Heteroaryl compounds for treating Huntington's disease

Abstract

This specification relates to compounds, forms thereof and pharmaceutical compositions, and methods of using such compounds, forms thereof or compositions for treating or ameliorating Huntington's disease. In particular, this specification relates to compounds of formula (I), forms thereof and pharmaceutical compositions, and methods of using such compounds, forms thereof or compositions for treating or ameliorating Huntington's disease. TIFF2024528066000087.tif57139

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is an international application claiming the benefit of U.S. Provisional Application No. 63 / 203,761, filed July 30, 2021, the entirety of which is incorporated herein by reference.

[0002] Aspects of the present specification relate to compounds, forms thereof, and pharmaceutical compositions useful for treating or ameliorating Huntington's disease, as well as methods of using such compounds, forms thereof, or compositions. In particular, another aspect of the present specification relates to substituted bicyclic heteroaryl compounds, forms thereof, and pharmaceutical compositions, as well as methods of using such compounds, forms thereof, or compositions, for treating or ameliorating Huntington's disease. [Background technology]

[0003] Huntington's disease (HD) is a progressive autosomal dominant neurodegenerative disorder of the brain with symptoms characterized by involuntary movements, cognitive impairment, and mental decline. Death is typically caused by pneumonia or coronary artery disease and usually occurs 13-15 years after the onset of symptoms. The prevalence of HD is 3-7 per 100,000 in populations of Western European descent. In North America, an estimated 30,000 people have HD, with an additional 200,000 at risk of inheriting the disease from an affected parent. The disease is caused by an expansion of consecutive trinucleotide CAG repeats in the "mutated" huntingtin (Htt) gene, which produces HTT (Htt protein) that contains an expanded poly-glutamine (polyQ) stretch, also known as the "CAG repeat" sequence. No current small molecule therapy targets the underlying cause of the disease, and there remains a high unmet need for drugs that can be used to treat or ameliorate HD. As a result, there remains a need to identify and provide small molecule compounds for treating or ameliorating HD. All other documents referred to herein are incorporated by reference into this application as if fully set forth herein. Summary of the Invention

[0004] An embodiment of the present disclosure is a compound of formula (I): [ka] or in the form thereof, A , R A1 , R A2 , X 1 , X 2 , R B1 , and R B2 is as defined herein. Aspects herein also relate to a method of using a compound of formula (I), a form or composition thereof, to treat or ameliorate HD in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound, a form or composition thereof. Aspects herein further relate to the use of a compound of formula (I) or a form thereof for treating or ameliorating HD in a subject in need thereof, comprising administering to the subject an effective amount of the compound or a form thereof. Aspects herein further relate to the use of a compound of formula (I) or a form thereof for the preparation of a medicament useful for treating or ameliorating HD in a subject in need thereof, which use comprises administering an effective amount of the medicament to the subject. Aspects herein further relate to the use of a compound of formula (I) or a form thereof, in combination with another agent useful for treating or ameliorating HD, in a subject in need thereof, comprising administering to the subject an effective amount of the combination product to treat or ameliorate HD. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0005] An embodiment of the present invention is a compound of formula (I): [ka] or in relation to its form, wherein: RA is the following formula: [ka] and In the formula, p and q are each independently 0 or 1; X 1 is selected from the group consisting of CH, C-halogen, and N; X 2 is selected from the group consisting of C-halogen and CF; R 1 is hydrogen, hydroxyl, and C 1‐4 selected from the group consisting of alkyl; R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 are each independently hydrogen, halogen, hydroxyl, cyano, C 1‐4 Alkyl, Deuterium-C 1‐4 Alkyl, halo-C 1‐4 Alkyl, Amino, C 1‐4 Alkyl-amino, (C 1‐4 Alkyl) 2 - Amino, C 1‐4 Alkoxy and halo-C 1‐4 alkoxy; or R 2 and R 3 together with the atoms to which they are attached form a saturated 3-6 membered ring incorporating 0 or 1 heteroatom ring member selected from N, O, and S; or R 2 and R 4 form together with the atom to which they are attached a saturated 5- to 10-membered ring system; or R 2 and R 7 form together with the atom to which they are attached a saturated 5- to 10-membered ring system; or R 4 and R5 together with the atoms to which they are attached form a saturated 3-6 membered ring incorporating 0 or 1 heteroatom ring member selected from N, O, and S; R A1 and R A2 are independently hydrogen, deuterium, halogen, hydroxy, cyano, C 1‐4 Alkyl, Deuterium-C 1‐4 Alkyl, halo-C 1‐4 Alkyl, C 1‐4 Alkoxy, halo-C 1‐4 Alkoxy, C 1‐4 Alkoxy-C 1‐4 Alkyl, Amino, C 1‐4 Alkyl-amino, (C 1‐4 Alkyl) 2 -Amino, Amino-C 1‐4 Alkyl and hydroxy-C 1‐4 alkyl; and R B1 and R B2 are independently hydrogen, deuterium, halogen, hydroxyl, cyano, C 1‐4 Alkyl, Deuterium-C 1‐4 Alkyl, halo-C 1‐4 Alkyl, C 1‐4 Alkoxy, Deuterium-C 1‐4 Alkoxy and halo-C 1‐4 alkoxy; wherein the form of the compound is selected from the group consisting of its salts, racemates, enantiomers, diastereoisomers, stereoisomers, and tautomers.

[0006] Aspects of the specification One aspect of the present disclosure is a compound of formula (I): [ka] or in relation to its form, wherein: R A is the following formula: [ka] and In the formula, p and q are each independently 0 or 1; X 1 is selected from the group consisting of CH, C-halogen, and N; X 2 is selected from the group consisting of CH and C-halogen; R 1 is hydrogen, hydroxyl, and C 1‐4 selected from the group consisting of alkyl; R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 are each independently hydrogen, halogen, hydroxyl, cyano, C 1‐4 Alkyl, Deuterium-C 1‐4 Alkyl, halo-C 1‐4 Alkyl, Amino, C 1‐4 Alkyl-amino, (C 1‐4 Alkyl) 2 - Amino, C 1‐4 Alkoxy and halo-C 1‐4 alkoxy; or R 2 and R 3 together with the atoms to which they are attached form a saturated 3-6 membered ring incorporating 0 or 1 heteroatom ring member selected from N, O, and S; or R 2 and R 4 form together with the atom to which they are attached a saturated 5- to 10-membered ring system; or R 2 and R 7 form together with the atom to which they are attached a saturated 5- to 10-membered ring system; or R 4 and R 5 together with the atoms to which they are attached form a saturated 3-6 membered ring incorporating 0 or 1 heteroatom ring member selected from N, O, and S; R A1 and RA2 are independently hydrogen, deuterium, halogen, hydroxy, cyano, C 1‐4 Alkyl, Deuterium-C 14 Alkyl, halo-C 1‐4 Alkyl, C 1‐4 Alkoxy, halo-C 1‐4 Alkoxy, C 1‐4 Alkoxy-C 1‐4 Alkyl, Amino, C 1‐4 Alkylamino, (C 1‐4 Alkyl) 2 Amino, Amino-C 1‐4 Alkyl and hydroxy-C 1‐4 alkyl; and R B1 and R B2 are independently hydrogen, deuterium, halogen, hydroxyl, cyano, C 1‐4 Alkyl, Deuterium-C 1‐4 Alkyl, halo-C 1‐4 Alkyl, C 1‐4 Alkoxy, Deuterium-C 1‐4 Alkoxy and halo-C 1‐4 alkoxy; wherein the form of the compound is selected from the group consisting of a salt, a racemate, an enantiomeric, a diastereomeric, a stereomeric, and a tautomeric form thereof.

[0007] One embodiment includes compounds of formula (I), wherein R A is the following formula: [ka] and In the formula, p and q each independently represent 0 or 1.

[0008] One embodiment includes compounds of formula (I), wherein R A is the following formula: [ka] and In the formula, p and q are 0.

[0009] One embodiment includes compounds of formula (I), wherein R A is the following formula: [ka] and In the formula, p is 0 and q is 1.

[0010] One embodiment includes compounds of formula (I), wherein R A is the following formula: [ka] and In the formula, p is 1 and q is 0.

[0011] One embodiment includes compounds of formula (I), wherein R A is the following formula: [ka] and In the formula, p and q are 1.

[0012] Another embodiment includes compounds of formula (I), wherein R A is the group consisting of: [ka] and any stereoisomer thereof.

[0013] Another embodiment includes compounds of formula (I), wherein R A is the following formula: [ka] and any stereoisomer thereof.

[0014] Another embodiment includes compounds of formula (I), wherein R A is the following formula: [ka] and any stereoisomer thereof.

[0015] Another embodiment includes compounds of formula (I), wherein R A is the following formula: [ka] and any stereoisomer thereof.

[0016] Another embodiment includes compounds of formula (I), wherein R A is the following formula: [ka] and any stereoisomer thereof.

[0017] Another embodiment includes compounds of formula (I), wherein R A is the following formula: [ka] and any stereoisomer thereof.

[0018] Another embodiment includes compounds of formula (I), wherein R A is the following formula: [ka] and any stereoisomer thereof.

[0019] Another embodiment includes compounds of formula (I), wherein R A -2 is the following formula: [ka] or any further stereoisomers thereof.

[0020] Another embodiment includes compounds of formula (I), wherein R A is the following formula: [ka] It is.

[0021] Another embodiment includes compounds of formula (I), wherein R A is the following formula: [ka] It is.

[0022] Another embodiment includes compounds of formula (I), wherein R A is the following formula: [ka] It is.

[0023] Another embodiment includes compounds of formula (I), wherein R A is the following formula: [ka] It is.

[0024] Another embodiment includes compounds of formula (I), wherein R A is the following formula: [ka] It is.

[0025] Another embodiment includes compounds of formula (I), wherein R A is the following formula: [ka] It is.

[0026] Another embodiment includes compounds of formula (I), wherein R A -2-c is the following formula: [ka] It is.

[0027] Another embodiment includes compounds of formula (I), wherein R A -2-d is the following formula: [ka] It is.

[0028] Another embodiment includes compounds of formula (I), wherein R A -5 is the formula: [ka] or any further stereoisomers thereof.

[0029] Another embodiment includes compounds of formula (I), wherein R A is the following formula: [ka] It is.

[0030] Another embodiment includes compounds of formula (I), wherein R A is the following formula: [ka] It is.

[0031] Another embodiment includes compounds of formula (I), wherein R A -7 is the formula: [ka] or any further stereoisomers thereof.

[0032] Another embodiment includes compounds of formula (I), wherein R A is the following formula: [ka] It is.

[0033] Another embodiment includes compounds of formula (I), wherein R A is the following formula: [ka] It is.

[0034] Another embodiment includes compounds of formula (I), wherein R A -7 is the formula: [ka] It is.

[0035] Another embodiment includes compounds of formula (I), wherein R A -7-b is of the following formula: [ka] It is.

[0036] Another embodiment includes compounds of formula (I), wherein R A -8 is the formula: [ka] or any further stereoisomers thereof.

[0037] Another embodiment includes compounds of formula (I), wherein R A -10 is calculated using the following formula: [ka] or any further stereoisomers thereof.

[0038] Another embodiment includes compounds of formula (I), wherein R A is the following formula: [ka] It is.

[0039] Another embodiment includes compounds of formula (I), wherein R A is the following formula: [ka] It is.

[0040] Another embodiment includes compounds of formula (I), wherein R A -11 is the following formula: [ka] or any further stereoisomers thereof.

[0041] Another embodiment includes compounds of formula (I), wherein R A is the following formula: [ka] It is.

[0042] Another embodiment includes compounds of formula (I), wherein R A is the following formula: [ka] It is.

[0043] One embodiment includes a compound of formula (I), wherein X 1 is selected from the group consisting of CH, C-halogen, and N. Another embodiment includes compounds of formula (I), wherein X 1 is CH. Another embodiment includes compounds of formula (I), wherein X 1 is a C-halogen, wherein the halogen is selected from the group consisting of bromo, chloro, fluoro, and iodo. Another embodiment includes compounds of formula (I), wherein X 1 is C-F. Another embodiment includes compounds of formula (I), wherein X 1 is N. One embodiment includes a compound of formula (I), wherein X 2 is selected from the group consisting of CH and C-halogen. Another embodiment includes compounds of formula (I), wherein X 2 is CH. Another embodiment includes compounds of formula (I), wherein X 2 is a C-halogen, wherein the halogen is selected from the group consisting of bromo, chloro, fluoro, and iodo. Another embodiment includes compounds of formula (I), wherein X 2 is CF.

[0044] One embodiment includes compounds of formula (I), wherein R 1 is hydrogen, hydroxyl, and C 1‐4 is selected from the group consisting of alkyl. Another embodiment includes compounds of formula (I), wherein R 1 is hydrogen and C 1‐4 is selected from the group consisting of alkyl. Another embodiment includes compounds of formula (I), wherein R 1 is hydrogen. Another embodiment includes compounds of formula (I), wherein R 1 is hydroxyl. Another embodiment includes compounds of formula (I), wherein R 1 is C 1‐4 It is an alkyl. Another embodiment includes compounds of formula (I), wherein R 1 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl.1‐4 It is an alkyl. Another embodiment includes compounds of formula (I), wherein R 1 is methyl.

[0045] One embodiment includes compounds of formula (I), wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 are each independently hydrogen, halogen, hydroxyl, cyano, C 1‐4 Alkyl, Deuterium-C 1‐4 Alkyl, halo-C 1‐4 Alkyl, Amino, C 1‐4 Alkyl-amino, (C 1‐4 Alkyl) 2 - Amino, C 1‐4 Alkoxy and halo-C 1‐4 alkoxy is selected from the group consisting of: Another embodiment includes compounds of formula (I), wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 are each independently hydrogen, halogen, or C 1‐4 is selected from the group consisting of alkyl. Another embodiment includes compounds of formula (I), wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 are each independently hydrogen. Another embodiment includes compounds of formula (I), wherein R 2 , R 3 , R4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 are each independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl. 1‐4 It is an alkyl. Another embodiment includes compounds of formula (I), wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 are each independently methyl.

[0046] Another embodiment includes compounds of formula (I), wherein R 2 and R 3 are each independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl. 1‐4 It is an alkyl. Another embodiment includes compounds of formula (I), wherein R 2 is methyl. Another embodiment includes compounds of formula (I), wherein R 3 is methyl. Another embodiment includes compounds of formula (I), wherein R 2 and R 3 are each methyl. Another embodiment includes compounds of formula (I), wherein R 4 and R 5 are each independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl. 1‐4 It is an alkyl. Another embodiment includes compounds of formula (I), wherein R 4 is methyl. Another embodiment includes compounds of formula (I), wherein R 5 is methyl. Another embodiment includes compounds of formula (I), wherein R 4 and R 5 are each methyl.

