EA041957B1 - COMPOUNDS FOR THE TREATMENT OF HUNTINGTON'S DISEASE - Google Patents

Description

One aspect of the present description relates to compounds, their forms and pharmaceutical compositions, and methods of using such compounds, forms or compositions thereof, useful for the treatment or alleviation of Huntington's disease. In particular, another aspect of the present description relates to substituted monocyclic heteroaryl compounds, their forms and pharmaceutical compositions, and to methods of using such compounds, forms or compositions for the treatment or alleviation of Huntington's disease.

Prerequisites for the creation of the invention

Huntington's disease (HD) is a progressive autosomal dominant neurodegenerative disease of the brain with symptoms characterized by involuntary movements, cognitive impairment and mental impairment. Death, usually caused by pneumonia or coronary heart disease, usually occurs 13 to 15 years after the onset of symptoms. The prevalence of HD is three to seven per 100,000 in populations of Western European origin. In North America, about 30,000 people have HD, and another 200,000 people are at risk of inheriting the disease from an affected parent. The disease is caused by an increase in continuous CAG trinucleotide repeats in the mutant huntingtin (Htt) gene, resulting in the production of an HTT (Htt protein) with an extended polyglutamine (polyQ) region, also known as the CAG repeat sequence. There are currently no small molecule therapies that target the underlying cause of the disease, leaving a high unmet need for drugs that can be used to treat or improve HD. Therefore, there remains a need to identify and provide small molecule compounds for the treatment or alleviation of HD.

All other documents referenced in this application are incorporated by reference into this application as if they were fully set forth in this application.

The essence of the invention

One aspect of the present disclosure includes compounds comprising a compound of formula (I)

(R ₃ ) _n (I) or its form, where X, B, R ₃ and n have the meaning defined in this application.

One aspect of the present disclosure includes a method of treating or alleviating 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.

One aspect of the present disclosure includes a method of using a compound of formula (I) or a form or composition thereof to treat or alleviate HD in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I) or a form or composition thereof.

One aspect of the present disclosure includes the use of a compound of formula (I) or a form thereof for treating or alleviating HD in a subject in need thereof, which comprises administering to the subject an effective amount of a compound of formula (I) or a form thereof.

One aspect of the present disclosure includes the use of a compound of formula (I) or forms thereof for the manufacture of a medicament for the treatment or alleviation of HD in a subject in need thereof, which comprises administering to the subject an effective amount of the drug.

One aspect of the present disclosure includes the use of a compound of formula (I) or a form thereof in a combination product with one or more therapeutic agents for the treatment or alleviation of HD in a subject in need thereof, which comprises administering to the subject an effective amount of a compound of formula (I) or a form thereof in combinations with an effective amount of one or more agents.

Detailed description of the invention

One aspect of the present description relates to compounds comprising a compound of formula (I) ⁱⁿ

(R ₃ )n (I) or its form, where

- 1 041957

X is CHR _1a , C=O, O, NR _1b or a bond;

R _1a is independently selected from hydrogen, halogen, hydroxyl, cyano, C _1-4 alkyl, deutero-C _1-4 alkyl, halo-C _1-4 alkyl, amino, and hydroxyl-C _1-4 alkyl;

R _1b is independently selected from hydrogen, C _1-4 alkyl, deutero-C _1-4 alkyl and halo-C _1-4 alkylα;

B is a heterocyclyl wherein heterocyclyl is a saturated or partially unsaturated 3-7 membered monocyclic, 6-10 membered bicyclic or 13-16 membered polycyclic ring system containing 1, 2 or 3 heteroatoms as ring members, independently selected from N, O or S, each optionally substituted with 1, 2, 3, 4 or 5 substituents each selected from R2;

R ₂ is independently selected from halo, C _1-4 alkyl, deutero-C _1-4 alkyl, amino, C _1-4 alkylamino, and (C _1-4 alkyl) ₂ -amino;

R ₃ is independently selected from halo, hydroxyl, cyano, C _1-4 alkyl, deutero-C _1-4 alkyl, halo-C _1-4 alkyl, amino, C _1-4 alkylamino, (C _1-4 alkyl) ₂ - amino, C _1-4 alkoxy, halo-C _1-4 alkoxy, heteroaryl, heterocyclyl and phenyl, where heteroaryl is a 3-7 membered monocyclic or 6-10 membered bicyclic ring system containing 1, 2, 3 or 4 heteroatom as ring members independently selected from N, O or S, where heterocyclyl is a saturated or partially unsaturated 3-7 membered monocyclic, 6-10 membered bicyclic or 13-16 membered polycyclic ring system containing 1, 2 or 3 heteroatoms as ring members independently selected from N, O or S, and where in each occurrence phenyl, heteroaryl or heterocyclyl is optionally substituted with 1 or 2 substituents each selected from R ₄ ;

n is 1, 2, or 3; And

R ₄ is independently selected from halogen, hydroxyl, cyano, C _1-4 alkyl, deutero-C _1-4 alkylα, halo-C _1-4 alkyl, amino, C _1-4 alkylamino, (C _1-4 alkyl) ₂ - amino, C _1-4 alkoxy and halo-C _1-4 alkoxy;

where the form of the compound is selected from the group consisting of its salt form, hydrate, solvate, racemate, enantiomer, diastereomer, stereoisomer and tautomer.

Description aspects

Another aspect of the present description includes a compound of formula (I) X χ or its form, where

X is CHR _1a , C=O, O, NR _1b or a bond;

R _1a is independently selected from hydrogen, halogen, hydroxyl, cyano, C _1-4 alkyl, deutero-C _1-4 alkyl, halo-C _1-4 alkyl, amino and hydroxyl-C _1-4 alkyl;

R _1b is independently selected from hydrogen, C _1-4 alkyl, deutero-C _1-4 alkyl and halo-C _1-4 alkylα;

B is a heterocyclyl wherein heterocyclyl is a saturated or partially unsaturated 3-7 membered monocyclic, 6-10 membered bicyclic or 13-16 membered polycyclic ring system containing 1, 2 or 3 heteroatoms as 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 halo, C _1-4 alkyl, deutero-C _1-4 alkyl, amino, C _1-4 alkylamino, and (C _1-4 alkyl) ₂ -amino;

R ₃ is independently selected from halogen, hydroxyl, cyano, C _1-4 αalkyl, deutero-C _1-4 alkylα, halo-C _1-4 alkyl, amino, C _1-4 alkylamino, (C _1-4 alkyl) ₂ - amino, C _1-4 alkoxy, halo-C _1-4 alkoxy, heteroaryl, heterocyclyl and phenyl, where heteroaryl is a 3-7 membered monocyclic or 6-10 membered bicyclic ring system containing 1, 2, 3 or 4 heteroatom as ring members independently selected from N, O or S, where heterocyclyl is a saturated or partially unsaturated 3-7 membered monocyclic, 6-10 membered bicyclic or 13-16 membered polycyclic ring system containing 1, 2 or 3 heteroatoms as ring members independently selected from N, O or S, and where in each occurrence phenyl, heteroaryl or heterocyclyl is optionally substituted with 1 or 2 substituents each selected from R ₄ ;

- 2 041957 n is 1, 2 or 3; And

R4 is independently selected from halogen, hydroxyl, cyano, C _1-4 alkyl, deutero-C _1-4 alkyl, halo-C _1-4 alkyl, amino, C _1-4 alkylamino, (C _1-4 αalkyl) ₂ -amino , C _1-4 alkoxy and halo-C _1-4 α alkoxy.

One aspect includes a compound of formula (I) wherein X is selected from CHR _1a , C=O, O, NR _1b and a bond.

Another aspect includes a compound of formula (I) wherein X is CHR _1a .

Another aspect includes a compound of formula (I) wherein 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 NR _1b .

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

One aspect includes a compound of formula (I) wherein R _1a is selected from hydrogen, halogen, hydroxyl, cyano, C _1-4 alkyl, deutero-C _1-4 αkyl, halo-C _1-4 alkyl, amino, and hydroxyl-C _{1 -4} alkyl.

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 R _1a is cyano.

Another aspect includes a compound of formula (I) wherein R _1a is amino.

One aspect includes a compound of formula (I) wherein R _1b is selected from hydrogen, C _1-4 αalkyl, deutero-C _1-4 alkyl, and halo-C _1-4 alkyl.

Another aspect includes a compound of formula (I) wherein R _1b is selected from hydrogen and C _1-4 alkyl.

Another aspect includes a compound of formula (I) wherein R _1b is hydrogen.

Another aspect includes a compound of formula (I) wherein R _1b is C _1-4 alkyl selected from methyl, ethyl, propyl, isopropyl, butyl and t-butyl.

Another aspect includes a compound of formula (I) wherein R _1b 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 membered polycyclic ring system containing 1, 2 or 3 heteroatoms as ring members independently selected from N, O or S, each optionally substituted with 1, 2, 3, 4 or 5 substituents each selected from R ₂ .

Another aspect includes a compound of formula (I) wherein B is a 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[3,4b]pyrrol-(2H)-yl, (3aS,6aS) -hexahydropyrrolo[3,4-b]pyrrolo-(2Н)-yl, hexahydropyrrolo[3,4b]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, (3aR,6aS)-hexahydropyrrolo[3 ,4c]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-а]pyrazin-(1H)-yl, (7R,8aS)-hexahydropyrrolo [1,2-a]pyrazin-(1H)-yl, (8aS)-hexahydropyrrolo[1,2-а]pyrazin-(1H)-yl, (8aR)-hexahydropyrrolo[1,2-а]pyrazin-( 1H)-yl, hexahydro-1Hcyclobuta[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, 5-azaspiro[2,4]heptanyl, 2-oxa-6-azaspiro[3.4]octanyl, 3-azabicyclo[3.1.0]hexanyl, 8-azabicyclo[3.2.1]octanyl, (1R,5S )-8-azabicyclo[3.2.1]octanyl, 8azabicyclo[3.2.1]oct-2-en-yl, (1R,5S)-8-azabicyclo[3.2.1]oct-2-en-yl, 9- azabicyclo[3.3.1]nonanyl, (1R,5S)-9-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)-3,8diazabicyclo[3.2.1]octanyl, 1,4-diazabicyclo[3.2.2]nonanyl, azaspiro[3, 3]heptanyl, 4,7diazaspir o[2,5]octanyl, 2,6-diazaspiro[3,3]heptanyl, 2,6-diazaspiro[3,4]octanyl, 1,7-diazaspiro[4,4]nonanil, 1,7-diazaspiro[ 3,5]nonanil, 2,6-diazaspiro[3,5]nonanil, 2,7-diazaspiro[3,5]nonanil, 5,8-diazaspiro[3,5]nonanil, 2,7-diazaspiro[4, 4]nonanil, 2,7-diazaspiro[4,5]decanyl, 2,8diazaspiro[4,5]decanyl, 6,9-diazaspiro[4,5]decyl, 6-oxa-2,9-diazaspiro[4, 5]decanyl, 2,9diazaspiro[5,5]undecanil and 7-azadispiro[5,1,5 ⁸ ,3 ⁶ ]hexadecanyl optionally substituted with 1, 2, 3, 4 or 5 substituents each selected from R ₂ .

Another aspect includes a compound of formula (I) wherein B is a heterocyclyl selected from pyrrolidinyl, piperidinyl, hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, 8azabicyclo[3.2.1]octanyl, 2,6-diazaspiro [3.4]octanyl and 7-azadispiro[5.1.5 ⁸ .3 ⁶ ]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 a 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 R ₂ .

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

Another aspect includes a compound of formula (I) wherein B is a heterocyclyl selected from azetidin-1-yl, tetrahydrofuran-3-yl, pyrrolidin-1-yl, pyrrolidin-3-yl, piperidin-1-yl, piperidin-3 -yl, piperidin-4-yl, piperazin-1-yl, 1,4-diazepan-1-yl, 1,2-dihydropyridin-2-yl, 1,2dihydropyridin-3-yl, 1,2-dihydropyridin-4 -yl, 1,2-dihydropyridin-5-yl, 1,2-dihydropyridin-6yl, 1,2,5,6-tetrahydropyridin-5-yl, 1,2,3,6-tetrahydropyridin-4-yl, hexahydrocyclopentapyrrole2 (1H)-yl, hexahydropyrrolo[3,2-b]pyrrolo-1(2Н)-yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-1(2Н)-yl, 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(1Н)-yl, hexahydropyrrolo[3,4-с]pyrrol-5(1H)-yl, (3aR,6aS)-hexahydropyrrolo[3,4-с]pyrrol-2(1H)-yl, octahydro -2Hpyrrolo[3,4-c]pyridin-2-yl, octahide ro-5H-pyrrolo[3,2-c]pyridin-5-yl, octahydro-6H-pyrrolo[3,4

b]pyridin-6-yl, (4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl, pyrrolo[3,4-b]pyridin-6-yl, hexahydropyrrolo[1, 2-a]pyrazin-6(2H)-one, (4aS,7aS)-octahydro-6Hhexahydropyrrolo[1,2a]pyrazin-2(1H)-yl, (7R,8aS)-hexahydropyrrolo[1,2-a] pyrazin-2(1H)-yl, (8aS)-hexahydropyrrolo[1,2а]pyrazin-2(1H)-yl, (8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl , hexahydro-1 H-cyclobuta[1,2c:1,4-c']dipyrrol-2(3H)-yl, (8aS)-octahydropyrrolo[1,2-а]pyrazin-2(1H)-yl, ( 8aR)-octahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, octahydro-2H-pyrido[1,2-a]pyrazin-2-yl, hexahydropyrrolo[3,4b][1,4]oxazine -6(2H)-yl, 5-azaspiro[2.4]heptan-5-yl, 2-oxa-6-azaspiro[3.4]octan-6-yl, 3azabicyclo[3.1.0]hexan-3-yl, 8- azabicyclo[3.2.1]octan-3-yl, (1R,5S)-8-azabicyclo[3.2.1]octan-3-yl, 8-azabicyclo[3.2.1]oct-2-en-3-yl, (1R,5S)-8-azabicyclo[3.2.1]oct-2-en-3-yl, 9-azabicyclo[3.3.1]nonan3-yl, (1R,5S)-9-azabicyclo[3.3.1] nonan-3-yl, 2,5-diazabicyclo[2.2.1]heptan-2-yl, (1S,4S)-2,5diazabicyclo[2.2.1]heptan-2-yl, 1,4-d iazabicyclo[3.1.1]heptan-4-yl, 3,6-diazabicyclo[3.2.0]heptan-3yl, 3,6-diazabicyclo[3.2.0]heptan-6-yl, 2,5-diazabicyclo[2.2. 2]octan-2-yl, 1,4-diazabicyclo

[3.2.1]octan-4-yl, 3,8-diazabicyclo[3.2.1]octan-3-yl, (1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl, diazabicyclo [3.2.2]nonan-4-yl, azaspiro[3.3]heptan-2-yl, diazaspiro[2.5]octan-7-yl, diazaspiro[3.4]octan-6-yl, diazaspiro[3.5]nonan-7-yl , diazaspiro[3.5]nonan-2-yl, diazaspiro[4.4]nonan-2-yl, diazaspiro[4.5]decan-8-yl,

2,6-diazaspiro[3.3]heptan-2-yl, 1,7-diazaspiro[4.4]nonan-1-yl, 2,6-diazaspiro[3.5]nonan-2-yl, 2,7-diazaspiro[3.5] nonan-7-yl, 2,7-diazaspiro [4.5] decan-2-yl,

4,7-diazaspiro[2.5]octan-4-yl, 2,6-diazaspiro[3.4]octan-2-yl, 1,7-diazaspiro[4.4]nonan-7-yl, 2,6-diazaspiro[3.5] nonan-6-yl, 5,8-diazaspiro[3.5] nonan-8-yl, 2,7-diazaspiro[4.5] decan-7-yl,

1,44,72,61,72,72,72,86,9-diazaspiro[4.5]decan-9-yl and 7-azadispiro[5.1.5 ^8.36 ]hexadecan-15-yl, optionally substituted 1, 2 , 3, 4 or 5 substituents each selected from R ₂ .

Another aspect includes a compound of formula (I) wherein B is a heterocyclyl selected from pyrrolidin-1-yl, piperidin-4-yl, hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl, 8azabicyclo[3.2. 1]octan-3-yl, 2,6-diazaspiro[3.4]octan-2-yl and 7-azadispiro[5.1.5 ⁸ .3 ⁶ ]hexadecan-15-yl optionally substituted with 1, 2, 3, 4 or 5 substituents each selected from R ₂ .

Another aspect includes a compound of formula (I) wherein B is a heterocyclyl selected from pyrrolidin-1-yl and piperidin-4-yl, optionally substituted with 1, 2, 3, 4 or 5 substituents each selected from R ₂ .

One aspect includes a compound of formula (I) wherein R ₂ is selected from halo, C ₁ .4 alkyl, deutero-C ₁ .4 alkyl, amino, C ₁ .4 alkylamino, and (CmalkylD-amino.

Another aspect includes a compound of formula (I) wherein R ₂ is selected from C ₁ .4 alkyl and ^^ alkylamino.

Another aspect includes a compound of formula (I) wherein R ₂ is C ₁ .4 alkyl selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and t-butyl.

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

Another aspect includes a compound of formula (I) wherein R ₂ is Omalkylamino, wherein C1.4 alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and t-butyl.

Another aspect includes a compound of formula (I), where R ₂ represents Omalkylamino, where C1. ₄ alkyl is tert-butyl.

Another aspect includes a compound of formula (I), where R ₂ represents Omalkylamino, where C1. ₄ alkyl is tert-butylamino.

One aspect includes a compound of formula (I) wherein R3 is selected from halo, hydroxyl, cyano, C1. ₄ alkyl, deutero-C ₁ .4 alkyl, halo-C ₁ .4 alkyl, amino, C ₁ .4α alkylamino, (Omalkyl) ₂ -amino, C ₁ .4 α alkoxy, halogen-C ₁ .4 alkoxy, heteroaryl, heterocyclyl and phenyl, where heteroaryl is a 3-7 membered monocyclic or 6-10 membered bicyclic ring system containing 1, 2, 3 or 4 heteroatoms as ring members independently selected from N, O or S, where heterocyclyl is saturated or partially unsaturated 3-7 membered monocyclic, 6-10 membered bicyclic or 13-16 membered polycyclic ring system containing 1, 2 or 3 heteroatoms as ring members independently selected from N, O or

- 4 041957

S, and where in each occurrence phenyl, heteroaryl or heterocyclyl is optionally substituted with 1 or 2 substituents each selected from R ₄ .

Another aspect includes a compound of formula (I) wherein R ₃ is selected from halo, hydroxyl, cyano, C1-4 alkyl and heteroaryl, wherein heteroaryl is a 3-7 membered monocyclic or 6-10 membered bicyclic ring system containing 1, 2, 3 or 4 heteroatoms as ring members independently selected from N, O or S, where in each occurrence the heteroaryl is optionally substituted with 1 or 2 substituents each selected from R4.

Another aspect includes a compound of formula (I) wherein R3 is a halogen selected from bromine, chlorine, fluorine and iodine.

Another aspect includes a compound of formula (I) wherein R3 is a halogen selected from chlorine and fluorine.

Another aspect includes a compound of formula (I) wherein R ₃ is chlorine.

Another aspect includes a compound of formula (I) wherein R ₃ is fluoro.

Another aspect includes a compound of formula (I) wherein R ₃ is hydroxyl.

Another aspect includes a compound of formula (I) wherein R ₃ is cyano.

Another aspect includes a compound of formula (I) wherein R ₃ is C ₁ . ₄ alkyl 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, 1,3,4oxadiazolyl, 1 ,2,4-thiadiazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, 1Htetrazolyl, 2H-tetrazolyl, pyridinyl, pyridine-2(1H )-on-yl, pyrimidinyl, pyrimidin-4(3H)-onyl, pyridazinyl, pyridazin-3(2H)-on-yl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1H-indolyl, 1Hindazolyl, 2H-indazolyl, indolizinyl, benzofuranyl, benzothienyl, 1H-benzimidazolyl, 1,3benzoxazolyl, 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, 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[3, 4-b]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyrimidinyl, pyrazolo[1,5-а]pyridinyl, 1Н-pyrazolo[3,4-b]pyridinyl, 1 N -pyrazolo[4,3-b]pyridinyl, 2H-pyrazolo[4,3-b]pyridinyl,

H-pyrazolo[3,4-b]pyrazinyl, 1H

n-pyrazolo[3,4-c]pyridinyl, 1H

Н-pyrazolo[4,3-b]pyridinyl, 1Н

2Н-pyrazolo[4,3-с]pyridinyl, 5Н pyrrolo[2,3-b]pyrazinyl, pyrazolo[1,5-а]pyrazinyl, imidazo[1,2-а]pyridinyl, imidazo[1, 2a]pyridinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2c]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, 1b][1,3]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, [1,3]oxazolo[4,5-b]pyridinyl, [1,2,3]triazolo[ 1,5a]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 heteroaryl selected from 1H-pyrazolyl, 1H-imidazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, pyridinyl, pyridine-2 (1H)-on-yl, pyrimidinyl, 1,3,5-triazinyl, imidazo[1,2-b]pyridazinyl and imidazo[1,2a]pyrazinyl optionally substituted with 1 or 2 substituents each selected from R4.

