the art.

While the numerical ranges and parameters setting forth the broad scope of the present description are imations, the numerical values set forth in the examples set forth below are reported as ely as possible. Any numerical value, however, inherently ns certain errors necessarily resulting from the standard deviation found in their respective g measurements.

The starting als used in the examples provided are cially available or can be prepared according to methods known to one skilled in the art or can be ed by the proceedures disclosed herein.

COMPOUND ES As used above, and throughout the present description, the following abbreviations, unless otherwise indicated, shall be understood to have the following gs: Abbreviation Meaning  heating (chemistry) or deletion (biology) AcOH or HOAc acetic acid Ar argon ACN or CH3CN acetonitrile aq. aqueous atm atmosphere(s) BBr3 boron tribromide Abbreviation Meaning B2pin2 bis(pinacolato)diboron Boc tert-butoxy-carbonyl t-Bu tert-butyl t-BuOK or KOtBu postassium tert-butoxide BuOH or n-BuOH n-butanol oC degrees Centigrade Celite® or Celite diatomaceous earth /hrs/min/s day(d)/hour(h, hr or hrs)/minute(min)/second(s) DCM or CH2Cl2 dichloromethane DMF dimethylformamide DMSO dimethylsulfoxide EtOAc ethyl e EtOH ethanol Et2O diethyl ether equiv equivalents H2 hydrogen HBr hydrobromic acid HCl hydrochloric acid H2SO4 sulfuric acid K2CO3 potassium carbonate KOAc potassium acetate KOH potassium ide LC/MS, LCMS or liquid chromatographic mass spectroscopy LC-MS LiOt-Bu lithium tert-butoxide LiOH lithium hydroxide mCPBA meta-chloroperoxybenzoic acid MeOH methanol MeSO3H methanesulfonic acid MgSO4 magnesium sulfate mL ter MOM methoxymethyl MS mass spectroscopy Abbreviation Meaning NEt3 triethylamine NH4Cl ammonium chloride NH4OAc ammonium acetate Na2CO3 sodium carbonate NaH sodium hydride NaHCO3 sodium bicarbonate NaOH sodium hydroxide Na2SO4 sodium sulfate N2 nitrogen NH4Cl ammoniuim chloride NMP N-methylpyrrolidone NMR nuclear magnetic nce Pd palladium Pd/C ium on carbon Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0) Pd(dppf)Cl2 or [1,1'- Pd(dppf)Cl2-CH2Cl2 phenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane PhMe toluene Psi pounds per square inch pressure QPhos 1,2,3,4,5-pentaphenyl-1′-(di-tertbutylphosphino )ferrocene Rt or rt room temperature S-Phos, SPhos or Sphos 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl S-Phos G2 chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'- biphenyl)(2'-amino-1,1'-biphenylyl) palladium(II) TBAF tetrabutylammonium fluoride TBS tert-butyldimethylsilyl TEA, Et3N or NEt3 triethylamine Tf trifluoromethane yl or triflate TFA trifluoroacetic acid THF tetrahydrofuran THP tetrahydropyranyl TIPS tiisopropylsilane Abbreviation Meaning TLC thin layer chromatography UPLC Ulta performance liquid chromatography Preparation of Starting Material: 4-(3-(Methoxymethoxy)(4,4,5,5-tetramethyl-1,3,2- dioxaborolanyl)phenyl)(tetrahydro-2H-pyranyl)-1H-pyrazole Step 1: 2-Bromoiodophenol (54.9 g, 184 mmol), was dissolved in DMF (240 mL) at 0 °C.

Sodium tert-pentoxide (2.5 M in THF, 90 mL, 230 mmol) was added se. This was stirred at 0 oC for 15 minutes after addition was complete. Chloromethyl methyl ether (18 mL, 225 mmol) was added se over 30 minutes. The mixture was warmed to ambient temperature and was stirred for 16 hours. The mixture was diluted with 1.5 L of H2O and was extracted into 2x400 mL of EtOAc. The combined organic layers were washed with 300 mL of H2O, and then with brine. The organic layer was dried over MgSO4, filtered, and concentrated under vacuum.

The residue was flushed h a silica plug using 0-10% CH2Cl2 in hexanes to yield o iodo(methoxymethoxy)benzene (61 g, 97%) as a clear liquid. 1H NMR (acetone-d 6): δ 7.56 (d, J= 2 Hz, 1H), 7.38 (d, J= 8 Hz, 1H), 7.33 (dd, J= 8 Hz, 2 Hz, 1H), 5.35 (s, 2H), 3.50 (s, 3H).

Step 2: 1-Bromoiodo(methoxymethoxy)benzene (49 g, 143 mmol), 1-(tetrahydro-2H-pyran- 2-yl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole (48.4 g, 174 mmol), Pd(dppf)Cl2-dichloromethane adduct (3.1 g, 3.6 mmol), dioxane (500 mL), and aqueous K2CO3 (1M, 350 mL, 350 mmol) were heated at 90 °C for 2 hours. The reaction e was then partitioned n H2O and EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography eluting with a EtOAc/hexanes gradient (20-50% EtOAc), followed by trituration with hexanes, yielding 4-(4- bromo(methoxymethoxy)phenyl)(tetrahydro-2H-pyranyl)-1H-pyrazole (40.4 g, 77% yield) as an off-white solid. 1H NMR (acetone-d 6): δ 8.22 (s, 1H), 7.88 (s, 1H), 7.55 (d, J= 8.5 Hz, 1H), 7.47 (d, J= 2 Hz, 1H), 7.23 (dd, J= 8.5 Hz, 2 Hz, 1H), 5.44 (dd, J= 9.5 Hz, 2.5 Hz, 1H), 5.38 (s, 2H), 4.01 (m, 1H), 3.72 (m, 1H), 3.51 (s, 3H), 2.1-2.23 (m, 1H), 2.0-2.1 (m, 2H), 1.7-1.8 (m, 1H), 1.6-1.7 (m, 2H).

Step 3: A flask containing potassium acetate (22 g, 224 mmol) was pumped dry at 180 ºC for 2 hours, and then was filled with argon. 4-(4-Bromo(methoxymethoxy)phenyl)(tetrahydro- 2H-pyranyl)-1H-pyrazole (20 g, 54.5 mmol), Pd(dppf)Cl2-dichloromethane adduct (1.22 g, 1.47 mmol), bis(pinacolato)diboron (20.8 g, 81.9 mmol), and dry toluene (200 mL) were added.

The mixture was heated at 110 ºC for 48 h. After cooling, the mixture was filtered through celite, ed by rinsing with ether. The filtrate was concentrated under vacuum, re-dissolved in ether, and was filtered again h celite to remove solid impurities. Purification by silica gel chromatography eluting with a nt of EtOAc/hexanes (20-50% EtOAc) yielded 12 g of crude title product. The crude material was dissolved in 100 mL ether and was back-washed with 2x1.5 L of dilute aqueous NaHCO3. The ether layer was washed with brine, dried over MgSO4, and was filtered. The filtrate was trated to a glassy semi-solid. This al was hexane-triturated to yield 4-(3-(methoxymethoxy)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenyl) (tetrahydro-2H-pyranyl)-1H-pyrazole as a white crystalline solid (7.05 g, 32% yield). 1H NMR (acetone-d 6): δ 8.24 (s, 1H), 7.90 (s, 1H), 7.65 (d, J= 8 Hz, 1H), 7.33 (d, J= 1.5 Hz, 1H), 7.29 (dd, J= 8 Hz, 1.5 Hz, 1H), 5.45 (dd, J= 10 Hz, 2.5 Hz, 1H), 5.25 (s, 2H), 4.01 (m, 1H), 3.69-3.74 (m, 1H), 3.52 (s, 3H), 2.15-2.2 (m, 1H), 2.0-2.1 (m, 2H), 1.7-1.8 (m, 1H), 1.6-1.68 (m, 2H), 1.35 (s, 12H).

Using the procedure described, additional compounds described herein may be prepared by substituting the appropriate ng al, suitable reagents and on conditions, obtaining compounds such as those selected from: Structure Data MS m/z 345.5 [M+H]+; 1H NMR (methanol-d 4) δ: 7.94-8.03 (m, 1H), 7.84 (s, 1H), 7.64 (br d, J=7.6 Hz, 1H), 7.25 (s, 1H), 7.20 (d, J=7.3 Hz, 1H), .25 (s, 2H), 3.81-3.98 (m, 3H), 3.53 (s, 3H), 1.36 (s, 12H) MS m/z 348.5 [M+H]+; 1H NMR (methanol-d 4) δ: 8.00 (s, 1H), 7.85 (s, 1H), 7.64 (br d, J=7.6 Hz, 1H), 7.26 (s, 1H), 7.22 (d, J=7.6 Hz, 1H), 5.26 (s, 2H), 4.86 (s, 3H), 1.37 (s, 12H) Structure Data MS m/z 349.2 [M-THP+H]+ MS m/z 316.6 [M+H]+ MS m/z 391.5 [M+H]+ MS m/z 391.5 [M+H]+; 1H NMR (methanol-d 4) δ: 8.27-8.32 (m, 1H), 8.00-8.04 (m, 1H), 7.40- 7.52 (m, 2H), 5.42-5.56 (m, 1H), 4.08 (br d, J=11.5 Hz, 1H), 3.77 (br t, J=11.5 Hz, 1H), 2.12- 2.25 (m, 1H), 2.07 (br d, J=11.0 Hz, 2H), 1.60- 1.86 (m, 3H), 1.38 (s, 12H) MS m/z 391.5 [M+H]+ MS m/z 423.2,425.2 [M+H]+ Preparation of Starting Material: 2-[4-Chlorofluoro(methoxymethoxy)phenyl]-4,4,5,5- tetramethyl-1,3,2-dioxaborolane Step 1: 6-Bromochlorofluoro-phenol (900 mg, 4.0 mmol) was ved in DMF (4.5 mL) at 0 ºC. Sodium tert-pentoxide (2.5 M in THF, 2 mL, 5.0 mmol) was added dropwise, followed by dropwise addition of methyl methyl ether (405 μL, 5.34 mmol) and the reaction was stirred overnight at room ature. The reaction mixture was partitioned between water and EtOAc.

The organic layer was washed with water, and then brine. The organic layer was dried over MgSO4, ed, and concentrated under vacuum. The residue was purified by silica gel chromatography eluting with a EtOAc/hexanes gradient (30-100% EtOAc) to yield 1 -bromo chlorofluoro(methoxymethoxy)benzene (1.01 g, 94% yield) as a clear oil. 1H NMR (acetone-d6) δ: 7.50 (d, J= 9 Hz, 1H), 7.28 (t, J= 8 Hz, 1H), 5.26 (s, 2H), 3.62 (s, 3H).

Step 2: A mixture of dry KOAc (1.5 g, 15 mmol), bis(pinacolato)diboron (1.02 g, 4.02 mmol) , Pd(dppf)Cl2-CH2Cl2 (90 mg, 0.108 mmol), and a solution of 1 chlorofluoro (methoxymethoxy)benzene (900 mg, 3.3 mmol) in toluene (12 mL) was purged with argon for 15 min. The mixture was heated at 110 ºC for 16 h. Upon completion, the reaction was diluted with EtOAc and was filtered h celite. The filtrate was concentrated and purified by silica chromatography eluting with a MeOH/CH2Cl2 gradient (0 to 5% MeOH) to yield 2 -[4-chloro fluoro(methoxymethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (524 mg, 47% yield) as a light orange oil. 1H NMR (acetone-d 6) δ: 7.49 (d, J= 8 Hz, 1H), 7.29 (t, J= 7 Hz, 1H), 5.16 (s, 2H), 3.58 (s, 3H), 1.37 (s, 12H).

Using the procedure bed, additional compounds described herein may be prepared by substituting the appropriate starting al, suitable reagents and reaction conditions, obtaining nds such as those selected from: Structure Data MS m/z 299.3, 301.3 [M+H]+ Preparation of Starting Material: N-(tert-Butyl)pyrrolidinamine Step 1: A dry vial was charged with 1-benzylpyrrolidinone (4.0 g, 22.8 mmol), 2- methylpropanamine (3.8 g, 52.0 mmol) and Ti(OiPr)4 (6.0 mL, 20.2 mmol). The mixture was purged with N2 for 15 min and then allowed to stir at room temperature for 2 h. The resulting (E)- 1-benzyl-N-(tert-butyl)pyrrolidinimine was used without further cation.