[0047] Another embodiment includes compounds of formula (I), wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 are each independently a halogen selected from the group consisting of bromo, chloro, fluoro, and iodo. Another embodiment includes compounds of formula (I), wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 are each independently fluoro. Another embodiment includes compounds of formula (I), wherein R 7 , R 8 , R 10 , and R 11 are each independently a halogen selected from the group consisting of bromo, chloro, fluoro, and iodo. Another embodiment includes compounds of formula (I), wherein R 7 , R 8 , R 10 , and R 11 are each independently fluoro. Another embodiment includes compounds of formula (I), wherein R 7 is fluoro. Another embodiment includes compounds of formula (I), wherein R 8 is fluoro. Another embodiment includes compounds of formula (I), wherein R 10 is fluoro. Another embodiment includes compounds of formula (I), wherein R 11is fluoro.

[0048] One embodiment includes compounds of formula (I), wherein R 2 and R 3 together with the atoms to which they are attached form a saturated 3-6 membered ring incorporating 0 or 1 heteroatom ring member selected from N, O, and S. Another embodiment includes compounds of formula (I), wherein R 2 and R 3 forms a cyclopropane ring. Another embodiment includes compounds of formula (I), wherein R 2 and R 3 forms a cyclobutane ring. Another embodiment includes compounds of formula (I), wherein R 2 and R 3 forms a cyclopentane ring. One embodiment includes compounds of formula (I), wherein R 2 and R 4 form, together with the atom to which they are attached, a saturated 5- to 10-membered ring system. One embodiment includes compounds of formula (I), wherein R 2 and R 7 form, together with the atom to which they are attached, a saturated 5- to 10-membered ring system.

[0049] One embodiment includes compounds of formula (I), wherein R 4 and R 5 together with the atoms to which they are attached form a saturated 3-6 membered ring incorporating 0 or 1 heteroatom ring member selected from N, O, and S. Another embodiment includes compounds of formula (I), wherein R 4 and R 5 forms a cyclopropane ring. Another embodiment includes compounds of formula (I), wherein R 4 and R 5 forms a cyclobutane ring. Another embodiment includes compounds of formula (I), wherein R 4 and R 5 forms a cyclopentane ring.

[0050] One embodiment includes compounds of formula (I), wherein R A1 and R A2 are independently hydrogen, deuterium, halogen, hydroxy, cyano, C 1‐4 Alkyl, Deuterium-C 1‐4 Alkyl, halo-C 1‐4 Alkyl, C 1‐4 Alkoxy, halo-C 1‐4 Alkoxy, C 1‐4 Alkoxy-C 1‐4 Alkyl, Amino, C 1‐4 Alkyl-amino, (C 1‐4 Alkyl) 2 -Amino, Amino-C 1‐4 Alkyl and hydroxy-C 1‐4 is selected from the group consisting of alkyl. Another embodiment includes compounds of formula (I), wherein R A1 and R A2 are each independently hydrogen and C 1‐4 is selected from the group consisting of alkyl. Another embodiment includes compounds of formula (I), wherein R A1 and R A2 are each independently hydrogen. Another embodiment includes compounds of formula (I), wherein R A1 and R A2 are each independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl. 1‐4 It is an alkyl. Another embodiment includes compounds of formula (I), wherein R A1 and R A2 are each independently methyl. Another embodiment includes compounds of formula (I), wherein R A1 is hydrogen, deuterium, halogen, hydroxy, cyano, C 1‐4 Alkyl, Deuterium-C 1‐4 Alkyl, halo-C 1‐4 Alkyl, C 1‐4 Alkoxy, halo-C 1‐4 Alkoxy, C 1‐4 Alkoxy-C 1‐4 Alkyl, Amino, C1‐4 Alkyl-amino, (C 1‐4 Alkyl) 2 -Amino, Amino-C 1‐4 Alkyl and hydroxy-C 1‐4 is selected from the group consisting of alkyl. Another embodiment includes compounds of formula (I), wherein R A1 is hydrogen, deuterium, halogen, cyano, C 1‐4 Alkyl, Deuterium-C 1‐4 Alkyl and halo-C 1‐4 is selected from the group consisting of alkyl. Another embodiment includes compounds of formula (I), wherein R A1 is hydrogen. Another embodiment comprises a compound of formula (I), wherein R A2 is hydrogen, deuterium, halogen, hydroxy, cyano, C 1‐4 Alkyl, Deuterium-C 1‐4 Alkyl, halo-C 1‐4 Alkyl, C 1‐4 Alkoxy, halo-C 1‐4 Alkoxy, C 1‐4 Alkoxy-C 1‐4 Alkyl, Amino, C 1‐4 Alkyl-amino, (C 1‐4 Alkyl) 2 -Amino, Amino-C 1‐4 Alkyl and hydroxy-C 1‐4 is selected from the group consisting of alkyl. Another embodiment includes compounds of formula (I), wherein R A2 is hydrogen and C 1‐4 is selected from the group consisting of alkyl. Another embodiment includes compounds of formula (I), wherein R A2 is hydrogen. Another embodiment includes compounds of formula (I), wherein R A2 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl. 1‐4 It is an alkyl. Another embodiment includes compounds of formula (I), wherein R A2 is methyl.

[0051] One embodiment includes compounds of formula (I), wherein R B1 and R B2 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, C 1‐4 Alkyl, Deuterium-C 1‐4 Alkyl, halo-C 1‐4 Alkyl, C 1‐4 Alkoxy, Deuterium-C 1‐4 Alkoxy and halo-C 1‐4 alkoxy is selected from the group consisting of: Another embodiment includes compounds of formula (I), wherein R B1 and R B2 are each independently hydrogen, halogen, or C 1‐4 is selected from the group consisting of alkyl. Another embodiment includes compounds of formula (I), wherein R B1 and R B2 are each independently hydrogen. Another embodiment includes compounds of formula (I), wherein R B1 is hydrogen. Another embodiment includes compounds of formula (I), wherein R B2 is hydrogen. Another embodiment includes compounds of formula (I), wherein R B1 and R B2 are each independently C 1‐4 alkyl, wherein C 1‐4 The alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl. Another embodiment includes compounds of formula (I), wherein R B1 and R B2 are each independently methyl. Another embodiment includes compounds of formula (I), wherein R B1 is methyl. Another embodiment includes compounds of formula (I), wherein R B2 is methyl. Another embodiment includes compounds of formula (I), wherein R B1 and R B2is each independently a halogen selected from the group consisting of bromo, chloro, fluoro, and iodo. Another embodiment includes compounds of formula (I), wherein R B1 and R B2 each independently is chloro. Another embodiment includes compounds of formula (I), wherein R B1 is chloro.

[0052] Another embodiment of the compound of formula (I) is a compound of formula (Ia): [ka]

[0053] Another embodiment of the compound of formula (I) is a compound of formula (Ib): [ka]

[0054] Embodiments of the compound of formula (I) or forms thereof include compounds selected from the group consisting of: # " indicates that the compound is a racemic mixture of enantiomers: [ka] TIFF2024528066000046.tif140156 TIFF2024528066000047.tif135153 wherein the form of said compound is selected from the group consisting of its salts, hydrates, enantiomeric, diastereomeric, stereoisomeric, and tautomeric forms.

[0055] One embodiment of the compound of formula (I) or a form thereof (wherein the compound number embodiment indicates that the salt form is isolated) includes a compound selected from the group consisting of: [Table 1] TIFF2024528066000049.tif244170 TIFF2024528066000050.tif250165, wherein the compound is in a form selected from the group consisting of a salt, a racemate, an enantiomeric, a diastereomeric, a stereomeric, and a tautomeric form thereof.

[0056] Another embodiment of the compound of formula (I) or a form thereof is a salt of a compound selected from the group consisting of: [Table 2] TIFF2024528066000052.tif190170 wherein the compound salt form is selected from the group consisting of its racemic, enantiomeric, diastereomeric, stereoisomeric, and tautomeric forms.

[0057] Aspects herein include a method of using a compound of formula (I) or a form thereof to treat or ameliorate HD in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of formula (I) or a form thereof. Another aspect herein includes a method of using a compound of formula (I) or a form thereof to treat or ameliorate HD in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of formula (I) or a salt form thereof. Aspects herein include the use of a compound of formula (I) or a form thereof for treating or ameliorating HD in a subject in need thereof, the use comprising administering to the subject an effective amount of a compound of formula (I) or a form thereof. Another aspect herein includes the use of a salt of a compound of formula (I) or a form thereof for treating or ameliorating 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.

[0058] chemical definition The chemical terms used above and throughout the description herein shall be understood by those skilled in the art to have the meanings indicated below, unless otherwise defined. As used herein, "C 1‐4 The term "alkyl" generally refers to a saturated hydrocarbon radical having from 1 to 4 carbon atoms in a straight or branched arrangement, including, but not limited to, methyl, ethyl, n-propyl (also called propyl or propanyl), isopropyl, n-butyl (also called butyl or butanyl), isobutyl, sec-butyl, tert-butyl, and the like. In certain embodiments, C 1‐4 Alkyl is C 1‐4 Alkyl, etc., but are not limited to these. 1‐4 Alkyl radicals are optionally substituted, where available valences permit, with substituent types described herein.

[0059] As used herein, "C 2‐4 The term "alkenyl" generally refers to a partially unsaturated hydrocarbon radical having from 2 to 4 carbon atoms in a linear or branched arrangement and one or more carbon-carbon double bonds therein, and includes, but is not limited to, ethenyl (also called vinyl), allyl, propenyl, and butenyl. In certain embodiments, C 2‐4 Alkenyl is C 2‐3 Alkenyl and C 2‐4 Alkenyl, but not limited to alkenyl. 2‐4 Alkenyl radicals are optionally substituted, where available valences permit, with the types of substituents described herein. As used herein, "C 2‐4 The term "alkynyl" generally refers to a partially unsaturated hydrocarbon radical having from 2 to 4 carbon atoms in a linear or branched arrangement and one or more carbon-carbon triple bonds therein, and includes, but is not limited to, ethynyl, propynyl, and butynyl. 2‐4 Alkynyl is C 2‐3 Alkynyl and C 2‐4Including, but not limited to, alkynyl. 2‐4 Alkynyl radicals are optionally substituted, where available valences permit, with the types of substituents described herein.

[0060] As used herein, "C 1‐4 The term "alkoxy" generally refers to a group of the formula: -O-C 1‐4 Alkyl refers to a saturated hydrocarbon radical having from 1 to 4 carbon atoms in a straight or branched chain arrangement, including, but not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like. 1‐4 Alkoxy is C 1‐4 Alkoxy and the like. 1‐4 Alkoxy radicals are optionally substituted, where available valences allow, with substituent types described herein. As used herein, "C 3‐10 The term "cycloalkyl" generally refers to a saturated or partially unsaturated monocyclic, bicyclic, or polycyclic hydrocarbon radical, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1H-indanyl, indenyl, tetrahydro-naphthalenyl, and the like. 3‐10 Cycloalkyl is C 3‐8 Cycloalkyl, C 5‐8 Cycloalkyl, C 3‐10 cycloalkyl, etc. 3‐10 Cycloalkyl radicals are optionally substituted, where available valences permit, with the types of substituents described herein.

[0061] As used herein, the term "aryl" generally refers to a monocyclic, bicyclic or polycyclic aromatic carbon atom ring structure radical, including, but not limited to, phenyl, naphthyl, anthracenyl, fluorenyl, azulenyl, phenanthrenyl, etc. Aryl radicals are optionally substituted, where available valences permit, with substituent types described herein. As used herein, the term "heteroaryl" generally refers to a monocyclic, bicyclic or polycyclic aromatic carbon atom ring structure radical in which one or more carbon atom ring members are replaced, where structural stability permits, by one or more heteroatoms, such as O, S or N atoms, and includes furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, 1,3-thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetra ... azolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, indolyl, indazolyl, indolizinyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, 1,3-benzothiazolyl, 1,3-benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, 1,3-diazinyl, 1,2-diazinyl, 1,2-diazolyl, 1,4-diazanaphthalenyl, acridinyl, furo[3,2-b]pyri thieno[2,3-b]pyridinyl, 6H-thieno[2,3-b]pyrrolyl, thieno[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, pyrrolo[1,2-a]pyrazinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrazinyl, imidazo[1, Heteroaryl radicals include, but are not limited to, 2-a]pyridinyl, 3H-imidazo[4,5-b]pyridinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-c]pyrimidinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, imidazo[2,1-b][1,3]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, [1,2,4]triazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, etc. Heteroaryl radicals are optionally substituted on the carbon or nitrogen ring members, where available valences permit, with the types of substituents described herein.

[0062] In certain embodiments, the nomenclature of heteroaryl radicals may be different, for example, by way of non-limiting example, 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 1,3-benzooxazolyl. In certain other aspects, the terms relating to heteroaryl radicals include, for example, the term pyrrolyl may include 2H-pyrrolyl, 3H-pyrrolyl, etc., the term pyrazolyl may include 1H-pyrazolyl, etc., the term imidazolyl may include 1H-imidazolyl, etc., the term triazolyl may include 1H-1,2,3-triazolyl, etc., the term oxadiazolyl may include 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, etc. In non-limiting examples, the term may also include other positional isomers, such as the term tetrazolyl, 2H-tetrazolyl, the term indolyl, 1H-indolyl, indazolyl, 1H-indazolyl, 2H-indazolyl, benzimidazolyl, purinyl, 9H-purinyl, etc.

[0063] As used herein, the term "heterocyclyl" generally refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic carbon atom ring structure radical in which one or more carbon atom ring members are replaced, where structural stability permits, by a heteroatom, such as an O, S or N atom, and includes, for example, oxiranyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, isoxazolinyl, isoxazolidinyl, isothiazolinyl, isothiazolidinyl, ox ... azolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, triazolinyl, triazolidinyl, oxadiazolinyl, oxadiazolidinyl, thiadiazolinyl, thiadiazolidinyl, tetrazolinyl, tetrazolidinyl, pyranyl, dihydro-2H-pyranyl, thiopyranyl, 1,3-dioxanyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,4-diazepanyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl, 2, 3-Dihydro-1,4-benzodioxinyl, hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl, hexahydropyrrolo[3,4- c]pyrrol-(1H)-yl, (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, octahydro-5H-pyrrolo[3,2-c]pyridinyl, octahydro-6H-pyrrolo[3,4-b]pyridinyl, (4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridinyl, (4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridinyl, hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (7R,8aS)-Hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aS)-Hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aR)-Hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aS)-Octahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aR)-Octahydropyrrolo[1,2-a]pyrazin-(1H)-yl, Hexa Hydropyrrolo[1,2-a]pyrazin-(2H)-one, octahydro-2H-pyrido[1,2-a]pyrazinyl, 3-azabicyclo[3.1.0]hexyl, (1R,5S)-3-azabicyclo[3.1.0]hexyl, 8-azabicyclo[3.2.1]octyl, (1R,5S)-8-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]oct-2-enyl, (1R,5 S)-8-azabicyclo[3.2.1]oct-2-enyl, 9-azabicyclo[3.3.1]nonyl, (1R,5S)-9-azabicyclo[3.3.1]nonyl, 2,5-diazabicyclo[2.2.1]heptyl, (1S,4S)-2,5-diazabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.2]octyl, 3,8-diazabicyclo[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, 2,7-diazaspiro[3.5]nonyl, 5,8-diazaspiro[3.5]nonyl, 2,7-diazaspiro[4.4]nonyl, 6,9-diazaspiro[4.5]decyl, and the like. Heterocyclyl radicals are optionally substituted on the carbon or nitrogen ring members, where available valences permit, with the types of substituents described herein.