Another aspect includes a compound of formula (I) wherein R ₃ is heteroaryl selected from thien-2-yl, thien-3-yl, 1H-pyrazol-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol- 4-yl, 1H-pyrazol-5yl, 1H-imidazol-1-yl, 1H-imidazol-4-yl, 1,3-thiazol-2-yl, 1,3-thiazol-5-yl, oxazol-2- yl, oxazol4-yl, oxazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,3,4-oxadiazol-2-yl, 1,2,4-thiadiazol-5-yl, 1H- 1,2,3triazol-1-yl, 1H-1,2,3-triazol-4-yl, 1H-1,2,3-triazol-5-yl, 2H-1,2,3-triazol-2- yl, 2H-1,2,3-triazol4-yl, 1H-1,2,4-triazol-1-yl, 1H-1,2,4-triazol-3-yl, 1H-1,2,4- triazol-5-yl, 1Н-tetrazol-1-yl, 1Н-tetrazol-5-yl, 2Н-tetrazol-2-yl, 2Н-tetrazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin- 4-yl, pyridin-2(1H)-on-4-yl, pyridin-2(1H)-on-5-yl, pyridin-2(1H)-on-6-yl, pyrimidin-2-yl, pyrimidine -4-yl, pyrimidin-5-yl, pyrimidin-4(3H)-on-6-yl, pyridazin-3-yl, pyridazin-4-yl, pyridazin3(2H)-on-5-yl, 1.2 ,4-triazin-3-yl, 1,3,5-triazin-2-yl, 1H-indol-3-yl, 1H-indol-4-yl, 1H-indol-5yl, 1H-indol-6 -yl, 1H-indazol-5-yl, 2H-indazol-5-yl, indolizin-2-yl, benzofuran-2-yl, benzofuran-5-yl, benzothien-2-yl, benzothien-3-yl, 1H -benzimidazol-2-yl, 1H-benzimidazol-5-yl, 1Hbenzimidazol-6-yl, 1,3-benzoxazol-2-yl, 1,3-benzoxazol-5-yl, 1,3-benzoxazol-6-yl , 1,3-benzothiazol-2-yl, 1,3-benzothiazol-5-yl, 1,3-benzothiazol-6-yl, 1,3-benzodioxol-5-yl, 1,2,3

- 5 041957 benzotriazol-5-yl, 9H-purin-8-yl, furo[3,2-b]pyridin-2-yl, furo[3,2-c]pyridin-2-yl, furo[2,3c ]pyridin-2-yl, 1,3-oxazolo[5,4-b]pyridin-5-yl, thieno[3,2-c]pyridin-2-yl, thieno[2,3-4]pyrimidin6-yl , 1H-pyrrolo[2,3-b]pyridin-5-yl, 1H-pyrrolo[2,3-c]pyridin-4-yl, pyrrolo[1,2-a]pyrimidin-7yl, pyrrolo[1,2 -a]pyrazin-7-yl, pyrrolo[1,2-b]pyridazin-2-yl, pyrazolo[1,5-a]pyridin-2-yl, pyrazolo[1,5-a]pyridin-5-yl , 1H-pyrazolo[3,4-b]pyrazin-5-yl, 1H-pyrazolo[3,4-b]pyridin-5-yl, 1H-pyrazolo[3,4-b]pyridin-6-yl, 1H-pyrazolo [3,4-c]pyridin-1-yl, 1H-pyrazolo[3,4-c]pyridin-5-yl, 1Hpyrazolo[4,3-b]pyridin-5-yl, 1H-pyrazolo[4,3 -b]pyridin-6-yl, 1H-pyrazolo[4,3-c]pyrimidin-5-yl, 2H-pyrazolo[4,3-b]pyridin-5-yl, 2H-pyrazolo[4,3-c ]pyridin-5-yl, 5H-pyrrolo[2,3-b]pyrazin-2-yl, pyrazolo[1,5-а]pyrazin-2-yl, imidazo[1,2-а]pyridin-2-yl , imidazo[1,2-а]pyridin-6-yl, imidazo[1,2а]pyrimidin-2-yl, imidazo[1,2-а]pyrimidin-6-yl, imidazo[1,2-с]pyrimidine -2-yl, imidazo[1,2b]pyridazin-2-yl, and midazo[1,2-b]pyridazin-6-yl, imidazo[1,2-a]pyrazin-2-yl, imidazo[1,2a]pyrazin-6-yl, 1H-imidazo[4,5-b] pyridin-5-yl, 3H-imidazo[4,5-b]pyridin-5-yl, imidazo[2,1b][1,3]thiazol-6-yl, imidazo[2,1-b][1, 3,4]thiadiazol-6-yl, [1,3]oxazolo[4,5-b]pyridin-2-yl, [1,2,3]triazolo[1,5-a]pyridin-5-yl, [1,2,3]triazolo[1,5-a]pyridin-6-yl, 1H-[1,2,3]triazolo[4,5b]pyridin-5-yl, 3H-[1,2,3 ]triazolo[4,5-b]pyridin-5-yl, tetrazolo[1,5-a]pyridin-7-yl, tetrazolo[1,5b]pyridazin-7-yl, quinolin-6-yl, isoquinolin-6 -yl and quinoxalin-2-yl optionally substituted with 1 or 2 substituents each selected from R4.

Another aspect includes a compound of formula (I) wherein R ₃ is heteroaryl selected from 1H-pyrazol-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-imidazol-1-yl, 2Н-1,2,3-triazol-2yl, 1Н-1,2,4-triazol-1-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridin-2(1H) -on-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, 1,3,5-triazin-2-yl, imidazo[1,2-b]pyridazin-6-yl and imidazo[1,2a ]pyrazin-6-yl optionally substituted with 1 or 2 substituents each selected from R4.

One aspect includes a compound of formula (I) wherein R ₄ is selected from halogen, hydroxyl, cyano, C1-4 alkyl, deutero-C ₁ . ₄ alkyl, halo-C ₁ . ₄ αlkyl, amino, ^^alkylamino, (C ₁ .4αlkyl) ₂ -αmino, C ₁ . ₄ alkoxy and halo-C ₁ . ₄ alkoxy.

Another aspect includes a compound of formula (I) wherein R4 is selected from halogen, hydroxyl, cyano, C1.4 alkyl, deutero-C ₁ . ₄ alkyl, halo-C ₁ . ₄ αkyl, amino and C ₁ . ₄ alkoxy.

Another aspect includes a compound of formula (I), where R ₄ represents a halogen selected from bromine, chlorine, fluorine and iodine.

Another aspect includes a compound of formula (I) wherein R ₄ is halogen selected from chlorine and fluorine.

Another aspect includes a compound of formula (I) wherein R4 is chlorine.

Another aspect includes a compound of formula (I) wherein R4 is fluorine.

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 C ₁ . ₄ alkyl selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.

Another aspect includes a compound of formula (I) wherein R ₄ is methyl.

Another aspect includes a compound of formula (I) wherein R4 is deutero-C ₁ . ₄ alkyl, where C ₁ . The ₄ αalkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl partially or wholly substituted with one or more deuterium atoms where available valences permit.

Another aspect includes a compound of formula (I) wherein R4 is ( ² H ₃ )methyl.

Another aspect includes a compound of formula (I) wherein R4 is halo-C ₁ . ₄ alkyl, where C ₁ . ₄ αalkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl partially or completely substituted with one or more halogen atoms where available valences permit.

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

Another aspect includes a compound of formula (I) wherein R ₄ is amino.

Another aspect includes a compound of formula (I) wherein R4 is C ₁ . ₄ alkoxy selected from methoxy, ethoxy, propoxy, isopropoxy, butoxy and t-butoxy.

Another aspect includes a compound of formula (I) wherein R ₄ is methoxy.

One aspect includes a compound of formula (I) wherein 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.

One aspect of a compound of formula (I), or a form thereof, includes a compound selected from the group consisting of

- 6 041957

17 18 19 20

- 7 041957

- 8 041957

- 9 041957

where the form of the compound is selected from the group consisting of its salt form, hydrate, solvate, racemate, enantiomer, diastereomer, stereoisomer and tautomer.

One aspect of a compound of formula (I) or a form thereof (wherein the compound number (#1) indicates that the salt form has been isolated) includes a compound selected from the group consisting of the following:

- 10 041957

Comm.

2 ¹

6 ¹

7 ¹

8 ¹

10 ¹

13 ¹

Name

4-(3-hydroxy-4-{5-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin2-yl } phenyl)pyridin-2-ol

5-(1H-pyrazol-4-yl)-2-{5-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyrazin-2yl}phenol

2-{ 5-[(7-azadispiro[5.1.5 ⁸ .3 ⁶ ] hexadecan- 15-yl)(methyl)amino]pyrazin-2-yl }-5(1Н-pyrazol-4-yl)phenol

5-[2,5-dichloro-4-(1H-pyrazol-4-yl)phenyl]-LH-methyl-LH-(2,2,6,6tetramethylpiperidin-4-yl)pyrazin-2-amine

5-( 1 H-imide azol-1-yl)-2- {5- [methyl(2,2,6,6-tetramethylpiperidin-4yl)amino]pyrazin-2-yl}phenol

2-[5-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrazin-2-yl]-5-(1H-pyrazol4-yl)phenol

2-{5-[(piperidin-4-yl)oxy]pyrazin-2-yl}-5-(1H-pyrazol-4-yl)phenol

2-{5-[(piperidin-4-yl)amino]pyrazin-2-yl}-5-(1H-pyrazol-4-yl)phenol

2-{5-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin-2-yl }-5-[5(trifluoromethyl)-1H-pyrazol-4-yl]phenol

2-[2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl]-5-[(2,2,6,6-tetramethylpiperidin-4yl)oxy]pyrazine

5-[2-fluoro-5-methyl-4-(1H-pyrazol-4-yl)phenyl]-bx-methyl-bx-(2,2,6,6tetramethylpiperidin-4-yl)pyrazin-2-amine

5-(5-methyl-1H-pyrazol-4-yl)-2-{5-[methyl(2,2,6,6-tetramethylpiperidin-4yl)amino]pyrazin-2-yl}phenol

5-[2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl]-bx-methyl-bx-(2,2,6,6tetramethylpiperidin-4-yl)pyrazin-2-amine

5-(3-Amino-1 H-pyrazol-1-yl)-2-{5-[methyl(2,2,6,6-tetramethylpiperidin-4yl)amino]pyrazin-2-yl}phenol

5-[2,5-difluoro-4-(1H-pyrazol-4-yl)phenyl]-bx-methyl-bx-(2,2,6,6tetramethylpiperidin-4-yl)pyrazin-2-amine

5-[3-fluoro-4-(1H-pyrazol-4-yl)phenyl]-bx-methyl-bx-(2,2,6,6tetramethylpiperidin-4-yl)pyrazin-2-amine

5-[3,5-difluoro-4-(1H-pyrazol-4-yl)-phenyl]-bx-methyl-bx-(2,2,6,6-tetramethylpiperidin-4-yl)pyrazin-2-amine

4-(3-hydroxy-4-{5-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin- And 041957

25 ¹

2-yl } phenyl)-1-methylpyridin-2( 1 H)-one

2-{5-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin-2-yl}-5-(1Hpyrazol-1-yl)phenol

2-{5-[methyl(piperidin-4-yl)amino]pyrazin-2-yl}-5-(1H-pyrazol-4-yl)phenol 2-[5-(2,6-diazaspiro[3.4]octane -2-yl)pyrazin-2-yl]-5-(1H-pyrazol-4-yl)phenol 4-fluoro-2-{5-[methyl(2,2,6,6-tetramethylpiperidin-4-yl) amino]pyrazin-2-yl } -5(1H-pyrazol-4-yl)phenol

5-[5-Chloro-2-fluoro-4-(1H-pyrazol-4-yl)phenyl]-M-methyl-M-(2,2,6,6tetramethylpiperidin-4-yl)pyrazin-2-amine

4-fluoro-5-{5-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin-2-yl }-2(1H-pyrazol-4-yl)benzonitrile

2-[5-(8-azabicyclo[3.2.1]oct-3-yloxy)pyrazin-2-yl]-5-(1Н-pyrazol-4yl)phenol

2-{5-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin-2-yl}-5-(1Hpyrazol-4-yl)phenol

5-(1-methyl-1H-pyrazol-4-yl)-2-{5-[methyl(2,2,6,6-tetramethylpiperidin-4yl)amino]pyrazin-2-yl}phenol

5-[1-( ^2H3 )methyl-1H-pyrazol-4-yl]-2-{5-[methyl(2,2,6,6-tetramethylpiperidin-4yl)amino]pyrazin-2-yl}phenol ( 5-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyrazin-2-yl)(2,2,6,6tetramethylpiperidin-4-yl)methanone

2-(5-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyrazin-2-yl)-2-(2,2,6,6tetramethylpiperidin-4-yl)acetonitrile

2-(5-(Amino(2,2,6,6-tetramethylpiperidin-4-yl)methyl)pyrazin-2-yl)-5-(1Hpyrazol-4-yl)phenol

2-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyrazin-2-yl)-5-(1,3,5triazin-2-yl)phenol

4-(3-hydroxy-4-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyrazin2-yl)phenyl)-1,3,5-triazin-2-ol

5-(4-Amino-1,3,5-triazin-2-yl)-2-(5-(methyl(2,2,6,6-tetramethylpiperidin-4yl)amino)pyrazin-2-yl)phenol

5-(4-chloro-1,3,5-triazin-2-yl)-2-(5-(methyl(2,2,6,6-tetramethylpiperidin-4yl)amino)pyrazin-2-yl)phenol

5-(5-chloro-1H-pyrazol-4-yl)-2-(5-(methyl(2,2,6,6-tetramethylpiperidin-4yl)amino)pyrazin-2-yl)phenol

- 12 041957

4-(3-hydroxy-4-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyrazin- "uh/ 2-yl)phenyl)-1H-pyrazole-5-carbonitrile 5-(1,5-dimethyl-1H-pyrazol-4-yl)-2-(5-(methyl(2,2,6,6-tetramethylpiperidin-4- JO yl)amino)pyrazin-2-yl)phenol 5-(5-Chloro-Gmethyl-1H-pyrazol-4-yl)-2-(5-(methyl(2,2,6,6-tetramethylpiperidine- jy 4-yl)amino)pyrazin-2-yl)phenol 40 4-(3-hydroxy-4-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyrazin- 4u 2-yl)phenyl)-1-methyl-1H-pyrazole-5-carbonitrile 41 5-[2,3-difluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]-M-methyl-I-(2,2,6,6- ‘tA tetramethylpiperidin-4-yl)pyrazin-2-amine 4? 5-[2,5-difluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl]-M-methyl-M-(2,2,6,6- tetramethylpiperidin-4-yl)pyrazin-2-amine 43 ¹ 5-(3-fluoro-1 H-pyrazol-4-yl)-2-{5-[methyl(2,2,6,6-tetramethylpiperidin-4- 'r.J yl)amino]pyrazin-2-yl}phenol AL ¹ 5-(pyridin-4-yl)-2-{5-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin-2- ‘♦‘g yl}phenol 45 ¹ 5-(pyridin-3-yl)-2-{5-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin-2- yl}phenol 46 ¹ 5-(1H-pyrazol-4-yl)-2-{5-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin- 'TV 2-yl}phenol 47 ¹ 5-(pyrimidin-2-yl)-2-{5-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin- ‘τ / 2-yl}phenol ^4R1 5-(pyridin-2-yl)-2-{5-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin-2- 'That yl}phenol ^4Q1 5-(6-methoxypyrimidin-4-yl)-2-{5-[(2,2,6,6-tetramethylpiperidin-4- BC yl)amino]pyrazin-2-yl}phenol SP ¹ 5-(1H-imide azol-1-yl)-2-{5-[(2,2,6,6-tetramethylpiperide in-4- □ν yl)amino]pyrazin-2-yl}phenol 51 ¹ 2-{5-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin-2-yl}-5-(2H-1,2,3- DA triazol-2-yl)phenol 52 ¹ 2- {5- [3 - (tert-butylamino) pyrrolidin-1 -yl] pyrazin-2-yl} -5- ( 1 H-pyrazol-4- yl)phenol 53 ¹ 5-(imidazo[1,2-a]pyrazin-6-yl)-2-{5-[(2,2,6,6-tetramethylpiperidin-4- JJ yl)amino]pyrazin-2-yl}phenol 54 ¹ 5-(Hmethyl-1H-pyrazol-4-yl)-2-{5-[(2,2,6,6-tetramethylpiperidin-4-

- 13 041957

56 ¹

57 ¹

58 ¹

59 ¹

60 ¹

61 ¹

62 ¹

63 ¹

64 ¹

65 ¹ yl)amino]pyrazin-2-yl}phenol

5-(1-methyl-1H-pyrazol-3-yl)-2-{5-[(2,2,6,6-tetramethylpiperidin-4yl)amino]pyrazin-2-yl}phenol

5-(imidazo[1,2-b]pyridazin-6-yl)-2-{5-[(2,2,6,6-tetramethylpiperidin-4yl)amino]pyrazin-2-yl}phenol

5-(5-fluoro-1H-pyrazol-4-yl)-2-{5-[(2,2,6,6-tetramethylpiperidin-4yl)amino]pyrazin-2-yl}phenol

5-(1H-pyrazol-3-yl)-2-{5-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin2-yl (phenol

5-(4-fluoro-1H-pyrazol-1-yl)-2-{5-[(2,2,6,6-tetramethylpiperidin-4yl)amino]pyrazin-2-yl}phenol

2- {5- [3 - (tert-butylamino) pyrrolidin-1 -yl] pyrazin-2-yl } -5- [ 1 - ( ² H3) methyl-1Hpyrazol-4-yl] phenol

2-{5-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin-2-yl}-5-(2H-

1,2,3-triazol-2-yl)phenol

2- {5- [3 - (tert-butylamino) pyrrolidin-1 -yl] pyrazin-2-yl } -5- ( 1 -methyl-1H- pyrazol-4-yl) phenol

L-tert-butyl-1-{5-[2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl]pyrazin-2yl}pyrrolidin-3-amine

L-tert-butyl-1-{5-[2,5-difluoro-4-(1H-pyrazol-4-yl)phenyl]pyrazin-2yl}pyrrolidin-3-amine and

2-{5-[3-(tert-butylamino)pyrrolidin-1-yl]pyrazin-2-yl}-5-(3-fluoro-1Hpyrazol-4-yl)phenol;

where the form of the compound is selected from the group consisting of its salt form, hydrate, solvate, racemate, enantiomer, diastereomer, stereoisomer and tautomer.

Another aspect of a compound of formula (I) or a form thereof is a salt of the compound selected from the group consisting of the following:

Comm. Name

5-(1H-pyrazol-4-yl)-2-{5-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyrazin-22yl}phenol hydrochloride

2-[5-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrazin-2-yl]-5-(1H-pyrazol6 4-yl)phenol tetrahydrochloride

2-{5-[(piperidin-4-yl)oxy]pyrazin-2-yl}-5-(1H-pyrazol-4-yl)phenol trihydrochloride

- 14 041957

2-{5-[(Piperidin-4-yl)amino]pyrazin-2-yl}-5-(1H-pyrazol-4-yl)phenol tetrahydrochloride

2-[2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl]-5-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyrazine trihydrochloride

5-[2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl]-LH-methyl-N-(2,2,6,613 tetramethylpiperidin-4-yl)pyrazin-2-amine hydrochloride

2-[5-(8-azabicyclo[3.2.1]oct-3-yloxy)pyrazin-2-yl]-5-(1H-pyrazol-425yl)phenol hydrochloride

2-{5-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin-2-yl}-5-(1H-pyrazol-4-yl)phenol hydrobromide

5- [ 1 - ( ² H3)methyl-1 H-pyrazol-4-yl] -2- {5- [methyl (2,2,6,6-tetramethylpiper idin-4 yl) amino] pyrazin-2- yl}phenol dihydrochloride

5-(3-Fluoro-1H-pyrazol-4-yl)-2-{5-[methyl(2,2,6,6-tetramethylpiperidin-443yl)amino]pyrazin-2-yl}phenol dihydrochloride

5-(pyridin-4-yl)-2-{5-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin-244yl}phenol formate

5-(pyridin-3-yl)-2-{5-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin-245yl}phenol formate

5-(1Н-pyrazol-4-yl)-2-{5-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin46 2-yl}phenol formate

5-(pyrimidin-2-yl)-2-{5-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin47 2-yl}phenol formate

5-(pyridin-2-yl)-2-{5-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin-248yl}phenol formate

5-(6-methoxypyrimidin-4-yl)-2-{5-[(2,2,6,6-tetramethylpiperidin-449 yl)amino]pyrazin-2-yl}phenol formate

Phenol formate

2-{5-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin-2-yl}-5-(2H-1,2,351 triazol-2-yl)phenol formate

2-{5-[3-(tert-Butylamino)pyrrolidin-1-yl]pyrazin-2-yl}-5-(1H-pyrazol-452yl)phenol dihydrochloride

5-(imidazo[1,2-a]pyrazin-6-yl)-2-{5-[(2,2,6,6-tetramethylpiperide in-453yl)amino]pyrazin-2-yl}phenol formate

- 15 041957

5-(1-methyl-1H-pyrazol-4-yl)-2-{5-[(2,2,6,6-tetramethylpiperidin-454 yl)amino]pyrazin-2-yl}phenol formate

5-(imidazo[1,2-b]pyridazin-6-yl)-2-{5-[(2,2,6,6-tetramethylpiperidin-456yl)amino]pyrazin-2-yl}phenol formate

5-(5-Fluoro-1Н-pyrazol-4-yl)-2-{5-[(2,2,6,6-tetramethylpiperidin-457 yl)amino]pyrazin-2-yl}phenol formate

5-(1Н-pyrazol-3-yl)-2-{5-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin58 2-yl}phenol formate

Phenol formate

2-{5-[3-(tert-Butylamino)pyrrolidin-1-yl]pyrazin-2-yl}-5-[1-( ^2H3 )methyl-1H60 pyrazol-4-yl]phenol dihydrochloride

2-{5-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin-2-yl }-5-(2H61 1,2,3-triazol-2-yl)phenol dihydrochloride

2-{5-[3-(tert-Butylamino)pyrrolidin-1-yl]pyrazin-2-yl}-5-(1-methyl-1H62 pyrazol-4-yl)phenol dihydrochloride

M-tert-butyl-1-{5-[2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl]pyrazin-263yl}pyrrolidin-3-amine dihydrochloride

M-tert-butyl-1-{5-[2,5-difluoro-4-(1H-pyrazol-4-yl)phenyl]pyrazin-264yl}pyrrolidin-3-amine dihydrochloride and

2-{5-[3-(t-butylamino)pyrrolidin-1-yl]pyrazin-2-yl}-5-(3-fluoro-1H65 pyrazol-4-yl)phenol dihydrochloride;

where the form of the compound is selected from the group consisting of its salt form, hydrate, solvate, racemate, enantiomer, diastereomer, stereoisomer and tautomer.

One aspect of the present disclosure includes a method for preventing, treating, or alleviating 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.

One aspect of the present disclosure includes a method of treating or alleviating 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 disclosure includes a method of treating or alleviating HD in a subject in need thereof, comprising administering to the subject an effective amount of a salt of a compound of formula (I) or a form thereof.

One aspect of the present disclosure includes a method of using a compound of formula (I) or a form or composition thereof to treat or alleviate HD in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I) or a form or composition thereof.

Another aspect of the present disclosure includes a method of using a salt of a compound of formula (I) or a form or composition thereof to treat or alleviate HD in a subject in need thereof, comprising administering to the subject an effective amount of a salt of a compound of formula (I) or a form thereof.

One aspect of the present disclosure includes the use of a compound of formula (I) or a form thereof for treating or alleviating HD in a subject in need thereof, which comprises administering to the subject an effective amount of a compound of formula (I) or a form thereof.

Another aspect of the present disclosure includes the use of a salt of a compound of formula (I) or a form thereof to treat or alleviate HD in a subject in need thereof, which comprises administering to the subject an effective amount of a salt of the compound of formula (I) or a form thereof.

One aspect of the present disclosure includes the use of a compound of formula (I) or a form thereof for the manufacture of a medicament for the treatment or alleviation of HD in a subject in need thereof, which comprises administering to the subject an effective amount of the drug.

Another aspect of the present disclosure includes the use of a salt of a compound of formula (I) or a form thereof for the preparation of a medicament for the treatment or alleviation of HD in a subject in need thereof, which comprises administering to the subject an effective amount of the drug.

One aspect of the present disclosure includes the use of a compound of formula (I), or a form thereof, in a combination product with one or more therapeutic agents for the treatment or

Alleviating HD in a subject in need thereof, which comprises administering to the subject an effective amount of a compound of formula (I) or a form thereof in combination with an effective amount of one or more agents.

Another aspect of the present disclosure includes the use of a salt of a compound of formula (I) or a form thereof in a combination product with one or more therapeutic agents for the treatment or alleviation of HD in a subject in need thereof, which comprises administering to the subject an effective amount of a salt of the compound of formula (I) or its form in combination with an effective amount of one or more agents.

Chemical definitions

The chemical terms used above and throughout the description, unless specifically stated otherwise, are to be understood by those skilled in the art as having the following indicated meanings.

In the context of this application, the term _{C1_4} alkyl generally refers to saturated hydrocarbon radicals having from one to four carbon atoms in a linear or branched chain configuration, including, but not limited to, methyl, ethyl, n-propyl (also referred to as as propyl or propanyl), isopropyl, n-butyl (also referred to as butyl or butanyl), isobutyl, sec-butyl, tert-butyl, and the like. _C1 . _{The 4αalkyl} radical is optionally substituted with the substituent groups described herein, where available valences permit.

As used herein, the term _{C2_4} alkenyl generally refers to partially unsaturated hydrocarbon radicals having two to four carbon atoms in a straight or branched chain configuration and one or more carbon-carbon double bonds therein, including but not limited to that, ethenyl (also referred to as vinyl), allyl, propenyl, and the like. The _{C2_4} alkenyl radical is optionally substituted with the substituent groups described herein, where available valences permit.