Step 2: To the mixture from step 1 was added dry methanol (40 mL) and the reaction was cooled to 0 ºC in an ice bath. NaBH4 (1.6 g, 42.3 mmol) was added slowly in ns (caution: very exothermic reaction). Once evolution of the gas ed, the mixture was warmed to room temperature and d for 2h at room temperature. Upon completion, 0.1M NaOH solution (20 mL) was added to precipitate the titanium salts. The biphasic mixture was filtered through celite and washed with methanol. The solvent was removed under vacuum and the crude oil was purified by reverse phase chromatography using a acetonitrile/H2O gradient (10% - 100% acetonitrile) to afford 1-benzyl-N-(tert-butyl)pyrrolidineamine (3.2 g, 60% yield) as a colorless Step 3: To an ry round bottom flask containing palladium hydroxide on activated carbon (320 mg) was added 1-benzyl-N-(tert-butyl)pyrrolidineamine (3.2 g, 13.8 mmol) dissolved in MeOH (20 mL). The mixture was d with H2 for 5 minutes and a balloon of H2 was placed on top of the flask and the reaction was stirred for 2 h at room temperature. The reaction mixture was filtered through celite, washed with MeOH and concentrated to afford N-(tertbutyl )pyrrolidinamine (1.89g, 96% yield) as a colorless oil which solidified upon standing. 1H NMR (methanol-d 4) δ: 4.21 (dq, J= 14.4, 7.0 Hz, 1H), 3.80 (dd, J= 12.7, 8.0 Hz, 1H), 3.58- 3.50 (m, 2H), 3.38-3.32 (m, 1H), .56 (m, 1H), 2.28-2.20 (m, 1H), 1.42 (s, 9H); 2 NHs not observed.

Preparation of Compound 1 Step 1: A e of 2,5-dibromopyrazine (610 mg, 2.56 mmol) and 6,6- pentamethylpiperidinamine (480 mg, 2.8 mmol) in n-BuOH (3.0 mL) was stirred at 120 °C for 16 h until LCMS showed complete consumption of the starting material. The reaction mixture was cooled to room temperature, the solvent was evaporated under reduced pressure, and the residue was partitioned between EtOAc and aqueous saturated NaHCO3. The organic layers were dried over Na2SO4, and the solvent was evaporated to provide 5-bromo-N-methyl-N-(2,2,6,6- tetramethylpiperidinyl)pyrazinamine (646 mg, 77%) as a ish solid. MS m/z 326.2, 328.2 [M+H]+.

Step 2: An oven-dried flask was equipped with a ic stir bar and d with 5-bromo-N- methyl-N-(2,2,6,6-tetramethylpiperidinyl)pyrazinamine (570 mg, 1.74 mmol), tert-butyl(3- methoxy(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenoxy)dimethylsilane (64 mg, 0.24 mmol, tetrakis(triphenylphosphine)palladium(0) (196 mg, 0.17 mmol), Na2CO3 (553 mg, 5.22 mmol). The flask was sealed with a rubber septum and then evacuated and backfilled with argon.

Dioxane (10 mL) and water (2.5 mL) were added, and the reaction was heated to 90 °C for 16 h.

The reaction mixture was cooled to room temperature, diluted with water (5 mL), and extracted with EtOAc. The organic layers were combined, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with gradient CH2Cl2/MeOH (0 to 30% MeOH) to afford 5-(4-((tert-butyldimethylsilyl)oxy) methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidinyl)pyrazinamine (529 mg, 63%) as a clear oil which partially solidified. MS m/z 485.6 [M+H]+.

Step 3: To a solution of 5-(4-((tert-butyldimethylsilyl)oxy)methoxyphenyl)-N-methyl-N- (2,2,6,6-tetramethylpiperidinyl)pyrazinamine (529 mg, 1.09 mmol) in CH2Cl2 (3 mL) was added 4N oxane (0.5 mL, 2.0 mmol) followed by MeOH (0.2 mL). The reaction mixture was stirred for 5 h at room temperate until LCMS showed complete consumption of the starting material. The solvent were removed under reduced pressure, and the e was suspended in CH2Cl2 (20 mL). 1,1,1-Trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (584 mg, 1.63 mmol) and trimethylamine (0.45 mL, 3.27 mmol) were added. The on mixture was stirred at room temperature for 16 h, then washed with water (2 mL) followed by brine. The organic layers were dried over Na2SO4, and the solvent was evaporated under reduced pressure. The residue was ed by silica gel column chromatography eluting with gradient CH2Cl2/MeOH (0 to 20% MeOH) to afford 3-methoxy(5-(methyl(2,2,6,6-tetramethylpiperidin- 4-yl)amino)pyrazinyl)phenyl trifluoromethanesulfonate (402 mg, 73%) as a tan solid.

MS m/z 503.6 [M+H]+; 1H NMR (acetone-d 6) δ: 8.77 (d, J=1.6 Hz, 1H), 8.25 (d, J=1.6 Hz, 1H), 8.06 (d, J=8.8 Hz, 1H), 7.26 (d, J=2.4 Hz, 1H), 7.15 (dd, J=8.7, 2.4 Hz, 1H), 5.32 (tt, J=13.2, 3.5 Hz, 1H), 4.05 (s, 3H), 3.00 (s, 3H), 2.08-2.10 (m, 2H), 1.84 (dd, J=13.2, 3.5 Hz, 2H), 1.63 (s, 6H), 1.55 (s, 6H); 1H not observed (NH).

Step 4: An oven-dried flask was equipped with a magnetic stir bar and charged with 3-methoxy (5-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyrazinyl)phenyl trifluoromethanesulfonate (180 mg, 0.35 mmol), oxy(4,4,5,5-tetramethyl-1,3,2- dioxaborolanyl)pyridine (101 mg, 0.43 mmol, tetrakis(triphenylphosphine)palladium(0) (40 mg, 0.35 mmol), Na2CO3 (111 mg, 1.05 mmol). The flask was sealed with a rubber septum and then evacuated and backfilled with argon. Dioxane (6 mL) and water (1.5 mL) were added and the reaction was heated to 90 °C for 16 h. The reaction was cooled to room temperature, diluted with water (5 mL), and extracted with EtOAc. The organic layers were combined, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column tography eluting with nt CH2Cl2/MeOH (0 to 30% MeOH) to afford ethoxy- 4-(2-methoxypyridinyl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidinyl)pyrazin amine (86 mg, 53%) as a tan solid.

MS m/z 462.6 [M+H]+; 1H NMR (methanol-d4) δ: 8.69 (d, J=1.3 Hz, 1H), 8.20 (dd, J=5.4, 0.6 Hz, 1H), 8.12 (d, J=1.3 Hz, 1H), 7.82 (d, J=8.2 Hz, 1H), 7.41 (dd, J=8.2, 1.9 Hz, 1H), 7.38-7.40 (m, 1H), 7.32 (dd, J=5.4, 1.6 Hz, 1H), 7.13 (dd, J=1.6, 0.9 Hz, 1H), 5.15 (tt, J=12.6, 3.6 Hz, 1H), 4.00 (s, 3H), 3.99 (s, 3H), 3.01 (s, 3H), 1.67 (dd, J=12.6, 3.6 Hz, 2H), 1.56 (t, J=12.6 Hz, 2H), 1.39 (s, 6H), 1.25 (s, 6H); 1H not observed (NH).

Step 5: A solution of 5-(2-methoxy(2-methoxypyridinyl)phenyl)-N-methyl-N-(2,2,6,6- tetramethylpiperidinyl)pyrazinamine (70 mg, 0.15 mmol) in 2 mL of dry CH2Cl2 was cooled in ice-water bath. Boron tribromide (1.0 M in CH2Cl2, 1.5 mL, 1.5 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction was quenched with 2 mL of MeOH, stirred for 30 min, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with gradient CH2Cl2/MeOH (2.5% NH4OH) (0 to 30% MeOH/NH4OH) to afford 4-(3-hydroxy(5-(methyl(2,2,6,6- ethylpiperidinyl)amino)pyrazinyl)phenyl)pyridinol (33 mg, 51 %) as a yellow solid.

MS m/z 434.6 [M+H]+; 1H NMR (methanol-d 4) δ: 8.94 (d, J=1.6 Hz, 1H), 8.17 (d, J=1.3 Hz, 1H), 7.93-8.00 (m, 1H), 7.53 (dd, J=6.9, 0.9 Hz, 1H), 7.25-7.28 (m, 1H), 7.24 (d, J=1.9 Hz, 1H), 6.79- 6.84 (m, 1H), 6.78 (dd, J=6.9, 1.9 Hz, 1H), 5.32-5.42 (m, 1H), 3.09 (s, 3H), 1.94 (d, J=7.9 Hz, 4H), 1.65 (s, 6H), 1.53 (s, 6H); 3Hs not observed (NH and 2 OHs).

Using the procedure described for Example 1, additional compounds bed herein may be ed by substituting the appropriate starting al, suitable reagents and reaction ions, obtaining compounds such as those selected from: Cpd Data MS m/z 407.2 [M+H]+;1H NMR (DMSO-d6) δ: 8.99 (d, J=1.6 Hz, 1H), 8.31 (s, 1H), 8.15 (d, J=1.2 Hz, 1H), 8.04 (d, J=8.8 Hz, 1H), 7.79 (d, J=1.2 Hz, 1H), 7.19 (s, 1H), 7.18 (d, J=2.4 Hz, 1H), 7.10 (s, 1H), 4.93-5.01 (m, 1H), 2.94 (s, 3H), 1.48 (dd, J=12.0, 3.6 Hz, 2H), 1.41 (t, J=12.0 Hz, 2H), 1.24 (s, 6H), 1.08 (s, 6H); 2Hs not ed (NH and OH). 9 MS m/z 475.1 [M+H]+; 1H NMR (methanol-d 4) δ: 8.86 (s, 1H), 8.05 (s, 1H), 7.96 (s, 1H), 7.84 (d, J=8.4 Hz, 1H), 6.96-7.02 (m, 2H), 5.11-5.23 (m, 1H), 3.01(s, 3H), 1.66 (dd, J=12.8, 3.2 Hz, 2H), 1.55 (t, J=12.8 Hz, 2H), 1.37 (s, 6H), 1.23 (s, 6H); 3Hs not observed (2NHs and OH). 12 MS m/z 421.1 [M+H]+; 1H NMR (methanol-d 4) δ: 8.85 (s, 1H), 8.04 (s, 1H), 7.82 (s, 1H), 7.68 (s, 1H), 7.26 (dd, J=1.6, 8.4 Hz, 1H), 6.93 (d, J=8.4 Hz, 1H), 5.13-5.26 (m, 1H), 3.00 (s, 3H), 2.42 (s, 3H), 1.51-1.75 (m, 4H), 1.38 (s, 6H), 1.25 (s, 6H); 3Hs not observed (2NHs and OH).

Cpd Data 14 MS m/z 422.5 [M+H]+; 1H NMR (methanol-d 4) δ: 8.70 (d, J=1.5 Hz, 1H), 7.91 (d, J=1.5 Hz, 1H), 7.83 (d, J=2.4 Hz, 1H), 7.74 (d, J=9.5 Hz, 1H), 6.97-7.06 (m, 2H), .78 (d, J=2.7 Hz, 1H), 5.05 (tt, J=12.5, 3.4 Hz, 1H), 2.89 (s, 3H), 1.54 (dd, J=12.5, 3.4 Hz, 2H), 1.44 (t, J=12.5 Hz, 2H), 1.26 (s, 6H), 1.12 (s, 6H); 4Hs not observed (3NHs and OH). 18 MS m/z 448.4 [M+H]+; 1H NMR (methanol-d 4) δ: 8.94 (s, 1H), 8.08 (dd, J=1.6, 8.8 Hz, 2H), 7.69 (d, J=8.8 Hz, 1H), 7.53 (d, J=8.8 Hz, 1H), 6.98 (d, J=8.8 Hz, 1H), 6.71- 6.77 (m, 2H), 5.27-5.35 (m, 1H), 3.59 (s, 3H), 3.03 (s, 3H), 1.94 (t, J=12.8 Hz, 2H), 1.86 (dd, J=12.8, 3.6 Hz, 2H), 1.51 (s, 6H), 1.28 (s, 6H); 2Hs not observed (NH and 27 MS m/z 421.4 [M+H]+; 1H NMR (DMSO-d 6) δ: 12.39 (br. s., 1H), 8.95 (d, J=1.6 Hz, 1H), 8.15 (s, 1H), 8.13 (d, J=1.3 Hz, 1H), 7.88-7.92 (m, 1H), 7.87 (d, J=0.9 Hz, 1H), 6.94-7.15 (m, 2H), 4.88-5.01 (m, 1H), 3.87 (s, 3H), 2.91-2.98 (m, 3H), 1.49 (dd, J=12.1, 3.5 Hz, 2H), 1.41 (t, J=12.1 Hz, 2H), 1.25 (s, 6H), 1.09 (s, 6H); 1H not observed (OH or NH). 28 MS m/z 424.5 [M+H]+; 1H NMR (DMSO-d 6) δ: 9.02 (d, J=1.3 Hz, 1H), 8.14 (d, J=1.3 Hz, 1H), 8.10 (d, J=0.9 Hz, 1H), 7.94-7.97 (m, 1H), 7.79 (d, J=8.2 Hz, 1H), 7.23 (dd, J=8.2, 1.6 Hz, 1H), 7.18 (d, J=1.6 Hz, 1H), .41 (m, 1H), 3.12 (s, 3H), 1.92-2.05 (m, 4H), 1.61-1.68 (m, 6H), 1.56 (s, 6H); 2Hs not observed (OH and NH). 44 MS m/z 404.2 [M+H]+; 1H NMR (DMSO-d 6) δ: 8.90 (s, 1H), 8.62 (d, J = 6.0 Hz, 2H), 8.39 (s, 1H), 7.98-8.02 (m, 2H), 7.70 (d, J = 6.0 Hz, 2H), 7.45 (d, J = 7.6 Hz, 1H), 7.31-7.34 (m, 2H), 4.30 (br s, 1H), 1.95-1.99 (m, 2H), .38 (m, 14H); 1H not observed (OH or NH) 45 MS m/z 404.2 [M+H]+; 1H NMR (DMSO-d 6) δ: 8.88-8.91 (m, 2H), 8.56 (dd, J = 4.8, 1.2 Hz, 1H), 8.40 (s, 1H), 8.07-8.10 (m, 1H), 7.97-8.00 (m, 2H), 7.46-7.50 (m, 1H), 7.41 (d, J = 7.6 Hz, 1H), .26 (m, 2H), 4.27-4.31 (m, 1H), 1.94-1.98 (m, 2H), 1.27-1.37 (m, 14H); 1H not ed (OH or NH) 46 MS m/z 393.2 [M+H]+; 1H NMR (DMSO-d 6) δ: 8.84 (s, 1H), 8.39 (s, 1H), 8.07 (s, 2H), 7.94 (s, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.35 (d, J = 7.2 Hz, 1H), 7.11-7.14 (m, 1H), 4.27-4.30 (m, 1H), 1.94-1.99 (m, 2H), 1.28-1.39 (m, 14H); 3Hs not observed (OH and NH) 54 MS m/z 407.3 [M+H]+; 1H NMR d 6) δ: 12.00 (br s, 1H), 8.82 (s, 1H), 8.40 (br s, 1H), 8.14 (s, 1H), 7.92 (s, 1H), 7.82-7.86 (m, 2H), 7.31 (d, J = 7.6 Hz, 1H), 7.06- 7.08 (m, 2H), 4.25-4.28 (m, 1H), 3.86 (s, 3H), 1.91-1.96 (m, 2H), 1.24-1.35 (m, 14H) Preparation of Compound 26 Step 1: An oven-dried flask was equipped with a magnetic stir bar and charged with 5-bromo-N- methyl-N-(2,2,6,6-tetramethylpiperidinyl)pyrazinamine (255 mg, 0.97 mmol), 4-(3- methoxy(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenyl)(tetrahydro-2H-pyranyl)- 1H-pyrazole (273 mg, 0.71 mmol), tetrakis(triphenylphosphine)palladium(0) (60 mg, 0.05 mmol), and Na2CO3 (160 mg, 1.5 mmol). The flask was sealed with a rubber septum and then evacuated and backfilled with argon. Dioxane (8 mL) and water (2 mL) were added, and the reaction was heated to 90 °C for 16 h. The reaction was cooled to room temperature, diluted with water (5 mL), and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with nt CH2Cl2/MeOH (0 to 30% MeOH) to afford 5-(2-methoxy- 4-(1-(tetrahydro-2H-pyranyl)-1H-pyrazolyl)phenyl)-N-methyl-N-(2,2,6,6- tetramethylpiperidinyl)pyrazinamine (160 mg, 45%) as a yellow solid. MS m/z 505.6 [M+H]+.