[0064] In certain embodiments, the nomenclature of heterocyclyl radicals may differ, for example, in a non-limiting example, 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 2,3-dihydrobenzo[b][1,4]dioxinyl. As used herein, "deuterium-C1‐4 The term "alkyl" refers to a group of the formula: 1‐4 Refers to the alkyl-deuterium radical, and where possible due to available valences, C 1‐4 The alkyl is partially or fully substituted with one or more deuterium atoms. As used herein, "C 1‐4 Alkoxy-C 1‐4 The term "alkyl" refers to a group of the formula: 1‐4 Alkyl-O-C 1‐4 Refers to an alkyl radical. As used herein, "C 1‐4 The term "alkyl-amino" refers to a group of the formula: -NH-C 1‐4 Refers to an alkyl radical.

[0065] As used herein, "(C 1‐4 Alkyl) 2 The term "-amino" refers to a group of the formula: -N(C 1‐4 Alkyl) 2 Refers to the radical of As used herein, "C 1‐4 The term "alkyl-thio" refers to a group of the formula: -S-C 1‐4 Refers to an alkyl radical. As used herein, "amino-C 1‐4 The term "alkyl" refers to a group of the formula: 1‐4 Alkyl-NH 2 Refers to the radical of

[0066] As used herein, the term "halo" or "halogen" generally refers to halogen atom radicals, including fluoro, chloro, bromo, and iodo. As used herein, "halo-C 1‐4 The term "alkoxy" refers to a group of the formula: -O-C 1‐4 Refers to the alkyl-halo radical, C 1‐4 The alkyl may be partially or fully substituted with one or more halogen atoms, where available valences permit.

[0067] As used herein, "halo-C1‐4 The term "alkyl" refers to a group of the formula: 1‐4 Refers to the alkyl-halo radical, C 1‐4 The alkyl may be partially or fully substituted with one or more halogen atoms, where available valences permit. As used herein, the term "hydroxy" refers to a radical of the formula: --OH.

[0068] As used herein, "hydroxy-C 1‐4 The term "alkyl" refers to a group of the formula: 1‐4 Refers to the alkyl-OH radical, C 1‐4 The alkyl is partially or fully substituted, where available valences permit, with one or more hydroxyl radicals. As used herein, the term "substituent" refers to a positional variable on an atom of a core molecule that replaces one or more hydrogens on the specified atom and is substituted at the specified atomic position, provided that the normal valence of the specified atom is not exceeded and the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. Those of skill in the art should note that any carbon and heteroatom that appears to have an unsatisfied valence as described or shown herein is presumed to have a sufficient number of hydrogen atoms (or atoms) to satisfy the valence as described or shown. In some instances, one or more substituents having a double bond as a point of attachment (e.g., "oxo" or "=O") may be described, shown, or listed in the substituents herein, and the structure may show only a single bond as a point of attachment to the core structure of formula (I). Those of skill in the art will understand that a double bond is intended for such a substituent even if only a single bond is shown.

[0069] As used herein, with respect to the definitions of chemical terms provided herein, the term "such as" means that variations in chemical structures that one of ordinary skill in the art would expect include, but are not limited to, isomers (including chain, branched or positional structural isomers), hydration of ring systems (including saturated or partially unsaturated monocyclic, bicyclic or polycyclic ring structures), and all other variations that result in stable compounds, where available valences permit. For purposes of this description, when one or more substitutent variables of a compound of formula (I) or a form thereof include functional groups incorporated in a compound of formula (I), each functional group appearing anywhere within the disclosed compound can be independently selected and, where appropriate, independently and / or optionally substituted.

[0070] As used herein, the term "independently selected" or "each selected" refers to a functional variable in the list of substituents that may occur more than once on the structure of formula (I), and the substitution pattern at each occurrence is independent of the pattern at any other occurrence. Furthermore, it is understood that the use of a generic substituent variable on any formula or structure to compounds described herein includes replacement of the generic substituent with a species of substituent included within the particular genus, for example, aryl can be replaced with phenyl or naphthalenyl, etc., and the resulting compound would be within the scope of the compounds described herein. As used herein, the term "in each instance" or "in each instance, if present" is intended to include, for example, "...C 3‐14 Cycloalkyl, C 3‐14 Cycloalkyl-C 1‐4 Alkyl, aryl, aryl-C 1‐4 Alkyl, Heteroaryl, Heteroaryl-C 1‐4 Alkyl, Heterocyclyl and Heterocyclyl-C 1‐4 When used preceding the term "alkyl", each when present alone or as a substituent, is a C 3‐14 It is intended to refer to cycloalkyl, aryl, heteroaryl and heterocyclyl ring systems. As used herein, the term "optionally substituted" means optional substitution with the specified substituted variable, group, radical or moiety.

[0071] compound form As used herein, the term "form" refers to a compound of formula (I) having a form selected from the group consisting of its free acid, free base, salt, hydrate, solvate, racemate, enantiomeric, diastereomeric, stereoisomeric, and tautomeric forms. In certain embodiments described herein, the compound of formula (I) is in the form of a free acid, a free base, or a salt thereof. In certain embodiments described herein, the compounds of formula (I) are in the form of salts thereof.

[0072] In certain embodiments described herein, the compound of formula (I) is in the form of a stereoisomer, racemate, enantiomer, or diastereoisomer thereof. In certain embodiments described herein, the compounds of formula (I) may be in the form of a tautomer thereof. In certain embodiments described herein, the compounds of formula (I) are in the form of their isotopically substituted versions. In certain embodiments described herein, the compound of formula (I) is in a pharma- ceutically acceptable form. In certain embodiments described herein, the compound of formula (I) or a form thereof is isolated for use.

[0073] As used herein, the term "isolated" refers to the physical state of a compound of formula (I) or a form thereof after it has been isolated and / or purified from a synthetic process (e.g., from a reaction mixture), or from a natural source, or a combination thereof, in sufficient purity to be characterized by standard analytical techniques described herein or known to those of skill in the art, according to an isolation or purification process or processes described herein or known to those of skill in the art (e.g., chromatography, recrystallization, etc.). As used herein, the term "protected" means that a functional group in a compound of formula (I) or in its form is in a form modified to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those skilled in the art and by reference to standard textbooks such as, for example, TW 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 (e.g., 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 carboxylic acid include alkyl, aryl or arylalkyl esters. In some examples, the protecting group can be a polymer resin, such as Wang resin or 2-chlorotrityl chloride resin. Protecting groups can be added and removed according to standard techniques well known to those skilled in the art and described herein. As will also be appreciated by those skilled in the art, such protected derivatives of the compounds described herein may not have pharmacological activity themselves, but may be metabolized in the body after administration to a subject to form a pharmacologically active compound described herein.

[0074] One or more of the compounds described herein may exist in unsolvated as well as solvated forms with pharma- ceutically acceptable solvents such as water, ethanol, and the like, and the description herein is intended to include both the solvated and unsolvated forms. The term "solvate" as used herein refers to a physical association of a compound described herein with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In some instances, a solvate is capable of isolation, for example when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. As used herein, "solvate" encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. As used herein, the term "hydrate" refers to a solvate where the solvent molecule is water.

[0075] The compound of formula (I) may form salts, which are intended to be included within the scope of the present specification. Reference herein to a compound of formula (I) or a form thereof is understood to include reference to its salt forms, unless otherwise indicated. The term "salt(s)" as used herein refers to acid salts formed with inorganic and / or organic acids, and basic salts formed with inorganic and / or organic bases. Furthermore, when a compound of formula (I) or a form thereof contains both a basic moiety, such as, but not limited to, an amine moiety, and an acidic moiety, such as, but not limited to, a carboxylic acid, zwitterions ("internal salts") may be formed and may be included within the term "salt(s)" as used herein. As used herein, the term "pharmaceutical acceptable salt(s)" refers to salts of the compounds described herein that are safe and effective (i.e., non-toxic, physiologically acceptable) for use in mammals and that possess biological activity, although other salts are also useful. Salts of compounds of formula (I) can be formed, for example, by reacting a compound of formula (I) or a form thereof with an amount, e.g., an equivalent amount, of an acid or base in a medium, e.g., in which the salt is precipitated or in an aqueous medium, followed by lyophilization.

[0076] Pharmaceutically acceptable salts include salts of one or more of the acidic or basic groups present in the compounds described herein. Specific embodiments 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, gentisate, gluconate, glucaronate, glutamate, iodide, isonicotinate, lactate, maleate, methanesulfonate, naphthalenesulfonate, nitrate, oxalate, pamoate, pantothenate, phosphate, propionate, saccharate, salicylate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate (also known as tosylate), trifluoroacetate, and the like. Certain detailed embodiments of acid addition salts include chlorides, bromides, or dichlorides. Additionally, acids that are generally considered suitable for forming medicamentously useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al., Camille G. (ed.) 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 (on the Food & Drug Administration, Washington, DC website), the disclosures of which are incorporated herein by reference.

[0077] Suitable base salts include, but are not limited to, aluminum, ammonium, calcium, lithium, magnesium, potassium, sodium and zinc salts. All such acid and base salts are intended to be included within the scope of pharma- ceutically acceptable salts described herein, and furthermore, all such acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes herein.

[0078] Compounds of formula (I) and forms thereof may further exist in tautomeric forms, and all such tautomeric forms are assumed and intended to be included within the scope of the compounds of formula (I) and forms thereof described herein. The compounds of formula (I) or forms thereof may contain asymmetric or chiral centers and therefore may exist in different stereoisomeric forms. This specification is intended to include all stereoisomeric forms of the compounds of formula (I) as well as mixtures thereof, including racemic mixtures.

[0079] The compounds described herein may contain one or more chiral centers and may exist as racemic mixtures (R / S) or as substantially pure enantiomers and diastereoisomers. The compounds may also exist as substantially pure (R) or (S) enantiomers (if one chiral center is present). In one detailed aspect, the compounds described herein are (S) isomers and may exist as enantiomerically pure compositions that include substantially only the (S) isomer. In another detailed aspect, the compounds described herein are (R) isomers and may exist as enantiomerically pure compositions that include substantially only the (R) isomer. As those skilled in the art will recognize, if more than one chiral center is present, the compounds described herein may also exist as (R,R), (R,S), (S,R) or (S,S) isomers as defined by the IUPAC nomenclature recommendations. The term "chiral" as used herein refers to a carbon atom bonded to four non-identical substituents. Stereochemical definitions and conventions used herein generally follow those of S.P. Parker, ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York, and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. In describing optically active compounds, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule around its chiral center(s). The substituents attached to the chiral center under consideration are ranked according to the Cahn-Ingold-Prelog ranking rules (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511).

[0080] As used herein, the term "substantially pure" refers to a compound that consists essentially of a single isomer in an amount of 90% or more, 92% or more, 95% or more, 98% or more, 99% or more, or equal to 100% of that single isomer. In one aspect herein, the compound of formula (I) or a form thereof is a substantially pure (S) enantiomeric form present in an amount of 90% or more, 92% or more, 95% or more, 98% or more, 99% or more, or an amount equal to 100%.

[0081] In one aspect herein, the compound of formula (I) or a form thereof is a substantially pure (R) enantiomeric form present in an amount of 90% or more, in an amount of 92% or more, in an amount of 95% or more, in an amount of 98% or more, in an amount of 99% or more, or in an amount equal to 100%. As used herein, a "racemate" is any mixture of isometric forms that is not "enantiomerically pure", including, for example and without limitation, mixtures in ratios of about 50 / 50, about 60 / 40, about 70 / 30, or about 80 / 20. Furthermore, all geometric and positional isomers are encompassed herein. For example, when a compound of formula (I) or a form thereof incorporates a double bond or a fused ring, both cis- and trans-forms, as well as mixtures, are encompassed within the scope of this specification. Diastereoisomeric mixtures can be separated into their individual diastereoisomers based on their physical chemical differences by methods well known to those skilled in the art, such as chromatography and / or fractional crystallization. Enantiomers can be separated by using chiral HPLC columns or other chromatographic methods known to those skilled in the art. Enantiomers can also be separated by conversion of the enantiomeric mixture to a diastereoisomeric mixture by reaction with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separation of the diastereoisomers, and conversion of the individual diastereoisomers to the corresponding pure enantiomers (e.g., hydrolysis). Some of the compounds of formula (I) may also be atropisomers (e.g., substituted biaryls), and are considered as part of this specification.

[0082] Use of the terms "salt," "solvate," and the like are intended to apply equally to the salts, solvates, enantiomers, stereoisomers, or tautomers of the present compounds. The term "isotopically enriched" refers to an isotopically enriched compound described herein that is identical to that described herein, except that one or more atoms are replaced with an atom having an atomic mass, or a mass number different from the atomic mass, or mass number normally found in nature. Examples of isotopes that can be incorporated into the compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, e.g., 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, 35 Cl, and 36 Cl, each also within the scope of the present specification.

[0083] Use of the compound Aspects herein relate to methods of using a compound of formula (I) or a form thereof to treat or ameliorate HD in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound or a form thereof. Another aspect herein relates to the use of a compound of formula (I) or a form thereof for treating or ameliorating HD in a subject in need thereof. Another aspect of the present specification relates to the use of compounds of formula (I) or forms thereof that are active against HD. One aspect of the present specification relates to the use of compounds of formula (I) or forms thereof in combination therapy to provide additive or synergistic activity, thereby enabling the development of combination products for treating or ameliorating HD.

[0084] In addition to use in monotherapy, the compounds are useful in combination therapy with current standard drugs and have additive or synergistic activity with one or more known drugs. Combination therapy using compounds described herein in combination with one or more known drugs may be used to treat HD, whether or not the HD is responsive to the known agent. Certain embodiments herein include the use of a compound of formula (I) or a form thereof in combination therapy for treating or ameliorating HD in a subject in need thereof, comprising administering an effective amount of a compound of formula (I) or a form thereof, and an effective amount of one or more agent(s). Certain embodiments herein include the use of a compound of formula (I) or a form thereof in combination therapy for treating or ameliorating HD in a subject in need thereof, the use comprising administering an effective amount of a compound of formula (I) or a form thereof and an effective amount of one or more agent(s).

[0085] In certain embodiments of the uses or methods provided herein, the compound of formula (I) or a form thereof used in combination with one or more additional agents can be administered to a subject or contacted with a cell(s) of a subject or patient before, simultaneously with, or after administration to the subject or patient or contacting the cell(s) with the additional agent(s). The compound(s) of formula (I) or a form thereof and the additional agent(s) can be administered to a subject or contacted with a cell in a single composition or in different compositions. In certain embodiments, the compound(s) of formula (I) or a form thereof is used in combination with genetic treatment to inhibit HTT expression (e.g., using a viral delivery vector) or administration of another small molecule HTT inhibitor. In another particular embodiment, 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 particular embodiment, 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, provided herein is the use of a compound of formula (I) or a form thereof in combination with supportive standard of care therapy, including palliative care.