In the context of this application, the term C2. ₈ alkynyl generally refers to partially unsaturated hydrocarbon radicals having two to eight carbon atoms in a straight or branched chain configuration and one or more carbon-carbon triple bonds therein, including but not limited to ethynyl, propynyl, butynyl, etc. In some aspects, C ₂ _ ₈ alkynyl includes, but is not limited to, C 2 _ ₆ alkynyl, C 2 _ ₄ alkynyl, and the like. The _{C2_8} alkynyl radical is optionally substituted with the substituent groups described herein, where available valences permit.

In the context of this application, the term C^alkoxy generally refers to saturated hydrocarbon radicals having from one to four carbon atoms in a linear or branched chain configuration, of the formula -O-C ₁ - ₄ alkyl, including, but not limited to, methoxy, ethoxy, npropoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, and the like. The C _1-4 alkoxy radical is optionally substituted with the substituent groups described herein, where available valences permit.

In the context of this application, the term C ₃ _ ₁₀ cycloalkyl generally refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic hydrocarbon radical, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, and the like. . The C ₃ _ ₁₀ cycloalkyl radical is optionally substituted with the substituent groups described herein, where available valences permit.

In the context of this application, the term aryl generally refers to a monocyclic, bicyclic or polycyclic aromatic radical with a ring structure of carbon atoms, including, but not limited to, phenyl, naphthyl, anthracenyl, fluorenyl, azulenyl, phenanthrenyl, and the like. The aryl radical is optionally substituted with the substituent groups described herein, where available valences permit.

In the context of this application, the term heteroaryl generally refers to a monocyclic, bicyclic or polycyclic aromatic radical with a carbon ring structure in which one or more carbon atoms that are ring members have been substituted, where possible from the point of view of the stability of the structure , one or more heteroatoms such as an O, S, or N atom, including, but not limited to, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, 1,3-thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, indolyl, indazolyl, indolizinyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, 1,3-benzothiazolyl, 1,3benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, 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]pyrr olyl, thieno[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, 1Hpyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl, 1H-pyrrolo[3, 2-b]pyridinyl, pyrrolo[1,2a]pyrazinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrazinyl, imidazo[1,2- a]pyridinyl, 3H-imidazo[4,5-b]pyridinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2c]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

- 17 041957

etc. The heteroaryl radical is optionally substituted on the ring member carbon or nitrogen atom with the substituent groups described herein, where available valences permit.

In some aspects, the nomenclature for the heteroaryl radical may differ, for example, 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 referred to as 1,3benzooxazolyl.

In some other aspects, the term for a heteroaryl radical may also include other regioisomers, for example, 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, etc. .p., the term imidazolyl may also include 1H-imidazolyl and the like, the term triazolyl may also include 1H1,2,3-triazolyl and the like, the term oxadiazolyl may also include 1,2,4-oxadiazolyl, 1 ,3,4oxadiazolyl 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 indazolyl may also include 1H-tetrazolyl, 2H -indazolyl and the like, the term benzoimidazolyl may also include 1H-benzoimidazolyl, and the term purinyl may also include 9H-purinyl and the like.

In the context of this application, the term heterocyclyl generally refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic radical with a ring structure of carbon atoms in which one or more carbon atoms that are ring members have been substituted, where possible from the point of view structural stability, a heteroatom such as an O, S or N atom, including but not limited to oxiranyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, isoxazolinyl, isoxazolidinyl, isothiazolinyl, isothiazolidinyl, oxazolinyl , oxazolidinyl, thiazolinyl, thiazolidinyl, triazolidinyl, triazolidinyl, oxadiazolidinyl, oxadiazolidinyl, thiadiazolidinyl, thiadiazolidinyl, tetrazolinyl, tetrazolidinyl, pyranyl, dihydro-2H-pyranyl, thiopyranyl, 1,3-dioxanyl, 1,2,5,6-tetrahydropyridinyl, 1,3-dioxanyl, 1,2,5,6-tetrahydropyridinyl ,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,4-diaz epanyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl, 2,3dihydro-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]pyrrolo-(2Н)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(2Н)-yl, hexahydropyrrolo[3,4- c]pyrrol-(1H)-yl, (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-(III)-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, (4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridinyl, hexahydropyrrolo[1,2-a]pyrazin(1H)-yl, (7R,8aS)-hexahydropyrrolo[1,2-a]pyrazine -(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)- he, octahydro2H-pi rido[1,2-a]pyrazinyl, 3-azabicyclo[3.1.0]hexyl, (1R,5S)-3-azabicyclo[3.1.0]hexyl, 8azabicyclo[3.2.1]octyl, (1R,5S)- 8-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]oct-2-enyl, (1R,5S)-8azabicyclo[3.2.1]oct-2-enyl, 9-azabicyclo[3.3.1] nonyl, (1R,5S)-9-azabicyclo[3.3.1]nonyl, 2,5diazabicyclo[2.2.1]heptyl, (1S,4S)-2,5-diazabicyclo[2.2.1]heptyl, 2,5- diazabicyclo[2.2.2]octyl, 3,8diazabicyclo[3.2.1]octyl, (1R,5S)-3,8-diazabicyclo[3.2.1]octyl, 1,4-diazabicyclo[3.2.2]nonyl, azaspiro[ 3.3]heptyl, 2,6-diazaspiro[3.3]heptyl, 2,6-diazaspiro[3.4]octyl, 2,7-diazaspiro[3.5]nonyl, 5,8diazaspiro[3.5]nonyl, 2,7-diazaspiro[4.4] nonyl, 6,9-diazaspiro[4.5]decyl, 7-azadispiro[5.1.5 ⁸ .3 ⁶ ]hexadecanyl, etc.

The heterocyclyl radical is optionally substituted on the carbon or nitrogen ring atom with the substituent groups described herein, where available valences permit.

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

In the context of the present application, the term C ₁ .4αlkoxy-C ₁ .4alkyl refers to a radical of formula -C1. ₄ alkyl-O-C ₁ .4 alkyl.

In the context of the present application, the term C ₁ .4alkoxy-C ₁ .4αalkylamino refers to a radical of the formula -NH-C ₁ .4αkyl-O-C ₁ - ₄ alkyl.

In the context of the present application, the term (C ₁ .4alkoxy-C ₁ .4alkyl)2-amino refers to a radical of the formula -N (C ₁ .4alkyl-O-C ₁ .4alkyl) 2 .

In the context of this application, the term C ₁ .4αlkoxy-C ₁ .4alkylamino-C ₁ .4alkoxy refers to a radical of the formula -O-C ₁ .4alkyl-NH-C ₁ .4αkyl-O-C ₁ .4alkyl.

In the context of this application, the term (C ₁ .4αlkoxy-C ₁ .4αkyl)2-amino-C ₁ .4alkoxy refers to a radical of the formula -O-C ₁ .4alkyl-N(C ₁ .4alkyl-O-C ₁ .4alkyl) 2.

- 18 041957

In the context of this application, the term (C _1-4 alkoxy-C _1-4 alkyl)(C _1-4 alkyl)amino-C _1-4 alkoxy refers to a radical of the formula -OC _1-4 alkyl-N(C _1-4 alkyl )(C _1-4 alkyl-O-C _1-4 alkyl).

In the context of this application, the term C _1-4 alkoxy-C _1-4 alkylamino-C _1-4 alkyl refers to a radical of the formula -C _1-4 alkyl-NH-C _1-4 alkyl-O-C _1-4 alkyl.

In the context of this application, the term (C _1-4 alkoxy-C _1-4 alkyl)2-amino-C _1-4 alkyl refers to a radical of formula -C _1-4 alkyl-N(C _1-4 αalkyl-O-C _{1 -4} alkyl) ₂ .

In the context of this application, the term (C _1-4 alkoxy-C _1-4 αalkyl)(C _1-4 αalkyl)amino-C _1-4 αalkyl refers to a radical of the formula -C _1-4 alkyl-N(C _1-4 alkyl )(C _1-4 alkyl-O-C _1-4 alkyl).

In the context of the present application, the term C _1-4 αlkoxycarbonyl refers to a radical of the formula -C(O)O-C _1-4 αkyl.

In the context of the present application, the term C _1-4 alkoxycarbonyl-C _2-8 alkenyl refers to a radical of formula -C _2-8 alkenyl-C(O)-O-C _1-4 alkyl.

In the context of this application, the term C _1-4 alkoxycarbonylamino refers to a radical of the formula -NH-C(O) -O -C । _-4 alkyl.

In the context of this application, the term C _1-4 alkylamino refers to a radical of the formula -NH-C _1-4 alkyl.

In the context of the present application, the term (C _1-4 αkyl) ₂ -amino refers to a radical of the formula -N(Ci _-4 alkyl) ₂ .

In the context of this application, the term C _1-4 alkylamino-C _2-8 alkenyl refers to a radical of the formula -C _2-8 alkenyl-NH-C _1-4 alkyl.

In the context of the present application, the term (C _1-4 alkyl) ₂ -amino-C _2-8 alkenyl refers to a radical of formula -C _2-8 alkenyl-N(C _1-4 αkyl) ₂ .

In the context of this application, the term C _1-4 alkylamino-C _1-4 alkoxy refers to a radical of the formula -O-C1 _-4 alkyl-NH -C । _-4 alkyl.

In the context of this application, the term (C _1-4 alkyl) ₂ -amino-C _1-4 alkoxy refers to a radical of the formula -O-C _{1 -4} alkyl-N (C 1 _-4 alkyl) ₂ .

In the context of this application, the term C _1-4 alkylamino-C _1-4 alkyl refers to a radical of the formula -C _1-4 αkyl-NH-C _{1 -4} alkyl.

In the context of the present application, the term (C _1-4 alkyl) ₂ -amino-C _1-4 alkyl refers to a radical of formula -C _1-4 alkyl-N(C _1-4 alkyl) ₂ .

In the context of this application, the term C _1-4 alkylamino-C _1-4 alkylamino refers to a radical of the formula -NH-C _1-4 alkyl-NH-C _1-4 αkyl.

In the context of the present application, the term (C _1-4 alkyl) ₂ -amino-C _1-4 alkylamino refers to a radical of the formula -NH-C _1-4 alkyl-N(C _1-4 alkyl) ₂ .

In the context of this application, the term (C _1-4 alkylamino-C _1-4 alkyl) ₂ -amino refers to a radical of the formula -N(C _1-4 alkyl-NH-C _1-4 alkyl) ₂ .

In the context of this application, the term [(C _1-4 alkyl) ₂ -amino-C _1-4 alkyl] ₂ -amino refers to a radical of the formula -N[C _1-4 alkyl-N(C _1-4 alkyl) ₂ ] ₂ .

In the context of this application, the term (C _1-4 alkylamino-C _1-4 alkyl)(C _1-4 alkyl)amino refers to a radical of the formula -N(C _1-4 alkyl)(C _1-4 alkyl-NH-C _{1 -4} alkyl).

In the context of this application, the term [(C _1-4 alkyl) ₂ -amino-C _1-4 alkyl](C _1-4 alkyl)amino refers to a radical of the formula -N(C _1-4 alkyl)[C _1-4 alkyl -N(C _1-4 alkyl) ₂ ].

In the context of the present application, the term C _1-4 alkylamino-C _2-8 alkynyl refers to a radical of formula -C _2-8 alkynyl-NH-C _1-4 alkyl.

In the context of the present application, the term (C _1-4 alkyl) ₂ -amino-C _2-8 alkynyl refers to a radical of formula -C _2-8 alkynyl-N(C _1-4 alkyl) ₂ .

In the context of the present application, the term C _1-4 alkylcarbonyl refers to a radical of the formula -C(O)C1-4 alkyl.

In the context of this application, the term C _1-4 alkylcarbonylamino refers to a radical of the formula -NH-C(O) -C । _-4 alkyl.

In the context of the present application, the term C _1-4 alkyl-thio refers to a radical of formula -SC _1-4 alkyl.

In the context of the present application, the term amino-C _2-8 alkenyl refers to a radical of the formula -C _2-8 alkenyl-NH ₂ .

In the context of this application, the term amino-C _1-4 alkoxy refers to a radical of the formula -O-C _1-4 alkyl-NH ₂ .

In the context of this application, the term amino-C _1-4 alkyl refers to a radical of the formula -C _1-4 alkylNH2.

In the context of this application, the term amino-C _1-4 alkylamino refers to a radical of the formula -NHC _1-4 αkyl-NH ₂ .

In the context of the present application, the term (amino-C _1-4 alkyl) ₂ -amino refers to a radical of the formula -N(C _1-4 alkyl-NH ₂ ) ₂ .

In the context of this application, the term (amino-C _1-4 alkyl)(C _1-4 alkyl)amino refers to the radical

- 19 041957 formula -N (C _1-4 αkyl)(C _1-4 alkyl-NH ₂ ).

In the context of the present application, the term amino-C _2-8 alkynyl refers to a radical of the formula -C _2-8 alkynyl-NH ₂ .

In the context of this application, the term aryl-C _1-4 alkoxycarbonyl refers to a radical of the formula

-C(O)-O -C _1-4 alkylaryl.

In the context of this application, the term aryl-C _1-4 alkyl refers to a radical of formula -C _1-4 alkylaryl.

In the context of this application, the term aryl-C _1-4 alkylamino refers to a radical of the formula -NHC _1-4 αkylaryl.

In the context of this application, the term (aryl-C _1-4 alkyl) ₂ -amino refers to a radical of the formula -N(C _1-4 alkylaryl) ₂ .

In the context of the present application, the term (aryl-C _1-4 alkyl)(C _1-4 αkyl)amino refers to a radical of formula -N(C _1-4 αkyl)(C _1-4 alkylaryl).

In the context of this application, the term aryl-C _1-4 alkylamino-C _1-4 alkyl refers to a radical of formula -C _1-4 alkyl-NH-C _1-4 alkylaryl.

In the context of the present application, the term (aryl-C _1-4 alkyl) ₂ -amino-C _1-4 alkyl refers to a radical of formula -C _1-4 αkyl-N(C _1-4 alkylaryl) ₂ .

In the context of this application, the term (aryl-C _1-4 alkyl)(C _1-4 αkyl)amino-C _1-4 alkyl refers to a radical of the formula -C _1-4 alkyl-N(C _1-4 alkyl)(C _{1 -4} alkylaryl).

In the context of this application, the term arylamino refers to a radical of the formula -NH-aryl.

In the context of the present application, the term arylaminocarbonyl refers to a radical of the formula -C(O)NH-aryl.

In the context of the present application, the term arylsulfonyloxy-C _1-4 αkyl refers to a radical of the formula -C _1-4 alkyl-O-SO ₂ -aryl.

In the context of this application, the term benzoxycarbonyl refers to a radical of the formula -C(O)-OCH ₂ -phenyl.

In the context of the present application, the term C _3-14 cycloalkyl-C _1-4 αalkyl refers to a radical of the formula -C _1-4 alkyl-C _3-14 cycloalkyl.

In the context of the present application, the term C _3-14 cycloalkylamino refers to a radical of the formula -NHC _3-14 cycloalkyl.

In the context of the present application, the term C _3-14 cycloalkyloxy refers to a radical of the formula -O-C _3-14 cycloalkyl.

In the context of this application, the term deutero-C _1-4 alkyl, refers to a radical of the formula -C _1-4 alkyldeutero, where C _1-4 alkyl is partially or completely substituted with one or more deuterium atoms, where available valences allow.

In the context of this application, the term halo or halogen generally refers to a halogen radical, including fluorine, chlorine, bromine and iodine.

In the context of this application, the term halo-C _1-4 αlkoxy refers to a radical of the formula -O-C _1-4 alkyl halo, where C _1-4 alkyl is partially or completely substituted by one or more halogen atoms, where available valences allow.

In the context of this application, the term halo-C _1-4 alkyl refers to a radical of the formula -C _1-4 alkyl halo, where C _1-4 alkyl is partially or completely substituted by one or more halogen atoms, where available valences allow.

In the context of this application, the term halo-C _1-4 alkylamino refers to a radical of the formula -NH-C _1-4 alkyl-halogen.

In the context of the present application, the term (halo-C _1-4 alkyl)(C _1-4 alkyl)amino refers to a radical of the formula -N (C _1-4 alkyl)(C _1-4 alkyl halo).

In the context of the present application, the term (halo-C _1-4 alkyl) ₂ -amino refers to a radical of formula -N (C _1-4 alkyl-halo) ₂ .

In the context of this application, the term heteroaryl-C _1-4 alkoxy refers to a radical of the formula -OC _1-4 alkyl-heteroaryl.

In the context of this application, the term heteroaryl-C _1-4 alkyl refers to a radical of the formula -C _1-4 alkyl-heteroaryl.

In the context of this application, the term heteroaryl-C _1-4 alkylamino refers to a radical of the formula -NH-C _1-4 alkyl-heteroaryl.

In the context of the present application, the term (heteroaryl-C _1-4 alkyl) ₂ -amino refers to a radical of the formula -N(C _1-4 alkyl-heteroaryl) ₂ .

In the context of the present application, the term (heteroaryl-C _1-4 alkyl)(C _1-4 alkyl)amino refers to a radical of the formula -N(C _1-4 alkyl)(C _1-4 αalkyl-heteroaryl).

In the context of this application, the term heteroaryl-C _1-4 alkylamino-C _1-4 alkyl refers to a radical of formula -C _1-4 αkyl-NH-C 1 _-4 alkyl-heteroaryl.

In the context of the present application, the term (heteroaryl-C _1-4 alkyl) ₂ -amino-C _1-4 alkyl refers to a radical of the formula -C ₁ . ₄ alkyl-N(C ₁ . ₄ αalkyl-heteroaryl) ₂ .

In the context of this application, the term (heteroaryl-C _{1 .4} alkyl)(C _{1 .4} alkyl)amino-C ₁ . ₄ alkyl refers to a radical of the formula -C ₁ . ₄ alkyl-N(C _{1 .4} alkyl)(C _{1 .4} alkyl-heteroaryl).

In the context of this application, the term heteroarylamino refers to a radical of the formula -NHheteroaryl.

In the context of this application, the term heterocyclyl-C ₁ . ₄ αlkoxy refers to a radical of the formula -O-C _1-4 alkyl-heterocyclyl.

In the context of this application, the term heterocyclyl-C ₁ . ₄ alkyl refers to a radical of the formula -C1_ ₄ alkyl-heterocyclyl.

In the context of this application, the term heterocyclyl-C ₁ . ₄ alkylamino refers to a radical of the formula -NH-C ₁ . ₄ alkyl-heterocyclyl.

In the context of the present application, the term (heterocyclyl-C _{1 .4} alkyl) ₂ -amino refers to a radical of the formula -N(C _{1 .4} αalkyl-heterocyclyl) ₂ .

In the context of this application, the term (heterocyclyl-C _{1 .4} alkyl)(C _{1 .4} alkyl)amino refers to a radical of the formula -N(C _{1 .4} alkyl)(C _{1 .4} alkyl-heterocyclyl).

In the context of this application, the term heterocyclyl-C ₁ . ₄ alkylamino-C ₁ . ₄ alkyl refers to a radical of the formula -C ₁ . ₄ alkyl-NH-C ₁ . ₄ alkyl-heterocyclyl.

In the context of this application, the term (heterocyclyl-C ₁ . ₄ alkyl) ₂ -amino-C ₁ . ₄ alkyl refers to a radical of the formula -C ₁ . ₄ alkyl-N(C ₁ . ₄ alkyl-heterocyclyl) ₂ .

In the context of this application, the term (heterocyclyl-C _{1 .4} alkyl)(C _{1 .4} alkyl)amino-C ₁ . ₄ alkyl refers to a radical of the formula: -Cl. ₄ alkyl-N(Cl. ₄ alkyl)(Cl. ₄ alkyl-heterocyclyl).

In the context of the present application, the term heterocyclylamino refers to a radical of the formula -NHheterocyclyl.

In the context of the present application, the term (heterocyclyl)(C _{1 .4} alkyl)amino refers to a radical of the formula -N (C _{1 .4} alkyl)(heterocyclyl).

In the context of this application, the term heterocyclylamino-C ₁ . ₄ alkyl refers to a radical of the formula -C ₁ . ₄ alkyl-NH-heterocyclyl.

In the context of the present application, the term heterocyclyl-carbonyl refers to a radical of the formula -C(O)-heterocyclyl.

In the context of the present application, the term heterocyclyl-carbonyloxy refers to a radical of the formula -O-C(O)-heterocyclyl.

In the context of the present application, the term heterocyclyloxy refers to a radical of the formula -Oheterocyclyl.

In the context of the present application, the term hydroxy refers to a radical of the formula -OH.

In the context of this application, the term hydroxy-C ₁ . ₄ alkoxy-C ₁ . ₄ alkyl refers to a radical of the formula -C ₁ . ₄ alkyl-O-C ₁ . ₄ alkyl-OH.

In the context of this application, the term hydroxy-C ₁ . ₄ alkyl refers to a radical of the formula -C ₁ . ₄ alkyl-OH, where C ₁ . ₄ alkyl is partially or completely substituted with one or more hydroxy radicals, where available valences permit.

In the context of this application, the term hydroxy-C ₁ . ₄ alkylamino refers to a radical of the formula -NH-C ₁ . ₄ αlkyl-OH.

In the context of the present application, the term (hydroxy-C _{1 .4} alkyl) ₂ -amino refers to a radical of formula -N(C _{1 .4} αkyl-OH) ₂ .

In the context of this application, the term (hydroxy-C _{1 .4} alkyl)(C _{1 .4} alkyl)amino refers to a radical of the formula -N (C _{1 .4} αkyl)(C _{1 .4} alkyl-OH).

In the context of this application, the term hydroxy-C ₁ . ₄ alkyl-amino-C ₁ . ₄ αkyl refers to a radical of the formula -C ₁ . ₄ alkyl-NH-C ₁ . ₄ alkyl-OH.

In the context of this application, the term (hydroxy-C ₁ . ₄ alkyl) ₂ -amino-C ₁ . ₄ alkyl refers to a radical of the formula -C ₁ . ₄ αalkyl-N(C ₁ . ₄ alkyl-OH) ₂ .

In the context of this application, the term (hydroxy-C _{1 .4} alkyl)(C _{1 .4} αkyl)amino-C ₁ . ₄ alkyl refers to a radical of the formula -C ₁ . ₄ alkyl-N (C ₁ . ₄ alkyl) (C ₁ . ₄ αkyl-OH).

In the context of this application, the term hydroxy-C ₁ . ₄ alkylamino-C ₁ . ₄ alkoxy refers to a radical of the formula -O-C ₁ . ₄ αlkyl-NH-C ₁ . ₄ alkyl-OH.

In the context of this application, the term (hydroxy-C ₁ . ₄ alkyl) ₂ -amino-C ₁ . ₄ alkoxy refers to a radical of the formula -O-C ₁ . ₄ alkyl-N(C ₁ . ₄ αalkyl-OH) ₂ .

In the context of this application, the term (hydroxy-C _{1 .4} alkyl)(C _{1 .4} alkyl)amino-C ₁ . ₄ alkoxy refers to a radical of the formula -OC ₁ . ₄ alkyl-N (C ₁ . ₄ alkyl) (C ₁ . ₄ alkyl-OH).

In the context of this application, the term hydroxy-C ₁ . ₄ alkylamino-C ₁ . ₄ alkylamino refers to a radical of the formula -NH-C ₁ . ₄ alkyl-NH-C ₁ . ₄ alkyl-OH.

In the context of the present application, the term (hydroxy-C _{1 .4} αkylamino-C _{1 .4} alkyl) ₂ -amino refers to a radical of the formula -N(C _{1 .4} alkyl-NH-C _{1 .4} alkyl-OH) ₂ .