Step 2: 5-(2-Methoxy(1-(tetrahydro-2H-pyranyl)-1H-pyrazolyl)phenyl)-N-methyl-N- (2,2,6,6-tetramethylpiperidinyl)pyrazinamine (80 mg, 0.15 mmol) was ded in dichloromethane (1 mL) at 0 ºC. Boron tribromide (1.5 mL, 1.5 mmol, 1M in CH2Cl2,) was added dropwise, and the mixture was stirred at 0 ºC for 1 h and followed by room temperature for 16 hours. The mixture was quenched with MeOH (5 mL) and stirred for 30 min at room temeperature. The solvents were removed under reduced pressure, and the residue was triturated with Et2O (1 mL). The precipitate was collected by filtration and dried to provide 2-(5- (methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyrazinyl)(1H-pyrazolyl)phenol romide (42 mg, 65%) as a brownish solid.

MS m/z 407.5 [M+H]+; 1H NMR (methanol-d 4) δ: 9.08 (d, J=1.6 Hz, 1H), 8.57 (s, 2H), 8.19 (d, J=1.6 Hz, 1H), 7.86 (d, J=8.2 Hz, 1H), 7.37 (dd, J=8.2, 1.6 Hz, 1H), 7.31 (d, J=1.6 Hz, 1H), 5.37 (tt, , 4.1 Hz, 1H), 3.15 (s, 3H), 2.05 (t, J=13.2 Hz, 2H), 1.99 (dd, J=13.2, 4.1 Hz, 2H), 1.66 (s, 6H), 1.58 (s, 6H); 3Hs not observed (2 NHs and OH).

Using the procedure described for Example 2, additional compounds described herein may be prepared by substituting the riate starting material, suitable reagents and reaction conditions, obtaining compounds such as those selected from: Cpd Data 19 MS m/z 407.6 [M+H]+; 1H NMR (methanol-d 4) δ: 8.86 (d, J=1.2 Hz, 1H), 8.24 (d, J=2.4 Hz, 1H), 8.05 (d, J=1.2 Hz, 1H), 7.94 (d, J=9.2 Hz, 1H), 7.74 (d, J=1.5 Hz, 1H), 7.25-7.34 (m, 2H), 6.55 (dd, J=2.4, 1.5 Hz, 1H), 5.18 (tt, J=12.5, 3.7 Hz, 1H), 3.02 (s, 3H), 1.66 (dd, , 3.7 Hz, 2H), 1.55 (t, J=12.5 Hz, 2H), 1.38 (s, 6H), 1.24 (s, 6H); 2Hs not observed (NH and OH). 22 MS m/z 425.5 [M+H]+; 1H NMR (methanol-d4) δ: 8.81 (d, J=1.5 Hz, 1H), 7.99-8.09 (m, 3H), 7.64 (d, J=12.5 Hz, 1H), 7.17 (d, J=6.7 Hz, 1H), 5.17 (tt, J=12.5, 3.4 Hz, 1H), 3.01 (s, 3H), 1.65 (dd, J=12.5, 3.4 Hz, 2H), 1.54 (t, J=12.5 Hz, 2H), 1.37 (s, 6H), 1.23 (s, 6H); 3Hs not observed (OH and 2NHs). 52 MS m/z 379.4 [M+H]+; 1H NMR (methanol-d 4) δ: 8.74 (s, 1H), 7.90-7.97 (m, 2H), 7.88 (s, 1H), 7.74-7.76 (m, 1H), 7.11 (s, 2H), 3.87-3.94 (m, 1H), 3.64-3.77 (m, 2H), 3.46-3.55 (m, 1H), 3.18-3.25 (m, 1H), 2.33-2.44 (m, 1H), 1.86-1.98 (m, 1H), 1.22 (s, 9H); 3Hs not ed (2NHs and OH) 60 MS m/z 396.5 ; 1H NMR (methanol-d 4) δ: 8.79 (s, 1H), 7.98 (s, 1H), 7.92-7.96 (m, 1H), 7.83 (s, 1H), 7.79 (d, J=8.2 Hz, 1H), 7.04-7.15 (m, 2H), .01 (m, 1H), 3.84-3.92 (m, 1H), 3.72-3.80 (m, 1H), .59 (m, 1H), 3.36-3.41 (m, 1H), 2.40- 2.55 (m, 1H), 1.97-2.11 (m, 1H), 1.32 (s, 9H); 2Hs not observed (NH and OH) 62 MS m/z 393.3 [M+H]+; 1H NMR (methanol-d 4) δ: 8.94 (s, 1H), 8.09 (br d, J=17.2 Hz, 2H), 7.93 (s, 1H), 7.82 (d, J=7.9 Hz, 1H), 7.20 (d, J=8.5 Hz, 1H), 7.13-7.17 (m, 1H), 4.29 (br d, J=6.9 Hz, 1H), 4.11-4.19 (m, 1H), 3.98 (s, 3H), 3.87-3.92 (m, 1H), 3.75- 3.81 (m, 1H), 3.69 (br d, J=8.2 Hz, 1H), 2.68 (br d, J=6.0 Hz, 1H), 2.32-2.40 (m, 1H), 1.52 (s, 9H); 2Hs not observed (NH and OH) Example 3 Preparation of Compound 13 Step 1: An oven-dried flask was equipped with a magnetic stir bar and charged with 5-bromo-N- methyl-N-(2,2,6,6-tetramethylpiperidinyl)pyrazinamine (150 mg, 0.46 mmol), 4-(2,3- difluoro(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenyl)(tetrahydro-2H-pyranyl)- 1H-pyrazole (215 mg, 0.55 mmol), is(triphenylphosphine)palladium(0) (58 mg, 0.05 mmol), and Na2CO3 (146 mg, 1.38 mmol). The flask was sealed with a rubber septum and then evacuated and backfilled with argon. Dioxane (4 mL) and water (1 mL) were added, and the reaction was heated to 90 °C for 16 h. The reaction was cooled to room temperature, diluted with water (5 mL), and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with gradient CH2Cl2/MeOH (0 to 30% MeOH) to afford 5-(2,3-difluoro- 4-(1-(tetrahydro-2H-pyranyl)-1H-pyrazolyl)phenyl)-N-methyl-N-(2,2,6,6- tetramethylpiperidinyl)pyrazinamine (166 mg, 71%) as a brownish solid. MS m/z 511.6 [M+H]+.

Step 2: To -difluoro(1-(tetrahydro-2H-pyranyl)-1H-pyrazolyl)phenyl)-N-methyl- N-(2,2,6,6-tetramethylpiperidinyl)pyrazinamine (166 mg, 0.33 mmol) in CH2Cl2 (2 mL) was added 4N HCl/dioxane (0.17 mL, 0.66 mmol) followed by MeOH (0.2 mL). The reaction was stirred at room temperature for 2 h. The solvents were removed under d pressure, and the residue was triturated in Et2O. The solid was ed, washed with excess Et2O and dried under vacuum to afford 5-(2,3-difluoro(1H-pyrazolyl)phenyl)-N-methyl-N-(2,2,6,6- tetramethylpiperidinyl)pyrazinamine hydrochloride (126 mg, 83%) as a yellow solid.

MS m/z 427.5 [M+H]+; 1H NMR (methanol-d4) δ: 8.65 (t, J=1.6 Hz, 1H), 8.47 (s, 2H), 8.35 (d, J=1.2 Hz, 1H), 7.80 (td, J=8.2, 1.8 Hz, 1H), 7.67 (td, J=8.2, 1.8 Hz, 1H), 5.36 (tt, J=12.0, 3.7 Hz, 1H), 3.13 (s, 3H), 1.98-2.04 (m, 2H), 1.95 (dd, J=13.7, 3.7 Hz, 2H), 1.66 (s, 6H), 1.56 (s, 6H); 2NHs not observed.

Using the procedure described for Example 3, additional nds described herein may be prepared by substituting the appropriate starting material, le reagents and reaction conditions, obtaining nds such as those selected from: Cpd Data 4 MS m/z 459.3, 461.3 [M+H]+; 1H NMR (methanol-d 4) δ: 8.38 (d, J= 1.2 Hz, 1H), 8.03 (d, J= 1.2 Hz, 1H), 7.99 (br s, 2H), 7.64 (s, 1H), 7.60 (s, 1H), 5.01-5.14 (m, 1H), 2.92 (s, 3H), 1.56 (dd, J= 12.2, 3.1 Hz, 2H), 1.45 (t, J= 12.2 Hz, 2H), 1.26 (s, 6H), 1.13 (s, 6H); 2NHs not observed Cpd Data 11 MS m/z 423.5 [M+H] +; 1H NMR (methanol-d 4) δ: 8.51-4.63 (m, 1H), 8.19 (d, J=1.2 Hz, 1H), 7.89 (s, 2H), 7.77 (d, J=7.9 Hz, 1H), 7.26 (d, J=12.5 Hz, 1H), 5.14-5.27 (m, 1H), 3.04 (s, 3H), 2.47 (s, 3H), 1.74 (dd, J=13.4, 3.5 Hz, 2H), 1.66 (t, J=13.4 Hz, 2H), 1.45 (s, 6H), 1.32 (s, 6H); 2NHs not ed.