[0086] Aspects herein include the preparation of kits and instructions comprising a compound of Formula (I) or a form thereof, and use of a compound of Formula (I) or a form thereof in administering an effective amount of a compound of Formula (I) or a form thereof and an effective amount of one or more drug(s) in combination therapy to treat or ameliorate HD in a subject in need thereof. Thus, the present specification relates to the use of compounds of formula (I) or forms thereof for treating or ameliorating HD. In accordance with the present specification, compounds useful in selectively treating or ameliorating HD are identified, and the use of these compounds for treating or ameliorating HD is provided. Another aspect of the uses herein relates to the use of a compound of formula (I) or a form thereof for treating or ameliorating HD in a subject in need thereof, which use comprises administering to the subject an effective amount of a compound of formula (I) or a form thereof. Another aspect of the use herein relates to a method of using a compound of formula (I) or a form thereof to treat or ameliorate HD in a subject in need thereof, the method comprising administering an effective amount of the compound to the subject.

[0087] Another aspect of the uses herein relates to a method of using a compound of formula (I) or a form thereof to treat or ameliorate HD in a subject in need thereof, the method comprising administering an effective amount of the compound to the subject. Another aspect of the uses herein relates to the use of a compound of formula (I) or a form thereof in the manufacture of a medicament for treating or ameliorating HD in a subject in need thereof, which use comprises administering an effective amount of the medicament to the subject. Another aspect of the uses herein relates to preparing a kit comprising a compound of formula (I) or a form thereof and instructions for use in administering said compound to treat or ameliorate HD in a subject in need thereof.

[0088] In one aspect, in each such embodiment, the subject is treatment naive. In another aspect, in each such embodiment, the subject is not treatment naive. As used herein, the term "treating" relates to: (i) preventing a disease, disorder, or condition from occurring in a subject who may be predisposed to the disease, disorder, and / or condition but has not yet been diagnosed as having the disease, disorder, and / or condition; (ii) inhibiting the disease, disorder, or condition, i.e., halting its progression; and / or (iii) palliating the disease, disorder, or condition, i.e., relieving the disease, disorder, and / or condition.

[0089] As used herein, the term "subject" refers to an animal or some living organism that has sensation and the power of voluntary movement and requires oxygen and organic food. Non-limiting examples include humans, primates, members of the Equidae, Porcine, Bovidae, Mus, Rattus, Canidae, and Felidae species. In certain aspects, the subject is a mammal or warm-blooded vertebrate. In other aspects, the subject is a human. As used herein, the term "patient" may be used interchangeably with "subject" and "human." As used herein, the term "effective amount" or "treatment effective amount" refers to an amount of a compound of formula (I), or a form, composition or medicament thereof, that achieves a target plasma concentration effective for the treatment or amelioration of HD as described herein, thereby producing the desired treatment, amelioration, inhibition or prevention effect in a subject in need thereof. In one aspect, an effective amount can be the amount required for the treatment of HD in a subject or patient, more specifically a human.

[0090] In another embodiment, the concentration-biological effect relationships observed for the compound of formula (I) or a form thereof indicate target plasma concentrations ranging from about 0.001 μg / mL to about 50 μg / mL, from about 0.01 μg / mL to about 20 μg / mL, from about 0.05 μg / mL to about 10 μg / mL, or from about 0.1 μg / mL to about 5 μg / mL. To achieve such plasma concentrations, the compounds described herein may be administered at doses ranging, for example, but not limited to, from 0.1 ng to 10,000 mg. In one aspect, the dose administered to achieve an effective target plasma concentration may be administered based on subject or patient specific factors, and may be administered on a weight basis from about 0.001 mg / kg / day 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 from about 0.001 mg / kg / day to about 500 mg / kg / day, or about 0.001 mg / kg / day to about 250 mg / kg / day, or about 0.001 mg / kg / day to about 200 mg / kg / day, or about 0.001 mg / kg / day to about 150 mg / kg / day, or about 0.001 mg / kg / day to about 100 mg / kg / day, or about 0.001 mg / kg / day to about 75 mg / kg / day, or about 0.001 mg / kg / day to about 50 mg / kg / day, or about 0.001 mg / kg / day to about 25 mg / kg / day, or about 0.001 mg / kg / day to about 10 mg / kg / day, or is from about 0.001 mg / kg / day to about 5 mg / kg / day, or from about 0.001 mg / 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, 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 / 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 , or about 0.01 mg / kg / day to about 1000 mg / kg / day, or about 0.01 mg / kg / day to about 500 mg / kg / day, or about 0.01 mg / kg / day to about 250 mg / kg / day, or about 0.01 mg / kg / day to about 200 mg / kg / day, or about 0.01 mg / kg / day to about 150 mg / kg / day, or about 0.01 mg / kg / day to about 100 mg / kg / day, or about 0.01 mg / kg / day to about 75 mg / kg / day, or about 0.01 mg / kg / day to about 50 mg / kg / day, or about 0.01 mg / kg / day to about 25 mg / kg / day, or about 0.0.01 mg / kg / day to about 10 mg / kg / day, or 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 about 0.01 mg / kg / day to about 0.1 mg / kg / day, or about 0.1 mg / kg / day to about 3500 mg / kg / day, or about 0.1 mg / kg / day to about 3000 mg / kg / day, or about 0.1 mg / kg / day to about 2500 mg / kg / day, or about 0.1 mg / kg / day to about 2000 mg / kg / day, or about 0.1 mg / kg / day to about 1500 mg / kg / day, or about 0.1 mg / kg / day to about 1 ...000 mg / kg / day, The dose may range from about 0.1 mg / 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 / kg / day to about 75 mg / kg / day, or from about 0.1 mg / kg / day to about 50 mg / kg / day, 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 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.

[0091] The effective amount for a given subject can be determined by routine experimentation within the skill and judgment of the clinician or person skilled in the art, taking into account factors related to the subject. Dosage regimens can be adjusted to provide sufficient levels of active agent(s) or to maintain the desired effect. Factors that can be considered include genetic screening, severity of disease state, status of disease progression, general health of the subject, ethnicity, age, weight, sex, diet, time and frequency of administration, drug combination(s), reaction sensitivity, experience with other treatments, and tolerance / response to treatment. The dose administered to achieve an effective target plasma concentration may be administered orally once (approximately once every 24 hours, i.e., "qd"), twice (approximately once every 12 hours, i.e., "bid" or "q.12h"), three times (approximately once every 8 hours, i.e., "tid" or "q.8h") or four times (approximately once every 6 hours, i.e., "qds", "qid" or "q.6h") daily.

[0092] In certain embodiments, the dose administered to achieve an effective target plasma concentration may be administered in single, divided, or continuous doses to patients or subjects having a body weight in the range of about 40 to about 200 kg (doses may be adjusted for patients or subjects above or below this range, particularly children under 40 kg). A typical adult subject is expected to have a median body weight in the range of about 70 kg. Long-acting pharmaceutical compositions may be administered every 2, 3, or 4 days, once every other week, or once every two weeks, depending on the half-life and clearance rate of the particular formulation. The compounds and compositions described herein can be administered to a subject via any drug delivery route known in the art, including, but not limited to, oral, ocular, rectal, buccal, topical, nasal, sublingual, transdermal, subcutaneous, intramuscular, intravenous (bolus and infusion), intracerebral, and pulmonary routes of administration.

[0093] In another aspect, the dose administered may be adjusted based on the dosage forms described herein and are 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 some compounds, the effective amount can be initially evaluated in cell culture assays or relevant animal models, such as mouse, guinea pig, chimpanzee, marmoset, or tamarin animal models. Relevant animal models can also be used to determine appropriate concentration ranges and routes of administration. Such information can then be used to determine useful doses and routes of administration in humans. Treatment efficacy and toxicity can be assessed using standard pharmaceutical procedures in cell cultures or experimental animals, such as the ED 50 (the dose therapeutically effective in 50% of the population) and LD 50 (the dose that is lethal in 50% of the population). The dose ratio between the therapeutic effect and the toxic effect is the therapeutic index, and the ratio LD 50 / ED 50 In particular embodiments, the effective amount is such that a high therapeutic index is achieved. In further detailed embodiments, the dosage is within the ED 50 The dosage may vary within this range depending on the dosage form used, sensitivity of the patient, and the route of administration.

[0094] In one aspect, provided herein is a method of modulating the amount of HTT (huntingtin protein), comprising contacting a human cell with a compound of formula (I) or a form thereof. In a particular aspect, provided herein is a method of modulating the amount of HTT, comprising contacting a human cell with a compound of formula (I) or a form thereof that modulates expression of HTT. The human cell can be contacted with the compound of formula (I) or a form thereof in vitro or in vivo, e.g., in a non-human animal or a human. In a particular aspect, the human cell is derived from or in a human. In another particular aspect, the human cell is derived from or in a human with HD. In another particular aspect, the human cell is derived from or 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 derived from a human with HD. In another aspect, the human cell is in a human with HD. In one aspect, the compound is in the form of a compound of formula (I). In certain embodiments, provided herein is a method for improving inhibition of mutant HTT transcribed from the Htt gene, comprising contacting a human cell with a compound of formula (I) or a form thereof. The human cell can be contacted with the compound of formula (I) or a form thereof in vitro or in vivo, e.g., in a non-human animal or a human. In certain embodiments, the human cell is derived from or in a human. In another particular embodiment, the human cell is derived from or in a human with HD. In another particular embodiment, the human cell is derived from or in a human with HD, caused by a CAG repeat in the Htt gene, resulting in loss of wild-type "normal" HTT expression and / or function. In another embodiment, the human cell is derived from a human with HD. In another embodiment, the human cell is in a human with HD. In one embodiment, the compound is in the form of a compound of formula (I).

[0095] In another aspect, provided herein is a method for modulating inhibition of mutant HTT transcribed from the Htt gene, comprising administering a compound of formula (I) or a form thereof to a non-human animal model for HD. In certain aspects, provided herein is a method for modulating inhibition of mutant HTT transcribed from the Htt gene, comprising administering a compound of formula (I) or a form thereof to a non-human animal model for HD. In certain aspects, the compound is in the form of a compound of formula (I). In another aspect, provided herein is a method for decreasing the amount of mutant HTT, comprising contacting a human cell with a compound of formula (I) or a form thereof. In a particular aspect, provided herein is a method for decreasing the amount of mutant HTT, comprising contacting a human cell with a compound of formula (I) that inhibits the transcription of mutant HTT (huntingtin mRNA) from the Htt gene. In another particular aspect, provided herein is a method for decreasing the amount of HTT, comprising contacting a human cell with a compound of formula (I) that inhibits the expression of mutant HTT transcribed from the Htt gene. The human cell can be contacted with a compound of formula (I) or a form thereof in vitro or in vivo, for example, in a non-human animal or a human. In a particular aspect, the human cell is derived from or in a human. In another particular aspect, the human cell is derived from or in a human with HD. In another particular aspect, the human cell is derived from or 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 embodiment, the human cell is from a human with HD. In another embodiment, the human cell is within a human with HD. In one embodiment, the compound is in the form of a compound of formula (I).

[0096] In certain embodiments, treating or ameliorating HD with a compound of formula (I) or a form thereof (alone or in combination with an additional agent) has a therapeutic effect and / or a beneficial effect. In certain embodiments, treating 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) reducing or ameliorating the severity of HD, (ii) delaying the onset of HD, (iii) inhibiting the progression of HD, (iv) reducing the length of hospitalization of a subject, (v) reducing the length of hospitalization of a subject, (vi) increasing the survival of a subject, (vii) ameliorating the quality of life of a subject, (viii) reducing the number of symptoms associated with HD, (ix) reducing or ameliorating the severity of the symptom(s) associated with HD, (x) reducing the duration of symptoms associated with HD, (xi) preventing the recurrence of symptoms associated with HD, (xii) inhibiting the onset or onset of symptoms of HD, and / or (xiii) inhibiting the progression of symptoms associated with HD.

[0097] Metabolites Also included within the scope of the present disclosure are the uses of in vivo metabolic products of the compounds described herein. Such products may result, for example, from the oxidation, reduction, hydrolysis, amidation, esterification, etc., of the administered compound, primarily by enzymatic processes. Thus, the present disclosure includes the use of compounds produced by a process comprising contacting a compound described herein with mammalian tissue or a mammal for a period of time sufficient to yield a metabolic product thereof.

[0098] Pharmaceutical Compositions Aspects herein include the use of a compound of formula (I) or a form thereof in a pharmaceutical composition for treating or ameliorating HD in a subject in need thereof, the use comprising administering an effective amount of a compound of formula (I) or a form thereof in admixture with one or more pharma- ceutically acceptable excipient(s). Aspects of the present disclosure include the preparation of kits and instructions comprising a compound of formula (I) or a pharmaceutical composition in that form, and the use of the compound of formula (I) or a pharmaceutical composition in that form in administering the compound to treat or ameliorate HD in a subject in need thereof. . As used herein, the term "composition" refers to a product containing specified ingredients in specified amounts, as well as any product that results, directly or indirectly, from the combination of specified ingredients in specified amounts. The pharmaceutical composition may be formulated to achieve a physiologically compatible pH ranging from about pH 3 to about pH 11. In certain embodiments, the pharmaceutical composition is formulated to achieve a pH of about pH 3 to about pH 7. In other embodiments, the pharmaceutical composition is formulated to achieve a pH of about pH 5 to about pH 8.

[0099] The term "pharmaceutical acceptable excipient" refers to an excipient for administering a pharmaceutical product, such as a compound described herein. This term refers to any pharmaceutical excipient that may be administered without undue toxicity. Pharmaceutically acceptable excipients can be determined in part by the particular composition to be administered, as well as by the particular mode of administration and / or dosage form. Non-limiting examples of pharmaceutical acceptable excipients include carriers, solvents, stabilizers, adjuvants, diluents, and the like. Thus, for the compounds of the invention described herein, a wide variety of suitable formulations of pharmaceutical compositions exist (see, for example, Remington's Pharmaceutical Sciences). Suitable excipients may be carrier molecules including large slowly metabolized macromolecules such as proteins, polysaccharides, polylactic acids, polyglycolic acids, polymeric amino acids, amino acid copolymers, and inactive antibodies.Other exemplary excipients include antioxidants such as ascorbic acid; chelating agents such as EDTA; carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose (e.g., also known as hydroxypropylmethylcellulose, HPMC), stearic acid; liquids such as oils, water, saline, glycerol, and ethanol; wetting or emulsifying agents; pH buffering substances, and the like.Liposomes are also included within the definition of pharma-ceutically acceptable excipients.

[0100] The pharmaceutical compositions described herein may be formulated in any form suitable for the intended use described herein.Formulations suitable for oral administration include solids, liquid solutions, emulsions and suspensions, while formulations suitable for inhalation for pulmonary administration include liquids and powders.Alternative formulations include syrups, creams, ointments, tablets, and lyophilized solids that can be reconstituted with a physiologically compatible solvent before administration. When intended for oral use, for example, tablets, troches, lozenges, aqueous or oily suspensions, non-aqueous liquids, dispersible powders or granules (including micronized or nanoparticles), emulsions, hard or soft capsules, syrups or elixirs may be prepared. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents, including sweeteners, flavoring agents, coloring agents, and preservatives, in order to obtain a palatable preparation.