In the context of this application, the term (hydroxy-C ₁ . ₄ αkyl) ₂ -amino-C ₁ . ₄ alkylamino refers to

- 21 041957 to a radical of the formula -NH-C ₁ . ₄ αalkyl-N (С ₁ . ₄ αalkyl-OH) ₂ .

In the context of this application, the term (hydroxy-C _{1 .4} alkylamino-C _{1 .4} alkyl)(C _{1 .4} αkyl)amino refers to a radical of the formula -N(C _{1 .4} alkyl)(C _{1 .4} αalkyl-NH- C _{1.4 αkyl} -OH).

In the context of this application, the term [(hydroxy-C ₁ . ₄ alkyl) ₂ -amino-C ₁ . ₄ alkyl](C ₁ . ₄ alkyl) amino refers to a radical of the formula -N(C ₁ . ₄ alkyl)[C ₁ . ₄ alkyl-N(C ₁ . ₄ alkyl-OH) ₂ ].

In the context of this application, the term (hydroxy-C _{1 .4} alkyl)(C _{1 .4} alkyl)amino-C ₁ . ₄ alkylamino refers to a radical of the formula -NH-C ₁ . ₄ alkyl-N(C ₁ . ₄ alkyl, C ₁ . ₄ alkyl-OH).

In the context of this application, the term ''[(hydroxy-C _{1 .4} αkyl)(C _{1 .4} αkyl)amino-C ₁ . ₄ αkyl](C ₁ . ₄ αkyl)amino refers to a radical of the formula -N(C ₁ . ₄ alkyl)[C ₁ . ₄ alkyl-N (C ₁ . ₄ alkyl) (C ₁ . ₄ alkyl-OH)].

In the context of this application, the term substituent means positional variables on the atoms of the nucleus of a molecule that are substituted at the specified position of the atom with the replacement of one or more hydrogen atoms on the specified atom, provided that the normal valency of the specified atom is not exceeded, and that the substitution leads to a stable connection. Combinations of substituents and/or variables are allowed only if such combinations result in stable compounds. It will be appreciated by those skilled in the art that any carbon, as well as a heteroatom with valencies that are found to be unsaturated as described or shown herein, are expected to have sufficient hydrogen atom(s) to satisfy the valences described or shown. In some cases, one or more substituents having a double bond (for example, oxo or =O) as the point of attachment may be described, shown or listed in this application in the group of substituents, where the structure can only show a single bond as the point of attachment to structure of the core of formula (I). One skilled in the art will appreciate that although only a single bond is shown, a double bond is contemplated for these substituents.

In the context of the present application, the term and the like. with reference to the definitions of chemical terms provided in this application means that variations in chemical structures that a person skilled in the art can expect include, without limitation, isomers (including chains, branching or positional structural isomers), hydration of ring systems ( including saturation or partial unsaturation of monocyclic, bicyclic or polycyclic ring structures) and all other variations, if allowed by the available valences, which result in a stable compound.

For the purposes of this specification, where one or more variables, such as substituents for a compound of formula (I) or a form thereof, encompasses functional groups included in a compound of formula (I), each functional group at any position in the disclosed compound may be independently selected and , if necessary, independently and/or optionally substituted.

In the context of this application, the terms independently selected or each selected refer to functional variables in a list of substituents that may occur more than once in the structure of formula (I), with the pattern of substitution in each case independent of the pattern in any other case. In addition, the use of a generic substituent in any formula or structure for a compound described herein is intended to include replacing the generic substituent with species substituents that are included in the particular genus, e.g., aryl can be replaced by phenyl or naphthalene, and the like. , and that the resulting compound should be included in the scope of the compounds described in this application.

In the context of this application, the terms are intended to be used in each case or in each case when present when used before a phrase such as ...C ₃ _ ₁₄ cycloalkyl, C ₃ - ₁₄ cycloalkylC ₁ . ₄ alkyl, aryl, aryl-C ₁ . ₄ alkyl, heteroaryl, heteroaryl-C ₁ . ₄ alkyl, heterocyclyl and heterocyclyl-C ₁ . ₄ alkyl refer to C ₃ _ ₁₄ cycloalkyl, aryl, heteroaryl and heterocyclyl ring systems when each of them is present either alone or as a substituent.

In the context of this application, the term optionally substituted means optional substitution with the indicated substituents, groups, radicals or fragments.

Connection forms

In the context of this application, the term form means a compound of formula (I) having a form selected from the group consisting of its free acid, free base, prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer.

In some aspects described in this application, the form of the compounds of formula (I) is its free acid, free base or salt.

In some aspects described in this application, the form of the compounds of formula (I) is its salt.

In some aspects described in this application, the form of the compounds of formula (I) is its isotopologue.

In some aspects described in this application, the form of the compounds of formula (I) is its stereoisomer, racemate, enantiomer or diastereomer.

- 22 041957

In some aspects described in this application, the form of the compounds of formula (I) is its tautomer.

In some aspects described in this application, the form of the compounds of formula (I) is its pharmaceutically acceptable form.

In some aspects described in this application, the compound of formula (I) or its form are isolated for use.

In the context of this application, the term isolated means the physical state of a compound of formula (I) or a form thereof after isolation and/or purification from a synthetic process (for example, from a reaction mixture) or a natural source, or a combination thereof, in accordance with the method or methods of isolation or purification described in this application or which are well known to those skilled in the art (eg, chromatography, recrystallization, etc.), with sufficient purity to be characterized by standard analytical methods described in this application or well known to experienced specialists.

In the context of the present application, the term protected means that the functional group in the compound of formula (I) or in its form is in a form modified to prevent unwanted side reactions at the protected site when the connection is subjected to interaction. Suitable protecting groups should be known to those skilled in the art and can also be found in standard reference books 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. Suitable protecting groups for hydroxy or phenol include trialkylsilyl or diarylalkylsilyl (eg, t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, substituted benzyl, methyl, methoxymethanol, and the like. Suitable protecting groups for amino, amidino, and guanidino include t-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitable protecting groups for a carboxylic acid include alkyl, aryl or arylalkyl esters. In some cases, the protecting group may also be a polymer resin such as Wang resin or 2-chlorotrityl chloride resin. Protecting groups may be added or removed in accordance with standard methods that are well known to those skilled in the art and as described herein. It should also be appreciated by those skilled in the art that while such protected derivatives of the compounds described herein may not have pharmacological activity per se, they may be administered to a subject and then metabolized in the body to form the compounds described herein. which are pharmacologically active. Therefore, such derivatives can be called prodrugs. All prodrugs of the compounds described in this application are included in the scope of use described in this application.

In the context of the present application, the term prodrug means a form of a compound of the present invention (eg, a drug precursor) which is converted in vivo to form the active compound of formula (I) or a form thereof. The conversion can occur through various mechanisms (eg, metabolic and/or non-metabolic chemical processes), such as, for example, hydrolysis and/or metabolism in the blood, liver and/or other organs and tissues. For a discussion of the use of prodrugs, see T. Higuchi and W. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

In one example, when a compound of formula (I) or a form thereof contains a carboxylic acid functional group, the prodrug may include an ester formed by replacing the hydrogen atom of the acidic group with a functional group such as alkyl and the like. In another example, when a compound of formula (I) or a form thereof contains a hydroxyl functional group, the prodrug form can be obtained by replacing the hydrogen atom of the hydroxyl with another functional group such as an alkyl, alkylcarbonyl, or phosphinic acid ester, and the like. In another example, when a compound of formula (I) or a form thereof contains an amine functional group, the prodrug form can be obtained by replacing one or more hydrogen atoms of the amine with a functional group such as an alkyl or substituted carbonyl. Pharmaceutically acceptable prodrugs of the compounds of formula (I) or forms thereof include compounds substituted with one or more of the following groups: carboxylic acid esters, sulfonic acid esters, amino acid esters, phosphinic acid esters and mono-, di- or triphosphate esters or alkyl substituents where appropriate. As described herein, those skilled in the art will appreciate that one or more of these substituents may be used to prepare a compound of formula (I) or a form thereof as a prodrug.

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

In the context of this application, the term solvate means the physical association of a compound,

- 23 041957 described in this application, with one or more solvent molecules. This physical association includes varying degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, the solvate may be isolated, for example, when one or more solvent molecules are included in the crystal lattice of a crystalline solid. In the context of the present application, a solvate encompasses both solution phase solvates and recoverable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like.

In the context of this application, the term hydrate means solvate, where the solvent molecule is water.

Compounds of formula (I) may form salts, which are intended to be included within the scope of this specification. Reference to a compound of formula (I) or form thereof in this application is intended to include reference to its salt forms, unless otherwise indicated. The term salt(s) in the context of the present application denotes acid salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. Furthermore, when a compound of formula (I) or a form thereof contains both an alkaline group, such as, but not limited to, an amino group, and an acidic group, such as, but not limited to, a carboxylic acid, zwitterions (internal salts) can be formed, and they are included in the term salt(s) as used in this application.

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

Pharmaceutically acceptable salts include one or more salts of acidic or alkaline groups present in the compounds described in this application. Specific aspects of acid addition salts include, but are not limited to, acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, bitartrate, 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, sucrose, salicylate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate (also known as tosylate), trifluoroacetate salts, etc. P. Some specific aspects of acid addition salts include chloride or dichloride.

In addition, acids that are generally considered suitable for the formation of pharmaceutically useful salts from alkaline pharmaceutical compounds are discussed, for example, in P. Stahl et al., Camille G. (eds.) Handbook of Pharmaceutical 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 website). These disclosures are incorporated into this application by reference.

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

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

The compounds of formula (I) and their forms may also exist in tautomeric form. All such tautomeric forms are intended to be included within the scope of the compounds of formula (I) or forms thereof as described herein.

The compounds of formula (I) or forms thereof may contain asymmetric or chiral centers and therefore exist in various stereoisomeric forms. The present description is intended to include 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 racemic mixtures (R/S) or as essentially pure enantiomers and diastereomers. Compounds can also exist as essentially pure (R) or (S) enantiomers (when one chiral center is present). In one specific aspect, the compounds described in this application are (S) isomers and can exist as enantiomerically pure compositions, essentially including only the (S) isomer. In another specific aspect, the compounds described in this application are (R) isomers and can exist as enantiomerically pure compositions, essentially including only the (R) isomer. As will be appreciated by those skilled in the art, when more than one chiral center is present, the compounds described in this application may also exist as (R,R), (R,S), (S,R) or (S,S) isomer as defined by the IUPAC Nomenclature Recommendations.

In the context of this application, the term essentially pure refers to compounds consisting essentially of a single isomer in an amount greater than or equal to 90%, greater than or equal to 92%, greater than or equal to 95%, greater than or equal to greater than or equal to 98%, in an amount greater than or equal to 99%, or in an amount equal to 100% of one isomer.

In one aspect of the description, a compound of formula (I) or a form thereof is the substantially pure (S) enantiomeric form present in an amount greater than or equal to 90%, greater than or equal to 92%, 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 essentially the pure (R) enantiomeric form present in an amount greater than or equal to 90%, greater than or equal to 92%, 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 the context of this application, racemate means any mixture of isomeric forms that are not enantiomerically pure, including mixtures such as, but not limited to, in a ratio of about 50/50, about 60/40, about 70/30, or about 80/20.

In addition, the present description covers all geometric and positional isomers. For example, if the compound of formula (I) or its form includes a double bond or a fused ring, both cis and trans forms, as well as mixtures, are covered by the scope of the description. Mixtures of diastereomers can be separated into individual diastereomers based on their physicochemical differences by methods well known to those skilled in the art, such as, for example, chromatography and/or fractional crystallization. Enantiomers can be separated using a chiral HPLC column or other chromatographic methods known to those skilled in the art. Enantiomers can also be separated by converting an enantiomeric mixture to a diastereomeric mixture by reacting with a suitable optically active compound (e.g., a chiral excipient such as a chiral alcohol or Mosher acid chloride), separating the diastereomers, and converting (e.g., by hydrolysis) the individual diastereomers to the corresponding pure enantiomers. In addition, some of the compounds of formula (I) may be atropisomers (eg, substituted biaryls) and are considered part of the present description.

All stereoisomers (e.g., geometric isomers, optical isomers, etc.) of the compounds of the invention (including salts, solvates, esters, and prodrugs of compounds, as well as salts, solvates, and esters of prodrugs), such as those which may exist due to asymmetric carbon atoms on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbon atoms), rotamer forms, atropisomers, and diastereomeric forms, are intended to be within the scope of this specification, as are position 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 described above.

Use of the terms salt, solvate, ester, prodrug, and the like. is intended to apply equally to the salt, solvate, ester, and prodrug of the enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates, or isotopologues of the compounds of the present invention.

The term isotopologue refers to compounds enriched in the isotopes described in this application, which are identical to those listed in this application, except 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 included in the compounds described in this application include isotopes ^of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ^2H , 3H, 13C, ^14C , ^15N , ^18O , ¹⁷ O, ³¹ P, ³² P, ³⁵ S, 18F, ³⁵ Cl and ³⁶ Cl, respectively, each of which is also included in the scope of this description.

Some of the isotopically enriched compounds described herein (eg, ³ H and ¹⁴ C labeled) are useful in tissue and/or substrate distribution assays. The isotopes of tritium (ie 3H) and carbon-14 (ie ¹⁴ C) are particularly preferred because of their ease of preparation and detection. In addition, substitution with heavier isotopes such as deuterium (i.e. ² H) may confer certain therapeutic advantages due to greater metabolic stability (e.g. increased in vivo half-life or reduced dosage requirements) and therefore may be preferred in some circumstances.

Polymorphic crystalline and amorphous forms of compounds of formula (I) and salts, solvates, hydrates, esters and prodrugs of compounds of formula (I) are also intended to be included

- 25 041957 in the present description.

Connection applications

Within the intended scope of the present disclosure, aspects of the present disclosure include compounds that have been identified and shown to be useful in the selective prevention, treatment, or alleviation of HD, and which are provided for use in the prevention, treatment, or alleviation of HD.

One aspect of the present disclosure includes a method for preventing, treating, or alleviating 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.

One aspect of the present disclosure includes a method of treating or alleviating 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.

One aspect of the present disclosure includes 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.

One aspect of the present disclosure includes a method of 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.

One aspect of the present disclosure includes a method of alleviating 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 disclosure includes a method of treating or alleviating HD in a subject in need thereof, comprising administering to the subject an effective amount of a salt of a compound of formula (I) or a form thereof.

One aspect of the present disclosure includes a method of using a compound of formula (I) or a form or composition thereof to treat or alleviate HD in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I) or a form or composition thereof.

Another aspect of the present disclosure includes a method of using a salt of a compound of formula (I) or a form or composition thereof to treat or alleviate HD in a subject in need thereof, comprising administering to the subject an effective amount of a salt of a compound of formula (I) or a form thereof.

One aspect of the present disclosure includes the use of a compound of formula (I) or a form thereof for treating or alleviating HD in a subject in need thereof, which comprises administering to the subject an effective amount of a compound of formula (I) or a form thereof.

Another aspect of the present disclosure includes the use of a salt of a compound of formula (I) or a form thereof to treat or alleviate HD in a subject in need thereof, which comprises administering to the subject an effective amount of a salt of the compound of formula (I) or a form thereof.

One aspect of the present disclosure includes the use of a compound of formula (I) or a form thereof for the manufacture of a medicament for the treatment or alleviation of HD in a subject in need thereof, which comprises administering to the subject an effective amount of the drug.

Another aspect of the present disclosure includes the use of a salt of a compound of formula (I) or a form thereof for the preparation of a medicament for the treatment or alleviation of HD in a subject in need thereof, which comprises administering to the subject an effective amount of the drug.

One aspect of the present disclosure includes the in vitro or in vivo use of a compound of formula (I) or a form thereof having activity against HD.

One aspect of the present disclosure includes the use of a compound of formula (I) or a form thereof in combination therapy to provide an additive or synergistic effect, thus allowing the development of a combination product for the treatment or alleviation of HD.

Another aspect of the present disclosure includes a combination therapy comprising the compounds described herein in combination with one or more known drugs or one or more known therapies that can be used to treat HD whether or not HD responds to a known drug. .

One aspect of the present disclosure includes the use of a compound of formula (I) or a form thereof in a combination product with one or more therapeutic agents for the treatment or alleviation of HD in a subject in need thereof, which comprises administering to the subject an effective amount of a compound of formula (I) or a form thereof in combinations with an effective amount of one or more agents.

Another aspect of the present disclosure includes the use of a salt of a compound of formula (I) or a form thereof in a combination product with one or more therapeutic agents for the treatment or alleviation of HD in a subject in need thereof, which comprises administering to the subject an effective amount of a salt of the compound of formula (I) or its form in combination with an effective amount of one or more agents.

In one aspect of the use or method provided herein, the compounds of formula (I) or forms thereof, used in combination with one or more additional agents, can be administered to a subject or brought into contact with the subject's or patient's cell(s) prior to, simultaneously, or after administration to a subject or patient or contact of a cell with an additional

- 26 041957 body tool(s). The compound(s) of formula (I), or form thereof, and additional agent(s) may be administered to a subject or brought into contact with a cell in the same composition or different compositions. In a specific aspect, the compound(s) of formula (I), or a form thereof, is used in combination with gene therapy to inhibit the expression of HTT (using, for example, viral delivery vectors) or with the administration of another small molecule HTT inhibitor. In another specific aspect, the compound(s) of formula (I), or a form thereof, is used in combination with cell replacement using differentiated non-mutant HTT stem cells. In another specific aspect, the compound(s) of formula (I), or a form thereof, is used in combination with cell replacement using differentiated HTT stem cells.

In one aspect, the present application provides the use of compounds of formula (I) or forms thereof in combination with supportive standard care, including palliative care.

One aspect of the present disclosure includes the use of a compound of formula (I) or a form thereof to provide a kit for treating or alleviating HD in a subject in need thereof, comprising a compound of formula (I) or a form thereof and instructions for administering an effective amount of a compound of formula (I) or its forms.

One aspect of the present disclosure includes the use of a compound of formula (I) or a form thereof to provide a kit for treating or alleviating HD in a subject in need thereof, comprising a compound of formula (I) or a form thereof and instructions for administering an effective amount of a compound of formula (I) or its form; and, optionally, administering to the subject an effective amount of a compound of formula (I) or a form thereof in a combination product with an effective amount of one or more therapeutic agents.

One aspect of the present disclosure includes the use of a compound of formula (I) or a form thereof to provide a kit for treating or alleviating HD in a subject in need thereof, comprising a compound of formula (I) or a form thereof and instructions for administering an effective amount of a compound of formula (I) or its form; and, optionally, administering to the subject an effective amount of a compound of formula (I) or a form thereof in a combination product with an effective amount of one or more therapeutic agents; and optionally administering to the subject an effective amount of a compound of formula (I) or a form thereof in a combination product with an effective amount of one or more therapeutic agents in combination therapy with maintenance standard care, where the maintenance standard treatment is palliative care.

In one respect, for each of these aspects, the subject has not previously received treatment. In another respect, for each of these aspects, the subject has previously received treatment.

As used herein, the term prophylaxis refers to preventing the onset of a disease, disorder, or condition in a subject who may be predisposed to the disease, disorder, and/or condition but has not yet been diagnosed with the disease, disorder, and/or condition.

In the context of this application, the term treatment refers to the inhibition of the progression of a disease, disorder or condition in a subject already showing symptoms of the disease, disorder and/or condition, i. to stop the development of a disease, disorder and/or condition already suffering from the subject.

In the context of the present application, the term alleviation refers to the alleviation of the symptoms of a disease, disorder or condition in a subject already exhibiting symptoms of the disease, disorder and/or condition, i. to the induction of regression of the disease, disorder and/or condition already suffering from the subject.

In the context of this application, the term subject refers to an animal or any living organism that has sensations and the ability to voluntary movement, and which requires oxygen and organic food. Non-limiting examples include humans, primates, horses, pigs, cattle, mice, rats, dogs and cats. In some aspects, the subject is a mammal or a warm-blooded vertebrate. In other aspects, the subject is a human. In the context of this application, the term patient can be used interchangeably with subject and human.

In the context of this application, the terms effective amount or therapeutically effective amount means an amount of a compound of formula (I) or form, composition or drug that provides a target plasma concentration that is effective in treating or alleviating HD, as described in this application, causing, thus, the desired therapeutic, ameliorating, inhibitory, or prophylactic effect in a subject in need thereof. In one aspect, an effective amount may be the amount needed to treat HD in a subject or patient, more specifically a human.

In another aspect, the concentration-biological effect relationship observed for a compound of formula (I) or a form thereof indicates a target plasma concentration in the range of about 0.001 µg/mL to about 50 µg/mL, from about 0.01 µg/mL up to about 20 µg/mL, from about 0.05 µg/mL to about 10 µg/mL, or from about

- 27 041957

0.1 µg/ml to about 5 µg/ml. To achieve such plasma concentrations, the compounds described herein can 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 effective target plasma concentration may be administered depending on specific factors associated with the subject or patient, where doses administered based on body weight may be in the range of about 0.001 mg/kg/day up to about 3500 mg/kg/day, or from about 0.001 mg/kg/day to about 3000 mg/kg/day, or from about 0.001 mg/kg/day to about 2500 mg/kg/day, or from about 0.001 mg /kg/day to about 2000 mg/kg/day, or from about 0.001 mg/kg/day to about 1500 mg/kg/day, or from 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 from about 0.001 mg/kg/day to about 150 mg/kg/day, or from about 0.001 mg/kg/day to about 100 mg/kg/day, or from 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 about 25 mg/kg/day, or from about 0.001 mg/kg/day to about 10 mg/kg/day, or from about 0.001 mg/kg/day to about 5 mg/kg/day, or from about 0.001 mg/day kg/day to about 1 mg/kg/day, or from about 0.001 mg/kg/day to about 0.5 mg/kg/day, or from about 0.001 mg/kg/day to about 0.1 mg/kg/day day, or from about 0.01 mg/kg/day to about 3500 mg/kg/day, or from about 0.01 mg/kg/day to about 3000 mg/kg/day, or from about 0.01 mg/day kg/day to about 2500 mg/kg/day, or from about 0.01 mg/kg/day to about 2000 mg/kg/day, or from about 0.01 mg/kg/day to about 1500 mg/kg/day day, or from about 0.01 mg/kg/day to about 1000 mg/kg/day, or from about 0.01 mg/kg/day to about 500 mg/kg/day, or from about 0.01 mg/day kg/day to about 250 mg/kg/day, or from about 0.01 mg/kg/day to about 200 mg/kg/day, or from about 0.01 mg/kg/day to about 150 mg/kg/day day, or from about 0.01 mg/kg/day to about 100 mg/kg/day, or from about 0.01 mg/kg/day to about 75 mg/kg/day, or from about 0.01 mg/day kg/day up to about 50 mg/kg/day, or from about 0.01 mg/kg/day to about 25 mg/kg/day, or from about 0.01 mg/kg/day to about 10 mg/kg/day, or from about 0.01 mg/kg/day to about 5 mg/kg/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 from 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 from about 0.1 mg/day kg/day to about 3000 mg/kg/day, or from about 0.1 mg/kg/day to about 2500 mg/kg/day, or from about 0.1 mg/kg/day to about 2000 mg/kg/day day, or from about 0.1 mg/kg/day to about 1500 mg/kg/day, or from about 0.1 mg/kg/day to about 1000 mg/kg/day, or from about 0.1 mg/day kg/day to about 500 mg/kg/day, or from about 0.1 mg/kg/day to about 250 mg/kg/day, or from about 0.1 mg/kg/day to about 200 mg/kg/ day, or from about 0.1 mg/kg/day to about 150 mg/kg/day, or from about 0.1 mg/kg/day to about 100 mg/kg/day, or from about 0.1 mg/day kg/day to about 75 mg/kg/day, or from about 0.1 mg/kg/day to about 50 mg/kg/de n, or from about 0.1 mg/kg/day to about 25 mg/kg/day, or from about 0.1 mg/kg/day to about 10 mg/kg/day, or from about 0.1 mg/kg/day kg/day to about 5 mg/kg/day, or from about 0.1 mg/kg/day to about 1 mg/kg/day, or from about 0.1 mg/kg/day to about 0.5 mg/ kg/day.