MS m/z 427.6 [M+H]+; 1H NMR nol-d 4) δ: 8.60-8.63 (m, 1H), 8.21 (d, J=1.5 Hz, 1H), 8.09-8.13 (m, 2H), 7.76 (dd, J=12.2, 6.4 Hz, 1H), 7.58 (dd, J=12.2, 6.4 Hz, 1H), 5.13-5.24 (m, 1H), 3.04 (s, 3H), 1.69 (dd, J=12.5, 3.4 Hz, 2H), 1.59 (t, J=12.5 Hz, 2H), 1.40 (s, 6H), 1.26 (s, 6H); 2NHs not observed. 16 MS m/z 409.5 [M+H] +; 1H NMR (methanol-d 4) δ: 8.63 (d, J=1.2 Hz, 1H), 8.15 (d, J=1.2 Hz, 1H), 8.08 (br. s., 2H), 7.68-7.80 (m, 3H), 5.11-5.25 (m, 1H), 3.03 (s, 3H), 1.70 (dd, J=12.5, 3.4 Hz, 2H), 1.60 (t, J=12.5 Hz, 2H), 1.41 (s, 6H), 1.28 (s, 6H); 2NHs not observed. 17 MS m/z 427.6 [M+H] +; 1H NMR (methanol-d 4) δ: 8.65 (d, J=1.5 Hz, 1H), 8.15 (d, J=1.5 Hz, 1H), 8.11 (s, 2H), 7.65 (d, J=10.7 Hz, 2H), 5.18 (tt, , 3.4 Hz, 1H), 3.04 (s, 3H), 1.66 (dd, J=12.2, 3.4 Hz, 2H), 1.57 (d, J=12.2 Hz, 2H), 1.38 (s, 6H), 1.24 (s, 6H); 2NHs not observed. 23 MS m/z 443.4 [M+H] +; 1H NMR nol-d 4) δ: 8.60 (s, 1H), 8.20 (d, J=1.2 Hz, 1H), 8.12 (s, 2H), 8.05 (d, J=7.3 Hz, 1H), 7.49 (d, J=12.2 Hz, 1H), 5.16 (s, 1H), 3.04 (s, 3H), 1.66 (dd, J=12.4, 3.5 Hz, 2H), 1.55 (t, J=12.5 Hz, 2H), 1.38 (s, 6H), 1.24 (s, 6H); 2NHs not observed. 24 MS m/z 434.5 [M+H] +; 1H NMR nol-d 4) δ: 8.57-8.67 (m, 1H), 8.38 (d, J=7.6 Hz, 1H), 8.26 (s, 2H), 8.23 (d, J=1.2 Hz, 1H), 7.63 (d, J=12.5 Hz, 1H), 5.07-5.27 (m, 1H), 3.05 (s, 3H), 1.67 (dd, J=12.2, 3.4 Hz, 2H), 1.57 (t, J=12.4 Hz, 2H), 1.39 (s, 6H), 1.25 (s, 6H); 2NHs not observed. 41 MS m/z 441.3 [M+H]+; 1H NMR (methanol-d 4) δ: 8.62-8.67 (m, 1H), 8.30 (d, J = 1.5 Hz, 1H), 8.01 (s, 1H), 7.86-7.93 (m, 1H), 7.47-7.51 (m, 1H), 7.29 (s, 1H), 5.33-5.44 (m, 1H), 3.11 (s, 3H), 2.30 (s, 3H), 1.89-2.02 (m, 4H), 1.65 (s, 6H), 1.53 (s, 6H); 1NH not observed 42 MS m/z 442.5 [M+H]+; 1H NMR (methanol-d 4) δ: 8.88 (d, J = 2.4 Hz, 1H), 8.64-8.69 (m, 1H), 8.24 (d, J = 1.5 Hz, 1H), 8.03 (dd, J = 12.4, 6.6 Hz, 1H), 7.78 (dd, J = 11.3, 6.1 Hz, 1H), 5.14-5.26 (m, 1H), 3.06 (s, 3H), 2.49 (s, 3H), 1.65-1.75 (m, 2H), 1.53- 1.65 (m, 2H), 1.40 (s, 6H), 1.26 (s, 6H); 1NH not observed 63 MS m/z 399.4 [M+H]+; 1H NMR (methanol-d 4) δ: 8.59 (s, 1H), 8.28 (s, 2H), 8.26 (s, 1H), 7.74 (dd, J=9.0, 7.8 Hz, 1H), 7.58 (t, J=7.6 Hz, 1H), 4.24-4.33 (m, 1H), 4.12- 4.18 (m, 1H), 3.84-3.94 (m, 1H), 3.65-3.79 (m, 2H), 2.62-2.73 (m, 1H), 2.27-2.39 (m, 1H), 1.51 (s, 9H); 2NHs not observed 64 MS m/z 399.4 [M+H]+; 1H NMR (methanol-d 4) δ: 8.64 (s, 1H), 8.17 (s, 2H), 8.02-8.09 (m, 1H), 7.78 (dd, J=12.1, 6.6 Hz, 1H), 7.60 (dd, J=12.1, 6.3 Hz, 1H), 4.26 (br t, J=6.9 Hz, 1H), 4.12 (dd, J=11.4, 7.1 Hz, 1H), 3.83-3.90 (m, 1H), .71 (m, 2H), 2.62-2.71 (m, 1H), 2.23-2.34 (m, 1H), 1.50 (s, 9H); 2NHs not observed Example 4 ation of Compound 2 Step 1: A mixture of 2,5-dibromopyrazine (610 mg, 2.56 mmol) and 2,2,6,6-tetramethylpiperidin- 4-ol (480 mg, 2.8 mmol) in THF (10.0 mL) was cooled to 0 °C, and 1.0 M t-BuOK in THF (9.1 mL, 9.1 mmol) was added dropwise. The reaction mixture was gradually warmed to room temperature and stirred for 16 h until LCMS showed complete consumption of the starting material. The solvent was evaporated under reduced pressure, and the residue was partitioned n EtOAc and water. The organic layers were dried over , the solvent was evaporated, and the e was purified by silica gel column chromatography eluting with gradient CH2Cl2/MeOH (0 to 10% MeOH) to afford o((2,2,6,6-tetramethylpiperidin yl)oxy)pyrazine (1.31 g, 55%) as a clear oil which solidified upon standing. MS m/z 313.1, 315.1 [M+H]+.

Step 2: An oven-dried flask was equipped with a magnetic stir bar and charged with 2-bromo ((2,2,6,6-tetramethylpiperidinyl)oxy)pyrazine (367 mg, 1.17 mmol), 4-(3-methoxy(4,4,5,5- tetramethyl-1,3,2-dioxaborolanyl)phenyl)(tetrahydro-2H-pyranyl)-1H-pyrazole (450 mg, 1.17 mmol, tetrakis(triphenylphosphine)palladium(0) (140 mg, 0.12 mmol), and Na2CO3 (372 mg, 3.51 mmol). The flask was sealed with a rubber septum and then evacuated and backfilled with argon. Dioxane (10 mL) and water (2.5 mL) were added, and the reaction was heated to 90 °C for 16 h. The reaction was cooled to room temperature, diluted with water (5 mL), and extracted with EtOAc. The ed organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with gradient CH2Cl2/MeOH (0 to 30% MeOH) to afford 2-(2-methoxy(1-(tetrahydro-2H- pyranyl)-1H-pyrazolyl)phenyl)((2,2,6,6-tetramethylpiperidinyl)oxy)pyrazine (420 mg, 73%) as a tan solid.

MS m/z 492.6 [M+H]+; 1H NMR ne-d6) δ: 8.80 (d, J=1.6 Hz, 1H), 8.31 (d, J=0.6 Hz, 1H), 8.23 (d, J=1.6 Hz, 1H), 7.98 (d, J=0.6 Hz, 1H), 7.92 (d, J=7.9 Hz, 1H), 7.44 (d, J=1.6 Hz, 1H), 7.36 (dd, J=8.2, 1.6 Hz, 1H), 5.60 (tt, J=11.5, 3.9 Hz, 1H), 5.47 (dd, J=9.8, 2.2 Hz, 1H), 4.04 (s, 3H), 3.99-4.04 (m, 1H), 3.67-3.83 (m, 1H), 2.15-2.29 (m, 1H), 2.12 (dd, J=12.5, 3.9 Hz, 2H), 2.07-2.09 (m, 1H), 2.02-2.06 (m, 1H), .87 (m, 2H), 1.59-1.72 (m, 3H), 1.31 (s, 6H), 1.18 (s, 6H); 1H not observed (NH).

Step 3: An oven-dried microwave vial was equipped with a magnetic stir bar and charged with 2- (2-methoxy(1-(tetrahydro-2H-pyranyl)-1H-pyrazolyl)phenyl)((2,2,6,6- tetramethylpiperidinyl)oxy)pyrazine (278 mg, 0.56 mmol), benzenethiol (59 µL, 0.56 mmol) and K2CO3 (77 mg, 0.56 mmol). The vial was sealed and then evacuated and backfilled with argon. NMP (1.5 mL) was added, and the reaction was heated to 190 °C in a microwave reactor for 20 min. The reaction was cooled to room temperature, diluted with water (5 mL), and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with gradient CH2Cl2/MeOH (0 to 30% MeOH) to afford tetrahydro-2H-pyranyl)-1H- pyrazolyl)(5-((2,2,6,6-tetramethylpiperidinyl)oxy)pyrazinyl)phenol (227 mg, 84%) as a tan solid.

MS m/z 478.6 [M+H]+; 1H NMR (acetone-d6) δ: 12.29 (s, 1H), 9.00 (d, J=1.3 Hz, 1H), 8.27 (d, J=0.6 Hz, 1H), 8.24 (br. s., 1H), 8.00 (d, J=8.2 Hz, 1H), 7.94 (d, J=0.9 Hz, 1H), 7.22-7.28 (m, 1H), 7.21 (d, J=1.9 Hz, 1H), 5.58-5.72 (m, 1H), 5.47 (dd, J=9.8, 2.2 Hz, 1H), 3.93-4.06 (m, 1H), 3.64-3.79 (m, 1H), 2.17-2.25 (m, 2H), 2.07-2.11 (m, 2H), 2.02-2.06 (m, 2H), 1.73-1.85 (m, 2H), 1.55-1.72 (m, 2H), 1.34 (s, 6H), 1.20 (s, 6H); 1H not ed (NH or OH).

Step 4: To a on of 5-(1-(tetrahydro-2H-pyranyl)-1H-pyrazolyl)(5-((2,2,6,6- tetramethylpiperidinyl)oxy)pyrazinyl)phenol (100 mg, 0.20 mmol) in CH2Cl2 (1 mL) and MeOH (few drops) was added HCl (4 mol/L) in 1,4-dioxane (0.25 mL, 1.0 mmol), and the reaction was stirred at room temperature for 2 h until UPLC showed complete ption of the starting material. The precipitate was collected by filtration and dried under vacuum to provide 2- [1-(4-piperidyl)pyrazolo[3,4-c]pyridazinyl](1H-pyrazolyl)phenol;hydrochloride (61 mg, 71%as a yellow solid.

MS m/z 394.5 [M+H]+; 1H NMR (DMSO-d 6) δ: 9.30 (d, J=12.3 Hz, 1H), 9.01 (d, J=1.3 Hz, 1H), 8.45 (d, J=12.3 Hz, 1H), 8.37 (d, J=1.6 Hz, 1H), 8.10 (s, 2H), 7.93 (d, J=8.8 Hz, 1H), 7.19-7.28 (m, 2H), 5.42-5.66 (m, 1H), 2.26 (dd, J=13.1, 3.9 Hz, 2H), 1.81 (dd, J=13.1, 11.0 Hz, 2H), 1.52 (s, 6H), 1.51 (s, 6H); 1H not observed (NH or OH).

Using the procedure described for Example 4, onal nds described herein may be prepared by tuting the appropriate starting material, suitable reagents and reaction conditions, obtaining compounds such as those selected from: Cpd Data MS m/z 414.1 [M+H]+; 1H NMR d 6) δ: 9.46 (d, J=10.8 Hz, 1H), 8.65 (s, 1H), 8.59 (d, J=10.8 Hz, 1H), 8.47 (d, J=1.2 Hz, 1H), 8.18 (s, 2H), 7.65-7.74 (m, 2H), .51-5.56 (m, 1H), 2.23 (dd, J=12.8, 3.6 Hz, 2H), 1.84 (t, J=12.8 Hz, 2H), 1.52 (s, 6H, 1.47 (s, 6H).

Example 5 Preparation of Compound 25 Step 1: 6 An oven-dried flask was equipped with a magnetic stir bar and charged with 2,5- dibromopyrazine (500 mg, 2.10 mmol), 4-(3-methoxy(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)phenyl)(tetrahydro-2H-pyranyl)-1H-pyrazole (970 mg, 2.52 mmol), tetrakis(triphenylphosphine)palladium(0) (121 mg, 0.105 mmol) and K2CO3 (870 mg, 6.30 mmol). The flask was sealed with a rubber septum and then evacuated and backfilled with argon.

Dioxane (12 mL) and water (3 mL) were added, and the on was heated to 90 °C for 5 h. The reaction was cooled to room temperature, diluted with water, and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with gradient hexanes/EtOAc (30-70% EtOAc) to afford 2-bromo(2-methoxy(1-(tetrahydro-2H-pyranyl)-1H-pyrazol- 4-yl)phenyl)pyrazine (690 mg, 79%) as an off-white solid. MS m/z 415.1, 417.1 [M+H]+.

Step 2: 2-Bromo[2-methoxy(1-tetrahydropyranylpyrazolyl)phenyl]pyrazine (316 mg, 0.76 mmol) and (1R,5S)-bicyclo[3.2.1]octanol (80 mg, 0.63 mmol) were mixed in dry DMF ( 1 mL) and cooled to 0 °C in ice-water bath. Sodium hydride (51 mg, 1.27 mmol, 60% in mineral oil) was added then. The on mixture was stirred at room ature for 16 h, then quenched with water. Precipitate was collected by filtration, dried under vaccum to provide 2- [[(1R,5S)bicyclo[3.2.1]octanyl]oxy][2-methoxy(1-tetrahydropyranylpyrazol yl)phenyl]pyrazine (220 mg, 75%) as an off white solid. MS m/z 461.5 .