[0101] Pharmaceutically acceptable excipients suitable for use 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 acacia, and lubricants such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques, including microencapsulation, to delay disintegration and adsorption in the gastrointestinal tract, thereby sustaining action over a longer period of time. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate may be used alone or with a wax. Formulations for oral use 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 oily medium, such as glycerin, propylene glycol, polyethylene glycol, peanut oil, liquid paraffin or olive oil.

[0102] In other aspects, the pharmaceutical compositions described herein may be formulated as suspensions comprising a compound of formula (I) or a form thereof in admixture with one or more pharma- ceutically acceptable excipient(s) suitable for the preparation of a suspension. In yet other aspects, the pharmaceutical compositions described herein may be formulated as dispersible powders and granules suitable for the preparation of a suspension by the addition of one or more excipient(s). Excipients suitable for use in connection with suspensions include suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum acacia, dispersing or wetting agents, such as naturally occurring phospholipids (e.g., lecithin), condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearates), condensation products of ethylene oxide with long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g., polyoxyethylene sorbitan monooleate), and thickening agents, such as carbomer, beeswax, hard paraffin or cetyl alcohol. Suspensions may also contain one or more preservatives, such as acetate, methyl and / or n-propyl p-hydroxy-benzoate; one or more coloring agents; one or more flavoring agents; and one or more sweetening agents, such as sucrose or saccharin.

[0103] 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 arachis oil, a mineral oil, such as liquid paraffin, or a mixture thereof. Suitable emulsifiers include naturally occurring gums, such as gum acacia and gum tragacanth; naturally occurring phospholipids, such as soybean lecithin, esters or partial esters derived from fatty acids; hexitol anhydrides, such as sorbitan monooleate; and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. Emulsions may also contain sweeteners and flavoring agents. Syrups and elixirs may be formulated with sweeteners, such as glycerol, sorbitol or sucrose. Such formulations may also contain analgesics, preservatives, flavorings or coloring agents. Furthermore, the pharmaceutical compositions described herein may be in the form of a sterile injectable preparation, for example, a sterile injectable aqueous emulsion or oleaginous suspension. Such emulsions or suspensions may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, a solution in 1,2-propanediol. The sterile injectable preparation may also be prepared as a lyophilized powder. Among the acceptable vehicles and solvents, water, Ringer's solution and isotonic sodium chloride solution may be used. In addition, sterile fixed oils may be used as a solvent or suspending medium. For this purpose, any sterile fixed oil may be used, including synthetic mono- or di-glycerides. Furthermore, fatty acids such as oleic acid may also be used in the preparation of injectables.

[0104] The compounds described herein may be substantially insoluble in water and sparingly soluble in most pharma- ceutically acceptable protic solvents and vegetable oils, but are generally soluble in medium-chain fatty acids (e.g., caprylic and capric acids) or triglycerides, and in propylene glycol esters of medium-chain fatty acids.Thus, compounds that are modified by substitution or addition of chemical or biochemical moieties, such as by esterification, glycosylation, PEGylation, etc., that make the compounds more suitable for delivery (e.g., improved solubility, biological activity, palatability, reduced side effects, etc.), are contemplated herein. In certain embodiments, the compounds described herein are formulated for oral administration as lipid-based compositions, which are suitable for low-solubility compounds. Lipid-based formulations can generally improve the oral bioavailability of such compounds. Thus, the pharmaceutical compositions described herein can include an effective amount of the compound of formula (I) or a form thereof, together with at least one pharma-ceutical acceptable excipient selected from medium-chain fatty acids or propylene glycol esters thereof (e.g., propylene glycol esters of edible fatty acids, such as caprylic and capric fatty acids), and pharma-ceutical acceptable surfactants, such as polysorbate 20 or 80 (also called Tween® 20 or Tween® 80, respectively), or polyoxyl 40 hydrogenated castor oil.

[0105] In other aspects, the bioavailability of poorly soluble compounds may be enhanced using particle size optimization techniques, including preparing nanoparticles or nanosuspensions using techniques known to those skilled in the art. The form of the compound present in such preparations may include amorphous, partially amorphous, partially crystalline or crystalline forms. In alternative embodiments, the pharmaceutical composition may further comprise one or more aqueous solubility enhancers(s), such as cyclodextrins. Non-limiting examples of cyclodextrins include hydroxypropyl, hydroxyethyl, glycosyl, maltosyl and maltotriosyl derivatives of α-, β- and γ-cyclodextrin, as well as hydroxypropyl-β-cyclodextrin (HPBC). In certain embodiments, the pharmaceutical composition further comprises 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 compound in the composition.

[0106] Preparation of compounds General synthesis method As disclosed herein, the general method for preparing the compounds of formula (I) or forms thereof described herein can be utilized by well-known standard synthetic methodology. Many of the starting materials are commercially available or, if not available, can be prepared using the routes described below using techniques known to those skilled in the art. The synthetic schemes provided herein include multiple reaction steps, each of which is intended to stand alone and can be carried out with or without any preceding or subsequent step(s). In other words, each of the individual reaction steps of the synthetic schemes shown herein is envisioned with respect to isolation.

[0107] Compounds of formula (I) may be prepared as described in Scheme 1 below. Scheme 1 [ka] Compound A1 (where W 1 , W 2 , and W 3 are independently bromo, chloro, etc.) in a suitable solvent (e.g., 1,4-dioxane) with a catalyst (Pd(dppf)Cl 2 etc.) and bases (aqueous K 2 CO 3 Compound A3 is converted to compound A3 by Suzuki coupling with pinacol boronic ester (or boronic acid) A2 in the presence of a base (such as N,N-diisopropylethylamine) in a suitable solvent (such as acetonitrile). A NH 2 ) to give compound A4. Compound A4 is converted to compound A5 by treatment with a suitable oxidizing agent (such as manganese dioxide) in a suitable solvent (such as toluene). Compound A5 is converted to compound A6 by treatment with a catalyst (such as Pd(dppf)Cl 2 etc.) and bases (aqueous K 2 CO 3Alternatively, compound A5 can be converted to compound A7 by Suzuki coupling with binding partner A6 (where Y is a boronic acid or boronic ester and P is a suitable protecting group) in the presence of a catalyst (such as Pd 2 (dba) 3 Alternatively, compound A5 can be converted to compound A7 by Stille coupling with binding partner A6 (wherein Y is a stannane) in the presence of a catalyst (such as Pd(PPh 3 ) 4 Compound A7 is converted to compound A8 by Negishi coupling with binding partner A6 (where Y is a zinc halide) in the presence of a suitable solvent (such as dioxane) and conditions appropriate for removal of the protecting group (such as HCl in dioxane for the MOM protecting group).

[0108] Alternatively, compounds of formula (I) may be prepared as described in Scheme 2 below. Scheme 2 [ka] Compound A4 can be prepared by reacting the catalyst (Pd(dppf)Cl 2 etc.) and bases (aqueous K 2 CO 3 Alternatively, compound A4 can be converted to compound A9 by Suzuki coupling with binding partner A6 (wherein Y is a boronic acid or boronic ester) in the presence of a catalyst (such as Pd 2 (dba) 3 Alternatively, compound A4 can be converted to compound A9 by Stille coupling with binding partner A6 (where Y is stannane) in the presence of a catalyst (Pd(PPh 3 ) 4Compound A9 is converted to compound A9 by Negishi coupling with binding partner A6 (where Y is a zinc halide and P is a suitable protecting group) in the presence of a suitable amine such as dimethylformamide (DMSO) or a dimethylformamide (DMSO). Compound A9 is converted to compound A7 by treatment with a suitable oxidizing agent (such as manganese dioxide) in a suitable solvent (such as toluene). Compound A7 is converted to compound A8 upon treatment in a suitable solvent (such as dioxane) under conditions suitable for removal of the protecting group (such as HCl in dioxane for the MOM protecting group).

[0109] Specific Synthesis Examples To more fully illustrate and aid in understanding, the following non-limiting examples are provided to more fully illustrate the scope of the compounds described herein, and are not to be construed as specifically limiting the scope thereof. Such variations of the compounds described herein that may be currently known or may be developed later within the scope of the skilled artisan are considered to be within the scope of the compounds described herein and are claimed below. These examples illustrate the preparation of certain compounds. Those skilled in the art will appreciate that the techniques described in these examples, as described by those skilled in the art, represent techniques that function well in the practice of synthesis and thus constitute preferred modes of practice. However, it should be appreciated that those skilled in the art will recognize in light of this disclosure that many variations can be made in the specific methods disclosed and still obtain the same or similar results without departing from the spirit and scope of the present specification. Except for the following examples of embodied compounds, unless otherwise indicated, all numbers expressing amounts of raw materials, reaction conditions, experimental data, and the like used in the specification and claims are understood to be modified by the term "about". Thus, all such numbers represent approximations that may vary depending on the desired properties sought to be obtained by the reaction or as a result of various experimental conditions. Thus, within the expected range of experimental reproducibility, the term "about" in reference to the resulting data refers to the range of the data, provided that it may vary according to the standard deviation from the mean. Similarly, for experimental results obtained, the resulting data may be rounded up or down consistently without loss of significant figures. At the very least, without attempting to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should be construed in light of the number of significant digits and rounding techniques used by those skilled in the art. Notwithstanding that the numerical ranges and parameters setting forth the broad ranges herein are approximations, the numerical values ​​set forth in the examples set forth below are reported as precisely as possible, however, any numerical value inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

[0110] Compound example As used above, and throughout the specification, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings: [Table 3] TIFF2024528066000056.tif182146

[0111] Preparation of starting materials Preparation of 1-(3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-1,2,3-triazole [ka] Step 1. To a solution of 1-bromo-4-iodo-2-methoxy-benzene (100 g, 319 mmol) in 100 mL of DCM, add BBr 3 (1M in DCM, 600 mL, 600 mmol) was added. The mixture was stirred at rt for 16 h, then poured onto crushed ice and extracted with DCM (200 mL x 3). The combined organic phases were concentrated and purified by flash column chromatography (PE / EtOAc = 10:1) to give 2-bromo-5-iodo-phenol (90 g, 94.2% yield).

[0112] Step 2. To a solution of NaH (60% in mineral oil, 25 g, 625 mmol) in 400 mL of THF at 0 °C, 2-bromo-5-iodo-phenol (92 g, 308 mmol) in 100 mL of THF was added dropwise. After the addition, the mixture was stirred at 0 °C for 30 min, and then MOMBr (46 g, 368 mmol) was added. The mixture was stirred at 0 °C for an additional 5-10 min before being quenched with 5% citric acid and concentrated. The residue was mixed with 500 mL of DCM, washed with water and brine, and concentrated with Na 2 SO 4 The mixture was dried at 40° C. and purified by flash column chromatography (PE / EtOAc=20:1) to give 1-bromo-4-iodo-2-(methoxymethoxy)benzene (110 g, 100% yield).

[0113] Step 3. To a solution of 1-bromo-4-iodo-2-(methoxymethoxy)benzene (110 g, 321 mmol) in 500 mL of DMF, 1H-1,2,3-triazole (35 g, 507 mmol), Cs 2 CO 3 (210 g, 645 mmol), CuI (6.5 g, 34 mmol), and iron(III) acetylacetonate (34 g, 96 mmol) were added. The mixture was stirred at 90 °C for 6 h and then cooled to rt. The mixture was filtered and the filtrate was concentrated and purified by flash column chromatography (PE / EtOAc = 2:1) to give 1-(4-bromo-3-(methoxymethoxy)phenyl)-1H-1,2,3-triazole (25 g, 27.4% yield).

[0114] Step 4. To a solution of 1-(4-bromo-3-(methoxymethoxy)phenyl)-1H-1,2,3-triazole (25 g, 88 mmol) in 250 mL of 1,4-dioxane, bis(pinacolato)diboron (38 g, 150 mmol), KOAc (17.5 g, 178 mmol) and Pd(dppf)Cl 2 (6.5 g, 8.9 mmol) was added. The reaction was stirred under Ar at 100° C. for 20 h and then concentrated. The residue was purified by flash column chromatography (PE / EtOAc=1.5:1) to give 1-(3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-1,2,3-triazole (20 g, 68.6%).

[0115] Preparation of 1-[3-fluoro-5-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]triazole. [ka] Step 1. To a solution of 5-bromo-2-chloro-1-fluoro-3-methoxy-benzene (1.0 g, 4.2 mmol), diphenylmethanimine (1.05 g, 5.79 mmol), tris(dibenzylideneacetone)dipalladium (0.39 g, 0.42 mmol), RuPhos (0.4 g, 0.84 mmol) in toluene (10 mL) was added sodium tert-butoxide (0.8 g, 8.2 mmol) under nitrogen protection at 25° C. The mixture was stirred at 100° C. for 16 h. After completion of the reaction, the mixture was extracted with EtOAc and washed with brine. The organic layer was extracted with Na 2 SO 4 The mixture was dried at 40° C., concentrated and purified by silica gel chromatography (PE:EtOAc=5:1) to give N-(4-chloro-3-fluoro-5-methoxy-phenyl)-1,1-diphenyl-methanimine (800 mg, 2.35 mmol, 56.3% yield) as a colorless oil. MS m / z 340.3 [M+H] + .

[0116] Step 2. To a solution of N-(4-chloro-3-fluoro-5-methoxy-phenyl)-1,1-diphenyl-methanimine (700 mg, 2.06 mmol) in tetrahydrofuran (5 mL), 2 mol / L hydrochloric acid (1 mL) was added and the mixture was stirred at 25° C. for 1 h. After completion of the reaction, Na 2 CO 3 was added, the pH was adjusted to 9, and the mixture was extracted with EtOAc and 2 SO 4 The mixture was dried at 40° C., concentrated and purified by silica gel chromatography (PE:EtOAc=5:1) to give 4-chloro-3-fluoro-5-methoxy-aniline (300 mg, 82.9% yield) as a pale yellow oil. MS m / z 176.2 [M+H] + .

[0117] Step 3. 4-Methylbenzenesulfonhydrazide (284 mg, 1.49 mmol) and 2,2-dimethoxyacetaldehyde (259 mg, 1.49 mmol, H) in methanol (5 mL) 2 A solution of 1-(4-chloro-3-fluoro-5-methoxy-phenyl)triazole (60% by weight in 2,4-dichloro-3-fluoro-5-methoxy-aniline) (250 mg, 1.42 mmol) and acetic acid (89 mg, 1.42 mmol) were then added successively. The mixture was stirred at 75° C. overnight. After completion of the reaction, the solvent was evaporated off. The residue was purified by column chromatography (0-50% EtOAc in PE) to give the product 1-(4-chloro-3-fluoro-5-methoxy-phenyl)triazole (200 mg, 61.7% yield). MS m / z 228.1 [M+H] + .