Effective amounts for a given subject can be determined by routine experimentation, which is within the purview and judgment of the clinician or practitioner in the art in light of factors associated with the subject. Dosage and administration may be adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors that may be taken into account include genetic screening, disease severity, disease progression status, subject's general health, ethnicity, age, body weight, sex, diet, time of day and frequency of administration, drug combination(s). agents, allergic reactions, experience with other therapies, and tolerability/response to therapy.

The dose administered to achieve the effective target plasma concentration can be administered orally once (once in about a 24-hour period; i.e. qd), twice (once in about a 12-hour period; i.e. two times a day b.i.d. or q.l2h), three times (once per approximately 8-hour period; i.e. t.i.d. or q.8h) or four times (once per approximately 6-hour period; i.e. q.d.s., q.i.d. or q.6h) per day.

In some aspects, the dose administered to achieve an effective target plasma concentration may also be administered as a single, divided, or continuous dose to a patient or subject having a body weight in the range of about 40 to about 200 kg (this dose may be adjusted for patients or subjects weighing above or below this range, especially children under 40 kg). A typical adult subject is expected to have an average body weight of about 70 kg. Long acting pharmaceutical compositions may be administered every 2, 3 or 4 days, once a week, or once every two weeks, depending on the half-life and clearance rate of the particular drug.

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

In another aspect, the dose administered may be adjusted depending on the dosage form,

- 28 041957 described in this application, which is formulated to deliver 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, 10, 20, 30, 40, 50, 100, 150, 200, 250, 300, 400, 500, 1000, 1500, 2000, 2500, 3000 or 4000 mg/day.

For any compound, an effective amount may be initially determined either in cell culture assays or in appropriate animal models such as a mouse, guinea pig, chimpanzee, marmoset, or tamarin animal model. Appropriate animal models can 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 of administration in humans. Therapeutic efficacy and toxicity can be determined using standard pharmaceutical procedures in cell cultures or experimental animals, for example, ED ₅₀ (therapeutically effective dose for 50% of the population) and LD ₅₀ (lethal dose for 50% of the population). The dose ratio between therapeutic and toxic effects is the therapeutic index and can be expressed as the ratio LD ₅₀ /ED ₅₀ . In some aspects, the effective amount is such that a large therapeutic index is achieved. In other specific aspects, the dose is in a circulating concentration range that includes the ED ₅₀ with little or no toxicity. The dose may vary within this range depending on the dosage form used, the sensitivity of the patient and the route of administration.

In one aspect, the present application provides 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, the present application provides methods for modulating the amount of HTT, including contacting a human cell with a compound of formula (I) or a form of this compound, which modulates the expression of HTT. A human cell may be contacted with a compound of formula (I) or a form thereof in vitro or in vivo, for example in a non-human animal or in a human. In a specific aspect, the human cell is derived from or resides in the human body. In another specific aspect, the human cell is derived from or resides in a human with HD. In another specific aspect, the human cell is human-derived or resides in a human with HD caused by a CAG repeat in the Htt gene, resulting in 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 a compound of formula (I).

In a specific aspect, the present application provides a method for enhancing inhibition of a mutant HTT transcribed from the Htt gene, comprising contacting a human cell with a compound of formula (I) or a form thereof. A human cell may be contacted with a compound of formula (I) or a form thereof in vitro or in vivo, for example in a non-human animal or in a human. In a specific aspect, the human cell is derived from or resides in the human body. In another specific aspect, the human cell is derived from or resides in a human with HD. In another specific aspect, the human cell is human-derived or resides in a human with HD caused by a CAG repeat in the Htt gene, resulting in loss of normal wild-type 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 a compound of formula (I).

In another aspect, the present application provides a method for modulating inhibition of a mutant HTT transcribed from an Htt gene, comprising administering a non-human animal model HD of a compound of formula (I) or a form thereof. In a specific aspect, the present application provides a method for modulating the inhibition of a mutant HTT transcribed from an Htt gene, comprising administering a non-human animal model HD of a compound of formula (I) or a form thereof. In a particular aspect, the compound is a form of a compound of formula (I).

In another aspect, the present application provides a method for reducing the amount of mutant HTT, comprising contacting a human cell with a compound of formula (I) or a form thereof. In a specific aspect, the present application provides a method for reducing the amount of mutant HTT, comprising contacting a human cell with a compound of formula (I) that inhibits transcription of mutant HTT (huntingtin mRNA) from the Htt gene. In another specific aspect, the present application provides a method for reducing the amount of HTT, comprising contacting a human cell with a compound of formula (I) that inhibits the expression of a mutant HTT transcribed from the Htt gene. A human cell may be contacted with a compound of formula (I) or a form thereof in vitro or in vivo, for example in a non-human animal or in a human. In a specific aspect, the human cell is derived from or resides in the human body. In another specific aspect, the human cell is derived from or resides in a human with HD. In another specific aspect, the human cell is human-derived or resides in a human with HD caused by a CAG repeat in the Htt gene, resulting in 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 a compound of the formula

- 29 041957 (I).

In some aspects, treatment or alleviation of HD using a compound of formula (I) or a form thereof (alone or in combination with an additional agent) has a therapeutic effect and/or a beneficial effect. In a specific aspect, treatment of HD with a compound of formula (I) or a form thereof (alone or in combination with an additional agent) results in one, two or more of the following effects:

(i) reduce or lessen the severity of HD;

(ii) delay the advance of the HD;

(iii) inhibits the progression of HD;

(iv) reduce the subject's hospitalizations;

(v) shorten the duration of the subject's hospital stay;

(vi) enhances the survival of the subject;

(vii) improves the subject's quality of life;

(viii) reduce the number of symptoms associated with HD;

(ix) reduce or alleviate the severity of the symptom(s) associated with HD;

(x) shortens the duration of a symptom associated with HD;

(xi) prevents the recurrence of a symptom associated with HD;

(xii) inhibits the development or occurrence of a symptom of HD; and/or (xiii) inhibits the progression of a symptom associated with HD.

Metabolites

Another aspect included in the scope of the present description includes the use of metabolic products of the compounds described in this application, in vivo. Such products may result from, for example, oxidation, reduction, hydrolysis, amidation, esterification, and the like. of the administered compound, primarily due to enzymatic processes. Accordingly, the description includes the use of compounds obtained by a method comprising contacting a compound described in this application with tissue of a mammal or a mammal for a period of time sufficient to obtain their metabolic product.

Identification of such products is typically accomplished by obtaining a radiolabeled isotopologue (eg, ¹⁴ C or ³ H) of a compound described herein, administering the radiolabeled compound at a detectable dose (eg, greater than about 0.5 mg/kg) to a mammal, such as rat, mouse, guinea pig, dog, monkey or human, allowing sufficient time for metabolism (typically about 30 seconds to about 30 hours) and identifying metabolic products from urine, bile, blood or other biological samples. The conversion products are easily isolated because they are radiolabeled due to the fact that they are isotopically enriched (others are isolated using antibodies capable of binding to epitopes that survived in the metabolite). The structures of the metabolites are determined in the usual way, for example using MS or NMR analysis. Typically, metabolite analysis can be performed in the same manner as conventional drug metabolism studies well known to those skilled in the art. The transformation products, provided that they are not otherwise present in vivo, are useful in diagnostic assays for therapeutic administration of the compounds described in this application, even if they do not have their own biological activity.

Pharmaceutical compositions

Within the intended scope of the present disclosure, aspects of the present disclosure include compounds that have been identified and shown to be useful in the selective prevention, treatment, or alleviation of HD, and which are provided for use as one or more pharmaceutical compositions for prophylaxis, treatment or relief of HD.

One aspect of the present disclosure includes the use of a compound of formula (I) or a form thereof for the preparation of a pharmaceutical composition for the treatment or alleviation of HD in a subject in need thereof, which comprises administering to the subject an effective amount of a compound of formula (I) or a form thereof in admixture with one or more pharmaceutically acceptable excipients.

One aspect of the present disclosure includes the use of a pharmaceutical composition of a compound of formula (I) or a form thereof to provide a kit for treating or alleviating HD in a subject in need thereof, comprising a pharmaceutical composition of a compound of formula (I) or a form thereof and instructions for administering the pharmaceutical composition.

In the context of this application, the term composition means a product that includes these ingredients in certain amounts, as well as any product that is directly or indirectly the result of a combination of these ingredients in certain amounts.

The pharmaceutical composition may be formulated to achieve a physiologically compatible pH in the range of about pH 3 to about pH 11. In some aspects, the pharmaceutical composition is formulated to achieve a pH of about pH 3 to about pH 7. In other aspects, the pharmaceutical composition is formulated to achieve a pH of about pH 5 to about pH 8.

- 30 041957

The term pharmaceutically acceptable excipient refers to an excipient for the administration of a pharmaceutical agent, such as the compounds described in this application. The term refers to any pharmaceutical excipient that can be administered without undue toxicity. Pharmaceutically acceptable excipients may be determined in part by the particular composition administered, as well as by the particular route of administration and/or dosage form. Non-limiting examples of pharmaceutically acceptable excipients include carriers, diluents, stabilizers, adjuvants, diluents, and the like. Accordingly, there is a wide range of suitable dosage forms for the pharmaceutical compositions of the compounds of the present invention described in this application (see, for example, Remington's Pharmaceutical Sciences).

Suitable excipients may be carrier molecules that include large, slowly metabolizing 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 (eg hydroxypropylmethylcellulose, also known as HPMC), stearic acid; liquids such as oils, water, saline, glycerol and ethanol; wetting agents or emulsifiers; pH buffering agents; and so on. Liposomes are also included in the definition of pharmaceutically acceptable excipients.

The pharmaceutical compositions described in this application may be formulated in any form suitable for the intended use described in this application. Suitable dosage forms for oral administration include solid dosage forms, liquid solutions, emulsions and suspensions, while suitable dosage forms for inhalation for pulmonary administration include liquids and powders. Alternative dosage forms include syrups, creams, ointments, tablets, and lyophilized solid preparations that can be reconstituted with a physiologically compatible vehicle before administration.

When intended for oral administration, for example, tablets, lozenges, lozenges, aqueous or oily suspensions, non-aqueous solutions, dispersible powders or granules (including micronized particles or nanoparticles), emulsions, hard or soft capsules, syrups or elixirs can be prepared. Compositions intended for oral use may be prepared by any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents, including sweeteners, flavors, colors, and preservatives, to provide a good palatability formulation.

Pharmaceutically acceptable excipients suitable for use in combination with tablets include, for example, inert diluents such as cellulose, calcium or sodium carbonate, lactose, calcium or sodium phosphate; disintegrants such as croscarmellose sodium, cross-linked povidone, corn starch or alginic acid; binders such as povidone, starch, gelatin or gum arabic; and lubricants such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known methods, including microencapsulation, to slow down degradation and absorption in the gastrointestinal tract and thereby provide sustained action over a longer period. For example, a time delay agent such as glyceryl monostearate or glyceryl distearate can be used alone or with a wax.

Oral dosage forms may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as cellulose, lactose, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with a non-aqueous or an oil medium such as glycerin, propylene glycol, polyethylene glycol, peanut oil, liquid paraffin or olive oil.

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

Suitable excipients for use in connection with suspensions include suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum arabic, dispersing or wetting agents such as natural phosphatide (e.g. lecithin), condensation of alkylene oxide with a fatty acid (for example, polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (for example, heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from fatty acid and hexitanhydride (for example, polyoxyethylene sorbitan monooleate); and thickeners such as carbomer, beeswax,

- 31 041957 solid paraffin or cetyl alcohol. Suspensions may also contain one or more preservatives such as acetic acid, methyl and/or n-propyl parahydroxybenzoate; one or more dyes; one or more flavors; and one or more sweeteners such as sucrose or saccharin.

The pharmaceutical compositions described herein may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil such as olive oil or peanut oil, a mineral oil such as liquid paraffin, or a mixture thereof. Suitable emulsifiers include natural gums such as gum arabic and gum tragacanth; natural phosphatides such as soy lecithin, esters or partial esters of fatty acids; hexitanhydrides such as sorbitan monooleate; and condensation products of these partial esters and ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners and flavors. Syrups and elixirs may be prepared with sweeteners such as glycerin, sorbitol, or sucrose. Such dosage forms may also contain an emollient, preservative, flavoring or coloring agent.

In addition, the pharmaceutical compositions described herein may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous emulsion or oily suspension. Such an emulsion or suspension may be formulated according to a method known in the art using the appropriate dispersing or wetting agents and suspending agents as mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic, parenterally acceptable diluent or solvent, such as a solution in 1,2-propanediol. The sterile injectable preparation may also be prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils can be used as a solvent or suspending medium. Any bland fixed oil can be used for this purpose, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can also be used to make injectables.

The compounds described herein may be substantially insoluble in water and sparingly soluble in most pharmaceutically acceptable protic solvents and vegetable oils, but they are generally soluble in medium chain fatty acids (e.g., caprylic and capric acids) or triglycerides. and in esters of propylene glycol and medium chain fatty acids. Thus, the description contemplates compounds that have been modified by substitution or addition of chemical or biochemical moieties that make them more suitable for delivery (eg, increase solubility, bioactivity, palatability, reduce side reactions, etc.), for example, by esterification, glycosylation, PEGylation, etc.

In some aspects, the compound described in this application is formulated for oral administration in the form of a composition based on lipids, suitable for compounds with low solubility. Lipid-based compositions can generally increase the oral bioavailability of such compounds. As such, the pharmaceutical compositions described herein may contain an effective amount of a compound of formula (I) or a form thereof, together with at least one pharmaceutically acceptable excipient selected from medium chain fatty acids or their propylene glycol esters (e.g. esters of propylene glycol and 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 compounds with low solubility can be improved using particle size optimization techniques, including the preparation of nanoparticles or nanosuspensions using methods known to those skilled in the art. Forms of the compounds present in such preparations include amorphous, partially amorphous, partially crystalline or crystalline forms.

In alternative aspects, the pharmaceutical composition may also include one or more water solubility enhancers such as cyclodextrin. Non-limiting examples of cyclodextrin include hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of α-, β- and γ-cyclodextrin and hydroxypropyl-v-cyclodextrin (HPBC). In some aspects, the pharmaceutical composition also includes HPBC in the range of about 0.1% to about 20%, about 1% to about 15%, or about 2.5% to about 10%. The amount of solubility enhancer used may depend on the amount of the compound in the composition.

Preparation of compounds General methods of synthesis

As disclosed in this application, general methods for preparing compounds of formula (I) or their forms are available using standard, well known synthetic methods, many of the starting materials are commercially available or, if they are not available, they can be obtained using the methods described below, using procedures known to those skilled in the art, the synthetic schemes presented herein include several reaction steps, each of which is intended to stand on its own and can be carried out with or without any preceding or subsequent step. in other words, each of the individual reaction steps of the presented synthesis schemes is considered separately.

Scheme A.

Compounds of formula (I) wherein B is heterocyclyl, X is O, NH or NR _1b where R _1b is C ₁ . ₄ αkyl can be prepared as described in Scheme A below.

Compound A1 (where W ₁ and W2 are independently bromine, chlorine, etc.) is converted to compound A2 by a nucleophilic substitution reaction with a primary or secondary amine or alcohol (VCN) in the presence of a suitable base (such as Et ₃ N and t .p.) in a suitable solvent (such as DMF, etc.). Alternatively, compound A1 is converted to compound A2 via a cross-coupling reaction with a primary or secondary amine or alcohol in the presence of a suitable catalyst (such as RuPhos Pd G2, etc.) and a base (such as sodium tert-butoxide, etc.) in a suitable solvent such as 1,4-dioxane, etc.). Compound A2 is converted to compound A3 by a Suzuki coupling reaction with aryl- or heteroarylboronic acid (or pinacolic ester of boronic acid) in the presence of a catalyst (such as Pd(dppf)Cl ₂ etc.) and a base (such as an aqueous solution of K ₂ CO ₃ etc.) in a suitable solvent (such as 1,4-dioxane etc.). Alternatively, compound A2 is converted to compound A3 by Stille coupling reaction with aryl or heteroaryl stannane in the presence of a catalyst (such as Pd ₂ (dba) ₃ and the like), a ligand (such as X-Phos and the like), and a base (such as CsF, etc.) in a suitable solvent (such as 1,4-dioxane, etc.). Any protecting groups can be removed by treatment with a suitable reagent (such as HCl in dioxane for a Boc protecting group, etc.) in a suitable solvent (such as dioxane, etc.).

Scheme B.

Compounds of formula (I) wherein (R ₃ ) _n is hydrogen, halogen, hydroxy or C _1-4 alkoxy, n is 0 or 1, R ₃ is heterocyclyl, heteroaryl or phenyl, B is heterocyclyl; X is O, NH or NR _1b and R _1b is C _1-4 αkyl can be obtained as described in Scheme B below.

Compound B1 (where W ₁ and W ₂ are independently bromine, chlorine, etc.) is converted to compound B3 by a Suzuki coupling reaction with arylboronic acid (or pinacol ester of boronic acid) B2 (where W ₃ is bromine, chlorine and (R ₃ ) _n is hydrogen, halogen, hydroxy, or C _1-4 alkoxy, and n is 0 or 1, and PG is a protecting group such as MOM, etc.) in the presence of a catalyst (such as Pd(dppf)Cl ₂ , etc.) and a base (such as an aqueous solution of K ₂ CO ₃ , etc.) in a suitable solvent (such as 1,4-dioxane, etc.) . Compound B3 is converted to compound B4 by a nucleophilic substitution reaction with a primary or secondary amine or alcohol (VHH where X is O, NH or NR _1b where R _1b is C _1-4 alkyl) in the presence of a suitable base (such as Et ₃ N etc.) in a suitable solvent

- 33 041957 (such as DMF, etc.). Alternatively, compound B3 is converted to compound B4 by cross-coupling with a primary or secondary amine or alcohol in the presence of a suitable catalyst (such as RuPhos Pd G2, etc.) and a base (such as sodium tert-butoxide, etc.) in a suitable solvent (such as 1,4-dioxane, etc.). Compound B4 is converted to compound B5 by a Suzuki coupling reaction with aryl- or heteroarylboronic acid (or pinacol ester of boronic acid) in the presence of a catalyst (such as Pd(dppf)Cl ₂ and the like) and a base (such as an aqueous solution of K ₂ CO ₃ etc.) in a suitable solvent (such as 1,4-dioxane etc.). Alternatively, compound B4 is converted to compound B5 by Stille coupling reaction with aryl or heteroaryl stannane in the presence of a catalyst (such as Pd ₂ (dba) ₃ and the like), a ligand (such as XPhos and the like), and a base ( such as CsF, etc.) in a suitable solvent (such as 1,4-dioxane, etc.). Alternatively, compound B4 is converted to compound B5 by treatment with pinacolate diboron and a base (such as KOAc, etc.) in the presence of a catalyst (such as Pd(dppf)Cl ₂ and the like) in a suitable solvent (such as 1.4 -dioxane, etc.), followed by the addition of an aryl or heteroaryl halide. Alternatively, compound B4 is converted to compound B5 by a Buchwald-Hartwig coupling reaction with a heteroaryl or amine in the presence of a catalyst (such as Pd ₂ (dba) ₃ or the like), a ligand (such as tBuX-Phos or the like) and a base (such as K3PO4 and the like) in a suitable solvent (such as 1,4-dioxane and the like). Compound B5 is converted to compound B6 by treatment using conditions suitable for deprotection (such as HCl in dioxane for the MOM protecting group) in a suitable solvent (such as dioxane, etc.).

Scheme C.

Following the general conditions described in Scheme B, but changing the order of steps 1 and 2, compound C1 can be converted to compound C6.

Specific Synthesis Examples

For a more detailed description and better understanding, the following non-limiting examples are provided to more fully illustrate the scope of the described compounds, and should not be construed as specifically limiting their scope. Such variations of the compounds described in this application, which may now be known or may be developed later, which should be within the competence of a person skilled in the art, are considered to be within the scope of the compounds described in this section and claimed hereinafter. These examples illustrate the preparation of some compounds. Those skilled in the art will appreciate that the techniques described in these examples are those known to those of ordinary skill in the art that work well in practice and as such constitute the preferred methods for their application. However, it should be appreciated that those skilled in the art should, in light of the present disclosure, appreciate that many changes can be made to the specific methods disclosed to achieve the same or similar result without departing from the spirit and scope of the present disclosure.

In addition to the following examples of embodied compounds, unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, experimental data, etc. used in the description and claims, should be understood as modified by the term about. Accordingly, all such numbers are approximations, which may vary depending on the desired properties that are sought to be obtained through the reaction or as a result of varying experimental conditions. Therefore, within the expected range of experimental reproducibility, the term about in the context of obtained data refers to the range of reported data, which may vary depending on the standard deviation from the mean. In addition, for the experimental results presented, the data obtained can be rounded up or down for a uniform presentation of the data without loss of significant numbers. At 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 considered in light of the number of significant digits and rounding methods used by those skilled in the art.

While the numerical ranges and parameters that define the broad scope of the present description are approximate, the numerical values presented in the examples below are given as accurately as possible. However, any numerical value inherently contains certain errors, necessarily resulting from the standard deviation found in the corresponding test measurements.

The starting materials used in the presented examples are commercially available or can be obtained in accordance with methods known to experts in this field, or can be obtained using the procedures disclosed in this application.

Connection examples

As used above and throughout this specification, the following abbreviations, unless otherwise indicated, should be understood to have the following meanings:

Abbreviations Meaning

Δ heating (chemistry) or deletion (biology) ASON or BUT Ac acetic acid Ag argon ACN or CH ₃ CN acetonitrile drive. water atm atmosphere(atmosphere) VVgz boron tribromide B ₂ pin ₂ bis(pinacolato)dibor Vos tert-butoxy-carbonyl t-Bu tert-butyl

- 35 041957

t-BuOK or KOtBu potassium tert-butoxide BuOH or n-BuOH //-butanol °C degrees Celsius Celite® or Celite diatomaceous earth d/h/h/min/sec day(d)/hour(h)/minute(min)/second(sec) DCM or CH ₂ C1 ₂ dichloromethane DMF dimethylformamide DMSO dimethyl sulfoxide EtOAc ethyl acetate EtOH ethanol _Et2O diethyl ether EKV. equivalents _H2 hydrogen HBr hydrobromic acid HCl hydrochloric acid _{H2SO4 _} sulfuric acid _{K2CO3 _} potassium carbonate KOAC potassium acetate KOH potassium hydroxide LC/MS, LCMS or Liquid chromatography/mass spectroscopy LC-MS LiOt-Bu lithium tert-butoxide LiOH lithium hydroxide mCPBA meta-chloroperoxybenzoic acid MeOH methanol MeSO ₃ H methanesulfonic acid _MgSO4 magnesium sulfate ML milliliter MOM methoxymethyl MS Mass spectroscopy NET ₃ triethylamine _NH4C1 ammonium chloride _NH4OAc ammonium acetate _{Na2CO3 _} sodium carbonate NaH sodium hydride

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_NaHCO3 bicarbonate of soda NaOH sodium hydroxide _Na2SO4 sodium sulfate n ₂ nitrogen _NH4C1 ammonium chloride NMP N-methylpyrrolidone NMR Nuclear magnetic resonance Pd palladium Pd/C palladium on carbon Pd ₂ (dba) ₃ tris(dibenzylndenacetone)dipalladium(0) Pd(dppf)Cl ₂ or [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), Pd(dppf)Cl ₂ -CH ₂ Cl ₂ complex with dichloromethane PhMe toluene psi ² pressure in psi Qphos 1,2,3,4,5-pentaphenyl-G-(di-t/?eot-butylphosphino)ferrocene Rt or rt room temperature S-Phos, S-Phos or 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl Sphos S-Phos G ₂ chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'- amino-1,1'-biphenyl-2-yl) palladium(II) TBAF tetrabutylammonium fluoride TBS tert-butyldimethylsilyl TEA, Et ₃ N or NEt ₃ triethylamine Tf trifluoromethanesulfonyl or triflate TFA trifluoroacetic acid THF tetrahydrofuran THP tetrahydropyranyl TIPS triisopropylsilane those thin layer chromatography UHPLC ultra high performance liquid chromatography

Preparation of starting material 4-(3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenyl)-1-(tetrahydro-2H-pyran-2-yl )-1 H-pyrazole

Step 1 2-Bromo-5-iodophenol (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 dropwise. The mixture was stirred at 0° C. for 15 minutes after addition was complete. Chloromethyl methyl ether (18 mL, 225 mmol) was added dropwise over 30 min. The mixture was warmed to ambient temperature and stirred for 16 h. The mixture was diluted with 1.5 L H ₂ O and extracted into 2x400 ml EtOAc. The combined organic layers were washed with 300 ml of H ₂ O and then with brine. The organic layer was dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was washed through a plug of silica gel using 0-10% CH ₂ Cl ₂ in hexane to give 1-bromo-4-iodo-2-(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).