Step 3: To a solution of 2-[[(1R,5S)bicyclo[3.2.1]octanyl]oxy][2-methoxy(1- tetrahydropyranylpyrazolyl)phenyl]pyrazine (220 mg, 0.48 mmol) in CH2Cl2 was added boron tribromide (1.0 M in CH2Cl2, 2.4 mL, 2.4 mmol), and the reaction was stirred at room temperature for 16 h until UPLC showed complete consumption of the starting material. The reaction was ed with MeOH (10 mL), concentrated under reduced pressure, and purified by silica gel column chromatography eluting with gradient CH2Cl2/MeOH(2.5% NH4OH) (0 to % MeOH/NH4OH). Provided 2-[5-[[(1S,5R)azabicyclo[3.2.1]octanyl]oxy]pyrazinyl]- -(1H-pyrazolyl)phenol (122 mg, 70%) as a yellow solid.

MS m/z 364.4 [M+H]+; 1H NMR (DMSO-d 6) δ: 9.00 (d, J=1.6 Hz, 1H), 8.76 (br. s., 1H), 8.69 (br. s., 1H), 8.36 (d, J=1.6 Hz, 1H), 8.09 (s, 2H), 7.92 (d, J=8.2 Hz, 1H), 7.18-7.23 (m, 2H), 5.32-5.45 (m, 1H), 4.08-4.18 (m, 2H), 2.28-2.41 (m, 4H), 1.98-2.08 (m, 2H), 1.87-1.97 (m, 2H); 1H not observed (OH or NH).

Using the procedure described for Example 5, additional compounds described herein may be prepared by substituting the appropriate starting al, le reagents and reaction conditions, obtaining compounds such as those selected from: Cpd Data 7 MS m/z 368.4 [M+H]+; 1H NMR nol-d 4) δ: 8.93 (d, J=1.5 Hz, 1H), 8.29 (d, J=1.5 Hz, 1H), 8.12 (br. s., 2H), 7.92 (d, J=8.2 Hz, 1H), 7.23 (dd, J=8.2, 1.5 Hz, 1H), 7.21 (s, 1H), 5.42-5.49 (m, 1H), 3.43-3.51 (m, 2H), .32 (m, 2H), 2.26-2.34 (m, 2H), 2.13-2.21 (m, 2H); 3 Hs not observed (2 NHs and OH).

Example 6 Preparation of Compound 8 Step 1: To a mixture of 2-bromo(2-methoxy(1-(tetrahydro-2H-pyranyl)-1H-pyrazol nyl)pyrazine (200 mg, 0.48 mmol) and tert-butyl 4-aminopiperidinecarboxylate (96 mg, 0.48 mmol) in EtOH (1 mL) was added a drop of conc. HCl. The reaction was sealed and heated at 120 °C for 16 h until LCMS analysis showed complete consumption of starting material. The mixture was cooled, and the solvent was evaporated providing crude 5-(2-methoxy(1- hydro-2H-pyranyl)-1H-pyrazolyl)phenyl)-N-(piperidinyl)pyrazinamine hydrobromide (248 mg) which was used in the next step without further purification. MS m/z 435.2 .

Step 2: To a suspension of 5-(2-methoxy(1-(tetrahydro-2H-pyranyl)-1H-pyrazol yl)phenyl)-N-(piperidinyl)pyrazinamine hydrobromide (248 mg, 0.48) in CH2Cl2 was added boron tribromide (1.0 M in CH2Cl2, 2.4 mL, 2.4 mmol), and the reaction was stirred at room temperature for 16 h until UPLC showed complete consumption of the starting material. The reaction was quenched with MeOH (10 mL), concentrated under reduced pressure, and purified by silica gel column chromatography g with gradient CH2Cl2/MeOH(2.5% NH4OH) (0 to % MeOH/NH4OH). ed 2-(5-(piperidinylamino)pyrazinyl)(1H-pyrazol yl)phenol (128 mg, 79%) as an orange solid.

MS m/z 337.4 ; 1H NMR (methanol-d 4) δ: 8.84 (d, J=1.6 Hz, 1H), 8.39 (s, 2H), 8.14-8.22 (m, 1H), 7.88 (d, J=7.9 Hz, 1H), 7.29 (dd, J=8.2, 1.9 Hz, 1H), 7.25 (s, 1H), 4.14-4.27 (m, 1H), 3.53 (dtd, J=13.0, 3.1, 0.9 Hz, 2H), 3.23 (tdd, J=13.0, 3.1, 0.9 Hz, 2H), 2.34 (ddd, J=14.3, 3.1, 0.9 Hz, 2H), 1.79-1.97 (m, 2H); 4Hs not observed (3NHs and OH).

Using the procedure described for e 6, additional compounds described herein may be prepared by substituting the appropriate starting material, suitable ts and reaction conditions, obtaining compounds such as those selected from: Cpd Data 3 MS m/z 487.6 [M+H]+; 1H NMR (methanol-d 4) δ: 8.82 (s, 1H), 8.03 (s, 1H), 7.97 (s, 2H), 7.81 (d, J=8.2 Hz, 1H), 7.14(d, J=8.2 Hz, 1H), 7.11 (s, 1H), 5.00-5.05 (m, 1H), 3.02 (s, 3H), 2.03-2.13 (m, 4H), 1.61-1.67 (m, 6H), 1.48-1.55 (m, 10H), 1.28-1.43 (m, 4H); 3 Hs not ed (2NHs and OH). 6 MS m/z 349.2 ; 1H NMR (DMSO-d 6) δ: 9.63 (br s, 2H), 8.89 (s, 1H), 8.11 (s, 2H), 7.96 (s, 1H), 7.86 (d, J=8.4 Hz, 1H), 7.14-7.17 (m, 2H), 4.16 (d, J=8.4 Hz, 2H), 4.05 (d, J=8.4 Hz, 2H), 3.37-3.41 (m, 2H), 3.17-3.22 (m, 2H), 2.19-2.25 (m, 2H); 1H is not observed (NH or OH).

MS m/z 351.4 [M+H]+; 1H NMR (methanol-d4) δ: 8.80 (d, J=1.5 Hz, 1H), 8.08 (d, J=1.5 Hz, 1H), 7.98 (br s, 2H), 7.81 (d, J=8.2 Hz, 1H), 7.16 (dd, J=8.2, 1.8 Hz, 1H), 7.13 (d, J=1.5 Hz, 1H), 4.68 (tt, J=12.5, 4.3 Hz, 1H), 3.26 (d, J=12.5 Hz, 2H), 3.05 (s, 3H), 2.86 (td, J=12.5, 3.0 Hz, 2H), 1.88 (ddd, J=25.3, 12.5, 4.3 Hz, 2H), 1.80 (d, J=12.5 Hz, 2H); 3Hs not observed (2NHs and OH). 21 MS m/z 349.2 [M+H]+; 1H NMR (DMSO-d 6) δ: 9.63 (br.s., 2H), 8.89 (s, 1H), 8.11 (s, 2H), 7.96 (s, 1H), 7.86 (d, J=8.4 Hz, 1H), 7.14-7.17 (m, 2H), 4.16 (d, J=8.4 Hz, 2H), 4.05 (d, J=8.4 Hz, 2H), 3.37-3.41 (m, 2H), 3.17-3.22 (m, 2H), 2.19-2.25 (m, 2H); 1H is not observed (NH or OH).

Example 7 Preparation of Compound 48 Step 1: A solution of 2,5-dibromopyrazine (9.0 g, 37.8 mmol), 2,2,6,6-tetramethylpiperidin amine (11.8 g, 75.5 mmol) and DIPEA (9.8 g, 76 mmol) in n-BuOH (100 mL) was stirred at 130 °C for 24 h. After cooling to room temperature, the solvent was removed, and the residue was purified using silica gel chromatography g with a MeOH/CH2Cl2 gradient (0 to 15% MeOH) to give 5-bromo-N-(2,2,6,6-tetramethylpiperidinyl)pyrazinamine (10 g, 84% yield) as an off-white solid. MS: m/z: 313.1, 315.1 [M+H]+.

Step 2: To round bottom flask were added: 5-bromo-N-(2,2,6,6-tetramethylpiperidin yl)pyrazinamine (10.0 g, 31.9 mmol), 3-(methoxymethoxy)(4,4,5,5-tetramethyl-1,3,2- dioxaborolanyl)phenyl 4-methylbenzenesulfonate (13.9 g, 32.0 mmol), K2CO3 (8.8 g, 64 mmol) and PdCl2dppf (234 mg, 0.32 mmol). The e was ed with nitrogen and 1,4- dioxane (100 mL) and water (10 mL) were then added. The mixture was stirred at 100 ºC for 16 h. After cooling to room temperature, the solvent was d, and the residue was purified using silica gel chromatography eluting with a MeOH/CH2Cl2 gradient (0 to 30% MeOH) to give 3-(methoxymethoxy)(5-((2,2,6,6-tetramethylpiperidinyl)amino)pyrazinyl)phenyl 4- methylbenzenesulfonate (4.5 g, 26% yield) as a brown solid. MS: m/z: 541.3 [M+H]+.

Step 3: To a solution of 3-(methoxymethoxy)(5-((2,2,6,6-tetramethylpiperidin yl)amino)pyrazinyl)phenyl 4-methylbenzenesulfonate (2.5 g, 4.6 mmol) in EtOH (10 mL) and water (1 mL) was added KOH (520 mg, 9.27 mmol). The mixture was stirred at 80 ºC for 2 h. The t was removed, and the residue was flushed through a silica plug using 0-10% MeOH in CH2Cl2 to yield crude 3-(methoxymethoxy)(5-((2,2,6,6-tetramethylpiperidin yl)amino)pyrazinyl)phenol (2.0 g) as a brown solid, which was used in the next step without further purification. MS: m/z: 387.3 [M+H]+.

Step 4: To a solution of 3-(methoxymethoxy)(5-((2,2,6,6-tetramethylpiperidin yl)amino)pyrazinyl)phenol (2.43 g, 6.29 mmol) in CH2Cl2 (40 mL) was added PhNTf2 (6.8 g, 19 mmol) and Et3N (1.9 g, 19 mmol). The reaction mixture was stirred at room temperature for 16 . The solvent was removed and the residue was purified using silica gel chromatography eluting with a H2Cl2 gradient (0 to 30% MeOH) to give 3-(methoxymethoxy)(5-((2,2,6,6- tetramethylpiperidinyl)amino)pyrazinyl)phenyl trifluoromethanesulfonate (1.9 g, 58% yield) as a pale yellow solid. MS: m/z: 519.2 [M+H]+.

Step 5: A mixture of 3-(methoxymethoxy)(5-((2,2,6,6-tetramethylpiperidin yl)amino)pyrazinyl)phenyl trifluoromethanesulfonate (1.5 g, 2.9 mmol), bis(pinacolato)diboron (773 mg, 3.05 mmol), Pd(dppf)Cl2 (220 mg, 0.30 mmol) and KOAc (568 mg, 5.8 mmol) was degassed with nitrogen. oxane (25 mL) was added and the reaction mixture was stirred at 100 °C for 16 h. The solvent was removed to give the crude product, which was purified by silica gel chromatography eluting with a MeOH/CH2Cl2 nt (0 to 30% MeOH) to yield methoxymethoxy)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenyl)- N-(2,2,6,6-tetramethylpiperidinyl)pyrazinamine (840 mg, 59% yield) as a brown-black solid. MS: m/z: 497.3 [M+H]+.

Step 6: A mixture of 5-(2-(methoxymethoxy)(4,4,5,5-tetramethyl-1,3,2-dioxaborolan yl)phenyl)-N-(2,2,6,6-tetramethylpiperidinyl)pyrazinamine (180 mg, 0.36 mmol), 2- bromopyridine (56 mg, 0.35 mmol), K2CO3 (100 mg, 0.73 mmol) and SPhos Pd G2 (26 mg, 0.036 mmol) was ed with nitrogen. 1,4-Dioxane (5 mL) and water (0.5 mL) were added, and the reaction mixture was stirred at 70 ºC for 16 h. The solvent was removed, and the residue was purified by silica gel tography eluting with a MeOH/CH2Cl2 gradient (0 to 30% MeOH) to give 5-(2-(methoxymethoxy)(pyridinyl)phenyl)-N-(2,2,6,6-tetramethylpiperidin- 4-yl)pyrazinamine (90 mg, 55% yield) as a brown solid. MS: m/z: 448.3 .

Step 7: To a solution of 5-(2-(methoxymethoxy)(pyridinyl)phenyl)-N-(2,2,6,6- tetramethylpiperidinyl)pyrazinamine (90 mg, 0.20 mmol) in CH2Cl2 (2 mL) was added 4N HCl in dioxane (2 mL) and the reaction mixture was stirred at room temperature for 2 h. The mixture was poured into ice water, lized with saturated aqueous NaHCO3 and extracted with CH2Cl2 (150 mL x 3). The combined organic phases were concentrated, and the residue was purified by PLC to give 5-(pyridinyl)(5-((2,2,6,6-tetramethylpiperidin yl)amino)pyrazinyl)phenol (34 mg, 42% yield) as a pale yellow solid.