[0118] Step 4. A solution of 1-(4-chloro-3-fluoro-5-methoxy-phenyl)triazole (120 mg, 0.52 mmol), potassium acetate (103 mg, 1.04 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (200 mg, 0.78 mmol), tris(dibenzylideneacetone)dipalladium (48 mg, 0.052 mmol), tricyclohexylphosphine (29 mg, 0.104 mmol) in 1,4-dioxane (3 mL) was heated under N 2 The mixture was stirred at 70° C. under atmospheric pressure for 16 hours. After completion of the reaction, the solvent was removed under vacuum. The crude residue was purified on silica gel using 30%-35% EtOAc / PE to give 1-[3-fluoro-5-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]triazole (80 mg, 47% yield) as a white solid. MS m / z 320.3 [M+H] + .

[0119] Preparation of 1-[2-fluoro-5-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]triazole. [ka] Step 1. To a solution of 5-bromo-2-chloro-4-fluoro-phenol (1 g, 4.4 mmol) in tetrahydrofuran (10 mL), sodium hydride (60% by weight) in mineral oil (230 mg, 5.7 mmol) was added below 0° C. The mixture was stirred at 25° C. for 1 h, followed by the addition of bromomethyl methyl ether (1.1 g, 8.8 mmol). The mixture was stirred at 25° C. for 1 h. After completion of the reaction, the mixture was quenched with water and extracted with EtOAc. The combined organic layers were evaporated to dryness in vacuum and purified by flash column chromatography (PE / EtOAc=20:1) to give 1-bromo-4-chloro-2-fluoro-5-(methoxymethoxy)benzene (800 mg, 66.9% yield) as a colorless oil.

[0120] Step 2. To a solution of 1-bromo-4-chloro-2-fluoro-5-(methoxymethoxy)benzene (1 g, 3.7 mmol), diphenylmethanimine (1.05 g, 5.79 mmol), tris(dibenzylideneacetone)dipalladium (0.39 g, 0.37 mmol), RuPhos (0.4 g, 0.76 mmol) in toluene (10 mL) was added sodium tert-butoxide (0.8 g, 8.2 mmol) under nitrogen atmosphere at 25 °C. The mixture was stirred at 100 °C for 16 h. The mixture was extracted with EtOAc and washed with brine. The organic layer was concentrated to Na 2 SO 4 The mixture was dried at 40° C., concentrated and purified by silica gel chromatography to give N-[4-chloro-2-fluoro-5-(methoxymethoxy)phenyl]-1,1-diphenyl-methanimine (0.6 g, 2 mmol, 40% yield) as a colorless oil. MS m / z 370.2 [M+H] + .

[0121] Step 3. To a solution of N-[4-chloro-2-fluoro-5-(methoxymethoxy)phenyl]-1,1-diphenyl-methanimine (600 mg, 1.6 mmol) in tetrahydrofuran (5 mL) was added hydrochloric acid (2 mol / L, 2 mL). The mixture was stirred at 25° C. for 1 h. After completion of the reaction, Na 2 CO 3 was added, the pH was adjusted to 9, and the mixture was extracted with EtOAc and 2 SO 4 The mixture was dried at 40° C., concentrated and purified by flash chromatography (PE:EtOAc=4:1) to give 4-chloro-2-fluoro-5-(methoxymethoxy)aniline (0.3 g, 90% yield) as a pale yellow oil. MS m / z 206.2 [M+H] + .

[0122] Step 4. H2O containing 4-methylbenzenesulfonhydrazide (194 mg, 0.5 mmol) and 2,2-dimethoxyacetaldehyde in methanol (5 mL) 2A solution of 2-chloro-4-fluoro-5-(triazol-1-yl)phenol (80 mg, 77% yield) was obtained by elution with 10% CO. The solution of 2-chloro-4-fluoro-5-(triazol-1-yl)phenol (80 mg, 77% yield) was stirred at rt for 1 h. 4-Chloro-2-fluoro-5-(methoxymethoxy)aniline (100 mg, 0.48 mmol) and acetic acid (61 mg, 0.5 mmol) were added sequentially. The mixture was stirred at 75° C. overnight. After completion of the reaction, the solvent was evaporated off. The residue was purified by column chromatography (0-60% EtOAc in PE) to give the product 2-chloro-4-fluoro-5-(triazol-1-yl)phenol (80 mg, 77% yield). MS m / z 214.1 [M+H] + .

[0123] Step 5. To a solution of 2-chloro-4-fluoro-5-(triazol-1-yl)phenol (80 mg, 0.37 mmol) in tetrahydrofuran (2 mL) was added sodium hydride (60% by weight) in mineral oil (36 mg, 0.45 mmol) at 0° C. The mixture was stirred at rt for 0.5 h. Bromomethyl methyl ether (112 mg, 0.45 mmol) was added and the reaction was stirred at rt for 2 h. After completion of the reaction, the mixture was quenched with water and extracted with EtOAc. The combined organic layers were evaporated to dryness in vacuo. The crude residue was purified on silica gel using 15% PE / EtOAc to give 1-[4-chloro-2-fluoro-5-(methoxymethoxy)phenyl]triazole (90 mg, 93% yield) as a pale yellow oil. MS m / z 258.1 [M+H] + .

[0124] Step 6. A solution of 1-[4-chloro-2-fluoro-5-(methoxymethoxy)phenyl]triazole (80 mg, 0.31 mmol), potassium acetate (60 mg, 0.62 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (118 mg, 0.45 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(ii) (24 mg, 0.03 mmol) in 1,4-dioxane (3 mL) was heated at 40° C. for 1 h under reduced pressure. 2The mixture was stirred at 80° C. under atmospheric pressure for 16 hours. The reaction was evaporated in vacuo. The crude residue was purified on silica gel using 30%-35% EtOAc / PE to give 1-[2-fluoro-5-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]triazole (90 mg, 83% yield) as a white solid. MS m / z 350.2 [M+H] + .

[0125] Preparation of 1-(3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-methyl-1H-1,2,3-triazole [ka] Step 1. To a solution of 4-methylbenzenesulfonohydrazide (500 mg, 2.7 mmol) in methanol (5.0 mL) was added 1,1-dimethoxypropan-2-one (350 mg, 2.9 mmol). The reaction was stirred at rt for 10 min. This material was used directly in the next step.

[0126] Step 2. To the mixture from step 1 was added 4-bromo-3-methoxy-aniline (586 mg, 2.9 mmol) and N,N-diisopropylethylamine (0.56 mL, 3.2 mmol). The reaction mixture was heated to 140° C. for 10 min, then cooled to rt and stirred at rt for 16 h. The mixture was partitioned between brine and DCM and extracted three times with DCM. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with a gradient hexane / EtOAc (0-100% EtOAc) to give 1-(4-bromo-3-methoxy-phenyl)-4-methyl-triazole (610 mg, 86% yield). MS m / z 270.0 [M+H] + ; 1H NMR (chloroform-d) δ: 7.74-7.87 (m, 1H), 7.66-7.71 (m, 1H), 7.42-7.50 (m, 1H), 7.04-7.15 (m, 1H), 4.02 (s, 3H), 2.50 (s, 3H).

[0127] Step 3. A solution of 1-(4-bromo-3-methoxy-phenyl)-4-methyl-triazole (610 mg, 2.27 mmol) in dichloromethane (2.0 mL) was cooled to -78 °C. Boron tribromide (4.5 mL, 4.5 mmol, 1.0 M in DCM) was added dropwise. The reaction was allowed to warm slowly to rt and stirred at rt for 16 h. sat.NaHCO 3 The reaction was quenched by dropwise addition of aq. and extracted three times with EtOAc. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with a gradient of DCM / MeOH (0-30% MeOH) to give 2-bromo-5-(4-methyltriazol-1-yl)phenol (305 mg, 52.7% yield). MS m / z 256.0 [M+H] + .

[0128] Step 4. To a solution of 2-bromo-5-(4-methyltriazol-1-yl)phenol (305 mg, 1.20 mmol) in DMF (6.0 mL) was added N,N-diisopropylethylamine (0.3 mL, 1.80 mmol). The reaction mixture was cooled to 0 °C and chloro(methoxy)methane (0.12 mL, 1.44 mmol) was added. The reaction was stirred at 0 °C for 2 h and then partitioned between brine and EtOAc. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with gradient hexane / EtOAc (0-100% EtOAc) to give 1-[4-bromo-3-(methoxymethoxy)phenyl]-4-methyl-triazole (325 mg, 90.8% yield). MS m / z 299.8 [M+H] + ; 1H NMR (chloroform-d) δ: 7.74 (s, 1H), 7.67-7.71 (m, 1H), 7.57-7.63 (m, 1H), 7.23-7.28 (m, 1H), 5.35 (s, 2H), 3.56 (s, 3H), 2.47 (s, 3H).

[0129] Step 5. To a dry screw-cap vial was added: 1-[4-bromo-3-(methoxymethoxy)phenyl]-4-methyl-triazole (325 mg, 1.1 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (414 mg, 1.63 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (73 mg, 0.10 mmol), and potassium acetate (301 mg, 2.18 mmol). The mixture was degassed with argon for 10 minutes, after which dioxane (2 mL) and water (0.5 mL) were added. The reaction was heated at 90° C. for 5 hours. The reaction was cooled and partitioned between water and ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with gradient hexane / EtOAc (0-100% EtOAc) to give 1-[3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-methyl-triazole (275 mg, 73.0% yield). MS m / z 346.1 [M+H] + ; 1 H NMR (chloroform-d) δ: 7.79-7.84 (m, 1H), 7.70-7.78 (m, 1H), 7.42-7.51 (m, 1H), 7.30-7.37 (m, 1H), 5.27 (s, 2H), 3.53 (s, 3H), 2.43 (s, 3H), 1.36 (s, 12H).

[0130] Preparation of 4-chloro-1-(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-1,2,3-triazole. [ka] Step 1. To a dry screw-cap vial was added: 4-azido-1-bromo-2-methoxy-benzene (1.0 g, 4.4 mmol), cuprous iodide (82 mg, 0.43 mmol), N,N-diisopropylethylamine (0.38 mL, 2.2 mmol), and ACN (3.0 mL). The vial was purged with Ar and ethynyl(trimethyl)silane (1.3 g, 13.1 mmol) was added. The resulting mixture was stirred at rt for 3 days. Upon completion, the reaction was partitioned between EtOAc and brine. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with a gradient hexane / EtOAc (0-100% EtOAc) to give [1-(4-bromo-3-methoxy-phenyl)triazol-4-yl]-trimethyl-silane (1.3 g, 91% yield). MS m / z 328 [M+H] + .

[0131] Step 2. To a solution of [1-(4-bromo-3-methoxy-phenyl)triazol-4-yl]-trimethyl-silane (800 mg, 2.45 mmol) in ACN (6.0 mL) was added CsF (547 mg, 3.6 mmol) and N-chlorosuccinimide (100 mg, 7.35 mmol). The mixture was heated to 90° C. and stirred for 16 h. The reaction was partitioned between EtOAc and brine. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with a gradient hexane / EtOAc (0-100% EtOAc) to give 1-(4-bromo-3-methoxy-phenyl)-4-chloro-triazole (385 mg, 54% yield). MS m / z 290.1,292.1 [M+H] + ; 1 H NMR (chloroform-d) δ: 7.96 (s, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.43 (d, J = 2.4 Hz, 1H), 7.09 (dd, J = 8.5, 2.4 Hz, 1H), 4.02 (s, 3H).

[0132] Step 3. To a dry screw-cap vial was added: 1-(4-bromo-3-methoxy-phenyl)-4-chloro-triazole (385 mg, 1.3 mmol), bis(pinacolato)diboron (675 mg, 2.7 mmol), potassium acetate (367 mg, 2.7 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (95 mg, 0.13 mmol). The mixture was degassed with argon for 10 min, and dioxane (2 mL) and water (0.5 mL) were added. The reaction was heated at 90 °C for 7 h. The reaction was cooled and partitioned between water and ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with gradient hexane / EtOAc (0-100% EtOAc) to give (400 mg, 89% yield) as a brownish oil. The product was not ionized by LC / MS.

[0133] Preparation of (2-(methoxymethoxy)-4-(5-methyl-1H-1,2,3-triazol-1-yl)phenyl)boronic acid [ka] Step 1. To a solution of 4-azido-1-bromo-2-methoxy-benzene (3 g, 13.15 mmol) in ACN (6.0 mL) was added 1,1,3,3-tetramethylguanidine (2.3 g, 19.7 mmol) and 1-dimethoxyphosphorylpropan-2-one (3.3 g, 19.73 mmol). The reaction was heated to 80° C. for 2 h. The reaction was partitioned between EtOAc and brine. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with a gradient DCM / EtOAc (0-100% EtOAc) to give 1-(4-bromo-3-methoxy-phenyl)-5-methyl-triazole (1.1 g, 31% yield). MS m / z 268.1,270.1 [M+H] + ; 1H NMR (chloroform-d) δ: 7.62 (d, J = 8.4 Hz, 1H), 7.51 (s, 1H), 7.01 (d, J = 2.0 Hz, 1H), 6.83 (dd, J = 8.4, 2.0 Hz, 1H), 3.87 (s, 3H), 2.30 (s, 3H).

[0134] Step 2. A solution of 1-(4-bromo-3-methoxy-phenyl)-5-methyl-triazole (1.1 g, 4.1 mmol) in DCM (10 mL) was cooled to -78 °C. Boron tribromide (0.77 mL, 8.2 mmol) was added dropwise. The reaction was allowed to warm slowly to rt and stirred at rt for 3 h before being added sat. NaHCO 3 The reaction mixture was quenched by dropwise addition of aq. and extracted three times with EtOAc. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give crude 2-bromo-5-(5-methyltriazol-1-yl)phenol, which was used in the next step without further purification.

[0135] Step 3. To a solution of 2-bromo-5-(5-methyltriazol-1-yl)phenol (1.0 g, 3.9 mmol) in DMF (10 mL) was added N,N-diisopropylethylamine (1.0 mL, 5.9 mmol). The mixture was cooled to -78 °C. Chloro(methoxy)methane (378 mg, 4.7 mmol) was added dropwise. The reaction was warmed to 0 °C and stirred at this temperature for 2 min. The reaction was partitioned between EtOAc and brine. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with gradient hexane / EtOAc (0-100% EtOAc) to give 1-[4-bromo-3-(methoxymethoxy)phenyl]-5-methyl-triazole (550 mg, 47% yield). MS m / z 298.1,300.1 [M+H] + ; 1 H NMR (chloroform-d) δ: 7.65-7.79 (m, 1H), 7.48-7.63 (m, 1H), 7.27-7.38 (m, 1H), 6.93-7.10 (m, 1H), 5.30 (s, 2H), 3.52 (s, 3H), 2.37 (s, 3H).