Stage 2. 1-Bromo-4-iodo-2-(methoxymethoxy)benzene (49 g, 143 mmol), 1-(tetrahydro-2H-pyran-2-yl)4-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)-1H-pyrazole (48.4 g, 174 mmol), Pd(dppf)Cl ₂ adduct dichloromethane (3.1 g, 3.6 mmol), dioxane (500 ml) and an aqueous solution of K ₂ CO ₃ (1M, 350 ml, 350 mmol) were heated at 90° C. for 2 hours. The reaction mixture was then partitioned between H ₂ O and EtOAc. The organic layer was dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with a gradient of EtOAc/hexane (20-50% EtOAc), followed by trituration with hexane to give 4-(4-bromo-3-(methoxymethoxy)phenyl)-1-(tetrahydro- 2H-pyran-2yl)-1H-pyrazole (40.4 g, 77% yield) as an off-white solid.

1H NMR (acetone-d6): 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), 2.12.23 (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 evacuated at 180° C. for 2 hours and then filled with argon. 4-(4-Bromo-3-(methoxymethoxy)phenyl)-1-(tetrahydro-2H-pyran2-yl)-1H-pyrazole (20 g, 54.5 mmol), Pd(dppf)Cl ₂ -dichloromethane adduct was added (1.22 g, 1.47 mmol), bis(pinacolato)diboron (20.8 g, 81.9 mmol) and anhydrous toluene (200 ml). The mixture was heated at 110° C. for 48 hours. After cooling, the mixture was filtered through celite, followed by washing with ether. The filtrate was concentrated in vacuo, redissolved in ether and filtered again through celite to remove solids. Purification by chromatography on silica gel eluting with a gradient of EtOAc/hexane (20-50% EtOAc) gave 12 g of the crude title product. The crude material was dissolved in 100 ml of simple ether and washed again using 2x1.5 l of dilute aqueous NaHCO ₃ . The ethereal layer was washed with brine, dried over MgSO ₄ and filtered. The filtrate was concentrated to give a glassy semi-solid. This material was triturated with hexane to give 4-(3-(methoxymethoxy)-4(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-(tetrahydro- 2H-pyran-2-yl)-1H-pyrazole as a white crystalline solid (7.05 g, 32% yield).

¹ H NMR (acetone-d6): δ 8.24 (s, 1H), 7.90 (s, 1H), 7.65 (d, J=8 Hz, 1H), 7.33 (d, J= 1.5Hz, 1H), 7.29(dd, J=8Hz, 1.5Hz, 1H), 5.45(dd, J=10Hz, 2.5Hz, 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 described procedure, additional compounds described in this application can be prepared using the appropriate starting material, suitable reagents and reaction conditions, to obtain compounds, such as compounds selected from

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Structure Data L MOMO ° Str A ^N bV ^z 7—<\ A MS m/z 345.5 [M+H] ⁺ ; 'H NMR (methanol ₄ ) δ: 7.948.03 (m, 1H), 7.84 (s, 1H), 7.64 (brd, J=7.6 Hz, 1H), 7.25 (s, 1H), 7.20 (d, J=7.3 Hz, 1H), 5.25 (s, 2H), 3.813.98 (m, ZN), 3.53 (s, ZN), 1 .36 (s, 12H) MOMO -A O AN -A A / VN, ° CD ₃ MS m/z 348.5 [M+H] ⁺ ; ¹ H NMR (methanol-c1 ₄ ) δ: 8.00 (s, 1H), 7.85 (s, 1H), 7.64 (brd, 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) 1 JpN ™ ^ρ Vo ohm MS m/z 349.2 [M-THP+H] ⁺ -O Ul ΡΎ' in (UCH T O \=/ N' MS m/z 316.6 [M+H] ⁺ F %° Ul An B - ί 7 - <\ ¹ -A A / VN. ° -\ THP F MS m/z 391.5 [M+H] ⁺ A FF gCh^UUa^m in - V y - 1 -A 4 \u003d / VN, ^u - TNR MS m/z 391.5 [M+H]+; A NMR (methanol ₄ ) δ: 8.278.32 (m, IH), 8.00-8.04 (m, 1H), 7.40-7.52 (m, 2H), 5.425.56 (m , IH), 4.08 (b.d, J=11.5 Hz, 1H), 3.77 (b.t, J=11.5 Hz, 1H), 2.12-2.25 (m, 1Н), 2.07 (br.d, J=ll.0 Hz, 2H), 1.60-1.86 (m, ZN), 1.38 (s, 12H) A F CHACHA in—with)—(\ । \ —/ VN, ° —\ ТНР F MS m/z 391.5 [M+H] ⁺ CI /A\ Α ^N in A /—(\ ¹ 7=/ VN ₄ ° —\ TNR CI MS m/z 423.2.425.2 [M+H] ⁺

Preparation of starting material 2-[4-chloro-3-fluoro-2-(methoxymethoxy)phenyl]-4,4,5,5-tetramethyl1,3,2-dioxaborolane

Step 1 6-Bromo-3-chloro-2-fluoro-phenol (900 mg, 4.0 mmol) was dissolved in DMF (4.5 ml) at 0°C. Sodium tert-pentoxide (2.5 M in THF, 2 mL, 5.0 mmol) was added dropwise followed by chloromethyl methyl ether (405 μL, 5.34 mmol) dropwise and the reaction mixture was stirred overnight at room temperature. The reaction mixture was partitioned between water and EtOAc. The organic layer was washed with water and then with brine. The organic layer was dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with an EtOAc/hexane gradient (30-100% EtOAc) to give 1-bromo-4-chloro-3-fluoro-2

- 39 041957 (methoxymethoxy)benzene (1.01 g, 94% yield) as a clear oil.

1H NMR (acetone-d ₆ ): δ 7.50 (d, J=9 Hz, 1H), 7.28 (t, J=8 Hz, 1H), 5.26 (s, 2H), 3.62 (s, 3H).

Stage 2. Mixture of dry KOAc (1.5 g, 15 mmol), bis(pinacolato)diboron (1.02 g, 4.02 mmol), Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (90 mg, 0.108 mmol ) and a solution of 1-bromo-4-chloro-3-fluoro-2-(methoxymethoxy)benzene (900 mg, 3.3 mmol) in toluene (12 ml) was purged with argon for 15 min. The mixture was heated at 110° C. for 16 hours. After completion, the reaction mixture was diluted with EtOAc and filtered through celite. The filtrate was concentrated and purified by silica chromatography eluting with a MeOH/CH ₂ Cl ₂ gradient (0 to 5% MeOH) to give 2-[4-chloro-3-fluoro-2-(methoxymethoxy)phenyl]-4.4 ,5,5tetramethyl-1,3,2-dioxaborolane (524 mg, 47% yield) as light orange oil.

¹ H NMR (acetone-d6): 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 described procedure, additional compounds described in this application can be prepared using the appropriate starting material, suitable reagents and reaction conditions, to obtain compounds, such as compounds selected from

Preparation of starting material N-(tert-butyl)pyrrolidine-3-amine

Step 1: 1-benzylpyrrolidin-3-one (4.0 g, 22.8 mmol), 2-methylpropan-2amine (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 left to stir at room temperature for 2 h. The resulting (E)-1-benzyl-N(tert-butyl)pyrrolidine-3-imine was used without further purification.

Step 2 Anhydrous methanol (40 ml) was added to the mixture from step 1 and the reaction mixture was cooled to 0° C. in an ice bath. NaBH ₄ (1.6 g, 42.3 mmol) was added slowly in portions (caution: very exothermic reaction). After gas evolution ceased, the mixture was warmed to room temperature and stirred for 2 hours at room temperature. Upon completion, a solution of 0.1 M NaOH (20 ml) was added to precipitate the titanium salts. The biphasic mixture was filtered through Celite and washed with methanol. The solvent was removed in vacuo and the crude oil was purified by reverse phase chromatography using an acetonitrile/H ₂ O gradient (10%-100% acetonitrile) to give 1-benzyl-N-(tert-butyl)pyrrolidine-3-amine (3.2 g, 60% yield) as a colorless oil.

Step 3 To an oven-dried round bottom flask containing palladium hydroxide on activated carbon (320 mg) was added 1-benzyl-N-(tert-butyl)pyrrolidine-3-amine (3.2 g, 13.8 mmol), dissolved in MeOH (20 ml). The mixture was sparged with H ₂ for 5 min and the H ₂ balloon was placed on top of the flask and the reaction mixture was stirred for 2 h at room temperature. The reaction mixture was filtered through celite, washed with MeOH and concentrated to give N-(tert-butyl)pyrrolidine-3-amine (1.89 g, 96% yield) as a colorless oil which solidified on standing.

1H NMR (methanol-d4) 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), 2.62-2.56 (m, 1H), 2.28-2.20 (m, 1H ), 1.42 (s, 9H); 2 NHs were not observed.

Example 1 Preparation of Compound 1

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Step 1: A mixture of 2,5-dibromopyrazine (610 mg, 2.56 mmol) and N,2,2,6,6-pentamethylpiperidine-4amine (480 mg, 2.8 mmol) in n-BuOH (3.0 ml ) was stirred at 120° C. for 16 h until LCMS analysis showed that the starting material was completely consumed. The reaction mixture was cooled to room temperature, the solvent was evaporated under reduced pressure and the residue was partitioned between EtOAc and saturated aqueous NaHCO ₃ . The organic layers were dried over Na ₂ SO ₄ and the solvent was evaporated to give 5-bromo-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4yl)pyrazine-2-amine (646 mg, 77%) as yellowish solid. MS m/z 326.2, 328.2 [M+H]+.

Step 2 An oven-dried flask was fitted with a magnetic stirrer and charged with 5-bromo-N-methylN-(2,2,6,6-tetramethylpiperidin-4-yl)pyrazin-2-amine (570 mg, 1.74 mmol), tert-Butyl-(3-methoxy-4(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)dimethylsilane (64mg, 0.24mmol, tetrakis(triphenylphosphine)palladium (0) (196 mg, 0.17 mmol), Na ₂ CO ₃ (553 mg, 5.22 mmol) The flask was sealed with a rubber cap and then evacuated and refilled with argon Dioxane (10 ml) and water (2 .5 ml) and the reaction mixture was heated to 90°C for 16 hours the Reaction mixture was cooled to room temperature, diluted with water (5 ml) and was extracted with EtOAc. The organic layers were combined, dried over Na ₂ SO ₄ and concentrated under reduced The residue was purified by silica gel column chromatography eluting with a CH ₂ Cl ₂ /MeOH gradient (0 to 30% MeOH) to give 5-(4-((tert-butyldimethylsilyl)oxy)-2-methoxyphenyl)-N-methyl -N-(2,2,6,6tetramethylpiperidin-4-yl)pyrazin-2-amine (529 m g, 63%) as a clear oil which has partially solidified. MS m/z 485.6 [M+H]+.

Step 3. To a solution of 5-(4-((tert-butyldimethylsilyl)oxy)-2-methoxyphenyl)-N-methyl-N-(2,2,6,6tetramethylpiperidin-4-yl)pyrazin-2-amine (529 mg, 1.09 mmol) in CH ₂ Cl ₂ (3 ml) was added 4N HCl/dioxane (0.5 ml, 2.0 mmol) followed by MeOH (0.2 ml). The reaction mixture was stirred for 5 h at room temperature until LCMS analysis showed that the starting material was completely consumed.

The solvents were removed under reduced pressure and the residue was suspended in CH ₂ Cl ₂ (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 reaction mixture was stirred at room temperature for 16 h, then washed with water (2 ml) then brine. The organic layers were dried over Na ₂ SO ₄ and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography eluting with a CH2Cl2/MeOH gradient (0 to 20% MeOH) to give 3-methoxy-4-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino )pyrazin-2-yl)phenyl trifluoromethanesulfonate (402 mg, 73%) as a tan solid. MS m/z 503.6 [M+H]+;

¹ H NMR (acetone-a 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 was not observed (NH).

Step 4 An oven-dried flask was fitted with a magnetic stirrer and charged with 3-methoxy-4-(5(methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyrazin-2-yl)phenyl trifluoromethanesulfonate (180 mg, 0.35 mmol), 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (101 mg, 0.43 mmol, tetrakis(triphenylphosphine )palladium(0) (40 mg, 0.35 mmol), Na ₂ CO ₃ (111 mg, 1.05 mmol). The flask was sealed with a rubber cap and then evacuated and refilled with argon. Dioxane (6 ml) and water were added (1.5 ml) and the reaction mixture was heated to 90°C for 16 hours the Reaction mixture was cooled to room temperature, diluted with water (5 ml) and was extracted with EtOAc The organic layers were combined, dried over Na ₂ SO ₄ and concentrated under reduced pressure The residue was purified by silica gel column chromatography eluting with a gradient of CH ₂ Cl ₂ /MeOH (0 to 30% MeOH) to give 5-(2-methoxy-4-(2-methoxypyridin-4-yl)phenyl) -N-methyl-N-(2,2,6,6tetramethylpiperidin-4-yl)pyrazin-2-amine ( 86 mg, 53%) as a tan solid.

MS m/z 462.6 [M+H]+;

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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 was not observed (NH).

Step 5. A solution of 5-(2-methoxy-4-(2-methoxypyridin-4-yl)phenyl)-N-methyl-N-(2,2,6,6tetramethylpiperidin-4-yl)pyrazin-2-amine ( 70 mg, 0.15 mmol) in 2 ml anhydrous CH ₂ Cl ₂ was cooled in an ice water bath. Boron tribromide (1.0 M in CH ₂ Cl ₂ 1.5 ml, 1.5 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture 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 a gradient of CH ₂ Cl ₂ /MeOH (2.5% NH4OH) (0 to 30% MeOH/NH ₄ OH) to give 4-(3-hydroxy-4-(5-( methyl-(2,2,6,6-tetramethylpiperidin-4yl)amino)pyrazin-2-yl)phenyl)pyridin-2-ol (33 mg, 51%) as a yellow solid.

MS m/z 434.6 [M+H]+;

1H NMR (methanol-d4) 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 was not observed (NH and 2OHs).

Using the procedure described for Example 1, additional compounds described herein can be prepared using the appropriate starting material, suitable reagents, and reaction conditions to provide compounds such as compounds selected from

Comm. Data 5 MS m/z 407.2 [M+LFH NMR (DMSO-d ₆ ) δ: 8.99 (d, J=l.6 Hz, 1H), 8.31 (s, 1H), 8.15 (d , J=l.2 Hz, 1H), 8.04 (d, J=8.8 Hz, 1H), 7.79 (d, J=l.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 was not observed (NH and OH). 9 MS m/z 475.1 [M+H] ⁺ ; 'H NMR (methanol-si) 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 was not observed (2NHs and OH). 12 MS m/z 421.1 [M+H] ⁺ ; 'H NMR (methanol-cU) δ: 8.85 (s, 1H), 8.04 (s, 1H), 7.82 (s, 1H), 7.68 (s, 1H), 7.26 ( dd, J=l.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 was not observed (2NHs and OH). 14 MS m/z 422.5 [M+H] ⁺ ; Ή NMR (methanol-cU) 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), 5.78 (d, J=2.7 Hz, 1H ), 5.05 (tg, J=12.5, 3.4 Hz, 1H), 2.89 (s, ZN), 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 was not observed (3NHs and OH). 18 MS m/z 448.4 [M+H] ⁺ ; 'H NMR (methanol-cU) δ: 8.94 (s, 1H), 8.08 (dd, J=l.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, ZN), 3.03 (s, ZN), 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 was not observed (NH and OH). 27 MS m/z 421.4 [M+H] ⁺ ; 'H NMR (DMSO-d ₆ ) δ: 12.39 (br s, 1H), 8.95 (d, J=l.6

- 42 041957

Hz, 1H), 8.15 (s, 1H), 8.13 (d, J=l.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, ZN), 1.49 (dd, J=12.l, 3.5 Hz, 2H), 1.41 (t, J=12.l Hz, 2H), 1.25 (s, 6H ), 1.09 (s, 6H); 1H was not observed (OH or NH). 28 MS m/z 424.5 [M+H] ⁺ ; Ή NMR (DMSO-d ₆ ) δ: 9.02 (d, J=l.3 Hz, 1H), 8.14 (d, J=l.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=l.6 Hz, 1H), 5.28-5.41 (m, 1H), 3.12 (s, 3H), 1.92-2 .05 (m, 4H), 1.61-1.68 (m, 6H), 1.56 (s, 6H); 2Hs was not observed (OH hNH). 44 MS m/z 404.2 [M+H] ⁺ ; 'H 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), 7.317.34 (m, 2H), 4 .30 (br.s, 1H), 1.95-1.99 (m, 2H), 1.28-1.38 (m, 14H); 1H not observed (OH or NH) 45 MS m/z 404.2 [M+H] ⁺ ; 'H 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), 7.23-7.26 (m, 2H), 4.27-4.31 (m, 1H), 1.94-1.98 (m, 2H), 1.27 -1.37 (m, 14H); 1H not observed (OH or NH) 46 MS m/z 393.2 [M+H] ⁺ ; 'H 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] ⁺ ; 'H NMR (DMSO-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)

Example 2 Preparation of Compound 26

TNR

Step 1 An oven-dried flask was fitted with a magnetic stirrer and loaded with 5-bromo-N-methylN-(2,2,6,6-tetramethylnu-peridin-4-yl)pyrazin-2-amine (255 mg, 0.97 mmol), 4-(3-methoxy-4-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-III-pyrazole (273 mg, 0.71 mmol), tetrakis(triphenylphosphine)palladium(0) (60 mg, 0.05 mmol) and Na ₂ CO ₃ (160 mg, 1.5 mmol).

The flask was sealed with a rubber cap and then evacuated and refilled with argon. Dioxane (8 ml) and water (2 ml) were added and the reaction mixture was heated to 90° C. for 16 hours. The reaction mixture was cooled to room temperature, diluted with water (5 ml) and extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with a CH ₂ Cl ₂ /MeOH gradient (0 to 30% MeOH) to give 5-(2-methoxy-4-(1-(tetrahydro-2H-pyran-2-yl)- 1Hpyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpineridin-4-yl)pyrazin-2-amine (160 mg, 45%) as a yellow solid. MS m/z 505.6 [M+H]+.

Step 2. 5-(2-Methoxy-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)-N-methyl-N(2,2,6, 6-tetramethylpiperidin-4-yl)pyrazin-2-amine (80 mg, 0.15 mmol) was suspended in dichloromethane (1 ml) at 0°C. Boron tribromide (1.5 mL, 1.5 mmol, 1M in CH ₂ Cl ₂ ) was added dropwise and the mixture was stirred at 0° C. for 1 h and then at room temperature for 16 h. The mixture was quenched with MeOH ( 5 ml) and stirred for 30 min at room temperature. The solvents were removed under reduced pressure and the residue was triturated with Et ₂ O (1 ml). The precipitate was collected by filtration and dried to give 2-(5-(methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyrazin-2-yl)-5-(Spyrazol-4-yl)phenol hydrobromide (42 mg, 65%) as a brownish solid.

MS m/z 407.5 [M+H] ⁺ ;

¹ H NMR (methanol^) 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, J=13.2, 4.1 Hz, 1H), 3.15 (s, 3H), 2.05 (t,

- 43 041957

J=13.2 Hz, 2H), 1.99 (dd, J=13.2, 4.1 Hz, 2H), 1.66 (s, 6H), 1.58 (s, 6H); 3Hs was not observed (2 NHs and OH).

Using the procedure described for Example 2, additional compounds described in this application can be prepared using the appropriate starting material, suitable reagents, and reaction conditions to give compounds such as those selected from

Comm. Data 19 MS m/z 407.6 [M+H] ⁺ ; Ή NMR (methanol-sc) δ: 8.86 (d, J=l.2 Hz, 1H), 8.24 (d, J=2.4 Hz, 1H), 8.05 (d, J=l .2 Hz, 1H), 7.94 (d, J=9.2 Hz, 1H), 7.74 (d, J=l.5 Hz, 1H), 7.25-7.34 (m, 2H ), 6.55 (dd, J=2.4, 1.5 Hz, 1H), 5.18 (tg, J=12.5, 3.7 Hz, 1H), 3.02 (s, ZN) , 1.66 (dd, J=12.5, 3.7 Hz, 2H), 1.55 (t, J=12.5 Hz, 2H), 1.38 (s, 6H), 1.24 ( s, 6H); 2Hs was not observed (NH and OH). 22 MS m/z 425.5 [M+H] ⁺ ; 1H NMR (methanol-sc) 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 (tg, J=12.5, 3.4 Hz, 1H), 3.01 (s, ZN), 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 was not observed (OH and 2NHs). 52 MS m/z 379.4 [M+H] ⁺ ; 'H NMR (methanol-sC) 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 observed (2NHs and OH) 60 MS m/z 396.5 [M+H] ⁺ ; 'H NMR (methanol-sC) δ: 8.79 (s, 1H), 7.98 (s, 1H), 7.927.96 (m, 1H), 7.83 (s, 1H), 7.79 ( d, J=8.2 Hz, 1H), 7.04-7.15 (m, 2H), 3.92-4.01 (m, 1H), 3.84-3.92 (m, 1H) , 3.72-3.80 (m, 1H), 3.50-3.59 (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] ⁺ ; 'H NMR (methanol-sc) δ: 8.94 (s, 1H), 8.09 (brd, 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 \u003d 6.9 Hz, 1H), 4.11-4.19 (m, 1H), 3.98 (s, ZN), 3.87-3.92 (m, 1H), 3.75-3, 81 (m, 1H), 3.69 (brd, J=8.2 Hz, 1H), 2.68 (brd, J=6.0 Hz, 1H), 2.32.40 (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 fitted with a magnetic stirrer and charged with 5-bromo-N-methylN-(2,2,6,6-tetramethylpiperidin-4-yl)pyrazin-2-amine (150 mg, 0.46 mmol), 4-(2,3-difluoro-4-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-(tetrahydro-2Н-pyran-2-yl)-1Н -pyrazole (215 mg, 0.55 mmol), tetrakis(triphenylphosphine)palladium(0) (58 mg, 0.05 mmol) and Na ₂ CO ₃ (146 mg, 1.38 mmol). The flask was sealed with a rubber cap and then evacuated and refilled with argon. Dioxane (4 ml) and water (1 ml) were added and the reaction mixture was heated to 90° C. for 16 hours. The reaction mixture was cooled to room temperature, diluted with water (5 ml) and extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with a CH ₂ Cl ₂ /MeOH gradient (0 to 30% MeOH) to give 5-(2,3-difluoro-4-(1-(tetrahydro-2H-pyran-2-yl )-1Hpyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyrazin-2-amine (166 mg, 71%) as a brownish solid. MS m/z 511.6 [M+H]+.