MS: m/z: 404.2[M+H]+; 1H NMR (DMSO-d6) δ: 8.89 (s, 1H), 8.66 (d, J = 4.4 Hz, 1H), 8.42 (s, 1H), 7.94-7.98 (m, 3H), 7.84-7.89 (m, 1H), 7.66 (d, J = 1.6 Hz, 1H ), 7.60 (dd, J = 8.4, 1.6 Hz, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.33-7.36 (m, 1H), 4.28-4.30 (m, 1H), 1.94-1.98 (m, 2H), 1.28-1.38 (m, 14H); 1H not observed (OH or NH).

Using the procedure described for Example 7, additional compounds described herein may be prepared by substituting the appropriate starting material, suitable reagents and reaction conditions, obtaining compounds such as those selected from: Cpd Data 43 MS m/z 425.5 [M+H]+; 1H NMR (DMSO-d 6) δ: 8.86 (s, 1H), 8.09 (s, 1H), 7.94 (s, 1H), 7.78 (d, J=9.8 Hz, 1H), 7.08-7.20 (m, 2H), 5.21-5.35 (m, 1H), 3.04 (s, 3H), 1.72- 1.88 (m, 4H), 1.53 (s, 6H), 1.40 (s, 6H); 3Hs not ed (2 NHs and OH) 47 MS m/z 405.2 [M+H]+; 1H NMR (DMSO-d 6) δ: 8.88-8.90 (m, 3H), 8.40 (s, 1H), 7.98- 8.02 (m, 2H), 7.89-7.94 (m, 2H), 7.43 (t, J = 4.8 Hz, 1H), 7.37 (d, J = 7.6 Hz, 1H), 4.27-4.30 (m, 1H), 1.92-1.96 (m, 2H), 1.22-1.33 (m, 14H); 1H not ed (OH or 49 MS m/z 435.2 [M+H]+; 1H NMR (DMSO-d 6) δ: 8.90 (s, 1H), 8.84 (s, 1H), 8.40 (br s, 1H), 7.98-8.00 (m, 2H), 7.73 (d, J = 1.6 Hz, 1H), 7.68 (dd, J = 8.4, 1.6 Hz, 1H), 7.45 (s, 2H), 4.27-4.30 (m, 1H), 3.98 (s, 3H), 1.94-1.98 (m, 2H), 1.26-1.37 (m, 14H); 1H not observed (OH or NH) 53 MS m/z 444.8 [M+H]+; 1H NMR (DMSO-d 6) δ: 9.24 (d, J = 1.2 Hz, 1H), 9.16 (s, 1H), 8.90 (s, 1H), 8.40 (br s, 1H), 8.13 (s, 1H), 7.97-8.00 (m, 2H), 7.85 (d, J = 0.8 Hz, 1H), 7.62 (d, J = 1.6 Hz, 1H), 7.55 (dd, J = 8.0, 1.6 Hz, 1H), 7.39 (d, J = 7.2 Hz, 1H), .32 (m, 1H),1.94-1.99 (m, 2H), 1.27-1.38 (m, 14H); 1H not observed (OH or Cpd Data 55 MS m/z 407.1 [M+H]+; 1H NMR (DMSO-d 6) δ: 11.95 (br s, 1H), 8.81 (s, 1H), 7.91 (s, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.72 (d, J = 2.0 Hz, 1H), 7.27-7.30 (m, 2H), 7.16 (d, J = 7.6 Hz, 1H), 6.68 (d, J = 2.4 Hz, 1H), 4.20-4.25 (m, 1H), 3.88 (s, 3H), 1.81-1.86 (m, 2H), 1.23 (s, 6H), 1.00-1.06 (m, 8H); 1H not observed (OH or NH) 56 MS m/z 444.1 [M+H]+; 1H NMR d 6) δ: 8.92 (s, 1H), 8.43 (br s, 1H), 8.35 (s, 1H), 8.20 (d, J = 9.6 Hz, 1H), 8.00-8.06 (m, 2H), 7.79-7.82 (m, 2H), 7.64 (d, J = 1.6 Hz, 1H), 7.58 (dd, J = 8.4,1.6 Hz, 1H), 7.47 (d, J = 7.6 Hz, 1H), 4.30-4.32 (m, 1H), .00 (m, 2H), 1.30-1.40 (m, 14H); 1H not observed (OH or NH) 57 MS m/z 411.2 [M+H]+; 1H NMR (DMSO-d 6) δ: 8.83 (s, 1H), 8.40 (br s, 1H), 8.18 (d, J = 2.0 Hz, 1H), 7.95 (s, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.34 (d, J = 7.6 Hz, 1H), 7.08- 7.10 (m, 2H), 4.26-4.30 (m, 1H), 1.94-1.98 (m, 2H), 1.27-1.37 (m, 14H); 2Hs not observed (OH and NH) 58 MS m/z 393.1 [M+H]+; 1H NMR (DMSO-d 6) δ: 8.84 (s, 1H), 8.38 (br s, 1H), 7.94 (s, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.70 (br s, 1H), 7.29-7.33 (m, 3H), 6.70 (d, J = 2.4 Hz, 1H), .28 (m, 1H), 1.91-1.96 (m, 2H), 1.22-1.34 (m, 14H); 2Hs not observed (OH and NH) 65 MS m/z 397.4 ; 1H NMR (methanol-d4) δ: 8.74-8.78 (m, 1H), 7.88-7.92 (m, 2H), 7.77 (d, J=7.3 Hz, 1H), 7.10-7.16 (m, 2H), 3.88-3.93 (m, 1H), 3.66-3.77 (m, 2H), 3.51 (br d, J=7.3 Hz, 1H), 3.19-3.24 (m, 1H), 2.33-2.41 (m, 1H), 1.89-1.98 (m, 1H), 1.23 (s, 9H); 3Hs not observed (2 NHs and OH) Example 8 Preparation of Compound 61 Step 1: A mixture of 5-bromo-N-methyl-N-(2,2,6,6-tetramethylpiperidinyl)pyrazinamine (0.8 g, 2.44 mmol), 2-(4-chloro(methoxymethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (0.87 g, 2.91 mmol), bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.17g, 0.23 mmol) and aq. 2N K2CO3 (5 mL, 4.89 mmol) was purged with argon for 15 min.

Dioxane (12 ml) was added and the reaction mixture was then heated to 100 ºC for 4 h. The reaction mixture was cooled to room temperature, the t was ated under d pressure, and the residue was partitioned between EtOAc and aqueous saturated NaHCO3. The organic layers were dried over Na2SO4, and the solvent was ated. The residue was purified using silica gel chromatography g with a MeOH/CH2Cl2 gradient (0 to 30% MeOH) to afford 5-(4-chloro(methoxymethoxy)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin yl)pyrazinamine (0.62 g, 60%). MS m/z 419.5 [M+H]+ Step 2: Tris(dibenzylideneacetone)dipalladium(0) (2.6 mg, 0.0028 mmol) and 2-di-tertbutylphosphino-3 ,4,5,6-tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl (3.5 mg, 0.0070 mmol) were ded in 5:1 toluene/dioxane (1 mL). The purple solution was sparged with argon for 5 minutes, then heated to 120 ºC for 5 minutes. The solution was cooled to room temperature and tripotassium phosphate (30 mg, 0.137 mmol) , 1,2,3-triazole (5 μL, 0.086 mmol) , and 5 -(4-chloro- 2-(methoxymethoxy)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidinyl)pyrazinamine (42 mg, 0.1 mmol) . The suspension was sparged once more with argon, then heated to 120 ºC for 1 h until complete consumption of aryl chloride, as monitored by UPLC. The reaction was cooled to room temperature and the product was purified using silica gel chromatography eluting with a MeOH/CH2Cl2 gradient (0 to 30% MeOH) to yield 5-(2-(methoxymethoxy)(2H-1,2,3-triazol- 2-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidinyl)pyrazinamine (40 mg, 88% yield).

MS m/z 452.4 [M+H]+; 1H NMR (methanol-d 4) δ: 8.70 (d, J=1.2 Hz, 1H), 8.15 (d, J=1.2 Hz, 1H), 8.03 (d, J=2.7 Hz, 1H), 7.95-7.96 (m, 2H), 7.82 (s, 2H), 5.38 (s, 2H), 5.15-5.21 (m, 1H), 3.51 (s, 3H), 3.03 (s, 3H), 1.68-1.72 (m, 2H), 1.57-1.62 (m, 2H), 1.41 (s, 6H), 1.27 (s, 6H); 1NH not observed.

Step 3: To a solution of 5-(2-(methoxymethoxy)(2H-1,2,3-triazolyl)phenyl)-N-methyl-N- ,6-tetramethylpiperidinyl)pyrazinamine (25 mg, 0.044 mmol) in MeOH (1 ml) was added 4N HCl in dioxane (1 mL). The reaction mixture was stirred at room temperature for 2 h.

The solvents were evaporated and the residue was purified using silica gel chromatography eluting with a MeOH/CH2Cl2 gradient (0 to 30% MeOH) to yield methyl(2,2,6,6- tetramethylpiperidinyl)amino)pyrazinyl)(2H-1,2,3-triazolyl)phenol (20 mg, 76% yield).

MS m/z 408.5 [M+H]+; 1H NMR (methanol-d 4) δ: 8.90 (s, 1H), 8.10 (s, 1H), 7.99 (d, J=8.5 Hz, 1H), 7.94 (s, 2H), 7.60-7.66 (m, 2H), 5.20-5.31 (m, 1H), 3.05 (s, 3H), 1.67-1.81 (m, 4H), 1.48 (s, 6H), .37 (m, 6H); 2Hs not observed (NH and OH).

Using the procedure described for Example 8, additional compounds described herein may be prepared by substituting the appropriate starting al, suitable reagents and reaction conditions, obtaining compounds such as those selected from: Cpd Data 50 MS m/z 393.2 ; 1H NMR (DMSO-d 6) δ: 8.88 (s, 1H), 8.40 (br s, 1H), 8.30 (s, 1H), 7.97-8.00 (m, 2H), 7.78 (s, 1H), 7.45 (d, J = 7.2 Hz, 1H), .22 (m, 2H), 7.10 (s, 1H), 4.27-4.30 (m, 1H), 1.97-2.00 (m, 2H), 1.31-1.40 (m, 14H); 1H not observed (OH or NH) 51 MS m/z 394.2 [M+H]+; 1H NMR (DMSO-d 6) δ: 8.84 (d, J = 1.2 Hz, 1H), 8.42 (br s, 1H), 8.12 (s, 2H), 8.02 (d, J = 8.8 Hz, 1H), 7.97 (d, J = 1.2 Hz, 1H), 7.52-7.57 (m, 2H), 7.32 (d, J = 7.6 Hz, 1H), 4.26-4.29 (m, 1H), 1.90-1.95 (m, 2H), 1.20-1.32 (m, 14H); 1H not observed (OH or NH) 59 MS m/z 411.2 [M+H]+; 1H NMR (DMSO-d 6) δ: 8.85 (s, 1H), 8.71 (d, J = 4.4 Hz, 1H), 8.42 (br s, 1H), 7.96-7.98 (m, 2H), 7.84 (d, J = 4.0 Hz, 1H), 7.36-7.41 (m, 2H), 7.30 (dd, J = 8.4, 2.0 Hz, 1H), 4.26-4.31 (m, 1H), .99 (m, 2H), 1.28-1.38 (m, 14H); 1H not observed (OH or NH) BIOLOGICAL EXAMPLES The following in vitro biological examples demonstrate the usefulness of the compounds of the present description for treating Huntington’s disease.

To describe in more detail and assist in understanding the present description, the following non-limiting ical examples are d to more fully illustrate the scope of the description and are not to be construed as ically limiting the scope f. Such variations of the present description that may be now known or later developed, which would be within the purview of one skilled in the art to ascertain, are considered to fall within the scope of the present description and as hereinafter claimed.

Compounds of a (I) were tested using the Meso Scale Discovery (MSD) Assay provided in International Application No. , filed on December 11, 2016 and claiming ty to United States Provisional Application U.S. 62/265,652 filed on December 10, 2015, the entire contents of which are incorporated herein by reference.

The Endogenous Huntingtin Protein assay used in Example 1 was developed using the ELISA-based MSD electrochemiluminescence assay platform.

Example 1 Endogenous Huntingtin Protein Assay Meso Scale Discovery (MSD) 96-well or 384-well plates were coated overnight at 4°C with MW1 (expanded polyglutamine) or MAB2166 monoclonal antibody (for capture) at a concentration of 1 µg/mL in PBS (30 µL per well). Plates were then washed three times with 300 µL wash buffer (0.05% Tween-20 in PBS) and blocked (100 µL blocking buffer; 5% BSA in PBS) for 4-5 hours at room temperature with rotational g and then washed three times with wash buffer.

Samples (25 µL) were transferred to the antibody-coated MSD plate and incubated overnight at 4°C. After removal of the lysates, the plate was washed three times with wash buffer, and 25 µL of #5656S (Cell signaling; rabbit monoclonal) secondary antibody (diluted to 0.25 µg/mL in 0.05% Tween-20 in blocking buffer) was added to each well and incubated with shaking for 1Hour at room temperature. Following incubation with the secondary antibody, the wells were rinsed with wash buffer after which 25 µL of goat anti-rabbit SULFO TAG secondary detection antibody (required aspect of the MSD system) ed to 0.25 µg/mL in 0.05% Tween- in blocking buffer) was added to each well and ted with shaking for 1 hour at room temperature. After rinsing three times with wash buffer, 150 µL of read buffer T with surfactant (MSD) were added to each empty well, and the plate was imaged on a SI 6000 imager (MSD) ing to manufacturers’ instructions provided for 96- or ll plates. The resulting IC50 values (µM) for compounds tested are shown in Table 1.