[0136] Step 4. To a dry screw-cap vial was added: 1-[4-bromo-3-(methoxymethoxy)phenyl]-5-methyl-triazole (550 mg, 1.84 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (700 mg, 2.76 mmol), XPhos Pd G3 (68 mg, 0.14 mmol), and potassium acetate (636 mg, 4.6 mmol). The mixture was degassed with argon for 10 min, and dioxane (2 mL) and water (0.5 mL) were added. The reaction was heated at 90° C. for 5 h. The reaction was cooled and partitioned between water and ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with gradient hexane / EtOAc (0-100% EtOAc) to give [2-(methoxymethoxy)-4-(5-methyltriazol-1-yl)phenyl]boronic acid (240 mg, 49% yield). MS m / z 264 [M+H] + ; 1 H NMR (methanol-d 4 )δ:7.57-7.75(m,2H),7.28-7.36(m,1H),7.13-7.24(m,1H),5.32(s,2H),3.51(s,3H),2.40(s,3H),1.93(s,3H).

[0137] Example 1 Preparation of compound 8 [ka] Step 1. To a solution of 4-bromo-3,6-dichloro-pyridazine (26.0 g, 114.1 mmol) in 260 mL of 1,4-dioxane and 65 mL of water, add 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (18.5 g, 120.1 mmol), K 2 CO 3(31.5 g, 228.3 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (4.25 g, 5.7 mmol) were added to the mixture. 2 After stirring at 50° C. for 5 hours under atmospheric pressure, the mixture was concentrated. The residue was purified by flash column chromatography (PE / EtOAc=4:1) to give 3,6-dichloro-4-vinyl-pyridazine (12.5 g, 58.3%) as a white solid. MS m / z 175.1, 176.1 [M+H] + .

[0138] Step 2. 3,6-Dichloro-4-vinyl-pyridazine (5.0 g, 28.6 mmol) in 25 mL of acetonitrile, Na 2 CO 3 (3.1 g, 29.2 mmol), (3S,4S)-3-fluoro-2,2,6,6-tetramethyl-piperidin-4-amine (5.5 g, 31.6 mmol) were added to a mixture of 2 The mixture was heated at 120° C. under atmospheric pressure for 16 hours. The mixture was cooled to room temperature and then concentrated. The residue was purified by flash column chromatography (DCM / MeOH=20:1) to give 3-chloro-7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethyl-4-piperidyl]-5,6-dihydropyrrolo[2,3-c]pyridazine (6.0 g, 67.1%) as a brown foam. MS m / z 313.4,315.4 [M+H] + .

[0139] Step 3. In a sealed tube, add 3-chloro-7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethyl-4-piperidyl]-5,6-dihydropyrrolo[2,3-c]pyridazine (6.0 g, 19.2 mmol), 300 mL of anhydrous toluene, and activated MnO 2(84 g, 966.2 mmol) and 2.0 g of 4 Å molecular sieves (freshly dried at elevated temperature) were added. The mixture was stirred at 135° C. for 16 h and then cooled to room temperature. The solids were removed by filtration and the filtrate was concentrated. The residue was purified by flash column chromatography (DCM / MeOH=20:1) to give 3-chloro-7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethyl-4-piperidyl]pyrrolo[2,3-c]pyridazine (3.9 g, 65.4%) as a brown solid. MS m / z 311.4,313.4 [M+H] + .

[0140] Step 4. In a dry screw-cap vial, add: 3-chloro-7-((3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl)-7H-pyrrolo[2,3-c]pyridazine (50 mg, 0.16 mmol), 1-(3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-1,2,3-triazole (85 mg, 0.25 mmol), XPhos Pd G4 (0.14 mg, 0.016 mmol), and K 2 CO 3 (66 mg, 0.48 mmol) was added. The mixture was degassed with argon for 10 min, then dioxane (2 mL) and water (0.5 mL) were added. The reaction was heated at 90° C. for 5 h. The reaction was cooled to rt and partitioned between EtOAc and water. The organic layer was extracted with Na 2 SO 4 Dry and concentrate with gradient (0-10%) CH 2 Cl 2 Purification by silica gel column chromatography eluting with 1,2,6,6-tetramethylpiperidin-4-yl)-3-(2-(methoxymethoxy)-4-(1H-1,2,3-triazol-1-yl)phenyl)-7H-pyrrolo[2,3-c]pyridazine (40 mg, 52% yield). MS m / z 480.5 [M+H] + ; 1 H NMR (500MHz, methanol-d 4)δ:8.66(s,1H),8.29(s,1H),8.02(br s,1H),7.96(s,1H),7.83-7.91(m,2H),7.66(d,J=8.24Hz,1H),6.71(m,1H),5.89(m,1H),5.37(s,2H),4.58(m,1H),3.44(s,3 H),2.36(d,J=13.12Hz,1H),1.90(dd,J=12.44,3.74Hz,1H),1.51(m,3H),1.47(s,3H),1.35(s,3H),1.28(s,3H);1H not detected (NH).

[0141] Step 5. CH 2 Cl 2 To a solution of 2-(7-((3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl)-7H-pyrrolo[2,3-c]pyridazin-3-yl)-5-(1H-1,2,3-triazol-1-yl)phenol (40 mg, 0.083 mmol) and 2 drops of MeOH in (1 mL) was added HCl (4 mol / L) in 1,4-dioxane (0.1 mL, 0.4 mmol). The reaction was stirred for 2 h. The solvent was removed under reduced pressure and the residue was purified by elution with gradient (0-30%) CH 2 Cl 2 / MeOH (2.5% NH 4 Purification by silica gel column chromatography eluting with 5-(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl)-7H-pyrrolo[2,3-c]pyridazin-3-yl)-5-(1H-1,2,3-triazol-1-yl)phenol (25 mg, 69% yield) was obtained as a tan solid. MS m / z 436.4 [M+H] + ; 1 H NMR (500MHz, methanol-d 4)δ:8.89(s,1H),8.67(m,2H),7.97(m,2H),7.72(s,1H),7.65br d,J=8.24Hz,1H),7.18(d,J=2.90Hz,1H),5.90(m,1H),5.12(d,J=50.96Hz,1H),2.88(br t,J=13.50Hz,1H),2.41(br d,J=11.44Hz,1H),1.82(s,3H),1.78(s,3H),1.69(s,3H),1.65(s,3H);2H not detected.

[0142] Additional compounds described herein can be prepared using the procedures described in Example 1 above, by substituting the appropriate starting materials, suitable reagents and reaction conditions to provide compounds as selected from the following: [Table 4] TIFF2024528066000065.tif207157 TIFF2024528066000066.tif212158 TIFF2024528066000067.tif82156

[0143] Example 2 Preparation of compound 14 [ka] Step 1. A stirred solution of benzyl (7S)-7-(3-bromopyrrolo[2,3-c]pyridazin-7-yl)-4-azaspiro[2.5]octane-4-carboxylate (265 mg, 0.6 mmol) in dry THF (6.0 mL) was cooled to -78 °C, followed by dropwise addition of a solution of nBuLi (1.6 mol / L in hexanes, 0.41 mL, 0.66 mmol). The reaction mixture was stirred for 15 min, then tributyltin chloride (0.20 mL, 0.71 mmol) was added slowly and the mixture was stirred for an additional 30 min. The cooling bath was removed, the solution was allowed to warm to rt and stirred at rt for an additional 1 h. The solvent was removed under reduced pressure, toluene (3.0 mL) was added and the mixture was filtered to remove the precipitate, which was washed with toluene. The filtrates were combined and used in step 2 without further purification.

[0144] Step 2. To the above solution of benzyl (R)-7-(3-(tributylstannyl)-7H-pyrrolo[2,3-c]pyridazin-7-yl)-4-azaspiro[2.5]octane-4-carboxylate, 2-iodo-3-(methoxymethoxy)-5-(triazol-1-yl)pyridine (100 mg, 0.3 mmol), Pd(dppf)Cl 2 -DCM complex (25 mg, 0.03 mmol) and CuI (11 mg, 0.058 mmol) were added. The reaction was stirred at 100° C. for 16 h. The reaction was cooled to rt, concentrated and the residue was purified with gradient ACN / H 2 Purification by reverse phase chromatography eluting with O / TFA (0-100% ACN (0.1% TFA)) afforded a mixture of benzyl (R)-7-(3-(3-(methoxymethoxy)-5-(1H-1,2,3-triazol-1-yl)pyridin-2-yl)-7H-pyrrolo[2,3-c]pyridazin-7-yl)-4-azaspiro[2.5]octane-4-carboxylate and benzyl (R)-7-(3-(3-hydroxy-5-(1H-1,2,3-triazol-1-yl)pyridin-2-yl)-7H-pyrrolo[2,3-c]pyridazin-7-yl)-4-azaspiro[2.5]octane-4-carboxylate (170 mg), which was used in the next step without further purification.

[0145] Step 3. A mixture of benzyl (R)-7-(3-(3-(methoxymethoxy)-5-(1H-1,2,3-triazol-1-yl)pyridin-2-yl)-7H-pyrrolo[2,3-c]pyridazin-7-yl)-4-azaspiro[2.5]octane-4-carboxylate from step 2 and benzyl (R)-7-(3-(3-hydroxy-5-(1H-1,2,3-triazol-1-yl)pyridin-2-yl)-7H-pyrrolo[2,3-c]pyridazin-7-yl)-4-azaspiro[2.5]octane-4-carboxylate was treated with TFA (2.0 mL, 26 mmol) at 60° C. for 2 h. The reaction was cooled to rt, concentrated and purified by elution with a gradient of ACN / H2O. 2 Purification by reverse phase chromatography eluting with O / TFA (0-100% ACN (0.1% TFA)) afforded 2-[7-[(7S)-4-azaspiro[2.5]octan-7-yl]pyrrolo[2,3-c]pyridazin-3-yl]-5-(triazol-1-yl)pyridin-3-ol; 2,2,2-trifluoroacetic acid (14 mg, 9% yield) as a tan foam. MS m / z 389.3 [M+H] + ; 1 H NMR (500MHz, methanol-d 4 )δ:9.10(s,1H),8.76-8.87(m,1H),8.71(s,1H),8.00-8.16(m,1H),7.96-8.00(m,1H),7.93(s,1H),6.88(br d,J=3.1Hz,1H),5.32(br t,J=11.9Hz,1H),3.69(br d,J=12.5Hz,1H),3.40-3.58(m,1H),3.32-3.39(m,1H),3.09(br t,J=12.7Hz,1H),2.60-2.75(m,1H),2.47-2.60(m,1H),1.91(br d, J = 14.0 Hz, 1H), 1.11-1.23 (m, 2H), 0.93-1.11 (m, 1H); 2H not detected (NH and OH).

[0146] Example 3 Preparation of compound 15 [ka] Step 1. In a dry screw-cap vial, add: 3-chloro-7-((3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl)-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazine (50 mg, 0.16 mmol), 1-(3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-methyl-1H-1,2,3-triazole (56 mg, 0.16 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (12 mg, 0.016 mmol), K 2 CO 3 (66 mg, 0.48 mmol) was added. The mixture was degassed with argon for 10 min, then dioxane (2 mL) and water (0.5 mL) were added. The reaction was heated at 90° C. for 5 h. The reaction was cooled to rt and partitioned between EtOAc and water. The organic layer was extracted with Na 2 SO 4 Dry and concentrate with gradient (0-10%) CH 2 Cl 2 Purification by silica gel column chromatography eluting with 1,2,6,6-tetramethylpiperidin-4-yl)-3-(2-(methoxymethoxy)-4-(4-methyl-1H-1,2,3-triazol-1-yl)phenyl)-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazine (58 mg, 73% yield). MS m / z 496.5 [M+H] + .

[0147] Step 2. In a sealed tube, add 7-((3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl)-3-(2-(methoxymethoxy)-4-(4-methyl-1H-1,2,3-triazol-1-yl)phenyl)-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazine (58 mg, 0.12 mmol), activated MnO 2(204 mg, 2.34 mmol) and anhydrous toluene (1.0 mL) were added. The mixture was stirred at 90° C. for 7 h and then cooled to room temperature. The solids were removed by filtration and the filtrate was concentrated to give crude 7-((3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl)-3-(2-(methoxymethoxy)-4-(4-methyl-1H-1,2,3-triazol-1-yl)phenyl)-7H-pyrrolo[2,3-c]pyridazine (57 mg, 99% yield) as a brown solid, which was used in the next step without further purification. MS m / z 494.5 [M+H] + .

[0148] Step 3. A solution of 7-((3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl)-3-(2-(methoxymethoxy)-4-(4-methyl-1H-1,2,3-triazol-1-yl)phenyl)-7H-pyrrolo[2,3-c]pyridazine (57 mg, 0.12 mmol) in TFA (1 mL) was heated to 70° C. for 5 min. The mixture was concentrated and the residue was purified by a gradient of ACN / H 2 Purification by reverse phase chromatography eluting with O / formic acid (0-100% ACN) afforded 2-(7-((3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl)-7H-pyrrolo[2,3-c]pyridazin-3-yl)-5-(4-methyl-1H-1,2,3-triazol-1-yl)phenol (25 mg, 48% yield) as a tan solid. MS m / z 450.5 [M+H] + ; 1 H NMR (methanol-d 4 ) δ: 8.80 (s, 1H), 8.36 (s, 2H), 8.02 (d, J = 8.63 Hz, 1H), 7.60 (d, J = 2.00 Hz, 2H), 7.04 (d, J = 3.50 Hz, 1H), 5.81-6.07 (m, 1H), 5.03-5.24 (m, 1H), 2.79-2.84 (m, 1H), 2.44 (s, 3H), 2.31-2.40 (m, 1H), 1.73-1.86 (m, 6H), 1.57-1.72 (m, 6H); 2H not detected (NH and OH).

[0149] By using the procedures set forth in Example 3 above and substituting the appropriate starting materials, suitable reagents, and reaction conditions, additional compounds described herein may be prepared to provide compounds such as those selected from the following: [Table 5] TIFF2024528066000071.tif51156

[0150] Biological Examples The following in vitro biological examples demonstrate the utility of the compounds herein for the treatment of Huntington's disease. In order to more fully illustrate and aid in the understanding of the present specification, the following non-limiting biological examples are provided to more fully illustrate the scope of the specification and should not be construed as specifically limiting the scope thereof. Similar variations of the present specification that may be currently known or may be developed later that should be within the scope of a person skilled in the art are considered to be within the scope of the present specification and are claimed below. Compounds of formula (I) were tested using the Meso Scale Discovery (MSD) assay described in International Application No. PCT / US2016 / 066042, filed December 11, 2016, which claims priority to U.S. Provisional Application No. US62 / 265,652, filed December 10, 2015, the entire contents of which are incorporated herein by reference. The endogenous huntingtin protein assay used in Example 1 was developed using the MSD ELISA-based electrochemiluminescence assay platform.

[0151] Example 1: Endogenous huntingtin protein assay Meso Scale Discovery (MSD) 96-well or 384-well plates were coated with MW1 (expanded polyglutamine) or MAB2166 monoclonal antibodies (for capture) at a concentration of 1 μg / mL (30 μL per well) in PBS overnight at 4° C. Plates were then washed 3 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 end-over-end shaking, then washed 3 times with wash buffer.