Step 2. To 5-(2,3-difluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)-N-methyl-N(2,2 ,6,6-tetramethylpiperidin-4-yl)pyrazin-2-amine (166 mg, 0.33 mmol) in CH ₂ Cl ₂ (2 ml) was added 4N HCl/dioxane (0.17 ml, 0.66 mmol) followed by the addition of MeOH (0.2 ml). The reaction mixture was stirred at room temperature for 2 hours. The solvents were removed under reduced pressure and the residue was triturated with Et ₂ O. The solid was filtered, washed with excess Et ₂ O and dried in vacuo to give 5-(2,3-difluoro -4-(1H-pyrazol-4-yl)phenyl)-N-methyl-N(2,2,6,6-tetramethylpiperidin-4-yl)pyrazin-2-amine hydrochloride (126 mg, 83%) as yellow solid.

MS m/z 427.5 [M+H] ⁺ ;

- 44 041957

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 were not observed.

Using the procedure described for example 3, additional compounds described in this application can be prepared using the appropriate starting material, suitable reagents and reaction conditions, to obtain compounds such as compounds selected from

Comm. Data 4 MS m/z 459.3, 461.3 [M+H] ⁺ ; 'H NMR (methanol-sC) 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 were not observed eleven MS m/z 423.5 [M+H] ⁺ ; 'H NMR (methanol-sc) δ: 8.51-4.63 (m, 1H), 8.19 (d, J=l.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, W ), 2.47 (s, ZN), 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 were not observed. 15 MS m/z 427.6 [M+H] ⁺ ; 'H NMR (methanol-cU) δ: 8.60-8.63 (m, 1H), 8.21 (d, J=l.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, 1=12.5, 3.4 Hz, 2H), 1.59 (t, 1=12.5 Hz, 2H), 1.40 (s, 6H); 1.26 (s, 6H); 2NHs were not observed. 16 MS m/z 409.5 [M+H] ⁺ ; 'H NMR (methanol-cU) δ: 8.63 (d, J=l.2 Hz, 1H), 8.15 (d, J=l.2 Hz, 1H), 8.08 (br s, 2H), 7.68-7.80 (m, ZN), 5.11-5.25 (m, 1H), 3.03 (s, ZN), 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 were not observed. 17 MS m/z 427.6 [M+H] ⁺ ; 'H NMR (miganol-sc) δ: 8.65 (d, J=l.5 Hz, 1H), 8.15 (d, J=l.5 Hz, 1H), 8.11 (s, 2H) , 7.65 (d, J=10.7 Hz, 2H), 5.18 (tg, J=12.2, 3.4 Hz, 1H), 3.04 (s, ZN), 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 were not observed. 23 MS m/z 443.4 [M+H] ⁺ ; 'H NMR (methanol-b ₄ ) δ: 8.60 (s, 1H), 8.20 (d, J=l.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

- 45 041957

(s, ZN), 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 were not observed. 24 MS m/z 434.5 [M+H] ⁺ ; 'H NMR (methanol-cU) δ: 8.57-8.67 (m, 1H), 8.38 (d, J=7.6 Hz, 1H), 8.26 (s, 2H), 8, 23 (d, J=l.2 Hz, 1H), 7.63 (d, J=12.5 Hz, 1H), 5.07-5.27 (m, 1H), 3.05 (s, ZN ), 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 were not observed. 41 MS m/z 441.3 [M+H] ⁺ ; 'H NMR (miganol-sc) δ: 8.62-8.67 (m, 1H), 8.30 (d, J=l.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] ⁺ ; 'H NMR (methanol-cU) δ: 8.88 (d, J=2.4 Hz, 1H), 8.64-8.69 (m, 1H), 8.24 (d, J=l.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] ⁺ ; 'H NMR (methanol-cU) 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), 4.124.18 (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 were not observed 64 MS m/z 399.4 [M+H] ⁺ ; Ή NMR (methanol-cU) δ: 8.64 (s, 1H), 8.17 (s, 2H), 8.028.09 (m, 1H), 7.78 (dd, J=12,l, 6, 6 Hz, 1H), 7.60 (dd, J=12,l, 6.3 Hz, 1H), 4.26 (bt, J=6.9 Hz, 1H), 4.12 (dd, J=11.4, 7.1 Hz, 1H), 3.83-3.90 (m, 1H), 3.63-3.71 (m, 2H), 2.62-2.71 (m, 1H), 2.23-2.34 (m, 1H), 1.50 (s, 9H); 2NHs were not observed

Example 4 Preparation of Compound 2

HCI

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 added dropwise 1.0M t-BuOK in THF (9.1 ml, 9.1 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 16 h until LCMS analysis showed that the starting material was completely consumed. The solvent was evaporated under reduced pressure and the residue was partitioned between EtOAc and water. The organic layers were dried over Na ₂ SO ₄ , the solvent was evaporated and the residue was purified by silica gel column chromatography eluting with a CH ₂ Cl ₂ /MeOH gradient (0 to 10% MeOH) to give 2-bromo 5-((2,2,6, 6-tetramethylpiperidin-4-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 fitted with a magnetic stirrer and charged with 2-bromo-5((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyrazine (367 mg, 1.17 mmol), 4-(3 -methoxy-4-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1 -(tetrahydro-2H-pyran-2-yl)-1 H-pyrazole (450 mg , 1.17 mmol, tetrakis(triphenylphosphine)palladium(0) (140 mg, 0.12 mmol) and Na ₂ CO ₃ (372 mg, 3.51 mmol) The flask was sealed with a rubber cap and then evacuated and refilled with argon Dioxane (10 ml) and water (2.5 ml) were added and the reaction mixture 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. dried over Na ₂ SO ₄ and concentrated under reduced pressure The residue was purified by column chromatography on silica gel eluting with a gradient of CH ₂ Cl ₂ /MeOH (0 to 30% MeOH) to give 2-(2-methoxy-4-(1- (tetrahydro-2H-pyran-2-yl)-1Hpyrazol-4-yl)phenyl)-5-((2,2,6,6-tetramethylpiperidin-4-yl) hydroxy)pyrazine (420 mg, 73%) as yellow

- 46 041957 brown solid.

MS m/z 492.6 [M+H]+;

1H NMR (acetone-d ₆ ): 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=1 1.5, 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), 1.74-1.87 (m, 2H), 1.59-1.72 (m, 3H), 1.31 (s, 6H), 1.18 ( s, 6H); 1H was not observed (NH).

Step 3: An oven-dried microwave vessel was fitted with a magnetic stirrer and loaded with 2-(2-methoxy-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)- 5-((2,2,6,6tetramethylpiperidin-4-yl)oxy)pyrazine (278 mg, 0.56 mmol), benzenethiol (59 µl, 0.56 mmol) and K ₂ CO ₃ (77 mg, 0.56 mmol) 56 mmol). The vessel was sealed and then evacuated and refilled with argon. NMP (1.5 ml) was added and the reaction mixture was heated to 190° C. in a microwave reactor for 20 minutes. The reaction mixture was cooled to room temperature, diluted with water (5 ml) and extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with a CH ₂ Cl ₂ /MeOH gradient (0 to 30% MeOH) to give 5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4yl)- 2-(5-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyrazin-2-yl)phenol (227 mg, 84%) as a tan solid.

MS m/z 478.6 [M+H]+;

1H NMR (acetone-a ₆ ): 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 was not observed (NH or OH).

Step 4. To a solution of 5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-2-(5-((2,2,6,6tetramethylpiperidin-4-yl) hydroxy)pyrazin-2-yl)phenol (100 mg, 0.20 mmol) in CH2Cl2 (1 ml) and MeOH (a few drops) was added HCl (4 mol/l) in 1,4-dioxane (0.25 ml, 1.0 mmol) and the reaction mixture was stirred at room temperature for 2 h until HPLC analysis showed that the starting material was completely consumed. The precipitate was collected by filtration and dried in vacuo to give 2-[1-(4-piperidyl)-pirazolo[3,4-c]pyridazin-5-yl]-5-(1H-n-pyrazol-4-yl)phenol; hydrochloride (61 mg, 71% as a yellow solid.

MS m/z 394.5 [M+H]+;

1H NMR (DMSO-d6) 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.l, 3.9 Hz, 2H), 1.81 (dd, J=13.l, 11.0 Hz, 2H), 1.52 (s, 6H), 1.51 (s, 6H); 1H was not observed (NH or OH).

Using the procedure described for example 4, additional compounds described in this application can be prepared using the appropriate starting material, suitable reagents and reaction conditions, to obtain compounds such as compounds selected from

Comm. Data

ΙΪ0 MS m/z 414.1 [M+H] ⁺ ; Ή NMR (DMSO-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=l.2 Hz, 1H), 8.18 (s, 2H), 7.65-7, 74 (m, 2H), 5.51-5.56 (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 An oven-dried flask was fitted with a magnetic stirrer and charged with 2,5-dibromopyrazine (500 mg, 2.10 mmol), 4-(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2yl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-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 cap and then evacuated and refilled with argon. Dioxane (12 ml) and water (3 ml) were added and the reaction mixture was heated to 90° C. for 5 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc. United Organic

- 47 041957 layers were dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with a hexane/EtOAc gradient (30-70% EtOAc) to give 2bromo-5-(2-methoxy-4-(1-(tetrahydro-2H-pyran-2-yl)-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-5-[2-methoxy-4-(1-tetrahydropyran-2-ylpyrazol-4-yl)phenyl]pyrazine (316 mg, 0.76 mmol) and (1R,5S)-bicyclo[ 3.2.1]octan-3-ol (80 mg, 0.63 mmol) was mixed in anhydrous DMF (1 ml) and cooled to 0° C. in an ice water bath. Sodium hydride (51 mg, 1.27 mmol, 60% in mineral oil) was then added. The reaction mixture was stirred at room temperature for 16 h, then quenched with water. The precipitate was collected by filtration, dried in vacuo to give 2-[[(1R,5S)-3bicyclo[3.2.1]octanyl]oxy]-5-[2-methoxy-4-(1-tetrahydropyran-2-ylpyrazol-4- yl)phenyl]pyrazine (220 mg, 75%) as an off-white solid. MS m/z 461.5 [M+H] ⁺ .

Step 3. To a solution of 2-[[(1R,5S)-3-bicyclo[3.2.1]octαnyl]oxy]-5-[2-methoxy-4-(1tetrahydropyran-2-ylpyrazol-4-yl)phenyl] pyrazine (220 mg, 0.48 mmol) in CH ₂ Cl ₂ was added boron tribromide (1.0 M in CH ₂ Cl ₂ , 2.4 ml, 2.4 mmol) and the reaction mixture was stirred at room temperature for 16 h until until the UHPLC analysis showed that the starting material was completely consumed. The reaction mixture was quenched with MeOH (10 mL), concentrated under reduced pressure and purified by silica gel column chromatography eluting with a gradient of CH ₂ Cl ₂ /MeOH (2.5% NH ₄ OH) (0 to 30% MeOH/NH ₄ OH ). 2-[5-[[(1S,5R)-8-azabicyclo[3.2.1]octan-3-yl]oxy]pyrazin2-yl]-5-(1H-pyrazol-4-yl)phenol (122 mg , 70%) as a yellow solid.

MS m/z 364.4 [M+H] ⁺ ;

1H NMR (DMSO-d6) 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 was not observed (OH or NH).

Using the procedure described for Example 5, additional compounds described in this application can be prepared using the appropriate starting material, suitable reagents and reaction conditions to give compounds such as those selected from

Comm. Data 7 MS m/z 368.4 [M+H] ⁺ ; 'H NMR (methanol-c1 ₄ ) δ: 8.93 (d, J=l.5 Hz, 1H), 8.29 (d, J=l.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), 3.27-3.32 (m, 2H), 2.26-2.34 (m, 2H) , 2.13-2.21 (m, 2H); 3 Hs was not observed (2 NHs and OH).

Example 6 Preparation of Compound 8

Step 1. To a mixture of 2-bromo-5-(2-methoxy-4-(1-(tetrahydro-2H-pyrαn-2-yl)-1H-pyrazol-4yl)phenyl)pyrazine (200 mg, 0.48 mmol ) and tert-butyl 4-aminopiperidine-1-carboxylate (96 mg, 0.48 mmol) in EtOH (1 ml) was added a drop of conc. HCl. The reaction mixture was sealed and heated at 120° C. for 16 h until LCMS analysis indicated that the starting material had been completely consumed. The mixture was cooled and the solvent was evaporated to give crude 5-(2methoxy-4-(1-(tetrahydro-2H-pyrαn-2-yl)-1H-pyrazol-4-yl)phenyl)-N-(piperidin-4-yl) pyrazin-2-amine hydrobromide (248 mg), which was used in the next step without further purification.

MS m/z 435.2 [M+H] ⁺ .

Step 2. To a suspension of 5-(2-methoxy-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)-N(piperidin-4-yl)pyrazin- 2-amine hydrobromide (248 mg, 0.48) in CH ₂ Cl ₂ was added boron tribromide (1.0 M in CH ₂ Cl ₂ , 2.4 ml, 2.4 mmol) and the reaction mixture was stirred at room temperature for 16 h until the UHPLC analysis showed that the starting material was completely consumed. The reaction mixture was quenched with MeOH (10 mL), concentrated under reduced pressure, and purified by silica gel column chromatography eluting with a gradient of CH2Cl2/MeOH (2.5% NH4OH) (0 to 30% MeOH/NH ₄ OH). Received 2-(5-(piperidin-4-ylamino)pyrazin-2-yl)-5-(1H-pyrazol4-yl)phenol (128 mg, 79%) as an orange solid.

MS m/z 337.4 [M+H] ⁺ ;

1H NMR (methanol-b 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 was not observed (3NHs and OH).

Using the procedure described for example 6, you can get additional compounds described in this application using the appropriate starting material, suitable reagents

- 48 041957 and reaction conditions, to obtain compounds, such as compounds selected from

Comm. Data 3 MS m/z 487.6 [M+H] ⁺ ; 'H NMR (methanol-sc) 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=8.2Hz, 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, YuN), 1.28-1.43 (m, 4H ); 3 Hs was not observed (2NHs and OH). 6 MS m/z 349.2 [M+H] ⁺ ; 'H 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 was not observed (NH or OH). 20 MS m/z 351.4 [M+H] ⁺ ; 1H NMR (methanol-b ₄ ) δ: 8.80 (d, J=l.5 Hz, 1H), 8.08 (d, J=l.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=l.5 Hz, 1H), 4.68 (tg, J=12.5, 4.3 Hz, 1H), 3.26 (d, J=12.5 Hz, 2H), 3.05 (s, ZN), 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 was not observed (2NHs and OH). 21 MS m/z 349.2 [M+H] ⁺ ; 'H 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 was 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-4-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 by chromatography on silica gel, eluting with a gradient of MeOH/CH ₂ Cl ₂ (0 to 15% MeOH) to give 5-6pom-N(2,2,6,6-tetramethylpiperidin-4-yl)pyrazin-2-amine (10 g, 84% yield) as an off-white solid.

MS: m/z: 313.1, 315.1 [M+H]+.

Step 2. To a round bottom flask was added: 5-bromo-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyrazin2-amine (10.0 g, 31.9 mmol), 3-(methoxymethoxy)- 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl 4methylbenzenesulfonate (13.9 g, 32.0 mmol), K ₂ CO ₃ (8.8 g, 64 mmol) and PdCl ₂ dppf (234 mg, 0.32 mmol). The mixture was degassed with nitrogen and then 1,4-dioxane (100 ml) and water (10 ml) were added. The mixture was stirred at 100° C. for 16 hours. After cooling to room temperature, the solvent was removed and the residue was purified by silica gel chromatography eluting with a MeOH/CH ₂ Cl ₂ gradient (0 to 30% MeOH) to give 3-(methoxymethoxy)- 4-(5-((2,2,6,6-tetramethylpiperidin-4-yl)amino)pyrazin-2-yl)phenyl 4methylbenzenesulfonate (4.5 g, 26% yield) as a brown solid.

MS: m/z: 541.3 [M+H] ⁺ .

- 49 041957

Step 3. To a solution of 3-(methoxymethoxy)-4-(5-((2,2,6,6-tetramethylpiperidin-4-yl)amino)pyrazin2-yl)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°C for 2 hours. The solvent was removed and the residue was washed through a plug of silica gel using 0-10% MeOH in CH ₂ Cl ₂ to obtain crude 3-(methoxymethoxy)-4-(5-((2, 2,6,6-tetramethylpiperidin-4-yl)amino)pyrazin-2-yl)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)-4-(5-((2,2,6,6-tetramethylpiperidin-4-yl)amino)pyrazin2-yl)phenol (2.43 g, 6.29 mmol) in CH ₂ Cl ₂ (40 ml) was added PhNTf ₂ (6.8 g, 19 mmol) and Et ₃ N (1.9 g, 19 mmol). The reaction mixture was stirred at room temperature for 16 hours. The solvent was removed and the residue was purified by silica gel chromatography eluting with a gradient of MeOH/CH ₂ Cl ₂ (0 to 30% MeOH) to give 3-(methoxymethoxy)-4-(5- ((2,2,6,6-tetramethylpiperidin-4-yl)amino)pyrazin2-yl)phenyl trifluoromethanesulfonate (1.9 g, 58% yield) as a pale yellow solid.

MS: m/z: 519.2 [M+H] ⁺ .

Step 5. Mixture of 3-(methoxymethoxy)-4-(5-((2,2,6,6-tetramethylpiperidin-4-yl)amino)pyrazin-2yl)phenyl trifluoromethanesulfonate (1.5 g, 2.9 mmol) , bis(pinacolato)diboron (773 mg, 3.05 mmol), Pd(dppf)Cl ₂ (220 mg, 0.30 mmol) and KOAc (568 mg, 5.8 mmol) were degassed with nitrogen. 1,4-dioxane (25 ml) was added and the reaction mixture was stirred at 100° C. for 16 h. The solvent was removed to give a crude product which was purified by silica gel chromatography eluting with a gradient of MeOH/CH ₂ Cl ₂ (0 to 30% MeOH), to give 5-(2-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)phenyl)-N-(2,2,6,6 -tetramethylpiperidin-4-yl)pyrazine-2-amine (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-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N(2,2,6,6 -tetramethylpiperidin-4-yl)pyrazin-2-amine (180 mg, 0.36 mmol), 2-bromopyridine (56 mg, 0.35 mmol), K ₂ CO ₃ (100 mg, 0.73 mmol) and SPhos Pd G2 (26 mg, 0.036 mmol) was degassed with nitrogen. 1,4-dioxane (5 ml) and water (0.5 ml) were added and the reaction mixture was stirred at 70° C. for 16 h. The solvent was removed and the residue was purified by silica gel chromatography eluting with a gradient of MeOH/CH ₂ Cl ₂ ( 0 to 30% MeOH), to give 5-(2-(methoxymethoxy)-4-(pyridin-2-yl)phenyl)-N-(2,2,6,6tetramethylpiperidin-4-yl)pyrazin-2-amine (90 mg, 55% yield) as a brown solid.

MS: m/z: 448.3 [M+H] ⁺ .

Step 7 To a solution of 5-(2-(methoxymethoxy)-4-(pyridin-2-yl)phenyl)-N-(2,2,6,6tetramethylpiperidin-4-yl)pyrazin-2-amine (90 mg, 0.20 mmol) in CH ₂ Cl ₂ (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, neutralized with saturated aqueous NaHCO ₃ and extracted at help CH ₂ Cl ₂ (150 ml x 3). The combined organic phases were concentrated and the residue was purified by preparative HPLC to give 5-(pyridin-2-yl)-2-(5-((2,2,6,6-tetramethylpiperidin-4yl)amino)pyrazin-2-yl)phenol ( 34 mg, 42% yield) as a pale yellow solid.

MS: m/z: 404.2 [M+H] ⁺ ;

¹ H 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 was not observed (OH or NH).

Using the procedure described for Example 7, additional compounds described in this application can be prepared using the appropriate starting material, suitable reagents, and reaction conditions to give compounds such as those selected from

Comm. Data 43 MS m/z 425.5 [M+H] ⁺ ; 'H 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 observed (2 NHs and OH) 47 MS m/z 405.2 [M+H] ⁺ ; 'H 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 observed (OH or NH) 49 MS m/z 435.2 [M+H] ⁺ ; 'H NMR (DMSO-d ₆ ) δ: 8.90 (s, 1H), 8.84 (s, 1H), 8.40

- 50 041957

(br.s, 1H), 7.98-8.00 (m, 2H), 7.73 (d, J=l.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] ⁺ ; 'H 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=l.6 Hz, 1H), 7.55 (dd, J=8.0, 1.6 Hz, 1H), 7.39 (d, J=7.2 Hz, 1H), 4.25- 4.32 (m, 1H), 1.94-1.99 (m, 2H), 1.27-1.38 (m, 14H); 1H not observed (OH or NH) 55 MS m/z 407.1 [M+H] ⁺ ; 'H 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] ⁺ ; 'H NMR (DMSO-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=l.6 Hz, 1H), 7, 58 (dd, J=8.4, l, 6 Hz, 1H), 7.47 (d, J=7.6 Hz, 1H), 4.30-4.32 (m, 1H), 1.96 -2.00 (m, 2H), 1.30-1.40 (m, 14H); 1H not observed (OH or NH) 57 MS m/z 411.2 [M+H] ⁺ ; 'H 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), 7.087.10 (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] ⁺ ; 'H 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, ZN), 6.70 (d, J=2.4 Hz, 1H), 4.26- 4.28 (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 [M+H] ⁺ ; 'H NMR (methanol-b ₄ ) 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-M-methyl-X-(2,2,6,6-tetramethylpiperidin-4-yl)pyrazin-2-amine (0.8 g, 2.44 mmol), 2-(4 -chloro-2-(methoxymethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.87 g, 2.91 mmol), [1,1'-bis(diphenylphosphino) ferrocene]dichloropalladium(II) (0.17 g, 0.23 mmol) and aq. 2N K ₂ CO ₃ (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° C. for 4 hours. The reaction mixture was cooled to room temperature, the solvent was evaporated under reduced pressure, and the residue was partitioned between EtOAc and saturated aqueous NaHCO ₃ . The organic layers were dried over Na ₂ SO ₄ and the solvent was evaporated. The residue was purified by silica gel chromatography eluting with a MeOH/CH ₂ C1 ₂ gradient (0 to 30% MeOH) to give 5-(4-chloro-2-(methoxymethoxy)phenyl)-M-methyl-M-(2.2 ,6,6-tetramethylpiperidin-4yl)pyrazine-2-amine (0.62 g, 60%).