As shown in Table 1, test compounds bed herein had the following IC50 values, an IC50 value between > 3 µM and ≤ 9 µM is ted by a single star (*), an IC50 value between > 1 µM and ≤ 3 µM is ted by two stars (**), an IC50 value between > 0.5 µM and ≤ 1 µM is indicated by three stars (***), an IC50 value between > 0.1 µM and ≤ 0.5 µM is indicated by four stars (****) and an IC50 value of ≤ 0.1 µM is indicated by five stars (*****).

Table 1 Cpd IC50 Cpd IC50 Cpd IC50 1 ***** 19 ** 49 ***** 2 *** 20 *** 50 **** 3 ** 21 ** 51 *** 4 ** 22 ***** 52 ***** Cpd IC50 Cpd IC50 Cpd IC50 *** 23 **** 53 **** 6 ** 24 ***** 54 ***** 7 ** 25 * 55 *** 8 ** 26 ***** 56 ***** 9 ** 27 **** 57 ***** ** 28 *** 58 **** 11 **** 41 *** 59 ** 12 *** 42 **** 60 ***** 13 ***** 43 **** 61 **** 14 ** 44 **** 62 ***** ***** 45 *** 63 **** 16 *** 46 ***** 64 ***** 17 **** 47 ** 65 ***** 18 ** 48 * t regard to whether a document cited herein was specifically and individually indicated as being incorporated by reference, all documents referred to herein are orated by reference into the present application for any and all purposes to the same extent as if each individual reference was fully set forth herein.

Having now fully described the t matter of the claims, it will be understood by those having ordinary skill in the art that the same can be performed within a wide range of equivalents without affecting the scope of the subject matter or particular aspects described herein. It is intended that the appended claims be interpreted to include all such equivalents.

Claims (18)

What is claimed is:

1. A compound comprising, a compound of Formula (I): or a form thereof, n: X is CHR1a, C=O, O, NR1b, or a bond; R1a is independently selected from hydrogen, halogen, hydroxyl, cyano, kyl, deutero-C1-4alkyl, halo-C1-4alkyl, amino, and yl-C1-4alkyl; R1b is independently selected from hydrogen, C1-4alkyl, deutero-C1-4alkyl, and halo-C1-4alkyl; B is heterocyclyl, wherein heterocyclyl is a saturated or partially unsaturated 3-7 membered monocyclic, 6-10 membered bicyclic or 13-16 membered polycyclic ring system having 1, 2, or 3 heteroatom ring members independently selected from N, O, or S, each optionally substituted with 1, 2, 3, 4, or 5 substituents each selected from R2; R2 is independently selected from halogen, C1-4alkyl, deutero-C1-4alkyl, amino, C1-4alkyl-amino, and (C1-4alkyl)2-amino; R3 is independently selected from halogen, hydroxyl, cyano, kyl, deutero-C1-4alkyl, halo-C1-4alkyl, amino, C1-4alkyl-amino, (C1-4alkyl)2-amino, C1-4alkoxy, halo-C1-4alkoxy, heteroaryl, heterocyclyl, and phenyl, wherein heteroaryl is a 3-7 membered clic or 6-10 membered bicyclic ring system having 1, 2, 3, or 4 heteroatom ring members independently ed from N, O, or wherein heterocyclyl is a saturated or partially unsaturated 3-7 ed monocyclic, 6-10 membered bicyclic or 13-16 membered polycyclic ring system having 1, 2, or 3 heteroatom ring members independently selected from N, O, or S, and wherein each instance of phenyl, heteroaryl or heterocyclyl is optionally substituted with 1 or 2 substituents each selected from R4; n is n is 1, 2 or 3; and R4 is independently ed from halogen, hydroxyl, cyano, C1-4alkyl, deutero-C1-4alkyl, halo-C1-4alkyl, amino, C1-4alkyl-amino, (C1-4alkyl)2-amino, koxy, and 1-4alkoxy; wherein a form of the compound is selected from the group consisting of a salt, hydrate, solvate, racemate, enantiomer, diastereomer, stereoisomer, and tautomer form thereof.

2. The compound of claim 1, wherein X is selected from NR1b and a bond.

3. The compound of claim 1, wherein B is selected from azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, zinyl, 1,4-diazepanyl, 1,2-dihydropyridinyl, 6-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl, hexahydrocyclopentapyrrol- (1H)-yl, hexahydropyrrolo[3,2-b]pyrrol-(2H)-yl, hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl, hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, aS)-hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, octahydro-2H-pyrrolo[3,4-c]pyridinyl, octahydro-5H-pyrrolo[3,2-c]pyridinyl, octahydro-6H-pyrrolo[3,4-b]pyridinyl, (4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridinyl, (4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridinyl, hexahydropyrrolo[1,2-a]pyrazin-(2H)-one, hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (7R,8aS)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aS)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, hexahydro-1H-cyclobuta[1.2-c:1,4- c']dipyrrol-(3H)-yl, (8aS)-octahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aR)-octahydropyrrolo[1,2-a]pyrazin-(1H)-yl, octahydro-2H-pyrido[1,2-a]pyrazinyl, hexahydropyrrolo[3,4-b][1,4]oxazin-(2H)-yl, piro[2.4]heptanyl, 2-oxa azaspiro[3.4]octanyl, 3-azabicyclo[3.1.0]hexanyl, 8-azabicyclo[3.2.1]octanyl, (1R,5S)azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]octen-yl, (1R,5S)azabicyclo[3.2.1]octen-yl, 9-azabicyclo[3.3.1]nonanyl, (1R,5S)azabicyclo[3.3.1]nonanyl, 2,5-diazabicyclo[2.2.1]heptanyl, (1S,4S)-2,5-diazabicyclo[2.2.1]heptanyl, 1,4-diazabicyclo[3.1.1]heptanyl, 3,6-diazabicyclo[3.2.0]heptanyl, 2,5-diazabicyclo[2.2.2]octanyl, 1,4-diazabicyclo[3.2.1]octanyl, 3,8-diazabicyclo[3.2.1]octanyl, )-3,8-diazabicyclo[3.2.1]octanyl, 1,4-diazabicyclo[3.2.2]nonanyl, azaspiro[3.3]heptanyl, 4,7-diazaspiro[2.5]octanyl, 2,6-diazaspiro[3.3]heptanyl, 2,6-diazaspiro[3.4]octanyl, 1,7,-diazaspiro[4.4]nonanyl, 1,7-diazaspiro[3.5]nonanyl, 2,6-diazaspiro[3.5]nonanyl, 2,7-diazaspiro[3.5]nonanyl, 5,8-diazaspiro[3.5]nonanyl, 2,7-diazaspiro[4.4]nonanyl,2,7-diazaspiro[4.5]decanyl, azaspiro[4.5]decanyl, 6,9-diazaspiro[4.5]decyl, and 7-azadispiro[5.1.58.36]hexadecanyl, optionally substituted with 1, 2, 3, 4, or 5 R2 substituents.

4. The compound of claim 1, wherein B is selected from idinyl, piperidinyl, hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, 8-azabicyclo[3.2.1]octanyl, 2,6-diazaspiro[3.4]octanyl, and 7-azadispiro[5.1.58.36]hexadecanyl, optionally substituted with 1, 2, 3, 4, or 5 R2 substituents.

5. The compound of claim 1, wherein R3 is heteroaryl selected from thienyl, 1H-pyrazolyl, 1H-imidazolyl, 1,3-thiazolyl, yl, 1,2,4-oxadiazolyl, thiadiazolyl, 1H-1,2,3- lyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, 1H-tetrazolyl, 2H-tetrazolyl, pyridinyl, pyridin-2(1H)-on-yl, pyrimidinyl, pyrimidin-4(3H)-on-yl, pyridazinyl, pyridazin-3(2H)- on-yl, triazinyl, 1,3,5-triazinyl, 1H-indolyl, 1H-indazolyl, 2H-indazolyl, indolizinyl, benzofuranyl, benzothienyl, 1H-benzimidazolyl, 1,3-benzoxazolyl, 1,3-benzothiazolyl, 1,3-benzodioxolyl, 1,2,3-benzotriazolyl, 9H-purinyl, furo[3,2-b]pyridinyl, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, 1,3-oxazolo[5,4-b]pyridinyl, thieno[3,2-c]pyridinyl, [2,3-d]pyrimidinyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl, pyrrolo[1,2-a]pyrimidinyl, pyrrolo[1,2-a]pyrazinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridin-yl, pyrazolo[1,5-a]pyridinyl, 1H-pyrazolo[3,4-b]pyrazinyl, 1H-pyrazolo[3,4-b]pyridinyl, 1H-pyrazolo[3,4-b]pyridinyl, 1H-pyrazolo[3,4-c]pyridinyl, 1H-pyrazolo[3,4-c]pyridinyl, 1H-pyrazolo[4,3-b]pyridinyl, 1H-pyrazolo[4,3-b]pyridinyl, azolo[4,3-d]pyrimidinyl, 2H-pyrazolo[4,3-b]pyridinyl, 2H-pyrazolo[4,3-c]pyridin-yl, 5H-pyrrolo[2,3-b]pyrazinyl, pyrazolo[1,5-a]pyrazinyl, o[1,2-a]pyridinyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-a]pyrimidinyl, o[1,2-c]pyrimidinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, imidazo[1,2-a]pyrazinyl, 1H-imidazo[4,5-b]pyridinyl, 3H-imidazo[4,5-b]pyridinyl, imidazo[2,1-b][1,3]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, [1,3]oxazolo[4,5-b]pyridinyl, ]triazolo[1,5-a]pyridinyl, [1,2,3]triazolo[1,5- a]pyridinyl, 1H-[1,2,3]triazolo[4,5-b]pyridinyl, 3H-[1,2,3]triazolo[4,5-b]pyridinyl, tetrazolo[1,5-a]pyridinyl, tetrazolo[1,5-b]pyridazinyl, inyl, isoquinolinyl, and quinoxalinyl, optionally substituted with 1 or 2 R4 substituents.

6. The compound of claim 1, wherein R3 is heteroaryl selected from 1H-pyrazolyl, 1H-imidazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, pyridinyl, pyridin-2(1H)-on-yl, pyrimidinyl, 1,3,5-triazinyl, imidazo[1,2-b]pyridazinyl, and imidazo[1,2-a]pyrazinyl, optionally substituted with 1 or 2 R4 substituents.

7. The compound of claim 1, wherein the form of the compound is a compound salt selected from hydrochloride, hydrobromide, oroacetate, formate, dihydrochloride, trihydrochloride, tetrahydrochloride, dihydrobromide and ditrifluoroacetate.