[0152] Samples (25 μL) were transferred to antibody-coated MSD plates and incubated overnight at 4° C. After removing the lysate, the plates were washed three times with wash buffer and 25 μL of #5656S (Cell signaling, rabbit monoclonal) secondary antibody (diluted in blocking buffer to 0.25 μg / mL in 0.05% Tween-20) was added to each well and incubated for 1 hour at room temperature with shaking. Following incubation with the secondary antibody, the wells were rinsed with wash buffer, after which 25 μL of goat anti-rabbit SULFO TAG secondary detection antibody (required aspect of the MSD system) (diluted in blocking buffer to 0.25 μg / mL in 0.05% Tween-20) was added to each well and incubated for 1 hour at room temperature with shaking. After rinsing three times with wash buffer, 150 μL of lead buffer T plus detergent (MSD) was added to each empty well and the plates were imaged on a SI 6000 imager (MSD) according to the manufacturer's instructions provided with the 96 or 384 well plates. The ICs obtained for the compounds tested were: 50 Values ​​(μM) are shown in Table 1.

[0153] As shown in Table 1, the test compounds described herein have the following IC 50 values, and one asterisk (*) indicates IC values ​​>3μM to ≦9μM 50 The IC values ​​are shown, and two asterisks (**) indicate IC values ​​>1 μM to ≦3 μM. 50 The values ​​shown are those of the IC5000 and IC5001 of >0.5 μM to ≦1 μM. 50The four asterisks (****) indicate IC values ​​between >0.1 μM and ≦0.5 μM. 50 Values ​​are shown, and five asterisks (*****) indicate IC ≤ 0.1 μM 50 Indicates the value. [Table 6]

[0154] Example 2 Comparison compound results: improved potency The comparative compounds are reported in WO 2020 / 005873 as compounds found to have activity in endogenous huntingtin protein assays. The comparative compounds lack various structural features compared to the compounds of the present invention encompassed by formula (I). The comparative compounds were tested according to the assay described in Example 1, and the results are shown in Table 2. Various changes in potency were observed due to structural modifications. A significant increase in potency of 223-fold was observed for Cpd1 of the present invention, which has a 7H-pyrrolo[2,3-c]pyridazine core, compared to Cpd72 of WO 2020 / 005873, which has a 3H-[1,2,3]-triazolo[4,5-c]pyridazine core. In contrast, similar potencies were observed for Cpd26 of WO 2020 / 005873, which has a 7H-pyrrolo[2,3-c]pyridazine core, and Cpd7 of WO 2020 / 005873, which has a 3H-[1,2,3]-triazolo[4,5-c]pyridazine core.

[0155] Comparison of Cpd7 and Cpd72 in WO 2020 / 005873 shows that the potency is significantly reduced by replacing the 1H-pyrazole moiety with a 1H-1,2,3-triazole moiety. In contrast, an 8-fold or greater increase in potency was observed with the same structural modification between Cpd1 of the present invention and Cpd26 in WO 2020 / 005873. [Table 7]

[0156] Regardless of whether a document cited in this specification is specifically and individually indicated to be incorporated by reference, all documents referred to in this specification are incorporated by reference into this application for any and all purposes to the same extent as if each individual reference was fully set forth herein. As the subject matter of the claims is fully described herein, those skilled in the art will appreciate that it may be practiced within a wide range of equivalents without affecting the scope of the subject matter or the detailed embodiments described herein, and it is intended that the appended claims be construed to include all such equivalents.

Claims

1. A compound of formula (I): 【Chemical 1】 or a form thereof, wherein: R Ａ is the following formula: 【Chemistry 2】 and In the formula, p and q are each independently 0 or 1; X １ is selected from the group consisting of CH, C-halogen, and N; X ２ is selected from the group consisting of CH and C-halogen; R １ is hydrogen, hydroxyl, and C １－４ selected from the group consisting of alkyl; R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , R ９ , R １０ , and R １１ are each independently hydrogen, halogen, hydroxyl, cyano, C １－４ Alkyl, Deuterium-C １－４ Alkyl, halo-C １－４ Alkyl, amino, C １－４ Alkyl-amino, (C １－４ alkyl) ２ - Amino, C １－４ Alkoxy and halo-C １－４ alkoxy; or R ２ and R ３ together with the atoms to which they are attached form a saturated 3-6 membered ring incorporating 0 or 1 heteroatom ring member selected from N, O, and S; or R ２ and R ４ together with the atoms to which they are attached form a saturated 5- to 10-membered ring system; or R ２ and R ７ together with the atoms to which they are attached form a saturated 5- to 10-membered ring system; or R ４ and R ５ together with the atoms to which they are attached form a saturated 3-6 membered ring incorporating 0 or 1 heteroatom ring member selected from N, O, and S; R Ａ１ and R Ａ２ are each independently hydrogen, deuterium, halogen, hydroxy, cyano, C １－４ Alkyl, Deuterium-C １４ Alkyl, halo-C １－４ Alkyl, C １－４ Alkoxy, halo-C １－４ Alkoxy, C １－４ Alkoxy-C １－４ Alkyl, amino, C １－４ alkylamino, (C １－４ alkyl) ２ -amino, amino-C １－４ Alkyl and hydroxy-C １－４ selected from the group consisting of alkyl; R Ｂ１ and R Ｂ２ are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, C １－４ Alkyl, Deuterium-C １－４ Alkyl, halo-C １－４ Alkyl, C １－４ Alkoxy, Deuterium-C １－４ Alkoxy and halo-C １－４ selected from the group consisting of alkoxy; wherein the compound is in the form selected from the group consisting of its salts, racemates, enantiomers, diastereoisomers, stereoisomers, and tautomers. Compound or its form.

2. The compound has the following formula (Ia): 【Chemistry 3】 having the structure 2. The compound of claim 1 or a form thereof.

3. The compound has the following formula (Ib): 【Chemistry 4】 having the structure 2. The compound of claim 1 or a form thereof.

4. R Ａ is the group consisting of: 【Chemistry 5】 【Chemistry 6】 Selected from The compound or a form thereof according to any one of claims 1 to 3.

5. R Ａ is the group consisting of: 【Chemistry 7】 Selected from The compound or a form thereof according to any one of claims 1 to 3.

6. R Ａ is the following formula: 【Chemistry 8】 is The compound or a form thereof according to any one of claims 1 to 3.

7. R Ａ is the group consisting of: 【Chemistry 9】 Selected from The compound or a form thereof according to any one of claims 1 to 3.

8. The compound according to any one of claims 1 to 3, wherein the compound is in the form of a salt.

9. The compound according to any one of claims 1 to 3, wherein the compound is in the form of a salt selected from the group consisting of hydrochloride, dihydrochloride, formate, diformate, and trifluoroacetate.

10. The group consists of: 2-[7-(2,2,6,6-tetramethylpiperidin-4-yl)-7H-pyrrolo[2,3-c]pyridazin-3-yl]-5-(1H-1,2,3-triazol-1-yl)phenol; 2-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazol-1-yl)phenol; 2-{7-[(3R,4R)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazol-1-yl)phenol; 2-{7-[(3R,4R)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazol-1-yl)phenol; 2-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazol-1-yl)phenol; 2-{7-[(3R,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazol-1-yl)phenol; 2-[7-(4-azaspiro[2.5]octan-7-yl)-7H-pyrrolo[2,3-c]pyridazin-3-yl]-5-(1H-1,2,3-triazol-1-yl)phenol; 2-{7-[(4RS)-2,2-dimethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazol-1-yl)phenol; 5-(1H-1,2,3-triazol-1-yl)-2-{7-[(4RS)-1,2,2-trimethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}phenol; 2-[7-(4-methyl-4-azaspiro[2.5]octan-7-yl)-7H-pyrrolo[2,3-c]pyridazin-3-yl]-5-(1H-1,2,3-triazol-1-yl)phenol; 2-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazol-1-yl)phenol); 2-[7-(4-azaspiro[2.5]octan-7-yl)-6-methyl-7H-pyrrolo[2,3-c]pyridazin-3-yl]-5-(1H-1,2,3-triazol-1-yl)phenol; 2-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-6-methyl-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazol-1-yl)phenol; 2-{7-[(7R)-4-azaspiro[2.5]octan-7-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazol-1-yl)phenol; 2-{7-[(4S,5R)-5-fluoro-2,2-dimethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazol-1-yl)phenol; 2-{7-[(4R,5S)-5-fluoro-2,2-dimethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazol-1-yl)phenol; 2-{7-[(7S)-4-Azaspiro[2.5]octan-7-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazol-1-yl)phenol; 2-{7-[(7S)-4-Azaspiro[2.5]octan-7-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazol-1-yl)pyridin-3-ol; 2-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(4-methyl-1H-1,2,3-triazol-1-yl)phenol; 2-{7-[(7S)-4-Azaspiro[2.5]octan-7-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(4-methyl-1H-1,2,3-triazol-1-yl)phenol; 2-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(5-methyl-1H-1,2,3-triazol-1-yl)phenol; 2-{7-[(7S)-4-Azaspiro[2.5]octan-7-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(5-methyl-1H-1,2,3-triazol-1-yl)phenol; 5-(4-chloro-1H-1,2,3-triazol-1-yl)-2-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}phenol; 2-{7-[(1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazol-1-yl)phenol; 2-{7-[(1R,2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazol-1-yl)phenol; 2-{7-[(1S,2R,3R,5R)-2-fluoro-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazol-1-yl)phenol; 2-{7-[(1R,2S,3S,5S)-2-fluoro-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazol-1-yl)phenol; 2-{7-[(4S,5R)-5-fluoro-2,2-dimethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazol-1-yl)phenol; 2-{7-[(8R,9R)-9-fluoro-5-azaspiro[3.5]nonan-8-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazol-1-yl)phenol; 2-{7-[(8S,9S)-9-fluoro-5-azaspiro[3.5]nonan-8-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazol-1-yl)phenol; 2-[7-(4-azadispiro[2.1.2 5 .3 3 ]decan-9-yl)-7H-pyrrolo[2,3-c]pyridazin-3-yl]-5-(1H-1,2,3-triazol-1-yl)phenol; 2-{7-[(8S,9R)-8-fluoro-6-azaspiro[4.5]decan-9-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazol-1-yl)phenol; 2-{7-[(8R,9S)-8-fluoro-6-azaspiro[4.5]decan-9-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazol-1-yl)phenol; 4-fluoro-2-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazol-1-yl)pheno; and 3-fluoro-2-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazol-1-yl)phenol; A compound selected from A compound wherein the form of said compound is selected from the group consisting of salts, racemates, enantiomers, diastereoisomers, stereoisomers, and tautomers thereof.

11. The group consists of: 2-[7-(2,2,6,6-tetramethylpiperidin-4-yl)-7H-pyrrolo[2,3-c]pyridazin-3-yl]-5-(1H-1,2,3-triazol-1-yl)phenol dihydrochloride; 2-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazol-1-yl)phenol dihydrochloride; 2-{7-[(3R,4R)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazol-1-yl)phenol dihydrochloride; 2-{7-[(3R,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazol-1-yl)phenol dihydrochloride; 2-{7-[(3S,4R)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazol-1-yl)phenol dihydrochloride; 2-[7-(4-azaspiro[2.5]octan-7-yl)-7H-pyrrolo[2,3-c]pyridazin-3-yl]-5-(1H-1,2,3-triazol-1-yl)phenol dihydrochloride; 2-{7-[(4RS)-2,2-dimethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazol-1-yl)phenol hydrochloride; 5-(1H-1,2,3-triazol-1-yl)-2-{7-[(4RS)-1,2,2-trimethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}phenol hydrochloride; 2-[7-(4-methyl-4-azaspiro[2.5]octan-7-yl)-7H-pyrrolo[2,3-c]pyridazin-3-yl]-5-(1H-1,2,3-triazol-1-yl)phenol hydrochloride; 2-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazol-1-yl)phenol dihydrochloride; 2-[7-(4-azaspiro[2.5]octan-7-yl)-6-methyl-7H-pyrrolo[2,3-c]pyridazin-3-yl]-5-(1H-1,2,3-triazol-1-yl)phenol diformate; 2-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-6-methyl-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazol-1-yl)phenol diformate; 2-{7-[(4S,5R)-5-fluoro-2,2-dimethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazol-1-yl)phenol hydrochloride; 2-{7-[(4R,5S)-5-fluoro-2,2-dimethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazol-1-yl)phenol hydrochloride; 2-{7-[(7S)-4-Azaspiro[2.5]octan-7-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazol-1-yl)phenol trifluoroacetate; 2-{7-[(7S)-4-Azaspiro[2.5]octan-7-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazol-1-yl)pyridin-3-ol trifluoroacetate; 2-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(4-methyl-1H-1,2,3-triazol-1-yl)phenol formate; 2-{7-[(7S)-4-Azaspiro[2.5]octan-7-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(4-methyl-1H-1,2,3-triazol-1-yl)phenol formate; 2-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(5-methyl-1H-1,2,3-triazol-1-yl)phenol formate; 2-{7-[(7S)-4-azaspiro[2.5]octan-7-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(5-methyl-1H-1,2,3-triazol-1-yl)phenol formate formate, and 5-(4-chloro-1H-1,2,3-triazol-1-yl)-2-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}phenol formate; A compound selected from A compound wherein the form of said compound is selected from the group consisting of its racemic, enantiomeric, diastereomeric, stereoisomeric, and tautomeric forms.

12. 10. A method for treating or ameliorating HD in a subject in need thereof, comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 3.

13. 13. The method of claim 12, wherein the effective amount of the compound ranges from about 0.001 mg / kg / day to about 500 mg / kg / day.

14. 10. Use of a compound according to any one of claims 1 to 3 for treating or ameliorating HD in a subject in need thereof, comprising administering to said subject an effective amount of said compound.

15. 15. The use of claim 14, wherein the effective amount of the compound ranges from about 0.001 mg / kg / day to about 500 mg / kg / day.

16. 10. Use of a compound according to any one of claims 1 to 3 in the manufacture of a medicament for treating or ameliorating HD in a subject in need thereof, wherein said treating or ameliorating comprises administering to said subject an effective amount of said medicament.

17. 17. The use of claim 16, wherein the effective amount of said compound in said medicament ranges from about 0.001 mg / kg / day to about 500 mg / kg / day.

18. 10. Use of a compound according to any one of claims 1 to 3, admixed with one or more pharmaceutically acceptable excipients in a pharmaceutical composition, for treating or ameliorating HD in a subject in need thereof, wherein said treating or ameliorating comprises administering to said subject an effective amount of said pharmaceutical composition.

19. 19. The use of claim 18, wherein the effective amount of the compound in the pharmaceutical composition ranges from about 0.001 mg / kg / day to about 500 mg / kg / day.

20. A pharmaceutical composition for use in the treatment or amelioration of HD, comprising an effective amount of a compound according to any one of claims 1 to 3 and a pharmaceutically acceptable excipient.

21. 12. A pharmaceutical composition for use in the treatment or amelioration of HD, comprising an effective amount of a compound according to claim 10 or 11 and a pharmaceutically acceptable excipient.

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