MS m/z 419.5 [M+H] ⁺

Stage 2. tris(dibenzylideneacetone)diialladium(0) (2.6 mg, 0.0028 mmol) and 2-di-tert

-51 041957 bugylphosphino-3,4,5,6-tetramethyl-2',4',6'-triisopropyl-1,G-biphenyl (3.5 mg, 0.0070 mmol) suspended in 5:1 toluene/dioxane (1 ml). The purple-red solution was sparged with argon for 5 minutes, then heated to 120° C. 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-tetramethylpiperidin-4-yl)pyrazine-2-amine (42 mg, 0.1 mmol). The suspension was sparged again with argon, then heated to 120° C. for 1 hour until the UHPLC analysis indicated that the aryl chloride was completely consumed. The reaction mixture was cooled to room temperature and the product was purified by silica gel chromatography eluting with a MeOH/CH ₂ Cl ₂ gradient (0 to 30% MeOH) to give 5-(2-(methoxymethoxy)-4-(2H-1.2, 3-triazol-2-yl)phenyl)N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyrazin-2-α-min (40 mg, 88% yield).

MS m/z 452.4 [M+H]+;

¹ H 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); 1 NH was not observed.

Step 3. To a solution of 5-(2-(methoxymethoxy)-4-(2H-1,2,3-triazol-2-yl)phenyl)-N-methyl-N-(2,2,6,6tetramethylpiperidine-4 -yl)pyrazin-2-amine (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 hours. The solvents were evaporated and the residue was purified by silica gel chromatography eluting with a gradient of MeOH/CH ₂ Cl ₂ (0 to 30% MeOH) to give 2-(5-(methyl-(2, 2,6,6-Tetramethylpiperidin-4yl)amino)pyrazin-2-yl)-5-(2H-1,2,3-triazol-2-yl)phenol (20 mg, 76% yield).

MS m/z 408.5 [M+H] ⁺ ;

1H NMR (methanol-ID 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), 1.33-1.37 (m, 6H), 2Hs was not observed (NH and OH).

Using the procedure described for example 8, additional compounds described in this application can be prepared using the appropriate starting material, suitable reagents and reaction conditions, to obtain compounds such as compounds selected from

Comm. Data 50 MS m/z 393.2 [M+H] ⁺ ; 'H 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), 7.16-7.22 (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] ⁺ ; 'H 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=l.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] ⁺ ; 'H 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), 1.95-1.99 (m, 2H), 1.28-1.38 (m, 14H); 1H not observed (OH or NH)

Biological examples

The following in vitro biological examples demonstrate the utility of the compounds of the present invention in the treatment of Huntington's disease.

For a more detailed description and for a better understanding of the present description, the following non-limiting biological examples are provided to more fully illustrate the scope of the description, and should not be construed as specifically limiting its scope. Such various variations of the present invention, which may be known or may be developed subsequently, which should be within the skill of the art to ascertain, are considered to be covered by the scope of the present description and are further claimed in the claims.

Compounds of formula (I) were tested using the Meso Scale Discovery (MSD) assay presented in International Application No. PCT/US 2016/066042 filed December 11, 2016 and claiming priority according to US Provisional Application No. 62/265652 filed December 10, 2015 g., the entire content of which is incorporated into this application by reference.

The endogenous huntingtin protein assay used in Example 1 was developed using the MSD ELISA-based electrochemiluminescent assay platform.

Example 1 Analysis of Endogenous Huntingtin Protein.

Meso Scale Discovery (MSD) 96-well or 384-well plates were plated overnight

- 52 041957 at 4°C MW1 (expanded polyglutamine) or MAB2166 monoclonal antibody (for capture) at a concentration of 1 μg/ml in PBS (30 μl per well). The 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 shaking and then washed three times with wash buffer.

Samples (25 μl) were transferred to an 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 1 h at room temperature. After incubation with the secondary antibody, the wells were washed with wash buffer, then 25 µl goat anti-rabbit SULFO TAG secondary detection antibody (a required aspect of the MSD system) (diluted to 0.25 µg/ml in 0.05% Tween-20 in blocking buffer) was added to each well. ) and incubated with shaking for 1 h at room temperature. After washing three times with wash buffer, 150 µl of surfactant (MSD) reading buffer T was added to each empty well and the plate was imaged on the SI 6000 Imaging Device (MSD) according to the manufacturer's instructions for 96- or 384-well tablets. The obtained IC ₅₀ values (μM) for the tested compounds are shown in the table.

As shown in the table, the tested compounds described in this application had the following IC ₅₀ values: IC ₅₀ value between >3 μM and <9 μM indicated by one asterisk (*), IC ₅₀ value between >1 μM and <3 μM indicated by two asterisks (**), IC ₅₀ value between >0.5 µM and <1 µM indicated by three asterisks (***), IC ₅₀ value between >0.1 µM and <0.5 µM indicated by four asterisks (*** *) and IC ₅₀ value <0.1 μM indicated by five asterisks (*****). __________________________

Comm. 1С ₅₀ Comm. ic ₅₀ Comm. ic ₅₀ 1 sjc 19 ** 49 2 *** 20 *** 50 **** 3 ** 21 ** 51 *** 4 ** 22 52 5 *** 23 **** 53 **** 6 ** 24 54 7 ** 25 * 55 *** 8 ** 26 56 9 ** 27 **** 57 10 ** 28 *** 58 **** eleven **** 41 *** 59 ** 12 *** 42 **** 60 13 43 **** 61 **** 14 ** 44 **** 62 15 45 *** 63 **** 16 *** 46 64 17 **** 47 ** 65 18 ** 48 *

Whether or not the cited document has been specifically and individually identified as being incorporated by reference, all documents cited in this application are incorporated by reference into this application for any and all purposes to the extent that each individual reference was set forth in its entirety in this application.

Having a full description of the claimed invention, it should be clear to those skilled in the art that the same can be carried out in a wide range of equivalents without affecting the scope of the claimed invention or the specific aspects described in this application. The appended claims are intended to be interpreted as including all such equivalents.

-

Claims (10)

CLAIM 1. A compound which is a compound of formula (I) or its salt, where X is CHR _1a , C=O, O, NR _1b or a bond; R _1a is independently selected from cyano and amino; R _1b is independently selected from hydrogen and C ₁ _ ₄ alkyl; B is a heterocyclyl wherein heterocyclyl is a saturated or partially unsaturated 3-7 membered monocyclic, 6-10 membered bicyclic or 13-16 membered polycyclic ring system containing 1, 2 or 3 heteroatoms as ring members, independently selected from N, O or S, each unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents each selected from R ₂ ; R ₂ is independently selected from C ₁ _ ₄ αalkyl and C ₁ _ ₄ alkylamino; R ₃ is independently selected from halogen, hydroxyl, cyano, C ₁ _ ₄ αalkyl and heteroaryl, where heteroaryl is a 3-7 membered monocyclic or 6-10 membered bicyclic ring system containing 1, 2, 3 or 4 heteroatoms as ring members independently selected from N, O or S, wherein the heteroaryl is unsubstituted or 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, C ₁ _ ₄ αalkyl, deutero-C ₁ _ ₄ alkyl, halo-C ₁ _ ₄ alkyl, amino, and C ₁ _ ₄ alkoxy. 2. The connection according to claim 1, where X is selected from NR _1b and communication. 3. A compound according to claim 1, wherein B is selected from azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, 1,4-diazepanyl, 1,2-dihydropyridinyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3, 6tetrahydropyridinyl, 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 [3,4-0]pyrrol-( 1 H)-yl, hexahydropyrrolo [3,4-c]pyrrol-( 1 H)-yl, hexahydropyrrolo[3,4-c] pyrrol-(1H)-yl, (3aR,6aS)octahydro-2H-pyrrolo[3,4-c]pyridinyl, octahydro-5Hpyrrolo[3,2-c]pyridinyl, octahydro-6H-pyrrolo[3,4-b ]pyridinylα, (4aR,7aR)-octahydro-6Hpyrrolo[3,4-b]pyridinyl, (4aS,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridinyl, hexahydropyrrolo[1,2а]pyrazine-( 2H)-one, a] pyrazin-( 1H) -yl, a] pyrazin-( 1H) -yl, hexahydropyrrolo[1,2-a] pyrazin-( 1 H)-yl, (7R,8aS)-hexahydropyrrolo[ 1.2( 8aS)-hexahydropyrrolo[1,2-а]pyrazin-(1H)-yl, (8aR)-hexahydropyrrolo[1,2hexahydro-1H-cyclobuta[1.2-с:1,4-с']dipyrrol-(3H)- silt, (8aS)-octahydropyrrolo [1,2-a]pyrazin-(1H)-yl, (8aR)-octahydropyrrolo[1,2-a]pyrazin-(1H)-ylα, octahydro-2H-pyrido[1,2a]pyrazinyl, hexahydropyrrolo[3 ,4-b][1,4]oxazin-(2H)-yl, 5-azaspiro[2.4]heptanyl, azaspiro [3.4]octanyl, 3-azabicyclo[3.1.0]hexanyl, 8-azabicyclo [3.2.1] octanyl, 2-oxa-6(1R,5S)-8azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]oct-2-en-yl, (1R,5S)-8-azabicyclo[3.2.1 ]oct-2-en-yl, 9azabicyclo[3.3.1]nonanyl, (1 R,5S)-9-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, 3,8diazabicyclo[3.2.1]octanyl, (1R,5S)-3,8-diazabicyclo[3.2.1]octanyl, 1,4-diazabicyclo[3.2.2]nonanyl, azaspiro[3.3]heptanyl, diazaspiro[3.4] octanyl, diazaspiro[3.5]nonanil, diazaspiro[4.4]nonanil, 4,7-diazaspiro[2.5] octanyl, 1,7-diazaspiro[4.4] nonanyl, 2,7-diazaspiro[3.5] nonanyl, 2,7-diazaspiro[4.5] decanyl, 2,6-diazaspiro[3.3]heptan-2-yl, 1,7-diazaspiro[3.5]nonanil, 5,8-diazaspiro[3.5]nonanil, 2,8-diazaspiro[4.5]decanyl, 2,62,62,76,9diazaspiro[4.5]decyl and 7-azadispiro[5.1.58.3 ⁶ ]hexadecanyl, unsubstituted or substituted with 1, 2, 3, 4 or 5 R ₂ substituents. 4. The compound of claim 1 wherein B is selected from pyrrolidinyl, piperidinyl, hexahydropyrrolo[3,4c]pyrrol-(1H)-yl, 8-azabicyclo[3.2.1]octanyl, 2,6-diazaspiro[3.4]octanyl, and 7-azadispiro[5.1.58.3 ⁶ ]hexadecanyl, unsubstituted or substituted with 1, 2, 3, 4 or 5 R ₂ substituents. 5. The compound according to claim 1, where R ₃ is a heteroaryl selected from thienyl, 1H-pyrazolyl, 1H-imidazolylα, 1,3-thiazolyl, oxazolyl, 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl , 1H-1,2,3triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, 1H-tetrazolyl, 2H-tetrazolyl, pyridinyl, - 54 041957 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, 1,3-benzothiazolyl, 1,3benzodioxolyl, 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, thieno[2,3d]pyrimidinyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[2,3-c] pyridinyl, pyrrolo[1,2a]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, 1H-pyrazolo[3,4-b]pyridinyl, 1H-pyrazolo[3,4-b]pyridinyl, 1H-pyrazolo[3,4-c]pyridinyl, 1H-pyrazolo[ 3,4-с]pyridinyl, 1Н-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[1,5a]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[1,2b]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, 3H-[1,2,3]triazolo[4,5-b]pyridinyl, tetrazolo[1,5-a]pyridinyl, tetrazolo[1, 5-b]pyridazinyl, quinolinyl, isoquinolinyl and quinoxalinyl, unsubstituted or substituted with 1 or 2 R4 substituents. 6. A compound according to claim 1 wherein R3 is heteroaryl selected from 1H-pyrazolyl, 1Himidazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, pyridinyl, pyridine-2(1H) -on-yl, pyrimidinyl, 1,3,5-triazinyl, imidazo[1,2-b]pyridazinyl and imidazo[1,2-a]pyrazinyl, unsubstituted or substituted with 1 or 2 R4 substituents. 7. The compound of claim 1 wherein the salt of the compound is selected from hydrochloride, hydrobromide, trifluoroacetate, formate, dihydrochloride, trihydrochloride, tetrahydrochloride, dihydrobromide, and ditrifluoroacetate. 8. A compound selected from the group consisting of the following compounds: 4-(3-hydroxy-4-{5-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin-2-yl}phenyl)pyridin-2-ol; 5-(1H-pyrazol-4-yl)-2-{5-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyrazin-2-yl}phenol; 2-{5-[(7-azadispiro[5.1.5 ^{8.3 6} ]hexadecan-15-yl)(methyl)amino]pyrazin-2-yl}-5-(1H-pyrazol-4yl)phenol; 5-[2,5-dichloro-4-(1H-pyrazol-4-yl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyrazine2-amine; 5-(1H-imidazol-1-yl)-2-{5-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin-2-yl}phenol; 2-[5-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrazin-2-yl]-5-(1H-pyrazol-4-yl)phenol; 2-{5-[(piperidin-4-yl)oxy]pyrazin-2-yl}-5-(1H-pyrazol-4-yl)phenol; 2-{5-[(piperidin-4-yl)amino]pyrazin-2-yl}-5-(1H-pyrazol-4-yl)phenol; 2-{5-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin-2-yl}-5-[5-(trifluoromethyl)-1Hpyrazol-4-yl]phenol; 2-[2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl]-5-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyrazine; 5-[2-fluoro-5-methyl-4-(1H-pyrazol-4-yl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4yl)pyrazin-2-amine; 5-(5-methyl-1H-pyrazol-4-yl)-2-{5-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin-2yl}phenol; 5-[2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyrazin2-amine; 5-(3-amino-1H-pyrazol-1-yl)-2-{5-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin-2yl}phenol; 5-[2,5-difluoro-4-(1H-pyrazol-4-yl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyrazin2-amine; 5-[3-fluoro-4-(1H-pyrazol-4-yl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyrazin-2-amine; 5-[3,5-difluoro-4-(1H-pyrazol-4-yl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyrazin2-amine; 4-(3-hydroxy-4-{5-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin-2-yl}phenyl)-1methylpyridin-2(1H)-one; 2-{5-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin-2-yl}-5-(1H-pyrazol-1-yl)phenol; 2-{5-[methyl-(piperidin-4-yl)amino]pyrazin-2-yl}-5-(1H-pyrazol-4-yl)phenol; 2-[5-(2,6-diazaspiro[3.4]octan-2-yl)pyrazin-2-yl]-5-(1H-pyrazol-4-yl)phenol; 4-fluoro-2-{5-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin-2-yl}-5-(1H-pyrazol-4yl)phenol; - 55 041957 5-[5-chloro-2-fluoro-4-(1H-pyrazol-4-yl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4yl)pyrazin-2-amine; 4-fluoro-5-{5-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin-2-yl}-2-(1H-pyrazol-4yl)benzonitrile; 2-[5-(8-azabicyclo[3.2.1]oct-3-yloxy)pyrazin-2-yl]-5-(1H-pyrazol-4-yl)phenol; 2-{5-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin-2-yl}-5-(1H-pyrazol-4-yl)phenol; 5-(1-methyl-1H-pyrazol-4-yl)-2-{5-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin-2yl}phenol; 5-[1-(2H3)methyl-1H-pyrazol-4-yl]-2-{5-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin2-yl}phenol; (5-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyrazin-2-yl)(2,2,6,6-tetramethylpiperidin-4-yl)methanone; 2-(5-(2-hydroxy-4-(III-pyrazol-4-yl)phenyl)pyrazin-2-yl)-2-(2,2,6,6-tetramethylpiperidin-4yl)acetonitrile; 2-(5-(amino-(2,2,6,6-tetramethylpiperidin-4-yl)methyl)pyrazin-2-yl)-5-(1H-pyrazol-4-yl)phenol; 2-(5-(methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyrazin-2-yl)-5-(1,3,5-triazin-2-yl)phenol; 4-(3-hydroxy-4-(5-(methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyrazin-2-yl)phenyl)-1,3,5triazin-2-ol ; 5-(4-Amino-1,3,5-triazin-2-yl)-2-(5-(methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyrazin-2yl)phenol ; 5-(4-chloro-1,3,5-triazin-2-yl)-2-(5-(methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyrazin-2yl)phenol ; 5-(5-chloro-1H-pyrazol-4-yl)-2-(5-(methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyrazin-2yl)phenol; 4-(3-hydroxy-4-(5-(methyl-(2,2,6,6-tetramethyln-ineridin-4-yl)amino)-n-pyrazin-2-yl)phenyl)-1Hpyrazole-5-carbonitrile; 5-(1,5-dimethyl-1H-pyrazol-4-yl)-2-(5-(methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyrazin-2yl)phenol; 5-(5-chloro-1-methyl-1H-pyrazol-4-yl)-2-(5-(methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyrazin-2-yl )phenol; 4-(3-hydroxy-4-(5-(methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyrazin-2-yl)phenyl)-1-methyl1 H-pyrazole-5 - carbonitrile; 5-[2,3-difluoro-4-(4-methyl-III-imidazol-1-yl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4yl)pyrazin-2- amine; 5-[2,5-difluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl]-N-methyl-K-(2,2,6,6-tetramethylpiperidine4- yl) pyrazine-2-amine; 5-(3-fluoro-1H-pyrazol-4-yl)-2-{5-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin-2yl}phenol; 5-(pyridin-4-yl)-2-{5-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin-2-yl}phenol; 5-(pyridin-3-yl)-2-{5-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin-2-yl}phenol; 5-(1H-pyrazol-4-yl)-2-{5-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin-2-yl}phenol; 5-(pyrimidin-2-yl)-2-{5-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin-2-yl}phenol; 5-(pyridin-2-yl)-2-{5-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin-2-yl}phenol; 5-(6-methoxypyrimidin-4-yl)-2-{5-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin-2yl}phenol; 5-(1H-imidazol-1-yl)-2-{5-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin-2-yl}phenol; 2-{5-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin-2-yl}-5-(2H-1,2,3-triazol-2-yl)phenol; 2-{5-[3-(t-butylamino)pyrrolidin-1-yl]pyrazin-2-yl}-5-(1H-pyrazol-4-yl)phenol; 5-(imidazo[1,2-a]pyrazin-6-yl)-2-{5-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin-2yl}phenol; 5-(1-methyl-1H-pyrazol-4-yl)-2-{5-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin-2-yl}phenol; 5-(1-methyl-1H-pyrazol-3-yl)-2-{5-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin-2-yl}phenol; 5-(imidazo[1,2-b]pyridazin-6-yl)-2-{5-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin-2yl}phenol; 5-(5-fluoro-1H-pyrazol-4-yl)-2-{5-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin-2-yl}phenol; 5-(1H-pyrazol-3-yl)-2-{5-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin-2-yl}phenol; 5-(4-fluoro-1H-pyrazol-1-yl)-2-{5-[(2,2,6,6-tetramethylpiperide in-4-yl)amino]pyrazin-2-yl}phenol; 2-{5-[3-(t-butylamino)pyrrolidin-1-yl]pyrazin-2-yl}-5-[1-2(H3)methyl-1H-pyrazol-4yl]phenol; 2-{5-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin-2-yl}-5-(2H-1,2,3-triazol-2yl)phenol; 2-{5-[3-(t-butylamino)pyrrolidin-1-yl]pyrazin-2-yl}-5-(1-methyl-1H-pyrazol-4-yl)phenol; N-tert-butyl-1-{5-[2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl]pyrazin-2-yl}pyrrolidin-3-amine; - 56 041957 M-tert-butyl-1-{5-[2,5-difluoro-4-(1H-pyrazol-4-yl)phenyl]pyrazin-2-yl}pyrrolidin-3-amine and 2-{5-[3-(t-butylamino)pyrrolidin-1-yl]pyrazin-2-yl}-5-(3-fluoro-1H-pyrazol-4-yl)phenol, or a salt thereof. 9. A compound according to claim 8, wherein the salt of the compound is selected from the group consisting of the following: 5-(1H-pyrazol-4-yl)-2-{5-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyrazin-2-yl}phenol hydrochloride; 2-[5-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrazin-2-yl]-5-(1H-pyrazol-4-yl)phenol tetrahydrochloride; 2-{5-[(piperidin-4-yl)oxy]pyrazin-2-yl}-5-(1H-pyrazol-4-yl)phenol trihydrochloride; 2-{5-[(piperidin-4-yl)amino]pyrazin-2-yl}-5-(1H-pyrazol-4-yl)phenol tetrahydrochloride; 2-[2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl]-5-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyrazine trihydrochloride; 5-[2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl]-M-methyl-M-(2,2,6,6-tetramethylpiperidin-4-yl)pyrazin2-amine hydrochloride; 2-[5-(8-azabicyclo[3.2.1]oct-3-yloxy)pyrazin-2-yl]-5-(1H-pyrazol-4-yl)phenol hydrochloride; 2-{5-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin-2-yl}-5-(1H-pyrazol-4-yl)phenol hydrobromide; 5-[1-2(Н3)methyl-1Н-pyrazol-4-yl]-2-{5-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin2-yl}phenol dihydrochloride; 5-(3-fluoro-1H-pyrazol-4-yl)-2-{5-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin-2yl}phenol dihydrochloride; 5-(pyridin-4-yl)-2-{5-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin-2-yl}phenol formate; 5-(pyridin-3-yl)-2-{5-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin-2-yl}phenol formate; 5-(1H-pyrazol-4-yl)-2-{5-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin-2-yl}phenol formate; 5-(pyrimidin-2-yl)-2-{5-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin-2-yl}phenol formate; 5-(pyridin-2-yl)-2-{5-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin-2-yl}phenol formate; 5-(6-methoxypyrimidin-4-yl)-2-{5-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin-2-yl}phenol formate; 5-(1H-imidazol-1-yl)-2-{5-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin-2-yl}phenol formate; 2-{5-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin-2-yl}-5-(2H-1,2,3-triazol-2-yl)phenol formate; 2-{5-[3-(t-butylamino)pyrrolidin-1-yl]pyrazin-2-yl}-5-(1H-pyrazol-4-yl)phenol dihydrochloride; 5-(imidazo[1,2-a]pyrazin-6-yl)-2-{5-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin-2-yl}phenol formate; 5-(1-methyl-1H-pyrazol-4-yl)-2-{5-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin-2-yl}phenol formate; 5-(imidazo[1,2-b]pyridazin-6-yl)-2-{5-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin-2yl}phenol formate; 5-(5-fluoro-1H-pyrazol-4-yl)-2-{5-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin-2-yl}phenol formate; 5-(1H-pyrazol-3-yl)-2-{5-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin-2-yl}phenol formate; 5-(4-fluoro-1H-pyrazol-1-yl)-2-{5-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin-2-yl}phenol formate; 2-{5-[3-(t-butylamino)pyrrolidin-1-yl]pyrazin-2-yl}-5-[1-2(H3)methyl-1H-pyrazol-4-yl]phenol dihydrochloride; 2-{5-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrazin-2-yl}-5-(2H-1,2,3-triazol-2-yl)phenol dihydrochloride; 2-{5-[3-(t-butylamino)pyrrolidin-1-yl]pyrazin-2-yl}-5-(1-methyl-1H-pyrazol-4-yl)phenol dihydrochloride; M-tert-butyl-1-{5-[2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl]pyrazin-2-yl}pyrrolidin-3-amine dihydrochloride; M-tert-butyl-1-{5-[2,5-difluoro-4-(1H-pyrazol-4-yl)phenyl]pyrazin-2-yl}pyrrolidin-3-amine dihydrochloride and 2-{5-[3-(t-butylamino)pyrrolidin-1-yl]pyrazin-2-yl}-5-(3-fluoro-1H-pyrazol-4-yl)phenol dihydrochloride. 10. A pharmaceutical composition containing an effective amount of a compound according to any one of claims 1, 8 or 9 in admixture with one or more pharmaceutically acceptable excipients. ^gj) Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky per., 2