8. A compound selected from the group consisting of: 4-(3-hydroxy{5-[methyl(2,2,6,6-tetramethylpiperidinyl)amino]pyrazin yl}phenyl)pyridinol; 5-(1H-pyrazolyl){5-[(2,2,6,6-tetramethylpiperidinyl)oxy]pyrazinyl}phenol; 2-{5-[(7-azadispiro[5.1.58.36]hexadecanyl)(methyl)amino]pyrazinyl}(1H- pyrazolyl)phenol; 5-[2,5-dichloro(1H-pyrazolyl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin- 4-yl)pyrazinamine; imidazolyl){5-[methyl(2,2,6,6-tetramethylpiperidinyl)amino]pyrazin yl}phenol; 2-[5-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrazinyl](1H-pyrazol yl)phenol; 2-{5-[(piperidinyl)oxy]pyrazinyl}(1H-pyrazolyl)phenol; 2-{5-[(piperidinyl)amino]pyrazinyl}(1H-pyrazolyl)phenol; 2-{5-[methyl(2,2,6,6-tetramethylpiperidinyl)amino]pyrazinyl}[5- (trifluoromethyl)-1H-pyrazolyl]phenol; -difluoro(1H-pyrazolyl)phenyl][(2,2,6,6-tetramethylpiperidin yl)oxy]pyrazine; 5-[2-fluoromethyl(1H-pyrazolyl)phenyl]-N-methyl-N-(2,2,6,6- tetramethylpiperidinyl)pyrazinamine; 5-(5-methyl-1H-pyrazolyl){5-[methyl(2,2,6,6-tetramethylpiperidin yl)amino]pyrazinyl}phenol; 5-[2,3-difluoro(1H-pyrazolyl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin- 4-yl)pyrazinamine; 5-(3-amino-1H-pyrazolyl){5-[methyl(2,2,6,6-tetramethylpiperidin yl)amino]pyrazinyl}phenol; 5-[2,5-difluoro(1H-pyrazolyl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin- yrazinamine; 5-[3-fluoro(1H-pyrazolyl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin yl)pyrazinamine; -difluoro(1H-pyrazolyl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin- 4-yl)pyrazinamine; 4-(3-hydroxy{5-[methyl(2,2,6,6-tetramethylpiperidinyl)amino]pyrazin nyl)methylpyridin-2(1H)-one; 2-{5-[methyl(2,2,6,6-tetramethylpiperidinyl)amino]pyrazinyl}(1H-pyrazol yl)phenol; 2-{5-[methyl(piperidinyl)amino]pyrazinyl}(1H-pyrazolyl)phenol; 2-[5-(2,6-diazaspiro[3.4]octanyl)pyrazinyl](1H-pyrazolyl)phenol; 4-fluoro{5-[methyl(2,2,6,6-tetramethylpiperidinyl)amino]pyrazinyl}(1H- pyrazolyl)phenol; 5-[5-chlorofluoro(1H-pyrazolyl)phenyl]-N-methyl-N-(2,2,6,6- tetramethylpiperidinyl)pyrazinamine; 4-fluoro{5-[methyl(2,2,6,6-tetramethylpiperidinyl)amino]pyrazinyl}(1H- pyrazolyl)benzonitrile; 2-[5-(8-azabicyclo[3.2.1]octyloxy)pyrazinyl](1H-pyrazolyl)phenol; 2-{5-[methyl(2,2,6,6-tetramethylpiperidinyl)amino]pyrazinyl}(1H-pyrazol yl)phenol; 5-(1-methyl-1H-pyrazolyl){5-[methyl(2,2,6,6-tetramethylpiperidin yl)amino]pyrazinyl}phenol; 5-[1-(2H3)methyl-1H-pyrazolyl]{5-[methyl(2,2,6,6-tetramethylpiperidin yl)amino]pyrazinyl}phenol; (5-(2-hydroxy(1H-pyrazolyl)phenyl)pyrazinyl)(2,2,6,6-tetramethylpiperidin yl)methanone; 2-(5-(2-hydroxy(1H-pyrazolyl)phenyl)pyrazinyl)(2,2,6,6- tetramethylpiperidinyl)acetonitrile; 2-(5-(amino(2,2,6,6-tetramethylpiperidinyl)methyl)pyrazinyl)(1H-pyrazol 2-(5-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyrazinyl)(1,3,5-triazin yl)phenol; 4-(3-hydroxy(5-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyrazin yl)phenyl)-1,3,5-triazinol; 5-(4-amino-1,3,5-triazinyl)(5-(methyl(2,2,6,6-tetramethylpiperidin yl)amino)pyrazinyl)phenol; 5-(4-chloro-1,3,5-triazinyl)(5-(methyl(2,2,6,6-tetramethylpiperidin yl)amino)pyrazinyl)phenol; 5-(5-chloro-1H-pyrazolyl)(5-(methyl(2,2,6,6-tetramethylpiperidin yl)amino)pyrazinyl)phenol; 4-(3-hydroxy(5-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyrazin yl)phenyl)-1H-pyrazolecarbonitrile; -dimethyl-1H-pyrazolyl)(5-(methyl(2,2,6,6-tetramethylpiperidin yl)amino)pyrazinyl)phenol; 5-(5-chloromethyl-1H-pyrazolyl)(5-(methyl(2,2,6,6-tetramethylpiperidin yl)amino)pyrazinyl)phenol; ydroxy(5-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyrazin yl)phenyl)methyl-1H-pyrazolecarbonitrile; 5-[2,3-difluoro(4-methyl-1H-imidazolyl)phenyl]-N-methyl-N-(2,2,6,6- tetramethylpiperidinyl)pyrazinamine; 5-[2,5-difluoro(3-methyl-1H-1,2,4-triazolyl)phenyl]-N-methyl-N-(2,2,6,6- tetramethylpiperidinyl)pyrazinamine; 5-(3-fluoro-1H-pyrazolyl){5-[methyl(2,2,6,6-tetramethylpiperidin yl)amino]pyrazinyl}phenol; 5-(pyridinyl){5-[(2,2,6,6-tetramethylpiperidinyl)amino]pyrazinyl}phenol; 5-(pyridinyl){5-[(2,2,6,6-tetramethylpiperidinyl)amino]pyrazinyl}phenol; 5-(1H-pyrazolyl){5-[(2,2,6,6-tetramethylpiperidinyl)amino]pyrazin yl}phenol; 5-(pyrimidinyl){5-[(2,2,6,6-tetramethylpiperidinyl)amino]pyrazin yl}phenol; 5-(pyridinyl){5-[(2,2,6,6-tetramethylpiperidinyl)amino]pyrazinyl}phenol; 5-(6-methoxypyrimidinyl){5-[(2,2,6,6-tetramethylpiperidinyl)amino]pyrazin- 2-yl}phenol; 5-(1H-imidazolyl){5-[(2,2,6,6-tetramethylpiperidinyl)amino]pyrazin yl}phenol; 2-{5-[(2,2,6,6-tetramethylpiperidinyl)amino]pyrazinyl}(2H-1,2,3-triazol yl)phenol; 2-{5-[3-(tert-butylamino)pyrrolidinyl]pyrazinyl}(1H-pyrazolyl)phenol; 5-(imidazo[1,2-a]pyrazinyl){5-[(2,2,6,6-tetramethylpiperidin yl)amino]pyrazinyl}phenol; 5-(1-methyl-1H-pyrazolyl){5-[(2,2,6,6-tetramethylpiperidinyl)amino]pyrazin- 2-yl}phenol; 5-(1-methyl-1H-pyrazolyl){5-[(2,2,6,6-tetramethylpiperidinyl)amino]pyrazin- 2-yl}phenol; 5-(imidazo[1,2-b]pyridazinyl){5-[(2,2,6,6-tetramethylpiperidin yl)amino]pyrazinyl}phenol; 5-(5-fluoro-1H-pyrazolyl){5-[(2,2,6,6-tetramethylpiperidinyl)amino]pyrazin- 2-yl}phenol; 5-(1H-pyrazolyl){5-[(2,2,6,6-tetramethylpiperidinyl)amino]pyrazin yl}phenol; 5-(4-fluoro-1H-pyrazolyl){5-[(2,2,6,6-tetramethylpiperidinyl)amino]pyrazin- 2-yl}phenol; 2-{5-[3-(tert-butylamino)pyrrolidinyl]pyrazinyl}[1-(2H3)methyl-1H-pyrazol- 4-yl]phenol; 2-{5-[methyl(2,2,6,6-tetramethylpiperidinyl)amino]pyrazinyl}(2H-1,2,3- triazolyl)phenol; 3-(tert-butylamino)pyrrolidinyl]pyrazinyl}(1-methyl-1H-pyrazol yl)phenol; N-tert-butyl{5-[2,3-difluoro(1H-pyrazolyl)phenyl]pyrazinyl}pyrrolidin amine; -butyl{5-[2,5-difluoro(1H-pyrazolyl)phenyl]pyrazinyl}pyrrolidin amine; and 3-(tert-butylamino)pyrrolidinyl]pyrazinyl}(3-fluoro-1H-pyrazol yl)phenol, wherein a form of the compound is selected from the group consisting of a salt, hydrate, solvate, racemate, enantiomer, diastereomer, stereoisomer, and tautomer form thereof.

9. The compound of claim 6, n the form of the compound is a compound salt or a form thereof selected from the group consisting of: 5-(1H-pyrazolyl){5-[(2,2,6,6-tetramethylpiperidinyl)oxy]pyrazinyl}phenol hydrochloride; 2-[5-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrazinyl](1H-pyrazol yl)phenol tetrahydrochloride; 2-{5-[(piperidinyl)oxy]pyrazinyl}(1H-pyrazolyl)phenol rochloride; 2-{5-[(piperidinyl)amino]pyrazinyl}(1H-pyrazolyl)phenol tetrahydrochloride; 2-[2,3-difluoro(1H-pyrazolyl)phenyl][(2,2,6,6-tetramethylpiperidin yl)oxy]pyrazine rochloride; 5-[2,3-difluoro(1H-pyrazolyl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin- 4-yl)pyrazinamine hydrochloride; 2-[5-(8-azabicyclo[3.2.1]octyloxy)pyrazinyl](1H-pyrazolyl)phenol hydrochloride; 2-{5-[methyl(2,2,6,6-tetramethylpiperidinyl)amino]pyrazinyl}(1H-pyrazol yl)phenol hydrobromide; 5-[1-(2H3)methyl-1H-pyrazolyl]{5-[methyl(2,2,6,6-tetramethylpiperidin yl)amino]pyrazinyl}phenol dihydrochloride; 5-(3-fluoro-1H-pyrazolyl){5-[methyl(2,2,6,6-tetramethylpiperidin yl)amino]pyrazinyl}phenol dihydrochloride; 5-(pyridinyl){5-[(2,2,6,6-tetramethylpiperidinyl)amino]pyrazinyl}phenol formate; 5-(pyridinyl){5-[(2,2,6,6-tetramethylpiperidinyl)amino]pyrazinyl}phenol formate; 5-(1H-pyrazolyl){5-[(2,2,6,6-tetramethylpiperidinyl)amino]pyrazin yl}phenol e; 5-(pyrimidinyl){5-[(2,2,6,6-tetramethylpiperidinyl)amino]pyrazinyl}phenol formate; 5-(pyridinyl){5-[(2,2,6,6-tetramethylpiperidinyl)amino]pyrazinyl}phenol formate; ethoxypyrimidinyl){5-[(2,2,6,6-tetramethylpiperidinyl)amino]pyrazin- 2-yl}phenol formate; 5-(1H-imidazolyl){5-[(2,2,6,6-tetramethylpiperidinyl)amino]pyrazin yl}phenol formate; 2-{5-[(2,2,6,6-tetramethylpiperidinyl)amino]pyrazinyl}(2H-1,2,3-triazol nol formate; 3-(tert-butylamino)pyrrolidinyl]pyrazinyl}(1H-pyrazolyl)phenol dihydrochloride; 5-(imidazo[1,2-a]pyrazinyl){5-[(2,2,6,6-tetramethylpiperidin yl)amino]pyrazinyl}phenol formate; 5-(1-methyl-1H-pyrazolyl){5-[(2,2,6,6-tetramethylpiperidinyl)amino]pyrazin- 2-yl}phenol formate; 5-(imidazo[1,2-b]pyridazinyl){5-[(2,2,6,6-tetramethylpiperidin yl)amino]pyrazinyl}phenol formate; 5-(5-fluoro-1H-pyrazolyl){5-[(2,2,6,6-tetramethylpiperidinyl)amino]pyrazin- 2-yl}phenol formate; 5-(1H-pyrazolyl){5-[(2,2,6,6-tetramethylpiperidinyl)amino]pyrazin yl}phenol formate; 5-(4-fluoro-1H-pyrazolyl){5-[(2,2,6,6-tetramethylpiperidinyl)amino]pyrazin- 2-yl}phenol formate; 2-{5-[3-(tert-butylamino)pyrrolidinyl]pyrazinyl}[1-(2H3)methyl-1H-pyrazol- 4-yl]phenol dihydrochloride; 2-{5-[methyl(2,2,6,6-tetramethylpiperidinyl)amino]pyrazinyl}(2H-1,2,3- lyl)phenol dihydrochloride; 2-{5-[3-(tert-butylamino)pyrrolidinyl]pyrazinyl}(1-methyl-1H-pyrazol yl)phenol dihydrochloride; N-tert-butyl{5-[2,3-difluoro(1H-pyrazolyl)phenyl]pyrazinyl}pyrrolidin amine dihydrochloride; N-tert-butyl{5-[2,5-difluoro(1H-pyrazolyl)phenyl]pyrazinyl}pyrrolidin amine dihydrochloride; and 2-{5-[3-(tert-butylamino)pyrrolidinyl]pyrazinyl}(3-fluoro-1H-pyrazol yl)phenol dihydrochloride, wherein a form of the compound is selected from the group consisting of a salt, hydrate, solvate, racemate, enantiomer, diastereomer, stereoisomer, and tautomer form thereof.

10. A method for treating or ameliorating HD in a subject in need thereof comprising, administering to the t an effective amount of the compound of any of claims 1, 8, or

11. The method of claim 10, wherein the effective amount of the nd is in a range of from about 0.001 mg/kg/day to about 500 mg/kg/day.

12. A use for the compound of any of claims 1, 8, or 9 for treating or ameliorating HD in a subject in need thereof comprising, stering to the subject an effective amount of the compound.

13. The use of claim 12, wherein the effective amount of the compound is in a range of from about 0.001 mg/kg/day to about 500 mg/kg/day.

14. A use for the nd of any of claims 1, 8, or 9 in the manufacture of a medicament for treating or ameliorating HD in a subject in need thereof comprising, administering to the subject an effective amount of the medicament.

15. The use of claim 14, wherein the ive amount of the compound in the medicament is in a range of from about 0.001 mg/kg/day to about 500 mg/kg/day.

16. A use for the compound of any of claims 1, 8, or 9 in the ation of a ceutical ition for treating or ameliorating HD in a subject in need thereof comprising, administering to the subject an effective amount of the compound of Formula (I) or a form thereof in admixture with one or more of the pharmaceutically acceptable excipients.

17. The use of claim 16, wherein the effective amount of the compound in the pharmaceutical composition is in a range of from about 0.001 mg/kg/day to about 500 mg/kg/day.

18. A pharmaceutical composition comprising the compound of any of claims 1, 8, or 9 in admixture with one or more pharmaceutically acceptable excipients.